Three practical synthetic entries of functionalized 6‐fluoro‐7‐substituted indole derivatives were developed in connection with the preparation of 7‐fluoro‐8‐substituted‐1,3,4,9‐tetrahydropyrano[3,4‐b]indole‐1‐acetic acid derivatives 11. The first route, which permits group modification about position 8 of the pyranoindole skeleton, employs 2‐bromo‐3‐fluoroaniline (18) as a key intermediate, the preparation of which was achieved by either a novel ortho metalation of 15 or via the intermediacy of 22. The second route utilizes 32 to append a terminally functionalized three carbon side chain onto the indole template and in addition leads to 43 from 40. The third route to the 7‐fluoro‐8‐substituted‐pyranoindole skeleton complements route two in that the synthetic pathway exploits 32 in a nucleophilic fashion to construct a terminally functionalized two carbon appendage onto the indole nucleus.

The synthesis of cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indole -1-acetic acid, pemedolac (USAN), is described. This compound has been found to be a potent analgesic agent in primary screening. Pemedolac has been resolved and the active (+)-enantiomer assigned a 1S,4R absolute configuration on the basis of a crystallographic analysis of its (S)-(-)-borneol ester.

206 ChemInform Abstract Several methods of preparing the title compound (X) from indole derivatives are described. One key intermediate is the (hydroxymethyl)phenylethylindole (IV) which is obtained from isatin (I) and the phenylpropionate (II) or from the indolylacetate (V) and benzyl chloride (VI). (IV) undergoes cyclocondensation with the methoxypentenoate (VIII), forming the dihydropyranoindolylacetates (IX). Saponification of the main diastereomer (IXa) yields pemedolac (X). An alternative pathway to (IX) starts with the oxime (XI) which is hydrogenated and reduced, giving the amino alcohol (XII). This is N-protected and then cyclized with (VIII), producing the fused aminodihydropyran derivative (XV) which is subjected to a complex formylation, dehydration, cleavage, and rearrangement procedure, followed by coupling with benzylmagnesium bromide (XVII), to yield (IX). Pemedolac (X) has analgesic activities. (X-ray analysis of (X) and its (S)-borneol ester).

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Vol. 79 from glacial acetic acid gave material melting sharply at 61-62°, but several additional recrystallizations from methanol gave the pure cis isomer, m.p. 74-74.5°. Carbon and hydrogen analysis of the material melting at 61-62°supported the conclusion that it was a mixture of cis-and trans-benzyl sulfones. A mixture of the cis-and ¿rans-sulfones melted at 62-76°.Isomerization of cú-2-Methylpentyl Benzyl Sulfone.-Treatment of either the pure c«-benzyl sulfone or the mixture of benzyl sulfones melting at 61-62°a ccording to the method used to isomerize ró-2-methylcydohexyl benzyl sulfone gave a 91% conversion to the /rans-sulfone, m.p. 98-100°.Attempts to isomerize the cA-thiol or cA-benzyl sulfide by this procedure were unsuccessful. cis-and Ao«s-2-Methylcyclohexyl Phenyl Sulfones.-cis-2-Methvlcyclohexylphenyl sulfide was prepared by heating a mixture of cA-2-methylcyclohexanethiol with iodobenzene and copper powder at 220°according to the procedure described _by Cunneen.4b The sulfide also was prepared in 70% yield from 1-methylcyclohexene and thiophene] by heating on the steam-bath in the presence of ¿-butyl peroxide. Oxidation of each of these samples with 30% hydrogen peroxide in glacial acetic acid gave the same sulfone, m.p. 107-108°after recrystallization from methanol; Cunneen4b reports the melting point as 108°. Isomerization of the sulfone by the method described above gave an 85% yield of Zra«s-2-methylcycIohexyl phenyl sulfone (m.p. 82-86°), which melted at 90-90.5°after recrystallization from methanol .