Synthesis of a novel pyrrolo[1,2-c][1.3]benzodiazepine analogue of VPA-985

Article abstract of DOI:10.1016/j.tet.2011.07.083

The seven-step synthesis of a novel structural isomer of VPA-985, N-[3-chloro-4-(5H-pyrrolo[1,2-c][1.3]benzodiazepin-6(11H)-ylcarbonyl)phenyl] -5-fluoro-2-methylbenzamide, is described. (2-Aminophenyl)(1H-pyrrol-2-yl) methanone was converted with thiophosgene into (2-isothiocyanatophenyl)(1H- pyrrol-2-yl)methanone which was cyclised in the presence of base to 5-thioxo-5,6-dihydro-11H-pyrrolo[1,2-c][1.3]benzodiazepin-11-one. The latter underwent desulfurisation with Raney nickel followed by reduction with lithium aluminium hydride in the presence of aluminium trichloride and the resulting 6,11-dihydro-5H-pyrrolo[1,2-c][1.3]-benzodiazepine acylated with 2-chloro-4-nitrobenzoyl chloride to afford 6-(2-chloro-4-nitrobenzoyl)-6,11- dihydro-5H-pyrrolo[1,2-c][1.3]benzodiazepine. The nitro group in the latter compound was reduced with zinc and ammonium chloride to give the corresponding aniline derivative which was then acylated with 2-methyl-5-fluorobenzoyl chloride to provide the final product.

Full text of DOI:10.1016/j.tet.2011.07.083

Tetrahedron 67 (2011) 7805e7810
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of a novel pyrrolo[1,2-c][1.3]benzodiazepine analogue of VPA-985
*
Georgios Rotas, Athanasios Kimbaris, George Varvounis
Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, GR-451 10 Ioannina, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
The seven-step synthesis of a novel structural isomer of VPA-985, N-[3-chloro-4-(5H-pyrrolo[1,2-c][1.3]
benzodiazepin-6(11H)-ylcarbonyl)phenyl]-5-fluoro-2-methylbenzamide, is described. (2-Aminophenyl)(1H-
pyrrol-2-yl)methanone was converted with thiophosgene into (2-isothiocyanatophenyl)(1H-pyrrol-2-yl)
methanone which was cyclised in the presence of base to 5-thioxo-5,6-dihydro-11H-pyrrolo[1,2-c][1.3]ben-
zodiazepin-11-one. The latter underwent desulfurisation with Raney nickel followed by reduction with
lithium aluminium hydride in the presence of aluminium trichloride and the resulting 6,11-dihydro-5H-
pyrrolo[1,2-c][1.3]-benzodiazepine acylated with 2-chloro-4-nitrobenzoyl chloride to afford 6-(2-chloro-4-
nitrobenzoyl)-6,11-dihydro-5H-pyrrolo[1,2-c][1.3]benzodiazepine. The nitro group in the latter compound
was reduced with zinc and ammonium chloride to give the corresponding aniline derivative which was then
acylated with 2-methyl-5-fluorobenzoyl chloride to provide the final product.
Received 9 January 2011
Received in revised form 4 July 2011
Accepted 26 July 2011
Available online 31 July 2011
Keywords:
Pyrrole
Reduction
Desulfurisation
Cyclisation
Ó 2011 Elsevier Ltd. All rights reserved.
Pyrrolobenzodiazepine
1. Introduction
develop vasopressin V2 receptor antagonists for the treatment of
disorders, such as congestive heart failure, hypertension, liver cir-
Pyrrolobenzodiazepines have attracted the attention of syn-
thetic chemists since the middle of the 1960s when anthramycin,
rhosis, renal disease, oedema and hyponatremia. VPA-985 is an
orally active, selective, non-peptide antagonist that blocks AVP
from binding to V2 receptors of the distal nephron and thus causing
retention of water by the kidneys. The pioneering work on VPA-985
has been undertaken by Albright and co-workers6 and developed
by Cardiokine Inc. in the U.S.A. VPA-985 is currently undergoing
phase III clinical trials that involve patients with hyponatremia
including those with concomitant heart failure.
Other efforts to discover non-peptidic, orally active V2 selective
antagonists for treating excessive renal reabsorption of water have
been exemplified by compounds, such as mozavaptan (OPC-
31260),7 a benzazepine marketed since 2006 by Otsuka Pharma-
ceutical Co. in Japan for the treatment of hyponatremia and tol-
vaptan (OPC-41061),8 also a benzazepine, developed by Otsuka
Pharmaceuticals (U.K.) Ltd. currently in phase III clinical trials for
cystic renal disease and is being filed for a licence for hyponatremia.
In 2001 SR-121463A a spiroindolinone,9 developed by Sanofi-Syn-
a
pyrrolo[2,1-c][1.4]benzodiazepine isolated from Streptomyces
rufuineus, was found to possess cytostatic and antitumour proper-
ties.1 The isolation of several related natural products, such as
tomamycin, sibiromycin, neothramycins (A and B), mazethramycin,
prothracarcin, DC-81, chicamycin, abbeymycin, porothramycins (A
and B) and sibanomycin, from other Streptomyces species, led to the
prolific synthesis of these compounds and their monomeric ana-
logues.2 Further development of this research area has been mostly
in the direction of the synthesis of pyrrolobenzodiazepine conju-
gates,3 dimers3c,4 and to a much lesser extent trimers.5 The bi-
ological importance of pyrrolo[2,1-c][1.4]benzodiazepines extends
to compounds, such as VPA-985 (Lixivaptan) (Figure) an arginine
vasopressin (AVP) antagonist. AVP is a cyclic disulfide peptide
hormone, synthesised in the hypothalamus, stored and released
into the blood from the posterior pituitary. The hormone exerts its
actions through three well-defined G-protein mediated receptor
sub-types: vascular V1a, hormone releasing V1b (also known as V3
receptor) and renal V2 receptors. The V2 receptors located in the
kidneys are responsible for controlling water reabsorption. There
are, however, also extrarenal V2 or V2-like receptors that are in-
volved in vascular and clotting factor responses that may also
contribute to pathophysiological states. Thus, there is potential to
ꢀ
thelabo, had entered phase IIa clinical trials for cardiovascular in-
dications such as congestive heart failure and hypertension but
never reached the marketplace. Pyrrolo[1,2-c][1.3]benzodiazepines
are profoundly less common than pyrrolo[2,1-c][1.4]benzodiaze-
pines. The first example of this ring system was reported by Hori-
kawa and co-workers10 who prepared methyl (2Z)-(5-oxo-
1,2,3,5,6,11a-hexahydro-11H-pyrrolo[1,2-c][1.3]benzodiazepin-11-
ylidene)acetate by a five step synthetic procedure. Methyl (2E)-3-
pyrrolidin-2-ylacrylate was obtained in three steps starting from
1-tert-butyl 2-methyl pyrrolidine-1,2-dicarboxylate and methyl
(triphenylphosphoranylidene)acetate and then coupled with
* Corresponding author. Tel.: þ30 26510 08382; fax: þ30 26510 08799; e-mail
address: gvarvoun@cc.uoi.gr (G. Varvounis).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.083

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G. Rotas et al. / Tetrahedron 67 (2011) 7805e7810
2-iodobenzoic acid to give methyl (2E)-3-(1-{[(2-iodophenyl)-
amino]carbonyl}pyrrolidin-2-yl)acrylate, which underwent an
intramolecular Heck reaction to afford the product. The other two
examples in the literature were prepared by our group.11 Cyclisa-
tion of (2-isothiocyanatophenyl)(1H-pyrrol-2-yl)methanone and 2-
(2-isothiocyanatobenzyl)-1H-pyrrole with potassium carbonate in
DMF afforded 5-thioxo-5,6-dihydro-11H-pyrrolo[1,2-c][1.3]benzo-
diazepin-11-one and 6,11-dihydro-5H-pyrrolo[1,2-c][1.3]benzodi-
azepine-5-thione, respectively. Herein, we report on the synthesis
of the first structural isomer of VPA-985, pyrrolo[1,2-c][1.3]benzo-
diazepine 1 (Fig. 1).
sulfonyl)-1H-pyrrol-2-yl](1H-pyrrol-2-yl)methanone by catalytic
hydrogenation with 5% palladium-on-carbon in methanol and then,
without isolation, detosylation by addition of aqueous sodium hy-
droxide and heating to give 8 in 80% overall yield.11
Alternatively, amine 8 was prepared in three steps. Treatment of
anthranilic acid 5 and benzoyl chloride with potassium carbonate
in tetrahydrofuran afforded 2-phenyl-4H-3,1-benzooxazin-4-one 6.
Compound 6 was then treated with pyrrole, previously reacted
with ethylmagnesium chloride, at room temperature for 24 h to
afford 7 in 95% yield. Earlier, Llopard and Joule13 reported that the
same reaction stirred for 45 min and then heated under reflux for
3 h gave 7 in 81% yield. Hydrolysis of 7 by heating in methanol
containing aqueous sodium hydroxide gave amine 8 in 79% overall
yield, a significant improvement over the previous method.
The conversion of amine 8 to isothiocyanate 9 required reaction
with thiophosgene in dry toluene in the presence of excess trie-
thylamine (Scheme 2). Isothiocyanate 9, obtained in 88% yield,
underwent intramolecular addition of the in situ generated pyrrolyl
anion to the isothiocyanate group, when treated with potassium
carbonate in DMF, to afford pyrrolobenzodiazepine 10 in 90% yield.
Reductive desulfurisation of thioamides to amines using Raney
nickel has been widely used since it is a mild reducing agent acting
with high selectivity in this reaction.14 Therefore, compound 10 was
subjected to hydrogenolysis with Raney nickel in boiling ethanol
for 5 min to afford amine 11 in 66% yield. Characteristic features in
the 1H NMR of 10 in DMSO-d6 are the chemical shifts at 6.65,
7.34e7.40 and 8.41e8.42 ppm corresponding to H-2, H-1 and H-3
appearing further downfield than the respective chemical shifts of
11 in CDCl3 at 6.22, 6.77e6.80 and 7.20e7.26 ppm corresponding to
the same protons. Furthermore, the thioamide proton of 10 appears
as a broad singlet at 12.61 ppm, while the signal due to the sec-
ondary amino proton of 11 appears also as a broad singlet upfield at
5.62 ppm and the adjacent methylene group as a doublet at
5.17 ppm. Measuring the NMR of sample 11 after D2O addition re-
sults in the disappearance of the NH signal and the appearance of
a singlet in the place of the doublet at 5.17 ppm, as expected.
The next step of our synthesis involved the reduction of the
carbonyl group in 11 to a methylene group. In the first attempt, so-
dium borohydride was used in boiling propan-2-ol that caused both
reduction of the carbonyl group and ring opening of the diazepine
ring to afford 12. Further attempts to reduce 11 with sodium boro-
hydride at lower temperature using various solvents resulted in
mixtures, as evidenced by TLC. Using lithium aluminium hydride in
THF at room temperature resulted in a black oily residue that pro-
duced a streak on TLC. Finally, the appropriate strength of reducing
agent was found using a 1:3 mol ratio of lithium aluminium hydride
to aluminium(III) chloride.15 Reduction of 11 occurred in 40 min at
room temperature using dry THFas solvent to give 13 in 65% yield. In
the 1H NMR spectrum of 13 in DMSO-d6 the singlet at 4.09 ppm
corresponds to protons of 11-CH2, whereas the doublet at 5.27 ppm
and triplet at 6.40 ppm correspond to protons 5-CH2 and NH, re-
spectively. From this point on, the synthesis of 1 can be realized by
two routes (Scheme 2). The first route would require preparation of
2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]-benzoic acid from
2-chloro-4-nitrobenzoic acid and 5-fluoro-2-methylbenzoic acid.
This would entail protection of the carboxylic acid group of 2-
chloro-4-nitrobenzoic acid as an ester group before reducing the
nitro group to an amino group, amide formation of methyl 4-amino-
2-chlorobenzoate with 5-fluoro-2-methylbenzoyl chloride, depro-
tection to give 2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]ben-
zoic acid, which would then be transformed into its acid chloride
and reacted with 13 in order to give product 1. The second route
would require the attachment of the benzene moieties, 2-chloro-4-
nitrobenzoic acid and 5-fluoro-2-methylbenzoic acid, stepwise onto
13 as depicted in Scheme 2. We chose the latter route in order to
avoid the extra protection/deprotection steps. Thus, 2-chloro-4-
Fig. 1. Biologically active VPA-985 and analogue 1.
2. Results and discussion
The route towards 1 involves seven steps starting from (2-
aminophenyl)(1H-pyrrol-2-yl)methanone 8 (Scheme 1). Amine 8
has been previously prepared in two steps by acylation of 1-[(4-
methylphenyl)sulfonyl]-1H-pyrrole 2 with 2-nitrobenzoyl chloride
and stannic chloride as catalyst, chromatographic separation of 3 in
56% yield from a mixture with its 3-isomer {1-[(4-methylphenyl)-
sulfonyl]-1H-pyrrol-3-yl}(2-nitrophenyl)methanone
4 that was
in 11% yield,12 reduction of 3 to (2-aminophenyl)[1-(toluene-4-
Scheme 1. Reagents and conditions: (i) 2-NO2C6H4COCl, ClCH2CH2Cl, SnCl4; 3 (56%), 4
(11%), (ii) (a) H2, 5% Pd/C, MeOH, rt, 8 h, (b) aq 2 M NaOH, MeOH, reflux, 5 h, 80%, (iii)
(a) Na2CO3, THF, 5 ꢀC, (b) benzoyl chloride, THF, (c) rt 48 h, (d) H2O 15 min, 90%, (iv) (a)
EtMgBr 2.8 M in THF, pyrrole, dry toluene, 3e15 ꢀC, (b) rt 30 min, (c) 6, dry THF, 15 min,
rt 16 h, reflux 5 h, (d) satd aq NH4Cl, rt 30 min, 95%, (v) (a) MeOH, aq 10 M NaOH, reflux
24 h, (b) H2O, rt 3 h, 93%.

G. Rotas et al. / Tetrahedron 67 (2011) 7805e7810
7807
H
N
preparation of 1, 5-fluoro-2-methylbenzoic acid was transformed
into 5-fluoro-2-methylbenzoyl chloride by heating in thionyl
chloride and without isolation reacted with 15 in dry methylene
chloride containing triethylamine to afford final product 1, in 61%
yield. In the 1H NMR spectrum of 1 in DMSO-d6 the amide proton
stands out as a singlet at 10.55 ppm while the 5-CH2 protons appear
as a broad singlet at 5.90 ppm. The 13C NMR spectrum of 1 in
DMSO-d6 shows two carbonyl groups that coincide at 167.73 ppm,
H
N
Cl
O
1
N
+
Cl
Me
O
F
13
00
whereas the characteristic doublet at 160.89 (JC-5 , F¼242 Hz) is due
H
N
to the C-500 coupled to the fluorine atom. Product 1 is colourless and
can be kept in the freezer for several weeks but at ambient tem-
perature it turns dark brown within a few days.
H
N
Cl
MeO2C
O
Cl
HO2C
O
Me
Me
F
+
3. Conclusion
F
In summary, we have described a facile seven-step synthetic
route to a novel pyrrolo[1,2-c][1.3]benzodiazepine analogue of
VPA-985 from (2-aminophenyl)(1H-pyrrol-2-yl)methanone. The
synthetic steps involve amine to isothiocyanate transformation,
intramolecular pyrrolyl anion addition to isothiocyanate leading to
Cl
O
Me
Cl
NH2
a
thioxopyrrolobenzodiazepinone, reductive desulfurisation of
F
MeO2C
thioamide to amine, reduction of ketone to methylene, amide for-
mation by acylation of a secondary amine, reduction of nitro to
amino and amide formation by acylation of a primary amine.
H
N
S
7
NCS
ii
i
8
5
3
N
8
9
11
4. Experimental
4.1. General
N
H
2
10
1
O
O
10
9
Melting points were taken on a Bchi 510 apparatus and are
uncorrected. Infrared spectra were recorded on a PerkineElmer 257
spectrometer, as Nujol mulls between sodium chloride discs. Ele-
mental analyses were performed on a Carlo Erba 1106 elemental
analyser. Nuclear magnetic resonance spectra were measured on
Brker Avance 250 or 400 spectrometers, using tetramethylsilane as
internal standard. Mass spectra were obtained by use of JEOL JMS-
AX 505W (low and high resolution) and Bruker Apex III (high res-
olution) instruments. Analytical TLC was carried out on Fluka silica
gel 60 F254. Preparative flash chromatography was carried out using
Merck 9385 silica gel. Solvents and reagents were used as received
from the manufacturers except for dichloromethane, ethyl acetate,
hexane and methanol that were purified and dried according to
recommended procedures.16
NO2
iii
O
H
N
H
N
Cl
N
vi
v
N
N
N
O
14
13
11
vii
NH2
iv
O
NHMe
Cl
N
viii
4.1.1. N-[2-(1H-Pyrrol-2-ylcarbonyl)phenyl]benzamide (7). To a stir-
red solution of ethylmagnesium chloride (97.5 mL, 0.27 mol, 2.8 M
in THF) in dry THF (200 mL) at 3 ꢀC under argon was added drop-
wise freshly distilled pyrrole (20.68 mL, 0.30 mol) in dry toluene
(20 mL) at a rate so that the temperature did not exceed 15 ꢀC. The
reaction mixture was stirred at room temperature for 30 min fol-
lowed by slow addition of 2-phenyl-4H-3,1-benzoxazin-4-one 613
(29 g, 0.13 mol) in dry THF (30 mL), left stirring for 16 h and then
heated for 5 h. Ammonium chloride solution (70 mL, satd aq) was
slowly added at room temperature, stirred for 30 min, Na2SO4
(75 g) added, stirred for 45 min and then filtered. The residue was
washed with dry THF and the filtrate evaporated to dryness. The
viscous oil was purified by dissolving in hot toluene, cooling and
then adding 50% v/v hexane. The title compound 7 (35.88 g, 95%)
was collected as light-green microcrystals; mp 141e142 ꢀC (lit.13
185 ꢀC); Rf (25% EtOAc/hexane) 0.34; vmax (Nujol) 3320, 3272,
1
N
N
H
12
15
Scheme 2. Reagents and conditions: (i) (a) 8, Et3N, dry toluene, 10 ꢀC, (b) CSCl2, dry
toluene, rt 1 h, 88%, (ii) K2CO3, dry DMF, rt 3 h, 88%, (iii) Raney nickel, absolute EtOH,
reflux, 5 min, 66%, (iv) NaBH4, IPA, reflux 18 h, 46%, (v) LiAlH4, AlCl3, dry THF, 65%, (vi)
(a) Et3N, CH2Cl2, 5 ꢀC, (b) 2-chloro-4-nitrobenzoyl chloride, CH2Cl2, rt 30 min, 84%, (vii)
Zn powder, NH4Cl, EtOH, H2O, rt 18 h, 98%, (viii) (a) Et3N, CH2Cl2, 5 ꢀC, (b) 5-fluoro-2-
methylbenzoyl chloride, CH2Cl2, rt 18 h, 84%.
nitrobenzoic acid was converted into 2-chloro-4-nitrobenzoyl
chloride with the use of thionyl chloride and without isolation
reacted with amine 13 in the presence of triethylamine. The yield of
compound 14 was optimized to 84% when 3 equiv of 2-chloro-4-
nitrobenzoic acid were used. Compound 14 is unstable but can be
stored for 1 week in the freezer. In the 1H NMR spectrum of 14 in
CDCl3 the 5-CH2 protons appear as a broad singlet at 5.91 ppm
probably due to its reduced mobility conferred by the adjacent
amide group.
3136, 1659, 1616 cmꢁ1
; dH (250 MHz, DMSO-d6) 6.29 (1H, d, J 2 Hz,
H-4), 6.79 (1H, s, H-3), 7.26e7.32 (2H, m, H-5, H-50), 7.50e7.65 (4H,
m, H-40, H-300, H-400, H-500), 7.85e7.92 (3H, m, H-30, H-200, H-600), 8.37
(1H, d, J 8.2 Hz, H-60), 11.21 (1H, s, NHCO), 12.22 (1H, br s, NH,
pyrrole); dC (63 MHz, DMSO-d6) 110.84, 120.59, 122.40, 123.67,
127.28 (3C), 127.41, 128.91 (2C), 131.11, 131.19, 132.13, 132.38, 134.62,
The reduction of 14 worked best with zinc and ammonium
chloride and gave amine 15 in 98% yield. In the last step towards the

7808
G. Rotas et al. / Tetrahedron 67 (2011) 7805e7810
138.20, 164.85, 184.90; m/z (EI) 290.1 (Mþ, 93), 289.1 (10), 224.1
(10), 196.1 (29), 185.1 (40), 169 (47), 105 (100), 77 (88), 67 (14%);
HRMS (EI): Mþ, found 290.1055. C18H14N2O2 requires 290.1055.
c][1.3]benzodiazepin-11-one 10 (4 g, 17.54 mmol) in EtOH (100 mL),
was added freshly prepared Raney nickel catalyst14 (10 mL catalyst
in EtOH) and the reaction mixture heated to reflux for 5 min. The
hot mixture was filtered over CeliteÒ, the filter aid washed with
CH2Cl2 (50 mL) and the combined organic filtrates evaporated
under reduced pressure to afford a residue that was purified by
flash chromatography (33%, 50% ethyl acetate/hexane) to give the
title compound 11 (2.30 g, 66%) as yellow microcrystals (ethyl ace-
tate/hexane); mp 100.5e102.5 ꢀC; Rf (50% EtOAc/hexane) 0.12; vmax
4.1.2. (2-Aminophenyl)(1H-pyrrol-2-yl)methanone (8). A mixture of
N-[2-(1H-pyrrol-2-ylcarbonyl)phenyl]benzamide 7 (30 g, 0.10 mol),
methanol (200 mL) and aqueous 10 M NaOH (50 mL) was heated to
reflux for 24 h. To the hot solution water (140 mL) was added, stirred
for 3 h at room temperature, and the precipitate filtered off and
washed with cold water. The residue was dried under vacuum and
crystallised from toluene to give the title compound8 (17.84 g, 93%)as
off-white microcrystals;mp 125e126 ꢀC; [found:C, 70.94; H, 5.40; N,
15.07. C11H10N2O requires C, 70.95; H, 5.41; N,15.04%]; Rf (25% EtOAc/
(Nujol) 3362, 1610 cmꢁ1
; dH (250 MHz, CDCl3) 5.17 (2H, d, J 4.4 Hz,
CH2-5), 5.62 (1H, br s, NH), 6.22 (1H, s, H-2), 6.77e6.80 (2H, m, H-1,
H-7), 6.97 (1H, t, J 7.4 Hz, H-9), 7.20e7.26 (1H, m, H-3), 7.32 (1H, t, J
7.2 Hz, H-8), 8.39 (1H, d, J 7.9 Hz, H-10); dC (63 MHz, CDCl3) 60.14,
109.78, 118.90, 119.18, 120.52, 123.52, 124.72, 132.25, 133.71, 134.95,
148.87, 178.65; m/z (EI) 198 (100 Mþ), 181 (41), 169 (37%); HRMS
(FAB) MHþ, found 199.0871. C18H15N2O2 requires 199.0870.
hexane) 0.10; vmax (Nujol) 3410, 3270, 1630 cmꢁ1
; dH (250 MHz,
CDCl3) 5.55 (2H, s, NH2), 6.30 (1H, dd, J 3.9, 2.6 Hz, H-4), 6.68e6.73
(2H, m, H-30, H-50), 6.84 (1H, dd, J 3.9,1.4 Hz, H-3), 7.07 (1H, dd, J 2.6,
1.4 Hz, H-5), 7.26 (1H, ddd, J 8.2, 7.1, 1.8 Hz, H-40), 7.85 (1H, dd, J 8.4,
1.8 Hz, H-60), 9.89 (1H, br s, NH); dC (63 MHz, CDCl3) 110.74, 116.17,
116.85, 118.96, 119.85, 124.58, 131.74, 132.07, 133.10, 149.23, 186.08;
m/z (EI) 187 (100 MHþ), 169 (82), 152 (18), 92 (58), 66 (11%).
4.1.6. N-Methyl-2-(1H-pyrrol-2-ylmethyl)aniline (12). A mixture of
5,6-dihydro-11H-pyrrolo[1,2-c][1.3]benzodiazepin-11-one
11
(70 mg, 0.35 mmol) and NaBH4 (34 mg, 0.88 mmol) in propan-2-ol
(7 mL) was heated to reflux for 18 h. The solvent was evaporated
under reduced pressure, water (30 mL) was added to the residue
and then extracted with CH2Cl2 (3ꢂ10 mL). The combined organic
extracts were dried (Na2SO4) and evaporated under reduced pres-
sure. The oily residue was purified by flash chromatography (11%
ethyl acetate/hexane) to afford the title compound 12 (30 mg, 46%)
as a brown oil; [found: C, 77.36; H, 7.55; N, 15.08. C12H14N2 requires
C, 77.38; H, 7.58; N, 15.04%]; Rf (50% CH2Cl2/hexane) 0.13; vmax
4.1.3. (2-Isothiocyanatophenyl)(1H-pyrrol-2-yl)methanone (9). To
a stirred solution of (2-aminophenyl)(1H-pyrrol-2-yl)methanone 8
(6 g, 0.04 mol) in dry toluene (250 mL) under an atmosphere of
argon was added triethylamine (7.26 mL, 0.1 mol) and the mixture
cooled to 10 ꢀC. A solution of thiophosgene (3.2 mL, 0.04 mol) in dry
toluene (50 mL) was added dropwise, the reaction mixture stirred
at room temperature for 1 h, poured into cold water (300 mL) and
neutralised with aqueous 10% NaHCO3. The organic layer was
separated and evaporated to dryness under reduced pressure. The
residue was dissolved in dichloromethane (80 mL) and the aqueous
layer is extracted with CH2Cl2 (3ꢂ50 mL). The combined organic
extracts were dried (Na2SO4), filtered and the solvent evaporated
under reduced pressure to give a residue. Crystallisation from ethyl
acetate gave the title compound 9 (6.24 g, 88%) as yellowish-brown
microcrystals; mp 103e104 ꢀC; [found: C, 63.12; H, 3.50; N, 12.31.
C12H8N2OS requires C, 63.14; H, 3.53; N, 12.27%]; Rf (16.5% EtOAc/
(Nujol) 3389, 3312 cmꢁ1
; dH (400 MHz, CDCl3) 2.77 (3H, s, CH3), 3.82
(1H, br s, NHCH3), 3.86 (2H, s, CH2), 6.02e6.03 (1H, m, H-3),
6.11e6.13 (1H, m, H-4), 6.61e6.63 (1H, m, H-5), 6.64 (1H, dd, J 8.1,
1.1 Hz, H-30), 6.72 (1H, dd, J 7.1, 1.1 Hz, H-50), 7.07 (1H, dd, J 7.3,
1.3 Hz, H-60), 7.21 (1H, dd, J 7.7, 1.4 Hz, H-40), 7.95 (1H, br s, NH
pyrrole); dC (100 MHz, CDCl3) 30.71, 30.90, 106.14, 108.35, 110.29,
117.16, 117.22, 123.29, 128.24, 129.11, 130.08, 147.55; m/z (EI) 186
(100 Mþ), 171 (19), 154 (12) 144 (26), 131 (14), 118 (19), 91 (10%).
hexane) 0.21; vmax (Nujol) 3280, 2120, 1620 cmꢁ1
;
dH (250 MHz,
4.1.7. 6,11-Dihydro-5H-pyrrolo[1,2-c][1.3]benzodiazepine
(13). To
CDCl3) 6.29 (1H, dd, J 4.0, 2.4 Hz, H-4), 6.66 (1H, dd, J 4.0, 2.9, 1.4 Hz,
H-3), 7.21 (1H, t, J 3.4 Hz, H-5), 7.32e7.37 (2H, m, H-30, H-50), 7.48
(1H, dd, J 9.2, 8.3, 1.5 Hz, H-40), 7.61 (1H, dd, J 8.3, 1.5 Hz, H-60), 11.00
(1H, br s, NH); dC (63 MHz, CDCl3) 111.06, 120.86, 126.62, 127.24
(2C), 129.10, 129.57, 129.72, 131.26, 131.34, 135.47, 182.16; m/z (EI)
228 (100 Mþ), 200 (7), 168 (44), 134 (13), 94 (47%).
a suspension of LiAlH4 (621 mg, 15.15 mmol) in dry THF (15 mL)
under argon, was added a solution of AlCl3 (4.05 g, 30.30 mmol) in
dry THF (20 mL) and the resulting mixture stirred at room tem-
perature for 15 min. A solution of 5,6-dihydro-11H-pyrrolo[1,2-c]-
[1.3]benzodiazepin-11-one 11 (1.5 g, 7.56 mmol) in dry THF (20 mL)
was added dropwise, the reaction mixture stirred at room tem-
perature for 1 h, cooled, poured into ice-water (100 mL) and then
basified with an aqueous 10% w/v solution of NaHCO3 to pH 8e8.5.
The mixture was extracted with CH2Cl2 (4ꢂ25 mL) and the com-
bined organic extracts dried (Na2SO4) and evaporated under re-
duced pressure to give a residue, which was purified by flash
chromatography (50% CH2Cl2/hexane) to afford the title compound
13 (0.90 g, 65%) as colourless microcrystals (ethyl acetate/hexane);
mp 140e141 ꢀC; Rf (50% CH2Cl2/hexane) 0.33; vmax (Nujol)
4.1.4. 5-Thioxo-5,6-dihydro-11H-pyrrolo[1,2-c][1.3]benzodiazepin-
11-one (10). To a stirred solution of (2-isothiocyanatophenyl)(1H-
pyrrol-2-yl)methanone 9 (6 g, 26.28 mmol) in dry DMF (60 mL)
under argon, K2CO3 (7.26 g, 52.56 mmol) was added and the
resulting mixture was stirred at room temperature for 2.5 h. The
mixture was poured into water (300 mL), neutralised with aqueous
2 M HCl, the precipitate filtered, washed with water and dried
under vacuum. Crystallisation from toluene gave the title compound
10 (5.26 g, 88%) as pale-yellow microcrystals; mp 189 ꢀC (dec);
[found: C, 63.10; H, 3.50; N, 12.31. C12H8N2OS requires C, 63.14; H,
3.53; N, 12.27%]; Rf (25% EtOAc/hexane) 0.24; vmax (Nujol) 3236,
3389 cmꢁ1
; dH (400 MHz, DMSO-d6) 4.09 (2H, s, CH2-11), 5.27 (2H,
d, J 6.1 Hz, CH2-5), 5.81e5.92 (1H, m, H-2), 5.84 (1H, t, J 3.0, Hz, H-1),
6.40 (1H, t, J 6.1 Hz, NH), 6.49e6.54 (2H, m, H-7, H-9), 6.74 (1H, dd, J
2.6, 1.8 Hz, H-3), 6.90 (1H, dd, J 7.6, 1.5 Hz, H-8), 6.95 (1H, dd, J 7.5,
1.5 Hz, H-10); dC (100 MHz, DMSO-d6) 31.74, 55.89, 105.39, 105.86,
117.74 (2C),119.03, 122.14, 127.40, 131.16,132.81, 146.18; m/z (EI) 184
(100 Mþ), 167 (21), 156 (21) 128 (8), 117 (13), 91 (11), 77 (9%); HRMS
(ESI): MNaþ, found 207.0882. C12H12N2Na requires 207.0893.
3188, 3113, 1608 cmꢁ1
; dH (250 MHz, DMSO-d6) 6.65 (1H, t, J 3.3 Hz,
H-2), 7.34e7.40 (2H, m, H-1, H-9), 7.58 (1H, d, J 7.9 Hz, H-7), 7.67
(1H, t, J 7.6 Hz, H-8), 7.97 (1H, d, J 7.9 Hz, H-10), 8.41e8.42 (1H, m, H-
3), 12.61 (1H, br s, NH); dC (63 MHz, DMSO-d6) 119.36, 127.13,
128.58, 131.15, 132.10, 134.56, 138.26, 139.65, 139.98, 140.68, 180.86,
182.10; m/z (EI) 228 (100 Mþ), 200 (10),195 (2),185 (3),170 (10),168
(51), 134 (15), 100 (11), 94 (35%).
4.1.8. 6-(2-Chloro-4-nitrobenzoyl)-6,11-dihydro-5H-pyrrolo[1,2-c]
[1.3]benzodiazepine (14). 2-Chloro-4-nitrobenzoic acid (2.62 g,
13.02 mmol) was heated in thionyl chloride (10 mL) for 2 h. The
solvent was distilled off and to the oily residue dry CH2Cl2 (5 mL)
was added and the solvents removed under reduced pressure. Dry
4.1.5. 5,6-Dihydro-11H-pyrrolo[1,2-c][1.3]benzodiazepin-11-one
(11). To a stirred solution of 5-thioxo-5,6-dihydro-11H-pyrrolo[1,2-

G. Rotas et al. / Tetrahedron 67 (2011) 7805e7810
7809
CH2Cl2 (5 mL) was added to the oily residue of 2-chloro-4-
nitrobenzoyl chloride and kept under argon. To a stirred mixture
of 11-dihydro-5H-pyrrolo[1,2-c][1.3]benzodiazepine 13 (800 mg,
4.34 mmol) and Et3N (1.8 mL, 13.02 mmol) in dry CH2Cl2 (20 mL)
under argon at 5 ꢀC, was added dropwise the solution of 2-chloro-
4-nitrobenzoyl chloride in CH2Cl2 described above. The reaction
mixture was stirred for 30 min at room temperature, cooled and
then a saturated aqueous solution of NaHCO3 (60 mL) was added
slowly. The aqueous suspension was extracted with CH2Cl2
(3ꢂ15 mL) and the combined organic extracts were washed with
brine (30 mL), dried (Na2SO4), filtered and the solvent evaporated
under vacuo to afford a residue that was purified by flash chro-
matography (16.5% ethyl acetate/hexane) to give the title compound
14 (1.34 g, 84%) as colourless microcrystals (ethyl acetate hexane);
mp 75e77 ꢀC; Rf (20% EtOAc/hexane) 0.20; vmax (Nujol) 1666, 1523,
a saturated aqueous solution of NaHCO3 (60 mL) was added slowly.
The aqueous suspension was extracted with CH2Cl2 (3ꢂ15 mL) and
the combined organic extracts were washed with brine (30 mL),
dried (Na2SO4), filtered and the solvent evaporated under vacuo to
afford a residue that was purified by flash chromatography (20%
ethyl acetate/hexane) to give the title compound 1 (600 mg, 84%) as
colourless microcrystals (ethyl acetate hexane); mp 130 ꢀC; Rf (50%
EtOAc/hexane) 0.38; vmax (Nujol) 3291, 1662, 1655 cmꢁ1
; dH
(400 MHz, DMSO-d6) 2.30 (3H, s, 3H, CH3), 4.26 (2H, s, CH2-11), 5.90
(2H, br s, CH2-5), 5.97 (1H, s, H-2), 6.00 (1H, s, H-1), 6.82 (1H, s, H-3),
7.04e7.46 (9H, m, H-7, H-8, H-9, H-10, H-50, H-60, H-300, H-400, H-600),
7.92 (1H, s, H-20), 10.55 (1H, s, NH); dH (100 MHz, DMSO-d6) 19.44,
32.76, 59.56, 108.28, 108.32, 115.22 (d, J 22 Hz), 118.64 (d, J 20 Hz),
118.47, 120.53, 121.21, 128.04 (2C), 128.47, 129.40, 129.48, 130.44,
130.95, 131.10, 132.55, 133.48 (d, J 8 Hz), 136.85, 138.69 (d, J 6 Hz),
141.43, 141.63, 160.89 (d, J 242 Hz, C-500), 167.73 (2C); dF (376 MHz,
DMSO-d6) ꢁ117.05 (s, 1F, F-500); m/z (EI) 475 (31 MHHþ), 473 (78
Mþ), 438 (5), 292 (34), 290 (93), 261 (4), 257 (5), 183 (93), 167 (12),
154 (11), 137 (100), 109 (32%); HRMS (ESI): MNaþ, found 496.1204.
C27H21FClN3NaO2 requires 496.1199.
1347 cmꢁ1
; dH (250 MHz, CDCl3) 4.27 (2H, s, CH2-11), 5.91 (2H, br s,
CH2-5), 6.07 (1H, s, H-2), 6.12 (1H, t, J 3.1 Hz, H-1), 6.75 (1H, t, J
2.5 Hz, H-3), 6.97e7.02 (2H, m, H-9, H-10), 7.11e7.19 (2H, m, H-7, H-
60), 7.27 (1H, d, J 7.5 Hz, H-7), 7.90 (1H, dd, J 8.4, 2.0 Hz, H-50), 8.14
(1H, d, J 2.0 Hz, H-30); dC (63 MHz, CDCl3) 32.79, 58.84, 108.08,
108.33, 118.45, 120.88, 121.49, 124.94, 126.95, 127.19, 127.58, 128.25,
128.86,130.13,134.92,139.44,141.35,148.05,165.76; m/z (ESI) 390.0
(MNaþ); HRMS (ESI): MNaþ, found 390.0628. C19H14ClN3NaO3 re-
quires 390.0618.
Acknowledgements
This research was funded by the programme ‘Heraklitos’ of the
Operational Programme for Education and Initial Vocational
Training of the Hellenic Ministry of Education under the third
Community Support Framework and the European Social Fund (to
G.R.) and partly by a PENED Grant (91ED102) (to A.K.) from the
General Secretariat of Research and Technology, Athens. We thank
Professor N. Hadjiliadis of the University of Ioannina for elemental
analyses. We appreciate the use of NMR spectrometry facilities
funded by the Network of Research Supporting Laboratories of the
University of Ioannina and thank Dr. V. Exarchou for measure-
ments. We are particularly grateful to A. Cakebread, R. Tye and M.
Cocksedge for mass spectra, and, J. Cobb for NMR spectra, obtained
on machines funded by the University of London Intercollegiate
Research Services Scheme.
4.1.9. 3-Chloro-4-(5H-pyrrolo[1,2-c][1.3]benzodiazepin-6(11H)-yl-
carbonyl)aniline (15). To
a stirred solution of 6-(2-chloro-4-
nitrobenzoyl)-6,11-dihydro-5H-pyrrolo[1,2-c][1.3]benzodiazepine
14 (1.0 g, 2.72 mmol) in ethanol (40 mL) was added zinc powder
(3.2 g, 48.96 mmol) and an ammonium chloride solution (15 mL.
1.31 g, 24.48 mmol). The resulting mixture was stirred at room
temperature for 18 h, filtered over CeliteÒ, the filter aid washed
with hot ethyl acetate (25 mL) and the combined filtrates evapo-
rated under reduced pressure to leave an aqueous suspension to
which water (90 mL) was added and then extracted with ethyl
acetate (4ꢂ20 mL). The combined organic extracts were dried
(Na2SO4), filtered and the solvent evaporated under vacuo to afford
a residue that was purified by flash chromatography (33% ethyl
acetate/hexane) to give the title compound 15 (896 mg, 98%) as pale-
yellow microcrystals (ethyl acetate/hexane); [found: C, 67.54; H,
4.74; N, 12.48. C19H16ClN3O requires C, 67.56; H, 4.77; N, 12.44%];
mp 182 ꢀC (dec); Rf (50% EtOAc/hexane) 0.23; vmax (Nujol) 3437,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.07.083. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
3357, 1656 cmꢁ1
; dH (250 MHz, CDCl3) 4.17 (2H, s, CH2-11), 5.63 (2H,
s, NH), 5.70 (1H, br s, CH2-5), 5.93e5.97 (2H, m, H-1, H-2), 6.31 (1H,
d, J 8.2 Hz, H-30), 6.53 (1H, s, H-50), 6.69 (1H, s, H-3), 6.87 (1H, d, J
8.2 Hz, H-20), 7.11e7.19 (3H, m, H-8, H-9, H-10), 7.34 (1H, d, J 7.0 Hz,
H-7); dH (63 MHz, DMSO-d6) 31.82, 59.90, 107.30, 107.48, 111.75,
113.39, 120.00, 121.28, 127.28, 127.52, 127.86, 128.07, 129.19, 129.37,
130.95, 135.89, 141.29, 151.02, 168.07; m/z (EI) 339 (15 MHHþ), 337
(36 Mþ), 183 (24), 167 (6), 156 (33), 154 (100), 128 (6), 126 (10), 99
(7), 90 (7%); HRMS (ESI): MNaþ, found 360.0843. C19H16ClN3NaO
requires 360.0877.
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