Asymmetric conjugate addition of copper reagents to α,β- unsaturated tert-butanesulfinyl imines

Article abstract of DOI:10.1021/ol051986q

(Chemical Equation Presented) Addition of organocuprates to N-sulfinyl α,β-unsaturated imines proceeds in good yields and with good diastereoselectivities. α,β-Unsaturated sulfinyl ketimines and aldimines have both been shown to be suitable substrates for this reaction.

Full text of DOI:10.1021/ol051986q

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5393-5396
Asymmetric Conjugate Addition of
Copper Reagents to -Unsaturated
tert-Butanesulfinyl Imines
r,â
Jeffrey P. McMahon and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California, Berkeley, California 94720
jellman@berkeley.edu
Received August 16, 2005 (Revised Manuscript Received September 30, 2005)
ABSTRACT
Addition of organocuprates to N-sulfinyl
r,â-unsaturated imines proceeds in good yields and with good diastereoselectivities. r,â-Unsaturated
sulfinyl ketimines and aldimines have both been shown to be suitable substrates for this reaction.
N-tert-Butanesulfinyl imines are extremely versatile synthetic
intermediates and are increasingly being used for the
asymmetric synthesis of amines. N-tert-Butanesulfinyl imines
are readily prepared by condensation of tert-butanesulfin-
amide with aldehydes or ketones. Subsequent diastereo-
selective addition of diverse nucleophiles followed by acidic
removal of the sulfinyl group efficiently provides enantio-
enriched amine products.1,2
enriched amine products. In initial efforts, we demonstrated
that R-deprotonation of N-tert-butanesulfinyl imines gener-
ates metalloenamides that react with high diastereoselectivity
with a number of electrophiles, including alkylating agents,
aldehydes, and Michael acceptors.3 Herein we report for the
first time that N-tert-butanesulfinyl imines with â-stereo-
centers can be accessed by the diastereoselective conjugate
addition of organocuprates to N-sulfinyl imines derived from
R,â-unsaturated aldehydes and ketones.4,5
Preparation of R,â-unsaturated N-tert-butanesulfinyl imines
1 required slight modification of our reported protocol for
the condensation of tert-butanesulfinamide with aldehydes
and ketones, in which 2 equiv of Ti(OEt)4 is used as a Lewis
acid catalyst and water scavenger. Under these conditions,
incomplete conversion to the imine product was observed.
Recently we have embarked on an effort to access more
complex amine products with multiple stereocenters by first
performing diastereoselective transformations upon starting
N-tert-butanesulfinyl imines to provide more complex imine
intermediates that are subsequently converted to enantio-
(1) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984-995. (b) Weix, D.; Shi, Y. L.; Ellman, J. A. J. Am. Chem. Soc.
2005, 127, 1092-1093. (c) Ballweg, D. M.; Miller, R. C.; Gray, D. L.;
Scheidt, K. A. Org Lett. 2005, 7, 1403-1406. (d) Lu, B. Z.; Senanayake,
C.; Li, N.; Han, Z.; Bakale, R. P.; Wald, S. A. Org. Lett. 2005, 7, 2599-
2602. (e) McMahon, J. P.; Ellman, J. A. Org. Lett. 2004, 6, 1645-1647.
(f) Zhong, Y.; Xu, M.; Lin, G. Org. Lett. 2004, 6, 3953-3956. (g) Ballweg,
D. M.; Miller, R. C.; Gray, D. L.; Scheidt, K. A. Org Lett. 2005, 7, 1403-
1406. (h) Kuduk, S. D.; DiPardo, R. M.; Chang, R. K.; Ng, C.; Bock, M.
G. Tetrahedron Lett. 2004, 45, 6641-6643. (i) Plobeck, N.; Powell, D.
Tetrahedron: Asymmetry 2002, 13, 303-310. (j) Wipf, P.; Nunes, R. L.;
Ribe, S. HelV. Chim. Acta 2002, 85, 3478-3488.
(3) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003,
125, 11276-11282. (b) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004,
126, 15652-15653. (c) Schenkel, L.; Ellman, J. A. Org. Lett. 2004, 20,
3621-3624. (d) Pelltier, H. M.; Ellman, J. A. J. Org. Chem., ASAP.
(4) For leading references and extensive literature on stereoselective
additions of organocuprates to R,â-unsaturated ketones and esters, see:
Alexakis, A.; Polet, D.; Rosset, S.; March, S. J. Org. Chem. 2004, 69, 5660-
5667. (b) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 13362-13363. (c) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem.
2002, 3221-3236. (d) Krause, N.; Hoffmann-Roder, A. Synthesis 2001,
171. (e) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (f) Krause, N. Angew.
Chem., Int. Ed. Engl. 1997, 36, 186-204.
(2) For a recent review on the applications of arenesulfinyl imines, see:
Zhou, P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60, 8003-8030.
10.1021/ol051986q CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/01/2005

However, good conversion could be obtained by increasing
the amount of Ti(OEt)4 in the reaction from 2 to 4 equiv.
Using this modified stoichiometry, both R,â-unsaturated
ketimines and aldimines 1 could be prepared in yields ranging
from 74% to 86% for a range of aromatic and aliphatic
substitution patterns (See Table 1).
Table 2. Optimization of Ketimine Additions
equiv
%
Table 1. Condensation of tert-Butanesulfinamide with
R,â-Unsaturated Aldehydes and Ketones
entry
Cu salt
CuI
CuI
CuBr
CuCN
CuBr‚SMe2
CuBr
CuCN
CuBr‚SMe2
CuBr
of BuLi additive solvent yielda
drb
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
1
1
1
1
2
2
2
2
2
none
Et2O
THF
THF
THF
THF
THF
THF
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
THF
71c
23
40
66
68
41
33
48
51
17
99
65
33
61c
33
58
68c
2:1
none
none
86:14
89:11
71:29
85:15
74:26
73:27
78:22
89:11
91:9
2:1
89:11
3:2
92:8
2:1
none
none
TMSCl
TMSCl
TMSCl
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
product
R1
Me
Ph
Me
Ph
-(CH2)3-
H
R2
temp
% yield
1a
1b
1c
1d
1e
1f
Me
Me
Ph
Ph
reflux
reflux
reflux
reflux
reflux
rt
74
74
81
77
86
82
9
10
11
12
13
14
15
16
17
CuBr
CuCN
CuCN
CuBr
Me
CuBr
CuCN
CuBr‚SMe2
CuCN
91:9
93:7
Sulfinyl ketimine 1a derived from 3-penten-2-one was first
selected to optimize conditions for the conjugate addition
reactions. The addition of the butyl Gilman cuprate was first
evaluated and provided addition product 2a in 71% yield,
but with a low 2:1 diastereomeric ratio (entry 1, Table 2).
Despite the low selectivity, this result provided an appropriate
starting point for optimization efforts.
Optimization focused on copper sources, solvent, and
additives to increase the diastereomeric ratio of the reaction
while maintaining good yields. Diastereomer ratios were
consistently higher with THF rather than Et2O as the solvent.
(Table 2). When no additives were used, CuBr was the
copper source that provided the highest selectivity (entry 3).
Additives that have previously been reported to improve
cuprate conjugate additions were tested next. TMSCl de-
creased the selectivity of the reaction with each of the copper
sources (entries 6-8). In contrast, the best results were seen
when BF3‚OEt2 was used in combination with 2 equiv of
the lithium reagent. Using CuBr as the copper source under
these conditions, a 61% yield and 92:8 diastereomer ratio
were obtained (entry 14). A slightly higher 68% yield and
93:7 diastereomer ratio were observed when CuCN was used
as the copper source (entry 17).
a Determined by NMR analysis of the crude mixture containing 2,6-
dimethoxytoluene as a standard. b Determined by HPLC analysis. c Deter-
mined by a mass balance of the purified product.
conjugate addition greatly exceeds this modest E/Z isomer
ratio, suggesting that one of the imine isomers preferentially
reacts with the cuprate concomitant with rapid imine isomer
equilibration. Enhanced diastereoselectivities over substrate
E/Z isomer ratios have previously been observed for nucleo-
philic additions to N-sulfinyl ketimines.6
The scope of the conjugate addition reaction was next
evaluated using the CuCN conditions for optimal yield and
diastereoselectivity. Addition of the butyl cuprate to sulfinyl
ketimine 1b also proceeds in good yield and diastereoselec-
tivity (entry 2, Table 3). Additions of methyl cuprates, which
are documented to be the least reactive of the alkyl cuprates,
were next investigated. Unfortunately, the optimal conditions
for the conjugate addition of butyl cuprate were not effective
for the less reactive methyl cuprate. Not only were the desired
addition products obtained in modest yield, but sulfenyl
ketimines were produced as major byproducts. Cuprates are
documented to be more reactive in Et2O than in THF. Indeed,
successful additions of Me2CuLi in Et2O were observed with
complete elimination of sulfenyl ketimine byproducts (entries
3-5). Good yields and diastereoselectivities were observed
with a phenyl substituent present at R2 (entry 3) and at both
R1 and R2 (entry 4), and in initial studies, addition of the
methyl cuprate to a cyclic imine also proceeded in good yield
with promising selectivity (entry 5).
The R,â-unsaturated ketimine starting material 1a existed
as a 2:1 mixture of E/Z isomers as determined by NMR
spectroscopy. It is notable that the diastereoselectivity of the
(5) Relatively few examples of asymmetric additions to R,â-unsaturated
aldimines and ketimines have been reported. None of these methods have
been utilized for the asymmetric synthesis of amines. For leading references,
see: (a) Esquivias, J.; Arrayas, R. G.; Carretero, J. C. J. Org. Chem. 2005,
70, 7451-7454. (b) Soeta, T.; Kuriyama, M.; Tomioka, K. J. Org. Chem.
2005, 70, 297-300. (c) Bonini, B. F.; Fochi, M.; Franchini, M. C.; Mazzanti,
G.; Ricci, A.; Picard, J. P.; Dunogues, J.; Aizpurua, J. M.; Palomo, C. Synlett
1997, 1321-1323. (d) Enders, D.; Heider, K. J.; Raabe, G. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 598-601.
(6) (a) Cogan, D.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268-
269. (b) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40,
6709-6712.
5394
Org. Lett., Vol. 7, No. 24, 2005

Table 3. Substrate Scope
Table 4. Optimization of Aldimine Additions
equiv
%
drb
entry
Cu salt
of BuLi additive yielda (3R:3S)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18e
19f
CuI
CuI
CuI
CuCN
CuCN
CuBr
CuBr
CuBr‚SMe2
CuBr‚SMe2
CuCN
CuCN
CuCN
CuCN
CuI
CuBr‚SMe2
(CuOTf)2‚benzene
CuOAc
CuCN
2
2
1
2
1
2
1
2
1
1
2
1
1
1
1
1
1
1
1
none
52d
78
15
71
62
92
48
64
4
73d
65
48d
52d
59
15
nr
1:1
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
PBu3
PBu3
PCy3
PPh3
PBu3
75:25
70:30
79:21
80:20
76:24
79:21
77:23
62:38
85:15
72:28
2:1
76:24
76:24
77:23
PBu3
PBu3
PBu3
PBu3
55
57d
48d
15:85
∼2:1
∼2:1
CuCN
PBu3
a Determined by NMR analysis of the crude mixture containing 2,6-
dimethoxytoluene as a standard. b Determined by HPLC analysis. c Reaction
was run in Et2O. d Determined by a mass balance of the purified product.
e Corresponding p-toluenesulfinyl imine was used as starting material.
f Corresponding 2,4,6-triisopropylbenzenesulfinyl imine was used as starting
material.
a Method A: 0.5 M solution of R,â-unsaturated imine in THF was added
to a -78 °C 0.5 M solution of Bu2CuCN‚BF3‚OEt2 in THF via cannula.
Method B: A 0.5 M solution of R,â-unsaturated imine in Et2O was added
to a -78 °C 0.5 M solution of Me2CuLi in Et2O via cannula. b Isolated
yield of purified mixture of diastereomers. c Isolated yield of purified major
diastereomer. d Determined by HPLC analysis.
which have previously been reported to enhance diastereo-
selectivities, were next evaluated. Indeed, when CuCN was
used as the copper source with tributylphosphine as the
additive, the product was obtained in a moderate 85:15 dr
and 73% yield (entry 10). Modification of the structure of
the phosphine additive resulted in a slight drop in the
diastereoselectivity (entries 12 and 13). Different copper
sources had a pronounced effect on the diastereoselectivity
observed when PBu3 was used as an additive (entries 14-
17). Most exciting was CuOAc, which gave an 85:15 dr
favoring the opposite diastereomer while maintaining an
acceptable 55% yield (entry 17). This allows for access of
either diastereomer of the addition product using the same
sulfinyl stereocenter. Conjugate additions to the R,â-unsatu-
rated sulfinyl imines prepared from p-toluenesulfinamide
(entry 18) and 2,4,6-triisopropylbenzenesulfinamide (entry
19) were also carried out using the optimized conditions
(CuCN as the copper source and PBu3 as an additive).
However, additions to these sulfinyl imine derivatives
proceeded with poor diastereoselectivities.
The absolute configuration at the â-stereocenter was
determined for the conjugate addition products in entries 1,
3, and 4 by hydrolysis to the corresponding ketones followed
by correlation with the literature optical rotations for these
compounds.7 The configuration of the conjugate addition
product in entry 5 was determined by comparison with the
imines prepared by condensation of (R)-tert-butanesulfin-
amide with the commercially available (R)- and (S)-3-methyl
cyclohexanones.1e
Conjugate additions to tert-butanesulfinyl aldimine 1f were
also investigated (Table 4). Initial experiments, however,
gave low diastereoselectivities. Addition of Bu2CuLi to
aldimine 1f proceeded in 52% yield and was not selective
(entry 1). Using the conditions optimized for butyl cuprate
addition to ketimine 1a gave a better diastereomer ratio, but
the selectivity was still low (entry 4). Reduction in the
stoichiometry of BuLi to CuCN (entry 5) or use of alternative
copper sources with BF3‚Et2O as an additive did not result
in any improvement in reaction diastereoselectivity (entries
6-9). Different copper(I) sources and phosphine additives,
The facial selectivity for conjugate additions to N-sulfinyl
R,â-unsaturated ketimines and aldimines can be rationalized
by the model shown in Figure 1. The cuprate coordinates to
the sulfinyl oxygen on the opposite face from the tert-butyl
group. Coordination both activates the molecule to conjugate
(7) (a) For entry 1, see: Yamaguchi, M.; Igarashi, Y.; Reddy, R. S.;
Shiraishi, T.; Hirama, M. Tetrahedron 1997, 53, 11223-11236. (b) For
entries 3 and 4, see: Oi, S.; Taira, A.; Honma, Y.; Inoue, Y. Org. Lett.
2003, 5, 97-99.
Org. Lett., Vol. 7, No. 24, 2005
5395

butanesulfinyl ketimines with aliphatic and aromatic substi-
tution patterns. Conditions were also identified for the
addition of butyl cuprate to R,â-unsaturated tert-butane-
sulfinyl aldimine 2f to provide either diastereomeric addition
product with 85:15 diastereomer ratios depending on the
copper source. These first examples of conjugate additions
to unsaturated N-tert-butanesulfinyl imines provide â-sub-
stituted imines that should serve as useful intermediates in
the asymmetric synthesis of a variety of γ-substituted amine
products.
Figure 1. Model for diastereofacial selectivity.
addition and aligns the cuprate for the addition reaction.8
Presumably, delivery of the organocuprate to the â-position
is only possible through one of the imine isomers, which
can be accessed through facile equilibration of the imine
isomers. Sufficient information is not available to rationalize
the reversal in selectivity observed for conjugate addition to
aldimine 1f under the Cu(OAc) reaction conditions (Table
4, entry 17).
Acknowledgment. This work was supported by the
National Science Foundation (CHE-0446173). The Center
for New Directions in Organic Synthesis is supported by
Bristol-Myers-Squibb as a sponsoring member and Novartis
as a supporting member. We would also like to thank
Shaheen Shamsavari for helpful contributions.
Supporting Information Available: Full experimental
details and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have shown that organocuprates can be
added with high diastereoselectivity to R,â-unsaturated tert-
(8) Woodward, S. Chem. Soc. ReV. 2000, 29, 393-401.
OL051986Q
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Org. Lett., Vol. 7, No. 24, 2005