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Synlett 2010(11): 1617-1622  
DOI: 10.1055/s-0030-1258086
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Metal- and Base-Free Three-Component Reaction of Ynones, Sodium Azide, and Alkyl Halides: Highly Regioselective Synthesis of 2,4,5-Trisubstituted 1,2,3-NH-Triazoles

Jihui Lia,b, Yuanqing Zhanga,b, Dong Wanga,b, Wen Wanga,b, Tingting Gaoa,b, Lu Wanga,b, Jiting Lic, Guosheng Huanga,b, Baohua Chen*a,b
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu Lanzhou 730000, P. R. of China
b Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou University, Gansu Lanzhou 730000, P. R. of China
Fax: +86(9319)8912582; e-Mail: chbh@lzu.edu.cn;
c College of Chemical Engineering, Northwest Minoritise University, Gansu Lanzhou 730030, P. R. of China

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Publication History

Received 7 April 2010
Publication Date:
11 June 2010 (online)

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Abstract

A base- and metal-free three-component reaction of ynones, sodium azide, and alkyl halides is developed for the ­regioselective synthesis of 2,4,5-trisubstituted-1,2,3-triazoles. The method is general, convenient, environmentally benign, atom-­economical, and high-yielding.

Key words

2,4,5-trisubstituted 1,2,3-NH-triazole - three-component reaction - green chemistry - click chemistry

1,2,3-Triazoles have become one of the most useful heterocycles because of their biological properties [¹] and wide applications in many research fields. [²] By now, there are many methods developed for the synthesis of 1,2,3-triazoles. [³] The classical method is the Huisgen 1,3-dipolar cycloaddition between organic azides and terminal alkynes, but this method is only useful for the synthesis of N1-substituted 1,2,3-triazoles and has other disadvantages. [4] Recently, several approaches have been developed for the synthesis of N2-substituted 1,2,3-triazoles. For examples, Yamamoto and co-workers reported that Pd(0)-Cu(I) catalyzed three-component coupling reaction between alkynes, allyl methyl carbonate, and TMSN3 afforded 2,4-disubstituted 1,2,3-triazoles, [5a] Shi and Wang described the substituted reaction between 1,2,3-triazoles and alkyl halides for the synthesis of 2,4,5-trisubstituted 1,2,3-tri­azoles. [5b-d] However, these methodologies need stoichiometric amount of bases or metal catalysts. Thus, it is highly desirable to devise novel, base- and catalyst-free and highly selective methods for synthesizing N2-substituted 1,2,3-triazoles concerning environment friendliness and atom economy.

Herein, we describe a novel and operationally simple strategy for the regioselective construction of 2,4,5-trisubstitued 1,2,3-triazoles via three-component reaction of ynones, sodium azide, and alkyl halides under metal- and base-free conditions.

Inspired by our previous work on the synthesis of 4,5-di­substituted 1,2,3-triazoles through the reaction of acid chlorides, terminal acetylenes, and sodium azide, [6] it was envisaged that reaction of ynones, sodium azide, and akyl halides might selectively produce 2,4,5-trisubstitued 1,2,3-triazoles. Hence, we carried out the experiment by mixing 1,3-diphenylprop-2-yn-1-one, sodium azide, and benzyl bromide in DMSO together at room temperature for three hours, a mixture of 1a/2a/3a (ratio: 9.3:1.0:1.7) trisubstituted 1,2,3-triazoles was obtained in 60% yield after column chromatography (Table  [¹] , entry 1). [7]

Scheme 1 Two parallel cascade reactions of ynones, sodium azide, and alkyl halides

It was found that two parallel reactions of ynones, sodium azide, and alkyl halides proceeded at the same time during the reaction (Scheme  [¹] , A and B), and the reaction B did not produce any N2-substituted 1,2,3-triazole. To suppress the side reaction B, the 1,3-dipolar cycloaddition reaction between 1,3-diphenylprop-2-yn-1-one and sodium azide was carried out first until completion (confirmed by TLC analysis). Benzyl bromide was then added and allowed to react with the in situ formed sodium salt for 160 minutes.

Table 1 Screening Conditions for the Reactiona

Entry R³X Solvent Time (h) Yield (%)c 1/2/3 d
1b BnBr DMSO 3 60 1a/2a/3a  9.3:1.0:1.7
2 - 3 98 1a/2a/3a 10.5:1.0:2.0
3b MeI 5.5 85 1b/2b/3b  5.7:1.0:2.3
4 - 1.5 99 1b/2b/3b 10.0:1.0:4.0
5 BnBr DMF 3 96 1a/2a/3a 10.0:1.0:1.8
6 - acetone 3 63 1a/2a/3a  7.6:1.0:1.6
7 - EtOH 3  5 1a/2a/3a   7.0:1.0:2.0
a The reactions were carried out with 1,3-diphenylprop-2-yn-1-one (0.25 mmol) and NaN3 (0.275 mmol) in solvent (1.5 mL) reacting at r.t. for 20 min first, then aliphatic alkyl halides (0.375 mmol) were added to the mixture and the reactions continued.
b The reactions were carried out by putting 1,3-diphenylprop-2-yn-1-one (0.25 mmol), NaN3 (0.275 mmol), and aliphatic alkyl halides (0.375 mmol) in DMSO (1.5 mL) together in one pot.
c Isolated yields of the combined 1, 2, and 3 after column chromatography.
d Ratios after column chromatography.

Figure 1  X-ray crystal structures of 4f and 9e [8]

Table 2 Substrate Scope of Aliphatic Alkyl Halidesa

Entry R³X Time (h) Yield (%)b 1/2/3 c
 1 BnCl 16 98 1a/2a/3a [9]  8.7:1.0:2.0
 2 2-ClC6H4CH2Cl  7 98 1c/2c/3c 19.0:1.0:2.5
 3 n-BuBr  4 76 (1d)e
 4 n-C5H11Br  6 98 1e/2e/3e 16.5:1.0:2.5
 5 i-C5H11Br 12 85 (1f)e
 6d s-BuBr 30 87 (1g)e
 7 n-C12H25Br  7 96 1h/2h/3h 21.0:1.0:2.5
 8f n-C16H33Cl 40 97 1i/2i/3i 20.0:1.0:2.8
 9 n-C16H33Br 60 96 1i/2i/3i 20.0:1.0:2.0
10 propen-3-yl  6 98 1j/2j/3j  6.6:1.0:1.7
11 propyn-3yl  2 98 1k/2k/3k 12.3:1.0:2.7
12g DCE 50 65 (1l)e
13 BrCH2COOMe  6 73 (1m)e
a The reactions were carried out with 1,3-diphenylprop-2-yn-1-one (0.25 mmol) and sodium azide (0.275 mmol) in DMSO (1.5 mL) reacting at r.t. for 20 min first, then aliphatic alkyl halides (0.375 mmol) were added to the mixture and the reactions continued.
b Isolated yields of the combined 1, 2, and 3 after column chromatography.
c Ratios after column chromatography. d The reaction temperature was 50 ˚C.
e Yields of 1 after column chromatography.
f After 1-chlorohexadecane was added, the reaction temperature was improved to 80 ˚C.
g The reactions were carried out with 1,3-diphenylprop-2-yn-1-one (0.25 mmol) and NaN3 (0.275 mmol) in DMSO (1 mL) reacting for 20 min at 50 ˚C first, then DCE (0.5 mL) was added to the mixture and continued the reaction at 50 ˚C.
Table 3 Substrate Scope of Aryl Halidesa

Entry R³X Time
(h) 		Temp
(˚C) 		Yield of 4 (%)b
 1 4-O2NC6H4Cl 48 120 4a 85
 2 2-ON2C6H4F  8 100 4b 97
 3 4-ON2C6H4I 36 120 4a 85
 4 2-O2NC6H4Cl 36 120 4b 90
 5 4-MeC6H4Cl  3 120  0
 6 2-O2NC6H4Cl 36 120 4b 90
 7 3-O2NC6H3Cl 36 120  0
 8 2-NC-4-O2NC6H4Cl  9 120 4c 97
 9 2-Cl-3-O2N-pyridine 12 120 4d 94
10 2-NCC6H4Cl 36 120 trace
11 2,4-diO2NC6H3Cl  8 120 4e 96
12 3,4-diFC6H3NO2 3 100 4f 93c
13 2,5-diFC6H3NO2 3 100 4g 94
14 2,5-diBrC6H3NO2 3 100 4h 88
a The reactions were carried out by putting 1,3-diphenylprop-2-yn-1-one (0.25 mmol), NaN3 (0.25 mmol), and aryl halides (0.375 mmol) in DMSO (1.5 mL) together in one pot.
b Isolated yields after column chromatography.
c Confirmed by X-ray crystallography (see Figure  [¹] , 4f).

As expected this reaction afforded superior total yield without increasing reaction time (Table  [¹] , entry 2, yield 98%, 1a/2a/3a: 10.5:1.0:2.0). It is evident that the two-step procedure can accelerate the reaction markedly and increase the yield and selectivity. In order to prove it absolutely, we also performed other similar reactions by taking methyl iodide place of benzyl bromide, the consistent results were obtained (Table  [¹] , entry 3 and 4). Secondly, the solvent’s impact on the reaction was investigated in detail, it was found that the reaction can conduct in several solvents including DMSO, DMF, ethanol, acetone (Table  [¹] , entries 1, 5-7), and the aprotic, polar solvent DMSO is the best for the reaction.

With the optimized conditions in hand, the substrate scope of the aliphatic alkyl halides was investigated through the two-step procedure. As seen in Table  [²] , various aliphatic alkyl halides can react moderately with sodium azide and 1,3-diphenylprop-2-yn-1-one and produce excellent yields and selectivities under mild reaction conditions. For example, when benzyl chloride was used, the reaction proceeded reasonably at room temperature and afforded 98% yield and 8.7:1.0:2.0 (1a/2a/3a) regioselectivity (Table  [²] , entry 1). While 2-ClC6H4CH2Cl was employed, the reaction was accelerated evidently with increasing regioselectivity compared with benzyl chloride (Table  [²] , entry 2). The saturated straight-chain aliphatic alkyl halides n-BuBr and n-C5H11Br reacted easily and provided good results (Table  [²] , entries 3 and 4), and the longer straight-chain aliphatic alkyl halides including n-C12H25Br, n-C16H33Cl, n-C16H33Br proceeded sluggishly and gave better regioselectivities, which is mainly caused by their poor solubility and steric efficiency (Table  [²] , entries 7-9).

The saturated branched chain s-BuBr and i-C5H11Br were also investigated. They reacted as well as the corresponding straight-chain aliphatic alkyl bromides under appropriate conditions (Table  [²] , entries 5 and 6). Importantly, the unsaturated aliphatic alkyl bromides including 3-bromoprop-1-ene and 3-bromoprop-1-yne were also suitable for the procedure (Table  [²] , entries 10 and 11). Moreover, 1,2-dichloroethane and ethyl 2-bromoacetate can produce good yields and selectivities under indicated reaction conditions (Table  [²] , entries 12 and 13). Notably, the procedure can accommodate many functional groups that are very useful for the synthesis of correlative derivatives.

Encouraged by these results, we turned our attentions to aryl halides. Interestingly, when the strongly electron-withdrawing nitro group was in the 2- or 4-position of phenyl halides, the reactions proceeded smoothly at higher temperature and only afforded corresponding 2,4,5-trisubstituted 1,2,3-triazoles in good yields (Table  [³] , entries 1, 2-4, and 6). Moreover, the aryl chlorides bearing two electron-withdrawing groups could accelerate the ­reactions greatly and converted into the corresponding N2-substituted 1,2,3-triazoles with highly good yields (Table  [³] , entries 8 and 11). The heterocyclic 2-Cl-3-O2N-pyridine was also suitable for the reaction and only yielded the desired N2-substituted 1,2,3-triazoles in 94% ­yield (Table  [³] , entry 9). However, as 3-O2NC6H4Cl, 2-NCC6H4Cl and 4-MeC6H4Cl were used, the yields decreased sharply (Table  [³] , entries 5, 7, and 10). Gratifyingly, when the substrate was extended to 3,4-diFC6H4NO2, the coupling step mainly took place at 4-position of 3,4-diFC6H3NO2 and generated the corresponding 2,4,5-trisubstitued 1,2,3-triazoles 4f with 93% isolated yield in shorter time (Table  [³] , entry 12). The structure of 4f was confirmed by X-ray crystallography (Figure  [¹] , 4f). As 2,5-diF-C6H3NO2 and 2,5-diBr-C6H3NO2 were employed, the reactions alternatively proceeded at 2-position of them and yielded the corresponding 2,4,5-trisubstituted 1,2,3-triazoles with 94% and 88% yields, respectively (Table  [³] , entries 13 and 14). It may be deduced that the electronic properties of aryl halides have a strong influence on the reaction.

Finally, using both aryl halides (5: 2,5-diFC6H3NO2, 6: 2-O2NC6H4Cl, 7: 2-ClC6H4CH2Cl, 8: 4-O2NC6H4Cl) and aliphatic alkyl halide (7) as coupling reagents, the scope of ynones was examined (Table  [4] ). Consistent with the above results, various ynones could react moderately with halides, and produced 2,4,5-trisubstituted 1,2,3-triazoles in excellent yields. For example, when the aryl-disubstituted ynones whose aryl R² are electron-poor or electron-rich were employed, they reacted as well as that diphenylprop-2-yn-1-one was used (entries 1-15). The aryl-disubstituted yones of which the aryl R¹ are electron-poor or electron-rich also produced the excellent results (Table  [4] , entries 18-21). When 1-(furan-2-yl)-3-phenylprop-2-yn-1-one was used, the reactions yielded the desired N2-substituted product in good yields (Table  [4] , entries 16 and 17). Interestingly, the reaction of 1-phenylhept-2-yn-1-one, sodium azide, and 1,4-difluoro-2-nitrobenzene produced product 9v in only 60% yield and another isomer which may be caused by the steric and electronic properties of the substrates (Table  [4] , entry 22), whereas the reaction between 1-phenylhept-2-yn-1-one, sodium azide, and 1-chloro-2-nitrobenzene only afforded the corresponding 2,4,5-trisubstituted 1,2,3-triazole 9w with 95% yield. In addition, 1-phenyl-3-ferrocenylprop-2-yn-1-one and 1-phenyl-3-(thiophen-3-yl)prop-2-yn-1-one were efficient with excellent yields and regioselectivities (Table  [4] , entries 24-27).

Table 4 Substrate Scope of Ynonesa

Entry R¹ R² R³X
 Yield of 9 (%)b
 1 Ph 4-ClC6H4 5 2,5-diFC6H4NO2 9a 95
 2c - - 7 2-ClC6H4CH2Cl 9b 86
 3 - 3-ClC6H4 5 2,5-diFC6H4NO2 9c 94
 4c - - 7 2-ClC6H4CH2Cl 9d 85
 5d - 2-ClC6H4 5 2,5-diFC6H4NO2 9e 97f
 6c - - 7 2-ClC6H4CH2Cl 9f 87
 7e - 3-MeC6H4 8 4-O2NC6H4Cl 9g 92
 8c - - 7 2-ClC6H4CH2Cl 9h 86
 9 - 3,5-diMeC6H4 5 2,5-diFC6H4NO2 9i 97
10c - - 7 2-ClC6H4CH2Cl 9j 90
11 - 4-MeOC(O)C6H4 5 2,5-diFC6H4NO2 9k 93
12 - 4-MeOC6H4 5 2,5-diFC6H4NO2 9l 94
13c - - 7 2-ClC6H4CH2Cl 9m 82
14 - 4-O2NC6H4 5 2,5-diFC6H4NO2 9n 95
15c - - 7 2-ClC6H4CH2Cl 9o 85
16 - furan-2-yl 5 2,5-diFC6H4NO2 9p 93
17c - - 7 2-ClC6H4CH2Cl 9q 82
18 4-MeOC6H4 Ph 5 2,5-diFC6H4NO2 9r 96
19c - - 7 2-ClC6H4CH2Cl 9s 83
20 4-FC6H4 - 5 2,5-diFC6H4NO2 9t 95
21c - - 7 2-ClC6H4CH2Cl 9u 84
22 n-Bu - 5 2,5-diFC6H4NO2 9v 60
23d - - 6 2-O2NC6H4Cl 9w 95
24 Fc - 5 2,5-diFC6H4NO2 9x 97
25c - - 7 2-ClC6H4CH2Cl 9y 88
26 thiophen-3-yl - 5 2,5-diFC6H4NO2 9z 98
27c - - 7 2-ClC6H4CH2Cl 9a′ 88
a The reactions were carried out by putting ynones (0.25 mmol), NaN3 (0.25 mmol), and aryl halides (0.375 mmol) in DMSO (1.5 mL) at 100 ˚C.
b Isolated yields after column chromatography.
c The reactions were carried out with ynones (0.25 mmol) and NaN3 (0.275 mmol) in DMSO (1.5 mL) reacting for 20 min at r.t. first, then aliphatic alkyl halides (0.375 mmol) were added to the mixture and continued the reaction for 24 h at r.t.
d The reaction time was 40 h, and the temperature was 120 ˚C.
e The reaction time was 36 h, and the temperature was 120 ˚C. f Confirmed by X-ray crystallography (see Figure  [¹] , 9e).

It is revealed that the regioselectivities of using aryl halides as coupling reagent are better than when using aliphatic alkyl halides due to the steric effect of alkyl halides.

In summary, we have developed a novel, metal- and base-free three-component reaction of simple raw materials ynones, sodium azide, and alkyl halides for regioselectively synthesizing 2,4,5-trisubstitued 1,2,3-triazoles. The procedure is efficient, convenient, environmentally friendly, and atom-economical. A variety of substrates are suitable for the method and even 3,4-diFC6H3NO2, 2,5-diFC6H3NO2, and 2,5-diBrC6H3NO2 can also produce excellent results. Further studies on regioselective synthesis of 1,2,3-triazoles are under investigation in our group.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

The project was sponsored by the Scientific Research Foundation for the State Education Ministry (No. 107108) and the Project of National Science Foundation of P. R. China (No. J0730425).

7

Three isomers can be readily isolated by column chroma-tography. According to the ref. 5b, N2-alkylation of 4,5-disubstituted 1,2,3-triazoles is the most favorable and the polarity of N2 product is the lowest. Additionally, N1-alkylation was the least favored in almost all cases due to the conformation of 1,4,5-trisubstituted 1,2,3-triazoles. Therefore, we can distinguish the N-1, N-2, and N-3 products easily.

8

The CCDC number of 4f (C21H13FN4O3): 752728, the CCDC number of 9e (C21H13ClN4O3): 752729.

9

Regioselective Synthesis of 2,4,5-Trisubstituted 1,2,3-Triazoles - General Procedure for the Reaction between Ynones, Sodium Azide, and Aliphatic Alkyl Halides, Regioselective Sythesis of (2-Benzyl-5-phenyl-2 H -1,2,3-triazol-4-yl)(phenyl)methanone (1a)
All reactions were performed on a 0.25 mmol scale relative to ynones. 1,3-Diphenylprop-2-yn-1-one (0.25 mmol), NaN3 (0.275 mmol) and DMSO (1.5 mL) were successively added to a round-bottom sidearm flask (10 mL) reacted at r.t. until ynones disappeared by TLC test (about 20 min), then benzyl bromide (0.375 mmol) was added to the mixture and the reaction continued at r.t. for 160 min. Following, to the reaction mixture was added H2O (2 mL), 20% HCl solution (1 mL), and extracted with ester (3 × 10 mL). The combined organic phases were washed with brine (2 × 3 mL), dried over anhyd MgSO4, and concentrated in vacuo. The residue was subjected to flash column chromatography with hexanes-EtOAc (40:1, 20:1, 5:1) as eluent to obtain the desired isomers 1a (1a: 63mg), 2a (6 mg), 3a (12 mg), 98% yield.
(2-Benzyl-5-phenyl-2 H -1,2,3-triazol-4-yl)(phenyl)-methanone (1a)
Mp 93-95 ˚C. IR: 3063.48, 1661.58, 1597.39 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 8.03-8.06 (m, 2 H), 7.79-7.82 (m, 2 H), 7.56-7.61 (m, 1 H), 7.35-7.48 (m, 10 H), 5.68 (s, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 187.84, 150.01, 142.24, 137.25, 134.47, 133.30, 130.44, 129.61, 129.07, 128.86, 128.71, 128.60, 128.32, 128.27, 128.17, 59.24. HRMS: m/z calcd for C22H18N3O [M + H]+: 340.14444; found: 340.14426.5b
General Procedure of the Reaction between Ynones, Sodium Azide, and Aryl Halides: Regioselective Synthesis of [2-(4-Nitrophenyl)-5-phenyl-2 H -1,2,3-triazol-4-yl](phenyl) Methanone (2a)
All reactions were performed on a 0.25 mmol scale relative to ynones. 1,3-Diphenylprop-2-yn-1-one (0.25 mmol), NaN3 (0.25 mmol), 4-O2NC6H4Cl (0.375 mmol), and DMSO (1.5 mL) were successively added to a round-bottom sidearm flask (10 mL) and reacted at 120 ˚C for 48 h, then H2O (2 mL), 20% HCl solution (1 mL) were added to the reaction mixture after cooled and extracted with ester (3 × 10 mL). The combined organic phases were washed with brine (2 × 3 mL), dried over anhyd MgSO4, and concentrated in vacuo. The residue was subjected to flash column chromatography with hexanes-EtOAc (20:1) as eluent to obtain the desired 4a (79 mg, yield 85%); mp 145-147 ˚C. IR: 3074.59, 2918.34, 1652.74, 1593.64 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.33-8.35 (m, 4 H), 8.11-8.13 (m, 2 H), 7.87-7.90 (m, 2 H), 7.64-7.67 (m, 1 H), 7.44-7.54 (m, 5 H). ¹³C NMR (100 MHz, CDCl3): δ = 187.45, 151.34, 146.89, 144.36, 143.09, 136.65, 133.90, 130.44, 129.82, 128.69, 128.58, 128.56, 128.52, 125.20, 119.50. MS (EI): m/z = 370 [M]+. Anal. Calcd for C21H14N4O3: C, 68.10; H, 3.81; N, 15.13. Found: C, 68.14; H, 3.79; N, 15.15.6 Copies of NMR spectroscopic, ESI-HRMS analysis, MS (EI) element analysis, and X-ray crystallography are found in the Supporting Information.

7

Three isomers can be readily isolated by column chroma-tography. According to the ref. 5b, N2-alkylation of 4,5-disubstituted 1,2,3-triazoles is the most favorable and the polarity of N2 product is the lowest. Additionally, N1-alkylation was the least favored in almost all cases due to the conformation of 1,4,5-trisubstituted 1,2,3-triazoles. Therefore, we can distinguish the N-1, N-2, and N-3 products easily.

8

The CCDC number of 4f (C21H13FN4O3): 752728, the CCDC number of 9e (C21H13ClN4O3): 752729.

9

Regioselective Synthesis of 2,4,5-Trisubstituted 1,2,3-Triazoles - General Procedure for the Reaction between Ynones, Sodium Azide, and Aliphatic Alkyl Halides, Regioselective Sythesis of (2-Benzyl-5-phenyl-2 H -1,2,3-triazol-4-yl)(phenyl)methanone (1a)
All reactions were performed on a 0.25 mmol scale relative to ynones. 1,3-Diphenylprop-2-yn-1-one (0.25 mmol), NaN3 (0.275 mmol) and DMSO (1.5 mL) were successively added to a round-bottom sidearm flask (10 mL) reacted at r.t. until ynones disappeared by TLC test (about 20 min), then benzyl bromide (0.375 mmol) was added to the mixture and the reaction continued at r.t. for 160 min. Following, to the reaction mixture was added H2O (2 mL), 20% HCl solution (1 mL), and extracted with ester (3 × 10 mL). The combined organic phases were washed with brine (2 × 3 mL), dried over anhyd MgSO4, and concentrated in vacuo. The residue was subjected to flash column chromatography with hexanes-EtOAc (40:1, 20:1, 5:1) as eluent to obtain the desired isomers 1a (1a: 63mg), 2a (6 mg), 3a (12 mg), 98% yield.
(2-Benzyl-5-phenyl-2 H -1,2,3-triazol-4-yl)(phenyl)-methanone (1a)
Mp 93-95 ˚C. IR: 3063.48, 1661.58, 1597.39 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 8.03-8.06 (m, 2 H), 7.79-7.82 (m, 2 H), 7.56-7.61 (m, 1 H), 7.35-7.48 (m, 10 H), 5.68 (s, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 187.84, 150.01, 142.24, 137.25, 134.47, 133.30, 130.44, 129.61, 129.07, 128.86, 128.71, 128.60, 128.32, 128.27, 128.17, 59.24. HRMS: m/z calcd for C22H18N3O [M + H]+: 340.14444; found: 340.14426.5b
General Procedure of the Reaction between Ynones, Sodium Azide, and Aryl Halides: Regioselective Synthesis of [2-(4-Nitrophenyl)-5-phenyl-2 H -1,2,3-triazol-4-yl](phenyl) Methanone (2a)
All reactions were performed on a 0.25 mmol scale relative to ynones. 1,3-Diphenylprop-2-yn-1-one (0.25 mmol), NaN3 (0.25 mmol), 4-O2NC6H4Cl (0.375 mmol), and DMSO (1.5 mL) were successively added to a round-bottom sidearm flask (10 mL) and reacted at 120 ˚C for 48 h, then H2O (2 mL), 20% HCl solution (1 mL) were added to the reaction mixture after cooled and extracted with ester (3 × 10 mL). The combined organic phases were washed with brine (2 × 3 mL), dried over anhyd MgSO4, and concentrated in vacuo. The residue was subjected to flash column chromatography with hexanes-EtOAc (20:1) as eluent to obtain the desired 4a (79 mg, yield 85%); mp 145-147 ˚C. IR: 3074.59, 2918.34, 1652.74, 1593.64 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.33-8.35 (m, 4 H), 8.11-8.13 (m, 2 H), 7.87-7.90 (m, 2 H), 7.64-7.67 (m, 1 H), 7.44-7.54 (m, 5 H). ¹³C NMR (100 MHz, CDCl3): δ = 187.45, 151.34, 146.89, 144.36, 143.09, 136.65, 133.90, 130.44, 129.82, 128.69, 128.58, 128.56, 128.52, 125.20, 119.50. MS (EI): m/z = 370 [M]+. Anal. Calcd for C21H14N4O3: C, 68.10; H, 3.81; N, 15.13. Found: C, 68.14; H, 3.79; N, 15.15.6 Copies of NMR spectroscopic, ESI-HRMS analysis, MS (EI) element analysis, and X-ray crystallography are found in the Supporting Information.

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Scheme 1 Two parallel cascade reactions of ynones, sodium azide, and alkyl halides

Figure 1  X-ray crystal structures of 4f and 9e [8]