Stereoselective synthesis of (E)-4-alkylidenecyclopent-2-en-1-ones by a tandem ring closure-Michael addition-elimination

Article abstract of DOI:10.1021/ol0069352

(equation presented) Reaction of (Z)-1,4-diketones with various functionalized nitroalkanes in the presence of DBU gives 4-alkylidenecyclopent-2-en-1-ones with E selectivity. A cyclopentadienone intermediate is probably formed by intramolecular aldol cond

Full text of DOI:10.1021/ol0069352

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1265-1267
Stereoselective Synthesis of
(E)-4-Alkylidenecyclopent-2-en-1-ones by
a Tandem Ring Closure−Michael
Addition−Elimination
Roberto Ballini,* Giovanna Bosica, Dennis Fiorini, Maria Victoria Gil,† and
Marino Petrini*
Dipartimento di Scienze Chimiche, UniVersita` di Camerino, Via S. Agostino, 1. I-62032
Camerino, Italy, and Departamento de Quimica Organica, Facultad de Ciencias,
UniVersidad de Extremadura, 06071Badajoz, Spain
petrini@camserV.unicam.it
Received November 29, 2000
ABSTRACT
Reaction of (Z)-1,4-diketones with various functionalized nitroalkanes in the presence of DBU gives 4-alkylidenecyclopent-2-en-1-ones with E
selectivity. A cyclopentadienone intermediate is probably formed by intramolecular aldol condensation, and this reacts with a nitroalkane
giving a Michael addition−elimination.
The cyclopentenone ring is one of the most recurring
structural unit in targets of relevant practical interest.1
Functionalized cyclopentenones are also important building
blocks that provide an efficient entry to substituted cyclo-
pentanone frameworks.2 The classical approach for the
synthesis of cyclopentenones makes use of an intramolecular
aldol condensation of 1,4-dicarbonyl derivatives.3 This
strategy is particularly effective when 1,4-keto aldehydes or
symmetrical 1,4-diketones are used as substrates but un-
doubtedly poses some chemoselectivity problems with
unsymmetrical diketo derivatives. To overcome this draw-
back, a number of alternative protocols involving multicom-
ponent couplings,4 rearrangements,5 and other transforma-
tions6 have been devised. A practical synthetic route to
4-substituted cyclopentenones may exploit the reactivity of
cyclopentadienones I that react with nucleophilic reagents
giving the corresponding addition products II (Scheme 1).
Unfortunately, cyclopentadienones are rather unstable com-
pounds, and this prevents their direct use although a
“masked” form of these reactive substrates has found some
synthetic applications.7
† Universidad de Extremadura.
(1) (a) Mikolajczyc, M.; Mikina, M.; Zurawinski, R. Pure Appl. Chem.
1999, 71, 473-480. (b) Collins, P. E.; Djuric, S. W. Chem. ReV. 1993, 93,
1533-1564. (c) Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed. Engl. 1984,
23, 847-876.
(2) For some recent references, see: (a) Pastor, I. M.; Yus, M.
Tetrahedron Lett. 2000, 41, 1589-1592. (b) Yakura, T.; Tanaka, K.;
Iwamoto, M.; Nameki, M.; Ikeda, M. Synlett 1999, 1313-1315. (c) Keller,
E.; Maurer, J.; Naasz, R.; Shader, T.; Meetsma, A.; Feringa, B. L.
Tetrahedron: Asymmetry 1998, 9, 2409-2413. (d) Grieco, P. A.; May, S.
A.; Kaufman, M. D. Tetrahedron Lett. 1998, 39, 7047-7050. (e) Yan, M.;
Yang, L.-W.; Wong, K.-Y.; Chan, A. S. C. Chem. Commun. 1999, 11-12.
(f) Kondo, Y.; Kon-i, K.; Iwasaki, A.; Ooi, T.; Maruoka, K. Angew. Chem.,
Int. Ed. Engl. 2000, 39, 414-416.
(4) (a) Trost, B. M.; Pinkerton, A. B. Org. Lett. 2000, 2, 1601-1603.
(b) Rajesh, T.; Perisamy, M. Organometallics 1999, 18, 5709-5712. (c)
Langer, P.; Ko¨hler, V. Org. Lett. 2000, 2, 1597-1599.
(5) (a) Iwasawa, N. Synlett 1999, 13-24. (b) Mahnteau-Betzer, F.;
Ghosez, L. Tetrahedron Lett. 1999, 40, 5183-5186.
(6) (a) Balaczewsky, P.; Mikolajczyk, M. Org. Lett. 2000, 2, 1153-
1155. (b) Sakai, A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 2000, 41,
6859-6863.
(7) (a) Sugahara, T.; Ogasawara, K. Synlett 1999, 419-420. (b) Dols,
P. P. M. A.; Klunder, A. J. H.; Zwanenburg, B. Tetrahedron 1994, 50,
8515-8538.
(3) Piancatelli, G.; D’Auria, M.; D’Onofrio, F. Synthesis 1994, 867-
889.
10.1021/ol0069352 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/03/2001

Scheme 1
Scheme 4
cycloaddition of alkynes.12 The nature of product 6 obtained
is consistent with a mechanism depicted in Scheme 5. A
A solution to this problem may be the exploitation of a
tandem process8 in which the cyclopentadienone readily
reacts with a nucleophile as soon as it is formed.
Recently, we have reported that nitroalkanes 1 react with
enones 2 in a tandem Michael addition-elimination process
giving unsaturated 1,4-diketones 3 with enhanced E stereo-
selectivity9 (Scheme 2).
Table 2. Synthesis of Cyclopentenones 6
entry
nitroalkane R1
R2
5
6
yield,a
%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1i
1c
1i
1j
Me
i-Pr
n-C5H11
n-C9H19
CH2dCH(CH2)3
dioxolanylethylb
HO(CH2)5
CH3COCH2CH2
MeO2CCH2CH2
MeO2C(CH2)4
Ph
Me
H
H
H
H
H
H
H
H
H
H
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5c
5d
5e
5e
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
77
63
81
76
68
73
78
84
80
67
65
79
87
68
73
93
67
Scheme 2
The application of this strategy to unsymmetrical 1,4-
diketones, usually leads to a regioisomeric mixture of
products that jeopardizes the efficiency of the synthetic
procedure.9a (Z)-1,4-Diketones 5 are easily obtained by ring
cleavage of furans 4 with m-CPBA10 (Scheme 3, Table 1).
1c
1j
b
a Yields of pure, isolated products.
Scheme 3
chemoselective intramolecular aldol condensation of enedi-
one 5, promoted by the presence of the aromatic ring, gives
cyclopentadienone 7 as reactive intermediate that, under the
same conditions, reacts with nitroalkane 1 to afford the
Michael adduct 8. As previously observed,9 the nitroenone
8 undergoes a base-assisted elimination of nitrous acid giving
cyclopentenone 6.13
Nitroalkanes 1 react with diketones 5 in the presence of DBU
in acetonitrile, affording 4-alkylidene-cyclopent-2-en-1-ones
6 in good yield and high E diastereoselectivity11 (Scheme 4,
Table 2).
(8) For some recent reviews on this topic, see: (a) Parsons, P. J.; Penkett,
C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195-206. (b) Bunce, R. A.
Tetrahedron 1995, 51, 13103-13159.
(9) (a) Ballini, R.; Barboni, L.; Bosica, G.; Petrini, M. Synlett 2000, 391-
393. (b) Ballini, R.; Bosica, G.; Petrelli, L.; Petrini, M. Synthesis 1999,
1236-1240. (c) Ballini, R.; Bosica, G. Tetrahedron 1995, 51, 4213-4222.
(10) Compounds 4 were prepared by alkylation of 2-alkylfurans: Pi-
ancatelli, G.; Scettri, A.; D’Auria, M. Tetrahedron 1980, 36, 661-663.
Oxidation of furan ring with peracids: (a) Dominguez, C.; Csa´ky, A. G.;
Plumet, J. Tetrahedron Lett. 1990, 31, 7669-7670. (b) Kobayashi, Y.;
Katsuno, H.; Sato, F. Chem. Lett. 1983, 1771-1774.
Cyclopentenones 6 are usually prepared by metal-mediated
Table 1. Synthesis of Diketones 5
(11) No detectable amount of the Z diastereoisomer was found in the
1H NMR spectra of compounds 6. General Procedure. To a solution of
enedione 5 (5 mmol) in acetonitrile (25 mL), the nitroalkane 1 (5 mmol)
followed by DBU (5 mmol) were added at room temperature. After the
solution was stirred for 6 h at room temperature, the solvent was evaporated
at reduced pressure and the residue was purified by column chromatography
(hexanes-ethyl acetate 8:2).
(12) (a) Ahmar, M.; Antras, F.; Cazes, B. Tetrahedron Lett. 1995, 36,
4417-4420. (b) Ahmar, M.; Chabanis, O.; Ghautier, J.; Cazes, B.
Tetrahedron Lett. 1997, 38, 5277-5280. (c) Pu¨rro, S.; Pryde, A.; Zsindely,
J.; Schmid, H. HelV. Chim. Acta 1978, 61, 266-278. (d) Martin, G. J.;
Rabiller, C.; Mabon, C. Tetrahedron 1972, 28, 4027-4037.
entry
furan R
Ar
diketone
yield,a
%
1
2
3
4
5
4a
4b
4c
4d
4e
Me
Et
Me
Et
C6H5
C6H5
3-MeOC6H4
4-FC6H4
3-ClC6H4
5a
5b
5c
5d
5e
88
79
91
85
83
Me
a Yields of pure, isolated products.
1266
Org. Lett., Vol. 3, No. 9, 2001

by comparison of spectral data obtained for compound 6k
with those appeared in the literature.14
Scheme 5
In conclusion, 4-alkylidenecyclopent-2-en-1-ones 6 are
now readily available compounds, achievable from (Z)-1,4-
diketones 5 by a simple procedure involving three different
reactions carried out in a tandem sequence. The efficiency
of the whole process is witnessed by the good yield and the
outstanding E stereoselectivity of products prepared.
Application of this synthetic methodology to other func-
tionalized enediones is currently in progress in our laboratory.
Acknowledgment. Financial support from University of
Camerino (National Project “Stereoselezione in Sintesi
Organica. Metodologie e Applicazioni”) is gratefully ac-
knowledged. D.F. thanks CINMPIS-Bari for a fellowship.
The proposed mechanistic pathway is also supported by
the lack, in the reaction mixture, of any regioisomeric product
as 9 that could arise by a conjugate addition of the
nitroalkanes 1 on diketones 5 before the ring closure.
Supporting Information Available: Spectral and physi-
cal data for new compounds prepared. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0069352
(13) Conjugate addition of the nitroalkane to a cyclopentenone, before
the elimination of the aldol, is also conceivable. At any event, this
dehydration process should occur before the elimination of nitrous acid,
since the presence of an acidic hydrogen at C-4 is necessary to afford the
exocyclic double bond (see ref 9).
(14) Pasto, J. D.; Huang, N.-Z.; Eigenbrot, C. W. J. Am. Chem. Soc.1985,
107, 3160-3172.
Any attempt to prepare the cyclopentadienone 7 carring
out the reaction in the absence of nitroalkane led to frustrating
results since only a complex mixture of various products was
obtained. The E configuration of the exocyclic double bond
in compounds 6 has been verified by NOE experiments and
Org. Lett., Vol. 3, No. 9, 2001
1267