ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Organocatalytic Knoevenagel
Condensations by Means of Carbamic
Acid Ammonium Salts
Nobuyuki Mase* and Takuya Horibe
Department of Molecular Science, Faculty of Engineering, Shizuoka University,
3-5-1 Johoku, Hamamatsu 432-8561, Japan
Received February 20, 2013
ABSTRACT
The Knoevenagel condensation between an active methylene compound and an aromatic aldehyde with a carbamic acid ammonium salt used as
an organocatalyst gave the desired Knoevenagel products in up to 98% yield. The reaction occurred at rt and in a short reaction time under
solvent-free conditions. In addition, no extraction, wash, or chromatography steps were needed to obtain a high-purity Knoevenagel product.
Although carbamic acid (H2NCO2H) is an unstable
compound that has not been isolated yet, it has been
detected by low-temperature IR measurements.1 In con-
trast, carbamic acid ammonium salts are quite stable com-
addition, DIMCARB is used as a reagent in the Willgerodtꢀ
Kindler synthesis of N,N-dimethylthiocarboxamides.8 Due
to the increasing awareness of environmental issues, DIM-
CARB recently attracted attention as a self-associated,
distillable ionic medium.4 Furthermore, this metal-free
ammonium salt promotes an aldol condensation through
an iminium intermediate (Mannich-type mechanism),9,10
and as reported by our group, it has been used for protec-
tion- and metal-free syntheses of [n]-shogaols.11 Although
dialkylammonium carbamates are potentially valuable not
only as reagents or reaction media but also as promoters
or catalysts, their use in organic synthesis is limited. Here,
we report the use of a carbamic acid ammonium salt in
Knoevenagel condensations as an easily removable organo-
catalyst under solvent-free conditions.
pounds.2 For instance, ammonium carbamate (NH4
þ
H2NCO2ꢀ), used as a mild ammoniating reagent, is readily
prepared by reacting solid carbon dioxide with liquid
ammonia.3 Similarly, the reaction of primary and/or second-
ary amines 1 with carbon dioxide provides alkyl-substituted
ammonium carbamates 3 via formation of a weakly acidic
and unstable alkylcarbamic acid 2 (Scheme 1).4,5
Dimethylammonium dimethylcarbamate (DIMCARB,
3a, R = Me), which is the only commercially available
dialkylammonium carbamate,6 is well-known to be a
useful dimethylamine source for preparative amidation
of carboxylic acids, anhydrides, or ester derivatives.7 In
The Knoevenagel condensation, discovered by E.
Knoevenagel in 1896,12 is widely used both in the aca-
demic environment and in the chemicalꢀpharmaceutical
and perfume industries. In general, a secondary amine
(1) Rossi, L. In Science of Synthesis; Knight, J., Ed.; Thieme: 2005;
Vol. 18, p 461.
(2) Roughton, F. J. W. J. Am. Chem. Soc. 1941, 63, 2930.
(3) Rossi, L. In Science of Synthesis; Knight, J., Ed.; Thieme, 2005;
Vol. 18, p 462.
(8) Schroth, W.; Andersch, J. Synthesis 1989, 202.
(9) Kreher, U. P.; Rosamilia, A. E.; Raston, C. L.; Scott, J. L.;
Strauss, C. R. Org. Lett. 2003, 5, 3107.
(4) Kreher, U. P.; Rosamilia, A. E.; Raston, C. L.; Scott, J. L.;
Strauss, C. R. Molecules 2004, 9, 387.
€
(5) Schroth, W.; Schadler, H.-D.; Andersch, J. Z. Chem. 1989,
29, 129.
(10) (a) Chowdari, N. S.; Barbas, C. F., III. Org. Lett. 2005, 7, 867. (b)
Rosamilia, A. E.; Giarrusso, M. A.; Scott, J. L.; Strauss, C. R. Green
Chem. 2006, 8, 1042. (c) Zoto, C. A.; Connors, R. E. J. Mol. Struct. 2010,
982, 121.
(11) Mase, N.; Kitagawa, N.; Takabe, K. Synlett 2010, 93.
(12) Knoevenagel, E. Ber. Dtsch. Chem. Ges. 1894, 27, 2345.
(6) Dimethylcarbamic acid, hydrochloride (CAS No. 22055-85-2)
and diethylcarbamic acid, and sodium salt (CAS No. 18869-61-9) are
other comercially available carbamic acid salts.
(7) Theodoropulos, S. Eur. Pat. Appl., EP 062161, 1982, p 23.
r
10.1021/ol400462d
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