N-hydroxyphthalimide/cobalt acetate, a new catalytic oxidative system for the synthesis of benzimidazoles

Article abstract of DOI:10.1080/00397910802162959

Benzimidazoles are readily prepared from 1,2-phenylenediamine and an aldehyde using air and catalytic N-hydroxyphthalimide/Co(OAc)2 as the oxidant. Both electron-donating and electron-withdrawing groups are tolerated. Copyright Taylor & Francis Group, LLC.

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N-Hydroxyphthalimide/Cobalt
Acetate, a New Catalytic
Oxidative System for the
Synthesis of Benzimidazoles
Gary M. Coppola a
a Department of Metabolic and Cardiovascular
Diseases, Novartis Institutes for Biomedical
Research, Cambridge, Massachusetts, USA
Version of record first published: 29 Sep 2008
To cite this article: Gary M. Coppola (2008): N-Hydroxyphthalimide/Cobalt Acetate,
a New Catalytic Oxidative System for the Synthesis of Benzimidazoles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:20, 3500-3507
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Synthetic Communications1, 38: 3500–3507, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802162959
N-Hydroxyphthalimide/Cobalt Acetate, a New
Catalytic Oxidative System for the Synthesis
of Benzimidazoles
Gary M. Coppola
Department of Metabolic and Cardiovascular Diseases, Novartis Institutes
for Biomedical Research, Cambridge, Massachusetts, USA
Abstract: Benzimidazoles are readily prepared from 1,2-phenylenediamine and
an aldehyde using air and catalytic N-hydroxyphthalimide=Co(OAc)2 as the oxi-
dant. Both electron-donating and electron-withdrawing groups are tolerated.
Keywords: Aerobic oxidation, aldehyde, benzimidazoles, N-hydroxyphthalimide
INTRODUCTION
The benzimidazole heterocycle is an important structural element present
in a variety of pharmacologically active molecules including the essential
vitamin B-12. 2-Arylbenzimidazoles play an important role as pharma-
cophores in molecules exhibiting antiviral,[1] antibacterial,[2] anti-
inflammatory,[2–4] antitumor,[5] anti-hypertensive,[6] and cardiotonic[7]
activities.
Classical preparation of 2-arylbenzimidazoles (5) involves acylation
of 1,2-phenylenediamine (1) to provide amide 2 followed by a dehydra-
tive cyclization under thermal conditions,[8] acidic conditions (e.g.,
HOAc,[9] p-TosOH,[10] HCl,[11] zeolite[12]), or neutral conditions using
reagents such as P2O5.[13] Another route that has gained popularity is a
single-step procedure involving the condensation of 1 with an aldehyde
Received January 2, 2008.
Address correspondence to Gary M. Coppola, Department of Metabolic
and Cardiovascular Diseases, Novartis Institutes for Biomedical Research, 100
Technology Square, Cambridge, MA 02139 E-mail: gary.coppola@novartis.com
3500

N-Hydroxyphthalimide/Cobalt Acetate
3501
to afford Schiff base 3, which then proceeds through the intermediacy of
benzimidazoline 4, which, in the presence of an oxidizing agent, affords
the desired benzimidazole 5. A wide variety of oxidants such as
Pb(OAc)4,[14] FeCl3,[15] sulfamic acid,[16] Yb(OTf)3,[17] Sc(OTf)3,[18]
oxone,[19] H2O2=HCl,[20] and KHSO4
have been employed to effect
[21]
the dehydrogenation step. Although many of these methods are practical,
some have liabilities such as dangerous or toxic reagents, stoichiometry of
the reactants, or the formation of N-benzylbenzimidazole side products
resulting from further reaction of the aldehyde with 4 prior to oxidation.
The organic catalyst N-hydroxyphthalimide (NHPI) has sporadically
been used in aerobic oxidations of hydrocarbons,[22] proceeding via a
phthalimide N-oxyl radical. Reactions are performed under an oxygen
atmosphere in benzonitrile at elevated temperatures. The scope of the
oxidation was broadened to include alcohols by enhancing the catalytic
activity of NHPI with small quantities of Co(acac)n (n ¼ 2 or 3)[23,24]
;
however, the process still required elevated temperature (100 ꢀC). It was
later found that using Co(OAc)2 as the cocatalyst allowed reactions to
be performed at ambient temperature.[25] This methodology has also been
applied to the oxidative aromatization of Hantzsch dihydropyridines to
pyridines with similar results. In the presence of only NHPI, aromatiza-
tion occurs in refluxing acetonitrile over several hours[26]; however, in the
presence of both NHPI and Co(OAc)2, the reaction proceeds at ambient
temperature.[27] These encouraging results prompted the investigation as
to whether this catalytic system could be used in the oxidative dehydro-
genation of 4 to 5.

3502
G. M. Coppola
RESULTS AND DISCUSSION
Because all previously reported oxidations using NHPI were conducted
under an oxygen atmosphere, we wanted to ascertain whether it is
imperative to use an oxygen atmosphere or if air would suffice. Gratify-
ingly, the reaction of 1 with 4-methoxybenzaldehyde catalyzed by
10 mol% NHPI and a minute amount of Co(OAc)2 in acetonitrile in air
furnished the benzimidazole in 83% yield. Because it had been reported
that benzimidazoles can be formed using only air as the oxidant, albeit
at elevated temperatures,[28] a parallel reaction was performed without
the NHPI=Co(OAc)2 catalyst, and no benzimidazole was produced.
The scope of the reaction was investigated using a variety of benzal-
dehydes possessing electron-donating or electron-withdrawing groups at
the ortho, meta or para positions, and the results are listed in Table 1.
Reactions using benzaldehydes containing electron-donating groups were
generally complete within 6 h; however, they were usually allowed to stir
Table 1. Substituted 2-arylbenzimidazoles
Lit. Mp
(ꢀC) [ref]
Entry
R1
R2
R3
R4 Yield (%) Mp (ꢀC)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
OMe
H
SMe
Me
H
Cl
Cl
H
H
H
H
H
H
OMe
H
OMe OMe
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
83
60
83
61
79
61
68
63
85
81
85
70
76
59
224–227 226[29]
165–168 171.7–173.9[30]
216–219 227–228[16]
H
H
Cl
H
H
CF3
H
H
H
NO2
H
H
H
H
Cl
H
222–224
—
220–222 221[31]
229–231 235–239[12]
224–226 227–228.5[32]
> 290
208–210
267
—
—
—
H
CF3
COOMe
SO2Me
H
228–231 220–222[33]
282 > 300[6]
H
CN
203–206 203–205[16]
H
248–250
—

N-Hydroxyphthalimide/Cobalt Acetate
3503
overnight. Reactions with benzaldehydes containing electron-withdrawing
groups generally required 18 h for completion, although two analogs,
p-CF3 and p-SO2Me (entries 10 and 12), took 72 h and the o-CN analog
(entry 14) was particularly sluggish, taking 6 days for complete conver-
sion. Performing the reaction under an oxygen atmosphere increases
the rate of oxidation somewhat. For example, parallel reactions were car-
ried out on the m-CF3 analog (entry 9), one in air and one under oxygen.
After 9 h, conversion of the corresponding benzimidazoline 4 to benzimi-
dazole 5 reached 57%, whereas under oxygen 79% conversion was
observed. In either case, complete conversion was achieved after 18 h.
In conclusion, it has been demonstrated that air and NHPI=Co
(OAc)2 is a viable catalytic oxidative system for the conversion of benzi-
midazolines to benzimidazoles in the reaction of 1,2-phenylenediamine
with benzaldehydes.
EXPERIMENTAL
Melting points were determined on a Thomas-Hoover Uni-melt or Buchi
¨
B-545 melting-point apparatus and are uncorrected. All 1H NMR spectra
were recorded on a Bruker 400 Ultrashield instrument, and chemical
shifts are relative to internal Me4Si.
General Procedure for the Preparation of Benzimidazoles
A solution of 216 mg (2mmol) of 1 and 2 mmol of the appropriate aldehyde
in 6 mL of MeCN was stirred at room temperature for 15 min, and then
32 mg (0.2mmol) of NHPI and 2 mg of Co(OAc)2 were added. The mixture
became dark brown and was stirred at room temperature for 18h. Water
was added, and the mixture was extracted with EtOAc. The organic phase
was washed with brine and dried over sodium sulfate. Removal of the sol-
vent under reduced pressure furnished the crude product, which was purified
either by trituration with methylene chloride or by silica-gel chromatogra-
phy using 10% EtOAc=methylene chloride as eluent.
Spectral Data for Compounds in Table 1
Entry 1: 1H NMR (DMSO-d6): d 12.74 (s, 1H), 8.12 (d, J ¼ 8.97 Hz, 2H),
7.56 (s, broad, 2H), 7.17 (m, 2H), 7.11 (d, J ¼ 8.97 Hz, 2H), 3.84 (s, 3H).
1
Entry 2: H NMR (DMSO-d6): d 12.12 (s, 1H), 8.32 (d, J ¼ 9.6 Hz,
1H), 7.65–7.60 (m, 2H), 7.48 (t, 1H), 7.25 (d, J ¼ 8.08 Hz, 1H), 7.19
(m, 2H), 7.12 (t, 1H), 4.03 (s, 3H).

3504
G. M. Coppola
1
Entry 3: H NMR (DMSO-d6): d 12.76 (s, broad, 1H), 7.78–7.73
(m, 2H), 7.57 (s, broad, 2H), 7.20–7.15 (m, 2H), 7.13 (d, J ¼ 8.34 Hz,
1H), 3.88 (s, 3H), 3.84 (s, 3H).
1
Entry 4: H NMR (DMSO-d6): d 12.69 (s, 1H), 7.74 (d, J ¼ 6.44 Hz,
1H), 7.68 (d, J ¼ 7.71 Hz, 1H), 7.53–7.44 (m, 3H), 7.31 (t, 1H), 7.26–7.18
(m, 2H), 2.43 (s, 3H).
1
Entry 5: H NMR (DMSO-d6): d 12.62 (s, 1H), 7.74 (d, J ¼ 7.20 Hz,
1H), 7.68 (d, J ¼ 7.58 Hz, 1H), 7.52 (d, J ¼ 7.45 Hz, 1H), 7.43–7.34
(m, 3H), 7.25–7.17 (m, 2H), 2.61 (s, 3H).
1
Entry 6: H NMR (DMSO-d6): d 13.05 (s, 1H), 8.23 (s, 1H), 8.15
(d, J ¼ 7.07 Hz, 1H), 7.69 (d, J ¼ 7.45 Hz, 1H), 7.62–7.54 (m, 3H), 7.23
(m, 2H).
1
Entry 7: H NMR (DMSO-d6): d 12.78 (s, 1H), 7.94 (d, J ¼ 8.46 Hz,
1H), 7.86 (s, 1H), 7.71 (d, J ¼ 7.58 Hz, 1H), 7.63 (d, J ¼ 10.61 Hz, 1H),
7.58 (d, J ¼ 7.58 Hz, 1H), 7.25 (m, 2H).
1
Entry 8: H NMR (DMSO-d): d 12.85 (s, 1H), 7.72–7.59 (m, 4H),
7.55 (d, J ¼ 8.34 Hz, 1H), 7.25 (m, 2H).
1
Entry 9: H NMR (DMSO-d6): d 13.18 (s, 1H), 8.53 (s, 1H), 8.49
(d, J ¼ 7.83 Hz, 1H), 7.88–7.79 (m, 2H), 7.71 (d, J ¼ 7.71 Hz, 1H), 7.58
(d, J ¼ 7.58 Hz, 1H), 7.25 (m, 2H).
Entry 10: 1H NMR (DMSO-d6): d 13.19 (s, 1H), 8.39 (d, J ¼ 8.08 Hz,
2H), 7.94 (d, J ¼ 8.21 Hz, 2H), 7.72 (d, J ¼ 7.71 Hz, 1H), 7.58
(d, J ¼ 7.33 Hz, 1H), 7.25 (m, 2H).
Entry 11: 1H NMR (DMSO-d6): d 13.15 (s, 1H), 8.32 (d, J ¼ 8.34 Hz,
2H), 8.13 (d, J ¼ 8.46 Hz, 2H), 7.71 (d, J ¼ 7.58 Hz, 1H), 7.57
(d, J ¼ 7.74 Hz, 1H), 7.25 (m, 2H).
Entry 12: 1H NMR (DMSO-d6): d 13.22 (s, 1H), 8.42 (d, J ¼ 8.46 Hz,
2H), 8.11 (d, J ¼ 8.46 Hz, 2H), 7.72 (d, J ¼ 7.83 Hz, 1H), 7.58
(d, J ¼ 7.71 Hz, 1H), 7.26 (m, 2H), 3.30 (s, 3H).
1
Entry 13: H NMR (DMSO-d6): d 13.31 (s, 1H), 9.02 (s, 1H), 8.62
(d, J ¼ 7.83 Hz, 1H), 8.34 (d, J ¼ 6.82 Hz, 1H), 7.87 (t, 1H), 7.73 (d,
broad, J ¼ 7.58 Hz, 1H), 7.59 (d, broad, J ¼ 7.45 Hz, 1H), 7.26 (m, 2H).
Entry 14: IR (ATR mode): 2226 cmꢁ1; 1H-NMR (DMSO-d6): d 13.11
(s, 1H), 8.09 (d, J ¼ 8.59 Hz, 1H), 8.04 (d, J ¼ 6.82 Hz, 1H), 7.90 (t, 1H),
7.76–7.68 (m, 2H), 7.60 (d, J ¼ 7.71 Hz, 1H), 7.28 (m, 2H).
REFERENCES
1. Roth, T.; Morningstar, M. L.; Boyer, P. L.; Hughes, S. H.; Buckheit, Jr.,
R. W.; Michejda, C. J. Synthesis and biological activity of novel nonnucleo-
side inhibitors of HIV-1 reverse transcriptase: 2-Aryl-substituted benzimida-
zoles. J. Med. Chem. 1997, 40, 4199–4207.

N-Hydroxyphthalimide/Cobalt Acetate
3505
2. Leonard, J. T.; Jeyaseeli, L.; Rajesh, O. S.; Murugesh, K.; Sivakumar, R.;
Gunasekaran, V. Synthesis, anti-inflammatory and antibacterial activities
of 4-substituted phenyl benzimidazoles. Asian J. Chem. 2006, 18,
1104–1108.
3. Sondhi, S. M.; Singh, N.; Kumar, A.; Lozach, O.; Meijer, L. Synthesis, anti-
inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition
activity evaluation of benzimidazole=benzoxazole derivatives and some
Schiff ’s bases. Bioorg. Med. Chem. 2006, 14, 3758–3765.
4. Lee-Dutra, A.; Arienti, K. L.; Buzard, D. L.; Hack, M. D.; Khatuya, H.;
Desai, P. J.; Nguyen, S.; Thurmond, R. L.; Karlsson, L.; Edwards, J. P.;
Breitenbucher, J. G. Identification of 2-arylbenzimidazoles as potent
human histamine H4 receptor ligands. Bioorg. Med. Chem. Lett. 2006, 16,
6043–6048.
5. White, A. W.; Curtin, N. J.; Eastman, B. W.; Golding, B. T.; Hostomsky, Z.;
Kyle, S.; Li, J.; Maegley, K. A.; Skalitzky, D. J.; Webber, S. E.; Yu, X.-H.;
Griffin, R. J. Potentiation of cytotoxic drug activity in human tumour
cell lines, by amine-substituted 2-arylbenzimidazole-4-carboxamide PARP-1
inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 2433–2437.
6. Rose, U. 2-Arylsubstituierte benzoanellierte 5-ring-heterocyclen als
potentielle wirkstoffe im kardiovaskula¨ren system. Pharmazie. 1991, 46,
775–777.
7. Gungo¨r, T.; Fouquet, A.; Teulon, J.-M.; Provost, D.; Cazes, M.; Cloarec, A.
¨
Cardiotonic agents: Synthesis and cardiovascular properties of novel 2-aryl-
benzimidazoles and azabenzimidazoles. J. Med. Chem. 1992, 35, 4455–
4463; (b) Mertens, A.; Muller-Beckmann, B.; Kampe, W.; Ho¨lck, J.-P.; von
¨
der Saal, W. Nonsteroidal cardiotonics, 1: 2-Pyridyl-6,7-dihydro-3H,5H-pyr-
rolo[2,3-f]benzimidazol-6-ones, a novel class of cardiotonic agents. J. Med.
Chem. 1987, 30, 1279–1287.
8. (a) Dunwell, D. W.; Evans, D.; Smith, C. E.; Williamson, W. R. N. Synthesis
and antiinflammatory activity of some 2-substituted a-methyl-5-benzimidazo-
leacetic acids. J. Med. Chem. 1975, 18, 692–694; (b) Dzvinchuk, I. B.;
Vypirailenko, A. V.; Lozinskii, M. O. Synthesis of 1-(5-pyrazolyl)benzimi-
dazoles by cyclocondensation of 5-[(o-acylaminophenyl)amino]pyrazoles.
Russian. J. Org. Chem. 1998, 34, 685–687.
9. (a) Gong, B.; Hong, F.; Kohm, C.; Bonham, L.; Klein, P. Synthesis and SAR
of 2-arylbenzoxazoles, benzothiazoles and benzimidazoles as inhibitors of
lysophosphatidic acid acyltransferase-b. Bioor. Med. Chem. Lett. 2004, 14,
1455–1459; (b) Huang, S.-T.; Hsei, I.-J.; Chen, C. Synthesis and anticancer
evaluation of bis(benzimidazoles), bis(benzoxazoles), and benzothiazoles.
Bioor. Med. Chem. 2006, 14, 6106–6119.
10. Kumar, D.; Jacob, M. R.; Reynolds, M. B.; Kerwin, S. M. Synthesis and
evaluation of anticancer benzoxazoles and benzimidazoles related to UK-1.
Bioor. Med. Chem. 2002, 10, 3997–4004.
11. Charles, E. S.; Rao, K. V. B.; Sharma, S. Synthesis of substituted benzamides
and benzimidazoles as anthelmintic and antimicrobial agents. Pharmazie
1982, 37, 423–415.

3506
G. M. Coppola
12. Heravi, M. M.; Tajbakhsh, M.; Ahmadi, A. N.; Mohajerani, B. Zeolites.
Efficient and eco-friendly catalysts for the synthesis of benzimidazoles.
Monatsh. Chem. 2006, 137, 175–179.
13. Biasotti, B.; Dallavalle, S.; Merlini, L.; Farina, C.; Gagliardi, S.; Parini, C.;
Belfiore, P. Synthesis of photoactivable inhibitors of osteoclast vacuolar
ATPase. Bioor. Med. Chem. 2003, 11, 2247–2254.
14. Stephens, F. F.; Bower, J. D. Preparation of benzimidazoles and benzoxa-
zoles from Schiff bases. J. Chem. Soc. 1949, 2971–2972.
15. Singh, M. P.; Sasmal, S.; Lu, W.; Chatterjee, M. N. Synthetic utility of
catalytic Fe(III)=Fe(II) redox cycling towards fused heterocycles: A facile
access to substituted benzimidazole, bis-benzimidazole and imidazopyridine
derivatives. Synthesis 2000, 1380–1390.
16. Chakrabarty, M.; Karmakar, S.; Mukherji, A.; Arima, S.; Harigaya, Y.
Application of sulfamic acid as an eco-friendly catalyst in an expedient
synthesis of benzimidazoles. Heterocycles 2006, 68, 967–974.
17. Curini, M.; Epifano, F.; Montanari, F.; Rosati, O.; Taccone, S. Ytterbium tri-
flate promoted synthesis of benzimidazole derivatives. Synlett. 2004, 1832–1834.
18. Nagata, K.; Itoh, T.; Ishikawa, H.; Ohsawa, A. Synthesis of 2-substituted
benzimidazoles by reaction of o-phenylenediamine with aldehydes in the
presence of Sc(OTf)3. Heterocycles 2003, 61, 93–96.
´
19. Beaulieu, P. L.; Hache, B.; von Moos, E. A practical oxone-mediated, high-
throughput, solution-phase synthesis of benzimidazoles from 1,2-phenylene-
diamines and aldehydes and its application to preparative scale synthesis.
Synthesis 2003, 1683–1692.
20. Bahrami, K.; Khodaei, M. M.; Kavianinia, I. A simple and efficient one-pot
synthesis of 2-substituted benzimidazoles. Synthesis 2007, 547–550.
21. Ma, H.; Wang, Y.; Wang, J. A simple KHSO4-promoted synthesis of 2-aryl-
substituted benzimidazoles by oxidative condensation of aldehydes with o-
phenylenediamine. Heterocycles 2006, 68, 1669–1673.
22. Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama, T.;
Nishiyama, Y. A novel catalysis of N-hydroxyphthalimide in the oxidation
of organic substrates by molecular oxygen. J. Org. Chem. 1995, 60, 3934–3935.
23. Iwahama, T.; Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. Aerobic oxidation of
alcohols to carbonyl compounds catalyzed by N-hydroxyphthalimide (NHPI)
combined with Co(acac)3. Tetrahedron Lett. 1995, 36, 6923–6926.
24. Ishii, Y.; Iwahama, T.; Sakaguchi, S.; Nakayama, K.; Nishiyama, Y. Alkane
oxidation with molecular oxygen using a new efficient catalytic system:
N-hydroxyphthalimide (NHPI) combined with Co(acac)n (n ¼ 2 or 3). J.
Org. Chem. 1996, 61, 4520–4526.
25. Yoshino, Y.; Hayashi, Y.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. Catalytic oxi-
dation of alkylbenzenes with molecular oxygen under normal pressure and
temperature by N-hydroxyphthalimide combined with Co(OAc)2. J. Org.
Chem. 1997, 62, 6810–6813.
26. Han, B.; Liu, Q.; Liu, Z.; Mu, R.; Zhang, W.; Liu, Z.-L.; Yu, W. A metal-free
catalytic aerobic aromatization of Hantzsch 1,4-dihydropyridines by
N-hydroxyphthalimide. Synlett 2005, 15, 2333–2334.

N-Hydroxyphthalimide/Cobalt Acetate
3507
27. Han, B.; Liu, Z.; Liu, Q.; Yang, L.; Liu, Z.-L.; Yu, W. An efficient aerobic
oxidative aromatization of Hantzsch 1,4-dihydropyridines and 1,3,5-trisubsti-
tuted pyrazolines. Tetrahedron 2006, 62, 2492–2496.
28. Lin, S.; Yang, L. A simple and efficient procedure for the synthesis of benzi-
midazoles using air as the oxidant. Tetrahedron Lett. 2005, 46, 4315–4319.
`
29. Alloum, A. B.; Bougrin, K.; Soufiaoui, M. Synthese chimioselective des
benzimidazoles sur silice traitee par le chlorure du thionyle. Tetrahedron
´
´
Lett. 2003, 44, 5935–5937.
ꢀ
ꢀ
30. Navarrete-Vazquez, G.; Moreno-Diaz, H.; Aguirre-Crespo, F.; Leon-Rivera,
~
~
I.; Villalobos-Molina, R.; Munoz-Muniz, O.; Estrada-Soto, S. Design, micro-
wave-assisted synthesis, and spasmolytic activity of 2-(alkyloxyaryl)-1H-
benzimidazole derivatives as constarined stilbene bioisosteres. Bioor. Med.
Chem. Lett. 2006, 16, 4169–4173.
31. Nardi, D.; Tajana, A.; Rossi, S. Heterocyclic compounds from 3,3-
dimercapto-1-aryl-2-propen-1-ones, note 1: 4-Aryl-1,3-dihydro-2H-1,5-
benzodiazepine-2-thiones. J. Heterocyc. Chem. 1973, 10, 815–819.
´
32. Zaika, L.; Joullie, M. M. 1,2,3-Benzotriazines, II: Reactions of benzimi-
dazo[1,2-c]benzotriazines and naphth[10,20(20,10):4,5]imidazo[1,2-c][1,2,3]
benzotriazine. J. Heterocyc. Chem. 1966, 3, 444–449.
33. Perry, R. J.; Wilson, B. D. A novel palladium-catalyzed synthesis of
2-arylbenzimidazoles. J. Org. Chem. 1993, 58, 7016–7021.