One-pot synthesis of α-hydroxyamides using alkyl isocyanides and aryl aldehydes

Article abstract of DOI:10.1007/s00706-011-0644-x

A simple and efficient approach for the synthesis of α-hydroxyamides in fairly good yields by the reaction of aromatic aldehydes and alkyl isocyanides at room temperature is presented. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0644-x

Monatsh Chem (2012) 143:801–804
DOI 10.1007/s00706-011-0644-x
ORIGINAL PAPER
One-pot synthesis of a-hydroxyamides using alkyl isocyanides
and aryl aldehydes
•
•
•
Mohammad Bayat Shima Nasri Hajar Hosseini
Fateme Hassanzadeh
Received: 13 May 2010 / Accepted: 29 August 2011 / Published online: 18 October 2011
Ó Springer-Verlag 2011
Abstract A simple and efficient approach for the syn-
thesis of a-hydroxyamides in fairly good yields by the
reaction of aromatic aldehydes and alkyl isocyanides at
room temperature is presented.
(usually a primary or secondary amine), a carbonyl com-
pound (aldehyde or ketone), an isocyanide, and a carboxylic
acid [14].
Cyclic variations of the MCRs are also possible in which
two or more components could be connected by a chain to
produce heterocycles. For example, the synthesis of
b-lactam rings using b-aminoacids has been known as the
Ugi four-center-three-component reaction since 1961 [15].
As part of our current studies on the development of new
routes to the synthesis of organic compounds and our
interest in isocyanide-based reactions [16, 17], we planned
to test the reaction between isocyanides and CS2 in the
presence of aryl aldehydes in CH2Cl2 (Scheme 1).
We found that this reaction yielded the corresponding
a-hydroxyamides rather than the expected MCR product
(Scheme 2). Thus, this reaction is an extension of the
Passerini three-component reaction.
Keywords a-Hydroxyamide Á Alkyl isocyanide Á
Aromatic aldehyde Á One-pot synthesis
Introduction
The a-hydroxyamides are useful building blocks for the
synthesis of biologically active compounds [1–6]. For
example, a-hydroxyamides have been identified as inhibi-
tors of methionine aminopeptidase-2 and as HIV protease
inhibitors [7, 8]. Mycalamides are a class of a-hydroxya-
mides that exhibit potent antitumor activity [9]. a-
Hydroxyamides are also valuable intermediates in the
synthesis of natural products and various biologically
active compounds [10–12]. Known methods for their
preparation can be divided into four main categories:
reactions of carboxylic acids and activated acid derivatives
with amines, reduction of a-ketoamides, miscellaneous
methods, and the synthesis of a-hydroxyamides via cyclic
precursors.
Results and discussion
The reaction of alkyl isocyanides 1 with aromatic alde-
hydes 2 in CH2Cl2 proceeded smoothly and had completed
after three days at room temperature, affording the corre-
sponding a-hydroxyamides
3 in fairly good yields
1
The two most important isocyanide-based multicompo-
nent reactions are the Passerini three-component reaction
[13] to produce a-acyloxyamides, and the Ugi four-com-
ponent reaction, which yields a-acylaminoamides. The Ugi
reaction usually refers to the reaction between an amine
(65–86%). H and 13C NMR spectra of the crude products
clearly indicated the formation of the a-hydroxyamides. As
shown in Table 1, aromatic aldehydes containing electron-
withdrawing groups gave excellent yields of the amide
product 3. The structures of the products were deduced
from their elemental analyses, IR, 1H, and 13C NMR
spectra. The mass spectra of compounds 3 displayed
molecular ion peaks at the calculated m/z values. The
results for the synthesis of a-hydroxyamides are given in
Table 1.
M. Bayat (&) Á S. Nasri Á H. Hosseini Á F. Hassanzadeh
Chemistry Department, Imam Khomeini International
University, Qazvin, Iran
e-mail: bayat_mo@yahoo.com
123

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M. Bayat et al.
Ar
O
O
H
+
C
R
N
O
S
C
H OH
CS2
ArCHO
+
R-N=C:
+
X
N
R
4
S
N
R
OH
OH
Scheme 1
HO
R
O
R
X
X
N
N
O
H
5
CH2Cl2
rt
R
Ar
O H
ArCHO
R-N=C:
1
+
+
H2O
N
H
Scheme 3
2
3
Scheme 2
isocyanides. The present procedure has the advantage that
the reaction occurs under neutral conditions, and moreover
that the substances can be mixed without any further
activation or modification.
Table 1 Synthesis of a-hydroxyamides using aromatic aldehydes and
alkyl isocyanides in CH2Cl2
Entry
Ar
R
Product
Yield / %
a
b
c
d
e
f
4-NO2Ph
4-NO2Ph
3-NO2Ph
Ph
Cyclohexyl
tert-Bu
3a
3b
3c
3d
3e
3f
86
76
82
72
65
74
70
68
Experimental
Cyclohexyl
tert-Bu
The alkyl isocyanides, aromatic aldehydes, and solvents
used in this work were obtained from Fluka (Buchs,
Switzerland) and used without further purification. NMR
spectra were recorded with Bruker Avance DRX-300 and
DRX-500 instruments, using CDCl3 as the solvent.
Chemical shifts are given in ppm (d) relative to internal
TMS, and coupling constants (J) are reported in hertz (Hz).
Melting points were measured with a Gallenkamp 9100
electrothermal apparatus. Elemental analyses were per-
formed using a Heraeus CHN-O-Rapid analyzer. The
results obtained experimentally agreed favorably with the
calculated values. Mass spectra (m/z, rel%) were recorded
with a Shimadzu QP-5050 GC/MS operating at an ioni-
zation potential of 70 eV. IR spectra (KBr) were measured
with a Bruker Tensor 27 spectrometer.
2,4-(MeO)2Ph
4-BrPh
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
g
h
2,6-Cl2Ph
Ph
3g
3h
The 1H NMR spectrum of 3a consisted of a multiplet of
signals for the cyclohexyl group (d = 1.05–1.94 ppm), a
broad signal for the hydroxyl group (d = 3.68–3.98 ppm),
one singlet for the methine group (d = 5.10 ppm) and one
signal (d = 6.34 ppm) for the N–H group, which appears
as doublet (3JHH = 7.2 Hz), in agreement with the sug-
gested structure. The H-decoupled 13C NMR spectrum of
1
3a showed ten sharp signals, in agreement with the pro-
posed structure. The characteristic signal of the C-atom in
the benzylic position was observed (d = 73.13 ppm). The
1H and 13C NMR spectra of 3b–3h are similar to those of
3a, except for the substituted phenyl ring, which exhibited
characteristic resonances with appropriate chemical shifts.
A plausible mechanism for the formation of a-hydroxy-
amides 3 is shown in Scheme 3. On the basis of the well-
established chemistry of isocyanides [18–21], it is reason-
able to assume that intermediate 4 results from the initial
addition of alkyl isocyanides 1 to the carbonyl group of the
aldehyde; protonation by the absorbing water then occurs,
which adds hydroxide to produce intermediate 5. This
intermediate is converted to product 3 by proton transfer.
In conclusion, we have reported a general method
for the synthesis of potentially interesting a-hydroxy-
amides from readily available aromatic aldehydes and alkyl
General procedure
To a stirred solution of 0.109 g cyclohexyl isocyanide
(1 mmol) in 10 cm3 CH2Cl2, 0.151 g p-nitrobenzaldehyde
(1 mmol) and 2 mmol H2O were added in 2 cm3 CH2Cl2 at
room temperature over 5 min via a syringe. The reaction
mixture was stirred at room temperature for three days.
The solvent was removed under reduced pressure and the
residue was purified by column chromatography (Merck
silica gel 60, 70–230 mesh) using hexane–ethyl acetate
(8:2) as eluent. The solvent was removed under reduced
pressure to afford the products 3.
The products 3d and 3h are known compounds and were
characterized by IR and NMR spectroscopic data, which
were in agreement with those published in the literature
[14].
123

One-pot synthesis of a-hydroxyamides
803
N-Cyclohexyl-a-hydroxy-4-nitrobenzeneacetamide
(3a, C14H18N2O4)
4-Bromo-N-cyclohexyl-a-hydroxybenzeneacetamide
(3f, C14H18BrNO2)
ꢀ
Yellow paste, yield 0.24 g (86%); IR (KBr): m = 3,410,
Pale yellow paste, yield 0.23 g (74%); IR (KBr):
ꢀm = 3,385, 1,655, 1,524 cm-1
1H NMR (300 MHz,
3,319, 1,685, 1,651, 1,520, 1,346 cm-1 1H NMR
;
;
(300 MHz, CDCl3): d = 1.05–1.94 (10H, m, 5CH2), 3.69
(1H, m, N–CH), 3.68–3.98 (1H, br s, OH), 5.10 (1H, s,
CDCl3): d = 1.05–1.98 (10H, m, 5CH2), 3.62 (1H, d,
3JHH = 4.0 Hz, OH), 3.75 (1H, m, CH), 4.96 (1H, d,
3
CH), 6.34 (1H, d, JHH = 7.2 Hz, NH), 7.61 (2H, d,
3
3JHH = 4.0 Hz, CH), 5.93 (1H, d, JHH = 7.2 Hz, NH),
3
3
3JHH = 8.9 Hz, CHar), 8.19 (2H, d, JHH = 8.7 Hz, CHar)
7.63 (2H, d, JHH = 8.7 Hz, CHar), 7.92 (2H, d,
ppm; 13C NMR (75.4 MHz, CDCl3): d = 24.67 (2CH2),
25.33 (CH2), 32.82 (2CH2), 48.52 (N–CH), 73.13 (CH),
123.77 (2CHar), 127.36 (2CHar), 146.68, 147.81 (2Car),
169.80 (C=O) ppm; MS (EI, 70 eV): m/z = 279 (0.8), 186
(9), 153 (100), 136 (29), 106 (12), 83 (32), 55 (27).
3JHH = 8.7 Hz, CHar) ppm; 13C NMR (75.4 MHz, CDCl3):
d = 24.65 (2CH2), 25.35 (CH2), 32.79 (2CH2), 48.51
(N–CH), 73.10 (CH), 123.35 (2CHar), 127.96 (2CHar),
130.98, 131.24 (2Car), 169.85 (C=O) ppm.
2,6-Dichloro-N-cyclohexyl-a-hydroxybenzeneacetamide
(3g, C14H17Cl2NO2)
N-tert-Butyl-a-hydroxy-4-nitrobenzeneacetamide
(3b, C11H13N2O4)
ꢀ
Viscous oil, yield 0.21 g (70%); IR (KBr): m = 3,400,
1
Yellow powder, yield 0.18 g (76%); m.p.: 156–158 °C; IR
3,305, 1,650, 1,529 cm-1; H NMR (300 MHz, CDCl3):
(KBr): m = 3,385, 1,655, 1,524, 1,350 cm-1; 1H NMR
d = 1.10–1.92 (10H, m, 5CH2), 3.72 (1H, m, N–CH),
3.66–3.80 (1H, br s, OH), 4.96 (1H, s, CH), 5.97 (1H, d,
3JHH = 7.2 Hz, NH), 7.33 (3H, s, CHar) ppm; 13C NMR
(75.4 MHz, CDCl3): d = 24.66 (2CH2), 25.39 (CH2),
32.85 (2CH2), 48.55 (N–CH), 73.10 (CH), 128.85,
129.11, 131.14, 139.98 (6Car), 169.78 (C=O) ppm.
ꢀ
(500 MHz, CDCl3): d = 1.37 (9H, s, CMe3), 3.61 (1H, d,
3
3JHH = 4.2 Hz, OH), 5.10 (1H, d, JHH = 4.0 Hz, CH),
3
6.01 (1H, br s, NH), 7.66 (2H, d, JHH = 8.7 Hz, 2 CH
arom), 8.28 (2H, d, 3JHH = 8.7 Hz, 2 CH arom) ppm; 13C
NMR (125.7 MHz, CDCl3): d = 28.51 (CMe3), 52.34
(CMe3), 73.23 (CH), 123.74 (2CH-arom), 127.38 (2CH-
arom), 146.69, 147.79 (2C-arom), 169.71 (C=O) ppm; MS
(EI, 70 eV): m/z = 259 (4), 215 (2), 172 (4), 160 (5), 152
(100), 136 (43), 119 (9), 104 (20), 77 (8), 57 (60).
References
1. Coppola GM, Schuster HF (1997) a-Hydroxy acids in enantio-
selective syntheses. VCH, Weinheim
N-Cyclohexyl-a-hydroxy-3-nitrobenzeneacetamide
(3c, C14H18N2O4)
Pale yellow paste, yield 0.23 g (82%); IR (KBr):
2. Kuduk SD, Chang RK, DiPardo RM, Di Marco CN, Murphy KL,
Ransom RW, Reiss DR, Tang C, Prueksaritanont T, Pettibone DJ,
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-1
;
1H
ꢀ
m = 3,385, 3,310, 1,655, 1,649, 1,524, 1,348 cm
NMR (300 MHz, CDCl3): d = 1.10–1.91 (10H, m, 5CH2),
3.72 (1H, m, N–CH), 3.81–3.95 (1H, br s, OH), 5.14 (1H, s,
3
CH), 6.33 (1H, br s, NH), 7.54 (1H, t, JHH = 8.1 Hz,
3
CHar), 7.79 (1H, d, JHH = 7.5 Hz, 2CHar), 8.18 (1H, d,
3JHH = 8.1 Hz, CHar), 8.32 (1H, s, CHar) ppm; 13C NMR
(75.4 MHz, CDCl3): d = 24.71, 25.36, 32.87 (5CH2),
48.57 (N–CH), 73.02 (CH), 121.46, 123.36, 129.66,
132.82 (4CHar), 141.72, 148.38 (2Car), 169.74 (C=O) ppm.
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N-Cyclohexyl-a-hydroxy-2,4-dimethoxybenzeneacetamide
(3e, C16H23NO4)
ꢀ
Viscous oil, yield 0.19 g (65%); IR (KBr): m = 3,325,
1,657, 1,523 cm-1 1H NMR (300 MHz, CDCl3):
;
d = 1.20–1.92 (10H, m, 5CH2), 3.73 (1H, m, N–CH),
3.69–3.81 (1H, br, OH), 4.21 (3H, s, OCH3), 4.25 (3H, s,
OCH3), 5.15 (1H, s, CH), 6.90 (1H, br s, NH), 6.21 (1H, s,
3
CHar), 6.26 (1H, d, JHH = 7.5 Hz, CHar), 6.97 (1H, d,
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12. Wipf P, Kim H (1993) J Org Chem 58:5592
3JHH = 7.5 Hz, CHar) ppm; 13C NMR (75.4 MHz, CDCl3):
d = 24.72, 25.34, 32.76 (5CH2), 48.52 (N–CH), 56.10,
56.31 (2OCH3), 73.12 (CH), 101.02, 107.14, 113.79,
131.76, 161.85, 163.41 (6Car), 170.67 (C=O) ppm.
123

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M. Bayat et al.
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123