Selective reduction of aromatic azides in solution/solid-phase and resin cleavage by employing BF3·OEt2/EtSH. Preparation of DC-81

Article abstract of DOI:10.1016/j.tetlet.2006.04.025

An efficient method for the reduction of aromatic azides in both solution and solid-phase has been developed by employing BF₃·OEt₂/EtSH. This report also describes resin cleavage employing this reagent system. Further, this protocol has been utilized for the solution as well as the solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepines, including the naturally occurring antibiotic DC-81 and fused [2,1-b]quinazolinones.

Full text of DOI:10.1016/j.tetlet.2006.04.025

Tetrahedron Letters 47 (2006) 4253–4257
Selective reduction of aromatic azides in solution/solid-phase
and resin cleavage by employing BF3ÆOEt2/EtSH.
Preparation of DC-81
Ahmed Kamal,* N. Shankaraiah, K. Laxma Reddy and V. Devaiah
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 14 March 2006; revised 28 March 2006; accepted 6 April 2006
Available online 4 May 2006
Abstract—An efficient method for the reduction of aromatic azides in both solution and solid-phase has been developed by employ-
ing BF3ÆOEt2/EtSH. This report also describes resin cleavage employing this reagent system. Further, this protocol has been utilized
for the solution as well as the solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepines, including the naturally occurring antibiotic
DC-81 and fused [2,1-b]quinazolinones.
Ó 2006 Elsevier Ltd. All rights reserved.
A variety of reagents have been reported in the litera-
ture1,2 for the reduction of azides including boro-
hydrides,3 triphenylphospine,4 benzyltriethylammonium
added boron triflouride diethyletherate (0.09 mL,
0.80 mmol), followed by ethanethiol (0.12 mL,
1.60 mmol). The reaction mixture was stirred for 1.5–
2 h and then neutralized with saturated aqueous NaH-
CO3 solution. After separation of the organic phase, it
was washed with brine, dried over Na2SO4 and evapo-
rated under reduced pressure. The crude product thus
obtained was purified by column chromatography
through a silica gel (60–120 mesh) pad employing ethyl
acetate/hexane (15:85) as eluent to afford the corre-
sponding amine 2. This procedure has been extended
for the reduction of azides 1a–g to the corresponding
amines 2a–g in excellent yields and the results are given
in Table 1.
tetrathiomolybdate,5hexamethyldisilathiane,6
SmI2,7
etc. However, in terms of their practical applicability,
reaction conditions or commercial availability, most of
these methods have certain disadvantages and hence
considerable effort has been devoted to explore further
more efficient and convenient methods.8
As part of ongoing research programmes, we have been
involved in the synthesis of some important biologically
active heterocyclic natural products.9 In this connection,
we have developed solution and solid-phase synthetic
methods for the synthesis of pyrrolo[2,1-c][1,4]benzo-
diazepines10 and quinazolinones.11 We herein report a
mild, efficient and selective method for the reduction
of aromatic azides 1 to their corresponding amines 2
by employing boron trifluoride diethyletherate and eth-
anethiol, as shown in Scheme 1.
This methodology has also been applied to the synthesis
of pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). These are
naturally occurring antitumour antibiotics that are
produced by various Streptomyces species, and exert
their biological activity by interacting with DNA in a
sequence selective manner.12 PBD-5,11-diones have
been employed as intermediates in the synthesis of nat-
urally occurring and synthetically modified PBD imines,
such as tomaymycin and chicamycin.13 They are also
precursors of PBD cyclic secondary amines,14 which
In a typical procedure, to a stirred solution of aromatic
azide (1, 100 mg, 0.32 mmol) in CH2Cl2 (5 mL) was
Keywords: Pyrrolo[2,1-c][1,4]benzodiazepines; Solid-phase synthesis;
Boron trifluoride diethyletherate; Resin cleavage; Reductive
cyclization.
BF3. OEt2/EtSH
R N3
R NH2
CH2Cl2, r.t.
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40
27193189; e-mail addresses: ahmedkamal@iict.res.in; ahmedkamal@
iictnet.org
2
1
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.025

4254
A. Kamal et al. / Tetrahedron Letters 47 (2006) 4253–4257
Table 1. Reduction of aromatic azides to amines employing BF3ÆOEt2/EtSH
Entry
Substrate 1
Product 2
NH2
Time (h)
1.5
Yield (%)
95
N3
a
N3
NH2
b
c
d
e
1.5
2
98
90
92
85
H3C
H3C
N3
NH2
Cl
Cl
N3
NH2
2
H3CO
O2N
H3CO
O2N
N3
N3
NH2
2.5
NH2
f
2
93
98
OCH3
OCH3
H3C
H3C
O
O
BnO
H3CO
N3
BnO
H3CO
NH2
g
1.5
OCH3
OCH3
O
O
can be converted to their PBD imines by a mild oxida-
tion process.15 Moreover, it is known that PBD-5,11-
diones are intermediates for the synthesis of compounds
with a wide range of biological activities.16 With a view
to develop new efficient solution and solid-phase proce-
dures,17 we have employed the BF3ÆOEt2/EtSH reagent
system for the azido reductive process of substrates18
3a–f to give the PBD-5,11-diones 4a–f in good yields,
as illustrated in Table 2. Similarly, in view of our interest
in the synthesis of fused [2,1-b]quinazolinones19 (e.g.,
deoxyvasacinone), this reagent system has also been em-
ployed to extend the azido reductive cyclization protocol
for substrates18 3g–j to afford fused quinazolinones 4g–j
in excellent yields, as shown in Table 2.
was separated and dried over Na2SO4. The solvent was
concentrated under reduced pressure and the crude
product thus obtained was purified by column chroma-
tography through a silica gel (60–120 mesh) pad employ-
ing ethyl acetate/hexane (40:60) as the eluent. The
debenzylated ethanethiol protected amine 6 upon depro-
tection21 with HgCl2/CaCO3 gave the naturally occur-
ring antibiotic DC-81 7. Benzylated DC-81 9 was
prepared in a similar manner instead by using boron
trifluoride diethyletherate (0.11 mL, 0.99 mmol) and
ethanethiol (0.14 mL, 1.98 mmol).
Interestingly, when this procedure was used for the
reduction of resin-linked aryl azides the corresponding
aminophenols were obtained, and the results are
described in Table 3. There are reports in the literature
where Lewis acid assisted cleavage of resins22 is em-
ployed, however, to the best of our knowledge this is
the first report of the cleavage of a resin by employing
BF3ÆOEt2/EtSH.
This approach has been further applied to the prepara-
tion of the naturally occurring PBD antibiotic DC-81
(7). This compound exerts its biological activity by cova-
lently binding to the N2 of guanine in the minor groove
of DNA. Various approaches towards compounds of
this type have been investigated over the past few
years,20 most of these methods have met with varying
degrees of success and have different limitations. Herein,
we report an efficient and simple method for the synthe-
sis of naturally occurring DC-81 by employing
BF3ÆOEt2/EtSH. By varying the quantities of BF3Æ
OEt2/EtSH, either benzylated DC-81 9 or debenzylated
DC-81 7 were obtained via ethanethiol protected inter-
mediates 6 and 8, as shown in Scheme 2.
During the course of our studies on the development of
solid-phase synthetic methods for the PBD ring system,
we reported procedures mainly based on reductive
cyclization approaches.10 In this connection, the boron
trifluoride diethyletherate reagent system was reacted
with resin-linked aryl azido proline esters 12 to afford
PBD-5,11-diones 13 by simultaneous reduction of the
azide functionality and cleavage of the resin as
shown in Scheme 3 and Table 4. This method is advan-
tageous as the reductive cyclization and the resin cleav-
age take place in the same step, unlike the previous
procedures,10b–d which employ TFA for cleavage of
the resin.
Typical procedure for the preparation of DC-81: To a
suspension of 518 (150 mg, 0.39 mmol) in CH2Cl2
(5 mL) was added boron trifluoride diethyletherate
(0.43 mL, 3.95 mmol) followed by ethanethiol (0.57
mL, 7.90 mmol), and the reaction mixture was stirred
for 6 h. The resulting mixture was neutralized with sat-
urated aqueous NaHCO3 solution and the organic layer
In a typical synthesis, to a suspension of Wang resin
1210b (200 mg, 0.8–1.1 mmol/g, 200–400 mesh and 1%

A. Kamal et al. / Tetrahedron Letters 47 (2006) 4253–4257
4255
Table 2. Synthesis of pyrrolo[2,1-c][1,4]benzodiazepines-5,11-diones and fused [2,1-b]quinazolinones through reductive cyclization employing
BF3ÆOEt2/EtSH
Entry
Substrate 3
Product 4
Time (h)
Yield (%)
N3
COOCH3
H
N
O
H
a
1.5
95
N
N
O
O
H
O
H
N3
COOCH3
N
b
c
d
1.5
2.5
2
95
92
90
N
Cl
N
Cl
O
O
H
O
H
N3
COOCH3
N
N
H3C
N
H3C
O
O
H
O
N3
BnO
COOCH3
N
BnO
H
N
H3CO
N
H3CO
O
O
H
N
O
N3 COOCH3
H
e
f
2.5
2.5
90
90
N
N
OH
OH
O
H
O
O
H
H3CO
H3CO
N3 COOCH3
N
H3CO
N
N
H3CO
N
OH
OH
O
O
N3 O
N
g
h
1.5
1.5
98
98
N
O
O
N3 O
N
N
N
H3C
H3C
O
O
H3CO
H3CO
BnO
N3
O
H3CO
H3CO
BnO
N
i
j
2
96
97
N
N
N
O
N
O
N3 O
2
N
H3CO
H3CO
O
O
NH
N3
BnO
2 CH(SEt)2
NH
BnO
CHO
2 CH(SEt)2
HO
ii
i
N
H3CO
N
N
H3CO
H3CO
O
O
O
iii
6
5
8
iii
N
N
HO
BnO
H
H
N
N
H3CO
H3CO
O
O
Benzylated DC-81 9
DC-81 7
Scheme 2. Reagents and conditions: (i) BF3ÆOEt2/EtSH (10:20 equiv), CH2Cl2, rt, 6 h; (ii) BF3ÆOEt2/EtSH (2.5:5 equiv), CH2Cl2, rt, 6 h; (iii) HgCl2–
CaCO3, CH3CN/H2O (1:1), rt, 12 h.

4256
A. Kamal et al. / Tetrahedron Letters 47 (2006) 4253–4257
Table 3. Solid-phase synthesis reduction of aromatic azides to amines employing BF3ÆOEt2/EtSH
Entry
Substrate 10
Product 11
Time (h)
2
Yield (%)
90
OH
O
NH2
N3
a
OH
O
NH2
N3
O
b
c
d
2
2
2
91
82
92
OCH3
OCH3
N3
O
NH2
OCH3
OCH3
O
HO
O
O
HO
H3CO
NH2
OCH3
O
N3
OCH3
H3CO
O
O
H
O
H
R
N3
R
N
COOCH3
CH2Cl2:BF3. OEt2:EtSH
2:1:0.25
N
N
O
OH
O
O
12
13
Scheme 3.
Table 4. Solid-phase synthesis reductive cyclization and resin cleavage employing BF3ÆOEt2/EtSH
Entry
Substrate 12
N3
Product 13
Time (h)
3
Yield (%)
90
H
N
O
H
COOCH3
a
N
N
O
O
OH
O
H
O
H
N3
COOCH3
N
b
c
d
e
f
3
3
6
2
2
90
89
85
80
82
N
H3C
N
H3C
O
OH
O
O
Br
Br
H
O
N
N3 COOCH3
H
N
N
Br
Br
O
COOCH3
OH
O
O
H
O
H
N3
BnO
H3CO
N
HO
N
N
N
N
H3CO
O
OH
O
O
H
O
H
COOCH3
N
O
N3
HO
N
N
H3CO
H3CO
O
O
H
O
H
COOCH3
OH
N
O
N3
HO
H3CO
H3CO
OH
O
O

A. Kamal et al. / Tetrahedron Letters 47 (2006) 4253–4257
4257
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(1 mL) and ethanethiol (0.25 mL) in CH2Cl2 (2 mL).
The reaction mixture was stirred for 2 h then filtered
through a glass funnel, and the filtrate was neutralized
with saturated aqueous NaHCO3 solution. The organic
layer was separated, dried over anhydrous Na2SO4 and
evaporated. The residue was purified by column chro-
matography through a silica gel (60–120 mesh) pad
employing ethyl acetate/hexane (60:40) as eluent to pro-
duce pyrrolo[2,1-c][1,4]benzodiazepines-5,11-diones 13.
10. (a) Kamal, A.; Reddy, G. S. K.; Raghavan, S. Bioorg.
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12. Thurston, D. E. In Molecular Aspects of Anticancer Drug
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In summary, a practical approach for the reduction of
aryl azides in solution as well as on solid-phase has been
described by employing boron trifluoride diethyletherate
and ethanethiol. This method has been extended to the
synthesis of PBD-5,11-diones and fused quinazolinones
via their azido intermediates by employing a reductive
cyclization process. This procedure also provides an
alternative, simple and short route for the preparation
of naturally occurring DC-81, and its analogues. More-
over, this protocol has been utilized for an efficient solid-
phase synthesis of PBD-5,11-diones.
13. (a) Kaneko, T.; Wong, H.; Doyle, T. W. J. Antibiot. 1984,
37, 300; (b) Kamal, A.; Reddy, B. S. P.; Reddy, B. S. N.
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Acknowledgement
14. Kamal, A.; Howard, P. W.; Reddy, B. S. N.; Reddy, B. S.
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(b) Kamal, A.; Rao, M. V.; Reddy, B. S. N. Khim.
Geterotsikl. Seodin. (Chem. Hetreocyl. Compd.) 1998,
1588; (c) Kamal, A.; Rao, N. V. Chem. Commun. 1996, 385.
16. (a) Carbateas, P. M. US Patent 3,732,212, 1973; Chem.
Abstr. 1973, 79, P42570x, US Patent 3,763,183, 1973;
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Ph.D. Thesis, Osmania University, 1995.
17. (a) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah,
N.; Reddy, Y. N. Tetrahedron Lett. 2004, 45, 7667; (b)
Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.
Synlett 2004, 2533; (c) Kamal, A.; Reddy, K. L.; Devaiah,
V.; Shankaraiah, N. Synlett 2004, 1841.
The authors N.S., K.L.R. and V.D. are grateful to CSIR,
New Delhi, for the award of Research fellowships.
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