Aldehyde to Ketone Homologation Enabled by Improved Access to Thioalkyl Phosphonium Salts

Abstract

Phosphines were previously unusable as Pummerer-type nucleophiles due to competing redox chemistry with sulfoxides. Here we circumvent this problem to achieve a formal phosphine Pummerer reaction that offers thioalkyl phosphonium salts that, in turn, give rise to diverse vinyl sulfides via Wittig olefinations. Thirty vinyl sulfides are thus prepared from (alkylthioalkyl)triphenyl phosphonium salts and aldehydes. The hydrolysis of these vinyl sulfides offers an efficient and versatile twostep one-carbon homologation of aldehydes to ketones.

Use of Vinyl Sulfides in Fischer Indole Reactions

“…2-Methyl-7-azaindole (4) (41), (42) TsOH‧H2O (173 mg, 0.91 mmol) was added to a solution of aminopyridyl vinyl sulfide 3 (88 mg, 0.45 mmol) (8) 3-Nitrophenylacetone (5ah) (43) Ketone 5ah, the hydrolysis product of vinyl sulfide 5a, was observed in NMR spectra of crude reactions during the optimization of the Fischer indole reaction in Table 1.…”

“…General Procedure B, 1-(4-methyl-3-nitrophenyl)-2-ethylthio-propene 5d (119 mg, 0.501 mmol, E/Z 62:38), (8)…”

“…General Procedure B, 1-(3-cyanophenyl)-2-ethylthio-propene 5e (102 mg, 0.502 mmol, E/Z 52:48), (8) 4-fluorophenylhydrazine hydrochloride 6a (85 mg, 0.53 mmol), TsOH‧H2O (103 mg, 0.541 mmol), EtOH (5 mL), reflux, 24 h. Flash chromatography (10→50% EtOAc/Hex) provided indole 8e as an off-white solid. Yield: 120 mg (0.479 mmol, 96%); Rf = 0.26 (30% EtOAc/Hex); Mp: 180-183 C.…”

“…Yield: 81 mg (0.33 mmol, 66%); Rf = 0.25 (20% EtOAc/Hex); Mp: 164-166 C. General Procedure B, 1-(4-methylphenyl)-2-ethylthio-ethene 5k (26 mg, 0.15 mmol, E/Z 55:45), (8) General Procedure B, 7-Phenyl-4-n-butylthio-hept-4-ene (5n) (36.1 mg, 0.138 mmol, E/Z 55:45), (8)…”

Dihydroquinazolinones as adaptative C(sp3) handles in arylations and alkylations via dual catalytic C–C bond-functionalization

“…Consequently, great interest exists for the development of new cross-coupling synthons that operate under ambient conditions, as this increases the structural diversity of accessible molecules within drug discovery programs 8 – 12 . The broad utility of ketones as chemical precursors 13 , 14 , the plethora of methods for their preparation 15 – 17 , and their prevalence as medicinal and commodity chemicals make them ideal targets for chemical innovation 18 – 21 . Synthetic manipulations of ketones generally rely on their latent polarity, specifically the electrophilicity of C=O bonds and nucleophilicity of enolate related structures (Fig.…”