Primary alkylboronic acids as highly active catalysts for the dehydrative amide condensation of α-hydroxycarboxylic acids

Article abstract of DOI:10.1021/ol401537f

Primary alkylboronic acids such as methylboronic acid and butylboronic acid are highly active catalysts for the dehydrative amide condensation of α-hydroxycarboxylic acids. The catalytic activities of these primary alkylboronic acids are much higher than those of the previously reported arylboronic acids. The present method was easily applied to a large-scale synthesis, and 14 g of an amide was obtained in a single reaction.

Full text of DOI:10.1021/ol401537f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Primary Alkylboronic Acids
as Highly Active Catalysts for the
Dehydrative Amide Condensation
of r‑Hydroxycarboxylic Acids
Risa Yamashita,† Akira Sakakura,*,‡ and Kazuaki Ishihara*,†,§
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku,
Nagoya 464-8603, School of Natural Science and Technology, Okayama University,
3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan, and JST, CREST, Japan
ishihara@cc.nagoya-u.ac.jp; sakakura@okayama-u.ac.jp
Received May 31, 2013
ABSTRACT
Primary alkylboronic acids such as methylboronic acid and butylboronic acid are highly active catalysts for the dehydrative amide condensation
of R-hydroxycarboxylic acids. The catalytic activities of these primary alkylboronic acids are much higher than those of the previously reported
arylboronic acids. The present method was easily applied to a large-scale synthesis, and 14 g of an amide was obtained in a single reaction.
Dehydrative amide condensation between carboxylic
acids and amines is a fundamental organic transformation
in not only enzymatic biosynthesis but also the chemical
synthesis of a variety of organic compounds.1 Recent ad-
vances in this field include the development of arylboronic
acids [ArB(OH)2] and boric acid [B(OH)3] as catalysts
for the dehydrative amide condensations.2À9 In 1996,
Yamamoto reported the first catalytic use of electron-
deficient arylboronic acid 1 for direct amidation (Figure 1).2
In 2006, Whiting reported that 2-[(diisopropylamino)methyl]-
phenylboronic acid 2 is also an effective catalyst.3 In 2008,
Hall demonstrated that 2-iodophenylboronic acids 3 were
catalytically active under mild conditions at rt ∼50 °C in
† Nagoya University.
‡ Okayama University.
§ JST, CREST.
4
˚
the presence of 4A molecular sieves.
(1) For recent reviews, see: (a) Charville, H.; Jackson, D.; Hodges,
G.; Whiting, A. Chem. Commun. 2010, 46, 1813. (b) Ishihara, K.
Tetrahedron 2009, 65, 1085. (c) Valeur, E.; Bradley, M. Chem. Soc.
Rev. 2009, 38, 606. (d) Carey, J. S.; Laffan, D.; Thomson, C.; Williams,
M. T. Org. Biomol. Chem. 2006, 4, 2337. (e) Montalbetti, C. A. G. N.;
Falque, V. Tetrahedron 2005, 61, 10827.
(2) (a) Maki, T.; Ishihara, K.; Yamamoto, H. Tetrahedron 2007,
63, 8645. (b) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 8,
1431. (c) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7,
5043. (d) Ishihara, K.; Ohara, S.; Yamamoto, H. Org. Synth. 2002, 79,
176. (e) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996,
61, 4196.
(5) (a) Mylavarapu, R. K.; GCM, K.; Kolla, N.; Veeramalla, R.;
Koilkonda, P.; Bhattacharya, A.; Bandichhor, R. Org. Process Res. Dev.
2007, 11, 1065. (b) Tang, P. Org. Synth. 2005, 81, 262.
(6) For the B(OH)3-catalyzed ester condensation of R-hydroxycar-
boxylic acids, see: (a) Levonis, S. M.; Bornaghi, L. F.; Houston, T. A.
Aust. J. Chem. 2007, 60, 821. (b) Maki, T.; Ishihara, K.; Yamamoto, H.
Org. Lett. 2005, 7, 5047. (c) Houston, T. A.; Wilkinson, B. L.; Blanchfield,
J. T. Org. Lett. 2004, 6, 679.
(7) For the boric acid catalyzed transamidation, see: Nguyen, T. B.;
Sorres, J.; Tran, M. Q.; Ermolenko, L.; Al-Mourabit, A. Org. Lett. 2012,
14, 3202.
(8) For the arylboronic acid catalyzed dehydrative condensation of
di- and tetracarboxylic acids, see: (a) Sakakura, A.; Yamashita, R.;
Ohkubo, T.; Akakura, M.; Ishihara, K. Aust. J. Chem. 2011, 64, 1458.
(b) Sakakura, A.; Ohkubo, T.; Yamashita, R.; Akakura, M.; Ishihara,
K. Org. Lett. 2011, 13, 892.
(3) (a) Arnold, K.; Davies, B.; Giles, R. L.; Grosjean, C.; Smith,
G. E.; Whiting, A. Adv. Synth. Catal. 2006, 348, 813. (b) Arnold, K.;
Batsanov, A. S.; Davies, B.; Whiting, A. Green Chem. 2008, 10, 124. (c)
Georgiou, I.; Ilyashenko, G.; Whiting, A. Acc. Chem. Res. 2009, 42, 756.
(4) (a) Gernigon, N.; Al-Zoubi, R. M.; Hall, D. G. J. Org. Chem.
2012, 77, 8386. (b) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew.
Chem., Int. Ed. 2008, 47, 2876. According to ref 4b, 3 is more active than
˚
1 and 2 under conditions of rt to 50 °C in the presence of 4A molecular
(9) Ishihara, K. In Boronic Acids; Hall, D. G., Ed.; Wiley-VCH:
Weinheim, 2005; pp 1À99.
sieves. See note 11.
r
10.1021/ol401537f
XXXX American Chemical Society

These boronic acids catalyze the dehydrative amide
condensation of a variety of carboxylic acids and amines.
For example, in the reaction of 3-phenylpropionic acid
with 3,5-dimethylpiperidine (1.0 equiv) conducted in tol-
uene (bp 110 °C) under azeotropic reflux conditions for 4 h,
arylboronic acids 1, 2, and 3a (10 mol %) showed good
catalytic activities, despite the fact that 3,5-dimethylpiperi-
dine is a less reactive secondary amine (Table 1, entries 1À3).
Especially, electron-deficient arylboronic acid 1 gave the best
result (89% yield) under these azeotropic reflux conditions.4b
However, these arylboronic acids were almost inert for the
reaction of mandelic acid, an R-hydroxycarboxylic acid
Table 1. Catalytic Activities of Boronic Acids for the Amide
Condensation of Mandelic Acida
yield (%)
entry
catalyst
R = PhCH(OH)
R = Ph(CH2)2
5
1
2
3
4
5
6
7
8
9
1
2
8
89
57
38
45
59
48
31
29
∼0
(6À8% yield). B(OH)3 and PhB(OH)2 also showed poor
8
results for the same reaction (1% and 21% yields, entries 4
and 5), although B(OH)3 catalyzes the dehydrative ester
condensation of R-hydroxycarboxylic acids.6
3a
6
B(OH)3
1
PhB(OH)2
MeB(OH)2
BuB(OH)2
iPrB(OH)2
no catalyst
21
On the basis of Marcelli’s theoretical mechanistic
study,10 the amide condensation may proceed through
nucleohpilic addition of amine to tetracoordinated mono-
acyl boronate I. Nevertheless, we cannot exclude the
possibility that I is dehydrated to give an equilibrium
mixture of monoacyl boronate intermediates II and III
prior to the amide condensation under the azeotropic
reflux conditions in toluene (Scheme 1A). An amine would
coordinate to the boron atom or interact with the B-OH
proton of monoacyl boronate. Although diacyl boronate
IV is also a possible intermediate,3 IV should be very
unstable and rapidly decompose to III under the reaction
conditions. These monoacyl boronates would provide
electrophilic activation through boron conjugation. Since
the intermediate III would be more favorable than II,
electron-withdrawing substituents on the aryl group (R1)
should increase the catalytic activity by enhancing the
Lewis acidity of the boronic acid catalyst.
73 (96)b
89 (99)b
2 (5)b
0
a The reaction of mandelic acid (1.25 mmol) and 3,5-dimethylpiper-
idine (1.25 mmol) was conducted in toluene (5 mL) in the presence of a
catalyst (10 mol %) and water (2.2 equiv) under azeotropic reflux
conditions for 14 h (for mandelic acid) or 4 h (for 3-phenylpropionic
acid). b The reaction was conducted in the presence of benzoic acid
(10 mol %).
the formation of cyclic intermediates. Because the carboxy-
late anion is a weaker base than the amine, carboxylate-
coordinated VII would be more reactive than amine-
coordinated VI. However, it is conceivable that VI was
more favorable than VII in the arylboronic acid catalyzed
reaction, and the electron-withdrawing substituents on
the aryl group further shifted the equilibrium toward VI
to decrease the reactivity. Thus, for successful promotion
of the dehydrative amide condensation of R-hydroxy-
carboxylic acids, a new boronic acid catalyst, which
could preferentially form plausible active species VII, is
required.
As a result of extensive studies, we found that primary
alkylboronic acids such as MeB(OH)2 and BuB(OH)2
successfully catalyzed the dehydrative amide condensation
of mandelic acid (Table 1, entries 6 and 7), despite the fact
that 3,5-dimethylpiperidine was a sterically hindered less
reactive secondary amine.12,13 The appropriate electron-
donating nature of methyl and butyl groups might suppress
the formation of less active VI to promote the dehydrative
amide condensation. In contrast to these primary alkyl-
boronic acids that were stable under heating conditions, a
secondary alkylboronic acid such as i-PrB(OH)2 showed
Figure 1. Arylboronic acids 1À3 as catalysts for the dehydrative
amide condensation reaction.
In a similar way, in the amide condensation of R-
hydroxycarboxylic acids, five-membered cyclic monoacyl
boronate intermediates VI and VII would be generated as
an equilibrium mixture through the dehydration of V
(Scheme 1B).10 X-ray single crystallographic analysis of a
complex of MeB(OH)2, phenylpyruvic acid, and 1,2,3,4-
tetrahydroquinoline11 and 11B NMR experiments suggested
(12) When the reaction of mandelic acid (1.1 equiv) with 3,5-di-
methylpiperidine was conducted in CH2Cl2 at ambient temperature in
4
the presence of 10 mol % of MeB(OH)2 or 3a and MS 4A, the
˚
corresponding amide was not obtained. See the Supporting Information
for details.
(10) Boronate V should be much less reactive than I due to the strong
coordination of hydroxide anion. Marcelli, T. Angew. Chem., Int. Ed.
2010, 49, 6840.
(11) CCDC-933866 contains supplementary crystallographic data
for this paper. This information can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. See the Supporting Information for details.
(13) When the MeB(OH)2-catalyzed reaction of mandelic acid
methyl ether with 3,5-dimethylpiperidine was conducted for 14 h, the
corresponding amide was obtained in 37% yield, while the use of 1 as a
catalyst gave the amide in 84% yield. These results suggested that the
R-methoxy functionality did not show the positive effect for the present
amide condensation. See the Supporting Information for details.
B
Org. Lett., Vol. XX, No. XX, XXXX

corresponding R-hydroxycarboxamide was obtained (99%
yield).14
Scheme 1. Plausible Active Intermediates for the Boronic Acid
Catalyzed Amide Condensationa
In contrast to the amide condensation in which
MeB(OH)2 showed excellent catalytic acitivity while B(OH)3
was almost inert, the use of MeB(OH)2 for the dehydrative
ester condensation of mandelic acid gave moderate results,
while B(OH)3 showed high catalytic activity6 (Scheme 2).
These results indicated that the catalysis of boronic and
boric acids for the amide condensation was quite different
from that for the ester condensation.
Scheme 2. Dehydrative Ester Condensation of Mandelic Acid
With the highly active catalysts in hand, the amide
condensation reactions of various R-hydroxycarboxylic
acids were examined to explore the generality and scope
of the present method (Figure 2). The reaction was con-
ducted in the presence of MeB(OH)2 (1 mol %). Both
3-phenyllactic acid and 2-hydroxyoctanoic acid were highly
reactive, and the reaction with both primary and secondary
amines gave the corresponding amides in high yields with-
out a measurable loss of optical purity (entries 1À11). In the
reaction with less reactive amines such as cyclododecyla-
mine, 3,5-dimethylpiperidine, and dibutylamine, the use of
10 mol % of the catalyst and the addition of benzoic acid
(10 mol %) successfully improved the yields (entries 5À7).
Mandelic acid was less reactive than 3-phenyllactic acid
and 2-hydroxyoctanoic acid. Although the amide conden-
sation with sterically hindered dibutylamine gave moder-
ate results (entry 15), the reaction of mandelic acid
generally gave the corresponding amides in good to high
yields (entries 12À15). In contrast to 3-phenyllactic acid,
mandelic acid was susceptible to racemization under the
reaction conditions. However, the use of 1,2-dichloro-
ethane (bp 83 °C) as the reaction solvent instead of toluene
(bp 110 °C) significantly suppressed racemization in the
reaction with 2-phenylethylamine (entry 12).
a (A) Reaction of carboxylic acids without an R-hydroxy group. (B)
Reaction of R-hydroxycarboxylic acids.
poor catalytic activity (entry 8), probably due to the
decomposition to B(OH)3.
Since both mandelic acid and 3,5-dimethylpiperidine
were less reactive in the dehydrative amide condensation,
yields of the corresponding R-hydroxyamide were not
sufficiently high (73% and 89%), even when Me- or Bu-
B(OH)2 was used as a catalyst. However, they were
increased to 96% and 99% when the reaction was con-
ducted in the presence of benzoic acid (10 mol %). It is
conceivable that benzoic acid promoted ligand exchange
between the product and the substrate on the catalyst. As
another possibility, more reactive intermediate VIII might
be generated in place of VII. In the dehydrative amide
condensation shown in Table 1, the boronic acid catalyst
was treated with a small amount of water (2.2 equiv) prior
to heating under azeotropic reflux to obtain the amide in a
highly reproducible yield. The use of water could facilitate
the hydrolysis of triboroxines, which are catalytically less
active trimers of boronic acids,9 to give catalytically active
monomeric boronic acids.7 The present method could be
easily applied to a gram-scale synthesis of R-hydroxycar-
boxamide. When the reaction of mandelic acid (50 mmol,
7.6 g) and 3,5-dimethylpiperidine (50 mmol, 6.8 mL) was
conducted in the presence of MeB(OH)2 (1 mol %),
benzoic acid (50 mol %) and water (2 mL), 14.0 g of the
Since MeB(OH)2 showed high catalytic activity for the
dehydrative amide condensation but was not efficient for
the ester condensation, it was envisioned that the selective
amide condensation with an aminoalcohol could be
achieved. Indeed, when the reaction of mandelic acid with
6-aminohexan-1-ol was conducted under the optimized
reaction conditions, the corresponding amide was selectively
(14) For another methodology of the synthesis of R-hydroxyamides,
see: Leighty, M. W.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2012,
134, 15233.
Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 2. Products of methylboronic acid catalyzed dehydrative amide condensation of R-hydroxycarboxylic acids. The reaction of an
R-hydroxycarboxylic acid (1.25 mmol) and an amine (1.25 mmol) was conducted in toluene (5 mL) in the presence of MeB(OH)2 (1 mol %)
and water (2.2 equiv) under azeotropic reflux conditions. Notes: a10 mol % of MeB(OH)2 was used. bThe reaction was conducted in the
presence of benzoic acid (10 mol %). cThe reaction was conducted in 1,2-dichloroethane. dThe reaction was conducted in o-xylene.
obtained in quantitative yield (entry 16).15 Amide condensa-
tion between 4-methoxymandelic acid and 2-(3,4-dimethoxy-
phenyl)ethylamine gave the corresponding amide in excellent
Scheme 3. Amide Condensation of Salicylic Acid
yield (entry 17). LiAlH4 reduction of this amide gave an
O-methyl derivative of denopamine, a β1 adrenergic receptor
agonist, in 78% yield.16,17 The reactivity of 2-hydroxy-2-
methylpropanoic acid was further reduced due to steric hin-
drance (entries 18À21). The use of benzoic acid (10 mol %) as
an additive successfully promoted the reaction of 2-hydroxy-2-
methylpropanoic acid with less reactive N-methylbenzylamine
and BuB(OH)2 successfully catalyzed the dehydrative
amide condensation of R-hydroxycarboxylic acids. The
catalytic activities of these primaryalkylboronic acids were
much higher than those of previously reported arylboronic
acids. For the reaction of less reactive substrates, the use of
benzoic acid (10À50 mol %) successfully improved the
reactivity. The β1-receptor agonist denopamine derivative
could be easily synthesized by the present method.
to give the desired amide in 79% yield (entry 21).
MeB(OH)2 was highly efficient for the dehydrative
amidation of salicylic acid, a β-hydroxycarboxylic acid
(Scheme 3). Since the reactivity of salicylic acid was very
low, the corresponding amide was not obtained when the
reaction was conducted in toluene. However, the use of
o-xylene (bp 144 °C) improved the reactivity and gave the
amide in almost quantitative yield.
In conclusion, we have demonstrated that commercially
available primary alkylboronic acids such as MeB(OH)2
Acknowledgment. Financial support for this project
was partially provided by JSPS.KAKENHI (23350039),
Mitsubishi Rayon Co., Ltd. and Program for Leading
Graduate Schools “Integrative Graduate Education and
Research in Green Natural Sciences”, MEXT, Japan. We
also thank Ms. Yanhui Lu for experimental support.
(15) Since the catalytic activity of MeB(OH)2 was rather low for the
transformation of ester to amide, the reaction with 6-aminohexan-1-ol
was proposed to proceed via the direct amide condensation.
(16) (a) Bristow, M. R.; Hershberger, R. E.; Port, J. D.; Minobe, W.;
Rasmussen, R. Mol. Pharmacol. 1989, 35, 295. (b) Yokoyama, H.;
Yanagisawa, T.; Taira, N. J. Cardiovasc. Pharmacol. 1988, 12, 323. (c)
Naito, K.; Nagao, T.; Ono, Y.; Otsuka, M.; Harigaya, S.; Nakajima, H.
Jpn. J. Pharmacol. 1985, 39, 541. (d) Naito, K.; Nagao, T.; Otsuka, M.;
Harigaya, S.; Nakajima, H. Jpn. J. Pharmacol. 1985, 38, 235. (e) Ikeo, T.;
Nagao, T.; Suzuki, T.; Yabana, H.; Nakajima, H. Jpn. J. Pharmacol.
1985, 39, 191.
Supporting Information Available. Experimental pro-
cedure and full characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Brown, R. F. C.; Donohue, A. C.; Jackson, W. R.;
McCarthy, T. D. Tetrahedron 1994, 50, 13739. (b) Jian-Xin, G.; Zu-Li,
L.; Gou-Qiang, L. Tetrahedron 1993, 49, 5805. (c) Corey, E. J.; Link,
J. O. J. Org. Chem. 1991, 56, 442.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX