Copper-catalyzed synthesis of N-unsubstituted 1,2,3-triazoles from nonactivated terminal alkynes

Article abstract of DOI:10.1002/ejoc.200400442

The [3+2] cycloaddition of nonactivated terminal alkynes and trimethylsilyl azide proceeded smoothly in the presence of Cu^I catalyst and DMF/MeOH, to give the corresponding N-unsubstituted triazoles in good to high yields. The reaction most pro

Full text of DOI:10.1002/ejoc.200400442

SHORT COMMUNICATION
Copper-Catalyzed Synthesis of N-Unsubstituted 1,2,3-Triazoles from
Nonactivated Terminal Alkynes
Tienan Jin,[a] Shin Kamijo,[a] and Yoshinori Yamamoto*[a]
Keywords: 1,2,3-Triazoles / Alkynes / Copper / Catalysis / Cycloaddition
The [3+2] cycloaddition of nonactivated terminal alkynes and
trimethylsilyl azide proceeded smoothly in the presence of
copper acetylide species and hydrazoic acid, followed by a
successive [3+2] cycloaddition reaction.
CuI catalyst and DMF/MeOH, to give the corresponding N- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
unsubstituted triazoles in good to high yields. The reaction
Germany, 2004)
most probably proceeds through the in situ formation of a
Introduction
1,2,3-Triazoles have found broad use in agrochemicals
and industrial applications such as dyes and corrosion in-
hibitors, and have been regarded as an interesting unit in
terms of biological activity.[1] Because of their potent use-
fulness, several synthetic methods have been developed re-
cently;[2] especially, the copper catalyzed addition of organo-
azide (RN3) to terminal alkynes has become a useful and
widely applicable method for the synthesis of N-substituted
triazoles [Equation (1)].[3] However, deprotection of the R
group from the triazole framework is difficult in the case of
R ϭ alkyl and aryl. Since the parent compounds N-unsub-
stituted 1,2,3-triazoles have also received much attention
because of their wide utilities,[4] we have been interested in
the synthesis of unsubstituted triazoles. The [3ϩ2] cycload-
dition between alkynes and metal azides has been well in-
vestigated for the construction of N-unsubstituted triazoles
(Scheme 1): the direct addition of dangerous and harmful
hydrazoic acid, which is generated in situ by cautiously re-
acting NaN3 with an acid,[5] to alkynes bearing electron-
withdrawing groups is straightforward.[6] Alternatively, the
addition of trimethylsilyl azide to terminal and internal
alkynes under harsh conditions and subsequent removal of
silyl group provides a much safer procedure.[7] In the stand-
ard procedures[5Ϫ7] for the formation of unsubstituted tria-
Scheme 1. General methods for the formation of N-unsubstituted
1,2,3-triazoles by [3ϩ2] cycloaddition reactions
zoles, it is usually required that starting alkynes are substituted
with an activating functional group, and the reactions are often
conducted at high temperatures for a prolonged period of time.
Therefore, it is desirable to develop a new and efficient synthetic
approach for the formation of N-unsubstituted 1,2,3-triazoles.[8] We
now report the synthesis of N-unsubstituted triazoles 3 by the cop-
per-catalyzed [3ϩ2] cycloaddition reaction of nonactivated ter-
minal alkynes 1 and trimethylsilyl azide 2 in the presence of MeOH/
DMF [Equation (2)].
(2)
(1)
Results and Discussion
[a]
In the cycloaddition between 4-ethynyltoluene 1a with 2,
we investigated the effect of solvents and copper salts on
the formation of the triazole 3a (Table 1). Among the sol-
vents that we tested (under a catalytic amount of CuCl),
Department of Chemistry, Graduate School of Science,
Tohoku University,
Sendai, 980-8578, Japan
Fax: (internat.) ϩ 81-22-217-6784
E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
Eur. J. Org. Chem. 2004, 3789Ϫ3791
DOI: 10.1002/ejoc.200400442
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3789

T. Jin, S. Kamijo, Y. Yamamoto
SHORT COMMUNICATION
protic solvents gave better results (Entries 1 and 2), and a
1:1 mixture of DMF and MeOH improved the yield of 3a
(Entry 3). Other protic solvents such as EtOH and PrOH
gave similar results. We next investigated the effect of the
copper catalysts. Among the copper catalysts that we tested,
CuI gave the highest yield of 3a (Entry 4). Other copper
catalysts such as CuBr2 and Cu powder were also effective
(Entries 5 and 6). The reaction without a copper catalyst
gave a low yield of 3a (Entry 7). Other metal catalysts such
as AuCl3, AgCl, and ZnCl2 were not effective (Entries
8Ϫ10). Very interestingly, the use of 5 mol % of CuI in-
creased the yield up to 88% (Entry 11). To our surprise, the
use of 5 mol % of CuI in a mixture of DMF and H2O also
gave 3a in a similar yield (Entry 12), and copper powder
exhibited high catalytic activity under the same conditions,
although a slightly prolonged reaction time was needed
(Entry 13).
The results of the [3ϩ2] cycloaddition of various terminal
alkynes 1 with 2 are summarized in Table 2. The reaction
of ethynyltoluene 1a with trimethylsilyl azide 2 was carried
out in a mixture of DMF and MeOH (9:1) at 100 °C in the
presence of 5 mol % CuI. The reaction was completed in
12 h to afford 4-tolyl-1,2,3-triazole 3a in 83% yield (Entry
1). As can be seen from the results of Entries 2Ϫ5, the [3ϩ2]
cycloaddition of aryl acetylenes 1bϪ1e gave the corre-
sponding triazoles 3bϪ3e, respectively, in good to high
yields, indicating that the EWG and/or EDG at the para-
position did not exert a significant influence on the reaction
progress. The reaction of alkylacetylenes such as 1-do-
decyne (1f) and tert-butylacetylene (1g) afforded the desired
triazoles 3f and 3g in high yields, although prolonged reac-
tion times were required (Entries 6 and 7). We then exam-
ined the reactions of the conjugated enyne 1h and diyne 1i
(Entries 8 and 9). The reaction took place selectively at the
terminal alkyne moiety to give the triazoles 3h and 3i in
55% and 84% yields, respectively. The alkynes 1j and 1k,
which have a heteroatom substituent at the propargyl-posi-
tion gave the corresponding triazoles 3j and 3k in good to
Table 1. Effect of catalysts and solvents on the formation of the
triazole 3a from 1a
Entry[a] Catalyst
Solvent
Yield (%)[b] high yields (Entries 10 and 11). Sterically bulky (triisoprop-
ylsilyl)acetylene (1l) also reacted without any problems to
give the corresponding triazole 3l in high yield (Entry 12).
1
2
3
4
5
6
7
8
CuCl (20 mol %)
DMF
MeOH
DMF/MeOH (1:1) (64)
DMF/MeOH (1:1) (69)
DMF/MeOH (1:1) 59
14
(55)
CuCl (20 mol %)
CuCl (20 mol %)
CuI (20 mol %)
CuBr2 (20 mol %)
Cu powder (20 mol %) DMF/MeOH (1:1) (64)
none
AuCl3 (20 mol %)
AgCl (20 mol %)
ZnCl2 (20 mol %)
CuI (5 mol %)
CuI (5 mol %)
A proposed mechanism for the reaction forming N-un-
substituted 1,2,3-triazole in the presence of copper catalyst
and MeOH (or H2O) is shown in Scheme 2. At the initial
stage of the catalytic cycle, the reaction of terminal alkynes
1 with CuX produces the copper acetylide A and HX; be-
sides, HN3 B forms in situ from the reaction of TMSN3
and MeOH.[9] The [3ϩ2] cycloaddition between the CϪC
triple bond of the copper acetylide A and HN3 B takes
place readily to form the intermediate C. The CϪC triple
bond is activated by forming a copper acetylide species,
which makes the [3ϩ2] cycloaddition feasible.[3,8a,8b] Pro-
tonolysis of the CϪCu bond of intermediate C by the ter-
minal alkynes 1, HX or MeOH affords the N-unsubstituted
1,2,3-triazoles 3.
DMF/MeOH (1:1) 13
DMF/MeOH (1:1)
DMF/MeOH (1:1)
DMF/MeOH (1:1)
DMF/MeOH (9:1) 88
DMF/H2O (9:1)
0
0
0
9
10
11[c]
12[c]
13[c]
87
86
Cu powder (5 mol %) DMF/H2O (9:1)
[a]
Unless otherwise noted, the reaction of alkyne 1a with TMSN3
(4.0 equiv.) was carried out in the presence of catalyst (20 mol %)
in MeOH/DMF (1:1, 0.5 ) at 100 °C for 12 h. [b] 1H NMR spec-
troscopic yield using dibromomethane as an internal standard. Iso-
[c]
lated yield is shown in parenthesis. 1.5 equiv. TMSN3 was used.
Scheme 2. Proposed mechanism for the formation of N-unsubstituted 1,2,3-triazoles 3
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Eur. J. Org. Chem. 2004, 3789Ϫ3791

Copper-Catalyzed Synthesis of N-Unsubstituted 1,2,3-Triazoles
Table 2. Synthesis of 1,2,3-triazoles 3 under copper catalyst
SHORT COMMUNICATION
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Entry[a]
R
1
Time (h)
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3
4
5
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7
8
p-Me-C6H4
p-MeO-C6H4
C6H5
p-Cl-C6H4
p-CO2Me-C6H4
CH3(CH2)9
tBu
isopropenyl
iPr3SiO(CH2)4CϵC 1i
BnOCH2
1a 12
1b 12
3a
3b
3c
3d
3e
3f
83
89
87
70
95
80
80
55
84
70
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´
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Experimental Section
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3a from 1a: Trimethylsilyl azide (0.1 mL, 0.75 mmol) was added to
a DMF and MeOH solution (1 mL, 9:1) of CuI (4.8 mg,
0.025 mmol) and ethynyltoluene (1a) (58 mg, 0.5 mmol) under Ar
in a pressure vial. The reaction mixture was stirred at 100 °C for
12 h. After consumption of 1a, the mixture was cooled to room
temperature and filtered through a short Florisil pad and concen-
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S. Kamijo, T. Jin, Y. Yamamoto,
1
zole (3a) in 83% yield (66 mg). H NMR (400 MHz, CDCl3): δ ϭ
[8c]
S. Kamijo, T. Jin, Z.
2.40 (s, 3 H), 7.27Ϫ7.24 (m, 2 H), 7.72Ϫ7.67 (m, 2 H), 7.93 (s, 1
H), 11.88 (br. s, 1 H) ppm. 13C NMR (67.80 MHz, CD3OD): δ ϭ
21.25, 126.82, 127.18, 128.17, 130.54, 139.54, 146.67 ppm. IR
(KBr): ν˜ ϭ 3156, 3124, 2898, 1479, 1076, 821 cmϪ1. C9H9N3
(159.2): calcd. C 67.57, H 5.67, N 26.26; found C 67.69, H 5.75, N
26.55. HRMS (EI): calcd. for C9H9N3 [Mϩ] 159.0791; found
159.0791.
[9]
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Received June 25, 2004
Eur. J. Org. Chem. 2004, 3789Ϫ3791
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