A Convenient Synthetic Route to 7,8-Fused Heterocyclic Ring Derivatives of (S)-2,3-Dihydro-1,4-benzodioxin-2-methanol

Abstract

A much improved synthesis of the dioxino [2,3-e]indolemethanol 9a is described, which is shorter, higher-yielding and less hazardous than the previous synthesis of its racemic form. This novel procedure now allows preparation of multigram quantities of the enantiomerically pure compound. Application of this methodology to different 5-hydroxyheterocycles enables access to furo [3,2-f] [1,4]benzodioxin, thieno[3,2-f][1,4]benzodioxin and 1,4-dioxino[2,3-e]indazole ring systems.During the course of our investigations to find a potent, novel antipyschotic agent, the dioxino[2,3-e]indolemethanol 9a was required as a key intermediate in the synthesis of a lead compound. The racemic form of 9a had previously been prepared by Ennis et al 1 but this process was long, low-yielding and used hazardous azide for construction of the indole nucleus. Consequently, an alternative preparation of the key intermediate 9a was sought. We now wish to report a novel, shorter, higher-yielding and less hazardous preparation of the indole 9a which is more suitable for scale-up (Schemes 1 and 2). Julia and Lallemand 2 had previously reported that reaction of ethyl 5-hydroxyindole-2-carboxylate (1a) with 4-methoxyaniline and triethyl orthoformate at 165°C and then subsequent acid hydrolysis of the intermediate imine (2a; R 2 = MeO) gave the aldehyde 3a in 48% yield. However, when we repeated this reaction a very low yield (9%) of the imine was isolated. A much more satisfactory preparation of the aldehyde 3a was achieved by treating 1a with commercially available ethyl N-phenylformimidate followed by hydrolysis of the intermediate imine (2a; R 2 = H) with 5 M hydrochloric acid. Not suprisingly, formylation of the much more reactive 5-hydroxyindole using these conditions produced very complex mixtures from which no pure product could be isolated. The aldehyde 3a was elaborated to the dioxino[2,3-e]indole 7a by the route outlined in Scheme 1. Alkylation of 3a with (R)-glycidyl tosylate and K 2 CO 3 in DMF at 60°C gave the epoxyether 4a; small amounts of the bis-alkylated product 5 were also isolated from the reaction. Treatment of 4a with 3-chloroperoxybenzoic acid (mCPBA) gave a moderate yield (47%) of the formate ester 6a. However, it is well known that trifluoroacetic acid (TFA) can be used to accelerate Baeyer-Villiger oxidations, 3 and to that end addition of one equivalent of TFA to the oxidation reaction at 0°C gave a 75% yield of 6a after only 30 minutes. Subsequent reaction of 6a with aqueous K 2 CO 3 in THF at room temperature furnished the dihydrodioxinoindole 7a. The phenolic alkylation described above is of a type known to proceed with retention of configuration at the glycidyl asymmetric centre, 4 leading eventually to (S)-(2,3-dihyro-1,4-benzodioxin-2-yl)methanol derivatives. Hydrolysis of 7a with lithium hydroxide monohydrate furnished 8a which was then decarboxylated with copper in quinoline to afford the key intermediate 9a (Scheme 2). It is worth noting that decarboxylation of 8a at 257°C following the procedure of Ennis et a...

Synthesis and validation of [18F]mBPET-1, a fluorine-18 labelled mTOR inhibitor derivative based on a benzofuran backbone

“…A two-step procedure to ortho-formylate benzofuran substrates using ethyl N-phenylformimidate to form the imine followed by hydrolysis under acidic conditions has been reported (Andrew et al 1999). A more convenient method published by Hofsløkken and Skattebøl describes the ortho-formylation of various phenols in one step (Hofsløkken and Skattebøl 1999).…”