Copper-Catalyzed Cross-Dehydrogenative N2-Coupling of NH-1,2,3-Triazoles with N,N -Dialkylamides: N-Amidoalkylation of NH-1,2,3-Triazoles

Article abstract of DOI:10.1021/acs.joc.7b00752

An efficient copper-catalyzed C-N bond formation by N-H/C-H cross-dehydrogenative coupling (CDC) between NH-1,2,3-triazoles and N,N-dialkylamides has been developed. The method provided N-amidoalkylated 1,2,3-triazoles with moderate to high yields, and th

Full text of DOI:10.1021/acs.joc.7b00752

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Article
Copper-Catalyzed Cross-Dehydrogenative N2-Coupling of NH-1,2,3-
Triazoles with N,N -Dialkylamides: N-Amidoalkylation of NH-1,2,3-Triazoles
Xiaocong Deng, Xue Lei, Gang Nie, Lihui Jia, Yuanxiang Li, and Yunfeng Chen
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 May 2017
Downloaded from http://pubs.acs.org on May 31, 2017
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Copper-Catalyzed Cross-Dehydrogenative N2-Coupling of
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NH-1,2,3-Triazoles
with
N,N
-Dialkylamides:
N-Amidoalkylation of NH-1,2,3-Triazoles
Xiaocong Deng,† Xue Lei,† Gang Nie,† Lihui Jia,† Yuanxiang Li,*,‡ and Yunfeng Chen*,†
†School of Chemistry and Environmental Engineering, Wuhan Institute of Technology,
Wuhan 430073, P. R. China.
‡College of Chemistry and Materials Engineering, Huaihua University, Huaihua 418008, P.
R. China.
R1
R1
N
N
2
N
N
O
R
O
NH
Cu(OAc)2
N
+
N
R'
N
R2
R
R2
R'
K2S2O8, Na2CO3
34 examples
up to 94% yield
ABSTRACT: An efficient copper-catalyzed C-N bond formation by N-H/C-H
cross-dehydrogenative coupling (CDC) between NH-1,2,3-triazoles and N,N-dialkylamides
has been developed. The method provided N-amidoalkylated 1,2,3-triazoles with moderate to
high yields, and the reactions showed high N2-selectivities when 4,5-disubstituted
NH-1,2,3-triazoles served as substrates.
INTRODUCTION
Cross-dehydrogenative coupling (CDC) reactions have emerged as powerful tools for organic
synthesis because of their high atom- and step-economical characteristics,1 which have also
been widely applied in the functionalization of heterocyclic compounds in recent years.2
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N-alkylamines and alkylamides, are good reaction partners for the CDC reactions. For
example, DMF (N,N-dimethylformamide), which is widely recognized as a common solvent,
can also be employed as a cheap, readily available reaction partner in CDC reactions.3
Moreover, the CDC reaction of DMF is a straightforward method to introduce an amide
group into a molecule. Indeed, some heterocyclic molecules with amide group have been
found to show a range of interesting biological activities.4
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1,2,3-triazoles have become important building blocks in organic chemistry in the past few
years. They have received considerable attention and shown many applications in medicinal
chemistry,5 material chemistry,6 synthetic organic chemistry7 and other fields8. Most
1,2,3-triazoles are obtained by reactions of organic azides with other partners, such as click
reactions of organic azides with alkynes9, multicomponent reactions of organic azides with
activated carbonyl compounds10, and condensation reactions of organic azides with activated
alkenes11. More recently, new azide-free strategies have also been developed.12 These
methods usually produce the N1 or N1'-substituted 1,2,3-triazoles, but are not suitable for
producing N2-substituted 1,2,3-triazole. N2-substituted 1,2,3-triazoles were obtained mostly
via post-N-functionalization of NH-1,2,3-triazoles with different reaction partners, including
alkyl halides, alcohols, alkynes and alkenes.13 Still, advances for the synthesis of diverse
N2-substituted 1,2,3-triazole were desirable.
In continuation of our research for synthesis of new 1,2,3-triazole related heterocyclic
compounds,14 herein, we report a copper-catalyzed N-H/C-H cross-dehydrogenative
coupling of NH-1,2,3-triazoles with different amides. By tuning the substituents, the
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reactions gave N2-coupling products with high yield.
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RESULTS AND DISCUSSION
4-Methyl-5-phenyl-2H-1,2,3-triazole (1a) and DMF (N,N-dimethylformamide) were chosen
as model substrates for the initial condition screening, the results are shown in Table 1. We
proposed that methyl and phenyl groups could block the N1 and N1' coupling sites, which
might lead to high N2-coupling selectivity.
Table 1. Optimization of Reaction Conditionsa
N
N
O
N
H
O
NH
+
N
N
N
H
N
2a
3a
conversionb
1a
entry catalyst
oxidant
additive
yield (%)c
1
2
3
4
CuCl
CuCl2
CuCl
CuBr
air
air
TBHP
TBHP
none
none
none
none
0
0
60
69
0
0
54
61
5
CuCl2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
H2O2
none
65
75
64
48
55
85
30
35
100
93
78
85
<5
<5
59
6
CuBr2
none
68
7
CuO
none
59
8
Cu(NO3)2
CuSO4
none
43
9
none
51
10
11
12
13
14
15
16
17
18
Cu(OAc)2
FeCl2
none
76
none
23
FeCl3
none
32
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Na2CO3
K2CO3
NaOAc
DBU
88
82
69
75
Na2CO3
Na2CO3
trace
trace
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22d
23
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
-
K2S2O8
BPO
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
100
<5
92
trace
trace
53
DDQ
<5
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K2S2O8
K2S2O8
60
100
90
aReaction conditions: 1a (0.3 mmol, 47.7 mg), 2a (3mL as solvent), and oxidant (0.6 mmol,
2.0 equivalent, 162.2 mg), Na2CO3 (0.33 mmol, 1.1 equivalent, 35.0 mg), catalyst (0.06
mmol, 0.2 equivalent, 12.0 mg), 110 oC, 8 h; bBased on 1a; cIsolated yields; d 80 oC.
First, the reaction was performed in the presence of 1a (0.3 mmol), CuCl (0.06 mmol, 0.2
equiv) in 3 mL DMF as solvent with air as the oxidant at 110 °C. After 5 hours there was no
reaction at all. When CuCl was changed to CuCl2, it gave the same result (Table 1, entries 1
and 2). However, when TBHP (tert-butyl hydroperoxide), a common oxidant, was used
instead of air, after 5 hours we found that the desired 3a was formed in 54% yield (entry 3).
Inspired by this, other common copper salts were examined, which showed that Cu(OAc)2
gave the best result (entries 4-10). Furthermore, other inexpensive iron salts were tested,
including FeCl2, FeCl3 (entries 11 and 12), however, their catalytic efficiency was inferior to
Cu(OAc)2. Therefore, Cu(OAc)2 was chosen as the catalyst for all further reactions.
Interestingly, it was found that the addition of a base could promote the reaction, and Na2CO3
gave a better result (entries 13-16). In addition, other different oxidants were also
investigated, including DTBP (di-tert-butyl peroxide), H2O2, BPO (benzoyl peroxide) and DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (entries 17-21), they failed to promote the
reaction; however, when K2S2O8 was chosen as the oxidant, the yield of 3a rose to 92%,
which also revealed high N2 selectivity.15 In addition, a relatively lower conversion and yield
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o
was detected with a reaction temperature of 80 C (entry 22). If the reaction run without
9
copper catalyst (entry 23),16 a satisfactory result was also obtained, the isolated yield of 3a
was up to 90%. In order to establish the best reaction condition, comparisons for different
methods have also been made (Scheme 1). When DMF was served as reactant, the yield of
the TBHP/TBAI protocol was only 36%, much lower than Cu or Cu-free protocols. When
DMA or NMP was served as substrate for the coupling reaction under copper-free reaction
condition, the yields were inferior to Cu-catalyzed reactions, while TBHP/TBAI was used
instead of Cu or Cu-free reaction conditions, the yields of 3a and 3x were up to 76% and
88%, which were similar as the Cu-catalyzed protocol. However, the colors of the Cu-free
reaction system or TBHP/TBAI protocol were darker than Cu-catalyzed reaction system
generally. We suspected that the polymerization of the imine cation intermediates was easier
under copper-free conditions. Thus, Cu(OAc)2/K2S2O8/Na2CO3 at 110 oC was chosen as the
optimal reaction condition.
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Scheme 1. Comparisons of the Reaction Conditions
N
N
O
N
N
N
NH
N
methods
N
O
R
+
R
3a
1a
R = H, Me
method 1: 92% (R = H); 80% (R = Me);
method 2: 90% (R = H); 60% (R = Me);
method 3: 36% (R = H); 76% (R = Me).
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Br
Br
N
N
N
methods
NH
N
O
O
N
+
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N
N
1x
3x
method 1: 90%; method 2: 64%; method 3: 88%.
Reaction condition: 1a and 1x (200 mg, 1 equivalent), solvent (10 mL); isolated yields.
method 1: Cu(OAc)2 (0.2 equivalent), K2S2O8 (2 equivalent), Na2CO3 (1.1 equivalent),
110oC; method 2: K2S2O8 (2 equivalent), Na2CO3 (1.1 equivalent), 110oC; method 3: TBHP
(3 equivalent), TBAI (0.1 equivalent), 110oC.
Then we set out to study the scope and limitation of this conversion with different
NH-1,2,3-triazoles and amides (Scheme 2). In general, the reactions all performed well, the
corresponding N2-substituted products were less polar than other isomers. Firstly, 4-Me (or
Br)-5-Ar-disubstituted NH-1,2,3-triazoles were checked due to the potentially high N2
regioselectivities. In fact, the Me group and Br atom could indeed block the N1 reaction sites.
In all cases, the N2-substituted product was formed predominantly. The structures of 3q was
identified by X-ray single crystal analysis.17
Then, other 4,5-disubstituted NH-1,2,3-triazoles, such as 4,5-diaryl 1,2,3-triazoles (3aa-3ac)
and 4-benzoyl-5-phenyl-1,2,3-triazole(3y, 3z), were suitable for this reaction and showed
high N2 regioselectivities. At the same time, both electron-donating functional groups, such
as methoxy or methyl substituents, and electron-withdrawing groups, such as
halogenated moieties in the aryl ring, were compatible with this transformation. The
yield of N2-coupling product was up to 94%. However, when the 1H-1,2,3-triazole and
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4-ethyl-5-methyl-1,2,3-triazole were tested, the reactions gave complex mixtures and
the products were hard to be identified.
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Scheme 2. Substrate Scope for the Synthesis of N2-Amidoalkylated 1,2,3-Triazolesa
R1
R1
N
N
N
O
N
R
O
NH
+
N
R'
N
N
R
R2
R'
R2
1
3
2
3a: R' = H; R = H, 92%
3b
3c: R' = CH3; R = H, 89%
O
R
: R' = H; R = CH3, 80%
O
R
H3C
N
N
H3C
N
N
N
N
3d: R' = CH3; R = CH3, 78%
N
N
3e
: R' = OMe; R = H, 88%
3f: R' = OMe; R = CH3, 72%
3g: R' = Cl; R = H, 91%
R'
: R' = Cl; R = H, 94%
3h
: R' = Cl; R = CH3, 75%
3i
R'
3j: R' = Cl; R = CH3, 87%
3k: R' = Br; R = CH3, 89%
O
R
O
R
H3C
Br
N
N
N
N
N
N
N
O
N
Br
N
N
N
R
Cl
N
R'
Cl
3n
3o
: R' = H; R = H, 91%
: R' = Cl; R = H, 92%
3l
: R = H, 89%
R'
: R' = H; R = H, 86%
3m
: R = CH3, 80%
Cl
3p: R' = Cl; R = CH3, 82%
3s
3t: R' = H; R = CH3, 81%
3q
: R' = Br; R = H, 91%
H3C
3r
: R' = Br; R = CH3, 84%
N
3u
: R' = Cl; R = CH3, 87%
N
Br
N
Ph
N
N
O
N
O
N
N
R
R'
N
N
O
3v
: R' = Br; R = H, 82%
3w: R' = Br; R = F, 92%
N
N
3x
: 90%
O
3y
: 89%
Ph
N
N
N
O
N
N
N
N
N
O
H
N
O
N
H
O
N
N
R
3z
: 85%
3aa: R = H, 89%
3ab: R = Br, 92%
3ac: 87%
aReaction conditions: 1 (0.3 mmol), 2 (3 mL as solvent), Cu(OAc)2 (0.06 mmol), K2S2O8
(0.6 mmol) and Na2CO3 (0.33 mmol), reaction temperature: 110 oC.
At the same time, commercially available amide solvents, such as DMF, DMA, were
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suitable reaction partners to couple with NH-1,2,3-triazoles, although the reactions with
DMA need more time to give the full conversion. However some side reactions or
decomposition of the products could be happened over extended reaction time, which
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resulted in the loss of isolated yields. Furthermore,
N-methyl-2-pyrrolidinone (NMP)
was also a suitable substrate, which gave the N2-coupling products with high yield. It
should be pointed out that the reactions could be finished in 30 mins under standard
reaction conditions. However, N,N-dimethylaniline piperidine-1-carbaldehyde
N,N-diethylformamide and N,N-dimethylbenzamide cannot react in this reaction
system.
To further investigate the reaction substrate scope, we tested 4-aryl substituted
NH-1,2,3-triazoles (Table 2). The reactions also performed well. The corresponding
N2-coupling product was the major product generally. However, the regioselectivities
were not very high, other N1 products were also obtained.18 The lower
regioselectivities were similar to the results for the alkylation, arylation and
alkenylation of 4-ary-1,2,3-triazoles.13
Table 2. 4-Aryl Substituted NH-1,2,3-Triazoles as Substratea
R1
R
N
N
2
N
R1
O
1
N
N
N
R
O
R1
O
NH
N
N
+
N
+
N
R
N
1
2
4
5
entry
1
R1
H-
R
4 yieldsb (%)
64 (4a)
5 yieldsb (%)
18 (5a)
H-
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H-
CH3-
CH3-
CH3-
CH3-
50 (4b)
59 (4c)
47 (4d)
57 (4e)
25 (5b)
21 (5c)
27 (5d)
20 (5e)
4-CH3-
4-OMe-
2-Br-
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aReaction conditions: 1 (0.3 mmol), 2 (3mL as solvent), Cu(OAc)2 (0.06 mmol), K2S2O8 (0.6
mmol) and Na2CO3 (0.33 mmol), 110 oC. bIsolated yields.
To identify the structures of
experiment19 was done in order to obtain the N1-coupling regioisomer (3q
The structure was also confirmed by X-ray single crystal analysis.17 Because the crystal
N-amidoalkylated 1,2,3-triazoles, a gram-scale
'
) of 3q.
structures of two regioisomers 3q and 3q
methods for the determination of the N2 regioisomers for other reactions.
According to the 13C NMR spectra of 3q and 3q
, there were significant differences between
the CH2 groups (which linked to 1,2,3-triazole) of the N1(3q ) and N2 (3q) isomers. The
' were obtained, it was beneficial to figure out the
'
'
chemical shift of CH2 group for N2 isomer was 67.8 and 61.5 ppm (for two conformers),
which located in lower field than N1 isomer’s (62.9 and 56.1 ppm, for two conformers).
Also, the corresponding 13C NMR spectra of two regioisomeric products for
4-aryl-substituted 1,2,3-triaoles gave the same information, such as 4e and its N1 isomer
(5e). The chemical shift of CH2 group for 4e was located in 67.8 and 63.6 ppm. By contrast,
the NMR spectra for 5e showed one conformer, and the 13C NMR chemical shift for CH2
group was 60.1 ppm, which located in higher field. For other DMF or DMA coupling
products, the corresponding N2 isomers gave higher 13C NMR chemical shifts for CH2
group, which located in about 67 and 62 ppm (two conformers), such as 3d and 3s, while N1
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isomer gave lower chemical shifts. Moreover, some N1 isomers only gave one conformer
signal (Figure 1). Indeed, the N1 and N2 isomers of other triazoles and benzotriaoles showed
the similar results.13, 20 As for the coupling reactions with NMP, it was found that the
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reactions gave only N2-coupling products because of a big steric hindrance.
R1
N1
3
R1
3N
R1
R1
N
CH2
N
N
R
2
O
R
N
N
N
C
1
2
O
H2
N2- isomer
N1- isomer
3q
3q
'
4e and its N1 isomer
3d
3s
Figure 1. Analysis of 13C NMR Spectra
In order to selectively synthesize 2,4-disubstituted 1,2,3-triazoles, a stepwise reaction
strategy was developed. As shown in Scheme 2, the 4-phenyltriazole was first reacted
with NBS (N ,
-bromosuccinimide) to introduce a Br atom on the triazole ring14b,21
then reacted with DMF or DMA. The corresponding N2-amidoalkylated
bromotriazoles were further reduced under catalytic hydrogenation condition (H2,
Pd/C) to give the 2-amidoalkylated 4-phenyl-1,2,3-triazoles in higher overall yields,
which provide a highly selective synthesis of 2-amidoalkylated 4-aryl-1,2,3-triazoles
(Scheme 3).
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1. NBS, EtOAc, r. t
N
N
N
N
NH
2. DMF/DMA, Cu(OAc)2, K2S2O8, Na2CO3, 110 oC
N
R
O
N
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3. H2, Pd/C, MeOH, rt
4a
: R= H, 84%
4b
: R = CH3, 78%
Scheme 3. An Alternative Synthesis of N2-Amidoalkylated 4-Aryl-1,2,3-Triazoles
Based on experimental results and existing literature2, 22, a postulated mechanism for this
transformation has been put forward (Scheme 3). The initiation step is proposed to be a
single electron transfer between Cu(II) and DMF to produce radical cation A. Next, the
successive hydrogen atom abstraction from the radical cation A in the aid of Cu(I)/ K2S2O8
forms the iminium ion B, which is selective attacked by N2 site of triazole 1a to form the
intermediate C. Then lose a proton to form the product 3a. The addition of a base is to
neutralize the formed acid and further improve the reaction conversion (Scheme 4).
O
H
O
H
O
H
Cu(II)
Cu(I)/K2S2O8
Cu(II)/KHSO4
Cu(I)
N
N
N
B
A
H3C
NH
N
N
H
1a
H3C
H3C
N
N
N
N
N
H
O
-H+
H
N
N
N
O
C
3a
Scheme 4. A Plausible Mechanism for Oxidative N2-Coupling
CONCLUSION
In conclusion, we report here a copper-catalyzed oxidative cross-dehydrogenative C-H/N-H
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coupling reaction between N,N-dialkylamides and NH-1,2,3-triazoles. This method can give
N-amidoalkylated 1,2,3-triazoles with high efficiency. By tuning the substituents on the
NH-1,2,3-triazoles, the N2-amidoalkylated 1,2,3-triazoles can be obtained in high selectivity
and yield.
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EXPERIMENTAL SECTION
General Information. All reagents were purchased from commercial sources and used
1
without further purification. H NMR spectra were determined on 400 and 600 MHz
spectrometer as solutions in CDCl3. Chemical shifts are expressed in parts per million (δ),
and the signals were reported as s (singlet), d (doublet), t (triplet), m (multiplet), dd (double
13
doublet), and coupling constants (J) were given in Hz. C NMR spectra were recorded at
100 and 150 MHz in CDCl3 solution. Chemical shifts as internal standard are referenced to
1
CDCl3 (δ = 7.26 ppm for H and δ = 77.0 ppm for 13C NMR) as internal standard.
High-resolution mass spectra (HRMS) were performed with Fourier-transform mass
spectrometer by electrospray ionization and time of flight mass spectrometer by
electrospray ionization. TLC was done on silica gel coated glass slides. All solvents were
dried before use. 4-phenyltriazoles and 4-Methyl-5-phenyl-2H-1,2,3-triazoles were
prepared according to literature procedure.14a
Typical Experimental Procedure: Synthesis of Br-substituted 1,2,3-triazole. To a
solution of 4-phenyltriazole (500 mg, 3.45 mmol) in EtOAc (10 mL), was added NBS
(920 mg, 5.18 mmol) at room temperature, the reaction was checked by TLC, After the
completion of the reaction, the mixture was poured into water, and extracted by ethyl
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acetate, washed with NaCl (aq), dried with anhydrous Na2SO4, then the solvent was
removed under reduced pressure to obtain a yellow solid, and the crude product was
purified by column chromatography [silica gel, PE-EtOAc (10:1 to 5:10)] to give (1n) a
white solid (90%, 694mg).
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Typical Experimental Procedure: Synthesis of N-amidoalkylated 1,2,3-triazoles. A 50
mL round-bottom flask equipped with a magnetic stir bar was charged with
4-methyl-5-phenyl-2H-1,2,3-triazole (47.7 mg, 0.3 mmol), DMF (3 mL as solvent), and
K2S2O8 (162.3 mg, 0.6 mmol), Na2CO3 (35 mg, 0.33 mmol), Cu(OAc)2 (12 mg, 0.05 mmol).
The mixture was then stirred at 110 °C in air for 0.5-6 h (TLC monitoring), then poured into
H2O (20 mL), adjusted the pH to neutral using 10% HCl, and extracted with EtOAc (3×20
mL). Next the organic phase was evaporated under vacuum, and the crude product was
purified by column chromatography [silica gel, PE-EtOAc (10:1 to 2:1)] to give (3a) a
white solid (89%, 61mg).
The procedure for the synthesis of 4a or 4b: To a solution of 4-phenyltriazole (200 mg,
1.38 mmol) in EtOAc (4 mL), was added NBS (367.8 mg, 2.07 mmol) at room temperature,
the reaction was checked by TLC. The work-up procedure was the same as the synthesis of
Br-substituted 1,2,3-triazoles, the obtained crude yellow solid can be used for the next step
without further purification. The yellow solid reacted with DMF or DMA (4 mL) to obtain
the N2-amidoalkylated 4-bromo-triazoles (mentioned above as Typical Experimental
Procedure: Synthesis of N-amidoalkylated 1,2,3-triazoles), then the N2-amidoalkylated
4-bromo-triazoles and 10% Pd/C in methanol (8 mL) was stirred under atmospheric H2 in a
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50 mL schlenk bottle for 2 hours. Then triethylamine (3 mmol) was added to the mixture.
After being stirred for 10 min, the mixture was filtered by diatomite. The filtrate was diluted
with ethyl acetate (20 mL) and washed with water (20 mL). Then the organic phase was
evaporated under vacuum, and the crude product was purified by column chromatography
[silica gel, PE-EtOAc (10:1 to 2:1)] to give product 4a (82%, 333mg) or 4b (78%, 332mg).
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4-bromo-5-phenyl-2H-1,2,3-triazole (1n) Whtie solid (90%, 694mg) m.p. 142–144 oC. H
NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.91 (s, 1H), 7.52–7.49 (m, 1H), 7.47 (d, J = 4.0
Hz, 1H), 7.46–7.42 (m, 1H), 3.52 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 129.2, 128.7,
127.4. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C8H6BrN3: 223.9818, found 223.9817.
4-bromo-5-(2-chlorophenyl)-2H-1,2,3-triazole (1o) White solid (88%, 633mg) m.p. 81–82
oC. H NMR (400 MHz, CDCl3) δ 7.54–7.52 (m, 1H), 7.50–7.47 (m, 1H), 7.45–7.41 (m,
1
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1H), 7.40–7.36 (m, 1H), 3.53 (s, 1H). C NMR (100 MHz, CDCl3) δ 133.9, 131.8, 130.9,
130.2, 127.1, 126.8, 123.2. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C8H6BrClN3:
257.9428, found 257.9427.
4-bromo-5-(2-bromophenyl)-2H-1,2,3-triazole (1q) White solid (85%, 575mg) m.p. 92–93
oC. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.4 Hz, 1H), 7.46–7.31 (m, 3H), 3.53 (d, J =
0.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 133.2, 131.8, 131.0, 127.3, 123.5. HRMS
(ESI-FTMS) m/z [M + H]+ calcd. for C8H6Br2N3: 301.89230, found 301.89246.
4-bromo-5-(4-chlorophenyl)-2H-1,2,3-triazole (1s) White solid (92%, 662mg) m.p.
1
192–193 oC. H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 2.0 Hz,
1H), 7.45 (d, J = 2.0 Hz, 1H), 3.50 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 123.0, 128.7.
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HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C8H6BrClN3: 257.9428, found 257.9426.
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4-bromo-5-(2,4-dichlorophenyl)-2H-1,2,3-triazole (1u) White solid (90%, 616mg) m.p.
1
148–152 oC. H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.0 Hz,
1H), 7.38–7.36 (m, 1H), 3.51 (d, J = 0.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 136.4,
134.8, 132.9, 130.1, 127.3. ESI-MS(m/z): 290.9 [M]+. HRMS (ESI-TOF) m/z [M + H]+
calcd. for C8H6BrCl2N3: 291.9038, found 291.9034.
N-methyl-N-((4-methyl-5-phenyl-2H-1,2,3-triazol-2-yl)methyl)formamide (3a) White solid
o
1
(92%, 132 mg) m.p. 60–62 C. H NMR (600 MHz, CDCl3) δ 8.34 (s, 0.73H), 8.01 (s,
0.25H), 7.56 (t, J = 7.8 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 5.71 (s,
0.49H), 5.53 (s, 1.59H), 2.87 (s, 0.7H), 2.80 (s, 2.16H), 2.35 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ 162.8, 162.6, 146.0, 145.5, 142.2, 141.8, 130.4, 130.3, 128.4, 128.0, 127.8, 126.9,
66.4, 60.1, 33.3, 29.1, 11.5. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C12H15N4O:
231.1240; found, 231.1235.
N-methyl-N-((4-methyl-5-phenyl-2H-1,2,3-triazol-2-yl)methyl)acetamide (3b) Light yellow
oil (80%, 123 mg). 1H NMR (600 MHz, CDCl3) δ 7.67 (t, J = 7.8 Hz, 2H), 7.42 (q, J = 7.8
Hz, 2H), 7.36–7.33 (m, 1H), 5.87 (s, 0.87H), 5.71 (s, 1.25H), 3.08 (s, 1.23H), 3.03 (s,
1.82H), 2.46 (s, 3H), 2.43 (s, 1.85H), 2.13 (s, 1.24H). 13C NMR (150 MHz, CDCl3) δ 171.2,
145.8, 145.5, 142.0, 141.7, 130.8, 130.6, 128.5, 128.1, 127.9, 127.1, 67.3, 63.1, 35.1, 33.0,
21.7, 11.7. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C13H17N4O: 245.1397; found,
245.1398.
N-methyl-N-((4-methyl-5-(p-tolyl)-2H-1,2,3-triazol-2-yl)methyl)formamide
(3c)
Light
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yellow solid (89%, 125mg) m.p. 66–68 C. H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 8.4
Hz, 0.64H), 8.11 (d, J = 9.0 Hz, 0.22H), 7.61–7.45 (m, 2H), 7.28–7.15 (m, 2H), 5.80 (d, J =
9.0 Hz, 0.48H), 5.61 (d, J = 9.0 Hz, 1.53H), 2.99–2.95 (m, 0.7H), 2.92–2.87 (m, 2.12H),
2.45–2.39 (m, 3H), 2.38–2.30 (m, 3H). 13C NMR (150 MHz, CDCl3) δ 162.9, 162.7, 146.3,
145.8, 142.2, 141.8, 138.0, 129.2, 127.5, 126.9, 66.5, 60.2, 33.4, 29.3, 21.1, 11.6. HRMS
(ESI-FTMS) m/z [M + H]+ calcd. for C13H17N4O: 245.1397; found, 245.1400.
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N-methyl-N-((4-methyl-5-(p-tolyl)-2H-1,2,3-triazol-2-yl)methyl)acetamide (3d) Colorless
1
oil (78%, 116 mg). H NMR (600 MHz, CDCl3) δ 7.61–7.52 (m, 2H), 7.25 (t, J = 8.4 Hz,
2H), 5.89 (s, 0.8H), 5.73 (s, 1.21H), 3.10 (s, 1.20H), 3.05 (s, 1.77H), 2.47 (s, 3H), 2.45 (s,
1.76H), 2.39 (d, J = 4.8 Hz, 3H), 2.16 (s, 1.14H). 13C NMR (150 MHz, CDCl3) δ 171.4,
171.3, 146.0, 145.7, 141.9, 141.7, 138.1, 137.9, 129.3, 128.1, 127.8, 127.1, 67.4, 63.2, 35.1,
33.2, 29.7, 21.8, 21.3, 11.8. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C14H19N4O:
259.1553; found, 259.1558.
N-((4-(4-methoxyphenyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide (3e)
1
Light yellow oil (88%, 120 mg). H NMR (600 MHz, CDCl3) δ 8.45 (s, 0.72H), 8.13 (s,
0.24H), 7.67–7.48 (m, 2H), 7.06–6.85 (m, 2H), 5.81 (s, 0.52H), 5.63 (s, 1.59H), 3.82 (d, J =
3.6 Hz, 3H), 2.99 (s, 0.69H), 2.92 (s, 2.10H), 2.44 (d, J = 1.2 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 163.0, 162.7, 159.5, 146.2, 145.7, 142.0, 141.7, 128.4, 123.0, 114.0, 66.6, 60.3,
55.2, 33.5, 29.4, 11.7. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C13H17N4O2: 261.1346;
found, 261.1340.
N-((4-(4-methoxyphenyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide (3f)
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Light yellow oil (72%, 104 mg). 1H NMR (600 MHz, CDCl3) δ 7.60 (t, J = 8.4 Hz, 2H),
6.96 (t, J = 7.8 Hz, 2H), 5.87 (s, 0.79H), 5.71 (s, 1.17H), 3.83 (d, J = 3.7 Hz, 3H), 3.09 (s,
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1.11H), 3.04 (s, 1.61H), 2.44 (d, J = 3.0 Hz, 4.79H), 2.15 (s, 1.2H). C NMR (150 MHz,
CDCl3) δ 171.3, 159.6, 159.4, 145.8, 145. 5, 141.6, 141.4, 128. 5, 123.5, 123.2, 114.1, 67.3,
63.1, 55.3, 35.1, 33.1, 21.8, 11.7. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C14H19N4O2:
275.1503; found, 275.1501.
N-((4-(4-chlorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide
(3g)
o
1
Light yellow solid (91%, 124mg) m.p. 74–76 C. H NMR (600 MHz, CDCl3) δ 8.45 (s,
0.73H), 8.14 (s, 0.23H), 7.60 (t, J = 7.8 Hz, 2H), 7.38 (t, J = 8.4 Hz, 2H), 5.82 (s, 0.5H),
5.65 (s, 1.5H), 3.01 (s, 0.77H), 2.91 (s, 2.23H), 2.44 (s, 3H). 13C NMR (150 MHz, CDCl3) δ
163.0, 162. 8, 145.3, 144.8, 142.4, 142.1, 134.2, 134.0, 129.2, 129.2, 129.0, 128.9, 128.8,
128.3, 66.8, 60.4, 33.6, 29. 5, 11.8. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for
C12H14ClN4O: 265.0851; found, 265.0844.
N-((4-(4-chlorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide
(3h)
1
Light yellow oil (75%, 108 mg). H NMR (600 MHz, CDCl3) δ 7.62 (t, J = 8.4 Hz, 2H),
7.43–7.36 (m, 2H), 5.87 (s, 0.93H), 5.73 (s, 1.22H), 3.11 (s, 1.27H), 3.04 (s, 1.7H), 2.46 (s,
13
3H), 2.44 (s, 1.67H), 2.15 (s, 1.32H). C NMR (150 MHz, CDCl3) δ 171.3, 144.9, 144.5,
142.0, 141.8, 134.2, 133.9, 129.4, 129.2, 128.8, 128.4, 67.5, 63.3, 35.3, 33.2, 21.8, 11.8.
HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C13H16ClN4O: 279.1007; found, 279.1012.
N-((4-(2-chlorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide
(3i)
1
Light yellow oil (94%, 129 mg). H NMR (600 MHz, CDCl3) δ 8.42 (s, 0.70H), 8.12 (s,
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0.23H), 7.44 (d, J = 7.8 Hz, 1H), 7.35–7.25 (m, 3H), 5.83 (d, J = 1.2 Hz, 0.54H), 5.66 (d, J
= 1.2 Hz, 1.59H), 2.97 (d, J = 1.2 Hz, 0.78H), 2.90 (d, J = 1.2 Hz, 2.22H), 2.22 (d, J = 1.2
Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 162.9, 162.7, 145.2, 144.7, 144.3, 143.9, 133.7,
131.6, 130.2, 130.0, 129.8, 129.7, 129.6, 129.3, 126.7, 126.6, 66.7, 60.4, 33.4, 29.4, 10.7.
HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C12H14ClN4O: 265.0851; found, 265.0844.
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N-((4-(2-chlorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide
(3j)
1
Light yellow oil (87%, 125 mg). H NMR (600 MHz, CDCl3) δ 7.50–7.44 (m, 1H),
7.38–7.29(m, 3H), 5.91 (s, 0.87H), 5.76 (s, 1.21H), 3.09 (s, 1.2H), 3.05 (s, 1.68H), 2.43 (s,
13
1.73H), 2.26 (s, 3H), 2.16 (s, 1.26H). C NMR (150 MHz, CDCl3) δ 171.4, 144.8, 144.5,
144.0, 143.7, 133.8, 131.8, 131.7, 130.1, 130.1, 130.0, 129.9, 129.8, 129.6, 126.7, 67.5, 63.3,
35.1, 33.2, 21.8, 10.8. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C13H16ClN4O: 279.1007;
found, 279.1004.
N-((4-(2-bromophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide
(3k)
White solid (89%, 121 mg) m.p. 122–124 oC. 1H NMR (400 MHz, CDCl3) δ 7.70–7.66 (m,
1H), 7.40–7.29 (m, 3H), 5.93 (s, 1H), 5.78 (s, 1.18H), 3.10 (s, 1.27H), 3.07 (s, 1.78H), 2.45
(s, 1.8H), 2.27 (s, 3H), 2.18 (s, 1.2H). 13C NMR (100 MHz, CDCl3) δ 171.4, 146.34, 143.8,
133.1, 132.2, 131.5, 130.3, 127.3, 123.9, 67.8, 63.3, 35.0, 33.2, 21.8, 10.8. HRMS
(ESI-FTMS) m/z [M + H]+ calcd. for C13H16BrN4O: 323.0502, found 323.0504.
N-((4-(2,4-dichlorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide (3l)
Light yellow oil (89%, 116 mg).1H NMR (600 MHz, CDCl3) δ 8.39 (s, 0.65H), 8.09 (s,
0.21H), 7.45–7.41(m, 1H), 7.27–7.20 (m, 2H), 5.79 (d, J = 1.2 Hz, 0.54H), 5.63 (d, J = 1.2
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Hz, 1.54H), 2.95 (d, J = 1.2 Hz, 0.77H), 2.87 (d, J = 1.2 Hz, 2.18H), 2.18 (d, J = 1.2 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 162.9, 162.7, 144.2, 143.9, 143.7, 135.4, 135.3, 134.4,
132.4, 129.6, 128.2, 128.0, 127.0, 66.8, 60.5, 33.5, 29.4, 10.7. HRMS (ESI-FTMS) m/z [M
+ H]+ calcd. for C12H13Cl2N4O: 299.0461; found, 299.0465.
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N-((4-(2,4-dichlorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide (3m)
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Light yellow oil (80%, 110 mg). H NMR (600 MHz, CDCl3) δ 7.51 (d, J = 9.0 Hz, 1H),
7.35–7.27 (m, 2H), 5.90 (s, 0.82H), 5.76 (s, 1.05H), 3.10 (s, 1.32H), 3.05 (s, 1.73H), 2.43 (s,
1.68H), 2.25 (s, 3H), 2.16 (s, 1.3H). 13C NMR (150 MHz, CDCl3) δ 171.4, 143.9, 143.6,
135.5, 135.3, 134.6, 132.6, 132.5, 129.8, 128.6, 128.3, 127.1, 67.6, 63.4, 35.2, 33.2, 21.8,
10.8. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C13H15Cl2N4O: 313.0617; found,
313.0624.
N-((4-bromo-5-phenyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide (3n) Light yellow
solid (91%, 118 mg) m.p. 68–70 oC. 1H NMR (600 MHz, CDCl3) δ 8.46 (s, 0.73H), 8.16 (s,
0.27H), 7.90 (d, J = 7.2 Hz, 2H), 7.48–7.40 (m, 3H), 5.87 (s, 0.61H), 5.70 (s, 1.66H), 3.05
(s, 0.86H), 2.95 (s, 2.25H). 13C NMR (150 MHz, CDCl3) δ 162.9, 146.8, 146.3, 129.2,
129.0, 128.7, 128.6, 128.5, 128.3, 127.3, 121.4, 121.0, 67.6, 61.3, 33.7, 29.6. HRMS
(ESI-FTMS) m/z [M + H]+ calcd. for C11H12BrN4O: 295.0189; found, 295.0186.
N-((4-bromo-5-(2-chlorophenyl)-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide
(3o)
1
White semisolid (92%, 117 mg). H NMR (400 MHz, CDCl3) δ 8.47 (s, 0.73H), 8.19 (s,
0.29H), 7.55–7.49 (m, 1H), 7.45–7.34 (m, 3H), 5.92 (s, 0.62H), 5.76 (s, 1.48H), 3.08 (s,
0.83H), 2.99 (s, 2.2H). 13C NMR (100 MHz, CDCl3) δ 162.9, 146.5, 134.0, 131.8, 130.9,
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130.1, 127.4, 126.7, 124.4, 124.0, 67.8, 61.5, 33.9, 29.7. HRMS (ESI-FTMS) m/z [M + H]+
calcd. for C11H11BrClN4O: 328.9799; found, 328.9800.
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N-((4-bromo-5-(2-chlorophenyl)-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide
(3p)
Colorless oil (82%, 109 mg). 1H NMR (400 MHz, CDCl3) δ 7.54–7.49 (m, 1H), 7.46–7.32
(m, 3H), 5.96 (s, 1H), 5.83 (s, 1.07H), 3.16 (s, 1.52H), 3.08 (s, 1.62H), 2.44 (s, 1.62H), 2.19
(s, 1.49H).13C NMR (100 MHz, CDCl3) δ 171.4, 171.2, 146.0, 145.7, 134.0, 131.9, 131.7,
130.8, 130.7, 130.1, 130.0, 127.9, 127.5, 126.7, 126.6, 123.9, 123.5, 68.5, 64.4, 35.4, 33.3,
21.7, 21.6. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C12H13BrClN4O: 342.9956, found
342.9962.
N-((4-bromo-5-(2-bromophenyl)-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide
(3q)
o
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White solid (91%, 112 mg) m.p. 78–80 C. H NMR (400 MHz, CDCl3) δ 8.48 (s, 0.75H),
8.19 (s, 0.28H), 7.71 (d, J = 7.2 Hz, 1H), 7.46–7.30 (m, 3H), 5.93 (s, 0.6H), 5.76 (s, 1.54H),
3.08 (s, 0.88H), 2.99 (s, 2.27H). 13C NMR (100 MHz, CDCl3) δ 162.9, 147.8, 133.2, 131.9,
131.1, 129.4, 127.3, 124.3, 123.7, 67.8, 29.6. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for
C11H11Br2N4O: 372.9294, found 372.9290.
N-((4-bromo-5-(2-bromophenyl)-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide
(3r)
1
Colorless oil (84%, 108 mg). H NMR (400 MHz, CDCl3) δ 7.75–7.65 (m, 1H), 7.43–7.38
(m, 2H), 7.37–7.30 (m, 1H), 5.97 (s, 1H), 5.84 (s, 1.11H), 3.15 (s, 1.51H), 3.08 (s, 1.65H),
2.44 (s, 1.66H), 2.19 (s, 1.52H). 13C NMR (100 MHz, CDCl3) δ 177.3, 171.4, 147.3, 146.9,
133.2, 131.9, 130.9, 129.89, 129.6, 127.2, 123.9, 123.6, 123.4, 77.3, 68.5, 64.4, 35.4, 33.3,
29.5, 21.7. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C12H13Br2N4O: 386.9451, found
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386.9449.
N-((4-bromo-5-(4-chlorophenyl)-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide
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(3s)
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White solid (86%, 110 mg) m.p. 65–66 C. H NMR (400 MHz, CDCl3) δ 8.48 (s, 0.71H),
8.18 (s, 0.28H), 7.94–7.81 (m, 2H), 7.49–7.37 (m, 2H), 5.88 (s, 0.59H), 5.72 (s, 1.46H),
3.08 (s, 0.88H), 2.97 (s, 2.16H). 13C NMR (100 MHz, CDCl3) δ 162.9, 145.9, 145.4, 135.3,
128.9, 128.6, 126.9, 121.5, 121.0, 67.8, 61.5, 33.8, 29.7. HRMS (ESI-FTMS) m/z [M + H]+
calcd. for C11H11BrClN4O: 328.9799; found, 328.9797.
N-((4-bromo-5-(4-chlorophenyl)-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide
(3t)
o
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White solid (81%, 108 mg) m.p. 89–90 C. H NMR (400 MHz, CDCl3) δ 7.98–7.76 (m,
2H), 7.53–7.33 (m, 2H), 5.92 (s, 1H), 5.80 (s, 1H), 3.16 (s, 1.47H), 3.06 (s, 1.46H), 2.44 (s,
1.5H), 2.18 (s, 1.53H). 13C NMR (100 MHz, CDCl3) δ 171.4, 171.2, 145.5, 145.0, 135.3,
135.0, 128.7, 127.3, 127.0, 121.0, 120.6, 68.5, 64.5, 35.6, 33.3, 21.7. HRMS (ESI-FTMS)
m/z [M + H]+ calcd. for C12H13BrClN4O: 342.9956, found 342.9959.
N-((4-bromo-5-(2,4-dichlorophenyl)-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide (3u)
Colorless oil (87%, 112 mg). 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 7.2, 1.6 Hz, 1H),
7.40–7.32 (m, 2H), 5.95 (s, 1H), 5.83 (s, 1H), 3.16 (s, 1.5H), 3.07 (s, 1.5H), 2.43 (s, 1.5H),
2.19 (s, 1.5H). 13C NMR (100 MHz, CDCl3) δ 171.5, 171.2, 145.0, 144.7, 136.3, 136.1,
134.9, 132. 6, 130.0, 127.1, 126.5, 126.1, 123.9, 123.5, 68.6, 64.6, 35.5, 33.3, 21.7. HRMS
(ESI-FTMS) m/z [M + H]+ calcd. for C12H12BrCl2N4O: 376.9566, found 376.9561.
5-(4-(2-bromophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)-1 methylpyrrolidin-2-one (3v) Light
yellow oil (82%, 115 mg). 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H), 7.38 (q,
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J = 7.2 Hz, 1H), 7.36–7.32 (m, 1H), 7.32–7.27 (m, 1H), 5.98 (m, 1H), 2.97–2.90 (m, 1H),
2.75 (s, 3H), 2.63–2.56 (m, 2H), 2.48 (m, 1H), 2.26 (s, 3H). 13C NMR (150 MHz, CDCl3) δ
175.1, 146.1, 143.6, 133.0, 131.7, 130.3, 127.2, 123.7, 76.8, 28.9, 27. 4, 24.9, 10.7. HRMS
(ESI-FTMS) m/z [M + H]+ calcd. for C14H16BrN4O: 335.0502; found, 335.0501.
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5-(4-(2-bromo-4-fluorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)-1-methylpyrrolidin-2-one
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(3w) Colorless oil (92%, 254 mg). H NMR (400 MHz, CDCl3) δ 7.43–7.38 (m, 1H),
7.32–7.25 (m, 1H), 7.12–7.05 (m, 1H), 5.94 (dd, J = 7.2, 2.4 Hz, 1H), 2.97–2.83 (m, 1H),
2.71 (s, 3H), 2.62–2.52 (m, 2H), 2.51–2.41 (m, 1H), 2.22 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 175.1, 163.7, 161.2, 145.3, 143.7, 132.7, 132.6, 127.93, 127.90, 124.2, 124.1,
120.5, 120.2, 114.7, 114.5, 78.5, 28.9, 27.5, 24.9, 10.7. HRMS (ESI-FTMS) m/z [M + Na]+
calcd. for C14H14BrFN4NaO: 375.0227, found 375.0223.
5-(4-bromo-5-phenyl-2H-1,2,3-triazol-2-yl)-1-methylpyrrolidin-2-one (3x) White solid
o
1
(90%, 258 mg) m.p. 116–118 C. H NMR (400 MHz, CDCl3) δ 7.92 (dd, J = 8.4, 1.6 Hz,
2H), 7.51–7.38 (m, 3H), 5.99 (dd, J = 7.6, 1.6 Hz, 1H), 2.99–2.85 (m, 1H), 2.78 (s, 3H),
2.68–2.56 (m, 1H), 2.55–2.44 (m, 2H).13C NMR (100 MHz, CDCl3) δ 175.1, 146.3, 129.2,
128.63, 128.57, 127.3, 120.9, 79.6, 28.7, 27.7, 25.1. HRMS (ESI-FTMS) m/z [M + Na]+
calcd. for C13H13BrN4NaO: 343.0165, found 343.0158.
5-(4-benzoyl-5-phenyl-2H-1,2,3-triazol-2-yl)-1-methylpyrrolidin-2-one (3y) White solid
(89%, 247 mg) m.p. 112–114 oC. 1H NMR (400 MHz, CDCl3) δ 8.10–7.97 (m, 2H), 7.80
(dd, J = 6.4, 3.2 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.42–7.37 (m,
3H), 6.10 (dd, J = 7.6, 1.6 Hz, 1H), 3.00–2.87 (m, 1H), 2.82 (s, 3H), 2.73–2.62 (m, 1H),
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2.62–2.46 (m, 2H).13C NMR (100 MHz, CDCl3) δ 187.6, 175.1, 150.2, 142.5, 136.9, 133.5,
130.3, 129.3, 129.1, 128.6, 128.4, 128.3, 79.6, 28.6, 27.8, 25.3. HRMS (ESI-FTMS) m/z [M
+ Na]+ calcd. for C20H18N4NaO2: 369.1322, found 369.1328.
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N-((4-benzoyl-5-phenyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide (3z) White solid
1
(85%, 218 mg) m.p. 116–118 oC. H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.18 (s, 1H),
7.58–7.52 (m, 4H), 7.39–7.33 (m, 6H), 5.94 (s, 1H), 5.75 (s, 2H), 3.07 (s, 1H), 3.01 (s, 2H).
13C NMR (100 MHz, CDCl3) δ 163.0, 162.7, 145.8, 145.3, 130.4, 130.2, 128.6, 128.5,
128.42, 128.40, 128.2, 128.1, 67.0, 60.7, 33.6, 29.6. HRMS (ESI-FTMS) m/z [M + Na]+
calcd. for C18H16N4NaO2: 343.1166, found 343.1169.
5-(4,5-diphenyl-2H-1,2,3-triazol-2-yl)-1-methylpyrrolidin-2-one (3aa) Light yellow solid
(89%, 256 mg) m.p. 92–94 oC. 1H NMR (400 MHz, CDCl3) δ 7.57–7.52 (m, 4H), 7.40–7.35
(m, 6H), 6.06 (dd, J = 6.8, 2.8 Hz, 1H), 3.04–2.93 (m, 1H), 2.83 (s, 3H), 2.68–2.58 (m, 2H),
2.56–2.46 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 175.3, 145.4, 130.5, 128.59, 128.55,
128.2, 78.9, 28.9, 27.7, 25.2. HRMS (ESI-FTMS) m/z [M + Na]+ calcd. for C19H18N4NaO:
341.1373, found 341.1379.
5-(4-(2-bromophenyl)-5-phenyl-2H-1,2,3-triazol-2-yl)-1-methylpyrrolidin-2-one
(3ab)
White solid (92%, 243 mg) m.p. 128–130 oC. 1H NMR (400 MHz, CDCl3) δ 7.68 (dd, J =
8.0, 0.8 Hz, 1H), 7.50–7.41 (m, 2H), 7.43–7.36 (m, 2H), 7.34–7.24 (m, 4H), 6.07 (t, J = 4.8
Hz, 1H), 3.05–2.92 (m, 1H), 2.81 (s, 3H), 2.72–2.60 (m, 2H), 2.56–2.46 (m, 1H).13C NMR
(100 MHz, CDCl3) δ 175.2, 146.0, 144.5, 133.2, 132.4, 131.8, 130.6, 130.1, 128.54, 128.47,
127.5, 126.8, 124.2, 79.0, 28.9, 27.6, 25.0. HRMS (ESI-FTMS) m/z [M + Na]+ calcd. for
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C19H17BrN4NaO: 419.0478, found 419.0483.
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N-((4,5-diphenyl-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide (3ac) White solid (87%,
229 mg) m.p. 105–107 oC.1H NMR (500 MHz, CDCl3) δ 8.49 (s, 1H), 8.17 (s, 1H), 8.03
(dd, J = 16.5, 7.5 Hz, 2H), 7.79–7.76 (m, 2H), 7.59 (d, J = 7.5 Hz, 1H), 7.50–7.43 (m, 2H),
7.43–7.34 (m, 3H), 5.96 (s, 1H), 5.79 (s, 1H), 3.07 (s, 1H), 2.99 (s, 2H). 13C NMR (125
MHz, CDCl3) δ 187.6,187.5, 162.9, 162.8, 150.4, 150.1, 143.0, 142.6, 136.8, 136.7, 133.6,
133.5, 130.3,130.2, 129.3, 129.2, 129.1, 128.9, 128.6, 128.5, 128.4, 128.32, 128.27, 67.6,
61.3, 33.8, 29.6. HRMS (ESI-FTMS) m/z [M + Na]+ calcd. for C17H16N4NaO: 315.1206,
found 315.1208.
N-((4-bromo-5-(2-bromophenyl)-2H-1,2,3-triazol-2-yl)methyl)-N-methylformamide
(3q')
o
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White solid (5%, 61 mg) m.p. 196–198 C. H NMR (600 MHz, CDCl3) δ 7.84 (s, 0.38H),
7.80 (dd, J = 7.8, 1.2 Hz, 0.57H), 7.74 (dd, J = 7.8, 1.2 Hz, 0.37H), 7.55–7.42 (m, 2.54H),
7.29–7.26 (m, 1.16H), 5.77 (d, J = 13.8 Hz, 0.4H), 5.69 (d, J = 4.8 Hz, 0.42H), 5.67 (d, J =
5.4 Hz, 0.56H), 5.62 (d, J = 14.4 Hz, 0.59H), 2.98 (s, 1.20H), 2.79 (s, 1.77H). 13C NMR
(150 MHz, CDCl3) δ 161.8, 161.5, 135.6, 135.1, 133.7, 133.2, 132.8, 132.3, 132.0, 131.7,
128.4, 127.9, 126.0, 125.9, 124.4, 124.2, 122.7, 122.4, 62.9, 56.1, 33.4, 29.1. HRMS
(ESI-FTMS) m/z [M + H]+ calcd. for C11H11Br2N4O: 372.9294, found 372.9288.
N-methyl-N-((4-phenyl-2H-1,2,3-triazol-2-yl)methyl)formamide (4a) Light yellow solid
(64%, 89 mg) m.p. 58–60 oC. 1H NMR (600 MHz, CDCl3) δ 8.50 (s, 0.74H), 8.16 (s, 0.26H),
7.90 (d, J = 3.6 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.43 (q, J = 7.2 Hz, 2H), 7.38 (d, J = 7.2
Hz, 1H), 5.92 (s, 0.57H), 5.75 (s, 1.4H), 3.02 (s, 0.76H), 2.94 (s, 2.25H). 13C NMR (150
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MHz, CDCl3) δ 162.9, 162.6, 159.8, 148.5, 131.5, 131.2, 127.0, 126.9, 122.0, 114.0, 66.7,
60.3, 54.9, 33.2, 29.1. HRMS (ESI-FTMS) m/z [M + Na]+ calcd. for C11H12N4NaO:
239.0903; found, 239.0900.
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N-methyl-N-((4-phenyl-2H-1,2,3-triazol-2-yl)methyl)acetamide (4b) Colorless oil (50%,
1
76 mg). H NMR (600 MHz, CDCl3) δ 7.89 (s, 1H), 7.79 (t, J = 7.8 Hz, 2H), 7.43 (d, J =
8.4 Hz, 2H), 7.37 (s, 1H), 5.97 (s, 0.91H), 5.82 (s, 1.01H), 3.11 (s, 1.42H), 3.05 (s, 1.4H),
2.47 (s, 1.48H), 2.16 (s, 1.46H). 13C NMR (150 MHz, CDCl3) δ 171.2, 159.9, 159.8, 148.4,
148.0, 131.2, 127.2, 122.5, 122.3, 114.1, 67.5, 63.4, 55.1, 35.1, 33.0, 21.5. HRMS
(ESI-FTMS) m/z [M + Na]+ calcd. for C12H14N4NaO: 253.1060; found, 253.1056.
N-methyl-N-((4-(p-tolyl)-2H-1,2,3-triazol-2-yl)methyl)acetamide (4c) Light yellow solid
o
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(59%, 86 mg) m.p. 84–86 C. H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.74–7.58 (m,
2H), 7.30–7.15 (m, 2H), 5.96 (s, 0.89H), 5.82 (s, 0.98H), 3.11 (s, 1.26H), 3.05 (s, 1.31H),
2.47 (s, 1.4H), 2.39 (d, J = 3.2 Hz, 3H), 2.17 (s, 1.32H). 13C NMR (150 MHz, CDCl3) δ
163.0, 135.4, 133.7, 130.9, 130.1, 129.9, 127.6, 121.9, 67.1, 60.8, 33.6, 29.6. HRMS
(ESI-FTMS) m/z [M + Na]+ calcd. for C13H16N4NaO: 267.1216; found, 267.1212.
N-((4-(4-methoxyphenyl)-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide (4d) Light
yellow solid (47%, 67 mg) m.p. 81–83 oC. 1H NMR (600 MHz, CDCl3) δ 7.81 (s, 1H), 7.71
(t, J = 7.8 Hz, 2H), 6.95 (t, J = 7.8 Hz, 2H), 5.94 (s, 0.85H), 5.79 (s, 1.13H), 3.82 (d, J = 4.2
Hz, 3H), 3.10 (s, 1.29H), 3.04 (s, 1.6H), 2.45 (s, 1.59H), 2.15 (s, 1.26H). 13C NMR (150
MHz, CDCl3) δ 162.9, 162.6, 148.8, 138.5, 131.9, 129.3, 129.2, 126.6, 125.6, 66.8, 60.4,
33.3, 29.2, 21.0. HRMS (ESI-FTMS) m/z [M + Na]+ calcd. for C13H16N4NaO2: 283.1166;
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N-((4-(2-bromophenyl)-2H-1,2,3-triazol-2-yl)methyl)-N-methylacetamide (4e) Light yellow
o
solid (57%, 78 mg) m.p. 92–94 C. 1H NMR (600 MHz, CDCl3) δ 8.15 (s, 1H), 7.78–7.64
(m, 2H), 7.40–7.36 (m, 1H), 7.28–7.20 (m, 7.4 Hz, 1H), 5.99 (s, 0.9H), 5.86 (s, 1H), 3.14 (s,
1.38H), 3.07 (s, 1.41H), 2.47 (s, 1.38H), 2.17 (s, 1.37H). 13C NMR (150 MHz, CDCl3) δ
171.3, 148.7, 148.3, 131.9, 128.8, 128.6, 126.0, 67.8, 63.6, 35.2, 33.2, 21.7. HRMS
(ESI-FTMS) m/z [M + H]+ calcd. for C12H14BrN4O: 309.0346; found, 309.0343.
Mixture of N1 [N-methyl-N-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)formamide] and N1'
[N-methyl-N-((5-phenyl-1H-1,2,3-triazol-1-yl)methyl)formamide] product (5a) (18%, 25
mg), ritio of N1': N1 =1:3 (based on 1H NMR).
N-methyl-N-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)acetamide (5b) Light yellow oil (25%,
1
38 mg). H NMR (600 MHz, CDCl3) δ 7.94 (s, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.29 (t, J =
7.8 Hz, 2H), 7.21 (t, J = 7.8 Hz, 1H), 5.72 (s, 2H), 3.03 (s, 3H), 2.00 (s, 3H). 13C NMR (150
MHz, CDCl3) δ 171.8, 147.9, 130.1, 128.6, 128.0, 125.8, 125.5, 125.4, 120.4, 59.9, 35.6,
21.4. HRMS (ESI-FTMS) m/z [M + Na]+ calcd. for C12H14N4NaO: 253.1060; found,
253.1058.
N-methyl-N-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl)acetamide (5c) Light yellow oil (21%,
1
31 mg). H NMR (600 MHz, CDCl3) δ 8.00 (s, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.22 (d, J =
7.2 Hz, 2H), 5.84 (s, 2H), 3.16 (s, 3H), 2.36 (s, 3H), 2.13 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ 172.0, 148.3, 138.0, 129.5, 129.4, 127.4, 125.9, 125.8, 125.5, 120.1, 60.0, 35.7,
21.5, 21.2. HRMS (ESI-FTMS) m/z [M + Na]+ calcd. for C13H16N4NaO: 267.1216; found,
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yellow oil (27%, 38 mg). H NMR (600 MHz, CDCl3) δ 7.95 (s, 1H), 7.75 (d, J = 8.4 Hz,
2H), 6.94 (d, J = 8.4 Hz, 2H), 5.83 (s, 2H), 3.83 (s, 3H), 3.16 (s, 3H), 2.13 (s, 3H). 13C
NMR (150 MHz, CDCl3) δ 172.0, 159.6, 148.0, 127.2, 126.9, 122.9, 119.6, 114.2, 114.1,
60.0, 55.2, 35.7, 21.5. HRMS (ESI-FTMS) m/z [M + Na]+ calcd. for C13H16N4NaO2:
283.1166; found, 283.1164.
N-((4-(2-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N-methylacetamide (5e) Light yellow
oil (20%, 27 mg). 1H NMR (600 MHz, CDCl3) δ 8.46 (s, 1H), 8.10–8.04 (m, 1H), 7.64 (d, J
= 7.8 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 0.6 Hz, 1H), 5.89 (s, 2H), 3.20 (s, 3H),
2.14 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 171.9, 145.8, 133.5, 131.1, 130.5, 129.4, 127.5,
123.9, 121.3, 60.1, 35.8, 21.6. HRMS (ESI-FTMS) m/z [M + H]+ calcd. for C12H14BrN4O:
309.0346; found, 309.0343.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: 10.1021/ x0xx00000x. Scanned copies of 1H and 13C NMR spectra of the synthesized
compounds (PDF) Crystallographic data for compound 3q and 3q
' (CIF).
AUTHOR INFORMATION
Corresponding Author
*,†E-mail: yfchen@wit.edu.cn
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*,‡E-mail: hhxyliyuanjun@163.com
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ORCID
Yunfeng Chen: 0000-0002-6220-5015
Yuanxiang Li: 0000-0001-8917-9294
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (21002076, and
21441007), Graduate Education Innovation Fund of Wuhan Institute of Technology
(CX2016162, CX2016167). Li, Y. thanks the Project of Natural Science Foundation of
Hunan Province (2016JJ4072), and the Scientific Research Fund of Hunan Provincial
Education Department (16A165).
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