Synthesis of Substrates for Aldolase-Catalysed Reactions: A Comparison of Methods for the Synthesis of Substituted Phenylacetaldehydes

Article abstract of DOI:10.1055/s-0036-1591963

Methods for the synthesis of phenylacetaldehydes (oxidation, one-carbon chain extension) were compared by using the synthesis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of 4-methoxyphenylethanol with activated DMSO (Swern oxidation) or manganese dioxide gave unsatisfactory results; whereas oxidation with 2-iodoxybenzoic acid (IBX) produced 4-methoxyphenylacetaldehyde in reasonable (75%) yield. However, Wittig-type one-carbon chain extension with methoxymethylene-triphenylphosphine followed by hydrolysis gave an excellent (81% overall) yield of 4-methoxyphenylacetaldehyde from 4-methoxybenzaldehyde (a cheap starting material). This approach was subsequently used to synthesise a set of 10 substituted phenylacetaldehydes in good to excellent yields.

Full text of DOI:10.1055/s-0036-1591963

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
D. Al-Smadi et al.
Letter
Synlett
Synthesis of Substrates for Aldolase-Catalysed Reactions:
A Comparison of Methods for the Synthesis of Substituted
Phenylacetaldehydes
Derar Al-Smadi
(COCl)2/DMSO
or MnO2
OH
O
O
Thilak Reddy Enugala
Thomas Norberg
Jan Kihlberg
R
R
H
H
O
1) [(Ph)3PCH2OCH3]Cl/t-BuOK
2) HCOOH/CH2Cl2
Mikael Widersten*
H
R
R
Department of Chemistry – BMC, Uppsala University,
PO Box 576, 75123 Uppsala, Sweden
mikael.widersten@kemi.uu.se
65–85%
R = 4-OMe, 4-NO2, 4-Me, 4-F, 4-Cl, 3-OMe, 3-NO2, 3-F, 3-Cl, 3,4-di-OMe (10 examples)
• Methoxymethylene-Wittig reagent/Hydrolysis
• Arylacetaldehydes (R-substituted)
• Operationally easy and scalable
• Substrates for aldolase catalysis
Received: 11.01.2018
Accepted after revision: 23.02.2018
Published online: 19.03.2018
of a lower-homolog aldehyde, or partial reduction of the
corresponding carboxylic acids or -esters. In this paper, we
present a comparison of the first two methods for the syn-
thesis of a model phenylacetaldehyde (4-methoxyphenyl-
acetaldehyde) and then application of the method that
proved most suitable (Wittig-type one-carbon extension)
to the synthesis of a set of 10 substituted phenylacetalde-
hydes. Partial reduction methods10 were not investigated
because of the reduction sensitivity of some of the required
ring substituents (e.g. the nitro group).
We considered oxidative methods based on activated
DMSO,11 hypervalent iodine,6 and transition metal oxides.12
These methods were applied to the model compound 4-
methoxybenzyl alcohol and the results are summarised in
Scheme 1. With DMSO/oxalyl chloride in dichloromethane
(Swern oxidation), TLC and NMR spectroscopy indicated a
multicomponent reaction mixture, and the desired 4-me-
thoxyphenylacetaldehyde (3a) was isolated by column
chromatography in only 20% yield. With the hypervalent
iodine reagent IBX (2-iodoxybenzoic acid), the expected al-
dehyde 3a was isolated in 75% yield after a tedious chro-
matographic purification. Revelant6b reports an 88% yield of
3a (without chromatographic purification) for the same
reaction. High phenylacetaldehyde yields have also been re-
ported7,14 for the oxidation of phenylethanols with Dess–
Martin periodinane, another hypervalent iodine reagent.
DOI: 10.1055/s-0036-1591963; Art ID: st-2018-d0025-l
Abstract Methods for the synthesis of phenylacetaldehydes (oxida-
tion, one-carbon chain extension) were compared by using the synthe-
sis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of
4-methoxyphenylethanol with activated DMSO (Swern oxidation) or
manganese dioxide gave unsatisfactory results; whereas oxidation with
2-iodoxybenzoic acid (IBX) produced 4-methoxyphenylacetaldehyde in
reasonable (75%) yield. However, Wittig-type one-carbon chain exten-
sion with methoxymethylene-triphenylphosphine followed by hydro-
lysis gave an excellent (81% overall) yield of 4-methoxyphenylacetalde-
hyde from 4-methoxybenzaldehyde (a cheap starting material). This
approach was subsequently used to synthesise a set of 10 substituted
phenylacetaldehydes in good to excellent yields.
Key words benzaldehyde, phenylacetaldehyde derivatives, homologa-
tion reaction
Aldolases are an important class of enzymes that take
part in fundamental metabolic processes. In nature, they
catalyse the stereoselective formation (or cleavage) of car-
bon–carbon bonds, and therefore they have also been con-
sidered for use in preparative organic synthesis.1 For such
applications, the properties (stereopecificity, substrate
scope) of the native enzymes need to be changed or tuned;
for example by the process of directed evolution.2 For the
characterization of E. coli fructose-6-phosphate aldolase3
(FSA) variants produced by directed evolution we required a
set of phenylacetaldehyde substrates with different ring
substituents. All aldehydes had been synthesised before, of-
ten as intermediates in syntheses of biologically active
compounds.4a,5,6b,7–9 However, very few, if any, were com-
mercially available and therefore all had to be chemically
resynthesised. Generally speaking, the three most popular
methods for the synthesis of aldehydes are: partial oxida-
tion of the corresponding alcohols, carbon-chain extension
a) DMSO/(COCl)2/
Et3N/CH2Cl2
OH
O
b) IBX/CH3CN
c) MnO2/DMF
H
MeO
MeO
3a
Scheme 1 Reaction of 4-methoxybenzyl alcohol with various
oxidation reagents. (a) 25% yield, (b) 75% yield, (c) 0% yield (but 77% of
4-methoxybenzaldehyde)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
D. Al-Smadi et al.
Letter
Synlett
Finally, with MnO2 in THF an aldehyde product was iso-
lated in 77% yield after chromatography. This product, how-
ever, turned out to be the next lower aldehyde homolog, 4-
methoxybenzaldehyde. Obviously, the bond between the
aldehyde carbonyl and the benzylic carbon atom had been
cleaved under the reaction conditions. A similar result has
Table 1 Reaction of Substituted Benzaldehydes 1a–j with Methoxymethylene-triphenylphosphine Followed by Hydrolysis of the Resulting Enol Ethers
2a–j to Give Phenylacetaldehydes 3a–j
O
OMe
O
HCOOH
[(Ph)3PCH2OCH3]Cl/t-BuOK
H
R
R
R
reflux, CH2Cl2
or ClCH2Cl2Cl
THF, r.t.
H
1a–j
2a–j
3a–j
Entry Starting aldehyde
Wittig
reaction time (2)
(h)
Enol ether
Yield
(%)
E/Z
Ref.
Hydrolysis Product
Yield
(%)
Ref.
(1)
time
(h)
aldehyde
(3)
O
OMe
O
5,15,16
6b,8,16,17
95a
97a
95a
91a
93a
1/1
16
16
16
16
16
85
88
80a
70
86
H
a
16
16
H
MeO
MeO
O2N
MeO
O
OMe
O
18,19
17,20
22,24
17,23
5,14
b
H
1/1
1/1
1/1
1/1
H
O2N
O2N
O
OMe
O
5
c
16
16
16
H
H
O
OMe
OMe
O
15,21
d
H
H
F
F
F
O
O
8
e
H
H
Cl
Cl
Cl
O
MeO
OMe
MeO
O
MeO
5,16
8,16
f
16
24
24
24
97a
95a
98a
98a
1/1
24
36
3
79a
68a
73a
65a
H
H
O
O2N
OMe
O2N
O
O2N
5
24
g
h
i
1/1
H
H
O
Cl
OMe
Cl
O
Cl
8
8,17,24
1/1,5
1/1,5
H
H
O
F
OMe
F
O
H
F
14
7,24
4
H
O
H
MeO
MeO
OMe
MeO
MeO
O
MeO
MeO
16
14,16
j
16
97a
1/1,3
3
81a
H
a Chromatographic purification
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
D. Al-Smadi et al.
Letter
Synlett
been reported for phenylethanol oxidations with pyridini-
um chlorochromate.6b
a reaction time of 24–36 hours was sufficient. However, for
the m-chloro-, m-fluoro- and 3,4-dimethoxy-substituted
derivatives dichloroethane heated to reflux and a reaction
time of 3–4 hours was optimal, longer times led to product
degradation/lower yields. Thus, the enol ether hydrolysis
reaction conditions were critical, as has been noted previ-
ously by others.9 The best results in our hands were ob-
tained with 10% formic acid in dichloromethane. Interest-
ingly, addition of extra water during hydrolysis resulted in
more complex reaction mixtures, indicating the initial for-
mation of an intermediate formic acid adduct. In many cas-
es, the crude aldehyde products were sufficiently pure for
further use without chromatographic purification. A gener-
al experimental procedure is given in the references25 and
further details of the experiments can be found in the
Supporting Information.
In summary, methods to synthesise substituted phenyl-
acetaldehydes (oxidation, one-carbon chain extension) have
been compared. The Wittig-type carbon-chain extension
protocol based on treatment of substituted benzaldehydes
with methoxymethylene-triphenylphosphine followed by
hydrolysis was found to be a very robust method and gave
consistently high yields. It also allowed use of reagents and
starting materials that are commercially available to a much
greater extent than methods based on oxidation. The meth-
od was used to prepare a set of substituted phenylacetalde-
hydes that will be used as test substrates in aldolase-
catalysed reactions.
In view of the above results with oxidation reagents and
in view of the fact that many of the required phenyletha-
nols are not commercially available (most have to be pre-
pared by reduction of the corresponding carboxylic acid de-
rivatives) we decided to turn our attention to methods
based on one-carbon chain extension of an existing alde-
hyde. We focused on a modification4,5 of the original13
Wittig-type reaction of an aldehyde with methoxymethy-
lene-triphenylphosphine. A reaction of the phosphine re-
agent (prepared in situ from the corresponding phosphoni-
um salt with potassium tert-butoxide in THF) was therefore
performed with 4-methoxybenzaldehyde (1a, Scheme 2).
The enol ether product (a 1:1 mixture of E and Z isomers,
95% yield) was hydrolysed (10% formic acid in dichloro-
methane) to give 4-methoxy phenylacetaldehyde (3a) in
81% overall yield. The high overall yield in this test reaction,
the relative simplicity of the procedure, and the fact that a
large variety of substituted benzaldehydes is commercially
available encouraged us to choose this method for the syn-
thesis of our desired set of substituted phenylacetalde-
hydes.
O
1) [(Ph)3PCH2OCH3]Cl/t-BuOK
O
2) HCOOH/CH2Cl2
H
H
MeO
MeO
1a
3a
Scheme 2 Reaction of 4-methoxybenzaldehyde with methoxy-
methylene-triphenylphosphine followed by hydrolysis
Funding Information
We subjected a series of substituted benzaldehydes
(Table 1) to the Wittig extension/hydrolysis reaction condi-
tions. Substituents ranged from strongly electron-donating
(methoxy) to electron-withdrawing (nitro) groups placed
either in para or meta positions of the benzaldehydes. A
m,p-dimethoxybenzaldehyde was also included in the set.
The results (starting aldehydes, enol ethers and product
aldehydes) are listed in Table 1, together with yields, enol
ether E/Z ratios, reaction times, and references for known
compounds. As can be seen in Table 1, the yields in both the
Wittig extension and hydrolysis steps were high through-
out. In particular, the Wittig reaction gave high yields
(>90%) regardless of benzaldehyde substituents, even after
chromatographic purification. The E/Z product ratios were
close to unity except for entries 8–10; the reason for these
minor discrepancies are unclear. Interestingly, the E prod-
ucts have been reported5 to dominate in similar reactions
employing a shorter reaction time and another base
(LiHMDS). The rate and yield in the enol ether hydrolysis
step were sensitive to structural variations, with yields be-
ing somewhat lower (by 5–20%) for meta- as compared to
para-substituted phenylacetaldehydes. For most enol
ethers, formic acid in dichloromethane heated to reflux and
The work was financed by Stiftelsen Olle Engkvist Byggare (M.W.) and
D. Al-Smadi was supported by a Graduate Student Fellowship funded
by the Department of Chemistry – BMC at Uppsala University.
)(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591963.
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References and Notes
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2)
To a stirred suspension of [(Ph)3PCH2OCH3]Cl (6.70 g, 19.5
mmol, 1.2 equiv) in dry THF (12 mL) was added t-BuOK (2.40 g,
21.4 mmol, 1.3 equiv) at 0 °C. The reaction mixture was stirred
for 20 min. Then, the benzaldehyde derivative (16.2 mmol,
1 equiv) was added, and the mixture was stirred for 16–24 h at
r.t. (see Table 1). The reaction mixtures were monitored by TLC,
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diethyl ether (3 × 100 mL). The combined organic layers were
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crude enol ether products were purified by column chromato-
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see Table 1. The purified enol ether product (E/Z mixture) was
dissolved in dichloromethane (30 mL, entries 1–5) or dichloro-
ethane (30 mL, entries 6–10). Then, formic acid (98%, 3 mL) was
added, and the mixture was heated to reflux for 3–36 h (see
Table 1). The reaction mixtures were monitored by TLC and
when the reactions were deemed complete, the mixtures were
cooled to r.t., diluted with dichloromethane, and washed with
aq NaHCO3. The organic layer was dried (MgSO4), filtered, and
the solvent was evaporated. In some cases (see Table 1) purifi-
cation of the crude products on a short silica gel column (100:0
to 95:5 toluene/ethyl acetate gradient) was performed. For NMR
spectroscopic data of the individual compounds, see Supporting
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D