Novel pyridine-catalyzed reaction of dimethyl acetylenedicarboxylate with aldehydes: Formal [2 + 2] cycloaddition leading to 2-oxo-3-benzylidinesuccinates

Article abstract of DOI:10.1021/ol016550z

(matrix presented) The 1,4-zwitterionic intermediate generated from pyridine and DMAD adds to aldehydes in a formal [2 + 2] manner, resulting in the facile synthesis of 2-oxo-3-benzylidinesuccinates.

Full text of DOI:10.1021/ol016550z

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3495-3497
Novel Pyridine-Catalyzed Reaction of
Dimethyl Acetylenedicarboxylate with
Aldehydes: Formal [2 + 2]
Cycloaddition Leading to
2-Oxo-3-benzylidinesuccinates†
Vijay Nair,* A. Ramachandran Sreekanth, and A. Unni Vinod
Organic Chemistry DiVision, Regional Research Laboratory, CSIR,
TriVandrum 695 019, India
gVn@csrrltrd.ren.nic.in
Received August 9, 2001
ABSTRACT
The 1,4-zwitterionic intermediate generated from pyridine and DMAD adds to aldehydes in a formal [2 + 2] manner, resulting in the facile
synthesis of 2-oxo-3-benzylidinesuccinates.
The carbon-carbon bond-forming reaction involving the
addition of nucleophiles to acetylenes is of great significance
in organic synthesis.1 The conceptual framework of a 1,4-
dipolar cycloaddition provided by Huisgen 2 has been realized
in the reaction of pyridine with dimethyl acetylenedicar-
boxylate (DMAD), leading to the quinazoline derivative, via
the 1,4-zwitterionic intermediate (Scheme 1).
This reaction has been studied in detail by Acheson,3,4 who
has further established the existence of the 1,4-zwitterionic
intermediate by trapping it with carbon dioxide.5 In another
study it was shown that the interception of the intermediate
can be effected by phenyl isocyanate.6 An isolated example
of the intramolecular addition of the 1,4-zwitterionic inter-
mediate to a carbonyl group is also known.7
In the context of our general interest in the construction
of heterocyclic systems via dipolar intermediates,8 we were
intrigued by the possibility of intermolecular trapping of the
1,4-zwitterionic intermediate generated from pyridine and
DMAD with carbonyl compounds. The preliminary results
of our investigation validating the usefulness of this process,
leading to a novel formal [2 + 2] cycloaddition, are presented
in this Letter.
† Dedicated with affection, respect, and best wishes to Prof. Gilbert Stork,
whose pathbreaking discoveries have profoundly changed the course of
organic synthesis, on the occasion of his 80th birthday.
In our initial experiment, the reaction of DMAD with
3-nitrobenzaldehyde in the presence of pyridine (20 mol %)
(1) (a) Dickstein, J. I.; Miller, S. I. The Chemistry of Functional Groups.
The Chemistry of Carbon-Carbon Triple Bond Part 2, Chapter 19; Patai,
S., Ed.; Wiley: Chichester, 1978; pp 813-955. (b) Winterfeldt, E. Chemistry
of Acetylenes; Viehe, H. G., Ed.; Dekker: New York, 1969; p 267. (c)
Winterfeldt, E. Angew. Chem., Int. Ed. Engl. 1967, 6, 423.
Scheme 1
(2) (a) Huisgen, R.; Grashey; Sauer, J. The Chemistry of Alkenes; Patai,
S., Ed.; Wiley- Interscience: New York, 1964; p 739. (b) Huisgen, R.;
Herbig, K. Liebigs Ann. Chem. 1965, 688, 98.
(3) Acheson, R. M. AdV. Heterocycl. Chem. 1963, 1, 125.
(4) (a) Acheson, R. M.; Taylor, G. A. Proc. Chem. Soc. 1959, 186. (b)
Acheson, R. M.; Taylor, G. A. J. Chem. Soc. 1960, 1691.
(5) Acheson, R. M.; Plunkett, A. O. J. Chem. Soc. 1964, 2676.
10.1021/ol016550z CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/10/2001

bonyl groups were observed at δ 3.68 and 3.81 as two
singlets, supporting the IR absorption at 1719 cm-1. The
olefinic proton resonated at δ 7.14. The 13C signals for the
two carbomethoxy groups were seen at δ 162.8 and 164.0.
The reaction appears to be general with a number of
aldehydes, affording the 2-oxo-3-benzylidenesuccinates in
moderate to excellent yields.9 The results are summarized
in Table 1.
Scheme 2
Mechanistically, the reaction may be rationalized to
involve [2 + 2] cycloaddition of the 1,4-zwitterion generated
from pyridine and DMAD to the carbonyl group of the
aldehyde to give an unstable oxetene, which undergoes
stereospecific ring opening to give the Z-isomer (Scheme
3).10,11
in DME at -10 °C to room temperature afforded 2-oxo-3-
benzylidenesuccinate 3 in 85% yield (Scheme 2).
The product was characterized on the basis of spectro-
scopic data. In the 1H NMR spectrum, the two methoxycar-
Table 1. Reaction of Aldehydes with DMAD in the Presence
of a Catalytic Amount of Pyridinea
Scheme 3
In this context it is interesting to note that only few reports
involving thermal [2 + 2] cycloaddition between activated
alkynes and carbonyl compounds are available in the
literature.12 In conclusion, we have devised a novel method
for formal [2 + 2] cycloaddition of dimethyl acetylenedi-
carboxylate with aldehydes resulting in the facile synthesis
of 2-oxo-3-benzylidenesuccinates. Further investigations with
other activated alkynes and dipolarophiles are in progress.
(6) Huisgen, R.; Morikawa, M.; Herbig, K.; Brunn, E. Chem Ber. 1967,
100, 1094.
(7) Winterfeldt, E. Chem Ber. 1965, 98, 3537.
(8) (a) Nair, V.; Vinod, A. U. Chem. Commun. 2000, 1019. (b) Nair,
V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001, 66, 4427. (c) Nair, V.;
Bindu, S.; Balagopal, L. Tetrahedron Lett. 2001, 42, 2043.
(9) General experimental procedure: A solution of dimethyl acety-
lenedicarboxylate (1 equiv) and aldehyde (1 equiv) under an argon
atmosphere in dry DME (10 mL) was cooled to -10 °C. To this, pyridine
(20 mol %) was added, and the reaction mixture was stirred for 3 h at
room temperature. The solvent was then removed under vacuum, and the
residue on chromatographic separation on silica gel using hexanes-ethyl
acetate (80:20) gave 2-oxo-3-benzylidenesuccinates. Compound 3: mp 97-
99 °C; IR (KBr) 2959, 1719, 1686, 1533, 1440, 1261, 1202, 1016 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 8.63 (s, 1H), 8.45 (d, J ) 8.1 Hz, 1H), 8.21
(d, J ) 7.74 Hz, 1H), 7.72 (t, J ) 7.92 Hz, 1H), 7.14 (s, 1H), 3.81 (s, 3H),
3.68 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 189.9, 164.0, 162.8, 148.5,
144.2, 136.9, 133.8, 131.3, 130.0, 127.8, 123.3, 53.3, 52.6. Anal. Calcd for
C13H11NO7: C, 53.25; H, 3.78; N, 4.78. Found: C, 53.40; H, 3.79; N, 4.91.
a See ref 9 for general experimental procedure. b Isolated yield.
3496
Org. Lett., Vol. 3, No. 22, 2001

Acknowledgment. A.R.S. and A.U.V. thank CSIR, New
Delhi, for research fellowships. The authors also thank Ms.
Saumini Mathew for high-resolution NMR spectra and Mrs.
S. Viji for CHN analysis.
Supporting Information Available: Spectroscopic data
(1H, 13C, and IR) for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL016550Z
(10) Recently Shindo et al. have proposed the mechanism for the [2 +
2] cycloaddition reactions of alkynoates with carbonyl compounds involving
an oxetene intermediate, see: (a) Shindo, M.; Sato, Y.; Shishido, K.
Tetrahedron Lett. 1998, 39, 4857. (b) Shindo, M.; Sato, Y.; Shishido, K. J.
Am. Chem. Soc. 1999, 121, 6507. (c) Shindo, M.; Sato, Y.; Shishido, K. J.
Org. Chem. 2000, 65, 5443.
(11) For a similar electrocyclic ring opening of oxetene, see: Friedrich,
L. E.; Bower J. D. J. Am. Chem. Soc. 1973, 95, 6869.
(12) (a) Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1967, 6, 767. (b)
Ficini, J. Tetrahedron 1976, 32, 1449. (c) Schollkopf, U.; Hoppe, I. Angew.
Chem., Int. Ed. Engl. 1975, 14, 765. (d) Schollkopf, U.; Hoppe, I. Liebigs
Ann. Chem. 1979, 219.
Org. Lett., Vol. 3, No. 22, 2001
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