Overcoming the limitations of the Morita-Baylis-Hillman reaction: A rapid and general synthesis of ?±-alkenyl-?2-hydroxy thioesters

Article abstract of DOI:10.1021/ol801896q

(Equation Presented) Acryloyl chlorides, aldehydes, and PhSLi undergo a direct aldol cascade sequence in the presence of MgBr₂-OEt ₂ via in situ derived thioester enolates, which is followed by oxidative elimination to give ?±-alkenyl-?2-hydroxy thioesters. Overall, the procedure is rapid, efficient, and generally applicable, even to ?2-substituted acryloyl chlorides, thus providing an alternative to the Morita-Baylis-Hillman reaction with substantially greater synthetic scope and utility. ? 2008 American Chemical Society.

Full text of DOI:10.1021/ol801896q

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4819-4822
Overcoming the Limitations of the
Morita-Baylis-Hillman Reaction: A
Rapid and General Synthesis of
r-Alkenyl-ꢀ′-hydroxy Thioesters
Emily Tarsis, Anna Gromova, Daniel Lim, Guoqiang Zhou, and Don M. Coltart*
Department of Chemistry, Duke UniVersity, Durham, North Carolina 27708
don.coltart@duke.edu
Received August 13, 2008
ABSTRACT
Acryloyl chlorides, aldehydes, and PhSLi undergo a direct aldol cascade sequence in the presence of MgBr2·OEt2 via in situ derived thioester
enolates, which is followed by oxidative elimination to give r-alkenyl-ꢀ′-hydroxy thioesters. Overall, the procedure is rapid, efficient, and
generally applicable, even to ꢀ-substituted acryloyl chlorides, thus providing an alternative to the Morita-Baylis-Hillman reaction with
substantially greater synthetic scope and utility.
The Morita-Baylis-Hillman (MBH) reaction enables straight-
forward access to R-alkenyl-ꢀ′-hydroxy carbonyl compounds
from aldehydes and R,ꢀ-unsaturated carbonyls.1,2 These
products are useful synthetic intermediates due to their
multifunctional composition and, consequently, have been
elaborated into a variety of natural products and related
compounds.2,3 The MBH reaction has been the subject of
extensive methodological studies. Despite this, it remains for
the most part remarkably slow, requiring up to days or even
weeks for completion, depending on the nature of the
substrates used.2 Furthermore, reaction yields are often quite
low, and it is by no means a general process, as it has
scarcely been reported in the context of ꢀ-substituted R,ꢀ-
unsaturated carbonyl species.2 Several modifications to this
reaction have been investigated in an effort to overcome these
shortcomings, including the use of Lewis acids,2 microwave
irradiation,4 high pressure,5,6 high temperature and ultra-
sound,7 and aqueous media.8 While some progress has been
made toward an improved MBH reaction, no general solution
exists and reaction rates and yields remain highly variable
and often low. Herein, we report an alternative approach to
the preparation of MBH adducts that is rapid, efficient, and
generally applicable, even to ꢀ-substituted R,ꢀ-unsaturated
compounds.
We recently reported an operationally simple MgBr2·OEt2-
promoted four-component, direct aldol addition between
aldehydes and a thioester enolate, obtained by conjugate
addition of lithium thiophenolate to an in situ-formed R,ꢀ-
(1) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41,
2815. Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972.
Baylis, A. B.; Hillman, M. E. D. Chem. Abstr. 1972, 77, 3417q
(2) Basavaiah, D.; Anumolu, J. R.; Satyanarayana, T. Chem. ReV. 2003,
103, 811–891
.
(4) Kundu, M. K.; Mukherjee, S. B.; Balu, N.; Padmakumar, R.; Bhat,
.
S. V. Synlett 1994, 444.
(3) See, for example: Krishna, P. R.; Narsingam, M.; Kannan, V.
Tetrahedron Lett. 2004, 45, 4773–4775. Mergott, D. J.; Frank, S. A.; Roush,
W. R. P. Natl. Acad. Sci. U.S.A. 2004, 101, 11955–11959. Trost, B. M.;
Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2002, 124, 11616–11617.
Brzezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997, 119,
4317–4318. Brzezinski, L. J.; Rafel, S.; Leahy, J. W. Tetrahedron 1997,
(5) Hill, J. S.; Isaacs, N. S. Tetrahedron Lett. 1986, 27, 5007–5010.
(6) Schuurman, R. J. W.; v. d. Linden, A.; Grimbergen, R. P. R.; Nolte,
R. J. M; Scheeren, H. W. Tetrahedron 1996, 52, 8307–8314
(7) Roos, G. H. P.; Rampersadh, P. Synth. Commun. 1993, 23, 1261–
1266.
(8) Auge´, J.; Lubin, N.; Lubineau, A. Tetrahedron Lett. 1994, 35, 7947–
7948.
.
53, 16423–16434
.
10.1021/ol801896q CCC: $40.75
Published on Web 10/10/2008
2008 American Chemical Society

Scheme 1
.
Proposed Four-Component Direct Aldol Addition/
Oxidative Elimination Sequence
Scheme 2
.
Studies on the Stepwise Aldol Addition, Oxidation,
and Elimination Sequence
unsaturated thioester (cf. Scheme 1, 1 f 4).9 The effective-
ness of this process stems from the highly nucleophilic nature
of thiolates in forming the requisite magnesium enolates,
coupled with the rapid addition of these species to alde-
hydes.10 Given the pronounced nucleophilicity of thiolates,
we reasoned that the scope of the coupling could be extended
to R,ꢀ-unsaturated carbonyl species having ꢀ-substituents.
If this were indeed the case, then we could potentially
connect this feature with the straightforward and rapid
oxidative elimination of thioethers (4 f 5),11 thereby
developing a two-step procedure that is formally equivalent
to the MBH reaction, yet potentially consistently high-
yielding, rapid, and most notably, general in scope.12 While
overall this approach would introduce the requirement of an
oxidation step, the resulting decrease in the duration of the
reaction and increase in scope would more than compensate
for the additional step.
Table 1. Studies on the Oxidative Elimination of 8 to 10
The aldol intermediates in this transformation (cf. 4)
contain a free alcohol and possess divalent sulfur in the form
of both a thioester and thioether. Consequently, chemose-
lective oxidation would be required during regeneration of
the R,ꢀ-unsaturation, and this would need to be managed in
such a way that the retro-aldol reaction would be suppressed.
Selective oxidation was not expected to be overly problem-
atic since the sulfur atom in the thioester is considerably
less nucleophilic than in the thioether. Furthermore, provided
that the oxidation conditions used were suitably mild, the
retro-aldol reaction should be avoidable.
a Determined by 1H NMR. b Compound 8 was treated with m-CPBA in
CH2Cl2 for 30 min, the solvent was evaporated, PhMe was added, and the
mixture was refluxed for 30 min. n.a. ) not applicable.
We began our exploration of the thiolate-promoted oxida-
tive MBH reaction by determining if the thioether function
could indeed be oxidized without competing side reactions.
To do this, compound 8 was prepared from acryloyl chloride,
benzaldehyde, and lithium thiophenolate using our previously
established method.9 Gratifyingly, when this compound was
treated with m-CPBA, the desired mono-oxidation product
(9) was obtained as a mixture of diastereomers, with neither
overoxidation of the thioester nor the retro-aldol reaction
detected (Scheme 2).13 On heating, the desired elimination
product was readily obtained in excellent yield (9 f 10). In
total, the process required 1.5 h of reaction time and gave a
(9) Zhou, G.; Yost, J. M.; Sauer, S.; Coltart, D. M. Org. Lett. 2007, 22,
4663–4665.
(10) Yost, J. M.; Zhou, G.; Coltart, D. M. Org. Lett, 2006, 8, 1503–
1506. Zhou, G.; Yost, J. M.; Coltart, D. M. Synthesis 2007, 478–482.
(11) For related applications of this strategy, see: Danishefsky, S. J.;
Armistead, D. M.; Wincott, F. E.; Selnick, H. G.; Hungate, R. J. Am. Chem.
Soc. 1987, 109, 8117–8119. Danishefsky, S. J.; Armistead, D. M. Tetra-
hedron Lett. 1987, 28, 4959–4962. Itoh, A.; Ozawa, S.; Oshima, K.; Nozaki,
H. Bull. Chem. Soc. Jpn. 1981, 54, 274–278. Itoh, A.; Ozawa, S.; Oshima,
K.; Nozaki, H. Tetrahedron Lett. 1980, 21, 361–364.
(12) For applications of R,ꢀ-unsaturated thioesters in MBH-like pro-
cesses, see, for example: Pei, W.; Wei, H.-X.; Li, G. Chem. Commun. 2002,
1856–1857. Kataoka, T.; Iwama, T.; Kinoshita, H.; Tsujiyama, S.-i.;
Tsurukami, Y.; Iwamura, T.; Watanabe, S.-i. Synlett 1999, 197–198.
(13) The corresponding sulfone (11) was obtained from this reaction in
7% yield due to the presence of a slight excess of m-CPBA.
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Org. Lett., Vol. 10, No. 21, 2008

Table 2. Four-Component Direct Aldol Addition Reaction and Oxidative-Elimination Sequence
a n.a. ) not applicable.
76% overall yield. By comparison, the Baylis-Hillman
reaction between methyl acrylate and benzaldehyde con-
ducted neat using DABCO as the catalyst has been reported
to give 39% yield of 12 after 6 days.14-16
To simplify the oxidative-elimination process, we set out
to develop a direct, one-pot protocol to circumvent isolation
and purification of the sulfoxide intermediate. Thus, a variety
of oxidizing conditions were surveyed using compound 8
Org. Lett., Vol. 10, No. 21, 2008
4821

as a model substrate (Table 1). Use of NaIO4 gave only
modest yields of the desired elimination product in standard
solvents (entries 1-3), and when MeOH was used a
considerable amount of the SfO acyl transfer product was
obtained (entry 1). Oxone proved to be an effective oxidant
for the transformation, providing a very good yield of the
desired product (entries 4 and 5), as did m-CPBA (entries 6
and 7), which gave even better yields.
Having developed effective conditions for the oxidative-
elimination sequence, we examined the scope of the four-
component aldol addition reaction further. This was done
using a variety of aldehydes and R,ꢀ-unsaturated acid
chlorides (Table 2), in addition to those that we had examined
previously (entries 1-5).9 The four-component direct aldol
addition proved very general and provided the desired
products in a reasonably short period of time (30 min to 2 h),
with both electron-rich and electron-poor aldehydes. Hin-
dered R-disubstituted aldehydes were also amenable to the
cascade sequence and gave very good product yields (entries
3 and 4). Notably, as we had hoped, the thiolate-promoted
aldol addition reaction proceeded effectively even in the case
of the ꢀ-substituted R,ꢀ-unsaturated acid chloride, crotonoyl
chloride (entries 7-9). An especially interesting example
appears in entry 9 where a hindered R-disubstituted aldehyde
and a ꢀ-substituted R,ꢀ-unsaturated acid chloride gave the
desired aldol product in good yield. The success of the aldol
addition in these hindered systems prompted us to examine
the ꢀ-disubstituted system, 3-methylbutenoyl chloride (entry
10), but the reaction was not successful with this very
hindered system.
Lastly, we undertook the conversion of the aldol addition
products into the corresponding R-alkenyl-ꢀ′-hydroxy thioesters
using the oxidative-elimination protocol developed above.
We were pleased to find that this transformation also proved
both general and reliable (Table 2). In all cases, the
elimination product was produced in very good to excellent
yield, within only 30 min. Entries 7-9 are especially
noteworthy as the products obtained equate to MBH cou-
plings that would be extremely difficult, if not impossible,
to achieve under conventional conditions.
In conclusion, we have developed a reliable, practical, and
general alternative to the MBH reaction that provides
straightforward access to R-alkenyl-ꢀ′-hydroxy thioesters.
Unlike the traditional MBH reaction, this procedure is
consistently rapid and high yielding and is amenable to the
use of both electron-rich and electron-poor aldehydes.
Moreover, it can be applied in situations involving both
sterically hindered aldehydes and ꢀ-substituted R,ꢀ-unsatur-
ated acid chlorides, thus providing access to structures that
would be difficult or impossible to generate using conven-
tional MBH reaction conditions.
Acknowledgment. E.M.T. and G.Z. hold C. R. Hauser
Fellowships (Department of Chemistry, Duke University);
D.L. holds a Burroughs Wellcome Fellowship (Department
of Chemistry, Duke University).
(14) Perlmutter, P.; Puniani, E.; Westman, G. Tetrahedron Lett. 1996,
37, 1715–1718.
(15) Recently, the same transformation has been reported to give 85%
yield after 3 days, although details of the reaction conditions used were
not given. See: Deng, J.; Hu, X.-P.; Huang, J.-D.; Yu, S.-B.; Wang, D.-Y.;
Duan, Z.-C.; Zheng, Z. J. Org. Chem. 2008, 73, 2015–2017.
(16) The Baylis-Hillman reaction of S-phenyl thioacrylate has been
reported to proceed extremely slowly and/or give numerous byproduct with
various aldehydes. See: Shi, M.; Li, C.-Q.; Jiang, J.-K. HelV. Chim. Acta
2002, 85, 1051–1057.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801896Q
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