New method of synthesis of 5,6-dihydro-4H-pyrrolo[1,2-a]-[1,4] benzodiazepines

Article abstract of DOI:10.3987/COM-08-11436

2,5-Dimethoxy-2-(dimethoxymethyl)tetrahydrofuran 1 reacted with anthranilic acid alkyl esters 2 in boiling acetic acid to give 2-(2-formylpyrrol-1-yl) benzoic acid esters 3. The reductive amination of 3 with primary arylalkylamines 4 led to 2-{2-[(arylalkylamino)methyl]pyrrol-1-yl}-benzoic acids esters 5. Heating of the aminoesters 5 in xylene under reflux resulted in 5-(arylalkyl)-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-ones 7. Lactams 7 were reduced by lithium aluminum hydride in toluene and and ether solutions to give 5-(arylalkyl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines 8. The solid products 8 were recrystallized and the liquid ones were transformed into their salts with oxalic acid. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-11436

HETEROCYCLES, Vol. 75, No. 11, 2008
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HETEROCYCLES, Vol. 75, No. 11, 2008, pp. 2713 - 2722. © The Japan Institute of Heterocyclic Chemistry
Received, 12th May, 2008, Accepted, 27th June, 2008, Published online, 3rd July, 2008. COM-08-11436
NEW METHOD OF SYNTHESIS OF 5,6-DIHYDRO-4H-PYRROLO[1,2-a]-
[1,4]BENZODIAZEPINES
Grigory V. Mokrov,a Arkady M. Likhosherstov,a Rainer Gewald,b and
Rudolf Schindlerb*
a
State Zakusov’s Institute of Pharmacology, Russian Academy of Medical
Sciences, Baltiyskaya street 8, 125315 Moscow, Russia
g.mokrov@gmail.com
b elbion GmbH, Meissner Str. 191, 01445 Radebeul, Germany
rudolf.schindler@elbion.com
Abstract - 2,5-Dimethoxy-2-(dimethoxymethyl)tetrahydrofuran 1 reacted
with anthranilic acid alkyl esters 2 in boiling acetic acid to give 2-(2-
formylpyrrol-1-yl)benzoic acid esters 3. The reductive amination of 3 with
primary arylalkylamines 4 led to 2-{2-[(arylalkylamino)methyl]pyrrol-1-yl}-
benzoic acids esters 5. Heating of the aminoesters 5 in xylene under reflux
resulted in 5-(arylalkyl)-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-
ones 7. Lactams 7 were reduced by lithium aluminum hydride in toluene and
ether solutions to give 5-(arylalkyl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzo-
diazepines 8. The solid products 8 were recrystallized and the liquid ones
were transformed into their salts with oxalic acid.
INTRODUCTION
2,5-Dialkoxytetrahydrofuranes are widely used compounds in synthetic heterocyclic chemistry.1
The presence of an additional reactive acetal group in these furan systems allows to exploit
them in obtaining pyrrolo[1,2-a]pyrazines2 and pyrrolo[1,2-a]diazepines3 derivatives, which can
be used in the synthesis of novel physiologically active substances.4,5 In particular, pyrrolo-
[1,2-a][1,4]benzodiazepines were described as CNS active agents with antidepressant,
neuropsychopharmacological activities.6 According to these examples, differently substituted
pyrrolo[1,2-a][1,4]benzodiazepines represent promising synthetic targets. Several synthetic
approaches based on Mannich reaction between 1-(2-aminomethylphenyl)-1H-pyrrole and

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HETEROCYCLES, Vol. 75, No. 11, 2008
aldehydes or ketones were developed.7,8 Ilyn reported a synthetic route to carboxamide
derivatives of pyrrolo[1,2-a][1,4]benzodiazepine based on a four-component Ugi reaction.9
Corelli described the
ring closure of
2-(2-hydroxyiminomethyl-1H-pyrrol-1-yl)benzene-
carboxylates using reductive conditions to obtain 4,5-dihydro-6H-pyrrolo[1,2-a][1,4]-
benzodiazepin-6-ones.10
The present work aimed at the synthesis of 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines
focusing on a specific furan intermediate with an exocyclic acetal group, 2,5-dimethoxy-2-
(dimethoxymethyl)tetrahydrofuran (acetal 1). This method allowed a new strategy in terms of the
possible substituents around the core scaffold.
RESULTS AND DISCUSSION
The key compound, Acetal 1, was synthesized by a 3 step sequence of reactions starting from
furan-2-carbaldehyde.11,12 Acetal 1 reacted with anthranilic acid alkyl esters 2 in boiling acetic
acid to give 2-(2-formylpyrrol-1-yl)benzoic acid esters 3 (Scheme 1).The optimum reaction
conditions were found to be 3 h reflux and a 10% excess of 1.
O
NH2
N
CO2R1
CO2R1
O
+
O
O
O
R2
R2
O
R2
R2
3a-c
1
2
3a, R1 = Me, R2 = H
3b, R1 = Et, R2 = H
3c, R1 = Me, R2 = OMe
Scheme 1
In the process of this reaction the acetal 1, containing three reactive centers, began to hydrolyze
by acid catalysis, starting with the less stable endocyclic ketal group. Simultaneously, the
resulting carbocation reacted with the amine group of compound 2 to give the intermediate
forming the five-membered cycle. After elimination of water and methanol aromatization led to
the pyrrole. The remaining 2-dimethoxymethyl group was then transformed into the aldehyde.

HETEROCYCLES, Vol. 75, No. 11, 2008
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The reductive amination of aldehydoesters 3 with primary arylalkylamines 4 by palladium on coal
(10% Pd) led to 2-{2-[(arylalkylamino)methyl]pyrrol-1-yl}benzoic acids esters 5 (Scheme 2).
H
N
H
N
(CH2)nAr
(CH2)nAr
N
N
(4)
CO2R1
NH2(CH2)nAr
CO2R1
(CO2H)2
3
10 mol% Pd/C
H2
(CO2H)2
R2
R2
R2
R2
6a-d
5
6a, R1 = Et, R2 = H, n = 2, Ar = Ph
6b, R1 = Et, R2 = H, n = 2, Ar = Ph(OMe)2-3,4
6c, R1 = Me, R2 = OMe, n = 2, Ar = Ph(OMe)2-3,4
6d, R1 = Me, R2 = OMe, n = 1, Ar = Ph(OMe)2-3,4
6e, R1 = Me, R2 =H, n = 1, Ar = Ph(OMe)2-3,4
Scheme 2
The reactions were carried out in ethanol solutions and the products 6 were isolated as salts
with oxalic acid.
Aminoesters 5 either obtained via reductive amination without isolation or by the treatment of
oxalates with potassium carbonate were heated in xylene under reflux to yield the desired 5-
(arylalkyl)-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-ones 7 (Scheme 3). The process
of cyclization was controlled by thin-layer chromatography. The time of lactamization depended
on the character of R1 and R2 substitutents and on the structure of the arylalkyl group, ranging
from 4 to 18 h. The reaction time showed a good correlation with theoretical information on the
rate of lactamization according to electronic properties of specific groups. For example, the
replacement of protons by methoxy groups, possessing a rather high +M effect, in the benzene
ring (R2) led to a reduction of the reaction rate by half due to the lower partial positive charge at
the carbonyl carbon. Also the rate of cyclization was lower for the replacement of methyl by
ethyl in the ester group (CO2R1) due to an increased +I effect of the alkoxy group.
Lactams 7 were reduced by lithium aluminum hydride in toluene and ether solutions to give the
corresponding 5-(arylalkyl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines 8. The solid

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HETEROCYCLES, Vol. 75, No. 11, 2008
products 8d and 8e were recrystallized and the liquid ones 8a-c were transformed into their
salts with oxalic acid.
xylene
LiAlH
1.
N
4
heating
N
N (CH2)nAr
(CO2H)2
N (CH2)nAr
O
5
2. (CO2H)2
4-18 h
R2
R2
R2
R2
7a-e
8a-d
7a, 8a, R2 = H, n = 2, Ar = Ph
7b, 8b, R2 = H, n = 2, Ar = Ph(OMe)2-3,4
7c, 8c, R2 = OMe, n = 2, Ar = Ph(OMe)2-3,4
7d, 8d, R2 = OMe, n = 1, Ar = Ph(OMe)2-3,4
7e, 8e R2 = H, n = 1, Ar = Ph(OMe)2-3,4
Scheme 3
Thus, as a result of our work, a new and convenient method of synthesis of N-arylalkyl-
substituted pyrrolo[1,2-a][1,4]benzodiazepines 7 and 8 was developed. It has considerable
advantages in comparison with previously reported procedures.8,13,14 Based on readily available
starting materials and providing high yields this new method has the potential to be used in the
synthesis of many other derivatives of this heterocyclic system.
EXPERIMENTAL
1H NMR spectra were determined on a Bruker AC-250 spectrometer in DMSO-d6 or CDCl3 as
solvent and TMS as internal standard. Analytical thin-layer chromatography (TLC) was
performed on Merck silica gel 60 F254, using aluminum plates with UV-detection and
toluene/acetone/heptane/triethylamine (14:9:3:1) as eluent.
Preparation of alkyl 2-(2-formyl-1H-pyrrol-1-yl)benzenecarboxylates (3). General
procedure.

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2717
A solution of 2,5-dimethoxy-2-(dimethoxymethyl)tetrahydrofuran 1 (0.22 mol) and 2-
aminobenzoic acid alkyl ester 2 (0.2 mol) in acetic acid (160 mL) was refluxed for 3 h. The
reaction mixture was distilled to dryness. The residue was dissolved in toluene, washed with
water, purified by column chromatography (alumina gel, toluene) and evaporated. Solids were
washed with toluene and liquid products were distilled.
Methyl 2-(2-formyl-1H-pyrrol-1-yl)benzenecarboxylate (3a). Orange oil; yield 70%; bp 140-
143 ºС at 1.5 mm Hg; nD25 = 1.6021; mp 53 ºС (lit.,6 mp 53-55 ºС).
Ethyl 2-(2-formyl-1H-pyrrol-1-yl)benzenecarboxylate (3b). Orange oil; yield 74%; bp
150-152 ºС at 1 mm Hg; n25 = 1.5870. 1H NMR (CDCl3, δ, ppm): 1.13 (t, J = 6.8 Hz, 3Н, СН3);
D
4.12 (q, J = 6.8 Hz , 2Н, СН2); 6.42 (m, 1Н, H-4); 6.98 (m, 1Н, Н-5); 7.11 (m, 1Н, Н-3); 7.32 (d,
J = 7.6 Hz, 1Н, 3`-H); 7.58 (m, 2Н, 4`,5`-H); 8.05 (d, J = 8.0 Hz, 1Н, 6`-H); 9.48 (s, 1Н, СОН).
Methyl 4,5-dimethoxy-2-(2-formyl-1H-pyrrol-1-yl)benzenecarboxylate (3c). Yellow crystals;
1
yield 75%; mp 124-125 ºС; Rf = 0.69. H NMR (CDCl3, δ, ppm): 3.64 (s, 3Н, СО2СН3); 3.88 (s,
3Н, 5`-OCH3); 3.97 (s, 3H, 4`-OCH3); 6.40 (m, 1Н, H-4); 6.76 (s, 1Н, Н-6`); 6.95 (m, 1Н, Н-5);
7.09 (m, 1Н, Н-3); 7.54 (s, 1Н, Н-3`); 9.46 (s, 1Н, СОН).
Preparation of alkyl 2-{2-[(arylalkylamino)methyl]pyrrol-1-yl}benzenecarboxylates hydro-
genoxalates (6). General procedure.
To a solution of alkyl 2-(2-formyl-1H-pyrrol-1-yl)benzenecarboxylate 3 (30.0 mmol) and
arylalkylamine (30.0 mmol) in EtOH (80 mL) 0.5 g of palladium on coal (10% Pd) was added.
The reaction mixture was hydrogenated at atmospheric pressure until the theoretical quantity of
hydrogen was absorbed. The catalyst was filtered off and a hot solution of oxalic acid (37.0
mmol) in EtOH was added to the filtrate to give crystals on cooling. The products were
recrystallized from EtOH.
Ethyl 2-{2-[(phenethylamino)methyl]pyrrol-1-yl}benzenecarboxylate hydrogenoxalate (6a).
1
White crystals; yield 81%; mp 140-142 ºC; Rf = 0.51. H NMR (DMSO-d6, δ, ppm): 1.01 (t, J =
6.7 Hz, 3Н, СН3); 2.86 (m, 2Н, СН2-Ph); 2.99 (m, 2Н, NH-CH2-CH2); 3.92 (q, J = 6.7 Hz, 2Н,
СН2-СН3); 4.08 (s, 2Н, СН2-Pyr); 6.21 (m, 1Н, 4-Н); 6.52 (m, 1Н, 3-Н); 6.80 (m, 1Н, 5-Н); 7.10-
7.38 (m, 5Н, PhH); 7.50 (d, J = 7.6 Hz, 1Н, 3`-H); 7.67 (m, 2Н, 4`,5`-H); 7.88 (d, J = 7.3 Hz, 1Н,
6`-H). Anal. Calcd for С22H24N2O2.C2H2O4 (438.49): C, 65.74; H, 5.98; N, 6.39. Found: C 65.56;
H 6.20; N 6.24.

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Ethyl 2-{2-[(3,4-dimethoxyphenethylamino)methyl]pyrrol-1-yl}benzenecarboxylate hydro-
1
genoxalate (6b). White crystals; yield 85%; mp 163-165 ºС; Rf = 0.47. H NMR (DMSO-d6, δ,
ppm): 1.01 (t, J = 6.7 Hz, 3Н, СН3); 2.75 (m, 2Н, СН2-Ph); 2.94 (m, 2Н, NH-CH2-CH2); 3.70 (s,
6Н, 2OCH3); 3.90 (q, J = 6.7 Hz, 2Н, СН2-СН3); 4.07 (s, 2Н, СН2-Pyr); 6.22 (m, 1Н, 4-Н); 6.50
(m, 1Н, 3-Н); 6.64 (d, J = 8.3 Hz, 1H, 6``-H); 6.74 (s, 1Н, 2``-H); 6.77 (m, 1Н, 5-Н); 6.83 (d, J =
8.3 Hz, 1Н, 5``-H); 7.48 (d, J = 7.7 Hz, 1Н, 3`-H); 7.66 (m, 2Н, 4`,5`-H); 7.87 (d, J = 7.3 Hz, 1Н,
6`-H). Anal. Calcd for С24H28N2O4.C2H2O4 (498.54): C, 62.64; H, 6.07; N 5.62. Found: C 62.55;
H 6.20; N 5.88.
Methyl
2-{2-[(3,4-dimethoxyphenethylamino)methyl]pyrrol-1-yl}-4,5-dimethoxybenzene-
1
carboxylate hydrogenoxalate (6c). White crystals; yield 82%; mp 154-155 ºС; Rf = 0.44. H
NMR (DMSO-d6, δ, ppm): 2.72 (m, 2Н, СН2-Ph); 2.97 (m, 2Н, NH-CH2-CH2); 3.51 (s, 3Н,
СО2СН3); 3.72 (s, 6Н, 3``-OCH & 4``-OCH3); 3.79 & 3.83 (2s, 6Н, 3`-OCH3 & 4`-OCH3); 4.01 (s,
2Н, СН2-Pyr); 6.19 (m, 1Н, 4-Н); 6.42 (m, 1Н, 3-Н); 6.63 (d, J = 8.4 Hz, 1H, 6``-H); 6.73 (m, 2Н,
5-H & 2``-H); 6.82 (d, J = 8.4 Hz, 1Н, 5``-H); 7.00 (s, 1Н, 3`-H); 7.38 (s, 1Н, 6`-H). Anal. Calcd
for С25H30N2O6.C2H2O4 (544.57): C, 59.55; H, 5.92; N, 5.14. Found: C 59.32; H 6.14; N 5.29.
Methyl
2-{2-[(3,4-dimethoxybenzylamino)methyl]pyrrol-1-yl}-4,5-dimethoxybenzene-
1
carboxylate hydrogenoxalate (6d). White crystals; yield 87%; mp 174-176 ºС; Rf = 0.39. H
NMR (DMSO-d6, δ, ppm): 3.55 (s, 3Н, СО2СН3); 3.67 & 3.73 (2s, 6Н, 3``-OCH & 4``-OCH3);
3.79 & 3.85 (2s, 6Н, 3`-OCH3 & 4`-OCH3); 3.95 (s, 2H, CH2-Ph); 4.03 (s, 2Н, СН2-Pyr); 6.17 (m,
1Н, 4-Н); 6.44 (m, 1Н, 3-Н); 6.73 (m, 1H, 6``-H); 6.82 (m, 2Н, 2``-H & 5-H); 6.95 (m, 1Н, 5``-H);
6.99 (s, 1Н, 3`-H); 7.30 (s, 1Н, 6`-H). Anal. Calcd for С24H28N2O6.C2H2O4 (530.53): C, 58.86;
H, 5.70; N, 5.28. Found: C 58.95; H 5.80; N 5.33.
Methyl 2-{2-[(3,4-dimethoxybenzylamino)methyl]pyrrol-1-yl}benzenecarboxylate hydro-
1
genoxalate (6e). White crystals; yield 85%; mp 132-134 ºС; Rf = 0.45. H NMR (DMSO-d6, δ,
ppm): 3.55 (s, 3Н, CO2СН3); 3.69 (s, 6Н, 2OCH3); 3.94 (s, 2H, CH2-Ph); 4.07 (s, 2Н, СН2-Pyr);
6.21 (m, 1Н, 4-Н); 6.48 (m, 1Н, 3-Н); 6.81 (m, 3H, 5-H, 6``-H & 5``-H); 6.97 (s, 1Н, 2``-H); 7.43
(d, J = 7.5 Hz, 1Н, 3`-H); 7.62 (m, 2Н, 4`,5`-H); 7.87 (d, J = 7.2 Hz, 1Н, 6`-H). Anal. Calcd for
С22H24N2O4.C2H2O4.0.5 H2O (479.49): C, 60.12; H, 5.68; N 5.84. Found: C 60.09; H 5.67; N
5.82.
Preparation of 5-(arylalkyl)-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-ones (7).
General procedure.
Alkyl 2-{2-[(arylalkylamino)methyl]pyrrol-1-yl}benzenecarboxylate hydrogenoxalate 6 (15.0
mmol) was added to a solution of K2CO3 (35.0 mmol) in water (30 mL). The free base was

HETEROCYCLES, Vol. 75, No. 11, 2008
2719
extracted with toluene and the organic layer was washed with water and evaporated. The
residue was dissolved in xylene and refluxed for 4-18 h (monitored by TLC). The solution was
evaporated to dryness and the residue was recrystallized from aqueous EtOH.
5-Phenethyl-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-one (7a). The compound
was prepared using 8 h reaction time as white crystals; yield 84%; mp 103-105 ºС; Rf = 0.70. 1H
NMR (CDCl3, δ, ppm): 2.94 (t, J = 7.6 Hz, 2Н, СН2-Ph); 3.63 & 3.97 (2m, 2Н, CH2-CH2-Ph);
3.95 & 4.24 (2d, J = 15.8 Hz, 2Н, (4)СН2); 6.08 (dd, 3J = 3.4 Hz, 4J = 1.6 Hz, 1Н, 3-Н); 6.26 (dd,
J = 3.4 Hz, J’ = 3.0 Hz, 1Н, 2-Н); 7.02 (dd, 3J = 3.0 Hz, 4J = 1.6 Hz, 1Н, 1-Н); 7.15-7.37 (m, 7Н,
4
PhH & 7-H & 9-H); 7.51 (ddd, 3J = 8.5 Hz, 3J’ = 7.1 Hz, J = 1.6 Hz, 1Н, 8-Н); 7.96 (dd, 3J = 8.5
4
Hz, J = 1.6 Hz, 1Н, 7-Н). Anal. Calcd for С20H18N2O (302.38): C, 79.44; H, 6.00; N, 9.26.
Found: C 79.41; H 6.09; N 8.99.
5-(3,4-Dimethoxyphenethyl)-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-one (7b).
The compound was prepared using 8 h reaction time as white crystals; yield 83%; mp 121-122
ºС; Rf = 0.60. 1H NMR (CDCl3, δ, ppm): 2.90 (t, J = 7.6 Hz, 2Н, СН2-Ph); 3.67 & 3.97 (2m & s,
8Н, CH2-CH2-Ph, 3’-(OCH3) & 4’-(OCH3)); 3.97 & 4.27 (2d, J = 15.7 Hz, J = 16 Hz, 2Н, (4)СН2);
6.10 (dd, 3J = 3.4 Hz, 4J = 1.6 Hz, 1Н, 3-Н); 6.26 (dd, J = 3.4 Hz, J’ = 3.0 Hz, 1Н, 2-Н); 6.7-6.85
(m, 3Н, 2`-H & 5`-H & 6`-H); 7.03 (dd, 3J = 3.0 Hz, 4J = 1.6 Hz, 1Н, 1-Н); 7.15-7.34 (m, 2Н, 10-H
4
& 9-H); 7.51 (ddd, 3J = 8.3 Hz, 3J’ = 7.6 Hz, J = 1.6 Hz, 1Н, 8-Н); 7.98 (dd, 3J = 8.35 Hz, 4J =
1.6 Hz, 1Н, 7-Н). Anal. Calcd for С22H22N2O3 (362.43): C, 72.91; H, 6.12; N, 7.73. Found: C
73.16; H 6.20; N 7.87.
5-(3,4-Dimethoxyphenethyl)-8,9-dimethoxy-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzo-
diazepin-6-one (7c). The compound was prepared using 13 h reaction time as white crystals;
1
yield 85%; mp 119-120 ºС; Rf = 0.51. H NMR (CDCl3, δ, ppm): 2.88 (m, 2Н, СН2-Ph); 3.64 &
3.95 (2m, 2Н, CH2-CH2-Ph); 3.84 (s, 6Н, 3`-OCH3 & 4`-OCH3); 3.94 (2s, 6H, 8-OCH3 & 9-
OCH3); 3.97 & 4.28 (2d, J = 15.6 Hz, 2Н, (4)СН2); 6.13 (dd, 3J = 3.4 Hz, 4J = 1.5 Hz, 1Н, 3-Н);
6.27 (dd, J = 3.4 Hz, J’ = 2.8 Hz, 1Н, 2-Н); 6.70-6.80 (m, 4Н, 2`-H & 5`-H & 6`-H & 10-H); 7.00
(dd, 3J = 2.8 Hz, 4J = 1.5 Hz, 1Н, 1-Н); 7,46 (s, 1Н, 7-Н). Anal. Calcd for С24H26N2O5 (422.49): C,
68.23; H, 6.20; N, 6.63. Found: C 67.93; H 6.40; N 6.60.
5-(3,4-Dimethoxybenzyl)-8,9-dimethoxy-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-
6-one (7d). The compound was prepared using 18 h reaction time as white crystals; yield 70%;
1
mp 154-156 ºС; Rf = 0.52. H NMR (CDCl3, δ, ppm): 3.77 (s, 3Н, 3`-ОСН3); 3.87 (s, 3Н, 4`-
ОСН3); 3.94 (s, 3Н, 8-ОСН3); 3.97 (s, 3Н, 9-ОСН3); 4.05 & 4.24 (2d, J = 15.5 Hz, 2Н, (4)СН2);
4.54 & 4.93 (2d, J = 15.8 Hz, 2Н, СН2-Ph); 5.89 (dd, 3J = 3.4 Hz, 4J = 1.6 Hz, 1Н, 3-Н); 6.22 (dd,

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HETEROCYCLES, Vol. 75, No. 11, 2008
J = 3.4 Hz, J’ = 3.2 Hz, 1Н, 2-Н), 6.74 (d, J = 1.9 Hz, 1Н, 5`-Н); 6.80 (s, 1Н, 10-Н); 6.83 (s, 1Н,
2`-H); 6.85 (d, J = 1.9 Hz, 1Н, 6`-H); 7.00 (dd, 3J = 3.2 Hz, 4J = 1.6 Hz, 1Н, 1-Н); 7.52 (s, 1Н, 7-
Н). Anal. Calcd for С23H24N2O5 (408.46): C, 67.63; H, 5.92; N, 6.86. Found: C 67.66; H 6.14; N
6.90.
5-(3,4-Dimethoxybenzyl)-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-one (7e). The
compound was prepared using 4 h reaction time as white crystals; yield 74%; mp 130-131 ºС;
1
Rf = 0.60. H NMR (CDCl3, δ, ppm): 3.77 (s, 3Н, 3`-ОСН3); 3.86 (s, 3Н, 4`-ОСН3); 4.04 & 4.23
(2d, J = 15.5 Hz, 2Н, (4)СН2); 4.53 & 4.92 (2d, J = 15.8 Hz, 2Н, СН2-Ph); 5.90 (dd, 3J = 3.4 Hz,
4J = 1.6 Hz, 1Н, 3-Н); 6.22 (dd, J = 3.4 Hz, J’ = 3.2 Hz, 1Н, 2-Н), 6.75 (d, J = 1.9 Hz, 1Н, 5`-Н);
3
4
6.83 (s, 1Н, 2`-H); 6.86 (d, J = 1.9 Hz, 1Н, 6`-H); 7.04 (dd, J = 3.2 Hz, J = 1.6 Hz, 1Н, 1-Н);
7.35 (m, 2Н, 8-Н & 10H); 7.37 (d, 1Н, 7-Н); 7.53 (m, 1Н, 9-Н); 8.04 (d, J = 8.1 Hz, 1Н, 7-Н).
Anal. Calcd for С21H20N2O3 (348.40): C, 72.40; H, 5.79; N, 8.04. Found: C 71.98; H 5.76; N 8.15.
Preparation of 5,6-Dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines (8). General procedure.
To a stirred suspension of lithium aluminum hydride (1 g) in dry Et2O a solution of 4,5-dihydro-
6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-one 7 (7.0 mmol) in dry Et2O (20 mL) and dry toluene (40
mL) was added dropwise. Then the reaction mixture was refluxed for 5 h. 1 mL of a 20%
solution of NaOH and 8 mL of water were added dropwise, the solution was decanted from the
precipitate and evaporated. The solid products were recrystallized from EtOH. The liquid
compounds were dissolved in EtOH (8 mL) and a hot solution of oxalic acid (8.0 mmol) in EtOH
(6 mL) was added. After cooling the precipitate was filtered off and recrystallized from EtOH.
5-Phenethyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine
hydrogenoxalate
(8a).
1
White crystals; yield 91%; mp 176-177 ºС. H NMR (DMSO-d6, δ, ppm): 3.08 (m, 2Н, CH2-Ph);
3.23 (m, 2Н, N-CH2); 3.98 (s, 2Н, (6)СН2); 4.12 (s, 2Н, (4)СН2); 6.31 (m, 1Н, 3-Н); 6.52 (m, 1Н,
2-Н); 7.20-7.46 (m, 7Н, PhH, 1-H, 7-H); 7.61 (m, 3Н, 8.9,10-Н). Anal. Calcd for
С20H20N2.C2H2O4.0,5 Н2О (387.45): C, 68.20; H, 5.98; N, 7.23. Found: C 68.26; H 6.00; N 7.35.
5-(3,4-Dimethoxyphenethyl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine hydrogeno-
1
xalate (8b). White crystals; yield 94%; mp 164-166 ºС. H NMR (DMSO-d6, δ, ppm): 3.00 (m,
2Н, CH2-Ph); 3.21 (m, 2Н, N-CH2); 3.70 & 3.72 (2s, 6H, 3’-OCH3 & 4’-OCH3); 4.00 (s, 2Н,
(6)СН2); 4.10 (s, 2Н, (4)СН2); 6.31 (m, 1Н, 3-Н); 6.50 (m, 1Н, 2-Н); 6.80 (d, J = 7.6 Hz, 1Н, 6`-
H); 6.89 (d, J = 7.6 Hz, 1H, 5`-H); 6.91 (s, 1Н, 2`-Н); 7.32 (m, 1Н, 1-Н); 7.41 (m, 1Н, 7-Н); 7.60
(m, 3Н, 8,9,10-Н). Anal. Calcd for С22H24N2O2.C2H2O4 (438.49): C; 65.74; H, 5.98; N 6.39.
Found: C 65.84; H 6.19; N 6.45.

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5-(3,4-Dimethoxyphenethyl)-8,9-dimethoxy-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzo-
diazepine hydrogenoxalate (8c). White crystals; yield 94%, mp 199-200 ºС. 1H NMR (DMSO-
d6, δ, ppm): 3.02 (m, 2Н, CH2-Ph); 3.22 (m, 2Н, N-CH2); 3.72 & 3.74 (2s, 6H, 3’-OCH3 & 4’-
OCH3); 3.79 & 3.86 (2s, 6Н, 8-ОСН3 & 9-ОСН3); 3.98 (m, 2Н, (6)СН2); 4.05 (m, 2Н, (4)СН2);
6.29 (m, 1Н, 3-Н); 6.45 (m, 1Н, 2-Н); 6.82 (d, J = 7.8 Hz, 1Н, 6`-H); 6.88 (d, J = 7.8 Hz, 1H, 5`-
H); 6.91 (s, 1Н, 2`-Н); 7.19 (s, 1Н, 7-Н); 7.23 (s, 1H, 10-H); 7.38 (m, 1Н, 1-Н). Anal. Calcd for
С24H28N2O4.C2H2O4 (498.54): C, 62.64; H, 6.07; N, 5.62. Found: C 62.77; H 6.26; N 5.56.
5-(3,4-Dimethoxybenzyl)-8,9-dimethoxy-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzo-
1
zepine (8d). White crystals; yield 91%; mp 148-149 ºС; Rf = 0.56. H NMR (CDCl3, δ, ppm):
3.38 (s, 2Н, (6)СН2); 3.49 (s, 2Н, СН2-Ph); 3.62 (s, 2Н, (4)СН2); 3.88 (2s, 6Н, 3`-OCH3 & 4`-
OCH3); 3.9 (s, 6Н, 8-ОСН3 & 9-ОСН3); 6.21 (m, 1Н, 3-Н); 6.28 (m, 1Н, 2-Н); 6.85 (m, 1Н, 5`-Н);
6.91-7.01 (m, 6Н, 1,2`,5`,6`,7,10-H). Anal. Calcd for С23H26N2O4 (394.47): С, 70.03; H, 6.64; N,
7.10. Found: C 69.94; H 6.74; N 7.41.
5-(3,4-Dimethoxybenzyl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine (8e).
1
White crystals; yield 90%; mp 111-113 ºС; Rf = 0.66. H NMR (CDCl3, δ, ppm): 3.50 (s, 4Н,
(6)СН2 & СН2-Ph); 3.64 (s, 2Н, (4)СН2); 3.91 (2s, 6Н, 3`-OCH3 & 4`-OCH3); 6.26 (m, 1Н, 3-Н);
6.31 (m, 1Н, 2-Н); 6.79-7.06 (m, 4Н, 1,2`,5`,6`-H); 7.25-7.46 (m, 4H, 7,8,9,10-H). Anal. Calcd for
С21H22N2O2 (334.42): С, 75.42; H, 6.63; N, 8.38. Found: C 75.31; H 6.65; N 8.47.
ACKNOWLEDGEMENTS
This work was funded by EFRE grants from the EU and by grants from the Free State of
Saxony (project no. 10843).
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