Synthesis of 2-Substituted Benzofurans and Indoles Using Functionalized Titanium Benzylidene Reagents on Solid Phase

Abstract

Titanium(IV) benzylidenes bearing a masked oxygen or nitrogen nucleophile in the ortho position were generated from thioacetals, using low-valent titanocene complex, Cp2Ti[P(OEt)3]2. Methylene acetal, alkyl ether, silyl ether, fluoro, tertiary amino, and N-alkyl, N-benzyl, N-prenyl, and N-silyl tert-butyl carbamate groups were tolerated in the titanium alkylidene reagents (Schrock carbenes). Aryl-chlorine bonds were stable to the titanium benzylidene functionality, but there was poor chemoselectivity for the reduction of the thioacetal in the presence of an aryl chloride. The titanium benzylidenes converted Merrifield and Wang resin-bound esters into enol ethers. The oxygen nucleophile was masked as a TMS ether, and when the resin-bound enol ethers bearing this ortho substituent were treated with 1% TFA in dichloromethane, benzofurans were released from resin in high yields. The chameleon catch strategy ensured excellent purity. In a similar way, N-alkylated and N-silylated tert-butyl carbamates were used for the synthesis of N-alkyl and N-Boc indoles, respectively. These traceless solid-phase syntheses of heterocycles are believed to involve postcleavage modification rather than cyclative termination.

High throughput synthesis of diverse 2,5-disubstituted indoles using titanium carbenoids bearing boronate functionality

“…Aryl bromides react under the conditions used to generate our titanium benzylidene reagents 9, precluding the introduction of aryl bromide or iodide functionality to the resin by our method. 7 However, immobilisation of the arylboronate component is advantageous as aryl halides are more widely and cheaply available than arylboronates. Therefore, it is surprising that the aryl halide is almost always the immobilised coupling partner for cross couplings in SPS.…”

“…The use of solid-phase synthesis facilitates the preparation of the libraries as it allows automation. 4 Recently, we have developed functionalised titanium carbenoids 5 to prepare benzofurans 2, 6,7 indoles 3, 7 benzothiophenes 4, 8 quinolines 5, 9 cyclic imines 10,11 6 and enantiomerically enriched piperidines 11 7 and 8 from resin-bound esters 1, so that each ester acts as a precursor to a range of privileged structures (Scheme 1). The general strategy involves using titanium carbenoids 9 containing a masked nucleophile to convert acid-stable, resin-bound esters 1 into acid-sensitive enol ethers 10 (Scheme 2).…”

Synthesis of spiroacetals using functionalised titanium carbenoids

“…We had used titanium carbenoids bearing masked oxygen nucleophiles, 26,27 but exclusively for solid-phase synthesis and never to prepare spiroacetals. As in this earlier work, 26 dithiane 6, was synthesized in two steps from 2-hydroxybenzaldehyde, and converted into a titanium carbenoid, presumably titanium benzylidene 7, using low valent titanium reagent 5 (Scheme 2).…”

Nitroaromatic bis(2-hydroxyethyl)dithioacetals and oxathioacetals using 2-mercaptoethanol in the presence of chlorosilanes

“…4 The fivemembered oxathiolane ring occurs in nucleoside congeners that possess a pronounced antiviral activity. 5 2-Aryl-1,3-oxathiolanes are efficiently converted into 2-aryl-1,4-oxathiane 6 , acetals 7 , monosulfoxides.…”