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Review
Large-Scale Applications of Amide Coupling
Reagents for the Synthesis of Pharmaceuticals
Joshua R. Dunetz, Javier Magano, and Gerald A. Weisenburger
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op500305s • Publication Date (Web): 15 Nov 2015
Downloaded from http://pubs.acs.org on November 16, 2015
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Large-Scale Applications of Amide Coupling Reagents for the Synthesis of
Pharmaceuticals
Joshua R. Dunetz,a* Javier Magano,b* and Gerald A. Weisenburgerb*
a
Process Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, United States
b
Chemical Research & Development, Pfizer Worldwide Research & Development, Eastern
Point Roguaad, Groton, CT 06340, United States
Joshua.Dunetz@Gilead.com
Javier.Magano@Pfizer.com
Gerald.A.Weisenburger@Pfizer.com
ABSTRACT
This review showcases various coupling reagents which have been implemented
specifically for large-scale amide synthesis via the condensation of an acid and amine, while
highlighting the benefits and drawbacks of each reagent on industrial scale.
TABLE OF CONTENTS
1.
Introduction
2.
Reagents for amide coupling
2.1
Coupling via acid chloride
2.2
Coupling via acid anhydride
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2.2.1
Carboxylic and carbonic acid mixed anhydrides
2.2.2
Sulfonate-based mixed anhydrides
2.2.3
Phosphorous-based mixed anhydrides
2.2.4
CDI
2.3
Coupling via activated ester
2.3.1
Carbodiimides
2.3.2
Phosphonium salts
2.3.3
Guanidinium and uronium salts
2.3.4
Triazine-based coupling reagents
2.4
Coupling via boron species
3.
Other methods for amide bond formation
3.1
Synthesis of amides from esters
3.2
Synthesis of amides via transamidation
3.3
Synthesis of amides catalyzed by Brönsted acids
4.
4.1
Case studies
Coupling via acid chloride
4.1.1
Thionyl chloride
4.1.2
Oxalyl chloride
4.1.3
Phosphorus oxychloride
4.1.4
Commercial Vilsmeier reagent
4.2
4.2.1
4.2.1.1
Coupling via acid anhydride
Carboxylic and carbonic acid mixed anhydrides
Acetic anhydride
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4.2.1.2
Pivaloyl chloride
4.2.1.3
Ethyl chloroformate
4.2.1.4
Isobutyl chloroformate
4.2.1.5
Boc anhydride
4.2.1.6
EEDQ
4.2.2
Sulfonate-based mixed anhydrides
4.2.2.1
Methanesulfonyl chloride
4.2.2.2
p-Toluenesulfonyl chloride
4.2.3
Phosphorus-based mixed anhydrides
4.2.3.1
T3P
4.2.3.2
EMPA
4.2.4
CDI
4.3
Coupling via activated ester
4.3.1
Carbodiimides
4.3.1.1
DCC
4.3.1.2
DIC
4.3.1.3
EDC
4.3.2
Phosphonium salts
4.3.2.1
BOP
4.3.3
Guanidinium and uronium salts
4.3.3.1
HBTU
4.3.3.2
HATU
4.3.3.3
TBTU
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4.3.3.4
TPTU
4.3.3.5
TOTU
4.3.4
Triazine-based coupling reagents
4.3.4.1
Cyanuric chloride
4.3.4.2
CDMT
4.3.4.3
DMTMM
4.4
Coupling via boron species
4.4.1
Boric acid
4.4.2
3-Nitrophenylboronic acid
5
Conclusions
6
Abbreviations
7
References
1.
Introduction
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Many reviews of amide bond formation have already been written.1 This manuscript
differentiates itself by evaluating coupling reagents used in the large-scale condensation of an
acid and amine for the synthesis of drug candidates, while highlighting the benefits and
drawbacks of each reagent on plant scale.
Amide bonds are very frequently incorporated into active pharmaceutical ingredients
(API).2 In fact, amide bond formation is one of the most prevalent transformations in the
pharmaceutical industry, accounting for 16% of all reactions carried out in medicinal chemistry
laboratories.3 However, the ideal method for amide synthesis, i.e., the direct condensation of a
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carboxylic acid and an amine with the formation of one equivalent of water as the only
byproduct,4 is not practical due to proton exchange between the coupling partners leading to an
ammonium carboxylate salt. Only under forcing conditions (such as high temperature5 and
microwave irradiation6) does this coupling can take place, which makes it incompatible with the
chemical complexity displayed by current drug candidates. As a result, acid activation is required
to promote the coupling with an amine, and the development of safe and efficient processes for
acid activation and amine condensation on industrial scale is of paramount importance.
There are many considerations when selecting an amide coupling reagent for plant
production. The ideal reagent is inexpensive, widely available, non-toxic, safe, simple to handle,
easy to purge from reaction mixtures, and contributes only minimally to waste streams.
Furthermore, the detection and purging of coupling byproducts to regulatory limits is high
priority when performing the amidation near the end of a manufacturing route.7 Of course, not all
coupling reagents perform equally well for a given pair of acid and amine substrates, and the
aforementioned process considerations must be balanced against the need for amidation
conditions that proceed with high yield and selectivity, excellent reproducibility, and in the case
of substrates bearing stereocenters, low epimerization.
The first half of this review introduces the various amide coupling reagents and compares
the merits of each for large-scale amidation. The second half of this review details case studies in
which these reagents were applied in an industrial setting. As with our previous reviews,8 the
referenced examples are limited to couplings which contain a detailed experimental procedure
above 100 mmol scale, which spans laboratory to plant reactions on grams to hundreds of
kilograms of substrate. This manuscript only covers examples which have appeared in the peerreviewed journals; while the patent literature contains many instances of amide coupling, the
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scientific details within these legal documents are often limited. Finally, the references at the end
of this review are indexed to provide quick access to lists of large-scale examples for each
coupling reagent.
2.
Reagents for amide coupling
Chart 1 below describes the number of reports above 100 mmol scale found in the
mainstream literature for each coupling reagent through June 2015. Based on the number of
publications, the preferred methods for large-scale acid activation are: (1) acid chloride
formation (80 instances) with thionyl chloride and oxalyl chloride as the preferred reagents, (2)
activated ester formation with carbodiimides (71 instances), with EDC and DCC as the top
choices, and (3) CDI (38 instances). Other reagents that have received considerable attention are
pivaloyl chloride (PivCl), isobutyl chloroformate (IBCF), and n-propanephosphonic acid
anhydride (T3P) for the preparation of mixed anhydrides.
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Chart 1. Number of references included in this review for each coupling reagent for amide bond
formation above 100 mmol scale through June 2015.
60
Number of publications
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Coupling reagent
(listed in the order introduced in this review)
2.1
Coupling via acid chloride
Activation of a carboxylic acid as the corresponding acid chloride and subsequent
reaction with an amine is one of the oldest approaches to amide bond formation.9 The high
reactivity of acid chlorides towards amines generally leads to fast couplings which can be
especially useful for sterically-hindered substrates. However, epimerization via the ketene or
azlactone is a potential problem if the acid contains an α-stereocenter.
Several reagents have been employed on large scale for acid chloride preparation: thionyl
chloride (SOCl2), oxalyl chloride ((COCl)2), phosphorus oxychloride (POCl3), and Vilsmeier
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reagent (Figure 1). SOCl2 and (COCl)2 are, by far, the two most widely employed reagents in
process chemistry. A drawback of these methods is that HCl is a byproduct of acid chloride
generation, which can lead to incompatibility with acid-sensitive functional groups.
Figure 1. Structures of reagents for amide bond formation via acid chloride
With reagents such as thionyl chloride, oxalyl chloride, and phosphorus oxychloride, a
small amount of DMF is typically added to serve as a catalyst for acid chloride formation.
Scheme 1 details the mechanism for acid chloride formation via SOCl2 and catalytic DMF,
which proceeds via Vilsmeier–Haack intermediate (Vilsmeier reagent10) and regenerates DMF
together with the desired acid chloride.11 The Vilsmeier reagent is commercially available as a
stable, free-flowing, crystalline solid which allows the purchasing chemist to bypass its
preparation and the associated safety risks related to the handling of SOCl2 or (COCl)2 (vide
infra). However, preformed Vilsmeier reagent is relatively expensive compared to alternatives
for amide bond formation, which contributes to the limited use of this commercial reagent in
process chemistry.12
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Scheme 1. Mechanism of acid chloride formation with SOCl2 catalyzed by DMF
Me
Me
N
O
+ Cl S Cl
H
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Vilsmeier-Haack intermediate
(Vilsmeier reagent)
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The subsequent reaction of the acid chloride with an amine can be implemented under
anhydrous conditions using an organic base, such as Et3N, i-Pr2NEt, or pyridine, to neutralize
byproduct HCl. Despite their water sensitivity, acid chlorides can react with amines in the
presence of an aqueous base (NaOH, NaHCO3, K2CO3, K3PO4) under Schotten–Baumann
conditions.
Thionyl chloride is the most common reagent in process chemistry for the conversion of a
carboxylic acid to an acid chloride.13 One of the primary factors is cost, since the reagent is
inexpensive and represents one of the most cost-efficient ways of preparing acid chlorides.14
However, one disadvantage of thionyl chloride is the potential formation of dimethylcarbamoyl
chloride, a known carcinogen in animal models, when used in combination with DMF as
catalyst.15 The mechanisms for the formation of this side-product are shown in Scheme 2.16
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Scheme 2. Mechanisms for the formation of dimethylcarbamoyl chloride
Common solvents for acid chloride formation with SOCl2 include toluene, THF, nheptane, MeCN, and DME. However, it is also possible to employ SOCl2 as both reactant and
solvent. Upon reaction completion, excess thionyl chloride can be removed by distillation before
isolating the acid chloride or telescoping the reaction mixture directly into the amidation.
Oxalyl chloride has also been commonly employed in process chemistry for acid chloride
generation.17 Advantages of this reagent relative to SOCl2 include: (1) its lower boiling point
(61 °C versus 75 °C) which allows for easier removal of excess reagent via distillation, and (2)
unlike the SOCl2/DMF combination, (COCl)2/DMF does not form dimethylcarbamoyl chloride
(2).15 However, equivalents of CO2 and highly toxic CO are generated as byproducts, and
adequate safety and engineering controls are required to accommodate the offgassing.
Acid chloride formation via (COCl)2 can be scaled in a number of solvents, such as
toluene, THF, EtOAc, i-PrOAc, or MeCN. Upon reaction completion, distillation can remove
excess oxalyl chloride; however, the acid chloride thus obtained is not usually isolated, but
carried directly into the amide bond formation with the corresponding amine.
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Phosphorus oxychloride (phosphoryl chloride) has been rarely reported on large scale for
carboxylic acid activation,18 although this reagent is readily available in bulk and represents a
cost-effective alternative to SOCl2.
No examples with phosphorus trichloride or phosphorus pentachloride for acid chloride
generation on large scale have been found in the peer-reviewed literature, despite the fact that
these reagents are readily available in bulk and are very competitive in cost.
Finally, amide bond formation through the acylation of commercially available acid
chlorides is also common practice on large scale and circumvents the need for acid activation.19
On the other hand, commercially available acid bromides have seen a much more limited use,20
most likely due to the higher cost and far smaller number of choices.
2.2
Coupling via acid anhydride
2.2.1
Carbon-based mixed anhydrides
Amide bond formation via mixed anhydride formation is one of the oldest approaches
and only the acyl chloride and acyl azide methods predate it. Carbon-based mixed anhydrides
can be subdivided into two categories depending on the type of activating reagent (Figure 2):
Figure 2. Reagents for amide coupling via mixed carboxylic and carbonic anhydrides
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1. Mixed carboxylic acid anhydrides, which are formed with reagents such as acetic
anhydride or pivaloyl chloride. There are two major drawbacks associated with
carboxylic acid mixed anhydrides: (1) regiochemical control, which can be avoided by
increasing the steric bulk of the reagent that is used to form the mixed anhydride; (2)
disproportionation to a mixture of the two possible symmetrical anhydrides. However,
disproportionation can be avoided by forming the mixed anhydride immediately prior to
reaction with the amine.
2. Mixed carbonic acid anhydrides, which are the result of carboxylic acids undergoing
reaction with reagents such as chloroformates or EEDQ. The two carbonyls of these
substrates are not equivalent, and amines typically add to the desired carbonyl due to the
lower electrophilicity of the undesired carbonyl (i.e., carbonate). That is the reason why
ethyl chloroformate affords good selectivity for amide bond formation at the desired
carbonyl despite lacking steric bulk.
Reagents to prepare these mixed carboxylic or carbonic anhydrides are typically added to
a solution of the carboxylic acid in the presence of a base, such as NMM or N-methylpiperidine.
These mixed anhydrides commonly are carried into coupling with the amine without isolation.
Acetic anhydride (Ac2O) is commonly used on large scale as an electrophile for amine
acetylation;13ah,21 however, it is rarely used as a reagent for acid activation in amide couplings13a
as the resulting mixed anhydride demonstrates poor regioselectivity for amine additions.
There are several large-scale examples in which pivaloyl chloride (PivCl), or
trimethylacetyl chloride, has been used to activate acids for amide coupling on large
scale.13aj,17d,22 Pivaloyl chloride affords mixed anhydrides with imposing steric bulk to drive the
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desired regioselectivity for amine addition. Furthermore, PivCl seems to be the coupling reagent
of choice for the acylation of chiral amine auxiliaries (oxazolidinones,22a,c,g,h,i or
pseudoephedrine13aj) on industrial scale. The advantages of PivCl for scaleup include its
relatively low cost, wide availability, and non-toxic pivalic acid as byproduct after aqueous
workup. As an acid chloride, however, this reagent is an irritant, can cause chemical burns on
skin contact, and must be handled on large scale with proper ventilation.
Ethyl chloroformate (ECF) has been used as a coupling reagent on large scale,19j,23
although less commonly than isobutyl chloroformate. The benefits of ethyl chloroformate
include its low cost (less expensive than isobutyl chloroformate) and widespread availability.
Although this reagent is highly toxic and more volatile than its isobutyl analog, its byproducts
(EtOH and CO2) are relatively benign, and EtOH is typically easier to remove via aqueous
extraction than the isobutanol byproduct of isobutyl chloroformate.23c The offgassing of
byproduct CO2 requires that waste streams are properly quenched to avoid the buildup of
pressure in sealed waste disposal containers.
Isobutyl chloroformate (IBCF) is a fairly common coupling reagent for large-scale amide
bond formations.13d,17d,19ah,24,25 This reagent is widely available in bulk quantities and
inexpensive. Compared to ethyl chloroformate, the isobutyl reagent is less toxic and its mixed
anhydride shows greater selectivity in the reaction of the amine (due to the greater steric demand
of isobutyl vs. ethyl). Its byproducts, namely isobutanol and CO2, are relatively innocuous, but as
for ethyl chloroformate, IBCF must be properly quenched to avoid pressurization of drummed
waste streams via the offgassing of CO2.
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Boc anhydride, or di-tert-butyl dicarbonate (Boc2O), is not a common acid-activating
reagent for large-scale amide couplings.26 As a low-melting solid (23 °C), this reagent is more
easily handled as a solution.
Finally, EEDQ, or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, was first described
as a reagent for amide couplings in 1968.27 The reagent converts a carboxylic acid to the same
mixed anhydride expected from ethyl chloroformate activation (Scheme 3). EEDQ is similar to
CDI and carbodiimides (vide infra) in that it mediates amide coupling without requiring
additional base. This reagent is relatively inexpensive, widely available, and its coupling
byproducts (quinoline, EtOH) can be purged by extraction into acidic aqueous media. Despite its
longevity, only one example of EEDQ on large scale has been found in the peer-reviewed
literature.28
Scheme 3. Amide bond formation via acid activation with EEDQ
2.2.2
Sulfonate-based mixed anhydrides
Methanesulfonyl chloride (MsCl) and p-toluenesulfonyl chloride (TsCl) are the two
reagents in this category that have been employed on large scale for amide bond formation
(Figure 3). Sulfonate-based mixed anhydrides derived either reagent display excellent selectivity
in which amines add preferentially to the activated carbonyl instead of the sulfonate ester.
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Figure 3. Reagents for amide coupling via sulfonate-based anhydrides
MsCl has not been used commonly for large-scale amide couplings.22f,29 MsCl is highly
toxic, corrosive, moisture sensitive, and a lachrymator,30 and these properties contribute to the
challenge of handling this reagent in industrial processes. However, MsCl is relatively
inexpensive and has been shown to suppress epimerization for the coupling of chiral acids.29b
TsCl is used even less frequently than MsCl for large-scale amide formation.31 TsCl is
widely available and inexpensive, but also toxic and hygroscopic.
2.2.3
Phosphorus-based mixed anhydrides
The first example of a mixed carboxylic-phosphoric anhydride was reported in 1972
using diphenylphosphoryl azide.32 However, no examples using this reagent for acid activation
have been found in the large scale literature, most likely due to the cost and high energy and
toxicity of the azido group. On the other hand, more scale-friendly reagents such as npropanephosphonic acid anhydride (T3P) and ethylmethylphosphinic anhydride (EMPA) (Figure
4) have been applied by process chemistry groups for the synthesis of drug candidates.
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Figure 4. Reagents for amide coupling via phosphorus-based anhydrides
n-Propanephosphonic acid anhydride, more commonly referred to as T3P (or PPA), was
developed in 198033 as a reagent for peptide couplings (Scheme 4).34 The past decade has
realized an uptake in this reagent for large-scale amide couplings.26,31a,35 Several factors
contribute to the attractiveness of T3P on industrial scale. This reagent has low toxicity (LD50
>2000 mg/kg),33b long shelf-life stability, easy handling (commercially available as 50%
solutions in organic solvents, such as EtOAc, DMF, or MeCN), and its water-soluble byproducts
are readily extracted into aqueous waste streams. Furthermore, T3P appears to be a reagent of
choice for suppressing epimerization in the coupling of chiral acids bearing a sensitive αstereocenter.26,35a,c,f–h Drawbacks of this reagent include its moderate cost and the environmental
impact of generating phosphonate waste streams.
Scheme 4. Mechanism of acid activation with T3P
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Ethylmethylphosphinic anhydride (EMPA) is far less common than T3P as a coupling
reagent for large-scale amidations.36 EMPA demonstrates enhanced stability toward hydrolysis
which allows for peptide synthesis in aqueous media; however, its relatively high toxicity (LD50
= 7 mg/kg) and the need for its low level purging from drug substances have contributed to the
limited use of this reagent on industrial scale.33b The mechanism of acid activation with EMPA is
similar to the one with T3P.
2.2.4
CDI
CDI, or 1,1’-carbonyldiimidazole, is a very attractive reagent for amide coupling on large
scale.13aa,19ac,19ae,35b,37 It is inexpensive, widely available on kilogram-scale as a crystalline solid,
relatively safe, and its byproduct imidazole is easily purged with aqueous workup. The reaction
of a carboxylic acid with CDI generates a transient mixed anhydride that rearranges to a carbonyl
imidazolide (Scheme 5). This carbonyl imidazolide is relatively easy to handle and may be
isolated if necessary. Rearrangement of the initial mixed anhydride to the carbonyl imidazolide
generates an equivalent of CO2 which can accelerate the rate of subsequent amide coupling.38 An
additional advantage is that CDI-promoted couplings are often performed without additional
base, as the liberated imidazole can serve this function. One drawback of this reagent is its
sensitivity toward atmospheric moisture.39
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Scheme 5. Mechanism for CDI-mediated amide coupling.
2.3
Coupling via activated ester
2.3.1
Carbodiimides
The use of DCC, or N,N’-dicyclohexylcarbodiimide, for the formation of peptide and
other amide bonds was first reported by Sheehan and Hess 60 years ago.40 Since that time,
carbodiimides have been an extremely important class of compounds for the efficient preparation
of amide bonds.41 Many carbodiimides have been investigated as coupling reagents, but only a
few are routinely used on scale based on availability, cost, isolation, and environmental
considerations
(Figure
diisopropylcarbodiimide),
5).
This
and
group
EDC
is
comprised
of
DCC,
DIC
(N,N’-
(1-ethyl-3-(3’-dimethylaminopropyl)-carbodiimide
hydrochloride; also known as EDAC, EDCI, or WSC (water-soluble carbodiimide)). These
compounds are skin sensitizers to varying degrees and should be handled with caution.
Figure 5. Carbodiimides routinely used on scale
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A primary consideration when selecting a carbodiimide is the preferred workup since the
method for removal of the urea byproduct can vary widely. For example, dicyclohexylurea from
DCC has very limited solubility in most organic solvents and, therefore, is typically removed by
filtration. Diisopropylurea from DIC has reasonable solubility in CH2Cl2 and is normally
removed by aqueous extraction. Finally, the byproduct urea from EDC is water soluble and can
be removed by aqueous workup.
The mechanism of carbodiimide-mediated coupling is complex and begins with proton
transfer from the carboxylic acid to the weakly alkaline nitrogen on the carbodiimide to give an
ion pair (Scheme 6). Addition of the resulting carboxylate anion forms the O-acylisourea, a very
reactive acylating agent that rapidly undergoes aminolysis with an amine to give the desired
amide. Alternatively, excess carboxylic acid can react with the O-acylisourea to form the
symmetrical anhydride, which is also a good acylating agent. Acylation of an amine with the
symmetrical anhydride also produces an equivalent of the starting acid.
Scheme 6. Pathways for carbodiimide mediated amidation
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The O-acylisourea can also rearrange by intramolecular acyl transfer to give the Nacylurea, which is an irreversible pathway that does not lead to desired amide. The use of
auxiliary nucleophiles is a common practice to reduce N-acylurea formation and α-stereocenter
epimerization by increasing the overall rate of amide coupling. Although many additives have
been reported, 1-hydroxybenzotriazole (HOBt)42 is by far the most commonly used for
carbodiimide-mediated reactions in either stoichiometric or catalytic fashion (Figure 6). HOBt is
shock sensitive and subject to travel regulations, whereas analog 1-hydroxy-7-azabenzotriazole
(HOAt) is more stable but considerably more expensive. These additives function by intercepting
the O-acylisourea before intramolecular acyl transfer to the N-acylurea. The resulting activated
ester is active enough to couple with the amine, which circumvents epimerization in many cases.
Figure 6. Epimerization suppressants HOBt and HOAt
The application of DCC for amide bond formation is showcased in the numerous reports
from pharmaceutical companies.22d,24a,35a,43 Despite being a strong sensitizer, its low cost is one
of the main drivers for its widespread use.
Compared to DCC, DIC has seen more limited use in process chemistry groups,24d,44
despite being a liquid which makes it easier to handle on plant scale.
EDC45 is by far the most widely used carbodiimide for the synthesis of drug
candidates.13r,17k,17l,17v,19m,19n,21l,24b,28,35b,46 The fact that the urea byproduct is water soluble and
can be removed during the aqueous workup offers a clear advantage over other carbodiimides
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such as DCC and DIC. However, the high cost of this reagent is an issue that may disfavor its
use over other alternatives on scale, especially in late development.
2.3.2
Phosphonium salts
BOP
((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate,
Castro’s reagent, Figure 7)47 was the first reagent of the HOBt-based onium salts to be
introduced for amide bond formation to avoid the epimerization and other side reactions that can
take place with carbodiimide reagents. Despite promoting fast couplings and containing the
epimerization suppressant HOBt in its structure, BOP has been restricted in process chemistry
due to the generation of one equivalent of hexamethylphosphoramide (HMPA), a known
carcinogen.
As
an
alternative,
(benzotriazol-1-yloxy)tris(pyrrolidine)phosphonium
hexafluorophosphate (PyBOP, Figure 7) was developed,48 which produces the more benign
tris(pyrrolidin-1-yl)phosphine oxide, but this reagent is relatively expensive and no examples
have been found describing its use on large scale. Another important consideration is the
presence of the high-energy benzotriazole moiety, which requires the implementation of
thorough safety studies to determine the viability of the protocol.49
Figure 7. BOP and PyBOP coupling reagents
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The mechanism of acid activation with BOP is shown in Scheme 7. In the presence of a
base such as Et3N or the preferred i-Pr2NEt, the acid carboxylate displaces the benzotriazolyloxy
anion from the phosphonium center to produce an acyloxyphosphonium intermediate. This
species then reacts with the benzotriazolyloxy anion to give an activated benzotriazole ester and
water-soluble HMPA as the byproduct. The final step involves the reaction of the benzotriazole
ester with the amine nucleophile to afford the desired amide product and HOBt as byproduct.
Scheme 7. Mechanism of acid activation with BOP
The application of BOP in process chemistry has been very limited due to the drawbacks
mentioned above and only one example is included in this review.50 Although PyBOP generates
the more benign tris(pyrrolidin-1-yl)phosphine oxide, no examples with this reagent for the large
scale synthesis of pharmaceuticals have been found.
2.3.3
Guanidinium and uronium salts
Benzotriazole-based HBTU, or N-[(1H-Benzotriazol-1-yl)(dimethylamino)methylene]-N-
methylmethanaminium hexafluorophosphate N-oxide,51 was introduced shortly after BOP for
amide coupling (Figure 8). Since then, a large number of guanidinium and uronium salts have
been reported,1k and the structural elucidation of these reagents as guanidinium versus uronium
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salts has been investigated.51c These reagents afford fast amide bond formations and can be very
useful for the coupling of sterically hindered amino acids in peptide synthesis. Despite these
advantages,
only
HBTU,
HATU
ylmethylene]-N-methylmethanaminium
(N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1hexafluorophosphate
N-oxide),
benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium
TBTU
(N-[(1H-
tetrafluoroborate
N-
oxide), TPTU (2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate) and
TOTU
(O-[(cyano(ethoxycarbonyl)methyleneamino]-N,N,N′,N′-tetramethyluronium
tetrafluoroborate) have found their way into large scale applications for the synthesis of
pharmaceuticals (Figure 8). In comparative studies between HATU and HBTU, it has been
shown that the counteranion has no appreciable effect on the outcome of the reaction.51a,52
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Figure 8. Guanidinium and uronium salts HBTU, HATU, TBTU, TPTU and TOTU
Some reasons for the limited application of these reagents in process chemistry include
their high molecular weight (which translates to high cost per mole),14 the formation of cytotoxic
N,N,N’,N’-tetramethylurea as a byproduct,53 and the presence of high energy functional groups
such as the triazolyl moiety in HBTU, HATU, and TBTU and the N–O bonds in TPTU and
TOTU. Nevertheless, the use of these reagents may be justified in situations where sensitive
functionality is present on the coupling partners and, as a consequence, mild reaction conditions
are required. A typical example is when the carboxylic acid contains an epimerizable α-
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stereocenter. In these cases, the addition of 1 equiv of either HOBt or HOAt (Figure 6) may
further suppress epimerization.
The mechanism of amide bond formation using guanidinium and uronium salts is similar
to the one described above for BOP and is exemplified in Scheme 8 for HBTU. Acid activation
requires the formation of the corresponding carboxylate anion with bases such as Et3N or
i-Pr2NEt as the first step. The carboxylate anion then reacts with HBTU to form an activated
HOBt ester and tetramethylurea as byproduct, which is the driving force for acid activation. The
reaction of the amine with the HOBt ester yields the desired amide product.
Scheme 8. Acid activation and amide bond formation with HBTU
Interestingly, although HBTU is widely used for solid-phase peptide synthesis, only one
application of this reagent have been found among process chemistry groups for the manufacture
of drug candidates.54
HATU55 is a structurally very close analog to HBTU but it provides faster couplings with
less epimerization. This reagent has seen widespread use as coupling reagent for amide bond
formation due to the mild reaction conditions and the usually high yields of amide product that it
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provides. It is also particularly efficient for sterically hindered couplings.55,56 For these reasons,
several process groups in pharmaceutical companies have reported HATU applications for the
synthesis of drug candidates.57
Several examples on the application of TBTU52 by process chemistry groups have been
reported.17d,37ae,58 The reagent provides very fast couplings and it can be particularly attractive
when the carboxylic acid contains an epimerizable α-stereocenter. HOBt can be used in
combination with TBTU to reduce epimerization further.
TPTU46b and TOTU35a,36 have seen very limited application on large scale, most likely
due to cost reasons.
2.3.4
Triazine-based coupling reagents
This family of reagents encompasses several compounds that have been employed on
scale (Figure 9). Due to conflicting reports on their type of acid activation (as acid chloride or
activated ester; vide infra), these reagents are grouped together in this section as converting
carboxylic acids to activated triazine esters.
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Figure 9. Structure of triazine-derived cyanuric chloride, CDMT, and DMTMM
Cyanuric chloride (1,3,5-trichlorotriazine) is a highly reactive coupling reagent produced
on industrial scale by the hundreds of thousands of metric tons per year via trimerization of
cyanogen chloride. As a result, it is one of the most cost effective coupling reagents for amide
bond formation. Due to the presence of three chlorine atoms on the molecule acting as leaving
groups, this reagent can be employed in substoichiometric quantities. The mechanism for acid
activation with cyanuric chloride has generally been described as proceeding via acid chloride
formation (Scheme 9).1b The acid must be in the carboxylate form to displace the chloride and
form the activated ester intermediate, which then undergoes attack by the chloride to afford the
desired acid chloride and byproduct 1,3-dichloro-5-hydroxytriazine. Reaction of this
intermediate with another two molecules of carboxylic acid can afford cyanuric acid as
byproduct.
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Scheme 9. Mechanism for acid chloride generation with cyanuric acid1b
However, there has also been a report from the process chemistry group at Rohm and
Haas Company in which an acid chloride from cyanuric chloride was not detected; instead, acid
activation was proposed to take place via an activated ester (Scheme 10).59
Scheme 10. Mechanism for activated ester generation with cyanuric acid59
O
Cl
RCO2 M
M = Na, Li, K
+
N
Cl
O
N
N
O
Cl
0.33 equiv
3 MCl
R
N
O
R
N
N
O
3
O
O
OH
3 R'NH2
R
R
activated
ester
NHR'
+
N
HO
N
N
OH
cyanuric acid
Amine bases such as Et3N and NMM are commonly used with cyanuric chloride, but
inexpensive inorganic bases such as NaOH can also be employed and the reaction can be
conducted in the presence of water. The resulting cyanuric acid byproduct can be easily removed
during workup via filtration and basic washes. In spite of these clear advantages, cyanuric
chloride has received little attention from process chemists in the pharmaceutical industry.17i,59
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CDMT, or 2-chloro-4,6-dimethoxy-1,3,5-triazine,60 can be easily synthesized from the
reaction of cyanuric chloride and 2 equiv of methanol in the presence of Na2CO3 as base. It is a
stable, crystalline solid that is commercially available in bulk. This reagent has been shown to be
effective at reducing epimerization and, also, to work with sterically hindered primary and
secondary alkyl and aryl amines.61 CDMT usually requires the use of a tertiary amine base, such
as NMM, for acid activation and the reaction can be carried out in solvents such as THF, DMF,
and EtOAc. In comparison to cyanuric chloride and DMTMM (vide infra), CDMT has seen more
widespread use across process groups in the pharmaceutical industry13d,61,62 despite the relatively
high cost per mole. A typical experimental procedure is the addition of the tertiary amine base to
a mixture of acid, amine and CDMT.61 The mechanism for acid activation with CDMT is also a
matter of debate and, as for cyanuric chloride, activation via acid chloride1a,1d or via activated
ester59 have been proposed. Regardless of the mode of activation, 1-hydroxy-3,5dimethoxytriazine is generated as byproduct.
DMTMM, or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,63 an
air and water-stable solid that can be easily prepared from CDMT by treatment with NMM, has
been scarcely used in process chemistry.62c An advantage of this reagent is that it can be
employed for amide bond formation in alcoholic or aqueous solvents without the generation of
the corresponding esters or hydrolysis product.64 DMTMM activation provides an activated ester
with NMM•HCl as byproduct (Scheme 11).1d The reagent can be added to a mixture of the acid
and amine coupling partners. The addition of acid carboxylate to DMTMM liberates NMM
which acts as a base to promote the amide coupling. 1-Hydroxy-3,5-dimethoxytriazine is a
water-soluble byproduct that can be removed by aqueous workup. However, as was mentioned
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previously for CDMT, the relatively high cost per mole of DMTMM is a deterring factor for its
application on large scale.
Scheme 11. Acid activation mechanism with DMTMM via activated ester
2.4
Coupling via boron species
The use of boron-derived reagents as catalysts for amide bond formation has increased
considerably in recent years.1g,65 The original reports required the use of stoichiometric amounts
of boron reagents66,67 but, more recently, Yamamoto and coworkers have described the first
examples with substoichiometric amounts.68,69
Many boron-based reagents have been reported for amide bond formation: boric acid,70
trimethoxyborane,66a boron trifluoride-etherate,66c catecholborane,66d borane-trimethylamine,66e
phenylboronic acid,71 o-bromo and o-iodoarylboronic acid,72,73 3,4,5-trifluorophenylboronic
acid,68a,74 N,N-diisopropylbenzylamine-2-boronic acid,74b,75 trifluoroethoxyborane,76 borate
esters,77 3,5-bis(perfluorodecyl)phenylboronic acid,68b N-alkyl-4-boronopyridinium halides,78
4,5,6,7-tetrachlorobenzo[d][1,3,2]dioxaborol-2-ol,79 and 3-nitrophenylboronic acid.68a However,
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despite the many choices available, boric acid clearly stands out as a very desirable reagent since
it is inexpensive and displays excellent atom economy (Figure 10). In addition, after reaction
completion, the water-soluble reagent can be extracted into an aqueous workup. On the other
hand, drawbacks of boric acid are reproductive toxicity at high doses80 and that the European
Chemical Agency may include it on the list of high concern substances which would restrict its
use in Europe.81
Figure 10. Boron-derived reagents used on scale
Boron reagents for amide bond formation82 have seen limited use in process chemistry
and only examples with boric acid83 and 3-nitrophenylboronic acid84 have been found (Figure
10).
The proposed mechanism for amide formation catalyzed by boric acid is shown in
Scheme 12,70 and a similar mechanism can be envisioned for arylboronic acids.85 Reaction of a
carboxylic acid and boric acid leads to the formation of an activated mixed anhydride
intermediate after the loss of a molecule of water (water must be removed azeotropically to
displace the equilibrium toward the acylated boronic acid intermediate). This intermediate then
reacts with the amine to afford the amide product and regenerate boric acid, which restarts the
catalytic cycle.
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Scheme 12. Mechanism for carboxylic acid activation and amide bond formation with boric acid
The mechanism for amide bond formation with arylboronic acids has also been
investigated in silico.86
3.
Other methods for amide bond formation
Not all of the following examples fall into the category of acid activation for amide bond
formation; however, they are referenced in this review since some approaches have been
employed frequently on large scale.
3.1
Synthesis of amides from esters
Esters have been converted to amides by direct treatment with the corresponding amine.
Reports employing methyl esters,21p,43i,46u,46z,87 ethyl esters,19e,19ah,19ap,88 tert-butyl esters,89
isobutyl esters,90 benzyl esters,19aa lactones,91 thioesters,92 pentafluorophenyl esters,24i,93 and Nhydroxysuccinimido esters18,43d,94 have been published.
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Synthesis of amides via transamidation
Although not commonly practiced, one example of intramolecular transamidation has
been reported on large scale for amide synthesis.22h
3.3
Synthesis of amides catalyzed by Brönsted acids
Finally, Brönsted acids can catalyze amide bond formation, as has been reported for
AcOH,95 H2SO4,96 and TFA.97
4.
Case studies
4.1
Coupling via acid chloride
4.1.1
Thionyl chloride
Stoner and coworkers at Abbott Laboratories have reported the preparation of HIV
protease inhibitor 4 (Scheme 13).13g The last step of the synthesis involved the coupling of acid 1
and amine 3, which the medicinal chemistry group had carried out using the EDC/HOBt
combination. However, the high cost and limited commercial availability of EDC as well as the
hazards involved in the handling of HOBt49 led to the search for a coupling method more
amenable for large-scale operations. In addition, it was necessary to obtain full consumption of
amine 3; otherwise, the isolation of 4 proved to be difficult. T3P/NMM gave partial conversion
and some degradation byproducts, whereas the preparation of activated esters (Nhydroxysuccinimide (NHS), N-hydroxybenzotriazole (HOBt)) via treatment with (COCl)2, acid
chlorides, or chloroformates provided low yields of the activated esters and polymeric
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byproducts derived from acid 1. However, treatment of 1 with either SOCl2 or POCl3 led to the
formation of acid chloride 2, which could be isolated as a crystalline solid. In order to get full
conversion to the desired API 4, a screen was carried out that looked at both organic (pyridine,
DMAP, NMM, imidazole) and inorganic (Na2CO3, NaHCO3) bases, which revealed imidazole as
the best choice. On laboratory scale, acid 1 in THF was treated with 1.25 equiv of SOCl2 and,
after stirring at 0 °C for 1 h, the mixture was concentrated followed by coevaporation with nheptane to azeotropically distill SOCl2. The residue was redissolved in DMF and this solution
was added to a solution of amine 3 and imidazole in EtOAc at 0 °C. After stirring overnight at rt,
an aqueous workup, and crystallization from n-heptane/EtOAc, amide 4 was isolated in 92%
yield (two crops).
Scheme 13. Amide bond formation during the synthesis of API 4
Walker and coworkers at Parke-Davis have described the synthesis of compounds 8 and
9, two candidates evaluated as antiretroviral agents for the treatment of AIDS (Scheme 14).13e
The synthesis of 8 commenced with the preparation of diacid chloride 6, which was obtained
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after treating diacid 5 with SOCl2 (2.8 equiv) and catalytic DMF in toluene. After 16 h at 70–75
°C, residual SOCl2 was removed by distillation, and 6 was crystallized from toluene in 83% yield
on multikilogram scale. With diacid chloride 6 on hand, the researchers investigated the amide
bond formation leading to 8. Several esters of L-isoleucine (methyl, benzyl, allyl) were tested in
amide coupling, but the subsequent ester cleavage step was not satisfactory in all three cases. As
a result, the direct coupling with L-isoleucine itself was attempted. Thus, a solvent screen
(dioxane, MTBE, di-n-butyl ether, THF) revealed that THF provided the best yield and purity.
Further optimization showed that inorganic bases such as NaHCO3 led to improved yields and
purities (NaHCO3 performed better than Na2CO3 and K2CO3 in this respect). In the plant, a
mixture of acid chloride, L-isoleucine, and NaHCO3 in THF was heated at 60–65 °C for 2 h.
After reaction completion, the mixture was quenched into diluted aqueous HCl (to neutralize the
base) and MTBE. Phase separation was greatly facilitated when the aqueous layer was kept
acidic. Following workup, diamide 8 was crystallized from n-hexane/THF and recrystallized
from the same solvent mixture to generate 53.6 kg of material in 75% yield and excellent purity
(98.7%, area% by HPLC). The experimental conditions including the use of L-isoleucine rather
than an ester derivative contributed to maintaining the chiral integrity of 7. The only two relevant
impurities detected in 8 were half acid 10 and compound 11 (Figure 11), which is produced due
to the presence of trace amounts of L-valine in commercial L-isoleucine.
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Scheme 14. Synthesis of drug candidates 8 and 9 via diamide bond formation
Figure 11. Impurities detected during the synthesis of diamide 8
Sugaya and coworkers at Sakai Research Laboratories in Japan have reported the
synthesis of L-alanyl-L-glutamine (16), a compound employed as a component of parenteral
nutrition (Scheme 15).13j The preparation of intermediate 15 involved the amide bond formation
between acid chloride 13 and amine 14. Originally, the α-bromo analog of 12 was employed and
treated with SOCl2 to generate the corresponding acid chloride. On scale, however, this acid
chloride tended to decompose under Schotten-Baumann conditions and the resulting amide
showed epimerization and lower purity than in laboratory experiments. As a result, D-2-
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chloropropionyl-L-glutamine (12) was chosen for further development due to the enhanced
chemical and optical stability of this substrate compared to the bromo analog. In addition, 12
could be prepared in higher optical purity than D-2-bromopropionyl-L-glutamine from Dalanine, L-lactate, or via enzymatic resolution of DL-chloropropionic acid or its ester. In the
plant, acid 12 was treated with a slight excess of SOCl2 at 85 °C for 1 h followed by dilution
with toluene to afford acid chloride 13 as a toluene solution. This mixture was then added to a
cold (0–5 °C) solution of L-glutamine (14) in an aqueous NaOH/toluene mixture and further
stirred at 10 °C and pH = 10 for 1 h. After reaction completion and aqueous workup, the aqueous
layer containing the Na salt of 15 was acidified to pH 2 with HCl which crystallized the
carboxylic acid in 82% yield and 99.7% de.
Scheme 15. Amide bond formation en route to L-alanyl-L-glutamine (16)
Zanka and coworkers at Fujisawa Pharmaceutical Co. Ltd. have reported the synthesis of
compound 23, a non-xanthine adenosine A1 receptor antagonist for the regulation of renal
function (Scheme 16).13i The penultimate step of the synthesis involved the coupling of acid 17
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and amine 19. Acid 17 was activated through treatment with equimolar amounts of SOCl2 and
DMF (in situ generation of Vilsmeier reagent) to afford acid chloride 18. Prior to the amide
forming step, the hydroxy group in amine 19 was protected as the TMS ether through reaction
with N,N’-bis(trimethylsilyl)urea (20) in CH2Cl2. During optimization of the amide coupling, the
use of NMM as base led to low yields whereas other bases such as Et3N or i-Pr2NEt generated
dark impurities. However, the addition of catalytic DMAP increased the coupling rate when
using Et3N as base and provided amide 22 in excellent yield. In the plant, a mixture of acid 17
and SOCl2 in CH2Cl2 was dosed with DMF (equimolar amount per SOCl2) to generate acid
chloride 18. Separately, a cooled solution of amine 21 in CH2Cl2 was dosed with DMAP and
Et3N followed by the solution of acid chloride 18. After 1 h, the reaction underwent an aqueous
workup and TMS-protected intermediate 22 was treated with methanolic K2CO3 to cleave the
TMS ether and afford crude 23. Recrystallization from EtOH/H2O afforded over 17 kg of API in
99.8% chemical purity and 99% ee.
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Scheme 16. Amide coupling of an amino alcohol via transient hydroxy protection
4.1.2
Oxalyl chloride
The process group at Albany Molecular Research has reported the coupling of acid
chloride 25 and trimethylhydrazine (26) as part of the synthesis of 28, a drug candidate with
growth hormone-releasing properties (Scheme 17).17e Several methods were attempted for the
coupling
of
acid
24
and
trimethylhydrazine.
Initial
efforts
with
PyBrop
(bromotripyrrolidinophosphonium hexafluorophosphate), T3P, CDI, or EDC led to poor
conversion or decomposition. The researchers mentioned that these attempts afforded the
activated acid species, but the subsequent coupling failed likely due to the steric hindrance
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provided by the quaternary center at the alpha position. Despite the presence of the acid-sensitive
Boc protecting group in 24, the researchers attempted this coupling through the preparation of
acid chloride 25. Thus, acid 24 was treated with 1.6 equiv of (COCl)2 followed by the addition of
catalytic DMF (in situ Vilsmeier reagent generation) and Et3N as base in CH2Cl2 to generate 25
which, without isolation, underwent reaction with a solution of trimethylhydrazine in dioxane at
–20 °C to provide 27 in 82–90% yield after aqueous workup and purification via silica gel plug.
Key to the success of this approach was the order of addition of reagents. Thus, when Et3N was
added prior to the (COCl)2 and DMF, only unreacted 24 was recovered, presumably due to the
different reactivity of the ammonium salt of acid 24. In addition, the Boc-protecting group was
found to be compatible with these reaction conditions and this protocol was carried out to
produce 3.2 kg of amide 27.
Scheme 17. Coupling of acid chloride 25 and trimethylhydrazine en route to drug candidate 28
Magnus and coworkers at Eli Lilly have described the synthesis of glucokinase activator
32 for the treatment of type 2 diabetes (Scheme 18).17q The last step of the synthesis involved the
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amide coupling of carboxylic acid 29 and 2-aminopyrazine (31). During a previous synthesis
implemented by the pharmaceutical company Prosidion,98 the aminopyrazine was added to acid
chloride 30 at –45 °C which led to the formation of peracylated products. The formation of these
impurities was prevented by reversing the order of addition. Thus, acid chloride 30, generated
with (COCl)2 and catalytic DMF in THF below 30 °C, was added to a solution of aminopyrazine
and pyridine while still maintaining the internal temperature below 30 °C. After 1 h, the
byproduct pyridine•HCl was removed via filtration. Following an aqueous workup to remove
excess pyridine and 4–5% of acid 29 via acid-base extractions, API 32 was crystallized from
MeOH in 74% yield (88–94% in situ yield). Despite the presence of an epimerizable chiral
center on the acid moiety, this protocol avoided racemization and 32 was obtained in >99% ee.
Scheme 18. Amide bond formation as the last step of the synthesis of API 32
Another report from the process group at Eli Lilly describes the synthesis of compound
38, a PPARα agonist for the potential treatment of dyslipidemia, coronary heart disease, and
diabetes (Scheme 19).17g The synthesis of intermediate amide 36 was initiated by treating
carboxylic acid 33 with 1.15 equiv of (COCl)2 and catalytic DMF in EtOAc below 30 °C which,
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after distillation of excess (COCl)2, afforded acid chloride 34 as a solution in EtOAc. The
removal of excess (COCl)2 was required to keep the level of impurity 39 below 1% (Figure 12).
Acid chloride 34 was then added to a solution of amine salt 35 and pyridine in EtOAc. Although
the coupling product 36 could be isolated via crystallization, the researchers decided to telescope
it into the subsequent cyclization involving camphorsulfonic acid at reflux to afford 37 and sideproduct 40 in 15:1 ratio. Treatment of the resulting solution with Amberlyst-15 resin allowed for
the selective removal of 40 via filtration, and 37 was crystallized from MTBE with an overall
yield of 55% from acid 33.
Scheme 19. Amide bond formation during the synthesis of PPARα agonist 38
• MsOH
i. (COCl)2 (1.15 equiv)
DMF (cat.), EtOAc
T < 30 ºC, 30 min
CO2Et
O
H2N
CO2Et
O
ii. concentration
OH
34
telescoped as
EtOAc solution
CO2Et
O
i. CSA, EtOAc
reflux, overnight
O
CO2R
O
N
H
36
telescoped as
EtOAc solution
N
NH2
O
35
(1 equiv)
py, EtOAc, T < 25 ºC, 1 h
Cl
33
NH2
O
O
O
N
N N
ii. Amberlyst 15
EtOAc, reflux, 1 h
55% (from 33)
N
H
O
37 (R = Et)
(1.03 kg)
aq NaOH, PhMe
38 (R = H)
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Figure 12. Side-products from the coupling of 34 and 35 in the presence of excess (COCl)2
4.1.3
Phosphorus oxychloride
An example of amide coupling via POCl3 has been reported by scientists at Otsuka
Pharmaceutical during the preparation of drug candidate 45, an inhibitor of superoxide anion
generation for the treatment of ischemia and inflammation (Scheme 20).18 Prior to the
pyrazinone cyclization, the required amide bond was generated from carboxylic acid 41 via
POCl3 activation in the presence of catalytic DMF to produce acid chloride 42, which was
telescoped as a CH2Cl2 solution. The amine coupling partner 43 was freebased with aqueous
K2CO3 and telescoped as a CH2Cl2 solution. In the amidation step, the acid chloride was added to
43 while holding the temperature between 4–19 °C, and after an aqueous workup, amide 44 was
crystallized from cold IPA/H2O in 88% yield on multikilogram scale.
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Scheme 20. Amide bond formation with POCl3 en route to 45
O
O
Cl
OH
N
POCl3 (1.1 equiv)
O
N
DMF (cat.), CH2Cl2
0–4 ºC to 30–35 ºC
1–2 h
CN
O
CN
42
telescoped as
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CO2Me
CO2Me
• HCl
K2CO3
HN
N
H
CN
HN
H2O, CH2Cl2
CN
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telescoped as
CH2Cl2 solution
43•HCl
CO2Me
O
42 + 43
CH2Cl2
4–19 ºC, 30 min
O
N
N
R
OR
N
H
44
(17.2 kg)
R = 2-cyanoethyl
88%
OMe
N
N
H
O
45
4.1.4
N
H
N
H
Commercial Vilsmeier reagent
The process group at Novartis in Switzerland has described the preparation of drug
candidate 50 for the treatment of inflammation (Scheme 21).12e The medicinal chemistry group
employed EDC/DMAP for the coupling of acid 46 and L-tert-leucine-N-methylamide (48), but
epimerization (>5%) was observed. As a result, alternative coupling reagents were investigated.
The formation of a mixed anhydride with isobutyl chloroformate (IBCF) was clean but led to
considerable amounts of recovered 46 due to competitive addition of amine to the undesired
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carbonyl of the mixed anhydride. Other reagents such as CDI and CDMT gave poor results as
well. However, commercially Vilsmeier reagent afforded a very clean coupling without
detectable epimerization and was therefore chosen for further development. On laboratory-scale,
acid 46 was treated with 1.5 equiv of Vilsmeier reagent in THF to afford acid chloride 47. After
the resulting suspension was stirred at 0 °C for 1 h, the addition of NMM followed by a solution
of amine 48 and catalytic DMF in THF provided almost 50 grams of amide 49 (98% yield).
Scheme 21. Amidation via Vilsmeier reagent acid activation en route to API 50
OMe
Cl
Me
N
Cl
Me
(1.5 equiv)
OH
OMe
Cl
THF, 0 ºC, 1 h
O
BnO
47
O
H2N
O
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46
OMe
NHMe
t-Bu
48
(1.1 equiv)
O
H
N
NMM, THF, DMF (cat.)
0 ºC to rt, 2 h
98%
BnO
O
NHMe
t-Bu
49
(49 g)
OMe
O
HO
N
H
HO
O
H
N
O
NHMe
t-Bu
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Coupling via acid anhydride
4.2.1
Carboxylic and carbonic acid mixed anhydrides
4.2.1.1 Acetic anhydride
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As noted above, acetic anhydride is not a common reagent for acid activation en route to
amide coupling. However, one such example was demonstrated by Hoekstra and coworkers at
Parke–Davis for the synthesis of pregabalin (LyricaTM, 54).13a As demonstrated in Scheme 22, 3isobutylglutaric acid (51) and Ac2O were heated at reflux for cyclization to the symmetrical
anhydride 52. Excess Ac2O (and AcOH byproduct) were distilled from the tank, and the
anhydride was treated with ammonium hydroxide to provide amide 53. The amide was
crystallized directly from the reaction mixture after distillation of MTBE and acidification of the
resulting aqueous solution to pH 1.
Scheme 22. Activation of a symmetrical diacid with acetic anhydride
4.2.1.2 Pivaloyl chloride
Li and coworkers at Neurocrine Biosciences synthesized amide 57 via the PivClmediated coupling of acid 55 and pseudoephedrine (56) en route to valnoctamide (59), a mild
sedative (Scheme 23).13aj The mixed anhydride was first prepared by dosing a cooled solution of
acid 55 and Et3N in CH2Cl2 with PivCl. After treating this mixed anhydride with a second charge
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of Et3N, pseudoephedrine was added portionwise while maintaining a temperature below 5 °C.
The amine was added as a solid to minimize reaction volume, and <1% of N,O-diacylated
byproduct was formed. Aqueous workup with successive acid and base washes removed any
residual coupling partners and reagents, and concentration of the organic layer provided the
pseudoephedrine amide 57 as an oil in quantitative yield. Interestingly, α-substitution on the acid
reversed the regioselectivity of coupling. The addition of pseudoephedrine to mixed anhydride
60, derived from α-ethyl acid 58, provided the undesired acylation product 61.
Scheme 23. PivCl-mediated coupling of acid 55 and pseudoephedrine
As an alternative to forming the mixed anhydride prior to charging the amine, it is also
possible to add PivCl to a solution of combined acid and amine. Alimardanov and coworkers at
Wyeth used this approach for the coupling of acrylic acid 62 and chiral oxazolidinone 63
(Scheme 24).22i In a one-pot process, the acid and oxazolidinone in THF were premixed with
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LiCl and cooled as PivCl and Et3N were charged sequentially. After aqueous workup and solvent
exchange, the amide was crystallized from IPA/H2O to provide 64 in 93% yield. These coupling
conditions were derived from a previous report by Merck Process Research on the N-acylation of
2-oxazolidinones mediated by PivCl, LiCl, and Et3N.99
Scheme 24. N-Acylation of chiral oxazolidinone via PivCl-activated acid
4.2.1.3 Ethyl chloroformate
Davulcu, Parsons, and coworkers at Bristol–Myers Squibb employed ethyl chloroformate
for the coupling of serine 65 and 2-chloroethylamine•HCl (66) in their synthesis of 69, an
agonist of the human growth hormone secretagogue receptor (Scheme 25).23b In the first step of a
telescoped process, serine 65 was first converted to the mixed anhydride using a slight excess of
ethyl chloroformate and NMM, and then chloroethylamine was dosed along with a second
charge of base. The authors noted that the chloroethylamine, a strong vesicant, was safely and
easily handled as the HCl salt. Its chemoselective addition to the mixed anhydride was controlled
by cooling the mixture between −30 and 0 °C, and byproducts from addition to the undesired
carbonyl were not detected. Furthermore, splitting the NMM charge into two portions minimized
the racemization (<2%) of mixed anhydride from exposure to excess base. Aqueous workup
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converted excess chloroethylamine to ethanolamine which was extracted into water alongside the
EtOH derived from ethyl chloroformate. In fact, ethyl chloroformate was specifically chosen
over isobutyl chloroformate for this coupling as the latter degrades to isobutanol which was
difficult to purge via similar aqueous extraction. The solution of amide 67 was carried forward to
tetrazole 68 for a 75% isolated yield over four steps.
Scheme 25. Coupling of serine derivative and 2-chloroethylamine with ethyl chloroformate
As shown in Scheme 26, chemists from the Universities of Cologne and Bielefeld in
Germany prepared Singh’s organocatalyst 73 on l00-mmol scale via the coupling of proline (70)
and amino alcohol 71.23c While both ethyl and isobutyl chloroformate performed well as the
coupling reagent, the former was chosen for scale up due to its lower cost. A one-pot process
was developed in which proline was first protected at the amine via Boc2O and excess Et3N
under conditions which do not carbonylate the acid. Subsequent charging of ethyl chloroformate
provided the mixed anhydride which was then treated with amino alcohol 71 in portions via
powder funnel. The crude mixture of amide 72 was evaporated to dryness and carried directly
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into acid-catalyzed deprotection and freebasing. The overall process provided 25 grams of
Singh’s organocatalyst 73 in 70% overall yield.
Scheme 26. Synthesis of Singh’s organocatalyst 73 via ClCO2Et-mediated amidation
4.2.1.4 Isobutyl chloroformate (IBCF)
In a series of publications,24a,24f,25 Novartis described the coupling of amino acid 74 and
N-methylbenzylamine (BnNHMe) via isobutyl chloroformate (IBCF) for the synthesis of a
tachykinin receptor antagonist (Scheme 27). The original development route converted acid 74 to
mixed anhydride 76 via IBCF and NMM in EtOAc, and subsequent treatment with BnNHMe
and HCl provided deprotected amide 75.24a However, this approach posed several processing
issues, including the need for multiple charges of IBCF and BnNHMe to drive the amidation of
74 to completion. The need for multiple reagent charges was attributed to one of two pathways:
(1) the reaction of BnNHMe at the undesired carbonyl (b) of mixed anhydride 76, or (2) the
competitive addition of amino acid to 74 to provide symmetrical anhydride 78 (via CO2
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evolution), which in turn reacts with BnNHMe to form the desired amide and regenerates amino
acid 74.25 Either of these pathways would also lead to the observed urethane 77 as a byproduct.
(The pathway via symmetrical anhydride 78 leaves unconsumed IBCF to react with BnNHMe.)
To better understand the mechanism for amidation and avoid the need for multiple reagent
charges, the offgassing of CO2 was analyzed from the initial reaction of amino acid 74 and
IBCF.25 The substantial amount of CO2 measured in this first step is consistent with the
formation of symmetrical anhydride 78. It was rationalized that the large excess of amino acid
relative to mixed anhydride 76 during slow chloroformate addition favors the symmetrical
anhydride, and that reversing the order of reagent addition would suppress this undesired
pathway. Thus, the inverse addition of amino acid 74 and base to IBCF provided the mixed
anhydride cleanly, and subsequent charging of BnNHMe generated the desired amide without
requiring additional charges of chloroformate or amine.24g Other process changes included
replacing NMM with BnNMe2 as the base, as the latter is easier to remove from aqueous waste
streams (which facilitates aqueous waste disposal). The solvent was also changed from EtOAc to
toluene for greater compatibility with concentrated HCl in the downstream Boc removal, which
provided the deprotected amide 75 in 93% overall yield.
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Scheme 27. Investigating the mechanism of amidation via IBCF
Busacca, Wei, and coworkers at Boehringer–Ingelheim completed their synthesis of HCV
protease inhibitor 82 via the amide coupling of proline 79 and cyclopropylamine 80 followed by
methyl ester saponification (Scheme 28).24j Initial couplings of 79 and 80 using EDC and HOBt
provided amide 81 in high yield; however, HOBt is relatively expensive and shock sensitive, and
the latter attribute makes it subject to transportation and storage restrictions.100 Furthermore,
couplings with HOBt alternatives in conjunction with EDC led to detectable amounts of proline
epimerization. Ultimately, the process group was able to replace EDC/HOBt with the
inexpensive IBCF and generate optically pure amide 81 by maintaining careful temperature
control during acid activation and amination. The chloroformate was added slowly to a THF
solution of proline 79 and NMM while holding the internal temperature at −10 °C. The resulting
mixed anhydride was treated sequentially with cyclopropylamine salt 80 and additional NMM at
rates which kept the internal temperature below −8 °C. The mixture was warmed to 10 °C, and
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after aqueous workup and solvent exchange, amide 81 was crystallized from aqueous EtOH in
88% yield.
Scheme 28. IBCF-mediated coupling of proline 79 and cyclopropylamine 80
4.2.1.5 Boc anhydride
Patterson and coworkers at GlaxoSmithKline employed Boc2O for the conversion of acid
83 to amide 86 en route to denagliptin (87), a drug candidate for the treatment of type 2 diabetes
(Scheme 29).26 The initial reaction of acid 83, Boc2O, and pyridine provided equal amounts of
mixed anhydride 84 and symmetrical anhydride 85. Whereas the addition of NH4OH solution
converted the mixed anhydride to desired amide 86, ammonolysis of the symmetrical anhydride
formed one equivalent each of amide and starting acid. However, since the overall
transformation of acid 83 to amide 86 proceeded to completion without additional reagent
charges, the authors suggested that regenerated acid is recycled to anhydride (via remaining
Boc2O) at a faster rate than the side reaction of Boc2O and NH3. This rationale is consistent with
another experiment in which the overall amide coupling still proceeded to >80% conversion
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when NH4OH solution was present before charging the Boc2O. On large scale, charging the
preformed mixture of anhydrides 84 and 85 with NH4OH solution led to strong offgassing from
CO2 evolution, and after 3 h at 25 °C, standard workup and crystallization provided 95.6 kg of
amide 86 for an excellent 96% yield.
Scheme 29. Anhydride intermediates in Boc2O-mediated amide coupling en route to denagliptin
4.2.1.6 EEDQ
As shown in Scheme 30, Ormerod, Willemsens, and coworkers at Johnson & Johnson
reported an amide coupling using EEDQ for the synthesis of cholecystokinin-2 receptor
antagonist 91.28 The process chemistry team retained EEDQ from the discovery synthesis for the
scaled coupling of amino acid 88 and aniline 89, as alternative reagents induced racemization.
Efforts to preactivate the amino acid with EEDQ prior to introducing the aniline led to the
evolution of CO2 (presumably from the addition of byproduct EtOH to the resulting mixed
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anhydride) and up to 20% of the corresponding ethyl ester of 88. This impurity was overcome by
adding EEDQ to a 1:1 mixture of amino acid and aniline, which provided amide 90 with
negligible racemization and excellent reproducibility. Solvent exchange to propylene glycol
monomethyl ether crystallized 90 in 92% yield.
Scheme 30. EEDQ as the activating agent for the synthesis of amide 90
4.2.2
Sulfonate-based mixed anhydrides
4.2.2.1 Methanesulfonyl chloride (MsCl)
Liu and coworkers from Novartis used MsCl for a pair of amide couplings in their
synthesis of peptide deformylase inhibitor 98 (Scheme 31).22f The coupling of acid 92 and 3aminopyridazine (93) was very difficult due to the poor nucleophilicity of the latter, and reagents
such as Ph2POCl, CDMT, and EDCI/HOBt provided the amide with low conversion or modest
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yield. Following a report in which proline carboxylic acids are coupled via mixed sulfonic
anhydrides,101 92 was activated with MsCl and N-methylimidazole (NMI) and then treated with
93. Performing this condensation in CH2Cl2 at 40 °C led to epimerization of the amide product
94, but changing the solvent to DMF and cooling at −10 °C minimized epimerization to 1–2%
while improving the yield from 65% to 77%. Amide 94 was crystallized directly from the
reaction mixture by diluting with NaCl solution. After Boc removal from 94, the liberated
pyrrolidine was subjected to a second amide coupling in which acid 95 was activated as the
mixed sulfonic anhydride via the same MsCl conditions. The resulting amide 97 was formed in
85% yield (in situ) and telescoped into hydrogenolysis of the benzyl ether leading to the active
pharmaceutical ingredient.
Scheme 31. Amide couplings via MsCl activation.
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4.2.2.2 p-Toluenesulfonyl chloride (TsCl)
Campeau and coworkers at Merck prepared the amide bond of 102, a potent renin
inhibitor for the treatment of hypertension, by activating acid 99 with TsCl in the presence of
NMI and then adding cyclopropylamine•MsOH 100 (Scheme 32).31a In this case, TsCl was
chosen as a cheaper alternative to HATU from the medicinal chemistry synthesis. A mixture of
acid 99 and TsCl in MeTHF/MeCN was cooled at −20 °C as NMI was dosed in portions to
control an exotherm. While still cooling the mixed anhydride (or acylimidazolium
intermediate102) at −20 °C, a solution of amine•MsOH 100 in CH2Cl2 was added portionwise
while controlling the internal temperature below −5 °C to suppress epimerization. The product
amide 101 was treated to an aqueous workup and carried directly into Boc removal under acidic
conditions to provide the drug substance in 83% overall yield.
Scheme 32. TsCl activation of acid 99 for amide coupling.
Me
N
O
Me
N
O
CO2H
N
Boc
99
i. TsCl (1.3 equiv)
NMI, MeTHF
MeCN, –20 ºC
ii. HN
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R
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• MsOH
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CH2Cl2, –20 to 20 ºC
Br
N
Br
MeO
3
101 (R = Boc)
H3PO4
CH2Cl2, MeOH
83% (from 99)
102 (R = H)
(2.62 kg)
Haddad and coworkers at Boehringer Ingelheim Pharmaceuticals have reported the
synthesis of dipeptide intermediate 108 en route to HCV protease inhibitor faldaprevir (109,
Scheme 33).31b Initial attempts to activate acid 103 via mixed anhydride formation with isobutyl
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chloroformate or pivaloyl chloride (monitored by ReactIR for the latter, with fast formation of
the mixed anhydride) and subsequent reaction with hydroxyproline ester 106 resulted in
moderate yields (70%) of desired product due to poor regioselectivity and the formation of the
corresponding acylated byproducts of 106. In addition, slow reactions rates were observed with
the mixed anhydride of PivCl. In an effort to avoid these issues, the researchers investigated the
use of MsCl and TsCl, which are known to promote faster reactions103 and be less electrophilic
groups104 and, therefore, provide better regioselectivity. After base and solvent screens, NMM
and MeCN were selected to afford over 90% isolated yield of 107 without any appreciable
epimerization. TsCl was preferred over MsCl for acid activation to avoid the possibility of
sulfene formation associated with the use of the latter. In the plant, to a mixture of 103 and
NMM in MeCN at –20 °C was added a solution of TsCl in MeCN over 80–100 min. After 1 h at
0 °C, a slurry of amine HCl salt 106 was added and the resulting mixture was stirred at 0–15 °C
for 1.5 h. Without isolation, the ester was cleaved by adding aqueous LiOH, and subsequent
addition of 6 N HCl promoted the crystallization of dipeptide 108 in 91% yield from 103
(99.91% HPLC purity). This report provides a very detailed study on ReactIR to monitor
intermediate formation and consumption to generate valuable kinetic data. Also discussed are
safety studies including calorimetry data used to develop a safe telescoped process.
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Scheme 33. Amide bond formation with TsCl for the synthesis of faldaprevir
4.2.3
Phosphorus-based mixed anhydrides
4.2.3.1 Propanephosphonic acid anhydride (T3P)
Dunetz, Berliner, and coworkers at Pfizer employed T3P for the synthesis of amide 112
en route to glucokinase activator 113 (Scheme 34).35h Various coupling reagents for the
condensation of α-imidazolyl acid 110 and aminonicotinate 111 led to racemization, including
T3P in initial screens, but the epimerization from T3P was reduced when switching the base
from Et3N to bulkier (TMP) or weaker alternatives (pyridines, morpholines). Several evolutions
of this coupling were demonstrated in the pilot plant, and ultimately the pairing of T3P and
pyridine afforded the amide with negligible epimerization. In the pilot plant, T3P was dosed to a
mixture of acid, amine, and pyridine in 2:1 v/v MeCN/EtOAc. This solvent ratio, upon
quenching with 0.5 M aqueous HCl, provided the direct-drop crystallization of free base amide
112 (34.1 kg, 88% yield) with high purity (>99% achiral, 0.5% ent-112) and purging of pyridine,
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excess aminonicotinate 111, and T3P byproducts to the mother liquor. A related study from
Pfizer demonstrated the combination of T3P and pyridine as a general method for suppressing
epimerization in the amide coupling of other carboxylic acids bearing a sensitive αstereocenter.35g
Scheme 34. T3P and pyridine to suppress epimerization in amidation
Patterson and coworkers at GlaxoSmithKline developed a one-pot amidation/dehydration
to complete their large-scale synthesis of denagliptin (87), a treatment for type II diabetes
(Scheme 35).26 The coupling of acid 114 and pyrrolidine 115 with T3P and Hünig’s base
provided amide 116 without any epimerization. The subsequent dehydration of primary
carboxamide to nitrile proved more difficult, as several reagents led to degradation or incomplete
conversion. Initially, the dehydration was accomplished on 150 kg scale by treating a solution of
116 in EtOAc (after aqueous workup and azeotropic drying distillation) with methanesulfonic
anhydride and pyridine to afford the nitrile in 90% yield. However, it was discovered that
performing the T3P coupling of acid 114 and pyrrolidine 115 at higher temperature led to 87 as a
dehydration byproduct, and this observation led to a second-generation process for a one-pot
amidation/dehydration with both steps facilitated by T3P. In this streamlined approach, the
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amide bond was formed with an initial dose of T3P (1.5 equiv) in EtOAc at 50 °C. After reaction
completion, a second dose of T3P (1.5 equiv) was added and the mixture was heated at reflux
(~78 °C) to effect the dehydration. After aqueous workup, 123 kg of denagliptin was crystallized
from IPA for an excellent 97% yield over two steps.
Scheme 35. Synthesis of denagliptin via one-pot amidation and dehydration using T3P
O
H2N
•TsOH
HN
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HN
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Ar
Ar
H2N
F
OH
114
Ar = 4-F-Ph
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Boc
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Ar
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(i-Pr)2NEt
EtOAc, 40–50 ºC
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Ar = 4-F-Ph
O
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O
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87
denagliptin
(123 kg)
Gudmundsson, Xie, and coworkers at GSK used T3P to convert picolinate salt 117 to
picolinamide 118, a treatment for human papillomavirus infections (Scheme 36).35d This is an
interesting case in which amine 117 was crystallized previously with one equivalent of 2picolinic acid, the same acid to be incorporated into the active pharmaceutical ingredient. A
solution of the amine salt and Hünig’s base in CH2Cl2 at 0 °C was dosed with T3P to cleanly
generate picolinamide 118, and an additional 0.1 equivalents of 2-picolinic acid were added to
ensure reaction completion. After aqueous workup to remove the T3P byproducts, solvent
exchange and crystallization from EtOH provided 9.7 kg of picolinamide 118. The authors
mentioned that this T3P procedure was more practical than alternative acylations via the acid
chloride or O-benzotriazole activation.
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Scheme 36. T3P-mediated conversion of picolinate salt to picolinamide
4.2.3.2 Ethylmethylphosphinic anhydride (EMPA)
Colleagues at Hoechst AG and Behring Werke used EMPA to install a piperidine amide
in their kilogram-scale synthesis of thrombin inhibitor 121 (Scheme 37).36 A solution of acid 119
and piperidine in EtOAc was dosed with a solution of EMPA in EtOAc to form amide 120.
Aqueous workup and solvent evaporation provided 5.7 kg of 120 as a yellow oil. The authors
also described similar EMPA-mediated couplings of two other acids with piperidine on
multigram scale.
Scheme 37. Forming a piperidine amide via ethylmethylphosphinic anhydride
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1,1’-Carbonyldiimidazole (CDI)
Neelakandan and coworkers at Emcure Pharmaceutical Limited and Annamalai
University incorporated CDI into an improved amidation process for the synthesis of
trimethobenzamide (125; TiganTM), an antiemetic agent for nausea (Scheme 38).37ac Various
reagents for the coupling of trimethoxybenzoic acid 122 and benzylamine 124, including SOCl2,
tert-butyl chloroformate, DCC/DMAP, EDC/HOBt, and boric acid, led to demethylation
impurities 126 and 127 that were difficult to purge from the desired amide without yield loss.
Alternatively, CDI provided a relatively clean amidation from the demethylation impurities;
however, the formation of urea 128 became an issue if this coupling reagent were used in too
large an excess. Stoichiometry studies identified 1.25 equiv of CDI as optimal for efficient
coupling while maintaining impurities 126–128 below regulatory limits after crystallizing the
product trimethobenzamide from acetone and aqueous HCl.
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Scheme 38. Amide coupling via imidazolide 123 for synthesis of trimethobenzamide (125)
Weisenburger and coworkers at Pfizer reported the process development of a CDImediated peptide coupling for the preparation of αvβ3 integrin antagonist 132 (Scheme 39).37q
The original route for preclinical supplies of 132 involved the reaction of amine 130 with the Nhydroxysuccinimide (NHS) ester of N-Boc glycine (129), but the high cost of this NHS ester
prompted the team to explore alternative reagents for the coupling of 129. Ultimately, CDI was
chosen for its relatively low cost and the ease of removing imidazole salt byproducts by aqueous
extraction. On laboratory scale, the carbonyl imidazolide of 129 was prepared by charging
solvent to dissolve equal amounts of amino acid and CDI (both solids); however, this approach
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led to the rapid release of CO2 which was unsuitable for pilot plant production. Alternatively, on
large scale, the imidazolide formation was controlled by adding a solution of 129 to a slurry of
CDI, which lead to minor foaming but no increase in pressure. The subsequent addition of amine
130 to the activated glycine led to a mixture of amide 131 and byproduct from the O-acetylation
of 132 at the phenolic alcohol. Aging this mixture for several hours improved the ratio of 131 to
over-acetylation byproduct, presumably from the addition of unreacted amine 130 to the
byproduct’s phenolic ester to provide two molecules of 131. The rate of O-acetylation increased
exponentially as the concentration of amine decreased, and the byproduct was held to <1%
during the initial stages of inverse addition of carbonyl imidazolide to a solution of amine 130.
This inverse addition to a solution of amine had the added practical benefit of avoiding solid
charges of agglomerated 130 to the tank in the pilot plant. The resulting solution of amide 131
was washed with 1 M aqueous HCl to remove imidazole and trace unreacted amine (<3%), and
the amide was crystallized from the ternary solvent system of EtOAc, toluene, and n-heptane.
This process furnished 342 kg of amidation product over two batches.
Scheme 39. Inverse addition of carbonyl imidazolide to amine 130
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Twiddle and coworkers at Pfizer used CDI for an improved amide coupling in the
synthesis of β-2 adrenoreceptor agonist 137 (Scheme 40).37ab In a previous commercial route,105
the condensation of acid 133 and benzylamine 134 was mediated by EDC•HCl and HOBt in
CH2Cl2, but this combination of reagents and solvent led to a protracted aqueous workup.
Alternatively, a revised coupling with CDI in EtOAc streamlined the aqueous workup via easyto-purge byproducts (imidazole) and facilitated solvent exchange to chloroacetonitrile and TFA
for a telescoped Ritter reaction. An interesting consideration for the CDI activation of acid 133
was competitive activation of the tertiary alcohol, which becomes dominant only after all the
carboxylic acid is consumed. This issue was circumvented by charging one equivalent of
coupling reagent in portions and tracking CDI consumption by in situ mid-IR monitoring.
Furthermore, avoiding an excess of CDI minimized the formation of urea derived from amine
134. The addition of 134 to the carbonyl imidazolide provided amide 135. After an aqueous
workup which included citric acid washes to extract imidazole, solvent exchange to ClCH2CN
and TFA promoted a subsequent Ritter reaction. The resulting diamide 136 was crystallized in
88% overall yield on multikilogram scale.
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Scheme 40. CDI-mediated amide coupling and Ritter reaction
Kuethe and coworkers at Merck concluded the synthesis of potent cholecystokinin 1R
receptor agonist 141 with the CDI-mediated condensation of acid 138 and piperazine 139.37p As
shown in Scheme 41, a solution of 138 in DMAc was charged with solid CDI in one portion and
aged at rt for 1 h. The amine was added to the resulting carbonyl imidazolide as the solid HCl
salt in one portion, and the slurry was warmed to 50 °C (heating was required for complete
conversion to amide 140). The liberated imidazole from acid activation was an effective base for
neutralizing the HCl salt of 139, and the amide bond was formed without the requirement of
additional base. Telescoped saponification of the methyl ester with aqueous NaOH followed by
pH adjustment with aqueous H3PO4 crystallized the drug substance in 86% overall yield.
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Scheme 41. CDI-mediated coupling of acid 138 and HCl salt 139 without added base
4.3
Coupling via activated ester
4.3.3
Carbodiimides
4.3.3.1 DCC
Prashad and coworkers at Novartis Pharma AG reported the synthesis of compound 144, a
human NK-1 tachykinin receptor antagonist for the treatment of chronic inflammatory and
neuropathic pain (Scheme 42).24a The last step of the synthesis involved an amide coupling to
generate the third amide bond on the molecule. Previous work carried out with N-Boc-L-proline
and 143 generated API that required chromatographic purification. With the goal of developing a
chromatography-free process, the synthetic route was redesigned and focused on the coupling of
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L-proline derivative 142 with the free base of 143. An extensive coupling agent screen was then
implemented. Reactions that employed IBCF, HBTU, or 2,2’-dithiobis(benzothiazole) yielded
API that required chromatographic purification. Cyanuric chloride in combination with pyridine
provided clean material but this base is undesirable on scale due to its toxicity and smell. EDC
also afforded pure API, but the high cost of this coupling reagent made this process not amenable
to scaleup. Finally, DCC and HOBt (1 equiv each) was identified as an inexpensive combination
that resulted in the generation of 144 in high yield with the desired purity. On laboratory scale, to
a solution of 142 and 143 in THF at rt was added HOBt. After cooling to 0 °C, DCC was added
as a THF solution and the reaction was warmed up to 22 °C. Upon reaction completion (4 h), the
mixture was filtered to remove some of the 1,3-dicyclohexylurea byproduct. Following an
aqueous workup that purged some impurities and extraction of 144 into toluene, the remaining
1,3-dicyclohexylurea was filtered off. After concentration, amorphous 144 was obtained from an
EtOH/H2O solvent mixture. A final crystallization from EtOH afforded crystalline API in 81%
overall yield with no detectable amounts of the other diastereomers.
Scheme 42. DCC-mediated coupling to avoid chromatography
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Another example using of DCC on scale has been reported by Storace and coworkers at
Bristol-Myers Squibb from the synthesis of human leukocyte elastase inhibitor 148 for the
treatment of cystic fibrosis and rheumatoid arthritis (Scheme 43).22d The amide forming step to
generate the acyl piperazine was carried out through two different approaches. The first involved
the use of PivCl in the presence of Et3N as base, which afforded 147 in 67% yield on kilogram
scale. Alternatively, the researchers developed a second method that employed DCC. On
laboratory scale, N-methylpiperazine (146) was added to acid 145 in EtOAc at 50–70 °C to
generate the corresponding ammonium salt, followed by the addition of a solution of DCC in
EtOAc over 1.5 h at 70–78 °C. After refluxing for 1 h and cooling, 2 M HCl was added and the
dicyclohexylurea byproduct was filtered off. Following an aqueous workup, amide 147 was
crystallized from n-BuOH in 84% yield. Due to the presence of the phenol functionality in 145,
DCC also reacted with the phenol, but heating shifted the equilibrium toward the formation of
the desired amide product. The need for high temperature in this coupling is in contrast with the
milder conditions typically employed for DCC-mediated amide bond formation (0 °C to ambient
temperature).
Scheme 43. DCC-mediated synthesis of amide 147
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4.3.3.2 DIC
Clark and coworkers at Pfizer employed DIC for the synthesis of αvβ3 integrin antagonist
132 by coupling acid 149 with amine 150 followed by ester hydrolysis (Scheme 44).44a A screen
of coupling reagents revealed multiple options, but the authors chose DIC because it was highly
chemoselective, easy to source, cost-effective, and known to provide greater operator safety
relative to DCC. The optimal solvent system of DMF/CH2Cl2 4.7:1 (v/v) provided the best
balance of efficiencies between coupling and isolation. Several auxiliary nucleophiles were
investigated and 0.2 equiv of a 12 wt% solution of HOBt in DMF was selected because it
accelerated the rate and reduced impurities. In the plant, a solution of DIC in CH2Cl2 was added
to a mixture of 149, 150 and HOBt in DMF at 20 °C. After stirring for 6 h, the sodium
carboxylate of 151 was accomplished by the addition of 2.5 M aqueous NaOH to the crude
coupling reaction mixture. After saponification was complete, the mixture was extracted with
CH2Cl2 to remove the isopropylurea byproduct, HOBt, and some DMF. Careful adjustment to
pH 5.8 with HCl solution resulted in precipitation of the zwitterion of 132. Chromatography and
salt formation provided the desired monohydrate, monophosphoric acid salt 132 in 62% overall
yield on multikilogram scale.
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Scheme 44. DIC/HOBt mediated amidation
The process group at LG Life Sciences in Korea has described the preparation of HIV-1
protease inhibitor 155 (Scheme 45).24d A reagent screen was carried out to couple acid 152 with
phenylvalinone•HCl (153) to produce amide 154. The researchers found that BOP, HATU, and
EDC provided yields in the 70–75% range, but the high cost of these reagents triggered a search
for a less expensive alternative. MsCl and IBCF afforded slightly lower yields of 154 (60% and
72%, respectively). On the other hand, DCC and DIC afforded 154 in 77–78% yield and the
addition of HOBt increased these yields to 83% and 94%, respectively. As a result, the
DIC/HOBt combination with NMM as base was chosen to generate 154. On laboratory scale,
DIC was added dropwise to a mixture of acid 152 and HOBt in CH2Cl2 while the internal
temperature was held below 15 °C. After warming up to rt for acid activation, the mixture was
cooled to 5–10 °C and NMM and amine•HCl 153 were added. Upon reaction completion and
following an aqueous workup, amide 154 was telescoped into the next step (epoxide formation)
as a CH2Cl2 solution.
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Scheme 45. Amidation with DIC during the synthesis of HIV-1 protease inhibitor 155
4.3.1.3 EDC
Researchers at Takeda Chemical Industries in Japan have employed EDC/HOBt to
couple acid 156 with 4-aminopiperidine 157 for the synthesis of 158, a compound found to
reduce plasma total- and low-density lipoprotein (LDL) (Scheme 46).46d Initial attempts to
couple 156 and 157 via the acid chloride generated from (COCl)2 or SOCl2 gave yields in the
71–78% range that suffered from the hygroscopicity of the two coupling partners. As an
alternative, EDC was tested in combination with N-hydroxyphthalimide, NHS, HONB, and
HOBt, and the best yield was obtained with the latter. In the plant, amine 157•bis-HCl salt was
freebased with Et3N in DMF and treated with carboxylic acid 156, HOBt (0.23 equiv), and EDC
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(1.05 equiv). The resulting mixture was heated at 70–80 °C for 2 h. The addition of aqueous
NaHCO3 resulted in the direct crystallization of amide 158 which, after filtration and
recrystallization from EtOH/water, was obtained in 76% yield on kilogram scale.
Scheme 46. EDC/HOBt-mediated amidation with direct-drop amide crystallization
Pu and coworkers at Lilly Research Laboratories have reported on a method for peptide
or amide bond formation using EDC in aqueous EtOH (Scheme 47).46s The process development
of tripeptide 164 required two amide couplings and previous work had carried them out in
CH2Cl2 with equimolar amounts of EDC and HOBt. These conditions did not produce any loss
of chirality and allowed the couplings to proceed without the need for protecting the hydroxy
group in valine. Further development focused on improving the yield and the researchers tried to
apply aqueous conditions for the couplings, as has been previously demonstrated for the
synthesis of peptides and proteins.
When the coupling of 159 and 160 was carried out in water with EDC and stoichiometric
HOBt, followed by in situ Boc cleavage with HCl, the subsequent coupling of deprotected amine
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162 and acid 163 did not take place. A two-step process via isolation of amide 161 did provide
tripeptide 164 in 85% yield, but the first coupling reaction was sluggish at rt after the
uncontrolled crystallization of 161 led to a heterogeneous mixture with impeded agitation. On
the other hand, the addition of an alcoholic solvent such as EtOH and a slightly elevated
temperature (40 °C) increased the reaction rate five-fold. It was also discovered that catalytic
HOBt afforded high yields of tripeptide 164 without observable epimerization or detection of
residual HOBt in the coupling product. In the plant, the first coupling was carried out by adding
EDC (1.1 equiv) to a mixture of acid 159, amine•HCl 160, catalytic HOBt (0.05 equiv), and
NMM in EtOH. After stirring the resulting mixture at rt for 10 h, the addition of water
precipitated amide 161 which was isolated via filtration in 91% yield. Prior to the second amide
coupling, the Boc group was removed from 161 with concentrated HCl in EtOH, and the solution
of liberated amine was then treated with NMM, HOBt (0.1 equiv), hydroxy acid 163 (1.1 equiv),
and EDC (1.2 equiv) and stirred at 40 °C for 3 h. Water addition and seeding crystallized 164
from solution on 41 kg scale and 99.5% ee.
In the same article, the researchers also explored the scope and generality of the
methodology by applying the process to several other coupling partners.
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Scheme 47. Aqueous EtOH media with EDC as activator
BocHN
+
CO2H
O
159
EDC (1.1 equiv)
HOBt (0.05 equiv)
• HCl
H2N
N
Me
NMM, EtOH
25 ºC, 10 h
OH
163
(1.1 equiv)
EDC (1.2 equiv)
HOBt (0.1 equiv)
NMM, H2O, 0–5 ºC, 1.5 h;
then 40 ºC, 3 h
81%
O
N
OH H
H
N
O O
91%
160
(1.02 equiv)
CO2H
BocHN
conc HCl
N
Me
EtOH, 70 ºC, 5 h;
then cooling to 40 ºC
161
(88.2 kg)
99.98% ee
H2N
• HCl
H
N
O O
N
Me
162
telescoped as
EtOH/H2O solution
H
N
O O
164
(41.4 kg)
99.5% ee
N
Me
Chung and coworkers at Merck reported an aqueous i-PrOAc, two-phase amidation using
EDC toward the synthesis of fibrinogen receptor antagonist 168, a drug candidate with a widespectrum platelet inhibitory activity (Scheme 48).46a The penultimate step of the synthesis
involved the coupling of the sodium salt of acid (R)-165 with 3-(R)-aminobutyrate hemisulfate
(166) in the presence of EDC. Thus, the quinine salt of acid 165 was converted to the
corresponding sodium salt, which was isolated as an aqueous solution. To this solution was
added amine salt 166, i-PrOAc, HOBt (0.075 equiv), and EDC (1.2 equiv). After reaction
completion and aqueous workup, amide 167 was telescoped in i-PrOAc (~95% assay yield) into
the hydrogenolysis of the benzyl ester to provide API 168. The authors reported that substantial
polyamidation of 167 occurred in the absence of i-PrOAc, since the organic phase efficiently
removed 167 from the aqueous phase and hence protected it from further reaction with 166.
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Scheme 48. EDC activation in biphasic aqueous/i-PrOAc media to prevent polyamidation
Although HOBt is widely used as the auxiliary nucleophile of choice in carbodiimidebased amidations, it is not always effective. Researchers at GlaxoSmithKline found that HOBt
actually increased epimerization in the synthesis of amide 171 en route to cathepsin K inhibitor
172, a therapy for the prevention of bone degradation (Scheme 49).46x EDC-promoted coupling
of the side chain 169 with azepane amino alcohol 170 gave 10% epimerization in the absence of
any additive. When either DMAP or HOBt were employed as auxiliary nucleophiles, the
epimerization level increased to 32% and 25%, respectively. Alternatively, HOOBt (173) was
found to considerably reduce this side reaction. Thus, 1 mol% HOOBt at rt or 0 °C afforded
1.2% and 0.4% epimerization, respectively, whereas only 0.1 mol% at rt provided a higher level
(5.3%). Based on these results, the process that was implemented in the plant called for the
addition of acid 169 (1 equiv) and HOOBt (1.1 mol%) to a CH2Cl2 solution of amino alcohol 170
(telescoped from the previous step) and cooling to 0 °C. EDC (1.1 equiv) was then added and the
resulting mixture was stirred at 0 °C for 5 h. After an aqueous quench and workup, amide 171
was crystallized from MTBE/toluene on 50-kg scale in 82% yield over two steps from a
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preceding olefin reduction to generate the saturated ring of azepane amino alcohol 170. No
information was provided in the experimental section of the article on the level of epimerization
observed on scale.
Scheme 49. HOOBt as an alternative to HOBt to prevent epimerization
4.3.2
Phosphonium salts
4.3.2.1 BOP
A recent application of BOP on large scale has been reported by Ishikawa and coworkers
at Meiji Seika Kaisha in Japan, who have described the synthesis of drug candidate 177, an
antagonist for integrins αVβ3 and αIIbβ3 for the treatment of coronary thrombosis (Scheme 50).50
The amide bond formation had been originally carried out by the medicinal chemistry group
using EDC and HOBt but it required 12 h to proceed to completion and chromatography to
purify amide 176. As a consequence, the researchers developed a more efficient protocol that
involved the addition of BOP (1.15 equiv) to a cold (4 °C) suspension of benzoic acid 174 and
NMM in DMF. After acid activation for 30 min, amine 175 was added while the internal
temperature was held below 7 °C and the resulting mixture was stirred for a further 23 h at 3–8
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°C. Amide 176 was isolated by pouring the reaction mixture into water followed by filtration to
afford over 200 g of material in 96% yield.
Scheme 50. Synthesis of intermediate 176 via amide bond formation with BOP
4.3.3
Guanidinium and uronium salts
4.3.3.1 HBTU
A very recent example on the use of HBTU for amide bond formation has been reported
through a collaboration between the process chemistry group at Genentech and scientists at
Array BioPharma during the synthesis of ipatasertib•HCl (182), an Akt inhibitor for the
treatment of cancer (Scheme 51).54 The penultimate step of the synthesis involved the coupling
of piperidine bis-HCl 179 and chiral acid 180. Thus, Boc-protected piperazine 178 was treated
with ethanolic HCl to effect Boc-removal and generate bis-HCl salt 179, which was telescoped
into the next step as a toluene suspension since its very high hygroscopicity made its isolation
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difficult. To this suspension were added CH2Cl2, i-Pr2NEt, acid 180, and finally HBTU as a solid
in two portions. After 3 h, the reaction underwent a complex aqueous workup to remove HBTU
related impurities. Thus, the organic phase was first washed with saturated, aqueous NaHCO3
and NH4Cl to remove HOBt. A solvent switch to i-PrOAc and thorough extraction of the organic
phase with 0.6 N NH4OH, 25 wt% NH4Cl, and water removed tetramethylurea and PF6– salts.
After slurrying the product-rich i-PrOAc phase with charcoal and SiliaMetS thiol (to scavenge
ruthenium from a previous asymmetric ketone reduction which set the alcohol of 178),
crystallization from MTBE/n-heptane provided 4.7 kg of amide 181 in 81% yield from 179.
Besides HBTU, no other information was provided in the article on alternative methods tested
for amide bond formation.
Scheme 51. Amide coupling with HBTU in the synthesis of ipatasertib•HCl (182)
4.3.3.2 HATU
O’Shea and coworkers at Merck have described the preparation of odanacatib (185), a
cathepsin K inhibitor for the treatment of osteoporosis (Scheme 52).57b The last step of the
synthesis involved the coupling of acid 183 and cyclopropylamine•HCl 184 and a screen of
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conditions was implemented. Simple protocols, such as (COCl)2, SOCl2 or mixed anhydride
formation with pivaloyl chloride afforded low yields of product. Higher conversions and yield
were observed with PyBOP, TBTU, and HATU, and the latter was selected for further
development. The experimental protocol called for the addition of i-Pr2NEt over 1.5 h to a slurry
of 183, 184, and HATU in DMAc at 3 °C while the internal temperature was held below 10 °C.
By the time the base addition was finalized, the reaction had gone to completion and the addition
of water precipitated odanacatib from solution in 79% yield and 98.5% de. A recrystallization
from THF/water increased the optical purity to 99.9% de for an overall 76% yield.
Scheme 52. HATU-mediated amide bond formation during the synthesis of odanacatib
F
CF3
N
H
HCl • H2N
CO2H
+
183
84% de
MeO2S
CN
184
(1.20 equiv)
i. HATU (1.2 equiv)
i-Pr2NEt, DMAc
3 ºC, 1.5 h
ii. recrystallization
from THF/water
76%
F
CF3
N
H
MeO2S
H
N
CN
O
185
odanacatib
(2.50 kg)
99.9% de
Fei and coworkers at Novartis in China and the United States have reported the
preparation of hydroxamic acid 189, a LpxC inhibitor for the treatment of bacterial infectious
diseases (Scheme 53).57c The synthesis of intermediate 188 required the coupling of benzoic acid
186 and amine 187 (freebased from its HCl salt by treatment with aqueous NaOH). Since amide
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188 is an oil and cannot be purified by crystallization, an efficient coupling protocol and workup
were needed to minimize impurities. Thus, the use of 1.2 equiv of amine 187 was necessary to
completely consume the benzotriazolyl-ester intermediate resulting from activation of 186 with
HATU, since this activated ester could not be removed during the aqueous workup. Upon
reaction completion, the mixture was diluted with i-PrOAc and washed sequentially with
aqueous HCl to remove i-Pr2NEt and remaining amine 187, aqueous Na2CO3 to remove the
byproduct HOAt, and water. After concentration, 188 was isolated as an oil in 94% yield and
>99% ee and used in the next step without any further purification.
Scheme 53. Synthesis of amide 188 via HATU-promoted coupling
NO2
• HCl
H2N
CO2Et
187•HCl
i. aq NaOH,
i-PrOAc
ii. concentration
HATU
(1.2 equiv)
NO2
CO2H
+
O
H2N
186
CO2Et
187
(1.2 equiv)
i-Pr2NEt, MeCN
22 ºC, 19 h
94%
NO2
NH2
O
O
N
H
N
H
CO2Et
O
O
188
(91 g)
>99% ee
OH
NH
O
189
Another example of amide bond formation promoted by HATU comes from a
collaboration between Princeton API Services, J-Star Research, ScinoPharm Taiwan, and the
International Partnership for Microbicides. This group published the kilogram-scale synthesis of
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HIV entry inhibitor 192 (Scheme 54).57e The last step of the synthesis effected the coupling of αketo acid 190 and piperidine 191. Based on previous work on a similar substrate, the researchers
tried the direct coupling of the methyl ester derivative of 190 with 191 in the presence of bases
such as NaHMDS, LiHMDS, or NaOt-Bu, but no desired API was obtained. As a result, an
amide coupling reagent screen was performed and it was found that acid chloride formation with
(COCl)2 afforded 192 in only 20% yield, and the addition of HOBt generated multiple
byproducts. The final conditions to couple 190 and 191 called for the addition of a DMF solution
of HATU to a mixture of 190, 191, and i-Pr2NEt in the same solvent at 25 °C. Upon reaction
completion, EtOH was added to precipitate crude 192. This material was further purified via
treatment with Darco KB in CH2Cl2 at 30 °C followed by crystallization from n-heptane. A final
slurry in n-propanol at 90 °C to obtain the desired polymorph afforded 953 g of API in 84%
overall yield.
Scheme 54. HATU-mediated amide coupling en route to HIV entry inhibitor 192
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4.3.3.3 TBTU
TBTU has been employed by Simoneau and coworkers at Boehringer-Ingelheim in
Canada for the large-scale preparation of orally active renin inhibitor 196 for the treatment of
hypertension (Scheme 55).17d The amide coupling to introduce amine fragment 194 had been
previously carried out with the fully elaborated 2-amino-4-thiazolylmethyl group on the
carboxylic acid moiety, which led to the formation of a substantial amount of the 2(R)butanediamide epimer. As an alternative, the coupling of thiazole precursor 193 and amine 194
was investigated through the screening of numerous coupling reagents (list not provided in the
article). Many of these reagents provided low epimerization levels (<1%) and the team selected
TBTU for further development. The experimental protocol called for the addition of i-Pr2NEt
portionwise to a solution of 193, 194, and TBTU in MeCN at 0–5 °C followed by warming to 20
°C. After an aqueous workup and two filtrations through a pad of silica gel, 195 was crystallized
from a concentrated EtOAc solution to afford 1.2 kg of material. A second crop was obtained
from the filtrates (189 g) for a combined 70% yield. The small amount of 2(R)-epimer (~0.5%)
could be removed via crystallization.
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Scheme 55. Amide bond formation during the synthesis of renin inhibitor 196
Br
Br
Me
N
N
OH
O
H2N
N
CO2H
O
Me
N
TBTU (1 equiv)
+
OH
i-Pr2NEt, MeCN
0 20 ºC, 2 h
H
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OH
70%
194
(1.05 equiv)
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O
195
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NH2
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O
O
S
H
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N
O
OH
OH
196
A second application on the use of TBTU has also been reported by researchers at
Boehringer-Ingelheim in Canada during the multigram preparation of macrolactam 200, an HCV
NS3 protease inhibitor for the treatment of hepatitis C (Scheme 56).58a The formation of amide
199 was carried out through the addition of TBTU (1.1 equiv) and Hünig’s base to a mixture of
acid 197 and amine•HCl 198. After an aqueous workup and concentration of the organic phase,
72 g of crude 199 was isolated as a yellow foam and carried into the next step without any
additional purification.
Scheme 56. Amide bond formation with TBTU en route to HCV NS3 protease inhibitor 200
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4.3.3.4 TPTU
An example of TPTU on large scale has been reported by scientists at Ciba-Geigy in
Switzerland during the preparation of aza-peptide 203, a treatment of AIDS (Scheme 57).46b The
last step of the synthesis involved the bis-coupling between diamine 201 and N(methoxycarbonyl)-L-tert-leucine (202). On laboratory scale, Hünig’s base (6 equiv) was added
to an ice-cooled suspension of 202 (3 equiv) and TPTU (3 equiv) in CH2Cl2. The activated ester
was then treated with trihydrochloride salt 201. Upon reaction completion, the reaction was
subjected to an aqueous workup to remove TPTU byproducts followed by silica filtration and
slurry in i-Pr2O to afford over half a kilogram of 203 in 73% yield. This material could be further
purified via recrystallization from water/EtOH.
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Scheme 57. Synthesis of 203 via amide coupling with TPTU
4.3.3.5 TOTU
Process chemists at Hoechst AG in Germany demonstrated two examples of amide
coupling via TOTU. First, they reported the synthesis of thrombin inhibitor 207 for the treatment
of unstable angina pectoris, myocardial infarction, venous thrombosis, and stroke (Scheme 58).36
The penultimate step in the synthesis coupled amine 204 and cyclohexylammonium carboxylate
salt 205 to generate amide 206. In the plant, NMM and TOTU (1.07 equiv) were added
sequentially to a solution of 204 and 205 in DMF at 0 °C. After 15 min at this temperature, DMF
was removed under vacuum and the residue was subjected to an aqueous work up to afford 206.
This crude amide was carried into the subsequent benzyl ester cleavage with ethanolic HCl to
generate the HCl salt of API 207. A potential problem in this coupling is the presence of
cyclohexylamine in the reaction medium coming from 205, which could give rise to the
corresponding amide, but this point was not discussed in the article.
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Scheme 58. TOTU as coupling agent during the synthesis of thrombin inhibitor 207
A second example from Hoechst AG reported on the use of TOTU for the preparation of
C2-symmetrical HIV protease inhibitor 211 (Scheme 59).35a Intermediate 210 was generated via
double amide bond formation by treating a mixture of 208 and 209 (2.5 equiv) in DMF at 0 °C
with Hünig’s base (8 equiv) followed by ethyl cyanooximoacetate (2.5 equiv; the reason for
using this reagent was not mentioned in the article but it may perform as an epimerization
suppressant) and TOTU (2.5 equiv). Upon warming to rt, the removal of DMF under vacuum
and addition of aqueous KHCO3 crystallized 210, which was then recrystallized from MTBE to
give 1.23 kg of 210 in 88% yield.
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Scheme 59. TOTU-mediated amidation en route to protease inhibitor 211
4.3.4
Triazine-based coupling reagents
4.3.4.1 Cyanuric chloride
The process group at Merck has published the large-scale preparation of taranabant (214),
a cannabinoid-1 receptor inverse agonist for the treatment of obesity (Scheme 60).17i The last
step of the synthesis involved the amide bond formation between amine 212 and acid 213 to
afford API 214. Originally, this step was carried out with EDC/HOBt and Et3N as base, but this
led to taranabant with a yellow color that could not be removed using Ecosorb. Further
optimization led to the replacement of Et3N with pyridine and the elimination of HOBt, but the
high cost of EDC required the identification of a more economical alternative and, thus, the
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researchers investigated the use of cyanuric chloride. When the typical protocol was employed
(preformation of the activated acid species through reaction of the acid with cyanuric chloride in
the presence of base) unsatisfactory results were obtained. On the other hand, the addition of
NMM to a mixture of the acid, amine, and cyanuric chloride (only 0.6 equiv required) at 50 °C
over 4 h provided taranabant in 94% yield after an aqueous workup and crystallization from
MTBE/n-heptane (seeding with the hemisolvate was required to induce crystallization). The
chiral purity of this material could be upgraded from 94% to 99% ee by slurrying in EtOH/H2O,
filtering off insoluble material with low ee (approximately 5% by weight with 31% ee), and
recrystallizing taranabant with 90% recovery.
Scheme 60. Cyanuric acid-mediated amide bond formation to complete the synthesis of
taranabant
4.3.4.2 CDMT
Johnson and coworkers at Novartis have reported the synthesis of compound 218, a
neutral endopeptidase/angiotensin-converting enzyme dual inhibitor for the treatment of
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hypertension, and mitigation of congestive heart failure, diuresis, natriuresis, and vasodilation
(Scheme 61).13d In previous work by this group, amine 216 had been coupled with (S)-2acetylthio-3-methylbutanoic acid using a number of coupling reagents (IBCF, PivCl,
DCC/HOBt, CDMT), but considerable impurity formation and loss of enantiomeric purity was
observed. As an alternative, (R)-2-bromoisovaleric acid was investigated as a coupling partner.
When this acid, as its stable i-Pr2NH salt (215, >98% ee), was treated with IBCF, significant
amounts of urethane and symmetrical urea were produced (similar to what had been observed
with (S)-2-acetylthio-3-methylbutanoic acid). Alternatively, the addition of CDMT and NMM as
base at –10 °C for 2 h afforded the corresponding activated acid. Without isolation, amine•HCl
216 was added to generate amide 217, which could be precipitated from solution upon water
addition to provide material with minor epimerization (>97% de). Further purification by
recrystallization from EtOH/water afforded amide product with >99% de in 74% yield.
Scheme 61. CDMT-promoted amide formation en route to 218
Br
CO2 i-Pr2NH2
215
(1.08 equiv)
OMe
ii.
• HCl
H2N
Br
N
H
CO2Et
216
H
N
O
H
N
N
H
O
O
OMe
OMe
i. CDMT (1.04 equiv)
NMM, THF, –10 ºC, 2 h
CO2Et
217
(94 g)
>99% de
AcS
O
O
N
H
CO2Et
218
–10 ºC, 2.5 h; then rt, 16 h
74%
The process group at Lilly has described the preparation of drug candidate 222, a
multitargeted antifolate for the treatment of cancer (Scheme 62).62a Acid 219 was activated using
CDMT in DMF at 25 °C for 1 h followed by the addition of L-glutamic acid diethyl ester•HCl
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(220). Upon reaction completion, an aqueous workup isolated the free base of 221 as a CH2Cl2
solution, which was converted to over 11 kg of the p-TsOH salt. An interesting observation is
that the amino group on the pyrimidone did not require protection prior to the amide bond step.
Scheme 62. Synthesis of API 222 via CDMT-promoted amide formation
4.3.4.3 DMTMM
An example of the application of DMTMM in process chemistry is found in the
preparation of cannabinoid-1 antagonist 226, a drug candidate for the treatment of obesity and
diabetes, by Villhauer, Shieh, and coworkers at Novartis (Scheme 63).62c One of the challenges
associated with the coupling of mandelic acid derivative 223 and secondary amine 224 was the
epimerization of the chiral center in 223. Initial experiments with DMTMM, CDMT, and IBCF
led to considerable racemization (8–30%), most likely due to the increased acidity of the
benzylic proton in 223 upon activated ester formation. At lower temperature, DMTMM provided
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the best results compared to CDMT and IBCF, and by using free base 224 rather than its HCl
salt, an increased reaction rate was observed which also contributed to minimizing racemization
to only 1.5% epimer. On laboratory scale, 224•HCl was treated with Cs2CO3 in aqueous THF
(19:1 v/v THF:H2O) at ambient temperature to generate the free base of 224. To this mixture was
then added a solution of acid 223 in toluene. Solid DMTMM was added in several portions and
the reaction was cooled at –5 °C for 16 h. Following an aqueous workup, amide 225 was isolated
as a toluene solution that was telescoped into the next step (ester and amide reduction with
BH3•THF). Amide 225 was obtained in 96:4 er with only 2% epimerization from acid 223 (98:2
er).
Scheme 63. DMTMM as coupling reagent en route to drug candidate 226
4.4
Coupling via boron species
4.4.1
Boric acid
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Boric acid has been employed by the process chemistry group at GlaxoSmithKline for the
preparation of efaproxiral (230), a commercial drug for the treatment of cancer (Scheme 64).83a
Substrates such as carboxylic acid 228, with a phenol functionality on the molecule, usually need
protection of the hydroxy group prior to amide bond formation. However, the use of B(OH)3 (0.1
equiv) allowed for the coupling of unprotected 228 and aniline 227 in toluene at reflux under
Dean–Stark conditions. The resulting efaproxiral crystallized upon cooling and was isolated in
86–95% yield on multigram scale. The addition of boric acid dramatically reduced the reaction
time and temperature in comparison to the protocol reported by the medicinal chemistry group,
which coupled 227 and 228 in xylene at reflux for 3 days with no catalyst.
Scheme 64. Synthesis of amide 229 en route to efaproxiral
HO
O
OH
228 (1.0 equiv)
B(OH)3 (0.1 equiv) HO
H2N
227 (1.2 equiv)
HO2C
PhMe
reflux, 18 h
(Dean-Stark
azeotrope)
86–95%
O
O
N
H
229
(56–62 g)
O
230
efaproxiral
N
H
Mathad and coworkers at Megafine Pharma and the chemistry department at B. H.
Commerce and A. M. Science College in India have published the syntheses of several
impurities detected during the industrial preparation of cinacalcet•HCl (231; SensiparTM,
MimparaTM; Figure 13), a calcimimetic agent for the treatment of hyperparathyroidism.83c
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Figure 13. Structure of cinacalcet•HCl
One of the impurities described in the article is compound 235 (Scheme 65), which
contains a cyclohexyl ring in place of the phenyl ring in cinacalcet. (The origin of this impurity
was tracked to 1-(3-bromopropyl)-3-(trifluoromethyl)benzene, one of the reagents employed in a
previous N-alkylation step.) The preparation of amide 234 was carried out by heating a solution
of acid 233 and chiral amine 232 to reflux in the presence of catalytic boric acid (5.5 mol%)
under Dean–Stark conditions. After 16–18 h, an aqueous workup was performed and crude
amide 234 was isolated in 76% yield and used in the next step (amide reduction) without further
purification.
Scheme 65. Boric acid-promoted synthesis of cinacalcet-related impurity
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3-Nitrophenylboronic acid
Brookes and coworkers at Celltech–Chiroscience in the U.K. have reported the large-
scale preparation of the two enantiomers of verapamil•HCl (235; Figure 14), a commercial drug
for the treatment of cardiovascular conditions.84 Verapamil is currently administered as the
racemate, but due to the different biological effects of the two enantiomers, the development of
routes to each individual enantiomer would be advantageous. For the preparation of (S)verapamil•HCl ((S)-235, Scheme 66), chiral acid 238 was obtained via classical resolution of its
racemate with (S)-α-methylbenzylamine (both enantiomers of this amine are readily available
and, thus, either enantiomer of the acid is accessible) to give diastereomeric salt 237. After salt
break, acid 238 (>95% ee) was telescoped as a xylenes solution into reaction with amine 239 in
the presence of catalytic 3-nitrophenylboronic acid68a (0.5 mol%) at reflux. Following an
aqueous workup and concentration, the amide solution was seeded with 240 and cooled to afford
480 g of desired amide in 85% yield. This amide bond formation step could also be carried out
with catalytic boric acid, but this reagent was less efficient and higher loadings were required
(10–20 mol%).
Figure 14. Structure of (±)-verapamil•HCl
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Scheme 66. Amide bond formation catalyzed by 3-nitrophenylboronic acid en route to (S)verapamil•HCl
5
Conclusions
The importance of amide bond formation in process chemistry for the synthesis of drug
candidates cannot be overstated. Process chemists have a wide array of methods at their disposal
to generate amides, but the limitations imposed by large-scale operations have focused the
selection to a narrower field of reagents. Based on the number of examples included in this
review, the top choices for acid activation by reagent are EDC, SOCl2, CDI, and (COCl)2,
followed by a second group that includes PivCl, IBCF, T3P, and DCC.
Most of the reagents presented in this review are used in stoichiometric amounts and
some of them, such as the guanidinium and uronium salts, are very atom-inefficient. As a
consequence, the American Chemical Society Green Chemistry Pharmaceutical Roundtable has
selected the development of more environmentally-friendly and efficient methods for amide
bond formation as one of their top priorities.106
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The development of catalytic processes for amide bond formation has seen a resurgence
in recent years. Boron-derived reagents, such as the ones described in sections 2.4 and 4.4 of this
review, have already been implemented on large scale in several instances. Besides boron,
catalytic methods that employ zinc,107 titanium,108 zirconium,109 aluminum,110 indium,111
silica,112 and niobium113 are very promising discoveries that, with further development, may have
the chance to enter the process chemistry arena and displace some of the more traditional
stoichiometric approaches. Also, enzymes have received considerable attention recently as a
green approach to synthesizing primary, secondary and tertiary amides,1p with lipases
encompassing most examples. This family of catalysts is highly selective and the amidation can
be carried out in a number of green solvents such as water and alcohols. However, current
technologies show very limited substrate scope and often require long reaction times (days).
Other efforts have investigated safer alternatives to benzotriazole-based coupling
reagents. As a result, oxyma-based reagents such as COMU (1-[(1-cyano-2-ethoxy-2oxoethylideneaminooxy)-dimethylamino-morpholinomethylene)]methanaminium
hexafluorophosphate)114 have emerged as safer replacements with comparable reactivities.
Finally, alternatives to the traditional coupling between a carboxylic acid and an amine
for amide synthesis have also been pursued. A remarkable example is the ruthenium-catalyzed
coupling of an amine and an alcohol which generates one equivalent of dihydrogen as the only
byproduct.115 High yields were obtained with as little as 0.1 mol% Ru catalyst and no additives
or stoichiometric oxidant were needed. This transformation has also been accomplished with
catalytic ZnI2 and stoichiometric tert-butyl hydroperoxide.107b Another example is the
preparation of amides from functionalized aldehydes (formylcyclopropanes, α,β-unsaturated
aldehydes, α-haloaldehydes, epoxyaldehydes).116
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Regardless of reagent choice, amide bond formation will undoubtedly continue to be one
of the most important transformations in process chemistry for the synthesis of pharmaceuticals.
Societal and economic pressures are already having a clear effect on driving safer, greener, and
cheaper reagents and methods. We are confident that, if proven scalable, many of these new
technologies will be routinely incorporated into large-scale operations for the synthesis of API.
6
Abbreviations
API: active pharmaceutical ingredient(s)
aq: aqueous
Bn: benzyl
Boc: tert-butoxycarbonyl
BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
Cbz: carbonylbenzyloxy
CDI: 1,1’-carbonyldiimidazole
CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine
CSA: camphorsulfonic acid
DCC: N,N’-dicyclohexylcarbodiimide
DCU: N,N’-dicyclohexylurea
de: diastereomeric excess
DIC: N,N’-diisopropylcarbodiimide
DMAc: N,N-dimethylacetamide
DMAP: N,N-dimethylaminopyridine
DME: 1,2-dimethoxyethane
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DMF: N,N-dimethylformamide
DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
ECF: ethyl chloroformate
EDAC: 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide
EDC or EDCI: 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide
EEDQ: 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
EMPA: ethylmethylphosphinic anhydride
ee: enantiomeric excess
equiv: equivalent(s)
er: enantiomeric ratio
GC: gas chromatography
HATU:
N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-
methylmethanaminium hexafluorophosphate N-oxide
HBTU:
N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium
hexafluorophosphate N-oxide
HCV: hepatitis C virus
HOAt: 1-hydroxy-7-azabenzotriazole
HOBt: N-hydroxybenzotriazole
HONB; N-hydroxy-5-norbornene-endo-2,3-dicarboxylic acid imide
HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-(1,2,3)-benzotriazine
HPLC: high performance liquid chromatography
IBCF: isobutyl chloroformate
IPA: isopropanol, or 2-propanol
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LD50: median lethal dose
LDA: lithium diisopropylamide
LiHMDS: lithium hexamethyldisilazide
MsCl: methanesulfonyl chloride
MTBE: tert-butyl methyl ether
NaHMDS: sodium hexamethyldisilazide
NHS: N-hydroxysuccinimide
NMI: N-methylimidazole
NMM: N-methylmorpholine
NMP: N-methyl-2-pyrrolidone
PPA: n-propanephosphonic acid anhydride
Piv: pivaloyl
py: pyridine
PyBOP: (benzotriazol-1-yloxy)tris(pyrrolidine)phosphonium hexafluorophosphate
PyBrop: bromotripyrrolidinophosphonium hexafluorophosphate
rt: room temperature
T3P: n-propanephosphonic acid anhydride
TBTU:
N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium
tetrafluoroborate N-oxide
TFA: trifluoroacetic acid
THF: tetrahydrofuran
TMP: 2,2,6,6-tetramethylpiperidine
TMS: trimethylsilyl
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TOTU:
O-[(cyano(ethoxycarbonyl)methyleneamino]-N,N,N′,N′-tetramethyluronium
tetrafluoroborate
TPTU: 2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate
TsCl: p-toluenesulfonyl chloride
WSC: water-soluble carbodiimide
7
1
References
Amidation reviews since 2004: (a) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447. (b)
Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827. (c) Bode, J. W. Curr. Opin.
Drug Discovery Dev. 2006, 9, 765. (d) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
(e) Ishihara, K. Tetrahedron 2009, 65, 1085. (f) Joullié, M. M.; Lassen, K. M. ARKIVOC 2010,
8, 189. (g) Charville, H.; Jackson, D.; Hodges, G.; Whiting, A. Chem. Commun. 2010, 46, 1813.
(h) Scheidt, K. Nature 2010, 465, 1020. (i) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480,
471. (j) Allen, C. L.; Williams, J. M. J. Chem. Soc. Rev. 2011, 40, 3405. (k) El-Faham, A.;
Albericio, F. Chem. Rev. 2011, 111, 6557. (l) Roy, S.; Roy, S.; Gribble, G. W. Tetrahedron
2012, 68, 9867. (m) Al-Warhi, T. I.; Al-Hazimi, H. M. A.; El-Faham, A. J. Saudi Chem. Soc.
2012, 16, 97. (n) Bode, J. W. Top. Organomet. Chem. 2013, 44, 13. (o) Lanigan, R. M.;
Sheppard, T. D. Eur. J. Org. Chem. 2013, 7453. (p) Lundberg, H.; Tinnis, F.; Selander, N.;
Adolfsson, H. Chem. Soc. Rev. 2014, 43, 2714. (q) Taylor, J. E.; Bull, S. D. In Comprehensive
Organic Synthesis, 2nd Edition; Knochel, P.; Molander, G. A., Eds., 2014, pp. 427–478.
2
Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337.
3
Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
103
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59
60
4
Page 104 of 138
Charville, H.; Jackson, D. A.; Hodges, G.; Whiting, A.; Wilson. M. R. Eur. J. Org. Chem.
2011, 5981.
5
(a) Jursic, B. S.; Zdravkovski, Z. Synth. Commun. 1993, 23, 2761. (b) Goossen, L. J. Ohlmann,
D. M.; Lange, P. P. Synthesis 2009, 160.
6
(a) Caddick, S. Tetrahedron, 1995, 51, 10403. (b) Varma, R. S. Green Chem. 1999, 1, 43. (c)
Perreux, L.; Loupy, A.; Volatron, F. Tetrahedron 2002, 58, 2155.
7
Wigman, L.; Remarchuk, T.; Gomez, S. R.; Kumar, A.; Dong, M. W.; Medley, C. D.; Chetwyn,
N. P. Amer. Pharm. Rev. 2014, 17, 20.
8
(a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177. (b) Magano, J.; Dunetz, J. R. Org.
Process Res. Dev. 2012, 16, 1156.
9
Fischer, E.; Otto, E. Ber. Deutsch. Chem. Ges. 1903, 36, 2106.
10
Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York, 1969; Vol. 1, p
286.
11
J. J. Li. In Name Reactions: a Collection of Detailed Mechanisms and Synthetic Applications;
3rd Edition, Springer, 2006, p. 605.
12
Commercial Vilsmeier reagent: (a) Zanka, A. Org. Process Res. Dev. 1998, 2, 418. (b)
Singh, J.; Kim, O. K.; Kissick, T. P.; Natalie, K. J.; Zhang, B.; Crispino, G. A.; Springer, D. M.;
Wichtowski, J. A.; Zhang, Y.; Goodrich, J.; Ueda, Y.; Luh, B. Y.; Burke, B. D.; Brown, M.;
Dutka, A. P.; Zheng, B.; Hsieh, D.-M.; Humora, M. J.; North, J. T.; Pullockaran, A. J.; Livshits,
J.; Swaminathan, S.; Gao, Z.; Schierling, P.; Ermann, P.; Perrone, R. K.; Lai, M. C.; Gougoutas,
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J. Z.; DiMarco, J. D.; Bronson, J. J.; Heikes, J. E.; Grosso, J. A.; Kronenthal, D. R.; Denzel, T.
W.; Mueller, R. H. Org. Process Res. Dev. 2000, 4, 488. (c) Totleben, M. J.; Prasad, J. S.;
Simpson, J. H.; Chan, S. H.; Vanyo, D. J.; Kuehner, D. E.; Deshpande, R.; Kodersha, G. A. J.
Org. Chem. 2001, 66, 1057. (d) Gibson, F. S.; Singh, A. K.; Soumeillant, M. C.; Manchand, P.
S.; Humora, M.; Kronenthal, D. R. Org. Process Res. Dev. 2002, 6, 814. (e) Koch, G.; Kottirsch,
G.; Wietfeld, B.; Küsters, E. Org. Process Res. Dev. 2002, 6, 652.
13
Thionyl chloride: (a) Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.;
Grote, T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Karrick, G.
L. Org. Process Res. Dev. 1997, 1, 26. (b) Wu, G.; Wong, Y.; Steinman, M.; Tormos, W.;
Schumacher, D. P.; Love, G. M.; Shutts, B. Org. Process Res. Dev. 1997, 1, 359. (c) Zhang, L.h.; Chung, J. C.; Costello, T. D.; Valvis, I.; Ma, P.; Kauffman, S.; Ward, R. J. Org. Chem. 1997,
62, 2466. (d) Johnson, E. P.; Cantrell, W. R.; Jenson, T. M.; Miller, S. A.; Parker, D. J.; Reel, N.
M.; Sylvester, L. G.; Szendroi, R. J.; Vargas, K. J.; Xu, J.; Carlson, J. A. Org. Process Res. Dev.
1998, 2, 238. (e) Fiore, P. J.; Puls, T. P.; Walker, J. C. Org. Process Res. Dev. 1998, 2, 151. (f)
Cook, D. C.; Jones, R. H.; Kabir, H.; Lythgoe, D. J.; McFarlane, I. M.; Pemberton, C.; Thatcher,
A. A.; Thompson, D. M.; Walton, J. B. Org. Process Res. Dev. 1998, 2, 157. (g) Stoner, E. J.;
Stengel, P. J.; Cooper, A. J. Org. Process Res. Dev. 1999, 3, 145. (h) Dale, D. J.; Dunn, P. J.;
Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A. S.
Org. Process Res. Dev. 1999, 3, 17. (i) Zanka, A.; Uematsu, R.; Morinaga, Y.; Yasuda, H.;
Yamazaki, H. Org. Process Res. Dev. 1999, 3, 389. (j) Sano, T.; Sugaya, T.; Inoue, K.; Mizutaki,
S.-i.; Ono, Y.; Kasai, M. Org. Process Res. Dev. 2000, 4, 147. (k) Pflum, D. A.; Wilkinson, H.
S.; Tanoury, G. J.; Kessler, D. W.; Kraus, H. B.; Senanayake, C. H.; Wald, S. A. Org. Process
Res. Dev. 2000, 4, 110. (l) Ikemoto, T.; Ito, T.; Hashimoto, H.; Kawarasaki, T.; Nishiguchi, A.;
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52
53
54
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Page 106 of 138
Mitsudera, H.; Wakimasu, M.; Tomimatsu, K. Org. Process Res. Dev. 2000, 4, 520. (m) Fang,
Q. K.; Grover, P.; Han, Z.; McConville, F. X.; Rossi, R. F.; Olsson, D. J.; Kessler, D. W.; Wald,
S. A.; Senanayake, C. H. Tetrahedron: Asymmetry 2001, 12, 2169. (n) Phillips, G.; Fevig, T. L.;
Lau, P. H.; Klemm, G. H.; Mao, M. K.; Ma, C.; Gloeckner, J. A.; Clark, A. S. Org. Process Res.
Dev. 2002, 6, 357. (o) Tan, L.; Chen, C.-y.; Chen, W.; Frey, L.; King, A. O.; Tillyer, R. D.; Xu,
F.; Zhao, D.; Grabowski, E. J. J.; Reider, P. J.; O'Shea, P.; Dagneau, P.; Wang, X. Tetrahedron
2002, 58, 7403. (p) Allegretti, M.; Anacardio, R.; Cesta, M. C.; Curti, R.; Mantovanini, M.;
Nano, G.; Topai, A.; Zampella, G. Org. Process Res. Dev. 2003, 7, 209. (q) Ager, D. J.; Babler,
S.; Erickson, R. A.; Froen, D. E.; Kittleson, J.; Pantaleone, D. P.; Prakash, I.; Zhi, B. Org.
Process Res. Dev. 2003, 7, 72. (r) Farr, R. N.; Alabaster, R. J.; Chung, J. Y. L.; Craig, B.;
Edwards, J. S.; Gibson, A. W.; Ho, G.-J.; Humphrey, G. R.; Johnson, S. A.; Grabowski, E. J. J.
Tetrahedron: Asymmetry 2003, 14, 3503. (s) Cai, S.; Dimitroff, M.; McKennon, T.; Reider, M.;
Robarge, L.; Ryckman, D.; Shang, X.; Therrien, J. Org. Process Res. Dev. 2004, 8, 353. (t)
Moher, E. D.; Tripp, A. E.; Creemer, L. C.; Vicenzi, J. T. Org. Process Res. Dev. 2004, 8, 593.
(u) Ikemoto, T.; Ito, T.; Nishiguchi, A.; Miura, S.; Tomimatsu, K. Org. Process Res. Dev. 2005,
9, 168. (v) Kotian, P. L.; Lin, T.-H.; El-Kattan, Y.; Chand, P. Org. Process Res. Dev. 2005, 9,
193. (w) Iida, T.; Satoh, H.; Maeda, K.; Yamamoto, Y.; Asakawa, K.-i.; Sawada, N.; Wada, T.;
Kadowaki, C.; Itoh, T.; Mase, T.; Weissman, S. A.; Tschaen, D.; Krska, S.; Volante, R. P. J.
Org. Chem. 2005, 70, 9222. (x) Nikitenko, A. A.; Winkley, M. W.; Zeldis, J.; Kremer, K.; Chan,
A. W. Y.; Strong, H.; Jennings, M.; Jirkovsky, I.; Blum, D.; Khafizova, G.; Grosu, G. T.;
Venkatesan, A. M. Org. Process Res. Dev. 2006, 10, 712. (y) Peters, R.; Althaus, M.; Diolez, C.;
Rolland, A.; Manginot, E.; Veyrat, M. J. Org. Chem. 2006, 71, 7583. (z) Oh, L. M.; Wang, H.;
Shilcrat, S. C.; Herrmann, R. E.; Patience, D. B.; Spoors, P. G.; Sisko, J. Org. Process Res. Dev.
106
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60
Organic Process Research & Development
2007, 11, 1032. (aa) Barkalow, J. H.; Breting, J.; Gaede, B. J.; Haight, A. R.; Henry, R.; Kotecki,
B.; Mei, J.; Pearl, K. B.; Tedrow, J. S.; Viswanath, S. K. Org. Process Res. Dev. 2007, 11, 693.
(ab) Satyanarayana, K.; Srinivas, K.; Himabindu, V.; Reddy, G. M. Org. Process Res. Dev.
2007, 11, 842. (ac) Moseley, J. D.; Brown, D.; Firkin, C. R.; Jenkin, S. L.; Patel, B.; Snape, E.
W. Org. Process Res. Dev. 2008, 12, 1044. (ad) Haycock-Lewandowski, S. J.; Wilder, A.;
Åhman, J. Org. Process Res. Dev. 2008, 12, 1094. (ae) Åhman, J.; Birch, M.; HaycockLewandowski, S. J.; Long, J.; Wilder, A. Org. Process Res. Dev. 2008, 12, 1104. (af) Busacca,
C. A.; Cerreta, M.; Dong, Y.; Eriksson, M. C.; Farina, V.; Feng, X.; Kim, J.-Y.; Lorenz, J. C.;
Sarvestani, M.; Simpson, R.; Varsolona, R.; Vitous, J.; Campbell, S. J.; Davis, M. S.; Jones, P.J.; Norwood, D.; Qiu, F.; Beaulieu, P. L.; Duceppe, J.-S.; Haché, B.; Brong, J.; Chiu, F.-T.;
Curtis, T.; Kelley, J.; Lo, Y. S.; Powner, T. H. Org. Process Res. Dev. 2008, 12, 603. (ag)
Agbodjan, A. A.; Cooley, B. E.; Copley, R. C. B.; Corfield, J. A.; Flanagan, R. C.; Glover, B. N.;
Guidetti, R.; Haigh, D.; Howes, P. D.; Jackson, M. M.; Matsuoka, R. T.; Medhurst, K. J.; Millar,
A.; Sharp, M. J.; Slater, M. J.; Toczko, J. F.; Xie, S. J. Org. Chem. 2008, 73, 3094. (ah) Klapars,
A.; Campos, K. R.; Waldman, J. H.; Zewge, D.; Dormer, P. G.; Chen, C.-y. J. Org. Chem. 2008,
73, 4986. (ai) Wallace, D. J.; Campos, K. R.; Shultz, C. S.; Klapars, A.; Zewge, D.; Crump, B.
R.; Phenix, B. D.; McWilliams, J. C.; Krska, S.; Sun, Y.; Chen, C.-y.; Spindler, F. Org. Process
Res. Dev. 2009, 13, 84. (aj) Li, B.-F.; Hughes, R. M.; Le, J.; McGee, K.; Gallagher, D. J.; Gross,
R. S.; Provencal, D.; Reddy, J. P.; Wang, P.; Zegelman, L.; Zhao, Y.; Zook, S. E. Org. Process
Res. Dev. 2009, 13, 463. (ak) Webel, M.; Palmer, A. M.; Scheufler, C.; Haag, D.; Müller, B.
Org. Process Res. Dev. 2010, 14, 142. (al) Bret, G.; Harling, S. J.; Herbal, K.; Langlade, N.;
Loft, M.; Negus, A.; Sanganee, M.; Shanahan, S.; Strachan, J. B.; Turner, P. G.; Whiting, M. P.
Org. Process Res. Dev. 2010, 14, 112. (am) Chandramouli, S. V.; Ayers, T. A.; Wu, X.-D.; Tran,
107
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Page 108 of 138
L. T.; Peers, J. H.; Disanto, R.; Roberts, F.; Kumar, N.; Jiang, Y.; Choy, N.; Pemberton, C.;
Powers, M. R.; Gardetto, A. J.; D’Netto, G. A.; Chen, X.; Gamboa, J.; Ngo, D.; Copeland, W.;
Rudisill, D. E.; Bridge, A. W.; Vanasse, B. J.; Lythgoe, D. J. Org. Process Res. Dev. 2012, 16,
484. (an) Sera, M.; Yamashita, M.; Ono, Y.; Tabata, T.; Muto, E.; Ouchi, T.; Tawada, H. Org.
Process Res. Dev. 2014, 18, 446. (ao) Rousseau, J.-F.; Chekroun, I.; Ferey, V.; Labrosse, J. R.
Org. Process Res. Dev. 2015, 19, 506. (ap) Oda, S.; Manaka, K.; Kakiya, K.; Hozumi, Y.; Fukui,
Y.; Omura, S.; Kurashita, M.; Nishiwaki, M.; Takeuchi, Y.; Kitamura, H. Org. Process Res. Dev.
2015, 19, 531.
14
Anderson, N. G. In Practical Process Research & Development: A Guide for Organic
Chemists. 2nd edition; Academic Press, 2012, p. 109.
15
Levin, D. Org. Process Res. Dev. 1997, 1, 182.
16
Stare, M.; Laniewski, K.; Westermark, A.; Sjögren, M.; Tian, W. Org. Process Res. Dev.
2009, 13, 857.
17
Oxalyl chloride: (a) Maligres, P. E.; Weissman, S. A.; Upadhyay, V.; Cianciosi, S. J.;
Reamer, R. A.; Purick, R. M.; Sager, J.; Rossen, K.; Eng, K. K.; Askin, D.; Volante, R. P.;
Reider, P. J. Tetrahedron 1996, 52, 3327. (b) Horgan, S. W.; Burkhouse, D. W.; Cregge, R. J.;
Freund, D. W.; LeTourneau, M.; Margolin, A.; Webster, M. E.; Henton, D. R.; Barton, K. P.;
Clouse, R. C.; DesJardin, M. A.; Donaldson, R. E.; Fetner, N. J.; Goralski, C. T.; Heinrich, G. P.;
Hoops, J. F.; Keaten, R. T.; McConnell, J. R.; Nitz, M. A.; Stolz-Dunn, S. K. Org. Process Res.
Dev. 1999, 3, 241. (c) Shi, Y.-J.; Wells, K. M.; Pye, P. J.; Choi, W.-B.; Churchill, H. R. O.;
Lynch, J. E.; Maliakal, A.; Sager, J. W.; Rossen, K.; Volante, R. P.; Reider, P. J. Tetrahedron
1999, 55, 909. (d) Simoneau, B.; Lavallée, P.; Bailey, M.; Duceppe, J.-S.; Grand-Maître, C.;
108
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57
58
59
60
Organic Process Research & Development
Grenier, L.; Ogilvie, W. W.; Poupart, M.-A.; Thavonekham, B. Can. J. Chem. 2000, 78, 739. (e)
García-Rubio, S.; Wilson, C. D.; Renner, D. A.; Rosser, J. O.; Patra, D.; Reid, J. G.; Pines, S. H.
Org. Process Res. Dev. 2004, 8, 360. (f) Li, H.; Xia, Z.; Chen, S.; Koya, K.; Ono, M.; Sun, L.
Org. Process Res. Dev. 2007, 11, 246. (g) Braden, T. M.; Coffey, D. S.; Doecke, C. W.;
LeTourneau, M. E.; Martinelli, M. J.; Meyer, C. L.; Miller, R. D.; Pawlak, J. M.; Pedersen, S.
W.; Schmid, C. R.; Shaw, B. W.; Staszak, M. A.; Vicenzi, J. T. Org. Process Res. Dev. 2007, 11,
431. (h) Beylin, V.; Boyles, D. C.; Curran, T. T.; Macikenas, D.; Parlett, R. V.; Vrieze, D. Org.
Process Res. Dev. 2007, 11, 441. (i) Chen, C.-y.; Frey, L. F.; Shultz, S.; Wallace, D. J.;
Marcantonio, K.; Payack, J. F.; Vazquez, E.; Springfield, S. A.; Zhou, G.; Liu, P.; Kieczykowski,
G. R.; Chen, A. M.; Phenix, B. D.; Singh, U.; Strine, J.; Izzo, B.; Krska, S. W. Org. Process Res.
Dev. 2007, 11, 616. (j) Miyazaki, H.; Ohmizu, H.; Ogiku, T. Org. Process Res. Dev. 2009, 13,
760. (k) O’Shea, P. D.; Gauvreau, D.; Gosselin, F.; Hughes, G.; Nadeau, C.; Roy, A.; Shultz, C.
S. J. Org. Chem. 2009, 74, 4547. (l) Sawai, Y.; Yamane, T.; Ikeuchi, M.; Kawaguchi, S.;
Yamada, M.; Yamano, M. Org. Process Res. Dev. 2010, 14, 1110. (m) Huang, X.; O’Brien, E.;
Thai, F.; Cooper, G. Org. Process Res. Dev. 2010, 14, 592. (n) Humphrey, G. R.; Pye, P. J.;
Zhong, Y.-L.; Angelaud, R.; Askin, D.; Belyk, K. M.; Maligres, P. E.; Mancheno, D. E.; Miller,
R. A.; Reamer, R. A.; Weissman, S. A. Org. Process Res. Dev. 2010, 14, 73. (o) Gauvreau, D.;
Dolman, S. J.; Hughes, G.; O’Shea, P. D.; Davies, I. W. J. Org. Chem. 2010, 75, 4078. (p)
Baxter, C. A.; Cleator, E.; Brands, K. M. J.; Edwards, J. S.; Reamer, R. A.; Sheen, F. J.; Stewart,
G. W.; Strotman, N. A.; Wallace, D. J. Org. Process Res. Dev. 2011, 15, 367. (q) Magnus, N. A.;
Braden, T. M.; Buser, J. Y.; DeBaillie, A. C.; Heath, P. C.; Ley, C. P.; Remacle, J. R.; Varie, D.
L.; Wilson, T. M. Org. Process Res. Dev. 2012, 16, 830. (r) Wang, X.-j.; Zhang, L.; Sun, X.;
Lee, H.; Krishnamurthy, D.; O’Meara, J. A.; Landry, S.; Yoakim, C.; Simoneau, B.; Yee, N. K.;
109
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50
51
52
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57
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60
Page 110 of 138
Senanayake, C. H. Org. Process Res. Dev. 2012, 16, 561. (s) Patil, G. D.; Kshirsagar, S. W.;
Shinde, S. B.; Patil, P. S.; Deshpande, M. S.; Chaudhari, A. T.; Sonawane, S. P.; Maikap, G. C.;
Gurjar, M. K. Org. Process Res. Dev. 2012, 16, 1422. (t) Ronn, M.; Zhu, Z.; Hogan, P. C.;
Zhang, W.-Y.; Niu, J.; Katz, C. E.; Dunwoody, N.; Gilicky, O.; Deng, Y.; Hunt, D. K.; He, M.;
Chen, C.-L.; Sun, C.; Clark, R. B.; Xiao, Z.-Y. Org. Process Res. Dev. 2013, 17, 838. (u)
Karlsson, S.; Brånalt, J.; Halvarsson, M. Ö. Bergman, J. Org. Process Res. Dev. 2014, 18, 969.
(v) Eisenbeis, S. A.; Chen, R.; Kang, M.; Barrila, M.; Buzon, R. Org. Process Res. Dev. 2015,
19, 244.
18
Phosphorus oxychloride: Tone, H.; Matoba, K.; Goto, F.; Torisawa, Y.; Nishi, T.;
Minamikawa, J.-i. Org. Process Res. Dev. 2000, 4, 312.
19
Commercially available acid chlorides: (a) Fang, F. G.; Bankston, D. D.; Huie, E. M.;
Johnson, M. R.; Kang, M.-C.; LeHoullier, C. S.; Lewis, G. C.; Lovelace, T. C.; Lowery, M. W.;
McDougald, D. L.; Meerholz, C. A.; Partridge, J. J.; Sharp, M. J.; Xie, S. Tetrahedron 1997, 53,
10953. (b) Zanka, A.; Nishiwaki, M.; Morinaga, Y.; Inoue, T. Org. Process Res. Dev. 1998, 2,
230. (c) Konoike, T.; Oda, K.; Uenaka, M.; Takahashi, K. Org. Process Res. Dev. 1999, 3, 347.
(d) Ennis, D. S.; McManus, J.; Wood-Kaczmar, W.; Richardson, J.; Smith, G. E.; Carstairs, A.
Org. Process Res. Dev. 1999, 3, 248. (e) Fleitz, F. J.; Lyle, T. A.; Zheng, N.; Armstrong, J. D.;
Volante, R. P. Synth. Commun. 2000, 30, 3171. (f) Caron, S.; Massett, S. S.; Bogle, D. E.;
Castaldi, M. J.; Braish, T. F. Org. Process Res. Dev. 2001, 5, 254. (g) Urban, F. J.; Anderson, B.
G.; Orrill, S. L.; Daniels, P. J. Org. Process Res. Dev. 2001, 5, 575. (h) Zhao, M. M.;
McNamara, J. M.; Ho, G.-J.; Emerson, K. M.; Song, Z. J.; Tschaen, D. M.; Brands, K. M. J.;
Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J.; Cottrell, I. F.; Ashwood, M. S.; Bishop, B. C. J.
110
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60
Organic Process Research & Development
Org. Chem. 2002, 67, 6743. (i) Magnus, N. A.; Confalone, P. N.; Storace, L.; Patel, M.; Wood,
C. C.; Davis, W. P.; Parsons, R. L. J. Org. Chem. 2002, 67, 754. (j) Reichard, G. A.; Spitler, J.;
Mergelsberg, I.; Miller, A.; Wong, G.; Raghavan, R.; Jenkins, J.; Gan, T.; McPhail, A. T.
Tetrahedron: Asymmetry 2002, 13, 939. (k) Kumar, Y.; Tewari, N.; Nizar, H.; Rai, B. P.; Singh,
S. K. Org. Process Res. Dev. 2003, 7, 933. (l) Hasegawa, T.; Kawanaka, Y.; Kasamatsu, E.;
Iguchi, Y.; Yonekawa, Y.; Okamoto, M.; Ohta, C.; Hashimoto, S.; Ohuchida, S. Org. Process
Res. Dev. 2003, 7, 168. (m) Gauthier, D. R.; Ikemoto, N.; Fleitz, F. J.; Szumigala, R. H.; Petrillo,
D.; Liu, J.; Reamer, R. A.; Armstrong, J. D.; Yehl, P. M.; Wu, N.; Volante, R. P. Tetrahedron:
Asymmetry 2003, 14, 3557. (n) Ashwood, M. S.; Alabaster, R. J.; Cottrell, I. F.; Cowden, C. J.;
Davies, A. J.; Dolling, U. H.; Emerson, K. M.; Gibb, A. D.; Hands, D.; Wallace, D. J.; Wilson,
R. D. Org. Process Res. Dev. 2004, 8, 192. (o) Bio, M. M.; Xu, F.; Waters, M.; Williams, J. M.;
Savary, K. A.; Cowden, C. J.; Yang, C.; Buck, E.; Song, Z. J.; Tschaen, D. M.; Volante, R. P.;
Reamer, R. A.; Grabowski, E. J. J. J. Org. Chem. 2004, 69, 6257. (p) Mani, N. S.; Jablonowski,
J. A.; Jones, T. K. J. Org. Chem. 2004, 69, 8115. (q) Ripin, D. H. B.; Bourassa, D. E.; Brandt, T.;
Castaldi, M. J.; Frost, H. N.; Hawkins, J.; Johnson, P. J.; Massett, S. S.; Neumann, K.; Phillips,
J.; Raggon, J. W.; Rose, P. R.; Rutherford, J. L.; Sitter, B.; Stewart, A. M.; Vetelino, M. G.; Wei,
L. Org. Process Res. Dev. 2005, 9, 440. (r) Peters, R.; Waldmeier, P.; Joncour, A. Org. Process
Res. Dev. 2005, 9, 508. (s) Bentley, D.; Godfrey, A. A.; Warren, K. E. H. Org. Process Res. Dev.
2006, 10, 553. (t) Henegar, K. E.; Ball, C. T.; Horvath, C. M.; Maisto, K. D.; Mancini, S. E. Org.
Process Res. Dev. 2007, 11, 346. (u) Henegar, K. E.; Cebula, M. Org. Process Res. Dev. 2007,
11, 354. (v) Belecki, K.; Berliner, M.; Bibart, R. T.; Meltz, C.; Ng, K.; Phillips, J.; Ripin, D. H.
B.; Vetelino, M. Org. Process Res. Dev. 2007, 11, 754. (w) Beutler, U.; Boehm, M.;
Fuenfschilling, P. C.; Heinz, T.; Mutz, J.-P.; Onken, U.; Mueller, M.; Zaugg, W. Org. Process
111
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Page 112 of 138
Res. Dev. 2007, 11, 892. (x) Guillaume, M.; Cuypers, J.; Dingenen, J. Org. Process Res. Dev.
2007, 11, 1079. (y) Reuman, M.; Hu, Z.; Kuo, G.-H.; Li, X.; Russell, R. K.; Shen, L.; Youells,
S.; Zhang, Y. Org. Process Res. Dev. 2007, 11, 1010. (z) Shu, L.; Wang, P. Org. Process Res.
Dev. 2008, 12, 298. (aa) Bowles, D. M.; Bolton, G. L.; Boyles, D. C.; Curran, T. T.; Hutchings,
R. H.; Larsen, S. D.; Miller, J. M.; Park, W. K. C.; Ritsema, K. G.; Schineman, D. C.; Tamm, M.
Org. Process Res. Dev. 2008, 12, 1183. (ab) Limanto, J.; Dorner, B. T.; Hartner, F. W.; Tan, L.
Org. Process Res. Dev. 2008, 12, 1269. (ac) Magnus, N. A.; Astleford, B. A.; Brennan, J.; Stout,
J. R.; Tharp-Taylor, R. W. Org. Process Res. Dev. 2008, 12, 280. (ad) Choy, A.; Colbry, N.;
Huber, C.; Pamment, M.; Duine, J. V. Org. Process Res. Dev. 2008, 12, 884. (ae) Achmatowicz,
M.; Thiel, O. R.; Wheeler, P.; Bernard, C.; Huang, J.; Larsen, R. D.; Faul, M. M. J. Org. Chem.
2008, 73, 795. (af) Hansen, M. M.; Borders, S. S. K.; Clayton, M. T.; Heath, P. C.; Kolis, S. P.;
Larsen, S. D.; Linder, R. J.; Reutzel-Edens, S. M.; Smith, J. C.; Tameze, S. L.; Ward, J. A.;
Weigel, L. O. Org. Process Res. Dev. 2009, 13, 198. (ag) Yu, K.; Sun, N.; Fang, S.; Mo, W.; Hu,
B.; Shen, Z.; Hu, X. Org. Process Res. Dev. 2009, 13, 815. (ah) McDermott, T. S.; Bhagavatula,
L.; Borchardt, T. B.; Engstrom, K. M.; Gandarilla, J.; Kotecki, B. J.; Kruger, A. W.; Rozema, M.
J.; Sheikh, A. Y.; Wagaw, S. H.; Wittenberger, S. J. Org. Process Res. Dev. 2009, 13, 1145. (ai)
N, S. K.; Reddy, S. B.; Sinha, B. K.; Mukkanti, K.; Dandala, R. Org. Process Res. Dev. 2009,
13, 1185. (aj) Rassias, G.; Stevenson, N. G.; Curtis, N. R.; Northall, J. M.; Gray, M.; Prodger, J.
C.; Walker, A. J. Org. Process Res. Dev. 2009, 13, 92. (ak) Miao, L.; Xu, L.; Narducy, K. W.;
Trudell, M. L. Org. Process Res. Dev. 2009, 13, 820. (al) Gosselin, F.; Lau, S.; Nadeau, C.;
Trinh, T.; O’Shea, P. D.; Davies, I. W. J. Org. Chem. 2009, 74, 7790. (am) Chavez, F.; Kennedy,
N.; Rawalpally, T.; Williamson, R. T.; Cleary, T. Org. Process Res. Dev. 2010, 14, 579. (an)
Faigl, F.; Thurner, A.; Molnár, B.; Simig, G.; Volk, B. Org. Process Res. Dev. 2010, 14, 617.
112
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(ao) Jin, Q.; Welch, M.; Fisher, L. Org. Process Res. Dev. 2010, 14, 470. (ap) Pippel, D. J.;
Mills, J. E.; Pandit, C. R.; Young, L. K.; Zhong, H. M.; Villani, F. J.; Mani, N. S. Org. Process
Res. Dev. 2011, 15, 638. (aq) Chen, J.; Przyuski, K.; Roemmele, R.; Bakale, R. P. Org. Process
Res. Dev. 2011, 15, 1063. (ar) Aalla, S.; Gilla, G.; Bojja, Y.; Anumula, R. R.; Vummenthala, P.
R.; Padi, P. R. Org. Process Res. Dev. 2012, 16, 682. (as) Ball, M.; Boyd, A.; Churchill, G.;
Cuthbert, M.; Drew, M.; Fielding, M.; Ford, G.; Frodsham, L.; Golden, M.; Leslie, K.; Lyons, S.;
McKeever-Abbas, B.; Stark, A.; Tomlin, P.; Gottschling, S.; Hajar, A.; Jiang, J.-l.; Lo, J.;
Suchozak, B. Org. Process Res. Dev. 2012, 16, 741. (at) Aalla, S.; Gilla, G.; Anumula, R. R.;
Kurella, S.; Padi, P. R.; Vummenthala, P. R. Org. Process Res. Dev. 2012, 16, 748. (au)
DeBaillie, A. C.; Jones, C. D.; Laurila, M. E.; Magnus, N. A.; Staszak, M. A. Org. Process Res.
Dev. 2013, 17, 231. (av) Henegar, K. E.; Lira, R.; Kim, H.; Gonzalez-Hernandez, J. Org. Process
Res. Dev. 2013, 17, 985. (aw) Chen, Y.; Crockett, R. D.; Wang, X.; Larsen, R. D.; Cui, S.; Faul,
M. M. Synlett 2013, 301. (ax) Sammons, M.; Jennings, S. M.; Herr, M.; Hulford, C. A.; Wei, L.;
Hallissey, J. F.; Kiser, E. J.; Wright, S. W.; Piotrowski, D. W. Org. Process Res. Dev. 2013, 17,
934. (ay) Ishimoto, K.; Fukuda, N.; Nagata, T.; Sawai, Y.; Ikemoto, T. Org. Process Res. Dev.
2014, 18, 122. (az) Hong, J.-B.; Davidson, J. P.; Jin, Q.; Lee, G. R.; Matchett, M.; O’Brien, E.;
Welch, M.; Bingenheimer, B.; Sarma, K. Org. Process Res. Dev. 2014, 18, 228. (ba) Yoshida,
S.; Marumo, K.; Takeguchi, K.; Takahashi, T.; Mase, T. Org. Process Res. Dev. 2014, 18, 1721.
20
Commercially available acid bromides: (a) Kim, B. C.; Kim, K.-Y.; Lee, H. B.; Shin, H.
Org. Process Res. Dev. 2008, 12, 626. (b) Straessler, N. A.; Lesley, M. W.; Cannizzo, L. F. Org.
Process Res. Dev. 2012, 16, 512.
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Ac2O for amine acetylation: (a) Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.;
Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L.
M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545. (b) Prabhakar, C.; Kumar, N. V.; Reddy,
M. R.; Sarma, M. R.; Reddy, G. O. Org. Process Res. Dev. 1999, 3, 155. (c) Kowalczyk, B. A.;
Robinson, J.; Gardner, J. O. Org. Process Res. Dev. 2001, 5, 116. (d) Karpf, M.; Trussardi, R. J.
Org. Chem. 2001, 66, 2044. (e) Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; Jeganathan, A.;
Yamagata, K.; Chen, J. J.; Lu, C. V.; Herrinton, P. M.; Gadwood, R. C.; Chan, L.; Lyster, M. A.;
Maloney, M. T.; Moeslein, J. A.; Greene, M. L.; Barbachyn, M. R. Org. Process Res. Dev. 2003,
7, 533. (f) Harrington, P. J.; Brown, J. D.; Foderaro, T.; Hughes, R. C. Org. Process Res. Dev.
2004, 8, 86. (g) Angibaud, P. R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny, Y. A.; Muller,
P.; Poncelet, V. S.; End, D. W. Eur. J. Org. Chem. 2004, 479. (h) Giles, M. E.; Thomson, C.;
Eyley, S. C.; Cole, A. J.; Goodwin, C. J.; Hurved, P. A.; Morlin, A. J. G.; Tornos, J.; Atkinson,
S.; Just, C.; Dean, J. C.; Singleton, J. T.; Longton, A. J.; Woodland, I.; Teasdale, A.; Gregertsen,
B.; Else, H.; Athwal, M. S.; Tatterton, S.; Knott, J. M.; Thompson, N.; Smith, S. J. Org. Process
Res. Dev. 2004, 8, 628. (i) Li, X.; Branum, S.; Russell, R. K.; Jiang, W.; Sui, Z. Org. Process
Res. Dev. 2005, 9, 640. (j) Liu, J.; Cameron, M.; Hoerrner, S.; Williams, J. M.; McNamara, J.
Org. Process Res. Dev. 2007, 11, 739. (k) Humphrey, C. E.; Furegati, M.; Laumen, K.; La
Vecchia, L.; Leutert, T.; Müller-Hartwieg, J. C. D.; Vögtle, M. Org. Process Res. Dev. 2007, 11,
1069. (l) Wang, Y.; Papamichelakis, M.; Chew, W.; Sellstedt, J.; Noureldin, R.; Tadayon, S.;
Daigneault, S.; Galante, R. J.; Sun, J. Org. Process Res. Dev. 2008, 12, 1253. (m) Maligres, P.
E.; Humphrey, G. R.; Marcoux, J.-F.; Hillier, M. C.; Zhao, D.; Krska, S.; Grabowski, E. J. J.
Org. Process Res. Dev. 2009, 13, 525. (n) Singh, H.; Gupta, N.; Kumar, P.; Dubey, S. K.;
Sharma, P. K. Org. Process Res. Dev. 2009, 13, 870. (o) Ainge, D.; Booker, J. E. M.; Pedge, N.;
114
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Sinclair, R.; Sleigh, C.; Stefinović, M.; Vaz, L.-M.; Way, E. Org. Process Res. Dev. 2010, 14,
72. (p) Fray, J. M.; Gillmore, A. T.; Glossop, M. S.; McManus, D. J.; Moses, I. B.; Praquin, C. F.
B.; Reeves, K. A.; Thompson, L. R. Org. Process Res. Dev. 2010, 14, 263. (q) Mao, Y.; Liu, Z.;
Yang, X.; Xia, X.; Zhang, R.; Li, J.; Jiang, X.; Xie, K.; Zheng, J.; Zhang, H.; Suo, J.; Shen, J.
Org. Process Res. Dev. 2012, 16, 1970. (r) Guz, N. R.; Leuser, H.; Goldman, E. Org. Process
Res. Dev. 2013, 17, 1066. (s) Li, Z.; Fang, L.; Wang, J.; Dong, L.; Guo, Y.; Xie, Y. Org. Process
Res. Dev. 2015, 19, 444.
22
Pivaloyl chloride: (a) Martinelli, M. J. J. Org. Chem. 1990, 55, 5065. (b) Beaulieu, P. L.;
Gillard, J.; Bailey, M.; Beaulieu, C.; Duceppe, J.-S.; Lavallée, P.; Wernic, D. J. Org. Chem.
1999, 64, 6622. (c) Prashad, M.; Har, D.; Chen, L.; Kim, H.-Y.; Repič, O.; Blacklock, T. J. J.
Org. Chem. 2002, 67, 6612. (d) Storace, L.; Anzalone, L.; Confalone, P. N.; Davis, W. P.;
Fortunak, J. M.; Giangiordano, M.; Haley, J. J., Jr.; Kamholz, K.; Li, H.-Y.; Ma, P.; Nugent, W.
A.; Parsons, R. L., Jr., Sheeran, P. J.; Silverman, C. E.; Waltermire, R. E.; Wood, C. C. Org.
Process Res. Dev. 2002, 6, 54. (e) Shieh, W.-C.; Chen, G.-P.; Xue, S.; McKenna, J.; Jiang, X.;
Prasad, K.; Repič, O.; Straub, C.; Sharma, S. K. Org. Process Res. Dev. 2007, 11, 711. (f) Liu,
Y.; Prashad, M.; Ciszewski, L.; Vargas, K.; Repič, O.; Blacklock, T. J. Org. Process Res. Dev.
2008, 12, 183. (g) Wang, Z.; Resnick, L. Tetrahedron 2008, 64, 6440. (h) Sasikala, C. H. V. A.;
Padi, P. R.; Sunkara, V.; Ramayya, P.; Dubey, P. K.; Uppala, V. B. R.; Praveen, C. Org. Process
Res. Dev. 2009, 13, 907. (i) Alimardanov, A.; Nikitenko, A.; Connolly, T. J.; Feigelson, G.;
Chan, A. W.; Ding, Z.; Ghosh, M.; Shi, X.; Ren, J.; Hansen, E.; Farr, R.; MacEwan, M.;
Tadayon, S.; Springer, D. M.; Kreft, A. F.; Ho, D. M.; Potoski, J. R. Org. Process Res. Dev.
2009, 13, 1161. (j) Xu, F.; Zacuto, M.; Yoshikawa, N.; Desmond, R.; Hoerrner, S.; Itoh, T.;
Journet, M.; Humphrey, G. R.; Cowden, C.; Strotman, N.; Devine, P. J. Org. Chem. 2010, 75,
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7829. (k) Tortoioli, S.; Marchal, D.; Kesselgruber, M.; Pabst, T.; Skranc, W.; Abele, S. Org.
Process Res. Dev. 2014, 18, 1759.
23
Ethyl chloroformate: (a) Hirokawa,Y.; Horikawa, T.; Noguchi, H.; Yamamoto, K.; Kato, S.
Org. Process Res. Dev. 2002, 6, 28. (b) Davulcu, A. H.; McLeod, D. D.; Li, J.; Katipally, K.;
Littke, A.; Doubleday, W.; Xu, Z.; McConlogue, C. W.; Lai, C. J.; Gleeson, M.; Schwinden, M.;
Parsons, R. L., Jr. J. Org. Chem. 2009, 74, 4068. (c) Berkessel, A.; Harnying, W.; Duangdee, N.;
Neudörfl, J.-M.; Gröger, H. Org. Process Res. Dev. 2012, 16, 123. (d) Rai, B. P.; Tewari, N.;
Nizar, H.; Prasad, M.; Joseph, S. Org. Process Res. Dev. 2014, 18, 662.
24
Isobutyl chloroformate: (a) Prashad, M.; Prasad, K.; Repič, O.; Blacklock. T. J.;
Prikoszovich, W. Org. Process Res. Dev. 1999, 3, 409. (b) Andersen, P.; Ankersen, M.; Jessen,
C. U.; Lehman, S. V. Org. Process Res. Dev. 2002, 6, 367. (c) Franzén, H. M.; Bessidskaia, G.;
Abedi, V.; Nilsson, A.; Nilsson, M.; Olsson, L. Org. Process Res. Dev. 2002, 6, 788. (d) Lee, K.
W.; Hwang, S. Y.; Kim, C. R.; Nam, D. H.; Chang, J. H.; Choi, S. C.; Choi, B. S.; Choi, H.-w.;
Lee, K. K.; So, B.; Cho, S. W.; Shin, H. Org. Process Res. Dev. 2003, 7, 839. (e) Yee, N. K.;
Nummy, L. J.; Frutos, R. P.; Song, J. J.; Napolitano, E.; Byrne, D. P.; Jones, P.-J.; Farina, V.
Tetrahedron: Asymmetry 2003, 14, 3495. (f) Prashad, M.; Har, D.; Hu, B.; Kim, H.-Y.; Girgis,
M. J.; Chaudhary, A.; Repič, O.; Blacklock, T. J.; Marterer, W. Org. Process Res. Dev. 2004, 8,
330. (g) Chen, J.; Corbin, S. P.; Holman, N. J. Org. Process Res. Dev. 2005, 9, 185. (h) Fan, X.;
Song, Y.-L.; Long, Y.-Q. Org. Process Res. Dev. 2008, 12, 69. (i) Berwe, M.; Jöntgen, W.;
Krüger, J.; Cancho-Grande, Y.; Lampe, T.; Michels, M.; Paulsen, H.; Raddatz, S.; Weigand, S.
Org. Process Res. Dev. 2011, 15, 1348. (j) Busacca, C. A.; Wei, X.; Haddad, N.; Kapadia, S.;
Lorenz, J. C.; Saha, A. K.; Varsolona, R. J.; Berkenbusch, T.; Campbell, S. C.; Farina, V.; Feng,
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X.; Gonnella, N. C.; Grinberg, N.; Jones, P.-J.; Lee, H.; Li, Z.; Neimeier, O.; Samstag, W.;
Sarvestani, M.; Schroeder, J.; Smoliga, J.; Spinelli, E. M.; Vitous, J.; Senanayake, C. H. Asian J.
Org. Chem. 2012, 1, 80.
25
Mechanism of amide couplings via isobutyl chloroformate: (a) Chaudhary, A.; Girgis, M. J.;
Prashad, M.; Hu, B.; Har, D.; Repič, O.; Blacklock, T. J. Org. Process Res. Dev. 2003, 7, 888.
(b) Chaudhary, A.; Girgis, M. J.; Prashad, M.; Hu, B.; Har, D.; Repič, O.; Blacklock, T. J.
Tetrahedron Lett. 2003, 44, 5543.
26
Boc anhydride: Patterson, D. E.; Powers, J. D.; LeBlanc, M.; Sharkey, T.; Boehler, E.; Irdam,
E.; Osterhout, M. H. Org. Process Res. Dev. 2009, 13, 900.
27
Belleau, B.; Malek, G. J. Am. Chem. Soc. 1968, 90, 1651.
28
EEDQ: Ormerod, D.; Willemsens, B.; Mermans, R.; Langens, J.; Winderickx, G.; Kalindjian,
S. B.; Buck, I. M.; McDonald, I. M. Org. Process Res. Dev. 2005, 9, 499.
29
Methanesulfonyl chloride: (a) Kobayashi, T.; Masui, Y.; Goto, Y.; Kitaura, Y.; Mizutani, T.;
Matsumura, I.; Sugata, Y.; Ide, Y.; Takayama, M.; Takahashi, H.; Okuyama, A. Org. Process
Res. Dev. 2004, 8, 744. (b) Norris, T.; VanAlsten, J.; Hubbs, S.; Ewing, M.; Cai, W.; Jorgensen,
M. L.; Bordner, J.; Jensen, G. O. Org. Process Res. Dev. 2008, 12, 447.
30
Vaillancourt, V., Cudahy, M. M., Kreilein, M. M. and Jacobs, D. L. 2007. Methanesulfonyl
Chloride. e-EROS Encyclopedia of Reagents for Organic Synthesis.
31
p-Toluenesulfonyl chloride: (a) Campeau, L.-C.; Dolman, S. J.; Gauvreau, D.; Corley, E.;
Liu, J.; Guidry, E. N.; Ouellet, S. G.; Steinhuebel, D.; Weisel, M.; O’Shea, P. D. Org. Process
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Res. Dev. 2011, 15, 1138. (b) Haddad, N.; Qu, B.; Lee, H.; Lorenz, J.; Varsolona, R.; Kapadia,
S.; Sarvestani, M.; Feng, X.; Busacca, C. A.; Hebrault, D.; Rea, S.; Schellekens, L.; Senanayake,
C. H. Org. Process Res. Dev. 2015, 19, 132.
32
(a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203. (b) Shioiri, T.;
Yamada, S.-I. Chem. Pharm. Bull. 1974, 22, 849.
33
(a) Wissmann, H.; Kleiner, H.-J. Angew. Chem., Int. Ed. 1980, 19, 133. (b) Wissmann, H.
Phosphorus and Sulfur 1987, 30, 645.
34
For a review of T3P chemistry: (a) Basavaprabhu; Vishwanatha, T. M.; Panguluri, N. R.;
Sureshbabu, V. V. Synthesis 2013, 1569. See also: (b) Schwarz, M. Synlett 2000, 1369. (c)
García, A. L. L. Synlett 2007, 1328.
35
T3P: (a) Kammermeier, B.; Beck, G.; Holla, W.; Jacobi, D.; Napierski, B.; Jendralla, H.
Chem. Eur. J. 1996, 2, 307. (b) Dunn, P. J.; Hughes, M. L.; Searle, P. M.; Wood, A. S. Org.
Process Res. Dev. 2003, 7, 244. (c) Paul, B. J.; Littler, B. J.; Jos, F.; Vogt, P. F. Org. Process
Res. Dev. 2006, 10, 339. (d) Boggs, S. D.; Cobb, J. D.; Gudmundsson, K. S.; Jones, L. A.;
Matsuoka, R. T.; Millar, A.; Patterson, D. E.; Samano, V.; Trone, M. D.; Xie, S.; Zhou, X.-m.
Org. Process Res. Dev. 2007, 11, 539. (e) Kopach, M. E.; Singh, U. K.; Kobierski, M. E.;
Trankle, W. G.; Murray, M. M.; Pietz, M. A.; Forst, M. B.; Stephenson, G. A.; Mancuso, V.;
Giard, T.; Vanmarsenille, M.; DeFrance, T. Org. Process Res. Dev. 2009, 13, 209. (f) Butcher,
K. J.; Denton, S. M.; Field, S. E.; Gillmore, A. T.; Harbottle, G. W.; Howard, R. M.; Laity, D.
A.; Ngono, C. J.; Pibworth, B. A. Org. Process Res. Dev. 2011, 15, 1192. (g) Dunetz, J. R.;
Xiang, Y.; Baldwin, A.; Ringling, J. Org. Lett. 2011, 13, 5048. (h) Dunetz, J. R.; Berliner, M. A.;
Xiang, Y.; Houck, T. L.; Salingue, F. H.; Chao, W.; Yuandong, C.; Shenghua, W.; Huang, Y.;
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Farrand, D.; Boucher, S. J.; Damon, D. B.; Makowski, T. W.; Barrila, M. T.; Chen, R.; Martínez,
I. Org. Process Res. Dev. 2012, 16, 1635. (i) Girardin, M.; Ouellet, S. G.; Gauvreau, D.; Moore,
J. C.; Hughes, G.; Devine, P. N.; O’Shea, P. D.; Campeau, L.-C. Org. Process Res. Dev. 2013,
17, 61. (j) Shavnya, A.; Tao, Y.; Lilley, S. C.; Bahnck, K. B.; Munchhof, M. J.; Nematalla, A.;
Waldo, M.; Bill, D. R. Org. Process Res. Dev. 2013, 17, 1510. (k) Lin, J.; Houpis, I. N.; Liu, R.;
Wang, Y.; Zhang, J. Org. Process Res. Dev. 2014, 18, 205. (l) Boiteau, J.-G.; Rodeville, N.;
Martin, C.; Tabet, S.; Moureou, C.; Muller, F.; Jetha, J.-C.; Cardinaud, I. Org. Process Res. Dev.
2015, 19, 646. (m) Kopach, M. E.; Heath, P. C.; Scherer, R. B.; Pietz, M. A.; Astleford, B. A.;
McCauley, M. K.; Singh, U. K.; Wong, S. W.; Coppert, D. M.; Kerr, M. S.; Houghton, P. G.
Org. Process Res. Dev. 2015, 19, 543.
36
Ethylmethylphosphinic anhydride: Jendralla, H.; Seuring, B.; Herchen, J.; Kulitzscher, B.;
Wunner, J.; Stüber, W.; Koschinsky, R. Tetrahedron 1995, 51, 12047. [Note: This reference
reports the use of “methyl-ethyl-phosphonic anhydride” for their amide coupling; however, this
is not a known reagent for acid activation. SciFinder has since corrected this reagent to
ethylmethylphosphinic anhydride, a known coupling reagent, and we have done the same for this
review.]
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CDI: (a) Pierce, M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.; Storace, L.; Waltermire, R.
E.; Wat, E.; Jadhav, P. K.; Emmett, G. C. J. Org. Chem. 1996, 61, 444. (b) Perrault, W. R.;
Shephard, K. P.; LaPean, L. A.; Krook, M. A.; Dobrowolski, P. J.; Lyster, M. A.; McMillan, M.
W.; Knoechel, D. J.; Evenson, G. N.; Watt, W.; Pearlman, B. A. Org. Process Res. Dev. 1997, 1,
106. (c) Dale, D. J.; Dunn, P. J.; Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.;
Searle, P. M.; Ward, G.; Wood, A. S. Org. Process Res. Dev. 2000, 4, 17. (d) Coutts, L. D.;
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Geiss, W. B.; Gregg, B. T.; Helle, M. A.; King, C.-H. R.; Itov, Z.; Mateo, M. E.; Meckler, H.;
Zettler, M. W.; Knutson, J. C. Org. Process Res. Dev. 2002, 6, 246. (e) Dale, D. J.; Draper, J.;
Dunn, P. J.; Hughes, M. L.; Hussain, F.; Levett, P. C.; Ward, G. B.; Wood, A. S. Org. Process
Res. Dev. 2002, 6, 767. (f) Stuk, T. L.; Assink, B. K.; Bates, R. C., Jr.; Erdman, D. T.; Fedij, V.;
Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Org. Process Res. Dev. 2003, 7, 851. (g)
Beaudin, J.; Bourassa, D. E.; Bowles, P.; Castaldi, M. J.; Clay, R.; Couturier, M. A.; Karrick, G.;
Makowski, T. W.; McDermott, R. E.; Meltz, C. N.; Meltz, M.; Phillips, J. E.; Ragan, J. A.;
Ripin, D. H. B.; Singer, R. A.; Tucker, J. L.; Wei, L. Org. Process Res. Dev. 2003, 7, 873. (h)
Chen, C.-y.; Dagneau, P.; Grabowski, E. J. J.; Oballa, R.; O’Shea, P.; Prasit, P.; Robichaud, J.;
Tillyer, R.; Wang, X. J. Org. Chem. 2003, 68, 2633. (i) Bänziger, M.; Cercus, J.; Hirt, H.;
Laumen, K.; Malan, C.; Spindler, F.; Struber, F.; Troxler, T. Tetrahedron: Asymmetry 2003, 14,
3469. (j) Liu, H.; Kerdesky, F. A.; Black, L. A.; Fitzgerald, M.; Henry, R.; Esbenshade, T. A.;
Hancock, A. A.; Bennani, Y. L. J. Org. Chem. 2004, 69, 192. (k) Magnus, N. A.; Aikins, J. A.;
Cronin, J. S.; Diseroad, W. D.; Hargis, A. D.; LeTourneau, M. E.; Parker, B. E.; Reutzel-Edens,
S. M.; Schafer, J. P.; Staszak, M. A.; Stephenson, G. A.; Tameze, S. L.; Zollars, L. M. H. Org.
Process Res. Dev. 2005, 9, 621. (l) Ashcroft, C. P.; Challenger, S.; Clifford, D.; Derrick, A. M.;
Hajikarimian, Y.; Slucock, K.; Silk, T. V.; Thomson, N. M.; Williams, J. R. Org. Process Res.
Dev. 2005, 9, 663. (m) Albaneze-Walker, J.; Murry, J. A.; Soheili, A.; Ceglia, S.; Springfield, S.
A.; Bazaral, C.; Dormer, P. G.; Hughes, D. L. Tetrahedron 2005, 61, 6330. (n) Scott, R. W.;
Neville, S. N.; Urbina, A.; Camp, D.; Stankovic, N. Org. Process Res. Dev. 2006, 10, 296. (o)
Challenger, S.; Dessi, Y.; Fox, D. E.; Hesmondhalgh, L. C.; Pascal, P.; Pettman, A. J.; Smith, J.
D. Org. Process Res. Dev. 2008, 12, 575. (p) Kuethe, J. T.; Childers, K. G.; Humphrey, G. R.;
Journet, M.; Peng, Z. Org. Process Res. Dev. 2008, 12, 1201. (q) Weisenburger, G. A.;
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Anderson, D. K.; Clark, J. D.; Edney, A. D.; Karbin, P. S.; Gallagher, D. J.; Knable, C. M.; Pietz,
M. A. Org. Process Res. Dev. 2009, 13, 60. (r) Thiel, O. R.; Achmatowicz, M.; Bernard, C.;
Wheeler, P.; Savarin, C.; Correll, T. L.; Kasparian, A.; Allgeier, A.; Bartberger, M. D.; Tan, H.;
Larsen, R. D. Org. Process Res. Dev. 2009, 13, 230. (s) Kuethe, J. T.; Childers, K. G.; Peng, Z.;
Journet, M.; Humphrey, G. R.; Vickery, T.; Bachert, D.; Lam, T. T. Org. Process Res. Dev.
2009, 13, 576. (t) Bellingham, R.; Buswell, A. M.; Choudary, B. M.; Gordon, A. H.; Moore, S.
O.; Peterson, M.; Sasse, M.; Shamji, A.; Urquhart, M. W. J. Org. Process Res. Dev. 2010, 14,
1254. (u) Bradley, P. A.; Carroll, R. J.; Lecouturier, Y. C.; Moore, R.; Noeureuil, P.; Patel, B.;
Snow, J.; Wheeler, S. Org. Process Res. Dev. 2010, 14, 1326. (v) Deng, X.; Liang, J. T.;
Peterson, M.; Rynberg, R.; Cheung, E.; Mani, N. S. J. Org. Chem. 2010, 75, 1940. (w) Sieser, J.
E.; Singer, R. A.; McKinley, J. D.; Bourassa, D. E.; Teixeira, J. J.; Long, J. Org. Process Res.
Dev. 2011, 15, 1328. (x) Yoshida, S.; Kasai, M.; Kimura, T.; Akiba, T.; Takahashi, T.;
Sakamoto, S. Org. Process Res. Dev. 2012, 16, 654. (y) Li, W.; Gao, J. J.; Lorenz, J. C.; Xu, J.;
Johnson, J.; Ma, S.; Lee, H.; Grinberg, N.; Busacca, C. A.; Lu, B.; Senanayake, C. H. Org.
Process Res. Dev. 2012, 16, 836. (z) Hu, B.; Song, Q.; Xu, Y. Org. Process Res. Dev. 2012, 16,
1552. (aa) Alorati, A. D.; Gibb, A. D.; Mullens, P. R.; Stewart, G. W. Org. Process Res. Dev.
2012, 16, 1947. (ab) Content, S.; Dupont, T.; Fédou, N. M.; Smith, J. D.; Twiddle, S. J. R. Org.
Process Res. Dev. 2013, 17, 193. (ac) Neelakandan, K.; Manikandan, H.; Santosha, N.;
Prabhakaran, B. Org. Process Res. Dev. 2013, 17, 981. (ad) Betti, M.; Genesio, E.; Panico, A.;
Coccone, S. S.; Wiedenau, P. Org. Process Res. Dev. 2013, 17, 1042. (ae) Andersen, S. M.;
Aurell, C.-J.; Zetterberg, F.; Bollmark, M.; Ehrl, R.; Schuisky, P.; Witt, A. Org. Process Res.
Dev. 2013, 17, 1543. (af) Kallemeyn, J. M.; Ku, Y.-Y.; Mulhern, M. M.; Bishop, R.; Pal, A.;
Jacob, L. Org. Process Res. Dev. 2014, 18, 191. (ag) Chung, C. K.; Bulger, P. G.; Kosjek, B.;
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Page 122 of 138
Belyk, K. M.; Rivera, N.; Scott, M. E.; Humphrey, G. R.; Limanto, J.; Bachert, D. C.; Emerson,
K. M. Org. Process Res. Dev. 2014, 18, 215. (ah) Betti, M.; Genesio, E.; Marconi, G.; Coccone,
S. S.; Wiedenau, P. Org. Process Res. Dev. 2014, 18, 699.
38
Vaidyanathan, R.; Kalthod, V. G.; Ngo, D. P.; Manley, J. M.; Lapekas, S. P. J. Org. Chem.
2004, 69, 2565.
39
Engstrom, K. M.; Sheikh, A.; Ho, R.; Miller, R. W. Org. Process Res. Dev. 2014, 18, 488.
40
Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067.
41
(a) Williams, A.; Ibrahim, I. T. Chem. Rev. 1981, 81, 589. (b) Mikolajczyk, M.: Kielbasinski,
P. Tetrahedron 1981, 37, 233.
42
König, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
43
DCC: (a) Cvetovich, R. J.; Chartrain, M.; Hartner, F. W.; Roberge, C.; Amato, J. S.;
Grabowski, E. J. J. J. Org. Chem. 1996, 61, 6575. (b) D'Andrea, S. V.; Bonner, D.; Bronson, J.
J.; Clark, J.; Denbleyker, K.; Fung-Tomc, J.; Hoeft, S. E.; Hudyma, T. W.; Matiskella, J. D.;
Miller, R. F.; Misco, P. F.; Pucci, M.; Sterzycki, R.; Tsai, Y.; Ueda, Y.; Wichtowski, J. A.;
Singh, J.; Kissick, T. P.; North, J. T.; Pullockaran, A.; Humora, M.; Boyhan, B.; Vu, T.; Fritz,
A.; Heikes, J.; Fox, R.; Godfrey, J. D.; Perrone, R.; Kaplan, M.; Kronenthal, D.; Mueller, R. H.
Tetrahedron 2000, 56, 5687. (c) Hilpert, H. Tetrahedron 2001, 57, 7675. (d) Singh, J.; Denzel,
T. W.; Fox, R.; Kissick, T. P.; Herter, R.; Wurdinger, J.; Schierling, P.; Papaioannou, C. G.;
Moniot, J. L.; Mueller, R. H.; Cimarusti, C. M. Org. Process Res. Dev. 2002, 6, 863. (e) Cohen,
J. H.; Bos, M. E.; Cesco-Cancian, S.; Harris, B. D.; Hortenstine, J. T.; Justus, M.; Maryanoff, C.
A.; Mills, J.; Muller, S.; Roessler, A.; Scott, L.; Sorgi, K. L.; Villani, F. J.; Webster, R. R. H.;
122
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51
52
53
54
55
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59
60
Organic Process Research & Development
Weh, C. Org. Process Res. Dev. 2003, 7, 866. (f) Zheng, N.; Armstrong, J. D.; Eng, K. K.;
Keller, J.; Liu, T.; Purick, R.; Lynch, J.; Hartner, F. W.; Volante, R. P. Tetrahedron: Asymmetry
2003, 14, 3435. (g) Sjövall, S.; Hansen, L.; Granquist, B. Org. Process Res. Dev. 2004, 8, 802.
(h) Srinivas, K.; Srinivasan, N.; Krishna, M. R.; Reddy, C. R.; Arunagiri, M.; Lalitha, R.; Reddy,
K. S. R.; Reddy, B. S.; Reddy, G. M.; Reddy, P. P.; Kumar, M. K.; Reddy, M. S. Org. Process
Res. Dev. 2004, 8, 952. (i) Wennerberg, J.; Björk, A.; Fristedt, T.; Granquist, B.; Jansson, K.;
Τhuvesson, I. Org. Process Res. Dev. 2007, 11, 674. (j) Kotagiri, V. K.; Suthrapu, S.; Reddy, J.
M.; Rao, C. P.; Bollugoddu, V.; Bhattacharya, A.; Bandichhor, R. Org. Process Res. Dev. 2007,
11, 910. (k) Goverdhan, G.; Reddy, A. R.; Sampath, A.; Srinivas, K.; Himabindu, V.; Reddy, G.
M. Org. Process Res. Dev. 2008, 12, 67.
44
DIC: (a) Clark, J. D.; Anderson, D. K.; Banaszak, D. V.; Brown, D. B.; Czyzewski, A. M.;
Edeny, A. D.; Forouzi, P. S.; Gallagher, D. J.; Iskos, V. H.; Kleine, H. P.; Knable, C. M.; Lantz,
M. K.; Lapack, M. A.; Moore, C. M. V.; Muellner, F. W.; Murphy, J. B.; Orihuela, C. A.; Pietz,
M. A.; Rogers, T. E.; Ruminski, P. G.; Santhanam, H. K.; Schilke, T. C.; Shah, A. S.; Sheikh, A.
Y.; Weisenburger, G. A.; Wise, B. E. Org. Process Res. Dev. 2009, 13, 1088. (b) Affouard, C.;
Crockett, R. D.; Diker, K.; Farrell, R. P.; Gorins, G.; Huckins, J. R.; Caille, S. Org. Process Res.
Dev. 2015, 19, 476.
45
Goyal, N. Synlett 2010, 335.
46
EDC: (a) Chung, J. Y. L.; Hughes, D. L.; Zhao, D.; Song, Z.; Mathre, D. J.; Ho, G.-J.;
McNamara, J. M.; Douglas, A. W.; Reamer, R. A.; Tsay, F.-R.; Varsolona, R.; McCauley, J.;
Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1996, 61, 215. (b) Bold, G.; Fässler, A.; Capraro,
H.-G.; Cozens, R.; Klimkait, T.; Lazdins, J.; Mestan, J.; Poncioni, B.; Rösel, J.; Stover, D.;
123
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Page 124 of 138
Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.; Eschbach, M.; Hürlimann, T.; Masso,
E.; Roussel, S.; Ucci-Stoll, K.; Wyss, D.; Lang, M. J. Med. Chem. 1998, 41, 3387. (c) Mase, T.;
Houpis, I. N.; Akao, A.; Dorziotis, I.; Emerson, K.; Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.;
Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.; Molina, A.; Nemoto,
T.; Okada, S.; Reamer, R.; Song, J. Z.; Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.;
Reider, P. J.; Tomimoto, K. J. Org. Chem. 2001, 66, 6775. (d) Ito, T.; Ikemoto, T.; Isogami, Y.;
Wada, H.; Sera, M.; Mizuno, Y.; Wakimasu, M. Org. Process Res. Dev. 2002, 6, 238. (e) Xu, Z.;
Singh, J.; Schwinden, M. D.; Zheng, B.; Kissick, T. P.; Patel, B.; Humora, M. J.; Quiroz, F.;
Dong, L.; Hsieh, D.-M.; Heikes, J. E.; Pudipeddi, M.; Lindrud, M. D.; Srivastava, S. K.;
Kronenthal, D. R.; Mueller, R. H. Org. Process Res. Dev. 2002, 6, 323. (f) Couturier, M.;
Tucker, J. L.; Andresen, B. M.; DeVries, K. M.; Vanderplas, B. C.; Ito, F. Tetrahedron:
Asymmetry 2003, 14, 3517. (g) Chung, J. Y. L.; Cvetovich, R. J.; Tsay, F.-R.; Dormer, P. G.;
DiMichele, L.; Mathre, D. J.; Chilenski, J. R.; Mao, B.; Wenslow, R. J. Org. Chem. 2003, 68,
8838. (h) Ashcroft, C. P.; Challenger, S.; Derrick, A. M.; Storey, R.; Thomson, N. M. Org.
Process Res. Dev. 2003, 7, 362. (i) Nelson, T. D.; LeBlond, C. R.; Frantz, D. E.; Matty, L.;
Mitten, J. V.; Weaver, D. G.; Moore, J. C.; Kim, J. M.; Boyd, R.; Kim, P.-Y.; Gbewonyo, K.;
Brower, M.; Sturr, M.; McLaughlin, K.; McMasters, D. R.; Kress, M. H.; McNamara, J. M.;
Dolling, U. H. J. Org. Chem. 2004, 69, 3620. (j) Maruyama, N.; Shimizu, H.; Sugiyama, T.;
Watanabe, M.; Makino, M.; Kato, M.; Shimizu, M. Org. Process Res. Dev. 2004, 8, 883. (k)
Hansen, K. B.; Balsells, J.; Dreher, S.; Hsiao, Y.; Kubryk, M.; Palucki, M.; Rivera, N.;
Steinhuebel, D.; Armstrong, J. D.; Askin, D.; Grabowski, E. J. J. Org. Process Res. Dev. 2005, 9,
634. (l) Angelaud, R.; Zhong, Y.-L.; Maligres, P.; Lee, J.; Askin, D. J. Org. Chem. 2005, 70,
1949. (m) Aikins, J. A.; Haurez, M.; Rizzo, J. R.; Van Hoeck, J.-P.; Brione, W.; Kestemont, J.124
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Organic Process Research & Development
P.; Stevens, C.; Lemair, X.; Stephenson, G. A.; Marlot, E.; Forst, M.; Houpis, I. N. J. Org.
Chem. 2005, 70, 4695. (n) Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.;
Gallou, F.; Wang, X.-j.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, Y.; Tan, J.; Zhang,
L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M.;
Donsbach, K.; Nicola, T.; Brenner, M.; Winter, E.; Kreye, P.; Samstag, W. J. Org. Chem. 2006,
71, 7133. (o) Benoit, G.-E.; Carey, J. S.; Chapman, A. M.; Chima, R.; Hussain, N.; Popkin, M.
E.; Roux, G.; Tavassoli, B.; Vaxelaire, C.; Webb, M. R.; Whatrup, D. Org. Process Res. Dev.
2007, 11, 88. (p) Nikitenko, A.; Alimardanov, A.; Afragola, J.; Schmid, J.; Kristofova, L.;
Evrard, D.; Hatzenbuhler, N. T.; Marathias, V.; Stack, G.; Lenicek, S.; Potoski, J. Org. Process
Res. Dev. 2008, 12, 91. (q) Abbas, S.; Ferris, L.; Norton, A. K.; Powell, L.; Robinson, G. E.;
Siedlecki, P.; Southworth, R. J.; Stark, A.; Williams, E. G. Org. Process Res. Dev. 2008, 12, 202.
(r) Becker, C. L.; Engstrom, K. M.; Kerdesky, F. A.; Tolle, J. C.; Wagaw, S. H.; Wang, W. Org.
Process Res. Dev. 2008, 12, 1114. (s) Pu, Y. J.; Vaid, R. K.; Boini, S. K.; Towsley, R. W.;
Doecke, C. W.; Mitchell, D. Org. Process Res. Dev. 2009, 13, 310. (t) Shu, C.; Zeng, X.; Hao,
M.-H.; Wei, X.; Yee, N. K.; Busacca, C. A.; Han, Z.; Farina, V.; Senanayake, C. H. Org. Lett.
2008, 10, 1303. (u) Wilmouth, S.; Bufferne-Perret, C.; Flouzat, C.; Humblot, G.; Ray, C.;
Simbille, N. Tetrahedron 2009, 65, 2689. (v) Molinaro, C.; Gauvreau, D.; Hughes, G.; Lau, S.;
Lauzon, S.; Angelaud, R.; O’Shea, P. D.; Janey, J.; Palucki, M.; Hoerrner, S. R.; Raab, C. E.;
Sidler, R. R.; Belley, M.; Han, Y. J. Org. Chem. 2009, 74, 6863. (w) Ohta, C.; Kuwabe, S.-i.;
Shiraishi, T.; Shinohara, I.; Araki, H.; Sakuyama, S.; Makihara, T.; Kawanaka, Y.; Ohuchida, S.;
Seko, T. J. Org. Chem. 2009, 74, 8298. (x) Wang, H.; Matsuhashi, H.; Doan, B. D.; Goodman, S.
N.; Ouyang, X.; Clark, W. M.. Tetrahedron 2009, 65, 6291. (y) Menzel, K.; Machrouhi, F.;
Bodenstein, M.; Alorati, A.; Cowden, C.; Gibson, A. W.; Bishop, B.; Ikemoto, N.; Nelson, T. D.;
125
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Page 126 of 138
Kress, M. H.; Frantz, D. E. Org. Process Res. Dev. 2009, 13, 519. (z) Broeders, F.; Defrère, L.;
Deltent, M.-F.; Driessens, F.; Gilson, F.; Grooters, L.; Ikonomakos, X.; Limauge, F.; Sergeef, E.;
Verstraeten, N. Org. Process Res. Dev. 2009, 13, 442. (aa) Savage, S. A.; Jones, G. S.;
Kolotuchin, S.; Ramrattan, S. A.; Vu, T.; Waltermire, R. E. Org. Process Res. Dev. 2009, 13,
1169. (ab) Lorenz, J. C.; Busacca, C. A.; Feng, X.; Grinberg, N.; Haddad, N.; Johnson, J.;
Kapadia, S.; Lee, H.; Saha, A.; Sarvestani, M.; Spinelli, E. M.; Varsolona, R.; Wei, X.; Zeng, X.;
Senanayake, C. H. J. Org. Chem. 2010, 75, 1155. (ac) Yoshikawa, N.; Xu, F.; Arredondo, J. D.;
Itoh, T. Org. Process Res. Dev. 2011, 15, 824. (ad) Song, Z. J.; Tellers, D. M.; Journet, M.;
Kuethe, J. T.; Lieberman, D.; Humphrey, G.; Zhang, F.; Peng, Z.; Waters, M. S.; Zewge, D.;
Nolting, A.; Zhao, D.; Reamer, R. A.; Dormer, P. G.; Belyk, K. M.; Davies, I. W.; Devine, P. N.;
Tschaen, D. M. J. Org. Chem. 2011, 76, 7804. (ae) Zhu, J.; Razler, T. M.; Xu, Z.; Conlon, D. A.;
Sortore, E. W.; Fritz, A. W.; Demerzhan, R.; Sweeney, J. T. Org. Process Res. Dev. 2011, 15,
438. (af) Crawford, J. B.; Chen, G.; Carpenter, B.; Wilson, T.; Ji, J.; Skerlj, R. T.; Bridger, G. J.
Org. Process Res. Dev. 2011, 15, 109. (ag) Ruck, R. T.; Huffman, M. A.; Stewart, G. W.;
Cleator, E.; Kandur, W. V.; Kim, M. M.; Zhao, D. Org. Process Res. Dev. 2012, 16, 1329. (ah)
Lafrance, D.; Caron, S. Org. Process Res. Dev. 2012, 16, 409. (ai) Shi, Z.; Kiau, S.; Lobben, P.;
Hynes, J.; Wu, H.; Parlanti, L.; Discordia, R.; Doubleday, W. W.; Leftheris, K.; Dyckman, A. J.;
Wrobleski, S. T.; Dambalas, K.; Tummala, S.; Leung, S.; Lo, E. Org. Process Res. Dev. 2012,
16, 1618. (aj) Shu, L.; Gu, C.; Dong, Y.; Brinkman, R. Org. Process Res. Dev. 2012, 16, 1940.
(ak) Liu, Y.; Prashad, M.; Shieh, W.-C. Org. Process Res. Dev. 2014, 18, 239. (al) Liu, Y.;
Prashad, M.; Shieh, W.-C. Org. Process Res. Dev. 2014, 18, 239. (am) Teleha, C. A.; Branum,
S.; Zhang, Y.; Reuman, M. E.; Van Der Steen, L.; Verbeek, M.; Fawzy, N.; Leo, G. C.; Kang,
F.-A.; Cai, C.; Kolpak, M.; Beauchamp, D. A.; Wall, M. J.; Russell, R. K.; Sui, Z.; Vanbaelen,
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60
Organic Process Research & Development
H. Org. Process Res. Dev. 2014, 18, 1622. (an) Teleha, C. A.; Branum, S.; Zhang, Y.; Reuman,
M. E.; Van Der Steen, L.; Verbeek, M.; Fawzy, N.; Leo, G. C.; Winters, M. P.; Kang, F.-A.;
Kolpak, M.; Beauchamp, D. A.; Lanter, J. C.; Russell, R. K.; Sui, Z.; Vanbaelen, H. Org.
Process Res. Dev. 2014, 18, 1630. (ao) Funel, J.-A.; Brodbeck, S.; Guggisberg, Y.; Litjens, R.;
Seidel, T.; Struijk, M.; Abele, S. Org. Process Res. Dev. 2014, 18, 1674. (ap) Chen, J.; Chen, T.;
Hu, Q.; Püntener, K.; Re, Y.; She, J.; Du, Z.; Scalone, M. Org. Process Res. Dev. 2014, 18,
1702. (aq) Mangion, I. K.; Chen, C.; Li, H.; Maligres, P.; Chen, Y.; Christensen, M.; Cohen, R.;
Jeon, I.; Klapars, A.; Krska, S.; Nguyen, H.; Reamer, R. A.; Sherry, B. D.; Zavialov, I. Org. Lett.
2014, 16, 2310. (ar) Littler, B. J.; Aizenberg, M.; Ambhaikar, N. B.; Blythe, T. A.; Curran, T. T.;
Dvornikovs, V.; Jung, Y. C.; Jurkauskas, V.; Lee, E. C.; Looker, A. R.; Luong, H.; Martinot, T.
A.; Miller, D. B.; Neubert-Langille, B. J.; Otten, P. A.; Rose, P. J.; Ruggiero, P. L. Org. Process
Res. Dev. 2015, 19, 270.
47
(a) Castro, B.; Dormoy, J. R. Bull. Soc. Chim. Fr. 1973, 12, 3359. (b) Castro, B.; Dormoy, J.
R. Tetrahedron Lett. 1973, 12, 3243. (c) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C.
Tetrahedron Lett. 1975, 14, 1219. (d) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. J. Chem.
Res. (S) 1977, 182. (e) Coste, J.; Le-Nguyen, D.; Evin, G.; Castro, B. Tetrahedron Lett. 1990, 31,
205.
48
(a) Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31, 205. (b) Wang, W.;
McMurray, J. S. Tetrahedron Lett. 1999, 40, 2501.
49
HOBt is potentially explosive in its anhydrous form (Class 1 explosive category), which has
led to retrictions for its shipping. See: Wehrstedt, K. D.; Wandrey, P. A.; Heitkamp, D. J.
Hazard. Mater. 2005, 126, 1.
127
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Page 128 of 138
BOP: Ishikawa, M.; Tsushima, M.; Kubota, D.; Yanagisawa, Y.; Hiraiwa, Y.; Kojima, Y.;
Ajito, K.; Anzai, N. Org. Process Res. Dev. 2008, 12, 596.
51
(a) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 19, 1269. (b) Dourtoglou,
V.; Ziegler, J.-C.; Gross, B. Synthesis 1984, 572. (c) Carpino, L. A.; Imazumi, H.; El-Faham, A.;
Ferrer, F. J.; Zhang, C.; Lee, Y.; Foxman, B. M.; Henklein, P.; Hanay, C.; Mügge, C.;
Wenschuh, H.; Klose, J.; Beyermann, M.; Bienert, M. Angew. Chem., Int. Ed. 2002, 41, 441.
52
Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1927.
53
N,N,N’,N’-tetramethylurea has been reported to be cytotoxic. Coste, D. L.-N.; Castro, B.
Tetrahedron Lett. 1990, 31, 205 and references therein.
54
HBTU: Remarchuk, T.; St-Jean, F.; Carrera, D.; Savage, S.; Yajima, H.; Wong, B.; Babu, S.;
Deese, A.; Stults, J.; Dong, M. W.; Askin, D.; Lane, J. W.; Spencer, K. L. Org. Process Res.
Dev. 2014, 18, 1652.
55
Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
56
Carpino, L. A.; El-Faham, A.; Albericio, F. Tetrahedron Lett. 1994, 35, 2279.
57
HATU: (a) Andrews, D. M.; Arnould, J.-C.; Boutron, P.; Délouvrie, B.; Delvare, C.; Foote, K.
M.; Hamon, A.; Harris, C. S.; Lambert-van der Brempt, C.; Lamorlette, M.; Matusiak, Z. M.
Tetrahedron 2009, 65, 5805. (b) O’Shea, P. D.; Chen, C.-y.; Gauvreau, D.; Gosselin, F.; Hughes,
G.; Nadeau, C.; Volante, R. P. J. Org. Chem. 2009, 74, 1605. (c) Fei, Z.; Kong, W.; Wang, H.;
Peng, J.; Sun, F.; Yin, Y.; Bajwa, J.; Jiang, X. Org. Process Res. Dev. 2012, 16, 1436. (d)
Roemmele, R. C.; Christie, M. A. Org. Process Res. Dev. 2013, 17, 422. (e) Pikul, S.; Cheng, H.;
128
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56
57
58
59
60
Organic Process Research & Development
Cheng, A.; Huang, C. D.; Ke, A.; Kuo, L.; Thompson, A.; Wilder, S. Org. Process Res. Dev.
2013, 17, 907.
58
TBTU: (a) Faucher, A.-M.; Bailey, M. D.; Beaulieu, P. L.; Brochu, C.; Duceppe, J.-S.;
Ferland, J.-M.; Ghiro, E.; Gorys, V.; Halmos, T.; Kawai, S. H.; Poirier, M.; Simoneau, B.;
Tsantrizos, Y. S.; Llinàs-Brunet, M. Org. Lett. 2004, 6, 2901. (b) Karlsson, S.; Sörensen, J. H.
Org. Process Res. Dev. 2012, 16, 586.
59
Cyanuric chloride: Rayle, H. L.; Fellmeth, L. Org. Process Res. Dev. 1999, 3, 172.
60
Kamiński, Z. J. Tetrahedron Lett. 1985, 26, 2901.
61
Garrett, C. E.; Jiang, X.; Prasad, K.; Repič, O. Tetrahedron Lett. 2002, 43, 4161.
62
CDMT: (a) Barnett, C. J.; Wilson, T. M.; Kobierski, M. E. Org. Process Res. Dev. 1999, 3,
184. (b) Walker, A. J.; Adolph, S.; Connell, R. B.; Laue, K.; Roeder, M.; Rueggeberg, C. J.;
Hahn, D. U.; Voegtli, K.; Watson, J. Org. Process Res. Dev. 2009, 13, 85. (c) Villhauer, E. B.;
Shieh, W.-C.; Du, Z.; Vargas, K.; Ciszewski, L.; Lu, Y.; Girgis, M.; Lin, M.; Prashad, M.
Tetrahedron 2009, 65, 9067. (d) Kallman, N. J.; Liu, C.; Yates, M. H.; Linder, R. J.; Ruble, J. C.;
Kogut, E. F.; Patterson, L. E.; Laird, D. L. T.; Hansen, M. M. Org. Process Res. Dev. 2014, 18,
501. (e) Kallman, N. J.; Liu, C.; Yates, M. H.; Linder, R. J.; Ruble, J. C.; Kogut, E. F.; Patterson,
L. E.; Laird, D. L. T.; Hansen, M. M. Org. Process Res. Dev. 2014, 18, 501.
63
Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S. Tetrahedron Lett. 1999, 40,
5327.
129
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Organic Process Research & Development
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54
55
56
57
58
59
60
64
Page 130 of 138
Kunishima, M.; Kawachi, C.; Morita, J.; Terao, K.; Iwasaki, F.; Tani, S. Tetrahedron 1999,
55, 13159.
65
Zheng, H.; Hall, D. G. Aldrichimica Acta 2014, 47, 41.
66
(a) Pelter, A.; Levitt, T. E.; Nelsoni, P. Tetrahedron 1970, 26, 1539. (b) Pelter, A.; Levitt, T.
E. Tetrahedron 1970, 26, 1545. (c) Tani, J.; Oine, T.; Inoue, I. Synthesis 1975, 714. (d) Collum,
D. B.; Chen, S.-C.; Ganem, B. J. Org. Chem. 1978, 43, 4393. (e) Trapani, G.; Reho, A.; Latrofa,
A. Synthesis 1983, 1013.
67
Carlson, R.; Lundstedt, T.; Nordahl, A.; Prochazka, M. Acta Chem. Scand., Ser. B 1986, 40,
522.
68
(a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196. (b) Ishihara, K.;
Kondo, S.; Yamamoto, H. Synlett 2001, 1371.
69
Ishihara, K.; Ohara, S.; Yamamoto, H. Org. Synth. 2002, 79, 176.
70
Tang, P. Org. Synth. 2005, 81, 262.
71
Reddy, J. M.; Kumar, K. V.; Raju, V.; Bhaskar, B. V.; Himabindu, V.; Bhattacharya, A.;
Sundaram, V.; Banerjee, R.; Reddy, G. M.; Bandichhor, R. Synth. Commun. 2008, 38, 2138.
72
Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed. 2008, 47, 2876.
73
Gernigon, N.; Al-Zoubi, R. M.; Hall, D. G. J. Org. Chem. 2012, 77, 8386.
130
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51
52
53
54
55
56
57
58
59
60
74
Organic Process Research & Development
(a) Ishihara, K.; Ohara, S.; Yamamoto, H. Macromolecules 2000, 33, 3511. (b) Arnold, K.;
Davies, B.; Giles, R. L.; Grosjean, C.; Smith, G. E.; Whiting, A. Adv. Synth. Catal. 2006, 348,
813.
75
(a) Georgiou, I.; Ilyashenko, G.; Whiting, A. Acc. Chem. Res. 2009, 42, 756. (b) Arnold, K.;
Batsanov, A. S.; Davies, B.; Whiting, A. Green Chem. 2008, 10, 124.
76
(a) Lanigan, R. M.; Starkov, P.; Sheppard, T. D. J. Org. Chem. 2013, 78, 4512. (b) Karaluka,
V.; Lanigan, R. M.; Murray, P. M.; Badland, M.; Sheppard, T. D. Org. Biomol. Chem, in press.
DOI: 10.1039/c5ob01801c.
77
Starkov, P.; Sheppard, T. D. Org. Biomol. Chem. 2011, 9, 1320.
78
Maki, T.; Ishihara, K.; Yamamoto, H. Tetrahedron 2007, 63, 8645.
79
Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 8, 1431.
80
(a) National Pesticide Information Centre (2001). http://npic.orst.edu/factsheets/boricgen.pdf
(accessed June 26, 2015). (b) Heindel, J. J.; Price, C. J.; Field, E. A.; Marr, M. C.; Myers, C. B.;
Morrissey, R. E.; Schwetz, B. A. Fundam. Appl. Toxicol. 1992, 18, 266. (c) Price, C. J.; Marr, M.
C.; Myers, C. B.; Seely, J. C.; Heindel, J. J.; Schwetz, B. A. Fundam. Appl. Toxicol. 1996, 34,
176.
81
Boric
Acid,
Substances
of
Very
High
Concern
(SVHC)
Support
Document
http://echa.europa.eu/doc/candidate_list/svhc_supdoc_boric_acid_publication.pdf (accessed June
26, 2015).
82
Ishihara, K.; Yamamoto, H. Eur. J. Org. Chem. 1999, 527.
131
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57
58
59
60
83
Page 132 of 138
Boric acid: (a) Anderson, J. E.; Davis, R.; Fitzgerald, R. N.; Haberman, J. M. Synth. Commun.
2006, 36, 2129. (b) Mylavarapu, R. K.; GCM, K.; Kolla, N.; Veeramalla, R.; Koilkonda, P.;
Bhattacharya, A.; Bandichhor, R. Org. Process Res. Dev. 2007, 11, 1065. (c) Shinde, G. B.;
Niphade, N. C.; Deshmukh, S. P.; Toche, R. B.; Mathad, V. T. Org. Process Res. Dev. 2011, 15,
455.
84
3-Nitrophenylboronic acid: Bannister, R. M.; Brookes, M. H.; Evans, G. R.; Katz, R. B.;
Tyrrell, N. D. Org. Process Res. Dev. 2000, 4, 467.
85
Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed. 2008, 47, 2876.
86
(a) Wang, C.; Yu, H.-Z.; Fu, Y.; Guo, Q.-X. Org. Biomol. Chem. 2013, 11, 2140. (b) Marcelli,
T. Angew. Chem., Int. Ed. 2010, 49, 6840.
87
Methyl esters: (a) Hartner, F. W.; Cvetovich, R. J.; Tsay, F.-R.; Amato, J. S.; Pipik, B.;
Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 7751. (b) Bankston, D.; Dumas, J.;
Natero, R.; Riedl, B.; Monahan, M.-K.; Sibley, R. Org. Process Res. Dev. 2002, 6, 777. (c)
Reichard, G. A.; Stengone, C.; Paliwal, S.; Mergelsberg, I.; Majmundar, S.; Wang, C.; Tiberi, R.;
McPhail, A. T.; Piwinski, J. J.; Shih, N.-Y. Org. Lett. 2003, 5, 4249. (d) Haight, A. R.; Bailey, A.
E.; Baker, W. S.; Cain, M. H.; Copp, R. R.; DeMattei, J. A.; Ford, K. L.; Henry, R. F.; Hsu, M.
C.; Keyes, R. F.; King, S. A.; McLaughlin, M. A.; Melcher, L. M.; Nadler, W. R.; Oliver, P. A.;
Parekh, S. I.; Patel, H. H.; Seif, L. S.; Staeger, M. A.; Wayne, G. S.; Wittenberger, S. J.; Zhang,
W. Org. Process Res. Dev. 2004, 8, 897. (e) Abe, M.; Nagai, M.; Yamamoto, K.; Yamazaki, H.;
Koga, I.; Satoh, Y.; Muraoka, Y.; Kurashige, S.; Ichikawa, Y.-i. Org. Process Res. Dev. 2005, 9,
570. (f) Chen, L.; Kim, Y. M.; Kucera, D. J.; Harrison, K. E.; Bahmanyar, S.; Scott, J. M.;
Yazbeck, D. J. Org. Chem. 2006, 71, 5468. (g) Mezei, T.; Mesterházy, N.; Bakó, T.; Porcs132
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54
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56
57
58
59
60
Organic Process Research & Development
Makkay, M.; Simig, G.; Volk, B. Org. Process Res. Dev. 2009, 13, 567. (h) Pesti, J.; Chen, C.K.; Spangler, L.; DelMonte, A. J.; Benoit, S.; Berglund, D.; Bien, J.; Brodfuehrer, P.; Chan, Y.;
Corbett, E.; Costello, C.; DeMena, P.; Discordia, R. P.; Doubleday, W.; Gao, Z.; Gingras, S.;
Grosso, J.; Haas, O.; Kacsur, D.; Lai, C.; Leung, S.; Miller, M.; Muslehiddinoglu, J.; Nguyen,
N.; Qiu, J.; Olzog, M.; Reiff, E.; Thoraval, D.; Totleben, M.; Vanyo, D.; Vemishetti, P.;
Wasylak, J.; Wei, C. Org. Process Res. Dev.2009, 13, 716. (i) Braish, T. F. Org. Process Res.
Dev. 2009, 13, 336. (j) van der Meijden, M. W.; Leeman, M.; Gelens, E.; Noorduin, W. L.;
Meekes, H.; van Enckevort, W. J. P.; Kaptein, B.; Vlieg, E.; Kellogg, R. M. Org. Process Res.
Dev. 2009, 13, 1195. (k) Vartak, A. P.; Crooks, P. A. Org. Process Res. Dev. 2009, 13, 415. (l)
Anelli, P. L.; Brocchetta, M.; Lattuada, L.; Manfredi, G.; Morosini, P.; Murru, M.; Palano, D.;
Sipioni, M.; Visigalli, M. Org. Process Res. Dev. 2009, 13, 739. (m) Anderson, K. R.; Atkinson,
S. P. L. G.; Fujiwara, T.; Giles, M. E.; Matsumoto, T.; Merifield, E.; Singleton, J. T.; Saito, T.;
Sotoguchi, T.; Tornos, J. A.; Way, E. L. Org. Process Res. Dev. 2010, 14, 58. (n) Walker, M. D.;
Andrews, B. I.; Burton, A. J.; Humphreys, L. D.; Kelly, G.; Schilling, M. B.; Scott, P. W. Org.
Process Res. Dev. 2010, 14, 108. (o) Magnus, N. A.; Campagna, S.; Confalone, P. N.; Savage,
S.; Meloni, D. J.; Waltermire, R. E.; Wethman, R. G.; Yates, M. Org. Process Res. Dev. 2010,
14, 159. (p) Zhao, Y.; Zhu, L.; Provencal, D. P.; Miller, T. A.; O’Bryan, C.; Langston, M.; Shen,
M.; Bailey, D.; Sha, D.; Palmer, T.; Ho, T.; Li, M. Org. Process Res. Dev. 2012, 16, 1652. (q)
Weiberth, F. J.; Yu, Y.; Subotkowski, W.; Pemberton, C. Org. Process Res. Dev. 2012, 16, 1967.
(r) McLaughlin, M.; Belyk, K.; Chen, C.-y.; Linghu, X.; Pan, J.; Qian, G.; Reamer, R. A.; Xu, Y.
Org. Process Res. Dev. 2013, 17, 1052.
88
Ethyl esters: (a) Wu, G.; Tormos, W. J. Org. Chem. 1997, 62, 6412. (b) Bundy, G. L.; Banitt,
L. S.; Dobrowolski, P. J.; Palmer, J. R.; Schwartz, T. M.; Zimmermann, D. C.; Lipton, M. F.;
133
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59
60
Page 134 of 138
Mauragis, M. A.; Veley, M. F.; Appell, R. B.; Clouse, R. C.; Daugs, E. D. Org. Process Res.
Dev. 2001, 5, 144. (c) Dorow, R. L.; Herrinton, P. M.; Hohler, R. A.; Maloney, M. T.; Mauragis,
M. A.; McGhee, W. E.; Moeslein, J. A.; Strohbach, J. W.; Veley, M. F. Org. Process Res. Dev.
2006, 10, 493. (d) Alimardanov, A.; Schmid, J.; Afragola, J.; Khafizova, G. Org. Process Res.
Dev. 2008, 12, 424. (e) Savage, S. A.; Waltermire, R. E.; Campagna, S.; Bordawekar, S.; Dalla
Riva Toma, J. Org. Process Res. Dev. 2009, 13, 510. (f) Giubellina, N.; Stabile, P.; Laval, G.;
Perboni, A. D.; Cimarosti, Z.; Westerduin, P.; Cooke, J. W. B. Org. Process Res. Dev. 2010, 14,
859. (g) Huang, B.-G.; Kubiak, G.; Shay, J. J.; Pemberton, C.; Peers, J.; Hanna, R. G.; Powers,
M. R.; Gamboa, J. A.; Gelormini, A. M.; Yarabe, H.; Rudisill, D. E. Org. Process Res. Dev.
2011, 15, 1040. (h) Das, P.; Srivastava, B.; Joseph, S.; Nizar, H.; Prasad, M. Org. Process Res.
Dev. 2014, 18, 665. (i) Rangappa, P.; Ghosh, A.; Chitrapadi, S.; Kantikar, G.; CH, V. K.;
Sythana, S.; Manjunath, S. G.; Nambiar, S.; R, S. Org. Process Res. Dev. 2014, 18, 947. (j) Patil,
Y. S.; Bonde, N. L.; Kekan, A. S.; Sathe, D. G.; Das, A. Org. Process Res. Dev. 2014, 18, 1714.
(k) Tian, Q.; Hoffmann, U.; Humphries, T.; Cheng, Z.; Hidber, P.; Yajima, H.; Guillemot-Plass,
M.; Li, J.; Bromberger, U.; Babu, S.; Askin, D.; Gosselin, F. Org. Process Res. Dev. 2015, 19,
416.
89
tert-Butyl esters: Bellingham, R. K.; Carey, J. S.; Hussain, N.; Morgan, D. O.; Oxley, P.;
Powling, L. C. Org. Process Res. Dev. 2004, 8, 279.
90
Isobutyl esters: Fleck, T. J.; McWhorter, W. W.; DeKam, R. N.; Pearlman, B. A. J. Org.
Chem. 2003, 68, 9612.
91
Lactones: (a) Wu, G.; Wong, Y.; Chen, X.; Ding, Z. J. Org. Chem. 1999, 64, 3714. (b) Xu, D.
D.; Waykole, L.; Calienni, J. V.; Ciszewski, L.; Lee, G. T.; Liu, W.; Szewczyk, J.; Vargas, K.;
134
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52
53
54
55
56
57
58
59
60
Organic Process Research & Development
Prasad, K.; Repič, O.; Blacklock, T. J. Org. Process Res. Dev. 2003, 7, 856. (c) Li, B.; Andresen,
B.; Brown, M. F.; Buzon, R. A.; Chiu, C. K. F.; Couturier, M.; Dias, E.; Urban, F. J.; Jasys, V.
J.; Kath, J. C.; Kissel, W.; Le, T.; Li, Z. J.; Negri, J.; Poss, C. S.; Tucker, J.; Whritenour, D.;
Zandi, K. Org. Process Res. Dev. 2005, 9, 466. (d) Abrecht, S.; Adam, J.-M.; Bromberger, U.;
Diodone, R.; Fettes, A.; Fischer, R.; Goeckel, V.; Hildbrand, S.; Moine, G.; Weber, M. Org.
Process Res. Dev. 2011, 15, 503. (e) Li, C.; Li, B.-F.; Chen, J.-G.; Sun, T.; Chen, Z. Org.
Process Res. Dev. 2012, 16, 2021. (f) Michida, M.; Takayanagi, Y.; Imai, M.; Furuya, Y.;
Kimura, K.; Kitawaki, T.; Tomori, H.; Kajino, H. Org. Process Res. Dev. 2013, 17, 1430. (g)
Bowles, P.; Brenek, S. J.; Caron, S.; Do, N. M.; Drexler, M. T.; Duan, S.; Dubé, P.; Hansen, E.
C.; Jones, B. P.; Jones, K. N.; Ljubicic, T. A.; Makowski, T. W.; Mustakis, J.; Nelson, J. D.;
Olivier, M.; Peng, Z.; Perfect, H. H.; Place, D. W.; Ragan, J. A.; Salisbury, J. J.; Stanchina, C.
L.; Vanderplas, B. C.; Webster, M. E.; Weekly, R. M. Org. Process Res. Dev. 2014, 18, 66. (h)
von Kieseritzky, F.; Wang, Y.; Axelson, M. Org. Process Res. Dev. 2014, 18, 643.
92
Thioesters: (a) Brands, K. M. J.; Jobson, R. B.; Conrad, K. M.; Williams, J. M.; Pipik, B.;
Cameron, M.; Davies, A. J.; Houghton, P. G.; Ashwood, M. S.; Cottrell, I. F.; Reamer, R. A.;
Kennedy, D. J.; Dolling, U.-H.; Reider, P. J. J. Org. Chem. 2002, 67, 4771. (b) Prasada Rao, K.
V. V.; Dandala, R.; Sivakumaran, M. S.; Rani, A.; Naidu, A. Synth. Commun. 2007, 37, 2275. (c)
Tewari, N.; Rai, B. P.; Mohammad, K.; Nizar, H.; Prasad, M. Org. Process Res. Dev. 2009, 13,
936.
93
Pentafluorophenyl esters: Zhang, H.; Schneider, S. E.; Bray, B. L.; Friedrich, P. E.;
Tvermoes, N. A.; Mader, C. J.; Whight, S. R.; Niemi, T. E.; Silinski, P.; Picking, T.; Warren, M.;
Wring, S. A. Org. Process Res. Dev. 2008, 12, 101.
135
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
94
Page 136 of 138
NHS esters: Westermann, J.; Schneider, M.; Platzek, J.; Petrov, O. Org. Process Res. Dev.
2007, 11, 200.
95
Acetic acid: (a) van der Linden, M.; Roeters, T.; Harting, R.; Stokkingreef, E.; Gelpke, A. S.;
Kemperman, G. Org. Process Res. Dev. 2008, 12, 196. (b) Sharma, P. K.; Shah, R. N.; Carver, J.
P. Org. Process Res. Dev. 2008, 12, 831. (c) Chen, H.; Chen, Y.; Yuan, L.; Zou, Q. Org. Process
Res. Dev. 2013, 17, 714.
96
Sufuric acid: Marzoni, G.; Varney, M. D. Org. Process Res. Dev. 1997, 1, 81.
97
Trifluoroacetic acid: Hansen, K. B.; Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.;
Krska, S.; Rosner, T.; Simmons, B.; Balsells, J.; Ikemoto, N.; Sun, Y.; Spindler, F.; Malan, C.;
Grabowski, E. J. J.; Armstrong, J. D. J. Am. Chem. Soc. 2009, 131, 8798.
98
(a) Fyfe, M. C. T.; Gardner, L. S.; Nawano, M.; Procter, M. J.; Rasamison, C. M.; Schofield,
K. L.; Shah, V. K.; Yasuda, K. (OSI Pharmaceuticals, Inc., USA; Prosidion Ltd, GB). PCT Int.
Appl. 2004, WO 2004072031 A2 20040826. (b) Briner, P. H.; Fyfe, M. C. T.; Madeley, J. P.;
Murray, P. J.; Procter, M. J. (Prosidion Ltd, GB); Spindler, F. (Solvias, AG). PCT Int. Appl.
2006, WO 2006016178 A1 20060216.
99
Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
100
Weisenburger, G. A.; Vogt, P. F. Org. Process Res. Dev. 2006, 10, 1246.
101
Ueki, H.; Ellis, T. K.; Martin, C. H.; Boettiger, T. U.; Bolene, S. B.; Soloshonok, V. A. J.
Org. Chem. 2003, 68, 7104.
102
Wakasugi, K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y. Adv. Synth. Catal. 2003, 345, 1209.
136
ACS Paragon Plus Environment
Page 137 of 138
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10
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44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
103
Organic Process Research & Development
Eckert, F.; Leito, I.; Kaljurand, I.; Kutt, A.; Klamt, A.; Diedenhofeni, M. J. Comput. Chem.
2008, 30, 799.
104
Um, I.; Chun, S. M.; Bae, S. K. Bull. Korean Chem. Soc. 2005, 26, 457.
105
de Koning, P. D.; Castro, N.; Gladwell, I. R.; Morrison, N. A.; Moses, I. B.; Panesar, M. S.;
Pettman, A. J.; Thomson, N. M. Org. Process Res. Dev. 2011, 15, 1256.
106
http://www.acs.org/content/acs/en/greenchemistry/industry-business/pharmaceutical.html
(accessed June 26, 2015)
107
(a) Shekhar, A. C.; Kumar, A. R.; Sathaiah, G.; Paul, V.L. ; Sridhar, M.; Rao, P. S.
Tetrahedron Lett. 2009, 50, 7099. (b) Wu, X.-F.; Sharif, M.; Pews-Davtyan, A.; Langer, P.;
Ayub, K.; Beller. M. Eur. J. Org. Chem. 2013, 2783. (c) Hosseini-Sarvari, M.; Sharghi, H. J.
Org. Chem. 2006, 71, 6652.
108
(a) Shteinberg, L. Y.; Kondratov, S. A.; Shein, S. M.; Mishchenko, S. E.; Dolmat, V. M.;
Dibrova, V. M. Kinet. Catal. 1999, 40, 511. (b) Shteinberg, L. Y.; Kondartiv, S. A.; Shein, S. M.
Russ. J. Org. Chem. 2005, 41, 304. (c) Shteinberg, L. Y.; Kondratov, S. A.; Shein, S. M.;
Marshalova, V. V. Kinet. Catal. 2007, 48, 632. (d) Shteinberg, L. Y.; Marshalova, V. V.;
Dibrova, V. M.; Shein, S. M. Russ. J. Org. Chem. 2008, 78, 1463. (e) Shteinberg, L.;
Marshalova, V. V.; Dibrova, V. M.; Shein, S. M. Russ J. Org. Gen. Chem. 2011, 81, 1839. (f)
Hosseini-Sarvari, M.; Sodagar, E.; Doroodmand, M. M. J. Org. Chem. 2011, 76, 2853. (g)
Lundberg, H.; Tinnis, F.; Adolfsson, H. Synlett 2012, 2201. (h) Deiana, C.; Sakhno, Y.;
Fabbiani, M.; Pazzi, M.; Vincenti, M.; Martra, G. ChemCatChem 2013, 5, 2832.
137
ACS Paragon Plus Environment
Organic Process Research & Development
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
109
Page 138 of 138
(a) Talukdar, D.; Saikia, L.; Thakur, A. J. Synlett 2011, 1597. (b) Allen, C. L.; Chhatwal, A.
R.; Williams, J. M. J. Chem. Commun. 2012, 48, 666. (c) Lundberg, H.; Tinnis, F.; Adolfsson, H.
Chem. Eur. J. 2012, 18, 3822.
110
Ghosh, S.; Bhaumik, A.; Mondal, J.; Mallik, A.; Sengupta, S.; Mukhopadhyay, C. Green
Chem. 2012, 14, 3220. For an example of stoichiometric AlMe3 applied to the synthesis of
amides, see: Li, J.; Subramaniam, K.; Smith, D.; Qiao, J. X.; Li, J. J.; Qian-Cutrone, J.; Kadow,
J. F.; Vite, G. D.; Chen, B.-C. Org. Lett. 2012, 14, 214.
111
Kim, J.-G.; Jang, D. O. Synlett 2010, 1231.
112
(a) Comerford, J. W.; Clark, J. H.; Macquarrie, D. J.; Breeden, S. W. Chem. Commun. 2009,
2562. (b) Comerford, J. W.; Farmer, T. J.; Macquarrie, D. J.; Breeden, S. W.; Clark, J. H.
ARKIVOC 2012, 7, 282.
113
Ali, M. A.; Siddiki, S. M. A. H.; Onodera, W.; Kon, K.; Shimizu, K.-i. ChemCatChem, in
press. DOI: 10.1002/cctc.201500672.
114
El-Faham, A.; Funosas, R. S.; Prohens, R.; Albericio, F. Chem. Eur. J. 2009, 15, 9404.
115
Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790.
116
(a) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798. (b) Vora, H. U.; Rovis, T. J.
Am. Chem. Soc. 2007, 129, 13796. (c) Chiang, P.-C.; Kim, Y.; Bode, J. W. Chem. Commun.
2009, 4566.
138
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