Influence of Michael acceptor stereochemistry on intramolecular Morita-Baylis-Hillman reactions

Article abstract of DOI:10.1021/jo051802l

A study of the effect of Michael acceptor stereochemistry on the efficiency of intramolecular Morita-Baylis-Hillman (MBH) reactions has been performed. The reactions were catalyzed by a phosphine, and the reaction substrates studied were enones containing

Full text of DOI:10.1021/jo051802l

media.5 We have had a longstanding interest in this reaction,6
especially versions in which N-sulfonated imines are used as
the electrophile,7 and the use of polymer-supported reagents to
catalyze them.8 While hundreds of reports have described
intermolecular MBH reactions, examples of intramolecular
MBH9-19 and related Rauhut-Currier reactions20,21 are very few
(Figure 1).
Influence of Michael Acceptor Stereochemistry
on Intramolecular Morita-Baylis-Hillman
Reactions
Wen-Dong Teng,† Rui Huang,† Cathy Kar-Wing Kwong,‡
Min Shi,*,† and Patrick H. Toy*,‡
Perhaps one reason for the limited number of examples of
intramolecular MBH reactions in the literature is the sensitivity
of MBH reactions in general to steric effects at the â-position
of the Michael acceptor. It has been reported that, when a
â-subsituent is present, either high pressure or microwave
irradiation is necessary for the desired reaction to occur.22,23 In
most intermolecular MBH reactions, the conjugated electrophile
is unsubstituted at this position. Therefore, when the reaction
is rendered intramolecular by tethering of the electrophile to
the Michael acceptor at its â-position (Figure 1, Type A
reaction), it can be expected that the reaction would be relatively
inefficient.9-16 However, when the electrophile is attached to
the Michael acceptor at its carbonyl center (Figure 1, Type B
reaction), no such steric hindrance occurs.17-19
School of Chemistry & Pharmaceutics, East China UniVersity of
Science and Technology, 130 Meilong Road, Shanghai 200237,
People’s Republic of China, and Department of Chemistry,
The UniVersity of Hong Kong, Pokfulam Road,
Hong Kong, People’s Republic of China
mshi@pub.sioc.ac.cn; phtoy@hku.hk
ReceiVed August 26, 2005
(1) (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653-
4670. (b) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52,
8001-8062. (c) Ciganek, E. Org. React. 1997, 51, 201-350. (d) Langer,
P. Angew. Chem., Int. Ed. 2000, 39, 3049-3052. (e) Kim, J. N.; Lee, K.
Y. Curr. Org. Chem. 2002, 6, 627-645. (f) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. ReV. 2003, 103, 811-892.
A study of the effect of Michael acceptor stereochemistry
on the efficiency of intramolecular Morita-Baylis-Hillman
(MBH) reactions has been performed. The reactions were
catalyzed by a phosphine, and the reaction substrates studied
were enones containing a pendant aldehyde moiety attached
at the â-position of the alkene group. In all cases examined
with PPh3 as the catalyst, cyclization substrates possessing
(Z)-alkene stereochemistry afforded a much higher yield of
the desired product than did the E isomeric substrates under
identical reaction conditions. This was also true when a
polymer-supported phosphine catalyst was used. While both
alkene isomers afforded the same product, in parallel
reactions, the Z isomer afforded 2.5-8.5 times higher yield
than did the corresponding E isomer. It is proposed that steric
effects are a possible source of this dramatic difference in
reactivity. Substrates where the â-substituent is cis to the
electron-withdrawing substituent are relatively more acces-
sible to react with the nucleophile catalyst than are their trans
counterparts. These findings are expected to be useful in the
design of synthetic intermediates, as intramolecular MBH
reactions are being increasingly used in the preparation of
complex synthetic targets.
(2) For a review of phosphine organocatalysis that includes a section
regarding MBH and Rauhut-Currier reactions, see: Methot, J. L.; Roush,
W. R. AdV. Synth. Catal. 2004, 346, 1035-1050.
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3790-3800 and references therein.
The Morita-Baylis-Hillman (MBH) reaction has become
an important tool in organic synthesis, since it allows for the
formation of densely functionalized carbon-carbon bonds under
mild, organocatalytic reaction conditions (Figure 1).1,2 While
early versions of this reaction were marked by some irrepro-
ducible results and long reaction times, recent years have seen
much advancement in the understanding of its mechanism3 and
the identification of highly efficient catalysts4 and reaction
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† East China University of Science and Technology.
‡ The University of Hong Kong.
10.1021/jo051802l CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/22/2005
368
J. Org. Chem. 2006, 71, 368-371

SCHEME 1
SCHEME 2
FIGURE 1. Representative intramolecular Morita-Baylis-Hillman
reactions.
During a survey of the literature we noted that despite the
potential importance of substrate stereochemical effects in
intramolecular MBH reactions, no analysis of the effect of the
Michael acceptor alkene stereochemistry on the reaction rate
of Type A reactions has been performed. Perhaps this is due to
the fact that both E and Z isomers of the starting material afford
the same cyclized product and, thus, ease of synthesis prevailed
in determining substrate stereochemistry. In all reports, the
cyclization precursors only possessed (E)-alkene stereochem-
istry. This is due to the fact that most of the reported
intramolecular MBH reaction substrates studied were prepared
by the Wittig reaction of an aldehyde with a stabilized
phosphorus ylide to form the Michael acceptor moiety. One
notable exception to this is the work by Koo et al., where the
cyclization substrates were prepared by oxidative cleavage of
vicinal diols.14 Under the reaction conditions used, the initially
formed Z isomers 1 rearranged to the corresponding E isomers
2 (Scheme 1). In their work, only E isomers 2 were subjected
to intramolecular MBH reactions, and they observed that
optimized reaction conditions for formation of 3 involved the
use of a stoichiometric amount of PPh3 as the catalyst in t-BuOH
at room temperature.
Considering the importance of intermolecular MBH reactions
and the potential power of intramolecular versions for preparing
densely functionalized cyclic structures, we sought to fill the
gap in the literature and determine what role, if any, Michael
acceptor stereochemistry has in determining the outcome of such
intramolecular MBH reactions. Herein we report the results of
comparative studies in which reactions of isomerically pure E
and Z ω-formyl R,â-unsaturated carbonyl compounds were
subjected to nucleophilic phosphine catalysis under identical
reaction conditions to form the corresponding intramolecular
MBH adduct and in which the isolated yields were used to judge
the efficiency of the reactions.
The methodology reported by Koo et al.14 was used to prepare
separable mixtures of cyclization substrates 1a-f and 2a-f from
2-cyclohexene-1-one (4) (Scheme 2). Treatment of 4 with Pb-
(OAc)4 in refluxing toluene afforded 6-acetoxy-2-cyclohexene-
1-one (5).24 Reaction of 5 with greater than 2 equiv of the
appropriate Grignard reagent, either alkyl or aryl, resulted in
simultaneous acetate cleavage and 1,2-addition to the ketone
group to afford 6a-f. Controlled oxidative cleavage of the
vicinal diol groups of 6a-f with Pb(OAc)4 afforded mixtures
of 1a-f and 2a-f. As noted previously, it was important to
control the duration of these oxidative cleavage reactions in
order to ensure that both E and Z isomers were present in the
isolated product mixture. By limiting the reaction times to
approximately 15 min, it was possible to obtain 1:2 ratios
ranging from 1.9:1 to 9.7:1 (see Table 1 in the Supporting
Information). If the reactions were allowed to continue for too
long, only 2a-f were recovered. Regardless of the mixture
composition, 1 and 2 were easily separable by silica gel column
(14) Yeo, J. E.; Yang, X.; Kim, H. J.; Koo, S. Chem. Commun. 2004,
236-237.
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10169.
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2002, 124, 2404-2405. (b) Mergott, D. J.; Frank, S. A.; Roush, W. R.
Org. Lett. 2002, 4, 3157-3160. (c) Methot, J. L.; Roush, W. R. Org. Lett.
2003, 5, 4223-4226.
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(b) Bertenshaw, S.; Kahn, M. Tetrahedron Lett. 1989, 30, 2731-2732. (c)
van Rozendaal, E. L. M.; Voss, B. M. W.; Scheeren, H. W. Tetrahedron
1993, 49, 6931-6936. (d) Kundu, M. K.; Mukherjee, S. B.; Balu, N.;
Padmakumar, R.; Bhat, S. V. Synlett 1994, 444. (e) Jenner, G. Tetrahedron
Lett. 2000, 41, 3091-3094.
(23) When N-sulfonated arylimines are used as electrophiles, MBH
reactions of trans-â-substituted enones take place in moderate yields at room
temperature: Shi, Y.-L.; Xu, Y.-M.; Shi, M. AdV. Synth. Catal. 2004, 346,
1220-1230.
(24) Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1978, 43, 1599-
1602.
J. Org. Chem, Vol. 71, No. 1, 2006 369

TABLE 1. Intramolecular MBH Reaction Results
entry
substrate
solvent
concn (M)
temp (°C)
time (h)
product
yield (%)a
1
2
3
4
5
6
7
8
1a, R ) Et
t-BuOH
t-BuOH
CH3CN
CH3CN
t-BuOH
t-BuOH
CH3CN
CH3CN
t-BuOH
t-BuOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
t-BuOH
t-BuOH
CH3CN
CH3CN
CH3CN
CH3CN
DCEb
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.1
0.05
0.1
0.05
0.1
0.1
0.1
40
40
40
40
40
40
60
60
48
48
24
24
32
32
12
12
96
96
72
72
72
72
24
36
72
72
72
72
48
48
3a
3a
3a
3a
3b
3b
3c
3c
3c
3c
3d
3d
3e
3e
3f
72
12
59
12
69
13
69
8
2a, R ) Et
1a, R ) Et
2a, R ) Et
1b, R ) Bu
2b, R ) Bu
1c, R ) Ph
room temp
room temp
room temp
room temp
room temp
room temp
room temp
room temp
room temp
room temp
40
room temp
room temp
40
room temp
40
2c, R ) Ph
9
1c, R ) Ph
55
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2c, R ) Ph
1d, R ) C6H4-4-Cl
2d, R ) C6H4-4-Cl
1e, R ) C6H4-3-Me
2e, R ) C6H4-3-Me
1f, R ) C6H4-4-Me
2f, R ) C6H4-4-Me
1b, R ) Bu
55
15
50
21
54
17
79
66
50
69
48
59
43c
10c
3f
3b
3b
3e
3e
3f
3f
3c
3c
1b, R ) Bu
1e, R ) C6H4-3-Me
1e, R ) C6H4-3-Me
1f, R ) C6H4-4-Me
1f, R ) C6H4-4-Me
1c, R ) Ph
room temp
room temp
2c, R ) Ph
DCE
a Isolated yield. b DCE ) 1,2-dichloroethane. c JandaJel-PPh3 (1 equiv) was used as the catalyst.
SCHEME 3
that, for a limited number of substrates, changing the reaction
solvent from CH3CN to t-BuOH or changing the reaction
temperature did not appear to dramatically affect reaction yields.
The results of these comparative reactions are summarized in
Table 1. It should be noted again that the reactions of 2a-f
were stopped when the corresponding reaction with 1a-f was
complete, so that the yields afforded under identical conditions
could be compared. Thus, in addition to the desired product
3a-f, and small amounts of undesired byproducts, much
unreacted 2a-f remained in these reactions. Furthermore, it
should also be noted that, in the reactions of 1a-f, trace amounts
of 2a-f were detected by thin-layer chromatography, but no
2a-f to 1a-f isomerization appeared to have occurred in the
reactions of 2a-f.
It is clearly evident from the data that, in all cases, the Z
isomer 1 exhibited much greater reactivity than did the E isomer
2 under the reaction conditions used and PPh3 was a better
catalyst than PBu3, as might have been expected14 (see Table 2
in the Supporting Information). Furthermore, the choice of
solvent did not dramatically influence the product distribution
(entries 1-4 and 7-10). The greatest reactivity disparity was
exhibited by substrates 1c and 2c, containing vinyl phenyl ketone
moieties, where 1c afforded more than 8.5 times the amount of
the desired product 3c than did substrate 2c (entries 7 and 8).
Substrates giving the most similar yields were the pairs 1d and
2d, 1e and 2e, and 1f and 2f, where the Z isomers only afforded
approximately 2.5-3.7 times the amount of desired product
3d-f than did the E isomers (entries 11-16). The vinyl alkyl
ketone substrate pairs 1a and 2a and 1b and 2b exhibited
intermediate differences in reactivity with their yield ratios
ranging from 6.0 to 4.9 (entries 1-6).
chromatography. The relatively modest product yields obtained
(39-66%) were a result of the inherent propensity of these
compounds to decompose on standing to form polar side
products.
With the reaction substrates in hand, we compared reaction
yields afforded by 1a-f and 2a-f under identical reaction
conditions (Scheme 3). The parallel intramolecular MBH
reactions comparing 1a to 2a, 1b to 2b, etc. were performed
using 1 equiv of PPh3 catalyst at 0.1 M concentration in either
t-BuOH or CH3CN at 40 °C or room temperature for the
indicated time, since these are the conditions previously reported
to be optimal for such reactions.14 Both of the reactions were
stopped when all of the starting material 1a-f had completely
disappeared, as determined by TLC analysis. These reaction
conditions are similar to those used previously, where t-BuOH
at slightly elevated temperature was the solvent for the alkyl-
substituted substrates and room temperature CH3CN was used
for substrates containing aryl substituents;14 however, we found
370 J. Org. Chem., Vol. 71, No. 1, 2006

We also examined the effect of substrate concentration for
representative examples of Z isomers 1. For example, when the
concentration for cyclization of 1b was doubled to 0.2 M, the
yield somewhat surprisingly increased slightly to 79% from 69%
at 0.1 M (entry 17). It might be expected that increasing substrate
concentration for such an intramolecular cyclization reaction
would lower, not increase, the yield as bimolecular reactions
become more favored. On the other hand, as expected, lowering
the temperature for the cyclization of 1b from 40 °C to room
temperature meant a longer reaction time was necessary for
complete disappearance of 1b (entry 18). For substrates 1e and
1f, lowering the concentration from 0.1 to 0.05 M did not have
any appreciable influence on reaction yield or time (entries 19
and 21). However, increasing the reaction temperature from
room temperature to 40 °C increased the yield of 3e from 1e
from 50% to 69% (entry 20) but did not significantly affect the
yield of 3f from 1f (entry 22). Regardless of the various changes
in reaction conditions, the pattern of Z substrate affording much
more product than did the corresponding E substrate held true.
Considering that a full 1 equiv of the catalyst was necessary
for all of the reactions of 1a-f to go to completion in a
reasonable amount of time, they are ideally suited for the use
of an easy to remove polymer-supported phosphine catalyst.25
Thus, polystyrene cross-linked with 1,4-bis(4-vinylphenoxy)-
butane26 functionalized by triphenylphosphine groups (JandaJel-
PPh3, 1.0 mmol of P/g)27 was used to catalyze the cyclization
reactions of 1c and 2c in 1,2-dichloroethane, a good swelling
solvent for this polymeric reagent, since this reagent/solvent
combination has previously produced good results in related
intermolecular aza-MBH reactions (entries 23 and 24).8b The
use of a polymer-supported catalyst in these reactions greatly
simplified product isolation, as it was removed at the end of
the reactions by simple filtration. Therefore, chromatographic
removal of 1 equiv of PPh3 was not necessary. While the yield
ratio between 1c and 2c obtained in these reactions dropped
compared to the ratio when PPh3 was the catalyst (4.3:1 vs 8.5:
1), it remained consistent with the entirety of the data, in that
1c afforded much more 3c than did 2c.
FIGURE 2. Steric effects in type A intramolecular MBH reactions.
reactions with acyclic â-substituted Michael acceptors. While
the success of these intramolecular reactions is at least due in
part to entropic factors, it seems reasonable to expect that alkene
stereochemistry should influence their efficiency to some extent.
Therefore, a better understanding of the stereochemical effects
on such reactions should increase their applicability and utility.
On the basis of current understanding of the mechanism of
the MBH reaction, the initial step of the process is nucleophilic
addition of the catalyst to the â-position of the Michael acceptor.
In the cases of the different alkene isomers 1 and 2, this results
in the zwitterionic intermediates 7a and/or 7b (Scheme 3), which
cyclize to eventually form the desired product 3. One reasonable
explanation for the observed differences in reactivity between
the E and Z isomers of the reaction substrates in this study is
that the initial nucleophilic attack by the phosphine catalyst is
relatively more hindered in the cases of the E isomers compared
to the Z isomers (Figure 2). Another possible source for the
different rates of reaction of 1 and 2 is that depending on their
preferred conformation (s-cis or s-trans), they may preferentially
form enolate 7a or 7b and that these two reactive species have
substantially different nucleophilic reactivities, resulting in the
observed lower reaction rates for the E isomers 2.
In conclusion, we have observed that dramatic differences
in reactivity exist between alkene isomers in intramolecular
MBH reactions. The Z isomers uniformly afford more desired
product than did the corresponding E isomers in identical
reactions, and we believe that the basis for this difference in
reactivity is either the relative accessibility of the â-positions
of the Michael acceptors to the nucleophile catalyst or a
difference in reactivity of potentially different enolate reactive
intermediates. These findings should improve the utility of the
intramolecular MBH reaction for the synthesis of complex cyclic
structures by guiding the design of the cyclization substrates.
It is striking to note that, considering the large amount of
research dedicated to understanding and exploiting the MBH
reaction, no analysis regarding Michael acceptor stereochemistry
and its effect on reaction efficiency had been previously
performed. However, a survey of the literature reveals that only
few examples of intermolecular MBH reactions with acyclic
â-substituted Michael acceptors such as crotononitrile and
methyl methacrylate have been reported,22,23 while a large body
of literature exists describing the use of cyclic alkenenones
(predominantly five- and six-membered rings) in such reac-
tions.28 In fact, even the number of reported intramolecular MBH
reactions of Type A far surpasses that of intermolecular MBH
Acknowledgment. This research was supported financially
by the University of Hong Kong, the Research Grants Council
of the Hong Kong Special Administrative Region, People’s
Republic of China (Project No. HKU 7027/03P), the State Key
Project of Basic Research (Project 973, No. G2000048007), the
Shanghai Municipal Committee of Science and Technology, and
the National Natural Science Foundation of China (Nos.
20025206, 203900502, and 20272069).
Supporting Information Available: Text, tables, and figures
1
giving experimental details, characterization data, and H and 13C
(25) For a review of polymer-supported organocatalysis, see: Benaglia,
M.; Puglisi, A.; Cozzi, F. Chem. ReV. 2003, 103, 3401-3430.
(26) (a) Toy, P. H.; Janda, K. D. Tetrahedron Lett. 1999, 40, 6329-
6332. (b) Toy, P. H.; Reger, T. S.; Garibay, P.; Garno, J. C.; Malikayil, J.
A.; Liu, G.-Y.; Janda, K. D. J. Comb. Chem. 2001, 3, 117-124. (c) Choi,
M. K. W.; Toy, P. H. Tetrahedron 2004, 60, 2903-2907.
(27) (a) Choi, M. K. W.; He, H. S.; Toy, P. H. J. Org. Chem. 2003, 68,
9831-9834. (b) Harned, A. M.; He, H. S.; Toy, P. H.; Flynn, D. L.; Hanson,
P. R. J. Am. Chem. Soc. 2005, 127, 52-53.
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051802L
(28) In addition to refs 4a-d and 5c, for representative examples of
intermolecular MBH reactions where cycloalkenenones are used as the
Michael acceptor, see the Supporting Information.
J. Org. Chem, Vol. 71, No. 1, 2006 371