Catalytic asymmetric conjugate addition of Grignard reagents to α,β-unsaturated sulfones

Article abstract of DOI:10.1021/ol801566n

(Chemical Equation Presented) A highly efficient method is reported for the asymmetric conjugate addition of Grignard reagents to α,β- unsaturated 2-pyridylsulfones. Using a Cu/TolBinap complex, excellent enantioselectivities and high yields are obtained

Full text of DOI:10.1021/ol801566n

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4219-4222
Catalytic Asymmetric Conjugate
Addition of Grignard Reagents to
r,ꢀ-Unsaturated Sulfones
Pieter H. Bos, Adriaan J. Minnaard, and Ben L. Feringa*
The Stratingh Institute for Chemistry, UniVersity of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
b.l.feringa@rug.nl
Received July 10, 2008
ABSTRACT
A highly efficient method is reported for the asymmetric conjugate addition of Grignard reagents to r,ꢀ-unsaturated 2-pyridylsulfones. Using
a Cu/TolBinap complex, excellent enantioselectivities and high yields are obtained for a wide variety of aliphatic substrates.
The conjugate addition of organometallic reagents to R,ꢀ-
unsaturated compounds is one of the most versatile of
methods for the formation of C-C bonds.1 This transforma-
tion is used as a key step in the synthesis of numerous natural
products and biologically active compounds and has been
the subject of intensive research over the past decade.2
The development of a catalytic method for the enantiose-
lective conjugate addition reaction of organometallic reagents
to R,ꢀ-unsaturated sulfones is an important goal in extending
the current methodology. Sulfones with a stereocenter at the
ꢀ-position are highly versatile synthons in organic chemistry
due to the ease of derivatization and access to a wide range
of building blocks, including aldehydes and ketones, alkynes,
alkenes, alkanes, and haloalkanes.3
Recently, Carretero et al.4 and Charette et al.5 both reported
a methodology for the catalytic asymmetric conjugate
reduction of ꢀ,ꢀ-disubstituted R,ꢀ-unsaturated sulfones lead-
ing to alkyl aryl sulfones in excellent yields and enantiomeric
excesses. A complementary approach to sulfones bearing ꢀ
stereocenters is the asymmetric conjugate addition of orga-
nometallic reagents to R,ꢀ-unsaturated sulfones. In 2004,
Mauleo´n and Carretero reported a rhodium-catalyzed asym-
metric conjugate addition of organoboronic acids to R,ꢀ-
unsaturated sulfones with high to excellent yields and good
enantioselectivities.6 The very recent report by Charette et
al. on a catalytic asymmetric conjugate addition of diorga-
nozinc reagents to ꢀ-substituted vinyl sulfones prompted us
to disclose our results on the enantioselective conjugate
addition of Grignard reagents to sulfones.7
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis.
Tetrahedron Organic Chemistry Series 9; Pergamon Press: Oxford, U.K.,
1992. (b) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771–806.
(2) For reviews, see: (a) Tomioka, K.; Nagaoka, Y. ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999; Vol. 3, pp 1105-1120. (b) Feringa, B. L. Acc.
Chem. Res. 2000, 33, 346–353. (c) Krause, N.; Hoffmann-Ro¨der, A.
Synthesis 2001, 171–196. (d) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold,
L. A. In Modern Organocopper Chemistry; Krause, N., Ed.; VCH:
Weinheim, Germany, 2002; pp 224-258. (e) Alexakis, A.; Benhaim, C.
Eur. J. Org. Chem. 2002, 3221–3236. (f) Hayashi, T.; Yamasaki, K. Chem.
ReV. 2003, 103, 2829–2844. (g) Woodward, S. Angew. Chem., Int. Ed. 2005,
44, 5560–5562. (h) Lo´pez, F.; Minnaard, A. J.; Feringa, B. L. Acc. Chem.
Res. 2007, 40, 179–188. (i) Lo´pez, F.; Minnaard, A. J.; Feringa, B. L. In
The Chemistry of Organomagnesium Compounds; Rappoport, Z., Marek,
I., Eds.; Wiley: Chichester, U.K., 2008; Part 2, Chapter 17. (j) Harutyunyan,
S. R.; den Hartog, T.; Geurts, K.; Minaard, A. J.; Feringa, B. L. Chem.
ReV. 2008, 108, 2824–2852.
(3) (a) Prilezhaeva, E. N. Russ. Chem. ReV. 2000, 69, 367. (b) Kelly,
S. E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 1, pp 792. (c) Trost, B. M. Bull. Chem.
Soc. Jpn. 1988, 61, 107.
(4) Llamas, T.; Arraya´s, R. G.; Carretero, J. C. Angew. Chem., Int. Ed.
2007, 46, 3329–3332.
(5) Desrosiers, J.-N.; Charette, A. B. Angew. Chem., Int. Ed. 2007, 46,
5955–5957.
10.1021/ol801566n CCC: $40.75
Published on Web 09/04/2008
2008 American Chemical Society

Catalytic methods for the addition of Grignard reagents
to R,ꢀ-unsaturated ketones, esters, and thioesters developed
in our group8 stimulated us to explore the extension of the
Cu-catalyzed Grignard addition to R,ꢀ-unsaturated sulfones.
Common Grignard reagents are complementary to diorga-
nozinc reagents and have in some cases distinct advantages
such as their ready availability and the transfer of all the
alkyl groups of the organometallic reagent.
In this paper, we describe the first asymmetric copper-
catalyzed conjugate addition of Grignard reagents to R,ꢀ-
unsaturated sulfones. The reaction shows a broad scope and
high yield and enantioselectivity.
Table 2. Solvent Dependence in the Addition of EtMgBr to
Sulfone 3aa,b
entry
solvent
DCM
eec,d (%)
1
2
3
4
5
6
7
87 (+)
80 (+)
88 (+)
92 (+)
8 (-)
toluene
t-BuOMe
t-BuOMee
THF
Initially, we studied the addition of ethylmagnesium
bromide to R,ꢀ-unsaturated sulfone 1 using bidentate phos-
phine ligands (L1-L4, Table 1). All reactions gave full
Et2O
76 (+)
68 (+)
CPMEf
a Conditions: 3a (1 equiv, 0.1 mmol), EtMgBr (1.2 equiv), CuI (5 mol
%), L1 (6 mol %) in solvent at -40 °C, 16 h. b Full conversion after 16 h,
determined by GC-MS. c Determined by chiral HPLC (see the Supporting
Information). d The absolute stereochemistry of the product is not known.
e Slow addition of substrate over 5 h. f CPME ) cyclopentyl methyl ether.
Table 1. Copper/Ligand Catalyzed Addition of EtMgBr to
Rꢀ-Unsaturated Sulfone 1a, b
Running the reaction in DCM or t-BuOMe resulted in similar
enantioselectivities (Table 2, entries 1 and 3).
Using toluene, Et2O, or CPME as a solvent provided a
slightly lower ee. However, slow addition of the substrate
over 5 h to the reaction mixture in t-BuOMe increased the
enantiomeric excess significantly (entry 4). Notably, the use
of THF resulted in a very low enantiomeric excess.10
entry
ligand
eec,d (%)
1
2
3
4
(R)-Tol-Binap (L1)
(S,RFc)-Josiphos (L2)
(R,RFc)-Taniaphos (L3)9
(R)-Binap (L4)
47 (R)
6 (S)
3 (S)
The influence of the 2-pyridyl group was examined by
applying the asymmetric conjugate addition to the corre-
sponding p-tolyl-substituted R,ꢀ-unsaturated sulfone instead
of a 2-pyridyl-substituted sulfone 3a. This decreased the
reaction rate and enantiomeric excess (35% conversion after
3 d, 31% ee) dramatically. This effect of the 2-pyridyl group
has also been noted also by Carretero4,6 and Charette and
co-workers7 for related systems. The 2-pyridyl group seems
to be necessary both in terms of enantioselectivity and
reactivity.
46 (R)
a Conditions: 1 (1 equiv, 0.1 mmol in DCM), EtMgBr (1.2 equiv), CuI
(with L1/L4) or CuBr·Me2S (with L2/L3) (5 mol %), L1-L4 (5 mol %)
in t-BuOMe at -40 °C, 16 h. b Full conversion after 16 h, determined by
GC-MS. c Enantiomeric excess determined by chiral HPLC (see the
Supporting Information). d Determined by comparison with literature data
based on the sign of the optical rotation.
conversion overnight, but the best results were obtained using
binaphthyl-type phosphine ligands L1 and L4, whereas
ferrocenyl-type ligands L2 and L3 gave negligible enanti-
oselectivity. Tol-Binap L1 provided a slightly higher enan-
tiomeric excess compared to Binap (L4) and was used for
further screening.
Next we switched to aliphatic substrates, and by applying
the Cu-TolBinap system, the addition to R,ꢀ-unsaturated
sulfone 3a in several solvents was examined (Table 2). In
all cases, full conversion was obtained overnight at -40 °C.
With the exception of copper(I) cyanide, which gave a
lower enantiomeric excess, all copper(I) and copper(II) salts
tested provided similar results in the conjugate addition
reaction of EtMgBr to sulfone 3a (Table 3). In all cases, a
quantitative conversion was obtained and no significant effect
of the change in counterion (except for CN-) was observed.
Slow addition of the substrate to the reaction mixture
increased the enantioselectivity in some cases (Table 3,
entries 4 and 5), and copper(I) chloride was found to be the
(6) (a) Mauleo´n, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195–3198. (b)
Mauleo´n, P.; Carretero, J. C. Chem. Commun. 2005, 4961–4963. (c)
Mauleo´n, P.; Alonso, I.; Rivero, M. R.; Carretero, J. C. J. Org. Chem. 2007,
72, 9924–9935.
(9) The correct stereochemistry of (+)-Taniaphos L3 is (+)-(R,RFc).
Based on information in the literature, previous articles have erroneously
depicted the ligand as its (R,SFc) diastereomer. See also: (a) Ireland, T.;
Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P. Angew. Chem., Int.
Ed. 2008, 47, 3666. (b) Fukuzawa, S.-i.; Yamamoto, M.; Hosaka, M.;
Kikuchi, S. Eur. J. Org. Chem. 2007, 5540–5545. (c) Fukuzawa, S.-i.;
Yamamoto, M.; Kikuchi, S. J. Org. Chem. 2007, 72, 1514–1517.
(10) This dependence is in contrast to that reported by Charette and
co-workers for organozinc reagents in which an increase in enantioselectivity
was observed with THF as solvent; see ref 7.
(7) Desrosiers, J.-N.; Bechara, W. S.; Charette, A. B. Org. Lett. 2008,
10, 2315–2318.
(8) (a) Feringa, B. L.; Badorrey, R.; Pen˜a, D.; Harutyunyan, S. R.;
Minnaard, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834–5838. (b)
Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2004, 126, 12784–12785. (c) Lo´pez, F.; Harutyunyan, S. R.; Meetsma,
A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 2752–
2756. (d) Des Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.;
Minaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966–9967.
(e) Ruiz, B. M.; Geurts, K.; Ferna´ndez-Iba´n˜ez, M. A.; Ter Horst, B.;
Minnaard, A. J.; Feringa, B. L. Org. Lett. 2007, 9, 5123–5126.
(11) Other sulfones with a substituted phenyl group at the γ-position
gave equally moderate results (p-CF3-1: 65% yield, 51% ee and p-Br-1:
76% yield, 70% ee) under the optimized conditions.
4220
Org. Lett., Vol. 10, No. 19, 2008

Table 3. Influence of Copper Source on the Addition of
EtMgBr to Sulfone 3aa,b
Table 5. Asymmetric Conjugate Addition of Various Grignard
Reagents to Sulfone 3aa, b
entry
[Cu] source
eec,d (%)
entry
R
product
yieldc (%)
eed,e (%)
1
2
3
4
5
6
7
CuCN
CuBr·Me2S
Cu(OTf)2
CuI
69 (+)
89 (+)
87 (+)
88 (+)
92 (+)
93 (+)
93 (+)
1
2
3
4
5
6
Et
Me
n-Bu
C6H5C2H4
But-3-enyl
Ph
4a
4b
4c
4d
4e
4f
97
80
88
87
95
80
93 (+)
89 (-)
93 (+)
87 (-)
94 (+)
0
CuIe
CuCl
CuCle
a Conditions: 3a (1 equiv), RMgBr (1.2 equiv), CuCl (5 mol %), L1 (6
mol %) in t-BuOMe at -40 °C, 16 h. b Full conversion after 16 h,
determined by GC-MS. c Isolated yields. d Enantiomeric excesses determined
by chiral HPLC (see Supporting Information). e The absolute stereochemistry
of the products is not known.
a Conditions: 3a (1 equiv, 0.1 mmol), EtMgBr (1.2 equiv), Cu salt (5
mol %), L1 (6 mol %) in t-BuOMe at -40 °C, 16 h. b Full conversion
after 16 h, determined by GC-MS. c Enantiomeric excesses determined
by chiral HPLC (see the Supporting Information). d The absolute stereo-
chemistry of the product is not known. e Slow addition of substrate over
5 h.
oselectivities and a slightly lower yield (Table 5, entries 3
and 4). Furthermore, the use of but-3-enylmagnesium
bromide also resulted in excellent yield and enantioselectivity
(Table 5, entry 5). Notably, the reaction using PhMgBr did
not proceed in an enantioselective manner (Table 5, entry
6).
most suitable copper source for this reaction giving quantita-
tive conversion and 93% ee (Table 3, entries 6 and 7).
Increasing the metal to ligand ratio to 2:1 results in a
decrease in enantioselectivity (Table 4). We attribute this to
The synthetic applicability of this highly enantioselective
procedure was extended using a set of R,ꢀ-unsaturated
substrates under the optimized conditions (Table 6). All
Table 4. Influence of Copper to Ligand Ratio on the Addition
of EtMgBr to Sulfone 3aa, b
Table 6. Asymmetric Conjugate Addition of EtMgBr to
Rꢀ-Unsaturated Sulfonesa, b
entry
CuCl (mol %)
L1 (mol %)
[Cu]/L1
eec,d (%)
1
2
3
4
5
10
5
5
5
10
1:1
2:1
1:2
1:1.2
83 (+)
62 (+)
85 (+)
93 (+)
entry
3
R
product yield (%)c eed,e (%)
5
6
1
2
3
4
5
6
7
3a
n-Pent
4a
5
97
90
88
93
94
91
91
93 (+)
92 (+)
94 (-)
88 (-)
94 (-)
92 (+)
93 (+)
a Conditions: 3a (1 equiv), EtMgBr (1.2 equiv), CuCl, and L1 in
t-BuOMe at -40 °C, 16 h. b Full conversion after 16 h, determined by
GC-MS. c Enantiomeric excesses determined by chiral HPLC (see the
Supporting Information). d The absolute stereochemistry of the product is
not known.
3b n-Oct
3c i-Bu
3d i-Pr
3e
3f
6
7
8
9
c-Hex
TBDPSOC2H4
C6H5C2H4
3g
10
a Conditions: 3 (1 equiv, 0.2 mmol), EtMgBr (1.2 equiv), CuCl (5 mol
%), L1 (6 mol %) in t-BuOMe at -40 °C, 16 h. b Full conversion after
16 h, determined by GC-MS. c Isolated yields. d Enantiomeric excesses
determined by chiral HPLC (see the Supporting Information). e The absolute
stereochemistry of the products is not known.
the fact that not all of the copper is bound to the ligand,
giving rise to a significant amount of ligand-free copper-
mediated reaction. It was found that a small excess of ligand
with respect to the copper gave the best result. Increasing
the ligand to metal ratio further (entry 3) did not improve
the enantioselectivity.
Several Grignard reagents were examined using the
conditions optimized for EtMgBr (Table 5). In all cases, full
conversion was observed after 16 h, and high isolated yields
and ee’s (except for entry 6) were obtained. With MeMgBr
a slightly lower enantiomeric excess and yield were attained.
Both n-BuMgBr and C6H5C2H4MgBr gave similar enanti-
sulfones provided the desired products in excellent yields
(88-97%) and excellent enantioselectivities (88-94%).
Substitution of the R,ꢀ-unsaturated sulfone at the γ- or
δ-position did not influence the enantioselectivities or yields
(Table 6, entries 1-5), and the reactions proceed with both
excellent yields and enantiomeric excesses. The presence of
Org. Lett., Vol. 10, No. 19, 2008
4221

a protected alcohol group or phenyl group at the δ-position
in the substrate did not affect this enantioselective transfor-
mation either and the reactions resulted in high isolated yields
of optically active ꢀ-substituted sulfones with excellent ee’s.
This is in sharp contrast with the results obtained for sulfone
1 substituted with a phenyl group at the γ-position (Table
1, 47% ee) which gave only moderate results under the
optimized conditions (75% yield, 50% ee).11
Acknowledgment. Financial support from The Nether-
lands Organization for Scientific Research (NWO-CW) is
acknowledged. T. den Hartog (Stratingh Institute for Chem-
istry, University of Groningen) is thanked for fruitful
discussions. We thank T. D. Tiemersma-Wegman (GC and
HPLC) and A. Kiewiet (MS) for technical assistance
(Stratingh Institute for Chemistry, University of Groningen).
In summary, we have developed a novel copper-catalyzed
asymmetric conjugate addition of Grignard reagents to a range
of aliphatic R,ꢀ-unsaturated sulfones. This procedure has a broad
scope for aliphatic substrates and provides ꢀ-substituted
2-pyridyl sulfones in both excellent yields (88-97%) and
enantioselectivities (88-94%). These enantioenriched sulfones
are versatile intermediates in the preparation of a wide variety
of functionalized chiral building blocks.
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.
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Org. Lett., Vol. 10, No. 19, 2008