Catalytic enantioselective reduction of β,β-disubstituted vinyl phenyl sulfones by using bisphosphine monoxide ligands

Article abstract of DOI:10.1002/anie.200701367

(Chemical Equation Presented) Synthesis of chiral sulfones: A copper-phosphine complex efficiently provided optically active alkyl phenyl sulfones by hydrosilylation at room temperature. The reduction of β,β-disubstituted vinyl sulfones in the presence of the Me-DuPhos monoxide ligand lead to excellent enantiomeric excesses and high yields (see scheme). The prepared chiral sulfones were desulfonylated and subjected to Julia olefination conditions.

Full text of DOI:10.1002/anie.200701367

Angewandte
Chemie
DOI: 10.1002/anie.200701367
Asymmetric Catalysis
Catalytic Enantioselective Reduction of b,b-Disubstituted Vinyl
Phenyl Sulfones by Using Bisphosphine Monoxide Ligands**
Jean-Nicolas Desrosiers and AndrØ B. Charette*
Sulfones with b stereocenters are important compounds in
organic chemistry that provide valuable intermediates in the
synthesis of biologically active compounds and natural
products.[1] These versatile synthons can be converted into
several functionalities by alkylation, halogenation, oxidation,
and desulfonylation reactions and by Julia olefinations.[2,3]
One attractive approach to generate this moiety is the
reduction of the carbon–carbon double bond of vinyl sulfones.
Optically active alkyl phenyl sulfones have been synthe-
sized by hydrogenation of b,b-disubstituted vinyl phenyl
sulfones with rhodium as a catalyst, but high hydrogen
pressure is required.[4] Misun and Pfaltz have also performed
a conjugate reduction of vinyl phenyl sulfones with sodium
borohydride and a catalytic amount of a chiral semicorrin
cobalt complex but the enantioselectivities were modest
(ꢀ 40% ee).[5] During the preparation of this manuscript,
Carretero and co-workers published an efficient methodology
to perform the asymmetric conjugate reduction of b,b-
disubstituted vinyl 2-pyridyl sulfones.[6] This method could
be applied to a wide variety of substrates with excellent yields
and enantioselectivities. However, when the 2-pyridyl sub-
stituent on sulfones was replaced by a phenyl group, the
resulting vinyl sulfones were inert under the developed
reaction conditions. Thus, the conjugate asymmetric reduc-
tion of vinyl phenyl sulfones has not been accomplished by a
convenient and general procedure. Herein, we report the
enantioselective reduction of vinyl phenyl sulfones catalyzed
by a copper–phosphine complex (Scheme 1).
Scheme 1. Reduction of vinyl phenyl sulfones 1.
efficiency of stoichiometric achiral copper hydride reagents to
reduce b,b-disubstituted vinyl sulfones,[12] we felt that a
copper–phosphine-catalyzed hydrosilylation, with silanes as
a safe source of hydride that tolerates sensitive functional
groups,[13] could be applicable to the conjugate reduction of
vinyl phenyl sulfones 1.
Our initial efforts focused on identifying the best chiral
phosphine and the optimal reaction conditions for the
reduction to enantioenriched 2 in high yields (Table 1). As a
first screening, we treated substrate 1a under reaction
Table 1: Enantioselective reduction of vinyl phenyl sulfones 1a.[a]
Over the last few years, the copper-catalyzed hydro-
silylation of prochiral unsaturated compounds bearing elec-
tron-withdrawing substituents has been successfully
employed to reduce b,b-disubstituted unsaturated carbon-
yls,[7] nitroalkenes,[8] imines,[9] ketones,[10] and nitriles.[11] This
approach can usually be accomplished at ambient pressure
and temperature with readily available reagents. Given the
Entry
Solvent
Silane ([equiv])
Yield[b] [%]
ee[c] [%]
1[d]
2
3
4
5
6
7
8
9
10
11[e]
12[f]
13[g]
toluene
DME
THF
PMHS (4)
22
19
31
50
66
19
28
39–78
51
36
92
95
85
92
99
99
99
99
99
99
99
99
99
97
98
99
PhSiH3 (1.5)
PhSiH3 (1.5)
PhSiH3 (1.5)
PhSiH3 (1.5)
PhMeSiH2 (2.0)
PMHS (2.0)
PhSiH3 (1.5)
PhSiH3 (2.3)
PhSiH3 (3.8)
PhSiH3 (1.5)
PhSiH3 (1.5)
PhSiH3 (1.5)
MTBE
toluene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
[*] J.-N. Desrosiers, A. B. Charette
DØpartement de Chimie
UniversitØ de MontrØal
P.O. Box 6128, Station Downtown, MontrØal, QuØbec H3S 3J7
(Canada)
Fax: (+1)514-343-5900
E-mail: andre.charette@umontreal.ca
Homepage: http://charette.corg.umontreal.ca
[a] Reactions were carried out overnight under argon at room temper-
ature. DME: 1,2-dimethoxyethane; THF: tetrahydrofuran; MTBE: tert-
butyl methyl ether; PMHS: polymethylhydrosiloxane; Tol-Binap: 2,2’-
bis(di-p-tolylphosphanyl)-1,1’-binaphthyl. [b] Determined by 1H NMR
spectroscopy with 1,3,5-trimethoxybenzene as an internal standard.
[c] Enantiomeric excess determined by chiral SFC. [d] Conditions: Tol-
Binap (10 mol%) instead of 3a, CuCl (5 mol%), no H2O, NaOtBu (5
mol%) as an additive. [e] With 20 mol% solid NaOH. [f] With 20 mol%
aq. KOH. [g] With 20 mol% aq. NaOH.
[**] This work was supported by NSERC (Canada), Merck Frosst Canada
Ltd., Boehringer Ingelheim (Canada) Ltd., the Canada Research
Chairs Program, the Canadian Foundation for Innovation, and the
UniversitØ de MontrØal. J.-N.D. is grateful to NSERC (CGS D) for a
postgraduate fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 5955 –5957
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5955

Communications
conditions developed by Buchwald and co-workers[7a] for the
Table 2: Synthesis of enantioenriched alkyl sulfones 2a–g.
reduction of b,b-disubstituted unsaturated esters. This
approach resulted in good enantioselectivities, but the
products were obtained in poor yields (Table 1, entry 1).
Recently, we have shown that the hemilabile bidentate ligand
Me-DuPhos monoxide is particularly effective in copper-
catalyzed nucleophilic addition reactions with sp2 centers. In
the presence of this ligand, the copper-catalyzed addition of
diorganozinc reagents to phosphinoylimines and nitroalkenes
proceeded with a high level of enantiocontrol.[14,15]
Entry
1
Vinyl sulfone
Yield[a] [%]
85 (83)
ee[b] [%]
99
Our initial attempt at reducing substrate 1a by using
ligand 3a and CuF2·H2O, as a cheap source of copper,
generated sulfone 2a with high enantioselectivity (99% ee).
However, the yield was mediocre in DME (Table 1, entry 2).
At that point, we focused on increasing the conversion
without affecting the enantiocontrol. Various solvents were
tested and it was found that ethers (Table 1, entries 3 and 4)
gave lower conversions than less polar aromatic solvents such
as toluene and benzene (Table 1, entries 5 and 8). Phenyl-
silane was superior to phenylmethylsilane and PMHS
(Table 1, entries 6 and 7); however, the yield of the reduction
product significantly decreased when more than 1.5 equiva-
lents were used (Table 1, entries 9 and 10).
2
3
93 (85)
85 (98)
98
98
4
97 (81)
99
99
5
90 (88)
Good conversion could be achieved in benzene with
1.5 equivalents of phenylsilane, but the results were not
constant and the yield varied from 39–78% (Table 1, entry 8).
Finally, we discovered that the addition of a basic additive was
necessary to obtain reproducible conversions. We believe that
the presence of NaOH or KOH is crucial in order to eliminate
the detrimental competitive silylation of water by PhSiH3 and,
consequently, to reach full conversion.[7b,16,17] When a catalytic
amount of solid NaOH or aqueous KOH was introduced into
the reaction mixture, a slight decrease in the enantioselectiv-
ity was observed (Table 1, entries 11 and 12), whereas
20 mol% of 5.5m aqueous NaOH afforded 85% yield and
99% ee (Table 1, entry 13).[18,19] It is important to mention
that the use of a hemilabile bidentate ligand is essential for
the efficient reduction of vinyl phenyl sulfones since Me-
DuPhos gave sulfone 2a with only 7% yield and JosiPhos[22]
led to 32% yield and 93% ee under these optimal conditions.
A variety of vinyl phenyl sulfones were submitted to these
optimized conditions, and the results are summarized in
Table 2. All of the reactions proceeded smoothly and were
complete after being stirred at room temperature for 12h.
Substrates bearing the a-methyl styryl subunit (Table 2,
entries 1–3) underwent the conjugate reduction with high
yields and excellent ee values. Excellent stereocontrol was
also observed in the case of cyclic substrates such as the
indenyl, 1d, and the tetrahydronaphthyl, 1e, derivatives, with
99% ee in both cases (Table 2, entries 4 and 5). For the acyclic
aliphatic sulfone 1 f, Me-DuPhos(O) gave moderate enantio-
selectivities (Table 2, entry 6). However, when the bulkier Et-
DuPhos(O) (3b) was used instead of 3a, the reaction afforded
2 f in 94% yield and 90% ee (Table 2, entry 7). When a
substrate with a longer lateral b-propyl chain was reduced
(Table 2, entry 8), the yield dropped to 61% but the
enantioselectivity remained very high (97% ee).
6[c]
7
89 (77)
94[d]
70
90[d]
8
61 (33)
97[e]
[a] Yields of isolated product; values in brackets are yields of isolated
product with 10 mol% of Bu3P instead of 3a. [b] Enantiomeric excess
determined by chiral SFC. [c] Tr: triphenylmethyl. [d] Ligand 3b was used
instead of 3a. [e] The absolute configuration could not be correlated.
replacing Me-DuPhos(O) with an achiral ligand. More s-
donating phosphines (such as Bu3P) led to higher conversions
than triarylphosphines (> 98% with Bu3P versus 74% with
Ph3P).[20] All aromatic vinyl sulfones reacted with good to
excellent yields. The g-oxygenated sulfone 2 f was isolated
with 77% yield and substrate 2g, flanked with a phenyl group
and an n-propyl chain at the b position, afforded the desired
product in 33% yield (Table 2).
Chiral sulfones 2 provide a convenient handle for further
transformations (Scheme 2). For example, sulfone 2e could
be treated under the Julia olefination conditions[3] to provide
the E alkene 4 as the major isomer (85:15) in 56% yield and
During the course of this study on the reduction of vinyl
phenyl sulfones, racemic mixtures were synthesized by
Scheme 2. Useful transformations of enantioenriched sulfones.
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 5955 –5957
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Chemie
[3] a) M. Julia, J.-M. Paris, Tetrahedron Lett. 1973, 14, 4833 – 4836;
without erosion of the enantiomeric excess. Moreover,
sulfone 2e could be desulfonylated[2b] to an unfunctionalized
tertiary chiral center by using Na(Hg). This approach is an
interesting alternative to the Ir-catalyzed hydrogenation of
alkenes by Pfaltz and co-workers.[21]
b) P. J. Kocienski, Phosphorus Sulfur Relat. Elem. 1985, 24, 97 –
127; c) J. M. J. Williams in Preparation of Alkenes: A Practical
Approach (Ed.: A. Armstrong), Oxford University, Oxford,
1996, pp. 71 – 77.
[4] J. M. Paul, C. Palmer, US 6,274,758, 2001.
In conclusion, we have developed a hydrosilylation of b,b-
disubstituted vinyl sulfones that provides racemic and opti-
cally active alkyl sulfones efficiently. Excellent enantiomeric
excesses and high yields were obtained at room temperature
by using the hemilabile bidentate ligands 3a or 3b. We have
demonstrated that these substrates have great potential in
total synthesis by performing various useful transformations
such as olefination and desulfonylation.
[5] M. Misun, A. Pfaltz, Helv. Chim. Acta 1996, 79, 961 – 972.
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Experimental Section
General procedure: A flame-dried 10-mL round-bottomed flask
equipped with an egg-shaped magnetic stirring bar was charged with
CuF2·H2O (3 mg, 0.025 mmol, 5 mol%) and ligand 3a (8.8 mg,
0.027 mmol, 5.5 mol%) in a glove box. Benzene (1.5 mL) was
added to the mixture and the resulting suspension was stirred under
argon at room temperature for 1 h. After that, PhSiH3 (92 mL,
0.75 mmol, 1.5 equiv) was added and the resulting mixture was stirred
for exactly 1 min. A 5.5m aqueous solution of NaOH (18 mL,
0.10 mmoles, 20 mol% of NaOH and equal to 2 equivalents of
water) was then added and, immediately afterwards, a solution of the
vinyl sulfone 1 (0.5 mmoles, 1 equiv) dissolved in a minimum amount
of benzene (1.5 to 4 mL) was added through a syringe under argon.
The heterogeneous mixture was stirred for 12h at room temperature.
The mixture was filtered over celite and the reaction flask was washed
twice with benzene (2” 2mL). The filtrate was evaporated under
reduced pressure. The crude product was purified by flash chroma-
tography on silica gel (10–20% EtOAc/hexane) to afford the desired
enantioenriched sulfone 2 as a white powder.
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Received: March 29, 2007
Published online: June 5, 2007
[15] For a review, see: V. V. Grushin, Chem. Rev. 2004, 104, 1629 –
1662.
Keywords: asymmetric catalysis · copper · phosphine ligands ·
[16] U. Schubert, C. Lorenz, Inorg. Chem. 1997, 36, 1258 – 1259.
[17] Various amounts of H2O and several alcohols (MeOH, EtOH,
iPrOH) were tested, but lower conversions were observed.
[18] The catalyst loading can be decreased to 2.5 mol% (85%, 98%
ee) or even to 1 mol% (63%, 97% ee).
[19] In the final optimized conditions, the benzene used as the
reaction media and washing solvent during the work-up
procedure can be replaced by toluene, with similar results
(84%, 99% ee).
[20] The use of 5 mol% of Bu3P was equally effective.
[21] S. Kaiser, S. P. Smidt, A. Pfaltz, Angew. Chem. 2006, 118, 5318 –
5321; Angew. Chem. Int. Ed. 2006, 45, 5194 – 5197.
[22] Me-DuPhos = 1,2-bis[(2R,5R)-2,5-dimethylphospholano]ben-
zene; JosiPhos = [(diphenylphosphanyl)ferrocenyl]ethyldicyclo-
hexylphosphine.
.
reduction · sulfones
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