Microwave-assisted amidation of arylacetic acids by reaction with 2-aryl-ethylamines

Article abstract of DOI:10.1080/00397911.2011.642925

Twenty-five amides were synthesized in almost quantitative yields by microwaveassisted condensation of arylacetic acids and 2-aryl-ethylamines under solventless conditions. The N-arylethyl-arylacetylamides are intermediates of the corresponding isoquinoli

Full text of DOI:10.1080/00397911.2011.642925

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Microwave-Assisted Amidation of
Arylacetic Acids by Reaction with 2-Aryl-
ethylamines
Alajos Grün a b , Mátyás Milen c , Tamás Földesi a , Péter Ábrányi-
Balogh a , László Drahos d & György Keglevich a
a Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest, Hungary
b Research Group of the Hungarian Academy of Sciences at the
Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest, Hungary
c EGIS Pharmaceuticals, Division for Chemical Research, Budapest,
Hungary
d Hungarian Academy of Sciences, Chemical Research Center,
Budapest, Hungary
Accepted author version posted online: 29 May 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Alajos Grün , Mátyás Milen , Tamás Földesi , Péter Ábrányi-Balogh , László Drahos
& György Keglevich (2013): Microwave-Assisted Amidation of Arylacetic Acids by Reaction with 2-
Aryl-ethylamines, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:11, 1491-1498
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Synthetic Communications1, 43: 1491–1498, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.642925
MICROWAVE-ASSISTED AMIDATION OF ARYLACETIC
ACIDS BY REACTION WITH 2-ARYL-ETHYLAMINES
3
1
Alajos Gru¨n,1,2 Matyas Milen, Tamas Foldesi,
´
Peter Abranyi-Balogh, Laszlo Drahos, and
´
´
¨
1
4
´
´
Gyorgy Keglevich
´
´
´
1
¨
1Department of Organic Chemistry and Technology, Budapest University of
Technology and Economics, Budapest, Hungary
2Research Group of the Hungarian Academy of Sciences at the Department of
Organic Chemistry and Technology, Budapest University of Technology and
Economics, Budapest, Hungary
3EGIS Pharmaceuticals, Division for Chemical Research, Budapest, Hungary
4Hungarian Academy of Sciences, Chemical Research Center, Budapest,
Hungary
GRAPHICAL ABSTRACT
Abstract Twenty-five amides were synthesized in almost quantitative yields by microwave-
assisted condensation of arylacetic acids and 2-aryl-ethylamines under solventless
conditions. The N-arylethyl-arylacetylamides are intermediates of the corresponding isoqui-
noline derivates.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Amidation; arylacetic acid; arylethylamine; microwave; solventless
INTRODUCTION
The amide function plays an important role in bioorganic chemistry and is
present in numerous natural products (proteins and peptides), plastics, drugs, and
pesticides.[1–4] Therefore, the synthesis of amides is significant and well-known in
organic chemistry.[5,6] The carboxylic amides may be prepared by the acylation of
amines by carboxylic acids directly above 100 ꢀC or in the presence of well-known
condensing agents, such as carbodiimides[7–9] or benztriazole derivatives[10–13] under
Received November 14, 2011.
Address correspondence to Gyo¨rgy Keglevich, Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics, 1521 Budapest, Hungary. E-mail: gkeglevich@
mail.bme.hu
1491

¨
A. GRUN ET AL.
1492
milder conditions. Additional coupling reagents are bis(2,2,2-trifluoroethoxy)-
triphenylphosphorane,[14] diethyl phosphorobromidate,[15] 2-oxo-3-oxazolinylpho-
sphonate,[16] which can be used under mild conditions and are efficient and cheap.
The activation of carboxylic acids for the preparation of carboxamides can be
achieved by other reagents, such as TiCl4,[17] Lawesson’s reagent,[18]
Sn[N(TMS)2]2,[19] N-halosuccinimide=Ph3P,[20] Cl3CCN=Ph3P,[21] SO2ClF,[22]
ArB(OH)2,[23] (R2N)2Mg,[24] and chlorosulfonyl isocyanate.[25] Amidations were also
described in the presence of trimethylamine-borane in boiling xylene.[26] Last but not
least, the easily available Fe3þ-K-10 montmorillonite clay is mentioned as an
efficient catalyst for amidation.[27] The only disadvantage is that the condensation
is carried out in boiling chloroform for prolonged (7.5–9 h) reaction times.
Microwave (MW) irradiation is a useful tool to conduct reactions efficiently
in short reaction times.[28] Condensation is a typical reaction that may be well
accomplished under MW conditions.[29] Not only thermally well-established
esterifications and amidations of carboxylic acids but also the otherwise thermally
impossible esterifications of phosphinic acids could be performed under MW
irradiation.[30,31] The use of the MW technique is often associated with solventless
conditions offering an additional advantage. Recently, the preparation of amides
under solvent-free conditions has been reported.[32–35]
It was a challenge for us to study the condensation of arylacetic acids with
2-aryl-ethylamines under MW and solventless conditions. The resulting amides
would be valuable intermediates of the Bischler–Napieralski ring-closure reactions.
Beside this, these amides may be the starting materials for a variety of alkaloids or
their synthetic derivatives. For example, amide A was converted to racemic lirinidine
belonging to the family of aporphine alkaloids or to racemic nuciferine, in seven or
eight steps, respectively.[36] Tilacorine belonging to bisbenzylizoquinolines with more
complicated structure, that is, among others, the alkaloid of Tilacora racemosa,[37]
was synthesized from amide B by Pachaly et al.[38–40] The simple preparation of
racemic dihydrothebainone, dihydrocodeinone, and nordihydrocodeinone was
described using amide C.[41]

MICROWAVE-ASSISTED AMIDATION
1493
Scheme 1. Amidation of phenylacetic acid with phenylethylamine.
RESULTS AND DISCUSSION
First we studied if the use of the MW technique offers an advantage in the con-
densation reaction of phenylacetic acid (1a) and 2-phenylethylamine (2a). Equimolar
mixtures of the reactants were irradiated at 130 ꢀC, 140 ꢀC, and 150 ꢀC to afford the
corresponding amide (3a) in practically quantitative yields after reaction times of
120 min, 60 min, and 22 min, respectively (Scheme 1, Table 1). In the comparative
thermal experiment carried out at 150 ꢀC, the reaction time was 100 min (Table 1).
It can be seen that on MW irradiation the amidation became much faster.
Then the optimum temperature of 150 ꢀC was adapted to the condensation of
other model compounds. To be sure, a reaction time of 30 min was applied to all
cases. On measuring together the acid (1) and the amine (2), the exothermic forma-
tion of the corresponding salt could be observed. For this, the vial was put into the
MW reactor only after cooling it back to 25 ꢀC.
In the first set of experiments, a series of substituted arylacetic acids (1a–c, f–h)
including 2-naphthyl-acetic acid and 3,4-methylenedioxy-acetic acid were reacted
with 2-phenylethylamine (2a). Next, the arylacetic acids (1a–h) were reacted with
4-methoxyphenylethylamine (2b) and then with 4-chlorophenylethylamine (2c). In
the final stage, the arylacetic acids (1a–h) were condensed with 3-trifluoromethylphe-
nylethylamine (2d) (Scheme 2, Table 2). With 4-nitro substituent in the arylacetic
acid, there was no reaction with any of the arylethylamines.
In all cases, the amides (3a–z) were obtained in almost quantitative yields after
flash column chromatography. Amides 3a–c, 3e, 3i, 3n, 3p, and 3r were described in
the literature but were not characterized. All of the amides (3a–z) (Table 2) prepared
by us have been characterized by 1H and 13C NMR, as well as high-resolution mass
spectrometric (HR-MS) spectral data.
To evaluate the effect of substituents on the reactivity, the amide formation was
carried out, in three different combinations at 140 ꢀC for 30 min. First, the unsubsti-
tuted model compounds 1a and 2a were reacted to give amide 3a in 63% conversion.
Then, 4-MeO-phenylacetic acid (1d) was reacted with 4-Cl-phenylethylamine (2c) to
afford amide 2g in a conversion of 69%. Finally, the reaction of 4-Cl-phenylacetic
Table 1. Amidation of PhCH2CO2H with Ph(CH2)2NH2 under MW
and thermal conditions
Mode of
heating
Temperature
(ꢀC)
Reaction
time (min)
Yield of
3a (%)
Entry
MW
MW
MW
D
130
140
150
150
120
60
95
95
1
2
3
4
22
100
ꢁ99
ꢁ97

¨
A. GRUN ET AL.
1494
Scheme 2. Amidation of arylacetic acids with arylethylamine.
acid (1b) with 4-MeO-phenylamine (2b) was carried out providing the amide (3o) in
57% conversion (Table 3). It can be seen that the most advantageous combination
is when the arylacetic acid has an electron-donating substituent (i.e., a MeO group)
in position 4 and the arylethylamine contains an electron-withdrawing substituent
(i.e., a chlorine atom) in the para position. An explanation may be that in this case
the reactants are more reactive. In case of the 4-MeO substituent, the arylacetic acid
=
(1) is deprotonated to a smaller extent, and hence the C O moiety remains more
Table 2. Products (3) from the amidation of arylacetic acids (1) and arylethylamines (2) along with the
yields
Acid Amine Product
R1
R2
R3
R4
R5
Yield (%)
Lit.
Entry
1a
1a
1a
1a
1d
1d
1d
1d
1e
1e
1f
2a
2b
2c
2d
2a
2b
2c
2d
2b
2d
2a
2b
2d
2a
2b
2c
2d
2a
2b
2d
2a
2b
2d
2a
2b
2d
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
H
MeO
Cl
H
H
99
95
98
99
99
99
99
99
99
99
99
99
99
99
99
99
98
99
93
99
96
99
99
99
98
99
[34]
[42,43]
[42,43]
—
1
2
H
H
H
H
3
H
H
H
H
CF3
H
4
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Cl
H
H
H
[44]
—
5
H
H
MeO
Cl
H
6
3g
3h
3i
H
H
H
—
—
7
H
H
H
CF3
H
8
MeO
MeO
MeO
MeO
MeO
H
H
MeO
H
[45]
—
9
3j
H
MeO
CF3
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3k
3l
H
MeO MeO
—
—
1f
H
1f
3m
3n
3o
3p
3q
3r
3s
3t
MeO
H
H
H
CF3
H
—
1b
1b
1b
1b
1c
1c
1c
1g
1g
1g
1h
1h
1h
[43]
—
Cl
Cl
H
H
MeO
Cl
H
H
H
H
[46]
—
Cl
F
H
H
H
CF3
H
H
H
H
[42]
—
F
H
H
MeO
H
H
F
H
H
CF3
H
—
—
=
=
–CH CH–CH CH–
3u
3v
3w
3x
3y
3z
H
H
=
–CH CH–CH CH–
=
H
MeO
H
H
—
—
=
=
–CH CH–CH CH–
–O–CH2–O–
–O–CH2–O–
H
CF3
H
H
H
—
—
H
MeO
H
H
CF3
–O–CH2–O–
H
—

MICROWAVE-ASSISTED AMIDATION
1495
Table 3. MW-assisted reactions of arylacetic acids (1) with arylethylamines
(2) at 140 ꢀC for 30 min
Acid
Amine
Amide
Conversion (%)
Entry
1a
1d
1b
2a
2c
2b
3a
2g
3o
63
69
57
1
2
3
electrophilic. At the same time, the 4-Cl substituent somewhat prevents the
protonation of the amino function of the arylethylamine (2), thus enhancing its
nucleophilicity.
In summary,
a
convenient and efficient synthesis of N-arylethyl-
arylacetylamides has been elaborated by the MW-assisted and solventless conden-
sation of a series of arylacetic acids and 2-arylethylamines.
EXPERIMENTAL
General Procedure for the Preparation of Amides 3a–z
The acid (1.0 mmol) and amine (1.0 mmol) were measured in vial. After 3 min,
the vial was placed in the MW reactor and the mixture was heated to 150 ꢀC in 3 min,
applying 30–50 W. After a 30-min reaction time, the crude product was taken up in
5 ml methanol and purified by flash column chromatography (using a silica column
of 10 cm and 3% methanol in dichloromethane as the eluent) to afford amides 3a–z,
mostly as crystalline products. Recrystallization from ethanol led to entirely pure
samples.
N-Phenylethyl-phenylacetic Amide (3a)
1
Mp 92–94 ꢀC (mp[34] 94–96 ꢀC), H NMR (CDCl3, 300 MHz) d 7.35–7.15 (m,
=
8H, ArH), 7.02 (d, 2H, J ¼ 6.2, ArH), 5.41 (bs, 1H, CONH), 3.52 (s, 2H, CH2C O),
3.45 (q, 2H, J ¼ 6.5, NCH2), 2.72 (t, 2H, J ¼ 6.8, CH2); 13C NMR (CDCl3, 75 MHz)
d 171.1 (C ¼ O), 138.8 (Ar), 135.0 (Ar), 129.6 (Ar), 129.2 (Ar), 128.9 (Ar), 128.7 (Ar),
þ
=
127.5 (Ar), 126.6 (Ar), 44.0 (NCH2), 40.9 (CH2C O), 35.6 (CH2). HRMS (M þ H) :
240.1393; C16H18NO requires 240.1388.
The spectral characterization of products 3b–z together with the H and 13C
NMR spectra of all compounds (3a–z) can be found online in the Supplementary
Information.
1
ACKNOWLEDGMENTS
This project was supported by the Hungarian Scientific and Research Fund
(OTKA K83118). This work is connected to the scientific program of the ‘‘Develop-
ment of Quality-Oriented and Harmonized RþDþI Strategy and Functional Model
´
at BME’’ project. This project is supported by the New Hungary Szechenyi Plan
´
(Project ID: TAMOP-4.2.1=B-09=1=KMR-2010-0002).

¨
A. GRUN ET AL.
1496
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