Tert-butoxide-assisted amidation of esters under green conditions

Article abstract of DOI:10.1055/s-0031-1289622

Efficient and green amidation reactions are of great importance. In this work, we demonstrate the tert-butoxide-assisted amidation of esters with amines under ambient conditions. Aliphatic and/or aromatic esters were converted into the corresponding amides under mild conditions in good to excellent yields. It is noteworthy that the reaction is highly efficient, rapid, versatile, green and economical, and will find great practical application in organic synthesis, biochemistry, and industrial chemistry. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289622

42
PAPER
tert-Butoxide-Assisted Amidation of Esters under Green Conditions
G
reenAmidation
o
of
E
sters Ram Kim,a Hyung-Geun Lee,a Seung-Beom Kang,a Gi Hyeon Sung,a Jeum-Jong Kim,b Jong Keun Park,*c
Sang-Gyeong Lee,a Yong-Jin Yoon*a
a
Department of Chemistry & Research Institute of Natural Sciences, Graduate School for Molecular Materials and Nanochemistry,
Gyeongsang National University, Jinju 660-701, Korea
Fax +82(55)7721489; E-mail: yjyoon@gnu.ac.kr
Advanced Solar Technology Research Department, ETRI, Daejeon 305-700, Korea
Department of Chemistry Education and Research Institute of Natural Science, Educational Research Institute Teachers College,
Gyeongsang National University, Jinju 660-701, Korea
b
c
Fax +82(55)7722229; E-mail: mc7@gnu.ac.kr
Received 4 August 2011; revised 26 September 2011
The aim of our study was to demonstrate the tert-butox-
ide-assisted amidation of esters. Herein, we report the re-
sults of the title reaction.
Abstract: Efficient and green amidation reactions are of great im-
portance. In this work, we demonstrate the tert-butoxide-assisted
amidation of esters with amines under ambient conditions. Aliphat-
ic and/or aromatic esters were converted into the corresponding
amides under mild conditions in good to excellent yields. It is note-
worthy that the reaction is highly efficient, rapid, versatile, green
and economical, and will find great practical application in organic
synthesis, biochemistry, and industrial chemistry.
O
X
O
1
KOt-Bu (2 equiv)
Key words: amidation, esters, radicals, potassium tert-butoxide,
amides
+
N
THF (tech.), r.t. in air
H
H2N
3a
2a
Carboxamides are one of the most important functional
groups in nature1,2 and in the chemical industry, their syn-
thesis is a fundamentally important process in organic
synthesis.3 Common routes for amide synthesis mostly in-
volve the acylation of amines with aldehydes4 and carbox-
ylic acid derivatives such as carboxylic acids, acid halides
anhydrides and esters using activating agents, additives or
catalysts.5 Although a myriad of methods have been re-
ported,6 each has at least one significant drawback, such
as use of toxic, corrosive and/or expensive materials, exo-
thermic reaction, shock sensitivity or complex condi-
tions.7 Recently, the American Chemical Society Green
Chemistry Institute Pharmaceutical Roundtable identified
amide formation as one of the most utilized and problem-
atic synthesis in the pharmaceutical industry and, as such,
has been labeled as a high priority research field.8
1a
1b
1c
1d
1e
X
OEt OMe OPh Cl
OH
3a 95% 67% trace 47% no reaction
Scheme 1 Reaction of benzoic acid derivatives 1 with aniline (2a)
in the presence of potassium tert-butoxide in tetrahydrofuran in air at
room temperature
Table 1 Screening of Substrates for Reaction of Benzoic Acid De-
rivatives 1 with Aniline (2a)a
O
X
O
1
KOt-Bu (2 equiv)
+
N
THF (tech.), r.t. in air
H
H2N
With the aim of developing a greener amidation reaction,
we attempted to study for the conversion of esters into
amides under transition-metal-free and mild conditions.
Because esters are stable and inexpensive compounds that
are abundant in nature, the direct conversion of esters into
amides is an especially useful reaction.9 Recently, we ob-
served the formation of N-phenyl acetamide (3b) from the
reaction of aniline with ethyl acetate (1f) in the presence
of potassium tert-butoxide in air. On the basis of this re-
sult, we attempted to develop the direct amidation of es-
ters under ambient conditions.
3a
2a
Entry
1
X
Time (min) Amide 3a (%)b
1
2
3
4
5
1a
1b
1c
1d
1e
OEt
OMe
OPh
Cl
20
30
60
30
60
95
67c
trace
47c
OH
no reaction
a Reaction conditions: KOt-Bu (2 equiv), THF (technical grade), r.t.,
air.
SYNTHESIS 2012, 44, 42–50
Advanced online publication: 24.11.2011
DOI: 10.1055/s-0031-1289622; Art ID: F77211SS
x
x.
x
x
.
2
0
1
1
b Isolated yield.
c Unreacted 1 was detected by TLC analysis.
© Georg Thieme Verlag Stuttgart · New York

PAPER
Green Amidation of Esters
43
To evaluate the reactivity of the system, we first attempted TLC analysis (Table 3, entry 4 and 5). Under water-free or
to react aniline with five benzoyl derivatives [PhCO2Et oxygen-free conditions, the amidation of 1a gave 3a ei-
(1a), PhCO2Me (1b), PhCO2Ph (1c), PhCOCl (1d) and ther in very low yield or in trace amounts (Table 3, entries
PhCO2H (1e)] in the presence of potassium tert-butoxide 2 and 3). According to the results of the screening trials,
(2 equiv) in tetrahydrofuran (THF; technical grade) in air the following optimized conditions were established: es-
at room temperature (Scheme 1, Table 1). Among the five ter (1 equiv), amine (1 equiv), potassium tert-butoxide (2
derivatives, use of 1a gave the best result (Table 1, entry equiv), oxygen (air), and tetrahydrofuran containing wa-
1). Therefore, we selected the ethyl ester as a carbonyl ter, at room temperature.
source for the amidation of aniline. From screening of
seven bases (NaOMe, NaOEt, NaOt-Bu, KOt-Bu,
NaOPh, NaOH, and KOH) we also obtained the corre-
sponding amides in excellent yields for ethyl acetate (1f)
Table 3 Optimization of the Reaction of Ethyl Benzoate (1a) with
Aniline (2a) in the Presence of Potassium tert-Butoxide
O
and ethyl benzoate (1a) when potassium tert-butoxide
was used (Table 2, entries 7 and 8). Six solvents were
OEt
screened by using the amidation of ethyl benzoate (1a)
with aniline (2a) in the presence of potassium tert-butox-
ide (2 equiv) as a model reaction (Table 3). Technical
O
1a
KOt-Bu (2 equiv)
+
N
solvent
H
NH2
grade tetrahydrofuran (containing ca. 0.2% H2O) showed
the best results among solvents tested (Table 3, entry 1).
When one equivalent or 10 mol% water was used, consid-
3a
2a
erable amounts of ester were converted into the corre-
sponding carboxylates or carboxylic acids, according to
Entry Solvents
Conditions
3a (%)a
95
1
2
3
4
THF (tech.)b
20 min, r.t., in air
20 min, r.t., in argon
20 min, r.t., in air
Table 2 Screening of Bases for the Reaction of Esters 1a and 1f
with Aniline (2a)a
THF (tech.)b
THF (anhyd)
THF (anhyd)
5
NH2
trace
56c
O
O
base
+
20 min, r.t., in air,
H2O (10 mol%)
THF, r.t.
in air
R
OEt
R
N
H
1a R = Ph
1f R = Me
2a
3a R = Ph
3b R = Me
5
THF (anhyd)
20 min, r.t., in argon,
H2O (1 equiv)
tracec
Entry
1
1
Base (equiv)
NaOMe (2)
NaOMe (2)
NaOEt (2)
NaOEt (2)
NaOt-Bu (2)
NaOt-Bu (2)
KOt-Bu (2)
KOt-Bu (2)
KOt-Bu (1)
KOt-Bu (1)
NaOPh (2)
NaOPh (2)
NaH (2)
Time (min) Amide 3 (%)b
6
7
Et2O (tech.)
20 min, r.t., in air
20 min, r.t., in air
20 min, r.t., in air
20 min, r.t., in air
20 min, r.t., in air
71d
55d
36d
10d
52d
29d
1a
1f
60
60
60
60
60
60
10
10
20
20
60
60
60
60
60
60
–
n-hexane (tech.)
toluene (tech.)
1,4-dioxane (tech.)
DMF (tech.)
2
–
8
3
1a
1f
–
9
4
–
10
11
5
1a
1f
3a (14)c
cyclohexane (tech.) 20 min, r.t., in air
6
3b (20)
a Isolated yield.
7
1a
1f
3a (95)
b THF technical grade contained ca. 0.2% H2O.
c The carboxylate and carboxylic acid were detected by TLC.
d Unreacted 1a was detected by TLC.
8
3b (92)
9
1a
1f
3a (45)c
10
11
12
13
14
15
16
3a (26)
We demonstrated the tert-butoxide-assisted amidation of
ethyl benzoate (1a) with aliphatic and aromatic amines
2b–i under the optimized conditions. Reaction of aromatic
esters such as ethyl benzoate (1a) and ethyl isonicotinate
(4) with aromatic and aliphatic primary amines gave the
corresponding amides 3c–j and 5a–f in good to excellent
yields (Table 4 and Table 5). Amidation of ethyl al-
kanoates 6a and 6b with aromatic and aliphatic primary
amines 2a, 2b, 2d and 2f gave the corresponding amides
7a–e in good to excellent yields (Table 6). We also at-
tempted the amidation of esters containing functional
groups such as carbonyl, double bond, hydroxy or amino
groups. Compound 6c reacted with aniline (2a) under the
1a
1f
–
–
–
–
–
–
1a
1f
NaH (2)
1a
1f
KOH (2)
KOH (2)
a Reaction conditions: THF (technical grade), r.t., air.
b Isolated yield.
c Unreacted 2a was detected by TLC analysis.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 42–50

44
B. R. Kim et al.
PAPER
optimized conditions to give the corresponding amide 7f On the other hand, Pryor et al.10 and Akiyama et al.11 also
(53%) together with unknown products (Table 6, entry 6). reported the production of hydroperoxide or peroxide rad-
Reaction of ethyl acrylate with aniline (2a) under the icals by the treatment of oxygen with potassium tert-bu-
same conditions, however, yielded several unknown toxide in the presence of water. Treatment of this peroxide
products instead of the corresponding amide. Treatment radical with ethyl benzoate may form tert-butyl peroxy-
of ethyl 2-hydroxypropanoate (6d) with 2a for 30 minutes benzoate. According to literature reports,12–15 tert-butyl
under the optimized conditions afforded the correspond- peroxybenzoate is of widespread use as an initiator of
ing amide 7g in very low yield (Table 6, entry 7). On the free-radical reactions and decomposes to the acyloxy rad-
other hand, reaction of ethyl 3-oxobutanoate, ethyl N-phe- ical and the tert-butoxy radical. Indeed, tert-butyl peroxy-
nylcarbamate and ethyl 2-amino-3-(4-hydroxyphe- benzoate was detected by TLC analysis of samples from
nyl)propanoate with 2a under the optimized conditions the reaction of ethyl benzoate (1a) and potassium tert-bu-
did not give the corresponding amides.
toxide or sodium tert-butoxide in technical grade tetrahy-
drofuran containing water, under air at room temperature.
However, when esters were treated with potassium tert-
The structures of the prepared compounds were estab-
lished by the IR, NMR and HRMS analyses.
Table 4 tert-Butoxide-Assisted Amidation of Ethyl Benzoate (1a) with Amines 2a
O
O
R
KOt-Bu (2 equiv)
OEt
N
+
RNH2
2
H
THF, r.t.
in air
1a
3
Entry
1
Amine 2
Time (min)
20
Amide 3 (Yield, %)b
O
NH2
2b
2c
2d
3c (90)
3d (85)
3e (92)
N
H
Cl
O
NH2
2
3
10
10
N
H
Cl
O
NH2
N
N
H
N
O
O
O
n-Bu
4
5
6
2e
2f
n-BuNH2
60
15
10
3f (79)
3g (93)
3h (82)
N
H
NH2
N
H
2
NH2
2g
N
H
O
O
NH2
7
8
2h
2i
20
60
3i (91)
3j (80)
N
H
NH
N
a Reaction conditions: KOt-Bu (2 equiv), THF(technical grade), r.t., air.
b Isolated yield. Average of three runs.
Synthesis 2012, 44, 42–50
© Thieme Stuttgart · New York

PAPER
Green Amidation of Esters
45
Table 5 tert-Butoxide-Assisted Amidation of Ethyl Isonicotinate (4) with Amines 2a
O
O
R
KOt-Bu (2 equiv)
THF, r.t., in air
N
OEt
+
RNH2
H
N
N
4
2
5
Entry
Amines 2
Time (min)
10
Amide 5 (Yield, %)b
O
NH2
1
2
2a
5a (92)
N
H
N
N
O
NH2
2b
20
5b (94)
N
H
O
n-Bu
3
4
2e
2g
n-BuNH2
10
5
5c (81)
5d (93)
N
H
N
O
NH2
N
H
N
O
O
NH2
5
6
2h
2i
10
30
5e (85)
5f (82)
N
H
N
N
NH
N
a Reaction conditions: KOt-Bu (2 equiv), THF (technical grade), r.t., air.
b Isolated yield. Average of three runs.
O
O
– HOR1
H2O
KOt-Bu
–
R1
•
O2
HOO
•
O2
Ph
O
1
Ph
O
OO•
KOt-Bu
O
•
Ph
OO
Ph
+
OOK
+
t-BuO•
O
O2
or
+
t-BuO•
(1)
(2)
+
•
Ph
O
O
O
t-BuOO •
Ph
O2Ot-Bu
+
Ph
OOt-Bu
O
Ph
•
or
O
(3)
t-BuO
•
+
•
OO
Ph
– t-BuOO
•
O
R2NH2
– t-BuOOH
•
NHR2
Ph
O
Ph
Scheme 2 Plausible mechanism for the tert-butoxide-assisted amidation of alkyl benzoate with amine
© Thieme Stuttgart · New York
Synthesis 2012, 44, 42–50

46
B. R. Kim et al.
PAPER
Table 6 tert-Butoxide-Assisted Amidation of Ethyl Alkanoates 6 with Amines 2a
O
O
KOt-Bu (2 equiv)
THF, r.t., in air
R1NH2
R1
+
R2
N
R2
OEt
H
6
2
7
Entry
1
Ester 6
Amine 2
Time (min) Amide 7 (Yield, %)b
O
O
NH2
6a
2a
10
7a (92)
7b (90)
OEt
N
H
O
O
NH2
2
6a
2b
10
OEt
N
H
NH2
NH2
O
O
3
4
6b
6b
2a
2d
10
7c (92)
7d (91)
N
OEt
2
2
H
O
O
10
N
N
OEt
2
N
2
H
O
NH2
O
5
6b
2f
5
7e (80)
N
2
2
H
OEt
2
O
O
NH2
NH2
6
7
6c
2a
2a
10
7f (53)c
7g (4)d
OEt
N
H
O
O
6d
30
OEt
N
H
OH
OH
a Reaction conditions: KOt-Bu (2 equiv), THF (technical grade), r.t., air.
b Isolated yield. Average of three runs.
c Some unknown products were detected by TLC.
d Large amounts starting material were detected by TLC.
butoxide in an argon atmosphere or in the absence of wa- There are some problems such as side reactions associated
ter, no tert-butyl peroxybenzoate could be detected. A with other radical species, however, we have now found
plausible mechanism for the amidation of esters with that these potential side reactions can be suppressed by the
amines may be represented as shown in Scheme 2. Reac- use of a suitable solvent.
tion of the ester with HOO· radicals may generate
In conclusion, we have developed a tert-butoxide-assisted
direct conversion of esters into the corresponding amides
under ambient conditions. The amidation may be of a nov-
el type that could occur via the acyl radical derived from
PhC(=O)OO· radicals; treatment of this peroxy radical
with KOt-Bu may form PhC(=O)O2O(t-Bu) in equilibri-
um.16 The intermediate PhC(=O)O2O(t-Bu) may decom-
pose into tert-butyl peroxybenzoate via process (1), (2)
the ester under ambient conditions. Our method is very
and/or (3), as shown in Scheme 3. According to a calcula-
simple, rapid, inexpensive, green, and effective, and is of
tion of the relative potential energies (eV) at the MP2/6-
high value for a wide range of synthetic applications. We
311+g* level,17 the dissociation of PhC(=O)O2O(t-Bu)
also believe that the tert-butoxide-assisted amidation
would be applicable practically to industrial processes.
into tert-butyl peroxybenzoate [(a) in Scheme 3] may fa-
vor processes (2) and (3) over process (1). tert-Butyl per-
oxybenzoate may also be formed from the benzoyloxy
radical and the tert-butoxy radical [(b) in Scheme 3].
Therefore, potassium tert-butoxide may be regarded as an
assistant for the conversion of the ester into the corre-
Further work, including the development of a detailed re-
action mechanism and an application and exploration of
the enormous potential of esters as an acyl source in or-
ganic synthesis is underway in our laboratory.
sponding acyl source under the present conditions.
Synthesis 2012, 44, 42–50
© Thieme Stuttgart · New York

PAPER
Green Amidation of Esters
47
O
O2
+
+
(1)
•
t-BuO•
O
Ph
•
•
+
•
t-BuOO
1.377
Ph
O
O
3.477
0.167
t-BuOO
• +
(2)
(3)
•O
Ph
O
O
0.982
0.117
•
t-BuO
+
Ph
O
Ph
O2Ot-Bu
O
t-BuO •
+
•OO
Ph
Ph
OOt-Bu
(a)
(b)
Scheme 3 Relative potential energies (eV) for the dissociative (associative) reactions of PhC(=O)O2O(t-Bu) into PhC(=O)O2(t-Bu) calculated
at the MP2/6-311+g** level15
IR (KBr): 3328, 3115, 3045, 2959, 1644, 1612, 1513, 1463, 1407,
1266, 1246, 1028, 822, 712 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.28 (s, 3 H), 7.15 (d, J =
8.36 Hz, 2 H), 7.49–7.60 (m, 3 H), 7.68 (d, J = 8.25 Hz, 2 H), 7.96
(d, J = 7.42 Hz, 2 H), 10.13 (br s, 1 H, NH, D2O exchangeable).
13C NMR (75 MHz, DMSO-d6): d = 20.46, 120.3, 127.5, 128.3,
128.9, 131.3, 132.5, 135.0, 136.6, 165.3.
Melting points were determined with a Thomas–Hoover capillary
apparatus and are uncorrected. The 1H and 13C NMR spectra were
recorded with a Bruker FT NMR Avance-300 spectrometer at 300
and 75 MHz, respectively, with chemical shift values (d) reported in
ppm relative to an internal standard (TMS). IR spectra were ob-
tained with a Varian 640-IR spectrophotometer. Mass spectra were
obtained with a GC Mate 2, JEOL instrument.
HRMS: m/z [M]+ calcd for C14H13NO: 211.0997; found: 211.0999.
Synthesis of Amides; General Procedure
KOt-Bu (6.6 mmol) was dissolved in THF (40 mL; technical grade,
containing ca. 0.2% H2O) with stirring in air at r.t. for 1 min. The
ester (3.3 mmol) and amine (3.3 mmol) were added immediately
and the mixture was stirred at r.t. until the amine was consumed. Af-
ter evaporating THF under reduced pressure, H2O (50 mL) and
CH2Cl2 (50 mL) were added and the organic layer was separated
and dried over anhydrous MgSO4. The solvent was evaporated un-
der reduced pressure and the corresponding amides 3, 5 and 7 were
obtained either by recrystallization of the residue (THF–n-hexane,
1:3) or by isolation by silica gel column chromatography (3 × 12–
15 cm; EtOAc–n-hexane, 1:3).
N-(4-Chlorophenyl)benzamide (3d)
Yield: 655 mg (85%); light-brown solid; mp 187–188 °C (Lit.21
190–191 °C).
IR (KBr): 3346, 3102, 3057, 1652, 1593, 1573, 1516, 1394, 1310,
1090, 821, 714 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.40–7.60 (m, 5 H), 7.83 (d,
J = 8.8 Hz, 2 H), 7.95 (d, J = 7.6 Hz, 2 H), 10.38 (br s, 1 H, NH,
D2O exchangeable).
13C NMR (75 MHz, DMSO-d6): d = 121.7, 127.2, 127.6, 128.3,
128.4, 131.6, 134.6, 138.1, 165.6.
N-Phenylbenzamide (3a)
HRMS: m/z [M]+ calcd for C13H10ClNO: 231.0451; found:
231.0451.
Yield: 625 mg (95%); pale-yellow solid; mp 160–162 °C (Lit.18
162 °C).
IR (KBr): 3342, 3302, 3051, 3024, 1653, 1599, 1578, 1531, 1494,
1437, 1393, 1321, 1299, 1260, 1074, 749, 689 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.98–7.98 (m, 10 H), 10.26 (br
s, 1 H, NH, D2O exchangeable).
13C NMR (75 MHz, DMSO-d6): d = 120.8, 124.1, 128.1, 128.8,
129.0, 131.9, 135.4, 139.6, 166.0.
HRMS: m/z [M]+ calcd for C13H11NO: 197.0841; found: 197.0846.
N-(Pyridine-3-yl)benzamide (3e)
Yield: 607 mg (92%); light-brown solid; mp 109–111 °C (Lit.22
112 °C).
IR (KBr): 3332, 3287, 3247, 3175, 3110, 3051, 3031, 1677, 1646,
1582, 1530, 1474, 1411, 1285, 1229, 794 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.40–7.43 (m, 1 H), 7.54–7.63
(m, 3 H), 7.99–8.02 (m, 2 H), 8.22–8.24 (m, 1 H), 8.33–8.34 (m,
2 H), 8.96 (d, J = 2.3 Hz, 1 H), 10.49 (br s, 1 H, NH, D2O exchange-
able).
N-Phenylacetamide (3b)
Yield: 414 mg (92%); white solid; mp 114–115 °C (Lit.19 113–
115 °C).
13C NMR (75 MHz, DMSO-d6): d = 123.4, 127.2, 127.6, 128.4,
131.8, 134.3, 135.7, 141.9, 144.5, 165.9.
HRMS: m/z [M]+ calcd for C12H10N2O: 198.0793; found: 198.0801.
IR (KBr): 3194, 3135, 3077, 3059, 3020, 2856, 2801, 1950, 1665,
1599, 1557, 1537, 1434, 1368, 1322, 1263, 1178, 1040, 961, 906,
694, 605, 532, 508 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.04 (s, 3 H), 7.01 (t,
J1 = 7.17 Hz, J2 = 7.12 Hz, 1 H), 7.28 (t, J1 = 7.20 Hz, J2 = 7.29 Hz,
2 H), 7.58 (d, J = 8.07 Hz, 2 H), 9.91 (br s, 1 H, NH, D2O exchange-
able).
13C NMR (75 MHz, DMSO-d6): d = 23.95, 118.9, 122.9, 128.5,
139.2, 168.2.
HRMS: m/z [M]+ calcd for C8H9NO: 135.0684; found: 135.0685.
N-Butylbenzamide (3f)
Yield: 466 mg (79%); yellow solid; mp 40–41 °C (Lit.23 39–41 °C).
IR (KBr): 3316, 3062, 2957, 2930, 2868, 1635, 1604, 1576, 1541,
1489, 1308, 1141, 696 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.89 (t, J = 7.2 Hz, 3 H), 1.28–
1.35 (m, 2 H), 1.46–1.53 (m, 2 H), 3.23–3.30 (m, 2 H), 7.41–7.50
(m, 3 H), 7.83–7.87 (m, 2 H), 8.45 (br s, 1 H, NH, D2O exchange-
able).
13C NMR (75 MHz, DMSO-d6): d = 14.1, 20.1, 31.7, 39.3, 127.5,
N-p-Tolylbenzamide (3c)
128.6, 131.3, 135.2, 166.5.
Yield: 632 mg (90%); light-brown solid; mp 156–157 °C (Lit.20
154–157 °C).
HRMS: m/z [M]+ calcd for C11H15NO: 177.1154; found: 177.1150.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 42–50

48
B. R. Kim et al.
PAPER
N-Phenethylbenzamide (3g)
N-p-Tolyisonicotinamide (5b)
Yield: 697 mg (93%); white solid; mp 115–116 °C (Lit.24 115 °C).
Yield: 659 mg (94%); light-brown solid; mp 160–161 °C (Lit.28
160 °C).
IR (KBr): 3340, 3056, 3023, 2967, 2929, 2860, 1637, 1600, 1542,
1312, 1190, 693 cm–1.
IR (KBr): 3322, 3037, 1648, 1597, 1527, 1405, 1323, 813 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.95 (t, J1 = J2 = 6.9 Hz, 3 H),
3.70–3.77 (m, 2 H), 6.29 (br s, 1 H, NH, D2O exchangeable), 7.24–
7.52 (m, 8 H), 7.71 (d, J = 8.1 Hz, 2 H).
1H NMR (300 MHz, DMSO-d6): d = 2.29 (s, 3 H), 7.18 (d,
J = 7.8 Hz, 2 H), 7.67 (d, J = 7.4 Hz, 2 H), 7.87 (d, J = 4.5 Hz, 2 H),
8.79 (m, J = 4.5 Hz, 2 H), 10.43 (br s, 1 H, NH, D2O exchangeable).
13C NMR (75 MHz, CDCl3): d = 35.7, 41.1, 126.5, 126.8, 128.5,
128.7, 128.8, 131.3, 134.6, 138.9, 167.5.
13C NMR (75 MHz, DMSO-d6): d = 20.4, 120.4, 121.5, 129.0,
133.1, 136.0, 141.9, 150.1, 163.6.
HRMS: m/z [M]+ calcd for C15H15NO: 225.1154; found: 225.1154.
HRMS: m/z [M]+ calcd for C13H12N2O: 212.0950; found: 212.0949.
N-Benzylbenzamide (3h)
N-Butylisonicotinamide (5c)
Yield: 576 mg (82%); light-brown solid; mp 90–91 °C (Lit.25
103 °C).
Yield: 477 mg (81%); light-brown solid; mp 41–42 °C (Lit.29 41–
43 °C).
IR (KBr): 3290, 3083, 3060, 3029, 2953, 2926, 2864, 2805, 1637,
1601, 1577, 1549, 1489, 1417, 1260, 985, 695 cm–1.
IR (KBr): 3290, 3063, 3047, 2958, 2931, 2871, 1645, 1547, 1490,
1308, 846, 749 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 4.49 (d, J = 5.9 Hz, 2 H), 7.23–
7.53 (m, 8 H), 7.91 (d, J = 7.1 Hz, 2 H), 9.06 (br s, 1 H, NH, D2O
exchangeable).
13C NMR (75 MHz, DMSO-d6): d = 42.55, 126.6, 127.1, 127.2,
128.2(4), 128.2(8), 132.2, 134.2, 139.6, 166.1.
1H NMR (300 MHz, DMSO-d6): d = 0.90 (t, J1 = J2 = 7.28 Hz, 3 H),
1.27–1.40 (m, 2 H), 1.48–1.57 (m, 2 H), 3.26–3.32 (m, 2 H), 7.75–
7.77 (m, 2 H), 8.72–8.74 [m, 3 H (2 HAr, 1 HNH); D2O exchange-
able].
13C NMR (75 MHz, DMSO-d6): d = 13.9, 20.0, 31.4, 60.1, 121.6,
142.0, 150.6, 164.9, 170.6.
HRMS: m/z [M]+ calcd for C14H13NO: 211.0997; found: 211.1001.
HRMS: m/z [M]+ calcd for C10H14N2O: 178.1106; found:178.1103.
N-Cyclohexylbenzamide (3i)
Yield: 615 mg (91%); ivory solid; mp 146–147 °C (Lit.26 146–
147 °C).
N-Benzylisonicotinamide (5d)
Yield: 652 mg (93%); light-brown solid; mp 87–88 °C (Lit.30 86–
88 °C).
IR (KBr): 3327, 3082, 3057, 3028, 2935, 2918, 2849, 1628, 1576,
1532, 1487, 1327, 1082, 889, 691 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17–1.29 (m, 3 H), 1.35–1.47 (m,
2 H), 1.62–1.76 (m, 2 H), 20.1 (d, J = 9.6 Hz, 2 H), 3.92–4.01 (m,
1 H), 6.12 (br s, 1 H, NH, D2O exchangeable), 7.37–7.49 (m, 3 H),
7.75 (d, J = 7.5 Hz, 2 H).
IR (KBr): 3324, 3066, 3028, 2958, 1645, 1542, 1421, 1315, 1250,
850, 728 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 4.50 (d, J = 6.0 Hz, 2 H), 7.23–
7.37 (m, 5 H), 7.79–7.81 (m, 2 H), 8.72–8.74 (m, 2 H), 9.35 (br s,
1 H, NH, D2O exchangeable).
13C NMR (75 MHz, CDCl3): d = 24.94, 25.57, 33.21, 48.69, 126.8,
128.4, 131.2, 135.1, 166.6.
13C NMR (75 MHz, DMSO-d6): d = 43.1, 121.7, 127.3, 127.7,
128.8, 139.5, 141.6, 150.7, 165.1.
HRMS: m/z [M]+ calcd for C13H17NO: 203.1310; found: 203.1310.
HRMS: m/z [M]+ calcd for C13H12N2O: 212.0950; found: 212.0951.
Phenyl(piperidin-1-yl)methanone (3j)
Yield: 504 mg (80%); pale-yellow liquid.
N-Cyclohexylisonicotinamide (5e)
Yield: 574 mg (85%); white solid; mp 140–142 °C (Lit.31 139–
140 °C).
IR (KBr): 3055, 3023, 2995, 2934, 2852, 1630, 1575, 1433, 1277,
1106, 999, 703 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.49–1.56 (m, 6 H), 3.25 (s,
2 H), 3.59 (s, 2 H), 7.38–7.42 (m, 5 H).
13C NMR (75 MHz, DMSO-d6): d = 24.0, 25.2, 25.9, 42.1, 47.9,
126.5, 128.2, 129.0, 136.5, 158.2, 168.7.
HRMS: m/z [M]+ calcd for C12H15NO: 189.1154; found: 189.1153.
IR (KBr): 3305, 2933, 2854, 1635, 1540, 1454, 1325, 1286, 1083,
889, 848, 673 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.10–1.18 (m, 1 H), 1.23–1.37
(m, 4 H), 1.59–1.63 (m, 1 H), 1.73–1.83 (m, 4 H), 3.73–3.77 (br s,
1 H, NH, D2O exchangeable), 7.73 (d, J = 4.8 Hz, 2 H), 8.49 (d,
J = 7.8 Hz, 1 H), 8.65 (d, J = 4.8 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 24.8, 25.15, 32.18, 48.50,
121.2, 141.7, 150.0, 163.7.
HRMS: m/z [M]+ calcd for C12H16N2O: 204.1263; found: 204.1263.
N-Phenylisonicotinamide (5a)
Yield: 603 mg (92%); light-brown solid; mp 186–187 °C (Lit.27
186–188 °C).
Piperidin-1-yl(pyridin-4-yl)methanone (5f)
Yield: 515 mg (82%); light-brown liquid.
IR (KBr): 3340, 3043, 2954, 1655, 1600, 1551, 1490, 1442, 1406,
1324, 1266, 1177, 846, 747, 689 cm–1.
IR (KBr): 3043, 3022, 2993, 2938, 2854, 1625, 1596, 1440, 1281,
627 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.45–1.46 (m, 2 H), 1.55–1.61
(m, 4 H), 3.17–3.21 (m, 2 H), 3.57–3.60 (m, 2 H), 7.35 (dd,
J1 = J2 = 1.58 Hz, 2 H), 8.65 (dd, J1 = 1.53 Hz, J2 = 1.55 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 23.8, 25.0, 25.7, 41.9, 47.6,
120.8, 143.8, 149.9, 166.4.
1H NMR (300 MHz, DMSO-d6): d = 7.38–7.43 (m, 1 H), 7.54–7.65
(m, 3 H), 8.00 (d, J = 7.78 Hz, 2 H), 8.21–8.24 (m, 1 H), 8.33 (d,
J = 4.53 Hz, 2 H), 8.96 (m, 1 H), 10.48 (br s, 1 H, NH, D2O ex-
changeable).
13C NMR (75 MHz, DMSO-d6): d = 123.4, 127.2, 127.6, 128.4,
131.8, 134.3, 135.7, 141.9, 144.5, 165.9.
HRMS: m/z [M]+ calcd for C12H10N2O: 198.0793; found: 198.0801.
HRMS: m/z [M]+ calcd for C11H14N2O: 190.1106; found: 190.1100.
Synthesis 2012, 44, 42–50
© Thieme Stuttgart · New York

PAPER
Green Amidation of Esters
49
N-Phenylisobutyramide (7a)
N-Phenylcinnamamide (7f)
Yield: 646 mg (92%); pale-yellow solid; mp 102–103 °C (Lit.32
102 °C).
Yield: 335 mg (53%); light-brown solid; mp 145–147 °C (Lit.37
147–149 °C).
IR (KBr): 3298, 3258, 3194, 3135, 3066, 3037, 2967, 2928, 2869,
1659, 1598, 1439, 1096, 755 cm–1.
IR (KBr): 3306, 3055, 2976, 2929, 1663, 1599, 1534, 1444, 1315,
1121, 1041, 755, 692 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.09 (d, J = 6.8 Hz, 6 H), 2.56–
2.61 (m, 1 H), 6.98–7.03 (m, 1 H), 7.25–7.30 (m, 2 H), 7.61 (t,
J = 7.6 Hz, 2 H), 9.81 (br s, 1 H, NH, D2O exchangeable).
1H NMR (300 MHz, DMSO-d6): d = 6.84 (d, J = 15.7 Hz, 1 H), 7.07
(t, J = 7.3 Hz, 1 H), 7.31–7.47 (m, 5 H), 7.56–7.71 (m, 5 H), 10.2
(br s, 1 H, NH, D2O exchangeable).
13C NMR (75 MHz, DMSO-d6): d = 19.9, 35.3, 119.5, 123.3, 129.0,
139.9, 175.6.
13C NMR (75 MHz, DMSO-d6): d = 119.1, 122.2, 123.3, 127.6,
128.7, 128.9, 129.7, 134.6, 139.2, 140.1, 163.4.
HRMS: m/z [M]+ calcd for C10H13NO: 163.0997; found: 163.0999.
HRMS: m/z [M]+ calcd for C15H13NO: 223.0997; found: 223.0096.
N-p-Toylisobutyramide (7b)
2-Hydroxy-N-phenylpropanamide (7g)
Yield: 27 mg (4%); yellow liquid.
Yield: 686 mg (90%); light-brown solid; mp 108–109 °C (Lit.33
108–109 °C).
IR (KBr): 3446, 3259, 3196, 3132, 3062, 1660, 1625, 1599, 1577,
1543, 1497, 1441, 1384, 1295, 1248, 1186, 1154, 1006, 988, 978,
761, 741 cm–1.
IR (KBr): 3277, 3246, 3210, 3187, 3120, 3060, 3032, 2969, 2928,
2871, 1676, 1657, 1600, 1540, 1513, 1253, 1097, 819 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.08 (d, J = 6.8 Hz, 6 H), 2.23
(s, 3 H), 2.50–2.58 (m, 1 H), 7.07 (d, J = 8.3 Hz, 2 H), 7.48 (d,
J = 8.3 Hz, 2 H), 9.70 (br s, 1 H, NH, D2O exchangeable).
13C NMR (75 MHz, DMSO-d6): d = 19.9, 20.8, 35.3, 119.5, 129.4,
132.1, 137.4, 175.3.
1H NMR (300 MHz, DMSO-d6): d = 1.31 (d, J = 6.7 Hz, 3 H), 4.13–
4.17 (m, 1 H), 5.75 (d, J = 5.1 Hz, 1 H), 7.05–7.07 (m, 1 H), 7.29 (t,
J1 = 7.8 Hz, J2 = 8.0 Hz, 2 H), 7.69–7.27 (m, 2 H), 9.62 (br s, 1 H,
NH, D2O exchangeable).
13C NMR (75 MHz, DMSO-d6): d = 20.85, 67.74, 119.5, 123.3,
128.5, 138.5, 173.4.
HRMS: m/z [M]+ calcd for C11H15NO: 177.1154; found: 177.1152.
HRMS: m/z [M]+ calcd for C9H11NO2: 165.0790; found: 165.0791.
N-3-Diphenylpropanamide (7c)
Yield: 581 mg (92%); light-brown solid; mp 98 °C (Lit.34 98 °C).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
IR (KBr): 3321, 3192, 3060, 3045, 3025, 2951, 2923, 2856, 1651,
1598, 1530, 1499, 1441, 1314, 1077, 751 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.66 (t, J = 7. 8 Hz, 2 H), 2.95
(t, J = 7. 4 Hz, 2 H), 7.05–7.08 (m, 1 H), 7.21–7.34 (m, 7 H), 7.62
(d, J = 8.5 Hz, 2 H), 9.95 (br s, 1 H, NH, D2O exchangeable).
13C NMR (75 MHz, DMSO-d6): d = 31.2, 38.4, 119.5, 123.4, 126.4,
128.7, 128.8, 129.1, 139.6, 141.6, 170.8.
References
(1) (a) Rimola, A.; Tosoni, S.; Sodupe, M.; Ugliengo, P. Chem.
Phys. Lett. 2005, 408, 295. (b) Comerford, J. W.; Clark, J.
H.; Macquarrie, D. J.; Breeden, S. W. Chem. Commun. 2009,
2562.
(2) Albericio, F. Curr. Opin. Chem. Biol. 2004, 8, 211.
(3) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; Wiley: New York, 1999, 494.
(b) Mulzer, J. In Comprehensive Organic Synthesis, Vol. 6;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
322.
HRMS: m/z [M]+ calcd for C15H15NO: 225.1154; found: 225.1154.
3-Phenyl-N-(pyridin-3-yl)propanamide (7d)
Yield: 577 mg (91%); pale-yellow solid; mp 121–123 °C (Lit.35
124–125 °C).
IR (KBr): 3303, 3242, 3174, 3059, 3025, 2997, 2949, 2898, 2847,
2785, 1698, 1612, 1584, 1423, 1302, 1191, 895, 698 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.66 (t, J1 = 7.53 Hz,
J2 = 7.8 Hz, 2 H), 2.92 (t, J1 = 7.89 Hz, J2 = 7.39 Hz, 2 H), 7.16–
7.34 (m, 6 H), 8.01–8.04 (m, 1 H), 8.24 (d, J = 4.6 Hz, 1 H), 8.71 (d,
J = 2.3 Hz, 1 H), 10.13 (br s, 1 H, NH, D2O exchangeable).
13C NMR (75 MHz, DMSO-d6): d = 30.6, 37.7, 123.5, 125.5, 128.2,
128.3, 135.7, 140.6, 140.9, 143.9, 170.9.
HRMS: m/z [M]+ calcd for C14H14N2O: 226.1106; found: 226.1108.
(4) Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983.
(5) Vogel, A. Practical Organic Chemistry; Longman Scientific
& Technical and Wiley: New York, 1989, 708.
(6) For selected examples, see: (a) Valeur, E.; Bradley, M.
Chem. Soc. Rev. 2009, 38, 606. (b) Kang, S. B.; Yim, H. S.;
Won, J. E.; Kim, M. J.; Kim, J. J.; Kim, H. K.; Lee, S. G.;
Yoon, Y. J. Bull. Korean Chem. Soc. 2008, 29, 1025.
(c) Kang, Y. J.; Chung, H. A.; Kim, J. J.; Yoon, Y. J.
Synthesis 2002, 733. (d) Wakasugi, K.; Nakamura, A.;
Tanabe, Y. Tetrahedron Lett. 2001, 42, 7427. (e) Katrizky,
A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210.
(f) Kondo, K.; Sekimoto, E.; Nakao, J.; Murakami, Y.
Tetrahedron 2000, 56, 5843. (g) Yasuhara, T.; Nagaoka, Y.;
Tomioka, K. J. Chem. Soc., Perkin Trans. 1 1999, 2233.
(h) Blagbrough, I. S.; Geall, A. J. Tetrahedron Lett. 1998,
39, 439. (i) Kartrizky, A. R.; Yang, B.; Semenzin, D. J. Org.
Chem. 1997, 62, 726. (j) Kartrizky, A. R.; Chang, H. X.
Synthesis 1995, 503. (k) Murahashi, S.-I.; Naota, T.
Synthesis 1993, 433. (l) Akikusa, N.; Mitsui, K.; Sakamoto,
T.; Kikugawa, Y. Synthesis 1992, 1058. (m) Kikukawa, Y.;
Mitsui, K.; Sakamoto, T.; Kawase, M.; Tamiya, H.
Tetrahedron Lett. 1990, 31, 243.
N-Phenethyl-3-phenylpropanamide (7e)
Yield: 568 mg (80%); pale-yellow solid; mp 95–96 °C (Lit.36 96–
97 °C).
IR (KBr): 3299, 3082, 3062, 3026, 2969, 2949, 2927, 2862, 1635,
1603, 1543, 1451, 1190, 745 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.40 (t, J = 7.7 Hz, 2 H), 2.71 (t,
J = 7.0 Hz, 2 H), 2.92 (t, J = 7.7 Hz, 2 H), 3.41–3.47 (m, 2 H), 5.61
(br s, 1 H, NH, D2O exchangeable), 7.08 (t, J = 6.80, 2 H), 7.14–
7.28 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 31.7, 35.6, 38.4, 40.6, 126.2, 126.4,
128.4, 128.5, 128.6, 128.78, 138.9, 140.9, 172.1.
HRMS: m/z [M]+ calcd for C17H19NO: 253.1467; found: 253.1467.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 42–50

50
B. R. Kim et al.
PAPER
(7) (a) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry, 5th ed.; Wiley: New York, 2001, 506.
(b) Urben, P. G. Bretherick’s Handbook of Reactive
Chemical Harzards; Butterworth-Heinemann: Oxford,
1999, 746.
(8) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G.
R.; Leazer, J. L. Jr.; Linderman, R. J.; Lorenz, K.; Manley,
J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green
Chem. 2007, 9, 411.
(9) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry, 5th ed.; Wiley: New York, 2001, 510.
(10) Pryor, W. A.; Gu, J. T.; Church, D. F. J. Org. Chem. 1985,
50, 185.
(20) Heine, H. W.; Zibuck, R.; Vanden, H.; William, J. A. J. Am.
Chem. Soc. 1982, 104, 3691.
(21) Singh, H.; Aggarwal, S. K.; Malhotra, N. Synthesis 1983,
791.
(22) Robert-Piessard, S.; Le Baut, G.; Courant, J.; Brion, J. D.;
Sparfel, L.; Bouhayat, S.; Petit, J. Y.; Sanchez, R. Y.; Juge,
M. Eur. J. Med. Chem. , 1990, 25, 9.
(23) Gajda, T.; Zweirzak, A. Synthesis 1981, 1005.
(24) Boyer, J. H.; Hamer, J. J. Am. Chem. Soc. 1955, 77, 951.
(25) Cromwell, N. H.; Creger, P. L.; Cook, K. E. J. Am. Chem.
Soc. 1956, 78, 4412.
(26) Alliger, G. Jr.; Smith, G. E. P.; Carr, E. L.; Stevens, H. P.
J. Org. Chem. 1949, 14, 962.
(11) Akiyama, S.; Tajima, K.; Nakatsuji, S.; Nakashima, K.;
Abiru, K.; Watanabe, M. Bull. Chem. Soc. Jpn. 1995, 68,
2043.
(27) Kumar, D. K.; Jose, D. A.; Dastidar, P.; Das, A. Langmuir
2004, 20, 10413.
(28) Stanovnik, B.; Tisler, M.; Golob, V.; Hvala, I.; Nikolic, O.
(12) Caldwell, S. E.; Porter, N. A. J. Am. Chem. Soc. 1995, 117,
8676.
(13) Nakanishi, W.; Ikeda, Y.; Iwamura, H. J. Org. Chem. 1982,
47, 2275.
J. Heterocycl. Chem. 1980, 17, 733.
(29) Motoshima, K.; Hiwasa, Y.; Yoshikawa, M.; Fujimoto, K.;
Tai, A.; Kakuta, H.; Sasaki, K. ChemMedChem 2007, 2,
1527.
(14) Staab, H. A.; Rohr, W.; Graf, F. Chem. Ber. 1965, 98, 1122.
(15) Hamada, Y.; Mizuno, A.; Ohno, T.; Shioiri, T. Chem.
Pharm. Bull. 1984, 32, 3683.
(16) Icli, S.; Kandil, K. A.; Thankachan, C.; Tidwell, T. T. Can.
J. Chem. 1975, 53, 979.
(17) Frish, M. J.; Rrucks, G. W.; Head-Gordon, M. H.; Gill, P. M.
W.; Wong, M. W.; Foresman, J. B.; Jhonson, B. G.;
Schlegel, H. B.; Robb, M. A.; Replogle, E. S.; Gomperts, R.;
Andres, J. L.; Raghavachari, K.; Binkley, J. S.; Gonzalez, C.;
Martin, R. L.; Fox, D. J.; Defrees, D. J.; Baker, J.; Stewart,
J. J. P.; Pople, J. A. Gaussian 03; Gaussian Inc.: Pittsburgh,
2003.
(30) Paruszewski, R.; Strupinska, M.; Rostafinska-Suchar, G.;
Stables, J. P. Protein Pept. Lett. 2003, 10, 475.
(31) Yeung, J. M.; Knaus, E. E. Eur. J. Med. Chem. 1986, 21,
181.
(32) Natta, G.; Pino, P.; Ercoli, R. J. Am. Chem. Soc. 1952, 74,
4496.
(33) Joshi, B. P.; Hosangadi, B. D. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1978, 16, 1067.
(34) Shiina, I.; Kawakita, Y. Tetrahedron 2004, 60, 4729.
(35) Barton, D. H. R.; Ozbalik, N.; Vacher, B. Tetrahedron 1988,
44, 3501.
(36) Kametani, T.; Umezawa, O. Chem. Pharm. Bull. 1966, 14,
369.
(37) Britsun, V. N. Russ. J. Org. Chem. 2006, 42, 1719.
(18) Saito, Y.; Ouchi, H.; Takahata, H. Tetrahedron 2008, 64,
11129.
(19) Voronkov, M. G.; Tsyrendorzhieva, I. P.; Parkhlin, V. I.
Russ. J. Org. Chem. 2008, 44, 481.
Synthesis 2012, 44, 42–50
© Thieme Stuttgart · New York