Electrocatalytic chain transformation of salicylaldehyde and CH acids into substituted 4H-chromenes

Article abstract of DOI:10.1007/s11172-008-0093-9

Electrochemically initiated catalytic chain transformation of salicylaldehydes and CH acids containing the cyano group in an ethanolic solution in an undivided cell produced substituted 4H-chromenes in 85-95% yields.

Full text of DOI:10.1007/s11172-008-0093-9

Russian Chemical Bulletin, International Edition, Vol. 57, No. 3, pp. 595—600, March, 2008
595
Electrocatalytic chain transformation
of salicylaldehyde and CH acids into substituted 4Hꢀchromenes
S. K. Feducovich, M. N. Elinson, A. S. Dorofeev, S. V. Gorbunov,
R. F. Nasybullin, N. O. Stepanov, and G. I. Nikishin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: elinson@ioc.ac.ru
Electrochemically initiated catalytic chain transformation of salicylaldehydes and CH acids
containing the cyano group in an ethanolic solution in an undivided cell produced substituted
4Hꢀchromenes in 85—95% yields.
Key words: electrocatalysis, electrosynthesis, salicylaldehyde, CH acids, 4Hꢀchromenes.
Chromene derivatives are important representatives
of biologically active natural compounds such as alkaꢀ
cyanoꢀ4Hꢀchromenꢀ4ꢀyl)malononitriles in 64% yields
(see Ref. 21). In acetic acid in the presence of piperidine,
the yield of the product reaches 90%, but the reaction
time is extended to 24 h (see Ref. 23). Thus, it follows
from the literature data that the reactions of salicylaldeꢀ
hydes with malononitrile or alkyl cyanoacetate are senꢀ
sitive to the reaction conditions and that the known
procedures either provide insufficiently low yields of the
final product or are characterized by a long reaction time.
That is why the development of novel, highly efficient
methods for the synthesis of 4Hꢀchromenes is still
of current interest.
1
—6
loids, flavonoids, tocopherol, and anthocyanins.
In
the last few years, functionalized chromenes have found
7—10
increasingly frequent use in biomedicinal chemistry.
For example, 4Hꢀchromenes containing the cyano group
especially (4Hꢀchromenꢀ4ꢀyl)malononitriles) are emꢀ
(
ployed for treatment of inflammatory arthritis and
some kinds of cancers. It has also been found that
(
4Hꢀchromenꢀ4ꢀyl)malononitriles hinder the mutagenꢀ
activated protein MKꢀ2 and suppress the tumor factor
TNFα in U937 cells.11 Cancer is treated with substituted
alkyl (4Hꢀchromenꢀ4ꢀyl)cyanoacetates, a novel class of
small molecules which can bind the protein Bclꢀ2 and
excite the apoptosis of tumor cells.1
An intensive development of the electrochemistry of
organic compounds in the last few decades have made
electrosynthesis competitive in modern organic chemisꢀ
2,13
2
4,25
Condensation of salicylaldehyde with active methylꢀ
ene compounds in the presence of ammonium acetate,
try,
which allows, in some cases, unique transformaꢀ
tions of organic compounds. With our investigations, we
have discovered a novel type of electrochemical processꢀ
es, viz., an electrocatalytic chain transformation initiated
by catalytic amounts of a base electrogenerated in an
undivided cell. The first example was the electrocatalytic
chain cyclization of tetracyanocyclopropanes into substiꢀ
tuted 4,4ꢀdialkoxyꢀ2ꢀaminoꢀ1,5ꢀdicyanoꢀ3ꢀazabicycloꢀ
[3.1.0]hexꢀ2ꢀenes in the presence of alkoxy anions generꢀ
1
4—19
pyridine, or piperidine normally gives coumarins
or
coumarin imines, which subsequently undergo hydrolyꢀ
sis to coumarins.16 It has been, however, reported that
4
Hꢀchromenꢀ4ꢀyl derivatives can be obtained from saliꢀ
cylaldehydes and alkyl cyanoacetates with ammonium
acetate,20 alumina, or zirconium phosphate as a cataꢀ
lyst. In the reaction catalyzed by ammonium acetate,
temperature control to within 5—10 °C is required to
ensure the selectivity of the process; the yield of the final
product is 40—80% (see Ref. 20). Solidꢀstate catalysis on
alumina partly simplifies the synthesis of 4Hꢀchromene
derivatives, their yields being 50—85% (see Ref. 21). The
highest yields of 4Hꢀchromenes (70—95%) were achieved
with catalysts based on zirconium phosphate; however,
this process is long enough (2—15 h) and requires
the temperature to be maintained at 60 °C (see Ref. 22).
Aluminaꢀcatalyzed reactions of salicylaldehydes
with malononitrile give the corresponding (2ꢀaminoꢀ3ꢀ
21
22
2
6
ated at the cathode (Scheme 1).
Scheme 1
Reagents and conditions: electrolysis, 0.05—0.10 F mol–1, R OH.
3
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 582—587, March, 2008.
066ꢀ5285/08/5703ꢀ595 © 2008 Springer Science+Business Media, Inc.
1

5
96
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
Feducovich et al.
Later, we have obtained 6ꢀsubstituted alkyl
1R*,5R*,6R*)ꢀ4,4ꢀdialkoxyꢀ5ꢀcyanoꢀ2ꢀoxoꢀ3ꢀazabiꢀ
cyclo[3.1.0]hexaneꢀ1ꢀcarboxylates from 3ꢀsubstituted
Scheme 3
(
O
R1
alkyl 2,2ꢀdicyanocyclopropaneꢀ1,1ꢀdicarboxylates via
CN
2
X
H
electrocatalytic chain transformation2 (Scheme 2).
7
+
OH
R2
a—e
2a—c
Scheme 2
X
CN
1
R1
X
O
NH2
R2
Reagents and conditions: electrolysis, 0.2 F mol–1, R2OH.
3a—e, g—n
Here, we employed the electrocatalytic chain method
for the synthesis of 4Hꢀchromenes 3a—p under mild
conditions by the coelectrolysis of salicylaldehydes 1a—f
and CH acids 2a—c (Scheme 3). The roomꢀtemperaꢀ
ture reaction in an undivided cell was completed over
X
CN
O
2a—c
X
H
OH
O
NH2
1
5—30 min in an ethanolic solution in the presence of
1
f
3f,o,p
NaBr as an electrolyte (for preliminary communication,
see Refs 28, 29).
Reagents and conditions: electrolysis, ROH, NaBr.
To estimate the synthetic potential of this reaction and
find optimum reaction conditions, first we studied transꢀ
formations of unsubstituted salicylaldehyde (1a) with two
equivalents of malononitrile (2a) and methyl cyanoaceꢀ
tate (2b) into 4Hꢀchromenes 3a and 3g, respectively,
under different conditions (Table 1).
R1
H
Br
NO2
H
Br
R2
H
H
H
OMe
OMe
R1
H
H
Br
Br
NO2
NO2
H
R2
1
a
b
c
d
e
2
a
b
c
X
CN
COOMe
COOEt
3
g
h
i
j
k
l
X
H
H
H
H
H
H
COOMe
COOEt
COOMe
COOEt
COOMe
COOEt
3
a
b
c
d
e
R1
H
Br
NO2
H
R2
H
H
H
OMe
OMe
X
m
n
OMe COOMe
OMe COOEt
CN
CN
CN
CN
CN
H
Table 1. Electrocatalytic transformations of salicylaldehyde (1a) and
malononitrile (2a) or methyl cyanoacetate (2b) into 4Hꢀchromene 3a
3
f
o
p
X
CN
COOMe
COOEt
Br
CH acid
τb
ic
Solvent
Qd
/F mol–1
Yield
(%)
e
/
min /mA cm–2
The highest yields of 4Hꢀchromenes 3a and 3g (95%)
2
a
15
15
15
15
15
15
30
30
30
30
50
25
10
5
10
10
50
25
10
5
EtOH
EtOH
EtOH
EtOH
MeOH
PrOH
EtOH
EtOH
EtOH
EtOH
0.23
0.12
0.05
0.02
0.05
0.05
0.47
0.23
0.09
0.05
3a, 75
3a, 80
3a, 85
3a, 78
3a, 69
3a, 95
3g, 68
3g, 75
3g, 95
3g, 79
were achieved at the current density j = 10 mA cm–
2
;
2
a
2
a
the quantity of electricity Q required for the electrolysis
–
1
2
a
was 0.05 F mol in the case of malononitrile and
–
1
2
a
0
.09 F mol in the case of methyl cyanoacetate. At
2
a
–2
j = 50 mA cm , the yield was somewhat lower, probably
because of undesired electrode processes resulting in oliꢀ
gomerization of the starting CH acids under these condiꢀ
tions. 4HꢀChromene 3a precipitated directly from
the reaction mixture at the end of the reaction. The elecꢀ
trolysis of salicylaldehyde and malononitrile in PrOH
provided the highest yield of 4Hꢀchromene 3a isolated by
simple filtration of the precipitate formed after the comꢀ
pletion of the electrolysis.
2
b
2
b
2
b
2b
a
Reagents and conditions: salicylaldehyde (1a) (10 mmol), CH
acid 2 (20 mmol), NaBr (1 mmol), ethanol (20 mL), iron cathode
2
2
(
5 cm ), graphite anode (5 cm ), 20 °C.
Reaction time.
b
c
d
e
Current density.
Quantity of electricity.
Coelectrolysis of substituted salicylaldehydes 1b—f
and two equivalents of CH acids 2a—c were carried out
Yield with respect to the isolated product. For 3a, m.p. 151—152 °C
cf. Ref. 21: m.p. 150—153 °C); for 3g, m.p. 121—123 °C (cf. Ref.
–
2
under the optimum reaction conditions (j = 10 mA cm
,
(
–1
2
1: m.p. 120—122 °C), the ratio of its diastereomers is 2 : 1
Q = 0.05—0.09 F mol ) (Table 2). The yields of 4Hꢀchroꢀ
menes 3b—p were 83—95%.
(NMR data).

Electrocatalytic synthesis of 4Hꢀchromenes
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
597
According to H and 13C NMR data, 4Hꢀchromeꢀ
nes 3h—p are mixtures of two diastereomers, one of
them being dominant (see Table 2). From thermodyꢀ
namic considerations, the major isomer should have
the 4αR*,4S*ꢀconfiguration.
1
Scheme 4
Based on the results obtained, as well as on previous
data for the mechanisms of the electrocatalytic chain
cyclization of tetracyanocyclopropanes26 and 3ꢀsubstiꢀ
tuted alkyl 2,2ꢀdicyanocyclopropaneꢀ1,1ꢀdicarboxyꢀ
lates,27 we proposed a mechanism for the electrocatalytic
chain transformations of salicylaldehydes and CH acids
into 4Hꢀchromenes (Scheme 4). The cathodic reaction
produces an alkoxide anion that deprotonates the CH
acid in solution. The resulting anion of the CH acid
enters into the Knoevenagel condensation with salicylꢀ
aldehyde, with elimination of the OH anion.30 Subseꢀ
quent steps involve intramolecular cyclization of the conꢀ
densation product and addition of a second molecule
of the CH acid, giving 4Hꢀchromene 3. The regeneꢀ
Table 2. Electrocatalytic transformations of substituted salicylaldeꢀ
hydes 1a—f and CH acids 2a—c into 4Hꢀchromenes 3a—p a
Aldeꢀ
hyde
СН
acid
Yieldb
(%) diastereomersc
Ratio of
M.p./°Cd
1
a
2a
2a
2a
2a
2a
2a
2c
2b
2c
2b
2c
2b
2c
2b
2c
3a, 95
3b, 85
3c, 93
3d, 95
3e, 86
3f, 91
3h, 91
3i, 93
3j, 88
3k, 85
3l, 87
3m, 84
3n, 89
3o, 85
3p, 83
—
—
—
—
—
151—152 (150—153)21
160—161
169—170
173—174 (173)21
166—167
1
b
1c
1
d
1
1
e
f
rated anion of the CH acid reacts with another saliꢀ
cylaldehyde molecule, thus opening the next cycle
of the catalytic chain process. Therefore, the forꢀ
mation of only one alkoxide anion at the cathode is
theoretically sufficient for the complete conversion of
salicylaldehyde and a CH acid into the corresponding
4Hꢀchromene.
2
1
—
159—160 (160)
141—143 (142—143)2
126—127
0
0
1
a
2 : 1
3 : 2
2 : 1
3 : 2
5 : 2
2 : 1
2 : 1
7 : 2
2 : 1
1
b
1
b
107—108 (104—105)2
155—156 (156)22
134—135
1c
1c
1e
1e
156—157 (150—153)2
125—126 (126—127)2
1
0
To sum up, functionalized 4Hꢀchromenes can be obꢀ
tained in high yields by direct transformation of salicylꢀ
aldehydes and CH acids containing the cyano group
in a simple electrocatalytic system under mild condiꢀ
tions. The advantages of the electrocatalytic chain proꢀ
cess we proposed include the short reaction time, simple
equipment, an undivided cell, inexpensive starting
reagents, and a simple procedure for isolation of the final
products.
1
f
150—152
127—128
1f
a
Reagents and conditions: salicylaldehyde 1 (10 mmol), CH acid 2
2
(20 mmol), NaBr (1 mmol), ethanol (20 mL), iron cathode (5 cm ),
2
graphite anode (5 cm ), 20 °C.
b
Yield with respect to the isolated product.
According to NMR spectroscopic data.
The literature data are given in parentheses.
c
d

5
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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
Feducovich et al.
Experimental
184 (17), 156 (9), 128 (31), 114 (6), 101 (27), 66 (100), 50 (31),
3
8 (41). IR (KBr), ν/cm– : 3436, 3336, 2908, 2196, 1596, 1528,
1
Melting points were determined on a Gallenkamp instrument
1432, 1268, 1220, 1092.
(3ꢀAminoꢀ2ꢀcyanoꢀ1Hꢀbenzo[f]chromenꢀ4ꢀyl)malononitrile
(3f), m.p. 159—160 °C (cf. Ref. 21: m.p. 160 °C). H NMR, δ: 5.03
(d, 1 H, J = 3.6 Hz); 5.30 (d, 1 H, J = 3.6 Hz); 7.33 (d, 1 H, J = 8.9
Hz); 7.50—7.75 (m, 4 H); 7.96—8.05 (m, 2 H); 8.30 (d, 1 H,
J = 8.3 Hz).
Methyl 2ꢀaminoꢀ4ꢀ(1ꢀcyanoꢀ2ꢀmethoxyꢀ2ꢀoxoethyl)ꢀ4Hꢀ
chromeneꢀ3ꢀcarboxylate (3g), m.p. 121—123 °C (cf. Ref. 21:
1
(
Sanyo). NMR spectra were recorded on Bruker WMꢀ250 (250 ( H)
1
3
1
1
and 63 MHz ( C)) and Bruker ACꢀ200 instruments (200 ( H) and
13
5
0 MHz ( C)) in DMSOꢀd . Chemical shifts are given on the δ scale
6
with reference to SiMe . IR spectra were recorded on a Specord
4
M82 FTIR spectrometer (KBr pellets) with the Soft Spectra softꢀ
ware. Mass spectra (EI, 70 eV) were recorded on a Finnigan MAT
INCOS 50 mass spectrometer (direct inlet probe).
The starting reagents (salicylaldehyde, substituted salicylaldeꢀ
hydes, malononitrile, and methyl and ethyl cyanoacetates) were
purchased from Aldrich and Acros.
1
m.p. 120—122 °C). Major diastereomer. H NMR, δ: 3.79 (s, 3 H,
OMe); 3.81 (s, 3 H, OMe); 4.00 (d, 1 H, CH, J = 3.8 Hz); 4.71
(d, 1 H, CH, J = 3.8 Hz); 7.05—7.91 (m, 6 H, Ar and NH ).
2
13
4HꢀChromenes 3 (general procedure). A solution of salicylaldeꢀ
C NMR, δ: 36.3, 46.9, 50.8, 53.1, 71.2, 116.1, 116.3, 120.3,
hyde 1 (10 mmol), CH acid 2 (20 mmol), and NaBr (1 mmol) in
PrOH or EtOH (20 mL) were subjected to roomꢀtemperature
electrolysis in a stirred undivided cell fitted with a graphite anode
124.6, 128.0, 129.4, 150.1, 162.6, 165.7, 167.7. Minor diastereꢀ
omer. H NMR, δ: 3.68 (s, 3 H, OMe); 3.77 (s, 3 H, OMe); 3.95
1
(d, 1 H, CH, J = 3.5 Hz); 4.62 (d, 1 H, CH, J = 3.5 Hz); 7.05—7.91
2
13
and an iron cathode (electrode surface area 5 cm ) at a constant
(m, 6 H, Ar and NH2). C NMR, δ: 36.7, 47.3, 50.6, 52.9, 70.4,
current density of 10 mA cm–2. The quantity of electricity
115.8, 116.2, 121.7, 124.8, 128.1, 129.1, 150.0, 162.8, 165.5, 167.9.
Ethyl 2ꢀaminoꢀ4ꢀ(1ꢀcyanoꢀ2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ4Hꢀchromeꢀ
neꢀ3ꢀcarboxylate (3h), m.p. 141—143 °C (cf. Ref. 20: m.p.
–
1
passed through the cell was 0.05 F mol for malononitrile 2a and
–1
0
.09 F mol for alkyl cyanoacetates 2b,c. After the electrolysis was
1
completed, the precipitates of 4Hꢀchromenes 3a—e,f were filtered
off, washed with cooled 85% EtOH, and dried in air. 4HꢀChromenes
142—143 °C). Major diastereomer. H NMR, δ: 1.17 (t, 3 H, Me,
J = 7.3 Hz); 1.25 (t, 3 H, Me, J = 7.3 Hz); 3.98—4.22 (m, 4 H,
3
d—n,o,p were isolated by evaporation of the solution to dryness
and crystallized from 85% EtOH.
2ꢀAminoꢀ3ꢀcyanoꢀ4Hꢀchromenꢀ4ꢀyl)malononitrile (3a),
2 OCH ); 4.33 (d, 1 H, CH, J = 3.7 Hz); 4.59 (d, 1 H, CH,
2
J = 3.7 Hz); 7.02—7.45 (m, 4 H, Ar); 7.80 (s, 2 H, NH ).
2
13
(
C NMR, δ: 13.8, 14.4, 36.4, 47.1, 59.2, 62.2, 71.4, 116.1, 116.2,
1
m.p. 151—152 °C (cf. Ref. 21: m.p. 150—153 °C). H NMR, δ: 4.59
d, 1 H, J= 3.8 Hz); 5.08 (d, 1 H, J= 3.8 Hz); 7.14 (d, 1 H, J= 8.2 Hz);
.27 (t, 1 H, J = 7.5 Hz, J = 7.5 Hz); 7.38—7.53 (m, 4 H).
120.4, 124.6, 128.1, 129.4, 150.1, 162.6, 165.2, 167.3. Minor
1
(
7
diastereomer. H NMR, δ: 1.11 (t, 3 H, Me, J = 7.4 Hz); 1.22
(t, 3 H, Me, J = 7.4 Hz); 3.97—4.22 (m, 5 H, 2 OCH and CH);
1
2
2
(
2ꢀAminoꢀ6ꢀbromoꢀ3ꢀcyanoꢀ4Hꢀchromenꢀ4ꢀyl)malononitrile
3b), m.p. 160—161 °C. Found (%): C, 49.43; H, 2.14; Br, 25.46;
N, 17.70. C H BrN O. Calculated (%): C, 49.55; H, 2.24;
4.54 (d, 1 H, CH, J = 3.7 Hz); 7.02—7.45 (m, 4 H, Ar); 7.80
13
(
(s, 2 H, NH2). C NMR, δ: 13.6, 14.3, 36.7, 46.4, 59.1, 61.9, 71.2,
115.8, 116.7, 121.5, 124.7, 128.7, 129.1, 149.9, 162.7, 165.0, 167.6.
Methyl 2ꢀaminoꢀ6ꢀbromoꢀ4ꢀ(1ꢀcyanoꢀ2ꢀmethoxyꢀ2ꢀoxoethꢀ
yl)ꢀ4Hꢀchromeneꢀ3ꢀcarboxylate (3i), m.p. 159—160 °C. Found
(%): C, 47.13; H, 3.53; Br, 20.81; N, 7.19. C H BrN O . Calcuꢀ
13
7
4
1
Br, 25.36; N, 17.78. H NMR, δ: 4.65 (d, 1 H, J = 3.8 Hz); 5.15
d, 1 H, J = 3.8 Hz); 7.12 (d, 1 H, J = 8.7 Hz); 7.55—7.65 (m, 3 H);
.73 (s, 1 H). C NMR, δ: 32.3, 36.7, 48.5, 112.6, 112.8, 116.3,
18.5, 119.0, 120.3, 131.3, 132.8, 149.0, 163.2. MS (EI, 70 eV),
m/z (Irel (%)): 315 [M] , (0.2), 248 (27), 221 (18), 170 (6), 143 (8),
14 (49), 88 (17), 66 (100), 50 (24), 38 (48). IR (KBr), ν/cm–
460, 3348, 2884, 2196, 1596, 1480, 1428, 1268, 1228, 1036.
(
3c), m.p. 169—170 °C. Found (%): C, 55.43; H, 2.61; N, 24.80.
C H N O . Calculated (%): C, 55.52; H, 2.51; N, 24.90. H NMR,
δ: 4.80 (d, 1 H, J = 3.8 Hz); 5.22 (d, 1 H, J = 3.8 Hz); 7.40 (d, 1 H,
J = 9.0 Hz); 7.78 (s, 2 H); 8.29 (d, 1 H, J = 9.0 Hz); 8.51 (s, 1 H).
C NMR, δ: 32.3, 36.7, 48.6, 112.5, 112.7, 117.8, 118.6, 119.2,
25.1, 125.7, 143.8, 154.0, 162.6. MS (EI, 70 eV), m/z (Irel (%)):
81 [M] (0.1), 215 (34), 185 (7), 158 (8), 142 (3), 114 (38),
8 (15), 66 (100), 50 (16), 38 (46). IR (KBr), ν/cm : 3408, 3320,
904, 2204, 1612, 1528, 1424, 1264, 1240, 1029.
(
(
7
1
13
1
5
13
2
5
–1
lated (%): C, 47.26; H, 3.44; Br, 20.96; N, 7.35. IR (KBr), ν/cm :
+
3428, 3312, 2956, 2252, 1744, 1688, 1524, 1436, 1232, 1024.
1
1
1
3
:
Major diastereomer. H NMR, δ: 3.65 (s, 3 H, OMe); 3.72 (s, 3 H,
OMe); 4.40 (d, 1 H, CH, J = 3.6 Hz); 4.52 (d, 1 H, CH, J = 3.6 Hz);
7.08 (d, 1 H, Ar, J = 8.7 Hz); 7.18 (s, 1 H, Ar); 7.57 (d, 1 H, Ar,
2ꢀAminoꢀ3ꢀcyanoꢀ6ꢀnitroꢀ4Hꢀchromenꢀ4ꢀyl)malononitrile
13
(
J = 8.7 Hz); 7.91 (s, 2 H, NH2). C NMR, δ: 36.0, 46.8, 50.9,
1
53.1, 70.7, 115.9, 116.2, 118.4, 124.2, 130.6, 132.2, 149.4, 162.2,
13
7
5 3
1
165.6, 167.5. Minor diastereomer. H NMR, δ: 3.57 (s, 3 H, OMe);
3.62 (s, 3 H, OMe); 4.26 (d, 1 H, CH, J = 3.0 Hz); 4.55 (d, 1 H,
CH, J = 3.0 Hz); 7.05 (d, 1 H, Ar, J = 8.5 Hz); 7.52 (d, 1 H, Ar,
13
13
1
2
8
2
J = 8.5 Hz); 7.62 (s, 1 H, Ar); 7.89 (s, 2 H, NH2). C NMR, δ:
36.3, 47.0, 50.8, 53.0, 69.9, 116.0, 116.1, 118.1, 122.9, 131.4,
132.0, 149.3, 162.5, 165.4, 167.7.
+
–
1
Ethyl 2ꢀaminoꢀ6ꢀbromoꢀ4ꢀ(1ꢀcyanoꢀ2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ
4Hꢀchromeneꢀ3ꢀcarboxylate (3j), m.p. 107—108 °C (cf. Ref. 20:
2ꢀAminoꢀ3ꢀcyanoꢀ8ꢀmethoxyꢀ4Hꢀchromenꢀ4ꢀyl)malonoꢀ
1
1
nitrile (3d), m.p. 173—174 °C (cf. Ref. 21: m.p. 173 °C). H NMR,
δ: 3.85 (s, 3 H); 4.55 (d, 1 H, J = 3.9 Hz); 5.05 (d, 1 H, J = 3.9 Hz);
m.p. 104—105 °C). Major diastereomer. H NMR, δ: 1.18 (t, 3 H,
Me, J = 7.3 Hz); 1.22 (t, 3 H, Me, J = 7.3 Hz); 4.02—4.23 (m, 4 H,
7
.02 (d, 1 H, J = 7.3 Hz); 7.10—7.25 (m, 2 H); 7.48 (s, 2 H).
2ꢀAminoꢀ6ꢀbromoꢀ3ꢀcyanoꢀ8ꢀmethoxyꢀ4Hꢀchromenꢀ4ꢀyl)ꢀ
two OCH ); 4.37 (d, 1 H, CH, J = 3.8 Hz); 4.54 (d, 1 H, CH,
J = 3.8 Hz); 7.08 (d, 1 H, Ar, J = 8.6 Hz); 7.20 (s, 1 H, Ar); 7.55
2
(
malononitrile (3e), m.p. 166—167 °C. Found (%): C, 48.64;
(d, 1 H, Ar, J = 8.6 Hz); 7.84 (s, 2 H, NH ). Minor diastereomer.
H NMR, δ: 1.12 (t, 3 H, Me, J= 7.3 Hz); 1.24 (t, 3 H, Me, J= 7.3 Hz);
2
1
H, 2.70; Br, 23.21; N, 16.16. C H BrN O . Calculated (%):
1
4
9
4
2
1
C, 48.72; H, 2.63; Br, 23.15; N, 16.23. H NMR, δ: 3.85 (s, 3 H);
4.02—4.23 (m, 5 H, two OCH and CH); 4.53 (d, 1 H, CH, J = 3.0
2
4
7
1
.56 (d, 1 H, J = 3.8 Hz); 5.09 (d, 1 H, J = 3.8 Hz); 7.23 (s, 1 H);
.30 (s, 1 H); 7.57 (s, 2 H). 13C NMR, δ: 32.2, 36.8, 48.5, 56.4,
Hz); 7.02 (d, 1 H, Ar, J = 8.4 Hz); 7.55 (d, 1 H, Ar, J = 8.4 Hz);
7.62 (s, 1 H, Ar); 7.89 (s, 2 H, NH ).
2
12.7, 112.8, 115.8, 116.2, 119.0, 120.5, 122.0, 138.6, 148.0, 163.1.
Methyl 2ꢀaminoꢀ4ꢀ(1ꢀcyanoꢀ2ꢀmethoxyꢀ2ꢀoxoethyl)ꢀ6ꢀnitroꢀ
4Hꢀchromeneꢀ3ꢀcarboxylate (3k), m.p. 155—156 °C (cf. Ref. 22:
+
MS (EI, 70 eV), m/z (Irel (%)): 345 [M] (0.1), 278 (97), 235 (11),

Electrocatalytic synthesis of 4Hꢀchromenes
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
599
1
1
m.p. 156 °C). Major diastereomer. H NMR, δ: 3.70 (s, 3 H,
1744, 1684, 1520, 1444, 1220, 1080. Major diastereomer. H NMR,
δ: 3.64 (s, 3 H, OMe); 3.82 (s, 3 H, OMe); 4.23 (d, 1 H, CH, J = 2.0
Hz); 5.20 (d, 1 H, CH, J = 2.0 Hz); 7.35 (d, 1 H, Ar, J = 9.2 Hz);
OMe); 3.75 (s, 3 H, OMe); 4.48 (d, 1 H, CH, J = 3.7 Hz); 4.67
d, 1 H, CH, J = 3.7 Hz); 7.33 (d, 1 H, Ar, J = 8.9 Hz); 7.91 (s, 3 H,
Ar and NH ); 8.20 (d, 1 H, Ar, J = 8.9 Hz). C NMR, δ: 36.1,
(
13
13
7.52—8.08 (m, 7 H, Ar, NH2). C NMR, δ: 33.7, 46.8, 50.9,
2
4
1
6.6, 50.9, 53.2, 70.5, 115.8, 117.4, 121.6, 124.1, 125.1, 143.4,
54.5, 161.5, 165.4, 167.2. Minor diastereomer. H NMR, δ: 3.65
53.2, 70.3, 114.5, 116.0, 116.6, 121.5, 125.4, 128.2, 129.3, 130.1,
130.3, 130.9, 148.0, 162.9, 165.9, 168.0. Minor diastereomer. H
1
1
(
4
(
s, 3 H, OMe); 3.78 (s, 3 H, OMe); 4.32 (d, 1 H, CH, J = 3.7 Hz);
.65 (d, 1 H, CH, J = 3.7 Hz); 7.30 (d, 1 H, Ar, J = 8.9 Hz); 7.91
NMR, δ: 3.47 (s, 3 H, OMe); 3.75 (s, 3 H, OMe); 4.31 (d, 1 H, CH,
J = 3.7 Hz); 5.24 (d, 1 H, CH, J = 3.7 Hz); 7.52—8.08 (m, 8 H, Ar,
NH2). C NMR, δ: 33.2, 46.1, 50.8, 52.9, 72.3, 114.0, 116.4,
13
13
s, 3 H, Ar and NH ); 8.25 (d, 1 H, Ar, J = 8.9 Hz). C NMR, δ:
2
3
1
6.0, 46.6, 50.8, 53.0, 69.9, 115.9, 117.5, 122.9, 124.1, 124.9,
43.7, 154.3, 161.7, 165.2, 167.4.
116.7, 122.1, 125.2, 127.4, 128.9, 130.2, 130.4, 130.6, 148.8,
162.8, 165.7, 167.7.
Ethyl 2ꢀaminoꢀ4ꢀ(1ꢀcyanoꢀ2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ6ꢀnitroꢀ
Hꢀchromeneꢀ3ꢀcarboxylate (3l), m.p. 134—135 °C. Found (%):
Ethyl 3ꢀaminoꢀ1ꢀ(1ꢀcyanoꢀ2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ1Hꢀbenzoꢀ
[f]chromeneꢀ2ꢀcarboxylate (3p), m.p. 127—128 °C. Found (%):
C, 66.19; H, 5.37; N, 7.18. C H N O . Calculated (%): C, 66.31;
4
C, 54.26; H, 4.62; N, 11.07. C H N O . Calculated (%): C, 54.40;
1
7
17
3
7
21 20
2
5
–
1
–1
H, 4.57; N, 11.20. IR (KBr), ν/cm : 3428, 3316, 2992, 2260,
740, 1692, 1520, 1472, 1228, 1040. Major diastereomer. H NMR,
H, 5.30; N, 7.36. IR (KBr), ν/cm : 3456, 3328, 2976, 2256,
1
1
1
1740, 1676, 1516, 1464, 1228, 1076. Major diastereomer. H NMR,
δ: 1.23 (t, 3 H, Me, J = 7.3 Hz); 1.28 (t, 3 H, Me, J = 7.3 Hz);
δ: 1.26 (t, 3 H, Me, J = 7.3 Hz); 1.29 (t, 3 H, Me, J = 7.3 Hz);
3.85—4.28 (m, 5 H, 2 OCH2 and CH); 5.22 (d, 1 H, CH,
J = 1.8 Hz); 7.34 (d, 1 H, Ar, J = 9.2 Hz); 7.50—8.10 (m, 7 H, Ar
4
4
.05—4.27 (m, 4 H, two OCH ); 4.47 (d, 1 H, CH, J = 3.7 Hz);
2
.75 (d, 1 H, CH, J = 3.7 Hz); 7.39 (d, 1 H, Ar, J = 9.1 Hz); 7.93
13
13
(
s, 2 H, NH ); 8.02 (s, 1 H, Ar); 8.28 (d, 1 H, Ar, J = 9.1 Hz).
C
and NH2). C NMR, δ: 13.9, 14.4, 33.5, 46.7, 59.2, 62.1, 71.0,
2
NMR, δ: 13.8, 14.2, 36.0, 46.9, 59.5, 62.5, 70.7, 116.0, 117.6,
21.8, 124.2, 125.3, 143.4, 154.6, 161.5, 165.0, 166.9. Minor
diastereomer. H NMR, δ: 1.07 (t, 3 H, Me, J = 7.3 Hz); 1.16
114.8, 116.1, 116.6, 121.6, 125.3, 128.1, 128.9, 129.1, 130.1, 130.9,
147.9, 162.8, 165.3, 167.6. Minor diastereomer. H NMR, δ: 0.99
(t, 3 H, Me, J = 7.3 Hz); 1.34 (t, 3 H, Me, J = 7.3 Hz); 3.85—4.28
1
1
1
(
(
(
t, 3 H, Me, J = 7.3 Hz); 4.05—4.27 (m, 4 H, two OCH ); 4.33
d, 1 H, CH, J = 3.0 Hz); 4.74 (d, 1 H, CH, J = 3.0 Hz); 7.34
(m, 5 H, 2 OCH and CH); 5.25 (d, 1 H, CH, J = 3.7 Hz);
2
2
13
7.50—8.10 (m, 8 H, Ar and NH2). C NMR, δ: 13.3, 14.3, 33.2,
46.2, 59.3, 62.0, 72.3, 114.1, 116.5, 116.7, 122.1, 125.1, 127.3,
128.8, 129.3, 130.0, 130.6, 148.7, 162.6, 165.2, 167.4.
d, 1 H, Ar, J = 8.5 Hz); 7.91 (s, 2 H, NH ); 8.26 (d, 1 H, Ar,
2
13
J = 8.5 Hz); 8.41 (s, 1 H, Ar); C NMR, δ: 13.6, 14.3, 35.8, 45.9,
5
1
9.4, 62.2, 70.5, 116.3, 117.3, 122.8, 124.9, 125.1, 143.6, 154.5,
61.6, 164.8, 167.2.
A. S. Dorofeev acknowledges financial support of
the Russian Science Support Foundation during his postꢀ
graduate studies in 2007.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 06ꢀ03ꢀ32181a)
and the Council on Grants of the President of the Rusꢀ
sian Federation (Program for Support of Leading Scienꢀ
tific Schools of the Russian Federation, Grant NSh
5022.2006.3).
Methyl 2ꢀaminoꢀ4ꢀ(1ꢀcyanoꢀ2ꢀmethoxyꢀ2ꢀoxoethyl)ꢀ8ꢀmethꢀ
oxyꢀ4Hꢀchromeneꢀ3ꢀcarboxylate (3m), m.p. 156—157 °C (cf. Ref. 21:
1
m.p. 150—153 °C). Major diastereomer. H NMR, δ: 3.67 (s, 3 H,
OMe); 3.71 (s, 3 H, OMe); 3.81 (s, 3 H, OMe); 4.38 (d, 1 H, CH,
J = 3.8 Hz); 4.50 (d, 1 H, CH, J = 3.8 Hz); 6.56 (d, 1 H, Ar
J = 8.8 Hz); 7.00—7.18 (m, 2 H, Ar); 7.88 (s, 2 H, NH ).
2
1
3
C NMR, δ: 36.4, 46.9, 50.8, 53.0, 55.7, 71.0, 112.1, 116.1, 118.9,
1
21.1, 124.5, 139.4, 147.2, 162.6, 165.6, 167.7. Minor diastereꢀ
1
omer. H NMR, δ: 3.57 (s, 3 H, OMe); 3.65 (s, 3 H, OMe); 3.80
(
s, 3 H, OMe); 4.14 (d, 1 H, CH, J = 3.7 Hz); 4.51 (d, 1 H, CH,
J = 3.7 Hz); 6.91 (d, 1 H, Ar, J = 8.8 Hz); 7.00—7.18 (m, 2 H, Ar);
References
7
1
.90 (s, 2 H, NH2). 13C NMR, δ: 36.8, 47.3, 50.7, 52.9, 55.8, 70.3,
11.8, 116.2, 119.6, 122.7, 124.7, 139.3, 147.0, 162.8, 165.5, 167.9.
Ethyl 2ꢀaminoꢀ4ꢀ(1ꢀcyanoꢀ2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ8ꢀmethꢀ
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oxyꢀ4Hꢀchromeneꢀ3ꢀcarboxylate (3n), m.p. 125—126 °C (cf. Ref. 20:
1
m.p. 126—127 °C). Major diastereomer. H NMR, δ: 1.17 (t, 3 H,
Me, J = 7.3 Hz); 1.20 (t, 3 H, Me, J = 7.3 Hz); 3.81 (s, 3 H, OMe);
3
.98—4.21 (m, 4 H, 2 OCH ); 4.30 (d, 1 H, CH, J = 3.7 Hz); 4.52
2
(
(
4
1
d, 1 H, CH, J = 3.7 Hz); 6.59 (d, 1 H, Ar, J = 8.6 Hz); 7.00—7.18
m, 2 H, Ar); 7.85 (s, 2 H, NH2). 13C NMR, δ: 13.8, 14.3, 36.5,
4. M. Gill, Aust. J. Chem., 1995, 48, 1.
5. V. S. Parmar, S. C. Jain, K. S. Bisht, R. Jain, P. Taneja, A. Jha,
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1
39.4, 147.2, 162.6, 165.1, 167.4. Minor diastereomer. H NMR,
δ: 1.10 (t, 3 H, Me, J = 7.3 Hz); 1.21 (t, 3 H, Me, J = 7.3 Hz); 3.81
s, 3 H, OMe); 3.98—4.21 (m, 5 H, 2 OCH and CH); 4.50 (d, 1 H,
CH, J = 3.7 Hz); 6.93 (d, 1 H, Ar, J = 8.8 Hz); 7.00—7.18 (m, 2 H,
Ar); 7.85 (s, 2 H, NH2). 13C NMR, δ: 13.5, 14.2, 36.7, 46.4, 55.7,
6. V. V. Polyakov, Chem. Nat. Compd., 1999, 35, 21.
7. W. Sun, L. J. Cama, E. T. Birzin, S. Warrier, L. Locco,
R. Mosley, M. L. Hammond, S. P. Rohrer, Bioorg. Med. Chem.
Lett., 2006, 16, 1468.
(
2
5
1
9.1, 61.9, 71.1, 111.7, 116.6, 119.6, 122.3, 124.5, 139.2, 147.0,
62.5, 165.0, 167.5.
Methyl 3ꢀaminoꢀ1ꢀ(1ꢀcyanoꢀ2ꢀmethoxyꢀ2ꢀoxoethyl)ꢀ1Hꢀ
8. A. V. Stachulski, N. G. Berry, A. C. L. Low, S. L. Moores,
E. Row, D. C. Warhurst, I. S. Adagu, J.ꢀF. Rossignol, J. Med.
Chem., 2006, 49, 1450.
benzo[f]chromeneꢀ2ꢀcarboxylate (3o), m.p. 150—152 °C. Found (%):
9. C. Garino, F. Bihel, N. Pietrancosta, Y. Laras, G. Quiliver,
I. Woo, P. Klein, J. Bain, J.ꢀL. Boucher, J.ꢀL. Kraus, Bioorg.
Med. Chem. Lett., 2005, 15, 135.
C, 64.61; H, 4.53; N, 7.81. C H N O . Calculated (%): C, 64.77;
1
9
16
2
5
–
1
H, 4.58; N, 7.95. IR (KBr), ν/cm : 3468, 3316, 2956, 2252,

6
00
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1. D. R. Anderson, S. Hedge, E. Reinhard, L. Gomez, W. F.
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1
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2. M. Curini, F. Epifano, S. Chimichi, F. Montanari, M. Noccꢀ
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in revised form January 10, 2008