Formation of aromatic rings through enamine annulation

Article abstract of DOI:10.1021/ol000093p

(matrix presented) Condensation of pyrrolidine enamine of ketones with 1,4-diacetoxy-2-butanone provides a new, concise synthetic route to substituted benzenes, dihydroindenes, tetrahydronaphthalenes, and di- and octahydrophenanthrenes. The reaction produced modest yields with regiocontrol of the secondary amine substituent.

Full text of DOI:10.1021/ol000093p

ORGANIC
LETTERS
2000
Vol. 2, No. 12
1773-1775
Formation of Aromatic Rings through
Enamine Annulation
,†
Chen Wang and Harold Kohn*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204-5641
harold_kohn@unc.edu
Received April 17, 2000
ABSTRACT
Condensation of pyrrolidine enamine of ketones with 1,4-diacetoxy-2-butanone provides a new, concise synthetic route to substituted benzenes,
dihydroindenes, tetrahydronaphthalenes, and di- and octahydrophenanthrenes. The reaction produced modest yields with regiocontrol of the
secondary amine substituent.
1
Condensation of enamines with R,â-unsaturated carbonyl
compounds provides a convenient, one-step method for
constructing nonaromatic rings.1 This procedure has been
used extensively in the synthesis of alkaloids, steroids, and
terpenes.2 One example of this transformation is the reaction
of 1-(1-pyrrolidino)cyclohexene (1) with methyl vinyl ketone
(2) to give hexahydronaphthalenes 3-5 in a combined yield
of 78% (eq 1).3
shifts and the H-1H coupling constants for 7 documented
the site of pyrrolidine substitution and that cyclization
proceeded with aromatization. The finding that reaction of
1 with 6 yielded an aromatic product while the corresponding
reaction with 2 did not indicated that the acetoxy moiety in
6 was necessary for the formation of the annulated benzene
ring.
We attributed the modest yield of 7, in part, to the lability
of 6. Compound 6 was observed to undergo polymerization
during overnight storage at 0 °C.4 Accordingly, we deter-
mined whether 1,4-diacetoxy-2-butanone (8) could be em-
ployed in place of 6. Reaction of 1 with 8 in benzene at
Recently, we found that the reaction of enamine 1 with
1-acetoxy-3-buten-2-one (6)4 gave a single product, 6-(1-
pyrrolidino)-1,2,3,4-tetrahydronaphthalene (7), in 27% iso-
lated yield (eq 2). The observed 1H and 13C NMR chemical
(2) (a) Kobayashi, K.; Furuta, Y.; Matsuoka, H.; Uchida, M.; Morikawa,
O.; Konishi. H. Chem. Lett. 1999, 6, 503. (b) Murphy, W. S.; Bertrand, M.
J. Chem. Soc., Perkin Trans. 1 1998, 4115. (c) Li, J.; Trivedi, B. K.; Rubin,
J. R.; Roth, B. D. Tetrahedron Lett. 1998, 39, 6111. (d) Schwarz, J. B.;
Meyers, A. J. Org. Chem. 1998, 63, 1619. (e) Kao, B. C.; Doshi, H.; Reyes-
Rivera, H.; Titus, D. D.; Yin, M.; Dalton, D. R. J. Heterocycl. Chem. 1991,
28, 1315.
(3) House, H. O. H.; Trost, B. M.; Magin, R. W.; Carlson, R. G.; Frank,
R. W.; Rasmusson, G. H. J. Org. Chem. 1965, 30, 2512.
(4) Hennion, G. F.; Kupiecki, F. P. J. Org. Chem. 1953, 18, 1601.
† Current address: School of Pharmacy, University of North Carolina,
Chapel Hill, NC 27599-7360.
(1) (a) Cook, A. G. Enamines, Synthesis, Structure, and Reaction, 2nd
ed.; Marcel Dekker: New York, 1998; Chapter 7, p 347. (b) Chinchilla,
R.; Backvall, J. E. The Chemistry of Enamines; Rappoport, Z., Ed.; John &
Wiley Sons: New York, 1994; Chapter 18, p 993.
10.1021/ol000093p CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/24/2000

room temperature afforded 7 (47% yield) along with a binary
mixture (∼ 7%) (eq 3). Spectroscopic analysis suggested that
the binary mixture consisted of 1-acetoxy-4,4a,5,6,7,8-
hexahydro-2(3H)-naphthalenone (9) and 1-acetoxy-1,4,5,6,7,8-
hexahydro-2(3H)-naphthalenone (10) in an approximately 2:1
ratio, respectively. Key to our assignments were the observa-
tion of two downfield 13C NMR signals, at 191.4 and 206.4
ppm, which we have attributed to the carbonyl carbons in 9
and 10, respectively. Reducing the reaction time from 18 to
4 h decreased the yield of 7 to 3% and increased the
combined yield of 9 and 10 to approximately 41%.
Table 1. Products from Pyrrolidine Enamines of Ketones and
8
These initial findings suggested a pathway for the forma-
tion of 7 from 1 and 8 (Scheme 1). Michael addition of
Scheme 1
a Isolated yields based on starting ketones.
enamine 1 to the in situ generated 6 gives zwitterion 11.
This species is in equilibrium with 12, which cyclizes to 13.
Loss of pyrrolidine from 13 generates 9 or 10. Condensation
of pyrrolidine with the newly formed ketone 9 or 10 and
loss of H2O and HOAc provides the aromatic derivative 7.
This pathway is an extension of an earlier route proposed
for the formation of compounds 3-5.3
Attempts to further improve the yield of 7 were unsuc-
cessful. Higher temperatures (60 °C) and longer reaction
times (24 h) did not improve the yield, and inclusion of
pyrrolidine (3 equiv) led to only trace amounts of 7.5
The generality of this one-step, aromatic annulation
procedure was investigated (Table 1). Ketones, varying in
structure, were used to generate the corresponding aromatic
derivatives. For ketones in entries 1-6, the corresponding
enamine was prepared by refluxing (3 h) an anhydrous
benzene solution of the ketone (1-2 mmol), pyrrolidine (2
equiv), and catalytic amounts of p-toluenesulfonic acid
(PTSA) with a modified Dean-Stark apparatus.6 For ketones
in entries 7 and 8, enamine formation required a longer
reaction time (30 h) and a larger excess of pyrrolidine (10
equiv).7 The enamines obtained were concentrated in vacuo,
and the crude enamines were directly added to an anhydrous
benzene solution containing 8 (1.5 equiv). The reaction
proceeded at room temperature (18 h), and the products were
isolated by preparative TLC.
(5) Compound 8 is unstable in the presence of amines (i.e., pyrrolidine,
triethylamine, DBU). 1,7-Diacetoxy-3-methylene-2,6-heptanedione was
obtained in 50% yield when a benzene solution of 8 and triethylamine (1
equiv) was stirred at room temperature (1 h).
(6) Masamune, T.; Takasngi, M.; Murai, A. Tetrahedron 1971, 27, 3369.
(7) Hellberg, L. H.; Milligan, R. J.; Wike, R. N. J. Chem. Soc. C 1970,
35.
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Org. Lett., Vol. 2, No. 12, 2000

We observed that acyclic (entry 1), carbocyclic (entries
2-4, 7, and 8), and heterocyclic (entries 5 and 6) ketones
underwent aromatization upon treatment with 8. The isolated
yields are based on the starting ketones and were from 28
to 65%. Interestingly, we observed only a single product for
dihydroindene, tetrahydronaphthalene, and di- and octahydro-
phenanthrene compounds. The reaction produced modest
yields with regiocontrol of the secondary amine substituent.
1
ketones 23 (entry 4)8 and 35 (entry 8) even though the H
Acknowledgment. We thank Dr. Lucia Carrano and
Biosearch Italia S.p.A. (Gerenzano, Italy) for their support
of this study.
and 13C NMR spectra for the corresponding enamines 24
and 36, respectively, showed the presence of two isomers.
Products 25 and 37, obtained in these reactions, were derived
from the major enamine isomers 24a and 36a, respectively.
Attempts to condense the pyrrolidine enamine from N-meth-
yl-4-piperidinone with 8 failed to give a cycloadduct.
In conclusion, we have found a concise enamine-induced
benzoannulation method that affords substituted benzene,
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 7, 9, 10, 16,
19, 22, 25, 28, 31, 34, and 37. This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) Gurowitz, W. D.; Joseph, M. A. Tetrahedron Lett. 1965, 3, 4433.
OL000093P
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