Synthesis of benzimidazoles by PIDA-promoted direct C(sp2)-H imidation of N-arylamidines

Article abstract of DOI:10.1002/chem.201202271

A metal-free synthesis of diversified benzimidazoles from N-arylamidines through a phenyliodine(III) diacetate (PIDA) promoted intramolecular direct C(sp²)-H imidation has been developed. The reaction proceeds smoothly at 0 °C or ambient temperature to provide the desired products in good to excellent yields. The synthesis of 2-alkyl- or 2-alkyl-fused benzimidazoles, which are generally inaccessible by similar Pd- or Cu-catalyzed approaches, can also be achieved. Copyright

Full text of DOI:10.1002/chem.201202271

COMMUNICATION
DOI: 10.1002/chem.201202271
2
À
Synthesis of Benzimidazoles by PIDA-Promoted Direct C
G
of N-Arylamidines**
Jinbo Huang, Yimiao He, Yong Wang, and Qiang Zhu*[a]
The development of effective methods for the construc-
À
tion of C N bonds has received considerable interest of or-
ganic chemists because of their ubiquitous existence in phar-
maceuticals, agrochemicals, and biologically relevant mole-
cules.[1] Transition-metal-catalyzed amination/amidation/imi-
dation reactions starting from aryl or vinylACTHNUGRTENUNG(pseudo)halides
have been recognized as powerful methods for the prepara-
tion of nitrogen-containing compounds.[2–3] Over the past
À
À
decade, direct C N formation of aromatic C H bonds cata-
lyzed by transition-metals has emerged as a step-efficient
Scheme 1. The main approaches to benzimidazole derivatives.
À
and environmentally benign alternative to traditional C N
À
bond-forming methods. The effective transition-metal cata-
lysts are mainly based on palladium,[4] copper,[5] and
others.[6] In general, these methods require high reaction
temperatures and high loading of the catalyst and/or metal
oxidant. In addition, the presence of heavy metal contami-
nants in the final product may limit their application in drug
synthesis in the later stages. Hence, the development of al-
Cu-catalyzed C N coupling of N-(ortho-haloaryl)amidines
or N-(ortho-haloaryl)amides (path b, Scheme 1).[12] A more
efficient strategy to build the benzimidazole scaffold was
À
À
based on direct Cu- or Pd-catalyzed C H activation/C N
bond formation of N-arylamidines developed by the groups
of Buchwald[13] and Shi,[14] respectively (path c, Scheme 1).
However, this approach was not reliable for the preparation
of 2-alkylbenzimidazoles except for 2-tert-butylbenzimida-
zoles.[13–14] Encouraged by the preliminary results developed
by Ramsden et al.[7a–b] for the synthesis of several 2-alkyl-
benzimidazoles promoted by PIDA in refluxing toluene and
2
À
ternative metal-free direct C
(sp ) H amination/amidation/
imidation reactions performed at milder conditions are
highly desirable.
Recently, the metal-free hypervalent iodineACTHUNRTGNEUNG(III)-promoted
À
amidation/imidation of C H bonds has been successfully ap-
plied intra- and intermolecularly under mild conditions.[7]
For instance, Antonchick et al. reported an efficient intra-
also the recent development of hypervalent iodineACTHNGUTRENNU(G III)-pro-
[7c–h]
À
moted C N formation under mild conditions,
we envis-
aged that this metal-free strategy could be applied as a gen-
eral approach for diversified benzimidazole synthesis start-
ing from readily available N-arylamidine derivatives.[15]
2
À
and intermolecular C
phenyliodine
phenyliodine
(sp ) H amidation method by using
(III) diacetate (PIDA) or the in situ-generated
(III) reagent as an oxidant at room tempera-
Since hypervalent iodineACHTNUGETRN(UNG III)-promoted amidation/imidation
ture.[8] Independently, the groups of Chang and DeBoef
of aromatic C H bonds is generally performed at ambient
temperature, a wider substrate scope and higher reaction
yields are expected.
À
have also described intermolecular PIDA-mediated oxida-
[9]
À
À
tive C H functionalization/C N bond-forming reactions.
Benzimidazole is an ubiquitous structural motif frequently
found in many natural products and synthetic molecules
with varied bioactivities.[10] This structural core can be con-
structed either by condensation of 1,2-phenylenediamines
with carbonyl derivatives[11] (path a, Scheme 1) or by Pd- or
We commenced the investigation with N-phenylbenzami-
dine 1a as a model substrate using PIDA as a promoter
(Table 1). Solvent screening experiments demonstrated that
the choice of solvent was crucial: When using non-polar tol-
uene or less polar THF as the solvent (Table 1, entries 1–2),
no desired product was formed, whereas polar solvents in-
cluding DMF, CH3CN, DMSO, and iPrOH aided the forma-
tion of the product, albeit in low yields (5–35%, Table 1, en-
tries 3–6). To our delight, the yield of the desired product 2-
phenyl-1H-benzimidazole 2a was improved significantly
when the polar non-nucleophilic fluorinated alcohol HFIP
or TFE was employed at room temperature, leading to 2a
in yields of 85 and 87%, respectively (Table 1, entries 7–
8).[8,16] The other two commonly used hypervalent iodine-
[a] Dr. J. Huang, Y. He, Y. Wang, Prof. Dr. Q. Zhu
State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health
Chinese Academy of Sciences,
190 Kaiyuan Avenue, Guangzhou 510530 (China)
Fax : (+86)20-3201-5299
E-mail: zhu_qiang@gibh.ac.cn
[**] PIDA=phenyliodineACTHUNTGRNEUNG(III) diacetate
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202271.
ACHUTNRGENNU(G III) oxidants, PIFA and PhICAHTUNGTRNE(NUGN OPiv)2, were less effective
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Table 1. Optimization of the reaction conditions.[a]
Entry
T
[8C]
Solvent
Oxidant
Additive
Yield
[%][b]
1
2
3
4
5
6
7
8
25
25
25
25
25
25
25
25
25
25
25
25
25
0
Toluene
THF
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIFA
0
0
5
10
35
5
85
87
76
71
95
93
90
97
DMF
MeCN
DMSO
iPrOH
HFIP
TFE
TFE
TFE
TFE
TFE
9
10
11[c]
12[c]
13
14[c]
PhIACTHNGURETNNU(G OPiv)2
PIDA
PIDA
PIDA
PIDA
Cs2CO3
K2CO3
Na2CO3
Cs2CO3
TFE
TFE
[a] Reaction conditions: 1a (0.2 mmol), oxidant (1.1 equiv), base
(1.1 equiv), and solvent (1 mL) at room temperature or 08C for 1.0 h in
air. PIDA=phenyliodineACHTNUTRGENN(UG III) diacetate, PIFA=phenyliodineACHUTNGTREN(NNGU III) bis(tri-
fluoroacetate), HFIP=1,1,1,3,3,3-hexafluoro-2-propanol, TFE=2,2,2-tri-
fluoroethanol. [b] Yield of isolated 2a. [c] The reaction was performed
for 0.5 h.
Scheme 2. Synthesis of 2-arylbenzimidazoles. Reaction conditions:
1
(0.2 mmol), PIDA (1.1 equiv), Cs2CO3 (1.1 equiv), in TFE (1 mL), at 08C
under air for 1.5 h, yields are for the isolated compound 2. For com-
pounds 2b, 2i, and 2m, the reaction was performed at 258C for 0.5 h.
than PIDA (Table 1, entries 9–10). Subsequent additive
screening revealed that interestingly the addition of inorgan-
ic bases was beneficial. The product 2a was isolated almost
quantitatively (95%, Table 1, entry 11) in the presence of
Cs2CO3 (1.1 equiv) in 30 min at 258C. The reaction proceed-
ed even better at 08C (Table 1, entry 14). The current reac-
tion conditions are much milder than that of the correspond-
ing Cu- or Pd-catalyzed processes with the same substrate
(1008C, 18–24 h, ꢀ70% yield).[13–14]
in Scheme 3. The size of the alkyl group on the 2-position of
the benzimidazoles ranges from simple Me (3a, 87%) to
bulky tert-butyl (3e, 96%). Other benzimidazole products
containing 2-alkyl groups, including cyclohexyl (3b), benzyl
AHCTUNGTREG(NNNU 3c), cyclopropyl (3d), and isobutyl (3 f), were formed in
good to excellent yields. The influence of the substituents on
N-aryl moiety of the 3-methylbutanamidines was also ex-
plored. Substrates bearing Me, F, Cl, and Br groups on the
para position were well tolerated, yielding the correspond-
ing products (3g–3j) in good yields (80–93%). The strong
electron-withdrawing NO2 group was also compatible with
the reaction conditions, albeit in a lower yield (3k, 74%).
Substituents on the sterically congested ortho position had
some influence on the product formation, depending on the
size of the group. For instance, N-(2-methylphenyl)-3-
methyl-butanamidine provided 3l in only 70% yield, which
is a significant decrease from 93% for 3g, in which the
methyl group is attached at the para position. However, a
smaller F group on the same position had no effect on the
yield (81% (3m) vs. 80% (3h)). Again, the regioselectivity
was poor for the meta-substituted substrate, from which a
mixture of two isomers 3h and 3m was obtained.
Finally, cyclic amidines 4 and 6 also cyclized smoothly at
ambient temperature in 2 h (Scheme 4). The corresponding
tricyclic 2-alkyl-fused benzimidazoles 5 and 7 were formed
in 96 and 86% yields, respectively. It is notable that these
fused-benzimidazole derivatives can be found in a number
of bioactive synthetic compounds,[17] which were synthesized
in multiple steps starting from 1-iodo-2-nitrobenzene and
A variety of N-arylbenzamidine substrates for the synthe-
sis of 2-arylbenzimidazoles were investigated first under the
optimized reaction conditions (Scheme 2). A range of func-
tional groups including Me, Cl, Br, and F located in the
ortho- or para position of the aniline moiety were well toler-
ated, furnishing the corresponding 2-arylbenzimidazoles
(2b–2 f) in good to excellent yields. A substrate bearing a
bulky tBu group in the ortho position also gave the cyclized
product 2g in 60% yield. However, para-iodo and methoxy-
substituted amidines were incompatible with the oxidative
conditions (less than 30% yield, structures not shown). Cyc-
lization of the meta-methyl-substituted substrate resulted in
a mixture of two regioisomers in a 1.2:1 ratio favoring the
À
less sterically hindered C H bond for imidation (2b and
2e). Positions of the substituents on the right phenyl ring
(R2) had little effect on the reaction yields (2h–2n). Nota-
bly, due to the compatibility of bromo- and chloro moieties
with the reaction conditions, there is an opportunity for fur-
ther elaboration of the scaffold.
Most importantly, a variety of 2-alkybenzimidazoles can
also be obtained by employing this method, as summarized
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Synthesis of Benzimidazoles
COMMUNICATION
cal intermediates may be involved in the catalytic cycle.
Based on this result, a plausible reaction pathway is pro-
posed in Scheme 5. Initially, PIDA reacts with the amidine
Scheme 5. Proposed mechanism.
substrate 1 to give an N-iodoimido species A upon release
of acetic acid. The following homolysis generates the N-cen-
tered free-radical intermediate B and hypervalent iodine-
AHCTUNGTREG(NNUN III)-centered radical C. Subsequently, the imidyl radical
adds on the aromatic ring to generate the intermediate D,
which is oxidized to cyclohexadienyl cation E through a
single electron transfer (SET) by the intermediate C. The
following H-abstraction by the in situ-generated acetate
anion gives the desired products 2 or 3.
In conclusion, we have developed an efficient and general
method for the construction of 2-substituted benzimidazoles
through the PIDA-mediated intramolecular oxidative imida-
À
tion of aromatic C H bonds of readily available N-arylami-
dines. The reactions were performed at 08C or ambient tem-
perature within short reaction times (0.5 to 1.5 h). Diversi-
fied 2-alkylbenzimidazoles, which are difficult to be pre-
pared by similar Pd- or Cu-catalyzed approaches, as well as
2-arylbenzimidazoles, were obtained in good to excellent
yields. Tricyclic 2-alkyl-fused benzimidazoles can also be
prepared by applying this method. A reaction mechanism
involving radical intermediates has also been proposed.
Scheme 3. Synthesis of 2-alkylbenzimidazoles. Reaction conditions: all re-
actions were carried out at 0.2 mmol scale, with PIDA (1.1 equiv),
Cs2CO3 (1.1 equiv), in TFE (1 mL), at 258C under air, 1.5 h, yields are
for the isolated product. For compound 3l, the reaction was carried out
at 08C.
Experimental Section
General procedure for the preparation of 2 and 3: To a solution of ami-
dine (0.20 mmol, 1 equiv) and Cs2CO3 (0.22 mmol, 1.1 equiv) in TFE
(1 mL) was added PIDA (0.22 mmol, 1.1 equiv) at 08C or 258C under
air. The resulting mixture was stirred at 0 or 258C for 0.5 to 2.0 h. The re-
action was monitored by TLC until the starting material was completely
consumed. The reaction mixture was diluted with EtOAc (5 mL) and
washed with brine (5 mL). The organic layer was dried over Na2SO4, and
concentrated under vacuum. The residue was purified by column chroma-
tography to give the corresponding products.
Scheme 4. Synthesis of 2-alkyl-fused benzimidazoles.
pyrrolidin-2-ones or piperidine-2-ones involving palladium
catalysis.[18]
To gain insight into the reaction mechanism, a radical-
trapping experiment was carried out. When 1.1 equiv of 1,1-
diphenylethylene (known as an effective radical scavenger)
was present in the reaction of 1a under otherwise identical
conditions, the reaction was inhibited significantly (see
Table S1, the Supporting Information), suggesting that radi-
Acknowledgements
We are grateful for financial support of this work by National Science
Foundation of China (21272233).
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Received: June 27, 2012
Published online: && &&, 2012
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Synthesis of Benzimidazoles
COMMUNICATION
Synthetic Methods
J. Huang, Y. He, Y. Wang,
Q. Zhu* ........................ &&&& — &&&&
A metal-free synthesis of diversified
benzimidazoles from N-arylamidines
through a phenyliodineACTHNUGTRNEUNG(III) diacetate-
desired products in good to excellent
yields. The synthesis of 2-alkyl- or 2-
alkyl-fused benzimidazoles, which are
generally inaccessible by similar Pd- or
Cu-catalyzed approaches, can also be
achieved.
Synthesis of Benzimidazoles by PIDA-
2
À
Promoted Direct C
of N-Arylamidines
N
promoted intramolecular direct C-
2
À
G
The reaction proceeds smoothly at 08C
or ambient temperature to provide the
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