An expedient route to aromatic pyrrolo[2,1-c][1,4]benzodiazepines and a study of their reactivity

Article abstract of DOI:10.1016/S0040-4039(01)00957-1

2-Hydroxypyrrolo[2,1-c][1,4]benzodiazepines were aromatised in refluxing thionyl chloride into 11-chloropyrrolo[2,1-c][1,4]benzodiazepines in high yield. This aromatic system is doubly reactive towards nucleophiles leading to rearranged products such as i

Full text of DOI:10.1016/S0040-4039(01)00957-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5183–5185
An expedient route to aromatic pyrrolo[2,1-c][1,4]benzodiazepines
and a study of their reactivity
Fre´de´ric Fabis, Jana Sopkova-de Oliveira Santos, Sandrine Fouchet-Jolivet and Sylvain Rault*
Centre d’Etudes et de Recherche sur le Me´dicament de Normandie, UFR des Sciences Pharmaceutiques, Universite´ de Caen,
5 rue Vaube´nard, 14032 Caen Cedex, France
Received 5 June 2001
Abstract—2-Hydroxypyrrolo[2,1-c][1,4]benzodiazepines were aromatised in refluxing thionyl chloride into 11-chloropyrrolo[2,1-c]-
[1,4]benzodiazepines in high yield. This aromatic system is doubly reactive towards nucleophiles leading to rearranged products
such as iminobenzoxazines and quinazolines. © 2001 Elsevier Science Ltd. All rights reserved.
In the course of our work aiming to develop new
heterocyclic systems usable in the field of medicinal
chemistry, we have already described several rearrange-
ments in the pyrrolo[2,1-c][1,4]benzodiazepine series.1–3
We also shown that heating of 2-hydroxypyrrolo[2,1-c]-
[1,4]benzodiazepine 1a in POCl3 in the presence of
pyridine led to a complex mixture of rearranged and
aromatic products from which we could isolate the
aromatic 11-chloropyrrolo[2,1-c][1,4]benzodiazepine 2a
(Fig. 1).4
Compound 2a became interesting because the chlorine
atom on C11 could reinforce its electrophilic character
and enhance its ability to react with nucleophiles, whilst
on the other hand it could also act as a scaffold for the
preparation of numerous tricyclic derivatives which
would have structures closely related to antipsychotic
drugs. So we investigated the efficient synthesis of 2a by
the use of thionyl chloride in the presence of one
equivalent of pyridine (reflux, 2 h), which led directly to
the aromatic structure 2a (70% yield, Scheme 1). The
reaction was generalised to the easily available 2-
hydroxypyrrolo[2,1-c][1,4]benzodiazepines differently
substituted on the benzene ring 1b–d7,8 (2b, 65%; 2c,
70%; 2d, 62%; Scheme 1). Moreover, we were able to
determine the crystallographic data of 2a.9
We were very interested in 2a because its chloroimine
moiety in the N10–C11 position is similar, in our mind,
to the imine or carbinolamine equivalent found in a
group of antitumor antibiotics such as anthramycin,
tomaymycin, DC-81, neothramycins A and B and
chicamycin.5 In these structures, the N10–C11 imine
moiety and the S configuration at the chiral C11a posi-
tion are required for DNA interaction.6 This interac-
tion proceeds via the formation of an aminal covalent
bond between the exocyclic C2-amino group of a gua-
nine and the N10–C11 imine functionality (Fig. 2);
however, the pyrrolo[2,1-c][1,4]benzodiazepine system
in which the pyrrole ring is fully unsaturated was
reported as having little interest from a biological
standpoint owing to the unreactivity of the imine dou-
ble bond toward nucleophiles5 (Fig. 3).
Figure 1.
Keywords: pyrrolo[2,1-c][1,4]benzodiazepine; aromatisation; thionyl
chloride; iminobenzoxazine; quinazoline.
* Corresponding author. Tel.: 33-2-31934169; fax: 33-2-31931188;
e-mail: rault@pharmacie.unicaen.fr
Figure 2.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00957-1

5184
F. Fabis et al. / Tetrahedron Letters 42 (2001) 5183–5185
exposed the dilactam 3 to different nucleophiles. As
for 2a, 3 opened under alkaline conditions to give the
anthranilic derivative 4 (Scheme 2). The reaction of 3
with ammonia, methylamine or sodium methoxide
led, respectively, to anthranilamides 5 and methyl
anthranilate 6 (Scheme 2). This particular reactivity
confirms the results of Carey who reported the open-
ing of the diazepine ring of 3 by treatment with
lithium aluminium hydride to form the aldehyde 710
(Scheme 2).
Figure 3.
The reaction of 2a with amines appeared to be more
complex since rearranged products were obtained.
Ammonia led to an anthranilonitrile derivative 8,
methylamine to the 4-methyliminobenzoxazine 9,
hydrazine to the 3-aminoquinazolin-4-one 1011 and
dimethylamine to the disubstituted product 11
(Scheme 3).
These structures are the evidence of a double reactiv-
ity of the aromatic pyrrolo[2,1-c][1,4]benzodiazepine
2a at both the N4–C5 carbonylpyrrole bond and the
N10–C11 chloroimine moiety. This original and readily
available method to synthesise aromatic pyrrolo[2,1-c]-
[1,4]benzodiazepines will permit us to study further
the reactivity of this system and the results will be
published in due course.
Scheme 1.
Exposed to air moisture for several days, compound
2a hydrolysed to give the dilactam 3. The synthesis of
3 was reported before by Carey from condensation of
isatoic anhydride and the potassium salt of pyrrole in
24% yield.10 We first tried to hydrolyse the imidoyl
chloride moiety of 2a under basic conditions (KOH
2N, acetone). After acidification we obtained the acid
411 in 95% yield (Scheme 2). However, in acidic con-
ditions (HCl 6N) 2a seemed to be much more stable
and the hydrolysis of the imidoyl chloride succeeded
to give the dilactam 3 in 86% yield (Scheme 2). Com-
pound 2a appeared to be very sensitive to nucleo-
philic attack at the N10–C11 chloroimine moiety as we
expected, but also in an unexpected way at the car-
bonylꢀpyrrole bond. To confirm this reactivity, we
Typical experimental procedure for aromatisation: to
a solution of 22 mmol (1.75 ml) of pyridine in 150 ml
of thionyl chloride, 22 mmol (5 g) of 2-hydroxy-
pyrrolobenzodiazepine 1a were added portionwise.
The solution was then refluxed for 2 h and thionyl
chloride was evaporated under reduced pressure. The
residue was triturated in crushed ice and the resulting
solid was filtrated and washed with water and a satu-
rated sodium hydrogencarbonate solution. The solid
was then dissolved in boiling cyclohexane, treated
with charcoal and filtered. The chloroimine 2a crys-
tallised as a yellow solid on cooling.
Scheme 2.

F. Fabis et al. / Tetrahedron Letters 42 (2001) 5183–5185
5185
Scheme 3.
References
[1,4]benzodiazepine (PBD) Antitumor Antibiotics.
Molecular Aspects of Anticancer Drug–DNA Interactions.
The Macmillan Press Ltd: London, 1993; pp. 54–88.
7. Reed, J. N.; Snieckus, V. Tetrahedron Lett. 1984, 25,
5505–5508.
8. Pena, M. R.; Stille, J. K. Tetrahedron Lett. 1987, 28,
6573–6576.
9. Suitable crystals of 2a were obtained by slow evaporation
from cyclohexane at room temperature.
1. Hinschberger, A.; Gillard, A. C.; Bureau, I.; Rault, S.
Tetrahedron 2000, 56, 1361–1367.
2. Jolivet-Fouchet, S.; Fabis, F.; Bovy, P.; Ochsenbein, P.;
Rault, S. Tetrahedron Lett. 1998, 39, 819–820.
3. Jolivet-Fouchet, S.; Fabis, F.; Bovy, P.; Ochsenbein, P.;
Rault, S. Heterocycle 1999, 51, 1257–1276.
4. Gillard, A. C.; Fabis, F.; Jolivet-Fouchet, S.; Rault, S.
Tetrahedron Lett. 1997, 38, 2271–2274.
5. Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94,
433–465.
10. Carey, F. A.; Giuliano, R. M. J. Org. Chem. 1981, 46,
1366–1371.
11. Looney-Dean, V.; Lindamood, B. S.; Papadopoulos, E.
P. Synthesis 1984, 68–71.
6. Thurston, D. E. Advances in the Study of Pyrrolo[2,1-c]-
.