Potassium tert-butoxide promoted cycloaddition reaction for the synthesis of 1,5-disubstituted 1,2,3-triazoles from aromatic azides and trimethylsilyl-protected alkynes

Article abstract of DOI:10.1055/s-0031-1291042

The cycloaddition reaction of aromatic azides and trimethylsilyl alkynes upon treatment with desilylating reagents was investigated. In the process, the use of t-BuOK in wet DMF generated 1,5-disubstituted 1,2,3-triazoles regioselectively in moderate to g

Full text of DOI:10.1055/s-0031-1291042

LETTER
▌1529
letter
Potassium tert-Butoxide Promoted Cycloaddition Reaction for the Synthesis of
1,5-Disubstituted 1,2,3-Triazoles from Aromatic Azides and Trimethylsilyl-
Protected Alkynes
Synthesis of 1,2,3-Triazoles
Luyong Wu,* Yuxue Chen, Mi Tang, Xinming Song, Guangying Chen, Xiaoping Song, Qiang Lin
College of Chemistry and Chemical Engineering, Hainan Normal University, No.99, Longkun South Road, Haikou 571158, P. R. of China
Fax +86(898)65889422.; E-mail: wuluyong@hainnu.edu.cn
Received: 03.01.2012; Accepted after revision: 25.03.2012
substituted 1,2,3-triazoles through direct desilylation of
Abstract: The cycloaddition reaction of aromatic azides and tri-
TMS-alkynes has not been reported.9
methylsilyl alkynes upon treatment with desilylating reagents was
investigated. In the process, the use of t-BuOK in wet DMF gener-
ated 1,5-disubstituted 1,2,3-triazoles regioselectively in moderate
to good yields at ambient temperature.
Table 1 Optimization of the Reaction Conditions for the Desi-
lylation–Cycloadditiona
Key words: alkynes, azides, cycloaddition, triazoles, desilylation
N
desilylating reagants
solvents
N
N
+
TMS
Ph
Ph N3
1a
2a
Ph
Because of their wide range of industrial applications and
biological activities, 1,2,3-triazoles have received wide-
spread attention.1 Among numerous synthetic approaches
to these compounds, the Huisgen cycloaddition of azides
and alkynes is one of the most widely used traditional
methods.2 However, when unsymmetrical alkynes with-
out bulky or electron-withdrawing substituents are used,
the low regioselectivity of the cycloaddition becomes a
major disadvantage. Since the copper(I)-catalyzed azide–
alkyne cycloaddition (CuAAC) reaction generating 1,4-
disubstituted 1,2,3-triazoles regioselectively was discov-
ered,3 considerable interest has been stimulated in devel-
oping new regioselective and convenient methodologies
to access triazole frameworks.4 1,5-Disubstituted 1,2,3-
triazoles, as isomers of 1,4-disubstituted 1,2,3-triazoles,
require distinctive synthetic approaches that differ from
the CuAAC reaction. Fokin and co-workers reported sev-
eral successful methodologies to produce 1,5-disubstitut-
ed 1,2,3-triazoles from azides and terminal alkynes.4f,g,5
Ph
3a
Entry Solvent
Desilylating reagent
Time (h) Yield (%)b,c
1
2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
KF
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
n.d.
13
TBAF (1 N in THF)
NaF
3
n.d.
n.d.
n.d.
70
4
KF·3H2O
TBAF·3H2O
KOH
5
6
7
KOH
68d
61
8
KOH (aq)
Me4NOH (aq)
KOH
9
17
10
11
12
13
14
15
16
17
18
19
56
THF
KOH
23
Trimethylsilyl-protected alkynes (TMS-alkynes) are very
important intermediates in organic chemistry6 and are eas-
ily available through Sonogashira coupling.7 Several au-
thors have reported the use of TMS-alkynes in the
regioselective synthesis of triazoles.8 In these reports, the
same process of desilylation and subsequent cycloaddi-
tion was necessary. Although the nucleophilic attack of
acetylenic anions to azides to form 1,5-disubstituted
1,2,3-triazoles is widely known, the synthesis of 1,5-di-
MeCN
toluene
DMSO
DMF
KOH
n.d.
62
KOH
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
t-BuOKf
57
58
toluene
DMF
n.d.
82e
65e
53e
R1 N3
N
desilylation
N
N
R2
DMF
R2
TMS
R1
DMF
R2
a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), desilylating re-
agent (1.0 mmol), solvent (2 mL), r.t.
b Isolated yield after flash column chromatography.
c n.d. = not determined.
Scheme 1 Synthesis of 1,5-disubstituted 1,2,3-triazole from TMS-al-
kynes and azides
d KOH powder (2.0 equiv) was used.
e Trace water was added.
SYNLETT 2012, 23, 1529–1533
Advanced online publication: 25.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
f t-BuOK (50 mol%) was used.
DOI: 10.1055/s-0031-1291042; Art ID: ST-2012-W0003-L
© Georg Thieme Verlag Stuttgart · New York

1530
L. Wu et al.
LETTER
Based on our interest in triazoles chemistry,10 we exam- replacement of KOH with t-BuOK in the solvents was in-
ined the feasibility of synthesizing 1,5-disubstituted 1,2,3- vestigated and found to afford similar yields (Table 1, en-
triazoles through the cycloaddition reaction from azides tries 14–16). Unexpectedly, when a trace of water (2 mg)
and TMS-alkynes (Scheme 1).
was added to DMF as solvent, the reaction became slow-
er, but the yield of 1,5-diphenyl triazole increased to 82%
(Table 1, entry 17). When t-BuONa used, a yield of 65%
was obtained (Table 1, entry 18). An attempt to reduce the
amount of t-BuOK (50 mol%) was undertaken, however,
the yield decreased to 53% (Table 1, entry 19).
In a screen of reaction conditions, 1-phenyl-2-trimethyl-
silylacetylene (1a) and phenyl azide (2a) were chosen as
the model substrates, as shown in Table 1. Initially, the re-
action was carried out in anhydrous dimethyl sulfoxide
(DMSO) with KF (1.0 equiv) as desilylating reagent at
room temperature (Table 1, entry 1). TMS-alkyne disap- To explore the scope of this reaction, the optimized con-
peared after 24 hours; however, no 1,5-diphenyl-1,2,3-tri- ditions were applied to a range of aromatic azides and
azole was observed (reaction monitored by TLC). Other TMS-alkynes; the results are summarized in Table 2.
fluoride salts, such as NaF, KF·3H2O, and TBAF·3H2O First, the reactions of various substituted phenyl azides
gave the same results (Table 1, entries 3–5). Employing with 1-phenyl-2-TMS-acetylene were conducted (Table
TBAF (1N in THF) as desilylating reagent in the reaction 2, entries 1–10). The reaction tolerated both electron-do-
gave 1,5-diphenyl-1,2,3-triazole albeit in a yield of only nating and electron-withdrawing substituents, and only
13% (Table 1, entry 2). Considering the result reported by slight substitution effects were observed. Steric hindrance
Forkin’s group,5c inclusion of various hydroxides and alk- did play a role in the reaction of azides with ortho-substit-
oxides in the reaction was then investigated. When KOH uents, and gave slightly lower yields (entries 6 and 8).
(1.0 equiv) powder was used, a yield of 70% was achieved Heterocyclic azide, 3-azidopyridine, was suitable as a
(Table 1, entry 6). Increasing the amount of KOH (2.0 substrate and gave the corresponding product in good
equiv) did not lead to an improvement in the yield (entry yield (entry 11). Moreover, the desilylation–cycloaddition
7). When aqueous KOH (1.0 equiv) was used, the yield re- reactions of other aromatic TMS-alkylene substrates with
mained moderate (61%; Table 1, entry 8). To our surprise, aromatic azide were investigated and the anticipated tri-
the use of Me4NOH (aq. 30%) gave a very poor yield azoles were obtained in good yields (entries 12–14). It
(17%; Table 1, entry 9). With the optimum base estab- should be noted that (E)-trimethyl(4-phenylbut-3-en-1-
lished (1.0 equiv KOH powder), the use of others solvents ynyl)silane participated in the reaction to give the corre-
(DMF, toluene, THF and MeCN) was investigated and sponding triazole in a yield of 40%. However, the reaction
found to deliver the corresponding triazoles in the poor to of benzyl azide with 1-phenyl-2-trimethylsilylacetylene
moderate yields (Table 1, entries 10–13). Subsequently, did not provide the expected triazole.
Table 2 Synthesis of 1,5-Disubstituted 1,2,3-Trizaolesa
N
KOt-Bu (1.0 equiv)
N
N
TMS
Entry
1
R2
+
R1 N3
DMF, trace H2O
R1
1
2
R2
3
R1
R2
Ph
Product
Yield (%)b
N
N
N
Ph
82
Ph
3a
3b
N
N
N
2
3
4-MeC6H4
4-ClC6H4
Ph
Ph
82
91
Ph
N
N
N
Ph
Cl
3c
Synlett 2012, 23, 1529–1533
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1,2,3-Triazoles
1531
Table 2 Synthesis of 1,5-Disubstituted 1,2,3-Trizaolesa (continued)
N
KOt-Bu (1.0 equiv)
N
N
TMS
Entry
4
R2
+
R1 N3
DMF, trace H2O
R1
1
2
R2
3
R1
R2
Ph
Product
Yield (%)b
N
N
N
4-MeOC6H4
71
77
Ph
MeO
3d
N
N
N
5
4-BrC6H4
Ph
Ph
Br
3e
N
Cl
N
N
6
7
8
9
2-ClC6H4
Ph
Ph
Ph
Ph
69
74
50
67
Ph
3f
N
N
N
4-Et2NCOC6H4
Ph
Et2NOC
3g
N
N
N
2-MeC6H4
Ph
3h
N
N
F3C
N
3-F3CC6H4
Ph
3i
N
N
N
10
4-O2NC6H4
Ph
42
Ph
O2N
3j
N
N
N
11
12
3-pyridyl
Ph
74
79
Ph
N
3k
N
N
N
Ph
4-MeC6H4
Ph
3l
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1529–1533

1532
L. Wu et al.
LETTER
Table 2 Synthesis of 1,5-Disubstituted 1,2,3-Trizaolesa (continued)
N
KOt-Bu (1.0 equiv)
N
N
R2
+
R1 N3
TMS
DMF, trace H2O
R1
1
2
R2
3
Entry
R1
R2
Product
Yield (%)b
N
N
N
13
4-ClC6H4
4-MeOC6H4
71
MeO
Cl
3m
N
N
N
Cl
14
15
4-MeC6H4
4-ClC6H4
81
40
Me
3n
N
N
N
Ph
Ph
(E)-2-phenylethenyl
Ph
3o
a Reaction conditions: azole (1.0 mmol), TMS-alkyne (1.0 mmol), t-BuOK (1.0 mmol), DMF (2 mL), H2O (2 mg), r.t., 24 h.
b Isolated yield after flash column chromatography.
S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003,
125, 7786. (c) Wu, Y.-M.; Deng, J.; Li, Y. L.; Chen, Q.-Y.
Synthesis 2005, 1314. (d) Li, J.; Wang, D.; Zhang, Y.; Li, J.;
Chen, B. Org. Lett. 2009, 11, 3024. (e) Baskin, J. M.;
Prescher, J. A.; Laughlin, S. T.; Agard, N. J.; Chang, P. V.;
Miller, I. A.; Lo, A.; Codelli, J. A.; Bertozzi, C. R. Proc.
Natl. Acad. Sci. U.S.A. 2007, 104, 16793. (f) Kwok, S. W.;
Fotsing, J. R.; Fraser, R. J.; Rodinov, V. O.; Fokin, V. V.
Org. Lett. 2010, 12, 4217. (g) Krasinski, A.; Fokin, V. V.;
Sharpless, K. B. Org. Lett. 2004, 6, 1237. (h) Meng, X.; Xu,
X.; Gao, T.; Chen, B. Eur. J. Org. Chem. 2010, 5409.
(5) (a) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett.
2004, 6, 1237. (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. Soc. 2005, 127, 15998. (c) Rasmussen, L. K.;
Boren, B. C.; Fokin, V. V. Org. Lett. 2007, 9, 5337.
(6) For recently selected examples, see: (a) Beesu, M.;
Periasamy, M. J. Org. Chem. 2011, 76, 543. (b) Wadhwa,
K.; Chintareddy, V. R.; Verkade, J. G. J. Org. Chem. 2009,
74, 6681. (c) Chintareddy, V. R.; Wadhwa, K.; Verkade, J.
G. J. Org. Chem. 2011, 76, 4482. (d) Aikawa, K.; Hioki, Y.;
Mikami, K. Org. Lett. 2010, 12, 5716. (e) Sakai, N.;
Komatsu, R.; Uchida, N.; Ikeda, R.; Konakahara, T. Org.
Lett. 2010, 12, 1300. (f) Kuninobu, Y.; Ishii, E.; Takai, K.
Angew. Chem. Int. Ed. 2007, 46, 3296. (g) Sa-ei, K.;
Montgomery, J. Org. Lett. 2006, 8, 4441.
In conclusion, the t-BuOK promoted cycloaddition reac-
tion of TMS-alkynes with aromatic azides in wet DMF
has been described. This procedure offers a convenient
methodology to synthesize a series of 1,5-disubstituted-
1,2,3-triazoles.11,12
Acknowledgment
This work was supported by the Education Department of Hainan
Province (No. hjkj2011-20) and the Natural Science Foundation of
Hainan Province (No. 211017).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References
(1) Fan, W.-Q.; Katritzky, A. R. Comprehensive Heterocyclic
Chemistry II; Elsevier: Oxford, 1996.
(2) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Wiley:
New York, 1984.
(3) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Tornøe,
C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057.
(4) For selected examples, see: (a) Zhang, L.; Chen, X.; Xue, P.;
Sun, H. H. Y.; Williams, I. D.; Sharpless, K. B.; Fokin, V.
V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998. (b) Kamijo,
(7) Austin, W. B.; Bilow, N.; Kelleghan, W. J.; Lau, K. S. Y.
J. Org. Chem. 1981, 46, 2280.
(8) (a) Fletcher, J. T.; Walz, S. E.; Keeney, M. E. Tetrahedron
Lett. 2008, 49, 7030. (b) Kamijo, S.; Jin, T.; Yamamoto, Y.
Tetrahedron Lett. 2004, 45, 689. (c) Hu, M.; Li, J.; Yao, S.
Synlett 2012, 23, 1529–1533
© Georg Thieme Verlag Stuttgart · New York

LETTER
Q. Org. Lett. 2008, 10, 5529. (d) Friscourt, F.; Boons, G.
Synthesis of 1,2,3-Triazoles
(12) Analytic data of selected products:
1533
Org. Lett. 2010, 12, 4936. (e) Cuevas, F.; Oliva, A. I.;
Pericàs, M. A. Synlett 2010, 1873. (f) Kloss, F.; Köhn, U.;
Jahn, B. O.; Hager, M. D.; Görls, H.; Schubert, U. S. Chem.
Asian J. 2011, 6, 2816.
1-(4-Methoxyphenyl)-5-phenyl-1H-1,2,3-triazole (3d):
Yield: 71%; pale-yellow solid; mp 83–85 °C; IR (KBr):
3112, 2931, 1511, 763 cm–1; 1H NMR (CDCl3, 400 MHz):
δ = 3.83 (s, 3 H), 6.92 (d, J = 8.8 Hz, 2 H), 7.22–7.24 (m,
2 H), 7.27 (d, J = 8.8 Hz, 2 H), 7.32–7.36 (m, 3 H), 7.85 (s,
1 H); 13C NMR (CDCl3, 100 MHz): δ = 55.4, 114.4, 126.5,
126.7, 128.4, 128.7, 129.0, 129.5, 133.0, 137.6, 160.0;
HRMS (ESI): m/z [M + H]+ calcd for C15H13N3O: 252.1131;
found: 252.1133.
1-Phenyl-5-p-tolyl-1H-1,2,3-triazole (3l): Yield: 79%; pale-
yellow solid; mp 150–151 °C; IR (KBr): 3106, 2924, 1494,
762 cm–1; 1H NMR (CDCl3, 400 MHz): δ = 2.35 (s, 3 H),
7.10–7.15 (m, 4 H), 7.35–7.39 (m, 2 H), 7.42–7.44 (m, 3 H),
7.83 (s, 1 H); 13C NMR (CDCl3, 100 MHz): δ = 21.2, 123.7,
125.1, 128.4, 129.1, 129.2, 129.5, 133.1, 133.2, 136.7,
137.8, 139.3. HRMS (ESI): m/z [M + H]+ calcd for
C15H13N3: 236.1182; found: 236.1182.
(9) Akimova, G. S.; Chistokletov, V. N.; Petrov, A. A. Zh. Org.
Khim. 1967, 3, 968.
(10) Wu, L.-Y.; Xie, Y.-X.; Chen, Z.-S.; Niu, Y.-N.; Liang,
Y.-M. Synlett 2009, 1453.
(11) Synthesis of 1,2,3-Triazoles; General Procedure: To a
mixture of azide (1.0 mmol) and TMS-alkyne (1.0 mmol) in
DMF (2.0 mL) with a trace of H2O (2 mg), was added t-
BuOK (1.0 mmol). The reaction mixture was stirred under
air at room temperature. After 24 hours, the reaction mixture
was quenched by addition of sat. aq NH4Cl (5 mL) and the
mixture was poured into EtOAc (45 mL) and washed with
H2O (3 × 15 mL). The organic layer was dried over
anhydrous Na2SO4 and filtered. The solvent was removed
under reduced pressure and the residue was purified by flash
chromatography (silica gel; EtOAc–petroleum ether).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1529–1533

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.