Regioselective Functionalization. 6.¹ Migratory Preferences in Hydroxylamine-O-sulfonic Acid and Schmidt Rearrangements of 7-Substituted Norcamphors

Abstract

Hydroxylamine-O-sulfonic acid reacted with syn-7-X- and anti-7-Y-substituted norcamphor derivatives [X = H, OMe, Cl, Br, OTos; Y = H, COOMe, Cl, Br, Tos, COOMe(5-exo-Br)], to give solely bridgehead migrated 2-azalactams, except for minor amounts of methylene migrated 3-azalactams from norcamphor (1) and the syn-7-Br ketone 19. Schmidt reactions of the same ketones provided varying mixtures of methylene and bridgehead migrated lactams, except for norcamphor (1) and anti-7-Br ketone 31, which provided solely 3-azalactams. Significant ratios (>0.4) of bridgehead migration to cleavage products were observed in the Schmidt reactions only with 7-OTos ketones 22 and 24 with exo-5-bromo-anti-7-methoxycarbonyl ketone 37. The Schmidt rearrangements most likely involve iminodiazonium ion intermediates in light of the large amounts of cleavage observed relative to lactam formation and the insensitivity of methylene migration to the substituent size in the reactions of syn-7-substituted norcamphors.

Regioselective Functionalization. 7.1 Unexpected Preferences for Bridgehead Migration in Schmidt Rearrangement Syntheses of Novel 2,6-Diazabicyclo[3.2.x]alkan-3-ones (x = 1−3)

“…The ketones in Table were prepared by our previously described regioselective ketofunctionalization method from known azabicycloalkenes (see Experimental Section) . Beckmann rearrangements of the ketones were performed in the presence of HOSA in refluxing acetic acid or formic acid to afford lactams . Schmidt reactions were carried out with sodium azide in concentrated sulfuric acid at 0−25 °C.…”

“…Recently, in an investigation of the Schmidt and Beckmann rearrangements of 7- syn - and 7- anti -substituted norbornan-2-ones 6 (Eq 3) we observed significant effects of β-halide, -alkoxy, -methoxycarbonyl and - O -tosyl substituents on the course of these reactions . Although Schmidt reactions of the parent norbornan-2-one ( 1a ) gave solely methylene migrated lactam 2a , the functionalized ketones 6 , except for the anti -7-bromoketone, gave mixtures of lactams 7 and 8 formed by competing methylene and bridgehead migration.…”

Toward the Scale-Up of a Bicyclic Homopiperazine via Schmidt Rearrangement and Photochemical Oxaziridine Rearrangement in Continuous-Flow

“…There is a single report of the Schmidt reaction of 2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]­octan-5-one, which bears an unsubstituted ethano bridge, giving rise to a mixture of 3,6-and 2,6-diazabicyclo[3.2.2]­nonanones in modest yields . The ratios of the migration products are affected by the presence of ring and bridge substituents and influenced by reaction conditions, including the acid used and the acid concentration, as demonstrated in acyclic systems …”

“…19 The reaction outcomes are heavily influenced by the substrate: whereas Beckmann rearrangements of the oximes derived from bicyclo[2.2.2]octanone and the related 2-azabicyclo[2.2.2]octanones give exclusively bridgehead migration products, 20,21 23 There is a single report of the Schmidt reaction of 2-(4-methoxyphenyl)-2azabicyclo[2.2.2]octan-5-one, which bears an unsubstituted ethano bridge, giving rise to a mixture of 3,6-and 2,6diazabicyclo[3.2.2]nonanones in modest yields. 24 The ratios of the migration products are affected by the presence of ring and bridge substituents 25 and influenced by reaction conditions, including the acid used and the acid concentration, as demonstrated in acyclic systems. 26 A promising yet underutilized strategy for controlling the regioselectivity of nitrogen insertion was reported by Lattes 27,28 and developed by Aubé2 9−32 and proceeds via the photochemical rearrangement of oxaziridines (Scheme 1).…”

Intramolecular Schmidt Reaction: Applications in Natural Product Synthesis

“…The regioselectivity of the Schmidt rearrangement is controlled by a delicate balance between the two mechanisms depicted in Scheme 1(b) and by the stereochemistry of the intermediate iminodiazonium salts. For example, the reaction of bicyclic ketone 3.1 affords a 77:23 mixture of 3.2 and 3.3 in 62% yield (Scheme 3) [12] [13]. The preferential formation of 3.2 results from the preferential formation of the E-iminodiazonium cation E-3.4 followed by 1,2-shift of the bridgehead substituent.…”