A metal-free multicomponent cascade reaction for the regiospecific synthesis of 1,5-disubstituted 1,2,3-triazoles

Article abstract of DOI:10.1002/anie.201307499

About specifics: A method for the regiospecific synthesis of the title compounds through an unprecedented Michael addition/deacylative diazo transfer/cyclization sequence has been established. The simple and practical method can be used for the modification of primary amines including chiral α-amines. The process involves the formation three covalent bonds and the cleavage of two covalent bonds (see scheme, Ts=4-toluenesulfonyl).

Full text of DOI:10.1002/anie.201307499

Angewandte
Chemie
DOI: 10.1002/anie.201307499
Synthetic Methods
A Metal-Free Multicomponent Cascade Reaction for the Regiospecific
Synthesis of 1,5-Disubstituted 1,2,3-Triazoles**
Guolin Cheng, Xiaobao Zeng, Jinhai Shen, Xuesong Wang, and Xiuling Cui*
The thermal Huisgen 1,3-dipolar cycloaddition of organic
azides and alkynes to build 1,2,3-triazoles usually requires
elevated temperatures and provides a mixture of regioisom-
ers.[1] The copper(I)-catalyzed azide–alkyne cycloaddition
(CuAAC)[2] and ruthenium(II)-catalyzed azide–alkyne cyclo-
addition (RuAAC)[3] have been developed as powerful
strategies for the regiospecific assembly of 1,4-disubstituted
1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles, respec-
tively. These reliable processes have quickly found many
applications in organic synthesis, chemical biology, and
materials science.[4] Nevertheless, the contamination of
Scheme 1. A proposed route to 1,5-disubstituted triazoles. Ts=4-
heavy metals limits their potential application in the pharma-
ceutical industry. Several metal-free methods, including the
azide–enamine cycloaddition,[5] the condensation of azides
with phosphonium ylides,[6] and the addition of acetylide
species to azides,[7] have also been developed for the
regiospecific synthesis of 1,2,3-triazoles. Considerable draw-
backs, however, exist with these processes, such as poor
functional-group tolerance or requiring functionalized sub-
strates. Westermann recently reported an improved Sakai
reaction to synthesize 1,4-disubstituted triazoles from primary
amines and a,a-dichlorotosylhydrazones (Scheme 1a).[8] This
procedure is limited to the synthesis of 1,4-disubstituted
regioisomers. Therefore, a general and metal-free procedure
to synthesize 1,5-disubstituted triazoles from readily available
substrates under mild reaction conditions is still of consid-
erable interest. Herein we report the synthesis of the 1,5-
disubstituted triazoles 5 from a three-component reaction of
aliphatic amines (1), propynones (2), and TsN3 by a Michael
addition/deacylative diazo transfer/cyclization sequence
(Scheme 1b).
toluenesulfonyl.
ketoenamine 4c.[9] The a-diazo iminoketone 7[9] and 1-tosyl
triazole 8[5] could be obtained from the Regitz diazo transfer
of 4b and 1,3-dipolar cycloaddition of 4c with TsN3,
respectively. We assumed that, in the presence of suitable
bases, 4a might react with TsN3 to give the a-diazoimine
intermediate 6, which could further cyclize to afford the
triazole 5 (Scheme 2).
Theoretically, the enaminone compounds 4 may exist as
three tautomers: the iminoenol 4a, iminoketone 4b, and
Scheme 2. Reactions between enaminones and sulfonyl azides.
[*] Dr. G. Cheng, X. Zeng, J. Shen, X. Wang, Prof. X. Cui
Engineering Research Center of Molecular Medicine
Ministry of Education, Key Laboratory of Xiamen Marine and
Gene Drugs, Institutes of Molecular Medicine and
School of Biomedical Sciences
To verify this hypothesis, 1,3-diphenyl-3-(nbutylamino)-2-
propen-1-one (4a) and the sulfonyl azides 3 were chosen as
the substrates to screen bases (Table 1). No reaction was
observed when weak bases, such as Et3N or K2CO3, were used
(Table 1, entries 1 and 2). However, in the presence of strong
bases, 1-nbutyl-5-phenyl-1H-1,2,3-triazole (5aa) could be
obtained from 4a and tosyl azide (Table 1, entries 3–6) as
we expected. LiOtBu gave the best result, thus affording 5aa
in 86% yield (Table 1, entry 4). Further investigation showed
that this transformation was highly solvent dependent
(Table 1, entries 7–12). Higher yields were achieved in
CH2Cl2 and toluene (Table 1, entries 4 and 7), while other
solvents, such as 1,4-dioxane, CH3CN, EtOH, DMF, and
DMSO, led to no reaction or lower yield (Table 1, entries 8–
Huaqiao University, Xiamen 361021 (P. R. China)
E-mail: cuixl@hqu.edu.cn
Prof. X. Cui
Department of Chemistry, Zhengzhou University
Zhengzhou 450052 (P. R. China)
[**] This work was supported by the National Natural Science
Foundation of China (21202048), Program for Minjiang Scholar
(10BS216), Science Research Item of Science and Technology of
Xiamen City (3502z201014), and the Natural Science Foundation of
Fujian Province, China (2013J01050).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307499.
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Table 1: Optimization of the reaction conditions for the reaction of 1,3-
Table 2: Scope of the aliphatic amines 1 and propynones 2.[a]
diphenyl-3-(n-butylamino)-2-propen-1-one (4a) with the sulfonyl azides
3.[a]
Entry
R1
R2
5
Yield [%][b]
Entry
Solvent
Base
R
Yield [%][b]
1
2
3
4
5
6
7
8
n-butyl
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
4-MeC6H4
4-MeOC6H4
4-FC6H4
nBu
5aa
5ab
5ac
5ad
5ae
5af
5ag
5ah
5ai
85 (86)[c]
81 (84)[c]
81 (83)[c]
83 (84)[c]
80 (86)[c]
70 (74)[c]
75
78
80
78
78
3-methoxypropyl
2-azidoethyl
allyl
benzyl
benzyl
2-(1H-indol-3-yl)ethyl
2-(4-NH2C6H4)ethyl
benzyl
benzyl
benzyl
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
1,4-dioxane
CH3CN
EtOH
Et3N
K2CO3
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-NO2C6H4
Me
0
0
3[c]
4
NaOEt
LiOtBu
NaOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
10
86
78
63
86
41
0
5
6
7
8
9
10
11
12
5aj
5ak
5al
9
10
11
12
13[d]
14
15
0
0
benzyl
76
DMF
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
0
[a] Reaction conditions: 1 (0.55 mmol), 2 (0.5 mmol), 2 mL toluene, at
808C. After the reaction mixture was cooled to RT, TsN3 (0.6 mmol), and
LiOtBu (1 mmol) were added. [b] Yield of isolated product based on 2.
[c] Yield of isolated product for the two-step reaction, based on 4.
78
84
61
[a] Reaction conditions: except where otherwise noted, all of the
reactions were performed with 4a (0.5 mmol), 3 (0.6 mmol), and base
(1 mmol) in solvent (2 mL) at RT for 0.5 h. [b] Yield of isolated product
based on 4a. [c] The reaction was performed for 24 h. [d] Used
0.75 mmol base. DMF=N,N-dimethylformamide, DMSO=dimethyl-
sulfoxide.
Since the conjugate addition of anilines to propynones
proceeds extremely slowly in nonpolar solvents because of
their lower nucleophilicity, the required N-aryl enaminones 4
were synthesized separately in EtOH in excellent yields.[11] As
shown in Table 3, various N-aryl enaminones could be
employed to form the corresponding 1,5-disubstitute triazoles
5ba–br in good to excellent yields. Compared with RuAAC,
the tolerance of an ethynyl group displayed another undeni-
12). Decreasing the amount of LiOtBu from 2 equivalents to
1.5 equivalents slightly lowered the yield (Table 1, entry 13).
Other commercially available sulfonyl azides did not give
better results (Table 1, entries 14 and 15).
Table 3: Scope of N-aryl enaminones 4.[a]
As the enaminones 4 could be readily prepared from the
Michael addition of the aliphatic amines 1 to propynones 2 in
nonpolar solvents, we employed a straightforward one-pot
strategy to synthesize the desired products 5 directly from the
aliphatic amines and propynones, without isolating the
intermediate enaminones 4 (Table 2). A mixture of 1 and 2
in toluene (2 mL) was stirred at 808C under an air atmosphere
until the starting materials were consumed completely, as
monitored by TLC. After the reaction mixture was cooled to
ambient temperature, TsN3 and LiOtBu were added. The
resulting mixture was then stirred at room temperature for
30 minutes. To our delight, the deacylative diazo transfer/
cyclization products 5 were obtained in similar yields to those
of the two-step reaction (Table 2, entries 1–6). A number of
functional groups, such as methoxy, allyl, and 1H-indol-3-yl,
were tolerated in this transformation. Notably, the azido
group was well tolerated and the desired product 5ac, which is
difficult to be synthesized by a 1,3-dipolar cycloaddition,
could be obtained in 81% yield. The mono(triazole) product
5ah was obtained in 78% yield using 4-aminophenylethyl-
amine as a substrate, thus showing good chemoselectivity of
an aliphatic amine over aniline (Table 2, entry 8). Further-
more, the scope of the propynones was also examined and
both aryl- and aliphatic-substituted propynones gave the
corresponding triazoles in good yields (Table 2, entries 6, 9–
12).
Entry
R1
R2, R3
5
Yield [%][b]
1
Ph
Ph, H
5ba
5bb
5bc
5bd
5be
5bf
5bg
5bh
5bi
5bj
5bk
5bl
5bm
5bn
5bo
5 bp
5bq
5br
5bs
91
87
88
80
75
78
71
83
96
81
82
87
93
99
82
87
77
85
trace
2
4-MeC6H4
Ph, H
3
4-MeOC6H4
Ph, H
4
4-FC6H4
Ph, H
5
4-ClC6H4
Ph, H
6
4-BrC6H4
Ph, H
7
4-IC6H4
Ph, H
8
3-EthynylC6H4
Ph, H
9
2-Me-3-MeOC6H4
Ph, H
10
11
12
13
14
15
16
17
18
19
1-Naphthalenyl
Ph, H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-MeC6H4, H
3-MeC6H4, H
4-MeC6H4, H
4-MeOC6H4, H
4-FC6H4, H
4-ClC6H4, H
Me, H
nBu, H
Me, Ph
[a] Reaction conditions: 4 (0.5 mmol), TsN3 (0.6 mmol), and LiOtBu
(1 mmol) in 2 mL CH2Cl2, RT. [b] Yield of isolated product based on 4.
2
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able advantage of this procedure (Table 3, entry 8). The
transformation was slightly influenced by electronic effects.
The substrates with electron-donating groups (Me, MeO)
gave higher yields than those with electron-withdrawing (F,
Cl, Br, I) groups. The reaction was not significantly affected
by steric hindrance at the b-position (Table 3, entries 9–11),
however, the 2-phenyl enaminone 4bs, which has a phenyl
substituent at the a-position, failed to provide the desired
product (Table 3, entry 19).
Next, a benzoylated substrate and acetylated substrate
were compared [Eq. (1)]. When the benzoyl group was
Scheme 3. Proposed reaction pathway.
replaced by an acetyl group, the corresponding triazole 5af
was generated in lower yield and the Regitz diazo transfer
product 9b was observed to be the side product. These results
suggested that the electron-donating effect of the methyl
group significantly made the enolization step more difficult.
Synthesis of optically active triazoles is still a chal-
lenge.[12,13] Notably, our procedure could be employed to
modify the useful biologically active compounds and syntheti-
cally important ligands containing chiral a-amines. For
example, the monosulfonylated diamine 1ah was modified
by this strategy and provided the chiral triazole 5am in 72%
yield as a single diastereomer, which could be used as a new
ligand in asymmetric synthesis [Eq. (2)].[14]
transfer. At last, the final products 5 were formed sponta-
neously by cyclization of 6.
In conclusion, we have developed a simple and efficient
synthetic methodology for preparing 1,5-disubtituted 1,2,3-
triazoles based on an unprecedented cascade Michael addi-
tion/deacylative diazo transfer/cyclization reaction of primary
amines, propynones, and sulfonyl azides. Various functional
groups, such as a terminal alkynes and azides, are well
tolerated in this transformation compared with the 1,3-
dipolar azide–alkyne cycloadditon. Moreover, chiral triazoles
could be obtained in high yield from readily available chiral
a-amines. This protocol could be expected to find wide
applications in synthetic chemistry and chemical biology.
Received: August 26, 2013
Revised: October 11, 2013
Published online: && &&, &&&&
Keywords: amines · cyclization · heterocycles ·
.
multicomponent reactions · synthetic methods
Moreover, the novel tri(triazole) compound 10 containing
two 1,5-disubstituted triazoles and one 1,4-disubstituted
triazole scaffold could be generated in 95% yield from 5ac
and 5bh by a CuAAC.[15] The product 10 might be applied in
materials science, organic synthesis, and chemical sensing
[Eq. (3); DIPEA = diisopropylethylamine].
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the results obtained (Scheme 3). The initial Michael addition
of primary amines and propynones provides the enaminones
4. Subsequent deprotonation of 4 by LiOtBu generates the
iminoenolate intermediates A. 1,3-Dipolar cycloaddition of A
with the tosyl azide 3 leads to the intermediates B, which
further gives the a-diazoimines 6 and 11 by deacylative diazo
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
G. Cheng, X. Zeng, J. Shen, X. Wang,
X. Cui*
&&&& — &&&&
A Metal-Free Multicomponent Cascade
Reaction for the Regiospecific Synthesis
of 1,5-Disubstituted 1,2,3-Triazoles
About specifics: A method for the regio-
specific synthesis of the title compounds
through an unprecedented Michael addi-
tion/deacylative diazo transfer/cycliza-
tion sequence has been established. The
simple and practical method can be used
for the modification of primary amines
including chiral a-amines. The process
involves the formation three covalent
bonds and the cleavage of two covalent
bonds (see scheme, Ts=4-toluenesul-
fonyl).
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!