Synthesis of novel heterocyclic structures via reaction of isocyanides with S-trans-enones

Article abstract of DOI:10.1021/ol061451c

The reaction of enone 1, bearing an internal nucleophilic moiety, i.e., furan or pyrrole (X = O, NR′), with isocyanides is presented. The formation of products resulting from the reaction of the zwitterionic intermediate 2 with a second equivalent of isocyanide prior to cyclization to give 3, as well as the direct formation of 4 from 2, is described.

Full text of DOI:10.1021/ol061451c

ORGANIC
LETTERS
2006
Vol. 8, No. 18
3975-3977
Synthesis of Novel Heterocyclic
Structures via Reaction of Isocyanides
with S-trans-Enones
Jeffrey D. Winkler* and Sylvie M. Asselin
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
winkler@sas.upenn.edu
Received June 13, 2006
ABSTRACT
The reaction of enone 1, bearing an internal nucleophilic moiety, i.e., furan or pyrrole (X
)
O, NR
′
), with isocyanides is presented. The
formation of products resulting from the reaction of the zwitterionic intermediate 2 with a second equivalent of isocyanide prior to cyclization
to give 3, as well as the direct formation of 4 from 2, is described.
The cycloaddition of isocyanides with heterodienes affords
a diverse array of five-membered ring products.1-3 Saegusa2
and subsequently Chatani3 have shown that addition of
Scheme 1. Reaction of Isocyanides with S-cis- and
S-trans-Enones
isocyanides to S-cis-enones leads to the formation of imi-
nolactone products, i.e., 7, via intramolecular collapse of the
zwitterionic intermediate 6 that is obtained on Lewis acid-
catalyzed addition of an isocyanide to the enone (Scheme
1). The analogous reaction of an S-trans-enone, i.e., cyclo-
hexenone 8, would generate a zwitterionic intermediate 9
(1) For examples of the cycloaddition of isocyanides with heterodienes
to give five-membered rings, see: (a) Deyrup, J. A.; Killion, K. K.
Heterocycl. Chem. 1972, 1045-1048. (b) Marchand, E.; Morel, G.;
Sinbandhit, S. Eur. J. Org. Chem. 1999, 133, 903-912. (c) Morel, G.;
Marchand, E.; Foucaud, A. J. Org. Chem. 1990, 55, 1721-1727. (d) Morel,
G.; Marchand, E.; Foucaud, A. J. Org. Chem. 1985, 50, 771-778. (e) Morel,
G.; Marchand, E.; Foucaud, A.; Toupet, L. J. Org. Chem. 1989, 54, 1185-
1191. (f) Morel, G.; Marchand, E.; Sinbandhit, S.; Carlier, R. Eur. J. Org.
Chem. 2001, 655-662. (g) Nair, V.; Mathew, B.; Vinod, A. U.; Mathen, J.
S.; Ros, S.; Monon, R. S.; Varma, R. L.; Srinivas, R. Synthesis 2003, 662-
664. (h) Rigby, R. H.; Laurent, S.; Cavezza, A.; Heeg, M. J. J. Org. Chem.
1998, 63, 5587-5591. (i) Rigby, R. H.; Qabar, M.; Ahmed, G.; Hughes,
R. C. Tetrahedron 1993, 49, 10219-10228. (j) Foucaud, A.; Razorilalana-
Rabearivony, C.; Loukakou, E.; Person, H. J. Org. Chem. 1983, 48, 3639-
3644. (k) Quai, M.; Frattini, S.; Vendrame, U.; Mondoni, M.; Dossena, S.;
Cereda, E. Tetrahedron Lett. 2004, 45, 1413-1416. (l) Rigby, J. H.; Qabar,
M. J. Am. Chem. Soc. 1991, 113, 8975-8976.
that could not undergo analogous intramolecular collapse.
However, incorporation of a nucleophilic substituent into 9
would result in intermediate 10, which could undergo
cyclization via addition of the pendant nucleophile (Nu) to
the nitrilium intermediate to give, after protonation, 11. We
report herein that such a strategy leads to a novel approach
to the synthesis of a diverse array of polycyclic ring systems.
(2) Ito, Y.; Kato, H.; Saegusa, T. J. Org. Chem. 1982, 47, 741-743.
(3) (a) Chatani, N.; Oshita, M.; Tobisu, M.; Ishii, Y.; Murai, S. J. Am.
Chem. Soc. 2003, 125, 7812-7813. (b) Oshita, M.; Yamashita, K.; Tobisu,
M.; Chatani, N. J. Am. Chem. Soc. 2005, 127, 761-766.
We first examined the proposed reaction sequence using
furan as the nucleophilic substituent, as shown with 1
10.1021/ol061451c CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/02/2006

(Scheme 2).4 Exposure of 1 (1 equiv) and methyl isocyanide
Table 1. Effect of Isocyanide Substitution and the Nature of
the Lewis Acid on the Cyclization Reaction
Scheme 2. Double-Addition Products in the Reaction of 1
with Methyl Isocyanide
products
Lewis acid
(equiv)
temp,
solvent °C
entry
R
3 (%)
4 (%)
a
a
a
1
2
3
4
5
6
7
Me, 12
t-Bu, 15
Et2AlCl (1.1) THF
Et2AlCl (1.2) THF
25 3a (37)
25 3b (58)
25 3c (43)
4-MeOPh, 16 Et2AlCl (1.2) THF
2,6-Me2Ph, 17 Et2AlCl (1.2) THF
2,6-Me2Ph, 17 Et2AlCl (1.2) PhMe
2,6-Me2Ph, 17 GaCl3 (1.0)
2,6-Me2Ph, 17 GaCl3 (0.1)
25 3d (47) 4d (14)
25 3d (52) 4d (16)
a
PhMe
PhMe
25 3d (79)
60 3d (77)
a
a Not observed.
We next examined a strategy for the selective formation
of the monoaddition product corresponding to 4 via introduc-
tion of methylene spacers between the enone and the
nucleophilic furan, i.e., 18 and 21 (Scheme 3). We reasoned
12 (0.9 equiv) to 1.1 equiv of diethylaluminum chloride in
THF at 23 °C for 18 h led to none of the expected
cyclopentafuran 4a, but instead to the formation of 3a, which
results from the reaction of intermediate 13 with a second
equivalent of isocyanide to give 14 prior to cyclization.
Similar double-addition products have been observed by
Rigby5 and Chatani3 in attempted [4+1] cycloadditions of
heterodienes with isocyanides.
Scheme 3. Monoaddition Products via Reaction of
Homologated Substrates 18 and 21 with Isocyanide 17
The effect of the alkyl substituent of the isocyanide in the
partitioning of intermediate 13 between cyclization to give
4 and reaction with an additional equivalent of isocyanide
to give 3 (via 14) was next examined. We reasoned that
increasing the steric effect of the alkyl group R could disfavor
the addition of a second equivalent of isocyanide that would
lead to the intermediate corresponding to 14 and therefore
promote the formation of the monoaddition product 4. In
the event, however, changing the R group on the isocyanide
from methyl to tert-butyl increased the yield of the double-
addition product 3b (R ) t-Bu) from 37 to 58%, and none
of the monoaddition product 4b (R ) t-Bu) was observed
(see Table 1, entry 2). The increased reactivity of tert-butyl
isocyanide could be attributed to the inductive electron-
donating effect of the tert-butyl group relative to methyl.
In contrast, the use of electron-rich aromatic isocyanides,
i.e., p-methoxyphenyl 16 (Table 1, entry 3), does not increase
the efficiency of the formation of 3c (R ) 4-MeOPh; 43%
yield). However, the effect of the more sterically demanding
2,6-dimethylphenyl isocyanide 17 on the course of the
cyclization is significant. Reaction of 1 and 17 gave the
double-addition product 3d (R ) 2,6-dimethylphenyl) in 47%
yield, accompanied by the formation of the monoaddition
product 4d (R ) 2,6-dimethylphenyl), albeit in 14% yield
(Table 1, entry 4). Replacement of diethylaluminum chloride
with stoichiometric or catalytic gallium chloride afforded 3d
in 77-79% yield, and none of the monoaddition product 4d
was observed (Table 1, entries 6 and 7).
that the zwitterionic intermediate 19 resulting from the
addition of isocyanide 17 to enone 18 would undergo facile
six-membered ring formation to generate 20, in analogy to
the facile six-membered ring formation observed with 14 to
give 3 with no further incorporation of isocyanide (Scheme
2).
In the event, reaction of 18, which was readily prepared
from Hagemann’s ester,6 with 2,6-dimethylphenyl isocyanide
17 led to the selective formation of 20 in 71% yield, as a
1.8:1 mixture of trans/cis stereoisomers. As expected, the
yield of the seven-membered ring formation is somewhat
attenuated. Cyclization of enone 21,7 similarly prepared from
(4) Enone 8 was prepared via Suzuki coupling of 2-bromocyclohexenone
with 3-furyl-boronic acid.
(5) Rigby, J. H.; Laurent, S. J. Org. Chem. 1999, 64, 1766-1767.
(6) The preparation of 17 was followed from: Chakraborty, A.; Kar, G.
K.; Ray, J. K. Tetrahedron 1997, 53, 2989-2996.
3976
Org. Lett., Vol. 8, No. 18, 2006

Hagemann’s ester, afforded imine 23 in 47% yield as a 1.1:1
mixture of trans/cis diastereomers.
We have also examined the replacement of the furan
moiety in 1 (Scheme 2) with pyrrole (Scheme 4). The
accompanied by minor amounts of the oxidation product 269
(57% combined yield), the analogous reaction of 3-pyrrole
27 led to the exclusive formation of 28 in 55% yield. The
exclusive formation of monoaddition products corresponding
to 4 (Scheme 2) in the reactions of both 24 and 27 is
consistent with the increased nucleophilicity of pyrrole
relative to furan, promoting five-membered ring formation
at the expense of the reaction of the zwitterionic intermediate
with a second equivalent of isocyanide.
Scheme 4. Monoaddition Products via Reaction of
Pyrroloenones with Isocyanide 17
These results establish that the reaction of substituted
enones with isocyanides can lead to the selective formation
of products that formally result from either [4+1] or
[4+1+1] cycloaddition products. The application of this
methodology to the synthesis of diverse polycyclic systems
is currently underway in our laboratories, and our results
will be reported in due course.
Acknowledgment. We would like to thank the NIH,
GlaxoSmithKline, Merck, and Amgen for their generous
support of this work.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
requisite substrates 248a and 278b were prepared by palladium-
catalyzed cross-coupling reactions. Although reaction of
2-pyrrole 24 with 2,6-dimethylphenyl isocyanide gave 25,
OL061451C
(9) The spontaneous oxidation of the C-H bond flanked between a
carbonyl and an indole or a pyrrole has been observed by others: (a) De la
Figuera, N.; Garc´ıa-Lo´pez, M. T.; Herranz, R.; Gonza´lez-Mun˜iz, R.
Heterocycles 1998, 48, 2061-2070. (b) Kurihara, T.; Nasu, K.; Inoue, M.;
Ishida, T. Chem. Pharm. Bull. 1982, 30, 383-385. (c) Kurihara, T.; Nasu,
K.; Haginaga, S.; Mihara, K. Chem. Pharm. Bull. 1984, 32, 4410-4418.
(d) Stojanovic, M. N.; Kishi, Y. Tetrahedron Lett. 1994, 35, 9343-9446.
(e) De la Figuera, N.; Garc´ıa-Lo´pez, M. T.; Herranz, R.; Gonza´lez-Mun˜iz,
R. Heterocycles 1998, 48, 2061-2070.
(7) Mal, S. K.; Kar, G. K.; Ray, J. K. Tetrahedron 2004, 60, 2805-
2811.
(8) (a) Compound 24 was prepared from the Stille reaction of 2-bromo-
2-cyclohexenone and N-methyl-2-tributylstannanepyrrole using PdCl2(PPh3)2
as the catalyst. (b) Compound 27 was prepared from the Negishi coupling
of 2-iodo-2-cyclohexenone and the pyrrolylzinc species of 1-(triisopropyl-
silyl)-3-iodopyrrole with Pd(PPh3)4 as the catalyst.
Org. Lett., Vol. 8, No. 18, 2006
3977