A novel multicomponent reaction involving isocyanide, dimethyl acetylenedicarboxylate (DMAD), and electrophilic styrenes: Facile synthesis of highly substituted cyclopentadienes

Article abstract of DOI:10.1021/ol036491k

Alkyl isocyanides, DMAD, and various activated styrenes furnish fully substituted cyclopentadienes in a one-pot three-component reaction.

Full text of DOI:10.1021/ol036491k

ORGANIC
LETTERS
2004
Vol. 6, No. 5
767-769
A Novel Multicomponent Reaction
Involving Isocyanide, Dimethyl
Acetylenedicarboxylate (DMAD), and
Electrophilic Styrenes: Facile Synthesis
of Highly Substituted Cyclopentadienes
Vijay Nair,* Rajeev S. Menon, P. B. Beneesh, V. Sreekumar, and S. Bindu
Organic Chemistry DiVision, Regional Research Laboratory (CSIR), TriVandrum, India
Vijaynair_2001@yahoo.com
Received December 23, 2003
ABSTRACT
Alkyl isocyanides, DMAD, and various activated styrenes furnish fully substituted cyclopentadienes in a one-pot three-component reaction.
The advent of the Huisgen reaction,1 which involves the
cycloaddition of 1,3-dipoles to a variety of π-systems,
heralded a new era in heterocyclic chemistry. Inter alia the
phenomenal success of this reaction provided a rationale for
generating a variety of unconventional dipoles, for example,
zwitterionic species, and their trapping by dipolarophiles to
afford heterocycles.
Zwitterionic species are known to arise from the addition
of nucleophiles such as triphenylphosphine,2 pyridine,3 and
a wide range of tertiary amines4 to activated acetylenes.5 Of
special interest to us has been the zwitterion derived from
isocyanide and DMAD.6 Earlier attempts to trap this species
with dipolarophiles to generate cyclic compounds have been
essentially unsuccessful.7 We have recently shown that this
species can be efficiently trapped by dipolarophiles such as
aryl aldehydes and N-tosylimines leading to a facile synthesis
of furan and pyrrole derivatives, respectively.8 Against this
background, we surmised that the zwitterion might undergo
cycloaddition to activated alkenes, thus constituting a
synthesis of highly substituted cyclopentadienoid systems.
Our preliminary results validating this concept are presented
in this letter.
In a pilot experiment, tert-butyl isocyanide (1), DMAD
(2), and 3-nitrobenzylidenemalononitrile (3a) were refluxed
in THF for 24 h. Column chromatography of the reaction
mixture on silica gel afforded the fully substituted cyclo-
pentadiene derivative 4a in 92% yield (Scheme 1).9
(1) (a) Huisgen, R. Proc. Chem. Soc. 1961, 357. (b) Huisgen, R. In 1,3-
Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-Interscience: New
York, 1984; Vol. 1, p 1. (c) Huisgen, R. In The AdVenture Playground of
Mechanisms and NoVel Reactions; American Chemical Society: Washing-
ton, DC, 1994; p 91.
(2) (a) Johnson, A. W.; Tebby, J. C. J. Chem. Soc. 1961, 2126. (b) Tebby,
J. C.; Wilson, I. F.; Grifiths, D. V. J. Chem. Soc., Perkin Trans. 1 1979,
2133. (c) Butterfield, P. J.; Tebby, J. C.; Griffiths, D. V. J. Chem. Soc.,
Perkin Trans. 1 1979, 1189.
(6) (a) Winterfeldt, E.; Schumann, D.; Dillinger, H. J. Chem. Ber. 1969,
102, 1656. (b) Dillinger, H. J.; Fengler, G.; Schumann, D.; Winterfeldt, E.
Tetrahedron 1974, 30, 2553. (c) Dillinger, H. J.; Fengler, G.; Schumann,
D.; Winterfeldt, E. Tetrahedron 1974, 30, 2561.
(7) Krebs, A.; Guntner, A.; Versteylen, S.; Schulz, S. Tetrahedron Lett.
1984, 25, 2333.
(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.;
Vinod, A. U.; Abhilash, N.; Menon, R. S.; Santhi, V.; Varma, L. R.; Viji,
S.; Mathew, S.; Srinivas, R. Tetrahedron 2003, 59, 10279.
(3) (a) Diels, O.; Alder, K. Liebigs Ann. Chem. 1932, 498, 16. (b)
Acheson, R. M. AdV. Heterocycl. Chem. 1963, 1, 125. (c) Acheson, R. M.;
Plunkett, A. O. J. Chem. Soc. 1964, 2676.
(4) (a) Winterfeldt, E. Chem. Ber. 1964, 97, 1952. (b) Winterfeldt, E.;
Dillinger, H. J. Chem. Ber. 1966, 99, 1558.
(5) Reviews: (a) Winterfeldt, E. Angew. Chem., Int. Ed. Engl. 1967, 6,
423. (b) Acheson, R. M. AdV. Heterocycl. Chem. 1963, 1, 125.
(9) Representative experimental procedure and spectral data: To a
refluxing solution of 1 mmol (142 mg) of DMAD 2 and 1.1 mmol (219
mg) of 3a in THF was added 1 mmol (83 mg) of tert-butyl isocyanide 1
via a syringe. The reaction mixture was refluxed for 24 h, solvent was
10.1021/ol036491k CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/05/2004

Scheme 1
Table 2. Reaction of Isocyanides and DMAD with Aryl
Cyanoacrylates
The structure 4a was assigned to the product on the basis
of spectroscopic analysis. Two methoxycarbonyl groups
resonated at δ 3.86 and 3.80 in the 1H NMR spectrum. The
ester carbonyl groups displayed 13C resonance signals at δ
164.8 and 164.6 supporting the IR absorption at 1724 cm-1.
The IR absorption at 2246 cm-1 and the 13C resonance signal
at δ 110.7 were attributed to the cyano group. The amino
proton appeared at δ 9.07 as a singlet, exchangeable with
D2O. The downfield shift and exchangeability of the NH
proton was suggestive of intramolecular hydrogen bonding
with the adjacent ester carbonyl group.
yield
product (%)
entry
1
styrene
isocyanide
Ar ) 3-nitrophenyl, 5a R ) tert-butyl
R ) cyclohexyl
Ar ) 4-chlorphenyl, 5b R ) tert-butyl
R ) cyclohexyl
6a
6b
6c
6d
6e
6f
67
77
73
54
70
50
2
3
Ar ) phenyl, 5c
R ) tert-butyl
R ) cyclohexyl
The variability of the MCR with respect to the alkyne
component was also tested. Dibenzoylacetylene10 gave the
corresponding cyclopentadiene derivative, albeit in low yield
(Scheme 2).
The isocyanide component of the multicomponent reaction
(MCR) was variable; cyclohexyl isocyanide also rendered
high-yielding reactions. The results are summarized in Table
1.
Scheme 2
Table 1. Reaction of Isocyanides and DMAD with
Dicyanostyrenes
A mechanistic rationalization for the reaction is given in
Scheme 3. The initial event is the formation of the zwitterion
yield
entry
styrene
isocyanide
product (%)
1
2
Ar ) 3-nitrophenyl, 3a
Ar ) 4-chlorphenyl, 3b
R ) cyclohexyl
R ) tert-butyl
R ) cyclohexyl
R ) tert-butyl
R ) cyclohexyl
4b
4c
4d
4e
4f
4g
4h
4i
79
91
68
78
74
93
87
50
Scheme 3
3
4
5
Ar ) phenyl, 3c
Ar ) methoxyphenyl, 3d R ) tert-butyl
R ) cyclohexyl
Ar ) trans-cinnamyl, 3e R ) tert-butyl
The alkene component of the MCR is also variable. When
aryl cyanoacrylates were used in the reaction instead of
arylidenemalononitriles, good to excellent yields of the
products were obtained (Table 2).
9 from the isocyanide 1 and DMAD (2). The zwitterion can
add to the electrophilic carbon-carbon double bond of 3c
resulting in the formation of 10, which then undergoes
cyclization to deliver the primary adduct 11. The latter then
isomerizes to the final product 4c via a [1,5] H shift.
Although less likely, the alternate concerted 1,3-dipolar
cycloaddition of the zwitterion to the styrene a la Huisgen
reaction cannot be ruled out at the present time.
removed on a rotary evaporator, and the residue was chromatographed on
a silica gel column with a hexanes-ethyl acetate mixture (95: 5) to afford
4a as a yellow crystalline solid (390 mg, 92%). Mp 160-161 °C. IR (KBr)
νmax 3431, 3213, 2986, 2955, 2246, 1724, 1667, 1589, 1537, 1444 cm-1
.
1H NMR δ 9.07 (s, 1H, exchangeable with D2O), 8.41 (s, 1H), 8.24 (d, J
) 8.08 Hz, 1H), 7.92 (d, J ) 7.82 Hz, 1H), 7.64 (uneven triplet, J1 ) 7.86
Hz, J2 ) 6.37 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 1.68 (s, 9H). 13C NMR
δ 164.8, 164.6, 158.1, 148.7, 140.1, 133.2, 131.2, 130.2, 123.7, 123.1, 117.6,
110.7, 103.1, 57.3, 52.9, 51.9, 43.3, 31.3. Anal. Calcd for C21H20N4O6: C,
59.43; H, 4.75; N, 13.20. Found; C, 59.44, H, 4.75; N, 13.10.
(10) Ott, W.; Kollenz, G.; Peters, K.; Peters, E.-M.; Schnering, H. G.
ν.; Quast, H. Liebigs Ann. Chem. 1983, 635.
It is conceivable that the products 4 and 6 can be
transformed to highly substituted cyclopentenones, which are
768
Org. Lett., Vol. 6, No. 5, 2004

important structural fragments in organic synthesis. In this
context a recent cyclopentenone synthesis involving the
reaction of zirconecenediethyl in stoichiometric amounts with
alkynes, benzylidene malononitrile, and isocyanates is note-
worthy.11
In conclusion, we have devised a novel three-component
one-pot reaction for the synthesis of fully substituted
cyclopentadiene derivatives. It is noteworthy that all three
components of the reaction are variable, thus making it a
versatile process. The reaction belongs to a rare class of
multicomponent cyclizations where a carbocycle is pro-
duced,11,12 which contrasts with the majority of such reactions
which deliver heterocycles.13,14 It is likely that the scarcity
of methods available for the synthesis of substituted cyclo-
pentadiene derivatives combined with the operational sim-
plicity of the present process will make it potentially
attractive for this purpose in the future. Investigations aimed
at exploring the scope of the reaction are currently underway.
Acknowledgment. R.S.M., V.S., and B.S. thank the
Council of Scientific and Industrial Research, New Delhi,
for research fellowships. The authors thank Ms. Saumini
Mathew for recording NMR spectra and Ms. S. Viji for
Elemental analysis.
Supporting Information Available: General experimen-
1
tal procedures and IR, H NMR, and 13C NMR data for
selected compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) Takahashi, T.; Li, Y.; Tsai, F. Y.; Nakajima, K. Organometallics
2001, 20, 595.
OL036491K
(12) Barleunga, J.; Perez-Sanchez, I.; Rubio, E.; Florez, J. Angew. Chem.,
Int. Ed. 2003, 42, 5860.
(13) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(14) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899.
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