Syntheses of N10-substituted 7-arylpyrrolo[2,1-c]-[1,4]benzodiazepine-5,11- diones

Article abstract of DOI:10.1002/jhet.1775

Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione and its 7-bromo derivative were alkylated at the N10 atom applying various methods. The resulting products were subjected to Suzuki-Miyaura reactions using a catalyst system consisting of Pd(Cl)₂(PPh₃)₂ and sodium tert-butanolate in toluene. Results of an X-ray single crystal analysis are presented.

Full text of DOI:10.1002/jhet.1775

March 2014
Syntheses of N10-substituted 7-Arylpyrrolo[2,1-c]-[1,4]benzodiazepine-
423
5,11-diones
a
a
b
a
*
Anika Sabine Lindner, Egor Geist, Mimoza Gjikaj, and Andreas Schmidt
aClausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
bClausthal University of Technology, Institute of Inorganic Chemistry, Paul-Ernst-Strasse 4, D-38678 Clausthal-
Zellerfeld, Germany
*
E-mail: schmidt@ioc.tu-clausthal.de
Received March 19, 2012
DOI 10.1002/jhet.1775
Published online 18 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione and its 7-bromo derivative were alkylated at the N10 atom
applying various methods. The resulting products were subjected to Suzuki–Miyaura reactions using a
catalyst system consisting of Pd(Cl)2(PPh3)2 and sodium tert-butanolate in toluene. Results of an X-ray single
crystal analysis are presented.
J Heterocyclic Chem., 51, 423 (2014).
INTRODUCTION
inhibitors of platelet aggregation [18]. Substitution patterns
at the A, B, and C rings as well as at N10 have been varied.
The methoxy-substituted PBD-dione 5 was isolated in
2009, in addition to 2-hydroxycircumdatine C, as a new
member of this interesting class of compounds [19].
Recently, a solid-phase synthesis of a library of related
compounds as potential antitubercular substances has been
developed [20] (Scheme 2).
In continuation of our interest in pyrrolobenzodiazepines
[21], natural product derivatives [22], heterocyclic chemistry
[23], N-heterocyclic carbenes [24], and their applications in
palladium-catalyzed reactions [25], we report here the substi-
tutions of the N10-position of PBD-diones and Suzuki–
Miyaura reactions of 7-bromopyrrolobenzodiazepinediones.
The 1,4-benzodiazepine ring system is the partial structure
of diverse chemical compounds that display a variety of
biological activities [1]. From those, four types of pharmaco-
phores have been identified, the 1,4-benzodiazepine-2-ones,
1,4-benzodiazepine-2,5-diones, the dibenzodiazepinones,
and the pyrrolobenzodiazepines 1 (PBDs) [1]. Some PBDs
are minor groove sequence-specific DNA alkylating agents
with considerable anticancer activities [2]. This class of com-
pounds is quite widespread in nature. Since the discovery of
anthramycin 2 in 1963 [3], other PBDs such as tomaymycin
[4], neothramycin A and B [5], abbeymycin [6], chicamycin
A [7], and sibiromycin [8] produced by micrococci and
streptomyces have been isolated and characterized, some of
which possess antimicrobial activities [9]. In addition,
numerous synthetically produced PBDs have been reported
that supplement the degrees and types of substitutions of
naturally occurring compounds (Scheme 1).
The (S)-configuration of C11a seemingly is conditio sine
qua non for biological activity. The substituents R2 of the
PDB ring system 3 often are saturated or unsaturated
groups in biologically active compounds, and a variety of
electron-donating substituents R7–R9 are described to
improve activity. Meanwhile, 10 pentacyclic PBDs, mem-
bers of the class of circumdatines, have been identified
from terrestrial and marine Aspergillus species [10].
Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione 4 has been
isolated from Isatis indigotica [11]. It is the parent com-
pound of a family of substances that are important precur-
sors in the synthesis [12], for example, of peptidomimetic
agents [13], anxiolytic drugs [14], anticonvulsants [15],
herbicides [16], APT1 inhibitors [17], and nonpeptidal
RESULTS AND DISCUSSION
We first studied the alkylations of the PBD ring system
at N10. Methylation of 4a to 6a, which is known to exhibit
anxiolytic activity [14], was achieved with methyliodide in
DMSO in the presence of potassium hydroxide (Scheme 3,
Table 1, entry 1). This method has been mentioned previ-
ously in the literature [26] for the syntheses of a series
N10-alkylated PBDs, among them 6a, 6b, and 6c [27].
Application of the alkylation agent in THF in the presence
of potassium-tert-butanolate is advantageous with respect
to a simpler work-up procedure. We used this method for
the preparation of 6b–6g and 6i,j (Table 1, entries 2–8).
Ethyl iodide (entry 2) and diethylsulfate (entry 3) gave
almost identical yields. The use of n-propyl bromide
(entry 4) resulted in considerably better yields in compari-
son to n-propyl iodide (33%). The benzyl derivative 6e was
© 2013 HeteroCorporation

424
A. S. Lindner, E. Geist, M. Gjikaj, and A. Schmidt
Vol 51
Scheme 1. Pyrrolobenzodiazepines.
prepared before by coupling of 1-(2-halobenzoyl)pyrroli-
dine-2-carboxylates with benzylamine and subsequent
cyclizations using copper catalysts [28]. The 7-bromopyr-
rolobenzodiazepinedione 4b was prepared according to
modified literature procedures [26] and then alkylated at
N10 (entries 9–11).
Single crystals of 6e were obtained by slow evaporation
of a concentrated solution in petroleum ether/EtOAc. The
molecular drawing (Figure 1) shows the characteristic
twisted configuration. Some selected bond lengths and
dihedral angles are listed in Table 2.
Bromination of 6a and 6e at position 7 of the A ring was
accomplished with bromine in concentrated acetic acid in
the presence of sodium acetate (Scheme 4).
We first optimized the reaction conditions for Suzuki–
Miyaura cross-couplings and began our studies with Pd
(OAc)2, sodium tert-butanolate, and phenylboronic acid
in toluene that gave only unsatisfactory yields even under
prolonged reaction times. Best results for the coupling
were achieved using the reaction conditions as shown in
Scheme 5, that is, PdCl2(PPh3)2, aromatic boronic acids,
and sodium tert-butanolate in toluene at 60–70ꢀC over a
period of 3 h (method A). Chromatographic work-up gave
the C7-substituted PBDs 7a–j in good yields (Table 3,
entries 1–10). PBD 6i did not react under these conditions.
Using Pd(PPh3)4 in toluene in the presence of potassium
phosphate (method B), however, resulted in the formation
of the expected product 7k in 76% yield (entry 11). These
reaction conditions have also been applied to the formation
of 7l–n starting from 6j (entries 12–14). Suzuki–Miyaura
reactions at C-2 of the PBD ring system have been per-
formed before starting from 2-triflates of unsaturated
PDB’s using Pd(PPh3)4 and Na2CO3 in aqueous ethanol
and toluene [29] or benzene [30]. C-7 of 11-hydroxy-7-
iodo-pyrrolobenzo-diazepine has been arylated before via
Pro-N-TROC protection and subsequent Suzuki–Miyaura
reaction employing Pd(PPh3)4 and Na2CO3 in the same
solvent mixtures [31].
Scheme 2. Pyrrolobenzodiazepinediones of natural origin.
Scheme 3. Alkylation of N10.
Table 1
Reaction conditions for the alkylation of N10.
Yield
Entry Educt
Reagent
R
Y
Product
(%)
1
2
3
4
5
6
7
8
4a MeI
4a EtI
4a Et2SO4
4a n-PrBr
4a n-BuBr
4a PhCH2Br
4a 4-NO2-PhCH2Br 4-NO2Bz
4a n-octylbromide
4b MeI
Me
Et
Et
n-Pr
n-Bu
H
H
H
H
H
H
H
H
6a
6b
6b
6c
6d
6e
6f
6g
6h
6i
83
94
96
84
75
75
96
93
75
81
97
Bz
n-octyl
Me
Bz
9
10
11
Br
Br
Br
4b PhCH2Br
4b n-octylbromide
n-octyl
6j
Figure 1. Molecular drawing of 6e.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Syntheses of N10-Substituted 7-Arylpyrrolo[2,1-c]-[1,4]benzodiazepine-5,11-diones
425
Table 2
Selected bond lengths and dihedral angles of 6e (for numbering, cf. Scheme 1).
N4-C5
N10-C11
C11-C11a
N4-C11a
C1-C2-C3-N4
C3-N4-C5-C5a
134.27(1) pm
136.61(1) pm
151.97(1) pm
147.46(2) pm
ꢁ25.919(7)ꢀ
C9-C9a-N10-C11
N10-C11-C11a-N4
N10-C11-C11a-C1
C11-C11a-C1-C2
C11-N10-CH2-Ph
C9-C9a-N10-CH2
ꢁ136.886(7)ꢀ
ꢁ71.812(7)ꢀ
174.093(6)ꢀ
95.297(6)ꢀ
ꢁ109.021(7)ꢀ
ꢁ172.636(6)ꢀ
42.642(9)ꢀ
Scheme 4. Bromination of N10-alkylated pyrrolobenzodiazepines.
EXPERIMENTAL
General. All boronic acids were purchased and used without
further purification. The solvents were dried over sodium according
to standard procedures. Flash-chromatography was performed with
silica gel 60 (0.040–0.063 mm). NMR spectra were obtained with
Bruker Avance 400 and Bruker Avance III 600MHz
spectrometers (Bruker, Ettlingen, Germany). 1H NMR spectra
were recorded at 400 or 600 MHz and 13C NMR spectra at 100 or
150 MHz, with the solvent peak or tetramethylsilane used as the
internal reference. Multiplicities are described by using the
following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet;
sept, septet; and m, multiplet. FTIR spectra were obtained on a
Bruker Vektor 22 (Bruker Vector, Bruker Optics, Bremen,
Germany) in the range of 400 to 4000 cmꢁ1. Solids were
measured as pellets (2.5%) in KBr, and oils were measured as
films in NaCl plates. The mass spectra were measured with a
Varian 320 MS Triple Quad GC/MS/MS with a Varian 450-GC
(Varian Deutschland GmbH Instrumentelle Analytik, Darmstadt,
Germany). Melting points are uncorrected and were determined in
an apparatus according to Dr Tottoli (Büchi). The CHN analyses
were performed in the Institute of Technical Chemistry of the
Clausthal University of Technology. Whenever partial
racemization during the reaction occurred, the optical rotation is
not given. All yields refer to amounts of isolated compounds.
Scheme 5. Suzuki–Miyaura reactions.
X-ray diffraction analysis.
C19H18N2O2, M = 306.35 g molꢁ1: a suitable single crystal of
the title compound was selected under polarization
X-ray structure analysis for
Table 3
a
microscope and mounted in a glass capillary (d = 0.3 mm). The
crystal structure was determined by X-ray diffraction analysis
using graphite monochromated Mo-Ka radiation (0.71073 Å)
[T = 223(2) K], whereas the scattering intensities were collected
with a single crystal diffractometer (STOE IPDS II). The crystal
structure was solved by direct methods using SHELXS-97 and
refined using alternating cycles of least squares refinements
against F2 (SHELXL-97) [32]. All non-H atoms were located in
difference Fourier maps and were refined with anisotropic
displacement parameters. The H positions were determined by a
Yields of the Suzuki–Miyaura reaction.
Yield
(%)
Entry Educt
Ar
R
Product
1
2
3
4
5
6
7
8
6h
6h
6h
6h
6h
6h
6h
6h
6h
6h
6i
Ph
2-MePh
2-EtPh
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bz
n-Octyl
n-Octyl
n-Ocytl
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
88
60
62
51
40
35
86
68
54
70
76
55
53
55
2,6-Me2Ph
2,4,6-Me3Ph
3-F3CPh
2-MeOPh
4-F3COPh
4-MeSPh
1-naphthyl
Ph
final difference Fourier synthesis.
C19H18N2O2 (6e) crystallized in the orthorhombic space group
P212121 (no. 19), lattice parameters a = 8.7305(9) Å, b = 11.402
(2) Å, c = 15.561(2) Å, V = 1548.9(3)Å3, Z = 4, dcalc = 1.314 g
cmꢁ3, F(000) = 648 using 2735 independent reflections and 270
parameters. R1 = 0.0497, wR2 = 0.1126 [I > 2s(I)], goodness of fit
9
10
11
12
13
14
6j
6j
6j
Ph
on F2 = 1.105, residual electron density= 0.170 and ꢁ0.181e Åꢁ3
.
4-MePh
2,6-Me2Ph
Further details of the crystal structure investigations have been
deposited with the Cambridge Crystallographic Data Center,
CCDC 834712. Copies of this information may be obtained free
of charge from The Director, CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK (Fax: +44(1223)-336 033; e-mail: fileserv@ccdc.
ac.uk or http://www.ccdc.cam.ac.uk).
In summary, we describe the reliable syntheses of novel
N10-alkylated and 7-arylated PBDs that might be of interest
as biologically active compounds.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

426
A. S. Lindner, E. Geist, M. Gjikaj, and A. Schmidt
Vol 51
(11aS)-7-Bromo-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]-
ether/EtOAc = 1/1), yield 0.247 g (96%), mp 126–128ꢀC;
1
diazepine-5,11-(10H,11aH)-dione (4b). A sample of 1.08 g
(5.00 mmol) of 2,3-dihydro-1H-benzo[e]pyrrolo-[1,2-a][1,4]
diazepine-5,11-(10H,11aH)-dione (4a) was dissolved in 10mL
of glacial acetic acid. After addition of 0.41g (5.00 mmol) of
sodium acetate, a solution of 0.25 mL (5.00 mmol, 0.8 g) of
bromine in 10 mL of glacial acetic acid was added slowly. After
the complete addition, the reaction mixture was stirred overnight
at room temperature, diluted with water, and extracted with
dichloromethane. The organic layer was washed twice with water
and dried over sodium sulfate. The solvent was then distilled
[a]2D0 = +381.5 (c = 1.0 in CHCl3); H NMR (deuteriochloroform):
d 1.20 (t, J = 6.8 Hz, 3H, 13-H), 1.95–2.05 (m, 2H, 1-H, 2-H),
2.09–2.21 (m, 1H, 2-H), 2.69–2.76 (m, 1H, 1-H), 3.52–3.59
(m, 1H, 3-H), 3.75–3.84 (m, 2H, 3-H, 12-H), 4.02–4.04 (m, 1H,
11a-H), 4.11–4.20 (m, 1H, 12-H), 7.29–7.33 (m, 2H, 7-H, 9-H),
7.50–7.55 (m, 1H, 8-H), 7.92 (dd, J = 1.6, 8.0 Hz, 1H, 6-H) ppm;
13C NMR (deuteriochloroform): d 13.6 (C-13), 23.9 (C-2), 26.6
(C-1), 43.8 (C-12), 46.6 (C-3), 57.3 (C-11a), 122.3 (C-9), 125.8
(C-7), 130.3 (C-6), 130.9 (C-5a), 132.0 (C-8), 139.5 (C-9a) ,
165.1 (C═O), 168.9 (C═O) ppm; ms: m/z (%) = 244 [M+] (30),
175 (50), 147 (10), 119 (35), 84 (100); ir (KBr): 2970, 2875,
1672, 1650, 1599, 1459, 1413, 1291, 1245, 1112, 1090, 848, 791,
760, 707 cmꢁ1; HRESIMS Calcd for C14H17N2O2: 245.1290.
Found: 245.1287.
off and the residue was chromatographed (silica gel/CH2Cl2
:
acetone = 20:1). Yield: 1.03 g (70%), mp 218–220ꢀC. [a]D20 = +420.0
(c= 1.0 in CHCl3); 1H NMR (deuteriochloroform): d 1.97–2.07
(m, 3H, 1-H, 2-H), 2.71–2.78 (m, 1H, 1-H), 3.57–3.64 (m, 1H,
3-H), 3.79–3.84 (m, 1H, 3-H), 4.07 (d, J = 7.6 Hz, 1H, 11a-H),
6.94 (d, J = 8.8 Hz, 1H, 9-H), 7.57 (dd, J = 2.4, 8.8 Hz, 1H, 8-H),
8.12 (d, J = 2.4Hz, 1H, 6-H), 9.65 (s, 1H, 10-H) ppm; 13C NMR
(deuteriochloroform): d 23.5 (C-2), 26.2 (C-1), 47.6 (C-3), 56.7
(C-11a), 118.4 (C-7), 122.9 (C-9), 128.5, (C-5a) 133.8 (C-6),
134.3 (C-9a), 135.5 (C-8), 164.2 (C═O), 176.9 (C═O) ppm; ms:
m/z (%)= 294/296 [M+] (100/98); ir (KBr): 3226, 3161, 2972,
2941, 2872, 1703, 1615, 1478, 1448, 1370, 1264, 940, 825,
(11aS)-10-n-Propyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]
benzodiazepine-5,11-(10H,11aH)-dione (6c). The synthesis
was accomplished in analogy to the preparation of 6b (method A).
A 0.19mL (0.340g, 2.00mmol) of iodopropane was used. The
residue was chromatographed with petroleum ether/EtOAc = 1/2.
Yield: 0.20g (84%), mp 90–92ꢀC; [a]D20 = +412.4 (c = 0.5 in
1
CHCl3); H NMR (deuteriochloroform): d 0.82 (t, J = 7.2 Hz, 3H,
14-H), 1.42–1.52 (m, 1H, 13-H), 1.53–1.66 (m, 1H, 13-H),
1.98–2.06 (m, 2H, 1-H, 2-H), 2.10–2.17 (m, 1H, 2-H), 2.70–2.76
(m, 1H, 1-H), 3.53–3.65 (m, 2H, 3-H, 12-H), 3.76–3.83 (m, 1H,
3-H), 4.03–4.05 (m, 1H, 11a-H), 4.16–4.24 (m, 1H, 12-H),
7.27–7.33 (m, 2H, 7-H, 9-H), 7.49–7.54 (m, 1H, 8-H), 7.92
(dd, J= 1.4, 7.6 Hz, 1H, 6-H) ppm; 13C NMR (deuteriochloroform):
d = 11.1 (C-14), 21.2 (C-13), 23.9 (C-2), 26.7 (C-1), 46.5 (C-3),
49.8 (C-12), 57.4 (C-11a), 122.6 (C-9), 125.8 (C-7), 130.2 (C-6),
131.1 (C-5a), 132.0 (C-8), 139.4 (C-9a), 165.1 (C═O), 169.3
(C═O) ppm; ms: m/z (%) = 258 [M+] (25), 189 (100), 146 (15),
132 (60), 104 (23); ir (KBr) 2963, 2876, 1679, 1648, 1601, 1462,
1411, 1247, 1226, 1136, 766, 710 cmꢁ1; HRESIMS Calcd for
C15H19N2O2: 259.1447. Found: 259.1445.
772 cmꢁ1
. HRESIMS Calcd for C12H12BrN2O2: 295.0082.
Found: 295.0081.
(11aS)-10-Methyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]
benzodiazepine-5,11(10H,11aH)-dione (6a). According to a
modified literature procedure [33], a solution of 0.112 g (20.00 mmol)
of potassium hydroxide in 10 mL of dimethylsulfoxide was
stirred for 10min. After the addition of 1.08g (5.00 mmol) of
PBD 4a and 0.63mL (10.00 mmol, 1.42g) of methyl iodide,
stirring was continued for 3 h. The reaction mixture was then
diluted with water and extracted twice with dichloromethane.
The combined organic layers were washed three times with water,
dried over sodium sulfate, and evaporated. Yield: 0.950g (83%),
mp 108–110ꢀC; [a]D20 = +281.2 (c = 1.0 in CHCl3); 1H NMR
(deuteriochloroform): d 1.95–2.15 (m, 3H, 1-H, 2-H), 2.71–2.77
(m, 1H, 1-H), 3.41 (s, 3H, CH3), 3.52–3.60 (m, 1H, 3-H),
3.78–3.84 (m, 1H, 3-H), 4.05–4.06 (m, 1H, 11a-H), 7.23
(dd, J = 0.8, 8.2 Hz, 1H, 9-H), 7.28–7.32 (m, 1H, 7-H), 7.51–7.55
(m, 1H, 8-H), 7.92 (dd, J = 1.7, 7.8 Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 23.8 (C-2), 26.7 (C-1), 36.0 (Me), 46.7
(C-3), 57.2 (C-11a), 121.8 (C-9), 125.5 (C-7), 129.9 (C-5a), 130.2
(C-8), 132.0 (C-6), 140.6 (C-9a), 165.2 (C═O), 169.9 (C═O)
ppm; ms: m/z (%)= 230 [M+] (60), 201 (15), 174 (15), 161 (95),
146 (30), 133 (100), 104 (100); ir (KBr): 3010, 2952, 2881, 1679,
1635, 1599, 1463, 1424, 1377, 1252, 1185, 1151, 1126,
762, 680cmꢁ1; HRESIMS Calcd for C13H15N2O2: 231.1134;
Found: 231.1135.
(11aS)-10-Ethyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]
benzodiazepine-5,11-(10H,11aH)-dione (6b). Method A. A
sample of 0.216g (1.00mmol) PBD 4a and 0.112g (1.00mmol)
of KOtBu was suspended in 10 mL of anhyd THF. After the
addition of 0.16 mL (0.312 g, 2.0 mmol) of iodoethane, the
mixture was heated for 3 h at reflux temperature. After
evaporation, the residue was chromatographed (petroleum ether/
EtOAc = 1/1), yield 0.229g (94%). Method B. A sample of
0.229g (1.10 mmol) PBD 4a and 0.119g (1.10 mmol) KOtBu
was suspended in 10mL of anhyd THF and stirred for 10min.
After the addition of 0.338 g (2.20 mmol) of diethyl sulfate,
the mixture was heated at reflux temperature for 4 h. After
evaporation, the resulting solid was chromatographed (petroleum
(11aS)-10-n-Butyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]
benzodiazepine-5,11-(10H,11aH)-dione (6d). Synthesis in
analogy to 6b (method A). A 0.22 mL (0.274 g, 2.00 mmol) of
bromobutane was used. The residue was chromatographed with
petroleum ether/EtOAc = 1/1. Yield: 0.205 g (0.75 mmol, 75%);
mp: 127ꢀC; [a]D20 = +455.2 (c= 1.0 in CHCl3); 1H NMR
(deuteriochloroform): d 0.86 (t, J = 7.2 Hz, 3H, 15-H), 1.20–1.30
(m, 2H, 14-H), 1.40–1.51 (m, 1H, 13-H), 1.51–1.61 (m, 1H,
13-H), 1.94–2.05 (m, 2H, 1-H, 2-H), 2.08–2.21 (m, 1H, 2-H),
2.62–2.77 (m, 1H, 1-H), 3.53–3.67 (m, 2H, 3-H, 12-H),
3.78–3.84 (m, 1H, 3-H), 4.02–4.05 (m, 1H, 11a-H), 4.20–4.28
(m, 1H, 12-H), 7.28–7.33 (m, 2H, 7-H, 9-H), 7.50–7.54
(m, 1H, 8-H), 7.92 (dd, J = 1.6, 8.0 Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 13.7 (C-15), 19.9 (C-14), 23.9 (C-2),
26.7 (C-1), 30.0 (C-13), 46.5 (C-3), 48.1 (C-12), 57.4
(C-11a), 122.6 (C-9), 125.8 (C-7), 130.2 (C-6), 131.1 (C-5a),
131.9 (C-8), 139.5 (C-9a), 165.1 (C═O), 169.2 (C═O) ppm; ms:
m/z (%) = 272 [M+] (80), 203 (100), 175 (72), 161 (35), 146
(42), 132 (100), 119 (50), 90 (20); ir (KBr) 2952, 2927, 2877,
1667, 1640, 1598, 1465, 1416, 1401, 1250, 1207, 792, 767,
715 cmꢁ1
;
HRESIMS Calcd for C16H21N2O2: 273.1603.
Found: 273.1603.
(11aS)-10-Benzyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]
benzodiazepine-5,11-(10H,11aH)-dione (6e).
Preparation in
analogy to 6b (method A). A 0.24mL (0.342g, 2.0mmol) of
benzyl bromide was used. The residue was chromatographed with
petroleum ether/EtOAc = 1/1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Syntheses of N10-Substituted 7-Arylpyrrolo[2,1-c]-[1,4]benzodiazepine-5,11-diones
427
Yield: 0.228 g (0.744 mmol, 75%), mp 206–208ꢀC; [a]
of 0.448 g (8.00 mmol) of potassium hydroxide was dissolved
in 10mL of DMSO and stirred for 10 min. After the addition of
0.432 g (2.00 mmol) of PBD 4b and 0.252 mL (4.00mmol,
0.568 g) of iodomethane, the reaction was stirred for 1 h at room
temperature. Then, the solution was diluted with water and
extracted twice with dichloromethane. The combined organic
layers were washed with water and dried over sodium sulfate.
Yield: 0.460 g (75%), mp: 150ꢀC. [a]D20 = +197.5 (c= 1.0 in
CHCl3); 1H NMR (deuteriochloroform): d 1.79–2.11 (m, 3H, 1-H,
2-H), 2.70–2.78 (m, 1H, 1-H), 3.38 (s, 3H, CH3), 3.52–3.58
(m, 1H, 3-H), 3.76–3.83 (m, 1H, 3-H), 4.04–4.07 (m, 1H, 11a-H),
7.01 (d, J = 8.6 Hz, 1H, 9-H), 7.62 (dd, J = 2.4, 8.6 Hz, 1H,
8-H), 8.04 (d, J = 2.4 Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 23.7 (C-2), 26.8 (C-1), 36.0 (Me), 46.9
(C-3), 57.2 (C-11a), 118.8 (C-7), 123.5 (C-9), 131.4 (C-5a), 132.9
(C-6), 135.0 (C-8), 139.6 (C-9a), 163.8 (C═O), 169.5 (C═O)
ppm; ms: m/z (%) = 308 [M+] (55), 240 (100); ir (KBr): 2950,
2874, 1679, 1640 cmꢁ1. HRESIMS Calcd for C13H14BrN2O2:
309.0237. Found: 309.0239.
20 = +413.3 (c = 1.0 in CHCl3); H NMR (deuteriochloroform)
1
D
d 1.96–2.22 (m, 3H, 1-H, 2-H), 2.72–2.81 (m, 1H, 1-H), 3.56–
3.63 (m, 1H, 3-H), 3.80–3.68 (m, 1H, 3-H), 4.18 (d, J = 5.6 Hz,
1H, 11a-H), 5.01 (d, J = 16 Hz, 1H, 12-H), 5.17 (d, J = 16 Hz,
1H, 12-H), 7.14–7.31 (m, 7H, Harom), 7.28–7.42 (m, 1H, 8-H),
7.90 (dd, J = 1.6, 7.6 Hz, 1H, 6-H) ppm; 13C NMR (deuterio-
chloroform): d 23.9 (C-2), 26.8 (C-1), 46.7 (C-3), 52.5 (C-12),
57.3 (C-11a), 122.3 (C-9), 126.0 (C-7), 126.8 (C-15), 127.4
(C-16), 128.8 (C-14), 130.3 (C-6), 130.5 (C-5a), 132.0 (C-8),
137.0 (C-13), 139.9 (C-9a), 165.2 (C═O), 169.5 (C═O) ppm;
ms: m/z (%) = 306 [M+] (45), 237 (75), 180 (35), 146 (100),
91 (45); ir (KBr): 3066, 3032, 2982, 2956, 2890, 1666, 1637,
1598, 1463, 1412, 1366, 1300, 1250, 1209, 978, 789, 763,
730 cmꢁ1
; HRESIMS Calcd for C19H19N2O2: 307.1447;
Found: 307.1440.
(11aS)-10-(4-Nitrobenzyl)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]
benzodiazepine-5,11-(10H,11aH)-dione (6f). Preparation in
analogy to 6b (method A).
A 0.432 g (2.00 mmol) of
(11aS)-7-Brom-10-benzyl-2,3-dihydro-1H-pyrrolo[2,1-c]
4-nitrobenzyl bromide was used. The residue was
chromatographed with petroleum ether/EtOAc = 2/1. Yield:
0.335 g (96%); mp 126–128ꢀC; [a]2D0 = +331.0 (c = 1.0 in
[1,4]benzodiazepine-5,11(10H,11aH)-dione (6i).
A sample
of 0.616 g (2.10 mmol) of PBD 4b and 0.260 g (2.30 mmol) of
KOtBu was suspended in 10 mL of anhyd THF and stirred for
10 min. After the addition of 0.714 g (4.20 mmol) of benzyl
bromide, the solution was refluxed for 12 h. After evaporation
to dryness, the resulting residue was chromatographed
(petroleum ether/EtOAC = 1/1). Yield: 0.65 g (81%); mp 189–
193ꢀC; 1H NMR (deuteriochloroform): d 1.98–2.21 (m, 4H,
1-H, 2-H), 3.59 ( m, 1H, 3-H), 3.82 (m, 1H, 3-H), 4.17 (m, 1H,
11a-H), 5.00 (d, J = 15.8 Hz, 1H, 12-H), 5.13 (d, J = 15.8 Hz,
1H, 12-H), 7.07 (d, J = 8.8 Hz, 1H, 9-H), 7.13 (d, J = 7.0 Hz,
1H, 16-H), 7.21–7.33 (m, 4H, 14-H, 15-H), 7.49 (dd, J = 8.8,
2.5 Hz, 1H, 8-H), 8.02 (d, J = 2.5 Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 23.8, 26.9, 46.9, 52.3, 57.3, 119.3,
124.0, 126.8, 127.6, 128.9, 132.1, 133.1, 134.9, 136.6, 138.8,
163.7, 169.2 ppm; ms: m/z (%) = 384/386 [M+] (17/16), 91
(100); ir (KBr): 3332, 3266, 3035, 2978, 2958, 2877, 1849,
1783, 1675, 1443, 1238, 1213, 832, 730, 692 cmꢁ1; Anal.
Calcd for C19H17BrN2O2 . 0.1 H2O: C, 58.95; H, 4.74; N, 7.23.
Found: C, 58.56; H, 4.26; N, 7.48.
1
CHCl3); H NMR (deuteriochloroform): d 2.01–2.21 (m, 3H,
1-H, 2-H), 2.72–2.80 (m, 1H, 1-H), 3.57–3.64 (m, 1H, 3-H),
3.80–3.86 (m, 1H, 3-H), 4.22 (d, J = 7.6 Hz, 1H, 11a-H), 5.18
(d, J = 4.0 Hz, 2H, 12-H), 7.14 (d, J = 8.4 Hz, 1H, 9-H),
7.28–7.34 (m, 3H, 7-H, 14-H), 7.43–7.47 (m, 1H, 8-H), 7.93
(dd, J = 1.6, 7.6 Hz, 1H, 6-H), 8.15 (d, J = 8.8 Hz, 2H, 15-H)
ppm; 13C NMR (deuteriochloroform): d 23.8 (C-2), 26.8
(C-1), 46.8 (C-3), 52.0 (C-12), 57.2 (C-11a), 121.9 (C-9),
124.1 (C-15), 126.5 (C-7), 127.6 (C-14), 130.5 (C-5a), 130.6
(C-6), 132.3 (C-8), 139.3 (C-9a), 144.5 (C-13), 147.3 (C-16),
164.9 (C═O), 169.7 (C═O) ppm; ms: m/z (%) 351 [M+]
(45), 282 (100), 254 (20), 226 (45), 179 (48), 146 (97), 106
(10), 90 (48); ir (KBr): 2945, 2882, 1678, 1639, 1600, 1531,
1457, 1414, 1350, 1244, 1201, 841, 793, 768, 737, 715 cmꢁ1
;
HRESIMS Calcd for C19H18N3O4: 352.1297. Found:
352.1294.
(11aS)-10-Octyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]
benzodiazepine-5,11(10H,11aH)-dione (6g).
A sample of
(11aS)-7-Brom-10-octyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]
benzodiazepine-5,11(10H,11aH)-dione (6j). A suspension of
0.250 g (0.85 mmol) of PBD 4b and 0.095 g (0.85 mmol) KOtBu
in 15 mL of anhyd THF was stirred for 10 min. After the addition
of 0.528 g (2.20 mmol) benzyl bromide, the mixture was
refluxed for 12 h. Evaporation to dryness gave a residue that
was chromatographed (petroleum ether/EtOAC = 1/1). The
0.230 g (1.10 mmol) PBD 4a and 0.119 g (1.10 mmol) of
KOtBu was suspended in 15 mL of anhyd THF and stirred for
10 min. After the addition of 0.511 g (2.10 mmol) of octyl
iodide, the mixture was heated at reflux temperature over a
period of 12 h. After evaporation to dryness, the residue was
chromatographed (petroleum ether/EtOAc = 1:1). The product
was obtained as an oil. Yield: 0.326 g (93%); 1H NMR
(deuteriochloroform): d 0.78 (t, J = 6.9 Hz, 3H, 19-H), 1.08–
1.22 (m, 10H, 14-H, 15-H, 16-H, 17-H, 18-H), 1.38 (m, 1H,
13-H), 1.45 (m, 1H, 13-H), 1.85–1.99 (m, 2H, 2-H), 1.99–2.13
(m, 2H, 1-H), 3.45–3.60 (m, 2H, 3-H), 3.73 (m, 1H, 12-H),
3.95 (m, 1H, 12-H), 4.14 (m, 1H, 11a-H), 7.19–7.26 (m, 2H,
7-H, 9-H), 7.44 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H, 8-H), 7.85 (dd,
J = 7.8, 1.7 Hz, 1H, 6-H) ppm; 13C NMR (deuteriochloroform):
d 14.1, 22.6, 23.9, 26.7, 27.9, 29.0, 29.2, 31.7, 46.5, 48.3, 57.4,
122.6, 125.8, 130.2, 131.1, 131.9, 139.5, 165.1, 169.2 ppm;
ms: m/z (%) 328 [M+] (35), 97 (75); ir (KBr): 3485, 2926,
1
compound 6j was obtained as an oil. Yield: 0.335 g (97%); H
NMR (deuteriochloroform): d 0.79 (t, J = 7.0 Hz, 3H, 19-H),
1.06–1.25 (m, 10H, 14-H, 15-H, 16-H, 17-H, 18-H), 1.37
(m, 1H, 13-H), 1.49 (m, 1H, 13-H), 1.87–2.00 (m, 2H, 2-H),
2.07 (m, 1H, 1-H), 2.65 (m, 1H, 1-H), 3.42–3.56 (m, 2H, 3-H),
3.72 (m, 1H, 12-H), 3.95 (m, 1H, 12-H), 4.13 (m, 1H, 11a-H),
7.09 (d, J = 8.6 Hz, 1H, 9-H), 7.54 (dd, J = 8.6, 2.5 Hz, 1H,
8-H), 7.97 (d, J = 2.5 Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 14.1, 22.6, 23.8, 26.6, 26.7, 27.9, 29.0,
29.2, 31.7, 46.7, 48.3, 57.4, 119.1, 124.3, 132.7, 133.0, 134.9,
138.4, 163.7, 168.9 ppm; ms: m/z (%) = 406/408 [M+] (29/28),
97 (100); ir (KBr): 3483, 3349, 3277, 2927, 1690, 1590, 1561,
1291, 1240, 1091, 715, 614, 571 cmꢁ1. Anal. Calcd for
C20H27BrN2O.2 0.1 H2O: C, 58.70; H, 6.62; N, 6.85. Found: C,
58.36; H, 6.11; N, 7.42.
2856, 2360, 2332, 1682, 1461, 1246, 1166, 764, 663 cmꢁ1
.
Anal. Calcd for C20H28N2O2 * 0.25 H2O: C, 72.15; H, 8.63; N,
8.41. Found: C, 72.08; H, 7.97; N, 8.73.
(11aS)-7-Bromo-10-methyl-2,3-dihydro-1H-benzo[e]pyrrolo
[1,2-a][1,4]diazepine-5,11-(10H,11aH)-dione (6h).
A sample
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

428
A. S. Lindner, E. Geist, M. Gjikaj, and A. Schmidt
Vol 51
General procedure for the Suzuki–Miyaura reactions.
A
1158, 1111, 837, 760cmꢁ1. HRESIMS Calcd for C21H23N2O2:
335.1760. Found: 335.1760.
sample of 0.152 g (0.50 mmol) of 6h, 0.112 g (1.00 mmol) of
sodium tert-butanolate, 36 mg (10 mol%, 0.05 mmol) of PdCl2
(PPh3)2, and 0.75 mmol of the boronic acid was suspended in
10 mL of anhyd toluene and heated at reflux temperature for
3 h. After cooling, the solvent was distilled off, and the residue
was chromatographed. Unless otherwise noted, a mixture of
petroleum ether/ethyl acetate (2:1) was used as eluent.
(11aS)-7-(2,6-Dimethylphenyl)-10-methyl-2,3-dihydro-1H-
benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11-(10H,11aH)-dione
(7d). A 0.113 g of 2,6-dimethylphenylboronic acid was used.
Yield: 0.086 g (51%), mp. 193ꢀC (dec.). [a]D20 = +129.4
1
(c = 1.0 in CHCl3); H NMR (deuteriochloroform): d 1.99–2.16
(m, 9H, 1-H, 2-H, 70-H), 2.73–2.80 (m, 1H, 1-H), 3.46 (s, 3H,
CH3), 3.53–3.60 (m, 1H, 3-H), 3.74–3.82 (m, 1H, 3-H),
4.19–4.16 (m, 1H, 11a-H), 7.10–7.13 (m, 2H, 30-H, 50-H),
7.17 (d, J = 7.8 Hz, 1H, 9-H), 7.27–7.34 (m, 2H, 40-H, 8-H),
7.74 (d, J = 1.6 Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 21.0 (Me), 21.1 (Me), 23.8 (C-2),
26.8 (C-1), 36.1 (Me), 46.8 (C-3), 57.3 (C-11a), 121.9 (C-9),
127.4 (C-4arom), 127.6 (C-3arom + C-5arom), 129.9 (C-5a),
130.8 (C-6), 133.0 (C-8), 135.8 (C-2arom), 136.2 (C-6arom),
138.5 (C-1arom), 139.3 (C-7), 139.8 (C-9a), 165.1 (C═O),
170.0 (C═O) ppm; ms: m/z (%) 334 [M+] (75), 84 (100); ir
(KBr): 3383, 2975, 2952, 1682, 1642, 1563, 1448, 1368,
1319, 1240, 1116, 773, 752 cmꢁ1. HRESIMS Calcd for
C21H23N2O2: 335.1760. Found: 335.1758.
(11aS)-7-Phenyl-10-methyl-2,3-dihydro-1H-benzo[e]pyrrolo
[1,2-a][1,4]diazepine-5,11-(10H,11aH)-dione (7a). A sample
of 92mg of phenylboronic acid was used. Yield: 0.134 g (88%),
mp 162–163ꢀC. [a]D20 = +464.8 (c= 1.0 in CHCl3); 1H NMR
(deuteriochloroform): d 1.97–2.06 (m, 2H, 1-H, 2-H), 2.08–2.16
(m, 1H, 2-H), 2.73–2.80 (m, 1H, 1-H), 3.45 (s, 3H, CH3), 3.56–
3.63 (m, 1H, 3-H), 3.81–3.87 (m, 1H, 3-H), 4.10–4.14 (m, 1H,
11a-H), 7.29 (d, J = 8.4 Hz, 1H, 9-H), 7.35–7.40 (m, 1H, 40-H),
7.44–7.48 (m, 2H, 30-H), 7.62–7.64 (m, 2H, 20-H), 7.75 (dd,
J = 2.4, 8.4 Hz, 1H, 8-H), 8.16 (d, J = 2.4 Hz, 1H, 6-H) ppm; 13C
NMR (deuteriochloroform): d 23.8 (C-2), 26.8 (C-1), 36.0 (Me),
46.8 (C-3), 57.3 (C-11a), 122.3 (C-9), 127.0 (C-3arom), 127.9
(C-4arom), 128.6 (C-8), 129.0 (C-2arom), 130.2 (C-5a), 130.5 (C-6),
138.4 (C-1arom), 139.0 (C-7), 139.7 (C-9a), 165.2 (C═O), 169.7
(C═O) ppm; ms: m/z (%) = 306 [M+] (25), 84 (100); ir (KBr):
2974, 1678, 1638, 1606, 1457, 1439, 1370, 1320, 1242, 1114,
(11aS)-7-(2,4,6-Trimethylphenyl)-10-methyl-2,3-dihydro-1H-
benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11-(10H,11aH)-dione
(7e).
A 0.123 g of 2,4,6-trimethylphenylboronic acid was
used. Yield: 0.069 g (40%), mp. 186ꢀC (dec.). 1H NMR
(deuteriochloroform): d 2.00–2.07 (m, 8H, 1-H, 2-H, 50-H), 2.10–
2.17 (m, 1H, 2-H), 2.33 (s, 3H, 60-H), 2.75–2.79 (m, 1H, 1-H),
3.46 (s, 3H, CH3), 3.55–3.60 (m, 1H, 3-H), 3.80–3.84 (m, 1H,
3-H), 4.14 (d, J = 6.0 Hz, 1H, 11a-H), 6.94 (s, 1H, 30-H), 6.96
(s, 1H, 30-H), 7.27 (d, J = 8.0 Hz, 1H, 9-H), 7.32 (dd, J = 8.0,
1.8 Hz, 1H, 8-H), 7.73 (d, J = 1.8 Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 20.8 (Me), 20.9 (Me), 21.1 (Me), 23.8
(C-2), 26.8 (C-1), 36.1 (Me), 46.8 (C-3), 57.3 (C-11a), 121.8
(C-9), 128.2 (C-3arom), 128.4 (C-3arom), 129.8 (C-5a), 131.1 (C-6),
133.3 (C-8), 135.7 (C-2arom), 136.1 (C-2arom), 137.0 (C-1arom),
137.2 (C-4arom), 138.6 (C-7), 139.2 (C-9a), 165.2 (C═O), 170.0
(C═O) ppm; ms: m/z (%) = 348 [M+] (100), 279 (95), 251 (55),
222 (10), 165 (10), 84 (90); ir (KBr): 3448, 2921, 1682, 1642,
1449, 1367, 1319, 1240, 1112, 850, 751cmꢁ1. HRESIMS Calcd
for C22H25N2O2: 349.1916. Found: 349.1910.
837, 765, 703 cmꢁ1
. HRESIMS Calcd for C19H19N2O2:
307.1447. Found: 307.1447. Anal. Calcd for C19H18N2O2: C,
74.49; H, 5.92; N, 9.14. Found: C, 73.92; H, 5.33; N, 8.73.
(11aS)-7-(2-Methylphenyl)-10-methyl-2,3-dihydro-1H-benzo
[e]pyrrolo[1,2-a][1,4]diazepine-5,11-(10H,11aH)-dione (7b).
A 0.102g of 2-methylphenylboronic acid was used. Yield:
0.097g (60%), mp 229ꢀC. 1H NMR (deuteriochloroform):
d 1.97–2.09 (m, 2H, 1-H, 2-H), 2.10–2.17 (m, 1H, 2-H), 2.31
(s, 3H, 70-H), 2.73–2.79 (m, 1H, 1-H), 3.45 (s, 3H, CH3), 3.54–
3.63 (m, 1H, 3-H), 3.80–3.85 (m, 1H, 3-H), 4.15 (d, J = 7.2 Hz,
1H, 11a-H), 7.22–7.29 (m, 5H, 30-H, 40-H, 50-H, 60-H, 9-H), 7.49
(dd, J = 2.2, 8.4 Hz, 1H, 8-H), 7.90 (d, J = 2.2 Hz, 1H, 6-H) ppm;
13C NMR (deuteriochloroform): d 20.5 (Me), 23.8 (C-2), 26.8
(C-1), 36.0 (Me), 46.8 (C-3), 57.3 (C-11a) , 121.5 (C-9), 126.0
(C-5arom), 127.8 (C-6arom), 129.6 (C-5a), 129.8 (C-3arom), 130.6
(C-4arom), 130.7 (C-6), 132.9 (C-8), 135.3 (C-2arom), 139.3
(C-1arom + C-7), 139.8 (C-9a), 165.1 (C═O), 170.0 (C═O) ppm;
ms: m/z (%) = 320 [M+] (95), 251 (100); ir (KBr): 2972, 2924,
1682, 1640, 1608, 1445, 1368, 1112, 835, 776cmꢁ1. HRESIMS
Calcd for C20H21N2O2: 321.1603. Found: 321.1607.
(11aS)-7-(2-Ethylphenyl)-10-methyl-2,3-dihydro-1H-benzo
[e]pyrrolo[1,2-a][1,4]diazepine-5,11-(10H,11aH)-dione (7c).
A 0.113 g of 2-ethylphenylboronic acid was used. Yield: 0.105g
(62%), mp: 163–164ꢀC. [a]D20 = +298.1 (c= 1.0 in CHCl3); 1H
NMR (deuteriochloroform): d 1.15 (t, J = 7.7 Hz, 3H, 80-H), 2-01–
2.08 (m, 2H, 1-H, 2-H), 2.10–2.16 (m, 1H, 2-H), 2.63
(q, J = 7.7Hz, 2H, 70-H), 2.74–2.80 (m, 1H, 1-H), 3.46 (s, 3H,
CH3) 3.55–3.62 (m, 1H, 3-H), 3.81–3.85 (m, 1H, 3-H), 4.16
(d, J = 5.4 Hz, 1H, 11a-H), 7.20–7.22 (m, 1H, 40-H), 7.24–7.26
(m, 1H, 50-H), 7.28–7.29 (m, 1H, 9-H), 7.33–7.35 (m, 2H, 30-H,
60-H), 7.49 (dd, J = 1.8, 7.8 Hz, 1H, 8-H), 7.90 (d, J = 1.8 Hz, 1H,
6-H) ppm; 13C NMR (deuteriochloroform): d 15.6 (Et), 23.8
(C-2), 26.1 (Et), 26.8 (C-1), 36.0 (Me), 46.8 (C-3), 57.3 (C-11a),
121.5 (C-9), 125.8 (C-5arom), 128.0 (C-6arom), 128.7 (C-3arom),
129.6 (C-5a), 130.0 (C-4arom), 130.7 (C-6), 132.9 (C-8), 139.4
(C-1arom + C-7), 139.6 (C-2arom), 141.6 (C-9a), 165.1 (C═O),
170.0 (C═O) ppm; ms: m/z (%) = 334 [M+] (100); ir (KBr): 2968,
2874, 1681, 1643, 1562, 1502, 1478, 1438, 1368, 1318, 1241,
(11aS)-7-(3-Trifluoromethylphenyl)-10-methyl-2,3-dihydro-
1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11-(10H,11aH)-
dione (7f). A 0.142 g of 3-trifluoromethylphenylboronic acid
was used. Column chromatography was performed with
petroleum ether/ethyl acetate = 3:1. Yield: 0.065 g (35%). 1H
NMR (deuteriochloroform): d 1.99–2.07 (m, 2H, 1-H, 2-H),
2-08–2.16 (m, 1H, 2-H), 2.72–2.79 (m, 1H, 1-H), 3.45 (s, 3H,
CH3), 3.58–3.62 (m, 1H, 3-H), 3.82–3.86 (m, 1H, 3-H), 4.11
(d,J = 6.8 Hz, 1H, 11a-H), 7.33 (d, J = 8.4 Hz, 1H, 9-H),
7.61–7.64 (m, 1H, 50-H), 7.61–7.64 (m, 1H, 40-H), 7.76 (dd, J
=2.4, 8.4 Hz, 1H, 8-H), 7.81 (d, J = 7.8 Hz, 1H, 60-H), 7.87 (s,
1H, 20-H), 8.17 (d, J = 2.4 Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 23.8 (C-2), 26.8 (C-1), 36.0 (Me),
46.9 (C-3), 57.3 (C-11a), 122.5 (C-9), 123.7 (q, J = 3.6 Hz;
C2arom), 124.0 (q, J = 270.8 Hz; CF3), 124.5 (q, J = 3.6 Hz; C-
4arom), 128.8 (C-6), 129.5 (C-5arom), 130.2 (C-6arom), 130.3
(C-5a), 130.4 (C-8), 131.4 (q, J = 32.0 Hz; C-3arom), 136.8
(C-7), 139.8 (C-1arom), 140.4 (C-9a), 165.0 (C═O), 169.7 (C═O)
ppm; ms: m/z (%) = 374 [M+] (30), 305 (55), 277 (30), 248 (15),
84 (100); ir (KBr): 2925, 2880, 1684, 1642, 1607, 1449, 1371,
1337, 1265, 1164, 1119, 1076, 802 cmꢁ1. HRESIMS Calcd for
C20H18F3N2O2: 375.1320. Found: 375.1320.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Syntheses of N10-Substituted 7-Arylpyrrolo[2,1-c]-[1,4]benzodiazepine-5,11-diones
429
(11aS)-7-(2-Methoxyphenyl)-10-methyl-2,3-dihydro-1H-
benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11-(10H,11aH)-dione
0.126 g (70%). [a]D20 = +307.1 (c = 1.0 in CHCl3); 1H NMR
(deuteriochloroform): d 1.98–2.11 (m, 2H, 1-H, 2-H), 2.17–2.19
(m, 1H, 2-H), 2.78–2.83 (m, 1H, 1-H), 3.50 (m, CH3), 3.58–3.63
(m, 1H, 3-H), 3.83–3.88 (m, 1H, 3-H), 4.22 (d, J = 6.0 Hz, 1H,
11a-H), 7.34 (d, J = 8.4 Hz, 1H, 9-H), 7.43–7.49 (m 2H,
HNaphthyl), 7.51–7.56 (m 2H, HNaphthyl), 7.67 (dd, J = 2.4, 8.4 Hz,
1H, 8-H), 7.89–7.91 (m 2H, HNaphthyl), 7.93–7.94 (m 1H,
HNaphthyl), 8.09 (d, J = 2.4Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 23.8, 26.8, 36.1, 46.9, 57.3, 121.7, 125.4,
125.5, 126.0, 126.4, 127.2, 128.3, 128.5, 129.9, 131.3, 131.5,
133.7, 133.8, 138.1, 138.2, 139.7, 165.1, 170.0ppm; ms:
m/z (%) = 356 [M+] (100); ir (KBr): 2978, 2925, 2877, 1680,
1641, 1606, 1563, 1447, 1395, 1369, 1317, 1158, 1106, 927, 838,
803, 751 cmꢁ1. HRESIMS Calcd for C23H21N2O2: 357.1603.
Found: 357.1599.
(7g).
A 0.114g of 2-methoxyphenylboronic acid was used.
Column chromatography was performed with petroleum ether/
ethyl acetate= 1/2. Yield: 0.144 g (86%), mp. 148–180ꢀC. [a]
20 = +187.8 (c = 0.5 in CHCl3); H NMR (deuteriochloroform):
1
D
d 1.96–2.05 (m, 2H, 1-H, 2-H), 2.08–2.15 (m, 1H, 2-H), 2.73–
2.78 (m, 1H, 1-H), 3.44 (s, 3H, N-CH3), 3.54–3.61 (m, 1H, 3-H),
3.78–3.85 (m, 4H, 3-H, O-CH3), 4.14–4.17 (m, 1H, 11a-H), 6.98–
7.06 (m, 2H, 30-H, 50-H), 7.23 (d, J = 8.5 Hz, 1H, 9-H), 7.32–7.37
(m, 2H, 40-H, 60-H), 7.72 (dd, J = 2.2, 8.5 Hz, 1H, 8-H), 8.09
(d, J = 2.2Hz, 1H, 6-H) ppm; 13C NMR (deuteriochloroform):
d 23.8 (C-2), 26.8 (C-1), 36.0 (Me), 46.7 (C-3), 55.6 (OMe), 57.2
(C-11a), 111.2 (C-3arom), 121.0 (C-5arom), 121.4 (C-9), 128.5
(C-1arom), 129.3 (C-6arom), 129.5 (C-5a), 130.7 (C-4), 131.0 (C-6),
133.2 (C-8), 136.0 (C-7), 139.3 (C-9a), 156.5 (C-2arom), 165.3
(C═O), 170.0 (C═O) ppm; ms: m/z (%) = 336 [M+] (80), 267
(100); ir (KBr): 2980, 1677, 1643, 1606, 1478, 1442, 1372, 1245,
1113, 1026, 828, 762 cmꢁ1. HRESIMS Calcd for C20H21N2O3:
337.1552. Found: 337.1551.
(11aS)-7-(4-Trifluoromethoxyphenyl)-10-methyl-2,3-dihydro-
1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11-(10H,11aH)-dione
(7h). A 0.155 g of 4-(trifluoromethoxy)phenylboronic acid was
used. Column chromatography was performed with petroleum
ether/ethyl acetate = 1/2. Yield: 0.132 g (68%), mp 175ꢀC (dec.),
1H NMR (deuteriochloroform): d 1.99–2.08 (m, 2H, 1-H, 2-H),
2.09–2.16 (m, 1H, 2-H), 2.71–2.80 (m, 1H, 1-H), 3.45 (s, 3H,
CH3), 3.56–3.63 (m, 1H, 3-H), 3.80–3.87 (m, 1H, 3-H), 4.09–
4.14 (m, 1H, 11a-H), 7.30 (d, J = 8.4 Hz, 3H, 30-H, 9-H
overlapped), 7.64 (d, J = 8.4 Hz, 2H, 20-H), 7.71 (dd, J = 8.4,
2.2 Hz, 1H, 8-H), 8.13 (d, J = 2.2 Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 23.8 (C-2), 26.8 (C-1), 36.0 (Me), 46.9
(C-3), 57.3 (C-11a), 120.5 (q, J = 256.0Hz; CF3), 121.4 (C-3arom),
122.4 (C-9), 128.3 (C2arom), 128.6 (C-6), 130.3 (C-5a), 130.4
(C-8), 137.0 (C-1arom), 137.8 (C-7), 140.1 (C-9a), 149.1 (C-4arom),
165.0 (C═O), 169.8 (C═O) ppm; ms: m/z (%) = 390 [M+] (75),
321 (100); ir (KBr): 2957, 1677, 1645, 1489, 1456, 1256, 1205,
1158, 1114, 839, 757cmꢁ1. HRESIMS Calcd for C20H17F3N2O3:
391.1270. Found: 391.1264.
(11aS)-7-(4-Methylthiophenyl)-10-methyl-2,3-dihydro-1H-
benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11-(10H,11aH)-dione
(7i). A 0.126g of 4-(methylthio)phenylboronic acid was used.
Column chromatography was performed with petroleum ether/
ethyl acetate = 1:2. Yield: 0.095 (54%), mp 184ꢀC. 1H NMR
(deuteriochloroform): d 1.97–2.06 (m, 2H, 1-H, 2-H), 2.07–2.16
(m, 1H, 2-H), 2.53 (s, 3H, S-CH3), 2.73–2.78 (m, 1H, 1-H), 3.44
(m, 3H, N-CH3), 3.55–3.62 (m, 1H, 3-H), 3.81–3.87 (m, 1H,
3-H), 4.09–4.14 (m, 1H, 11a-H), 7.27 (d, J = 8.4 Hz, 1H, 9-H),
7.32 (d, J = 8.4 Hz, 2H, 30-H), 7.55 (d, J = 8.4 Hz, 2H, 20-H), 7.72
(dd, J = 2.4, 8.4 Hz, 1H, 8-H), 8.13 (d, J = 2.4 Hz, 1H, 6-H) ppm;
13C NMR (deuteriochloroform): d 15.7 (Me), 23.8 (C-2), 26.8
(C-1), 36.0 (Me), 46.8 (C-3), 57.3 (C-11a), 122.3 (C-9), 126.8
(C-2arom), 127.2 (C-3arom), 128.2 (C-6), 130.1 (C-8), 130.2 (C-5a),
135.6 (C-4arom), 137.7 (C-1arom), 138.6 (C-7), 139.6 (C-9a), 165.2
(C═O), 169.8 (C═O) ppm; ms: m/z (%) = 352 [M+] (100), 283
(85), 255 (70), 227 (20), 180 (15), 152 (20); ir (KBr): 2952, 2864,
1676, 1634, 1483, 1448, 1368, 1241, 1117, 812 cmꢁ1. HRESIMS
Calcd for C20H21N2O2S: 353.1324. Found: 353.1324.
(11aS)-10-Benzyl-7-phenyl-2,3-dihydro-1H-pyrrolo[2,1-c]
[1,4]benzodiazepine-5,11(10H,11aH)-dione (7k). A mixture of
0.093 g (0.24 mmol) of PDB 6i and 0.012 g (5.00 mol%,
0.01mmol) of Pd(PPh3)4 in 5 mL of anhyd toluene was stirred
for 30min. After the addition of 0.032g (0.26mmol) of
phenylboronic acid and 0.200g (0.94mmol) of K3PO4, the
mixture was stirred for additional 10min. Then, 0.2 mL of
degassed water was added. After 24 h at reflux temperature,
the mixture was filtered, treated with 10 mL of dichloromethane,
and washed three times with 10mL portions of water.
After evaporation to dryness, the resulting residue was
chromatographed (petroleum ether/EtOAc= 5/1). Yield: 0.070 g
1
(76%), mp 146–149ꢀC. H NMR (deuteriochloroform): d 1.98–
2.11 (m, 2H, 2-H), 2.17 (m, 1H, 1-H), 2.80 (m, 1H, 1-H), 3.64
(m, 1H, 3-H), 3.86 (m, 1H, 3-H), 4.25 (m, 1H, 11a-H), 5.04
(d, J = 15.6Hz, 1H, 12-H), 5.22 (d, J = 15.6Hz, 1H, 12-H), 7.07
(d, J = 8.4 Hz, 1H, Harom), 7.17–7.21 (m, 2H, Harom), 7.21–7.38
(m, 4H, Harom), 7.41–7.46 (m, 2H, Harom), 7.57–7.61 (m, 2H,
Harom), 7.60 (dd, J = 8.4, 2.4 Hz, 1H, Harom), 8.14 (d, J = 2.4 Hz,
1H, Harom) ppm; 13C NMR (deuteriochloroform): d 23.9, 26.9,
46.8, 52.5, 57.3, 122.7, 126.8, 126.9, 127.4, 127.9, 128.6, 128.9,
129.0, 130.4, 130.8, 137.0, 138.7, 138.9 (2C), 165.2, 169.5ppm;
ms: m/z (%) = 382 [M+] (27), 97 (100); ir (KBr): 3266, 3062,
2871, 2638, 2357, 1640, 1457, 1243, 765, 724, 573cmꢁ1. Anal.
Calcd for C25H22N2O2: C, 78.51; H, 5.80; N, 7.32. Found: C,
78.03; H, 5.79; N, 7.91.
(11aS)-10-Octyl-7-phenyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]
benzodiazepine-5,11(10H,11aH)-dione (7l).
A suspension of
0.100 g (0.25 mmol) of PBD 6i and 0.015 g (5.00 mol%,
0.01mmol) of Pd(PPh3)4 in 5 mL anhyd toluene was stirred
for 30min. Then, 0.032g (0.26 mmol) of phenylboronic acid and
0.200 g (0.94mmol) of K3PO4 were added and stirring was
continued for 10 min. After the addition of 0.2 mL of degassed
water, the mixture was heated at reflux temperature for 24h. After
filtration, the mixture was treated with 10mL of dichloromethane
and washed three times with 10mL portions of water. After
evaporation to dryness, the residue was chromatographed
(petroleum ether/EtOAc = 7/1). The compound was obtained as
an oil. Yield: 0.055g (55%); 1H NMR (deuteriochloroform):
d 0.79 (t, J = 6.8 Hz, 3H, 19-H), 1.11–1.23 (m, 10H, 14-H,
15-H, 16-H, 17-H, 18-H), 1.45 (m, 1H, 13-H), 1.54 (m, 1H,
13-H), 1.91–2.01 (m, 2H, 2-H), 2.08 (m, 1H, 1-H), 2.67
(m, 1H, 1-H), 3.47–3.63 (m, 2H, 3-H), 3.74 (m, 1H, 12-H),
4.02 (m, 1H, 12-H), 4.17 (m, 1H, 11a-H), 7.28 (d, J = 8.6 Hz,
1H, 9-H), 7.29–7.33 (m, 1H, Harom), 7.36–7.41 (m, 4H,
Harom), 7.67 (dd, J = 8.6, 2.3 Hz, 1H, 8-H), 8.09 (d, J = 2.3 Hz,
1H, 6-H) ppm; 13C NMR (deuteriochloroform): d 14.1, 22.6,
(11aS)-7-(1-Naphthyl)-10-methyl-2,3-dihydro-1H-benzo[e]
pyrrolo[1,2-a][1,4]diazepine-5,11-(10H,11aH)-dione (7j).
A
0.129 g of naphthyl-1-boronic acid was used. Column chromatography
was performed with petroleum ether/ethyl acetate= 1/1. Yield:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

430
A. S. Lindner, E. Geist, M. Gjikaj, and A. Schmidt
Vol 51
23.9, 26.7 (2C), 28.0, 29.1, 29.2, 31.7, 46.6, 48.3, 57.4, 123.0,
127.0, 127.9, 128.6, 129.0, 130.4, 131.4, 138.5, 138.6, 139.0,
165.1, 169.2 ppm; ms: m/z (%) = 404 [M+] (73), 335 (77), 208
(75), 97 (100); ir (KBr): 3061, 3035, 2925, 2346, 1680, 1563,
1456, 1240, 764, 732 cmꢁ1. HRESIMS Calcd for C26H34N2O2:
406.2620. Found: 406.2623.
5793; (c) Leimgruber, W.; Stefanovic, V.; Schenker, F.; Karr, A.; Berger,
J. J Am Chem Soc 1965, 87, 5791.
[4] (a) Arima, K.; Kohsaka, M.; Tamura, J.; Manaka, H.; Sakai, H.
J Antibiot 1972, 25, 437; (b) Nishioka, Y.; Beppu, T.; Kohsaka, M.;
Arima, K. J Antibiot 1972, 25, 600.
[5] (a) Miyamoto, M.; Kondo, S.; Naganawa, H.; Maeda, K.;
Ohno, M.; Umezawa, H. J Antibiot 1977, 30, 340; (b) Takeushi, T.;
Miamota, M.; Ishizuka, M.; Naganawa, H.; Kondo, S.; Hamada, M.;
Umezawa, H. J Antibiot 1976, 29, 93.
[6] Hochlowski, J. E.; Acdres, W. W.; Theriault, R. J.; Jackson,
M.; McAlpine, J. B. J Antibiot 1987, 40, 145.
(11aS)-10-Octyl-7-(p-tolyl)-2,3-dihydro-1H-pyrrolo[2,1-c]
[1,4]benzodiazepine-5,11(10H,11aH)-dione (7m). Preparation
in analogy to 7l. 0.133 g (0.33 mmol) of 6i, 0.03 g (8mol%,
0.03 mmol) of Pd(PPh3)4, 0.050 g (0.36mmol) of p-tolylboronic
acid, and 0.270 g (1.26mmol) K3PO4 in 10mL of anhyd toluene
were used. Column chromatography was performed with
petroleum ether/EtOAC= 7/1. The compound was obtained as an
[7] Konishi, M.; Ohkuma, H.; Naruse, N.; Kawaguchi, H. J Antibiot
1984, 37, 200.
[8] Leber, J. D.; Holden, J. R. E.; Johnson, K. G.; Hecht, S. M. J
Am Chem Soc 1988, 110, 2992.
1
oil. Yield: 0.081g (53%); H NMR (deuteriochloroform): d 0.85
[9] (a) Cipolla, L.; Araujo, A. C.; Airoldi, C.; Bini, D. Anticancer
Agents Med Chem 2009, 9, 1; (b) Kamal, A.; Reddy, K. L.; Devaiah, V.;
Shankaraiah, N.; Reddy, D. R. Mini Rev Med Chem 2006, 6, 53; (c)
Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh, G.; Reddy, G. S. Curr
Med Chem Anticancer Agents 2002, 2, 215.
[10] (a) Ookura, R.; Kito, K.; Ooi, T.; Namikoshi, M.; Kusumi, T. J
Org Chem 2008, 73, 4245; (b) Rahbaek, L.; Breinholt, J.; Frisvad, J. C.;
Christophersen, C. J Org Chem 1999, 64, 1689; (c) Rahbaek, L.; Breinholt,
J. J Nat Prod 1999, 62, 904; (d) Dai, J.; Carte, B. K.; Sidebottom, P. J.; Sek
Yew, A. L.; Ng, S.; Huang, Y., Butler, M. S. J Nat Prod 2001, 64, 125; (e)
Zhang, D.; Yang, X.; Kang, J. S.; Choi, H. D.; Son, B. W. J Antibiot (Tokyo)
2008, 61, 40.
(t, J = 6.7 Hz, 3H, 19-H), 1.19–1.28 (m, 10H, 14-H, 15-H, 16-H,
17-H, 18-H), 1.50 (m, 1H, 13-H), 1.60 (m, 1H, 13-H), 1.96–2.06
(m, 2H, 2-H), 2.15 (m, 1H, 1-H), 2.39 (s, 3H, 70-H), 2.73 (m, 1H,
1-H), 3.54–3.69 (m, 2H, 3-H), 3.82 (m, 1H, 12-H), 4.08 (m, 1H,
12-H), 4.24 (m, 1H, 11a-H), 7.26–7.31 (m, 2H, Harom), 7.33
(d, J = 8.6Hz, 1H, Harom), 7.53–7.56 (m, 2H, Harom), 7.72
(dd, J = 8.6, 2.5Hz, 1H, Harom), 8.13 (d, J = 2.3Hz, 1H, 6-H)
ppm; 13C NMR (deuteriochloroform): d 14.1, 21.2, 22.6, 23.9,
26.7, 28.0, 29.1, 29.2, 31.7, 46.6, 48.3, 57.4, 123.0, 126.8, 128.3,
129.0, 129.7, 130.1, 131.3, 136.1, 137.8, 138.2, 138.6, 165.2,
169.2 ppm; ms: m/z (%)= 418 [M+] (20), 97 (100); ir (KBr):
3342, 3028, 2926, 2855, 2359, 2340, 1908, 1680, 1645, 1445,
813 cmꢁ1. HRESIMS Calcd for C27H36N2O2: 420.2777. Found:
420.2775.
[11] Wu, X.; Liu, Y.; Sheng, W.; Sun, J.; Qin, G. Planta Med 1997,
63, 55.
[12] (a) Kamal, A.; Reddy, B. S. N.; Reddy, G. S. K. Synlett 1999,
8, 1251; (b) Kamal, A.; Reddy, G. S. K.; Raghavan, S. Bioorg Med Chem
Lett 2001, 11, 387; (c) Madani, H.; Thompson, A. S.; Threadgill, M. D.
Tetrahedron 2002, 58, 8107; (d) Wang, J.-J.; Hu, W.-P.; Chung, H.-W.;
Wang, L.-F.; Hsu, M.-H. Tetrahedron 1998, 54, 13149.
[13] Blackburn, B. K.; Lee, A.; Baier, M.; Kohl, B.; Olivero, A. G.;
Matamoros, R.; Robarge, K. D.; McDowell, R. S. J Med Chem 1997,
40, 717.
[14] Wright, W. B.; Brabander, H. J.; Greenblatt, E. N.; Day, I. P.;
Hardy, R. A. J Med Chem 1978, 21, 1087.
[15] Di Martino, G.; Massa, S.; Corelli, F.; Pantaleoni, G.; Fanini,
D.; Palumbo, G. Eur J Med Chem 1983, 18, 347.
[16] Karp, G. M.; Manfredi, M. C.; Guaciaro, M. A.; Ortlip, C. L.;
Marc, P.; Szamosi, I. T. J Agric Food Chem 1997, 45, 493.
[17] Biel, M.; Deck, P.; Giannis, A.; Waldmann, H. Chem Eur J,
2006, 12, 4121.
[18] McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L.
R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.; Thorsett,
E. D.; Tischler, M.; Webb II, R. R.; Venuti, M. C. J Am Chem Soc 1994,
116, 5077.
(11aS)-7-(20,60-Dimethylphenyl)-10-octyl-2,3-dihydro-1H-
pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione
(7n). Preparation in analogy to 7l. 0.144 g (0.35 mmol) of PBD
6i, 0.03g (7mol%, 0.03 mmol) of Pd(PPh3)4, 0.060g (0.39mmol)
of 2,6-dimethylphenylboronic acid, and 0.299 g (1.4 mmol) of
K3PO4 in 10mL of anhyd toluene were used. Chromatography
was performed with petroleum ether/EtOAC = 7/1. Yield: 0.085 g
1
(55%); H NMR (deuteriochloroform): d 0.86 (t, J = 6.7 Hz, 3H,
19-H), 1.19–1.32 (m, 10H, 14-H, 15-H, 16-H, 17-H, 18-H), 1.54
(m, 1H, 13-H), 1.66 (m, 1H, 13-H), 2.00–2.06 (m, 3H, 2-H,
Haliph), 2.07–2.10 (m, 3H, Haliph) 2.16 (m, 1H, 1-H), 2.75 (m, 1H,
1-H), 3.56 (m, 1H, 3-H), 3.70 (m, 1H, 3-H), 3.82 (m, 1H, 12-H),
4.11 (m, 1H, 12-H), 4.20 (m, 1H, 11a-H), 7.08–7.14 (m, 4H,
Harom), 7.16–7.20 (m, 1H, Harom), 7.22 (d, 1H, J = 2.3 Hz, Harom),
7.30 (m, 1H, Harom), 7.74 (d, J = 2.0 Hz, 1H, 6-H) ppm; 13C NMR
(deuteriochloroform): d 14.1, 20.9, 21.0, 22.6, 23.9, 26.8, 28.1,
29.1, 29.2, 31.8, 46.7, 48.6, 57.5, 122.6, 127.4, 127.6, 130.8,
132.9, 135.8, 136.2, 138.3, 138.7, 139.8, 165.0, 169.2ppm; ms:
m/z (%) = 432 [M+] (70); ir (KBr): 3343, 2926, 2855, 1928, 1680,
1648, 1440, 1237, 771cmꢁ1. HRESIMS Calcd for C28H38N2O2:
434.2933. Found: 434.2933.
[19] Cui, C.-M.; Li, X.-M.; Li, C.-S.; Sun, H.-F.; Gao, S.-S.; Wang,
B.-G. Helv Chim Acta 2009, 92, 1366.
[20] Kamal, A.; Reddy, K.; Laxma, D. V.; Shankaraiah, N.; Reddy,
G. S. K.; Raghavan, S. J Comb Chem 2007, 9, 29, and literature cited therein.
[21] (a) Schmidt, A.; Gholipour Shilabin, A.; Lindner, A. S.; Nieger,
M. Tetrahedron 2008, 64, 2048; (b) Schmidt, A.; Gholipour Shilabin, A.;
Namyslo, J. C.; Nieger, M.; Hemmen, S. Eur J Org Chem 2005, 1781; (c)
Schmidt, A.; Gholipour Shilabin, A.; Nieger, M. Heterocycles 2005, 65,
625; (d) Schmidt, A.; Gholipour Shilabin, A. Heterocycles 2004, 63, 2851.
[22] (a) Schmidt, A.; Mordhorst, T. Arkivoc 2003, 14, 233; (b)
Schmidt, A. J Heterocyl Chem 2002, 39, 949; (c) Schmidt, A.; Nieger, M.
Heterocycles 1999, 51, 2119; (d) Wamhoff, H.; Schmidt, A. Heterocycles
1993, 35, 1055.
REFERENCES AND NOTES
[1] Herr, R. J. Sci. Synth. 2003, 17, 951.
[23] Schmidt, A.; Mordhorst, T. Synthesis 2005, 781.
[24] (a) Schmidt, A.; Beutler, A.; Albrecht, M.; Ramírez, F. J. Org
Biomol Chem 2008, 6, 287; (b) Schmidt, A.; Snovydovych, B.; Habeck,
T.; Dröttboom, P.; Gjikaj, M.; Adam, A. Eur J Org Chem 2007, 4909;
(c) Schmidt, A.; Beutler, A.; Habeck, T.; Mordhorst, T.; Snovydovych,
B. Synthesis 2006, 1882.
[25] (a) Schmidt, A.; Rahimi, A. Chem Commun 2010, 46, 2995;
(b) Rahimi, A.; Namyslo, J. C.; Drafz, M.; Halm, J.; Hübner, E.; Nieger,
M.; Rautzenberg, N.; Schmidt, A. J Org Chem 2011, 76, 7316.
[2] (a) Pepper, C. J.; Hambly, R. M.; Fegan, C. D.; Delavault, P.;
Thurston, D. E. Cancer Res 2004, 64, 6750; (b) Kumar, R.; Lown, J. W.
Mini Rev Med Chem 2003, 3, 323; (c) Thurston, D. E.; Bose, D. S.;
Howard, P. W.; Jenkins, T. C.; Leoni, A.; Baraldi, P. G.; Guiotto, A.;
Cacciari, B.; Kelland, L. R.; Foloppe, M. P.; Rault, S. J. Med Chem
1999, 42, 1951.
[3] (a) Tendler, M. D.; Korman, S. Nature 1963, 199, 501; (b)
Leimgruber, W.; Batcho, A. D.; Schenker, F. J Am Chem Soc 1965, 87,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Syntheses of N10-Substituted 7-Arylpyrrolo[2,1-c]-[1,4]benzodiazepine-5,11-diones
431
[26] Johnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35,
2169.
[27] Thurston, D. E.; Kaumaya, P. T. P.; Hurley, L. H. Tetrahedron
[30] Cooper, N.; Hagan, D. R.; Tiberghien, A.; Ademefun, T.;
Matthews, C. S.; Howard, P. W.; Thurston, D. E. Chem Commun 2002, 1764.
[31] Guiotto, A.; Howard, P. W.; Baraldi, P. G.; Thurston, D. E.
Bioorg Med Chem Lett 1998, 8, 3017.
Lett 1984, 25, 2649.
[28] Lu, X.; Shi, L.; Zhang, H.; Jiang, Y.; Ma, D. Tetrahedron
2010, 66, 5714.
[29] Howard, P. W.; Chen, Z.; Gregson, S. J.; Masterson, L. A.;
Tiberghien, A. C.; Cooper, N.; Fang, M.; Coffils, M. J.; Klee, S.; Hartley,
J. A.; Thurston, D. E. Bioorg Med Chem Lett 2009, 19, 6463.
[32] Sheldrick, G. M., SHELXS-97, SHELXL-97, A program
package for crystal structure solution and refinement; University of Göt-
tingen: Germany, 1997.
[33] Liu, R.; Zhang, P.; Gan, T.; McKernan, R. M.; Cook, J. M.
Med Chem Res 1997, 7.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet