Mild and efficient reduction of azides to amines: Synthesis of fused [2,1-b]quinazolinones

Article abstract of DOI:10.1016/S0040-4039(02)01454-5

FeCl₃/NaI has been employed for an efficient reduction of a variety of azides. This method is selective in the presence of a nitro functionality and has been extended for the synthesis of fused [2,1-b]quinazolinone ring systems such as deoxyvasicinone.

Full text of DOI:10.1016/S0040-4039(02)01454-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6861–6863
Mild and efficient reduction of azides to amines: synthesis of
fused [2,1-b]quinazolinones
Ahmed Kamal,* K. Venkata Ramana, Hari Babu Ankati and A. Venkata Ramana
Division of Organic Chemistry I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 2 May 2002; revised 25 June 2002; accepted 12 July 2002
Abstract—FeCl3/NaI has been employed for an efficient reduction of a variety of azides. This method is selective in the presence
of a nitro functionality and has been extended for the synthesis of fused [2,1-b]quinazolinone ring systems such as deoxyvasi-
cinone. © 2002 Elsevier Science Ltd. All rights reserved.
In recent years, azides1 have attracted much attention,
tem has not previously been investigated for the reduc-
not only as excellent protecting groups, but as key
intermediates for the synthesis of a large number of
organic compounds such as nucleosides, carbohy-
drates,2 N-containing heterocycles3 like quinolines,
quinazolines, benzodiazepines, lactams, cyclic imides
etc. A variety of reagents have been reported in the
literature4 for the reduction of azides, and the most
prominent employ borohydrides,5 triphenylphosphine,6
benzyltriethylammonium tetrathiomolybdate,7 hexam-
tion of the azide functionality. The role of NaI is not
clear in this process but a plausible explanation could
be attributed to the in situ formation of FeI3, which is
not known to exist in a pure state. The use of an excess
of NaI appears to be essential for this conversion as its
use at less than 5 equiv. not only decreased the amount
of conversion but also the rate of the reaction, thus
supporting the above proposition. However, the forma-
tion of a NaI/Lewis acid complex cannot be ruled out.
ethyldisilathiane,8 SmI2 etc. The majority of these
9
methods have some shortcomings in relation to their
general applicability, selectivity, commercial availability
and reaction conditions. In view of these factors there
has been considerable demand to further explore
efficient, milder and selective methodologies.10
As observed from the results in Table 1, this method
offers excellent selectivity in the presence of other func-
tionalities, particularly the nitro group, unlike some
other reagents such as SmI2. It is interesting to note
that 2-carboxylic acid substituted aryl azides undergo
intermolecular cyclization to produce dilactams. Addi-
tionally, this methodology can also be utilised for a
wide range of substrates including benzyl and alkyl
azides. However, demethylation of the methyl ether has
been observed as seen in entry c.
As a part of our continuing research work towards the
synthesis of heterocyclic natural products, we have
taken up the task of developing new versatile methods
for azido group reduction. In this connection, we have
recently reported the reduction of azides to amines by
employing reagents such as TMSI and FeSO4.11–15
In a typical procedure: to a solution of azide (1 mmol)
in acetonitrile (10 ml) was added NaI (9 mmol), fol-
lowed by FeCl3 (1.5 mmol). The resulting mixture was
stirred for 10–25 min and upon completion of the
reaction was diluted with CHCl3 (5 ml), then washed
with saturated aqueous Na2S2O3 and NaHCO3 solu-
tions. The organic layer was further washed with brine,
As a result of these efforts, we can now report a new
mild, efficient and selective method for the reduction of
azides 1 to the corresponding amines 2 in quantitative
yields employing FeCl3/NaI (Scheme 1). Although
FeCl3 in combinations with different reagents has been
reported for such reductions,16 the present reagent sys-
FeCl3/NaI
R
N3
R
NH2
MeCN, r.t.
Keywords: azides; amines; reductive cyclization; [2,1-b]quinazolines;
deoxyvasicinone.
2
1
* Corresponding author. Tel.: +91-40-7193157; fax: 91-40-7160512;
e-mail: ahmedkamal@iict.ap.nic.in
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01454-5

6862
A. Kamal et al. / Tetrahedron Letters 43 (2002) 6861–6863
Table 1. Reduction of azides to amines employing the FeCl3/NaI reagent system
____________________________________________________________________________________
Product 2
Entry
Substrate 1
Time (min)
% Yield
____________________________________________________________________________________
NH2
NH2
N3
N3
N3
95
97
10
10
a
Cl
Cl
Me
b
c
Me
NH2
NH2
20
10
75
98
MeO
HO
N3
d
e
O2N
O2N
O
H
N
N3
15
96
OH
NH
O
O
O
H
N
Cl
N3
Cl
f
98
85
OH
15
20
Cl
NH
O
O
NH2
N3
g
N3
(CH2)9
NH2
NH2
(CH2)9
h
i
85
88
25
25
N3
____________________________________________________________________________________
dried over Na2SO4 and concentrated under reduced
pressure. The residue thus obtained was filtered
through a silica gel (60–120 mesh) pad with ethyl
acetate/hexane (2:8) to afford the corresponding amine.
exploration of their biological potential.18 The develop-
ment of this new reductive cyclization method affords
an alternative route towards the preparation of these
pharmacologically important fused quinazolinones in
good yields ranging from 85 to 97% (Scheme 2).
Further, taking advantage of the intermolecular azido-
reductive cyclization, we have extended this procedure
to the preparation of the pyrrolo[2,1-b]quinazolinone
ring system, and related tetrahydropyrido and octahy-
droazepino fused quinazolinones. Deoxyvasicinone 6a
is a precursor for vasicinone, a bronchodilator.17 This
study is a continuation of our efforts towards the
synthesis of various fused [2,1-b]quinazolinones and the
In conclusion, we have demonstrated an efficient, mild
and spontaneous method for the reduction of the azide
functionality. Additionally, this method is selective for
the azide functionality in the presence of a nitro group.
Further, this protocol has been applied to the synthesis
of deoxyvasicinone19 6a, a precursor of vasicinone (a
bronchodilator) and related analogues.

A. Kamal et al. / Tetrahedron Letters 43 (2002) 6861–6863
6863
3. McDonald, F. E.; Danishefsky, S. J. J. Org. Chem. 1992,
57, 7001.
4. Ito, M.; Koyakumaru, K.; Takaya, T. H. Synthesis 1995,
376.
5. (a) Rao, H. S. P.; Siva, P. Synth. Commun. 1994, 24, 549;
(b) Alverez, S. G.; Fisher, G. B.; Singavam, B. Tetra-
hedron Lett. 1995, 36, 2567.
6. Molina, P.; Diaz, I.; Tarraga, A. Tetrahedron 1995, 51,
5617.
7. Ramesha, A. R.; Bhat, S.; Chandrasekaran, S. J. Org.
Chem. 1995, 60, 7682.
8. (a) Capperucci, A.; Degl’ Innocenti, A.; Funicello, M.;
Mauriello, G.; Scafato, P.; Spagnolo, P. J. Org. Chem.
1995, 60, 2254; (b) Kamal, A.; Reddy, B. S. P.; Reddy, B.
S. N. Tetrahedron Lett. 1996, 37, 6803.
9. Huang, Y.; Zhang, Y.; Wang, Y. Tetrahedron Lett. 1997,
38, 1065.
10. Molander, G. A. Chem. Rev. 1992, 92, 29.
11. Kamal, A.; Rao, N. V.; Laxman, E. Tetrahedron Lett.
1997, 38, 6945.
12. Forsee, J. E.; Smith, B. T.; Frank, K. E.; Aube, J. Synlett
1998, 1259.
13. Kamal, A.; Damayanthi, Y.; Reddy, B. S. N.; Lakshmi-
narayana, B.; Reddy, B. S. P. Chem. Commun. 1997,
1015.
Scheme 2.
14. Kamal, A.; Laxman, E.; Arifuddin, M. Tetrahedron Lett.
2000, 41, 7743.
15. Kamal, A.; Reddy, B. S. N. Chem. Lett. 1998, 593.
16. Pathak, D.; Laskar, D. D.; Prajapathi, D.; Sandhu, J. S.
Chem. Lett. 2000, 816.
Acknowledgements
17. Amin, A. H.; Mehta, D. R. Nature 1959, 183, 1317.
18. Kamal, A.; Ramana, K. V.; Rao, M. V. J. Org. Chem.
2001, 66, 997.
One of the authors (K.V.R.) is thankful to CSIR, New
Delhi, for the award of Research Fellowship.
19. Spectral characteristics of 2,3-dihydropyrrolo[2,1-
b]quinazolin-9-one 6a: mp 104–106°C, 1H NMR (200
MHz, CDCl3) l 2.3 (q, 2H, J=7.5 and 8.0 Hz), 3.2 (t,
2H, J=8.0 Hz), 4.2 (t, 2H, J=7.5 Hz), 7.5 (t, 1H, J=7.4
Hz), 7.6–7.8 (m, 2H), 8.3 (d, 1H, J=8.0 Hz); MS (EI)
m/z 186 (M+); HRMS calcd for C11H10N2O 186.0793,
found 186.0789.
References
1. Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
2. Smith, S. C.; Heathcock, C. H. J. Org. Chem. 1992, 57,
6379.