Enantioselective alkenylation via nickel-catalyzed cross-coupling with organozirconium reagents

Article abstract of DOI:10.1021/ja1017046

A new family of organometallic compounds, organozirconium reagents, are shown to serve as suitable partners in cross-coupling reactions of (activated) secondary alkyl electrophiles. Thus, the first catalytic method for coupling secondary a-bromoketones with alkenylmetal reagents has been developed, specifically, a mild, versatile, and stereoconvergent carbon-carbon bond-forming process that generates potentially labile β,-unsaturated ketones with good enantioselectivity.

Full text of DOI:10.1021/ja1017046

Published on Web 03/19/2010
Enantioselective Alkenylation via Nickel-Catalyzed Cross-Coupling with
Organozirconium Reagents
Sha Lou and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 28, 2010; E-mail: gcf@mit.edu
Because olefin-containing molecules are ubiquitous targets,1 the
development of effective methods for incorporating this functional
Table 1. Catalytic Asymmetric Alkenylations with Organozirconium
Reagents: Scope with Respect to the Nucleophilea
group is an important goal. If absolute stereochemistry can also be
defined during the bond construction, the utility of a new process is
further enhanced. The reaction of secondary alkyl electrophiles with
alkenylmetal reagents is an attractive approach to the introduction of
olefins, but there are relatively few reports of such cross-couplings.2,3
Furthermore, there has been only one investigation of an enantiose-
lective variant of this type of process (three examples of cross-couplings
of R-haloesters with alkenyltrimethoxysilanes).3b
Alkenylzirconium compounds are appealing alkenylmetals for
cross-couplings,4 in part because they are readily accessible by
reacting commercially available Schwartz’s reagent (Cp2ZrHCl)
with alkynes. Although secondary alkyl electrophiles have now been
coupled with many different families of organometallic partners
(e.g., boron, zinc, magnesium, silicon, tin, and indium compounds),5
to the best of our knowledge, they have not been cross-coupled
with organozirconium reagents.6 In this report, we describe a mild
and versatile method for coupling organozirconium compounds with
a All data are the average of two experiments. b Yield of purified
secondary alkyl halides, specifically, alkenylzirconium reagents with
racemic R-bromoketones; in addition, we establish that this ste-
product. c Catalyst loading: 10% NiCl2 ·glyme/12% (-)-1.
reoconvergent carbon-carbon bond-forming process can be ac-
complished with good enantioselectivity to generate potentially
labile ꢀ,γ-unsaturated ketones (eq 1).7–9
Carbon-carbon bond formation occurs below ambient temperature
(10 °C) and without the need for any additives (e.g., Brønsted bases)
that might erode the enantioselectivity. As illustrated in Table 1, a
broad array of alkenylzirconium reagents are suitable cross-coupling
partners. Thus, the R2 group can range in steric demand from hydrogen
to tert-butyl (entries 1-5). Furthermore, functional groups such as
aromatic rings, oxygen substituents, and alkenes are compatible with
the reaction conditions (entries 3 and 6-9).
We have also examined the scope of this new cross-coupling
process with respect to the R-bromoketone. As illustrated in Table
2, a diverse set of aryl alkyl ketones are suitable electrophiles. A
Table 2. Catalytic Asymmetric Alkenylations with Organozirconium
Reagents: Scope with Respect to the Aryl Alkyl Ketone (for the
Reaction Conditions, See Eq 1)a
In initial studies, we attempted to apply previously described
methods for nickel-catalyzed asymmetric cross-couplings8,9 to the
alkenylation of 2-bromo-1-phenylpropan-1-one; unfortunately, we did
not obtain the desired product in satisfactory yield or ee. We therefore
decided to explore the potential utility of a new family of coupling
partners, alkenylzirconium reagents. In addition to their ready avail-
ability, we anticipated that they could provide another crucial attribute:
carbon-carbon bond formation might be achieved under sufficiently
mild, nonbasic conditions that racemization of the R stereocenter and
isomerization to the R,ꢀ-unsaturated isomer would be avoided. Such
complications have thus far precluded a Buchwald-Hartwig-type
approach to the catalytic asymmetric alkenylation of carbonyl com-
pounds to generate R tertiary stereocenters.10
We have determined that, under the appropriate conditions, a nickel/
bis(oxazoline) catalyst can achieve the stereoconvergent cross-coupling
of racemic R-bromoketones with alkenylzirconium compounds to
generate ꢀ,γ-unsaturated ketones in good yield and ee (Table 1).11
a All data are the average of two experiments. b Yield of purified
product.
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5010 J. AM. CHEM. SOC. 2010, 132, 5010–5011
10.1021/ja1017046  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Catalytic Asymmetric Alkenylations with Organozirconium
Reagents: Scope with Respect to the Dialkyl Ketone (for the
Reaction Conditions, See Eq 1)a
In summary, we have demonstrated that a new family of
organometallic compounds, organozirconium reagents, can serve
as suitable partners in cross-coupling reactions of (activated)
secondary alkyl electrophiles. Thus, we have developed the first
catalytic method for coupling secondary R-haloketones with al-
kenylmetal reagents, specifically, a mild, versatile, and stereo-
convergent carbon-carbon bond-forming process that generates
potentially labile ꢀ,γ-unsaturated ketones with good enantioselec-
tivity. Additional efforts to expand the scope of cross-couplings of
alkyl electrophiles are underway.
Acknowledgment. Support has been provided by the National
Institutes of Health (National Institute of General Medical Sciences,
Grant R01-GM62871), Merck Research Laboratories, and Novartis.
We thank Shaun D. Fontaine, Dr. Peter Mueller, and Dr. Michael
R. Reithofer for assistance.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
a All data are the average of two experiments. b Yield of purified
product. c The reaction was run at 40 °C.
References
variety of different types of substituents can be present on the
aromatic ring (electron-donating or electron-withdrawing: entries
4-7; ortho, meta, or para: entries 4-9), and the aromatic group
can be a heterocycle (e.g., a thiophene in entry 10). In addition, an
array of alkyl groups on the ketone and R2 substituents on the
alkenylzirconium reagent are tolerated.
The same method can be applied directly to enantioselective
cross-couplings of dialkyl ketones with alkenylzirconium reagents
(Table 3). This contrasts with our study of asymmetric Kumada
reactions of ketones with aryl Grignard reagents, wherein different
coupling conditions (ligand and temperature) were necessary for
aryl alkyl ketones versus dialkyl ketones.9c
The chiral nickel/bis(oxazoline) catalyst can dictate the stereo-
chemical outcome of a cross-coupling of an R-bromoketone that
bears another stereocenter (i.e., catalyst-controlled stereoselectivity:
eqs 2 and 3). Furthermore, stereoselective functionalizations of the
cross-coupling product can be achieved (eq 4).
(1) For example, see quinine, epothilone A, and palytoxin.
(2) For leading references to reactions of aryl electrophiles with alkenylmetal
reagents, see: Denmark, S. E.; Butler, C. R. Chem. Commun. 2009, 20–33.
(3) For some examples, see: (a) Unactivated electrophiles: Zhou, J.-R.; Fu,
G. C. J. Am. Chem. Soc. 2004, 126, 1340–1341. Powell, D. A.; Maki, T.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 510–511. Gue´rinot, A.; Reymond,
S.; Cossy, J. Angew. Chem., Int. Ed. 2007, 46, 6521–6524. Czaplik, W. M.;
Mayer, M.; von Wangelin, A. J. Angew. Chem., Int. Ed. 2009, 48, 607–
610. (b) Activated electrophiles (asymmetric): Dai, X.; Strotman, N. A.;
Fu, G. C. J. Am. Chem. Soc. 2008, 130, 3302–3303.
(4) For an overview, see: Negishi, E.-i.; Zeng, X.; Tan, Z.; Qian, M.; Hu, Q.;
Huang, Z. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: New York, 2004; pp 815-889.
(5) For leading references, see: Rudolph, A.; Lautens, M. Angew. Chem., Int.
Ed. 2009, 48, 2656–2670.
(6) We are aware of one report of the cross-coupling of a primary alkyl
electrophile with an organozirconium reagent: Wiskur, S. L.; Korte, A.;
Fu, G. C. J. Am. Chem. Soc. 2004, 126, 82–83.
(7) For a catalytic asymmetric method for the R-alkenylation of aldehydes to
generate tertiary stereocenters, see: Kim, H.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2008, 130, 398–399.
(8) For an overview and leading references to asymmetric cross-couplings of
secondary alkyl halides, see: Glorius, F. Angew. Chem., Int. Ed. 2008, 47,
8347–8349.
(9) For recent work on asymmetric cross-couplings of secondary alkyl halides,
see: (a) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645–
12647. (b) Lundin, P. M.; Esquivias, J.; Fu, G. C. Angew. Chem., Int. Ed.
2009, 48, 154–156. (c) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132,
1264–1266.
(10) For a discussion and leading references to catalytic asymmetric alkenylations
of enolates to generate quaternary stereocenters, see: Taylor, A. M.; Altman,
R. A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900–9901.
(11) Notes: (a) In the absence of NiCl2•glyme or ligand 1, the desired product
is generated in <5% yield. NiBr2•glyme or Ni(cod)2 may be used in place
of NiCl2•glyme. (b) For the cross-coupling illustrated in entry 3 of Table
1: a reaction on a gram scale proceeded at room temperature in 90% yield
and 92% ee; use of 1.1, rather than 2, equiv of the organozirconium reagent
led to a slower reaction (after 3 days at room temperature: 85% yield, 91%
ee). (c) During the cross-coupling, no kinetic resolution of the starting
material (the racemic secondary alkyl bromide) is detected, and the ee of
the product is constant. (d) After a competition experiment with an
R-bromoketone, an unactivated secondary alkyl bromide was recovered in
essentially quantitative yield. (e) In preliminary studies under our standard
conditions, an R-chloroketone, a cyclic R-bromoketone, and an alkenylzir-
conium reagent derived from hydrozirconation of an internal alkyne were
not suitable cross-coupling partners. (f) The rate law for the cross-coupling
is first-order in the catalyst and in the nucleophile, and it is zero-order in
the electrophile (NMR studies in d8-THF).
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