Novel application of phosphonium salts as co-catalysts for the Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.tetlet.2004.07.155

Excellent yields have been obtained when the Baylis-Hillman reaction is conducted in the presence of phosphonium salts.

Full text of DOI:10.1016/j.tetlet.2004.07.155

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7359–7361
Novel application of phosphonium salts as co-catalysts for the
Baylis–Hillman reaction
Claire L. Johnson, Rachel E. Donkor, Wafaa Nawaz and Nazira Karodia*
Chemical and Forensic Sciences, School of Life Sciences, University of Bradford, Bradford, W. Yorkshire BD7 1DP, UK
Received 4 May 2004; revised 20 July 2004; accepted 30 July 2004
Available online 23 August 2004
Abstract—Excellent yields have been obtained when the Baylis–Hillman reaction is conducted in the presence of phosphonium salts.
Ó 2004 Elsevier Ltd. All rights reserved.
The Baylis–Hillman reaction is an elegant route to
multifunctional products. The reaction traditionally
involves the coupling of an unsaturated carbonyl com-
pound with aldehydes; it is catalysed by tertiary amines.1
The key limitation of the reaction is the slow reaction
rate, which entails prolonged reaction times. There have
been a number of substantial contributions to improving
the reaction rates including the use of phosphines as cat-
alysts, addition of Lewis acids, high pressure, ultrasound
and microwave irradiation.2 Modest improvements in
reaction rates and yields have been reported in the pres-
ence of water (hydrophobic effects); or fluorinated sol-
vents (fluorophobic effects) and the presence of
hydrogen bond donors in the reagents used.2 The in-
crease in the rate in the latter case can be attributed to
either stabilisation of intermediate 1 (Scheme 1) or acti-
vation of the aldehyde. Recently, imidazolium-based
ionic liquids have been used as solvents for the Baylis–
Hillman reaction, with moderate success.3,4 Aggarwal
et al. have subsequently shown that these solvents are
not inert.4
O
OH
O
OMe
Ph
OMe
NR3
MeO
Ph
NR3
O
O
1
O
Ph
R3N
OMe
RDS
O
H
Scheme 1. Reaction of methyl acrylate with benzaldehyde.
The reaction conditions were selected so that meaningful
comparisons could be made with literature data. Initial
reactions using methyl acrylate, benzaldehyde, DABCO
(50mol%) and ethyltri-n-butylphosphonium tosylate,
[Bu3P+Et]ÀOTs, (50mol%) as the co-catalyst showed
that the presence of the phosphonium salt caused an
increase in the yields; no side products were observed.
In refining the method it was discovered that the amount
of phosphonium salt could be decreased to 10mol%
without a detrimental effect on the yield of the product
and subsequent reactions were performed with this re-
duced amount.8 The yield (92%) (Table 1, entry 3) is
an improvement over the neat reaction (entry 1) and is
superior to that obtained (65%) in the imidazolium ionic
liquid, [bmim][PF6].3 Next we evaluated the effects of
changing the groups on phosphorus and varying the
anion. The excellent yields were maintained irrespective
of the groups on phosphorus. For example, only a small
increase in yield was obtained on changing from the
We have found that phosphonium tosylates are effective
ionic solvents for hydroformylation reactions,5 hydro-
gen transfer reactions6 and Diels–Alder reactions.7 This
success prompted us to explore the use of phosphonium
tosylates as co-catalysts for the Baylis–Hillman reaction.
Like the Aggarwal group we believed that their high
polarity would provide a higher concentration of the
zwitterionic intermediate aza-enolate 1, therefore facili-
tating the reaction.
*
Corresponding author. E-mail: n.karodia@bradford.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.155

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C. L. Johnson et al. / Tetrahedron Letters 45 (2004) 7359–7361
Table 1. Baylis–Hillman reactions with phosphonium salts as co-
catalysts
anisaldehydes (entires 10–11). The aliphatic aldehyde,
isobutyraldehyde, gave a yield of 97% (entry 15), which
is superior to the yield obtained in the conventional
reaction.
Entry
Aldehyde
[R3P+R1] XÀ
Neat
Yield (%)
1
2Benzaldehyde
Benzaldehyde
68a
65a
92
95
92
95
97
95
95
95
[Bmim][PF
]
6
[Bu3P+Et]ÀOTs
[Ph3P+Et]ÀOTs
[Bu3P+Et]ÀOMs
[Ph3P+Et]ÀOMs
[Bu3P+Et]BrÀ
[Ph3P+Et]BrÀ
[Bu3P+Et]IÀ
In view of the results obtained with the phosphonium
salt/DABCO system, we explored the utility of the reac-
tion with the other activated alkenes traditionally used
in this reaction. The conventional reaction with acrylate
esters requires lengthy reaction times, for example, the
reaction of ethyl acrylate and benzaldehyde requires
seven days to produce a reasonable yield of the Bay-
lis–Hillman adduct, and the same reaction with t-butyl
acrylate affords 65% yield after 28days.9 Excellent yields
were obtained using our reaction conditions with acryl-
ate esters (Table 3, entries 1–3) and a 35% yield (entry 4)
was obtained for the t-butyl analogue after 24h. Acrylo-
nitrile gave a quantitative yield; surprisingly, however, a
low yield was obtained with methyl vinyl ketone (entry
5). The yields for the reactions with t-butyl acrylate
and methyl vinyl ketone improve when the reactions
are continued for a longer time. No product was isolated
for the reactions with phenyl vinyl sulfone and diethyl
vinyl phosphonate (entries 6–7).
3
Benzaldehyde
Benzaldehyde
4
5
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
6
7
8
9
10
[Ph3P+Et]IÀ
Reactions conducted on a 5.0mmol scale using a ratio of 1:1.1:0.5:0.1
of aldehyde:methyl acrylate:DABCO:phosphonium salt at room tem-
perature for 24h.
a 100% DABCO3.
tetraalkyl salt, [Bu3P+Et]ÀOTs, to the triarylalkyl salt,
[Ph3P+Et]ÀOTs (entry 4). Changing the anion to the
mesylate, bromide or iodide did not affect the yield
(entries 5–10).
Lewis acids have been reported to be efficient co-cata-
lysts for the reaction. We selected Cu(OTf)2, Zn(OTf)2,
Sc(OTf)3 and LiClO4 and found that they had a detri-
mental effect on the yields. This trend was also observed
for the reactions performed in the presence of imidazo-
lium salts.3,4
The phosphonium salt could perform a number of roles
in the reaction; it can be involved in activating the alk-
ene, activating the aldehyde and in stabilising the zwit-
terionic intermediate 1.10 Also, it is puzzling that the
combination of DABCO/phosphonium salt/Lewis acid
additive has a detrimental effect on the reaction.
In order to investigate the generality of the DABCO/
phosphonium salt catalytic system, a series of aldehydes
was investigated. The results are displayed in Table 2.
The trend for the methyl-substituted benzaldehydes
(entries 1–3) is similar to that observed previously; a
poor yield was obtained for 2-methylbenzaldehyde
(31%) and moderate yields were obtained for the 3-
and 4-methylbenzaldehydes (entries 2–3). Excellent
yields were obtained for the 3- and 4-fluoro-, 4-bromo
and 4-chlorobenzaldehydes (entries 4–8). Disappoint-
ingly, no success was observed for the highly deactivated
There are some limitations in the use of the phospho-
nium salt/DABCO catalytic system, for example, poor
yields with the anisaldehydes, and we are currently con-
ducting further experiments that could address these
problems and explain the mechanism of the reaction.
In conclusion, this study demonstrates the use of an
attractive (readily available, stable and cheap) alterna-
tive co-catalyst for the Baylis–Hillman reaction. In addi-
tion, the practical procedure for the phosphonium salt/
DABCO catalysed reaction is straightforward; there is
no need for special precautions such as an inert atmos-
phere or dry reagents.
Table 2. Reactions of methyl acrylate with aldehydes
Entry Aldehyde
AdditiveÀ
Yield (%)
1 2-Methylbenzaldehyde
23-Methylbenzaldehyde
[Bu3P+Et]ÀOTs 31
3P+Et]ÀOTs 64
[Bu
[Bu3P+Et]ÀOTs 56
[Bu3P+Et]ÀOTs 99
[Bu3P+Et]ÀOTs 86
[Bu3P+Et]ÀOTs 99
[Bu3P+Et]ÀOTs 96
[Bu3P+Et]ÀOTs 96
[Bu3P+Et]ÀOTs 96
[Bu3P+Et]ÀOTs <1
Table 3. Reactions of benzaldehydes with activated alkenes
3
4-Methylbenzaldehyde
4
3-Fluorobenzaldehyde
4-Fluorobenzaldehyde
2-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
4-Nitrobenzaldehyde
2-Anisaldehyde
Entry Alkene
Additive
Yield (%)
5
1
2Ethyl acrylate
Methyl acrylate
[Bu3P+Et]ÀOTs 88
3P+Et]ÀOTs 90
[Bu3P+Et]ÀOTs 80
[Bu3P+Et]ÀOTs 35
[Bu3P+Et]ÀOTs 100
[Bu3P+Et]ÀOTs 35
[Bu3P+Et]ÀOTs 0a
6
[Bu
7
3
4
5
6
7
8
n-Butyl acrylate
t-Butyl acrylate
8
9
Acrylonitrile
Methyl vinyl ketone
Phenyl vinyl sulfone
Diethyl vinyl phosphonate [Bu3P+Et]ÀOTs 0a
10
11
12
13
14
15
15
16
4-Anisaldehyde
trans-Cinnamaldehyde
[Bu3P+Et]ÀOTs
2
[Bu3P+Et]ÀOTs 58
[Bu3P+Et]ÀOTs 95
[Bu3P+Et]ÀOTs 95
4-Pyridinecarboxaldehyde
2-Furaldehyde
Cyclohexanecarboxaldehyde [Bu3P+Et]ÀOTs 20
Reactions conducted on a 5.0mmol scale using a ratio of 1:1.1:0.5:0.1
of aldehyde:acrylate:DABCO:phosphonium salt at room temperature
for 24h.
a Only unreacted starting materials were isolated.
Butylaldehyde
Isobutyraldehyde
[Bu3P+Et]ÀOTs 97
[Bu3P+Et]ÀOTs 58
Reactions conducted on a 5.0mmol scale using a ratio of 1:1.1:0.5:0.1
of aldehyde:methyl acrylate:DABCO:phosphonium salt at room tem-
perature for 24h.
We thank the Nuffield Foundation and the University of
Bradford for financial support for this work, and Pro-

C. L. Johnson et al. / Tetrahedron Letters 45 (2004) 7359–7361
7361
6. Comyns, C.; Karodia, N.; Zeler, S.; Andersen, J. Catal.
Lett. 2000, 67, 113.
fessor Aggarwal (Bristol University) for helpful
suggestions.
7. Ludley, P.; Karodia, N. Tetrahedron Lett. 2001, 42,
2011; Ludley, P.; Karodia, N. ARKIVOC, 2002, 172.
8. Illustrative procedure: benzaldehyde (5mmol) and methyl
acrylate (5.5mmol) were added to a round-bottomed flask
containing the phosphonium salt (0.5mmol) and DABCO
(2.5mmol). The flask was stoppered and the mixture was
stirred at room temperature for 24h. The mixture was
diluted with dichloromethane (10cm3) and washed suc-
cessively with aq HCl (2M), NaOH, (2M) and water. The
organic phase was dried and concentrated. The residue
was purified by flash chromatography (ethyl acetate/
hexane, 1:3) to give methyl 3-hydroxy-2-methylidene-3-
phenylpropionate. The spectra for all the compounds were
compared with the literature data.
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