{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T11:56:42Z","timestamp":1792151802862,"version":"4.4.0"},"reference-count":58,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T00:00:00Z","timestamp":1712793600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM125926"],"award-info":[{"award-number":["R01GM125926"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002429","name":"Amgen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002429","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Adv Synth Catal"],"published-print":{"date-parts":[[2024,5,21]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Azetidines are valuable nitrogenous heterocycles. Herein, we disclose a strategy for the modular assembly of 3\u2010azetidines and related spirocyclic congeners featuring all\u2010carbon quaternary centers. This approach leverages titanacyclobutanes generated from ketones or alkenes. Halogenation of these organotitanium species gives rise to functionalized alkyl dihalides that can be subsequently captured by amines to afford azetidine building blocks. This strategy facilitated the synthesis of a small molecule anti\u2010tuberculosis drug. It also enabled access to carbon\u201013 isotopologs of diazaspiro[3.3]heptane fragments that are challenging to prepare by any other means.<\/jats:p>","DOI":"10.1002\/adsc.202301527","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T23:34:25Z","timestamp":1710891265000},"page":"2214-2219","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Access to 3\u2010Azetidines via Halogenation of Titanacyclobutanes"],"prefix":"10.1002","volume":"366","author":[{"given":"Tyler D.","family":"Weinhold","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry Florida State University  95 Chieftan Way Tallahassee FL 32306 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Law","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Florida State University  95 Chieftan Way Tallahassee FL 32306 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2077-4436","authenticated-orcid":false,"given":"James H.","family":"Frederich","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Florida State University  95 Chieftan Way Tallahassee FL 32306 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,11]]},"reference":[{"key":"e_1_2_2_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14007"},{"key":"e_1_2_2_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.0c01115"},{"key":"e_1_2_2_4_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9NP00039A"},{"key":"e_1_2_2_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c00829"},{"key":"e_1_2_2_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200907108"},{"key":"e_1_2_2_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.0c01414"},{"key":"e_1_2_2_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01473"},{"key":"e_1_2_2_9_1","unstructured":"Spirochem home page.https:\/\/spirochem.com(accessed November 10 2023)."},{"key":"e_1_2_2_10_1","unstructured":"A search of the patent literature returned over 700 results for the use of 2 6-diazaspiro[3.3]heptanes in drug discovery programs since 2019: patents.google.com."},{"key":"e_1_2_2_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.9b00248"},{"key":"e_1_2_2_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol801293f"},{"key":"e_1_2_2_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00576"},{"key":"e_1_2_2_14_1","unstructured":"For leading reviews see:"},{"key":"e_1_2_2_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm901241e"},{"key":"e_1_2_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2022.05.021"},{"key":"e_1_2_2_17_1","unstructured":"For comprehensive reviews see:"},{"key":"e_1_2_2_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr500127b"},{"key":"e_1_2_2_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.202100857"},{"key":"e_1_2_2_20_1","unstructured":"For select recent examples see:"},{"key":"e_1_2_2_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c12649"},{"key":"e_1_2_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202102754"},{"key":"e_1_2_2_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c01173"},{"key":"e_1_2_2_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202101445"},{"key":"e_1_2_2_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.9b00321"},{"key":"e_1_2_2_26_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b01513"},{"key":"e_1_2_2_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c06710"},{"key":"e_1_2_2_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557-020-0541-1"},{"key":"e_1_2_2_29_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1378722"},{"key":"e_1_2_2_30_1","unstructured":"\u00a0"},{"key":"e_1_2_2_31_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00479a061"},{"key":"e_1_2_2_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00511a053"},{"key":"e_1_2_2_33_1","unstructured":"\u00a0"},{"key":"e_1_2_2_34_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00542a050"},{"key":"e_1_2_2_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00390a017"},{"key":"e_1_2_2_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202103278"},{"key":"e_1_2_2_37_1","unstructured":"The estimated cost to prepare Tebbe's reagent (3) is ~$1.3\/mmol starting from Cp2TiCl2and AlMe3. We recommend preparing3before use as commercial sources are more expensive and gave irreproducible results. Details regarding the preparation and titration of3used in this study are outlined in reference 21."},{"key":"e_1_2_2_38_1","unstructured":"There are two examples of this transformation in the literature. Notably reference 23b is a review and does not contain experimental procedures or NMR data:"},{"key":"e_1_2_2_39_2","unstructured":"reference 21;"},{"key":"e_1_2_2_40_2","doi-asserted-by":"publisher","DOI":"10.1351\/pac198355111733"},{"key":"e_1_2_2_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(98)00681-4"},{"key":"e_1_2_2_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(00)01055-3"},{"key":"e_1_2_2_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00317a084"},{"key":"e_1_2_2_44_1","unstructured":"N-Boc-3-azetidinone (6) can be purchased from Biosynth [FB18887] for $0.9\/gram."},{"key":"e_1_2_2_45_1","unstructured":"Protonolysis of4\u2009aprepared from6under these conditions affordedgem-dimethyl product9in 93% isolated yield (>95% conversion)."},{"key":"e_1_2_2_46_1","unstructured":"See the Supporting Information for details."},{"key":"e_1_2_2_47_1","unstructured":"Whereas9results from unproductive halogenation of4\u2009a side product10arises from protonolysis of intermediate7. We suspect that the nature of ligand Y on the Ti(IV) center of7augments in the nucleophilicity of the pendant Ti\u2212C \u03c3-bond. This might explain the variation in product ratios observed across the halogen equivalents surveyed in Table\u2005."},{"key":"e_1_2_2_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c05748"},{"key":"e_1_2_2_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00292a056"},{"key":"e_1_2_2_50_1","unstructured":"Spirocycle14could be stored for several weeks at 23\u2009\u00b0C; however long-term storage required converting14to the corresponding oxalate salt as described by Carreira and co-workers in reference 11."},{"key":"e_1_2_2_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c00754"},{"key":"e_1_2_2_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/om00072a020"},{"key":"e_1_2_2_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.7b00174"},{"key":"e_1_2_2_54_1","unstructured":"As noted in reference 21 2\u2005equiv. of3are required to convert \u03b1-methyl styrene derivatives to titanacyclobutanes."},{"key":"e_1_2_2_55_1","unstructured":"Bromination of titanacyclobutanes derived from unsubstituted styrene derivatives afforded the expected dihalides; however cyclization to the desired azetidines was not possible. As exemplified in equation\u20051 below allyl amines were formed as the main product. See the Supporting Information for details."},{"key":"e_1_2_2_56_1","doi-asserted-by":"crossref","unstructured":"P. De\u2005Francisco\u2005Esther R.\u2005M. Jes\u00fas B. Marilyne D. Benoit D. Geoffroy W. Nicolas. Novel Compounds. WO2019034702\u2005A1 February 02 2021.","DOI":"10.26754\/uz_comedic\/comedic_CMDC9"},{"key":"e_1_2_2_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlcr.2914"},{"key":"e_1_2_2_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacsau.2c00030"},{"key":"e_1_2_2_59_1","unstructured":"Bromine (99.8%) was purchased from Thermo Scientific (catalog number 000905.30) and used as received."}],"container-title":["Advanced Synthesis &amp; Catalysis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adsc.202301527","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T19:44:20Z","timestamp":1759779860000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/adsc.202301527"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,11]]},"references-count":58,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,5,21]]}},"alternative-id":["10.1002\/adsc.202301527"],"URL":"https:\/\/doi.org\/10.1002\/adsc.202301527","archive":["Portico"],"relation":{},"ISSN":["1615-4150","1615-4169"],"issn-type":[{"value":"1615-4150","type":"print"},{"value":"1615-4169","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,11]]},"assertion":[{"value":"2023-12-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}