Synthesis of ethylenetetracarboxylic acid derivatives

Article abstract of DOI:10.1007/s00706-007-0754-7

The three-component reaction of the zwitterions generated from dialkyl acetylenedicarboxylate and isocyanides with isocyanates is described. The reaction afforded the corresponding special type of ethylenetetracarboxylic acid derivatives in good yields.

Full text of DOI:10.1007/s00706-007-0754-7

Monatshefte fu¨r Chemie 139, 49–52 (2008)
DOI 10.1007/s00706-007-0754-7
Printed in The Netherlands
Synthesis of Ethylenetetracarboxylic Acid Derivatives
ꢀ
Abdolali Alizadeh , Sadegh Rostamnia, Nasrin Zohreh, and Hamid Reza Bijanzadeh
Department of Chemistry, Tarbiat Modares University, Tehran, Iran
Received June 17, 2007; accepted June 23, 2007; published online November 15, 2007
# Springer-Verlag 2007
Summary. The three-component reaction of the zwitterions
to serve as amide surrogates, with unique physical
generated from dialkyl acetylenedicarboxylate and isocya-
nides with isocyanates is described. The reaction afforded
the corresponding special type of ethylenetetracarboxylic acid
derivatives in good yields.
properties, have made them ideal functional groups
for the development of novel peptidomimetics [4]. In
addition, sulfonamides have served as key functional
groups in the development of novel nonpeptidal HIV
protease inhibitors, matrix metalloproteinase in-
hibitors, thrombin inhibitors, and fibrinogen recep-
tor antagonists. The sulfonamide structural motif is
widely found in molecules of medicinal interest, par-
ticularly antibacterial agents [5–9]. More recently,
sulfonamides have been found to be potent cysteine
protease inhibitors, which could possibly extend
their therapeutic applications to include conditions
such as Alzheimer’s disease, arthritis, and cancer
[10, 11].
Ethylenetetracarboxylic acid derivatives are versa-
tile building blocks for conversion to other tetrafunc-
tionalized olefins, such as ethylenetetracarboxylic
dianhydride, and is used in Diels-Alder reaction as
a dienophile, and also can be converted to methyl
propiolate by controlled pyrolysis [12–14].
Recently, we have reported and developed the
multicomponent reaction mediated by zwitterionic
intermediates produced by a variety of nuclephiles
[15–20]. Although the trapping of the 1:1 intermedi-
ate formed between dialkyl acetylenedicarboxylate
and isocyanides with activated alkenes, aldehydes,
imines, and isothiocyanides has been studied, trap-
ping of the initially formed 1:1 intermediate with iso-
cyanates has not been reported [21–25]. In this paper,
we present the results of an extended investigation
of the reactivity of the zwitterion with arylsulfonyl
Keywords. Alkyl isocyanide; Dialky acetylenedicarboxyl-
ate; Arylsulfonyl isocyanate; Multicomponent reaction;
Sulfonamide.
Introduction
An important goal in the preparation of relevant or-
ganic compounds, such as natural products and ana-
logues, drugs, and diagnostics is the improvement
of synthetic efficiency. Moreover, other essential
issues are the care of our environment, the preserva-
tion of our resources, and economical advantages. A
general way to improve synthetic efficiency and also
to address the other criteria is the development of mul-
ticomponent reactions [1]. In 1969 Winterfeldt et al.
first described the reaction of isocyanides and acet-
ylenes [2]. This early finding forms the basis for a
large class of new backbones thus accessible. The
chemistry is based upon the initial formation of a zwit-
terionic adduct of the isocyanide with the acetylene.
Isocyanides, by virtue of their carbenic character, react
readily with most common multiple bonds [3].
Sulfonamide-containing compounds have a high
potential as pharmaceutical and agricultural agents
due to their diverse biological profiles. The ability
ꢀ
Corresponding author. E-mail: aalizadeh@modares.ac.ir

50
A. Alizadeh et al.
isocyanates or aryl isocyanates in CH2Cl2 leading to
the formation of the corresponding ethylenetetracar-
boxylic acid derivatives.
cyanides. The structures of compounds 3a–3d were
deduced from their elemental analyses, IR, and high-
1
field H and 13C NMR spectra. The mass spectrum
of 3a displayed the molecular ion peak at m=z ¼ 426,
which is consistent with the 1:1:1:1 adduct of tert-
butyl isocyanide:dimethyl acetylenedicarboxylate:
benzenesulfonyl isocyanate:water. The IR spectrum
of 3a exhibited absorption bands due to the carbonyl
group of esters at 1727 cmꢁ1, and NH groups at 3400
and 3295 cmꢁ1, the absorption bands of the sulfonyl
Results and Discussion
Arylsulfonyl isocyanates offer sp carbon electrophil-
ic sites, and therefore it was of interest to examine
the reactivity profile of the zwitterion towards sul-
fonamide derivatives. Thus, when arysulfonyl- or
aryl isocyanate 2 were treated with the in situ
generated zwitterion from DMAD and tert-butyl iso-
cyanide in CH2Cl2 at room temperature, the ethyl-
enetetracarboxylic acid derivatives 3 were obtained
in 65–80% yield after 12 h (Scheme 1).
1
moiety appeared at 1363 and 1142 cmꢁ1. The H
NMR spectrum of 3a exhibited three single sharp
singlets readily recognized as arising from tert-butyl
(ꢀ ¼ 1.43 ppm) and methoxy (ꢀ ¼ 3.56 and 3.84 ppm),
protons along with two NH triplets (ꢀ ¼ 7.43 ppm,
J ¼ 6.8 and ꢀ ¼ 7.59ppm, J ¼ 7.0 Hz). The aryl moi-
ety exhibited characteristic signals in the aromatic
Analogous reactions were observed with other
arylsulfonyl isocyanates, DMAD, and tert-butyl iso-
Scheme 1
Scheme 2

Ethylenetetracarboxylic Acid Derivatives
51
region of the spectrum. The 1H-decoupled 13C
NMR spectrum of 3a showed 14 distinct resonances
in agreement with the dimethyl 2-[(tert-butylamino)-
carbonyl]-3-[[[(phenyl)sulfonyl]amino]carbonyl]-2-
butenedioate structure. Partial assignment of these
resonances is given in the Experimental Section.
10min. The reaction mixture was then stirred for 12 h. The
solvent was removed under reduced pressure, and the residue
was separated by silica gel (Merck 230–240 mesh) column
chromatography using n-hexane:ethyl acetate mixture (4:1) as
eluent to give 3a as yellow crystals, mp 110–112ꢂC, yield
0.28g, 66%; IR (KBr): ꢁꢀ¼ 3400, 3295 (NH), 1727 (C¼O),
1600 (C¼C), 1547, 1433 (Ar), 1363, 1142 (SO2), 1208, 1142,
1086, 1018 (C–O) cmꢁ1 1H NMR (500.1 MHz, CDCl3):
;
1
The H and 13C NMR spectra of compound 3b–
t
ꢀ ¼ 1.43 (9H, s, Bu), 3.56 (3H, s, OMe), 3.84 (3H, s, OMe),
3d are similar to those of 3a except for the ester
groups and the aryl moiety which exhibit character-
istic signals with appropriate chemical shifts (see
Experimental Section).
Although we have not established the mechanism
of the reaction between the isocyanides and the acet-
ylenic esters in the presence of the isocyanate 2 in an
experimental manner, a possible explanation is pro-
posed in Scheme 2.
On the basis of the well-established chemistry of
isocyanides [26–31], it is reasonable to assume that
the functionalized ethylenetetracarboxylic acid de-
rivatives 3 apparently result from initial addition of
the isocyanide to the acetylenic ester and subse-
quent attack of the resulting zwitterion 4 at the
arylsulfonyl isocyanate or aryl isocyanate 2 to yield
zwitterion 5, followed by attack of H2O on the zwit-
terion 5 to form 6 as intermediate. Then the latter
rearranges under the reaction condition employed to
produce the ethylenetetracarboxylic acid derivatives 3
(Scheme 2).
3
3
7.43 (1H, t, JHH ¼ 6.8Hz, NH), 7.51 (1H, t, JHH ¼ 7.1 Hz,
3
1CH of Ar), 7.59 (1H, t, JHH ¼ 7.0Hz, NH), 7.83 (2H, t,
3JHH ¼ 7.1 Hz, 2CH of Ar), 7.97 (2H, d, JHH ¼ 6.9 Hz,
3
2CH of Ar) ppm; 13C NMR (125.7 MHz, CDCl3): ꢀ ¼
28.02 (CMe3), 49.49 (OMe), 52.20 (OMe), 53.40 (CMe3),
126.24 (C¼C), 126.56 (2CH of Ar), 127.42 (2CH of Ar),
129.12 (C¼C), 140.84 (Cipso of SO2), 156.75 (CONtBu),
157.68 (CO2Me), 163.38 (CO2Me), 168.69 (CON) ppm;
MS (EI, 70eV): m=z (%) ¼ 426 (Mþ, 2), 353 (6), 299 (12),
241 (32), 196 (4), 141 (43), 138 (6), 105 (7), 77 (100), 57 (35),
41 (26).
Dimethyl (E)-2-[(tert-butylamino)carbonyl]-3-[[[(4-methyl-
phenyl)sulfonyl]amino]carbonyl]-2-butenedioate
(3b, C19H24N2O8S)
Yellow crystals, mp 108–110ꢂC, yield 0.31 g, 70%; IR (KBr):
ꢁꢀ¼ 3320, 3315 (NH), 1733 (C¼O), 1667 (C¼C), 1585, 1430
(Ar), 1369, 1168 (SO2), 1277, 1250, 1168, 1080 (C–O) cmꢁ1
;
t
1H NMR (500.1MHz, CDCl3): ꢀ ¼ 1.40 (9H, s, Bu), 2.43
(3H, s, Me), 3.38 (3H, s, OMe), 3.91 (3H, s, OMe), 7.28
3
3
(1H, t, JHH ¼ 8.3Hz, NH), 7.32 (1H, t, JHH ¼ 7.6 Hz, NH),
3
3
7.73 (2H, d, JHH ¼ 8.3 Hz, 2CH of Ar), 8.04 (2H, d, JHH
¼
8.3 Hz, 2CH of Ar) ppm; 13C NMR (125.7MHz, CDCl3):
ꢀ ¼ 21.65 (Me), 27.92 (Me3C), 52.87 (OMe), 53.58 (OMe),
56.68 (Me3C), 129.49 (2CH of Ar), 129.91 (2CH of Ar),
133.75 (C¼C), 136.71 (C¼C), 145.06 (Cipso of SO2), 147.06
(Cipso of CH3), 156.71 (CONtBu), 158.26 (CO2Me), 160.89
(CO2Me), 161.83 (CON) ppm; MS (EI, 70 eV): m=z (%) ¼
440 (Mþ, 2), 407 (5), 343 (3), 299 (3), 270 (2), 238 (2), 197
(5), 155 (3), 108 (5), 91 (100), 77 (9), 57 (54), 41 (43).
Experimental
Dimethyl-, diethyl acetylenedicarboxylates, and tert-butyl iso-
cyanide were obtained from Merck (Germany) and Fluka
(Switzerland) and were used without further purification.
Melting points were measured on an Electrothermal 9100
apparatus. Elemental analyses for C, H, and N were performed
using a Heraeus CHN–O-rapid analyzer; their results were
in good agreement with the calculated data. Mass spectra were
recorded on a FINNIGAN-MATT 8430 mass spectrometer
operating at an ionization potential of 20eV. 1H and 13C
NMR spectra were measured (CDCl3 solution) with a Bruker
DRX-500 AVANCE spectrometer at 500.1 and 125.8 MHz.
IR spectra were recorded on a Shimadzu IR-460 spectrometer.
Chromatography columns were prepared from Merck silica
gel 230–240 meshes.
Dimethyl (E)-2-[(tert-butylamino)carbonyl]-3-(3-toluidino-
carbonyl)-2-butenedioate (3c, C19H24N2O6)
Brown powder, mp 168–170ꢂC, yield 0.3 g, 80%; IR (KBr):
ꢁꢀ¼ 3425, 3245 (NH), 1723 (CO2Me), 1650 (CON), 1635
(CON), 1588 (C¼C), 1540, 1444 (Ar) cmꢁ1
;
1H NMR
t
(500.1 MHz, CDCl3): ꢀ ¼ 1.30 (9H, s, Bu), 2.33 (3H, s, Me),
3.82 (3H, s, OMe), 3.83 (3H, s, OMe), 6.48 (1H, s, NH), 6.96
3
3
(1H, d, JHH ¼ 7.5 Hz, CH of Ar), 7.21 (1H, t, JHH ¼ 7.8 Hz,
CH of Ar), 7.38 (1H, d, 3JHH ¼ 7.9 Hz, CH of Ar), 7.42 (1H, s,
CH of Ar), 8.78 (1H, s, NH) ppm; 13C NMR (125.7 MHz,
CDCl3): ꢀ ¼ 21.44 (CH3), 28.36 (Me3C), 52.96 (Me3C),
53.34 (OMe), 53.37 (OMe), 117.21 (CH of Ar), 120.68 (CH
of Ar), 125.98 (CH of Ar), 128.86 (CH of Ar), 135.53 (C¼C),
136.80 (C¼C), 137.10 (Cipso of NHCO), 138.98 (Cipso of CH3),
160.32 (CONPh), 161.69 (CONtBu), 164.29 (CO2Me), 164.46
(CO2Me) ppm; MS (EI, 70 eV): m=z (%) ¼ 377 (Mþ, 1), 304
(1), 270 (6), 244 (1), 214 (68), 182 (6), 171 (3), 107 (100), 91
(4), 77 (3), 57 (18), 53 (3), 41 (10).
Dimethyl (E)-2-[(tert-butylamino)carbonyl]-3-[[(phenyl)-
sulfonyl)amino]carbonyl]-2-butenedioate (3a, C18H22N2O8S)
Typical procedure: To a magnetically stirred solution of
0.14g dimethyl acetylenedicarboxylate (1mmol) and 0.18g
benzenesulfonyl isocyanate (1mmol) in 3 cm3 dry CH2Cl2
was added dropwise a solution of 0.08g tert-butyl isocya-
nide (1mmol) in 3 cm3 dry CH2Cl2 at room temperature over

52
A. Alizadeh et al.: Ethylenetetracarboxylic Acid Derivatives
[7] a) Kim SW, Hong CY, Lee K, Lee EJ, Koh JS (1998)
Bioorg Med Chem Lett 8: 735; b) Jones-Hertzog DK,
Jorgensen WL (1997) J Med Chem 40: 1539
[8] Askew BC, Mclntyre CJ, Hunt CA, Claremon
DA, Baldwin JJ, Anderson PS, Gould RJ, Lynch RJ,
Chang C-T, Cook JJ, Lynch JJ, Holahan MA, Sitko GR,
Stranieri MT (1997) Bioorg Med Chem Lett 7: 1531
[9] Maren TH (1976) Annu Rev Pharmacol Toxicol 16: 309
[10] Roush WR, Gwaltney SL, Cheng J, Scheidt KA,
McKerrow JH, Hansell E (1998) J Am Chem Soc 120:
10994
[11] Roush WR, Cheng J, Knapp-Reed B, Alvarez-
Hernandez A, McKerrow JH, Hansell E, Engel JC
(2001) Bioorg Med Chem Lett 11: 2759
[12] Nakano Y, Hamaguchi M, Nagai T (1989) J Org Chem
54: 5912
Diethyl (E)-2-[(tert-butylamino)carbonyl]-3-(3-toluidino-
carbonyl)-2-butenedioate (3d, C21H28N2O6)
Colorless crystals, mp 171–173ꢂC, yield 0.26 g, 64%; IR
(KBr): ꢁꢀ¼ 3335 (NH), 1727 (CO2Me), 1656 (CON), 1670
(CON), 1617 (C¼C), 1525, 1446 (Ar) cmꢁ1
;
1H NMR
t
(500.1 MHz, CDCl3): ꢀ ¼ 1.29 (9H, s, Bu), 1.30 (3H, t,
3
3JHH ¼ 7.0 Hz, OCH2CH3), 1.31 (3H, t, JHH ¼ 6.9 Hz,
3
OCH2CH3), 2.32 (3H, s,CH3), 4.27 (2H, q, JHH ¼ 7.0 Hz,
3
OCH2CH3), 4.30 (3H, q, JHH ¼ 6.9 Hz, OCH2CH3), 6.34
3
(1H, s, NH), 6.94 (1H, d, JHH ¼ 7.5 Hz, CH of Ar), 7.19
3
3
(1H, t, JHH ¼ 7.7 Hz, CH of Ar), 7.33 (1H, d, JHH
¼
8.1 Hz, CH of Ar), 7.39 (1H, s, CH of Ar), 8.59 (1H, s, NH)
ppm; 13C NMR (125.7MHz, CDCl3): ꢀ ¼ 13.77 (OCH2CH3),
13.85 (OCH2CH3), 21.42 (CH3), 28.36 (Me3C), 52.92 (Me3C),
62.67 (OCH2CH3), 62.69 (OCH2CH3), 117.17 (CH of Ar),
120.64 (CH of Ar), 125.96 (CH of Ar), 128.86 (CH of Ar),
136.01 (C¼C), 136.45 (C¼C), 136.99 (Cipso of NHCO),
139.00 (Cipso of CH3), 160.24 (CONPh), 161.99 (CONtBu),
163.84 (CO2Et), 163.96 (CO2Et) ppm; MS (EI, 70eV): m=z
(%) ¼ 404 (Mþ, 1), 336 (6), 335 (15), 334 (31), 298 (11), 242
(51), 186 (10), 168 (9), 142 (6), 107 (100), 91 (8), 77 (6), 57
(45), 41 (20).
[13] Norton JA (1942) Chem Rev 31: 319
[14] Patterson JM, Haidar NF, Braun LL, Smith WT Jr (1981)
J Anal Appl Pyrolysis 2: 331
[15] Alizadeh A, Masrouri H, Rostamnia S, Movahedi F
(2006) Helv Chim Acta 89: 923
[16] Alizadeh A, Rostamnia S, Zhu LG (2006) Tetrahedron
62: 5641
[17] Alizadeh A, Rostamnia S, Hu ML (2006) Synlett: 1592
[18] Alizadeh A, Rostamnia S, Esmaili AA (2007) Synthesis
5: 709
References
[1] Tietze LF (1996) Chem Rev 96: 115
[2] Winterfeldt E, Schumann D, Dillinger HJ (1969) Chem
Ber 102: 1656
[19] Alizadeh A, Movahedi F, Masrouri H, Zhu LG (2006)
Synthesis 20: 3431
[20] Alizadeh A, Movahedi F, Esmaili AA (2006) Tetrahe-
dron Lett 47: 4469
¨
[3] Domling A (2006) Chem Rev 106: 17
[4] a) Gennari C, Salom B, Potenza D, Williams A (1994)
Angew Chem Int Ed Engl 33: 2067; b) Moree WJ, van
der Marel GA, Liskamp RMJ (1995) J Org Chem 60:
5157; c) Gennari C, Nestler HP, Salom B, Still WC
(1995) Angew Chem Int Ed Engl 34: 1765; d) Decicco
CP, Seng JL, Kennedy KE, Covington MB, Welch PK,
Arner EC, Magolda RL, Nelson DJ (1997) Bioorg Med
Chem Lett 7: 2331
[21] Nair V, Vinod AU (2000) Chem Commun: 1019
[22] Nair V, Vinod AU (2001) J Org Chem 66: 4427
[23] Nair V, Vinod AU, Nair JS, Sreekanth AR, Rath NP
(2000) Tetrahedron Lett 41: 6675
[24] Nair V, Menon RS, Beneesh PB, Sreekumar V, Bindu S
(2004) Org Lett 6: 767
[25] Yavari I, Djahaniani H (2005) Tetrahedron Lett 46:
7491
[5] a) Ghosh AK, Kincaid JF, Cho W, Waiters DE, Krishnan
K, Hussain KA, Koo Y, Cho H, Rudall C, Holland
L, Buthod J (1998) Bioorg Med Chem Lett 8: 687; b)
Janakiraman MN, Watenpaugh KD, Tomich PK,
Chong K-T, Turner SR, Tommasi RA, Thaisrivongs S,
Strohbach JW (1998) Bioorg Med Chem Lett 8: 1237; c)
Radkiewicz JL, McAllister MA, Goldstein E, Houk KN
(1998) J Org Chem 63: 1419
[6] Tamura T, Watanabe F, Nakatani T, Yasui K, Fuji M,
Komurasaki T, Tsuzuki H, Maekawa R, Yoshioka T,
Kawada K, Sugita K, Ohtani M (1998) J Med Chem
41: 640
[26] Ugi I (1971) Isonitrile Chemistry. Academic Press,
London
[27] Ugi I (1982) Angew Chem Ed Engl 21: 810
¨
[28] Domling A, Ugi I (2000) Angew Chem Int Ed 39:
3168
[29] Nair V, Viond AU, Nair JS, Sreekanth AR, Rath NP
(2000) Tetrahedron Lett 41: 6675
[30] Walborsky HM, Presiasamy MP (1983) In: Patai S,
Rappaport Z (eds) The Chemistry of Functional Groups,
Supplement C. Wiley, New York, Chapter 20, p 835
[31] Marcaccini S, Torroba T (1993) Org Prep Proced Int
25: 141