One-pot synthesis of highly functionalized stable ketenimines of 2,2,2-trifluoro-N-aryl-acetamides

Article abstract of DOI:10.1016/j.jfluchem.2008.12.003

Three-component reaction of alkyl isocyanides and dialkyl acetylenedicarboxylates in the presence of 2,2,2-trifluoro-N-aryl-acetamides in dichloromethane at ambient temperature afforded dialkyl 2-(N-(aryl)-2,2,2-trifluoroacetamido)-3-(alkylimino) methylene-succinate derivatives in excellent yields.

Full text of DOI:10.1016/j.jfluchem.2008.12.003

Journal of Fluorine Chemistry 130 (2009) 368–371
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Journal of Fluorine Chemistry
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Short communication
One-pot synthesis of highly functionalized stable ketenimines of
2,2,2-trifluoro-N-aryl-acetamides
a
b
Mohammad Anary-Abbasinejad a, , Mohammad H. Moslemine , Hossein Anaraki-Ardakani
*
a Department of Chemistry, Islamic Azad University, Yazd Branch, P.O. Box 89195-155, Yazd, Iran
b Department of Chemistry, Islamic Azad University, Mahshahr Branch, Mahshahr, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
Three-component reaction of alkyl isocyanides and dialkyl acetylenedicarboxylates in the presence of
2,2,2-trifluoro-N-aryl-acetamides in dichloromethane at ambient temperature afforded dialkyl 2-(N-
(aryl)-2,2,2-trifluoroacetamido)-3-(alkylimino) methylene-succinate derivatives in excellent yields.
ß 2008 Elsevier B.V. All rights reserved.
Received 12 November 2008
Received in revised form 5 December 2008
Accepted 15 December 2008
Available online 25 December 2008
Keywords:
Isocyanides
Ketenimines
NH-acids
Acetylenic esters
Trifluoroacetamide
1. Introduction
mides as N–H acids in dichloromethane leading to the formation
of thermally stable ketenimine derivatives in good yields. Alkyl
Modern synthetic design demands high efficiency in terms of
minimization of synthetic steps together with maximization of
complexity [1]. One of the ways to fulfill these goals is the
development and use of multicomponent reactions which consist
of several simultaneous bond-forming reactions and allow the high
efficient synthesis of complex molecules starting from simple
substrates in a one-pot manner [2–4]. In recent years, the synthetic
applications of multifunctional heteroallenes have been widely
investigated [5,6]. In spite of extensive developments in the
chemistry of modified ketenes and isocyanates [7], little attention
has been paid to the synthesis of ketenimines [8]. Ketenimines are
important reactive intermediates that occur as transient com-
pounds in many thermal and photochemical reactions [9–12].
There has been intense interest in their addition reactions, such as
cycloaddition [13–15], nucleophilic [11,16,17], and electrophilic
[18,19] addition. The trapping of the 1:1 intermediate formed
between dialkyl acetylenedicarboxylates and isocyanides with OH,
NH, and CH acids has been widely studied [20–24]. In continuation
of our works on the reaction between isocyanides and acetylenic
esters in the presence of organic acids [25–28], in this paper we
present the results of an extended investigation on the reactivity of
the intermediate zwitterion with 2,2,2-trifluoro-N-aryl-aceta-
isocyanides 1 and dialkyl acetylenedicarboxylates 2 in the
presence of 2,2,2-trifluoro-N-aryl-acetamides 3 undergo a smooth
1:1:1 addition reaction in dichloromethane at ambient tempera-
ture to produce dialkyl 2-(N-(aryl)-2,2,2-trifluoroacetamido)-3-
(alkylimino) methylene-succinate derivatives 4 in excellent yields
(Scheme 1). Previously, we reported similar reaction between alkyl
isocyanides, acetylene diesters and N-phenyl-acetamide to pro-
duce unsaturated amidines [25].
2. Results and discussion
The results on the synthesis of ketenimines are given in Table 1.
The structures of compounds 4a–f were deduced from their
elemental analyses and their IR, 1H NMR, 13C NMR spectra. The
mass spectrum of 4a displayed the molecular ion peak at m/z = 474
which is consistent with the formation of a 1:1:1 adduct of
dimethyl acetylenedicarboxylate, cyclohexyl isocyanide, and N-(4-
chlorophenyl)-2,2,2-trifluoroacetamide. The IR spectra of the
ketenimines exhibit
a
strong absorption band at about
2030 cmꢀ1. The IR spectrum of 4a exhibited the absorption band
for the ketenimine moiety at 2060 cmꢀ1and for the ester carbonyl
groups at 1747 and 1696 cmꢀ1
.
The 1H NMR spectrum of compound 4a exhibited three sharp
singlet signals readily recognized as arising from methoxy ( = 3.65
and 3.77), and CH ( = 5.59) protons. The NCH proton was appeared
as a multiplet at 3.62 ppm and the signals related to methylene
d
d
* Corresponding author. Fax: +98 351 8211109.
E-mail address: mohammadanary@yahoo.com (M. Anary-Abbasinejad).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.12.003

M. Anary-Abbasinejad et al. / Journal of Fluorine Chemistry 130 (2009) 368–371
369
Scheme 1.
groups of cyclohexyl moiety were observed as multiplets at 1.27–
1.82 ppm.
The protons of the aryl group exhibited characteristic signals in
ketenimine residue appeared at
electron delocalization. Partial assignments of these resonances
are given in Section 4.
d
= 60.8 ppm, as a result of strong
the aromatic region of the spectrum. The 13C NMR spectrum of
compound 4a showed 19 distinct resonances in agreement with
the proposed structure. The sp2-hybridized carbon atom of the
Although we have not established the mechanism of the
reaction between an isocyanide and an acetylenic ester in the
presence of 2,2,2-trifluoro-N-phenyl-acetamide 3 experimentally,
Table 1
Synthesis of ketenimines.
Entry
1
Substrate
R0
R
Product
Yielda (%)
85
Cyclohexyl
Me
Cl
O
N
O
CF3
N
CF3
N
H
Cl
C
MeO2C
CO2Me
4a
2
3
4
Cyclohexyl
Me
Me
Me
89
90
82
O
N
O
CF3
CF3
N
N
H
C
MeO2C
CO2Me
4b
tert-Buty
CH3O
O
O
CF3
N
CF3
N
CH3O
N
C
H
MeO2C
CO2Me
4c
Cyclohexyl
H3C
O
N
O
CF3
CF3
N
N
H3C
C
H
MeO2C
CO2Me
4d
5
Cyclohexyl
Me
80
CH3O
O
N
O
CF3
N
CF3
N
CH3O
C
H
MeO2C
CO2Me
4e
6
Cyclohexyl
Et
85
Me
O
N
O
CF3
CF3
N
N
Me
C
H
EtO2C
CO2Et
4f
a
Isolated yields.

370
M. Anary-Abbasinejad et al. / Journal of Fluorine Chemistry 130 (2009) 368–371
Scheme 2.
a possible explanation is proposed in Scheme 2. On the basis of the
well-established chemistry of isocyanides [29–33], it is reasonable
to assume that the functionalized ketenimine 4 results from the
initial addition of the isocyanide to the acetylenic ester and
subsequent protonation of the 1:1 adduct 5 by 2,2,2-trifluoro-N-
phenyl-acetamide. Then, the positively charged ion 6 is attacked by
anion 7 to give the product 4 (Scheme 2).
of cyclohexyl), 3.65 (3 H, s, OCH3), 3.77 (3 H, s, OCH3), 5.59 (1 H, s,
CH), 7.25–7.35 (4 H, aromatic) ppm. 13C NMR (125.7 MHz, CDCl3):
d
= 24.2, 24.2, 25.1, 33.4 and 33.5 (5 CH2 of cyclohexyl), 52.2
(OCH3), 53.7 (OCH3), 57.6 (CH of cyclohexyl), 60.8 (N
C C), 62.1
(CH), 118.2 (q, 1JFC = 285 HZ, CF3), 129.5, 129.7, 136.0 and 136.3 (C
2
aromatic), 157.4 (q, JFC = 36 HZ, COCF3),160.6 (N
(CO2Me), 169.8 (CO2Me) ppm.
C C), 167.0
19F NMR (470.56 MHz, CDCl3)
d
= ꢀ75.6 (CF3) ppm.
3. Conclusion
4.3.2. Dimethyl 2-(2,2,2-trifluoro-N-phenylacetamido)-3-
In conclusion, here we report a simple one-pot reaction between
alkyl isocyanides and dialkyl acetylenedicarboxylates in the
presence of 2,2,2-trifluoro-N-aryl-acetamides that provides access
to stable ketenimine derivatives of potential synthetic interest. The
present procedure has the advantage that not only is the reaction
performed under neutral conditions, but also the reactants can be
mixed without any prior activation or modification.
(cyclohexylimino) methylene-succinate (4b)
Yellow oil; yield 0.78 g (89%); IR (KBr) (
C), 1745, 1702 (C O, ester). Analyses: Calcd. for
21H23F3N2O5: C, 57.27; H, 5.26; N, 6.36%. Found: C, 57.36; H,
5.22; N, 6.39%. MS (m/z, %): 440 (M+, 9). 1H NMR (500.1 MHz,
CDCl3): = 1.21–1.77 (10 H, 5 CH2 of cyclohexyl), 3.58 (1 H, m, CH
n
max, cmꢀ1): 2075
(N
C
C
d
of cyclohexyl), 3.61 (3 H, s, OCH3), 3.74 (3 H, s, OCH3), 5.61 (1 H, s,
CH), 7.25–7.34 (5 H, aromatic) ppm. 13C NMR (125.7 MHz, CDCl3):
4. Experimental
d = 23.0, 23.1, 25.4, 33.3 and 33.4 (5 CH2 of cyclohexyl), 52.1
(OCH3), 53.3 (OCH3), 57.9 (CH of cyclohexyl), 60.7 (N
C C), 62.1
4.1. General
(CH), 117.6 (q, 1JFC = 286 HZ, CF3), 128.9, 129.6, 130.0 and 137.8 (C
2
aromatic), 157.5 (q, JFC = 36 HZ, COCF3), 161.4 (N
(CO2Me), 169.8 (CO2Me) ppm.
C C), 168.7
Melting points were determined with an electrothermal 9100
apparatus. Elemental analyses were performed using a Heraeus
19F NMR (470.56 MHz, CDCl3)
d
= ꢀ75.6 (CF3) ppm.
CHN-O-Rapid analyzer. Mass spectra were recorded on
a
FINNIGAN-MAT 8430 mass spectrometer operating at an ioniza-
tion potential of 70 eV. IR spectra were recorded on a shimadzu IR-
470 spectrometer. 1H, 13C and 19F NMR spectra were recorded on
Bruker DRX-500 Avance spectrometer at 500.13, 125.77 and
470.56 MHz, respectively. 1H, 13C, and 19F NMR spectra were
obtained on solution in CDCl3 using TMS or CFCl3 as internal
standard. 2,2,2-Trifluoro-N-aryl-acetamides were prepared by
treatment of anilines and trifluoroacetic acid in microwave [34].
The chemicals used in this work purchased from Fluka (Buchs,
Switzerland) and were used without further purification.
4.3.3. Dimethyl 2-(2,2,2-trifluoro-N-(4-methoxyphenyl)acetamido)-
3-(tert-butylimino) methylene-succinate (4c)
Yellow oil; yield 0.79 g (90%); IR (KBr) (
C), 1745, 1696 (C O, ester). Analyses: Calcd. for
20H23F3N2O6: C, 54.05; H, 5.22; N, 6.30%. Found: C, 54.12; H,
5.26; N, 6.27%. MS (m/z, %): 444 (M+, 9). 1H NMR (500.1 MHz,
CDCl3): = 1.30 (9 H, s, CMe3), 3.37 (3 H, s, OCH3), 3.71 (3 H, s,
OCH3), 3.76 (3 H, s, OCH3), 5.53 (1 H, s, CH), 6.96–7.49 (4 H,
aromatic) ppm. 13C NMR (125.7 MHZ, CDCl3):
= 30.6 (CMe3), 52.1
C), 62.6
n
max, cmꢀ1): 2070
(N
C
C
d
d
(OCH3), 52.2 (OCH3), 52.6 (OCH3), 53.3 (CMe3), 57.2 (N
C
(CH), 118.3 (q, 1JFC = 287 HZ, CF3), 129.7, 130.0, 135.3 and 139.8 (C
2
4.2. Typical procedure for the preparation of 4a–f
aromatic), 157.5 (q, JFC = 36 HZ, COCF3), 161.8 (N
(CO2Me), 171.2 (CO2Me) ppm.
C C), 168.9
To a magnetically stirred solution of dialkyl acetylenedicarbox-
ylate (2 mmol) and 2,2,2-trifluoro-N-phenyl-acetamide (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 title compounds.
19F NMR (470.56 MHz, CDCl3)
d
= ꢀ75.6 (CF3) ppm.
4.3.4. Dimethyl 2-(2,2,2-trifluoro-N-p-tolylacetamido)-3-
(cyclohexylimino) methylene-succinate (4d)
Yellow oil; yield 0.74 g (82%); IR (KBr) (
C), 1744, 1699 (C O, ester). Analyses: Calcd. for
22H25F3N2O5: C, 58.15; H, 5.54; N, 6.16%. Found: C, 58.06; H,
5.63; N, 6.21%.. MS (m/z, %): 454 (M+, 5). 1H NMR (500.1 MHz,
CDCl3): = 1.20–1.84 (10 H, 5 CH2 of cyclohexyl), 2.37 (3 H, s, CH3),
n
max, cmꢀ1): 2075
(N
C
C
4.3. Spectral data
d
3.68 (3 H, s, OCH3), 3.74 (1 H, m, CH of cyclohexyl), 3.81 (3 H, s,
OCH3), 5.60 (1 H, s, CH), 6.95–7.48 (4 H, aromatic) ppm. 13C NMR
4.3.1. Dimethyl 2-(N-(4-chlorophenyl)-2,2,2-trifluoroacetamido)-3-
(cyclohexylimino) methylene-succinate (4a)
(125.7 MHZ, CDCl3):
CH2 of cyclohexyl), 52.2 (OCH3), 53.3 (OCH3), 58.1 (CH of
cyclohexyl), 60.8 (N
CF3), 129.8, 130.2, 136.5 and 139.8 (C aromatic), 156.86 (q, 2JFC = 36
HZ, COCF3), 164.4 (N C), 169.1 (CO2Me), 169.9 (CO2Me) ppm.
19F NMR (470.56 MHz, CDCl3)
= ꢀ75.5 (CF3) ppm.
d = 21.3 (CH3), 24.3, 24.8, 26.1, 33.3 and 33.4 (5
Yellow oil; yield 0.80 g (85%); IR (KBr) (
C), 1747, 1696 (C O, ester). Analyses: Calcd. for
21H22ClF3N2O5: C, 53.12; H, 4.67; N, 5.90%. Found: C, 53.19; H,
4.57; N, 5.81%. MS (m/z, %): 474 (M+, 4). 1H NMR (500.1 MHz,
CDCl3): = 1.27–1.82 (10 H, 5 CH2 of cyclohexyl), 3.62 (1 H, m, CH
n
max, cmꢀ1): 2060
1
(N
C
C C), 62.1 (CH), 117.2 (q, JFC = 285 HZ,
C
C
d
d

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371
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(125.7 MHZ, CDCl3):
d = 23.1, 24.2, 25.2, 33.3 and 33.4 (5 CH2 of
cyclohexyl), 52.2 (OCH3), 53.0 (OCH3), 53.4 (OCH3), 57.2 (CH of
cyclohexyl), 60.9 (N
128.9, 130.3, 133.5 and 137.8 (C aromatic), 157.2 (q, JFC = 36 HZ,
C
C), 62.3 (CH), 118.2 (q, 1JFC = 286 HZ, CF3)
2
COCF3), 160.59 (N
C
C), 169.81 (CO2Me), 171.28 (CO2Me) ppm.
= ꢀ75.6 (CF3) ppm.
19F NMR (470.56 MHz, CDCl3)
d
4.3.6. Diethyl 2-(2,2,2-trifluoro-N-p-tolylacetamido)-3-
(cyclohexylimino) methylene-succinate (4f)
Yellow oil; yield 0.82 g (85%); IR (KBr) (
C), 1745, 1693 (C O, ester). Analyses: Calcd. for
24H29F3N2O5: C, 59.74; H, 6.06; N, 5.81%. Found: C, 59.71; H,
6.12; N, 5.74%. MS (m/z, %): 482 (M+, 11). 1H NMR (500.1 MHz,
CDCl3):
= 1.23 (3 H, t, 3JHH = 7 HZ, OCH2CH3), 1.32 (3 H, t, 3JHH = 7
n
max, cmꢀ1): 2070
(N
C
C
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3
CH3), 3.76 (1 H, m, CH of cyclohexyl), 4.13 (2 H, q, JHH = 7 HZ,
3
OCH2CH3), 4.26 (2 H, q, JHH = 7 HZ, OCH2CH3), 5.58 (1 H, s, CH),
7.06–7.48 (4 H, aromatic) ppm. 13C NMR (125.7MHZ, CDCl3):
d
= 14.7, 14.5 (2 OCH2CH3), 21.6 (CH3), 24.1, 24.2, 25.5, 33.3 and
33.4 (5 CH2 of cyclohexyl), 58.7 (CH of cyclohexyl), 60.7 (N C),
C
1
60.9 (CH), 62.3, 62.5 (2 OCH2CH3), 118.34 (q, JFC = 286 HZ, CF3),
120.9, 129.8, 130.1, and 139.7 (aromatic), 156.9 (q, JFC = 36 HZ,
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C
C), 168.5 (CO2Me), 169.5 (CO2Me) ppm.
= ꢀ75.5 (CF3) ppm.
19F NMR (470.56 MHz, CDCl3)
d
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