Chemoselective Addition of Halomethyllithiums to Functionalized Isatins:A Straightforward Access to Spiro‐Epoxyoxindoles

Abstract

An efficient, chemoselective approach to spiro-epoxyoxindoles via the addition of chloromethyllithium followed by ring-closure of the intermediate alkoxide is reported. Chemoselectivity is fully preserved in the presence of different electrophilic sites.T he synthetic potentialo fs elected spiro-epoxyindoles has been exploited in the copper(I)-catalyzed intramolecular oxyarylation of an alkyne andinthe formation of N,N-dimethylisoindigo via the addition of dihalocarbenoids.

Lithium Halomethylcarbenoids: Preparation and Use in the Homologation of Carbon Electrophiles

“…However, this lithium base, as shown in more recent studies, is the reagent of choice for performing deprotonations rather than exchange reactions31 and, thus, MeLi and n ‐BuLi have emerged as the optimal lithium sources 25b. In recent years, the commercially available MeLi–LiBr complex in Et 2 O has become an excellent reagent for generating chloromethyllithium 3a starting from chloroiodomethane 12 (Scheme ) 32…”

A practical guide for using lithium halocarbenoids in homologation reactions

“…In recent years, our group launched a research program [23] focused on the use of carbenoid-type reagents for the homologation of different carbon (Weinreb amides [24–32], ketones [33, 34], isocyanates [35–38]) or heteroatom electrophiles [39] for preparing in a single step α-halo or rearranged (thereof) derivatives [40]. We observed a paramount importance of the conditions employed for generating the carbenoid and, herein, we disclose full details on how to prepare and use these highly reactive species under Barbier type conditions [41, 42].…”

A Straightforward Homologation of Carbon Dioxide with Magnesium Carbenoids en Route to α‐Halocarboxylic Acids

“…[11] Although under significant chemocontrol, the diazotization (i. e. Sandmeyer chemistry) requires the use of the highly toxic nitrous acid salts, thus posing important hazard limitations (Scheme 1b). [12] In line with research currently undergoing in our group on the employment of a-functionalized organometallic reagents, [13] we conceived a conceptually simple homologative approach based on the addition to carbon dioxide (CO 2 , electrophile) of a nucleophilic halomethyl metal derivative (MCHRX, [14] Scheme 1c). Both these reactive elements present unique and advantageous features in terms of efficiency: 1) Carbon dioxide is a non-toxic, renewable C1 building block abundant in the atmosphere, constituting nowadays a precious synthon for organic transformations; [15] 2) The good nucleophilic behaviour of MCHRX reagents allows to overcome the (catalytic) activation of the electrophile, [15c,16] as also suggested by the heterocumulene nature of this electrophile; [17] 3) Paved on our own previous studies, MCHRX reagents enable the formal insertion of CHRX fragments presenting the exact degree of functionalization thus, circumventing de facto selectivity issues (polyhalogenation).…”

“…de 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Importantly, during the reaction with CO 2 , inversion of configuration at the carbon atom was noticed in analogy with previous reports by Hoffmann dealing with alkylation of analogous reagents. The acids (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) were obtained together with cyclohexyl phenyl sulfoxide 2 d, which could be separated through a trivial acid-basic work-up. Readily accessible benzyl-type sulfoxides served as excellent placeholders for the corresponding Mg carbenoids by simple treatment with CyMgCl for the appropriate metallation time (see SI) prior to CO 2 bubbling.…”

“…The acids (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) were obtained together with cyclohexyl phenyl sulfoxide 2 d, which could be separated through a trivial acid-basic work-up. [27] Furthermore: 1) substitution across the cyclopropyl ring was perfectly tolerated; 2) the concomitant presence of a reactive ester (13) and an acid (14) were fully compatible with the reaction conditions. The steric hindrance on aromatic sulfoxides did not constitute a limitation (e. g. 2-phenyl, 2,6-dimethyl derivatives 5, 6), thus delivering the desired achloroacids in excellent yields.…”