Dehydrodechlorination of Methylene Chloride, Chloroform, and Chlorodiphenylmethane in the Presence of Ga/N Lewis Pairs

Transmetalation occurs upon addition of GaCl₃ to (quinolin-8-yl)­trimethyl­stannane. The compound dissolves immediately in pyridine, and recrystallization gives dichloro­pyridinyl­(quinolin-8-yl)­gallium­(III). In chloroform, the compound bis-μ-(quinolin-8-yl)-μ-chloro-dichloro­digallium­(III) tetra­chloro­gallate could be isolated in small quantities; however, the major product was trichloro­(quinolinium-8-yl)­gallate­(III) zwitterion. The zwitterion also formed upon addition of methylene chloride or chloro­diphenyl­methane. We hypothesize that the highly electrophilic digallyl cation abstracts chloride to form a carbocation and that proton transfer from the carbocation to the quinoline nitrogen affords transient carbenes. In particular, diphenyl carbene forms from dehydro­dechlorination of chloro­diphenyl­methane in toluene/​cyclohexene to give a well-defined mixture of products due to cyclopropanation and C–H insertion reactions. Dichloro­pyridinyl­(quinolin-8-yl)­gallium­(III) undergoes reaction with chloroform only at elevated temperature to yield quinolinium tetra­chloro­gallate salt as the product. This salt also forms in the reaction of chloroform with GaCl₃ and quinoline at elevated temperature. The zwitterion could be converted to quinolinium tetra­chloro­gallate upon heating, which supports the idea that it was formed initially as an intermediate. Thus, the Ga/N Lewis pairs appear capable of dehydro­dechlorination of chloroalkanes

Dehydrodechlorination of Methylene Chloride, Chloroform, and Chlorodiphenylmethane in the Presence of Ga/N Lewis Pairs

Transmetalation occurs upon addition of GaCl₃ to (quinolin-8-yl)­trimethyl­stannane. The compound dissolves immediately in pyridine, and recrystallization gives dichloro­pyridinyl­(quinolin-8-yl)­gallium­(III). In chloroform, the compound bis-μ-(quinolin-8-yl)-μ-chloro-dichloro­digallium­(III) tetra­chloro­gallate could be isolated in small quantities; however, the major product was trichloro­(quinolinium-8-yl)­gallate­(III) zwitterion. The zwitterion also formed upon addition of methylene chloride or chloro­diphenyl­methane. We hypothesize that the highly electrophilic digallyl cation abstracts chloride to form a carbocation and that proton transfer from the carbocation to the quinoline nitrogen affords transient carbenes. In particular, diphenyl carbene forms from dehydro­dechlorination of chloro­diphenyl­methane in toluene/​cyclohexene to give a well-defined mixture of products due to cyclopropanation and C–H insertion reactions. Dichloro­pyridinyl­(quinolin-8-yl)­gallium­(III) undergoes reaction with chloroform only at elevated temperature to yield quinolinium tetra­chloro­gallate salt as the product. This salt also forms in the reaction of chloroform with GaCl₃ and quinoline at elevated temperature. The zwitterion could be converted to quinolinium tetra­chloro­gallate upon heating, which supports the idea that it was formed initially as an intermediate. Thus, the Ga/N Lewis pairs appear capable of dehydro­dechlorination of chloroalkanes

Correction to “Diverting Reactive Intermediates Toward Unusual Chemistry: Unexpected Anthranil Products from Davis–Beirut Reaction”

Correction to “Diverting Reactive Intermediates Toward Unusual Chemistry: Unexpected Anthranil Products from Davis–Beirut Reaction

Diverting Reactive Intermediates Toward Unusual Chemistry: Unexpected Anthranil Products from Davis–Beirut Reaction

The discovery of a new variation on the Davis–Beirut reaction is described in which an atypical heterocyclic framework (the anthranil or benzo­[<i>c</i>]­isoxazole framework) is formed as the result of diversion of a key reactive intermediate away from its expected reactivitya potentially general approach to reaction design and development. Experimental and computational support for the proposed mechanism and origins of altered reactivity are described

Davis–Beirut Reaction: Alkoxide versus Hydroxide Addition to the Key <i>o</i>‑Nitrosoimine Intermediate

Reaction options, alkoxide vs hydroxide vs amine addition to the key intermediate (<i>o</i>-nitrosoimine) generated in the Davis–Beirut reaction of an <i>o</i>-nitrobenzylamine substrate, are reported to explain the nucleophilic addition selectivity of this one-pot indazole-forming process. The hydroxide addition/deprotection pathway as well as the fate of the resulting <i>o</i>-nitrosobenzaldehyde were both uncovered with several <i>o</i>-nitrobenzylamine substrates, and design elements required for an efficient double Davis–Beirut reaction, inspired by new mechanistic insights, were defined

N–N Bond Formation between Primary Amines and Nitrosos: Direct Synthesis of 2‑Substituted Indazolones with Mechanistic Insights

A concise, one-step route to indazolones from primary alkyl amines and <i>o</i>-nitrobenzyl alcohols is reported. The key step in this readily scalable indazolone forming process involves base-mediated <i>in situ o</i>-nitrobenzyl alcohol → <i>o</i>-nitrosobenzaldehyde conversion. Although this functional group interconversion is known to be useful for 2<i>H</i>-indazole synthesis, its reactivity was modulated for indazolone formation

High-Potency Phenylquinoxalinone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activators

We previously identified phenylquinoxalinone CFTR_act-J027 (<b>4</b>) as a cystic fibrosis transmembrane conductance regulator (CFTR) activator with an EC₅₀ of ∼200 nM and demonstrated its therapeutic efficacy in mouse models of constipation. Here, structure–activity studies were done on 36 synthesized phenylquinoxalinone analogs to identify compounds with improved potency and altered metabolic stability. Synthesis of the phenylquinoxalinone core was generally accomplished by condensation of 1,2-phenylenediamines with substituted phenyloxoacetates. Structure–activity studies established, among other features, the privileged nature of a properly positioned nitro moiety on the 3-aryl group. Synthesized analogs showed improved CFTR activation potency compared to <b>4</b> with EC₅₀ down to 21 nM and with greater metabolic stability. CFTR activators have potential therapeutic indications in constipation, dry eye, cholestatic liver diseases, and inflammatory lung disorders