ORGANIC
LETTERS
2009
Vol. 11, No. 15
3202-3205
Diverse Alkanones by Catalytic Carbon
Insertion into the Formyl C-H Bond.
Concise Access to the Natural
Precursor of Achyrofuran
Andrew J. Wommack, David C. Moebius, Austin L. Travis,
and Jason S. Kingsbury*
Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
Received May 18, 2009
ABSTRACT
Over a century ago, the first reactions of diazomethane with aldehydes delivered methyl ketones. In the interim, aldehydes have been homologated
with trimethylsilyldiazomethane, diazoacetates, and aryldiazomethanes, on rare occasion with catalysis. This work describes a mild procedure
for convergent ketone assembly from nonstabilized diazoalkanes, including examples of chiral ketone synthesis with disubstituted (internal)
nucleophiles. The method’s remarkable tolerance to steric crowding is showcased in a simple approach to achyrofuran, a complex dibenzofuran.
Ketones are prepared chemically by a variety of means,
one of the more common being a two-step process
involving organometal addition to an aldehyde followed
by oxidation. The aldehyde f ketone conversion can also
be achieved in a single step by reaction with diazo
compounds,1 yet limitations to the scope and efficiency
of the reaction are largely unaddressed. Anselme and co-
workers have reported benzyl ketone synthesis with
aryldiazomethanes in diethyl ether saturated with lithium
bromide, but hindered electrophiles such as pivaldehyde
failed to react.2 Angle and Aggarwal independently
developed in situ procedures3 based upon the dual role
ofalcohol3a orwater3b asbothasolventforBamford-Stevens
reaction and a promoter for diazoalkyl insertion, but
desoxybenzoin products were still the focus. In a lone
report on catalysis with an Fe(III) salt, competing epoxide
formation led to pronounced reductions in chemical yield.4
Additionally, and to the best of our knowledge, the use
of nonstablilized, internal diazoalkanes for the synthesis
of chiral ketones is without precedent.5 Herein, we offer
a broadly useful protocol for aryl-benzyl, aryl-alkyl, and
dialkyl ketone synthesis based on catalytic carbon insertion
(see Abstract). The method performs well in functional-
(4) Mahmood, S. J.; Saha, A. K.; Hossain, M. Tetrahedron 1998, 54,
349–358.
(5) For the conversion of aldehydes to methyl ketones or ꢀ-keto esters
with TMSCHN2 and ethyldiazoacetate (respectively), see: (a) Aoyama, T.;
Shioiri, T. Synthesis 1988, 228–229. (b) Maruoka, K.; Concepcion, A. B.;
Yamamoto, H. Synlett 1994, 521–523. (c) Maruoka, K.; Concepcion, A. B.;
Yamamoto, H. Synthesis 1994, 1283–1290. (d) Holmquist, C. R.; Roskamp,
E. J. J. Org. Chem. 1989, 54, 3258–3260. Aryldiazoacetates have been used
to prepare R-quaternary aldehydes, but the chiral ketone is just a trace
byproduct; see: (e) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem.
Soc. 2008, 130, 2434–2435. See also: (f) Dias, E. L.; Brookhart, M.; White,
P. S. J. Am. Chem. Soc. 2001, 123, 2442–2443. (g) Aggarwal, V. K.;
Sheldon, C. G.; Macdonald, G. J.; Martin, W. P. J. Am. Chem. Soc. 2002,
124, 10300–10301.
(1) Pioneers in the earliest known reactions of CH2N2 and aldehydes
were Buchner and Curtius (1885), v. Pechman (1895), Meyer (1905), and
Schlotterbeck (1907). For a review, see: Gutsche, C. D. Org. React. 1954,
8, 364–429. For a modern example, see: Werner, R. M.; Shokek, O.; Davis,
J. T. J. Org. Chem. 1997, 62, 8243–8246.
(2) Loeschorn, C. A.; Nakajima, M.; McCloskey, P. J.; Anselme, J.-P.
J. Org. Chem. 1983, 48, 4407–4410.
(3) (a) Angle, S. R.; Neitzel, M. L. J. Org. Chem. 2000, 65, 6458–
6461. (b) Aggarwal, V. K.; de Vicente, J.; Pelotier, B.; Holmes, I. P.;
Bonnert, R. V. Tetrahedron Lett. 2000, 41, 10327–10331.
(6) (a) Moebius, D. C.; Kingsbury, J. S. J. Am. Chem. Soc. 2009, 131,
878–879. (b) Our approach involves modification of two modern protocols
for low-temperature hydrazone oxidation. See Supporting Information.
10.1021/ol9010932 CCC: $40.75
Published on Web 07/09/2009
2009 American Chemical Society