Nearly Neutral Allylation of Oxygen Nucleophiles An Honors Thesis (HONRS 499) By Matthew H. Bunner Thesis Advisor
Ball State University Muncie, Indiana May 2014
Expected Date of Graduation
May 2014
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Abstract
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. -<:;6
The following document describes a qualitative investigation into the ability of 2­
allyloxy-l-methylpyridinium trifluoromethanesulfonate (AOPT) (1) and derivatives to form allyl
esters and ethers under mildly basic conditions (Scheme 1). These ester and ether moieties are
useful to protection chemistry and are very common in biological synthesis of large molecules.
R-OH
or
~
~o
1
~ ~
j;J
N
I e OTf
~o
or
2
N
I e OTf
R/O~
or
"
Scbeme 1
Results show that 1 was successful as an allylating reagent under mild conditions, 2­
allyloxy-l,4-dimethylquinolinium trifluoromethanesulfonate (AOdMQT) (2) was also successful.
Optimal conditions as determined in this study for performing each reaction are found in the
discussion, along with reasoning and motivation toward each change.
Acknowledgements
Dr. Philip A. Albiniak, my thesis advisor, for the opportunity and support
Ball State University
Ball State Department of Chemistry
Ball state Honors College
CRISP Program
Honor" rolJpop TTncipror::lcill::ltp
rp"p::lr~h
FplJow"hin for fllnciino
Author's Statement
The subject of my thesis is the research I have been doing under Dr. Albiniak of the Ball
State Department of Chemistry since spring semester 2013. I have been working to develop a
reagent capable of falling apart when heated (thermolysis) to give a reactive allyl cation without
the use of strong acid or base catalysts. This is of great benefit to synthetic chemistry because it
widens the range of substrates that this reactive allyl cation can be installed upon, which in tum
opens up new possibilities for pharmaceutical and biological molecular synthesis. Details and
examples supporting both claims are within the document, along with experimental evidence and
proof of success.
The research has taught me a lot about developing new scientific literature and
methodology, as well as increasing my laboratory skill set. The experiment was created and
changed with a systematic approach using scientific methods and careful record keeping. Details
of the decisions made, reasoning behind those decisions, and motivation for pursuing this study
are also given in the document.
Writing the document has drastically increased my comprehension of scientific literature
and familiarized me with journals and resources that will enable me to independently find
answers to problems and implement the discoveries of others in pursuit of my own work. I have
often been told by my professors that the true skill I have been learning is problem solving, and
this new knowledge has dramatically increased my ability to find answers to my own problems
and questions. The first chapter of this document is a literature review with other examples of the
same chemical reaction as well as a review of the scientific importance of the chemistry being
developed. This chapter and the accompanying sources in the references section of the document
will serve to illustrate this point.
The document features a lot of scientific language and graphical representations. The
work is in organic chemistry and we chemists like to express our ideas in picture form. The
document contains many picture forms of chemical equation and molecular structure.
Explanations of the importance of each image are included in the document. Regrettably, these
can only be sinlplified or generalized so far without losing meaning. I feel I have done what I can
within the document by using colors and arrows to indicate important features.
Best of luck reading the document, I really hope you manage. It represents a lot of hard
work.
Matthew H Bunner
2
Contents
Abstract ........................................................................................................................................... 1 Acknowledgements ......................................................................................................................... 1 Introduction: Theory of Protection Chemistry ................................................................................ 3 Chapter 1: 2-Benzyloxy-l-methlpyridinium Trifluoromethanesulfonate (BnOPT) ....................... 4 1.1
Benzyl Ethers and Esters .................................................................................................. 4 1.2
Mechanism ..................................................................................................................... 10 1.2.1
1.3
Supporting evidence ................................................................................................ 10 Summary ........................................................................................................................ 13 Chapter 2: 2-Allyloxy-l-methlpyridinium Trifluoromethanesulfonate and Derivatives .............. 14 2.1
Theory ............................................................................................................................ 14 2.2
Allyl Esters and Ethers ................................................................................................... 14 2.3
Allyloxypyridinium Salts and Derivatives ..................................................................... 17 Appendix A: Experimental Procedures ......................................................................................... 21 General Notes ............................................................................................................................ 21 Preparation of 2-allyloxypyridine ............................................................................................. 21 Initial Base Screen of AOPT..................................................................................................... 21 Solvent Screen of AOPT........................................................................................................... 21 Base Screen of AOdMQT ......................................................................................................... 22 Appendix B: Spectral Data ........................................................................................................... 23 References ..................................................................................................................................... 44 3
Introduction: Theory of Protection Chemistry
A common difficulty in the synthesis of increasingly complex molecules is the presence
of mUltiple sites with the same reactivity at each stage in the process. To achieve the desired
transformation, reactive sites that are to remain unchanged must be blocked. J The reagents used
to block other reactive sites are called protection groups or protective groups. The continually
increasing complexity of synthetic chemistry demands the development of better and better
protective groups to achieve the desired regio-, sterio-, and enantio-selective transformations
under conditions that will not compromise the material being transformed. New and more
satisfactory protective groups, and methods of utilizing those protective groups, are constantly
being developed to enable the synthesis of natural and unnatural products that were previously
unattainable due to their complexity. J
Protection chemistry has three major steps: installation, where the protection group masks
the target site; transformation, where the desired change is made to a molecule and the protected
site is unchanged; and removal, where the protection group is removed and the masked site is
restored to previous functionality. The example below (Scheme 2) shows a Wittig reaction with
(installation, transformation and removal steps) and without (unprotected step) a type of
protection for carbonyls called acetal formation. Formation of the acetal favors masking the
aldehyde over the ketone because the carbon in question is less hindered and more electrophilic.
This ability to select protected sites is vital to protection chemistry.
o
0
o
o
o~
~O
~+
o~
~o
InstalIa tion
Transformation
Wittig Reaction
•
Removal or Cleavage
Scheme 2
The installation and removal steps have the same goals for "effective" protection chemistry:
reactions must be fast, efficient, and must not change and other sites of the molecule. High yields
are especially important for the installation and removal steps because these steps are lateral
moven1ents in a synthesis instead of steps forward. That is, installation and removal of protection
groups to not advance an overall synthesis any closer to the goal. The transformation step must
allow the desired transformation to occur without interference from the installed protection group
while protecting the masked site from any changes. The protection group should also be devoid
of any additional functional sites and should not exert any electronic influence on the masked
molecule. Because of these strict requirements, the development of protective groups and
methodology is a challenging field and development of an efficient material and method for
protection is a significant achievement.
4
Chapter 1: 2-Benzyloxy-1-methlpyridinium Trifluoromethanesulfonate (BnOPT)
1.1
Benzyl Ethers and Esters
The benzyl group is a good protective group for synthesizing benzyl ethers and esters by
masking alcohols and carboxylic acids. The benzyl group imparts little electric influence and
contains little competing reactivity.} Benzyl groups are particularly versatile owing to the variety
of mild cleavage reactions for the removal step.2 The ease of cleavage does lead to some trouble,
as strong acid or base conditions can remove the benzyl group before the intended time, giving a
small drawback to limitation imposed by conditions in the transformation step.}The benzyl
protection group does suffer from another drawback, it's a bulky piece to attach to a molecule. So,
while useful for many syntheses of unhindered products, the use of benzyl ethers or esters is not
recommended for syntheses of complex natural products and their derivatives due to the amount
of hindrance such compounds contain.
The following are some recently developed methods of installing benzyl protective
groups under mild conditions. Some, like the reaction of benzyl halide and free alcohol in the
presence of silver oxide (Scheme 3), also provide unique results that are very useful in synthetic
chemistry.
HO~
3
0
BnBr, Ag2 0
•_
DMF, 48 h, rt
780/0
Scheme 32
Bno~o=
_
0
The oxygen of the primary alcohol is exclusively benzylated without any loss or change to the
lactone when 5-methoxy-4,4-dimethyl-2(3H)-furanone (3) reacts with benzyl bromide in the
presence of silver oxide (Scheme 3).2 This method was developed in a previous paper,3 but the
utility was not discovered until it was used to perform the reaction above when all other methods
failed.
HO~~
HO~OH
reflux
.
2. BnBr, PbMe
N- Metbylimidazole
920/0
HO~~
BnO~OBn
Scheme 44
Equatorial hydroxyl groups are protected preferentially to axial groups in the reaction shown
above (Scheme 4).4 Tributyltin oxide reacts with hydroxyl groups to give a stannylated oxygen
species which mediated the benzylation when presented with an electrophilic benzyl synthon. 4
Tributyltin oxide can also be used to cleave carboxylic esters. 4 Both uses rely on principles of
hard-soft acid base chemistry, so substrates much be chosen accordingly. 5
5
m
Xi;(
Br
HO
Williamson Ether Synthesis
M
fI
BoBr, NaIl, DMF
-70·C, 40 miD, 97%'
OH
Scheme 56
Br
Me
~OBn
Exclusive benzylation of a primary alcohol can be achieved at -70°C by reacting with benzyl
bromide in the presence of sodium hydride (Scheme 5).6 This reaction is an example of a
Williamson ether synthesis. The low energy due to temperature and the difference in reactivity
between primary and secondary alcohols additively contribute to the selectiveness of this
reaction.
One of it's the greatest benefits of the benzyl protective group is its propensity for mild
methods 0 selective cleavage. Cleavage by palladium catalyzed hydrogenolysis is particularly
mild and successful (Scheme 6). 7 Palladium is preferred over platinum to avoid reducing
aromatic rings/
V
I
~
0
"R
Pd-C,Hz ,
EtOH
~
V
+
ROH
Scheme 67
Another possible method of cleavage is single electron reduction using dry sodium metal and
liquid ammonia. 8 The benzyl protection group is removed as bibenzyl and the protected reagent
can be quenched with a proton source in a second step (Scheme 7).
~O' R
V
_lo_N_3_1NH_3• •,O>
+
ROH
2. [H30+]
Scheme 78
Oxidative methods of cleavage can also be used for substrates that are senSItIve to
hydrogenolysis or dissolved metal. The method shone in Scheme 8 was used successfully on
carbohydrates with such sensitivities. 9 Esters are stable to this n1ethod, but glycosides and acetals
are also cleaved. 9
o
ROH
50%,
Scheme 89
+
~O'H
6
Generic schemes of two common benzylation reactions, Williamson ether synthesis and
protonating trichloroacetimidates, are shown below (Figure 1). Benzyl esters can be prepared
from many of the common methods of generating esters, such as reacting an acid halide or
anhydride with benzyl alcohol in the presence of a catalytic amount of base or Fischer
esterification.}
ROe
R?H
~A~
V
...
'----.....
Br
V
hOTf
Williamson ether synthesis
o
)lOH
CCl3
+
protonating trichloroacetimidates
[H+)
MeOH
Fischer Esterification
Figure 1
Williamson ether synthesis and use of protonated trichloroacetimidate are the most
common ways of preparing benzyl ethers, but both reactions have large drawbacks. Williamson
ether synthesis uses strongly basic conditions, deprotonating an alcohol and using the resulting
alkoxide to attack an electrophilic benzyl synthon, such as BnBr. One problem with this strategy
is the basic conditions; fragile bonds with a lot of electrophilic character will also be subject to
attack by the resulting alkoxide because it is such a good nucleophile. The other problem is that
the reaction relies on the nucleophilic character of the alkoxide, which decreases as the alkoxide
becomes more heavily substituted, primary to secondary to tertiary. Because bulky alkoxides are
more likely to fonn a double bond by elimination than to perfoml the desired SN2 attack, 13­
elimination can occur on substrates with an available 13 hydrogen. Milder methods, like that
shown in Scheme 3, are abundant in literature and each addresses a unique problem associated
with a specific reaction. The drawback of many of these reactions is that they take longer to
complete. Scheme 3 calls for a 48 hour period, while scheme 4 is complete in under an hour.
Protonating trichloroacetimidates as a leaving group and attacking the electrophilic
benzylic position features its own problems. The triflic acid (pKa : : :; -15), which is several billion
times more acidic than sulfuric acid, is used to protonate the imide. Having this acid in the
reaction mixture can also protonate and break many other areas with nucleophile functionality.
The harshness can be toned down by changing acids, but this again adds time to the length of the
reaction.
Benzyl esters can be prepared by Fischer esterification, the reaction of a catalytic amount
of acid with an alcohol and a carboxylic acid, or by reacting an alcohol and acid halide or acid
anhydride in the presence of a catalytic amount of base. Limitations again stem from the
presence of an acid or base catalyst. General pKa of carboxylic acids is : : :; 4.5, so the pKa of the
catalyst must be lower, which is relatively acidic for many biological compounds. Carboxylic
acids also have restricted conditions because of the ability for Claisen condensation and enolate
chemistry to occur.
2-Benzyloxy-l-methylpyridinium Trifluoronlethanesulfonate (BnOPT) (4) was
developed as a reagents capable of producing benzyl ethers upon heating in the presence of an
alcohol substrate. JO,ll,12,}3 BnOPT was made in two steps (Scheme 9). First, benzyl alcohol was
reacted with 2-chloropyridine to generate 2-benzyloxypyridine (5) in a SNAr reaction. 2­
7
Benzyloxypyridine was then reacted with methyl triflate to generate BnOPT in an SN2 reactio.
BnOPT is a bench stable, crystalline salt easily stored at room temperature under an inert
atmosphere.
KOH, BoOH
18-C-6,Pb~e.
reflux
~
BoO
~I
~
)l~)
---..-.BoO
O°C - rt 86-91 %
N
95%
1.1 MeOTf
tolueoe
5
N GOTf
4 I
Scheme 910
Benzylation of alcohols occurred most efficiently with magnesium oxide present as an
acid scavenger in ratios with BnOPT as shown above. The reaction can be performed in one vial
under argon with heating. The table below (Table 1) illustrates the success of the reagent both in
installing the benzyl protective group and in retaining the structure of a broad array of substrates.
Scheme 10 13
R-OH
2 eq. BoOPT
2 eq. MgO
..
R/
PbCF3, 83°C, 1 day
Entry
ROH
MeO~OH
-
I:
ROBn
#
0
114
O~
#
YieldQ
6
85%
44%
0
5
MeO~OBo
-
Me
Me
Me
Me
I:
214
~OH
7
~OBn
~e
8
314
MeO~O~OH
9
MeO~O~OBo
10
Piv ~
~e
Piv ~
tI ?-t-Bu
414
tI ?-t-Bu
11
TBDPSO
o
N
\
OH
13
H
PbO,PP~
P-O
OH
6 16
II
15
~2~e
o
N
\
OBo
14
75%
16
73%
H
PbO,PP~
p-o
ODo
II
0
o BoO'"
a
95%
TBDPSO
f)C~e
15
12
B00-<;=O-0-I-BU
H0-<;=O-0-t-BU
5
93%b
"'OBo
BoO'\ '
-"OBn
OH
OBo
Yields eStimated from I H NRM spectroscopy. tJ Isolated Yield of pure product. Table 1 8
Each of the examples in Table 1 displays some benefit of using BnOPT over traditional
methods. Entry 1 features none of the racemization that could occur under Williamson ether
synthesis conditions. Entry 2 is possible, where using the hindered, tertiary alkoxide to attack a
benzyl synthon would be very hard to do as the tertiary alkoxide is a poor nucleophile and is
more like7- to perform ~-elimination. Entry 3 features no fragmentation at either of the 2 ether
moieties. I Use of BnOPT was reported to be the only successful method for benzylation of 11 in
enrty 4.14 4 was successful in benzylating 13 at the desire location in spite of the presence of a
nucleophilic lactam moiety. Entry 6 could be benzylated by 4 with no formation of cyclic
16
phosphates which would occur under Williamson ether synthesis conditions.
Optimal conditions for benzylation of carboxylic acids using BnOPT are shown above
and a table showing the success of this procedure is shown below (Table 2). Of particular note,
by using Et3N as a base, it is possible to selectively benzylate a carboxylic acid over an alcohol. 17
This was discovered during a base screen undertaken during the optimization of the reaction. The
base screen had to be conducted because MgO was much less effective for benzylation of
carboxylic acid than for alcohols. Indeed, using no base was more effective than MgO. 17 A
dibenzyl ether byproduct also formed during the reaction. 17 Bases were tested both for efficiency
and minimization of byproduct, where K 2C03 was the most efficient base but Et3N gave no
byproduct. 18 This dual role of weak base to activate the carboxylic acid and phenylcarbeniun1
scavenger is the reason Et3N was used over K2C03.17
0.
Scheme 11/7
RADH
Entry
1
2 eq. BnDPT
2 eq. Et3N
PhCF3, 83°C, 1 day
#
ROOBn
#
C>-CD2H
17
C>-CD 2Bn
18
HD
I~
( J C 02H
I ~
N
H
N
[}-CD2H
19
Boc
/N~CD2H
-
--
""""'DH
n,./'I· . ...--D .Co..,H
20
81%b
( J C 02Bn
21
23
I ~
22
N
H
N
[}-CD2Bn
H
5
~
HD
86%
24
H
25
Boc
Yield
98%
91%a
H3COOC02Bn
H3COOC02H
4
RADBn
ROOH
2
3
0.
•
/N~CD2Bn
-
--
""""'DH
n,./'I· . ...--D .CD.,Bn
91%
26
>99%
9
Again, each of the entries in Table 2 (above) displays a result different fron1 what would
be expect using more common methods. The cyclopropane ring remains unbroken in entry 1,
which is significant because of the amount of strain present in this highly reactive structure.
Entry 2 demonstrates that, by using Et3N, it is possible to selectively benzylate carboxylic acids
over alcohols. Entries 3 and 4 shows benzylation of the carboxylic acid with some electron
density drawn away and no benzylation occurring at the nitrogen of the ring. Entry 5 shows
benzylation of a carboxylic acid over an alcohol, no racemization, no benzylation of the nitrogen,
and no loss of the Boc group, which would be removed under strongly acidic conditions found in
some common methods. Entry 6 shows a quantitative yield with no disruption of the many ether
moieties or racemization. Strong base would cause heavy fragmentation in 27.17
For all the utility and efficiency displayed above, BnOPT is not without its own unique
set of problems. The salt is insoluble in most organic solvent, so the reaction only occurs at the
surface where the solvent containing the substrate interacts with solid BnOPT. The reaction also
proceeds best at roughly 80°C, when the salt melts and mixing can occur slightly more
efficiently.12 This temperature limits possible substrate to compound that can withstand the
temperature. Reaction efficiency is also limited from tertiary alcohols and phenols. That being
said, using BnOPT made it possible to benzyl ate some compounds that previously lacked
methods.
10
1.2 Mechanism
Figure 2 (below) shows the extreme boarders of reaction pathways that the benzylation
reaction could occur along. In an SN1 reaction, 4 would break apart at the weak bond (shown in
red) between the benzyl cation and the oxygen at the 2 position in the pyridine ring. The benzyl
cation would then be attacked by alcohol, forming the benzyl ether. 1-methyl-2-pyridone (29)
would be generated as a byproduct as electrons push around the ring to neutralize the charge on
nitrogen. The SN2 pathway would occur with the alcohol attacking the electrophilic benzylic
position first and ejecting 29 second. In the SN2 pathway, the benzylic position is made
progressively more reactive as temperature is increased, whereas decomposition is the thermally
dependant portion in SN 1. The true reaction probabillies somewhere between SN 1 and SN2 on a
linear spectrum, with more SN 1 character than SN2.1
~O
V
4
~
~
/
R/
o~
+
N GOTf
I
f)
~
/
o
N
I
29
Figure 212
1.2.1 Supporting evidence
Several observations of phenomena support the mechanism above. The supporting
evidence is described in sections below.
4 has been shown to be a successful reagent for Friedel-Crafts alkylations (Scheme 12).18
Generic Friedel-Crafts
Scheme 12 18
4 undergoes thermolysis producing a benzyl cation and I-methyl-2-pyridone. 18 An aryl species
attached to an electron donor can then attack the strongly electrophilic benzyl cation and form a
11
new carbon-carbon bond. 29 can then deprotonate the aryl species. This shows the same general
behavior as the alunlinum chloride complex used to generate a cation in this general Friedels
Craft scheme (Scheme 12). While Friedel-Crafts alkylation typically features strong Lewis acids
to generate the cation, this reaction is acid free. The fact that Friedel-Crafts can occur using this
method shows the strong SN 1 character of the mechanisnl/ 8 For Friedel-Crafts to occur, the
strength of the bond highlighted in mechanism 1 must be negligible so the cationic character of
the benzylic position is not stabilized. The success of this reaction is displayed in Table 3.
Scheme 14 18
V
O
4
//
Entry
ED{ )
~
5-10eq.
'­
80°C, 24 h
N GOTf
I
Arene
6
//
2
a
I
//
//
Yielda (ratio)b
&Bn
OMe
//
OMe
100 (12:88)
OMe
Ol)
0
.
Ol)
ED­
Product
OMe
1
•
//
43
//
I
YIelds refer to Isolated product judged to be >95 Yo by H NMR spectroscopy. AI) comounds provIded
characterization data in accord with the literature reports. b Regioisomer ratios estimated by I H NMR.
0
Table 318
The entries in Table 3 show the results of using 4 as a reagent for performing Firedel­
Crafts alkylation. Entry 1 is a typical example with donor groups present at both ortho positions.
Entry 2 has alkyl donor groups at both ortho and the para position. Entry 3 features a bromo
group in the ortho position, which is slightly deactivating, but the reaction still proceeds fairly
well. Entry 4 shows that the reaction can proceed without any activation, using only benzene. 18
Another piece of evidence for the predominantly SN1 behavior of the mechanism is the
difference in reactivity of generating a methyl cation verses a (-butyl cation from analogous
substrates (30 and 31).
..
)(
,~
o
30
N GOTf
I
~~
o
N GOTf
31
I
-~
Figure 3
Other members of the research group have explored both reagents to gauge the utility of the
reagents in protection chemistry. Observed results have shown that methyl groups cannot be
transferred through this method ,even when stirred in the presence of simple alcohols at 83°C for
24 hours.19 (-Butyl groups can be transferred at room temperature or below in less than 3 hours
(Table 4).20 This evidence supports SN 1 because the cation intermediate would be extremely
unstable for a methyl group, but relatively stable for a (-butyl group.
12
~D
o
Scheme 15 20
N
+
ROH
1 eq
VO
H
1
/o~ ~OH
2
0
· R'ok
PhCF3
O°C 1 hour, to 23°C 90 min
RO-tBu
Yield
Vo~
I~
90%
/o~o~°i<
92%
ROH
Rnx
1.3 eq. MeOTf
Table 4ILU
Adding an electron donating group to the benzyl ring (Reaction A of Scheme 16)21 pushes
electron density into the ring and helps stabilize the positive the charge of the benzyl cation. This
stabilization enables decomposition to occur at a lower temperature, ;: : ; 0°C. 21 Alternatively,
adding an electron withdrawing group, such as a halogen, destabilizes the cation and raises the
reaction temperature (Reaction C of Scheme 16).22 In the case of halogens, the temperature
increases from 80°C to 100°C. The magnitude of the change created by adding and electron
donating or withdrawing group differentiates between an SN2 and SN 1 mechanism according to
the Hammett equation; the larger the difference between electron donating and electron
withdrawing groups, the more cation character is displayed.
~O
X
~
~
N GOTf
I
X = CI, Br, I
~O
V
~
~O
MeO~ N GOTf
I
~
~
GOTf Scheme 16
When strong electron withdrawing groups are placed in meta positions on the pyridine ring
of 4, decomposition to give the benzyl cation occurred at a reduced temperature, ;: : ; 60°C./ 9 While
this has benefits for the utility of the reaction because it becomes possible to use more sensitive
substrates as the reaction temperature lowers, the electron withdrawing groups make 5 a poorer
nucleophile and it becomes harder to generate 4 from reacting 5 with MeOTf (Scheme 9).
13
1.3
Summary
The literature and discussion presented in chapter 1 has demonstrated the utility of 4 as a
reagent for mix-and-heat benzylation of oxygen nuc1eophiles in mildly basic conditions.
Conditions for benzylation using 4 are comparatively mild because the benzyl cation is produced
through thermolysis. Mechanistic extremes for the reaction have been defined and experimental
evidence has been presented to support the supposed tendency of the mechanism within those
extremes. 4 has been used as a benzylation reagent successfully where no other methodology
would work. Because 4 decomposes by them10lysis, it should be possible to generate other
carbocations the same way. Experimentation has already shown that methyl cations cannot be
transferred through this method and that t-butyl cation can be transferred extremely well. The
allyl group is another common alkyl protection group used for oxygen nuc1eophiles. It should be
possible to transfer an allylic cation through an analogous reagent (Figure 4).
~O
V
4
~
N 80Tf
I
AT
~j;J
o
1
N
I
80Tf
Figure 4
14
Chapter 2: 2-Allyloxy-l-methlpyridinium Trifluoromethanesulfonate and Derivatives
2.1
Theory
The allyl group has significant utility as a protective groups across a wide range of
substrates/ Allylic cations are more stable than methyl cations, so it may be possible to install an
allyl cation with a reagent similar to 4. However, allyl cations are more unstable than benzyl
cations and installing allyl groups as protection groups can require harsh methods.
2.2
Allyl Esters and Ethers
Allyl esters and ethers are both particularly important as protective groups in biological
synthesis of carboxamide drug precursors (Scheme 17)1,23 and glycopeptides (Scheme 18)1,24
because of the stability exhibited under nloderately acid or basic conditions and because of the
potential for selective removal of the protection group under mild conditions. 25
o
Rl.JlO~
Pd(PPh 3)4
PhSiH3
Scheme 1723
In Scheme 17, the allyl ester protection group is converted directly to a dialkyl amide through
use of Pd (0) catalyst and phenylsilane. The reaction can be carried out in one step at room
temperature with primary and secondary amines giving high yields with high purity.23 This
shows the value of the allyl protection group as a synthon.
Z
\
BnO~O\ /Ser: ~
BnO~O\
BnO~OH
OBn
1. NaH
-2-.-C-C-I-C-N-3
BnO~
BnO--=-~ l
BnO 0
Z-Ser-OAII
r
BnO~
0
OBn
+
CCI3
HN
BnO~\
BnO~
BnOSer,
/
Scheme 1824
0
~
Z
In Scheme 18, an allyl group is used to mask a hydroxyl group in Z-serine before reacting serine
with the trichloroimidate to generate the two serine glycosides shown. 24 The two isomers could
then be separated by chromatographic methods. 24 This method also worked for threonine. 24
Allyl ethers can be synthesized in one step under neutral conditions using carbonic acid
allyl ethyl ester and a catalytic amount of palladium (Scheme 19).26
15
65°C, 4 h, 700/0
Scheme 1~6
The reaction occurs preferentially at the anomeric hydroxyl,26 making this particularly useful in
modifying monomers of carbohydrates before polymerization. The method is also effective for
primary and secondary alcohols. 26 Scheme 20 shows protection of a naphthol group and
isoxazoline group by allyl bromide and potassium fluoride impregnated alumina. 27 This method
was developed to prevent the Beckmann fragmentation of the isoxazoline in typical alkylation
conditions using strongly basic metals. 28
KF-alumina
Allyl bromide
CH3CN, 80%
Scheme 2027
I~
. :
6
0
o~ ~
Alcohols can also be nlasked with allyl esters. An allyl ester can be synthesized from an alcohol
with an allyl s~nthon and carbonate. Scheme 21 displays this method being used on Boc-Asp­
Phe-NH2 (32). 9
o
N
0
H
OH
o
o
.--::
32
Scheme 21 29
N
0
.--::
H
O~
o
Allyl esters can also be generated from carboxylic acids in mild conditions using
vinyldiazomethane. 3o The method is scene here used on Cefalotin (33), a cephalosporin (Scheme
22).30
N=N~ DCM,80-920/0 Scheme 22 30 16
Cephalosporins are a class of antibiotic. The protective function carried out here by the allyl
group is valuable to making new varieties of antibiotic with the cephalosporin frame. Caution
should be used when attempting this method as alkyldiazo compounds are explosive. All of these
methods address unique problem associated with the reaction they were used in. Allyl esters and
ethers can also be prepared using the general methods discussed in chapter 1.
Allyl ethers are typically cleaved through SN2' isomerization, where a strong base
attacks the terminal end of the allyl protective group, followed by mild acid catalyzed hydrolysis
(Scheme 23).31
t-BuOKDMSO
R,O~
ROH
100°C, 20 min
82%
Scheme 2331
Isomerization can occur through the use of transition metal catalyst instead of strong base. This
allows for neutral cleavage conditions and adds preserved the medicinal chemistry utility of the
protective group.32Palladium can retro-insert into allyl-carbonyl bond in an allyl ester and then
recombine a different ligand with the carboxylate anion to form a new ester in a process called
transesterification (Scheme 24).25
.L
'
( Pd
\
Scheme 2425
~~
This reaction is very mild, requiring no acid, base, or heat. The cleavage is also highly selective,
poorly cleaving allyl ethers and allyl amine species. 25 The only requirement is that the ester
formed be more stable than the allyl ester, or that the allyl group be a better ligand than the
pieces it is di~lacing. Samarium iodide is another good complexing reagent for the removal of
allyl groups.3 This reaction uses bases of moderate strength, but progresses very quickly.
Isopropyl amine is quite basic (pKa ~ 10.6), but give quantitative yields in one minute (Scheme
25).33
c=:r0~
___
i_o_r_ii_ ___
_
i = SmI21H201Et3N, rt, 2 h, >99%
ii = SmI 21H20li-PrNH2 , rt, 1 min, >99%)
Scheme 2533
The limitations of many of these methods are similar to the limitations discussed in
chapter 1, mostly that the method requires that the substrate is able to withstand the conditions
the reaction calls for. It is worth noting that reactions with allylic cation character in an
intermediate will have a higher transition energy than the benzyl intermediate, but less problems
with steric hindrance.
17
2.3
AUyloxypyridinium Salts and Derivatives
Because allyl and benzyl structures have similar properties, it should be possible to install
each as a protective group using similar methods. Allyl cations are less stable than benzyl cations,
but are also less sterically hindered. There is also the possibility for SN2' chemistry to occur at
the terminal carbon when changing from the benzyl group to the allyl group.
2-allyloxypyridine (34) can be prepared by reaction 2-chlropyridine with allyl alcohol in
the presence of potassium hydroxide and 18-crown-6 ether (Scheme 26).34
CI
J)
N~
o
KOH, 18-C-6
~OH
Toluene, reflux, 1 day
95%
~O)lN)
-
M~Tf ~ ~
--------
0
1
34
N
I
GOTf
Scheme 26
Unlike BnOPt, 1 is not a crystalline salt. 1 is amorphous and adsorptive, so 1 is generated in situ
for each reaction to avoid adding impurities to reactions. 34
My research began with testing the effectiveness of 1 as an allylating agent against
hexanoic acid and benzoic acid. The reaction was then being done with Et3N as a base because it
was the best base for carboxylic acids in the benzyl methodology.17 Here however, Et3N is
believed to be outcompeting the carboxylates as nucleophiles. Because of this potential for
competition, another base screen investigation was begun as described above. The results of the
investigation are shown below in Table 5. K2 C03 was the best base out of those tested with
DBU also being noted for not allowing any byproduct to form. DBU does not sufficiently
activate the carboxylic acid to prevent methyl benzoate from forming, so K2 C03 is still more
highly recommended.
Scheme 27
0
c{OH
Base
None
K2 C03
NaHC0 3
M&O
Et3N
Lutidine
DBU
DIPEA
~
. ~~
I ®~
o
I
N
I
0 0 Tf
+ Base
PhCf'3Io.5J\oI), 104°C, o\o'ernigbt
0
c{O~
Ih
Products (%)
Allyl
Benzoate
67
85
50
27
63
13
80
53
Methyl
Benzoate
11
",0
----0
3
6
----0
20
23
Total
Recovery?
Byproduct
22
10
50
72
23
47
----0
23
Benzoic Acid
",0
5
----0
....,0
2
40
----0
nJO
Yes
Yes
No....,77%
Yes
Yes
Yes
Yes
Yes
ThIS table gives ratIOs of product formed based on mtegratlon of I H NMR of an Isolated, crude product. Table 5 18
Methyl ester was being created along with the desired allyl ester. Methyl ester could be
created from two sources in reactions generating 1 in situ (Figure 5), the methyl attached to the
nitrogen of the pyridine ring or directly from methyl triflate.
~
~O
~----
~
I
N
~.
(0
GOTf
Me-OTf
R~
..
Figure 5
Of the two,. methyl triflate is the more reactive, but both are comparatively reactive to the allyl
site if 1 does not decompose. Not only is methyl triflate a highly reactive source of a methyl
cation, it is also extremely toxic and carcinogenic. Finding a way to handle methyl triflate less
would increase the appeal of this reaction and remove one possible route of generating unwanted
methyl ester.
Because decomposition of 1 is reliant on temperature, the logical step would be to crank
up the heat. The reaction was already being run at 104°C, roughly the boiling temperature of the
PhCF3, so another screening to find a replacement solvent had to take place. Xylenes and
chIoro benzene were both tested as replacement solvents for their higher boiling points. The
results are shown below in Table 5. The xylenes mixture was unsuccessful as a replacement
solvent because the reagents dissolved even less in xylenes than in PhCF3. Chlorobenzene was a
success and showed better decomposition of 1. During the solvent trials, it was also noted that a
reduction in excess molar ratios of 1 and base would nlinimize the amount of byproduct from
Table 4 that formed. A clear structure of this byproduct was never obtained and the byproduct
would blacken when exposed to air. Based on these two observations, it is hypothesized that
remaining allyl cation would polymerize into a branching chain with the aid of remaining
carbonate.
Solvent
Temp ee)
Improvement (YIN) I
PhCF3
100
Orig.
Xylenes
100
No
Xylenes
130
Yes
Chlorobenzene
100
No
Chlorobenzene
130
Yes
Chlorobenzene
125
Yes 2
Improvement meant either an mcrease ill crude recovery of allyl ester Without an
increase in impurity, or a decrease in methyl ester and byproduct formation without
a decrease in overall yield. 2 This result was more successful than the previous trial
after changing ratios of reagents (Table 6).
Table 5
19
Ratiol Ratio 2 Ratio 3
Reagent
Benzoic Acid
1
1
1
2
1.2
1.2
34
MeOTf
2.4
1.2
1.3
Base
1.2
1
2
O.SM
O.SM
0.5M
Solvent
Table 6
1 has proven capable of transferring an allyl group, but fall short of the initial goal in two
categories: mild conditions and reliability. Decomposition of 1 was approaching 100% at 135°C,
but the products of the reaction also has a tendency to decompose at this high temperature. The
reaction was 55°C hotter than the benzylation reaction and still not at completion. The reaction
was also unreliable. There was a window of ± 10% yield to consecutive reactions based on the
extent of decomposition of the salt and the efficiency of mixing. The source of allyl cation was
changed from 1 to 2-allyloxy-1,4-dimethylquinolinium trifluoromethanesulfonate (AOdMQT)
(2) to deal with these problems. 2 can be prepared from 2-chloro-4-methylquinoline (35) and
allyl alcohol using a procedure analogous to that shown in Scheme 26.
in
o
N
36
I
~
1)
o
N
37
I
Figure 6
2 is a bench stable, crystalline salt that can be stored under inert gas and added as needed to
reactions. Changing from 1 to 2 lessens the need to handle methyl triflate and removes one
pathways for the generation of methyl ester. The extra ring in 2 adds enough stability to the
structure to make 2 a solid crystal at room temperature. The ring may also increase solubility of
the triflate salt in organic solvents. The added stability also allows the reaction to proceed faster
and at a lower temperature of 104°C. The change removes two large problems, but adds one
small inconvenience. 1,4-dimethyl-2-quinolinone (36) is not water soluble and must be separated
from the desired product by flash column chromatography, whereas I-methyl-2-pyridone (37)
was water soluble. By comparing results from crude IH NMR spectroscopy, it was found that the
change in reagent increased repeatability and efficiency of reaction.
At this point, a colleague continued to work on carboxylic acids as I moved to beginning
the work on alcohols. Another base screen like those described above found that K2C0 3 was
again the best base to use with 2. The screen was ran again because BnOPT could select for
carboxylic acid or alcohol depending on the base used. I8 TLC and IH NMR both showed
complete consumption of the salt, so a solvent screen for higher temperatures was deemed
unnecessary. After implementing changes discovered from results of kinetics experiments run on
carboxylic acids, this method will be ready to test against a broad array of alcohols to test utility
and develop further.
This discussion has shown that 2 is an effective reagent for synthesizing allyl esters under
mild conditions for use as protective groups when used as discussed above. The method is mild,
efficient, and reliable, fulfilling three of the goals in the installation step of protection group
20
theory. Other methodology and literature has been referenced and discussed detailing the merit
of allyl protection groups in the transformation and cleavage steps of protection chemistry, which
this method will not interfere with. The hypothesis that 1 and 2 would be effective reagents for
allylation of oxygen nucleophiles has been proven true.
21
Appendix A: Experimental Procedures
General Notes
All glass was dried overnight in an oven at and cooled in a desiccator. All reaction were
set up with positive argon pressure. Reflux reactions were allowed to reflux with open
atmosphere.
Preparation of 2-aUyloxypyridine
7.0 g of2-chloropyridine was reacted with 5.0 mL of allyl alcohol in 60 mL of toluene in
a 250 mL round bottom 3-neck flask with a reflux column at 83°C overnight. The reaction is
driven by 14.5 g of freshly ground KOH pellets with 0.163 g of 18-C-6 ether to help solubility of
KOH. Completeness of the reaction can be judged by using thin layer chromatography (TLC).
With a 49: 1 hexane: ethyl acetate eluent and an h chamber for staining, the allyl group on
unconsumed alcohol and on 34 can be visually compared. Allyl alcohol had an Rf ~ 0, 34 has an
Rf~ 0.6, and 2-chloropyridine had an Rf ~ 0.3. The mixture can be isolated by a normal separate
and wash organic workup using brine and ethyl acetate. After transferring the solubilized
reaction mixture to a separatory funnel with distilled water and ethyl acetate, the mixture was
separated into aqueous and organic soluble layers. The organic layers were washed with three
measures of concentrated brine solution, which was then added to the aqueous layer. Three
measures of ethyl acetate were then used to extract any remaining organic material from the
aqueous layer and added to the organic layer. The organic layer was dried over Na2S04, vacuum
filtered, and rotovapped to dryness for a crude yield 8.203 g (98.3%). The crude mixture is
purified by purification by Kugelrohr distillation, giving 7.932 g of pure product (95% yield).
The purity of34 can then be tested with IH NMR spectroscopy. Methyl triflate can then be added
to 34 to generate 1, best done at O°C to minimize undesirable side reactions.
Initial Base Screen of AOPT
Benzoic acid (80 mg/ 0.6551 mmol, 1 eq.) was reacted with 34 (176.5 J.lL, 1.310 mmol, 2
eq.), MeOTf (172.2 J.lL, 1.572 mmol, 2.4 eq.), and desired base (2 eq.)in 2.5 mL of dry
trifluorotoluene in a 5 mL reaction vial or a 5 mL round bottom flask at 104°C overnight. The
reaction was separated after completion using dichloromethane and brine. Separation procedure
same as above, with DCm replacing ethyl acetate. Completion could be tested with TLC in the
same eluent as 34, where allyl benzoate and 34 had an Rf~ 0.3, nonpolar particulate like grease
had an Rf~ 1, unconsunled 1 and benzoic acid had an Rf~ O. Unconsumed benzoic acid did not
appear in a KMn0 4 stain, but did appear under a UV lamp, as did allyl benzoate.
Solvent Screen of AOPT
The same reaction scheme and setup were used as discussed in the base screen section
(above). This time temperature and solvent were varied instead of base, which was K2C03 for all
trials. Solvents were tested both at 104°C and at reflux. Improvement was based on a qualitative
comparison of 1H NMR spectra of crude reaction mixture isolated after workup in a separatory
funnel. Ratio of reagents was also varied and ratio 2 from Table 6 eventually replaced ratio 1 for
lack of byproduct generated.
22
Base Screen of AOdMQT
The base screen of2 proceeded as outline for the base screen of 1, with the exception that
the lower molar ratios of reagents discussed in the solvent optimization section were used in
place of the initial molar ratios (Table 6, ratio 3 was used in place of ratio 1) and the amount of
benzyl alcohol used each trial was dropped to 40 mg (.328 mmol). No MeOTf was used, as 2
was a prefonned salt. Separation and purification procedures are the same as the base screen for
compound 1.
23
Appendix B: Spectral Data
2-8 lIyloxypy rid ine
Prepared according to procedure listed under preparation of 2-allyloxypyridine in Appendix A.
2-allyloxypyridine (34) (7.9319 g of clear, colorless oil, 95% yield) (--- 97% purity); IH NMR
(CDCh, 400 MHz) a: 4.85 (d, J = 5.52 Hz, 2 He), 5.26 (dd, J = 10.64 Hz, 1.08 Hz, 1 Hh), 5.40
(dd, J = 17.24 Hz, 1.48 Hz, 1 Hg), 6.11 (nl, 1 Hf), 6.77 (d, J = 8.08 Hz, 1 Hd), 6.8643 (t, J = 6.04
Hz, 1 H b), 7.57 (dt, J = 8.44 Hz, 6.96 Hz, 1.76 Hz, 1 He), 8.15 (dd, J = 4.76 Hz, 2.02 Hz, 1 Ha).
Peaks of lower ppm on spectrum are persistent impurities, "'3.5% of signal.
Allyl benzoate
Product of all testing/screening procedures in Appendix A.
Allyl benzoate. (white crystal); IH NMr (CDCh, 400 MHz) a: 4.83 (d, J = 5.48 Hz, 2 Hd), 5.30
(dd,J= 10.46 Hz, 1.3 Hz, 1 He), 5.42 (dd,J= 17.24 Hz, 1.48 Hz, 1 Hr), 6.05 (m, 1 Hg), 7.45 (t,J
= 7.68 Hz, 2 Hb), 7.57 (t, J = 7.32 Hz, 1 Ha), 8.07 (d, J = 7.32 Hz, 1 He). Singlet present
downfield is from water contamination in deuterated chloroform solvent.
24
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base was best suited in the base screen for allylating benzoic acid with 1. The procedure is
described in the experimental section. Each spectra is marked with arrows to highlight
diagnostically releveant areas of the spectrum. The blue area allows us to judge the completeness
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be used to judge how much methyl ester byproduct was also developed.
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The next spectrum, MHB_I_39_Crude, was from the solvent screen portion of the
experimental procedures. This reaction again used PhCF3, but at a temperature of 125°C. The
base was K2C03, like the spectrum MHB_I_14_Crude. By comparing differences in the
relationship of the peaks highlighted by the red and green arrows in each spectrum (14 and 39), it
appears that the increased temperature has increased consumption of 1, but has also increased
fragmentation of the desired product. The relationships among peaks in MHB_1_39_Crude
suggests that decomposition is occurring to some degree. This degradation is an example of the
limitations of increasing temperature, as temperature increases, molecules fall apart more readily.
36
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The following spectrums, MHB_I_{43&46}_Crude, are initial tests of2 with K2C03 as a
base and PhCF3 as a solvent at 104°C. MHB_I_43_Crude was perfonned with o-chlorobenzoic
acid and MHB_I_46_Crude used oleic acid. The red and green peaks from the above spectra are
indicative of the allyl group and are used to judge the success of the reaction.
~
N
.
..;
.
....
t.
...
~
9.0 X : parb per MilHoD : IH
10.0
I '
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r--r--r--r-- .... r--r-- ....
i~~iai£!a
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Procedure: Base screen of
~~ AOdMQT *ortho­
chlorobenzoic acid replaces benzy I alcohol Solvent: PhCF 3 ;! -j Temperature: 100°C Base: K2C03 Ratio of reagents: Ratio 3 MBB_I_43_Cl'llde-3.jdf
:~ I
::1.
~
w
OC)
~ l "'lll
I
!~
c:>
~
•
~.
~
:l
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t
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i T
t "eel
X : para per Million: lH
10.0
, .... \
8.0
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r--r--r--r--r--r--r--r--
l-;l-;VI"l"l"lI'!"1
~s~~i~~!
II IIJ\I
:; ,..,"ti
Procedure: Base screen of
AOdMQT *oleic acid replaces
~ benzyl alcohol Solvent: PhCF 3 Temperature: 100°C Base: K2C0 3 i ~ Ratio of reagents: Ratio 3
] MHB_I_46_cr.de--4.jdr
~
..
....N
~~111
~!~
:;!~~
5.0
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6)\\ )f\\
..
~
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A
....
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NNNN .... N
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40
The following spectra are crude results of an initial base screen of AOdMQT The
procedure is explained above. Again, the red and green arrows are indicative of the allyl group
and are used to judge completeness of the reaction and ratios of desired product to byproduct
produced.
~ ~
f~
Q
II!
g
Q
~
Q
~
Q
~
.....
=
Q
i
Q
q
~
!
~
Q
~
=
co
X: parta per Million: IB
~ Ratio of reagents: Ratio 3
Base: No Base !l Temperature: 100°C ~ Solvent: PhCF 3
AOdMQT ...................................
i~~E;~~5
":"l"l"l"l f'1
!1Procedure:
Base screen of MHB_I_!lit _r.l'llde-3.~r
'0
i"!
./.A
6.0
~.".,,111
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)\ \ 5.0
(S
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f')
... ...
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..... ...!:; I"i g
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M
S
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....
or,
III
:s
=
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~
f'1
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0.
Q
I
~
Q
cD i
~
........ C!
~
~
i
=
'=!
~
~
=
~
r-­
=
i
~
=
S
j
X: part. per Million: IH
Procedure: Base screen of
AOdMQT
!1 Solvent: PhCF3
Temperature: 1000 e
Base: MgO
Ratio of reagents: Ratio 3
i
i
j
=
~
'=!
E~~5~~
""""1"1"1
.... r--r--r--r--r-­
~
l~
on
..~
...
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~
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Ir J
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M
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N
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on
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on
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a
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.,J::..
C
J
i
9.0
X: partl per Million: IB
10.0
8.0
1"-1"-1"-1"-1"-1"-1"-
~~~~~~~
:!""I::I"-t:l o ."
u ' ~/~ 7.0
O)'i~_ p~'!o"1qt""."'''''''''''11h~/'V«'·~
i
~
Procedure: Base screen of AOdMQT Solvent: PhCF 3 Temperature: 100°C ~ 1 Base: K2 C03 ~ Ratio of reagents: Ratio 3
MHB_I_61_Crude-4.Jdr
...
..
;
r;:~""'"
~i1I~~
.":1.".,,
-~.
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44
References
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Hoboken, NJ, 2007.
2 Brummond, K.M.; Sang-phyo, H. A Formal Total Synthesis of (..)-FR90 1483, Using a Tandem Cationic Aza-Cope
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14 Stecko, S.; Solecka, J. Synthesis of casuarine-related derivatives via I ,3-dipolar cycloaddition between a cyclic
nitrone and an unsaturated 'Y-Iactone. Carbohydrate Res. 2009, 344, 167.
15 Legeay, lC.; Langlois, N. Nitrone [2+3]-Cycloadditions in Stereocontrolled Synthesis of a Potent Proteasome
Inhibitor: (-)-Omuralide.1. Org. Chem. 2007, 72, 10108.
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phosphate and their Behavior as Stabilizers of Enzyme Activity at Extreme Temperatures. Angew. Chem.
Int. Ed. Eng!. 2009,48,4158.
17 Tummatom, I; Albiniak, P.A.; Dudley, G.B. Synthesis of Benzyl esters Using 2-Benzyloxy-1-methylpyridinium
Tritlate. J. Org. Chem. 2007, 72, 8962-8964.
18 Albiniak, P.A.; Dudley, G.B. Thermally generated phenylcarbenium ions: acid-free and self-quenching FriedelCrafts reactions. Tetrahedron Letters. 2007,48, 8097-8100.
19 Tayyebeh Bakhshi, current group member.
20 Anna Salvati, current group member.
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25 Jeffrey, P.D.; McCombie, S.W. Homogeneous, Palladiwn(O)-Catalyzed Exchange Deprotection of Allylic Esters,
Carbonates, and Carbamates. J. Org. Chem. 1982, 47, 587.
I
45
Lakhmiri, R.; Lhoste, P.; Sinou, D. Allyl ethyl carbonate/palladium (0), a new system for the one step conversion
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27 Yin, H.; Franck, R.W.; Chen, S.-L.; Quigley, GJ.; todaro, T. A convergent Synthetic Approach to a Chiral,
Nonracemic CDEF Analogue ofNogalamvcin. J Org. Chern. 1992,57,644-651.
28 Jager, V. The Tenth International Congress ofHeterocyclic Chernistry, 1985.
29 Kunz, H.; waldmann, H.; Unverzagt, C. Allyl ester as temporary protecting group for the ~-carboxyl function of
aspartic acid. Int. J Pept. Protein res. 1985, 54, 751.
30 Waddel, S.T.; Santorelli, G.M. Mild prepatation of cephalosporin allyl and p-methoxybenzyl esters using
diaoalkanes. Tetrahedron Lett. 1996,37, 1971.
31 Gigg, J.; Gigg, R. The allyl ether as a protecting group in carbohydrate chemistry. J Chern. Soc. C. 1966,0,86.
32 Corey, E.J.; Suggs, l.W. Selective Cleavage of Allyl ethers under Mild Conditions by Transition Metal Reagents.
J Org. Chern. 1973,38,3224.
33 Dahlen, A.; Sundgren, A.; Lahmann, M.; Oscarson, S.; hilrnersson, G. Sml2lWater/Amine Mediates Cleavage of
Allyl Ether Protected Alcohols: Application in Carbohydrate Synthesis and Mechanistic Considerations.
Org. Lett. 2003, 5, 4085-4088.
34 Previous work of someone in Albiniak research group.
26