Boric acid catalyzed Ugi three-component reaction in aqueous media

Article abstract of DOI:10.1039/c3ra23087b

B(OH)₃ catalyzed Ugi three-component reaction for the synthesis of 2-arylamino-2-phenylacetamide has been developed using aldehydes, amines, and isocyanides in water. The synthesized 2-arylamino-2-phenylacetamides were efficiently converted int

Full text of DOI:10.1039/c3ra23087b

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Boric acid catalyzed Ugi three-component reaction in
aqueous media3
Cite this: DOI: 10.1039/c3ra23087b
Atul Kumar,* Deepti Saxena and Maneesh Kumar Gupta
Received 28th November 2012,
Accepted 21st January 2013
B(OH)3 catalyzed Ugi three-component reaction for the synthesis of 2-arylamino-2-phenylacetamide has
been developed using aldehydes, amines, and isocyanides in water. The synthesized 2-arylamino-2-
phenylacetamides were efficiently converted into a-amino acid via acidic hydrolysis.
DOI: 10.1039/c3ra23087b
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antagonists in neuropsychiatric disorders.8–10 Enalapril and
Quinapril are potent inhibitors of angiotensin-converting
Introduction
enzyme (ACE)11 and are widely used in clinics (Fig. 1).
Inspired from these, we focused our efforts towards the
development of green synthesis of multi-component reactions
(MCRs)12 to synthesize various biologically important scaf-
folds. Herein, we wish to report the first boric acid catalyzed
Ugi three-component reaction in water for the synthesis of
2-arylamino-2-phenylacetamide 4 (Scheme 2). The synthesized
2-arylamino-2-phenylacetamides were conveniently hydrolyzed
to afford biologically important a-amino acids 5.
Over the past decades, multi-component reactions (MCRs)
have demonstrated their ability and efficiency in the genera-
tion of chemical diversity.1 MCRs are useful for the expedient
creation of chemical libraries of drug-like compounds and
optimization in drug discovery programmes.2 In addition the
advantages of multicomponent reactions are high atom-
economy, selectivity, structural multiplicity and simple proce-
dure. The Ugi four-component reaction (Ugi4-CR) is a powerful
synthetic method for the synthesis of various novel nitrogen
containing biologically active molecules.
Recently, List and Pan have done a fascinating modification
in Ugi-4CR by converting it into Ugi-3CR (ABC type MCRs) for
the synthesis of 2-arylamino-2-phenylacetamide by using
phenyl phosphinic acid.3 Shaabani et al. also reported
cellulose-SO3H as a biodegradable solid acid catalyzed Ugi
three-component reaction.4 However, it involved prolonged
reaction time and non-green solvent (Scheme 1). Therefore, it
is desirable to develop a green and eco-friendly protocol for the
preparation of 2-arylamino-2-phenylacetamide.
Nowadays, there has been increasing interest in develop-
ment of green synthetic pathways and processes.5 This
technique led to a growing interest in the field of organic
synthesis in water.6 In relation to this, significant efforts have
been dedicated to develop organic reactions in water with
many inherent advantages over reactions in conventional
organic solvents. Therefore, development of an Ugi three-
component reaction operated in water will be of great practical
value.
Results and Discussion
Initially, we intended to find an efficient catalyst for the
synthesis of a tandem one-step Ugi three-component reaction
from aniline 1, benzaldehyde 2 and tert-butylisocyanide 3
(Table 1) as a model reaction. At the outset we explored the
three-component reaction catalyzed by several metal Lewis
acids such as Zn(OTf)2, Fe(OTf)3, and Cu(OTf)2, but these
Lewis acids proved to be ineffective promoters (Table 1, entries
1, 2 and 3). We further optimized the reaction with other metal
Lewis acids e.g. In(OTf)3, Bi(OTf)3 and CuBr (Table 1, entries 4,
5 and 6) but the desired product was obtained in poor yield.
Employing this stepwise catalyst screening procedure, we have
also tried the reaction with TiCl4 and NiCl4 but the stable
product was isolated from the reaction with lower yield
(Table 1, entries 7 and 8). These experiments were carried
out at constant 5 mol% amount of catalyst, over reaction times
Phenylacetamide and a-amino acid scaffolds display a wide
range of biological activities (Fig. 1). Etidocain is used for
treatment of neuronal voltage-gated sodium channels (NVSC)7
and NPPG is a class of CRF (corticotropin releasing factor)
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR,
Lucknow, India. E-mail: dratulsax@gmail.com; Fax: +91-522-26234051;
Tel: +91-522-2612411
Electronic supplementary information (ESI) available. See DOI: 10.1039/
3
Scheme 1 Ugi three-component reaction.
c3ra23087b
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Table 2 Boric acid catalyzed synthesis of 2-amino-2-phenylacetamide 4 deriva-
tives in watera
Entry R1
R2
R3
Prod. Time (min) Yield (%)b
Fig. 1 Biologically active compounds containing amide and amino acid skeleton.
1
2
3
4
5
6
7
8
H
H
tBuNC
4a
60 min
55 min
55 min
60 min
50 min
60 min
50 min
60 min
45 min
45 min
60 min
55 min
60 min
60 min
60 min
90
80
78
82
81
80
75
80
83
80
77
75
81
79
75
4-OMe
4-OMe
2,4-diMe
4-Cl
4-Cl
4-Cl
H
4-Cl
H
4-Br
4-Cl
H
cHexNC 4b
tBuNC 4c
cHexNC 4d
tBuNC
tBuNC
tBuNC
cHexNC 4h
cHexNC 4i
tBuNC
4e
4f
4g
4-Cl
4-OMe
3-OMe
4-OMe
2,4-diMe 4-Cl
H
9
10
11
12
13
14
15
4j
4k
3,5-OMe tBuNC
3,5-OMe cHexNC 4l
4-Br
4-F
4-Br
H
3-OMe
4-OMe
H
tBuNC
tBuNC
tBuNC
4m
4n
4o
Scheme 2 Boric acid catalyzed Ugi three-component reaction for the synthesis
of 2-arylamino-2-phenylacetamide 4.
a
Reaction conditions : aniline (1 mmol), aldehyde (1 mmol),
isocyanide (1 mmol), and 10 mol% boric acid in water (5 mL) at r.t.
b
for a given time. Isolated yield.
ranging from 3 to 8 h and the desired product was not
obtained in good yield (Table 1, entries 1–8). After screening
these catalysts we go with 5 mol% of boric acid as a catalyst
but we obtain a moderate yield (Table 1, entry 9). Next we tried
the reaction with 10 mol% boric acid and the best result was
observed within 1 h (Table 1, entry 10). Boric acid is a
homogenous and useful catalyst for a number of synthetic
transformations for example, aza-Michael addition,13 thia-
Michael addition,14 and Biginelli reaction.15
It was observed that the loading of catalyst (5 to 10 mol%)
plays an important role in the reaction and 10 mol% of boric
acid was found to be sufficient to obtain the desired product
4a in good to excellent yield (Table 2, entries 1–15).
In order to study the solvent effect on the reaction of
aniline benzaldehyde, and tert-butylisocyanide catalyzed by
boric acid, we performed the reaction in different solvents.
First we choose polar protic solvents like EtOH, MeOH and iso-
propanol the desired product was obtained in lower yield 4a
(Table 3, entries 1, 2 and 3). A similar attempt using non-polar
solvents like CH2Cl2 and toluene under the same conditions
again gave 4a with poor yield (Table 3, entries 4 and 5). We
further carried out this experiment in CH3CN, DMF and DMSO
at room temperature and isolated the product in moderate
Table 1 Effect of catalysts for synthesis of 2-arylamino-2-phenylacetamide 4a
Table 3 Effect of solvents for the synthesis of 2-amino-2-phenylacetamidea
Entry
Catalyst
Time (h)
Yield (%)d
Entry
Solvent
Time/(h)
Yield (%)b
1
2
3
4
5
6
7
8
9
Zn(OTf)2
Fe(OTf)3
Cu(OTf)2
In(OTf)3
Bi(OTf)3
CuBr
3
4
3
6
6
7
8
6
25
30
20
35
38
39
30
26
52
90
1
2
3
4
5
6
7
8
9
EtOH
3
4
3
6
8
5
6
5
1
22
25
30
20
28
41
45
50
90
MeOH
iso-Propanol
CH2Cl2
Toluene
CH3CN
DMF
TiCl4
NiCl4
b
B(OH)3c
3.5
1
DMSO
H2O
10
B(OH)3
a
Reaction conditions: aniline (1 mmol), benzaldehyde (1 mmol),
a
Reaction conditions: aniline (1 mmol), benzaldehyde (1 mmol),
tert-butylisocyanide, (1 mmol), and catalyst (10 mol%) in water (5
mL) at rt. 5 mol% boric acid. 10 mol% boric acid. Isolated
yield.
b
c
d
and tert-butylisocyanide (1 mmol) with 10 mol% boric acid at r.t. for
a given time. Isolated yield.
b
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reaction mixture was cooled at room temperature then
extracted with ethyl acetate. The organic layer was dried over
sodium sulphate to obtain the crude product, which was
purified by column chromatography (silica gel, 100–200 mesh)
to afford the corresponding product 5.
Scheme 3 Synthesis of N-substituted a-amino acid 5.
Acknowledgements
D. S. and M. K. G. acknowledge the CSIR-UGC, New Delhi for
the award of a SRF. The authors also acknowledge the SAIF-
CDRI for providing spectral and analytical data. CDRI
communication number 8404.
yield (Table 3, entries 6, 7 and 8). By keeping the vital aspect of
water in mind we tried the reaction in the same and obtained
the best result (Table 3, entry 9). From the above discussion it
is clear that the picking of water with boric acid was the right
choice, because boric acid is a fine catalyst and plays a very
essential catalytic role in organic reactions.16 The result of
solvents effect with boric acid are shown in Table 3.
References
Under these optimized reaction conditions a number of
2-arylamino-2-phenylacetamide derivatives were synthesized
using various aromatic anilines, aldehydes and isocyanides.
The results of this study are summarized in Table 2.
The structures of the desired products 4 were fully character-
ized by spectroscopic technique like mass spectroscopy, 1H NMR,
13C NMR, and elemental analysis. Searching for the utility of 4 we
further converted it into N-substituted a-amino acid 5 derivatives
via acidic hydrolysis, accomplished by heating in 6N HCl at 100
´
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Conclusion
In conclusion, we have developed first aqueous strategy for an
Ugi three-component reaction for the synthesis of 2-arylamino-
2-phenylacetamide from aniline, aldehyde and isocyanide by
using boric acid as a catalyst. N-substituted a-amino acids can
be also synthesized from 2-arylamino-2-phenylacetamide
derivatives via acidic hydrolysis. The advantage of this
improved methodology is to construct the chemical library of
phenylacetamide and a-amino acid derivatives.
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Experimental
General experimental procedure for synthesis of compounds (4)
In a typical experiment, the aniline (1 mmol), aldehyde (1
mmol), isocyanide (1 mmol), and boric acid (10 mol%) were
taken in 5 mL water. The reaction mixture was vigorously
stirred at room temperature, until the completion of the
reaction (monitored by thin layer chromatography). After
completion the reaction mixture was extracted with ethyl
acetate. The organic layer was dried over sodium sulphate and
concentrated under vacuum to give the crude product. The
crude product was purified by column chromatography (silica
gel, 100–200 mesh) to afford the corresponding product 4.
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General experimental procedure for synthesis of compounds (5)
In a 25 mL round-bottom flask, 2-arylamino-2-phenylaceta-
mide 4 (1 mmol) in 6N HCl (10 mL) was stirred at 100 uC. The
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