Base-Promoted Synthesis of N-Substituted 1,2,3-Triazoles via Enaminone-Azide Cycloaddition Involving Regitz Diazo Transfer

Article abstract of DOI:10.1021/acs.orglett.6b02975

The domino reactions between NH-based secondary enaminones and tosyl azide have been developed for the synthesis of various N-substituted 1,2,3-triazoles by employing t-BuONa as the base promoter. Through a key Regitz diazo-transfer process with tosyl azi

Full text of DOI:10.1021/acs.orglett.6b02975

Letter
pubs.acs.org/OrgLett
Base-Promoted Synthesis of N‑Substituted 1,2,3-Triazoles via
Enaminone−Azide Cycloaddition Involving Regitz Diazo Transfer
Jie-Ping Wan,* Shuo Cao, and Yunyun Liu
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P.R. China
S
* Supporting Information
ABSTRACT: The domino reactions between NH-based
secondary enaminones and tosyl azide have been developed
for the synthesis of various N-substituted 1,2,3-triazoles by
employing t-BuONa as the base promoter. Through a key
Regitz diazo-transfer process with tosyl azide, the reactions
proceed efficiently at room temperature with good substrate
tolerance.
ver the past several decades, the chemistry of 1,2,3-
triazoles has become a prominent area of chemical
Scheme 1. Different Cycloaddition Reactions for 1,2,3-
Triazole Synthesis
O
research owing to their application in organic synthesis,
chemical biology, medicinal chemistry, and new materials
synthesis.1 Thanks to the landmark discovery of the alkyne
azide cycloaddition (AAC) reactions disclosed by Huisgen,2
Sharpless3 and Meldal,4 respectively, research both in the
synthesis as well as the application of 1,2,3-triazoles has to date
reached unprecedented sophistication and height. Representa-
tively, the syntheses of 1,2,3-triazoles with improved sustain-
ability and product diversity by means of metal catalysis,5
metal-free AAC,6 and alternative azide-free synthetic method-
ologies7 constitute the major contemporary interests in 1,2,3-
triazole synthesis.
In the available sites allowing substructural variation, the N-
substitution of 1,2,3-triazoles is a key point in the generation of
molecular diversity, which is highly crucial for biological
investigations. In the classical AAC model, the synthesis of
N-substituted 1,2,3-triazoles relies on the utilization of different
organo azide starting materials,8 which are well known for their
limited commercial availability and challenging synthetic
preparation (A, Scheme 1).9 Domino reactions involving the
N-alkylation of in situ generated NH-1,2,3-triazoles by use of
alkyl halides as electrophiles are also able to provide N-
substituted 1,2,3-triazoles.10 However, this approach suffers
from the restriction of tolerating only highly active benzyl
halides and a few other alkyl halides. On the other hand,
employing commercially available azides such as sodium azide
or tosyl azide only gives NH or N-sulfonyl 1,2,3-triazoles.11 In
this context, devising alternative synthetic methodologies that
are capable of providing various N-substituted 1,2,3-triazoles
without relying on various organo azides remains highly
desirable.
C−C bond cleavage in an enaminone substrate (B, Scheme 1).
During our research on enaminone-based organic synthesis, we
have identified a transamination between N,N-disubstituted
enaminones and primary amines that has been proved to be a
highly practical tactic for the generation of NH-functionalized
enaminones, which enables the designation of various domino
reactions toward the synthesis of diversified organic products.13
Inspired by this facile NH-enaminone generation process, we
envisioned that the synthesis of 1,2,3-triazoles with enriched N-
substitution from the NH-enaminones could derive from
enaminone−azide cycloaddition.14
Unlike the transformations involving a C−C bond cleavage
in Cui’s work, we have now identified a new route to 1,4-
disubstituted 1,2,3-triazoles that does not involve C−C bond
cleavage during the reaction (C, Scheme 1). Herein, we report
Recently, Cui and co-workers reported that NH-function-
alized enaminones bearing a β-substituent react with sulfonyl
azides to provide 1,5-disubstituted 1,2,3-triazoles under metal-
free conditions12 to afford N-aryl/alkyl-1,2,3-triazoles via a key
Received: October 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02975
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
our results on this novel transition-metal-free cycloaddition
reaction of enaminones and tosyl azide for the synthesis of
various N-substituted 1,2,3-triazoles.
Table 2. Synthesis of Different 1,2,3-Triazoles
In an initial effort, the reaction of enaminone 1a, aniline 2a,
and tosyl azide 3 was tentatively run in a one-pot stepwise
operation. Although the transamination between 1a and 2a was
known to proceed well with the catalysis of various Brønsted
and Lewis acids,15 FeCl3 was selected as the first-step catalyst
since a base promoter was required as the second-step catalyst.
While the first-step transformation was easy and highly efficient,
optimization experiments focused on the second cycloaddition
step. As outlined in Table 1, after the transamination of 1a and
b
entry
R1
R2
product
yield (%)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
86
83
84
81
72
80
79
85
81
84
81
75
84
84
85
75
70
66
75
70
75
74
66
59
63
2
4-MeC6H4
4-MeOC6H4
2,4-Me2C6H3
3-ClC6H4
2-MeC6H4
2-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
2-MeC6H4
4-MeC6H4
Ph
3
4
5
6
a
7
4g
4h
4i
Table 1. Optimization of Reaction Conditions
8
4-MeC6H4
4-MeC6H4
4-MeOC6H4
2-MeC6H4
4-FC6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4j
4k
4l
3,4-CH2O2C6H3
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
4-BrC6H4
4m
4n
4o
4p
4q
4r
b
entry
catalyst
solvent
CH2Cl2
yield (%)
1
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
Et3N
62
53
2-ClC6H4
4-BrC6H4
Ph
2
EA
3
CH3CN
EtOH
86
4
25
4-CF3C6H4
naphth-1-yl
naphth-2-yl
thiophene-2-yl
furan-2-yl
Ph
4s
4t
5
ClCH2CH2Cl
dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
63
4-MeOC6H4
2,4-Me2C6H3
4-MeC6H4
2-MeC6H4
Ph
6
56
4u
4v
4w
4x
4y
7
trace
14
8
MeONa
EtONa
9
17
Me
10
11
12
KOH
56
c
25
Ph
Bn
NaOH
43
a
General conditions: enaminone 1 (0.3 mmol), amine 2 (0.4 mmol),
and FeCl3 (0.15 mmol) in 2 mL of MeCN stirred for 2 h at rt. Then
TsN3 3 (0.4 mmol) and t-BuONa (0.45 mmol) were added followed
by stirring at rt for 2 h. Yields of isolated products based on 1. N-
Benzyl-NH-enaminone (0.3 mmol) prepared from 1a and benzyl-
amine was directly used as starting material.
Cs2CO3
t-BuONa
t-BuONa
t-BuONa
47
c
13
67
d
b
c
14
e
86
15
41
a
General conditions: 1 (0.3 mmol), 2 (0.4 mmol), FeCl3 (0.15 mmol)
in 2 mL of solvent, stirred for 2 h at rt. Then 3 (0.4 mmol) and base
b
(0.6 mmol) were added followed by stirring at rt for 2 h. Yield of
c
d
Table 2). As for the amine component, anilines containing
substituents of different properties in ortho-, meta-, as well as
para-sites generally afforded target products. While the
transamination between enaminone 1 and alkylamine was not
practical, employing a prior prepared N-alkyl compound such
as the N-benzyl NH enaminone could give the corresponding
N-alkylated 1,2,3-triazole product (entry 25, Table 2), but the
yield was lower than equivalent entries using N-aryl
enaminones.
On the other hand, when 2-aminopyridine, a typical
heteroarylamine, was employed, the expected N-pyridinyl-
1,2,3-triazole was not acquired via the one-pot operation.
Instead, directly utilizing the previously prepared N-pyridinyl
enaminones 5 and tosyl azide was found to afford a practical
route for the synthesis of N-pyridinyl-1,2,3-triazoles 6 under the
standard cycloaddition conditions. As shown in Table 3, the
direct cycloaddition between enaminones 5 and tosyl azide
displayed satisfactory efficiency and diversity for the synthesis
of N-pyridinyl-1,2,3-triazoles 6.
isolated products based on 1. t-BuONa (0.3 mmol). t-BuONa (0.45
e
mol). t-BuONa (0.75 mol).
2a, the reaction providing 1,2,3-triazole product 4a was found
to run well in the presence of t-BuONa in different reaction
media, with MeCN being determined to be the best medium
(entries 1−6, Table 1). Subsequent variation of the base
additive indicated that Et3N was not practical, and entries
utilizing MeONa, EtONa, NaOH, and KOH as well as Cs2CO3
gave significantly inferior product yields than the entry with t-
BuONa (entries 7−12, Table 1). Finally, a change in the
loading of the base proved that neither reducing nor increasing
the amount of t-BuONa was positive (entries 13−15, Table 1).
The scope of this metal-free synthesis of 1,2,3-triazoles 4 was
investigated by employing various enaminones 1 and primary
amines 2. The results acquired from this study (Table 2)
suggested generality for this synthetic protocol. First, the
enaminone component exhibited tolerance when both aryl and
alkyl substructures were involved where the alkyl-functionalized
enaminone gave the corresponding product with lower yield
(4x, Table 2). Heteroaryl-based enaminones also smoothly
participated in the transformation to provide heteroaryl-
functionalized triazole products with good yield (4v and 4w,
To further demonstrate the application scope of the present
method for additional 1,2,3-triazole syntheses, NH-enaminones
7 and 9, which contained β-substitution, were employed with
tosyl azide, and the corresponding 1,4,5-substituted 1,2,3-
triazoles 8 and 10 were smoothly obtained under the standard
B
DOI: 10.1021/acs.orglett.6b02975
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Synthesis of 1,2,3-Triazoles
Scheme 3. Postulated Reaction Mechanism
b
entry
Ar
R
product
yield (%)
1
2
3
4
5
6
7
8
9
10
4-MeOC6H4
thiophene-2-yl
4-BrC6H4
H
6a
6b
6c
6d
6e
6f
90
86
83
88
91
84
90
84
85
80
H
H
naphth-2-yl
3,4-(MeO)2C6H3
4-ClC6H4
H
H
4-Cl
4-Me
4-Me
6-Me
4-Me
4-MeC6H4
6g
6h
6i
The nucleophilic addition of anion 14 to the N−N triple bond
in tosyl azide could then yield intermediate 15. The diazo
intermediate 16 would then be generated via a typical Regitz
diazo transfer.17 Finally, the 1,2,3-triazole products would be
produced via the intramolecular cyclization of intermediate 16.
In conclusion, by employing the NH-enaminones and tosyl
azide as easily available starting materials, we have accom-
plished the synthesis of 1,2,3-triazoles via cycloaddition
reactions mediated by t-BuONa. The generation of various
N-substitutions in the products via N-substituted enaminones
rather than organo azides, as well as the metal-free, room-
temperature operation, demonstrate it to be a highly useful
complementary strategy for the synthesis of 1,2,3-triazoles.
4-ClC6H4
naphth-2-yl
3,4-Cl2C6H3
6j
a
General conditions: enaminone 5 (0.3 mmol), TsN3, 3 (0.4 mmol),
and t-BuONa (0.45 mmol) in 2 mL of MeCN were stirred for 2 h at rt.
Yields of isolated products based on 5.
b
reaction conditions (Scheme 2). In addition, use of bis-NH-
enaminone 11 afforded the useful bis-1,2,3-triazole product 12
in satisfactory yield (Scheme 2).
Scheme 2. Synthesis of Additional 1,2,3-Triazoles
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02975.
1
Experimental procedures, characterization data, H/13C
NMR spectra of all products (PDF)
Crystallographic data of 4b (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wanjieping@jxnu.edu.cn.
ORCID
Jie-Ping Wan: 0000-0002-9367-8384
Notes
In addition to full spectroscopic characterization, the
structure of the products was further confirmed by the X-ray
analysis on the single crystal of 4b (Figure 1).16
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
According to the known literature on the reactions involving
■
the NH-enaminones and related azide cycloaddition,12,14,15,17
a
This work is financially supported by the National Natural
Science Foundation of China (21562025), the Natural Science
Foundation of Jiangxi Province (20161ACB21010), and the
Science Fund for Distinguished Young Scholars of Jiangxi
Province.
possible mechanism for the present 1,2,3-triazole formation has
been proposed, as outlined in Scheme 3. First, NH-enaminones
of type 5 resulting from the transamination of 1 and 2 could
afford the anion 14 in the presence of base via the tautomer 13.
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C
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Org. Lett. XXXX, XXX, XXX−XXX