New approach to the functionalization of δ-carboline derivatives

Article abstract of DOI:10.1023/A:1012749426699

The possibility of transformation of 3-cyano-1-p-nitrophenyl-δ-carbolin-2-one into 2-amino-3-cyano-1-p-nitrophenyl-1H-pyrido[3,2-b]indole derivatives and 2-imino-3-cyano-1-p-nitrophenyl-5H-pyrido[3.2-b]indole derivatives (δ-carbolines) is demonstrated. Methylation of 1-p-nitrophenyl-2-piperidino-1H-δ-carboline followed by treatment with acetone in an alkaline medium yields 4-acetonyl-5-methyl-1,4-dihydro-5H-pyrido[3,2-b]indole derivative. The rearrangement of 2-arylimino-3-cyano-1-p-nitrophenyl-5H-pyrido[3,2-b]indoles into 2-(aryl)nitrophenylamino-3-cyano-5H-pyrido[3,2-b]indoles was accomplished or heating above the melting point or on treatment with potassium terf-butoxide. The structures of the resulting compounds were proved by ¹H and ¹³C NMR spectroscopy and X-ray diffraction analysis.

Full text of DOI:10.1023/A:1012749426699

Russian Chemical Bulletin, International Edition, Vol. 50, No. 8, pp. 1449—1456, August, 2001
1449
New approach to the functionalization of δ-carboline derivatives
S. Yu. Ryabova,a L. M. Alekseeva,a E. A. Lisitza,a A. S. Shashkov,b V. V. Chernyshev,c
G. B. Tichomirova,a M. S. Goyzman,a and V. G. Granika«
aRussian Federation State Scientific Center
"Scientific Research Institute of Organic Intermediates and Dyes",
1, building 4, Bol´shaya Sadovaya, 103787 Moscow, Russian Federation.
Fax: +7 (095) 254 6574. E-mail: makar-cl@ropnet.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328
cDepartment of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gory,
119899 Moscow, Russian Federation.
Fax: +7 (095) 939 3654. E-mail: cher@biocryst.phys.msu.su
The possibility of transformation of 3-cyano-1-p-nitrophenyl-δ-carbolin-2-one into
2-amino-3-cyano-1-p-nitrophenyl-1H-pyrido[3,2-b]indole derivatives and 2-imino-3-cyano-
1-p-nitrophenyl-5H-pyrido[3,2-b]indole derivatives (δ-carbolines) is demonstrated. Methyla-
tion of 1-p-nitrophenyl-2-piperidino-1H-δ-carboline followed by treatment with acetone in
an alkaline medium yields 4-acetonyl-5-methyl-1,4-dihydro-5H-pyrido[3,2-b]indole deriva-
tive. The rearrangement of 2-arylimino-3-cyano-1-p-nitrophenyl-5H-pyrido[3,2-b]indoles into
2-(aryl)nitrophenylamino-3-cyano-5H-pyrido[3,2-b]indoles was accomplished on heating above
the melting point or on treatment with potassium tert-butoxide. The structures of the resulting
compounds were proved by 1H and 13C NMR spectroscopy and X-ray diffraction analysis.
Key words: δ-carboline, pyrido[3,2-b]indole, adduct with POCl3, nucleophilic reagents,
rearrangement, methylation, NMR, UV spectroscopy, X-ray diffraction analysis.
Fused heterocyclic systems containing indole and
pyridine fragments arouse considerable interest.1 Well-
known medicines such as diazoline and dimebone
(γ-carboline derivatives) and incazan (β-carboline de-
rivative) are also substituted carbolines.2 However, δ-car-
boline derivatives, which are somewhat less readily avail-
able, have not been adequately studied yet.1 Recently,3
we found that 3-p-nitrophenylaminoindole can be readily
transformed into 3-cyano-1-p-nitrophenyl-5H-pyri-
do[3,2-b]indol-2-one (1), which is a convenient synthon
for the synthesis of pyrido[3,2-b]indole (δ-carboline)
derivatives. This paper deals with investigation of the
methods of functionalization of δ-carboline 1. The syn-
thetic strategy chosen here is based on the known
approach4 to the activation of the amide fragment upon
conversion of 1 upon the reaction with POCl3. This type
of activation of the amide function has been studied in
detail for simple amides and lactams5—7 but much less
studied for more complicated representatives of these
classes.8—10
ample, triethylamine hydrochloride, a mixture of com-
plexes 2 and 3 is apparently formed.11,12
Scheme 1
C6H4NO2-F
N
O
POCl3
N
H
CN
C6H4NO2-F
N
+
OPOCl2
ꢀ
–
Cl
N
H
CN
C6H4NO2-F
N
+
Cl
N
H
CN
–
Cl
It was found that heating δ-carboline 1 with POCl3
gives an adduct, which was identified as compound 2 on
the basis of published data11,12 (Scheme 1). The reac-
tion involved can be represented as initial O-acylation
of 1 followed by an attack of the chloride anion on
position 2. In the case where the reaction mixture
–
OPOCl2
C6H4NO2-F
N
+
Cl
–
Cl
N
H
CN
–
contains an additional source of Cl anions, for ex-
!
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1379—1385, August, 2001.
1066-5285/01/5008-1449 $25.00 ©ꢀ2001 Plenum Publishing Corporation

1450
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
Ryabova et al.
Scheme 2
Although the positive charge of the cations of the
complexes is efficiently delocalized, the reactions with
nucleophiles are expected to proceed rather smoothly to
give 2-substituted δ-carbolines. Indeed, the reactions of
complex 2 or 3 with highly basic amines, viz.,
dimethylamine and piperidine, occur without heating
giving rise to 2-dimethylamino- and 2-piperidino-sub-
stituted 3-cyano-1-p-nitrophenyl-1H-pyrido[3,2-b]indoles
(4a,b), whose structure follows unambiguously from the
data of the 1H NMR spectra. These compounds tend to
undergo double bond migration and, although they are
aromatic in accordance with the known principle of
(4n+2) π-electrons, the indole fragment in them is not
aromatized and can be subjected to N-alkylation to give
a 1-R-pyrido[3,2-b]indolium system. As indicated by
our previous publications,13,14 cations of this type should
add carbanionic species at position 4 of the molecule.
Indeed, on treatment with MeI, compound 4b is readily
converted into 3-cyano-5-methyl-1-p-nitrophenyl-2-
piperidino-5H-pyrido[3,2-b]indolium iodide (5), which
is converted into 4-acetonyl-3-cyano-5-methyl-1-p-
nitrophenyl-2-piperidino-1,4-dihydropyrido[3,2-b]indole
(6) on heating in acetone in the presence of potassium
carbonate (Scheme 2).
C6H4NO2-F
NR2
N
R2NH
MeI
ꢁor !
(for ">)
N
CN
"=,>
C6H4NO2-F
Me2CO, K2CO3
N
+
N
∆
–
I
N
CN
Me
#
C6H4NO2-F
N
N
R2 = Me2 (=),
(CH2)5 (>)
N
CN
H CH2COMe
Me
$
The high reactivity of complexes 2 or 3 toward
nucleophilic reagents is also demonstrated by the fact
that they readily react with weakly basic amines, viz.,
aniline and p-chloroaniline to give 3-cyano-1-p-
nitrophenyl-2-phenylimino- (7a) and 3-cyano-1-p-
nitrophenyl-2-p-chlorophenylimino-1,2-dihydro-5H-
pyrido-[3,2-b]indoles (7b) (Scheme 3). The imine struc-
ture of the compounds synthesized was confirmed by
the data of 1H NMR spectra (see Table 1), in particular,
by the presence of singlet signals at δ ∼11.5, correspond-
ing to the indole NH protons. An important feature of
the spectra of 2-imino-δ-carbolines 7a,b is that the
signals for the protons in position 9 are located in a
rather high field (δ ∼ 6 ppm), pointing to an anisotropic
influence of the C6H4NO2-group benzene ring, which is
deflected from the plane of the tricyclic system. The
imine structure of compounds 7a,b is also confirmed by
the fact that they are readily protonated at the imino-
group nitrogen atom being thus converted into hydro-
chlorides 8a,b. The 1H NMR spectra of salts 8a and 8b
are virtually identical. All the signals in the spectra of
hydrochlorides are shifted downfield with respect to
those in the spectra of the initial bases. The spectrum of
hydrochloride 8b measured in DMSO-d6 is almost iden-
tical to the spectrum of base 7b recorded in CF3COOD,
except that the spectrum of 8b contains a singlet for
N+H at δ 9.56.
A rather interesting phenomenon is observed when
2-imino-δ-carbolines 7a,b are heated above the melting
Table 1. 1H NMR spectra of compounds 7a,b, 9a,b
Com-
pound
δ
C6H4NO2
C6H4-R-p
H(4)
NH
H(6)—H(9)
(R = H, Cl)
7a
7b
7.90, 8.50 (AA´XX´,
6.68—7.13
8.26 (s, 1 H) 11.50 (br.s, 1 H)
8.29 (s, 1 H) 11.53 (br.s, 1 H)
5.92 (da, 1 H, H(9)); 6.80 (tb, 1 H, H(8));
7.30 (tb, 1 Í, H(7)); 7.47 (da, 1 H, H(6))
5.93 (da, 1 H, H(9)); 6.80 (tb, 1 H, H(8));
7.31 (tb, 1 Í, H(7)); 7.48 (da, 1 H, H(6))
4 Í, N(1)—C6H4NO2) (m, 5 Í, Ñ6Í5)
7.89, 8.49 (AA´XX´, 6.70, 7.14
4 Í, N(1)—C6H4NO2) (AA´XX´,
4 Í, C6H4Cl)
6.89, 8.11 ((AA´XX´, 7.20—7.46
4 H, N(2)—C6H4NO2) (m, 5 Í, Ñ6Í5)
6.94, 8.11 (AA´XX´,
4 H, N(2)—C6H4NO2) (AA´XX´,
4 Í, C6H4Cl)
9a
9b
8.58 (s, 1 H) 12.02 (br.s, 1 H)
8.59 (s, 1 H) 12.11 (br.s, 1 H)
8.13 (da, 1 H, H(9)); 7.66 (m, 2 Í, Í(6),
H(7))c
8.11 (da, 1 H, H(9)); 7.28 (tb, 1 H, H(8));
7.63 (tb, 1 Í, H(7)); 7.68 (da, 1 H, H(6))
7.28, 7.49
a J9,8 = Jortho = 8.4 Hz.
b J7,8 = J7,6 = 8.4 Hz; J8,9 = J8,7 = 8.4 Hz.
c The signal for H(8) falls in the 7.20—7.46 ppm region.

New δ-carboline derivatives
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
1451
Scheme 3
downfield by more than 2 ppm. Attention is attracted by
the great difference in the change of the chemical shifts
of protons of the aryl substituents. Indeed, the signals of
p-NO2C6H4 in the spectrum of 9b are shifted upfield by
0.95 (H(2), H(6)) and by 0.38 ppm (H(3), H(5)) with
respect to those in the spectrum of 7b, while the signals
of p-ClC6H4 are displaced downfield by 0.58 and
0.35 ppm, respectively. Important information was gained
from the ROESY spectra: the spectrum 7b contains no
correlation peaks corresponding to the coupling of pro-
tons of p-NO2C6H4 and p-ClC6H4; conversely, in the
spectrum of 9b, this correlation is observed between the
6.94/7.49 and 6.94/7.28 ppm signals. This indicates that
the aryl substituents in compounds 7a,b are spatially
separated, while in compounds 9a,b, they are brought
close in space. The differential NOE spectra of both
types of isomers exhibit responses of signals of the
protons in positions 4 and 6 upon pre-saturation of the
N(5)H protons; this indicates unambiguously that the
molecule contains an aromatic indole system. Finally,
as has already been noted, the addition of acids to 7a,b
results in protonation at the exocyclic N atom. Com-
pounds 9a,b, unlike 7a,b, cannot be protonated and
form no hydrochlorides; the spectra of 9a,b, recorded in
CF3COOD virtually do not differ in chemical shifts
from the spectra recorded in DMSO-d6.. The data of
UV spectra (Table 2) of carbolines 7a,b recorded in the
presence of an acid also imply protonation of these
C6H4NO2-F
N
NC6H4R-F
F-RC6H4NH2
HCl
, !
N
H
CN
%=,>
C6H4NO2-F
+
N
NC6H4R-F
H
N
CN
–
Cl
H
&=,>
R = H (=), Cl (>)
point. In this case, both substances are irreversibly
transformed into isomers; on the basis of spectral data,
the isomers should be identified as the corresponding
3-cyano-2-diarylamino-5H-pyrido[3,2-b]indoles 9a,b
1
(Scheme 4). The H NMR spectra of compounds 7a,b
and 9a,b differ in the chemical shifts of like protons (the
proton signals for the fused benzene ring were assigned
based on the COSY spectrum). In the spectra of com-
pounds 9a,b, the signal of the H(9) proton is shifted
Scheme 4
NO2
3″
2″
5″
6″
1″
C6H4NO2-F
2
5
´
9
6
N1
N
1
´
∆ or
Bu OK
–
9a
9b
t
N
NC6H4R-F
H+
3
´
8
7
2
3
4
´
–H+
5
4a
N
CN
R
´
4
N
CN
H
ꢀꢀ
%=,>
C6H4NO2-F
C6H4NO2-F
N—C6H4R-F
N
N—C6H4R-F
t
Bu OK
N
MeI
N
H
CN
–
N
CN
'=,>
C6H4NO2-F
N—C6H4R-F
N
N
CN
Me
R = H (=), Cl (>)
ꢀꢂ=,>

1452
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
Ryabova et al.
Table 2. Physicochemical properties of the compounds synthesized
Com-
pound(sol-
vent)a
M.p./°C Yield (%)
(method of
synthesis)
MS,
m/z (Irel (%))
Molecular
formula
Found
Calculated
UV, λmax/nm (logε)
(%)
C
H
N
Cl
—
MeOH
MeOH + HCl
—
4a b
295—297
(DMF)
14
357 [M]+ (100),
C20H15N5O2 67.20 4.09 19.38
67.22 4.23 19.60
—
342[M – Me]+ (51),
327 [M – Me2]+ (10),
311 [M –NO2]+ (14),
254 [M – C6H4
–
– HCN] (10),
235 [M – C6H4NO2]+ (17),
194 [M – Me – C6H4NO2
– CN]+ (38)
4b b
321 dec.
29
91
53
397 [M]+ (100),
Ñ23H19N5O2 69.58 5.11 17.36
69.51 4.82 17.62
—
—
—
—
—
—
—
—
—
351 [M – NO2]+ (3),
275 [M – C6H4NO2]+ (6)
5
311 dec.
(PriOH—acetone,
2 : 1)
C24H22N5JO2
—
—
12.88
12.99
6
214—216
(MeOH—
dioxane,
469 [M]+ (7),
412 [M – CH2COMe]+
(100)
C27H27N5O3 69.71 6.00 14.86
69.06 5.80 14.92
4 : 1)
7a b
205—206
(MeOH—
acetone,
14
52
405[M]+ (83),
404[M – H]+ (100),
358[M – H – NO2]+ (45)
C24H15N5O2 71.05 4.16 17.10
71.10 3.73 17.28
—
259 (4.37),
294 (4.14),
357 (4.11),
440 sh (3.74),
484 (3.85)
385 (4.21),
284 sh (4.17),
419 sh (4.07)
1 : 1)
7b b
253
439 [M]+ (100),
C24H14ÑlN5O2 65.23 3.44 16.09 8.04 235 (4.42),
212 sh (4.52),
241 (4.35),
284 sh (4.13),
385 (4.18),
(MeOH—
acetone,
1 : 1)
393 [M – NO2]+ (25),
358 [M – NO2 – Cl]+ (9)
65.53 3.21 15.92 8.06 256 (4.38),
298 (4.15),
357 (4.13),
434—448
415 sh (4.01)
sh (3.76),
485 (3.87)
8a
266
60
63
—
C
24H16ÑlN5O2 65.18 3.79 15.64 7.81
65.24 3.65 15.85 8.02
—
—
—
(DMF—
acetone,
1 : 4)
229—230
(MeOH—
acetone,
1 : 9)
8b
—
C24H15Ñl2N5O2
—
—
—
—
—
—
14.75
14.89
—
9a c
327—329
70 (A) [M]+ 405, 1206
60 (B)
C24H15N5O2
—
—
—
256 (4.44),
295 (4.34),
351 sh
256 (4.42),
296 (4.33),
351 sh (4.25),
380 (4.32)
d
(H2O—
DMF,
1 : 4)
M = 405, 425
82 (C)
(4.26),
379 (4.32)
261 (4.43),
299 (4.37),
354 sh
9b c
10a
196—199
(MeOH)
61
439 [M]+ (100),
393 [M – NO2]+ (12)
C24H14ÑlN5O2 64.94 3.47 15.62
65.53 3.21 15.92
261 (4.41),
298 (4.36),
354 sh (4.25),
376 (4.29)
(4.26),
376 (4.30)
228 (4.45),
259 br
(4.42),
295 (4.39),
356 sh
260—260.5 58 (A) 419 [M]+ (100),
C25H17N5O2 71.91 4.21 16.77
71.59 4.00 16.70
228 (4.44),
262 br
(4.41),
295 (4.39),
359 sh
(MeOH—
acetone,
1 : 1)
88 (B) 373 [M – NO2]+ (27),
358 [M – NO2 – Me]+ (9)
(4.29),
(4.29),
377 (4.32)
377 (4.32)
(to be continued)

New δ-carboline derivatives
Table 2 (continue)
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
1453
Com-
pound(sol-
vent)a
M.p./°C Yield (%)
(method of
synthesis)
MS,
m/z (Irel (%))
Molecular
formula
Found
Calculated
UV, λmax/nm (logε)
(%)
C
H
N
Cl
MeOH
MeOH + HCl
10b c 265.5—266 22 (A) 453 [M]+ (100),
C25H16ÑlN5O2 66.38 3.59 14.98 7.38 264 (4.45),
265 (4.44),
299 (4.42),
357 sh
(MeOH—
acetone,
1 : 2)
84 (B) 439 [M – Me]+ (3),
407 [M – NO2]+ (11),
66.15 3.55 15.43 7.81 298 (4.43),
359 sh
(4.29),
392 [M – Me – NO2]+ (4)
(4.28),
378 (4.31)
379 (4.31)
a Solvent for crystallization.
b The yield of compound was calculated for δ-carbolin-2-one 1.
c To record the UV spectrum, the compound was dissolved in DMSO and the solution was diluted with MeOH.
d High-resolution mass spectra were recorded on a Finnigan-Mat TSQ 700 instrument (triple quadrupole) with direct sample
injection into the ion source.
compounds, whereas 9a,b are not protonated under the
same conditions. An important difference between the
electronic spectra of the isomers under study is that the
long-wavelength band of 7a,b undergoes a strong
bathochromic shift (by about 100 nm) compared to that
of 9a,b, indicating that the chromophore is much more
extended in the former type of compound.
spectra of compounds 7b and 9b shows that only the
chemical shifts of carbon atoms located in immediate
vicinity of the pyridine nucleus differ substantially
(Table 3). Thus the signal of the C(9b) atom in com-
pound 9b is shifted downfield by 13.3 ppm, that of
C(4a) is shifted by 9.7 ppm, that for C(3), by 7.9 ppm,
and the signal of C(9a) is displaced by 5.9 ppm with
respect to similar signals in the spectrum of 7b. Con-
versely, the signal of C(4) is shifted 11.7 ppm upfield on
The HMBC spectra of both types of isomers contain
identical correlation peaks. Comparison of the 13C NMR
Table 3. 13C NMR spectra of compounds 7à,b and 9b, 10b and proton—carbon correlations in the HÌÂC spectrum
C atoms
δ
b
c
7a a
7b
9b
10b
2
3
146.8 (H(4))
94.8
147.5
94.8
149.4 (H(4))
102.7
149.4 (H(4))
102.7
4
137.1
137.3
120.5
140.3
112.9
127.8
119.9
120.3
114.2
130.1
148.7
123.1
128.3
125.1
145.5
130.7
125.6
147.5
125.6
130.2
143.0 (H(7), H(9))
112.5 (H(8))
129.9 (H(9))
120.5 (H(6))
121.2 (H(7))
120.1 (H(8))
143.4 (H(4))
142.6 (H(3´), H(5´))
127.2 (H(2´), H(6´))
129.9 (H(3´), H(5´))
127.2 (H(2´), H(6´))
152.3 (H(3″), H(5″))
118.3 (H(2″), H(6″))
125.4 (H(3″), H(5″))
140.6 (H(2″), H(3″),
H(5″), H(6″))
116.5 (H(4))
124.4
131.5 (Me)
143.6 (H(9), H(7), Me)
110.5 (H(8))
130.0 (H(9))
120.7 (H(6))
121.2 (H(7))
119.9 (H(6), H(8))
142.6 (H(4))
d
4a
5a
6
7
8
140.0 (H(7), H(9))
112.8 (H(8))
127.6 (H(9))
119.9 (H(6))
120.2 (H(7))
114.2 (H(6), H(8))
130.0 (H(4))
149.4 (H(3´), H(5´))
121.4 (H(2´), H(6´), H(4´))
128.5 (H(3´), H(5´))
121.6
145.6 (H(3″), H(5″))
130.7 (H(2″), H(6″))
125.5 (H(3″), H(5″))
147.4 (H(2″), H(6″))
9
9a
9b
1´e
2´6´e
3´5´e
4´e
142.6 (H(3´), H(5´))
127.2 H(2´)) (H(6´)
129.8 (H(3´), H(5´))
127.2 H(2´), H(6´))
152.2 (H(3″), H(5″))
118.4 (H(2″), (H(6″))
125.4 (H(3″), H(5″))
140.6 (H(2″), H(3″),
H(5″), H(6″))
f
1″
f
2″6″
f
3″5″
4″b
ÑN
116.3 (H(4))
116.4
116.5 (H(4))
a The protons found to be involved in correlation are given in parentheses.
b The HMBC spectrum could not be recorded due to the low solubility of 7b.
c δC NMe is 29.5.
d The signal cannot be isolated due to noise.
f The numbering of C atoms in the C6H4NO2-p fragment.
e The numbering of C atoms in the C6H4R-p fragment.

1454
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
Ryabova et al.
passing from 7b to 9b. This altogether indicates that
structural changes involve predominantly the pyridine
fragment of the molecule.
To prove unambiguously the structures of compounds
7a and 9a, a powder X-ray diffraction study was per-
formed for them (we were unable to prepare single
crystals of an appropriate size) (Figs. 1 and 2).
of potassium tert-butoxide. It was found that, whereas
the 7→9 thermal transformation requires heating to
300 °C, isomerization in the presence of a strong base
occurs at a much lower temperature to give products in
high yields. This led to the conclusion that the forma-
tion of the intermediate anion greatly facilitates isomer-
ization.
A detailed description of the powder X-ray diffrac-
tion experiment, the solution and refinement of the
molecular and crystal structures of 7a and 9a, and atom
coordinates are reported in another publication.17
Methylation of compounds 7a,b and 9a,b with me-
thyl iodide in the presence of potassium tert-butoxide
gives rise to N-methyl derivatives 10a,b, whose spectral
characteristics are very close to those of 9a,b (1H and
13C NMR, UV). However, the rate of methylation of
7a,b (TLC) is much lower than that in the case of 9a,b.
In addition, TLC monitoring of the methylation of 7a,b
allows one to observe the intermediate formation of
compounds 9a,b. Naturally, the next stage of our work
was an attempt to perform isomerization in the presence
Thus, in all probability, treatment of carbolines 7a,b
with methyl iodide in the presence of ButOK induces
their rearrangement into isomers 9a,b and only after
that, methylation products 10a,b are formed.
The 7→9 isomerization process can be interpreted
rather reliably (Scheme 5). Apparently, a four-mem-
bered transition state is produced similar to that postu-
lated for the Chapman thermal rearrangement.15,16 It is
clear that the "imino ester" rearrangement described in
the study cited and the "amidine" rearrangement de-
scribed here are somewhat different. This can be seen
from the mere fact that in our case, the process is
markedly facilitated upon the formation of anion 11.
Scheme 5
NO2
–
δ
ꢀꢀ
'
N δ+
N
N
CN
R
H B
B — base.
To summarize, in this study, we have developed a
new pathway to various pyrido[3,2-b]indole (δ-carbo-
line) derivatives and have found a rearrangement of
1,2-diaryl-2-imino-δ-carbolines into 2-diarylamino-δ-
carbolines.
Fig. 1. Crystal structure of molecule 7a.
Experimental
The IR spectra of compounds were recorded on
Perkin—Elmer 457 instruments in mineral oil. Mass spectra
(EI) were recorded on a Finnigan SSQ-710 mass spectrometer
with direct sample injection into the ion source. 1H NMR
spectra were recorded on a Bruker ÀC-200 spectrometer; and
two-dimensional HÌÂC NMR spectra were run on a Bruker
DRX-500 instrument using standard procedures of the com-
pany. UV spectra were measured on a Perkin-Elmer Lambda 9
instrument. The reactions were monitored and the purity of
compounds was checked on Silufol UV-254 plates in a 9 : 1
chloroform—methanol mixture (visualization under UV radia-
tion) and in a 5 : 3 : 1 ethyl acetate—propan-2-ol—ammonia
mixture (for compounds 4a,b, 7a,b, 8a,b). X-ray diffraction
measurements were carried out in a Guinier—Johansson cham-
Fig. 2. Crystal structure of molecule 9a.

New δ-carboline derivatives
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
1455
ber. The structures of compounds 7a and 9a were solved by the
systematic search method.18
Physicochemical characteristics and the yields of substances
are presented in Table 2.
pound 6. Cooling of the methanolic mother liquor gave an
additional 0.03 g of compound 6. The overall yield of 6 was
0.11 g. 1H NMR (DMSO-d6), δ: 1.10—1.50 (both m, 6 H,
2 H(3), 2 H(5), 2 H(4) piperidine); 3.20 (br.m, 4 H, 2 H(2),
2-Chloro-3-cyano-2-dimethylamino-1-p-nitrophenyl-1H-
pyrido[3,2-b]indole (4a). A suspension (3.3 g, 1 mmol) of
δ-carbolin-2-one 1 and triethylamine hydrochloride (1.4 g,
2 H(6) piperidine); 3.73 (m, 3 H, NMe); 2.1 (s, 3 H,
C(4)—CH2COMe); 2.83 (d, 2 H, C(4) CH2COMe, J = 6.1 Hz);
4.35 (t, 1 H, H(4)); 6.98 (d, 1 H, H(9)); 7.15 (t, 1 H, H(8));
7.28 (t, 1 H, H(7)); 7.46 (d, 1 H, H(6)); 7.72, 8.34 (AA´XX´,
4 H, C6H4NO2). IR, ν/cm–1: 2180 (C≡N), 1710 (C=O).
3-Cyano-1-p-nitrophenyl-2-phenylimino-1,2-dihydro-5H-
pyrido[3,2-b]indole (7a) and its hydrochloride (8a). Aniline
(2.22 mL, 24 mmol) was added with stirring at 20 °C to a
suspension of salt 2 (or 3) (1.45 g) in 15 mL of DMF. The
resulting red solution was stirred for 5—6 h and allowed to
stand for 16 h. The resulting precipitate was filtered off and
washed with DMF and ether to give 0.8 g of bright yellow
hydrochloride 8a. The mother liquor was concentrated, water
(30 mL) was added to the oily residue, and the mixture was
stirred and acidified with ∼1 mL of concentrated HCl (to
pH 2). The red precipitate was filtered off, washed with water,
and dried at 100 °C to give 0.94 g of a mixture of compound 7a
and its hydrochloride 8a. Methanol (20 mL) and several drops
of 40% NaOH were added to this mixture, the mixture was
heated to boiling with stirring and cooled, and the precipitate
was filtered off, washed with methanol, and dried to give 0.3 g
of compound 7a.
3
1 mmol) in 160 mL of POCl3 was refluxed for 6 h. (After
1—1.5 h, the reaction mixture became homogeneous and sub-
sequently a precipitate formed). The mixture was allowed to
stand for 12 h at 20 °C and the precipitate was filtered off,
washed with POCl3 and water, and refluxed with 50—70 mL of
acetone. The precipitate was filtered off, washed with acetone,
and dried at 100 °C to give 2.86 g of salt 2 (or 3) (m.p. > 300 °C).
Dimethylamine was passed for 2 h through a suspension of
1.2 g of salt 2 (or 3) in 30 mL of CH2Cl2 with stirring and ice-
water cooling. Then the reaction mixture was refluxed for 2 h
and allowed to stand for 16 h at 20 °C. The dimethylamine
hydrochloride precipitate was filtered off and the mother liquor
was concentrated. The residue was triturated with water. The
precipitate was separated, washed with water, and refluxed with
propan-2-ol. The hot suspension was filtered to give 0.35 g of a
substance, which was then refluxed for 5 min with 15 mL of
concentrated HCl. The mixture was cooled and the precipitate
was filtered off and dissolved in 100 mL of boiling water. The
solution was filtered and combined with the acidic mother
liquor, the mixture was decolorized by adding activated carbon,
and then 11 mL of 40% NaOH was added. The resulting red
precipitate was filtered off and washed with water, isopropyl
alcohol, and ether to give 0.21 g of compound 4a. 1H NMR
(DMSO-d6) δ: 2.81 (both s, each 3 H, NMe2); 6.12 (d, 1 H,
H(9), J = 8.4 Hz); 6.73 (t, 1 H, H(8)); 7.36 (t, 1 H, H(7)); 7.65
(d, 1 H, H(6)); 8.92 (s, 1 H, H(4)); 8.66, 8.13 (AA´XX´, 4 H,
C6H4NO2).
2-p-Chlorophenylimino-3-cyano-1-p-nitrophenyl-1,2-di-
hydro-5H-pyrido[3,2-b]indole (7b) was prepared similarly to
compound 7a from salt 2 (or 3) (1 g), p-chloroaniline (1.33 g,
1.04 mmol) in 15 mL of DMF. After keeping (16 h), the
reaction solution was filtered to remove a slight amount of a
resinous precipitate and concentrated. The subsequent workup,
the same as described for compound 7a, gave 0.8 g of com-
pound 7b.
3-Cyano-1-p-nitrophenyl-2-piperidinî-1H-pyrido[3,2-b]in-
dole (4b). Piperidine (0.3 mL, 3 mmol) was added with stirring
and cooling to a suspension of salt 2 (or 3) (0.2 g) in 10 mL of
CH2Cl2. The red solution thus formed was stirred for 24 h at
20 °C. The resulting red precipitate was filtered off and washed
with CH2Cl2 and acetone to give 0.08 g of compound 4b.
1H NMR (DMSO-d6), δ: 0.80, 1.42, 3.17 (all br.s, 10 H,
5 piperidine CH2); 6.18 (d, 1 H, H(9)); 6.74 (t, 1 H, H(8));
7.36 (t, 1 H, H(7))); 7.65 (d, 1 H, H(6)); 8.92 (s, 1 H, H(4));
8.12, 8.67 (AA´XX´, 4 H, C6H4NO2).
3-Cyano-5-methyl-1-p-nitrophenyl-2-piperidinî-5H-pyri-
do[3,2-b]indolium iodide (5). Methyl iodide (0.4 mL) was
added to a suspension of carboline 4b (0.34 g, 0.86 mmol) in
20 mL of benzene and the mixture was refluxed for 28 h.
Portions of MeI (0.6 mL) were added every 7 h. The precipitate
was filtered off and washed with benzene to give 0.42 g of
iodide 5. 1H NMR (DMSO-d6), δ: 1.22, 1.40, 3.20 (all br.m,
10 H, 5 piperidine CH2); 4.20 (m, 3 H, NMe); 6.37 (d, 1 H,
H(9)); 7.21 (t, 1 H, H(8)); 7.85 (t, 1 H, H(7)); 7.98 (d, 1 H,
H(6)); 9.70 (s, 1 H, H(4)); 8.22, 8.76 (AA´XX´, 4 H, C6H4NO2).
IR, ν/cm–1: 2220 (C≡N).
4-Acetonyl-3-cyano-5-methyl-1-p-nitrophenyl-2-piperidinî-
1,4-dihydropyrido[3,2-b]indole (6). A mixture of iodide 5
(0.27 g, 0.5 mmol), potassium carbonate (0.4 g, 2.8 mmol), and
15 mL of acetone was refluxed with stirring for 10 h. The
inorganic salts were filtered off and washed with acetone. The
mother liquor was concentrated and the residue was triturated
with water. The precipitate was filtered off and washed with
water and methanol to give 0.16 g of a solid material, which
was refluxed with 15 mL of methanol. The insoluble precipitate
was filtered off from the hot solution to give 0.08 g of com-
Preparation of hydrochlorides 8a,b from bases 7a,b.
δ-Carboline 7a or 7b (0.36 mmol) was dissolved in 10 mL of
acetone. The solution was filtered, and HCl-saturated ether was
added with cooling and stirring until the red color changed to
yellow. After 2 h, the resulting precipitate (colored yellow) was
filtered off and washed with acetone to give chlorides 8a or 8b
in ∼60% yield. The melting point of a mixed sample consisting
of chloride 8a and the salt isolated upon the reaction of salt 2
(or 3) with aniline (see above) was undepressed. 1H NMR
(hydrochloride 8a) (DMSO-d6), δ: 7.20—7.50 (m, 5 H, C6H5);
6.08 (d, 1 H, H(9)); 7.05 (t, 1 H, H(8)); 7.63 (t, 1 H, H(7));
7.78 (d, 1 H, H(6)); 9.18 (s, 1 H, H(4)); 8.27, 8.73 (AA´XX´,
4 H, C6H4NO2); 9.64 (br.s, 1 H, N(2)H); 13.37 (br.s, 1 H,
N(5)H). 1H NMR (hydrochloride 8b) (DMSO-d6), δ: 7.38
(AA´XX´, 4 H, C6H4Cl); 6.09 (d, 1 H, H(9)); 7.05 (t, 1 H,
H(8)); 7.63 (t, 1 H, H(7)); 7.77 (d, 1 H, H(6)); 9.16 (s, 1 H,
H(4)); 8.24, 8.71 (AA´XX´, 4 H, C6H4NO2); 9.56 (br.s, 1 H,
N+H); 12.13 (br.s, 1 H, N(5)H).
3-Cyano-2-p-nitrophenyl(phenyl)amino-5H-pyrido[3,2-b]in-
dole (9a). Method À. 2-Phenylimino-δ-carboline 7a (red) (0.2 g,
0.49 mmol) was placed in a bath with Wood´s alloy heated to
300 °C and then heated to 330 °C until the compound com-
pletely melted (2—3 min). Column chromatography on SiO2
(chloroform as the eluent) gave 0.14 g of compound 9a (col-
ored yellow).
Method B. Potassium tert-butoxide (0.02 g, 0.18 mmol) was
added to a solution of 2-phenylimino-δ-carboline 7a (0.05 g,
0.12 mmol) in 3 mL of DMF, the mixture was refluxed for
5 min, and DMF was evaporated. Water (5—7 mL) and
concentrated HCl (0.02 mL) were added to the residue. The
precipitate was filtered off and washed with water and methanol

1456
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 8, August, 2001
Ryabova et al.
to give 0.03 g of compound 9a. The melting point of a mixed
sample of this product with the compound prepared by method À
was undepressed.
NMe); 7.27—7.48 (AA´XX´, 4 H, C6H4Cl); 8.10 (d, 1 H,
H(9)); 7.31 (t, 1 H, H(8)); 7.70 (t, 1 H, H(7)); 7.77 (d, 1 H,
H(6)); 8.82 (s, 1 H, H(4)); 6.93, 8.11 (AA´XX´, 4 H, C6H4NO2).
Method C. 2-Phenylimino-δ-carboline hydrochloride 8a
(0.8 g, 1.8 mmol) was dissolved with heating in 20 mL of
DMF, ButOK (0.8 g, 7.3 mmol) was added, and the mixture
was refluxed for 25—30 min and worked-up by the procedure
described above (B) to give 0.6 g of compound 9a. The melting
point of a mixed sample of this product with the compound
prepared by method À was undepressed.
The authors are grateful to A. I. Bokanov for assis-
tance in determining the structures of the rearranged
products.
References
3-Cyano-2-p-nitrophenyl(p-chlorophenyl)amino-5H-pyri-
do[3,2-b]indole (9b) was prepared from 2-p-chlorophenylimino-
δ-carboline 7b (0.13 g, 0.3 mmol), similarly to method À
described for compound 9a, but with a bath temperature of
200—260 °C. The residue was purified by recrystallization from
methanol to give 0.08 g of compound 9b.
1. R. A. Abramovitch and I. D. Spenser, Adv. Heterocycl.
Chem., 1964, 3, 79.
2. M. D. Mashkovskii, Lekarstvennye sredstva [Medicinals],
Novaya volna, Moscow, 2000, I, 279, 278, 97 (in Russian).
3. S. Yu. Ryabova, L. M. Alekseeva, and V. G. Granik,
Khimiya Geterotsikl. Soedin., 2000, 362 [Chem. Heterocycl.
Compd., 2000 (Engl. Transl.)]
4. W. Kantlehner, in Iminium Salts in Organic Chemistry,
Ed. H. Bohme and H. G. VieHe, J. Wiley and Sons, New
York—London—Sydney—Toronto, 1979, Part 2, 6.
5. H. Bredereck and K. Bredereck, Chem. Ber., 1961, 94, 2278.
6. H. Bredereck, R. Gompper, K. Klemm, and H. Rempfer,
Chem. Ber., 1959, 92, 837.
3-Cyano-5-methyl-2-p-nitrophenyl(phenyl)aminopyri-
do[3,2-b]indole (10a). Method À. Potassium tert-butoxide (0.1 g,
0.89 mmol) was added to a red-colored solution of 2-phenyl-
imino-δ-carboline (0.3 g, 0.74 mmol) 7a in 10 mL of DMF,
the mixture was refluxed for 3—5 min, and ∼5—8 mL of a
mixture of DMF with ButOH was distilled off. Fresh DMF
(8 mL) and MeI (2 mL) were added, and the mixture was
allowed to stand for 24 h at 20 °C. The KI precipitate was
filtered off, DMF was evaporated, and the residue was mixed
with water. The resulting precipitate was filtered off and washed
with water and isopropyl alcohol on the filter with stirring to
give 0.18 g of compound 10a. 1H NMR (DMSO-d6), δ: 4.00 (s,
3 H, NMe); 6.89, 8.11 (AA´XX´, 4 H, C6H4NO2); 7.25—7.38
(m, 4 H, H(2´), H(6´), H(4´), H(8)); 7.47 (t, 2 H, H(3´),
H(5´)); 7.77 (m, 2 H, H(6), H(7)); 8.13 (d, 1 H, H(9)); 8.83
(s, 1 H, H(4)).
Method B. The reaction of δ-carboline 9a (0.11 g,
0.27 mmol), ButOK (0.04 g, 0.33 mmol), DMF (5 mL), and
MeI (1 mL) as described in method À gave 0.1 g of compound
10a. The melting point of a mixed sample of this product with
the compound prepared from 7a was undepressed. The 1H NMR
spectra of the samples were identical.
3-Cyano-5-methyl-2-p-chlorophenyl(p-nitrophenyl)amino-3-
cyanopyrido[3,2-b]indole (10b). Method À. The transformation
of δ-carboline 7b (0.18 g, 0.41 mmol) gave 0.04 g of compound
10b (red-colored), which was purified by column chromatogra-
phy on SiO2 (chloroform as the eluent). The synthesis was
similar to the synthesis of 10a (with the difference that the
reaction mixture was allowed to stand for 48 h).
7. K. Bredereck, F. Effenberger, and H. Botsch, Chem. Ber.,
1964, 97, 3397.
8. K. Bredereck and S. Humburger, Chem. Ber., 1966, 99, 3227.
9. I. M. Ovcharova and E. S. Golovchinskaya, Zh. Obshch.
Khim., 1964, 34, 2472 [Chem. Abstrs., 1964, 61: 9497d].
10. V. G. Granik, V. F. Knyazeva, I. V. Persianova, N. P.
Solov´eva, and R. G. Glushkov, Khimiya Geterotsikl. Soedin.,
1982, 1095 [Chem. Heterocycl. Compd., 1982, 18(8), 838
(Engl. Transl.)].
11. Z. Arnold and A. Holy, Collection Czech, Chem. Commun.,
1962, 27, 2886.
12. H. H. Bosshard and H. Zollinger, Helv. Chim. Acta, 1959,
42, 1659.
13. S. Yu. Ryabova, L. M. Alekseeva, and V. G. Granik,
Mendeleev Commun., 1995, 107.
14. S. Yu. Ryabova, L. M. Alekseeva, and V. G. Granik,
Khim.-Farm. Zhurn., 1996, 30(9), 29 [Pharm. Chem. J.,
1996, 30(9), 579 (Engl. Transl.)].
15. A. W. Chapman, J. Chem. Soc., 1925, 127, 1992.
16. O. H. Wheeler, F. Roman, and O. J. Rosado, J. Org.
Chem., 1969, 34, 966.
Method B. The transformation of δ-carboline 9b (0.19 g,
0.43 mmol) gave 0.16 g of 10b. The synthesis was similar to the
synthesis of 10a by method B (with the difference that the time
of keeping the reaction mixture was 3 h). The melting point of
a mixed sample of this product with the compound prepared by
method À was undepressed. The 1H NMR spectra of the
samples were identical. 1H NMR (DMSO-d6), δ: 3.99 (s, 3 H,
17. V. V. Chernyshev, V. A. Tafeenko, S. Yu. Ryabova, E. J.
Sonneveld, and H. Schenk, Acta Crystallogr., Sec. C, 2001,
C57, 982.
18. V. V. Chernyshev and H. Schenk, Z. Kristallogr., 1998, 213, 1.
Received April 11, 2001