ORGANIC
LETTERS
2012
Vol. 14, No. 6
1476–1479
Synthesis of Functionalized Dialkyl
Ketones from Carboxylic Acid Derivatives
and Alkyl Halides
Alexander C. Wotal and Daniel J. Weix*
Department of Chemistry, University of Rochester, Rochester, New York 14627-0216,
United States
Received January 26, 2012
ABSTRACT
Unsymmetrical dialkyl ketones can be directly prepared by the nickel-catalyzed reductive coupling of carboxylic acid chlorides or (2-pyridyl)-
thioesters with alkyl iodides or benzylic chlorides. A wide variety of functional groups are tolerated by this process, including common nitrogen
protecting groups and CꢀB bonds. Even hindered ketones flanked by tertiary and secondary centers can be formed. The mechanism is proposed
to involve the reaction of a (L)Ni(alkyl)2 intermediate with the carboxylic acid derivative.
Besides being frequently found in natural products,
ketones are a nexus for organic synthesis.1 Methods to
chemoselectively convert ketones to a variety of functional
groups have long been important to organic synthesis, but
recently, it has also become important for the chemoselec-
tive linking of functionalized fragments in vitro and in vivo.2
The most often used method for the synthesis of ketones
from carboxylic acid derivatives is acylation of a carbon
nucleophile, usually a preformed organometallic reagent.1
The synthesis of functionalized dialkyl ketones and hindered
dialkyl ketones requires protecting group manipula-
tions and more reactive nucleophiles. The development of
transition metal catalysts to mediate these couplings has
enabled the use of less reactive carbon nucleophiles,3 such
as alkyltin,4 alkylzinc,5,6 dialkylzinc,7 or alkylboron8
derivatives. While these methods have allowed for the
synthesis of more functionalized ketones than previously
possible, the synthesis of hindered ketones remains
challenging9 and acidic protons, such as NꢀH protons
on a biotin precursor, must still be protected.6 A second,
less developed route is the coupling of a nucleophilic acyl
group with an organic halide (Figure 1).10
(1) (a) Dieter, R. K. Tetrahedron 1999, 55, 4177. (b) Lawrence, N. J.
J. Chem. Soc., Perkin Trans. 1 1998, 1739. (c) Singh, J.; Satyamurthi, N.;
Aidhen, I. J. Prakt. Chem. 2000, 342, 340.
(2) Ketones form stable linkages with hydrazide, hydroxylamino,
and thiosemicarbazide groups under physiological conditions: (a)
Stephanopoulos, N.; Francis, M. B. Nat. Chem. Biol. 2011, 7, 876. (b)
Kalia, J.; Raines, R. T. Curr. Org. Chem. 2010, 14, 138. (c) Sletten, E. M.;
Bertozzi, C. R. Angew. Chem., Int. Ed. 2009, 48, 6974.
Both of these approaches rely upon a nucleophilic car-
bon reagent, which limits commercial availability of these
reagents11 and/or limits functional group compatibility.
(6) (a) Fukuyama, T.; Tokuyama, H. Aldrichimica Acta 2005, 37, 87.
For references on industrial uses, see: (b) Mori, Y.; Seki, M. Adv. Synth.
Catal. 2007, 349, 2027.
(3) An alternative strategy is the use of functionalized RMgX:
€
Scheiper, B.; Bonnekessel, M.; Krause, H.; Furstner, A. J. Org. Chem.
2004, 69, 3943.
(7) Zhang, Y.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 15964.
(8) (a) Tatamidani, H.; Kakiuchi, F.; Chatani, N. Org. Lett. 2004, 6,
3597. (b) Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554. (c)
Zhang, Z.; Lindale, M. G.; Liebeskind, L. S. J. Am. Chem. Soc. 2011,
133, 6403.
(9) Metal-catalyzed coupling of tertiary carboxylic acid derivatives
with organometallic reagents to form 3°/1°-dialkyl ketones, refs 4a, 8b,
5g, and 12d; 3°/2°-dialkyl ketones, refs 5d and 5e.
(10) Schmink, J. R.; Krska, S. W. J. Am. Chem. Soc. 2011, 133, 19574.
(11) Ten times more alkyl iodides are commercially available than
alkyl organometallic reagents: 70 alkylZnBr vs 958 alkyl iodides.
(4) (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. (b)
Li, H.; Yang, H.; Liebeskind, L. S. Org. Lett. 2008, 10, 4375.
(5) (a) Sato, T.; Naruse, K.; Enokiya, M.; Fujisawa, T. Chem. Lett.
1981, 10, 1135. (b) Negishi, E.-i.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.;
Miller, J. A.; Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181. (c) Tamaru,
Y.; Ochiai, H.; Sanda, F.; Yoshida, Z.-i. Tetrahedron Lett. 1985, 26,
5529. (d) Harada, T.; Kotani, Y.; Katsuhira, T.; Oku, A. Tetrahedron
Lett. 1991, 32, 1573. (e) Asaoka, M.; Kosaka, A.; Tanaka, M.; Ueda, T.;
Houkawa, T.; Takei, H. J. Chem. Soc., Perkin Trans. 1 1997, 2949. (f)
Wang, D.; Zhang, Z. Org. Lett. 2003, 5, 4645. (g) Yus, M.; Ortiz, R. Eur.
J. Org. Chem. 2004, 2004, 3833.
r
10.1021/ol300217x
Published on Web 02/23/2012
2012 American Chemical Society