4196
J . Org. Chem. 1996, 61, 4196-4197
Ta ble 1. Am id a tion Rea ction betw een 4-P h en ylbu tyr ic
Acid a n d 3,5-Dim eth ylp ip er id in e Ca ta lyzed by Va r iou s
Ar ylbor on ic Acid sa
3,4,5-Tr iflu or oben zen ebor on ic Acid a s a n
Extr em ely Active Am id a tion Ca ta lyst
Kazuaki Ishihara, Suguru Ohara, and
Hisashi Yamamoto*
Graduate School of Engineering, Nagoya University,
Furo-cho, Chikusa, Nagoya 464-01, J apan
Received April 16, 1996
There are several different routes to carboxamides.1
In most of these reactions, a carboxylic acid is converted
to a more reactive intermediate, e.g., the acid chloride,
which is then allowed to react with an amine. For
practical reasons, it is preferable to form the reactive
intermediate in situ. A carboxamide-forming reaction of
the latter type has attracted our interest in the develop-
ment of a reaction between carboxylic acids and primary
or secondary amines promoted by a catalytic amount of
metallic compounds. There have been some reports on
this reaction in the literature,2 but an efficient catalytic
procedure has not yet been developed. We report here
that arylboronic acids with electron-withdrawing groups,
3,4,5-trifluorobenzeneboronic acid (1) and 3,5-bis(trifluo-
romethyl)benzeneboronic acid (2), act as highly efficient
catalysts in the amidation between carboxylic acids and
amines.
Acyloxyboron intermediates generated from carboxylic
acids and boron reagents such as BR3 (R ) C8H17, OMe),3a
ClB(OMe)2,3a HB(OR)2 (R ) i-Pr, t-Am),3a BH3‚R3N (R )
Me, Bu),3b BF3‚Et2O,3c and catecholborane3d react with
amines to furnish amides in moderate to good yield, but
only in uniformly stoichiometric reactions. In these
boron-mediated amidations, boron reagents transform
into inactive boron species after the reaction of (acyloxy)-
boron derivatives and amines. We reasoned that aryl-
boronic acids with electron-withdrawing substituents at
the aryl group could be used to circumvent these difficul-
ties, since they are water-, acid-, and base-tolerant Lewis
acids that can generate (acyloxy)boron species. They are
also thermally stable and can be readily handled in air.4
We theorized that their strong Lewis acidity might
enhance the rate of the generation of (acyloxy)boron
species and their reactivity with amines.
yieldb
(%)
yieldb
(%)
entry
Ar
entry
Ar
1
2
3
4
3,4,5-F3C6H2
3-NO2C6H4
3,5-(CF3)2C6H3
4-CF3C6H4
74
60
56
54
5
6
7
8
C6H5
23
21
11
2,4,6-(CF3)3C6H2
2,3,4,5-F4C6H
c
<2
a
In the presence of 5 mol % of arylboronic acid, a mixed solution
of 1 equiv of 4-phenylbutyric acid (0.2 M) and 1 equiv of 3,5-
dimethylpiperidine (0.2 M) in toluene was refluxed with removal
b
of water (4-Å molecular sieves in a Soxhlet thimble). Isolated
yield. c No catalyst was added.
entry 1). 3-Nitrobenzeneboronic acid and 3,5-bis(trifluo-
romethyl)benzeneboronic acid (2),6 which are commer-
cially available, were also effective amidation catalysts
(Table 1, entries 2 and 3). The ortho-substituted ben-
zeneboronic acids 2,4,6-tris(trifluoromethyl)benzene-
boronic acid and 2,3,4,5-tetrafluorobenzeneboronic acid
were less effective than simple benzeneboronic acid, even
if the substituent group was a sterically small electron-
withdrawing group like fluorine (Table 1, entries 6 and
7 vs entry 5). Amidation rarely occurred in the absence
of catalysts (Table 1, entry 8).
To explore the generality and scope of boronic acid
1-catalyzed amidation, the reaction was examined with
various structurally diverse carboxylic acids and primary
or secondary amines (Table 2). In most cases, the
reactions proceeded cleanly, and the desirable carboxylic
amides were obtained in high yields. Although the
isolated yield by column chromatography on silica gel is
indicated in Table 2, adequate purification is obtained
by aqueous workup. The catalyst was useful for reacting
not only primary but also secondary amines with various
carboxylic acids. Surprisingly, sterically-hindered 1-ada-
mantanecarboxylic acid was easily amidated at reflux in
mesitylene. Aromatic substrates such as anilines and
benzoic acid also reacted well under similar conditions.
The catalytic amidation of optically active aliphatic
R-hydroxycarboxylic acids with benzylamine proceeded
with no measurable loss (<2%) of enantiomeric purity
under conditions of reflux in toluene. However, slight
racemization was observed in the case of (S)-(+)-mandelic
acid. In all cases, no esters were observed.
We first investigated the catalytic activities of various
arylboronic acids (5 mol %), which promote the model
reaction of 4-phenylbutyric acid (1 equiv) with 3,5-
dimethylpiperidine (1 equiv) in toluene at reflux with
removal of water (4-Å molecular sieves in a Soxhlet
thimble) for 1 h (Table 1). The boronic acid 15 with m-
and p-fluorine substituents on the phenyl group was the
most effective catalyst for the present reaction (Table 1,
(1) For a review of the synthesis of amides and related compounds,
see: Benz, G. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Heathcock, C. H., Eds.; Pergamon Press: New York, 1991;
Vol. 6, Chapter 2.3.
(2) For catalytic amidations between carboxylic acids and amines,
see the following. TiCl4: (a) Nordahl, A° .; Carlson, R. Acta Chem.
Scand., Ser. B. 1988, 28. Ti(O-i-Pr)4: (b) Mader, M.; Helquist, P.
Most amino acids are barely soluble in nonaqueous
solvents. Nevertheless, their lactams can be prepared
by the present technique under heterogeneous conditions.
For example, when 6-aminocaproic acid and 1 mol % of
boron catalyst 1 were suspended in xylene at reflux, the
solid slowly dissolved and caprolactam was formed in
93% yield (Table 3). 5-Aminovaleric acid similarly gave
Tetrahedron Lett. 1988, 59, 3049. Ph3SbO/P4S10
: (c) Nomura, R.;
Nakano, T.; Yamada, Y.; Matsuda, H. J . Org. Chem. 1991, 56, 4076.
Sb(OEt)3: (d) Ishihara, K.; Kuroki, Y.; Hanaki, N.; Ohara, S.; Yama-
moto, H. J . Am. Chem. Soc. 1996, 118, 1569.
(3) (a) Pelter, A.; Levitt, T. E.; Nelson, P. Tetrahedron 1970, 26, 1539.
(b) Trapani, G.; Reho, A.; Latrofa, A. Synthesis 1983, 1013. (c) Tani,
J .; Oine, T.; Inoue, I. Synthesis 1975, 714. (d) Collum, D. B.; Chen,
S.-C.; Ganem, B. J . Org. Chem. 1978, 43, 4393.
(4) We were unable to prepare aliphatic perfluoroalkylboronic acids.
(5) Boronic acid 1 was prepared by addition of trimethyl borate to
Grignard reagent, which was generated in situ from 3,4,5-trifluoro-
bromobenzene and magnesium (turnings) in THF.
(6) We previously used 2 as an efficient Lewis acid catalyst; see:
(a) Ishihara, K.; Mouri, M.; Gao, Q.; Maruyama, T.; Furuta, K.;
Yamamoto, H. J . Am. Chem. Soc. 1993, 115, 11490. (b) Ishihara, K.;
Maruyama, T.; Mouri, M.; Gao, Q.; Furuta, K.; Yamamoto, H. Bull.
Chem. Soc. J pn. 1993, 66, 3483. (c) Ishihara, K.; Kurihara, H.;
Yamamoto, H. J . Am. Chem. Soc. 1996, 118, 3049.
S0022-3263(96)00656-1 CCC: $12.00 © 1996 American Chemical Society