Organomediated Morita-Baylis-Hillman cyclization reactions

Article abstract of DOI:10.1021/ja052146+

We have developed the Morita-Baylis-Hillman reaction to include, for the first time in a completely organomediated process, intramolecular examples bearing allylic leaving groups as the electrophilic partner providing a facile, high yielding, straightforw

Full text of DOI:10.1021/ja052146+

Published on Web 07/02/2005
Organomediated Morita-Baylis-Hillman Cyclization Reactions
Marie E. Krafft* and Thomas F. N. Haxell
Department of Chemistry and Biochemistry, Florida State UniVersity, Tallahassee, Florida 32306
Received April 4, 2005; E-mail: mek@chem.fsu.edu
Continuing development in synthetic organic chemistry relies
DABCO, quinuclidine, DBU, and DMAP, which are commonly
employed in the traditional Morita-Baylis-Hillman coupling, were
found to be ineffective at promoting cyclization of either tosylate
5 or mesylate 6 in solvents, such as THF, 1,4-dioxane, acetone,
EtOAc, CHCl3, CH3CN, MeOH, EtOH, t-BuOH, and amyl-OH at
temperatures from ambient to 63 °C. Accordingly, various tertiary
phosphines, such as Bu3P, Cy3P, Ph3P, and Me3P, also traditional
nucleophilic catalysts for the Morita-Baylis-Hillman reaction,9
were investigated. We found that Bu3P provided the cyclization
adduct 8 in moderate yield from either tosylate 5 or mesylate 6 (eq
2). Optimal yields were obtained using mesylate 6 at ambient
temperature, providing cyclic enone 8 in 40% yield within 5 h.
Noting that a base might facilitate the process, a variety of bases
were screened, including Et3N, EtNiPr2, DBU, NaH, KH, NaOMe,
t-BuOK, NaOH and KOH in THF, t-BuOH, or MeOH, but despite
these additional attempts at optimization, we were unable to improve
on this initial result.
on discovering new, high yielding, selective reactions. The Morita-
Baylis-Hillman reaction, originating from both German1 and
Japanese2 patents, is an organocatalytic reaction involving coupling
of the R-position of activated alkenes with carbonyl electrophiles
under the catalytic influence of a nucleophilic species, providing a
simple and convenient method for the synthesis of interesting
densely functionalized molecules.3 Over the last two decades, the
intermolecular Morita-Baylis-Hillman (MBH) reaction has seen
tremendous development of all three components and now encom-
passes a wide range of activated alkenes, electrophiles, and
nucleophilic catalysts. However, there has been significantly less
research into the intramolecular Morita-Baylis-Hillman reaction.4,5
While a variety of electrophiles, aldehydes, R-keto esters, 1,2-
diketones, and aldimine derivatives have been studied extensively
in this valuable carbon-carbon bond-forming reaction, the direct
organomediated application of allylic electrophiles in the Morita-
Baylis-Hillman reaction has not been thoroughly investigated.
Basavaiah has demonstrated the use of ethyl 2-bromomethyl acrylate
in an intermolecular allylation to generate 1,4-pentadienes.6 Using
primary allylic carbonates, Krische has cleverly blended organo-
mediated and transition metal-catalyzed reactions in an enone
cycloallylation reaction generating monosubstituted alkenes.7
Herein, we now report a new intramolecular variant of the
Morita-Baylis-Hillman reaction which, for the first time, encom-
passes allylic leaving groups as the electrophilic partner in a
completely organomediated process (eq 1). Both mono- and
disubstituted alkenes are readily generated in this reaction. Initial
studies evaluated the effectiveness of different leaving groups and
organocatalysts. Primary allylic alcohols 1-4 were selected as initial
test substrates and were readily prepared in good overall yield
beginning from 4-pentenal or 5-hexenal (Scheme 1). Due to
At this point, we turned our attention to changing the leaving
group to chloride. It was discovered that, upon treatment with 1
equiv of Bu3P in t-BuOH (0.5 M) and similar screening of bases,
chloride 7 gave an impressive 80% isolated yield of the desired
cyclization adduct 8 when KOH was used as the base under phase
transfer conditions with BnEt3NCl (entry 1, Table 1).11
To gain insight into the mechanism of this interesting reaction,
two reactions were performed using primary and secondary allylic
chlorides 12 and 13, respectively. These were each treated with 1
equiv of Bu3P in t-BuOH under the same conditions as the
cyclization reactions. After 5 h, a 90% recovery of each allylic
chloride was obtained, discounting the possibility of initial direct
SN2 attack of the phosphine at the allylic chloride moiety to give
a phosphonium salt which could also serve as a leaving group (eq
3).
Scheme 1. Synthesis of Allylic Alcohols 1-4
problems with low conversions, it was necessary to use the allylic
acetate rather than the allylic alcohol for better results in the alkene
cross-metathesis reaction.
To further probe the scope of this transformation, we tested the
tolerance of the organomediated cyclization to structural alterations
at both the enone and allyl moieties. Both aryl enones and sterically
more encumbered alkyl enones readily underwent the Morita-
Baylis-Hillman cyclization (entries 2 and 3, Table 1). Given these
results, we set out to evaluate the tolerance of the cyclization toward
substitution at the allylic leaving group. Consequently, a series of
secondary alcohols (14-17) was synthesized.
Our early efforts then focused on the reactions of allylic
mesylates and tosylates.8 Use of amine nucleophiles, such as
9
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10.1021/ja052146+ CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Organomediated Cyclizationsa
We then turned our attention to the generation of six-membered
rings in the cyclization event. Thus, subjecting alcohols 4 and 17
(entries 7 and 8, Table 1) to the optimized cyclization conditions
(Bu3P, t-BuOH, CH2Cl2, KOH, BnEt3NCl) gave enones 11 and 23
also in excellent yield.
In summary, we have successfully developed a novel, entirely
organomediated one-pot convenient method for the synthesis of
densely functionalized cyclic enones via the use of an alternative
electrophile in the Morita-Baylis-Hillman reaction. This reaction
tolerates modification of the enone and the use of primary and
secondary allylic chlorides and generates both five- and six-
membered rings in excellent yields. Both mono- and disubstituted
alkenes are formed with excellent selectivity in the absence of a
transition metal catalyst. Further studies will focus on related
transformations, changes in the electrophilic partner, and substitu-
tions on the tether.
Acknowledgment. This work was supported by the NSF and
the MDS Research Foundation.
Supporting Information Available: Experimental and analytical
data for allylic alcohols and enones (1H NMR, 13C NMR, IR, HRMS,
CHN) (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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a Regioisomeric mixtures of allylic chlorides. b Isolated yields after
purification by silica gel chromatography. c Me3P was used.
Conversion of alcohol 14 to the desired allylic chloride 18 using
methanesulfonyl chloride resulted in a regioisomeric mixture (10:
1) in favor of chloride isomer 18 (eq 4). Changing the chlorinating
agent to SOCl2, unfortunately, gave a 1:2 ratio in favor of
regioisomer 19. Remarkably, however, subjecting either regioiso-
meric mixture of allylic chlorides to the optimized cyclization
conditions gave the desired cyclization product 20 (entry 4, Table
1) in 78% yield under equivalent reaction conditions. From a
practical standpoint, preparation of the chloride using SOCl2 became
the method of choice. These secondary alcohols also tolerated other
alkyl groups alpha to the enone without reduction in yield (entries
5 and 6). At this point, we cannot speculate whether the allylic
isomers are interconverting under the reaction conditions or if SN2′
and SN2 mechanisms are operative. Given the result described in
eq 3, allylic isomerization is not likely since no isomerization was
observed in the control experiment. Thus, direct displacement of
the secondary halide under the mild reaction conditions remains a
viable option. However, the presence of SN1 character in the bond-
forming step cannot be ruled out and is still under investigation.
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(11) Typical procedure: To SOCl2 (2 equiv) in Et2O (0.1 M) at ambient
temperature was added dropwise over 5 min a 0.1 M Et2O solution of the
alcohol with pyridine (2 equiv). After stirring for 20 min, the Et2O layer
was washed with saturated NaHCO3(aq), dried over Na2SO4, and
concentrated in vacuo to provide the crude allylic chloride, which was
used without further purification. PBu3 (100 mol %) was then added to a
0.5 M solution of the allylic chloride in tert-butyl alcohol, and the mixture
was allowed to stir at room temperature until complete consumption of
starting material (TLC), at which point CH2Cl2-H2O (1:1) was added to
the mixture followed by addition of KOH (200 mol %) and BnEt3NCl
(10 mol %) and stirred until complete (2 h).
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