Facile synthesis of highly functionalized stable ketenimines by a three-component reaction of alkyl isocyanides, dialkyl acetylenedicarboxylates and ethyl carbazones

Article abstract of DOI:10.1007/s00706-008-0039-9

The reactive intermediate generated by the reaction of alkyl isocyanides and dialkyl acetylenedicarboxylates was trapped by ethyl carbazones to produce stable ketenimine derivatives in good yield. The reaction is characterized by mild conditions, high sel

Full text of DOI:10.1007/s00706-008-0039-9

Monatsh Chem (2009) 140:397–400
DOI 10.1007/s00706-008-0039-9
ORIGINAL PAPER
Facile synthesis of highly functionalized stable ketenimines
by a three-component reaction of alkyl isocyanides,
dialkyl acetylenedicarboxylates and ethyl carbazones
Mohammad Anary-Abbasinejad Æ
Hossein Anaraki-Ardakani Æ Fatemeh Ghanea
Received: 4 May 2008 / Accepted: 4 July 2008 / Published online: 2 September 2008
Ó Springer-Verlag 2008
Abstract The reactive intermediate generated by the
reaction of alkyl isocyanides and dialkyl acetylenedicarb-
oxylates was trapped by ethyl carbazones to produce stable
ketenimine derivatives in good yield. The reaction is
characterized by mild conditions, high selectivity, and
tolerance to various functional groups.
interesting chemical properties. The change in attitude can
be attributed primarily to the renaissance of isocyanide-
based multicomponent reactions (IMCRs) [11–13]. The
trapping of the 1:1 intermediate formed between dialkyl
acetylenedicarboxylates and isocyanides with OH, NH, and
CH acids has been widely studied [14–19]. In continuation
of our works on the reaction between isocyanides and
acetylenic esters in the presence of organic acids [20–22],
we wish to report the results of our studies on the reaction
between alkyl isocyanides and dialkyl acetylenedicarb-
oxylates in the presence of ethyl carbazones of aromatic
aldehydes. Thus, alkyl isocyanides 1 and dialkyl acety-
lenedicarboxylates 2 in the presence of ethyl carbazones 3
undergo a smooth 1:1:1 addition reaction in dichloro-
methane at ambient temperature to produce dialkyl 2-(N0-
benzylidene-N-ethoxycarbonyl-hydrazino)-3-alkyliminom-
ethylene-succinate derivatives 4a–g in excellent yields
(Scheme 1).
Keywords Isocyanides ꢀ Ethyl carbazones ꢀ
Ketenimines ꢀ Multicomponent reactions ꢀ
Acetylenic esters
Introduction
Ketenimines are heterocumulenes which have recently
attracted interest as dehydrating agents for peptide syn-
thesis, as complexing agents for transition metal ions, and
as coreagents for oxidations with DMSO [1, 2]. They have
also found widespread use as reactive starting materials for
the formation of four-, five-, and six-membered heterocy-
clic ring systems [3–7]. Recently, methods for the synthesis
of ketenimines have been extensively reviewed [8].
Results and discussion
MCRs are powerful tools in modern drug discovery
processes and allow fast, automated and high-throughput
generation of organic compounds [9, 10]. Isocyanides,
regarded for many years as compounds with unpleasant
odors and very few chemical and pharmaceutical applica-
tions, are now looked upon as useful synthons with
The structures of compounds 4a–g were deduced from their
elemental analyses and their IR, 1H NMR, 13C NMR
spectra. The mass spectrum of 4a displayed a molecular
ion peak at m/z = 443 which is consistent with the
formation of a 1:1:1 adduct of dimethyl acetylenedicar-
boxylate, cyclohexyl isocyanide, and benzaldehyde ethyl
carbazone. The IR spectra of the ketenimines exhibit a
strong absorption band at about 2,030 cm-1. In addition,
the sp2 hybridized carbon atoms of the ketenimines
(N=C=C) in the 13C NMR spectra appear at about
62.00 ppm. The IR spectrum of 4a exhibited an absorption
band for the ketenimine moiety at 2,062 cm-1and bands
M. Anary-Abbasinejad (&) ꢀ H. Anaraki-Ardakani ꢀ F. Ghanea
Department of Chemistry, Islamic Azad University,
Yazd Branch, Yazd, Iran
for the ester carbonyl groups at 1,733 and 1,698 cm-1
.
e-mail: mohammadanary@yahoo.com
123

398
M. Anary-Abbasinejad et al.
CO2R
+
CO2R
H
under neutral conditions, and requires no activation or
modification of the reagents.
OEt
OEt
N
CH2Cl2
R'
N
C
N
R' N+
C
+
O
N
O
r.t., 24 h
RO2C
Ar
N
CO2R
1
Ar
2
3
4
Experimental
%Yield
Ar
phenyl
4
R
R'
Me
Me
Me
Et
Elemental analyses were performed using a Heraeus
(Banau, Germany) CHN-O-Rapid analyzer; the results
were found to be in favorable agreement with the calcu-
lated values. Mass spectra were recorded on a Finnigan-
MAT (San Jose, CA, USA) 8430 mass spectrometer
operating at an ionization potential of 70 eV. IR spectra
were recorded on a Shimadzu (Tokyo, Japan) IR-470
spectrometer. 1H and 13C NMR spectra were recorded on a
Bruker (Rheinstetten, Germany) DRX-500 Avance spec-
trometer while solvated in CDCl3. Ethyl carbazones were
prepared by treating ethyl carbazide and aldehyde in eth-
anol [27]. The chemicals used in this work were purchased
from Fluka (Buchs, Switzerland) and were used without
further purification.
Cy
a
b
91
90
89
92
p-CH3O-phenyl
Cy
c p-CH3-phenyl
Cy
p-Cl-phenyl
Cy
d
Me
t-Bu
phenyl
92
94
92
e
Me
Me
t-Bu
t-Bu
p-Cl-phenyl
f
g p-CH3-phenyl
Scheme 1
1
The H NMR spectra of compound 4a exhibited three
sharp singlet signals readily recognized as arising from
methoxy (d = 3.70 and 3.77), and CH (d = 6.01) protons.
Protons of the ethyl group are observed as a triplet at
d = 1.33 ppm (3JHH = 7.1 HZ) and a quartet at d = 4.32
(3JHH = 7.1 HZ). The NCH proton appeared as a multiplet
at 3.78–3.80 ppm, and the signals related to methylene
groups of cyclohexyl moiety were observed as multiplets at
1.21–2.05 ppm. The protons of the aryl group exhibited
characteristic signals in the aromatic region of the spec-
trum. A single signal was observed at 8.66 ppm, which
arises from the N=CH proton. The 13C NMR spectrum of
compound 4a showed twenty-one distinct resonances in
agreement with the proposed structure.
Elemental analytical data for compounds 4a–g
Compound
% N found
(calculated)
% C found
(calculated)
% H found
(calculated)
4a (C23H29N3O6)
4b (C24H31N3O7)
4c (C24H31N3O6)
9.45 (9.47)
8.80 (8.87)
9.23 (9.18)
62.32 (62.29) 6.57 (6.59)
60.92 (60.88) 6.65 (6.60)
63.11 (63.00) 6.80 (6.83)
59.41 (59.34) 6.32 (6.37)
4d (C25H32ClN3O6) 8.26 (8.30)
4e (C21H27N3O6)
4f (C21H26ClN3O6)
4g (C22H29N3O6)
10.12 (10.07) 60.45 (60.42) 6.50 (6.52)
Although we have not established the mechanism of the
reaction between an isocyanide and an acetylenic ester in
the presence of ethyl carbazones 3 experimentally, a pos-
sible explanation is proposed in Scheme 2. On the basis of
the well-established chemistry of isocyanides [13, 23–26],
it is reasonable to assume that the functionalized keteni-
mine 4 results from the initial addition of the isocyanide to
the acetylenic ester and subsequent protonation of the 1:1
adduct 5 by ethyl carbazones. Then, the positively charged
ion 6 is attacked via the conjugate addition of anion 7 to
give the product 4 (Scheme 2).
9.38 (9.30)
9.71 (9.74)
55.78 (55.81) 5.91 (5.80)
61.29 (61.24) 6.71 (6.77)
General procedure
To a magnetically stirred solution of dialkyl acetylenedi-
carboxylate (2 mmol) and ethyl carbazone (2 mmol) in
CH2Cl2 (10 mL) was added a solution of alkyl isocyanide
(2 mmol) in CH2Cl2 (5 mL) dropwise at r.t. over 10 min.
The mixture was then allowed to stir for 24 h. The solvent
was removed under reduced pressure, and the residue was
separated by column chromatography (silica gel, hexane–
EtOAc, 5:1) to afford the pure compounds.
In summary, the simple one-pot reaction between iso-
cyanides and dialkyl acetylenedicarboxylates in the
presence of ethyl carbazones provides access to stable
ketenimine derivatives of potential synthetic interest. The
presented method has the advantage of being performed
Dimethyl 2-(N0-benzylidene-N-ethoxycarbonyl-hydrazino)-
3-cyclohexyliminomethylene-succinate(4a,C23H29N3O6)
Yellow oil; yield 0.80 g (91%); Rf = 0.21; IR (KBr) (mmax
,
cm-1): 2,062 (N=C=C), 1,733, 1,698 (C=O, ester). MS
CO2R
_
CO2R
H
+
N
1
(m/z, %): 443 (M+, 6). H NMR (500.1 MHz, CDCl3):
OEt
R' N+
C
3
1 + 2
R'
C
4
_
N
N
O
d = 1.21–2.05 (10 H, m, 5 CH2 of Cy), 1.33 (3 H, t,
3JHH = 7.1 HZ, OCH2CH3), 3.70 (3 H, s, OCH3), 3.77 (3
H, s, OCH3), 3.78–3.80 (1 H, m, CHN), 4.32 (2 H, q,
3JHH = 7.1 HZ, OCH2CH3), 6.01 (1 H, s, CH), 7.37–7.40
RO2C
RO2C
5
6
7
Ar
Scheme 2
123

Facile synthesis of highly functionalized stable ketenimines
399
3
3OCH2CH3), 5.91 (1 H, s, CH), 7.28 (2 H, d, J = 6.7 Hz,
(3 H, m, 3 CH of Ph), 7.68–7.70 (2 H, m, 2 CH of Ph), 8.66
(1 H, s, N=CH) ppm. 13C NMR (125.7 MHz, CDCl3):
d = 14.9 (OCH2CH3), 24.3, 24.4, 25.5, 33.5, and 33.6
(Cy), 52.1 (OCH3), 53.2 (OCH3), 59.9 (CHN), 60.4
(N=C=C), 60.1 (CH), 63.0 (OCH2CH3), 127.9, 128.9,
130.0, and 135.4 (C arom), 151.1 (N=CH),154.1 (CO2Et),
165.6 (N=C=C), 169.7 (CO2Me), 170.5 (CO2Me) ppm.
3
2 CH of 4-ClC6H4), 7.50 (2 H, d, J = 6.8 Hz, 2 CH of
4-ClC6H4), 8.67 (1 H, s, N=CH) ppm. 13C NMR
(125.7 MHz, CDCl3): d = 14.6, 14.8, 14.8 (OCH2CH3),
24.2, 24.2, 25.5, 33.4, and 33.50 (Cy), 51.9 (OCH2CH3),
53.0 (OCH2CH3), 55.7 (OCH2CH3), 59.4 (CHN), 60.4
(N=C=C), 60.7, and 60.8 (OCH2CH3), 62.2 (CH), 63.8
(OCH2CH3), 129.0, 129.1, 134.1, and 136.0 (C arom),
149.0 (N=CH), 154.0 (CO2Et), 166.5 (N=C=C), 169.0
(CO2Et), 170.1 (CO2Et) ppm.
Dimethyl 2-cyclohexyliminomethylene-3-[N-ethoxycarbonyl-
N0-(4-methoxy-benzylidene)-hydrazino]-
succinate (4b, C24H31N3O7)
Yellow oil; yield 0.85 g (90%); Rf = 0.25; IR (KBr) (mmax
,
Dimethyl 2-(N0-benzylidene-N-ethoxycarbonyl-hydrazino)-
3-(tert-butylimino-methylene)-succinate
(4e, C21H27N3O6)
cm-1): 2,065 (N=C=C), 1,744, 1,699 (C=O, ester). MS (m/
z, %): 473 (M+, 2). 1H NMR (500 MHz, CDCl3):
d = 1.20–1.89(m, 10 H, 5 CH2 of Cy), 1.38 (3 H, t,
3JHH = 7.1HZ, OCH2CH3), 3.58 (3 H, s, OCH3), 3.61 (3 H,
s, OCH3), 3.69 (3 H, s, OCH3), 3.72–3.74 (1 H, m, CHN),
4.14 (2 H, q, 3JHH = 7.1 HZ, OCH2CH3), 5.81 (1 H, s, CH),
Yellow oil; yield 0.76 g (92%); Rf = 0.20; IR (KBr) (mmax
,
cm-1): 2,070 (N=C=C), 1,756, 1,722(C=O, ester). MS
1
(m/z, %): 417 (M+, 9). H NMR (500.1 MHz, CDCl3):
d = 1.34 (3 H, t, 3JHH = 7.2 HZ, OCH2CH3), 1.39 (9 H, s,
tert-C4H9), 3.71 (3 H, s, OCH3), 3.73 (3 H, s, OCH3), 4.29
3
6.78 (2 H, d, J = 8.7 Hz, 2 CH of 4-OCH3C6H4), 7.50 (2
3
3
(2 H, q, JHH = 7.1 HZ, OCH2CH3), 5.95 (1 H, s, CH),
H, d, J = 7.3 Hz, 2 CH of 4-OCH3C6H4), 8.47 (1 H, s,
N=CH) ppm. 13C NMR (125.7 MHz, CDCl3): d = 14.8
(OCH2CH3), 24.2, 24.3, 25.4, 33.5, and 33.5 (Cy), 52.0
(OCH3), 53.0 (OCH3), 55.6 (OCH3), 59.4 (CHN), 60.4
(N=C=C), 60.8 (CH), 62.8 (OCH2CH3), 114.4, 127.8,
129.4, and 161.6 (C arom), 151.2 (N=CH), 154.1 (CO2Et),
165.9 (N=C=C), 169.8 (CO2Me), 170.4 (CO2Me) ppm.
7.27–7.35 (3 H, m, 3 CH of Ph), 7.65–7.68 (2 H, m, 2 CH
of Ph), 8.66 (1 H, s, N=CH) ppm. 13C NMR (125.7 MHz,
CDCl3): d = 14.8 (OCH2CH3), 30.5 [C(CH3)3], 52.1
(OCH3), 53.1 (OCH3), 59.9 [C(CH3)3], 61.7 (N=C=C),
62.6 (CH), 63.0 (OCH2CH3), 128.0, 128.8, 130.3, and
135.3 (C arom), 150.0 (N=CH), 154.0 (CO2Et), 165.8
(N=C=C), 169.6 (CO2Me), 170.5 (CO2Me) ppm.
Dimethyl 2-cyclohexyliminomethylene-3-[N-ethoxycarbonyl-
N0-(4-methyl-benzylidene)-hydrazino]-succinate
(4c, C24H31N3O6)
Dimethyl 2-(tert-butylimino-methylene)-3-[N0-(4-chloro-
benzylidene)-N-ethoxycarbonyl-hydrazino]-succinate(4f,
C21H26ClN3O6)
Yellow oil; yield 0.81 g (89%); Rf = 0.20; IR (KBr) (mmax
,
cm-1): 2,065 (N=C=C), 1,751, 1,699 (C=O, ester). MS
Yellow oil; yield 0.84 g (94%); Rf = 0.25; IR (KBr) (mmax,
1
(m/z, %): 457 (M+, 5). H NMR (500.1 MHz, CDCl3):
cm-1): 2,060 (N=C=C), 1,750, 1,702 (C=O, ester). MS
1
d = 1.20–1.99 (10 H, m, 5 CH2 of Cy),1.35 (3 H, t,
3JHH = 7.1 HZ, OCH2CH3), 2.37 (3 H, s, CH3), 3.72 (3 H,
s, OCH3), 3.75 (3 H, s, OCH3), 3.80–3.82 (1 H, m, CHN),
4.30 (2 H, q, 3JHH = 7.1 HZ, OCH2CH3), 5.97 (1 H, s, CH),
7.18 (2 H, d, 3J = 7.9 Hz, 2 CH of 4-CH3C6H4), 7.56 (2 H,
d, 3J = 7.8 Hz, 2 CH of 4-CH3C6H4), 8.65 (1 H, s, N=CH)
ppm. 13C NMR (125.7 MHz, CDCl3): d = 14.7
(OCH2CH3), 24.3, 24.4, 25.5, 33.5, and 33.6 (Cy), 21.9
(CH3), 52.0 (OCH3), 53.2 (OCH3), 59.9 (CHN), 60.4
(N=C=C), 60.9 (CH), 63.0 (OCH2CH3), 128.0, 129.6,
132.6, and 140.6 (C arom), 151.4 (N=CH), 154.2 (CO2Et),
166.1 (N=C=C), 169.8 (CO2Me), 170.6 (CO2Me) ppm.
(m/z, %): 451 (M+, 6). H NMR (500.1 MHz, CDCl3):
d = 1.34 (3 H, t, 3JHH = 7.1 HZ, OCH2CH3), 1.41 (9 H, s,
tert-C4H9), 3.71 (3 H, s, OCH3), 3.74 (3 H, s, OCH3), 4.29
(2 H, q, 3JHH = 7.1 HZ, OCH2CH3), 5.94 (1 H, s, CH), 7.33
3
(2 H, d, J = 6.9 Hz, 2 CH of 4-ClC6H4), 7.80 (2 H, d,
3J = 6.9 Hz, 2 CH of 4-ClC6H4), 8.68 (1 H, s, N=CH) ppm.
13C NMR (125.7 MHz, CDCl3): d = 14.8 (OCH2CH3),
30.6 [C(CH3)3], 52.1 (OCH3), 53.2 (OCH3), 59.7
[C(CH3)3], 61.7 (N=C=C), 62.7 (CH), 63.1 (OCH2CH3),
127.3, 129.1, 134.0, and 136.0 (C arom), 148.8 (N=CH),
153.9 (CO2Et), 167.3 (N=C=C), 169.6 (CO2Me), 170.5
(CO2Me) ppm.
Diethyl 2-[N0-(4-chloro-benzylidene)-N-ethoxycarbonyl-
hydrazino]-3-cyclohexyliminomethylene-succinate
(4d, C25H32ClN3O6)
Dimethyl 2-(tert-butylimino-methylene)-3-[N-ethoxycarbonyl-
N0-(4-methyl-benzylidene)-hydrazino]-succinate(4g,
C22H29N3O6)
Yellow oil; yield 0.92 g (92%); Rf = 0.25; IR (KBr) (mmax
,
Yellow oil; yield 0.79 g (92%); Rf = 0.22; IR (KBr) (mmax,
cm-1): 2,060 (N=C=C), 1,746, 1,685 (C=O, ester). MS
cm-1): 2,060 (N=C=C), 1,743, 1,712 (C=O, ester). MS
1
1
(m/z, %): 505 (M+, 7). H NMR (500.1 MHz, CDCl3):
(m/z, %): 431 (M+, 5). H NMR (500.1 MHz, CDCl3):
d = 1.20–2.1(10 H, m, 5 CH2 of Cy), 1.21 (9 H, m,
3OCH2CH3), 3.72–3.78 (1 H, m, CHN), 4.12–4.28 (6H, m,
d = 1.35 (3 H, t, 3 JHH = 7.1 HZ, OCH2CH3), 1.41 (9 H, s,
tert-C4H9), 2.36 (3 H, s, CH3), 3.72 (s, 3 H, OCH3), 3.76 (3
123

400
M. Anary-Abbasinejad et al.
H, s, OCH3), 4.31 (2 H, q, 3JHH = 7.1 HZ, OCH2CH3), 5.96
(1 H, s, CH), 7.18 (2 H, d, 3J = 7.9 Hz, 2 CH of
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3
4-CH3C6H4), 7.58 (2 H, d, J = 7.9 Hz, 2 CH of
4-CH3C6H4), 8.65 (1 H, s, N=CH) ppm. 13C NMR
(125.7 MHz, CDCl3): d = 14.8 (OCH2CH3), 21.8 (CH3),
30.5 [C(CH3)3], 52.1 (OCH3), 53.1 (OCH3), 59.5
[C(CH3)3], 61.8 (N=C=C), 62.6 (CH), 63.0 (OCH2CH3),
128.08, 129.8, 132.6, and 140.6 (C arom), 151.0 (N=CH),
154.1 (CO2Et),166.0 (N=C=C), 169.7 (CO2Me), 170.6
(CO2Me) ppm.
¨
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