An efficient and improved procedure for preparation of triflyl azide and application in catalytic diazotransfer reaction

Article abstract of DOI:10.1016/j.tetlet.2005.10.103

An efficient and improved procedure for preparation of triflyl azide and application in catalytic diazotransfer reaction are described. The amount of highly toxic reagents NaN₃ and Tf₂O, is significantly reduced comparing with the pr

Full text of DOI:10.1016/j.tetlet.2005.10.103

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8993–8995
An efficient and improved procedure for preparation of triflyl
azide and application in catalytic diazotransfer reaction
Ri-Bai Yan, Fan Yang, Yanfen Wu, Li-He Zhang and Xin-Shan Ye*
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Xue Yuan Rd #38, Beijing 100083, China
Received 19 September 2005; revised 21 October 2005; accepted 21 October 2005
Available online 7 November 2005
Abstract—An efficient and improved procedure for preparation of triflyl azide and application in catalytic diazotransfer reaction are
described. The amount of highly toxic reagents NaN3 and Tf2O, is significantly reduced comparing with the previous protocol.
Ó 2005 Elsevier Ltd. All rights reserved.
Azides play important roles in synthetic chemistry and
chemical biology. For example, they can be used as
protective groups for amines,1 photoaffinity labeling
reagents for biomolecules,2 precursors in the Ôclick
chemistryÕ to form linkages for various conjugates or
to introduce heterocyclic structures,3 and bioorthogonal
chemical reporters or their reactive partners for tagging
in biological system.4 Preparation of azides from amines
via diazotransfer reaction with triflyl azide (TfN3) as a
diazo donor,5 has several advantages such as high yield,
complete retention of configuration, mild reaction con-
ditions, and good compatibility with most functional
groups. This method was improved by the WongÕs
group6 via the addition of metal catalyst and now has
been applied in numerous works.1,7,8 But the procedure
employed still has some drawbacks. Firstly, two highly
toxic reagents, NaN3 and Tf2O, have to be used with
large excess. Secondly, in the diazotransferring step,
three solvents, H2O/MeOH/CH2Cl2, are used. The ratio
of the solvents has to be balanced with particular cau-
tion, because it has a dramatic influence on the outcome
of the reaction. Thirdly, the procedure seems to be still
unpredictable and somewhat troublesome. In this
report, the problems mentioned above are well solved.
hardly gained any substantial improvement since the
first application described by Shiner et al. over 30 years
ago.5,9 In the classical procedure, triflic anhydride was
added to the biphasic mixture of dichloromethane and
saturated NaN3 aqueous directly while vigorous stirring.
After extraction, a solution of triflyl azide in CH2Cl2
was then obtained. Obviously, there existed at least
two drawbacks in this procedure. In the presence of
water, triflic anhydride would be hydrolyzed inevitably.
For minimizing the hydrolysis, a large excess of re-
agents, usually 6 equiv of NaN3 and 3 equiv of Tf2O,
had to be employed. On the other hand, the resulting tri-
flyl azide is distributed in CH2Cl2, which is not a versa-
tile solvent for the subsequent diazotransfer reaction
because of the poor solubility to many substrates. For
the sake of a homogeneous phase, a complicated solvent
system has to be used. Wong et. al. have developed a
H2O/MeOH/CH2Cl2 (v/v/v = 3:10:3) solvent system,6b
but in our operations, cautious balance of the ratio is re-
quired especially when the solubility of substrates is not
good and the yields are still unpredictable.
We reasoned that if a more polar solvent such as aceto-
nitrile (CH3CN) or pyridine (Py) instead of dichloro-
methane was used in the absence of water, the
hydrolysis of Tf2O would be effectively avoided. In fact,
in our procedure, NaN3 was soluble enough in CH3CN
or Py to ensure almost complete conversion of Tf2O to
TfN3. In our practice, only 1.44 equiv of NaN3 and
1.20 equiv of Tf2O were needed for the diazotransfer
reaction of per amine group. The resulting reaction mix-
ture mainly contained TfN3 and two salts, namely
NaOTf and unreacted NaN3. These two salts had
Triflyl azide is a key reagent for this transformation.
However, by searching the literatures, we found that
the procedure for the preparation of triflyl azide had
Keywords: Diazotransfer reaction; Azide; Amine; Functional group
transformation; Synthesis.
*
Corresponding author. Tel.: +86 10 8280 1570; fax: +86 10 6201
4949; e-mail: xinshan@bjmu.edu.cn
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.103

8994
R.-B. Yan et al. / Tetrahedron Letters 46 (2005) 8993–8995
considerable solubility in CH3CN or Py but had no
influence on the subsequent transfer reaction. Except a
filtration if necessary, any other purification such as
extraction required in the previous literature procedure
was no longer needed.10 Instead, the TfN3-containing
solution was directly added to the amine reactants.
Because the amine substrates could easily dissolve in
the resulting TfN3 solution, the careful ratio balance
of the multiple solvents for a homogeneous phase was
thus avoided. The results of diazotransfer reaction on
some representative substrates were summarized in
Table 1.11
In summary, a simple, efficient, and reliable procedure
for preparation of triflyl azide and application in catal-
ytic diazotransfer reaction were reported, the operations
were more convenient. The disclosed procedure signifi-
cantly reduced the amount of the reagents and large
excessive usage of the highly toxic NaN3 and Tf2O
was avoided. The yield of diazotransfer reaction by
using our procedure was as good as that of the WongÕs
improved protocol. We anticipate that this improved
protocol will be of broad interest and of wide use.
Acknowledgments
Simple amino sugars such as glucosamine and galactos-
amine underwent the reaction very smoothly to afford
the desired products in good isolated yields (entries 1
and 2). When this method was extended to polyamine
substrates (entries 5 and 6), good yields were also
gained. It should be noted that when neamine was trea-
ted under the same conditions with Py as the solvent,
90% total isolated yield was obtained after reexamina-
tion by peracetylation.12 The amino acid derivative
reacted effectively, providing the diazotransferred
product in excellent yield (entry 3). In the case of trypt-
amine containing both a primary aliphatic amino and a
secondary aromatic amino group, the use of CH3CN
gave better yield than the use of Py (entry 4).13
This work was financially supported by the National
Natural Science Foundation of China, Ô973Õ grant from
the Ministry of Science and Technology of China, and
Ô985Õ program from the Ministry of Education of China.
References and notes
1. For examples see: (a) Lohman, G. J. S.; Seeberger, P. H.
J. Org. Chem. 2004, 69, 4081–4093; (b) Fridman, M.;
Belakhov, V.; Lee, L. V.; Wong, C.-H. Angew. Chem., Int.
Ed. 2005, 44, 447–452.
2. For a review, see: Radominska, A.; Drake, R. R. Methods
Enzymol. 1994, 230, 330–339.
Table 1. Diazotransfer reaction of representative amines
Entry
Amine
Azide
Isolated yield (%)
a
b
OH
OAc
O
O
HO
HO
AcO
AcO
1
92
94
OAc
OAc
OH
N3
NH HCl
2
OH
OAc
O
HO
HO
AcO
AcO
O
2
3
4
95
92
45
79
95
85
OH
NH2HCl
N3
COOCH
COOCH3
3
.
NH2 HCl
N
3
N3
NH2
N
N
H
H
N3
H2N
2HBr
OH
HO
HO
AcO
AcO
5
6
82
90
83
76
NH2
N3
OAc
N
NH
O
N
O
2
3
.
4HCl
H2N
HO
HO
AcO
AcO
3
H2N
N
3
O
O
AcO
N
3
HO
NH
2
OAc
OH
a Pyridine as solvent.
b Acetonitrile as solvent.

R.-B. Yan et al. / Tetrahedron Letters 46 (2005) 8993–8995
8995
3. For reviews, see: (a) Kolb, H. C.; Finn, M. G.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–2021; (b)
Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003,
8, 1128–1137.
4. For a review, see: Bertozzi, C. R.; Prescher, J. A. Nat.
Chem. Bio. 2005, 1, 13–21.
5. Caveander, C. J.; Shiner, V. J. J. Org. Chem. 1972, 37,
3567–3569.
6. (a) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron
Lett. 1996, 37, 6029–6032; (b) Nyffeler, P. T.; Liang, C.-H.;
Koeller, K. M.; Wong, C.-H. J. Am. Chem. Soc. 2002, 124,
10773–10778.
7. (a) Bertsch, U.; Moroder, L. ChemBioChem 2005, 6, 625–
628; (b) Horne, W. S.; Stout, C. D.; Ghadiri, M. R. J. Am.
Chem. Soc. 2003, 125, 9372–9376; (c) Traub, S.; Kubasch,
N.; Morath, S.; Kresse, M.; Hartung, T.; Schmidt, R. R.;
Hermann, C. J. Bio. Chem. 2004, 279, 8694–8700.
8. Liu, Q.; Tor, Y. Org. Lett. 2003, 5, 2571–2572.
9. Ruff first reported the preparation of TfN3 with NaN3 and
Tf2O: Ruff, J. K. Inorg. Chem. 1965, 4, 567–570.
10. A typical experimental procedure for the preparation of
triflyl azide was as following: A suspension of sodium azide
(436 mg, 6.70 mmol) in 8 mL of acetonitrile (pyridine) was
cooled in ice bath. Then triflic anhydride (1.57 g,
5.56 mmol) was added to the mixture by a syringe during
5 min while stirring. After the reaction was maintained for
2 h in ice bath, the TfN3-containing solution (filtration of
the salts can be done if necessary) was added directly to the
amine solution for the subsequent diazotransfer reaction.
11. General procedure for the reaction of triflyl azide with
amines. For organic soluble substrates, 1.0 g of substrate
was dissolved in 5 mL of acetonitrile (pyridine). In case of
saline substrates, water was employed instead. Then 1%
equiv of CuSO4 and 2 equiv of NEt3 per substrate amine
were added into the solution while stirring. The mixture
was cooled in an ice bath for a while, acetonitrile
(pyridine) solution of triflyl azide (1.2 equiv per amino
group, based on the amount of triflic anhydride used in the
preparation of TfN3) was then added into the mixture
dropwise. The reaction mixture was allowed to warm to
room temperature. Generally speaking, a homogeneous
solution could be obtained after the addition of triflyl
azide, and the reaction normally went to completion
within 12 h. The solvent was removed under reduced
pressure. The residue was purified by column chromatog-
raphy on silica gel or treated with Ac2O/Py and catalytic
amount of DMAP to gain the acetylated product.
12. Although the tetraazido neamine without being acetylated
can be isolated on silicon gel column, it is occasionally
contaminated by an unknown white solid, which cannot
be stained with any stains.6b In result, the yield may
sometimes be nearly quantitative. To examine the yield,
peracetylation with Py/Ac2O and DMAP was employed.
The unknown white solid is probably triflamide.
13. With pyridine as solvent, the starting material was almost
exhausted detected on TLC, as it did with CH3CN as
solvent. But the products were complicated. The reason of
the reduced yield is undergoing further research.