Synthesis of stable ketenimines via a four-component reaction

Article abstract of DOI:10.1007/s00706-011-0538-y

An efficient one-pot synthesis of ketenimine derivatives is described. It involves a four-component reaction between benzylamines, 2,2-dichloroethanoyl chloride, alkyl isocyanide, and dialkyl acetylenedicarboxylates under mild conditions at ambient temper

Full text of DOI:10.1007/s00706-011-0538-y

Monatsh Chem (2011) 142:1249–1252
DOI 10.1007/s00706-011-0538-y
ORIGINAL PAPER
Synthesis of stable ketenimines via a four-component reaction
•
Abdolali Alizadeh Mahdi Ahmadi
Received: 4 December 2010 / Accepted: 30 May 2011 / Published online: 28 June 2011
Ó Springer-Verlag 2011
Abstract An efficient one-pot synthesis of ketenimine
derivatives is described. It involves a four-component
reaction between benzylamines, 2,2-dichloroethanoyl
chloride, alkyl isocyanide, and dialkyl acetylenedicarb-
oxylates under mild conditions at ambient temperature.
formation of four, five, and six-membered heterocyclic ring
systems [7–11].
The trapping of the 1:1 intermediate formed between
dialkyl acetylenedicarboxylates and isocyanides with OH,
NH, and CH acids has been widely studied [12–16]. Pre-
viously, we reported a similar reaction between alkyl
isocyanides, acetylenic esters, and oximes to produce
thermally stable ketenimines [15].
Keywords Amine Á 2,2-Dichloroethanoyl chloride Á
Dialkyl acetylenedicarboxylate Á Alkyl isocyanide Á
Multicomponent reaction
Here we report a simple one-pot preparation of stable
ketenimines using alkyl isocyanides, dialkyl acetylenedi-
carboxylates, and, as N–H acids, N-benzyl-2,2-dichloro-
acetamides, which were obtained by reaction of benzylamine
derivatives with 2,2-dichloroethanoyl chloride.
Introduction
Multicomponent reactions (MCRs) are at a premium for
achievement of high diversity and brevity, because they
enable three or more simple and flexible building blocks to
be combined in practical, one-pot operations. MCRs have
attracted much interest owing to their exceptional synthetic
efficiency [1]. A multitude of MCRs exist today, of which
isocyanide-based MCRs are the most documented. Isocy-
anide-based MCRs are most frequently exploited because
the isocyanide is an extraordinary functional group.
Results and discussion
Alkyl isocyanides 1, dialkyl acetylenedicarboxylates 2, and
benzylamine derivatives 3 in the presence of 2,2-dichlo-
roethanoyl chloride undergo a addition reaction in CH2Cl2
at ambient temperature to produce dialkyl 2-[benzyl
(2,2-dichloroacetyl)amino]-3-(alkylcarbonimidoyl)succinate
derivatives 4 in excellent yields (Scheme 1). The structures
of compounds 4a–4h were deduced from their mass, IR,
Ketenimines are extensively involved in cascade reac-
tions and have attracted much attention in recent years
because of their easy formation, the relative reactivity,
tolerance of different procedures, and the diversity of the
products [2]. Ketenimines are important reactive interme-
diates that occur as transient compounds in many thermal
and photochemical reactions [3–6]. They have also found
widespread use as reactive starting materials for the
1
and high-field H and 13C NMR spectra. The mass spec-
trum of 4a contained the molecular ion peak at m/z = 443,
which is in agreement with the proposed structure. The IR
spectrum of this compound contained absorption bands at
2,055, 1,744, and 1,684 cm-1 arising from the stretching
frequencies of ketenimine, CO2Me, and NCO groups,
1
respectively. The H NMR spectrum of 4a contained five
singlets for t-Bu, two methoxy, CHCl2, and CH groups
at d = 1.45, 3.66, 3.72, 5.09, and 6.14 ppm, respectively,
and an AB system for the diastereotopic benzylic hydro-
gen atoms at d = 4.84 ppm (2JHH = 16.9 Hz). Aromatic
A. Alizadeh (&) Á M. Ahmadi
Department of Chemistry, Tarbiat Modares University,
P.O. Box 14115-175, Tehran, Iran
e-mail: aalizadeh@modares.ac.ir; abdol_alizad@yahoo.com
123

1250
A. Alizadeh, M. Ahmadi
O
O
O
+
+
Cl
CHCl2
Ar
N
H
CHCl2
Ar
NH2
Ar
NH2
+
Cl
CHCl2
3
O
5
CH2Cl2
r.t., 24 h
Ar
N
CHCl2
CO2R'
CO2R'
R'O2C
CO2R'
5
+
1
2
R N C
R'O2C
2
+
C
N
R
6
R'O2C
C
N
R
1
O
N
CO2R'
H
4
R N C
4
Ar
CHCl2
R'O2C
4
R
R'
Ar
Ph
7
8
a
b
c
d
e
f
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
Me
Me
Me
Et
Et
Me
4-MeC6H4
4-MeOC6H4
4-ClC6H4
Ph
4-MeC6H4
Ph
Scheme 2
corresponding dialkyl 2-[benzyl(2,2-dichloroacetyl)amino]-
3-(alkylcarbonimidoyl)succinate derivatives 4 (Scheme 2).
In summary, this simple one-pot reaction between
isocyanides, dialkyl acetylenedicarboxylates, and benzyl-
amine derivatives in the presence of 2,2-dichloroethanoyl
chloride provides access to stable ketenimine derivatives of
potential synthetic interest. The method presented has the
advantage of being performed under neutral conditions and
requires no activation or modification of the reagents.
g
h
Cyhex
Cyhex
Et
4-MeC6H4
Scheme 1
hydrogens gave rise to characteristic signals in the aromatic
region of the spectrum. The 1H-decoupled 13C NMR
spectrum of 4a contained 16 distinct resonances, in
agreement with the suggested structure. In the aliphatic
region there were six signals related to two methoxy,
CHCl2, t-Bu, CH, and CH2 groups. The characteristic
carbon (RN=C=C) of the compound 4a resonates at
164.07 ppm. The other important region of the spectrum is
related to carbonyl groups which produce two C=O signals
at 168.26 and 170.63 ppm. The 1H and 13C NMR spectra of
compounds 4b–4h are similar to those of 4a except for the
aromatic and OR which give characteristic signals with
appropriate chemical shifts.
Experimental
Dimethyl, diethyl, and the isocyanides were obtained from
Merck (Germany) and Fluka (Switzerland) and were used
without further purification. Mass spectra were recorded on
a Finnigan MAT 8430 mass spectrometer operating at an
1
electron energy of 70 eV. H NMR and 13C NMR spectra
were measured in CDCl3 solution, at 500.1 and
125.7 MHz, respectively, using a Bruker DRX-500 Avance
spectrometer. IR spectra were recorded on a Shimadzu IR-
460 spectrometer. Chromatography columns were prepared
from Merck silica gel (230–240 mesh).
The ketenimine structure was established by IR
(2,055 cm-1 absorbance) and NMR spectroscopy. In the
off-resonance 13C NMR spectrum of 4a, the CH signal
(d = 64.40 ppm) is a doublet, and no exchange is observed
in the 1H NMR spectrum of the same compound in
deuterium oxide solution.
Typical procedure: dimethyl 2-[benzyl(2,2-
dichloroacetyl)amino]-3-(tert-butylcarbonimidoyl)-
succinate (4a, C20H24Cl2N2O5)
Although we have not established the mechanism of the
reaction between an isocyanide and an acetylenic ester in
the presence of an N-benzyl-2,2-dichloroacetamide 5
experimentally, a possible explanation is proposed in
Scheme 2. On the basis of the well-established chemistry
of isocyanides [17–21], it is reasonable to assume that the
functionalized ketenimine 4 results from initial addition of
the isocyanide to the acetylenic ester and subsequent
protonation of the 1:1 adduct 6 by N-benzyl-2,2-dichloro-
acetamide 5 as N–H acid; this is followed by attack of
the anion 8 on the positively charged ion 7 to give the
To a magnetically stirred solution of 0.22 g benzylamine
(2 mmol) and 0.15 g 2,2-dichloroethanoyl chloride
(1 mmol) dissolved in 2 cm3 dry CH2Cl2, a solution of
0.14 g dimethyl acetylenedicarboxylate (1 mmol) in 2 cm3
dry CH2Cl2 and a solution of 0.08 g t-BuNC (1 mmol) in
2 cm3 dry CH2Cl2 were added simultaneously dropwise at
room temperature over 10 min. The mixture was then
stirred for 24 h, and the progress of the reaction was
followed by thin-layer chromatography. After completion,
123

Synthesis of stable ketenimines via a four component reaction
1251
the reaction mixture was filtered and the precipitate of
benzylammonium chloride was separated. Solvent was
removed from the filtrate under reduced pressure, and the
residue was separated by column chromatography (silica
gel, hexane–EtOAc, 5:1) to give the product 4a as yellow
oil, yield 0.38 g (86%). IR (KBr): m = 2,055 (N=C=C),
1,744 (CO2Me), 1,684 (NCO), 1,531, 1,493 (Ph), 1,256,
43.85 (CH2), 51.71 (OCH3), 52.66 (OCH3), 55.31 (4-
CH3OC6H4), 58.45 (CH), 60.1 (C(CH3)3), 62.31 (C=C=N),
64.82 (CHCl2), 114.94 (2CH of Ar), 128.78 (2CH of Ar),
129.19 (Cipso–CH2), 159.52 (Cipso–OCH3), 162.61 (C=O),
163.85 (C=C=N), 168.25 (CO2Me), 170.74 (CO2Me) ppm;
MS (EI, 70 eV): m/z (%) = 473 (M?, 1), 351 (12), 295
(23), 246 (9), 226 (8), 170 (7), 122 (46), 121 (100), 91 (8),
77 (9), 57 (75), 41 (23).
1,236 (C–O of esters), 1,175 (C–N) cm-1 1H NMR
;
(500.1 MHz, CDCl3): d = 1.45 (9H, s, C(CH3)3), 3.66
(3H, s, OCH3), 3.72 (3H, s, OCH3), 4.84 (2H, AB system,
2JHH = 16.9 Hz, CH2), 5.09 (1H, s, CHCl2), 6.14 (1H, s,
CH), 7.32–7.41 (5H, m, 5CH of Ph) ppm; 13C NMR
(125.7 MHz, CDCl3): d = 30.07 (C(CH3)3), 51.72 (CH2),
52.08 (OCH3), 52.69 (OCH3), 58.75 (CHCl2), 60.02
(C(CH3)3), 62.43 (C=C=N), 64.40 (CH), 127.18 (2CHmeta
of Ph), 128.10 (CHpara of Ph), 128.86 (2CHortho of Ph),
135.32 (Cipso), 162.51 (C=O), 164.07 (C=C=N), 168.26
(CO2Me), 170.63 (CO2Me) ppm; MS (EI, 70 eV): m/z
(%) = 443 (M?, 26), 387 (16), 327 (10), 260 (10), 226
(100), 170 (6), 91 (94), 57 (65), 41 (28).
Dimethyl 2-(tert-butylcarbonimidoyl)-3-[(4-chlorobenzyl)-
(2,2-dichloroacetyl)amino]succinate
(4d, C20H23Cl3N2O5)
White wax, yield 0.43 g (90%); IR (KBr): m = 2,071
(N=C=C), 1,745 (CO2Me), 1,684 (NCO), 1,540, 1,493
1
(Ph), 1,266 (C–O of esters), 1,178 (C–N) cm-1; H NMR
(500.1 MHz, CDCl3): d = 1.45 (9H, s, C(CH3)3), 3.67
(3H, s, OCH3), 3.72 (3H, s, OCH3), 4.83 (2H, AB system,
2JHH = 16.9 Hz, CH2), 4.99 (1H, s, CHCl2), 6.12 (1H, s,
CH), 7.24 (2H, d, 3JHH = 8.4 Hz, 2CH of Ar), 7.34 (2H, d,
3JHH = 8.4 Hz, 2CH of Ar) ppm; 13C NMR (125.7 MHz,
CDCl3): d = 30.06 (C(CH3)3), 43.56 (CH2), 51.50
(OCH3), 52.76 (OCH3), 58.58 (CH), 59.80 (C(CH3)3),
62.39 (C=C=N), 64.77 (CHCl2), 129.00 (2CH of Ar),
Dimethyl 2-(tert-butylcarbonimidoyl)-3-[(2,2-
dichloroacetyl)(4-methylbenzyl)amino]succinate
(4b, C21H26Cl2N2O5)
129.07 (2CH of Ar), 133.95 (Cipso–Cl), 134.07 (Cipso
–
Yellow wax, yield 0.39 g (85%); IR (KBr): m = 2,055
(N=C=C), 1,746 (CO2Me), 1,671 (NCO), 1,553, 1,513
CH2), 162.00 (C=O), 163.88 (C=C=N), 168.13 (CO2Me),
170.34 (CO2Me) ppm; MS (EI, 70 eV): m/z (%) = 478
(M?, 1), 420 (5), 361 (6), 295 (20), 263 (12), 125 (100),
112 (13), 91 (43), 70 (20), 57 (75), 41 (29).
1
(Ph), 1,256, 1,236 (C–O of esters), 1,173 (C–N) cm-1; H
NMR (500.1 MHz, CDCl3): d = 1.45 (9H, s, C(CH3)3),
2.36 (3H, s, Me), 3.66 (3H, s, OCH3), 3.71 (3H, s, OCH3),
2
4.79 (2H, AB system, JHH = 16.9 Hz, CH2), 5.07 (1H, s,
Diethyl 2-[benzyl(2,2-dichloroacetyl)amino]-3-
3
CHCl2), 6.14 (1H, s, CH), 7.18 (2H, d, JHH = 6.5 Hz,
(tert-butylcarbonimidoyl)succinate (4e, C22H28Cl2N2O5)
Yellow oil, yield 0.40 g (85%); IR (KBr): m = 2,055
(N=C=C), 1,744 (CO2Et), 1,684 (NCO), 1,532, 1,493 (Ph),
1,248, 1,227 (C–O of esters), 1,175 (C–N) cm-1; 1H NMR
3
2CH of Ar), 7.28 (2H, d, JHH = 7.95 Hz, 2CH of Ar)
ppm; 13C NMR (125.7 MHz, CDCl3): d = 21.11 (Me),
30.06 (C(CH3)3), 44.11 (CH2), 51.92 (OCH3), 52.66
(OCH3), 58.68 (CH), 60.11 (C(CH3)3), 62.33 (C=C=N),
64.77 (CHCl2), 127.18 (2CH of Ar), 127.77 (2CH of Ar),
132.21 (Cipso–Me), 133.70 (Cipso–CH2), 162.65 (C=O),
164.02 (C=C=N), 168.28 (CO2Me), 170.63 (CO2Me) ppm;
MS (EI, 70 eV): m/z (%) = 457 (M?, 11), 401 (3), 232
(17), 198 (35), 196 (99), 160 (67), 117 (22), 105 (100), 91
(16), 77 (16), 65 (8), 51 (6).
3
(500.1 MHz, CDCl3): d = 1.20 (3H, t, JHH = 7.1 Hz,
OCH2CH3), 1.25 (3H, t, JHH = 7.1 Hz, OCH2CH3), 1.43
3
(9H, s, C(CH3)3), 4.10 (2H, q, 3JHH = 7.1 Hz, OCH2CH3),
3
4.15 (2H, q, JHH = 7.1 Hz, OCH2CH3), 4.84 (2H, AB
2
system, JHH = 16.9 Hz, CH2), 5.03 (1H, s, CHCl2), 6.14
(1H, s, CH), 7.30–7.41 (5H, m, 5CH of Ph) ppm; 13C NMR
(125.7 MHz, CDCl3): d = 14.04 (OCH2CH3), 14.12
(OCH2CH3), 30.06 (C(CH3)3), 52.16 (CH2), 58.85
(CHCl2), 60.35 (OCH2CH3), 60.54 (C(CH3)3), 61.90
(OCH2CH3), 62.23 (C = C=N), 64.67 (CH), 127.27 (2
CHmeta of Ph), 128.04 (CHpara of Ph), 128.79 (2CHortho of
Ph), 135.41 (Cipso), 163.41 (C=O), 163.88 (C=C=N),
167.63 (CO2Et), 170.29 (CO2Et) ppm; MS (EI, 70 eV):
m/z (%) = 471 (M?, 12), 415 (13), 341 (12), 288 (8), 254
(67), 198 (15), 91 (100), 57 (48), 41 (16).
Dimethyl 2-(tert-butylcarbonimidoyl)-3-[(2,2-
dichloroacetyl)(4-methoxybenzyl)amino]succinate
(4c, C21H26Cl2N2O6)
White wax, yield 0.41 g (87%); IR (KBr): m = 2,068
(N=C=C), 1,746 (CO2Me), 1,669 (NCO), 1,514, 1,460 (Ph),
1,253, 1,228 (C–O of esters), 1,177 (C–N) cm-1; 1H NMR
(500.1 MHz, CDCl3) : d = 1.45 (9H, s, C(CH3)3), 3.67
(3H, s, OCH3), 3.70 (3H, s, OCH3), 3.81 (3H, s, OCH3),
2
Diethyl 2-(tert-butylcarbonimidoyl)-3-[(2,2-dichloroacetyl)-
(4-methylbenzyl)amino]succinate (4f, C23H30Cl2N2O5)
Yellow wax, yield 0.39 g (80%); IR (KBr): m = 2,058
(N=C=C), 1,743 (CO2Et), 1,670 (NCO), 1,555, 1,512 (Ph),
4.77 (2H, AB system, JHH = 16.3 Hz, CH2), 5.02 (1H, s,
3
CHCl2), 6.17 (1H, s, CH), 6.91 (2H, d, JHH = 8.55 Hz,
2CH of Ar), 7.34 (2H, d, 3JHH = 8.6 Hz, 2CH of Ar) ppm;
13C NMR (125.7 MHz, CDCl3): d = 30.05 (C(CH3)3),
123

1252
A. Alizadeh, M. Ahmadi
3
(1H, m, CHN), 4.13 (2H, q, JHH = 7.1 Hz, OCH2CH3),
1,249, 1,206 (C–O of esters), 1,176 (C–N) cm-1; 1H NMR
3
3
4.16 (2H, q, JHH = 7.2 Hz, OCH2CH3), 4.80 (2H, AB
(500.1 MHz, CDCl3): d = 1.22 (3H, t, JHH = 7.1 Hz,
OCH2CH3), 1.26 (3H, t, JHH = 7.1 Hz, OCH2CH3), 1.45
3
2
system, JHH = 16.9 Hz, CH2), 5.04 (1H, s, CHCl2), 6.15
(9H, s, C(CH3)3), 2.36 (3H, s, Me), 4.12 (2H, q,
3
(1H, s, CH), 7.18 (2H, d, 3JHH = 7.9 Hz, 2CH of Ar), 7.30
3
3JHH = 7.1 Hz, OCH2CH3), 4.17 (2H, q, JHH = 7.2 Hz,
(2H, d, JHH = 7.9 Hz, 2CH of Ar) ppm; 13C NMR
2
OCH2CH3), 4.80 (2H, AB system, JHH = 16.9 Hz, CH2),
(125.7 MHz, CDCl3): d = 13.85 (OCH2CH3), 14.4
(OCH2CH3), 21.10 (Me), 23.79, 25.30, 32.9, 32.96 (Cy),
52.08 (CH2), 59.07 (CH), 59.25 (C=C=N), 60.35
(OCH2CH3), 61.90 (CHN), 61.84 (OCH2CH3), 64.70
(CHCl2), 127.96 (2CH of Ar), 129.48 (2CH of Ar),
132.33 (Cipso–Me), 137.8 (Cipso–CH2), 163.09 (C=O),
163.91 (C=C=N), 167.68 (CO2Et), 170.32 (CO2Et) ppm;
MS (EI, 70 eV): m/z (%) = 511 (M?, 12), 427 (12), 405
(29), 355 (17), 323 (30), 299 (16), 280 (84), 252 (10), 226
(32), 198 (29), 170 (12), 105 (100), 83 (26), 55 (58), 41
(26).
5.02 (1H, s, CHCl2), 6.15 (1H, s, CH), 7.18 (2H, d,
3
3JHH = 7.9 Hz, 2CH of Ar), 7.30 (2H, d, JHH = 7.9 Hz,
2CH of Ar) ppm; 13C NMR (125.7 MHz, CDCl3):
d = 14.04 (OCH2CH3), 14.34 (OCH2CH3), 21.11 (4-
MeC6H4), 30.08 (C(CH3)3), 44.12 (CH2), 52.04
(C(CH3)3), 58.83 (C=C=N), 60.35 (OCH2CH3), 61.81
(CH), 64.73 (OCH2CH3), 66.45 (CHCl2), 127.77 (2CH of
Ar), 129.61 (2CH of Ar), 133.68 (Cipso–CH3), 137.85
(Cipso–CH2), 163.85 (C=O), 163.96 (C=C=N), 167.67
(CO2Et), 170.35 (CO2Et) ppm; MS (EI, 70 eV): m/z
(%) = 485 (M?, 8), 429 (15), 355 (17), 323 (22), 277
(10), 254 (55), 198 (15), 170 (6), 106 (36), 105 (100), 79
(9), 57 (72), 41 (25).
References
Dimethyl 2-[benzyl(2,2-dichloroacetyl)amino]-3-
(cyclohexylcarbonimidoyl)succinate
(4g, C22H26Cl2N2O5)
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Tetrahedron 59:1289
Yellow oil, yield 0.38 g (81%); IR (KBr): m = 2,060
(N=C=C), 1,741 (CO2Me), 1,708 (CO2Me), 1,674 (NCO),
1,525, 1,492 (Ph), 1,246, 1,206 (C–O of esters), 1,163
1
(C–N) cm-1; H NMR (500.1 MHz, CDCl3): d = 1.26–
1.60 (10H, m, 5CH2 of Cy), 3.66 (3H, s, OCH3), 3.72 (3H,
s, OCH3), 3.60–3.64 (1H, m, CHN), 4.84 (2H, AB system,
2JHH = 18.0 Hz, CH2), 5.09 (1H, s, CHCl2), 6.14 (1H, s,
CH), 7.30–7.40 (5H, m, 5CH of Ph) ppm; 13C NMR
(125.7 MHz, CDCl3) : d = 23.95, 25.22, 32.99 (Cy), 44.31
(CH2), 51.68 (C=C=N), 52.13 (OCH3), 52.76 (OCH3),
60.05 (CH), 64.71 (CHN), 66.42 (CHCl2), 127.2 (2CHmeta
of Ph), 128.05 (CHpara of Ph), 128.97 (2CHortho of Ph),
136.76 (Cipso), 162.30 (C=O), 164.15 (C=C=N), 168.30
(CO2Me), 170.62 (CO2Me) ppm; MS (EI, 70 eV): m/z
(%) = 469 (M?, 2), 427 (16), 403 (27), 375 (23), 343 (19),
295 (17), 271 (54), 239 (27), 212 (88), 171 (20), 113 (21),
92 (43), 91 (100), 65 (28), 55 (77), 41 (55).
13. Yavari I, Alizadeh A, Anari-Abbasinejad M, Bijanzadeh HR
(2003) Tetrahedron 59:6083
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Chem 137:191
15. Alizadeh A, Rostamnia S (2008) Synthesis 57
16. Anary-Abbasinejad M, Moslemine MH, Anaraki-Ardakani H
(2009) J Fluorine Chem 130:368
Diethyl 2-(cyclohexylcarbonimidoyl)-3-[(2,2-dichloroacetyl)-
(4-methylbenzyl)amino]succinate (4h, C25H32Cl2N2O5)
Yellow oil, yield 0.43 g (84%); IR (KBr): m = 2,075
(N=C=C), 1,739 (CO2Et), 1,680 (NCO), 1,520, 1,449 (Ph),
17. Ugi I (1982) Angew Chem Int Ed 21:810
¨
19. Domling A (2006) Chem Rev 106:17
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20. Walborsky HM, Periasamy MP (1983) In: Patai S, Rappoport Z
(eds) The chemistry of functional groups, Suppl C, Chap 20,
Wiley, New York
1,264 (C–O of esters), 1,105 (C–N) cm-1 1H NMR
;
(500.1 MHz, CDCl3): d = 1.36–1.96 (10H, m, 5CH2 of
Cy), 1.22 (3H, t, JHH = 7.1 Hz, OCH2CH3), 1.25 (3H, t,
3
21. Marcaccini S, Torroba T (1993) Org Prep Proced Int 25:141
3JHH = 7.1 Hz, OCH2CH3), 2.35 (3H, s, Me), 3.84–3.88
123