Iodine-mediated synthesis of 2-arylbenzoxazoles, 2-arylbenzimidazoles, and 1,3,5-trisubstituted pyrazoles

Article abstract of DOI:10.1080/00397910600638879

2-Arylbenzoxazoles and 2-arylbenzimidazoles were synthesized by the reaction of aldehydes with 2-aminophenol and O-phenylenediamines in the presence of iodine. 1,3,5-Trisubstituted pyrazoles were synthesized from chalcones and hydrazines in the presence o

Full text of DOI:10.1080/00397910600638879

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Iodine‐Mediated Synthesis of
2‐Arylbenzoxazoles, 2‐Arylbenzimidazoles,
and 1,3,5‐Trisubstituted Pyrazoles
Shashikanth Ponnala a & Devi Prasad Sahu a
a Division of Medicinal and Process Chemistry, Central Drug Research
Institute, Lucknow, India
Version of record first published: 16 Feb 2007
To cite this article: Shashikanth Ponnala & Devi Prasad Sahu (2006): Iodine‐Mediated Synthesis of
2‐Arylbenzoxazoles, 2‐Arylbenzimidazoles, and 1,3,5‐Trisubstituted Pyrazoles, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:15, 2189-2194
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Synthetic Communicationsw, 36: 2189–2194, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600638879
Iodine-Mediated Synthesis of
2-Arylbenzoxazoles, 2-Arylbenzimidazoles,
and 1,3,5-Trisubstituted Pyrazoles
Shashikanth Ponnala and Devi Prasad Sahu
Division of Medicinal and Process Chemistry,
Central Drug Research Institute, Lucknow, India
Abstract: 2-Arylbenzoxazoles and 2-arylbenzimidazoles were synthesized by the
reaction of aldehydes with 2-aminophenol and O-phenylenediamines in the presence
of iodine. 1,3,5-Trisubstituted pyrazoles were synthesized from chalcones and
hydrazines in the presence of iodine.
Keywords: Benzimidazoles, benzoxazoles, iodine, oxidative aromatization, single
pot, 1,3,5-trisubstituted pyrazoles
2-Arylbenzimidazoles, 2-arylbenzoxazoles, and pyrazoles scaffolds are important
constituents that exist in various bioactive compounds.[1–9] Among available
methods of their syntheses, oxidative intramolecular cyclization of Schiff
bases of 2-aminophenol was a widely used method of synthesizing
2-substituted benzoxazoles. Various oxidants that are capable of converting
phenolic Schiff base to 2-aryl benzoxazole include Pb(OAc)4,[10] PhI(OAc)2,[11]
Mn(OAc)3,[12] thianthrene radical cation,[13] Ba(MnO4)2,[14] NiO2,[15] 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),[16] and molecular oxygen/
activated carbon.[17] On the other hand, Schiff base derived from
Received in the USA January 6, 2006
CDRI Communication No. 6509.
Address correspondence to Devi Prasad Sahu, Division of Medicinal and Process
Chemistry, Central Drug Research Institute, Lucknow 226001, India. E-mail:
dpsahuin@yahoo.com
2189

2190
S. Ponnala and D. P. Sahu
orthophenylenediamine and aldehyde can be oxidatively cyclized to 2-substituted
benzimidazoles with similar oxidizing agents. 1,3,5-Trisubstituted pyrazolines
readily prepared by condensation of chalcones with phenyl hydrazine are aroma-
tized to furnish corresponding pyrazoles. Oxidizing agents that have been
employed for aromatization of pyrazolines include PhI(OAc)2,[18] MnO2,[19]
KMnO4,[20] AgNO3,[21] Pb(OAc)4,[22] HgO,[23] Zr(NO3)4,[24] and molecular
oxygen/activated carbon.[25]
The oxidants that are effect via oxidative cyclization or aromatization of
these heterocycles belong to the following categories: (1) salts of transition
metals, (2) DDQ, (3) organohypervalent iodine reagents, and (4) molecular
oxygen catalyzed by palladium on charcoal or activated carbon. The transition
metal salts employed in stoichiometric amounts usually produce toxic waste,
which is environmentally nonconducive and requires tedious chromatographic
purification of the desired product.[12,16] DDQ, though a versatile and efficient
oxidizing agent, led to the formation of 2,3-dichloro-5,6-dicyano-4-hydroxy-
phenol (DDP) as a by-product. Molecular oxygen–promoted activated
carbon, though environmentally benign and a replenishable agent used in
the direct synthesis of 2-arylbenzoxazoles, benzimidazoles,[17] and 1,3,5-tri-
substituted pyrazoles, requires long period of reaction at elevated temperature
(1208C), and moderate yield of products make it less attractive. Organohyper-
valent iodine reagents such as iodobenzene diacetate (IBD), an efficient
oxidant, have been employed in oxidative cyclization of Schiff base 3 to ben-
zoxazoles 5 rather than direct synthesis of these heterocycles from
aldehydes.[11] Hence an additional step is required to prepare Schiff base
from aldehyde and 2-aminophenol. Iodine is much less expensive than orga-
nohypervalent iodine reagent; hence its use in large-scale preparation is
preferable.
Herein we report a practical, single-pot, environmentally benign
synthesis of 2-arylbenzoxazoles, 2-aryl benzimidazoles, and 1,3,5-trisubsti-
tuted pyrazoles using iodine. We envisioned that iodine would be an
efficient reagent for the oxidative cyclization[26] of phenolic Schiff bases
to produce 2-substituted benzoxazoles, and we expected that hydroiodic
acid (HI), the reduced product of iodine and unreacted iodine, could
easily be removed from reaction mixture by aqueous workup, enabling
easy purification of the product. Thus aldehydes 2 and of 2-aminophenol
or ortho-phenylenediamines 1 in dry DMF at ambient temperature led to
the formation of corresponding Schiff bases 3 within 2–3 h. The addition
Scheme 1.

Iodine-Mediated Synthesis
2191
Table 1. Bezoimidazoles and benazoxazoles with variation of aldehydes
Entry Comp. no.
XH
R
Yield (%) Mp (8C) Lit. mp (8C)
1
2
3
5a
5b
5c
2NH2
81
74
78
298
299–301[17]
2NH2
2NH2
236–237 238[27b]
234–236 235–236[27a]
4
5d
2NH2
72
203–205 204–206[16b]
5
6
7
8
5e
5f
2NH2
2NH2
2NH2
2OH
68
70
69
81
298–300 297–299[16b]
310–312 315[27c]
5g
5h
288–290 287–289[16b]
155–156 153–154[17]
9
5i
5j
2OH
2OH
74
86
268–300 268[11]
10
102–104 101–103[17]
of 1 equivalent of iodine to the reaction mixture and stirring at 35–408C for
4 h smoothly oxidized the intermediate to corresponding product 5
(Scheme 1). As shown in Table 1, 2-arylbenzoxazoles and 2-benzimidazoles
were produced in good yields by this method. A solution of aldehyde
Scheme 2.

2192
S. Ponnala and D. P. Sahu
Table 2. Pyrazoles with variation of chalcones
Comp.
no.
Yield
(%)
Mp
(8C)
Lit. mp
(8C)
Entry
R1
R2
1
2
9a
86
78
142–143 139–140[25]
9b
78–81
115
78–80[25]
3
9c
88
114–115[25]
4
5
9d
9e
70
74
140–141 140–141[24]
127–129 127–128[24]
(1 mmol) in 2 mL of DMF was added to a stirred solution of o-aminophenol
or o-phenylenediamine (1 mmol) in 3 mL of dry DMF over a period of
30 min, and stirring was continued for 2–3 h. I2 (0.25 g, 1 mmol) was
added to the reaction mixture, and the resulting mixture was further
stirred for 4 h at 408C. After the completion of the reaction, the product
mixture was poured into crushed ice and treated with sodium hydrogen
carbonate and sodium sulphite. The precipitated solid was filtered, washed
with water, and dried. The solid was either purified by silica-gel chromato-
graphy or recrystallized from ethanol.
Synthesis of pyrazoles (9) from the hydrazines 7 and chalcones 6 in
AcOH led to the formation of pyrazolines 8 in the presence of one
equimolar iodine followed by refluxing for 3 h (Scheme 2). As shown in
Table 2, a number of pyrazoles were produced in excellent yields by this
method. Phenyl hydrazine (0.130 g, 1.2 mmol) was added to a stirred
solution of chalcone (1 mmol) in 5 mL of AcOH, and resulting solution was
refluxed for 3 h. To this reaction mixture I2 (0.253 g, 1 mmol) was added,
and refluxing continued for 3–4 h. After the completion of the reaction, the
product mixture was poured into crushed ice and treated with sodium
hydrogen carbonate and sodium sulphite. The precipitated solid was filtered,
washed with water, dried, and purified by silica-gel column chromatography
or recrystallized from ethanol.
In conclusion, we have demonstrated that iodine can be employed as an
efficient agent to promote the formation and dehydrogenation of dihydroben-
zoxazoles and dihydrobenzimidazoles under mild conditions and for synthesis
of pyrazoles from chalcone and phenyl hydrazine under reflux conditions.

Iodine-Mediated Synthesis
2193
This contributes a novel, general, and convenient one-pot procedure for
preparing benzoxazoles, benzoimidazoles, and pyrazoles.
ACKNOWLEDGMENT
We are thankful to Sophisticated Instrumentation Analytical Facility, Central
Drug Research Institute (SAIF, CDRI) Lucknow, for providing spectroscopic
data.
REFERENCES
1. Spasov, A. A.; Iezhitsa, I. N.; Bugaeva, L. I.; Anisimova, V. A. Khim.-Farm.
Zhurn. 1999, 33 (5), 6–17.
2. O’Sullivan, D. G.; Wallis, A. K. J. Med. Chem. 1972, 15 (1), 103–104.
3. (a) Iemura, R.; Kawashima, T.; Fukuda, T.; Ito, K.; Tsukamoto, G. J. Med. Chem.
1986, 29 (7), 1178–1183; (b) Nakano, H.; Inoue, T.; Kawasaki, N.; Miyataka, H.;
Matsumoto, H.; Taguchi, T.; Inagaki, N.; Nagai, H.; Satoh, T. Chem. Pharm. Bull.
(Tokyo) 1999, 47, 1573–1578.
4. Nawrocka, W. Bull. Chim. Farm. 1996, 135, 18–23; Winstanley, P. Lancet 1998,
352, 1080–1081.
5. Carpio, A. J. Neurol., Neurosurg. Psychiatry 1999, 66, 411–412.
6. (a) Temiz, O.; Rren, I.; Sener, E.; Yalcin, I.; Ucarturk, N. Farmaco 1998, 53, 337;
(b) Aotsuka, T.; Wagatsuma, N.; Kato, H.; Ashizawa, N. PCT Int. Appl. WO
9,846,594, 1998; (c) Sato, Y.; Yamada, M.; Kobayashi, K.; Iwamatsu, K.;
Konno, F.; Shudo, K. Eur. Pat. Appl. EP 806,419, 1997; (d) Deluca, M. R.;
Kerwin, S. M. Tetrahedron Lett. 1997, 38, 199.
7. Sato, S.; Kajiura, T.; Noguchi, M.; Takehana, K.; Kobayashi, T.; Tsuji, T.
J. Antibiot. 2001, 54, 102.
8. (a) Kameyama, T.; Niwa, H. Chem. Abstr. 1968, 69, 106704; (b) Batulin, Y. M.
Chem. Abstr. 1969, 70, 2236.
9. Polevoi, L. G. Chem. Abstr. 1966, 65, 19147.
10. Stephens, F. F.; Bower, J. D. J. Chem. Soc. 1949, 2971.
11. Varma, R. S.; Saini, R. K.; Prakash, O. Tetrahedron Lett. 1997, 38, 2621.
12. Varma, R. S.; Kumar, D. J. Heterocycl. Chem. 1998, 35, 1539.
13. Park, K. H.; Jun, K.; Shin, S. R.; Oh, S. W. Tetrahedron Lett. 1996, 37, 8869.
14. Srivastava, R. G.; Venkataramani, P. S. Synth. Commun. 1988, 18, 1537.
15. Nakagawa, K.; Onoue, H.; Sugita, J. Chem. Pharm. Bull. 1964, 12, 1135.
16. Chang, J.; Zhaob, K.; Pana, S. Tetrahedron Lett. 2002, 43, 951–954;
(b) Vanden Eynde, J. J.; Delfosse, F.; Lor, P.; Haverbeke, Y. V. Tetrahedron 1995,
51, 5813–5818.
17. Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Org. Lett. 2003, 5,
3713–3715.
18. Singh, S. P.; Kumar, D.; Prakash, O.; Kapoor, R. P. Synth. Commun. 1997, 27, 2683.
19. Bhatnager, I.; George, M. V. Tetrahedron 1968, 24, 1293.
20. (a) Strauss, F.; Muffat, C.; Heitz, W. Ber. Dtsch. Chem. Ges. 1918, 51, 1457;
(b) Smith, L. I.; Howard, K. L. J. Am. Chem. Soc. 1943, 65, 159.
21. Dodwadmath, R. P.; Wheeler, T. S. Proc. Ind. Acad. Sci. 1935, 2A, 438.
22. Gladstone, W. A. F.; Norman, R. O. C. J. Chem. Soc. Chem. Commun. 1966, 1536.

2194
S. Ponnala and D. P. Sahu
23. Auwers, K.; Heimke, P. Liebigs Ann. 1927, 458, 186.
24. Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Fatima, N.; Yadav, J. Synthesis
2003, 1267, and references cited therein.
25. Nakamichi, N.; Kawashita, Y.; Hayashi, M. Synthesis 2004, 7, 1015–1020.
26. Bhat, B. A.; Sahu, D. P. Synth. Commun. 2004, 34 (12), 2169–2176.
27. (a) Deluca, M. R.; Kerwin, S. M. Tetrahedron 1997, 53, 457–464;
(b) Anthony, W. A.; Burke, P. J. J. Heterocyl. Chem. 1981, 18, 803–805;
(c) Lee, I. S. H.; Jeoung, E. H.; Lee, C. K. J. Heterocyl. Chem. 1996, 33, 1711–1716.