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

Article abstract of DOI:10.1039/b917269f

An efficient method is reported for the highly enantioselective copper-catalyzed conjugate addition of dialkylzinc reagents to α,β-unsaturated sulfones using a monodentate phosphoramidite ligand. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b917269f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Catalytic asymmetric conjugate addition of dialkylzinc reagents to
a,b-unsaturated sulfones†
´
Pieter H. Bos, Beatriz Macia´, M. Angeles Ferna´ndez-Iba´n˜ez, Adriaan J. Minnaard and Ben L. Feringa*
Received 21st August 2009, Accepted 21st September 2009
First published as an Advance Article on the web 1st October 2009
DOI: 10.1039/b917269f
Table 1 Optimization of solvent and temperaturea
An efficient method is reported for the highly enantioselective
copper-catalyzed conjugate addition of dialkylzinc reagents
to a,b-unsaturated sulfones using a monodentate phospho-
ramidite ligand.
The conjugate addition of organometallic reagents to a,b-
Solvent
Temperature (◦C)
Conversionb (%)
eec,d (%)
unsaturated compounds is one of the most versatile and widely
used synthetic methods for carbon–carbon bond formation.1
Enantioselective metal-catalyzed versions of this transformation
are used as key-steps in the synthesis of numerous natural
products and biologically active compounds and have been studied
extensively over the past decade.2
1e
2e
3e
4e
5
Toluene
Toluene
Toluene
Toluene
Toluene
THF
-40
-25
-10
0
0
0
100 (72 h)
100 (48 h)
100 (24 h)
100 (24 h)
100 (24 h)
0 (24 h)
94 (S)
95 (S)
95 (S)
92 (S)
88 (S)
nd
6
An important goal in extending the current methodology is
the development of an enantioselective catalytic method for the
addition of organometallic reagents to a,b-unsaturated sulfones.
Optically active sulfones with a stereocenter at the b-position
are valuable intermediates in organic chemistry due to their ease
of derivatization yielding a variety of building blocks, including
aldehydes or ketones, alkenes, alkynes, alkanes and haloalkanes.3
In 2007, Carretero et al.4 and Charette and Desrosiers5 both
reported methodology for the catalytic asymmetric conjugate
reduction of b,b-disubstituted a,b-unsaturated sulfones leading
to alkyl aryl sulfones. Using a hydrosilylation approach excellent
yields and enantiomeric excesses were obtained.
A complementary approach to sulfones bearing b stereocenters
is the asymmetric conjugate addition of organometallic reagents
to a,b-unsaturated sulfones. In 2004, Mauleo´n and Carretero
reported a rhodium-catalyzed asymmetric conjugate addition of
organoboronic acids to a,b-unsaturated sulfones giving high to
excellent yields and enantioselectivities.6
Recently, Charette et al. reported a method for the catalytic
asymmetric conjugate addition of diorganozinc reagents to b-
substituted vinyl sulfones using a bidentate phosphorus based
ligand (Binap) and elevated temperatures (60 ◦C) with good
results.7 Performing the reaction in benzene gave high yields and
lower enantioselectivities while using THF gave an increase in
ee, but lower yields. Our group recently developed a copper-
catalyzed asymmetric conjugate addition of Grignard reagents to
a,b-unsaturated sulfones giving excellent results using a bidentate
phosphorus based ligand (Tol-Binap) and aliphatic substrates.8
In this paper we describe the first asymmetric conjugate addition
of diorganozinc reagents to a,b-unsaturated sulfones using a
7
8
9
Et2O
t-BuOMe
DCM
0
0
0
25 (24 h)
30 (24 h)
12 (24 h)
nd
nd
nd
a Conditions: 1 (1 equiv., 0.1 mmol), Et2Zn (3.2 equiv.), Cu(OTf)2
(5 mol%), (S,R,R)-L1 (10 mol%). b Conversion determined by GC-
MS. c Enantiomeric excess determined by chiral HPLC (See the ESI†).
d Determined by comparison with literature data based on the sign of
optical rotation. e Slow addition of the substrate 1a over 5 h.
monodentate phosphoramidite ligand (L1). Among all the ligands
used so far in the field of copper-catalyzed conjugate addition
of organometallic reagents, phosphoramidites stand out as read-
ily accessible, inexpensive and easily modified.9 The excellent
enantioselectivities that phosphoramidites give in the conjugate
addition of dialkylzinc reagents to a variety of substrates10
encouraged us to use them as ligands in the conjugate addition
of diorganozinc reagents to a,b-unsaturated sulfones.
Initially, we studied the addition of diethylzinc to a,b-
unsaturated sulfone 1a using phosphoramidite L1 (Fig. 1) at
various temperatures and in different solvents (Table 1).
Fig. 1 Structure of ligand (S,R,R)-L1.
At -40 ◦C in toluene, full conversion was obtained after 3 days
giving the product with excellent ee (entry 1). Upon increasing the
reaction temperature full conversion was obtained in 24 h while
the enantioselectivity remained excellent (entries 2–4). Upon direct
addition of the substrate to the reaction mixture the enantiomeric
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands. E-mail: b.l.feringa@rug.nl; Fax: +31
50 363 4278; Tel: +31 50 363 4296
† Electronic supplementary information (ESI) available: General proce-
dures for the synthesis of substrates and products; 1H and 13C NMR
spectral data of all products. See DOI: 10.1039/b917269f
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 47–49 | 47
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Table 2 Influence of copper sourcea
Table 4 Addition of various diorganozinc reagents to sulfone 1a
[Cu] source
Conversionb (%)
eec,d (%)
R
Product
Conversionb (%)
eec,d (%)
1
2
3
4
5
Cu(OTf)2
CuI
CuTC
CuBr2
CuOTf·benzene
100
0
0
5
40
88 (S)
nd
nd
nd
83 (S)
1
2
3
4
5
Et
2a
2b
2c
2d
2e
100 (70)
0
92(S)e
nd
66(+)
85(S)
nd
Me
n-Bu
i-Pr
Phg
84 (73)f
100 (61)
0
a Conditions: 1 (1 equiv., 0.1 mmol), Et2Zn (3.2 equiv.), Cu salt (5 mol%),
(S,R,R)-L1 (10 mol%) in toluene at 0 ◦C. b Conversion determined by GC-
MS after 24 h. c Enantiomeric excess determined by chiral HPLC (See the
ESI†). d Determined by comparison with literature data based on the sign
of optical rotation.
a Conditions: 1 (1 equiv., 0.25 mmol), R2Zn (3.2 equiv.), Cu(OTf)2
(7.5 mol%), (S,R,R)-L1 (11 mol%) in toluene at 0 ◦C. b Conversion deter-
mined by GC-MS after 24 h. Isolated yields in parentheses. c Enantiomeric
excess determined by chiral HPLC (See the ESI†). d Determined by
comparison with literature data based on the sign of optical rotation.
e Slow addition of the substrate over 5 h. f Conversion determined by GC-
MS after 5 days. g In this case 2-naphthyl substituted sulfone 1i was used.
excess dropped only slightly (entry 5). Use of either ethereal
solvents or DCM resulted in a large decrease in conversion (entries
6–9).
obtained after 24 h (entry 2). Di n-butylzinc gave less than
10% conversion after 24 h. Even after 5 days the conversion
was not complete, nevertheless the product could be isolated in
good yield and with moderate enantiomeric excess (entry 3). The
more reactive diisopropylzinc gave full conversion after 24 h and
both the isolated yield and enantiomeric excess dropped slightly
compared with diethylzinc (entry 4). Unfortunately, the use of
diphenylzinc did not give any reaction (entry 5).
Using optimized conditions we then studied the influence of the
substitution pattern of the substrate on the conjugate addition of
diethylzinc (Table 5). Because excellent results have been obtained
using Grignard reagents on aliphatic substrates,8 we focused our
efforts on a range of aromatic substrates for which excellent ee’s
were found. Introduction of a chloride at the ortho position gave
a drop in ee (entry 2). Moving the chloride further away from the
After optimization of reaction temperature and solvent the
influence of the copper source was examined (Table 2).
The catalyst based on copper(II) triflate gave full conversion
after 24 h and high enantiomeric excess. Changing the counterion
of the copper source had a dramatic effect on the conversion
of substrate 1a. This effect was observed for both copper(I) and
copper(II) salts and almost no conversion was obtained after 24 h
(entries 2–4). When copper(I) triflate was used the conversion
increased again, but both the conversion and the enantiomeric
excess were lower than the result obtained with copper(II) triflate
(entry 5). The nature of the counterion is of extreme importance
and it seems that the triflate counterion is necessary in order to
give good results.11
Changing the metal to ligand ratio did not have any effect on
the enantioselectivity, but upon using a ratio of 1:1.5 of copper to
ligand the conversion after 24 h increased slightly (Table 3).
After establishing the optimal conditions for the addition of
diethylzinc, several other diorganozinc reagents were examined
(Table 4). With the less reactive dimethylzinc no conversion was
Table 5 Asymmetric conjugate addition of Et2Zn to a,b-unsaturated
sulfonesa
Table 3 Influence of copper to ligand ratioa
R
Product
Yieldb,c (%)
eed,e (%)
1
2
3
4
5
6
7
8
9
Ph
2a
3
70
85
66
68
46g
84
52g
86
83
92 (S)f
70 (+)
84 (+)
89 (+)
92 (+)
96 (S)
90 (+)
96 (+)
93 (S)
o-Cl Phenyl
m-Cl Phenyl
p-Cl Phenyl
p-Me Phenyl
p-CF3 Phenyl
p-i-Pr Phenyl
p-Br Phenyl
2-Naphthyl
4
5
6
Cu(OTf)2 (mol%) L1 (mol%) [Cu]/L1 Conversionb (%) eec,d (%)
7
8
1
2
3
5
11
7.5
11
11
11
1:2.2
1:1
1:1.5
82
82
85
88 (S)
88 (S)
88 (S)
9
10
a Conditions: 1 (1 equiv., 0.25 mmol), Et2Zn (3.2 equiv.), Cu(OTf)2
(7.5 mol%), (S,R,R)-L1 (11 mol%) in toluene at 0 ◦C. b Full conversion
after 24 h determined by GC-MS. c Isolated yield. d Enantiomeric excess
determined by chiral HPLC (See the ESI†). e Determined by comparison
with literature data based on the sign of optical rotation. f Slow addition
of the substrate over 5 h. g Incomplete conversion.
a Conditions: 1 (1 equiv., 0.1 mmol), Et2Zn (3.2 equiv.), Cu(OTf)2,
(S,R,R)-L1 in toluene at 0 ◦C. b Conversion determined by GC-MS after
16 h. c Enantiomeric excess determined by chiral HPLC (See the ESI†).
d Determined by comparison with literature data based on the sign of
optical rotation.
48 | Org. Biomol. Chem., 2010, 8, 47–49
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reaction centre increased the enantiomeric excess (entries 2–4). We
attribute this effect to steric hindrance.
Ro¨der, Synthesis, 2001, 171–196; (d) B. L. Feringa, R. Naasz, R. Imbos
and L. A. Arnold, in Modern Organocopper Chemistry, ed. N. Krause,
VCH, Weinheim, Germany, 2002, pp. 224–258; (e) A. Alexakis and C.
Benhaim, Eur. J. Org. Chem., 2002, 3221–3236; (f) T. Hayashi and K.
Yamasaki, Chem. Rev., 2003, 103, 2829–2844; (g) S. Woodward, Angew.
Chem., Int. Ed., 2005, 44, 5560–5562; (h) F. Lope´z, A. J. Minnaard and
B. L. Feringa, in The Chemistry of Organomagnesium Compounds, ed.
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17; (i) S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard
and B. L. Feringa, Chem. Rev., 2008, 108, 2824–2852.
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in Comprehensive Organic Synthesis, ed. B. M. Trost, I. Flemming,
Pergamon Press, Oxford, 1991, Vol. 1, pp. 792; (c) B. M. Trost, Bull.
Chem. Soc. Jpn., 1988, 61, 107; (d) N. S. Simpkins, Sulphones in Organic
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In the instance of electron donating substituents such as
the para methyl and para isopropyl substituted substrates full
conversion was not achieved after 24 h giving lower isolated yields.
Fortunately, the lower reaction rate did not negatively influence the
enantiomeric excess and excellent ee’s were obtained (entries 5 and
7). Furthermore, para trifluoromethyl-, p-bromo- and 2-naphthyl-
substituted substrates gave good yields and excellent enantiomeric
excesses (entries 6, 8 and 9).
In summary, we have developed a highly enantioselective
copper-catalyzed conjugate addition of dialkylzinc reagents to a
range of aromatic a,b-unsaturated sulfones using a monodentate
phosphoramidite ligand. This procedure provided b-substituted
2-pyridyl sulfones in moderate to good yields (46–86%) and good
to excellent enantiomeric excess (70–96%) and is complementary
to our recent publication on the addition of Grignard reagents to
aliphatic substrates.8 These enantioenriched sulfones are poten-
tially useful intermediates in the preparation of a wide variety of
functionalized chiral building blocks.
4 T. Llamas, R. G. Arraya´s and J. C. Carretero, Angew. Chem., Int. Ed.,
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Mauleo´n, I. Alonso, M. R. Rivero and J. C. Carretero, J. Org. Chem.,
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8 P. H. Bos, A. J. Minnaard and B. L. Feringa, Org. Lett., 2008, 10,
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Acknowledgements
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Minnaard, B. L. Feringa, L. Lefort and J. G. de Vries, Acc. Chem.
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and J. G. de Vries, in Phosphorus Ligands in Asymmetric Catalysis, ed.
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11 This dependence is in contrast to that reported for the asymmetric
conjugate addition of Grignard reagents to a,b-unsaturated sulfones
where the nature of the counterion hardly had an effect on conversion
and enantioselectivity, see ref. 8.
Financial support from The Netherlands Organization for
Scientific Research (NWO-CW) is acknowledged. We thank
T. D. Tiemersma-Wegman (GC and HPLC) and A. Kiewiet
(MS) for technical assistance (Stratingh Institute for Chemistry,
University of Groningen).
Notes and references
1 (a) P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry Series 9, Pergamon Press, Oxford, U.K.,
1992; (b) B. E. Rossiter and N. M. Swingle, Chem. Rev., 1992, 92, 771–
806.
2 (a) For reviews, see: K. Tomioka and Y. Nagaoka, in Comprehensive
Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz, H. Yamamoto,
Springer, New York, 1999, Vol. 3, pp. 1105–1120; (b) B. L. Feringa,
Acc. Chem. Res., 2000, 33, 346–353; (c) N. Krause and A. Hoffmann-
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 47–49 | 49
©