Synthesis of N-unsubstituted 1,2,3-triazoles via aerobic oxidative N-dealkylation using copper(II) acetate

Article abstract of DOI:10.1016/j.tet.2017.03.068

A copper-catalyzed aerobic oxidative C[sbnd]N bond cleavage reaction was developed for the synthesis of 4-substituted-NH-1,2,3-triazoles. Diverse β-ketotriazoles derivatives, which are the starting materials for the aerobic oxidative C[sbnd]N bond cleavage reaction, were prepared from nine aryl and seven alkyl alkynes and α-azidoacetophenone by a copper(I)-catalyzed [3?+?2]cycloaddition reaction. The aerobic oxidation of α-(1,2,3-triazol-1-yl)acetophenones using a catalytic amount of copper(II) acetate in the presence oxygen under neutral conditions gave the title compounds in high yield.

Full text of DOI:10.1016/j.tet.2017.03.068

Accepted Manuscript
Synthesis of N-unsubstituted 1,2,3-triazoles via aerobic oxidative N-dealkylation using
copper(II) acetate
Hyojin Cha, Kyongkyu Lee, Dae Yoon Chi
PII:
S0040-4020(17)30313-7
10.1016/j.tet.2017.03.068
TET 28574
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 January 2017
Revised Date: 20 March 2017
Accepted Date: 23 March 2017
Please cite this article as: Cha H, Lee K, Chi DY, Synthesis of N-unsubstituted 1,2,3-triazoles via aerobic
oxidative N-dealkylation using copper(II) acetate, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.068.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis of N-unsubstituted 1,2,3-triazoles
via aerobic oxidative N-dealkylation using
copper(II) acetate
Hyojin Chaa , Kyongkyu Lee and Dae Yoon Chi
Leave this area blank for abstract info.
Department of Chemistry, Sogang University, 35 Baekbeomro Mapogu, Seoul 04107, Korea

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of N-unsubstituted 1,2,3-triazoles via aerobic oxidative N-dealkylation
using copper(II) acetate
Hyojin Chaa , Kyongkyu Lee and Dae Yoon Chi
Department of Chemistry, Sogang University, 35 Baekbeomro Mapogu, Seoul 04107, Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A copper-catalyzed aerobic oxidative C-N bond cleavage reaction was developed for the
synthesis of 4-substituted-NH-1,2,3-triazoles. Diverse β-ketotriazoles derivatives, which are the
starting materials for the aerobic oxidative C-N bond cleavage reaction, were prepared from nine
aryl and seven alkyl alkynes and α-azidoacetophenone by
a
copper(I)-catalyzed
Available online
[3+2]cycloaddition reaction. The aerobic oxidation of α-(1,2,3-triazol-1-yl)acetophenones using
a catalytic amount of copper(II) acetate in the presence oxygen under neutral conditions gave the
title compounds in high yield.
Keywords:
Aerobic Oxidative N-Dealkylation
NH-1,2,3-Triaoles
Oxidation using molecular oxygen
Copper(II) acetate
2017 Elsevier Ltd. All rights reserved
.
Click chemistry
———
Corresponding author. Tel.: +82-10-9077-7686; fax: +82-2-715-2411; e-mail: dychi@sogang.ac.kr

2
Tetrahedron
ACCEPTED MANUSCRIPT
generation of HN3,10 2) using auxiliary group such as HCHO with
1. Introduction
NaN3 to make hydroxymethyl azide,11 and or using polymeric
azide,12 followed by ACC and the removal of the auxiliary group,
and 3) using a catalyst, such as palladium in an inert
atmosphere13 or p-TsOH.14 These methods work well for aryl
alkynes, but not for alkyl alkynes. This paper reports the new
chemoselective synthesis of N-unsubstituted 4-aryl and alkyl
1,2,3-triazoles by the oxidative C-N cleavage of 1,4-substituted
1,2,3-triazoles with a catalytic amount of copper(II) acetate in the
presence of molecular oxygen as an oxidant.
Molecular oxygen has been considered to be as an ideal
oxidant. A range of copper enzymes, such as peptidylglycine-α-
hydroxylating monooxygenase (PHM) (Scheme 1a) and
dopamine β-monooxygenase (DBH), use molecular oxygen as an
oxidant in living cell.1 Based on the biomimic system, copper-
catalyzed aerobic oxidation was studied in oxidation reactions in
the laboratory, because the oxygen molecule is considered to be
an atom-economical and eco-friendly oxidant. Few studies have
reported C-C bond cleavage mediated by copper and O2 at rt.2 In
the case of C-N bond cleavage, aerobic oxidative N-dealkylations
have been investigated intensively to understand their
mechanisms in biological systems.3
Scheme 2. Previous and this works of the synthesis 4-aryl-
NH-1,2,3-triazoles
Scheme 1. Previous works of amine oxidative dealkylation
R
H
N
O
R
O
O2
H2O
NH2
H
+
OH
R
(a)
(b)
OH
H
H
O
O
O
R
N
N
H
N
N
Cu
H2O
R
Cu
O
HCHO
or
PhCHO
N
N
OH
+
N
N
N
N
R = CH3
= CH2Ph
Recently, hemolytic cleavage of the C-N bond via cupric
hydroperoxide by site specific Fenton chemistry was reported
(Scheme 1b).3h The Yin group in 2014, and the Lei group in 2015
reported two metal-free-aerobic oxidative C-N bond cleavage to
prepare N-heteroaromatic derivatives.4 Molecular oxygen is a
better oxidant than peroxide in practical aspects. In addition,
cupric hydroperoxide is formed from peroxide to cleave the C-N
bond. Thus, it is worthwhile to develop an aerobic oxidative N-
dealkylation. Regardless of aerobic oxidation, phenacyl group
was developed as a new protective group of amino and thio
groups.5
2. Results and discussion
The starting α-(1,2,3-triazol-1-yl)acetophenones (1) were
prepared from α-azidoacetophenone and alkynes by a copper(I)-
catalyzed [3+2] cycloaddition reaction. Table 1 lists the finding
reaction and optimization of the conditions for the synthesis of 4-
phenyl- and 4-n-butyl-NH-1,2,3-triazole (2a and 2j) from α-(4-
phenyl-1,2,3-triazol-1-yl)acetophenones (1a and 1j, respectively)
via aerobic oxidation using copper(II) acetate. First, as a model
substrate, 4-phenyl triazole 1a was subjected to an oxidative N-
dealkylation reaction under a range of reaction conditions. When
1a was treated with 20 mol% of Cu(OAc)2, 40 mol% of ligand
2,2-bipyridyl, and 1.0 equiv of pyridine in toluene (4 mL) with an
O2 balloon for 2 h at 80 ºC, the desired N-unsubstituted triazole
2a was obtained in 68% yield (Table 1, entry 1). Without
pyridine, the yield decreased from 68% to 41% (entry 2). In
entries 1 and 2, the color of the solution changed from pale
yellow to green. Decreasing the amount of solvent from 4 mL
(0.063 M) to 1 mL (0.25 M) gave 87% of the desired product
without any starting material remaining (entry 3). In addition,
when the amounts of the catalyst and ligand 2,2-bipyridyl were
decreased, there was no change in the optimized yields compared
to the previous conditions (entries 4 and 5). As ligand 2,2-
bipyridyl has a similar Rf value to that of 4-substituted-1,2,3-
triazole in TLC, it was inconvenient to isolate the product and
2,2-bipyridyl. No change in yield was observed in the absence of
a ligand 2,2-bipyridyl but the reaction time required up to 5 h to
Figure 1. Useful N-unsubstituted 1,2,3-triazole derivatives.
1,2,3-Triazoles are used broadly in medicinal chemistry,
agrochemistry and material chemistry.6 The increasing
importance of the representative 1,2,3-triazoles (Figure 1) has
highlighted the need for new synthetic methods of 1,2,3-triazoles:
1) 4-phenyl-NH-1,2,3-triazole, which is a simple derivative of N-
unsubstituted triazole as an inhibitor of indoleamine 2,3-
dioxygenase (IDO); 2) azahistidine, which is unnatural amino
acid; and 3) a N-carbamoyl derivative of triazole, which is a
monoacylglycerol lipase ABHD6 selective inhibitor.
After the Huisgen alkyne-azide 1,3-dipolar cycloaddition
(ACC)7 was discovered, Cu-catalyzed8 and Ru-catalyzed9 ACCs
have been developed as types of click reactions. On the other
hand, as shown in Scheme 2, there are still some difficulties in
synthesizing N-unsubstituted 1,2,3-triazoles. The previous
methods could be classified by three strategies involving the use
of highly toxic and explosive hydrazoic acid: 1) In situ

3
be complete (entry 6). This suggests that the ligand 2,2-bipyridyl
is not essential under these reaction condition.
Continuously reducing the amount of catalyst copper(II)
ACCEPTED MANUSCRIPT
acetate to 1 mol% and 0% gave the desired product 2a in 72%
and 0% yield, respectively (entries 8 and 9). When O2 was
replaced with air or argon gas, the yields were 81% and 0%,
respectively (entries 10 and 11). This means that oxygen and
copper(II) acetate are essential for this oxidation reaction. A
further search of solvents indicated trifluoromethylbenzene to be
the best among DMSO, DMF, H2O, CH2Cl2, and CH3CN (entries
12-15). The yield decreased to 37% under the optimized
conditions when the 4-substituted group was n-butyl instead of
phenyl. Increasing the reaction time from 5 h to 24 h increased
the yield of the desired product 2j to 84% after quenching with
MeOH.
Table 1. Optimization of 1,2,3-triazoles via aerobic oxidation
using copper(II) acetate a
en
try
R
Cu
2,2-bi-
pyridyl
(mol%)
oxy- solvent
time yieldb
gen
(mL)
(h)
(%)
(OAc)2
(mol%)
1
2c
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
20
20
20
10
5
40 O2
toluene
(4)
2
2
2
2
2
5
5
5
5
5
5
5
68
41
87
84
83
84
91
72
0
Table 2. Aerobic oxidations of various triazolylacetophenones
1 catalyzed by copper(II) acetate to synthesize 4-substituted-NH-
1,2,3-triazolesa,b
40 O2
40 O2
20 O2
10 O2
toluene
(4)
Cu(OAc)2 (5 mol%),
pyridine (1.0 mmol)
N
N
O
N
N
N
toluene
(1)
R
R
Tz
R
HN
PhCF3 (4 mL)
O2, 80 °C, 5 h
Ph
toluene
(1)
1 (1.0 mmol)
2
toluene
(1)
5
0
0
0
0
0
0
0
O2
O2
O2
O2
air
Ar
O2
toluene
(1)
5
PhCF3
(1)
1
PhCF3
(1)
0
PhCF3
(1)
10 Ph
11 Ph
12 Ph
5
PhCF3
(1)
81
0
5
PhCF3
(1)
5
DMSO
(1)
80
13 Ph
14 Ph
5
5
0
0
O2
O2
H2O (1)
5
5
0d
CH2Cl2
(1)
23
15 Ph
5
5
5
0
0
0
O2
O2
O2
CH3CN
(1)
5
71
aCondition:
1
(1.0 mmol), Cu(OAc)2, pyridine, and
16 n-Bu
17 n-Bu
PhCF3
(1)
5
37
trifluoromethylbenzene in round-bottomed 50 mL flask with
b
c
balloon O2 at 80 ºC. Isolated yield in parenthesis. Reaction
time: 24 h. dReaction time: 3 days.
PhCF3
(1)
24
84e
The scope for the formation of 4-substituted-NH-1,2,3-triaozle
2 was investigated under the optimized conditions (Table 1, entry
7 for 4-aryl groups, entry 17 for 4-alkyl groups), as listed in
Table 2. Regardless of 4-substituents of either aryl or aliphatic
groups, the reaction proceeded well except for the difference in
reaction time. This can be explained by the electron densities of
the triazole ring by 4-substitutants influencing the reactivity
between the aryl and aliphatic groups. In the case of aryl
substituents, compounds 2 with electron withdrawing groups,
such as 4-trifluoromethyl 2c, 4-trifluoromethoxy 2g, and 4-
phenyl 2i groups, were obtained in good yield. On the other hand,
compounds 2 with electron donating groups, such as methyl 2b
and methoxy 2d and 2e groups, were also obtained in good yield.
However, 2e in ortho position could be obtained in 52% yield for
5 h. The yield was improved in longer reaction time (80% at 3
days). Compound 2f having methoxy group in meta positon was
aCondition: 1 (0.25 mmol), Cu(OAc)2, solvent, and pyridine
(0.25 mmol) in round-bottomed 50 mL flask with balloon O2 at
80 ºC. bIsolated yield. cWithout pyridine. dReaction did not
proceed due to low solubility. Before work up, the reaction
mixture was quenched with MeOH and stirred for 30 min.
e
When toluene was used as a solvent, trace amounts of
benzaldehyde and benzyl alcohol from the oxidation of toluene
were isolated. The oxidation of toluene might reduce the yield of
the desired product. Therefore, the solvent was changed from
toluene to trifluoromethylbenzene for further optimization. As a
result, no side product was formed, such as benzaldehyde and
benzyl alcohol, but the desired product was isolated in 91% yield
(entry 7, optimized condition).

4
Tetrahedron
ACCEPTED MANUSCRIPT
obtained in good yield. The electronic effects of the 4-
species on the α-carbon of ketone by a radical source with copper
substituents at the 4-phenyl group on triazole did not influence
the yields in this reaction. In the case of 4-aliphatic groups on the
triazole ring (2j-2p), however, the reactions proceeded much
slower than those of the aryl group cases, but the yields of the
desired products were between 71 and 84% with seven examples.
The synthesis of an important histidine surrogate, azahistidine
(1,2,3-triazole analogue of histidine, Figure 1), was reported by
Ikeda at al. in 2003 in seven steps and by Cintrat et al. in 2010.15
This unprotected azahistidine could be prepared efficiently using
the synthetic routes in 50% yield (two steps, 69% and 72%).
acetate was formed in an Ar atmosphere. Without pyridine
(Scheme 3(6)), the starting material 1a, desired product 2a, and
TEMPO adduct 3a were isolated in 13, 7, and 80% yield,
respectively. In the presence of TEMPO, pyridine assisted the
oxidation of the α-position of the ketone as a base.
Scheme 3. Oxidation Reactions with TEMPO
Several control experiments, including radical trapping using
TEMPO, were performed to determine if the reaction mechanism
involves radical formation, as shown in Scheme 3. As the
reaction involves oxygen, radical trapping experiments were
performed. The optimized conditions (Table 1, entry 7) with one
equiv of TEMPO are called Condition A (see Scheme 3). In
Condition A, only 23% of the desired product 2a was obtained
with the adduct 3a (X-ray crystallographic structure, see
Supporting Information) of TEMPO (77%). The fact that the
adduct 3a of TEMPO was formed means that the reaction has a
radical pathway. TEMPO traps the radical pathway, and the
desired products 2a were produced in 23% yield under Condition
A (Scheme 3(1)). The reaction was not active without Cu(OAc)2,
oxygen, and pyridine in Condition A (Scheme 3(3)). Without
oxygen and pyridine (Scheme 3(4)), the TEMPO adduct 3a was
obtained in only 34% yield. When two equiv of TEMPO were
added without oxygen and pyridine (Scheme 3(5)), a TEMPO
adduct 3a was obtained in 58% yield. This means that the radical
Scheme 4. Plausible Mechanism
Based on the above TEMPO experimental results and the
literature,16 a plausible mechanism is proposed, as shown in
Scheme 4. α-(1,2,3-Triazol-1-yl)acetophenone 1 gives one
electron to Cu(OAc)2 by single electron transfer (SET). The
hydrogen atom of radical cation 4 was transferred to the
Cu(II)OO radical, called hydrogen atom transfer (HAT). The
Cu(II)OO radical was generated from dioxygen and copper(I)
cation. The cation 5 undergoes two different reaction pathways.
One is to form a radical cation 6 by SET, which is trapped by
TEMPO, consequently giving an adduct 3a. The other is to give
the radical cation 7 by a reaction with Cu(II)OOH, giving 1,2-
diketone compound 8 after the removal of α-hydrogen of 7 with
pyridine. Acyl triazole compound 8 was hydrolyzed providing
phenylglyoxylic acid 9 and the desired triazole 2.
under mild conditions. This means that these reactions will
expand the selective utility of C-N cleavage for targeting the
1,2,3-triazole group. Furthermore, studies of the detailed
mechanism for the aerobic oxidation of the α-carbon of various
keto compounds are ongoing.
4. Experimental section
4.1. Typical Procedure for the Preparation of α-(1,2,3-
Triazol-1-yl)acetophenones.
4.1.1. 1-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-one
(1a).
Phenylacetylene (1.50 mL, 13.7
mmol) and α-azidoacetophenone
3. Conclusion
(2.00 g, 12.4 mmol) were suspended
in a 1:1 mixture of water and tert-
butyl alcohol (24 mL). Sodium
ascorbate (491 mg, 2.48 mmol) was added, followed by copper
sulfate pentahydrate (310 mg, 1.24 mmol). After the
This paper described an efficient synthesis of 4-substituted-
NH-1,2,3-triazoles via aerobic oxidation using copper(II) acetate.
The reaction can be performed smoothly without the strict
exclusion of moisture and with good functional group tolerance

5
+
heterogeneous mixture was stirred for 12 h, the reaction mixture
2836, 1699. HRMS (ESI): m/z calcd for C17 H15N3NaO2
[M+Na]+ 316.1062. Found 316.1056.
ACCEPTED MANUSCRIPT
was diluted with water (100 mL). The product was extracted with
ethyl acetate (80 mL x 2), and dried over MgSO4. After removal
of solvent, the crude mixture was purified by flash column
chromatography (silica gel, ethyl acetate/hexane = 40/60) to
furnish pure white solid 1a (2.78 g, 85%): mp 166-167 °C; 1H
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 2H), 7.95 (s, 1H),
7.87 (d, J = 7.2 Hz, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.8
Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 5.89
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 190.4, 148.4, 134.8,
134.0, 130.6, 129.3, 129.0, 128.33, 128.30, 126.0, 121.6, 55.6;
FT-IR: (cm-1) 3087, 2933, 1700; MS (IE) m/z 263 (M+, 30), 234,
206, 130, 105 (100), 91, 77. Anal. calcd for C16H13N3O: C, 72.99;
H, 4.98; N, 15.96. Found; C, 72.98; H, 4.91; N, 15.90.
4.1.7.
1-Phenyl-2-(4-(4-(trifluoromethoxy)phenyl)-1H-1,2,3-
triazol-1-yl)ethan-1-one (1g). White crystal (71%): mp 186-187
°C; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.11 (d, J =
7.5 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.75 (t, J = 7.2 Hz, 1H),
7.63 (t, J = 7.6 Hz, 2H), 7.47 (t, J = 8.3 Hz, 2H), 6.29 (s, 2H); 13
C
NMR (100 MHz, DMSO-d6) δ 192.2, 147.8, 145.1, 134.3, 134.1,
130.1, 129.0, 128.3, 127.0, 123.6, 121.6, 118.9, 56.1; FT-IR: (cm-
1) 3132, 3100, 2977, 2936, 1694; MS (EI) m/z 347 (M+, 40), 318,
290, 262, 214, 187, 128, 105 (100), 77. Anal. calcd for
C17H12F3N3O2: C, 58.79; H, 3.48; N, 12.10. Found; C, 58.83; H,
3.65; N, 12.32.
4.1.8.
2-(4-(4-Bromophenyl)-1H-1,2,3-triazol-1-yl)-1-
4.1.2. 1-Phenyl-2-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)ethan-1-
one (1b). White solid (82%): mp 166-168 °C; H NMR (400
phenylethan-1-one (1h). White crystal (82%): mp 213-214 °C; 1H
NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.10 (d, J = 7.6 Hz,
2H), 7.85 (d, J = 8.2 Hz, 2H), 7.75 (t, J = 7.3 Hz, 1H), 7.67 (d, J
= 8.3 Hz, 2H), 7.62 (t, J = 7.6 Hz, 2H), 6.29 (s, 2H); 13C NMR
(100 MHz, DMSO-d6) 192.2 145.3, 134.4, 134.1, 132.0, 130.0,
129.1, 128.3, 127.2, 123.5, 120.9, 56.1; FT-IR: (cm-1) 3143, 2939,
1690; MS (ESI) m/z 341 (M+-H, 100). Anal. calcd for
C12H12BrN3O: C, 56.16; H, 3.53; N, 12.28. Found: C, 56.14; H,
3.59; N, 12.32.
1
MHz, CDCl3) δ 8.01 (d, J = 7.4 Hz, 2H), 7.90 (s, 1H), 7.75 (d, J
= 8.1 Hz, 2H), 7.66 (d, J = 7.5 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H),
7.24 (d, J = 7.9 Hz, 2H), 5.87 (s, 2H), 2.38 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 190.5, 148.4, 138.2, 134.7, 134.1, 129.6,
129.3, 128.3, 127.8, 125.8, 121.3, 55.6, 21.4; FT-IR: (cm-1) 3099,
2959, 2902, 1711; MS (EI) m/z 277 (M+, 50), 248, 234, 220, 144
(100), 130, 115, 91, 71, 51. Anal. calcd for C17H15N3O: C, 73.63;
H, 5.45; N, 15.15. Found; C, 73.72; H, 5.42; N, 15.11.
4.1.9.
2-(4-((1,1'-Biphenyl)-4-yl)-1H-1,2,3-triazol-1-yl)-1-
4.1.3.
1-Phenyl-2-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-
phenylethan-1-one (1i). White crystal (75%): mp 222-223 °C; 1H
NMR (400 MHz, DMF-d7) δ 8.73 (s, 1H), 8.23 (d, J = 7.5 Hz,
2H), 8.11 (d, J = 8.0 Hz, 2H), 7.91-7.76 (m, 5H), 7.68 (t, J = 7.5
Hz, 2H), 7.54 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H), 6.43
(s, 2H); 13C NMR (100 MHz, DMF-d7) δ 193.3, 147.7, 141.3,
141.1, 135.6, 135.4, 131.6, 130.2, 130.1, 129.4, 128.7, 128.4,
127.8, 127.0, 124.2, 56.2; FT-IR: (cm-1) 3088, 3064, 3033, 2971,
2930, 1702; MS (EI) m/z 339 (M+, 50), 311, 282, 206, 178 (100),
152, 103, 77. Anal. calcd for C22H17N3O: C, 77.86; H, 5.05; N,
12.38. Found; C, 77.86; H, 4.94; N, 12.37.
triazol-1-yl)ethan-1-one (1c). White crystal (73%): mp 222-223
°C; 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.15-8.06 (m,
4H), 7.83 (d, J = 8.2 Hz, 2H), 7.75 (t, J = 7.4 Hz, 1H), 7.63 (t, J =
7.7 Hz, 2H), 6.33 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ
192.1, 145.0, 134.7, 134.4, 134.1, 134.1, 129.1, 128.3, 126.02,
125.98, 125.7, 124.4, 56.2; FT-IR: (cm-1) 3143, 2942, 1689; MS
(EI) m/z 331 (M+, 40), 302, 274, 198, 178, 151, 105 (100), 77, 51.
Anal. calcd for C17H12F3N3O2: C, 61.63; H, 3.65; N, 12.68,
Found; C, 61.65; H, 3.61; N, 12.61.
4.1.4.
2-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-1-
4.1.10. 2-(4-n-Butyl-1H-1,2,3-triazol-1-yl)-1-phenylethan-1-
one (1j). White crystal (74%): mp 73-74 °C; 1H NMR (400 MHz,
CDCl3): δ 7.96 (d, J = 7.4 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.50
(t, J = 7.7 Hz, 2H), 7.43 (s, 1H), 5.79 (s, 2H), 2.72 (t, J = 8.6 Hz,
2H), 1.72-1.57 (m, 2H), 1.43-1.31 (m, 2H), 0.91 (t, J = 7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3): 190.8, 148.8, 134.6, 134.1,
129.2, 128.2, 122.6, 55.4, 31.5, 25.5, 22.4, 13.9; FT-IR: (cm-1) =
3134, 2925, 2857, 1698; MS (ESI) m/z 242 (M+-H, 100). Anal.
calcd for C14H17N3O: C, 69.11; H, 7.04; N, 17.27. Found; C,
69.13; H, 7.03; N, 17.11.
phenylethan-1-one (1d). White crystal (78%): mp 189-191 °C;1H
NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.11 (d, J = 7.3 Hz,
2H), 7.82 (d, J = 8.8 Hz, 2H), 7.75 (t, J = 7.4 Hz, 1H), 7.62 (t, J =
7.7 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.26 (s, 2H), 3.29 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ 192.3, 159.0, 146.3, 134.3,
134.1, 129.1, 128.3, 126.6, 123.4, 122.2, 114.4, 56.0, 55.2; FT-IR:
(cm-1) 3049, 2964, 1703; MS (ESI) m/z 292 (M+-H, 100). Anal.
calcd for C17H12F3N3O2: C, 58.79; H, 3.48; N, 12.10. Found; C,
58.83; H, 3.65; N, 12.32.
4.1.5
2-(4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-1-
4.1.11. 2-(4-n-Hexyl-1H-1,2,3-triazol-1-yl)-1-phenylethan-1-
one (1k). White crystal (79%): mp 89-90 °C; 1H NMR (400 MHz,
CDCl3): δ 7.94 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.48
(t, J = 7.8 Hz, 2H), 7.42 (s, 1H), 2.70 (t, J = 7.6 Hz, 2H), 1.65
(quin, J = 7.6 Hz, 2H), 1.40-1.20 (m, 6H), 0.85 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): 190.7, 148.8, 134.5, 134.0,
129.1, 128.1, 122.6, 55.4, 31.6, 29.4, 29.0, 25.8, 22.6, 14.1; FT-
IR: (cm-1) 3099, 2959, 2092, 1711; MS (ESI) m/z 270 (M+-H,
100), 242. Anal. calcd for C14H17N3O: C, 70.82; H, 7.80; N,
15.49. Found; C, 70.83; H, 7.75; N, 15.38.
phenylethan-1-one (1e). White powder (82%): mp 198-200 °C;
1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 7.6 Hz, 2H), 8.19 (s,
1H), 8.03 (d, J = 8.0 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.54 (t, J
= 5.2 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H),
6.98 (d, J = 8.0 Hz, 2H), 5.89 (s, 2H), 3.93 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 190.6, 155.8, 143.8, 134.6, 134.2, 129.3,
129.1, 128.3, 127.8, 124.9, 121.1, 119.5, 110.9, 55.6; FT-IR: (cm-
1) 3171, 2929, 2837, 1703. HRMS (ESI): m/z calcd for C17 H15
N3NaO2 [M+Na]+ 316.1062. Found 316.1058.
+
4.1.6
2-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-1-
4.1.12. Ethyl 1-(2-Oxo-2-phenylethyl)-1H-1,2,3-triazole-4-
carboxylate (1l). white powder (83%): mp 176-178 °C; 1H NMR
(400 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.10 (d, J = 7.3 Hz, 2H),
7.75 (t, J = 7.4 Hz, 1H), 7.62 (t, J = 7.7 Hz, 2H), 6.32 (s, 2H),
4.34 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, DMSO-d6): 191.7, 160.4, 139.0, 134.4, 133.9, 130.8,
129.0, 128.3, 60.6, 56.3, 14.2; FT-IR: (cm-1) 3112, 2979, 1715;
MS (ESI) m/z 258 (M+-H, 100), 232, 231, 185. Anal. calcd for
phenylethan-1-one (1f). White powder (84%): mp 108-110 °C;
1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 2H), 7.94 (s,
1H), 7.68 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.47 (s,
1H), 7.39 (d, J = 7.6 Hz, 2H), 7.33 (t, J = 8.0 Hz, 2H), 6.90 (d, J
= 8.0 Hz, 2H), 5.89 (s, 2H), 5.87 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 190.4, 160.0, 147.9, 134.6, 133.9, 131.9, 129.9, 129.2,
128.2, 122.0, 118.2, 114.3, 110.8, 55.5; FT-IR: (cm-1) 3135, 2937,

6
Tetrahedron
C13H13N3O3: C, 60.23; H, 5.05; N, 16.21. Found; C, 60.28; H,
4.2.2. 4-(p-Tolyl)-1H-1,2,3-triazole (2b). White crystal (84%):
ACCEPTED MANUSCRIPT
5.07; N, 16.12. .
mp 158-160 °C; 1H NMR (400 MHz, DMSO-d6, 1 drop of TFA)
δ 8.25 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H),
2.30 (s, 3H); 13C NMR (100 MHz, DMSO-d6, 1 drop of TFA) δ
145.2, 137.9, 129.7, 127.6, 127.3, 125.8, 21.0; FT-IR: (cm-1)
3148 (w, N-H), 2856 (w, arom C-H), 1668 (w, C-N). HRMS
(ESI): m/z calcd for C9H9N3Na+ [M+Na]+ 182.0695. Found:
182.0687; Anal. calcd for C9H9N3: C, 67.90; H, 5.70; N, 26.40.
Found; C, 67.91; H, 5.66; N, 26.50.
4.1.13. 1-Phenyl-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-yl)ethan-
1-one (1m). White powder (74%): mp 62-64 °C H NMR (400
1
MHz, CDCl3) δ 7.98 (d, J = 7.1 Hz, 2H), 7.70 (s, 1H), 7.65 (t, J =
7.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 5.88 (s, 2H), 0.33 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 190.7, 147.1, 134.6, 134.1, 130.9,
129.2, 128.2, 54.9, -1.0; FT-IR: (cm-1) 3099, 2959, 1711. HRMS
(ESI) m/z calcd for C13H17N3NaOSi+ [M+Na]+: 282.1033. Found:
282.1032.
4.2.3. 4-(4-(Trifluoromethyl)phenyl)-1H-1,2,3-triazole (2c).
White crystal (85%): mp 189-190 °C; 1H NMR (400 MHz,
DMSO-d6, 1 drop of TFA) δ 8.52 (s, 1H), 8.09 (d, J = 8.0 Hz,
2H), 7.79 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6, 1
drop of TFA) δ 144.4, 135.0, 128.3 (q, JCF = 31.6 Hz), 126.1,
126.0 (q, JCF = 3.7 Hz), 125.7, 123.0; FT-IR: (cm-1) 3143 (w, N-
H), 2869 (w, arom C-H), 1621 (w, C-N). HRMS (ESI): m/z
calcd. for C9H6F3N3Na+ [M+Na]+ 236.0406. Found: 236.0404;
Anal. calcd for C9H6F3N3: C, 50.71; H, 2.84; N, 19.71. Found; C,
50.63; H, 2.95; N, 19.78.
4.1.14. 2-(4-Cyclopentyl-1H-1,2,3-triazol-1-yl)-1-phenylethan-
1-one (1n). White crystal (80%): mp 101-103 °C; 1H NMR (400
MHz, CDCl3) δ 7.97 (d, J = 7.2 Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H),
7.50 (t, J = 7.6 Hz, 2H), 7.42 (s, 1H), 5.79 (s, 1H), 3.19 (quintet,
J = 8.7 Hz, 1H), 2.15–2.03 (m, 2H) 1.79–1.60 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 190.8, 153.1, 134.6, 134.1, 129.2, 128.2,
121.6, 55.4, 36.9, 33.2, 25.2; FT-IR: (cm-1) 2947, 2868, 1700;
MS (ESI) m/z 254 (M+-H, 100). Anal. calcd for C15H17N3O: C,
70.56; H, 6.71; N, 16.46. Found: C, 70.58; H, 6.69; N, 16.44.
4.2.4. 4-(4-Methoxyphenyl)-1H-1,2,3-triazole (2d). White
crystal (72%): mp 167-172 °C;1H NMR (400 MHz, DMSO-d6, 1
drop of TFA) δ 8.20 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.69 (d, J
= 8.0 Hz, 2H), 3.76 (s, 3H) 13C NMR (100 MHz, DMSO-d6, 1
drop of TFA) δ 159.7, 145.1, 133.4, 127.3, 122.8, 114.6, 55.3;
FT-IR: (cm-1) 3153 (w, N-H), 2834 (w, arom C-H), 1613 (w, C-
N). HRMS (ESI): m/z calcd. for C9H9N3NaO+ [M + Na]+
198.0643. Found: 198.0640; Anal. Calc. for C9H9N3O: C, 61.70;
H, 5.18; 23.99. Found; C, 61.88; H, 5.14; N, 23.81.
4.1.15. t-Butyl ((1-(2-Oxo-2-phenylethyl)-1H-1,2,3-triazol-4-
yl)methyl)carbamate (1o). White powder (91%): mp 141-142 °C;
1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 7.6 Hz, 2H), 7.87
(s, 1H), 7.74 (t, J = 7.4 Hz, 1H), 7.61 (t, J = 7.7 Hz, 2H), 7.42 (t,
J = 5.8 Hz, 1H), 6.16 (s, 2H), 4.22 (d, J = 5.9 Hz, 2H), 1.39 (s,
9H); 13C NMR (100 MHz, DMSO-d6) δ 192.3, 155.7, 145.7,
134.22, 134.20, 129.0, 128.2, 124.3, 77.9, 55.8, 35.7, 28.3; FT-IR:
(cm-1) 3401, 2980, 1710, 1680; MS (ESI) m/z 315 (M+-H, 100).
Anal. calcd for C16H20N4O3: C, 60.75; H, 6.37; N, 17.71. Found:
C, 60.73; H, 6.40; N, 17.78.\
4.2.5
4-(2-methoxyphenyl)-1H-1,2,3-triazole (2e). White
powder (58%): mp 148-152 °C; 1H NMR (500 MHz, CDCl3) δ
8.18 (s, 1H), 7.93 (br, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.04 (t, J =
7.5 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 156.1, 139.7, 130.1, 130.0, 128.2, 121.3,
117.2, 111.4, 55.7; FT-IR: (cm-1) 3171 (w, N-H), 2929 (w, arom
C-H), 1703 (w, C-N). HRMS (ESI): m/z calcd. for C9H9N3NaO+
[M + Na]+ 198.0643. Found: 198.0637.
4.1.16.
2-((t-Butoxycarbonyl)amino)-3-(1-(2-oxo-2-
phenylethyl)-1H-1,2,3-triazol-4-yl)propanoic Acid (1p). Yellow
1
amorphous solid (69%): mp 129-130°C; H NMR (400 MHz,
DMSO-d6) δ 8.04 (d, J = 7.6 Hz, 2H), 7.75 (s, 1H), 7.71 (t, J =
7.5 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H), 6.40 (br s, 1H), 6.17-6.01
(m, 2H), 4.06 (s, 1H), 3.17 (d, J = 11.7 Hz, 1H), 2.99 (dd, J =
14.4, 7.6 Hz, 1H), 1.33 (s, 9H); 13C NMR (100 MHz, DMSO-d6)
δ 192.4, 155.0, 144.1, 134.3, 134.2, 129.0, 128.2, 124.4, 77.7,
55.6, 54.7, 28.7, 28.3, 28.1; FT-IR: (cm-1) 2979, 2934, 1698.
4.2.6 4-(3-methoxyphenyl)-1H-1,2,3-triazole (2f). pale yellow
oil (72%): 1H NMR (400 MHz,CDCl3) δ 7.99 (s, 1H), 7.38-7.29
(m, 3H), 6.90 (d, J = 8.0 Hz, 2H), 3.81 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 160.1, 146.6, 131.0, 130.2, 128.7, 118.7, 114.8,
111.4, 55.5; FT-IR: (cm-1) 3134 (w, N-H), 2934 (w, arom C-H),
1669 (w, C-N). HRMS (ESI): m/z calcd. for C9H9N3NaO+ [M +
Na]+ 198.0643. Found: 198.0640.
+
HRMS (ESI) m/z calcd for C18H22N4NaO5 [M+Na]+ 397.1482.
Found, 397.1484.
4.2. Typical Procedure for the Synthesis of 4-Aryl-1H-
1,2,3-triazoles.
4.2.1. 4-Phenyl-1H-1,2,3-triazole (2a).
4.2.7. 4-(4-(Trifluoromethoxy)phenyl)-1H-1,2,3-triazole (2g).
White powder (85%): mp 146-148 °C; H NMR (400 MHz,
1
Pyridine (79 mg, 1.0 mmol) was added to a
CDCl3) δ 7.99 (s, 1H) 7.31 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0
Hz, 2H); 13C NMR (100 MHz, CD3OD) δ 150.3, 146.2, 130.7,
128.6, 127.6, 122.5 (d, JCF = 8.0 Hz), 121.9 (q, JCF = 25.5); FT-IR:
(cm-1) 3159 (w, N-H), 2866 (w, arom C-H). HRMS (ESI): m/z
calcd for C9H6F3N3NaO+ [M+Na]+: 252.0355. Found: 252.0356;
Anal. calcd for C9H6F3N3O: C, 47.13, H, 2.64, N, 18.34. Found;
C, 47.13; H, 2.77; N, 18.43.
mixture
of
α-(4-aryl-1,2,3-triazol-1-yl)
acetophenones (1a, 263 mg, 1.00 mmol) and
Cu(OAc)2 (9.0 mg, 5.0 mmol%) in a PhCF3 (4 mL) under O2 and
stirred at 80 °C for 5 h. The reaction mixture was quenched with
water (20 mL), and resulting mixture was extracted with CH2Cl2
(3 x 30 mL). Combined organic fractions were washed with brine
(3 x 10 mL), dried Na2SO4, and evaporated under reduced
pressure. The crude product was purified with flash column
chromatography (ethyl acetate/hexane = 40/60) to give the
product 2a (131 mg, 91%) as a white crystal: mp 149-150 °C; 1H
NMR (400 MHz, DMSO-d6, 1 drop of TFA) δ 8.34 (s, 1H) 7.86
(d, J = 8.0 Hz, 2H) 7.45 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 8 Hz,
1H); 13C NMR (100 MHz, DMSO-d6, 1 drop of TFA) δ 145.9,
130.7, 128.4, 128.5, 125.7, 126.0; FT-IR: (cm-1) 3149 (w, N-H),
2846 (w, arom C-H), 1700 (m, C-N). HRMS (ESI): m/z calcd for
C8H7N3Na+ [M+Na]+ 168.0538. Found: 168.0530; Anal. calcd for
C8H7N3: C, 66.19; H, 4.86; N, 28.95. Found; C, 66.27; H, 4.80;
N, 28.77.
4.2.8. 4-(4-Bromophenyl)-1H-1,2,3-triazole (2h). White
1
powder (72%): mp 185-189 °C; H NMR (400 MHz, DMSO-d6)
δ 8.39 (s, 1H) 7.82 (d, J = 8.0 Hz, 2H) 7.62 (d, J = 8.0 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δ 144.5, 131.9 129.8, 127.6,
121.0; FT-IR: (cm-1) 3149 (w, N-H), 2836 (w, arom C-H).
HRMS (ESI): m/z calcd for C8H6BrN3Na+ [M+Na]+ 245.9637.
Found: 245.9636; Anal. Calc. for C8H6BrN3: C, 42.88; H, 2.70;
N, 18.75. Found; C, 42.86; H, 2.70; N, 18.65.
4.2.9. 4-([1,1’-Biphenyl]-4-yl)-1H-1,2,3-triazole (2i). White
1
powder (81%): mp 261-263 °C; H NMR (400 MHz, DMSO-d6)

7
δ 8.41 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.72 (t, J = 8.0 Hz, 4H),
7.47 (t, J = 8.0 Hz, 2H), 7 .37 (t, J = 8.0 Hz, 1H); 13C NMR (100
MHz, DMSO-d6, 1 drop of TFA) δ 139.8, 139.6, 129.5, 129.1,
127.7, 126.6, 126.2, 126.2; FT-IR: (cm-1) 3149 (w, N-H), 2852 (s,
arom C-H), 1674 (w, C-N). HRMS (ESI): m/z calcd. for
C14H11N3Na+ [M+Na]+ 244.0845. Found: 244.0847; Anal. calcd
for C14H11N3 : C,76.00; H, 5.01; N, 18.99. Found: C, 76.02; H,
5.09; N, 18.87.
4.3.6. 4-(N-Boc-aminomethyl)-1H-1,2,3-triazole (2o). White
ACCEPTED MANUSCRIPT
powder (75%): mp 86-93 °C; 1H NMR (400 MHz, CDCl3) δ 7.66
(s, 1H), 5.30 (d, J = 8.0 Hz, 1H), 4.44, (d, J = 8.0 Hz, 2H), 1.44
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.3, 144.2, 130.4, 80.3,
85.7, 35.7, 28.1; FT-IR: (cm-1) 3311 (m, N-H), 2974 (s, aliphatic
+
C-H), 1683 (w, C-N). HRMS (ESI): m/z calcd for C8H14N4NaO2
[M+Na]+ 221.1009. Found 221.1010; Anal. calcd for C8H14N4O2:
C, 48.47; H, 7.12; N, 28.26. Found; C, 48.94; H, 7.12; N, 28.11.
4.3. Typical Procedure for the Synthesis of 4-Alkyl
Substituted-1H-1,2,3-triazole.
4.3.7. N-Boc-β-(1H-1,2,3-triazol-4-yl)alanine (2p). Without
work-up, the crude mixture was purified with flash column
chromatography (CH2Cl2/MeOH = 80/20) to give the product as
white solid amorphous 2p (71%): mp: 116-119 °C; 1H NMR (400
MHz, CD3OD) δ 7.61 (s, 1H), 4.39-4.15 (m, CαH, 1H), 3.36-3.24
(m, CβH, 1H), 3.13 (dd, J = 16.0, 8.0 Hz, CβH, 1H), 1.37 (s, 9H);
13C NMR (100 MHz, CD3OD) δ 179.0, 157.6, 130.9, 129.7, 80.4,
56.3, 28.7; FT-IR: (cm-1) 3150 (m, N-H), 2977 (s, aliphatic C-H),
4.3.1. 4-n-Butyl-1H-1,2,3-triazole (2j).
Pyridine (79 mg, 1.0 mmol) was added to a
mixture
of
α-(4-butyl-1,2,3-triazol-1-yl)
acetophenone (2i, 243 mg, 1.00 mmol) and
Cu(OAc)2 (9.0 mg, 5.0 mol%) in a PhCF3 (4
+
1694 (w, C-N). HRMS (ESI): m/z calcd for C10H16N4NaO4
mL) under O2 and stirred at 80 °C for 5 h. After 3 mL of
methanol was added, crude mixture was stirred for 30 min. After
the solvent was removed under reduced pressure, crude mixture
was extracted with CH2Cl2 (3 x 30 mL). Combined organic layer
was washed with brine (3 x 10 mL), dried Na2SO4, and
evaporated under reduced pressure. The crude product was
purified with flash column chromatography (ethyl acetate/hexane
= 20/80) to give the product 2j (105 mg, 84%) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 2.75 (t, J = 8.0 Hz,
2H), 1.66 (quin, J = 8.0 Hz, 2H), 1.36 (sex, J = 8.0 Hz, 1H), 0.91
(t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 146.0, 130.4,
31.4, 24.6, 22.3, 13.9; FT-IR: (cm-1) 3137 (w, N-H), 2956 (s,
aliphatic C-H), 1664 (w, C-N). HRMS (ESI): m/z calcd for
[M+Na]+ 279.1069. Found 279.1066.
4.4. TEMPO Scavenger Experiment.
4.4.1. 1-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-2-((2,2,6,6-
tetramethylpiperidin-1-yl)oxy) ethan-1-one (3a).
White powder 3a: mp 109-110 °C;
1H NMR (400 MHz, CDCl3) δ
8.13 (d, J = 8.0 Hz, 2H), 8.01 (s,
1H), 7.82 (d, J = 8.0 Hz, 2H), 7.57
(t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0
Hz, 2H), 7.42-7.35 (m, 2H), 7.31
(t, J = 8.0 Hz, 1H), 1.92-1.39 (m,
+
C8H14N4NaO2 [M+Na]+ 221.1009. Found 221.1010; Anal. calcd
6H), 1.38-1.28 (m, 1H), 1.21 (s, 3H), 1.10 (s, 3H), 1,08 (s, 3H),
0.55 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.9, 148.5, 134.5,
133.5, 130.1, 129.2, 129.0, 128.8, 128.4, 125.7, 118.1, 92.0, 61.9,
59.9, 40.0, 39.7, 32.8, 32.1, 20.4, 20.1, 17.0; FT-IR: (cm-1) 2972
(w), 2933 (w), 2933 (w), 1702(s). HRMS (ESI): m/z calcd for C10
for C8H14N4O2 : C, 48.47; H, 7.12; N, 28.26. Found; C, 48.51; H,
7.18; N, 28.14.
4.3.2. 4-n-Hexyl-1H-1,2,3-triazole (2k). Colorless oil (82%):
1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 2.75 (t, J = 8.0 Hz,
2H), 1.71-1.64 (m, 2H), 1.34-1.28 (m, 6H), 0.86, (t, J = 8.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 146.3, 130.6, 31.5, 29.1,
28.8, 24.9, 22.5, 14.0; FT-IR: (cm-1) 3138 (w, N-H), 2954 (s,
aliphatic C-H. HRMS (ESI): m/z calcd for C8 H15 N3Na+ [M+Na]+
176.1158. Found 176.1154; Anal. Calc. for C8H14N4O2: C, 62.71;
H, 9.87; N, 27.42. Found; C, 62.72; H, 9.91; N, 27.44.)
+
H16 N4NaO4 [M+Na]+ 441.2266. Found 441.2260. X-ray
crystallographic structure, see Supporting Information.
4.5. Cupric Phenylglyoxylate.
We
could
isolate
phenylglyoxylic acid 9, and
benzoic acid without work-up
at the standard condition. But
4.3.3. 4-Ethoxycarbonyl-1H-1,2,3-triazole (2l). White
1
crystal(72%): mp 109-110 °C; H NMR (400 MHz, CDCl3) δ
to obtain the isolated yield of
8.34 (s, 1H), 4.43 (q, J = 8.0 Hz, 2H), 1.37, (t, J = 8.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 161.3, 139.2, 131.8, 61.9, 14.3;
FT-IR: (cm-1) 3343, 3119, 2921, 2851, 1729(C=O), 1704. HRMS
(ESI): m/z calcd for C8 H15 N3Na+ [M+Na]+ 176.1158. Found
176.1154; Anal. calcd for C5H7N3O2: C, 42.55; H, 5.00; N, 29.77.
Found; C, 42.55; H, 4.98; N, 29.79.
phenylglyoxylic acid was not easy, because it is water soluble.
After quenching by water of the reaction mixture and freezing
drying of the aqueous phase, cupric phenylglyoxylate were
isolated cleanly. It was reported that decarboxylation of
phenylglyoxylic acid is possible to give benzoic acid at the
copper catalyzed condition.17 Pale yellow powder as
a
1
4.3.4. 4-Trimethylsilyl-1H-1,2,3-triazole (2m). White powder
monohydrate: H NMR (400 MHz, D2O) δ 7.88 (d, J = 8.0 Hz,
2H), 7.67 (t, 1H), 7.53 (t, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
D2O) δ 196.8, 173.0, 135.0, 131.7, 129.5, 129.0; FT-IR: (cm-1)
3327 (w), 3062 (w), 1595 (s). HRMS (ESI): m/z calcd for
C8H5Na2O3 [M+2Na]+ 195.0034. Found 195.0027; Anal. calcd
for C16H12CuO7: C, 50.60; H, 3.18; Cu, 16.73; O, 29,49. Found;
C, 50.88; H, 3.01.
1
(71%): mp 99-100 °C; H NMR (400 MHz, CDCl3) δ 7.79 (s,
1H), 0.87 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 138.6, 137.1,
1.1; FT-IR: (cm-1) 3113 (w, N-H), 2896 (s, aliphatic C-H), 1667
(w, C-N). HRMS (ESI): m/z calcd for C8H15N3Na+ [M+Na]+
176.1158. Found 176.1154; Anal. calcd for C5H7N3O2: C, 42.52;
H, 7.85; N, 29.75. Found; C, 42.46; H, 7.83; N, 28.47.
4.3.5. 4-Cyclopentyl-1H-1,2,3-triazole (2n). Colorless oil
(79%): 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 3.19 (quint, J
= 8.0 Hz, 2H), 2.18-2.01 (m, 2H), 1.86-1.56 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 149.6, 129.0, 35.9, 33.1, 25.1; FT-IR: (cm-1)
3133 (w, N-H), 2952 (s, aliphatic C-H), 1664 (w, C-N). HRMS
(ESI): m/z calcd for C7H11N3Na+ [M+Na]+ 160.0851. Found
160.0843; Anal. calcd for C7H11N3: C, 61.29; H, 8.08; N, 30.63.
Found; C, 61.21; H, 8.03; N, 30.68.
Acknowledgments
This work was supported by the Converging Research Center
Program through the Ministry of Science, ICT and Future
Planning, Korea (2014M3C1A8066306).

8
Tetrahedron
ACCEPTED MANUSCRIPT
Nakagawa, Y.; Yamaguchi, K.; Mizuno, N. J. Am. Chem. Soc.
2008, 130, 15304-15310. (d) Hein, J. E.; Tripp, J. C.; Krasnova, L.
References and notes
B.; Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2009,
48, 8018-8021.
1. Prigge, S. T.; Eipper, B. A.; Mains, R. E.; Amzel, L. M. Science
2004, 304, 864-867.
9. (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, 15998-15999. (b) Majireck, M. M.; Weinreb, S. M. J. Org.
Chem. 2006, 71, 8680-8683. (c) Tam, A.; Arnold, U.; Soellner, M.
B.; Raines, R. T. J. Am. Chem. Soc. 2007, 129, 12670-12671. (d)
Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.;
Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923-
8930.
10. Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org. Chem. 2004, 3789-
3791.
11. Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2008, 10,
3171-3174.
12. Cohrt, A. E.; Jensen, J. F.; Nielsen, T. E. Org. Lett. 2010, 12,
5414-5417.
13. Barluenga, J.; Valdes, C.; Beltran, G.; Escribano, M.; Aznar, F.
Angew. Chem., Int. Ed. 2006, 45, 6893-6896.
14. Quan, X. J.; Ren, Z. H.; Wang, Y. Y.; Guan, Z. H. Org. Lett.
2014, 16, 5728-5731.
15. (a) Ikeda, Y.; Kawahara, S.-I.; Taki, M.; Kuno, A.; Hasegawa, T.;
Taira, K. Protein Eng. 2003, 16, 699-706. (b) Roux, S.; Ligeti, M.;
Buisson, D. A.; Rousseau, B.; Cintrat, J. C. Amino Acids 2010, 38,
279-86.
2. (a) Atlamasani, A; Zhang, T.-M. Synthesis 1993, 79-81. (b) Cossy,
J.; Belotti, D.; Bellosta, V.; Brocca, D. Tetrahedron Lett. 1994, 35,
6089-6092. (c) Allpress, C. J.; Grubel, K.; Szajna-Fuller, E.; Arif,
A. M.; Berreau, L. M. J. Am. Chem. Soc. 2013, 135, 659-668. (d)
Allpress, C. J.; Milaczewska, A.; Borowski, T.; Bennett, J. R.;
Tierney, D. L.; Arif, A. M.; Berreau, L. M. J. Am. Chem. Soc.
2014, 136, 7821-7824. (e) Allen, S. E.; Walvoord, R. R.; Padilla-
Salinas, R.; Kozlowski, M, C. Chem. Rev. 2013, 113, 6234-6258.
(f) Chen, F.; Wang, T.; Jiao N. Chem. Rev. 2014, 114, 8613-8661.
3. (a) Murahashi, S.-I.; Watanabe, T. J. Am. Chem. Soc. 1979, 101,
7429-7430. (b) Murahashi, S.-I.; Maota, T.; Yonemura, K. J. Am.
Chem. Soc. 1988, 110, 8256-8259. (c) Reddy, K. V.; Jin, S.-J.;
Arora, P. K.; Sfeir, D. S.; Maloney, S. C. F.; Urbach, F. L.; Sayre,
L. M. J. Am. Chem. Soc. 1990, 112, 2332-2340. (d) Capdevielle,
P.; Maumy, M. Tetrahedron Lett. 1991, 32, 3831-3834. (e)
Mahapatra, S.; Halfen, J. A. Tolman, W. B. J. Am. Chem. Soc.
1996, 118, 11575-11586. (f) Maiti, D.; Sarjeant, A. A. N.; Karlin,
K. D. J. Am. Chem. Soc. 2007, 129, 6720-6721. (g) Ling, Z.; Yun,
L.; Liu, L.; Wu, B.; Fu, X. Chem. Commun. 2013, 49, 4214-4216.
(h) Kim, S.; Ginsbach, J. W.; Lee, J. Y.; Peterson, R. L.; Liu, J. J.;
Siegler, M. A.; Sarjeant, A. A.; Solomon, E. I.; Karlin, K. D. J.
Am. Chem. Soc. 2015, 137, 2867-2874.
4. (a) Chen, X.; Chen, T.; Zhou, Y.; Han, D.; Han, L.-B.; Yin, S.-F.
Org. Biomol. Chem. 2014, 12, 3802-3807. (b) Wu, K.; Huang, Z.;
Liu, C.; Zhang, H.; Lei. A. Chem. Commun. 2014, 51, 2286-2289.
5. Tang, G.; Ji, T.; Hu, A.-F.; Zhao, Y.-F. Synthesis 2008, 1907-
1909.
6. (a) Röhrig, U. F.; Majjigapu, S. R.; Grosdidier, A.; Bron, S.;
Stroobant, V.; Pilotte, L.; Colau, D.; Vogel, P.; Van den Eynde, B.
J.; Zoete, V.; Michielin, O. J. Med. Chem.2012, 55, 5270-5290.
(b) Röhrig, U. F.; Majjigapu, S. R.; Vogel, P.; Zoete, V.;
Michielin, O. J. Med. Chem. 2015, 56, 8270-8279. (c) Hsu, K. L.;
Tsuboi, K.; Chang, J. W.; Whitby, L. R.; Speers, A. E.; Pugh, H.;
Cravatt, B. F. J. Med Chem. 2013, 56, 8270-8279. (d) Liu, Y.-H.;
Zhang, L.; Xu, X.-N.; Li, Z.-M.; Zhang, D.-W.; Zhao, X.; Li, Z.-
T. Org. Chem. Front. 2014, 1, 494-500. (e) Agard, N. J.; Prescher,
J. A.; Bertozzi, C. R. J. Am. Chem. Soc. 2004, 126, 15046-15047.
(f) Chen, G.; Zhou, Y.; Cai, C.; Zhang, X. Molecules 2014, 19,
5674-5691.
16. (a) Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc.
2012, 134, 5317-5325. (b) Ratnikov, M. O.; Doyle, M. P. J. Am.
Chem. Soc. 2013, 135, 1549-1557. (c) Yang, B.; Yang, T.-T.; Li,
X.-A.; Wang, J.-J.; Yang, S.-D. Org. Lett. 2013, 15, 5024-5027.
(d) Ueda, H.; Yoshida, K.; Tokuyama, H. Org. Lett. 2014, 16,
4194-4197. (e) Xu, X.; Ding, W.; Lin, Y.; Song, Q. Org. Lett.
2015, 17, 516-519.
17. Menendez, C.; Gau, S.; Ladeira, S.; Lherbet, C.; Baltas, M. Eur. J.
Org. Chem. 2012, 12, 409-416.
Supplementary Material
1H and 13C NMR spectra of compounds. X-ray
crystallographic structure of 3a.
7. Huisgen, R. 1,3-Dipolar Cycloaddition-Introduction, Survey,
Mechanism. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; John Wiley: New York, 1984; Vol. 1, pp1-176.
8. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004-2021. (b) Tornøe, C. W.; Christensen, C.;
Meldal, M. J. Org. Chem. 2002, 67, 3057-3064. (c) Kamata, K.;
Click here to remove instruction text...