On the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyl compounds

Abstract

The scope and limitations are described of reacting unsaturated tosylhydrazones with O3 followed by Et3N for the generation of 1,4- and 1,5-diazocarbonyl systems. Tosylhydrazones, from tosylhydrazide condensation with readily available δ- and ε-unsaturated α-ketoesters, led in the former case to a 2-pyrazoline whereas the latter cases led to α-diazo-ε-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Using the ozonolysis-Et3N strategy, tosylhydrazones from cyclic enones give 2,5- and 2,6-diazoketones with aldehyde or ester functionality at the 1-position; the α-diazoaldehydes prefer the s-trans conformation, with a rotation barrier of 74 kJ mol-1 at 25 °C determined by NMR. This one-pot ozonolysis/Bamford-Stevens chemistry demonstrates both the tolerance of tosylhydrazones to ozone, and the subsequently added amine playing a dual role to directly transform the intermediate tosylhydrazone ozonides into products containing reactive diazo and ketone functionalities; such adducts are of particular value as precursors to cyclic carbonyl ylides for 1,3-dipolar cycloadditions.

Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids

“…The general viability of the α-ketoester to α-diazoester functional group interconversion envisaged in Scheme 2 ( 10 → 3 ) was readily established on a simpler but closely structurally-related system (Scheme 3). Thus, the known Z -hydrazone 12 , previously prepared by us from α-ketoester 11 in 75% yield [21], gave α-diazo ester 13 in 76% yield following reaction with NaOMe. Furthermore, our earlier racemic model study had established that deprotection and oxidation of a secondary silyl ether in the presence of α-diazo ester functionality was feasible, which constitutes precedent for the generation of the ketone functionality in 3 [14].…”

Evolution of a Cycloaddition–Rearrangement Approach to the Squalestatins: A Quarter-Century Odyssey

“…In order to further explore the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyl compounds, several other unsaturated tosylhydrazones 120 were designed to examine their reactivity with O 3 (at -78°C ), followed by hydrazone decomposition with Et 3 N (Scheme 40). 43 We found that this chemistry is viable to diazo--ketoester 121, while an -diazo--ketoester was not observed under the same conditions and instead only keto hydrazone 122 was isolated; switching from Et 3 N to DBU as a stronger base led to the 2-pyrazoline 123 (41%). Interestingly, terminal alkene hydrazones 120 (R = H) pro-vide a route to cyclic systems (124 and 125) rather than to diazoaldehydes; the latter being presumed unstable intermediates.…”

Oxidative Alkoxylation/Dehydrogenation of Unactivated Cyclic Ketones with Simple Alcohols: Direct Route to α‐Alkoxy Cycloenones

“…Moreover, α‐alkoxy cycloenones could also be obtained from cyclohex‐2‐en‐1‐one and sodium alkoxide via a tandem per‐oxidation and ring‐opening reaction (Scheme 1b). [ 4 ] However, narrow substrate scope, unsatisfactory yield and tedious operation have limited their further applications. Therefore, the development of a simple and efficient protocol for the synthesis of α‐alkoxy cycloenones remains highly desirable.…”