deprotonation to form the enehydrazine, whereas under weakl NINH acidic conditions tautomerization is sufficiently rapid that the [3, 3]-sigmatropic rearrangement is rate determining. MNDO AMI calculations have been performed on the conformation CF3CO2H HOAC heat and sigmatropic rearrangement ethyl pyruvate and acetaldehyde 5.76 Murakami and co-workers continue their investigations of the effects of ortho-substituents on the regiochemistry and rate of Fischer indole cyclizations, -and, as shown in Scheme 10, hydrazone 13 undergoes cyclization to the more electron-rich Zncl2 HOAc F3C R= CH2C3Hs. CH2 CH=CH2 Scheme 10 R=H Me A novel abnormal rearrangement has been uncovered in the ischer idolization of the naltrexone N-methyl-N-(5, 6, 7, 8 tetrahydro-l-naphthyl)hydrazone. 0 Huisgen and co-workers have found that under fischer indole reaction conditions ene- hydrazine 14 stops at the 2-aminoindoline stage 15, since indole formation is precluded by ring strain in the product (Scher l1).81.2 hormone secretagogue. The Fischer indole sequence has been used on an industrial scale in the manufacture of a pharm aceutical intermediate, to prepare pyrrolo[2, 3-d]pyrimidines synthesize 7-bromo-2, 3-bis( methoxycarbonyl)indole as a useful COoMe ubstrate for Pd-catalyzed cross coupling reactions leading to 7-substituted indoles. COM er,on rare occasions the Fischer indole synthesis proceeds poorly or even fails altogether. For example, hydra zone 11 afforded only 15% of the indole product, the major Scheme 11 product (41%)being an indazole, and hydrazone 12 failed to cyclize to an indole under all conditions tried(Scheme 9), 2.2 Gassman indole synthesis presumably because of the deactivating effect of the (proton- ated) pyridine ring. The beautiful Gassman indole-oxindole synthesis, -b6 which features a [2, 31-sigmatropic rearrangement, has been used to prepare efficiently 6.7-dihydroxyoxindole, a subunit of the alkaloids paraherquamide a and marcfortine A. Wright et al ylene 135C ave developed a modification of the Gassman synthesis that affords improved yields in many cases. The key feature of the OMs Wright modification is the facile formation of the chlorosulf- onium salt 16, which avoids elemental chlorine(Scheme 12) OMs COC CCH2CO2Et CH2 C2 /+CH,CO,Et Scheme 9 CO,Et SMe 2.1.3 Mechanism 1以N.人 M An exhaustive study of the effects of acidity on the mechanism 2. 2M HCl of the Fischer indole synthesis reveals that four different mech- anistic variations can occur over the acidity range of Ho=+2 to-8. Thus, in strong acid the rate-determining step is Scheme 12 1048. Chem. Soc.. Perkin Trans. 1.2000. 1045-10751048 J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 hormone secretagogue.67 The Fischer indole sequence has been used on an industrial scale in the manufacture of a pharm￾aceutical intermediate,68 to prepare pyrrolo[2,3-d]pyrimidines as potential new thymidylate synthase inhibitors,69,70 and to synthesize 7-bromo-2,3-bis(methoxycarbonyl)indole as a useful substrate for Pd-catalyzed cross coupling reactions leading to 7-substituted indoles.71 However, on rare occasions the Fischer indole synthesis proceeds poorly or even fails altogether. For example, hydra￾zone 11 afforded only 15% of the indole product, the major product (41%) being an indazole,72 and hydrazone 12 failed to cyclize to an indole under all conditions tried73 (Scheme 9), presumably because of the deactivating effect of the (proton￾ated) pyridine ring. 2.1.3 Mechanism An exhaustive study of the effects of acidity on the mechanism of the Fischer indole synthesis reveals that four different mech￾anistic variations can occur over the acidity range of H0 = 2 to 8.74 Thus, in strong acid the rate-determining step is Scheme 8 Scheme 9 deprotonation to form the enehydrazine, whereas under weakly acidic conditions tautomerization is sufficiently rapid that the [3,3]-sigmatropic rearrangement is rate determining. MNDO AM1 calculations have been performed on the conformations and sigmatropic rearrangement of the phenylhydrazones of ethyl pyruvate and acetaldehyde.75,76 Murakami and co-workers continue their investigations of the effects of ortho-substituents on the regiochemistry and rate of Fischer indole cyclizations,77–79 and, as shown in Scheme 10, hydrazone 13 undergoes cyclization to the more electron-rich benzene ring.77 A novel abnormal rearrangement has been uncovered in the Fischer indolization of the naltrexone N-methyl-N-(5,6,7,8- tetrahydro-1-naphthyl)hydrazone.80 Huisgen and co-workers have found that under Fischer indole reaction conditions ene￾hydrazine 14 stops at the 2-aminoindoline stage 15, since indole formation is precluded by ring strain in the product (Scheme 11).81,82 2.2 Gassman indole synthesis The beautiful Gassman indole-oxindole synthesis,83–86 which features a [2,3]-sigmatropic rearrangement, has been used to prepare efficiently 6,7-dihydroxyoxindole, a subunit of the alkaloids paraherquamide A and marcfortine A.87 Wright et al. have developed a modification of the Gassman synthesis that affords improved yields in many cases.88 The key feature of the Wright modification is the facile formation of the chlorosulf￾onium salt 16, which avoids elemental chlorine (Scheme 12). Scheme 10 Scheme 11 Scheme 12