Ipso electrophilic aromatic substitution. I. Synthesis and nitration of 4-(2-phenylethyl) indan. II. Intramolecular cyclizations with carbon electrophiles: attempted synthesis of a steroid

Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)




Roger C. Hahn


Organic chemistry

Subject Categories

Organic Chemistry


Part I.

4-(2-Phenylethyl)indan (7) was synthesized by reaction of cuprous phenyl acetylide and 4-iodoindan. The phenethylindan was nitrated in acetyl nitrate in acetic anhydride at 0(DEGREES)C. Work-up and chromatography yielded the 5- and 7-nitro isomers (33.5 and 62.5%, 13 and 14, respectively), and ca. 4% of 6-acetoxyphenethylindan (15). No trace of intramolecular coupling product 12 was detected. Reasons for the low yield of acetoxy product were explored. Nitration of 7 at -20(DEGREES)C for 24 hours gave virtually no nitration. The possibility of rearrangement of ipso dienes to nitro compounds during work-up was discounted by following the nitration at 0(DEGREES)C by ('1)H NMR spectroscopy. This revealed formation of a maximum of ca. 2% dienes. Nitration with acetyl nitrate in methylene chloride gave results virtually identical to nitration in acetic anhydride, indicating that attack of acetate on the ipso arenium ion is not a slow step.

Part II.

Synthesis of acid 29 was accomplished by the outlined scheme. Reaction of 29 in anhydrous HF for 8 hours at room temperature did not give the hoped for ipso attack at the methyl group to produce estrone methyl ether precursor 31, but gave virtually exclusive attack para to the methoxy substitution, forming cyclononanone 68 in 76% yield. Reaction at 0(DEGREES)C for 45 minutes gave virtually no product. Cyclononanone 68 was unexpected, yet 68 and the transition state leading to its formation show little transannular interactions as seen by molecular models. Cyclization of the acylium ion generated from the acid chloride of 29 by tin tetrachloride in methylene chloride at -78(DEGREES)C gave only a 5% yield of 68, and a large number of unidentified products. Analysis of the partially separated mixture (('1)H NMR) gave no indication of desired products. Variations in reactant ratios and raising the temperature to 0(DEGREES)C gave virtually identical results.

Cyclization by the use of a less reactive electrophile, the oxycarbonium ion, was attempted by reaction of the ethylene glycol acetal of aldehyde 73 with tin tetrachloride in both hexane and methylene chloride at temperatures up to room temperature. However, this reaction only gave recovered acetal and/or aldehyde.

Synthesis of butyric acid derivative 74 and reaction in anhydrous HF gave only starting material after 15 hours at room temperature. It was concluded that formation of cyclodecanone 75 was precluded because of severe transannular interactions. It was hoped that this would force reaction at the methyl substitution, giving rise to a D-homoestrone precursor. Reasons for this apparent lack of reactivity include insufficient activation of the ipso position, insufficiently long lived ipso arenium ion to permit closure, or, possibly, large steric requirements that are necessary to achieve the proper coupling geometry by the methoxylated ring (although this possibility is not obvious from molecular models).


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