reactions appeared recently.9 Moreover, interesting stoichio-
metric reactions between NHCs and various substrates have
been reported.10 In the majority of these reactions, NHCs
are generated by deprotonation of cationic precursors.
Alternative approaches for the generation of N-heterocyclic
carbenes are thermal eliminations, either starting from
2-alkoxy-substituted imidazolidines or 2,3-dihydro-1H-imi-
dazoles11 or from pseudo-cross-conjugated heterocyclic me-
someric betaines (PCCMB). Thus, pyrazolium-3-carbox-
ylates,12 indazolium-3-carboxylates,13,14 imidazolium-2-carbox-
ylates,15 pyridinium-2-carboxylates,16 and quinolinium-2-
carboxylates17 undergo thermal decarboxylations to N-
heterocyclic carbenes, whereas indazolium-3-amidates ex-
trude isocyanates to NHCs.13 We report here unexpected
reactions between the NHC of indazole and aldehydes as
well as ketones.
Scheme 1. Reaction of NHC 2 with Ketones
In situ generation of the N-heterocyclic carbene 2 by
thermal decarboxylation of 1,2-dimethylindazolium-3-car-
boxylate 114 in acetone resulted in the formation of the stable
1:1 adduct 4a in 80% yield (Scheme 1). We assume that the
carbene deprotonates the acetone (pKa 26.5)18 and that the
resulting enolate adds to the iminium bond of the indazolium
cation 3. This is in accord with the observation that
indazolium salts can be silylated with t-BuPh2SiLi or
methylated with methyllithium at C-3.19
This reaction was also applied to cyclic ketones such as
cyclopentanone (pKa 25.8), cyclohexanone (pKa 26.4), and
2-cyclohexylcyclohexanone, which gave the adducts 4b-d,
respectively.20 Under the reaction conditions applied, the
latter mentioned ketone formed a 1:1 mixture of isomers,
resulting from deprotonation of either R-hydrogen atom.
Acetophenone (pKa 24.7) gave 4e in 87% yield. Acetyl-
acetone (pKa 13.3) reacted via the terminal methyl group to
give the adduct 4f, 83% of which exists in its enol form in
CDCl3 solution at rt. To the best of our knowledge, no
analogous reaction have been observed with known N-
heterocyclic carbenes. N-Alkoxycarbonyl-substituted imida-
zolium, thiazolium, and benzothiazolium salts, however, are
able to add in situ generated silyl enol ethers to 2-substituted
imidazolines and thiazolines.21 On performing similar reac-
tions with aromatic aldehydes in alcohols, oxidative esteri-
fications were observed. Thus, heating a mixture of meso-
meric betaine 1 and the aldehydes 5a-f in ethanol, n-propanol,
and n-butanol, respectively, resulted in the formation of
benzoates 6a-i (Scheme 2).22 Unreacted aldehydes were
recovered.
In order to gain information about the mechanism of this
redox esterification, we carefully analyzed the reaction
mixtures and performed ab initio calculations23 as well as
model reactions. Tetrahedral intermediates such as I (Scheme
3) are formulated in essentially all N-heterocyclic carbene
catalyzed transformations of aldehydes, and a common
premise in the additions of umpolung species to aldehydes
(9) Zeitler, K. Angew. Chem. 2005, 117, 7674; Angew. Chem., Int. Ed.
2005, 44, 7506.
(10) (a) Nair, V.; Sreekumar, V.; Bindu, S.; Suresh, E. Org. Lett. 2005,
7, 2297. (b) Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. P. Org. Lett.
2003, 5, 665.
(11) (a) Enders, D.; Breuer, K.; Raabe, G.; Runsink, J.; Teles, J. H.;
Melder, J.-P.; Ebel, K.; Brode, S. Angew. Chem., Int. Ed. Engl. 1995, 34,
1021. (b) Teles, J. H.; Melder, J.-P.; Ebel, K.; Schneider, R.; Gehrer, E.;
Harder, W.; Brode, S.; Enders, D.; Breuer, K.; Raabe, G. HelV. Chim. Acta
1996, 79, 61. (c) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953.
(12) Schmidt, A.; Habeck, T., Lett. Org. Chem. 2005, 2, 37.
(13) (a) Schmidt, A.; Habeck, T.; Lindner, A. S.; Snovydovych, B.;
Namyslo, J. C.; Adam, A.; Gjikaj, M. Eur. J. Org. Chem. 2007, in press.
(b) Schmidt, A.; Beutler, A.; Habeck, T.; Mordhorst, T.; Snovydovych, B.
Synthesis 2006, 1882. (c) Schmidt, A.; Habeck, T.; Merkel, L.; Ma¨kinen,
M.; Vainiotalo, P. Rapid Comm. Mass Spectrom. 2005, 19, 2211.
(14) Schmidt, A.; Merkel, L.; Eisfeld, W. Eur. J. Org. Chem. 2005, 2124.
(15) (a) Voutchkova, A. M.; Appelhans, L. N.; Chianese, A. R.; Crabtree,
R. H. J. Am. Chem. Soc. 2005, 127, 17624. (b) Crabtree, R. H. J. Organomet.
Chem. 2006, 691, 3146.
(16) Katritzky, A. R.; Faid-Allah, H. M. Synthesis 1983, 149.
(17) Quast, H.; Schmitt, E. Liebigs Ann. 1970, 732, 43.
(18) All pKa values determined in DMSO and were taken from the
Beilstein CrossFire database.
(19) Gonza´lez-Nogal, A. M.; Calle, M.; Calvo, L. A.; Cuadrado, P.;
Gonza´lez-Ortega, A. Eur. J. Org. Chem. 2005, 4663.
(21) Itoh, T.; Miyazaki, M.; Nagata, K.; Ohsawa, A. Tetrahedron 2000,
56, 4383.
(20) Typical procedure: The mesomeric betaine 1 (95 mg, 0.5 mmol)
was suspended in 4.5 mL of the ketone and heated at 60-75 °C for 1-2
h. The reaction was monitored by TLC. The excess ketone was distilled
off under reduced pressure, and the residue was chromatographed (silica
gel, petroleum ether/ethyl acetate ) 4 / 1). Thus, 2-(1,2-dimethyl-2,3-
dihydro-1H-indazol-3-yl)cyclopentanone 5b was obtained as a yellow oil,
yield 30 mg (30 %).
(22) Typical procedure: The mesomeric betaine 1 (0.25 mmol, 48 mg)
and benzaldehyde (0.25 mmol) were dissolved in 10 mL of alcohol. The
mixture was then heated over a period of 3 h. After evaporation of the
solvent, the mixture was chromatographed on silica gel with petroleum
ether/ethyl acetate (30:1) to separate ethyl benzoate 6a (13 mg) from
unconsumed benzaldehyde (34 mg).
3516
Org. Lett., Vol. 9, No. 18, 2007