Regioselective synthesis of triazoles via base-promoted oxidative cycloaddition of chalcones with azides in aqueous solution

Article abstract of DOI:10.1039/c5ra16974g

A base-promoted oxidative cycloaddition of chalcones with azides in aqueous solution has been developed under transition-metal-free conditions, which provides a green method for the regioselective synthesis of trisubstituted triazoles in good yields.

Full text of DOI:10.1039/c5ra16974g

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Received 00th January 20xx,
Accepted 00th January 20xx
Regioselective synthesis of triazoles via base-promoted oxidative
cycloaddition of chalcones with azides in aqueous solution
DOI: 10.1039/x0xx00000x
Wenchao Yang,a Tao Miao,*a Pinhua Li,a and Lei Wang*a,b
www.rsc.org/advances
A baseꢀpromoted oxidative cycloaddition of chalcones with azides in aqueous solution has been developed under transitionꢀ
metalꢀfree conditions, which provides a green method for the regioselective synthesis of trisubstituted triazoles in good
yields.
ketones, βꢀketo esters and enals) with organic azides,6 an
enaminoneꢀazide multicomponent cascade reaction of aldehydes,
Introduction
Triazole represents a unique building block for organic synthesis,
and as a key skeleton has been found in many bioactive compounds
and synthetic drugs.1,2 As we known, the classic method for the
synthesis of triazoles is Huisgen 1,3ꢀdipolar cycloaddition of organic
azides with terminal alkynes.3 However, this reaction suffered from
poor regioselectivity and harsh reaction conditions. Subsequently,
the advent of click chemistry has been proven to be the most
straightforward and powerful approach for the preparation of triazole
derivatives, in which the terminal alkynes are necessary and restrict
the scope of Cuꢀ or Ruꢀcatalyzed cycloaddition reactions.4 Recently,
some alternative methods have been established for the synthesis of
triazole derivatives including the reactions of azides with alkenes or
ketones.5 For example, Chen and coꢀworkers disclosed a CuOꢀ
promoted oxidative cycloaddition of sodium azides with chalcones
and further arylation of N−H under mild reaction conditions.5f Yao et
al have also reported a copper(I)ꢀcatalyzed aerobic oxidative azideꢀ
alkene cycloaddition for the preparation of substituted 1,2,3ꢀ
triazoles.5g More recently, Zhang group described a novel Cuꢀ
mediated synthesis of 1,2,3ꢀtriazoles from Nꢀtosylhydrazones and
anilines.5h It was found that most of these methods often utilized
significant amount of toxic transition metal catalysts, which are not
ideal for the biological applications in view of their toxicity.
Therefore, a simple and green protocol is still highly desirable for
the construction of trizaole and its derivatives.
nitroalkanes, and organic azides,7 a TsOHꢀcatalyzed nitroolefinꢀ
azide cycloaddition8 and a condensation of Nꢀtosylhydrazones with
primary amines.9 Although these ecoꢀfriendly approaches to triazoles
were achieved, we considered exploring the alternative transitionꢀ
metalꢀfree cycloaddition is essential in the preparation of triazoles.
In continuation of our interest in developing green synthetic methods
in organic synthesis,10 herein we have reported a novel and simple
protocol for the synthesis of 1,2,3ꢀtriazoles from the cycloaddition
reactions of chalcones with azides under transitionꢀmetalꢀfree
conditions (Scheme 1).
R2
N
K2CO3 (2.0 equiv)
N
O
N
H2O/1,4-Dioxane (5:1)
R2 N3
Ar
Ar
R1
air, 80 oC, 11 h
R1
O
Transition-Metal-Free
Scheme 1. Transitionꢀmetalꢀfree synthesis of triazoles.
Results and discussion
As shown in Table 1, our efforts to accomplish such a
transformation by employing the simple chalcone (1a) and
BnN3 (2a) as the standard substrates. The reaction of 1a with 2a
was carried out in the mixture of H2O/dioxane (5:1), with Et3N
(2.0 equiv) as a base. To our delight, the desired triazole 3a was
isolated in 45% yield (Table 1, entry 1). The structure of 3a was
To address this issue, transitionꢀmetalꢀfree strategies have been
developed for the preparation of specific 1,2,3ꢀtriazoles, such as an
organocatalytic enamineꢀmediated amino acid or amine catalyzed
[3+2] cycloaddition of different carbonyl compounds (enones,
1
characterized by H, 13C NMR spectroscopy, and confirmed by
singleꢀcrystal Xꢀray diffraction analysis.11 The addition of
piperidine instead of Et3N led to a comparable yield of 3a
(Table 1, entry 2). Subsequently, inorganic bases, such as
NaOAc, KOAc, t-BuOLi and t-BuOK were found to be
ineffective in the cycloaddition of 1a with 2a, and poor yields
of 3a were obtained (Table 1, entries 3−6). However, an
enhanced yield (61%) of 3a was achieved when Na2CO3 was
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Table 1 Optimization of base and solvent a
used as a base (Table 1, entry 7). To our delight, K2CO3 was the
most effective base among the tested bases and the desired
product 3a was obtained in 81% yield (Table 1, entry 8).
Employing a shorter reaction time of 5 hours resulted in an
isolated yield of 41% (Table 1, entry 9). Prolonging reaction
time to 24 hours did not improve this transformation (Table 1,
entry 10). We also found that reaction temperature and the
amount of K2CO3 could dramatically affect the formation of the
product 3a (Table 1, entries 11−14). Especially, the reaction did
not proceed in absence of K2CO3 (Table 1, entry 15). Moreover,
we performed the model reaction in the presence of an oxygen
atmosphere, the reaction furnished the desired product (3a) in
80% yield (Table 1, entry 16). However, this reaction has been
almost prohibited under a nitrogen atmosphere (Table 1, entry
17), which probably indicated that oxidative process was
involved in this transformation. The optimization of solvent
was also carried out under above reaction conditions. When
DMF and DMSO were used as solvent in the reaction of 1a
with 2a, 14% and 34% yields of 3a were isolated, respectively
(Table 1, entries 18 and 19). The use of toluene as reaction
medium could result into lower yield of the corresponding
product 3a (Table 1, entry 20). Changing the solvent from
toluene to dioxane increased the yield from 11% to 33% (Table
1, entry 20 vs 21). Then, experiments with THF, CH3CN and
ethanol as solvent had no good yield of 3a (Table 1, entries
Entry
1
Base (equiv)
Et3N (2.0)
Solvent
Yield (%)b
45
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
H2O:dioxane (5:1)
DMF
2
piperidine (2.0)
NaOAc (2.0)
KOAc (2.0)
t-BuOLi (2.0)
t-BuOK (2.0)
Na2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (1.0)
K2CO3 (3.0)
−
42
3
47
4
24
5
26
6
21
7
61
8
81
9c
41
10d
11e
12f
13
14
15
16g
17h
18
19
20
21
22
23
24
25
26
27
28
29
30
80
50
76
61
22−24). An increased yield of 3a was obtained when H2O was
used as solvent (Table 1, entry 25). The ratio of dioxane and
H2O have obvious effect to this reaction, and decreased yields
were observed when the dioxane/H2O ratio was changed from
1:5 to 1:3 and 1:6 (Table 1, entries 26 and 27). Other reaction
media such as the mixtures of DMF, CH3CN and ethanol with
H2O showed poor performance of the reaction (Table 1, entries
28−30).
Having the optimized reaction conditions in our hand, the
scope and limitation of this reaction with respect to the
chalcones and benzyl azides were investigated. As shown in
Scheme 2, a series of substituted chalcones containing electronꢀ
donating groups (methoxy and methyl), electronꢀwithdrawing
groups (cyano and nitro) and halogens (F, Cl, Br) were
synthesized and evaluated in this transformation. Generally,
chalcones with electronꢀdonating groups provided the desired
products in moderate to good yields. In contrast, the presence of
electronꢀdonating groups including cyano and nitro groups
efficiently accelerated this transformation and better results
74
0
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
80
trace
14
DMSO
34
toluene
11
dioxane
33
THF
12
CH3CN
34
ethanol
38
H2O
46
H2O:dioxane ( 3:1)
H2O:dioxane ( 6:1)
H2O: DMF (5:1)
H2O: CH3CN (5:1)
H2O: ethanol (5:1)
54
were obtained
(3g and 3h). Moreover, the reaction of
benzalacetone with benzyl azide generated the corresponding
product 3m in excellent yield (92%). However, the reactions of
methyl acrylate, ethyl acrylate, methyl vinyl ketone and
benzoquinone with benzyl azide failed to the corresponding
1,4ꢀdisubstituted 1,2,3ꢀtriazole products. Benzyl azides bearing
methyl, methoxy, fluoro, chloro, cyano and nitro groups on the
aromatic rings reacted with chalcone (1a) smoothly to afford
the corresponding products (3n−3w) in 59–76% yields. Phenyl
azide was also suitable substrate, and reacted with
benzalacetone to give the expected 1,2,3ꢀtriazole product 3x in
60
47
44
40
a
Reaction conditions: chalcone (1a, 0.30 mmol), BnN3 (2a, 0.60 mmol),
b
c
base (0.60 mmol), solvent (2.0 mL), at 80 ℃, 11 hours. Isolated yield.
d
e
Reaction time is 5 hours.
Reaction time is 24 hours.
Reaction
temperature is 60 ℃. Reaction temperature is 100 ℃. g Under oxygen
atmosphere. h Under nitrogen atmosphere.
f
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added into the above reaction system, and the reaction
proceeded to generate the corresponding triazoles in the
acceptable yields (3a, 3e, 3h and 3l, Scheme 3).
R1 = Ph, R2 = Bn
Ar = Ph, 3a, 81%
Ar = 4-MeO-Ph, 3b, 65% Ar = 4-NO2-Ph, 3h, 90%
Ar = 4-Me-Ph, 3c, 71% Ar = 2-MeO-Ph, 3i, 55%
Ar = 4-F-Ph, 3d, 75%
Ar = 4-Cl-Ph, 3e, 80%
Ar = 4-Br-Ph, 3f, 73%
Ar = 4-CN-Ph, 3g, 87%
Bn
N
N
N
Ar
Ar = 3-Me-Ph, 3j, 64%
Ar = 2,4-diCl-Ph, 3k, 75%
Ar = Pyridyl, 3l, 85%
R1
O
Ar = Ph, R1 = Me, R2 = Bn, 3m, 92%
Condition A: ArCHO (0.30 mmol), PhCOCH3 (0.30 mmol), K2CO3 (2.0
equiv), H2O/1,4ꢀdioxane (5: 1), room temperature, 14 h.
Ar = Ph, R1 = Ph
R2
R2 = 4-MeO-Bn, 3n, 76% R2 = 3-Me-Bn, 3s, 59%
Condition B: BnN3 (2a, 0.6 mmol), K2CO3 (2.0 equiv), 80 °C for 11 h.
N
N
R2 = 3-Cl-Bn, 3t, 70%
R2 = 2-Me-Bn, 3u, 61%
R2 = 2-Cl-Bn, 3v, 60%
3w, 62%
R2 = 4-Me-Bn, 3o, 65%
R2 = 4-Cl-Bn, 3p, 67%
R2 = 4-F-Bn, 3q, 65%
N
Scheme 3 Oneꢀpot synthesis of triazole derivatives
Ph
R1
O
Although exact mechanism of the reaction is still not clear,
on the basis of above observations and the previous literature,5hꢀ
R2 = 4-NO2-Bn, 3r, 74% R2 = 2-CN-Bn,
Ar = Ph, R1 = Me, R2 = Ph, 3x, 75%
i,6bꢀc,9c
N3
a possible mechanism for the regioselective synthesis of
triazole from
stepwise 1,3ꢀdipolar cycloaddition reaction of chalcone
azide might be involved in this transformation, producing
triazoline intermediate in presence of an inorganic base
(K2CO3). Subsequently, triazoline intermediate would be
1
and
2
is illustrated in Scheme 4. Initially, a
1
and
N3
2
N
N
I
N
I
Ph
underwent 1,3ꢀhydride shift to generate intermediate II. Finally,
the oxidation of intermediate II led to the formation of product
Ph
N
N
N
O
N
N
N
3
in the presence of oxidant (O2).9c
Ph
3y, 75%
Ph
Ph
R1
Ph
3aa, 60%
O
Ar
Ar
R
O
3z, 57%
2
O
O
N
R2
Scheme 2 Substrate scope of chalcones and azides [Reaction
conditions: chalcone (1, 0.30 mmol), BnN3 (2, 0.60 mmol), K2CO3
(0.60 mmol), H2O/dioxane (5:1, 2.0 mL), 80 °C for 11 h.]
N
N
N
N
R2
N
1
R1
R1
R1
75% yield. Notably, This reaction was tolerant with halogen
substituents, such as fluoro, chloro and bromo groups on the
aromatic rings of chalcones and benzyl azides, providing good
yields of substituted triazoles, which are the potential substrates
for the further transitionꢀmetalꢀcatalyzed functionalization.
O
O
O
Ar
Ar
Ar
1,3-hydride shift
O2
N
N
N
N
N
N
N
N
R2
N
R2
R2
H
I
3
II
Furthermore,
cycloaddition reactions (3b vs 3i
a
sight steric effect was found in this
3p vs 3t and 3v). When more
Scheme 4 Proposed reaction mechanism.
,
bulky 1ꢀ(azidomethyl)naphthalene was used to react with
chalcone (1a), good yield of product 3y was obtained. It should
be noted that the reaction of 1,4ꢀbis(azidomethyl)benzene with
chalcone (1a) could selectively generate the corresponding
triazole 3z, with one azide unit retained in the product. The
similar result was also observed when 4,4'ꢀbis(azidomethyl)ꢀ
1,1'ꢀbiphenyl was used to react with 1a, providing 3aa in 60%
yield.
Conclusion
In summary, we have successively developed a transitionꢀ
metalꢀfree oxidative cycloaddition reaction of chalcones with
azides, which provides an alternative approach to a broad scope
of triazoles in good yields. With the growing interest in green
chemistry, further mechanistic studies of this process and
application of this strategy to construct other useful compounds
is currently under investigation in our laboratory.
In order to simplify the construction of triazole, a oneꢀpot
strategy was examined, as described in Scheme 3. Firstly,
benzaldehyde reacted with acetophenone to give the chalcone
in H2O/1,4ꢀdioxane (5:1) in the presence of K2CO3 as a base.
After 14 hours, benzylazide and K2CO3 were successively
Acknowledgements
This work was financially supported by the National Science
Foundation of China (Nos. 21172092 and 20102039).
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7.32−7.30 (m, 3H), 7.23−7.21 (m, 2H), 7.12−7.11 (m, 2H),
6.98−6.96 (m, 2H), 5.49 (s, 2H), 3.86 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 186.3, 160.7, 143.5, 141.6, 137.1, 134.7, 132.8, 131.1,
130.5, 128.7, 128.3, 128.0, 127.4, 117.9, 114.0, 55.2, 51.7.
Experimental Section
General
All the chemicals and solvents were purchased from commercial
suppliers and used without further purification. 1H and 13C NMR
spectra were measured on a Bruker Avance NMR spectrometer (400
MHz and 100 MHz, respectively) with CDCl3 as solvent and
recorded in ppm relative to internal tetramethylsilane standard. The
peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet;
m, multiplet; q, quartet. The coupling constants, J, are reported in
Hertz (Hz). High resolution mass spectroscopy data of the product
were collected on a Waters Micromass GCT instrument. or an
Agilent Technologies 6540 UHD AccurateꢀMass QꢀTOF LC/MS
using ESI.
(1-Benzyl-5-(p-tolyl)-1H-1,2,3-triazol-4-yl)(phenyl)methanone,
3c. Yellow solid, m.p. 77–79 °C. 1H NMR (400 MHz, CDCl3): δ
8.31 (d, J = 7.6 Hz, 2H), 7.60−7.56 (m, 1H), 7.50−7.46 (m, 2H),
7.32−7.30 (m, 3H), 7.28−7.26 (m, 2H), 7.19−7.17 (m, 2H),
7.12−7.11 (m, 2H), 5.48 (s, 2H), 2.43 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 186.2, 143.6, 141.8, 140.1, 137.1, 134.7, 132.8, 130.5,
129.5, 129.2, 128.7, 128.3, 128.0, 127.5, 123.1, 51.7, 21.3. HRMS
(ESI) ([M+H]+) Calcd. for C23H20N3O: 354.1606, Found: 354.1603.
(1-Benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)
methanone, 3d.12 Yellow solid, m.p. 241–243 °C. 1H NMR (400
MHz, CDCl3): δ 8.31 (d, J = 7.6 Hz, 2H), 7.61−7.58 (m, 1H),
7.51−7.47 (m, 2H), 7.32−7.30 (m, 3H), 7.27−7.24 (m, 2H),
7.16−7.12 (m, 2H), 7.08−7.06 (m, 2H), 5.48 (s, 2H); 13C NMR (100
MHz, CDCl3): δ 186.2, 163.5 (d, JCF = 251.7 Hz), 143.8, 140.7,
136.8, 134.4, 133.0, 131.8 (d, JCF = 8.6 Hz), 130.5, 128.8, 128.4,
128.1, 127.4, 122.1 (d, JCF = 3.7 Hz), 115.8 (d, JCF = 22.2 Hz), 52.0.
Typical procedure for K2CO3-promoted synthesis of
trisubstituted triazoles
Under air atmosphere, a 10 mL ovenꢀdried sealable reaction vessel
equipped with a magnetic stir bar charged with (E)ꢀchalcone (1a,
62.5 mg, 0.30 mmol), K2CO3 (83 mg, 0.60 mmol), solvent
(H2O:dioxane = 5:1, 2.0 mL) and benzyl azide (2a, 80 mg, 0.60
mmol) were added to the sealed vessel in oneꢀportion. The rubber
septum was then replaced by a Teflonꢀcoated screw cap, and the
reaction vessel placed in an oil bath at 80 °C for 11 h. After the
reaction was completed, it was cooled to room temperature and
diluted with ethyl acetate. Then the resulting solution was extracted
with EtOAc (25 mL x 3). The combined organic extracts were dried
over MgSO4 and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (eluant:
petroleum ether/ethyl acetate = 5:1 to 7:1, V/V) to obtain the desired
pure product, (1ꢀbenzylꢀ5ꢀphenylꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl)(phenyl)
methanone (3a).
(1-Benzyl-5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)
methanone, 3e.5j Yellow solid, m.p. 142–143 °C. 1H NMR (400
MHz, CDCl3): δ 8.31 (d, J = 7.6 Hz, 2H), 7.62−7.58 (m, 1H),
7.52−7.48 (m, 2H), 7.44−7.42 (m, 2H), 7.32−7.31 (m, 3H),
7.22−7.20 (m, 2H), 7.09−7.08 (m, 2H), 5.48 (s, 2H); 13C NMR (100
MHz, CDCl3): δ 186.1, 143.8, 140.6, 136.8, 136.3, 134.3, 133.0,
131.1, 130.6, 128.9, 128.8, 128.5, 128.1, 127.4, 124.6, 52.0.
(1-Benzyl-5-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)
1
methanone, 3f. White solid, m.p. 137–139 °C. H NMR (400 MHz,
CDCl3): δ 8.32 (d, J = 8.0 Hz, 2H), 7.62−7.58 (m, 3H), 7.52−7.48
(m, 2H), 7.32−7.31 (m, 3H), 7.15−7.13 (m, 2H), 7.09−7.08 (m, 2H),
5.48 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 186.0, 143.8, 140.6,
136.8, 134.3, 133.0, 131.8, 131.2, 130.6, 128.8, 128.5, 128.1, 127.4,
125.2, 124.6, 52.0. HRMS (ESI) ([M+H]+) Calcd. for C22H17BrN3O:
418.0555, Found: 418.0552.
Typical procedure for the one-pot synthesis of trisubstituted
triazoles
Under air atmosphere, to a solution of benzaldehyde (32 mg, 0.30
mmol) in H2O/1,4ꢀdioxane (5:1, 2.0 mL) were added K2CO3 (83 mg,
0.60 mmol) and acetophenone (36 mg, 0.30 mmol), then the reaction
mixture was stirred at room temperature for 14 h. Subsequently,
benzylazide (80 mg, 0.60 mmol) and K2CO3 (83 mg, 0.60 mmol)
4-(4-Benzoyl-1-benzyl-1H-1,2,3-triazol-5-yl)benzonitrile,
Yellow solid, m.p. 165–177 °C. 1H NMR (400 MHz, CDCl3): δ 8.32
3g.12
were added to the above system, and stirred at 80 °C for 11 h. After (d, J = 7.6 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.64−7.60 (m, 1H),
reaction completion, the mixture was then extracted with EtOAc (15
mL x 3). The organic layers were dried with anhydrous MgSO4,
filtered and concentrated under reduced pressure, and the residue
was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 5:1 to 7:1, V/V) to give the desired product.
7.53−7.49 (m, 2H), 7.37−7.27 (m, 5H), 7.03−7.02 (m, 2H), 5.49 (s,
2H); 13C NMR (100 MHz, CDCl3): δ 185.8, 144.2, 139.8, 136.4,
133.9, 133.3, 132.1, 131.2, 130.6, 130.5, 128.9, 128.7, 128.2, 127.3,
117.8, 113.8, 52.3.
(1-Benzyl-5-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)
methanone, 3h.12 Yellow solid, m.p. 159–162 °C. 1H NMR (400
MHz, CDCl3): δ 8.34 (d, J = 7.6 Hz, 2H), 8.28 (d, J = 8.8 Hz, 2H),
7.63−7.60 (m, 1H), 7.52−7.49 (m, 2H), 7.44−7.42 (m, 2H),
7.30−7.27 (m, 3H), 7.04−7.03 (m, 2H), 5.51 (s, 2H); 13C NMR (100
MHz, CDCl3): δ 185.7, 148.5, 144.3, 139.6, 136.4, 133.9, 133.3,
133.1, 130.9, 130.6, 128.9, 128.7, 128.2, 127.3, 123.5, 52.4.
(1-Benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)methanone,
3a.5j Colorless liquid. 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 7.6
Hz, 2H), 7.60−7.57 (m, 1H), 7.50−7.44 (m, 5H), 7.31−7.27 (m, 5H),
7.09−7.07 (m, 2H), 5.49 (s, 2H); 13C NMR (100 MHz, CDCl3): δ
186.2, 143.7, 141.7, 137.0, 134.5, 132.8, 130.5, 129.9, 129.6, 128.7,
128.5, 128.3, 128.0, 127.5, 126.2, 51.9.
(1-Benzyl-5-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)(phenyl)
methanone, 3i. Yellow liquid. H NMR (400 MHz, CDCl3): δ 8.28
(d, J = 7.6 Hz, 2H), 7.57−7.53 (m, 1H), 7.47−7.43 (m, 3H),
7.26−7.24 (m, 3H), 7.12−7.10 (m, 1H), 7.05−7.00 (m, 3H),
(1-Benzyl-5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)(phenyl)
methanone, 3b.5j Yellow liquid. 1H NMR (400 MHz, CDCl3): δ
8.29 (d, J = 7.6 Hz, 2H), 7.60−7.56 (m, 1H), 7.50−7.46 (m, 2H),
1
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6.98−6.94 (m, 1H), 5.43 (s, 2H), 3.60 (s, 3H); 13C NMR (100 MHz, MHz, CDCl3): δ 8.29 (d, J = 7.6 Hz, 2H), 7.60–7.56 (m, 1H), 7.51–
CDCl3): δ 186.3, 156.6, 144.3, 138.5, 137.1, 134.5, 132.6, 131.6, 7.45 (m, 5H), 7.28–7.25 (m, 4H), 7.01 (d, J = 8.4 Hz, 2H), 5.44 (s,
131.3, 130.4, 128.4, 128.0, 127.9, 127.7, 120.6, 115.3, 111.0, 55.2, 2H); 13C NMR (100 MHz, CDCl3): δ 186.1, 143.7, 141.6, 136.9,
52.1. HRMS (ESI) ([M+H]+) Calcd. for C23H20N3O2: 370.1556, 134.4, 132.9, 130.5, 130.0, 129.6, 129.0, 128.9, 128.6, 128.1, 126.1,
Found: 370.1552.
51.2. HRMS (ESI) ([M+H]+) Calcd. for C22H17ClN3O: 374.1060,
Found: 374.1054.
(1-Benzyl-5-(m-tolyl)-1H-1,2,3-triazol-4-yl)(phenyl)methanone,
3j. Yellow solid, m.p. 93–96 °C. 1H NMR (400 MHz, CDCl3): δ (1-(4-Fluorobenzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)
8.31 (d, J = 7.6 Hz, 2H), 7.60–7.57 (m, 1H), 7.51−7.47 (m, 2H), methanone, 3q. Yellow solid, m.p. 287–288 °C. 1H NMR (400
7.37−7.31 (m, 5H), 7.10 (br, 3H), 7.02 (s, 1H), 5.47 (s, 2H), 2.35 (s, MHz, CDCl3): δ 8.29 (d, J = 7.6 Hz, 2H), 7.60–7.56 (m, 1H), 7.53–
3H); 13C NMR (100 MHz, CDCl3): δ 186.3, 143.6, 141.9, 138.3, 7.45 (m, 5H), 7.28–7.26 (m, 2H), 7.07–7.03 (m, 2H), 6.99–6.95 (m,
137.0, 134.7, 132.9, 130.7, 130.5, 130.2, 128.7, 128.4, 128.3, 128.1, 2H), 5.45 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 186.1, 162.5 (d,
127.6, 126.7, 126.0, 51.9, 21.2. HRMS (ESI) ([M+H]+) Calcd. for JCF = 248.1 Hz), 143.7, 141.5, 136.9, 132.9, 130.5, 130.3 (d, JCF
=
=
C23H20N3O: 354.1606, Found: 354.1602.
3.3 Hz), 129.9, 129.6, 129.5, 128.6, 128.1, 126.2, 115.7 (d, JCF
21.7 Hz), 51.2. HRMS (ESI) ([M+H]+) Calcd. for C22H17FN3O:
358.1356, Found: 358.1350.
(1-Benzyl-5-(2,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)
methanone, 3k. Yellow solid, m.p. 161–163 °C. 1H NMR (400
MHz, CDCl3): δ 8.37 (d, J = 8.0 Hz, 2H), 7.61–7.58 (m, 1H), 7.52– (1-(4-Nitrobenzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)
7.47 (m, 3H), 7.29–7.25 (m, 4H), 7.02–6.99 (m, 3H), 5.60 (d, J = methanone, 3r. Yellow solid, m.p. 234–236 °C. 1H NMR (400
14.8 Hz, 1H), 5.30 (d, J = 14.8 Hz, 1H); 13C NMR (100 MHz, MHz, CDCl3): δ 8.27 (d, J = 8.0 Hz, 2H), 8.15 (d, J = 8.4 Hz, 2H),
CDCl3): δ 185.6, 144.9, 137.8, 136.9, 136.5, 134.7, 133.6, 133.1, 7.61–7.57 (m, 1H), 7.53–7.44 (m, 5H), 7.26–7.22 (m, 4H), 5.58 (s,
132.2, 130.5, 129.7, 128.7, 128.6, 128.2, 127.8, 127.3, 124.7, 52.6. 2H); 13C NMR (100 MHz, CDCl3): δ 186.0, 147.8, 143.8, 141.8,
HRMS (ESI) ([M+H]+) Calcd. for C22H16Cl2N3O: 408.0670, Found: 141.3, 136.7, 133.1, 130.5, 130.2, 129.4, 128.8, 128.4, 128.1, 125.7,
408.0665.
123.9, 51.0. HRMS (ESI) ([M+H]+) Calcd. for C22H17N4O3:
385.1301, Found: 385.1296.
(1-Benzyl-5-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)(phenyl)
methanone, 3l. Yellow liquid. 1H NMR (400 MHz, CDCl3): δ 8.78– (1-(3-Methylbenzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)
8.77 (m, 1H), 8.24 (d, J = 8.0 Hz, 2H), 7.74–7.70 (m, 1H), 7.62–7.57 methanone, 3s. Yellow liquid. H NMR (400 MHz, CDCl3): δ 8.32
1
(m, 2H), 7.50–7.46 (m, 2H), 7.38–7.35 (m, 1H), 7.21–7.20 (m, 3H), (d, J = 7.6 Hz, 2H), 7.60–7.57 (m, 1H), 7.51–7.44 (m, 5H), 7.29 (d, J
7.05–7.04 (m, 2H), 5.88 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 7.6 Hz, 2H), 7.20–7.16 (m, 1H), 7.12–7.10 (m, 1H), 6.90–6.85 (m,
186.8, 149.3, 146.2, 143.7, 139.1, 136.9, 136.4, 134.6, 133.0, 130.6, 2H), 5.45 (s, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
128.5, 128.1, 128.1, 127.8, 126.9, 124.1, 52.6. HRMS (ESI) 186.2, 143.6, 141.7, 138.5, 137.0, 134.4, 132.9, 130.6, 129.9, 129.7,
([M+H]+) Calcd. for C21H17N4O: 341.1402, Found: 341.1400.
129.1, 128.6, 128.5, 128.3, 128.1, 126.3, 124.6, 51.9, 21.2. HRMS
(ESI) ([M+H]+) Calcd. for C23H20N3O: 354.1606, Found: 354.1603.
1-(1-Benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)ethanone,
Yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.50–7.42 (m, 3H), (1-(3-Chlorobenzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)
3m.5g
1
7.28ꢀ7.27 (m, 3H), 7.22ꢀ7.20 (m, 2H), 7.04ꢀ7.03 (m, 2H), 5.43 (s, methanone, 3t. Yellow solid, m.p. 99–101 °C. H NMR (400 MHz,
2H), 2.69 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.6, 143.7, CDCl3): δ 8.30 (d, J = 7.6 Hz, 2H), 7.61–7.57 (m, 1H), 7.52ꢀ7.46 (m,
139.4, 134.5, 129.9, 129.5, 128.7, 128.5, 128.3, 127.4, 125.9, 51.8, 5H), 7.29–7.21 (m, 5H), 7.05 (s, 1H), 6.96–6.94 (m, 1H), 5.45 (s,
27.8.
2H); 13C NMR (100 MHz, CDCl3): δ 186.1, 143.7, 141.7, 136.9,
136.3, 134.6, 132.9, 130.5, 130.1, 130.0, 129.5, 128.7, 128.6, 128.1,
127.8, 126.0, 125.7, 51.2. HRMS (ESI) ([M+H]+) Calcd. for
C22H17ClN3O: 374.1060, Found: 374.1052.
(1-(4-methoxybenzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)
methanone, 3n.12 White solid, m.p. 114–117 °C. 1H NMR (400
MHz, CDCl3): δ 8.29 (d, J = 7.6 Hz, 2H), 7.59–7.56 (m, 1H), 7.51–
7.46 (m, 5H), 7.30–7.28 (m, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.81 (d, J (1-(2-Methylbenzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)
= 8.4 Hz, 2H), 5.42 (s, 2H) 3.78 (s, 3H); 13C NMR (100 MHz, methanone, 3u. White solid, m.p. 270–272 °C. 1H NMR (400 MHz,
CDCl3): δ 186.2, 159.5, 143.7, 141.4, 137.0, 132.8, 130.5, 129.8, CDCl3): δ 8.32 (d, J = 7.6 Hz, 2H), 7.61–7.57 (m, 1H), 7.51–7.42
129.7, 129.1, 128.5, 128.0, 126.5, 126.4, 114.0, 55.1, 51.4.
(m, 5H), 7.28–7.27 (m, 2H), 7.20–7.18 (m, 1H), 7.15–7.08 (m, 2H),
6.78–6.76 (m, 1H), 5.49 (s, 2H), 2.17 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 186.2, 143.6, 141.8, 137.0, 135.5, 132.9, 132.8, 130.6,
130.4, 129.8, 129.5, 128.5, 128.3, 128.1, 127.7, 126.3, 126.3, 49.6,
18.9. HRMS (ESI) ([M+H]+) Calcd. for C23H20N3O: 354.1606,
Found: 354.1601.
(1-(4-Methylbenzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)
methanone, 3o. White solid, m.p. 123–124 °C. 1H NMR (400 MHz,
CDCl3): δ 8.30 (d, J = 7.6 Hz, 2H), 7.60–7.57 (m, 1H), 7.50ꢀ7.45 (m,
5H), 7.31–7.27 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0
Hz, 2H), 5.45(s, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
186.3, 143.6, 141.6, 138.2, 137.0, 132.9, 131.5, 130.6, 129.9, 129.7, (1-(2-Chlorobenzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)
129.4, 128.5, 128.1, 127.5, 126.3, 51.7, 21.0. HRMS (ESI) ([M+H]+) methanone, 3v. Yellow solid, m.p. 142–146 °C. 1H NMR (400
Calcd. for C23H20N3O: 354.1606, Found: 354.1602.
MHz, CDCl3): δ 8.32 (d, J = 7.6 Hz, 2H), 7.61–7.58 (m, 1H), 7.52–
7.42 (m, 5H), 7.37–7.35 (m, 1H), 7.30–7.26 (m, 2H), 7.24–7.21 (m,
2H), 6.95–6.93 (m, 1H), 5.62 (s, 2H); 13C NMR (100 MHz, CDCl3):
(1-(4-Chlorobenzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)(phenyl)
methanone, 3p. Yellow solid, m.p. 222–225 °C. 1H NMR (400
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δ 186.2, 143.5, 142.1, 136.9, 132.9, 132.5, 130.6, 130.0, 129.5,
129.5, 129.4, 128.7, 128.6, 128.1, 127.2, 126.3, 125.9, 49.2. HRMS
(ESI) ([M+H]+) Calcd. for
374.1050.
C22H17ClN3O: 374.1060, Found:
2-((4-Benzoyl-5-phenyl-1H-1,2,3-triazol-1-yl)methyl)
benzonitrile, 3w. Yellow solid, m.p. 209–212 °C. 1H NMR (400
MHz, CDCl3): δ 8.29 (d, J = 7.6 Hz, 2H), 7.62–7.54 (m, 3H), 7.50–
7.41 (m, 6H), 7.28–7.26 (m, 2H), 7.15–7.13 (m, 1H), 5.72 (s, 2H);
13C NMR (100 MHz, CDCl3): δ 186.0, 143.7, 142.1, 137.9, 136.8,
133.3, 133.0, 132.8, 130.5, 130.2, 129.3, 128.8, 128.8, 128.2, 128.1,
125.5, 116.2, 111.3, 49.6. HRMS (ESI) ([M+H]+) Calcd. for
C23H17N4O: 365.1402, Found: 365.1395.
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1-(1,5-diphenyl-1H-1,2,3-triazol-4-yl)ethanone, 3x.6i Yellow solid,
m.p. 103–106 °C. 1H NMR (400 MHz, CDCl3): δ 7.41–7.34 (m,
6H), 7.30–7.26 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 192.8,
143.5, 139.0, 135.8, 130.2, 129.9, 129.4, 129.3, 128.3, 125.7, 125.2,
28.3.
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(1-(Naphthalen-1-ylmethyl)-5-phenyl-1H-1,2,3-triazol-4-yl)
1
(phenyl)methanone, 3y. Yellow solid, m.p. 213–216 °C. H NMR
(400 MHz, CDCl3): δ 8.33 (d, J = 7.6 Hz, 2H), 8.00–7.98 (m, 1H),
7.89–7.87 (m, 1H), 7.83–7.81 (m, 1H), 7.61–7.58 (m, 1H), 7.53–
7.48 (m, 6H), 7.43–7.41 (m, 2H), 7.31–7.27 (m, 2H), 6.84–6.83 (m,
1H), 5.99 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 186.2, 143.6,
142.1, 137.0, 133.5, 132.9, 130.6, 130.4, 130.0, 129.9, 129.5, 129.2,
128.8, 128.6, 128.1, 126.8, 126.4, 126.3, 126.0, 125.0, 122.6, 50.0.
HRMS (ESI) ([M+H]+) Calcd. for C26H20N3O: 390.1606, Found:
390.1604.
5
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(1-(4-(Azidomethyl)benzyl)-5-phenyl-1H-1,2,3-triazol-4-yl)
1
(phenyl)methanone, 3z. Yellow solid, m.p. 158–160 °C. H NMR
(400 MHz, CDCl3): δ 8.29 (d, J = 7.6 Hz, 2H), 7.60–7.56 (m, 1H),
7.50–7.43 (m, 5H), 7.27–7.23 (m, 4H), 7.08 (d, J = 8.0 Hz, 2H), 5.48
(s, 2H), 4.31 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 186.2, 143.7,
141.7, 136.9, 135.6, 134.6, 132.9, 130.5, 130.0, 129.6, 128.6, 128.5,
128.1, 128.0, 126.1, 54.0, 51.5. HRMS (ESI) ([M+H]+) Calcd. for
C23H19N6O: 395.1620, Found: 395.1616.
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(1-((4'-(Azidomethyl)-[1,1'-biphenyl]-4-yl)methyl)-5-phenyl-1H-
1,2,3-triazol-4-yl)(phenyl)methanone, 3aa. Yellow solid, m.p. 99–
101 °C. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 7.6 Hz, 2H),
7.59–7.57 (m, 3H), 7.54–7.48 (m, 7H), 7.39 (d, J = 8.0 Hz, 2H), 7.33
(d, J = 7.2 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.53 (s, 2H), 4.38 (s,
2H); 13C NMR (100 MHz, CDCl3): δ 186.2, 143.7, 141.7, 140.5,
140.1, 137.0, 134.6, 133.7, 132.9, 130.6, 130.0, 129.7, 128.6, 128.6,
128.1, 127.4, 127.3, 126.2, 54.3, 51.6. HRMS (ESI) ([M+H]+) Calcd.
for C29H23N6O: 471.1933, Found: 471.1929.
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