Preparation of vinylphenols from 2- and 4-hydroxybenzaldehydes

Article abstract of DOI:10.1016/j.tetlet.2005.08.011

A straightforward, high-yielding procedure has been developed for the manufacture of substituted vinylphenols from 2- and 4-hydroxybenzaldehydes utilising classical Knoevenagel condensation reaction conditions.

Full text of DOI:10.1016/j.tetlet.2005.08.011

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6893–6896
Preparation of vinylphenols from 2- and 4-hydroxybenzaldehydes
Carol J. Simpson,b Matthew J. Fitzhenrya and N. Patrick J. Stamforda,b,
*
aOrganic Synthesis Centre, School of Chemistry F11, University of Sydney, Sydney 2006, Australia
bSchool of Chemical Sciences, University of East Anglia, Norwich NR4 7TJ, UK
Received 1 June 2005; revised 28 July 2005; accepted 2 August 2005
Available online 16 August 2005
Abstract—A straightforward, high-yielding procedure has been developed for the manufacture of substituted vinylphenols from
2- and 4-hydroxybenzaldehydes utilising classical Knoevenagel condensation reaction conditions.
ꢀ 2005 Elsevier Ltd. All rights reserved.
O
Reactions of aldehydes or ketones with active methylene
compounds in the presence of a weak base to give alkyl-
idene-dicarbonyls or analogous compounds are gener-
ally termed Knoevenagel condensations.1 In a valuable
variation of the reaction, in which malonic acid is used
as the active methylene compound, the reaction is
accompanied by decarboxylation to give the corre-
sponding a,b-unsaturated monocarboxylic acid. Where
condensations with malonic acid are performed in the
presence of aromatic aldehydes, the product obtained
is exclusively the trans-cinnamic acid.
1. malonic acid (1.5 equiv.),
piperidine (4 equiv.),
pyridine, reflux 4 h.
Me
Me
2. toluene,
evaporate in vacuo, 30-40 ˚C.
OMe
OMe
1
3
OH
OH
Scheme 1.
afford the crude product.3 In order to establish the gen-
erality and utility of this phenomenon, we decided to
test a range of aldehyde substrates bearing variations
of all substituents of the 4-hydroxy-5-methoxy-2-
methyl-benzaldehyde 1 utilised in our original prepara-
tion using both the classical and new work-up condi-
tions (Table 1).
During the construction of a substituted 4-hydroxy-
trans-cinnamic acid related to our research (4-hydroxy-
5-methoxy-2-methyl-trans-cinnamic acid, 2) we ob-
served the formation of a single new compound which
was plainly not the expected trans-cinnamic acid.2 In-
1
deed, the H NMR spectrum clearly indicated the pres-
These results demonstrate that styrene formation occurs
only in reactions where a 2- or 4-hydroxybenzaldehyde
substrate is utilised in conjunction with the new work-
up conditions. The product in all other cases, regardless
of the conditions utilised, was the expected trans-
cinnamic acid. With 2-hydroxybenzaldehyde 4, both
the expected trans-cinnamic acid 5 and the correspond-
ing vinylphenol 6 were generated in the same reaction.
ence of an ABX system characteristic of a styrene and
further analysis of the purified compound confirmed
that we had generated 2-methoxy-5-methyl-4-vinylphe-
nol 3 directly from the corresponding aldehyde 1
(Scheme 1).
The reaction conditions utilised for the preparation
of 2-methoxy-5-methyl-4-vinylphenol 3 were identical
to those of classical Knoevenagel reactions. However,
instead of quenching the reaction by pouring it into
concentrated HCl on ice, the pyridine reaction solvent
was removed in vacuo in the presence of toluene to
When utilising benzaldehydes and malonic acid, the
Knoevenagel reaction is accompanied by decarboxyl-
ation to give the corresponding substituted trans-cin-
namic acid (Scheme 2).1 In the presence of 1ꢁ and 2ꢁ
amines, the reaction proceeds via the Knoevenagel
mechanism.4 Following initial addition of the activated
methylene, the decarboxylated intermediate (R = piper-
idine) outlined in Scheme 2 is most likely generated in
the reaction. Subsequent b-elimination of the amine
Keywords: Organic synthesis methodology mechanism.
*
Corresponding author. Tel.: +61 2 9351 7231; fax: +61 2 9351
3329; e-mail: p.stamford@chem.usyd.edu.au
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.011

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C. J. Simpson et al. / Tetrahedron Letters 46 (2005) 6893–6896
Table 1. Products and yields following Knoevenagel condensation of benzaldehydes and malonic acid (reactions were not optimised)
Substrate
HCl/H2O
Toluene
Product
Yield (%)
56
Product
Yield (%)
50
MeO
Acrylic acid 2
Vinylphenol 3
HO
O
O
1
Me
OH
Acrylic acid 5
Acrylic acid 8
48
35
Acrylic acid 5 and vinylphenol 6
Vinylphenol 9
50 and 38
4
HO
67
O
O
7
MeO
HO
Acrylic acid
Acrylic acid
35
87
Vinylphenol
Acrylic acid
86
23
MeO
O
Acrylic acid
78
Acrylic acid
82
O
HO
HO
Acrylic acid
Acrylic acid
27
61
Vinylphenol
Acrylic acid
58
96
O
OMe
O
HO
O
HO
O
H
HO
O
HO
O
O
O
H
R
OH
R
R
O
-CO2
-RH
-CO2
-RH
Scheme 2.
O
O
OH
H
Scheme 3.
from this intermediate generates only the expected trans-
cinnamic acid.
ation necessary to afford a vinylphenol. We propose that
following the initial decarboxylation, the phenolic oxy-
gen participates in elimination of the amine function
in the condensation product through the generation of
a quinone methide (Scheme 3). This intermediate is identi-
cal to that invoked for the decarboxylation of 4-hydroxy-
trans-cinnamic acid in aqueous weak alkali solution.5
Decarboxylation then proceeds readily to give the corres-
ponding vinyl phenol either through conjugate addition
to give the unstable b-lactone or more likely by direct
decarboxylation (as shown).
The addition of 4-hydroxy-3-methoxy-trans-cinnamic
acid 8 to Knoevenagel condensation reaction conditions
and subsequent removal of the pyridine solvent in vacuo
in the presence of toluene did not lead to the corre-
sponding vinylphenol. This suggests that formation of
the trans-cinnamic acid through elimination of water
during the Knoevenagel reaction is effectively non-
reversible under these conditions. Therefore, the second
decarboxylation must occur prior to formation of an
a,b-unsaturated carboxylic acid.
The fact that only 2- and 4-hydroxybenzaldehydes gen-
erate the unexpected vinylphenols strongly suggests the
participation of a quinone in the double decarboxyl-
Interestingly, the generation of the ortho-quinone
methide competes with b-elimination leading to the
generation of both the corresponding vinylphenol and

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.

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C. J. Simpson et al. / Tetrahedron Letters 46 (2005) 6893–6896
4 h, then cooled to room temperature. For standard work-
up to afford the corresponding acrylic acid, the cooled
reaction mixture was poured into a solution (50 mL) of
concentrated HCl and ice (50% by volume) and the
resulting precipitate was filtered and washed with acidified
water to give a crude product. The crude product was
dissolved in aqueous NaOH (1 M, 20 mL) and extracted
with CH2Cl2 (3 · 20 mL). The aqueous solution was
acidified to pH = 1 and the resultant precipitate washed
with acidified water to give the corresponding trans-
cinnamic acid. For the alternate work-up required to
afford the corresponding vinyl phenol, toluene (40 mL)
was added to the cooled reaction mixture and the solvent
volume reduced in vacuo at 30–40 ꢁC. Additional toluene
(20 mL) was then added and the solvent again removed in
vacuo eliminating all traces of pyridine to afford the crude
product. If the crude product obtained was the trans-
cinnamic acid, then further purification was performed as
for the standard work-up procedure. Otherwise, purifica-
tion by column chromatography over silica gel (eluting
with 2:1 hexane/ethyl acetate) gave the corresponding
vinylphenol.
A very brief description of the preparation of 1,2-dihy-
droxy-4-vinylbenzene through the repeated distillation
of products of a Knoevenagel condensation, has previ-
ously been reported.12 Furthermore, since the comple-
tion of this work, others have also reported the
formation of vinylphenols from 4-hydroxybenzalde-
hydes in much lower yields using microwave heating.13
However, in this report we present for the first time
the systematic investigation of this straightforward,
high-yielding and clean procedure for the manufacture
of substituted vinylphenols directly from 2- and 4-
hydroxybenzaldehydes utilising classical Knoevenagel
condensation reaction conditions.
Acknowledgements
Grateful acknowledgement is made to the Engineering
and Physical Sciences Research Council (U.K.) for an
award to C.J.S. and to the Organic Synthesis Centre
for an award to M.J.F.
4. Knoevenagel, E. Chem. Ber. 1898, 31, 2585.
5. Cohen, L. A.; Jones, W. M. J. Am. Chem. Soc. 1960, 82,
1907–1911.
6. Hann, A. C. O.; Lapworth, A. J. Chem. Soc. 1904, 85, 46.
7. Tanaka, M.; Oota, O.; Hiramatsu, H.; Fujiwara, K. Bull.
Chem. Soc. Jpn. 1988, 61, 2473.
8. Takemoto, M.; Achiwa, K. Tetrahedron Lett. 1999, 40,
6595–6598.
9. Dale, W. J.; Hennis, H. E. J. Am. Chem. Soc. 1958, 80,
3645–3649.
References and notes
1. For general reviews on the Knoevenagel reaction: Jones,
G. Org. React. 1967, 15, 204–599; Tietze, L. F.; Beifuss, U.
In Comprehensive Organic Synthesis; Trost, B. M., Flem-
ing, I., Eds.; Pergamon Press: Oxford, 1996; Vol. 2, pp
341–394.
2. Simpson, C. J. Ph.D. Dissertation, University of East
Anglia, 2003.
10. Bettach, N.; Le Bigot, Y.; Mouloungui, Z.; Delmas, M.;
Gaset, A. Synth. Commun. 1992, 22, 513–518.
3. A general procedure was followed for all Knoevenagel
11. Fujiwara, H.; Yamazaki, H.; Ozawa, K. Eur. Pat. Appl.,
EP 128984 A1, 1984; Chem. Abstr. 1985, 102, 184819.
12. Tiedcke, C. Z. Unters. Lebensm. 1936, 71, 393.
13. Sinha, A. K.; Joshi, B.P.; Sharma, A. U.S. Pat. Appl., US
20040118673 A1, 2004; Chem. Abstr. 2004, 141, 71343.
condensation reactions. To
a solution of aldehyde
(5 mmol) and malonic acid (20 mmol) in pyridine
(21 mL) was added piperidine (0.75 mL, 7.6 mmol). The
stirred reaction solution was heated at reflux (115 ꢁC) for