The Palladium(II)-Catalyzed Nazarov Reaction

Article abstract of DOI:10.1021/ol036017e

(Equation presented) The PdCl₂-catalyzed cyclization of α-alkoxy dienones leads to 2-hydroxycyclopentenones, whereas the Pd(OAc)₂-catalyzed reaction leads to cross-conjugated cyclopentenones through an oxidative process.

Full text of DOI:10.1021/ol036017e

ORGANIC
LETTERS
2003
Vol. 5, No. 26
4927-4930
The Palladium(II)-Catalyzed Nazarov
Reaction
Cisco Bee, Eric Leclerc, and Marcus A. Tius*
Department of Chemistry, 2545 The Mall, UniVersity of Hawaii,
Honolulu, Hawaii 96822, and The Cancer Research Center of Hawaii,
1236 Lauhala Street, Honolulu, Hawaii 96813
tius@gold.chem.hawaii.edu
Received October 15, 2003
ABSTRACT
The PdCl2-catalyzed cyclization of r-alkoxy dienones leads to 2-hydroxycyclopentenones, whereas the Pd(OAc)2-catalyzed reaction leads to
cross-conjugated cyclopentenones through an oxidative process.
During the course of a survey of Lewis acids for use in a
catalytic asymmetric version1 of the Nazarov reaction,2 we
examined the effect of PdCl2(MeCN)2 on dienone 1a.
Cyclization to 2-hydroxycyclopentenone 2a took place in
91% yield in the presence of 1 mol % palladium at room
temperature in acetone. An observation made by Kocienski
suggests that the presence of the electron-donating alkoxy
substituent in 1a lowers the activation barrier for the proton-
catalyzed Nazarov cyclization.3 This presumably takes place
because of the polarization of the enol ether and the resulting
increase in electron density at the terminal sp2-hybridized
carbon atom. We were therefore concerned that small
amounts of adventitious HCl might have catalyzed the
conversion of 1a to 2a. To rule this out, 1a was treated with
1 mol % 1 N HCl at room temperature in acetone. This led
to R-diketone 3, the product of enol ether hydrolysis, in
nearly quantitative yield. None of the cyclic product 2a was
detected in the product mixture (Scheme 1). To determine
Scheme 1a
a Conditions: (a) 1 mol % PdCl2(MeCN)2, acetone (H2O), rt, 1
day, 91%; (b) 1 mol % 1 N HCl, acetone (H20), rt, 3 days, ca.
100%.
whether the palladium-catalyzed reaction that we observed
for 1a is general, we examined the series of reactions
summarized in Table 1. The dienone starting materials 1a-i
were prepared by adding 1-ethoxy-1-lithioethene or 2-lithiodi-
hydropyran to the appropriate morpholino enamides. Di-
enones 1j-l were prepared nonstereospecifically according
to the method that is summarized in Scheme 2. In the case
of 1j and 1k, the two geometric isomers were separated by
flash column chromatography and cyclized independently.
In the case of 1l, the mixture of (E)- and (Z)-isomers was
cyclized.
(1) For examples of asymmetric Nazarov reactions, see: (a) Kerr, D. J.;
Metje, C.; Flynn, B. L. J. Chem. Soc., Chem. Commun. 2003, 1380-1381.
(b) Pridgen, L. N.; Huang, K.; Shilcrat, S.; Tickner-Eldridge, A.; DeBrosse,
C.; Haltiwanger, R. C. Synlett 1999, 10, 1612-1514. (c) Hu, H.; Smith,
D.; Cramer, R. E.; Tius, M. A. J. Am. Chem. Soc. 1999, 121, 9895-9896.
(d) Harrington, P. E.; Murai, T.; Chu, C., Tius, M. A. J. Am. Chem Soc.
2002, 124, 10091-10100.
(2) For a review of the Nazarov reaction, see: Habermas, K. L.; Denmark,
S.; Jones, T. K. In Organic Reactions; Paquette, L. A., Ed.; John Wiley &
Sons: New York, 1994; Vol. 45, pp 1-158.
(3) (a) Casson, S.; Kocienski, P. J. Chem. Soc., Perkin Trans. 1 1994,
1187-1191. (b) Tius, M. A.; Kwok, C.-K.; Gu, X.-q.; Zhao, C. Synth.
Commun. 1994, 24, 871-885.
10.1021/ol036017e CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/25/2003

Scheme 2a
Table 1. 2-Hydroxycyclopentenones
a Conditions: (a) Cy2NLi; (b) R1COR2; (c) SOCl2, Et3N; (d)
t-BuOK.
The yields of cyclic products were generally good. Some
of the results in Table 1 require some discussion. In the case
of 1g, the difference in the ratio of products 2g and 4 that
was observed under the two reaction conditions is a function
of the reaction time. A low catalyst load (1 mol %) requires
a longer reaction time (1 day vs 10 min) leading to a greater
proportion of hydrolysate 4 in the product. The stereochem-
istry of 2g is cis. Upon standing, slow isomerization to the
trans isomer takes place.4 Cyclopentenones 2i-l show that
quaternary carbon atoms can be incorporated into the cyclic
products. It is noteworthy that 2l bears two adjacent
quaternary carbon atoms. The acid-catalyzed Nazarov reac-
tion often fails in such cases and leads to mixtures of products
resulting from Wagner-Meerwein rearrangement of the
intermediate cation(s).5 Cyclization of (E)- and (Z)-isomers
1j and 1k, respectively, was completely stereospecific and
led to 2j and 2k in 90 and 74% yields, respectively. The
relative stereochemistry in 2j and 2k was determined by
NOE. The cyclization failed to take place in the case of
dienones 8-11.
Failure of the cyclization in the case of 8 can be rationalized
in terms of conformational preferences, as has been done
for the acid-catalyzed Nazarov reaction.3b Failure of 9 to
undergo the cyclization is certainly due to the electron-
withdrawing effect of the fluorine atom, whereas failure of
10 and 11 suggests that the R alkoxy group is required. The
probable mechanism was suggested by these results, as well
as by an observation that we made during our examination
of Pd(OAc)2 as a catalyst.
Exposure of 1a to 20 mol % Pd(OAc)2 in DMSO6 under
an oxygen atmosphere led to cross-conjugated cyclopenten-
one 12a in 50% yield following flash column chromatog-
raphy. The reaction was carried out with dienones 1b, 1d,
1e, and 1i with the results that are summarized in Figure 1.
Product yields were lower for this process than for the PdCl2-
mediated process. This can be attributed in part to losses
(4) Stereochemistry was determined by NOE.
(5) (a) Motoyoshiya, J.; Yazaki, T.; Hayashi S. J. Org. Chem. 1991, 56,
735-740. (b) Morel-Fourrier, C.; Dulcere, J. P.; Santelli, M. J. Am. Chem.
Soc. 1991, 113, 8062-8069. The rearrangement may be the desired process;
see: Bender, J. A.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121,
7443-7444.
a All reactions were conducted in wet acetone at room temperature with
the indicated quantity of PdCl2(MeCN)2. b These products were isolated as
volatile solids.
(6) Toyota, M.; Sasaki, M.; Ihara, M. Org. Lett. 2003, 5, 1193-1195.
4928
Org. Lett., Vol. 5, No. 26, 2003

reaction is initiated by activation of the carbonyl group by
an acid, this seems unlikely in the present case. Instead,
activation of the electron-poor olefin by complexation to
palladium seems a more likely first step.8 Complexation of
the electrophilic palladium salt to the electron-rich enol ether
(see 14) is probably preferred but does not lead to cyclic
product.9 If the association of 1a with palladium is reversible,
π complex 13 can form and undergo intramolecular attack
to produce palladium enolate 15. When Pd(OAc)2 is used,
proton loss from 15 (X ) OAc) leads to 16, which undergoes
â elimination to 12a. In the absence of an oxidant, the
palladium hydride that is also generated from reductive
elimination leads to Pd(0) irreversibly. When PdCl2 is used,
15 (X ) Cl) undergoes hydrolysis with loss of ethanol to
produce 17 and HCl. Decomposition of the palladium enolate
by the strong acid regenerates the Pd(II) catalyst and leads
to 2a. The difference in reaction pathways between the
Pd(OAc)2- and the PdCl2-catalyzed reactions may be due to
the difference in basicity of the counterion. In the case of
acetate, proton loss leading to 16 is fast. Failure of 9 to
undergo cyclization in the presence of PdCl2 can be
understood in terms of an unfavorable equilibrium for the
initial complexation of Pd(II). Failure of 10 and 11 under-
scores the critical role played by the enol ether. The
stereochemical outcome in the case of 1j and 1k is consistent
with attack of the enol ether anti to the palladium.
Figure 1. Cross-conjugated cyclopentenones. All reactions were
performed with 20 mol % Pd(OAc)2 in DMSO under an oxygen
atmosphere at 80 °C for 24 h. Numbers in parentheses correspond
to the yield of crude product. Crude product was obtained by
evaporating the DMSO at 80 °C/1 mm Hg, dissolving the residue
in toluene, filtering to remove solids, and stirring overnight at 80
°C with activated carbon.
During our survey of reaction conditions for the Pd(OAc)2-
catalyzed reaction, PPh3 was used as an additive. In the
presence of a small molar excess of palladium and 0.5 equiv
of PPh3, the major reaction product (39% yield) from 1a
was 18, in which the exocyclic alkene unexpectedly bears
an (E)-phenyl substituent (Scheme 4). Exposure of 12a to
the same reaction conditions led to 18 in 44% yield, which
suggests that the phenyl group was transferred from PPh3.
Insertion of palladium into the phosphorus-carbon bond of
triarylphosphines is uncommon.10
during purification, since the yield of crude products was
much higher (see Figure 1, 12a, 12d, and 12i). Many cross-
conjugated cyclopentenones can be made from allenes;
however, the products in Figure 1 cannot be made from
allenes, since they are unsubstituted at the â endocyclic
carbon atom. Moreover, the preparation of 12e through our
allene chemistry7 would be very challenging, at best.
The observations suggest the mechanistic scheme that is
summarized for 1a (Scheme 3). Although the Nazarov
In summary, two variants of a Pd(II)-catalyzed Nazarov
cyclization have been described. The reaction takes place
under mild conditions and, in the case of the PdCl2-catalyzed
Scheme 3
Org. Lett., Vol. 5, No. 26, 2003
4929

additional C-C bonds through cascade processes involving
the intermediate palladium enolate.
Scheme 4a
Acknowledgment. We thank the National Institutes of
Health (GM57873) for generous support and Professor Dirk
Trauner for sharing his results with us.
a Conditions: 1.1 equiv of Pd(OAc)2, 0.5 equiv of PPh3, acetone,
3 days, rt.
Note Added after ASAP Posting. Conditions a and b of
the abstract and TOC graphic were interchanged in the
version posted ASAP November 25, 2003; the corrected
version was posted December 3, 2003.
process, with high efficiency. The reaction offers opportuni-
ties for asymmetric catalysis and for the formation of
(7) Tius, M. A. Acc. Chem. Res. 2003, 36, 284-290.
Supporting Information Available: General procedures
for the synthesis of 1a-l, 2a-l, 12a, 12b, 12d, 12e, 12i,
(8) Hegedus, L. S. Transition Metals. In Synthesis of Complex Organic
Molecules; University Science Books: Sausalito, 1999; Chapter 7.
(9) R-Diketone 3, the product of enol ether hydrolysis, is the only
significant byproduct of these reactions.
1
and 18; H and 13C NMR data for 1a-l; and spectroscopic
1
(10) (a) Kong, K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113, 6313-
6315. (b) O’Keefe, D. F.; Dannock, M. C.; Marcuccio, S. M. Tetrahedron
Lett. 1992, 33, 6679-6680. (c) Segelstein, B. E.; Butler, T. W.; Cherard,
B. L. J. Org. Chem. 1995, 12, 12-13. (d) Moiseev, I. I.; Kozitsyna, N. Y.;
Kochubey, D. I.; Kolomijchuk, V. N.; Zamaraev, K. I. J. Organomet. Chem.
1993, 451, 231-241. (e) Morita, D. K.; Stille, J. K.; Norton, J. R. J. Am.
Chem. Soc. 1995, 117, 8576-8581.
data and reproductions of H NMR spectra for 2a-l, 12a,
12b, 12d, 12e, 12i, 18. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL036017E
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Org. Lett., Vol. 5, No. 26, 2003