Acid-mediated synthesis of fully substituted 1,2,3-triazoles: Multicomponent coupling reactions, mechanistic study, synthesis of serine hydrolase inhibitor and its derivatives

Article abstract of DOI:10.1016/j.tet.2014.10.076

We describe the full details of multicomponent coupling reactions in acid-mediated synthesis of fully substituted 1,2,3-triazoles syntheses, and their applications to bioactive molecule synthesis. For substitution with wide range of nucleophiles, selectio

Full text of DOI:10.1016/j.tet.2014.10.076

Accepted Manuscript
Acid-mediated Synthesis of Fully Substituted 1,2,3-Triazoles: Multicomponent
Coupling Reactions, Mechanistic Study, Synthesis of Serine Hydrolase Inhibitor and
Its Derivatives
Huan Zhang , Hiroki Tanimoto , Tsumoru Morimoto , Yasuhiro Nishiyama , Kiyomi
Kakiuchi
PII:
S0040-4020(14)01541-5
10.1016/j.tet.2014.10.076
TET 26146
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 September 2014
Revised Date: 30 October 2014
Accepted Date: 31 October 2014
Please cite this article as: Zhang H, Tanimoto H, Morimoto T, Nishiyama Y, Kakiuchi K, Acid-mediated
Synthesis of Fully Substituted 1,2,3-Triazoles: Multicomponent Coupling Reactions, Mechanistic
Study, Synthesis of Serine Hydrolase Inhibitor and Its Derivatives, Tetrahedron (2014), doi: 10.1016/
j.tet.2014.10.076.
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Acid-mediated Synthesis of Fully Substituted 1,2,3-
Triazoles: Multicomponent Couplings, Mechanistic
Study, Synthesis of Serine Hydrolase Inhibitor and Its
Derivatives
Leave this area blank for abstract info.
Huan Zhang, Hiroki Tanimoto,* Tsumoru Morimoto, Yasuhiro Nishiyama and Kiyomi Kakiuchi
Graduate school of materials science, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama-
cho, Ikoma, Nara 630-0192, Japan

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Tetrahedron
journal homepage: www.elsevier.com
Acid-mediated Synthesis of Fully Substituted 1,2,3-Triazoles: Multicomponent
Coupling Reactions, Mechanistic Study, Synthesis of Serine Hydrolase Inhibitor and
Its Derivatives
Huan Zhang, Hiroki Tanimoto, Tsumoru Morimoto, Yasuhiro Nishiyama, and Kiyomi Kakiuchi
aGraduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5 Takayamacho, Ikoma, Nara 630-0192, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We describe the full details of multicomponent coupling reactions in acid-mediated synthesis of
fully substituted 1,2,3-triazoles syntheses, and their applications to bioactive molecule synthesis.
For substitution with wide range of nucleophiles, selection of acids or activating reagents was
important, and various types of multicomponent coupling reactions were demonstrated, allowing
functionalization with alcohols, amines, thiol, azide, and carbon nucleophiles. Four-component
couplings including double triazolations were also tested. The efficiency of this method was
demonstrated by the synthesis of serine hydrolase inhibitor and its novel substituted derivatives.
Available online
Keywords:
Organic azides
Multicomponent coupling reactions
triazoles
2009 Elsevier Ltd. All rights reserved
.
Reaction mechanism
Bioactive compounds
1. Introduction
N
N
N
Organic azides are important functional compounds that
facilitate the introduction of amino groups, chemical bond
rearrangements, and C–H insertions via nitrenes.1 Because of the
specific reactivity and various applications, organic azides have
been well studied in the fields of synthetic organic chemistry and
natural product synthesis.1b
N3 R4
azides
R1
R2
R1
R2
R4
R3
•
C1 C3
R3
allenylaminodiazonium
intermediates
propargyl cations
from alcohols
In recent years, azide–alkyne cycloadditions (AAC) under Cu-
catalyzed (CuAAC) and Cu-free conditions have been
extensively developed to produce 1,2,3-1H-triazoles;2 many
studies have reported their numerous applications, especially in
chemical biology,2,3 ligand/material design,4 pharmaceuticals,5
and new reactions of triazoles as the synthetic precursors.6
However, triazole syntheses by CuAAC and metal-activated
AAC are mostly limited to terminal alkynes, and one-pot or
cascade transformation of triazole compounds have been
requested toward synthesis of multifunctional molecules in short
steps.
N
R4
N
R4
Nu
N
N
then
Nucleophiles
N
N
R1
R2
C1
C3
R3
R1
R3
Nu
R2
methylene-
triazolium ions
fully substituted
triazoles
bioactive molecules
or functional materials
Scheme 1. Triazole synthesis with propargyl cations,
organic azides, and additional nucleophiles.
The reactions of organic azides with carbocations have been
well studied (Schmidt–Aubé reaction).1a,7 However, the reactions
of organic azides with delocalized carbocations such as
allyl/propargyl cations have rarely been studied. Recently, we
investigated the reactions of organic azides with allyl cations,
smoothly affording cyclic unsaturated imines under moderate
the unstable iminium venom alkaloid of Costa Rican ants.8 Based
on the research,8a we previously reported novel triazole synthesis
with propargyl cations (Scheme 1).9 In this reactions, organic
azides can attack at both the C1 and C3 positions of propargyl
cations as shown in Scheme 1, and it has been reported that the
temperature conditions, and this method enabled the synthesis of
———
Corresponding author. Tel.: +81-743-72-6085; fax: +81-743-72-6089; e-mail: tanimoto@ms.naist.jp

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2
Tetrahedron
attacks at the C1 positions simply proceeded by the Schmidt
reaction to produce the corresponding ynimines.10 On the other
hand, if the attack of azides can be controlled, then the C–N bond
Table 1. Scope of nucleophiles
formation
at
the
C3
position
would
produce
allenylaminodiazonium compounds—a type of allenylazides.11
We anticipated that these unstable species could immediately be
transformed to cyclic triazolium intermediates possessing exo-
methylene units, to which nucleophiles could be reacted. Because
fully substituted and functionalized triazoles are difficult to
prepare by CuAAC, our approach could provide an efficient
synthetic method for promising compounds for developing novel
bioactive molecules and functional materials.12,13 Herein we
report the full detail of the three/four-component coupling
reactions of acid-mediated triazole synthesis via carbocations and
applications to the syntheses of serine hydrolase inhibitor and its
derivatives, which are difficult to prepare by CuAAC.
Entry Nucleophiles and Products
Yield (%)a
Cond. A
Cond. B
1
2
5a
5b
82 (10)
73 (11)
69 (trace)
2. Results and discussions
In previous paper, we mainly disclosed introduction of
hydroxy group into the triazole products in one-pot by quenching
with aqueous media as nucleophiles.9 However, considering the
proposed reaction mechanism (Scheme 1), the products could be
functionalized using other additional nucleophiles instead of a
hydroxy group. Although we have already demonstrated a few
examples of three-component couplings including intramolecular
substitution, the true source of hydroxy groups is unclear. Thus,
before testing the generality of multicomponent coupling
reactions, we reinvestigated the origin of the hydroxy group
(Scheme 2). The treatment of methyl ether 1 with stoichiometric
amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf),9
which were used in previous work, only afforded the triazole
possessing methoxy group 2 at both –90 and –60 °C, even after
quenching with an aqueous medium. However, boron trifluoride
etherate (BF3·OEt2) gave hydroxy compound 3a as the major
product. This indicates that the origin of the hydroxy group
depends on the acid used, and the resulting silanols or silyl ethers
may be the source of hydroxy groups in the case of TMSOTf.
With BF3·OEt2, the benzylic position was successfully substituted
by external water. This indicates that BF3·OEt2 is a suitable acid
for the substitution of triazolium intermediates with additional
nucleophiles probably because hydroxy group donation activity
of the resulting boronates or borinates are limited. For
introduction of hydroxy groups, TMSOTf seems to be better
reagent. Methyl ether 2 was not obtained from 3a by acid
treatments in the presence of methanol. Thus, the
functionalization of the benzylic position should be performed as
one-pot reactions.
58 (11)
3
4
5c
76 (12)
74 (12)
63 (0)
5d
53 (trace)
5
5e
77 (10)
61 (0)
6
7
5f
81 (7)
62 (0)
55 (0)
5g
78 (11)
8
5h
77 (12)
60 (0)
9b
5i
5j
85 (10)
65 (0)
70 (0)
42 (0)
10
11c
12d
5k
5l
69 (3)
54 (trace)
43 (25)
55 (35)
TMSOTf
N
Bn
N
N
Ph
Ph
MeO
(1.2 equiv)
nBu
13e
5m
Ph
Ph
68 (20)
55 (14)
BnN3
(1.5 equiv)
CH2Cl2
nBu
1
OMe
2 (97%)
a Isolated yields of 5a–m and 3a (in parentheses). b
–60 °C, 5 min
then sat. NaHCO3 aq.
Azidotrimethylsilane was used as the nucleophile. c Allyltributyltin
was used as the nucleophile. d Ethyl vinyl ether was used as the
nucleophile. e 1-Ethoxy-1-trimethylsilyloxyethylene was used as the
nucleophile.
Ph
Ph
Ph
Ph
BF3·OEt2 (1.2 equiv)
OH
BnN3 (1.5 equiv)
CH2Cl2
–60 °C, 5 min
OMe
2 (17%)
Based on these results, three-component coupling reactions
with various nucleophiles were investigated to functionalize the
benzylic position with BF3·OEt2 (Table 1, Condition A). In order
to avoid quenching reaction by moisture, the reactions were
performed under nitrogen gas atmosphere. The reactions with
primary alcohols afforded the desired ether products (5a–e) in
good yields (entries 1–5). Although the reactions with secondary
alcohols failed to afford the coupling products, naphthalenethiol,
3a (67%)
then sat. NaHCO3 aq.
BF3·OEt2 (1.2 equiv)
CH2Cl2, –60 °C, 5 min
then MeOH (3 equiv)
Scheme 2. Investigation of the origin of hydroxy group

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3
and diethylamine were successfully introduced to the products
similar to allylamine (entries 6–8). Azido product 5i was also
obtained in a good yield from azidotrimethylsilane (entry 9). Not
only heteroatom nucleophiles, but also carbon nucleophiles were
investigated to form quaternary carbon centers. Indole gave
desired coupling compound 5j selectively (entry 10). The allyl
group was successfully introduced with allyltributyltin (entry 11),
while allylsilanes did not afford 5k. The C–C bonds could also be
formed by silyl enol ethers to afford aldehyde 5l and ethyl ester
5m (entries 12 and 13). Addition of molecular sieves did not
improve the results.
Generation of three-component coupling products indicated
the presence of methylenetriazolium intermediates or
carbocations of triazole (Scheme 1). Other evidence of the
methylenetriazolium intermediates was obtained from 6 (Scheme
3). When electron-withdrawing methoxycarbonyl group was
placed instead of one of the phenyl groups on the C1 position, 6
was converted into triazole 7 at ambient temperature, possessing
an azide on C1 position. Because these types of azido triazoles
were not found in other cases, the azide group of 7 may be
introduced by the [3 + 2] cycloaddition of an additional benzyl
azide to unsaturated ester moiety of triazolium intermediate 6’.
To achieve these three-component coupling reactions at
ambient temperature, the same reactions were investigated with
methanesulfonic acid (MsOH) (Table 1, Condition B),9 and the
desired coupling products were successfully obtained in 40 min.
Interestingly, although the product yields were slightly lower
than those obtained under condition A, lesser amount of by-
product 3a were generated. Considering the generation of 3a in
Scheme 2, boronic acids or borates were still active as
nucleophiles, and water molecule generated by MsOH was
relatively weeker nucleophiles than those acids.
To further develop the one-pot functionalization of triazoles
by multicomponent coupling reactions, double [3
+ 2]
triazolation reactions were investigated (Scheme 4). Based on the
previous successful results, we conducted four-component
coupling reactions consisted by double [3 + 2] reactions followed
by substitutions with nucleophiles. When allylamine was used as
the nucleophile, the reactions successfully afforded the desired
products 9 and 10 in moderate yields along with trace amount of
Meyer-Schuster rearrangement product, hydroxy-substituted
compound, and unidentified polymeric materials. In these cases,
introduction of carbon nucleophiles like indole were unsuccessful,
and hydroxylated compunds were produced. For introduction of
hydroxyl groups, use of TMSOTf was efficient in double
triazolation reactions.9 Notably, the triazole synthesis could be
controlled to afford monotriazole 11 by reducing the amount of
TMSOTf
(1.2 equiv)
N
Bn
N
N
Ph
Ph
MeO
N
Bn
BnN3 (1.5 equiv)
TMSOTf (1.2 equiv)
nBu
Ph
Ph
N
N
BnN3
(1.5 equiv)
CH2Cl2
Ph
Ph
HO
nBu
Ph
Ph
13
R
R
CH2Cl2
–90 °C, 5 min
then
OMe
14 (97%)
OH
3a–f
–60 °C, 5 min
4a–f
then sat. NaHCO3 aq.
sat. NaHCO3 aq.
Ph
Ph
Ph
Ph
O
BF3·OEt2 (1.2 equiv)
OH
Cl
N
BnN3 (1.5 equiv)
CH2Cl2
–60 °C, 5 min
OMe
14 (17%)
O
N
N
12
2a (67%)
N
N
then sat. NaHCO3 aq.
1) H2, Pd/C, EtOH
Ph
Ph
BF3·OEt2 (1.2 equiv)
CH2Cl2, –60 °C, 5 min
then MeOH (3 equiv)
R
2) 12, THF / Et3N (3/1)
OH
13a–f
Scheme 2. Synthesis of Co
Scheme 3. Azidation of benzylic position with organic
azide.
13d
(33%, X-ray)
13a
(80%)
OTBS
R =
nBu
13b
13e
(40%, X-ray)
OBz
3
H
(30%, ref 5d, 15)
13f
(58%)
13c
(67%)
TMS
13e
13d
Scheme 5. Synthesis of serine hydrolase inhibitor urea and
5-substituted derivatives.
organic azide and the use of TMSOTf (2% of bistriazole 12 was
obtained).
Scheme 4. Four-component coupling reactions, and control
of triazolation.

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4
Tetrahedron
To demonstrate the efficiency of our method for bioactive
was carefully handled, and transferred with plastic spatulas.
Regiochemistry of all synthesized triazoles were determined by
NOE experiment or X-ray crystallographic analysis. For
analytical data and NMR spectra that are not shown in this
article, see previous report.9
molecule synthesis, we carried out the synthesis of triazole urea
13b reported as a serine hydrolase inhibitor by Cravatt et al.5d
and its 5-substituted derivatives (Scheme 5). Serine hydrolases
have been used as the targets of clinical drugs to treat various
diseases such as diabetes and Alzheimer’s disease.14 However,
the biochemical activities of these enzymes are yet to be
understood. For this reason, it is important to produce efficient
synthetic methods to prepare selective inhibitors of these
enzymes and preparation of its derivatives as candidates of more
active drug molecules. 1,4,5-Trisubstituted triazoles 3a,c–f and
1,4-disubstituted 3b were prepared from appropriate propargyl
alcohols with TMSOTf followed by quenching with aqueous
media.9 The obtained N-benzyltriazoles were deprotected by
hydrogenolysis, and the obtained unprotected triazoles were
coupled with carbamoyl chloride 12 to afford serine hydrolase
inhibitor triazole urea 13b and its 5-substituted derivatives
13a,c–f. In all cases, desired 2H-triazole ureas 13a–f were
obtained regioselectively. Since it is difficult to prepare triazole
ureas 13a,c–f obtained from internal alkynes by CuAAC, our
method could prove to be an efficient way to explore the property
and activity of fully substituted triazole molecules. The NMR
data of the synthesized inhibitor molecule 13b were identical to
those provided.15
4.1. 1,1-Diphenyl-1-methoxyhept-2-yne (1)
To a stirred solution of sodium hydride (39.4 mg, 0.983
mmol) in THF (3 mL) at 0 ºC under nitrogen atmosphere was
added 4a (200 mg, 0.757 mmol) in THF (1 mL) dropwise and
stirred for 30 min at the same temperature. After 30 min,
iodomethane (0.141 mL, 2.27 mmol) was then added at same
temperature and the mixture was warmed up to room
temperature. After 2h, reaction mixture was quenched with
water. The mixture was diluted with ethyl acetate and washed
with water and brine. Then the collected organic layer was dried
over magnesium sulfate and concentration in vacuo followed by
silica gel column chromatography (ethyl acetate/hexane = 1/5 ) to
give 1 (187.7 mg, 46%).; Colorless oil; Rf value 0.76 (ethyl
acetate/hexane = 1/5); IR (NaCl, neat) νmax 2933, 1488, 1449,
1082, 763, 698 cm-1; 1H NMR(500 MHz, CDCl3) δ 7.56–7.54 (m,
4H), 7.31–7.27 (m, 4H), 7.24–7.20 (m, 2H), 3.33 (s, 3H), 2.38 (t,
2H, J = 7.0 Hz), 1.60 (tt, 2H, J = 7.5, 7.0 Hz), 1.47 (tq, 2H, J =
7.0, 7.5 Hz), 0.94 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz,
CDCl3) δ 143.9, 128.0, 127.3, 126.6, 90.4, 80.9, 79.4, 52.2, 30.8,
22.0, 18.6, 13.6; LRMS (EI) 278 (M+,27%), 247 (60), 221 (57),
201 (100); HRMS (EI) calcd for C20H22O (M+) 278.1670, found
278.1668.
3. Conclusion
We have developed regioselective rapid azide–alkyne
cycloaddition to produce fully substituted 1H-1,2,3-triazoles. via
propargyl cations derived from the corresponding alcohols.
Various types of multicomponent coupling reactions, including
double triazolations and functionalizations of triazoles with
additional nucleophiles in one-pot, were demonstrated. The
presence of methylenetriazolium intermediates was indicated.
The synthesized triazoles were successfully converted to serine
hydrolase inhibitor triazole urea and its derivatives. Our method
can provide new preparation method of highly substituted
triazoles and exploration of their uses in synthetic organic
chemistry and pharmaceutical research.
4.2. 1-Benzyl-5-butyl-4-(methoxydiphenylmethyl)-1H-1,2,3-
triazole (2)
To a mixture of propargyl ether 1 (34.7 mg, 0.125 mmol) and
benzyl azide (24.9 mg, 0.187 mmol) in dichloromethane (1.5
mL) under nitrogen atmosphere, TMSOTf (27 µL, 0.150 mmol)
was added at room temperature dropwise. After five minutes, the
reaction was quenched with saturated sodium bicarbonate
aqueous solution, and was washed with brine. Then the collected
organic layer was dried over magnesium sulfate followed by
concentration in vacuo and silica gel column chromatography
(ethyl acetate/hexane = 1/5) to afford 2 (49.8 mg, 97%) as a
colorless oil.; Rf value 0.19 (ethyl acetate/hexane = 1/4); IR
4. Experimental Section
1H and 13C NMR were recorded on a JEOL JNM-ECP500
1
1
(NaCl, neat) νmax 2927, 2855, 1456, 1070, 744, 703 cm-1; H
spectrometer (500 MHz for H NMR, 126 MHz for 13C NMR).
NMR (500 MHz, CDCl3) δ 7.43 (d, 4H, J = 7.0 Hz),7.19–7.10
(m, 7H), 7.03 (tt, 2H, J = 7.5, 7.0 Hz), 6.98 (d, 2H, J = 7.0 Hz),
5.33 (s, 2H), 2.91 (s, 3H), 1.96 (t, 2H, J = 8.0 Hz), 0.83–0.74 (m,
4H), 0.50 (t, 3H, J = 7.0 Hz); 13C NMR (126 MHz, CDCl3) δ
146.1, 143.9, 136.9, 135.3, 128.9, 128.1, 127.8, 127.6, 126.9,
126.8, 82.6, 51.9, 51.8, 29.8, 22.8, 22.6, 13.4; LRMS (EI) LRMS
(EI) 411(M+,7%), 381(35), 105(12), 91(100); HRMS (EI) calcd
for C27H29N3O (M+) 411.2311, found 411.2314.
Chemical shifts are reported as δ values in ppm and calibrated by
1
residual solvent peak (CDCl3: δ 7.26 for H NMR, δ 77.00 for
1
13C NMR, CD2Cl2: δ 5.32 for H NMR, δ 53.80 for 13C NMR,
1
CD3OD: δ 49.00 for 13C NMR) or tetramethylsilane (δ 0 for H
NMR). Abbreviations are following: s (singlet), d (doublet), t
(triplet), q (quartet), br (broad peak), m (complex multiplet).
Infrared spectra were measured on a JASCO FT/IR-4200
spectrometer. Mass spectra were recorded on a double-focusing
mass spectrometer JEOL JMS-700 MStaion [EI (70 eV), CI,
FAB and ESI]. X-ray crystallography was performed on Rigaku
R-AXIS RAPID/S imaging plate diffractometer. Flash column
chromatography was performed by MERCK Silica gel 60. The
progress of reactions was monitored by silica gel thin layer
chromatography plates (MERCK TLC Silicagel 60 F254).
Phosphomolybdic acid ethanol solution, ninhydrin-acetic acid
butanol solution and anisaldehyde-acetic acid-sulfuric acid
ethanol solution were used as TLC stain. All reagents were
purchased from Sigma-Aldrich, Wako pure chemical industries,
Ltd, TCI (Tokyo Chemical Industry, Co. Ltd), Kanto Chemical
Co. Inc., and Nakalai Tesque. Used Dehydrated solvents —
tetrahydrofuran, dichloromethane and toluene— were purchased
from Kanto Chemical, Wako pure chemical industries, Ltd, and
Nakalai Tesque. Sodium azide purchased from Nakalai Tesque
4.3. General procedures of three-component coupling reactions
(Condition A) To a solution of 4a (1 equiv), benzyl azide (1.5
equiv) in dichloromethane (0.1 M to alcohols) under nitrogen
atmosphere, boron trifluoride diethyl etherate (1.2 equiv) was
added at –60 °C dropwise. Then nucleophile reagent (3 equiv)
was added at the same temperature and the mixture was warmed
up to 0 °C. After 30 min, the reaction was quenched with
saturated sodium bicarbonate aqueous solution, and was washed
with brine. Then the collected organic layer was dried over
magnesium sulfate followed by concentration in vacuo and silica
gel column chromatography to afford three-component coupling
products.; (Condition B) To a solution of 4a (1 equiv), benzyl
azide (1.5 equiv) in dichloromethane (0.1 M to alcohol) under
nitrogen atmosphere, methanesulfonic acid (1.2 equiv) was added

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5
at 0 °C dropwise. Then nucleophiles (3 equiv) were added at the
same temperature and the mixture was warmed up to 0 °C. After
30 min, the mixture was treated as same as above to obtain three-
component coupling products.
and trace amount of 3a from 4a (52.8 mg, 0.200 mmol);
Colorless oil ; Rf value 0.29 (ethyl acetate/hexane = 1/5); IR
(NaCl, neat) νmax 3448, 3303, 2956, 2871, 1449, 1071, 705 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.59 (d, 4H, J = 8.0 Hz), 7.33–
7.25 (m, 7H), 7.18–7.12 (m, 4H), 5.46 (s, 2H), 3.22 (t, 2H, J =
6.5 Hz), 2.81 (t, 2H, J = 7.5 Hz), 2.03 (t, 2H, J = 8.5 Hz), 1.78–
4.3.1. 1-Benzyl-5-butyl-4-
((nonyloxy)diphenylmethyl)-1H-1,2,3-triazole (5a)
1.73 (m, 3H), 0.95–0.86 (m, 4H), 0.63 (t, 3H, J = 7.0 Hz); 13
C
(Condition A) 5a (85.9 mg, 82%) and 3a (7.7 mg, 10%) from
4a (53.0 mg, 0.200 mmol) [silica gel purification (ethyl
acetate/hexane = 1/30 to 1/20 to 1/10)]. (Condition B) 5a (72.2
mg, 69%) and trace amount of 3a from 4a (53.0 mg, 0.200
mmol).; Colorless oil ; Rf value 0.38 (ethyl acetate/hexane = 1/5);
Rf value 0.38 (ethyl acetate/hexane = 1/5); IR (NaCl, neat) νmax
2927, 2855, 1457, 1070, 704 cm-1; 1H NMR (500 MHz, CDCl3) δ
7.59 (d, 4H, J = 7.0 Hz), 7.33–7.25 (m, 7H), 7.17 (dd, 2H, J =
6.0, 7.5 Hz), 7.11 (d, 2H, J = 6.0 Hz), 5.47 (s, 2H,) 3.09 (t, 2H, J
= 7.0 Hz), 2.07 (t, 2H, J = 8.0 Hz), 1.54 (tt, 2H, J = 7.0, 8.0 Hz),
1.28–1.22 (m, 12H), 0.96–0.86 (m, 7H),0.65 (t, 3H, J = 7.0 Hz);
13C NMR (126 MHz, CDCl3) δ 146.6, 144.4, 136.9, 135.4, 128.8,
128.1, 127.8, 127.5, 126.9, 126.7, 81.8, 63.7, 51.8, 31.9, 29.9,
29.52, 29.46, 29.2, 26.3, 22.9, 22.7, 22.6, 14.1, 13.5; HRMS
(ESI) calcd for C35H45N3ONa [M+Na]+ 546.34603, found
546.34558.
NMR (126 MHz, CDCl3) δ 146.2, 144.2, 137.0, 135.3, 128.9,
128.1, 127.8, 127.4, 126.9, 126.7, 83.8, 81.8, 68.4, 62.0, 51.8,
29.9, 29.0, 22.8, 22.6, 15.5, 13.4; HRMS (ESI) calcd for
C31H33N3ONa [M+Na]+ 486.25213, found 486.25226.
4.3.5. 1-Benzyl-5-butyl-4-((naphthalen-2-
ylthio)diphenylmethyl)-1H-1,2,3-triazole (5f)
(Condition A) 5f (87.8 mg, 81%) and 3a (5.2 mg, 7%) from
4a (53.0 mg, 0.200 mmol) [silica gel purification (ethyl
acetate/hexane = 1/10 to 1/5)]. (Condition B) 5f (62.7 mg, 62%)
from 4a (52.8 mg, 0.200 mmol).; Colorless oil; Rf value 0.28
(ethyl acetate/hexane = 1/5); IR (NaCl, neat) νmax 3054, 2975,
1
1495, 1455, 728, 698 cm-1; H NMR (500 MHz, CDCl3) δ 7.76
(d, 1H, J = 8.0 Hz), 7.57 (d, 1H, J = 7.5 Hz), 7.54–7.53 (m, 2H),
7.48–7.43 (m, 6H), 7.32–7.22 (m, 10H), 7.04 (d, 2H, J =7.5 Hz),
5.49 (s, 2H), 2.18 (t, 2H, J = 8.5 Hz), 0.97 (tq, 2H, J = 7.5, 8.0
Hz), 0.73 (m, 2H), 0.64 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz,
CDCl3) δ147.1, 142.9, 135.9, 135.1, 133.9, 133.0, 132.3, 131.5,
131.1, 129.4, 128.7, 128.0, 127.7, 127.6, 127.4, 127.2, 126.9,
126.7, 126.1, 125.9, 64.0, 52.0, 29.0, 23.3, 22.7, 13.3; HRMS
(ESI) calcd for C36H33N3SNa [M+Na]+ 562.22929, found
562.22952.
4.3.2. 1-Benzyl-4-(((6-
bromohexyl)oxy)diphenylmethyl)-5-butyl-1H-1,2,3-
triazole (5b)
(Condition A) 5b (81.5 mg, 73%) and 3a (8.7 mg, 11%) from
4a (53.0 mg, 0.200 mmol) [silica gel purification (ethyl
acetate/hexane = 1/15 to 1/10)]. (Condition B) 5b (64.8 mg,
58%) and trace amount of 3a from 4a (53.0 mg, 0.200 mmol).;
Colorless oil ; Rf value 0.29 (ethyl acetate/hexane = 1/5); IR
4.3.6. N-((1-Benzyl-5-butyl-1H-1,2,3-triazol-4-
yl)diphenylmethyl)prop-2-en-1-amine (5h)
1
(NaCl, neat) νmax 2933, 2868, 1456, 1071, 896, 704 cm-1; H
(Condition A) 5h (68.2 mg, 77%) and 3a (9.4 mg, 12%) from
4a (53.8 mg, 0.204 mmol) [silica gel purification (ethyl
acetate/hexane = 1/10 to 1/4)]. (Condition B) 5h (53.4 mg, 60%)
from 4a (53.6 mg, 0.200 mmol).; Colorless oil; Rf value 0.29
(ethyl acetate/hexane = 1/5); IR (NaCl, neat) νmax 3320, 2957,
NMR (500 MHz, CDCl3) δ 7.58 (d, 4H, J = 8.0 Hz), 7.34–7.25
(m, 7H), 7.17 (dd, 2H, J = 7.5, 6.5 Hz), 7.12 (d, 2H, J = 6.5 Hz),
5.47 (s, 2H), 3.35 (t, 2H, J = 7.0 Hz), 3.11 (t, 2H, J = 6.5 Hz),
2.04 (t, 2H, J = 8.0 Hz), 1.80 (tt, 2H, J = 7.0, 6.5 Hz), 1.55 (tt,
2H, J = 6.5, 7.0 Hz), 1.35 (m, 4H), 0.96–0.86 (m, 4H), 0.65 (t,
3H, J = 7.0 Hz); 13C NMR (126 MHz, CDCl3) δ 146.4, 144.3,
136.9, 135.3, 128.8, 128.1, 127.8, 127.4, 126.9, 126.7, 81.8, 63.4,
51.8, 33.8, 32.7, 29.9, 29.7, 27.9, 25.5, 22.8, 22.7, 13.4; LRMS
1
2870, 1491, 1456, 728, 704 cm-1; H NMR (500 MHz, CDCl3) δ
7.45 (d, 4H, J = 7.0 Hz), 7.32–7.23 (m, 7H), 7.18 (dd, 2H, J =
7.0, 6.5 Hz), 7.10 (d, 2H, J = 7.0 Hz), 5.91 (ddt, 1H, J = 17.0,
10.5, 5.0 Hz), 5.43 (s, 2H), 5.18 (dd, 1H, J = 17.0, 1.5 Hz), 5.01
(dd, 1H, J = 10.5, 1.5 Hz), 2.92 (d, 2H, J = 5.0 Hz), 2.18 (t, 2H, J
= 8.5 Hz), 2.07 (s, 1H, NH), 0.98 (td, 2H, J = 7.5, 7.0 Hz), 0.81–
0.75 (m, 2H), 0.64 (t, 3H, J = 7.0 Hz); 13C NMR (126 MHz,
CDCl3) δ 148.3, 144.4, 137.0, 135.3, 135.1, 128.8, 128.3, 128.0,
127.7, 126.8, 126.5, 114.9, 66.6, 51.8, 46.6, 29.8, 22.9, 22.7,
13.4; HRMS (ESI) calcd for C29H32N4Na [M+Na]+ 459.2525,
found 459.2524.
(EI)
;
HRMS (ESI) calcd for C32H38BrN3ONa [M+Na]+
582.20959, found 582.20950.
4.3.3. 1-Benzyl-5-butyl-4-[(2-
methoxyethoxy)diphenylmethyl]-1H-1,2,3-triazole
(5c)
(Condition A) 5c (105.7 mg, 76%) and 3a (14.3 mg, 12%)
from 4a (80.5 mg, 0.196 mmol) [silica gel purification (ethyl
acetate/hexane = 1/60 to 1/50 to 1/40 to 1/30 to 1/20 to 1/10)].
(Condition B) 5c (57.9 mg, 63%) from 4a (52.9 mg, 0.201
mmol).; Colorless oil; Rf value 0.18 (ethyl acetate/hexane = 1/4);
IR (NaCl, neat) νmax 2955, 2929, 1449, 1080, 705 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.60 (d, 4H, J = 8.0 Hz), 7.26–7.34 (m, 7H),
7.18 (dd, 2H, J = 7.5, 7.0 Hz), 7.14 (d, 2H, J = 7.5 Hz), 5.46 (s,
2H), 3.49 (t, 2H, J = 4.0 Hz), 3.30–3.31 (m, 5H), 2.13 (m, 2H),
0.89–1.02 (m, 4H), 0.67 (t, 3H, J = 7.0 Hz); 13C NMR (126 MHz,
CDCl3) δ 146.5, 143.8, 137.0, 135.3, 128.9, 128.1, 127.8, 127.7,
127.0, 126.8, 82.3, 72.0, 62.9, 58.7, 51.8, 30.0, 22.9, 22.7, 13.5;
LRMS (EI) 455 (3%, M+), 381 (26), 91 (100); HRMS (EI) calcd
for C29H33N3O2 (M+) 455.2573, found 455.2573.
4.3.7. 1-Benzyl-5-butyl-4-(1,1-diphenylbut-3-en-1-
yl)-1H-1,2,3-triazole (5k)
(Condition A) 5k (57.9 mg, 69%) and 3a (2.1 mg, 3%) from
4a (53.0 mg, 0.200 mmol) [silica gel purification (ethyl
acetate/hexane = 1/15 to 1/10 to 1/4)]. (Condition B) 5k (39.1 mg,
54%) with trace amount of 3a from 4a (45.5 mg, 0.172 mmol).;
White solid; Rf value 0.28 (ethyl acetate/hexane = 1/5); m.p.
128.9–130.1 °C; IR (NaCl, neat) νmax 3081, 2959, 1466, 907, 700
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.43–7.38(m, 3H), 7.34–7.31
(m, 4H), 7.28–7.24 (m, 6H), 7.20 (t, 2H, J = 7.0 Hz), 6.02 (tdd,
1H, J = 17.0, 6.5, 7.5 Hz), 5.53 (s, 2H), 4.97–4.92 (m, 2H), 3.63
(d, 2H, J = 6.5 Hz), 1.90 (m, 2H), 0.89 (tt, 2H, J = 7.5, 7.5 Hz),
0.62 (t, 3H, J = 7.5 Hz), 0.51–0.45 (m, 2H); 13C NMR (126 MHz,
CDCl3) δ 149.1, 144.6, 136.2, 135.4, 135.3, 128.9, 128.8, 128.1,
127.7, 126.8, 126.2, 117.0, 52.1, 51.8, 47.1, 29.1, 23.1, 22.7,
13.4; HRMS (ESI) calcd for C29H31N3Na [M+Na]+ 444.24157,
found 444.23930.
4.3.4. 1-Benzyl-5-butyl-4-((pent-4-yn-1-
yloxy)diphenylmethyl)-1H-1,2,3-triazole (5e)
(Condition A) 5e (71.8 mg, 77%) and 3a (8.1 mg, 10%) from
4a (53.0 mg, 0.200 mmol) [silica gel purification (ethyl
acetate/hexane = 1/10 to 1/4)]. (Condition B) 5e (57.1 mg, 61%)

ACCEPTED MANUSCRIPT
6
Tetrahedron
4.3.8. 3-(1-Benzyl-5-butyl-1H-1,2,3-triazol-4-yl)-
minutes, the reaction was quenched with saturated sodium
3,3-diphenylpropanal (5l)
bicarbonate aqueous solution, and was washed with brine. Then
the collected organic layer was dried over magnesium sulfate
followed by concentration in vacuo and silica gel column
chromatography (ethyl acetate / hexane = 1 / 5) to afford 7 (34.3
(Condition A) 5l (45.8 mg, 55%) and 3a (27.6 mg, 35%) from
4a (52.4 mg, 0.198 mmol) [silica gel purification (ethyl
acetate/hexane = 1/10 to 1/5 to 1/4)]. (Condition B) 5l (28.3 mg,
43%) and 3a (15.6 mg, 25%) from 4a (41.2 mg, 0.156 mmol).;
Colorless oil; Rf value 0.14 (ethyl acetate/hexane = 1/5); IR
mg, 31%) as
a colorless solid.; Rf value 0.18 (ethyl
acetate/hexane = 1/5); m.p. 158.7–159.4 °C; IR (NaCl, neat) νmax
1
2957, 2112, 1746, 1241 cm-1; H NMR (500 MHz, CDCl3) δ
(NaCl, neat) νmax 2957, 2858, 1715, 1455, 1023, 700 cm-1; H
1
7.44–7.42 (m, 2H), 7.35–7.30 (m, 6H), 7.11 (d, 2H, J = 7.0 Hz),
5.54 (d, 1H, J = 16.0 Hz), 5.47 (d, 1H, J = 16.0 Hz), 3.89 (s, 3H),
2.19 (m, 1H), 2.02 (m, 1H), 1.06–0.84 (m, 4H), 0.62 (t, 3H, J =
7.0 Hz); 13C NMR (126 MHz, CDCl3) δ 169.8, 143.3, 136.6,
136.2, 134.7, 129.0, 128.5, 128.3, 128.1, 127.4, 126.8, 71.1, 53.6,
52.1, 29.7, 22.5, 22.4, 13.2; HRMS (ESI) calcd for
C22H24N6NaO2 [M+Na]+ 427.1858, found 427.1856.
NMR (500 MHz, CDCl3) δ 9.84 (t, 1H, J = 2.5 Hz), 7.56–7.51
(m, 3H), 7.49–7.41 (m, 6H), 7.35 (d, 2H, J = 7.0 Hz), 7.25 (d,
4H, J = 8.5 Hz), 5.65 (s, 2H), 3.80 (d, 2H, J = 2.5 Hz), 1.96 (t,
2H, J = 8.5 Hz), 0.95 (qt, 2H, J = 7.5, 7.5 Hz), 0.71 (t, 3H, J =
7.5 Hz), 0.59–0.53 (m, 2H); 13C NMR (126 MHz, CDCl3) δ
202.5, 148.0, 143.8, 135.8, 135.1, 129.0, 128.5, 128.4, 128.3,
127.0, 126.99, 55.2, 52.0, 49.7, 29.3, 23.0, 22.7, 13.3; HRMS
(ESI) calcd for C28H29N3ONa [M+Na]+ 446.22083, found
446.22063.
4.6. N-(Bis(1-benzyl-5-butyl-1H-1,2,3-triazol-4-
yl)(phenyl)methyl)prop-2-en-1-amine (9)
4.3.9. Ethyl 3-(1-benzyl-5-butyl-1H-1,2,3-triazol-4-
yl)-3,3-diphenylpropanoate (5m)
To a mixture of 8 (55.3 mg, 0.206 mmol),9 benzyl azide (82.3
mg, 0.618 mmol) in dichloromethane (2.1 mL) was added boron
trifluoride diethyl ether complex (66.7 µL, 0.247 mmol) at –60
°C. After five minutes, allylamine (36.6 µL, 0.618 mmol) was
added at the same temperature, and then warmed up to room
temperature. After 30 min, the mixture the reaction was
quenched with saturated sodium bicarbonate aqueous solution,
and was washed with brine. Then the collected organic layer was
dried over magnesium sulfate followed by concentration in vacuo
and silica gel column chromatography (ethyl acetate/hexane =
1/10 to 1/5 to 1/3) to afford 9 (56.1 mg, 48%).; Colorless oil: Rf
value 0.31 (ethyl acetate/hexane = 1/2); IR (NaCl, neat) νmax 3344,
2957, 2870, 1455, 1241, 905, 725, 699 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.43 (d, 2H, J = 8.5 Hz), 7.30–7.27 (m, 8H), 7.22 (dd,
1H, J = 7.5, 8.5 Hz), 7.12–7.10 (m, 4H), 5.90–5.83 (m, 1H), 5.45
(s, 4H), 5.15 (dd, 1H, J = 1.5, 17.0 Hz), 4.98 (d, 1H, J = 10.5
Hz), 2.95 (d, 2H, J = 5.0Hz), 2.37–2.23 (m, 4H), 1.07–1.03 (m,
4H), 0.86–0.76 (m, 4H), 0.68 (t, 6H, J = 7.5 Hz); 13C NMR (126
MHz, CDCl3) δ 147.1, 142.8, 136.9, 135.7, 135.4, 128.8, 128.4,
128.1, 127.6, 126.9, 126.8, 114.8, 62.6, 51.8, 46.3, 29.8, 22.9,
22.7, 13.5; HRMS (ESI) calcd for C36H43N7Na [M+Na]+
596.34776, found 596.35051.
Used 1-ethoxy-1-trimethyl-silyloxyethylene was prepared
according to known procedure.16 (Condition A) 5m (63.1 mg,
68%) and 3a (15.3 mg, 20%) from 4a (52.5 mg, 0.199 mmol)
[silica gel purification (ethyl acetate/hexane = 1/80 to 1/70 to
1/50 to 1/30 to 1/20 to 1/4)]. (Condition B) 5m (38.7 mg, 55%)
and 3a (8.1 mg, 14%) from 4a (39.7 mg, 0.150 mmol).; Colorless
oil; Rf value 0.14 (ethyl acetate/hexane = 1/5); IR (NaCl, neat)
1
νmax 2957, 2870, 1742, 1151, 700 cm-1; H NMR (500 MHz,
CDCl3) δ 7.33–7.28 (m, 3H), 7.25–7.22 (m, 4H), 7.21–7.15 (m,
6H), 7.10 (d, 2H, J = 7.0 Hz), 5.42 (s, 2H), 3.95 (q, 2H, J = 7.0
Hz), 3.78 (s, 2H), 1.84 (t, 2H, J = 8.5 Hz), 1.06 (t, 3H, J = 7.0
Hz), 0.77 (qt, 2H, J = 7.0, 7.5 Hz), 0.51 (t, 3H, J = 7.5 Hz), 0.37–
0.30 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 170.8, 148.0, 144.2,
135.4, 135.2, 128.9, 128.7, 128.1, 127.9, 126.8, 126.5, 60.0, 51.9,
50.8, 46.9, 29.0, 23.3, 22.7, 13.9, 13.4; HRMS (ESI) calcd for
C30H34N3O2 [M+H]+ 468.26510, found 468.26574.
4.4. Methyl 2-hydroxy-2-phenyloct-3-ynoate (6)
To a stirred solution of 1-hexyne (0.487 mL, 4.26 mmol) in
THF (31 mL) at 0 ºC under nitrogen atmosphere was added
lithium bis(trimethylsilyl)amide (1.0 M in THF, 4.57 mL, 4.57
mmol) dropwise. After 30 min, methyl benzoylformate (500.0
mg, 3.05 mmol) was then added at the same temperature and the
mixture was warmed up to room temperature. After 12 h,
reaction mixture was quenched with saturated ammonium
chloride aqueous solution. The mixture was diluted with ether
and washed with water and brine. Then the collected organic
layer was dried over magnesium sulfate and concentration in
vacuo followed by silica gel column chromatography (ethyl
acetate/hexane = 1/ 20 to 1/15) to give 6 (344.8 mg, 46%).;
Colorless oil; Rf value 0.29 (ethyl acetate/hexane = 1/5); IR
4.7. N-((1-Benzyl-5-butyl-1H-1,2,3-triazol-4-yl)(5-butyl-1-
cinnamyl-1H-1,2,3-triazol-4-yl)(phenyl)methyl)prop-2-en-1-
amine (10)
To a mixture of 8 (77.6 mg, 0.289 mmol), benzyl azide (40.4
mg, 0.304 mmol) in dichloromethane (3.0 mL) was added boron
trifluoride diethyl ether complex (101.3 µL, 0.376 mmol) at –60
°C. After 1 min, cinnamyl azide (69.0 mg, 0.434 mmol)
dissolved in 0.5 mL of dichloromethane was added to the
mixture. After five minutes, allylamine (51.3 µL, 0.867 mmol)
was added at the same temperature, and then warmed up to room
temperature. After 30 min, the mixture the reaction was
quenched with saturated sodium bicarbonate aqueous solution,
and was washed with brine. Then the collected organic layer was
dried over magnesium sulfate followed by concentration in vacuo
and silica gel column chromatography (ethyl acetate/hexane =
1/12 to 1/10 to 1/5 to 1/3) to afford 10 (45.9 mg, 27%).; Colorless
oil; Rf value 0.30 (ethyl acetate/hexane = 1/2); IR (NaCl, neat)
νmax 3344, 2957, 2931, 2870, 1456, 1241, 904, 728 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.47 (dd, 2H, J = 7.5, 2.0 Hz), 7.39–7.25
(m, 11H), 7.16 (dd, 2H, J = 6.5, 1.5 Hz), 6.49 (d, 1H, J = 16.0
Hz), 6.33 (td, 1H, J =16.0, 6.5 Hz), 5.92 (ddt, 1H, J = 17.0, 10.0
Hz), 5.50 (s, 2H), 5.21 (dd, 1H, J = 17.0, 2.0 Hz), 5.06–5.02 (m,
3H), 3.01 (d, 2H, J = 4.0 Hz), 2.58–2.29 (m, 4H), 1.21–1.15 (m,
2H), 1.09–1.05 (m, 4H), 0.86–0.78 (m, 5H), 0.70 (t, 3H, J = 7.5
Hz); 13C NMR (126 MHz, CDCl3) δ 147.2, 146.9, 142.9, 136.9,
(NaCl, neat) νmax 3496, 3029, 1736, 1256, 1063, 698 cm-1; H
1
NMR (500 MHz, CDCl3) δ 7.68 (d, 2H, J = 6.5 Hz), 7.39–7.32
(m, 3H), 4.18 (s, 1H, OH), 3.76 (s, 3H), 2.33 (t, 2H, J = 7.5 Hz),
1.58 (tt, 2H, J = 7.5, 8.0 Hz), 1.46 (tq, 2H, J = 8.0, 7.5 Hz), 0.93
(t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ 172.7, 139.6,
128.5, 128.2, 126.2, 87.6, 78.1 72.8, 54.0, 30.3, 21.9, 18.4, 13.5;
HRMS (CI) calcd for C15H19O3 [M+H]+ 247.1334, found
247.1335.
4.5. Methyl 2-azido-2-(1-benzyl-5-butyl-1H-1,2,3-triazol-4-yl)-2-
phenylacetate (7, CCDC 950507)
To a mixture of propargyl alcohol 6 (68.3 mg, 0.277 mmol)
and benzyl azide (55.4 mg, 0.416 mmol) in dichloromethane (2.8
mL) under nitrogen atmosphere, TMSOTf (110.2 µL, 0.610
mmol) was added at room temperature dropwise. After five

ACCEPTED MANUSCRIPT
7
135.7, 135.6, 135.3, 133.5, 128.8, 128.6, 128.4, 128.2, 128.1,
127.6, 126.9, 126.8, 126.5, 123.0, 114.8, 62.6, 51.8, 50.2, 46.4,
30.2, 29.8, 22.91, 22.87, 22.76, 22.67, 13.61, 13.55; HRMS (ESI)
calcd for C38H45NaN7 [M+Na]+ 622.36341, found 622.36220.
0.23 (ethyl acetate/hexane = 1/2); m.p. 156.7–157.7 °C; IR
1
(NaCl, neat) νmax 3363, 2917, 1697, 1264, 1058, 699 cm-1; H
NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 7.33–7.29 (m, 10H),
3.76 (t, 2H, J = 6.5 Hz), 3.70 (t, 2H, J = 6.5 Hz), 1.96–1.92 (m,
4H); 1H NMR (500 MHz, CD2Cl2) δ 7.61 (s, 1H), 7.35–7.27 (m,
10H), 3.72 (t, 2H, J = 6.0 Hz), 3.63 (t, 2H, J = 6.0 Hz), 1.95–1.90
(m, 4H); 1H NMR (500 MHz, CD3OD) δ 7.84 (s, 1H), 7.37–7.23
(m, 10H), 3.73 (t, 2H, J = 6.0 Hz), 3.64 (t, 2H, J = 6.0 Hz), 1.94–
1.90 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 155.6, 147.7, 144.9,
135.3, 128.2, 127.8, 127.1, 77.2, 50.1, 48.7, 26.4, 24.0; 13C NMR
(126 MHz, CD2Cl2) δ 155.8, 147.9, 145.5, 135.4, 128.4, 128.1,
127.4, 77.4, 50.4, 48.9, 26.7, 24.4; 13C NMR (126 MHz, CD3OD)
δ 158.0, 149.6, 147.1, 136.7, 128.9, 128.5, 128.4, 78.0, 51.5, 49.8,
27.4, 25.0; HRMS (ESI) calcd for C20H20N4O2Na [M+Na]+
371.14839, found 371.14822.
4.8. 1-(1-Benzyl-5-butyl-1H-1,2,3-triazol-4-yl)-1-phenylhept-2-
yn-1-ol (11)
To a mixture of 8 (70.0 mg, 0.261 mmol), benzyl azide (36.5
mg, 0.274 mmol) in dichloromethane (2.6 mL) was added
trimethylsilyl trifluoromethanesulfonate (56.6 µL, 0.313 mmol)
at –90 °C. After five minutes, the reaction was quenched with
saturated sodium bicarbonate aqueous solution, and was washed
with brine. Then the collected organic layer was dried over
magnesium sulfate followed by concentration in vacuo and silica
gel column chromatography (ethyl acetate/hexane = 1/15 to 1/5
to 1/2) to afford 11 (57.9 mg, 55%) and 12 (2.1 mg, 2%)9.;
Colorless oil; Rf value 0.29 (ethyl acetate/hexane = 1/5); IR
4.9.3. (4-Cyclohexyl-5-(hydroxydiphenylmethyl)-2H-1,2,3-
triazol-2-yl)(pyrrolidin-1-yl)methanone (13c)
1
(NaCl, neat) νmax 3352, 2957, 1455, 1003, 733, 698 cm-1; H
152.0 mg (0.353 mmol, 67%) for two steps from 3c (260.0 mg,
0.614 mmol) [silica gel chromatography (hexane/ethyl acetate =
5:1 to 3:1 to 1:1, dichloromethane/methanol = 40:1)].; White
solid; Rf value 0.26 (ethyl acetate/hexane = 1/2); m.p. 226.8–
227.0 °C; IR (NaCl, neat) νmax 3334, 3061, 2925, 2854, 1694,
1423, 1340, 1260 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.34–7.26
(m, 10H), 3.73 (s, 1H), 3.72 (t, 2H, J = 7.0 Hz), 3.68 (t, 2H, J =
7.0Hz), 2.17–2.11 (m, 1H), 1.91 (m, 4H), 1.69–1.53 (m, 3H),
1.46–1.37 (m, 4H), 1.16–1.10 (m, 1H), 0.96–0.89 (m, 2H); 13C
NMR (126 MHz, CDCl3) δ 153.1, 151.5, 148.0, 144.5, 128.0,
127.8, 127.7, 78.0, 50.1, 48.6, 35.2, 26.5, 26.3, 25.7, 24.0;
HRMS (ESI) calcd for C26H30N4O2Na [M+Na]+ 453.22664,
found 453.22670.
NMR (500 MHz, CDCl3) δ 7.83 (d, 2H, J = 7.5 Hz), 7.55 (m,
6H), 7.35 (d, 2H, J = 7.0 Hz), 5.67 (d, 1H, J = 15.5 Hz), 5.64 (d,
1H, J = 15.5 Hz), 4.63 (s, 1H, OH), 2.59–2.61 (m, 1H), 2.52 (td,
2H, J = 1.5, 7.0 Hz), 2.41–2.46 (m, 1H), 1.75 (tt, 2H, J = 7.5, 7.5
Hz), 1.62 (tq, 2H, J = 7.5, 7.5 Hz), 1.24–1.27 (m, 3H), 1.10 (t,
3H, J = 7.5 Hz), 0.92–1.02 (m, 1H), 0.89 (t, 3H, J = 7.5 Hz); 13C
NMR (126 MHz, CDCl3) δ 147.8, 143.5, 134.9, 133.7, 128.9,
128.3, 128.1, 128.0, 127.1, 126.5, 88.2, 80.9, 69.7, 52.0, 30.5,
29.9, 22.6, 22.5, 22.0, 18.6, 13.6, 13.5; HRMS (ESI) calcd for
C26H31N3NaO [M+Na]+ 424.2365, found 424.2365.
4.9. General procedure of synthesis of triazole ureas:
A slurry of 30wt% (based on starting material triazole) of 10%
Pd/C in ethanol was added to a stirred solution of 1,4,5-
trisubstituted triazoles under nitrogen and the resulting mixture
was stirred under an atmosphere of hydrogen gas for 20 h. The
reaction mixture was filtered through a plug of celite washing
with methanol. The filtrate was evaporated under reduced
pressure to give a white solid residue which was used to the next
step without further purification. The crude unprotected triazoles
(1.2 equiv), pyrrolidine carbonyl chloride 12 (1.0 equiv), and 4-
dimethylaminopyridine (0.2 equiv) were dissolved in 5:1
THF/triethylamine (0.1 M based on triazoles), and the mixture
was stirred for 10 h at 60 °C. The solvents were removed, and
then the crude material was purified by silica gel chromatography
to afford triazole ureas.
4.9.4. (4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-
(hydroxydiphenylmethyl)-2H-1,2,3-triazol-2-yl)(pyrrolidin-1-
yl)methanone (13d, CCDC 1014155)
39.1 mg (0.079 mmol, 33%) for two steps from 3d (139.6 mg,
0.287 mmol) [silica gel chromatography (hexane/ethyl acetate =
5:1 to 3:1 to 1:1)].; White solid; Rf value 0.2 (ethyl
acetate/hexane = 1/2); m.p. 146.8–147.9 °C; IR (NaCl, neat) νmax
3403, 2928, 2884, 1717, 1410, 1259, 1059, 993 cm-1; 1H NMR
(500 MHz, CD2Cl2) δ 7.38–7.36 (m, 4H), 7.33–7.27 (m, 6H),
5.68 (s, 1H), 4.65 (s, 2H), 3.59 (t, 2H, J = 6.5 Hz), 3.54 (t, 2H, J
= 6.5 Hz), 1.90–1.84 (m, 4H), 0.82 (s, 9H), –0.02(s, 6H); 13C
NMR (126 MHz, CD2Cl2) δ 153.9, 147.9, 146.5, 145.3, 128.1,
127.7, 127.5, 76.9, 58.4, 50.4, 48.9, 26.7, 25.8, 24.4, 18.4, –5.7;
HRMS (ESI) calcd for C27H36N4O3SiNa [M+Na]+ 515.24544,
found 515.24415.
4.9.1. (4-Butyl-5-(hydroxydiphenylmethyl)-2H-1,2,3-triazol-2-
yl)(pyrrolidin-1-yl)methanone (13a)
121.7mg (0.300mmol, 80%) for two steps from 3a (220.1 mg,
0.554mmol) [silica gel chromatography (hexane/ethyl acetate =
3:1 to 1:1, dichloromethane/methanol = 40:1)].; White solid; Rf
value 0.45 (ethyl acetate/hexane = 1/2); m.p. 168.7–170.4 °C; IR
(NaCl, neat) νmax 3333, 2958, 2871, 1694, 1448, 1418, 1264,
4.9.5. 3-(5-(Hydroxydiphenylmethyl)-2-(pyrrolidine-1-carbonyl)-
2H-1,2,3-triazol-4-yl)propyl benzoate (13e, CCDC 1014154)
117.7 mg (0.231 mmol, 40%) for two steps from 3e (349.3 mg,
0.694 mmol) [silica gel chromatography (hexane/ethyl acetate =
5:1 to 3:1 to 2:1, dichloromethane / methanol = 60:1)].; White
solid; Rf value 0.2 (ethyl acetate/hexane = 1/2); m.p. 184.7–
185.5 °C; IR (NaCl, neat) νmax 3403, 2928, 2884, 1717, 1410,
1259, 1059, 993 cm-1; 1H NMR (500 MHz, CDCl3) δ7.92 (dd, 2H,
J = 8.0, 1.0 Hz), 7.53 (td, 1H, J = 7.0, 1.0 Hz), 7.39 (tt, 2H, J =
7.0, 8.0 Hz), 7.30–7.23 (m, 10H), 4.18 (t, 2H, J = 5.5 Hz), 3.63 (s,
1H), 3.64–3.60 (m, 4H), 2.52 (t, 2H, J = 7.5 Hz), 1.97–1.81 (m,
2H), 1.89–1.84 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 166.5,
152.2, 147.81, 147.76, 144.3, 132.9, 130.1, 129.5, 128.3, 128.1,
127.9, 127.4, 77.9, 64.2, 50.1, 48.6, 27.1, 26.5, 24.0, 22.7;
HRMS (ESI) calcd for C30H30N4O4Na [M+Na]+ 533.21647,
found 533.21563.
1
1171, 941 cm-1; H NMR (500 MHz, CDCl3) δ 7.27–7.19 (m,
10H), 3.67 (s, 1H), 3.64–3.58 (m, 4H), 2.20 (t, 2H, J = 8.0 Hz),
1.83 (br, 4H), 1.27 (tt, 2H, J = 7.5, 8.0 Hz), 1.07 (tt, 2H, J = 7.5,
7.5 Hz), 0.66 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ
152.2, 148.9, 147.9, 144.4, 128.0, 127.8, 127.5, 77.9, 50.1, 48.6,
30.3, 26.5, 25.5, 24.0, 22.4, 13.6; HRMS (ESI) calcd for
C24H28N4O2Na [M+Na]+ 427.21099, found 427.21052.
4.9.2. (4-(Hydroxydiphenylmethyl)-2H-1,2,3-triazol-2-
yl)(pyrrolidin-1-yl)methanone (13b)5d,15
17.9 mg (30%) for two steps from 3b (70.0 mg, 0.206 mmol)
[silica gel chromatography (hexane/ethyl acetate = 20:1 to 10:1
to 5/1 to 3/1 to 2/1 to 1/1 to ethyl acetate)].; White solid; Rf value

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Tetrahedron
Nomura, M.; Takao, Y.; Fujioka, A.; Hashimoto, A.; Itou, K.;
4.9.6. (4-(Hydroxydiphenylmethyl)-5-(trimethylsilyl)-2H-1,2,3-
Yamamura, K.; Shuto, S.; Nagasawa, H.; Fukuoka, M. J. Med.
Chem. 2012, 55, 6427–6437. (d) Adibekian, A.; Martin, B. R.;
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see: (e) Sagalave, S. G.; Maujan, S. R.; Pore, V. S. Chem.—Asian
J. 2011, 6, 2696–2718.
triazol-2-yl)(pyrrolidin-1-yl)methanone (13f)
82.1 mg (0.195 mmol, 58%) for two steps from 3f (164.7 mg,
0.404 mmol) [silica gel chromatography (hexane/ethyl acetate =
5:1 to 3:1 to 2:1 to 1:1)].; White solid; Rf value 0.34 (ethyl
acetate/hexane = 1/2); m.p. 168.7–169.4 °C; IR (NaCl, neat) νmax
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3350, 2959, 1697, 1252, 1048, 928, 761 cm-1; H NMR (500
1
MHz, CDCl3) δ 7.32–7.28 (m, 10H), 3.66 (t, 2H, J = 7.0 Hz),
3.58 (t, 2H, J = 7.0 Hz), 2.88 (s, 1H), 1.92–1.84 (m, 4H), 0.22 (s,
9H); 13C NMR (126 MHz, CDCl3) δ 160.1, 148.6, 148.2, 145.6,
128.0, 127.7, 127.4, 78.7, 49.9, 48.4, 26.4, 24.1, –0.4; HRMS
(ESI) calcd for C23H28N4O2SiNa [M+Na]+ 443.18792, found
443.18773.
5. Acknowledgement
7. Wrobleski, A.; Coombs, T. C.; Huh, C. W.; Li, S.-W.; Aubé, J.
We thank Prof. Alexander Adibekian of University of Geneva
and Prof. Benjamin F. Cravatt of the Scripps Research Institute
for kindly providing copies of the 1H and 13C NMR spectra of the
serine hydrolase inhibitor 13b. We acknowledge the presidential
special research support fellowship of NAIST for H.Z. We also
thank Ms. Mika Yamamura, Ms. Yuriko Nishiyama, Ms.
Yoshiko Nishikawa (HRMS measurement), and Mr. Shohei
Katao (X-ray crystallographic analysis) of NAIST.
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(ref 5d), and one peak of benzylic sp3 carbon was found to overlap
with the solvent peak in the 13C NMR spectra. After discussion
with one of the authors, incorrect NMR assignments were found in
the reference article. Finally, our NMR data of 13b were identical
to those in CD3OD, which were newly provided by the author
(personal communications). The analytical data correction of ref
5d should be submitted by the authors in near future. We also
recorded NMR data of 13b in CD2Cl2 which seems to be suitable
for clarity of the peak observation and the solubility. For provided
NMR spectra of 13b in CD3OD, see Supporting Information.
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Supporting information of
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Acid-mediated Regioselective Rapid Synthesis of Fully substituted 1,2,3-Triazoles: Reactions,
Multicomponent Couplings, Synthesis of Serine Hydrolase Inhibitor and Its Derivatives
Huan Zhang, Hiroki Tanimoto,* Tsumoru Morimoto, Yasuhiro Nishiyama,
and Kiyomi Kakiuchi
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5
Takayamacho, Ikoma, Nara 630-0192, Japan
tanimoto@ms.naist.jp
1H and 13C NMR Spectra of Synthesized Compounds
Provided 1H and 13C NMR Spectra of 13b
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