Metal-Free Cascade [4 + 1] Cyclization Access to 4-Aryl- NH-1,2,3-triazoles from N-Tosylhydrazones and Sodium Azide

Article abstract of DOI:10.1021/acs.joc.9b02250

A molecular iodine-mediated coupling cyclization reaction for the synthesis of 4-aryl-NH-1,2,3-triazoles has been developed from N-tosylhydrazones and sodium azide. This metal-free cascade [4 + 1] cyclization reaction could rapidly synthesize valuable com

Full text of DOI:10.1021/acs.joc.9b02250

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Note
Metal-Free Cascade [4+1] Cyclization Access to 4-Aryl-
NH-1,2,3-Triazoles from N-Tosylhydrazones and Sodium Azide
Wen-Ming Shu, Xun-Fang Zhang, Xiang-Xiang Zhang, Min Li, An-Jing Wang, and An-Xin Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02250 • Publication Date (Web): 15 Oct 2019
Downloaded from pubs.acs.org on October 15, 2019
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Metal-Free Cascade [4+1] Cyclization Access to
4-Aryl-NH-1,2,3-Triazoles from N-Tosylhydrazones
and Sodium Azide
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Wen-Ming Shu*,†, Xun-Fang Zhang,† Xiang-Xiang Zhang,† Min Li,† An-Jing Wang,†
and An-Xin Wu*, ‡
† College of Chemistry and Environmental Engineering, Yangtze University, Jingzhou 434023, P.
R. China
‡ Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan 430079, P. R. China
†
E-mail: shuwm@yangtzeu.edu.cn.
‡ E-mail: chwuax@mail.ccnu.edu.cn.
NNHTs
R
N
I2
DMSO,100 °C
N
MsOH,
NH
+
NaN3
Ar
Ar
R
 Metal-free
 Readily available substrates
 C-N and N-N bond formation
ABSTRACT: A molecular iodine mediated coupling cyclization reaction for the
synthesis of 4-aryl-NH-1,2,3-triazoles has been developed from N-tosylhydrazones
and sodium azide. This metal-free cascade [4+1] cyclization reaction could rapidly
synthesize valuable compounds via a sequential C-N and N-N bond formation.
Mechanistic studies demostrate that the nitrogen-atoms of the 1,2,3-triazoles are not
entirely from sodium azide.
N-Tosylhydrazones are versatile reagents that have wide application in the
formation of diverse compounds in organic chemistry.1 They can facilitate a variety of
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useful chemical transformations, including insertion,2 olefination,3 alkynylation,4
cyclization5 and others.6 One of the most important conversion approaches is the
cross-coupling reaction of N-tosylhydrazones, which as masked diazo compounds
react with different nucleophiles (C, N, O, S, and P) under metal-free conditions.2a-c,7
For example, Barluenga and coworkers reported a metal-free reductive coupling
reaction of N-tosylhydrazones with sodium azide to obtain primary and secondary
alkyl azides (Scheme 1a).8 Moreover, cyclization reactions involving
N-tosylhydrazones have achieved substantial progress in recent years, demonstrating
excellent potential advantages for pharmaceuticals and material science.3e,5f,6b,9 For
example, Zhang and coworkers developed a copper-medidated oxidation cyclization
reaction for the synthesis of N-substituted 1,2,3-triazoles from N-tosylhydrazones and
anilines (Scheme 1b).10 Metal-free methods that produce N-substituted 1,2,3-triazoles
from N-tosylhydrazones have also been developed by the Zhang and Ji group.11 It is
worth noting that these synthetic products are N-substituted 1,2,3-triazoles rather than
NH-1,2,3-triazoles. Thus, developing methods to access N-unsubstituted
1,2,3-triazoles from N-tosylhydrazones represents a necessary approach.
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NH-1,2,3-Triazoles, an important class of heterocyclic compounds, have
widespread applications in pharmaceutical, material, and synthetic fields.12 Compared
to the N-substituted triazoles, the direct synthesis of NH-1,2,3-triazoles is fairly
challenging, with few methods available.13 For example, Yang et.al explored a
convenient and efficient preparation method for N-unsubstituted 1,2,3-triazoles by
1,3-dipolar cycloaddition of nitroolefins and sodium azide for the synthesis of
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Scheme 1. Previous Works and Present Study.
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(a) Valdes's work: reductive azidation of tosylhydrazones
N3
8
9
NNHTs
R2
K2CO3, TBAB
R2
NaN3
+
R1
R1
dioxane,110 °C
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(b) Zhang's work: copper-mediated oxidation cyclization of tosylhydrazones
N
NNHTs
R2
Cu(OAc)2, PivOH
toluene,100 °C
N
N
R3
R3 NH2
+
R1
R1
R2
(c) This work: intramolecular N-N coupling cyclization
NNHTs
R
N
MsOH, I2
N
+
NH
NaN3
Ar
DMSO,100 °C
Ar
R
4-aryl-NH-1,2,3-triazoles.15 Additionally, there are other synthetic strategies that use
TMSN3 and a one-pot procedure to access NH-1,2,3-triazoles.16 Despite the
importance of these reported methods, they still suffer from transition-metal catalyst
usage, limited substrate scope, inaccessible starting materials, and harsh reaction
conditions.17 Therefore, the development of a versatile and practical method for the
synthesis of NH-1,2,3-triazoles under metal-free conditions from simple substrates is
still readily needed. Herein, we report a molecular iodine-promoted N–N coupling
cyclization of N-tosylhydrazones with sodium azide for the construction of
NH-1,2,3-triazoles (Scheme 1c).
To establish the optimal reaction conditions, we utilized N-tosylhydrazone 1a and
sodium azide (2) as model substrates (Table 1). The desired product
4-phenyl-1H-1,2,3-triazole (3a) was furnished with a 56% yield when the reaction
proceeded in the presence of 0.5 equivalent iodine at 100 °C for 8 h in DMSO (entry
1). Encouraged by these results, we examined the effect of the amount of iodine on
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the reaction (entries 1-3). The yield of 3a increased to 78% when 1.0 equivalent
iodine was used (entry 2). Further increasing the amount of iodine was not favorable
for this reaction (entry 3). To increase the yield of the desired product 3a, various
additives (TfOH, TsOH, TFA, HCl, H2SO4, and MsOH) were also investigated
(entries 4-9). The results exhibited that TfOH, H2SO4, and MsOH could promote the
reaction to varying degrees. MsOH was the most effective additive and increased the
product yield to 85% (entry 9). Prolonged reaction time and varied reaction
temperature reduced the yield (entries 10-11). Both other azide (TMSN3) and iodine
sources (HI, and KI) could not increase the product yield (entries 12-14). We could
not obtain the desired product 3a in the absence of iodine (entry 15). Subsequently,
various solvents were screened, and DMSO was the best choice for this reaction. The
desired product 3a was not obtained in other solvents (toluene, DCE, CH3NO2,
dioxane, and DMF) (entries 16-20).
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Table 1. Optimization of the Reaction Conditionsa
N
N
NNHTs
NH
I2,
adictive
+
NaN3
solvent, 100 °C
2
1a
3a
entry
1
2
3
4
5
6
7
8
solvent
I2 (equiv)
0.5
additive
-
yieldb (%)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
56c
78c
43c
56
1.0
-
1.5
-
1.0
HCl
1.0
H2SO4
TFA
TsOH
TfOH
MsOH
MsOH
MsOH
82
1.0
72
1.0
71
1.0
83
1.0
85
9
10
11
1.0
75d
82e
1.0
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DMSO
DMSO
DMSO
DMSO
toluene
DCE
1.0
1.0
1.0
-
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
34f
25g
8h
0
12
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20
1.0
1.0
1.0
1.0
1.0
0
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0
CH3NO2
dioxane
DMF
0
0
0
aReactions were carried out with 1a (0.5 mmol, 1.0 equiv), NaN3 (0.65 mmol, 1.2
equiv), and addictive (0.5 mmol, 1.0 equiv) in DMSO (3 mL) at 100 °C for 3 h.
bIsalated yield. cReaction time is 8 h. dReaction at 90 °C. eReaction temperature is 110
°C. fTMSN3 instead of NaN3. gI2 replaced by HI. hKI as iodine source.
After optimizing the reaction conditions, we explored the substrate scope of
N-tosylhydrazones (3), as shown in Scheme 2. Notably, the electronic properties of
the substituents on the aromatic ring system were shown to have no major influence
on the efficiency of this transformation. The N-tosylhydrazones bearing
electron-neutral (H), electron-donating (2-Me, 4-Me, 3,4-2Me 3-OMe, 4-OMe,
3,4-2OMe, 3,4-OCH2O), and electron-withdrawing (4-NO2, 4-CN) groups attached to
the benzene ring transformed smoothly into their corresponding products in good to
high yields (3a-3h, 3q and 3r; 68-89%). In addition, the halo-substituted (2-Cl, 3-Cl,
4-Cl, 3,4-2Cl, 2-Br, 3-Br, 4-Br) groups were suitable in this reaction, affording the
corresponding products in high yields (76-91%; 3i-3p). Much to our satisfaction,
α-naphthyl and β-naphthyl group substrates were also compatible, giving the expected
products in good to excellent yields (3s-3t; 83-93%). Furthermore, when the
substituents were heterocyclic (2-furyl, 2-thienyl, and 3-pyridyl), the desired products
3u-3w were obtained in moderate to good yields (54-89%). Moreover, the
α-substituted (methyl and phenyl) N-tosylhydrazones could also participate in this
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reaction, affording the products 3x-3y in 46-58% yield. Unfortunately, alkyl and
cycloalkyl N-tosylhydrazones were not tolerated in this [4+1] cyclization reaction and
we could not obtained the correspounding products (3z and 3za).
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Scheme 2. Scope of N-tosylhydrazonesa
N
N
I2, MsOH
NH
NNHTs
R2
R1
+
NaN3
R1
DMSO, 100 °C
R2
3
2
1
N
NH
N
NH
N
NH
N
NH
N
N
N
N
N
NH
N
N
N
MeO
NH
MeO
Me
Me
Me
Me
3a
3f
, 85%
N
, 76%
N
3c
3b
, 89%
3d
3e
, 82%
, 73%
, 81%
N
N
N
NH
N
N
NH
N
NH
N
N
N
N
NH
NH
NH
Cl
O
O
Cl
F
MeO
Cl
OMe
3h
, 68%
3i
, 87%
3l
3j
, 77%
3g
, 83%
3k
, 72%
, 79%
N
N
N
NH
N
NH
N
N
N
NH
N
N
NH
N
N
N
NH
NH
Br
Br
O2N
NC
Cl
Br
Cl
3m
3p
, 84%
, 82%
3q
, 75%
N
3r
3o
, 88%
, 91%
N
3n
, 76%
N
N
N
N
N
NH
N
NH
N
NH
N
N
N
NH
NH
NH
O
S
Me
N
3t
3u
, 54%
, 93%
3v
, 87%
3s
3w
, 89%
, 83%
3x
, 46%
N
N
N
NH
N
N
NH
N
NH
Me
Me
3za
3z
, 0%
, 0%
3y
, 58%
a Reactions were performed with 1 (1.0 mmol, 1.0 equiv), 2 (1.2 mmol, 1.2 equiv),
I2 (1.0 mmol, 1.0 equiv), and MsOH (1.0 mmol, 1.0 equiv) in DMSO (5 mL) at 100
°C for 3 h. Isolated products.
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To gain insight into the reaction process, a series of control experiments were
performed (Scheme 3). The α-iodo N-tosylhydrazone 1a′ was obtained by the reaction
of N-tosylhydrazone (1a) with iodine in CH3CN at room temperature for 1 h.5f Later,
the reaction between 1a′ and sodium azide in DMSO at 100 °C for 3 h in the presence
of MsOH proceeded smoothly to give the target product 3a in 83% yield. Moreover,
2-azido-1-phenylethan-1-one (4) reacted with p-toluenesulfonyl hydrazide (5) leading
to α-azido N-tosylhydrazone B, which could be transformed into product 3a in 80%
yield under standard conditions. Furthermore, the desired product 3a was not afforded
when using ethynylbenzene 6 as a substrate. These results indicate that compounds
1a′ and B are probably intermediates for this reaction and that ethynylbenzene 6
cannot serve as an intermediate.
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Scheme 3. Control Experimentsa
N
N
NNHTs
I
NNHTs
I2
NH
NaN ,
MsOH
3
CH3CN, rt, 1 h
DMSO, 100 °C, 3 h
1a'
1a
3a
, 83%
NNHTs
O
I2, MsOH
N3
N3
3a
, 80%
+
TsNHNH2
CH3CN, rt, 1 h
DMSO, 100 °C, 3 h
B
4
5
standard conditions
+
3a
NaN3
2
, 0%
6
aIsolated yields.
Based on the above experimental results, a possible reaction mechanism is
proposed as shown in Scheme 4 (with 3a as an example). Initially, α-iodination of
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N-tosylhydrazone 1a generates intermediate 1a′ in the presence of I2.11b Next, two
possible approaches were proposed for the conversion from 1a′ to intermediate B.
Elimination of HI from 1a′ gives the intermediate 1-tosyl-2-vinyldiazene A,10a which
undergoes an aza-Michael addition with NaN3 to obtain the intermediate B (path I).
Direct nucleophilic substitution of NaN3 onto intermediate 1a′ is another possible
route for the formation of intermediate B (path II). Subsequently, the intermediate B
could be smoothly cyclized to intermediate C by formation of an N-N bond. Finally,
the intermediate C produced to the intermediate D with the elimination of nitrogen,
which is converted to the final product 3a via a [1,5]-H shift.
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Scheme 4. A Possible Mechanism
Ts
N
N
path I
NaN3
Ts
NH
N
NNHTs
NNHTs
A
I2
N
I
N
N
N
MsOH
B
NaN3
1a'
1a
Ts
path II
H
NH
N
N
N
NH
N
N
N
N
N
[1,5]-H shift
 N2
H
C
D
3a
To demonstrate the potential applications for organic synthesis, the reaction of
tosylhydrazone 1a and NaN3 was performed on a gram scale (Scheme 5).
Gratifyingly, the reaction carried out very well, and the phenyl-1H-1,2,3-triazole 3a
was furnished in 86% yield.
Scheme 5. Gram Scale Experiment
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NNHTs
N
NH
N
I2, MsOH
+
NaN3
DMSO, 100 °C
86%
2
1a
(5.77 g, 20 mmol)
(1.56 g, 24 mmol)
3a
, 2.49 g
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CONCLUSION
In summary, we developed a molecular iodine-promoted [4+1] cyclization of
N-tosylhydrazones with sodium azide for the synthesis of 4-aryl-NH-1,2,3-triazole
derivatives. This metal-free strategy could rapidly synthesize valuable compounds via
sequential C–N and N–N bond formation in a single step. Further studies on this
method for the synthesis of other bioactive compounds and applications are in
progress in our laboratory.
EXPERIMENTAL SECTION
General Information. N-tosylhydrazones 1 were prepared according to the
literature procedure.18 Other substrates and reagents were commercial and used
without further purification. TLC analysis was performed using pre-coated glass
1
plates. Column chromatography was performed using silica gel (200-300 mesh). H
NMR spectra were determined at 25 °C on a Varian Mercury 400 or 600 MHz
spectrometer. 13C NMR spectra were recorded in CDCl3 or DMSO-d6 on 100/150
MHz. Chemical shifts are given in ppm relative to the internal standard of
tetramethylsilane (TMS). HRMS were obtained on an Thermo Scientific LTQ
Orbitrap XL equipped with an atmospheric-pressure chemical ionization (APCI)
source or electrospray ionization (ESI) source. The X-ray crystal-structure
determinations were obtained on a Bruker APEX DUO CCD system.
General Procedure for the Synthesis of 3a-3y (3a as example). The mixture of
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N-tosylhydrazone 1a (288.4 mg, 1.0 mmol), sodium azide (78.0 mg, 1.2 mmol),
iodine (253.8 mg, 1.0 mmol), and methylsulphonic acid (96.1 mg, 1.0 mmol) was
added in DMSO (5 mL), and the resulting mixture was stirred at 100 °C for 3 h. After
the reaction completed, and then added 100 mL water to the mixture, extracted with
EtOAc three times (3 × 100 mL). Dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was purified by column chromatography on silica
gel (CH2Cl2/EtOAc = 30/1) to afford the desired product 3a.
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4-phenyl-1H-1,2,3-triazole (3a):15a,19
Yield 85% (123.4 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.06
13
(s, 1H), 8.30 (s, 1H), 7.92–7.91 (m, 2H), 7.48 (s, 2H), 7.38 (s, 1H); C{1H} NMR
(100 MHz, DMSO-d6): δ (ppm) 146.3, 130.9, 129.0, 128.3, 125.7, 119.5; ITMS (ESI,
LCQ-fleet): m/z [M+H]+ C8H8N3: 145.92 (100), 146.91 (13.6).
4-(o-tolyl)-1H-1,2,3-triazole (3b):21
Yield 82% (130.5 mg); yellow oil; 1H NMR (400 MHz, CDCl3): δ (ppm) 13.22 (s,
1H), 7.84 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.28 – 7.20 (m, 2H), 7.20 – 7.14 (m, 1H),
13
2.38 (s, 3H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 144.6, 135.8, 130.8, 129.4,
129.0, 128.6, 128.5, 126.0, 20.8; HRMS (ESI, LTQ-Orbitrap): m/z [M+H]+ calcd for
C9H10N3: 160.0869, found: 160.0862.
4-(p-tolyl)-1H-1,2,3-triazole (3c):15a,19a
Yield 89% (141.7 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.13
(s, 1H), 8.31 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 2.34 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 145.9, 137.6, 129.6, 129.2, 127.8,
125.6, 20.9; ITMS (ESI, LCQ-fleet): m/z [M+H]+ C9H10N3: 159.98 (100), 160.95
(8.71).
4-(3,4-dimethylphenyl)-1H-1,2,3-triazole (3d):
Yield 73% (126.4 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.14
(s, 1H), 8.30 (s, 1H), 7.71 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.35–6.96 (m, 1H), 2.28 (s,
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3H), 2.24 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 146.3, 136.9, 136.4,
130.1, 128.1, 126.8, 123.2, 19.5, 19.2; HRMS (ESI, LTQ-Orbitrap): m/z [M+H]+
calcd for C10H12N3: 174.1026, found: 174.1023.
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4-(3-methoxyphenyl)-1H-1,2,3-triazole (3e):19a,20
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Yield 81% (141.9 mg); yellow oil; 1H NMR (400 MHz, CDCl3): δ (ppm) 13.97 (s,
1H), 7.99 (s, 1H), 7.52–7.35 (m, 2H), 7.32 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H),
13
3.83 (s, 3H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 160.0, 146.4, 130.8, 130.0,
128.5, 118.5, 114.6, 111.3, 55.3; HRMS (ESI, LTQ-Orbitrap): m/z [M+H]+ calcd for
C9H10N3O : 176.0818, found: 176.0819.
4-(4-methoxyphenyl)-1H-1,2,3-triazole (3f):15a,19
Yield 76% (133.2 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.02
(s, 1H), 8.25 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 159.3, 146.1, 129.9, 127.0, 123.1,
114.4, 55.2; ITMS (ESI, LCQ-fleet): m/z [M+H]+ C9H10N3O: 175.95 (100), 176.96
(10.66).
4-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole (3g):20-21
Yield 72% (147.7 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 14.93
(s, 1H), 8.24 (s, 1H), 7.47 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H),
3.86 (s, 3H), 3.81 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 149.1,
146.3, 130.2, 123.5, 118.2, 112.1, 109.3, 55.6, 55.5; ITMS (ESI, LCQ-fleet): m/z
[M+H]+ C10H12N3O2: 206.02 (100), 207.08 (25.02), 207.83 (7.81).
4-(benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole (3h):19a
1
Yield 68% (128.7 mg); white solid; H NMR (400 MHz, DMSO-d6): δ (ppm)
15.11 (s, 1H), 8.28 (s, 1H), 7.47–7.44 (m, 1H), 7.43–7.41 (m, 1H), 7.02 (d, J = 8.0 Hz,
1H), 6.10 (s, 2H); 13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 147.9, 147.3, 145.6,
128.5, 124.5, 119.4, 108.8, 106.1, 101.3; HRMS (ESI, LTQ-Orbitrap): m/z [M+H]+
calcd for C9H8N3O2 : 190.0611, found 190.0615.
4-(4-fluorophenyl)-1H-1,2,3-triazole (3i):15a,21
Yield 87% (142.0 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.29
(s, 1H), 8.41 (s, 1H), 8.01–7.98 (m, 2H), 7.35 (t, J = 8.4 Hz, 2H); 13C{1H} NMR (100
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MHz, DMSO-d6): δ (ppm) 162.1 (d, JCF = 243.4 Hz), 144.8, 129.9, 127.7 (d, JCF = 8.1
Hz), 115.9 (d, JCF = 21.6 Hz) ; ITMS (ESI, LCQ-fleet): m/z [M+H]+ C8H7FN3: 163.92
(100), 164.92 (9.46).
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4-(2-chlorophenyl)-1H-1,2,3-triazole (3j):15a, 19b
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Yield 83% (149.1 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.41
(s, 1H), 8.39 (s, 1H), 7.98 (s, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.52–7.37 (m, 2H);
13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 143.0, 133.1, 130.9, 130.2, 129.6,
129.4, 127.5, 122.8; HRMS (ESI, LTQ-Orbitrap): m/z [M+H]+ calcd for C8H7ClN3:
180.0323, found: 180.0329.
4-(3-chlorophenyl)-1H-1,2,3-triazole (3k):19a
Yield 79% (141.9 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.33
(s, 1H), 8.51 (s, 1H), 8.04–7.94 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.8 Hz,
13
1H), 7.44 (d, J = 8.0 Hz, 1H); C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 144.5,
133.8, 132.6, 130.9, 127.9, 125.2, 124.1; ITMS (ESI, LCQ-fleet): m/z [M+H]+
C8H7ClN3: 179.91 (100), 180.97 (11.72), 181.99 (34.50), 183.0 (4.80).
4-(4-chlorophenyl)-1H-1,2,3-triazole (3l):15a,19b
Yield 77% (138.3 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.41
(s, 1H), 8.46 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H); 13C{1H} NMR
(100 MHz, DMSO-d6): δ (ppm) 144.67, 132.8, 129.4, 129.0, 127.3; ITMS (ESI,
LCQ-fleet): m/z [M+H]+ C8H7ClN3: 179.94 (100), 180.92 (11.81), 181.88 (34.50),
182.98 (4.67).
4-(3,4-dichlorophenyl)-1H-1,2,3-triazole (3m):
Yield 84% (179.8 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.45
(s, 1H), 8.53 (s, 1H), 8.20–8.13 (m, 1H), 7.94–7.88 (m, 1H), 7.69 (d, J = 8.4 Hz, 1H);
13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 143.7, 131.9, 131.2, 131.0, 130.5,
127.1, 125.5; HRMS (ESI, LTQ-Orbitrap): m/z [M+H]+ calcd for C8H6Cl2N3:
213.9933, found 213.9932.
4-(2-bromophenyl)-1H-1,2,3-triazole (3n):20, 21
1
Yield 76% (170.3 mg); yellow solid; H NMR (400 MHz, DMSO-d6): δ (ppm)
15.40 (s, 1H), 8.38 (s, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.6 Hz,
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1H), 7.35 (t, J = 7.6 Hz, 1H); C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 144.5,
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133.5, 131.5, 131.0, 130.0, 128.0, 121.2; HRMS (ESI, LTQ-Orbitrap): m/z [M+H]+
calcd for C8H7BrN3: 223.9818, found: 223.9819.
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Yield 91% (203.9 mg); yellow solid; H NMR (400 MHz, DMSO-d6): δ (ppm)
15.27 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz,
1H), 7.46 (t, J = 8.0 Hz, 1H); C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 144.9,
13
133.1, 131.1, 130.8, 128.1, 124.5, 122.4, 120.4; ITMS (ESI, LCQ-fleet): m/z [M+H]+
C8H7BrN3: 223.92 (99.99), 224.99 (11.58), 225.90 (100), 227.01 (9.87).
4-(4-bromophenyl)-1H-1,2,3-triazole (3p):15a
1
Yield 82% (183.7 mg); yellow solid; H NMR (400 MHz, DMSO-d6): δ (ppm)
15.36 (s, 1H), 8.45 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.72–7.65 (m, 2H); 13C{1H}
NMR (100 MHz, DMSO-d6): δ (ppm) 144.7, 131.9, 129.8, 127.8, 127.6, 121.2; ITMS
(ESI, LCQ-fleet): m/z [M+H]+ C8H7BrN3: 223.89 (100), 225.00 (12.67), 225.88
(97.56), 226.99 (10.77).
4-(4-nitrophenyl)-1H-1,2,3-triazole (3q):19
1
Yield 75% (142.6 mg); yellow solid; H NMR (400 MHz, DMSO-d6): δ (ppm)
15.39 (s, 1H), 8.65 (s, 1H), 8.33 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H); 13C{1H}
NMR (100 MHz, DMSO-d6): δ (ppm) 146.8, 143.9, 137.1, 126.4, 124.4; HRMS (ESI,
LTQ-Orbitrap): m/z [M+H]+ calcd for C8H7N4O2: 191.0564, found: 191.0560.
4-(1H-1,2,3-triazol-4-yl)benzonitrile (3r):15a
Yield 88% (149.8 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.31
(s, 1H), 8.60 (s, 1H), 8.13 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H); 13C{1H} NMR
(100 MHz, DMSO-d6): δ (ppm) 144.3, 135.1, 132.9, 127.7, 126.2, 118.9, 110.4;
ITMS (ESI, LCQ-fleet): m/z [M+H]+ C9H7N4: 171.02 (100), 102.04 (9.12).
4-(naphthalen-1-yl)-1H-1,2,3-triazole (3s):22
Yield 83% (162.0 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm)
15.46 (s, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 8.02 (t, J = 7.6 Hz, 2H), 7.87 (d, J = 6.4 Hz,
1H), 7.65–7.58 (m, 3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 145.7, 133.7,
130.5, 128.8, 128.5, 128.1, 127.2, 126.8, 126.2, 125.6; ITMS (ESI, LCQ-fleet): m/z
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[M+H]+ C12H10N3: 195.98 (100), 197.03 (32.36), 198.77 (12.45).
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4-(naphthalen-2-yl)-1H-1,2,3-triazole (3t):19b,21
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8
9
Yield 93% (181.5 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm)
15.39 (s, 1H), 8.59 (s, 1H), 8.36 (s, 1H), 8.02 (t, J = 7.6 Hz, 2H), 7.83 (d, J = 6.4 Hz,
1H), 7.73–7.37 (m, 3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 145.7, 133.6,
130.5, 128.8, 128.5, 128.0, 127.2, 126.8, 126.2, 125.6, 125.5; ITMS (ESI, LCQ-fleet):
m/z [M+H]+ C12H10N3: 196.01 (100), 196.97 (17.58), 198.81 (23.13).
4-(furan-2-yl)-1H-1,2,3-triazole (3u):15a,19b,21
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Yield 54% (73.0 mg); brown solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.14
13
(s, 1H), 8.14 (s, 1H), 7.79 (s, 1H), 6.93–6.80 (m, 1H), 6.65–6.63 (m, 1H); C{1H}
NMR (100 MHz, DMSO-d6): δ (ppm) 146.0, 143.0, 138.9, 130.2, 111.7, 107.2; ITMS
(ESI, LCQ-fleet): m/z [M+H]+ C6H6N3O: 135.88 (100), 136.95 (10.48).
4-(thiophen-2-yl)-1H-1,2,3-triazole (3v):15a,21
Yield 87% (131.5 mg); brown solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm)
14.96 (s, 1H), 8.15 (s, 1H), 8.13 (d, J = 8.0 Hz, 2H), 7.60–7.43 (m, 2H), 7.16–7.13 (m,
1H); 13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 141.6, 132.7, 130.3, 127.9, 125.8,
125.0; ITMS (ESI, LCQ-fleet): m/z [M+H]+ C6H6N3S: 151.91 (100), 152.84 (12.50).
3-(1H-1,2,3-triazol-4-yl)pyridine (3w):23
Yield 89% (130.1 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 15.23
(s, 1H), 9.12 (s, 1H), 8.59 (s, 1H), 8.41 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.54–7.50 (m,
1H); 13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 149.3, 146.8, 133.0, 131.3, 126.5,
124.1, 120.3; ITMS (ESI, LCQ-fleet): m/z [M+H]+ C7H7N4: 223.89 (100), 225.00
(12.67).
5-methyl-4-phenyl-1H-1,2,3-triazole (3x):14b,15a,22
Yield 46% (73.2 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 14.69
13
(s, 1H), 7.80–7.71 (m, 2H), 7.48 (s, 2H), 7.40–7.35 (m, 1H), 2.46 (s, 3H); C{1H}
NMR (100 MHz, DMSO-d6): δ (ppm) 131.4, 128.7, 127.7, 127.1, 126.8, 126.2, 11.5;
ITMS (ESI, LCQ-fleet): m/z [M+H]+ C9H10N3: 159.95 (100),160.92 (24.77).
4,5-diphenyl-1H-1,2,3-triazole (3y):14b,15a
Yield 58% (128.3 mg); white solid; 1H NMR (400 MHz, DMSO-d6): δ (ppm)
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15.22 (s, 1H), 7.54 (s, 4H), 7.41 (s, 6H); 13C{1H} NMR (100 MHz, DMSO-d6): δ
(ppm) 143.2, 131.2, 128.6, 128.2, 128.0; HRMS (ESI, LTQ-Orbitrap) m/z [M+H]+
calcd for C14H12N3: 222.1026, found 222.1029.
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Supporting Information
Copies of 1H and 13C NMR spectra of compounds 3a-3y. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (Grants
21772051 and 21801022) for financial support. This work was also supported by the
Yangtze Youth Talents Fund (No. 2016cqn25) and the Doctoral Scientific Research
Startup Foundation of Yangtze University (No. 801090010135).
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J.; Bao, W.; Zhang, K. Zinc-promoted cyclization of tosylhydrazones and
2-(dimethylamino)malononitrile: an efficient strategy for the synthesis of substituted
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Table of Contents
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NNHTs
R
N
I2
N
MsOH,
NH
+
NaN3
Ar
Ar
DMSO,100 °C
R
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Simple substrates Metal-free
 C-N and N-N bond formation
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