The implementation of cyanation chemistry at manufacturing scales using batch equipment can be challenging because of the hazardous nature of the reagents employed and the tight control of reaction parameters, including cryogenic temperatures, that help to afford acceptable selectivity and conversion for the desired reaction. Application of continuous flow chemistry offers a means to mitigate the risk associated with handling large amounts of hazardous reagents and to better control the reaction parameters. A case study describing the cyanation of a glycoside using continuous flow chemistry toward the synthesis of the drug candidate remdesivir is presented.
The palladium-catalyzed selective β-carboelimination and cross-coupling chemistry of benzocyclobutenols is described. In contrast to the base-mediated ring-opening reactions of benzocyclobutenols, this variant proceeds with exclusive cleavage of the proximal bond.
A palladium-catalyzed tandem semipinacol rearrangement/direct arylation reaction using α-aryl isopropenyl-tert-cyclobutanols has been developed. This reaction gives access to benzodiquinanes in moderate to good yields and tolerates alkyl-, alkoxy-, and halogen-substituted aryl groups.
This
manuscript describes the development and implementation of
a scalable additive system, consisting of a lanthanide salt and a
solubilizing quaternary ammonium salt, to improve the yield and robustness
of the addition of an organomagnesium reagent to a ribonolactone en
route to remdesivir. This system was found to be generally applicable
in enhancing other challenging organomagnesium additions to enolizable
and hindered carbonyl-containing compounds.
A series of 9-substituted fluorenols and 9,9'-disubstituted-9,9'-bifluorenyls were irradiated to give products derived from fluorenyl radicals. Product distribution was solvent dependent. A TEMPO adduct was isolated from the photoexcitation of 9-fluorenol. An unusual unsymmetrical 3,9'-bifluorenyl was observed from the photolysis of 9-trifluoromethylfluorenol and 9,9'-di(trifluoromethyl)-9,9'-bifluorenyl in more polar or hydrogen-bonding solvents. The electronic nature of 9-substituted fluorenyl radicals was probed using theoretical calculations showing the dipolar character of species with electron-deficient groups. These constitute the first examples of "doubly destabilized" radicals.
The 9-fluorenyl cation is a member of the 4N Hückel antiaromatic series of intermediates, first observed by time-resolved spectroscopy on UV photo-excitation of 9-fluorenol.[1] 9-Trifluoromethyl-9-fluorenol incorporating an electron-withdrawing substituent was subjected to preparative and laser flash photolysis. Photoproduct studies in methanol indicated products derived from the corresponding fluorenyl cation and radical intermediates. Time-resolved spectroscopy in hexafluoroisopropanol (HFIP) showed a transient which was assigned to the corresponding cation as evident from methanol quenching. The lifetimes and methanol quenching rates of this transient was compared with that of 9-methylfluorenyl cation. The kinetic stabilities of these ions were compared to thermodynamic parameters obtained from theoretical calculations.
Allyl benzocyclobutyl carbonates yield ortho-allyl α-aryl ketones through a palladium-catalyzed decarboxylative allylation, fragmentation, and cross-coupling process.Due to their inherent reactivity, highly strained carbocyclic systems provide unusual opportunities for synthesis. Transition-metal catalysts are capable of modulating the reactivity of such systems, thereby furnishing useful products with a good degree of selectivity and in good yields. We have been interested in developing reactions in which the palladium-catalyzed β-carboelimination 1 of tertiary alcohols is a key design element. 2 Recently we reported the selective and high-yielding cross-coupling reaction of benzocyclobutenols with aryl bromides 3 (Scheme 1, equation 1). Here we extend this chemistry to the use of allyl benzocyclobutenyl carbonates, and show that these substrates undergo a decarboxylative allylation and fragmentation reaction to yield ortho-allyl α-arylated ketones (Scheme 1, equation 2).
Scheme 1We envisioned that allyl benzocyclobutenyl carbonates would participate in a tandem reaction combining the palladium-catalyzed decarboxylative allylation chemistry of allyl carbonate 4 functions with the selective, palladiumcatalyzed cleavage 5 of benzocyclobutenols. 6 Such a process would result in the preparation of ortho-functionalized aryl rings bearing allyl and ketone groups. 7 A plausible catalytic cycle for this transformation would involve palladium-catalyzed ionization of the allyl benzocyclobutenyl carbonate, followed by decarboxylation to generate an ion pair consisting of a cationic allylpalladium intermediate and an alkoxide anion (I to II, Scheme 2). Coordination of palladium to the alkoxide oxygen (II to III), selective β-carboelimination (III to IV), and reductive elimination (IV to V) would furnish the allylated product.Scheme 2 Plausible catalytic cycle for the proposed tandem decarboxylative allylation and fragmentation reaction Benzocyclobutenols 8 have featured in complex molecule synthesis 9 and a number of synthetic methods. Their generation via nucleophilic addition to the corresponding benzocyclobutenone is a common preparative method, however the preparation of the benzocyclobutenone 10 moiety itself suffers from lengthy reaction sequences that often require the use of ortho-difunctionalized aryl substrates. 11 With the aim of developing a streamlined synthetic method, we decided to prepare substrates for the proposed reaction from the corresponding bromobenzenes. Durst has shown that treatment of bromo-and iodobenzenes with a strong, non-nucleophilic base in the presence of a ketone results in the formation of benzocyclobutenols. 12,13 Addition of the ketone enolate to the benzyne generated in situ results in the formation of an aryl anion that undergoes a subsequent 1,2-addition to the ke-O H OH Br R 1 R 2 R 2 Pd 2 dba 3 DavePhos Ag 2 CO 3 toluene, 65 °C + R 1 (1) H O O O O ( ) n ( ) n ( ) n ( ) n (2) this work H O O O ( ) n O ( ) n H O ( ) n H O PdLn O ( ) n ( ) n LnPd LnPd(0) PdLn CO 2
Tandem Decarboxylative Allylation and Fragmentation of Allyl Benzocyclobutenyl Carbonates: Access to ortho-Functionalized Aryls from Aryl Bromides. -Benzocyclobutenols (IV) and (VI) undergo Pd-catalyzed decarboxylative allylation and selective β-elimination leading to ortho-substituted arenes (V) and (VII), generally in good yields. -(ROSA, D.; CHTCHEMELININE, A.; ORELLANA*, A.; Synthesis 2012, 12, 1885-1891, http://dx.doi.org/10.1055/s-0031-1290943 ; Dep. Chem., York Univ., North York, Toronto, Ont. M3J 1P3, Can.; Eng.) -Mais 40-110
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