An efficient, inexpensive, and shelf-stable diazotransfer reagent: Imidazole-1-sulfonyl azide hydrochloride

Article abstract of DOI:10.1021/ol701581g

The design and synthesis of a new diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride, are reported. This reagent has proven to equal triflyl azide in its ability to act as a "diazo donor" in the conversion of both primary amines into azides and activated methylene substrates into diazo compounds. Crucially, this reagent can be prepared in a one-pot reaction on a large scale from inexpensive materials, is shelf-stable, and is conveniently crystalline.

Full text of DOI:10.1021/ol701581g

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3797-3800
An Efficient, Inexpensive, and
Shelf-Stable Diazotransfer Reagent:
Imidazole-1-sulfonyl Azide Hydrochloride
Ethan D. Goddard-Borger* and Robert V. Stick
Chemistry M313, School of Biomedical, Biomolecular & Chemical Sciences,
The UniVersity of Western Australia, Crawley WA 6009, Australia
goddae01@student.uwa.edu.au
Received July 8, 2007
ABSTRACT
The design and synthesis of a new diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride, are reported. This reagent has proven to
equal triflyl azide in its ability to act as a “diazo donor” in the conversion of both primary amines into azides and activated methylene
substrates into diazo compounds. Crucially, this reagent can be prepared in a one-pot reaction on a large scale from inexpensive materials,
is shelf-stable, and is conveniently crystalline.
In recent times, organic azides have experienced something
of a renaissance, owing, in no small part, to the immense
Scheme 1. Useful Reactions of Organic Azides
popularity of the CuI-catalyzed reaction between azides and
terminal alkynes (Scheme 1A).1 Indeed, Sharpless and Fokin,
in their seminal paper on this reaction, describe the reluctance
of modern organic chemists to embrace the azide moiety as
“azidophobia”.2 Fueled by the findings of this same publica-
tion, one could argue the chemistry community presently
experiences quite the opposite conditions“azidophilia”.
The utility of the azide moiety is not limited to the
synthesis of 1,2,3-triazoles. It also provides great service as
a latent amino group. As a protecting group, azides circum-
vent many of the problems encountered with amides and
carbamates, as well as providing the option of a mild
Indeed, such is the reliability of the Huisgen and Staudinger
reduction, via a Staudinger phosphazene, to give a primary
reactions that they have found application in the study of
amine,3 amide,4 or carbamate (Scheme 1B).5
biological systems, as exemplified by the work of Wong6
and Bertozzi.7
(1) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem.
2006, 51-68.
(2) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596-2599.
(3) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353-
1406.
(4) Bosch, I.; Gonza´lez, A.; Urp´ı, F.; Vilarrasa, J. J. Org. Chem. 1996,
61, 5638-5643.
(5) Ariza, X.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 1999, 40, 7515-
7517.
10.1021/ol701581g CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/22/2007

Most commonly, an azide group is introduced into a
molecule by the formation of a C-N bond, usually by the
nucleophilic displacement of a nucleofuge by an azide ion.
Although largely successful, this approach can, in some
systems, lead to the formation of elimination products or
products with incorrect stereochemical configuration.
In contrast to the former approach is the diazotransfer
reaction. This process utilizes trifluoromethanesulfonyl azide
(TfN3) as a “diazo donor” in the CuII-catalyzed conversion
of an existing primary amine into an azide (Scheme 2).8 The
to act as a diazotransfer reagent but might also be less costly
to prepare, more stable (hopefully crystalline), and produce
more easily removed byproducts.
The synthesis of 1 was easily accomplished by the addition
of two mole equivalents of imidazole to chlorosulfonyl azide,
preformed in situ by the reaction of equimolar quantities of
sodium azide and sulfuryl chloride in acetonitrile.13 Subse-
quent aqueous workup and flash chromatography afforded
1 as a colorless liquid in good yield (72%) (Scheme 3).
Scheme 3. Synthesis of 1 and 1‚HCl
Scheme 2. TfN3 in the Diazotransfer Reaction
elegance of this process lies in its mild reaction conditions,
high yields, and, crucially, the preservation of any pre-
existing stereochemistry.
However, this process is not without its problems. The
explosive nature of neat TfN3 and its relatively poor shelf
life necessitate its preparation in solution prior to use.9
Furthermore, inconsistent yields in the preparation of TfN3
mean that the solution must either be standardized or used
in a liberal excess. The removal of trifluoromethanesulfona-
mide from polar products has in the past also required
specialized workup procedures.10 Perhaps most significantly,
the expense of trifluoromethanesulfonic anhydride, used in
the preparation of TfN3, prohibits the deployment of this
reaction on a large scale. To circumvent these problems and
establish the diazotransfer reaction as a commonplace and
industrially useful synthetic transformation, a cheap, robust,
and safe alternative to TfN3 is required.
The challenge in designing such an alternative lies in find-
ing an electron-withdrawing group capable of replacing the
trifluoromethanesulfonyl moiety. Simple arylsulfonyl azides
have, in the past, proven to be inadequate,11 and although
other fluoroalkylsulfonyl groups are available, they would
do little to address the aforementioned shortcomings of TfN3.
Hanessian and Vate`le first demonstrated the imidazole-
1-sulfonate (imidazylate) group’s capacity as an excellent
nucleofuge.12 Imidazylates exhibit very similar reactivity to
trifluoromethanesulfonates but often enjoy a longer shelf life,
are a great deal less expensive to prepare, and produce a
hydrolytically labile counterion.12 We envisaged that imi-
dazole-1-sulfonyl azide 1 would mimic TfN3 in its ability
To assess the ability of 1 to behave as a diazo donor,
D-glucosamine hydrochloride was treated with 1 under typical
diazotransfer conditions to give, following acetylation, the
azide (1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-D-glucose) in
good yield (entry 1, Table 1).
This result, a boon though it was, failed to satisfy us in
one respect: to deliver a crystalline diazotransfer reagent,
desired for reasons of stability, ease of purification, and
convenience of measure. Fortuitously, the hydrochloride of
1 proved to be a colorless crystalline solid that, not sur-
prisingly, gave the same reaction with D-glucosamine
hydrochloride as observed for 1 (entry 1, Table 1). Modifica-
tion of the synthesis of 1 permitted the one-pot preparation
of 1‚HCl on a large scale, without the need for chromatog-
raphy, in good yield and high purity (Scheme 3).
Impact tests, vigorous grinding, and prolonged heating (at
80 °C) of 1‚HCl failed to invoke any explosive reaction.
Heating 1‚HCl above its melting point resulted in the slow
evolution of gas, presumably dinitrogen, to give a yellow
liquid, most likely the corresponding diazene. Differential
scanning calorimetry revealed this to be an exothermic
process (Figure 1). Further strong heating (>150 °C) of the
(6) Sawa, M.; Hsu, T.-L.; Itoh, T.; Sugiyama, M.; Hanson, S. R.; Vogt,
P. K.; Wong, C.-H. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 12371-12376.
(7) Vocadlo, D. J.; Bertozzi, C. R. Angew. Chem., Int. Ed. 2004, 43,
5338-5342.
(8) (a) Cavender, C. J.; Shiner, V. J. J. Org. Chem. 1972, 37, 3567-
3569. (b) Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. HelV.
Chim. Acta 1991, 74, 2073-2077. (c) Alper, P. B.; Hung, S.-C.; Wong,
C.-H. Tetrahedron Lett. 1996, 37, 6029-6032.
(9) Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. J. Am.
Chem. Soc. 2002, 124, 10773-10778.
(10) Lundquist, J. T., IV; Pelletier, J. C. Org. Lett. 2001, 3, 781-783.
(11) Araki, K.; Hashimoto, H.; Yoshimura, J. Carbohydr. Res. 1982,
109, 143-160.
Figure 1. Differential scanning calorimetry of 1‚HCl.
3798
Org. Lett., Vol. 9, No. 19, 2007

Table 1. Synthesis of Azides from Primary Amines Utilizing 1 and 1‚HCla
a
In a typical experiment, 1‚HCl (1.2 mmol) was added to a stirred suspension of the amine or its hydrochloride (1.0 mmol), potassium carbonate (2.0
mmol), and copper(II) sulfate pentahydrate (10 µmol, 1 mol %) in methanol (5 mL). Upon completion of the reaction (TLC), the mixture was concentrated.
For non-carbohydrate substrates (entries 3-13), a workup and flash chromatography furnished the corresponding azide. For carbohydrate substrates (entries
1 and 2), acetic anhydride (8 mmol) was added to the residue in pyridine (5 mL). Upon completion of the reaction (TLC), the mixture was concentrated; a
workup and flash chromatography then furnished the corresponding peracetylated azides. b The reaction was performed independently with 1 and 1‚HCl to
give indentical results. c For the comparable reaction with TfN3, where such a value is available. d The product is volatile, resulting in reduced yields. e This
literature value was obtained using 15 mol % of CuII catalyst as opposed to the 1 mol % used here.
residue resulted in violent decomposition. We thus advocate
the use of 1‚HCl at temperatures well below its decomposi-
tion point, preferably at room temperature, in line with
accepted experimental procedures employing TfN3.
Various amines were converted into the corresponding
azides by the action of 1‚HCl (Table 1). In general and where
possible, yields and reaction times compared favorably to
those obtained in the literature with TfN3.10,14-16 The results
presented in Table 1 clearly demonstrate the reliability of
1‚HCl to perform the diazotransfer reaction in good to
excellent yield and reasonable reaction time, with good
(14) Yan, R.-B.; Yang, F.; Wu, Y.; Zhang, L.-H.; Ye, X.-S. Tetrahedron
Lett. 2005, 46, 8993-8995.
(12) (a) Hanessian, S.; Vate`le, J.-M. Tetrahedron Lett. 1981, 22, 3579-
3582. (b) Vate`le, J.-M.; Hanessian, S. Tetrahedron 1996, 52, 10557-10568.
(13) Griffiths, J. J. Chem. Soc. C 1971, 3191-3195.
(15) Manabe, S.; Sakamoto, K.; Nakahara, Y.; Sisido, M.; Hohsaka, T.;
Ito, Y. Bioorg. Med. Chem. 2002, 10, 573-581.
(16) Liu, Q.; Tor, Y. Org. Lett. 2003, 5, 2571-2572.
Org. Lett., Vol. 9, No. 19, 2007
3799

functional group tolerance and a propensity to react even
with electron-deficient amines.
insertion reactions (where X is C, O, N, S, P, or Si), and
ylide preparation.18
Although CuII salts have emerged as the catalysts of choice
for the diazotransfer reaction with TfN3, the reaction is also
catalyzed by NiII and ZnII salts.8c Qualitative experiments
conducted on D-glucosamine hydrochloride indicated that the
diazotransfer reaction utilizing 1‚HCl is catalyzed by CuII,
NiII, ZnII, and CoII salts (1 mol % of MCl2‚nH2O).
As a diazo donor, TfN3 has also been used in the
preparation of various diazo compounds from substrates
containing activated methylene groups.17 Diazo compounds
have proven to be of use in cyclopropane synthesis, X-H
Preliminary investigations into the use of 1‚HCl in the
preparation of diazo compounds were conducted, the results
of which are presented in Table 2. It should be noted that
the volatile nature of the products resulted in only moderate
yields, not truly representative of the reaction’s efficacy.
In conclusion, an inexpensive, shelf-stable, and efficient
alternative to TfN3 in the diazotransfer reaction has been
designed and prepared in a simple one-pot procedure. The
utility of this new reagent, imidazole-1-sulfonyl azide
hydrochloride 1‚HCl, in the conversion of a diverse range
of amines into the corresponding azides, with excellent
results, has been demonstrated. Further, the preparation of
several diazo compounds using 1‚HCl has been accom-
plished.
Table 2. Synthesis of Some Diazo Compounds Utilizing
1‚HCla
Acknowledgment. E.D.G.-B. would like to thank The
University of Western Australia for a Hackett postgraduate
scholarship.
R
time (h)
yield [lit.]b (%)
65 [56]17
59
Supporting Information Available: All experimental
procedures and characterization data for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
CO2Et
C(O)Me
CN
SO2Ph
P(O)(OEt)2
16
16
9
48
48
61 [79]17
c
-
c
-
OL701581G
a
In a typical experiment, the substrate (1.0 mmol), 1‚HCl (1.2 mmol),
and a non-nucleophilic base (5.0 mmol) (pyridine or potassium carbonate)
were stirred in acetonitrile. Upon completion of the reaction (TLC), the
mixture was concentrated, and a workup and flash chromatography furnished
the diazo compound. b For the comparable reaction with TfN3, where such
(17) Wurz, R. P.; Lin, W.; Charette, A. B. Tetrahedron Lett. 2003, 44,
8845-8848.
(18) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; John Wiley & Sons: New York, 1998.
c
a value is available. No reaction was observed (TLC and NMR).
3800
Org. Lett., Vol. 9, No. 19, 2007