Simple and efficient method for the synthesis of azides in water-THF solvent system

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Simple and Efficient Method for the
Synthesis of Azides in Water-THF Solvent
System
M. Swetha a , P. Venkata Ramana b & S. G. Shirodkar a
a Department of Chemistry, N. S. B. College, Vazirabad, Nanded,
Maharashtra, India, - 431 601
b Department of Chemistry, University College of Science, Osmania
University, Hyderabad, Andhra Pradesh, India, - 500 007
Version of record first published: 02 Aug 2011.
To cite this article: M. Swetha , P. Venkata Ramana & S. G. Shirodkar (2011): Simple and Efficient
Method for the Synthesis of Azides in Water-THF Solvent System, Organic Preparations and Procedures
International: The New Journal for Organic Synthesis, 43:4, 348-353
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Organic Preparations and Procedures International, 43:348–353, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2011.594002
Simple and Efficient Method for the Synthesis
of Azides in Water-THF Solvent System
M. Swetha,1 P. Venkata Ramana,2 and S. G. Shirodkar1
1Department of Chemistry, N. S. B. College Vazirabad, Nanded, Maharashtra,
India - 431 601
2Department of Chemistry, University College of Science, Osmania University,
Hyderabad, Andhra Pradesh, India - 500 007
The azide functionality is a common progenitor for the synthesis of N-containing com-
pounds and not only reacts with nucleophiles and electrophiles but also serves as a nitrene
precursor upon thermolysis or photolysis.1,2 Over the past decade, new perspectives have
been developed for the use of azides in peptide chemistry,3,4 combinatorial chemistry5,6
and heterocyclic synthesis.7,8 Current leading anti-HIV 1 drugs of purine and pyrimi-
dine nucleotides contain an azide group.9–11 In addition, azides can serve as precursors to
biologically active compounds.12,13 Recently, a set of synthetic protocols termed “Click
Chemistry” has attracted enormous attention in medicinal chemistry and related areas of
research, in which azides undergo 1,3-dipolar cycloaddition with terminal alkynes in the
presence of a copper catalyst.14–17
Alkyl azides are generally obtained by heating an alkyl halide with sodium azide
in DMSO or DMF. The work-up for this procedure involves extraction into an organic
solvent (e.g. DCM/CHCl3/EtOAc/Et2O) followed by evaporation to yield the azide.18,19
However, simple alkyl azides have low boiling points and their isolation is difficult as
their boiling points are often close to those of the organic solvents. In such cases, the
isolation of the azides requires the laborious Criegee20 or Claisen distillation.21 In recent
years, trimethylsilyl azide has been developed to introduce the azide moiety into organic
molecules22; however, the reaction of trimethylsilyl azide with unactivated alkyl halides
occurs with difficulty because of the low nucleophilicity of this azide compared to alkali
metal azides. This method is no more successful with secondary halides. Due to the
drawbacks of the above methods, there is a need to develop a mild and simple procedure
for the preparation of alkyl azides from their corresponding alkyl halides and esters such
as mesylates, triflates, acetates and tosylates.
Herein we report the synthesis of azides under mild conditions using a simple work-up.
The present method gives excellent results and offers a direct method for the synthesis of
Received December 31, 2010; in final form May 5, 2011.
Address correspondence to S. G. Shirodkar, Department of Chemistry, N.S.B College Vazirabad,
Nanded, Maharashtra, India 431601. E-mail: shirodkar sg@yahoo.com
348

Synthesis of Azides in Water-THF Solvent System
349
azides. Various alkyl halides, mesylates, triflates, acetates and tosylates were treated with
sodium azide in a water-THF solvent system under reflux to yield the corresponding alkyl
azides (Scheme 1).
Water-THF
R-N3
R-X
+
NaN3
reflux
R = alkyl; X= Cl, Br, OMs, OTf, OAc, OTs
Scheme 1
Primary, secondary as well as tertiary alkyl halides reacted efficiently under these reac-
tion conditions. This reaction can also be carried out with acid chlorides (aromatic/aliphatic)
to give acyl azides (Scheme 2).
O
O
Water-THF
reflux
+
NaN3
RCCl
RCN3
R = alkyl or aryl
Scheme 2
The alkyl halide was added to a saturated solution of sodium azide in a water and THF
solution. Being denser, the alkyl halide initially settled to the bottom, however, upon reflux
for the required time (Table), the alkyl halide was converted to the azide which, being less
dense, floated on top of the aqueous layer. The azide was separated from the aqueous layer
and its purity was determined by a gas chromatographic method or by gas chromatography-
mass spectrometry (GC-MS). Even low melting solids such as phenacyl bromide (Entry 15)
and (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxazolidin-5-yl)methyl mesylate reacted un-
der these conditions to produce azides. The azides were generally obtained in acceptable
purities (81–98%) and may be used for subsequent transformations without any further
purification; purer samples may be obtained by careful distillation. Allyl azide (Entry 12)
and 3-azido-1-propyne (Entry 13) produced in 84% and 80% purities, respectively, were
distilled under reduced pressure (less than 100 Torr) at 50◦C to afford products of 96 and
98% purities, respectively. 1,2-Dibromoethane required a longer reaction time (12 h) to be
converted to 1,2-diazidoethane. The azides derived from 2-chloro-1-morpholinoethanone
(Entry 16) and benzoyl chloride (Entry 27), on standing for two or three days, crystallized
as white or off-white solids. The azides from 3,4,5-trifluorobenzoyl chloride (Entry 28),
2,3,4,5-tetrafluorobenzoyl chloride (Entry 29) and 2-furoyl chloride (Entry 30) gave solid
products directly on reaction with sodium azide. Benzyl bromide reacted faster than benzyl
chloride. Due to the low boiling points of 1,2-dibromoethane and methyl 2-azidoacetate,
their reactions were performed below 40◦C. Alkyl mesylates, triflates, acetates and tosylates
and the respective azides have lower densities than the aq. sodium azide-THF and float on
top of the aqueous medium. Completion of the reactions was monitored by GC analysis.
The linezolid intermediate (R)-5-azidomethyl-3-(3-fluoro-4-morpholinphenyl)-
oxazolidin-2-one was prepared from the corresponding mesylate as shown in Scheme 3.
Previously this conversion has been reported in DMF as solvent,23 here water-THF solvent
system also achieved this azide with 93% yield.

350
Swetha, Ramana, and Shirodkar
Table 1
Azides from Alkyl Halides and Esters and Sodium Azide in aqueous THF (95:5)
(◦C)
Time Yield Purity bp.(◦C)
(min) (%) (GC)a [760 Torr]
Entry
Substrate
(◦C)
Torr
690
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
PhCH2Br
15
25
35
21
38
45
180
60
90
90
180
240
600
720
225
95
76
95
95
65
95
99
90
88
96
86
97
91
89
86
90
74
80
79
84
96
96
93
87
96
97
89
84
75
95
94
97
93
90
97
89
91
94
96
97
89
98
95
99
93
87
93
98b
96b
89
81c
90c
97
90
89
93
91
92
87
85
93
90
91c
83c
211
119
49
81–82
107
130
98
69
82
33–34
164
92
190
4-OMeC6H4CH2Br
CH3CH2Br
CH3CH2CH2Br
CH3 (CH2)2CH2Br
CH3(CH2)3CH2Br
Me2CHCH2Br
118–118.5 760
48
79
106.5
132
43
67
79
35
74–75
62
755
760
760
760
100
760
760
760
23
690
—
11
0.5
—
21
Me2 CHBr
Me3CBr
CH3O2CCH2Br
EtO2CCH2Br
H2C CHCH2Br
HC≡CCH2Br
78
—
Br CH2CH2Br
169
116
62d
54–55
116
60–63
68.5–69
81–82
62
72
81–82
75
198
94
—
190
31–32
—
PhCOCH2Br
O(CH2CH2)2NCOCH2Cl
C6H11OMs
CH3(CH2)3CH(C2H5)CH2OTf
CH3(CH2)8CH2OTf
CH3CH(C2H5)CH2OTf
162
189
172
157
189
164
200
225
136
211
30–32d
>300d
20
0.02
138
20
16
760
12
—
92
—
—
CH3(CH2)3CH(C2H5)CH2OAc 540
CH3(CH2)5CH2OAc
CH3(CH2)6CH2OAc
3-MeC6H4CH2OTs
CH3CH2OCH2CH2OTs
PhCH2OTs
480
675
120
75
145
130
180
65
PhCOCl
3,4,5-F3C6H2COCl
2,3,4,5-F4C6HCOCl
2-Furoyl chloride
CH3(CH2)4COCl
98c 188–90d
—
62–63
—
—
—
—
180
150
94c
93
66d
107
aPurity based on GC analysis: column OV-1carrier gas flow H2/N2:18 mL/min. sample size
0.2 mL.
bPurity by GC after distillation.
cPurity based on GC-MS analysis: Isolated compound subjected to GC-MS by dissolving in DCM.
dMelting point.

Synthesis of Azides in Water-THF Solvent System
351
O
O
O
O
Water: THF
N
N
N
N
O
O
N3
OMs
NaN3
8h, reflux
F
F
Sc
Scheme 3
In the absence of THF, many of the reactions failed to give the desired product even
after prolonged reaction times, and an optimization study showed that 5% THF was best
1
choice for the highest yields. The products were characterized by H NMR, 13C NMR,
IR and MS and their spectra were compared with authentic samples. The IR spectrum
of obtained azido compounds exhibited an absorption maximum at around 2100 cm−1
characteristic of N3. In conclusion, we have developed a novel and efficient nucleophilic
substitution reaction of various alkyl halides or alkoxy esters (mesylates, triflates, acetates
and tosylates) or acid chlorides with sodium azide in a 95:5 water-THF solvent system to
generate the corresponding azides in good yields.
Experimental Section
All chemicals were purchased from Sigma-Aldrich and used as received. IR spectra were
recorded as chloroform solution or KBr pellets on a Shimadzu FTIR-8300 spectropho-
tometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) were obtained on a Bruker Avance
spectrometer in CDCl3 using tetramethylsilane as an internal standard. Chemical shift val-
ues are given in δ. Mass spectra were determined on a Shimadzu GC MS-QP 1000 EX
mass spectrometer. All distillations should be performed in a hood behind a safety shield.
Typical Procedure
To a solution of sodium azide (14.3 g, 0.22 mol) in water (28 mL) in a two necked round
bottom flask equipped with a stirring bar and reflux condenser was added a solution of the
alkyl halide or acid chloride or alkoxy ester (0.15 mol) in THF (5.8 mL) and the mixture
was heated to reflux for an the appropriate time (Table). The progress of the reaction was
monitored by GC/GC-MS (sample injected by dissolving in methylene chloride). When
the alkyl halide (or other substrate) was completely consumed, the reaction mixture was
allowed to cool to room temperature. The new upper layer was separated by using separating
funnel, washed with H2O (2 × 10 mL) and dried over sodium sulfate. The product was
isolated by filtration from Na2SO4.
Spectral Data for Selected Products
3-Azido-1-propyne: light yellow oil; 1H NMR (CDCl3, 400 MHz): δ 2.61 (t, J = 2.4 Hz,
2H), 3.94 (t, J = 2.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 76.5, 75.4, 39.1; IR (neat):
3285, 2985, 2145, 2121 cm−1; MS (EI): m/z (%) 81 (26) [M] +.
Anal. Calcd for C3H3N3: C, 44.44; H, 3.73; N, 51.83. Found: C, 44.70; H, 3.52; N,
52.03.

352
Swetha, Ramana, and Shirodkar
3,4,5-Trifluorobenzoyl Azide: colorless solid; 1H NMR (CDCl3, 400 MHz): δ 7.42 (m,
2H); 13C NMR (CDCl3, 100 MHz): δ 186.5, 153.2, 147.4, 135.5, 110.9; IR (neat): 3057,
2872, 2012, 1645 cm−1; MS (EI): m/z (%) 202 [M + H] +, 224 [M + Na]+.
Anal. Calcd for C7H2F3N3O: C, 41.81; H, 1.00; N, 20.89. Found: C, 41.56; H, 0.89;
N, 21.14.
1
2,3,4,5-Tetrafluorobenzoyl Azide: pale yellow solid; H NMR (CDCl3, 400 MHz):
δ 7.38 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ 187.5, 149.2, 147.8, 145.5, 143.7, 126.4,
113.9; IR (neat): 2987, 2864, 2069, 1674 cm−1; MS (EI): m/z (%) 220 [M + H] +, 242 [M
+ Na]+.
Anal. Calcd for C7HF4N3O: C, 38.37; H, 0.46; N, 19.18. Found: C, 38.64; H, 0.48; N,
18.94.
1
Hexanoyl Azide: light yellow oil; H NMR (CDCl3, 400 MHz): δ 2.52 (t, 2H), 1.79
(m, 2H), 1.40 (m, 2H), 1.12 (m, 2H), 0.89 (t, 2H); 13C NMR (CDCl3, 100 MHz): δ 192.5,
33.2, 29.1, 26.7, 21.4, 11.0; IR (neat): 2962, 1960, 1651 cm−1; MS (EI): m/z (%) 141 (34)
[M] +.
Anal. Calcd for C6H11N3O: C, 51.05; H, 7.85; N, 29.77. Found: C, 50.87; H, 7.85; N,
30.02.
1-Azido-2-ethoxyethane: light yellow oil; 1H NMR (CDCl3, 400 MHz): δ 3.87 (d, J =
7.2 Hz, 2H), 3.47 (d, J = 7.2 Hz, 2H), 3.39 (q, J = 6.9 Hz, 2H), 1.31 (t, J = 6.9 Hz, 3H);
13C NMR (CDCl3, 100 MHz): δ 72.1, 68.3, 52.4, 13.7; IR (neat): 2901, 2039 cm−1; MS
(EI): m/z (%) 115 (15) [M]+.
Anal. Calcd for C4H9N3O: C, 41.73; H, 7.88; N, 36.50. Found: C, 41.47; H, 7.51; N,
36.22.
Acknowledgement
Authors M. S. and P. V. R. acknowledge the Principal, N. S. B. College, Nanded and the
Director, Central Facility Building for Research and Development, Osmania University,
Hyderabad for providing spectral facilities.
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