A safe and convenient method for the preparation of triflyl azide, and its use in diazo transfer reactions to primary amines

Article abstract of DOI:10.1016/j.tetlet.2006.01.157

A safe and convenient method for the copper(II)-catalyzed diazo transfer from triflyl azide to primary amines is reported. By replacing CH₂Cl₂ by toluene the formation of hazardous side products, for example, azido-chloromethane and diazidomethane can be avoided.

Full text of DOI:10.1016/j.tetlet.2006.01.157

Tetrahedron Letters 47 (2006) 2383–2385
A safe and convenient method for the preparation of triflyl
azide, and its use in diazo transfer reactions to primary amines
Alexander Titz, Zorana Radic, Oliver Schwardt and Beat Ernst*
Institute of Molecular Pharmacy, University of Basel, Klingelbergstrasse 50, 4055 Basel, Switzerland
Received 21 December 2005; revised 30 January 2006; accepted 31 January 2006
Available online 21 February 2006
Abstract—A safe and convenient method for the copper(II)-catalyzed diazo transfer from triflyl azide to primary amines is reported.
By replacing CH2Cl2 by toluene the formation of hazardous side products, for example, azido-chloromethane and diazidomethane
can be avoided.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
reaction conditions, nucleophilic substitutions on
CH2Cl2 leading to azido-chloromethane and/or diazido-
methane tend to occur. Thus, the formation of perilous
diazidomethane has been reported by Hassner et al.7,8
upon shaking an azide anion source in CH2Cl2. When
this reaction mixture was pipetted or used for IR
spectroscopy (films between NaCl plates) explosions
occurred.8 As a consequence of the formation of
diazidomethane several additional explosions were
reported, leading to the destruction of facilities and
severely injured staff. Therefore, several laboratories
reported that they banned the use of halogenated
solvents in combination with sodium azide.9–11
Azides are versatile functional groups that undergo a
variety of reactions, such as 1,3-dipolar cycloadditions
and rearrangement processes, or act as precursors for
nitrene chemistry.1 In addition, azides are widely used
as convenient protecting groups for primary amines.
Traditionally, the introduction of azides has been
achieved by substituting appropriate leaving groups
with inorganic azide. However, in the last 15 years, di-
azo transfer from triflyl azide (TfN3) to primary amines
has found wide use. Although this approach has already
been published by Cavender and Shiner2 in 1972, it was
rarely applied until the early 1990s.3
In 1996, Wong and co-workers introduced4 a mild tran-
sition metal-catalyzed modification of the original diazo
transfer procedure, and in 2002, he elucidated5 its cop-
per(II)-catalyzed mechanism. A successful application
in aminoglycoside synthesis was published by the same
group.6
2. Results and discussion
In order to avoid the formation of azido-chloromethane
and diazidomethane, as well as high concentrations
thereof, we tested various replacements for CH2Cl2. Tolu-
ene was identified as a solvent replacement for the
preparation of TfN3 to avoid the formation of hazard-
ous diazidomethane and potentially hazardous azido-
chloromethane byproducts in the typical solvent used,
and furthermore, for the application of TfN3 in the
diazo transfer reaction. Toluene is inert towards sodium
azide under the employed conditions and, because of its
boiling point, high concentrations of TfN3 can easily be
avoided (Fig. 1).
However, a general drawback of diazo transfer is the
formation of hazardous intermediates, for example,
TfN3, which can only be handled in solution.2 Further-
more, in all published procedures for the preparation of
triflyl azide and its application in the diazo transfer to
primary amines, triflic anhydride and sodium azide are
used in a biphasic system of CH2Cl2/H2O. Under these
Wong reported that carefully adjusted homogeneous
reaction conditions are a prerequisite for a successful
diazotransfer.4,5 Therefore, three different solvent ratios
leading to monophasic mixtures (see ternary phase
*
Corresponding author. Tel.: +41 61 267 1551; fax: +41 61 267
1552; e-mail: beat.ernst@unibas.ch
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.157

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A. Titz et al. / Tetrahedron Letters 47 (2006) 2383–2385
Table 1. Diazo transfer reaction 1 ! 2 using different solvent ratios
Entry
Solvent ratios (H2O/PhMe/MeOH)
Yielda (%)
1
2
3
4
1/1.7/6.7, homogeneous
1.3/1/5.4, homogeneous
1/4.3/10, homogeneous
1/1/1, heterogeneous
Quant.
74
Quant.
96
a Isolated yields.
glucopyranoside (1) as starting material. Under all three
conditions, the desired azide 2 was obtained in good to
excellent yield. Furthermore, the diazo transfer also
turned out to be successful under heterogeneous condi-
tions (Table 1, entry 4).
Figure 1. Preparation of TfN3 and diazo transfer to a primary amine
using toluene as co-solvent.
diagram13) for H2O/PhMe/MeOH were tested (Table 1,
entries 1–3), using methyl 6-amino-6-deoxy-a-D-
To test the scope of this modified version of the diazo
transfer reaction, a number of primary amines were
Table 2. Results of the diazo transfer under homogeneous conditions using H2O/PhMe/MeOH 1/1.7/6.7 (see also Refs. 12 and 14–17)
Entry
Amine
Azide
Time (h)
Yielda (%)
Quant.
N3
.
NH2 HCl
O
1
14
HO
HO
O
HO
HO
HO
212
HO
OMe
OMe
1
OAc
OH
O
O
HO
HO
AcO
AcO
2
21
72
OAc
.
OH
N3
4b,3
HCl NH2
3
OAc
OH
AcO
AcO
HO
HO
O
O
3
4
36
36
50
19
OH
OAc
.
HCl NH2
5
N3
6b,3
OH
OAc
N3
.
HCl
NH2
O
O
HO
HO
AcO
AcO
OH
OAc
8b,3
7
NH2
N3
HO
HO
HO
HO
OH
OH
5
6
14
14
Quant.
HO
1014
9
O
O
.
HO
N3
NH2 HCl
83
OH
1215
OH
11
O
O
MeO
HO
NH2
MeO
HO
N3
7
14
14
93
52
OH
13
OH
1416
6NH2
15
6N3
8
1617
a Isolated yields.
b For purification the crude products were acetylated.

A. Titz et al. / Tetrahedron Letters 47 (2006) 2383–2385
2385
investigated. The reactions were carried out in a mono-
phasic solvent mixture of H2O/PhMe/MeOH 1/1.7/6.7.
The triflyl azide solution in toluene was added to a mix-
ture of the amine, sodium hydrogencarbonate and cop-
per(II) sulfate in water, followed by methanol to obtain
a homogeneous turquoise solution. The TLC indicated
the reactions to be complete within 14 h, except for the
amines 3, 5 and 7. Even after 21 and 36 h, respectively,
they yielded the corresponding azides 4, 6 and 8 only in
moderate yields (Table 2, entries 2–4). The decrease in
yield for 4, 6 and 8 is probably due to the increasing
steric hindrance, which is in agreement with results
reported by Vasella et al.3
(2.2 mg, 0.01 mmol) were dissolved in water (0.3 mL).
Triflic azide stock solution (0.51 mL) was added, fol-
lowed by the addition of methanol (1.98 mL) to yield
a homogeneous system. Subsequently, the blue mixture
was stirred vigorously at room temperature. Complete
consumption of the amine was monitored by TLC and
is also indicated by a colour change of the reaction mix-
ture from blue to green. Solvents were removed in vacuo
with a rotary evaporator keeping the temperature
strictly below 25 ꢁC. The residue was purified by chro-
matography on silica gel (eluant: dichloromethane–
methanol). Fully unprotected sugars were transformed
into their acetates with Ac2O/pyridine prior to
chromatography.
In conclusion, we have shown that (1) toluene can be
used instead of dichloromethane for the generation of
triflyl azide and (2) the TfN3/toluene solution can
directly be applied to the diazo transfer to primary
amines. This method is therefore significantly safer than
the previously reported procedure, because highly
hazardous diazidomethane can no longer be formed.
Furthermore, the reaction proceeds smoothly under
homogeneous, but also heterogeneous conditions (Table
1). This is a significant improvement, considering the
necessity of the reported delicate adjustment of the sol-
vent ratio using CH2Cl2.5 Because the safety risk origi-
nating from the formation of azido-chloromethane and
diazidomethane can be avoided, even an industrial
application of this novel diazo transfer methodology is
possible.
References and notes
1. Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 117, 5188–5240.
2. Cavender, C. J.; Shiner, V. J., Jr. J. Org. Chem. 1972, 37,
3567–3569.
3. Vasella, A.; Witzig, C.; Chiara, J. L.; Martin-Lomas, M.
Helv. Chim. Acta 1991, 74, 2073–2077.
4. Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett.
1996, 37, 6029–6032.
5. Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H.
J. Am. Chem. Soc. 2002, 124, 10773–10778.
6. Greenberg, W. A.; Priestley, E. S.; Sears, P. S.; Alper, P.
B.; Rosenbohm, C.; Hendrix, M.; Hung, S.-C.; Wong,
C.-H. J. Am. Chem. Soc. 1999, 121, 6527–6541.
7. Hassner, A.; Stern, M.; Gottlieb, H. E.; Frolow, F. J. Org.
Chem. 1990, 55, 2304–2306.
8. Hassner, A.; Stern, M. Angew. Chem., Int. Ed. Engl. 1986,
25, 478–479.
3. Experimental
9. Hruby, V. J.; Boteju, L.; Li, G. Chem. Eng. News 1993, 71,
2.
3.1. Preparation of the triflyl azide stock solution
10. Peet, N. P.; Weintraub, P. M. Chem. Eng. News 1993, 71,
4.
11. Peet, N. P.; Weintraub, P. M. Chem. Eng. News 1994, 72,
4.
12. Tagaki, Y.; Tsuchiya, T.; Umezawa, S. Bull. Chem. Soc.
Jpn. 1973, 46, 1261–1262.
After sodium azide (545 mg, 8.38 mmol) was dissolved
in water (1.37 mL), toluene (1.37 mL) was added. The
mixture was cooled to 0 ꢁC under vigorous stirring.
After the dropwise addition of triflic anhydride
(896 lL, 4.19 mmol) and further vigorous stirring for
30 min at 0 ꢁC, the temperature was raised to 10 ꢁC
and the biphasic mixture was stirred for 2 h. A saturated
aqueous solution of sodium hydrogencarbonate was
added dropwise until gas evolution had ceased. The
two phases were separated and the aqueous layer was
extracted with toluene (2 · 1.37 mL). The combined
organic layers were used in the subsequent diazo
transfer reactions.
13. Mason, L. S.; Washburn, E. R. J. Am. Chem. Soc. 1937,
59, 2976–2977.
1
14. Trishydroxymethyl-methyl azide (10). H NMR (DMSO-
d6, 500.1 MHz): d 3.48 (d, 3J = 5.5 Hz, 6H, 3CH2OH),
4.85 (t, 3J = 5.5 Hz, 3H, 3CH2OH); 13C NMR (DMSO-d6,
125.8 MHz): d 61.4 (CH2), 68.9 (C). IR (film, cmꢀ1): 759
(s), 822 (s), 2104 (s, N3), 2250 (s), 3431 (br s, O-H); ESI-
MS, pos. ionization: 147.98 [M+H]+; neg. ionization:
145.89 [MꢀH]ꢀ, 191.91 [M+HCO2]ꢀ.
15. Dureault, A.; Tranchepain, I.; Depezay, J. C. Synthesis
1997, 5, 491–493.
3.2. Typical procedure for the diazo transfer reaction
16. Neustadt, B. R.; Smith, E. M.; Tulshian, D. WO 9403481,
1994.
The amine (0.23 mmol), sodium hydrogencarbonate
(78 mg, 0.93 mmol) and copper(II) sulfate pentahydrate
17. Speers, A. E.; Adam, G. C.; Cravatt, B. F. J. Am. Chem.
Soc. 2003, 125, 4686–4687.