Copper-Catalyzed Domino Three-Component Approach for the Assembly of 2-Aminated Benzimidazoles and Quinazolines

Article abstract of DOI:10.1021/acs.joc.5b00614

A copper-promoted three-component synthesis of 2-aminobenzimidazoles (1) or of 2-aminoquinazolines (2) involving cyanamides, arylboronic acids, and amines has been developed. The operationally simple oxidative process, performed in the presence of K₂

Full text of DOI:10.1021/acs.joc.5b00614

Article
pubs.acs.org/joc
Copper-Catalyzed Domino Three-Component Approach for the
Assembly of 2‑Aminated Benzimidazoles and Quinazolines
Lam Quang Tran, Jihui Li, and Luc Neuville*
́
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, Laboratoire International Associe, CNRS, 91198
Gif-sur-Yvette Cedex, France
S
* Supporting Information
ABSTRACT: A copper-promoted three-component synthesis of 2-aminobenzimidazoles (1) or of 2-aminoquinazolines (2)
involving cyanamides, arylboronic acids, and amines has been developed. The operationally simple oxidative process, performed
in the presence of K2CO3, a catalytic amount of CuCl2·2H2O, 2,2′-bipyridine, and an O2 atmosphere (1 atm), allows the rapid
assembly of either benzimidazoles or quinazolines starting from aryl- or benzyl-substituted cyanamides, respectively. In this
process, the copper promotes the formation of three bonds, two C−N bonds, and an additional bond resulting from C−H
functionalization event.
of the precursors. Limitations have been reduced through the
development of strategies relying on metal-catalyzed C−N
bond-forming reactions,8 allowing more accessible ortho-
functionalized aryl halides (Scheme 1c) to be used.9 Addition-
ally, ingenious domino processes combining the in situ
formation of a properly functionalized precursor followed by
cyclization have also been studied for the synthesis of
benzimidazoles, rendering the overall process easier.10 Direct
functionalization of the C−H bond is an attractive strategy that
is gaining in popularity, featuring an easy access to precursors.11
In this context, copper-catalyzed C−H functionalization has
recently been used in a number of strategies toward heterocycle
assembly.12 Following Buchwald’s work,13a various oxidative
processes dealing with the synthesis of benzimidazoles or
quinazolines have been reported, including intermolecular C−
H amination of 1H-benzo[d]imidazole (Scheme 1d) and metal-
free promoted reaction.13−15 Notwithstanding the efficiency of
these reaction sequences, alternative simple and modulable
protocols, which would allow working from simple precursors,
are still in demand.
INTRODUCTION
■
Nitrogen-containing heterocycles are fundamental targets in the
pharmaceutical industry as well as in materials science.1 Among
these, benzimidazoles2and quinazolines3 have been successfully
explored as drug-like scaffolds, and some of their 2-aminated
counterparts have, for example, led to the commercialization of
compounds such as astemizole4 or prazosin.5
Several strategies can be adopted to build such heterocycles.
Performing a nucleophilic aromatic substitution (SNAr)
between 2-halogenated azoles and amines constitute one
approach to build 2-aminated targets (Scheme 1a).6 Alter-
natively, condensations of 1,2-disubstituted aromatic units such
as 1,2-diaminated arenes or ortho-carbonylated anilines, with
carbodiimides, thioisocyanates, or amino-ureas followed by
dehydrative cyclization, have also been reported (Scheme 1b).7
While valuable, these methods suffer from the poor availability
Scheme 1. Major Disconnections for the Synthesis of 2-
Aminated Benzimidazoles and Quinazolines
We have been involved in exploring metal-catalyzed
transformation for the synthesis of heterocyclic structures16
including strategies based on C−H bond functionalization and
C−N bond formation.17 Focusing on copper-catalyzed aerobic
transformations18 we reported a direct synthesis of benzimida-
zoles in which a single catalytic system promoted a Chan−
Lam−Evans N-arylation19 and a C−H activation/C−N bond-
forming process in a tandem way and developed an oxidative
Received: March 18, 2015
© XXXX American Chemical Society
A
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copper promoted three-component synthesis of N,N′,N″
trisubstituted guanidines.20 With this multicomponent reaction
in hand, we became interested in performing a cyclizative
postfunctionalization21 to build 2-aminated benzimidazoles. On
the basis of Bao’s elegant one-pot synthesis of benzimidazoles
using carbodiimides as precursor and involving a discrete
guanidine (12) as intermediate (Scheme 2a),22 we anticipated
Table 1. Copper-Catalyzed Three-Component Domino
Process: Survey of Reaction Conditions
Scheme 2. Copper-Catalyzed Three-Component Synthesis of
2-Aminobenzimidazoles
13a
11a
yield
b
entry
1
(equiv) (equiv)
ligand
base
(%)
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.0
1.5
BiPy
BiPy
BiPy
BiPy
BiPy
−
K2CO3
K2CO3
−
Cs2CO3
t-BuOK
−
K2CO3
K2CO3
K2CO
63
60
30
10
5
c
2
3
4
5
6
20
56
30
36
c
7
Phen
c
8
c
OPPh3
9
N,N′-dimethylethylene
diamine
10
1.5
1.5
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.5
1.0
1.0
1.0
1.0
N-methylimidazole
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
59
42
63
48
82
37
14
72
d
11
BiPy
BiPy
BiPy
BiPy
BiPy
BiPy
BiPy
e
12
e
13
e
14
ef
,
that copper should be a suitable promotor for the
postfunctionalization and decided to explore whether 2-
aminated benzimidazoles could be directly obtained from
cyanamides in a multicomponent cascades reaction using a
single catalyst (Scheme 2b).
From this study, we now report conditions allowing the
construction of 2-aminated benzimidazoles or quinazolines,
depending on the substitution of the cyanamide, through an
aerobic copper-promoted three-component reaction involving
amines, arylboronic acids, and cyanamides.23
15
16
17
eg
,
eh
,
a
General conditions: CuCl2·H2O (0.2 equiv), ligand (0.2 equiv), base
(2.25 equiv), O2 (1 atm), cyanamide 14a (1.0 equiv), p-tolylboronic
b
c
acid 13a, piperidine 11a, toluene, 100 °C, 24 h. Isolated yield. Base
(1.5 equiv). Under air instead of O2 at 50 °C for 24 h, then at 100 °C
for 24 h. 1.5 equiv of cyanamide 14a. Reaction performed with 0.075
equiv of CuCl2·H2O and ligand. Reaction performed with 2.0 equiv of
CuCl2·H2O and ligand under N2. Cu(OAc)2 was used instead of
CuCl2·H2O.
d
e
f
g
h
RESULTS AND DISCUSSION
■
We began to evaluate the reaction by reacting p-tolyl boronic
acid (13a), piperidine (11a), and p-tolylcyanamide (14a) under
the conditions previously established for the three-component
synthesis of N-arylated guanidines [Table 1, entry 1].
Delightfully, the expected benzimidazole could be isolated in
63% yield upon extending the reaction time from 0.5 h to 24 h.
Further evaluation led to the following conclusion (Table 1):
K2CO3 proved to be clearly superior to stronger bases such as
Cs2CO3 or t-BuOK and its stoichiometry was best established
as 2.25 equiv even if reducing its amount to 1.5 equiv only
marginally affected the yield. Several additives/ligands have
been evaluated: (1,10-phenanthroline (Phen), 2,2′-bipyridine
(BiPy), triphenylphosphine oxide, N,N′-dimethylethylenedi-
amine, N-methylimidazole), and we found that BiPy was the
most effective. Reactions performed under air instead of an O2
atmosphere (entry 11) or with 2 equiv of copper under
anaerobic conditions (N2 atmosphere, entry 16) resulted in low
yields. We also noticed that a temperature of 100 °C was
necessary to induce the cyclization step. Indeed, at 50 °C, the
reaction stalled at the guanidine stage and degradation was
observed over extended time. Using Cu(OAc)2 in place of
CuCl2·H2O (entry17) or lowering the amount of CuCl2·H2O
to 7.5 mol % (entry 15) reduced the outcome of the reaction.
Finally, as in many multicomponent reactions, the ratio
between the reacting partners had an influence and 1.5/1.0/
1.5 (13a/ 11a/14a) was found to be optimal for the reaction.
With suitable conditions in hand [Table 1 entry 14], the
scope was investigated (Figure 1).
Various N-arylated 2-amino benzimidazoles were prepared
from aryl cyanamides as illustrated in Figure 1. The presence of
an electron-donating or -withdrawing group at the para-
position of arylcyanamides (OMe for 14b or CF3 for 14c)
was tolerated in the sequence, but N-(4-(trifluoromethyl)-
phenyl)cyanamide (14c) furnished a reduced yield of
benzimidazole 1j. In the latter case, while the intermediate
amidine was formed uneventfully, the cyclization step was more
sluggish. Using two different aryl groups in the cyanamide and
the boronic acid residue resulted in the formation of an
isomeric mixture as found with the synthesis of compound 1k
and 1k′. It should be noted that cyclization on the most
electronically enriched arene did predominate. Steric hindrance
was clearly detrimental in the reaction, as observed using o-tolyl
cyanamide (14d) and o-tolylboronic acid (13c) to assemble
benzimidazole 1l, isolated in 36% yield. Increasing the reaction
temperature to 130 °C (in xylene) and applying prolonged
reaction (48 h) was however necessary to reach this yield. A
competitive pathway accounted for the modest yield observed
in such case. Indeed, we were able to isolate from the reaction a
side product resulting from a Csp3-H activation/cyclization
process,24 namely 2-amino-1-phenylquinazolin-4(1H)-one 15,
albeit in a low 15% yield.
B
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2-aminoquinazoline 2a was isolated in 36% yield (Figure 2).
The yield could not be improved by performing the reaction in
Figure 1. Scope of the Cu-catalyzed synthesis of 2-aminated
N1‑arylbenzimidazoles.
Figure 2. Scope of the Cu-catalyzed synthesis of 4-arylquinazolin-2-
amines.
Secondary amines, whether cyclic or acyclic, produced the
corresponding 2-amino-benzimidazoles 1b, 1d, and 1e in good
yields. A significant but reduced yield of 39% of compound 1c
was obtained when performing the reaction with the relatively
crowded N-methylcyclohexylamine. Primary amines can also be
engaged in the reaction but proved to be less efficient probably
due to the competitive N-dealkylation under oxidative
conditions.25 Biologically relevant NH2 N1-aryl-2-aminobenzi-
midazoles26 could not be directly obtained using aqueous
ammonia in the three-component process.27 However, as
illustrated in Scheme 3, deprotection of N2-tert-butyl amino-
benzimidazole 1h was easily achieved by refluxing in trifluoro-
acetic acid in the presence of anisole, which acts as a butyl
cation scavenger.
DMF, with or without base, but interestingly when the reaction
was run under air, the yield only slightly decreased (32%).
Nevertheless, considering that three bonds were formed during
the process, such a result represents an average of 70% yield per
bond, making the process still valuable.
On the basis of this sequence, other 2-aminoquinazolines
could be prepared as shown in Figure 2. The electronic nature
and the position of the substituent on the arylboronic acid
significantly influence the outcome of the reaction. The
presence of an electron-withdrawing group at the para position
was beneficial, as can be seen when comparing the results
obtained for compounds 2b and 2c, isolated in 50% and 25%
yields, respectively. Compound 2d was isolated in 55% yield,
demonstrating that ortho-substituted arylboronic acids were
not only tolerated but apparently beneficial in the process when
compared to the para position. Nevertheless, the electronic/
steric picture is not clear, as the highest isolated yield was
observed using (3,5-dimethoxyphenyl)boronic acid as reacting
species. Interestingly, the presence of an additional cyano group
did not interfere in the reaction leading to compound 2f
isolated in a decent yield of 41%. Variation of the amine
constituent was possible even if the yield remained rather low
(2j, 27%). In addition, the reaction was not limited to the sole
benzylcyanamide 17a, as nitro- or methoxy-substituted benzyl
cyanamides could also be successfully transformed into their
corresponding quinazolines. It should be noted that in all
reactions we observed variable amounts of benzaldehyde,
accounting for the modest yield obtained.
N-Alkylcyanamides (n-propyl, isopropyl, and tert-butyl) were
not suitable reacting partners for the sequence leading to
degradation, even if the intermediate guanidines were properly
formed. When benzylcyanamide (17a) was used in the
sequence, a different outcome occurred, and the anticipated15,22
Scheme 3. Synthesis of 6-Methyl-1-(p-tolyl)-1H-
benzo[d]imidazol-2-amine (16)
C
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Mechanism. The mechanism of the overall transformation
is not clear, but several facts have been established based on
current knowledge28 (Scheme 4): (1) N-arylguanidine is clearly
of the procedure (single step), the inexpensive and relatively
ecofriendly catalytic system (O2 as terminal oxidant), and the
readily available precursors should make it attractive, allowing a
rapid introduction of three points of diversity.31
Scheme 4. Possible Reaction Pathway of the Domino Three-
Component/C−H Functionalization Process
EXPERIMENTAL SECTION
■
General Information. Melting points (mp) were obtained in open
capillary tubes using a micro melting point apparatus and are
uncorrected. Infrared spectra were measured using FT-IR spectrom-
eter and reported in cm−1. High resolution mass spectra were obtained
through electrospray ionization using a time-of-flight (TOF) analyzer
in a positive-ion or negative-ion detection mode (ES+ or ES−). NMR
spectra are reported relative to residual proton signals in CDCl3 (δ =
7.26, 77.16) using the following abbreviations: s = singlet, d = doublet,
t = triplet, q = quartet, qu = quintet, sex. = sextet, m = multiplet, and
br = broad resonance. Reagents were obtained from commercial
suppliers and solvent routinely dried and/or distilled prior to use.
CuCl2·H2O > 99.0% was purchased from Sigma-Aldrich. Spectral
properties of known products are consistent with literature values.
Synthesis of Cyanamides. Cyanamides were commonly prepared
by reacting the corresponding amine with cyanogen bromide (BrCN)
either in toluene or in a 1/1 mixture of tert-butyl methyl ether/
tetrahydrofuran with or without base (NaHCO3).30
General Procedure for the Preparation 1-Aryl-1H-benzo[d]-
imidazol-2-amines 1 and 4-Arylquinazolin-2-amines 2. To a
round-bottom flask were added successively cyanamide 14 or 17 (1.5
equiv), CuCl2·H2O (0.2 equiv), 2,2′-bipyridine (0.2 equiv), K2CO3
(2.25 equiv), and boronic acid 13 (1.5 equiv). The reaction was sealed
with a rubber stopper, evacuated, and backfilled with oxygen (balloon).
Toluene and amine 11 (1.0 equiv) were added, and the reaction was
heated to 100 °C and stirred for 24 h. The reaction mixture was cooled
to room temperature, filtered through a glass funnel, and washed with
EtOAc. The filtrate was concentrated under reduced pressure to give a
residue, which was purified by preparative TLC (SiO2), using a
mixture of 4/1:hept/EtOAc or 20/1/1/1:heptane/EtOAc/MeOH/
Et3N as eluent.
Reactions were performed using 0.2 mmol of amines 11 as limiting
reagent in 1 mL of toluene for the synthesis of benzimidazoles and for
the synthesis of 2j. Reactions were performed using 0.25 mmol of
amines 11 in 1.5 mL of toluene for the synthesis of quinazolines.
6-Methyl-2-(piperidin-1-yl)-1-(p-tolyl)-1H-benzo[d]imidazole
(1a).22 Following the general procedure, the title compound was
obtained as a light yellow solid (50 mg, 82%). mp 100−102 °C (lit.:
94−96 °C). 1H NMR (300 MHz, CDCl3): δ 7.46 (d, J = 8.0 Hz, 1H),
7.32−7.39 (m, 4H), 6.98 (dd, J = 8.0, 0.6 Hz, 1H), 6.87 (broad s, 1H),
3.17 (t, J = 5.0 Hz, 4H), 2.44 (s, 3H), 2.36 (s, 3H), 1.52 (br s, 6H).
13C NMR (75 MHz, CDCl3): δ 157.15, 139.4, 137.6, 136.1, 134.9,
130.5, 130.3, 125.7, 123.0, 116.7, 108.9, 50.0, 25.3, 24.2, 21.6, 21.2. IR
(neat, cm−1): ν 2930, 2835, 1514, 1529, 1396, 1279, 1254, 827, 804.
4-(6-Methyl-1-(p-tolyl)-1H-benzo[d]imidazol-2-yl)-
morpholine (1b).22 Following the general procedure, the title
compound was obtained as light yellow solid (48 mg, 78%). mp 127−
129 °C (lit.: 123 °C). 1H NMR (300 MHz, CDCl3): δ 7.48 (d, J = 7.9
Hz, 1H), 7.33−7.38 (m, 4H), 7.0 (d, J = 7.9 Hz, 1H), 6.87 (s, 1H),
3.65 (t, J = 4.5 Hz, 4H), 3.21 (t, J = 4.5 Hz, 4H), 2.45 (s, 3H), 2.37 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 155.9, 139.1, 138.0, 136.1, 134.3,
131.0, 130.2, 125.8, 123.2, 117.0, 109.0, 66.3, 49.1, 21.6, 21.2. IR (neat,
cm−1): ν 2917, 2856, 1610, 1528, 1514, 1402, 1274, 1120, 929, 828,
806.
one intermediate in the reaction, as it can be isolated at the
beginning of the reaction or at lower temperature. Such a
compound does not result from a sequence of nucleophilic
addition of amine to cyanamide followed by a Cu-catalyzed
Chan−Lam−Evans type N-arylation with boronic acid as
established previously.20b (2) Intramolecular cyclization occurs
in a distinct subsequent step. In that event, the reaction could
be initiated by the formation of a copper complex C or D
through coordination and deprotonation of the guanidine.
Activation of the C−H bond and subsequent reductive
elimination via intermediate E or nucleophilic attack of the
arene on the activated copper-bound nitrogen via intermediate
F followed by aromatization could be invoked for the
benzimidazole formation. Oxidation of the copper from state
II to state III either by oxygen or by copper itself by
disproportionation is probably involved before the intra-
molecular C−N formation.13a For the quinazoline formation,
oxidation of the benzylic position of complex D would first
furnish imine G. Such an oxidation might proceed through a
hydrogen atom transfer or a single electron transfer achieved
with a copper peroxo species, generated from O2 and copper.29
A Pictet−Spengler type cyclization, probably assisted by
copper, would next lead to 3,4-dihydroquinazoline H, which
upon oxidative aromatization should deliver the quinazoline
and liberate the copper that can re-enter the cycle.
N-Cyclohexyl-N,6-dimethyl-1-(p-tolyl)-1H-benzo[d]imidazol-
CONCLUSIONS
2-amine (1c). Following the general procedure, the title compound
■
1
was obtained as a yellow oil (26 mg, 39%). H NMR (300 MHz,
We have disclosed a novel Cu-catalyzed three-component
reaction of arylboronic acids, arylcyanamides, and amines
leading to the direct synthesis of 2-aminated benzimidazoles.
The analogous reaction performed with benzyl-substituted
cyanamides delivered 2-amino quinazolines. The yields of the
present transformations ranged from poor to good, but the ease
CDCl3): δ 7.44 (d, J = 7.9 Hz, 1H), 7.28−7.35 (m, 4H), 6.96 (dd, J =
7.9, 1.0 Hz, 1H), 6.78 (s, 1H), 3.32 (tt, J = 11.6, 3.5 Hz, 1H), 2.81 (s,
3H), 2.45 (s, 3H), 2.35 (s, 3H), 1.35−1.67 (m, 7 H), 0.93−1.01 (m,
3H). 13C NMR (75 MHz, CDCl3): δ 157.5, 139.6, 137.8, 136.7, 135.4,
130.3, 130.0, 126.4, 122.8, 116.3, 108.8, 59.5, 31.9, 29.5, 25.8, 25.6,
21.5, 21.2. IR (neat, cm−1): ν 2926, 2855, 1595, 1532, 1514, 1400,
D
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1270, 805, 728. HRMS (m/z, ESI+) calcd for C22H28N3 ([M + H]+)
334.2283, found 334.2278.
34.5 Hz, CCF ), 127.7, 126.3, 125.1 (q, J = 269.2 Hz, CAr‑CF ), 123.7 (q,
3
3
J = 272.5 Hz, CAr‑CF ), 123.4 (q, J = 32.3 Hz, CCF ), 120.1, 117.5, 105.9,
3
3
6-Methyl-2-(pyrrolidin-1-yl)-1-(p-tolyl)-1H-benzo[d]-
imidazole (1d).10c Following the general procedure, the title
compound was obtained as a light yellow solid (47 mg, 81%). mp
139−141 °C (lit.: 135−137 °C). 1H NMR (300 MHz, CDCl3): δ 7.38
(d, J = 8.2 Hz, 1H), 7.26−7.33 (m, 4H), 6.93 (dd, J = 8.1, 0.9 Hz, 1H),
6.66 (s, 1H), 3.28 (qu, J = 3.5 Hz, 4H), 2.45 (s, 3H), 2.33 (s, 3H), 1.82
(qu, J = 3.5 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 155.3, 140.08,
138.1, 137.1, 134.7, 130.1, 129.2, 127.5, 122.7, 115.5, 108.6, 49.7, 25.5,
21.5, 21.2. IR (neat, cm−1): ν 2968, 2870, 1597, 1542, 1514, 1408,
1268, 804, 727.
N,N-Diethyl-6-methyl-1-(p-tolyl)-1H-benzo[d]imidazol-2-
amine (1e).22 Following the general procedure, the title compound
was obtained as a light yellow oil (38 mg, 65%). 1H NMR (300 MHz,
CDCl3): δ 7.46 (d, J = 8.1 Hz, 1H), 7.29−7.36 (m, 4H), 6.98 (dd, J =
8.1, 1.1 Hz, 1H), 6.79 (s, 1H), 3.20 (q, J = 7.1 Hz, 4H), 2.45 (s, 3H),
2.36 (s, 3H), 1.04 (t, J=7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ
156.5, 139.7, 137.8, 136.6, 134.9, 130.3, 130.18, 126.4, 122.9, 116.4,
108.8, 44.7, 21.5, 21.2, 12.7. IR (neat, cm−1): ν 3031, 2931, 2862,
1602, 1535, 1514.48, 1404, 1279, 805.
50.2, 25.2, 23.9. IR (neat, cm−1): ν 2962, 2855, 1616, 1541, 1454,
1324, 1259, 1058, 1008, 793, 737. HRMS (m/z, ESI+) calcd for
C20H17F6N3 ([M + H]+) 414.1414, found 414.1394.
1-(4-Methoxyphenyl)-6-methyl-2-(piperidin-1-yl)-1H-benzo-
[d]imidazole and 6-Methoxy-2-(piperidin-1-yl)-1-(p-tolyl)-1H-
benzo[d]imidazole (1k/1k′). Following the general procedure, a
mixture of the title compounds was obtained as a white waxy solid (48
1
mg, 75%). H NMR (300 MHz, CDCl3): δ 7.44−7.48 (m, 0.8H),
7.31−7.40 (m, 3.2H), 7.02−7.07 (m, 0.8 H), 6.97 (dd, J = 8.1, 1.0 Hz,
0.2H), 6.83 (s, 0.2H), 6.78 (dd, J = 8.7, 2.4 Hz, 0.8 H), 6.62 (d, J = 2.4
Hz, 0.8 H), 3.88 (s, 0.8H),), 3.75 (s, 2.2H), 3.14−3.18 (m, 4H), 2.44
(s, 2.2H), 2.36 (s, 0.8H), 1.51 (br, 6H). 13C NMR (75 MHz, CDCl3):
δ 158.8, 157.25, 157.1, 155.3, 139.3, 137.6, 136.4, 136.3, 135.8, 134.7,
130.5, 130.3, 130.2, 127.2, 125.6, 122.9, 117.5, 116.7, 114.8, 109.3,
108.8, 94.3, 55.9, 55.5, 50.1, 50.0, 25.3, 25.3, 24.1, 21.6, 21.2. IR (neat,
cm−1): ν 2935, 2831, 1618, 1597, 1534, 1513, 1482, 1399, 1273, 1255,
1212, 1160, 1032, 924, 817, 728. HRMS (m/z, ESI+) calcd for
C20H24N3O ([M + H]+) 322.1919, found 322.1918.
4-Methyl-2-(piperidin-1-yl)-1-(o-tolyl)-1H-benzo[d]imidazole
(1l).22 Following the general procedure (using xylene as solvent and
reaction temperature of 130 °C), the title compound was obtained as a
light yellow waxy solid (22 mg, 36%). 1H NMR (300 MHz, CDCl3): δ
7.26−7.41 (m, 4H), 6.89−6.99 (m, 2H), 6.60 (d, J = 7.7 Hz, 1H),
3.15−3.33 (m, 4H), 2.65 (s, 3H), 2.11 (s, 3H), 1.43−1.51 (m, 6H).
13C NMR (75 MHz, CDCl3): δ 156.94, 140.8, 136.5, 135.9, 135.6,
131.5, 128.6, 128.1, 127.2, 126.9, 122.4, 120.4, 106.4, 49.7, 25.47, 24.2,
17.8, 16.7. IR (neat, cm−1): ν 2934, 2852, 1605, 1531, 1452, 1399,
1291, 919, 745.
6-Methoxy-1-(4-methoxyphenyl)-2-(piperidin-1-yl)-1H-
benzo[d]imidazole (1f).22 Following the general procedure, the title
compound was obtained as a yellow solid (49 mg, 73%). mp 97−98
1
°C. H NMR (300 MHz, CDCl3): δ 7.37−7.47 (m, 3H), 7.05 (br s,
2H), 6.77 (dd, J = 8.5, 2.5 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 3.88 (s,
3H), 3.74 (s, 3H), 3.13 (t, J = 4.7 Hz, 4H), 1.50 (br s, 6H). 13C NMR
(75 MHz, CDCl3): δ 158.8, 157.2, 155.3, 136.6, 135.6, 130.0, 127.1,
117.5, 114.9, 109.2, 94.1, 55.9, 55.5, 50.1, 25.3, 24.1. IR (neat, cm−1): ν
2932, 2823, 1617, 1533, 1509, 1401, 1254, 1244, 1031, 924, 814.
HRMS (m/z, ESI+) calcd for C19H24N3 ([M + H]+) 294.1970, found
294.1963.
2-(Piperidin-1-yl)-3-(o-tolyl)quinazolin-4(3H)-one (15). Fol-
lowing the general procedure, the title compound was obtained as a
N-Cyclohexyl-6-methyl-1-(p-tolyl)-1H-benzo[d]imidazol-2-
1
white solid (9.5 mg, 15%). mp 142−143 °C. H NMR (300 MHz,
amine (1g). Following the general procedure, the title compound was
1
CDCl3): δ 8.18 (dd, J = 7.9, 1.6 Hz, 1H), 7.67 (dt, J = 7.9, 1.6 Hz,
1H), 7.53 (d, J = 7.9, 1H), 7.35−7.25 (m, 5H), 3.16 (m, 2H), 3.06 (m,
2H), 2.11 (s, 3H), 1.40 (m, 2H), 1.24 (m, 4H). 13C NMR (75 MHz,
CDCl3): δ 164.1, 155.3, 148.4, 137.2, 135.7, 134.6, 131.3, 129.8, 128.5,
127.5, 126.5, 126.0, 124.6, 119.4, 50.6, 25.3, 24.3, 18.1. IR (neat,
cm−1): ν 2934, 2851, 1682, 1609, 1578, 1560, 1464, 1552, 1370, 1305,
1256, 1240, 1105, 1000, 906, 882, 767, 728. HRMS (m/z, ESI−) calcd
for C20H21N3O ([M − H]−) 318.1612, found 318.1652.
obtained as a yellow solid (51 mg, 80%). mp 71−73 °C. H NMR
(300 MHz, CDCl3): δ 7.37−7.40 (m, 3H), 7.26−7.30 (m, 2H), 6.92
(dd, J = 7.9, 0.9 Hz, 1H), 6.70 (s, 1H), 3.89−4.01 (m, 2H: 1 CH and
NH), 2.47 (s, 3H), 2.34 (s, 3H), 2.08−2.13 (m, 2 H), 1.58−1.72 (m,
3H), 1.37−1.50 (m, 2H), 1.07−1.19 (m, 3H). 13CNMR (75 MHz,
CDCl3): δ 152.8, 140.5, 138.7, 135.4, 132.2, 131.0, 129.2, 126.8, 122.5,
115.6, 108.1, 51.5, 33.7, 25.6, 24.8, 21.2, 21.2. IR (neat, cm−1): ν 2927,
2854, 1600, 1555, 1516, 1261, 805. HRMS (m/z, ESI+) calcd for
C21H26N3 ([M + H]+) 320.2127, found 320.2136.
6-Methyl-1-(p-tolyl)-1H-benzo[d]imidazole-2-amine (16).9d
To a round-bottom flask were added benzimidazole 1h (59 mg, 0.20
mmol), TFA (3 mL), and anisole (70 μL, 0.6 mmol, 3.0 equiv), and
the mixture was heated at reflux for 3 h. After cooling to room
temperature, the reaction was diluted with dichloromethane,
concentrated under vacuum, and purified by flash column chromatog-
raphy (SiO2, AcOEt) to deliver the title compound as a light brown
N-(tert-Butyl)-6-methyl-1-(p-tolyl)-1H-benzo[d]imidazol-2-
amine (1h).22 Following the general procedure, the title compound
1
was obtained as a yellow waxy solid (33 mg, 57%). H NMR (300
MHz, CDCl3): δ 7.37−7.44 (m, 3H), 7.27 (d, J = 8.1 Hz, 2H), 6.93
(dd, J = 7.3, 0.6 Hz, 1H), 6.69 (s, 1H), 4.04 (s, NH), 2.47 (s, 3H), 2.35
(s, 3H), 1.48 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 151.9, 140.9,
138.7, 134.9, 132.5, 131.0, 129.2, 127.1, 122.3, 116.0, 108.05, 51.96,
29.38, 21.44, 21.21. IR (neat, cm−1): ν 3417, 2964, 2921, 1599, 1551,
1515, 1366, 1204, 805, 730.
1
solid (35 mg, 74%). mp 116−118 °C (lit.: 108−109 °C). H NMR
(300 MHz, CDCl3): δ 7.39 (d, J = 7.1 Hz, 2H), 7.31−7.29 (m, 2H),
6.98 (d, J = 7.1 Hz, 1H), 6.75 (s, 1H), 2.45 (s, 3H), 2.34 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 152.8, 139.3, 132.1, 131.7, 131.2, 130.4,
126.8, 123.4, 122.9, 115.7, 109.1, 21.7, 21.4. IR (neat, cm−1): ν 2924,
1670, 1517, 1452, 1263, 1037, 806, 732.
N-Butyl-6-methyl-1-(p-tolyl)-1H-benzo[d]imidazol-2-amine
(1i). Following the general procedure, the title compound was
1
obtained as a purple waxy solid (22 mg, 38%). H NMR (300 MHz,
6-Methyl-4-phenyl-2-(piperidin-1-yl)quinazoline (2a).22 Fol-
lowing the general procedure, the title compound was obtained as a
CDCl3): δ 7.37−7.40 (m, 3H), 7.29 (d, J = 8.3 Hz, 2H), 6.93 (d, J =
7.9 Hz, 1H), 6.71 (s, 1H), 4.09 (s, NH) 3.50 (q, J = 7.0 Hz, 2H), 2.46
(s, 3H), 2.35 (s, 3H), 1.60 (qu, J = 7.3 Hz, 2H), 1.36 (sex., J = 7.3 Hz,
2H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 153.5,
140.4, 138.8, 135.5, 132.2, 131.0, 129.4, 126.8, 122.5, 115.8, 108.2,
43.0, 31.9, 21.5, 21.2, 20.0, 13.8. IR (neat, cm−1): ν 2957, 2925, 2963,
1601, 1559, 1516, 1482, 1278, 1258, 804. HRMS (m/z, ESI+) calcd for
C19H24N3 ([M + H]+) 294.1970, found 294.1957.
2-(Piperidin-1-yl)-6-(trifluoromethyl)-1-(4-(trifluoromethyl)-
phenyl)-1H-benzo[d]-imidazole (1j). Following the general
procedure, the title compound was obtained as a white solid (34
mg, 41%). mp 142−143 °C. 1H NMR (300 MHz, CDCl3): δ 7.86 (d, J
= 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.44
(d, J = 8.1 Hz, 1H), 7.26 (s, 1H), 3.21 (m, 4H), 1.55 (m, 6H). 13C
NMR (75 MHz, CDCl3): δ 158.4, 144.3, 140.1, 135.1, 130.5 (q, J =
1
yellow solid (27 mg, 36%). mp 109−110 °C (lit.: 108−109 °C). H
NMR (300 MHz, CDCl3): δ 7.73−7.76 (m, 2H), 7.52−7.57 (m, 5H),
7.46 (dd, J = 8.7, 1.7 Hz, 1H), 3.96 (t, J = 5.7 Hz, 4H), 2.37 (s, 3H),
1.63−1.68 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 168.2, 158.6,
152.2, 138.3, 135.4, 131.2, 129.8, 129.3, 128.2, 125.9, 125.9, 117.3,
45.0, 25.9, 25.0, 21.3. IR (neat, cm−1): ν 2930, 2851, 1543, 1474, 1441,
1250, 1228, 1127, 961, 827, 730, 699.
6-Chloro-4-phenyl-2-(piperidin-1-yl)quinazoline (2b).22 Fol-
lowing the general procedure, the title compound was obtained as a
1
yellow solid (40 mg, 50%). mp 125−126 °C (lit. 116−117 °C). H
NMR (300 MHz, CDCl3): δ 7.74−7.73 (m, 1H), 7.71−7.67 (m, 2H),
7.56−7.50 (m, 5H), 3.96−3.95 (m, 4H), 1.66−1.22 (m, 6H). 13C
NMR (75 MHz, CDCl3): δ 168.5, 158.9, 152.6, 138.6, 137.7, 134.2,
E
DOI: 10.1021/acs.joc.5b00614
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Article
130.0, 129.9, 128.6, 127.9, 126.2, 117.9, 45.2, 26.2, 25.1. IR (neat,
cm−1): ν 2934, 1562, 1542, 1459−1444, 1250, 1024, 960, 834, 733,
700.
131.0, 127.6, 127.1, 126.6, 126.5, 121.1, 119.2, 111.6, 55.7, 45.2, 26.1,
25.1. IR (neat, cm−1): ν 2927−2852, 1568−1541, 1444, 1250, 1020,
794, 750. HRMS (m/z, ESI+) calcd for C20H2035ClN3O ([M + H]+)
354.1355, found 354.1364. calcd for C20H2037ClN3O ([M + H]+)
356.1377, found 356.1371.
6-Methoxy-4-phenyl-2-(piperidin-1-yl)quinazoline (2c).22
Following the general procedure, the title compound was obtained
6-Methyl-N,N-diethyl-4-phenylquinazolin-2-amine (2j).22
Following the general procedure, the title compound was obtained
1
as a yellow solid (20 mg, 25%). mp 75−77 °C. H NMR (300 MHz,
CDCl3): δ 7.76−7.73 (m, 2H), 7.58−7.50 (m, 4H), 7.31 (dd, J = 8.9,
2.8 Hz, 1H), 7.14 (d, J = 2.8 Hz, 1H), 3.93−3.91 (m, 4H), 3.74 (s,
3H), 1.65−1.62 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 167.6, 158.5,
154.6, 150.0, 138.6, 129.8, 129.6, 128, 127.9, 125.7, 117.6, 105.5, 55.7,
45.2, 26.1, 25.2. IR (neat, cm−1): ν 2929−2853, 1580−1546, 1477−
1411, 1253−1216, 1030, 792−661. HRMS (m/z, ESI+) calcd for
C20H22N3O ([M + H]+) 320.1763, found 320.1751.
1
as a yellow solid (16 mg, 27%). mp 80−82 °C (lit.: 83−84 °C). H
NMR (300 MHz, CDCl3): δ 7.74−7.71 (m, 2H), 7.54−7.41 (m, 6H),
3.77 (q, J = 6.8 Hz, 4H), 2.34 (s, 3H), 1.26−1.21 (t, J = 7.1 Hz, 6H).
13C NMR (75 MHz, CDCl3): δ 168.2, 158.2, 152.7, 138.6, 135.4,
130.9, 130.0, 129.4, 128.4, 127.0, 126.1, 126.0, 117.3, 41.8, 21.5, 13.2.
IR (neat, cm−1): ν 2934, 1562, 1542, 1459−1444, 1250, 831, 700.
8-Methyl-4-phenyl-2-(piperidin-1-yl)quinazoline (2d). Fol-
lowing the general procedure, the title compound was obtained as a
yellow solid (42 mg, 55%). mp 118−120 °C. H NMR (300 MHz,
ASSOCIATED CONTENT
■
1
S
* Supporting Information
CDCl3): δ 7.73−7.72 (m, 2H), 7.65−7.62 (m, 1H), 7.50−7.46 (m,
4H), 6.98 (dd, J = 7.4 Hz, 1H), 3.98 (m, 4H), 2.6 (s, 3H), 1.68 (m,
6H). 13C NMR (75 MHz, CDCl3): δ 169.4, 158.4, 152.9, 138.7, 134.3,
133.1, 130.1, 129.5, 128.4, 125.1, 121.3, 117.2, 45.2, 26.1, 25.3, 17.7. IR
(neat, cm−1): ν 3002−2850, 1609−1551, 1258, 1023, 853−698.
HRMS (m/z, ESI+) calcd for C20H21N3 ([M + H]+) 304.1774, found
304.1780.
Copies of 1H and 13C NMR spectra of each benzimidazole and
quinazoline. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.joc.5b00614.
AUTHOR INFORMATION
Corresponding Author
*E-mail: luc.neuville@cnrs.fr.
Notes
■
5,7-Dimethoxy-4-phenyl-2-(piperidin-1-yl)quinazoline (2e).
Following the general procedure, the title compound was obtained
as a yellow solid (61 mg, 70%). mp 120−122 °C. 1H NMR (300 MHz,
CDCl3): δ 7.50−7.47 (m, 2H), 7.39−7.36 (m, 3H), 6.61 (s, 1H), 6.08
(s, 1H) 3.93−3.90 (m, 4H), 3.89 (s, 3H), 3.47 (s, 3H), 1.64−1.60 (m,
6H). 13C NMR (75 MHz, CDCl3): δ 167.0, 164.6, 158.8, 158.3, 157.5,
142.6, 128.8, 128.2, 127.1, 105.9, 97.7, 95.1, 55.7, 55.1, 44.9, 26.1, 25.1.
IR (neat, cm−1): ν 2928−2851, 1614, 1571−1541, 1392, 1274−1206,
828, 697. HRMS (m/z, ESI+) calcd for C21H23N3O2 ([M + H]+)
350.1842, found 350.1830.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from ICSN and CNRS. L.Q.T. thanks ICSN
for a doctoral fellowship. J.L. thanks the Government of China
for a National Graduate Student Program of Building World-
Class Universities.
8-Methyl-4-phenyl-2-(piperidin-1-yl)quinazoline-6-carboni-
trile (2f). Following the general procedure, the title compound was
1
obtained as a yellow solid (34 mg, 41%). mp 138−140 °C. H NMR
(300 MHz, CDCl3): δ 8.02 (s, 1H), 7.70−7.69 (m, 2H), 7.6−7.57 (m,
3H), 4.06−4.04 (m, 4H), 2.62 (s, 3H), 1.76−1.70 (m, 6H). 13C NMR
(75 MHz, CDCl3): δ 170.2, 158.9, 154.9, 137.3, 136.0, 133.3, 132.0,
130.4, 129.9, 128.8, 119.9, 116.3, 103.5, 45.2, 26.2, 25.1, 17.6. IR (neat,
cm−1): ν 2961−2853, 2223, 1551, 1258, 1082−1013, 791. HRMS (m/
z, ESI+) calcd for C21H20N4 ([M + H]+) 329.1766, found 329.1770.
6-Chloro-4-(4-methoxyphenyl)-2-(piperidin-1-yl)quinazoline
(2g). Following the general procedure, the title compound was
REFERENCES
■
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893−930.
(2) For a monograph, see: (a) Alamgir, M.; Black, D. St. C.; Kumar,
N. Synthesis, Reactivity and Biological Activity of Benzimidazoles. In
Topics In Heterocyclic Chemistry; Springer: Berlin, Germany, 2007; Vol.
9, pp 87−118. (b) Carvalho, L. C. R.; Fernandes, E.; Marques, M. M.
B. Chem.Eur. J. 2011, 17, 12544−12555. (c) Bansal, Y.; Silakari, O.
Bioorg. Med. Chem. 2012, 20, 6208−6236.
1
obtained as a yellow solid (33 mg, 38%). mp 158−160 °C. H NMR
(300 MHz, CDCl3): δ 7.79 (s, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.51 (m,
2H), 7.04 (d, J = 8.7 Hz, 1H), 3.95−3.93 (m, 4H), 3.88 (s, 3H), 1.66−
1.63 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 167.9, 161.3, 158.9,
152.6, 134.1, 131.6, 130.2, 127.9, 126.7, 126.2, 118.0, 114.1, 55.7, 45.1,
26.2, 25.2. IR (neat, cm−1): ν 3003−2851, 1608−1539, 1458, 1247,
1028, 829. HRMS (m/z, ESI+) calcd for for C20H2035ClN3O ([M +
H]+) 354.1373, found 354.1375. calcd for C20H2037ClN3O ([M + H]+)
356.1350, found 356.1347.
(3) Khan, I.; Ibrar, A.; Ahmed, W.; Saeed, A. Eur. J. Med. Chem. 2015,
90, 124−169.
(4) Cooper, D. G.; Young, R. C.; Durant, G. J.; Gamelline, C. R. In
Comprehensive Medicinal Chemistry; Hansch, C., Sammes, P. G., Taylor,
J. B., Eds.; Pergamon Press: Oxford, UK, 1990; Vol. 3, p 323.
(5) Campbell, S. F.; Davey, M. J.; Hardstone, J. D.; Lewis, B. N.;
Palmer, M. J. J. Med. Chem. 1987, 30, 49−57.
(6) For a monograph, see: (a) Modern Nucleophilic Aromatic
Substitution; Terrier, F., Ed.; Wiley-VCH: Weinheim, 2013. (b) Barrett,
I. C.; Kerr, M. A. Tetrahedron Lett. 1999, 40, 2439−2442. (c) Kawasaki,
I.; Taguchi, N.; Yoneda, Y.; Yamashita, M.; Ohta, S. Heterocycles 1996,
43, 1375−1379. (d) Martínez-Viturro, C. M.; Domínguez, D. J.
Heterocycl. Chem. 2007, 44, 1035−1043.
6-Chloro-4-(4-nitrophenyl)-2-(piperidin-1-yl)quinazoline
(2h). Following the general procedure, the title compound was
1
obtained as a yellow solid (31 mg, 34%). mp 139−140 °C. H NMR
(300 MHz, CDCl3): δ 8.34 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.7 Hz,
2H), 7.54−7.47 (m, 3H), 3.89−3.86 (m, 4H), 1.67−1.55 (m, 6H). 13C
NMR (75 MHz, CDCl3): δ 166.1, 158.6, 152.7, 148.8, 143.7, 134.8,
130.8, 128.3, 127.5, 125.1, 123.9, 117.4, 45.2, 26.12, 25.0. IR (neat,
cm−1): ν 2923, 2852, 1566, 1542, 1459, 1348, 1250, 1015, 775. HRMS
(m/z, ESI+) calcd for C19H1735ClN4O2 ([M + H]+) 369.1118, found
369.1117. calcd for C19H1737ClN4O2 ([M + H]+) 371.1122, found
371.1115.
(7) For a recent example, see: Deasy, R. E.; Slattery, C. N.; Maguire,
A. R. J. Org. Chem. 2014, 79, 3688−3695.
(8) For reviews involving copper, see: (a) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400−5449. (b) Monnier, F.;
Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954−6971. (c) Liu, T.;
Fu, H. Synthesis 2012, 44, 2805−2824. For reviews involving
palladium, see: (d) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534−
1544. (e) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27−50.
(9) Selected examples. For benzimidazoles, see: (a) Rivas, F. M.;
Giessert, A. J.; Diver, S. T. J. Org. Chem. 2002, 67, 1708−1711.
(b) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133−136. (c) Wang,
6-Chloro-4-(2-methoxyphenyl)-2-(piperidin-1-yl)quinazoline
(2i). Following the general procedure, the title compound was
1
obtained as a yellow solid (40 mg, 45%). mp 123−125 °C. H NMR
(300 MHz, CDCl3): δ 7.50−7.47 (m, 3H), 7.37−7.30 (m, 2H), 7.12−
7.02 (m, 2H), 3.93−3.89 (m, 4H), 3.73 (s, 3H), 1.64−1.60 (m, 6H).
13C NMR (75 MHz, CDCl3): δ 167.7, 159.2, 157.1, 151.5, 134.0,
F
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The Journal of Organic Chemistry
Article
F.; Cai, S.; Liao, Q.; Xi, C. J. Org. Chem. 2011, 76, 3174−3180.
(d) Ramana, T.; Punniyamurthy, T. Chem.Eur. J. 2012, 18, 13279−
13283. (e) Vlaar, T.; Cioc, R. C.; Mampuys, P.; Maes, B. U. W.; Orru,
R. V. A.; Ruijter, E. Angew. Chem., Int. Ed. 2012, 51, 13058−13061.
For quinazolines, see: (f) Huang, X.; Yang, Y.; Qiao, R.; Zhao, Y.
Synthesis 2009, 2679−2688. (g) Liu, Q.; Zhao, Y.; Fu, H.; Cheng, C.
Synlett. 2013, 24, 2089−2094.
Lett. 2013, 15, 1752−1755. (c) Li, J.; Neuville, L. Org. Lett. 2013, 15,
6124−6127.
(21) (a) Marcaccini, S.; Torroba, T. In Multicomponent Reaction; Zhu,
́
J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005; pp 33−75.
(b) Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125−
147.
(22) He, H.-F.; Wang, Z.-J.; Bao, W. Adv. Synth. Catal. 2010, 352,
2905−2912.
(23) Larraufie, M.-H.; Maestri, G.; Malacria, M.; Ollivier, C.;
(10) (a) Yang, D. S.; Fu, H.; Hu, L. M.; Jiang, Y. Y.; Zhao, Y. F. J.
Org. Chem. 2008, 73, 7841−7844. (b) Deng, X. H.; McAllister, H.;
Mani, N. S. J. Org. Chem. 2009, 74, 5742−5745. (c) Lv, X.; Bao, W. J.
Org. Chem. 2009, 74, 5618−5621. (d) Deng, X. H.; Mani, N. S. Eur. J.
Org. Chem. 2010, 680−686. (e) Jin, H.; Xu, X.; Gao, J.; Zhong, J.;
Wang, Y. Adv. Synth. Catal. 2010, 352, 347−350. (f) Shen, G.; Bao, W.
Adv. Synth. Catal. 2010, 352, 981−986. (g) Wang, F.; Cai, S.; Liao, Q.;
Xi, C. J. Org. Chem. 2011, 76, 3174−3180.
̂
Fensterbank, L.; Lacote, E. Synthesis 2012, 44, 1279−1292.
(24) (a) Li, Y.; Li, Z.; Xiong, T.; Zhang, Q.; Zhang, X. Org. Lett.
2012, 14, 3522−3525. (b) Zhang, M.; Zhang, A.-Q.; Peng, Y. J.
Organomet. Chem. 2013, 723, 224−232.
(25) (a) Mahapatra, S.; Halfen, J. A.; Wilkinson, E. C.; Pan, G.;
Wang, X.; Young, V. G.; Cramer, C. J.; Que, L.; Tolman, W. B. J. Am.
Chem. Soc. 1996, 118, 11555−11574. (b) Mahapatra, S.; Halfen, J. A.;
Tolman, W. B. J. Am. Chem. Soc. 1996, 118, 11575−11586.
(26) Ding, K.; Wang, A.; Boerneke, M. A.; Dibrov, S. M.; Hermann,
T. Bioorg. Med. Chem. Lett. 2014, 24, 3113−3117.
(11) For a monograph, see: (a) C−H Activation. In Topics in Current
Chemistry; Yu, J.-Q., Shi, Z., Eds.; Springer: New York, 2010; Vol. 292,
pp 1−380. (b) For selected reviews, see: Wencel-Delord, J.; Droge,
̈
T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740−4761. (c) Cho,
S.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068−
5083. (d) Stokes, B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 4071−
4088. (e) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int.
Ed. 2012, 51, 8960−9009. (f) Hickman, A.; Sanford, M. S. Nature
2012, 484, 177−185. (g) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord,
J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236−10254. (h) For
metal-free C−H functionalization processes, see: Samanta, R.;
Matcha, K.; Antonchick, A. P. Eur. J. Org. Chem. 2013, 5769−5804.
(12) Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W. Chem. Rev. 2015,
115, 1622−1651.
(27) Alternative preparation of N1-arylated 2-aminobenzimidazoles,
see: (a) Ueda, S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51,
10364−10367. (b) Rao, N.; Rasheed, Sk.; Vishwakarma, R. A.; Das, P.
Chem. Commun. 2014, 50, 12911−12914.
(28) (a) See ref 18a and references cited therein, as well as refs 15
and 22 for relevant mechanistic pathways. (b) CuCl2·H2O and
Cu(OAc)2 were both suitable metals salts (Table 1) in promoting the
reaction; however, as pointed out by one referee, we cannot exclude
that metal contaminants other than copper could be responsible for
the present sequence. For the importance of metal impurities, see:
Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5586−5587.
(29) Kim, S.; Ginsbach, J. W.; Lee, J. Y.; Peterson, R. L.; Liu, J. J.;
Siegler, M. A.; Sarjeant, A. A.; Solomon, E. I.; Karlin, K. D. J. Am.
Chem. Soc. 2015, 137, 2867−2874.
(30) (a) Cockerill, A. F.; Deacon, A.; Harrison, R. G.; Osborne, D. J.;
Prime, D. M.; Ross, W. J.; Todd, A.; Verge, J. P. Synthesis 1976, 591−
593. (b) Kumar, V.; Kaushik, M. P.; Mazumdar, A. Eur. J. Org. Chem.
2008, 1910−1916.
(13) (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932−1934. (b) Masters, K.-S.; Rauws, T. R. M.; Yadav, A. K.;
Herrebout, W. A.; van der Veken, B.; Maes, B. U. W. Chem.Eur. J.
2011, 17, 6315−6320. (c) Lv, Y.; Li, Y.; Xiong, T.; Pu, W.; Zhang, H.;
Sun, K.; Liu, Q.; Zhang, Q. Chem. Commun. 2013, 49, 6439−6441.
(14) (a) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178−5180.
(b) Yang, D.; An, B.; Wei, W.; Tian, L.; Huang, B.; Wang, H. ACS
Comb. Sci. 2015, 17, 113−119. For a related process involving copper
nanoparticles, see: (c) Satish, G.; Harsha Vardhan Reddy, K.; Anil, B.
S. P.; Shankar, J.; Uday Kumar, R.; Nageswar, Y. V. D. Tetrahedron
Lett. 2014, 55, 5533−5538.
(15) Selected metal-free C−H functionalization processes: (a) Xue,
D.; Long, Y.-Q. J. Org. Chem. 2014, 79, 4727−4734. (b) Lin, J.-P.;
Zhang, F.-H.; Long, Y.-Q. Org. Lett. 2014, 16, 2822−2825. (c) Yan, Y.
Z.; Zhang, Y. H.; Feng, C. T.; Zha, Z. G.; Wang, Z. Y. Angew. Chem.,
Int. Ed. 2012, 51, 8077−8081. (d) Yan, Y. Z.; Wang, Z. Y. Chem.
Commun. 2011, 47, 9513−9515.
(31) For a discussion defining diversity, see: O’Connell, K. M. G.;
Galloway, W. R. J. D.; Spring, D. R. in Diversity-Oriented Synthesis:
Basics and Applications in Organic Synthesis, Drug Discovery, and
Chemical Biology; Trabocchi, A., Ed.; John Wiley & Sons, Inc.,
Hoboken, NJ, 2013; pp 5−8.
(16) (a) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem.Eur. J. 2007,
13, 961−967. (b) Salcedo, A.; Neuville, L.; Rondot, C.; Retailleau, P.;
Zhu, J. Org. Lett. 2008, 10, 857−860.
(17) (a) Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2007,
46, 3291−3295. (b) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem.,
Int. Ed. 2009, 48, 572−577. (c) Jaegli, S.; Dufour, J.; Wei, H.-L.; Piou,
T.; Duan, X.-H.; Vors, J.-P.; Neuville, L.; Zhu, J. Org. Lett. 2010, 12,
4498−4501. (d) Piou, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed.
2012, 51, 11561−11565.
(18) For reviews, see: (a) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S.
Angew. Chem., Int. Ed. 2011, 50, 11062−11087. (b) Campbell, A. N.;
Stahl, S. S. Acc. Chem. Res. 2012, 45, 851−863. (c) Shi, Z.; Zhang, C.;
Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381−3429.
(19) For reviews, see: (a) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011,
829−856. (b) Rao, K. S.; Wu, T.-S. Tetrahedon 2012, 68, 7735−7754.
Selected recent examples: (c) Racine, E.; Monnier, F.; Vors, J.-P.;
Taillefer, M. Chem. Commun. 2013, 49, 7412−7414. (d) Huang, F.;
Quach, T. D.; Batey, R. A. Org. Lett. 2013, 15, 3058−3061. (e) Moon,
S.-Y.; Nam, J.; Rathwell, K.; Kim, W.-S. Org. Lett. 2014, 16, 338−341.
(f) El Khatib, M.; Molander, G. A. Org. Lett. 2014, 16, 4944−4947.
(20) (a) Li, J.; Ben
5980−5983. For related sequences, see: (b) Li, J.; Neuville, L. Org.
́
ard, S.; Neuville, L.; Zhu, J. Org. Lett. 2012, 14,
G
DOI: 10.1021/acs.joc.5b00614
J. Org. Chem. XXXX, XXX, XXX−XXX