1438
P. Langer, M. Döring
LETTER
Table Synthesis of 5-alkylidene-5H-pyrrol-2-ones 3a-z
trast, employment of 2-acetylcyclohexanone resulted in
formation of a 1:1-mixture of regioisomers. The reaction
of bis(imidoyl)chlorides 2a-b with the dianions of
2-acetyltetralone, 2-acetyldecalone, 3-acetyl-2,3-dihydro-
benzofuran-2-one, N-methyl-3-acetyl-2-oxindole and
2-acetylbenzocyclopentan-1-one afforded the 5-alky-
lidene-5H-pyrrol-2-ones 3t-x with very good E-diastereo-
selectivities. The reaction of 2a with dilithiated
cyclohexanediones gave the bicyclic 5-alkylidene-5H-
pyrrol-2-ones 3y-z.
In summary, we have developed a new domino reaction
for the synthesis of N-aryl-5-alkylidene-5H-pyrrol-2-
ones. The protecting group of the enamine function can be
chemoselectively removed. Preliminary results indicate
that benzyl-substituted bis(imidoyl)chlorides can also be
used in our cyclization reaction.
Work is now in progress to further study the selective
deprotection and functionalization of the 5-alkylidene-
5H-pyrrol-2-ones and to study the application of the cy-
clization reaction to the synthesis of natural products.
Acknowledgement
P. L. thanks Professor A. de Meijere for his support. Financial sup-
port from the Fonds der Chemischen Industrie e. V. (Liebig-schol-
arship and funds for P. L.) and the Deutsche Forschungs-
gemeinschaft (SFB 416) is gratefully acknowledged.
References and Notes
(1) (a) Langer, P.; Stoll, M. Angew. Chem. Int. Ed. 1999, 38,
1803; (b) Langer, P.; Schneider, T.; Stoll, M. Chem. Eur. J.
2000, 6, 3204.
(2) Grundon, M. F. Nat. Prod. Rep. 1987, 4, 89; (b) Lewis, J. R.
Nat. Prod. Rep. 1993, 10, 291; (c) Lewis, J. R. Nat. Prod. Rep.
ibid. 1994, 11, 329; (d) Rigby, J. H.; Hughes, R. C.; Heeg, M.
J. J. Am. Chem. Soc. 1995, 117, 7834; (e) Rigby, J. H.
Tetrahedron 1996, 52, 10569 and literature cited therein;
(f) Simmons, C. J.; Marner, F.-J.; Cardellina, J. H.; Moore, R.
E.; Seff, K. Tetrahedron Lett. 1979, 2003; (g) Cardellina, J.
H.; Moore, R. E. Tetrahedron Lett. 1979, 2007.
(a)1H NMR of isolated products. (b)Isolated yields. (c)Mixture of regio-
isomers (1:1)
(3) James, G. D.; Mills, S. D.; Pattenden, G. J. Chem. Soc., Perkin
Trans. 1 1993, 2581.
(4) (a) Abell, A. D.; Taylor, J. M. J. Org. Chem. 1993, 58, 14 and
cited literature; (b) Abell, A. D.; Oldham, M. D.; Taylor, J. M.
J. Org. Chem. 1995, 60, 1214.
(5) For a review of domino reactions: Tietze, L. F.; Beifuss, U.
Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
(6) Basato, M.; Corain, B.; Veronese, A. C.; D’Angeli, F.; Valle,
G.; Zanotti, G. J. Org. Chem. 1984, 49, 4696.
Starting with the dianions of ethyl acetoacetate, acetyl ac-
etone, benzoyl acetone, N,N-diethyl-acetylacetic amide
and N-(o-tolyl)-acetylacetic amide the 5H-pyrrol-2-ones
3a-h were prepared with very good regio- and E-diastere-
oselectivities. Reaction of the dianions of ethyl 2-methyl-
acetoacetate 1i and ethyl 2-ethyl-acetoacetate 1j with ox-
alic acid-bis(phenylimidoyl)chloride 2b gave the E-con-
figured heterocycles 3i-j containing a substituent at the
exocyclic double bond. Cyclization of 2b with the dian-
ions of methyl 3-oxopentanoate and ethyl 3-oxohexanoate
afforded the Z-configured 5-alkylidene-5H-pyrrol-2-ones
3k-l. The change from E- to Z-configuration can be ex-
plained by the steric influence of the substituent R1. Reac-
tion of 2b with the trianion of methyl 3,5-dioxohexanoate
1m afforded the 5H-pyrrol-2-one 3m.
(7) Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702.
(8) Lindauer, D.; Beckert, R.; Döring, M.; Fehling, P.; Görls, H.
J. Prakt. Chem. 1995, 337, 143.
(9) General procedure for the preparation of 5-alkylidene-5H-
pyrrol-2-ones 3: A THF solution of LDA was prepared by
addition of n-BuLi (8.25 ml, 13.2 mmol, 1.6 M solution in
hexane) to a THF solution (20 mL) of diisopropylamine (1.34
g, 1.86 ml, d = 0.722, 13.2 mmol). To the LDA solution was
added a THF solution (20 mL) of ethyl acetoacetate (0.78 g,
d = 1.021, 0.76 mL, 6.0 mmol) at 0 °C. The yellow coloured
solution was stirred at 0 °C for 60 min and was subsequently
transferred to a THF solution (80 mL) of oxalic acid-bis(p-
tolylimidoyl)chloride (1.83 g, 6.0 mmol) at 78 °C. The
Starting with
-acetyl- -butyrolactones 1n-q and
2-acetyl-cyclopentanone, heterocycles 3n-r were isolated
with very good regio- and E-diastereoselectivities. In con-
Synlett 2001, No. 9, 1437–1439 ISSN 0936-5214 © Thieme Stuttgart · New York