Three-component reaction between alkyl isocyanides, dialkyl acetylenedicarboxylates, and carboxylic acids

Article abstract of DOI:10.3184/174751911X13202454406382

Protonation of the reactive intermediates produced in the reaction between alkyl isocyanides and dialkyl acetylenedicarboxylates by carboxylic acids leads to vinylnitrilium cations which then undergo nucleophilic addition of the conjugate bases of the car

Full text of DOI:10.3184/174751911X13202454406382

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 661
NOVEMBER, 661–663
Three-component reaction between alkyl isocyanides, dialkyl
acetylenedicarboxylates, and carboxylic acids
Alireza Hassanabadia*, Mohammad H. Mossleminb, Sonia Singhb and Seyyed Ali Shaterchib
aDepartment of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978, Zahedan, Iran
bDepartment of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
Protonation of the reactive intermediates produced in the reaction between alkyl isocyanides and dialkyl acetylene-
dicarboxylates by carboxylic acids leads to vinylnitrilium cations which then undergo nucleophilic addition of
the conjugate bases of the carboxylic acids. This intermediate rearranges to produce dialkyl (E)2-{[(aryl)acetyl(alkyl-
amino)]carbonyl}-2-butenedioate derivatives.
Keywords: multicomponent reaction, alkyl isocyanide, dialkyl acetylene dicarboxylate, carboxylic acids
Isocyanide based reactions have been the most studied
multi-component reactions, by organic chemists. The Ugi
four component reaction1–3 and the Passerini three component
reaction4 are among the most important isocyanide based
multi-component reactions. The Ugi four component reaction
and the Passerini three component reaction involve the reac-
tion of isocyanides with carboxylic acids in the presence of
imines or aldehydes, respectively. Recently another type of
isocyanide based multi-component reaction has been devel-
oped and extensively investigated. Isocyanides react easily
with electron-deficient acetylene diesters such as dimethyl
acetylenedicarboxylate (DMAD) to produce a reactive zwit-
terionic intermediate which can be trapped by an electrophile.
A wide variety of electrophiles have been applied to trap the
isocyanide-DMAD intermediate, among them are carbon elec-
trophiles such as aldehydes, imines, quinones,5 1,2-diketones,6
1,2,3-tricarbonyl compounds,7 isocyanates,8 and hydrogen
electrophiles such as pyrrole,9 amides,10 hydroxy-coumarin,11
phenols,12 phthalic anhydride,13 and isatoic anhydride.14
Reaction of the isocyanide-DMAD adduct with aromatic-
substituted acetic acids has been reported to afford 2,5-diam-
inofuran derivatives in the presence of two equivalents of an
isocyanide.15 In the context of our previous works on isocya-
nide based multi-component reactions,9–11,16,17 we now report
the results of our investigations on the reaction of carboxylic
acids and dialkyl acetylenedicarboxylates in the presence of
alkyl isocyanides.
(δ = 1.31). The 13C NMR spectrum of compound 4a showed 18
distinct resonances in agreement with the proposed structure.
The IR spectrum of 4a exhibited absorption of the vinylic
moiety at 1645 cm−1 and of the carbonyl groups at 1726 and
1675 cm−1.
On the basis of the well established chemistry of isocya-
nides19–24 it is reasonable to assume that the compound 4 arises
from initial addition of the isocyanide 1 to the acetylenic ester
2 and subsequent protonation of the 1:1 adduct 5 by compound
3. This is followed by attack of the carboxylate anion 7 on the
positively charged ion 6 to form an imidoyl carboxylate 8,
which undergoes rearrangement25–27 under these reaction
conditions to produce compound 4 (Scheme 2).
In conclusion, we report that the three-component reaction
between alkyl isocyanides, dialkyl acetylenedicarboxylates
and carboxylic acids is a simple and efficient route for the syn-
thesis of dialkyl (E)2-{[(aryl)acetyl(alkylamino)]carbonyl}-
2-butenedioate derivatives. The advantages of this method are
the inexpensive and easily available starting materials, neutral
reaction conditions, high yields, single-product reaction and
simple work-up processes.
Experimental
Elemental analyses were performed using a Costech ECS 4010
CHNS-O analyser at the analytical laboratory of Islamic Azad Univer-
sity Yazd branch. IR spectra were recorded on a Shimadzu IR-470
spectrometer.1H, 19F and 13C NMR spectra were recorded on a Bruker
DRX-500 Avance spectrometer at solution in CDCl3 using TMS as
internal standard. The chemicals used in this work were purchased
from Fluka (Buchs, Switzerland) and were used without further
purification.
Results and discussion
Reaction of carboxylic acid 3 and dialkyl acetylenedicarboxyl-
ate 2 in the presence of alkyl isocyanide 1 affords dialkyl
(E)2-{[(aryl)acetyl(alkylamino)]carbonyl}-2-butenedioate
derivatives 4 in excellent yields (Scheme 1).
The structures of compounds 4a–f were deduced from their
elemental analyses, IR and 1H, 13C and 19F NMR.
The 1H NMR spectra of products 4a–f revealed the restricted
rotation around the carbon–carbon double bond. The stereo-
chemistry of the double bond has the E-configuration in 4.
The vinyl proton of the E isomer is expected to resonate at
lower field than the proton of the Z isomer.18
General procedure
A mixture of alkyl isocyanide (1 mmol) in 2 mL acetone was added
to a magnetically stirred solution of carboxylic acid (1 mmol) and
dialkyl acetylenedicarboxylate (1 mmol) in 10 mL acetone at room
temperature. The reaction mixture was then stirred for 24 hours. The
solvent was removed and the residue was purified by silica gel column
chromatography using hexane-ethyl acetate (3:1) as eluent. The
solvent was removed under reduced pressure to afford the product.
Dimethyl (E)2-{[(3-trifluoromethyl-phenyl)acetyl (tert-butylamino)]
carbonyl}-2-butenedioate (4a): Yellow oil, yield 90%; IR (KBr) (νmax
,
The mass spectrum of compound 4a showed the molecular
cm−1): 1726 (OCNCO), 1675 (CO2Me), 1645 (C=C). Anal.Calcd for
C20H22F3NO6: C, 55.94; H, 5.16; N, 3.26. Found: C, 55.78; H, 5.31;
N, 3.39%. MS (m/z, %): 429 (M+, 7). 1H NMR (500.13 MHz, CDCl3):
δ = 1.31 (9H, s, CMe3), 3.74 and 3.79 (6H, 2s, 2 OCH3), 3.81 (2H, s,
CH2), 6.86 (1H, s, CH), 7.42 (1H, t, 3JHH = 7.8 Hz, HAr), 7.47 (1H, d,
ion peak at 429.
19F NMR spectrum of compound 4a displayed a signal at
–63.31 ppm.
1
The H NMR spectrum of compound 4a was simple and
3
3JHH = 7.4 Hz, HAr), 7.51 (1H, d, JHH = 7.9 Hz, HAr), 7.57 (1H, s,
exhibited two sharp signals at 3.74 and 3.79 ppm for two
methoxy groups. The protons of methylene were observed as
a singlet at δ = 3.81 ppm and vinylic proton at δ = 6.86.
The aromatic protons resonated at δ = 7.31–7.57 ppm. One
sharp singlet signal was assigned to the methyls of the t-Bu
HAr). 13C NMR (125.75 MHz, CDCl3): δ = 28.21(methyl groups
of tert-butyl), 42.28 (CH2), 52.07 and 52.53 (2 OCH3), 59.37 (C of
1
3
t-butyl), 123.96 (q, JFC = 272 Hz, CF3), [125.85 (q, JFC = 3.7 Hz),
128.59, 130.46 (q, 2JFC = 32 Hz,), 132.67, 135.89 and 138.59 6C aro-
matic], 129.43 and 141.57 (C=CH), 163.01 (NCO), 164.79 (CO2CH3),
167.25 (CO2CH3), 171.82 (CH2CON). 19F NMR (470.56 MHz, CDCl3)
δ = –63.31 (CF3) ppm.
* Correspondent. E-mail: ar_hasanabadi@yahoo.com

662 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 1 Reaction between carboxylic acids and dialkyl acetylenedicarboxylates in the presence of alkyl isocyanides.
Scheme 2 Suggested mechanism for formation compound 4.
Dimethyl (E)2-{[(3-trifluoromethyl-phenyl)acetyl (cyclohexylamin
o)]carbonyl}-2-butenedioate (4b): Yellow oil, yield 88%; IR (KBr)
(νmax, cm−1): 1723 (OCNCO), 1683 (CO2Me), 1644, (C=C). Anal.
Calcd for C22H24F3NO6: C, 58.02; H, 5.31; N, 3.08. Found: C, 58.19;
H, 5.44; N, 3.27%. MS (m/z, %): 455 (M+, 3). 1H NMR (500.13 MHz,
CDCl3): δ = 1.13–1.78 (10H, 5CH2 of cyclohexyl), 3.70 and 3.77
(6H, 2 s, 2 OCH3), 3.79 (1H, m, CH of cyclohexyl), 4.05 (2H, s, CH2),
3JHH = 7.9 Hz, HAr), 7.51 (1H, s, HAr). 13C NMR (125.75 MHz,
CDCl3): δ = 13.61 and 14.07 (2 CH3), 27.88 (methyl groups of
tert-butyl), 42.25 (CH2), 59.61 (C of t-butyl), 60.71 and 61.26
(2 OCH2), 123.95 (q, 1JFC = 272 Hz, CF3), [125.84 (q, 3JFC = 3.7 Hz),
128.53, 130.38 (q, 2JFC = 32 Hz,), 132.71, 135.94 and 138.01 6C aro-
matic], 129.02 and 141.38 (C=CH), 162.78 (NCO), 164.36 (CO2CH3),
166.81 (CO2CH3), 171.86 (CH2CON). 19F NMR (470.56 MHz, CDCl3)
δ = –63.38 (CF3) ppm.
6.62 (1H, s, CH), 7.40 (1H, t, 3JHH = 7.8 Hz, HAr), 7.44 (1H, d, 3JHH
=
7.4 Hz, HAr), 7.49 (1H, d, 3JHH = 7.9 Hz, HAr), 7.52 (1H, s, HAr). 13
C
Dimethyl (E)2-{[(2,4-dinitrophenyl)acetyl (tert-butylamino)] car-
NMR (125.75 MHz, CDCl3): δ = 25.12, 25.31, 26.40, 31.20 and 32.51
bonyl}-2-butenedioate (4d): Yellow oil, yield 91%; IR (KBr) (νmax,
(5 CH2 of cyclohexyl), 43.70 (CH2), 48.73 (CH of cyclohexyl), 52.08
cm−1): 1728 (OCNCO), 1707 (CO2Me), 1608, (C=C). Anal.Calcd for
C19H21N3O10: C, 50.56; H, 4.69; N, 9.31. Found: C, 50.37; H, 4.80; N,
and 52.81 (2 OCH3), 123.93 (q, 1JFC = 272 Hz, CF3), [125.92 (q, 3JFC
=
3.7 Hz), 128.92, 130.71(q, 2JFC = 32 Hz,), 132.76, 134.71 and 138.43
6C aromatic], 128.54 and 143.18 (C=CH), 162.83 (NCO), 164.64
(CO2CH3), 166.84 (CO2CH3), 174.13 (CH2CON). 19F NMR (470.56
MHz, CDCl3) δ = –63.35 (CF3) ppm.
9.15%. MS (m/z, %): 451 (M+, 7). H NMR (500.13 MHz, CDCl3):
1
δ = 1.35 (9H, s, CMe3), 3.72 and 3.80 (6H, 2s, 2 OCH3), 3.83 (2H, s,
CH2), 6.96 (1H, s, CH), 7.50 (1H, d, 3JHH = 8.4 Hz, HAr), 8.39 (1H, m,
3
HAr), 8.83 (1H, d, JHH = 7.9 Hz, HAr).13C NMR (125.75 MHz,
Diethyl (E)2-{[(3-trifluoromethyl-phenyl)acetyl (tert-butylamino)]
CDCl3): δ = 28.08 (methyl groups of tert-butyl), 42.15 (CH2), 52.64
and 53.08 (2 OCH3), 59.48 (C of t-butyl), 120.51, 126.81, 128.64,
133.85, 140.64, 143.75, 146.31 and 159.11 (8C aromatic and olefinic),
161.32 (NCO), 165.63 (CO2CH3), 166.25 (CO2CH3), 172.43
(CH2CON).
carbonyl}-2-butenedioate (4c): Yellow oil, yield 85%; IR (KBr) (νmax
,
cm−1): 1719 (OCNCO), 1672 (CO2Me), 1639, (C=C). Anal.Calcd for
C22H26F3NO6: C, 57.76; H, 5.73; N, 3.06. Found: C, 57.59; H, 5.61; N,
1
3.23%. MS (m/z, %): 457 (M+, 5). H NMR (500.13 MHz, CDCl3):
3
δ = 1.25 and 1.34 (6H, 2t, JHH = 7 Hz, 2CH3), 1.28 (9H, s, CMe3),
Dimethyl (E)2-{[(2,4-dinitrophenyl)acetyl (cyclohexylamino)]carb
3.80 (2H, s, CH2), 4.22 (4H, m, 2OCH2), 6.82 (1H, s, CH), 7.35 (1H,
onyl}-2-butenedioate (4e): Yellow oil, yield 88%; IR (KBr) (νmax
,
t, 3JHH = 7.8 Hz, HAr), 7.42 (1H, d, 3JHH = 7.4 Hz, HAr), 7.47 (1H, d,
cm−1): 1727 (OCNCO), 1705 (CO2Me), 1603, (C=C). Anal.Calcd for

JOURNAL OF CHEMICAL RESEARCH 2011 663
2
3
4
5
6
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C21H23N3O10: C, 52.83; H, 4.86; N, 8.80. Found: C, 53.05; H, 4.64; N,
1
8.93%. MS (m/z, %): 477 (M+, 3). H NMR (500.13 MHz, CDCl3):
δ = 1.23–1.93 (10H, 5CH2 of cyclohexyl), 3.67 and 3.80 (6H, 2 s,
2 OCH3), 3.87 (1H, m, CH of cyclohexyl), 4.01 (2H, s, CH2), 6.66
(1H, s, CH), 7.59 (1H, d, 3JHH = 8.4 Hz, HAr), 8.34 (1H, m, HAr), 8.78
3
(1H, d, JHH = 7.9 Hz, HAr). 13C NMR (125.75 MHz, CDCl3):
7
8
δ = 24.97, 25.52, 25.68, 31.31 and 33.26 (5 CH2 of cyclohexyl), 43.35
(CH2), 48.64 (CH of cyclohexyl), 52.16 and 52.97 (2 OCH3), 120.06,
126.89, 128.86, 133.98, 140.65, 143.70, 146.32 and 159.05 (8C
aromatic and olefinic), 161.52 (NCO), 164.88 (CO2CH3), 166.48
(CO2CH3), 171.76 (CH2CON).
9
M. Anary-Abbasinejad, M.H. Mosslemin, H. Anaraki-Ardakani and
S. Tahan, J. Chem. Res., 2006, 30, 306.
10 M. Anary-Abbasinejad, M.H. Mosslemin, S. Tahan and H. Anaraki-
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Diethyl (E)2-{[(2,4-dinitrophenyl)acetyl (tert-butylamino)] car-
bonyl}-2-butenedioate (4f): Yellow oil, yield 87%; IR (KBr) (νmax
,
cm−1): 1728 (OCNCO), 1705 (CO2Me), 1602, (C=C). Anal.Calcd for
C21H25N3O10: C, 52.61; H, 5.26; N, 8.76. Found: C, 52.50; H, 5.43;
N, 8.56%. MS (m/z, %): 479 (M+, 4). 1H NMR (500.13 MHz, CDCl3):
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381.
3
δ = 1.18 and 1.31 (6H, 2t, JHH = 7 Hz, 2CH3), 1.21 (9H, s, CMe3),
3.83 (2H, s, CH2), 4.18 (4H, m, 2OCH2), 6.74 (1H, s, CH), 7.58 (1H,
d, 3JHH = 8.4 Hz, HAr), 8.32 (1H, m, HAr), 8.72 (1H, d, 3JHH = 7.9 Hz,
HAr).13C NMR (125.75 MHz, CDCl3): δ = 13.45 and 14.05 (2 CH3),
29.33 (methyl groups of tert-butyl), 42.17 (CH2), 58.14 (C of t-butyl),
61.91 and 62.15 (2 OCH2), 119.87, 126.82, 128.51, 133.99, 140.55,
143.71, 146.22 and 159.04 (8C aromatic and olefinic), 161.02 (NCO),
164.97 (CO2CH3), 166.37 (CO2CH3), 172.58 (CH2CON).
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18 E.L. Eliel, S.H. Wilen and L.N. Mander, Stereochemistry of organic
compounds, Wiley, New York, 1994, p. 569.
We gratefully acknowledge financial support from the Research
Council of Islamic Azad University of Yazd and The Islamic
Azad University of Zahedan of Iran.
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Received 26 October 2011; accepted 1 November 2011
Paper 1100928 doi: 10.3184/174751911X13202454406382
Published online: 22 November 2011
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