Published on Web 02/26/2002
The Vinylogous Intramolecular Morita-Baylis-Hillman Reaction: Synthesis
of Functionalized Cyclopentenes and Cyclohexenes with Trialkylphosphines
as Nucleophilic Catalysts
Scott A. Frank, Dustin J. Mergott, and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
Received September 20, 2001; Revised Manuscript Received January 10, 2002
The Morita-Baylis-Hillman (MBH) reaction involves the
R-hydroxyalkylation and R-aminoalkylation of Michael acceptors
by electrophilic carbonyl compounds or imines in the presence of
a nucleophilic catalyst such as a tertiary amine or phosphine.1-5
Surprisingly, there have been relatively few applications of this
technology to cyclization processes.6-9 We are also unaware of
examples of a potentially important variant, which we term the
vinylogous intramolecular Morita-Baylis-Hillman reaction, in
which an R,â-unsaturated carbonyl compound serves as a Michael
acceptor in the electrophile capture step (see 1 f 2 or 3 f 4). It
is known that acrylates and enones will dimerize under MBH
reaction conditions,10-13 and that enones can be R-alkylated in a
Michael reaction with acrylates and acrylonitrile in the presence
of DBU at 185 °C.14 Ring closing reactions are known that proceed
via 1,4-addition of organometallic and heteronucleophilic reagents
to enones or enoates such as 1 and 3, with subsequent addition of
the initial enolate to the second Michael acceptor.15-17 Lithium
amides and thiolates have been used to initiate such cyclizations;
however, the nucleophiles remain covalently attached in the
cyclization products.18,19 In principle, a subsequent elimination step
could be employed to access the targeted unsaturated ring systems
2 and 4.9 The advantages of using a nucleophilic catalyst to effect
cyclizations of 1 f 2 and 3 f 4 under mild conditions are readily
apparent. We report herein the first examples of the vinylogous
intramolecular Morita-Baylis-Hillman reaction for the synthesis
of substituted cyclopentenes and cyclohexenes 2 and 4.
suffered under these conditions (compare entries 1-2 and 6-7),
presumably as a consequence of competitive bimolecular reactions
of 1a.
Results of the Me3P-catalyzed cyclizations of 1c-e, 5, and 6
are summarized in Table 1. Substrates 1c-e underwent efficient
cyclizations under conditions closely resembling those developed
for 1a. However, it was necessary to use CH2Cl2 as the solvent to
achieve efficient cyclization of 1c; the competitive aldol cyclization
of the product 2c that was observed in tert-amyl alcohol was
suppressed in CH2Cl2 (entries 8 and 9). It also proved necessary to
perform the cyclization of enal-enoate 1e at 0.01 M, owing
presumably to the tendency of 1e to self-condense in the presence
of Me3P at higher concentrations. In all cases, the major product
resulted from a sequence in which the phosphine catalyst added to
the most electrophilic of the two Michael acceptors, with the less
electrophilic unsaturated carbonyl system serving as the Michael
acceptor for the ring-closing step. This regioselectivity was also
observed in the Me3P-promoted cyclizations of 5, in which case
the â,â-disubstituted enoate served as the electrophilic acceptor for
the ring closure step with establishment of a quaternary center in
product 7, and of 6 where the vinylogous ester served as the
acceptor unit for the Michael cyclization. Finally, the Bu3P-
catalyzed cyclization reaction of bis-enal 9 proceeded in excellent
yield with synthetically useful diastereoselectivity.16
Initial studies were performed with enone-enoate 1b as the
substrate (see Supporting Information). Amine nucleophiles such
as DABCO, DBU, Et2NH, and DMAP, which are commonly
employed in the traditional Morita-Baylis-Hillman reaction, were
ineffective in promoting the cyclization of 1b in solvents such as
THF, MeOH, and CH2Cl2 at temperatures from ambient to 65 °C.
Similarly, stoichiometric Ph3P (CH2Cl2, 23 °C) gave no reaction
with 1b, while use of 0.25 equiv of (c-Hex)3P gave only 15%
conversion to 2b over a 6 h period. Ultimately, we found that
excellent results were obtained by using catalytic amounts of Bu3P
in CH3CN or, better still, Me3P in tert-amyl alcohol (Table 1). A
direct comparison of these catalysts and conditions with 1a as the
substrate (Table 1, entries 1-7) demonstrated that 0.1 equiv of Me3P
in tert-amyl alcohol was optimal, a combination that provided 2a
in 95% yield with 97:3 regioselectivity (entry 6). Reactions
catalyzed by Me3P were faster in tert-amyl alcohol than in
CH3CN (entries 4 and 6).20 While the cyclizations were also faster
when performed at higher reaction concentrations, the efficiency
Applications of this methodology to the cyclization of substituted
heptadienes 3a-d and 11 are summarized in Table 2. Typically
0.25-1.0 equiv of the phosphine catalyst was required for these
reactions to proceed at reasonable rates. While 3a-b (entries 1-3),
3d (entries 6,7), and 11 (entry 8) cyclized in moderate to good
yields, cyclization of 3c was less productive (entries 4,5) owing to
its tendency to undergo bimolecular coupling reactions, as well as
the propensity of the product 4c to undergo an intramolecular aldol
9
2404 VOL. 124, NO. 11, 2002 J. AM. CHEM. SOC.
10.1021/ja017123j CCC: $22.00 © 2002 American Chemical Society
Frank, Scott A.
