On the mechanism of the copper-catalyzed enantioselective 1,4-addition of Grignard reagents to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1021/ja0585634

The mechanism of the enantioselective 1,4-addition of Grignard reagents to α,β-unsaturated carbonyl compounds promoted by copper complexes of chiral ferrocenyl diphosphines is explored through kinetic, spectroscopic, and electrochemical analysis. On the basis of these studies, a structure of the active catalyst is proposed. The roles of the solvent, copper halide, and the Grignard reagent have been examined. Kinetic studies support a reductive elimination as the rate-limiting step in which the chiral catalyst, the substrate, and the Grignard reagent are involved. The thermodynamic activation parameters were determined from the temperature dependence of the reaction rate. The putative active species and the catalytic cycle of the reaction are discussed.

Full text of DOI:10.1021/ja0585634

Published on Web 06/23/2006
On the Mechanism of the Copper-Catalyzed Enantioselective
1,4-Addition of Grignard Reagents to r,â-Unsaturated
Carbonyl Compounds
Syuzanna R. Harutyunyan, Fernando Lo´pez,† Wesley R. Browne, Arkaitz Correa,
Diego Pen˜a,† Ramon Badorrey,‡ Auke Meetsma, Adriaan J. Minnaard,* and
Ben L. Feringa*
Contribution from the Department of Organic Chemistry and Molecular Inorganic Chemistry,
Stratingh Institute, UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen,
The Netherlands
Received December 18, 2005; E-mail: B.L.Feringa@rug.nl
Abstract: The mechanism of the enantioselective 1,4-addition of Grignard reagents to R,â-unsaturated
carbonyl compounds promoted by copper complexes of chiral ferrocenyl diphosphines is explored through
kinetic, spectroscopic, and electrochemical analysis. On the basis of these studies, a structure of the active
catalyst is proposed. The roles of the solvent, copper halide, and the Grignard reagent have been examined.
Kinetic studies support a reductive elimination as the rate-limiting step in which the chiral catalyst, the
substrate, and the Grignard reagent are involved. The thermodynamic activation parameters were
determined from the temperature dependence of the reaction rate. The putative active species and the
catalytic cycle of the reaction are discussed.
also.4c-e The inherently low reactivity of organozinc reagents
toward unsaturated carbonyl compounds has facilitated the
development of a plethora of chiral phosphorus-based ligands
(i.e. phosphoramidites, phosphines, phosphonites) capable of
providing highly efficient ligand-accelerated catalysis with
excellent enantioselectivities over a broad range of substrates.2,3
Introduction
The copper-catalyzed conjugate addition (CA) of organo-
metallic reagents to R,â-unsaturated carbonyl compounds is one
of the most versatile synthetic methods for the construction of
C-C bonds.1 Catalytic enantioselective versions of this trans-
formation employing chiral copper complexes2-5 have been
achieved primarily with organozinc reagents,2-4a,b although
organoaluminum compounds have proven to be successful
In contrast, the application of Grignard reagents, which are
among the most widely used of organometallic compounds, in
the CA to R,â-unsaturated carbonyl systems has received much
less attention.6 Despite intensive research over the last two
decades, only modest selectivity in the CA of Grignard reagents
was observed in comparison to dialkyzinc reagents.6 This is most
probably due to the higher reactivity of Grignard reagents, which
† Present address: Departamento de Qu´ımica Orga´nica, Facultad de
Qu´ımica, Universidad de Santiago de Compostela, 15706 Santiago de
Compostela, Spain.
‡ Present address: Departamento de Qu´ımica Orga´nica, Facultad de
Ciencias, Instituto de Ciencia de Materiales de Arago´n, Universidad de
Zaragoza, Consejo Superior de Investigaciones Cient´ıficas, 50009 Zaragoza,
Spain.
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry, Series 9; Pergamon: Oxford, 1992. (b)
Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771-806..
(2) (a) Feringa, B. L.; de Vries, A. H. M. In Asymmetric Chemical Transforma-
tions; Doyle, M. D., Ed.; Advances in Catalytic Processes; JAI Press Inc.:
Greenwich, 1995; Vol. 1, pp 151-192. (b) Krause, N. Angew. Chem., Int.
Ed. 1998, 37, 283-285. (c) Tomioka, K.; Nagaoka, Y. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: New York, 1999; Vol. 3, pp 1105-1120. (d) Sibi, M.
P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061. (e) Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171-196.
(3) (a) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; pp 224-258. (b) de Vries, A. H. M.; Meetsma, A.; Feringa,
B. L. Angew. Chem., Int. Ed. Engl. 1996, 35, 2374-2376. (c) Feringa, B.
L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2620-2623.
(4) (a) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 779-781. (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002,
3221-3236 and references therein. (c) For an addition of AlMe3 to linear
aliphatic enones, see: Frase, P. K.; Woodward, S. Chem.sEur. J. 2003, 9,
776-783. (d) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508-11509. (e) Alexakis, A.; Albrow, V.; Biswas,
K.; d’Augustin, M.; Prieto, O.; Woodward, S. Chem. Commun. 2005, 22,
2843-2845.
(5) For recent advances in the catalytic enantioselective conjugate reduction
of R,â-unsaturated carbonyl compounds, which provides an alternative route
to the optically active â-substituted carbonyl compounds see: (a) Lipshutz,
B. H.; Servesko, J. M. Angew. Chem., Int. Ed. 2003, 42, 4789-4792. (b)
Lipshutz B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004, 126,
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2005, 44, 6345-6348.
(6) (a) Villacorta, G. M.; Rao, C. P.; Lippard, S. J. J. Am. Chem. Soc. 1988,
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metallics 1990, 9, 3178-3181. (c) Lambert, F.; Knotter, D. M.; Janssen,
M. D.; van Klaveren, M.; Boersma, J.; van Koten, G. Tetrahedron:
Asymmetry 1991, 2, 1097-1100. (d) Knotter, D. M.; Grove, D. M.; Smeets,
W. J. J.; Spek, A. L.; van Koten, G. J. Am. Chem. Soc. 1992, 114, 3400-
3410. (e) Spescha, D.; Rihs, G. HelV. Chim. Acta 1993, 76, 1219-1230.
(f) Zhou, Q.-L.; Pfaltz, A. Tetrahedron 1994, 50, 4467-4478. (g) Braga,
A. L.; Silva, S. J. N.; Lu¨dtke, D. S.; Drekener, R. L.; Silveira, C. C.; Rocha,
J. B. T.; Wessjohann, L. A. Tetrahedron Lett. 2002, 43, 7329-7331. (h)
Seebach, D.; Jaeschke, G.; Pichota, A.; Audergon, L. HelV. Chim. Acta
1997, 80, 2515-2519. (i) Pichota, A.; Pregosin, P. S.; Valentini, M.; Wo¨rle,
M.; Seebach, D. Angew. Chem., Int. Ed. 2000, 39, 153-156. (j) Kanai,
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Y.; Kanai, M.; Nagaoka, Y.; Tomioka, K. Tetrahedron 1998, 54, 10295-
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3843-3854. (m) Stangeland, E. L.; Sammakia, T. Tetrahedron 1997, 53,
16503-16510.
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A R T I C L E S
Harutyunyan et al.
Scheme 2. Proposed Mechanistic Pathway for the Stoichiometric
1,4-Addition of Organocuprates
widely accepted mechanism (Scheme 2) for noncatalytic organo-
cuprate addition is supported by kinetic studies,9a,b in particular
kinetic isotope effect measurements9c,d and NMR spectroscopy9e,f
of intermediates observed during the reaction. The current
mechanistic view is that the CA of organometallic compounds
proceeds through reversible formation of a copper-olefin
π-complex, involving d,π* back-donation,9e-h followed by a
formal oxidative addition to the â-carbon leading to a d8
copper(III) intermediate9h-k and, finally, reductive elimination
to form the enolate (Scheme 2).
Figure 1. Chiral ligands used in the CA of Grignard reagents.
Scheme 1. Enantioselective CA of Grignard Reagents to
R,â-Unsaturated Compounds
Although π-complexes for R, â-unsaturated esters, ketones,
and nitriles have been observed by low-temperature NMR
spectroscopy,10 direct observation of copper(III) intermediates
has not been achieved in organocuprate CA, and their involve-
ment is supported primarily through quantum-chemical calcula-
tions.11 Experimental and theoretical studies made by Snyder
et al.9c and Krause et al.9d on organocuprate CAs indicate that
the rate-determining step is the C-C bond formation via
reductive elimination of the copper(III) intermediate (Scheme
2).
On the basis of the cumulative mechanistic data obtained for
the stoichiometric organocuprate CA, a similar mechanism for
the copper-catalyzed enantioselective CA of dialkylzinc re-
agents, involving an oxidative addition-reductive elimination
pathway, has been postulated.12 However, relatively few mecha-
nistic studies have been reported to date for the enantioselective
copper-catalyzed CA of any class of organometallic reagent.13
Moreover, these studies are related, exclusively, to the catalytic
CA of dialkylzinc reagents and have not, as yet, led to a general
leads to uncatalyzed 1,2- and 1,4-additions. Moreover, the
presence of several competing organometallic complexes in
solution (typical of cuprate chemistry) further complicates access
to effective enantioselective catalysis.
Recently, we demonstrated that high enantioselectivities (up
to 99% ee) can be achieved in the CA of Grignard reagents to
R,â-unsaturated carbonyl compounds using catalytic amounts
of chiral ferrocenyl diphosphine ligands and Cu(I) salts (Figure
1, Scheme 1).7 Most notably, the Josiphos- and Taniaphos-type
ligands (Figure 1) allow for a broad substrate scope to be used
successfully in these reactions, including cyclic and acyclic
enones, enoates, and thioenoates (Scheme 1). Despite these
breakthroughs, the nature of the complexes involved and a
rationalization of the electronic factors, which govern the
substrate specificity of the various Cu(I)-ferrocenyl-diphosphine
complexes is highly desirable. A detailed understanding of the
reaction mechanism, including the generation of the active
species, insight into key steps in the catalytic cycle, and kinetic
information is essential for the elucidation of the mechanism
and future rational improvement of this important transforma-
tion.
(9) For mechanistic studies in organocuprates chemistry, see: (a) Krauss, S.
R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103, 141-148. (b) Canisius, J.;
Gerold, A.; Krause, N. Angew. Chem., Int. Ed. 1999, 38, 1644-1645. (c)
Frantz, D. E.; Singleton, D. A.; Snyder, J. P. J. Am. Chem. Soc. 1997, 116,
3383-3384. (d) Mori, S.; Uerdingen, M.; Krause, N.; Morokuma, K.
Angew. Chem., Int. Ed. 2005, 44, 4715-4719. (e) Bertz, S. H.; Miao, G.;
Eriksson, M. Chem. Commun. 1996, 815-816. (f) Murphy, M. D.; Ogle,
G.; Bertz, S. H. Chem. Commun. 2005, 854-856. (g) Nilson, K.; Anderson,
C.; Ullenius, A.; Gerold, A.; Krause, N. Chem.sEur. J. 1998, 4, 2051-
2058 and references therein. (h) Mori, S.; Nakamura, E. Teterahedron Lett.
1999, 40, 5319-5322. (i) Kingsbury, C. L.; Smith, R. A. J. Am. Chem.
Soc. 1997, 62, 4629-4634. (j) Casey, C. P.; Cesa, M. J. Am. Chem. Soc.
1979, 101, 4236-4244. (k) Corey, E. J.; Boaz, N. Tetrahedron Lett. 1985,
26, 6015-6018. (l) Lipshutz, B. H.; Aue, D. H.; James, B. Teterahedron
Lett. 1996, 37, 8471-8474.
(10) For low-temperature NMR studies in CAs of cuprates, see: (a) Christenson,
B.; Olsson, T.; Ullenius, C. Tetrahedron 1989, 45, 523-534. (b) Bertz, S.
H.; Smith, R. A. J. Am. Chem. Soc. 1989, 111, 8276-8277. (c) Bertz, S.
H.; Carlin, M. K.; Deadwyler, D. A.; Murphy, M.; Ogle, C. A.; Seagle, P.
H. A. J. Am. Chem. Soc. 2002, 124, 13650-13651. (d) Krause, N.; Wagner,
R.; Gerold, A. J. Am. Chem. Soc. 1994, 116, 381-382 (e) Nilsson, K.;
Ullenius, C.; Krause, N. J. Am. Chem. Soc. 1996, 118, 4194-4195. (f)
Krause, N.; Wagner, R.; Gerold, A. J. Am. Chem. Soc. 1994, 116, 381-
382. (g) See also refs 8 b, e-g.
(11) For the calculations that support the participation of Cu(III) intermediates
in the CA of cuprates, see: (a) Nakamura, E.; Mori, S.; Morokuma, K. J.
Am. Chem. Soc. 1997, 119, 4900-4910. (b) Yamanaka, M.; Nakamura, E.
J. Am. Chem. Soc. 2004, 126, 6287-6293. (c) Nakanishi, W.; Yamanaka,
M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 1446-1453. (d) Nakamura,
E.; Yamanaka, M.; Mori, S. J. Am. Chem. Soc. 2000, 122, 1826-1827. (e)
Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697-4706.
(f) Yamanaka, M.; Nakamura, E. Organometallics 2001, 20, 5675-5681.
(12) (a) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.;
Feringa, B. L. Tetrahedron 2000, 56, 2865-2878. (b) Alexakis, A.;
Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262-
5263.
The mechanism of the copper-catalyzed enantioselective CA
of organometallic compounds may follow similar principles as
proposed for the noncatalytic organocuprate addition.8,9
A
(7) (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.; 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.; Minnaard, A.
J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966-9967. (e) Woodward,
S. Angew. Chem., Int. Ed. 2005, 44, 5560-5562.
(8) For reviews on reaction mechanisms of organocuprates, see: (a) Woodward,
S. Chem. Soc. ReV. 2000, 29, 393-401 and references therein. (b) Nakamura
E.; Mori S. Angew. Chem., Int. Ed. 2000, 39, 3750-3771. (c) Krause, N.;
Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186-204. (d) Mori, S.;
Nakamura, E. In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; pp 315-346.
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Cu-Catalyzed Enantioselective CA of Grignard Reagents
A R T I C L E S
agreement regarding the rate-determining step. Noyori,13a
Kitamura,13b and co-workers have proposed a catalytic cycle
for the Cu/sulfonamide-catalyzed 1,4-addition of diethylzinc to
cyclohexenone based on kinetic data and 12C/13C isotope effect
studies. Their results point toward a concerted mechanism. In
another report, the CA of dialkylzincs involving copper
complexes of Schiff base ligands was studied by Gennari et
al.13c The oxidative addition of a Cu-complex to cyclohexenone
was proposed as the rate-limiting step in this reaction. Alter-
natively, Schrader and co-workers13d proposed, on the basis of
kinetic studies in a related copper-catalyzed CA using phos-
phorus ligands, a different mechanism involving a reductive
elimination as the rate-limiting step.
Scheme 3. Formation of the Copper (I) Diphosphine Complexes
Thus far, a detailed mechanistic study of the copper-catalyzed
CA of Grignard reagents is lacking. A single, general mechanism
for the catalytic CA of different organometallic reagents may
not be possible due to the sensitivity of the CA reaction to almost
any variation in the reaction parameters (i.e. ligand, copper
source, solvent, temperature). The difficulties in mechanistic
interpretations are complicated further by the absence of
structural information regarding the intermediate species under
catalytic conditions.14
The majority of the studies related to the mechanism of the
copper-catalyzed 1,4-addition postulates the transmetalation
between the organometallic compounds and the copper species
as the first step in the catalytic cycle. However, in the enantio-
selective catalytic CA, transmetalated copper intermediates
derived from organometallic compounds have not been charac-
terized to date.15 In only one case a dramatic (107 ppm) upfield
shift in the 31P NMR spectra of the copper complex with a chiral
diphosphite ligand was reported upon addition of Et2Zn.16 This
shift was assigned to the presence of an Et-Cu species.
In the present report, we explore the mechanism of the
copper-catalyzed enantioselective CA of Grignard reagents,
through spectroscopic, structural, and kinetic methods. On the
basis of these mechanistic studies we identify catalytically active
species and propose a possible catalytic cycle that is consistent
with the results observed in enantioselective CA.
shown that these copper complexes could be recovered easily
and reused without loss in catalytic activity.
Thus, prior to discussing the species which are present during
catalysis, it is pertinent to consider first the formation and
properties of the copper(I) phosphine complexes employed and
their dynamic behavior in solution. An interesting aspect of this
class of complex is the rapid equilibration to form either a
mononuclear (1′ and 2′) or a binuclear complex (1 and 2),
depending on the solvent employed (Scheme 3).
Structures of the Cu-Halide complexes. The air-stable
copper complexes are prepared by addition of equimolar
amounts of a copper(I) salt and the chiral ligands L1 or L2,
respectively, in the appropriate solvent (Scheme 3). Interestingly,
a solvent-dependent equilibrium between dinuclear (1) and a
mononuclear (1′) species is established in solution.7c For
example, the preparation of the bromide complex from CuBr‚
t
SMe2 and L1 using ethereal (Et2O, BuOMe) or halogenated
(CH2Cl2, CHCl3) solvents led to the dinuclear structure 1a, as
deduced by ESI-MS and IR spectroscopy.17a Attempts to obtain
crystals suitable for X-ray analysis of 1a from these solvents
(Et2O, tBuOMe, CH2Cl2), commonly used in the CA of Grignard
reagents,7a-d were unsuccessful thus far.
In a similar manner, the dinuclear complex 2a was prepared
from CuBr‚SMe2 and L2 in tBuOMe. Suitable crystals for X-ray
analysis of this complex were obtained from an Et2O solution.
The asymmetric unit consists of one moiety of a dinuclear
copper complex, which is bridged by two Br atoms resulting in
a C2-symmetric unit. A molecule of the water is also present
Results and Discussion
In our earlier communication7c we demonstrated that equally
high enantioselectivity can be obtained by using either pre-
formed, air-stable Cu-complexes 1a and 2a or the same
complexes prepared in situ from the chiral diphosphine ligands
(L1 and L2) and CuBr‚SMe2 (Scheme 3). Furthermore, we have
t
in the cell (Figure 2). The dimeric structure of 2a in BuOMe,
(13) To date only four mechanistic studies on copper-catalyzed CA of organozinc
reagents have been reported: (a) Kitamura, M.; Miki, T.; Nakano, K.;
Noyori, R. Bull. Chem. Soc. Jpn. 2000, 73, 999-1014. (b) Nakano, K.;
Bessho, Y.; Kitamura, M. Chem. Lett. 2003, 32, 224-225. (c) Gallo, E.;
Ragaini F.; Bilello, L.; Cenini, S.; Gennari, C.; Piarulli, U. J. Organomet.
Chem. 2004, 689, 2169-2176. (d) Pfretzschner, T.; Kleemann, L.; Janza,
B.; Harms, K.; Schrader, T. Chem.sEur. J. 2004, 10, 6049-6057.
(14) Two structural types of organocuprates formed by the addition of Grignard
reagents to a Cu(I) source, in a 1:1 ratio, have been proposed; e.g. a “RCu‚
MgX2”14a species and an ate complex “R(X)CuMgX”.14b The latter is
considered more relevant and has been proposed in the related 1,4-additions
of allylic copper species prepared from Grignard reagents. (a) Alexakis,
A.; Commercon, A.; Coulentianos, C.; Normant, J. F. Pure Appl. Chem.
1983, 55, 1759-1766. (b) Lipshutz, B. H.; Hackmann, C. J. Org. Chem.
1994, 59, 7437-7444.
(15) Hypothetical structures of the species formed by transmetalation (with
organomagnesium, organolithium, or organoaluminum compounds) of
copper complexes bearing chiral ligands only have been proposed for
enantioselective CA.12 In contrast, a number of studies have been reported
towards elucidation of the structures of nonchiral transmetalated copper
salts (organocuprates).8a,10,14
Figure 2. X-ray structure of (S,R)-2a (hydrogen atoms are omitted for
clarity).
(16) Yan, M.; Yang, L.; Wong, K.; Chan, A. S. C. Chem. Commun. 1999, 11-
12.
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Harutyunyan et al.
Figure 3. X-ray structure of 1a′ (hydrogen atoms are omitted for clarity).
Figure 4. X-ray structure of (R,S,S,R)-3 (hydrogen atoms are omitted for clarity).
CH2Cl2 and Et2O solutions was also confirmed by ESI-MS.17b
In a similar manner the preparation of copper chloride and
copper iodide complexes from L1 (Scheme 3) in halogenated
solvents led to the formation of dinuclear complexes 1b and
1c. The dimeric structure of 1b and 1c in CH2Cl2 was confirmed
by ESI-MS.
crystal structure copper exhibits distorted trigonal coordination
geometry with the copper ion bound to two phosphorus and
one bromide atoms. The metal forms a six-member chelate ring
with the ligand, in a boatlike conformation.
The propensity of the Cu complexes of L1 and L2 to form
dinuclear structures in solvents used in the CA reaction (Et2O,
CH2Cl2, tBuOMe) is demonstrated also by the formation of the
stable heterocomplex 3 (Figure 4).
A different behavior, however, was observed when these
complexes were prepared in more polar solvents, such as
CH3CN (or MeOH). Thus, the mixture of CuBr and L1 in
CH3CN led to the formation and precipitation of the mono-
nuclear complex 1a′. This mononuclear Cu-complex 1a′ can
be prepared by dissolving the dinuclear complex 1a in CH3CN
also (by ESI-MS and IR).7c In contrast to the dinuclear complex
1a, the mononuclear complex 1a′ is insoluble in Et2O and
tBuOMe. However, in halogenated solvents, such as CH2Cl2 or
CHCl3, 1a′ dissolves readily yielding the dinuclear complex 1a
(Scheme 3). Interestingly, both 1a′ and 1a in CD3CN and
CD2Cl2, respectively, showed nearly identical 1H and 31P NMR
spectra, thus, precluding the use of NMR spectroscopy to
distinguish mono- or dinuclear structures. Further evidence of
the monomeric structure of 1a′ was obtained by X-ray diffraction
of crystals obtained by slow evaporation of a CH3CN solution.
The crystal structure shows a trigonal planar mononuclear
Cu-complex 1a′ (Figure 3). No solvent molecules are coordi-
nated to the copper center. The asymmetric unit consists of two
molecules of the monomeric complex 1a′. The difference
between the two molecules in the unit cell is due to a
conformational change in the dicyclohexyl moieties. In the
Complex 3 was prepared by mixing, (R,S)-L1, (S,R)-L2, and
CuBr‚SMe2 in ratio 1:1:2 in CH2Cl2. Complete formation of
the heterocomplex 3 was monitored by TLC.17c The dinuclear
structure of heterocomplex 3 was confirmed by X-ray analysis
(Figure 4). The asymmetric unit consists of one molecule of
dinuclear Cu-complex 3 and two highly disordered hexane
solvent molecules.
In conclusion, in solution the copper complexes exhibit a
mononuclear structure in CH3CN and MeOH, while in ethereal
and halogenated solvents the dinuclear structure is dominant.
Importantly, the mononuclear complex is insoluble in ethereal
solvents and dissolves in the halogenated solvent due to its rapid
conversion to the dinuclear form.
Redox Properties of Cu-Halide Complexes. It is apparent
from our earlier reports7a-c that there is a considerable sensitivity
of the outcome of the copper(I)-catalyzed, enantioselective CA
of Grignard reagents to the nature of the ligand and substrate
class employed. This sensitivity is expected to arise from both
steric and electronic differences between the various Cu(I)
diphosphine complexes. Electrochemistry represents a powerful
tool in probing the electronic properties of redox active systems,
and in the present study, it enables a direct measurement of the
(17) (a) For full spectroscopic details, see ref 7c. (b) See Supporting Information.
(c) The Rf value for the heterocomplex 3 is different from the Rf value of
the dinuclear complexes 1a and 2a.
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Cu-Catalyzed Enantioselective CA of Grignard Reagents
A R T I C L E S
Figure 5. (Left) Oxidative electrochemistry of (a) 1a and (b) 2a in CH2Cl2 (0.1 M TBAPF6) at -78 °C, scan rate ) 25 mV s-1. (Right) Oxidative
electrochemistry of (c) 1b (Cl-), (d) 1c (I-) in CH2Cl2 (0.1 M TBAPF6) at -78 °C, scan rate ) 50 mV s-1
.
different electronic properties of the copper(I) complexes (1,
2) and, in particular, the effect of ligand and halide variation.
The electrochemical properties of the copper(I) complexes
of the ligands L1 and L2 both prepared in situ and as preformed
complexes were investigated (Figures 5, 6).18a At room tem-
perature, in MeCN or CH2Cl2 (0.1 M TBAPF6) all complexes
exhibit a single reversible oxidation at ∼0.65 V (vs SCE)
assigned to the ferrocene component of the ligand and additional
ill-defined redox chemistry at more anodic potentials assigned
to irreversible Cu(II)/Cu(I) redox processes.
separation (Ep,a - Ep,c), which is close to the 59 mV associated
with ideal Nernstian behavior. As the temperature is increased,
the two return waves become a single reversible redox wave
(vide supra).
Surprisingly, the chloro, bromo, and iodo (1a-c) complexes
give almost identical electrochemistry with the exception of the
ferrocenium reduction, in which a decrease in the separation of
the first and second reductive processes (at ∼0.5 V) is observed
on going from chloro to bromo to iodo (Figure 5, respectively
c, a, d).
Importantly, for the free ligands, L1 and L2, an irreversible
oxidative process is observed prior to the ferrocene oxidation
allowing for facile detection of free ligand in solution. This
process is assigned to oxidation of the phosphine moieties of
the ligands. At lower temperature (-78 °C), the redox process
of the free ligand shows some reversibility indicating that the
irreversible oxidation is due to an EC mechanism (i.e. the
electrochemical oxidation is followed by a chemical reaction).18b,c
The absence of this process in the voltammetry of the copper
complexes formed both in situ and ex situ confirms that
copper(I) coordinates to the ligands in a 1:1 ratio and that the
formation constant is very high.
In contrast to ambient conditions, at lower temperatures (e.g.,
-20 to -80 °C) a considerable improvement in the reversibility
of the Cu(II)/Cu(I) redox processes of the complexes is observed
(Figure 5). For both 1a and 2a electrochemically reversible
processes are observed at ∼0.70 [2 e-], 0.95 [1 e-], and 1.30
[1 e-] V (vs SCE). The bielectronic nature of the first redox
process is assigned on the basis of both the intensity of the
anodic wave relative to the two subsequent anodic waves and
on the presence of two return waves of equal intensity. The
presence of two one-electron Cu(II)/Cu(I) redox processes
supports the assignment of the solution structure in CH2Cl2 as
being a dinuclear halide-bridged complex (Figure 5, left: a, b).
For both 1a and 2a the first oxidation wave corresponds to
single-electron oxidations of each of the ferrocene units of the
binuclear complex (Figure 5, left). That at least one of the
oxidations is electrochemically reversible is clear from the
For the halide-free complex 4 prepared in situ from [Cu(I)-
(CH3CN)4]PF6 and L2 (1:1), no evidence of free ligand or
oxidative instability was observed at -70 °C in CH2Cl2. In
contrast to the halide-based complexes two electrochemically
reversible 1 e- processes are observed (Figure 6).18d The first
oxidation (assigned to the ferrocene redox couple of the
coordinated ligand) is similar to that observed for the halide
complexes; however, only a single reductive ferrocenium/
ferrocene wave is observed. The Cu(II)/Cu(I) redox process is
considerably more anodic than that observed for both of the
copper-based oxidation steps in the halide complexes. This is
as expected, considering the weaker donor strength of MeCN
in comparison to that of Cl- and Br-. Addition of 1 equiv of
TBABr to the CH2Cl2 solution resulted in a dramatic change to
the cyclic voltammetry with the appearance of new redox waves
at positions identical to that observed for 2a and a reduction in
the reversibility of the ferrocene redox process with a second
ferrocenium reduction wave being observed (Figure 6). This
confirms that the binuclear halide-bridged complex is the ther-
modynamically most favored complex in halogenated solvents.
Although overall similar electrochemical behavior is observed
for all complexes, the potentials of the two Cu(II)/Cu(I) redox
processes and the separation of the first and second ferrocenium
reductions is dependent on the ligand involved. This demon-
strates clearly that, although all of the complexes examined are,
essentially, structurally similar, the electron density on the
copper(I) centers is distinctly different in each case.
The identification of significant differences in the redox
properties of the copper(I) centers with ligand variation suggests
that electronic factors may play an important role in determining
the specificity of the ligands to particular substrate classes. For
example, in comparison to 1a, complex 2a was found to be
more selective toward nonactivated substrates.7c From electro-
chemistry, it is apparent that 2a is easier to oxidize and hence
(18) (a) For the electrochemistry measurements of the copper complexes and
free ligands performed at room temperature, see Supporting Information.
(b) Ong, J. H. L.; Nataro, C.; Golen, J. A.; Rheingold, A. L. Organometallics
2003, 22, 5027-5032. (c) Pinto, P.; Calhorda, M. J.; Felix, V.; Aviles, T.;
Drew, M. G. B. Monatsh. Chem. 2000, 131, 1253-1265. (d) The halide-
free copper complex 4, prepared from equimolar amounts of L1 and
[Cu(CH3CN)4]PF6, provides similar catalytic activity for the enantioselective
conjugate addition of Grignard reagents to enoates. Complex 4 was prepared
only in situ due to instability in solid state.
9
J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006 9107

A R T I C L E S
Harutyunyan et al.
Figure 6. Oxidative electrochemistry (at -78 °C) of (left) L2/[Cu(I)(CH3CN)4]PF6 (1:1, red) in CH2Cl2 (0.1 M TBAPF6), in the presence of 1 equiv of
TBABr (blue) and the oxidative electrochemistry of 2a (black) at -78 °C, scan rate ) 25 mV s-1; and of (right) L2 in CH2Cl2 (0.1 M TBAPF6). Scan rate
) 25 mV s-1
Scheme 4. CA of MeMgBr to Octenone 5a
Table 2. Enantioselective CA of MeMgBr to 5 Catalyzed by 5 mol
% Copper Bromide Complex 1aa
entry
solvent
conv. [%]b
6a:6bb
ee[%]c
1
2
3
4
CH2Cl2
toluene
tBuOMe
Et2O
THF
CH2Cl2
CH2Cl2
88
89
90
87
67
35
25
86:14
88:12
97:3
83:17
2:98
92
91
96
87
2
a Reagents and conditions: (1) uncatalyzed reaction MeMgBr (1.5 equiv).
(2) Racemic series: CuBr‚SMe2 (5 mol %); MeMgBr (1.5 equiv). (3)
Enantioselective series: 1a-c (5 mol %); MeMgBr (1.1 equiv).
5
6d
7e
75:25
42:58
80
75
Table 1. CA of MeMgBr to Octenone 5
entry
[Cu] [5 mol %]
solvent
conv. [%]a
6a:6ba
a Reaction conditions: reaction time 1 h, 5 0.35 M, MeMgBr 1.5 equiv,
-78 °C. b Conversion and regioselectivity determined by GC. c Determined
by GC (chiral dex-CB column). d Dioxane (1 equiv) was added to the
mixture of catalyst and MeMgBr in CH2Cl2 prior to addition of 5. e Me2Mg
(1.5 equiv) was used instead of MeMgBr for this reaction.
1b
2b
3c
4c
-
-
Et2O
CH2Cl2
Et2O
52
55
88
85
1:99
1:99
55:45
42:58
CuBr‚SMe2
CuBr‚SMe2
CH2Cl2
a Conversion and regioselectivity were determined by GC. b Conditions
(1), Scheme 4, reaction time 1 h, 5 (0.35 M). c Conditions (2), Scheme 4,
reaction time 1 h, 5 (0.35 M).
conversion and regioselectivity of the CA of the MeMgBr to 5
in the absence of catalyst, and catalyzed by CuBr‚SMe2 (in
CH2Cl2 and Et2O) (Scheme 4, Table 1).
is more electron rich than 1a. Hence, the difference in reactivity
may be related to the energy match of substrate and catalyst.
However, further investigation over a broader range of catalysts
is necessary to determine if a correlation between measured
redox potentials and substrate specificity is justifiable. Neverthe-
less, the present results indicate that such a correlation is
plausible.
The Influence of the Solvent and Halide on the Enantio-
selective CA Reaction. Having established the structures and
basic redox properties of the initial copper complexes, a more
detailed examination of the various reaction parameters was
performed. Previously, we have demonstrated the importance
of carrying out the reaction at low temperature to achieve good
levels of regio- and enantioselectivity;7b-d hence, in the present
study reactions were carried out at -78 °C.
As expected, the addition of MeMgBr to enone 5 at -78 °C
in Et2O led to the 1,2-addition product 6b as the major
compound with 52% conversion in 1 h (Table 1, entry 1).
Similar results were obtained in CH2Cl2 (entry 2). Employing
a catalytic amount of CuBr‚SMe2 under the same conditions
provided higher conversion and afforded the 1,4-addition
product 6a with modest regioselectivity (entries 3, 4).
Enantioselective Series: Solvent Dependence. Table 2
summarizes the results obtained in the CA of MeMgBr to 5
catalyzed by chiral copper catalyst 1a and the solvent depen-
dence observed. The reaction proved to be remarkably tolerant
to a range of solvents (Table 2, entries 1-3). For instance, in
CH2Cl2 and toluene 6a was obtained in excellent yield and with
high regio- and enantioselectivity (entries 1, 2).
In ethereal solvents high regio- and enantioselectivity was
observed also, albeit with higher selectivity in tBuOMe than in
Et2O (entries 3, 4). Interestingly, employing THF as a solvent
resulted in a significant decrease in the rate of the reaction and
a near complete loss of regio- and enantioselectivity (2% ee),
(entry 5).
As a model system for the present study we choose the CA
of MeMgBr to octenone 5 under three different sets of
conditions (Scheme 4): (1) in the absence of catalyst, (2) using
5 mol % of CuBr‚SMe2 (racemic series), (3) in the presence of
5 mol % of chiral complexes 1a-c (enantioselective series).
MeMgBr was employed as the Grignard reagent in this reaction
to take advantage of its relatively low reactivity. The decreased
reactivity of MeMgBr compared to those of its homologues is
attributed to the significantly higher strength of the C-Mg bond
(MeMgBr > 250 kcal/mol > EtMgBr g PrMgBr g BuMgBr
We reasoned that the Schlenk equilibrium20 could be the most
important factor in determining the solvent dependence in the
(19) Silverman, G. S., Rakita, P. E., Eds. Handbook of Grignard Reagents;
Marcel Decker Inc.: New York, 1996.
(20) Schlenk, W.; Schlenk, Jr. Ber. Dt. Chem. Ges. 1929, 62B, 920-924.
t
> 200 kcal/mol > BuMgBr).19 Initially, we determined the
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9108 J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006

Cu-Catalyzed Enantioselective CA of Grignard Reagents
A R T I C L E S
Table 3. CA of MeMgX to 5 Catalyzed by 5 mol % Copper
Complex 1 in CH2Cl2
72% ee. In addition, the regioselectivity decreased (entry 5).
Furthermore, when MeMgI was used in combination either with
1a or 1c, low enantioselectivity, accompanied with a noticeable
decrease in the regioselectivity was observed (entries 6, 7).24b
1H NMR and 31P NMR Spectroscopy. From ESI-MS, IR
spectroscopy, X-ray crystallography, and electrochemistry stud-
ies, the copper complexes 1a and 2a exist as bromide-bridged
dinuclear complexes in the solvents used in the CA reaction
a
entry
CuX
1
MeMgX
conv. [%]b
6a:6bb
ee [%]c
1
2
3
4
5
6
7
CuBr
CuCl
CuI
CuBr
CuCl
CuBr
CuI
1a
1b
1c
1a
1b
1a
1c
MeMgBr
MeMgBr
MeMgBr
MeMgCl
MeMgCl
MeMgI
88
95
85
88
99
94
95
86:14
85:15
85:15
82:18
50:50
77:23
71:29
92
94
90
91
72
30
36
MeMgI
t
(CH2Cl2, Et2O, BuOMe). However, the copper-halide com-
plexes studied in this asymmetric CA are precursors to the
catalytically active species generated upon addition of the
Grignard reagents. By analogy with the formation of an
organocuprate via transmetalation of an organometallic reagent
with a copper source, it is proposed that a similar process occurs
upon addition of Grignard reagents to the Cu-halide com-
plexes.14 To detect and characterize the reaction intermediates
in the present system, a detailed NMR spectroscopic study was
performed.
a Reaction conditions: reaction time 1 h, 5 (0.35 M), MeMgBr 1.5 equiv,
-78 °C. b Conversion and regioselectivity determined by GC. c Determined
by GC (chiral dex-CB column).
CA of MeMgBr. Benn and co-workers21a demonstrated that the
Schlenk equilibrium between EtMgBr and Et2Mg in Et2O
favored the solvent-coordinated monoalkylmagnesium species
EtMgBr‚OEt2. By contrast, in THF, R2Mg and MgBr2 are the
dominant species present in solution.21b Furthermore, it is known
that the Schlenk equilibrium can be driven, partially, toward
the formation of R2Mg in any solvent by the addition of dioxane
to a solution of the Grignard reagent.22
Two different experiments were performed to establish
whether the involvement of the Me2Mg species in THF could
be responsible for the decrease in the rate and enantioselectivity
of the reaction. (1) Addition of 1 equiv of dioxane to a mixture
of 1a and MeMgBr in CH2Cl2 prior to addition of substrate 5
had a dramatic, negative, effect on the reaction, providing
product 6a with low conversion and with a significant decrease
in enantioselectivity (entry 6).23a (2) The involvement of the
Schlenk equilibrium in THF was supported further by the direct
use of Me2Mg instead of MeMgBr. The CA of Me2Mg to 5 in
CH2Cl2, led to the product with low conversion and modest
enantioselectivity (entry 7), similar to that observed in the
presence of dioxane.23b
Halide Dependence. The CA to 5 employing different
combinations of CuX and MeMgX was examined to explore
the effect of halide on the outcome of the reaction (Table 3).24a
It is apparent that the CA reaction is dependent both on the
nature of the halide present in the Grignard reagent and in the
Cu(I) salt (Table 3). The presence of bromide, either in the
Grignard reagent or in the copper salt, is essential to achieve
full conversion and high regio- and enantioselectivity. For
instance, the combination of MeMgBr with the copper chloride
complex 1b or the copper iodide complex 1c provided product
6a with high regio- and enantioselectivity in both cases,
comparable with results using CuBr (entries 1-3). In a similar
manner the CA of MeMgCl to 5 catalyzed by 1a proceeds with
high regio- and enantioselectivity (entry 4).
First, complexes 1a-c were investigated in solution prior to
1
addition of both the Gringard reagent and the enone. The H
NMR and 31P NMR spectra of complex 1a in CD2Cl2 are
presented in Figure 7a. 31P NMR shows two doublets with a
JP-P ) 186 Hz corresponding to the dicyclohexyl (8.21 ppm)
and diphenylphosphine (-24.06 ppm) groups.25 Variable-
1
temperature H NMR spectroscopy showed a slight variation
in the chemical shifts of the aromatic protons. Particularly, the
absorption at 7.0 ppm corresponding to two ortho protons of
the phenyl group, observed at low temperature (below -30 °C)
was shifted downfield at RT and overlapped with the signal at
7.2 ppm. 31P NMR did not reveal significant temperature-
dependent changes in the chemical shifts of 1a.
To determine the structure of the species formed during the
reaction, complex 1a and an excess (1.5-10.0 equiv) of
MeMgBr were mixed in CD2Cl2 at -78 °C, and the resulting
mixture was studied by NMR spectroscopy at -60 °C. 31P NMR
spectroscopy showed upfield shifts of both phosphorus reso-
nances (Figure 7b). In the 31P NMR two doublets corresponding
to dicyclohexyl (6.41 ppm) and diphenylphosphine (-27.13
ppm) moieties were shifted by 1.8 ppm and 3.1 ppm, respec-
tively, relative to those of the initial complex 1a, indicating the
formation of a new species, A.26 These chemical shifts can be
compared with the large 31P NMR upfield shift, assigned by
Chan and co-workers to a (L)nCuEt species, generated from
Et2Zn, Cu(OTf)2, and a phosphine ligand.16
In the present study, the value of the P-P coupling constant
changed from Jp-p ) 186 Hz in the initial complex 1a to Jp-p
) 143 Hz. Formation of A was confirmed by 1H NMR
spectroscopy also (Figure 7b). A new sharp singlet was observed
at -0.3 ppm, which is attributed tentatively to a CuMe species.27
However, the use of MeMgCl together with CuCl resulted
in a significant decrease in the enantioselectivity from 92% to
(21) (a) Benn, R.; Lehmkuhl, H.; Mehler K.; Rufin´ska, A. Angew. Chem., Int.
Ed. Engl. 1984, 23, 534-535. (b) Smith, M. B.; Becker, W. E. Tetrahedron
1966, 22, 3027-3036.
(22) Dioxane is a common reagent for synthesis of R2Mg from RMgX due to
irreversible coordination with MgX2. For the synthesis of R2Mg, see: (a)
Tadeusz, F.; Molinski, T. F.; Ireland, C. M. J. Org. Chem. 1989, 54, 4256-
4259. (b) von dem Bussche-Hu¨nnefeld, J. L.; Seebach, D. Tetrahedron
1992, 48, 5719-5730.
(23) (a) Significant precipitation, observed after addition of dioxane to the
mixture of catalyst with Grignard reagent, was attributed to a complex of
dioxane with MgBr2. (b) Solvent- and halide-dependent experiments were
performed on the CA of EtMgX to methyl crotonate also. For the results,
see Supporting Information.
(24) (a) Similar results were obtained employing both preformed and prepared
in situ copper complexes. (b) Explanation for the results obtained with
MeMgI arose from the NMR studies, vide infra.
(25) The saturation 31P NMR experiments and phase-sensitive phosphor-
phosphor COSY spectrum (for the spectrum see Supporting Information)
showed no passive coupling to the copper, indicating only phosphorus-
phosphorus coupling. Attempts to observe 63Cu NMR spectra were
unsuccessful possibly due to fast quadrupolar relaxation and broken
symmetry (see refs 29 a and c).
(26) (a) Employing 1 equiv of MeMgBr did not provide complete formation of
the new species A. (b) When the CA to octenone 5 was performed in Et2O,
a significant amount of a precipitate was observed after the addition of
MeMgBr to 1a, and prior to the addition of the enone. This suggests that
the newly formed species is not soluble in Et2O. (c) Attempts to crystallize
species A were unsuccessful.
(27) Besides the signal attributed to the CuMe group, another singlet at δ 1.64
ppm was detected and assigned to the excess of MeMgBr used in these
experiments. For a full range of the NMR spectra, see Supporting
Information.
9
J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006 9109

A R T I C L E S
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1
Figure 7. 31P NMR (left) and H NMR (right) spectra in CD2Cl2 at -60 °C: (a) complex 1a, (b) complex 1a with 3 equiv of MeMgBr.
Chart 1. Structures Proposed for the Alkyl Copper(I) Complexes
The general procedure applied for the synthesis of the
complexes presented in Chart 1 differs from the one used in
the present study by the order of addition and reacting
components. The experimental procedures reported previously
were based on the direct reaction of organometallic compounds
(Me2AlOEt, MeLi, Me2Mg) with Cu(II) salts and phosphine
ligands,28,29 whereas in our case the synthesis of the alkyl copper
complexes is carried out by the addition of organometallic
reagents to the preformed copper(I) bromide complexes of
diphosphine ligands (L1, L2) (vide supra).
The integration indicates that only 1 methyl group is bound to
the copper, even in the presence of up to 10 equiv of MeMgBr.
The observed CuMe shift may be compared with the 1H NMR
absorptions of related achiral alkylcopper species “(PR3)xCuMe”
for which chemical shifts of +0.3 to -1.0 ppm were reported
previously.28
The dynamic equilibrium of the newly formed species A was
studied by variable-temperature 31P NMR spectroscopy. No
changes in the spectra were observed over the temperature range
-30 to -78 °C. Moreover, species A proved to be stable in
solution at these temperatures under an inert atmosphere for
several days. However, increasing the temperature to 23 °C
resulted in decomposition of A, with concomitant formation of
a black precipitate due to release of metallic copper. Despite
this instability in CD2Cl2 at RT, species A proved to be more
stable in Et2O, and no decomposition was detected over 30 min
at room temperature.26b,c
As can be seen in Figure 7, the formation of species A in
CD2Cl2 was accompanied by the appearance of traces of two
new doublets (species B) in the 31P NMR spectrum at 13.6 and
-19.1 ppm (vide infra). The importance of this species in the
CA reaction will be discussed below.
On the basis of literature precedents, several structures can
be proposed for species A. Thus, alkyl copper(I) complexes of
achiral phosphine ligands with the general structures presented
in Chart 1 were proposed previously on the basis of spectro-
scopic data and X-ray structure analysis.28a-c,29
To establish whether the species observed in our system are
analogous to the complexes shown in Chart 1, the preparation
of species A directly from the free ligand L1, a copper(II) salt
and the Grignard reagent was attempted following literature
procedures.28,29 Unfortunately, clear results from these experi-
ments were not obtained due to the appearance of a number of
new signals indicating formation of several complexes, whereas
no trace of species A was observed.
Alternatively, we wondered whether the species A might be
generated by using MeLi instead of MeMgBr. Interestingly, the
addition of 1.0-2.0 equiv of MeLi to 1a, at -78 °C in CD2Cl2,
led to the formation of a single, new copper species C (Figure
8b).
Two doublets in the 31P NMR spectrum appeared at 11.61
ppm and -25.44 ppm (Jp-p ) 163 Hz) with concomitant
disappearance of the characteristic signals of 1a.30a The 1H NMR
absorption of CuMe appeared at -0.77 ppm, which was shifted
upfield by 0.49 ppm with respect to A. Interestingly, addition
of more than 2 equiv of MeLi to 1a led to the formation of C,
with simultaneous decomplexation of the ligand L1 (-28.5 ppm
in the 31P NMR spectrum, Figure 8b) and formation of LiCuMe2
1
(detected in the H NMR spectrum, -1.17 ppm).30b
The roles of Mg2+ and Li+ ions in the structures of A and C,
respectively, were investigated by addition of selective additives
to remove those ions from the coordination sphere of the copper
atom. Addition of 1.5 equiv of 12-crown-4 to a solution of C
(formed by addition of 1.5 equiv MeLi at -78 °C in CH2Cl2)
(28) (a) Dempsey, D. F.; Girolami, G. S. Organometallics 1988, 7, 1208-1213.
(b) House, H. O.; Fischer, W. F. J. Org. Chem. 1968, 33, 949-956. (c)
Miyashita, A.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1977, 50, 1102-1108.
(d) Ikariya, T.; Yamamoto, A. J. Organomet. Chem. 1975, 72, 145-151.
(e) Pasynkiewicz, S.; Poplawska, J.; J. Organomet. Chem. 1985, 282, 427-
434. (f) Pasynkiewicz, S.; Pikul, S.; Poplawska, J. J. Organomet. Chem.
1986, 293, 125-130.
(29) (a) Gambarotta, S.; Strologo, S.; Floriani, A.; Chiesi-Villa, A.; Guastini,
C. Organometallics 1984, 3, 1444-1445. (b) Coan, S. P.; Folting, K.;
Huffman, J. C.; Caulton, K. G. Organometallics 1989, 8, 2724-2728. (c)
Schaper, F.; Foley, S. R.; Jordan, R. F. J. Am. Chem. Soc. 2004, 126, 2114-
2124. (d) Mankad, N. P.; Gray, T. G.; Laitar, D. S.; Sadigi, J. P.
Organometallics 2004, 23, 1191-1193.
(30) (a) The observed value of the Jp-p coupling constant was 20 Hz lower
compared to the Jp-p obtained for the species A (Jp-p ) 143 Hz). (b) The
assignment was made by the correlation of observed chemical shift and
the chemical shift reported for LiCuMe2 in the literature (δ ) -1.0 to δ
-1.4). See: (a) Lipshutz, B. H.; Kozlowski, J. A.; Breneman, C. M. J.
Am. Chem. Soc. 1985, 107, 3197-3204. (b) House, H. O.; Respass, W.
L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128-3141.
9
9110 J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006

Cu-Catalyzed Enantioselective CA of Grignard Reagents
A R T I C L E S
Figure 8. 31P NMR (left) and 1H NMR (right) spectra in CD2Cl2 at -60 °C: (a) complex 1a, (b) complex 1a with 3 equiv of MeLi (signal at δ -28.5 ppm
in the 31P spectrum corresponds to the free ligand L1 usually formed when more than 2 equiv of MeLi are used).
1
Figure 9. 31P NMR (left) and H NMR (right) spectra in CD2Cl2 at -60 °C: (a) complex 1a; (b) complex 1a with 3 equiv of MeMgBr; (c) complex 1a
with 3 equiv of MeMgBr followed by addition of 3 equiv of dioxane.
Scheme 5. Possible Structures for the Species A and C Formed
by Transmetalation of 1a with MeMgBr and MeLi, Respectively
resulted in the formation of a precipitate; however, the 31P NMR
spectrum of species C was unaffected. This suggests that Li+
is not involved in the structure of species C, i.e. Li+ is not
present within the first coordination sphere of complex C.
On the other hand, dioxane could be employed to drive the
formation of R2Mg from RMgX (vide supra) since it coordinates
strongly to MgBr2 and results in precipitation of the dioxane
complex from the reaction mixture.22 If MgBr2 is part of the
complex A, then addition of dioxane will, necessarily, have an
influence on its structure.
Addition of 3 equiv of dioxane at -78 °C to a CD2Cl2
solution of A (formed by addition of 3 equiv of MeMgBr)
resulted in the immediate conversion of species A to species C
(Figure 9b, c), with concomitant formation of a precipitate.
Importantly, it was found that the addition of Me2Mg, instead
With respect to species C, formed upon addition of MeLi
of MeMgBr or MeLi to complex 1a afforded C as the major
(as well as after addition of Me2Mg) to 1a, complexes III or
species also.17b
IV (Scheme 5b) can be excluded due to the experimentally
Thus, these experimental results demonstrate clearly that
observed conversion of A to C upon addition of dioxane. This
MgBr2 is an intimate component of the transmetalated species
is supported further by the absence of an effect of 12-crown-4
A. On the basis of these experiments, two different structures
ether on C formed after addition of MeLi, as well as by the
I or II (Scheme 5a) can be proposed for the species A, formed
after addition of MeMgBr to 1. However, the 1:1 ratio of Cu/
Me revealed by 1H NMR allows us to exclude II and to postulate
I as the most appropriate structure for species A.31
(31) Hence, the complex 1a was prepared from CuBr and ligand L1 in 1:1 ratio;
1
consequently 1:1 ratio of Me to L1, observed in H NMR after adding of
MeMgBr, indicates that only one Me group is coordinated to the copper
atom.
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A R T I C L E S
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Scheme 6. Stoichiometric Addition of Octenone 5 to the Species
A and C
generation of C by addition of Me2Mg to 1a. One of the
structures V-VII, could also be a priori attributed to C. Type
V structures for alkylcopper phosphine complexes have been
proposed by several groups.28,29 On the basis of X-ray structures
Girolami et al. suggested that alkylcopper complexes can adopt
structure VI, depending on the bulkiness of phosphine ligands
and alkyl group and, more significantly, the nature of the solvent
(vide infra).28a
Figure 10. 31P NMR spectra at -60 °C: (a) complex 1a with 2 equiv of
MeMgBr in toluene-d8; (b) complex 1a with 2 equiv of MeMgBr in THF-
Nevertheless in the present case we can exclude complex VI
as a possible structure for species C, as it would result in a
more complicated 31P NMR spectrum than those which are
obtained experimentally for C. There are no literature precedents
for the viability of the complexes of structure VII where alkyl
groups bridge two copper centers.32 On the basis of the data
analysis given above we propose structure I for species A and
structure V for species C.
d8.
supra). In toluene-d8, the alkylcopper species, formed after the
addition of MeMgBr to the complex 1a with chemical shifts at
5.9 and -27.4 and Jp-p ) 143 Hz, is assigned to complex A
(Figure 10a).34a By contrast, the addition of MeMgBr to 1a in
THF-d8 led to formation of a Cu complex with two doublets
(11.0 ppm and -23.9 ppm). On the basis of the coupling
constant Jp-p ) 163 Hz, we assigned the species formed in THF
as complex C (Figure 10b).34b
The formation of A in toluene and C in THF is in agreement
with the experimental results, which show a high regio- and
enantioselectivity in toluene and poor selectivity in THF (Table
2, entries 2, 5). These results again confirm the importance of
species A in the catalytic cycle, to achieve high levels of regio-
and enantioselectivity. Any reaction parameter that contributes
to the formation of species A appears to provide highly efficient
catalysis, while all the reaction parameters promoting the
formation of C lead to lower efficiency and selectivity of the
present catalytic system.
Based on the product distribution and level of enantioselec-
tivity, a second parameter which may have an impact on the
formation of either A or C could be the halide employed in the
copper source and Grignard reagent (Table 3). 31P NMR spectra
of complexes 1a (X ) Br) (Figure 7a), 1b (X ) Cl) (Figure
11a), 1c (X ) I) (Figure 12a) show only slight differences in
the 31P chemical shifts and in the value of the P-P coupling
constant which depends on the type of halogen.
Addition of 4 equiv of MeMgCl to 1b, led exclusively to the
formation of the complex C, with no indication for the formation
of complex A (Figure 11b). This correlates well with the poor
result obtained in the CA of MeMgCl to 5, catalyzed by copper
chloride complex 1b (Table 3, entry 5). In contrast, when 10
equiv of MeMgBr were added to 1b, only formation of species
A was observed (Figure 11c), which is in good agreement with
CA results (Table 3, entry 2).35
To establish the relevance of species A and C in the catalytic
CA we performed stoichiometric additions of octenone 5 to their
solutions at -78 °C, and the changes in the resulting mixtures
1
were followed by H and 31P NMR spectroscopy (Scheme 6).
Addition of an equimolar amount of 5 to either species A or
C led to instantaneous and quantitative formation of the initial
complex 1a with concomitant formation of the addition products
6. Addition of 1 equiv of 5 to A provided the 1,4-adduct 6a
with regioselectivity of 96% and 92% ee.
These values are in agreement with those obtained for the
CA of MeMgBr to 5, catalyzed by 1a (Table 2, entry 1). In
contrast, the addition of 1 equiv of 5 to C (obtained from MeLi)
led to the 1,4-adduct 6a with regioselectivity of 10% and
enantioselectivity of 62%. Considering that species C can be
formed by either addition of Me2Mg to 1a or of dioxane to A,
the data correlates well with the low conversion and enantio-
selectivity obtained in the catalytic reactions performed with
Me2Mg (Table 2, entry 7) and with MeMgBr and dioxane as
an additive (Table 2, entry 6). Thus, we can postulate that the
generation of species A, rather than C, is essential to obtain
high levels of regio- and enantioselectivity in the catalytic CA
of Grignard reagents to unsaturated carbonyl compounds.
As shown in Table 2, the nature of the solvent has a
significant influence on the selectivity of the reaction. Similarly,
it can be expected that the nature of the solvent could lead to
a preference for the formation of A or C. The influence of
several solvents on the distribution of the copper species was
studied by 31P NMR spectroscopy (Figure 10a, b).33
In Et2O and CH2Cl2 the Cu-complex A is the major
component obtained after addition of MeMgBr to 1a (vide
The situation for the copper iodide complex 1c was quite
different (Figure 12 a-c). In this case the addition of MeMgI
(32) However, related diphosphine copper complexes bridged by alkyne moieties
have been reported, for instance, see: Janssen, M. D.; Kohler, K.; Herres,
M.; Dedieu, A.; Smeets, W. J. J.; Spek, A. L.; Grove, D. M.; Lang, H.;
van Koten, G. J. Am. Chem. Soc. 1996, 118, 4817-4829.
(34) (a) We assigned the alkylcopper species observed in toluene to the complex
A based on the value of the Jp-p coupling constant. (b) Slight difference in
chemical shifts is due to changing the solvent from CH2Cl2 to THF.
(35) The formation of A in this case of 1b can be explained by the exchange of
chloride (or iodide in the case of 1c) by a bromide in the copper complex,
due to presence of an excess of MeMgBr.
(33) Due to the 1H NMR downfield shift of the CuMe signal and overlap with
several other peaks in the above-mentioned solvents, the following studies
were monitored by 31P NMR spectroscopy only.
9
9112 J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006

Cu-Catalyzed Enantioselective CA of Grignard Reagents
A R T I C L E S
Alkene Geometry. The geometry of R,â-unsaturated carbonyl
compounds is considered an important parameter to understand
the mechanism of the stereocontrol in CAs. Therefore, the
influence of the alkene (cis/trans) geometry on the enantio-
selective CA of EtMgBr to enones and enoates was examined,
and a remarkable difference between ketones and esters was
observed. (Scheme 7and Chart 2).
Surprisingly, in the present study, the CA of EtMgBr to both
trans-7 and cis-7 enones, catalyzed by complex 1a, afforded
the product 12a with the same absolute configuration and an
equal level of enantioselectivity (Table 4, entries 1 and 2). In
contrast, the CA of EtMgBr to both trans-8 and cis-8 enoates,
catalyzed by 1a led to the products 12b with opposite
configurations (entries 3, 4).
Analysis of the reaction mixture at different times led to the
conclusion that an isomerization of the cis-enoates to the trans-
isomer was occurring during the CA reaction of EtMgBr to
enoates 9-11 (entries 6-13).
Figure 11. 31P NMR spectra in CD2Cl2 at -60 °C: (a) CuCl complex 1
b. (b) 1b with 4 equiv of MeMgCl. (c) 1b with 10 equiv of MeMgBr.
Lower enantioselectivities in the CA to the cis-enoates were
achieved in these cases, and a cis-trans isomerization within
the time scale of the reactions could be demonstrated also. The
observation of this partial isomerization during the reaction
provides an explanation for the low enantioselectivity obtained
in the CA to cis-enoates 9-11.37a
Furthermore, although no CA reaction occurred between
MeMgBr and the less active p-OMe cinnamate trans-11 or cis-
11, isomerization was observed when the reaction was carried
out with cis-11. Control experiments confirmed that the isomer-
ization process is only initiated when both the chiral copper
complex (2a) and the Grignard reagent are present in solution
together with the cis-enoate.37b
This suggests that the activated copper complex A may
interact directly, but reversibly, with the alkene moiety allowing
the cis-trans isomerization of the double bond to occur, and
therefore causing a decrease in the enantioselectivity of the
reaction. When the cis-trans isomerization is much faster than
the final irreversible step leading to the product, the formation
of the adduct with the same absolute configuration either starting
from the cis- or trans-unsaturated system may be expected.
Indeed, this appears to be the case for the enones trans-7 and
cis-7.
Kinetic Analysis. The intermediate species derived from the
substrate (enone or enoate) and complex A, which is postulated
to be the key complex involved in the catalytic cycle, could
not be detected directly due to their transient existence and
hence, low concentration. A kinetic analysis of the CA reaction
could provide insight into the reaction mechanism; however,
several difficulties are associated with the model reaction (the
addition of MeMgBr to octenone) discussed thus far with regard
to kinetic studies. In particular, the very high reaction rate even
at -78 °C, an incomplete regioselectivity (∼85%), and the
Figure 12. 31P NMR spectra in CD2Cl2 at -60 °C: (a) CuI complex 1c.
(b) 1c with 3 equiv of MeMgI. (c) 1c with 10 equiv of MeMgBr.
caused signal broadening, corresponding to the initial complex
1c and formation of a minor amount of B (vide supra and Figure
12b). A 3-fold increase in the concentration of MeMgI resulted
in a slight increase in B and further broadening of the remaining
resonances. Since no appreciable amount of species A or C is
formed with MeMgI, the background reaction is most probably
responsible for the low enantioselectivity observed in the
catalytic reaction (Table 3, entries 6, 7). As for 1b, when 10
equiv of MeMgBr were added to 1c, only formation of species
A was observed (Figure 12c), again in good agreement with
the CA results.35
Finally, the sensitivity of the reaction to water and air was
examined. A CD2Cl2 solution of A, being in contact with air,
was transformed slowly to species B, as determined by 31P NMR
and 1H NMR spectroscopy (Figure 13). The phosphorus
resonances of B are shifted downfield to 13.62 ppm and -19.07
1
ppm relative to those of A. The H NMR absorption of CuMe
appeared as a sharp singlet at -0.32 ppm, shifted upfield by
0.03 ppm compared to complex A. When 1 equiv of dioxane
was added to B, no changes were observed by NMR spectros-
copy.
(36) Interestingly, 90% ee was obtained when the stoichiometric reaction with
the 5 was performed with species B. Nevertheless, the participation of
species B in the catalytic cycle is unlikely, since under reaction conditions
and accordingly, in the presence of large excess of Grignard reagent and
5, fast formation and consumption of species A will prevent any role of
species B.
(37) (a) The higher enantioselectivity observed in the CA of EtMgBr to cis-8
(Table 4, entry 3) is attributed to the faster conjugate addition to â-alkyl-
compared to â-aryl R,â-unsubstituted esters (Table 4, entries 7, 10, 13).
(b) In the absence of Grignard reagent, or Cu complex (1a or 2a), or in the
presence of Grignard reagent with CuBr‚SMe2 instead of the chiral complex
no isomerization was observed.
Thus, we can consider that B is a side product accompanying
the formation of the species A and C. Unfortunately, the precise
structure of species B cannot be discerned from the data
available.36
9
J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006 9113

A R T I C L E S
Harutyunyan et al.
Figure 13. 31P NMR (left) and 1H NMR (right) spectra in CD2Cl2 at -60 °C: (a) species A formed from complex 1a with 4 equiv of MeMgBr. (b) Species
B formed from A under influence of air.
Scheme 7. Enantioselective CA of EtMgBr to cis- and
trans-R,â-unsaturated Compounds
Scheme 8. CA of EtMgBr to Methyl Crotonate 13, Catalyzed by
Cu-Bromide Complex 1a
Chart 2
between MeMgBr and enoates prompted us to use the more
reactive EtMgBr for these studies. Thus, the addition of EtMgBr
to methyl crotonate 13, catalyzed by the Cu-complex 1a in
CH2Cl2 at -87 °C, was chosen as model reaction for the kinetic
study (Scheme 8).
The reaction rates were measured at varying concentrations
of substrate, Grignard reagent, and catalyst. The effects of the
initial concentrations of 13 and EtMgBr were examined within
a range of 0.09 to 0.36 M (see Supporting Information).38a By
measuring the reaction rate at different concentrations of
EtMgBr (up to 80% conversion) an enhancement of the reaction
rate was found at increased concentration of the Grignard
reagent. The kinetic analysis for the substrate 13 were impeded
by a side reaction,38b which occurred at increased substrate
concentrations (more than 2 equiv of 13). Nevertheless, as for
EtMgBr, an increase in reaction rate with increasing substrate
concentration was observed (1-2 equiv). The dependence of
the reaction rate on [EtMgBr] (vide supra) and [13] suggests
that both reactants are involved in the rate-limiting step.
The rate constant calculated at different initial concentrations
of the precatalyst allowed determination of the order of the
reaction with respect to the catalyst (1.17 for complex 1a), by
plotting the (ln k) against ln[Co] of catalyst 1a (Figure 14).38c
From the spectroscopic and electrochemical analysis of the
copper complexes (vide supra) it is clear that complex 1a in
CH2Cl2 forms a dimeric structure and that the association
constant is very high. However, complex 1a is only a precatalyst,
and after addition of Grignard reagents, formation of the
catalytically active species (i.e. A) occurs (vide supra). If the
catalyst is a dinuclear species, then the order of the reaction
Table 4. CA of EtMgBr and cis-trans Isomerization of
Substratesa
entry
substrate
catalystb
conv. 12 [%]c
cis:trans [%]d
ee [%]c
1
2
3
trans-7
cis-7
trans-8
cis-8
cis-8
trans-9
cis-9
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
2a
2a
100 (12a)
100 (12a)
100 (12b)
100 (12b)
50 (12b)
100 (12c)
100 (12c)
10 (12c)
100 (12d)
100 (12d)
85 (12d)
70 (12e)
-
95 (+)
95 (+)
90 (R)
90 (S)
90 (S)
98 (S)
53 (R)
59 (R)
96 (+)
63 (-)
67 (-)
90 (-)
40 (+)
-
-
-
4
5e
6
99:1
-
7
-
8e
9
cis-9
94:6
-
trans-10
cis-10
cis-10
trans-11
cis-11
10
11e
12f
13e,f
-
86:14
-
77 (12e)
1:99
a Reaction conditions: tBuOMe as a solvent, EtMgBr 1.5 equiv, -78
°C. b 5 mol % (R,S)-1a or (S,R)-2a. c Determined by GC. d cis:trans ratio
of the recovered starting material. e Reaction was stopped after ∼10-80%
conversion. f 5 mol % (R,S)-2a.
background reaction prevents the collection of reliable data. On
the other hand, CA of Grignard reagent to enoates proceeds
with high enantioselectivity similar to that of enones and shows
comparable dependence on the reaction solvent and copper
halide.7c Moreover, this reaction offers considerable advantages
for kinetic analysis due to its significantly slower rate, higher
regioselectivity (99%), and the absence of any side products or
background reaction at low temperature. The very low reactivity
(38) (a) Graphical representation of the experimental kinetic data is presented
in the Supporting Information. Due to the formation of a side product and
the presence of a suspension at the conditions required for a pseudo-first-
order kinetic analysis this approach could not be applied to this reaction to
determine the reaction order in both Grignard reagent and substrate. (b)
The side product detected corresponds to the Michael addition of the
generated enolate to another molecule of substrate 13. (c) Best-fit lines
were obtained by the least-squares method.
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9114 J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006

Cu-Catalyzed Enantioselective CA of Grignard Reagents
A R T I C L E S
Figure 14. Rate measurements for the CA of EtMgBr to 13, catalyzed by 1a in CH2Cl2 at -87 °C: (a) kinetic data obtained for different catalyst concentrations,
(b) reaction order with respect to 1a.
Table 5. CA of EtMgBr to 9 in CH2Cl2, Catalyzed by Copper
Bromide Complexes 1a, 2a, and 3a
entry
catalyst [mol %]
conv. [%]b
ee [%]c (R/S)
1
2
3
4
(R,S)-1a [2.5]
(S,R)-2a [2.5]
3 [2.5]
4
69
32
65
72 (S)
98 (R)
95 (R)
96 (R)
3 [5.0]
a Reaction conditions: concentration of 9 0.35 M, EtMgBr 1.5 equiv,
-78 °C, 3 h. b Conversion (GC) after 3 h. c Determined by GC on chiral
dex-CB column.
1a and 2a, in the CA of EtMgBr to methyl cinnamate 9
(Scheme 9).
As demonstrated in a previous report,7c complex 1a is a very
poor catalyst in the CA of Grignard reagents to R,â-unsaturated
aromatic esters, while complex 2a (prepared from L2 and CuBr)
is very efficient in this reaction. Indeed, complex (R,S)-1a shows
very poor catalysis in the present reaction leading to the product
12c with only 4% conversion and 72% ee (Scheme 9, Table 5,
entries 1). In contrast, complex (S,R)-2a afforded, in the same
reaction time, the desired product with a good conversion of
69% and an excellent ee (98%) (Table 5, entries 1, 2).
If a mononuclear complex derived from complex 3 (Scheme
10) is the active catalyst, then it would be expected that the
outcome of the reaction would be almost identical to that
obtained with the most efficient catalyst 2a. That this is indeed
the case is supported by the experimental results (Table 5, entries
3 and 4).
The rate and enantioselectivity observed in the reaction
catalyzed by 3 were nearly identical to those obtained with (S,R)-
2a (entries 3, 4). This result suggests that the dimeric copper
bromide complex 3 is dissociated upon addition of the Grignard
reagent (Scheme 10) and a catalytically active mononuclear
complex derived from 2a is responsible for the stereoselective
reaction.
Figure 15. Linear relationship between ee of ligand L1 and ee of the
products 6 ([) and 14 (solid red square) obtained by the addition of
MeMgBr and EtMgBr to octenone 5 and methyl crotonate 13, respectively,
catalyzed by 1a in CH2Cl2 at -78 °C.
Scheme 9. CA of EtMgBr to Methyl Cinnamate
with respect to the precatalyst will be between one and two
with the exact value depending upon the equilibrium constant
between the mononuclear and the dinuclear species. However,
if the catalyst is a mononuclear copper species (as attributed
for species A above), then the order of the reaction with respect
to the precatalyst should be closer to one. The latter is consistent
with the experimental results (1.17) and indicates that the active
form of the catalyst is a mononuclear complex. This assignment
is supported by the linear relationship between the product and
the catalyst enantiomeric purity (Figure 15).
Additional evidence for the mononuclearity of the catalytically
active species was obtained by the comparison of the catalytic
activity of heterocomplex 3 with that of homocomplexes
Finally, the activation parameters were determined for the
CA of EtMgBr to 13 (Scheme 8) from kinetic measurements
Scheme 10. Dissociation of the Complex 3 upon Addition of Grignard Reagent
9
J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006 9115

A R T I C L E S
Harutyunyan et al.
A. The monomeric complex A is formed from dimeric precata-
lyst 1a via transmetalation with Grignard reagent (Scheme 11).
Most probably, complex A functions in a similar manner as
organocuprates with the additional advantage that it bears a
chiral diphosphine ligand which accelerates the CA process and
stabilizes the reaction intermediates, thus overcoming back-
ground 1,4- and 1,2-additions.
The first intermediate in the proposed cycle is the π-complex
in which A forms, reversibly, a complex with the double bond
of the enone (enoate) through copper with an additional
interaction of Mg2+ with the oxygen atom of the carbonyl
moiety (Scheme 11). The importance of Mg2+ is reflected in
the inhibitory effects of solvent (THF), additive (dioxane), and
halide (absence of bromide) on the conversion and stereo-/
regioselectivity of the reaction. These inhibitory effects are due
to the formation of species C (Scheme 6), which is triggered
by removal of Mg2+ from the system.
Figure 16. Arrhenius plot for the CA of EtMgBr to 13, catalyzed by 1a
in CH2Cl2.
Table 6. Thermodynamic Parameters for CA of EtMgBr to Methyl
Crotonate 13 Catalyzed by 1a
thermodynamic parameters
values
Ea (kJ‚mol-1
∆Hq (kJ‚mol-1
∆Sq (J‚K-1‚mol-1
∆G°(20 °C) (kJ‚mol-1
k0 (20 °C) (L‚mol -1‚s-1
1/2 (20 °C) (s)
)
28
26
-138
)
)
The results indicate that Mg2+ not only activates the enone
(enoate) via coordination with oxygen (Lewis acid effect), but
also associates to the Cu-complex through the bridging halogen.
The importance of bromide in the halide bridge is evident from
the observations that its presence in either the initial Cu-complex
or Grignard reagent is essential to form species A. The origin
of this effect is unclear; however, the size and electronegativity
of bromide may be critical in achieving a balance between
stabilization of the π- and σ-complexes, which are intermediates
in the reaction. Furthermore we have shown that the CuI and
CuCl bonds in the complexes 1b, 1c are sufficiently labile to
be exchanged by the bromide present in the Grignard reagent.
The formation of a π-complex is possibly followed by intra-
molecular rearrangement to a Cu(III)-intermediate where copper
forms a σ-bond with the â-carbon of the enone (enoate). This
σ-complex is in fast equilibrium with the π-complex, and the
equilibrium constant between both complexes depends on the
stability of the Cu(III)-intermediate. Theoretical calculations
reported by Nakamura and co-workers11d for organocuprate CA
to enones indicate that this type of Cu(III) intermediate should
be very unstable. These authors propose that thermodynamic
stabilization of the Cu/substrate species and kinetic lability
toward reductive elimination, are the most important factors to
accelerate the rate of C-C bond formation. Thermodynamic
stabilization can be achieved by using soft donor ligands, while
kinetic lability will depend mostly on geometry of the species
formed. In the present system this is realized through a
combination of Grignard reagent and a diphosphine ligand,
which provides donor ligands and the necessary geometry in
the σ-complex to afford excellent regio- and stereocontrol.
The proposed catalytic cycle can rationalize the observed cis-
trans isomerization of enoates. This isomerization provides
strong evidence for the presence of a fast equilibrium between
the π-complex and the Cu(III) species (σ-complex), which is
followed by the rate-limiting, reductive elimination step (Scheme
11). The observation that cis-trans isomerization occurs even
in the case of the reaction between MeMgBr and the unsaturated
enoate cis-11, which does not afford any detectable amounts
of the product, is in agreement with the mechanism proposed.
Cuprate-induced isomerization of a cis-enone to a trans-enone
was reported previously by House40 and was explained via
)
66
4.8
23.3
)
t
Scheme 11. Proposed Catalytic Cycle for the CA Addition of
Grignard Reagents to R,â-Unsaturated Carbonyl Compounds
carried out at -65, -70, -80, -85 °C. The Arrhenius plot of
rate constants vs reciprocal temperature (T-1) is presented in
Figure 16.
An Eyring analysis of the kinetic data for the reaction
provides the activation parameters which are presented in Table
6. The energy of activation, Ea ) 27.7 (kJ‚mol-1), for the present
reaction can be compared with the value of Ea ) 76 (kJ‚mol-1
)
obtained by Krause for the noncatalytic 1,4-organocuprate
addition.9b,39
Mechanistic Discussion of the Enantioselective CA of
Grignard Reagents to r,â-Unsaturated Carbonyl Com-
pounds. A reaction pathway, which is consistent with the
experimental results and kinetic and spectroscopic data collected
in this study, is proposed in Scheme 11. The pathway of the
CA reaction involves formation of an intermediate species via
π-complexation followed by formation of a magnesium enolate
through a Cu(III) intermediate. The first step in the catalytic
cycle is initiated by formation of the catalytically active complex
(39) The lower value of the Ea obtained for the present reaction as opposed to
the system studied by Krause (ref 9b) might be due to the diphosphine
moiety present in the structure of the catalyst, which significantly lowers
the activation barrier of the transition state in the rate-limiting step.
(40) (a) House, H. O. Acc. Chem. Res. 1976, 9, 59. (b) House, H. O.; Weeks,
P. D. J. Am. Chem. Soc, 1975, 97, 2770-2778.
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9116 J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006

Cu-Catalyzed Enantioselective CA of Grignard Reagents
A R T I C L E S
Figure 17. Working model for the enantioselective CA of Grignard reagents (P1-diphenyl-substituted phosphine, P2-dicyclohexyl-substituted phosphine).
formation of a radical anion involving electron transfer from
the cuprate to the enone. Similar observations were subsequently
reported by Corey and co-workers9k for CA of organocuprates.
These authors concluded that the CA reaction of cuprates
proceeds via a reversible d,π-complex and a Cu(III) adduct and
that the initial electron-transfer step from cuprate to enone is
not obligatory. The latter proposition is in good agreement with
the properties observed for this catalytic system.
Additional support for the complexation of alkylcopper
species A with the alkene moiety of the substrate as well as the
rate-limiting alkyl-transfer step arises from the fact that any
additional substitution at the R- or â-carbons of the substrate
prevents formation of the 1,4-product. The presence of substit-
uents at these positions might impede the coordination of the
bulky diphosphine copper complex with the double bond, and
consequently the 1,2-addition becomes the most favorable
reaction for the active enone substrates, whereas no reaction
with less active enoates was observed.
noted that [reversible] formation of a copper-alkene complex
is well precedented, and this is supported by the ability of the
catalytic system to effect cis-trans isomerization (vide supra).
In the next step the formation of a transition structure with the
chairlike seven-membered ring conformation is proposed, where
copper forms a σ-bond approaching from the bottom side of
the â-carbon. Most probably the absolute configuration is
already fixed in the Cu(III) intermediate, and to avoid steric
interactions with the dicyclohexyl moieties at the nearby
phosphorus, the final transfer of methyl group occurs as shown
in Figure 17. Although this model predicts the correct sense of
asymmetric induction, it is nevertheless a hypothetical model
and should be considered with care as it is difficult to rule out
other possibilities due to the complex nature of the present
system. Further mechanistic studies and DFT or ab initio
calculations will be performed soon to shed light on to the
factors that determine the origin of the enantioselectivity.
Conclusions
Finally, the proposed catalytic cycle correlates well with the
results of the kinetic studies. The dependence of the reaction
rate on the substrate and Grignard reagent indicates that both
reactants are involved in the rate-limiting step preceded by fast
equilibria between reactants and reaction intermediates. Fur-
thermore, the rate of the decomposition of the Cu(III) species
to the π-complex must be faster than the rate of its formation
(k-2 . k2, Scheme 11). This instability of the Cu(III) intermedi-
ate will prevent its accumulation in the rate-limiting step. The
dependence of the reaction rate on the Grignard reagents
suggests that it acts to displace the product from the Cu(III)
intermediate and reform the catalytically active complex A
directly (Scheme 11). Consequently, increasing the concentration
of both reactants will enhance the reaction rate.
Optimized semiempirical [PM3(tm)] calculations indicate that
complex A adopts a distorted tetrahedral structure with the
positioning of the Grignard reagent at the bottom face of the
complex (Figure 17).41
In the working model that we proposed for the enantio-
selective 1,4-addition of Grignard reagents it can be envisioned
that the enone approaches the alkylcopper complex A from the
least hindered side and binds to the top apical position. This
forces the complex to adopt a square pyramidal geometry, which
is stabilized via π-complexation of the alkene moiety to the
copper and, importantly, through the interactions between Mg
and the carbonyl moiety of the skewed enone.42-44 It should be
The combination of spectroscopic studies to identify the
catalytically active species, kinetic analysis, and variation of
reaction parameters provides a mechanistic scheme for the
enantioselective CA of Grignard reagents to R,â-unsaturated
carbonyl compounds, catalyzed by ferrocenyl diphosphine
complexes. We have identified several parameters (the influence
of solvent, halide, and additives) that affect the selectivity and
rate of the CA reaction and define the structures of catalytically
active species formed via transmetalation of a chiral copper
complex by a Grignard reagent. Furthermore, the formation and
structure of the active species was found to be highly dependent
on the Schlenk equilibrium, which also depends on the solvent,
nature of the halide, and the presence of additives. Moreover,
we have demonstrated and rationalized that the presence of
Mg2+ and Br- ions is a necessary condition to achieve high
selectivity and efficiency in the present system. Our results
demonstrate furthermore that the rate of the reaction is dependent
on all the reacting components, and is first order in catalyst.
The data presented supports a model in which the rate-limiting
step is a reductive elimination, which is preceded by a fast
(42) In this construct, the BrMgBr occupied the less hindered side next to
diphenylphosphine moieties (P1), while the smaller methyl group shifts to
the more bulky dicyclohexylphosphine (P2) moieties.
(43) The resulting structure could also be obtained and its energy minimized;
however, the distance between the Cu and the double bond turned out to
be much higher than that required to establish a π interaction, suggesting
that the semiempirical level is not suitable to model these interactions
between Cu and double bonds.
(41) Calculations were carried out using HyperChem, release 6.0 for Windows,
Molecular Modelling system; Hypercube, Inc., 2000. Preliminary semi-
empirical [PM3(tm)] calculations were performed in the Cu complex 1a′,
to show the viability of this theoretical level to describe these Cu-halide
complexes. The minimization of the complex at this level of theory provided
a structure which retained the trigonal planar structure and which is
qualitatively in accordance with the original structure obtained by X-ray
analysis.
(44) We propose the π-complex formation from the S-trans conformer of the
enone, and although the S-cis conformer cannot be excluded, appropriate
binding of Mg and Cu simultaneously with the enone in the S-cis
conformation is less favorable. For studies on S-trans/S-cis conformational
preferences of R,â-unsaturated carbonyl compounds, see: (a) Garcia, J. I.;
Mayoral, J. A.; Salvatella, L.; Assfeld, X.; Ruiz-Lopez, M. F. J. Mol. Struct.
1996, 362, 187-197. (b) Shida, N.; Kabuto, C.; Niva, T.; Ebata, T.;
Yamamoto, Y. J. Org. Chem. 1994, 59, 4068-4075.
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A R T I C L E S
Harutyunyan et al.
equilibrium involving a Cu(I)-π-complex/Cu(III)-σ complex
adduct. The influence of olefin geometry on the reaction
selectivity and the observation of cis-trans isomerization for
enoates along the reaction pathway support this mechanistic
model. Although these investigations clarify a significant portion
of the mechanistic pathway, there are still important aspects
that remain to be elucidated, most importantly, a detailed picture
of the mechanism of stereoselection in this reaction.
the Departamento de Educacio´n, Universidades e Investigacio´n
del Gobierno Vasco. D.P. thanks the European Community (IHP
Program) for the award of a Marie Curie Fellowship (Contract
HPMF-CT-2002-01612). We are grateful to Dr. H.-U. Blaser
(Solvias, Basel) for a generous gift of Josiphos ligands, and we
thank T. D. Tiemersma-Wegman for GC and HPLC support.
Supporting Information Available: Experimental proce-
dures and spectroscopic data, X-ray data, solvent and halide
dependence of CA of EtMgX to enoates and kinetic data.
This material is available free of charge via the Internet at
http://pubs.acs.org
Acknowledgment. Financial support from the Dutch Ministry
of Economic Affairs (EET scheme; Grant Nos.: EETK-97107
and 99104) and the European Community’s 6th Framework
Program (Marie Curie IntraEuropean Fellowship to F.L.) is
acknowledged. A.C. was supported by a predoctoral grant from
JA0585634
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9118 J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006