Highly efficient preparation of amides from aminium carboxylates using N-(p-toluenesulfonyl) imidazole

Article abstract of DOI:10.3184/174751916X14531325057887

Treatment of aminium carboxylates with N-(p-toluenesulfonyl)imidazole in the presence of triethylamine in DMF at 100 °C afforded the corresponding amides in good to excellent yields. N-(p-Toluenesulfonyl)imidazole proved to be a highly efficient coupling reagent for the preparation of numerous structurally diverse primary, secondary and tertiary amides.

Full text of DOI:10.3184/174751916X14531325057887

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 FEBRUARY, 101–106
RESEARCH PAPER 101
Highly efficient preparation of amides from aminium carboxylates using
N-(p-toluenesulfonyl) imidazole
Somayeh Behrouz*, Mohammad Navid Soltani Rad and Elham Forouhari
Medicinal Chemistry Research laboratory, Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
Treatment of aminium carboxylates with N-(p-toluenesulfonyl)imidazole in the presence of triethylamine in DMF at 100 °C afforded the
corresponding amides in good to excellent yields. N-(p-Toluenesulfonyl)imidazole proved to be a highly efficient coupling reagent for the
preparation of numerous structurally diverse primary, secondary and tertiary amides.
Keywords: aminium carboxylate, coupling reagent, N-(p-toluenesulfonyl)imidazole, amide
An amide group is an important functional group which plays
a vital role in organic and medicinal chemistry.1–5 Therefore, a
wide variety of synthetic approaches have been developed.6–8
The direct reaction of carboxylic acids with amines is the most
extensively used procedure for the synthesis of amides in the
laboratory and on the industrial scale. However, harsh reaction
conditions like high temperature and long reaction time are
essential for the direct conversion of the preformed aminium
carboxylate to the corresponding amide.9 Up to now, numerous
coupling reagents including carbodiimides, pyrocarbonates,
borates, triazine derivatives, isoxazolium, phosphonium,
phosphonic, uronium, immonium, aminium, thiazolium,
imidazolium and benzimidazolium salts were employed for the
direct condensation of carboxylic acids with amines.6 Solid-
phase synthesis6 and microwave activation10 have also been
reported. However, most of the coupling reagents used are toxic,
expensive, commercially unavailable and moisture sensitive.
Thus, there is still a need to develop a practical and robust
method for preparing amides directly from carboxylic acids
under mild and safe conditions. The use of aminium carboxylates
instead of free carboxylic acids and amines for the preparation of
amides would be a highly advantageous and attractive strategy
due to the enhancement of the carboxylic acid’s nucleophilic
power towards the coupling reagent and also to prevent the side
reaction of amine with the coupling reagent. To the best of our
knowledge, there has been no report yet on the direct synthesis
of amides from aminium carboxylates using coupling reagents.
N-(p-Toluenesulfonyl)imidazole (TsIm) is a cheap, non-toxic,
stable, commercially available reagent which has been applied
efficiently by us for the preparation of several important classes
of organic compounds (see reference11 and references cited
therein). Our successful preparation of esters by the TsIm-
catalysed reaction of alcohols R’OH with sodium carboxylates
RCO2Na12 is particularly relevant, since our plan was to carry
out a similar reaction replacing the alcohol with an amine to
prepare an amide. We report here a simple procedure for the
direct synthesis of amides from aminium carboxylates using
TsIm as an efficient coupling reagent.
Results and discussion
In view of solubility issues with salts, we chose to use dimethyl
formamide (DMF) as solvent for the conversion of aminium
carboxylates to amides (Scheme 1). To optimise the reaction
conditions, morpholinium benzoate 1t was selected as the test
compound and the influence of various parameters, including
temperature, solvent type, base and coupling reagent on its
conversion to the corresponding amide 2t were evaluated. The
results obtained are shown in Table 1.
The conversion of morpholinium benzoate 1t to the
corresponding benzamide 2t was performed using TsIm as
the coupling reagent, firstly using trimethylamine as base, at
various temperatures. At room temperature, even after heating
for 48 h, the desired amide was not formed (entry 1). However,
raising the temperature progressively to 60, 75 and 90 °C
resulted in increasing yields (entries 2–4). The best result, 96%
O
O
TsIm, base
NH2R2R3
R1
O
R1
NR2R3
DMF, heat, 2-6 h
1
2
O
N
S
H C
3
N
TsIm:
O
2j: R1= PhCH2, R2= H, R3= 3-pyridinylCH2
2k: R1= BocNHCH2, R2= H, R3= H
2a: R1= 4-MeO-C6H4, R2= H, R3= H
2b: R1= 4-MeO-C6H4, R2= H, R3= PhCH2
2l: R1= CbzNHCH2, R2,R3= (CH2)5
2c: R1= 3-Me-C6H4, R2= H, R3= Et2NCH2CH2
2d: R1= 4-NO2-C6H4, R2= H, R3= H
2e: R1= 4-NO2-C6H4, R2= H, R3=CH3(CH2)5
2f: R1= 2-Br-C6H4, R2= Me, R3= Me
2g: R1= 4-CF3-C6H4, R2= H, R3=PhCH2
2h: R1= 2-pyridinyl, R2= H, R3= MeO2CCH2
2i: R1= PhCH2, R2= H, R3= PhCH2
2m: R1= CH3, R2= H, R3= PhCH2
2n: R1= CH3CH2, R2= H, R3= CH3(CH2)15
2o: R1= CH3(CH2)14, R2= H, R3= CH3(CH2)5
2p: R1= phenyl, R2= H, R3= H
2q: R1= phenyl, R2= H, R3= PhCH2CH2
2r: R1= phenyl, R2= H, R3= Me2NCH2CH2CH2
O
O
O
O
N
N
N
N
N
H
O
N
O
2v
2s
2t
2u
Scheme 1
* Correspondent. E-mail: behrouz@sutech.ac.ir

102 JOURNAL OF CHEMICAL RESEARCH 2016
Table 1 Effects of various reaction parameters on the yields of N,N-disubstituted benzamide 2t prepared by treatment of morpholinium benzoate
(Scheme 1) with TsIm and other coupling agents 3–11 (Fig. 1)
Entry
1
2
3
4
5
6
7
8
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
HMPA
DMSO
NMP
Toluene
Xylene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Base
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
NaH
DBU
DMAP
DABCO
MgO
K2CO3
Cs2CO3
Basic Al2O3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Reagent
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
TsIm
3
4
5
6
7
8
9
10
11
Temperature/°C
r.t.
Time/h
Yielda/%
NRb
18
48
20
15
8
2
2
1.8
7
4
3
3
15
18
20
3
3
5
24
10
9
20
5
60
75
90
100
110
27
78
96
96
94
80
84
78
83
85
81
29
90
87
86
NR
58
62
32
80
84
82
65
68
NR
41
130
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
4
6
10
10
36
10
15
15
8
8
8
8
8
28
24
45
41
52
56
60
CH3SO2Cl
CF3SO2Cl
C6H5SO2Cl
4-Me–C6H4SO2Cl
4-NO2–C6H4SO2Cl
Et3N
aIsolated yield.
bNo reaction.
was obtained when the reaction was carried out at 100 °C for
2 h (entry 5). Further increases in the reaction temperature did
not improve the yield (entries 6 and 7).
experiments, we also studied other TsIm analogues as coupling
reagents. The structures of the examined coupling reagents
are shown in Fig. 1. As the results in Table 1 indicate, a higher
yield of amide and shorter reaction time were obtained using
TsIm (entry 5) in comparison with other sulfonyl analogues.
Replacing the tolyl group in TsIm with methyl, trifluoromethyl
and phenyl (to give 3,4 and 5 respectively) produced 2t in
80–84% yield in longer reaction times (entries 22–24). The
use of the other azole analogues of TsIm 6,7 and 11 resulted
in low to moderate yields of 2t (entries 25, 26, and 30). The
N-tosyl imide, N-tosylphthalimide was inactive even if the
reaction time was prolonged to 36 h (entry 27). In addition, the
benzenesulfonyl derivatives of benzimidazole 9 and indole 10
did not give satisfactory results (entries 28 and 29).
We also investigated the effect of several sulfonyl chlorides
instead of TsIm for conversion of morpholinium benzoate to 2t.
However, low to moderate yields were obtained when sulfonyl
chlorides were employed as the coupling reagents (entries 31–
35), despite being more reactive than TsIm. We rationalised this
observation by considering the role of the leaving group in TsIm,
which is an imidazolyl residue, with respect to the chloride ion
in sulfonyl chlorides. While the former is a base that can help to
Then, we examined the effect of various solvents on the
progress of the reaction. As shown in Table 1, DMF proved
to be the most efficient solvent and hence it was the solvent of
choice for all subsequent reactions (entry 5). The use of MeCN,
HMPA, DMSO and NMP (N-methyl-2-pyrrolidone) produced
2t in reasonable yields but in longer reaction times (entries
8–11). Toluene and xylene also provided reasonable yields of
2t; however, longer times were needed for completion of the
reaction (entries 12 and 13).
We also investigated the effect of several organic and
inorganic bases on the conversion of morpholinium benzoate to
2t (Table 1). Among tested bases, Et3N is the most appropriate
base for efficient progress of reaction (entry 5). In general, 2t
was obtained in low to moderate yields using inorganic bases
(entries 14 and 18–21). Employing other organic bases such as
DBU, DMAP, and DABCO (entries 15–17) afforded satisfactory
results, but they were not as effective as Et3N.
The optimised amount of TsIm was found to be 1.2 equiv.
per equivalent of aminium carboxylate. In a series of other

JOURNAL OF CHEMICAL RESEARCH 2016 103
O
S
O
S
O
S
O
S
N
N
N
N
N
N
F3C
N
N
Me
N
N
O
O
O
O
TsIm
3
4
5
O
O
O
S
O
S
Fig. 1 The structures of TsIm analogues used as the
coupling reagents.
N
S
N
N
N
N
N
O
NO2
O
O
O
6
7
8
O
S
O
O
S
N
S
N
O
O
O
9
10
11
Table 2 Yields and duration of reaction for the preparation of amides
2a–v from aminium carboxylates 1a–v using TsIm in DMF (Scheme 1)
progress the reaction, the latter is a non-basic anion. However,
imidazole is not a strong enough base to progress the reaction
alone. Hence the presence of an efficient base is mandatory.
Having obtained the optimised reaction conditions, we then
applied them to a variety of structurally diverse aminium
carboxylates (Table 2). As can be seen in Table 2, TsIm proved
to be an efficient coupling reagent for the production of a wide
range of primary, secondary and tertiary amides. The chemistry
works well and tolerates many labile functionalities present in
both carboxylate and aminium residues.
Entryref.
Producta
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
Time/h
3.5
3
4
2
3
4
2.5
4
4.5
5
5
5
5
6
6
2.5
3
2
2
Yieldb/%
85
88
90
91
90
85
90
87
92
90
87
91
93
89
113
214
315
413
515
616
714
814
Aminium carboxylates in which the carboxylate residues
are aliphatic, heteroaromatic or aromatic carboxylic acids
bearing electron-donating or electron-withdrawing functional
groups were efficiently converted to the corresponding amides.
Moreover, aminium carboxylates having various structurally
diverse aminium residues like benzylic, alicyclic, primary
and secondary aliphatic amine derivatives were efficiently
acylated using TsIm under the optimised condition, whereas
aromatic amines were unreactive. In addition, amidation of
N-protected (as Boc and Cbz derivatives) and/or O-protected
(as methyl ester) amino acids afforded satisfactory results using
the current protocol (entries 8, 11 and 12). Furthermore, this
method is also applicable for fatty acids and amines to provide
the corresponding amides in excellent yields (entries 14 and
917
1018
1113
1217
13
149
1518
1613
1719
18
19
2015
21
90
87
90
90
92
96
94
93
2s
2t
2u
2v
2
2
3
1
15). All the synthesised compounds were characterised by H
NMR and 13C NMR, mass spectroscopy and IR spectroscopy
methods and by their elemental analysis.
22
aReaction Conditions: A mixture of aminium carboxylate 1 (0.01 mol) and TsIm (0.012
mol) in DMF (15 mL) was heated at 100 °C for 1 h and then Et3N (0.012 mol) was added
and heating of the reaction mixture was continued at 100 °C for 2–6 h.
bIsolated yield.
A plausible mechanism for the TsIm-catalysed preparation
of amides from aminium carboxylates, exemplified by
morpholinium benzoate, is shown in Scheme 2. In the first step,
O
O
O
O
N
S
O
O
N
H N
2
O
+
O
(i)
S
N
O
H2N
+
+
N
O
Benzoic Acid Tosyl Ester
(Mixed Anhydride)
TsIm
Morpholinium Benzoate
N
Et NH
-
(ii)
3
O
H2N
+ Et3N and also
O
O
HN
or (-imidazole)
N
O
O
H
Et3N
N
S
O
Et3NH
and also
+
O
N
O
HN
(iii)
+
or imidazole
NH
O
2t
Scheme 2

104 JOURNAL OF CHEMICAL RESEARCH 2016
reaction, the solvent was evaporated in vacuo (Note). The remaining
foam was then dissolved in CHCl3 (100 mL) and subsequently
washed with water (2 × 100 mL). Then, the organic layer was dried
over anhydrous sodium sulfate and evaporated. The crude product
was purified by column chromatography on silica gel eluting with
n-hexane:EtOAc.
(Note: DMF (b.p. 153 °C) can be evaporated in a rotary evaporator
if the vacuum system is capable of sufficiently low pressure. For
instance, DMF can be boiled below 80 °C if the vacuum is reduced to
5 torr or less. However, if an efficient vacuum pump is not available,
then an alternative procedure can be employed in which the reaction
mixture is diluted in water (100 mL). Then, CHCl3 (100 mL) is added
and the organic phase is separated. The separated CHCl3 is washed
subsequently with water (4 × 100 mL). The CHCl3 is evaporated to
obtain the crude product.)
1-Methylsulfonylimidazole (3): CAS Number: 40736-26-3; m.p.
85–86 °C (lit.21 86 °C).
1-(Trifluoromethylsulfonyl)-1H-imidazole (4): CAS Number:
29540-81-6; m.p. 19–20 °C (lit.22 19 °C).
1-(Phenylsulfonyl)-1H-imidazole (5): CAS Number: 46248-01-5;
m.p. 81–82 °C (lit.21 83 °C).
4-Nitro-1-tosyl-1H-imidazole (6): CAS Number: 71100-56-6; foam.23
1-Tosyl-1H-1,2,4-triazole (7): CAS Number: 13578-51-3; foam.24
2-Tosylisoindoline-1,3-dione (8): CAS Number: 27722-45-8; m.p.
239–240 °C (lit.25 239 °C).
the benzoate anion in morpholinium benzoate undertakes a
nucleophilic attack on TsIm which affords benzoic acid tosyl
ester as a reactive mixed anhydride.20 The in situ generation of
benzoic acid tosyl ester was detected at an early stage of the
reaction using TLC monitoring and also by comparing to an
authentic sample. In the second step, the in situ activated amine
(liberated from its aminium salt by triethylamine or imidazole)
reacts with the mixed anhydride to give 2t.
In summary, we have described the application of TsIm as a
highly efficient and useful coupling reagent for the preparation
of amides from aminium carboxylates in the presence of
Et3N in DMF at 100 °C. The mild reaction conditions, simple
experimental procedure and high yields which afforded a
variety of structurally diverse primary, secondary and tertiary
amides are the advantages of the method. Furthermore, the use
of aminium carboxylates as substrates overcomes the problems
usually associated with handling toxic, odorous and corrosive
amines and carboxylic acids or their corresponding acid halide
derivatives.
Experimental
All chemical reagents were purchased from either Fluka or Merck.
Solvents were purified by standard procedures and stored over 3 Å
molecular sieves. Reactions were followed by TLC using SILG/UV
254 silica-gel plates. Column chromatography was performed on
silica gel 60 (0.063–0.200 mm, 70–230 mesh; ASTM). Melting points
were determined using an Electrothermal IA 9000 melting point
apparatus in open capillary tubes and are uncorrected. IR spectra were
1-(Phenylsulfonyl)-1H-benzo[d]imidazole (9): CAS Number:
15728-43-5; m.p. 105–106 °C (lit.26 104 °C).
1-(Phenylsulfonyl)-1H-indole (10): CAS Number: 40899-71-6; m.p.
78–79 °C (lit.27 78 °C).
1-Tosyl-1H-pyrrole (11): CAS Number: 17639-64-4; m.p. 99–100 °C
(lit.28 98 °C).
1
obtained using a Shimadzu FTIR-8300 spectrophotometer. H NMR
and 13C NMR spectra were recorded in CDCl3 on a Brüker Avance-
DPX-250 spectrometer operating at 250 and 62.5 MHz respectively.
Chemical shifts are given in δ relative to tetramethylsilane (TMS)
as an internal standard and coupling constants J are given in Hz.
Abbreviations used for 1H NMR signals are: s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet, br = broad. GC/MS was performed
4-Methoxybenzamide (2a): Off-white prism crystals; yield 85%;
m.p. 115–116 °C (lit.13 114–116 °C); IR (νmax): 3300, 3176, 3069, 2981,
1
1650, 1611, 1449, 1235 cm–1; H NMR: δ 3.80 (s, 3H, OCH3), 7.15 (d,
J = 8.0 Hz, 2H, aryl), 7.79 (d, J = 8.0 Hz, 2H, aryl), 7.95 (s, 2H, NH2,
exchangeable with D2O); 13C NMR: δ 57.8, 116.4, 127.0, 128.6, 163.5,
169.8; MS (EI) m/z (%): 151 (10.5) (M+). Anal. calcd for C8H9NO2: C,
63.56; H, 6.00; N, 9.27; found: C, 63.69; H, 6.14; N, 9.35%.
on
a Shimadzu GC/MS-QP 1000-EX apparatus (m/z; rel.%).
Elemental analyses were performed on a PerkinElmer 240-B micro-
analyser.
N-Benzyl-4-methoxybenzamide (2b): Yellow prism crystals;
yield 88%; m.p. 130–131 °C (lit.14 129–130 °C); IR (νmax): 3367,
Synthesis of aminium carboxylates; general procedure
1
3040, 2968, 1655, 1600, 1449, 1218 cm–1; H NMR: δ 3.72 (s, 3H,
The carboxylic acid (1 equiv.) was added to a solution of the amine (1
equiv.) in a minimum amount of H2O–MeOH (70:30). The reaction
mixture was stirred at room temperature and the reaction was complete
when pH paper indicated that the solution was neutral. The solution
was then evaporated under vacuum and the crude product was dried in
a vacuum oven for 24 h at 50 °C. The aminium carboxylates were then
stored in a desiccator.
OCH3), 4.64 (d, J = 5.9, 2H, NHCH2), 6.37 (s, 1H, NH, exchangeable
with D2O), 6.93–6.98 (m, 3H), 7.35–7.41 (m, 2H), 7.64–7.70 (m, 4H,
aryl); 13C NMR: δ 44.9, 54.0, 114.3, 126.1, 127.9, 128.5, 128.9, 129.4,
137.0, 163.8, 169.5; MS (EI) m/z (%): 241 (14.7) (M+). Anal. calcd for
C15H15NO2: C, 74.67; H, 6.27; N, 5.81; found: C, 74.53; H, 6.16; N,
5.89%.
N-[2-(Diethylamino)ethyl]-3-methylbenzamide
(2c):
Yellow
liquid; yield 90%; IR (νmax): 3280, 3067, 2934, 1679, 1612, 1476 cm–1;
1H NMR: δ 1.18 (t, J = 7.3 Hz, 6H, 2CH3), 2.42 (s, 3H, Ph–CH3), 2.59
(q, J = 7.3 Hz, 4H, 2CH2CH3), 2.74 (t, J = 6.1 Hz, 2H, NCH2), 3.60 (q,
J = 6.1 Hz, 2H, NHCH2), 6.78 (br s, 1H, NH, exchangeable with D2O),
7.39–7.50 (m, 3H, aryl), 7.65 (s, 1H, aryl); 13C NMR: δ 13.8, 22.7, 45.7,
52.0, 56.8, 121.9, 126.1, 128.0, 133.0, 134.0, 138.6, 169.1; MS (EI) m/z
(%): 234 (16.7) (M+). Anal. calcd for C14H22N2O: C, 71.76; H, 9.46; N,
11.95; found: C, 71.70; H, 9.49; N, 11.87%.
4-Nitrobenzamide (2d): Off-white prism crystals; yield 91%; m.p.
128–129 °C (lit.13 128–130 °C); IR (νmax): 3347, 3168, 3072, 1683, 1621,
1549, 1442, 1340 cm–1; 1H NMR: δ 7.89 (d, J = 7.9 Hz, 2H, aryl), 8.10
(d, J = 7.9 Hz, 2H, aryl), 8.26 (s, 2H, NH2, exchangeable with D2O);
13C NMR: δ 125.9, 129.4, 141.7, 153.0, 170.2; MS (EI) m/z (%): 166
(9.1) (M+). Anal. calcd for C7H6N2O3: C, 50.61; H, 3.64; N, 16.86;
found: C, 50.74; H, 3.71; N, 16.75%.
Synthesis of TsIm analogues 3–11; general procedure21
The appropriate N-heterocycle (0.01 mol) and KOH (0.01 mol) was
added in DMSO (15 mL) to a round bottom flask (50 mL) and the
mixture was cooled to 0 °C. Then, the appropriate sulfonyl chloride
(0.012 mol) was added portionwise and the reaction mixture was
stirred at 0 °C for 1–2 h (TLC control). After completion of the
reaction, the mixture was poured into water (100 mL) and extracted
with CHCl3 or EtOAC (100 mL). The organic layer was then washed
with water (4 × 100 mL), dried over anhydrous sodium sulfate
and evaporated. The crude product was purified by short column
chromatography on silica gel eluting with n-hexane:EtOAc.
Synthesis of amides from aminium carboxylates using TsIm; general
procedure
A mixture of the appropriate aminium carboxylate (0.01 mol) and
TsIm (0.012 mol) was added in DMF (15 mL) to a round bottom flask
(50 mL) and the reaction mixture was heated at 100 °C for 1 h. Then,
Et3N (0.012 mol) was added and the heating of the reaction mixture
was continued at 100 °C until TLC monitoring indicated no further
progress in the conversion (2–6 h, see Table 2). After completion of the
N-Hexyl-4-nitrobenzamide (2e): White needle crystals; yield 90%;
m.p. 79–80 °C (lit.15 80–81 °C); IR (νmax): 3268, 3100, 2983, 1678,
1615, 1528, 1475, 1335 cm–1; 1H NMR: δ 0.91 (t, J = 7.1 Hz, 3H, CH3),
1.26–1.31 (m, 6H, 3CH2), 1.67 (quint, J = 7.1 Hz, 2H, NCH2CH2), 3.38
(q, J = 7.1 Hz, 2H, NHCH2), 7.42–7.49 (m, 4H, aryl), 8.51 (s, 1H, NH,

JOURNAL OF CHEMICAL RESEARCH 2016 105
exchangeable with D2O); 13C NMR: δ 14.5, 21.9, 25.7, 29.3, 32.4, 42.0,
124.1, 129.0, 143.2, 150.9, 168.0; MS (EI) m/z (%): 250 (12.9) (M+).
Anal. calcd for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19; found: C, 62.31;
H, 7.29; N, 11.26%.
2-Bromo-N,N-dimethylbenzamide (2f): Yellow oil; yield 85%; IR
(νmax): 3087, 2934, 1631, 1602, 1427, 650 cm–1; 1H NMR: δ 2.98 (s, 3H,
CH3), 3.10 (s, 3H, CH3), 7.19–7.25 (m, 2H, aryl), 7.35 (d, J = 7.8 Hz, 1H,
aryl), 7.59 (d, J = 7.8 Hz, 1H, aryl); 13C NMR: δ 34.0, 37.3, 123.8, 124.9,
131.7, 132.0, 133.4, 140.6, 169.2; MS (EI) m/z (%): 228 (7.8) (M+).
Anal. calcd for C9H10BrNO: C, 47.39; H, 4.42; N, 6.14; found: C, 47.47;
H, 4.51; N, 6.08%.
(11.5) (M+). Anal. calcd for C9H11NO: C, 72.46; H, 7.43; N, 9.39; found:
C, 72.34; H, 7.51; N, 9.45%.
N-Hexadecylpropanamide (2n): White prism crystals; yield 89%;
m.p. 67–68 °C (lit.9 68–69 °C); IR (νmax): 3294, 2960, 1627, 1591 cm–1;
1H NMR: δ 0.91 (t, J = 7.1 Hz, 3H, CH3), 1.19 (t, J = 7.5 Hz, 3H, CH3),
1.38–1.47 (m, 28H, 14CH2), 2.28 (q, J = 7.5 Hz, 2H, CH2CO), 3.41 (q,
J = 7.1 Hz, 2H, NHCH2), 5.82 (br s, 1H, NH, exchangeable with D2O);
13C NMR: δ 10.3, 14.5, 23.0, 27.6, 28.0, 28.8, 29.1, 29.3, 29.5, 29.7, 29.9,
30.1, 30.4, 32.5, 42.7, 171.6; MS (EI) m/z (%): 297 (18.6) (M+). Anal.
calcd for C19H39NO: C, 76.70; H, 13.21; N, 4.71; found: C, 76.79; H,
13.32; N, 4.75%.
N-Benzyl-4-(trifluoromethyl)benzamide (2g): Yellow needle
crystals; yield 90%; m.p. 168–169 °C (lit.14 168–170 °C); IR (νmax):
N-Hexylhexadecanamide (2o): White needle crystals; yield 90%;
m.p. 63–64 °C (lit.18 62–64 °C); IR (νmax): 3297, 2961, 1668, 1596 cm–1;
1H NMR: δ 0.89–0.94 (m, 6H, 2CH3), 1.41–1.57 (m, 34H, 17CH2), 2.33
(t, J = 7.5 Hz, 2H, CH2CO), 3.49 (q, J = 6.8 Hz, 2H, NHCH2), 5.98 (s,
1H, NH, exchangeable with D2O); 13C NMR: δ 13.1, 21.5, 22.9, 23.4,
24.9, 27.0, 28.7, 29.0, 29.2, 29.3, 29.4, 29.6, 29.8, 30.2, 30.5, 31.8, 32.4,
35.9, 38.7, 171.8; MS (EI) m/z (%): 339 (20.7) (M+). Anal. calcd for
C22H45NO: C, 77.81; H, 13.36; N, 4.12; found: C, 77.72; H, 13.30; N,
4.05%.
1
3285, 3050, 2944, 1674, 1609, 1427, 1126 cm–1; H NMR: δ 4.58 (d, J
= 5.6 Hz, 2H, NHCH2), 6.68 (br s, 1H, NH, exchangeable with D2O),
7.34–7.42 (m, 5H, aryl), 7.53 (d, J = 8.0 Hz, 2H, aryl), 7.80 (d, J = 8.0
Hz, 2H, aryl); 13C NMR: δ 43.9, 124.3, 126.1, 127.4, 128.0, 128.7, 130.5,
134.2, 136.0, 138.9, 168.0; MS (EI) m/z (%): 279 (18.3) (M+). Anal.
calcd for C15H12F3NO: C, 64.51; H, 4.33; N, 5.02; found: C, 64.66; H,
4.41; N, 5.12%.
Methyl 2-(picolinamido)acetate (2h): White prism crystals; yield
87%; m.p. 83–84 °C (lit.14 82–84 °C); IR (νmax): 3354, 3063, 2924, 1735,
Benzamide (2p): Off-white prism crystals; yield 87%; m.p.
127–128 °C (lit.13 127–129 °C); IR (νmax): 3300, 3194, 3082, 1671, 1615,
1
1
1673, 1600, 1446, 1240 cm–1; H NMR: δ 3.70 (s, 3H, CH3), 4.36 (d,
1457 cm–1; H NMR: δ 6.07 (br s, 2H, NH2, exchangeable with D2O),
J = 6.1 Hz, 2H, NHCH2), 7.95–8.07 (m, 3H, aryl), 8.17 (d, J = 7.9 Hz,
1H, aryl), 8.40 (s, 1H, NH, exchangeable with D2O); 13C NMR: δ 42.0,
53.1, 123.0, 127.1, 136.9, 147.6, 150.9, 165.4, 171.0; MS (EI) m/z (%):
194 (11.7) (M+). Anal. calcd for C9H10N2O3: C, 55.67; H, 5.19; N, 14.43;
found: C, 55.73; H, 5.14; N, 14.49%.
N-Benzyl-2-phenylacetamide (2i): White prism crystals; yield 92%;
m.p. 77–78 °C (lit.17 76–78 °C); IR (νmax): 3290, 3038, 2979, 1650,
1598, 1433 cm–1; 1H NMR: δ 3.71 (s, 2H, CH2CO), 4.52 (d, J = 6.4 Hz,
2H, NHCH2), 5.89 (br s, 1H, NH, exchangeable with D2O), 7.21–7.32
(m, 6H, aryl), 7.42–7.54 (m, 4H, aryl); 13C NMR: δ 42.9, 43.5, 126.7,
127.0, 127.4, 128.9, 129.5, 130.1, 134.8, 139.0, 170.8; MS (EI) m/z (%):
225 (15.9) (M+). Anal. calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22;
found: C, 79.83; H, 6.82; N, 6.28%.
7.38–7.46 (m, 3H, aryl), 7.65–7.74 (m, 2H, aryl); 13C NMR: δ 126.8,
128.5, 132.9, 134.7, 170.1; MS (EI) m/z (%): 121 (8.1) (M+). Anal. calcd
for C7H7NO: C, 69.41; H, 5.82; N, 11.56; found: C, 69.49; H, 5.95; N,
11.62%.
N-Phenethylbenzamide (2q): Colourless oil; yield 90%; IR (νmax):
1
3310, 3048, 2973, 1682, 1619, 1470 cm–1; H NMR: δ 2.90 (t, J = 5.9
Hz, 2H, Ph–CH2), 3.79 (q, J = 5.9 Hz, 2H, NHCH2), 6.31 (s, 1H, NH,
exchangeable with D2O), 7.30–7.48 (m, 8H, aryl), 7.75–7.82 (m, 2H,
aryl); 13C NMR: δ 34.0, 40.6, 125.9, 127.1, 128.2, 128.7, 129.4, 132.1,
133.8, 137.6, 168.8; MS (EI) m/z (%): 225 (14.5) (M+). Anal. calcd
for C15H15NO: C, 79.97; H, 6.71; N, 6.22; found: C, 79.85; H, 6.80; N,
6.31%.
N-(3-(Dimethylamino)propyl)benzamide (2r): Creamy foam; yield
1
2-Phenyl-N-(pyridin-3-ylmethyl)acetamide (2j): White needle
crystals; yield 90%; m.p. 102–103 °C (lit.18 100–102 °C); IR
90%; IR (νmax): 3343, 3065, 2968, 1674, 1612, 1469 cm–1; H NMR: δ
1.62 (quint, J = 6.0 Hz, 2H, CH2), 2.19 (s, 6H, 2CH3), 2.37 (t, J = 6.0
Hz, 2H, Me2NCH2), 3.42 (q, J = 6.0 Hz, 2H, NHCH2), 7.28–7.40 (m,
3H, aryl), 7.68–7.72 (m, 2H, aryl), 8.39 (s, 1H, NH, exchangeable with
D2O); 13C NMR: δ 27.1, 38.7, 46.5, 58.4, 126.9, 128.0, 133.6, 135.8,
169.2; MS (EI) m/z (%): 206 (12.8) (M+). Anal. calcd for C12H18N2O: C,
69.87; H, 8.80; N, 13.58; found: C, 69.80; H, 8.94; N, 13.63%.
1
(νmax): 3297, 3069, 2948, 1667, 1602, 1472 cm–1; H NMR: δ 3.75
(s, 2H, CH2CO), 4.69 (d, J = 5.5 Hz, 2H, NHCH2), 6.62 (s, 1H, NH,
exchangeable with D2O), 7.14–7.17 (m, 1H, aryl), 7.22 (d, J = 8.0 Hz,
1H, aryl), 7.31–7.40 (m, 5H, aryl), 7.98 (d, J = 8.0 Hz, 1H, aryl), 8.37
(s, 1H, aryl); 13C NMR: δ 44.1, 45.3, 120.8, 121.9, 126.4, 128.5, 129.3,
135.0, 137.1, 150.9, 157.0, 170.8; MS (EI) m/z (%): 226 (13.4) (M+).
Anal. calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38; found: C, 74.23;
H, 6.29; N, 12.34%.
N-(3-Morpholinopropyl)benzamide (2s): White prism crystals; yield
92%; m.p. 274–275 °C; IR (νmax): 3300, 3037, 2950, 1680, 1602, 1437,
1
1210 cm–1; H NMR: δ 1.77 (quint, J = 6.3 Hz, 2H, CH2), 2.53–2.61
tert-Butyl 2-amino-2-oxoethylcarbamate (2k): Off-white cube
crystals; yield 87%; m.p. 86–87 °C (lit.13 85–87 °C); IR (νmax): 3312,
3184, 2925, 1715, 1674, 1613 cm–1; 1H NMR: δ 1.48 (s, 9H, 3CH3), 3.65
(d, J = 6.7 Hz, 2H, NHCH2), 7.16 (br s, 2H, NH2, exchangeable with
D2O), 8.04 (s, 1H, NH, exchangeable with D2O); 13C NMR: δ 29.1,
48.6, 78.9, 157.0, 170.5; MS (EI) m/z (%): 174 (9.1) (M+). Anal. calcd
for C7H14N2O3: C, 48.26; H, 8.10; N, 16.08; found: C, 48.40; H, 8.21; N,
16.19%.
Benzyl 2-oxo-2-(piperidin-1-yl)ethylcarbamate (2l): White cube
crystals; yield 91%; m.p. 114–115 °C (lit.17 113–116 °C); IR (νmax):
3290, 3100, 2962, 1712, 1653, 1593, 1426 cm–1; 1H NMR: δ 1.60–1.68
(m, 6H, 3CH2), 3.41 (t, J = 6.5 Hz, 4H, 2NCH2), 4.01 (d, J = 5.8 Hz,
NHCH2), 5.12 (s, 2H, OCH2), 6.08 (s, 1H, exchangeable with D2O),
7.26–7.39 (m, 5H, aryl); 13C NMR: δ 24.8, 25.6, 42.9, 44.7, 46.9, 66.1,
127.4, 128.0, 129.2, 135.8, 158.7, 168.6; MS (EI) m/z (%): 276 (17.3)
(M+). Anal. calcd for C15H20N2O3: C, 65.20; H, 7.30; N, 10.14; found: C,
65.26; H, 7.38; N, 10.21%.
(m, 6H, 3NCH2), 3.53 (q, J = 6.3 Hz, 2H, NHCH2), 3.70–3.73 (m, 4H,
2OCH2), 7.38–7.52 (m, 3H, aryl), 7.80–7.84 (m, 2H, aryl), 8.20 (s, 1H,
NH, exchangeable with D2O); 13C NMR: δ 28.5, 39.2, 50.9, 53.7, 68.2,
127.8, 129.0, 133.2, 135.4, 168.6; MS (EI) m/z (%): 248 (16.1) (M+).
Anal. calcd for C14H20N2O2: C, 67.71; H, 8.12; N, 11.28; found: C, 67.86;
H, 8.25; N, 11.20%.
(Morpholin-4-yl)(phenyl)methanone (2t): Yellow liquid; yield
1
96%; IR (νmax): 3067, 2968, 1676, 1610, 1476, 1229 cm–1; H NMR: δ
3.53–3.70 (m, 8H, 4CH2), 7.28–7.37 (m, 5H, aryl); 13C NMR: δ 41.9,
46.4, 67.3, 127.9, 129.2, 131.5, 134.8, 170.0; MS (EI) m/z (%): 191
(12.4) (M+). Anal. calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32;
found: C, 69.20; H, 6.98; N, 7.41%.
(4-Ethylpiperazin-1-yl)(phenyl)methanone (2u): Bright brown oil;
1
yield 94%; IR (νmax): 3051, 2940, 1662, 1607, 1463 cm–1; H NMR: δ
1.38 (t, J = 6.9 Hz, 3H, CH3), 2.49 (q, J = 6.9 Hz, 2H, CH2CH3), 2.83 (t,
J = 5.8 Hz, 4H, 2CH2), 3.57 (t, J = 5.8 Hz, 4H, 2CH2), 7.19–7.24 (m, 3H,
aryl), 7.32–7.37 (m, 2H, aryl); 13C NMR: δ 14.8, 47.1, 50.2, 53.1, 56.8,
126.9, 128.5, 130.0, 134.8, 170.6; MS (EI) m/z (%): 218 (15.6) (M+).
Anal. calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83; found: C, 71.41;
H, 8.39; N, 12.94%.
N-Benzylacetamide (2m): White prism crystals; yield 93%;
m.p. 56–57 °C; IR (νmax): 3280, 3068, 2983, 1661, 1602, 1449 cm–1;
1H NMR: δ 1.95 (s, 3H, CH3), 4.65 (d, J = 6.2 Hz, 2H, NHCH2), 6.97 (s,
1H, NH, exchangeable with D2O), 7.36–7.42 (m, 5H, aryl); 13C NMR:
δ 25.7, 44.9, 127.6, 128.0, 129.8, 139.0, 170.0; MS (EI) m/z (%): 149
(4-Benzylpiperidin-1-yl)(phenyl)methanone (2v): Pale-yellow foam;
1
yield 93%; IR (νmax): 3060, 2935, 1657, 1605, 1428 cm–1; H NMR: δ

106 JOURNAL OF CHEMICAL RESEARCH 2016
11 M.N.S. Rad, S. Behrouz and A.-R. Nekoei, Phosphorus, Sulfur Silicon
Relat. Elem., 2014, 189, 465.
12 M.N.S. Rad, S. Behrouz, M.A. Faghihi and A. Khalafi-Nezhad,
Tetrahedron Lett., 2008, 49, 1115.
13 A. Khalafi-Nezhad, A. Zare, A. Parhami, M.N.S. Rad and G.R. Nejabat,
Phosphorus, Sulfur Silicon Relat. Elem., 2007, 182, 657.
14 R.M. Lanigan, P. Starkov and T.D. Sheppard, J. Org. Chem., 2013, 78, 4512.
15 M. Tamura, D. Murase and K. Komura, Synthesis, 2015, 47, 769.
16 D. Saberi, S. Mahdudi, S. Cheraghi and A. Heydari, J. Organomet. Chem.,
2014, 772–773, 222.
17 D. Dev, N.B. Palakurthy, K. Thalluri, J. Chandra and B. Mandal, J. Org.
Chem., 2014, 79, 5420.
18 N. Gernigon, R.M. Al-Zoubi and D.G. Hall, J. Org. Chem., 2012, 77, 8386.
19 A. Leggio, E.L. Belsito, M.L. Di Gioia, V. Leotta, E. Romio, C. Siciliano
and A. Liguori, Tetrahedron Lett., 2015, 56, 199.
1.48–1.54 (m, 4H, 2CH2), 1.91–1.94 (m, 1H, CH), 2.65 (s, 2H, PhCH2),
3.32–3.37 (m, 4H, 2NCH2), 7.15–7.21 (m, 5H, aryl), 7.60–7.66 (m, 3H,
aryl), 7.85–7.89 (m, 2H, aryl); 13C NMR: δ 24.1, 30.5, 40.7, 43.9, 47.1,
126.0, 127.2, 128.0, 128.5, 129.0, 129.7, 134.6, 139.5, 173.0; MS (EI)
m/z (%): 279 (17.3) (M+). Anal. calcd for C19H21NO: C, 81.68; H, 7.58;
N, 5.01; found: C, 81.79; H, 7.71; N, 5.15%.
The authors wish to thank Shiraz University of Technology
Research Council for partial support of this work.
Received 11 November 2015; accepted 16 December 2015
Paper 1503710 doi: 10.3184/174751916X14531325057887
Published online: 29 January 2016
20 Y. Mazur and M.H. Karger, J. Org. Chem., 1971, 36, 528.
21 D. Bellus, M.R. Grimmett, G. Hajos, F. Mathey, R. Neier, Z. Riedl, A.
Schmidpeter, W. Stadlbauer and B. Stanovnik, Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations. Georg Thieme
Verlag, Stuttgart, 2014, Vol. 12.
22 R.G. Kalkhambkar, S.D. Bunge and K.K. Laali, Tetrahedron Lett., 2011,
52, 5184.
23 http://www.molbase.com/en/cas-71100-56-6.html [Accessed 19 January
2016].
References
1
2
3
A. El-Faham and F. Albericio, Chem. Rev., 2011, 111, 6557.
S.C. Stolze and M. Kaiser, Molecules, 2013, 18, 1337.
E. Busseron, Y. Ruff, E. Moulin and N. Giuseppone, Nanoscale, 2013, 5,
7098.
4
5
X. Yu and D. Sun, Molecules, 2013, 18, 6230.
A. Kleeman, J. Engel, B. Kutscher and D. Reichert, Pharmaceutical
substances, 3rd edn. Thieme, Stuttgart, 1999.
24 W. Milton, US Patent US3293259 A, 1966.
6
7
M.M. Joullié and K.M. Lassen, Arkivoc, 2010, viii, 189.
H. Lundberg, F. Tinnis, N. Selander and H. Adolfsson, Chem. Soc. Rev.,
2014, 43, 2714.
25 S. Ozturk and H. Kutuk, Inter. J. Org. Chem., 2011, 1, 202.
26 K.B. Abdireimov, N.S. Mukhamedov, M.Z. Aiymbetov and K.M.
Shakhidoyatov, Chem. Heterocycl. Compd., 2012, 48, 458.
27 P. Lehr and A. Winiski, Patent WO2008095908 A1, 2008.
28 C.B. Bheeter, J.K. Bera and H. Doucet, Tetrahedron Lett., 2012, 53, 509.
8
9
R.M. Lanigan and T.D. Sheppard, Eur. J. Org. Chem., 2013, 2013, 7453.
A. Yildirim, Monatsh. Chem., 2015, 146, 947.
10 N. Lukasik and E. Wagner-Wysiecka, Curr. Org. Synth., 2015, 11, 592.