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

Article abstract of DOI:10.1055/s-0030-1258086

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.

Full text of DOI:10.1055/s-0030-1258086

LETTER
1617
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
R
egiosele
i
h
nthesis of
2
u
i
N
L
H
-Triazoles i,a,b Yuanqing Zhang,a,b Dong Wang,a,b Wen Wang,a,b Tingting Gao,a,b Lu Wang,a,b Jiting Li,c
Guosheng Huang,a,b Baohua Chen*a,b
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu Lanzhou 730000, P. R. of China
Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou University,
b
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
Received 7 April 2010
chlorides, terminal acetylenes, and sodium azide,6 it was
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.
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
Key words: 2,4,5-trisubstituted 1,2,3-NH-triazole, three-compo-
nent reaction, green chemistry, click chemistry
1,2,3-Triazoles have become one of the most useful het-
erocycles because of their biological properties1 and wide
applications in many research fields.2 By now, there are
many methods developed for the synthesis of 1,2,3-triaz-
oles.3 The classical method is the Huisgen 1,3-dipolar cy-
cloaddition between organic azides and terminal alkynes,
but this method is only useful for the synthesis of N1-sub-
stituted 1,2,3-triazoles and has other disadvantages.4 Re-
cently, 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) cat-
alyzed three-component coupling reaction between
alkynes, allyl methyl carbonate, and TMSN3 afforded 2,4-
disubstituted 1,2,3-triazoles,5a Shi and Wang described
R1CCCOR2
NaN3
(A)
O
O
O
O
R2
+
R2
R2
R2
R1
R1
R1
R1
R3
R3X
N
+
N
N
R3
N
N
N
N
N
N
N
N
N
Na
R3
N-2
N-3
N-1
R1CCCOR2
NaN3
(B) R3X
R3N3
N-1 + N-3
Scheme 1 Two parallel cascade reactions of ynones, sodium azide,
the substituted reaction between 1,2,3-triazoles and alkyl and alkyl halides
halides for the synthesis of 2,4,5-trisubstituted 1,2,3-tri-
azoles.5b–d However, these methodologies need stoichio-
It was found that two parallel reactions of ynones, sodium
metric 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-substi-
tuted 1,2,3-triazoles concerning environment friendliness
and atom economy.
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 sup-
press the side reaction B, the 1,3-dipolar cycloaddition re-
action 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 al-
lowed to react with the in situ formed sodium salt for 160
minutes.
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.
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 ab-
solutely, we also performed other similar reactions by tak-
ing methyl iodide place of benzyl bromide, the consistent
Inspired by our previous work on the synthesis of 4,5-di-
substituted 1,2,3-triazoles through the reaction of acid
SYNLETT 2010, No. 11, pp 1617–1622
x
x
.x
x
.2
0
1
0
Advanced online publication: 11.06.2010
DOI: 10.1055/s-0030-1258086; Art ID: W05510ST
© Georg Thieme Verlag Stuttgart · New York

1618
J. Li et al.
LETTER
Table 1 Screening Conditions for the Reactiona
O
O
O
Ph
Ph
Ph
Ph
Ph
R3
Ph
O
r.t., solvents
Ph
N
R3
NaN3
N
+
+
+
R3X
N
N
N
N
N
N
Ph
R3
1
2
3
Entry
R3X
BnBr
–
Solvent
DMSO
Time (h)
Yield (%)c
1/2/3d
1b
2
3
60
98
85
99
96
63
5
1a/2a/3a
1a/2a/3a
1b/2b/3b
1b/2b/3b
1a/2a/3a
1a/2a/3a
1a/2a/3a
9.3:1.0:1.7
10.5:1.0:2.0
5.7:1.0:2.3
10.0:1.0:4.0
10.0:1.0:1.8
7.6:1.0:1.6
7.0:1.0:2.0
3
3b
4
MeI
–
5.5
1.5
3
5
BnBr
–
DMF
6
acetone
EtOH
3
7
–
3
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.
results were obtained (Table 1, entry 3 and 4). Secondly, good results (Table 2, entries 3 and 4), and the longer
the solvent’s impact on the reaction was investigated in straight-chain aliphatic alkyl halides including n-
detail, it was found that the reaction can conduct in several C12H25Br, n-C16H33Cl, n-C16H33Br proceeded sluggishly
solvents including DMSO, DMF, ethanol, acetone and gave better regioselectivities, which is mainly caused
(Table 1, entries 1, 5–7), and the aprotic, polar solvent by their poor solubility and steric efficiency (Table 2, en-
DMSO is the best for the reaction.
tries 7–9).
With the optimized conditions in hand, the substrate scope The saturated branched chain s-BuBr and i-C5H11Br were
of the aliphatic alkyl halides was investigated through the also investigated. They reacted as well as the correspond-
two-step procedure. As seen in Table 2, various aliphatic ing straight-chain aliphatic alkyl bromides under appro-
alkyl halides can react moderately with sodium azide and priate conditions (Table 2, entries 5 and 6). Importantly,
1,3-diphenylprop-2-yn-1-one and produce excellent the unsaturated aliphatic alkyl bromides including 3-bro-
yields and selectivities under mild reaction conditions. moprop-1-ene and 3-bromoprop-1-yne were also suitable
For example, when benzyl chloride was used, the reaction for the procedure (Table 2, entries 10 and 11). Moreover,
proceeded reasonably at room temperature and afforded 1,2-dichloroethane and ethyl 2-bromoacetate can produce
98% yield and 8.7:1.0:2.0 (1a/2a/3a) regioselectivity good yields and selectivities under indicated reaction con-
(Table 2, entry 1). While 2-ClC6H4CH2Cl was employed, ditions (Table 2, entries 12 and 13). Notably, the proce-
the reaction was accelerated evidently with increasing re- dure can accommodate many functional groups that are
gioselectivity compared with benzyl chloride (Table 2, very useful for the synthesis of correlative derivatives.
entry 2). The saturated straight-chain aliphatic alkyl ha-
lides n-BuBr and n-C5H11Br reacted easily and provided
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 high-
er temperature and only afforded corresponding 2,4,5-
trisubstituted 1,2,3-triazoles in good yields (Table 3, en-
tries 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 yield-
ed the desired N2-substituted 1,2,3-triazoles in 94%
Figure 1 X-ray crystal structures of 4f and 9e8
yield (Table 3, entry 9). However, as 3-O2NC6H4Cl,
Synlett 2010, No. 11, 1617–1622 © Thieme Stuttgart · New York

LETTER
Regioselective Synthesis of 2,4,5-Trisubstituted 1,2,3-NH-Triazoles
1619
Table 2 Substrate Scope of Aliphatic Alkyl Halidesa
O
O
O
Ph
Ph
Ph
Ph
R3
Ph
Ph
O
DMSO
R3
NaN3
+
+
+
N
N
Ph
R3X
N
N
N
N
N
N
Ph
R3
1
2
3
Entry
1
R3X
Time (h)
Yield (%)b
98
1/2/3c
BnCl
16
7
1a/2a/3a9
1c/2c/3c
8.7:1.0:2.0
2
2-ClC6H4CH2Cl
n-BuBr
98
19.0:1.0:2.5
3
4
76 (1d)e
98
4
n-C5H11Br
i-C5H11Br
s-BuBr
6
1e/2e/3e
16.5:1.0:2.5
5
12
30
7
85 (1f)e
87 (1g)e
96
6d
7
n-C12H25Br
n-C16H33Cl
n-C16H33Br
propen-3-yl
propyn-3yl
DCE
1h/2h/3h
1i/2i/3i
21.0:1.0:2.5
20.0:1.0:2.8
20.0:1.0:2.0
6.6:1.0:1.7
12.3:1.0:2.7
8f
40
60
6
97
9
96
1i/2i/3i
10
11
12g
13
98
1j/2j/3j
1k/2k/3k
2
98
50
6
65 (1l)e
73 (1m)e
BrCH2COOMe
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.
2-NCC6H4Cl and 4-MeC6H4Cl were used, the yields de- halides, and produced 2,4,5-trisubstituted 1,2,3-triazoles
creased sharply (Table 3, entries 5, 7, and 10). Gratifying- in excellent yields. For example, when the aryl-disubsti-
ly, when the substrate was extended to 3,4-diFC6H4NO2, tuted ynones whose aryl R2 are electron-poor or electron-
the coupling step mainly took place at 4-position of 3,4- rich were employed, they reacted as well as that diphenyl-
diFC6H3NO2 and generated the corresponding 2,4,5- prop-2-yn-1-one was used (entries 1–15). The aryl-disub-
trisubstitued 1,2,3-triazoles 4f with 93% isolated yield in stituted yones of which the aryl R1 are electron-poor or
shorter time (Table 3, entry 12). The structure of 4f was electron-rich also produced the excellent results (Table 4,
confirmed by X-ray crystallography (Figure 1, 4f). As entries 18–21). When 1-(furan-2-yl)-3-phenylprop-2-yn-
2,5-diF-C6H3NO2 and 2,5-diBr-C6H3NO2 were employed, 1-one was used, the reactions yielded the desired N2-sub-
the reactions alternatively proceeded at 2-position of them stituted product in good yields (Table 4, entries 16 and
and yielded the corresponding 2,4,5-trisubstituted 1,2,3- 17). Interestingly, the reaction of 1-phenylhept-2-yn-1-
triazoles with 94% and 88% yields, respectively (Table 3, one, sodium azide, and 1,4-difluoro-2-nitrobenzene pro-
entries 13 and 14). It may be deduced that the electronic duced product 9v in only 60% yield and another isomer
properties of aryl halides have a strong influence on the which may be caused by the steric and electronic proper-
reaction.
ties of the substrates (Table 4, entry 22), whereas the reac-
tion 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
Finally, using both aryl halides (5: 2,5-diFC6H3NO2, 6: 2-
O2NC6H4Cl, 7: 2-ClC6H4CH2Cl, 8: 4-O2NC6H4Cl) and al-
iphatic 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
Synlett 2010, No. 11, 1617–1622 © Thieme Stuttgart · New York

1620
J. Li et al.
LETTER
Table 3 Substrate Scope of Aryl Halidesa
Acknowledgment
O
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).
Ph
O
Ph
DMSO
R3X
+
+
NaN3
Ph
N
N
Ph
N
R3
References
4
(1) (a) Al-Masoudim, N. A.; Al-SoudY, A. Tetrahedron Lett.
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Entry R3X
Time
Temp
Yield of 4 (%)b
(h)
48
8
(°C)
120
100
120
120
120
120
120
120
120
120
120
100
100
100
1
2
4-O2NC6H4Cl
2-ON2C6H4F
4-ON2C6H4I
2-O2NC6H4Cl
4-MeC6H4Cl
2-O2NC6H4Cl
3-O2NC6H3Cl
4a
4b
4a
4b
85
97
85
90
0
3
36
36
3
4
5
6
36
36
9
4b
90
0
7
(2) (a) Wacharasindhu, S.; Bardhan, S.; Wan, Z.-K.; Tabei, K.;
Mansour, T. S. J. Am. Chem. Soc. 2009, 131, 4174.
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V. Org. Biomol. Chem. 2007, 5, 971. (c) Costa, M. S.;
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M. C. S.; Wardell, S.; Ferreira, V. F. Bioorg. Med. Chem.
2006, 14, 8644. (d) Sivakumar, K.; Xie, F.; Cash, B. M.;
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J. Am. Chem. Soc. 2004, 126, 12809.
(3) Selected examples of methods of synthesizing 1,2,3
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Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.
(b) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams,
I. D.; Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem.
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C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (e) Chen,
Z.-Y.; Wu, M.-J. Org. Lett. 2005, 7, 475. (f) Sreedhar, B.;
Reddy, P. S.; Krishna, V. R. Tetrahedron Lett. 2007, 48,
5831. (g) Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta, D. J.
Org. Lett. 2005, 7, 1469.
(4) (a) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem. 1994, 59,
6184. (b) Sasaki, T.; Eguchi, S.; Yamaguchi, M.; Esaki, T.
J. Org. Chem. 1981, 46, 1800. (c) Howell, S. J.; Spencer,
N.; Philp, D. Tetrahedron 2001, 57, 4945. (d) Scriven,
E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
(5) Recent developed methods of synthesizing N2-substitued
1,2,3 triazoles: (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto,
Y. J. Am. Chem. Soc. 2003, 125, 7786. (b) Chen, Y.; Liu,
Y.; Petersena, J. L.; Shi, X. Chem. Commun. 2008, 3254.
(c) Liu, Y.; Yan, W.; Chen, Y.; Petersen, J. L.; Shi, X. Org.
Lett. 2008, 10, 5389. (d) Wang, X.; Zhang, L.; Lee, H.;
Haddad, N.; Krishnamurthy, D.; Senanayake, C. H. Org.
Lett. 2009, 11, 5026. (e) Kalisiak, J.; Sharpless, K. B.;
Fokin, V. V. Org. Lett. 2008, 10, 3171.
8
2-NC-4-O2NC6H4Cl
4c
97
94
trace
96
93c
94
88
9
2-Cl-3-O2N-pyridine 12
4d
10
11
12
13
14
2-NCC6H4Cl
36
8
2,4-diO2NC6H3Cl
3,4-diFC6H3NO2
2,5-diFC6H3NO2
2,5-diBrC6H3NO2
4e
4f
3
3
4g
3
4h
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).
with excellent yields and regioselectivities (Table 4, en-
tries 24–27).
It is revealed that the regioselectivities of using aryl ha-
lides as coupling reagent are better than when using ali-
phatic 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 regioselec-
tively 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 ex-
cellent results. Further studies on regioselective synthesis
of 1,2,3-triazoles are under investigation in our group.
(6) Li, J.; Wang, D.; Zhang, Y.; Li, J.; Chen, B. Org. Lett. 2009,
11, 3024.
(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
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 11, 1617–1622 © Thieme Stuttgart · New York

LETTER
Regioselective Synthesis of 2,4,5-Trisubstituted 1,2,3-NH-Triazoles
1621
Table 4 Substrate Scope of Ynonesa
O
R2
R1
O
DMSO, R3X
R1
+
NaN3
N
N
R2
N
R3
9
Entry
1
R1
R2
R3X
5
7
5
7
5
7
8
7
5
7
5
5
7
5
7
5
7
5
7
5
7
5
6
5
7
5
7
Yield of 9 (%)b
Ph
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
4-ClC6H4
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
4-O2NC6H4Cl
9a
9b
9c
9d
9e
9f
95
86
94
85
97f
87
92
86
97
90
93
94
82
95
85
93
82
96
83
95
84
60
95
97
88
98
88
2c
–
3
3-ClC6H4
4c
–
5d
2-ClC6H4
6c
–
7e
3-MeC6H4
–
9g
9h
9i
8c
2-ClC6H4CH2Cl
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
2,5-diFC6H4NO2
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
2,5-diFC6H4NO2
2-O2NC6H4Cl
9
3,5-diMeC6H4
–
10c
11
12
13c
14
15c
16
17c
18
19c
20
21c
22
23d
24
25c
26
27c
9j
4-MeOC(O)C6H4
9k
9l
4-MeOC6H4
–
9m
9n
9o
9p
9q
9r
9s
4-O2NC6H4
–
furan-2-yl
–
Ph
–
4-MeOC6H4
–
4-FC6H4
–
9t
–
–
9u
9v
9w
9x
9y
9z
9a¢
n-Bu
–
–
–
Fc
–
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
2,5-diFC6H4NO2
2-ClC6H4CH2Cl
–
–
thiophen-3-yl
–
–
–
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).
Synlett 2010, No. 11, 1617–1622 © Thieme Stuttgart · New York

1622
J. Li et al.
LETTER
13C NMR (75 MHz, CDCl3): d = 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
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-2H-1,2,3-
triazol-4-yl)(phenyl)methanone (1a)
General Procedure of the Reaction between Ynones,
Sodium Azide, and Aryl Halides: Regioselective
Synthesis of [2-(4-Nitrophenyl)-5-phenyl-2H-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): d = 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): d = 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
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-2H-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): d = 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).
Copies of NMR spectroscopic, ESI-HRMS analysis, MS
(EI) element analysis, and X-ray crystallography are found
in the Supporting Information.
Synlett 2010, No. 11, 1617–1622 © Thieme Stuttgart · New York