K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zaks and
T. Y. Zhang, Green Chem., 2007, 9, 411.
4 Reviews: (a) V. R. Pattabiraman and J. W. Bode, Nature, 2011,
480, 471; (b) C. L. Allen and J. M. J. Williams, Chem. Soc. Rev.,
2011, 40, 3405.
5 For selected examples of transition-metal catalyzed oxidative
acylations of alcohols and amines see: (a) C. Gunanathan,
Y. Ben-David and D. Milstein, Science, 2007, 317, 790;
(b) J. Zhang, G. Leitus, Y. Ben-David and D. Milstein, J. Am.
Chem. Soc., 2005, 127, 10840; (c) S. Musa, I. Shaposhnikov,
S. Cohen and D. Gelman, Angew. Chem., Int. Ed., 2011,
50, 3533; (d) J. H. Dam, G. Osztrovszky, L. U. Nordstrøm and
R. Madsen, Chem.–Eur. J., 2010, 16, 6820; (e) T. Zweifel,
J.-V. Naubron and H. Grutzmacher, Angew. Chem., Int. Ed.,
2009, 48, 559. These dehydrogenation reactions generally require
heating for extended periods for full conversion.
6 For NHC catalyzed amide formation from aldehydes with an
external oxidant, see: (a) S. De Sarkar and A. Studer, Org. Lett.,
2010, 12, 1992. For NHC catalyzed oxidative esterification see:
(b) B. E. Maki and K. A. Scheidt, Org. Lett., 2008, 10, 4331;
(c) B. E. Maki, A. Chan, E. M. Phillips and K. A. Scheidt,
Org. Lett., 2007, 9, 371.
7 There have been several reports on NHC catalyzed internal redox
reshuffling of a-functionalized aldehydes with formation of esters
and amides without an external oxidant. For a recent review see:
A. Grossmann and D. Enders, Angew. Chem., Int. Ed., 2012,
51, 314. See also ref. 4a. For some recent examples see:
(a) B. Zhang, P. Feng, Y. Cuia and N. Jiao, Chem. Commun.,
2012, 48, 7280; (b) S. De Sarkar, A. Biswas, C. H. Song and
A. Studer, Synthesis, 2011, 1974.
8 Selected examples of direct oxidation of alcohols to amides and
aldehydes to esters mediated by stoichiometric reagents:
(a) F. Xiao, Y. Liu, C. Tang and G.-J. Deng, Org. Lett., 2012,
14, 984; (b) B. R. Travis, M. Sivakumar, G. O. Hollist and
B. Borhan, Org. Lett., 2003, 5, 1031.
Scheme 2 Direct oxidative esterification using catalytic TEMPO and 9.
secondary alcohols as well as phenol in excellent yields
(entries 1–3). Secondary and even tertiary amides are pro-
duced cleanly by the action of excess amine. The primary
benzylamine and the secondary amine piperidine afforded the
corresponding amides in yields of 55–95% (entries 4–14).
Weinreb amides are important intermediates in the synthesis
of ketones. We found that exposing the mixed anhydride to
1.5 equivalents of N,O-dimethylhydroxylamine hydrochloride
and 4 equivalents of pyridine afforded the Weinreb amides in
excellent yields (entries 15–18). Amides were purified by a
standard aqueous workup and flash chromatography. The
esters may be purified by loading the concentrated reaction
mixture directly onto the chromatography column.
While the use of 2-methyl-6-nitrobenzoic acid (9) instead of
pivalic acid (8) generally leads to lower yields of esters and
amides (50–70%), 9 has other notable qualities. It was found
that aldehydes could be oxidized directly to 2-propyl esters in
the presence of sub-stoichiometric amounts of both TEMPO
(1) and acid 9 as well as an excess of 2-propanol, to afford the
corresponding esters (Scheme 2). The success of this reaction is
presumably due to the ability of TEMPO (1) to oxidize the
incipient hemiacetal ester 4 (see Scheme 1, Nu–H = 9)
selectively over 2-propanol, combined with the rapid reaction
of the mixed anhydride with 2-propanol.
9 General reviews on the chemistry of TEMPO: (a) J. M. Bobbitt,
C. Bruckner and N. Merbouh, Org. React. (N.Y., Engl. Transl.),
2010, 74, 103; (b) L. Tebben and A. Studer, Angew. Chem., Int. Ed.,
2011, 50, 5034.
10 A. Abramovich, H. Toledo, E. Pisarevsky and A. M. Szpilman,
Synlett, 2012, 23, 2161.
In conclusion, we have discovered that aldehydes may be
activated for oxidation by carboxylic acids. This novel concept
was developed into an efficient process for the TEMPO
catalyzed oxidation of aldehydes to mixed anhydrides with
pivalic acid. The mixed anhydrides may be converted in situ
into a wealth of esters and amides in yields that certainly rival
those of the multistep protocols,16 without their operational
disadvantages and chemical waste production.
11 I. Shiina, R. Ibuka and M. Kubota, Chem. Lett., 2002, 286.
12 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and M. Yamaguchi,
Bull. Chem. Soc. Jpn., 1979, 52, 1989.
13 The few examples of direct formation of anhydrides from alde-
hydes in the literature appear to proceed via different mechanisms.
See: (a) A. C. Estrada, M. M. Q. Simoes, I. C. M. S. Santos,
M. G. P. M. S. Neves, J. A. S. Cavaleiro and A. M. V. Cavaleiro,
ChemCatChem, 2011, 3, 771; (b) S.-I. Hirashima and A. Itoh,
Chem. Pharm. Bull., 2007, 55, 156.
14 I. Shiina, M. Kubota, H. Oshiumi and M. Hashizume, J. Org.
Chem., 2004, 69, 1822.
Financial support from the German-Israeli Foundation for
Scientific Research and Development (grant no. I-2234-2067/
2009) is gratefully acknowledged. Alex M. Szpilman is the
incumbent of the Chaya Career Development Chair.
15 I. Dhimitruka and J. SantaLucia, Jr., Org. Lett., 2006, 8, 47.
16 For some selected examples see the following: esterification:
C. A. Lewisa, J. Merkel and S. J. Miller, Bioorg. Med. Chem.
Lett., 2008, 18, 6007. Amide formation: M. Lee, D. Hesek,
M. Suvorov, W. Lee, S. Vakulenko and S. Mobashery, J. Am.
Chem. Soc., 2003, 125, 16322. Weinreb amides: T. Raghurama,
S. Vijaysaradhia, I. Singha and J. Singh, Synth. Commun., 1999,
29, 3215. C–C bond formation: L. J. Goossen and N. Rodriguez,
Chem. Commun., 2004, 724.
Notes and references
1 P. A. Wender, V. A. Verma, T. J. Paxton and T. H. Pillow, Acc.
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2 T. Newhouse, P. S. Baran and R. W. Hoffmann, Chem. Soc. Rev.,
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3 (a) J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Org.
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J. D. Hayler, G. R. Humphrey, J. L. Leazer Jr., R. J. Linderman,
17 t-BuOCl is commercially available and also readily prepared from
bleach and t-butanol in the presence of acetic acid: M. J. Mintz and
C. Walling, Org. Synth., 1969, 49, 9.
18 P. P. Pradhan, J. M. Bobbitt and W. F. Bailey, J. Org. Chem.,
2009, 74, 9501.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.