An unexpected phosphine-catalyzed [3 + 2] annulation. Synthesis of highly functionalized cyclopentenes

Article abstract of DOI:10.1021/ol8011452

(Chemical Equation Presented) An unexpected phosphine-catalyzed [3 + 2] annulation from electron-deficient allenes and substituted alkylidenemalononitriles was realized in which the allylic moiety of the substituted alkylidenemalononitriles served as the

Full text of DOI:10.1021/ol8011452

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3267-3270
An Unexpected Phosphine-Catalyzed
[3 + 2] Annulation. Synthesis of Highly
Functionalized Cyclopentenes
Zheng Lu,† Suqing Zheng,† Xumu Zhang,‡ and Xiyan Lu*,†
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China,
and Department of Chemistry and Chemical Biology & Department of Pharmaceutical
Chemistry, Rutgers, The State UniVersity of New Jersey, Piscataway, New Jersey 08854-8020
xylu@mail.sioc.ac.cn
Received May 21, 2008
ABSTRACT
An unexpected phosphine-catalyzed [3 + 2] annulation from electron-deficient allenes and substituted alkylidenemalononitriles was realized
in which the allylic moiety of the substituted alkylidenemalononitriles served as the three carbon unit of the cyclopentenes instead of the
electron-deficient allenes.
The chemistry and biological properties of cyclopentenoids
are of continual interest because of their occurrence in a wide
range of natural products and drugs.1 Effective methods to
establish cyclopentene structure with substituents in different
positions remain a continuing challenge.2 Among them,
phosphine-catalyzed [3 + 2] reaction of allenoates and
alkenes is an efficient methodology in constructing cyclo-
pentenes.3 In the original discovery of this reaction,3a it was
found that only terminal alkenes can be used as the two-
carbon partner except those for the intramolecular annulation
or dual-activated olefins (such as diethyl fumarate or diethyl
maleate). A pair of regioisomers was also produced in almost
every case.
Recently, the reaction was improved by the use of alkenes
with strong electron-withdrawing groups (e.g., dinitriles4a or
ketones4b–d ) so that alkenes with ꢀ-substituents could react
effectively. In the formed cyclopentenes (3), three carbon
atoms come from the allenoate (1) and two carbon atoms
are from the alkylidenemalononitrile (2).4
† Shanghai Institute of Organic Chemistry.
‡ Rutgers, The State University of New Jersey.
(1) (a) Straus, D. S.; Glass, C. K. Med. Res. ReV. 2001, 21, 185. (b)
Conti, M. Anti-Cancer Drugs 2006, 17, 1017.
The question arose if the reaction could still occur when
another ꢀ-substituent was introduced into the alkenes. 2-(1′-
Phenylbenzylidene)malononitrile was first chosen to test the
reaction. To our disappointment, no reaction was observed
(2) For reviews, see: (a) Hudlicky, T.; Price, J. D Chem. ReV. 1989, 89,
1467. (b) Hartley, R. C.; Caldwell, S. T. J. Chem. Soc., Perkin Trans. 1
2000, 477. (c) Silva, L. F. Tetrahedron 2002, 58, 9137.
(3) (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b)
Methot, J. L. W.; Roush, R. AdV. Synth. Catal. 2004, 346, 1035. (c) Lu,
X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 77, 1985. (d) Ung, A. T.; Schafer,
K.; Lindsay, K. B.; Pyne, S. G.; Amornraksa, K.; Wouters, R.; Van der
Linden, I.; Biesmans, I.; Lesage, A. S. J.; Skelton, B. W.; White, A. H. J.
Org. Chem. 2002, 67, 227. (e) Yong, S. R.; Williams, M. C.; Pyne, S. G.;
Ung, A. T.; Skelton, B. W.; White, A. H.; Turner, P. Tetrahedron 2005,
61, 8120. (f) Wallace, D. J.; Sidda, R. L.; Reamer, R. A. J. Org. Chem.
2007, 72, 1051.
(4) (a) Lu, X.; Lu, Z.; Zhang, X. Tetrahedron 2006, 62, 457. (b) Wang,
J. C.; Ng, S. S.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 3682. (c)
Wang, J. C.; Krische, M. J. Angew. Chem., Int. Ed. 2003, 42, 5855. (d)
Wilson, J. E.; Fu, G. C. Angew Chem., Int. Ed. 2006, 45, 1426. (e) See the
Supporting Information.
10.1021/ol8011452 CCC: $40.75
Published on Web 07/03/2008
2008 American Chemical Society

with allenoate in the presence of triphenylphosphine in
toluene even under reflux. Isopropylidenemalononitrile gave
a complicated mixture under the same reaction conditions.
When 2-(1′-phenylethylidene)malononitrile (4a) was used,
the reaction with allenoate (1) did occur in the presence of
triphenylphosphine in toluene at 60 °C to give two products.
Surprisingly, the result was not the one we expected since
the signal of methyl group could not be found in the proposed
products from the 1H NMR spectra. One of the products was
assigned as 5a as confirmed by X-ray diffraction5 and another
product was 6a. Unlike other reported phosphine-catalyzed
annulation reaction of allenoates and alkenes,3,4a allenoate
1 here just acted as the two-carbon unit in this [3 + 2]
reaction (Scheme 1).6
Table 2. Effect of Alkyl Substituents on the Reactiona
entry
R
product
yieldb (%)
1
2
3
4
5
6
7
Me (7a)
Et (7b)
i-Pr (7c)
Ph (7d)
p-NO2C6H4(7e)
CO2Et(7f)
n-C11H23(7g)
8a
8b
8c
8d
8e
8f
77
77
56
77
75
82
8g
a 1 (1.2 mmol), 7 (1 mmol), and PPh3 (0.1 mmol) in toluene (3 mL),
reflux, 15 h. b Isolated yield.
Scheme 1
3,4-Pentadien-2-one (1′) reacted similarly with 4a giving
5a′ in 46% yield (Scheme 2).4e Compound 2b reacted with
Scheme 2
With this unexpected result in hand, optimization of the
reaction conditions was carried out. No product could be
isolated when solvents with low boiling point (e.g.,
acetone, THF, and DCE) were used. In refluxing toluene
or xylene, both the yield and the selectivity got better.
Other tertiary phosphines were also tested as the catalyst,
and triphenylphosphine gave the highest yield of 5a.
Finally, triphenylphosphine in refluxing xylene or toluene
was chosen as the optimized condition of this reaction.
Different substrates were studied as shown in Tables 1
and 2 and Scheme 2.
Table 1. Effect of Substituents of the Aryl Group on the
Reactiona
1 giving the normal [3 + 2] reaction product 3b (eq 1).4e
The results that reactions of the allenoate 1 with 9a-d in
toluene or xylene gave the addition products 11a-d (Scheme
2) indicated that this [3 + 2] reaction of alkylidenemalono-
nitriles could proceed even without the aryl group; thus, a
rather broad class of compounds can be used as the
substrates. These results also showed that a ꢀ,ꢀ-disubstituted
olefin with one methyl substituent is necessary for this kind
entry
Ar
Ph (4a)
p-ClC6H4 (4b)
p-BrC6H4 (4c)
p-MeC6H4 (4d)
p-MeOC6H4 (4e)
p-NO2C6H4 (4f)
o-MeC6H4 (4g)
product
yieldb (%)
1c
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
70
61
64
69
65
disordered
50
(5) For a CIF file of 5a, see the Supporting Information.
(6) For other examples that allenoates acted as two-carbon unit in the
[3 + 2] reactions, see: (a) Zhu, X. F.; Henry, C. E.; Wang, J.; Dudding, T.;
Kwon, O. Org. Lett. 2005, 7, 1387. (b) Henry, C. E.; Kwon, O. Org. Lett.
2007, 9, 3069.
5g
a 1 (0.45 mmol), 4 (0.36 mmol), and PPh3 (0.036 mmol) in xylene (3
mL), reflux, 3 h. b Isolated yield. c Compound 6a was isolated in 5% yield.
3268
Org. Lett., Vol. 10, No. 15, 2008

of new [3 + 2] reaction. The products dinitriles can be easily
converted to the cyclopentene derivatives which are useful
in natural products and drug synthesis.7
Scheme 4
In the reaction of the allenoate 1 with 9a, a noncyclized
product 10a was also isolated. Compound 10a could not be
transformed to 11a in toluene using triphenylphosphine only
as the catalyst, but the reaction did occur in the presence of
both 1 and triphenylphosphine. This might be due to the
formation of the intermediate A from 1 and triphenylphos-
phine (Scheme 3) which could act as a base in the next
Scheme 3
intramolecular conjugate addition step (Scheme 4).8 When
ethyl acrylate, which could also react with triphenylphosphine
to produce a basic intermediate like A9 (Scheme 3), was used
instead of 1, the reaction proceeded similarly. These results
indicated that the reaction proceeded first with the formation
of 10a followed by the intramolecular conjugate addition to
form 11a.
Thus, a plausible mechanism is shown in Scheme 4. The
methyl group of 4 is believed to be deprotonated by the
zwitterion A first to form the carbanion because of its acidic
property (Scheme 4).7b,10 The formed carbanion could react
with other substrates via the γ-addition10 in phosphine-
catalyzed reactions. The first cycle is the γ-addition of
compound 4 to the allenoate 1 to give the diene 12 under
the catalysis of PPh3.3a,b,11 Cyclization of intermediate 12
in the presence of A gives compound 5 (path a in Scheme
4). Another possible pathway is the addition of the diene 12
to another molecule of the dipole intermediate B to give the
triene intermediate D, followed by cyclization under the
action of A to yield compound 6 (path b).To obtain more
information of this reaction, a PPh3-catalyzed reaction of
deuterium labeled D-9a and 1 in toluene was carried out to
give products D-10a and D-11a (Scheme 5). In the γ-addition
Scheme 5
(7) (a) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12632. (b)
Chen, Y. C.; Xue, D.; Deng, J. G.; Cui, X.; Zhu, J.; Jiang, Y. Z. Tetrahedron
Lett. 2004, 45, 1555.
(8) For references on phosphine-catalyzed conjugate addition to electron-
deficient alkenes, see: (a) White, D. A.; Baizer, M. M. Tetrahedron Lett.
1973, 3597. (b) Yoshida, T.; Saito, S. Chem. Lett. 1982, 1587. (c) Gomez-
Bengoa, E.; Cueva, J. M.; Mateo, C.; Echavarren, A. M. J. Am. Chem.
Soc. 1996, 118, 8553. (d) Lumbierres, M.; Marchi, C.; Moreno-Man˜as, M.;
Sebastia´n, R. M.; Vallribera, A.; Lago, E.; Molins, E. Eur. J. Org. Chem.
2001, 2321. (e) Lu, C.; Lu, X. Org. Lett. 2004, 4, 4677.
product D-10a, nearly total hydrogen was deuteriated on
carbon 3, and half was deuteriated on both carbon 5 and 6.
In product D-11a, nearly half was deuteriated on carbon 5,
and totally half was deuteriated for the two hydrogen atoms
(9) Hoffmann, H. Chem. Ber. 1961, 94, 1331.
(10) For references on the chemical properties of alkylidenemalononi-
triles, see: (a) Karlsen, H.; Songe, P. H.; Sunsby, L. K.; Hagen, L. C.;
Kolsaker, P.; Romming, C. J. Chem. Soc., Perkin Trans. 1 2001, 497. (b)
Xue, D.; Chen, Y. C.; Wang, Q. W.; Cun, L. F.; Zhu, J.; Deng, J. G. Org.
Lett. 2005, 7, 5293. (c) Xie, J. W.; Yue, L.; Xue, D.; Ma, X. L.; Chen,
(11) For references on phosphine catalyzed γ-addition, see: (a) Trost,
B. M.; Li, C. J. J. Am. Chem. Soc. 1994, 116, 3167. (b) Zhang, C.; Lu, X.
Synlett 1995, 645. (c) Trost, B. M.; Li, C. J. J. Am. Chem. Soc. 1994, 116,
10819. (d) Trost, B. M.; Dake, G. R. J. Org.Chem. 1997, 62, 5670.
Y. C.; Wu, Y.; Zhu, J.; Deng, J. G. Chem. Commun. 2006, 1563
.
Org. Lett., Vol. 10, No. 15, 2008
3269

on carbon 6. These results are in compatible with our
proposed mechanism.
1 in which a different deuteriated product will be obtained
(Scheme 6).
The results of deuteriated experiments also exclude the
possibility of direct addition of the anion of D-9a to allenoate
In summary, we developed a highly efficient method for
synthesizing substituted cyclopentenes from allenoates and
substituted alkylidenemalononitriles via an unexpected method
of phosphine-catalyzed [3 + 2] annulation, in which allenoate
1 acted as the two-carbon unit in the formed cyclopentenes.
This strategy offers a convenient method for constructing
cyclopenenoids under neutral conditions with high atom
economy.
Scheme 6
Acknowledgment. We thank the National Natural Science
Foundation of China (20572121) and Chinese Academy of
Sciences for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL8011452
3270
Org. Lett., Vol. 10, No. 15, 2008