Facile reduction of aromatic nitro/azido functionality on solid support employing Al/NiCl2·6H2O and Al/NH4Cl: Synthesis of pyrrolo[2,1-c][1,4]benzodiazepines

Article abstract of DOI:10.1016/S0040-4039(03)01049-9

An efficient and mild method for the reduction of aromatic nitro and azido groups on solid support using Al/NiCl₂·6H₂O and Al/NH₄Cl is described. This solid phase reduction technique has been applied towards the synthesis

Full text of DOI:10.1016/S0040-4039(03)01049-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4741–4745
Facile reduction of aromatic nitro/azido functionality on solid
support employing Al/NiCl2·6H2O and Al/NH4Cl: synthesis of
pyrrolo[2,1-c][1,4]benzodiazepines
Ahmed Kamal,* K. Laxma Reddy, V. Devaiah and G. Suresh Kumar Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 11 March 2003; revised 17 April 2003; accepted 17 April 2003
Abstract—An efficient and mild method for the reduction of aromatic nitro and azido groups on solid support using
Al/NiCl2·6H2O and Al/NH4Cl is described. This solid phase reduction technique has been applied towards the synthesis of DNA
binding pyrrolo[2,1-c][1,4]benzodiazepine antitumour antibiotics. © 2003 Published by Elsevier Science Ltd.
The preparation of small molecules on solid phase is
emerging as an expedient method and is being utilized
towards generating compounds for screening against
biological systems, and enhance the drug discovery
effort.1 In this connection, the development of new
solid-phase methodologies is an essential component
for increasing the range of compounds that could be
accessible by this approach. The reduction of nitro
compounds to amines2 is a very useful synthetic trans-
formation, for which a vast array of reagents is known
in solution phase. However, relatively few reagents are
known for this synthetically and industrially important
reaction on a solid support. Moreover, a large number
of solution phase methods are not suitable for applica-
tion to solid phase organic chemistry. The most com-
mon methods presently in use for the reduction of solid
phase bound nitro and azido groups utilizes tin(II)
chloride,3 phosphines for azido groups4 and borohy-
dride/copper salts for nitro groups.5 In spite of the
advantages of tin reduction there are instances in the
literature where substantial quantities of tin by-prod-
ucts remain bound within the resin matrix and are
liberated upon acidic cleavage of the desired product.
Furthermore, most of the cell lines biologically screened
have proven intolerant to tin at these levels. Attempts
to wash away any residual tin remaining within the
resin have only been partly successful.6
produced by various Streptomyces species. The cyto-
toxic and antitumour effects of these compounds are
believed to arise from modification of DNA, which
leads to inhibition of nucleic acid synthesis and produc-
tion of excision-dependent single and double strand
breaks in cellular DNA. These antibiotics bind selec-
tively in the minor groove of DNA via a covalent
aminal bond between the electrophilic C11-position
of the PBD and the nucleophilic C2-amino group of
the guanine base, resulting in the observed biological
activity. Anthramycin, tomaymycin, neothramycin,
chicamycin, abbeymycin, DC-81 and its dimers are
well-known examples of PBDs. Recently, PBD imines
have been used in the development of gene-targeting
agents with the potential to down-regulate genes of
therapeutic interest. Among the well known methods
for the synthesis of these compounds8 the imino-
thioether approach has been extensively employed for
Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group
of potent,7 naturally occurring antitumour antibiotics
* Corresponding author. Tel.: +91-40-27193157; fax: +91-40-
27193189; e-mail: ahmedkamal@iict.ap.nic.in
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)01049-9

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A. Kamal et al. / Tetrahedron Letters 44 (2003) 4741–4745
the synthesis of naturally occurring PBD imines or their
methyl ethers such as tomamycin, chicamycin and also
for the synthesis of structurally modified synthetic
PBDs9 wherein pyrrolo[2,1-c][1,4]benzodiazepine-5,11-
diones are the intermediates. PBD-5,11-diones are also
useful precursors for the PBD cyclic secondary amines
which have recently been converted in our laboratory
to PBD imines through a mild oxidative method.10
Moreover, it is well known that PBD-5,11-diones are
intermediates for the synthesis of compounds with a
broad spectrum of biological activity such as antiphase
activity, analgesic antagonist, anti-inflammatory, psy-
chomotor depressant activity and even herbicidal
properties.11
Furthermore, the C2-hydroxy substituent in the PBD
ring system plays an important role in non-covalent
interactions with the DNA and therefore generation of
compounds with hydroxyl group at the C2-position is
helpful in investigating the SARs.
Table 1. Reduction of nitro/azido groups followed by TFA cleavage

A. Kamal et al. / Tetrahedron Letters 44 (2003) 4741–4745
4743
During the course of our studies on the development of
solid phase synthetic methodologies for PBD ring sys-
tems,12 we have earlier reported a procedure employing
indium for nitro and azido reductive cyclization. In
continuation of these efforts, we have been interested in
the development of a cost-effective and efficient method
for such a process by employing Al/NiCl2·6H2O and
Al/NH4Cl reagent systems. This method provides a
useful and high yielding solid phase procedure for a
variety of substituted aryl amines from their nitro and
azido precursors as shown in Table 1. Interestingly, this
solid phase reduction of nitro and azido groups is a key
step in the synthesis of a large number of biologically
important heterocyclic compounds.13 Moreover, in this
investigation the solid phase procedure has been applied
for the synthesis of imine-containing PBD ring systems
and their 5,11-diones as illustrated in Table 2. The
present synthetic strategy for the PBD ring system
(Scheme 1) is based partially on the solution phase
approach of Lown and Joshua,14 which involves the
reductive cyclization of N-2-(nitrobenzoyl)pyrrolidine-2-
carboxaldehyde with H2/catalyst. It was observed that
Al/NiCl2·6H2O offers several advantages over Al/
NH4Cl. The solid phase reductive process with the
former reagent system takes place at room temperature
in comparison to the latter which requires reflux condi-
tions. Further, not only the yields are higher, the reaction
rates are faster using Al/NiCl2·6H2O.
Preparation of 4a:15 To the suspension of resin 1a12c (0.60
g, 0.83 mequiv./g) in CH2Cl2 (10 mL) was added DIBAL-
H (1 mL of a 1 M solution in hexane, 1 mmol) dropwise
at −78°C under dry nitrogen, and the mixture stirred at
the same temperature for 2 h. The reaction was quenched
by the addition of 10 mL of 0.5% HCl. The resin 2a was
filtered off and rinsed with hexane, water, THF, CH2Cl2
and dried in vacuo. To the suspension of resin 2a (0.60
g, 0.83 meq./g), in freshly distilled THF, a freshly mixed
solid mixture of aluminium powder (0.22 g, 8.3 mmol)
and nickel chloride hexahydrate (2.95 g, 12.45 mmol) was
added then the mixture was stirred for 75 min at rt. The
imine resin 3a was filtered off and rinsed with 5% HCl
(after stirring or sonicating for about 10 min) and this
process was repeated thrice, followed by water, THF,
Table 2. Synthesis of PBD imines and dilactams by nitro/azido reductive cyclization followed by TFA cleavage

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A. Kamal et al. / Tetrahedron Letters 44 (2003) 4741–4745
Scheme 1. Reagents and conditions: (i) DIBAL-H, CH2Cl2, −78°C, 2 h; (ii) Al/NiCl2·6H2O, THF, rt or Al/NH4Cl, DMF or EtOH,
reflux, 3 h; (iii) TFA/CH2Cl2 (1:3).
MeOH and CH2Cl2. Alternatively, to the suspension of
resin 2a (0.60 g, 0.83 meq./g), in EtOH or DMF (10
mL) was added aluminium powder (0.11 g, 4.15 mmol)
and saturated ammonium chloride solution (3 mL) and
the mixture was refluxed for 3 h. The imine resin 3a was
filtered and rinsed with 5% HCl (after stirring or soni-
cating for about 10 min) and this process was repeated
thrice, followed by water, EtOH, DMF, MeOH and
CH2Cl2 and dried in vacuo. Finally, 3a was cleaved
from the solid support using TFA/CH2Cl2 (1:3) to yield
the crude product 4a, which was further purified by
column chromatography.
MeOH and CH2Cl2 and dried in vacuo. The resin was
filtered and rinsed with toluene and CH2Cl2. The sus-
pension of 5a in TFA/CH2Cl2 (1:3, 10 mL) was allowed
to stir at 25°C for 2 h. The resin was filtered and
washed with CH2Cl2 (3×10 mL). The combined filtrates
were evaporated to afford the crude product 6a, which
was further purified by column chromatography.
In summary an efficient and cost effective solid phase
synthesis of substituted arylamines from their corre-
sponding nitro and azido substrates has been demon-
strated. This procedure has been further extended
towards the synthesis of pyrrolo[2,1-c][1,4]benzodiaze-
pines and their dilactams in good yields. This method is
expected to generate combinatorial libraries for
pyrrolo[2,1-c][1,4]benzodiazepines based compounds
particularly those having a 2-hydroxy substituent on
the C-ring.
Synthesis of 6a: To the suspension of resin 1a (0.60 g,
0.83 meq./g), in distilled THF, a freshly mixed solid
mixture of aluminium powder (0.22 g, 8.3 mmol) and
nickel chloride hexahydrate (2.95 g, 12.45 mmol) was
added and the mixture stirred for 70 min at rt to afford
the lactam resin derivative 5a by reductive cyclization.
This was filtered off and rinsed with 5% HCl (after
stirring or sonicating for about 10 min) and this process
was repeated thrice, followed by water, THF, MeOH
and CH2Cl2 and dried in vacuo. Alternately, to the
suspension of resin 5a (0.60 g, 0.83 meq./g), in EtOH or
DMF (10 mL) was added aluminium powder (0.11 g,
4.15 mmol) and saturated ammonium chloride solution
(3 mL) and the mixture was refluxed for 3 h to afford
the reductively cyclized lactam resin derivative 5a. This
was filtered off and rinsed with 5% HCl (after stirring
or sonicating for about 10 min) and this process was
repeated thrice, followed by water, EtOH, DMF,
Acknowledgements
Three of the authors K.L.R., V.D. and G.S.K.R. thank
the CSIR New Delhi for the award of Research
Fellowships.
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1.70–1.80 (m, 1H, C1), 1.95–2.10 (m, 1H, C1), 3.50–3.75
(m, 2H, C3), 4.02 (m, 1H, C11a), 4.17–4.26 (m, 1H, C2),
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m/z 216.