Synthesis and properties of [1,4]diazepino[6,5-b]indoles

Article abstract of DOI:10.1023/A:1015520621450

1-Aryl-2-oxo-1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indole N-oxides were synthesized based on 3-(N'-aryl-N'-chloroacetyl)amino-2-formylindoles. Deoxidation of 2-oxo-1-phenyl-1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indole N-oxide afforded 1,2,3,6-tetrahydro- and 1,2,3,4,5,6-hexahydro[1,4]diazepino[6,5-b]indole derivatives. A new approach to the synthesis of pyrido[3,2-b]indole and pyrimido[5,4-b]indole derivatives was developed.

Full text of DOI:10.1023/A:1015520621450

506
Russian Chemical Bulletin, International Edition, Vol. 51, No. 3, pp. 506—512, March, 2002
Synthesis and properties of [1,4]diazepino[6,5ꢀb]indoles
N. A. Lantsetti,a S. Yu. Ryabova,a L. M. Alekseeva,a A. S. Shashkov,b and V. G. Granika
ꢀ
аState Scientific Center of the Russian Federation "Organic Intermediate Products and Dyes Institute" (NIOPIK),
1/4 Bol'shaya Sadovaya ul., 103787 Moscow, Russian Federation.
Fax: +7 (095) 254 6574. Eꢀmail: makarꢀcl@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
1ꢀArylꢀ2ꢀoxoꢀ1,2,3,6ꢀtetrahydro[1,4]diazepino[6,5ꢀb]indole Nꢀoxides were synthesized
based on 3ꢀ(N´ꢀarylꢀN´ꢀchloroacetyl)aminoꢀ2ꢀformylindoles. Deoxidation of 2ꢀoxoꢀ1ꢀpheꢀ
nylꢀ1,2,3,6ꢀtetrahydro[1,4]diazepino[6,5ꢀb]indole Nꢀoxide afforded 1,2,3,6ꢀtetrahydroꢀ and
1,2,3,4,5,6ꢀhexahydro[1,4]diazepino[6,5ꢀb]indole derivatives. A new approach to the syntheꢀ
sis of pyrido[3,2ꢀb]indole and pyrimido[5,4ꢀb]indole derivatives was developed.
Key words: 3ꢀarylaminoꢀ2ꢀformylindole, [1,4]diazepino[6,5ꢀb]indole, Nꢀoxide, deoxidaꢀ
tion, pyrido[3,2ꢀb]indole, pyrimido[5,4ꢀb]indole.
Many of indoleꢀcontaining polycyclic compounds can
course of the reaction, for example, with ammonia. With
this in mind, we chose the procedure, which involves the
reaction of 3ꢀ(N´ꢀarylꢀN´ꢀchloroacetyl)aminoꢀ2ꢀformylꢀ
indoles 1a,b with pyridine followed by the pyridineꢀring
opening in the resulting pyridinium salts 2 under the acꢀ
tion of amines12 to give products containing the primary
amino group and subsequent cyclization of the latter comꢀ
pounds.
be used as efficient pharmaceuticals.1—3 As an example
we refer to the following antidepressants: pyrazidole,
tetrindole, incazan, the neuroleptic agent carbidine, and
antihystamine drugs dimebon and diazolin. It is known
that compounds containing the benzo[1,4]diazepine ring
are also among important pharmaceuticals. These are anꢀ
ticonvulsive drug clonazepam and numerous tranquilizꢀ
ers of the benzodiazepine series, such as chlozepid,
sibazon, phenazepam, hydazepam, etc.1—3 Hence, fused
systems involving the indole and [1,4]diazepine rings are
of interest from the viewpoint of a search for new
biologically active compounds. Thus, some [1,4]diꢀ
azepino[1,2ꢀa]indole derivatives were found to exꢀ
hibit pronounced psychotropic activity.4—7 At the same
time, [1,4]diazepino[6,5ꢀb]indoles remain poorly studꢀ
ied8 due apparently to the fact that they are difficult to
synthesize.
The reaction of aldehyde 1a with pyridine readily proꢀ
ceeded even at room temperature. However, (2ꢀoxoꢀ1ꢀ
phenylꢀ1,2ꢀdihydropyrido[3,2ꢀb]indolꢀ3ꢀyl)pyridinium
chloride (3) was isolated in quantitative yield instead of
the expected salt 2. Apparently, the initial formation of
pyridinium salt 2 led to a substantial increase in the acidꢀ
ity of the resulting CH acid such that intramolecular cyꢀ
clization involving the formyl group proceeded even unꢀ
der the action of an excess of pyridine to produce
δꢀcarbolinone 3. Systems of this type are characterized by
a substantial upfield shift of the signal for the H(9) proton
due to rotation and the anisotropic effect of the phenyl
The aim of the present study was to examine the apꢀ
proach to the synthesis of [1,4]diazepino[6,5ꢀb]indoles
based on 3ꢀ(N´ꢀarylꢀN´ꢀchloroacetyl)aminoꢀ2ꢀformylꢀ
indoles, which have been prepared by us previously.9
It should be noted that we have already used dechloroꢀ
acetylated 3ꢀN´ꢀarylaminoꢀ2ꢀformylindole derivatives in
the synthesis of threeꢀ and tetracyclic systems.9—11
We believed that the most simple approach to the
synthesis of the target products consists in replacing the
Cl atom in the side chain by the amino group followed by
cyclization at the 2ꢀformyl group to form the diazepine
ring. However, the presence of the reactive chlorine atom
simultaneously with the aldehyde fragment in the molꢀ
ecule of an indole derivative can lead to the ambiguous
1
ring at position 1.10,11 Thus the H NMR spectrum of
compound 3 has a doublet for the proton at position 9
(with the oneꢀproton intensity) at δ 6.09 (see the Experiꢀ
mental section). Heating of pyridinium salt 3 with benzylꢀ
amine in methanol proceeded through the pyridiniumꢀ
ring opening to give 3ꢀaminoꢀ2ꢀoxoꢀ1ꢀphenylꢀ1,2ꢀdiꢀ
hydropyrido[3,2ꢀb]indole (4), which was characterized
also as 3ꢀacetylamino derivative 5. The structures of comꢀ
pounds 4 and 5 were unambiguously confirmed by the
1H NMR spectra (see the Experimental section).
Hence, the proposed procedure, while providing a way
for synthesizing previously inaccessible δꢀcarbolines, unꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 470—475, March, 2002.
1066ꢀ5285/02/5103ꢀ506 $27.00 © 2002 Plenum Publishing Corporation

[1,4]Diazepino[6,5ꢀb]indole
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
507
Scheme 1
R = H (a), 4ꢀCl (b)
fortunately does not allow the preparation of the target
[1,4]diazepino[6,5ꢀb]indoles.
The mass spectrum of compound 7a has a lowꢀintensity
molecular ion peak [M]+ at m/z (Irel (%)) 291 (9). The
highest intensity was observed for the ion [M – 16]+ at
m/z 275 (93). In the mass spectrum of compound 7b, the
molecular ion peak is absent; the most intense peak is
observed at m/z (Irel (%)) 309 [M – 16]+ (100). In the
1H NMR spectra of compounds 7a and 7b (see the Exꢀ
perimental section), the upfield shift of the signal for
H(10) (δ ≈ 6.4) is noteworthy. This shift is caused by the
anisotropic effect of the 1ꢀphenyl or 1ꢀpꢀchlorophenyl
fragments and it has been observed previously for carꢀ
bolinones 3—5.
Because of this, we examined oximation of the startꢀ
ing aldehydes 1a,b. However, we succeeded in isolating
only oxime 6b, which was characterized by mass specꢀ
trometry and 1H NMR spectroscopy (see the Experimenꢀ
tal section). It should be noted that we failed to obtain
this oxime in the analytically pure form. Oxime 6a underꢀ
went cyclization already in the course of the reaction.
Refluxing of compounds 1a,b with hydroxylamine in ethaꢀ
nol afforded 1ꢀarylꢀ2ꢀoxoꢀ1,2,3,6ꢀtetrahydro[1,4]diꢀ
azepino[6,5ꢀb]indole 4ꢀoxides (7a,b) in 90 and 70% yields,
respectively.
The preparation of diazepinoindole Nꢀoxides 7a,b by
cyclization gave impetus to the development of a proceꢀ
Scheme 2
Scheme 3
R = H (a), 4ꢀCl (b)
The structures of Nꢀoxides 7a,b were confirmed by the
data from mass spectrometry and 1H NMR spectroscopy.

508
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
Lantsetti et al.
dure for the synthesis of the corresponding Nꢀdeoxidated
tricyclic compounds. Generally, these reactions proceed
smoothly. However, in the case under consideration, we
observed a series of unexpected transformations. First we
studied reduction with zinc in acetic acid, which is comꢀ
monly used in these reactions.13,14 However, it appeared
that the process performed under these conditions was
not terminated at the stage of deoxidation of Nꢀoxide 7a,
but proceeded further to reduce the 4,5ꢀdouble bond folꢀ
lowed by acetylation of the resulting NH group at posiꢀ
acterized by doubling of most of the expected signals (the
spectrum is given in the Experimental section) due to the
soꢀcalled amide isomerism, viz., the hindered rotation
with respect to the N(4)COMe bond.
We also used formamidinesulfinic (9) acid, which
readily and smoothly reduces carbonyl compounds and
sulfoxides,15 for reduction of the Nꢀoxide group. In this
case, deoxidation followed by reduction of the C=N bond
to form hexahydrodiazepinoindole 10 also proved to be
the major direction of the reaction. Compound 10 was
subjected to acetylation to obtain the aboveꢀdescribed
tricyclic compound 8. At the same time, the reaction with
the use of reagent 9 afforded not only compound 10 but
1
tion 4 of tricyclic fragment. The H NMR spectrum of
the 4ꢀacetylaminoꢀ2ꢀoxoꢀ1ꢀphenylꢀ1,2,3,4,5,6ꢀhexaꢀ
hydro[1,4]diazepino[6,5ꢀb]indole (8) that formed is charꢀ
1
Table 1. Chemical shifts in the 13C NMR spectra (δ) of compounds 4 and 11—13 and the H—13C correlaꢀ
tions (through two and three bonds) in the HMBC spectrum*
C Atom
δ
4
11
12
13
2
156.0 (H(4))
163.2 (3ꢀСН2)
161.8 (CH2),
162.1 (CH2)
—
45.5 (CHO)
49.4
155.9 (H(4))
3
4
137.1 (H(4))
99.8 (NH)
57.6 (H(5))
—
—
143.6
4а
123.6 (H(4), NH)
—
121.0 (NH, 4ꢀCH2),
121.6 (NH, 4ꢀCH2)
—
133.3 (H(4), NH)
5
5а
—
135.8
156.5 (3ꢀСН2)
**
—
136.9
132.0
(NH, H(9), H(7))
(NH, H(9), H(7)),
132.1
(NH, H(9), H(7))
(NH, H(9), H(7))
111.6 (H(8)),
112.2 (H(8))
—
120.5 (H(9)),
120.6 (H(9))
119.1 (H(6)),
119.5 (H(6))
163.3 (H(7))
116.3
6
111.1 (H(8))
—
112.4 (H(8))
6а
7
—
136.6 (NH, H(8), H(9))
112.7 (H(9))
—
121.3 (H(8), H(9))
125.9 (H(9))
8
118.2 (H(6), H(7))
125.5 (H(10))
119.4 (H(6))
9
9a
116.6 (H(7))
117.0
119.8 (H(7))
—
119.6 (H(7))
113.8
(NH, H(6), H(8))
(NH, H(6), H(8)),
117.7
(NH, H(6), H(8))
(NH, H(6), H(8))
105.3 (NH, H(9)),
106.5 (NH, H(9))
—
9b
114.3
(H(4), NH, H(9))
—
115.6
(NH, H(9))
—
10
—
—
—
139.2
128.4
129.6
128.7
—
119.9 (H(8))
118.9 (NH, H(7), H(9))
10a
10b
1´
2´, 6´
3´, 5´
4´
—
—
137.4
128.1
129.1
128.0
158.8,
—
—
124.2 (NH, H(5))
140.4
127.5
129.0
127.5
—
137.0
127.8
129.9
129.6
—
CHO
161.0
* The ordinal numbers of the protons, which show correlation peaks in the HMBC spectrum are given in
parentheses.
** The signal is not observed.

[1,4]Diazepino[6,5ꢀb]indole
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
509
Table 2. Physicochemical characteristics of compounds 3—5, 7a,b, 8, and 10—13
Comꢀ Yield M.p./°C Mol.
pound (%) (solvent)* weight
Found
Calculated
Molecular
formula
MS,
m/z (Irel (%))
IR,
max/cm–1
(%)
ν
С
H
—
N
NH (NH2) CO
3310 1620
3
99
70
70
90
235—237 373
decomp.
(ether)
275—277 275 74.21 5.01 15.31 C17H13N3O
(PriOH)
74.16 4.76 15.26
—
11.18 C22H16N3OCl
11.24
—
4
275 [M]+ (100), 247 [M – CO]+ (17),
219 [M – HCO – HCN]+ (26),
170 [M – CO – Ph]+ (20)
317 [M]+ (42), 275 [M – Ac]+ (100),
247 [M – Ac – CO]+ (19),
3423, 1638
3340
5
358—360 317 72.17 5.00 13.51 C19H15N3O2
(PriOH)
71.91 4.76 13.24
3205, 1631,
3281 1669
219 [M – HCO – HCN]+ (35)
291 [M]+ (9), 275 [M – O]+ (93),
247 [M – O – CO]+ (33),
246 [M – O – HCO]+ (100),
219 [M – O – HCO – HCN]+ (39),
170 [M – O – HCO – Ph]+ (37)
7a
282—283 291 69.87 4.67 14.45 C17H13N3O2
(DMF) 70.09 4.49 14.42
3141 1668
3180 1668
7b**
70
280—282 325 62.51 3.65 12.64 C17H12N3O2Cl 309 [M – O]+ (58),
(DMF)
62.67 3.71 12.90
280 [M – O – HCO]+ (100),
254 [M – O – CO – HCN]+ (6),
170 [M – O – CO – C6H4Cl]+ (34)
319 [M]+ (64), 305 [M – CH2]+ (3),
291 [M – CH2 – CO]+ (3),
8
38 (A) 218—220 319 71.65 5.75 13.20 C19H17N3O2
46 (B) (EtOAc) 71.45 5.36 13.15
3266 1638,
1671
276 [M – Ac]+ (6),
260 [M – Ac – NH2]+ (17),
248 [M – Ac – NCH2]+ (10),
219 [M – Ac – COCH2NH]+ (100)
277 [M]+ (92), 275 [M – H2]+ (95),
246 [M – H2 – NCH2]+ (90),
219 [M – COCH2NH2]+ (100)
10
11
75
252—254 277
(MeOH)
—
—
15.40 C17H15N3O
15.15
3276 1655
46 (A) 249—251 275 73.99 5.20 15.27 C17H13N3O
6 (B) (MeOH) 74.16 4.76 15.36
275 [M]+ (100), 246 [M – HCO]+ (75), ***
218 [M – COCH2NH]+ (22),
1666
170 [M – HCO – C6H5]+ (27)
12
13
60
44
260—262 291 70.22 4.70 14.49 C17H13N3O2
(MeOH) 70.09 4.49 14.42
276—278 261 73.76 4.43 16.03 C16H11N3O
(EtOH) 73.54 4.24 16.08
291 [M]+ (91), 262 [M – HCO]+ (49), 3443 1628,
234 [M – HCO – CO]+ (100)
261 [M]+ (100), 233 [M – CO]+ (83),
205 [M – CO – CH2N]+ (38)
1678
3175 1645
* For recrystallization.
** Found (%): Cl, 10.59; calculated (%): Cl, 10.88.
*** The absorption band of the NH group is observed at 3254 cm–1 in the spectrum, which was measured in a film precipitated from
chloroform.
also the target compound, viz., 2ꢀoxoꢀ1ꢀphenylꢀ1,2,3,6ꢀ
tetrahydro[1,4]diazepino[6,5ꢀb]indole (11), in low yield.
The structure of the latter compound was confirmed by
the data from mass spectrometry, 1H NMR spectroscopy,
and HMBC* experiments (see the Experimental section,
Table 1).
Reduction of Nꢀoxide 7a with sodium hydrosulfide
proved to be a more convenient procedure for the syntheꢀ
sis of deoxidated compound 11. In the latter case, the
reaction afforded derivative 11 as the major product in
46% yield.
We studied yet another procedure for deoxidation,16,17
viz., the reaction of Nꢀoxide 7a with phosphorus trichloꢀ
ride. However, the reaction of compound 7a with PCl3 unꢀ
expectedly produced 3ꢀformylꢀ2ꢀoxoꢀ1ꢀphenylꢀ2,3,4,5ꢀ
tetrahydroꢀ1Hꢀpyrimido[5,4ꢀb]indole (12). Benzodiꢀ
azepines are characterized by contraction of the sevenꢀ
membered ring to the sixꢀmembered ring.18 As far as we
know, this contraction under the action of phosphorus
halides has not been observed previously. The structure of
tricyclic compound 12 was established by mass spectromꢀ
1
etry, H NMR spectroscopy, and HMBC experiments.
The mass spectrum of compound 12 has the ion peak M+
at m/z 291 (100) (Table 2).
* HMBC is heteronuclear multipleꢀbond connectivity.

510
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
Lantsetti et al.
Scheme 4
Doubling of most of the signals in the 1H and
To summarize, we carried out the new synthesis of
[1,4]diazepino[6,5ꢀb]indoles and studied some properties
of these compounds. New procedures were developed for
the preparation of previously inaccessible δꢀcarbolines and
pyrimido[5,4ꢀb]indoles.
13C NMR spectra (see the Experimental section and
Table 1) as well as the identity of the correlation peaks for
all pair signals observed in the HMBC spectrum suggest
the occurrence of the amide isomerism. The signals at
1
δ 8.37 and 8.87 in the H NMR spectrum and the signals
at δ 158.8 and 161.0 in the 13C NMR spectrum are indicaꢀ
tive of the presence of the N—CHO group in compound
12. Heating of compound 12 with piperidine in methanol
led to deformylation followed by aromatization of the
pyrimidine ring to form 2ꢀoxoꢀ1ꢀphenylꢀ1,2ꢀdihydroꢀ
pyrimido[5,4ꢀb]indole (13). The structure of the latꢀ
ter compound was established by the data from the
HMBC experiment, which were compared with those for
δꢀcarbolinone 4. As can be seen from Table 1, the chemiꢀ
cal shifts of the quaternary carbon atoms in compounds
13 and 4 have close values. The observed shift of the
signal for the C(4a) atom in the spectrum of pyrimidinone
13 as compared to that for δꢀcarbolinone 4 (at δ ∼10) is
apparently associated with the effect of the N atom at
position 3. Since the H(4)/C(9b) correlation peak is abꢀ
sent in the spectrum of compound 13, the structure of
13 was unambiguously established by the NOESY exꢀ
periment. This spectrum shows the correlation peaks
7.99/12.09 (H(4)/NH) and 7.46/12.09 (H(6)/NH), which
indicate that the proton of the NH group is in spatial
proximity to the protons of the CH groups at positions 4
and 6. These data provide support for the validity of the
structure of 13 and, consequently, of the structure of 12.
The formation of compounds 12 and 13 can be repreꢀ
sented by Scheme 4.
Experimental
The IR spectra were measured on a Perkin—Elmer 457 inꢀ
strument in Nujol mulls. The mass spectra were obtained on a
JSQꢀ900 mass spectrometer with direct inlet of the sample into
the ion source. The 1H NMR spectra were recorded on a Bruker
ACꢀ200 spectrometer. The 2D HMBC NMR spectra were meaꢀ
sured on a Bruker DRXꢀ500 spectrometer using the standard
Bruker software. The course of the reactions and the purities of
the compounds were monitored on Silufol UVꢀ254 plates using
10 : 1 chloroform—methanol (for compounds 3, 4, 5, 8, 11, and
12), 9 : 1 benzene—methanol (for compounds 6b and 7a,b), and
6 : 2.5 : 1.4 : 0.1 ethyl acetate—hexane—ethanol—ammonia
(for compound 10) systems. The physicochemical characterisꢀ
tics and the yields of the compounds are given in Table 2.
(2ꢀOxoꢀ1ꢀphenylꢀ1,2ꢀdihydropyrido[3,2ꢀb]indolꢀ3ꢀyl)pyriꢀ
dinium chloride (3). A mixture of aldehyde 1a (2.5 g, 8 mmol)
and pyridine (18.7 mL) was stirred at ∼20 °C for 48 h. The
precipitate was filtered off and washed with pyridine and ether.
Then ether was added and the reaction mixture was kept in a
refrigerator for 16 h. The yellow precipitate that formed was
filtered off and dried at 20 °C. Salt 3 was obtained in a yield of
2.93 g. 1H NMR (DMSOꢀd6), δ: 6.09 (d, 1 H, H(9), J9,8
=
8.4 Hz); 6.85 (t, 1 H, H(8), J8,7 = J8,9 = 8.4 Hz); 7.35 (t, 1 H,
H(7), J7,6 = J7,8 = 8.4 Hz); 7.50—7.80 (m, 6 H, H(6) and
C6H5); 8.33 (m, 2 H, H(3´), H(5´)); 8.79 (m, 1 H, H(4´)); 8.82
(d, 1 H, H(4), J4,5 = 1.5 Hz); 9.34 (m, 2 H, H(2´), H(6´)); 12.70
(br.s, 1 H, N(5)H).
3ꢀAminoꢀ2ꢀoxoꢀ1ꢀphenylꢀ1,2ꢀdihydropyrido[3,2ꢀb]indole (4).
Benzylamine (2.5 mL, 12 mmol) was added to a solution of
pyridinium chloride 3 (0.75 g, 2 mmol) in methanol (6 mL). The
reaction mixture was refluxed for 3 h and concentrated to dryꢀ
ness. The resulting oil was washed with lowꢀboiling light petroꢀ
leum (3×5 mL) and diethyl ether (3×5 mL) and then triturated
Apparently, the first step of this reaction involves the
formation of adduct 14 followed by the N→C rearrangeꢀ
ment, which is also typical of benzodiazepines (see, for
example, the synthesis of the tranquilizer nozepam19),
the cleavage of the C(2)—C(3) bond, and the pyrimidineꢀ
ring closure.

[1,4]Diazepino[6,5ꢀb]indole
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
511
with water (30 mL). The precipitate that formed was filtered off,
washed with cold propanꢀ2ꢀol, and dried. Compound 4 was
obtained in a yield of 0.34 g. 1H NMR (DMSOꢀd6), δ: 5.37
(br.s, 2 H, 3ꢀNH2); 5.87 (d, 1 H, H(9), J9,8 = 8.2 Hz); 6.65 (t,
1 H, H(8), J8,9 = J8,7 = 8.2 Hz); 6.98 (s, 1 H, H(4)); 6.99 (m,
1 H, H(7)); 7.32 (d, 1 H, H(6), J6,7 = 8.2 Hz); 7.43 and 7.64
(both m, 5 H each, C6H5); 10.97 (br.s, 1 H, N(5)H).
excess of cold water. The precipitate that formed was filtered
off, washed with water, and dried. Compound 8 was obtained in
a yield of 0.21 g. 1H NMR (DMSOꢀd6), δ: 2.18 and 2.20 (both s,
3 H each, 4ꢀCOMe); 4.30 and 4.32 (both s, 2 H each, 3ꢀCH2);
4.93 and 5.01 (both s, 2 H each, 5ꢀCH2); 6.40 (m, 1 H, H(10));
6.75 (m, 1 H, H(9)); 7.05 (m, 1 H, H(8)); 7.20—7.50 (m, 6 H,
H(7) and C6H5); 11.35 (br.s, 1 H, N(6)H).
3ꢀAcetylaminoꢀ2ꢀoxoꢀ1ꢀphenylꢀ1,2ꢀdihydropyrido[3,2ꢀb]inꢀ
dole (5). A mixture of 3ꢀaminoꢀδꢀcarboline 4 (0.07 g, 0.25 mmol)
and acetic anhydride (6 mL) was heated on a water bath at
50—60 °C for 5—7 min. The precipitate that formed was filtered
off, washed with acetic anhydride and diethyl ether, and dried.
Compound 5 was obtained in a yield of 0.03 g. 1H NMR
Method B. Acetic anhydride (0.05 mL, 0.6 mmol) was added
to a solution of compound 10 (0.15 g, 0.54 mmol) in AcOH
(5 mL) and the mixture was heated to 50 °C. After 15 min, the
reaction solution was cooled and poured into cold water (20 mL).
The precipitate that formed was filtered off and washed with
water and ether. Compound 8 was obtained in a yield of 0.08 g.
A mixture with the sample prepared according to the method A
did not give a melting point depression. The IR spectra of these
compounds are identical.
(DMSOꢀd6), δ: 2.19 (s, 3 H, COMe); 6.00 (d, 1 H, H(9), J9,8
=
8.4 Hz); 6.75 (t, 1 H, H(8), J8,9 = J8,7 = 8.4 Hz); 7.15 (t, 1 H,
H(7), J7,6 = J7,8 = 8.4 Hz); 7.30—7.90 (m, 6 H, H(6) and
C6H5); 8.83 (s, 1 H, H(4)); 9.24 (br.s, 1 H, NHCOMe); 11.37
(br.s, 1 H, N(5)H).
2ꢀOxoꢀ1ꢀphenylꢀ1,2,3,4,5,6ꢀhexahydro[1,4]diazepiꢀ
no[6,5ꢀb]indole (10). A suspension of compound 7a (0.5 g,
1.7 mmol) in an aqueous solution of NaOH (26 mL), which was
prepared from NaOH (0.51 g, 12.75 mmol) and water (43 mL),
was mixed with stirring with a solution of formamidinesulfinic
acid (9) (0.74 g, 6.8 mmol) in the remaining solution of NaOH
(∼17 mL) at 20 °C. The reaction mixture was heated on a boiling
water bath for 1 h 15 min. The suspension was cooled and the
precipitate was filtered off and washed with water. Compound
3ꢀ[N´ꢀChloroacetylꢀN´ꢀ(4ꢀchlorophenyl)]aminoꢀ2ꢀformylꢀ
indole oxime (6b). Aldehyde 1b (0.3 g, 0.86 mmol) was dissolved
in ethanol (10 mL) upon heating and then the reaction solution
was cooled to 20 °C. Hydroxylamine hydrochloride (0.066 g,
0.95 mmol) and potassium acetate (0.038 g, 0.95 mmol) were
added with stirring. The reaction mixture was kept at 20 °C for
3 days. The precipitate that formed was filtered off and washed
with water and ethanol. Oxime 6b was obtained in a yield of 0.15 g
(48%), m.p. 227—229 °C (from ethanol). MS, m/z (Irel (%)):
318 [M – H – CH=NOH]+ (50), 241 [M – H – CH=NOH –
COCH2Cl]+ (100), 206 [M – H – C6H4Cl]+ (40), 129 [M –
H – C6H4Cl – COCH2Cl]+ (35). IR, ν/cm–1: 3306 (NH, OH);
1
10 was obtained in a yield of 0.36 g. H NMR (DMSOꢀd6), δ:
3.45 (s, 2 H, 3ꢀCH2); 4.24 (s, 2 H, 5ꢀCH2); 6.32 (d, 1 H, H(10),
J10,9 = 8 Hz); 6.65 (t, 1 H, H(9), J9,10 = J9,8 = 8 Hz); 6.95 (t,
1 H, H(8), J8,9 = J8,7 = 8 Hz); 7.20—7.50 (m, 6 H, H(7) and
C6H5); 11.05 (br.s, 1 H, N(6)H).
1
1679 (CO). H NMR (DMSOꢀd6), δ: 4.24 (s, 2 H, COCH2Cl);
2ꢀOxoꢀ1ꢀphenylꢀ1,2,3,6ꢀtetrahydro[1,4]diazepino[6,5ꢀb]inꢀ
dole (11). Method A. A solution of sodium hydrosulfite (3.2 g,
15.3 mmol) in water (8 mL) was added with stirring to a suspenꢀ
sion of Nꢀoxide 7a (1.5 g, 5.1 mmol) in DMF (38 mL). The
reaction mixture was refluxed for 3.5 h and then kept at 20 °C
for 16 h. The inorganic precipitate was filtered off, the mother
liquor was concentrated to dryness, and the residue was trituꢀ
rated with water. The precipitate was filtered off, washed with
water, and dried. A compound, which was isolated in a yield of
1.32 g, was crystallized from MeOH. Compound 11 was obꢀ
tained in a yield of 0.65 g. 1H NMR (DMSOꢀd6), δ: 4.50 (s, 2 H,
3ꢀCH2); 6.23 (d, 1 H, H(10), J10,9 = 8.4 Hz); 6.81 (t, 1 H, H(9),
J9,10 = J9,8 = 8.4 Hz); 7.40—7.60 (m, 7 H, H(7), H(8), C6H5);
9.13 (s, 1 H, H(5)); 12.10 (br.s, 1 H, N(6)H).
Method B. An aqueous mother liquor, which was obtained
after filtration of hexahydro[1,4]diazepino[6,5ꢀb]indole (10), was
acidified with concentrated HCl (5 mL). The precipitate that
formed was filtered off and washed with water. Compound 11
was obtained in a yield of 0.03 g.
The 1H NMR spectra of the compounds obtained according
to the methods A and B are identical. The chemical shifts of the
corresponding protons are somewhat different. The spectrum of
a mixture of the samples has one set of signals.
7.05 and 7.16 (both t, 2 H each, H(5), H(6), J5,4 = J5,6 = J6,5
=
J6,7 = 8 Hz); 7.30—7.55 (m, 6 H, H(4), H(7), 4ꢀClC6H4); 7.71
(d, 1 H, CH=N—OH, J = 2.5 Hz); 11.40 (br.s, 1 H, N(5)H).
The signal for the proton of N—OH is not observed in the
spectrum.
1ꢀArylꢀ2ꢀoxoꢀ1,2,3,6ꢀtetrahydro[1,4]diazepino[6,5ꢀb]indole
4ꢀoxides (7a,b). Aldehyde 1a (1.92 g, 6.4 mmol) or 1b (2.14 g,
6.4 mmol) was dissolved in ethanol (67 mL) upon heating and
the solution was cooled to 20 °C. Then hydroxylamine hydroꢀ
chloride (0.48 g, 7 mmol) and potassium acetate (1.36 g,
14 mmol) were added. The reaction mixture was stirred at 20 °C
for 1.5 h and then refluxed for 2.5 h. The precipitate that formed
was filtered off and washed with water and ethanol. Compounds
7a and 7b were obtained in yields of 1.67 and 1.44 g, respecꢀ
1
tively. H NMR of compound 7a (DMSOꢀd6), δ: 4.75 (s, 2 H,
3ꢀCH2); 6.35 (d, 1 H, H(10), J10,9 = 8.2 Hz); 6.78 (t, 1 H, H(9),
J9,10 = J9,8 = 8.2 Hz); 7.15 (t, 1 H, H(8), J8,9 = J8,7 = 8.2 Hz);
7.20—7.60 (m, 6 H, Ph, H(7)); 8.17 (s, 1 H, H(5)); 11.49 (br.s,
1 H, N(6)H). 1H NMR of compound 7b (DMSOꢀd6), δ: 4.75 (s,
2 H, 3ꢀCH2); 6.42 (d, 1 H, H(10), J10,9 = 8.2 Hz); 6.85 (t, 1 H,
H(9), J9,10 = J9,8 = 8.2 Hz); 7.17 (t, 1 H, H(8)), J8,7 = J8,9
=
8.2 Hz); 7.43 (d, 1 H, H(7), J7,8 = 8.2 Hz); 7.33, 7.50 (AA´XX´,
4 H, 4ꢀClC6H4); 8.16 (s, 1 H, H(5)); 11.50 (br.s, 1 H, N(6)H).
4ꢀAcetylaminoꢀ2ꢀoxoꢀ1ꢀphenylꢀ1,2,3,4,5,6ꢀhexaꢀ
hydro[1,4]diazepino[6,5ꢀb]indole (8). Method A. A suspension
of Nꢀoxide 7a (0.5 g, 1.7 mmol) in glacial acetic acid (10 mL)
was heated to boiling. Then zinc dust (0.56 g, 8.5 mmol) was
added portionwise, the mixture was refluxed for 1 h, and acetic
anhydride (0.16 mL, 1.7 mmol) was added. The reaction mixꢀ
ture was refluxed for 30 min and then poured into a 10ꢀfold
3ꢀFormylꢀ2ꢀoxoꢀ1ꢀphenylꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyrimiꢀ
do[5,4ꢀb]indole (12). Phosphorus trichloride (0.9 mL,
10.2 mmol) was added dropwise with stirring to a suspension of
Nꢀoxide 7a (1 g, 3.4 mmol) in dry chloroform (12 mL). The
reaction mixture was refluxed for 10 min and then cooled. The
precipitate that formed was filtered off, washed with chloroform
and water, and dried. Compound 12 was obtained in a yield of
0.6 g. 1H NMR (DMSOꢀd6), δ: 4.63 and 4.75 (both s, 2 H each,

512
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
Lantsetti et al.
C(4)H2); 5.93 (m, 1 H, H(9)); 6.71 (m, 1 H, H(8)); 6.98 (m,
1 H, H(7)); 7.20—7.70 (m, 6 H, H(6), Ph); 8.37 and 8.87 (both s,
1 H each, CHO); 11.50 and 11.75 (both br.s, 1 H each, N(5)H).
2ꢀOxoꢀ1ꢀphenylꢀ1,2ꢀdihydropyrimido[5,4ꢀb]indole (13).
A mixture of compound 12 (0.6 g, 2 mmol), methanol (10 mL),
and piperidine (0.78 mL, 8 mmol) was refluxed for 5.5 h. The
reaction solution was concentrated to oneꢀhalf of the initial
volume and cooled on an ice bath. The precipitate that formed
was filtered off and washed with methanol. Compound 13 was
6. US Pat 3,689,503; Chem. Abstrs., 1972, 77, 152241y.
7. US Pat 3,641,030; Chem. Abstrs., 1972, 76, 140919s.
8. T. T. Garcia, L. E. Berjamin, and R. Ian Fryer, J. Heterocycl.
Chem., 1973, 10, 51.
9. S. Yu. Ryabova, N. Z. Tugusheva, L. M. Alekseeva, and
V. G. Granik, Khim.ꢀfarm. Zh., 1996, 30, No. 7, 42 [Pharm.
Chem. J., 1996, 30, No. 7, 472 (Engl. Transl.)].
10. S. Yu. Ryabova, L. M. Alekseeva, and V. G. Granik,
Khim.ꢀfarm. Zh., 1996, 30, No. 9, 29 [Pharm. Chem. J.,
1996, 30, No. 9, 579 (Engl. Transl.)].
1
obtained in a yield of 0.23 g. H NMR (DMSOꢀd6), δ: 6.16 (d,
1 H, H(9), J9,8 = 8.4 Hz); 6.83 (t, 1 H, H(8), J8,9 = J8,7
=
11. S. Yu. Ryabova, L. M. Alekseeva, and V. G. Granik, Khim.
Geterotsikl. Soedin., 2000, 36, 362 [Chem. Heterocycl. Compd.,
2000, 36, 301 (Engl. Transl.)].
12. A. Albert, J. Chem. Soc., 1951, 1376.
13. T. I. Mukhanova, L. M. Alekseeva, E. F. Kuleshova, and
V. G. Granik, Mendeleev Commun., 1993, 146.
8.4 Hz); 7.28 (t, 1 H, H(7), J7,6 = J7,8 = 8.4 Hz); 7.46 (d, 1 H,
H(6), J6,7 = 8.4 Hz); 7.55 and 7.69 (both m, 2 H each,
H(2´), H(3´), H(4´), H(5´), H(6´); 7.99 (s, 1 H, H(4)); 12.09
(br.s, 1 H, N(5)H).
14. T. I. Mukhanova, L. M. Alekseeva, E. F. Kuleshova, and
V. G. Granik, Khim.ꢀfarm. Zh., 1996, 30, No. 3, 54 [Pharm.
Chem. J., 1996, 30, No. 3, 200 (Engl. Transl.)].
15. J. Dzabowicz and M. Mikolajczyk, Synthesis, 1978, 542.
16. E. Ochiai, J. Org. Chem., 1953, 18, 534.
17. J. M. Essery and K. Schofield, J. Chem. Soc., 1960, 4953.
18. R. Ian Fryer, J. Heterocycl. Chem., 1972, 9, 747.
19. S. IacobescuꢀCilianu, D. Belu, M. Lazarescu, G. Neubauer,
C. Ilie, and A. Ciuceanu, Rev. Chim., 1974, 25, 869.
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Received October 29, 2001;
in revised form December 14, 2001