Catalytic enantioselective addition of diorganozinc reagents to vinyl sulfones

Article abstract of DOI:10.1021/ol800747v

(Chemical Equation Presented) An efficient method for the catalytic asymmetric conjugate addition of diorganozinc reagents to vinyl sulfones is reported. Using a Binap·Cu complex, enantioselectivities up to 98% ee and high yields can be attained for a variety of substrates. Several dialkylzinc reagents are also compatible with this procedure.

Full text of DOI:10.1021/ol800747v

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2315-2318
Catalytic Enantioselective Addition of
Diorganozinc Reagents to Vinyl
Sulfones
Jean-Nicolas Desrosiers, William S. Bechara,* and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al (Que´bec), Canada H3C 3J7
andre.charette@umontreal.ca
Received April 2, 2008
ABSTRACT
An efficient method for the catalytic asymmetric conjugate addition of diorganozinc reagents to vinyl sulfones is reported. Using a Binap•Cu
complex, enantioselectivities up to 98% ee and high yields can be attained for a variety of substrates. Several dialkylzinc reagents are also
compatible with this procedure.
Sulfones bearing ꢀ stereocenters are powerful tools for
synthesizing complex natural or biologically active mol-
Scheme 1. Approaches to Enantioenriched Alkyl Aryl Sulfones
ecules.1 The value of these subunits stems from the ease with
which they can be derivatized to provide a variety of building
blocks, such as aldehydes or ketones, alkynes, alkenes,
alkanes, and haloalkanes.2 Indeed, their versatility has been
exploited by different research groups for the total synthesis
of the immunosuppressive agent rapamycin.3,4
Optically active sulfones 2 may be accessed by the
catalytic enantioselective reduction of ꢀ,ꢀ-disubstituted vinyl
sulfones (Scheme 1).5 Our group6 and Carretero et al.7 have
simultaneously developed conditions which lead to enan-
tioenriched alkyl aryl sulfones in excellent yields and
enantiomeric excesses using a hydrosilylation approach.
A complementary convergent approach to chiral sulfones
2 is the 1,4-addition of organometallic reagents to ꢀ-mono-
substituted vinyl sulfones (Scheme 1). Nonasymmetric and
diastereoselective conjugate nucleophilic additions to vinyl
sulfones, to produce ꢀ chiral centers, have been known for
years and are still present in today’s literature.8 The first
(1) Prilezhaeva, E. N. Russ. Chem. ReV. 2000, 69, 367.
(2) (a) Kelly, S. E. In ComprehensiVe Organic Synthesis, Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, p 792. (b) Trost,
B. M. Bull. Chem. Soc. Jpn 1988, 61, 107. Na´jera, C.; Yus, M. Tetrahedron
1999, 55, 10547.
(3) Kahan, B. D.; Podbielski, J.; Napoli, K. L.; Katz, S. M.; Meier-
Kriesche, H.-U.; Van Buren, C. T. Transplantation 1998, 66, 1040
.
(4) (a) Linde, R. G., II; Egbertson, M.; Coleman, R. S.; Jones, A. B.;
Danishefsky, S. J. J. Org. Chem. 1990, 55, 2771. (b) Romo, D.; Johnson,
D. D.; Plamondon, L.; Miwa, T.; Schreiber, S. L. J. Org. Chem. 1992, 57,
5060. (c) Ley, S. V.; Norman, J.; Pinel, C. Tetrahedron Lett. 1994, 35,
2095. (d) Bellingham, R.; Jarowicki, K.; Kocienski, P.; Martin, V. Synthesis
1996, 285. (e) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer,
J. L., Jr.; Leahy, J. W.; Maleckza, R. E., Jr. J. Am. Chem. Soc. 1997, 119,
(5) For hydrogenation systems leading to ꢀ-chiral sulfones substituted
with carboxylic acids and ꢀ-hydroxy sulfones, see: (a) Paul, J. M.; Palmer,
C. U.S. Patent 6,274,758, August 14, 2001. (b) Wan, X.; Meng, Q.; Zhang,
H.; Sun, Y.; Fan, W.; Zhang, Z. Org. Lett. 2007, 9, 5613.
(6) Desrosiers, J.-N.; Charette, A. B. Angew. Chem., Int. Ed. 2007, 46,
5955.
(7) Llamas, T.; Arraya`s, R. G.; Carretero, J. C. Angew. Chem., Int. Ed
2007, 46, 3329.
947
.
10.1021/ol800747v CCC: $40.75
Published on Web 05/08/2008
2008 American Chemical Society

catalytic enantioselective addition to vinyl sulfones was
reported by Hayashi and consisted of the rhodium-catalyzed
1,4-addition of an aryltitanium species followed by a cine-
substitution leading to the elimination of the sulfonyl group.9
Later, Carretero published a catalytic enantioselective con-
jugate addition of aromatic boronic acids onto ꢀ-mono- and
ꢀ,ꢀ-disubstituted vinyl sulfones with high to excellent yields
and good enantioselectivities.10
sulfones were optimal to generate E,Z-dienes using the
Julia-Kocienski olefination.14 This information, combined
with our background expertise on heteroaryl-substituted
sulfones, led us to study the effect of having a 2-pyridyl-
sulfone as the electron-withdrawing substituent on the
efficiency of the addition. Interestingly, the 2-pyridyl group
allowed the formation of the desired adduct in 10% yield
and 6% ee with Me-DuPHOS(O).
In order to enhance both the reactivity and the enantiose-
lectivity of the system, we screened several chiral phosphines
(Figure 1).15 We first tested the bisphosphine Me-DuPHOS
We recently developed copper-catalyzed additions of
diorganozinc reagents to sp2 centers, such as phosphi-
noylimines11 and nitroalkenes,12 using the hemilabile Me-
DuPHOS(O) (L1) as a chiral ligand. We envisioned extend-
ing this system to vinyl sulfones which could circumvent
the problem of synthesizing enantioenriched ꢀ,ꢀ-dialkylsub-
stituted sulfones with sterically similar substituents. Herein,
we describe the asymmetric copper-catalyzed addition of
diorganozinc reagents to ꢀ-monosubstituted vinyl sulfones.
Initially, we tested our optimized conditions for the
addition of diorganozinc reagents to phosphinoylimines.
However, treating Me and Ph vinyl sulfones 1a and 1b with
diethylzinc and a catalytic amount of copper(I) triflate and
Me-DuPHOS(O) in toluene (eq 1) gave none of the addition
product.
It has been shown, in several copper-catalyzed systems,
that reactivity may be enabled or accelerated by the presence
of a proximal Lewis basic group such as a pyridine moiety
by complexation to the catalyst.13 Furthermore, Carretero
discovered that such a substituent promoted the rhodium-
catalyzed 1,4-addition of boronic acid to vinyl sulfones.
Previously, in our research group, we found that 2-pyridyl
Figure 1. Various chiral phosphines tested.
(L2, Table 1, entry 1), and an improvement in the enanti-
oselectivity was observed compared to its hemilabile equiva-
lent Me-DuPHOS(O). We then turned our attention to
ferrocenyl-type ligands. Josiphos (L3) gave comparable
results to those obtained with Me-DuPHOS(O), whereas
Mandyphos (L4) offered 17% yield and 64% ee (entries 2
and 3). Seeing that P,N-ligands offered promising results,
we studied the impact of ligands L5 and L6 of the same
family. While iPr-PHOX provided very low activity, the
binaphthyl Quinap increased conversions and enantioselec-
tivities (entries 4 and 5). In general, the C2 symmetric
bisphosphine ligands with a binaphthyl scaffold (L7-10)
seemed to afford better yields and enantiomeric excesses.
Best results were achieved with Binap which gave 50% yield
and 89% ee (entry 6).16 The bulkier Tol-Binap ligand (L8)
led to the addition product with similar enantiocontrol but
with a much lower reactivity (entry 7).
(8) For reviews, see: (a) Fuchs, P. L.; Braish, T. F. Chem. ReV. 1986,
86, 903. (b) Simpkins, N. G. Tetrahedron 1990, 46, 6951. (c) Forristal, I.
J. Sulfur Chem. 2005, 26, 163. For recent examples, see: (d) Grimaud, L.;
Rotulo, D.; Ros-Perez, R.; Guitry-Azam, L.; Prunet, J. Tetrahedron Lett.
2002, 43, 7477. (e) Fahrat, S.; Marek, I. Angew. Chem., Int. Ed. 2002, 41,
1410. (f) Liza Luis, A.; Krische, M. J. Synlett 2004, 2579.
(9) Yoshida, K.; Hayashi, T. J. Am. Chem. Soc. 2003, 125, 2872.
(10) (a) Mauleo´n, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195. (b)
Mauleo´n, P.; Carretero, J. C. Chem. Commun. 2005, 4961. (c) Mauleo´n,
P.; Alonso, I.; Rivero, M. R.; Carretero, J. C. J. Org. Chem. 2007, 72,
9924.
(11) (a) Boezio, A. A.; Pytkowicz, J.; Coˆte´, A.; Charette, A. B. J. Am.
Chem. Soc. 2003, 125, 14260. (b) Coˆte´, A.; Boezio, A. A.; Charette, A. B.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5405. (c) Desrosiers, J.-N.; Coˆte´,
A.; Charette, A. B. Tetrahedron 2005, 61, 6186. (d) Charette, A. B.; Boezio,
A. A.; Coˆte´, A.; Moreau, E.; Pytkowicz, J.; Desrosiers, J.-N.; Legault, C.
Pure Appl. Chem. 2005, 77, 1259. (e) Desrosiers, J.-N.; Coˆte´, A.; Boezio,
A. A.; Charette, A. B. Org. Synth. 2006, 83, 5.
(12) Coˆte´, A.; Lindsay, V. N. G.; Charette, A. B. Org. Lett. 2007, 9,
85.
(13) (a) Han, H.; Bae, I.; Yoo, E. J.; Lee, J.; Do, Y.; Chang, S. Org.
Lett. 2004, 6, 4109. (b) Kamei, T.; Fujita, K.; Itami, K.; Yoshida, J.-I. Org.
Lett. 2005, 7, 4725. (c) Nakamura, S.; Sano, H.; Nakashima, H.; Kubo, K.;
Shibata, N.; Toru, T. Tetrahedron Lett. 2007, 48, 5565. For a 2-pyridyl
directed radical addition to vinyl sulfoxides, see: (d) Mase, N.; Watanabe,
Y.; Higuchi, K.; Nakamura, S.; Toru, T. J. Chem. Soc., Perkin Trans. 1
2002, 2134.
(14) Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett.
2001, 42, 5149.
(15) Carbophos, BDPP, Phanephos, Segphos, Diop, and Chiraphos
ligands all gave e10% conversion.
(16) For a review on Binap, see: Berthod, M.; Mignani, G.; Woodward,
G.; Lemaire, M. Chem. ReV. 2005, 105, 1801.
2316
Org. Lett., Vol. 10, No. 11, 2008

solvents were tested (entries 3-5). Conversely, THF gave a
significant increase in enantioselectivities with 98% (entry
5).17 The concentration of the reaction media was another
factor that dramatically influenced the conversions. Concen-
trating the reaction down to 0.2 M provided an improvement
of 18% yield (entry 6). Also, by adding an excess of
diorganozinc reagent and warming the reaction mixture to
60 °C, 81% yield and 97% ee were obtained (entry 10).
Finally, increasing the catalyst loading to 10 mol % gave
87% yield and 98% ee. Having two sets of conditions in
hand, one in benzene that provides high yields (entry 12)
and another in THF that generates excellent enantioselec-
tivities (entry 11), we explored the scope of the reaction.
Table 1. Ligand Screening for the Addition of Et2Zn on Vinyl
Sulfone 1c
entry
ligand
yield (%)a
ee (%)b
configurationc
1
2
3
4
5
6
7
8
9
10
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
4
15
17
7
42
50
23
43
9
32
10
64
4
65
89
78
34
49
53
R
R
R
R
S
R
S
R
R
S
Table 3. Copper-Catalyzed Asymmetric Diorganozinc Addition
to Vinyl Sulfones under Optimal Conditions
21
a Determined by 1H NMR with 1,3,5-trimethoxybenzene as an internal
standard. b Enantiomeric excesses determined by SFC using a chiral
stationary phase. c Determined by comparison with literature data of the
sign of optical rotation.
entry
R
solventa
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph (1c)
Ph (1c)
A
B
A
B
A
B
A
B
A
B
A
B
72
93
61
80
57
83
63
77
55
67
93
92
98
92
98
91
94
84
97
88
96
93
88
93
A systematic optimization of the enantioselective addition
of Et2Zn to vinyl sulfone 1c (Table 2) showed that the less
4-MeOC6H4 (1d)
4-MeOC6H4 (1d)
4-CF3C6H4 (1e)
4-CF3C6H4 (1e)
2-naphthyl (1f)
2-naphthyl (1f)
iPr (1g)
iPr (1g)
Me (1h)
Me (1h)
Table 2. Optimization of the Addition of Et2Zn on Vinyl
Sulfone 1c
9
10
11
12
a Solvent A ) THF, solvent B ) benzene. b Isolated yields. c Enantiomeric
excesses determined by SFC using a chiral stationary phase.
solvent
Et2Zn temperature
entry (concentration) (equiv)
(°C)
yielda (%) eeb (%)
We submitted a variety of vinyl sulfones 1 to the optimized
conditions in benzene and in THF (Table 3). Vinyl sulfones
with aromatic substituents at the ꢀ position 1c-f (entries
1-8) underwent the catalytic conjugate addition with excel-
lent enantioselectivities (94-98%) and moderate to good
yields (57-72%) in THF. The same reactions carried out in
benzene afforded very high yields (80-93%) and good
enantioselectivities (84-92%) of the sulfones 2. Vinyl
sulfones bearing electron-donating groups (1d) provided the
desired products with slightly better enantioselectivities than
those bearing electron-withdrawing groups (1e), but with
similar yields. The more hindered 2-naphthyl sulfone 2f was
generated in high yields and enantioselectivities.
1
2
3
4
5
6
7
8
9
toluene (0.1)
benzene (0.1)
DME (0.1)
Et2O (0.1)
THF (0.1)
THF (0.2)
THF (0.2)
THF (0.2)
THF (0.2)
2
2
2
2
2
2
3
3
3
3
3
3
25
25
25
25
25
25
25
40
60
60
60
60
50
62
18
36
41
59
66
70
89
94
93
90
98
98
98
97
95
97
98
92
76
10c THF (0.2)
11d THF (0.2)
12d benzene (0.2)
81
87 (72)e
99 (93)e
a Determined by 1H NMR with 1,3,5-trimethoxybenzene as an internal
standard. b Enantiomeric excesses determined by chiral SFC using a chiral
stationary phase. c Binap (7 mol %) and (CuOTf)2·Tol (3.5 mol %) were
used. d Binap (10 mol %) and (CuOTf)2·Tol (5 mol %) were used. e Isolated
yield in parentheses.
Notably, R,ꢀ-unsaturated sulfones with a propensity to
isomerize to the γ,ꢀ position under basic conditions18 were
compatible with this system and led to addition products in
good to excellent yields and enantioselectivities (entries
polar aromatic benzene afforded better yields and enanti-
oselectivities than toluene (Table 2, entry 2). Lower conver-
sions to the desired product 2 were observed when etheral
(17) Cu(OTf)2, Cu(PF6)2•4MeCN, CuBr, CuOAc, Cu(OMe)2, and CuCl
all gave lower yields and/or enantioselectivities.
(18) Sataty, I.; Meyers, C. Y. Tetrahedron Lett. 1974, 47, 4161.
Org. Lett., Vol. 10, No. 11, 2008
2317

obtained with neat dialkylzinc reagents could be achieved.
Due to the lower reactivity of Me2Zn,21 an excess of this
reagent was used to reach 81% yield and 98% ee (entry 1).
Dipropyl- and dibutylzinc gave the same level of enantio-
control as the addition of Et2Zn performed in THF (entries
2 and 3). Finally, organometallic reagents bearing long
aromatic functionalized chains are tolerated as well (entry
4). As shown in entry 5, the system is limited to primary
diorganozinc reagents since the R-branched dicyclohexylzinc
afforded only 14% yield of the addition product 3e (17%
ee), traces of reduction, and mainly the starting material 1c.
Table 4. Several Diorganozinc Reagents Added to Vinyl
Sulfone 1c
entry
R
product
yield (%)a
ee (%)b
In summary, we developed a novel copper-catalyzed
enantioselective addition of diorganozinc reagents to vinyl
sulfones. This approach allows the formation of optically
active alkyl sulfones with good to excellent yields and
enantiomeric excesses and is complementary to already
known procedures. Additionally, we have shown that several
dialkylzinc reagents are compatible with this methodology.
1c,d
2
Me
n-Pr
n-Bu
PhCH2CH2
c-Hex
3a
3b
3c
3d
3e
81
52
53
72
14
98
89
90
90
17
3
4d
5
a Isolated yields. b Enantiomeric excesses determined by SFC using a
chiral stationary phase. c Neat R2Zn was used. d Six equiv of R2Zn was
used.
Acknowledgment. This work was supported by NSERC
(Canada), Merck Frosst Canada, Boehringer Ingelheim
(Canada), Ltd., the Canada Research Chairs Program, the
Canadian Foundation for Innovation and the Universite´ de
Montre´al. J.N.D. is grateful to NSERC (BESC D) and TD
Bank Financial Group for a postgraduate fellowship. W.S.B.
is grateful to NSERC (USRA) for an undergraduate fellow-
ship. We would like to thank the research group of P. L.
Fuchs for a generous supply of the (cyclohexa-1,5-dien-1-
ylsulfonyl)benzene.
9-12).19 The formation of these enantioenriched sulfones
(2g and 2h), which are ꢀ,ꢀ-dialkylsubstituted with sterically
unbiased groups, clearly demonstrates the efficiency of this
new process. Compounds with such substituents cannot be
accessed with good enantiodifferentiation by the reduction
of ꢀ,ꢀ-disubstituted vinyl sulfones due to the lack of facial
selectivity induced by the copper hydride. Moreover, these
ꢀ,ꢀ-dialkylsubstituted sulfones are not accessible using the
rhodium-catalyzed boronic acid addition since these additions
require aromatic or alkenyl nucleophiles.10
We recently reported a straightforward procedure to
generate salt-free diorganozinc reagents in Et2O from Grig-
nard reagents and Zn(OMe)2.20 Using this method, we
synthesized various diorganozinc reagents and submitted
them to our system (Table 4). Similar results to those of
Supporting Information Available: Experimental pro-
cedures for the preparation of compounds and spectroscopic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL800747V
(19) We submitted the cyclic vinyl sulfones (cyclohexa-1,5-dien-1-
ylsulfonyl)benzene and 2-(cyclohex-1-en-1-ylsulfonyl)pyridine to our op-
timized conditions in benzene, but none of the addition product was observed
in both cases.
(20) Coˆte´, A.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 2771.
(21) For a theoretical study, see: Haaland, A.; Green, J. C.; McGrady,
G. S.; Downs, A. J.; Gullo, E.; Lyall, M. J.; Timberlake, J.; Tutukin, A. V.;
Volden, H. V. Dalton Trans. 2003, 4356.
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Org. Lett., Vol. 10, No. 11, 2008