Herein, a nickel-catalyzed divergent reductive-Heck reaction of 1-bromo-2-((2-(aryl/alkyl ethynyl)phenoxy)methyl)benzene and 2-(aryl/alkyl ethynyl)phenyl 2-bromobenzenesulfonate derivatives has been demonstrated through the regulation of reducing agents and solvent systems. This scalable protocol offers regio- and stereoselective access to functionalized dibenzo[b,e]oxepine and dibenzo[c,f][1,2]oxathiepine 6,6-dioxide scaffolds in high to excellent yields under a mild set of reaction conditions. This methodology offers a predictable route for the synthesis of medium ring oxygen heterocycles and demonstrates wide substrate scope and outstanding tolerance to various functional groups like hydroxyl and, of course, practical instance via the synthesis of doxepin and nordoxepin molecules. We validate the experimentally proposed reaction mechanism using the density functional theory method. Further, molecular docking interactions were investigated accommodating some of our synthesized molecules.

Department of Chemistry Jadavpur University Kolkata 700032 India

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences v v i Flemingovo nám 2 16000 Prague 6 Czech Republic

Zobrazit více v PubMed

Millán A.; Alvarez de Cienfuegos L.; Miguel D.; Campaña A. G.; Cuerva J. M. Water Control over the Chemoselectivity of a Ti/Ni Multimetallic System: Heck- or Reductive-Type Cyclization Reactions of Alkyl Iodides. Org. Lett. 2012, 14, 5984–5987. 10.1021/ol3028913. PubMed DOI

Jung J.-K.; Choi N.-S.; Suh Y.-G. Functional Divergency Oriented Synthesis of Azoninones as the Key Intermediates for Bioactive Indolizidine Alkaloids Analogs. Arch. Pharmacol. Res. 2004, 27, 985–989. 10.1007/BF02975418. PubMed DOI

Villar H.; Frings M.; Bolm C. Ring closing enyne metathesis: A powerful tool for the synthesis of heterocycles. Chem. Soc. Rev. 2007, 36, 55–66. 10.1039/B508899M. PubMed DOI

Clark J. S.; Grainger D. M.; Ehkirch A. A.-C.; Blake A. J.; Wilson C. Synthesis of the Fused Polyether Core of Hemibrevetoxin B by Two-Directional Ring-Closing Metathesis. Org. Lett. 2007, 9, 1033–1036. 10.1021/ol0630651. PubMed DOI

Mondal S.; Debnath S. Ring-closing metathesis in the synthesis of fused sultones. Tetrahedron Lett. 2014, 55, 1577–1580. 10.1016/j.tetlet.2014.01.074. DOI

Potukuchi H. K.; Colomer I.; Donohoe T. J. Synthesis of Aromatic Heterocycles Using Ring-Closing Metathesis. Adv. Heterocycl. Chem. 2016, 120, 43–65. 10.1016/bs.aihch.2016.04.006. DOI

Gutiérrez-Loriente A.; Martín-Álvarez J. M.; Prieto E.; Andrés C.; Nieto J. Synthesis of Enantiopure Oxygen- and Nitrogen-Containing Heterocycles by Diastereoselective Ring-Closing Metathesis Reaction in Perhydro-1,3-benzoxazine Derivatives. Adv. Synth. Catal. 2019, 361, 1042–1063. 10.1002/adsc.201801454. DOI

Sinka V.; Martín V. S.; Cruz D. A.; Padrón J. I. Synthesis of Seven Membered Oxacycles: Recent Developments and New Approaches. Eur. J. Org. Chem. 2020, 43, 6704–6717. 10.1002/ejoc.202000850. DOI

Trost B. M.Homogeneous Transition Metal Catalyzed Reactions; Moser W. R.; Slocum D. W., Eds.; American Chemical Society: Washington DC, 1992; p. 463. Chapter 31.

Yet L. Metal-Mediated Synthesis of Medium-Sized Rings. Chem. Rev. 2000, 100, 2963–3008. 10.1021/cr990407q. PubMed DOI

Rosillo M.; Domínguez G.; Casarrubios L.; Pérez-Castells J. Arene–Chromium Tricarbonyl Complexes in the Pauson–Khand Reaction. J. Org. Chem. 2005, 70, 10611–10614. 10.1021/jo0519965. PubMed DOI

Coulter M. M.; Dornan P. K.; Dong V. M. Rh-Catalyzed Intramolecular Olefin Hydroacylation: Enantioselective Synthesis of Seven- and Eight-Membered Heterocycles. J. Am. Chem. Soc. 2009, 131, 6932–6933. 10.1021/ja901915u. PubMed DOI

Majumdar K. C.; Ghosh T.; Ponra S. A reductive Mizoroki–Heck approach to dibenzo[b,e]oxepine. Tetrahedron Lett. 2013, 54, 4661–4665. 10.1016/j.tetlet.2013.06.070. DOI

Choury M.; Lopes A. B.; Blond G.; Gulea M. Synthesis of Medium-Sized Heterocycles by Transition-Metal-Catalyzed Intramolecular Cyclization. Molecules 2020, 25, 3147.10.3390/molecules25143147. PubMed DOI PMC

Wiegand M. H. Antidepressants for the Treatment of Insomnia. Drugs 2008, 68, 2411–2417. 10.2165/0003495-200868170-00001. PubMed DOI

Jolidon S.; Alberati D.; Dowle A.; Fischer H.; Hainzl D.; Narquizian R.; Norcross R.; Pinard E. Design, synthesis and structure-activity relationship of simple bis-amides as potent inhibitors of GlyT1. Bioorg. Med. Chem. Lett. 2008, 18, 5533–5536. 10.1016/j.bmcl.2008.09.005. PubMed DOI

Pinder R. M.; Brogden R. N.; Speight T. M.; Avery G. S. Doxepin Up-to-Date: A Review of its Pharmacological Properties and Therapeutic Efficacy with Particular Reference to Depression. Drugs 1977, 13, 161–218. 10.2165/00003495-197713030-00001. PubMed DOI

Midha K. K.; Hubbard J. W.; Mckay G.; Haws E. M.; Korchinski E. D.; Gurnsy T.; Cooper J. K.; Schwede R. Stereoselective pharmacokinetics of doxepin isomers. Eur. J. Clin. Pharmacol. 1992, 42, 539–544. 10.1007/BF00314865. PubMed DOI

Kaliner M. A.; Oppenheimer J.; Farrar J. R. Comprehensive review of olopatadine: the molecule and its clinical entities. Allergy Asthma Proc. 2010, 31, 112–119. 10.2500/aap.2010.31.3317. PubMed DOI

Weinstabl H.; Suhartono M.; Qureshi Z.; Lautens M. Total Synthesis of (+)-Linoxepin by Utilizing the Catellani Reaction. Angew. Chem., Int. Ed. Engl. 2013, 52, 5305–5308. 10.1002/anie.201302327. PubMed DOI PMC

Paduraru M. P.; Wilson P. D. Synthesis of the Polycyclic Ring Systems of Artocarpol A and D. Org. Lett. 2003, 5, 4911–4913. 10.1021/ol0360703. PubMed DOI

Majumdar K. C.; Chattopadhyay B.; Ray K. Novel synthesis of medium-sized oxa-heterocycles by palladium-catalyzed intramolecular Heck reaction. Tetrahedron Lett. 2007, 48, 7633–7636. 10.1016/j.tetlet.2007.08.121. DOI

Richey R. N.; Yu H. Development of an Efficient Palladium-Catalyzed Intramolecular Carbometalation Reaction for the Synthesis of a Dibenzoxapine Containing Tetra-substituted Exocyclic Alkene. Org. Process Res. Dev. 2009, 13, 315–320. 10.1021/op800231b. DOI

Rafiee F.; Hasani S. Exciting progress in the transition metal-catalyzed synthesis of oxepines, benzoxepines, dibenzoxepines, and other derivatives. Appl. Organomet. Chem. 2022, 36, e655510.1002/aoc.6555. DOI

Metz P.; Stölting J.; Läge M.; Krebs B. A Short and Highly Stereoselective Synthesis of the 1,10-seco-Eudesmanolide Ivangulin. Angew. Chem., Int. Ed. Engl. 1994, 33, 2195–2197. 10.1002/anie.199421951. DOI

Merten J.; Fröhlich R.; Metz P. Enantioselective Total Synthesis of the Highly Oxygenated 1,10-seco-Eudesmanolides Eriolanin and Eriolangin. Angew. Chem., Int. Ed. 2004, 43, 5991–5994. 10.1002/anie.200460936. PubMed DOI

Flohic A. L.; Meyer C.; Cossy J. Total Synthesis of (±)-Mycothiazole and Formal Enantioselective Approach. Org. Lett. 2005, 7, 339–342. 10.1021/ol047603q. PubMed DOI

Merten J.; Hennig A.; Schwab P.; Fröhlich R.; Tokalov R. V.; Gutzeit H. O.; Metz P. A Concise Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides–Enantioselective Total Synthesis of the Antileukemic Sesquiterpene Lactones(−)-Eriolanin and (−)-Eriolangin. Eur. J. Org. Chem. 2006, 5, 1144–1161. 10.1002/ejoc.200500739. DOI

Mondal S. Recent Developments in the Synthesis and Application of Sultones. Chem. Rev. 2012, 112, 5339–5355. 10.1021/cr2003294. PubMed DOI

Johansson Seechurn C. C. C.; Kitching M. O.; Colacot Y. J.; Snieckus V. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize. Angew. Chem., Int. Ed. 2012, 51, 5062–5085. 10.1002/anie.201107017. PubMed DOI

Metal Catalyzed Cross-Coupling Reactions and More; de Meijere A.; Bräse S.; Oestreich M., Eds.; Wiley: Hoboken, 2013; vol. 3.

Henrion M.; Ritleng V.; Chetcuti M. J. Nickel N-Heterocyclic Carbene-Catalyzed C–C Bond Formation: Reactions and Mechanistic Aspects. ACS Catal. 2015, 5, 1283–1302. 10.1021/cs5014927. DOI

Egorova K. S.; Ananikov V. P. Which Metals are Green for Catalysis? Comparison of the Toxicities of Ni, Cu, Fe, Pd, Pt, Rh, and Au Salts. Angew. Chem., Int. Ed. 2016, 55, 12150–12162. 10.1002/anie.201603777. PubMed DOI

Lin B.-L.; Liu L.; Fu Y.; Luo S.-W.; Chen Q.; Guo Q.-X. Comparing Nickel- and Palladium-Catalyzed Heck Reactions. Organometallics 2004, 23, 2114–2123. 10.1021/om034067h. DOI

Menezes da Silva V. H.; Braga A. A. C.; Cundari T. R. N-Heterocyclic Carbene Based Nickel and Palladium Complexes: A DFT Comparison of the Mizoroki–Heck Catalytic Cycles. Organometallics 2016, 35, 3170–3181. 10.1021/acs.organomet.6b00532. DOI

Lv H.; Kang H.; Zhou B.; Xue X.; Engle K. M.; Zhao D. Nickel-catalyzed intermolecular oxidative Heck arylation driven by transfer hydrogenation. Nat. Commun. 2019, 10, 5025.10.1038/s41467-019-12949-1. PubMed DOI PMC

Huang X.; Teng S.; Chi Y. R.; Xu W.; Pu M.; Wu Y.-D.; Zhou J. S. Enantioselective Intermolecular Heck and Reductive Heck Reactions of Aryl Triflates, Mesylates, and Tosylates Catalyzed by Nickel. Angew. Chem., Int. Ed. 2021, 60, 2828–2832. 10.1002/anie.202011036. PubMed DOI

Lin C.; Chen S.; Wang Y.; Gao F.; Shen L. Ni(ii)-Catalyzed intermolecular selective Heck-type arylation of unactivated alkenes with arylboronic acids. Org. Chem. Front. 2022, 9, 608–614. 10.1039/D1QO01579F. DOI

Matsubara R.; Jamison T. F. Nickel-Catalyzed Allylic Substitution of Simple Alkenes. J. Am. Chem. Soc. 2010, 132, 6880–6881. 10.1021/ja101186p. PubMed DOI PMC

Matsubara R.; Gutierrez A. C.; Jamison T. F. Nickel-Catalyzed Heck-Type Reactions of Benzyl Chlorides and Simple Olefins. J. Am. Chem. Soc. 2011, 133, 19020–19023. 10.1021/ja209235d. PubMed DOI PMC

Chen Y.-G.; Shuai B.; Xu X.-T.; Li Y.-Q.; Yang Q.-L.; Qiu H.; Zhang K.; Fang P.; Mei P.-S. Nickel-catalyzed Enantioselective Hydroarylation and Hydroalkenylation of Styrenes. J. Am. Chem. Soc. 2019, 141, 3395–3399. 10.1021/jacs.8b13524. PubMed DOI

Bhakta S.; Ghosh T. Emerging Nickel Catalysis in Heck Reactions: Recent Developments. Adv. Synth. Catal. 2020, 362, 5257–5274. 10.1002/adsc.202000820. DOI

Saper N. I.; Ohgi A.; Small D. W.; Semba K.; Nakao Y.; Hartwig J. Nickel-catalysed anti-Markovnikov hydroarylation of unactivated alkenes with unactivated arenes facilitated by non-covalent interactions. Nat. Chem. 2020, 12, 276–283. 10.1038/s41557-019-0409-4. PubMed DOI PMC

Bhakta S.; Ghosh T. Nickel-Catalyzed Cascade Reactions. Eur. J. Org. Chem. 2021, 29, 4201–4215. 10.1002/ejoc.202100660. DOI

Zhang Y.; Ma J.; Chen J.; Meng L.; Liang Y.; Zhu S. A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates. Chem. 2021, 7, 3171–3188. 10.1016/j.chempr.2021.10.015. DOI

Bhakta S.; Ghosh T. Nickel-catalyzed hydroarylation reaction: a useful tool in organic synthesis. Org. Chem. Front. 2022, 9, 5074–5103. 10.1039/D2QO00826B. DOI

Lin J.; Wu C.; Tian X. Nickel-Catalyzed Cascade Reaction of 2-Vinylanilines with gem-Dichloroalkenes. Org. Lett. 2022, 24, 4855–4859. 10.1021/acs.orglett.2c01492. PubMed DOI

Boldrini G. P.; Savoia D.; Tagliavini E.; Trombini C.; Ronchi A. U. Nickel-catalyzed coupling of activated alkenes with organic halides. J. Organomet. Chem. 1986, 301, C62–C64. 10.1016/0022-328X(86)80050-X. DOI

Mondal S.; Debnath S.; Das B. Synthesis of seven-membered fused sultones by reductive Heck cyclization: an investigation for stereochemistry through DFT study. Tetrahedron 2015, 71, 476–486. 10.1016/j.tet.2014.11.068. DOI

Mondal S.; Debnath S. Regioselective and Stereoselective Synthesis of Pyridine-Fused Benzoxepine Derivatives by Intramolecular Reductive Heck Cyclization. J. Heterocyclic Chem. 2016, 53, 80–88. 10.1002/jhet.2357. DOI

Ghosh T. Nickel-catalyzed regioselective access to dibenzo[c,f]oxocine framework via reductive Heck reaction. Synth. Commun. 2018, 48, 1338–1345. 10.1080/00397911.2018.1445865. DOI

Bhakta S.; Ghosh T. Nickel Nanocatalysis: An Efficient Tool for Heck Reaction. ChemCatChem. 2021, 13, 828–835. 10.1002/cctc.202001425. DOI

Cheng Z.; Guo J.; Lu Z. Recent advances in metal-catalysed asymmetric sequential double hydrofunctionalization of alkynes. Chem. Commun. 2020, 56, 2229–2239. 10.1039/D0CC00068J. PubMed DOI

Zheng Y.; Zi W. Transition-metal catalyzed enantioselective hydrofunctionalization of alkynes. Tetrahedron Lett. 2018, 59 (23), 2205–2213. 10.1016/j.tetlet.2018.04.057. DOI

Hamada M.; Adachi K.; Hikawa H.; Yokoyama Y. Synthesis of a Key Intermediate for the Preparation of FTY720 Analogs. Chem. Pharm. Bull. 2012, 60, 1395–1398. 10.1248/cpb.c12-00477. PubMed DOI

Donets P. A.; Eycken E. V. V. Efficient Synthesis of the 3-Benzazepine Framework via Intramolecular Heck Reductive Cyclization. Org. Lett. 2007, 9, 3017–3020. 10.1021/ol071079g. PubMed DOI

Majumdar K. C.; Chakravorty S.; Ghosh T.; Sridhar B. Palladium-Mediated Reductive Heck Cyclization for the Formation of Dibenzoazepinone Framework. Synlett 2009, 2009, 3127–3130. 10.1055/s-0029-1218298. DOI

Armstrong M. K.; Lalic G. Differential Dihydrofunctionalization of Terminal Alkynes: Synthesis of Benzylic Alkyl Boronates Through Reductive Three-Component Coupling. J. Am. Chem. Soc. 2019, 141 (15), 6173–6179. 10.1021/jacs.9b02372. PubMed DOI PMC

Reed A. E.; Curtiss L. A.; Weinhold F. Chem. Rev. 1988, 88, 899–926. 10.1021/cr00088a005. DOI

Weber J.; Siddiqui M. A.; Wagstaff A. J.; McCormack P. L. Low-Dose Doxepin In the Treatment of Insomnia. CNS Drugs. 2010, 24, 713–720. 10.2165/11200810-000000000-00000. PubMed DOI

Shimamura T.; Shiroishi M.; Weyand S.; Tsujimoto H.; Winter G.; Katritch V.; Abagyan R.; Cherezov V.; Liu W.; Won Han G.; Kobayashi T.; Stevens R. C.; Iwata S. Structure of the human histamine H1 receptor complex with doxepin. Nature 2011, 475, 65–70. 10.1038/nature10236. PubMed DOI PMC

Wang D.; Guo Q.; Wu Z.; Li M.; He B.; Du Y.; Zhang K.; Tao Y. Molecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor. Nat. Commun. 2024, 15, 84.10.1038/s41467-023-44477-4. PubMed DOI PMC

Xu Y.; Zhang Z.; Shi J.; Liu X.; Tang W. Recent developments of synthesis and biological activity of sultone scaffolds in medicinal chemistry. Ara. J. Chem. 2021, 14, 10303710.1016/j.arabjc.2021.103037. DOI

Košak U.; Knez D.; Coquelle N.; Brus B.; Pišlar A.; Nachon F.; Brazzolotto X.; Kos J.; Colletier J.-P.; Gobec S. N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer’s agents. Bioor. Med. Chem. 2017, 25, 633–645. 10.1016/j.bmc.2016.11.032. PubMed DOI