An efficient reduction of azides to amines: Synthesis of DNA interactive pyrrolo[2, 1-c][1,4]benzodiazepines

Article abstract of DOI:10.1016/S0040-4039(00)01319-8

Reaction of a variety of azido compounds with FeSO₄·7H₂O/NH₃ results in quantitative yields of the corresponding amino compounds. This reductive methodology has been extended towards the synthesis of pyrrolo[2,1-c][1,4]benzodiazepine antibiotics. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01319-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7743–7746
An efficient reduction of azides to amines: synthesis of
DNA interactive pyrrolo[2,1-c][1,4]benzodiazepines†
Ahmed Kamal,* E. Laxman and M. Arifuddin
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 15 May 2000; revised 24 July 2000; accepted 1 August 2000
Abstract
Reaction of a variety of azido compounds with FeSO4·7H2O/NH3 results in quantitative yields of the
corresponding amino compounds. This reductive methodology has been extended towards the synthesis of
pyrrolo[2,1-c][1,4]benzodiazepine antibiotics. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: azides; amines; reductive cyclization; pyrrolobenzodiazepines.
Azide chemistry has attracted significant attention in view of its application in organic
synthesis. Azides can be prepared with good regio-, stereo- and enantioselectivity and their
transformation into amino functionality provides a large amount of applications in organic
synthesis1 such as nitrogen containing heterocycles,2 carbohydrate3 and nucleoside chemistry. A
number of reagents have been reported in the literature4 for this reductive process including the
borohydrides,5 triphenylphosphine,6 benzyltriethylammonium tetrathiomolybdate,7 hexamethyl
disilathiane8 and samarium iodide,9 etc. Most of these methods have some disadvantages in
relation to the general applicability, selectivity, reaction conditions or commercial availability.
Therefore, there is considerable interest in exploring more efficient and selective methodolo-
gies.10 In our continuing research programme on the synthesis of natural products, we have been
confronted with the challenge of exploring new versatile methods for the reduction of the azido
functionality. In this endeavor, we have recently reported a facile reduction of azides to amines
employing iodotrimethylsilane.11 In continuation of these efforts, we wish to report a new and
convenient method for the reduction of azides (1) to the corresponding amines (2) with
Scheme 1. (i) FeSO4·7H2O/NH3, MeOH, rt.
* Corresponding author.
†
IICT Commun. No. 4543.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01319-8

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Table 1
Reduction of azides to amines
FeSO4·7H2O/NH3 in excellent yields (Scheme 1). Although in the literature FeSO4 in aqueous
NH3 has been reported for the reduction of nitro arenes,12 this reagent system has not been
investigated for the reduction of azido groups.
As seen from the results described in Table 1, this method is applicable for the reduction of
4b-azidopodophyllotoxins to its 4b-amino analogue (f). 4b-Amino podophyllotoxins are impor-
tant building blocks for the DNA-topoisomerase II inhibiting podophyllotoxin congeners. It is
interesting to note that these reductions take place in the presence of CH3NH2 (40% aqueous
solution) instead of aqueous ammonia. This observation eliminates the possibility of a substitu-
tion reaction, particularly for the substrates e, g and h, which have been reduced to their

7745
corresponding amines without the formation of N-methyl substituted amino/amido compounds.
Further, during this reaction process addition of the base (ammonia or methylamine) to the
reaction mixture produces a dark brown colour, probably due to the formation of a complex.
A typical procedure: to a stirred solution of 4a (244 mg, 1 mmol) in dichloromethane (10 ml),
FeSO4·7H2O (1.4 g, 5 mmol) and 25% ammonia solution (1 ml) were added. This reaction
mixture was stirred continuously at room temperature for 4 h. On the completion of reaction as
indicated by TLC, the mixture was diluted with dichloromethane and filtered through a celite
bed. This filtrate was washed with water. The organic layer was dried over MgSO4 and
evaporated under reduced pressure. The residue was purified by column chromatography on
silica gel (ethyl acetate–hexane 9:1) to afford the imine (6a) in 70% yield (Scheme 2).
Scheme 2. (i) DIBAL-H, CH2Cl2, −78°C, 45 min, 72–75%; (ii) FeSO4·7H2O/NH3, CH2Cl2, 4 h, rt.
The usefulness of this method has also been extended to preparation of the DNA-binding
pyrrolo[2,1-c][1,4]benzodiazepine (PBD) ring system. These compounds interact with DNA in a
sequence selective manner and as such have potential as antitumour agents and gene targeting
drugs.13 Many approaches have been investigated for the preparation of these compounds and
have met with varying degrees of success having different limitations, particularly for the
introduction of imine functionality.14 Hence, development of this new reductive cyclization
method affords an alternate route towards the synthesis of these biologically important PBDs
(as illustrated in Scheme 2). The PBD dilactams (5a–d) have been obtained in 90–95% yields,
while PBD imines (6a–d) have been obtained in 68–72% yields.15
In conclusion, we have provided a new practical, cost-effective approach for the reduction of
azides to the corresponding amines by employing FeSO4·7H2O/NH3. This protocol has also
been applied to the preparation of 4b-amino podophyllotoxin (precursors of DNA topoiso-
merase II inhibitors) and DNA interactive pyrrolo[2,1-c][1,4]benzodiazepines.
Acknowledgements
Two of the authors (E. L., M. A.) are thankful to CSIR (New Delhi) for the award of Senior
Research Fellowships.

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15. Spectroscopic data of compound 6a. [h]2D7 +318 (c 0.5, CHCl3); 1H NMR (CDCl3): l 1.90–2.36 (m, 4H), 3.52–3.92
(m, 3H), 7.28–7.56 (m, 3H), 7.78 (d, 1H, J=4.6 Hz), 8.05 (d, 1H, J=5.2 Hz): IR (CHCl3) 3320, 2970, 2880, 1620,
1575, 1485, 1460, 1255, 1160, 1125, 1030, 875, 830 cm−1 MS: m/e 200 (M+, 100), 171, 160, 144, 120, 103, 83, 70
HRMS: calc. for 200.0950 (C12H12ON2), found 200.0936.
.