A simple one-pot procedure for the direct conversion of alcohols into azides using TsIm

Article abstract of DOI:10.1016/j.tetlet.2007.03.049

A facile and efficient method for one-pot conversion of alcohols into azides using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this method, alcohols are refluxed with a mixture of NaN₃, TsIm and triethylamine in the presence of catalytic amounts of tetra-n-butylammonium iodide (TBAI) in DMF affording the corresponding alkyl azides in good yields. This methodology is highly efficient for various structurally diverse alcohols with selectivity for ROH: 1° > 2° > 3°.

Full text of DOI:10.1016/j.tetlet.2007.03.049

Tetrahedron Letters 48 (2007) 3445–3449
A simple one-pot procedure for the direct conversion of alcohols
into azides using TsIm
Mohammad Navid Soltani Rad,a,* Somayeh Behrouzb and Ali Khalafi-Nezhadb
aDepartment of Chemistry, Faculty of Basic Sciences, Shiraz University of Technology, Shiraz 71555-313, Iran
bDepartment of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
Received 24 January 2007; revised 28 February 2007; accepted 7 March 2007
Available online 12 March 2007
Abstract—A facile and efficient method for one-pot conversion of alcohols into azides using N-(p-toluenesulfonyl)imidazole (TsIm)
is described. In this method, alcohols are refluxed with a mixture of NaN3, TsIm and triethylamine in the presence of catalytic
amounts of tetra-n-butylammonium iodide (TBAI) in DMF affording the corresponding alkyl azides in good yields. This method-
ology is highly efficient for various structurally diverse alcohols with selectivity for ROH: 1ꢀ > 2ꢀ > 3ꢀ.
ꢁ 2007 Elsevier Ltd. All rights reserved.
Alkyl azides1 are versatile substrates in organic synthesis
and have been used extensively for the introduction of
primary amino groups and the construction of N-het-
erocycles.2 The most common routes to aliphatic azides
involve nucleophilic substitution of alkyl halides or sul-
fonates with inorganic azides or addition of hydrazoic
acid (HN3) to alkenes.3 Direct synthesis of azides from
the corresponding alcohols would be a highly advanta-
geous and attractive strategy. There are a few methods
established for accessing alkyl azides from alcohols
using Mitsunobu reactions.4 These methods use hydra-
zoic acid as the azide source for alkyl, benzylic, and
allylic alcohols. However, the use of highly toxic and
explosive hydrazoic acid limits the applicability of this
method. Alternatives to HN3 include diphenyl phospho-
razidate (DPPA)5 or zinc azide/bis-pyridine complex6 as
the azide source. Other methods for direct conversion of
alcohols to azides include; NaN3/BF3–Et2O7 and HN3/
TiCl4.8 Thompson and co-workers established a proce-
dure using diphenyl phosphorazidate (DPPA)/1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU)9 for conversion of
diverse alcohols to azides. Modifications using bis-
(2,4-dichlorophenyl)chlorophosphate/NaN3/4-(dimethyl-
amino)pyridine (DMAP)10 and bis(p-nitrophenyl)phos-
phorazidate/DBU11 have been reported. The one-pot
synthesis of allyl azides from allyl alcohols using
NaN3/triphosgene has also been described.12 Alkyl
azides were prepared from alcohols with CBr4/Ph3P/
NaN3 and exemplified by syntheses of azidonucleo-
sides13a and mappicin.13b In contrast to Mitsunobu con-
ditions, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)
was used instead of diethyl azodicarboxylate (DEAD)
for conversion of alcohols to azides.14
The aforementioned methods are effective for the con-
version of alcohols to azides, but they have several
drawbacks including the use of highly toxic and explo-
3,4,8
sive HN3
and expensive DEAD,4 the limitation of
various reactions to allylic, benzylic and tertiary alco-
hols,7,8,12 ineffectiveness with some alcohols,9–11 tedious
work-up as well as cumbersome separation from gener-
ated Ph3P@O and unreacted Ph3P.4–6,13,14 In order to re-
duce the above problems and also in our efforts towards
azidation of acyclic nucleosides, we report N-(p-toluene-
sulfonyl)imidazole (TsIm) as a highly efficient, cheap
and stable reagent for conversion of alcohols to azides
in the presence of NaN3, triethylamine (TEA) and cata-
lytic amounts of tetra-n-butylammonium iodide (TBAI)
in DMF (Scheme 1).
TsIm/TBAI/TEA
+ NaN
R OH
R N3
3
DMF,reflux, 5-12 h
Keywords: Azide; Alcohol; N-(p-Toluenesulfonyl)imidazole (TsIm);
Triethylamine (TEA); Tetrabutylammonium iodide (TBAI).
R = 1, 2 and 3 alkyl
˚
˚
˚
O
N
H3C
S
N
TsIm:
*
Corresponding author. Tel.: +98 711 7261392; fax: +98 711
7354523; e-mail addresses: soltani@sutech.ac.ir; nsoltanirad@gmail.
com
O
Scheme 1.
0040-4039/$ - see front matter ꢁ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.049

3446
M. N. Soltani Rad et al. / Tetrahedron Letters 48 (2007) 3445–3449
Table 1. Effect of various solvents on the conversion of N-(2-
Table 3. Effect of various PTCs on the conversion of N-(2-hydroxy-
hydroxyethyl)phthalimide into the corresponding azide
ethyl)phthalimide into the corresponding azide
Entry
Solvent
Time (h)
Yieldb (%)
Entry
PTC
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DMSO
DMF
12
5
30
91
10
NRc
20
1
2
3
4
5
6
7
8
None
TBAF
TBAC
TBAB
48
18
12
12
5
24
22
12
NRc
25
43
50
91
15
33
70
DMFa
24
48
18
18
48
24
48
THF
MeCN
HMPA
Toluene
Acetone/H2Od
H2O
TBAI
a
20
(n-Bu4N)HSO4
(n-Bu4N)N3
TBAI/TBAB
NR
Trace
NR
a Two equivalents of TEA was used.
b Isolated yield.
c No reaction.
a Anhydrous DMF.
b Isolated yield.
c No reaction.
d (1:1) Ratio.
The optimized amount of TsIm was found to be 1.5–
2.0 equiv per equivalent of alcohol. We also examined
other TsIm analogues (Table 4).
To obtain optimized reaction conditions, we chose
the reaction of N-(2-hydroxyethyl)phthalimide with
excess NaN3 (3 equiv), freshly prepared TsIm15
(1.5 equiv) and a catalytic amount of TBAI as a reaction
model; the effect of various solvents on reaction
times and yields was studied. The results are depicted
in Table 1.
As the data in Table 4 indicates, a higher yield of azide
and short reaction time were obtained with TsIm (Table
4, entry 3) in comparison with other sulfonyl analogues.
Replacing the tolyl in TsIm with methyl, trifluromethyl
and phenyl gave no improvement in reaction yield
(Table 4, entries 1, 2 and 4). Furthermore, changing
the imidazole residue to other azole derivatives did not
affect the reaction efficiency (Table 4, entries 5 and 6).
N-Tosyl phthalimide and tosyl azide2a (Table 4, entries
7 and 8) were inactive for the conversion of N-(2-
hydroxyethyl)phthalimide to the corresponding azide
even after reflux for 48 h.
As Table 1 indicates, DMF (Table 1, entry 2) was the
most efficient solvent hence it was the solvent of choice.
Using anhydrous DMF afforded a low yield of the cor-
responding azide. The role of base in the reaction was
critical for activation of the alcohols to react with TsIm.
In this case, we evaluated the potency of various organic
and inorganic bases on reaction times and yields of the
model reaction (Table 2). The results in Table 2 demon-
strate that among the examined bases TEA (Table 2,
entry 7) was the most appropriate for activation of
N-(2-hydroxyethyl)phthalimide.
Table 4. Comparison of TsIm reactivity with analogues in the
conversion of N-(2-hydroxyethyl)phthalimide into the corresponding
azide
Entry
Reagent
Time (h)
Yielda (%)
O
We also investigated the role of phase transfer catalysts
(PTC) on the reaction (Table 3). In the absence of PTC
no reaction occurred even when reflux was prolonged up
to 48 h. Other PTCs (Table 3, entries 2–4, 6 and 7) were
not as effective as TBAI (Table 3, entry 5). Moreover,
the use of an equal mixture of TBAI and TBAB (Table
3, entry 8) was less efficient. Using further amounts of
TBAI and other PTCs had negligible effects on the
reaction.
N
N
Me
S
N
N
1
24
20
O
O
S
2
3
24
5
32
91
F3C
O
O
S
N
N
N
N
N
O
O
S
4
5
6
12
12
12
60
54
48
O
O
S
N
Table 2. Effect of various bases on the conversion of N-(2-hydroxy-
ethyl)phthalimide into the corresponding azide
O
NO2
Entry
Base
Time (h)
Yielda (%)
O
S
N
N
1
2
3
4
5
6
7
8
DBU
48
24
24
48
18
48
5
Trace
20
20
Trace
35
NRb
91
N
O
DABCO
DMAP
MgO
Cs2CO3
K2CO3
TEA
O
O
S
7
8
N
48
48
NRb
NR
O
O
O
S
N3
NaH
12
45
O
a Isolated yield.
b No reaction.
a Isolated yield.
b No reaction.

M. N. Soltani Rad et al. / Tetrahedron Letters 48 (2007) 3445–3449
3447
Table 5. Effect of various sulfonyl chlorides in the conversion of N-(2-
Table 6. One-pot conversion of alcohols to azides using TsIm/TBAB/
hydroxyethyl)phthalimide into the corresponding azide
TEA in refluxing DMF
Yielda (%)
31
Entryref.
R–N3
mb (cmꢀ1
)
Time Yieldc
a
Entry
Sulfonyl chloride
Time (h)
(h)
(%)
O
Me
S
Cl
Cl
1
24
N3
O
17d,14,17a–c
26,14
2097
2097
7
86
O
S
2
3
24
24
24
38
27
22
F3C
N3
6
8
93
92
O
O
S
Cl
Cl
N3
314
2098
2166
2106
O
O
S
NO2
4
O
4
10
8
82
90
N3
a Isolated yield.
N3
517b
O2N
Various sulfonyl chlorides were examined instead of
TsIm (Table 5). Lower yields of azide were obtained
when sulfonyl chlorides were used for sulfonylation of
(2-hydroxyethyl)phthalimide instead of TsIm. This
probably results from the fact that the highly reactive
sulfonyl chlorides have less selectivity for reaction with
alcohols.
66,7d
2096
2100
8
6
83
88
N3
711,14,17a–d
N3
811,14
917e
2167
2098
10
12
62
56
N3
N3
To evaluate the general applicability and versatility of
the method, the optimized conditions were applied to
various structurally diverse alcohols (Table 6). As the
results in Table 6 indicate, various alcohols including:
primary, secondary and tertiary were successfully con-
verted into the corresponding azides in good yields.
The generality of the method was confirmed with respect
to allylic (Table 6, entry 6), benzylic (Table 6, entries 1,
4, 5, 13–15 and 19), aliphatic (Table 6, entries 7–9), ali-
cyclic (Table 6, entries 10–12 and 20) and other alcohols
containing N-heterocycles (Table 6, entries 16–19 and
21). Furthermore, the conversion of complex or natu-
rally occurring alcohols into their corresponding azides
is feasible using this method (Table 6, entries 20 and
21). For example, 50-trityl-thymidine was converted into
its azide (Table 6, entry 21) which can be transformed
into AZT (Zidovudine)4d,16 after detritylation.
1014
2168
12
50
N3
1114,17c,d
1217c
136,9,11,17c
2090
2103
9
9
79
82
N3
N3
N3
2106
2099
8
75d
73
N3
147d,14,7d
10
N3
157d
2156
11
67
O
O
Mechanistically, we suggest that firstly reaction of base-
activated alcohol with TsIm affords an alkyl tosylate.
Subsequently, the azide ion reacts with the alkyl tosylate
to give the alkyl azide via nucleophilic substitution. Two
roles for TBAI can be considered: (1) by anion exchange
more azide anions enter as (n-Bu4N)N3; (2) some tosyl-
ate can be exchanged by iodide which is a better leaving
group than tosylate for nucleophilic substitution.
Indeed, iodide ions considerably catalyze the reaction
(Table 3). We also examined other sources of iodide
including: LiI, NaI and KI for the conversion of N-(2-
hydroxyethyl)phthalimide to the corresponding azide.
The azide was obtained in 25%, 31% and 32% yields,
respectively. This experiment manifested the significance
of the tetrabutylammonium cation and iodide anion
simultaneously. Using our method for the conversion
of optically pure R-(+)-1-phenylethanol into its corre-
sponding azide (Table 6, entry 13) was followed with a
reduction in optical purity (64% ee). This can be ex-
plained as a result of partial inversion and retention of
N3
16
17
N
2112
2102
5
6
91
90
O
O2N
N
N3
N
CH3
N
N3
O
N
18
19
2102
2187
10
12
65
54
N
N
N3
( )
3
209
2114
12
41
N
3
(continued on next page)

3448
M. N. Soltani Rad et al. / Tetrahedron Letters 48 (2007) 3445–3449
(c) Boyer, J. H.; Canter, F. C. Chem. Rev. 1954, 54, 1–57;
Table 6 (continued)
a
Entryref.
R–N3
mb (cmꢀ1
)
Time
(h)
Yieldc
(%)
(d) Smith, P. A. S. Org. React. 1946, 3, 337–349.
3. Smith, P. A. S. In Open Chain Nitrogen Compounds; W.A.
Benjamin: New York, 1966; Vol. II, p 211.
O
N
4. (a) Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc.
1972, 94, 679–680; (b) Hughes, D. L. Org. React. 1992, 42,
358–359; (c) Loibner, H.; Zbiral, E. Helv. Chim. Acta
1977, 60, 417–425; (d) Mitsunobu, O. Synthesis 1981, 1–
28; (e) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28,
127–164; (f) Saito, A.; Saito, K.; Tanaka, A.; Oritani, T.
Tetrahedron Lett. 1997, 38, 3955–3958; (g) Mizuno, M.;
Shior, T. Chem. Commun. 1997, 2165–2166; (h) Fabiano,
E.; Golding, B. T.; Sadeghi, M. M. Synthesis 1987, 190–
192; (i) Bessodes, M.; Abushanab, E.; Antonakis, K.
Tetrahedron Lett. 1984, 25, 5899–5902; (j) Mitsunobu, O.
Bull. Chem. Soc. Jpn. 1967, 40, 4235–4238; (k) Lee, S.-H.;
Yoon, J.; Chung, S.-H.; Lee, Y.-S. Tetrahedron 2001, 57,
2139–2145.
HN
2116,4d
2085
12
47
O
TrO
O
N3
a All products were characterized by 1H and 13C NMR, IR, CHN and
MS analysis.
b IR signal of azide in wavenumbers (cmꢀ1).
c Isolated yield.
20
d Also obtained from optically pure R-(+)-1-phenylethanol, ½aꢁD þ45
(c 5, in MeOH) in 64% ee.
configuration at the same time. Finally, it is interesting
to note that there was a remarkable tendency for TsIm
to react with alcohols rather than nucleophiles present
in the reaction mixture: no tosyl azide was observed
through the course of reactions even in trace amounts.
5. Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1977, 1977–1980.
6. Viaud, M. C.; Rollin, P. Synthesis 1990, 130–132.
7. (a) Khuong-Huu, Q.; Pancrazi, A.; Kabore, I. Tetrahedron
1974, 30, 2579–2586; (b) Adam, G.; Andrieux, J.; Plat, M.;
Viossat, B.; Rodier, N. Bull. Soc. Chim. Fr. 1984, 101–108;
(c) Adam, G.; Andrieux, J.; Plat, M. Tetrahedron 1985, 41,
399–407; (d) Kumar, H. M. S.; Reddy, B. V. S.; Anjane-
yulu, S.; Yadav, J. S. Tetrahedron Lett. 1998, 39, 7385–
7388.
8. Hassner, A.; Fibiger, R.; Andisik, D. J. Org. Chem. 1984,
49, 4237–4244.
9. Thompson, A. S.; Humphrey, G. R.; Demarco, A. M.;
Mathre, D. J.; Grabowski, J. J. J. Org. Chem. 1993, 58,
5886–5888.
In conclusion, a convenient method has been established
for the one-pot conversion of alcohols into the corre-
sponding azides using TsIm/TEA/TBAI (cat.) in reflux-
ing DMF. This method has favorable generality and
applicability for primary, secondary and tertiary alco-
hols with selectivity: 1ꢀ > 2ꢀ > 3ꢀ.
General procedure for the one-pot conversion of alcohols
to azides: In a double-necked round bottom flask
(100 mL) equipped with a condenser was added a
mixture, consisting of alcohol (0.01 mol), TsIm
(0.015 mol),15 TEA (0.02 mol), NaN3 (0.03 mol) and a
catalytic amount of TBAI (0.1 g) in DMF (30 mL).
The mixture was refluxed, and in most cases, darkening
occurred. Reflux was continued until TLC monitoring
indicated no further improvement in the conversion
(Table 6). The solvent was evaporated under vacuum
and the remaining foam was dissolved in CHCl3
(100 mL) and subsequently washed with water
(2 · 100 mL). The organic layer was dried (Na2SO4)
and evaporated. The crude product was purified by
column chromatography on silica gel eluting with
n-hexane–EtOAc (15:1).18
10. Yu, C.; Liu, B.; Hu, L. Org. Lett. 2000, 2, 1959–1961.
11. Mizuno, M.; Shioiri, T. Chem. Commun. 1997, 2165–2166.
12. Jayanthi, A.; Gumaste, V. K.; Deshmukh, A. R. A. S.
Synlett 2004, 979–982.
13. (a) Li, Z.-S.; Qiao, R.-P.; Yang, Z. J.; Zhang, L.-R.;
Zhang, L. H. Tetrahedron: Asymmetry 2006, 17, 1056–
1061; (b) Toyota, M.; Komori, C.; Ihara, M. J. Org.
Chem. 2000, 65, 7110–7113.
14. Iranpoor, N.; Firouzabadi, H.; Akhalaghinia, B.; Now-
rouzi, N. Tetrahedron Lett. 2004, 45, 3291–3294.
15. N-(p-Toluenesulfonyl)imidazole (TsIm) is a cheap and
stable reagent that was applied previously for selective
tosylation of alcohols (see: Lanman, B. A.; Myers, A. G.
Org. Lett. 2004, 6, 1045–1047) and carbohydrates (see:
Teranishi, K. Carbohydr. Res. 2002, 337, 613–619; Hicks,
D. R.; Fraser-Reid, B. Synthesis 1974, 203; Byun, H.-S.;
Zhong, N.; Bittman, R. Org. Synth. Coll. Vol. 10, p 690;
Vol. 77, p 225). It was also used for polynucleotide
synthesis (see: Berlin, Y. A.; Chakhmakhcheva, O. G.;
Efimov, V. A.; Kolosov, M. N.; Korobko, V. G. Tetra-
hedron Lett. 1973, 1353–1354) and esterification of
FMOC-amino acids with hydroxyl functionalized solid
supports (see: Blankemeyer-Menge, B.; Nimtz, M.; Frank,
R. Tetrahedron Lett. 1990, 31, 1701–1704). Although, this
reagent is commercially available, in our experience the
use of freshly prepared TsIm is better. This reagent can be
easily prepared (see: Stabb, H. A. Angew. Chem., Int. Ed.
Engl. 1962, 1, 351–367; Stabb, H. A.; Wendel, K. Chem.
Ber. 1960, 93, 2902–2915; and also see: Hicks, D. R.;
Fraser-Reid, B. Synthesis 1974, 203; Byun, H.-S.; Zhong,
N.; Bittman, R. Org. Synth. Coll. Vol. 10, p 690; Vol. 77, p
225). We prepared this reagent very efficiently on a large
scale using a solvent-free technique: In a well-dried mortar
a mixture consisting of tosyl chloride (1 equiv) and
imidazole (2.2 equiv) was ground vigorously at room
temperature. The reaction started immediately and the
Acknowledgements
We wish to thank the Shiraz University of Technology
and Shiraz University Research Councils for partial sup-
port of this work.
References and notes
1. (a) Sheradsky, T. In The Chemistry of the Azido Group;
Patai, S., Ed.; Interscience: New York, 1971; p 331; (b)
March, J. Advanced Organic Chemistry, 4th ed.; John
Wiley& Sons (Asia) pte. Ltd: Singapore, 2005.
2. (a) Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V.
Angew. Chem., Int. Ed. 2005, 44, 5188–5240; (b) Scriven,
E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297–368;

M. N. Soltani Rad et al. / Tetrahedron Letters 48 (2007) 3445–3449
3449
1
mixture melted and solidified after 2 min. The resulting
white solid was dissolved in CHCl3 and washed with
several portions of water. The organic layer was dried
(Na2SO4) and evaporated to afford white crystals which
could be used without further purification.
crystals; Rf (EtOAc–n-hexane) (1:1) 0.69; mp 44.6 ꢀC; H
NMR (CDCl3, 250 MHz) dppm: 3.46 (t, 2H, J = 6.0 Hz,
N3CH2), 3.79 (t, 2H, J = 6.0 Hz, NCH2), 7.55–7.6 (m, 2H,
aryl), 7.72–7.79 (m, 2H, aryl); 13C NMR (CDCl3,
62.5 MHz) dppm: 36.84, 48.94, 123.42, 131.83, 134.17,
167.97; IR (KBr) m cmꢀ1: 2112(N3); MS [m/z (%)]: 216.06
(81.3); Anal. Calcd for C10H8N4O2: C, 55.55; H 3.73; N
25.91. Found: C, 55.50; H 3.76; N 25.95. 1-(2-Azido-
ethyl)-2-methyl-4-nitro-1H-imidazole: Pale-yellow crys-
tals; Rf (EtOAc–n-hexane) (1:1) 0.12; mp 72.3 ꢀC; 1H
NMR (CDCl3, 250 MHz) dppm: 2.39 (s, 3H, Me), 3.72 (t,
2H, J = 5.5 Hz, N3CH2), 4.07 (t, 2H, J = 5.5 Hz, NCH2),
8.17 (s, 1H, C(5)-H, imidazole);13C NMR (CDCl3,
62.5 MHz) dppm: 13.02, 46.10, 50.79, 120.29, 145.26,
146.45; IR(KBr) m cmꢀ1: 2102 (N3); MS [m/z (%)]:
196.07 (61.4); Anal. Calcd for C6H8N6O2: C, 36.74; H
4.11; N 42.84. Found: C, 36.72; H 4.16; N 42.80.
16. Lin, T.-S.; Mancini, W. R. J. Med. Chem. 1983, 26, 544–
548.
17. (a) Ju, Y.; Kumar, D.; Varma, R. S. J. Org. Chem. 2006,
71, 6697–6700; (b) Varma, R. S.; Naicker, K. P. Tetra-
hedron Lett. 1998, 39, 2915–2918; (c) Alvarez, S. G.;
Alvarez, M. T. Synthesis 1997, 413–414; (d) Ito, M.;
Koyakumaru, K.-I.; Ohta, T.; Takaya, H. Synthesis 1995,
376–378; (e) Hassner, A.; Fibiger, R.; Andisik, D. J. Org.
Chem. 1984, 49, 4237–4244.
18. Selected data for N-(2-azidoethyl)phthalimide and 1-(2-
azido-ethyl)-2-methyl-4-nitro-1H-imidazole (Table 5,
entries 16 and 17). N-(2-azidoethyl)phthalimide: White