TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6629–6631
Simple and facile reduction of azides to amines: synthesis of
DNA interactive pyrrolo[2,1-c][1,4]benzodiazepines
Ahmed Kamal,* P. S. M. M. Reddy and D. Rajasekhar Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 30 April 2002; revised 25 June 2002; accepted 12 July 2002
Abstract—The reduction of aromatic azido compounds to the corresponding amines with hydriodic acid has been investigated and
found to result in high yields. This reductive methodology which proceeds under non refluxing condition has been extended for
the synthesis of DNA-interactive pyrrolo[2,1-c][1,4] benzodiazepine antibiotics. © 2002 Elsevier Science Ltd. All rights reserved.
The reduction of aromatic azido compounds to the
corresponding amines is an important chemical trans-
formation in synthetic organic chemistry. Azides can be
prepared with good regio-, stereo- and enantioselectiv-
ity, and their transformation into amines provides a
large amount of applications in organic synthesis,1 such
as in the preparation of nitrogen containing
heterocycles2 and carbohydrates3 and in nucleoside
chemistry. A number of reagents have been described in
the literature4 for this reductive process includes boro-
hydrides,5 triphenylphosphine,6 benzyltriethylammo-
nium tetrathiomolymbdate,7 hexamethyl-disilathiane8
and samarium iodide,9 etc. In terms of practical appli-
cability, reaction conditions or commercial availability,
most of these methods have some disadvantages. Hence
there is a continuing need to explore more efficient and
convenient methodologies.10 We have been involved in
the development of new versatile methods for the
reduction of azides which were required for the synthe-
sis of natural products and recently we reported such a
reduction employing iodotrimethylsilane.11 In continua-
tion of these efforts, we wish to report a simple and
efficient method for the reduction of azido compounds
1 to the corresponding amines 2 with hydriodic acid
(HI) in excellent yields (Scheme 1).
Hydrogen iodide mediated reduction of aromatic nitro
compounds to aromatic amines has been extensively
studied12 and recently reinvestigated.13 However, the
reduction of aromatic azido compounds by employing
HI has not been examined. In continuation of our
efforts in the development of new synthetic methodolo-
gies for the preparation of biologically important hete-
rocyclic natural products, we have investigated HI for
the reduction azide functionality, particularly in view of
its ready availability. It can be observed from the
results described in Table 1, that this method is applica-
ble for the reduction of azides in a wide variety of
substrates ranging from aryl to sulphonyl azides.
It is interesting to observe that in the case of entry f, the
O-benzyl groups are intact after this reduction in con-
trast to the conventional methods for azide reduction
employing Pd/C. There are some selective reagents for
such azido reductions but most of these reagents are
expensive.
Furthermore, this method has been extended for the
preparation of the DNA-binding pyrrolo[2-1-c][1,4]-
benzodiazepine (PBD) ring system. PBDs have been
known to interact with DNA in a sequence selective
manner and as such have potential as antitumor agents
and gene targeting drugs.14 A large number of methods
have been examined for the preparation of PBDs but
most of these have met with varying degrees of success
having different limitations.15
HI, rt
R
N3
R
NH2
1
2
Scheme 1.
This has necessitated the exploration and development
of the new azido reductive cyclization method as an
alternative route for the synthesis of these biologically
important PBDs. As described in Scheme 2, the PBD
Keywords: amines; reductive cyclization; hydriodic acid; pyrroloben-
zodiazepines.
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