Hydrolysis of (Z)-2-alkoxy-3-arylpropenals as a short-cut to benzylglyoxals

Article abstract of DOI:10.1016/j.mencom.2016.09.023

Hydrolysis of the C=C bond in 2-alkoxy-3-aryl(hetaryl)-propenals, depending upon substituents in the molecule, can proceed according to Markovnikov or Michael rule or with heterolytic opening of the cycle (in the case of 2-alkoxy-3-furylpropenal). Hydrolysis of 3-phenyl substituted alkoxypropenals bearing electron-withdrawing substituents (Cl, NO₂) in the p-position has allowed a method for the preparation of corresponding benzylglyoxals (stable in enol form) to be developed.

Full text of DOI:10.1016/j.mencom.2016.09.023

Mendeleev
Communications
Mendeleev Commun., 2016, 26, 431–433
Hydrolysis of (Z)-2-alkoxy-3-arylpropenals as a short-cut to benzylglyoxals
Natalia A. Keiko,* Nadezhda V. Vchislo, Ekaterina A. Verochkina, Yurii A. Chuvashev and Lyudmila I. Larina
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
664033 Irkutsk, Russian Federation. Fax: +7 3952 419 346; e-mail: keiko@irioch.irk.ru
DOI: 10.1016/j.mencom.2016.09.023
Hydrolysis of the C=C bond in 2-alkoxy-3-aryl(hetaryl)-
propenals, depending upon substituents in the molecule,
R
H+/H2O
R
can proceed according to Markovnikov or Michael rule or
with heterolytic opening of the cycle (in the case of 2-alkoxy-
3-furylpropenal). Hydrolysis of 3-phenyl substituted alkoxy-
propenals bearing electron-withdrawing substituents (Cl, NO2)
in the p-position has allowed a method for the preparation of
corresponding benzylglyoxals (stable in enol form) to be
developed.
H
OAlk
O
MeCN
50–60 °C, 4–8 h
O
O
R = Cl, NO2
Alk = Me, Bu
56–62%
2-Alkoxy(aryloxy)propenals represent a poorly studied, but struc-
turally diverse family of secondary metabolites of plants1(a),(b)
and animals.1(c) Unlike acrolein, 2-alkoxypropenals 1 (R1 = R2 = H)
are capable of adding water molecule according to Markovnikov
rule leading finally to methylglyoxal (2-oxopropanal) (Scheme 1).2
In 1965, it was shown that similar hydrolysis is inherent in b-aryl
OEt
OEt
Ph
H2O
O
Ph
OH
60 °C, 1.5 h
2
H
OH
1,4-Add
substituted a-methoxy-a,b-unsaturated ketones and acids 1
EtO H
(see Scheme 1, R1, R2 ¹ H).3 However, it remains unclear
whether the corresponding b-arylaldehydes (R1 = Ar, R2 = H)
tolerate this reaction.
Ph
O
H
PhCHO + EtOCH2CHO
H
OH
A
OAlk
O
Scheme 2
H2O, H+
R1
R2
R1
R2
For example, condensation of 3-(4-acetoxyphenyl)-2-oxo-
propanal with a pyrazine derivative, coelenteramine, affords
coelentrazine, bioluminescent imidazopyrazine.8 The reaction of
benzylglyoxals with a pyridine derivative delivers imidazo-
[1,2-a]pyridines.9
O
O
50%
1
R1 = H, Ph, 2-NO2C6H4, R2 = H, Me, OEt
Scheme 1
We have found that hydrolysis of 2-alkoxy-3-arylpropenals
3a–d, bearing electron-withdrawing groups in the p-position of
the aromatic ring, under appropriate conditions (pH 2–3,
50–60°C, 4–8 h) proceeds in the desired direction giving rise to
substituted benzylglyoxals 5a,b in 56–62% yields.† Notably,
Earlier we reported4 that, contrary to compounds 1, 2-ethoxy-
3-phenylpropenal 2 undergoes hydrolysis in acidic medium
according to Michael rule (1,4-addition). Subsequent retro-
aldol decomposition of the intermediate A gives benzaldehyde
(1H NMR), whose content in the reaction mixture grows in
time (Scheme 2). Similar direction of the C=C bond hydrolysis
was observed while attempting to convert 2-methoxy-3-(2-pyridyl)-
propenal into its 2,4-dinitrophenylhydrazone in the presence of
acids.4 Eventually, pyridine-3-carbaldehyde hydrazone was
obtained in 65% yield. Apparently, the direction of hydration for
these reactants is explained by the formation of all-in-one
conjugation system between the aliphatic chain and aromatic or
heteroaromatic cycle.
The aim of this work was to study the direction of hydrolysis
of hitherto unknown 2-alkoxy-3-aryl(hetaryl)propenals in acidic
medium as well as to elucidate a possibility to access benzyl-
glyoxals or furylmethylglyoxals by the reaction of the C=C bond
hydrolysis according to Markovnikov rule (Schemes 3 and 4).
Unlike well-studied arylglyoxals,5 the reports on benzyl-
glyoxals, rather promising compounds, remain sporadic.6–9
†
The 1H, 13C and 15N NMR spectra were recorded in DMSO-d6 and
CDCl3 at room temperature on Bruker DPX-400 and AV-400 spectro-
meters (400.13, 100.61 and 40.56 Hz, respectively). Chemical shifts were
referred to TMS (1H, 13C) and nitromethane (15N). GC-MS analysis was
performed on an Agilent Technologies 5975C (EI, 70 eV, mass-selective
detector),AT-6890N chromatograph, Ultra-2 column (5% phenylmethyl-
silicone), injector temperature 260°C, column thermostat temperature
70–280°C, temperature rasing 20 K min–1. IR spectra were recorded on a
Bruker IFS25 spectrophotometer. Melting points were determined on a
Micro-Hot-Stage Poly Term A instrument. Elemental analysis was per-
formed on a Thermo Finnigan 1112ser analyzer. Column chromatography
was carried out on silica gel 60 (70–200 mesh; Merck).
Hydrolysis of (Z)-2-alkoxy-3-(4-chlorophenyl)propenals 3a,b (general
procedure). To a solution of compound 3a (1.5 mmol) in 1.5 ml MeCN,
H2O (1.5 mmol) and 28.6% hydrochloric acid (0.55 mmol) (pH 3) were
added. The solution was stirred at 50–60°C for 8 h. The residue was
filtered and washed with diethyl ether.
© 2016 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2016, 26, 431–433
O
R
R
O
OAlk
i
O
N
O
O
O
i
CHO
NO2
3a R = Cl, Alk = Me
3b R = Cl, Alk = Bu
4a
R = Cl
OEt
OEt
ii or iii
4b R = NO2
O
3c R = NO2, Alk = Me
3d R = NO2, Alk = Bu
N
O
H
7
NO2
iv
3
6
8
R
4
2
1
H
O
O
OH
OH
O
5
H1
5a
5b
R = Cl
R = NO2
56–62%
H2 H3
O
2
R
NO2
9
ii
OH
Scheme 4 Reagents and conditions: i, H3O+; ii, 2,4-(O2N)2C6H3NHNH2,
HCl, H2O, pH 3, 20°C, 10 min, 75%; iii, H3O+, MeCN, 55°C, 6 h, then
2,4-(O2N)2C6H3NHNH2, 20°C, 24 h, 29%; iv, H3O+, pH 3, 60°C.
N
N
H
NO2
6a
6b
R = Cl (63%)
(51%)
In contrast to 2-alkoxypropenals 1, which are quantitatively
transformed to methylglyoxal in acidic medium for 1 h at 50–60°C,2
2-ethoxy-3-furylpropenal 7 is more resistant to hydrolysis at
heating under acidic aqueous (H2O/MeCN) conditions at 55°C
for > 6 h that is confirmed by consequent formation of hydrazone
8 (Scheme 4).§ Note that alkenal 7 also does not decompose to
furfural and ethoxyacetic aldehyde for 10 min as it is observed
R = NO2
Scheme 3 Reagents and conditions: i, H+/H2O, MeCN, 50–60°C, 4–8 h;
ii, H+, 2,4-(O2N)2C6H3NHNH2.
the precipitated crystals of the compounds do not require
additional purification. The 1H NMR study (in CDCl3 and
DMSO-d6) has revealed that the compounds exist in enol form,
which is retained even in iminium derivatives 6a and 6b obtained
from enol aldehydes 5.‡
Stability of the enol forms is likely due to the formation of
strong hydrogen bonding and the prevailing dative effect of the
OH group, which is in agreement with electron-withdrawing
influence of the Cl and NO2 substituents.
(C=N), 128.9 (C3, C5), 130.8 (C2, C6), 131.3 (C1), 132.1 (C5'), 135.4 (C4),
137.8 (C2'), 144.8 (C4'), 146.7 (C1'), 149.2 (COH). 15N NMR (DMSO)
d:
–11.2 (p-NO2), –28.4 (o-NO2), –67.1 (C=N), –222.8 (NH). Found (%):
C, 49.74; H, 3.07; N, 15.70; Cl, 9.61. Calc. for C15H11N4ClO5 (%): C, 49.67;
H, 3.06; N, 15.45; Cl, 9.77.
(Z)-2-Hydroxy-3-(4-nitrophenyl)propenal 2,4-dinitrophenylhydrazone 6b
1
was prepared as above. Yield 0.24 g, 51%, mp 191°C (ethanol). H NMR
(Z)-3-(4-Chlorophenyl)-2-hydroxypropenal 5a: yield 59%, mp 161°C
(cf. ref. 10). IR (n/cm–1): 3192, 1643, 1586, 1489, 1417, 1360, 1289, 1158,
925, 858, 724. 1H NMR (CDCl3) d: 6.10 (s, 1H, =CH), 6.72 (s, 1H, OH),
7.36 (d, 2H, H3, H5, J 8.2 Hz), 7.75 (d, 2H, H2, H6, J 8.2 Hz), 9.24 (s, 1H,
CHO). 13C NMR (CDCl3) d: 121.2 (=C), 129.1 (C3, C5), 131.7 (C2, C6),
132.15 (C1), 135.3 (C4), 149.0 (COH), 188.0 (CHO). GC-MS, m/z (%):
182 (47) [M]+, 165 (2) [M–OH]+, 147 (23) [M–Cl]+, 125 (100), 89 (36)
[C6H4CH]. Found (%): C, 59.43; H, 3.81; Cl, 19.35. Calc. for C9H7ClO2
(%): C, 59.20; H, 3.86; Cl, 19.41.
Hydrolysis of (Z)-2-butoxy-3-(4-chlorophenyl)propenal 3b was carried
out as above, the same product 5a was obtained in 62% yield.
Hydrolysis of (Z)-2-methoxy-3-(4-nitrophenyl)propenal 3c was carried
out similarly, but reaction time was 4 h. (Z)-2-Hydroxy-3-(4-nitrophenyl)-
propenal 5b was obtained in 56% yield, mp 175 °C (cf. ref. 10). IR
(n/cm–1): 3074, 2919, 1676, 1594, 1515, 1344, 1160, 1105, 926, 865,
693. 1H NMR (CDCl3) d: 6.20 (s, 1H, =CH), 7.95 (d, 2H, H2, H6, J 8.8 Hz),
8.24 (d, 2H, H3, H5, J 8.8 Hz), 9.33 (s, 1H, CHO). 13C NMR (CDCl3) d:
119.2 (=C), 123.55 (C3, C5), 130.4 (C2, C6), 140.5 (C1), 146.7 (C4), 152.0
(COH), 188.6 (CHO). 15N NMR (CDCl3) d: –10.0. GC-MS, m/z (%): 193
(100) [M]+, 176 (45) [M–OH]+, 164 (55) [M–CHO]+, 147 (34) [M–NO2]+,
136 (86), 118 (38) [M – NO2–CHO]+, 89 (72) [C6H4CH]. Found (%):
C, 55.81; H, 3.72; N, 6.98. Calc. for C9H7NO4 (%): C, 55.96; H, 3.65;
N, 7.25.
(DMSO-d6) d: 5.91 (s, 1H, =CH), 8.01 (d, 2H, H2, H6, J 8.8 Hz), 8.21
(d, 2H, H3, H5, J 8.8 Hz), 8.33 (s, 1H, HC=N), 8.38 (dd, 1H, H5', 3J 9.7 Hz,
4J 2.5 Hz), 8.52 (d, 1H, H6', 3J 9.7 Hz), 8.86 (d, 1H, H3', 4J 2.5 Hz), 10.12
(s, 1H, OH), 11.78 (s, 1H, NH). 13C NMR (DMSO-d6) d: 111.8 (C=),
117.3 (C6'), 121.2 (C3'), 128.4 (C=N), 127.9 (C3, C5), 130.3 (C2, C6), 129.6
(C1), 132.31 (C5’), 137.8 (C2'), 144.8 (C4'), 145.4 (C4), 146.8 (C1'), 151.4
(COH). 15N NMR (DMSO-d6) d: –10.3 (PhNO2), –12.3 (p-NO2), –27.8
(o-NO2), –61.4 (C=N), –224.6 (NH). Found (%): C, 48.06; H, 2.98;
N, 18.41. Calc. for C15H11N5O7 (%): C, 48.26; H, 2.97; N, 18.77.
§
2-Ethoxy-3-(2-furyl)propenal 2,4-dinitrophenylhydrazone 8 was
obtained from 2-ethoxy-3-(2-furyl)propenal 7.
MethodA. To a mixture of aldehyde 7 (0.2 g, 1.2 mmol), H2O (1.7 ml)
and DMF (6 ml), conc. HCl was slowly added (pH 3). Then, 2,4-dinitro-
phenylhydrazine (0.22 g, 1.1 mmol) in EtOH was added within 10 min.
The solution was stirred at room temperature for 24 h to give 0.31 g
(75%) of compound 8, mp 210°C (EtOH). 1H NMR (CDCl3) d: 1.47 (t,
3H, Me, J 7.0 Hz), 4.28 (q, 2H, OCH2, J 7.0 Hz), 6.27 (s, 1H, =CH), 6.51
(dd, 1H, H4, 3J 3.4 Hz, 4J 1.7 Hz), 6.97 (d, 1H, H3, 3J 3.4 Hz), 7.45 (d,
1H, H5, 4J 1.7 Hz), 7.64 (s, 1H, HC=N), 7.92 (d, 1H, H6', 3J 9.6 Hz), 8.33
(dd, 1H, H5', 3J 9.6 Hz, 4J 2.4 Hz), 9.12 (d, 1H, H3', 4J 2.4 Hz), 11.24 (s,
1H, NH). 13C NMR (DMSO-d6) d: 16.2 (Me), 67.5 (OCH2), 104.4 (=CH),
108.7 (C6'), 113.1 (C4), 117.1 (C3), 124.1 (C3'), 128.1 (C=N), 132.6 (C5'),
136.1 (C2'), 138.8 (C4'), 146.8 (C5), 148.7 (C1'), 149.2 (C2), 150.1 (COH).
Found (%): C, 51.73; H, 4.06; N, 16.01. Calc. for C15H14N4O6 (%):
C, 52.02; H, 4.05; N, 16.18.
Method B. The solution of aldehyde 7 (0.1 g, 0.6 mmol) in 1 ml of MeCN,
H2O (0.01 g, 0.6 mmol) and HCl (0.021 g, 0.16 mmol) (pH 3) was
heated on stirring at 50–60°C for 6 h. Then 2,4-dinitropenylhydrazine
(0.12 g, 0.6 mmol) in EtOH was added and the mixture was left at
room temperature for 24 h. Product 8 (0.06 g, 29%) was obtained. In
addition, black powder 9, insoluble in water and organic solvents, was
also formed. IR (KBr, n/cm–1): 3434, 2922, 1708, 1628, 1393, 1236,
1089. Hourly monitoring of the liquid phase of the reaction mixture
(1H NMR) confirms the increase of dimer 9 concentration (up to 1:4
molar ratio for 7:9, CH2Br2 as internal standard). 1H NMR (CDCl3) d:
4.11 (s, 2H, CH2), 5.1 (d, 1H, H3, J 10.5 Hz), 5.23 (d, 1H, H1, J 17.1 Hz),
5.98 (m, 1H, H2), 6.65 (s, 1H, CH). Found (%): C, 53.66; H, 5.32.
Calc. for C7H8O4 (%): C, 53.85; H, 5.13.
Hydrolysis of (Z)-2-butoxy-3-(4-nitrophenyl)propenal 3d was carried
out as described for 3c, the product 5b was obtained in 56% yield.
‡
(Z)-3-(4-Chlorophenyl)-2-hydroxypropenal 2,4-dinitrophenylhydrazone
6a. To a solution of compound 3a (0.38 g, 1.93 mmol) in 2 ml of MeCN,
H2O (0.035 g, 1.93 mmol) and 28.6% HCl (0.072 g, 0.56 mmol) (pH 3)
were added. The solution was stirred at 50–60 °C for 8 h. Then
2,4-dinitrophenylhydrazine (0.35 g, 1.76 mmol) dissolved in ethanol was
added, the solution was stirred at room temperature for 1 h. Compound
6a (0.4 g, 63%) was obtained after recrystallization from ethanol, mp
186°C. IR (KBr, n/cm–1): 3404, 3373, 3250, 1619, 1594, 1521, 1502,
1414, 1343, 1319, 1280, 1213, 1135. 1H NMR (DMSO-d6)
d: 5.75 (s, 1H,
=CH), 7.40 (d, 2H, H3, H5, J 8.6 Hz), 7.80 (d, 2H, H2, H6, J 8.6 Hz), 8.29
(s, 1H, HC=N), 8.36 (dd, 1H, H5', 3J 9.6 Hz, 4J 2.4 Hz), 8.50 (d, 1H, H6',
3J 9.6 Hz), 8.85 (d, 1H, H3', 4J 2.4 Hz), 9.53 (s, 1H, OH), 11.71 (s, 1H,
NH). 13C NMR (DMSO) : 112.6 (C=), 118.4 (C6'), 123.3 (C3'), 128.7
d
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Mendeleev Commun., 2016, 26, 431–433
in the case of 2-methoxy-3-(2-pyridyl)propenal (cf. ref. 4).
References
The prolongation of the reaction or raising the temperature to
70°C in the case of aldehyde 7 results in precipitation of black
powder insoluble in water and organic solvents. The structure of
its dimer or oligomer with chemical composition (C7H8O4)n may
be assigned to product 9 according to data of elemental analysis,
mass spectrometry ([M+ –1] = 311) and 1H NMR spectroscopy.
In conclusion, we have found that hydrolysis of 2-alkoxy-
3-aryl(hetaryl)propenals is substrate dependent and is affected
by the nature of substituents in the aromatic ring as well as
structure of the 3-positioned heteroaromatic moiety. Combina-
tion of capto-dative effect of the substituents in 2-alkoxy-
3-phenylpropenals with electron-withdrawing substituents
(Cl, NO2) promotes hydration of the C=C bond according to
Markovnikov rule. This effect allows hydrolysis of these
aldehydes to be considered as a convenient access to the
corresponding benzylglyoxals.
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2016.09.023.
Received: 10th February 2016; Com. 16/4841
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