Mild Radical Oxidative sp³-Carbon–Hydrogen Functionalization: Innovative Construction of Isoxazoline and Dibenz[b,f]oxepine/azepine Derivatives

Abstract

Direct carbon–hydrogen bond functionalization has emerged as a powerful synthetic method for the straightforward and modular functionalization of organic molecules. In this account, we described our latest contributions in the area of oxidative sp³-carbon–hydrogen bond functionalization using mild radical oxidants for the construction of structurally important heterocycles. We have developed two new methodologies in which a new class of substrate and an uncommon nucleophilic reagent have been introduced to the existing palette of reaction partners for oxidative carbon–hydrogen functionalization. To achieve these results, the 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) radical and a benzoyl peroxide/copper(I) system have been employed as oxidants for the dehydrogenative one-pot synthesis of N-alkoxycarbonyl-protected isoxazolines from hydroxylamines and for the synthesis of dibenz[b,f]oxepines, dibenzo[b,f]thiepines, and dibenz[b,f]azepines from simple xanthenes, thioxanthenes, and acridanes, respectively.

1 Introduction

2 2,2,6,6-Tetramethylpiperidinyloxyl-Mediated Dehydrogenative Formation and Trapping of Unstable Nitrones: Synthesis of N-Alkoxycarbonyl-Protected Isoxazoline Derivatives

3 Oxidative sp³-Carbon–Hydrogen Bond Functionalization and Ring Expansion with Trimethylsilyldiazomethane: Synthesis of Dibenzoxepines, Dibenzothiepines, and Dibenzazepines

4 Conclusions and Outlook

Key words

carbon–hydrogen functionalization - oxidations - radicals - peroxides - heterocycles

• References

• 1a The Logic of Chemical Synthesis . Corey EJ, Cheng XM. John Wiley and Sons; New York: 1989
• 1b Handbook of C–H Transformations . Dyker G. Wiley-VCH; Weinheim: 2005
• 2a Metal-Catalyzed Cross-Coupling Reactions . de Meijere A, Diederich F. Wiley-VCH; Weinheim: 2004
• 2b New Trends in Cross-Coupling: Theory and Applications . Colacot T. The Royal Society of Chemistry; Cambridge: 2015

See also:
• 2c Trost BM. Science 1991; 254: 1471
• 2d Li C.-J, Trost BM. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 13197
• 2e Shi W, Liu C, Lei A. Chem. Soc. Rev. 2011; 40: 2761 ; and references cited therein

For example, see:
• 3a Newhouse T, Baran PS, Hoffmann RW. Chem. Soc. Rev. 2009; 38: 3010
• 3b Newhouse T, Baran PS. Angew. Chem. Int. Ed. 2011; 50: 3362
• 3c Liu C, Liu D, Lei A. Acc. Chem. Res. 2014; 47: 3459
• 3d Sun CL, Shi ZJ. Chem. Rev. 2014; 114: 9219
• 3e Roschangar F, Sheldon RA, Senanayake CH. Green Chem. 2015; 17: 752

For selected recent reviews on oxidative carbon-hydrogen functionalization, see:
• 4a Scheuermann CJ. Chem. Asian J. 2010; 5: 436
• 4b Klussmann M, Sureshkumar D. Synthesis 2011; 3: 353
• 4c Yeung CS, Dong VM. Chem. Rev. 2011; 111: 1215
• 4d Liu C, Zhang H, Shi W, Lei A. Chem Rev. 2011; 111: 1780
• 4e Rohlmann R, García Mancheño O. Synlett 2013; 24: 6
• 4f Girard SA, Knauber T, Li CJ. Angew. Chem. Int. Ed. 2014; 53: 74
• 4g Narayan R, Matcha K, Antonchick AP. Chem. Eur. J. 2015; 21: 14678

For selected recent examples of carbon-hydrogen functionalization with molecular oxygen, see:
• 5a Vasseur A, Harakat D, Muzart J, Le Bras J. Adv. Synth. Catal. 2013; 355: 59
• 5b Liu W, Wang S, Zhan H, Lin J, He P, Jiang Y. Tetrahedron Lett. 2014; 55: 3549
• 5c Gigant N, Bäckvall J.-E. Chem. Eur. J. 2014; 20: 5890
• 5d Lu Y, Wang H.-W, Spangler JE, Chen K, Cui P.-P, Zhao Y, Sun W.-Y, Yu J.-Q. Chem. Sci. 2015; 6: 1923 ; and references cited therein

For a comprehensive overview, see:
• 5e Basle O In From C-H to C-C Bonds: Cross-Dehydrogenative-Coupling . Li C.-J. Royal Society of Chemistry; Cambridge: 2014. RSC Green Chemistry No. 26, 197

For recent examples of carbon-hydrogen functionalization with DDQ, see:
• 6a Correia CA, Li CJ. Adv. Synth. Catal. 2010; 352: 1446
• 6b Mitsudera H, Li CJ. Tetrahedron Lett. 2011; 52: 1898
• 6c Li Y, Cao L, Luo X, Deng WP. Tetrahedron 2014; 70: 5974
• 6d Liu X, Sun S, Meng Z, Lou H, Liu L. Org. Lett. 2015; 17: 2396

For selected recent examples of carbon-hydrogen functionalization with TBHP, see:
• 7a He T, Yu L, Zhang L, Wang L, Wang M. Org. Lett. 2011; 13: 5016
• 7b Zhou MB, Song RJ, Ouyang XH, Liu Y, Wei WT, Denga GB, Li JH. Chem. Sci. 2013; 4: 2690
• 7c Min C, Sanchawala A, Seidel D. Org. Lett. 2014; 16: 2756
• 7d Niu B, Zhao W, Ding Y, Bian Z, Pittman CU, Zhou A, Ge H. J. Org. Chem. 2015; 80: 7251

Organic peroxides are not suitable for substrates with easily oxidable functional groups leading to overoxidation of the starting material or product; for example, see:
• 8a Kim M, Sharma S, Park J, Kim M, Choi Y, Jeon Y, Hwan J, In K, Kim S. Tetrahedron 2013; 69: 6552
• 8b Zhao J, Fang H, Han J, Pan Y. Org. Lett. 2014; 16: 2530
• 8c Niu B, Xu L, Xie P, Wang M, Zhao W, Pittman CU, Zhou A. ACS Comb. Sci. 2014; 16: 454
• 8d Ali W, Behera A, Guin SK, Patel BK. J. Org. Chem. 2015; 80: 5625
• 9a Lebedev OL, Kazarnovskii SN. Tr. Khim. Khim. Tekhnol. 1959; 2: 649 ; Chem. Abstr. 1962, 56, 15479f
• 9b Lebedev OL, Kazarnovskii SN. Zh. Obshch. Khim. 1960; 30: 1631 ; Chem. Abstr. 1961, 55, 1473

For selected reviews on TEMPO chemistry, see:
• 10a Sheldon RA, Arends IW. C. E. Adv. Synth. Catal. 2004; 346: 1051
• 10b Vogler T, Studer A. Synthesis 2008; 1979
• 10c Tebben L, Studer A. Angew. Chem. Int. Ed. 2011; 50: 5034
• 10d García Mancheño O, Stopka T. Synthesis 2013; 45: 1602

For reviews on N-oxoammonium chemistry, see:
• 10e Bobbitt JM, Flores MC. L. Heterocycles 1988; 27: 509
• 10f Bobbitt JM, Brückner C, Merbouh N. Oxoammonium- and nitroxide-catalyzed oxidations of alcohols . In Organic Reactions . Vol. 74. Denmark SE. Wiley; New York: 2009: 103

See also:
• 10g Mercadante MA, Kelly CB, Bobbitt JM, Tilley LJ, Leadbeater NE. Nat. Protoc. 2013; 8: 666
• 11 Richter R, García Mancheño O. Eur. J. Org. Chem. 2010; 4460
• 12 Richter H, Rohlmann R, García Mancheño O. Chem. Eur. J. 2011; 17: 11622
• 13 Richter R, García Mancheño O. Org. Lett. 2011; 13: 6066
• 14 Rohlmann R, Stopka T, Richter H, García Mancheño O. J. Org. Chem. 2013; 78: 6050
• 15 Richter H, Fröhlich R, Daniliuc CG, García Mancheño O. Angew. Chem. Int. Ed. 2012; 51: 8656
• 16 Gini A, Segler M, Kellner D, García Mancheño O. Chem. Eur. J. 2015; 21: 12053
• 17 Stopka T, Marzo L, Zurro M, Janich S, Würthwein E.-U, Daniliuc CG, Alemán J, García Mancheño O. Angew. Chem. Int. Ed. 2015; 54: 5049

For selected reviews, see:
• 18a Grünanger P, Vita-Finzi P. Isoxazolines (Dihydroisoxazoles) . In The Chemistry of Heterocyclic Compounds . Taylor EC, Weissberger A. John Wiley and Sons; Hoboken, NJ: 1991. Part 1, Vol. 49, 417
• 18b Pinho e Melo TM. V. D. Eur. J. Org. Chem. 2010; 3363

For example, see:
• 19a Brandi A, Cardona F, Cicchi S, Cordero FM, Goti A. Chem. Eur. J. 2009; 15: 7808
• 19b Wei H, Qiao C, Liu G, Yang Z, Li C. Angew. Chem. Int. Ed. 2013; 52: 620 ; and references cited therein
• 20a Bloch R. Chem. Rev. 1998; 98: 1407
• 20b Merino P In Science of Synthesis . Vol. 27. Padwa A. Thieme; Stuttgart: 2004: 511
• 20c Grigor’ev IA In Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis: Novel Strategies in Synthesis. Feuer H. John Wiley and Sons; Hoboken, NJ: 2008. 2nd ed. 129

See also:
• 20d Cardona F, Goti A. Angew. Chem. Int. Ed. 2005; 44: 7832 ; and references cited therein

For stable N-protected nitrones, such as benzyl, allyl, or glycosyl derivatives, see:
• 21a Confalone PN, Pizzolato G, Lollar-Confalone D, Uskokovic MR. J. Am. Chem. Soc. 1980; 102: 1954
• 21b Vaseila A, Voeffray R. Helv. Chim. Acta 1982; 65: 1953
• 21c Cicchi S, Marradi M, Corsi M, Faggi C, Goti A. Eur. J. Org. Chem. 2003; 4152
• 21d Ben Ayed K, Beauchard A, Poisson J.-F, Py S, Laurent MY, Martel A, Ammar H, Abid S, Dujardin G. Eur. J. Org. Chem. 2014; 2924

For the use of α-sulfonyl N-(alkoxycarbonyl)hydroxylamine precursors, see:
• 22a Guinchard X, Vallée Y, Denis J.-N. Org. Lett. 2005; 7: 5147
• 22b Gioia C, Fini F, Mazzanti A, Bernardi L, Ricci A. J. Am. Chem. Soc. 2009; 131: 9614

For other in-situ approaches, see:
• 22c Partridge KM, Anzovino ME, Yoon TP. J. Am. Chem. Soc. 2008; 130: 2920
• 22d Hussain SA, Sharma AH, Perkins MJ, Griller D. J. Chem. Soc., Chem. Commun. 1979; 289

For examples of the in-situ formation of stable nitrones, see ref. 21a.
For a recent photocatalytic oxidative approach, see:
• 23a Hou H, Zhu S, Pan F, Rueping M. Org. Lett. 2014; 16: 2872

See also:
• 23b Morita N, Kono R, Fukui K, Miyazawa A, Masu H, Azumaya I, Ban S, Hashimoto Y, Okamoto I, Tamura O. J. Org. Chem. 2015; 80: 4797 . See also refs. 19 and 20
• 24 Vaalizadeh H, Dinparast L. Heteroat. Chem. 2009; 20: 177 ; and references cited therein

For an example of the addition of hydroxyl radicals to activated olefins, see:
• 25a Grant RD, Rizzardo E, Solomon DH. J. Chem. Soc., Perkin Trans. 2 1985; 379

For related additions with TEMPO, see:
• 25b Babiarz JE, Cunkle GT, DeBellis AD, Eveland D, Pastor SD, Shum P. J. Org. Chem. 2002; 67: 6831
• 25c Coseri S, Ingold KU. Org. Lett. 2004; 6: 1641
• 25d Kang Y.-W, Choi Y.-J, Jang H.-Y. Org. Lett. 2014; 16: 4842
• 26 König B, Pitsch W, Kleon M, Vasold R, Prall M, Schreiner PR. J. Org. Chem. 2001; 66: 1742
• 27 For an example of the nucleophilic addition of secondary hydroxylamines to Michael acceptors, such as DMAD, see: Crescenzi B, Kinzel O, Muraglia E, Orvieto F, Pescatore G, Rowley M, Summa V. WO2004058756, 2004

Calculated relative enthalpy profiles (kcal/mol) by DFT in the gas phase (B2PLYP-D3/def2-TZVP//BP86-D3/def2-TZVP). The calculations were performed using Turbomole 6.5 within Gaussian basis sets. For an article on Turbomole, see:
• 28a Furche F, Ahlrichs R, Hättig C, Klopper W, Sierka M, Weigend F. WIREs Comput. Mol. Sci. 2014; 4: 91

Gaussian software:
• 28b Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr. JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Rhaghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. Gaussian09 (Revision B.01). Gaussian Inc; Wallingford CT: 2010
• 29a Benfatti F, Capdevila MG, Zoli L, Benedetto E, Cozzi PG. Chem. Commun. (Cambridge) 2009; 5919
• 29b Ho X.-H, Mho S.-i, Kang H, Jang H.-Y. Eur. J. Org. Chem. 2010; 4436
• 29c Zhang B, Cuia Y, Jiao N. Chem. Commun. 2012; 48: 4498
• 29d Schweitzer-Chaput B, Sud A, Pint R, Dehn S, Schulze P, Klussmann M. Angew. Chem. Int. Ed. 2013; 52: 13228
• 29e Pandey G, Jadhav D, Tiwari SK, Singh B. Adv. Synth. Catal. 2014; 356: 2813
• 30 Trumbull KA, Branchaud BP. Bioorg. Med. Chem. Lett. 2005; 15: 5544
• 31 Pintér Á, Klussmann M. Adv. Synth. Catal. 2012; 354: 701

For example, see:
• 32a Akhavan-Tafti H, De Silva R, Sandison M, Handley R. US20030232405, 2003
• 32b Chen W, Xie Z, Zheng H, Lou H, Liu L. Org. Lett. 2014; 16: 5988
• 32c Muramatsu W. Nakano K. 2015; 17: 1549

For the alternative use of a strong base, see:
• 32d Sha SC, Zhang J, Carroll PJ, Walsh PJ. J. Am. Chem. Soc. 2013; 135: 17602

For some examples implying a multistep approach, see:
• 33a Barton DH. R, Bould L, Clive DL. J, Magnus PD, Hase T. J. Chem. Soc. C 1971; 2204
• 33b Jones GW, Chang KT, Shechter H. J. Am. Chem. Soc. 1979; 101: 3906
• 33c Lapin SC, Schuster GB. J. Am. Chem. Soc. 1985; 107: 4243
• 34 For an example of the undesired oxidation of diazomethane derivatives to ketones, see: Aoyama T, Shioiri T. Tetrahedron Lett. 1986; 27: 2005
• 35a Lappert MF, Lorberth J. Chem. Commun. 1967; 836
• 35b Seyferth D, Dow AW, Menzel H, Flood TC. J. Am. Chem. Soc. 1968; 90: 1080
• 35c Seyferth D, Menzel H, Dow AW, Flood TC. J. Organomet. Chem. 1972; 44: 279

For examples of carbon-hydrogen methylations with TMSCHN₂, see:
• 36a Aoyama T, Shioiri T. Synthesis 1988; 228
• 36b Maruoka K, Concepcion AB, Yamamoto H. Synthesis 1994; 1283

For examples of methylenation-type reactions, see:
• 36c Lebel H, Paquet V, Proulx C. Angew. Chem. Int. Ed. 2001; 40: 2887
• 36d Dabrowski JA, Moebius DC, Wommack AJ, Kornahrens AF, Kingsbury JS. Org. Lett. 2010; 12: 3598

For example, see:
• 37a Hoshimoto N, Aoyama T, Shioiri T. Tetrahedron Lett. 1980; 21: 46199
• 37b Cesar I, Dolenc MS. Tetrahedron Lett. 2001; 42: 7099 ; and references cited therein

For some examples of transformations with TMSCHN₂, see:
• 38a Aoyama T, Shioiri T. Tetrahedron Lett. 1990; 31: 5507
• 38b Kühnel E, Laffan DD. P, Lloyd-Jones GC, Martinez del Campo T, Shepperson IR, Slaughter JL. Angew. Chem. Int. Ed. 2007; 46: 7075
• 38c Francais A, Leyva-Pérez A, Etxebarria-Jardi G, Pena J, Ley SV. Chem. Eur. J. 2011; 17: 329
• 38d Cheng J, Qi X, Li M, Chen P, Liu G. J. Am. Chem. Soc. 2015; 137: 2480
• 39a Doyle MP, Tamblyn WH, Bagheri V. J. Org. Chem. 1981; 46: 5094
• 39b Zhao X, Zhang Y, Wang J. Chem. Commun. 2012; 48: 10162 ; and references cited therein
• 40 Salomon RG, Kochi JK. J. Am. Chem. Soc. 1973; 95: 3300
• 41 Okuma K, Nojima A, Matsunaga N, Shioji K. Org. Lett. 2009; 11: 169

For some examples of bioactive derivatives, see:
• 42a Bischoff S, Vassout A, Delini-Stula A, Waldmeier P. Pharmacopsychiatry 1986; 19: 306
• 42b Michael-Titus A, Costentine J. Pain 1987; 31: 391
• 42c Bougerolle AM, Dordain G, Berger JA, Eschalier A. Life Sci. 1992; 50: 161
• 42d Möller H.-J, Volz HP, Reimann LW, Stoll K.-D. J. Clin. Psychopharmacol. 2001; 21: 59
• 42e Kalis MM, Huff NA. Clin. Ther. 2001; 23: 680
• 42f Fernández B, Romero L, Montero A In Antidepressants, Antipsychotics, Anxiolytics: From Chemistry and Pharmacology to Clinical Application . Buschmann H, Díaz JL, Holenz J, Párraga A, Torrens A, Vela JM. Wiley-VCH; Weinheim: 2007: 248

For examples based on the Wagner-Meerwein rearrangement, see:
• 43a Stolle RJ. Prakt. Chem. Naturforsch. 1922; 105: 137
• 43b Martinet J, Dansette A. Bull. Soc. Chim. Fr. 1929; 45: 101
• 43c Anet FA, Bavin PM. G. Can. J. Chem. 1957; 35: 1084
• 43d Newman MS, Powell WH. J. Org. Chem. 1961; 26: 812
• 43e Razavi Z, McCapra F. Luminescence 2000; 15: 239
• 43f Elliott E.-C, Bowkett ER, Maggs JL, Bacsa J, Park BK, Regan SL, O’Neill PM, Stachulski AV. Org. Lett. 2011; 13: 5592

For examples of the copper-catalyzed homolytic cleavage of peroxide oxygen-oxygen bonds, see:
• 44a Kochi JK. Tetrahedron 1962; 18: 483
• 44b Gephart RT. III, McMullin CL, Sapienzynski NG, Jang ES, Aguila MJ. B, Cundari TR, Warren TH. J. Am. Chem. Soc. 2012; 134: 17350

See also:
• 44c Walling C, Zao C. Tetrahedron 1982; 38: 1105
• 44d Li P, Qiu K.-Y. Macromolecules 2002; 35: 8906
• 44e Cui Z, Shang X, Shao X.-F, Liu Z.-Q. Chem. Sci. 2012; 3: 2853
• 44f Chena H.-H, Wanga G.-Z, Hana J, Xua M.-Y, Zhaoa Y.-O, Xua H.-J. Tetrahedron 2014; 70: 212
• 45 With nonsymmetrical xanthenes and acridanes, a competitive addition takes place leading to a mixture of products where the carbon atom of the nucleophile TMSCHN₂ ends up either at C-9 or C-10 in favor of the attack of the more electron-rich phenyl ring. This was recognized by the reaction with bis-deuterated C-9-2D 5b providing a 1.8:1 mixture of C-9-D and C-10-D 8b.
• 46 The relative energies (kcal/mol) were calculated by DFT in the gas phase (B2PLYP-D3/def2-TZVP//B3LYP/6-311+G(d,p)) within Gaussian basis sets, see also ref. 28b.