Synthesis of pyrrolo[1,2-a][1,6]benzodiazonines from pyrrolo[1,2-a][1,4] benzodiazepines and alkynes containing electron-acceptor substituents

Article abstract of DOI:10.1007/s10593-013-1340-z

It has been established that the reaction of pyrrolo[1,2-a][1,4] benzodiazepines with activated alkynes gives pyrrolo[1,2-a][1,6]benzodiazonines as the products of diazepine ring expansion. In the case of pyrrolo[1,2-a][1,4] benzodiazepine, substituted wi

Full text of DOI:10.1007/s10593-013-1340-z

Chemistry of Heterocyclic Compounds, Vol. 49, No. 7, October, 2013 (Russian Original Vol. 49, No. 7, July, 2013)
SYNTHESIS OF PYRROLO[1,2-a][1,6]BENZODIAZONINES
FROM PYRROLO[1,2-a][1,4]BENZODIAZEPINES AND
ALKYNES CONTAINING ELECTRON-ACCEPTOR
SUBSTITUENTS
L. G. Voskressensky1*, T. N. Borisova1, M. I. Babakhanova1,
T. M. Chervyakova1, A. A. Titov1, A. V. Butin2,3, T. A. Nevolina2,3,
V. N. Khrustalev4, and A. V. Varlamov1
It has been established that the reaction of pyrrolo[1,2-a][1,4]benzodiazepines with activated alkynes
gives pyrrolo[1,2-a][1,6]benzodiazonines as the products of diazepine ring expansion. In the case of
pyrrolo[1,2-a][1,4]benzodiazepine, substituted with formyl group at the pyrrole ring, both expansion
and cleavage of the diazepine fragment can occur.
Keywords: pyrrolo[1,2-a][1,4]benzodiazepines, pyrrolo[1,2-a][1,6]benzodiazonines, activated alkynes,
diazepine ring expansion, diazepine ring opening.
Benzodiazonines show high and diverse biological activity, viz. nervous system excitation,
antidepressant and antihypertensive effects [1], and they are CCK2 receptor antagonists [2]. The diazonine ring
occurs in the composition of alkaloids such as teleocidin and lyngbyatoxin [3]. However, methods for
synthesizing condensed diazonines are extremely limited and pyrrolobenzodiazonines have not been reported in
the literature at all. We have carried out an expansion of the azepine ring in hexahydroazepinoindoles by two
carbon atoms using activated alkynes and have synthesized azoninoindoles in 64-88% yields [4].
The diazepine ring in tetrahydrobenzo[1,4]diazepines proved resistant to the action of dimethyl
acetylenedicarboxylate (DMAD) and to methyl propiolate. Benzodiazepines containing a lactam fragment
_______
*To whom correspondence should be addressed, e-mail: lvoskressensky@sci.pfu.edu.ru.
1Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russia.
2Research Institute for Heterocyclic Compounds, Kuban State University of Technology, 2 Moscow St.,
Krasnodar 350072, Russia.
3Perm State National Research University, 15 Bukirev St., Perm 614990, Russia, e-mail:
alexander_butin@mail.ru.
4A. N. Nesmeyanov Institute of Organoelemental Compounds, Russian Academy of Sciences, 28 Vavilov St.,
Moscow 119991, Russia, e-mail: vkh@xray.incos.ac.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1098-1107, July, 2013. Original
article submitted October 24, 2012; revision submitted February 6, 2013.
1024
0009-3122/13/4907-1024©2013 Springer Science+Business Media New York

react quite readily by several routes. The principal of these is an N-vinylation of the amide fragment to form
type 1 compounds and the formation of compounds 2, 3 as the products of a Stevens rearrangement. The
expected benzodiazonine 4 was isolated in only a single case in 4% yield [5].
MeO2C
H
O
CO2Me
N
MeO2C
O
N
MeO2C
N
N
2
Me
1
O
MeO2C
MeO2C
H
N
MeO2C
O
COMe
N
N
N
CO2Me
3
4
This work relates to a study of the reaction of pyrrolo[1,2-a][1,4]benzodiazepines with acetylacetylene,
methyl propiolate, or DMAD as a result of which pyrrolo[1,2-a][1,4]benzodiazonines have been synthesized for
the first time.
4-Phenyl- and 4-(thien-2-yl)-substituted pyrrolobenzodiazepines 7a,b were prepared via a multistage
synthesis. Using a Bischler-Napieralski reaction the N-(o-aminomethylphenyl)pyrrole through the
corresponding amides 5a,b was converted to the dihydropyrrolobenzodiazepines 6a,b. Methylation with methyl
iodide and subsequent reduction of the quaternary salt with sodium borohydride gave pyrrolobenzodiazepines
7a,b.
RCOCl
MeCN, K2CO3
R
N
N
O
N
POCl3
N
MeCN
, 3 h
room temp., 2 h
NH2
N
R
H
6a,b
5a,b
1) MeI, acetone
MW, 150°C, 25 min
R
N
N
2) NaBH4, MeOH, EtOH, H2O
room temp., 10 min
Me
7a,b
a R = Ph, b R = 2-thienyl
1-Methyl-substituted pyrrolo[1,2-a][1,4]benzodiazepines 8-10 were prepared by the reduction of the
corresponding pyrrolobenzodiazepines [6]. A Vilsmeier-Haack reaction of the pyrrolobenzodiazepine 10 gave
the aldehyde 11.
All of the reactions of the pyrrolobenzodiazepines with alkynes gave multicomponent mixtures and
were accompanied by marked tarring.
The diazepine 7a reacted with acetylacetylene in methanol at 30ºC and in acetonitrile at 50ºC over
1 day. Chromatography of the reaction mixtures gave the pyrrolobenzodiazonine 12 in 28 and 25% yields,
respectively. The diazepine 7a reacted more slowly with methyl propiolate in acetonitrile at 50ºC over 3 days.
The diazonine 13 was isolated from the reaction mixture in 22% yield.
1025

O
H
Me
R
Me
R
Me
N
LiAlH4
N
N
(from 10)
N
N
N
Dioxane
97°C
DMF, POCl3
20°C, 15 h
Me
Me
Me
O
8–10
8 R = Ph, 9 R = Me, 10 R = H
11
The methyl-substituted at pyrrole ring pyrrolobenzodiazepine 8 reacted with methyl propiolate in
methanol at 20ºC over 1 day similarly to compound 7a to yield a multicomponent mixture from which the
pyrrolobenzodiazonine 14 can be chromatographically isolated. The 1,4-dimethyl-substituted diazepine 9
reacted with methyl propiolate and acetylacetylene both in methanol and in acetonitrile at 20C over 3 days to
give a multicomponent mixtures. Only in the reaction with methyl propiolate could the pyrrolo[1,2-a]-
[1,6]benzodiazonine 15 be isolated in 18% yield.
H
R1
R
N
R
+
R1
X
N
HC
X
Me
7a, 8, 9
–
N +
N
MeOH or MeCN
20–50°C, 1–3 days
Me
–
A
X
B
R
X
N
R1
N
Me
12–15
12–14 R = Ph, 15 R = Me; 12, 13 R1 = H, 14, 15 R1 = Me; 12 X = COMe, 13–15 X = CO2Me
Carrying out the reaction of the pyrrolobenzodiazepine 10 (without the phenyl group at position 4) with
methyl propiolate in methanol a multicomponent mixture was obtained which was assumed to contain the
products of vinylation of the pyrrole ring and polymeric type products but these could not be separated
chromatographically. With the aim of lowering the activity of the pyrrole ring, its formylation was carried out
under Vilsmeier-Haack conditions to give the pyrrolo[1,2-a][1,4]benzodiazepinecarbaldehyde 11. However, its
reaction with methyl propiolate in methanol was little selective as before. None the less, column
chromatography of the reaction mixture gave a 7% yield of the product of cleavage of the diazepine fragment,
namely the pyrrolylmethylamino acrylate 16. This reaction in acetonitrile gave the pyrrolobenzodiazonine 17 in
an 8% yield.
O
CO2Me
O
H
CO2Me
H
HC
CO2Me
HC
CO2Me
Me
N
N
11
Me
N
Me
MeOH
20°C, 1 day
MeCN
50°С, 12 days
N
Me
OMe
17
16
1026

We believe that the reaction of the alkynes with diazepines 7a, 8, 9, 11 begins with the formation of an
ammonium type zwitterion of type A via addition of the tertiary nitrogen to the triple bond. The cleavage of the
C(4)–N+ bond then follows to generate cation B which is stabilized by the substituent donor effect. Formation of
an alternative benzyl cation seems less likely. One of the routes for the reaction of B is the formation of
diazonines. After formation of the type A zwitterion in the case of diazepine 11, the formaion of the carbocation
of type B becomes impossible, and bimolecular nucleophilic processes begin to predominate [7].
Diazepines 7b and 8 did not react with DMAD in acetonitrile upon prolonged heating and with an
excess of the reagent. In methanol multicomponent mixtures are obtained from which respectively the
pyrrolobenzodiazonines 18 and 19 could be isolated in low yields.
R
CO2Me
R1
R
N
MeO2C
CO2Me
CO2Me
Me
N
R1
N
MeOH, 35–65°С
N
Me
14 days
18 (from 7b, 18%)
19 (from 8, 5%)
7b, 8
18 R = 2-thienyl, R1 = H; 19 R = Ph, R1 = Me
The structure of all of the pyrrolo[1,2-a][1,6]benzodiazonines 12-15, 17-19 was confirmed by
spectroscopic data. Their mass spectra showed molecular ions corresponding to the empirical formulae. The
1H NMR spectra of compounds 12-15, 17 showed singlet signals for the enamine fragment H-7 protons in the
region 7.32-7.61 ppm and also signals for the NCH2 groups at 3.78-3.94 ppm. The 1H NMR spectrum of pyrrole
16 was characterized by the presence of a singlet for the methoxy group protons of the CH2OCH3 at 3.11 ppm
and two doublets with J = 13.1 Hz for the protons of the vinyl group at 4.57 and 7.33 ppm.
Fig. 1. Molecular structure of compound 13 with representation of atoms by thermal
vibration ellipsoids of 50% probability.
The structure of compound 13 was confirmed by X-ray structural analysis (Fig. 1). Compound 13 is
polycyclic and contains three fused rings, viz. the five-membered pyrrole, six-membered benzene, and nine-
membered diazonine. The conformation of the central nine-membered ring can be regarded as a distorted
"chair" with the atoms C(4A), N(13), C(13A), C(7), and C(8) deviating from the mean square plane of the
remaining ring atoms by -1.479, -0.672, -1.716, 1.007, and 1.057 Å, respectively. The angle between the planes
of the pyrrole and fused benzene (C(1)C(2)C(3)C(4)C(4A)C(13A)) rings is 56.5. The compound 13
molecule has an E-configuration of substituents at the C(7)=C(8) double bond. Due to conjugation, the carboxyl
1027

substituent lies in the plane of the C(7)=C(8) double bond (torsion angle C(7)=C(8)C(15)=O(1) 180.0(1)).
The nitrogen atom N(6) has a trigonal-pyramidal configuration (sum of valence angle values at the N(6) atom
354.9) whereas the N(13) atom is planar (sum of valence angles at N(13) 360.0). Compound 13 is chiral and
has one asymmetric center at the C(9) carbon atom. The compound 13 crystal occurs as a racemate.
Thus, we have shown for the first time the possibility of synthesizing pyrrolobenzodiazonines by a
domino reaction of pyrrolobenzodiazepines with activated alkynes. The process of expanding the diazepine ring
occurs via cleavage of the C(4)N bond in the initially formed zwitterionic ammonium salt which is formed
through a Michael addition of the tertiary nitrogen to the triple bond. The substituent at position C-4 of the
pyrrolobenzodiazepine ring stabilizes the carbocation formed via cleavage of the bond indicated above.
EXPERIMENTAL
IR spectra were recorded on an Infralum FT-801 Fourier spectrometer for KBr pellets (for crystalline
1
substances) or as a film (for oils). H NMR spectra were recorded on a Bruker WP-400 instrument (400 MHz)
using CDCl3 with TMS as internal standard. LC-MS spectra for compounds 11, 13, 16 were recorded on a
system consisting of an Agilent 1100 liquid chromatograph and an Agilent Technologies LC/MSD VL, ELSD
Sedex 75 mass spectrometer. The mass spectra of the remaining compounds were recorded on a Thermo
Scientific MAT 95XL chromato-mass spectrometer (EI, 70 eV). Elemental analysis was performed on a Carlo
Erba 1106 instrument. Melting points were determined on an SMP 10 instrument. TLC was carried out on
Sorbfil plates with fixed silica gel layer and visualized using KMnO4 and H2SO4. The chromatographic
separation used Fluka-507C neutral alumina (0.05-0.15 mm) and Merck silica gel (230-400 mesh). Microwave
activation of the quaternization of pyrrolobenzodiazepines 7a,b was carried out using a Monowave 300 Anton
Paar type microwave oven.
Preparation of N-[2-(1H-Pyrrol-1-yl)benzyl]benzamides 5a,b (General Method). PhCOCl or
thiophene-2-carbonyl chloride (64 mmol) was added dropwise to a solution of calcined K2CO3 (10.5 g,
75 mmol) and 2-(1-pyrrolyl)benzylamine (10.0 g, 58 mmol) in absolute MeCN at 20C. The mixture was stirred
for 2 h (monitoring by TLC using EtOAc–hexane (1:2) as eluent), solvent was evaporated in vacuo, and water
(40 ml) was added to the residue. The precipitate formed was filtered off and crystallized from a mixture of
EtOAc–hexane (1:3).
N-[2-(1H-Pyrrol-1-yl)benzyl]benzamide (5a). Yield 13.5 g (84%), light-brown crystals, mp
1
138-139°C. IR spectrum, ν, cm-1: 3340 (NH), 1628 (CO). H NMR spectrum, δ, ppm (J, Hz): 4.58 (2Н, d,
J = 6.1, CH2NН); 5.95 (1Н, br. s, NH); 6.38 (2Н, t, J = 2.1, H-3,4 pyrrole); 6.84 (2Н, t, J = 2.1, Н-2,5 pyrrole);
7.30-7.33 (1Н, m, Н Ar); 7.35-7.40 (4Н, m, Н Ar, H Ph); 7.44-7.47 (1Н, m, Н Ph); 7.53-7.55 (1Н, m, Н Ph);
7.62-7.65 (2Н, m, Н Ph). Mass spectrum, m/z (Irel, %): 276 [M]+ (1), 169 (13), 155 (100), 105 (34), 77 (54).
Found, %: С 78.21; Н 5.80; N 10.08. C18H16N2O. Calculated, %: С 78.24; Н 5.84; N 10.14.
N-[2-(1H-Pyrrol-1-yl)benzyl]thiophene-2-carboxamide (5b). Yield 14.7 g (90%), brown crystals, mp
119-120°С. IR spectrum, ν, cm-1: 3319 (NH), 1624 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 4.54 (2Н, d, J = 6.4,
СН2NH); 5.80 (1Н, br. s, NH); 6.40 (2Н, t, J = 2.4, H-3,4 pyrrole); 6.84 (2Н, t, J = 2.4, Н-2,5 pyrrole); 7.03 (1Н, dd,
J = 4.6, J = 3.7, Н-4 thiophene); 7.31–7.34 (2Н, m, Н Ar); 7.35-7.39 (2Н, m, Н Ar); 7.44 (1Н, br. d, J = 4.6, Н-3
thiophene); 7.53 (1Н, dd, J = 3.7, J = 4.6, Н-5 thiophene). Mass spectrum, m/z (Irel, %): 282 [M]+ (1), 155 (100), 154
(54), 111 (30). Found, %: C 68.10; H 5.05; N 9.87. C16H14N2OS. Calculated, %: C 68.06; H 5.00; N 9.92.
Preparation of 6H-Pyrrolo[1,2-a][1,4]benzodiazepines 6a,b (General Method). POCl3 (30.0 g,
196 mmol) was added dropwise to a solution of the amide 5a,b (49 mmol) in absolute MeCN (80 ml) under an
argon atmosphere. The mixture was refluxed for 3 h monitoring by TLC using EtOAc–hexane (1:3) as eluent.
The solvent was evaporated, and the dark oil was poured into 25% ammonia solution and extracted with EtOAc
(400 ml). The extract was dried over MgSO4, and the solvent was evaporated in vacuo. The residue was
triturated in ether, and the precipitate was filtered off.
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4-Phenyl-6H-pyrrolo[1,2-a][1,4]benzodiazepine (6a). Yield 9.4 g (74%), beige crystals, mp
110-111°C. 1H NMR spectrum, δ, ppm (J, Hz): 4.64 (2Н, br. s, СН2N); 6.40-6.45 (1Н, m, H-3); 6.46-6.49 (1Н,
m, H-2); 7.26-7.30 (1Н, m, Н Ar); 7.32-7.42 (5Н, m, Н-1, Н Аr, H Ph); 7.49 (2Н, d, J = 7.5, Н Ph); 7.69 (2Н, d,
J = 7.5, Н Ph). Mass spectrum, m/z (Irel, %): 282 [M]+ (94), 230 (12), 181 (8), 154 (100), 128 (34). Found, %:
С 83.65; Н 5.43; N 10.81. C18H14N2. Calculated, %: С 83.69; Н 5.46; N 10.84.
4-(2-Thienyl)-6H-pyrrolo[1,2-a][1,4]benzodiazepine (6b). Yield 11.9 g (92%), beige crystals, mp
1
160-162°C. H NMR spectrum, δ, ppm (J, Hz): 4.38 (1Н, br. d, J = 10.5) and 4.81 (1Н, br. d, J = 10.5, СН2N);
6.46 (1Н, t, J = 3.6, Н-2); 6.83 (1Н, dd, J = 1.4, J = 3.6, Н-3); 7.02 (1Н, dd, J = 3.7, J = 4.6, Н-4'); 7.26-7.30
(1Н, m, Н-8); 7.33–7.35 (1Н, m, Н-1); 7.36-7.39 (3Н, m, Н-7,9,5'); 7.42 (1Н, d, J = 3.7, Н-3'); 7.49 (1Н, d,
J = 7.3, Н-10). Mass spectrum, m/z (Irel, %): 264 [M]+ (100), 263 (92), 236 (30), 155 (52), 154 (83). Found, %:
С 72.74; Н 4.53; N 10.62. C16H12N2S. Calculated, %: С 72.70; Н 4.58; N 10.60.
Preparation of 5,6-Dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines 7a,b (General Method). A
mixture of the diazepine 6a,b (2.7 mmol) and MeI (1.93 g, 13.6 mmol) in absolute acetone (10 ml) underwent
microwave irradiation (50 W) at 150C over 25 min. The solvent was evaporated in vacuo. The residue was
dissolved in a mixture of MeOH (16 ml) and 60% aqueous EtOH (24 ml), and NaBH4 (0.09 g, 2.5 mmol) was
added at 20ºC. A precipitate was formed after 10 min. Water (50 ml) was added to the reaction mixture, and the
precipitated crystals were filtered off and dried in air.
5-Methyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine (7a). Yield 0.68 g (92%),
beige crystals, mp 96-98°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.24 (3Н, s, NCH3); 3.51 (1Н, d, J = 14.0) and
4.13 (1Н, d, J = 14.0, CH2N); 3.93 (1Н, s, 4-СН); 5.48 (1Н, d, J = 2.8, Н-2); 6.15 (1Н, t, J = 2.8, Н-3); 6.96
(1Н, d, J = 1.4, Н-1); 7.27-7.30 (3Н, m, H Ph); 7.35 (2Н, t, J = 6.9, H Ph); 7.41-7.49 (4Н, m, Н Ar). Mass
spectrum, m/z (Irel, %): 274 [M]+ (20), 197 (100), 154 (18), 42 (16). Found, %: C 83.21; H 6.58; N 10.25.
C19H18N2. Calculated, %: C 83.18; H 6.61; N 10.21.
5-Methyl-4-(2-thienyl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine (7b). Yield 0.62 g (82%),
beige crystals, mp 90-91°С. 1H NMR spectrum, δ, ppm (J, Hz): 2.37 (3Н, s, NСН3); 3.50 (1Н, d, J = 14.0) and
4.10 (1Н, d, J = 14.0, СН2N); 4.36 (1Н, s, 4-СН); 5.85 (1Н, br. s, Н-3); 6.21 (1Н, br. s, Н-2); 6.91-6.97 (3Н, m,
Н-1, Н Ar); 7.29-7.34 (3Н, m, Н Ar); 7.41-7.45 (3Н, m, Н-3',4',5'). Mass spectrum, m/z (Irel, %): 280 [M]+ (54),
197 (100), 155 (100), 154 (46), 97 (24). Found, %: C 72.79; H 5.81; N 10.02. C17H16N2S. Calculated, %:
C 72.82; H 5.75; N 9.99.
Preparation of 5,6-Dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines 8-10 (General Method). The
corresponding pyrrolo[1,2-a][1,4]benzodiazepin-6-one (20.0 mmol) was added portionwise to a suspension of
LiAlH4 (1.52 g, 40.0 mmol) in absolute dioxane (30 ml) at 0-5C under an argon atmosphere. The mixture was
heated at 97C for 1-4 h, cooled, and treated sequentially with water (5 ml), 15% aqueous NaOH solution
(5 ml), water (5 ml) again, and then stirred for 1 h. The precipitate formed was filtered off and washed with
CH2Cl2. The filtrate was separated and dried over MgSO4, and the solvent was evaporated in vacuo.
1,5-Dimethyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine (8). The reaction was
carried out for 4 h (TLC monitoring, eluent EtOAchexane, 1:3). Yield 0.45 g (78%), beige crystals,
mp 160-161°C (Et2O). 1H NMR spectrum, δ, ppm (J, Hz): 2.18 (3Н, s, 1-CH3); 2.30 (3Н, s, NCH3); 3.49 (1Н, d,
J = 13.7) and 4.04 (1Н, d, J = 13.7, СН2N); 3.79 (1Н, s, 4-СН); 5.37 (1Н, d, J = 2.9, Н-2); 5.91 (1Н, d, J = 2.9,
Н-3); 7.28-7.34 (4Н, m, Н Ar); 7.38-7.40 (2Н, m, H Ph); 7.45-7.49 (3Н, m, Н Ph). Mass spectrum, m/z (Irel, %):
288 [M]+ (38), 273 (64), 211 (100), 197 (24). Found, %: С 83.26; Н 6.95; N 9.68. C20H20N2. Calculated, %:
С 83.30; Н 6.99; N 9.71.
1,4,5-Trimethyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine (9). The reaction was carried out
1
for 1 h (TLC monitoring, eluent EtOAc–hexane, 1:1). Yield 0.38 g (83%), yellow oil. H NMR spectrum, δ,
ppm (J, Hz): 1.44 (3Н, d, J = 6.4, 4-СН3); 2.29 (3Н, s, 1-СН3); 2.31 (3Н, s, NСН3); 3.02 (1Н, d, J = 6.4, 4-СН);
3.41 (1Н, d, J = 13.3) and 3.55 (1Н, d, J = 13.3, CH2N); 6.04 (1Н, d, J = 3.4, Н-2); 6.13 (1Н, d, J = 3.4, Н-3);
7.28-7.35 (3Н, m, Н Аr); 7.40-7.45 (1Н, m, Н Аr). Mass spectrum, m/z (Irel, %): 226 [M]+ (22), 211 (100), 170
(18), 154 (9), 105 (7). Found, %: C 79.64; H 8.07; N 12.31. C15H18N2. Calculated, %: C 79.61; H 8.02; N 12.38.
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1,5-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine (10). The reaction was carried out
1
for 3.5 h (TLC monitoring, eluent EtOAc–hexane, 1:1). Yield 0.36 g (85%), yellow oil. H NMR spectrum, δ,
ppm (J, Hz): 2.33 (3Н, s, 1-СН3); 2.38 (3Н, s, NСН3); 3.19 (1Н, d, J = 11.7) and 3.57 (1Н, d, J = 11.7, 6-СН2);
3.25-3.34 (1Н, m) and 3.39-3.49 (1Н, m, 4-СН2); 6.03 (1Н, d, J = 2.8, Н-3); 6.14 (1Н, d, J = 2.8, Н-2);
7.27-7.31 (2Н, m, Н Ar); 7.39-7.44 (2Н, m, Н Ar). Mass spectrum, m/z (Irel, %): 212 [M]+ (100), 197 (96), 180
(28), 168 (55), 154 (83), 42 (25). Found, %: C 79.25; H 7.57; N 13.27. C14H16N2. Calculated: C 79.21; H 7.60;
N 13.20.
1,5-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-2-carbaldehyde
(11).
POCl3
(0.4 g, 2.8 mmol) was added dropwise and slowly to a flask containing DMF (0.6 g, 8.5 mmol) cooled to -5C.
The mixture was stirred at 20ºC for 40 min. A solution of the pyrrolobenzodiazepine 10 (0.3 g, 1.4 mmol) in
DMF (3 ml) was added dropwise (TLC monitoring, eluent EtOAc–hexane, 1:1). After 15 h, the solution was
basified with 10% Na2CO3 solution to pH 10 and extracted with Et2O. The extract was dried over MgSO4, and
the solvent was evaporated. Yield 0.1 g (31%), yellow crystals, mp 109-111°C (Et2O). IR spectrum, ν, cm-1:
1658 (CНО). 1H NMR spectrum, δ, ppm (J, Hz): 2.35 (3Н, s, 1-CH3); 2.57 (3Н, s, NCH3); 3.15 (1Н, d, J = 12.6)
and 3.54 (1Н, d, J = 12.6, 4-СН2); 3.25 (1Н, d, J = 13.8) and 3.48 (1Н, d, J = 13.8, 6-СН2); 6.58 (1Н, s, Н-3);
7.28 (1H, d, J = 7.9, Н Ar); 7.36-7.48 (3Н, m, Н Ar); 9.94 (1Н, s, СНО). Mass spectrum, m/z: 241 [M+Н]+.
Found, %: C 74.92; H 6.75; N 11.63. C15H16N2О. Calculated, %: C 74.97; H 6.71; N 11.66.
1-(6-Methyl-9-phenyl-6,9-dihydro-5H-pyrrolo[1,2-a][1,6]benzodiazonin-8-yl)ethanone (12). A.
Acetylacetylene (0.09 g, 1.3 mmol) was added to a solution of the benzodiazepine 7a (0.30 g, 1.1 mmol) in
MeOH (10 ml). The reaction was carried out for 1 day at 30C (TLC monitoring, eluent EtOAc–hexane, 1:5).
The solvent was distilled off in vacuo. The oil obtained was crystallized from EtOAc. Yield 0.11 g (28%).
B. Acetylacetylene (0.15 g, 2.2 mmol) was added to a solution of the benzodiazepine 7a (0.30 g,
1.1 mmol). The reaction was carried out for 1 day at 50C (TLC monitoring, eluent EtOAc–hexane, 1:5).
Solvent was evaporated in vacuo, and the oil produced was crystallized from EtOAc. Yield 0.09 g (25%), white
1
crystals, mp 197-199°C. IR spectrum, ν, cm-1: 1641 (COMе), 1598 (C=C). H NMR spectrum, δ, ppm (J, Hz):
2.14 (3Н, s, СОСН3); 3.31 (3Н, s, NСН3); 3.94 (2Н, s, СН2N); 4.92 (1Н, s, 9-СН); 6.39-6.40 (1Н, m, Н-10);
6.60-6.64 (1Н, m, Н-11); 6.70-6.71 (1Н, m, Н-12); 6.89-7.04 (3Н, m, Н Ar); 7.09-7.14 (3Н, m, H Ar, H Ph);
7.35-7.38 (3Н, m, H Ph); 7.48 (1Н, s, Н-7). Mass spectrum, m/z (Irel, %): 342 [M]+ (17), 299 (26), 254 (20), 247
(47), 154 (76), 43 (100). Found, %: C 80.62; H 6.51; N 8.13. C23H22N2О. Calculated, %: C 80.67; H 6.48;
N 8.18.
Methyl 6-Methyl-9-phenyl-6,9-dihydro-5H-pyrrolo[1,2-a][1,6]benzodiazonine-8-carboxylate (13).
Methyl propiolate (0.2 g, 3.1 mmol) was added to a solution of the benzodiazepine 7a (0.4 g, 1.3 mmol) in
MeCN (10 ml) and stirred at 50C for 72 h (TLC monitoring, eluent EtOAc-hexane, 1:3). Solvent was distilled
off in vacuo. The residue was chromatographed on a silica gel column (d 1.8 cm, l 18 cm) using EtOAc–hexane
(1:15) as eluent. Yield 0.09 g (22%), white crystals, mp 164-165°C (Et2O). IR spectrum, ν, cm-1: 1687
(CO2Me), 1606 (С=С). 1H NMR spectrum, δ, ppm (J, Hz): 3.25 (3Н, s, NCH3); 3.90 (2Н, s, СН2N); 4.49 (3Н, s,
СО2CH3); 4.98 (1Н, br. s, 9-CH); 6.41 (1Н, t, J = 3.2, Н-11); 6.58 (1Н, dd, J = 1.8, J = 3.2, Н-10); 6.72 (1Н, dd,
J = 1.8, J = 3.2, Н-12); 7.04-7.06 (3Н, m, Н Ph); 7.12-7.16 (2Н, m, Н Ph); 7.34-7.39 (3Н, m, Н Ar); 7.53-7.55
(1Н, m, Н Ar); 7.61 (1Н, s, H-7). Mass spectrum, m/z: 359 [M+Н]+. Found, %: C 77.05; H 6.22; N 7.79.
C23H22N2О2. Calculated, %: C 77.07; H 6.19; N 7.82.
Methyl 6,12-Dimethyl-9-phenyl-6,9-dihydro-5H-pyrrolo[1,2-a][1,6]benzodiazonine-8-carboxylate
(14). Methyl propiolate (0.24 g, 2.8 mmol) was added to a solution of the benzodiazepine 8 (0.404 g, 1.4 mmol)
in MeOH (10 ml) and stirred at 50C for 24 h (TLC monitoring, eluent EtOAc–hexane, 1:3). Solvent was
distilled off in vacuo, and the residue was separated by column chromatography on silica gel (l 18 cm, d 1 cm)
using EtOAc–hexane (1:7) as eluent. Yield 0.027 g (5%), white crystals, mp 187-189°C (EtOAc–hexane, 1:3).
1
IR spectrum, ν, cm-1: 1690 (CO2Me), 1606 (C=C). H NMR spectrum, δ, ppm (J, Hz): 2.10 (3Н, s, 12-СН3);
3.23 (3Н, s, NСН3); 3.46 (3Н, s, СО2СН3); 3.85 (2Н, s, СН2N); 4.85 (1Н, s, 9-СН); 6.12 (1Н, d,
1030

J = 3.1, Н-11); 6.42 (1Н, d, J = 3.1, Н-10); 7.02-7.06 (1Н, m, Н Ar); 7.08-7.15 (4Н, m, 3H Ar, Н Ph);
7.23-7.25 (1Н, m, Н Ph); 7.32-7.40 (2Н, m, Н Ph); 7.53 (1Н, s, Н-7); 7.55-7.57 (1Н, m, Н Ph). Mass
spectrum, m/z (Irel, %): 372 [M]+ (30), 313 (52), 204 (61), 202 (100), 168 (48), 154 (52), 42 (32). Found, %:
С 77.35; Н 6.46; N 7.48. C24H24N2О2. Calculated, %: С 77.39; Н 6.49; N 7.52.
6,9,12-Trimethyl-6,9-dihydro-5H-pyrrolo[1,2-a][1,6]benzodiazonine-8-carboxylate (15). Methyl
propiolate (0.24 g, 2.9 mmol) was added to the pyrrolobenzodiazepine 9 (0.34 g, 1.5 mmol) in MeOH (10 ml).
The reaction was carried out for 1 day at 20C (TLC monitoring, eluent EtOAc–hexane, 1:5). Solvent was
removed in vacuo, and the oil obtained was crystallized from Et2O. Yield 0.08 g (18%), white crystals, mp
140-142°C. IR spectrum, ν, cm-1: 1733 (CO2Mе), 1615 (C=С). 1H NMR spectrum, δ, ppm (J, Hz): 1.35 (3Н, d,
J = 6.9, 9-СН3); 2.04 (3Н, s, 12-СН3); 3.15 (3Н, s, NСН3); 3.50-3.45 (1Н, m, 9-СН); 3.38 (3Н, s, CO2СН3);
3.79 (2Н, s, СН2N); 6.00 (1Н, d, J = 3.1, H-10); 6.35 (1Н, d, J = 3.1, H-11); 7.32 (1Н, s, H-7); 7.39-7.45 (3Н,
m, Н Ar); 7.58-7.55 (1Н, m, Н Ar). Mass spectrum, m/z (Irel, %): 310 [M]+ (53), 263 (38), 252 (48), 202 (100),
180 (86), 167 (61), 154 (46), 106 (55). Found, %: C 73.57; H 7.11; N 9.06. C19H22N2О2. Calculated, %:
C 73.52; H 7.14; N 9.02.
Methyl (2E)-3-[({4-Formyl-1-[2-(methoxymethyl)phenyl]-5-methyl-1H-pyrrol-2-yl}methyl)(methyl)-
amino]acrylate (16). Methyl propiolate (0.27 g, 3.2 mmol) was added to a solution of the
pyrrolobenzodiazepine carbaldehyde 11 (0.53 g, 2.2 mmol) in MeOH (15 ml). The reaction was carried out for
1 day at 20C (TLC monitoring, eluent EtOAc). Solvent was removed in vacuo, and the residue was
chromatographed on an alumina column (d 1.8 cm, l 18 cm) using EtOAc–hexane (1:7) as eluent. Solvent was
removed in vacuo, and the yellow oil obtained was crystallized from Et2O. Yield 0.07 g (7%), white crystals,
1
mp 96-97°C. IR spectrum, ν, cm-1: 1655 (CНО). H NMR spectrum, δ, ppm (J, Hz): 2.20 (3Н, s, 5-CH3); 2.92
(3H, br. s, NCH3); 3.11 (3Н, s, СН2ОCH3); 3.60 (3Н, s, СО2CH3); 3.98-4.09 (4Н, m, СН2ОMе, СН2N); 4.57
(1Н, d, J = 13.1, NCH=CH); 6.72 (1Н, s, Н-3); 7.20 (1Н, d, J = 7.5, Н Ar); 7.29 (1Н, d, J = 7.5, Н Ar), 7.33
(1Н, d, J = 13.1, CН=CHCOOMe); 7.45 (1Н, t, J = 6.9, Н Ar); 7.51 (1Н, d, J = 6.9, Н Ar); 9.90 (1Н, s, СНО).
Mass spectrum, m/z: 357 [M+Н]+. Found, %: C 67.46; H 6.72; N 7.81. C20H24N2О4. Calculated, %: C 67.40;
H 6.79; N 7.86.
Methyl
11-Formyl-6,12-dimethyl-6,9-dihydro-5H-pyrrolo[1,2-a][1,6]benzodiazonine-8-carboxylate
(17). Methyl propiolate (0.15 g, 1.8 mmol) was added to a solution of the pyrrolobenzodiazepine carbaldehyde
11 (0.29 g, 1.2 mmol) in MeCN (17 ml). The reaction was carried out for 12 days at 50C (TLC monitoring,
eluent EtOAc). Solvent was removed in vacuo, and the residue obtained was recrystallized from a mixture of
Et2O and hexane. Yield 0.03 g (8%), white crystals, mp 180-182°С. IR spectrum, ν, cm-1: 1649 (CO2Me), 1620
1
(C=C). H NMR spectrum, δ, ppm (J, Hz): 2.34 (3Н, s, 12-СН3); 2.63 (1Н, d, J = 15.6) and 3.80 (1Н, d,
J = 15.6, 9-СН2); 3.25 (3Н, s, NСН3); 3.74 (3Н, s, CO2СН3); 3.78 (1Н, d, J = 15.1) and 3.86 (1Н, d, J = 15.1,
СН2N); 6.59 (1Н, s, Н-10); 7.24 (1Н, d, J = 7.3, Н-4); 7.45 (1Н, s, Н-7); 7.46-7.54 (2Н, m, Н-2,3); 7.63 (1Н, d,
J = 7.3, Н-1); 9.89 (1Н, s, СНО). Mass spectrum, m/z (Irel, %): 324 [M]+ (14), 265 (15), 202 (21), 167 (18), 59
(66), 42 (100). Found, %: C 70.39; H 6.18; N 8.71. C19H20N2O3. Calculated, %: C 70.35; H 6.21; N 8.64.
Dimethyl 6-Methyl-9-(2-thienyl)-6,9-dihydro-5H-pyrrolo[1,2-a][1,6]benzodiazonine-7,8-dicarboxylate
(18). DMAD (0.44 g, 3.1 mmol) was added to a solution of the pyrrolobenzodiazepine 7b (0.35 g, 1.3 mmol) in
MeOH (12 ml). The reaction was carried out for 13 days at 35C (TLC monitoring, eluent EtOAc–hexane,
1:10). Solvent was removed in vacuo, and the residue was chromatographed on a silica gel column (l 15, d 1.8 cm)
using EtOAc–hexane (1:10) as eluent. Yield 0.99 g (18%), colorless crystals, mp 206-207°С (EtOAc–hexane,
1:3). IR spectrum, ν, cm-1: 1733 (CO2Me), 1688 (CO2Me), 1573 (C=C). 1H NMR spectrum, δ, ppm (J, Hz): 3.02
(3Н, s, NСН3); 3.58 (3Н, s, СО2СН3); 3.89 (3Н, s, СО2СН3); 3.99 (1Н, d, J = 15.1) and 4.07 (1Н, d, J = 15.1,
СН2N); 5.33 (1Н, s, 9-СН); 6.36 (1Н, t, J = 3.2, Н-11); 6.59-6.60 (1Н, m, Н-3'); 6.64-6.65 (1Н, m, Н-10); 6.67-
6.68 (1Н, m, Н-12); 6.82 (1Н, dd, J = 3.7, J = 5.0, Н-4'); 7.03 (1Н, d, J = 5.0, Н-5'); 7.36-7.43 (3Н, m, Н Ar);
7.53 (1Н, d, J = 7.8, Н Ar). Mass spectrum, m/z (Irel, %): 422 [M]+ (3), 363 (5), 331 (3), 260 (6), 154 (15), 59
(100). Found, %: C 65.32; H 5.29; N 6.65. C23H22N2O4S. Calculated, %: C 65.39; H 5.25; N 6.63.
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Dimethyl 6,12-Dimethyl-9-phenyl-6,9-dihydro-5H-pyrrolo[1,2-a][1,6]benzodiazonine-7,8-dicarboxylate
(19). DMAD (0.60 g, 4.2 mmol) was added to a solution of the pyrrolobenzodiazepine 8 (0.29 g, 1.0 mmol) in
MeOH (20 ml) and refluxed for 14 h (TLC monitoring, eluent EtOAc–hexane, 1:7). Solvent was removed in
vacuo, and the residue was chromatographed on a silica gel column (l 26 cm, d 1.8 cm) using EtOAc–hexane
(1:8) as eluent. Yield 0.02 g (5%), colorless crystals, mp 230-232°C (Et2O). IR spectrum, ν, cm-1: 1736
1
(CO2Me), 1688 (CO2Me), 1573 (C=C). H NMR spectrum, δ, ppm (J, Hz): 2.03 (3Н, s, 12-CН3); 2.96 (3Н, s,
NCН3); 3.47 (3Н, s, СО2CН3); 3.86 (3Н, s, СО2CН3); 3.90 (1Н, d, J = 15.0) and 3.94 (1Н, d, J = 15.0, CH2N);
5.08 (1Н, s, 9-СН); 6.08 (1Н, d, J = 3.1, Н-10); 6.22 (1Н, br. s, Н-11); 7.08 (1Н, t, J = 6.9, H-4); 7.13-7.20 (4Н,
m, H Ph); 7.25-7.26 (1Н, m, H Ph); 7.36 (1Н, t, J = 7.1, H-2); 7.38 (1Н, t, J = 7.1, H-3); 7.52-7.55 (1Н, m,
H-1). Mass spectrum, m/z (Irel, %): 430 [M]+ (30), 371 (12), 168 (38), 154 (32), 59 (100). Found, %: C 72.48;
H 6.11; N 6.55. C26H26N2O4. Calculated, %: C 72.54; H 6.09; N 6.51.
X-ray Structural Analysis of Compound 13. Crystals of compound 13 (C23H22N2O2, M 358.43) were
grown from a mixture of EtOAc and hexane and are triclinic with space group P1. At 100 K: a 8.7269(4),
b 9.1525(5), c 12.0253(6) Å,  80.874(1),  83.560(1),  75.925(1); V 917.15(8) Å3; Z 2; dcalc 1.298 g/cm3;
F(000) 380;  0.083 mm-1. Unit cell parameters and intensities of 12040 reflections (5329 independent with
Rint 0.024) were measured on an automatic, three-circle diffractometer fitted with Bruker APEX-II CCD
bicoordinate detector (MoK radiation, graphite monochromator, - and -scanning,  max 60º). To obtain the
data, X-ray absorption was calculated using the SADABS program [6]. The structure was solved by the direct
method and refined in F2 full-matrix least squares analysis in the anisotropic approximation for non-hydrogen
atoms. The hydrogen atoms were placed in the geometrically calculated positions and included in the refinement
in the isotropic approximation with fixed positions ("rider" model) and thermal parameters (Uiso(H) =
1.2Ueq(C)). The final values of the probability factors were R1 0.041 for 4329 independent reflections with I >
2(I) and wR2 0.107 for all independent reflections, GOOF 1.002. All calculations were performed using the
SHELXTL program package [7]. Tables of atomic coordinates, bond lengths, valence angles, and anisotropic
temperature parameters for compound 13 have been placed at the Cambridge Crystallographic Data Center
(deposit CCDC 902180).
This work was carried out within the scope of the Presidential grant in support of young Russian
scientists (MK-182.2012.3). The authors thank the Collective Use Center of the Peoples' Friendship University
of Russia for help with recording the 1H NMR spectra.
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