General Synthesis of Tri-Carbo-Substituted N2-Aryl-1,2,3-triazoles via Cu-Catalyzed Annulation of Azirines with Aryldiazonium Salts

Article abstract of DOI:10.1021/acs.joc.0c01433

The general synthesis of fully substituted N2-aryl-1,2,3-triazoles is hitherto challenging compared with that of the N1-aryl counterparts. Herein, we describe a Cu-catalyzed annulation reaction of azirines and aryldiazonium salts. This regiospecific metho

Full text of DOI:10.1021/acs.joc.0c01433

Subscriber access provided by University of Birmingham
Article
General Synthesis of Tri-carbo-substituted N2-Aryl-1,2,3-Triazoles
via Cu-catalyzed Annulation of Azirines with Aryldiazonium Salts
Fangfang Feng, Jun-Kuan Li, Xuan-Yu Liu, Fa-Guang Zhang, Chi Wai Cheung, and Jun-An Ma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01433 • Publication Date (Web): 20 Jul 2020
Downloaded from pubs.acs.org on July 23, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
General Synthesis of Tri-carbo-substituted N2-Aryl-1,2,3-Triazoles via
Cu-catalyzed Annulation of Azirines with Aryldiazonium Salts
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Fang-Fang Feng,† Jun-Kuan Li,† Xuan-Yu Liu,† Fa-Guang Zhang,†,‡ Chi Wai Cheung,*,†,‡and
Jun-An Ma*,†,‡
†
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for
Synthetic Biology (Ministry of Education), and Tianjin Collaborative Innovation Centre of Chemical Science &
Engineering, Tianjin University, Tianjin 300072, P. R. of China
Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University,
‡
Binhai New City, Fuzhou 350207, P. R. of China
Supporting Information Placeholder
FG
FG
R
FG
N
N
MeO
Cu
R'
R'
N
N
O
N
N
N
+
N
N
N
N
N
N
N
DABCO
R'
BF4
R
N
R
R'
R
R'
R
R, R' = (hetero)aryl, alkyl
potential
chiral ligands
35 examples
intermediates of
up to 96% yields druglike molecules
ABSTRACT: The general synthesis of fully substituted N2-aryl-1,2,3-triazoles are hitherto challenging compared with the N1-
aryl counterparts. Herein we describe a Cu-catalyzed annulation reaction of azirines and aryldiazonium salts. This
regiospecific method allows access to a broad spectrum of tri-carbo N2-aryl-1,2,3-triazoles substituted with diverse aryl and
alkyl moieties. Its utility is highlighted by the synthesis of several triazole precursors applicable in drug discovery, as well as
novel chiral binaphthyl ligands bearing triazole moieties.
synthons for Cu-mediated or -catalyzed annulation with
Introduction
aryldiazonium salts were recently described by Tang,8a
1,2,3-Triazoles are prevalent functional compounds in
Yu,8d and our group8e to access a plethora of tri-substituted
medicinal and materials chemistry.1,2 Among them, N2-aryl-
N2-aryl-1,2,3-triazoles bearing aryl, thio, keto, and ester
1,2,3-triazoles are important structural scaffolds found in
moieties. Importantly, Jiang and co-workers described a Cu-
numerous biologically active molecules in drug discovery,
catalyzed annulation reaction of oxime acetates with
as exemplified in the orexin receptor antagonists,
electron-rich p-methoxyphenyl-diazonium salt in order to
Suvorexant,3 Nemorexant,4 and Seltorexant,5 for treating
obtain tri-carbo N2-aryl-1,2,3-triazoles in high yields8b
insomnia. Transition metal-catalyzed N-arylations have
(Scheme 1a). Recently, azirines, a class of reactive and
long been employed as the conventional methods to access
readily accessible substrates capable of bearing di-aryl- or
the target N2-aryl-1,2,3-triazoles,6 but the concomitant
aryl-/alkyl-substituents, have been employed as atom-
formations of N1-aryl regioisomeric side products are
economic synthons to access a vast number of nitrogen
generally inevitable. Alternatively, annulation reactions
heterocyclic compounds.10 Based on our continuous
using various synthetic synthons are the reliable strategies
endeavors in utilizing aryldiazonium salts for heterocycle
to deliver N2-aryl-1,2,3 triazoles in regiospecific manners.7,8
synthesis,8e,11 we envisioned that the annulation of azirines
In this context, annulation reactions of nitrogen-based
with aryldiazonium salts would also be feasible to access
synthons with aryldiazonium salts have emerged as
structurally diverse tri-carbo N2-aryl-1,2,3-triazoles
promising approaches to synthesize N2-aryl-1,2,3-triazoles8
(Scheme 1b). This alternative strategy complements the
thanks to the convenient preparations and broad scope of
precedented protocols, further extending the scope of tri-
aryldiazonium salts.9 Noteworthily, fully substituted N2-
carbo N2-aryl-1,2,3-triazole compounds. Herein we
aryl-1,2,3-triazoles are especially valuable heterocycles due
describe our discoveries based on this subject.
to the multiple versatilities and functionalities governed by
the possible existence of three distinct substituents
attached to the triazole rings. To this end, streamlined and
modular strategies based on the judicious use of suitable
Scheme 1. Cu-catalyzed annulation of aryldiazonium salts
for construction of tri-carbo N2-aryl-1,2,3-triazoles.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 14
+
(a) Jiang's work: Cu-catalyzed cycloaddition of Ac-oximes with ArN2
PMP
10
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
K2CO3
toluene
toluene
toluene
toluene
Et2O
18
<5
25
75
47
74
89
93
93
80
85
86
1
2
3
4
5
6
7
8
11
Et3N
AcO
N
N
Cu catalyst
base
BF
N
PMP
N
N
N
+
12
DBU
4
R
R'
R, R' = aryl, alkyl
13
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
R
R'
requires electron-rich p-methoxyphenyl (PMP)-diazonium
14
+
15
EtOH
(b) This work: Cu-catalyzed cycloaddition of azirines with ArN2
Ar
16
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
N
N
Cu catalyst
N
N
17
BF
N N
+
Ar
4
R'
R
9
organic base
18c,d
19c,e
20c,f
21c,g
R, R' = aryl, alkyl
R
R'
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
structurally diverse azirines & aryldiazonium salts
wide variety of tri-carbo N2-aryl 1,2,3-triazoles
potential precursors in drug synthesis & novel ligands
a Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Cu catalyst
(20 mol %), additive, solvent (2 mL), argon atmosphere, 40 oC, 16
Results and Discussions
b
c
h. Isolated yield. Reaction was conducted at room temperature
for 16 h. d 2a (2 equiv.). 2a (1.5 equiv.). DABCO (0.5 equiv.).
e
f
g
Initially,
2,3-diphenyl-2H-azirine
(1a)
and
4-
tolyldiazonium tetrafluoroborate (2a) were used as model
substrates for study (Table 1). To our delight, 1a reacted
with 3 equivalents of 2a in the presence of CuCl catalyst (20
mol %) and Li2CO3 (1 equiv) as base additive in toluene
solvent at 40 oC in 12 h, furnishing the desired product, 4,5-
diphenyl-2-(p-tolyl)-2H-1,2,3-triazole (3a), in 48% yield
(Entry 1). Cu catalyst was crucial in this transformation, as
no product was formed when CuCl was omitted (Entry 2).
Base was also essential in the reaction, as the yield dropped
in the absence of base (Entry 3). CuBr was found to be the
superior Cu catalyst, slightly improving the yield to 50%
(Entries 4-8). In the presence of organic base 1,4-
diazabicyclo[2.2. 2]octane (DABCO), the yield of 3a was
enhanced to 75%, presumably owing to its moderate
basicity and better solubility (Entry 9-13). Additionally, the
yield of 3a could be promoted to 93% using acetonitrile
(MeCN) as the polar aprotic solvent (Entries 14-17). The
reaction remained efficient at room temperature and in the
presence of 2 equivalents of 2a without loss of yield (Entry
18). Subsequent reducing the loadings of 2a, base, and
catalyst slightly diminished the yields accordingly (Entry
19-21).
CuBr (10 mol %).
The optimized reaction protocol (Table 1, entry 17)
proved to be versatile (Scheme 2). Electron-rich (3a-3h),
electron-neutral (3i), and electron-deficient aryldiazonium
salts (3j-3r) all reacted to give the corresponding N2-aryl
1,2,3-triazoles in generally good to excellent yields (65%-
96%). Likewise, para-, meta-, and ortho-substituted
aryldiazonium salts underwent annulation to afford the
triazoles in similar yields (3f-3h, 3o-3q). Additionally, di-
halo-substituted diazonium salts (3r), as well as sterically
bulky 2-naphthyl- (3s) and 2-phenylbenzene-diazonium
salts (3t), were suitable reaction substrates to deliver the
triazoles in good to high yields. Furthermore, thienyl (3u)
and quinoline moieties (3v) could also be incorporated to
the triazole products. A wide range of functional groups
were compatible in this protocol, including amino (3e),
trifluoromethyl (3j), keto (3k), iodo (3l), bromo (3m),
fluoro (3n), chloro (3o-3q), and ester groups (3u). This
protocol was amenable to the large-scale synthesis of
triazole 3f in equally high yield. However, monosubstituted
3-phenylazirine reacted to give
a trace of triazole,
Table 1. Optimizations of reaction conditions.a
suggesting that the additional substituent is necessary to
assist the stabilization of reaction intermediates.
p-Tolyl
The protocol also allowed for the use of a variety of 2,3-
di-sibstituted azirines, affording the unsymmetrical N2-
aryl-1,2,3-triazoles in good to excellent yields (Scheme 3).
Electron-rich (4a, 4f) and electron-withdrawing aryl
groups (4b, 4c, 4g, 4i), as well as heteroaryl groups (4d),
could all be incorporated on both 2- and 3-positions of the
azirine rings for triazole synthesis. Moreover, triazoles
bearing methyl (4h, 4m), cyclopropyl (4i), n-pentyl (4j), 2-
phenylethyl (4k), and 1-phenylethyl groups (4l) in either 3-
or 4- positions were generated smoothly. Notably, the
substituents at the 2- or 3-positions of azirine substrates
were interchangeable, giving the identical triazole products
in similar yields (4a and 4f; 4c and 4g; 4h and 4m). Given
the broad scope and ready accessibility of aziridines as well
as the scalability of the protocol, the method could offer an
expedient and convenient synthesis of N2-aryl triazole for
various industrial settings. Unfortunately, the monoalkyl-
N
N
Cu catalyst (20 mol %)
N
N
BF
N
+
-Tolyl
N
p
4
Ph
Ph
additive (1 equiv)
solvent, 40 oC, 12 h
Ph
Ph
1a
(1 equiv)
2a
3a
(3 equiv)
Entry Cu catalyst base
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Yield (%)b
1
2
3
4
5
6
7
8
9
CuCl
none
CuCl
CuBr
CuI
Li2CO3
Li2CO3
none
48
0
40
50
8
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Na2CO3
CuTc
CuOAc
CuCl2
CuBr
48
5
45
20
ACS Paragon Plus Environment

Page 3 of 14
The Journal of Organic Chemistry
N
p-Tolyl
CuBr (20 mol %)
or dialkyl substituted azirines were either unstable or
inaccessible for further study.
BF
N
p-Tolyl
N
+
N
N
4
R'
R
1
DABCO (1 equiv)
MeCN, rt, 16 h
N
2a
1a'-1l'
2
(2 equiv)
(1 equiv)
R
R'
3
4
5
6
7
8
R, R' = aryl:
Scheme 2. Substrate scope of aryldiazonium salts.a
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
FG
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
FG
N
CuBr (20 mol %)
BF
N
N
Ph
Ph
O
4
Ph
Ph
Ph
+
N
Ph
Ph
DABCO (1 equiv)
MeCN, rt, 16 h
N
N
1a
(1 equiv)
2a-2y
(2 equiv)
F
Cl
Me
Br
Ph
Ph
4a, 84%
4b, 96%
4c, 90%
4d, 58%
4e, 85%
9
iPr
tBu
Me
NMe2
OMe
R = alkyl; R' = aryl:
p-Tolyl
p-Tolyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
Me
N
N
N
p-Tolyl
p-Tolyl
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
F
Ph
Ph
N
N
N
N
N
N
N
N
N
N
Me
Ph
Ph
3c, 90%
Ph
Ph Ph
Ph
Ph
Ph
3b, 80%
Ph
Ph
3e, 70%
Ph
3f, 85%
Ph
Ph
Me
4f (4a),b 93%
Cl
4g (4c),b 86%
4h, 88%
3a, 93%
3d, 65%
4i, 61%
(6 mmol: 81%)b
R = aryl; R' = alkyl:
I
CF3
O
Me
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
OMe
N
N
N
N
N
N
N
N
N
N
N
N
OMe
Ph
Ph
Ph
Ph
4m (4h),b 94%
Ph
4j, 80%
Me
C5H11
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
4l, 72%c
N
Ph
N
N
4k, 83%
Ph
Ph
Ph
Ph
Ph
3j, 70%
Ph
Ph
Ph Ph
Ph
Ph
Ph
a
Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), CuBr (0.06
mmol), DABCO (0.3 mmol), MeCN (3 mL), argon atmosphere, rt, 16
3l, 88%
3i, 88%
3h, 86%
3k, 88%
3g, 94%
Br
F
F
Cl
b
h. Identical products were formed using two different azirines.
Cl
Br
Isolated yields were presented. c Reaction was conducted at 40 oC.
Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ph
The derivatization of the tri-carbo N2-aryl-1,2,3-triazole
products were viable. Triazole 3f could react with ceric
ammonium nitrate (CAN)12 to give the N2-H free, 3,4-
diphenyl 1,2,3-triazole 5 (Scheme 4a). 5 could further
undergo various N-alkyations13 to affords the
corresponding N2- and N1-alkylated triazole congeners 6-8
(Scheme 4b). In addition, regiospecific N2-arylation of 5 was
accessible via nucleophilic aromatic substitution with
various fluoroarenes to afford 9a-9f,14 allowing access to
1,2,3-triazole compounds with electron-deficient aryl
groups and pyridyl groups at N2-positions (Scheme 4c).
Indeed, triazoles 6-9 were difficult to directly produce using
the current protocol. Overall, this N2-aryl triazole synthesis
and N-dearylation strategy for elaborations would provide
alternative routes to access a broad range of structurally
and electronically diverse N2-substituted and NH-free
triazoles.15
Ph
Ph
3m, 88%
Ph
3n, 85%
Ph
Ph Ph
Ph
3q, 84%
Ph
3r, 83%
Ph
Ph
Ph
3p, 96%
3o, 86%
S
N
N
CO2Me
Ph
N
N
N
N
N
N
N
N
N
N
N
Ph
3u, 80%
Ph
Ph
3t, 90%
Ph
Ph
3s, 60%
Ph
Ph
3v, 42%
Ph
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), CuBr (0.06
mmol), DABCO (0.3 mmol), MeCN (3 mL), argon atmosphere, rt, 16
h. Isolated yields were presented. b 1.16 g of 1a was used.
Scheme 3. Substrate scope of azirines.a
Scheme 4. Derivatizations of the triazole products.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 14
(a) Synthesis of triazole scaffolds as drug precursors
(a) Dearylation of triazole:
Ph
Ph
FG
N
N
1
2
3
4
5
6
7
8
Ph
N
CAN (2.7 equiv)
FG
HN
F
MeO
N
CH3CN / H2O (10:1)
-10 oC, 6 d
standard
conditions
N
N
Ph
CO2Me
CO2Me
+
3f
(b) N-Alkylations of triazole:
5, 68%
Ph
Ph
N
N
N
N
BF4
2a
N
N
N
N
Me
precurors for synthesis of
analogues of Suvorexant,
Nemorexant & Selorexant
(refs 3-5)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
Ph
Ph
CH I
(2 equiv)
N
N
N
N
3
10c, 91%
FG = Me: 10a, 88%
FG = OMe: 10b, 61%
Me
Bn
N
HN
K2CO3 (2 equiv)
DMF, 0 oC, 7 h
+
+
6a, 49%
6b, 49%
5
(b) Incoporation of triazole groups to bisnaphthyl skeletons
9
Bn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
BnBr
Ph
N
N
standard conditions
(1.5 equiv)
DBU (1.5 equiv)
Ph
Ph
N
N
N
N
N2
N2
BF4
BF4
N
N
N
HN
+
p-Tol
Ph
Ph
THF, rt, 8 h
Ph
2f'
5
7b, 32%
7a, 64%
p-Tol
p-Tol
Ph
CO2Et
N
N
N
N
Ph
Ph
Ph
EtO2C
BrCH CO Et
(2 equiv)
Ph
N
N
Ph
Ph
2
2
N
N
N
N
N
N
N
Potential chiral
ligands
asymmetric
catalysis
+
N
K2CO3 (2 equiv)
N
HN
+
for
N
N
Ph
DMF, rt, 8 h
Ph
p-Tol
8a, 75%
5
8b, 15%
11a, 26%
11b, 24%
(c) N-Arylations of triazole:
Ph
N
Ph
EWG
To probe the mechanism of the Cu-catalyzed annulation
reaction, 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)
was added as radical scavenger (Scheme 6a). The reaction
became sluggish in the presence of 2 equivalents of TEMPO
to form a trace of product 3a. The adduct between TEMPO
and azirine was also detected by HRMS analysis,10d
indicating that radical pathways are likely involved in the
reaction process. In the proposed reaction mechanism
(Scheme 6b), CuBr catalyst initially cleaves the C-N single
bond of azirine to form radical intermediate A,10d which
further couples with aryldiazonium ion to form radical
cation species B. Deprotonation of species B by DABCO
furnishes radial species C, which then cyclizes to form the
triazole product and regenerates CuBr for subsequent
catalytic cycles.
N
N
EWG
K2CO3 (1 equiv)
HN
N
N
F
+
DMF
70-120 oC, 5 h
N
Ph
Ph
5
CN
NO2
Ph
N
Ph
Ph
Ph
N
N
N
N
O2N
N
N
N
Ph
Ph
9a, 95%
F
9c, 95%
9b, 94%
NO2
Ph
Ph
Ph
Ph
N
N
N
N
Ph
Ph
N
N
N
O2N
N
O2N
N
N
N
9d, 85%
9e, 96%
9f, 87%
Under this protocol, several methyl 2-(4’,5’-diaryl-2’-
triazolyl)arenoate compounds 10a-10c were readily
synthesized using the corresponding azirines and
aryldiazonium salts (Scheme 5a). These compounds could
serve as precursors16 towards the modular synthesis of the
analogues of orexin receptor antagonists.3-5 Moreover, (S)-
[1,1'-binaphthalene]-2,2'-diamine was readily converted to
the corresponding bis(diazonium) salt, which reacted with
azirine 2a’ under the standard conditions to afford both
mono- and bis-triazolyl substituted binaphthalenes, 11a
and 11b (Scheme 5b). These novel class of chiral triazolyl-
binaphthalenes would be potentially applicable in
asymmetric transition metal-catalyzed transformations or
photocatalysis.17
Scheme 6. Probing of the reaction mechanism.
Scheme 5. Synthetic utility of the reaction protocol.
ACS Paragon Plus Environment

Page 5 of 14
The Journal of Organic Chemistry
performed on precoated GF254 silica gel plates (Qingdao
(a) Radical trap experiment
N
Me
N
1
Marine Chemical Inc.) and compounds were visualized with
a UV light at 254 nm. Flash chromatography separations
were carried out using silica gel (200–300 mesh, Qingdao
Marine Chemical Inc.). Aryldiazonium salts 211a were
prepared according to the reported procedures.
Me
N
Ph
Ph
2
3
4
5
6
7
Me
1a
standard
conditions
( 1 equiv)
HN
Ph
O
+
N
N
+
TEMPO
(2 equiv)
Me
PhMe
BF
N
Me
N
4
Ph
Ph
12, detected by HRMS:
[M+H]+ = 351.2431
3a
trace
2a
General procedure for synthesis of 2H-azirine (1).
(2 equiv)
8
9
(b) Proposed mechanism
Ar
(i) Method A (for synthesis of 1a, 1a' -1g' and 1i')18
N
CuIBr
HO
N
MsCl, Et3N
DBU
1)
2)
NH2OH HCl
NaOAc
R
R'
N
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
N
N
R2
R2
for 1a, 1a' -1g' and 1i'
R1
R2
R1
R1
THF, 0 o
C
MeOH / H2O, rt
R'
R
Br CuII
Br CuII
Step 1: A solvent mixture of MeOH/H2O (20:1) was added
N
Ar
to a mixture of ketone (10 mmol, 1 equiv), NH2OH·HCl (1.5
equiv) and sodium acetate (1.5 equiv) in a round bottom
flask. The resulting solution was stirred at room
temperature and the reaction was monitored by TLC. After
the reaction was completed, the solvent was removed in
vacuo and CH2Cl2 (30 mL) was then added. The mixture was
washed with saturated NaHCO3 solution followed by brine.
The organic fraction was dried over anhydrous Na2SO4 and
concentrated in vacuo to give the oxime as the residue,
which was used directly for the next step. Step 2: To a
solution of the crude oxime (1 equiv, from step 1) in dry THF
(30 mL) was added triethylamine (1.5 equiv) and
methanesulfonyl chloride (1.5 equiv) sequentially at room
temperature or at 0 oC. The solution became cloudy after the
addition of methanesulfonyl chloride. The resulting mixture
was stirred for 30 min, and DBU (1.5 equiv) was then added
over 1 min. After stirring for additional 30 min, the reaction
mixture was passed through a pad of silica gel and washed
with Et2O (30 mL x 3). The filtrate was concentrated in
vacuo and the residue was purified by column
chromatography using peteroleum ether and ethyl acetate
(20:1) as eluent to afford the 2H-azirine 1a, 1a'-1g' and 1i'.
N
N Ar
N
N
N
R
R
R'
(A)
R'
(C)
Br CuII
Ar
N
N
N
R
R3NH
R'
H
R3N
(B)
R3N = DABCO
In conclusion, we have developed an annulation reaction
of azirines with aryldiazonium salts. A diverse collection of
tri-carbo N2-aryl-1,2,3-triazoles substituted with both aryl
and alkyl moieties can be accessed in association with good
functional group tolerance. The triazole compounds are
readily diversified to other derivatives. The protocol also
allows expedient access to several potential precursors of
druglike molecules as well as novel chiral binaphthyl
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ligands. Preliminary study suggests that
a radical
mechanism likely takes place. Further expansion of the
substrate scope and the catalytic applications of chiral
ligand 11a and 11b are underway in our laboratory.
(ii) Method B (for synthesis of 1j' -1m')19
Experimental Section
General information
1) NaN3, ICl
N
N3
MeCN, 0 o
C
R3
3) toluene
100 oC, 4 h
R3
Ph
1H, 13C and 19F NMR spectra were recorded on Bruker AV
400 MHz instrument at 400 MHz (1H NMR), 100 MHz (13C
NMR), and 376 MHz (19F NMR). Chemical shifts were
reported in ppm down field from internal Me4Si and
external CHCl3, respectively. Multiplicity was indicated as
follows: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), dd (doublet of doublet), and br (broad signal).
Coupling constants were reported in Hertz (Hz). High
resolution mass spectrometry (HRMS) spectra were
obtained on a Bruker miorOTOF-QII instrument. Melting
points were measured on a SGW X-4A digital melting point
apparatus and are uncorrected. Optical rotations were
determined using an Autopol IV automatic polarimeter.
HPLC analyses were carried out on a HewlettPackard Model
HP 1200 instrument. X-ray structural analysis was
conducted on a Bruker APEX-II CCD instrument.
Ph
R3
Ph
2) t-BuOK, Et2O
0 oC,4 h
1j' -m'
Step 1: To a suspension of NaN3 (452 mg, 7.0 mmol, 2.5
equiv) in acetonitrile (2.2 mL) was added dropwise a
solution of iodine monochloride (680 mg, 4.2 mmol, 1.5
equiv) in CH2Cl2 (3.6 mL) at -20℃, and the mixture was
stirred at the same temperature. After 30 min, a solution of
the corresponding alkene (2.8 mmol, 1.0 equiv) in CH2Cl2
(3.6 mL) was added slowly, and the mixture was stirred for
additional 1 h. After the reaction, the reaction was quenched
with saturated aqueous Na2S2O3 (5 mL), and the reaction
mixture were extracted with Et2O (10 mL x 3). The
combined organic fraction was washed with brine and dried
over anhydrous Na2SO4. After evaporation of solvent, the
resulting crude material was used immediately for the next
step without any further purification. Step 2: To a solution
of the crude material (from step 1) in Et2O (8 mL) was added
t-BuOK (374 mg, 3.3 mmol, 1.2 equiv) at 0℃, and the
mixture was stirred for 1 h at the same temperature. After
the reaction, the reacion mixture was quenched with H2O
Tetrahydrofuran (THF), diethyl ether (Et2O), and toluene
were distilled from sodium/benzophenone prior to use;
CH2Cl2 and CCl4 was distilled from CaH2; CH3CN was distilled
from P2O5. All purchased reagents were used without
further purification. Thin-layer chromatography (TLC) was
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
(10 mL), and the organic materials were extracted with Et2O (petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 86.8 mg
o
1
1
2
3
4
5
6
7
8
(20 mL x 3). The combined organic fraction was washed
with brine, dried over anydrous Na2SO4, and then dried in
vacuo. The residue was purified by flash column
chromatography using peteroleum ether and ethyl acetate
(10:1) as eluent to give the corresponding vinyl azide. Step
3: A solution of the vinyl azide (from step 2) in toluene (15
mL) was heated at 100 ℃ for 4 h. After evaporation of
solvent, the crude mixture was purified by flash column
chromatography using peteroleum ether and ethyl acetate
(20:1) as eluent to give the 2H-azirines 1j'-1m'.
(0.28 mmol), 93% yield, m.p. 105‒107 C. H NMR (400
MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 2H), 7.65 (dd, J = 6.5, 3.1
Hz, 4H), 7.40 (dd, J = 4.9, 1.7 Hz, 6H), 7.30 (d, J = 8.3 Hz, 2H),
2.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 145.8, 137.8,
137.4, 131.1, 129.9, 128.7, 128.7, 128.6, 118.9, 21.2. HRMS
+
(ESI) m/z calcd. for C21H18N3 312.1501, found 312.1500
[M+H]+.
2-(3,5-dimethylphenyl)-4,5-diphenyl-2H-1,2,3-triazole
(3b). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 78.1 mg
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(iii) Method C (for synthesis of 1h')19
o
1
(0.24 mmol), 80% yield, m.p. 108‒110 C. H NMR (400
MHz, CDCl3) δ 7.82 (s, 2H), 7.66 (m, 4H), 7.45 – 7.33 (m, 6H),
7.00 (s, 1H), 2.42 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ
145.9, 139.8, 139.3, 131.0, 129.3, 128.7, 128.7, 128.6, 116.7,
21.5. HRMS (ESI) m/z calcd. for C22H20N3+ 326.1657, found
326.1658 [M+H]+.
1) NaN3, NaI
CAN, MeOH
N
Me
Me
3) toluene
100 oC, 1.5 h
Ph
Ph
Me
Ph
2) t-BuOK, Et2O
N3
1h'
Step 1: To a mixture of alkene (6.0 mmol, 1.0 equiv), NaN3
(390 mg, 6.0 mmol, 1.0 equiv), and NaI (900 mg, 6.0 mmol,
1.0 equiv) in methanol (9.0 mL) at 0 oC was added dropwise
a solution of ceric ammonium nitrate (590 mg, 12.6 mmol,
2.1 equiv) in methanol (36 mL). Upon completion of the
reaction as indicated by TLC, saturated aqueous NaHSO3 (20
mL) was added, and the resulting mixture was extracted
with CH2Cl2 (10 mL x 3) The combined organic fraction was
washed with distilled water (24 mL) and saturated brine
(24 mL), dried over anhydrous Na2SO4, and dried in vacuo.
The resulting crude material was used immediately for the
next step without any further purification. Step 2: To a
solution of the crude material (from step 1) in dry Et2O (20
mL) in an ice bath was added t-BuOK (1.34 g, 12.0 mmol, 2.0
equiv). The reaction mixture was stirred for 4 h at 0 oC and
then washed with water (50 mL x 2). The combined organic
fraction was dried over anhydrous Na2SO4, and the solvent
was removed in vacuo. The residue was purified by column
chromatography using peteroleum ether and ethyl acetate
as eluent (10:1) to give the crresponding vinyl azide. Step
3: A solution of the vinyl azide (from step 2) in toluene (15
mL) was heated at 100℃ for 1.5 h. After evaporation of
solvent, the crude mixture was purified by flash column
chromatography using peteroleum ether and ethyl acetate
(20:1) as eluent to give the 2H-azirines 1h'.
2-(4-isopropylphenyl)-4,5-diphenyl-2H-1,2,3-
triazole (3c). Following the geneal procedure A, the
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.3), 93.8 mg (0.27 mmol), 90% yield, m.p. 108‒110 oC. 1H
NMR (400 MHz, CDCl3) δ 8.19 – 8.04 (m, 2H), 7.68 (s, 4H),
7.50 – 7.29 (m, 8H), 3.08 – 2.87 (m, 1H), 1.32 (d, J = 6.6 Hz,
6H). 13C{1H} NMR (100 MHz, CDCl3) δ 148.4, 145.8, 137.9,
131.1, 128.7, 128.7, 128.6, 127.3, 119.0, 33.9, 24.1. HRMS
+
(ESI) m/z calcd. for C23H22N3 340.1814, found 340.1808
[M+H]+.
2-(4-(tert-butyl)phenyl)-4,5-diphenyl-2H-1,2,3-
triazole (3d). Following the geneal procedure A, the
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
1
= 0.3), 68.9 mg (0.20 mmol), 65% yield, m.p. 70‒72 oC. H
NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz, 2H), 7.65 (dd, J
= 6.5, 3.1 Hz, 4H), 7.51 (d, J = 8.8 Hz, 2H), 7.42 – 7.37 (m, 5H),
7.36 – 7.29 (m, 1H), 1.38 (s, 9H). 13C{1H} NMR (100 MHz,
CDCl3) δ 150.8, 145.8, 137.6, 131.1, 128.7, 128.7, 128.6,
+
126.3, 118.7, 34.8, 31.5. HRMS (ESI) m/z calcd. for C24H24N3
354.1970, found 354.1968 [M+H]+.
General procedure A: Annulation Reaction of 2H-
Azirines 1 and aryldiazonium salt 2. An oven-dried 10 mL
Schlenk tube equipped with a stirring bar and capped with
a rubber septum was charged with 2H-azirine (1, 1 equiv,
0.3 mmol), arene-diazonium salt (2, 2 equiv, 0.6 mmol),
CuBr (20 mol%, 0.06 mmol), and DABCO (1 equiv, 0.3
mmol). The tube was evacuated under vacuo and then
backfilled with argon (for three times). CH3CN (3.0 mL) was
transferred into the tube via a syringe. The resulting
mixture was stirred under an argon atmosphere at room
temperature for 16 h. The reaction mixture was
concentrated in vacuo, and the residue was purified by flash
chromatography on silica gel (eluting with petroleum ether
/ ethyl acetate) to give the desired N2-aryl-1,2,3-triazole
products 3 and 4.
4-(4,5-diphenyl-2H-1,2,3-triazol-2-yl)-N,N-
dimethylaniline (3e). Following the geneal procedure A,
the product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.2), 71.5 mg (0.21 mmol), 70% yield, m.p. 145‒147 oC. 1H
NMR (400 MHz, CDCl3) δ 8.03 (d, J = 9.1 Hz, 2H), 7.66 (dd, J
= 7.4, 1.9 Hz, 4H), 7.46 – 7.29 (m, 6H), 6.80 (d, J = 9.1 Hz, 2H),
3.02 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 150.0, 145.1,
131.4, 130.4, 128.7, 128.5, 128.5, 120.2, 112.4, 40.7, 40.5.
+
HRMS (ESI) m/z calcd. for C22H21N4 341.1766, found
341.1768 [M+H]+.
2-(4-methoxyphenyl)-4,5-diphenyl-2H-1,2,3-triazole
(3f). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.2), 83.5 mg
(0.26 mmol), 85% yield, m.p. 84‒86 oC. 1H NMR (400 MHz,
CDCl3) δ 8.14 (d, J = 9.1 Hz, 2H), 7.70 (dd, J = 6.5, 3.0 Hz, 4H),
7.50 – 7.35 (m, 6H), 7.05 (d, J = 9.1 Hz, 2H), 3.89 (s, 3H).
4,5-diphenyl-2-(p-tolyl)-2H-1,2,3-triazole
(3a).
Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
ACS Paragon Plus Environment

Page 7 of 14
The Journal of Organic Chemistry
13C{1H} NMR (100 MHz, CDCl3) δ 159.2, 145.7, 133.8, 131.2,
129.9, 129.1, 128.8, 128.6, 118.5, 26.8. HRMS (ESI) m/z
calcd. for C22H18N3O+ 340.1450, found 340.1458 [M+H]+.
1
2
3
4
5
6
7
8
128.8, 128.7, 128.6, 120.4, 114.5, 55.8. HRMS (ESI) m/z
calcd. for C21H18N3O+ 328.1450, found 328.1451 [M+H]+. For
the reacton based on 6 mmol (1.16 g) of 2H-azirines, the
product 3f was obtained in 81% yield (1.59 g).
2-(4-iodophenyl)-4,5-diphenyl-2H-1,2,3-triazole
(3l). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.4), 111.7 mg
2-(3-methoxyphenyl)-4,5-diphenyl-2H-1,2,3-triazole
(3g). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.2), 92.3 mg
o
1
(0.26 mmol), 88% yield, m.p. 138‒140 C. H NMR (400
MHz, CDCl3) δ 7.95 (d, J = 8.9 Hz, 2H), 7.82 (d, J = 8.9 Hz, 2H),
7.71 – 7.58 (m, 4H), 7.48 – 7.33 (m, 6H). 13C{1H} NMR (100
MHz, CDCl3) δ 146.4, 139.5, 138.4, 130.6, 128.9, 128.8,
128.6, 120.5, 92.1. HRMS (ESI) m/z calcd. for C20H15N3I+
424.0311, found 424.0316 [M+H]+.
9
o
1
(0.28 mmol), 94% yield, m.p. 100‒102 C. H NMR (400
MHz, CDCl3) δ 7.87 – 7.74 (m, 2H), 7.75 – 7.62 (m, 4H), 7.42
(dd, J = 4.0, 2.8 Hz, 7H), 6.98 – 6.86 (m, 1H), 3.92 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 160.5, 146.1, 140.9, 130.9,
130.2, 128.8, 128.7, 128.6, 113.7, 111.2, 104.3, 55.7. HRMS
(ESI) m/z calcd. for C21H18N3O+ 328.1450, found 328.1451
[M+H]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(4-bromophenyl)-4,5-diphenyl-2H-1,2,3-triazole
(3m). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.4), 99.3 mg
o
1
2-(2-methoxyphenyl)-4,5-diphenyl-2H-1,2,3-triazole
(3h). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.1), 84.5 mg
(0.26 mmol), 86% yield, m.p. 92‒94 oC. 1H NMR (400 MHz,
CDCl3) δ 7.65 (dd, J = 6.4, 2.1 Hz, 5H), 7.50 – 7.41 (m, 1H),
7.38 (dd, J = 5.0, 1.7 Hz, 5H), 7.15 – 7.03 (m, 2H), 3.90 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 153.9, 145.7, 131.0, 130.6,
129.9, 128.7, 128.6, 128.6, 127.4, 120.8, 113.0, 56.5. HRMS
(ESI) m/z calcd. for C21H18N3O+ 328.1450, found 328.1447
[M+H]+.
(0.26 mmol), 88% yield, m.p. 117‒119 C. H NMR (400
MHz, CDCl3) δ 8.08 (d, J = 8.9 Hz, 1H), 7.71 – 7.54 (m, 6H),
7.52 – 7.29 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 146.5,
138.9, 132.5, 130.7, 128.9, 128.8, 128.6, 121.0, 120.3. HRMS
(ESI) m/z calcd. for C20H15N3Br+ 376.0449, found 376.0443
[M+H]+.
2-(4-fluorophenyl)-4,5-diphenyl-2H-1,2,3-triazole
(3n). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 80.4 mg
o
1
(0.26 mmol), 85% yield, m.p. 106‒108 C. H NMR (400
MHz, CDCl3) δ 8.27 – 8.05 (m, 2H), 7.73-7.56 (m, 4H), 7.49 –
7.36 (m, 6H), 7.19 (t, J = 8.6 Hz, 2H). 19F NMR (376 MHz,
CDCl3) δ -114.71. 13C{1H} NMR (100 MHz, CDCl3) δ 161.9 (d,
J = 246.9 Hz), 146.2, 136.2, 130.8, 128.9, 128.8, 128.6, 120.6
(d, J = 8.4 Hz), 116.2 (d, J = 23.1 Hz). HRMS (ESI) m/z calcd.
for C20H15N3F+ 316.1250, found 316.1255 [M+H]+.
2,4,5-triphenyl-2H-1,2,3-triazole (3i). Following the
geneal procedure A, the product was obtained as a yellow
solid after column chromatography (petroleum ether/ethyl
acetate = 30:1, Rf = 0.3), 78.5 mg (0.26 mmol), 88% yield,
m.p. 93‒95 oC. 1H NMR (400 MHz, CDCl3) δ 8.26 – 8.12 (m,
2H), 7.72 – 7.60 (m, 4H), 7.51 (t, J = 7.9 Hz, 2H), 7.47 – 7.37
(m, 6H), 7.36 (d, J = 7.5 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 146.1, 139.9, 130.9, 129.4, 128.8, 128.7, 128.6,
127.5, 118.9. HRMS (ESI) m/z calcd. for C20H16N3+ 298.1344,
found 298.1349 [M+H]+.
2-(4-chlorophenyl)-4,5-diphenyl-2H-1,2,3-triazole
(3o). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.4), 85.6 mg
(0.26 mmol), 86% yield, m.p. 83‒85 oC. 1H NMR (400 MHz,
CDCl3) δ 8.24 – 8.01 (m, 2H), 7.77 – 7.56 (m, 4H), 7.47 (d, J =
9.0 Hz, 2H), 7.45 – 7.35 (m, 6H). 13C{1H} NMR (100 MHz,
CDCl3) δ 146.4, 138.3, 133.0, 130.7, 129.5, 128.9, 128.7,
128.6, 120.0. HRMS (ESI) m/z calcd. for C20H15N3Cl+
332.0955, found 332.0959 [M+H]+.
4,5-diphenyl-2-(4-(trifluoromethyl)phenyl)-2H-1,2,3-
triazole (3j). Following the geneal procedure A, the
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.2), 76.7 mg (0.21 mmol), 70% yield, m.p. 107‒109 oC. 1H
NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.5 Hz, 2H), 7.77 (d, J =
8.6 Hz, 2H), 7.70 – 7.56 (m, 4H), 7.50 – 7.37 (m, 5H), 7.36 –
7.29 (m, 1H). 19F NMR (376 MHz, CDCl3) δ -62.31. 13C{1H}
NMR (100 MHz, CDCl3) δ 147.3 (d, J = 261.7 Hz), 147.1,
142.1, 138.7, 130.3 (d, J = 43.6 Hz), 129.2, 128.8, 128.6,
128.4, 126.8 (q, J = 3.7 Hz). HRMS (ESI) m/z calcd. for
C21H15N3F3+ 366.1218, found 366.1218 [M+H]+.
2-(3-chlorophenyl)-4,5-diphenyl-2H-1,2,3-triazole
(3p). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.4), 95.6 mg
(0.29 mmol), 96% yield, m.p. 76‒78 oC. 1H NMR (400 MHz,
CDCl3) δ 8.24 (t, J = 1.9 Hz, 1H), 8.15 – 8.03 (m, 1H), 7.72 –
7.57 (m, 4H), 7.43 (dd, J = 9.6, 6.3 Hz, 8H), 7.37 – 7.28 (m,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 146.6, 140.7, 135.3,
130.6, 130.5, 129.0, 128.8, 128.6, 127.4, 119.1, 116.9. HRMS
(ESI) m/z calcd. for C20H15N3Cl+ 332.0955, found 332.0948
[M+H]+.
1-(4-(4,5-diphenyl-2H-1,2,3-triazol-2-
yl)phenyl)ethanone (3k). Following the geneal procedure
A, the product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.2), 89.6 mg (0.26 mmol), 88% yield, m.p. 140‒142 oC. 1H
NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.6 Hz, 2H), 8.10 (d, J =
8.6 Hz, 2H), 7.75 – 7.55 (m, 4H), 7.50 – 7.28 (m, 6H). 13C{1H}
NMR (100 MHz, CDCl3) δ 197.0, 147.1, 142.8, 135.7, 130.5,
2-(2-chlorophenyl)-4,5-diphenyl-2H-1,2,3-triazole
(3q). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
o
1
(petroleum ether/ethyl acetate = 30:1, Rf = 0.4), 83.6 mg
(0.25 mmol), 84% yield, m.p. 78‒80 oC. 1H NMR (400 MHz,
CDCl3) δ 7.82 – 7.72 (m, 1H), 7.72 – 7.63 (m, 4H), 7.64 – 7.54
(m, 1H), 7.48 – 7.32 (m, 8H). 13C{1H} NMR (100 MHz, CDCl3)
δ 146.2, 138.1, 131.2, 130.7, 130.2, 129.5, 128, 128.7, 128.6,
127.7, 127.5. HRMS (ESI) m/z calcd. for C20H15N3Cl+
332.0955, found 332.0960 [M+H]+.
(0.13 mmol), 42% yield, m.p. 157‒159 C. H NMR (400
MHz, CDCl3) δ 9.82 (d, J = 2.4 Hz, 1H), 8.85 (d, J = 2.1 Hz, 1H),
8.19 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.74 (dd, J =
11.3, 4.0 Hz, 1H), 7.69 (dd, J = 6.5, 2.9 Hz, 4H), 7.62 (t, J = 7.5
Hz, 1H), 7.52 – 7.34 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3)
δ 147.2, 147.0, 142.7, 133.2, 130.5, 129.7, 129.7, 129.1,
128.9, 128.7, 128.3, 127.9, 127.7, 123.5. HRMS (ESI) m/z
calcd. for C23H17N4+ 349.1453, found 349.1459 [M+H]+.
1
2
3
4
5
6
7
8
9
2-(3-bromo-4-fluorophenyl)-4,5-diphenyl-2H-1,2,3-
triazole (3r). Following the geneal procedure A, the
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
4-phenyl-2,5-di-p-tolyl-2H-1,2,3-triazole
(4a).
Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 82.0 mg
(0.25 mmol), 84% yield, m.p. 90‒92 oC. 1H NMR (400 MHz,
CDCl3) δ 8.06 (d, J = 8.5 Hz, 2H), 7.73 – 7.60 (m, 2H), 7.54 (d,
J = 8.1 Hz, 2H), 7.41 (ddd, J = 7.0, 6.2, 1.9 Hz, 3H), 7.30 (d, J =
8.3 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 2.42 (s, 3H), 2.40 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 145.9, 145.7, 138.6 ，
137.8, 137.3, 131.2, 129.9, 129.4, 128.7, 128.6, 128.6, 128.5,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
= 0.3), 98.2 mg (0.25 mmol), 83% yield, m.p. 82‒84 oC. H
NMR (400 MHz, CDCl3) δ 7.87 (t, J = 8.3 Hz, 1H), 7.69 – 7.58
(m, 4H), 7.51 (dd, J = 10.3, 2.0 Hz, 1H), 7.47 – 7.42 (m, 1H),
7.42 – 7.34 (m, 6H). 19F NMR (376 MHz, CDCl3) δ -118.35.
13C{1H} NMR (100 MHz, CDCl3) δ 154.2 (d, J = 260.9 Hz),
146.9, 130.4, 129.0, 128.8, 128.6, 128.0 (d, J = 4.0 Hz), 127.7
(d, J = 9.0 Hz), 125.9, 121.8 (d, J = 8.3 Hz), 121.3 (d, J = 23.0
Hz). HRMS (ESI) m/z calcd. for C20H15N3FBr+ 394.0355,
found 394.0361 [M+H]+.
+
128.1, 118.8, 21.5, 21.2. HRMS (ESI) m/z calcd. for C22H20N3
326.1657, found 326.1650 [M+H]+.
2-(naphthalen-1-yl)-4,5-diphenyl-2H-1,2,3-triazole
(3s). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 62.5 mg
(0.18 mmol), 60% yield, m.p. 42‒44 oC. 1H NMR (400 MHz,
CDCl3) δ 8.51 – 8.42 (m, 1H), 8.00 (d, J = 5.7 Hz, 1H), 7.96 (d,
J = 6.5 Hz, 2H), 7.73 (dd, J = 6.5, 3.1 Hz, 4H), 7.64 – 7.57 (m,
3H), 7.49 – 7.36 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ
146.1, 136.9, 135.0, 134.7, 130.9, 130.1, 129.6, 129.3, 129.3,
129.2, 128.9, 128.8, 128.7, 128.4, 127.6, 127.6, 126.8, 125.2,
124.0, 122.9. HRMS (ESI) m/z calcd. for C24H18N3+ 348.1501,
found 348.1494 [M+H]+.
4-(4-fluorophenyl)-5-phenyl-2-(p-tolyl)-2H-1,2,3-
triazole (4b). Following the geneal procedure A, the
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
1
= 0.3), 94.9 mg (0.29 mmol), 96% yield, m.p. 93‒95 oC. H
NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 2H), 7.62 (td, J
= 5.3, 2.2 Hz, 4H), 7.41 (dd, J = 5.0, 1.7 Hz, 3H), 7.30 (d, J =
8.2 Hz, 2H), 7.16 – 6.97 (m, 2H), 2.42 (s, 3H). 19F NMR (376
MHz, CDCl3) δ -112.80. 13C{1H} NMR (100 MHz, CDCl3) δ
163.1 (d, J = 248.2 Hz), 145.7, 144.9, 137.7, 137.5, 130.9,
130.4, 130.4, 130.0, 128.8, 128.6, 127.1 (d, J = 3.3 Hz), 118.8,
115.8 (d, J = 21.7 Hz), 21.2. HRMS (ESI) m/z calcd. for
C21H17N3F+ 330.1407, found 330.1406 [M+H]+.
2-([1,1'-biphenyl]-2-yl)-4,5-diphenyl-2H-1,2,3-
triazole (3t). Following the geneal procedure A, the
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.4), 100.8 mg (0.27 mmol), 90% yield, m.p. 82‒84 oC. 1H
NMR (400 MHz, CDCl3) δ 7.89 – 7.81 (m, 1H), 7.61 – 7.50 (m,
3H), 7.44 (dd, J = 6.6, 2.9 Hz, 4H), 7.39 – 7.29 (m, 9H), 7.23
(dd, J = 6.6, 2.9 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ
145.5, 139.1, 138.6, 137.9, 131.3, 130.9, 129.3, 128.6, 128.6,
128.5, 128.4, 128.3, 128.2, 127.3, 126.0. HRMS (ESI) m/z
calcd. for C26H20N3+ 374.1657, found 374.1660 [M+H]+.
4-(4-chlorophenyl)-5-phenyl-2-(p-tolyl)-2H-1,2,3-
triazole (4c). Following the geneal procedure A, the
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.3), 93.4 mg (0.27 mmol), 90% yield, m.p. 109‒101 oC. 1H
NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 2H), 7.63 (dd, J
= 6.6, 3.0 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.42 (dd, J = 4.9,
1.6 Hz, 3H), 7.37 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H),
2.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 145.8, 144.6,
137.6, 137.6, 134.7, 130.8, 129.9, 129.8, 129.5, 129.0, 128.9,
128.8, 128.6, 118.8, 21.2. HRMS (ESI) m/z calcd. for
C21H17N3Cl+ 346.1111, found 346.1109 [M+H]+.
methyl
3-(4,5-diphenyl-2H-1,2,3-triazol-2-
yl)thiophene-2-carboxylate (3u). Following the geneal
procedure A, the product was obtained as a yellow solid
after column chromatography (petroleum ether/ethyl
acetate = 30:1, Rf = 0.3), 86.7 mg (0.24 mmol), 80% yield,
4-(furan-2-yl)-5-phenyl-2-(p-tolyl)-2H-1,2,3-triazole
(4d). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 52.4mg
(0.17 mmol), 58% yield, m.p. 58‒60 oC. 1H NMR (400 MHz,
CDCl3) δ 8.05 (d, J = 8.4 Hz, 2H), 7.81 – 7.65 (m, 2H), 7.54 (s,
1H), 7.51 – 7.40 (m, 3H), 7.29 (d, J = 8.3 Hz, 2H), 6.68 (d, J =
3.2 Hz, 1H), 6.56 – 6.36 (m, 1H), 2.42 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 145.8, 145.7, 143.1, 137.7, 137.6, 130.6,
129.9, 129.0, 128.8, 128.7, 119.0, 111.5, 109.8, 100.1, 21.2.
HRMS (ESI) m/z calcd. for C19H16N3O+ 302.1293, found
302.1298 [M+H]+.
1
m.p. 111‒113 oC. H NMR (400 MHz, CDCl3) δ 7.64 (dd, J =
6.3, 2.8 Hz, 4H), 7.56 (d, J = 5.3 Hz, 1H), 7.48 (d, J = 5.3 Hz,
1H), 7.44 – 7.29 (m, 6H), 3.85 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 160.9, 146.2, 140.6, 130.6, 129.9, 128.8,
128.7, 128.6, 126.1, 124.4, 52.5. HRMS (ESI) m/z calcd. for
C20H16N3O2S+ 362.0963, found 362.0966 [M+H]+.
3-(4,5-diphenyl-2H-1,2,3-triazol-2-yl)quinoline (3v).
Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.1), 43.9 mg
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
4-(4-bromophenyl)-5-phenyl-2-(p-tolyl)-2H-1,2,3-
δ 160.2 (d, J = 249.7 Hz), 149.9, 142.1, 137.8, 137.0, 131.6
(d, J = 3.1 Hz), 130.5 (d, J = 8.0 Hz), 129.8, 124.4 (d, J = 3.7
Hz), 119.2 (d, J = 14.7 Hz), 118.6, 116.3 (d, J = 21.7 Hz), 21.2,
8.6, 6.8. HRMS (ESI) m/z calcd. for C18H17N3F+ 294.1407,
found 294.1411 [M+H]+.
1
2
3
4
5
6
7
8
triazole (4e). Following the geneal procedure A, the
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.3), 99.5 mg (0.26 mmol), 85% yield, m.p. 106‒108 oC. 1H
NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.5 Hz, 2H), 7.62 (dd, J
= 6.6, 3.0 Hz, 2H), 7.53 (s, 4H), 7.46 – 7.37 (m, 3H), 7.30 (d, J
= 8.2 Hz, 2H), 2.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 145.9, 144.7, 137.7, 131.9, 131.6, 131.6, 130.8, 130.1,
130.0, 128.9, 128.9, 128.6, 122.9, 118.9, 21.2. HRMS (ESI)
m/z calcd. for C21H17N3Br+ 390.0606, found 390.0608
[M+H]+.
4-pentyl-5-phenyl-2-(p-tolyl)-2H-1,2,3-triazole (4j).
Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 48.9 mg
(0.16 mmol), 80% yield, m.p. 40‒42 oC. 1H NMR (400 MHz,
CDCl3) δ 8.02 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 7.3 Hz, 2H), 7.51
(t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.35 – 7.21 (m, 2H),
3.03 – 2.87 (m, 2H), 2.43 (s, 3H), 1.84 (dt, J = 15.3, 7.6 Hz,
2H), 1.48 – 1.34 (m, 4H), 0.95 (t, J = 7.0 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 147.0, 146.0, 137.9, 136.9, 131.4,
129.8, 128.8, 128.3, 127.7, 118.6, 31.8, 28.7, 26.1, 22.5, 21.1,
14.1. HRMS (ESI) m/z calcd. for C20H24N3+ 306.1970, found
306.1968 [M+H]+.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-phenyl-2,5-di-p-tolyl-2H-1,2,3-triazole
(4f).
Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 90.8 mg
(0.28 mmol). 93% yield, m.p. 90‒92 oC. 1H NMR (400 MHz,
CDCl3) δ 8.06 (d, J = 8.5 Hz, 2H), 7.73 – 7.60 (m, 2H), 7.54 (d,
J = 8.1 Hz, 2H), 7.41 (ddd, J = 7.0, 6.2, 1.9 Hz, 3H), 7.30 (d, J =
8.3 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 2.42 (s, 3H), 2.40 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 145.9, 145.7, 138.6 ，
137.8, 137.3, 131.2, 129.9, 129.4, 128.7, 128.6, 128.6, 128.5,
4-phenethyl-5-phenyl-2-(p-tolyl)-2H-1,2,3-triazole
(4k). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 84.5 mg
(0.25 mmol), 83% yield, m.p. 77‒79 oC. 1H NMR (400 MHz,
CDCl3) δ 8.03 (d, J = 8.5 Hz, 2H), 7.80 – 7.66 (m, 2H), 7.49 (t,
J = 7.4 Hz, 2H), 7.46 – 7.38 (m, 1H), 7.38 – 7.18 (m, 7H), 3.35
– 3.23 (m, 2H), 3.21 – 3.10 (m, 2H), 2.44 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 146.2, 146.0, 141.5, 137.9, 137.0,
131.2, 129.9, 128.9, 128.6, 128.4, 127.7, 126.3, 118.7, 35.1,
+
128.1, 118.8, 21.5, 21.2. HRMS (ESI) m/z calcd. for C22H20N3
326.1657, found 326.1650 [M+H]+. Compound 4f was
identidical as 4a.
4-(4-chlorophenyl)-5-phenyl-2-(p-tolyl)-2H-1,2,3-
triazole (4g). Following the geneal procedure A, the
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.3), 89.2 mg (0.26 mmol), 86% yield, m.p. 109‒101 oC. 1H
NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 2H), 7.63 (dd, J
= 6.6, 3.0 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.42 (dd, J = 4.9,
1.6 Hz, 3H), 7.37 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H),
2.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 145.8, 144.6,
137.6, 137.6, 134.7, 130.8, 129.9, 129.8, 129.5, 129.0, 128.9,
128.8, 128.6, 118.8, 21.2. HRMS (ESI) m/z calcd. for
C21H17N3Cl+ 346.1111, found 346.1109 [M+H]+. Compound
4g was identidical as 4c.
+
28.3, 21.2. HRMS (ESI) m/z calcd. for C23H22N3 340.1814,
found 340.1814 [M+H]+.
4-phenyl-5-(1-phenylethyl)-2-(p-tolyl)-2H-1,2,3-
triazole (4l). Following the geneal procedure A, the
o
product was conducted at 40 C with a heating mantle and
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 76.7 mg
(0.22 mmol), 72% yield, m.p. 60‒62 oC. 1H NMR (400 MHz,
CDCl3) δ 8.14 (d, J = 8.5 Hz, 2H), 7.65 (dd, J = 8.0, 1.4 Hz, 2H),
7.52 – 7.41 (m, 5H), 7.41 – 7.32 (m, 4H), 7.29 (d, J = 7.9 Hz,
1H), 4.51 (q, J = 7.2 Hz, 1H), 2.48 (s, 3H), 1.85 (d, J = 7.2 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 149.4, 146.3, 145.0,
138.0, 137.0, 131.0, 129.8, 128.7, 128.6, 128.4, 128.3, 127.7,
126.5, 118.7, 37.1, 23.3, 21.2. HRMS (ESI) m/z calcd. for
C23H22N3+ 340.1814, found 340.1813 [M+H]+.
4-methyl-5-phenyl-2-(p-tolyl)-2H-1,2,3-triazole (4h).
Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 92.2 mg
(0.26 mmol), 88% yield, m.p. 68‒70 oC. 1H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 8.5 Hz, 2H), 7.90 – 7.73 (m, 2H), 7.51
(dd, J = 10.3, 4.7 Hz, 2H), 7.45 – 7.36 (m, 1H), 7.30 (d, J = 8.2
Hz, 2H), 2.61 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 146.2, 142.6, 137.8, 137.0, 131.2, 129.9, 128.9,
128.3, 127.5, 118.5, 21.2, 12.1. HRMS (ESI) m/z calcd. for
C16H16N3+ 250.1344, found 250.1345 [M+H]+.
4-methyl-5-phenyl-2-(p-tolyl)-2H-1,2,3-triazole
(4m). Following the geneal procedure A, the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 30:1, Rf = 0.3), 98.5 mg
(0.28 mmol), 94% yield, m.p. 68‒70 oC. 1H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 8.5 Hz, 2H), 7.90 – 7.73 (m, 2H), 7.51
(dd, J = 10.3, 4.7 Hz, 2H), 7.45 – 7.36 (m, 1H), 7.30 (d, J = 8.2
Hz, 2H), 2.61 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 146.2, 142.6, 137.8, 137.0, 131.2, 129.9, 128.9,
128.3, 127.5, 118.5, 21.2, 12.1. HRMS (ESI) m/z calcd. for
4-cyclopropyl-5-(2-fluorophenyl)-2-(p-tolyl)-2H-
1,2,3-triazole (4i). Following the geneal procedure A, the
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
+
C16H16N3 250.1344, found 250.1345 [M+H]+. Compound
= 0.3), 53.7 mg (0.18 mmol), 61% yield, m.p. 41‒43 oC. H
1
4m was identidical as 4h.
NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 2H), 7.74 (t, J =
6.9 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.38 – 7.28 (m, 4H), 2.46
(s, 3H), 2.12 – 1.85 (m, 1H), 1.18 – 0.96 (m, 4H). 19F NMR
(376 MHz, CDCl3) δ -113.06.13C{1H} NMR (100 MHz, CDCl3)
Synthesis of 4,5-diphenyl-2H-1,2,3-triazole (5). A 10
mL Schlenk tube equipped with a stirring bar and capped
with a rubber septum was charged with 3f (0.5 mmol) and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
CAN (1.35 mmol). The tube was degassed and backfilled evaporator, the mixture was purified by flash column
1
2
3
4
with argon (3 times). CH3CN (5 mL) and H2O (0.5 mL) was
added into the tube via a syringe. The reaction mixture was
cooled down to -10 oC, and was stirred under an argon
chromatography on silica gel (eluting with petroleum
ether/ethyl acetate = 6:1) to give 7a and 7b.
2-benzyl-4,5-diphenyl-2H-1,2,3-triazole
(7a).
atmosphere. The reaction was complete in
6 days
Obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 6:1, Rf = 0.5), 49.8 mg
(0.16 mmol), 64% yield, m.p. 79–81 oC. 1H NMR (400 MHz,
CDCl3) δ 7.60 (dd, J = 6.5, 3.1 Hz, 4H), 7.47 (d, J = 6.9 Hz, 2H),
7.45 – 7.31 (m, 9H), 5.68 (s, 2H). 13C{1H} NMR (100 MHz,
CDCl3) δ 144.9, 135.4, 131.2, 128.9, 128.6, 128.4, 128.4,
128.2, 58.9. HRMS (ESI) m/z calcd. for C21H18N3+ 312.1501,
found 312.1504 [M+H]+.
(monitored by TLC). The resulting mixture was extracted
with CH2Cl2 (15 mL × 3) and water (10 mL), and the
combined organic layers were dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (eluting with
petroleum ether/ethyl acetate = 10:1 and then 5:1) to give
5. The title compound was obtained as a white solid after
column chromatography (petroleum ether/ethyl acetate =
6:1, Rf = 0.2), 75.2 mg (0.34 mmol), 68% yield, m.p. 128–130
oC. 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 4H), 7.36 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3) δ 142.7, 130.2, 128.8, 128.7,
128.4. HRMS (ESI) m/z calcd. for C14H12N3+ 222.1031, found
222.1031 [M+H]+.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-benzyl-4,5-diphenyl-1H-1,2,3-triazole
(7b).
Obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 6:1, Rf = 0.2), 24.9 mg
(0.08 mmol), 32% yield, m.p. 102-104 oC.1H NMR (400 MHz,
CDCl3) δ 7.60 (dd, J = 7.8, 1.7 Hz, 2H), 7.51 (d, J = 7.3 Hz, 1H),
7.45 (t, J = 7.3 Hz, 2H), 7.35 – 7.22 (m, 6H), 7.23 – 7.14 (m,
2H), 7.07 (m, 2H), 5.45 (s, 2H). 13C{1H} NMR (100 MHz,
CDCl3) δ 144.6, 135.5, 134.0, 131.1, 130.2, 129.8, 129.3,
128.8, 128.5, 128.2, 128.0, 127.8, 127.6, 126.8, 52.2. HRMS
Synthesis of Triazoles 6a and 6b via N-Methylations.
A 10 mL Schlenk tube equipped with a stirring bar and
capped with a rubber septum was charged with 5 (44.2 mg,
0.2 mmol) and K2CO3 (55.2 mg, 0.4 mmol). The tube was
degassed and backfilled with argon gas (3 times). DMF
(1mL) was added into the tube via a syringe and the
reaction mixture was cooled down to 0 oC. Then the addition
of CH3I (56.8 mg, 0.4 mmol) was added. The reaction
mixture was stirred at 0 oC for 8 h. Upon completion of the
reaction (monitored by TLC), the reaction mixture was
purified by flash column chromatography on silica gel
(eluting with petroleum ether/ethyl acetate = 6:1) to give
6a and 6b.
+
(ESI) m/z calcd. for C21H18N3 312.1501, found 312.1503
[M+H]+.
Synthesis of Triazoles 8a and 8b via N-alkylations. A
10 mL Schlenk tube equipped with a stirring bar and capped
with a rubber septum was charged with 5 (44.0 mg, 2 mmol)
and K2CO3 (55.2 mg, 0.4 mmol). The tube was degassed and
backfilled with argon gas (3 times). DMF (2mL) was added
into the tube via a syringe. Then BrCH2CO2Et (66.8 mg, 0.4
mmol) was added and the resulting reaction mixture was
stirred at room temperature for 8 h. Upon completion of the
reaction (monitored by TLC), the solvent was removed by
rotary evaporator, the mixure was purified by flash column
chromatography on silica gel (eluting with petroleum
ether/ethyl acetate = 6:1) to give 8a and 8b.
2-methyl-4,5-diphenyl-2H-1,2,3-triazole
(6a).
Obtained as a white solid after column chromatography
(petroleum ether/ethyl acetate = 6:1, Rf = 0.5), 23.1 mg
(0.01 mmol), 49% yield, m.p. 58–60 oC. 1H NMR (400 MHz,
CDCl3) δ 7.55 (dd, J = 6.4, 2.9 Hz, 4H), 7.42 – 7.29 (m, 6H),
4.27 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 144.7, 131.2,
128.7, 128.4, 128.3, 41.9. HRMS (ESI) m/z calcd. for
C15H14N3+ 236.1188, found 236.1188 [M+H]+.
ethyl 2-(4,5-diphenyl-2H-1,2,3-triazol-2-yl)acetate
(8a). Obtained as
a
yellow solid after column
chromatography (petroleum ether/ethyl acetate = 6:1, Rf =
o
0.6), 46.0 mg (0.16 mmol), 75% yield, m.p. 101-103 C. 1H
1-methyl-4,5-diphenyl-1H-1,2,3-triazole
(6b).
NMR (400 MHz, CDCl3) δ 7.56 (d, J = 3.3 Hz, 4H), 7.36 (s, 6H),
5.27 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 166.9, 145.7, 130.9, 128.7,
128.6, 128.5, 62.3, 55.8, 14.3. HRMS (ESI) m/z calcd. for
C18H18N3O2+ 308.1399, found 308.1400 [M+H]+.
Obtained as a white solid after column chromatography
(petroleum ether/ethyl acetate = 6:1, Rf = 0.2), 23.1 mg
1
(0.01 mmol), 49% yield, m.p. 122–124 oC. H NMR (400
MHz, CDCl3) δ 7.62 – 7.54 (m, 2H), 7.55 – 7.45 (m, 3H), 7.41
– 7.32 (m, 2H), 7.28 (d, J = 7.2 Hz, 3H), 3.94 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 144.5, 134.2, 131.1, 13.0, 129.8,
129.5, 128.6, 128.0, 127.8, 127.0, 35.4. HRMS (ESI) m/z
calcd. for C15H14N3+ 236.1188, found 236.1190 [M+H]+.
ethyl 2-(4,5-diphenyl-1H-1,2,3-triazol-1-yl)acetate
(8b). Obtained as
a
yellow solid after column
chromatography (petroleum ether/ethyl acetate = 6:1, Rf =
0.3), 9.2 mg (0.03 mmol), 15% yield, m.p. 42-44 oC. 1H NMR
(400 MHz, CDCl3) δ 7.58 (dd, J = 7.5, 2.2 Hz, 2H), 7.54 – 7.45
(m, 3H), 7.31 – 7.27 (m, 2H), 5.99 (s, 2H), 4.19 (q, J = 7.1 Hz,
2H), 1.22 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 166.6, 144.5, 134.7, 130.9, 130.1, 130.1, 129.6, 128.6,
128.0, 127.6, 127.0, 62.4, 49.4, 14.2. HRMS (ESI) m/z calcd.
for C18H18N3O2+ 308.1399, found 308.1403 [M+H]+.
Synthesis of Triazoles 7a and 7b via N-Benzylations.
A 10 mL Schlenk tube equipped with a stirring bar and
capped with a rubber septum was charged with 5 (55.3 mg,
0.25 mmol) and K2CO3 (69.1 mg, 0.5 mmol). The tube was
degassed and backfilled with argon gas (3 times). Acetone
(3mL) was added into the tube via a syringe. Then BnBr
(64.1 mg, 0.38 mmol) was added and the resulting reaction
o
mixture was stirred at room temperature for 12 h at 30 C
Generation Procedure B: Synthesis of 1,2,3-Traizoles
bearing Electron-Deficient N-aryl groups (9). A 10 mL
Schlenk tube equipped with a stirring bar and capped with
with a heating mantle. Upon completion of the reaction
(monitored by TLC), the solvent was removed by rotary
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
a rubber septum was charged with 5 (0.05 mmol), ArX (0.05 2-(4,5-diphenyl-2H-1,2,3-triazol-2-yl)-5-
1
2
3
4
5
6
7
8
mmol) and K2CO3 (0.05 mmol). The tube was degassed and
backfilled with argon gas (3 times). DMF (0.5 mL) was
added into the tube via a syringe. The reaction mixture was
nitropyridine (9e). Following the Generation Procedure B,
the reaction mixture was stirred for 5 h at 80 C and the
o
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 6:1, Rf =
o
stirred for 5 h at 70-120 C with a heating mantle. Upon
1
completion of the reaction (monitored by TLC), the solvent
was removed by rotary evaporator. The residue was
purified by flash column chromatography on silica gel
(eluting with petroleum ether/ethyl acetate = 10:1) to give
9.
0.4), 16.5 mg (0.05 mmol), 96% yield, m.p. 170‒172 oC. H
NMR (400 MHz, CDCl3) δ 9.25 (d, J = 2.5 Hz, 1H), 8.67 (dd, J
= 9.1, 2.6 Hz, 1H), 8.35 (d, J = 9.1 Hz, 1H), 7.66 (dd, J = 7.6,
1.5 Hz, 4H), 7.51 – 7.33 (m, 6H). 13C{1H} NMR (100 MHz,
CDCl3) δ 153.4, 149.4, 145.7, 143.0, 134.4, 129.7, 129.6,
9
+
128.8, 113.6. HRMS (ESI) m/z calcd. for C19H14N5O2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
344.1147, found 344.1145 [M+H]+.
2-(4-nitrophenyl)-4,5-diphenyl-2H-1,2,3-triazole
(9a). Following the Generation Procedure B, the reaction
o
mixture was stirred for 5 h at 120 C and the product was
2-(4,5-diphenyl-2H-1,2,3-triazol-2-yl)-3-
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 10:1, Rf = 0.5), 16.3 mg
nitropyridine (9f). Following the Generation Procedure B,
the reaction mixture was stirred for 5 h at 120 C and the
o
o
1
(0.05 mmol), 95% yield, m.p. 151‒153 C. H NMR (400
MHz, CDCl3) δ 8.44 – 8.30 (m, 4H), 7.65 (dd, J = 6.5, 2.9 Hz,
4H), 7.51 – 7.33 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ
147.9, 146.4, 143.7, 130.1, 129.4, 128.9, 128.6, 125.4, 118.9.
product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 6:1, Rf =
0.2), 14.9 mg (0.04 mmol), 87% yield, m.p. 126‒128 oC. H
1
NMR (400 MHz, CDCl3) δ 8.82 (dd, J = 4.7, 1.5 Hz, 1H), 8.22
(dd, J = 8.0, 1.5 Hz, 1H), 7.71 – 7.58 (m, 4H), 7.55 (dd, J = 8.0,
4.8 Hz, 1H), 7.7 – 7.32 (m, 6H). 13C{1H} NMR (100 MHz,
CDCl3) δ 151.5, 148.6, 142.2, 139.5, 134.2, 129.7, 129.4,
+
HRMS (ESI) m/z calcd. for C20H15N4O2 343.1195, found
343.1194 [M+H]+.
+
2-(2-nitrophenyl)-4,5-diphenyl-2H-1,2,3-triazole
128.9, 128.8, 123.5. HRMS (ESI) m/z calcd. for C19H14N5O2
344.1147, found 344.1147 [M+H]+.
(9b). Following the Generation Procedure B, the reaction
o
mixture was stirred for 5 h at 70 C and the product was
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 6:1, Rf = 0.6), 16.1 mg
(0.05 mmol), 94% yield, m.p. 51‒53 oC. 1H NMR (400 MHz,
CDCl3) δ 8.09 (d, J = 8.1 Hz, 1H), 7.85 (dd, J = 8.0, 1.1 Hz, 1H),
7.77 – 7.67 (m, 1H), 7.61 (dd, J = 6.5, 3.1 Hz, 4H), 7.55 (dd, J
= 11.3, 4.3 Hz, 1H), 7.46 – 7.33 (m, 6H). 13C{1H} NMR (100
MHz, CDCl3) δ 147.5, 132.8, 132.3, 130.2, 129.2, 128.8,
128.7, 128.7, 125.0, 125.0, 99.8. HRMS (ESI) m/z calcd. for
C20H15N4O2+ 343.1195, found 343.1194 [M+H]+.
methyl
2-(4,5-diphenyl-2H-1,2,3-triazol-2-yl)-5-
methylbenzoate (10a). Following the geneal procedure A,
the product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.3), 97.5 mg (0.26 mmol), 88% yield, m.p. 105‒107 oC. 1H
NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz, 1H), 7.63 (dd, J
= 6.5, 3.0 Hz, 4H), 7.56 (s, 1H), 7.47 – 7.32 (m, 7H), 3.78 (s,
3H), 2.45 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 168.2,
146.0, 138.5, 135.7, 132.3, 130.8, 130.3, 128.7, 128.7, 128.6,
128.5, 126.5, 123.5, 52.7, 21.1. HRMS (ESI) m/z calcd. for
C23H20N3O2+ 370.1556, found 370.1563 [M+H]+.
2-(4,5-diphenyl-2H-1,2,3-triazol-2-yl)benzonitrile
(9c). Following the Generation Procedure B, the reaction
o
mixture was stirred for 5 h at 120 C and the product was
methyl
2-(4,5-diphenyl-2H-1,2,3-triazol-2-yl)-5-
obtained as a yellow solid after column chromatography
(petroleum ether/ethyl acetate = 6:1, Rf = 0.4), 15.3 mg
(0.05 mmol), 95% yield, m.p. 99‒101 oC. 1H NMR (400 MHz,
CDCl3) δ 8.19 (d, J = 8.3 Hz, 1H), 7.87 (dd, J = 7.8, 1.3 Hz, 1H),
7.79 – 7.64 (m, 5H), 7.54 – 7.35 (m, 7H). 13C{1H} NMR (100
MHz, CDCl3) δ 147.3, 140.5, 135.4, 133.7, 130.2, 129.2,
128.8, 128.7, 127.7, 122.2, 117.2, 104.6. HRMS (ESI) m/z
calcd. for C21H15N4+ 323.1297, found 323.1297 [M+H]+.
methoxybenzoate (10b). Following the geneal procedure
A, the product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.3), 70.5 mg (0.18 mmol), 61% yield, m.p. 43‒45 oC. H
1
NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.9 Hz, 1H), 7.63 (dd, J
= 6.4, 2.8 Hz, 4H), 7.47 – 7.34 (m, 6H), 7.31 – 7.26 (m, 1H),
7.13 (dd, J = 8.9, 2.8 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 159.3, 145.8, 131.7,
130.9, 128.7, 128.5, 128.0, 125.6, 117.6, 114.6, 55.9, 52.7.
+
2-(2-fluoro-4-nitrophenyl)-4,5-diphenyl-2H-1,2,3-
triazole (9d). Following the Generation Procedure B, the
reaction mixture was stirred for 5 h at 90 oC and the product
HRMS (ESI) m/z calcd. for C23H20N3O3 386.1505, found
386.1506 [M+H]+.
was obtained as
a
yellow solid after column
methyl
2-(4,5-diphenyl-2H-1,2,3-triazol-2-yl)-6-
chromatography (petroleum ether/ethyl acetate = 6:1, Rf =
fluorobenzoate (10c). Following the geneal procedure A,
the product was obtained as a yellow solid after column
chromatography (petroleum ether/ethyl acetate = 30:1, Rf
= 0.3), 101.9 mg (0.27 mmol), 91% yield, m.p. 113‒115 oC.
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 1H), 7.63 (dd,
J = 6.6, 2.9 Hz, 4H), 7.52 (td, J = 8.3, 6.0 Hz, 1H), 7.45 – 7.32
(m, 6H), 7.14 (t, J = 8.5 Hz, 1H), 7.14 (t, J = 8.5 Hz, 1H), 3.93
(s, 3H). 19F NMR (376 MHz, CDCl3) δ -114.13. 13C{1H} NMR
(100 MHz, CDCl3) δ 164.6, 160.0 (d, J = 250.0 Hz), 146.6,
137.4 (d, J = 6.0 Hz), 131.5 (d, J = 9.4 Hz), 130.3, 129.1, 128.7,
0.6), 15.3 mg (0.04 mmol), 85% yield, m.p. 128‒130 oC. H
1
NMR (400 MHz, CDCl3) δ 8.30 (t, J = 8.2 Hz, 1H), 8.27 – 8.17
(m, 2H), 7.64 (dd, J = 7.1, 2.4 Hz, 4H), 7.41 – 7.26 (m, 6H). 19
F
NMR (376 MHz, CDCl3) δ -115.50. 13C{1H} NMR (100 MHz,
CDCl3) δ 153.0 (d, J = 261.9 Hz), 148.1 (d, J = 2.0 Hz), 146.7
(d, J = 7.6 Hz), 132.9 (d, J = 8.2 Hz), 129.9, 129.4, 128.9,
128.7, 124.3, 120.1 (d, J = 4.0 Hz), 114.3 (d, J = 25.2 Hz).
HRMS (ESI) m/z calcd. for C20H14N4O2F+ 361.1101, found
361.1109 [M+H]+.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 14
128.5, 116.4 (d, J = 3.3 Hz), 115.1 (d, J = 23.0 Hz), 114.7,
ASSOCIATED CONTENT
114.5, 53.2. HRMS (ESI) m/z calcd. for C22H17N3O2F+
1
2
374.1305, found 374.1308 [M+H]+.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental details and spectral data of all new compounds
(PDF).
3
4
5
6
7
8
9
Synthesis of 1,1‘-Binaphthalene Scaffolds bearing
1,2,3-Triazoles (11a and 11b). An oven-dried 10 mL
Schlenk tube equipped with a stirring bar and capped with
a rubber septum was charged with 2H-azirine (1f’, 0.3
mmol), arene-diazonium salt (0.6 mmol), CuBr (0.06 mmol),
and DABCO (0.3 mmol). The tube was evacuated under
vacuo and then backfilled with argon (for three times).
CH3CN (3.0 mL) was transferred into the tube via a syringe.
The resulting mixture was stirred under an argon
atmosphere at room temperature for 16 h. The reaction
mixture was concentrated in vacuo, and the residue was
purified by flash chromatography on silica gel (eluting with
petroleum ether / ethyl acetate) to give the desired product
11a and 11b.
AUTHOR INFORMATION
Corresponding Author
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
* E-mail: zhiwei.zhang@tju.edu.cn (C.W.C.)
* E-mail: majun_an68@tju.edu.cn. (J.-A.M.)
ORCID
Fa-Guang Zhang: 0000-0002-0251-0456
Chi Wai Cheung: 0000-0003-4415-0767
Jun-An Ma: 0000-0002-3902-6799
2-([1,1'-binaphthalen]-2-yl)-4-phenyl-5-(p-tolyl)-
2H-1,2,3-triazole (11a). Obtained as a yellow solid after
column chromatography (petroleum ether/ethyl acetate =
30:1, Rf = 0.3), 38.0 mg (0.01 mmol), 26% yield, m.p. 56‒55
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
1
oC. [α]D20 = ‒167.8 (c 1.0, CH2Cl2). H NMR (400 MHz, CDCl3)
δ 8.15 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.2 Hz, 1H), 7.95 (d, J =
7.9 Hz, 2H), 7.63 – 7.32 (m, 7H), 7.29 (d, J = 8.2 Hz, 1H), 7.25
– 7.17 (m, 3H), 7.17 – 7.10 (m, 2H), 7.09 – 6.96 (m, 4H), 2.32
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 145.1, 144.9,
138.2, 136.9, 134.9, 133.8, 133.7, 133.5, 133.1, 132.0, 130.9,
129.3, 129.1, 128.8, 128.4, 128.3, 128.2, 128.1, 128.1, 127.8,
127.6, 127.1, 126.8, 126.9, 126.3, 125.8, 125.4, 122.6, 21.4.
We thank the National Key Research and Development
Program of China (No. 2019YFA0905100), the National Natural
Science Foundation of China (No. 21532008, 21772142,
21901181, and 21971186) and Tianjin University (start-up
grants) for financial support.
+
REFERENCES
HRMS (ESI) m/z calcd. for C35H26N3 488.2127, found
488.2126 [M+H]+.
(1) For selected reviews on the synthesis and applications of
N1-substituted 1,2,3-triazoles, see: (a) Kolb, H. C.; Sharpless, K.
B. The growing impact of click chemistry on drug discovery.
Drug. Discov. Today. 2003, 8, 1128–1137. (b) Moses, J. E.;
Moorhouse, A. D. The growing applications of click chemistry.
Chem. Soc. Rev. 2007, 36, 1249–1262. (c) Wu, P.; Fokin, V. V.
Catalytic Azide–Alkyne Cycloaddition: Reactivity and
Applications. Aldrichim. Acta. 2007, 40, 7–17. (d) Nandivada,
H.; Jiang, X. W.; Lahann, J. Click Chemistry: Versatility and
Control in the Hands of Materials Scientists. Adv. Mater. 2007,
19, 2197–2208. (e) Moses, J. E.; Moorhouse, A. D. The growing
applications of click chemistry. Chem. Soc. Rev. 2007, 36, 1249–
1262. (f) Meldal, M.; Tornøe, C. W. Cu-Catalyzed Azide-Alkyne
Cycloaddition. Chem. Rev. 2008, 108, 2952–3015. (g) Tron, G.
C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba, G.;
Genazzani A. A. Click Chemistry Reactions in Medicinal
Chemistry: Applications of the 1,3-dipolar Cycloaddition
Between Azides and Alkynes. Med. Res. Rev. 2008, 28, 278–308.
(h) Agalave, S. G.; Maujan, S. R.; Pore, V. S. Click Chemistry:
1,2,3-Triazoles as Pharmacophores. Chem. Asian J. 2011, 6,
2696–2718. (i) Thirumurugan, P.; Matosiuk, D.; Jozwiak, K.
Click Chemistry for Drug Development and Diverse
Chemical−Biology Applications. Chem. Rev. 2013, 113,
4905−4979.
2,2'-bis(4-phenyl-5-(p-tolyl)-2H-1,2,3-triazol-2-yl)-
1,1'-binaphthalene (11b). Obtained as a yellow solid after
column chromatography (petroleum ether/ethyl acetate =
30:1, Rf = 0.3), 51.9 mg (0.01 mmol), 24% yield, m.p.
110‒112 oC. [α]D20 = +123 (c 1.0, CH2Cl2). 1H NMR (400 MHz,
CDCl3) δ 8.23 (d, J = 8.9 Hz, 2H), 8.11 (d, J = 8.9 Hz, 2H), 8.00
(d, J = 8.1 Hz, 2H), 7.55 – 7.41 (m, 4H), 7.36 – 7.29 (m, 2H),
7.24 – 7.19 (m, 2H), 7.17 (d, J = 7.9 Hz, 3H), 7.13 (d, J = 7.7
Hz, 5H), 7.02 (d, J = 8.1 Hz, 4H), 6.96 (d, J = 8.1 Hz, 4H), 2.30
(s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 145.2, 145.0,
138.0, 136.9, 134.4, 132.8, 131.1, 129.3, 129.0, 128.3, 128.2,
128.2, 128.1, 128.0, 128.0, 127.4, 127.3, 126.5, 121.9, 21.4.
+
HRMS (ESI) m/z calcd. for C50H37N6 721.3080, found
721.3081 [M+H]+.
Radical trap experiment. An oven-dried 10 mL Schlenk
tube equipped with a stirring bar and capped with a rubber
septum was charged with 2H-azirine (1a, 0.3 mmol),
aryldiazonium salt (2a, 0.6 mmol), CuBr (0.06 mmol),
DABCO (0.3 mmol), and TEMPO (0.6 mmol). The tube was
evacuated under vacuo and then backfilled with argon (for
three times). CH3CN (3.0 mL) was transferred into the tube
via a syringe. The resulting mixture was stirred under an
argon atmosphere at room temperature for 16 h and then
subjected to HRMS analysis. The mass spectra presented a
peak at m/z 351.2430, which likely corresponded to the
TEMPO-trapped product 12.
(2) For examples of the applications of N2-aryl-1,2,3-
triazoles, see: (a) Cox, C. D.; Breslin, M. J.; Whitman, D. B.;
Schreier, J. D.; McGaughey, G. B.; Bogusky, M. J.; Roecker, A. J.;
Mercer, S. P.; Bednar, R. A.; Lemaire, W.; Bruno, J. G.; Reiss, D. R.;
Harrell, C. M.; Murphy, K. L.; Garson, S. L.; Doran, S. M.;
Prueksaritanont, T.; Anderson, W. B.; Tang, C. Y.; Roller, S.;
Cabalu, T. D.; Cui, D. H.; Hartman, G. D.; Young, S. D.; Koblan, K.
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
S.; Winrow, C. J.; Renger, J. J.; Coleman, P. J. Discovery of the Dual
Azide-Chalcone Oxidative Cycloaddition and Post-Triazole
1
2
3
4
5
6
7
8
Orexin Receptor Antagonist [(7R)-4-(5-Chloro-1,3-benzoxazol-
2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-
triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment
of Insomnia. J. Med. Chem. 2010, 53, 5320-5332. (b) Baxter, C.
A.; Cleator, E.; Brands, K. M. J.; Edwards, J. S.; Reamer, R. A.;
Sheen, F. J.; Stewart, G. W.; Strotman, N. A.; Wallace, D. J. The
Arylation. Org. Lett. 2012, 14, 26–29. (e) Lopes, A. B.; Wagner,
P.; Souza, R. O. M. A.; Germain, N. L.; Uziel, J.; Bourguignon, J. J.;
Schmitt, M.; Miranda, L. S. Functionalization of 2H-1,2,3-
Triazole C-Nucleoside Template via N2 Selective Arylation. J.
Org. Chem. 2016, 81, 4540−4549. (f) Alexandra, B. L.; Patrick,
W.; Arthur, E. K.; Frédéric, B.; Bourguignon, J. J; Martine, S.;
Leandro, S. M. M. Development of a L-Tryptophan-Based
Ligand for Regioselective Copper Catalyzed N2-Arylation of
1,2,3-Triazoles. ChemistrySelect. 2017, 2, 6544–6548.
First Large-Scale Synthesis of MK-4305:
A Dual Orexin
Receptor Antagonist for the Treatment of Sleep Disorder. Org.
Process. Res. Dev. 2011, 15, 367-375. (c) Watanabe, T.;
Umezawa, Y. J.; Takahashi, Y.; Akamatsu, Y. Novel pyrrole- and
1,2,3-triazole-based 2,3-oxidosqualene cyclase inhibitors.
Bioorg. Med. Chem. Lett. 2011, 20, 5807–5810. (d) Roecker, A.
J.; Mercer, S. P.; Harrell, C. M.; Garson, S. L.; Fox, S. V.; Gotter, A.
L.; Prueksaritanont, T.; Cabalu, T. D.; Cui, D. H.; Lemaire, W.;
Winrow, C. J.; Renger, J. J.; Coleman, P. J. Discovery of dual
orexin receptor antagonists with rat sleep efficacy enabled by
expansion of the acetonitrile-assisted/diphosgene-mediated
2,4-dichloropyrimidine synthesis. Bioorg. Med. Chem. Lett.
2014, 24, 2079–2085. (e) Raheem, I. T.; Breslin, M. J.; Bruno, J.;
Cabalu, T. D.; Cooke, A.; Cox, C. D.; Cui D. H.; Garson, S.; Gotter,
A. L.; Fox, S. V.; Harrell, C. M.; Kuduk, S. D.; Lemaire, W.;
Prueksaritanont, T.; Renger, J. J.; Stump, C.; Tannenbaum, P. L.;
Williams, P. D.; Winrow, C. J.; Coleman, P. J. Discovery of
piperidine ethers as selective orexin receptor antagonists
(SORAs) inspired by filorexant. Bioorg. Med. Chem. Lett. 2015,
25, 444–450.
9
(7) For examples, see: (a) Hann, R. M.; Hudson, C. S. The
action of copper sulfate on phenylosazones of the sugars.
Phenyl-D-glucosotriazole. J. Am. Chem. Soc. 1944, 66, 735–738.
(b) Riebsomer, J. L.; Sumrell, G. 2-Phenyl-2,1,3-Triazole-4-
Carboxaldehyde and Derivatives. J. Org. Chem. 1948, 13, 807–
814. (c) El Sekily, M.; Mancy, S.; El Kholy, I.; El Ashry, E. S. H.; El
Khadem, H. S.; Swartz, D. L. Reactions of the 3-oxime 2-
phenylhydrazone and mixed bishydrazones of dehydro-L-
ascorbic acid: Conversion into substituted triazoles and
pyrazolinediones. Carbohydr. Res. 1977, 59, 141–149. (d) Guru,
M. M.; Punniyamurthy, T. Copper(II)-Catalyzed Aerobic
Oxidative Synthesis of Substituted 1,2,3- and 1,2,4-Triazoles
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
from
Bisarylhydrazones
via
C−H
Functionalization/C−C/N−N/C−N Bonds Formation. J. Org.
Chem. 2012, 77, 5063−5073. (e) Xu, B.; Hu, Y. Another Way to
the Synthesis of 1, 2, 3-Triazoles. J. Heterocycl. Chem. 2013, 50,
1217–1222. (f) Wu, L. Y.; Guo, S.; Wang, X. H.; Guo, Z. F.; Yao, G.
G.; Lin, Q.; Wu, M. S. Tandem synthesis of 2-aryl-1,2,3-triazoles
from α-arylhydrazonoketones with NH4OAc via copper-
catalyzed aerobic oxidation. Tetrahedron. Lett. 2015, 56, 2145–
2148. (g) Shastin, A. V.; Tsyrenova, B. D.; Sergeev, P. G.;
Roznyatovsky, V. A.; Smolyar I. V.; Khrustalev, V. N.;
(3) For examples, see: (a) Hopkins, C. R. Molecule Spotlight
on Suvorexant. ACS. Chem. Neurosci. 2012, 3, 647−648. (b) Sun,
H.; Kennedy, W. P.; Wilbraham, D.; Lewis, N.; Calder, N.; Li, X.;
Ma, J.; Yee, K. L.; Ermlich, S.; Mangin, E.; Lines, C.; Rosen, L.;
Chodakewitz, J.; Murphy, G. M. Effects of Suvorexant, an Orexin
Receptor Antagonist, on Sleep Parameters as Measured by
Polysomnography in Healthy Men. Sleep 2013, 36, 259–267. (c)
Bennett, T.; Bray, D.; Neville, M. W. Suvorexant, a Dual Orexin
Receptor Antagonist for the Management of Insomnia. P.T.
2014, 39, 264–266.
Nenajdenko, V. G. Synthesis of
a New Family of 1,1-
Diazidoethenes: One-Pot Construction of 4-Azido-1,2,3-
triazoles via Nitrene Cyclization. Org. Lett. 2018, 20, 7803–
7806.
(8) For synthesis of N2-aryl 1,2,3-triazoles via annulation of
aryldiazonium salts, see: (a) Liu, Z. H.; Ji, H. M.; Gao, W.; Zhu, G.
Y.; Tong, L. L.; Lei, F. C.; Tang, B. Copper(I)-mediated
carboamination of vinyl azides by aryldiazonium salts:
synthesis of N2-substituted 1,2,3-triazoles. Chem. Commun.
2017, 53, 6259−6262. (b) Zhu, C. L.; Zeng, H.; Chen, F. L.; Liu, C.;
Zhu, R.; Wu, W. Q.; Jiang, H. F. Copper-catalyzed coupling of
oxime acetates and aryldiazonium salts: an azide-free strategy
toward N-2-aryl-1,2,3-triazoles. Org. Chem. Front. 2018, 5,
571−576. (c) Zhu, C. L.; Zeng, H.; Chen, F. L.; Liu, C.; Jiang, H. F.
Copper-Catalyzed Cyclization of Aryl Amines and Aryldiazonium
salts under Air: Access to N-2-Aryl-Naphthotriazoles. Adv. Synth.
Catal. 2019, 361, 5149−5159. (d) Wu, P.; He, Y.; Wang, H.; Zhou,
(4) For examples, see: Hoyer, D.; Allen, A.; Jacobson, L. H.
Hypnotics with novel modes of action. Br. J. Clin. Pharmacol.
2020, 86, 244–249.
(5) For examples, see: (a) Gentile, T. A.; Simmons, S. J.;
Barker, D. J.; Shaw, J. K.; España, R. A.; Muschamp, J. W.
Suvorexant, an orexin/hypocretin receptor antagonist,
attenuates motivational and hedonic properties of cocaine.
Addict. Biol. 2017, 23, 247–255. (b) Peter, D. B.; Drevets, W. C.;
Rofael, H.; Ark, V. P.; Kent, J. M.; Kezic, I.; Parapatics, S.; Dorffner,
G.; Gerven, J. V.; Beneš, H.; Keicher, C.; Jahn, H.; Seiden, D. J.;
Luthringer, R. A randomized Phase 2 study to evaluate the
orexin-2 receptor antagonist seltorexant in individuals with
insomnia without psychiatric comorbidity. J. Psychopharmacol.
2018, 32, 668–677.
Y.-G.;
Yu,
Z.
Copper(II)-Catalyzed
C-H
Nitrogenation/Annulation Cascade of Ketene N, S-Acetals with
Aryldiazonium Salts: A Direct Access to N2-Substituted Triazole
and Triazine Derivatives. Org. Lett. 2020, 22, 310−315. (e) Liu,
H.-N.; Cao, H.-Q.; Cheung, C. W.; Ma, J.-A. Cu-Mediated
Expeditious Annulation of Alkyl 3‑Aminoacrylates with
Aryldiazonium Salts: Access to Alkyl N2‑Aryl 1,2,3-
Triazolecarboxylates for Druglike Molecular Synthesis. Org.
Lett. 2020, 22, 1396−1401.
(6) For examples, see: (a) Liu, Y. X.; Yan, W. M.; Chen, Y. F.;
Petersen, J. L.; Shi, X. D. Efficient Synthesis of N-2-Aryl-1,2,3-
Triazole Fluorophores via Post-Triazole Arylation. Org. Lett.
2008, 10, 5389–5392. (b) Wang, X. J.; Zhang, L.; Krishnamurthy,
D.; Senanayake, C. H.; Wipf, P. General Solution to the Synthesis
of N-2-Substituted 1,2,3-Triazoles. Org. Lett. 2010, 12, 4632–
4635. (c) Satoshi, U.; Su, M.; Buchwald, S. L. Highly N2-Selective
Palladium-Catalyzed Arylation of 1,2,3-Triazoles. Angew. Chem.
Int. Ed. 2011, 50, 8944–8947. (d) Zhang, Y. Q.; Li, X. L.; Li, J. H.;
Chen, J. Y, Meng, X.; Zhao, M. M.; Chen, B. H. CuO-Promoted
Construction of N-2-Aryl-Substituted-1,2,3-Triazoles via
(9) For recent examples of synthesis of other nitrogen
heterocycles based on aryldiazonium salts, see: (a) Liu, J.-Q.; Shen,
X. Y.; Wang, Y. H.; Wang, X.-S.; Bi, X. H. [3 + 2] Cycloaddition of
Isocyanides with Aryl Diazonium Salts: Catalyst-Dependent
Regioselective Synthesis of 1,3- and 1,5-Disubstituted 1,2,4-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 14
Triazoles. Org. Lett. 2018, 20, 6930−6933. (b) Chuprun, Sergey.;
(12) Butler, R. N.; Hanniffy, J. M.; Stephens, J. C.; Burke, L. A. A
Dar’in, D.; Kantin, G.; Krasavin, M. [3+2]-Cycloaddition of α-
Diazocarbonyl Compounds with Arenediazonium Salts Catalyzed
by Silver Nitrate Delivers 2,5-Disubstituted Tetrazoles. Synthesis
2019, 51, 3998−4005. (c) Wang, M.; Tang, B.-C.; Xiang, J.-C.; Chen,
X.-L.; Ma, J.-T.; Wu, Y.-D.; Wu, A.-X. Aryldiazonium Salts Serve as a
Dual Synthon: Construction of Fully Substituted Pyrazoles via
Rongalite-Mediated Three-Component Radical Annulation
Reaction. Org. Lett. 2019, 21, 8934−8937. (d) Yu, X.-Y.; Xiao, W.-J.;
Chen, J.-R. Synthesis of Trisubstituted 1,2,4-Triazoles from
Ceric Ammonium Nitrate N-Dearylation of N-p-Anisylazoles
Applied to Pyrazole, Triazole, Tetrazole, and Pentazole Rings:
Release of Parent Azoles. Generation of Unstable Pentazole,
1
2
3
4
5
6
7
8
-
HN5/N5 , in Solution. J. Org. Chem. 2008, 73, 1354–1364.
(13) (a) Panda, S.; Maity, P.; Manna, D. Transition Metal, Azide,
and Oxidant-Free Homo- and Heterocoupling of Ambiphilic
Tosylhydrazones to the Regioselective Triazoles and Pyrazoles.
Org. Lett. 2017, 19, 1534-1537. (b) Lai, Qi.; Liu, Q.; He, Y.; Zhao, K.;
Wei, C.Y.; Wojtas, L.; Shi, X. D.; Song, Z. G. Triazole-Imidazole (TA-
IM) as Ultrafast Fluorescent Probes for Selective Ag+ Detection.
Org. Biomol. Chem. 2018, 16, 7801–7805.
Azlactones
and
Aryldiazonium
Salts
by
a
9
Cycloaddition/Decarboxylation Cascade. Eur. J. Org. Chem. 2019,
6994–6998. (e) Liu, J.; Xu, E.; Jiang, J.; Huang, Z.; Zheng, L.; Liu, Z.-Q.
Copper-mediated tandem ring-opening/cyclization reactions of
cyclopropanols with aryldiazonium salts: synthesis of N-
arylpyrazoles. Chem. Commun. 2020, 56, 2202–2205.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14) Wang, X. J.; Zhang, L.; Lee, H.; Haddad, N.; Krishnamurthy,
D.; Senanayake, C. H. Highly Regioselective N-2 Arylation of 4,5-
Dibromo-1,2,3-triazole: Efficient Synthesis of 2-Aryltriazoles. Org.
Lett. 2009, 11, 5026–5028.
(10) For recent examples of synthesis of nitrogen heterocycles
based on azirines, see: (a) Li, T. F.; Xu, F.; Li, X. C.; Wang, C. X.; Wan,
B. S. Ruthenium-Catalyzed C-C Bond Cleavage of 2H-Azirines: A
Formal [3+2+2] Cycloaddition to Fused Azepine Skeletons. Angew.
Chem. Int. Ed. 2016, 55, 2861–2865. (b) Ding, H. L.; Wang, Z. B.; Bai,
S. L.; Lu, P.; Wang, Y. G. Rh-Catalyzed Conversion of 3-Diazoindolin-
2-imines to 5H-Pyrazino[2,3-b]indoles with Photoluminescent
Properties. Org. Lett. 2017, 19, 6514−6517. (c) Shi, S. J.; Xu, K.;
Jiang, C.; Ding, Z. H. ZnCl2-Catalyzed [3 + 2] Cycloaddition of
Benzimidates and 2H-Azirines for the Synthesis of Imidazoles. J.
Org. Chem. 2018, 83, 14791−14796. (d) Zhao, M.-N.; Ren, Z.-H.;
Yang, D.-S.; Guan, Z.-H. Iron-Catalyzed Radical Cycloaddition of 2H-
Azirines and Enamides for the Synthesis of Pyrroles. Org. Lett.
2018, 20, 1287−1290. (e) Huang, Y.-J.; Qiao, B.; Zhang, F.-G.; Ma, J.-
A. Facile construction of trifluoromethyl-azirines via one-pot
metal-free Neber reaction. Tetrahedron 2018, 74, 3791−3796. (f)
Cai, B.-G.; Chen, Z.-L.; Xu, G.-Y.; Xuan, J.; Xiao, W.-J. [3 + 2]-
Cycloaddition of 2H-Azirines with Nitrosoarenes: Visible-Light-
Promoted Synthesis of 2,5-Dihydro-1,2,4-oxadiazoles. Org. Lett.
2019, 21, 4234−4238. (g) Wu, Y.F.; Tian, B.; Witzel, S.; Jin, H. M.;
Tian, X. H.; Rudolph, M.; Rominger, F.; Hashmi. A. S. K. AuBr3-
Catalyzed Chemoselective Annulation of Isocyanates with 2H-
Azirine. Chem. Eur. J. 2019, 25, 4093–4099.
(15) For other reports on synthesis of N2-H free 1,2,3-triazoles,
see: (a) Tsai, C.-W., Yang, S.-C.; Liu, Y.-M.; Wu, M.-J. Microwave-
assisted cycloadditions of 2-alkynylbenzonitriles with sodium
azide: selective synthesis of tetrazolo[5,1a]pyridines and 4,5-
disubstituted-2H-1,2,3-triazoles. Tetrahedron 2009, 65, 8367–
8372. (b) Berger, O.; Kaniti, A.; Tran vanꢀBa, C.; Vial, H.; Ward., S. A.;
Biagini. G. A.; Bray, P. G.; O'Neill, P. M. Synthesis and Antimalarial
Activities of a Diverse Set of Triazole-Containing Furamidine
Analogues. ChemMedChem 2011, 6, 2094–2018. (c) Hu, L.; Mìck-
Lichtenfeld, C.; Wang, T.; He, G.; Gao, M.; Zhao, J. Reaction between
Azidyl Radicals and Alkynes: A Straightforward Approach to NH-
1,2,3-Triazoles. Chem. Eur. J. 2016, 22, 911–915. (d) Bjerknes, M.;
Cheng, H.; McNitt, C. D; Popik, V. V. Facile Quenching and Spatial
Patterning of Cylooctynes via Strain-Promoted Alkyne−Azide
Cycloaddition of Inorganic Azides. Bioconjugate Chem. 2017, 28,
1560−1565.
(16) (a) Sang, R.; Zheng, Y.; Zhang, H. L.; Wu, X. H.; Wang, Q. T.;
Hai, L.; Wu, Y. Palladium-catalyzed direct C–H ethoxycarbonylation
of 2-aryl-1,2,3-triazoles and efficient synthesis of suvorexant. Org.
Chem. Front. 2018, 5, 648–652. (b) Zhang, H. L.; Jing, L.; Zheng, Y.;
Sang, R.; Zhao, Y.; Wang, Q. T.; Wu, Y. Rhodium-Catalyzed ortho-
Cyanation of 2-Aryl-1,2,3-triazole: An Alternative Approach to
Suvorexant. Eur. J. Org. Chem. 2018, 723–729.
(11) Our groups have been interested in utilizing aryldiazonium
salt for heterocycle synthesis, see: (a) Chen, Z.; Fan, S.-Q.; Zheng, Y.;
Ma, J.-A. Silver-catalyzed regioselective [3 + 2] cycloaddition of
arene-diazonium salts with 2,2,2-trifluorodiazoethane (CF3CHN2):
(17) Cai, R L.; Yan, W. M L.; Bologna, M. G L.; Silva, K. D.; Ma, Z.;
Finklea, H. O.; Petersen, J. L.; Li, M. Y.; Shi, X. D. Synthesis and
characterization of N-2-aryl-1,2,3-triazole based iridium
complexes as photocatalysts with tunable photoredox potential.
Org. Chem. Front. 2015, 2, 141–144.
a
facile access to 2-aryl-5-trifluoromethyltetrazoles. Chem.
Commun. 2015, 51, 16545−16548. (b) Peng, X.; Xiao, M.-Y.; Zeng, J.-
L.; Zhang, F.-G.; Ma, J.-A. Construction of Difluoromethylated
Tetrazoles via Silver-Catalyzed Regioselective [3
+
2]
Cycloadditions of Aryl Diazonium Salts. Org. Lett. 2019, 21,
4808−4811. (c) Zhai, S.-J.; Peng, X.; Zhang, F.-G.; Ma, J.-A. Catalytic
Direct Regioselective Synthesis of Phosphonylated Tetrazoles from
Aryl Diazonium Salts and Seyferth-Gilbert Reagent. Org. Lett. 2019,
21, 9884−9888. (d) Xiao, M.-Y.; Chen, Z.; Zhang, F. G.; Ma. J.- A.
Regioselective synthesis of carboxylic and fluoromethyl tetrazoles
enabled by silver-catalyzed cycloaddition of diazoacetates and aryl
diazonium salts. Tetrahedron 2020, 76, 131063. (e) For most
recent related review, see: Zhang, F.-G.; Chen, Z.; Cheung, C. W.; Ma,
J.-A. Aryl Diazonium Salt-Triggered Cyclization and Cycloaddition
Reactions: Past, Present, and Future. Chin. J. Chem. 2020, 38,
1132−1152.
(18) Xuan, J.; Xia, X. D.; Zeng, T. T.; Feng, Z. J.; Chen, J. R.; Lu, L. Q.;
Xiao, W. J. Visible-light-induced Formal [3+2] Cycloaddition for
Pyrrole Synthesis Under Metal-Free Conditions. Angew. Chem. Int.
Ed. 2014, 53, 5653–5656.
(19) Wang, Y.; Lei X.; Tang, Y. Rh(ii)-catalyzed cycloadditions of
1-tosyl 1,2,3-triazoles with 2H-azirines: switchable reactivity of
Rh-azavinylcarbene as [2C]- or aza-[3C]-synthon. Chem. Commun.
2015, 51, 4507–4510.
ACS Paragon Plus Environment