Copper-Catalyzed Double C-N Bond Formation for the Synthesis of Diverse Benzimidazoles from N -Alkyl-2-iodoaniline and Sodium Azide

Article abstract of DOI:10.1055/s-0036-1588086

An efficient approach to the synthesis of benzimidazole derivatives has been achieved by copper-catalyzed double C-N bonds formation of N-alkyl-2-iodoaniline and sodium azide. The reaction was supposed to proceed through copper-catalyzed tandem reaction of S_NAr reaction, aerobic oxidation of C(sp³)-H bond and intramolecular C-N bond formation sequence. Structurally diverse 2-aryl, alkenyl and alkyl benzoimidazole derivatives were assembled by this methodology.

Full text of DOI:10.1055/s-0036-1588086

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
Z. Chen et al.
Letter
Synlett
Copper-Catalyzed Double C–N Bond Formation for the Synthesis
of Diverse Benzimidazoles from N-Alkyl-2-iodoaniline and Sodium
Azide
Zhengkai Chen*
H
N
CuI/TMEDA
R2
Hongli Li
N
R2
R1
NaN3
+
Gangjian Cao
Jianfeng Xu
R1
tandem reaction
N
H
I
readily available reagents
broad substrate scope
29 examples (25–76%)
R2 = aryl, alkenyl or
alkyl
Maozhong Miao
Hongjun Ren*
Department of Chemistry, Zhejiang Sci-Tech University,
Hangzhou 310018, P. R. of China
zkchen@zstu.edu.cn
renhj@zstu.edu.cn
Received: 05.09.2016
Accepted after revision: 05.10.2016
Published online: 15.11.2016
folds could also be readily constructed through direct
C(sp2)–H amination strategy by Pd- or Cu-catalyzed or met-
al-free mediated C–H activation/C–N bond formation of N-
arylamidines, albeit the synthesis of 2-alkylbenzimidazoles
has been unsuccessful with respect to transition-metal-cat-
alyzed synthetic protocol (Scheme 1, c).6
DOI: 10.1055/s-0036-1588086; Art ID: st-2016-w0584-l
Abstract An efficient approach to the synthesis of benzimidazole de-
rivatives has been achieved by copper-catalyzed double C–N bonds for-
mation of N-alkyl-2-iodoaniline and sodium azide. The reaction was
supposed to proceed through copper-catalyzed tandem reaction of
SNAr reaction, aerobic oxidation of C(sp3)–H bond and intramolecular
C–N bond formation sequence. Structurally diverse 2-aryl, alkenyl and
alkyl benzoimidazole derivatives were assembled by this methodology.
NH2
R2 CHO
R2 COOH
or
R1
(a)
NH2
H
Key words copper catalyst, C–N bond formation, benzimidazoles,
N
R2
Pd or Cu
tandem reaction, N-heterocyclic compounds
R1
(b)
NH(O)
X
X = halogen
Benzimidazole derivatives are one of the most import-
ant classes of heterocyclic compounds ubiquitously existing
in a myriad of natural products and functional materials.1 A
wide variety of biological and pharmaceutical properties of
benzimidazole scaffolds, including anticancer, antifungal,
antibacterial, antihypertensive, and antiviral activities,2
have received tremendous interest among organic and me-
dicinal chemists. In addition, benzimidazoles have found
extensive applications in the fields of dyes, chemical sensor,
fluorescence, and corrosion science.3 Considering the
unique character and great utility value of benzimidazole
core, the development of facile and straightforward strate-
gies for their synthesis is of great significance.
H
N
R2
R2
R2
N
Pd or Cu or I(III)
R1
R1
R1
(c)
(d)
R1
R2
NH
H
N
H
H
N
benzimidazoles
TEMPO
NH2
H
N
Cu, NaN3
this work
(e)
I
Scheme 1 Different synthetic routes leading to benzimidazole deriva-
tives
The traditional methods for the preparation of benzim-
idazoles include two pathways. One method is the conden-
sation reaction of 1,2-phenylenediamines with aldehydes
or carboxylic acids, which has several drawbacks, such as
necessity of stoichiometric oxidant or harsh reaction condi-
tions (Scheme 1, a).4 The alternative synthetic route consti-
tutes the transition-metal-catalyzed intramolecular C–N
bond formation of N-(o-haloaryl)amidines or N-(o-
haloaryl)amides (Scheme 1, b).5 The benzimidazole scaf-
Another noteworthy synthetic method to access ben-
zimidazoles was metal-free TEMPO-promoted intramolec-
ular C(sp3)–H amination reaction of N1-benzyl/alkyl-1,2-
phenylenediamines developed by the group of Long
(Scheme 1, d).7 Apart from aforementioned pioneering
works, an array of other useful strategies for the construc-
tion of benzimidazole moieties had been demonstrated.8
Encouraged by the recently reported functionalization of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
Z. Chen et al.
Letter
Synlett
the active α-C(sp3)–H of amines to build diverse nitrogen-
containing heterocyclics,9 we present a general protocol for
the rapid assembly of benzimidazole derivatives from read-
ily accessible N-alkyl-2-iodoaniline and sodium azide via
copper-catalyzed tandem reaction through double C–N
bonds formation (Scheme 1, e).10
Table 1 Optimization of the Reaction Conditionsa
cat. (20 mol%)
ligand (40 mol%)
H
N
N
Ph
Ph
NaN3
+
base (2 equiv)
N
H
solvent, 130 °C, 24 h
I
1b
2b
We started our investigation by the use of N-benzyl-2-
iodo-4-methylaniline (1b) as the model substrate and the
results of the optimization of the reaction conditions are
shown in Table 1. Initially, the reaction between substrate
1b and sodium azide in the presence of different Cu cata-
lysts and TMEDA in DMSO at 130 °C was carried out and CuI
exhibited the best reactivity to give the desired product in
54% yield (Table 1, entries 1–4). Then, through the employ-
ment of a variety of solvents including NMP, DMF, toluene
and 1,4-dioxane we examined the solvent effect, and the
results were inferior to that of DMSO (Table 1, entries 5–8).
The replacement of TMEDA with other ligands, such as L-
proline, 1,10-phenanthroline or DMEDA, led to a slight de-
crease in the reactivity of the reaction (Table 1, entries 9–
11). The effect of different bases was also evaluated and a
60% yield of benzimidazole 2b could be observed when the
organic base DIPEA was applied (Table 1, entries 12–15).
The role of Cu catalyst was essential to the reaction as the
transformation did not proceed at all in the absence of CuI
(Table 1, entry 16). Furthermore, when the reaction was
preformed under N2 or O2 atmosphere, a decrease in the re-
action yield was observed (Table 1, entries 17 and 18). Rela-
tively low temperature exerted a negative impact on the ef-
ficiency of the reaction and further increasing the reaction
temperature to 140 °C failed to improve the reactivity of the
transformation (Table 1, entries 19 and 20).
Entry Cat. (mol%) Ligand (mol%) Base (equiv)Solvent (mL) Yield (%)b
1
2
CuCl
CuBr
CuI
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
L-proline
1,10-Phen
DMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
–
DMSO
DMSO
DMSO
DMSO
NMP
32
–
46
3
–
54
4
Cu(OAc)2
CuI
–
25
5
–
43
6
CuI
–
DMF
37
7
CuI
–
toluene
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
trace
trace
52
8
CuI
–
9
CuI
–
10
11
12
13
14
15
16
17
18
19
20
CuI
–
53
CuI
–
50
CuI
K2CO3
Cs2CO3
Et3N
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
43
CuI
15
CuI
50
CuI
–
60
NR
45c
34d
30e
60f
CuI
CuI
CuI
CuI
a Reaction conditions: 1b (0.3 mmol), NaN3 (0.6 mmol), catalyst (20 mol%),
Having established the optimal reaction conditions, our
attention was next turned toward exploring the scope and
limitation of the methodology. A range of N-benzyl-2-iodo-
anilines were treated with sodium azide under the stan-
dard conditions and to our delight, the corresponding 2-
phenyl benzimidazoles were furnished in moderate to good
yield (Scheme 2).11 Substrates bearing electron-donating
(2b–d) or electron-withdrawing groups (2e–j) participated
smoothly in the reaction. Notably, the electronic factors of
N-benzyl-2-iodoanilines exerted a negligible influence on
the reaction. Some strong electron-withdrawing substitu-
ents, including CN and CF3, could be successfully tolerated
under the current conditions to afford the desired products
2i and 2j in relatively lower to moderate yields. The large
steric effect of N-benzyl-2-iodo-6-methylaniline appeared
to substantially inhibit the reactivity of reaction since only
a trace amount of benzimidazole product 2k was observed.
The generality of the present synthetic protocol was
further demonstrated by the employment of diverse N-sub-
stituted 2-iodoanilines as starting materials (Scheme 3).
Generally, the reaction proceeded smoothly with a range of
different benzyl-substituted 2-iodoanilines to afford vari-
ligand (40 mol%), base (2 equiv) in solvent (1 mL) under air at 130 °C for 24
h.
b Isolated yields.
c Under N2 atmosphere.
d Under O2 atmosphere.
e At 100 °C.
f At 140 °C. NR = no reaction. TMEDA = tetramethylethylenediamine, 1,10-
Phen = 1,10-phenanthroline, DMEDA = N,N′-dimethylethanediamine, DIPEA
= N,N-diisopropylethylamine.
ous 2-aryl benzimidazoles in reasonable yields (3a–l). The
reactivity of electron-rich substrates (3a–d) was mostly
higher than that of electron-deficient ones (3e–l). The ori-
entation of substituents on the aromatic ring system had a
marginal effect on the efficiency of the transformation (3a–
c). Noteworthy was that higher reactivity could be observed
when the electron-withdrawing group was located at the
meta position (3f and 3h), presumably owing to a decreased
conjugation effect. The naphthyl group could also be em-
bedded into the benzimidazole with good reactivity under
the current reaction system (3m). It was worth mentioning
that with respect to alkyl- and alkenyl-substituted 2-iodo-
anilines, a number of 2-alkyl benzimidazole and 2-alkenyl
benzimidazole products (3n–q) were produced in accept-
able yields, further expanding the applicability of the trans-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
Z. Chen et al.
Letter
Synlett
formation. In addition, N-cyclohexyl-2-iodoaniline was
identified as a viable substrate to give the desired 1,2,3,4-
tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine (3r), albeit in
relatively lower yield. To our delight, the phthalimidyl
group could be successfully attached into the benzimidaz-
ole ring in 30% yield (3s).
To gain further insights into the reaction mechanism, a
series of control experiments were implemented as illus-
trated in Scheme 4. We prepared compound 4 and treated it
with sodium azide under the standard conditions. Not sur-
prisingly, the desired product 2a could be afforded in 89%
yield (Scheme 4, eq 1). However, the transformation could
not occur when compound 4 was replaced with the amide
substrate 5, implying that the compound 5 was not the in-
termediate of the reaction (Scheme 4, eq 2). The azido sub-
strates 6 and 7 were also successfully converted into the
benzoimidazole 2a under the optimized conditions in 45%
and 84% yield, respectively (Scheme 4, eqs 3 and 4). It is
worth mentioning that the azido substrate 6 could be
smoothly transformed into the desired product 2a with ac-
ceptable efficiency in the absence of Cu catalyst. The obser-
vation data indicated that the Cu catalyst was not indis-
pensable once the sodium azide coupled with N-alkyl-2-io-
doaniline.
H
N
CuI (20 mol%)
TMEDA (40 mol%)
N
Ph
Ph
R
NaN3
+
R
DIPEA (2 equiv)
DMSO, 130 °C, 24 h
N
H
I
1
2
N
N
N
Ph
Ph
N
Ph
N
H
N
n-Bu
H
H
2c, 76%
2b, 60%
2a, 53%
N
N
N
Ph
Ph
Ph
Ph
N
H
N
Cl
N
t-Bu
F
H
H
2f, 51%
2i, 30%
2d, 59%
2e, 53%
N
N
N
N
N
I
Ph
standard conditons
standard conditons
standard conditons
Ph
Ph
(1)
Ph
NaN3
+
N
H
N
H
N
H
Br
EtOOC
NC
N
H
4
2a, 89%
2g, 31%
2h, 69%
H
N
N
N
Ph
N
Ph
(2)
Ph
NaN3
+
Ph
O
N
H
N
H
F3C
N
H
I
5
2a, 0%
2j, 59%
2k, trace
H
Ph
N
N
Scheme 2 Synthesis of different 2-phenylbenzimidazoles. Reagents
and conditions: 1 (0.3 mmol), NaN3 (0.6 mmol), CuI (20 mol%), TMEDA
(40 mol%) and DIPEA (0.6 mmol) in DMSO (1 mL) under air at 130 °C for
24 h. Isolated yield is given in parentheses.
(3)
(4)
Ph
N
H
N3
6
with CuI, 2a, 45%
without CuI, 2a, 53%
H
N
CuI (20 mol%)
TMEDA (40 mol%)
N
R
N
Ph
N
R
standard conditons
NaN3
+
Ph
DIPEA (2 equiv)
DMSO, 130 °C, 24 h
N
H
I
N
H
N3
1
3
7
2a, 84%
3a, X = 4-Me, 54%
3b, X = 3-Me, 70%
3c, X = 2-Me, 69%
3d, X = 4-t-Bu, 41%
3e, X = 4-F, 38%
3f, X = 3-F, 69%
3g, X = 4-Cl, 39%
3h, X = 3-Cl, 76%
3i, X = 4-Br, 32%
3j, X = 4-NO2, 36%
3k, X = 4-CF3, 62%
3l, X = 3,4-Cl, 48%
Scheme 4 Control experiments
N
X
N
H
On the basis of the results from the control experiments
and in previous reports, a tentative reaction mechanism
has been proposed as depicted in Scheme 5. First, copper-
catalyzed SNAr reaction of the substrate 1a with NaN3 pro-
ceeds to afford the azido intermediate I.12 Then, the inter-
mediate I undergoes a copper-promoted single-electron-
transfer oxidation with oxygen to lead to the imine-type in-
termediate II.9c,d,13 Subsequently, the intermediate III, de-
rived from intermediate II, could go through intramolecular
cyclization via nucleophilic attack by the azide to forge the
C–N bond with the release of N2 (path A). Finally, the proton
elimination of intermediate IV produces the desired ben-
zimidazole product 2a. Alternatively, a concerted process
was also possibly involved in the transformation, whereby
the intermediate IV could be directly formed through intra-
molecular cyclization of intermediate II without the gener-
ation of intermediate III (path B).8c
N
N
N
N
H
N
H
N
H
3m, 72%
3n, 50%
3o, 52%
N
N
N
N
N
H
N
H
3p, 62%
3q, 29%
3r, 25%
O
N
N
NH
O
3s, 30%
Scheme 3 Synthesis of various 2-substituted benzoimidazoles. Re-
agents and conditions: 1 (0.3 mmol), NaN3 (0.6 mmol), CuI (20 mol%),
TMEDA (40 mol%) and DIPEA (0.6 mmol) in DMSO (1 mL) under air at
130 °C for 24 h. Isolated yield is given in parentheses.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
Z. Chen et al.
Letter
Synlett
H
H
N
Ph
N
Ph
CuI, NaN3
[Cu], O2
copper-catalyzed SNAr
copper-promoted SET oxidation
Cu N3
I
I
1a
I
N
Ph
Ph
path A
path B
CuI
N
Ph
N
–
N2
+
N
N
– H+
CuI
III
Ph
Ph
Cu N3
I
H
N
N
H
N
N2
IV
II
2a
Cu
I
N
N2
+
-
II
Scheme 5 Plausible reaction mechanism
In conclusion, we have disclosed an approach for the
rapid assembly of benzimidazole derivatives from readily
accessible N-alkyl-2-iodoaniline and sodium azide in the
presence of copper catalysts. CuI was regarded as a versatile
catalyst to trigger the SNAr reaction and to assist single-
electron-transfer oxidation process, as well as promote the
subsequent denitrogenation/cyclization sequences. Further
investigations to understand the exact mechanism of the
reaction and to extend the practical application of this
methodology are underway.
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Acknowledgment
We thank the financial support from the National Nature Science
Foundation of China (Grant Nos. 21302169, 21602202), the Science
Foundation of Zhejiang Sci-Tech University (Grant Nos. 15062092-Y,
1206820-Y and 1206821-Y) as well as the Zhejiang Provincial Top Key
Academic Discipline of Chemical Engineering and Technology of Zhe-
jiang Sci-Tech University.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588086.
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After the evaporation, the residue was purified by column chro-
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to afford the product 2b. Yield: 60% (37 mg); light yellow solid;
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H), 8.17 (d, J = 7.6 Hz, 2 H), 7.30–7.60 (m, 5 H), 7.02 (t, J = 4.4 Hz,
1 H), 2.43 (s, 3 H). 13C NMR (100 MHz, DMSO-d6): δ = 150.7,
144.2, 135.3, 131.8, 129.6, 128.9, 126.3, 124.0, 123.2, 118.4,
111.0, 21.4. HRMS (ES+–TOF): m/z [M + H]+ calcd for C14H13N2:
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1b (0.3 mmol) and NaN3 (39 mg, 0.6 mmol) in DMSO (1 mL).
The mixture was stirred at 130 °C under air for 24 h. After the
completion of the reaction (monitored by TLC), the reaction
mixture was cooled to ambient temperature, quenched by H2O
and extracted with EtOAc (3 × 15 mL). The combined organic
layer was washed with brine (25 mL), and dried over Na2SO4.
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