Synthesis of Substituted 1,4-Dioxenes through O–H Insertion and Cyclization Using Keto-Diazo Compounds

Abstract

1,4-Dioxenes present interesting potential as synthetic intermediates, and as unusual motifs for incorporation into biologically active compounds. Here, an efficient synthesis of functionalized 1,4-dioxenes is achieved in two steps. Using keto-diazo compounds, a ruthenium catalyzed O-H insertion with b-halohydrins followed by treatment with base results in cyclization with excellent selectivity, through O-alkylation of the keto-enolate. A variety of halohydrins and anionstabilizing groups in the diazo-component are tolerated, affording novel functionalized dioxenes.Enantioenriched b-bromohydrins provide enantioenriched 1,4-dioxenes.

Regioselective and Enantiospecific Synthesis of Dioxepines by (Cyclopentadienyl)ruthenium‐Catalyzed Condensations of Diazocarbonyls and Oxetanes

“…Finally, Bull and co‐workers have described recently the formation of 1,4‐dioxenes in two steps using β‐halogeno alcohols as substrates . In a first step, CpRu‐catalyzed O–H insertions of α‐diazo‐β‐keto esters occur, followed by intramolecular cyclizations under basic conditions.…”

“…Alsoo fm echanistic importance,a cid-sensitive furan 5c could be isolated from the reactiono fo xetane 2c with 3B (Scheme 3). [22] In af irst step, CpRu-catalyzed O-H insertions of a-diazo-b-keto esterso ccur, followed by intramolecular cyclizations under basic conditions.U sing this protocol, only O-alkylations of ketoenolatei ntermediates are observed leading to al arge variety of dioxenes.I nv iewo ft he efficiency of the method, care was takent oa pply it for the synthesis of 1,4-dioxepines.R eactions under CpRu catalysis of alcohols 6c and 6h with 3B afforded halogenated keto esters 7c and 7h in good yields,9 0% and 79% respectively (Scheme4). [20] Thef ormation of 5c can be explained by as econd route starting from intermediates C or D (Scheme 3).…”

Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation

“…The synthetic utility of diazo compounds for the formation of a variety of unique and challenging chemical bonds is well appreciated . Of these transformations, metal-catalyzed reactions utilizing diazoacetates have been widely applied in the synthetic community to construct challenging C–C and C-heteroatom bonds via X–H (X = C, N, O, S, P, Si) insertion, cyclopropanation, cycloaddition, etc. However, one challenge that remains in the wider application of this chemistry for drug development is the danger associated with synthesis and use of these highly reactive diazo intermediates at scale .…”

Preparation and Structural Characterization of [CpRu(1,10‐phenanthroline)(CH3CN)][X] and Precursor Complexes (X=PF6, BArF, TRISPHAT‐N)

“…[37][38][39] Of interest in our laboratory, the [CpRu] fragment is also an attractive alternative to transition metal salts and complexes for the decomposition of diazo derivatives providing metal carbene or carbenoid intermediates upon dinitrogen extrusion. [40][41][42][43][44][45] In fact, in the presence of combinations of [CpRu(CH 3 CN) 3 ][PF 6 ] (as pre-catalysts) and diimine ligands (Phen = 1,10-phenanthroline, in particular), [8,46,47] α-diazo-β-ketoesters react smoothly and provide selective 1,3-CÀ H insertions into THF [48] and OÀ H insertions into alcohols. [49] This catalytic system also promotes condensation reactions with nitriles, ketones, aldehydes and more recently with lactones and cyclic carbonates to generate the corresponding heterocycles (Scheme 1).…”