Synthesis and reactivity of sulfamoyl azides and 1-sulfamoyl-1,2,3- triazoles

Article abstract of DOI:10.1021/ol201705k

Sulfamoyl azides are readily generated from secondary amines and a novel sulfonyl azide transfer agent, 2,3-dimethyl-1H-imidazolium triflate. They react with alkynes in the presence of a CuTC catalyst forming 1-sulfamoyl-1,2,3- triazoles. The latter are shelf-stable progenitors of rhodium azavinyl carbenes, versatile reactive intermediates that, among other reactions, readily and asymmetrically add to olefins.

Full text of DOI:10.1021/ol201705k

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4578–4580
Synthesis and Reactivity of Sulfamoyl
Azides and 1-Sulfamoyl-1,2,3-triazoles
Jeffrey C. Culhane and Valery V. Fokin*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
fokin@scripps.edu
Received June 24, 2011
ABSTRACT
Sulfamoyl azides are readily generated from secondary amines and a novel sulfonyl azide transfer agent, 2,3-dimethyl-1H-imidazolium triflate.
They react with alkynes in the presence of a CuTC catalyst forming 1-sulfamoyl-1,2,3-triazoles. The latter are shelf-stable progenitors of rhodium
azavinyl carbenes, versatile reactive intermediates that, among other reactions, readily and asymmetrically add to olefins.
Sulfamoyl azides make only a fleeting appearance in
organic synthesis. Their first preparation from sulfamoyl
chlorides and sodium azide was reported in 1956 by
Scheme 1. Synthesis of the Sulfonyl Azide Transfer Reagent
American Cyanamid chemists.1 However, this generally
reliable route fails when preparation of arylsulfamoyl
azides is attempted due to the undesired chlorination of
the aromatic ring by sulfuryl chloride. Shozda and
Vernon,2 and later Griffiths,3 developed an alternative
synthesis of arylsulfamoyl azides using chlorosulfonyl
azide. While this method circumvented the problem of
ring chlorination, the chlorosulfonyl azide reagent was
highly explosive and difficult to handle. Furthermore, the
yields were modest at best, remaining generally in the
15À50% range.
Recently, imidazole-1-sulfonyl azide hydrochloride was
and Sticks for the synthesis of imidazole-1-sulfonyl azide
hydrochloride.4 The added methyl group at C-2 of the
shown to be an efficient and convenient diazo transfer
reagent.4 During our investigations, we found that alkyla-
organic solvents5 and is also expected to increase its
tion of the imidazole nitrogen eliminated its diazo transfer
imidazole ring improves the solubility of this derivative in
reactivity and instead led to the transfer of the sulfonyl
azide group. In this study, we introduce the imidazolium
stability. The free base of the imidazole 1 was efficiently
alkylated with methyl triflate. The product was isolated as
salt 2asa noveland efficientsulfonylazide transferreagent.
The 2-methylatedderivative1waspreparedusingaslight
modification of the method developed by Goddard-Borger
a crystalline solid, yielding the imidazolium sulfonyl azide
transfer reagent 2 in high yield and purity (Scheme 1).
Reagent 2 is a stable solid that can be stored refrigerated
at 0À4 °C for at least three months without detectable
decomposition.
(1) Hardy, W. B.; Adams, F. H. U.S. Patent 2,863,866.
(2) Shozda, R. J.; Vernon, J. A. J. Org. Chem. 1967, 32, 2876.
(3) Griffiths, J. J. Chem. Soc. C 1971, 19, 3191.
(4) Goddard-Borger, E. D.; Sticks, R. V. Org. Lett. 2007, 9, 3797–
3800.
(5) Ingram, L. J.; Desoky, A.; Ali, A. M.; Taylor, S. D. J. Org. Chem.
2009, 74, 6479.
r
10.1021/ol201705k
Published on Web 08/03/2011
2011 American Chemical Society

Conditions for the transfer reaction of the sulfonyl azide
group to secondary amines were next investigated using
N-methylbenzylamine as a model substrate to yield N-benzyl-
N-methyl-sulfamoyl azide 3a (Table 1). Similar group
transfers that rely on sulfuryl imidazolium salts call for
the inclusion of a superstoichiometric organic base.4 In our
experience, the addition of an organic base rapidly decom-
posed the imidazolium transfer agent and led to low yields
or no product formation altogether. In the absence of an
exogenous base, the sulfonyl azide transfer reaction pro-
ceeded smoothly at low temperature in polar aprotic
solvents. Interestingly, yields were inversely related to the
amount of 2 used in the reaction: the highest yields were
observed with 1 equiv of the transfer agent, indicating that
the azide product was degraded by reagent 2.
complete consumption of amine and the polarity differ-
ence of side products.
Scheme 2. Synthesis of Sulfamoyl Azides from 2° Aminesa
Table 1. Optimization of Sulfamoyl Azide Transfera
a NR = no product was isolated.
concn,
Mb
t,
equiv
yield,
c
entry
solvent
°C
of 2
%
Sulfamoyl azides 3aÀd,f were subjected to the copper-
catalyzed azideÀalkyne cycloaddition reaction utilizing
copper(I) thiophene-2-carboxylate (CuTC) in dry toluene.7
As expected, the use of copper sulfate and sodium ascor-
bate under aqueous conditions led to the formation of
N-acylsulfamoylcontainingcompounds, aswaspreviously
demonstrated with sulfonyl azides.8 Sulfamoyl triazoles
4aÀd,f were synthesized in high yield and isolated as solids
or oils following an aqueous ammonium hydroxide work-
up (Scheme 3).
1
THF
0.2
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
1
2
3
4
1
1
1
1
1
1
1
1
1
1
1
84
80
76
72
90
86
84
79
75
85
88
89
98
99
96
2
THF
0.2
3
THF
0.2
4
THF
0.2
5
THF
0.05
0.1
6
THF
7
THF
0.2
8
THF
0.4
9
THF
0.8
10
11
12
13
14
15
dioxane
CH2Cl2
THF
0.05
0.05
0.05
0.05
0.05
0.2
Sulfamoyl triazoles are generally more hydrolytically
stable as compared to the sulfonyl triazoles congeners.
Thus, after three days in 0.5 M sodium hydroxide in
acetonitrile/water, triazole 4a displayed only minor degra-
dation to the NH-triazole, with an estimated 80% of 4a
remaining intact. Conversely, in 0.5 M hydrochloric acid in
acetonitrile/water, triazole 4a showed significant degrada-
tion with an estimated 33% of 4a remaining after three
days. Under neutral acetonitrile/water conditions no de-
gradation was detected over a two week period.
EtOAc
MeCN
THF
a 0.5 mmol of N-methylbenzylamine was added neat to a stirred
solution (suspension in the case of entry 4) of 2. b N-Methylbenzylamine.
c Yields were determined by LC-MS by linear regression using authentic
3a, after 1.5 h.
Underthese optimizedconditions(CH3CN, 0°C, 0.1 M)
sulfamoyl azides 3aÀj were synthesized and isolated in
high yields from a variety of secondary amines (Scheme 2).
The exclusive use of secondary amines is necessary to
prevent hydrolysis of the sulfamoyl azide product due to
N-H proton abstraction, which leads to the corresponding
sulfamic and hydrazoic acids.6 Isolation of the sulfamoyl
azides by filtration through a short plug of silica proved
to be a simple and efficient purification step due to the
Reactions of azavinyl carbenes9 obtained from sulfa-
moyl triazoles were next examined. In the presence of a
chiral rhodium(II) catalyst, sulfamoyl triazole4a smoothly
(7) Raushel, J.; Fokin, V. V. Org. Lett. 2010, 12, 4952.
(8) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005,
127, 16046. Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int.
Ed. 2006, 45, 3154. Raushel, J.; Pitram, S. M.; Fokin, V. V. Org. Lett.
2008, 10, 3385.
(9) Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.;
Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972. Chuprakov, S.; Kwok,
S. W.; Zhang, L.; Lercher, L.; Fokin, V. V. J. Am. Chem. Soc. 2009, 131,
18034.
(6) Matier, W. L.; Comer, W. T. J. Med. Chem. 1972, 15, 538.
Org. Lett., Vol. 13, No. 17, 2011
4579

under trivial conditions, producing the propargyl amine
derivative 8 in a high yield (Scheme 4).
Scheme 3. Synthesis of Sulfamoyl Triazolesa
Scheme 4. Transformations of Sulfamoyl Triazoles
a Isolated yields after column chromatography reported in
parentheses.
cyclopropanated styrene. Optimal conditions for cyclo-
propanation with catalytic Rh2(S-NTTL)4 were deter-
mined based on GC-MS and chiral HPLC analysis of the
isolated aldehyde 5, (the hydrolysis product of the sulfa-
moyl imine produced during cyclopropanation, Table 2).9
Table 2. Asymmetric Cyclopropanation with Sulfamoyl Tria-
zolesa
As described in this report, the readily available and
stable imidazolium reagent is immediately useful in synthesis.
It efficiently converts secondary amines to alkyl- and
arylsulfamoyl azides, which readily participate in copper-
catalyzed azideÀalkyne cycloadditions providing sulfa-
moyl triazoles. These sulfamoyl triazoles retain many of
the properties of the sulfonyl congeners and engage in the
rhodium-catalyzed cyclopropanation with olefins, while
offering the increased stability of both starting materials
and imine products.
t,
dr
(trans:cis)b
ee,
yield,
c
d
entry
solvent
°C
%
%
1
2
3
4
5
1,2-DCE
1,2-DCE
1,1,2,2-TCE
CHCl3
65
80
3:1
50:1
88e
90
89
94
90
30
80
60
63
79
100
80
25:1
>50:1
>50:1
Toluene
80
a Reactions consistedof0.5mmol triazole4a, Rh2(S-NTTL)4 (1mol%),
Styrene (3.0 equiv). b Determined by GC/MS. c Trans diastereomer,
determined by chiral HPLC. d Isolated yield of 5.
Acknowledgment. We thank Mr. Brady Worrell (TSRI)
for help with compound characterization and Prof. K. B.
Sharpless (TSRI) for helpful discussions. This work was
supported by the National Institutes of Health, National
Institute of General Medical Sciences (GM087620) and
National Science Foundation (CHE-0848982).
In contrast to the relatively unstable sulfonyl imines
produced bythe reaction ofsulfonyltriazoles and olefins in
the presence of rhodium(II) catalysts, we were able to
isolate sulfamoyl imine 6 in a high yield as a stable solid
following silica gel chromatography (Scheme 4). Alterna-
tively, the sulfamoyl imine could be efficiently reduced
with sodium borohydride to yield sulfamoyl amine 7, which
can be further functionalized via simple transformations.
For example, a propargyl group was easily introduced
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
4580
Org. Lett., Vol. 13, No. 17, 2011