Direct amide synthesis from equimolar amounts of carboxylic acid and amine catalyzed by mesoporous silica SBA-15

Article abstract of DOI:10.1055/s-0034-1379966

Direct amide synthesis from equimolar amounts of carboxylic acid and amine using mesoporous silica as a versatile heterogeneous catalyst is reported.

Full text of DOI:10.1055/s-0034-1379966

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 769–776
paper
769
M. Tamura et al.
Paper
Synthesis
Direct Amide Synthesis from Equimolar Amounts of Carboxylic
Acid and Amine Catalyzed by Mesoporous Silica SBA-15
Mizuki Tamura
Daisuke Murase
Kenichi Komura*
Department of Materials Science and Technology, Faculty of
Engineering, Gifu University, Yanagido 1-1, Gifu City, 501-1193, Japan
kkomura@gifu-u.ac.jp
Received: 15.10.2014
Accepted after revision: 09.12.2014
Published online: 26.01.2015
also been revealed. Recently the application of Ph3P as well
as and boronic acid anchored onto the inorganic support
catalysts has been reported.8
DOI: 10.1055/s-0034-1379966; Art ID: ss-2014-f0617-op
Our group is interested in condensation reactions such
as esterification and amidation using an equimolar
amounts of substrates and has reported that multi-valent
metal salt such as FeCl3·6H2O is a highly active homoge-
neous catalyst for producing esters or amides in good to ex-
cellent yields.3d,9 In addition, we have recently reported the
direct amidation of fatty acids with long-chain amines over
mesoporous silica MCM-41 catalyst and claimed that only
siliceous material with mesoporosity exhibited the highest
catalytic activity to afford the amides in excellent yields,
and that the catalyst can be easily separated from the reac-
tion medium and reused without loss of its catalytic activi-
ty.10 The catalytic activity of mesoporous silica catalyst re-
sults from the surface silanol (SiOH), which has an ex-
tremely weak acidity. It is interesting that uniformed pore
structure and proper pore size trigger the sufficient catalyt-
ic performance; however, detailed reasons as to why ex-
tremely weak silanol should act as an acid catalyst is un-
clear.
Abstract Direct amide synthesis from equimolar amounts of carboxyl-
ic acid and amine using mesoporous silica as a versatile heterogeneous
catalyst is reported.
Key words amides, amines, carboxylic acids, heterogeneous catalysis,
green chemistry
Amidation reaction of carboxylic acids with amines is
one of the pivotal tools in organic synthesis, providing am-
ides as valuable chemicals, which are found in the fields of
life science, medicines, and engineering polymers, etc. Con-
ventionally, the activation of a carboxylic acid by adding
hazardous or toxic reagents such as SOCl2 or N,N′-dicyclo-
hexylcarbodiimide (DCC) has been required to achieve suf-
ficient formation of amides, and this process always suffers
from huge waste production.1,2 However, with wide-
spreading demands for environmental benign chemical
processes, a sophisticated reaction system has been de-
sired; that is, the direct amidation reaction – the amide for-
mation utilizing an equimolar amount of a carboxylic acid
and an amine in the presence of catalytic amount of an acti-
vator.3 Of course, the utilization of homogeneous activators
seems to be attractive; however, there are still drawbacks
such as recovery and reusability after the reaction. Thus,
the development for heterogeneous catalysts is a challeng-
ing task, and some potential reports have appeared. For ex-
ample, the polymer-supported boronopyridinium ion as an
organic heterogeneous catalyst has been reported by
Ishihara and Yamamoto et al.3g,4 The use of inorganic cata-
lysts, for example, activated silica gel,5 sulfated tungstate,6
and molecular sieves (3Å MS)7 in the amidation process has
Here, we report the heterogeneous direct amidation
over mesoporous silica SBA-15 catalyst using lower molec-
ular weight substrates by varying combinations of acids and
amines as illustrated in Scheme 1 to disclose the substrates
scope of limitations in this reaction system over meso-
porous silica catalyst.
O
mesoporous silica
R3
R1 COOH +
HNR2R3
R1
N
R2
solvent, reflux
1
2
1.0 equiv
1.0 equiv
3
Scheme 1 Direct amidation reaction of an equimolar amount of car-
boxylic acid and amine over mesoporous silica SBA-15 catalyst
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Table 1 Results of Direct Amidation of Benzoic Acid (1a) with Amines
larger pore size than that of MCM-41. Mesoporous silica
SBA-15 was used in our amidation reaction as the catalyst,
which was prepared according to the reported procedure
and characterized by powder-XRD, nitrogen isotherm, and
TG-DTA analyses.11
in the Presence of SBA-15 Catalysta
O
R2
COOH
SBA-15
HNR1R2
N
+
Table 1 shows the results of the direct amidation of ben-
zoic acid (1a) with various amines such as aniline (2a), ben-
zylamine (2b), n-hexylamine (2c), and morpholine (2d).
First, the reaction of 1a with 2a was demonstrated as a
model reaction. In the absence of the SBA-15 catalyst, no
amide formation was observed; however, the catalyst gave
the amide 3aa in a low 26% yield (Table 1, entry 1). Our re-
cent finding revealed that the reaction is strongly depen-
dent on the reaction temperature. Therefore, use of higher
boiling point aromatic solvent such as m-xylene and mesi-
tylene was examined.3d,9g A two-fold enhanced yield of 3aa
in 50% was obtained under refluxing m-xylene; unfortu-
nately, further increase of the temperature did not afford
3aa in sufficiently excellent yield. Aliphatic amines with
higher basicity such as 2b and 2c gave quantitative yields of
amides 2ab and 2ac by conducting the reaction for 8 hours
(entries 2 and 3). However, reaction of secondary amine 2d
showed only moderate amide formation due to its steric
hindrance. Nevertheless, the reaction of the sterically hin-
dered secondary amine (N,N′-dihexylamine) with 1a gave
toluene, reflux
R1
1a
3aa–ad
2a–d
Entry
1
Amine
Product
R1, R2
H, Ph
Yield (%)b
2a
3aa
26 (0)c
50d
58e
2f
3
2b
2c
2d
3ab
3ac
3ad
H, Bn
>99
>99
78
H, (CH2)5Me
–(CH2)2O(CH2)2–
4f
a Reactions were performed by using benzoic acid (1a; 3.0 mmol) and
amine (3.0 mmol) in anhydrous toluene (15mL) in the presence of the cata-
lyst (0.5 g) under reflux for 24 h.
b Isolated yield.
c The yield obtained in the absence of catalyst is indicated between paren-
theses.
d Under m-xylene reflux.
e Under mesitylene reflux.
f Reaction time: 8 h.
Mesoporous silica SBA-15 is also a siliceous material
having the same structural group (p6mm) as MCM-41;
however, SBA-15 has higher hydrothermal stability and
Table 2 Results of Direct Amidation Reaction of 1b–d and 2a–d over SBA-15 Catalysta
O
R3
COOH
SBA-15
HNR2R3
+
N
toluene, reflux
R2
R1
R1
1b,c
2a–d
Amine
3ba–dd
Entry
Acid
R1
4-MeO
R2
R3
Product
Yield (%)b
1
2c
3c
4
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
H
Ph
Bn
3ba
3bb
3bc
3bd
3ca
3cb
3cc
24
63
75
76
56
87
62
88
24
78
58
64
4-MeO
4-MeO
4-MeO
4-F
H
H
(CH2)5Me
–(CH2)2O(CH2)2–
5
H
Ph
6
4-F
H
Bn
7
4-F
H
(CH2)5Me
8
4-F
–(CH2)2O(CH2)2–
3cd
3da
3db
3dc
3dd
9
4-O2N
4-O2N
4-O2N
4-O2N
H
Ph
10
11
12
H
Bn
H
(CH2)5Me
–(CH2)2O(CH2)2–
a Reactions were performed by using benzoic acid (1a; 3.0 mmol) and amine (3.0 mmol) in anhydrous toluene (15mL) in the presence of the catalyst (0.5 g)
under reflux for 24 h.
b Isolated yield.
c Reaction time: 8 h.
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the corresponding amide in 15% by refluxing in xylene for
24 hours (data not shown). This result is similar to our orig-
inal report.10
The direct amidation of acetic acid (1h) with hexyl-
amine (2c) for 8 hours proceeded well to afford 5hc in
quantitative yield (>99%, Scheme 2, eq. 1). It is interesting to
note that the reaction of acetic anhydride with a two-fold
amount of 2c for 8 hours also gave the amide 5hc in excel-
lent yield. This indicates that the excess hexylamine (2c) re-
acted with acetic anhydride to afford 2hc via a noncatalytic
manner at the first step, and then, the amidation of acetic
acid (1h) formed in this process reacted with 2c in the pres-
ence of SBA-15 catalyst. These results obviously imply that
mesoporous silica is a versatile catalyst for acetylation reac-
tion of amine, which is often utilized in the acetyl protec-
tion of, for example, amino acids. This part of research topic
is in progress and will be reported in near future.
Table 2 shows the results of direct amidation of three
aromatic carboxylic acids bearing selected substituents at
para-position (MeO, 1b; F, 1c; and NO2, 1d) and four amines
2a–d over SBA-15 catalyst. All yields are isolated yields af-
ter column chromatography. The yields from the less reac-
tive aniline 2a are low as in the cases of 3ba (24%) and 3da
(24%); however, the use of 1c with a highly electron-with-
drawing group fluorine exhibited an increasing yield of the
amide 3ca up to 56% (entries 1, 5, and 9). Other results by
varying the combination of aromatic acids and amines are
found to be moderate to good with respect to the yields of
the corresponding amides. These results evidently demon-
strate the effectiveness of mesoporous silica catalyst in a
heterogeneous amidation reaction.
Interestingly, 3-phenylpropionic acid (1g), a more flexi-
ble aliphatic carboxylic acid, was used as a substrate in this
reaction with amines 2a–g to furnish the corresponding
amides 4ga–gg in quantitative yields within 8 hours (Table
3). Further, aromatic amines 2e–g possessing either an elec-
tron-donating group and or an electron-withdrawing group
at the para-position afforded the corresponding amides
4ge–gg in excellent yields (GC) irrespective of their elec-
tronic environment associated with nucleophilicity (Table
3, entries 5–7). Thus, aliphatic carboxylic acids seem to be
more favorable substrates for this reaction system. This is
because the less steric hindrance of 1g enables for sufficient
acceptance of nucleophilic attack of amine.
O
O
SBA-15
N (CH2)5Me
2c
1.0 equiv
+
(1)
(2)
OH
toluene, reflux, 8 h
H
1h
1.0 equiv
5hc >99%
O
O
SBA-15
+
2c
5hc
O
toluene, reflux, 8 h
1.0 equiv 2.0 equiv
>99%
(based on 2c)
Scheme 2 Direct amidation of acetic acid (1h) with 2c, and acetic an-
hydride with 2c over SBA-15 catalyst
With an efficient heterogeneous amidation reaction cat-
alyzed by mesoporous silica SBA-15 in hand, the reaction
was applied to valuable and practical chemical synthesis.
Procainamide (6) is one of the widely used important phar-
maceuticals as arrhythmic agent and conventionally syn-
thesized via acid chloride of 1d and amine 2h accompanied
by hazardous waste of gaseous HCl. Thus, the reaction must
require the neutralization by base, which then produces a
huge amount of salt and/or polluted water as a waste.
Table 3 Results of Direct Amidation of 3-Phenylpropionic Acid (1g)
with Amine in the Presence of SBA-15 Catalysta
O
SBA-15
R2
HNR1R2
COOH
+
Ph
N
R1
Ph
toluene, reflux
1g
2a–g
The direct amidation reaction of 1d with N,N-diethyl-
ethylenediamine (2h) over SBA-15 catalyst is shown in
Scheme 3. The corresponding amide 6dh, an important in-
termediate of procainamide, can be obtained in 95% isolat-
ed yield after 24 hours, and this is subjected to reduction to
afford procainamide 6 in 95% yield. The reduction step by
Sn catalyst is also a heterogeneous reaction medium, thus
our new heterogeneous synthetic strategy allows to obtain
the procainamide from 1d in two steps in 90% total yield in
heterogeneous manners, and the calculated environmen-
tal-factor (E-factor) value and atom economy are found to
be 0.07 and 94%, respectively12 (E-factor and atom economy
of conventional method via acid chloride activation are 0.80
and 54%). In addition, the reusability of the catalyst reveals
that the activity did not decline and the yields of 6dh were
>99% (GC) until the 5th recycle. It obviously suggests that
this synthetic method should be an alternative method for
practical production of procainamide (6) as an environ-
mentally benign process. This result encouraged us to ex-
4ga–gg
Entry
Amine
R1
R2
Product
Yield (%)b
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
H
H
H
Ph
4ga
4gb
4gc
4gd
4ge
4gf
>99
>99
>99
>99
>99
>99
>99
Bn
(CH2)5Me
–(CH2)2O(CH2)2–
H
H
H
4-MeOC6H4
4-Me2NC6H4
4-FC6H4
2g
4gg
a Reactions were performed by using benzoic acid (1a; 3.0 mmol) and
amine (3.0 mmol) in anhydrous toluene (15mL) in the presence of the cat-
alyst (0.5 g) under reflux for 8 h.
b Yield was determined by GC by comparing with an authentic sample.
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amine the direct amidation reactions of 2h with aromatic
acids 1a–c, 1e, 1f, and 1i–1k, which can produce the pro-
cainamide derivatives. In the absence of the catalyst, the re-
action of benzoic acid (1a) and 2h allowed the formation of
the product only in poor yield (23%). However, the SBA-15
catalyst sufficiently promoted the reaction in quantitative
yield (96%, Table 4, entry 1). Further, the reactions utilizing
2h for synthesizing the procainamide derivatives gave the
corresponding amides in good to excellent yields (entries 2
to 5). The effect of the isomers on this reaction were per-
formed by using toluic acids (ortho, 1i; meta, 1j; para, 1k);
of note are the excellent yields of 6jh and 6kh in 89% and
88% (entries 7 and 8). However, the reaction of 1i having a
steric methyl group at the ortho-position gave only a mod-
erate yield of the corresponding 6ih due to the effect of ste-
ric hindrance via promotion of catalysis at the surface.
Table 4 Results of Direct Amidation of Various Carboxylic Acids with
N,N-Diethylethylenediamine (2h) in the Presence of SBA-15 Catalysta
O
COOH
NEt2
SBA-15
N
+ 2h
H
xylene, reflux
24 h
R
R
1a–c,e,f,i–k
Entry
Acid
Product
R
Yield (%)b
1
1a
1b
1c
1e
1f
6ah
6bh
6ch
6eh
6fh
6ih
H
96 (23)c
88
2
4-MeO
4-F
3d
4d
5d
6d
6d
6d
99
4-F3C
4-NC
2-Me
3-Me
4-Me
90
77
1i
65
O
1j
6jh
89
NEt2
SBA-15
toluene, reflux, 24 h
N
1k
6kh
88
1d + 2h
a Reactions were performed by using acid 1 (3.0 mmol) and amine 2h (3.0
mmol) in anhydrous m-xylene (15 mL) in the presence of the catalyst (0.10
g) under reflux for 24 h.
H
O2N
6dh: 95% (>99%, 1st)
(>99%, 2nd
)
b Isolated yield.
(>99%, 3rd
)
O
c The yield obtained in the absence of the catalyst SBA-15 is given in paren-
theses.
(>99%, 4th)
(>99%, 5th)
NEt2
d Reaction was performed under refluxing toluene.
Sn, HCl (aq)
N
H
60 °C, 10 min
95%
H2N
6
procainamide
In conclusion, the heterogeneous direct amidation reac-
tions of various combinations of carboxylic acids and
amines were examined over mesoporous silica SBA-15 cat-
alyst. The reaction proceeds in moderate to excellent yields,
except for aniline, affording the corresponding amides over
mesoporous silica SBA-15 catalyst. By demonstrating the
synthesis of procainamide and its derivatives, the efficient
availability and potentials as a green chemical process are
obviously suggested. Mesoporous silica catalyst is a sili-
ceous material having recyclability and reusability, thus it
can be an alternative synthetic strategy for amide produc-
tion with environmentally benign chemistry. Further inves-
tigations are ongoing in our laboratory.
Scheme 3 Preparation of procainamide intermediate (6dh) by the di-
rect amidation 1d with 2h over SBA-15 catalyst, and the preparation of
procainamide (6). Numbers in parentheses are the GC yields of 6dh in
recycled experiments.
The amidation of the selected N-Boc (tert-butoxycar-
bonyl)-protected amino acid 1l with 2b was examined and
the result is shown in Scheme 4. The benzyl esters of N-
Boc-protected amino acids are versatile intermediates, be-
cause the benzyl moiety and Boc protecting group allow for
facile deprotection to the corresponding acid or amine for
connecting further molecular units. The reaction of N-Boc-
L-Ala-OH with 2b over SBA-15 gave the corresponding am-
ide 7lb in 87% isolated yield without formation of by-prod-
ucts (i.e., deprotected compounds), indicating that meso-
porous silica catalyst is tolerant for substrates having acid
sensitive moiety. Further investigation on valuable amino
acid derivatives by this system are in progress in our labora-
tory.
Powder X-ray diffraction (XRD) was measured by a Shimadzu XRD-
6000 diffractometer with Kα radiation (α = 1.5418 Å). Nitrogen ad-
sorption isotherm measurements were carried out on a Belsorp 28SA
apparatus (Bel, Japan). Thermal gravimetric (TGA) and differential
thermal (DTA) analyses were carried out by using a Shimadzu DTG-50
analyzer at a ramping rate of 10 K/min under an air stream. 1H and 13
C
NMR spectra were recorded at 500 and 125 MHz on a JEOL ECA-500
NMR spectrometer. FT-IR spectra were recorded on PerkinElmer
Spectrum 100 by KBr technique for solids and neat for liquid com-
pounds. All reagents are commercially available and used without pu-
rification.
O
SBA-15
toluene, reflux, 24 h
N
1l
+
2b
H
NHBoc
7lb (87%)
Scheme 4 Direct amidation of N-Boc-Ala-OH (1l) with 2b over SBA-15
catalyst
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Direct Amide Synthesis from Carboxylic Acids and Amines Cata-
lyzed by Mesoporous Silica SBA-15; General Procedure
IR (KBr): 3335, 1635, 1542, 1226, 1159 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 3.83 (3 H, s), 7.04–7.08 (3 H, m),
7.32 (2 H, t, J = 7.8 Hz), 7.75 (2 H, d, J = 7.5 Hz), 7.95 (2 H, d, J = 9.2 Hz).
13C NMR (125 MHz, DMSO-d6): δ = 55.4, 113.6, 120.3, 123.4, 127.0,
128.5, 129.6, 139.3, 161.9, 164.9.
The amidation was carried out in a 50 mL single-necked round-bot-
tomed flask equipped with a Teflon-coated magnetic stirring bar and
a Dean–Stark apparatus. Unless otherwise noted, all reactions were
performed by using the carboxylic acid 1 (3.0 mmol) and amine 2 (3.0
mmol) in anhydrous toluene (15 mL) in the presence of catalyst (0.5
g) under reflux conditions for the prescribed reaction period (Tables
1–4). After cooling to r.t., the suspended catalyst was removed by fil-
tration and rinsed with CHCl3 (10 mL). The collected small amount of
an aliquot filtrate was then analyzed by gas chromatography to deter-
mine the yield of amide (Shimadzu 18A, column: Ultra ALLOY+-65) by
comparing with an authentic sample. All reactions produce the corre-
sponding amide without any by-product and residual substrate. The
remaining filtrate was purified by column chromatography to give
the pure product. The filtered catalyst was subjected to calcination
under air flow (10 mL/min) at 550 °C for 5 h to evacuate the occluded
organic residue.10
N-Benzyl-4-methoxybenzamide (3bb)
[CAS Reg. No.: 7465-87-4]
Yield: 450 mg (63%); white solid; mp 124–125 °C.
IR (KBr): 3266, 1632, 1559, 1254, 1180 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.82 (3 H, s), 4.60 (2 H, d, J = 5.7 Hz),
6.53 (1 H, br s), 6.89 (2 H, d, J = 9.2 Hz), 7.26–7.33 (5 H, m), 7.75 (2 H,
d, J = 8.6 Hz).
13C NMR (125 MHz, CDCl3): δ = 44.1, 55.5, 113.8, 126.8, 127.6, 128.0,
128.8, 128.9, 138.6, 162.3, 167.0.
N-Hexyl-4-methoxybenzamide (3bc)
[CAS Reg. No.: 330467-48-6]
N-Phenylbenzamide (3aa)
[CAS Reg. No.: 93-98-1]
Yield: 525 mg (75%); white solid; mp 59–60 °C.
IR (KBr): 3330, 1633, 1533, 1253, 1107 cm–1
1H NMR (500 MHz, CDCl3): δ = 0.89 (3 H, t, J = 6.9 Hz), 1.30–1.37 (6 H,
m), 1.59 (2 H, q, J = 7.4 Hz), 3.42 (2 H, q, J = 6.9 Hz), 3.84 (3 H, s), 6.21
(1 H, br s), 6.90 (2 H, d, J = 8.6 Hz), 7.74 (2 H, d, J = 9.2 Hz).
Yield: 155 mg (26%); white solid; mp 161–163 °C.
.
1H NMR (500 MHz, DMSO-d6): δ = 7.10 (1 H, t, J = 7.5 Hz), 7.35 (2 H, t,
J = 8.0 Hz), 7.53 (2 H, t, J = 7.5 Hz), 7.59 (1 H, t, J = 7.2 Hz), 7.79 (2 H, d,
J = 8.0 Hz), 7.96 (2 H, d, J = 6.9 Hz), 10.23 (1 H, br s).
13C NMR (125 MHz, DMSO-d6): δ = 120.3, 123.6, 127.6, 128.3, 128.5,
131.5, 135.0, 139.1, 165.5.
13C NMR (125 MHz, CDCl3): δ = 11.4, 22.7, 26.8, 29.8, 31.6, 40.2, 55.5,
113.8, 127.3, 128.7, 162.1, 167.1.
N-Benzylbenzamide (3ab)
N-Morpholinyl-4-methoxybenzamide (3bd)
[CAS Reg. No.: 7504-58-7]
[CAS Reg. No.: 1485-70-7]
Yield: 630 mg (>99%); white solid; mp 104–106 °C.
Yield: 500 mg (76%); yellow liquid.
1H NMR (500 MHz, CDCl3): δ = 4.63 (2 H, d, J = 5.7 Hz), 6.55 (1 H, br s),
7.28–7.34 (5 H, m), 7.40 (2 H, t, J = 7.5 Hz), 7.48 (2 H, t, J = 7.5 Hz), 7.78
(2 H, d, J = 8.1 Hz).
13C NMR (125 MHz, CDCl3): δ = 44.2, 127.1, 127.7, 128.0, 128.7, 128.9,
131.7, 134.5, 138.3, 167.5.
IR (neat): 1633, 1114 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.69 (8 H, br s), 3.83 (3 H, s), 6.92 (2 H,
d, J = 9.2 Hz), 7.39 (2 H, d, J = 8.6 Hz).
13C NMR (125 MHz, CDCl3): δ = 31.0, 55.5, 67.0, 113.9, 127.4, 129.3,
161.0, 170.5.
N-Hexylbenzamide (3ac)
N-Phenyl-4-fluorobenzamide (3ca)
[CAS Reg. No.: 366-63-2]
[CAS Reg. No.: 4773-75-5]
Yield: 610 mg (>99%); yellow liquid.
Yield: 360 mg (56%); white solid; mp 157–159 °C.
IR (KBr): 3351, 1655, 1531, 1227 cm–1
1H NMR (500 MHz, DMSO-d6): δ = 7.09 (1 H, t, J = 7.5 Hz), 7.35 (4 H,
m), 7.75 (2 H, d, J = 8.6 Hz), 8.01–8.04 (2 H, m), 10.3 (1 H, br s).
1H NMR (500 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.9 Hz), 1.28–1.37 (6 H,
m), 1.60 (2 H, quint, J = 7.3 Hz), 3.42 (2 H, q, J = 6.9 Hz), 6.44 (1 H, br s),
7.39 (2 H, t, J = 7.4 Hz), 7.47 (1 H, t, J = 6.5 Hz), 7.77 (2 H, d, J = 7.5 Hz).
13C NMR (125 MHz, CDCl3): δ = 14.1, 22.6, 26.8, 29.7, 31.6, 40.2, 127.0,
128.6, 131.3, 135.0, 167.7.
.
13C NMR (125 MHz, DMSO-d6): δ = 115.3 (d, JC,F = 21.5 Hz), 120.4,
2
3
1
123.7, 128.6, 130.4 (d, JC,F = 8.4 Hz), 131.4, 139.0, 164.0 (d, JC,F
=
246.8 Hz).
N-Morpholinylbenzamide (3ad)
[CAS Reg. No.: 1468-28-6]
N-Benzyl-4-fluorobenzamide (3cb)
[CAS Reg. No.: 725-38-2]
Yield: 550 mg (78%); yellow liquid.
1H NMR (500 MHz, CDCl3): δ = 3.45–3.75 (8 H, br), 7.39–7.42 (5 H, m).
13C NMR (125 MHz, CDCl3): δ = 42.6, 48.3, 66.9, 127.1, 128.6, 130.0,
135.4, 170.5.
Yield: 595 mg (87%); white solid; mp 144–145 °C.
IR (KBr): 3324, 1642, 1553, 1255 cm–1
1H NMR (500 MHz, CDCl3): δ = 4.61 (2 H, d, J = 5.9 Hz), 6.52 (1 H, br s),
.
7.07–7.10 (2 H, m), 7.29–7.36 (5 H, m), 7.78–7.81 (2 H, m).
N-Phenyl-4-methoxybenzamide (3ba)
[CAS Reg. No.: 7465-88-5]
2
13C NMR (125 MHz, CDCl3): δ = 44.3, 115.7 (d, JC−F = 21.5 Hz), 127.8,
3
1
128.0, 128.9, 129.4 (d, JC−F = 8.4 Hz), 130.6, 138.2, 164.9 (d, JC−F
=
Yield: 160 mg (24%); white solid; mp 172–173 °C.
250.4 Hz), 166.4.
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N-Hexyl-4-fluorobenzamide (3cc)
[CAS Reg. No.: 234449-90-2]
1H NMR (500 MHz, DMSO-d6): δ = 3.26 (2 H, br s), 3.53 (2 H, br s),
3.64–3.65 (4 H, br), 7.68 (2 H, d, J = 8.6 Hz), 8.27 (2 H, d, J = 8.6 Hz).
13C NMR (125 MHz, DMSO-d6): δ = 42.0, 47.4, 65.9, 123.8, 141.9,
Yield: 418 mg (62%); white solid; mp 43–44 °C.
IR (KBr): 3332, 1635, 1535, 1245 cm–1
147.8, 167.2.
.
1H NMR (500 MHz, CDCl3): δ = 0.89 (3 H, t, J = 7.2 Hz), 1.29–1.37 (6 H,
m), 1.60 (2 H, quint, J = 7.5 Hz), 3.42 (2 H, q, J = 6.7 Hz), 6.27 (1 H, br s),
7.07–7.10 (2 H, m), 7.76–7.79 (2 H, m).
13C NMR (125 MHz, CDCl3): δ = 14.1, 22.7, 26.8, 29.8, 31.6, 40.3, 115.6
(d, 2JC,F = 22.7 Hz), 129.3 (d, 3JC,F = 8.4 Hz), 164.7 (d, 1JC,F = 249.2 Hz).
N-Phenyl-3-phenylpropanamide (4ga)
[CAS Reg. No.: 3271-81-6]
Yield: 580 mg (86%); white solid; mp 97–98 °C.
1H NMR (500 MHz, DMSO-d6): δ = 2.63 (2 H, t, J = 7.7 Hz), 2.92 (2 H, t,
J = 7.7 Hz), 7.02 (1 H, t, J = 7.2 Hz), 7.18 (1 H, t, J = 6.9 Hz), 7.25–7.30 (6
H, m), 7.58 (2 H, d, J = 8.0 Hz), 9.89 (1 H, br s).
13C NMR (125 MHz, DMSO-d6): δ = 30.8, 37.9, 119.0, 123.0, 125.9,
128.2, 128.3, 128.6, 139.2, 141.2, 170.3.
N-Morpholinyl-4-fluorobenzamide (3cd)
[CAS Reg. No.: 1978-65-0]
Yield: 555 mg (88%); yellow liquid.
IR (neat): 1634 cm–1
1H NMR (500 MHz, CDCl3): δ = 3.50–3.71 (8 H, br), 7.09–7.12 (2 H, m),
7.41–7.44 (2 H, m).
13C NMR (125 MHz, CDCl3): δ = 67.0, 115.8 (d, 2JC,F = 21.5 Hz), 129.6 (d,
3JC,F = 8.4 Hz), 131.4, 163.6 (d, 1JC,F = 248.0 Hz), 169.6.
.
N-Βenzyl-3-phenylpropanamide (4gb)
[CAS Reg. No.: 10264-10-5]
Yield: 600 mg (83%); white solid; mp 80–82 °C.
1H NMR (500 MHz, CDCl3): δ = 2.48 (2 H, t, J = 7.5 Hz), 2.96 (2 H, t, J =
7.7 Hz), 4.35 (2 H, d, J = 5.7 Hz), 5.88 (1 H, br s), 7.14–7.28 (10 H, m).
13C NMR (125 MHz, CDCl3): δ = 31.8, 38.5, 43.6, 126.3, 127.5, 127.8,
128.5, 128.6, 128.7, 138.3, 140.8, 172.1.
N-Phenyl-4-nitrobenzamide (3da)
[CAS Reg. No.: 3460-11-5]
Yield: 177 mg (24%); yellow solid; mp 218–219 °C.
N-Hexyl-3-phenylpropanamide (4gc)
[CAS Reg. No.: 10264-22-9]
IR (KBr): 3322, 1652, 1533, 1519, 1348, 1264 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 7.13 (1 H, t, J = 7.5 Hz), 7.37 (2 H, t,
J = 8.0 Hz), 7.77 (2 H, d, J = 7.5 Hz), 8.17 (2 H, d, J = 8.6 Hz), 8.36 (2 H, d,
J = 8.6 Hz), 10.6 (1 H, br s).
13C NMR (125 MHz, DMSO-d6): δ = 120.5, 123.6, 124.2, 128.7, 129.2,
138.7, 140.6, 149.1, 163.9.
Yield: 550 mg (80%); yellow liquid.
1H NMR (500 MHz, CDCl3): δ = 0.87 (3 H, t, J = 6.9 Hz), 1.22–1.29 (6 H,
m), 1.40 (2 H, quint, J = 7.2 Hz), 2.46 (2 H, t, J = 7.7 Hz), 2.96 (2 H, t, J =
7.7 Hz), 3.19 (2 H, q, J = 6.9 Hz), 5.46 (1 H, br s), 7.18–7.29 (5 H, m).
13C NMR (125 MHz, CDCl3): δ = 14.1, 22.6, 26.6, 29.6, 31.6, 31.9, 38.6,
39.7, 126.3, 128.4, 128.6, 141.0, 172.2.
N-Benzyl-4-nitrobenzamide (3db)
[CAS Reg. No.: 2585-26-4]
N-Morpholinyl-3-phenylpropanamide (4gd)
[CAS Reg. No.: 17077-46-2]
Yield: 600 mg (78%); white solid; mp 141–142 °C.
IR (KBr): 3309, 1640, 1537, 1514, 1356, 1278 cm–1
1H NMR (500 MHz, DMSO-d6): δ = 4.50 (2 H, d, J = 6.3 Hz), 7.23–7.27
(1 H, m), 7.33 (4 H, d, J = 4.6 Hz), 8.11 (2 H, d, J = 9.2 Hz), 8.32 (2 H, d,
J = 8.6 Hz), 9.38 (1 H, br t, J = 5.7 Hz).
.
Yield: 440 mg (80%); yellow liquid.
1H NMR (500 MHz, CDCl3): δ = 2.61 (2 H, t, J = 8.0 Hz), 2.98 (2 H, t, J =
7.7 Hz), 3.34 (2 H, t, J = 4.9 Hz), 3.50 (2 H, t, J = 4.9 Hz), 3.61 (4 H, s),
7.19–7.30 (5 H, m).
13C NMR (125 MHz, CDCl3): δ = 31.5, 34.8, 42.0, 46.0, 66.5, 66.9, 126.3,
128.5, 128.6, 141.1, 170.9.
13C NMR (125 MHz, DMSO-d6): δ = 42.8, 123.6, 126.9, 127.3, 128.4,
128.8, 139.1, 139.9, 149.0, 164.6.
N-Hexyl-4-nitrobenzamide (3dc)
[CAS Reg. No.: 89399-21-3]
N-(4-Methoxyphenyl)-3-phenylpropanamide (4ge)
[CAS Reg. No.: 97754-31-9]
Yield: 430 mg (58%); white solid; mp 80–81 °C.
IR (KBr): 3281, 1631, 1537, 1515, 1347, 1283 cm–1
1H NMR (500 MHz, DMSO-d6): δ = 0.85 (3 H, t, J = 6.9 Hz), 1.28–1.30 (6
H, m), 1.592 (2 H, quint, J = 6.9 Hz), 3.26 (2 H, q, J = 6.5 Hz), 8.77 (1 H,
br t, J = 5.3 Hz).
Yield: 700 mg (92%); white solid; mp 130–131 °C.
1H NMR (500 MHz, CDCl3): δ = 2.61 (2 H, t, J = 7.7 Hz), 3.02 (2 H, t, J =
7.7 Hz), 3.76 (3 H, s), 6.80 (2 H, d, J = 9.2 Hz), 7.20–7.31 (8 H, m).
13C NMR (125 MHz, CDCl3): δ = 31.8, 39.3, 55.6, 114.2, 122.1, 126.5,
128.5, 128.7, 131.0, 140.9, 156.6, 170.5.
.
13C NMR (125 MHz, DMSO-d6): δ = 13.9, 22.0, 26.1, 28.9, 31.0, 123.5,
128.6, 140.3, 148.9, 164.4.
N-(4-Dimethylaminophenyl)-3-phenylpropanamide (4gf)
[CAS Reg. No.: 349431-89-6]
N-Morpholinyl-4-nitrobenzamide (3dd)
[CAS Reg. No.: 5397-76-2]
Yield: 800 mg (99%); light purple solid; mp 157–158 °C.
1H NMR (500 MHz, CDCl3): δ = 2.60 (2 H, t, J = 7.7 Hz), 2.88 (6 H, s),
3.02 (2 H, t, J = 7.7 Hz), 6.65 (2 H, d, J = 9.2 Hz), 7.12 (1 H, br s), 7.18–
7.29 (8 H, m).
Yield: 470 mg (64%); yellow solid; mp 104–105 °C.
IR (KBr): 1636, 1521, 1353 cm–1
.
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13C NMR (125 MHz, CDCl3): δ = 31.9, 39.4, 41.2, 113.1, 122.1, 126.4,
127.7, 128.5, 128.7, 141.0, 148.2, 170.3.
1H NMR (500 MHz, CDCl3): δ = 1.07 (6 H, t, J = 7.2 Hz, CH3), 2.62 (4 H,
q, J = 7.2 Hz, CH2), 2.71 (2 H, J = 6.0 Hz, CH2), 3.53 (2 H, J = 5.5 Hz, CH2),
7.93 (1 H, br s, NH), 7.99 (2 H, d, J = 8.6 Hz, CH), 8.28 (2 H, d, J = 9.2 Hz,
CH).
N-(4-Fluorophenyl)-3-phenylpropanamide (4gg)
[CAS Reg. No.: 5298-86-2]
13C NMR (125 MHz, CDCl3): δ = 11.8, 37.4, 46.9, 51.3, 123.8, 140.3,
149.5, 165.2.
Yield: 700 mg (97%); white solid; mp 116–118 °C.
1H NMR (500 MHz, CDCl3): δ = 2.63 (2 H, t, J = 7.7 Hz), 3.02 (2 H, t, J =
7.7 Hz), 6.95 (2 H, d, J = 8.6 Hz), 7.20–7.37 (8 H, m).
N-[2-(Diethylamino)ethyl]trifluoromethylbenzamide (6eh)
[CAS Reg. No.: 827582-99-0]
2
13C NMR (125 MHz, CDCl3): δ = 31.7, 39.4, 115.7 (d, JC,F = 21.5 Hz),
Yield: 780 mg (90%); dark yellow liquid.
3
122.0 (d, JC,F = 7.2 Hz), 126.6, 128.5, 128.8, 133.8, 140.6, 159.5 (d,
1JC,F = 242.0 Hz), 170.7.
1H NMR (500 MHz, CDCl3): δ = 1.05 (6 H, t, J = 7.2 Hz), 2.60 (4 H, q, J =
7.1 Hz), 2.69 (2 H, t, J = 5.7 Hz), 3.50 (2 H, q, J = 5.5 Hz), 7.16 (1 H, br s),
7.70 (2 H, d, J = 8.1 Hz), 7.89 (2 H, d, J = 8.0 Hz).
1
N-[2-(Diethylamino)ethyl]-4-aminobenzamide (6, Procainamide)
[CAS Reg. No.: 51-06-9]
13C NMR (125 MHz, CDCl3): δ = 12.0, 37.4, 46.9, 51.2, 123.9 (d, JC,F
=
3
2
270.7 Hz), 125.7 (d, JC,F = 3.6 Hz), 127.5, 133.1 (d, JC,F = 32.2 Hz),
Yield: 223 mg (95%); yellow liquid.
138.2, 166.1.
1H NMR (500 MHz, CDCl3): δ = 1.00 (6 H, t, J = 7.2 Hz), 2.52 (4 H, q, J =
7.1 Hz), 2.59 (2 H, t, J = 6.3 Hz), 3.43 (2 H, q, J = 5.7 Hz), 4.35 (2 H, br s),
6.59 (2 H, d, J = 8.6 Hz), 7.00 (1 H, br s), 7.59 (2 H, d, J = 8.6 Hz).
13C NMR (125 MHz, CDCl3): δ = 11.8, 37.1, 46.6, 51.3, 113.8, 123.3,
128.4, 149.9, 167.2.
N-[2-(Diethylamino)ethyl]-4-cyanobenzamide (6fh)
[CAS Reg. No.: 1016671-87-6]
Yield: 567 mg (77%); dark yellow liquid.
1H NMR (500 MHz, DMSO-d6): δ = 1.04 (6 H, t, J = 7.2 Hz), 2.66 (4 H, q,
J = 7.1 Hz), 2.73 (2 H, t, J = 6.9 Hz), 3.43 (2 H, q, J = 6.5 Hz), 7.98 (2 H, d,
J = 8.0 Hz), 8.02 (2 H, d, J = 8.1 Hz), 8.35 (1 H, br s).
13C NMR (125 MHz, DMSO-d6): δ = 11.2, 37.2, 46.7, 51.0, 113.5, 118.3,
128.0, 132.4, 138.4, 164.8.
N-[2-(Diethylamino)ethyl]benzamide (6ah)
[CAS Reg. No.: 3690-53-7]
Yield: 637 mg (96%); dark yellow liquid.
1H NMR (500 MHz, CDCl3): δ = 1.06 (6 H, t, J = 7.2 Hz), 2.60 (4 H, q, J =
7.1 Hz), 2.69 (2 H, t, J = 6.0 Hz), 3.51 (2 H, q, J = 5.7 Hz), 7.26 (1 H, br s),
7.40 (2 H, t, J = 7.4 Hz), 7.47 (1 H, t, J = 7.5 Hz), 7.81 (2 H, d, J = 7.4 Hz).
13C NMR (125 MHz, CDCl3): δ = 11.6, 37.0, 46.7, 51.2, 126.8, 128.3,
131.1, 134.5, 167.2.
N-[2-(Diethylamino)ethyl]-2-methylbenzamide (6ih)
[CAS Reg. No.: 62556-26-7]
Yield: 457 mg (65%); yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 1.03 (6 H, t, J = 7.1 Hz), 2.46 (3 H, s),
2.57 (4 H, q, J = 7.2 Hz), 2.66 (2 H, t, J = 5.9 Hz), 3.49 (2 H, q, J = 5.7 Hz),
6.59 (1 H, br s), 7.20 (2 H, t, J = 8.5 Hz), 7.30 (1 H, m), 7.38 (1 H, d, J =
7.3 Hz).
13C NMR (100 MHz, CDCl3): δ = 11.8, 20.0, 37.2, 46.7, 51.5, 125.8,
127.0, 129.8, 131.1, 136.1, 136.8, 170.1.
N-[2-(Diethylamino)ethyl]-4-methoxybenzamide (6bh)
[CAS Reg. No.: 32276-18-9]
Yield: 665 mg (88%); dark yellow liquid.
1H NMR (500 MHz, CDCl3): δ = 1.04 (6 H, t, J = 7.2 Hz), 2.56 (4 H, q, J =
7.1 Hz), 2.64 (2 H, t, J = 6.0 Hz), 3.47 (2 H, q, J = 5.5 Hz), 3.84 (3 H, s),
6.86 (1 H, br s), 6.92 (2 H, d, J = 9.2 Hz), 7.75 (2 H, d, J = 8.6 Hz).
13C NMR (125 MHz, CDCl3): δ = 12.2, 37.3, 46.9, 51.5, 55.5, 113.8,
127.3, 128.7, 162.1, 167.0.
N-[2-(Diethylamino)ethyl]-3-methylbenzamide (6jh)
[CAS Reg. No.: 93808-02-7]
Yield: 620 mg (89%); yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 1.04 (6 H, t, J = 7.1 Hz), 2.40 (3 H, s),
2.57 (4 H, q, J = 7.0 Hz), 2.65 (2 H, t, J = 6.0 Hz), 3.48 (2 H, q, J = 5.7 Hz),
6.94 (1 H, br s), 7.31 (2 H, m), 7.54 (1 H, d, J = 6.0 Hz), 7.62 (1 H, s).
13C NMR (100 MHz, CDCl3): δ = 12.1, 21.5, 46.9, 51.5, 55.5, 113.8,
127.3, 128.7, 162.1, 167.0.
N-[2-(Diethylamino)ethyl]-4-fluorobenzamide (6ch)
[CAS Reg. No.: 120690-13-3]
Yield: 700 mg (99%); dark yellow liquid.
1H NMR (500 MHz, CDCl3): δ = 1.04 (6 H, t, J = 5.0 Hz), 2.60 (4 H, q, J =
8.3 Hz), 2.66 (2 H, t, J = 7.5 Hz), 3.48 (2 H, q, J = 5.0 Hz), 7.08 (2 H, t, J =
7.5 Hz), 7.27 (1 H, br s), 7.82 (2 H, m).
N-[2-(Diethylamino)ethyl]-4-methylbenzamide (6kh)
[CAS Reg. No.: 58028-41-4]
13C NMR (125 MHz, CDCl3): δ = 11.8, 37.3, 46.8, 51.3, 115.4 (d, JC,F
=
2
3
1
21.5 Hz), 129.2 (d, JC,F = 8.4 Hz), 130.9, 164.5 (d, JC,F = 249.2 Hz),
Yield: 620 mg (88%); yellow liquid.
166.3.
1H NMR (400 MHz, CDCl3): δ = 1.04 (6 H, t, J = 7.1 Hz), 2.39 (3 H, s),
2.57 (4 H, q, J = 7.2 Hz), 2.65 (2 H, t, J = 6.2 Hz), 3.48 (2 H, q, J = 5.7 Hz),
6.97 (1 H, br s), 7.23 (2 H, d, J = 8.2 Hz), 7.68 (2 H, d, J = 8.4 Hz).
13C NMR (100 MHz, CDCl3): δ = 12.1, 21.5, 46.9, 51.5, 55.5, 113.8,
127.3, 128.7, 162.1, 167.0.
N-[2-(Diethylamino)ethyl]-4-nitrobenzamide (6dh)
[CAS Reg. No.: 1664-52-4]
Yield: 530 mg (95%); yellow liquid.
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Synthesis
tert-Butyl (S)-[1-(Benzylamino)-1-oxopropan-2-yl]carbamate
(7lb)
Crooks, P. A. Chem. Lett. 2008, 37, 528. (i) Allen, C. L.; Chhatwal,
A. R.; Williams, J. M. J. Chem. Commun. 2012, 48, 666. (j) Chung,
S. W.; Uccello, D. P.; Choi, H.; Montgomery, J. I.; Chen, J. Synlett
2011, 2072. (k) Lundberg, H.; Tinnis, F.; Adolfsson, H. Synlett
2012, 23, 2201. (l) Liu, S.; Yang, Y.; Liu, X.; Ferdousi, F. K.;
Batsanov, A. S.; Whiting, A. Eur. J. Org. Chem. 2013, 5692.
(m) Gernigon, N.; Al-Zoubi, R. M.; Hall, D. G. J. Org. Chem. 2012,
77, 8386.
[CAS Reg. No.: 51814-55-2]
Yield: 726 mg (87%); white solid; mp 105–107 °C.
1H NMR (400 MHz, CDCl3): δ = 1.37 (3 H, d, J = 6.9 Hz), 1.40 (9 H, s),
4.23 (1 H, br s), 4.42 (2 H, s), 5.20 (1 H, br s), 6.82 (1 H, br s), 7.56 (5 H,
m).
13C NMR (100 MHz, CDCl3): δ = 18.5, 28.4, 43.4, 50.2, 80.2, 127.5,
(4) (a) Charville, H.; Jackson, D.; Hodges, G.; Whiting, A. Chem.
Commun. 2010, 46, 1813. (b) Latta, R.; Springsteen, G.; Wang, D.
Synthesis 2001, 1611.
127.6, 128.7, 138.2, 155.7, 172.8.
(5) Comerford, J. W.; Clark, J. H.; Macquarrie, D. J.; Breeden, S. W.
Chem. Commun. 2009, 2562.
(6) Chaudhari, P. S.; Salim, S. D.; Sawant, R. V.; Akamanchi, K. G.
Green Chem. 2010, 12, 1707.
Supporting Information
Supporting information for this article is available online at
(7) Gooßen, L. J.; Ohlmann, D. M.; Lange, P. P. Synthesis 2009, 160.
(8) (a) Kawagoe, Y.; Moriyama, K.; Togo, H. Tetrahedron 2013, 69,
3971. (b) Gu, L.; Lim, J.; Cheong, J. L.; Lee, S. S. Chem. Commun.
2014, 50, 7017.
http://dx.doi.org/10.1055/s-0034-1379966.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 769–776