An efficient and high-yielding one-pot synthesis of 4-acyl-1,2,3-triazoles via triisopropylsilyl-protected ynones

Article abstract of DOI:10.1016/j.tet.2011.12.025

A practical and efficient process has been developed for the synthesis of 1-substituted 4-acyl-1H-1,2,3-triazoles using a three-step one-pot synthetic approach. This transformation involves an initial preparation of triisopropylsilyl (TIPS)-protected ynon

Full text of DOI:10.1016/j.tet.2011.12.025

Tetrahedron 68 (2012) 1460e1465
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An efficient and high-yielding one-pot synthesis of 4-acyl-1,2,3-triazoles via
triisopropylsilyl-protected ynones
*
Soonho Hwang, Hoon Bae, Sumin Kim, Sanghee Kim
College of Pharmacy, Seoul National University, San 56-1, Shilim, Kwanak, Seoul 151-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 October 2011
Received in revised form 10 December 2011
Accepted 10 December 2011
Available online 16 December 2011
A practical and efficient process has been developed for the synthesis of 1-substituted 4-acyl-1H-1,2,3-
triazoles using a three-step one-pot synthetic approach. This transformation involves an initial prepa-
ration of triisopropylsilyl (TIPS)-protected ynones from acid chlorides and TIPS-acetylene, followed by
a AgF-mediated TIPS deprotection and Cu-catalyzed Huisgen cycloaddition. The increased chemical
stability of TIPS-protected ynones was an important factor in the high overall product yield.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Click chemistry
Cross-coupling
1,2,3-Triazole
TIPS-acetylene
AgF
1. Introduction
One-pot multi-step processes are one of the most useful syn-
thetic methods because they allow rapid and convergent con-
struction of complex molecules without the isolation of
intermediates.1 This process is especially useful when the reaction
intermediates are unstable and difficult to isolate.
Recently, Boons and co-workers reported
a
micro-
waveeassisted one-pot three-step process for the synthesis of 1-
substituted 4-acyl-1H-1,2,3-triazoles (1, Scheme 1).2 Their
copper(I)-catalyzed azideealkyne cycloaddition (CuAAC)3 based
one-pot reaction entails the in situ generation of unstable
ynones.4,5 Specifically, as shown in Scheme 1, the first step of Boons
one-pot process was the Sonogashira cross-coupling of acid chlo-
rides 2 with trimethylsilyl (TMS)-acetylene to generate TMS-
Scheme 1. The synthetic concept of a one-pot three-step synthesis of 4-acyl-triazoles 1.
€
protected ynones 3, which was developed earlier by Muller and
co-workers.6 The second and third steps were the in situ desily-
lation to give terminal ynones 5 and subsequent CuAAC with azides
in the presence of copper ion and a fluoride source under micro-
wave irradiation at 120 ꢀC.
1-Substituted 4-acyl-1H-1,2,3-triazoles 1 exhibit various in-
teresting biological activities,7 and thus may serve as a novel
structural scaffold for drug development. As part of our drug dis-
covery efforts, we were confronted with the task of generating
libraries of 1-substituted 4-acyl-triazole compounds. We felt that
the direct application of the Boons’ protocol to our library synthesis
would not be appropriate, particularly because the reported yields
of the 4-acyl-triazoles 1 from the one-pot reactions varied from low
to good, depending on the substrate. Thus, we re-investigated the
Boons’ one-pot process to determine the practical and high-
yielding reaction conditions. Herein, we report our studies on this
subject and describe an improved and convenient one-pot process
for the synthesis of 1-substituted 4-acyl-1,2,3-triazoles 1 under
normal reaction conditions that eliminates the need for microwave
irradiation.
* Corresponding author. Tel.: þ82 2 880 2487; fax: þ82 2 888 0649; e-mail ad-
dress: pennkim@snu.ac.kr (S. Kim).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.025

S. Hwang et al. / Tetrahedron 68 (2012) 1460e1465
1461
2. Results and discussion
reacted with azides by exposure to a mixture of TBAF/CuI or CuF2
under microwave irradiation at high temperature. Because the
complete removal of excess TBAF and TBAF-derived materials is
sometimes problematic10 and CuF2 is known to be an inefficient
reagent for the deprotection of the bulkier TIPS-alkynes under
normal reaction conditions,11 we needed to develop alternative
conditions for the in situ TIPS-deprotection/CuAAC reaction.
In our previous studies, we found that AgF was an efficient re-
agent for the removal of the TIPS group from alkynes.12 To test the
feasibility of employing AgF as a fluoride source in the in situ TIPS-
deprotection/CuAAC reaction, we conducted studies with the pu-
rified TIPS-protected ynone 4c as a model substrate (Table 2). THF
was chosen as the solvent because it was the solvent for the first
step of the three-step process. When a solution of 4c, benzyl azide,
and CuI (1.0 equiv) in THF was treated with a slight excess
(1.5 equiv) of AgF at room temperature, only unreacted starting
materials were recovered. This poor result was attributed to the low
solubility of AgF in THF. Interestingly, when the same reaction was
performed in the presence of triethylamine (3.0 equiv), the desired
triazole 1c was obtained in 64% yield (entry 1). The yield could be
improved to 92% when the reaction was conducted at 60 ꢀC in an oil
bath (entry 2). This successful result was presumably due to the
increased solubility of AgF caused by the presence of triethylamine.
When the amount of CuI was reduced to 0.5 equiv, the yield of 1c
decreased slightly to 89% (entry 3). The amount of CuI and reaction
temperature could be lowered without any substantial decrease in
the product yield when the electron-rich 1,10-phenanthroline li-
gand13 was added prior to the addition of AgF to the reaction
mixture. With the inclusion of 1,10-phenanthroline (0.02 equiv),
the reaction could be performed with 0.1 equiv of CuI at room
temperature giving 1c in 91% yield (entry 4).
We surmised that triisopropylsilyl (TIPS)-protected ynones 4
would be more stable than their corresponding TMS-protected
ynones 3 because the bulky TIPS group more effectively shields
the reactive carbonecarbon triple bond than does the TMS group.8,9
It was anticipated that the increased chemical stability of bulky
TIPS-protected ynones would allow us to thoroughly explore re-
action conditions to find the optimum experimental conditions for
high-yielding one-pot process.
As the beginning our studies on the one-pot process for the
creation of 4-acyl-1,2,3-triazoles 1 via TIPS-protected ynones, we
6
€
re-examined Muller’s TMS-protected ynone synthesis that was
€
utilized by Boons. Muller employed Sonogashira conditions for the
coupling of acid chlorides 2 with TMS-acetylene using only 1 equiv
of triethylamine. The presence of excess of triethylamine was re-
ported to cause a significant decrease in the product yield, pre-
sumably because of the instability of the products under the
reaction conditions. When we employed TIPS-acetylene instead of
TMS-acetylene, we observed that the yield increased to 94% under
€
the same reaction conditions described by Muller (Table 1, entry 1
vs 3). Interestingly, unlike in Muller’s case, the use of excess trie-
€
thylamine did not lower the yield of the reaction. Instead, in-
creasing the amount of triethylamine allowed the isolation of TIPS-
protected ynone 4a in slightly higher yield (entries 4 and 5). When
the acid chloride contained an electron-withdrawing nitro group in
place of a methoxy group, the reaction with TIPS-acetylene gave
a higher product yield than the reaction with TMS-acetylene (entry
2 vs 6). Increasing the amount of triethylamine also caused the
yield to increase (entries 7 and 8). The same trends were also ob-
served in the preparation of TIPS-protected ynone 4c from benzoyl
chloride 2c (entries 9e11).
Table 2
The one-pot synthesis of triazole 1c via the AgF-mediated TIPS-deprotection/CuAAC
Table 1
reactiona
The preparation of ynones 3 and 4 by the coupling of acid chlorides 2 with silyl-
protected acetylene
Entry
CuI (equiv)
Temperature
Time (h)
Triazole 1c (yield, %)b
1
2
1.0
1.0
0.5
0.1
rt
13
13
13
5
64
92
89
91
60 ꢀC
60 ꢀC
rt
Entrya,b
2aec (R1)
Acetylene (SiR3)
NEt3 (equiv)
3, 4 (yield, %)c
3
1
2
3
4
5
6
7
8
2a (4-OMe)
2b (4-NO2)
2a (4-OMe)
2a (4-OMe)
2a (4-OMe)
2b (4-NO2)
2b (4-NO2)
2b (4-NO2)
2c (H)
TMS
TMS
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
1
1
1
3
5
1
3
5
1
3
5
3a (82)
3b (65)
4a (94)
4a (95)
4a (97)
4b (89)
4b (90)
4b (93)
4c (87)
4c (94)
4c (98)
4c
a
Reaction conditions: 1.0 equiv of ynone 4c (1.0 mmol), 1.5 equiv of BnN3, CuI
(0.1, 0.5 or 1.0 equiv), 3.0 equiv of NEt3, and 1.5 equiv of AgF, THF (10 mL/mmol
ynone 4c).
b
Isolated yield.
c
1,10-Phenanthroline of 0.02 equiv was used as a ligand.
9
10
11
Having established higher-yielding reaction conditions for the
synthesis of TIPS-protected ynones and the in situ TIPS-
deprotection/CuAAC reaction, we examined the possibility of con-
ducting these three reactions in a sequential manner under one-pot
conditions (Table 3). After completion of the coupling reaction
between benzoyl chloride 2c and TIPS-acetylene with 3.0 equiv of
triethylamine,14 1.5 equiv of benzyl azide and an additional
0.5 equiv of CuI were added to the reaction mixture. Then, solid AgF
was added and the mixture was heated to 60 ꢀC (entry 1, method
A). Addition of extra triethylamine was not necessary because the
first step was carried out in the presence of excess of triethylamine.
Gratifyingly, this one-pot process produced the expected 4-acyl-
1,2,3-triazole 1c in high yield (83%). Alternatively, the inclusion of
1,10-phenanthroline (0.02 equiv) and a reduction in the amount of
CuI (0.1 equiv) used provided 1c at room temperature, also in high
yield (85%) (entry 1, method B).
2c (H)
2c (H)
a
The data in entries 1 and 2 were taken from the reported results.6 Reaction
conditions: 1.0 equiv of acid chloride 2, 1.0 equiv of TMS-acetylene (1.0 mmol),
1.0 equiv of NEt3, 0.02 equiv of Pd(PPh3)2Cl2, and 0.04 equiv of CuI in THF (5 mL/
mmol acid chloride 2), 1 h.
b
The data in entries 3e11 were from our experimental results of with TIPS-
acetylene. Reaction conditions: 1.0 equiv of acid chloride 2, 1.0 equiv of TIPS-
acetylene (1.0 mmol), NEt3 (1.0, 3.0 or 5.0 equiv), 0.02 equiv of Pd(PPh3)2Cl2, and
0.05 equiv of CuI in THF (5 mL/mmol acid chloride 2), 0.5 h.
c
Isolated yield.
After confirming the utility of the bulky TIPS protecting group as
a replacement for the TMS group in the synthesis of silyl-protected
ynones, we next investigated the reaction conditions for the in situ
TIPS-deprotection/CuAAC reaction. It was reported by Boons and
co-workers that TMS-protected ynones could be desilylated and

1462
S. Hwang et al. / Tetrahedron 68 (2012) 1460e1465
Table 3
1-substituted 4-acyl-1H-1,2,3-triazoles from acid chlorides using
a three-step one-pot synthetic approach. The one-pot trans-
formation described herein, which builds upon the work of Boons
The one-pot three-step synthesis of 1-substituted 4-acyl-1H-1,2,3-triazoles 1
and co-workers, involves the initial preparation of
a TIPS-
protected ynone followed by a AgF-mediated TIPS deprotection
and CuAAC reaction. The crucial change that allowed this high-
yielding process was the employment of TIPS-acetylene as a sur-
rogate for the previously applied TMS-acetylene. The increased
chemical stability of TIPS-protected ynone intermediates enabled
us to find the optimum experimental conditions. This one-pot
process can be applied to various substrates and should be of
general utility for the synthesis of a wide range of 1-substituted
4-acyl-1,2,3-triazoles, which are potentially useful as a scaffold
for drug development. In addition, given the broad synthetic
utility of ynones, the described in situ procedure for accessing
unstable ynones in high yield should provide an expedient route
to a wide range of other heterocyclic compounds besides triazole
products.
Entry
2 (R1)
6 (R2)
Method Aa
(yield, %)
1
Method Bb
(yield, %)
1
1
2
3
4
H
Benzyl
Benzyl
Benzyl
Benzyl
1c (83)
1a (81)
1b (68)
1d (84)
1c (85)
1a (86)
1b (65)
1d (83)
4-OMe
4-NO2
4-F
5
Benzyl
1e (82)
1e (84)
6
7
8
9
H
H
H
H
4-Methoxybenzyl
4-Nitrobenzyl
n-Octyl
1f (83)
1g (82)
1h (81)
1i (82)
1f (82)
1g (80)
1h (86)
1i (83)
2-Thienylmethyl
4. Experimental section
4.1. General methods
10
H
1j (82)
1j (85)
11
12
13
14
H
H
H
H
Phenyl
1k (79)
1l (81)
1m (84)
dc
1k (78)
1l (80)
1m (84)
dc
All chemicals were of reagent grade and used as received. All
reactions were performed under an inert atmosphere of dry
nitrogen using distilled dry solvents. Reactions were monitored
by TLC analysis using silica gel 60 F-254 thin layer chromatog-
raphy plates. Flash column chromatography was carried out on
silica gel (230e400 mesh). 1H NMR (300, 400 or 500 MHz) and
4-Methoxyphenyl
2,6-Diethylphenyl
4-Nitro
a
The reaction conditions for method A: (i) 1.0 equiv of acid chloride 2, 1.0 equiv of
TIPS-acetylene (1.0 mmol), 3.0 equiv of NEt3, 0.02 equiv of Pd(PPh3)2Cl2, and
0.05 equiv of CuIinTHF (5 mL/mmol acidchloride2), rt, 0.5 h;(ii)1.5 equiv ofR2eN3 6,
0.5 equiv of CuI and 1.5 equiv of AgF in THF (10 mL/mmol acid chloride 2), 60 ꢀC, 13 h.
b
13C NMR (75, 100 or 125 MHz) spectra were recorded in
d units
The reaction conditions for method B: (i) identical to method A; (ii) 1.5 equiv of
R2-N3 6, 0.1 equiv of CuI, 1.5 equiv of AgF, and 0.02 equiv of 1,10-phenanthroline in
THF (10 mL/mmol acid chloride 2), rt, 5 h.
relative to the non-deuterated solvent as the internal reference.
IR spectra were measured on a Fourier Transform Infrared
spectrometer. Mass spectra (MS) and high resolution mass
spectra (HRMS) were recorded using fast atom bombardment
(FAB).
c
Triazole product was not detected.
After establishing optimal one-pot processes, the scope and
limitation were examined with various acid chlorides and azides.
As can be seen from Table 3, both processes (methods A and B)
allowed us to obtain the corresponding triazoles 1 in high overall
yield in most cases. The yields for both processes were very similar.
Aromatic acid chlorides 2 bearing electron-donating (entry 2) or
electron-withdrawing (entries 3 and 4) substituents could be car-
ried through the one-pot sequence without difficulties. Also het-
eroaromatic acid chloride could be coupled efficiently (entry 5).
Various types of azides were smoothly converted into the triazole
products, except 4-nitrophenyl azide. For most of the aliphatic
azides, yields were above 80% (entries 6e10). In the case of aro-
matic azides, the substituents on the aromatic ring exhibited
a significant effect on the yield. The aryl azides bearing electron-
neutral or electron-donating substituents participated well in this
one-pot process (entries 11 and 12). Even sterically demanding aryl
azide gave triazole 1m in good yield (entry 13). However, the
presence of strongly electron-withdrawing nitro group made it
difficult to obtain corresponding triazole product (entry 14). This
result was not unexpected because it was reported that CuAAC
reaction with highly electron-deficient azides was less favorable
and hence side product formation might occur.15
4.2. A general procedure for synthesis of TIPS-protected
ynone 4 via the Sonogashira cross-coupling reaction
The indicated amount of NEt3 (0.14 mL (1.0 mmol, 1.0 equiv),
0.42 mL (3.0 mmol, 3.0 equiv) or 0.70 mL (5.0 mmol, 5.0 equiv)),
the appropriate acid chloride 2 (2.0 M solution in THF, 0.50 mL,
1.0 mmol, 1.0 equiv), and TIPS-acetylene (2.0 M solution in THF,
0.50 mL, 1.0 mmol, 1.0 equiv) were added to
a solution of
Pd(PPh3)2Cl2 (14.1 mg, 0.02 mmol, 0.02 equiv) and CuI (9.6 mg,
0.05 mmol, 0.05 equiv) in THF (4.0 mL) under a N2 atmosphere. The
reaction mixture was stirred for 30 min at room temperature. The
reaction was quenched with saturated NH4Cl solution and the
resulting mixture was extracted with EtOAc two times. The com-
bined organic layers were washed with brine, dried over MgSO4,
and concentrated. This residue was purified by column chroma-
tography on silica gel using an appropriate hexane/EtOAc mixture
as the eluent to give TIPS-protected ynone 4.
4.2.1. 1-(4-Methoxyphenyl)-3-(triisopropylsilyl)prop-2-yn-1-one
It is noteworthy that the obtained yields of 1 are considerably
higher than those of Boons’ one-pot three-step process in most
cases. In addition, this one-pot process is simple and efficient be-
cause it does not require microwave irradiation at high temperature.
(4a). Colorless oil. Rf¼0.38 (hexane/EtOAc, 20:1). 1H NMR
(400 MHz, CDCl3)
d 1.02e1.18 (m, 21H), 3.80 (s, 3H), 6.89 (d,
J¼8.8 Hz, 2H), 8.08 (d, J¼8.8 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d
10.94 (3C), 18.37 (6C), 55.33, 96.39, 103.11, 113.67 (2C), 130.00,
131.66 (2C), 164.31, 175.83.
3. Conclusion
4.2.2. 1-(4-Nitrophenyl)-3-(triisopropylsilyl)prop-2-yn-1-one
In summary, this investigation identified efficient and high-
yielding reaction conditions for the regioselective formation of
(4b). White solid. Mp 54e56 ꢀC. Rf¼0.30 (hexane/EtOAc, 20:1). 1H
NMR (400 MHz, CDCl3) d
1.08e1.21 (m, 21H), 8.28 (s, 4H). 13C NMR

S. Hwang et al. / Tetrahedron 68 (2012) 1460e1465
1463
(75 MHz, CDCl3)
130.22 (2C), 140.68, 150.72, 175.12.
d
10.94 (3C), 18.37 (6C), 100.77, 102.26, 123.68 (2C),
quenched with saturated NH4Cl solution and the resulting mixture
was extracted with EtOAc two times. The combined organic layers
were washed with brine, dried over MgSO4, and concentrated. The
residue was purified by column chromatography on silica gel using
a hexane/EtOAc mixture as the eluent to give 1,2,3-triazole 1.
4.2.3. 1-Phenyl-3-(triisopropylsilyl)prop-2-yn-1-one (4c). Colorless
oil. Rf¼0.40 (hexane/EtOAc, 20:1). 1H NMR (400 MHz, CDCl3)
d
1.08e1.25 (m, 21H), 7.46 (t, J¼7.7 Hz, 2H), 7.58 (t, J¼7.4 Hz, 1H),
8.16 (d, J¼7.3 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d
11.04 (3C), 18.48
4.4.3. (1-Benzyl-1H-1,2,3-triazol-4-yl)(4-methoxyphenyl)methanone
(1a). Yield 81% (method A), 86% (method B). White solid. Mp
130e131 ꢀC. Rf¼0.25 (hexane/EtOAc, 3:1). 1H NMR (500 MHz,
(6C), 97.82, 103.02, 128.50 (2C), 129.44 (2C), 133.97, 136.69, 177.37.
4.3. The synthesis of triazole 1c via the AgF-mediated TIPS-
deprotection/CuAAC reaction from TIPS-protected ynone 4c
CDCl3)
d
3.83 (s, 3H), 5.55 (s, 2H), 6.94 (d, J¼9.0 Hz, 2H), 7.27e7.38
(m, 5H), 8.15 (s, 1H), 8.47 (d, J¼9.0 Hz, 2H). 13C NMR (125 MHz,
CDCl3) d 54.20, 55.33, 113.52 (2C), 128.06, 128.19 (2C), 128.90, 129.11
4.3.1. Method
A
(without 1,10-phenanthroline). Benzyl azide
(2C), 129.28, 132.93 (2C), 133.77, 148.60, 163.66, 183.69. IR (CHCl3)
nmax 3153, 1636, 1597, 1572, 1506 cmꢁ1. MS (FAB) (m/z) 294 [Mþ1]þ.
HRMS (FAB) calcd for C17H16N3O2 [MþH]þ 294.1243, found
294.1248.
(0.22 mL, 1.5 mmol, 1.5 equiv), CuI (95.3 mg (0.5 mmol, 0.5 equiv)
or 190.4 mg (1.0 mmol, 1.0 equiv)), NEt3 (0.42 mL, 3.0 mmol,
3.0 equiv), and AgF (190.4 mg, 1.5 mmol, 1.5 equiv) were added to
a solution of ynone 4c (286.5 mg, 1.0 mmol, 1.0 equiv) in THF
(10.0 mL) under a N2 atmosphere. The reaction mixture was stirred
for 13 h at room temperature or 60 ꢀC. The reaction was quenched
with saturated NH4Cl solution and the resulting mixture was
extracted with EtOAc two times. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated. This res-
idue was purified by column chromatography on silica gel (hexane/
EtOAc, 3:1) to give trizaole 1c.
4.4.4. (1-Benzyl-1H-1,2,3-triazol-4-yl)(4-nitrophenyl)methanone
(1b). Yield 68% (method A), 65% (method B). Slightly brown solid.
Mp 138e140 ꢀC. Rf¼0.25 (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
CDCl3)
d 5.61 (s, 2H), 7.28e7.35 (m, 2H), 7.35e7.42 (m, 3H), 8.23 (s,
1H), 8.29 (d, J¼8.6 Hz, 2H), 8.57 (d, J¼8.7 Hz, 2H). 13C NMR (75 MHz,
CDCl3) d 54.52, 123.33 (2C), 128.35 (2C), 128.68, 129.23, 129.32 (2C),
131.56 (2C), 133.36, 140.98, 147.59, 150.15, 183.67. IR (CHCl3) nmax
3131, 1658, 1602, 1524 cmꢁ1. MS (FAB) (m/z) 309 [Mþ1]þ. HRMS
(FAB) calcd for C16H13N4O3 [MþH]þ 309.0988, found 309.0979.
4.3.2. Method B (with 1,10-phenanthroline). Benzyl azide (0.22 mL,
1.5 mmol, 1.5 equiv), CuI (19.0 mg, 0.1 mmol, 0.1 equiv), NEt3
(0.42 mL, 3.0 mmol, 3.0 equiv), 1,10-phenanthroline (3.6 mg,
0.02 mmol, 0.02 equiv), and AgF (190.4 mg, 1.5 mmol, 1.5 equiv)
were added to a solution of ynone 4c (286.5 mg, 1.0 mmol,
1.0 equiv) in THF (10.0 mL) under a N2 atmosphere. The reaction
mixture was stirred for 5 h at room temperature. The reaction was
quenched with saturated NH4Cl solution and the resulting mixture
was extracted with EtOAc two times. The combined organic layers
were washed with brine, dried over MgSO4, and concentrated. This
residue was purified by column chromatography on silica gel
(hexane/EtOAc, 3:1) to give trizaole 1c.
4.4.5. (1-Benzyl-1H-1,2,3-triazol-4-yl)(phenyl)methanone (1c). Yield
83% (method A), 85% (method B). White solid. Mp 115e116 ꢀC.
Rf¼0.30 (hexane/EtOAc, 3:1). 1H NMR (400 MHz, CDCl3)
d 5.58 (s,
2H), 7.28e7.34 (m, 2H), 7.34e7.42 (m, 3H), 7.48 (t, J¼7.6 Hz, 2H),
7.58 (t, J¼7.2 Hz, 1H), 8.15 (s, 1H), 8.39 (d, J¼7.7 Hz, 2H). 13C NMR
(75 MHz, CDCl3)
d 54.44, 128.21, 128.35 (2C), 128.36 (2C), 129.16,
129.32 (2C), 130.56 (2C), 133.24, 133.66, 136.47, 148.37, 185.61. IR
(CHCl3) nmax 3120, 1637, 1599, 1575, 1519 cmꢁ1. MS (FAB) (m/z) 264
[Mþ1]þ. HRMS (FAB) calcd for C16H14N3O [MþH]þ 264.1137, found
264.1138.
4.4. A general procedure for synthesis of 1,2,3-triazole 1 via
the one-pot three-step sequence
4.4.6. (1-Benzyl-1H-1,2,3-triazol-4-yl)(4-fluorophenyl)methanone
(1d). Yield 84% (method A), 83% (method B). Slightly yellow solid.
Mp 145e146 ꢀC. Rf¼0.41 (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
4.4.1. Method
A
(without 1,10-phenanthroline). NEt3 (0.42 mL,
CDCl3)
d
5.57 (s, 2H), 7.14 (t, J¼8.6 Hz, 2H), 7.28e7.33 (m, 2H),
3.0 mmol, 3.0 equiv), the appropriate acid chloride 2 (2.0 M solu-
tion in THF, 0.50 mL,1.0 mmol,1.0 equiv), and TIPS-acetylene (2.0 M
solution in THF, 0.50 mL, 1.0 mmol, 1.0 equiv) were added to a so-
lution of Pd(PPh3)2Cl2 (14.1 mg, 0.02 mmol, 0.02 equiv) and CuI
(9.6 mg, 0.05 mmol, 0.05 equiv) in THF (4.0 mL) under a N2 atmo-
sphere. The reaction mixture was stirred for 30 min at room tem-
perature. After the Sonogashira coupling was complete, THF
(5.0 mL), azide 6 (1.5 mmol, 1.5 equiv), additional CuI (97.5 mg,
0.5 mmol, 0.5 equiv), and AgF (190.4 mg, 1.5 mmol, 1.5 equiv) were
added sequentially. The reaction mixture was stirred for 13 h at
60 ꢀC. The reaction was quenched with saturated NH4Cl solution
and the resulting mixture was extracted with EtOAc two times. The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated. The residue was purified by column
chromatography on silica gel using a hexane/EtOAc mixture as the
eluent to give 1,2,3-triazole 1.
7.33e7.40 (m, 3H), 8.17 (s, 1H), 8.50 (dd, J¼5.6, 8.7 Hz, 2H). 13C NMR
(75 MHz, CDCl3)
d
54.35, 115.42 (d, J¼21.6 Hz, 2C), 128.28 (2C),
128.35, 129.07, 129.23 (2C), 132.65 (d, J¼2.9 Hz, 1C), 133.33 (d,
J¼9.4 Hz, 2C), 133.59, 148.19, 165.84 (d, J¼253.8 Hz, 1C), 183.71. IR
(CHCl3) nmax 3134, 1643, 1599, 1519, 1502 cmꢁ1. MS (FAB) (m/z) 282
[Mþ1]þ. HRMS (FAB) calcd for C16H13FN3O [MþH]þ 282.1043, found
282.1042.
4.4.7. (1-Benzyl-1H-1,2,3-triazol-4-yl)(thiophen-2-yl)methanone
(1e). Yield 82% (method A), 84% (method B). Slightly yellow solid.
Mp 141e143 ꢀC. Rf¼0.25 (hexane/EtOAc, 3:1). 1H NMR (500 MHz,
CDCl3)
d
5.57 (s, 2H), 7.18 (t, J¼4.0 Hz, 1H), 7.27e7.38 (m, 5H), 7.70
(dd, J¼0.9, 4.9 Hz, 1H), 8.16 (s, 1H), 8.71 (dd, J¼0.8, 3.8 Hz, 1H). 13C
NMR (125 MHz, CDCl3)
d 54.37, 127.62, 128.25 (2C), 128.33, 129.02,
129.20 (2C), 133.66, 134.94, 136.15, 142.19, 147.76, 177.08. IR (CHCl3)
nmax 3129, 1618, 1535 cmꢁ1. MS (FAB) (m/z) 270 [Mþ1]þ. HRMS
(FAB) calcd for C14H12N3OS [MþH]þ 270.0701, found 270.0703.
4.4.2. Method B (with 1,10-phenanthroline). A THF (5.0 mL), azide 6
(1.5 mmol, 1.5 equiv), additional CuI (19.0 mg, 0.1 mmol, 0.1 equiv),
1,10-phenanthroline (3.6 mg, 0.02 mmol, 0.02 equiv), and AgF
(190.4 mg, 1.5 mmol, 1.5 equiv) were added sequentially to the
completed Sonogashira coupling reaction (the reaction conditions
were identical to those described in method A). The reaction mix-
ture was stirred for 5 h at room temperature. The reaction was
4.4.8. (1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)(phenyl)meth-
anone (1f). Yield 83% (method A), 82% (method B). White solid. Mp
119e120 ꢀC. Rf¼0.30 (hexane/EtOAc, 3:1). 1H NMR (500 MHz,
CDCl3)
d
3.78 (s, 3H), 5.50 (s, 2H), 6.89 (d, J¼8.7 Hz, 2H), 7.26 (d,
J¼8.6 Hz, 2H), 7.47 (t, J¼7.9 Hz, 2H), 7.57 (t, J¼7.4 Hz, 1H), 8.11 (s,
1H), 8.38 (d, J¼7.3 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 53.92, 55.29,

1464
S. Hwang et al. / Tetrahedron 68 (2012) 1460e1465
114.61 (2C), 125.56, 128.00, 128.29 (2C), 129.93 (2C), 130.49 (2C),
133.16, 136.46, 148.18, 160.13, 185.60. IR (CHCl3) nmax 3132, 2836,
1639, 1613, 1575, 1519 cmꢁ1. MS (FAB) (m/z) 294 [Mþ1]þ. HRMS
(FAB) calcd for C17H16N3O2 [MþH]þ 294.1243, found 294.1239.
J¼7.4 Hz, 2H), 7.61 (t, J¼7.0 Hz, 1H), 7.68 (d, J¼8.6 Hz, 2H), 8.48 (d,
J¼7.5 Hz, 2H), 8.60 (s, 1H). 13C NMR (75 MHz, CDCl3)
d 55.63, 114.95
(2C), 126.32, 128.38 (2C), 129.69, 130.60 (2C), 133.30, 136.49, 148.39,
160.35, 185.53. IR (CHCl3) nmax 3135, 3060, 2959, 2936, 2835,
1891 cmꢁ1. MS (FAB) (m/z) 280 [Mþ1]þ. HRMS (FAB) calcd for
C16H14N3O2 [MþH]þ 280.1086, found 280.1082.
4.4.9. (1-(4-Nitrobenzyl)-1H-1,2,3-triazol-4-yl)(phenyl)methanone
(1g). Yield 82% (method A), 80% (method B). Slightly brown solid.
Mp 175e177 ꢀC. Rf¼0.25 (hexane/EtOAc, 2:1). 1H NMR (400 MHz,
4.4.15. (1-(2,6-Diethylphenyl)-1H-1,2,3-triazol-4-yl)(phenyl)meth-
anone (1m). Yield 84% (method A), 84% (method B). Brown oil.
DMSO-d6)
d
5.91 (s, 2H), 7.56e7.67 (m, 4H), 7.70 (t, J¼7.2 Hz, 1H),
8.24 (t, J¼9.0 Hz, 4H), 9.08 (s, 1H). 13C NMR (75 MHz, DMSO-d6)
Rf¼0.33 (hexane/EtOAc, 5:1). 1H NMR (400 MHz, CDCl3)
d 1.06 (t,
d
52.22, 123.98 (2C), 128.57 (2C), 129.25 (2C), 129.91 (2C), 130.69,
J¼7.5 Hz, 6H), 2.23 (q, J¼7.5 Hz, 4H), 7.21 (d, J¼7.7 Hz, 2H), 7.40 (t,
J¼7.7 Hz, 1H), 7.50 (t, J¼7.7 Hz, 2H), 7.59 (t, J¼7.3 Hz, 1H), 8.36 (s,
133.33, 136.53, 142.77, 146.68, 147.36, 185.07. IR (CHCl3) nmax 3121,
1634, 1596, 1519 cmꢁ1. MS (FAB) (m/z) 309 [Mþ1]þ. HRMS (FAB)
calcd for C16H13N4O [MþH]þ 309.0988, found 309.0997.
1H), 8.51 (d, J¼7.4 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 14.93 (2C),
24.07 (2C), 126.74 (2C), 128.24 (2C), 130.45 (2C), 130.75, 130.83,
133.19 (2C), 133.84, 136.35, 140.92, 147.62, 185.29. IR (CHCl3) nmax
3133, 3070, 2971, 2935, 2879, 1650 cmꢁ1. MS (FAB) (m/z) 306
[Mþ1]þ. HRMS (FAB) calcd for C19H20N3O [MþH]þ 306.1606, found
306.1603.
4.4.10. (1-Octyl-1H-1,2,3-triazol-4-yl)(phenyl)methanone (1h). Yield
81% (method A), 86% (method B). Slightly brown solid. Mp 35e37 ꢀC.
Rf¼0.35 (hexane/EtOAc, 3:1). 1H NMR (500 MHz, CDCl3)
d 0.85 (t,
J¼6.8 Hz, 3H), 1.18e1.38 (m, 12H), 1.93 (p, J¼7.1 Hz, 2H), 4.41 (t,
J¼7.2 Hz, 2H), 7.49 (t, J¼7.9 Hz, 2H), 7.58 (t, J¼7.3 Hz,1H), 8.23 (s,1H),
Acknowledgements
8.41 (d, J¼8.0 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 13.99, 22.51, 26.35,
28.83, 28.94, 30.09, 31.61, 50.58, 128.11, 128.31 (2C), 130.54 (2C),
133.17, 136.52, 147.99, 185.71. IR (CHCl3) nmax 3134, 3069, 2927, 2856,
1650, 1599, 1577 cmꢁ1. MS (FAB) (m/z) 286 [Mþ1]þ. HRMS (FAB)
calcd for C17H24N3O [MþH]þ 286.1919, found 286.1913.
This work was supported by the SRC/ERC program (R-11-2007-
107-02001-0) and the WCU program (R32-2008-000-10098-0) of
the National Research Foundation of Korea (NRF) grant founded by
Korea government (MEST). We are grateful to the Research Institute
of Pharmaceutical Sciences at Seoul National University for pro-
viding some experimental equipment.
4.4.11. Phenyl(1-(thiophen-2-ylmethyl)-1H-1,2,3-triazol-4-yl)meth-
anone (1i). Yield 82% (method A), 83% (method B). Slightly brown
solid. Mp 110e112 ꢀC. Rf¼0.40 (hexane/EtOAc, 2:1). 1H NMR
Supplementary data
(400 MHz, CDCl3)
d
5.75 (s, 2H), 6.97 (t, J¼4.8 Hz, 1H), 7.13 (d,
J¼3.1 Hz, 1H), 7.31 (d, J¼5.1 Hz, 1H), 7.46 (t, J¼7.5 Hz, 2H), 7.56 (t,
NMR spectra (1H, 13C) of ynones 4aec and 1,2,3-triazoles 1aem.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.12.025. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
J¼7.4 Hz, 1H), 8.22 (s, 1H), 8.37 (d, J¼7.7 Hz, 2H). 13C NMR (75 MHz,
CDCl3)
d 48.47, 127.39, 127.49, 127.97, 128.24 (2C), 128.73, 130.41
(2C), 133.16, 134.83, 136.32, 148.07, 185.45. IR (CHCl3) nmax 3121,
1636, 1599, 1574, 1519 cmꢁ1. MS (FAB) (m/z) 270 [Mþ1]þ. HRMS
(FAB) calcd for C14H12N3OS [MþH]þ 270.0701, found 270.0697.
References and notes
4.4.12. (2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-(4-benzoyl-1H-1,2,3-
triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1j). Yield
82% (method A), 85% (method B). Slightly yellow solid. Mp
65e67 ꢀC. Rf¼0.35 (hexane/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3)
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their inherently high reactivity toward nucleophiles.
d
1.86 (s, 3H), 1.96 (s, 3H), 1.98 (s, 3H), 2.18 (s, 3H), 4.09e4.19 (m,
2H), 4.28 (t, J¼6.2 Hz, 1H), 5.28 (dd, J¼3.3, 10.3 Hz, 1H), 5.53 (t,
J¼9.6 Hz, 2H), 5.94 (d, J¼9.2 Hz, 1H), 7.47 (t, J¼7.7 Hz, 2H), 7.56 (t,
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€
CDCl3) d 20.09, 20.35, 20.47, 20.50, 61.16, 66.71, 68.02, 70.43, 74.04,
86.18, 127.18, 128.31 (2C), 130.35 (2C), 133.29, 136.26, 148.10,
168.90, 169.66, 169.86, 170.16, 185.11. IR (CHCl3) nmax 3138, 3023,
1753, 1654, 1599, 1577, 1526 cmꢁ1. MS (FAB) (m/z) 504 [Mþ1]þ.
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504.1615.
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79% (method A), 78% (method B). Slightly brown solid. Mp
129e131 ꢀC. Rf¼0.28 (hexane/EtOAc, 5:1). 1H NMR (400 MHz, CDCl3)
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7.39e7.54 (m, 5H), 7.58 (t, J¼7.3 Hz, 1H), 7.77 (d, J¼7.8 Hz, 2H), 8.44
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d 120.57 (2C),
126.33, 128.29 (2C), 129.31, 129.78 (2C), 130.47 (2C), 133.27, 136.15,
136.26, 148.33, 185.32. IR (CHCl3) nmax 3133, 3071, 2970, 2955,
2876 cmꢁ1. MS (FAB) (m/z) 250 [Mþ1]þ. HRMS (FAB) calcd for
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ꢀ
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solid. Mp 150e152 ꢀC. Rf¼0.32 (hexane/EtOAc, 2:1). 1H NMR
(400 MHz, CDCl3)
d
3.85 (s, 3H), 7.02 (d, J¼8.6 Hz, 2H), 7.51 (t,

S. Hwang et al. / Tetrahedron 68 (2012) 1460e1465
1465
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