A new method for the synthesis of 1,5-disubstituted 1,2,3-triazoles via triazolium salt intermediates

Article abstract of DOI:10.1055/s-0032-1316806

A new transition metal free procedure for the synthesis of 1,5-disubstituted 1,2,3-triazoles, which proceeds via a triazolium salt intermediate is described. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316806

PAPER
▌3603
paper
A New Method for the Synthesis of 1,5-Disubstituted 1,2,3-Triazoles via
Triazolium Salt Intermediates
Synthesis of 1,5-Disubstituted 1,2,3-Triazoles
Shinichi Koguchi,* Kazuki Izawa
Department of Chemistry, School of Science, Tokai University, 4-1-1 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan
Fax +81(463)502094; E-mail: koguchi@tokai-u.jp
Received: 06.08.2012; Accepted after revision: 25.09.2012
This work is dedicated on the occasion of the birth of my son. His name is Shigemasa.
1) NaN3,
DMPM-Cl
CuAAC
Abstract: A new transition metal free procedure for the synthesis
of 1,5-disubstituted 1,2,3-triazoles, which proceeds via a triazolium
salt intermediate is described.
R1
R1
deprotection
R1
N
N
R2
2) R2-X
N
N
DMPM
N
R2
Key words: triazoles, triazolium salts, azides, alkynes, regioselec-
N
tive
X
Scheme 1 The synthesis of 1,5-disubstituted 1,2,3-triazoles
Substituted 1,2,3,-triazoles are important structural com-
ponents of a variety of biologically active compounds.
They possess antibacterial,1 anti-allergic,2 anti-HIV,3 and
antineoplastic activities.4 Additionally, they have been
widely used in various research fields, including materials
science5 and synthetic organic chemistry.6
Initially, we investigated the copper-catalyzed regioselec-
tive Huisgen cycloaddition of an alkyne and an azide (the
so-called click reaction). The substrates, 1-(3,4-dimeth-
oxybenzyl)-4-substituted 1,2,3-triazoles 1a–c, were syn-
thesized in good yields as white solids, via one-pot
reactions of 4-(chloromethyl)-1,2-dimethoxybenzene, so-
dium azide and the appropriate alkyne under the Sharpless
protocol13 (Scheme 2). The obtained products were puri-
fied by recrystallization.
Many procedures have been developed for the synthesis
of 1,4-disubstituted 1,2,3-triazoles, with the copper(I)-
catalyzed azide–alkyne cycloaddition (CuAAC) between
organic azides and terminal alkynes representing a useful
and extensively applied method.7
R1
1) NaN3
However, there are only a few reported methods describ-
ing the synthesis of 1,5-disubstituted 1,2,3-triazoles from
organic azides and terminal alkynes. Fokin and co-work-
ers have described the ruthenium(II)-catalyzed [CpRu-
Cl(PPh3)2] regioselective synthesis of 1,5-disubstituted
1,2,3-triazoles from azides and alkynes.8 Chuprakov and
co-workers reported the synthesis of 1,5-disubstituted
1,2,3-triazoles via direct palladium-catalyzed C-5 aryla-
tion from 4,5-unsubstituted 1,2,3-triazoles.9 Both meth-
ods are disadvantaged by their use of expensive transition
metals. In contrast, transition metal free click reactions us-
ing a silyl acetylene or a bromomagnesium acetylide have
been reported for the synthesis of 1,5-disubstituted 1,2,3-
triazoles.10,11 However, these methods need an expensive
silyl reagent or anhydrous reaction conditions. 1,5-Disub-
stituted 1,2,3-triazoles have also been prepared in the
presence of hydroxide bases, but the substituent on the tri-
azole ring was limited to an aryl group.12
DMPM Cl
N
N
DMPM
R1
N
2)
sodium ascorbate
CuSO4
1a R1= Ph
1b R1= n-Bu
1c R1= c-Pr
73%
36%
63%
t-BuOH
H2O, r.t.
Scheme
2
Synthesis of 1-(3,4-dimethoxybenzyl)-4-substituted
1,2,3-triazoles 1a–c
We prepared the 3,4-disubstituted-1,2,3-triazolium salt
intermediates from 1,4-disubstituted-1,2,3-triazoles 1a–c
in the following manner. A mixture of triazole 1a–c (3.5
mmol), alkyl halide (7.0 mmol), and acetonitrile (2.0 mL)
was sealed in a glass vial and warmed to 80 °C overnight.
The solvent was then removed under reduced pressure and
the products were obtained by silica gel column chroma-
tography using chloroform–methanol as the eluent. A va-
riety of functional groups could be incorporated into the
triazolium salt (Table 1).
In this paper, we describe the catalytic formation of 1,5-
disubstituted 1,2,3,-triazoles via a 1-protected-3,4-disub-
stituted 1,2,3-triazolium salt intermediate without the re-
quirement of a transition-metal catalyst (Scheme 1).
Next, the effect of varying the halogen component on the
synthesis of the triazolium salt was investigated. The re-
activity of benzyl chloride was found to be the same as
that of benzyl bromide (Table 1, entry 4). Also, the length
of the alkyl chain was found to influence the reactivity of
triazolium salt formation. Alkyl halides possessing longer
carbon chains (ethyl iodide or n-butyl iodide) led to lower
yields of the corresponding salts (Table 1, entries 1, 5 and
SYNTHESIS 2012, 44, 3603–3608
Advanced online publication: 17.10.2012
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0
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7
8
8
1
1
4
3
7
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2
1
0
X
DOI: 10.1055/s-0032-1316806; Art ID: SS-2012-F0633-OP
© Georg Thieme Verlag Stuttgart · New York

3604
S. Koguchi, K. Izawa
PAPER
6). However, the synthesis of 1-(3,4-dimethoxybenzyl)-3- the triazolium salt using ceric ammonium nitrate (CAN)
(2-hydroxyethyl)-4-phenyl-1H-1,2,3-triazolium bromide in N,N-dimethylformamide. The deprotection of 3-ben-
(2g) using 2-bromoethanol only proceeded in 35% yield zyl-1-(3,4-dimethoxybenzyl)-4-phenyl-1H-1,2,3-triazoli-
(Table 1, entry 7).
um bromide (2d) using method B gave 1-benzyl-5-
phenyl-1H-1,2,3-triazole (3d) in 72% yield (Table 1, en-
try 4). However, removal of the protecting group did not
progress smoothly with compounds containing a non-aro-
matic group (n-butyl and cyclopropyl) at C-4 of the triazo-
lium salt (2b and 2c) under the conditions of method B
(Table 1, entries 2 and 3). Hence, the synthesis of 1,2,3-
triazoles 3 with aliphatic substituents at C-5 was possible
using method A. Finally, we examined the deprotection of
the 3,4-dimethoxybenzyl-1,2,3-triazolium salts using pal-
ladium on carbon (Pd/C) in the presence of hydrogen gas,
or with trifluoroacetic acid, albeit without success.
We have developed two methods for the deprotection
(methods A and B) of triazolium salts 2. Ammonium ni-
trate (NH4NO3) proved to be an efficient reagent for
cleavage of the 3,4-dimethoxybenzyl group. Thus, treat-
ment of salts 2a–c with ammonium nitrate (2 equiv) in
N,N-dimethylformamide at 120 °C gave the expected 1,5-
disubstituted 1,2,3-triazoles in good to excellent yields
(Table 1, entries 1–3, method A). However, this method
only gave a poor yield (6%) of the corresponding benzyl-
substituted product 3d (Table 1, entry 4). The alternative
developed procedure (method B) involved deprotection of
Table 1 Synthesis of 1,5-Disubstituted 1,2,3-Triazoles 3a–j
Entry 1,4-Disubstituted
1,2,3-triazolea
Alkyl halide
3,4-Disubstituted
Yieldc
quant.
1,5-Disubstituted
1,2,3-triazoled
Yieldc
1,2,3-triazolium saltb
Ph
Ph
Ph
method A: quant.
method B: 99%
N
N
N
I–
1
MeI
N
N
N
N
DMPM
Me
N
N
DMPM
Me
N
N
N
N
N
N
1a
3a
2a
n-Bu
n-Bu
n-Bu
method A: 92%
method B: trace
N
I–
DMPM
Me
N
N
N
2
3
4
5
6
7
MeI
quant.
96%
90%
77%
50%
35%
DMPM
Me
N
N
N
N
N
N
1b
3b
2b
c-Pr
c-Pr
c-Pr
method A: 80%
method B: trace
N
N
N
N
N
N
I–
DMPM
Me
Bn
Et
N
N
N
MeI
DMPM
Me
N
N
N
N
N
1c
3c
2c
Ph
Ph
method A: 6%
method B: 72%
N
Br–
DMPM
N
N
1a
1a
1a
1a
BnBr
EtI
Bn
3d
2d
Ph
Ph
method A: 71%
method B: 72%
N
I–
DMPM
N
N
Et
3e
2e
Ph
Ph
method A: 93%
method B: 51%
N
I–
DMPM
n-Bu
N
N
n-BuI
n-Bu
3f
2f
Ph
Ph
method A: 58%
method B: 46%
N
Br–
DMPM
N
N
(CH2)2OH
HO(CH2)2Br
(CH2)2OH
3g
2g
Synthesis 2012, 44, 3603–3608
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 1,5-Disubstituted 1,2,3-Triazoles
3605
Table 1 Synthesis of 1,5-Disubstituted 1,2,3-Triazoles 3a–j (continued)
Entry 1,4-Disubstituted
1,2,3-triazolea
Alkyl halide
3,4-Disubstituted
Yieldc
84%
1,5-Disubstituted
1,2,3-triazoled
Yieldc
1,2,3-triazolium saltb
Ph
Ph
method A: 49%
method B: 36%
N
N
N
Br–
8
1a
4-BrC6H4CH2Br
DMPM
CH2C6H4-4-Br
N
N
CH2C6H4-4-Br
CH2C6H4-4-Me
CH2C6H4-3-Br
N
N
N
N
N
3h
2h
Ph
Ph
N
method A: 35%
method B: 31%
DMPM
CH2C6H4-4-Me
N
N
9
1a
1a
4-MeC6H4CH2Br
3-BrC6H4CH2Br
66%
68%
Br–
3i
2i
Ph
Ph
method A: 28%
method B: 33%
N
N
Br–
DMPM
CH2C6H4-3-Br
N
N
10
N
3j
2j
a DMPM = 3,4-dimethoxybenzyl.
b Reagents and conditions: 1-(3,4-dimethoxybenzyl)-4-substituted-1,2,3-triazole 1a–c (3.5 mmol), alkyl halide (7.0 mmol), MeCN (2.0 mL),
80 °C, 11 h.
c Yield of isolated product.
d Reagents and conditions: Method A: 3,4-disubstituted-1,2,3-triazolium salt 2a–j (1.5 mmol), NH4NO3 (3.0 mmol), DMF (5 mL), 120 °C, 11
h. Method B: 3,4-disubstituted-1,2,3-triazolium salt 2a–j (1.0 mmol), CAN (2.0 mmol), DMF (5 mL), 120 °C, 13 h.
(dd, J = 8.2, 1.9 Hz, 1 H), 7.32 (t, J = 7.4 Hz, 1 H), 7.40 (t, J = 7.7
Hz, 2 H), 7.64 (s, 1 H), 7.80 (d, J = 7.7 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 54.1, 55.89, 55.92, 111.1, 111.2,
In summary, we have demonstrated the synthesis of 1,5-
disubstituted 1,2,3-triazoles via a triazolium salt interme-
diate. The reactions proceeded under cost-effective and
environmentally benign conditions without using any tox-
119.3, 120.8, 125.6, 126.9, 128.1, 128.7, 130.6, 149.4, 149.4.
ic reagents or expensive transition metal catalysts. Further HRMS (APCI): m/z [M + H]+ calcd for C17H18N3O2: 296.1399;
found: 296.1452.
study of this chemistry is under way.
4-Butyl-1-(3,4-dimethoxybenzyl)-1H-1,2,3-triazole (1b)
Yield: 791 mg (2.73 mmol; 36%); white solid; mp 86–87 °C.
All chemicals (reagent grade) were obtained from commercial sup-
pliers and were used as supplied. The progress of the reactions was
monitored by TLC using aluminum sheets coated with silica gel 60
1H NMR (500 MHz, CDCl3): δ = 0.91 (t, J = 7.4 Hz, 3 H), 1.36 (q,
J = 7.4 Hz, 2 H), 1.60–1.64 (m, 2 H), 2.69 (t, J = 7.8 Hz, 2 H), 3.84
(s, 3 H), 3.89 (s, 3 H), 5.42 (s, 2 H), 6.77 (s, 1 H), 6.85 (s, 2 H), 7.15
(s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 13.7, 22.2, 25.4, 31.5, 53.8, 55.9,
111.0, 111.2, 120.2, 120.6, 127.4, 149.3, 149.4.
F254 (Merck). Column chromatography was performed using silica
gel 60 (Kanto Chemical). Melting points were obtained with a
Yamato MP-21 melting point apparatus. NMR spectra were record-
ed on a Bruker Avance DRX 500 (1H: 500 MHz, 13C: 125 MHz)
spectrometer with CDCl3 as the solvent. Chemical shifts (δ) are ex-
pressed in ppm and refer to the residual peak of the solvent or TMS
as an internal standard; coupling constants (J) are in Hz. The mass
analyses were obtained using a JEOL AccuTOF LC-plus JMS-
T100LP spectrometer.
HRMS (APCI): m/z [M + H]+ calcd for C15H22N3O2: 276.1712;
found: 276.1765.
4-Cyclopropyl-1-(3,4-dimethoxybenzyl)-1H-1,2,3-triazole (1c)
Yield: 1272 mg (4.90 mmol; 63%); white solid; mp 74–75 °C.
1H NMR (500 MHz, CDCl3): δ = 0.78–0.83 (m, 2 H), 0.89–0.94 (m,
2 H), 1.87–1.94 (m, 1 H), 3.84 (s, 3 H), 3.88 (s, 3 H), 5.39 (s, 2 H),
6.78 (s, 1 H), 6.85 (s, 2 H), 7.11 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 6.7, 7.6, 53.8, 55.87, 55.89,
111.1, 111.2, 119.3, 120.7, 127.2, 149.3, 149.4.
HRMS (APCI): m/z [M + H]+ calcd for C14H18N3O2: 260.1399;
found: 260.1456.
1-(3,4-Dimethoxybenzyl)-4-substituted-1H-1,2,3-triazoles 1a-c;
General Procedure
A soln of 4-(chloromethyl)-1,2-dimethoxybenzene (40 mmol) and
distilled H2O (25 mL) in t-BuOH (75 mL) was added to NaN3 (40
mmol). The resulting mixture was stirred at r.t. for 24 h and then
added to a mixture of ethynylbenzene (40 mmol), CuSO4 (8 mmol)
in distilled H2O (25 mL), and sodium ascorbate (16 mmol) in H2O
(25 mL). After stirring for 24 h at r.t., the solvent was removed un-
der vacuum and the mixture extracted with CHCl3, and the organic
layer was washed with H2O, dried (MgSO4) and evaporated. The
residue was purified by recrystallization from CHCl3–Et2O.
1-(3,4-Dimethoxybenzyl)-3,4-disubstituted-1H-1,2,3-triazoli-
um Salts 2a–j; General Procedure
A soln of 1-(3,4-dimethoxybenzyl)-4-substituted-1H-1,2,3-triazole
1a–c (3.5 mmol) and an alkyl halide (7.0 mmol) in MeCN (2.0 mL)
was stirred at 80 °C for 11 h. H2O was added and the mixture ex-
tracted with CHCl3. The organic layers were combined, washed
with distilled H2O and dried (MgSO4). The solvent was removed
1-(3,4-Dimethoxybenzyl)-4-phenyl-1H-1,2,3-triazole (1a)
Yield: 4195 mg (14.20 mmol; 73%); white solid; mp 120–121 °C.
1H NMR (500 MHz, CDCl3): δ = 3.85 (s, 3 H), 3.89 (s, 3 H), 5.51
(s, 2 H), 6.83 (d, J = 1.9 Hz, 1 H), 6.87 (d, J = 8.2 Hz, 1 H), 6.92
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3603–3608

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S. Koguchi, K. Izawa
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under vacuum and the product was isolated by silica gel column
chromatography (CHCl3–MeOH).
HRMS (APCI): m/z [M – I]+ calcd for C19H22N3O2: 324.1712;
found: 324.1760.
1-(3,4-Dimethoxybenzyl)-3-methyl-4-phenyl-1H-1,2,3-triazoli-
um Iodide (2a)
Yield: 1404 mg (3.21 mmol; quant.); orange oil.
3-Butyl-1-(3,4-dimethoxybenzyl)-4-phenyl-1H-1,2,3-triazoli-
um Iodide (2f)
Yield: 476 mg (0.99 mmol; 50%); orange oil.
1H NMR (500 MHz, CDCl3): δ = 3.89 (s, 3 H), 3.98 (s, 3 H), 4.29
(s, 3 H), 5.98 (s, 2 H), 6.89 (d, J = 8.2 Hz, 1 H), 7.23 (dd, J = 8.2,
1.9 Hz, 1 H), 7.49 (d, J = 1.9 Hz, 1 H), 7.54–7.62 (m, 3 H), 7.65–
7.68 (m, 2 H), 9.37 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 39.1, 55.9, 56.9, 57.4, 111.4,
113.3, 121.7, 122.8, 123.4, 129.1, 129.5, 129.7, 132.0, 143.0, 149.5,
150.2.
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 5.2 Hz, 3 H), 1.30–
1.36 (m, 2 H), 1.90–1.93 (m, 2 H), 3.87 (s, 3 H), 3.97 (s, 3 H), 4.54
(t, J = 6.2 Hz, 2 H), 6.03 (s, 2 H), 6.88 (d, J = 8.2 Hz, 1 H), 7.26 (dd,
J = 8.2, 2.0 Hz, 1 H), 7.52–7.56 (m, 5 H), 7.57–7.59 (m, 1 H), 9.46
(s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 13.0, 19.2, 30.7, 51.7, 55.6, 55.8,
56.7, 111.2, 113.1, 121.7, 122.6, 123.4, 129.3, 129.4, 129.5, 131.7,
142.3, 149.2, 150.0.
HRMS (APCI): m/z [M – I]+ calcd for C18H20N3O2: 310.1556;
found: 310.1606.
HRMS (APCI): m/z [M – I]+ calcd for C21H26N3O2: 352.2025;
found: 352.2038.
4-Butyl-1-(3,4-dimethoxybenzyl)-3-methyl-1H-1,2,3-triazoli-
um Iodide (2b)
1-(3,4-Dimethoxybenzyl)-3-(2-hydroxyethyl)-4-phenyl-1H-
1,2,3-triazolium Bromide (2g)
Yield: 742 mg (1.12 mmol; 35%); colorless oil.
Yield: 1106 mg (2.56 mmol; quant.); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 0.95 (t, J = 7.4 Hz, 3 H), 1.45 (q,
J = 7.4 Hz, 2 H), 1.73–1.77 (m, 2 H), 2.84 (t, J = 8.0 Hz, 2 H), 3.87
(s, 3 H), 3.96 (s, 3 H), 4.23 (s, 3 H), 5.87 (s, 2 H), 6.87 (d, J = 8.2
Hz, 1 H), 7.16 (dd, J = 8.2, 2.0 Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H),
9.19 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 13.4, 22.0, 23.6, 28.8, 38.6, 55.9,
56.7, 57.0, 111.3, 112.9, 122.5, 123.5, 128.6, 144.4, 149.4, 150.1.
1H NMR (500 MHz, CDCl3): δ = 3.88 (s, 3 H), 3.94 (s, 3 H), 4.11–
4.14 (m, 2 H), 4.52 (t, J = 4.5 Hz, 2 H), 5.87 (s, 2 H), 6.89 (d, J = 8.1
Hz, 1 H), 7.20 (dd, J = 8.1, 1.5 Hz, 1 H), 7.38 (d, J = 1.5 Hz, 1 H),
7.46 (t, J = 7.4 Hz, 2 H), 7.53 (t, J = 7.4 Hz, 1 H), 7.69 (d, J = 7.4
Hz, 2 H), 8.74 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 54.1, 55.8, 56.4, 57.4, 59.5,
111.3, 113.2, 123.0, 123.1, 128.4, 129.3, 130.0, 131.5, 143.8, 149.4,
150.1.
HRMS (APCI): m/z [M – I]+ calcd for C16H24N3O2: 290.1869;
found: 290.1913.
HRMS (APCI): m/z [M – Br]+ calcd for C19H22N3O3: 340.1661;
found: 340.1712.
4-Cyclopropyl-1-(3,4-dimethoxybenzyl)-3-methyl-1H-1,2,3-tri-
azolium Iodide (2c)
Yield: 1175 mg (2.92 mmol; 96%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 1.12–1.16 (m, 2 H), 1.23–1.28 (m,
2 H), 1.90–1.97 (m, 1 H), 3.87 (s, 3 H), 3.96 (s, 3 H), 4.31 (s, 3 H),
5.81 (s, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 7.16 (dd, J = 8.2, 2.1 Hz, 1
H), 7.38 (d, J = 2.1 Hz, 1 H), 9.21 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 4.4, 8.3, 38.3, 55.9, 56.8, 57.2,
111.4, 113.1, 122.6, 123.5, 128.0, 146.2, 149.5.
HRMS (APCI): m/z [M – I]+ calcd for C15H20N3O2: 274.1556;
found: 274.1620.
3-(4-Bromobenzyl)-1-(3,4-dimethoxybenzyl)-4-phenyl-1H-
1,2,3-triazolium Bromide (2h)
Yield: 1427 mg (2.80 mmol; 84%); orange oil.
1H NMR (500 MHz, CDCl3): δ = 3.88 (s, 3 H), 3.95 (s, 3 H), 5.63
(s, 2 H), 6.08 (s, 2 H), 6.87 (d, J = 8.2 Hz, 2 H), 6.96 (d, J = 8.2 Hz,
2 H), 7.48–7.57 (m, 8 H), 9.91 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 54.8, 55.8, 56.4, 57.3, 111.3,
113.0, 122.6, 124.1, 129.5, 129.6, 129.82, 129.84, 132.3, 142.7,
149.3, 150.0.
HRMS (APCI): m/z [M – Br]+ calcd for C24H23N3O2Br: 464.0974
(79Br), 466.0953 (81Br); found: 464.0944 (79Br), 466.0919 (81Br).
3-Benzyl-1-(3,4-dimethoxybenzyl)-4-phenyl-1H-1,2,3-triazoli-
um Bromide (2d)
Yield: 375 mg (0.79 mmol; 90%); yellow oil.
1-(3,4-Dimethoxybenzyl)-3-(4-methylbenzyl)-4-phenyl-1H-
1,2,3-triazolium Bromide (2i)
Yield: 1000 mg (2.08 mmol; 66%); orange oil.
1H NMR (500 MHz, CDCl3): δ = 2.35 (s, 3 H), 3.88 (s, 3 H), 3.96
(s, 3 H), 5.59 (s, 2 H), 6.17 (s, 2 H), 7.12–7.30 (m, 4 H), 7.37–7.66
(m, 8 H), 10.10 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 20.4, 54.7, 55.2, 55.7, 56.1,
121.0, 127.3, 127.5, 128.1, 128.7, 128.9, 129.0, 129.1, 138.65,
138.68, 141.9, 148.5, 149.2.
1H NMR (500 MHz, CDCl3): δ = 3.88 (s, 3 H), 3.96 (s, 3 H), 5.66
(s, 2 H), 6.17 (s, 2 H), 6.88 (d, J = 8.2 Hz, 1 H), 7.08 (d, J = 7.1 Hz,
2 H), 7.29 (dd, J = 8.2, 1.8 Hz, 1 H), 7.34–7.41 (m, 3 H), 7.46–7.54
(m, 5 H), 7.58 (d, J = 1.8 Hz, 1 H), 10.10 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 55.2, 55.7, 56.3, 57.2, 111.1,
112.8, 121.6, 122.5, 123.9, 127.8, 129.1, 129.4, 129.5, 129.6, 131.2,
131.7, 142.6, 149.2, 149.9.
HRMS (APCI): m/z [M – Br]+ calcd for C24H24N3O2: 386.1869;
found: 386.1878.
HRMS (APCI): m/z [M – Br]+ calcd for C25H26N3O2: 400.2025;
found: 400.2035.
1-(3,4-Dimethoxybenzyl)-3-ethyl-4-phenyl-1H-1,2,3-triazolium
Iodide (2e)
3-(3-Bromobenzyl)-1-(3,4-dimethoxybenzyl)-4-phenyl-1H-
1,2,3-triazolium Bromide (2j)
Yield: 1216 mg (2.23 mmol; 68%); orange oil.
1H NMR (500 MHz, CDCl3): δ = 3.87 (s, 3 H), 3.97 (s, 3 H), 5.63
(s, 2 H), 6.15 (s, 2 H), 7.20–7.62 (m, 12 H), 9.90 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 54.3, 55.4, 56.0, 56.8, 110.9,
121.1, 122.4, 126.6, 129.08, 129.16, 129.18, 130.3, 130.4, 142.3,
149.8, 150.0.
Yield: 1181 mg (2.61 mmol; 77%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 1.65 (t, J = 7.3 Hz, 3 H), 3.89 (s,
3 H), 3.99 (s, 3 H), 4.57 (q, J = 7.3 Hz, 2 H), 6.04 (s, 2 H), 6.89 (d,
J = 8.2 Hz, 1 H), 7.23 (dd, J = 8.1, 2.1 Hz, 1 H), 7.54 (d, J = 2.1 Hz,
1 H), 7.56–7.64 (m, 5 H), 9.41 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 14.4, 47.6, 55.9, 56.8, 57.5,
111.4, 113.3, 121.8, 122.8, 123.5, 129.3, 129.5, 129.7, 131.9, 142.4,
149.5, 150.2.
HRMS (APCI): m/z [M – Br]+ calcd for C24H23N3O2Br: 464.0974
(79Br), 466.0953 (81Br); found: 464.0944 (79Br), 466.0922 (81Br).
Synthesis 2012, 44, 3603–3608
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 1,5-Disubstituted 1,2,3-Triazoles
3607
1,5-Disubstituted 1H-1,2,3-triazoles 3a–j; General Procedure
(Method A)
1-Ethyl-5-phenyl-1H-1,2,3-triazole (3e)
Yield: 54 mg (0.31 mmol; 71%) using method A; 213 mg (1.23
mmol; 72%) using method B; orange oil.
1H NMR (500 MHz, CDCl3): δ = 1.49 (t, J = 7.3 Hz, 3 H), 4.41 (q,
J = 7.3 Hz, 2 H), 7.39 (m, 2 H), 7.47–7.51 (m, 3 H), 7.70 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 15.5, 43.3, 127.1, 128.6, 129.0,
129.3, 133.0, 137.3.
HRMS (APCI): m/z [M + H]+ calcd for C10H12N3: 174.1031; found:
174.0943.
A soln of 1-(3,4-dimethoxybenzyl)-3,4-disubstituted-1H-1,2,3-tri-
azolium salt 2a–j (1.5 mmol) and NH4NO3 (3.0 mmol) in DMF (5
mL) was stirred at 120 °C for 11 h. The solvent was removed under
vacuum and the mixture was extracted with CHCl3 and washed with
H2O. The organic layers were combined, washed with H2O, and
dried (MgSO4). The solvent was removed under vacuum and the
product was isolated by silica gel column chromatography (CHCl3–
MeOH).
1,5-Disubstituted 1H-1,2,3-triazoles 3a–j; General Procedure
(Method B)
1-Butyl-5-phenyl-1H-1,2,3-triazole (3f)
Yield: 115 mg (0.57 mmol, 93%) using method A; 90 mg (0.45
mmol; 51%) using method B; orange oil.
1H NMR (500 MHz, CDCl3): δ = 0.86 (t, J = 6.2 Hz, 3 H), 1.25–
1.31 (m, 2 H), 1.80–1.84 (m, 2 H), 4.35 (t, J = 6.2 Hz, 2 H), 7.37–
7.40 (m, 2 H), 7.47–7.51 (m, 3 H), 7.69 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 13.2, 19.4, 31.9, 47.8, 125.4,
127.0, 128.50, 128.54, 128.9, 129.2, 132.7, 137.5.
HRMS (APCI): m/z [M + H]+ calcd for C12H16N3: 202.1344; found:
A soln of 1-(3,4-dimethoxybenzyl)-3,4-disubstituted-1H-1,2,3-tri-
azolium salt 2a–j (1.0 mmol) and CAN (2.0 mmol) in DMF (5 mL)
was stirred at 120 °C for 13 h. The solvent was removed under vac-
uum and the mixture was extracted with CHCl3 and washed with
H2O. The organic layers were combined, washed with H2O, and
dried (MgSO4). The solvent was removed under vacuum and the
product was isolated by silica gel column chromatography (CHCl3–
MeOH).
202.1448.
1-Methyl-5-phenyl-1H-1,2,3-triazole (3a)
Yield: 263 mg (1.65 mmol; quant.) using method A, 176 mg (1.11
mmol; 99%) using method B; yellow oil.
1H NMR (500 MHz, CDCl3): δ = 4.08 (s, 3 H), 7.40–7.43 (m, 2 H),
7.47–7.51 (m, 3 H), 7.74 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 36.0, 127.3, 128.1, 128.3, 128.5,
128.6, 132.0, 137.4.
HRMS (APCI): m/z [M + H]+ calcd for C9H10N3: 160.0874; found:
160.0824.
2-(5-Phenyl-1H-1,2,3-triazol-1-yl)ethanol (3g)
Yield: 38 mg (0.20 mmol; 58%) using method A; 30 mg (0.16
mmol; 46%) using method B; colorless oil.
1H NMR (500 MHz, CDCl3): δ = 4.14 (t, J = 5.0 Hz, 2 H), 4.42 (t,
J = 5.0 Hz, 2 H), 7.42–7.46 (m, 2 H), 7.48–7.52 (m, 3 H), 7.72 (s, 1
H).
13C NMR (125 MHz, CDCl3): δ = 50.4, 61.0, 126.6, 129.00, 129.04,
129.5, 132.6, 138.8.
HRMS (APCI): m/z [M + H]+ calcd for C10H12N3O: 190.0980;
found: 190.1083.
5-Butyl-1-methyl-1H-1,2,3-triazole (3b)
Yield: 253 mg (1.82 mmol; 92%) using method A; trace using
method B; yellow oil.
1H NMR (500 MHz, CDCl3): δ = 0.96 (t, J = 7.4 Hz, 3 H), 1.39–
1.45 (m, 2 H), 1.62–1.66 (m, 2 H), 2.62 (t, J = 7.7 Hz, 2 H), 3.95 (s,
3 H), 7.45 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 13.4, 21.9, 22.5, 29.7, 34.0,
131.7, 137.2.
HRMS (APCI): m/z [M + H]+ calcd for C7H14N3: 140.1187; found:
140.1154.
1-(4-Bromobenzyl)-5-phenyl-1H-1,2,3-triazole (3h)
Yield: 191 mg (0.61 mmol; 49%) using method A; 142 mg (0.45
mmol; 36%) using method B; yellow oil.
1H NMR (500 MHz, CDCl3): δ = 5.51 (s, 2 H), 7.50 (m, 1 H), 7.16
(m, 1 H), 7.21–7.28 (m, 3 H), 7.40–7.46 (m, 4 H), 7.74 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 53.4, 119.4, 122.8, 125.8, 128.2,
128.75, 128.83, 129.0, 129.6, 131.9, 132.2, 133.7, 148.3.
HRMS (APCI): m/z [M + H]+ calcd for C15H13N3Br: 314.0293
(79Br), 316.0272 (81Br); found: 314.0343 (79Br), 316.0321 (81Br).
5-Cyclopropyl-1-methyl-1H-1,2,3-triazole (3c)
Yield: 211 mg (1.71 mmol; 80%) using method A; trace using
method B; orange oil.
1H NMR (500 MHz, CDCl3): δ = 0.68–0.72 (m, 2 H), 1.03–1.08 (m,
2 H), 1.67–1.72 (m, 1 H), 4.05 (s, 3 H), 7.26 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 3.4, 6.3, 34.1, 130.3, 139.5.
1-(4-Methylbenzyl)-5-phenyl-1H-1,2,3-triazole (3i)
Yield: 90 mg (0.36 mmol; 35%) using method A; 80 mg (0.32
mmol; 31%) using method B; yellow oil.
1H NMR (500 MHz, CDCl3): δ = 2.31 (s, 3 H), 5.51 (s, 2 H), 6.99
(d, J = 8.0 Hz, 2 H), 7.09 (d, J = 8.0 Hz, 2 H), 7.25–7.28 (m, 2 H),
7.41–7.46 (m, 3 H), 7.74 (s, 1 H).
HRMS (APCI): m/z [M + H]+ calcd for C6H10N3: 124.0874; found:
124.1042.
13C NMR (125 MHz, CDCl3): δ = 20.9, 51.4, 126.8, 127.0, 128.7,
128.8, 129.3, 129.6, 132.3, 133.0, 137.7, 137.9.
HRMS (APCI): m/z [M + H]+ calcd for C16H16N3: 250.1344; found:
250.1410.
1-Benzyl-5-phenyl-1H-1,2,3-triazole (3d)
Yield: 11 mg (0.05 mmol; 6%) using method A; 213 mg (0.91
mmol; 72%) using method B; orange oil.
1H NMR (500 MHz, CDCl3): δ = 5.55 (s, 2 H), 7.06–7.09 (m, 2 H),
7.24–7.29 (m, 5 H), 7.39–7.44 (m, 3 H), 7.75 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 51.8, 126.8, 127.1, 128.1, 128.77,
128.84, 128.9, 129.5, 133.2, 135.4.
HRMS (APCI): m/z [M + H]+ calcd for C15H14N3: 236.1187; found:
236.1261.
1-(3-Bromobenzyl)-5-phenyl-1H-1,2,3-triazole (3j)
Yield: 100 mg (0.32 mmol; 28%) using method A; 115 mg (0.37
mmol; 33%) using method B; colorless oil.
1H NMR (500 MHz, CDCl3): δ = 5.50 (s, 2 H), 6.98 (m, 1 H), 7.14–
7.27 (m, 4 H), 7.37–7.50 (m, 4 H), 7.65 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 51.0, 125.7, 129.0, 129.6, 130.2,
130.3, 130.9, 131.3, 131.9, 133.3, 137.5, 138.1.
HRMS (APCI): m/z [M + H]+ calcd for C15H13N3Br: 314.0292
(79Br), 316.0272 (81Br); found: 314.0336 (79Br), 316.0320 (81Br).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3603–3608

3608
S. Koguchi, K. Izawa
PAPER
(6) (a) Wacharasindhu, S.; Bardhan, S.; Wan, Z.-K.; Tabei, K.;
Mansour, T. S. J. Am. Chem. Soc. 2009, 131, 4174. (b) Liu,
Y.; Yan, W.; Chen, Y.; Petersen, J. L.; Shi, X. Org. Lett.
2008, 10, 5385. (c) Katritzky, A. R.; Bobrov, S.; Kirichenko,
K.; Ji, Y.; Steel, P. J. J. Org. Chem. 2003, 68, 5713. (d) Reid,
A. K.; McHugh, C. J.; Richie, G.; Graham, D. Tetrahedron
Lett. 2006, 47, 4201. (e) Verma, A. K.; Singh, J.; Chaudhary,
R. Tetrahedron Lett. 2007, 48, 7199. (f) Dai, Q.; Gao, W.;
Liu, D.; Kapzes, L. M.; Zhang, X. J. Org. Chem. 2006, 71,
3928.
(7) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Tornoe, C.
W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057. (c) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin,
V. V. Org. Lett. 2004, 6, 2853. (d) Rodionov, V. O.;
Presolski, S. I.; Díaz Díaz, D.; Fokin, V. V.; Finn, M. G.
J. Am. Chem. Soc. 2007, 129, 12705.
References
(1) (a) Genin, M. J.; Allwine, D. A.; Anderson, D. J.;
Barbachyn, M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D.
R.; Grega, K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.;
Reischer, R. D.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.;
Schaadt, R. D.; Stapert, D.; Yagi, B. H. J. Med. Chem. 2000,
43, 953. (b) Holla, B. S.; Mahalinga, M.; Karthikeyan, M. S.;
Poojary, B.; Akberali, P. M.; Kumari, N. S. Eur. J. Med.
Chem. 2005, 40, 1173.
(2) (a) Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A.
J. Med. Chem. 1986, 29, 2262. (b) Buckel, D. R.; Outred, D.
J.; Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med. Chem.
1983, 26, 251. (c) Buckel, D. R.; Rockell, C. J. M.; Smith,
H.; Spicer, B. A. J. Med. Chem. 1984, 27, 223.
(3) Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.; De
Clercq, E.; Perno, C.-F.; Karlsson, A.; Balzarini, J.;
Camarasa, M. J. J. Med. Chem. 1994, 37, 4194.
(4) Al-Masoudim, N. A.; Al-Soud, Y. A. Tetrahedron Lett.
2002, 43, 4021.
(8) 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.
(5) (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.;
Scheel, A.; Voit, B.; Pyun, J.; Fréchet, J. M. J.; Sharpless, K.
B.; Fokin, V. V. Angew. Chem. Int. Ed. 2004, 43, 3928.
(b) Aucagne, V.; Hänni, K. D.; Leigh, D. A.; Lusby, P. J.;
Walker, D. B. J. Am. Chem. Soc. 2006, 128, 2186. (c) Ye, C.
F.; Gard, G. L.; Winter, R. W.; Syvret, R. G.; Twamley, B.;
Shreeve, J. M. Org. Lett. 2007, 9, 3841. (d) Liu, Q.; Zhao, P.;
Chen, Y. J. Polym. Sci., Part A: Polym. Chem. 2007, 45,
3330. (e) Nandivada, H.; Jiang, X. W.; Lahann, J. Adv.
Mater. 2007, 19, 2197. (f) Angelos, S.; Yang, Y. W.; Patel,
K.; Stoddart, J. F.; Zink, J. I. Angew. Chem. Int. Ed. 2008,
45, 1435.
(9) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V.
Org. Lett. 2007, 12, 2333.
(10) (a) Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta, D. J. Org.
Lett. 2005, 7, 1469. (b) Kloss, F.; Kohn, U.; Jahn, B. O.;
Hager, M. D.; Gorls, H.; Schubert, U. S. Chem. Asian J.
2011, 6, 2816.
(11) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004,
6, 1237.
(12) Kwok, S. W.; Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.;
Fokin, V. V. Org. Lett. 2010, 12, 4217.
(13) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.;
Sharpless, K. B.; Chang, S. Angew. Chem. Int. Ed. 2007, 46,
1730.
Synthesis 2012, 44, 3603–3608
© Georg Thieme Verlag Stuttgart · New York