Iodobenzene catalyzed C-H amination of N-substituted amidines using m-chloroperbenzoic acid

Article abstract of DOI:10.1021/ol400274f

The oxidative C-H amination of N″-aryl-N′-tosyl/N′- methylsulfonylamidines and N,N′-bis(aryl)amidines has been accomplished using iodobenzene as a catalyst to furnish 1,2-disubstituted benzimidazoles in the presence of mCPBA as a terminal oxidant at room temperature. The reaction is general, and the target products can be obtained in moderate to high yields.

Full text of DOI:10.1021/ol400274f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iodobenzene Catalyzed CꢀH Amination
of N‑Substituted Amidines Using
m‑Chloroperbenzoic Acid
Santhosh Kumar Alla, Rapolu Kiran Kumar, Pradeep Sadhu, and
Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati,
Guwahati-781039, India
tpunni@iitg.ernet.in
Received January 30, 2013
ABSTRACT
The oxidative CꢀH amination of N00-aryl-N0-tosyl/N0-methylsulfonylamidines and N,N0-bis(aryl)amidines has been accomplished using
iodobenzene as a catalyst to furnish 1,2-disubstituted benzimidazoles in the presence of mCPBA as a terminal oxidant at room temperature.
The reaction is general, and the target products can be obtained in moderate to high yields.
The benzimidazole moiety has become important over
the past decades, as it displays a broad range of biological
and therapeutical activities.1 The accustomed method for
the construction of this basic core structure involves con-
densation followed by oxidative cyclization of benzene-
1,2-diamine with carboxylic acids or its equivalent.2 In
addition, CꢀN bond formation via a cross-coupling reac-
tion and direct aromatic CꢀH activation, catalyzed by
transition metals, have also been reported for the construc-
tion of the structural unit.3 Although these protocols are
effective under relatively milder conditions compared to
the classical methods, the high cost and toxicity of some of
the metal salts restrict theirpracticalutility on a largerscale
process. Hence, the development of new routes for the
construction of the benzimidazole structural framework
under metal-free conditions will be valuable. Ramsden
et al. reported the synthesis of benzimidazoles using
phenyliodine(III) diacetate (PIDA) in refluxing toluene.4
More recently, PIDA-promoted cyclization of amidine to
benzimidazole has been shown at room temperature.5a
The development of the concept of direct functionaliza-
tion of CꢀH bonds under metal-free conditions by using
hypervalent iodine(III) reagents6 has proven valuable in
the area of organic synthesis, developing effective, safe,
(1) For some examples, see: (a) Zhu, Z.; Lippa, B.; Drach, J. C.;
Townsend, L. B. J. Med. Chem. 2000, 43, 2430. (b) Hauel, N. H.; Nar,
H.; Priepke, H.; Ries, U.; Stassen, J.-M.; Wienen, W. J. Med. Chem.
2002, 45, 1757. (c) Morphy, R.; Rankovic, Z. J. Med. Chem. 2005, 48,
6523. (d) 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 87ꢀ118 and
references cited therein. (e) Puratchikody, A.; Nagalakshmi, G.; Doble,
M. Chem. Pharm. Bull. 2008, 56, 273. (f) Gupta, S. K.; Pancholi, S. S.;
Gupta, M. K.; Agarwal, D.; Khinchi, M. P. J. Pharm. Sci. Res. 2010, 2,
228. (g) Gaba, M.; Singh, D.; Singh, S.; Sharma, V.; Gaba, P. Eur. J.
Med. Chem. 2010, 45, 2245.
(2) For some recent examples, see: (a) Grimment, M. R. Imidazoles
and their Benzo Derivatives. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, U.K., 1984; Vol. 5, pp
457ꢀ487. (b) Lin, S.-Y.; Isome, Y.; Stewart, E.; Liu, J.-F.; Yohannes,
D.; Yu, L. Tetrahedron Lett. 2006, 47, 2883. (c) Lim, H.-J.; Myung, D.;
Lee, I. Y. C.; Jung, M. H. J. Comb. Chem. 2008, 10, 501.
(3) For recent reviews and references on benzimidazole synthesis, see:
(a) Carvalho, L. C. R.; Fernandes, E.; Marques, M. M. B. Chem.ꢀEur.
J. 2011, 17, 12544 and references cited therein. (b) Brain, C. T.; Steer,
J. T. J. Org. Chem. 2003, 68, 6814. (c) Hirano, K.; Biju, A. T.; Glorius, F.
J. Org. Chem. 2009, 74, 9570. (d) Zheng, N.; Anderson, K. W.; Huang,
X.; Nguyen, H. N.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46,
7509. (e) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932. (f) Saha, P.; Ali, M. A.; Ghosh, P.; Punniyamurty, T. Org. Biomol.
Chem. 2010, 8, 5692. (g) Kumar, R. K.; Punniyamurty, T. RSC Adv.
2012, 2, 4616. (h) Xiao, Q.; Wang, W.-H.; Liu, G.; Meng, F.-K.; Chen,
J.-H.; Yang, Z.; Shi, Z.-J. Chem.;Eur. J. 2009, 15, 7292. (i) Jin, H.; Xu,
X.; Gao, J.; Zhong, J.; Wang, Y. Adv. Synth. Catal. 2010, 352, 347. (j) Fu,
S.; Jiang, H.; Deng, Y.; Zeng, W. Adv. Synth. Catal. 2011, 353, 2795.
(4) (a) Ramsden, C. A.; Rose, H. L. J. Chem. Soc., Perkin Trans. 1
1995, 615. (b) Ramsden, C. A.; Rose, H. L. J. Chem. Soc., Perkin Trans. 1
1997, 2319.
(5) (a) Huang, J.; He, Y.; Wang, Y.; Zhu, Q. Chem.;Eur. J. 2012, 18,
13964. (b) Zhu, J.; Xie, H.; Chen, Z.; Li, S.; Wu, Y. Synlett 2009, 20, 3299.
r
10.1021/ol400274f
XXXX American Chemical Society

and environmentally benign protocols for carbonꢀcarbon7
and carbonꢀheteroatom8,9 bond formation. These reac-
tions use a hypervalentiodine(III) reagent in a stoichio-
metric amount and generate undesired iodoarenes in an
equimolar amount. To overcome these limitations, in 2005,
the Ochiai10a and Kita10b groups independently reported a
catalytic process involving in situ oxidation of iodo(I)arenes
using meta-chloroperbenzoic acid (mCPBA). Since then,
this concept has been extensively used for the synthesis of
a variety of organic molecules.11 Herein, we report an
iodobenzene catalyzed oxidative CꢀH amination for the
preparation of N-substituted benzimidazoles from N00-
aryl-N0-tosyl/N0-methylsulfonylamidines and N,N0-bis-
(aryl)amidines using mCPBA as a terminal oxidant at
room temperature.
First, the reaction conditions were optimized using (Z)-
N00-4-isopropylphenyl-N0-tosylacetamidine 1c as a model
substrate that can be readily prepared from acetanilide and
toluene-4-sulfonamide12 (Table 1). Treating the substrate
1c with 20 mol % of iodobenzene and 1.5 equiv of mCPBA
as an oxidant in 0.5 mL of CH2Cl2 as solvent for 12 h at
room temperature did not afford the target benzimida-
zole 2c (entry 1). Further screening with solvents such as
MeOH, DME, DMSO, DMF, and CF3COOH proved
unsuccessful (entries 2ꢀ6). However, to our delight, the
target benzimidazole was obtained in 76% conversion
using 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvent
(entry 7). Employing other substituted iodoarenes gave
inferior results (entries 8ꢀ9). In addition, oxidants such as
tert-butyl hydroperoxide (TBHP), H2O2, K2S2O8, and
oxone were not successful (entries 10ꢀ13). Lowering the
quantity of iodobenzene to 10 mol % led to the product
formation in 53% conversion (entry 14). The control ex-
periment confirmed that, without iodobenzene, the forma-
tion of the product 2c was not observed (entry 15). In the
presence of 1.0 equiv of PhIO in HFIP, 1c underwent
cyclization togivethe benzimidazole2cin 62% yield (eq2).
(6) For recent reviews, see: (a) Stang, P. J.; Zhdankin, V. V. Chem.
Rev. 1996, 96, 1123. (b) Varvoglis, A. Hypervalent Iodine in Organic
Synthesis; Academic Press: San Diego, 1997. (c) Zhdankin, V. V.; Stang, P. J.
Chem. Rev. 2002, 102, 2523. (d) Hypervalent Iodine Chemistry; Wirth, T.,
Ed.; Springer-Verlag: Berlin, 2003. (e) Wirth, T. Angew. Chem., Int. Ed.
2005, 44, 3656. (f) Ochiai, M.; Miyamoto, K. Eur. J. Org. Chem. 2008,
4229. (g) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073. (h) Tellitu, I.;
Domınguez, E. Trends Heterocycl. Chem. 2011, 15, 23.
(7) For recent examples of CꢀC bond formation using hypervalent
iodine(III) reagents, see: (a) Samanta, R.; Lategahn, J.; Antonchick,
A. P. Chem. Commun. 2012, 48, 3194. (b) Wang, J.; Yuan, Y.; Xiong, R.;
Zhang-Negrerie, D.; Du, Y.; Zhao, K. Org. Lett. 2012, 14, 2210. (c) Gu,
Y.; Wang, D. Tetrahedron Lett. 2010, 51, 2004. (d) Kita, Y.; Morimoto,
K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am. Chem. Soc. 2009, 131,
1668. (e) Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett.
2006, 8, 2007. (f) Dohi, T.; Morimoto, K.; Kiyono, Y.; Maruyama, A.;
Tohma, H.; Kita, Y. Chem. Commun. 2005, 2930.
(8) For recent examples of CꢀO bond formation using hypervalent
iodine(III) reagents, see: (a) Zheng, Y.; Li, X.; Ren, C.; Zhang-Negrerie,
D.; Du, Y.; Zhao, K. J. Org. Chem. 2012, 77, 10353. (b) Yu, Z.; Ma, L.;
yu, W. Synlett 2012, 23, 1534. (c) Liu, H.; Wang, X.; Gu, Y. Org. Biomol.
Chem. 2011, 9, 1614. (d) Kang, Y.-B.; Gade, L. H. J. Am. Chem. Soc.
2011, 133, 3658. (e) Kang, Y.-B.; Gade, L. H. J. Org. Chem. 2012, 77,
1610. (f) Zhong, W.; Yang, J.; Meng, X.; Li, Z. J. Org. Chem. 2011, 76,
9997. (g) Zhong, W.; Liu, S.; Yang, J.; Meng, X.; Li, Z. Org. Lett. 2012,
14, 3336. (h) Fujita, M.; Wakita, M.; Sugimura, T. Chem. Commun.
2011, 47, 3983.
Table 1. Optimization of the Reaction Conditionsa
(9) For recent examples of CꢀN bond formation using hypervalent
iodine(III) reagents, see: (a) Kim, H. J.; Cho, S. H.; Chang, S. Org. Lett.
2012, 14, 1424. (b) Farid, U.; Wirth, T. Angew. Chem., Int. Ed. 2012, 51,
~
3462. (c) Souto, J. A.; Zian, D.; Muniz, K. J. Am. Chem. Soc. 2012, 134,
7242. (d) Ban, X.; Pan, Y.; Lin, Y.; Wang, S.; Du, Y.; Zhao, K. Org.
Biomol. Chem. 2012, 10, 3606. (e) Kantak, A. A.; Potavathri, S.;
Barham, R. A.; Romano, K. M.; Deboef, B. J. Am. Chem. Soc. 2011,
133, 19960. (f) Du, Y.; Liu, R.; Linn, G.; Zhao, K. Org. Lett. 2006, 8,
5919. (g) Kikugawa, Y.; Nagashima, A.; Sakamoto, T.; Miyazawa, E.;
Shiiya, M. J. Org. Chem. 2003, 68, 6739. (h) Richardson, R. D.; Desaize,
M.; Wirth, T. Chem.;Eur. J. 2007, 13, 6745. (i) Tellitu, I.; Urrejola, A.;
Serna, S.; Moreno, I.; Herrero, M. T.; Domınguez, E.; SanMartin, R.;
Correa, A. Eur. J. Org. Chem. 2007, 437. (j) Souto, J. A.; Martınez, C.;
entry
R
oxidant
solvent
conversion (%)b
1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
mCPBA CH2Cl2
mCPBA MeOH
mCPBA DME
mCPBA DMSO
mCPBA DMF
mCPBA CF3COOH
mCPBA HFIP
mCPBA HFIP
mCPBA HFIP
0
2
0
3
0
4
0
5
0
~
€
Velilla, I.; Muniz, K. Angew. Chem., Int. Ed. 2013, 52, 1324. (k) Roben,
6
5
ꢀ
~
C.; Souto, J. A.; Gonzalez, Y.; Lishchynskyi, A.; Muniz, K. Angew.
Chem., Int. Ed. 2011, 50, 9478. (l) Souto, J. A.; Becker, P.; Iglesias, A.;
7
76
33
55
5
8
4-OMe-C6H4
4-Me-C6H4
C6H5
~
Muniz, K. J. Am. Chem. Soc. 2012, 134, 15505. (m) Yoshimura, A.;
9
Nemykin, V. N.; Zhdankin, V. V. Chem.;Eur. J. 2011, 17, 10538. (n)
~
Lishchynskyi, A.; Muniz, K. Chem.;Eur. J. 2012, 18, 2212. (o) Samanta,
10
11
12
13
14c
15
TBHP
H2O2
HFIP
HFIP
HFIP
HFIP
R.; Bauer, J. O.; Strohmann, C.; Antonchick, A. P. Org. Lett. 2012, 14,
C6H5
3
ꢀ
5518. (p) Souto, J. A.; Gonzalez, Y.; Iglesias, A.; Zian, D.; Lishchynskyi,
~
C6H5
K2S2O8
Oxone
0
A.; Muniz, K. Chem.;Asian J. 2012, 7, 1103.
C6H5
0
(10) (a) Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto,
K. J. Am. Chem. Soc. 2005, 127, 12244. (b) Dohi, T.; Maruyama, A.;
Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem., Int.
Ed. 2005, 44, 6193.
C6H5
mCPBA HFIP
mCPBA HFIP
53
0
ꢀ
a 1c (0.5 mmol), aryl iodide (20 mol %), oxidant (1.5 equiv), solvent
(11) For examples, see: (a) Dohi, T.; Maruyama, A.; Minamitsuji,
Y.; Takenaga, N.; Kita, Y. Chem. Commun. 2007, 1224. (b) Uyanik, M.;
Yasui, T.; Ishihara, K. Bioorg. Med. Chem. Lett. 2009, 19, 3848. (c)
Yakura, T.; Omoto, M. Chem. Pharm. Bull. 2009, 57, 643. (d) Ishiwata,
Y.; Togo, H. Tetrahedron Lett. 2009, 50, 5354. (e) Ngatimin, M.; Frey,
R.; Andrews, C.; Lupton, D. W.; Hutt, O. E. Chem. Commun. 2011, 47,
11778. (f) Dohi, T.; Takenaga, N.; Fukushima, K.-I.; Uchiyama, T.;
Kato, D.; Shiro, M.; Fujioka, H.; Kita, Y. Chem. Commun. 2010, 46,
7697. (g) Dohi, T.; Nakae, T.; Ishikado, Y.; Kato, D.; Kita, Y. Org.
Biomol. Chem. 2011, 9, 6899. (h) Antonchick, A. P.; Samanta, R.;
Kulikov, K.; Lategahn, J. Angew. Chem., Int. Ed. 2011, 50, 8605. (i)
Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed. 2006, 45, 4402. (j)
Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185.
(1 mL), rt, 12 h. b Determined by 1H NMR. c Iodobenzene (10 mol %) used.
With the optimized conditions in hand, the scope of the
procedure was studied for the reaction of a series of
substituted acetamidines (Scheme 1). (Z)-N00-Phenyl-N0-
tosylacetamidine 1a reacted to give 2-methyl-1-tosyl-1H-
(12) Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893.
Org. Lett., Vol. XX, No. XX, XXXX
B

Scheme 1. Reaction of N0-Aryl Substituted Acetamidinesa
Figure 1. ORTEP diagram of 6-chloro-2-methyl-1-tosyl-1H-
benzo[d]imidazole 2i.13 H-Atoms are omitted for clarity.
Scheme 2. Reaction of 2-Substituted N00-(4-Chlorophenyl)-N0-
tosylamidinesa
a Substrates 1aꢀb, 1d, and 1fꢀl (0.5 mmol), iodobenzene (20 mol %),
mCPBA (1.5 equiv), HFIP (1 mL), rt. 2b, 2h: Iodobenzene (40 mol %)
used. Isolated yield.
benzo[d]imidaozle 2a in 68% yield. Similarly, (Z)-N00-aryl-
N0-tosylacetamidines 1b, 1d, and 1fꢀg with R0 having
2-methyl, 4-methyl, 3,4-dimethyl, and 3,5-dimethyl substi-
tuents reacted to give the corresponding substituted benz-
imidazoles 2b, 2d, and 2fꢀg in 59ꢀ64% yields, while the sub-
strates 1hꢀj bearing halogen substituents such as 2-bromo,
4-chloro, and 4-fluoro gave the target products 2hꢀj in
42ꢀ91% yields. In contrast, the substrate 1k with R0 having
a 4-nitro substituent showed no reaction and the starting
material was recovered intact. However, (Z)-N00-(naphthalen-
4-yl)-N0-tosylacetamidine proceeded to cyclize to give the
target heterocycle 2l in 34% yield. In case of the substrate
1e, a 1.3:1 mixture of regioisomers 2ea and 2eb was obtained
in 59% yield (eq 1). Crystallization of 6-chloro-2-methyl-1-
tosyl-1H-benzo[d]imidazole 2i in CH2Cl2 gave a crystal whose
structure was confirmed by X-ray analysis (Figure 1).
The reaction of the amidines with R00 having alkyl, aryl,
and vinyl substituents was studied next (Scheme 2). The
procedure was general, and the reaction proceeded to give
the target heterocycles in moderate to high yields. The sub-
strates 1mꢀo having R00 with alkyl groups, ethyl, n-pentyl,
and tert-butyl, exhibited greater reactivity compared to
that bearing phenyl and styryl substituents 1pꢀq affording
the corresponding heterocyles 2mꢀq in 58ꢀ90% yields.
a Substrates 1mꢀq (0.5 mmol), iodobenzene (20 mol %), mCPBA
(1.5 equiv), HFIP (1 mL), rt. Isolated yield.
Finally, the cyclization of different N0-substituted acetami-
dines was studied (Scheme 3). As in the above-mentioned
cases, the substrates having N0-methylsulfonyl acetamidine 1r
and N0-aryl acetamidines 1sꢀu underwent reaction to give
the benzimidazoles 2rꢀu in 56ꢀ93% yields. The substrate
with electron-withdrawing substituent 1t exhibited enhanced
reactivity compared to that bearing electron-donating group
1u. In contrast, N0-unsubstituted and N0-cyclohexyl acetami-
dines 1vꢀw showed no reaction and the starting materials
(13) Recrystallization of 6-chloro-2-methyl-1-tosyl-1H-benzo[d]-
imidazole in CH2Cl2 afforded single crystals whose X-ray data were
collected on a Bruker SMART APEX equipped with a CCD area detector
using Mo KR radiation in the scan range 1.42° to 24.99°. C15H13ClN2O2S,
˚
Mw = 320.78, monoclinic; space group P2(1)/c, a = 14.7051 (5) A, b =
˚
˚
12.7004 (4) A, c = 7.9795 (2) A; R = 90°, β = 102.019°, γ = 90°, V =
3
1457.59(8) A , Z = 4, Dcalcd = 1.462 Mg/m3, T = 296(2) K, crystal
˚
dimension 0.30 ꢁ 0.18 ꢁ 0.12 mm3; 2420 reflections; I > 2σ(I); R1
0.0397, wR2 = 0.1152, GOF (on F2) = 0.891.
=
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Reaction of N0-Substituted Acetamidesa
Scheme 4. Proposed Catalytic Cycle
arene attacks to the nitrenium ion may lead to the forma-
tion of the target benzimidazoles, accompanied by the
liberation of iodobenzene A, which could be reoxidized to
B by mCPBA.
In summary, we have developed a new protocol for
the synthesis of 2-substituted N-sulfonyl benzimida-
zoles and N-aryl benzimidazoles using iodobenzene as
the catalyst in the presence of mCPBA as a terminal
oxidant at room temperature. The reaction is simple
and general to afford the target products in moderate to
good yields.
a Substrates 1rꢀw (0.5 mmol), iodobenzene (20 mol %), mCPBA
(1.5 equiv), HFIP (1 mL), rt. Isolated yield.
were recovered intact. These results suggest that the nature
of the N0-substituent is crucial for the cyclization process.
Acknowledgment. We thank the Department of Sci-
ence and Technology, New Delhi, and Council of Sci-
entific and Industrial Research, New Delhi, for financial
support.
Supporting Information Available. Experimental pro-
cedure, characterization data, and scan of NMR spectra
(1H and 13C) of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
A putative reaction mechanism is shown in Scheme 4.
The oxidation of iodobenzene A using mCPBA may give
the activehypervalent iodine(III) species11a that could react
with 1 to generate nitrenium ion C.9f,11h The nucleophilic
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX