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Organic Preparations and Procedures

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Simple and Efficient Method for the

Synthesis of Azides in Water-THF Solvent
System
a b a
M. Swetha , P. Venkata Ramana & S. G. Shirodkar
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

1
Department of Chemistry, N. S. B. College Vazirabad, Nanded, Maharashtra,
India - 431 601
2
Department of Chemistry, University College of Science, Osmania University,
Hyderabad, Andhra Pradesh, India - 500 007
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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/Et2 O) 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-X + NaN3 R-N 3
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
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RCCl + NaN 3 RCN 3

reflux
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)
Entry Substrate (min) (%) (GC)a [760 Torr] (◦ C) Torr

1 PhCH2 Br 15 95 91 211 190 690

2 4-OMeC6 H4 CH2 Br 25 99 94 119 118–118.5 760
3 CH3 CH2 Br 35 90 96 49 48 755
4 CH3 CH2 CH2 Br 21 88 97 81–82 79 760
5 CH3 (CH2 )2 CH2 Br 38 96 89 107 106.5 760
6 CH3 (CH2 )3 CH2 Br 45 86 98 130 132 760
7 Me2 CHCH2 Br 180 97 95 98 43 100
8 Me2 CHBr 60 91 99 69 67 760
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9 Me3 CBr 90 89 93 82 79 760

10 CH3 O2 CCH2 Br 90 86 87 33–34 35 760
11 EtO2 CCH2 Br 180 90 93 164 74–75 23
12 H2 C CHCH2 Br 240 74 98b 92 62 690
13 HC≡CCH2 Br 600 80 96b 78 — —
14 Br CH2 CH2 Br 720 79 89 169 54–55 11
15 PhCOCH2 Br 225 84 81c 116 116 0.5
16 O(CH2 CH2 )2 NCOCH2 Cl 95 96 90c 62d 60–63 —
17 C6 H11 OMs 76 96 97 162 68.5–69 21
18 CH3 (CH2 )3 CH(C2 H5 )CH2 OTf 95 93 90 189 81–82 20
19 CH3 (CH2 )8 CH2 OTf 95 87 89 172 62 0.02
20 CH3 CH(C2 H5 )CH2 OTf 65 96 93 157 72 138
21 CH3 (CH2 )3 CH(C2 H5 )CH2 OAc 540 97 91 189 81–82 20
22 CH3 (CH2 )5 CH2 OAc 480 89 92 164 75 16
23 CH3 (CH2 )6 CH2 OAc 675 84 87 200 198 760
24 3-MeC6 H4 CH2 OTs 120 75 85 225 94 12
25 CH3 CH2 OCH2 CH2 OTs 75 95 93 136 — —
26 PhCH2 OTs 145 94 90 211 190 92
27 PhCOCl 130 97 91c 30–32d 31–32 —
28 3,4,5-F3 C6 H2 COCl 180 93 83c >300d — —
29 2,3,4,5-F4 C6 HCOCl 65 90 98c 188–90d — —
30 2-Furoyl chloride 180 97 94c 66d
62–63 —
31 CH3 (CH2 )4 COCl 150 89 93 107 — —
a
Purity based on GC analysis: column OV-1carrier gas flow H2 /N2 :18 mL/min. sample size
0.2 mL.
b
Purity by GC after distillation.
c
Purity based on GC-MS analysis: Isolated compound subjected to GC-MS by dissolving in DCM.
d
Melting point.
 Synthesis of Azides in Water-THF Solvent System 351

O O
O Water: THF O
O N N O N N
OMs NaN3 N3
F 8h, reflux 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
choice for the highest yields. The products were characterized by 1H 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
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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 H2 O (2 × 10 mL) and dried over sodium sulfate. The product was
isolated by filtration from Na2 SO4 .

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 C3 H3 N3 : 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 C7 H2 F3 N3 O: C, 41.81; H, 1.00; N, 20.89. Found: C, 41.56; H, 0.89;
N, 21.14.
2,3,4,5-Tetrafluorobenzoyl Azide: pale yellow solid; 1H 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 C7 HF4 N3 O: C, 38.37; H, 0.46; N, 19.18. Found: C, 38.64; H, 0.48; N,
18.94.
Hexanoyl Azide: light yellow oil; 1H 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)
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[M] +.
Anal. Calcd for C6 H11 N3 O: 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);
13
C 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 C4 H9 N3 O: 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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