7,8,9-trimethyl-1-phenyl-3H-pyrrolo[2,1-d][1,2,5]triazepin-4(5H)-one. Synthesis and reactions

Article abstract of DOI:10.1134/S1070428017050153

A strategy was developed for the synthesis of 7,8,9-trimethyl-1-phenyl-3H-pyrrolo[2,1-d][1,2,5]-triazepin-4(5H)-one, reactions of its functionalization at the С⁴ atom and aza rings fusion at the С⁴?N³ bond were explored. The formation mechanism of the pyrrolo-1,2,5-triazepinone scaffold was suggested.

Full text of DOI:10.1134/S1070428017050153

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 5, pp. 738–745. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © A.O. Kharaneko, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 5, pp. 727–734.
7,8,9-Trimethyl-1-phenyl-3H-pyrrolo[2,1-d][1,2,5]triazepin-
4
(5H)-one. Synthesis and Reactions
A. O. Kharaneko*
Litvinenko Institute of Physical Organic and Coal Chemistry, ul. R. Luxemburg 70, Donetsk, 83114 Ukraine
*
e-mail: antonhar08@rambler.ru
Received February 1, 2017
Abstract—A strategy was developed for the synthesis of 7,8,9-trimethyl-1-phenyl-3H-pyrrolo[2,1-d][1,2,5]-
4
4
3
triazepin-4(5H)-one, reactions of its functionalization at the С atom and aza rings fusion at the С ‒N bond
were explored. The formation mechanism of the pyrrolo-1,2,5-triazepinone scaffold was suggested.
DOI: 10.1134/S1070428017050153
Pyrrolo[1,2-b][1,2,5]triazepine 1 exhibits an anal-
gesic, anxiolytic, and anticonvulsant activity [1],
pyrrolo[1,2-b][1,2,5]benzotriazepine 2 possesses an
anti-HIV action [2]. Compounds of isomeric structure
The simultaneous presence of the benzoyl group in the
position 2 and the methyl group in the position 5 of the
pyrrole ring of compound 5а considerably hampers its
alkylation at the nitrogen atom and requires more
stringent conditions than the reaction with 2-
aroylpyrrole. In search for optimum conditions of
compound 5а N-alkylation with ethyl iodoacetate we
performed a series of experiments where solvent, base,
and reaction temperature were varied.
3
and 4 with a pyrrolotriazepine structure remain
practically unexplored. The first information on
derivatives of compounds 3 and 4 appeared in 2013‒
2
014 (synthesis [1, 3], ring contraction of the
triazepine cycle of compound 3 [1], N-alkylation,
triazepine ring opening, hetero-fusion of compound 4
The best results were obtained in reaction at 60–70°C
in a strongly basic environment DMSO–KОН at the
molar ratio 5а‒KОН 1 : 4. Further increase in the
KОН concentration did not result in a higher yield of N
-alkylation product and was accompanied with the
hydrolysis of the formed ester to (2-benzoyl-3,4,5-
trimethyl-1Н-pyrrol-1-yl)acetic acid 6a. Unreacted
compound 5a and acid 6a were separated without
application of column chromatography.
[3, 4]).
We have synthesized 7,8,9-trimethyl-1-phenyl-3H-
pyrrolo[2,1-d][1,2,5]triazepin-4(5H)-one 9а (Scheme 1),
4
and have studied its functionalization at the С atom
4
3
and aza rings fusion at the С ‒N bond.
In contrast to [3] where sterically unhindered 2-
aroylpyrroles had been utilized we selected 2-benzoyl-
3
,4,5-trimethylpyrrole 5a [5] as an initial reagent. The
attempts to extend the alkylation procedure of [3] to
compound 5а were unsuccessful. The treatment of
compound 5а with ethyl iodoacetate gave the N-
alkylation product in a yield not exceeding 5–10%.
The esterification of acid 6a by boiling in ethanol in
the presence of dry HCl led to the elimination of the
benzoyl group affording ethyl benzoate and ethyl
(2,3,4-trimethyl-1H-pyrrol-1-yl)acetate (Scheme 1). The
1
H spectrum of this mixture contains, on the one hand,
a triplet at 1.37 (3Н), a quartet at 4.31 (2H), a triplet at
7
7
.44 (2H), a triplet at 7.58 (1H), and a doublet at
.95 (2H) ppm corresponding to ethyl benzoate. On the
Ph
O
O
Ar
other hand, the spectrum contains signals belonging to
ethyl (2,3,4-trimethyl-1H-pyrrol-1-yl)acetate: three
singlets at 1.84, 1.89, and 1.97 ppm (3 methyl groups
in the pyrrole ring), a triplet at 1.25, and a quartet at
N
N
N
N
N
N
N
N
N
N
N
N
R
R
O
Me
O
4
.12 ppm (ester ethyl group), a singlet at 4.48 ppm
1
2
3
4
7
38

7
,8,9-TRIMETHYL-1-PHENYL-3H-PYRROLO[2,1-d][1,2,5]TRIAZEPIN-4(5H)-ONE
739
Scheme 1.
R3
R3
Me
R3
R2
R1
R2
R1
Me
Me
R4
O
R4
R2
TsOH,
AcOH
Ph
N
R4
ICH C(O)OEt
2
N H
2 4
N
N
NNH2
N
R1
N
O
H
NH
O
O
5
a, 5b
O
O
R5
NHNH
2
6
a, 6b
8a, 8b
9a
EtOH, HCl,
reflux
EtOH, HCl,
N H
HCl
2
4
2
0oC
R3
R3
R3
R2
Me
R4
R2
R4
R2
R1
R4
Me
+
PhC(O)OEt
R1
N
O
N
N
N
R1
N
O
N
Me
O
O
O
NHNH2
O
9b
O
O
Et
Et
7
a
10b
1
2
3
4
5
1
2
3
4
5
R = R = R = Me, R = Ph, R = H (а); R + R = CH=CHC(Me)=CH, R + R = (CH
2
)
3
, R = Et (b).
(
CH of pyrrole), a singlet at 6.23 ppm (CH of
E-isomer reported in EXPERIMENTAL the signals of
the Z-isomer were observed: 2.19 q (2Н, СН , J
.6 Hz), 2.44 s (3Н, СН ), 2.55 t (2Н, СН , J 5.2 Hz),
2
pyrrole).
The acid 6a esterification in milder conditions
stirring in ethanol at room temperature for 20–40 min)
led to the formation of ethyl (2-benzoyl-3,4,5-trimethyl-
2
5
2
3
2
.98 t (2Н, СН , J 5.2 Hz), 6.08 br.s (2Н, NH ), 5.16 s
2
2
(
(
2Н, СН ), 7.17 d (1Нarom, J 8.0 Hz), 7.26 d (1Нarom, J
2
8
.4 Hz), 7.42 s (1Нarom), 9.14 br.s (1Н, NH).
1
Н-pyrrol-1-yl)acetate 7а (Scheme 1).
The identification of hydrazide 8b isolated after
Boiling of compound 7a in hydrazine hydrate
afforded in a quantitative yield 2-{2-[(E)-hydra-
zinylidene(phenyl)methyl]-3,4,5-trimethyl-1H-pyrrol-
-yl}acetohydrazide 8a whose cyclization into pyrrolo-
2,1-d][1,2,5]triazepinone 9a occurred in a quantitative
boiling with hydrazine hydrate as an Е-isomer was
based on the data in [3] where the Е-isomer was found
to be more thermodynamically stable, therefore under
more stringent conditions (boiling in hydrazine
hydrate) should form only the Е-isomer.
1
[
yield in acetic acid containing a catalytic quantity of p-
toluenesulfonic acid (TsOH).
The cyclization of compound 8b in 9-methyl-
3
,5,6,7-tetrahydro[1,2,5]triazepino[3,4,5-jk]carbazol-2-
6
-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one 5b [6]
(
1H)-one 9b proceeded quantitatively in dioxane in the
may be regarded as a substituted pyrrole. The alkylation
of compound 5b with ethyl iodoacetate occurred quantita-
tively under milder conditions (in dimethylformamide in
the presence of potassium carbonate) giving ethyl (6-me-
thyl-1-oxo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetate
presence of a double excess of HCl. In the reaction
occurring in acetic acid with catalytic quantity of
TsOH the hydrazone suffered a hydrolysis providing
2
-(6-methyl-1-oxo-1,2,3,4-tetrahydro-9H-carbazol-9-
yl)acetohydrazide 10b.
6
b. The boiling of carbazolylacetate 6b in hydrazine
hydrate afforded in a quantitative yield 2-[(1E)-1-hydra-
zinylidene-6-methyl-1,2,3,4-tetrahydro-9H-carbazol-9-
yl]acetohydrazide 8b. Boiling of carbazolylacetate 6b
in methanol with a twofold quantity of hydrazine
hydrate resulted in a mixture of E- and Z-isomers 8b
It is known [1, 7, 8] that 1-phenacyl-2-acylarenes
and 1-acetonyl-2-benzoylarenes at boiling in alcohol
with an equimolar amount of hydrazine hydrate afford
the corresponding hetero-fused 1,2-diazepines (or 1,2,5-
triazepines). The probable mechanism of their
formation consists in an intermolecular reaction
between the arene and hydrazine (Scheme 2).
1
with a slight excess of the Е-isomer. In the H NMR
spectrum of this sample along with the signals of the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

7
40
KHARANEKO et al.
Scheme 2.
Ar
O
O
Alk
X
O
O
Ar
Alk
N H
2
X
4
X
or
N
or
N
X
N
N
Ar
Alk
Alk
Ar
Х = C or N
Scheme 3.
H
N
OH
O
N
N
N
OH
N
O
H N
H
2
N
OH
2
N
H+
N
H O
N
2
N
NH2
N
N
NH
_
_H
O
2
N H
2
4
O
N
N
NH2
NH
2
Ar
Ar
Ar
Ar
Ar
1
In the Н NMR spectra of such structures the
mechanism of seven-membered ring from diketones
(Scheme 2).
methylene group protons of the seven-membered ring
appear as two one-proton doublets. It means that the
methylene group deviates from the seven-membered
ring plane thus relieving its strain.
The closure of hydrazinylidenehydrazide in a
triazepinone ring occurs in acid media. Under these
conditions a hydrolysis occurs of the hydrazinylidene
fragment and the amide-imidol tautomerizm proceeds
in the hydrazide fragment resulting in a lesser strain in
the molecule at the closure of the seven-membered
The mechanism of compounds 9a and 9b formation
Scheme 3) from the respective hydrazinylidene-
hydrazides is apparently similar to the formation
(
Scheme 4.
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
LR
N H
CH COCH COCH
3 2 3
2
4
9
a
N
N
N
N
N
N
N
N
N
Me
SH
HN
N
Me
NH2
N
1
1
12
Me
1
3
HN
MeI
CH =CHC(O)OMe
2
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Ph
Ph
N
N
N
N
N
N
N
Me
N
N
N
S
S
Me
O
1
4
15
Me
O
1
6
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

7
,8,9-TRIMETHYL-1-PHENYL-3H-PYRROLO[2,1-d][1,2,5]TRIAZEPIN-4(5H)-ONE
741
Scheme 5.
Me
Me
O
O
Me
Me
Ph
Me
O
NH
O
H N
2
Me
N
N
N
1
1
O
Me
Ph
N
N
1
7
Me
Me
Me
Me
Me
Me
Ph
HNO2
(EtO) CH
3
1
2
N
N
N
N
N
N
N
N
N
N
N
1
8
19
1
ring. In the H NMR spectrum the signal of the
methylene group of the 1,2,5-triazepinone ring appears
as a singlet thus indicating the planar form of the seven
The geometry of the seven-membered ring affects
1
the signal pattern of the СН group in the H NMR spec-
2
trum. In the spectrum of compound 14 the methylene
group signals appear as two broadened one-proton
doublets at 3.90 and 5.03 ppm thus indicating the non
planar seven-membered ring. In the spectrum of
-
membered ring.
Compound 9b (mp >400°C) is poorly soluble in
many organic solvents. This fact strongly impedes its
functionalization and fusion. All reactions of
functionalization and fusion we further carried out
only with compound 9a (Scheme 4).
compound 16 the signals of the СН group are obser-
2
ved at 4.72 and 5.08 ppm, but they degenerate in broade-
ned singlets and in the spectrum of triazepine 13 the signal
of the methylene group degenerates in a broadened
singlet at 5.22 ppm. The methylene group of triazepine
The conversion of triazepinone 9a in 7,8,9-
trimethyl-1-phenyl-5H-pyrrolo[2,1-d][1,2,5]triazepine-
1
5 appears as a narrow singlet in the region 4.50 ppm.
4
-thiol 11 by
a
standard procedure utilizing
It is presumable that the energy of transition from
Lawesson’s reagent (LR) [9] applied earlier to 2,3-
benzodiazepinones opens the opportunities of the
seven-membered ring functionalization. The sulfur
atom in the thiol 11 can be replaced by a primary or
secondary amine to obtain 4-hydrazinyl-7,8,9-trime-
thyl-1-phenyl-5H-pyrrolo[2,1-d][1,2,5]triazepine 12
and 7,8,9-trimethyl-1-phenyl-4-piperidin-1-yl-5H-
pyrrolo[2,1-d][1,2,5]triazepine 14. The alkylation with
alkyl halide and the Michael addition to the double
C=C bond provided substituted sulfanyltriazepines:
one conformational triazepine form into another
depends on the size and spatial mobility of the
substituent at the atom C of the triazepine ring. With
the growing mass of the substituent and its decreasing
mobility the non planar structure of the triazepine ring
becomes more favorable by energy.
4
In Scheme 5 reaction of fusion are presented of the
4
3
triazole ring at the С ‒N bond of the pyrrolotriazepine
1 and of the triazole and the tetrazole rings of
1
pyrrolotriazepine 12.
7
,8,9-trimethyl-4-(methylsulfanyl)-1-phenyl-5H-
pyrrolo[2,1-d][1,2,5]triazepine 15 and methyl 3-[(7,8,9-
trimethyl-1-phenyl-5H-pyrrolo[2,1-d][1,2,5]-triazepin-4-
yl)sulfanyl]propanoate 16 respectively. In common
with all monosubstituted hydrazines, hydrazinyl-
triazepine 12 reacted with acetylacetone to afford 4-
3-(3,4-Dimethoxyphenyl)-7,8,9-trimethyl-6-phenyl-
11H-pyrrolo[1,2-e][1,2,4]triazolo[4,3-b][1,2,5]tria-
zepine 17 was obtained as described in [10], and 7,8,9-
trimethyl-6-phenyl-11H-pyrrolo[1,2-e]tetrazolo[1,5-b]-
[1,2,5]triazepine 18 and 7,8,9-trimethyl-6-phenyl-11H-
pyrrolo[1,2-e][1,2,4]triazolo[4,3-b][1,2,5]triazepine
19, as described in [11].
(
3,5-dimethyl-1H-pyrazol-1-yl)-7,8,9-trime-thyl-1-
phenyl-5H-pyrrolo[2,1-d][1,2,5]triazepine 13.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

7
42
KHARANEKO et al.
1
In the H NMR spectra of the fusion products 17‒
K СО in 15 mL of DMF was added at vigorous
2 3
1
9 the CH group of the triazepine ring appears as a
stirring 1.4 mL (12.00 mmol) of ethyl iodoacetate, the
mixture was stirred for 4 h at heating on a boiling
water bath. The solution was poured in 100 mL of water.
The precipitated crystals were filtered off and washed
with water. After recrystallization from methanol yield
2
singlet at 5.35 (17), 5.59 (18), and 5.34 (19) ppm,
indicating the planarity of the obtained structures.
In summary, we have developed a method of N-
alkylation of 2-benzoyl-3,4,5-trimethylpyrrole and the
synthesis therefrom of 7,8,9-trimethyl-1-phenyl-3H-pyr-
rolo[2,1-d][1,2,5]triazepin-4(5H)-one. The reactions of
functionalization of the triazepinone ring and of fusion
of azole cycles can be performed applying standard
procedures formerly developed for hetero-fused 1,2-
diazepinones.
2
.45 g (86%), colorless needle crystals, mp 138–139°С.
–
1
IR spectrum, ν, cm : 1720 s (C=O), 1640 s (Ar), 1200.
1
Н NMR spectrum, δ, ppm: 1.29 t (3Н, СН , J 6.8 Hz),
3
2
.22 q (2Н, СН , J 5.6 Hz), 2.46 s (3Н, СН ), 2.55 t
2
3
(
(
2Н, СН , J 5.2 Hz), 2.56 t (2Н, СН , J 5.2 Hz), 4.16 q
2
2
2Н, СН , J 6.8 Hz), 5.24 s (2Н, СН ), 7.18 d (1Н, СН,
2
2
J 8.0 Hz), 7.26 d (1Н, СН, J 7.6 Hz), 7.41 s (1Н,
CH). Found, %: C 71.51; H 6.72; N 4.95. С H NO .
1
7
19
3
EXPERIMENTAL
Calculated, %: C 71.56; H 6.71; N 4.91.
1
13
Н and С were registered on a spectrometer
Ethyl (2-benzoyl-3,4,5-trimethyl-1Н-pyrrol-1-yl)
-acetate (7a). A solution of 7.6 g (28.04 mmol) of
compound 6a in 40 mL of ethanol was saturated under
stirring with gaseous HCl at room temperature; the
stirring continued till complete dissolution of initial 6a
and then for 20 min more. The mixture was diluted
with 150 mL of water. The separated precipitate was
filtered off and washed with water. Yield 7.9 g (94%),
light-violet crystals, mp 113–114°С. IR spectrum, ν,
Bruker Аvance (400 and 100 MHz respectively) in
DMSO-d , internal reference TMS. IR spectra were
recorded on a spectrophotometer IR-75 from pellets
with KBr. Melting points were measured on a Boёtius
heating block and were not corrected.
6
(
2-Benzoyl-3,4,5-trimethyl-1Н-pyrrol-1-yl)-
acetic acid (6а). To 10 g (46.95 mmol) of 2-benzoyl-
,4,5-trimethylpyrrole 5a and 21 g (375.60 mmol) of
3
–1
1
cm : 1730 s (CO), 1680 s (Ph), 1400, 1240. Н NMR
finely crushed potassium hydroxide in 80 mL of DMSO
was added at vigorous stirring 11.1 mL (93.90 mmol)
of ethyl iodoacetate. The mixture was stirred for 5 h at
spectrum, δ, ppm: 1.26 t (3Н, СН , J 7.2 Hz), 1.59 s
3
(
(
3Н, СН ), 1.91 s (3Н, СН ), 2.15 s (3Н, СН ), 4.15 q
3 3 3
2Н, СН , J 7.2 Hz), 4.90 s (2Н, СН ), 7.43 t (2Н, СН,
2
2
6
0–70°С, poured in 500 mL of water, and neutralized
J 7.2 Hz), 7.47–7.59 m (3H, Ph). Found, %: C 72.16;
H 7.11; N 4.69. С H NO . Calculated, %: C 72.22; H
with 50 mL of acetic acid. The solution was left
overnight at room temperature, the separated crystals
were filtered off, washed with water, and dried. After
washing from impurities with heptane in a Soxhlet
apparatus the crystals were recrystallized from 20 mL
of toluene. Yield 5 g (39%), dark-brown crystals, mp
70–171°С. IR spectrum, ν, cm : 2800 br (O‒H),
700 s (C=O), 1600 s (Ph), 1400, 1240. Н NMR
spectrum, δ, ppm: 1.58 s (3Н, СН ), 1.91 s (3Н, СН ),
.15 s (3Н, СН ), 4.86 s (2Н, СН ), 7.42–7.56 m (5Н,
18
21
3
7
.07; N 4.68.
2-{2-[(E)-Hydrazinylidene(phenyl)methyl]-3,4,5-
trimethyl-1H-pyrrol-1-yl}-acetohydrazide (8a). A
solution of 12.15 g (40.64 mmol) of compound 7a in
50 mL of hydrazine hydrate was boiled for 45 min.
The solution was cooled to room temperature and
diluted with 50 mL of water. The precipitated crystals
were filtered off and washed with water. Yield 7.8 g
(64%), colorless porous crystals, mp 139–140°С. IR
–
1
1
1
1
3
3
2
3 2
1
3
CH). C NMR spectrum, δ, ppm: 8.8 (CH ), 9.6
CH ), 11.0 (CH ) 46.5 (CH ), 115.9, 127.3, 127.3,
28.2, 128.3, 131.1, 135.3, 141.0, 170.3 (C=О), 185.93
C=О). Found, %: C 70.78; H 6.35; N 5.17.
3
–
1
(
1
(
spectrum, ν, cm : 3380 br (NH
2
), 3280 br (NH), 1670
(CO), 1590 s (Ph), 1400. Н NMR spectrum, δ, ppm:
1.57 s (3Н, СН ), 1.90 s (3Н, СН ), 2.15 s (3Н, СН ),
3.56 br.s (4Н, 2NH ), 4.79 s (2Н, СН ), 7.43 t (2Н, Ph,
J 7.2 Hz), 7.51 t (1Н, Ph, J 6.8 Hz), 7.59 d (2Н, Ph, J
3
3
2
1
3
3
3
С H NO . Calculated, %: C 70.83; H 6.32; N 5.16.
2
2
1
6
17
3
From the mother liquor after evaporation of heptane
g of initial compound 5а was isolated.
13
7
.2 Hz), 9.21 br.s (1Н, NН). C NMR spectrum, δ,
5
ppm: 8.9 (CH ), 9.7 (CH ), 11.9 (CH ), 45.8 (CH ),
3
3
3
2
Ethyl (6-methyl-1-oxo-1,2,3,4-tetrahydro-9H-
115.8, 127.1, 127.8, 128.2, 128.5, 131.2, 135.4, 141.1,
167.3 (C=О), 186.1 (C=О). Found, %: C 64.17; H
7.11; N 23.42. С H N O. Calculated, %: C 64.19; H
carbazol-9-yl)-acetate (6b). To a mixture of 2 g
10.00 mmol) of 6-methyl-2,3,4,9-tetrahydro-1Н-car-
bazol-1-one 5b and 4 g (30.00 mmol) of finely crushed
(
1
6
21
5
7.07; N 23.39.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

7
,8,9-TRIMETHYL-1-PHENYL-3H-PYRROLO[2,1-d][1,2,5]TRIAZEPIN-4(5H)-ONE
743
2
-[(1E)-1-Hydrazinylidene-6-methyl-1,2,3,4-
21.0 (CH ), 26.2 (CH ), 45.3 (CH ), 108.6, 118.0,
2
2
2
tetrahydro-9H-carbazol-9-yl]-acetohydrazide (8b).
A mixture of 0.5 g (1.75 mmol) of compound 6b in 6 mL
of hydrazine hydrate was boiled for 0.5 h. The solution
was cooled to room temperature and diluted with 15 mL
of water. The separated precipitate was filtered off and
washed with water and methanol. Yield 0.37 g (83%),
fine light-brown crystals, mp 261–262°С. IR spectrum,
122.9, 123.7, 126.0, 126.6, 127.3, 137.0, 165.7 (C=N),
166.7 (C=О). Found, %: C 71.09; H 5.98; N 16.63.
С H N O. Calculated, %: C 71.13; H 5.97; N 16.59.
1
5
15
3
2
-(6-Methyl-1-oxo-1,2,3,4-tetrahydro-9H-carba-
zol-9-yl)-acetohydrazide (10b). A mixture of 1.0 g
3.50 mmol) of compound 8b and 0.20 g of TsOH was
(
–
1
boiled in 5 mL of acetic acid for 1 h. On cooling the
precipitate was filtered off, washed with acetic acid,
the mother liquor was diluted with 20 mL of water. The
separated precipitate was filtered off and washed with
ν, cm : 3240 br (2NH ), 2990 br (NH), 1640 s (CO),
2
1
1
600 s (Ar). Н NMR spectrum, δ, ppm: 1.99 q (2Н,
СН , J 5.6 Hz), 2.41 s (3Н, СН ), 2.51 t (2Н, СН , J
2
3
2
5
2
7
.2 Hz), 2.76 t (2Н, СН , J 5.2 Hz), 3.04 br.s (4Н,
2
water. Yield 0.463 g (49%), yellow crystals, mp 212–
NH ), 5.13 s (2Н, СН ), 6.92 d (1Нarom, J 8.0 Hz),
2
2
–1
2
13°С. IR spectrum, ν, cm : 3200 br (NH ), 2900 br
2
.11 d (1Н , J 8.4 Hz), 7.19 s (1Нarom), 8.66 br.s
arom
1
1
3
(NH), 1640 s (CO), 1620 s (Ar), 1380. Н NMR spec-
(
1Н, NH). C NMR spectrum, δ, ppm: 19.3 (CH2),
trum, δ, ppm: 2.09 q (2Н, СН , J 6.4 Hz), 2.40 s (3Н,
2
1
1
1
9.8 (CH ), 20.9 (CH ), 22.3 (CH ), 45.3 (CH ), 107.8,
13.2, 116.6, 122.4, 124.9, 126.1, 130.1, 135.4, 139.8,
66.7 (C=О). Found, %: C 63.11; H 6.73; N 24.56.
3 2 2 2
СН ), 2.65 t (2Н, СН , J 4.4 Hz), 2.84 t (2Н, СН , J
3
2
2
5
.2 Hz), 4.80 s (2Н, СН ), 7.15 d (1Нarom, J 8.0 Hz), 7.34
2
s (1Нarom), 7.50 d (1Нarom, J 8.0 Hz), 10.87 br.s (1Н, NH).
С H N O. Calculated, %: C 63.14; H 6.71; N 24.54.
1
5
19
5
13
C NMR spectrum, δ, ppm: 20.5 (CH ), 20.9 (CH ), 24.1
2
3
7
,8,9-Trimethyl-1-phenyl-3H-pyrrolo[2,1-d]-
(
CH ), 33.0 (CH ), 49.0 (CH ), 110.2, 118.0, 118.8,
2 2 2
[1,2,5]triazepin-4(5H)-one (9a). To 7.3 g (24.41 mmol)
1
1
19.2, 119.3, 126.2, 129.0, 129.1, 135.4, 148.4 (C=O),
66.3 (C=О). Found, %: C 66.05; H 5.99; N 16.68.
of compound 8a in 35 mL of acetic acid was added 1.3 g
of TsOH, and the mixture was boiled for 2 h, cooled,
and diluted with 200 mL of water. The separated
precipitate was filtered off and washed with water.
Yield 6.35 g (97%), light-yellow crystals, mp 226–
С H N O . Calculated, %: C 66.40; H 6.32; N 15.49.
1
5
17
3
2
7
,8,9-Trimethyl-1-phenyl-5H-pyrrolo[2,1-d]-
[
(
1,2,5]triazepine-4-thiol (11). A mixture of 4.35 g
16.29 mmol) of compound 9a and 40 mL of toluene
–
1
2
(
27°С. IR spectrum, ν, cm : 2900 br (NH), 1670 s
1
was heated to boiling, and 6.6 g (16.29 mmol) of
Lawesson’s reagent was added. The mixture was
boiled for 2 h, cooled to room temperature, and diluted
at stirring with 60 mL of heptane. The separated
precipitate was filtered off, was washed with heptane
and after drying it was boiled in 30 mL of methanol for
CO), 1600 w (Ph), 1400. Н NMR spectrum, δ, ppm:
1
4
.45 s (3Н, СН ), 1.91 s (3Н, СН ), 2.25 s (3Н, СН ),
3 3 3
.45 s (2Н, СН ), 7.33–7.40 m (3Н, Ph), 7.57 d (2Н,
2
1
3
СН, J 6.8 Hz), 10.74 br.s (1Н, NН). C NMR
spectrum, δ, ppm: 11.1 (CH ), 11.2 (CH ), 12.7 (CH ),
3
3
3
5
1
0.6 (CH ), 118.6, 120.9, 123.2, 128.8, 130.3, 130.7,
2
0
.5 h. The solution was cooled, the separated
31.7, 139.9, 156.1 (C=N), 168.89 (C=О). Mass
+
precipitate was filtered off. On removing 20 mL of
methanol 0.9 g of the reaction product was additionally
isolated from the mother liquor. Overall yield 3.2 g
spectrum: m/z 268.2 [M + H] . Found, %: C 71.87; H
6
6
.42; N 15.75. С H N O. Calculated, %: C 71.89; H
16 17 3
.41; N 15.72. M 267.33.
-Methyl-3,5,6,7-tetrahydro[1,2,5]triazepino-
3,4,5-jk]carbazol-2(1H)-one (9b). To 0.5 g (1.85 mmol)
(
69%), light-yellow crystals, mp 197–198°С. IR
9
–1
spectrum, ν, cm : 2895 br (SH), 1560 m (Ph), 1540,
[
1
1
1
7
380. Н NMR spectrum, δ, ppm: 1.45 s (3Н, СН ),
3
of compound 8b in 5 mL of dioxane was added 0.5 mL
of 30% HCl. The solution was boiled for 5 min and
cooled to room temperature. The separated crystals
were filtered off and washed with dioxane. Yield 0.42 g
.92 s (3Н, СН ), 2.32 s (3Н, СН ), 4.83 s (2Н, СН ),
3
3
2
.38–7.49 m (3Н, Ph), 7.58 d (2Н, Ph, J 7.6 Hz), 12.57
13
br.s (1Н, SН). C NMR spectrum, δ, ppm: 11.1 (CH ),
3
1
1
1
1
1
1.2 (CH ), 12.7 (CH ), 56.4 (CH ), 119.7, 122.4,
3 3 2
(
96%), red-orange crystals, mp >400°С. IR spectrum,
22.7, 130.2, 130.4, 131.1, 132.5, 139.1, 159.5 (C=N),
92.3 (C–S). Found, %: C 67.79; H 6.08; N 14.85; S
1.29. С H N S. Calculated, %: C 67.81; H 6.05; N
–
1
ν, cm : 2900 br (NH), 1700 s (CO), 1600 s (Ph), 1450.
1
Н NMR spectrum, δ, ppm: 2.04 q (2Н, СН , J 5.6 Hz),
2
16
17
3
2
.42 s (3Н, СН ), 2.88 t (2Н, СН , J 6.0 Hz), 2.95 t
3 2
4.83; S 11.31.
(
2Н, СН , J 5.2 Hz), 5.21 s (2Н, СН ), 7.12 d (1Н, Ar,
2
2
J 8.0 Hz), 7.30–7.40 m (2Н, Ar), 11.33 br.s (1Н, NH).
4-Hydrazinyl-7,8,9-trimethyl-1-phenyl-5H-
1
3
C NMR spectrum, δ, ppm: 19.2 (CH ), 19.7 (CH ),
pyrrolo[2,1-d][1,2,5]triazepine (12). To 1.5
g
2
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

7
44
KHARANEKO et al.
(
5.29 mmol) of compound 11 in 40 mL of methanol
СН, J 12.0 Hz), 5.03 br.d (1Н, СН, J 12.0 Hz), 7.30–
1
3
was added at stirring 2.7 mL (52.90 mmol) of
hydrazine hydrate. The mixture at vigorous stirring
was heated to boiling and was stirred for 1 h. The
yellow precipitate of the initial thiol gradually
dissolved, and the solution decolorized. From the
solution 20 mL of methanol was distilled off, and the
reaction mixture was cooled to room temperature. The
separated precipitate was filtered off and washed with
methanol. The filtrate was evaporated to 8 mL to
separate an additional portion of the reaction product.
Overall yield 1.35 g (91%), white crystals, mp 159–
7.45 m (3Н, Ph), 7.57 d (2Н, Ph, J 3.2 Hz). C NMR
spectrum, δ, ppm: 11.1 (CH ), 11.3 (CH ), 12.7 (CH ),
3
3
3
26.0 (CH ), 27.2 (2CH ), 41.8 (CH ), 48.5 (2CH ),
2
2
2
2
117.8, 118.7, 123.6, 126.4, 130.0, 130.4, 130.9, 140.9,
152.6 (C=N), 152.7 (C=N). Found, %: C 75.38; H
7.86; N 16.76. С H N . Calculated, %: C 75.41; H
2
1
26
4
7.84; N 16.75.
7
,8,9-Trimethyl-4-(methylsulfanyl)-1-phenyl-5H-
pyrrolo[2,1-d][1,2,5]triazepine (15). To 0.2
g
(0.71 mmol) of compound 11 and 0.087 mL (1.40 mmol)
–
1
of methyl iodide in 5 mL of acetone was added at
stirring 0.078 g (1.40 mmol) of KОН, and the mixture
was heated at 50°С. The solution was stirred for 50 min,
cooled to room temperature and diluted with 40 mL of
water. The separated precipitate was filtered off and
washed with water. Yield 0.13 g (62%), light-brown
1
(
60°С. IR spectrum, ν, cm : 3400 br (NH ), 1620 s
2
1
Ph), 1420. Н NMR spectrum, δ, ppm: 1.43 s (3Н,
СН ), 1.89 s (3Н, СН ), 2.25 s (3Н, СН ), 4.52 s (2Н,
3
3
3
СН ), 7.30–7.40 m (3Н, Ph), 7.55 d (2Н, Ph, J 3.2 Hz).
2
1
3
C NMR spectrum, δ, ppm: 11.0 (CH ), 11.2 (CH ),
3
3
1
1
2.8 (CH ), 47.7 (CH ), 117.7, 120.1, 123.0, 128.0,
3 2
–1
crystals, mp 164–167°C. IR spectrum, ν, cm : 1550 s
30.2, 130.3, 130.9, 140.8, 147.6 (C=N), 151.5 (C=N).
1
(
Ph), 1410. Н NMR spectrum, δ, ppm: 1.52 s (3Н,
Found, %: C 68.26; H 6.82; N 24.90. С H N .
1
6
19
5
СН ), 1.92 s (3Н, СН ), 2.23 s (3Н, СН ), 2.37 s (3Н,
3
3
3
Calculated, %: C 68.30; H 6.81; N 24.89.
-(3,5-Dimethyl-1H-pyrazol-1-yl)-7,8,9-trime-
thyl-1-phenyl-5H-pyrrolo[2,1-d][1,2,5]triazepine
13). A mixture of 0.2 g (0.71 mmol) of compound 12
СН ), 4.49 s (2Н, СН ), 7.38–7.47 m (3Н, Ph), 7.59 d
3
2
1
3
4
(
2Н, Ph, J 6.8 Hz). C NMR spectrum, δ, ppm: 10.9
(
CH ), 11.2 (CH ), 12.6 (CH ), 14.9 (CH ), 48.0 (CH ),
3
3
3
3
2
(
1
1
6
6
19.1, 121.9, 122.8, 128.8, 130.3, 131.1, 132.1, 139.6,
53.7 (C=N), 155.9 (C=N). Found, %: C 68.63; H
.48; N 14.12; S 10.77. С H N S. Calculated, %: C
and 0.073 mL (0.73 mmol) of acetylacetone in 2 mL of
methanol was boiled for 20 min. On distilling off 1.5 mL
of methanol the solution was cooled, and the separated
precipitate was filtered off. Yield 0.05 g (20%), color-
less crystals, mp 190–191°С. IR spectrum, ν, cm :
1
1
7
19
3
8.65; H 6.44; N 14.13; S 10.78.
–
1
Methyl 3-[(7,8,9-trimethyl-1-phenyl-5H-pyrrolo-
1
[
(
2,1-d][1,2,5]triazepin-4-yl)sulfanyl]propanoate
16). A mixture of 0.2 g (0.71 mmol) of compound 11,
580 s (Ph), 1400. Н NMR spectrum, δ, ppm: 1.55 s
(
(
3Н, СН ), 1.91 s (3Н, СН ), 2.23 s (3Н, СН ), 2.34 s
3
3
3
0
.076 mL (0.85 mmol) of methyl acrylate, and a cata-
3Н, СН ), 2.51 s (3Н, СН ), 5.22 br.s (2Н, СН ), 6.08
3
3
2
lytic quantity of NaOH was boiled in 3 mL of methanol
for 0.5 h. On cooling 10 mL of water was added to the
solution. The separated precipitate was filtered off and
washed with water. Yield 0.17 g (65%), yellow crystals,
s (1Н, СН), 7.40–7.49 m (3Н, Ph), 7.65 d (2Н, Ph, J
1
3
6
.8 Hz). C NMR spectrum, δ, ppm: 8.9 (CH ), 9.1
3
(
CH ), 10.6 (CH ), 13.3 (CH ), 14.5 (CH ), 41.4 (CH ),
3 3 3 3 2
1
1
10.1, 116.7, 119.7, 120.7, 126.9, 127.9, 128.9, 129.7,
37.5, 141.6, 146.4, 149.1 (C=N), 152.1 (C=N).
–1
mp 123–124°С. IR spectrum, ν, cm : 1720 s (CO), 1420,
1
1
200. Н NMR spectrum, δ, ppm: 1.49 s (3Н, СН ), 1.93
Found, %: C 73.01; H 6.73; N 20.25. С H N .
3
2
1
23
5
s (3Н, СН ), 2.34 s (3Н, СН ), 2.76 t (2Н, СН , J 6.8 Hz),
Calculated, %: C 73.02; H 6.71; N 20.27.
,8,9-Trimethyl-4-(piperidin-1-yl)-1-phenyl-5H-
pyrrolo[2,1-d][1,2,5]triazepine (14). A mixture of 0.2 g
0.71 mmol) of compound 11 and 1 mL (10.14 mmol)
3
3
2
3
.57 s (3Н, СН ), 4.45 t (2Н, СН , J 14.0 Hz), 4.71 br.s
3 2
7
(
1Н, СН), 5.08 br.s (1Н, СН), 7.43 t (2Н, Ph, J 7.2 Hz),
.51 t (1Н, Ph, J 6.8 Hz), 7.60 d (2Н, Ph, J 7.2 Hz).
7
(
13
C NMR spectrum, δ, ppm: 8.9 (CH ), 9.0 (CH ), 10.5
3
3
of piperidine was boiled for 1 h. The solution was
cooled to room temperature and diluted with 15 mL of
water. The separated precipitate was filtered off and
washed with water. Yield 0.12 g (51%), brown
(
CH ), 30.8 (CH ), 51.4 (CH ), 51.5 (CH ), 55.0 (CH ),
3 2 2 2 3
1
17.9, 120.0, 121.2, 128.3, 129.5, 130.9, 136.3, 158.1
(
6
C=N), 171.1 (C=O), 188.04 (C=N). Found, %: C
4.98; H 6.28; N 11.39; S 8.67. С H N O S.
–
1
20 23
3
2
crystals, mp 164–167°С. IR spectrum, ν, cm : 1625 s
Calculated, %: C 65.01; H 6.27; N 11.37; S 8.68.
1
(
Ph), 1420. Н NMR spectrum, δ, ppm: 1.53 s (3Н,
СН ), 1.55–1.65 m (6Н, 3СН ), 1.92 s (3Н, СН ), 2.20
3-(3,4-Dimethoxyphenyl)-7,8,9-trimethyl-6-phe-
3
2
3
s (3Н, СН ), 3.30–3.45 m (4Н, 2СН ), 3.90 br.d (1Н,
nyl-11H-pyrrolo[1,2-e][1,2,4]triazolo[4,3-b][1,2,5]-
3
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

7
,8,9-TRIMETHYL-1-PHENYL-3H-PYRROLO[2,1-d][1,2,5]TRIAZEPIN-4(5H)-ONE
745
triazepine (17). A mixture of 0.2 g (0.71 mmol) of
compound 11 and 0.15 g (0.78 mmol) of veratric acid
hydrazide was boiled for 24 h in 4 mL of 1-butanol.
The solvent was removed in a vacuum, and the viscous
oily residue was diluted with 5 mL of ethyl ether. On
triturating with a glass bar the viscous mass first
dissolved and afterwards crystals precipitated. The
reaction mixture was left standing at room temperature
for 3 h, the precipitated crystals were filtered offand
washed with ethyl ether. Yield 0.1 g (33%), colorless
ether. Yield 90 mg (43%), yellow crystals, mp 206–
207°С. IR spectrum, ν, cm : 1520 s (Ar), 1405. Н
–
1
1
NMR spectrum, δ, ppm: 1.35 s (3Н, СН ), 1.88 s (3Н,
3
СН ), 2.35 s (3Н, СН ), 5.34 s (2Н, СН ), 7.46 t (2Н,
3
3
2
Ph, J 7.2 Hz), 7.53 t (2Н, Ph, J 7.6 Hz), 7.69 d (2Н,
1
3
Ph, J 7.2 Hz), 8.60 s (1Н, СН). C NMR spectrum, δ,
ppm: 11.1 (CH ), 11.6 (CH ), 13.3 (CH ), 41.1 (CH ),
3
3
3
2
119.7, 122.5, 127.2, 130.5, 131.6, 132.7, 132.9, 139.5,
145.0, 149.2 (C=N), 160.8 (C=N). Found, %: C 70.05;
H 5.92; N 24.06. С H N . Calculated, %: C 70.08; H
17
17
5
–
1
crystals, mp 186–187°С. IR spectrum, ν, cm : 1620 s
5.88; N 24.04.
1
(
Ph), 1380. Н NMR spectrum, δ, ppm: 1.38 s (3Н,
REFERENCES
. Mengeş, N., Sari, O., Abdullayev, Y., Erdem, S.S., and
СН ), 1.89 s (3Н, СН ), 2.36 s (3Н, СН ), 3.88 s (3Н,
3
3
3
OСН ), 3.89 s (3Н, OСН ), 5.35 s (2Н, СН ), 7.10 d
3
3
2
1
(
(
(
(
1Н, Ph, J 8.0 Hz), 7.46–7.54 m (3Н, Ph), 7.61–7.75 m
Balci, M., J. Org. Chem., 2013, vol. 78, p. 5184. doi
10.1021/jo4001228
2. Castellano, S., Stefancich, G., La Colla, P., and
Musiu, C., J. Heterocycl. Chem., 2000, vol. 37, p. 1539.
doi 10.1002/jhet.5570370
1
3
2Н, Ph). C NMR spectrum, δ, ppm: 9.0 (CH ), 9.5
3
CH ), 11.2 (CH ), 39.3 (CH ), 55.3 (OCH ), 55.3
3
3
2
3
OCH ), 111.2, 111.3, 117.5, 118.8, 120.5, 121.2,
3
1
1
1
1
25.0, 128.3, 129.4, 130.2, 130.6, 137.5, 148.2, 148.4,
50.3, 150.8, 158.3. Found, %: C 69.87; H 6.37; N
6.31. С H N O . Calculated, %: C 69.91; H 6.34; N
3
4
5
6
7
. Milen, M., Ábrányi-Balogh, P., Dancsó, A., Simig, G.,
and Volk, B., Tetrahedron, 2014, vol. 70, p. 465. doi
10.1016/j.tet.2013.11.032
. Milen, M., Foldesi, T., Dancso, A., Simig, G., and
Volk, B., Synlett., 2015, vol. 26, p. 2418. doi 10.1055/
2
5
27
5
2
6.30.
,8,9-Trimethyl-6-phenyl-11H-pyrrolo[1,2-e]-
tetrazolo[1,5-b][1,2,5]triazepine (18). To 0.2 g
0.71 mmol) of compound 12 in 4 mL glacial acetic
acid was added at vigorous stirring by portions 0.06 g
0.85 mol) of NaNO . The solution was stirred at room
7
9
-0034-1380538
(
. Alberola, A., Andrés, J.M., Gonzalez, A., Pedrosa, R.,
and Vicente, M., Heterocycles, 1989, vol. 29, p. 1973.
doi 10.3987/COM-89-5096
. Yakhontov, L.N. and Glushkov, R.G., Sinteticheskie
lekarstvennye sredstva (Synthetic Drugs), Moscow:
Meditsina, 1983.
(
2
temperature for 1 h, diluted with 20 mL of water, the
separated precipitate was filtered off and washed with
water and then with 4 mL of ethyl ether. Yield 0.13 g
1
(
63%), light-brown crystals, mp 232–233°C. Н NMR
. Kharaneko, O.I. and Bogza, S.L., Russ. J. Org. Chem.,
spectrum, δ, ppm: 1.37 s (3Н, СН ), 1.89 s (3Н, СН ),
2016, vol. 52, p. 1043. doi 10.1134/S1070428016070228
3
3
2
7
6
.36 s (3Н, СН ), 5.59 s (2Н, СН ), 7.51 t (2Н, Ph, J
3 2
8. Kibal’nyi, A.V., Nikolyukin, Yu.A., and Dulenko, V.I.,
Chem. Heterocycl. Compd., 1994, vol. 30, p 895. doi
10.1007/BF01165026
.2 Hz), 7.58 t (2Н, Ph, J 6.4 Hz), 7.76 d (2Н, Ph, J
1
3
.8 Hz). C NMR spectrum, δ, ppm: 9.7 (CH ), 10.3
3
(
1
(
CH ), 12.0 (CH ), 37.9 (CH ), 119.3, 121.3, 128.0,
29.2, 130.4, 131.9, 133.1, 137.4, 147.5 (C=N), 160.0
C=N). Found, %: C 65.71; H 5.53; N 28.74.
9. Chimirri, A., De Sarro, G., De Sarro, A., Gitto, R.,
Quartarone, S., Zappala, M., Constanti, A., and Libri, V.,
J. Med. Chem., 1998, vol. 41, p. 3409. doi 10.1021/
jm9800393
3
3
2
С H N . Calculated, %: C 65.74; H 5.52; N 28.75.
1
6
16
6
1
1
0. Gitto, R., Orlando, V., Quartarone, S., De Sarro, G.,
De Sarro, A., Russo, E., Ferreri, G., and Chimirri, A.,
J. Med. Chem., 2003, vol. 46, p. 3758. doi 10.1021/
jm030821p
1. Khabarov, K.M., Kharaneko, O.I., and Bogza, S.L.,
Chem. Heterocycl. Compd., 2009, vol. 4, p. 468. doi
10.1007/s10593-009-0280-0
7
,8,9-Trimethyl-6-phenyl-11H-pyrrolo[1,2-e][1,2,4]-
triazolo[4,3-b][1,2,5]triazepine (19). A mixture of 0.2 g
0.17 mmol) of compound 12 and 2 mL (12.04 mmol)
of triethyl orthoformat was boiled for 1 h. On cooling
0 mL of ethyl ether was added. The separated
precipitate was filtered off and washed with ethyl
(
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017