Org. Synth. 2002, 79, 176
DOI: 10.15227/orgsyn.079.0176
(3,4,5-TRIFLUOROPHENYL)BORONIC ACID-CATALYZED AMIDE FORMATION
FROM CARBOXYLIC ACIDS AND AMINES: N-BENZYL-4-PHENYLBUTYRAMIDE
[
Benzenebutanamide, N-(phenylmethyl)-
]
Submitted by Kazuaki Ishihara
1
, Suguru Ohara
2
, and Hisashi Yamamoto
2
.
Checked by David T. Amos and Rick L. Danheiser.
1. Procedure
A.
(3,4,5-Trifluorophenyl)boronic
acid
.
A 500-mL, three-necked, round-bottomed flask containing
magnesium
turnings (1.94 g, 80 mmol) is equipped with
a rubber septum, a 20-mL pressure-equalizing dropping
funnel fitted with a rubber septum, a Teflon-coated
magnetic stirring bar, and a reflux condenser fitted
with an argon inlet adapter. The system is flame-dried and
flushed with argon. Anhydrous ether
(200 mL, Note 1)
is introduced to cover the
magnesium
,
a crystal of
iodine
is added, and the mixture is heated to reflux in an oil bath.
The dropping funnel is filled with
1-bromo-3,4,5-trifluorobenzene
(8.36 mL, 14.8 g, 70.0 mmol, Note 2) and ca. 1 mL is added to the boiling
reaction mixture. After reaction has commenced, the oil bath
is removed, and the remainder of the aryl bromide is added slowly at a rate sufficient
to maintain reflux (addition time ca. 1 hr). The resulting mixture is stirred for
an additional 2 hr. During this period, a flame-dried, 500-mL, single-necked,
round-bottomed flask equipped with a Teflon-coated magnetic
stirring bar, a rubber septum, and an argon
inlet is charged with dry tetrahydrofuran
(THF, 50 mL, Note 3)
and
trimethyl borate (15.7
mL, 14.5 g, 140 mmol, Note 4). The mixture is cooled to 0°C, and the ether solution of
(3,4,5-trifluorophenyl)magnesium bromide
prepared above is introduced in one portion via a double-ended needle.
The reaction mixture is allowed to warm to room temperature, stirred for 1 hr, and
then treated with
200 mL of saturated ammonium
chloride solution. The organic layer is separated and the aqueous
layer is extracted with three 100-mL portions
of ethyl acetate
. The combined organic layers are
washed with brine (100 mL), dried
over anhydrous magnesium sulfate
,
filtered, and concentrated under reduced pressure. The resulting white solid is dissolved
in a minimal amount of hot (65°C)
ethyl acetate
,
allowed to cool to room temperature, and then
600
mL of hexane
is added. The resulting solution
is allowed to stand overnight and then filtered to afford pure
(3,4,5-trifluorophenyl)boronic
acid
as white crystals. Further recrystallization of the mother
liquor 3-4 times provides a total of 6.3
g (51%) of
(3,4,5-trifluorophenyl)boronic acid
(Notes 5 and 6).
B.
N-Benzyl-4-phenylbutyramide
.
A flame-dried, 200-mL, single-necked, round-bottomed flask
is equipped with a Teflon-coated magnetic stirring bar and
a Soxhlet extractor containing a thimble filled with
3 g of calcium hydride
and topped with a reflux condenser fitted with an argon
inlet
(Note 7). The reaction flask is charged with
4-phenylbutyric acid (5.42 g,
33.0 mmol, Note 8),
benzylamine (3.28 mL,
30.0 mmol, Note 9),
and
(3,4,5-trifluorophenyl)boronic acid
(52.8 mg, 0.300 mmol) in
toluene
(60 mL) and then heated in an oil bath.
The reaction mixture is brought to reflux (bath temperature 120°C), and after 16 hr
is cooled to ambient temperature and diluted with
80
mL of dichloromethane
. The organic layer
(Note 10) is washed with 1.0 M hydrochloric
acid (HCl, 100 mL) and brine
(100 mL), dried over anhydrous
magnesium sulfate
, filtered, and concentrated under
reduced pressure. The resulting yellow residue is recrystallized from
ethyl
acetate
and
hexane
to provide pure
N-benzyl-4-phenylbutyramide
(ca. 6-7 g) as white crystals.
The mother liquor is concentrated and the residue is purified by flash chromatography
on silica gel (Note 11) to provide additional product as a white
solid. The total combined yield of
N-benzyl-4-phenylbutyramide
is 7.11-7.18 g (94-95%, Note 12).
2. Notes
1.
Ethyl ether
was distilled from
sodium-benzophenone
ketyl
before use.
2.
1-Bromo-3,4,5-trifluorobenzene
was purchased from Aldrich Chemical Company, Inc.
,
and used without further purification.
3.
Tetrahydrofuran
was distilled from
sodium-benzophenone
ketyl
before use.
4.
Trimethyl borate
was purchased from Tokyo Kasei Kogyo Co., Ltd. or Aldrich
Chemical Company, Inc.
and used without further purification.
5.
The product consists of a mixture of
(3,4,5-trifluorophenyl)boronic
acid
and varying amounts of
(3,4,5-trifluorophenyl)boronic
anhydride
.
6.
The submitters obtained the product in
89% yield.
(3,4,5-Trifluorophenyl)boronic
acid
has the following physical properties: TLC R
f
= 0.63 (
10:1 ethyl acetate/methanol
);
mp 249-252°C, IR (KBr) cm
−1: 3077, 2359,
1616, 1530, 1217, 1038
;
1H NMR (300 MHz,
CDCl
3) δ: 4.74-4.82 [br, 0.28 H (for monomer)], 7.35
(t, 0.28 H, J = 7.0 (for monomer)), 7.77 [t, 1.72 H, J = 7.9 (for trimer)]
;
13C NMR (125
MHz, CD
3OD) δ: 118.6 (dd, J = 4.6, 15.0), 130.5-132.6
(br m), 142.2 (dt, J = 249.8, 15.1), 152.2 (ddd, J = 249.7,
9.4, 2.3)
. Anal. Calcd for (C
6H
2OBF
3)
3:
C, 45.64; H, 1.28. Found: C, 45.32; H, 1.64 (microanalysis was carried out on a sample
that was dried at 60-80°C under high vacuum for 2 hr).
7.
The submitters used a
10-mL, pressure-equalized addition
funnel [containing a cotton plug,
calcium
hydride (ca. 3 g, lumps), and sea sand (ca. 1 g)]
in place of the
Soxhlet extractor. The submitters employed
calcium hydride (ca. 1-10 mm, No. 068-34)
purchased from Nacalai Tesque, Inc.
Alternatively,
4Å molecular sieves can be used in place of
calcium
hydride
.
8.
4-Phenylbutyric acid
(>99%) was purchased from Tokyo Kasei Kogyo Co., Ltd.
or Aldrich Chemical Company, Inc.
, and used without
further purification.
9.
The submitters purchased
benzylamine
(99%) from Nacalai Tesque, Inc.
and used it without further purification. The checkers obtained the
amine
from Aldrich Chemical Company, Inc.
, and distilled
it from
calcium hydride
.
10.
The submitters report obtaining a two-phase mixture upon cooling
and adding
dichloromethane
.
The organic layer was separated and the aqueous layer was extracted with
dichloromethane (80 mL),
and treated with
1.0 M aqueous sodium hydroxide
solution (100 mL). The combined organic layers were then
washed with HCl and brine as described in the procedure.
11.
Chromatography was performed using a 3-cm × 10-cm column packed
with
35 g of silica gel (230-400 mesh, No. 9385)
purchased from E. Merck Co.
The product was eluted
with
100 mL of 25% and
200 mL of 33%
ethyl acetate-hexane
.
The checkers observed that
N-benzyl-4-phenylbutyramide
has a TLC R
f value of 0.4 in
50%
ethyl acetate-hexane
.
12.
N-Benzyl-4-phenylbutyramide
has the following physical properties:
mp 79-80°C;
IR (CH
2Cl
2) cm
−1:
1671, 1510, 1460, 1271, 1260
;
1H NMR (300 MHz,
CDCl
3) δ: 1.96-2.06 (m, 2 H), 2.22 (t, 2 H, J
= 6.9), 2.67 (t, 2 H, J = 8.0), 4.44 (d, 2 H, J = 6.0),
5.62 (br, 1 H), 7.15-7.34 (m, 10 H)
;
13C NMR (75.4 MHz, CD
3OD)
δ: 28.8, 36.2, 36.4, 44.0,
126.9, 128.1, 128.5, 129.3, 129.4,
129.5, 140.0, 142.8, 175.6 (C=O)
.
Anal. Calcd for C
17H
19NO: C, 80.60; H, 7.56; N, 5.53. Found:
C, 80.34; H. 7.67; N, 5.58.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
There are several different routes to carboxamides.
3 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.
4 Arylboronic acids with electron-withdrawing
groups such as
(3,4,5-trifluorophenyl)boronic
acid
act as highly efficient catalysts in the amidation between
carboxylic acids and amines.
5
(3-Nitrophenyl)boronic
acid
and
[3,5-bis(trifluoromethyl)phenyl]boronic
acid
are also effective amidation catalysts and commercially
available.
Acyloxyboron intermediates generated from carboxylic acids and
boron
reagents such as BR
3 (R=C
8H
17, OMe),
6a
CIB(OMe)
2,
6a HB(OR)
2
(R=i-Pr, t-Am),
6a BH
3·Et
3N
(R=Me, Bu),
6b BF
3·Et
2O
6c and
catecholborane
6d react with amines to furnish amides in moderate to
good yield, but only in uniformly stoichiometric reactions. In these amidations,
boron
reagents transform into inactive
boron species after the reaction
of acyloxyboron derivatives and amines. However, arylboronic acids with electron-withdrawing
substituents at the aryl group can be used to circumvent these difficulties, since
they are water-, acid-, and base-tolerant Lewis acids that can generate acyloxyboron
species. Their strong Lewis acidity enhances the rate of the generation of acryloxyboron
species and their reactivity with amines.
To indicate the generality and scope of
(3,4,5-trifluorophenyl)boronic
acid
-catalyzed amidation, the reaction is examined with various
structurally diverse carboxylic acids and primary or secondary amines (Table I). In
most cases, the reactions proceed cleanly, and the desired carboxylic amides are obtained
in high yields. The catalyst is useful for effecting reaction not only of primary
but also of secondary amines with various carboxylic acids. Sterically-hindered
1-adamantanecarboxylic acid
is easily
amidated at reflux in
mesitylene
.
Aromatic substrates such as anilines and
benzoic
acid
also react well under similar conditions. The catalytic
amidation of optically active aliphatic α-hydroxycarboxylic acids with
benzylamine
proceeds with no measurable
loss (<2%) of enantiomeric purity under conditions of reflux in toluene. However,
slight racemization is observed in the case of (S)-(+)-mandelic acid.
In addition, lactams can be prepared by the present technique under heterogeneous
conditions although most amino acids are barely soluble in nonaqueous solvents (Table
II). Interestingly, (S)-(−)-proline selectively gives the
cyclic dimer with no measurable loss of enantiomeric purity.
The proposed mechanism of the boron-catalyzed amidation is depicted in the Figure.
5 It has been ascertained by
1H NMR analysis that monoacyloxyboronic
acid
1 is produced by heating the 2:1 mixture of
4-phenylbutyric
acid
and
[3,5-bis(trifluoromethyl)phenyl]boronic
acid
in
toluene
under reflux with removal of water. The corresponding diacyloxyboron derivative is
not observed at all. When 1 equiv of
benzylamine
is added to a solution of
1 in
toluene
,
the amidation proceeds even at room temperature, but the reaction stops before 50%
conversion because of hydrolysis of
1. These experimental results suggest that
the rate-determining step is the generation of
1.
Figure. Proposed Catalytic Cycle
Table 1
Table II
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(3,4,5-Trifluorophenyl)boronic acid:
Boronic
acid, (3,4,5-trifluorophenyl)- (13); (143418-49-9)
N-Benzyl-4-phenylbutyramide:
Benzenebutanamide,
N-(phenylmethyl)- (13); (179923-27-4)
Magnesium (8,9); (7439-95-4)
Iodine (8,9); (7553-56-2)
1-Bromo-3,4,5-trifluorobenzene:
Benzene,
5-bromo-1,2,3-trifluoro- (13); (138526-69-9)
Trimethyl borate:
Boric acid, trimethyl ester
(8,9); (121-43-7)
4-Phenylbutyric acid:
Butyric acid, 4-phenyl-
(8);
Benzenebutanoic acid (9); (1821-12-1)
Benzylamine (8);
Benzenemethanamine
(9); (100-46-9)
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