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Topic: Enantioselective Olefin Addition Reactions
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1
OLEFIN
Olefins are reactive functional groups because of their C=C π bond. They can be readily transformed to
other functional groups by adding suitable reagents across the double bond. There are two general types of
addition to olefins: electrophilic and nucleophilic.
Frontier molecular orbitals of transition structures in electrophilic and nucleophilic addition to olefins
Houk Science 1986, 231, 1108.
In this chapter, epoxidation, dihydroxylation, hydroboration, cyclopopanation and hydroamination
will be discussed in detail.
1
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2
EPOXIDATION
2.1
Diastereoselective Epoxidation
2.1.1 Steric effects
Epoxidation occurs on the less hindered face
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Carreira C9.2; Brown JACS 1970, 92, 6914.
2.1.2 Chemoselectivity
Epoxidation occurs on the more nucleophilic alkene
Carreira C9.2; Vandewalle Tetrahedron 1983, 39, 3049.
2.1.3 Directing group effects
Hydrogen bonding or metal coordination leads to directed reactions.
Hoveyda Chem. Rev. 1993, 93, 1307
Stereoselective allylic alcohol epoxidation via “butterfly” mechanism.
Amides direct epoxidation as well.
Hoveyda Chem. Rev. 1993, 93, 1307
Stereochemical outcome of directed epoxidations of acyclic , allylic substrates:
2
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Carreira C9.2
2.2
Enantioselective epoxidation
2.2.1 Sharpless asymmetric epoxidation of allylic alchohols
 Barry Sharpless was awarded the 2001 Nobel Prize for his contributions in stereoselective
oxidations on olefins (epoxidation, dihydroxylation).
 His titanium-tartrate complexes with t-BuOOH readily epoxidize allylic alcohols catalytically and
enantioselectively.
 In his subsequent reports, Sharpless found that addition of 3Å or 4Å increase the scope of Ti(IV)catalyzed epoxidation and decrease the catalyst loading to 5-10 mol%.
Sharpless JACS 1980, 102, 5974; Sharpless JACS 1987, 109, 5765.
Application of Sharpless asymmetric epoxidation to total synthesis of Amphotericin B and Venustatriol
3
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Nicolaou JACS 1988, 110, 4672.
Carreira C9.3; Sharpless JACS 1987, 109, 5765; Corey TL 1988, 29, 3171.
2.2.2 Yamamoto’s vanadium-catalyzed enantioselective epoxidations
Epoxidation of allylic alcohols with Vanadium and bishydroxamic acid complex is highly enantioselective.
Other great features include mild reaction conditions, 1 mol % or less catalyst loading is needed and
aqueous t-BuOOH(TBHP) can be used as achiral oxidant.
Yamamoto ACIE 2005, 44, 4389.
Recently, Yamamoto reported catalytic enantioselective epoxidation of homoallylic and bishomoallylic
alcohols (more challenging substrates) using Zirconium(IV) and Hafnium(IV) with bishydroxamic acid (BHA).
- Hafnium(IV) catalyzed system gives better yield and ee’s.
- Works very well with homoallylic alcohols.
- Bishomoallylic alcohols show lower reactivities and require higher catalyst loading (10 mol%).
4
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Yamamoto JACS 2010, 132, 7878.
2.2.3



Jacobsen and Katsuki’s Mn-salen complex catalyzed epoxidations
Unfunctionalized olefins that lack the specific directing group (e.g. allylic alcohol) are limited to
enantioselective oxidation by Sharpless asymmetric epoxidation.
Because of the lack of efficient catalytic system, enantioselective epoxidation of unfunctionalized
olefins has since been a long-standing goal.
The first breakthrough in epoxidizing unfunctionalized olefins was made by Jacobsen and Katsuki
independently in 1990 (Katsuki Tet. Lett. 1990, 31, 7345 and Jacobsen JACS 1990, 112, 2801).
Chiral Mn-salen complexes povide a convenient and inexpensive procedure for efficient asymmetric
epoxidation of unfunctionalized olefins. Cis-olefins works very well for this catalysis, however, trans-olefins
tend to be poor substrates (low reactivity and enantioselectivity).
Jacobsen JACS 1991, 113, 7063.
5
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2.3
Shi’s dioxirane catalyzed epoxidation
 Complimentary to Mn-salen catalyzed asymmetric epoxidation of cis-olefins, Shi’s fructose-derived
chiral ketone enantioselectively epoxidize trans-olefin in combination with oxone.
 The first procedure Shi reported was highly enantioselective for trans-olefin, but not catalytic.
 Subsequent optimizations showed that higher pH (10.5 compared to 7-8 previously) increase the
efficiency of the ketone catalyst. At higher pH, the competing ketone decomposition pathway via
Baeyer-Villiger reaction is suppressed since high pH favors the equilibrium of intermediate 2 towards
3 (see mechanism below).
 Great enantioselectivities can be obtained with trans-olefins. Very low enantioselectivities observed
with cis-olefins.
6
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Shi JACS 1996, 118, 9806; JOC 1997, 62, 2328; JACS 1997, 119, 11224.
Synthesis of Shi’s catalyst 1 and its enantiomer.
Catalyst 1 and ent-1 both show same enantioselectivity for epoxidation reaction.
Shi JACS 1997, 119, 11224.
2.4
Shibasaki’s Lanthanoid complex catalysis
Shibasaki catalyst using La(OiPr)3 and BINOL efficiently catalyze asymmetric epoxidation of ,-unsaturated
ketones with high yields and enantioselectivities.
Shibasaki JACS 2001, 123, 2725.
7
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2.5
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Jorgensen’s chiral pyrrolidine catalysis of ,-unsaturated aldehydes
Jorgensen JACS 2005, 127, 6964.
3
ALKENE DIHYDROXYLATION
 Another great contribution of Sharpless in the field of asymmetric catalysis is his asymmetric
dihydroxylation.
 Initially, asymmetric dihydroxylation was performed with stoichiometric amounts of cinchona
alkaloids and osmium tetroxide, upon addition of cooxidant NMO or later K3Fe(CN)6, the process
became catalytic with both osmium and the chiral ligand.
 In the case with K3Fe(CN)6 as the cooxidant, the reaction is performed under biphasic conditions.
 K2OsO2(OH)4 is used as the Os source because it’s not volatile.
 Premixes called “AD-mix” containing K2OsO2(OH)4, K3Fe(CN)6 and chiral bidentate ligand were
formulated and available commercially.
 Dihydroxylation is applicable to almost all alkene substrates (see substrate scope below).
 MeSO2NH2 was found to increase the rate and catalytic turnovers of dihydroxylation. It was added to
all reaction, except in the case of terminal olefins.

8
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Sharpless Chem. Rev. 1994, 94, 2483.
Chemoselectivity of asymmetric dihydroxylation:
Application in exhaustive dihydroxylation of Squalene:
Sharpless JACS 1992, 114, 7570; Science 1993, 259, 64.
4
ALKENE HYDROBORATION
Hydroboration of alkene leads to the addition of a boron group and a hydride across its double bond. The
organoborane generated by hydroboration serves as a very useful handle for further functionalizations.
Experimentally, hydroborations are simple to carry out, they have low toxicity and the reagents used are
inexpensive and readily available.
4.1
Uncatalyzed hydroboration reaction
The uncatalyzed hydroboration is regioselective, giving anti-Markovnikov product.
Dougherty Modern Physical Organic Chemistry, C10.7, p555.
4.2
Enantioselective hydroboration
Chiral boronate ester products of alkene hydrobration are useful synthetic intermediates. These substrates
can be formed either using chiral reagents or asymmetric catalysis. Catalytic hydroboration and subsequent
oxidation to the alcohol remained as the most common reaction sequence. Transformation of the C-B bond
into C-N and C-C bonds with retention of stereochemistry significantly expanded the synthetic utility of the
catalytic enantioselective hydroboration reaction.
9
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Crudden EJOC 2003, 4695.
4.2.1 Rhodium-catalyzed enantioselective hydroboration with chiral bisphosphane ligands
4.2.1.1 BINAP
 In 1991, Hayashi reported catalytic enantioselective hydroboration of styrenes in the presence of
Rh(I) and BINAP. An intriguing feature of this reaction is the complete reversal of regioselectivity
observed in the catalytic hydroboration relative to the uncatalyzed reaction.
1.
Ph
OH
Anti-Markovnikov
product
O
BH
,
O
[Rh(COD)2]+BF4- (1%),
(+)BINAP (2%), DME, -78 °C,
2 hrs, MeOH quench
Uncatalyzed
Ph
OH
Ph
2. H2O2/NaOH
CH3
91% yield
96% ee
Catalyzed
Markovnikov
product
Crudden EJOC 2003, 4695.

The high regioselectivity observed in the rhodium-catalyzed hydroboration of styrenes was
rationalized by the formation of -benzyl complex (see catalytic cycle below).
Hayashi Tetrahedron: Asymmetry 1991, 2, 601.
4.2.1.2 C2-Symmetrical 1,2-diphosphanes
 Knochel’s chiral diphosphanes demonstrated excellent chemo-, regio- and enantioselectivity in the
Rh-catalyzed hydroboration of styrene derivatives.
10
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Knochel ACIE 2001, 40, 1235.
4.2.2 Rhodium catalyzed enantioselective hydroboration with chiral P,N ligand
4.2.2.1 QUINAP
 QUINAP is one of the P,N class of ligand that are highly successful in asymmetric hydroboration.
 The substrate scope using QUINAP is wider; moderate to high levels of enantioselectivity can be
induced on electron-rich and electron poor styrenes, vinylarenes and -substituted vinylarenes.
 Electron-rich styrenes generally give better ee than electron-poor styrenes.
Brown CEJ 1999, 5, 1320.
5
CYCLOPROPANATIONS [Reviews: Charette Chem. Rev. 2003, 103, 977-1050 and Pellissier
Tetrahedron 2008, 64, 7041]
5.1
Classes of cyclopropanation reactions
The importance of cyclopropanes is exemplified in the following ways:
- The occurrence of cyclopropanes in natural and medicinally important compounds
- The function of cyclopropanes as a mechanistic probe
- The use of cyclopropanes in key synthetic transformations including vinylcyclopropane rearrangements and
divinylcyclopropane Cope rearrangements
11
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5.2
Simmons-Smith type cyclopropanations
5.2.1 Simmons-Smith reaction overview
 Applicable to a wide range of olefins (simple, electron deficient, electron rich)
 Electron rich alkenes react faster (because of electrophilicty of zinc reagent)
 Stereospecific (cis alkenes give syn cyclopropanes and trans alkenes give anti cyclopropanes)
 Butterfly-like transition state
 Typical conditions: Zn/Cu, CH2I2, Et2O (In current procedures, Zn/Cu is often generated by the
treatment of zinc powder with a CuSO4 solution.)
Seminal publications: Simmons and Smith J. Am. Chem. Soc. 1958, 80, 5323 and ibid. 1959, 81, 4256
5.2.2
Directing effects and Modifications
 The Simmons-Smith reaction exhibits a strong directing effect and rate enhancement (with zinc
and also samarium (see Molander modification, below) when the alkene bears a heteroatomcontaining functional group, and the methylene is delivered to the face of the alkene that is
proximal to the heteroatom.
Charette J. Organomet. Chem. 2001, 702
Furukawa: Use of Et2Zn instead of Zn/Cu [to form presumably EtZnCH2I or Zn(CH2I)2] in a noncoordinating solvent
- Preferred for less nucleophilic alkenes
Furukawa Tetrahedron Lett. 1966, 7, 3353 and Tetrahedron 1968, 24, 53
Molander: Use of a samarium/mercury amalgam instead of zinc
-
Selectively cyclopropanates allylic alcohols in the presence of other olefins
12
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Molander JOC, 1989, 54, 3525 and ibid. 1987, 52, 3942
Yamamoto: Use of trialkylaluminums and CH2I2 (yielding R2AlCH2I)
-
Selectively cyclopropanates unfunctionalized olefins
Yamamoto JOC, 1985, 50, 4412
5.2.3 Use of chiral auxiliaries in the Simmons-Smith reaction
Allylic ether chiral auxiliary approach using carbohydrates:
Charette Tetrahedron Lett. 1993, 34, 7157
Acetal approach using tartaric acid derivatives:
Yamamoto JACS 1985, 107, 8254
Mash JOC 1990, 55, 2045
5.2.4 Enantioselective Simmons-Smith reactions using stoichiometric chiral additives
First reports of controlling absolute stereochemistry in Simmons-Smith reaction:
 Inoue:  15% yield and  3.4% ee using ()-menthol and IZnCH2I (JOC 1968, 33, 1767 and ibid.
2141)
 Furukawa: cyclopropanation of vinyl ethers using L-leucine as an additive (Tetrahedron Lett. 1968,
9, 3495)
 Denmark: modest enantioselectivities using (1R,2S)-N-methylephedrine-modified halomethylzinc
reagent to cyclopropanate cinnamyl alcohol (Synlett 1992, 229)
First practical report of a stoichiometric chiral additive:
Fujisawa Chem. Lett. 1992, 61
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Charette’s dioxaborolane
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
Major breakthrough by Charette in 1994: Use of amphoteric, bifunctional ligands derived from (R,R)()-N,N,N’,N’-tetramethyltartartic acid diamide and butylboronic acid.
Me2NOC
1.
O
CONMe2
O
B
(1.1 equiv)
CH2Cl2
Bu
Ph
Ph
OH
2. Zn(CH2)I2 (2.2 equiv)
CH2Cl2, 25 °C, 2 h
OH
> 98% yield, 93% ee
Charette JACS 1994, 116, 2651

Reaction proceeds well with cis- and trans-disubstituted allylic alcohols and with tetra-substituted
allylic alcohols but only with some tri-substituted allylic alcohols.

For > 1 mmol scale, DME complex, Zn(CH2I)2DME, is used due to the exothermicity of Zn(CH2I)2 or
zinc alkoxide formation (Charette JOC 1995, 60, 1081)

Extended to the cyclopropanation of homoallylic alcohols (Charette JACS 1998, 120, 11943)
Paterson Angew. Chem., Int. Ed. 2001, 40, 603
Shi’s dipeptide

In 2003, Shi reported the use of a chiral dipeptide that could be used stoiciometrically to
enantioselectively cyclopropanate unfunctionalized (i.e., lacking a directing group) olefins (in 72–
91% ee).
14
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Boc
N
H
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N
O
CO2Me
Boc
(1.25 equiv)
N
Zn
H 2C
I
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N-Boc-L-Val-L-Pro-OMe
ZnEt2, CH2I2
CH2Cl2, -40 °C, 48 h
71% yield, 72% ee
unfunctionalized olefins
N
O
CO2Me
proposed active chiral cyclopropanating reagent
Shi JACS 2003 125, 13632

In preliminary efforts, the Shi group found that by using an achiral additive (e.g., ethyl
methoxyacetate) to coordinate the zinc methylenating reagent (e.g., Zn(CH 2I)2), background
cyclopropanation could be reduced and substoichiometric amounts of the chiral ligand could be
used:
Shi Tetrahedron Lett. 2005, 2737
5.2.5 Catalytic enantioselective Simmons-Smith cyclopropanations
C2-symmetric chiral disulfonamide ligands
 Kobayashi reported in 1992 that the Simmons-Smith cyclopropanation could be accelerated by a
chiral Lewis acid. Thus, they were able to use C2-symmetric chiral disulfonamide ligands in catalytic
amounts to effect cyclopropanations in 13-82% ee.
Kobayashi Tetrahedron Lett. 1992, 33, 2575
Tetrahedron 1995, 51, 12013

Kobayashi et al. also showed that zinc may be replaced by aluminum in this reaction (Kobayashi
Chem. Lett. 1994, 177)

Denmark conducted an in-depth study of the chiral disulfonamide-catalyzed reaction and found that:
o
It is important to preform the ethylzinc alkoxide and Zn(CH2I)2
o
The reaction displays autocatalytic behavior due to the generation of ZnI2 and using ZnI2 as
an additive is beneficial to the reaction.
NHSO2Me
NHSO2Me
o
The most efficient promoter is:
o
One or two substituents on the 3-position of the allylic alcohol are well tolerated, but
substituents on the 2-position are not.
15
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Denmark Tetrahderon Lett. 1995, 36, 2215; ibid. 2219
Pure Appl. Chem. 1996, 68, 23
Angew. Chem., Int. Ed. 1998, 37, 1149
JOC 1997, 584; ibid. 3390
5.3
Cyclopropanations using diazoalkane-generated carbenoids
5.3.1
General catalytic cycle
 Metal-carbenoid cyclopropanation is a concerted but asynchronous process which involves a buildup of positive charge on one of the olefin carbons.
Salvatella and García JACS, 2001, 123, 7616
Rasmussen et al. Chem. Eur. J. 2002, 8, 177
Moser, JACS 1969, 91, 1135
5.3.2

Seminal publication
In 1966, Nozaki reported that homogeneous, chiral copper complexes could catalyze the
decomposition of diazo compounds to yield carbenoids that react with olefins to yield the
corresponding cyclopropanes with a small degree of optical activity.
Nozaki Tetrahedron Lett. 1966, 5239 and Tetrahedron 1968, 24, 3655
5.3.3

Cyclopropanation using diazomethane
Diazomethane can be decomposed by palladium to yield cyclopropane products (with good dr for
cyclic olefins but poor dr for acyclic olefins), but efforts by Denmark to perform an enantioselective
cyclopropanation using diazomethane failed likely due to decomplexation of the ligand during the
reaction.
Denmark JOC 1997, 62, 3375

Charette has studied the cyclopropanation of simple cinnamate derivatives using diazomethane with
16
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chiral bis(oxazoline)-copper(I) complexes and has achieved good to moderate ee’s. (Charette
Tetrahedron: Asymm. 2003 14, 867)
Copper: Intermolecular (and intramolecular) cyclopropanations using -diazoesters
Copper is the most effective and general metal for intermolecular cyclopropanations using diazoesters when the trans diastereomer is desired.
o In general, a bulky ester is required to maximize the trans:cis ratio.
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5.3.4


Following Nozaki’s report of a chiral salicylaldiminato copper complex in 1966 (see above), Aratani
and coworkers further developed this ligand scaffold, though generality was moderate:
Aratani Tetrahedron Lett. 1977, 18, 2599
Pure Appl. Chem. 1985, 57, 1839

Chiral, C2-symmetric bidentate bisoxazoline ligands are most widely used for enantioselective,
copper-catalyzed cylopropanations
Pfaltz Angew. Chem., Int. Ed. 1986, 25, 1005
Pfaltz Tetrahedron 1992, 48, 2143
Masamune Tetrahedron Let. 1990, 31, 6005
Evans JACS 1991, 113, 726

Bisoxazoline ligands are very effective for the intermolecular copper-catalyzed cyclopropanation of
mono- and 1,1-disubstituted alkenes.
o BHT (BHT = 2,6-di-tert-butyl-4-methylphenyl) esters can be cleaved to the corresponding
primary alcohol by reduction with LiAlH4
17
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
Preferred approach of olefin for cyclopropanation using Pfaltz ligand:

Reiser showed that furans could be successfully cyclopropanated with good ee and has applied this
methodology to the synthesis of the core of several natural products.
Reiser Tetrahedron: Asymm. 2003, 14, 765; Chem.Eur. J. 2003, 9, 260; Org. Lett. 2003, 5, 941

Intramolecular application of Evan’s bisoxalzoline-copper(I) catalyst in natural product synthesis:
Overman JACS 1999, 121, 5467

Corey’s synthesis of sirenin using a “non-traditional” bisoxazoline ligand scaffold for an
enantioselective, intramolecular cyclopropanation.
18
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Corey Tetrahedron Lett. 1995, 36, 8745

Macrocyclic cyclization cyclopropanations typically work well using CuPF 6 with Evans’ bisoxazoline
ligand:
Doyle JACS 2000, 122, 5718
5.3.5

Rhodium
For intermolecular cyclopropanation reactions using vinyl and aryl diazoesters, rhodium catalysts are
generally preferred.
Rhodium complexes efficiently decompose
unsaturated diazoaceates to yield cyclopropane
products with high diastereocontrol
[Rh2]
CO2R'
CO2R'
R
N2
R
Model for diastereoselectivity in rhodium-catalyzed cyclopropanation:

The presence of an electron-withdrawing substituent (ester) and electron-donating substituent (vinyl
group) is important for high diastereoselectivity. Alkene approaches from the side of the ester; the
developing positive charge on the more substituted alkene carbon may be stabilized by the carbonyl
oxygen.
OR
R
O
OR
OR
clockwise
rotation
O
Rh
bulky ligand

R
Rh
R
R
O
OR
Rh
bulky ligand
bulky ligand
O
For diazo compounds of the type (H)(EWG)C=N 2, diastereocontrol is generally inferior to that
obtained with copper, ruthenium, and cobalt carbenes.
Representative rhodium(II) catalysts: (“paddle-wheel”/”Schaufelrad” structure)
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Chiral carboxamidate catalyst
(Doyle)
Achiral catalyst
Chiral carboxylate catalyst
(Davies)
R
Me
O
O
O
MeO2C
Rh
Rh
CO2Me
N
O
O
O
O
O
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O
O
Me
N
Me
Rh
Rh
MeO2C
O
Me
Rh2(OAc)4
O
N
O
H
O
N
O
SO2
N
O
Rh
Rh
O
CO2Me
O
O
O
R
Rh2(S-DOSP)4
11
Rh2(5S-MEPY) 4
Rh
H O
N
SO2
CO2Me
Rh
O
Me
N
R
Rh
Rh
O
Rh
O
Rh
O
4
4
11

4
Doyle pioneered the use of chiral dirhodium(II) (specifically, using carboxamidate ligands) catalysts
with-diazo carbonyl compounds to generate reactive rhodium carbenoids capable of efficient
asymmetric cyclopropanation.
CO2Me
N
Rh
O
Me
4
H
Me
Rh
O
N2
Me
H
Me
Rh2(5S-MEPY)4 (1 mol%)
O
H
O
O
82% yield, 99% ee
Doyle JACS 1991, 113, 1423

Davies has developed a series of chiral dirhodium(II) carboxylate catalysts which efficiently
decompose unsaturated diazoacetates to the corresponding rhodium carbenoids that participate in
enantioselective cyclopropanation reactions:
Rh
H O
O
O
Ph
N
SO2
Rh2(DOSP)4
Ph
Rh
O
OMe
OMe
Ph
N2
68% yield, 98% ee
11
4
Davies JACS 1996, 118, 6897

Davies showed that alkynyl diazoesters are also competent in Rh(II)-catalyzed enantioselective
cyclopropanations.
Rh
H O
Ph
Ph
Rh2(DOSP)4
AcO
N2
CO2Me
pentane, -78 °C
N
SO2
AcO
Rh
O
CO2Me
61% yield, >94% de, 95% ee
11
4
Davies Tetrahedron Lett. 2000, 41, 8189

Doyle demonstrated that alkynes could be cyclopropanated using his rhodium carboxamidate
catalyst system to form cyclopropenes:
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Doyle JACS 1994, 116, 8492
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
The Davies group has developed a method for the tandem enantioselective diene
cyclopropanation/Cope rearrangement, which leads to a seven-membered ring product. This
process has been applied to the total sythesis of ()-5-epi-vibsanin E:
Davies JACS 1998, 120, 3326 and JACS 2007, 129, 10312 & Davies and Williams JACS 2009, 131, 8329
5.3.6


Cobalt
Cobalt catalysts are usually used in cis-selective cyclopropanations though the ligands are complex
Katsuki has developed chiral Co(II)-salen complexes that yield cyclopropanes with high cis
diastereoselectivities.
N
N
Co
O
O
Ph Ph
H
N2
CO2t-Bu
CO2t-Bu
N
CO2t-Bu
N
cis
trans
(98:2 cis:trans, 98% ee)
Katsuki Synlett 1995, 825 and Tetrahedron 1997, 53, 7201
6
HYDROAMINATION [Review: Schulz Chem. Eur. J. 2013, 19, 4972]
 The hydroamination reaction, which is the addition of an amine to an unsaturated carbon–carbon
bond is a reaction with great synthetic potential, as it not only reduces the formation of waste owing
to its atom economy, but it also utilizes very simple starting materials.

This transformation, thermodynamically feasible under normal conditions, suffers from a high
activation barrier due to electrostatic repulsions between the lone pair of the nucleophilic nitrogen
atom and the π-orbital of the electron-rich double bond.

Reviews have stated that the hydroamination of olefins is thermodynamically favored but
experimental equilibrium constants, enthalpies, and entropies for olefin hydroamination in solution
are lacking. In 2006, Hartwig reported direct measurements of the equilibrium constants for addition
of aromatic amines with varied steric and electronic properties to several types of vinyl arenes.
21
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Hartwig JACS 2006, 128, 9306; JACS 2000, 122, 9546

Overall, the reactions are exothermic but nearly ergoneutral. The electronic effect on this reaction is
almost purely a result of kinetic, not thermodynamic, factors as the equilibrium constants for these
additions are similar (entries 2 vs. 1, 3 vs. 1). In contrast, steric properties of the amine significantly
affected the equilibrium constant. The addition of aniline to styrene occurred at a much higher
conversion than the addition of N-methylaniline under equilibrium conditions (entries 4 vs. 1-2).
Because disubstituted olefins are more stable than monosubstituted olefins, the reactions of aniline
to indene and 1,2-dihydronaphthalene (entries 5-6) were limited by thermodynamics. These precise
measurements of the thermodynamic parameters for the reactions between amines and olefins of
varied structures established benchmark values that can be used to predict which types of
hydroaminations will be favorable and which will be unfavorable.

The development of novel catalyst systems for hydroamination has seen significant progress in the
last two decades but the intermolecular hydroamination of unactivated alkenes with simple amines
remains very challenging. It is not too surprising that asymmetric hydroamination reactions have
been studied predominantly in intramolecular reactions. Intermolecular reactions have been
reported only sporadically and all of these studies were limited to the reaction between aniline
derivatives and activated alkenes, such as vinyl arenes, 1,3-dienes and strained bicyclic alkenes.

The main limitations of these procedures lie undeniably in the incompatibility of the catalysts with
high substrates functionalization.
22
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6.1
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Metal-catalysed Hydroamination
Activation of Amine:

Group 1–5 metal-based catalysts have been proposed to proceed by activation of the amine through
a rapid protonolysis, leading to the formation of a metal amido (or imido) complex that will further
react through a insertive, non-insertive, or [2π + 2π] mechanism to generate the hydroamination
product. On the other hand, oxidative addition of the N-H bond on a late transition metal in low
oxidation state may occur to form a metal hydride complex. Subsequent insertion of the C-C double
bond into the metal-hydride complex and reductive elimination reaction will afford the
hydroamination product.
Activation of Alkene:

π-Activation of the alkene by a Lewis acidic late transition metal may lead to the nucleophilic attack
of the lone electron pair of the nitrogen on the coordinated alkene. The cleavage of the carbon–
metal bond by protonolysis will liberate the hydroamination product.
6.1.1

Iridium
Togni was the first to report in 1997, an asymmetric intermolecular hydroamination reaction
promoted by transition metals. They discovered that binuclear Ir(I) complexes associated to
enantiopure diphosphine ligands (JosiPhos, BINAP) delivered the targeted product in high
selectivities, in the presence of Schwesinger’s naked fluoride anion as co-catalyst.
Togni JACS 1997, 119, 10857

Hartwig have then described the efficient use of an organic base instead of added fluoride, as an
attempt to accelerate the reaction through generation of a small amount of aryl amide. The reaction
proceeded indeed in the presence of SegPhos, with a low iridium amount delivering the addition
product of aniline derivatives to norbornene with very high enantioselectivities and high yields.
23
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Hartwig JACS 2008, 130, 12220

Hartwig and his group also succeeded in reacting unactivated aliphatic alkenes and sulfonamides.
Applying this methodology to the addition onto bicycloalkenes in the presence of DTBM-SegPhos
delivered the hydroamination product in both high yields and enantioselectivities.

Other nitrogen-containing heteroaromatic amines have recently been used as the nucleophiles in the
intermolecular amination of styrene derivatives catalysed by a cationic Ir-TunePhos complex.
Hartwig JACS 2012, 134, 11960
Shibata OL 2012, 14, 780
6.1.2

6.1.3

Palladium
Significant studies have been published by the group of Hartwig devoted to the Pd-catalyzed
intermolecular hydroamination, allowing the fine-tuning of phosphine-based ligands for the
enantioselective hydroamination with enantiomeric excesses of up to 95%.
Hartwig JACS 2001, 123, 4366
Rhodium
Buchwald reported the first examples of late transition-metal-catalyzed enantioselective
intramolecular hydroamination of unactivated olefins. By using [Rh(COD)2]BF4 with binaphthyl-based
electron-rich phosphines, they successfully cyclized N-benzyl protected aminoolefins in the
corresponding pyrrolidine derivatives under mild conditions in dioxane in high yield and with up to 91
% ee. This reaction could also be performed with substrates lacking gem-substitutions.
24
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Buchwald ACIE 2010, 49, 564
6.1.4

Rare-Earth Metals
Intermolecular hydroamination reaction of alkenes catalyzed by rare-earth metals has been
underdeveloped and remains challenging compared with the cyclohydroamination reaction. The first
and only disclosure to date of rare-earth catalyzed asymmetric intermolecular hydroamination of
alkenes was reported by Hultzsch in 2010 by using lutetium and yttrium complexes based on chiral
3,3’-bis-substituted binaphthol ligands. Various linear and branched alkenes (ratio alkene/amine 9:1
to 15:1) were converted into their corresponding secondary amines in high conversion (85–100%)
and with ee values of up to 61%.
Hultzsch ACIE 2010, 49, 1-5
6.1.5


Copper
Copper has been recently used as a potential cheap catalyst and Cu(II) triflate and acetate were
demonstrated to promote the intermolecular hydroamination of alkenes.
In 2013, Miura developed a copper-catalyzed intermolecular formal hydroamination of styrenes with
polymethylhydrosiloxane and O-benzoylhydroxylamines with high regioselectivities.
Miura ACIE 2013, 52, 10830

In the same year, Buchwald also reported a similar copper-catalyzed hydroamination for
synthesizing chiral tertiary amines with high enantioselectivities. They proposed that the insertion of
an alkene into a chiral ligand-bound LCu(I)H species would form an alkyl-copper complex (see
below). Subsequent oxidative addition of an electrophilic hydroxylamine source followed by reductive
elimination would form the C−N bond enantioselectively. The copper(I) species generated would
then undergo transmetalation with an external hydride-transfer reagent to reform LCu(I)H species.
25
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Buchwald JACS 2013, DOI: 10.1021/ja4092819

Substitution occurs in a regioselective manner to generate a C−N bond at the α-position of styrene
derivatives. This method has been shown to be compatible with various substituted styrene
derivatives, and styrenes with β-substitution. Additionally, this method allows the development of
copper-catalyzed anti-Markovnikov hydroaminations of terminal aliphatic alkenes.
Other metals (Au, Pt, Fe, group 4 and 5 metals, alkali bases) have also been tackled as potential catalysts
for enantioselective hydroamination. Some breakthroughs are still expected before the successful use of
asymmetric metal-mediated hydroamination as a key synthetic procedure for the preparation of scalemic
amines or nitrogen-containing heterocycles.
6.2

Metal-free Enantioselective Hydroamination
In 2011, Beauchemin described a metal-free catalytic tethered strategy to promote an
enantioselective intermolecular hydroamination reaction. The rate of such entropically unfavored
transformation could be enhanced by the use of a catalytic organic molecule, appropriately designed
as tether for temporary bringing together both reaction partners to react intramolecularly through a
Cope-type reaction. Acetaldehyde derivatives were used as the catalyst for the intermolecular Copetype hydroamination of allylic amines and hydroxylamine with high yields and with ee values of up to
97% at room temperature.
26
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Beauchemin JACS 2011, 133, 20100; Chem. Eur. J. 2013, 19, 2597

Catalysis of Cope-type rearrangements of bis-homoallylic hydroxylamines are also demonstrated
using chiral thiourea derivatives. This intramolecular hydroamination reaction provides access to
highly enantioenriched α-substituted pyrrolidine products and represents a complementary approach
to metal-catalyzed methods.
Jacobsen JACS 2013, 135, 6747

Toste reported that chiral dithiophosphoric acids could catalyze the intramolecular hydroamination
and hydroarylation of dienes and allenes to generate heterocyclic products in good yield and
enantioselectivity. Dithiophosphoric acid is strong enough to protonate an alkene, but which also
possesses a nucleophilic conjugate base. The mechanistic hypothesis of this transformation involves
the addition of the acid catalyst to the diene, followed by nucleophilic displacement of the resulting
dithiophosphate intermediate. The presence of the sulfur atoms was necessary to reach high
conversion and selectivity.
27
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28
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Toste Nature 2011, 470, 245