Direct synthesis of organic azides from alcohols using 2-azido-1,3- dimethylimidazolinium hexafluorophosphate

Article abstract of DOI:10.1055/s-0031-1290958

Direct synthesis of organic azides from alcohols was developed. Azide transfer of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP) to alcohols proceeds to give the corresponding azides under mild reaction conditions, which were easily isolated because the byproducts are highly soluble in water. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290958

LETTER
▌1335
lDettierrect Synthesis of Organic Azides from Alcohols Using 2-Azido-1,3-dimethyl-
imidazolinium Hexafluorophosphate
Direct Synthesis of Organic Azides from Alcohols
Mitsuru Kitamura,* Tatsuya Koga, Masakazu Yano, Tatsuo Okauchi
Department of Applied Chemistry, Kyushu Institute of Technology, 1-1 Sensuicho, Tobata, Kitakyushu 804-8550, Japan
Fax +81(93)8843304; E-Mail: kita@che.kyutech.ac.jp
Received: 22.02.2012; Accepted after revision: 13.03.2012
– N
–
PF6
Abstract: Direct synthesis of organic azides from alcohols was de-
veloped. Azide transfer of 2-azido-1,3-dimethylimidazolinium
hexafluorophosphate (ADMP) to alcohols proceeds to give the cor-
responding azides under mild reaction conditions, which were eas-
ily isolated because the byproducts are highly soluble in water.
N
N
DBU
R
OH
+
R
N3
NMe
NMe
ADMP (1)
Key words: ADMP, azides, diazo compounds, azide transfer, het-
erocycles
Scheme 1 Direct synthesis of alkyl azides from alcohols using
ADMP (1)
Organic azides are useful intermediates for the synthesis
of nitrogen-containing compounds.1 For example, organic
azides are used as equivalents of primary amines and are
employed in the Staudinger reaction.2 Photoinduced ni-
trene formation of organic azides3 and 1,3-dipole reaction
of organic azides with terminal alkynes (Huisgen reac-
tion)4 are widely used in the fields of biological and poly-
mer chemistry.
azides (Scheme 1). In this letter, we describe the outcome
of this investigation.
First the azide-transfer reaction of ADMP (1) to 4-phenyl-
benzyl alcohol (2a) was examined under several reaction
conditions. In entries 1–6 (Table 1), the effects of differ-
ent bases are shown. DBU was found to be the best base
for the formation of organic azides among those we exam-
ined. In the presence of DBU, the azide-transfer reaction
proceeded at room temperature in THF within ten minutes
Various synthetic methods for organic azides have been
developed.1 In general, alkyl azides are prepared from
corresponding alcohols by two steps: 1) transformation to
alkyl halides/alkyl sulfonates (RX) and 2) nucleophilic
substitution of RX with an azide ion.1 Direct transforma-
tion of alcohols to azides is an attractive and efficient
strategy for the synthesis of alkyl azides, but currently
only few reports on this efficient direct synthesis exist.5,6
Of the limited synthetic methods reported, Mitsunobu-
type reaction5,7 using diphenylphosphoryl azide
(DPPA),5b in the presence of triphenylphosphine (Ph3P)
and a dehydrogenating reagent such as diethyl azodicar-
boxylate (DEAD) is known to be the most efficient. How-
ever, these reactions frequently require isolation of the
desired azide compounds from triphenylphosphineoxide
(Ph3P=O), which is a byproduct derived from Ph3P. The
direct transformation of alcohols to organic azides with-
out Ph3P can be achieved via the DPPA–1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) method6a reported by
Thompson or the bis(p-nitrophenyl) phosphorazidate
(p-NO2DPPA)–DBU method reported by Shioiri.6b
Table 1 Optimization of the Azide Transfer of ADMP (1) to Alcohol
2aa
base
THF
OH
1
+
Ph
O
2a
N3
+
NMe
NMe
Ph
3a
4
Yield (%)b
Entry
Base (equiv)
Conditions
3a
2a
DMAPc (1.3)
Et3N (1.3)
NaH (1.3)
1
2
3
4
5
6
7
r.t., 1 h
r.t., 1 h
r.t., 2 h
r.t., 1 h
r.t., 3 h
r.t., 10 min
56
31
28
47
61
93
91
30
51
35
46
23
0
dimsyl sodiumd
KOt-Bu (1.3)
DBU (1.3)
During the course of our study on 2-azido-1,3-dimethyl-
imidazolinium salts,8 we found that 2-azido-1,3-dimethyl-
imidazolinium hexafluorophosphate (ADMP, 1)9 could
be employed for the direct transformation of alcohols to
DBU (1.3)
0 °C, 10 min
1
a Unless otherwise shown, the reaction was performed with 2a (1
mmol), ADMP (1, 1.2 mmol), and base (1.3 mmol) in THF (5 mL).
b Isolated yield.
c N,N-Dimethyl-4-aminopyridine.
SYNLETT 2012, 23, 1335–1338
Advanced online publication: 14.05.2012
d The reaction was carried out with 2a (1 mmol), ADMP (1, 1.2
mmol), and dimsyl sodium [prepared by NaH (3 mmol) and DMSO
(1 mL)] in THF (2 mL).
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290958; Art ID: ST-2012-U0158-L
© Georg Thieme Verlag Stuttgart · New York

1336
M. Kitamura et al.
LETTER
to give the corresponding azide 3a in 93% yield (Table 1, treatment of 1 (1.2 equiv) and DBU (1.5 equiv), as shown
entry 6).10 At 0 °C, the reaction also proceeded efficiently in entries 1–11 (Table 2). Benzylic alcohols 2d and 2e
as shown in entry 7 (Table 1).
having strong electron-donating groups (NMe2 or OMe)
on their phenyl groups were somewhat less reactive than
nonsubstituted benzylic alcohol or benzylic alcohols sub-
stituted with electron-withdrawing groups (Table 2, en-
tries 4 and 5). The reaction of bulky ortho-dimethyl-
substituted benzyl alcohol 2i proceeded smoothly to give
the azide 3i in 88% yield (Table 2, entry 10).
In all experiments, the formation of 2-imidazolidinone 4
was observed, which was easily separated from the azide
3a by washing with water because 4 was highly soluble in
water. This is one of the merits of this azide-formation
reaction compared with Mitsunobu-type azide synthesis.5
To explore the scope of the azide-transfer reaction, vari-
ous benzylic alcohols 2 were subjected to the reaction
with 1 in the presence of DBU (Table 2). Primary benzylic
alcohols 2 (R1 = Ar and R2 = R3 = H) were transformed to
the corresponding azides 3 in good to high yields by the
The results of the reaction with secondary benzylic alco-
hols (R1 = Ar, R2 = Alk or Ar, and R3 = H) are shown in
entries 12–18 (Table 2). Using three equivalents of DBU,
benzylic alcohol 2k (R1 = Ph and R2 = Me) was trans-
formed to azide in 74% yield (Table 2, entry 12). The
Table 2 Direct Synthesis of Organic Azides from Benzylic Alcohols by Reaction with ADMP (1)a
R2 R3
R2 R3
DBU
+
1
R1
OH
R1
N3
THF, r.t.
2
3
R1
Ph
R2
R3
Yield (%)b
Entry
2
1 (equiv)
DBU (equiv) Time (min)
3
1
2
H
H
H
H
H
H
H
H
H
H
H
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Me
2b
2c
2c
2d
2e
2f
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3
10
10
60
60
60
60
60
10
60
60
60
90
90
90
60
60
90
60
120
20
90
3b
3c
3c
3d
3e
3f
83
4-MeC6H4
4-MeC6H4
4-(Me2N)C6H4
4-MeOC6H4
4-FC6H4
4-IC6H4
4-(CO2Me)C6H4
4-(CO2Me)C6H4
2,6-Me2C6H3
3-O2NC6H4
Ph
93
3
96
4
65
5
62
6
93
7
2g
2h
2h
2i
3g
3h
3h
3i
quant.
93
8
9
98
10
11
12
13
14
15
16
17
18
19
20
21
88
2j
3j
quant.
74
2k
2l
3k
3l
Ph
3
62
Ph
n-Bu
2m
2m
2n
2n
2o
2p
2p
2q
3
3m
3m
3n
3n
3o
3p
3p
3q
24
Ph
n-Bu
Me
Me
Ph
3
44
4-PhC6H4
4-PhC6H4
Ph
1.2
2
3
68
3
87
1.2
2
3
91
0c
Ph
Ph
3
1.8d
1.5d
Ph
Ph
2
88
0e
Ph
Ph
1.2
a Unless otherwise indicated, the reaction was performed with 2 (1 mmol), ADMP (1), and DBU in THF (5 mL).
b Isolated yield.
c Compound 2p was recovered.
d KOt-Bu was used instead of DBU.
e 1,1-Diphenylethene (5) was obtained in 29% yield, and 2q was recovered in 51% yield.
Synlett 2012, 23, 1335–1338
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct Synthesis of Organic Azides from Alcohols
1337
yield of azide decreased to 62% then 24% as the substitu-
ent R2 became bulkier (Me → Et → n-Bu; Table 2, entries
12–14). In certain cases, the yield of azide 3 was improved
when excess amount of 1 was used (Table 2, entry 14 vs.
15 and entry 16 vs. 17). However, diphenylmethanol 2o
was efficiently converted into the azide 3o in high yield
even though only a slightly excess amount of 1 was used
(Table 2, entry 18).
Acknowledgment
This work was partially supported by Daiichi Sankyo Co., Ltd. and
JGC-S Scholarship Foundation.
References and Notes
(1) (a) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
(b) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem. Int. Ed. 2005, 44, 5188. (c) Bräse, S.; Banert, K.
Organic Azides 2010.
In the reaction of triphenylmethanol (2p), the correspond-
ing azide 3p was not formed when DBU was used as the
base (Table 2, entry 19), but was obtained in 88% yield
when KOt-Bu was used as the base (Table 2, entry 20). As
shown in entry 21 (Table 2), 1,1-diphenylethanol (2q) was
not transformed to azide but to the elimination product
1,1-diphenylethene (5), in 29% yield.
(2) For reviews, see: (a) Stuckwisch, C. G. Synthesis 1973, 469.
(b) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F.
Tetrahedron 1981, 37, 437. (c) Gololobov, Y. G.; Kasukhin,
L. F. Tetrahedron 1992, 48, 1353. (d) Mölina, P.; Vilaplana,
M. J. Synthesis 1994, 1197. (e) Dehnicke, K.; Weller, F.
Coord. Chem. Rev. 1997, 158, 103. (f) Kohn, M.;
Breinbauer, R. Angew. Chem. Int. Ed. 2004, 43, 3106.
(3) For reviews, see: (a) Bayley, H.; Knowles, J. R. Methods
Enzymol. 1977, 46, 69. (b) Bayley, H. Photogenerated
Reagents in Biochemistry and Molecular Biology; Elsevier:
New York, 1983. (c) Fedan, J. S.; Hogaboom, G. K.;
O’Donnell, J. P. Biochem. Pharmacol. 1984, 33, 1167.
(d) Radominska, A.; Rdrake, R. Methods Enzymol. 1994,
230, 330.
Table 3 Reaction of Nonbenzylic Alcohol with ADMP (1)a
DBU
n-octyl
Ph
N
+
1
R
OH
R
N3
THF
0 °C, 1.5 h
N
N
2
3
6
(4) For reviews, see: (a) Huisgen, R. In 1,3-Dipolar
Cycloaddition Chemistry, Vol. 1; Padwa, A., Ed.; Wiley:
New York, 1984, 1–176. (b) Kolb, H. C.; Finn, M. G.;
Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004.
(c) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J.
Org. Chem. 2006, 51. (d) Binder, W. H.; Sachsenhofer, R.
Macromol. Rapid Commun. 2007, 28, 15. (e) Becer, C. R.;
Hoogenboom, R.; Schubert, U. S. Angew. Chem. Int. Ed.
2009, 48, 4900. (f) Amblard, F.; Cho, J. H.; Schinazi, R. F.
Chem. Rev. 2009, 109, 4207.
(5) Direct synthesis of organic azides from alcohols by
Mitsunobu-type reaction using Ph3P, see: (a) Loibner, H.;
Zbiral, E. Helv. Chim. Acta 1976, 59, 2100. (b) Lal, B.;
Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 1977. (c) ZnN3: Viaud, M. C.; Rollin, P.
Synthesis 1990, 130. (d) Saito, A.; Saito, K.; Tanaka, A.;
Oritani, T. Tetrahedron Lett. 1997, 38, 3955.
(6) Direct synthesis of organic azides from alcohols without
Ph3P. Methods using DPPA (-type reagent), see:
(a) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.;
Mathre, D. J.; Grabowski, E. J. J. J. Org. Chem. 1993, 58,
5886. (b) Mizuno, M.; Shioiri, T. Chem. Commun. 1997,
2165. For other methods, see: (c) Sampath Kumar, H. M.;
Subba Reddy, B. V.; Anjaneyulu, S.; Yadav, J. S.
Tetrahedron Lett. 1998, 39, 7385. (d) Yu, C.; Hu, L. Org.
Lett. 2000, 2, 1959. (e) Iranpoor, N.; Firouzabadi, H.;
Akhlaghinia, B.; Nowrouzi, N. Tetrahedron Lett. 2004, 45,
3291. (f) Rad, M. N. S.; Behrouz, S.; Khalafi-Nezhad, A.
Tetrahedron Lett. 2007, 48, 3445.
Yield (%)b
Entry
R
2
Product
1
2
3
4
5
6
(E)-PhCH=CHCH2
Ph(CH2)3
2r
2s
3r
3s
6
84
86
72c
70
68
n-octyl
2t
t-Bu(Me)2SiO(CH2)10
Et3SiO(CH2)10
PhCH2CH2CH(n-Bu)
2u
2v
2w
3u
3v
3w
10 (22)d
a Unless otherwise shown, the reaction was performed with 2 (1
mmol), ADMP (1, 2 mmol), and DBU (3 mmol) in THF (5 mL).
b Isolated yield.
c After the reaction of 2t with ADMP (1),a phenyl acetylene (1.2
mmol) and CuSO4·5H2O (0.1 mmol) were added to the reaction mix-
ture (one-pot reaction), which was stirred for 2 h at r.t.
d The reaction was carried out with 2w (1 mmol), ADMP (1, 2 mmol),
and dimsyl sodium [prepared by NaH (3 mmol) and DMSO (1 mL)]
in THF (2 mL).
Next, we examined the reaction of nonbenzylic alcohols
with ADMP (1, Table 3). Allylic alcohol and various pri-
mary alkyl alcohols reacted with ADMP (1) to afford cor-
responding azides in good to high yields (Table 2, entries
1–5). As shown in entries 4 and 5 (Table 3), silyloxy
groups were found to survive under these reaction condi-
tions. The secondary alcohol 2d reacted with 1 to give the
azide 3w in 10% yield when DBU was used as the base.
The yield of 3w was improved to 22% when sodium meth-
ylsulfinylmethylide (dimsyl anion) was used as the base.
(7) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380.
(8) (a) Kitamura, M.; Tashiro, N.; Okauchi, T. Synlett 2009,
2943. (b) Kitamura, M.; Tashiro, N.; Takamoto, Y.;
Okauchi, T. Chem. Lett. 2010, 39, 732. (c) Kitamura, M.;
Tashiro, N.; Sakata, R.; Okauchi, T. Synlett 2010, 2503.
(d) Kitamura, M.; Yano, M.; Tashiro, N.; Miyagawa, S.;
Sando, M.; Okauchi, T. Eur. J. Org. Chem. 2011, 458.
(e) Kitamura, M.; Miyagawa, S.; Okauchi, T. Tetrahedron
Lett. 2011, 52, 3158. (f) Kitamura, M.; Tashiro, N.;
Miyagawa, S.; Okauchi, T. Synthesis 2011, 1037.
In conclusion, we developed a new method for the direct
synthesis of organic azides from alcohols. Various ben-
zylic alcohols and n-alkanols converted into the corre-
sponding azides under mild conditions. The azides formed
are easily isolated because byproducts are highly soluble
in water.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1335–1338

1338
M. Kitamura et al.
LETTER
afford the crude compounds that were purified by flash
column chromatography (silica gel, hexane–EtOAc) to give
pure 4-biphenylmethylazide (3a) in 93% yield as a white
solid.
(9) ADMP (1) is a crystalline diazo transfer reagent having high
thermal stability and low explosibility[8d,f] and is now
commercially available from TCI (cat. No. A2457).
(10) Typical Procedure for the Synthesis of Organic Azides
from Alcohols with ADMP (1; Table 1, Entry 6)
Physical Data for 3a
To a solution of 4-phenylbenzyl alcohol (2a, 185 mg, 1.0
mmol) in THF (5 mL), 2-azide-1,3-dimethylimidazolinium
hexafluorophosphate (1, 332 mg, 1.2 mmol), and DBU (0.15
mL, 1.3 mmol) were added at r.t., and the mixture was stirred
for 10 min. The reaction was quenched with sat. aq NH4Cl,
and organic materials were extracted with CH2Cl2. The
combined extracts were washed with brine, and then dried
over anhyd Na2SO4. The solvent was removed in vacuo to
Mp 35–36 °C. 1H NMR (400 MHz, CDCl3): δ = 7.62–7.57
(m, 4 H), 7.48–7.42 (m, 2 H), 7.42–7.32 (m, 3 H), 4.36 (s, 2
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 141.3, 140.5,
134.4, 128.9, 128.7, 127.6, 127.5, 127.1, 54.5 ppm. IR
(Nujol): 2098, 1463, 1253, 823 cm–1. Anal. Calcd for
C13H11N3: C, 74.62; H, 5.30; N, 20.08. Found: C, 74.76; H,
5.42; N, 19.99.
Synlett 2012, 23, 1335–1338
© Georg Thieme Verlag Stuttgart · New York

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