Copper(i) catalyzed asymmetric 1,2-addition of Grignard reagents to α-methyl substituted α,β-unsaturated ketones

Article abstract of DOI:10.1039/c1cc16725a

The first catalytic enantioselective 1,2-addition of Grignard reagents to ketones is presented. This additive-free copper(i) catalyzed 1,2-addition provides chiral allylic tertiary alcohols with an er of up to 98:2 and excellent yields due to the complete shift of overwhelming 1,4-selectivity of copper(i)-catalysts towards 1,2-selectivity in the addition reaction to enones.

Full text of DOI:10.1039/c1cc16725a

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COMMUNICATION
Copper(I) catalyzed asymmetric 1,2-addition of Grignard reagents to
a-methyl substituted a,b-unsaturated ketoneswz
Ashoka V. R. Madduri, Adriaan J. Minnaard* and Syuzanna R. Harutyunyan*
Received 30th October 2011, Accepted 16th November 2011
DOI: 10.1039/c1cc16725a
The first catalytic enantioselective 1,2-addition of Grignard
reagents to ketones is presented. This additive-free copper(I)
catalyzed 1,2-addition provides chiral allylic tertiary alcohols
with an er of up to 98 : 2 and excellent yields due to the complete
shift of overwhelming 1,4-selectivity of copper(I)-catalysts
towards 1,2-selectivity in the addition reaction to enones.
We envisioned that chiral copper(I) based catalysts could
be suitable candidates for achieving asymmetric induction in
the 1,2-addition of Grignard reagents to ketones. Several
examples of copper catalyzed 1,2-additions of organosilanes
and organoboranes have been reported by Shibasaki et al.8
Recently it was also reported that copper(I) is capable of
catalysing the asymmetric 1,2-reduction of a-substituted enones,
thereby providing access to chiral secondary allylic alcohols.9
Interestingly, copper(I) based catalysts have never been reported
for application in the 1,2-addition of highly reactive organo-
metallic reagents to ketones. The main reason is perhaps, that
after the pioneering work of Gilman and Straley in 193610a
and the discovery of the inherent reactivity of organocopper
compounds towards 1,4-addition, copper(I) based reagents and
catalysts have been used as the synthetic tool par excellence to
obtain 1,4-selectivity in addition reactions of Zn-, Al-, Mg- and
Li-based organometallic reagents.10
The catalysed addition of organometallic reagents to aldehydes
and ketones is in principle one of the most straightforward
methods for the synthesis of chiral enantiopure secondary and
tertiary alcohols.1–3 In spite of their cost, and the transfer of
only one of the alkyl groups, the catalytic asymmetric addition
of diorganozinc reagents has been particularly well developed
and is currently the method of choice.1–3
In order to use the inexpensive and readily accessible, but
also more reactive, Grignard reagents in these reactions,4
typically (super)stoichiometric amounts of a chiral additive
are required to achieve acceptable enantioselectivities.4c First
example of the catalytic enantioselective addition of Grignard
reagents to aldehydes has been demonstrated recently, albeit
requiring a large excess of titanium tetraisopropoxide.5 The
catalytic addition to ketones is considerably more challenging
due to enolisation and competitive reduction via b-H transfer.2d
Indeed catalytic non-asymmetric addition of Grignard reagents
to ketones has become possible only recently using Zn(II) salts
as a catalyst.6 The asymmetric version of these reactions is
further complicated due to the smaller steric and electronic
differences between the two substituents on the carbonyl
group.2d Catalytic methods for the asymmetric 1,2-addition
of Grignard reagents, to date, are not known.
An initial screening of reaction conditions indicated that in
the presence of 5 mol% of a copper(I) salt, without a chiral
ligand present, the reaction proceeded with complete lack of
chemoselectivity providing a mixture of products including
as expected the 1,2-addition product 3 (Table 1, entry 1).
Intriguingly, ligand L1–L4 significantly increased the chemo-
selectivity and reactivity of the system toward the 1,2-addition
product, albeit with very poor stereoselectivity (entries 2–5).
Remarkably, ferrocenyl based diphosphine ligand L5 turned
out to be superior both in terms of 1,2-selectivity and stereo-
induction (entry 6). The catalyst precursor CuBrꢀSMe2 was
compared to other commonly applied Cu(I) salts (entries 6,
7–10) but turned out to be superior. Whilst CuCl, CuI,
and Cu-thiophene-2-carboxylate provided the 1,2-addition
product with some enantioselectivity, Cu(OAc)2 provided a
racemic mixture.
Here we report on the first enantioselective 1,2-addition
of highly reactive Grignard reagents to a-methyl substituted
a,b-unsaturated ketones, catalyzed by a Cu(I) salt in combination
with a chiral ferrocenyl diphosphine ligand,7 providing access
to highly valuable chiral tertiary allylic alcohols.
The influence of the solvent on the selectivity of the 1,2-addition
was studied with the CuBrꢀSMe2/L5 catalyst. This revealed
that ethereal solvents performed better both in terms of regio-
and stereoselectivity of the reaction. Whereas Et2O furnished
the 1,2-addition product with good chemoselectivity, the
sterically more bulky ethers tBuOMe and (iPr)2O provided
the best regio- and enantioselectivities (entries 6, 11 and 12).
Other solvents such as THF and DCM led to almost racemic
products (entries 13 and 14). tBuOMe was the solvent of
choice for further studies. Importantly, with branched-chain
Grignard reagents such as iBuMgBr a dramatic improvement
Stratingh Institute for Chemistry, University of Groningen,
Nijenborgh 4, 9747 AG, Groningen, The Netherlands.
E-mail: s.harutyunyan@rug.nl, a.j.minnaard@rug.nl;
Fax: +31-50-363-4296; Tel: +31-50-363-3539
w This article is part of the ChemComm ‘Emerging Investigators 2012’
themed issue.
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc16725a
c
1478 Chem. Commun., 2012, 48, 1478–1480
This journal is The Royal Society of Chemistry 2012

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Table 1 Optimization of the 1,2-addition of Grignard reagents to
ketone 1
Table 2 Scope of the CuBrꢀSMe2/L5 catalyzed 1,2-addition of
Grignard reagents to a-methyl substituted a,b-unsaturated ketones 1
Entrya
1
R, R1, 1
R2MgBr, 2
3
er (yield)b,c (%)
70 : 30 (95)
Ph, Me
3a
2
Ph, iPr
3c
3d
83 : 17 (95)
81 : 19 (83)
Entry
CuX
L
Solvent
3a : 4 : 5a (%)
3a, er (%)
3d
Ph, Ph
1b
2
3
4
5
6
7
8
CuBrꢀSMe2
CuBrꢀSMe2
CuBrꢀSMe2
CuBrꢀSMe2
CuBrꢀSMe2
CuBrꢀSMe2
CuCl
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
Et2O
(iPr)2O
THF
DCM
tBuOMe
tBuOMe
25 : 21 : 9 : 45
82 : 15 : 3
84 : 13 : 3
89 : 7 : 4
95 : 2 : 3
97 : 2 : 1
96 : 2 : 2
94 : 2 : 4
92 : 3 : 5
80 : 6 : 14
95 : 3 : 2
95 : 3 : 2
90 : 3 : 7
40 : 1 : 59
96 : 2 : 2
97 : 1 : 2
—
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
50 : 50
50 : 50
52 : 48
52 : 48
70 : 30
64 : 36
63 : 37
59 : 41
51 : 49
59 : 41
69 : 31
51 : 49
53 : 47
91 : 9
4
Ph, Ph
Ph, Ph
3e
3f
92 : 8 (94)
5d
88 : 12 (87)
CuI
CuTC
6
7
Ph, Me
Ph, Me
3b
3g
92 : 8 (96)
96 : 4 (95)
9c
10
11
12
13
14
15d
16e
Cu(OAc)2
CuBrꢀSMe2
CuBrꢀSMe2
CuBrꢀSMe2
CuBrꢀSMe2
CuBrꢀSMe2
CuBrꢀSMe2
8
Ph, Me
Ph, Me
Ph, iBu
3h
3i
3j
96 : 4 (96)
94 : 6 (95)
98 : 2 (92)
92 : 8
a
b
Ratio of 3a : 4 : 5 was determined by GC analysis. ‘45’ refers to
c
unreacted substrate 1. CuTC refers to Cu-thiophene-2-carboxylate.
9
d
e
iBuMgBr was used instead of EtMgBr. Grignard reagent was
added to the reaction mixture over 3 h.
10
of the enantioselectivity to an er of 91: 9 was observed (entries 6
and 15). A small gain in chemo- and enantioselectivity was
obtained by switching from direct to slow addition of the
Grignard reagent (entry 16). With optimized conditions in
hand the scope of this new reaction was explored.
11
3k
84 : 16 (81)
12d
Me, Me
3l
74 : 26 (85)
71 : 29 (82)
The scope of the reaction was studied on a variety of
a-methyl substituted enones 1 using different Grignard reagents
(Table 2). High 1,2-chemoselectivity and yield were obtained
for all the substrate and Grignard reagent combinations. Use of
the less reactive MeMgBr resulted in complete recovery of the
starting material, while addition of PhMgBr led to a racemic
1,2-addition product. Importantly, increasing the sterics in R1
of the substrate and increasing the sterics of the Grignard
reagent provided higher enantioselectivity. Remarkably, we
were able to introduce b-branched Grignard reagents with high
stereoinduction and yields. iBuMgBr afforded the 1,2-addition
product in high yield and an er of 92 : 8 (entry 6). Similarly,
Grignard reagents bearing a carbocycle afforded the 1,2-addition
product in high yield and enantioselectivity (entries 5 and 9).
The addition of (2-ethylbutyl)magnesium bromide led to the
corresponding product with an er of 96 : 4 and 95% yield
(entry 7). Racemic (2-ethyl)hexylmagnesium bromide proved
equally effective, with no negative effect on the newly formed
stereocenter (entry 8). The results we have obtained with
branched-chain Grignard reagents contrast with those known
13d
3m
a
Conditions: addition of 1.3 equiv. R2MgBr to a 0.15 M solution of 1
b
c
in tBuOMe at ꢁ78 1C. Yield of the isolated product 3. The er of 3
d
was determined by chiral HPLC analysis (see ESI). The reaction was
performed at ꢁ60 1C.
for the 1,2-addition methodologies to ketones based on diorgano
Zn/Ti2,3 systems which are restricted to the use of linear alkyl
groups and aryl moieties. Replacing a methyl with a phenyl
substituent at the a-position of the enone led to a slight decrease
in selectivity (Table 2, compare entries 6 and 11). Due to their
lower inherent reactivity, the aliphatic enones were recovered
unchanged at ꢁ78 1C. Increasing the reaction temperature to
ꢁ60 1C furnished the 1,2-addition product with both cyclic and
acyclic aliphatic eneones in high yields albeit with lower enantio-
selectivity (entries 12 and 13).
The presence of Cu in the catalytic system is essential for all
the reactions discussed so far; no tertiary alcohols are formed
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1478–1480 1479

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Notes and references
1 (a) E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Comprehensive
Asymmetric Catalysis: Suppl. 2, Springer-Verlag, Berlin, 2004;
(b) P. J. Walsh and M. C. Kozlowski, Fundamentals of Asymmetric
Catalysis, University Science Books, California, 2009.
2 Reviews on addition of organometallic reagents to ketones and
aldehydes: (a) M. R. Luderer, W. F. Bailey, M. R. Luderer,
J. D. Fair, R. J. Dancer and M. B. Sommer, Tetrahedron: Asymmetry,
2009, 20, 981; (b) L. Pu and H.-B. Yu, Chem. Rev., 2001, 101, 757;
(c) C. M. Binder and B. Singaram, Org. Prep. Proced. Int., 2011,
43, 139; (d) M. Hatano and K. Ishihara, Synthesis, 2008, 1647.
3 Selected examples on addition of organozinc reagents to ketones:
(a) P. I. Dosa and G. Fu, J. Am. Chem. Soc., 1998, 120, 445;
(b) D. J. Ramo
(c) H. Li and P. J. Walsh, J. Am. Chem. Soc., 2004, 126, 6538;
(d) D. J. Ramon and M. Yus, Angew. Chem., Int. Ed., 2004,
43, 284; (e) S.-J. Jeon, H. Li, C. Garcıa, L. K. LaRochelle and
P. J. Walsh, J. Org. Chem., 2005, 70, 448–455; (f) E. F. DiMauro
and M. C. Kozlowski, J. Am. Chem. Soc., 2002, 124, 12668–12669;
(g) D. K. Friel, M. L. Snapper and A. H. Hoveyda, J. Am. Chem.
Soc., 2008, 130, 9942–9951; (h) M. Hatano, T. Miyamoto and
K. Ishihara, Org. Lett., 2007, 9, 4535.
4 (a) B. J. Wakefield, Organomagnesium Methods in Organic Chemistry,
Academic Press, San Diego, CA, 1995; (b) P. Knochel, Handbook of
Functionalized Organometallics, Wiley-VCH, Weinheim, Germany,
2005; (c) J. L. von dem Bussche-Huennefeld and D. Seebach,
Tetrahedron, 1992, 48, 5719.
5 (a) Y. Muramatsu and T. Harada, Angew. Chem., Int. Ed., 2008,
47, 1088; (b) Y. Muramatsu, S. Kanehira, M. Tanigawa,
Y. Miyawaki and T. Harada, Bull. Chem. Soc. Jpn., 2010, 83, 19;
´
n and M. Yus, Tetrahedron Lett., 1998, 39, 1239;
Scheme 1 Tentative mechanistic pathway for the 1,2-addition
of Grignard reagents to a,b-unsaturated ketones catalyzed by
CuBrꢀSMe2/L5.
´
´
when using only L5. Furthermore, our experimental results
show that the presence of an a-substituent and an adjacent
unsaturation in the substrate are important to obtain the desired
1,2-addition products with high regio- and enantioselectivity.
The use of aliphatic ketones led to the 1,2-addition products in
low yields and no enantiodiscrimination. The importance of
Cu, an adjacent unsaturation and the formation of 1–2% of
1,4-addition product shows a mechanistic similarity to the
well-studied Cu(I) catalyzed 1,4-addition of organometallics.11
Equipped with the experimental findings presented here, the
working hypothesis is that our system initially follows the
trends observed in 1,4-addition which consists of formation of
copper/ligand complex 11, its transmetallation by the Grignard
reagent (complex 12), reversible formation of a copper–olefin
p-complex followed by formal oxidative addition to the b-carbon
leading to a Cu(III) intermediate (s-complex) (Scheme 1).11
Most probably, the presence of an a-substituent prevents the
formation/accumulation of Cu(III) species, which in turn prevents
1,4-addition and favors 1,2-addition.
(c) E. Fernandez-Mateos, B. Macia, D. J. Ramon and M. Yus,
´ ´ ´
Eur. J. Org. Chem., ASAP; (d) C.-S. Da, J.-R. Wang, X.-G. Yin,
X.-Y. Fan, Y. Liu and S.-L. Yu, Org. Lett., 2009, 11, 5578.
6 (a) M. Hatano, O. Ito, S. Suzuki and K. Ishihara, J. Org. Chem.,
2010, 75, 5008; (b) M. Hatano, S. Suzuki and K. Ishihara, J. Am.
Chem. Soc., 2006, 128, 9998; (c) M. Hatano, O. Ito, S. Suzuki and
K. Ishihara, Chem. Commun., 2010, 46, 2674.
7 (a) A. Borner, in Trivalent Phosphorus Compounds in Asymmetric
¨
Catalysis: Synthesis and Applications, ed. W. Chen and H. U. Blaser,
Wiley-VCH, 2008, p. 359; (b) L.-X. Dai, T. Tu, S.-L. You, W.-P. Deng
and X.-L. Hou, Acc. Chem. Res., 2003, 36, 659; (c) We thank Dr B.
Pugin (Solvias) for a generous gift of a ligand kit for initial screening.
8 (a) M. Shibasaki and M. Kanai, Chem. Rev., 2008, 108, 2853;
(b) D. Tomita, M. Kanai and M. Shibasaki, Chem.–Asian J., 2006,
1, 161; (c) D. Tomita, R. Wada, M. Kanai and M. Shibasaki,
J. Am. Chem. Soc., 2005, 127, 4138.
9 R. Moser, Z. V. Boskovic, C. S. Crowe and B. H. Lipshutz, J. Am.
Chem. Soc., 2010, 132, 7852.
10 (a) H. Gilman and J. M. Straley, Recl. Trav. Chim. Pays-Bas, 2010,
55, 821; (b) N. Krause, Modern organocopper chemistry, Wiley-VCH,
Weinheim, 2002; (c) S. R. Harutyunyan, T. den Hartog, K. Geurts,
A. J. Minnaard and B. L. Feringa, Chem. Rev., 2008, 108, 2824;
In summary, for the first time we have been able to
demonstrate that it is possible to achieve Cu(I) catalyzed
asymmetric 1,2-additions to a-substituted enones using
inexpensive, highly reactive Grignard reagents and the use of
stoichiometric amounts of additives is not required. The
discovery of this novel catalytic system gives access to chiral
branched tertiary alcohols with excellent yields and an er up
to 98 : 2.
(d) A. Alexakis, J. E. Backvall, N. Krause, O. Pamies and
¨
M. Die
B. L. Feringa, Chem. Commun., 2011, 47, 2679.
11 (a) S. R. Harutyunyan, F. Lopez, W. R. Browne, A. Correa,
´
guez, Chem. Rev., 2008, 108, 2796; (e) J. F. Teichert and
Application of this concept to simple aromatic ketones as
well as mechanistic studies to address the current limitations of
the methodology which are lower enantioselectivities with
aliphatic substrates and non-branched Grignard reagents are
ongoing and will be reported in due course.
´
D. Pena, R. Badorrey, A. Meetsma, A. J. Minnaard and
B. L. Feringa, J. Am. Chem. Soc., 2006, 128, 9103; (b) S. Mori
and E. Nakamura, in Modern Organocopper Chemistry,
ed. N. Krause, Wiley-VCH, Weinheim, 2002, p. 315.
c
1480 Chem. Commun., 2012, 48, 1478–1480
This journal is The Royal Society of Chemistry 2012