Copper-catalyzed cycloaddition of sulfonyl azides with alkynes to synthesize N-sulfonyltriazoles 'on water' at room temperature

Article abstract of DOI:10.1002/adsc.200800291

We have developed a green and practical method for the Huisgen cycloaddition of water-insoluble sulfonyl azides with alkynes 'on water' at room temperature under catalysis of the inexpensive catalyst system CuX/PhSMe, and addition of the ligand (thioaniso

Full text of DOI:10.1002/adsc.200800291

FULL PAPERS
DOI: 10.1002/adsc.200800291
Copper-Catalyzed Cycloaddition of Sulfonyl Azides with
Alkynes to Synthesize N-Sulfonyltriazoles ꢀon Waterꢁ at
Room Temperature
Feng Wang,a Hua Fu,a,* Yuyang Jiang,a,b and Yufen Zhaoa
a
Key Laboratory of Bioorganic Phosphorus Chemistry and ChemicalBiool gy (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Fax : (+86)-10-6278-1695; e-mail: fuhua@mail.tsinghua.edu.cn
Key Laboratory of ChemicalBiool gy (Guangdong Province), Graduate Schoolof Shenzhen, Tsinghua University,
b
Shenzhen 518057, Peopleꢀs Republic of China
Received: May 12, 2008; Revised: June 19, 2008; Published online: July 24, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
1
2
À
Abstract: We have developed a green and practical
N N bond in the 5-cuprated N-sulfonyltriazole in-
method for the Huisgen cycloaddition of water-in- termediates to amides and improved the yields of N-
soluble sulfonyl azides with alkynes ꢁon waterꢀ at sulfonyltriazoles.
room temperature under catalysis of the inexpensive
catalyst system CuX/PhSMe, and addition of the Keywords: copper-catalyzed reaction; on water; S li-
ligand (thioanisole) greatly inhibited cleavage of the gands; sulfonyl azides; N-sulfonyltriazoles
Introduction
cluding the type of azides and alkynes, reaction
medium, temperature and so on.[5–7] Among them, the
Compounds containing triazole building blocks find type of azides is especially important.[8] When R is
1
2
À
various applications in both materials science and alkyl or aryl, the N N bond is stable, and the corre-
drug discovery because of the stability of triazole part sponding 1,2,3-triazoles are easily obtained. However,
in strongly acidic and basic media, as well as towards when R is a strong electron-withdrawing group (such
oxidizing and reducing conditions.[1] The Huisgen [3+ as sulfonyl), the electron density on the N1 atom of
2]cycloaddition,[2] especially the copper-catalyzed cy- the intermediate A is low, and the N N bond is
cloaddition of azides and alkynes,[3,4] offers an almost readily cleaved. For example, the copper-catalyzed
unlimited array of inert triazole-containing architec- three-component coupling of sulfonyl azides, alkynes
tures. As shown in Scheme 1, the copper-catalyzed with amines, alcohols or water produced amidines,
coupling reaction of azides with alkynes firstly produ- imidates, or amides, respectively, because of cleavage
1
2
À
1
2
[9]
À
ces 5-cuprated N-substituted triazole intermediates of the N N bond. Very recently, Fokin and Chang
(A) whose stability is governed by various factors in- have cooperatively developed a useful copper-cata-
Scheme 1. Possible copper-catalyzed cycloaddition of azides with alkynes and opening process of triazoles[8]
.
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Copper-Catalyzed Cycloaddition of Sulfonyl Azides with Alkynes
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lyzed approach to N-sulfonyltriazoles, but the reac- that the copper-catalyzed three-component reaction
tions were carried out in anhydrous chloroform, and a of terminal alkynes, sulfonyl azides in the presence of
lower temperature (08C) was required.[8] Herein, we water produced amides.[9b] Herein, we want to find
report a simple, inexpensive and highly efficient cata- out whether thioanisole can inhibit the hydrolysis of
lyst system, CuBr/PhSMe, for cycloadditions of water- the 5-cuprated N-sulfonyltriazole intermediates to
insoluble sulfonyl azides with alkynes ꢁon waterꢀ at amides and promote the formation of N-sulfonyltria-
room temperature.
zoles in aqueous medium. As shown in Table 1, thioa-
nisole was firstly used as the ligand with CuBr in the
cycloaddition of p-toluenesulfonyl azide with phenyla-
cetylene in water as medium; a good yield (88%) was
obtained in the presence of 10 mol% CuBr and 20
Results and Discussion
Since the type of ligand in intermediates A in mol% thioanisole (relative to sulfonyl azide) for 12 h
Scheme 1 can affect the distribution of electron densi- (entry 1) (caution: p-toluenesulfonyl azide and phe-
ty on the copper, C5 and N1 atoms, the addition of an nylacetylene are insoluble in water). Other organic sol-
electron-rich ligand increases the electron density at vents (tert-butanol, CHCl3, CH3CN and tert-butanol/
copper and N1 and decreases the binding energy of H2O mixed solvent) were also investigated, and they
5
À
the C Cu bond, which improves the stability of the provided lower yields than water (entries 2–5). When
1
2
À
N
N bond and desorption of CuL from A. In addi- the reaction time was prolonged to 16 h in water, the
tion, the solvent also affects this dissociative process, yield increased to 92%. Reaction efficiency greatly
and the protonic solvents are usually favored. There- improved when the amounts of CuBr and ligand were
fore, we initialized the copper-catalyzed optimum increased (entry 7). Other copper salts (CuI, CuCl,
conditions for coupling of sulfonyl azides with al- CuSO4) were tested in the presence of thioanisole
kynes. Because compounds containing sulfur (such as (entries 8–10), and copper (I) salts showed higher ac-
MeSMe) are efficient ligands in the copper-catalyzed tivity. No N-sulfonyltriazole was found in the absence
cross-coupling reactions,[10] addition of a ligand con- of copper catalyst (entry 11). The effect of ligands
taining sulfur can be a good choice. Very recently, we was also investigated, various compounds containing
found that thioanisole could greatly promote the sulfur (dimethyl sulfide, thiophene, tetrahydrothio-
copper-catalyzed cycloaddition of aliphatic or aryl phene and dimethyl sulfoxide) were evaluated (en-
azides with alkynes.[11] Chang and co-workers found tries 12–15 in Table 1), but they are inferior to thio-
Table 1. Copper-catalyzed cycloaddition of p-toluenesulfonyl azide with phenylacetylene: optimization of conditions.[a]
Entry
Catalyst/Ligand
Solvent
Time
Yield [%][b]
1
2
3
4
5
6
7
8
0.1 equiv. CuBr/0.2 equiv. L1
0.1 equiv. CuBr/0.2 equiv. L1
0.1 equiv. CuBr/0.2 equiv. L1
0.1 equiv. CuBr/0.2 equiv. L1
0.1 equiv. CuBr/0.2 equiv. L1
0.1 equiv. CuBr/0.2 equiv. L1
0.2 equiv. CuBr/0.4 equiv. L1
0.1 equiv. CuI/0.2 equiv. L1
0.1 equiv. CuCl/0.2 equiv. L1
0.1 equiv. CuSO4/0.2 equiv. L1
0.2 equiv. L1
0.1 equiv. CuBr/0.2 equiv. L2
0.1 equiv. CuBr/0.2 equiv. L3
0.1 equiv. CuBr/0.2 equiv. L4
0.1 equiv. CuBr/0.2 equiv. L5
0.1 equiv. CuBr
H2O
12 h
12 h
12 h
12 h
12 h
16 h
2 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
88
22
6
24
61
92
94
34
62
0
t-BuOH
CHCl3
CH3CN
t-BuOH/H2O (2:1)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
9
10
11
12
13
14
15
16
0
50
36
32
63
3
[a]
Reaction conditions: p-toluenesulfonyl azide (0.5 mmol), phenylacetylene (0.6 mmol), solvent (0.5 mL).
Conversion yield determined by H NMR using 1,3-benzodioxole as the internal standard.
[b]
1
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Feng Wang et al.
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Table 2. Copper-catalyzed cycloaddition of sulfonyl azides with alkynes.[a]
Entry
1
Alkyne
Product
Yield [%][b]
90
2a
3a
2
3
2b
2c
3b
3c
86
61[c]; 88[d]
4
2d
2e
2f
2g
2h
2i
3d
3e
3f
3g
3h
3i
84
90
87
90
85
92
86
5
6
7
8
9
10
11
12
2j
3j
2k
2a
2g
3k
3l
45[c]; 80[d]
91
94
13
3m
[a]
Reaction conditions: sulfonyl azide (0.5 mmol), alkyne (0.6 mmol), PhSMe (0.1 mmol), CuBr (0.05 mmol), H2O (0.5 mL).
Isolated yield.
Reaction time 30 h.
[b]
[c]
[d]
Solid alkyne was previously dissolved in 1 mL of ethyl acetate, and then the resulting solution was added to the flask.
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Copper-Catalyzed Cycloaddition of Sulfonyl Azides with Alkynes
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ACHTREUNGanisole. Only a trace amount of cycloaddition product exclusion of air; (f) heterogeneous reactions are feasi-
was obserevd in the absence of ligand (entry 16). The ble; (g) outstanding functional group tolerance; (h)
experiments showed that the reaction was not influ- easy work-up procedure. All these results show that
enced by oxygen in air.
the method will be of wide practical applications in
Therefore, the copper-catalyzed cycloadditions of many research fields. Further synthetic applications of
sulfonyl azides with alkynes were performed under the catalyst system are currently ongoing in our labo-
our standard conditions: 10 mol% CuBr as the cata- ratory.
lyst, 20 mol% thioanisole as the ligand relative to sul-
fonylazide, water as the reaction medium at room
temperature without exclusion of air. As shown in Experimental Section
Table 2, the coupling reactions performed quite well
for all the substrates examined, and the desired N-sul- General Procedure for the Preparation of N-
fonyltriazoles were obtained in excellent yields. We Sulfonyltriazoles 3a–m
found that the reaction rates depended on the states
(solid and liquid) of the substrates. The liquid sub-
strates showed higher reaction rates, while the reac-
Water (0.5 mL), alkyne (0.6 mmol) (solid alkynes 2c, 2k or
the solution of 2c, 2k in 1 mL of ethylacetate), p-toluenesul-
fonyl azide or methylsulfonyl azide (0.5 mmol), CuBr
tions with the solid substrates were slower. For exam-
ple, reactions of the solid alkynes 2c and 2k with sul-
fonylazides for 30 h provided the corresponding
products in 61% and 45% yields, respectively. When
2c or 2k was previously dissolved in ethyl acetate, the
resulting solution was added to the flask with water,
and the coupling reaction was complete within 16 h
(entries 3 and 11). The reactions of the hydrophobic
and generally highly insoluble substrates in water
were named as organic synthesis ꢁon waterꢀ by Sharp-
less.[12] In fact, water is not a good solvent for the sub-
strates, but it shows excellent solubility for copper
salts which is favorable for the coordination of cop-
per(I) ion with alkyne and ligand, and the addition of
water could improve the desorption of CuL from in-
termediates A in Scheme 1. Electronic variation in
(0.05 mmol), anisole (0.1 mmol, 13 mg) were added to a
flask with a stir bar, and the mixture was stirred at room
temperature (~258C) without exclusion of air. After 16 h
(30 h for solid alkynes 2c and 2k), most of the starting
azides (determination by TLC) were consumed. The result-
ing solution was poured into water/ethyl acetate mixture.
After extraction of the aqueous phase with ethylacetate,
the combined organic phase was dried over magnesium sul-
fate and filtered. The solvent was removed by rotary evapo-
ration, and the crude product was isolated on a short silica
gel column (using EtOAc/petroleum ether as eluent) to
afford the pure triazole.
Acknowledgements
the alkynes and sulfonyl azides did not obviously This work was supported by the National Natural Science
Foundation of China (Grant 20672065), Chinese 863 Project
(Grant No. 2007AA02Z160), Programs for New Century Ex-
cellent Talents in University (NCET-05–0062) and Chang-
jiang Scholars and Innovative Research Team in University
(PCSIRT) (No. IRT0404) in China and the Key Subject
Foundation from Beijing Department of Education
(XK100030514).
affect the efficiency of the reactions, and the coupling
reactions tolerated a variety of functional groups,
such as hydroxy (entries 5 and 6) and amide
(entry 11). Since some of N-sulfonyl heterocyclic com-
pounds are bioactive molecules,[13] and the sulfonyl
group can be easily removed with magnesium in
methanolunder midl conditions [14] to provide 4-substi-
tuted N-H-triazoles,[9] this method has potentialfor
many practicalappilcations.
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