Arylation of Click Triazoles with Diaryliodonium Salts

Article abstract of DOI:10.1021/acs.joc.9b02197

A robust, selective, and highly efficient method for the preparation of 1,3,4-triaryl 1,2,3-triazolium salts has been developed. It features arylation of a click triazole with a diaryliodonium salt in the presence of a copper catalyst under neat condition

Full text of DOI:10.1021/acs.joc.9b02197

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Article
Arylation of Click Triazoles with Diaryliodonium Salts
Miha Virant, and Janez Košmrlj
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02197 • Publication Date (Web): 25 Sep 2019
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Arylation of Click Triazoles with Diaryliodonium Salts
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Miha Virant and Janez Košmrlj*
Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Večna pot 113, SI 1000, Ljubljana, Slovenia
TOC Graphics
Abstract: A robust, selective, and highly efficient method for the preparation of
,3,4-triaryl 1,2,3-triazolium salts has been developed. It features arylation of a click
1
triazole with a diaryliodonium salt in the presence of a copper catalyst under neat
conditions. The presence of pyridine functionality is tolerated, enabling the first access to
key precursors of pyridyl-mesoionic carbene ligands. The method has been integrated into a
one-pot protocol with a terminal alkyne, sodium azide, and diaryliodonium salt as starting
compounds.
INTRODUCTION
1
2
1
,3,4-Trisubstituted-1H-1,2,3-triazolium salts I and II (Figure 1; R , R = alkyl, aryl,
heteroaryl) upon deprotonation yield 1H-1,2,3-triazol-5-ylidenes III and IV, a class of
1
N-heterocyclic carbenes (NHCs) that belong to the family of mesoionic carbenes (MICs).
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Due to unique electronic properties, triazolylidene MICs stood out from NHCs, as well as
many other ligand classes, not only in the preparation of efficient catalysts and
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photosensitizers, but also in other chemical and material fields of science.
Figure 1. Triazolium salts (left) and triazolylidene ligands (right).
In a highly modular approach that includes CuAAC (Copper Catalyzed Azide-Alkyne
Cycloaddition) reaction with subsequent N3 alkylation of the resulting 1,2,3-triazole, the
4d
3
-alkyltriazolium salts I are easily accessed almost at will. This strategy is even
1
2 5
applicable for triazoles having tethered a competing nucleophilic pyridyl moiety R or R .
In contrast, the synthesis of 1,3-diaryl counterparts II is limited to a single protocol that
6
was discovered by Wirschun and Jochims and subsequently greatly developed by Bertrand
7
et al. It is a formal 1,3-dipolar cycloaddition of an alkyne with a 1,3-diaza-2-azoniaallene
salt that is formed from 1,3-diaryltriazene (Figure 2a). The cycloaddition is carried out as a
one-pot operation by the addition of tert-butyl hypochlorite to a solution of
1,3-diaryltriazene, potassium hexafluorophosphate, and alkyne in dichloromethane as a
reaction solvent, at –78 °C. Although showing broad scope in alkyne partners, from the
selectivity reasons the method is limited to symmetrical 1,3-diaryltriazene substrates. Low
reaction temperatures can cause some solubility issues, and to our knowledge, it has not
been used to access N1/N3-heteroary functionalized counterparts.
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Figure 2. Triazolium salts (left) and triazolylidene ligands (right).
An approach that may potentially address the above limitations is N3 arylation of
1-aryl-1H-1,2,3-triazole derivatives. Whereas examples of arylation with a (hetero)aryl
halogenide are scarce, limited to the reaction of 1,5-diphenyl-1H-1,2,3-triazole with
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-bromopyridine (Figure 2b), the use of diaryliodonium salt is sought as an attractive
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alternative. Discovered in the 1890’s by Wilgerodt, and owing to the group of Olofsson
11
and others who have made this hypervalent iodine reagents readily accessible,
1
2
diaryliodonium salts found many synthetic applications. These include N-arylation of
13
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nitrogen containing heterocycles like pyridine,
imidazole, benzimidazole and
1
6
1
,2,4-triazole. The potential breadth of arylation of 1,2,3-triazole with diaryliodonium salt
1
4
was first demonstrated by Gao et al. in 2013 (Figure 2c). Although a few related examples
1
7
emerged in the literature since then the method remained undeveloped.
The motivation to develop reliable and robust method for the synthesis of
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,3-diaryl-1H-1,2,3-triazol-5-ylidene precursors, II, stems from the fact that these MICs,
4d,7
IV, exhibit enhanced stability in comparison to their alkylated counterparts III.
To get
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desired ligand properties and architecture an access to differently N1 and N3 diaryl and
heteroaryl substituted 1,2,3-triazolium salts is sought. In this respect, pyridine may be
considered as one of highly desired substituents giving rise to the emerging class of
hemilabile/bifunctional pyridyl-MIC ligands of intriguing overall donor capacities to the
2
,4g
metal.
diaryliodonium salts 2 (Figure 2d) as an easy access to pyridyl-MIC precursors (IV, Figure
).
Herein, we report on arylation of pyridyl- and picolyl-1H-1,2,3-triazoles 1 with
1
RESULTS AND DISCUSSION
To assess preliminary parameters for the arylation of triazoles 1 we conducted a series
1
2
of test experiments in which 4-phenyl-1-(p-tolyl)-1H-1,2,3-triazole (1b; R = p-tolyl, R =
Ph, Figure 2d) was let to react with diaryliodonium salts (2) under different reaction
conditions. For example, mesityl(phenyl)iodonium triflate (2a) and diphenyliodonium
tetrafluoroborate (2b) were used as reagents in solvents like DMF and THF, with or without
the addition of CuSO . Unsymmetrical mesityl(aryl)iodonium triflates were selected out of
4
the iodonium salts because of well documented selective transfer of the aryl group in the
1
8
metal catalyzed arylations and their easy access from aryl iodides, mesitylene, and triflic
11a,19
acid.
In addition, to demonstrate that symmetrical diaryliodonium salts can also be
employed, bis(4-methoxyphenyl)iodonium tetrafluoroborate (2e) was selected in all
subsequent experiments for the introduction of 4-methoxyphenyl group to the triazole. The
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reactions were monitored by H NMR spectroscopy of aliquots taken from the reaction
mixtures. The formation of triazolium salt 3 was indicated by the appearance of
characteristic H-5 resonance, shifted ca. 1 ppm downfield as compared to the starting
1
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,20
triazole 1, similar to the N-3 alkylated triazolium salts.
The results of optimization of the reaction conditions are presented in Table 1 and can
be summarized as follows. Copper salts and elevated temperatures are typically required in
12–16
arylations of heterocycles with diaryliodonium salt,
of triazoles 1. As evident from Table 1, stirring the solution of
-phenyl-1-(p-tolyl)-1H-1,2,3-triazole (1b) and 2a in DMF at 100 °C in the absence of
which is also the case in arylation
4
copper salt (entry 1) or at room temperature in the presence of 10 mol% of CuSO (entry 2)
4
returned unreacted starting reagents. The formation of product 3b (16%) could only be seen
by applying 10 mol% of CuSO at 100 °C (entry 3). In comparison to the report of Gao et
4
1
4a
al.
who arylated monosubstituted 1-phenyl-1H-1,2,3-triazole under similar reaction
conditions (entry 4), the initial result on arylation of 3b is modest. However, an additional
optimization of the reaction from entry 3 in terms of temperature, time and loading of
iodonium salt (entries 5–7) finally furnished complete conversion into 3b (86% isolated
yield, entry 7). Higher loadings of iodonium salts proved beneficial, probably due to its
decomposition at higher temperatures (see below). Triazole 1b also readily reacted with 2b
in THF as a reaction solvent (entries 8 and 9). In addition to the above experiments, test
reaction was also run neat, which gave the same result in terms of the reaction time and
conversion to product 3, yet being the most economic from the solvent cost and isolation
perspective (entry 10). As indicated above, thermal stability of iodonium salts was tested
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under neat conditions. Heating 2a at 130 °C for 17 h led to decomposition with formation
of mesityl iodide along with other unidentified products.
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a
Table 1. Optimization of the Reaction Conditions for Arylation of 1.
b
Entry 2a (equiv) Solvent Catalyst (mol%) Temp (°C) Time (h) Conversion (yield)
1
2
3
1.8
1.8
1.5
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
THF
Neat
none
100
rt
4
0
0
CuSO (10)
17
4
4
CuSO (10)
100
100
130
130
130
100
100
130
16
(91)
51
53
4
c
d
e
4
1.5
1.3
1.8
1.8
CuSO (5)
40
17
5
4
5
6
7
8
9
CuSO (10)
4
CuSO (10)
4
CuSO (10)
17
17
17
17
100 (86)
4
d
f
1.3
1.8
CuSO (10)
82
4
d
f
CuSO (10)
100
4
1
0
1.8
CuSO (10)
100 (97)
4
a
Reaction conditions: 1b (0.2 mmol, 1 equiv), 2a (0.36 mmol, 1.8 equiv), CuSO (0.02
4
b
c
mmol, 0.1 equiv), V(solvent) = 0.5 mL. Isolated yield (%). For comparison reasons, the
1
4a
data are adopted from Gao et al.
who arylated monosubstituted
d
e
1-phenyl-1H-1,2,3-triazole.
2b was used instead of 2a.
Corresponds to
f
1
,3-diphenyl-1H-1,2,3-triazol-3-ium tetrafluoroborate. As tetrafluoroborate salt.
As a result of the above test experiments, the optimal reaction conditions for arylation
employed heating a mixture of triazole 1 (0.2 mmol, 1.0 equiv), diaryliodonium salt 2 (0.36
mmol, 1.8 equiv) and anhydrous CuSO (0.02 mmol, 0.1 equiv) neat in a sealed glass vial
4
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at 130 °C overnight (17 h). Analytically pure triazolium salts 3 were isolated by column
chromatography. Having established the general reaction conditions, we investigated the
scope of the arylation of 1,4-diarly-1H-1,2,3-triazoles 1 (Table 2). Phenyl groups having
strongly electron-withdrawing and electron-releasing substituents were successfully
introduced affording triazolium salts 3(c,f,g,m) and 3(e,j,k,n,o), respectively, regardless of
the electronic effects in the starting triazoles 1. Functional groups present in reagents 1 and
1
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2
were found to be compatible, including methyl, trifluoromethyl, methoxy and nitro, and
the yields of the products were generally excellent. The exception was the coupling of 1d
with 2h where the low yield of dimethylamino functionalized compound 3j was a result of
undesired arylation at the NMe nucleophilic center. Synthesis of 3b from 1b and 2a was
2
also conducted on a larger (10×) scale also with an excellent result, demonstrating the
preparative applicability of the method.
a
Table 2. Scope of Arylation of 1,4-Diarly-1H-1,2,3-triazoles 1 into 3.
1
2
3
b
1
R
R
2
R
Product Yield
1
a
b
b
b
b
b
b
H
H
H
H
H
H
H
H
2a
2a
2c
2d
H
H
3a
3b
3c
3d
97
c
1
1
1
1
1
1
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
97 (94)
88
4-CF
3
4-CH
4-OMe
4-NO
3-CF
92
3
d
e
2e
2f
3e
3f
99
61
2
2g
3
3g
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c
OMe
H
H
H
H
H
H
2a
2a
H
H
3h
3i
95
94
32
93
98
95
88
84
1
1
1
1
1
d
d
d
d
d
NO
NO
NO
NO
NO
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2
2
2
2
2h 4-NMe
3j
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d
e
2e
2d
2f
4-OMe
4-CH
4-NO
3k
3l
3
2
3m
d
e
1
e
OMe NO
2
2e
4-OMe
4-OMe
3n
d
e
1
f
NO OMe 2e
2
3o
a
Reaction conditions: 1 (0.2 mmol, 1 equiv), 2 (0.36 mmol, 1.8 equiv), CuSO (0.02 mmol,
4
b
c
d
0
.1 equiv), 130 °C, 17 h. Isolated yield (%). 2 mmol scale of 1b. 2e refers to
+
– e
(
4-MeO-C H ) I BF . As tetrafluoroborate salt.
6 4 2 4
To highlight the real utility of this protocol, aimed at the synthesis of
4g
hemilabile/bifunctional NHC ligands, we moved to arylation of 4-pyridyl triazoles. Since
the introduction of pyridine functionality into the triazole molecule could potentially
introduce incompatibility with the copper catalyst as well as some selectivity issues, the
effect of a broader selection of copper additives and anions of iodonium salt was
re-examined. For this, 2-(1-(p-tolyl)-1H-1,2,3-triazol-4-yl)pyridine (1h) was selected as a
model compound. As a result, some minor effects on selectivity were observed in case of
iodonium salts with different anions as shown in Table 3, and some differences could also
be noticed in conversions with different copper catalysts as well (Table 4). Although CuBr2
performed better in arylation of 1h with 2a (compare entries 6 and 13 in Table 4), its
catalytic activity was somehow diminished in arylations of other tested triazoles as
compared to CuSO (Table 5, compare entry 10 with 11, and entry 13 with 14). As a result,
4
in analogy to the above findings for diaryl triazole 1b, CuSO and CuBr as well as
4
2
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iodonium salts having triflate anion proved superior for the arylation of pyridyl triazole 1h
in terms of the yield of triazolium salt (4c).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
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1
2
3
4
5
6
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0
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3
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3
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a
Table 3. Test arylation of 1h with phenyl(mesityl)iodonium salts 2a,m–q.
–
Iodonium salt Anion (X ) %Conversion to 4c(X)
–
2
a
TfO
TsO
74
68
61
59
60
64
–
2
m
–
2
n
BF
4
–
2
o
p
q
ClO
4
–
2
HSO
4
–
2
PF
6
a
Reaction conditions: 1h (0.2 mmol, 1 equiv), 2 (0.36 mmol, 1.8 equiv), CuSO (0.02
4
mmol, 0.1 equiv), 130 °C, 17 h.
a
Table 4. Test arylations of 1h with different copper salts.
Entry
[Cu]
CuI
%Conversion to 4c
1
2
3
4
5
6
7
74
64
59
60
56
78
66
Cu(PPh ) Br
3
3
CuCl2
Cu(OAc) · H O
2
2
Cu(OTf)2
CuBr2
Cu(NO ) · 3 H O
3
2
2
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1
1
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
9
CuBr
70
59
Cu(OAc)
1
0
6
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
2
3
CuCN
CuCl
66
63
73
1
1
CuSO4
a
Reaction conditions: 1h (0.2 mmol, 1 equiv), 2a (0.36 mmol, 1.8 equiv), [Cu] (0.02 mmol,
0.1 equiv), 130 °C, 17 h.
a
Table 5. Scope of Arylation of 1-Aryl-4-pyridyl-1H-1,2,3-triazoles 1 into 4.
1
3
b
Entry Triazole
R
2
R
Product Conversion (yield)
1
2
1g
1g
1h
1h
1h
1h
1h
1h
1h
1i
Ph
Ph
2a
Ph
4a
71 (63)
77 (70)
73 (69)
(51)
c
e
2e 4-MeO-C H4
4b
4c
6
3
4-CH -C H
2a
Ph
Ph
3
6
4
4
4
4
4
4
4
c
e
4
4-CH -C H
2b
2c
4c
3
6
5
4-CH -C H
4-CF -C H
4
4d
(63)
3
6
3
6
c
e
6
4-CH -C H
2e 4-MeO-C H4
4e
4f
4g
4h
4i
72 (59)
3
6
6
7
4-CH -C H
2i
2j
4-Cl-C H4
57 (44)
3
6
6
d
8
4-CH -C H
2-CF -C H
3
6
3
6
4
9
4-CH -C H
2k
2a
2a
Mes
21 (17)
70 (58)
3
6
10
4-MeO-C H
Ph
Ph
6
4
4
4
f
11
1i
4-MeO-C H
4i
62
6
c
e
12
1i
4-MeO-C H
2e 4-MeO-C H4
4j
78 (64)
71 (60)
6
6
1
3
1j
4-NO -C H
2d 4-CH -C H
4k
4k
2
6
4
3
6
4
4
f
14
1j
4-NO -C H
2d 4-CH -C H
48
2
6
4
4
3
6
c
e
1
5
1j
4-NO -C H
2e 4-MeO-C H4
4l
68 (57)
73 (62)
2
6
6
16
1k
4-NMe -C H
4
2a
Ph
4m
2
6
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c
e
1
7
1l
Et
2e 4-MeO-C H4
4n
80 (65)
6
a
Reaction conditions: 1 (0.2 mmol, 1 equiv), 2 (0.36 mmol, 1.8 equiv), CuSO (0.02 mmol,
4
b
c
+
–
d
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0.1 equiv), 130 °C, 17 h. Isolated yield (%). 2e refers to (4-MeO-C H ) I BF .
6 4 2 4
e
f
Complex mixture of products (see text). As tetrafluoroborate salt. CuBr was used
2
instead of CuSO4.
With these results in hand, the scope of the arylation of 4-pyridyl triazoles 1g–l with
mesityl(aryl)iodonium triflates 2a,c,d,i–k, diphenyliodonium tetrafluoroborate (2b), and
bis(4-methoxyphenyl)iodonium tetrafluoroborate (2e) was investigated as shown in Table 5.
With some exception (see below) triazolium salts 4a–n having pyridine substituent at C-4
were obtained in good yields. Somewhat lower yields of the products from Table 5 as
Py
compared to those from Table 2 were likely due to the formation of N -arylated side
products and the need for chromatographic purification. In one instance, that of the
arylation of triazole 1j with iodonium salt 2d, the undesired pyridine monoarylated side
product (2-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)-1-(p-tolyl)pyridine-1-ium triflate, 4k')
could be isolated and fully characterized by NMR and HRMS. Nevertheless, the protocol
enabled acceptable yields of the pyridyl-triazolium salts 4, having both the
electron-withdrawing and releasing substituents, with no need for the pyridine nitrogen
5
atom protection as it was in the case of alkylation.
Arylation of
2
-(1-ethyl-1H-1,2,3-triazol-4-yl)pyridine (1l) with 2e also worked well with 4n being
isolated in 65% yield. In contrast to the above, an attempt to introduce a bulky mesityl
group was less successful, yielding in the reaction of 1h with dimesityliodonium triflate
(2k) the corresponding triazolium salt 4h in only 17% yield (Table 5). Interestingly, the
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reaction of 1h with mesityl(2-(trifluoromethyl)phenyl)iodonium triflate (2j) resulted in a
complex mixture of products, from which unreacted 1h (79%), 4g (3%), and 4h (5%) could
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
be identified by H NMR spectral analysis and comparison with the spectra of the
corresponding authentic samples.
The scope of arylation of 4-aryl-1-picolyl triazoles 1m–o was also briefly investigated
as shown in Table 6. An introduction of a CH bridge between the pyridine and MIC dents
2
should drastically influence electronic effects, bite angle, and conformational mobility of
4
d,4g,21
the chelating ligand as compared to the Py-MIC (4a–n).
conditions as above (Table 5) the corresponding products 5a–d were obtained in excellent
8–98% yields (Table 6). Surprisingly, undesired pyridine arylation was not observed in
these experiments. 1-Picolyl-4-pyridyl-1H-1,2,3-triazole (1p), an interesting ligand that has
By using the same reaction
8
2
2
been used to achieve multimetallic coordination architectures, has also been arylated with
iodonium salt 2a to give triazolium salt 5e, albeit in a modest 43% yield (Table 6). Lower
yield is somehow consistent with the results on the arylation of 4-pyridyl triazoles from
Table 5.
a
Table 6. Scope of Arylation of 1-Picolyl-1H-1,2,3-triazoles.
2
3
b
Triazole
R
2
R
Product Yield
1m
Ph
4-CH -C H
6 4
2a
2a
2a
H
H
H
5a
5b
5c
94
98
88
91
1
n
3
1o
4-MeO-C
6
H
H
4
4
c
e
1
o
4-MeO-C
6
2e OMe
5d
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1
p
2-Py
2a
H
5e
43
a
Reaction conditions: 1 (0.2 mmol, 1 equiv), 2 (0.36 mmol, 1.8 equiv), CuSO (0.02 mmol,
4
b
c
+
– e
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0.1 equiv), 130 °C, 17 h. Isolated yield (%). 2e refers to (4-MeO-C H ) I BF . As
6 4 2 4
tetrafluoroborate salt.
One-pot CuAAC–Arylation. The fact that both, the 1,4-disubstituted triazole forming
CuAAC reaction, and the above developed arylation procedure require Cu-catalysts,
prompted us to test whether the triazolium salt could be prepared in a one-pot procedure
starting from an organic azide, a terminal acetylene and iodonium salt. For this purpose
Cu(PPh ) Br (5 mol%) was selected as a pre-catalyst. This temperature and oxidation
3
3
2
0a
resistant Cu(I) salt already efficiently promoted demanding CuAAC reactions as well as
2
3
arylation of triazoles with iodonium salts. In contrast to Cu(PPh ) Br (Table 7, entry 1),
3
3
attempts to use other copper salts for this process, i.e., CuSO , Cu(OAc) ·H O, and CuI,
4
2
2
proved unsuccessful (entries 2–4). The result of a brief substrate scope screening to produce
triazolium salts (3–5)a, one from each of the product classes presented in Tables 2, 5, and 6,
are shown in Table 8, and demonstrate a remarkable utility of the method. Although by
conducting reactions on a 2 mmol scale in sealed ACE glass reaction tubes we have not
observe any uncontrollable behavior, the reactions with azides should be done with caution
and on small scales due to their potentially explosive character.
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Table 7. Copper-catalyst For One-pot CuAAC-Arylation.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
Entry
Copper salt
%Conversion to 4a (Yield)
1
2
Cu(PPh ) Br
100 (92)
< 10
3
3
CuSO4
3
Cu(OAc) · H O
< 10
2
2
4
CuI
< 10
a
Reaction conditions: 2a (1.6 mmol, 1.6 equiv), 6a (1 mmol, 1 equiv), 7a (1.2 mmol, 1.2
b
equiv), copper salt (0.05 mmol, 0.05 equiv), 130 °C, 3 h. Refers to conversion (isolated %
yield).
a
Table 8. One-pot CuAAC-Arylation.
a
Reaction conditions: 2a (1.6 mmol, 1.6 equiv), 6 (1 mmol, 1 equiv), 7 (1.2 mmol, 1.2
b
equiv), Cu(PPh ) Br (0.05 mmol, 0.05 equiv), 130 °C, 3 h. Refers to conversion
3
3
c
(
isolated % yield). For comparison reasons, the result is taken from Table 7, entry 1.
Finally, we decided to extend the two-step one-pot protocol from Table 8 by including
an in situ generation of the organic azide (Table 9). Namely, it has been documented that
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7
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9
iodonium salts readily undergo nucleophilic displacement with sodium azide into aryl
24
azides. Thus, heating the mixture of phenylacetylene 7a, diphenyliodonium triflate 2l, and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
sodium azide in the presence Cu(PPh ) Br (5 mol%) resulted in quantitative formation of
3
3
3a. Similarly, products 4a and 4j were obtained from 2-etynylpiridine 7b and the
corresponding iodonium salts 2l and 2e. Although this method enables an access to N1/N3
identically substituted molecules, just like in the case of 1,3-dipolar cycloaddition of
7
alkynes with diaryltriazene products (1,3-diaza-2-azoniaallene salts, Figure 2a), the scope
can be easily expanded to the preparation of heteroaromatic derivatives like 4a and 4j. In
contrast, attempts to react diphenyltriazene with 2-ethynylpyridine (7b) through the
reaction from Figure 2a failed to provide 1,3-diphenyl-4-(pyridin-2-yl)-1H-1,2,3-triazolium
salt returning unidentified polymeric material instead.
a
Table 9. One-pot Azide-Formation-CuAAC-Arylation.
a
Reaction conditions: 2 (0.936 mmol, 2.6 equiv), 7 (0.36 mmol, 1 equiv), NaN (0.36
3
b
mmol, 1 equiv), Cu(PPh ) Br (0.018 mmol, 0.05 equiv), 130 °C, 3 h. Refers to conversion
3
3
(isolated % yield).
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
It is noteworthy that the above developed one-pot protocols may be suitable for small
scale high throughput combinatorial screening experiments, aimed at identifying hit
compounds, having desired coordination properties or biological activity, for example.
Once the hit compound is identified, its synthesis on the preparative scale can easily be
conducted through the protocols from Tables 2, 5, and 6.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CONCLUSIONS
In summary, we have developed a robust and highly efficient method for N-3 arylation
of click triazoles with diaryliodonium salts. Great functional group tolerance enables the
preparation of products with strongly electron-withdrawing or donating characteristics and
those possessing a push-pull effect. In contrast to the method that employs
1
,3-diaryltriazenes as the starting compounds, this protocol allows for the preparation of
N1/N3 differently substituted products as well as those having pyridyl and picolyl moieties,
which are inaccessible through other methods. All these features will be of prime
importance in future design of organometallic compounds with bifunctional
mesoionic-carbene ligands and their application in catalysis. This is the first method for the
synthesis of N3-arylated 1-picolyl and/or 4-pyridyl functionalized 1,2,3-triazolium salts.
EXPERIMENTAL SECTION
General considerations. The reagents and solvents in general procedures were used as
obtained from the commercial sources (Merck, Fluorochem), unless indicated otherwise.
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4
5
6
7
8
9
Dichloromethane used for the syntheses was dried over sodium and distilled prior to use.
THF used for the syntheses was dried over sodium and distilled prior to use. Anhydrous
DMF (99.8%) used in reactions was purchased at Merck and stored under Sure/Seal™ and
argon atmosphere. Silica gel column chromatography was carried out on silica gel 60N.
Analytical thin-layer chromatography (TLC) was carried out on Fluka Silica Gel TLC cards,
visualized with a UV lamp (254 nm and/or 366 nm).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Melting points were determined on a Kofler micro hot-stage microscope and are
uncorrected. The reactions were monitored by TLC on TLC-CARDS SILICA GEL, 220–
4
40 mesh. IR spectra were obtained with a Perkin–Elmer Spectrum 100, equipped with a
Specac Golden Gate Diamond ATR as a solid sample support. High resolution mass spectra
HRMS) were recorded with an Agilent 6224 time-of-flight (TOF) mass spectrometer
equipped with a double orthogonal electrospray source at atmospheric pressure ionization
(
(ESI) coupled to an HPLC instrument.
NMR spectra were recorded with a Bruker Avance III 500 MHz NMR instrument
1
19
13
15
operating at 500 MHz ( H), 471 MHz ( F), 126 MHz ( C), and 51 MHz ( N) at 296 K in
DMSO-d . Proton and carbon spectra are referenced to the residual solvent shifts of δ 2.50
6
2
5 19
and δ39.52 ppm, respectively.
F spectra were referenced to CCl F as external standards
3
15
1
15
at δ 0 ppm. N chemical shifts were extracted from H– N gs-HMBC spectra (with 4.5 Hz
digital resolution in the indirect dimension and the parameters adjusted for a long-range
1
15
H– N coupling constant of 5 Hz), determined with respect to external nitromethane and
corrected to external ammonia by addition of 380.5 ppm.
Assignments of proton, carbon and nitrogen resonances were performed by 2D NMR
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6
7
8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
1
13
1
13
1
15
techniques ( H− H gs-COSY, H− C gs-HSQC, H− C gs-HMBC and H− N gs-HMBC).
Coupling constants (J) are given in Hz. Multiplicities are indicated as follows: s (singlet), d
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
doublet), t (triplet), q (quartet) or m (multiplet). Resonances of NMe carbon atoms were
2
superimposed with that for DMSO-d solvent and were identified through the assistance of
6
1
13
H− C HSQC spectra.
20
26
20a
Starting triazoles 1, diaryliodonium salts 2, aromatic and benzyl azides (6) and
2
7
Cu(PPh ) Br were prepared according to the known literature procedures.
3
3
Caution! The handling of azides is dangerous because of their explosive character and
2
8
all reactions should be carried out on a small scale.
Preparation of triazoles 1
2
0a
Triazoles 1 were synthesized according to a slightly modified literature procedure as
follows. A mixture of organic azide 6 (1 mmol, 1 equiv), acetylene 7 (1 mmol, 1 equiv), and
Cu(PPh ) Br (0.01 mmol, 9 mg, 1 mol%) was stirred at room temperature overnight. The
3
3
reaction mixture was dissolved in hot ethyl acetate and the product was precipitated by the
1
addition of light petroleum with cooling, filtered, and dried. H NMR data of the isolated
2
0,22
products were in agreement with the literature reports.
1
2
1
,4-Diphenyl-1H-1,2,3-triazole (1a, R =R =Ph). Following the general procedure
employing azidobenzene (119 mg, 1 mmol) and phenylacetylene (7a, 102 mg, 1 mmol).
1
Off-white solid (137 mg, 0.620 mmol, 62%). H NMR (500 MHz, DMSO-d ) δ 9.31 (s, 1H),
6
8
.00–7.90 (m, 4H), 7.68–7.60 (m, 2H), 7.56–7.47 (m, 3H), 7.42–7.35 (m, 1H). Spectral
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data are in agreement with the literature.
1
2
4
-Phenyl-1-(p-tolyl)-1H-1,2,3-triazole (1b, R =4-CH -C H , R =Ph). Following the
3
6
4
1
1
1
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1
1
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general procedure employing azidotoluene (133 mg, 1 mmol) and phenylacetylene (7a, 102
1
mg, 1 mmol). Off-white solid (199 mg, 0.846 mmol, 85%). H NMR (500 MHz, DMSO-d )
6
δ 9.26 (s, 1H), 7.97–7.92 (m, 2H), 7.86–7.81 (m, 2H), 7.53–7.47 (m, 2H), 7.46–7.42 (m,
20c
2
H), 7.41–7.36 (m, 1H), 2.40 (s, 3H). Spectral data are in agreement with the literature.
1
2
1
-(4-Methoxyphenyl)-4-phenyl-1H-1,2,3-triazole (1c, R =4-MeO-C H , R =Ph).
6 4
Following the general procedure employing 1-azido-4-methoxybenzene (149 mg, 1 mmol)
1
and phenylacetylene (7a, 102 mg, 1 mmol). Brown solid (216 mg, 0.864 mmol, 86%). H
NMR (500 MHz, DMSO-d ) δ 9.20 (s, 1H), 7.96–7.91 (m, 2H), 7.88–7.83 (m, 2H), 7.52–
6
7
.47 (m, 2H), 7.40–7.35 (m, 1H), 7.21–7.15 (m, 2H), 3.85 (s, 3H). Spectral data are in
2
0d
agreement with the literature.
1
2
1
-(4-Nitrophenyl)-4-phenyl-1H-1,2,3-triazole (1d, R =4-NO -C H , R =Ph). Following
2 6 4
the general procedure employing 1-azido-4-nitrobenzene (164 mg, 1 mmol) and
1
phenylacetylene (7a, 102 mg, 1 mmol). Yellow solid (169 mg, 0.635 mmol, 64%). H NMR
(500 MHz, DMSO-d ) δ 9.54 (s, 1H), 8.56–8.46 (m, 2H), 8.30–8.25 (m, 2H), 8.05–7.89 (m,
6
2
H), 7.59–7.47 (m, 2H), 7.46–7.36 (m, 1H). Spectral data are in agreement with the
20b
literature.
1
1
-(4-Methoxyphenyl)-4-(4-nitrophenyl)-1H-1,2,3-triazole
(1e,
R =4-MeO-C H ,
6 4
2
R =4-NO -C H ). Following the general procedure employing 1-azido-4-methoxybenzene
2
6
4
(
149 mg, 1 mmol) and 1-ethynyl-4-nitrobenzene (147 mg, 1 mmol). Off-white solid (266
1
mg, 0.897 mmol, 90%). H NMR (500 MHz, DMSO-d ) δ 9.46 (s, 1H), 8.40–8.35 (m, 2H),
6
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.22–8.17 (m, 2H), 7.90–7.84 (m, 2H), 7.22–7.16 (m, 2H), 3.85 (s, 3H). Spectral data are in
20e
agreement with the literature.
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1
4
-(4-Methoxyphenyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole
(1f,
R =4-NO -C H ,
2 6 4
2
R =4-MeO-C H ). Following the general procedure employing 1-azido-4-nitrobenzene
6
4
(164 mg, 1 mmol) and 1-ethynyl-4-methoxybenzene (132 mg, 1 mmol). Yellow solid (262
1
mg, 0.884 mmol, 88%). H NMR (500 MHz, DMSO-d ) δ 9.43 (s, 1H), 8.58–8.44 (m, 2H),
6
8
.30–8.23 (m, 2H), 7.93–7.84 (m, 2H), 7.17–7.04 (m, 2H), 3.82 (s, 3H). Spectral data are in
2
0f
agreement with the literature.
1
2
2
-(1-Phenyl-1H-1,2,3-triazol-4-yl)pyridine (1g, R =Ph, R =2-Py). Following the general
procedure employing azidobenzene (119 mg, 1 mmol) and 2-ethynylpyridine (7b, 103 mg,
1
1
mmol). Off-white solid (186 mg, 0.837 mmol, 84%). H NMR (500 MHz, DMSO-d ) δ
6
9.34 (s, 1H), 8.66 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.13 (dt, J = 7.9, 1.1 Hz, 1H), 8.06–8.01
(m, 2H), 7.95 (td, J = 7.7, 1.8 Hz, 1H), 7.67–7.59 (m, 2H), 7.56–7.49 (m, 1H), 7.41 (ddd, J
20a
=
7.6, 4.8, 1.2 Hz, 1H). Spectral data are in agreement with the literature.
1
2
2
-(1-(p-Tolyl)-1H-1,2,3-triazol-4-yl)pyridine (1h, R =4-CH -C H , R =2-Py). Following
3 6 4
the general procedure employing 4-azidotoluene (133 mg, 1 mmol) and 2-ethynylpyridine
1
(7b, 103 mg, 1 mmol). Off-white solid (220 mg, 0.931 mmol, 93%). H NMR (500 MHz,
DMSO-d ) δ 9.27 (s, 1H), 8.66 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H), 8.14–8.10 (m, 1H), 7.95 (td,
6
J = 7.7, 1.8 Hz, 1H), 7.93–7.88 (m, 2H), 7.46–7.36 (m, 4H), 2.40 (s, 3H). Spectral data are
2
0a
in agreement with the literature.
-(1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)pyridine (1i, R =4-MeO-C H , R =2-Py).
1
2
2
6
4
Following the general procedure employing 1-azido-4-methoxybenzene (149 mg, 1 mmol)
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and 2-ethynylpyridine (7b, 103 mg, 1 mmol). H NMR (500 MHz, DMSO-d ) δ 9.23 (s,
6
1
H), 8.65 (d, J = 4.6 Hz, 1H), 8.13–8.08 (m, 1H), 7.97–7.91 (m, 3H), 7.40 (ddd, J = 7.5, 4.8,
.2 Hz, 1H), 7.18–7.13 (m, 2H), 3.84 (s, 3H). Off-white solid (239 mg, 0.947 mmol, 95%).
1
1
1
1
1
1
1
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1
1
2
2
2
2
2
2
2
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9
0
1
2
0a
Spectral data are in agreement with the literature.
1
2
2
-(1-(4-Nitrophenyl)-1H-1,2,3-triazol-4-yl)pyridine (1j, R =4-NO -C H , R =2-Py).
2 6 4
Following the general procedure employing 1-azido-4-nitrobenzene (164 mg, 1 mmol) and
1
2
-ethynylpyridine (7b, 103 mg, 1 mmol). Off-white solid (252 mg, 0.943 mmol, 94%). H
NMR (500 MHz, DMSO-d ) δ 9.57 (d, J = 2.4 Hz, 1H), 8.70–8.65 (m, 1H), 8.50–8.45 (m,
6
2
H), 8.40–8.33 (m, 2H), 8.14 (dt, J = 8.0, 1.1 Hz, 1H), 7.97 (td, J = 7.7, 1.8 Hz, 1H), 7.44
20a
(
ddd, J = 7.6, 4.8, 1.2 Hz, 1H). Spectral data are in agreement with the literature.
1
N,N-Dimethyl-4-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)aniline (1k, R =4-NMe -C H ,
2
6
4
2
R =2-Py). Following the general procedure employing 4-azido-N,N-dimethylaniline (162
1
mg, 1 mmol) and 2-ethynylpyridine (7b, 103 mg, 1 mmol). H NMR (500 MHz, DMSO-d )
6
δ 9.12 (s, 1H), 8.69–8.57 (m, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.97–7.88 (m, 1H), 7.83–7.75
(
m, 2H), 7.43–7.35 (m, 1H), 6.90–6.84 (m, 2H), 2.98 (s, 6H). Off-white solid (123 mg,
2
0a
0.462 mmol, 46%). Spectral data are in agreement with the literature.
1
2
2
-(1-Ethyl-1H-1,2,3-triazol-4-yl)pyridine (1l, R =Et, R =2-Py). Following a slightly
19g
modified literature procedure, ethyl iodide (702 mg, 4.5 mmol, 1 equiv) and sodium
azide (878 mg, 13.5 mmol, 3 equiv) were stirred in 35 mL of THF/water/tert-butanol
mixture (2:2:1 v/v/v) at room temperature for 1 h. Afterwards, Cu(PPh ) Br (52 mg, 55
3
3
µmol, 1 mol%) was added followed by addition of 2-ethynylpyridine (7b, 284 mg, 2.75
mmol, 0.6 equiv). The reaction mixture was stirred at 70 °C for 20 h. Products were
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extracted with dichloromethane and washed with brine and saturated water solution of
ammonium chloride. The organic layers were dried over sodium sulfate and evaporated.
Crude product was purified with column chromatography on silica (dichloromethane :
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0
acetone = 50:1→5:1). Brown oil (340 mg, 1.95 mmol, 71% relative to 2-ethynylpyridine).
1
H NMR (500 MHz, DMSO-d ) δ 8.63 (s, 1H), 8.59 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.02 (dt,
6
J = 7.8, 1.1 Hz, 1H), 7.89 (td, J = 7.7, 1.8 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H),
4
.45 (q, J = 7.3 Hz, 2H), 1.48 (t, J = 7.3 Hz, 3H). Spectral data are in agreement with the
2
0g
literature.
1
2
2
-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridine (1m, R =2-Pic, R =Ph). Following
the general procedure employing 2-(azidomethyl)pyridine (134 mg, 1 mmol) and
1
phenylacetylene (7a, 102 mg, 1 mmol). White solid (193 mg, 0.817 mmol, 82%). H NMR
(500 MHz, DMSO-d ) δ 8.66 (s, 1H), 8.55 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.89–7.81 (m,
6
3
H), 7.47–7.42 (m, 2H), 7.39–7.31 (m, 4H), 5.76 (s, 2H). Spectral data are in agreement
20a
with the literature.
1
2
2
-((4-(p-Tolyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine (1n, R =2-Pic, R =4-CH -C H ).
3 6 4
Following the general procedure employing 2-(azidomethyl)pyridine (134 mg, 1 mmol) and
1
1
1
7
-azido-4-methylbenzene (133 mg, 1 mmol). H NMR (500 MHz, DMSO-d ) δ 8.59 (s,
6
H), 8.55 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.77–7.72 (m, 2H),
.36 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H), 7.34–7.30 (m, 1H), 7.27–7.22 (m, 2H), 5.74 (s, 2H),
2.32 (s, 3H). White solid (200 mg, 0.799 mmol, 80%). Spectral data are in agreement with
2
0a
the literature.
-((4-(p-Tolyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine (1o, R =2-Pic, R =4-MeO-C H ).
1
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Following the general procedure employing 2-(azidomethyl)pyridine (134 mg, 1 mmol) and
1
-azido-4-methoxylbenzene (149 mg, 1 mmol). White solid (219 mg, 0.822 mmol, 82%).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
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2
2
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1
H NMR (500 MHz, DMSO-d ) δ 8.55 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H), 8.54 (s, 1H), 7.83 (td,
6
J = 7.7, 1.8 Hz, 1H), 7.81–7.76 (m, 2H), 7.36 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H), 7.34–7.30 (m,
1
H), 7.05–6.97 (m, 2H), 5.73 (s, 2H), 3.78 (s, 3H). Spectral data are in agreement with the
20a
literature.
2
-((4-(Pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridine (1p). Following the general
procedure employing 2-(azidomethyl)pyridine (134 mg, 1 mmol) and 2-ethynylpyridine (7b,
03 mg, 1 mmol). Off-white solid (136 mg, 0.573 mmol, 57%). Mp 76.4–77.3 °C. IR: 3424,
1
–
1
3149, 3056, 2997, 2958, 1593, 1475, 1440, 1420, 1228, 1195, 1149, 1090, 784, 728 cm .
1
H NMR (500 MHz, DMSO-d ) δ 8.68 (s, 1H, H-5), 8.60 (ddd, J = 4.8, 1.9, 1.0 Hz, 1H,
6
H-6''), 8.55 (ddd, J = 4.8, 1.9, 1.0 Hz, 1H, H-6'), 8.04 (dt, J = 7.9, 1.1 Hz, 1H, H-3''), 7.89
(td, J = 7.7, 1.8 Hz, 1H, H-4''), 7.83 (td, J = 7.7, 1.8 Hz, 1H, H-4'), 7.39–7.31 (m, 3H, H-5',
1
3
1
H-5'', H-3'), 5.80 (s, 2H, CH ). C{ H} NMR (126 MHz, DMSO-d ) δ 154.9 (C-2'), 149.9
2
6
(C-2''), 149.7 (C-6''), 149.5 (C-6'), 147.4 (C-4), 137.5 (C-4'), 137.3 (C-4''), 124.2 (C-5),
15
1
23.3 (C-5''), 123.1 (C-5'), 122.2 (C-3'), 119.5 (C-3''), 54.5 (CH ). N NMR (DMSO-d ) δ
2
6
3
65 (N-3), 349 (N-2), 313 (N-1'), 306 (N-1''), 248 (N-1). HRMS (ESI+): calcd. for
+
5
+
C H N [M + H] 238.1087, found 238.1085. Spectral and analytical data are in
13
12
2
2
agreement with those reported in the literature.
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Preparation of diaryliodonium salts 2
General experimental procedure for the preparation of diaryliodonium triflates 2a, 2c,
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2
6a
2
d, 2f, 2g, 2i–k (adopted from Ref. ) Aryl iodide (20 mmol, 1 equiv) and mesitylene
(3.13 g, 26 mmol, 1.3 equiv) were dissolved in dry dichloromethane (80 mL) in an
oven-dried round-bottomed flask. mCPBA (5.40 g, ~22 mmol, ~1.1 equiv, ~70 wt%) was
added to the stirred solution followed by dropwise addition of triflic acid (6.0 g, 40 mmol,
3
.5 mL, 2 equiv). The reaction mixture was stirred at room temperature overnight (16 h),
and concentrated under reduced pressure, and then triturated with diethyl ether. The
precipitate was collected by filtration and washed with diethyl ether to obtain pure
1
iodonium salt 2 as a white to off-white solid. H NMR data were in agreement with those
1
9,26a
reported in the literature.
bis(4-Methoxyphenyl)iodonium tetrafluoroborate (2e). Oven dried glass flask was
equipped with a magnetic stirring bar followed by the addition of mCPBA (7.40 g, ~30
mmol, ~1.5 equiv, ~70 wt%) and dry dichloromethane (100 mL). 4-Iodoanisole (4.68 g, 20
mmol, 1 equiv), anisole (2.60 g, 24 mmol, 1.2 equiv), and p-toluenesulfonic acid
monohydrate (4.57 g, 24 mmol, 1.2 equiv) were added. The reaction mixture was stirred at
reflux for 2 h. After cooling down to room temperature, the reaction mixture was
concentrated under reduced pressure and triturated with diethyl ether. After resting in a
fridge (–20 °C) overnight, the precipitate was collected by filtration. The filtrate was
dissolved in methanol (200 mL), followed by the addition of water-methanol (300 mL, 1:1,
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v/v) suspension of KBF (200 mmol). After 30 min of stirring, the precipitate was collected
4
by filtration, washed with water (6 × 250 mL), and dried to give pure iodonium salt 2e
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
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4
4
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(7.83 g, 18.3 mmol, 91%). NMR data were in agreement with those reported in the
2
9 1
literature. H NMR (500 MHz, DMSO-d ) δ 8.16–8.09 (m, 2H), 7.09–7.02 (m, 2H), 3.79
6
1
9
1
(
s, 3H). F{ H}NMR (471 MHz, DMSO-d ) δ –148.3 (d, J = 26 Hz, BF ). HRMS (ESI+):
6
4
+
+
calcd. for C H IN [M] 366.0713, found 366.0714.
1
7
21
(4-(Dimethylamino)phenyl)(mesityl)iodonium triflate (2h). This compound was
2
6b
prepared by a slightly modified procedure of Bielawski et al.,
N-oxidation at the amine nitrogen atom, as follows. 4-Iodo-N,N-dimethylaniline (12.35 g,
0 mmol) was dissolved in 200 mL of dry dichloromethane and TfOH (15.5 mL, 175 mmol,
to avoid potential
5
3.5 equiv) was added dropwise while stirring on an ice bath (the reaction is exothermic).
The stirring was continued for 15 minutes at room temperature, followed by the addition of
mesitylene (7.81 g, 65 mmol, 1.3 equiv). mCPBA (15.41 g, ~62.5 mmol, ~1.25 equiv, ~70
wt%) was added portionwise and the resulting reaction mixture was refluxed for 1 h. After
cooling down to room temperature, the reaction mixture was filtered through a pad of basic
Al O and eluted with a sufficient amount of a mixture of MeOH : dichloromethane 1:1
2
3
(v/v) to isolate all product from the pad (TLC monitoring). The eluate was concentrated
under reduced pressure and diethyl ether was added to precipitate pure product 2h as a
1
white solid, which was isolated by filtration (19.7 g, 38.2 mmol, 76%). H NMR (500 MHz,
DMSO-d ) δ 7.80–7.70 (m, 2H, H-2, H-6), 7.16 (s, 2H, H-3', H-5'), 6.72–6.64 (m, 2H, H-3,
6
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5
5
6
1
3
1
H-5), 2.93 (s, 6H, NMe ), 2.60 (s, 6H, o-CH ), 2.27 (s, 3H, p-CH ). C{ H} NMR (126
2
3
3
MHz, DMSO-d ) δ 151.9 (C-4), 142.6 (C-4'), 141.2 (C-2', C-6'), 136.3 (C-2, C-6), 129.6
6
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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6
7
8
9
0
1
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0
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0
(
C-3', C-5'), 123.4 (C-1'), 114.4 (C-3, C-5), 96.1 (C-1), 39.6 (NMe ) 26.3 (CH -2', CH -6'),
2 3 3
1
5
19
1
20.5 (CH -4'). N NMR (DMSO-d ) δ 57 (NMe ). F{ H} NMR (471 MHz, DMSO-d ) δ
3
6
2
6
–
77.73 (TfO).
Diphenyliodonium salts 2b and 2l. A mixture of iodobenzene (4.08 g, 20 mmol, 1 equiv)
and benzene (2.03 g, 26 mmol, 1.3 equiv) was dissolved in dry dichloromethane (80 mL) in
an oven-dried round-bottomed flask. mCPBA (5.40 g, ~22 mmol, ~1.1 equiv, ~70 wt%)
was added to the solution followed by dropwise addition of boron trifluoride etherate (9.8
mL, 78 mmol, 3 equiv; for the preparation of 2b) or triflic acid (6.0 g, 40 mmol, 3.5 mL, 2
equiv; for the preparation of 2l). The reaction mixture was stirred overnight (16 h) and
concentrated under reduced pressure. Diethyl ether was added and the precipitate was
collected by filtration and washed with diethyl ether to obtain pure iodonium salt 2b (5.09 g,
1
19
1
3.8 mmol, 69 %) or 2l (6.12 g, 14.2 mmol, 71 %) as a white solid. H and F NMR data
1
9,26a
were in agreement with those reported in the literature.
General procedure for the preparation of diaryliodonium triflates 2m–q
A mixture of aryl iodide (20 mmol) and mesitylene (3.13 g, 26 mmol, 1.3 equiv) was
dissolved in dry dichloromethane (80 mL) in an oven-dried round-bottomed flask. mCPBA
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(
5.40 g, ~22 mmol, ~1.1 equiv, ~70 wt%) was added, followed by the addition of 40 mmol
(2 equiv) of selected acid (TsOH · H O for 2m; BF OEt for 2n; HClO for 2o; H SO for
2
3
2
4
2
4
1
1
1
1
1
1
1
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1
2
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5
5
6
0
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0
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9
0
2
p; 55% water solution of HPF for 2q). The reaction mixture was stirred overnight (16 h)
6
and then concentrated under reduced pressure. After the addition of diethyl ether the
precipitate was formed, which was collected by filtration and washed with diethyl ether to
1
obtain pure iodonium salts 2m–q as white to off-white solids. H NMR data were in
1
9,26a
agreement with those reported in the literature.
General procedure for arylation of triazoles (Tables 2, 5, 6)
ACE glass reaction tube equipped with a magnetic stirring bar, pre-dried in an oven at
1
30 °C and cooled in a stream of nitrogen gas, was charged with the corresponding triazole
1
(0.2 mmol, 1 equiv), diaryliodonium salt 2 (0.36 mmol, 1.8 equiv), and anhydrous CuSO4
(3 mg, 0.02 mmol, 10 mol%). The reaction mixture was flushed with nitrogen gas, sealed,
and placed into a preheated metal block at 130 °C. The reaction mixture was stirred
overnight (17 h) at 130 °C to obtain tar-like crude product. After cooling down to ambient
temperature, the crude product was dissolved in acetone and triturated with light petroleum
to obtain triazolium salt 3–5. Analytically pure triazolium salts 3–5 were obtained by using
column chromatography on silica (MeOH : dichloromethane = 1:30→1:10, v/v).
Triazolium salts 3a–o (Table 2)
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1
,3,4-Triphenyl-1H-1,2,3-triazol-3-ium triflate (3a, R =R =R =H). Following the
general procedure employing 1,4-diphenyl-1H-1,2,3-triazole (1a, 44 mg, 0.2 mmol) and
mesityl(phenyl)iodonium triflate (2a, 170 mg, 0.36 mmol). Analytically pure samples were
obtained using column chromatography on silica (MeOH : dichloromethane = 1:10, v/v).
Off-white solid (87 mg, 0.194 mmol, 97%). Mp 106–108 °C. IR 3106, 3067, 1604, 1491,
–1
1
1
255, 1230, 1169, 1157, 1079, 763, 695, 634 cm . H NMR (500 MHz, DMSO-d ) δ 10.07
6
(
s, 1H, H-5), 8.20–8.14 (m, 2H, H-2', H-6'), 7.86–7.79 (m, 3H, H-3', H-5', and H-4'), 7.77–
7.72 (m, 3H, H-2'', H-6'', and H-4''), 7.69 (ddd, J = 7.6, 4.5, 1.8 Hz, 2H, H-3'', H-5''), 7.62–
.58 (m, 1H, H-4'''), 7.58–7.53 (m, 2H, H-3''', H-5'''), 7.49–7.45 (m, 2H, H-2''', H-6''').
7
13
1
C{ H} NMR (126 MHz, DMSO-d ) δ 143.4 (C-4), 134.8 (C-1'), 133.9 (C-1''), 132.32
6
(
C-4''), 132.26 (C-4'), 131.7 (C-4'''), 130.7 (C-3', C-5'), 130.2 (C-3'', C-5''), 129.4 (C-3''',
C-5'''), 129.3 (C-2''', C-6'''), 127.7 (C-5), 126.3 (C-2'', C-6''), 122.5 (C-1'''), 121.7 (C-2',
1
5
19
1
C-6'). N NMR (DMSO-d ) δ 254 (N-1), 249 (N-3). F{ H} NMR (471 MHz, DMSO-d )
6
6
+
+
δ –77.76 (TfO). HRMS (ESI+): calcd. for C H N [M ] 298.1339, found 298.1349.
2
0
16
3
–
–
HRMS (ESI–): calcd. for CF O S [M ] 148.9526, found 148.9530.
3
3
1
2
3
3,4-Diphenyl-1-(p-tolyl)-1H-1,2,3-triazol-3-ium triflate (3b, R =CH , R =R =H).
3
Following the general procedure employing 4-phenyl-1-(p-tolyl)-1H-1,2,3-triazole (1b, 47
mg, 0.2 mmol) and mesityl(phenyl)iodonium triflate (2a, 170 mg, 0.36 mmol). Analytically
pure samples were obtained using column chromatography on silica (MeOH :
dichloromethane = 1:10, v/v). Off-white solid (90 mg, 0.194 mmol, 97%). Mp 125–128 °C.
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IR 3099, 3074, 1610, 1566, 1512, 1490, 1455, 1282, 1255, 1222, 1168, 1149, 1029, 820,
–1
1
7
66, 694 cm . H NMR (500 MHz, DMSO-d ) δ 10.03 (s, 1H, H-5), 8.09–8.04 (m, 2H,
6
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1
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H-2', H-6'), 7.76–7.73 (m, 3H, H-2'', H-6'' and H-4''), 7.69 (ddt, J = 8.8, 5.7, 1.5 Hz, 2H,
H-3'', H-5''), 7.64–7.61 (m, 2H, H-3', H-5'), 7.61–7.58 (m, 1H, H-4'''), 7.55 (ddd, J = 8.5,
1
3
1
7
.1, 1.0 Hz, 2H, H-3''', H-5'''), 7.49–7.45 (m, 2H, H-2''', H-6'''), 2.48 (s, 3H, CH ). C{ H}
3
NMR (126 MHz, DMSO-d ) δ 143.3 (C-4), 142.5 (C-4'), 134.0 (C-1''), 132.5 (C-1'), 132.2
6
(C-4''), 131.6 (C-4'''), 131.0 (C-3', C-5'), 130.2 (C-3'', C-5''), 129.33 (C-3''', C-5'''), 129.30
(C-2''', C-6'''), 127.4 (C-5), 126.3 (C-2'', C-6''), 122.6 (C-1'''), 121.4 (C-2', C-6'), 20.8 (CH3).
1
5
19
1
N NMR (DMSO-d ) δ 255 (N-1), 249 (N-3). F{ H} NMR (471 MHz, DMSO-d ) δ –
6
6
+
+
7
7.75 (TfO). HRMS (ESI+): calcd. for C H N [M ] 312.1495, found 312.1497. HRMS
21 18 3
–
–
(
ESI–): calcd. for CF O S [M ] 148.9526, found 148.9521.
3 3
The synthesis of triazolium salt 3b (871 mg, 1.89 mmol, 94%) was also conducted on a
larger scale by general procedure described above with
-phenyl-1-(p-tolyl)-1H-1,2,3-triazole (1b, 471 mg, 2 mmol), phenyl(mesityl)iodonium
4
triflate (2a, 1700 mg, 3.6 mmol, 1.8 equiv), and anhydrous CuSO (32 mg, 0.2 mmol, 10
4
mol%).
4
-Phenyl-1-(p-tolyl)-3-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-3-ium triflate (3c,
1
2
3
R =CH , R =H, R =4-CF ). Following the general procedure employing
3
3
4-phenyl-1-(p-tolyl)-1H-1,2,3-triazole
(1b,
47
mg,
0.2
mmol)
and
mesityl(4-(trifluoromethyl)phenyl)iodonium triflate (2c, 194 mg, 0.36 mmol). Analytically
pure samples were obtained using column chromatography on silica (MeOH :
dichloromethane = 1:10, v/v). Off-white solid (93 mg, 0.176 mmol, 88%). Mp 69–72 °C. IR
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