Solvent-free pivalic acid/copper chloride jointly promoted chlorination of 1,2,3-triazoles

Article abstract of DOI:10.1055/s-0032-1317446

A novel chlorination reaction on the 5-position of 1,2,3-triazoles, directly from 5H-substituted 1,2,3-triazoles was developed by using copper(II) chloride in pivalic acid. A series of triazoles were thus chlorinated in low to good yields.

Full text of DOI:10.1055/s-0032-1317446

LETTER
▌2623
lSetoterlvent-Free Pivalic Acid/Copper Chloride Jointly Promoted Chlorination of
1,2,3-Triazoles
Chlorination of 1,2,3-Triazoles
Christophe Menendez,a,b Nathalie Saffon,c Christian Lherbet,*a,b Michel Baltas*a,b
a
CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, SPCMIB, UMR-5068, 118 Route de Narbonne,
31062 Toulouse cedex 9, France
b
Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, SPCMIB, 118 route de
Narbonne, 31062 Toulouse cedex 9, France
c
Université de Toulouse, UPS, and CNRS, ICT FR2599, 118 route de Narbonne, 31062 Toulouse, France
Fax +33(5)61556011; E-mail: lherbet@chimie.ups-tlse.fr; E-mail: baltas@chimie.ups-tlse.fr
Received: 26.06.2012; Accepted after revision: 20.09.2012
1). Among them, the interception of 5-cuprated 1,2,3-tri-
Abstract: A novel chlorination reaction on the 5-position of 1,2,3-
azoles with an electrophile, for example ICl or I2, permits
triazoles, directly from 5H-substituted 1,2,3-triazoles was devel-
the desired 5-iodo-1,2,3-trisubstituted triazoles to be de-
oped by using copper(II) chloride in pivalic acid. A series of tri-
azoles were thus chlorinated in low to good yields.
livered.9 Another method involves coupling functional-
ized alkynes (i.e., 1-iodoalkynes) with azides, as
Key words: chlorination, triazole, copper chloride, pivalic acid
described by Fokin et al.10
N
N
R1
R2 N3 X = Cl, Br, I
R1
I
1,2,3-Triazoles are fundamental motifs in numerous ap-
plications, particularly in biological areas.1,2 Over the
years, major advances have been accomplished for their
synthesis, especially to improve regioselectivities and re-
duce reaction time through application of the Huisgen 1,3-
dipolar cycloaddition reaction. Sharpless and Meldal re-
ported that this reaction could be accelerated by the use of
copper catalysts to afford 1,4-disubstituted 1,2,3-tri-
azoles.3,4 Recently, the family of catalytic alkyne-azide
cycloaddition reactions has expanded with the use of ru-
thenium complexes [Cp*RuCl] enabling 1,5-disubstituted
1,2,3-triazoles to be obtained with high regioselectivities.5
ref. 9
ref. 10
X = I
N
R2
R2 N3
R1
X
our work
X = Cl
N
N
N
R2
R1
H
Scheme 1 Synthetic approaches to halogenated triazoles
With the increasing importance of triazoles in medicinal
chemistry, it has become necessary to develop new tech-
niques to obtain halogenated 1,2,3-triazoles. These com-
pounds can be considered as useful synthons in the
elaboration of 5-substituted 1,2,3-triazoles. Wu et al. re-
ported a Suzuki cross-coupling reaction of iodo-1,2,3-tri-
azoles with arylboronic acid catalyzed by palladium(0),
affording 5-aryl-1,2,3-triazoles.6 Interestingly, 5-haloge-
nated 1,2,3-triazoles might be valuable compounds with
biological activities, as was recently reported for haloge-
nated aryl derivatives by Diederich et al.7 The authors
have reported the conception of halogenated compounds
with higher affinities, depending on the nature of halo-
gens, for the active site of human Cathepsin L and MEK1
kinase. In the same way, Leonidas et al. showed that hal-
ogen interactions could be used in the rational design of
potent halogen derivatives of glucosyl(hydro)quinones
that can be used to inhibit glycogen phosphorylase activi-
ty.8 Various useful methodologies have been developed
for the synthesis of 5-halogenated 1,2,3-triazoles (Scheme
In this paper, we wish to report for the first time the chlo-
rination of 1,2,3-triazoles at the 5-position, directly from
5H-triazoles. The reaction is performed in the presence of
stoichiometric amounts of copper(II) chloride in pivalic
acid.
We initially investigated the reaction of 4-hexyl-1-
phenethyl-1H-1,2,3-triazole under various conditions. All
reactions were followed by TLC until no further evolution
was observed. Selected results are presented in Table 1.
Copper(II) chloride was initially used as a source of halo-
gen. The first experiment was carried out in the presence
of CuCl2 and pivalic acid in toluene to give the corre-
sponding chlorinated product in 39% yield (entry 1). It is
noteworthy that when halogenation was performed in the
presence of CuCl2 (1 equiv) in toluene, and in the absence
of pivalic acid, no product was observed (entry 2). Inter-
estingly, the same reaction conducted in the presence of
only pivalic acid as additive led to successful halogena-
tion of triazole; nevertheless a substantial amount of start-
ing material was recovered (entry 3). Longer reaction time
(46 h) afforded the product in 62% yield (entry 4). The
presence of pivalic acid was crucial, because no reaction
occurred when it was omitted (entry 5); when pivalic acid
was replaced by acetic acid, only traces of the product
SYNLETT 2012, 23, 2623–2626
Advanced online publication: 18.10.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317446; Art ID: ST-2012-D0545-L
© Georg Thieme Verlag Stuttgart · New York

2624
C. Menendez et al.
LETTER
Table 1 Synthesis of 5-Chlorotriazolea
N
N
N
N
N
CuX2
N
conditions
Cl
Entry
CuX2 (equiv)
Additive (mg)
Solvent (mL)
Temp (°C)
Time (h)
Yield (%)b
1
2
CuCl2 (1)
CuCl2 (1)
CuCl2 (1)
CuCl2 (1)
CuCl2 (1)
CuCl2 (1)
CuCl2 (2)
CuCl (1)
–
PivOH (500)
–
toluene (3)
140
23
23
23
46
46
46
46
23
23
23
23
23
39
toluene (3)
Reflux
140
NR
3
PivOH (500)
PivOH (500)
–
–
40c
4
–
140
62
5
–
140
NR
6
AcOH (500)
PivOH (500)
PivOH (500)
–
Reflux
140
trace
7
–
46
8
–
140
36
9
NaCl (2 equiv), PivOH (500)
LiCl (2 equiv), PivOH (500)
LiCl (2 equiv), PivOH (500)
–
140
0d
10
11
12
–
–
140
0d
CuCl2 (0.2)
–
–
140
5
DDQ (2 equiv), LiCl (2 equiv)
toluene (3)
110
no product
a Substrate (0.3 mmol) was used.
b Isolated yield.
c Starting material (30%) was also recovered.
d Checked by HPLC.
were observed (entry 6). Increasing the amount of cop-
per(II) salts afforded the desired monochlorinated com-
pound in 46% yield along with unidentified side products
(entry 7). Use of copper(I) salt did not result in a signifi-
cant difference in yield compared with the result obtained
using copper(II) (entry 8). Finally, other sources of halo-
gen such as NaCl or LiCl, either in the presence or ab-
sence of copper, were not suitable for the reaction (entries
9–11).11 Using 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ) as an oxidant in the presence of LiCl
(2 equiv) was found to be ineffective after 23 hours of re-
action (entry 12).
The scope and limitations of this methodology were then
explored by using different triazoles, as shown in Table
2.12 All reactions were conducted for 46 h at 140 °C in the
presence of pivalic acid. First, 1,4-disubstituted triazoles
bearing an alkyl chain at the carbon or nitrogen atom were
tested (entries 1–4). The chlorinated compounds were ob-
tained in fair to moderate yields (43–62%). Starting mate-
rial was observed by TLC along with degradation
products that were not characterized.
Figure 1 X-ray crystal structures of 8a and 13. Thermal ellipsoids are
shown at the 50% probability level. Hydrogen atoms are omitted for
clarity (crystallographic data for 8a and 13 are provided in the Sup-
porting Information).
Triazole systems possessing electron-rich arenes bearing
one (or two) methoxy groups on the aromatic moiety were
tested. Compounds bearing a single 4-OMe group on the
phenyl ring led to moderate results (Table 2, entries 5 and
6). In contrast, the 2-methoxy-substituted compound (en-
try 7) afforded the corresponding chlorinated adduct in
Synlett 2012, 23, 2623–2626
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chlorination of 1,2,3-Triazoles
Table 2 Scope of the Reaction (continued)
2625
N
N
N
N
+ CuCl2
– CuCl
+ CuCl2
N
N
N
R2
N
N
N
R2
R2
N
(a)
(b)
N
N
CuCl2 (1 equiv)
– CuCl, HCl
N
N
R1
R1
R1
N
R2
N
R2
H
Cl
PivOH, 140 °C
46 h
R1
R1
Cl
H
Cl
Cu(II)Cl2
Cu(I)
Cl
– CuCl, – H+
N
N
N
Entry Product
Yield (%)
29
N
N
N
R2
N
R2
R2
R1
R1
R1
N
N
OMe
H
Cl
8
N
7
7
Scheme 2 Proposed mechanisms for the chlorination of 1,2,3-tri-
azoles
Cl
N
N
N
low yield (29%) along with degradation products. Finally,
use of the triazole bearing a 3,4-dimethoxy electron-rich
aryl moiety (entry 8) led to a mixture of compounds that
were identified after purification by silica gel chromatog-
raphy as the aryl halide 8b (31% yield) and the dichlori-
nated derivative 8a (53% yield) . The structure of the
latter compound was confirmed by X-ray crystallographic
analysis (Figure 1).13 This result shows that halogenation
of the aryl moiety is favored over the triazolo moiety.
Stahl and co-workers14 have recently reported mono- or
dihalogenation of 1,3-dimethoxybenzene in the presence
of CuCl2 (25–200 mol%) in O2 and acetic acid at 110 °C.
8
MeO
Cl
MeO
Cl
8a
8b
53 (X-ray)
31
8
N
N
N
8
MeO
MeO
Cl
N
N
6
8
N
9
9
53
60
Cl
Table 2 Scope of the Reaction
N
N
N
N
CuCl2 (1 equiv)
N
N
R2
N
R2
N
N
10
10
PivOH, 140 °C
46 h
R1
R1
Cl
H
Cl
Cl
Entry Product
Yield (%)
62
N
N
N
11
11
49
N
N
Cl
4
Cl
N
1
1
8
4
Cl
N
N
N
N
12
13
12
13
30
7
N
N
2
3
4
2
3
4
5
43
47
53
46
Cl
Cl
N
N
N
N
N
N
39 (X-ray)
Cl
Cl
Cl
4
N
N
N
N
N
14
14
mixture
N
10
Cl
N
N
N
4
Triazoles for which the phenyl ring was substituted with
methyl or chlorine groups were also evaluated and afford-
ed the corresponding chlorinated compounds in either fair
yields (Table 2, entries 9, 10, and 11) or low yields (entry
12). Finally, triazole systems possessing aromatic remote
groups at both the 1- and 4-positions led to either a low
yield or a mixture (entries 13 and 14). The structure of
5
Cl
N
MeO
N
N
8
6
6
43
Cl
MeO
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2623–2626

2626
C. Menendez et al.
LETTER
(8) Alexacou, K.-M.; Zhang, Y. Z.; Praly, J.-P.; Zographos, S.
E.; Chrysina, E. D.; Oikonomakos, N. G.; Leonidas, D. D.
Bioorg. Med. Chem. 2011, 19, 5125.
(9) (a) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005,
1314. (b) Malnuit, V.; Duca, M.; Manout, A.; Bougrin, K.;
Benhida, R. Synlett 2009, 2123.
(10) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.;
Fokin, V. V. Angew. Chem. Int. Ed. 2009, 48, 8018.
(11) Bromination of triazole was also performed with CuBr2
without success.
(12) General procedure: To a solution of triazole (0.3 mmol, 1
equiv) in pivalic acid (500 mg), was added CuCl2 (1 equiv)
at room temperature. The reaction mixture was warmed to
140 °C and stirred under air for 46 h. Pivalic acid was
evaporated under reduced pressure and the residue was
dissolved in EtOAc. The organic layer was washed with
water (3 × 20 mL), dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by flash
chromatography.
compound 13 was also confirmed by X-ray crystallo-
graphic analysis.15
Although there is no precedent in the literature for direct
chlorination of 1,2,3-triazoles, Stahl et al. indicated in a
recently published review16 various single electron trans-
fer (SET) mechanisms for halogenation of electron-rich
arenes. As substituted triazoles can be considered elec-
tron-rich heterocycles, we would tentatively propose two
mechanisms. The first involves formation of a triazole
radical cation that would undergo chlorination of the ring
through reaction with CuCl2 and loss of a proton, as pro-
posed for electron-rich arenes (Scheme 2a).17 The second
possibility could be a reaction initiated by a SET from the
tertiary amine function of triazole chelated to copper to
form an amine radical cation that could undergo intramo-
lecular chlorination and loss of a proton, as proposed for
chelate directed C–H oxidation reactions (Scheme 2b).18
Pivalic acid, which is more basic and has a higher boiling
point than acetic acid, is crucial for the reaction to occur.
It could intervene by forming a three partner intermediate
(triazole/pivalate/copper), perhaps in a manner similar to
palladium complexes in the concerted metalation-deprot-
onation (CMD) pathways.19 Nevertheless, its exact role
has still to be elucidated.
5-Chloro-4-hexyl-1-phenethyl-1H-1,2,3-triazole (1):
Yield: 62%; light-yellow oil; 1H NMR (CDCl3): δ = 7.26 (m,
3 H), 7.12 (dd, J = 7.6, 1.8 Hz, 2 H), 4.50 (t, J = 7.5 Hz, 2 H),
319 (t, J = 7.2 Hz, 2 H), 2.62 (t, J = 6.9 Hz, 2 H), 1.67 (m,
2 H), 1.30 (m, 6 H), 0.89 (t, J = 6.7 Hz, 3 H); 13C NMR
(CDCl3): δ = 136.7, 128.72, 128.71, 127.0, 49.5, 36.0, 31.5,
28.7, 28.4, 24.5, 22.5, 14.0; HRMS: (DCI/CH4): m/z calcd
for C16H23N3Cl: 292.1581; found: 292.1605.
1-Benzyl-5-chloro-4-hexyl-1H-1,2,3-triazole (3): Yield:
47%; yellow oil; 1H NMR (CDCl3): δ = 7.28 (m, 5 H), 5.48
(s, 2 H), 2.63 (t, J = 7.6 Hz, 2 H), 1.68 (m, 2 H), 1.30 (m,
6 H), 0.86 (t, J = 6.7 Hz, 3 H); 13C NMR (CDCl3): δ = 144.1,
134.1, 128.9, 128.4, 127.7, 122.3, 51.9, 31.4, 28.8, 28.4,
24.6, 22.5, 14.0, HRMS: (DCI/CH4): m/z calcd for
C15H21N3Cl: 278.1424; found: 278.1415.
In conclusion, we have demonstrated that a series of sub-
stituted 1,2,3-triazoles could be chlorinated at the 5-posi-
tion using copper chloride and pivalic acid under solvent-
free conditions. Further mechanistic studies are required
to fully explain the role of copper in the reaction. This
transformation represents a useful method that provides
access to 4,5-disubstituted 1,2,3-triazoles.
(13) Crystal data for compound 8a: C22H33Cl2N3O2; M =
442.41; monoclinic; space group P21/c; a = 27.1442(7) Å, b
= 4.9516(1) Å, c = 17.6348(5) Å, β = 101.803(2)°;
V=2320.13(10) Å3; Z = 4; crystal size 0.28 × 0.10 × 0.03
mm3; 26260 reflections collected (5307 independent,
Rint=0.0494), 265 parameters, R1 [I>2σ(I)] = 0.0429, wR2
[all data] = 0.1004, largest diff. peak and hole: 0.267 and –
0.234 e·Å–3. CCDC 876301 (8a) contains the supplementary
crystallographic data for this Letter. These data can be
obtained free of charge from The Cambridge
Acknowledgment
The authors are grateful to the CNRS and the Université Paul
Sabatier for their financial support.
Supporting Information for this article is available online at
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(14) Yang, L.; Lu, Z.; Stahl, S. S. Chem. Commun. 2009, 6460.
(15) Crystal data for compound 13: C18H18ClN3; M = 311.80;
monoclinic; space group P 21/c; a = 8.7163(11) Å, b =
10.9837(13) Å, c = 17.052(2) Å, β = 98.365(6)°; V =
1615.2(3) Å3; Z = 4; crystal size 0.30 × 0.20 × 0.12 mm3;
References and Notes
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=
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www.ccdc.cam.ac.uk/data_request/cif.
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Synlett 2012, 23, 2623–2626
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