Regioselective halogenation of 2-substituted-1,2,3-triazoles via sp 2 C-H activation

Article abstract of DOI:10.1039/c3ob41558a

A highly regioselective halogenation of 2-substituted-1,2,3-triazoles was developed via sp² C-H activation. This method is compatible with halogen atoms, as well as electron-donating and electron-withdrawing groups. Meanwhile, the strategy is a

Full text of DOI:10.1039/c3ob41558a

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Regioselective halogenation of 2-substituted-
1,2,3-triazoles via sp2 C–H activation†
Cite this: Org. Biomol. Chem., 2013, 11,
7830
Qingshan Tian,a Xianmin Chen,a Wei Liu,a Zechao Wang,a Suping Shia and
Chunxiang Kuang*a,b
Received 30th July 2013,
Accepted 2nd September 2013
DOI: 10.1039/c3ob41558a
www.rsc.org/obc
A
highly regioselective halogenation of 2-substituted-1,2,3-
triazoles was developed via sp2 C–H activation. This method is
compatible with halogen atoms, as well as electron-donating and
electron-withdrawing groups. Meanwhile, the strategy is also
efficient for the synthesis of a key intermediate of Suvorexant.
Aromatic halides, important starting materials utilized in
complex structure and natural product syntheses, are exten-
sively used in cross-coupling.1 By far the most prevalent strat-
egies for preparing aromatic halides are still the classic
directed ortho lithiation, electrophilic aromatic substitution,
and the Sandmeyer reaction.2 However, these methods usually
suffer from many limitations including poor regioselectivity,
low yields, harsh reaction conditions, and tedious and danger-
ous reaction procedures. In the past decade, Pd(II)-catalyzed
C–H halogenation utilizing directing groups has been
studied extensively.3 High yields and monoselectivities could
be achieved with the assistance of some directing groups,
including amides,3a,e,i pyridines,3c,f,g carboxylic acids,3d and
oxazolines.3h
Scheme 1 Halogenation of 2-substituted-1,2,3-triazoles.
remain a challenge.5 In 2012, Mongin for the first time
reported
a deproton-iodination of 2-substituted-1,2,3-tri-
azoles.6 However, this method was limited by a poor regios-
electivity and a low yield, as well as harsh reaction conditions
(Scheme 1a). Therefore, a general and practical method that
enables the direct halogenation of 2-substituted-1,2,3-triazoles
is of prime synthetic value. In this paper, we report on a palla-
dium-catalyzed highly regioselective halogenation of 2-substi-
tuted-1,2,3-triazoles using NXS (X = Cl, Br, I) as halogenating
reagents (Scheme 1b).
2-Substituted-1,2,3-triazoles, essential structural motifs in
material science and medicinal chemistry (Fig. 1 Suvorexant
and β3-AR agonist),4 have unique chemical and structural pro-
perties. The synthesis and derivation of such compounds
Based on the key contributions of Sanford and Ackermann,7
the 2-phenyl-1,2,3-triazole (1a) and NBS (1.1 equiv.) reaction
was initially selected to optimize the reaction conditions
(Table 1). The reaction did not occur without the catalyst
(Table 1, entry 1). At 100 °C, with Pd(OAc)2 as a catalyst and no
additive added, ortho-bromination product 2a was obtained
with 31% yield, and no reaction occurred in position 4 or 5 of
the triazole cycle. When PivOH (1.0 eq.) was added, the yield
increased to 88%. The yield increased to 90% (Table 1, entry 4)
when the reaction was performed with half the amount of
PivOH (0.5 eq.). No evident yield improvement was achieved by
increasing the catalyst loading to 10 mol% (Table 1, entry 5).
By contrast, when the catalyst loading was decreased to 3 mol
%, the yield was reduced to 79% (Table 1, entry 6). Pd(OAc)2
seemed to be an efficient catalyst for this transformation, and
other palladium species such as Pd(TFA)2, PdCl2 and
Pd(PPh3)4 were tested and found to be substantially less
Fig. 1 Present medicines containing 2-substituted-1,2,3-triazoles.
aDepartment of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092,
China
bKey Laboratory of Yangtze River Water Environment, Ministry of Education,
Siping Road 1239, Shanghai 200092, China. E-mail: kuangcx@tongji.edu.cn
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob41558a
7830 | Org. Biomol. Chem., 2013, 11, 7830–7833
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Table 1 Optimization of the bromination conditionsa
Table 2 ortho-Bromination of 2-substituted-1,2,3-triazolesa
Entry
1
1
Product (2)
Yieldb (%)
90
Entry
Catalyst
Additive (eq.)
Solvent
Yieldb (%)
1
2
3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PivOH (0)
PivOH (1)
31
88
90
92
79
55
20
Trace
55
50
67
56
45
73
61
55
86
2
3
4
5
94
91
77
69
4
PivOH (0.5)
PivOH (0.5)
PivOH (0.5)
PivOH (0.5)
PivOH (0.5)
PivOH (0.5)
TFA (0.5)
AcOH (0.5)
TsOH (0.5)
MsOH (0.5)
CF3SO3H (0.5)
PivOH (0.5)
PivOH (0.5)
PivOH (0.5)
5c
6d
7
8
9
10
11
12
13
14
15
16
17
18
CH3CN
Dioxane
AcOH
6
7
70
68
a Reaction conditions: 1a (0.5 mmol), NBS (0.55 mmol), Pd(OAc)2
(0.025 mmol), additive (0.25 mmol), solvent (2.0 mL), stirred at 100 °C
over 18 h. b Isolated yields. c Pd(OAc)2 (0.05 mmol). d Pd(OAc)2
(0.015 mmol).
effective (Table 1, entries 7–9). An acidic additive was proven to
be essential for this reaction. Some additives such as PivOH,
TFA, AcOH, TsOH, MsOH, and CF3SO3H were screened among
which PivOH gave the best result in this reaction. Compared
with other solvents (DCE, CH3CN, dioxane and AcOH), toluene
was the most suitable for this reaction (Table 1, entries 15–18).
Under the optimized conditions, the scope of 2-substituted-
1,2,3-triazoles bearing diverse substituents on the arene ring
was examined (Table 2). Electron-rich substituents, such as
methyl and methoxyl, were well tolerated, resulting in the for-
mation of the desired products in high yields (Table 2, entries
2 and 3). Other electron-deficient substrates bearing the ester
group, a potential second chelating group, could undergo bro-
mination in moderate yields (Table 2, entries 4 and 5).
Notably, bromination occurred at the less sterically hindered
ortho-position in moderate yields for substrates bearing substi-
tuents in the meta position (Table 2, entries 5, 6, and 7). The
inclusion of potential reactive groups such as halogen atoms
(Table 2, entries 7, 8, and 11) further highlighted the func-
tional group compatibility of this catalytic system. Moreover,
expanding the scope from the phenyl to the naphthyl system
facilitated the formation of the 2-position bromination
product with 83% yield (Table 2, entry 9). An additional aro-
matic ring on the 2-substituted-1,2,3-triazoles was tolerated as
well, and bromination occurred efficiently (Table 2, entries 10
and 11). Notably, when 1.1 equivalent of NBS was added to the
reaction system, only monohalogenation occurred, but the
presence of excess NBS could result in a good di-bromination
8
9
70
86
10
11
97
74
12c
13
70
a Reaction conditions: 1a (0.5 mmol), NBS (0.55 mmol), Pd(OAc)2
(0.025 mmol), PivOH (0.25 mmol), toluene (2.0 mL), stirred at 100 °C
over 18 h. b Isolated yields. c 2.2 eq. NBS was used.
product yield (Table 2, entry 12). The bromination of 1-substi-
tuted-1,2,3-triazoles (1 m) did not occur under identical con-
ditions (Table 2, entry 13).
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Table 3 ortho Chlorination and iodination of 1a
Scheme 2 Halogenation of 2-substituted-1,2,3-triazole N-oxides.
under otherwise identical conditions. At an increased reac-
tion temperature (120 °C), we observed excellent yields of
monohalogenated products (6). Notably, only mono-haloge-
nated products were obtained even when 2.2 equivalents of
halogenating reagents were added to the reaction system. The
second ortho-halogenation was completely inhibited, which is
presumably attributed to the steric interactions between the
oxygen atom in the N − 1 position and the halogen atom.
Compounds (6) were readily deoxygenated and halogenated
2-substituted-1,2,3-triazoles were produced using typical
methods in high yields.
The application of transition-metal-catalyzed C–H function-
alization in the synthesis of medicinal compounds remains a
challenge.8 The synthesis of compound 7, a part of the existing
Suvorexant pharmacophore,9 previously depended on the
copper-catalyzed amination of 2-iodo-5-methylbenzoic acid. The
high cost, low regioselectivity, and tedious purification for
isomer removal limit the rapid synthesis of Suvorexant.10
Currently, 2-substituted-1,2,3-triazoles 2b can be readily converted
to compound 7 through simple synthetic operations (Scheme 3).11
Based on our results and previous studies on the palla-
dium-catalyzed halogenation of aromatic compounds,7,12
we proposed a catalytic cycle for the halogenation of 2-substi-
tuted-1,2,3-triazoles (Scheme 4). First, 1,2,3-triazole
1 is
a Reaction conditions: 1a (0.5 mmol), NBS (0.55 mmol), Pd(OAc)2
(0.025 mmol), PivOH (0.25 mmol), toluene (2.0 mL), stirred at 100 °C
over 18 h. b Isolated yields.
We then investigated the chlorination and iodination of
2-substituted-1,2,3-triazoles under similar reaction conditions
(Table 3). Similar to the ortho-bromination described above,
we used the catalytic system in the ortho-chlorination for most
of the 2-substituted-1,2,3-triazoles, despite which ortho-iodina-
tion remained efficient. Electron-rich and electron-withdraw-
ing groups in the para or meta positions of the aromatic ring
were well tolerated, resulting in good to moderate yields of the
desired products. However, substituents in the meta position
facilitated chlorination, and iodination still occurred at a less
sterically hindered ortho-position with moderate yield. Good
tolerance to the chemically active functional groups was also
revealed. For example, halogen atoms and ester groups on sub-
strates remained after the palladium-catalyzed reaction. Another
aromatic phenyl group on the triazoles was also tolerated.
Scheme 3 Synthesis of precursor 7 of Suvorexant.
Additionally, we examined the possibility of performing
the ortho-halogenation of 2-substituted-1,2,3-triazole N-oxides
(Scheme 2). The ortho-halogenation of N-oxide 5 was sluggish Scheme 4 Plausible reaction mechanism.
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coordinated with Pd(OAc)2 to form cyclopalladated intermedi-
ate A. The presumed participation of acetate in aromatic
proton abstraction to generate an intermediate B is followed
by the addition of NXS to form C. Finally, subsequent reduc-
tive elimination occurs, yielding the ortho-halogenated product
2 and the regenerated PdII catalyst.
In summary, the first example of a palladium-catalyzed
ortho-halogenation of 2-substituted-1,2,3-triazoles via C–H acti-
vation was developed. This catalytic system is compatible with
the halogen atom, as well as with electron-rich and electron-
withdrawing groups. The unprecedented reaction provides
potential access to valuable structures for drug discovery and
materials science.
The present work was supported by the NSFC (no. 21272174),
the Key Projects of Shanghai in Biomedicine (no. 08431902700)
and the Scientific Research Foundation of the State Education
Ministry for Returned Overseas Chinese Scholars. We would
like to also thank the Center for Instrumental Analysis, Tongji
University, China.
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