Copper-Catalyzed Tandem Reaction of Terminal Alkynes and Sulfonyl Azides for the Assembly of Substituted Aminotriazoles

Article abstract of DOI:10.1021/acs.orglett.7b01729

A simple combination of CuI/LiOtBu/DMF enables the tandem Huisgen [3 + 2] cycloaddition/amidation reaction of terminal alkynes and sulfonyl azides to 5-sulfamide-1-(N-sulfonyl)-1,2,3-triazoles I, which can undergo an alkylation/desulfonation sequence to deliver highly substituted aminotriazoles II by one-pot or one-pot, two-step procedures.

Full text of DOI:10.1021/acs.orglett.7b01729

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Tandem Reaction of Terminal Alkynes and
Sulfonyl Azides for the Assembly of Substituted Aminotriazoles
†
†
‡
Xuchun Zheng, Yanjun Wan, Fei Ling, and Cheng Ma*
Department of Chemistry, Zhejiang University, 20 Yugu Road, Hangzhou 310027, China
*
S Supporting Information
ABSTRACT: A simple combination of CuI/LiOtBu/DMF
enables the tandem Huisgen [3 + 2] cycloaddition/amidation
reaction of terminal alkynes and sulfonyl azides to 5-sulfamide-
1
-(N-sulfonyl)-1,2,3-triazoles I, which can undergo an
alkylation/desulfonation sequence to deliver highly substituted
aminotriazoles II by one-pot or one-pot, two-step procedures.
he copper-catalyzed azide−alkyne cycloaddition
tion tendency, very limited attention has been devoted to
T
(CuAAC) is among the most important click reactions
capturing these N-sulfonyltriazole species with an electrophile
1
,2
5c,7
because of its efficiency and biocompatibility. This stepwise
Huisgen [3 + 2] cycloaddition process provides a reliable
method for the regioselective construction of 1,4-disubstituted-
to produce 1,4,5-trisubstituted triazoles, although significant
progress has recently been achieved in the similar trans-
formations of their N-alkyl/aryl counterparts with a wide scope
8
1
(
,2,3-triazoles with 5-cuprated triazole I as the key intermediate
of electrophiles (Scheme 1, path c). In the latter case, notably,
3
Scheme 1). In this regard, it is well-known that the
terminal alkynes have been successfully employed to assemble
9
alkynyl-substituted triazoles via C−C bond formation.
Scheme 1. Copper-Catalyzed Reactions of Organic Azides
and Terminal Alkynes
Herein, we present a chemo- and regioselective Cu-catalyzed
tandem reaction of two sulfonyl azides and a terminal alkynes
upon treatment with stochimetric amounts of LiOtBu in DMF,
leading to the formation of 5-sulfamide-1-(N-sulfonyl)-1,2,3-
triazoles (Scheme 1, path d). Intriguingly, the combination of
this transformation with a subsequent alkylation/desulfonation
sequence provides an expedient access to highly substituted
aminotriazoles. To the best of our knowledge, the use of
organic azides to capture the cuprated triazole intermediates
deriving from a CuAAC reaction remains unsuccessful in the
published literature, although these reagents have recently
emerged as versatile amino sources in organic synthesis for
10
transition-metal-catalyzed C−H amination reactions.
This study was initiated by a serendipitous finding that the
mixture of ethynylbenzene (1a) and 4-methylbenzenesulfonyl
azide (2a) in THF could give 5-sulfamide-1,2,3-triazole 3a in
3
5% yield upon treatment with CuI (10 mol %) and LiOtBu
11
(
120 mol %); however, compound 3a was unstable in the
12
case of being free of any solvents (Scheme 2). Given the
transformations of sulfonyl azide substrates appear somewhat
increasing significance of substitued 1,2,3-triazole units as
different from those of alkyl or aryl azides because the
13
corresponding N-sulfonyltriazole intermediates (I, R2
=
ubiquitous structural motifs in bioactive molecules and
14
functional materials as well as readily accessible scaffolds in
−
SO R) are less stable than the N-alkyl/aryltriazole species
2
4 5
15
2
organic synthesis, preliminary investigation on the formation
(
I, R = alkyl or aryl). The pioneering investigations by
of triazole 3a was carried out. While switching the solvent THF
to CH Cl could not afford any desired product, the use of
Chang, Fokin, and Sharpless have elegantly demonstrated that
judicious choice of reaction conditions could enable the Cu-
catalyzed conversion of sulfonyl azides and terminal alkynes to
either conventional triazoles (Scheme 1, path a) or
denitrogenation/hydration products (Scheme 1, path b) with
excellent selectivity, which cannot be attained by Huisgen
2
2
DMF instead furnished 3a in excellent yield. Remarkably, in
DMF, both the ratio of substrates (1a/2a = 1:1, 0.6:1, and
0
.3:1) and the addition of H O showed slightly influence on the
2
6
thermal approaches. On the other hand, probably due to the
Received: June 8, 2017
obstacle arising from their inherent ring-opening/denitrogena-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01729
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Copper-Catalyzed Reaction of Two Azides and an
Alkyne
Table 1. Optimization of Reaction Conditions
a
b
entry
variation of standard conditions
4a (%)
1
none
73
72
70
40
25
54
29
2
5a was added after the reaction of 1a and 2a
5 mol % of CuI and 6 h
3
4
CuCl and 4 h instead of CuI and 1 h
5
Cu(OAc) and 4 h
2
6
CuTC and 4 h
7
THF and 4 h instead of DMF and 1 h
CH Cl and 4 h
8
2
2
9
60 mol % LiOtBu
45
32
58
61
a
Reaction conditions: 2a (0.4 mmol), 1a, LiOtBu (x mol %), CuI
10
11
12
13
KOtBu and 2 h instead of LiOtBu and 1 h
LiOH and 4 h
(
0.04 mmol, 10 mol %), solvent (2 mL), 30 °C, 0.5 h. Yields were
1
determined by H NMR analysis. Yield in parentheses for an entry in
Cs CO and 4 h
2
3
the presence of H O (4 mmol).
2
Et N and 4 h
3
1
4
5
4 mmol of H O was added
67
70
2
1
N instead of air
2
product yield and cleanly furnished 3a without detectable 1,4-
disubstituted triazole 3a′ or imide 3a″. As expected, reducing
the amount of LiOtBu from 120 to 60 mol % also prompted
this reaction with comparable results. However, when triethyl-
amine (120 mol %) was used as the base in DMF, imide 3a″
was isolated as the product (35%) instead. To our delight, it
was found that 2,4,5-trisubstituted triazole 4a could be readily
afforded by in situ methylation using excess amounts of
iodomethane (5a) with concurrent elimination of a tosyl group.
This result demonstrated the feasibility of N-tosyltriazole 3a as
a
Standard conditions: 2a (0.4 mmol), 1a (0.24 mmol), MeI (0.6
mmol), CuI (0.04 mmol, 10 mol %), LiOtBu (0.48 mmol, 120 mol %)
in DMF (2.0 mL), 30 °C, under air for 1 h. Isolated yield. CuTC =
copper(I) thiophene-2-carboxylate.
b
With the optimized reaction conditions in hand, we next
evaluated the scope of substrates (Scheme 3). Thus, a set of
benzenesulfonylazides containing different substituents readily
underwent the reaction with alkyne 1a and MeI (5a) to afford
products 4a, 4c, and 4d along with their regioisomers in 87−
96% combined yields, respectively. On the other hand, the
scope of monosubstituted acetylenes 1 was also tested with 2a
2
an easily available substrate for the synthesis of N -substituted
16
triazole compounds.
Encouraged by these results, we chose alkyne 1a and azide 2a
as the model substrates with iodide 5a as the alkylating reagent
to prepare highly substituted triazole compounds (Table 1).
Intriguingly, the Cu-catalyzed reaction of 1a and 2a could be
accomplished in the presence of 5a and directly gave the
1
and 5a as the reaction partners. Variation of substituent R
showed that different ethynylbenzenes bearing an electron-
donating group (−OMe, −Me) or an electron-withdrawing
group (−NO ), as well as a chlorine at the para-position of
2
desired N -alkylated product 4a in 73% isolated yield with 10
2
mol % of CuI and 120 mol % of LiOtBu in DMF at 30 °C for 1
benzene rings, partook in the reaction efficiently, giving
triazoles 4e−h and their isomers. 2-Ethynylbenzaldehyde was
also a suitable partner, albeit with reduced yield (4i). Other aryl
alkynes including 4-ethynylbenzo[d][1,3]dioxole, 1-ethynyl-
naphthalene, and 2-ethynylthiophene readily underwent this
conversion to furnish 4j−l. Aliphatic substituents such as
phenylethynyl, 1-cyclohexenyl, cyclopropyl, and 3-chloropropyl
could also be introduced to this reaction, delivering the targeted
compounds 4m−p in reasonably good yields, considering the
functional group tolerance. Meanwhile, it was observed that
alkylating agents 5 could control the regioselectivity of N-
alkylation reactions presumably due to a steric hindrance effect;
h under air atmosphere (Table 1, entry 1), along with 23% of
1
3
an unseparated mixture of N - and N -methyl isomers 4a′ and
4
a″. Control experiments showed that no obvious variation in
the yield was observed when this reaction was manipulated by a
one-pot, two-step procedure (Table 1, entry 2). While
decreasing the amount of CuI from 10 to 5 mol % also
worked well despite requiring an extended reaction time (6 h),
other copper salts such as CuCl, Cu(OAc) , and CuTC
2
reduced the yield significantly (Table 1, entries 3−6). It
appeared that solvents dramatically influenced the reaction
outcomes; for example, the yield was reduced to 29% with THF
as the solvent instead, and the targeted product was not
detected in CH Cl (Table 1, entries 7 and 8). Several
2
for example, the use of benzyl bromide 5b gave N -alkylation
compounds 4q (65%), 4r (81%), and 4s (72%), respectively,
2
2
1
3
inorganic bases including LiOtBu, KOtBu, LiOH, and Cs CO3
accompanied by trace amounts of N - and N -isomers.
While a mixture of 1a, 2a, and allylic bromides 6 under the
standard conditions led to complicated products, an alternative
one-pot, two-step procedure worked well and cleanly gave the
desired products 4t and 4u in 79% and 71% yield, respectively
(eq 1).
2
performed this reaction in varying yields, while Et N could not
3
give the desired product (Table 1, entries 9−13). Finally, in the
presence of H O or under nitrogen atmosphere, the reaction
2
proceeded smoothly to produce the targeted compound 4a in
similar yields (Table 1, entries 14 and 15).
B
DOI: 10.1021/acs.orglett.7b01729
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scopes for One-Pot Synthesis of 4
indicating that neither ynamidate II nor its tautomer metalated
ketenimine II′ was a key intermediate leading to product 3a
18
through a possible [3 + 2] cycloaddition. On the other hand,
addition of norbornylene (8) to a reaction of 1a and 2a did not
19
1
result in azacyclopropane analogue 9 according to H NMR
analysis (eq 3, see the Supporting Information). The absence of
9
cannot give a direct evidence to support the intermediacy of a
20
copper−nitrenoid species herein.
A tentative pathway for this copper-catalyzed conversion of
two sulfonyl azides and an alkyne is proposed in Scheme 4.
Scheme 4. Proposed Reaction Pathway
I
Initial Cu -mediated stepwise [3 + 2] cycloaddition of alkyne 1
3
and azide 2 generates 5-cuprated triazole I, which can be
a
converted into cuprated amide IV upon treatment with another
molecular azide 2. This process presumably proceeds via a high
2
(0.4 mmol), 1 (0.24 mmol), 5 (0.6 mmol), CuI (0.04 mmol, 10
mol %), LiOtBu (0.48 mmol, 120 mol %), DMF (2.0 mL), 30 °C, air,
1
III
valent Cu species III by oxidative addition and subsequent
−4 h. Yields are of the isolated products. Yields in parentheses are of
21
b
reductive elimination. Formal metal exchange of IV delivers
the mixtures of 4′ and 4′′. Mixtures of 4m and one isomer in 2.3:1
1
I
ratio according to H NMR spectra.
lithium salt V and the Cu catalyst, and final acidic workup gives
triazole 3. However, we cannot rule out a reasonable copper−
nitrenoid intermediate III′ in this process despite the
unsuccessful trapping experiment (eq 3). Although the detailed
action is currently not very clear, it is proposed that both DMF
and lithium salts facilitate the transformation of I into IV to
overcome competing protodecupration or ring-opening de-
nitrogenization sequences.
In conclusion, we have presented an unprecedented copper-
catalyzed conversion of sulfonyl azides and terminal alkynes
upon treatment with stoichiometric amounts of LiOtBu in
DMF at 30 °C under air atmosphere, providing a direct access
to 5-sulfamide-1-(N-sulfonyl)-1,2,3-triazoles in high chemo-
and regioselectivity. The resulting triazole products constitute
accessible precursors for the preparation of highly substituted
aminotriazoles through one-pot alkylation/desulfonation pro-
cedures. Further investigations are underway to elucidate the
mechanistic details and to exploit the synthetic application of
readily available 5-sulfamide-1-(N-sulfonyl)-1,2,3-triazoles.
ASSOCIATED CONTENT
Supporting Information
To gain insight into this copper-catalyzed transformation to
■
*
S
3
, control experiments using 1-sulfonyltriazole 7 and azide 2a
5c,17
were conducted (eq 2). After complete decomposition
of 7,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01729.
as detected by TLC, subsequent addition of azide 2a could not
generate triazole 3a at all in the presence or absence of CuI,
C
DOI: 10.1021/acs.orglett.7b01729
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures and characterization data of
Letter
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new compounds (PDF)
X-ray crystallographic data of compounds A and 4a
(
9) For copper-catalyzed reactions of two alkynes and an alkyl or aryl
(
CIF)
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AUTHOR INFORMATION
Corresponding Author
E-mail: mcorg@zju.edu.cn.
■
*
(
10) For recent reviews on organic azides as amino source in C−H
functionalization, see: (a) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res.
2015, 48, 1040. (b) Intrieri, D.; Zardi, P.; Caselli, A.; Gallo, E. Chem.
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ORCID
(
11) For our related works, see: (a) Cheng, D.; Ling, F.; Li, Z.; Yao,
Cheng Ma: 0000-0002-2456-6725
Present Address
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‡(
F.L.) Key Laboratory of Pharmaceutical Engineering of
Ministry of Education, College of Pharmaceutical Science,
Zhejiang University of Technology, 18 Chaowang Road,
Hangzhou 310014, China.
(
12) The structure of 3a was unambiguously confirmed upon single-
crystal X-ray diffraction analysis of its analogue A, which was obtained
from 1-ethynyl-4-methoxybenzene and 2a.
Author Contributions
†X.Z. and Y.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
21372196 and 21572199) for financial support.
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Org. Lett. XXXX, XXX, XXX−XXX