Combining Sanford Arylations on Benzodiazepines with the Nuisance Effect

Abstract

Abstract5‐Phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐ones react under palladium‐ and visible light photoredox catalysis, in refluxing methanol, with aryldiazonium salts to afford the respective 5‐(2‐arylphenyl) analogues. With 2‐ or 4‐fluorobenzenediazonium derivatives, both fluoroaryl‐ and methoxyaryl‐ products were obtained, the latter resulting from a SNAr on the fluorobenzenediazonium salt (“nuisance effect”). A computational DFT analysis of the palladium‐catalysed and the palladium/ruthenium‐photocalysed mechanism for the functionalization of benzodiazepines indicated that, in the presence of the photocatalyst, the reaction proceeds via a low‐energy SET pathway avoiding the high‐energy oxidative addition step in the palladium‐only catalysed reaction pathway.

Visible Light Promoted, Catalyst‐Free Radical Carbohydroxylation and Carboetherification under Mild Biomimetic Conditions

“…[15c] Regarding the resultsf rom furtherr eactions combining irradiationa nd the presence of potassium acetate, it turned out that upon variation of the diazonium salt (Scheme 4, upper part), most yields were slightly improved relative to the basefree conditions (Scheme 3), with the only exceptiono ft he 4fluoro derivative 5b.T his deviation can however be rationalized by the low stability of the 4-fluorophenyl diazonium ion under less acidic conditions, as it may undergo substitution at the 4-position. [24] The variations of the styrene (Scheme 4, lower part) not only show an enlarged scope, but also support the reactionm echanism depicted in Scheme2.W hile the 4-methoxy substitution on the styrene increases the yield (5k:8 4%), the corresponding 4-nitro derivatived oes not give any product 5l due to the strongly destabilizing effect of the nitro group on the related cation 6 (Scheme 2). In line with that, unsubstituted styrene leads to al ow yield (5n:1 5%)d ue to the lack of the methyl group,w hich can to some extentb ec ounterbalanced by a4methoxys ubstituent (5o:4 6%)t hat again stabilizes the cation 6.S uch significant deviations were not likely to occur if the mechanism proceeded via some coupling of radical 4 (c.f.…”

“…Regarding the results from further reactions combining irradiation and the presence of potassium acetate, it turned out that upon variation of the diazonium salt (Scheme 4, upper part), most yields were slightly improved relative to the base‐free conditions (Scheme 3), with the only exception of the 4‐fluoro derivative 5 b . This deviation can however be rationalized by the low stability of the 4‐fluorophenyl diazonium ion under less acidic conditions, as it may undergo substitution at the 4‐position [24] …”

“…Scheme 4). [24] The successful variation of the alcohols included increased chain length and cyclic moieties ( 8 e – i , l ), allyl and benzyl alcohol ( 8 j and 8 k ) as well protected and unprotected diols ( 8 m and 8 n ), and gave yields in the range of 46 to 69 %. Allylic and benzylic positions, which are often troublesome in radical arylations, [29] are thus well tolerated in the present functionalization.…”

2‐Fluoro‐5‐nitrophenyldiazonium: A Novel Sanger‐Type Reagent for the Versatile Functionalization of Alcohols

“…While the increased reactivity of 3 compared to 1 and 2 could enable substitutions with even weakly nucleophilic reagents like aliphatic alcohols under mild conditions, such substitution on the aromatic core of 3 would have to proceed under acidic or at most neutral conditions due to the reactivity of the diazonium unit [3] . Generally, nucleophilic aromatic substitutions on diazonium salts are yet rare in literature with few synthetic applications, [4] whereas drawbacks arise from the necessity to use the nucleophile as solvent (Scheme 1 B) [4a] or the requirement to protect the diazonium unit as a triazene (Scheme 1 C). [4b] On the other hand, the presence of a diazonium group on an aryl‐alkyl ether such as 4 would enable a broad range of further functionalizations, [5, 6] which cannot be achieved with the traditional dinitro substitution pattern.…”

Deliberately Losing Control of C−H Activation Processes in the Design of Small‐Molecule‐Fragment Arrays Targeting Peroxisomal Metabolism

“…Recent, complementary, studies on the visible light mediated "Sanford" arylation [16][17][18] of benzodiazepines using diazonium salts and dual Ru/Pd catalysis led mainly to mono-functionalised product. [19] However, in the case of 2-or 4-substituted fluorobenzene diazonium salt coupling partners, further competing S N Ar reactions were observed ("nuisance effect"), when a nucleophilic solvent such as methanol or ethanol was used.…”