Asymmetric nickel-catalyzed Negishi cross-couplings of secondary α-bromo amides with organozinc reagents

Article abstract of DOI:10.1021/ja0506509

A Ni/Pybox catalyst achieves the asymmetric cross-coupling of secondary α-bromo amides with organozinc reagents. The process tolerates a variety of functional groups and affords the desired product in good yield and in high enantiomeric excess. Copyright

Full text of DOI:10.1021/ja0506509

Published on Web 03/12/2005
Asymmetric Nickel-Catalyzed Negishi Cross-Couplings of Secondary
r-Bromo Amides with Organozinc Reagents
Christian Fischer and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 1, 2005; E-mail: gcf@mit.edu
Table 1. Asymmetric Negishi Cross-Couplings of Secondary
R-Bromo Amides with Organozinc Reagents (eq 1; all data are the
average of two experiments)
Recently, considerable progress has been described in the quest
for catalysts that can cross-couple alkyl electrophiles.1 Although
most investigations have focused on reactions of primary electro-
philes, there have also been noteworthy advances in the develop-
ment of catalysts that achieve couplings of secondary alkyl
electrophiles.2,3
For cross-couplings of unsymmetrical secondary electrophiles,
a stereocenter may be produced at the carbon that bears the leaving
group. This stereochemical aspect adds an important new dimension
to these carbon-carbon bond-forming processes, control of which
would greatly increase their utility. In this report, we describe the
first catalytic enantioselective cross-couplings of secondary alkyl
electrophiles (eq 1; DMI ) 1,3-dimethyl-2-imidazolidinone).4
In 2003, we reported that Ni(cod)2/(s-Bu)-Pybox catalyzes
Negishi reactions of secondary alkyl bromides and iodides.3a Our
observation that the cross-couplings proceed particularly well in
the presence of (s-Bu)-Pybox clearly opened the door to the
possibility of achieving an asymmetric variant.5 Upon exploring
several different families of secondary alkyl electrophiles, we
obtained promising results with R-bromo amides (for some illustra-
tive data, see eqs 2 and 3). Optimization of the reaction conditions
led to a catalyst system that furnishes the desired product in both
high enantiomeric excess and yield (eq 4).6
a Isolated yield. b The coupling was conducted at room temperature. c For
the second run (data given in parentheses), the product was recrystallized,
which leads to an enrichment of the enantiomeric excess of the product.
This method has proved to be general for catalytic asymmetric
Negishi cross-couplings of a range of R-bromo amides with an array
of organozinc reagents (Table 1).7 Not only unfunctionalized (entries
1-7) but also functionalized (entries 8-12) organozincs serve as
useful coupling partners, affording the target compounds in very
good enantiomeric excess. Thus, asymmetric carbon-carbon bond
formation proceeds smoothly in the presence of groups such as an
olefin (entry 8), a benzyl ether (entry 9), an acetal (entry 10), an
imide (entry 11), and a nitrile (entry 12).8
Several other observations are worthy of note. First, this catalyst
system is highly selective for coupling an R-bromo amide in the
presence of either an unactivated primary or secondary alkyl
bromide (eq 5). Second, there is no evidence for kinetic resolution
during the catalytic asymmetric cross-coupling (eq 6). Third, the
amide can be converted into other useful functional groups (eq 7).
We have not yet had the opportunity to systematically investigate
the mechanism(s) of the nickel-based catalysts that we have
described for cross-coupling alkyl electrophiles.3 Recently, Vicic
suggested that, for Negishi reactions, carbon-carbon bond forma-
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C O M M U N I C A T I O N S
116, 882-893 (iron). (b) Donkervoort, J. G.; Vicario, J. L.; Jastrzebski,
J. T. B. H.; Gossage, R. A.; Cahiez, G.; van Koten, G. J. Organomet.
Chem. 1998, 558, 61-69 (copper). (c) Tsuji, T.; Yorimitsu, H.; Oshima,
K. Angew. Chem., Int. Ed. 2002, 41, 4137-4139 (cobalt). (d) Nakamura,
M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686-
3687 (iron). (e) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297-1299
(iron). (f) Martin, R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955-
3957 (iron).
(3) For nickel-catalyzed couplings, see: (a) (organozinc reagents) Zhou, J.;
Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727. (b) (organoboron
reagents) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341.
(c) (organosilicon reagents) Powell, D. A.; Fu, G. C. J. Am. Chem. Soc.
2004, 126, 7788-7789. (d) (organotin reagents) Powell, D. A.; Maki, T.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 510-511.
(4) For examples of other types of metal-catalyzed asymmetric cross-coupling
processes, see: (a) Hayashi, T. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; Chapter 25. (b) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000,
122, 12051-12052. (c) Shimada, T.; Cho, Y.-H.; Hayashi, T. J. Am. Chem.
Soc. 2002, 124, 13396-13397. (d) Hamada, T.; Chieffi, A.; Åhman, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268. (e) Willis,
M. C.; Powell, L. H. W.; Claverie, C. K.; Watson, S. J. Angew. Chem.,
Int. Ed. 2004, 43, 1249-1251.
(5) For reviews of applications of oxazoline-based chiral ligands, including
pybox, in asymmetric catalysis, see: (a) McManus, H. A.; Guiry, P. J.
Chem. ReV. 2004, 104, 4151-4202. (b) Nishiyama, H. In AdVances in
Catalytic Processes; Doyle, M. P., Ed.; JAI Press: Greenwich, CT, 1997;
Volume 2, pp 153-188.
(6) Notes: (a) NiCl2‚glyme, unlike Ni(cod)2, is air-stable; both are com-
mercially available. NiBr2‚diglyme and NiCl2‚diglyme can also be used,
although they are somewhat less effective. (b) (i-Pr)-Pybox, unlike (s-
Bu)-Pybox, is commercially available. (c) We have not been able to
employ commercially available HexZnBr (Aldrich) in this process. We
recommend that pure organozinc reagents be prepared from the corre-
sponding alkyl bromides according to the straightforward procedure of
Huo: Huo, S. Org. Lett. 2003, 5, 423-425. (d) At room temperature, the
product is generated in 91% ee. At -20 °C, the cross-coupling process is
slow.
(7) General Procedure for Table 1: In the air (no special precautions are
necessary), a 10 mL Schlenk flask was charged with NiCl2‚glyme (22.0
mg, 0.100 mmol), (R)-(i-Pr)-Pybox (39.2 mg, 0.130 mmol), and the
R-bromo amide (1.00 mmol). The flask was purged with argon for 5 min,
and then DMI (2.2 mL) and THF (0.5 mL) were added. The resulting
orange solution was stirred at room temperature for 20 min, and then the
flask was placed into a 0 °C bath. The reaction mixture was stirred for 10
min, and then the organozinc reagent (1.0 M in DMI; 1.3 mL, 1.3 mmol)
was added. The resulting dark-brown reaction mixture was stirred for 12
h at 0 °C. Then, the excess organozinc reagent was quenched by the
addition of ethanol (0.5 mL), and the brown mixture was passed through
a plug of silica gel (eluted with Et2O) to remove inorganic salts and most
of the DMI. The filtrate was concentrated, and the resulting orange oil
was purified by flash chromatography.
(8) Notes: (a) The yield of the reaction is sensitive to the steric demand of
the coupling partners. Thus, we have not been able to efficiently cross-
couple a secondary organozinc reagent or an R-isopropyl-R-bromo amide.
(b) Under the standard conditions, benzylzinc reagents are not suitable
substrates. (c) For the cross-coupling illustrated in entry 1 of Table 1,
when the reaction is run on a 10 mmol scale, we obtain the product in
88% yield (3.0 g) and 95% ee. (d) The process is not highly sensitive to
oxygen or moisture; when we conduct a coupling under air in a closed
vial with 1.6 equiv of the organozinc reagent, we obtain essentially
identical yield and enantiomeric excess. (e) Under identical conditions,
R-bromoesters furnish lower yield and lower enantiomeric excess.
(9) Anderson, T. J.; Jones, G. D.; Vicic, D. A. J. Am. Chem. Soc. 2004, 126,
8100-8101.
tion may proceed via radical-radical coupling.9 In view of the high
enantioselectivity that we observe under the conditions described
in eq 1, we believe that for this system the Vicic mechanism is
unlikely to be operative.
In conclusion, we have developed the first method that achieves
catalytic asymmetric cross-couplings of alkyl electrophiles. These
Ni/(i-Pr)-Pybox-catalyzed reactions of secondary R-bromo amides
with organozinc reagents are tolerant of an array of functional
groups and generally proceed in good yield and in high enantiomeric
excess. This advance further highlights the potential impact of cross-
couplings of alkyl electrophiles on synthetic organic chemistry.
Acknowledgment. This paper is dedicated to our colleague,
Prof. Richard R. Schrock, on the occasion of his 60th birthday.
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, R01-GM62871),
the German Academic Exchange Service (postdoctoral fellowship
to C.F.), Merck Research Laboratories, and Novartis. Funding for
the MIT Department of Chemistry Instrumentation Facility has been
furnished in part by the National Science Foundation (CHE-9808061
and DBI-9729592).
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.
References
(1) For a recent review, see: Frisch, A. C.; Beller, M. Angew. Chem., Int.
Ed. 2005, 44, 674-688.
(2) For pioneering studies of iron-, copper-, and cobalt-catalyzed couplings
of Grignard reagents, see: (a) Brinker, U. H.; Ko¨nig, L. Chem. Ber. 1983,
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