A unified strategy towards N-aryl heterocycles by a one-pot copper-catalyzed oxidative C-H amination of azoles

Article abstract of DOI:10.1002/ejoc.201402868

An efficient one-pot synthesis of N-aryl-substituted heterocycles by a Cu-catalyzed two-fold C-N bond formation is reported. This strategy involves a Cu^I-catalyzed C-N bond-forming reaction between azoles and electron-deficient bromopyridines followed by an intramolecular sp² C-H amination. One of the products thus formed has been successfully used as a ligand for the synthesis of a Pd complex. An efficient one-pot synthesis of N-aryl heterocycles by a Cu-catalysed double C-N bond formation is reported. This strategy involves a Cu^I-catalysed C-N bond-forming reaction between azoles and electron-deficient bromopyridines followed by an intramolecular sp² C-H amination.

Full text of DOI:10.1002/ejoc.201402868

FULL PAPER
DOI: 10.1002/ejoc.201402868
A Unified Strategy Towards N-Aryl Heterocycles by a One-Pot Copper-
Catalyzed Oxidative C–H Amination of Azoles
Parthasarathi Subramanian[a] and Krishna P. Kaliappan*[a]
Keywords: Synthetic methods / C–H activation / Amination / Nitrogen heterocycles / Copper / Reaction mechanisms
An efficient one-pot synthesis of N-aryl-substituted heterocy- bromopyridines followed by an intramolecular sp2 C–H
cles by a Cu-catalyzed two-fold C–N bond formation is re-
ported. This strategy involves a CuI-catalyzed C–N bond-
forming reaction between azoles and electron-deficient
amination. One of the products thus formed has been suc-
cessfully used as a ligand for the synthesis of a Pd complex.
azobenzimidazole derivatives (Figure 1).[20,21] However, the
methods developed thus far suffer from harsh conditions,
narrow functional group tolerance, poor atom economy
and low yields. During the course of our study, Fu and co-
workers[22] reported an elegant synthesis of N-arylimidazo-
benzimidazoles by a copper-catalysed intramolecular C–H
amination from pre-arylated 2-(1H-imidazol-1-yl)anilines
(Scheme 1). This protocol also requires a couple of steps
for the construction of imidazobenzimidazoles, including
the preparation of the N-arylated starting material, which
is cumbersome and low yielding (23–60%). However, we
anticipated that N-pyridyl heterocycles could be ac-
complished by a cascade two-fold C–N bond formation in-
volving a direct oxidative sp2 C–H activation.
Introduction
Nitrogen-containing heterocycles continue to attract the
attention of synthetic chemists due to their applications in
pharmaceuticals,[1] functional materials[2] and agrochemical
products.[3] Thus, several methods have been developed to
synthesize various heterocycles with different architec-
tures.[4] The last two decades have witnessed a renaissance
in the synthesis of heterocycles since the pioneering work
of Buchwald on direct sp2 C–H activation/intramolecular
C–N bond formation,[5] leading to various heterocycles
such as carbazoles,[6] benzimidazoles,[7] indazoles,[8]
indolines,[9] and N-methoxylactams.[10]
Although most of these methods involve the use of ex-
pensive palladium, rhodium and ruthenium catalysts,[11]
they have provided a new dimension in the development
of an atom-economic and orthogonal C–N bond formation
protocol for the synthesis of nitrogen-containing heterocy-
clic compounds. Subsequently, several inexpensive methods
involving Cu-catalysed sp2 C–H activation have been devel-
oped for the construction of N heterocycles.[12–16] However,
the transition-metal-catalysed C–H activation of unsubsti-
tuted anilines is susceptible to poisoning of the catalyst[17]
due to the basic nature of the amine moiety.[18] Further-
more, a Cu-catalysed route to C–N bond formation with
a free amine on a deactivated pyridine nucleus is thus far
unexplored. Thus, herein we report a one-pot Cu-catalysed
synthesis of N-arylimidazobenzimidazoles by a cascade
two-fold C–N bond formation from readily available start-
ing materials involving an sp2 C–H activation.
Owing to their interesting biological properties,[19] con-
siderable efforts have been made to synthesize various imid-
[a] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai 400076, India
E-mail: kpk@chem.iitb.ac.in
http://www.chem.iitb.ac.in/~kpk/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402868.
Figure 1. Previously synthesized imidazobenimidazoles.
5986
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5986–5997

A Unified Strategy Towards N-Aryl Heterocycles
Results and Discussion
To test this hypothesis, we selected 2-(1H-imidazol-1-yl)-
aniline (1a) and 2-bromopyridine (2a) as model substrates
for the cascade reaction. Our optimization studies com-
menced with the identification of a suitable catalytic system
for the reaction. Our initial attempt with 20 mol-% CuI as
catalyst, 30 mol-% phen and K3PO4 as base gave the desired
product in 23% yield (Table 1; entry 1). Further optimiza-
tion to improve the yield by using various additives/oxi-
dants along with CuI were unsuccessful. However, encour-
aged by the formation of the product, we focused our atten-
tion on the use of divalent copper salts as catalyst. The use
of CuCl2 or CuBr2 as catalyst gave poor yields of 20 and
18%, respectively (entries 2 and 3), whereas CuSO4 was
found to be ineffective for this transformation. Neverthe-
less, an improved yield (50%) was achieved when we used
a mixture of 20 mol-% CuI and excess Cu(OAc)2·H2O (en-
try 4). Further to our search for improved reaction condi-
tions, we found that 20 mol-% CuCl2 and excess Cu(OAc)2·
H2O gave the best yield of 87% (entry 6). Despite the satis-
Scheme 1. C–H bond functionalization of heterocycles.
Table 1. Optimization of the reaction conditions for the cascade reaction.[a]
Entry Catalyst/additive
Ligand[b]
Base
Solvent
Isolated yield[c] [%]
1
2
3
4
5
6
7
8
20 mol-% CuI
20 mol-% CuCl2
20 mol-% CuBr2
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
23
20
18
50
31
87
39
20 mol-% CuI/1 equiv. Cu(OAc)2·H2O
20 mol-% CuI/1 equiv. CuCl2
20 mol-% CuCl2/1 equiv. Cu(OAc)2·H2O
1 equiv. Cu(OAc)2·H2O
20 mol-% Cu(OAc)2·H2O
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
30 mol-% phen
18 (8)
23 (11)
37 (5)
58 (trace)
21 (18)
30 (10)
67 (7)
65 (11)
67 (5)
72
9
40 mol-% Cu(OAc)2·H2O
10
11
12
13
14
15
16
17
18
60 mol-% Cu(OAc)2·H2O
80 mol-% Cu(OAc)2·H2O
20 mol-% Cu(OAc)2·H2O
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
40 mol-% Cu(OAc)2·H2O
60 mol-% Cu(OAc)2·H2O
20 mol-% Cu(OAc)2·H2O/10 mol-% TBAI
20 mol-% Cu(OAc)2·H2O/50 mol-% TBAI
20 mol-% Cu(OAc)2·H2O/100 mol-% TBAI
20 mol-% Cu(OAc)2·H2O/100 mol-% TBAI
n.d.
[a] Reaction conditions: 1a (0.31 mmol), 2a (0.63 mmol), catalyst (20 mol-%), base (3 equiv.), solvent (3 mL), 130 °C. [b] Ligands tested
in screening process are shown below. [c] Yield of byproduct are given in parentheses.
Eur. J. Org. Chem. 2014, 5986–5997
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5987

P. Subramanian, K. P. Kaliappan
FULL PAPER
factory yields obtained, it was difficult to identify the na- furnished 67% of product when we used 60 mol-% of
ture of the reactive copper species that is responsible for the Cu(OAc)2·H2O with 30 mol-% phen and 3 equiv. K3PO4
transformation. Thus, the reaction was carried out without (entry 14). To improve the yield further, we used TBAI as
CuCl2 and phenanthroline to examine the role of excess an additive with 20 mol-% Cu(OAc)2, 30 mol-% phen and
Cu(OAc)2·H2O. Interestingly, this reaction yielded 39% of 3 equiv. K3PO4 (entries 15–18). Addition of 1 equiv. TBAI
the required product (entry 7). Then we studied the reaction improved the yield significantly to 72% and no byproduct
extensively by using Cu(OAc)2·H2O as the sole catalyst for was observed (entry 17). Notably, when we performed the
this cascade two-fold C–N bond protocol. To determine the reaction under these improved conditions in toluene, no
required amount of Cu(OAc)2·H2O for the reaction, we product was obtained. We also examined the use of various
screened various quantities of the catalyst with or without ligands in place of phenanthroline under the improved con-
the base. In the absence of base, our initial optimization ditions [20 mol-% Cu(OAc)2·H2O, 30 mol-% ligand,
with 20 mol-% of Cu(OAc)2·H2O and 30 mol-% phen gave 1 equiv. TBAI and 2 equiv. K3PO4], however, the yield of
the required product in 18% yield along with 8% of a by- the product was not improved. Hence, we chose 20 mol-%
product with the same molecular mass (entry 8). When Cu(OAc)2·H2O, 30 mol-% phen, 1 equiv. TBAI and 2 equiv.
80 mol-% of Cu(OAc)2·H2O was used, the product was ob- K3PO4 (entry 17) as the optimized conditions to scrutinize
tained in 58% yield with trace amounts of the byproduct the substrate scope of the reaction.
(entry 11). Although the yield of the reaction was improved
To explore the scope and generality of this method, we
with 80 mol-% of Cu(OAc)2·H2O in the absence of base, it selected a range of N-(o-aminoaryl)azoles 1a–1i (Scheme 2
was far from satisfactory . Therefore we wanted to explore and Scheme 3) and bromopyridines to explore the forma-
the influence of base on the catalytic system. The reaction tion of N-pyridyl heterocycles. In all cases, the reaction pro-
Scheme 2. Substrate scope for the cascade reaction between azoles and 2-bromopyridines.
5988
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5986–5997

A Unified Strategy Towards N-Aryl Heterocycles
Scheme 3. Substrate scope for the cascade reaction between azoles and 2-bromopyridines and the competitive C–H activations.
ceeded smoothly to provide the expected N-pyridyl hetero- desired products (3da–3dc) in excellent yields. The tolerance
cycles in good-to-excellent yields (Scheme 2). In the case of of the reaction conditions to the presence of triazole offers
2,3-bis(triazol-1-yl)-1-aminobenzene (1d), despite the pres- an ideal opportunity for further synthetic manipulation
ence of four potentially activated C–H bonds, the reaction towards the preparation of N-heterocyclic carbenes (NHCs)
with pyridyl bromides proceeded efficiently to afford the and related products. Remarkably, when we used azole 1e,
Scheme 4. Reaction of azoles and aryl bromides.
Eur. J. Org. Chem. 2014, 5986–5997
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5989

P. Subramanian, K. P. Kaliappan
FULL PAPER
we could selectively functionalize one of the amine moieties
to provide products 3ea–3ec in good yields. This desymme-
trization could be useful in further structural modifications.
Unfortunately, azole 1f was found to be unreactive under
the optimized conditions.
In the case of CF3-substituted N-(o-aminoaryl)azoles 1g
and 1h, an inseparable regioisomeric mixture of the ex-
pected N-pyridyl heterocycles and benzimidazo[1,2-a]pyr-
idines were obtained in good yields (Scheme 3). Such benzi-
midazo[1,2-a]pyridine motifs are of synthetic[23] and bio-
logical interest.[24] The formation of regioisomers may be
due to the CF3 substituent enhancing the acidity of the or-
tho-H and hence the o-C–H activation resulting in the re-
gioisomeric mixture of products. The formation of the
benzimidazo[1,2-a]pyridines was confirmed unambiguously
by various NMR studies of the representative compounds
Scheme 5. Synthesis of benzimidazokinetin.
Scheme 6. Reactions carried out during a study of the mechanism.
5990
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5986–5997

A Unified Strategy Towards N-Aryl Heterocycles
3ga2 and 3ha2. Interestingly, when 1g was treated with 2- imidazokinetin 5 in 62% yield. Thus, the cascade two-fold
bromo-6-methylpyridine (2c), only the N-pyridyl heterocy- C–N bond methodology becomes more general for the C–
cle 3gc1 was obtained in 51% yield. With the intention of H activation of similar kinds of azoles and the synthesis of
obtaining only the product 3a2 from the competing reac- the corresponding heterocyclic compounds.
tion, we performed this reaction with 2-methylimidazole 1i.
To gain more insight into the reaction mechanism, sev-
However, to our surprise, this substrate was very reluctant eral control experiments were carried out (Scheme 6). Ini-
to couple with various 2-bromopyridines under our opti- tially a blank reaction was carried out without the Cu cata-
mized conditions.
lyst to rule out the possibility of a SNAr displacement reac-
Having successfully accomplished the one-pot synthesis tion [Equation (1)]. The reaction was then studied under
of N-aryl heterocycles with 2-bromopyridines, we then oxygen; it was found that product formation was completely
looked at extending the scope of this reaction to simple aryl inhibited [Equation (2)]. It is thus likely that the CuI cata-
bromides 2d–f (Scheme 4). Our initial attempts with azole lyst generated in situ under the reaction conditions might be
1b and bromobenzene (2d) under our optimized conditions completely re-oxidized to CuII by oxygen [Equation (4)],[26b]
provided only 7% of the N-phenyl heterocycle 3bd. Never- and that the unavailability of the active CuI catalyst led to
theless, encouraged by the formation of the product, we isolation of unchanged starting materials. This explains the
looked at changing the base to improve the yield of this importance of the CuI species, which is required for the po-
reaction. After a thorough screening, this reaction success- larization of the 2-bromopyridines. In further support of a
fully furnished the desired N-phenyl heterocycle 3bd in 85% mechanism involving CuI, when this reaction was carried
yield when tBuONa was used instead of K3PO4. Then we out in the presence of CuI as catalyst, 28% of the required
explored the scope of the reaction with various azoles and product was isolated [Equation (3)]. Moreover, it is well es-
a few aryl bromides. All of them gave good yields and, tablished that CuII can be reduced to CuI by the mild reduc-
interestingly, the reaction of azole 1e with 2d provided the ing action of DMF.[26] During this process, the reaction
best yield (98%). In addition, the reaction of azole 1h with should produce an equivalent amount of dimethylamine
bromobenzene (2d) afforded heterocycle 3hd as the sole [DMA; Equation (5)], which was also observed under our
product (76%) without affecting other competitive C–H reaction conditions.[27] The DMA generated was success-
bonds. As expected, the sterically demanding mesityl brom- fully trapped with 1-fluoro-2-nitrobenzene to give N,N-di-
ide (2f) was found to be unreactive under the optimized methyl-2-nitroaniline in 92% yield [Equation (6)]. When the
conditions with azole 1b.
reaction was carried out with the N-phenyl intermediate
This strategy has also been extended to the biologically using CuOAc as a catalyst and degassed solvent under an
important anti-aging drug analogue[25] benzimidazokinetin inert atmosphere [Equation (7)], product formation was not
(Scheme 5). In our initial attempts to synthesize this hybrid observed. However, when the solvent was not degassed, the
natural product, N-pyridylbenzimidazokinetin 5, the azole product was obtained in 54% yield [Equation (8)]. These
4 under the optimized conditions A gave a mixture of prod- observations lead to the conclusions that CuII is the active
ucts 5 and 6 in a ratio of 0.4:1 in 85% yield, whereas condi- species involved in the C–H activation reaction; also, this
tions B exclusively provided the product N-pyridylbenz- active species could be generated in situ by the oxidation of
Scheme 7. Proposed mechanism.
Eur. J. Org. Chem. 2014, 5986–5997
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5991

P. Subramanian, K. P. Kaliappan
FULL PAPER
CuI with small quantities of dissolved oxygen present in the and also allows access to biologically active heterocyclic hy-
solvent system.[23b,28] Although the role of tetrabutylammo- brid natural products.
nium iodide (TBAI) as an additive is not yet clear, GC–
MS analysis showed that a substantial amount of iodine
exchange[29] had taken place under the blank reaction con-
ditions – see Equation (9) – which might facilitate the initial
oxidative addition.
Experimental Section
General Methods: Unless otherwise noted, all starting materials
and reagents were obtained from commercial suppliers and used
after further purification as detailed below. N,N-Dimethylform-
amide and MeOH were freshly distilled from calcium hydride. All
Based on the above investigations, a plausible mechanism
for the synthesis of N-aryl or N-pyridyl heterocycles using
Cu(OAc)2·H2O is outlined here (Scheme 7). According to solvents for routine isolation of products and chromatography were
literature precedent,[26,27] the reductive generation of the
reagent grade and glass distilled. Reaction flasks were dried in an
active catalyst phenCuI A was achieved from Cu(OAc)2·
oven at 130 °C for 12 h. Air- and moisture-sensitive reactions were
H2O by the mild reducing action of DMF.[23] Then phen-
performed under argon/UHP nitrogen. Column chromatography
was performed by using silica gel (100–200 mesh, Acme) with indi-
CuI A undergoes oxidative addition[30] of 2-bromo- or 2-
cated solvents. Thin-layer chromatography (TLC) was conducted
with Merck silica gel 60 F254 precoated plates (0.25 mm) and visu-
alized with UV, potassium permanganate, ceric ammonium molyb-
date, and iodine staining. Optical rotation was recorded with an
iodopyridine to yield the CuIII species B. Subsequently, re-
ductive C–N coupling takes place to give the CuI species D.
This CuI species is oxidized in situ to provide CuII interme-
diate E,[23b,28] which in turn undergoes acetate-ligand-as-
Autopol IV automatic polarimeter. Melting points of the com-
sisted, concerted C–H activation to afford F. Finally, re-
pounds were determined by using a Büchi B-545 melting point ap-
ductive elimination gives product 3aa and concomitant Cu0 paratus. IR spectra were recorded with a Thermo Nicolet Avater
oxidation regenerates the CuII catalyst.
320 FTIR and a Nicolet Impact 400 machine. Mass spectra were
obtained with a Waters Micromass-Q-Tof microTM (YA105) spec-
In addition to the biological relevance of these heterocy-
trometer. GCMS analysis was done with an Agilent 7890A GC
system connected with 5975C inert XL EI/CI MSD (with triple
cles, we explored the coordination of the products with met-
als. Thus, a representative electron-rich product, N-pyridyl
axis detector). 1H NMR spectra were recorded with a Bruker
heterocycle 3bc was chosen as a ligand for the preparation
400 MHz and a Bruker 500 MHz spectrometer and are reported in
ppm by using the solvent as an internal standard [CDCl3 at δ =
of a Pd complex[31] (Figure 2).
7.26 ppm, (CD3)2SO at δ = 2.50 ppm]. Data reported as: s = singlet,
d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet,
sept = septet, m = multiplet, br. = broad, ap =apparent; coupling
constant(s) in Hz; integration. Proton-decoupled 13C NMR spectra
were recorded with a Bruker 400 MHz and a Bruker 500 MHz
spectrometer and are reported in ppm using the solvent as an in-
ternal standard [CDCl3 at δ = 77.2 ppm, (CD3)2SO at δ =
39.5 ppm].
General Procedure for the Synthesis of N-Pyridyl Heterocycles: The
azole 1 (1 equiv.) and 2-bromopyridine 2 (2 equiv.) were added to
an oven-dried screw-cap reaction tube charged with a magnetic stir-
ring bar, Cu(OAc)2·H2O (20 mol-%), 1,10-phenanthroline mono-
hydrate (30 mol-%), K3PO4 (3 equiv.) and TBAI (1 equiv.) in dry
DMF (3 mL) at room temp. Then the reaction tube was closed with
the screw cap, and the mixture was stirred at 130 °C for 17 h. The
reaction mixture was cooled to room temperature, water (5 mL)
was added and the mixture extracted with ethyl acetate (3ϫ 5 mL).
Then the combined organic layers were further washed with water
(7ϫ 5 mL), dried with anhyd. Na2SO4 and concentrated to give the
crude product. Purification by silica gel column chromatography
afforded the N-pyridyl heterocycles.
Figure 2. Coordination of product 3bc to palladium.
Conclusions
We have developed an efficient, one-pot, copper-cata-
lysed sp2 C–H cascade amination to synthesize various N-
3aa: Following the general procedure, the reaction was carried out
aryl and -pyridyl heterocycles from various azoles and aryl between 2-(1H-imidazol-1-yl)aniline (1a; 50 mg, 0.314 mmol,
1 equiv.) and 2-bromopyridine (2a; 60 μL, 0.63 mmol, 2.0 equiv.).
Column chromatography (10% ethyl acetate in hexanes) on silica
gel yielded 53 mg (72%) of the title compound 3aa as a white solid.
Rf = 0.45 (20% ethyl acetate in hexanes); m.p. 141–143 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.80 (dd, J = 8.3, 0.7 Hz, 1 H), 8.71
(d, J = 8.4 Hz, 1 H), 8.55 (ddd, J = 4.8, 2.8, 0.7 Hz, 1 H), 7.89
(ddd, J = 8.4, 7.3, 2.8 Hz, 1 H), 7.56 (dd, J = 7.7, 0.6 Hz, 1 H),
7.44 (d, J = 1.6 Hz, 1 H), 7.38 (td, J = 7.7, 0.7 Hz, 1 H), 7.30 (td,
J = 8.3, 0.6 Hz, 1 H), 7.26 (d, J = 1.6 Hz, 1 H), 7.16 (ddd, J = 7.7,
4.8, 0.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.5,
bromides or 2-bromopyridines. To the best of our knowl-
edge, this is the first report of the use of an inexpensive CuII
salt as catalyst for a cascade two-fold C–N bond-forming
reaction involving an oxidative sp2 C–H activation.
Furthermore, we believe that many of the synthesized elec-
tron-rich triazole derivatives could serve as ligands for
metal catalysis and also be elaborated (3da–3dc) as N-het-
erocyclic carbenes by using known N-alkylation protocols.
Thus, the method described herein serves as a straightfor-
ward protocol for the synthesis of N-pyridyl heterocycles 147.8, 138.6, 134.1, 131.4, 125.3, 124.3, 122.4, 119.7, 117.3, 114.2,
5992
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5986–5997

A Unified Strategy Towards N-Aryl Heterocycles
110.6, 106.7 ppm. FTIR (neat, KBr): ν = 1591, 1574, 1561, 1338,
3bc: Following the general procedure, the reaction was carried out
between 2-(1H-benzimidazol-1-yl)aniline (1b; 50 mg, 0.239 mmol,
1 equiv.) and 2-bromo-6-methylpyridine (2c; 57 μL, 0.478 mmol,
2.0 equiv.). Column chromatography on silica gel (7% ethyl acetate
in hexanes) yielded 48 mg (67%) of the title compound 3bc as a
white solid. Rf = 0.53 (20% ethyl acetate in hexanes); m.p. 137–
140 °C. 1H NMR (400 MHz, CDCl3): δ = 8.88 (dd, J = 5.1, 3.6 Hz,
1 H), 8.60 (d, J = 8.3 Hz, 1 H), 7.86–7.82 (m, 3 H), 7.78–7.76 (m,
1 H), 7.41–7.36 (m, 3 H), 7.32 (td, J = 7.9, 1.0 Hz, 1 H), 7.07 (d,
J = 7.5 Hz, 1 H), 2.66 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 157.3, 151.5, 150.5, 146.9, 139.1, 134.0, 127.7, 125.9, 123.8,
123.3, 123.0, 121.0, 119.8, 119.2 117.1, 111.9, 110.4, 110.2,
˜
1262, 771 cm–1. HRMS (ESI): calcd. for C14H11N4 [M + H]+
235.0984; found 235.0983.
3ab: Following the general procedure, the reaction was carried out
between 2-(1H-imidazol-1-yl)aniline (1a; 50 mg, 0.314 mmol,
1 equiv.) and 2-bromo-4-methylpyridine (2b; 70 μL, 0.628 mmol,
2.0 equiv.). Column chromatography on silica gel (7% ethyl acetate
in hexanes) yielded 61 mg (78%) of the title compound 3ab as a
white solid. Rf = 0.50 (20% ethyl acetate in hexanes); m.p. 104–
107 °C. 1H NMR (400 MHz, CDCl3): δ = 8.85 (dd, J = 8.4, 0.5 Hz,
1 H), 8.50 (s, 1 H), 8.40 (d, J = 5.0 Hz, 1 H), 7.54 (dd, J = 7.8,
0.8 Hz, 1 H), 7.43 (d, J = 1.3 Hz, 1 H), 7.37 (td, J = 7.8, 1.3 Hz, 1
H), 7.28 (td, J = 8.4, 1.2 Hz, 1 H), 7.29 (d, J = 1.4 Hz, 1 H), 6.99
(d, J = 5.0 Hz, 1 H), 2.50 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 151.5, 150.1, 147.6, 134.2, 131.3, 125.2, 124.2, 122.3,
24.4 ppm. FTIR (neat, KBr): ν = 1641, 1606, 1557, 1442, 1324,
˜
1231, 1163, 750 cm–1. HRMS (ESI): calcd. for C19H15N4 [M + H]
+
299.1297; found 299.1296.
121.2, 117.2, 114.6, 110.6, 106.7, 21.6 ppm. FTIR (neat, KBr): ν =
3bc – Gram-Scale Reaction: Azole 1b (1 g, 4.78 mmol, 1 equiv.) and
2-bromo-6-methylpyridine (2c; 1.07 mL, 9.56 mmol, 2 equiv.) were
added to a mixture of Cu(OAc)2·H2O (189 mg, 0.956 mmol,
20 mol-%), 1,10-phenanthroline monohydrate (284 mg, 1.43 mmol,
30 mol-%), K3PO4 (3.02 g, 14.35 mmol, 3 equiv.) and TBAI (1.73 g,
1 equiv.) in dry DMF (8 mL) at room temp. Then the reaction tube
was closed with a screw cap and stirred at 130 °C for 17 h. The
reaction mixture was then cooled to room temperature, water
(7 mL) was added and the mixture extracted with ethyl acetate (3ϫ
15 mL). Then the combined organic layers were further washed
with water (7ϫ 20 mL), dried with anhyd. Na2SO4 and concen-
trated to give the crude product. Purification by column
chromatography (7% ethyl acetate in hexanes) afforded the N-pyr-
idyl heterocycle (0.89 g, 63%).
˜
1608, 1568, 1453, 1218, 769 cm–1. HRMS (ESI): calcd. for
C15H13N4 [M + H]+ 249.1140; found 249.1140.
3ac: Following the general procedure, the reaction was carried out
between 2-(1H-imidazol-1-yl)aniline (1a; 50 mg, 0.314 mmol,
1 equiv.) and 2-bromo-6-methylpyridine (2c; 71 μL, 0.628 mmol,
2.0 equiv.). Column chromatography on silica gel (7% ethyl acetate
in hexanes) yielded 65 mg (83%) of the title compound 3ac as a
white solid. Rf = 0.50 (20% ethyl acetate in hexanes); m.p. 118–
121 °C. 1H NMR (500 MHz, CDCl3): δ = 8.87 (d, J = 8.3 Hz, 1
H), 8.46 (d, J = 8.2 Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.56 (d, J
= 7.7 Hz, 1 H), 7.43 (d, J = 1.5 Hz, 1 H), 7.39 (td, J = 8.5, 1.1 Hz,
1 H), 7.31 (td, J = 7.7, 1.1 Hz, 1 H), 7.28 (d, J = 1.5 Hz, 1 H), 7.02
(d, J = 7.4 Hz, 1 H), 2.51 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 157.4, 150.5, 139.0, 134.1, 130.7, 125.2, 124.4, 122.4,
3ca: Following the general procedure, the reaction was carried out
between 2-(1H-1,2,4-triazol-1-yl)aniline (1c; 50 mg, 0.312 mmol,
1 equiv.) and 2-bromopyridine (2a; 60 μL, 0.624 mmol, 2.0 equiv.).
Column chromatography on silica gel (14% ethyl acetate in hex-
anes) yielded 55 mg (75%) of the title compound 3ca as a white
solid. Rf = 0.40 (20% ethyl acetate in hexanes); m.p. 163–166 °C.
1H NMR (400 MHz, CDCl3): δ = 8.93 (dd, J = 8.9, 1.1 Hz, 1 H),
8.60 (dd, J = 4.7, 0.9 Hz, 1 H) 8.52 (d, J = 8.4 Hz, 1 H), 8.13 (s, 1
H), 7.93 (ddd, J = 9.2, 6.5, 1.8 Hz, 1 H), 7.88 (dd, J = 7.5, 1.3 Hz,
1 H), 7.49–7.41 (m, 2 H), 7.25–7.23 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 154.6, 152.3, 150.7, 148.3, 138.9, 133.5,
125.1, 124.9, 123.6, 120.7, 117.7, 114.3, 110.9 ppm. FTIR (neat,
119.4, 117.3, 111.1, 110.7, 106.7, 24.5 ppm. FTIR (neat, KBr): ν =
˜
2922, 1609, 1494, 1156, 743 cm–1. (ESI): calcd. for C15H13N4 [M +
H]+ 249.1140; found 249.1137.
3ba: Following the general procedure, the reaction was carried out
between 2-(1H-benzimidazol-1-yl)aniline (1b; 50 mg, 0.239 mmol,
1 equiv.) and 2-bromopyridine (2a; 45 μL, 0.478 mmol, 2.0 equiv.).
Column chromatography on silica gel (10% ethyl acetate in hex-
anes) yielded 60 mg (88%) of the title compound 3ba as a white
solid. Rf = 0.50 (20% ethyl acetate in hexanes); m.p. 155–157 °C.
1H NMR (400 MHz, CDCl3): δ = 8.87–8.83 (m, 2 H), 8.60 (dd, J
= 4.2, 1.1 Hz, 1 H), 7.97 (ddd, J = 9.2, 7.4, 1.9 Hz, 1 H), 7.87–7.80
(m, 3 H), 7.44–7.39 (m, 3 H), 7.38–7.39 (m, 1 H), 7.26–7.22 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.3, 151.1, 148.0,
146.8, 138.8, 133.9, 127.7, 125.9, 123.9, 123.3, 123.1, 121.0, 120.4,
KBr): ν = 1575, 1562, 1504, 1480, 1467, 1326, 1176, 1160, 775,
˜
745 cm–1. HRMS (ESI): calcd. for C13H10N5 [M + H]+ 236.0936;
found 236.0943.
119.2, 116.9, 115.1, 110.4, 110.2 ppm. FTIR (neat, KBr): ν = 1632,
3cb: Following the general procedure, the reaction was carried out
between 2-(1H-1,2,4-triazol-1-yl)aniline (1c; 50 mg, 0.312 mmol,
1 equiv.) and 2-bromo-4-methylpyridine (2b; 60 μL, 0.624 mmol,
2.0 equiv.). Column chromatography on silica gel (12% ethyl acet-
ate in hexanes) yielded 61 mg (78%) of the title compound 3cb as
a white solid. Rf = 0.45 (20% ethyl acetate in hexanes); m.p. 165–
168 °C. 1H NMR (400 MHz, CDCl3): δ = 8.90 (dd, J = 8.9, 1.2 Hz,
1 H), 8.42 (d, J = 5.0 Hz, 1 H), 8.29 (s, 1 H), 8.13 (s, 1 H), 7.87
(dd, J = 7.4, 0.8 Hz, 1 H), 7.47–7.39 (m, 2 H), 7.06 (d, J = 5.0 Hz,
1 H), 2.50 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.5,
152.3, 150.8, 150.6, 147.9, 133.6, 125.1, 124.8, 123.4, 122.0, 117.7,
˜
1606, 1566, 1548, 1455, 1400, 1235, 1217, 750, 736 cm–1. HRMS
(ESI): calcd. for C18H13N4 [M + H]+ 285.1140; found 285.1149.
3bb: Following the general procedure, the reaction was carried out
between 2-(1H-benzimidazol-1-yl)aniline (1b; 50 mg, 0.239 mmol,
1 equiv.) and 2-bromo-4-methylpyridine (2b; 50 μL, 0.478 mmol,
2.0 equiv.). Column chromatography on silica gel (8% ethyl acetate
in hexanes) yielded 58 mg (82%) of the title compound 3bb as a
white solid. Rf = 0.50 (20% ethyl acetate in hexanes); m.p. 131–
133 °C. 1H NMR (400 MHz, CDCl3): δ = 8.82–8.80 (m, 1 H), 8.63
(t, J = 0.5 Hz, 1 H), 8.45 (d, J = 5.0 Hz, 1 H), 7.86–7.83 (m, 2 H),
7.82–7.78 (m, 1 H), 7.42–7.37 (m, 3 H), 7.33 (td, J = 7.8, 1.2 Hz,
1 H), 7.06 (dd, J = 4.5, 0.6 Hz, 1 H), 2.55 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 151.3, 151.1, 150.3, 147.6, 146.8, 134.0,
127.6, 125.8, 123.7, 123.2, 122.9, 121.7, 120.9, 119.1, 116.8, 115.5,
114.7, 110.8, 21.6 ppm. FTIR (neat, KBr): ν = 1612, 1561, 1505,
˜
1471, 1373, 1164, 744 cm–1. HRMS (ESI): calcd. for C14H12N5 [M
+ H]+ 250.1093; found 250.1094.
3cc: Following the general procedure, the reaction was carried out
110.3, 110.1, 21.7 ppm. FTIR (neat, KBr): ν = 1633, 1551, 1498, between 2-(1H-1,2,4-triazol-1-yl)aniline (1c; 50 mg, 0.312 mmol,
˜
1443, 1237, 1216, 1160, 768 cm–1. HRMS (ESI): calcd. for
C19H15N4 [M + H]+ 299.1297; found 299.1287.
1 equiv.) and 2-bromo-6-methylpyridine (2c; 57 μL, 0.624 mmol,
2.0 equiv.). Column chromatography on silica gel (12% ethyl acet-
Eur. J. Org. Chem. 2014, 5986–5997
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5993

P. Subramanian, K. P. Kaliappan
FULL PAPER
ate in hexanes) yielded 54 mg (69%) of the title compound 3cc as
a white solid. Rf = 0.45 (20% ethyl acetate in hexanes); m.p. 152–
(ddd, J = 4.8, 1.9, 0.9 Hz, 1 H), 8.46 (dt, J = 8.3, 0.9 Hz, 1 H),
8.18 (dd, J = 8.4, 0.7 Hz, 1 H), 8.08 (s, 1 H), 7.90 (ddd, J = 8.3,
155 °C. 1H NMR (400 MHz, CDCl3): δ = 8.89 (dd, J = 7.5, 1.2 Hz, 7.4, 1.9 Hz, 1 H), 7.26–7.19 (m, 2 H), 6.70 (dd, J = 8.4, 0.7 Hz, 1
1 H), 8.43 (d, J = 5.1 Hz, 1 H), 8.30 (s, 1 H), 8.13 (s, 1 H), 7.88–
7.86 (m, 1 H), 7.48–7.39 (m, 2 H), 7.07 (dd, J = 5.0, 0.4 Hz, 1 H),
H), 4.60 (br. s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.8,
151.4, 150.7, 148.2, 138.7, 134.3, 133.1, 125.9, 120.5, 114.1, 113.3,
2.51 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.5, 152.3, 109.5, 106.8 ppm. FTIR (neat, KBr): ν = 3340, 2926, 1652, 1593,
˜
150.8, 150.6, 147.9, 133.6, 125.1, 124.8, 123.4, 122.0, 117.7, 114.7,
1481, 1378, 1019, 767 cm–1. HRMS (ESI): calcd. for C13H11N6 [M
+ H]+ 251.1045; found 251.1040.
110.8, 21.6 ppm. FTIR (neat, KBr): ν = 1612, 1561, 1504, 1471,
˜
1373, 1164, 754, 744 cm–1. HRMS (ESI): calcd. for C14H12N5 [M
+ H]+ 250.1093; found 250.1100.
3eb: Following the general procedure, the reaction was carried out
between 2-(1H-1,2,4-triazol-1-yl)benzene-1,3-diamine (1e; 50 mg,
0.285 mmol, 1 equiv.) and 2-bromo-4-methylpyridine (2b; 63 μL,
0.570 mmol, 2.0 equiv.). Column chromatography on silica gel
(18% ethyl acetate in hexanes) yielded 63.2 mg (84%) of the title
3da: Following the general procedure, the reaction was carried out
between
2,3-di(1H-1,2,4-triazol-1-yl)aniline
(1d;
50 mg,
0.220 mmol, 1.0 equiv.) and 2-bromopyridine (2a; 41 μL,
0.440 mmol, 2.0 equiv.). Column chromatography on silica gel compound 3eb as a white solid. Rf = 0.30 (30% ethyl acetate in
1
(17% ethyl acetate in hexanes) yielded 49 mg (74%) of the title
hexanes); m.p. 148–151 °C. H NMR (400 MHz, CDCl3): δ = 8.41
(d, J = 5.0 Hz, 1 H), 8.25 (d, J = 0.5 Hz, 1 H), 8.17 (dd, J = 8.3,
0.6 Hz, 1 H), 8.09 (s, 1 H), 7.21 (t, J = 8.1 Hz, 1 H), 7.04 (dd, J =
5.0, 0.5 Hz, 1 H), 6.70 (dd, J = 8.0, 0.6, Hz, 1 H) 4.60 (br. s, 2 H),
2.50 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.6, 153.9,
150.1, 143.9, 139.0, 134.5, 133.1, 125.9, 119.9, 113.3, 111.0, 109.5,
compound 3da as a white solid. Rf = 0.25 (20% ethyl acetate in
1
hexanes); m.p. 242–245 °C. H NMR (500 MHz, CDCl3): δ = 9.44
(s, 1 H), 9.05 (dd, J = 8.4, 0.9 Hz, 1 H), 8.64–8.62 (m, 1 H), 8.55
(d, J = 8.3 Hz, 1 H), 8.24 (s, 1 H), 8.12 (s, 1 H), 8.00–7.96 (m, 1
H), 7.85 (dd, J = 8.2, 0.9 Hz, 1 H), 7.60 (t, J = 8.3 Hz, 1 H), 7.33–
7.30 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 154.9, 152.8, 107.1, 24.4 ppm. FTIR (neat, KBr): ν = 3351, 2925, 1597, 1555,
˜
152.8, 148.4, 145.5, 139.2, 135.1, 125.7, 121.4, 118.7, 117.4, 1480, 1455, 1377, 1218, 1033, 768 cm–1. HRMS (ESI): calcd. for
114.8 ppm. FTIR (neat, KBr): ν = 2925, 1564, 1485, 1278, C14H13N6 [M + H]+ 265.1202; found 265.1193.
˜
773 cm–1. HRMS (ESI): calcd. for C15H10N8Na [M + Na]+
3ec: Following the general procedure, the reaction was carried out
between 2-(1H-1,2,4-triazol-1-yl)benzene-1,3-diamine (1e; 50 mg,
0.285 mmol, 1 equiv.) and 2-bromo-6-methylpyridine (2c; 63 μL,
325.0921; found 325.0921.
3db: Following the general procedure, the reaction was carried out
between
0.220 mmol, 1.0 equiv.) and 2-bromo-4-methylpyridine (2b; 49 μL,
0.440 mmol, 2.0 equiv.). Column chromatography on silica gel compound 3ec as a white solid. Rf = 0.30 (30% ethyl acetate in
2,3-di-(1H-1,2,4-triazol-1-yl)aniline
(1d;
50 mg, 0.570 mmol, 2.0 equiv.). Column chromatography on silica gel
(18% ethyl acetate in hexanes) yielded 53.5 mg (72%) of the title
1
(15% ethyl acetate in hexanes) yielded 60 mg (86%) of the title
hexanes); m.p. 147–150 °C. H NMR (400 MHz, CDCl3): δ = 8.25
(d, J = 8.2 Hz, 1 H), 8.24 (dd, J = 8.3, 0.7 Hz, 1 H), 7.78 (t, J =
8.3 Hz, 1 H), 8.07 (s, 1 H), 7.22 (t, J = 8.2 Hz, 1 H), 7.06 (d, J =
compound 3db as a white solid. Rf = 0.35 (20% ethyl acetate in
1
hexanes); m.p. 243–247 °C. H NMR (400 MHz, CDCl3): δ = 9.44
(s, 1 H), 8.99 (d, J = 8.5, 0.9 Hz, 1 H), 8.45 (d, J = 5.0 Hz, 1 H), 8.2 Hz, 1 H), 6.70 (dd, J = 8.3, 0.7 Hz, 1 H), 4.60 (br. s, 2 H), 2.64
8.32 (s, 1 H), 8.24 (s, 1 H), 8.12 (s, 1 H), 7.82 (dd, J = 8.2, 0.9 Hz,
1 H), 7.57 (t, J = 8.2 Hz, 1 H), 7.21 (dd, J = 5.0, 0.4 Hz, 1 H), 2.53
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.8, 151.3,
150.8, 150.3, 147.8, 134.4, 133.0, 125.8, 121.8, 114.5, 113.2, 109.6,
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.8, 152.2, 106.8, 21.5 ppm. FTIR (neat, KBr): ν = 3435, 3342, 2924, 1651,
˜
150.9, 150.3, 147.9, 145.5, 135.1, 125.6, 122.8, 122.7, 118.5, 117.3,
1556, 1477, 1417, 1161, 761 cm–1. HRMS (ESI): calcd. for
117.2, 115.2, 21.6 ppm. FTIR (neat, KBr): ν = 1668, 1611, 1568, C14H13N6 [M + H]+ 265.1202; found 265.1207.
˜
1482, 1278, 756, 734 cm–1. HRMS (ESI): calcd. for C16H13N8 [M
3ga1 and 3ga2: Following the general procedure, the reaction was
+ H]+ 317.1263; found 317.1252.
carried out between 2-(1H-imidazol-1-yl)-5-(trifluoromethyl)anil-
ine (1g; 100 mg, 0.440 mmol, 1 equiv.) and 2-bromopyridine (2a;
84 μL, 0.88 mmol, 2.0 equiv.). Column chromatography on silica
gel (10% ethyl acetate in hexanes) yielded 75 mg (56%) of an in-
3dc: Following the general procedure, the reaction was carried out
between
2,3-di(1H-1,2,4-triazol-1-yl)aniline
(1d;
50 mg,
0.220 mmol, 1.0 equiv.) and 2-bromo-6-methylpyridine (2c; 49 μL,
0.440 mmol, 2.0 equiv.). Column chromatography on silica gel separable mixture of regioisomeric products 3ga1* and 3ga2 (0.3:1)
(15% ethyl acetate in hexanes) yielded 61 mg (88%) of the title
as a white solid. Rf = 0.50 (20% ethyl acetate in hexanes); m.p.
134–137 °C. 1H NMR (400 MHz, CDCl3): δ = 9.25* (s, 0.3 H),
8.75* (s, 0.3 H), 8.71 (d, 8.3 Hz, 1 H), 8.60* (dd, J = 4.5, 0.8 Hz,
0.3 H), 8.46 (dd, J = 4.8, 1.0 Hz, 1 H), 8.11 (d, J = 2.76 Hz, 1 H),
8.08 (s, 1 H), 7.94 (td, J = 6.6, 1.8 Hz, 1 H), 7.92* (td, J = 8.1,
1.8 Hz, 0.3 H) 7.70 (d, J = 8.3 Hz, 1 H), 7.66–7.58* (m, 0.9 H),
compound 3dc as a white solid. Rf = 0.35 (20% ethyl acetate in
1
hexanes); m.p. 258–261 °C. H NMR (400 MHz, CDCl3): δ = 9.44
(s, 1 H), 9.07 (dd, J = 8.4, 0.8 Hz, 1 H), 8.33 (d, J = 8.4 Hz, 1 H),
8.24 (s, 1 H), 8.11 (s, 1 H), 7.86 (t, J = 7.6 Hz, 1 H), 7.84 (d, J =
7.6 Hz, 1 H), 7.59 (t, J = 8.4 Hz, 1 H), 7.16 (d, J = 7.6 Hz, 1 H),
2.69 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.9, 154.9, 7.48–7.47 (m, 1 H), 7.47–7.46* (m, 0.3 H), 7.43 (d, J = 2.7 Hz, 1
152.9, 152.7, 149.6, 145.5, 139.4, 135.1, 125.6, 122.8, 120.8, 118.6,
H), 7.31* (d, J = 1.5 Hz, 0.3 H), 7.21 (dd, J = 7.2, 4.8 Hz, 1
117.5, 111.6, 24.4 ppm. FTIR (neat, KBr): ν = 1635, 1483, 1213, H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.0, 148.6, 148.5,
˜
788, 771 cm–1. HRMS (ESI): calcd. for C16H13N8 [M + H]+
317.1263; found 317.1266.
148.1, 146.7, 139.2, 138.8, 132.3, 128.8, 126.4, 125.4, 120.9, 120.3,
119.6, 116.8, 116.7, 116.7, 116.6, 116.6, 115.1, 114.1, 113.2, 110.6,
110.3, 107.0, 106.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –60.5
3ea: Following the general procedure, the reaction was carried out
between 2-(1H-1,2,4-triazol-1-yl)benzene-1,3-diamine (1e; 50 mg,
0.285 mmol, 1 equiv.) and 2-bromopyridine (2a; 54 μL,
0.570 mmol, 2.0 equiv.). Column chromatography on silica gel
(20% ethyl acetate in hexanes) yielded 58.4 mg (82%) of the title
compound 3ea as a white solid. Rf = 0.25 (30% ethyl acetate in
(1.0), –60.8 (0.3) ppm. FTIR (neat, KBr): ν = 2928, 2851, 2101,
˜
1640, 1446, 1321, 1102, 772, 667 cm–1. HRMS (ESI): calcd. for
C15H10N4F3 [M + H]+ 303.0858; found 303.0851.
Note: The identity of 3ga2 was confirmed by a partial purification
of the above isomeric mixtures. The experimental data for pure
compound 3ga2 is given below.
1
hexanes); m.p. 175–178 °C. H NMR (400 MHz, CDCl3): δ = 8.56
5994
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5986–5997

A Unified Strategy Towards N-Aryl Heterocycles
M.p. 141–143 °C. 1H NMR (500 MHz, CDCl3): δ = 8.68 (d, J = 121.5, 120.7, 119.5, 118.0, 117.9, 117.2, 116.7, 116.6, 115.1, 114.9,
8.2 Hz, 1 H), 8.46–8.44 (m, 1 H), 8.08 (d, J = 2.7 Hz, 1 H), 8.06
(s, 1 H), 7.93–7.89 (m, 1 H), 7.65 (dd, J = 8.4, 0.5 Hz, 1 H), 7.46–
7.44 (m, 1 H), 7.41 (d, J = 2.8 Hz, 1 H), 7.19 (ddd, J = 7.3, 4.8,
0.9 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 149.9, 148.6,
148.5, 146.7, 139.2, 128.8, 126.1, 125.4, 123.9, 120.9, 116.8, 116.6,
113.2, 110.3, 106.9 ppm. HRMS (ESI): calcd. for C15H10F3N4 [M
+ H]+ 303.0852; found 303.0855.
110.5, 110.4, 109.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –60.5
(1.0), –60.8 (0.23) ppm. FTIR (neat, KBr): ν = 3019, 2927, 1732,
˜
1609, 1571, 1448, 1325, 1284, 1158, 756, 667 cm–1. HRMS (ESI):
calcd. for C19H12N4F3 [M + H]+ 353.1014; found 353.1025.
Note: The identity of 3ha2 was confirmed through a partial purifi-
cation of the above isomeric mixtures. The experimental data for
the pure compound 3ha2 is noted below.
Rf = 0.53 (20% ethyl acetate in hexanes); m.p. 121–124 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.87–8.82 (m, 1 H), 8.78 (d, J =
8.4 Hz, 1 H), 8.59 (d, J = 3.7 Hz, 1 H), 8.08 (s, 1 H), 7.97 (ddd, J
= 8.4, 7.4, 1.9 Hz, 1 H), 7.88 (d, J = 8.3 Hz, 1 H), 7.78 (td, J =
4.0, 1.6 Hz, 1 H), 7.58 (dd, J = 8.3, 0.8 Hz, 1 H), 7.46–7.39 (m, 2
H), 7.26 (td, J = 4.0, 0.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 150.8, 148.1, 146.6, 138.9, 134.0, 125.4, 124.6, 123.6,
123.4, 120.8, 118.1, 118.0, 117.2, 116.7, 116.6, 115.2, 110.5,
110.5 ppm. 19F NMR (376 MHz, CDCl3): δ = –60.5 ppm.
3gb1 and 3gb2: Following the general procedure, the reaction was
carried out between 2-(1H–imidazol-1-yl)-5-(trifluoromethyl)anil-
ine (1g; 100 mg, 0.440 mmol, 1 equiv.) and 2-bromo-4-methylpyr-
idine (2b; 95 μL, 0.880 mmol, 2.0 equiv.). Column chromatography
on silica gel (6% ethyl acetate in hexanes) yielded 98 mg (70%) of
an inseparable mixture of the regioisomeric products 3gb1* and
3gb2 (0.7:1) as a white solid. Rf = 0.50 (20% ethyl acetate in hex-
1
anes); m.p. 126–129 °C. H NMR (400 MHz, CDCl3): δ = 9.22 (s,
1 H), 8.52 (s, 1 H), 8.52* (s, 0.7 H), 8.43 (d, J = 5.0 Hz, 1 H), 8.30*
(d, J = 5.0 Hz, 0.7 H), 8.09* (s, 0.7 H), 8.08 (s, 1 H), 7.68* (d, J =
8.3 Hz, 0.7 H), 7.62 (d, J = 8.3 Hz, 1 H), 7.57* (dd, J = 1.1 Hz,
0.7 H), 7.46 (d, J = 1.4 Hz, 1 H), 7.48–7.45* (m, 0.7 H), 7.41* (d,
J = 2.7 Hz, 0.7 H), 7.32 (d, J = 1.1 Hz, 1 H), 7.03 (d, J = 4.32 Hz,
1 H), 7.05–7.01* (m, 0.7 H), 2.53* (s, 2.1 H), 2.50 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 151.1, 151.0, 150.4, 148.7, 148.0,
147.7, 133.9, 132.3, 127.1, 126.6, 126.3, 122.2, 121.6, 119.5, 119.5,
117.0, 116.6, 115.2, 115.1, 114.5, 113.6, 110.6, 110.2, 106.9, 106.7,
21.6 ppm. 19F NMR (376 MHz, CDCl3): δ = –60.5 (0.7), –60.8
3hc1 and 3hc2: Following the general procedure, the reaction was
carried out between 2-(1H-benzo[d]imidazol-1-yl)-5-(trifluorome-
thyl)aniline (1h; 50 mg, 0.180 mmol, 1 equiv.) and 2-bromo-6-meth-
ylpyridine (2c; 50 μL, 0.451 mmol, 2.5 equiv.). Column chromatog-
raphy on silica gel (9% ethyl acetate in hexanes) yielded 55 mg
(82%) of an inseparable mixture of the regioisomeric products
3hc1* and 3hc2 (0.9:1) as a white solid. Rf = 0.53 (20% ethyl acetate
in hexanes); m.p. 132–135 °C. 1H NMR (400 MHz, CDCl3): δ =
9.26* (s, 0.9 H), 8.89–8.87* (dd, J = 4.7, 0.9 Hz, 0.9 H), 8.56 (d, J
= 8.2 Hz, 1 H), 8.09 (s, 1 H), 7.90–7.79* (m, 3.6 H), 7.90–7.79 (m,
4 H), 7.68 (d, J = 8.1 Hz, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.45–
7.40* (m, 1.8 H), 7.45–7.40 (m, 1 H), 7.35* (t, J = 7.6 Hz, 0.9 H),
7.11* (dd, J = 7.4, 1.8 Hz, 0.9 H), 7.11 (dd, J = 7.4, 1.8 Hz, 1 H),
2.68* (s, 2.7 H), 2.68 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 157.5, 157.5, 152.5, 151.7, 150.1, 150.0, 147.0, 146.6, 139.3,
139.2, 134.1, 133.8, 129.5, 127.9, 127.4, 125.8, 125.5, 125.4, 124.5,
124.0, 123.3, 121.5, 120.3, 120.3, 120.2, 119.6, 117.9, 117.9, 117.3,
116.6, 116.6, 114.8, 114.8, 112.0, 111.7, 110.5, 110.5, 110.4, 110.0,
24.4, 24.3 ppm. 19F NMR (376 MHz, CDCl3): δ = –60.5 (1.0),
(1.0) ppm. FTIR (neat, KBr): ν = 2927, 2852, 2104, 1644, 1609,
˜
1571, 1448, 1325, 1158, 1118, 755, 668 cm–1. HRMS (ESI): calcd.
for C16H12N4F3 [M + H]+ 317.1014; found 317.1027.
3gc1: Following the general procedure, the reaction was carried out
between
2-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline
(1g;
100 mg, 0.440 mmol, 1 equiv.) and 2-bromo-6-methylpyridine (2c;
95 μL, 0.880 mmol, 2.0 equiv.). Column chromatography on silica
gel (7% ethyl acetate in hexanes) yielded 71 mg (51%) of the title
compound 3gc1 as a white solid. Rf = 0.50 (20% ethyl acetate in
1
hexanes); m.p. 136–139 °C. H NMR (400 MHz, CDCl3): δ = 9.30
–61.0 (0.93) ppm. FTIR (neat, KBr): ν = 3020, 1729, 1640, 1556,
˜
(s, 1 H), 8.50 (d, J = 8.2 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.63
(d, J = 8.2 Hz, 1 H), 7.57 (dd, J = 8.2, 0.9 Hz, 1 H), 7.46 (d, J =
0.9 Hz, 1 H), 7.30 (s, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 2.65 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.4, 150.3, 139.1,
133.8, 132.2, 127.1, 123.2, 119.7, 119.4, 119.4, 115.2, 115.1, 110.9,
1457, 1324, 1215, 758, 669 cm–1. HRMS (ESI): calcd. for
C20H14N3F3 [M + H]+ 367.1171; found 367.1186.
Benzimidazokinetins 5 and 6: Following the general procedure, the
reaction was carried out between kinetin-derived azole 4 (100 mg,
0.326 mmol, 1 equiv.) and 2-bromopyridine (2a; 100 μL,
0.816 mmol, 2.5 equiv.). Column chromatography on silica gel
yielded 126 mg (85%) of 5 and 6 (0.4:1) as a viscous liquid. Rf =
110.6, 106.9, 24.3 ppm. 19F NMR (376 MHz, CDCl3):
δ =
–61.1 ppm. FTIR (neat, KBr): ν = 2927, 2852, 2102, 1730, 1597,
˜
1577, 1456, 1123, 770, 669 cm–1. HRMS (ESI): calcd. for
C16H12N4F3 [M + H]+ 317.1014; found 317.1005.
1
0.30 (50% ethyl acetate in hexanes). H NMR (400 MHz, CDCl3):
δ = 8.90–8.87 (m, 1 H), 8.63 (s, 1 H), 8.55–8.51 (m, 2 H), 8.38 (d,
J = 8.4 Hz, 1 H), 8.12–8.10 (m, 1 H), 7.76–7.35 (m, 2 H), 7.44–
7.35 (m, 3 H), 7.31–7.30 (m, 1 H), 7.18–7.14 (m, 2 H), 6.26–6.23
(m, 2 H), 5.84 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
155.8, 152.4, 152.3, 150.9, 150.0, 148.4, 147.9, 147.7, 141.7, 138.6,
138.2, 137.0, 134.3, 125.1, 124.5, 124.4, 123.5, 120.8, 120.2, 117.3,
3ha1 and 3ha2: Following the general procedure, the reaction was
carried out between 2-(1H-benzo[d]imidazol-1-yl)-5-(trifluorome-
thyl)aniline (1h; 50 mg, 0.180 mmol, 1 equiv.) and 2-bromopyridine
(2a; 40 μL, 0.451 mmol, 2.5 equiv.). Column chromatography on
silica gel (9% ethyl acetate in hexanes) yielded 46 mg (73%) of an
inseparable mixture of the regioisomeric products 3ha1* and 3ha2
(0.2:1) as a white solid. Rf = 0.53 (20% ethyl acetate in hexanes);
m.p. 107–110 °C. H NMR (400 MHz, CDCl3): δ = 9 ppm. 17* (s,
0.2 H), 8.82* (d, J = 8.3 Hz, 0.2 H), 8.81 (dd, J = 9.0, 2.5 Hz, 1
H), 8.75 (d, J = 8.3 Hz, 1 H), 8.62–7.89* (m, 0.2 H), 8.57 (d, J =
114.4, 112.4, 110.3, 108.0, 45.5 ppm. FTIR (neat, KBr): ν = 3414,
˜
3066, 1644, 1442, 1025, 773 cm–1. HRMS (ESI): calcd. for
C26H19N8O [M + H]+ 459.1676; found 459.1675.
1
General Procedure for the Synthesis of N-Aryl Heterocycles: The
4.0 Hz, 1 H), 8.05 (s, 1 H), 7.96–7.93* (m, 0.2 H), 7.95 (td, J = 8.7, starting amine 1 (100 mg, 1 equiv.) and aryl bromide (2 equiv.) were
1.7 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 1 H), 7.79–7.76* (m, 0.4 H), 7.73
(dd, J = 5.3, 2.1 Hz, 1 H), 7.65* (d, J = 8.2 Hz, 0.2 H), 7.55 (d, J
added to an oven-dried screw-cap reaction tube charged with a
magnetic stirring bar, Cu(OAc)2·H2O (20 mol-%), 1,10-phen-
= 8.2 Hz, 1 H), 7.42–7.38* (m, 0.2 H), 7.41–7.36 (m, 2 H), 7.32* anthroline monohydrate (30 mol-%), tBuONa (3 equiv.) and TBAI
(t, J = 8.3 Hz, 0.2 H), 7.24 (dd, J = 7.5, 2.6 Hz, 1 H), 7.25–7.22* (1 equiv.) in dry DMF at room temp. Then the reaction mixture
(m, 0.4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.3, 150.8, was closed with a screw cap and the mixture was stirred at 130 °C
148.1, 146.5, 138.9, 138.8, 133.9, 129.4, 125.3, 124.5, 124.0, 123.4,
for 17 h. It was then cooled to room temperature, water (5 mL) was
Eur. J. Org. Chem. 2014, 5986–5997
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5995

P. Subramanian, K. P. Kaliappan
FULL PAPER
added and the mixture extracted with ethyl acetate (3ϫ 5 mL).
Then the combined organic layers were washed with water (7ϫ
5 mL), dried with anhyd. Na2SO4 and concentrated to give the
crude product. Purification by column chromatography afforded
the N-aryl heterocycles.
2923, 1629, 1458, 1156, 746 cm–1. HRMS (ESI): calcd. for
C13H10N5Na [M + Na]+ 272.0907; found 272.0907.
3hd: Following the general procedure, the reaction was carried out
between
2-(1H-benzo[d]imidazol-1-yl)-5-(trifluoromethyl)aniline
(1h; 100 mg, 0.360 mmol, 1 equiv.) and 2-bromobenzene (2d; 75 μL,
0.72 mmol, 2.0 equiv.). Column chromatography on silica gel
yielded 96 mg (76%) of the title compound 3hd as a white solid. Rf
3bd: Following the general procedure, the reaction was carried out
between
2-(1H-benz[d]imidazol-1-yl)aniline
(1b;
100 mg,
1
= 0.35 (20% ethyl acetate in hexanes); m.p. 169–172 °C H NMR
0.478 mmol, 1 equiv.) and bromobenzene 2d (100 μL, 0.956 mmol,
2.0 equiv.). Column chromatography on silica gel (15% ethyl acet-
ate in hexanes) yielded 115 mg (85%) of the title compound 3bd as
a white solid. Rf = 0.20 (20% ethyl acetate in hexanes); m.p. 128–
131 °C. 1H NMR (400 MHz, CDCl3): δ = 7.85–7.82 (m, 4 H), 7.78
(d, J = 7.9 Hz, 1 H), 7.62 (t, J = 7.6 Hz, 2 H), 7.56–7.54 (m, 1
H), 7.44 (t, J = 7.5 Hz, 1 H), 7.39–7.28 (m, 4 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 147.2, 135.3, 135.3, 130.2, 128.2, 127.7,
125.7, 124.8, 123.5, 123.3, 122.3, 120.4, 119.1, 111.0, 110.9,
(500 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.89 (d, J = 8.3 Hz, 1 H),
7.85–7.81 (m, 3 H), 7.65–7.62 (t, J = 8.3 Hz, 2 H), 7.58–7.55 (m, 2
H), 7.47 (t, J = 7.5 Hz, 1 H), 7.42–7.37 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 153.7, 146.9, 135.4, 134.9, 130.3, 128.1,
126.1, 125.5, 124.8, 124.2, 123.9, 122.6, 117.4, 116.4, 111.3, 111.2,
110.3 ppm. FTIR (neat, KBr): ν = 2923, 1640, 1321, 1095,
˜
797 cm–1. HRMS (ESI): calcd. for C20H13N3F3 [M + H]+ 352.1056;
found 352.1058.
110.3 ppm. FTIR (neat, KBr): ν = 2924, 1630, 1324, 1122,
˜
Benzimidazokinetin 5: Following the general procedure, the reaction
746 cm–1. HRMS (ESI): calcd. for C19H14N3 [M + H]+ 284.1182;
found 284.1176.
was carried out between kinetin-derived azole
4 (100 mg,
0.326 mmol, 1 equiv.) and 2-bromopyridine (2a; 100 μL,
0.956 mmol, 2.5 equiv.) in the presence of tBuONa (241 mg,
1.14 mmol, 3 equiv.). Column chromatography on silica gel yielded
92 mg (62%) of the title compound 5 as a white solid. Rf = 0.30
(50% ethyl acetate in hexanes); m.p. 236–239 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.76 (dd, J = 6.9, 1.6 Hz, 1 H), 8.67 (d, J
= 8.3 Hz, 1 H), 8.54 (dd, J = 4.8, 1.1 Hz, 1 H), 8.46 (s, 1 H), 8.04–
8.07 (m, 1 H), 7.90–7.85 (m, 1 H), 7.40–7.33 (m, 3 H), 7.24–7.16
(m, 1 H), 6.29 (s, 2 H), 5.86 (br. t, J = 5.3 Hz, 1 H), 4.86 (br. d, J
= 5.4 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 150.9,
148.3, 148.2, 142.4, 138.7, 134.4, 125.1, 124.8, 123.6, 120.6, 117.0,
3cd: Following the general procedure, the reaction was carried out
between 2-(1H-triazol-1-yl)aniline (1c; 100 mg, 0.624 mmol,
1 equiv.) and bromobenzene (2d; 130 μL, 1.24 mmol, 2.0 equiv.).
Column chromatography on silica gel (19% ethyl acetate in hex-
anes) yielded 107 mg (73%) of the title compound 3cd as a white
solid. Rf = 0.35 (30% ethyl acetate in hexanes); m.p. 104–106 °C.
1H NMR (500 MHz, CDCl3): δ = 8.05 (s, 1 H), 7.90–7.88 (m, 1
H), 7.76 (d, J = 1.1 Hz, 1 H), 7.75–7.74 (m, 1 H), 7.65–7.63 (m, 1
H), 7.60–7.57 (m, 2 H), 7.44–7.41 (m, 1 H), 7.39–7.35 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.8, 153.3, 135.1,
134.4, 130.1, 127.8, 124.6, 124.5, 123.8, 122.7, 111.9, 111.5 ppm.
114.9, 112.6, 110.6, 107.7, 38.1 ppm. FTIR (neat, KBr): ν = 2960,
˜
1616, 1441, 771 cm–1. HRMS (ESI): calcd. for C21H15N7NaO [M
+ Na]+ 404.1230; found 404.1238.
FTIR (neat, KBr): ν = 2923, 1563, 1160, 747 cm–1. HRMS (ESI):
˜
calcd. for C14H11N4 [M + H]+ 235.0978; found 235.0982.
Supporting Information (see footnote on the first page of this arti-
cle): Starting material preparations, mechanistic studies, NMR
spectra, XRD data.
3ce: Following the general procedure, the reaction was carried out
between 2-(1H-triazol-1-yl)aniline (1c; 100 mg, 0.624 mmol,
1 equiv.) and 2-bromonaphthalene (2e; 259 mg, 1.24 mmol,
2.0 equiv.). Column chromatography on silica gel (23% ethyl acet-
ate in hexanes) yielded 119 mg (67%) of the title compound 3ce as Acknowledgments
a white solid. Rf = 0.40 (20% ethyl acetate in hexanes); m.p. 177–
180 °C. 1H NMR (500 MHz, CDCl3): δ = 8.20 (d, J = 1.8 Hz, 1
The authors thank the Board of Research in Nuclear Sciences
H), 8.09 (s, 1 H), 8.07 (d, J = 8.7 Hz, 1 H), 7.96–7.92 (m, 3 H),
7.89 (dd, J = 8.7, 2.1 Hz, 1 H), 7.75–7.71 (m, 1 H), 7.60–7.55 (m,
2 H), 7.43–7.40 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
154.8, 153.3, 135.1, 134.4, 130.1, 127.8, 124.6, 124.5, 123.8, 122.7,
(BRNS) – Department of Atomic Energy (DAE), Mumbai for fin-
ancial support, the University Grants Commission (UGC), New
Delhi for a fellowship to P. S., and the XRD facility of the Depart-
ment of Chemistry, IIT Bombay.
111.9, 111.5 ppm. FTIR (neat, KBr): ν = 2931, 1566, 1476, 1160,
˜
747 cm–1. HRMS (ESI): calcd. for C18H12N4Na [M + Na]+
307.0954; found 307.0952.
[1] a) M. C. Bagley, J. W. Dale, E. A. Merritt, X. Xiong, Chem.
Rev. 2005, 105, 685–714; b) J. Kim, M. Movassaghi, Chem. Soc.
Rev. 2009, 38, 3035–3050.
[2] a) E. Hao, B. Fabre, F. R. Fronczek, M. G. H. Vicente, Chem.
Mater. 2007, 19, 6195–6205; b) Y. G. Lee, Y. Koyama, M.
Yonekawa, T. Takata, Macromolecules 2009, 42, 7709–7717.
[3] a) Q. Du, W. Zhu, Z. Zhao, X. Qian, Y. Xu, J. Agric. Food
Chem. 2012, 60, 346–353; b) N. Jacobsen, L.-E. K. Pedersen,
Pestic. Sci. 1983, 14, 90–97.
[4] a) I. Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127–
2198; b) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem.
Int. Ed. 2005, 44, 4442–4489; Angew. Chem. 2005, 117, 4516;
c) D. Zhao, J. You, C. Hu, Chem. Eur. J. 2011, 17, 5466–5492.
[5] W. C. P. Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem. Soc.
2005, 127, 14560–14561.
[6] a) W. C. P. Tsang, R. H. Munday, G. Brasche, N. Zheng, S. L.
Buchwald, J. Org. Chem. 2008, 73, 7603–1610; b) J. A. Jordan-
Hore, C. C. C. Johansson, M. Gulias, E. M. Beck, M. J. Gaunt,
J. Am. Chem. Soc. 2008, 130, 16184–16186.
3ed: Following the general procedure, the reaction was carried out
between 2-(1H-1,2,4-triazol-1-yl)benzene-1,3-diamine (1e; 200 mg,
1.142 mmol, 1 equiv.) and bromobenzene (2d; 359 μL, 2.28 mmol,
2.0 equiv.). Column chromatography on silica gel (27% ethyl acet-
ate in hexanes) yielded 279 mg (98%) of the title compound 3ed as
a white solid. Rf = 0.30 (40% ethyl acetate in hexanes); m.p. 154–
1
157 °C. H NMR (500 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.76 (d, J
= 7.8 Hz, 2 H), 7.58 (t, J = 7.6 Hz, 2 H), 7.41 (t, J = 7.4 Hz, 1 H),
7.16 (t, J = 8.1 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.66 (d, J =
7.9 Hz, 1 H) ppm; Note: When the 1H NMR spectrum of com-
pound 3ed in CDCl3 was recorded, we did not observe the presence
of an NH2 peak. Therefore the 1H NMR spectrum was re-analysed
in [D6]DMSO (see the spectrum in the Supporting Information).
13C NMR (100 MHz, CDCl3): δ = 154.2, 136.4, 135.3, 133.7, 130.0,
127.5, 125.5, 123.7, 108.5, 101.3 ppm. FTIR (neat, KBr): ν = 3431,
˜
5996
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5986–5997

A Unified Strategy Towards N-Aryl Heterocycles
[7] a) Q. Xiao, W.-H. Wang, G. Liu, F.-K. Meng, J.-H. Chen, Z.
Yang, Z.-J. Shi, Chem. Eur. J. 2009, 15, 7292–7296; b) R. K.
Kumar, T. Punniyamurthy, RSC Adv. 2012, 2, 4616–4619.
[8] a) K. Inamoto, T. Saito, M. Katsuno, T. Sakamoto, K. Hiroya,
Org. Lett. 2007, 9, 2931–2939; b) D. Eom, Y. Jeong, Y. R. Kim,
E. Lee, W. Choi, P. H. Lee, Org. Lett. 2013, 15, 5210–5213.
[9] a) T.-S. Mei, X. Wang, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131,
10806–10807; b) J. J. Neumann, S. Rakshit, T. Dröge, F. Glor-
ius, Angew. Chem. Int. Ed. 2009, 48, 6892–6895; Angew. Chem.
2009, 121, 7024.
[10] M. Wasa, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130, 14058–14059.
[11] a) L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. Int.
Ed. 2009, 48, 9792–9826; Angew. Chem. 2009, 121, 9976; b) J.
Wencel-Delord, T. Drçge, F. Liu, F. Glorius, Chem. Soc. Rev.
2011, 40, 4740–4761; c) C. S. Yeung, V. M. Dong, Chem. Rev.
2011, 111, 1215–1292; d) C. Liu, H. Zhang, W. Shi, A. Lei,
Chem. Rev. 2011, 111, 1780–1824; e) H. Wang, C. Grohmann,
C. Nimphius, F. Glorius, J. Am. Chem. Soc. 2012, 134, 19592–
19595.
[12] a) X. Chen, X.-S. Hao, C. E. Goodhue, J.-Q. Yu, J. Am. Chem.
Soc. 2006, 128, 6790–6791; b) D. Monguchi, T. Fujiwara, H.
Furukawa, A. Mori, Org. Lett. 2009, 11, 1607–1610; c) Q.
Wang, S. L. Schreiber, Org. Lett. 2009, 11, 5178–5180; d) A. E.
King, L. M. Huffman, A. Casitas, M. Costas, X. Ribas, S. S.
Stahl, J. Am. Chem. Soc. 2010, 132, 12068–12073; e) A. Arm-
strong, J. C. Collins, Angew. Chem. Int. Ed. 2010, 49, 2282–
2285; Angew. Chem. 2010, 122, 2332; f) T. Kawano, K. Hirano,
T. Satoh, M. Miura, J. Am. Chem. Soc. 2010, 132, 6900–6901;
g) Y. Xie, R. Zhang, K. Jin, X. Wang, C. Duan, J. Org. Chem.
2011, 76, 5444–5449; h) A. John, K. M. Nicholas, J. Org.
Chem. 2011, 76, 4158–4162; i) N. Matsuda, K. Hirano, T. Sa-
toh, M. Miura, Org. Lett. 2011, 13, 2860–2863; j) M. Miya-
saka, K. Hirano, T. Satoh, R. Kowalczyk, C. Bolm, M. Miura,
Org. Lett. 2011, 13, 359–361; k) S. Guo, B. Qian, Y. Xie, C.
Xia, H. Huang, Org. Lett. 2011, 13, 522–525; l) H.-Q. Do, O.
Daugulis, J. Am. Chem. Soc. 2011, 133, 13577–13586.
[13] a) G. Brasche, S. L. Buchwald, Angew. Chem. Int. Ed. 2008,
47, 1932–1934; Angew. Chem. 2008, 120, 1958; b) S. Ueda, H.
Nagasawa, Angew. Chem. Int. Ed. 2008, 47, 6411–6413; Angew.
Chem. 2008, 120, 6511; c) J. Lu, Y. Jin, H. Liu, Y. Jiang, H.
Fu, Org. Lett. 2011, 13, 3694–3697; d) S. H. Cho, J. Yoon, S.
Chang, J. Am. Chem. Soc. 2011, 133, 5996–6005; e) Y. Oda, K.
Hirano, T. Satoh, M. Miura, Org. Lett. 2012, 14, 664–667; f)
M. M. Guru, T. Punniyamurthy, J. Org. Chem. 2012, 77, 5063–
5073; g) S. H. Cho, J. Yoon, S. Chang, J. Am. Chem. Soc. 2013,
133, 5996–6005.
Chem. Commun. 2012, 48, 9418–9420; c) Q. Liu, H. Yang, Y.
Jiang, Y. Zhao, H. Fu, RSC Adv. 2013, 3, 15636–15644; d) M.
Wang, Y. Jin, H. Yang, H. Fu, L. Hu, RSC Adv. 2013, 3, 8211–
8214; e) P. Hu, Q. Wang, Y. Yan, S. Zhang, B. Zhang, Z. Wang,
Org. Biomol. Chem. 2013, 11, 4304–4307; f) G. Li, C. Jia, K.
Sun, Org. Lett. 2013, 15, 5198–5201; g) T. W. Liwosz, S. R.
Chemler, Chem. Eur. J. 2013, 19, 12771–12777; h) T. Liu, H.
Yang, Y. Jiang, H. Fu, Adv. Synth. Catal. 2013, 355, 1169–
1176; i) X. Li, L. He, H. Chen, W. Wu, H. Jiang, J. Org. Chem.
2013, 78, 3636–3646; j) Á. M. Martínez, N. Rodriguez, R. G.
Arrayas, J. C. Carretero, Chem. Commun. 2014, 50, 2801–2803.
C. Tang, N. Jiao, J. Am. Chem. Soc. 2012, 134, 18924–18927.
a) Q. Shen, S. Shekhar, J. P. Stambuli, J. F. Hartwig, Angew.
Chem. Int. Ed. 2005, 44, 1371–1375; Angew. Chem. 2005, 117,
1395; b) Q. Shen, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129,
7734–7735; c) P. Subramanian, K. P. Kaliappan, Eur. J. Org.
Chem. 2013, 595–604; d) M. Su, N. Hoshiya, S. L. Buchwald,
Org. Lett. 2014, 16, 832–835.
a) X. Han, S. S. Pin, K. Burris, L. K. Fung, S. Huang, M. T.
Taber, J. Zhang, G. M. Dubowchik, Bioorg. Med. Chem. Lett.
2005, 15, 4029–4032; b) M. S. Christodoulou, F. Colombo, D.
Passarella, G. Ieronimo, V. Zuco, M. D. Cesare, F. Zunino, Bi-
oorg. Med. Chem. 2011, 19, 1649–1657.
V. A. Anisimova, A. A. Spasov, V. A. Kosolapov, I. E. Tolpy-
gin, V. I. Porotikov, A. F. Kucheryavenko, V. A. Sysoeva, E. V.
Tibir’kova, L. V. El’tsova, Pharm. Chem. J. 2009, 43, 491–494.
K. M. Dawood, N. M. Elwan, B. F. Abdel-Wahab, ARKIVOC
2011, 111–195.
X. Wang, Y. Jin, Y. Zhao, L. Zhu, H. Fu, Org. Lett. 2012, 14,
452–455.
a) S. Ueda, H. Nagasawa, J. Am. Chem. Soc. 2009, 131, 15080–
15081; b) H. Wang, Y. Wang, C. Peng, J. Zhang, Q. Zhu, J. Am.
Chem. Soc. 2010, 132, 13217–13219; c) K.-S. Masters, T. R. M.
Rauws, A. K. Yadav, W. A. Herrebout, B. Van der Veken,
B. U. W. Maes, Chem. Eur. J. 2011, 17, 6315–6320.
a) L. Almirante, L. Polo, A. Mugnaini, E. Provinciali, P. Ru-
garli, A. Biancotti, A. Gamba, W. Murmann, J. Med. Chem.
1965, 8, 305–312; b) H. T. Swainston, G. M. Keating, CNS
Drugs 2005, 19, 65–89.
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25] a) S. I. S. Rattan, J. Anti-Aging Med. 2002, 5, 113–116.
[26] a) J. J. Teo, Y. Chang, H. C. Zeng, Langmuir 2006, 22, 7369–
7377; b) A. Y. S. Malkhasian, M. E. Finch, B. Nikolovski, A.
Menon, B. E. Kucera, F. A. Chavez, Inorg. Chem. 2007, 46,
2950–2952; c) Y.-F. Wang, K. K. Toh, J.-Y. Lee, S. Chiba, An-
gew. Chem. Int. Ed. 2011, 50, 5927–5931.
[14] a) F. Collet, R. H. Dodd, P. Dauban, Chem. Commun. 2009,
5061–5074; b) A. Armstrong, J. C. Collins, Angew. Chem. Int.
Ed. 2010, 49, 2282–2285; Angew. Chem. 2010, 122, 2332; c) S.
Guo, B. Qian, Y. Xie, C. Xia, H. Huang, Org. Lett. 2010, 12,
522–525; d) K. Hirano, T. Satoh, M. Miura, Org. Lett. 2011,
13, 2395–2397; e) T. Ikawa, T. Nishiyama, T. Shigeta, S. Mohri,
S. Morita, S.-i. Takayanagi, Y. Terauchi, Y. Morikawa, A. Tak-
agi, Y. Ishikawa, S. Fujii, Y. Kita, S. Akai, Angew. Chem. Int.
Ed. 2011, 50, 5674–5677; f) H. Xu, H. Fu, Chem. Eur. J. 2012,
18, 1180–1186; g) M.-L. Louillat, F. W. Patureau, Org. Lett.
2013, 15, 164–167.
[15] For reviews, see: a) S. S. Stahl, Angew. Chem. Int. Ed. 2004, 43,
3400–3420; Angew. Chem. 2004, 116, 3480; b) T. Punniyamur-
thy, S. Velusamy, J. Iqbal, Chem. Rev. 2005, 105, 2329–2364.
[16] a) D. Lubriks, I. Sokolovs, E. Suna, J. Am. Chem. Soc. 2012,
134, 15436–15442; b) Z.-L. Wang, L. Zhao, M.-X. Wang,
[27] Unable to trace the product when the reaction was carried out
in toluene.
[28] a) G. Brasche, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47,
1932–1934; Angew. Chem. 2008, 120, 1958; b) P. Sang, Y. Xie,
J. Zou, Y. Zhang, Org. Lett. 2012, 14, 3894–3897; c) G.-R. Qu,
L. Liang, H. Y. Niu, W.-H. Rao, H.-M. Guo, J. S. Fossey, Org.
Lett. 2012, 14, 4494–4497.
[29] a) S. Iyer, C. Ramesh, Tetrahedron Lett. 2000, 41, 8981–8984;
b) F. Karimi, B. Långström, J. Chem. Soc. Perkin Trans. 1 2002,
2111–2115.
[30] a) L. M. Huffman, S. S. Stahl, Dalton Trans. 2011, 40, 8959–
8963; b) S. Zhang, Y. Ding, Organometallics 2011, 30, 633–641.
[31] M. Trivedi, G. Singh, R. Nagarajan, N. P. Rath, Inorg. Chim.
Acta 2013, 394, 107–116.
Received: July 6, 2014
Published Online: August 5, 2014
Eur. J. Org. Chem. 2014, 5986–5997
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5997