C-H arylation of azaheterocycles: A direct ligand-free and Cu-catalyzed approach using diaryliodonium salts

Article abstract of DOI:10.1039/c4ob01061b

An efficient and high yielding Cu-catalyzed direct C-H arylation of azaheterocycles including oxadiazoles, thiadiazoles, benzoxazoles and benzothiazoles has been achieved by employing easily accessible diaryliodonium salts. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01061b

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C–H arylation of azaheterocycles: a direct
ligand-free and Cu-catalyzed approach using
Cite this: DOI: 10.1039/c4ob01061b
diaryliodonium salts†
Received 22nd May 2014,
Accepted 30th June 2014
Dalip Kumar,* Meenakshi Pilania, V. Arun and Savita Pooniya
DOI: 10.1039/c4ob01061b
www.rsc.org/obc
An efficient and high yielding Cu-catalyzed direct C–H arylation of
azaheterocycles including oxadiazoles, thiadiazoles, benzoxazoles
and benzothiazoles has been achieved by employing easily acces-
sible diaryliodonium salts.
Metal-mediated direct functionalization of the C–H bond is
one of the powerful and promising organic tools to introduce
various functional groups and construct biologically active
molecules.1 The C–H functionalization protocol is a relatively
better alternative to traditional cross-coupling methods as it
avoids organic halides and pre-functionalization steps. In
recent years, significant attention has been devoted to C–C
bond formation via C–H activation of heterocycles followed by
their couplings with aryl halides, aryl triflates, arylboronic
acids or arenes in the presence of expensive palladium,
rhodium based catalysts and ligands.2 Due to the ubiquity of
heteroaromatic nuclei in a variety of natural products and syn-
thetic therapeutic agents and organic materials, their construc-
tion and functionalization have been continuously pursued
with increasing interest and special attention.3 Particularly,
C–H functionalization of bioactive heterocycles has received
increasing attention due to many advantages such as the use
of catalytic amounts of reagents and avoidance of activating
agents, thereby generating fewer by-products. Arylazoles,
especially oxadiazoles, thiadiazoles, benzoxazoles and benzo-
thiazoles, are privileged motifs present in numerous bioactive
and pharmaceutical agents (Fig. 1).4
Fig. 1 Some important bioactive azaheterocycles.
lyst.7 Manolikakes and Umierski have successfully developed
an efficient and high yielding route to diaryl sulfones by utiliz-
ing diaryliodonium salts.8 Recently, we have prepared 1,2,3-
triazoles and diaryl sulfones effectively utilizing diaryliodo-
nium salts.9 In continuation of our work, we now disclose a
copper-catalyzed direct C–H arylation of various azahetero-
cycles, e.g. oxadiazoles, thiadiazoles, benzoxazoles, and benzo-
thiazoles, by employing readily accessible diaryliodonium salts.
Initially, the C–H arylation of easily accessible 2-phenyl-
1,3,4-oxadiazole (3a) with diphenyliodonium salt (5a) was
explored to generate 2,5-diphenyl-1,3,4-oxadiazole (6a)
(Table 1). Miura et al. have prepared 2,5-diaryl-1,3,4-oxadia-
zoles based on C–H functionalization of sp2-carbon involving
copper and 1,10-phenanthroline combination at 120 °C for
4 h.10 The C5–H in 3a being next to a heteroatom, initially we
tried to generate an anion using bases (Na2CO3, Cs2CO3 and
t-BuOK) in polyethylene glycol-400 (PEG-400) and DMSO. The
arylation of 3a using a catalytic amount of CuBr (20 mol%)
and a stronger base (t-BuOK) was examined in PEG-400 at
100 °C (Table 1); CuBr triggered the arylation of 3a after 18 h
to deliver 6a in 68% yield (Table 1, entry 2). To optimize the
reaction conditions further, various bases, copper salts and
solvents were screened. Interesting results were obtained,
however, when an alternate form of energy, microwave (MW)
irradiation, was deployed; the same reaction conducted in a
focused MW system for 30 min afforded 6a in 80% yield
(Table 1, entry 3) substantiating earlier MW-enhanced acceler-
In recent years, remarkable improvement in the synthesis
and utilities of diaryliodonium salts has been documented.5
Pioneering work on the selective arylation of sp2 C–H was
explored by Gaunt and co-workers using copper catalysts.6 In
2007, Sanford and Deprez studied the arylation of sp2 C–H
involving diaryliodonium salts in the presence of the Pd-cata-
Department of Chemistry, Birla Institute of Technology and Science, Pilani 333031,
Rajasthan, India. E-mail: dalipk@pilani.bits-pilani.ac.in; Fax: +91-1596-244183;
Tel: +91-1596-245073-5238
†Electronic supplementary information (ESI) available: Detail optimization
tables, typical experimental procedure and NMR spectra copies for all the com-
pounds. See DOI: 10.1039/c4ob01061b
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Table 1 Optimization of arylation of 1,3,4-oxadiazolesa
Table 2 Arylation of 1,3-azoles 3 and 4 with diaryliodonium salts 5
Entrya
Catalyst
Base
Solvent
X
Yielde (%)
1b
2b
3c
—
t-BuOK
t-BuOK
t-BuOK
Cs2CO3
K3PO4
t-BuOK
t-BuOK
t-BuOLi
Cs2CO3
t-BuOLi
DMSO
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
BF4
NR
68
80
Trace
NR
Trace
80
89
NR
65
CuBr
CuBr
CuBr
CuBr
CuI
CuBr
CuBr
CuBr
CuBr
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
DMSO
DMSO
DMSO
DMSO
4c
5c
6d
7d
8d
9d
10d
Reaction conditions: a 3a (1 equiv.), 5a (1 equiv.), Cu catalyst (20 mol%),
base (3 equiv.) was stirred in DMSO for 15 min at rt. b Conventional
heating at 100 °C for 18–24 h. c Microwave irradiation at 100 °C for
15–20 min. d Stirring at rt for 10–15 min. NR = no reaction. e Yield of
isolated product.
ated C–C bond formation.11 Among other bases, Cs2CO3 and
K3PO4 failed to deliver 6a. Similar fate was met by replacing
CuBr with CuI; no improvement in the yield was observed. The
arylation was then examined at room temperature in DMSO
using a stronger base (t-BuOLi) when efforts were amply
rewarded with a much higher yield of 6a (89%) in 15 min by
simply changing the solvent from PEG-400 to DMSO and the
base from t-BuOK to t-BuOLi (Table 1, entry 8), presumably
due to the better solubility of the substrate, catalyst and base
in DMSO. For the arylation of 3a–e, the use of CuBr (20 mol%)
and t-BuOLi (3.0 equiv.) at room temperature in DMSO was the
ideal optimized condition. During the arylation of oxadiazoles,
we found that the use of the corresponding iodonium triflate
was more effective when compared to iodonium salts with Br,
OTs and BF4 counter ions. In some cases iodonium salts with
OTs or Br counterions were preferred due to their easy access.
Having optimized the reaction conditions, we explored this
protocol for the arylation of various oxadiazoles 3 by utilizing
different symmetrical (5a–f, 5j, 5p) and unsymmetrical (5g–i)
diaryliodonium salts and prepared a variety of 2,5-diaryl-1,3,4-
oxadiazoles 6a–q (Table 2). Substituted oxadiazoles 3 having
nitro (3b), tolyl (3c) and dimethoxyphenyl moieties were ary-
lated smoothly to furnish 6h–l (75–88%) and 6p (60%) in good
to excellent yields. Alkyl substituted oxadiazole (3d) could also
be coupled to furnish 6n in 74% yield. Interestingly, when 3a
was coupled with 5g, 6o was obtained in 70% yield along with
6q in 8% yield.
and the CuI catalytic system at 105 °C for 12 h.12 A screening
study was initiated for the reaction between 4 and 5a by
employing a catalytic amount of copper salts (CuI and CuBr)
and bases (t-BuOK, Cs2CO3, K3PO4) in DMSO and PEG-400 at
room temperature, but the phenylation did not proceed as
expected. In some cases traces of 7a was obtained (see the
ESI†). Gratifyingly, the arylation of thiadiazole 4 proceeded ele-
gantly with a catalytic amount of CuBr (30 mol%) and t-BuOLi
(3.5 equiv.) in DMF at room temperature within 15 min and
affording 7a in 83% yield. With these optimized reaction con-
ditions, we conducted the C–H arylation of thiadiazole 4 by
employing various diaryliodonium salts 5a–f (Table 2) and
could successfully generate a variety of 2,5-diaryl-1,3,4-thiadia-
zoles 7a–f in 72–84% yields.
Next the arylation of benzo-fused heterocycles13 e.g., benz-
oxazoles and benzothiazoles was explored to synthesize diverse
2-arylbenzoxazoles and 2-arylbenzo-thiazoles endowed with
interesting biological properties (2, Fig. 1).4c,d,19 Daugulis and
Miura have independently studied the copper-mediated direct
C–H arylation of various heterocycles using different con-
ditions.14 Later, Huang et al. reported arylation of benzoxa-
zoles using the Pd(OAc)2/Cu(II)/PPh3 co-catalytic system.15 In
our efforts various benzoxazoles were coupled with diaryliodo-
nium salts under the optimized reaction conditions identified
for 2-aryl-1,3,4-oxadiazoles 3. It was found that benzoxazoles 8
could react with a relatively broad range of iodonium salts 5 to
afford 2-arylbenzoxazoles 10a–n in 79–89% yields (Table 3).
Substituted benzoxazoles 8b (Me) and 8c (Cl) furnished 10j–l
in excellent yields (80–85%); ortho-substituted diaryliodonium
salts 5k (OMe) and 5m (NO2) were well tolerated under these
conditions to obtain 10h–i in good yields.
Next, we carried out the arylation of structurally similar
2-phenyl-1,3,4-thiadiazole (4) to prepare diversely substituted
2,5-diaryl-1,3,4-thiadiazoles 7a–f which are of paramount
importance in medicinal chemistry due to their interesting
biological activities (1b, Fig. 1).4e,f There is only solitary pre-
cedence for the direct C–H arylation of 1,3,4-thiadiazoles using
aryl halides/aryl triflates involving Pd(OAc)2, Xantphos, Cs2CO3
Finally, the scope of arylation reaction was extended to ben-
zothiazoles 9 to prepare 2-arylbenzothiazoles 11; such C–H
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(81–89%). The tolerance of the bromo and chloro groups is
particularly useful for further synthetic manipulations by tra-
ditional cross coupling methods. In unsymmetrical iodonium
salts 5g–i and 5m–o the bulky mesityl moiety acts as a non-
transferrable group, so only 6a, 6g, 6o, 10f, 10i and 10m were
formed selectively in excellent yields. Iodonium salts 5b–c and
5k with electron-donating groups (Me and OMe) delivered
6b–c, 7c, 10f, 10h, 11b–c and 11g in relatively good yields. The
bulky naphthyl and heteroaromatic thienyl motifs were suc-
cessfully transferred using iodonium salts 5j and 5l giving 6m,
10g and 11h in excellent yields.
Table 3 Arylation of benzoazoles 8 and 9 with diaryliodonium salts 5
To illustrate the synthetic utility of this copper-catalyzed
arylation of diverse azoles, we prepared various useful mole-
cules. From the reactions of benzoazoles and iodonium salts,
we successfully prepared efficient ESIPT fluorescent and che-
lating agents including 2-(4′-metho-xyphenyl)benzoxazole
(10f), 2-(2′-methoxyphenyl)-benzoxazole (10h) and 2-(2′-
methoxy-phenyl)benzothiazole (11g) (Table 3).19 2,5-Diaryl-
1,3,4-oxadiazoles 6c and 6p, analogues of anticancer agents
(1a–b), were easily prepared from the reactions of an appropri-
ate oxadiazole 3 with diphenyl iodonium salts. Successful
installation of the 3,5-dichlorophenyl moiety onto benzoxazole
using 5p allowed us to prepare the methyl ester (10n) of Tafa-
arylations have been achieved using various catalysts such as midis in 67% yield (Table 3).20
Pd,16 Pd/Cu/additive17 combination and aryl halides. Our
To check the feasibility of the developed protocol on the
earlier optimized C–H arylation conditions, however, failed to gram-scale, we conducted the reaction of 2-phenyl-1,3,4-oxa-
deliver 2-phenylbenzo-thiazole (11a). Therefore, we explored diazole (3a, 1 g) with diphenyliodonium triflate 5a; 6a was
the reaction between 9 and 5a in the presence of CuBr by
obtained in 83% yield. Arylation of various azaheterocycles
varying bases, solvents and reaction temperature from rt to involving different equivalents of base (3.0 and 3.5 equiv.) and
130 °C (see the ESI†). Bases such as t-BuOLi and AgOAc could reaction conditions (rt and MW) revealed that the acidity of
not produce 11a even under conventional heating. So, next we
the C2–H bond plays a pivotal role. From the aforementioned
attempted the arylation of 9 with 5a in DMF under MW results, it was observed that the reactivity of various azoles
irradiation; however, it was unsuccessful. Various copper salts (oxadiazoles = benzoxazoles (pKa = 24.8) > thiadiazoles >
benzothiazoles (pKa = 27.3)) parallels the acidity of C2–H.14b,21
such as CuI, Cu(OAc)2, Cu/Pd and Cu/Ag catalytic combi-
nations also failed to give 11a. No desired product was Based on our results and literature reports,22,23 mechanistically
detected by varying bases and ligand combinations (K3PO4/ it is postulated that an initial cupration of 1,3-azoles A with the
PPh3 and K3PO4/1,10-phenanthroline) in the presence of CuI.
aid of t-BuOLi affords an azolyl-copper species B. Subsequent
After successive failures under conventional heating and at oxidative addition of B to the diaryliodonium salt facilitates the
ambient temperature, the arylation reaction of 9 was per- formation of an electrophilic Cu(III)-aryl species C with the gene-
formed under MW in the presence of CuI and t-BuOLi in
ration of an appropriate iodoarene. Finally, the reductive elimin-
DMSO or DMF. Interestingly, under these conditions for- ation of C is assumed to afford the arylated azoles D with the
mation of 2-aminothiophenol was observed instead of the concomitant release of the Cu(I) catalyst (Fig. 2).
desired 11a. This indicated that the polar-aprotic solvents such
In summary, we have developed a facile, high yielding, scal-
as DMSO and DMF enhanced the ring opening of benzothia- able and ligand-free copper-catalyzed direct C–H arylation pro-
zole to produce aminothiophenol.18 To diminish the ring- tocol that enables the synthesis of diverse class of bioactive
opening of benzothiazole, we attempted the arylation of
azaheterocycles, namely aryloxadiazoles, arylthiadiazoles, aryl-
9 using 5a in dioxane and obtained the desired 2-phenylben- benzoxazoles and arylbenzothiazoles, by employing readily
zothiazole (11a) in 85% yield. Finally, we found that CuI accessible diaryliodonium salts. The present method offers
(30 mol%) and t-BuOLi (3.5 equiv.) in dioxane under MW
advantages including shorter reaction times, milder reaction
irradiation (30 min, 130 °C) were the best conditions to conditions, a wider substrate scope with high yields of the
prepare 11a. With an optimized set of reaction conditions, we
studied the arylation of benzothiazole 9 by employing various
diaryliodonium salts 5a–h (Table 3) and prepared diversely
substituted 2-arylbenzothiazoles 11a–h.
Notably, the halo-substituted diaryliodonium salts 5d–f
afforded 6d–f, 7d–f, 10c–e and 11d–f in good to excellent yields Fig. 2 Proposed mechanism for the arylation of azoles.
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products. The arylmesityl iodonium salts can be effectively uti-
lized to prepare appropriate arylated azaheterocycles in high
yields. The generalized protocols enable easy access to an array
of potentially useful molecules, halo-substituted azahetero-
cycles and prospective precursors to acquire complex bioactive
heteroaryls.
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Acknowledgements
The authors gratefully acknowledge CSIR, New Delhi and UGC,
New Delhi for financial support. MP and SP thank CSIR,
New Delhi for awarding Junior Research Fellowship.
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