A new series of selectively dichlorinated and dibrominated five to eight-membered ring [1,2-a] fused benzimidazoles and [1,4]oxazino[4,3-a]benzimidazoles are synthesized in mostly high yields of >80% using the reaction of hydrogen peroxide and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl is also capable of a one-pot ring-closure and chlorination

Andrzejewska M.

Bahrami K.

Barhate N. B.

Ben-Daniel R.

Bogdal D.

Borowski P.

Carpenter R. D.

Dakka J.

De Rosa M.

Fagan V.

Fahey K.

Fawaz Aldabbagh

Gobis K.

Koini E. N.

Kuznetsov Y. V.

Martin J.

Martin Sweeney

Michael Gurry

Nair M. D.

Patrick McArdle

Sivey J. D.

Voudrias E. A.

Šukalović V.

A new series of selectively dichlorinated and dibrominated five- to eight-membered-ring [1,2-a]-fused benzimidazoles and [1,4]oxazino[4,3-a]benzimidazoles are synthesized in mostly high yields of &amp;gt;80% using the reaction of hydrogen peroxide and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl can also be used for a one-pot ring closure and chlorination

Gurry, Michael

Sweeney, Martin

McArdle, Patrick

Aldabbagh, Fawaz

Access to Research at National University of Ireland, Galway

One-pot hydrogen peroxide and hydrohalic acid induced ring closure and selective aromatic halogenation to give new ring-fused benzimidazoles

A new series of selectively dichlorinated and dibrominated five- to eight-membered-ring [1,2-a]-fused benzimidazoles and [1,4]oxazino[4,3-a]benzimidazoles are synthesized in mostly high yields of &gt;80% using the reaction of hydrogen peroxide and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl can also be used for a one-pot ring closure and chlorination.College of Science, National University of Ireland Galway (NUI Galway), for a Postgraduate Scholarship for M.G.
and the Irish Research Council (IRC) for a Government of Ireland Postgraduate Scholarship for M.S.peer-reviewed2016-05-1

University of Galway Research Repository

Organic Letters

A new
series of selectively dichlorinated and dibrominated five-
to eight-membered-ring [1,2-a]-fused benzimidazoles
and [1,4]­oxazino­[4,3-a]­benzimidazoles are synthesized
in mostly high yields of >80% using the reaction of hydrogen peroxide
and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl can
also be used for a one-pot ring closure and chlorination

Michael Gurry (1672642)

Martin Sweeney (1672636)

Patrick McArdle (1457956)

Fawaz Aldabbagh (1672639)

The Francis Crick Institute

One-Pot Hydrogen Peroxide and Hydrohalic Acid Induced
Ring Closure and Selective Aromatic Halogenation To Give New Ring-Fused
Benzimidazoles

Crossref

One-Pot Hydrogen Peroxide and Hydrohalic Acid Induced Ring Closure and Selective Aromatic Halogenation To Give New Ring-Fused Benzimidazoles

A new series of selectively dichlorinated and dibrominated five- to eight-membered-ring [1,2-a]-fused benzimidazoles and [1,4]oxazino[4,3-a]benzimidazoles are synthesized in mostly high yields of  > 80% using the reaction of hydrogen peroxide and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl can also be used for a one-pot ring closure and chlorination

Kingston University Research Repository

This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Organic Lettters, copyright © American Chemical Society after peer review. To ac-cess the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b01317   One-Pot Hydrogen Peroxide and Hydrohalic acid Induced Ring Closure and Selective Aromatic Halogenation to give New Ring-Fused Benzimidazoles   Michael Gurry, Martin Sweeney, Patrick McArdle, and Fawaz Aldabbagh* School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland Supporting Information     ABSTRACT: A new series of selectively dichlorinated and dibrominated five to eight-membered ring [1,2-a] fused benzimidazoles and [1,4]oxazino[4,3-a]benzimidazoles are synthesized in mostly high yields of >80% using the reaction of hydrogen peroxide and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl is also capable of a one-pot ring-closure and chlorination.The combination of hydrogen peroxide and hydrohalic acid (HX, where X = Cl, Br) is a source of electrophilic chlorine and bromine that can be used for facile aromatic halogenations.1-4 Moreover H2O2 and HCl has been reported to give 4,6-dichlorination of 5-hydroxybenzimidazole.5 1-Chlorobenzimidazole can be formed by reacting benzimidazole with sodium hypochlorite (NaOCl) in CCl4.6 The intermediate of the reaction between H2O2 and HCl is hypochlorous acid (HOCl), which is commonly used to disinfect water, and its salt is the ac-tive ingredient in domestic bleaches. The oxidizing solution is very cheap, low in molecular weight, and allows the in situ gener-ation of elemental chlorine and bromine with the by-product being water. Therefore there are significant green and technical ad-vantages to using H2O2-HX in organic synthesis.                                                                 More than fifty years ago, it was recognized that a combina-tion of H2O2 and trifluoroacetic acid could be used to prepare ring-fused benzimidazoles in good yields from o-cyclic amine substituted anilines.7 The use of o-tert-aminoacetanilides with peroxide (including H2O28 and Oxone9) in formic acid is recog-nized as a versatile method for preparing ring-fused benzimidaz-oles and imidazobenzimidazoles. The preparation of 2-aryl substi-tuted benzimidazoles was reported from the condensation of aryl aldehydes with o-phenylenediamines in the presence of H2O2-HCl.10 Moderate yields of benzimidazoles and ring-fused benzim-idazoles with tetrachlorination of the fused benzene part was re-ported using the reaction of sulfuryl chloride with o-aminodialkylanilines.11 Halogenated benzimidazoles have anti-cancer,12, 13 anti-protozoal,13 anti-tuberculosis,14 and anti-hepatitis activity,15 as well as, dopamine-receptor binding.16 In addition to their biologi-cal activity, benzimidazoles chlorinated and brominated at specif-ic sites provide promise as valuable synthetic intermediates. Hal-ogenations of heterocycles are generally carried out in subsequent synthetic step(s) and require the use of difficult to handle Cl2, Br2 or organic reagents prepared from them. The halogenation of the heterocycle is often associated with low selectivity and when organic reagents are used waste by-products are generated. Our objective was thus to accomplish a one-pot reaction that combined the aromatic halogenation capacity of H2O2-HX with the oxida-tive cyclization of o-cyclic amine substituted anilines to form a new series of valuable halogenated ring-fused benzimidazoles. Herein, is reported the first preparation of specifically dichlorinat-ed and dibrominated ring-fused benzimidazoles from commercial-ly available anilines.  Table 1. Optimization of Reaction Conditions        Conditions: Aniline 1a (1.0 mmol), oxidant (10 mmol), HCl (12 mmol), solvent (10 mL); a4 h; brecovery of 1a (38%); cPlus 3a in 15% yield; d20 mL of Parazone® thin bleach; e1 h  Initially we attempted to establish the one-pot oxidative cy-clization and chlorination on 5-bromo-2-piperidin-1-ylaniline 1a in acetonitrile (Table 1). Excess molar amounts of concentrated HCl relative to H2O2 were found necessary, and the reaction times were reduced on heating. Monitoring of the reaction by TLC showed the total consumption of aniline 1a within 20 minutes using the optimized conditions (entry 4). 6,8-Dichloroinated pyri-do[1,2-a]benzimidazole 2a was isolated in 90% yield after basic work-up without the requirement for chromatography. This trans-formation was found to also work in THF and methanol, however yields of 2a were reduced, and a cleaner reaction occurred in ace-tonitrile. The sodium salt of hypochlorous acid formed in situ is commonly used in domestic bleaches. We thus decided to replace   entry oxidant solvent temp yield of 2a (%) 1 H2O2 MeCN rt trace 2 H2O2 MeCN rta 73 3 H2O2 MeCN 50 °C 81 4 H2O2 MeCN reflux 90 5 H2O2 THF reflux 83 6 H2O2 MeOH reflux 50b 7 NaOCl MeCN reflux 68c 8 household bleachd MeCN refluxe 56        3 H2O2 with NaOCl solution, and found that the desired 2a could be isolated in 68% yield, although chromatography was required to separate some trichlorinated benzimidazole 3a formed in 15% yield. The reaction was then carried out using a well-known brand of household bleach (containing an unspecified quantity of NaOCl) to exclusively give 6,8-dichloro adduct 2a in 56% yield with the reduced yield attributed to the purification by chromatog-raphy, which separated a number of additives (presumably surfac-tants and perfumes) in the bleach.  Scheme 1. One-Pot Ring-Fused Benzimidazole Formation with Aromatic Trihalogenation        Using the optimized conditions (Table 1, entry 4) the scope and versatility was explored. Firstly we attempted to investigate o-cyclic amine substituted anilines devoid of other aromatic sub-stituents (Scheme 1). 2-Piperdin-1-ylaniline (1b) and 2-morpholin-4-ylaniline (1c) gave the respective trichlorinated ring-fused benzimidazoles 2b and 2c in 71 and 89% yield. Tetrachlo-rination product 3b in 12% yield was separated by column chro-matography from 2b. Replacing HCl by concentrated HBr trans-formed piperidine 1b into dibrominated pyrido[1,2-a]benzimidazole 4b in 94% yield (Table 3), although under the same conditions the morpholine analogue was tribrominated to give 4c in 87% yield (Scheme 1). Attempts at isolating dibromin-ated benzimidazole from the reaction of 1c at shorter reaction times were unsuccessful due to the isolation of mixtures of bro-minated benzimidazoles, and a clean transformation occurred by increasing the reaction time to 18 hours to give exclusively 4c.  The preparation of selectively dichlorinated ring-fused ben-zimidazoles from various o-cyclic amine substituted anilines con-taining electron-donating and electron-withdrawing groups proved mostly facile with yields of 72-92% obtained of ring-fused ben-zimidazoles (Table 2). The substitution of the chlorine atoms was consistent, and did not vary with the nature of the substituent on the aniline, as confirmed by X-ray crystal structures of adducts 2d and 2i (Figure 1).17 In some cases chromatography was required to separate small amounts of fully chlorinated benzimidazoles 3b and 3h, although 5-fluoro-2-piperidin-1-ylaniline (1f) tended to prefer cyclization with monochlorination to give 3f in 62% yield with the dichlorinated adduct 2f given in smaller yield of 27%.  Beginning with the optimized conditions (Table 1, entry 4) and replacing HCl with HBr, the preparation of dibrominated ring-fused benzimidazoles was investigated (Table 3). In some cases the latter reaction conditions used successfully to yield di-chlorinated ring-fused benzimidazoles (Table 2) did not require modification, although significantly longer reaction times were required for resonance activators (NHAc and OMe) on the aniline.  Table 2. One-Pot Ring-Fused Benzimidazole Formation with Aromatic Dichlorination     Conditions: Same as in Table 1, entry 4 Figure 1. Crystal Structures of 7,9-dichloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazoles                 Nevertheless dibrominated ring-fused benzimidazoles were isolat-ed in excellent yield of 74-94% and without the requirement for chromatography, save for three anilines containing electron-withdrawing groups (F, CN, CF3). The substitution pattern was the same as for the chlorination, and the positions for the bro-mination did not vary with the nature of the substituent on the aniline, as confirmed by X-ray crystal structures of dibrominated adducts 4b, 4f and 4m (Figure 2).17 Analogous to the results ob-tained with H2O2-HCl, 5-fluoro-2-piperidin-1-ylaniline (1f) gave significant monobromination at pyrido[1,2-a]benzimidazole C-8 with 5f separated in 31% yield from the desired dibrominated adduct 4f isolated in 56% yield. Surprisingly, the benzonitrile 1h, which gave some polychlorination with H2O2-HCl after only 20 minutes, was found difficult to dibrominate with only the mono-bromide 5h isolated in 62% yield. Further, no brominated benzim-idazoles could be cleanly separated from the attempted reaction with 5-(trifluoromethyl)aniline 1i, although the same substrate gave selectively 7,9-dichlorinated [1,4]oxazino[4,3-a]benzimidazole 2i in 72% yield using H2O2-HCl (Table 2). Thus, it seems that the bromination is more strongly affected by substit-uents on the aniline than the chlorination with electron-withdrawing substituents making dibromination difficult. Table 3. One-Pot Ring-Fused Benzimidazole Formation with Aromatic Dibromination           1       R       Y                  yield (%)       1a       Br       CH2                 2a,     90       1d       Br       O                 2d, 92       1e       Cl       CH2                 2b, 73  +   3b,   15       1f       F       CH2                 2f, 27  +   3f,    62       1g      Me       CH2                 2g, 82       1h      CN       CH2                 2h, 79  +   3h,   12       1i      CF3       O                 2i, 72       1j      NHAc       CH2                 2j, 88       1k      OMe       O                 2k, 87 2d 2i   4 Conditions: Aniline 1 (1.0 mmol), H2O2 (10 mmol), HBr (12 mmol) in MeCN (10 mL); aAdditional times and equivalents produced similar re-sults; b4h observed but was not isolated; cIntractable mixture of mono and non-brominated ring-fused benzimidazole; dH2O2 (20 mmol), HBr (24 mmol) in MeCN (10 mL). Figure 2. Crystal Structures of 6,8-dibromo-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazoles                      The synthesis of alternative [1,2-a] alicyclic ring-fused ben-zimidazoles was examined (Table 4). Selectively dichlorinated five to eight-membered [1,2-a] alicyclic ring fused benzimidaz-oles 2l-2o were isolated in 78-93% yield after reaction times of 20 minutes. The brominations were found to be significantly slower than the analogous chlorinations, and double the number of equivalent of H2O2-HBr were required to obtain the desired prod-ucts. This is in agreement with literature kinetic studies for the halogenation of p-xylene, where Br2 was found to react more than 200 times slower than Cl2.18 Attempts were made to reduce reac-tion times by activating bromine towards electrophilic attack by adding a quaternary ammonium salt (TBAB),2 but no effect on rate was observed. Our system is however different to the litera-ture,2 as there is an absence of a two-phase system due to the sol-ubility of acetonitrile in water. It is conceivable that steric factors might be also influencing the rate of electrophilic aromatic bro-mination, since one would have expected greater polarizability in suspected bromination species, H2O+-Br and Br2 compared to the chlorine analogues.3 Nevertheless selectively dibrominated pyri-do-, azepino- and azocino [1,2-a] ring-fused benzimidazoles 4m-4o were isolated in high yields of 70-86%. Monitoring the reac-tion of 1l with H2O2-HBr using 1H NMR showed after 20 minutes the formation of a mixture of monobromides; 5- and 7-bromobenzimidazoles in an approximate 1:3 ratio and after 20 hours a mixture of di- and tribromides 4l and 5l remained in an approximate 2:1 ratio. It was thus not possible to cleanly isolate 5,7-dibromopyrrolo[1,2-a]benzimidazole 4l, and it was decided to allow the tribromide 5l to be regioselectively formed in 87% yield.  Table 4. One-Pot Five to Eight-Membered [1,2-a] Ring-Fused Benzimidazole Formation with Aromatic Dihalogenation        Conditions: Aniline 1 (1.0 mmol) in MeCN (10 mL) with H2O2 (10 mmol) and HCl (12 mmol) for X = Cl or with H2O2 (20 mmol) and HBr (24 mmol) for X = Br.    In conclusion we have successfully established a simple and inexpensive H2O2-HX preparation of halogenated ring-fused ben-zimidazoles with 31 new compounds now reported from commer-cial anilines. In most cases the one-pot transformation gives regi-oselectively the novel dihalogenated heterocycle in high yields.  ■  ASSOCIATED CONTENT  Supporting Information Experimental procedures and spectroscopic data for all com-pounds, including X-ray crystallographic data for compounds 2d, 2i, 4b, 4f and 4m is available free of charge via the Internet at http://pubs.acs.org.   ■  AUTHOR INFORMATION Corresponding Author *Email: fawaz.aldabbagh@nuigalway.ie; Tel.: +353 (0) 91 493120. Fax: +353 (0) 91 49557.     1 R Y  time       yield (%)     1a Br CH2  20 min      4a, 89     1b H CH2  20 min      4b, 94     1d Br O  20 min      4c, 92     1e Cl CH2  40 min      4e, 93     1f F CH2  20 min      4f, 56a +   5f,   31a     1g Me CH2  20 min      4g, 84     1h CN CH2  20 min      5h, 62a,b      1i CF3 O  20 min      4i,   0a,c     1j NHAc CH2  2 d      4j, 74d     1k OMe O  8 h      4k, 92   1       X       n    time yield (%)   1l Cl 1    20 min 2l,        93   1m Cl 2    20 min 2m,      90   1n Cl 3    20 min 2n,       89   1o Cl 4    20 min 2o,      78   1l Br 1      4 d 5l,        87   1m Br 2      4 d  4m,     86   1n Br 3      5 d  4n,      80   1o Br 4      5 d  4o,      70 4b 4f 4m   5 Notes The Authors declare no competing financial interest. ■  ACKNOWLEDGMENT  The authors thank the College of Science, National University of Ireland Galway (NUI Galway) for a Postgraduate Scholarship for M.G. and the Irish Research Council (IRC) for a Government of Ireland Postgraduate Scholarship for M.S. ■  REFERENCES 1. (a) Ben-Daniel, R.; de Visser, S. P.; Shaik, S.; Neumann, R. J. Am. Chem. Soc. 2003, 125, 12116-12117; (b) Sivey, J. D.; Roberts, A. L. Environ. Sci. Technol. 2012, 46, 2141-2147. 2. Dakka, J.; Sasson, Y. J. Chem. Soc. Chem. Commun. 1987, 1421-1422. 3. Sivey, J. D.; Arey, J. S.; Tentscher, P. R.; Roberts, A. L. Environ. Sci. Technol. 2013, 47, 1330-1338. 4. (a) Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron Lett. 1998, 39, 6349-6350. (b) Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetra-hedron 1999, 55, 11127-11142. (c) Bogdal, D.; Lukasiewicz, M.; Pielichowski, J. Green Chem. 2004, 6, 110-113. (d) Koini, E. N.; Avlonitis, N.; Calogeropoulou, T. Synlett 2011, 1537-1542.  5. Kuznetsov, Y. V.; Stolyarova, L. G.; Lezina, V. P.; Smirnov, L. D. Bull. Acad. Sci. USSR. Div. Chem. Sci. 1989, 38, 1494-1500. 6. De Rosa, M.; Canudas, N.; Arnold, D.; Yennawar, H. J. Org. Chem. 2013, 78, 7264-7267. 7. Nair, M. D.; Adams, R. J. Am. Chem. Soc. 1961, 83, 3518-3521. 8. Fahy, K.; Aldabbagh, F. Tetrahedron Lett. 2008, 49, 5235-5237. 9. Fagan, V.; Bonham, S.; McArdle, P.; Carty, M.P.; Aldab-bagh, F. Eur. J. Org. Chem. 2012, 1967-1975 10. Bahrami, K.; Khodaei, M. M.; Kavianinia, I. Synthesis 2007, 547-550. 11. Martin, J.; Meth-Cohn, O.; Suschitzky, H. Tetrahedron Lett. 1973, 14, 4495-4498. 12. Carpenter, R. D.; Natarajan, A.; Lau, E. Y.; Andrei, M.; Solano, D. M.; Lightstone, F. C.; DeNardo, S. J.; Lam, K. S.; Kurth, M. J. Cancer Res. 2010, 70, 5448-5456. 13. Andrzejewska, M.; Yépez-Mulia, L.; Cedillo-Rivera, R.; Tapia, A.; Vilpo, L.; Vilpo, J.; Kazimierczuk, Z. Eur. J. Med. Chem. 2002, 37, 973-978. 14. Gobis, K.; Foks, H.; Serocki, M.; Augustynowicz-Kopeć, E.; Napiόrkowska, A. Eur. J. Med. Chem. 2015, 89, 13-20. 15. Borowski, P.; Deinert, J.; Schalinski, S.; Bretner, M.; Ginal-ski, K.; Kulikowski, T.; Shugar, D. Eur. J. Biochem. 2003, 270, 1645-1653. 16. Šukalović, V.; Andrić, D.; Roglić, G.; Kostić-Rajačić, S.; Šoškić, V. Arch. Pharm. 2004, 337, 376-382. 17. Crystallographic data (excluding structure factors) has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 1054365 for (2d) CCDC 1054369 for (2i), CCDC 1054366 for (4b), CCDC 1054368 for (4f), and CCDC 1054367 for (4m).  18. Voudrias, E. A.; Reinhard, M. Environ. Sci. Technol. 1988, 22, 1049-1056.    

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One-pot hydrogen peroxide and hydrohalic acid induced ring closure and selective aromatic halogenation to give new ring-fused benzimidazoles

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