One pot synthesis of aromatic azide using sodium nitrite and hydrazine hydrate

Article abstract of DOI:10.1016/j.tetlet.2012.12.112

A simple, rapid, and efficient protocol for the synthesis of aryl azide using sodium nitrite and hydrazine hydrate at room temperature is discussed. The short reaction time, simple work-up procedure, and use of inexpensive reagents are advantages of this method.

Full text of DOI:10.1016/j.tetlet.2012.12.112

Accepted Manuscript
One pot synthesis of aromatic azide using sodium nitrite and hydrazine hydrate
Afsar Ali Siddiki, Balaram S. Takale, Vikas N. Telvekar
PII:
S0040-4039(12)02265-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.12.112
TETL 42360
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 October 2012
26 December 2012
26 December 2012
Please cite this article as: Siddiki, A.A., Takale, B.S., Telvekar, V.N., One pot synthesis of aromatic azide using
sodium nitrite and hydrazine hydrate, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2012.12.112
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Graphical Abstract
One pot synthesis of aromatic azide using
sodium nitrite and hydrazine hydrate
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Afsar Ali Siddiki, Balaram S. Takale, Vikas N. Telvekar*

1
Tetrahedron
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journal homepage: www.elsevier.com
One pot synthesis of aromatic azide using sodium nitrite and hydrazine hydrate
Afsar Ali Siddiki, Balaram S. Takale, Vikas N. Telvekar*
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga,
Mumbai-400 019, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Simple, rapid and efficient protocol for the synthesis of aryl azide using sodium nitrite
and hydrazine hydrate at room temperature is discussed. The short reaction time, simple
work-up procedure and use of inexpensive reagents are advantages of this method.
Available online
Keywords:
Amines
Azides
Hydrazine hydrate
Sodium nitrite
Aromatic azides are versatile intermediates with a diverse
range of applications in organic and bioorganic chemistry.1
Organic azides are important components in click
chemistry.2 Cycloaddition between organic azides and
terminal alkynes has found widespread application,3 e.g., in
combinatorial drug discovery,4 material science,5 and bio
conjugation.6, 7Among various types of 1, 3-dipoles, organic
azides are particularly important as they provide an entry
into the synthesis of triazoles and tetrazoles.8 These
heterocyclic derivatives have found use in important
applications such as pharmaceuticals, chemical biology9 or
energetic material.10 Diazo compounds can also be coupled
with arylboronic acids to form C–C bonds without the use
of metal catalysts.11
reagents (12 equiv of t-BuONO, 3 equiv of NaN3), which is
undesirable considering the hazards associated with NaN3.
As most of the methods involves multistep reaction and
explosive reagent such as NaN3, the method which avoid
use of NaN3 for aromatic azidation will be very much
important from economical point. There are other methods
where phenyl hydrazine derivatives act as a starting material
for the synthesis of aromatic azides20a which involves no. of
methods such as using Br2/PPh3 in ACN solvent at 273K20b
,
N2O4/CCl4 in ACN solvent20c and O2/NO in
dichloromethane solvent.20d Dutt et al., reported the
synthesis of aryl azide by using diazonium salt and
sulphonamide, however formation of sulphonic acid as
byproduct is a major drawback of this method. 20f
Aryl azides are found to be prepared from organoboron
compounds using copper (II) catalyst,12 Reaction of
[ArN2][BF4] salts immobilized in [BMIM][PF6] ionic liquid
with TMSN3 represents an efficient method for the
preparation of azido-derivatives via diazotization.13
However, the synthesis of aryl azides relies upon a more
limited selection of transformations.14 They are commonly
prepared from the corresponding amines via their
diazonium salts.15 This may sometimes be problematic with
respect to the presence of incompatible functional groups.
Alternative methods have been investigated, for example,
reactions of organometallic aryls (derived from the
corresponding aryl halide) with p-tosyl azide.16More
recently, Liu and Tor has applied Wong’s (TfN3)
methodology toward the efficient preparation of aryl
azides.17 Although powerful, this procedure presents some
drawbacks. First, toxic and potentially explosive NaN3, and
the highly reactive Tf2O are used in excess. Second, TfN3
has been reported to be explosive when not in solvent.18
Recently, Das et al. reported the use of tert-butyl nitrite (t-
BuONO) in combination with NaN3 in the synthesis of
aromatic azides.19 This procedure requires a large excess of
We are continuously working on the development of new
efficient methodologies; recently we explored application of
sodium nitrite for decarboxylative bromination.21 Here in
we have developed a simple, single step procedure for
azidation from aromatic amines.
For our initially study we have taken aniline as a model
substrate. When aniline is treated with NaNO2 and
hydrazine hydrate in the presence of acetic acid it was found
that phenyl azide could be achieved in moderate to good
yield (Scheme 1).
Scheme 1. Aniline converted into azide using sodium nitrite
and hydrazine hydrate

2
NH2
N3
8
9
40
30
76
80
Different solvents were screened for this reaction (Table 1)
and the dichloromethane was found to be the best solvent.
Highly polar solvent like DMSO is found to give low yield
of desired product.
H3C
CH3
H3C
CH3
Table 1. Conversion of aniline to azide in presence of various
solvents.
NH2
N3
Entry
Solvents
Time (min) % Yielda
1
2
3
4
5
Dichlorormethane
Chloroform
Toluene
Acetonitrile
DMSO
30
90
85
80
80
40
120
120
120
120
COOH
NH2
COOH
N3
10
11
35
35
80
75
aIsolated yields after silica gel column chromatography
COOH
COOH
NH2
N3
Further screening of the equivalent of sodium nitrite and
hydrazine hydrate required for the reaction, it was found
that 2 equivalent of sodium nitrite and 5 equivalent of 99%
hydrazine hydrate were sufficient to provide the desired
product in 90% yield.
To establish further scope of the reaction we applied these
optimized conditions on activated and deactivated aromatic
amines and results are summarized in Table 222
NO2
N3
NO2
NH2
12
13
9h
8h
50
55
COOH
COOH
NO2
NO2
Table 2. Azidation using Sodium nitritea
NH2
N3
COOH
COOH
Entry
1
Reactant
Product
Time
(min)
Yield
(%)b
Cl
Cl
S
N
S
14
15
40
40
75
75
NH2
N3
NH2
N3
30
90
N
S
S
N3
NH2
N3
NH2
2
COOC2H5
COOC2H5
OH
30
85
OH
NH2
N3
16
17
40
40
75
75
NH2
N3
3
4
35
30
80
90
N3
N3
NH2
NH2
OH
OH
Cl
Cl
NH2
N3
CH3
CH3
N3
NH2
aReaction condition: substrate (1.45 mmol), NaNO2 (2.92 mmol),
AcOH (11.7 mmol), H2NNH2.H2O (7.3 mmol), DCM, r.t.
bIsolated yield after column chromatography and structure were
confirmed by comparison of IR, mp/bp, MS and 1H NMR with
literature reports
OCH3
NH2
OCH3
N3
5
6
7
35
80
80
From Table 2 it is clearly seen that both electron donating
and electron withdrawing substrates are suitable for this
conversion and gave good to moderate yield of desired
product in 30-40 min (Table 2, entry 2-11). When the
aromatic ring is strongly deactivated, product could be
achieved in poor yield (Table 2, entry 12, 13). Heterocyclic
amines were also found to be suitable substrates to give
moderate yields (Table 2, entry 14, 15) and it was
interesting to know that free ester group tolerated reaction
conditions without formation of hydrazide. In the case of p-
phenylenediamines both amine groups were converted to
azide through formation of monoazide and give 1, 4-
diazides as a major product (Table 2, entry 16, 17).
Cl
NH2
Cl
N3
30
Br
Br
N3
NH2
30
85
Cl
Cl
Cl
Cl
To find out role of reagents we altered the reaction
conditions and checked the effect on the reaction by their
absence. It was observed that all the three reagents were

3
4. (a) Moorhouse, A. D.; Santos, A. M.; Gunaratnam, M.;
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2006, 45, 5292.
necessary for the reaction. To check the role of hydrazine
hydrate, it was replaced with benzhydrazide and found that
the expected product could be achieved in good yield,
however there is formation of side product which after
characterization, was confirmed as phenylisocyanate
(Scheme 2).
6. Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless,
K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192.
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1398.
Scheme 2. Reaction of aniline in the presence of benzhydrazide
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1976, 100, 2949.
Plausible mechanism of the conversion of amine to azide is
predicted as shown in scheme 3. One mole of sodium nitrite
react with aniline to give diazonium salt followed by
nucleophilic substitution with azide ion which was formed
in situ by reaction between second mole of sodium nitrite
and hydrazine hydrate in the presence of acidic medium.
9. (a) Nomiya K., Noguchi R. and Oda M., Inorg. Chim. Acta,
2000, 298, 24; (b) van Berkel S. S., Dirks A. J., Debets M.
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T., Chem Bio Chem, 2007, 8, 1504; (c) Tam A., Arnold U.,
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129, 12670; (d) Bokor E., Docsa T., Gergely P. and Somsák
L., Bioorg. Med. Chem., 2010, 18, 1171; (e) Sletten E. M.
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M., Angew. Chem., Int. Ed., 2006, 45, 3584; (b) Tappan B.
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73, 316.
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of the Azido Group; Patai, S., Ed.; Wiley: New York, 1971;
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1998, 7, 986
16. (a) Smith, P. A. S.; Rowe, C. D.; Bruner, L. B. J. Org.
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Organometallics 2002, 21, 5549
Scheme 3. Plausible mechanism
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19. Das, J.; Patil, S. N.; Awasthi, R.; Narasimhulu, C. P.;
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In summary, we have described a simple, efficient and
single step procedure for conversion of aromatic amines
into corresponding aryl azides using sodium azide and
hydrazine hydrate in short reaction time.
20. (a) Nguyen, D.M.; Miles, D.H.; Syn. Comm. 2011, 41,
1759-1771. (b) Iranpoor, N.; Firouzabadi, H.; Nowrouzi,
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Y.H.; Kim, K.; Shim, S.B.; Tetrahedron Lett,
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Am. Chem. Soc. 2005, 127, 1084-1085. (d) Matsuya, Y.;
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Acknowledgment
A.A.S thank the University Grant Commission (UGC-
Green Tech.) and B.S.T. the Council of Scientific and
Industrial Research (CSIR), New Delhi for financial
support.
21. Telvekar, V.; Takale, B. Tetrahedron Lett. 2011, 52, 2394.
22. Typical Procedure for the azidation of aromatic amines:
A finely ground mixture (in case of solid) of aromatic amine
(1 equiv) and sodium nitrite (2 equiv) was stirred in
dichloromethane solvent at r.t. for 5 min followed by
addition of AcOH (8 equiv) and hydrazine hydrate (5 equiv,
99%) at r.t. for 30 min. The reaction mixture was then
washed with H2O (3 × 20 mL) and finally with brine
solution (2 × 20 mL). The organic layer dried over anhyd
Na2SO4, filtered and concentrated under reduced pressure to
give the crude product. The crude product was purified
using silica gel column chromatography (plane hexane).
Azido benzene (Table 2, Entry 1) 23a
References
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Yellow liquid, bp 44oC, IR: 2120, 2091, 1592, 1490, 1292,
1
1280 cm-1, H NMR (400 MHz, CDCl3): δ = 7.4 (m, 2H),
7.09 (m, 3H), GC/MS: 120[M] +.
1-azido-2-hydroxybenzene (Table 2, Entry 2) 23b

4
Brown red solid, mp 40 oC, IR (KBr): 3400, 2120, 1610,
Off white solid, mp 174 o C: IR (KBr): 2959, 2541, 2101,
1672, 1600, 1577, 1507, 1424, 1330, 1317, 1281, 1177,
1138, 1121, 859 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.09
(d, 8.4 Hz, 2H), 7.09 (d, 8.4 Hz, 2H), GC/MS: 163 [M] +
23. (a) Nguyen D.M., and Miles D.H., Synthetic comm., 2011,
41, 1759; (b) Madhusudhan G., Reddy M.S., Reddy Y.N.,
Vijayalakshmi V., Suribabu M., Balraju V., Ind J Chem,
Sec. B: Organic Chemistry Including Medicinal Chemistry,
2010, 49, 978; (c) Barral K., Moorhouse A. D., and Moses
J. E., Org. Lett.,2007, 9, 1809; (d) Ankati H., Biehl E.,
Tetrahedron Lett.,2009, 50, 4677; (e) Narumi A., Zeidler S.,
Barqawi H., Enders C., Binder W.G., J Poly Sci: Part A:
1
1514, 1150, 1092, 860 cm-1, H NMR (CDCl3, 400MHz) δ:
5.3 (s, 1H), 6.9-7.2 (m, 4H), GC/MS: 135[M] +.
1-Azido-4-methoxybenzene (Table 2, Entry 4) 23c
Yellow oil, IR: 2097, 1501, 1284, 1241 cm-1. 1H NMR
(CDCl3, 400MHz) δ: 3.70 (s, 3H), 6.81 (d, J = 8.8 Hz, 2H),
6.88 (d, J = 8.8 Hz, 2H), GC/MS: 149 [M] +.
1-azido-4-Chlorobenzene (Table 2, Entry 5) 23d
Yellow liquid bp 54 o C, IR: 3043, 2930, 2094, 1604, 1520,
1
1340, 1220, 1156, 1096, 822, 768 cm-1, H NMR (CDCl3,
400MHz) δ: 3.70 (s, 3H), 7.3 (d, J = 8.6 Hz, 2H), 6.9 (d, J =
8.6 Hz, 2H), GC/MS: 153 [M] +.
4-azido benzoic acid (Table 2, Entry 9) 23e
Polymer
Chemistry,
2010,
48,
3402.