N-methylcarbazole-3-carboxylic acid and its amides

Article abstract of DOI:10.1023/B:RUJO.0000034974.67198.15

N-Methylcarbazole-3-carboxylic acid was synthesized from N-methyl-2-amino-4-carboxydiphenyl-amine through the corresponding diazo compound by a modified Pschorr procedure. The acid was converted into N-methylcarbazole-3-carbonyl chloride which was treated

Full text of DOI:10.1023/B:RUJO.0000034974.67198.15

Russian Journal of Organic Chemistry, Vol. 40, No. 3, 2004, pp. 372–376. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 3, 2004,
pp. 402–405.
Original Russian Text Copyright © 2004 by Plekhanova, Ovchinnikov, Glibin.
N-Methylcarbazole-3-carboxylic Acid and Its Amides
N. G. Plekhanova, D. V. Ovchinnikov, and E. N. Glibin
St. Petersburg State Institute of Technology, Moskovskii pr. 26, 198013, St. Petersburg, 198013 Russia
Received October 3, 2003
Abstract—N-Methylcarbazole-3-carboxylic acid was synthesized from N-methyl-2-amino-4-carboxydiphenyl-
amine through the corresponding diazo compound by a modified Pschorr procedure. The acid was converted
into N-methylcarbazole-3-carbonyl chloride which was treated with amines containing benzo- and aza-crown
ether moieties, as well as with 3-(dimethylamino)propylamine, to obtain the respective N-substituted amides.
Heterocyclic compounds of the carbazole series
occur in nature and exhibit valuable pharmacological
properties [1, 2]. Some carbazole derivatives are
capable of forming complexes with DNA [2, 3]. We
anticipated that, like Tilorone [4] and xanthene-
carboxamides [5], carbazolecarboxamides will form
complexes with DNA and that some of these will
exhibit antitumor activity. Antitumor agents [6, 7 ] and
DNA-binding compounds [8, 9] were found among
actinocin amides having a 3-dimethylaminopropyl
moiety or a benzocrown ether fragment in the amide
group. Therefore, we expected that N-methylcarba-
zolecarboxamides possessing analogous fragments in
the amide group will also be interesting from the
viewpoint of antitumor activity.
(I) [10]. The replacement process is facilitated by the
presence of two strong electron-acceptor substituents.
We have found that hydrolysis of ester group is
preceded by formation of diphenylamine. Nitro com-
pounds IIa and IIb were reduced to the corresponding
amines IIIa and IIIb by catalytic hydrogenation in the
presence of 5% Pd/C. Amines IIIa and IIIb were
treated with sodium nitrite to obtain diazo compounds
IVa and IVb which were then converted into carbazole
derivatives Va and Vb via high-temperature intra-
molecular cyclization in the presence of copper
powder (Scheme 1). The yields of both ester Va and
carboxylic acid Vb were fairly high (72 and 70%,
respectively). Intermediate products IIIa, IIIb and
IVa, IVb were not isolated because of their instability.
We have synthesized methyl 4-methyl(phenyl)-
amino-3-nitrobenzoate IIa and the respective acid IIb
in satisfactory yields by nucleophilic substitution of
the chlorine atom in methyl 4-chloro-3-nitrobenzoate
By treatment of acid Vb with thionyl chloride we
obtained chloride VI which (without isolation) was
brought into reaction with amines. As a result,
N-methylcarbazol-3-carboxamides VII–XV were
Scheme 1.
COOMe
COR
COR
PhNHMe
H2/Pd
NO2
NO2
NH2 · HCl
Cl
N(Me)Ph
N(Me)Ph
I
IIa, IIb
IIIa, IIIb
Cl–
+N2
COR
COR
NaNO2
Cu
N
N
Me
IVa, IVb
Me
Va, Vb
R = OMe (a), OH (b).
1070-4280/04/4003-0372 © 2004 MAIK “Nauka/Interperiodica”

N-METHYLCARBAZOLE-3-CARBOXYLIC ACID
373
Scheme 2.
COCl
COR
N
N
Me
VI
Me
VII–XV
VII, R = NHCH2CH2CH2NMe2; VIII, R = NH-4'-benzo-15-crown-5; IX, R = NH-4'-benzo-18-crown-6; X, R = NHCH2CONH-
4'-benzo-15-crown-5; XI, R = NHCH2CONH-4'-benzo-18-crown-6; XII, R = NHCH2CH2CONH-4'-benzo-15-crown-5; XIII, R =
NHCH2CH2CONH-4'-benzo-18-crown-6; XIV, R = 1-aza-15-crown-5; XV, R = 1-aza-18-crown-6.
obtained (Scheme 2). While studying the synthesis of
actinocin amides, we previously showed that the most
convenient procedure for the preparation of ω-amino
acid amides involves the corresponding azides as
intermediate products [11, 12 ]. In the present work we
have found that ω-amino acid amides can be obtained
in satisfactory yields by a simpler procedure, via
activation of the amino acid by mixed anhydrides
using ethyl 2-ethoxy-1,2-dihydroquinoline-1-car-
boxylate [13]. The subsequent hydrogenation of
amides XVI–XIX over Pd/C gave glycine and
β-alanine amides XX–XXIII (Scheme 3), and treat-
ment of the latter with N-methylcarbazole-3-carbonyl
chloride (VI) afforded compounds X–XIII.
Methyl 4-methyl(phenyl)amino-3-nitrobenzoate
(IIa) and 4-methyl(phenyl)amino-3-nitrobenzoic
acid (IIb). A mixture of 3.23 g (15 mmol) of methyl
4-chloro-3-nitrobenzoic acid (I) [10], 2.96 g
(15 mmol) of barium carbonate, and 8.2 g (75 mmol)
of N-methylaniline was stirred for 4–5 h at 140–150°C
(until initial compound I disappeared completely;
TLC, system C). The mixture was cooled and treated
with 200 ml of diethyl ether. The extract was washed
with 1 N hydrochloric acid, 200 ml of a 3% aqueous
solution of NaHCO3, and water, dried over Na2SO4,
and evaporated, and the residue was recrystallized
from methanol to obtain 2.49 g (58%) of ester IIa,
mp 102–104°C; the product was chromatographically
pure (systems A–C). Found, %: C 62.77, 62.69;
H 4.86, 4.98. C15H14N2O4. Calculated, %: C 62.93;
H 4.93.
Scheme 3.
ZNH(CH2)nCOOH
+
HR
ZNH(CH2)nCOR
The solution obtained by washing of the extract
with 3% aqueous NaHCO3 was washed with 50 ml of
diethyl ether and acidified with concentrated hydro-
chloric acid to pH ~1–2. The orange precipitate of
compound IIb was filtered off, washed with water,
dried, and recrystallized from methanol. Yield 0.57 g
(14%), mp 194–196°C. The product was chromatog-
raphically pure (systems A–C). Found, %: C 61.56,
61.83; H 4.39, 4.35. C14H12N2O4. Calculated, %:
C 61.76; H 4.41.
XVI–XIX
H2N(CH2)nCOR
XX–XXIII
XVI, XX, R = NHCH2CONH-4'-benzo-15-crown-5; XVII,
XXI, R = NHCH2CONH-4'-benzo-18-crown-6; XVIII,
XXII, R = NHCH2CH2CONH-4'-benzo-15-crown-5; XIX,
XXIII, R = NHCH2CH2CONH-4'-benzo-18-crown-6;
Z = OCOCH2Ph.
Methyl 3-amino-4-[methyl(phenyl)amino]ben-
zoate hydrochloride (IIIa). Compound IIa, 1 g, was
reduced with hydrogen at room temperature under
atmospheric pressure in the presence of 0.15 g of
5% Pd/C in 50 ml of anhydrous methanol until the
initial nitro compound disappeared completely from
the reaction mixture (TLC, systems B and C). The
catalyst was filtered off, and the filtrate was acidified
with a saturated solution of hydrogen chloride in
ethanol and evaporated. The residue was treated with
dry benzene, the mixture was evaporated, the residue
was ground with dry diethyl ether, and the precipitate
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
instrument at 300 MHz in CDCl3 using HMDS as
reference. The melting points were determined on
an NMK Koefler apparatus. TLC analysis was per-
formed on Silufol UV-254 (360) plates using the
following solvent systems: chloroform–methanol–
25% aqueous ammonia, 20:2:1 (A); chloroform–
methanol–acetic acid, 48:1:1.5 (B); benzene (C); ethyl
acetate (D); chloroform–methanol, 10:1 (E), 5:1 (E');
ethyl acetate–hexane, 1:1 (F).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 3 2004

PLEKHANOVA et al.
374
was filtered off. Yield 0.93 g (91%); the product was
chromatographically pure (systems A–C).
was added, and the mixture was heated for 30 min
under reflux. The mixture was evaporated, dry benzene
was added to the residue, and the solvent was removed
on a rotary evaporator; this procedure was repeated
three times. Acid chloride VI thus obtained was
dissolved in 10 ml of dry benzene, 0.57 ml of
3-dimethylaminopropylamine was added to the solu-
tion, and the mixture was stirred for 2 h at room
temperature and was left to stand for 15 h. The
benzene solution was washed with a 3% aqueous
solution of NaHCO3 (2×10 ml) and with water and
dried over Na2SO4. The solvent was distilled off to
obtain 31 g (85%) of compound VII, mp 121–122°C
(from benzene–hexane); the product was chromatog-
3-Amino-4-[methyl(phenyl)amino]benzoic acid
(IIIb) was synthesized as described above for com-
pound IIIa from 0.9 g of acid IIb. The progress of
the reaction was monitored by TLC (system A). Yield
0.65 g (71%); the product was chromatographically
pure (systems A–C).
Methyl N-methylcarbazole-3-carboxylate (Va).
Hydrochloride IIIa, 1 g (3.42 mmol), was dissolved in
40 ml of hydrochloric acid (1:9), the solution was
cooled to 0°C, a solution of 0.26 g (3.76 mmol) of
NaNO2 in 1 ml of water was added under stirring, and
the mixture was stirred for 10 min. Copper powder,
1 g, was then added, and the mixture was stirred for
30 min at room temperature, heated to 60–70°C, and
stirred at that temperature until the diazonium com-
pound completely disappeared (test with 2-naphthol).
The mixture was treated with 200 ml of diethyl ether,
the extract was washed in succession with water,
a 3% aqueous solution of NaHCO3, and water again,
dried over Na2SO4, and evaporated, and the residue
was recrystallized from methanol. Yield 0.59 g (72%),
mp 130–132°C (from methanol); the product was
chromatographically pure (systems A–C). Found, %:
C 74.74, 74.66; H 5.76, 5.71. C15H13NO2. Calculated,
%: C 75.30; H 5.48.
1
raphically pure (systems A–C). H NMR spectrum, δ,
ppm: 2.21 s and 2.26 s [6H, N(CH3)2]; 1.92 m, 2.43 m,
and 3.53 m (6H, 3CH2); 3.88 s (1H, NCH3); 6.81–
7.58 m (4H, Harom); 8.01 d and 8.12 d (2H, Harom);
8.86 s (1H, Harom). Found, %: C 73.54, 73.44; H 7.54,
7.60. C19H23N3O. Calculated, %: C 73.76; H 7.49.
N-(2,3,5,6,8,9,11,12-Octahydro-1,4,7,10,13-ben-
zopentaoxacyclopentadecin-15-yl)-9-methylcarba-
zole-3-carboxamide (VIII). A solution of 4'-amino-
benzo-15-crown-5 (obtained by hydrogenation of
0.328 g of 4'-nitrobenzo-15-crown-5 [14]) and 0.14 ml
of triethylamine were added to a solution of acid
chloride VI (prepared from 0.225 g of acid Vb) in 6 ml
of dry benzene. The mixture was stirred for 2 h at
room temperature and was left to stand for 15 h. The
precipitate was filtered off and washed with benzene.
Yield 0.34 g (70%), mp 213–215°C (from acetone).
The product was chromatographically pure (systems
N-Methylcarbazole-3-carboxylic acid (Vb).
a. The procedure was analogous to that utilized in the
synthesis of ester Va; 0.5 g of acid IIIb and 0.14 g of
NaNO2 were used. The only difference was that the
extract containing compound Vb was washed only
with water (washing with a solution of NaHCO3 was
excluded). Yield 0.27 g (70%), mp 256–258°C (from
acetone); the product was chromatographically pure
(systems A–C). Found, %: C 75.01, 75.03; H 5.02,
4.94. C14H11NO2. Calculated, %: C 74.65; H 4.92.
1
A–C). H NMR spectrum, δ, ppm: 3.45–4.31 m (23H,
OCH2CH2O, NCH3), 6.76–7.54 m (6H, Harom), 8.01 d
and 8.13 d (2H, Harom), 8.61 s and 8.82 s (2H, Harom).
Found, %: C 68.43, 68.54; H 6.14, 6.25. C28H30N2O6.
Calculated, %: C 68.56; H 6.16.
N-(2,3,5,6,8,9,11,12,14,15-Decahydro-1,4,7,10,-
13,16-benzohexaoxacyclooctadecin-18-yl)-9-methyl-
carbazole-3-carboxamide (IX) was synthesized as
desribed above for compound VIII from 0.225 g
of compound Vb and 0.375 g of 4'-nitrobenzo-18-
crown-6 [14]. Yield 0.374 g (70%), mp 204–206°C
(from acetone); The product was chromatographically
pure (systems A–C). 1H NMR spectrum, δ, ppm: 3.45–
4.31 m (23H, OCH2CH2O, NCH3), 6.76–7.54 m (6H,
b. A mixture of 0.5 g of compound Va and 25 ml of
a saturated solution of NaOH in methanol was heated
for 30 min under reflux. The mixture was diluted with
20 ml of water, treated with diethyl ether (2×10 ml),
and acidified with hydrochloric acid to pH 1–2, and the
precipitate was filtered off, washed with water, and
dried. Yield 0.42 g (90%), mp 256–258°C. The product
was chromatographically identical to a sample ob-
tained as described in a, and no depression of the
melting point was observed on mixing with the latter.
Harom), 8.01 d and 8.13 d (2H, Harom), 8.61 s and 8.82 s
(2H, Harom). Found, %: C 67.45, 67.52; H 6.90, 6.76.
C30H34N2O7. Calculated, %: C 67.40; H 6.41.
Compounds X–XV were synthesized in a similar
way. Their yields, systems for TLC, melting points,
N-(3-Dimethylaminopropyl)-9-methylcarbazole-
3-carboxamide (VII). Acid Vb, 0.26 g, was dissolved
in 15 ml of dry benzene, 0.25 ml of thionyl chloride
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 3 2004

N-METHYLCARBAZOLE-3-CARBOXYLIC ACID
375
solvents for crystallization, 1H NMR spectra, and
elemental analyses are listed below.
N,N-(3,6,9,12,15-Pentaoxaheptadecane-1,17-di-
yl)-9-methylcarbazole-3-carboxamide (XV). Yield
50%; TLC: systems A, D; mp 84–86°C (from ethyl
N-(2,3,5,6,8,9,11,12-Octahydro-1,4,7,10,13-ben-
zopentaoxacyclopentadecin-15-yl)(9-methylcarba-
zole-3-carbonylamino)acetamide (X). Yield 48%;
1
acetate–methanol). H NMR spectrum, δ, ppm: 3.32–
3.85 m (27H, OCH2CH2O, NCH3), 6.82–7.65 m (4H,
Harom), 8.03 d and 8.12 d (2H, Harom), 8.85 s (1H,
Harom). Found, %: C 65.92, 65.98; H 7.37, 7.35.
C26H34N2O6. Calculated, %: C 66.36; H 7.28.
1
TLC: system E'; mp 208–210°C (from methanol); H
NMR spectrum, δ, ppm: 3.4–4.3 m (19H, OCH2CH2O,
NCH3), 4.42 m (2H, NHCH2CO), 6.83–7.68 m (6H,
Harom), 8.05 d and 8.12 d (2H, Harom), 8.65 s and 8.84 s
(2H, Harom). Found, %: C 65.61, 65.64; H 6.03, 6.08.
C30H33N3O7. Calculated, %: C 65.80; H 6.07.
4'-[ω-(Benzyloxycarbonylamino)alkylcarbonyl-
amino]benzocrown ethers XVI–XIX (general proce-
dure). To a suspension of 1 mmol of N-benzyloxy-
carbonyl amino acid in 5 ml of anhydrous tetra-
hydrofuran we added under stirring in a dry inert
atmosphere 0.3 g (1.2 mmol) of ethyl 2-ethoxy-1,2-
dihydroquinoline-1-carboxylate and then a solution of
4'-aminobenzocrown ether in a few milliliters of
anhydrous THF. The mixture was stirred at room
temperature until the initial aminobenzocrown ether
disappeared (TLC), the solvent was removed under
reduced pressure on a rotary evaporator, and the
residue was recrystallized from ethyl acetate.
N-(2,3,5,6,8,9,11,12,14,15-Decahydro-1,4,7,10,-
13,16-benzohexaoxacyclooctadecin-18-yl)(9-methyl-
carbazole-3-ylcarbonylamino)acetamide (XI). Yield
67%; TLC: system E; mp 118–120°C (from ethyl
1
acetate–methanol, 5:3). H NMR spectrum, δ, ppm:
3.6–4.1 m (23H, OCH2CH2O, NCH3), 4.41 m (2H,
NHCH2CO), 6.81–7.56 m (6H, Harom); 8.02 d and
8.14 d (2H, Harom), 8.63 s and 8.82 s (2H, Harom).
Found, %: C 65.25, 65.32; H 6.36, 6.41. C32H37N3O8.
Calculated, %: C 64.96; H 6.30.
N-(2,3,5,6,8,9,11,12-Octahydro-1,4,7,10,13-ben-
zopentaoxacyclopentadecin-15-yl)(benzyloxycar-
bonylamino)acetamide (XVI). Yield 82%; TLC:
systems E', F; mp 136–138°C (from ethyl acetate–
acetone). Found, %: C 60.43, 60.47; H 6.41, 6.43.
C24H30N2O8. Calculated, %: C 60.75; H 6.37.
N-(2,3,5,6,8,9,11,12-Octahydro-1,4,7,10,13-ben-
zopentaoxacyclopentadecin-15-yl)-3-(9-methylcar-
bazole-3-carbonylamino)propionamide (XII). Yield
28%; TLC: system E'; mp 178–180°C (from ethyl
1
acetate–methanol). H NMR spectrum, δ, ppm: 3.5–
4.05 m (19H, OCH2CH2O, NCH3), 4.3 m (4H,
NHCH2CH2CO), 6.80–7.58 m (6H, Harom), 8.04 d and
8.11 d (2H, Harom), 8.65 s and 8.79 s (2H, Harom).
Found, %: C 66.52, 66.57; H 6.36, 6.38. C31H35N3O7.
Calculated, %: C 66.30; H 6.28.
N-(2,3,5,6,8,9,11,12,14,15-Decahydro-1,4,7,10,-
13,16-benzohexaoxacyclooctadecin-18-yl)(benzyl-
oxycarbonylamino)acetamide (XVII). Yield 89%;
TLC: systems E', F; mp 153–156°C (from ethyl
acetate–acetone). Found, %: C 59.91, 60.03; H 6.69,
6.67. C26H34N2O9. Calculated, %: C 60.22; H 6.61.
N-(2,3,5,6,8,9,11,12,14,15-Decahydro-1,4,7,10,-
13,16-benzohexaoxacyclooctadecin-18-yl)-3-(9-
methylcarbazole-3-ylcarbonylamino)propionamide
(XIII). Yield 26%; TLC: system E; mp 138–140°C
N-(2,3,5,6,8,9,11,12-Octahydro-1,4,7,10,13-ben-
zopentaoxacyclopentadecin-15-yl)-3-(benzyloxycar-
bonylamino)propionamide (XVIII). Yield 77%;
TLC: systems E', F; mp 125–127°C (from ethyl
acetate–acetone). Found, %: C 61.21, 61.24; H 6.65,
6.70. C25H32N2O8. Calculated, %: C 61.46; H 6.60.
1
(from ethyl acetate–methanol). H NMR spectrum, δ,
ppm: 3.62–4.14 m (23H, OCH2CH2O, NCH3), 4.27 m
(NHCH2CH2CO), 6.76–7.62 m (6H, Harom), 8.05 d and
8.17 d (2H, Harom), 8.67 s and 8.82 s (2H, Harom).
Found, %: C 65.61, 65.52; H 6.63, 6.70. C33H39N3O8.
Calculated, %: C 65.44; H 6.49.
N-(2,3,5,6,8,9,11,12,14,15-Decahydro-1,4,7,10,-
13,16-benzohexaoxacyclooctadecin-18-yl)-3-(ben-
zyloxycarbonylamino)propionamide (XIX). Yield
91%; TLC: systems E', F; mp 141–142°C (from ethyl
acetate–acetone). Found, %: C 60.71, 60.74; H 6.86,
6.89. C27H36N2O9. Calculated, %: C 60.89; H 6.81.
N,N-(3,6,9,12-Tetraoxatetradecane-1,14-diyl)-9-
methylcarbazole-3-carboxamide (XIV). Yield 72%;
TLC: systems A, D; mp 115–117°C (from ethyl
1
acetate–methanol). H NMR spectrum, δ, ppm: 3.34–
3.82 m (23H, OCH2CH2O, NCH3), 6.80–7.58 m (4H,
Harom), 8.05 d and 8.13 d (2H, Harom), 8.82 s (1H,
Crown-containing amino acid amides XX–XXIII
were synthesized by catalytic hydrogenation of com-
pounds XVI–XIX under atmospheric pressure in
methanol over 5% Pd/C. The progress of the reaction
Harom). Found, %: C 67.26, 67.18; H 7.12, 7.14.
C26H34N2O6. Calculated, %: C 67.58; H 7.08.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 3 2004

PLEKHANOVA et al.
376
5. Golubeva, I.S., Cand. Sci. (Biol.) Dissertation, Moscow,
was monitored by TLC using system E'. The solvent
was removed under reduced pressure on a rotary
evaporator, and compounds XX–XXIII were brought
into reaction with chloride VI without isolation and
purification. The procedure was the same as in the
synthesis of compound VIII. The properties of
products X–XIII are given above.
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6. Yavorskaya, N.P., Golubeva, I.S., Kubasova, I.Yu.,
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