Silica gel promotes cascade synthesis of 2-(heteroaryl)acetamide derivatives from isocyanides, dialkylamines, and heteroarylcarbaldehydes

Article abstract of DOI:10.1080/00397911.2010.486509

Addition of an isocyanide to an iminium ion intermediate that forms from the reaction between a heteroarylcarbaldehyde and a secondary amine leads to formation of sterically congested 2-(heteroaryl)acetamide derivatives in the presence of silica gel at ro

Full text of DOI:10.1080/00397911.2010.486509

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Silica Gel Promotes Cascade Synthesis
of 2-(Heteroaryl)acetamide Derivatives
from Isocyanides, Dialkylamines, and
Heteroarylcarbaldehydes
Ali Ramazani a , Aram Rezaei a , Amir Mahyari a , Morteza Rouhani
a , Mehdi Khoobi a , Elham Yaaghubi b , Hana Shabrendi b , Esmail
Vessally b , Vahid Azizkhani c , Issa Amini c , Hamed Lashgari c ,
Ghafar Noohi c , Zahra Shaghaghi c & Fariba Sadri c
a Chemistry Department , Zanjan University , Zanjan , Iran
b Chemistry Department , Payam Noor University , Zanjan , Iran
c Chemistry Department , Payam Noor University, Abhar , Zanjan ,
Iran
Published online: 30 Mar 2011.
To cite this article: Ali Ramazani , Aram Rezaei , Amir Mahyari , Morteza Rouhani , Mehdi Khoobi ,
Elham Yaaghubi , Hana Shabrendi , Esmail Vessally , Vahid Azizkhani , Issa Amini , Hamed Lashgari ,
Ghafar Noohi , Zahra Shaghaghi & Fariba Sadri (2011) Silica Gel Promotes Cascade Synthesis of 2-
(Heteroaryl)acetamide Derivatives from Isocyanides, Dialkylamines, and Heteroarylcarbaldehydes,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:10, 1444-1454, DOI: 10.1080/00397911.2010.486509
To link to this article: http://dx.doi.org/10.1080/00397911.2010.486509
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Synthetic Communications1, 41: 1444–1454, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.486509
SILICA GEL PROMOTES CASCADE SYNTHESIS OF
2-(HETEROARYL)ACETAMIDE DERIVATIVES FROM
ISOCYANIDES, DIALKYLAMINES, AND
HETEROARYLCARBALDEHYDES
Ali Ramazani,1 Aram Rezaei,1 Amir Mahyari,1
Morteza Rouhani,1 Mehdi Khoobi,1 Elham Yaaghubi,2
Hana Shabrendi,2 Esmail Vessally,2 Vahid Azizkhani,3
Issa Amini,3 Hamed Lashgari,3 Ghafar Noohi,3
Zahra Shaghaghi,3 and Fariba Sadri3
1Chemistry Department, Zanjan University, Zanjan, Iran
2Chemistry Department, Payam Noor University, Zanjan, Iran
3Chemistry Department, Payam Noor University, Abhar, Zanjan, Iran
GRAPHICAL ABSTRACT
Abstract Addition of an isocyanide to an iminium ion intermediate that forms from the
reaction between a heteroarylcarbaldehyde and a secondary amine leads to formation of
sterically congested 2-(heteroaryl)acetamide derivatives in the presence of silica gel at
room temperature. The structures of the products were deduced from their 1H NMR,
13C NMR, and infrared spectra and mass spectrometry.
Keywords Heteroarylcarbaldehyde; iminium ion; isocyanide; multicomponent reaction;
secondary amine; silica gel
INTRODUCTION
Multicomponent reactions (MCRs)[1–9] have recently emerged as valuable tools
in the preparation of structurally diverse chemical libraries of druglike heterocyclic
compounds.[1–3] In 1921, Passerini[10] pioneered the use of isocyanides and success-
fully developed a three-component synthesis of a-acyloxycarboxamides by reaction
of carboxylic acid, an aldehyde, and an isonitrile.[11] However, the most important
breakthrough came in 1959 when Ugi[12,13] described a four-component synthesis
of a -acylamino amides from an aldehyde, an amine, an acid, and an isocyanide.[12,13]
Received November 21, 2009.
Address correspondence to Ali Ramazani, Chemistry Department, Zanjan University, P.O. Box
45195-313, Zanjan, Iran. E-mail: aliramazani@gmail.com
1444

SYNTHESIS OF 2-(HETEROARYL)ACETAMIDES
1445
Scheme 1. Preparation of 2-(heteroaryl)acetamide derivatives 7 (see Table 1).
This reaction, named after Ugi (Ugi 4CR or U-4CR) has become one of the most
investigated transformations during the past decade, in conjunction with enabling
technologies such as high-throughput screening and combinatorial chemistry.[14–20]
The ability of an isonitrile to undergo easy R-addition with a nucleophile and an
electrophile under mild conditions has made them popular reactants for the develop-
ment of novel MCRs.[21] Isocyanides,[22] regarded for many years as compounds with
an unpleasant odor and very few chemical and pharmaceutical applications, are now
looked upon as useful synthons, attributed primarily to the renaissance of the
isocyanide-based MCR[14,23] for the Passerini three-component (P-3CR)[24,25] and
more importantly the Ugi four-component (U-4CR) reactions.[12,13,26]
Thiophene and pyridine derivatives are important heterocyclic compounds that
are widely used as building blocks in many agrochemicals and pharmaceuticals.[27]
The benzene ring of a biologically active compound may often be replaced by a thio-
phene without loss of activity.[28] This is seen in examples such as the nonsteroidal
anti-inflammatory drug (NSAID) lornoxicam, the thiophene analog of piroxicam.[28]
As part of our ongoing program to develop efficient and robust methods for the
preparation of organic compounds,[29–39] we sought to develop a convenient prep-
aration of sterically congested 2-(heteroaryl)acetamide derivatives 7 from an isocya-
nide, a secondary amine, and heteroarylcarbaldehydes in the presence of silica gel at
room temperature in excellent yields under neutral conditions (Scheme 1).
RESULTS AND DISCUSSION
As part of our ongoing program to develop efficient and robust methods for
the preparation of organic compounds,[29–39] we sought to develop an efficient route
for the one-pot synthesis of sterically congested 2-(heteroaryl)acetamide deriva-
tives[40–43] 7 from simple and readily available isocyanides 4, secondary amines 1,
and heteroarylcarbaldehydes 2 (Scheme 1 and Table 1). The reaction occurs
smoothly in the presence of silica-gel powder at ambient temperature to produce
2-(heteroaryl)acetamide derivatives 7 in 78–96% yields (Scheme 1 and Table 1).
The completion of the reaction was checked by thin-layer chromatography (TLC).

1446
7
A. RAMAZANI ET AL.
Table 1. Synthesis of 2-(heteroaryl)acetamide derivatives 7 (see Scheme 1)
HetAryl
R2
R1
R
Yield (%)
a
b
c
d
e
f
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
4-Pyridyl
4-Pyridyl
Cyclohexyl
tert-Butyl
2,6-Dimethylphenyl
Cyclohexyl
tert-Butyl
tert-Butyl
Cyclohexyl
tert-Butyl
Cyclohexyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Methyl
Methyl
Benzyl
Benzyl
Methyl
Methyl
Benzyl
Methyl
Benzyl
Benzyl
90
87
85
78
82
93
96
87
88
92
90
80
83
g
h
i
j
k
l
Benzyl
Cyclohexyl
tert-Butyl
m
The reaction proceeds smoothly and cleanly under mild conditions, and no side reac-
tions were observed. In the absence of silica-gel powder, the reactions did not lead to
the compounds 6, and in the all cases several products were observed (based on TLC
investigations). We also used benzaldehyde in this reaction, but the yield of the cor-
responding product 7 was very low in the presence of silica-gel powder, and several
by-products were observed. It seems that electron-poor aldehyde derivatives such as
2-thiophenecarbaldehyde, 2-pyridinecarbaldehyde, and 4-pyridinecarbaldehyde are
more reactive in the reaction.
1
The structures of compounds 7a–m were deduced from their H NMR, 13C
NMR, infrared (IR), and mass spectra. For example, the IR spectrum of 7a showed
strong adsorption at 3346 cmꢀ1 indicating the presence of amide, and sharp bands at
1669 and 1500 cmꢀ1, were assigned to the amide carbonyl and the aromatic rings,
respectively. The 1H NMR spectrum of 7a consisted of two multiplets for the cyclo-
hexyl ring d ¼ 0.86–2.01 (10H, m, Cy) and d ¼ 3.91–3.93 (1H, m, CH-N of Cy), two
2
methylenes (d ¼ 3.46 and 3.81, JHH ¼ 14.0 Hz, 2CH2 of two benzyls), a methyne
(d ¼ 4.73 ppm), and an amide hydrogen atom (d ¼ 6.94 ppm), exchangeable by
D2O. The presence of diastereotopic group (PhCHAHB) in the benzyl moieties
resulted from the existence of stereogenic center (aliphatic CH) in the molecule of
7a. The phenyl and thiophene rings gave rise to characteristic signals in the aromatic
1
region. The H decoupled 13C NMR spectrum of 7a showed 17 resonances; for
example, the benzylic carbon, the aliphatic carbon (CH), and the amidic carbon were
observed at d ¼ 54.6, 62.7, and 169.1 ppm respectively. The 1H and 13C NMR spectra
of compounds 7b–m were similar to those of 7a, except for the aromatic and hetero-
aromatic moieties and the alkyl groups, which exhibited characteristic signals with
appropriate chemical shifts.
Although we have not established the mechanism of the reaction between the
alkyl isocyanides 4, secondary amines 1, and heteroarylcarbaldehyde 2 in the pres-
ence of the silica gel in an experimental manner, a plausible reaction sequence that
accounts for the formation of the product 7 is shown in Scheme 2. Thus, conden-
sation of a heteroarylcarbaldehyde 2 and a secondary amine 1 gave the iminium
ion intermediate 3, which reacted with the alkyl isocyanides 4 to afford the

SYNTHESIS OF 2-(HETEROARYL)ACETAMIDES
1447
Scheme 2. Proposed mechanism for the formation of 2-(heteroaryl)acetamide derivatives 7.
intermediate 5. The ionic intermediate 5 was converted to intermediate 6, and the
intermediate 6 was unstable and quickly converted to compound 7 (Scheme 2).
CONCLUSIONS
In summary, we develop an efficient route for the one-pot synthesis of sterically
congested 2-(heteroaryl)acetamide derivatives 7 from simple and readily available
alkyl isocyanides 4, secondary amine 1, and heteroarylcarbaldehyde 2 in the presence
of silica gel (Scheme 1 and Table 1). Its ease of workup and good yields makes it a
useful addition to modern synthetic methodologies.[44–55]
EXPERIMENTAL
Starting materials and solvents were obtained from Merck (Germany) and
Fluka (Switzerland) and were used without further purification. The methods used
to follow the reactions were TLC and NMR. TLC and NMR indicated that there
was no side product. Melting points were measured on an Electrothermal 9100
apparatus and are uncorrected. IR spectra were measured on a Shimadzu IR-460
1
spectrometer. H and 13C NMR spectra were measured (CDCl3 solution) with a
Bruker DRX-250 Avance spectrometer at 250.0 and 62.5 MHz, respectively. Elemen-
tal analyses were performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra
were recorded on a Finnigan-MAT 8430 mass spectrometer operating at an ioniza-
tion potential of 20 eV. Flash chromatography columns were prepared from Merck
silica-gel powder.
General Procedure for the Preparation of Compounds 7a–e,
Exemplified by 7a
A mixture of dibenzylamine (0.19 ml, 1 mmol) and 2-thiophenecarbaldehyde
(0.09 ml, 1 mmol) in dry CH2Cl2 (5 mL) was stirred at room temperature for 0.5 h.

1448
A. RAMAZANI ET AL.
A solution of cyclohexylisocyanide (0.13 ml, 1 mmol) in 2 mL dry CH2Cl2 at
ꢀ10 ꢁC was added rapidly to this mixture, and the mixture stirred for 5 min. at
ꢀ10 ꢁC. Silica-gel powder (Merck, 1 g) was quickly poured into the reaction mixture,
and the mixture was allowed to warm up to room temperature. The solvent was
removed under reduced pressure, and the residue was allowed to remain for 24 h
in solvent-free conditions at room temperature and then placed over a flash column
of silica-gel powder (5 g). Flash column chromatography was washed using pet-
roleum ether–diethyl ether (10:1) as eluent. The solvent was removed under reduced
pressure, and the products were obtained.
Selected Data
N-Cyclohexyl-2-(dibenzylamino)-2-(2-thienyl)acetamide
(7a). Orange
oil; yield 90%. IR (KBr): t ¼ 3346 (NH), 3030, 2930, 1669, 1500, 1453, 1369 and
1253 cmꢀ1. 1H NMR (CDCl3): d ¼ 0.86–2.01 (m, 10H, Cy), 3.46 and 3.81 (AB quar-
2
tet, 4H, JHH ¼ 13.8 Hz, 2CH2 of benzyl groups), 3.91–3.93 (m, 1H, CH-N of Cy),
4.73 (s, 1H, CH), 6.94 (bs, 1H, NH, exchanged by D2O addition), 7.01–7.06 (m,
3H, thiophene), 7.26–7.68 (m, 10H, 2C6H5).13C NMR (CDCl3): d ¼ 24.6 and 24.7
(2CH2, b of Cy), 25.5 (1CH2, c of Cy), 33.0 and 33.2 (2CH2, a of Cy), 48.0 (CHNH
of Cy), 54.6 (2CH2 of benzyl groups), 62.7 (CH), 125.8, 126.3, 127.4 (3CH of thio-
=
phene), 138.6 (Cipso of thiophene), 128.4, 128.6, 128.7 (10 CH), 136.7 [2 Cipso, (C C)
of 2C6H5]; 169.1 (CONH). MS: m=z (%); 418 (Mþ, 2), 294 (10), 292 (100), 196 (20),
and 91 (100). C26H30N2OS (418.21): C, 74.60; H, 7.22; N, 6.69; S, 7.66%. Found: C,
74.30; H, 7.19; N, 6.57; S, 7.51%.
N-(tert-butyl)-2-(dibenzylamino)-2-(2-thienyl)acetamide (7b). Colorless
oil; ylide: 87%. IR (KBr): t ¼ 3361 (NH), 3030, 2969, 1684, 1515, 1453, 1369, and
1
1230 cmꢀ1. H NMR (CDCl3): d ¼ 1.40 (s, 9H, CMe3), 3.44 and 3.82 (AB quartet,
2
4H, JHH ¼ 13.8 Hz, 2CH2 of benzyl groups), 4.57 (s, 1H, CH), 6.99 (bs, 1H, NH,
exchanged by D2O addition), 7.04–7.07 (m, 3H, thiophene), 7.26–7.38 (m, 10H, 2
C6H5). 13C NMR (CDCl3): d ¼ 28.8 (3CH3 of CMe3), 51.1 (C of CMe3NH), 54.6
(2CH2 of benzyl groups), 63.2 (CH), 125.9, 126.3, 127.4 (3CH of thiophene), 138.7
=
(Cipso of thiophene), 128.6, 128.7 (10 CH), 136.2 (2Cipso,(C C) of 2C6H5), 169.5
(CONH). MS: m=z (%): 393 (Mþ, 4), 294 (10), 292 (100), 279 (5), 216 (5), 196
(20), 181 (15), 111 (10) and 91 (100). Anal. calcd. for C24H28N2OS (392.19): C,
73.43; H, 7.19; N, 7.14%. Found: C, 72.90; H, 7.17; N, 7.12%.
2-(Dibenzylamino)-N-(2,6-dimethylphenyl)-2-(2-thienyl)acetamide (7c).
Colorless oil; ylide: 85%. IR (KBr): t ¼ 3423 (NH), 3030, 2923, 1646, 1500, 1453,
1392, and 1230 cmꢀ1
.
1H NMR (CDCl3): d ¼ 1.84 and 1.91 (s, 6H, 2CH3 of
2
C6H3), 3.56 and 4.38 (AB quartet, 2H, JHH ¼ 14 Hz, CH2 of benzyl), 4.16 and
2
4.27 (AB quartet, 2H, JHH ¼ 16.3 Hz, CH2 of benzyl), 5.24 (s, 1H, CH), 6.99 (bs,
1H, NH, exchanged by D2O addition), 6.53–6.85 (m, 3H, C6H3), 6.96–7.03 (m,
3H, thiophene), 7.16–7.69 (m, 10H, 2C6H5). 13C NMR (CDCl3): d ¼ 19.0 and 19.4
(2CH3 of C6H3), 52.0 and 54.7 (2CH2 of benzyl groups), 60.8 (CH), 125.1, 126.5,
127.3 (3CH of thiophene), 126.9, 127.0, 127.5 (3CH of C6H3), 139.6 (Cipso of
thiophene), 128.2, 129.1 (10CH of 2C6H5), 137.8 (2Cipso(C¼C) of 2C6H5), 139.4
(2Cipso(C¼C) of C6H3), 166.1 (CONH). MS: m=z (%); 440 (Mþ, 9), 294 (10), 292

SYNTHESIS OF 2-(HETEROARYL)ACETAMIDES
1449
(100), 279 (5), 216 (5), 196 (20), 181 (15), 111 (45), and 91 (100). Anal. calcd. for
C28H2 8N2OS (440.19): C, 76.33; H, 6.41; N, 6.36%. Found: C, 76.27; H, 6.32; N,
6.25%.
2-[Benzyl(methyl)amino]-N-cyclohexyl-2-(2-thienl)acetamide (7d). Col-
orless oil; yield: 78%. IR (KBr): t ¼ 3301 (NH), 2931, 1650, 1519, 1450, 1388 and
1
1249 cmꢀ1. H NMR (CDCl3): d ¼ 1.18–1.94 (m, 10H, Cy), 2.13 (s, 3H, NCH3),
2
3.43 and 3.61 (AB quartet, 2H, JHH ¼ 13.3 Hz, CH2 of benzyl), 3.12 (m, 1H,
CH-N of Cy), 4.36 (s, 1H, CH), 7.18 (bs, 1H, NH, exchanged by D2O addition),
6.97–7.05 (m, 3H, thiophene) 7.26–7.69 (m, 5H, C6H5). 13C NMR (CDCl3):
d ¼ 24.7 (2CH2,b of Cy), 25.5 (1CH2,c of Cy), 33.0 (2CH2, a of Cy), 39.4 (NCH3),
47.8 (CH-N of Cy), 59.3 (CH2 of benzyl), 69.3 (CH), 125.8, 126.5, 127.4 (3CH of
thiophene), 138.3 (Cipso of thiophene), 128.3, 128.5, 128.7 (5CH of C6H5),
(2Cipso(C¼C) of C6H5), 169.6 (CONH). MS: m=z (%); 342 (Mþ, 2), 279 (9), 211
(16), 196 (18), 167 (14), 149 (23), 123 (20), 106 (83), 91 (100), 78 (15), 65 (22), 51
(19), and 41 (7). Anal. calcd. for C20H26N2OS (342.18): C, 70.14; H, 7.65; N,
8.18%. Found: C, 70.12; H, 7.62; N, 8.15%.
2-[Benzyl(methyl)amino]-N-(tert-butyl)-2-(2-thienyl)acetamide
(7e).
White crystals; yield: 82%. IR (KBr): t ¼ 3292 (NH), 2923, 1669, 1515, 1461,
1392, and 1230 cmꢀ1
.
1H NMR (CDCl3): d ¼ 1.39 (s, 9H, CMe3), 2.12 (s, 3H,
2
NCH3), 3.43 and 3.58 (AB quartet, 2H, JHH ¼ 13.5 Hz, CH2 of benzyl), 4.28 (s,
1H, CH), 7.19 (bs, 1H, NH, exchanged by D2O addition), 6.98–7.03 (m, 3H, thio-
phene), 7.26–7.33 (m, 5H, C6H5). 13C NMR (CDCl3): d ¼ 28.6 (3CH3 of CMe3),
39.4 (NCH3), 50.8 (1C of CMe3NH), 59.3 (CH2 of benzyl), 70.0 (CH), 125.7,
126.4, 127.3 (3CH of thiophene), 138.5 (Cipso of thiophene), 128.3, 128.5 (5CH of
C6H5), 138.2 (Cipso(C¼C) of C6H5), 169.8 (CONH). MS: m=z (%); 316 (Mþ, 5), 297
(5), 287 (75), 211 (9), 196 (13), 181 (4), 106 (18), 91 (100), 65 (12), 51 (5), and 41
(5). Anal. calcd. for C18H24N2OS (316.16): C, 68.32; H, 7.64; N, 8.85%. Found: C,
68.22; H, 7.62; N, 8.55%.
N-(tert-butyl)-2-(dibenzylamino)-2-(2-pyridyl)acetamide (7f). Green vis-
cous oil; yield: 93%. IR (KBr): t ¼ 3343 (NH), 3035, 2959, 1699, 1524, 1479, 1367,
and 1258 cmꢀ1. 1H NMR (CDCl3): d ¼ 1.38 (s, 9H, CMe3), 3.50 and 3.94 (AB quar-
2
tet, 4H, JHH ¼ 13.75 Hz, 2CH2 of benzyl groups), 4.49 (s, 1H, CH), 7.21 (bs, 1H,
NH, exchanged by D2O addition), 7.26–8.66 (m, 14H, arom). 13C NMR (CDCl3):
d ¼ 28.8 (3CH3 of CMe3), 51.0 (C of CMe3NH), 55.0 (2CH2 of benzyl groups),
68.9 (CH), 127.6, 128.5, 128.9 (10CH of 2C6H5), 138.7 (2Cipso(C¼C) of 2C6H5),
122.5, 125.4, 136.1, 148.9 (4CH of pyridine), 156.1 (Cipso of pyridine), 169.7
(CONH). Anal. calcd. for C25H29N3O (387.52): C, 77.48; H, 7.54; N, 10.84%.
Found: C, 77.41; H, 7.49; N, 7.50%.
N-Cyclohexyl-2-(dibenzylamino)-2-(2-pyridyl)acetamide (7g). Colorless
oil; yield: 96%. IR (KBr): t ¼ 3342 (NH), 3029, 2934, 1678, 1509, 1453, 1372, and
1252 cmꢀ1. 1H NMR (CDCl3): d ¼ 1.25–1.92 (m, 10H, Cy), 3.50 and 3.93 (AB quar-
2
tet, 4H, JHH ¼ 13.75 Hz, 2CH2 of benzyl groups), 3.70–3.85 (m, 1H, CH-N of Cy),
4.54 (s, 1H, CH), 7.21 (bs, 1H, NH, exchanged by D2O addition), 7.24–8.65 (m, 14H,
arom). 13C NMR (CDCl3): d ¼ 24.6 and 24.7 (2CH2, b of Cy), 25.6 (1CH2, c of Cy),
33.0 and 33.1 (2CH2, a of Cy), 47.8 (CHNH of Cy), 54.8 (2CH2 of benzyl groups),

1450
A. RAMAZANI ET AL.
68.2 (CH), 127.3, 128.5, 128.9 (10CH of 2C6H5), 138.6 (2Cipso(C¼C) of 2C6H5), 122.5,
125.3, 136.2, 148.9 (4CH of pyridine), 156.2 (Cipso of pyridine), 169.2 (CONH). MS:
m=z (%); 414 (Mþ, 2), 287 (80), 218 (35), 197 (12), 196 (25), 180 (10), 119 (7) and 91
(100). Anal. calcd. for C27H31N3O (413.55): C, 78.42; H, 7.56; N, 10.16%. Found: C,
78.40; H, 7.53; N, 10.11%.
2-[Benzyl(methyl)amino]-N-(tert-butyl)-2-(2-pyridyl)acetamide (7h). Red
viscous oil; yield: 87%; IR (KBr): t ¼ 3365 (NH), 3031, 2964, 1684, 1520, 1435,
1364, and 1227 cmꢀ1
.
1H NMR (CDCl3) d ¼ 1.37 (s, 9H, CMe3), 2.11 (s, 3H,
2
NCH3), 3.54 and 3.67 (AB quartet, 2H, JHH ¼ 13.25 Hz, CH2 of benzyl), 4.16 (s,
1H, CH), 7.19 (bs, 1H, NH, exchanged by D2O addition), 7.22–8.64 (m, 9H, arom).
13C NMR (CDCl3): d ¼ 28.7 (3CH3 of CMe3), 39.3 (NCH3), 50.9 (1C of CMe3NH),
59.7 (CH2 of benzyl), 77.22 (CH), 127.3, 128.4, 128.8 (5CH of C6H5), 138.9
(Cipso(C¼C) of C6H5), 122.7, 124.5, 136.4, 149.4 (4CH of pyridine), 162.2 (Cipso of
pyridine), 169.6 (CONH). MS: m=z (%); 312 (Mþ, 20), 287 (2), 211 (100), 196 (2),
192 (7), 121 (10), 107 (3), and 91 (30). Anal. calcd. for C19H25N3O (311.42): C,
73.28; H, 8.09; N, 13.49%. Found: C, 73.25; H, 8.05; N, 13.43%.
2-[Benzyl(methyl)amino]-N-cyclohexyl-2-(2-pyridyl)acetamide
(7i).
Colorless oil; yield: 88%; IR (KBr): t ¼ 3332 (NH), 3031, 2939, 1677, 1530, 1455,
1
1372, and 1251 cmꢀ1. H NMR (CDCl3): d ¼ 1.18–1.94 (m, 10H, Cy), 2.10 (s, 3H,
2
NCH3), 3.53 and 3.66 (AB quartet, 2H, JHH ¼ 13.25 Hz, CH2 of benzyl),
3.74–3.82 (m, 1H, CH-N of Cy), 4.21 (s, 1H, CH), 7.20 (bs, 1H, NH, exchanged
by D2O addition), 7.22–8.63 (m, 9H, arom). 13C NMR (CDCl3): d ¼ 24.7 (2CH2,
b of Cy), 25.5 (1CH2,c of Cy), 32.9 and 33.0 (2CH2, a of Cy), 39.3 (NCH3), 47.7
(CH-N of Cy), 59.8 (CH2 of benzyl), 75.7 (CH), 127.2, 128.4, 129.0 (5CH of
C6H5), 138.2 (Cipso(C¼C) of C6H5), 122.8, 124.5, 136.4, 149.4 (4CH of pyridine),
156.4 (Cipso of pyridine), 169.5 (CONH). MS: m=z (%); 338 (Mþ, 2), 211 (100),
182 (3), 170 (4), 121 (10), 105 (4) and 91 (55). Anal. calcd. for C21H27N3O
(337.46) C, 74.74; H, 8.06; N, 12.45%. Found: C, 74.70; H, 8.01; N, 12.39%.
N-Benzyl-2-(dibenzylamino)-2-(2-pyridyl)acetamide (7j). Yellow viscous
oil; yield: 92%. IR (KBr): t ¼ 3339 (NH), 3028, 2930, 1677, 1515, 1455, 1366, and
2
1250 cmꢀ1. 1H NMR (CDCl3): d ¼ 3.49 and 3.96 (AB quartet, 4H, JHH ¼ 13.75 Hz,
2CH2 of benzyl groups), 4.55 (m, 2H, CH2-NH), 4.64 (s, 1H, CH), 6.98 (bs, 1H, NH,
exchanged by D2O addition), 7.36 (m, 19H, arom). 13C NMR (CDCl3): d ¼ 43.4
(CH2-NH), 54.9 (2CH2 of benzyl groups), 68.0 (CH), 127.3, 127.4, 127.7, 128.5,
128.7, 128.9 (15CH of 3C6H5), 138.3 and 138.5 (3Cipso(C¼C) of 3C6H5), 122.6,
125.4, 136.3, 148.9 (4CH of pyridine), 155.9 (Cipso of pyridine), 170.4 (CONH).
MS: m=z (%); 422 (Mþ, 30), 287 (95), 226 (45), 211 (5), 197 (23), 195 (40), 180
(10), 106 (13), and 91 (100). Anal. calcd. for C28H27N3O (421.22): C, 79.78; H,
6.46; N, 9.97%. Found: C, 79.75; H, 6.40; N, 9.80%.
N-Benzyl-2-[benzyl(methyl)amino]-2-(2-pyridyl)acetamide (7k). Yellow
viscous oil; yield: 90%. IR (KBr): t ¼ 3339 (NH), 3030, 2932, 1680, 1519, 1454,
1
1362, and 1240 cmꢀ1. H NMR (CDCl3): d ¼ 2.13 (s, 3H, NCH3), 3.56 and 3.63
2
(AB quartet, 2H, JHH ¼ 13.5 Hz, CH2 of benzyl), 4.33 (1H, s, CH), 4.53 (m, 2H,
CH2-NH), 7.22 (bs, 1H, NH, exchanged by D2O addition), 7.27–8.65 (m, 14H,
arom). 13C NMR (CDCl3): d ¼ 39.5 (NCH3), 43.3 (CH2-NH), 59.8 (CH2 of benzyl),

SYNTHESIS OF 2-(HETEROARYL)ACETAMIDES
1451
75.2 (CH), 127.2, 127.3, 127.7, 128.3, 128.6, 129.0 (10CH of C6H5), 138.1 and 138.3
(2Cipso(C¼C) of 2C6H5), 122.9, 124.8, 136.5, 149.5 (4CH of pyridine), 156.0 (Cipso of
pyridine), 170.6 (CONH). MS: m=z (%); 345 (Mþ, 4), 226 (7), 211 (25), 120 (20), 106
(15), 91 (50), 58 (28), and 43 (100). Anal. calcd. for C22H23N3O (345.44): C, 76.49; H,
6.71; N, 12.16%. Found: C, 76.40; H, 6.68; N, 12.13%.
N-Cyclohexyl-2-(dibenzylamino)-2-(4-pyridyl)acetamide (7 l). Colorless
oil; yield: 80%. IR (KBr): t ¼ 3324 (NH), 3033, 2924, 1666, 1500, 1453, 1375, and
1258 cmꢀ1. 1H NMR (CDCl3): d ¼ 1.25–2.03 (m, 10H, Cy), 3.32 and 3.83 (AB quar-
2
tet, 4H, JHH ¼ 13.75 Hz, 2CH2 of benzyl groups), 3.86–3.99 (m, 1H, CH-N of Cy),
4.34 (s, 1H, CH), 7.12 (bs, 1H, NH, exchanged by D2O addition), 7.15–8.64 (m, 14H,
arom). 13C NMR (CDCl3): d ¼ 24.6 and 24.7 (2CH2, b of Cy), 25.5 (1CH2, c of Cy),
33.0 and 33.4 (2CH2, a of Cy), 48.0 (CHNH of Cy), 54.6 (2CH2 of benzyl groups),
66.3 (CH), 127.6, 128.5, 128.8 (10CH of 2C6H5), 138.1 (2Cipso(C¼C) of 2C6H5), 125.3,
149.6 (4CH of pyridine), 149.8 (Cipso of pyridine), 168.8 (CONH). MS: m=z (%); 413
(Mþ, 2), 279 (5), 211 (13), 196 (15), 106 (80), and 91 (100). Anal. calcd. for
C27H31N3O (413.55): C, 78.42; H, 7.56; N, 10.16%. Found: C, 78.39; H, 7.50; N,
10.11%.
N-(tert-Butyl)-2-(dibenzylamino)-2-(4-pyridyl)acetamide (7 m). Colorless
oil; yield: 83%. IR (KBr): t ¼ 3334 (NH), 3032, 2964, 1696, 1520, 1481, 1365, and
1
1258 cmꢀ1. H NMR (CDCl3): d ¼ 1.42 (s, 9H, CMe3), 3.29 and 3.85 (AB quartet,
2
4H, JHH ¼ 13.75 Hz, 2CH2 of benzyl groups), 4.29 (s, 1H, CH), 7.10 (bs, 1H,
NH, exchanged by D2O addition), 7.22–8.86 (m, 14H, arom). 13C NMR (CDCl3):
d ¼ 28.8 (3CH3 of CMe3), 51.3 (C of CMe3NH), 54.7 (2CH2 of benzyl groups),
66.8 (CH), 127.6, 128.5, 128.8 (10CH of 2C6H5), 139.7 (2Cipso(C¼C) of 2C6H5),
125.4, 149.6 (4CH of pyridine), 150.3 (Cipso of pyridine), 169.2 (CONH). MS: m=z
(%); 388 (Mþ, 2), 297 (4), 287 (75), 196 (12), 106 (19), and 91 (100). Anal. calcd.
for C25H29N3O (387.52): C, 77.48; H, 7.54; N, 10.84%. Found: C, 77.40; H, 7.50;
N, 10.73%.
ACKNOWLEDGMENT
This work was supported by the Iranian National Science Foundation.
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