Reaction of Baylis-Hillman products with Swern and Dess-Martin oxidants

Article abstract of DOI:10.1016/S0040-4039(01)00587-1

The Baylis-Hillman adducts of aryl aldehydes and alkyl acrylates are efficiently oxidized to the corresponding α-methylene-β-keto esters with the Dess-Martin periodinane. The attempted Swern oxidation of the same adducts resulted in S_N2′-type substitution of the allylic hydroxyl group by chloride.

Full text of DOI:10.1016/S0040-4039(01)00587-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3939–3941
Reaction of Baylis–Hillman products with Swern and
Dess–Martin oxidants
Nicholas J. Lawrence,a,* J. Paul Crump,b,c Alan T. McGownb and John A. Hadfieldb
aDepartment of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
bCRC Department of Drug Development and Imaging, Paterson Institute for Cancer Research, Christie Hospital NHS Trust,
Wilmslow Road, Manchester M20 4BX, UK
cDepartment of Chemistry, UMIST, PO Box 88, Manchester M60 1QD, UK
Received 22 March 2001; accepted 6 April 2001
Abstract—The Baylis–Hillman adducts of aryl aldehydes and alkyl acrylates are efficiently oxidized to the corresponding
a-methylene-b-keto esters with the Dess–Martin periodinane. The attempted Swern oxidation of the same adducts resulted in
SN2%-type substitution of the allylic hydroxyl group by chloride. © 2001 Elsevier Science Ltd. All rights reserved.
The Baylis–Hillman1 reaction provides an effective
method for the synthesis of functionalized allylic alco-
hols.2 The reaction is characterized by the simple con-
version of an aldehyde and an activated alkene, usually
an acrylate, into an allylic alcohol, under mild condi-
tions by the action of an appropriate nucleophilic cata-
lyst (e.g. 1“2) (Scheme 1). The reaction, first
documented in 1972 continues to attract great atten-
tion. Improvements to the breadth, scope, yield and
selectivity of the reaction are regularly reported.3–6 The
closely associated functionality present in the product
alcohols 2 accompanied by their rich chemistry com-
bines to provide potentially important synthetic build-
ing blocks.
agents. Ketones of type 3 (Scheme 1) represented an
important target, since possessing a doubly activated
alkene they are highly electrophilic. We report herein
some surprising aspects of the synthesis of these a-
methylene-b-keto esters.
The desired allylic alcohols 2 were obtained using previ-
ously reported conditions for the Baylis–Hillman reac-
tion (Table 1) with either DABCO™ or DBU as the
catalyst. In general the reaction proceeded well for
Table 1.
Ar
R
Yield 2 (%)
Yield 4 (%)
Our interest in new electrophilic anticancer agents7
prompted us to investigate the biological activity of
a,b-unsaturated carbonyl compounds derived from the
Baylis–Hillman reaction. The ability of similar a,b-
unsaturated carbonyl derivatives, such as sesquiterpene
a-methylene lactones, to act as biological alkylating
agents is well documented.8 We therefore developed a
program to investigate the use of Baylis–Hillman
adducts and selected derivatives as potential alkylating
a
b
c
Ph
Ph
2-ClC6H4
4-MeC6H4
Me
Et
Et
84a
76a
64b
73b
58
66
70
62
d
Et
a DBU (1 equiv.), methyl or ethyl acrylate (1 equiv.), ArCHO (1
equiv.), rt, overnight (Ref. 5)
b DABCO™ (0.5 equiv.), ethyl acrylate (2 equiv.), ArCHO (1 equiv.),
rt (1–7 days) (Ref. 13).
OH
O
O
O
O
ArCHO
[O]
Ar
OR
Ar
OR
OR
Nu
1
2
3
Scheme 1.
* Corresponding author. Tel.: +44-29-2087-4000, ext. 7109; fax: +44-29-2087-4030; e-mail: lawrencenj1@cardiff.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00587-1

3940
N. J. Lawrence et al. / Tetrahedron Letters 42 (2001) 3939–3941
good electrophiles, and still worthy of biological study.
The adduct 2e, derived from terephthalaldehyde gave
the bisallylic chloride 4e, which we hoped would act as
a biological cross-linking agent (Scheme 3).
benzaldehydes possessing electron-withdrawing sub-
stituents, as is usual for the Baylis–Hillman reaction.
This suited our requirements, since these types of aryl
groups should ultimately give rise to enones of type 3
that are highly electrophilic.
The product clearly arises from a substitution pathway
probably after the alcohol has been activated by the
Swern reagent system. The alkoxy(dimethyl)sulfonium
We first chose to oxidize the alcohol 2a by using the
Swern reaction.9 The Swern reaction has been used to
successfully oxidize many simple and complex allylic
alcohols.10,11 The alcohol was treated with a mixture of
DMSO and oxalyl chloride at −60°C in the usual
manner (Scheme 1). However, it was clear that the
oxidation had not proceeded as expected. The isotope
pattern of the molecular ion in the mass spectrum
revealed that chlorine had been incorporated into the
salt
5
formed from
2
by the action of the
chlorodimethylsulfonium chloride, must be highly sus-
ceptible to attack by chloride ion as indicated in
Scheme 4. This substitution process may occur via a
simple SN2% mechanism. However, the Swern oxidation
of the related alcohols of type 7 occurs in the normal
way without competing substitution.11 To emphasize
the influence of the ester group the mechanism is drawn
as a sequential conjugate addition/elimination process
via the enolate 6. Allylic chlorides of type 4 have also
been obtained from Baylis–Hillman adducts by other
reagents which transform the hydroxyl into a nucleo-
fuge in the presence of chloride.12,14 It is interesting to
note that the Corey–Kim15 reaction of alcohols of type
1, in which the aryl group has been replaced by an alkyl
group, with NCS/Me2S generate the allylic chloride
analogous to 4.16 This supports the general mechanism
shown in Scheme 4.
1
product. The key H NMR diagnostic signals (l 4.55
ppm, 2H, singlet; l 7.94 ppm, 1H, singlet) indicated
that the product was actually the allylic chloride Z-
4a.12 The reaction is highly stereoselective; no other
1
isomer was detectable in the H NMR spectrum. The
substitution process is not unique to 1a. Other sub-
strates were also subjected to the conditions of the
Swern reaction and also yielded the corresponding
allylic chloride (Table 1 and Schemes 2 and 3). It is
interesting to note that substitution products 4 are also
O
OH
O
1. DMSO, oxalyl chloride
Ar
OR
Ar
OR
2. Et3N
2
4
Cl
Scheme 2.
O
OH
O
O
O
Cl
OEt
1. DMSO, oxalyl chloride
2. NEt3
H
OEt
OEt
DABCO
EtO
H
EtO
Cl
O
OH
O
O
2e
4e
Scheme 3.
O
S
Me
S+
Me
S+
Cl
Me
Me
OH
O
-HCl
Me
O
O
Cl
Me
Ar
and
O
OR
Ar
OR
Cl
Cl
2
5
O
Cl
Me
S+
O
Me
O
O
OH
Ar
OR
alkyl
Ar
OR
Ar
Cl
7
4
6
Cl
Scheme 4.

N. J. Lawrence et al. / Tetrahedron Letters 42 (2001) 3939–3941
3941
Table 2. Oxidation of Baylis–Hillman adducts 2 with the
Dess–Martin periodinane
5. Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311–
2312.
6. Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem.
Commun. 1998, 2533–2534.
Ar
R
Yield 2 (%)
Yield 2“3 (%)
7. Lawrence, N. J.; McGown, A. T.; Nduka, J.; Hadfield, J.
A.; Pritchard, R. G. Bioorg. Med. Chem. Lett. 2001, 11,
429–431.
8. (a) Beekman, A. C.; Woerdenbag, H. J.; van Uden, W.;
Pras, N.; Konings, A. W. T.; Wikstro¨m, H. V.; Schmidt,
T. J. J. Nat. Prod. 1997, 60, 252–257; (b) Picman, A. K.
Biochem. Syst. Ecol. 1986, 14, 255–281; (c) Schmidt, T. J.
Curr. Org. Chem. 1999, 3, 577–608.
a
b
c
d
f
Ph
Ph
Me
Et
Et
Et
Et
See Table 1
See Table 1
See Table 1
See Table 1
86a
84
78
71
67
63
64
51
2-ClC6H4
4-MeC6H4
3,4-F2C6H3
4-FC6H4
4-(CF3)C6H4
g
h
Me
Me
78a
72a
a DABCO™ (0.5 equiv.), ethyl or methyl acrylate (2 equiv.), ArCHO
(1 equiv.), rt (1–7 days) (Ref. 13).
9. (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185; (b)
Tidwell, T. T. Synthesis 1990, 857870; (c) Tidwell, T. T.
Org. React. (NY) 1990, 39, 297–572.
The successful oxidation of Baylis–Hillman adducts has
been achieved by Hoffmann and co-workers17 using
Jones reagent. However we were concerned that trace
toxic chromium-containing residues might possibly com-
plicate the subsequent assessment of the cytotoxicity of
the ketones and sought an alternative reagent. The
Dess–Martin periodinane is often used when a mild,
selective oxidant is required (Table 2).18 Significantly for
us it has been used to effect the synthesis of a-methylene-
cycloalkanones from the corresponding alcohol.19 We
soon found that the reagent met our requirements and
was able to efficiently transform the Baylis–Hillman
adducts into the desired a-methylene-b-keto esters.
Clearly the reaction mixture does not contain a species
sufficiently nucleophilic to react with the product.
10. (a) Cambie, R. C.; Hay, M. P.; Larsen, L.; Rickard, C. E.
F.; Rutledge, P. S.; Woodgate, P. D. Aust. J. Chem. 1991,
44, 821–842; (b) Trost, B. M.; Matelich, M. C. J. Am.
Chem. Soc. 1991, 113, 9007–9009; (c) Bhaskar, K. V.; Chu,
W.-L. A.; Gaskin, P. A.; Mander, L. N.; Murofushi, N.;
Pearce, D. W.; Pharis, R. P.; Takahashi, N.; Yamaguchi,
I. Tetrahedron Lett. 1991, 32, 6203–6206; (d) Castellaro, S.
J.; MacMillan, J.; Willis, C. L. J. Chem. Soc., Perkin Trans.
1 1991, 2999–3004.
11. (a) Atkinson, R. S.; Ulukanli, S.; Williams, P. J. J. Chem.
Soc., Perkin Trans. 1 1999, 2121–2128; (b) Barnhart, R. W.;
Wang, X.; Noheda, P.; Bergens, S. H.; Whelan, J.; Bosnich,
B. J. Am. Chem. Soc. 1994, 116, 1821–1830.
12. Yuasa, Y.; Yuasa, Y.; Tsuruta, H. Aust. J. Chem. 1998, 51,
511–514.
13. Fort, Y.; Berthe, M.-C.; Caube`re, P. Synth. Commun. 1992,
22, 1265–1275.
In conclusion we have shown that Baylis–Hillman
adducts are efficiently oxidized by the Dess–Martin
periodinane but not by DMSO/oxalyl chloride. The
biological activity of the ketones 3 and the unintentional
series of allylic chlorides 4 will be reported in due course.
14. (a) Chavan, S. P.; Ethiraj, K. S.; Kamat, S. K. Tetrahedron
Lett. 1997, 38, 7415–7416; (b) McFadden, H. G.; Harris,
R. L. N.; Jenkins, C. L. D. Aust. J. Chem. 1989, 42,
301–314; (c) Ameer, F.; Drewes, S. E.; Houston-McMillan,
M. S.; Kaye, P. T. J. Chem. Soc., Perkin Trans. 1 1985,
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Acknowledgements
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1991, 124, 2475–2480.
18. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287; (b) Boeckman, Jr., R. J. In Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.;
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141–152.
We thank the EPSRC and AstraZeneca (CASE) for a
studentship (to J.P.C.) and for Research Grants (GR/
L52246: NMR spectrometer; GR/L84391: chromato-
graphic equipment) and the Chemical Database Service
at Daresbury.20 We thank the Cancer Research Cam-
paign for additional support.
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