4,5,6,7-Tetrachlorobenzo[d][1,3,2]dioxaborol-2-ol as an effective catalyst for the amide condensation of sterically demanding carboxylic acids

Article abstract of DOI:10.1021/ol060216r

4,5,6,7-Tetrachlorobenzo[d][1,3,2]dioxaborole (4a) and 4,5,6,7- tetrachlorobenzo[d][1,3,2]dioxaborol-2-ol (4b) are effective catalysts for the dehydrative amide condensation between an equimolar mixture of carboxylic acids and amines. In particular, these catalysts are greatly superior to 3,5-bis(trifluoromethyl)phenylboronic acid (1) for the amide condensation of sterically demanding carboxylic acids. In contrast, 4c, which is prepared from a 1:2 molar mixture of B(OH)₃ and tetrachlorocatechol, is effective as a Lewis acid-assisted Bronsted acid (LBA) catalyst for Ritter reaction.

Full text of DOI:10.1021/ol060216r

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1431-1434
4,5,6,7-Tetrachlorobenzo[d][1,3,2]dioxaborol-
2-ol as an Effective Catalyst for the
Amide Condensation of Sterically
Demanding Carboxylic Acids
Toshikatsu Maki,† Kazuaki Ishihara,*,† and Hisashi Yamamoto*,‡
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa, Nagoya
464-8603, Japan, and Department of Chemistry, The UniVersity of Chicago,
5735 South Ellis AVenue, Chicago, Illinois 60637
ishihara@cc.nagoya-u.ac.jp; yamamoto@uchicago.edu
Received January 25, 2006
ABSTRACT
4,5,6,7-Tetrachlorobenzo[d][1,3,2]dioxaborole (4a) and 4,5,6,7-tetrachlorobenzo[d][1,3,2]dioxaborol-2-ol (4b) are effective catalysts for the
dehydrative amide condensation between an equimolar mixture of carboxylic acids and amines. In particular, these catalysts are greatly
superior to 3,5-bis(trifluoromethyl)phenylboronic acid (1) for the amide condensation of sterically demanding carboxylic acids. In contrast, 4c,
which is prepared from a 1:2 molar mixture of B(OH)3 and tetrachlorocatechol, is effective as a Lewis acid-assisted Brønsted acid (LBA)
catalyst for Ritter reaction.
We have previously found that the dehydrative condensation
of an equimolar mixture of carboxylic acids and primary or
secondary amines or ureas proceeds under azeotropic reflux
conditions with the removal of water in less polar solvents
such as toluene and xylene in the presence of arylboronic
acids bearing electron-withdrawing groups at the meta or
para positions, such as 3,4,5-trifluorophenylboronic acid,1
3,5-bis(trifluoromethyl)phenylboronic acid (1),1 3,5-bis(per-
fluorodecyl)phenylboronic acid,2 and N-alkyl-4-borono-
pyridinium halides.3
Before our discovery in 1978, Ganem et al. reported that
carboxylic acids condense with amines via 2-acyloxy-1,3,2-
benzodioxaborolane (2) in the presence of stoichiometric
amounts of catecholborane under mild conditions (THF, -78
°C to rt) (Figure 1).4 Two equivalents of amine are required
because the reaction proceeds via nucleophilic attack of
amine to [2‚amine]. One equivalent of catecholborane is
required because benzo[d][1,3,2]dioxaborol-2-ol (3), which
is afforded together with amide, is inert as a condensing
reagent under the same conditions. Nevertheless, taking our
† Nagoya University.
(3) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. 78th Spring Mtg Chem.
Soc. Jpn. 2000, 3-B5-10. (b) Ishihara, K.; Yamamoto, H. Jpn. Kokai Tokkyo
Koho JP 2001-270939 (2001-10-02); Application JP 2000-87495 (2000-
03-27). (c) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 5043-
5046. (d) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 5047-
5050. (e) Latta, R.; Springsteen, G.; Wang, B. Synthesis 2001, 1611-1613.
(4) Collum, D. B.; Chen, S.; Ganem, B. J. Org. Chem. 1978, 43, 4393-
4394.
‡ The University of Chicago.
(1) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61,
4196-4197. (b) Ishihara, K.; Ohara, S.; Yamamoto, H. Macromolecules
2000, 33, 3511-3513. (c) Ishihara, K.; Ohara, S.; Yamamoto, H. Org. Synth.
2002, 79, 176-185. (d) Maki, T.; Ishihara, K.; Yamamoto, H. Synlett 2004,
1355-1358.
(2) Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett 2001, 1371-1374.
10.1021/ol060216r CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/04/2006

Table 1. Catalytic Activities of 1,3,2-Dioxaborolan-2-ol
Derivatives for the Amide Condensation of 4-Phenylbutyric
Acids with Benzylamine
Figure 1. Ganem’s amide condensation of carboxylic acids with
amines using catecholborane as a condensing reagent and a possible
catalytic pathway.
results into consideration, we envisaged that 3 as well as
arylboronic acids such as 1 might serve as dehydrative
catalysts under azeotropic reflux conditions with the removal
of water in less polar solvents (Figure 1).
a B(OH)3 and 1 were used instead of 1,3,2-dioxaborolan-2-ol derivatives.
B(OH)3 is also available at a rather low price, 4b, which
can be prepared from them in situ, is very economical and
practical. In contrast, B(OH)3-oxalic acid and B(OH)3-2-
hydroxy-2-methylpropanoic acid were less active than 4b,
probably due to the instability of their 1,3,2-dioxaborolan-
2-ol structures (entries 3 and 4).
Next, the catalytic activities of 4b, 1, and B(OH)3 were
examined for the dehydrative condensation of cyclohexane-
carboxylic acid, which is a more sterically demanding
carboxylic acid than 4-phenylbutyric acid, with benzylamine
(Table 2). Interestingly, 4b was geatly superior to 1 as a
We report here that 4,5,6,7-tetrachlorobenzo[d][1,3,2]-
dioxaborol-2-ol (4b), which is prepared from tetrachloro-
catechol and B(OH)3 in situ, is sufficiently active as a catalyst
for the dehydrative condensation of an equimolar mixture
of carboxylic acids and amines. Notably, 4b was greatly
superior to arylboronic acids for the amide condensation of
sterically demanding carboxylic acids. In addition, we found
that Lewis acid-assisted Brønsted acid (LBA)5 4c, which was
prepared from a 1:2 molar mixture of B(OH)3 and 4,5,6,7-
tetrachlorocatechol, was quite effective for the Ritter reaction
to give amides from the corresponding nitriles and benzylic
alcohols.
First,benzo[d][1,3,2]dioxaborol-2-ol 3, which was prepared
in situ from an equimolar mixture of B(OH)3 and catechol
in toluene under azeotropic reflux conditions, was examined
as a catalyst (5 mol %) for the dehydrative condensation of
4-phenylbutyric acid and benzylamine (entry 1, Table 1).
Expectedly, 3 was usable as a dehydration catalyst and more
Table 2. Catalytic Activities of B(III) Compounds for the
Dehydrative Condensation of Cyclohexanecarboxylic Acid with
Benzylamine
6
active than B(OH)3 (entry 5), but its activity was insufficient.
Fortunately, 4,5,6,7-tetrachlorobenzo[d][1,3,2]dioxaborol-2-
ol 4b was much more active than 3 (entry 2). Surprisingly,
the catalytic activity of 4b was almost the same as that of 1
(entry 6). According to Chemicals price catalog (Chemicals,
33rd ed.; Wako Pure Chemical Industries, Ltd.: Japan, 2004),
1 is 40 times more expensive than tetrachlorocatechol. Since
(5) (a) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561-
1562. (b) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J.
Am. Chem. Soc. 1994, 116, 10520-10524. (c) Ishihara, K.; Kurihara, H.;
Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049-3050. (d) Ishihara, K.;
Kondo, S.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62, 3026-
3027. (e) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J. Am.
Chem. Soc. 1998, 120, 6920-6930.
a 4b and 4c were prepared from B(OH)3 and tetrachlorocatechol in situ
before the addition of carboxylic acids and amines.
(6) Tang, P. Org. Synth. 2005, 81, 262-272.
1432
Org. Lett., Vol. 8, No. 7, 2006

[1,3,2]dioxaborole (4a), which was isolable,7,8 gave slightly
better results than 4b (entry 1). However, 4c, which was
prepared in situ from a 1:2 molar mixture of B(OH)3 and
tetrachlorocatechol, was almost inert probably due to the lack
of any hydroxy groups on the boron atom of 4c (entry 5).
When tetrachlorocatechol, B(OH)3, cyclohexanecarboxylic
acid, and benzylamine were added to toluene at once, the
amide condensation almost did not occur probably due to
the lack of generation of 4b (Scheme 1). As shown in Table
2, the in situ preparation of 4b was required before the
addition of carboxylic acids and amines.
Scheme 1. Control Experiment for Entry 2 in Table 2
To explore the generality and scope of the amide con-
densation reaction catalyzed by 4a, catalytic activities of 4a
were compared with that of 1 in the amide condensation
reaction of various substrates in toluene or o-xylene in the
presence of 5 mol % of them. Representative results are
shown in Table 3. Although 4a gave slightly inferior results
compared to 1 for sterically small aliphatic and aromatic
carboxylic acids (entries 1-4), it still showed adequate
catalytic activity for these substrates. In contrast, 4a was
greatly superior to 1 for not only sterically bulky aliphatic
and aromatic carboxylic acids but also functionalized car-
boxylic acids such as Boc-L-Ala-OH (entries 5-14). Without
exception, the amide condensation reactions were completed
within 24 h in the presence of 5 mol % of 4a. The scope of
suitable carboxylic acids was extended by using 4a as a
catalyst instead of 1. In contrast, 1 and 4a showed a similar
trend in catalytic activity with regard to the steric bulkiness
of amines (entries 2, 4, and 12). Less hindered 4b should
have an advantage over 1 at the regeneration step from
hydroxyboron compounds to acyloxyboron species.
catalyst (entry 2 vs entry 3). 4,5,6,7-Tetrafluoro- and 4,5,6,7-
tetrabromobenzo[d][1,3,2]dioxaborol-2-ols also exhibited
good catalytic activities, as well as 4b. B(OH)3 was almost
inert (entry 4).6 Furthermore, 4,5,6,7-tetrachlorobenzo[d]-
Table 3. Amide Condensation of Various Carboxylic Acids
with Amines Catalyzed by 1 or 4a
In the course of our present study, we were interested in
the utility of 4c as an acid catalyst for the amidation of
alcohols with nitriles, which is known as the Ritter reaction.9
This method works well only under strongly acidic conditions
(e.g., cat. concd H2SO4,9,10a cat. BF3‚Et2O,10b formic acid as
Table 4. Ritter Reaction Catalyzed by 4c
4c
time
(h)
yield
(%)
entry (mol %)
product (7, 19-25)
Ph2CHNHCOMe 19
Ph2CHNHCOEt 20
Ph2CHNHCOPh 21
1
2
3a
4a
5a
6
10
5
5
10
10
10
5
11
4
3
5
3
3
3
3
93
92
94
80
78
84
93
96
BnNHCOPh7
p-MeC6H4CH2NHCOPh 22
(p-MeC6H4)2CHNHCOEt 23
(2-Naphthyl)PhCHNHCOEt 24
(p-FC6H4)2CHNHCOEt 25
7
8
5
a Optical purity of the amide was reduced from >99% ee to 86% ee
through amide condensation.
a The reaction was carried out at 120 °C.
Org. Lett., Vol. 8, No. 7, 2006
1433

a solvent,9c and so on) in strongly ionizing solvents, which
limits its applicability to compounds containing functional
groups that are stable to acid. Although tetrachlorocatechol
and B(OH)3 were much milder acidic compounds than
traditional strong acid catalysts, it was expected that their
ate complex 4c might synergistically serve as a Lewis acid
assisted Brønsted acid (LBA).5 The Ritter reaction of several
benzylic alcohols with nitriles was examined in nitriles in
the presence of 5-10 mol % of 4c under reflux conditions
(Table 4). In all cases, the corresponding amides were
isolated in high yield.
In conclusion, compounds 4 are economically and practi-
cally useful catalysts for the direct amide condensation of
sterically demanding carboxylic acids. Catalyst 4b could be
isolated and stored as 4a. Furthermore, 4c is useful as an
LBA catalyst for the Ritter reaction.
Acknowledgment. Financial support for this project was
provided by SORST, JST, the 21st Century COE Program
of MEXT, and the Iwatani Naoji Foundation. T.M. also
acknowledges a JSPS Fellowship for Japanese Junior Sci-
entists.
(7) 4,5,6,7-Tetrafluoro- and 4,5,6,7-tetrabromobenzo[d][1,3,2]dioxaborol-
2-ols could not be isolated by distillation techniques.
(8) Lang, A.; No¨th, H.; Thomann-Albach, M. Chem. Ber./Recueil 1997,
130, 363-369. In this paper, 4a was prepared from 3,4,5,6-tetrachlorocy-
clohexa-3,5-diene-1,2-dione and BH3‚THF. We prepared 4a from tetra-
chlorocatechol and BH3‚SMe2 in Et2O because THF was decomposed due
to the strong Lewis acidity of 4a under the distillation conditions.
(9) (a) Benson, F. R.; Ritter, J. J. J. Am. Chem. Soc. 1949, 71, 4128-
4129. (b) Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213-325.
(10) (a) Reddy, K. L. Tetrahedron Lett. 2003, 44, 1453-1455. (b)
Firouzabadi, H.; Sardarian, A. R.; Badparva, H. Synth. Commun. 1994, 24,
601-607. (c) Gullickson, G. C.; Lewis, D. E. Synthesis 2003, 681-684.
Supporting Information Available: Experimental pro-
cedures and full characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060216R
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Org. Lett., Vol. 8, No. 7, 2006