Catalytic cross-coupling of alkylzinc halides with α-chloroketones

Article abstract of DOI:10.1021/ja0467768

The cross-coupling of alkylzinc halides with α-chloroketones catalyzed by Cu(acac)₂ is described. Using this method, primary and secondary alkyl groups are introduced adjacent to a ketone carbonyl under mild reaction conditions and in good yield. Cyclic, acyclic, aromatic, and aliphatic α-chloroketones are suitable substrates. Optically active α-chloroketones are converted to optically active products. The reaction was found to proceed stereospecifically with inversion of stereochemistry. The reaction is proposed to occur by direct substitution of the chloride with the alkyl group of an organocopper, -magnesium, or -zinc species. Copyright

Full text of DOI:10.1021/ja0467768

Published on Web 07/31/2004
Catalytic Cross-Coupling of Alkylzinc Halides with r-Chloroketones
Chrysa F. Malosh and Joseph M. Ready*
Department of Biochemistry, The UniVersity of Texas Southwestern Medical Center at Dallas,
5323 Harry Hines BouleVard, Dallas, Texas 75390-9038
Received June 1, 2004; E-mail: Joseph.Ready@utsouthwestern.edu
Scheme 1. Syntheses of R-Substitured Ketones
Ketones with multiple substitutents on the R-carbon (R-
substituted ketones, 1) represent important targets for chemical
synthesis. The value of this structural motif stems from its
prevalence in both natural products and pharmaceutical compounds
and from the ability of R-substituted ketones to participate in
stereoselective 1,2-additions, olefinations, and enolate reactions.
Traditionally, enolate anions have been exploited in the synthesis
of R-branched ketones. Thus, deprotonation with a strong base
followed by reaction of the resultant enolate with an alkyl
electrophile furnishes the substituted ketone (Scheme 1, path a).
This strategy has found widespread application,1 and catalytic
variants have been reported.2 Currently, however, enolate alkylation
remains useful primarily for the introduction of sterically unhindered
alkyl groups.3 Additionally, enolate alkylation can be plagued by
overalkylation and poor regiocontrol stemming from equilibria
between various enolate species.
To address some of the limitations of enolate alkylation, we
considered alternative approaches to the synthesis of R-substituted
ketones. In particular, we wondered whether R-haloketones could
undergo cross-coupling reactions with suitable organometallic
reagents (Scheme 1, path b).4 We report herein the development
of a copper-catalyzed reaction of organozinc halides5 with R-chlo-
roketones.6 The cross-coupling enables the introduction of primary
and secondary alkyl groups adjacent to a ketone carbonyl in high
yield and under mild reaction conditions.
Table 1. Cross-Coupling of 2a with Organometallic Reagents
entry
catalyst
R−M
time (h)
yield (%)a
1
2
3
4
5c
6
7
8
Cu(acac)2
CuCl
CuCl2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
none
i-PrMgCl+ZnCl2
i-PrMgCl+ZnCl2
i-PrMgCl+ZnCl2
(i-Pr)2Zn
(i-Pr)2Zn
n-C4H9Li+ZnCl2
c-C5H9ZnCl
0.25
0.25
0.25
1
1
18
>95
>95
>95
0b
25
0d
18
18
0e
i-PrMgCl+ZnCl2
21
a GC yields relative to an internal standard. b 93% conversion of 2a to
unidentified products. c 1,2-trans-diaminocyclohexane added. d >90% re-
covery of 2a. e 35% conversion of 2a to unidentified products.
Scheme 2. Potential Reaction Mechanisms
Initial efforts to develop the cross-coupling reaction were
frustrated by competitive reductive dehalogenation and dimerization
of the R-chloroketones. Evaluation of various combinations of
organometallic reagents and catalysts led to the discovery that
simple Cu(I) and Cu(II) salts catalyze the addition of isopropylzinc
chloride to 2-chlorocyclohexanone (2a) in excellent yield (Table
1, entries 1-3). Generation of the alkylzinc halide through
transmetalation of the Grignard reagent with ZnCl2 proved critical.
For example, Mg-free diorganozinc reagents were ineffective (entry
4), although the use of diisopropyl zinc in conjunction with trans-
1,2-diaminocyclohexane was moderately successful (entry 5).
Similarly, organozinc halides obtained from transmetalation of an
organolithium reagent or from Zn(0) insertion into an alkyl halide
failed to provide any of the desired product (entries 6-7).
The copper-catalyzed cross-coupling of organozinc halides with
R-chloroketones tolerates substantial variation in both reacting
partners (Table 2). Both cyclic and acyclic R-chloroketones are
suitable substrates. Primary, secondary acyclic, and secondary cyclic
alkylzinc halides participate similarly well in the cross-coupling
reaction. Aryl triflates (entry 20) and aryl nitriles (entry 21) are
compatible with the reaction conditions, while â-disubstituted R,â-
unsaturated ketones provide the coupling products in substantially
reduced yield.7
path a). Similar reactivity has been observed with Grignard reagents
under forcing conditions.8 The intermediacy of a tertiary carbinol
in the catalytic reaction can be ruled out by the observation that
9
halohydrin 5 is stable to the reaction conditions (eq 1).
A second potential mechanism for the copper-catalyzed cross-
coupling features an alkylcopper enolate (4, Scheme 2, path b).10
Reductive elimination would provide the substituted ketone product
as a mixture of stereoisomers. Finally, direct substitution of the
alkyl chloride by an organometallic reagent (Scheme 2, path c, M
Three different mechanisms could account for the observed cross-
coupling. One potential pathway involves 1,2-addition to the ketone
followed by 1,2-migration with concurrent loss of Cl- (Scheme 2,
9
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10.1021/ja0467768 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Synthesis of R-Substituted Ketonesa
copper, zinc, or magnesium to the R-carbon of the ketone substrate
(Scheme 2, path c). Metal coordination to the chloride or carbonyl
may occur, although no evidence currently implicates these modes
of activation. The copper-catalyzed substitution of R-chloroketones
thus appears mechanistically distinct from copper-catalyzed allylic
substitution reactions.13
The copper-catalyzed cross-coupling of organozinc halides with
R-chloroketones represents a general strategy for the synthesis of
R-branched ketones. Furthermore, the use of optically active
chloroketones has enabled the preparation of enantiomerically
enriched substituted ketones. Notably, the products derived from
addition of secondary alkyl zinc reagents would be difficult to access
using conventional enolate alkylation. Current efforts are directed
toward expanding this reaction manifold to include other classes
of nucleophiles and electrophiles.
Acknowledgment. We acknowledge assistance from Dr. Carlos
A. Amezcua and Dr. Sanjay C. Panchal (UT Southwestern) with
NMR experiments. J.M.R. is a Southwestern Medical Foundation
Scholar in Biomedical Research.
Supporting Information Available: Experimental procedures for
cross-coupling reactions and eqs 1-2; spectral data for all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) Cain, D. In Carbon-Carbon Bond Formation; Augustine, R. L., Ed.; M.
Dekker: New York, 1979; Vol. 1, pp 86-249.
(2) (a) Inoue, Y.; Toyofuku, M.; Taguchi, M.; Okada, S.; Hashimoto, H. Bull.
Chem. Soc. Jpn. 1986, 59, 885-891. (b) Imai, M.; Hagihara, A.; Kawasaki,
H.; Manabe, K.; Koga, K. Tetrahedron 2000, 56, 179-185. (c) Cho, C.
S.; Kim, B. T.; Kim, T.-J.; Sim, S. C. Tetrahedron Lett. 2002, 43, 7987-
7989. (d) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem.,
Int. Ed. 2002, 41, 3492-3495. (e) Vignola, N.; List, B. J. Am. Chem.
Soc. 2004, 126, 450-451.
(3) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry; HarperCollins: New York, 1987; pp 376-379.
(4) Cross-couplings of R-halo carbonyl compounds: (a) Amano, T.; Yoshika-
wa, K.; Sano, T.; Ohuchi, Y.; Shiono, M.; Ishiguro, M.; Fujita, Y. Synth.
Comm. 1986, 16, 499-507. (b)Yasuda, M.; Tsuji, S.; Shigeyoshi, Y.;
Baba, A. J. Am. Chem. Soc. 2002, 124, 7440-7447. (c) See also Hennessy,
E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084-12085.
(5) Copper-catalyzed reactions of alkyl zinc reagents: (a) Fujii, N.; Nakai,
K.; Habashita, H.; Yoshizawa, H.; Ibuka, T.; Garrido, F.; Mann, A.;
Chounan, Y.; Yamamoto, Y. Tetrahedron Lett. 1993, 34, 4227-4230.
(b) Dubner, F.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 379-381.
(c) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley: New York, 2002; pp
224-258. (d) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004,
126, 5680-5681.
a Reactions were carried out under N2 for 14 h at 25 °C. See Supporting
Information for complete experimental details. b Alkyl zinc halide reagents
were prepared as suspensions in Et2O ([RZnX] ) 0.2 M) via treatment of
ZnX2 with RMgX. c Isolated yields.
) Cu, Zn, or Mg) would occur with inversion of stereochemistry.
To distinguish between the latter two mechanistic possibilities, the
stereochemical course of the reaction was investigated. Cross-
coupling with optically active chloroketone 2j indicated that the
substitution reaction occurs with inversion of stereochemistry (eq
2).11
(6) Reactions of lithium dialkyl cuprates with R-bromo ketones: (a) Posner,
G. H.; Sterling, J. J.; Whitten, C. E.; Lentz, C. M.; Brunelle, D. J. J. Am.
Chem. Soc. 1975, 97, 107-118 and references therein. (b) Vaillancourt,
V.; Albizati, K. F. J. Org. Chem. 1992, 57, 3627-3631.
(7) Tertiary alkylzinc reagents and tertiary R-chloro ketones provide negligible
yields of the cross-coupled products.
(8) (a) Bartlett, P. D.; Rosenwald, R. H. J. Am. Chem. Soc. 1934, 56, 1990-
1994. (b) Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K.
Tetrahedron 1981, 37, 3967-3975.
(9) Control experiments verified formation of the zinc alkoxide under the
conditions of eq 1. At elevated temperatures, ring contraction to generate
cyclopentyl isopropyl ketone predominates. See the Supporting Information
for details.
(10) The copper enolate could exist primarily in the η-1 O-bound, η-1 C-bound
or η-3 oxallyl form. For a theoretical study, see: Rosi, M.; Sgamellotti,
A.; Floriani, C. J. Mol. Stuct. (THEOCHEM) 1999, 459, 57-65.
(11) Additional examples can be found in the Supporting Information.
(12) The uncatalyzed reaction occurs with inversion of configuration. See the
Supporting Information for details.
A final observation pertinent to the mechanistic discussion relates
to the reaction of chloroketone 2a with isopropylzinc chloride in
the absence of copper (Table 1, entry 8).12 This unusual example
of an uncatalyzed substitution reaction with an alkyl zinc reagent
indicates that a direct displacement pathway is accessible.5d
Taken together, the data are most simply explained by a
mechanism in which an alkyl group is directly transferred from
(13) Yamanaka, M.; Kato, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126,
6287-6293 and references therein.
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