An easy access to aryl azides from aryl amines under neutral conditions

Article abstract of DOI:10.1055/s-2005-869974

A variety of substituted aryl amines were transformed into aryl azides using t-BuONO and moist NaN₃ in t-BuOH in good to excellent yields. Smooth transformation was observed with anilines, having electron withdrawing and donating groups. Both acid- and base-sensitive groups survived the reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869974

PAPER
1801
An Easy Access to Aryl Azides from Aryl Amines under Neutral Conditions
Aryl
Azid
a
esfrom Ar
y
g
l
Aminesun
a
der
N
eutra
t
l
Condi
t
tions aran Das,* Santoshkumar N. Patil, Riti Awasthi, C. Prasad Narasimhulu, Sanjay Trehan
Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500 049, India
Fax +91(40)23045438; E-mail: jagat@drreddys.com
Received 13 December 2004; revised 3 March 2005
tBuONO
DMF,
NaN3
Abstract: A variety of substituted aryl amines were transformed
into aryl azides using t-BuONO and moist NaN3 in t-BuOH in good
to excellent yields. Smooth transformation was observed with
anilines, having electron withdrawing and donating groups. Both
acid- and base-sensitive groups survived the reaction conditions.
R
R
N3
NH2
Scheme 2
Key words: amines, azides, anilines, diazo compounds, sodium
azide
Deamination of aryl amines with alkyl nitrite is being car-
ried out in our laboratories as a routine work (Scheme 1).
We reasoned that in the presence of a strong nucleophile
such as azide, a deamination reaction could be diverted to
azide formation (Scheme 2), since aryl amines do undergo
diazotization with alkyl nitrite.8
Azides are versatile intermediates in organic synthesis.1 A
major application of this class of compounds is 1,3-dipo-
lar cycloaddition with an unsaturated reactant to give a va-
riety of five-membered heterocycles.2 While numerous
methods are available for the preparation of aliphatic
azides, there is a limited choice for aryl azides. The most
straightforward route for the preparation of aryl azides in-
volves diazotization of amines with nitrous acid followed
by addition of sodium azide at low temperature.3 Alterna-
tively, aryl amines have been transformed into aryl azides
by treating the former with para-toluenesulfonyl azide in
the presence of a Grignard reagent or strong base.4 Aryl
azides have also been prepared from arylmagnesium ha-
lides or aryl lithium reagents, generated from aryl halides,
and para-toluenesulfonyl azide.5 The above conversion
has also been accomplished under mild condition using a
combination of triflyl azide, CuSO4, and triethylamine.6
Very recently, the coupling of aromatic and vinyl halides
with sodium azide under catalysis with CuI–L-proline was
reported to produce aryl/vinyl azides in good to excellent
yields.7 However, all these transformations require either
acidic or basic conditions, which are not compatible with
many functional groups present in a substrate. This has
prompted us to report our results for the same transforma-
tion.
F
F
NH2
O
N
N
N3
O
2
1
Scheme 3
We chose compound 1 as a model substrate to optimize
the reaction conditions for the transformation to azide 2
(Scheme 3). Initially, the reaction was carried out in DMF
in the presence of excess t-BuONO9 (10 equiv) and NaN3
(5 equiv) at 80 °C leading to decomposition of the amine.
Although azide formation was observed at room tempera-
ture, the reaction was not complete even after 24 hours.
Subsequently, reactions were carried out in other solvents
such as toluene, chloroform and t-BuOH. Reactions in tol-
uene and chloroform were found to be very slow because
of the poor solubility of NaN3 in these solvents. Addition
of a phase transfer catalyst, benzyltriethylammonium bro-
mide, produced a mixture of products. On the other hand,
the reaction proceeded well in t-BuOH and was completed
within two hours with an isolated yield of 59%. Further,
we observed that addition of small quantities of water10 in-
creased the rate of the reaction considerably and the reac-
tion was complete within 10–15 minutes.
During the course of our ongoing investigations, we need-
ed a process for the preparation of aryl azides from aryl
amines, having acid- and base-sensitive groups. This led
us to investigate neutral conditions for the preparation of
aryl azides. Here we describe our successful efforts to-
wards this endeavor.
It is important to note that when commercial isoamyl
nitrite11 was used, the reaction was slow and 50% conver-
sion was observed after 72 hours.
1. tBuONO
R
To find out the optimum quantity of reagents, we carried
out several reactions with a varied quantity of t-BuONO
and NaN3. However, six equivalents of t-BuONO and
three equivalents of NaN3 were found to be the optimum
quantity required for the transformation (0.25 h, 60%).
R
DMF,
2. aq. HCl
H
NH2
Scheme 1
SYNTHESIS 2005, No. 11, pp 1801–1806
x
x.
x
x
.
2
0
0
5
A variety of substituted amines were converted to the cor-
responding azides and the results are presented in Table 1.
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-869974; Art ID: T15104SS
© Georg Thieme Verlag Stuttgart · New York

1802
J. Das et al.
PAPER
Table 1 Conversion of Aryl Amines into the Corresponding Aryl
Azides
Table 1 Conversion of Aryl Amines into the Corresponding Aryl
Azides (continued)
Entry
1
Azide
Time (h)
1
Yield (%)
70
Entry
17
Azide
Time (h)
4
Yield (%)
64a
F
F
N3
O
O
N
N
N3
C2H5
N3
C2H5
2
3
74
18
19
3
50b
60a
N3
F
N
3
4
0.25
1
60
80
N3
N
0.25
Si O
N
N3
N
N3
MeO
F
20
21
4
4
70
68
OMe
N3
BocN
AcN
N
N3
5
6
7
8
3
2
1
1
71
73
85
92
F
MeO
N
N3
CH3
N3
F
O
O2N
H3C
22
7
70
Me
S
N
N
N3
CH3
N3
NO2
O
a Reactions were carried out with the usual 6 equiv of t-BuONO; 12
equiv of t-BuONO was used in all other examples.
b Reaction was carried out in DMF as solvent.
O2N
F
In most of the cases, the azides were isolated in very good
yields. 2-Amino-1,3-diethylbenzene, a hindered amine,
was converted to the corresponding azido compound (en-
try 2) in 74% yield. Similarly anilines having methoxy
substituents (entries 4 and 5) or anilines having different
electron withdrawing groups as substituents (entries 6–
10) were converted into the corresponding azides in yields
ranging from 61–92%. It is worthy of mention that pyra-
zole having a carboxylic ester as a substituent and also an
unprotected NH group (entry 11) produced azide from the
corresponding amine in 64% yield. 5-Aminoindole (entry
12) and 2-aminobenzothiazole12 (entry 13) were trans-
formed into the corresponding azides in 50% and 54%
yield, respectively. Anilines having different heterocycles
attached to it underwent smooth transformation to azides
(entries 14–17) in good yields. Pyridyl azide, which is
otherwise impossible to prepare by the nitrous acid meth-
od, was obtained from the corresponding amine in moder-
ate yield (50%, entry 18). In this case, DMF was found to
be a suitable solvent, although the reaction proceeded well
in t-BuOH, albeit in low yield. A compound having a tert-
butyldimethylsilyl protecting group (entry 19) underwent
amine to azide conversion within 10–15 min in 60% yield,
whereas the same conversion under nitrous acid condi-
tions led to deprotection of the silyl ether. The acid labile
tert-butyloxycarbonyl group in entry 20 survived the reac-
tion conditions and the product was obtained in 70%
yield. Some of these reactions were carried out on a large
scale (10–20 mmol).
N3
COOMe
N3
9
10
11
1
4
5
91
Br
O
61a
64a
H2N
S
N3
O
COOEt
N3
HN
N
H
N
12
13
14
3
6
1
50
N3
N3
N
54a
60a
S
F
N
N
N3
N
F
15
16
1
61a
60a
N
N
N3
F
0.25
O
N
N3
Synthesis 2005, No. 11, 1801–1806 © Thieme Stuttgart · New York

PAPER
Aryl Azides from Aryl Amines under Neutral Conditions
1803
after the completion of the reaction (monitored by TLC) and the
mixture was extracted with EtOAc (5 mL × 3). Combined EtOAc
layers were dried (Na2SO4). Removal of volatiles and purification
of the resulting residue by column chromatography gave the title
compound.
In conclusion, we have demonstrated a facile conversion
of various aryl amines having a variety of substituents,
ranging from electron donating groups to electron with-
drawing groups, to the corresponding azides under mild
and neutral conditions. Even sterically hindered amines
were converted to the corresponding azides in good
yields. Protecting groups that are susceptible to cleavage
under nitrous acid conditions survived the present reac-
tion conditions. Most of the reactions were carried out at
r.t. and common laboratory reagents were used. A large-
scale preparation of azides is feasible using this method-
ology.
Yield: 84 mg (70%); brown liquid.
IR (neat): 2122 (s), 1507 (m) cm–1.
1H NMR (CDCl3): d = 7.21 (d, J = 8.4 Hz, 2 H), 6.95 (d, J = 8.4 Hz,
2 H), 2.89–2.86 (m, 1 H), 1.23 (d, J = 6.7 Hz, 6 H).
13C NMR (CDCl3): d = 145.7, 137.3, 127.7, 118.9, 33.59, 23.9.
MS: m/z = 162 (M+ + 1), 134, 91.
Anal. Calcd for C9H11N3: C, 67.06; H, 6.88; N, 26.07. Found: C.
66.89; H, 6.76; N, 26.19.
Caution! Although no untoward incident has taken place during our
experiments, azides should be handled carefully as some of them
may be explosive.
2-Azido-1,3-diethylbenzene (Entry 2)
Using the general procedure at 50 °C, with 2,6-diethylphenylamine
(100 mg, 0.67 mmol), sodium azide (131 mg, 2.01 mmol), H2O (200
mL), t-BuONO (1.6 mL, 8.04 mmol) and t-BuOH (1 mL) as solvent,
the title compound was obtained.
All the reactions were carried out at r.t. unless otherwise mentioned.
Column chromatography was performed using 60–120 mesh silica
gel and solvents used for chromatography were a mixture of petro-
leum ether (bp 60–80 °C) and EtOAc. The majority of the com-
pounds were eluted with petroleum ether–EtOAc (4:1). Compounds
were washed with a small quantity of petroleum ether after isolation
from column chromatography in order to check the melting points.
Melting points were recorded on capillary melting point apparatus
and are uncorrected. 1H NMR and 13C NMR were recorded at 200
and 50 MHz, respectively. Chemical shifts are reported in d units
with respect to TMS as internal standard. IR peaks have been
marked as w, m or s to represent weak, medium and strong intensi-
ties. Mass spectra were recorded on a HP-5989A spectrometer (CI
mode; isobutane was used as chemical ionization gas). Combustion
analysis was obtained using a Perkin–Elmer 2400 analyzer. All an-
alytical works were carried out at the Analytical Research Depart-
ment of Discovery Research.
Yield: 87 mg (74%); light brown liquid.
IR (neat):2970 (w), 2099 (s), 1449 (m) cm–1.
1H NMR (CDCl3): d = 7.09–7.02 (m, 3 H), 2.75 (q, J = 7.6 Hz, 4 H),
1.26 (t, J = 7.6 Hz, 6 H).
13C NMR (CDCl3): d = 138.4, 127.1, 126.2, 124.2, 24.9, 14.7.
MS: m/z = 176 (M+ + 1), 148, 102.
Anal. Calcd for C10H13N3: C, 68.54; H, 7.46; N, 23.98. Found: C.
68.69; H, 7.37, N, 23.86.
(4-Azidophenyl)dimethylamine (Entry 3)
Using the general procedure, with N,N-dimethylbenzene-1,4-di-
amine (100 mg, 0.73 mmol), sodium azide (143 mg, 2.2 mmol),
H2O (219 mL), t-BuONO (1.7 mL, 8.76 mmol) and t-BuOH (1 mL)
as solvent, the title compound was obtained.
Yield: 71 mg (60%); brown solid; mp 42–43 °C (lit.14 42.5–
43.5 °C).
Aryl amines (entries 1–13) were obtained from commercial sources
and used without further purification. Aryl amines (entries 14–22)
were prepared using well-established methods13 in the pure form.
IR (KBr): 2120 (s) cm–1.
t-BuONO
To an ice-cold solution of concd H2SO4 (155 g, 84 mL, 1.58 mol)
and H2O (84 mL) was added t-BuOH (117.9 g, 150 mL) dropwise
followed by the addition of a solution of sodium nitrite (120 g in 475
mL of H2O). The reaction was kept at 0 °C during the addition,
which was complete after 1 h. The reaction mixture was warmed to
r.t. and stirred overnight. The aq layer was separated and the organic
portion was washed with aq NaHCO3 (10 g) and NaCl (54 g) in H2O
(200 mL). The organic portion was then dried (Na2SO4) and dis-
tilled at normal pressure. A light yellow fraction (ca. 100–120 mL)
collected at 80–90 °C was used for all the reactions. It was stored at
4 °C and protected from light.
1-Azido-4-methoxybenzene15 (Entry 4)
Using the general procedure, with 4-methoxyaniline (500 mg, 4.06
mmol), sodium azide (793 mg, 12.2 mmol), H2O (610 mL), t-
BuONO (9.6 mL, 48.7 mmol) and t-BuOH (4 mL) as solvent, the
title compound was obtained.
Yield: 520 mg (86%); brown liquid.
IR (neat): 2119 (s) cm–1.
2-Azido-1,4-dimethoxybenzene16 (Entry 5)
Using the general procedure, with 2,5-dimethoxyaniline (500 mg,
3.27 mmol), sodium azide (637 mg, 9.8 mmol), H2O (980 mL), t-
BuONO (3.9 mL, 19.62 mmol) and t-BuOH (3 mL) as solvent, the
title compound was obtained.
GC Conditions for the Analysis of t-BuONO
Column, DB 1701 (30m × 0.25mm × 1mm), carrier gas N2, inj.
temp. 250 °C, det. temp. 270 °C, oven prog. 40 °C (5 min), 10 °C/
min→250 °C (5 min). tR = 3.52 min (t-BuOH) and 4.0 min (t-
BuONO).
Yield: 415 mg (71%); liquid.
IR (neat): 2120 (s), 1506 (m), 1220 (s) cm–1.
1-Azido-4-isopropylbenzene (Table 1, Entry 1); General Proce-
dure
1-Azido-2-methyl-4-nitrobenzene (Entry 6)
Using the general procedure, with 2-methyl-4-nitrophenylamine
(100 mg, 0.66 mmol), sodium azide (128 mg, 1.97 mmol), H2O (198
mL), t-BuONO (1.56 mL, 7.92 mmol) and t-BuOH (1 mL) as sol-
vent, the title compound was obtained.
Yield: 85 mg (73%); brown solid; mp 64–65 °C (lit.17 64–65 °C).
IR (KBr): 2122 (s) cm–1.
t-BuOH (1 mL) was added to sodium azide (144 mg, 2.22 mmol)
moistened with H2O (222 mL) in a round bottom flask. 4-Isopropyl-
phenylamine (100 mg, 0.74 mmol) was added to the stirring solu-
tion followed by the addition of t-BuONO (1.0 mL, 8.88 mmol).
Stirring was continued at r.t. (at elevated temperature wherever
mentioned) for 1 h. H2O (3 mL) was added to the reaction mixture
Synthesis 2005, No. 11, 1801–1806 © Thieme Stuttgart · New York

1804
J. Das et al.
PAPER
2-Azido-3,4-dimethyl-1-nitrobenzene (Entry 7)
Anal. Calcd for C6H7N5O2: C, 39.77; H, 3.89; N, 38.66. Found: C,
39.56; H, 3.86; N, 38.79.
Using the general procedure, with 2,3-dimethyl-6-nitrophenyl-
amine (100 mg, 0.60 mmol), sodium azide (117 mg, 1.8 mmol),
H2O (180 mL), t-BuONO (1.4 mL,7.2 mmol) and t-BuOH (1 mL) as
solvent, the title compound was obtained.
Yield: 98 mg (85%); light yellow solid; mp 67–69 °C (lit.18 67–
68 °C; reported yield, 91%).
5-Azido-1H-indole (Entry 12)
Using the general procedure at 45 °C, with 5-amino-1H-indole (250
mg, 1.89 mmol), sodium azide (364 mg, 5.6 mmol), H2O (567 mL),
t-BuONO (4.5 mL, 22.7 mmol) and t-BuOH (2 mL) as solvent, the
title compound was obtained.
IR (KBr): 2151 (m), 1517 (s) cm–1.
Yield: (149 mg, 50%); light brown solid; mp 75–78 °C.
IR (KBr): 2112 (s) cm–1.
4-Azido-1-fluoro-2-nitrobenzene (Entry 8)
Using the general procedure, with 4-fluoro-3-nitrophenylamine
(100 mg, 0.64 mmol), sodium azide (125 mg, 1.92 mmol), H2O (192
mL), t-BuONO (1.52 mL, 7.68 mmol) and t-BuOH (1 mL) as sol-
vent, the title compound was obtained.
Yield: 107 mg (92%); brown solid; mp 54 °C (lit.19 53–55 °C; re-
ported yield, 43%).
1H NMR (CDCl3): d = 8.17 (br s, 1 H), 7.41–7.18 (m, 3 H), 6.90 (d,
J = 8.1 Hz, 1 H), 6.52 (s, 1 H).
13C NMR (CDCl3): d = 133.5, 132.2, 128.7, 125.6, 114.1, 112.1,
110.2, 102.5.
MS: m/z = 159 (M+ + 1), 143, 131.
IR (KBr): 2129 (m), 1538 (s) cm–1.
Anal. Calcd for C8H6N4: C, 60.75; H, 3.82; N, 35.42. Found: C,
60.55; H, 3.81; N, 35.54.
Methyl 2-Azido-5-bromobenzoate (Entry 9)
2-Azidobenzothiazole (Entry 13)
Using the general procedure, with methyl 2-amino-5-bromoben-
zoate (100 mg, 0.43 mmol), sodium azide (84 mg, 1.29 mmol), H2O
(129 mL), t-BuONO (1.0 mL, 5.16 mmol) and t-BuOH (0.5 mL) as
solvent, the title compound was obtained.
Using the general procedure, with 2-aminobenzothiazole (500 mg,
3.33 mmol), sodium azide (650 mg, 10.0 mmol), H2O (500 mL), t-
BuONO (3.96 mL, 20 mmol) and t-BuOH (3.5 mL) as solvent, the
title compound was obtained.
Yield: 100 mg (90%); white solid; mp 68–70 °C.
IR (KBr):2951 (w), 2125 (m), 2084 (m), 1730 (s), 1483 (m) cm–1.
1H NMR (CDCl3): d = 7.98 (d, J = 2.2 Hz, 1 H), 7.61 (dd, J = 2.3,
8.4 Hz, 1 H), 7.10 (d, J = 8.4 Hz, 1 H), 3.90 (s, 3 H).
13C NMR (CDCl3): d = 166.6, 147.6, 135.9, 134.6, 121.5, 117.2,
52.6.
MS: m/z = 257 (M+ + 1), 229, 198, 150, 107.
Yield: 316 mg (54%); brown, low-melting solid.
IR (neat): 2132 (s) cm–1.
1H NMR (CDCl3): d = 7.54 (d, J = 7.8 Hz, 2 H), 7.10 (d, J = 7.8 Hz,
2 H).
13C NMR (CDCl3): d = 142, 132.2, 129.9, 129.7, 120.6, 119.4,
110.2.
MS: m/z = 177 (M+ + 1), 151.
Anal. Calcd for C8H6BrN3O2: C, 37.53; H, 2.36; N, 16.41. Found:
C. 37.61; H, 2.39; N, 16.48.
Anal. Calcd for C7H4N4S: C, 47.72; H, 2.29; N, 31.80. Found: C,
47.49; H, 2.16; N, 31.71.
4-Azidobenzensulfonamide (Entry 10)
1-(4-Azido-2-fluorophenyl)-1H-1,2,4-triazole (Entry 14)
Using the general procedure, with 1-(4-amino-2-fluorophenyl)-1H-
1,2,4-triazole (500 mg, 2.80 mmol), sodium azide (547 mg, 8.42
mmol), H2O (425 mL), t-BuONO (3.3 mL, 16.8 mmol) and t-BuOH
(3 mL) as solvent, the title compound was obtained.
Using the general procedure, with 4-aminobenzensulfonamide (500
mg, 2.91 mmol), sodium azide (567.5 mg, 8.73 mmol), H2O (435
mL), t-BuONO (3.46 mL, 17.5 mmol) and t-BuOH (3 mL) as sol-
vent, the title compound was obtained.
Yield: 351 mg (61%); white solid; mp 157–160 °C.
IR (KBr): 3349 (m), 2924 (w), 2132 (m), 2099 (m), 1589 (w) cm–1.
1H NMR (CDCl3 + DMSO-d6): d = 7.91 (d, J = 8.3 Hz, 2 H), 7.13
(d, J = 8.8 Hz, 2 H), 3.95 (br s, 2 H).
13C NMR (DMSO-d6): d = 142.8, 140.4, 127.5, 119.4.
MS: m/z = 199 (M+ + 1), 182, 173, 158.
Yield: 345 mg (60%); solid; mp 53–55 °C.
IR (KBr): 2119 (s) cm–1.
1H NMR (CDCl3): d = 8.62 (s, 1 H), 8.12 (s, 1 H), 7.88 (t, J = 8.5
Hz, 1 H), 7.01–6.85 (m, 2 H).
13C NMR (DMSO-d6): d = 154.3 (d, J = 250 Hz), 152.2, 145.0 (d,
J = 7 Hz), 141.3 (d, J = 10 Hz), 126.5, 121.0 (d, J = 9 Hz), 116.0 (d,
J = 3 Hz), 108.2 (d, J = 24 Hz).
Anal. Calcd for C6H6N4O2S: C, 36.36; H, 3.05; N, 28.27. Found: C.
36.88; H, 3.14; N, 28.40.
MS: m/z = 205 (M+ + 1), 179.
Anal. Calcd for C8H5FN6: C, 47.05; H, 2.47; N, 41.16. Found: C,
46.98; H, 2.31; N, 41.27.
Ethyl 3-Azido-1H-pyrazole-4-carboxylate (Entry 11)
Using the general procedure, with ethyl 3-amino-1H-pyrazole-4-
carboxylate (500 mg, 3.23 mmol), sodium azide (630 mg, 9.7
mmol), H2O (485 mL), t-BuONO (3.84 mL, 19.4 mmol) and t-
BuOH (3.5 mL) as solvent, the title compound was obtained.
1-(4-Azido-2-fluorophenyl)-1H-pyrazole (Entry 15)
Using the general procedure, with 1-(4-amino-2-fluorophenyl)-1H-
pyrazole (500 mg, 2.82 mmol), sodium azide (550 mg, 8.46 mmol),
H2O (423 mL), t-BuONO (3.3 mL, 16.9 mmol) and t-BuOH (3 mL)
as solvent, the title compound was obtained.
Yield: 374 mg (64%); white solid; mp 110–112 °C.
IR (KBr): 2128 (m), 1668 (s), 1550 (m) cm–1.
1H NMR (CDCl3): d = 8.10 (s, 1 H), 4.32 (q, J = 6.8 Hz, 2 H), 1.36
(t, J = 6.8, 3 H).
13C NMR (DMSO-d6): d = 161.3, 147.0, 135.0, 103.4, 59.6, 14.2.
MS: m/z = 182 (M+ + 1), 154, 126.
Yield: 350 mg (61%); white solid; mp 90–91 °C.
IR (KBr): 2112 (s) cm–1.
1H NMR (CDCl3): d = 7.96–7.85 (m, 2 H), 7.73 (s, 1 H), 6.92 (t,
J = 8.3 Hz, 2 H), 6.48 (s, 1 H).
Synthesis 2005, No. 11, 1801–1806 © Thieme Stuttgart · New York

PAPER
Aryl Azides from Aryl Amines under Neutral Conditions
1805
13C NMR (DMSO-d6): d = 153.7 (d, J = 248 Hz), 140.9, 139.4 (d,
J = 10 Hz), 131.2 (d, J = 7.5 Hz), 125.8 (d, J = 1.5 Hz), 124.8 (d,
J = 10 Hz), 115.9 (d, J = 3.5 Hz), 108.1 (d, J = 2.5 Hz), 107.6.
mL), t-BuONO (0.74 mL, 3.72 mmol) and t-BuOH (0.3 mL) as sol-
vent, the title compound was obtained.
Yield: 65 mg (60%); liquid.
IR (KBr): 2115 (s), 1521 (s) cm–1.
MS: m/z = 204 (M+ + 1), 178.
Anal. Calcd for C9H6FN5: C, 53.19; H, 2.98; N, 34.47. Found: C,
53.10; H, 3.02, 34.66.
1H NMR (CDCl3): d = 7.70 (s, 1 H), 7.36 (t, J = 8.3 Hz, 1 H), 7.11
(s, 1H), 6.91–6.96 (m, H), 4.76 (s, 2 H), 0.94 (s, 9 H), 0.13 (s, 6 H).
13C NMR (CDCl3): d = 155.4 (d, J = 251.1 Hz), 143.7, 140.8 (d,
J = 10 Hz), 136.5 (d, J = 4.1 Hz), 126 (d, J = 1.9 Hz), 116.4 (d,
J = 2.2 Hz), 115.4 (d, J = 3.4 Hz), 108.4, 107.9, 60.1, 25.9, 18.4,
–5.3.
4-(4-Azido-2-fluorophenyl)morpholine (Entry 16)
Using the general procedure, with 4-(4-amino-2-fluorophenyl)mor-
pholine (500 mg, 2.55 mmol), sodium azide (497 mg, 7.65 mmol),
H2O (382 mL), t-BuONO (3.03 mL, 15.3 mmol) and t-BuOH (2.5
mL) as solvent, the title compound was obtained,
MS: m/z = 348 (M+ + 1), 307, 238.
Yield: 340 mg (60%); brown semi-solid.
IR (neat): 2113 (s) cm–1.
Anal. Calcd for C16H22FN5OSi: C, 55.31; H, 6.38; N, 20.16. Found:
C, 55.49; H, 6.36; N, 20.02.
1H NMR (CDCl3): d = 6.95–6.65 (m, 2 H), 6.48–6.32 (m, 1 H),
tert-Butyl 4-(4-Azido-2-fluorophenyl)piperazine-1-carboxylate
(Entry 20)
Using the general procedure with an exception (reaction carried out
at 70 °C), with tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-
carboxylate (3.0 g, 10.2 mmol), sodium azide (2.0 g, 30.6 mmol),
H2O (1.5 mL), t-BuONO (24.2 mL, 122.4 mmol) and t-BuOH (10
mL) as solvent, the title compound was obtained.
3.95–3.75 (br s, 4 H), 3.10–3.01 (m, 2 H), 3.00–2.88 (m, 2 H).
13C NMR (CDCl3): d = 158.5 (d, J = 250 Hz), 137.2 (d, J = 8.7),
134.5 (d, J = 10 Hz), 119.6 (d, J = 4.2 Hz), 114.8 (d, J = 3.0 Hz),
107.7 (d, J = 24.3 Hz), 66.9, 51.0 (d, J = 3.5 Hz).
MS: m/z = 223 (M+ + 1), 208, 194, 163, 136, 103.
Anal. Calcd for C10H11FN4O: C, 54.05; H, 4.99; N, 25.21. Found:
C, 53.87; H, 4.76; N, 25.11.
Yield: 2.3 g (70%); yellow solid; mp 58–60 °C.
IR (KBr): 2115 (m), 1686 (w) cm–1.
4-(4-Azido-2,6-difluorophenyl)morpholine (Entry 17)
Using the general procedure, with 4-(4-amino-2,6-difluorophe-
nyl)morpholine (500 mg, 2.34 mmol), sodium azide (456 mg, 7.02
mmol), H2O (350 mL), t-BuONO (2.78 mL, 14 mmol) and t-BuOH
(2.5 mL) as solvent, the title compound was obtained.
1H NMR (CDCl3): d = 6.91 (t, J = 8.8 Hz, 1 H), 6.78–6.72 (m, 2 H),
3.59 (t, J = 4.8 Hz, 4 H), 2.98 (t, J = 4.8 Hz, 4 H), 1.48 (s, 9 H).
13C NMR (CDCl3): d = 156.6 (d, J = 200 Hz), 153.7 (d, J = 6.5 Hz),
135.9 (dd, J = 10, 120 Hz), 120.1 (d, J = 5.5 Hz), 114.8 (d, J = 3
Hz), 107.7 (d, J = 25 Hz), 79.8, 50.6, 43.7, 28.4.
Yield: 359 mg (64%); brown solid; mp 69–70 °C.
IR (KBr): 2121 (s) cm–1.
1H NMR (CDCl3): d = 6.55 (d, J = 9.4 Hz, 2 H), 3.80 (t, J = 4.3 Hz,
4 H), 3.15 (t, J = 4.3 Hz, 4H).
MS: m/z = 322 (M+ + 1), 293, 266, 237.
Anal. Calcd for C15H20FN5O2: C, 56.05; H, 6.28; N, 21.79. Found:
C, 55.89; H, 6.16; N, 21.87.
13C NMR (DMSO-d6): d = 158.0 (dd, J = 9, 247 Hz), 136.1 (t,
J = 13 Hz), 124.1 (t, J = 13.5 Hz), 104.0 (m), 66.7, 51.1 (t, J = 3
Hz).
1-Acetyl-4-(4-azido-2-fluorophenyl)piperazine (Entry 21)
Using the general procedure, with 1-[4-(4-amino-2-flurorophe-
nyl)piperazin-1-yl]ethanone (100 mg, 0.42 mmol), sodium azide
(82 mg, 1.26 mmol), H2O (63 mL), t-BuONO (1 mL, 5.0 mmol) and
t-BuOH (0.5 mL) as solvent, the title compound was obtained.
MS: m/z = 241 (M+ + 1), 215, 200, 169, 113, 97.
Anal. Calcd for C10H10F2N4O: C, 49.98; H, 4.20; N, 23.32. Found:
C, 50.10; H, 4.28; N, 23.39.
Yield: 75 mg (68%); orange solid; mp 108–110 °C.
IR (KBr): 2116 (m), 1647 (m), 1508 (s) cm–1.
4-(5-Azidopyridin-2-yl)morpholine (Entry 18)
1H NMR (CDCl3): d = 6.95–6.67 (m, 3 H), 3.83–3.70 (m, 2 H),
Using the general procedure, with 4-(5-aminopyridin-2-yl)morpho-
line (500 mg, 2.79 mmol), sodium azide (544 mg, 8.37 mmol), H2O
(418 mL), t-BuONO (6.6 mL, 33.5 mmol) and DMF (3 mL) as sol-
vent, the title compound was obtained.
3.68–3.55 (m, 2 H), 3.08–2.94 (m, 4 H), 2.14 (s, 3 H).
13C NMR (CDCl3): d = 168.9, 156.0 (d, J = 250 Hz), 135.6 (dd,
J = 10, 85 Hz), 120.2 (d, J = 4 Hz), 114.8 (d, J = 3.5 Hz), 107.7 (d,
J = 25 Hz), 51.0 (d, J = 3 Hz), 50.4 (d, J = 3 Hz), 46.3, 41.4, 21.2.
Yield: 287 mg (50%); brown solid; mp 60–62 °C.
IR (KBr): 2097 (s) cm–1.
1H NMR (CDCl3): d = 7.96 (d, J = 2.4 Hz, 1 H), 7.22 (dd, J = 2.9,
9.2 Hz, 1 H), 6.64 (d, J = 8.8 Hz, 1 H), 3.82 (t, J = 4.9 Hz, 4 H), 3.46
(t, J = 4.9 Hz, 4 H).
13C NMR (CDCl3): d = 157.2, 138.8, 128.3, 127.1, 107.1, 66.6, 45.8.
MS: m/z = 206 (M+ + 1), 178, 150.
MS: m/z = 264 (M+ + 1), 235, 223.
Anal. Calcd for C12H14FN5O: C, 54.75; H, 5.36; N, 26.60. Found:
C, 54.42; H, 5.21; N, 26.71.
1-(4-Azido-2-fluorophenyl)-4-methylsulfonylpiperazine (Entry
22)
Using the general procedure, with 3-fluoro-4-(4-methylsulfonylpip-
erazin-1-yl)phenylamine (100 mg, 0.37 mmol), sodium azide (72
mg, 1.1 mmol), H2O (111 mL), t-BuONO (0.9 mL, 4.44 mmol) and
t-BuOH (0.4 mL) as solvent, the title compound was obtained.
Anal. Calcd for C9H11N5O: C, 52.66; H, 5.41; N, 34.13. Found: C,
52.83; H, 5.41; N, 34.01.
Yield: 70 mg (64%); yellow solid; mp 118–120 °C.
IR (KBr): 2118 (m) cm–1.
1-(4-Azido-2-fluorophenyl)-4-(tert-butyldimethylsilanyloxy-
methyl)-1H-imidazole (Entry 19)
Using the general procedure at 70 °C, with 1-(4-amino-2-fluo-
rophenyl)-4-(tert-butyldimethylsilanyloxymethyl)-1H-imidazole
(100 mg, 0.31 mmol), sodium azide (60 mg, 0.93 mmol), H2O (93
1H NMR (CDCl3): d = 7.10–6.82 (m, 2 H), 6.78–6.68 (m, 1 H),
3.46–3.28 (m, 4 H), 3.22–3.05 (m, 4 H), 2.83 (s, 3 H).
Synthesis 2005, No. 11, 1801–1806 © Thieme Stuttgart · New York

1806
J. Das et al.
PAPER
13C NMR (CDCl3): d = 156 (d, J = 248 Hz), 136.0 (dd, J = 10, 50
Hz), 123.5 (d, J = 3 Hz), 120.3 (d, J = 3.5 Hz), 114.8 (d, J = 3 Hz),
108 (d, J = 25 Hz), 50.3 (d, J = 3 Hz), 50.2 (d, J = 2.5 Hz), 46.1 (d,
J = 2.5 Hz).
(9) GC analysis showed the presence of ca. 40% t-BuOH in t-
BuONO. This reagent could be stored in the refrigerator
(4 °C) for one week. However, t-BuONO stored more than a
week was not as effective and larger excess of reagent was
needed for completion of the reaction. The amount of t-
BuONO was calculated on the basis of 60% purity.
(10) Rate enhancement of a reaction by addition of minute
quantities of H2O has been observed before: (a) Liotta, C.
L.; Burgess, E. M.; Ray, C. C.; Black, E. D.; Fair, B. E.
Phase Transfer Catalysis New Chemistry Catalysts and
Applications; Starks, C. M., Ed.; ACS Symposium Series
326;American Chemical Society: Washington DC, 1987,
15. (b) Liotta, C. L.; Burgess, E. M.; Ray, C. C.; Black, E.
D.; Fair, B. E. Prepr. – Am. Chem. Soc., Div. Pet. Chem.
1985, 30, 367. Similar was the observation by
MS: m/z = 300 (M+ + 1), 274, 259.
Anal. Calcd for C11H14FN5O2S: C, 44.14; H, 4.71; N, 23.40. Found:
C, 43.95; H, 4.53; N, 23.47.
Acknowledgment
We thank analytical department of Discovery Research for analysis
of all the samples. We are also thankful to Drs. R. Rajagopalan and
J. Iqbal for their encouragement.
DRL Publication No. 348-C.
Chandrasekaran’s group in heterogeneous permanganate
oxidation of olefins in presence of small quantities of t-
BuOH and H2O: (c) Baskaran, S.; Das, J.; Chandrasekaran,
S. J. Org. Chem. 1989, 54, 5182.
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Synthesis 2005, No. 11, 1801–1806 © Thieme Stuttgart · New York