C. J. Simpson et al. / Tetrahedron Letters 46 (2005) 6893–6896
Table 3. Variation of the ratio of catalyst to substrate
6895
Table 2. Solvent variationa
Solvent
Products observedb
Ratio of starting material
to piperidine
Time (h)
Products
observeda
Reflux
50 ꢁC
Styrene
Styrene
Acid
Styrene
Acid
Acid
1:0.0
1:0.1
1:0.5
1:1
1:5
1:10
4
4
4
4
4
3
0
14
58
100
100
100
100
86
42
0
0
0
Toluene
Pyridine
Water
Acetonitrile
THF
100
100
33
0
0
0
67
100
100
0
0
0
0
0
100
100
100
100
100
0
a The reaction conditions described are for the initial Knoevenagel
addition conditions. The work-up for all reactions followed solvent
removal in vacuo in the presence of toluene at 30–40 ꢁC.
a As a percentage of total product observed in the reaction. Analyses of
reactions were carried out using the 1H NMR spectra of crude
products. Product ratios were obtained from comparative integration
of the protons furthest downfield in the exocyclic double bonds of the
a,b-unsaturated carboxylic acid and vinylphenol.
b As a percentage of total product observed in the reaction. Analyses of
reactions were carried out using the 1H NMR spectra of crude
products. Product ratios were obtained from comparative integration
of the protons furthest downfield in the exocyclic double bonds of the
a,b-unsaturated carboxylic acid and vinylphenol.
Table 4. Variation of base in the reactiona
Base
Starting material
Products observedb
trans-cinnamic acid in this reaction. In this case, it is
quite likely that formation of the ortho-quinone methide
is less easy than formation of the para-quinone methide.
In the latter reaction, the formation of products from
competing side reactions was not observed.
Styrene
Acid
HO
DBU
100
0
O
7
MeO
The effect of solvent on the reaction was also investi-
gated (Table 2). It was found that whilst the preparation
of 4-hydroxy-3-methoxy vinylphenol 9 from 4-hydroxy-
3-methoxy benzaldehyde 7 was effective using toluene,
water or pyridine during the Knoevenagel condensation,
the only observed product from the reaction performed
in acetonitrile or tetrahydrofuran was the corresponding
a,b-unsaturated monocarboxylic acid 8. In addition, the
only product observed when the condensation reaction
was performed at 50 ꢁC was the carboxylic acid 8
regardless of the solvent used.
MeO
DBU
0
100
O
HO
HO
TEA
TEA
40.5
0
59.5
100
O
7
MeO
MeO
O
HO
a The ratio of base to aldehyde in each reaction was 1:1.
b As a percentage of total product observed in the reaction. Analyses of
reactions were carried out using the 1H NMR spectra of crude
products. Product ratios were obtained from comparative integration
of the protons furthest downfield in the exocyclic double bonds of the
a,b-unsaturated carboxylic acid and vinylphenol.
As stated, in the presence of 1ꢁ and 2ꢁ amines, the reac-
tion proceeds via the Knoevenagel mechanism.4 In their
absence, the transformation is known to proceed via the
Hann–Lapworth mechanism with the development of a
b-hydroxy intermediate generated directly from the
aldehyde.6,7 However, under conditions that favour the
Knoevenagel mechanism, the Hann–Lapworth mecha-
nism may also compete.7
ables the phenolic oxygen to participate in elimination
of the hydroxyl function through the generation of a
quinone methide. Decarboxylation then proceeds read-
ily to give the corresponding vinylphenol.
In order to investigate the effect of piperidine on the
reaction, a study on the variation of the ratio of catalyst
to substrate was performed (Table 3). From these
results, it is apparent that the piperidine catalyst is
critical for vinylphenol formation under these reaction
conditions and that a Hann–Lapworth mechanism inter-
mediate does not enable a secondary decarboxylation.
To evaluate the scope of this reaction, a range of alter-
native substrates was utilised. In these investigations,
both 4-hydroxybenzophenone and 3-thiophene carbox-
aldehyde gave only the a,b-unsaturated monocarboxylic
acid as a product. On the other hand, trace amounts of
isoeugenol were detected by NMR analysis of reactions
performed with vanillin 7 and methyl malonic acid.
Nonetheless, it was discovered that if a strong hindered
base, such as DBU or TEA, is substituted for piperidine
in the reaction, then a secondary decarboxylation
affording the corresponding vinylphenol was observed
(Table 4). Again, the formation of the corresponding
vinylphenol was only achieved if the substrate was 4-
hydroxybenzaldehyde. In this case, the reaction interme-
diate must necessarily be a b-hydroxy carboxylic acid.
This strongly suggests that a strong hindered base en-
Common methods for the synthesis of vinylphenols
utilise the enzymic decarboxylation8 of trans-cinnamic
acids, the synthetic decarboxylation of trans-cinnamic
acids at elevated temperature in the presence of a metal,9
Grignard addition9 to an aldehyde, Wittig synthesis10 or
the catalytic dehydrogenation11 of ethyl phenols. More-
over, in at least two of these reactions, prior protection
of the phenolic oxygen is generally required.