Methyl-and ethyl carbonates derived from vanillin and vanillal in the synthesis of nitrogen-containing compounds

Article abstract of DOI:10.1134/S1070363207050155

Reactions of 4-hydroxy-3-methoxybenzaldehyde and 3-ethoxy-4- hydroxybenzaldehyde with methyl and ethyl chloroformates in the presence of pyridine gave the corresponding methyl and ethyl carbonates which were brought into condensation with biphenyl-4-amine, naphthalen-1-and-2-amines, and 3-and 4-aminobenzoic acids to obtain the corresponding Schiff bases. Alkyl 4-(9,9-dimethyl-11-oxo-7,8,9,10,11,12-hexahydrobenzo[a]acridin-12-yl) -2-alkoxyphenyl carbonates were selectively synthesized by cascade heterocyclization of naphthalen-2-amine, 5,5-dimethylcyclohexane-1,3-dione, and 4-formyl-2-methoxy(or ethoxy)phenyl methyl(or ethyl) carbonates. Ammonium salts were obtained from the benzoacridine derivatives and Schiff bases derived from aminobenzoic acids. Nauka/Interperiodica 2007.

Full text of DOI:10.1134/S1070363207050155

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 5, pp. 905 910.
Pleiades Publishing, Ltd., 2007.
Original Russian Text E.A. Dikusar, N.G. Kozlov, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 5, pp. 809 814.
Methyl- and Ethyl Carbonates Derived from Vanillin
and Vanillal in the Synthesis of Nitrogen-containing Compounds
E. A. Dikusar and N. G. Kozlov
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
e-mail: loc@ifoch.bas-net.by
Received November 8, 2006
Abstract Reactions of 4-hydroxy-3-methoxybenzaldehyde and 3-ethoxy-4-hydroxybenzaldehyde with
methyl and ethyl chloroformates in the presence of pyridine gave the corresponding methyl and ethyl car-
bonates which were brought into condensation with biphenyl-4-amine, naphthalen-1- and -2-amines, and 3-
and 4-aminobenzoic acids to obtain the corresponding Schiff bases. Alkyl 4-(9,9-dimethyl-11-oxo-7,8,9,10,
11,12-hexahydrobenzo[a]acridin-12-yl)-2-alkoxyphenyl carbonates were selectively synthesized by cascade
heterocyclization of naphthalen-2-amine, 5,5-dimethylcyclohexane-1,3-dione, and 4-formyl-2-methoxy(or
ethoxy)phenyl methyl(or ethyl) carbonates. Ammonium salts were obtained from the benzoacridine derivatives
and Schiff bases derived from aminobenzoic acids.
DOI: 10.1134/S1070363207050155
Vanillin (4-hydroxy-3-methoxybenzaldehyde) and
vanillal (3-ethoxy-4-hydroxybenzaldehyde) are natural
phytogenous aromatic hydroxy aldehydes. They are
convenient synthons for the design of biologically
active compounds and introduction of pharmacophoric
fragments thereinto [1 3]. The presence of reactive
hydroxy and formyl groups in their molecules ensures
preparation of compounds having various pharmaco-
phoric moieties and functional groups [4, 5].
of a catalyst to give 70 75% of benzo[a]acridinones
Va Vd. Alkyl 4-(9,9-dimethyl-11-oxo-7,8,9,10,11,12-
hexahydrobenzo[a]acridin-12-yl)-2-alkoxyphenyl car-
bonates Va Vd were also synthesized by another
method, three-component condensation of the cor-
responding aldehydes with naphthalen-2-amine and
dimedone. As shown in [9 12], such condensations
provide effective and selective synthetic routes to
fused nitrogen-containing heterocycles. The use in
these condensations of aldehydes having an alkyl
carbonate moiety could give rise to functionalized aza
heterocycles containing a partially hydrogenated
quinoline ring, which can be regarded as analogs of
quinoline antibiotics, pesticides, and compounds
exhibiting antitumor, bactericide, and antienzyme
activity [13 17].
In the present article we report on the synthesis of
previously unknown alkyl 2-alkoxy-4-formyl carbo-
nates by reactions of vanillin (Ia) and vanillal (Ib)
with methyl and ethyl chloroformate in anhydrous
benzene in the presence of pyridine. The reactant ratio
I alkyl chloroformate pyridine was equimolar, as in
the procedure we developed previously for the
synthesis of analogous carboxylic acid esters [6, 7].
The corresponding methyl and ethyl carbonates IIa
IIe were isolated in 90 93% yield.
The condensation of aldehydes IIa IId with
naphthalen-2-amine and dimedone was performed
with equimolar amounts of the reactants on heating in
ethanol in the absence of a catalyst. The formation of
fused heterocyclic product is the result of a series of
transformations. Presumably, initial reaction of al-
dehyde II with naphthalen-2-amine gives Schiff base
III, and addition of dimedone to the latter produces
the corresponding amino diketone which undergoes
hydramine fission in alcoholic medium. The exocyclic
double bond in 2-arylmethylidenecyclohexane-1,3-
dione thus formed is activated due to conjugation with
the neighboring carbonyl group, and it takes up
naphthalene-2-amine at the most electron-rich carbon
By condensation of carbonates IIa IId with bi-
phenyl-4-amine, naphthalen-1- and -2-amines, and 3-
and 4-aminobenzoic acids in boiling anhydrous
methanol we obtained new Schiff bases IIIa IIIl and
IVa IVh in 83 92% yield. The reactions were com-
plete in 15 20 min in the absence of a catalyst, which
favored conservation of labile carbonate moeties [5, 8].
Schiff bases IIIi IIIl smoothly reacted with an
equimolar amount of dimedone (5,5-dimethylcyclo-
hexane-1,3-dione) on heating in ethanol in the absence
905

906
DIKUSAR, KOZLOV
NR3
O
O
H2NR3
R2OCOCl
Py
R1O
R1O
R1O
OR2
OR2
O
OH
O
O
O
Ia, Ib
IIa IId
IIIa IIIl
NH2
+
HO
O
NH2
HOOC
HO
O
HOOC
OR1
R2O
O
O
N
O
NH
R1O
OR2
O
O
IVa IVh
Va Vd
OR1
R4O
O
R2O
O
O
O
O
+ NH2
OR5
N
OOC
VIa VIp
I, R1 = Me (a), Et (b); II, R1 = R2 = Me (a), R = Me, R2 = Et (b), R = Et, R2 = Me (c), R = R2 = Et (d); III, R1 = R2 =
Me, R3 = 4- PhC6H4 (a), R1 = Me, R2 = Et, R3 = 4-PhC6H4 (b), R1 = Et, R2 = Me, R3 = 4-PhC6H4 (c), R1 = R2 = Et,
R3 = 4-PhC6H4 (d); R1 = R2 = Me, R3 = 1-C10H7 (e), R1 = Me, R2 = Et, R3 = 1-C10H7 (f), R1 = Et, R2 = Me, R3 =
1-C10H7 (g), R1 = R2 = Et, R3 = 1-C10H7 (h), R1 = R2 = Me, R2 = 2-C10H7 (i), R1 = Me, R2 = Et, R3 = 2-C10H7 (j), R1 =
Et, R2 = Me, R3 = 2-C10H7 (k), R1 = R2 = Et, R3 = 2-C10H7 (l); IV, 3-COOH, R1 = R2 = Me (a), R1 = Me, R2 = Et (b),
R1 = Et, R2 = Me (c), R1 = R2 = Et (d), 4-HOCO, R1 = R2 = Me (e), R1 = Me, R2 = Et (f), R1 = Et, R2 = Me (g), R1 =
R2 = Et (h); V, R1 = R2 = Me (a), R1 = Me, R2 = Et (b), R1 = Et, R2 = Me (c), R1 = R2 = Et (d); VI, 3-COOH, R1 = R2 =
R3 = R4 = Me (a), 3-COOH, R1 = R2 = R4 = Me, R3 = Et (b), 4-COOH, R1 = R2 = R3 = Me, R4 = Et (c), 4-COOH, R1 =
R2 = Me, R3 = R4 = Et (d), 3-COOH, R1 = R3 = R4 = Me, R2 = Et (e), 3-COOH, R1 = R4 = Me, R2 = R3 = Et (f),
4-COOH, R1 = R3 = Me, R2 = R4 = Et (g), 4-COOH, R1 = Me, R2 = R3 = R4 = Et (h), 3-COOH, R1 = Et, R2 = R3 = R4 =
Me (i), 3-COOH, R1 = R3 = Et, R2 = R4 = Me (j), 4-COOH, R1 = R4 = Et, R2 = R3 = Me (k), 4-COOH, R1 = R3 = R4 =
Et, R2 = Me (l), 3-COOH, R1 = R2 = Et, R3 = R4 = Me (m), 3-COOH, R1 = R2 = R3 = Et, R4 = Me (n), 4-COOH, R1 =
R2 = R4 = Et, R3 = Me (o), 4-COOH, R1 = R2 = R3 = R4 = Et (p).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

METHYL- AND ETHYL CARBONATES DERIVED FROM VANILLIN
position with respect to the amino
907
atom in the
(3000); Schiff bases IIIa IIIl and IVa IVh: 206
(48000), 273 (29000), 331 (24000) (IIIa IIId); 207
(27000), 227 (26000), 260 (8000), 290 (5000), 305
(6000), 340 (3000) (IIIe IIIh); 225 (28000), 270
(17000), 325 (10000), 357 (7000) (IIIi IIIl); 204
(17000), 221 (29000), 250 (10000), 306 (3000)
(IVa IVd); 205 (23000), 220 (18000), 280 (22000),
295 (22000), 315 (12000) (IVe IVh); benzo[a]acri-
dinones Va Vd: 217 (29000), 232 (35000), 270
(10000), 281 (14000), 292 (15000), 326 (3000), 339
(13000), 370 (8000); salts VIa, VIb, VIe, VIf, VIi,
VIj, VIm, and VIn derived from 3-aminobenzoic acid:
217 (58000), 231 (61000), 265 (25000), 280 (27000),
292 (27000), 325 (15000), 338 (15000), 370 (15000);
salts VIc, VId, VIg, VIh, VIk, VIl, VIo, and VIp
derived from 4-aminobenzoic acid: 207 (76000), 216
(80000), 231 (80000), 281 (58000), 292 (62000),
326 (21000), 336 (22000), 375 (18000).
group. Dehydrocyclization of the adduct leads to
selective formation of alkyl 4-(9,9-dimethyl-11-oxo-
7,8,9,10,11,12-hexahydrobenzo[a]acridin-12-yl)-2-
alkoxyphenyl carbonates V in 79 89% yield. It should
be noted that, by analogy with the data of [18], the
above transformation of one amino diketone into
another can be regarded as a version of the Hofmann
Martius rearrangement (migration of alkyl groups in
N-alkylanilines to the aromatic ring [19]).
Benzo[a]acridinones Va Vd reacted with car-
boxylic acids IVa IVh in anhydrous chloroform to
give the corresponding ammonium salts VIa VIp in
92 96% yield. Previously unknown salts VIa VIh
were obtained by reaction of acids IVa IVh with
benzo[a]acridinones Va Vd at a ratio of 1:1. The
reaction was complete in 10 15 min under reflux. It
is known that ammonium salts derived from pharma-
cophoric acids and bases exhibit a high biological
activity [20 23].
1
In the H NMR spectra of IIa IId, IIIa IIIl, IVa
IVh, Va Vd, and VIa VIp we observed the follow-
ing signals that unambiguously confirm their structure,
, ppm: 3.93 3.99 s (MeO), 1.20 1.70 t (CH2CH3),
3.90 4.50 q (CH2CH3); IIa IId: 7.15 7.55 m
(C6N3), 9.91 s (CHO); IIIa IIIl, IVa IVh: 8.40
8.60 s (HC=N), 9.98 10.20 s (COOH); 6.65 7.60 m
(C6H3, C6H4, C6H5, IIIa IIId), 7.00 8.05 m (C6H3,
C10H7, IIIe IIIl), 6.90 8.05 m (C6H3, C6H4, IVa
IVd), 6.40 8.10 m (C6H3, C6H4, IVe IVh). The
1H NMR spectra of benzo[a]acridinones Va Vd were
identical to those reported in [9, 10, 12], , ppm:
0.89 0.90 s and 1.04 1.05 s (Me2C), 2.10 2.20 d and
2.45 2.60 d (CH2), 5.80 5.85 s (CH), 6.45 8.20 m
(C6H3, C10H6), 9.69 9.75 s (NH). Salts VIa VIp
showed in the spectra signals from both acid and base
components. The NH+2 signal was a broadened singlet
The structure of compounds IIa IId, IIIa IIIl,
IVa IVh, Va Vd, and VIa VIp was confirmed by
elemental analysis, molecular weight determination
(by cryoscopy or alkalimetry; see table), and IR, UV,
1
and H NMR spectroscopy.
The IR spectra of IIa IId, IIIa IIIl, IVa IVh,
Va Vd, and VIa VIp contained the following ab-
1
sorption bands, , cm : 3100 3000 (C Harom), 2990
2700 (C Haliph), 1770 1758 (C=O, carbonate), 1600
1367 (C Carom), 1280 1027 (C O), 900 583 (C
Harom). Compounds IIa IId showed absorption bands
1
due to aldehyde carbonyl group at 1700 1685 cm ,
and stretching vibrations of the C=N bond in Schiff
bases IIIa IIIl and IVa IVh appeared at 1630
1
at
8.90 9.30 ppm [22].
EXPERIMENTAL
The IR spectra were recorded in KBr on a Nicolet
1625 cm . The carboxy group in IVa IVh gave rise
to absorption at 1700 1680 (C=O) and 2100
1
3650 cm (several bands, OH). In the IR spectra of
Va Vd, absorption bands corresponding to stretching
and bending vibrations of the NH group in the di-
hydropyridine ring were located at 3270 3260 and
Protege-460 spectrometer with Fourier transform. The
1
UV spectra were measured on a Specord UV-Vis
1635 1630 cm , respectively. Stretching vibrations
4
spectrophotometer from 1 10
M solutions in
of the carbonyl group conjugated with the enamine
1
1
methanol. The H NMR spectra were obtained on a
Tesla BS-587A instrument (100 MHz) from 5% solu-
tions in DMSO-d6 using tetramethylsilane as internal
reference. The elemental compositions were determined
on a Vario EL-III Elementar C,H,N,O,S-analyzer with
an accuracy of 0.1%. The molecular weights of IIa
IId, IIIa IIIl, and Va Vd were determined by
cryoscopy in benzene, and those of IVa IVh and
VIa VIp, by alkalimetric titration of carboxy groups
with a 0.1 N solution of NaOH in the presence of
phenolphthalein as indicator.
fragment had a frequency of 1645 1640 cm . The
spectra of ammonium salts VIa VIp contained ab-
sorption bands typical of both initial carboxylic acids
IVa IVh and heterocyclic bases Va Vd with the
difference that the intensities of the acid C=O and NH
bands were lower as the result of salt formation.
The UV spectra of the isolated compounds were
characterized by the presence of the following absorp-
1
tion maxima, max, nm ( , l mol 1 cm ): carbonates
IIa IId: 206 (9000), 225 (15 000), 260 (8000), 310
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

908
DIKUSAR, KOZLOV
Yields, melting points, elemental analyses, and molecular weights of compounds IIa IId, IIIa IIIl, IVa IVh, Va Vd,
and VIa VIp
Found, %
H
Calculated, %
H
M
Comp. Yield,
mp,
C
Fomula
no.
%
C
N
C
N
found calculated
IIa
IIb
IIc
IId
93
92
90
91
90
90
91
93
85
90
87
84
87
86
85
85
84
86
88
83
92
91
92
91
81
89
87
79
94
96
95
92
93
94
96
95
93
95
94
94
95
96
94
93
77 78
63 64
35 36
34 35
57.39
59.14
59.09
60.67
5.02
5.41
5.48
6.13
5.38
5.83
5.80
6.12
5.25
5.59
5.63
5.97
5.14
5.64
5.70
6.05
4.68
5.17
5.09
5.46
4.70
5.18
5.12
5.38
6.08
6.33
6.29
6.43
5.51
5.68
5.61
5.80
5.65
5.81
5.70
6.03
5.62
5.80
5.77
5.92
5.82
6.00
5.90
6.15
C10H10O5
C11H12O5
C11H12O5
C12H14O5
57.14
58.93
58.93
60.50
73.12
73.58
73.58
74.02
71.63
72.19
72.19
72.71
71.63
72.19
72.19
72.71
62.04
62.97
62.97
63.86
62.04
62.97
62.97
63.86
73.51
73.87
73.87
74.21
68.69
68.99
68.99
69.28
68.99
69.28
69.28
69.55
68.99
69.28
69.28
69.55
69.28
69.55
69.55
69.82
4.80
5.39
5.39
5.92
5.30
5.64
5.64
5.95
5.11
5.48
5.48
5.82
5.11
5.48
5.48
5.82
4.59
4.99
4.99
5.36
4.59
4.99
4.99
5.36
5.95
6.20
6.20
6.43
5.38
5.54
5.54
5.69
5.54
5.69
5.69
5.84
5.54
5.69
5.69
5.84
5.69
5.84
5.84
5.98
202.1
211.8
216.6
229.4
355.0
361.7
364.5
378.2
322.6
332.7
337.9
352.0
328.1
330.3
339.4
352.7
328.8
341.6
341.0
357.1
327.6
342.0
342.5
355.8
440.2
450.7
455.4
467.3
775.0
791.6
796.5
810.7
794.7
811.9
812.1
822.3
796.2
810.0
811.4
828.0
812.5
825.7
826.3
839.8
210.2
224.2
224.2
238.2
361.4
375.4
375.4
389.5
335.4
349.4
349.4
363.4
335.4
349.4
349.4
363.4
329.3
343.3
343.3
357.4
329.3
343.3
343.3
357.4
457.5
471.6
471.6
485.6
786.8
800.9
800.9
814.9
800.9
814.9
814.9
828.9
800.9
814.9
814.9
828.9
814.9
828.9
828.9
842.9
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IIIj
IIIk
IIIl
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
Va
133 134 73.36
3.60
3.51
3.62
3.40
3.89
3.84
3.80
3.56
4.02
3.75
3.78
3.49
3.90
3.82
3.91
3.73
3.98
3.87
3.90
3.85
2.86
2.78
2.80
2.62
3.40
3.21
3.32
3.25
3.38
3.27
3.20
3.05
3.30
3.19
3.21
3.12
3.33
3.14
3.07
3.18
C22H19NO4
C23H21NO4
C23H21NO4
C24H23NO4
C20H17NO4
C21H19NO4
C21H19NO4
C22H21NO4
C20H17NO4
C21H19NO4
C21H19NO4
C22H21NO4
C17H15NO6
C18H17NO6
C18H17NO6
C19H19NO6
C17H15NO6
C18H17NO6
C18H17NO6
C19H19NO6
C28H27NO5
C29H29NO5
C29H29NO5
C30H31NO5
C45H42N2O11
C46H44N2O11
C46H44N2O11
C47H46N2O11
C46H44N2O11
C47H46N2O11
C47H46N2O11
C48H48N2O11
C46H44N2O11
C47H46N2O11
C47H46N2O11
C48H48N2O11
C47H46N2O11
C48H48N2O11
C48H48N2O11
C49H50N2O11
3.88
3.73
3.73
3.60
4.18
4.01
4.01
3.85
4.18
4.01
4.01
3.85
4.25
4.08
4.08
3.92
4.25
4.08
4.08
3.92
3.06
2.97
2.97
2.88
3.56
3.50
3.50
3.44
3.50
3.44
3.44
3.38
3.50
3.44
3.44
3.38
3.44
3.38
3.38
3.32
96 97
82 83
84 85
72 73
95 96
62 63
60 61
55 56
86 87
52 53
61 62
73.72
73.66
74.23
71.84
72.37
72.50
72.95
71.88
72.25
72.37
73.05
135 136 62.21
66 67 63.23
118 119 63.17
125 126 64.00
198 199 62.32
186 187 63.19
145 146 63.22
137 138 63.98
284 285 73.84
252 253 74.04
254 255 73.98
262 263 74.56
140 141 68.82
154 155 69.22
183 184 69.15
149 150 69.38
138 139 69.24
122 123 69.43
180 181 69.39
139 140 69.84
138 139 69.15
123 124 69.44
182 183 69.50
144 145 69.83
146 147 69.42
140 141 69.70
184 185 69.76
154 155 70.05
Vb
Vc
Vd
VIa
VIb
VIc
VId
VIe
VIf
VIg
VIh
VIi
VIj
VIk
VIl
VIm
VIn
VIo
VIp
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

METHYL- AND ETHYL CARBONATES DERIVED FROM VANILLIN
909
Methyl or ethyl 2-alkoxy-4-formylphenyl car-
bonates IIa IId (general procedure). A solution of
0.02 mol of pyridine in 10 ml of benzene was added
under shaking to a solution of 0.02 mol of hydroxy
aldehyde Ia or Ib and 0.02 mol of methyl or ethyl
chloroformate in 100 ml of anhydrous benzene. The
reaction flask was tightly capped and left to stand
for 10 12 h at 20 23 C with intermittent careful
shaking. The mixture was then transferred into a
separatory funnel, thoroughly washed with water, a
20% solution of NaCl (to avoid emulsification), and
2 3 portions of a 5% solution of NaHCO3, and the
organic phase was separated and filtered through a
filter paper. The solvent was removed under reduced
pressure, and the residue was recrystallized from a
benzene hexane mixture.
IVa, IVc, IVf, or IVh and 0.01 mol of benzo[a]-
acridinone Va Vd was thoroughly ground in an agate
mortar until a homogeneous powder-like material was
obtained. To complete the complex formation process,
the mixture was heated for 10 15 min in 30 ml of
boiling anhydrous chloroform until it became homo-
geneous. The solvent was removed under reduced
pressure to leave salt VIa VIp as a brittle porous
material.
REFERENCES
1. Kozlov, N.G., Basalaeva, L.I., and Dikusar, E.A.,
Khim. Prirodn. Soedin., 2004, no. 1, p. 70.
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Abstracts of Papers, V Vserossiiskii nauchnyi seminar
Novye lekarstvennye sredstva: uspekhi i perspektivy
Schiff bases IIIa IIIl and IVa IVh (general
procedure). Compound IIa IId, 0.01 mol, was dis-
solved in 30 ml of anhydrous methanol, 0.01 mol of
biphenyl-4-amine, naphthalen-1- or -2-amine, or 3- or
4-aminobenzoic acid was added, and the mixture was
heated for 15 20 min under reflux and left to stand
for 15 20 h at 5 C. The precipitate was filtered off
through a glass filter, washed with a small amount of
methanol, and dried under reduced pressure. Schiff
bases IIIa IIIl and IVa IVh thus obtained were
sufficiently pure, and no additional recrystallization
was necessary.
(V Russian Scientific Seminar
New Drugs:
Advances and Perspectives ), Ufa: Gilem, 2005, p. 61.
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Alkyl 2-alkoxy-4-(9,9-dimethyl-11-oxo-7,8,9,10,
11,12-hexahydrobenzo[a]acridin-12-yl)phenyl
carbonates Va Vd (general procedure). a. A mixture
of 0.005 mol of Schiff base IIIi IIIl and 0.005 mol
of dimedone in 20 ml of ethanol was heated for 3 4 h
under reflux. After cooling, the precipitate was filtered
off, washed on a filter with two portions of diethyl
ether to remove unreacted initial compounds, and
dried under reduced pressure. Compounds Va Vd
thus obtained were pure, and no additional recrystal-
lization was necessary.
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b. A mixture of 0.005 mol of aldehyde IIa IId,
0.005 mol of naphthalen-2-amine, and 0.005 mol of
dimedone in 20 ml of ethanol was heated for 3 4 h
under reflux. After cooling, the precipitate was filtered
off, washed on a filter with two portions of diethyl
ether to remove unreacted initial compounds, and
dried under reduced pressure. Compounds Va Vd
thus obtained were pure, and no additional recrystal-
lization was necessary.
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