Iodine-Mediated Aryl C?H Amination for the Synthesis of Benzimidazoles and Pyrido[1,2-a]benzimidazoles

Article abstract of DOI:10.1002/adsc.201600455

An intramolecular aryl C?H amination reaction has been achieved using molecular iodine as the sole oxidant for the synthesis of benzimidazole derivatives. The required substrates were readily prepared by addition or coupling of arylamines with the corresponding nitriles or aryl iodides. Iodine-mediated oxidative cyclization of these substrates in the presence of potassium carbonate (K₂CO₃) as base afforded the corresponding products in moderate to good yields. The transition metal-free protocol presented here is insensitive to air and operationally simple. This versatile and eco-friendly synthetic methodology is broadly applicable to a variety of N-aryl-substituted amidines and pyridin-2-amines, and provides direct access to both 1H-benzo[d]imidazole and pyrido[1,2-a]benzimidazole derivatives from the corresponding precursors. (Figure presented.).

Full text of DOI:10.1002/adsc.201600455

FULL PAPERS
DOI: 10.1002/adsc.201600455
À
Iodine-Mediated Aryl C H Amination for the Synthesis of
Benzimidazoles and Pyrido[1,2-a]benzimidazoles
Zhigang Lv,a Jing Liu,a Wei Wei,a Jie Wu,a Wenquan Yu,a,* and Junbiao Changa,*
a
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan Province 450001, Peopleꢀs
Republic of China
Fax : +86-(0)371-6778-1588; phone: +86-(0)371-6778-1788; e-mail: wenquan_yu@zzu.edu.cn or changjunbiao@zzu.edu.cn
Received: April 28, 2016; Revised: June 13, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600455.
À
Abstract: An intramolecular aryl C H amination re- sented here is insensitive to air and operationally
action has been achieved using molecular iodine as simple. This versatile and eco-friendly synthetic
the sole oxidant for the synthesis of benzimidazole methodology is broadly applicable to a variety of N-
derivatives. The required substrates were readily pre- aryl-substituted amidines and pyridin-2-amines, and
pared by addition or coupling of arylamines with the provides direct access to both 1H-benzo[d]imidazole
corresponding nitriles or aryl iodides. Iodine-mediat- and pyrido[1,2-a]benzimidazole derivatives from the
ed oxidative cyclization of these substrates in the corresponding precursors.
presence of potassium carbonate (K2CO3) as base af-
forded the corresponding products in moderate to Keywords: amination; benzimidazoles; iodine; oxida-
good yields. The transition metal-free protocol pre- tive cyclization; pyrido[1,2-a]benzimidazoles
Introduction
racycles, respectively, and Liang[13] and Huang[14] re-
ported intermolecular examples for regioselective
As an inexpensive and eco-friendly oxidant, molecu- amination at C-2 of indoles. As a continuation of our
À
lar iodine has been extensively applied to promote research on I2-mediated C H functionalization, we
transformations, including oxidation of O/S-contain- envisioned an aryl C H amination reaction for the
À
ing functional groups,[1] aromatization,[2] and iodocy- synthesis of benzimidazoles from N-arylamidines and
ACHTUNGTRENNUNG
clization/cyclodehydroiodination.[3] In recent years, pyrido[1,2-a]benzimidazoles from N-aryl-2-aminopyri-
numerous oxidative annulation reactions have been dines, and describe the results in this paper
developed with this readily available reagent to con- (Scheme 1).
struct diverse heterocyclic skeletons.[4] In particular,
The benzimidazole scaffold is an important struc-
iodine (I2)-mediated oxidative C N bond formation is ture in medicinal chemistry.[15] Mebendazole
a valuable tool for the synthesis of N-containing het- (Figure 1), for example, is a highly effective antihel-
erocycles. For example, utilizing in-situ generated a- mintic for the treatment of a number of worm infec-
keto aldehydes through oxidation of methyl ketones
À
by I2/DMSO, Wu et al. have prepared compounds
such as, quinazoline-4(3H)-ones,[5] isoquinolines,[6] and
imidazo[1,2-a]pyridines.[7] In 2013, Zhang[8] described
a route to indoles and indolines from N-protected b-
2’-aminophenyl ketones in the presence of iodine.
Earlier, we synthesized pyrazoles[9] and 1,3-diazahet-
ACHTUNGTRENNUNG
erocyclic derivatives[10] via iodine-promoted, one-pot
reactions, but most of these methods were achieved
À
through functionalization of vinyl or a-C=O C H
bonds. Direct aryl C H amination reactions using mo-
À
lecular iodine as the sole oxidant are rarely reported.
Scheme 1. Proposed route to benzimidazole derivatives via
Batra[11] and Sekar[12] disclosed such intramolecular
À
aryl C H amination [Eq. (2)] based on the previous vinyl
reactions to prepare quinolines and indole-fused tet- C H amination reactions [Eq. (1)].
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Table 1. Optimization of the reaction conditions for the syn-
thesis of pyrido[1,2-a]benzimidazole 2a.[a]
En- I2
try (equiv.)
Base
Sol-
vent
Temp. Time Yield[b]
1
2
3
4
5
2.0
3.0
3.0
3.0
3.0
K2CO3 1,4-dioxane 608C 9 h
K2CO3 1,4-dioxane 608C 5 h
K2CO3 1,4-dioxane 808C 5 h
Cs2CO3 1,4-dioxane 608C 5 h
44%
70%
55%
39%
50%
Figure 1. Representative molecules containing benzimida-
zole or pyrido[1,2-a]benzimidazole skeletons.
K2CO3 DMSO
608C 5 h
[a]
Optimal reaction conditions (entry 2): 1a (0.5 mmol), I2
(1.5 mmol), K2CO3 (2 mmol), 1,4-dioxane, 608C.
Isolated yields.
[b]
tions. As a selective and irreversible proton pump in-
hibitor, omeprazole is another important medication
essential to a basic health system. Veliparib, a potent
and orally active PARP inhibitor, is currently in phase ing groups (EDGs) (1a–c) on the N-phenyl ring
II clinical trials[16] and TDR86919, a pyrido[1,2-a]ben- afford the desired pyrido[1,2-a]benzimidazoles (2a–c)
zimidazole derivative, has been identified as having in good yield; while the presence of electron-with-
promising antimalarial activity both in vitro and in drawing groups (EWGs, e.g., halogen) on this ring
vivo.[17] Furthermore, some pyrido[1,2-a]benzimida- make the reaction more complex (not shown). Inter-
zoles also display interesting photophysical and fluo- estingly, the substrate with an unsubstituted phenyl
rescence properties.[18] A variety of synthetic methods
have been developed for the preparation of this class
of compounds.[19] Recently, significant progress has
been made in transition metal-catalyzed aerobic oxi-
dation[20] and hypervalent iodine-mediated oxidative
cyclization.[21] These reactions proceed through direct
À
C H cycloamination of readily available N-arylami-
dines without prefunctionalization of the reaction
centers, making the synthesis simpler and more effi-
cient. We report such a reaction employing molecular
iodine.
Results and Discussion
We used N-(p-tolyl)pyridin-2-amine (1a) as the model
substrate in an oxidative cyclization producing
pyrido[1,2-a]benzimidazole 2a (Table 1). An initial
screening of the reaction conditions indicated that
1,4-dioxane is the most effective solvent for this con-
version. Full consumption of substrate 1a requires at
least 3.0 equiv. of iodine at 608C (entry 2). The con-
version becomes slower at lower temperature (not
shown) and produces the desired product 2a in
a lower yield at 808C with some by-products which
remain unidentified (entry 3). The use of Cs2CO3 as
base (entry 4) or replacement of 1,4-dioxane with
DMSO (entry 5) also results in decreased yields.
Various N-arylpyridin-2-amines (Table 2) were sub-
jected to the optimal reaction conditions above
À
Scheme 2. Proposed mechanisms for the I2-mediated aryl C
H amination: (A) oxidative cyclization of 1a to 2a; (B) for-
(Table 1, entry 2). Substrates bearing electron-donat- mation of 2d’ from 1d; (C) synthesis of 2f and 2i from 1k, l.
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Table 2. Substrate scope for the synthesis of pyrido[1,2-a]benzimidazoles 2.[a]
[a]
Optimal reaction conditions: 1 (0.5 mmol), I2 (1.5 mmol), K2CO3 (2 mmol), 1,4-dioxane, 608C.
Isolated yields.
2.5 mmol of I2 and 3 mmol of K2CO3 were used.
[b]
[c]
moiety (1d) gives the product 2d’ which when aminat- (A) generates intermediate B which contains a new
À
ed by a second molecule of the substrate reacts fur- C N bond. Finally, the subsequent proton elimination
ther (Scheme 2B). This was confirmed by X-ray (see by base and rearomatization lead to the pyrido[1,2-
the Supporting Information).[22] This methodology can a]benzimidazole skeleton (2a). For substrate 1d
tolerate both EDGs (1e–h) and EWGs (1i–j) on the (Scheme 2B), due to the absence of substituents at
pyridine ring, with the methyl-substituted substrates the para-position of the N-phenyl ring (C), a second
giving higher yields (2e–h). It is worthy of note that molecule of 1d attacks the para-carbon before the
both 2,4,6-trimethylphenylpyridin-2-amines (1k, l) cyclization step to form a dimer (E). Further I2-medi-
also produce the cyclized products through a demethy- ated oxidative cyclization of E eventually affords
lation process. A plausible mechanism for this conver- compound 2d’. For the substrates with a 2,4,6-trime-
sion is shown in Scheme 2C.
A plausible mechanism for this I2-mediated aryl C
H amination reaction is proposed in Scheme 2A. can then undergo demethylation to give the corre-
thylphenyl moiety (1k, l) (Scheme 2C), cyclization of
the iodide F generates first the intermediate G, which
À
Using the formation of 2a as an example, the base- sponding product.
mediated oxidative iodination of substrate 1a produ-
ces an N-iodo species (A). Then the N I bond is scope of this aryl C H amination reaction to synthe-
cleaved, and consequently, cyclization of the iodide size benzimidazoles from N-arylamidines (Table 3).
In light of these results, we further extended the
À
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Table 3. Optimization of the reaction conditions for the syn-
thesis of benzimidazole 4a.[a]
amidines and 2-aminopyridines to produce 1H-ben-
zo[d]imidazole and pyrido[1,2-a]benzimidazole deriv-
atives, respectively. Further application of this I2-
mediated cycloamination method to construct other
heterocyclic skeletons is currently in progress in our
laboratory.
En- I2
try (equiv.) tive
Addi- Sol-
Temp. Time Yield[b]
Experimental Section
vent
1
2
3
4
5
6
7
3.0
3.0
3.0
3.0
1.5
1.2
1.5
–
–
–
KI
KI
KI
KI
1,4-dioxane 608C
1,4-dioxane reflux 11 h 34%
22 h trace
General Information
1H and 13C NMR spectra were recorded on an Agilent
400 MHz (100 MHz for 13C NMR) spectrometer. Chemical
shift values are given in parts per million (ppm) with tetra-
methylsilane (TMS) as the internal standard. The peak pat-
terns are indicated as follows: s, singlet; d, doublet; t, trip-
let; q, quartet; quint, quintet; sext, sextet; m, multiplet; dd,
doublet of doublets; dt, doublet of triplets. The coupling
constants (J) are reported in Hertz (Hz). Melting points
were determined on an XT4A micromelting point apparatus
and are uncorrected. High-resolution mass spectra (HR-MS)
were obtained on a Bruker MicrOTOF-Q II mass spectrom-
eter equipped with an electrospray ion source (ESI), operat-
ed in the positive mode. Flash column chromatography was
performed over silica gel 200–300 mesh and the eluents
were distilled prior to use. 1,4-Dioxane and DMSO were
dried over 4ꢂ molecular sieves before use. All the chemi-
cals (AR grade) were purchased from Aladdin or Sino-
pharm Chemical Reagent Co., Ltd. (Shanghai, China), and
were used without further purification.
DMSO
DMSO
DMSO
DMSO
DMSO
1208C 6 h
1208C 0.5 h 62%
1208C 0.5 h 70%
1208C 1 h
1108C 1 h
46%
68%
66%
[a]
Optimal reaction conditions (entry 5): a well-stirred mix-
ture of I2 (0.75 mmol) and KI (0.75 mmol) in DMSO
(5 mL) was treated with 3a (0.5 mmol), followed by the
addition of K2CO3 (1.75 mmol) and DMSO (5 mL), and
then heated to 1208C.
[b]
Isolated yields.
However, the cyclization of substrate 3a under the
above conditions is very slow and only a trace
amount of product 4a was formed (entry 1). At reflux
temperature the reaction produced 4a in 34% yield
(entry 2). Replacement of 1,4-dioxane with DMSO re-
sults in a better yield but the total consumption of 3a
still required a longer time (entry 3). Based upon our
À
General Procedure for the Synthesis of Products 2
experience with the I2/KI-mediated N N bond forma-
tion reaction,[23] we added KI to the reaction system.
This greatly accelerated the transformation and im-
proved the yield of the product (entry 4). Further-
more, in the presence of KI, 1208C is the optimal
A stirred solution of N-arylpyridin-2-amine 1 (0.5 mmol) in
1,4-dioxane (10 mL) was treated sequentially with iodine
(381 mg, 1.5 mmol) and K2CO3 (276 mg, 2 mmol). The re-
sulting mixture was heated to 608C until TLC indicated that
temperature and 1.5 equiv. of iodine are sufficient for the conversion was complete. After cooling to room temper-
ature, the reaction was quenched with 5% Na2S2O3 (15 mL)
and extracted with EtOAc (3ꢃ15 mL). The combined or-
ganic layer was dried over anhydrous Na2SO4, concentrated,
and purified by column chromatography using a mixture of
EtOAc and petroleum ether as the eluent to afford product
2.
the transformation (entry 5).
With the optimum reaction conditions (Table 3,
entry 5) in hand, we examined the substrate scope for
benzimidazole synthesis (Table 4). N-Arylamidines
bearing both EDGs and EWGs on the N-phenyl ring
(3a–i) are compatible with this oxidative cyclization
protocol. The chlorinated (3d) and unsubstituted (3e)
substrates give lower yields. Both 2-aryl (4a–n) and 2-
alkyl (4o–p) substituted benzimidazoles were pre-
8-Methylbenzo[4,5]imidazo[1,2-a]pyridine (2a): 5 h; yield:
64 mg (70%); brown solid; mp 111–1128C; Rf =0.32
1
(EtOAc/PE 50:50); H NMR (400 MHz, DMSO-d6): d=8.96
(d, J=6.8 Hz, 1H), 8.07 (s, 1H), 7.66 (d, J=8.4 Hz, 1H),
pared by replacing the phenyl moiety at the R3 posi- 7.60 (d, J=9.2 Hz, 1H), 7.50–7.46 (m, 1H), 7.30 (d, J=
8.4 Hz, 1H), 6.94 (t, J=6.8 Hz, 1H), 2.51 (s, 3H); 13C NMR
tion (Table 4) with the corresponding substituents.
(100 MHz, DMSO-d6): d=147.9, 142.4, 130.6, 130.1, 129.1,
127.5, 127.2, 119.0, 117.4, 111.8, 110.6, 21.9; HR-MS: m/z=
183.0917 [M+H]+, calcd. for C12H11N2: 183.0917.
Conclusions
2,8-Dimethylbenzo[4,5]imidazo[1,2-a]pyridine (2b): 5 h;
yield: 90 mg (92%); brown solid; mp 135–1368C; Rf =0.30
In summary, we have established a new I2-mediated
1
(EtOAc/PE 50:50); H NMR (400 MHz, DMSO-d6): d=8.78
À
intramolecular aryl C H amination reaction for ben-
(s, 1H), 8.00 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.54 (d, J=
zimidazole synthesis. This transition metal-free and
versatile protocol is not sensitive to air and operation-
9.2 Hz, 1H), 7.37–7.34 (m, 1H), 7.29–7.26 (m, 1H), 2.50 (s,
3H), 2.33 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d=
ally simple. It works well with both N-aryl-substituted 147.0, 142.4, 133.2, 130.3, 129.0, 127.2, 124.4, 119.8, 118.9,
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Table 4. Substrate scope for the synthesis of benzimidazoles 4.[a]
[a]
Optimal reaction conditions: A well-stirred mixture of I2 (0.75 mmol) and KI (0.75 mmol) in DMSO (5 mL) was treated
with 3a (0.5 mmol), followed by the addition of K2CO3 (1.75 mmol) and DMSO (5 mL), and then heated to 1208C.
[b]
Isolated yields.
[c]
1
The ratio was determined by H NMR.
116.8, 111.7, 21.9, 18.0; HR-MS: m/z=197.1072 [M+H]+,
calcd. for C13H13N2: 197.1073.
solid; mp 189–1918C; Rf =0.41 (EtOAc); 1H NMR
(400 MHz, DMSO-d6): d=9.01 (d, J=6.8 Hz, 1H), 8.26 (d,
J=2.0 Hz, 1H), 8.10–8.08 (m, 1H), 7.79 (d, J=8.8 Hz, 1H),
7.63 (d, J=9.2 Hz, 1H), 7.53–7.48 (m, 2H), 7.34–7.26 (m,
3H), 7.20 (s, 1H), 7.18 (s, 1H), 7.09 (t, J=7.2 Hz, 1H), 6.92
(t, J=7.2 Hz, 1H), 6.82–6.79 (m, 1H), 6.60 (d, J=8.4 Hz,
1H); 13C NMR (100 MHz, DMSO-d6): d=159.2, 148.9,
148.1, 146.5, 142.4, 139.2, 138.1, 130.5, 129.7, 127.6, 126.7,
126.2, 124.5, 120.4, 117.5, 116.1, 112.4, 111.9, 110.9; HR-MS:
m/z=337.1445 [M+H]+, calcd. for C22H17N4: 337.1448.
8-Methoxy-2-methylbenzo[4,5]imidazo[1,2-a]pyridine
(2c): 5.5 h; yield: 97 mg (91%); black solid; mp 169–1708C;
Rf =0.36 (EtOAc/PE 50:50); 1H NMR (400 MHz, DMSO-
d6): d=8.79 (d, J=1.2 Hz, 1H), 7.82 (s, 1H), 7.65 (d, J=
8.8 Hz, 1H), 7.51 (d, J=9.6 Hz, 1H), 7.33–7.29 (m, 1H),
7.11–7.07 (m, 1H), 3.87 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d=155.0, 146.8, 138.8, 132.3, 129.1,
124.1, 120.0, 119.6, 116.9, 116.0, 94.8, 56.2, 18.0; HR-MS:
m/z=213.1023 [M+H]+, calcd. for C13H13N2O: 213.1022.
N-Phenyl-N-(pyridin-2-yl)benzo[4,5]imidazo[1,2-a]pyri-
din-8-amine (2d’): 6 h; yield: 158 mg (94%); light yellow
1,6,8-Trimethylbenzo[4,5]imidazo[1,2-a]pyridine
(2e):
4.5 h; yield: 104 mg (ꢀ95%); yellow solid; mp 154–1558C;
Rf =0.28 (EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-
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d6): d=7.91 (s, 1H), 7.54 (d, J=9.2 Hz, 1H), 7.43–7.39 (m,
1H), 7.17 (s, 1H), 6.73 (d, J=6.4 Hz, 1H), 3.02 (s, 3H), 2.63
(s, 3H), 2.51 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d=
148.5, 142.5, 139.9, 129.8, 129.6, 129.4, 128.1, 126.9, 115.0,
112.9, 110.8, 22.0, 21.2, 17.3; HR-MS: m/z=211.1229 [M+
H]+, calcd. for C14H15N2: 211.1230.
fied by silica gel column chromatography using a mixture of
EtOAc and petroleum ether as the eluent to afford the de-
sired product 4.
6-Methyl-2-phenyl-1H-benzo[d]imidazole (4a): 0.5 h;
yield: 73 mg (70%); yellow solid; mp 251–2528C; Rf =0.26
(EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-d6): d=
12.76 (br, s, 1H), 8.17–8.15 (m, 2H), 7.56–7.45 (m, 4H), 7.38
(s, 1H), 7.02 (d, J=8.0 Hz, 1H), 2.43 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d=151.0, 131.3, 130.4, 129.6, 128.9,
126.4, 123.6, 21.4; HR-MS: m/z=209.1074 [M+H]+, calcd.
for C14H13N2: 209.1073.
2,6,8-Trimethylbenzo[4,5]imidazo[1,2-a]pyridine (2f): 9 h;
yield: 104 mg (ꢀ95%); black solid; mp 108–1098C; Rf =0.39
1
(EtOAc/PE 50:50); H NMR (400 MHz, DMSO-d6): d=8.73
(s, 1H), 7.80 (s, 1H), 7.54 (d, J=9.6 Hz, 1H), 7.33 (d, J=
9.2 Hz, 1H), 7.09 (s, 1H), 2.57 (s, 3H), 2.47 (s, 3H), 2.33 (s,
3H); 13C NMR (100 MHz, DMSO-d6): d=146.5, 142.1,
132.6, 130.2, 128.48, 128.46, 127.1, 124.4, 119.7, 117.0, 109.0,
21.9, 18.0, 17.2; HR-MS: m/z=211.1235 [M+H]+, calcd. for
C14H15N2: 211.1230.
6-Methoxy-2-phenyl-1H-benzo[d]imidazole (4b): 1 h;
yield: 71 mg (63%); yellow solid; mp 152–1538C; Rf =0.53
1
(EtOAc/PE 50:50); H NMR (400 MHz, DMSO-d6, mixture
of tautomers, *peaks of the minor tautomer): d=12.78* (br,
s, 0.41H), 12.76 (br, s, 0.53H), 8.16–8.12 (m, 2H), 7.56–7.41
(m, 4H), 7.22* (s, 0.40H), 7.00 (s, 0.54H), 6.87–6.82 (m,
1H), 3.82 (s, 1.74H), 3.81* (s, 1.25H); 13C NMR (100 MHz,
DMSO-d6, mixture of tautomers, *peaks of the minor tauto-
mer): d=156.1, 155.4*, 151.4*, 150.4, 144.7*, 138.3, 135.7,
130.4, 129.6*, 129.4, 128.9, 126.2*, 126.1, 119.4, 112.3*,
111.6*, 111.2, 101.3*, 94.4, 55.5; HR-MS: m/z=225.1021
[M+H]+, calcd. for C14H13N2O: 225.1022.
6-Isopropyl-2-phenyl-1H-benzo[d]imidazole (4c): 1 h;
yield: 96 mg (81%); brown solid; mp 90–918C; Rf =0.33
(EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-d6): d=
12.76 (br, s, 1H), 8.17–8.14 (m, 2H), 7.55–7.44 (m, 4H), 7.41
(s, 1H), 7.09 (dd, J=8.4, 1.6 Hz, 1H), 3.05–2.94 (m, 1H),
1.25 (d, J=7.2 Hz, 6H); 13C NMR (100 MHz, DMSO-d6):
d=151.5, 143.2, 130.8, 130.1, 129.4, 126.7, 121.5, 34.1, 24.94,
24.89; HR-MS: m/z=237.1391 [M+H]+, calcd. for
C16H17N2: 237.1386.
3,6,8-Trimethylbenzo[4,5]imidazo[1,2-a]pyridine (2g): 4 h;
yield: 96 mg (91%); gray solid; mp 136–1378C; Rf =0.45
1
(EtOAc/PE 50:50); H NMR (400 MHz, DMSO-d6): d=8.77
(d, J=6.8 Hz, 1H), 7.79 (s, 1H), 7.38 (s, 1H), 7.07 (s, 1H),
6.75 (dd, J=7.2, 1.6 Hz, 1H), 2.56 (s, 3H), 2.46 (s, 3H), 2.39
(s, 3H); 13C NMR (100 MHz, DMSO-d6): d=147.8, 142.2,
140.3, 129.8, 128.6, 128.2, 127.1, 126.2, 115.4, 113.1, 109.0,
21.84, 21.75, 17.2; HR-MS: m/z=211.1230 [M+H]+, calcd.
for C14H15N2: 211.1230.
4,6,8-Trimethylbenzo[4,5]imidazo[1,2-a]pyridine
(2h):
3.5 h; yield: 104 mg (ꢀ95%); brown solid; mp 99–1008C;
Rf =0.46 (EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-
d6): d=8.73 (d, J=6.8 Hz, 1H), 7.81 (s, 1H), 7.24 (dd, J=
6.8, 1.2 Hz, 1H), 7.09 (s, 1H), 6.81 (t, J=6.8 Hz, 1H), 2.59
(s, 3H), 2.53 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): d=148.0, 141.7, 130.3, 129.2, 128.6, 127.5, 127.3,
127.0, 124.7, 110.4, 109.2, 21.9, 17.6, 17.3; HR-MS: m/z=
211.1230 [M+H]+, calcd. for C14H15N2: 211.1230.
2-Chloro-6,8-dimethylbenzo[4,5]imidazo[1,2-a]pyridine
(2i): 4 h; yield: 97 mg (84%); brown solid; mp 144–1458C;
Rf =0.42 (EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-
d6): d=9.23 (d, J=4.0 Hz, 1H), 7.90 (s, 1H), 7.68–7.64 (m,
1H), 7.50–7.45 (m, 1H), 7.13 (s, 1H), 2.58 (s, 3H), 2.47 (s,
3H); 13C NMR (100 MHz, DMSO-d6): d=145.5, 142.4,
131.2, 130.2, 128.9, 128.7, 127.8, 125.4, 118.5, 117.2, 109.5,
21.9, 17.1; HR-MS: m/z=231.0673 [M+H]+, calcd. for
C13H12ClN2: 231.0684.
2-Bromo-6,8-dimethylbenzo[4,5]imidazo[1,2-a]pyridine
(2j): 5 h; yield: 89 mg (65%); yellow solid; mp 138–1398C;
Rf =0.43 (EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-
d6): d=9.30 (s, 1H), 7.92 (s, 1H), 7.62–7.52 (m, 2H), 7.13 (s,
1H), 2.57 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): d=145.6, 142.2, 132.3, 131.2, 128.8, 128.6, 127.8,
127.6, 118.7, 109.5, 103.9, 21.9, 17.1; HR-MS: m/z=275.0177
[M+ H]+, calcd. for C13H12BrN2: 275.0178.
6-Chloro-2-phenyl-1H-benzo[d]imidazole (4d): 1.5 h;
yield: 50 mg (44%); white solid; mp 176–1778C; Rf =0.41
1
(EtOAc/PE 25:75); H NMR (400 MHz, DMSO-d6, mixture
of tautomers, *peaks of the minor tautomer): d=13.11 (s,
0.51), 13.08* (s, 0.45H), 8.18–8.16 (m, 2H), 7.72* (s, 0.45H),
7.67 (d, J=8.8 Hz, 0.52H), 7.58–7.49 (m, 4H), 7.25–7.20 (m,
1H); 13C NMR (100 MHz, DMSO-d6): d=153.1, 130.7,
130.1, 129.5, 127.0, 122.8; HR-MS: m/z=229.0527 [M+H]+,
calcd. for C13H10ClN2: 229.0527.
2-Phenyl-1H-benzo[d]imidazole (4e): 0.5 h; yield: 45 mg
(46%); brown solid; mp 278–2798C; Rf =0.34 (EtOAc/PE
25:75); 1H NMR (400 MHz, DMSO-d6): d=12.92 (br, s,
1H), 8.19–8.16 (m, 2H), 7.60–7.46 (m, 5H), 7.21–7.18 (m,
2H); 13C NMR (100 MHz, DMSO-d6): d=151.6, 130.6,
130.3, 129.4, 126.9, 122.5; HR-MS: m/z=195.0916 [M+H]+,
calcd. for C13H11N2: 195.0917.
4-Methyl-2-phenyl-1H-benzo[d]imidazole (4f): 1 h; yield:
56 mg (54%); yellow solid; mp 251–2528C; Rf =0.32
(EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-d6): d=
12.79 (br, s, 1H), 8.19 (d, J=6.8 Hz, 2H), 7.55–7.38 (m,
4H), 7.08 (t, J=7.2 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 2.56
(s, 3H); 13C NMR (100 MHz, DMSO-d6): d=130.8, 130.1,
129.3, 127.0, 17.4; HR-MS: m/z=209.1071 [M+H]+, calcd.
for C14H13N2: 209.1073.
5,7-Dimethyl-2-phenyl-1H-benzo[d]imidazole (4h): 1 h;
yield: 71 mg (64%); yellow solid; mp 190–1918C; Rf =0.31
(EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-d6): d=
12.62 (br, s, 1H), 8.17 (d, J=7.6 Hz, 2H), 7.54–7.49 (m,
2H), 7.47–7.42 (m, 1H), 7.16 (s, 1H), 6.80 (s, 1H), 2.52 (s,
3H), 2.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d=
General Procedure for the Synthesis of Products 4
A mixture of KI (125 mg, 0.75 mmol) and iodine (191 mg,
0.75 mmol) in DMSO (5 mL) was stirred at room tempera-
ture for 10 min and then treated with N-arylamidine 3
(0.5 mmol), followed by the addition of K2CO3 (242 mg,
1.75 mmol) and DMSO (5 mL). The reaction mixture was
maintained at 1208C until TLC indicated the conversion
was complete. After cooling to room temperature, it was
quenched with 5% Na2S2O3 (5 mL), followed by the addi-
tion of 5% aqueous ammonia (15 mL), and then extracted
with EtOAc (3ꢃ15 mL). The combined organic layer was
dried over anhydrous Na2SO4, concentrated, and then puri-
Adv. Synth. Catal. 0000, 000, 0 – 0
6
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130.5, 129.5, 128.8, 126.4, 21.3, 16.8; HR-MS: m/z=223.1231
[M+H]+, calcd. for C15H15N2: 223.1230.
2-Hexyl-6-methyl-1H-benzo[d]imidazole
(4o):
0.5 h;
yield: 51 mg (47%); brown oil; Rf =0.24 (EtOAc/PE 25:75);
1H NMR (400 MHz, DMSO-d6): d=7.31 (d, J=8.0 Hz, 1H),
7.22 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 2.75 (t, J=7.6 Hz,
2H), 2.37 (s, 3H), 1.76–1.68 (m, 2H), 1.32–1.21 (m, 6H),
0.84 (t, J=6.8 Hz, 3H); 13C NMR (100 MHz, DMSO-d6):
d=155.2, 130.4, 122.8, 31.4, 29.0, 28.8, 28.0, 22.5, 21.7, 14.4;
HR-MS: m/z=217.1692 [M+H]+, calcd. for C14H21N2:
217.1699.
2-(tert-Butyl)-6-methyl-1H-benzo[d]imidazole (4p): 4.5 h;
yield: 43 mg (46%); yellow solid; mp 205–2068C; Rf =0.25
(EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-d6): d=
11.94 (br, s, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.25 (s, 1H), 6.93
(d, J=8.0 Hz, 1H), 2.39 (s, 3H), 1.38 (s, 9H); 13C NMR
(100 MHz, DMSO-d6): d=162.2, 130.5, 122.8, 33.6, 29.7,
21.8; HR-MS: m/z=189.1386 [M+H]+, calcd. for C12H17N2:
189.1386.
5,6-Dimethyl-2-phenyl-1H-benzo[d]imidazole (4i): 1 h;
yield: 42 mg (38%); yellow solid; mp 255–2568C; Rf =0.22
(EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-d6): d=
12.63 (br, s, 1H), 8.14–8.11 (m, 2H), 7.53–7.48 (m, 2H),
7.45–7.41 (m, 1H), 7.34 (s, 2H), 2.30 (s, 6H); 13C NMR
(100 MHz, DMSO-d6): d=150.8, 130.9, 129.9, 129.3, 126.6,
20.5; HR-MS: m/z=223.1230 [M+H]+, calcd. for C15H15N2:
223.1230.
4,5-Dimethyl-2-phenyl-1H-benzo[d]imidazole (4i’): 1 h;
yield: 41 mg (37%); yellow solid; mp 197–1988C; Rf =0.33
(EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-d6): d=
12.58 (br, s, 1H), 8.18 (d, J=7.2 Hz, 2H), 7.54–7.50 (m,
2H), 7.47–7.43 (m, 1H), 7.27 (d, J=7.2 Hz, 1H), 6.98 (d, J=
8.4 Hz, 1H), 2.49 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): d=130.9, 130.0, 129.2, 126.9, 124.8, 19.5, 14.0;
HR-MS: m/z=223.1229 [M+H]+, calcd. for C15H15N2:
223.1230.
2-(4-Methoxyphenyl)-6-methyl-1H-benzo[d]imidazole
(4j): 1.5 h; yield: 88 mg (74%); yellow solid; mp 159–1608C;
Rf =0.53 (EtOAc/PE 50:50); 1H NMR (400 MHz, DMSO-
d6): d=12.59 (br, s, 1H), 8.08 (d, J=8.8 Hz, 2H), 7.42 (d,
J=8.0 Hz, 1H), 7.32 (s, 1H), 7.08 (d, J=8.8 Hz, 2H), 6.98
(d, J=8.0 Hz, 1H), 3.82 (s, 3H), 2.41 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d=160.9, 151.5, 128.3, 123.6, 123.3,
114.8, 55.8, 21.8; HR-MS: m/z=239.1179 [M+H]+, calcd.
for C15H15N2O: 239.1179.
2-(4-Fluorophenyl)-6-methyl-1H-benzo[d]imidazole (4k):
1.5 h; yield: 72 mg (64%); yellow solid; mp 180–1818C; Rf =
0.40 (EtOAc/PE 25:75); 1H NMR (400 MHz, DMSO-d6):
d=12.75 (br, s, 1H), 8.21–8.16 (m, 2H), 7.46–7.35 (m, 4H),
7.02 (d, J=8.0 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): d=164.6, 162.2, 129.0 (d, J=8.6 Hz), 127.4 (d,
J=3.0 Hz), 116.4 (d, J=21.7 Hz), 21.8; HR-MS: m/z=
227.0984 [M+H]+, calcd. for C14H12FN2: 227.0979.
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 81302637, 81330075) and Outstanding Young Talent
Research Fund of Zhengzhou University (No. 1521316004)
for financial support.
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Iodine-Mediated Aryl C H Amination for the Synthesis of
Benzimidazoles and Pyrido[1,2-a]benzimidazoles
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Adv. Synth. Catal. 2016, 358, 1 – 9
Zhigang Lv, Jing Liu, Wei Wei, Jie Wu, Wenquan Yu,*
Junbiao Chang*
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