{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:14:07Z","timestamp":1760058847234,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21901220","ZR2024MB079","2023KJ244","HY19B06"],"award-info":[{"award-number":["21901220","ZR2024MB079","2023KJ244","HY19B06"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["21901220","ZR2024MB079","2023KJ244","HY19B06"],"award-info":[{"award-number":["21901220","ZR2024MB079","2023KJ244","HY19B06"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Qingchuang Technology Support Program of University in Shandong Province","award":["21901220","ZR2024MB079","2023KJ244","HY19B06"],"award-info":[{"award-number":["21901220","ZR2024MB079","2023KJ244","HY19B06"]}]},{"name":"Young Scholars Research Fund of Yantai University","award":["21901220","ZR2024MB079","2023KJ244","HY19B06"],"award-info":[{"award-number":["21901220","ZR2024MB079","2023KJ244","HY19B06"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A facile and efficient synthesis of functionalized 1,4-benzodiazepine derivatives under mild conditions was developed. The CuI\/N,N-dimethylglycine-catalyzed intramolecular cross-coupling reaction of 1-(2-bromobenzyl)azetidine-2-carboxamides proceeded smoothly under mild conditions to provide 1,4,9,10a-tetrahydroazeto[1,2-a]benzo[e][1,4]diazepin-10(2H)-ones. The resulting azetidine-fused 1,4-benzodiazepine compounds underwent consecutive N-methylation with methyl triflate and the opening of the four-membered heterocyclic ring by NaN3, KCN and PhSNa to produce diverse 1,4-benzodiazepine derivatives in good to excellent yields. Upon treatment with methyl chloroformate, on the other hand, the 1,4,9,10a-tetrahydroazeto[1,2-a]benzo[e][1,4]diazepin-10(2H)-ones were straightforwardly converted into 2-chloroethyl-substituted 1,4-benzodiazepine derivatives.<\/jats:p>","DOI":"10.3390\/molecules30092014","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T06:49:02Z","timestamp":1746082142000},"page":"2014","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis of 1,4-Benzodiazepines via Intramolecular C\u2013N Bond Coupling and Ring Opening of Azetidines"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3015-9050","authenticated-orcid":false,"given":"Xin-Ming","family":"Xu","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sen","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shao-Lei","family":"Duan","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang-Min","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Scienses, Yantai University, Yantai 264005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0041-6044","authenticated-orcid":false,"given":"Kai","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.2174\/092986706775197999","article-title":"Privileged Structures as Leads in Medicinal Chemistry","volume":"13","author":"Costantino","year":"2006","journal-title":"Curr. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Katritzky, A.R., and Rees, C.W. (1984). Comprehensive Heterocyclic Chemistry, Pergamon.","DOI":"10.1016\/B978-0-08-030726-8.50006-3"},{"key":"ref_3","first-page":"13","article-title":"1,4-benzodiazepine: An overview of biological properties","volume":"5","author":"Khan","year":"2015","journal-title":"Sci. Rev. Chem. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yet, L. (2018). Benzodiazepines. Privileged Structures in Drug Discovery, John Wiley & Sons, Inc.","DOI":"10.1002\/9781118686263"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1021\/jm00187a001","article-title":"The Benzodiazepine Story","volume":"22","author":"Sternbach","year":"1979","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4582","DOI":"10.1021\/jo034286c","article-title":"Expedient One-pot Synthesis of Novel Chiral 2-Substituted 5-phenyl-1,4-Benzodiazepine Scaffolds from Amino Acid-derived Amino Nitriles","volume":"68","author":"Herrero","year":"2003","journal-title":"J. Org. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/j.1742-1241.2000.tb11838.x","article-title":"Treatment of Satus Epilepticus with Midazolam in the Critical Care Setting","volume":"54","author":"Hanley","year":"2000","journal-title":"Int. J. Clin. Pract."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1021\/jm970517u","article-title":"Class III Antiarrhythmic Activity in vivo by Selective Blockade of the Slowly Activating Cardiac Delayed Rectifier Potassium Current IKs by (R)-2-(2,4-trifluoromethyl)-N-[2-oxo-5phenyl-1-(2,2,2-trifluoroethyl)-2,3-Dihydro-1Hbenzo[e][1,4]diazepin-3-yl]acetamide","volume":"40","author":"Selnick","year":"1997","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1126\/science.1763331","article-title":"Inhibition of HIV Replication in Acute and Chronic Infections in vitro by a TAT Antagonist","volume":"254","author":"Hsu","year":"1991","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1124\/jpet.107.132456","article-title":"Inhibition of the Cardiac L-Type Calcium Channel Current by Antidepressant Drugs","volume":"324","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1021\/jm960669+","article-title":"(3R)-N-(1-(tert-Butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N\u2019-(3-(methylamino)phenyl)urea (YF476): A Potent and Orally Active Gastrin\/CCK-B Antagonist","volume":"40","author":"Semple","year":"1997","journal-title":"J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5791","DOI":"10.1021\/ja00952a050","article-title":"Isolation and Characterization of Anthramycin, a New Antitumor Antibiotic","volume":"87","author":"Leimgruber","year":"1965","journal-title":"J. Am. Chem. Soc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.chembiol.2007.05.009","article-title":"Benzodiazepine Biosynthesis in Streptomyces refuineus","volume":"14","author":"Hu","year":"2007","journal-title":"Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1007\/s12272-012-0806-3","article-title":"Design and Synthesis of Novel 1,4-Benzodiazepine Derivatives and Their Biological Evaluation as Cholinesterase Inhibitors","volume":"35","author":"Mohamed","year":"2012","journal-title":"Arch. Pharmacol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1039\/B514937A","article-title":"Practical Synthesis of Potential Endothelin Receptor Antagonists of 1,4-Benzodiazepine-2,5-dione Derivatives Bearing Substituents at the C3-, N1-and N4-Positions","volume":"4","author":"Cheng","year":"2006","journal-title":"Org. Biomol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1080\/00397911.2013.772202","article-title":"Synthetic Strategies Applicable in the Synthesis of Privileged Scaffold: 1,4-Benzodiazepine","volume":"44","author":"Kaur","year":"2014","journal-title":"Synth. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8935","DOI":"10.1021\/jo961517p","article-title":"A Remarkable Two-Step Synthesis of Diverse 1,4-Benzodiazepine-2,5-diones Using the Ugi Four-Component Condensation","volume":"61","author":"Keating","year":"1996","journal-title":"J. Org. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5916","DOI":"10.1021\/ol302837h","article-title":"Multicomponent Synthesis of Diverse 1,4-Benzodiazepine Scaffolds","volume":"14","author":"Huang","year":"2012","journal-title":"Org. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9056","DOI":"10.1016\/j.tet.2013.08.034","article-title":"A Simple and One-pot Synthesis of 2,3,4,5-Tetrasubstituted 4,5-dihydro-3H-1,4-Benzodiazepines","volume":"69","author":"Wang","year":"2013","journal-title":"Tetrahedron"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1021\/jo026860a","article-title":"New Synthesis of 1,3-Dihydro-1,4-benzodiazepin-2(2H)-ones and 3-Amino-1,3-dihydro-1,4-benzodiazepin-2(2H)-ones:\u2009 Pd-Catalyzed Cross-Coupling of Imidoyl Chlorides with Organoboronic Acids","volume":"68","author":"Nadin","year":"2003","journal-title":"J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cclet.2019.05.048","article-title":"Recent Advances in Sulfenylation of C(sp3)-H Bond Under Transition Metal-Free Conditions","volume":"31","author":"Xu","year":"2020","journal-title":"Chin. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4094","DOI":"10.1002\/adsc.201800781","article-title":"Expedient Synthesis of 1,4-Benzodiazepines via a Tandem Condensation\/[1,5]-Hydride Transfer\/Cyclization Process","volume":"360","author":"Liu","year":"2018","journal-title":"Adv. Synth. Catal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10015","DOI":"10.1002\/slct.202002523","article-title":"Oxidative Dearomatization as a Strategy for a Facile, Metal-Free Synthesis of Vanillyl Benzodiazepines","volume":"5","author":"Nunewar","year":"2020","journal-title":"ChemistrySelect"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1021\/jo7024306","article-title":"A New Strategy for the Synthesis of 1,4-Benzodiazepine Derivatives Based on the Tandem N-Alkylation-Ring Opening-Cyclization Reactions of Methyl 1-Arylaziridine-2-carboxylates with N-[2-Bromomethyl(phenyl)]trifluoroacetamides","volume":"73","author":"Wang","year":"2008","journal-title":"J. Org. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1002\/ejoc.201403261","article-title":"A Metal-Catalyzed Tandem 1,4-Benzodiazepine Synthesis Based on Two Hydrogen-Transfer Reactions","volume":"2015","author":"Jumde","year":"2015","journal-title":"Eur. J. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1016\/j.tet.2016.02.019","article-title":"A New Approach to Monoprotected 1,4-Benzodiazepines via a One-pot N-Deprotection\/Reductive Cyclization Procedure","volume":"72","author":"Popp","year":"2016","journal-title":"Tetrahedron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1016\/j.bmcl.2006.12.001","article-title":"Amino Acid-based Enantiomerically Pure 3-substituted 1,4-Benzodiazepin-2-ones: A New Class of Anti-ischemic Agents","volume":"17","author":"Mishra","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.1016\/S0040-4020(01)80106-X","article-title":"Syntheses of 3b,4,6,7-Tetrahydro-5h,9h-pyrazino [2,1-c] phyrolo [1,2-a] [1,4] benzodiazepine, A Valuable Precursor of Potential Central Nervous System Agents","volume":"45","author":"Massa","year":"1989","journal-title":"Tetrahedron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8493","DOI":"10.1016\/j.tetlet.2003.09.108","article-title":"Solid Phase Synthesis of Tetrahydro-1,4-benzodiazepin-2-ones","volume":"44","author":"Hone","year":"2003","journal-title":"Tetrahedron Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.bmcl.2003.11.052","article-title":"Benzodiazepine-based Selective Inhibitors of Mitochondrial F1F0 ATP Hydrolase","volume":"14","author":"Hamann","year":"2004","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/j.tetasy.2007.05.015","article-title":"A One-Step Synthesis of Enantiopure 2-Substituted 4,5-Dihydro-1,4-benzodiazepine-3-ones via Intramolecular Azide Cycloaddition","volume":"18","author":"Molteni","year":"2007","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1039\/C4QO00179F","article-title":"Synthesis of 1,4-Benzodiazepinones and 1,4-Benzoxazepinones via Palladium-Catalyzed Amino and Oxyacetoxylation","volume":"1","author":"Manick","year":"2014","journal-title":"Org. Chem. Front."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1002\/adsc.202000047","article-title":"Nicke-Catalyzed Decarboxylative Cyclization of Isatoic Anhydrides with Carbodiimides: Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones","volume":"362","author":"Zhang","year":"2020","journal-title":"Adv. Synth. Catal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1021\/ol200429a","article-title":"Synthesis of Saturated 1,4-Benzodiazepines via Pd-Catalyzed Carboamination Reactions","volume":"13","author":"Neukom","year":"2011","journal-title":"Org. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5627","DOI":"10.1021\/jo0495135","article-title":"Regioselective Formation of Six- and Seven-Membered Ring by Intramolecular Pd-Catalyzed Amination of N-Allyl-anthranilamides","volume":"69","author":"Beccalli","year":"2004","journal-title":"J. Org. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8273","DOI":"10.1016\/S0040-4039(02)02019-1","article-title":"A Novel and Efficient Iodine(III)-Mediated Access to 1,4-Benzodiazepin-2-ones","volume":"43","author":"Herrero","year":"2002","journal-title":"Tetrahedron Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1021\/jo402413g","article-title":"Construction of 1,4-Benzodiazepine Skeleton From 2-(Arylamino)benzamides Through PhI(OAc)2-Mediated Oxidative C-N Bond Formation","volume":"79","author":"Li","year":"2014","journal-title":"J. Org. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1002\/ajoc.201500224","article-title":"Syntheses of Tetrahydrobenzodiazepines via SN2-Type Ring-Opening of Activated Aziridines with 2-Bromobenzylamine Followed by Copper-Powder-Mediated C-N Bond Formation","volume":"4","author":"Ghorai","year":"2015","journal-title":"Asian J. Org. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6077","DOI":"10.1021\/jo9011656","article-title":"Highly Efficient and Enantioselective Biotransformations of Racemic Azetidine-2-carbonitriles and Their Synthetic Applications","volume":"74","author":"Leng","year":"2009","journal-title":"J. Org. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0957-4166(02)00076-9","article-title":"A Straightforward Synthesis of Enantiopure 2-Cyano Azetidines from \u03b2-Amino Alcohols","volume":"13","author":"Agami","year":"2002","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3653","DOI":"10.1016\/S0040-4020(01)85996-2","article-title":"Synthesis of Azetidines From \u03b2-Chloro Imines","volume":"44","author":"Sulmon","year":"1988","journal-title":"Tetrahedron"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4162","DOI":"10.1021\/jm070105d","article-title":"Design, Synthesis, and Biological Activity of 5,10-Dihydro-dibenzo[b,e][1,4]diazepin-11-one-Based Potent and Selective Chk-1 Inhibitors","volume":"50","author":"Wang","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1016\/j.bmcl.2008.02.080","article-title":"Investigation of Novel 7,8-Disubstituted-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones as Potent Chk1 Inhibitors","volume":"18","author":"Hasvold","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1021\/jo062221e","article-title":"Strained Azetidinium Ylides: New Reagents for Cyclopropanation","volume":"72","author":"Couty","year":"2007","journal-title":"J. Org. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1021\/jo01266a010","article-title":"Ring-opening Alkylations of 1,1-Dialkyl-3-substituted Azetidinium Cations. Substituent Entropy-controlled Strained Ring-chain Equilibria","volume":"33","author":"Gaertner","year":"1968","journal-title":"J. Org. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5861","DOI":"10.1021\/ol052388e","article-title":"3-Aminopyrrolidines via Ring Rearrangement of 2-Aminomethylazetidines. Synthesis of (\u2212)-Absouline","volume":"7","author":"Couty","year":"2005","journal-title":"Org. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5441","DOI":"10.1021\/ol7023218","article-title":"Lewis Acid-Mediated Unprecedented Ring-Opening Rearrangement of 2-Aryl-N-Tosylazetidines to Enantiopure (E)-Allylamines","volume":"9","author":"Ghorai","year":"2007","journal-title":"Org. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1021\/acs.joc.4c02955","article-title":"Photocatalytic Three-Component Reductive Coupling Synthesis of gem-Difluorohomoallyl Secondary Amines","volume":"90","author":"Feng","year":"2025","journal-title":"J. Org. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5501","DOI":"10.1021\/ol062128c","article-title":"Reaction of Azetidines with Chloroformates","volume":"8","author":"Lakhdar","year":"2006","journal-title":"Org. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.tetlet.2006.11.033","article-title":"Preparation of Enantiopure 2-Acylazetidines and Their Reactions with Chloroformates","volume":"48","author":"Ma","year":"2007","journal-title":"Tetrahedron Lett."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/9\/2014\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:25:29Z","timestamp":1760030729000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/9\/2014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,30]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["molecules30092014"],"URL":"https:\/\/doi.org\/10.3390\/molecules30092014","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2025,4,30]]}}}