Grob-type fragmentation reaction

Ozonolysis of diketone carbonate 417 in methanol afforded an almost quantitative yield of the bicyclic diene triketone hydroxy-ester 418 (119). This remarkable transformation can also be readily explained. Ozonolysis of 417 produces the tetraketone intermediate 419 followed by methanol addition to produce the hemi-ketal 420 which undergoes a retro-Claisen reaction to 421. Then, loss of carbon dioxide from 421 yields 418. Again, 420 could also undergo a Grob type fragmentation to yield 418 directly. 

Unsymmetrical alkenes can be prepared by mixed intermolecular reactions if one of the components, commonly acetone, is used in excess (equation 83). As the isopropyl group is a common subunit of many terpenes this method provides a valuable route for its introduction. Pattenden and Robertson used such a reaction followed by a Grob-type fragmentation in their preparation of the daucenone (42) from the readily enolized ketone (43). The bicycle (42) was used as an intermediate for the synthesis of the diterpene ( )-isoamijiol (44 equation 84). Mixed couplings are not restricted to acetone, and almost any carbonyl may be used. For example, Paquette et al. employed the aldehyde (45) in a synthesis of ( )-a-vetispirene (46 equation 85). More complex mixed couplings are also possible. For example, the aldehydes (47) and (48) are coupled efficiently to the stilbene (49), which in turn is converted to phenan-threne alkaloids such as atherosperminine and thalictuberine (equation 86). ... 

The reaction of cis- and fra j-methyl-substituted l-(trimethylsiloxy)bicyclo[n.l.O]alkanes (n = 3,4,5) is stereospecific. When treated with lead(IV) acetate, followed by diazomethane, these substrates give the methyl ( )- and (Z)-alkenoates, respectively. The reaction is interpreted by assuming electrophilic attack of lead(IV) acetate on the cyclopropane carbon to cleave the ring, followed by a Grob-type fragmentation with lead(II) acetate as the leaving group. 

The bis-trimethylsilyl ethers of stereoisomeric 5,7-undecanediol 78 (as well as the free diols) give upon chemical ionization (protonation with QH9) MH+ ions, which show two major processes (reaction 41). One corresponds to a Grob-type fragmentation 05-cleavage) of the ion 79 (formed by loss of Me3SiOH from protonated 78) to yield the silylated aldehyde 80. The second major reaction path involves loss of CH4 from MH+, followed by cyclization of the intermediate 81 (siloxy transfer) to 82 and ft-cleavage (loss of 1-hexene) to generate 8467. This reaction sequence, in which a centrally located structural unit rather than a peripheral one is eliminated, is rarely observed under chemical ionization and deserves further study. 

Fragmentation of five-and six-membered rings. Semmelhack and Tomesch have reported a mild and efficient Grob-type fragmentation. The reaction of 1,2-epoxycyclohexane (I) with the anion of bis(phenylthio)methane (6, 267) gives... 

The occurrence of carbocationic intermediates in the Hofer-Moest variant of the Kolbe reaction can lead to numerous rearrangement processes. For example, electrolysis of carboxylic acid 68 in methanol results in the oxidative ring opening of the norbomane skeleton[30]. In a similar manner, GroB-type fragmentation of the decaline derivative 70 affords the 10-membered-ring ketone 71 in good yield (Scheme 12) [31]. 

The classification fragmentation applies to reactions in which a carbon-carbon bond is broken. One structural feature that permits fragmentation to occur readily is the presence of a carbon that can accommodate carbocationic character (3 to a developing electron deficiency. This type of reaction, known as the Grob fragmentation, occurs particularly readily when the y-atom is a heteroatom, such as nitrogen or oxygen, that has an unshared electron pair that can stabilize the new cationic center.96... 

Unsaturated macrolides such as (115) or (117) (Scheme 38) have been synthesized by Eschenmoser using a fragmentation reaction as a key step. The tricyclic ketal carboxylate (114) can be cleaved as an amidinium salt to give (115) in excellent yield simply on heating. Similarly, the macrolide (117) with ( , )-configuration is obtained from (116). This decarboxylative double fragmentation represents a nine-center Grob type. 

Quite related to the above reaction type is the reductive a,p-ffagmentation of 7-halocyclobutyl ketones (Scheme 58). Oppolzer used this reaction in a new approach to the acorane system, and the mechanism was discussed. It remains to be clarified as to what extent this type of reaction entails similar ste-reoelectronic constraints as the classical Grob fragmentation. 

This reaction type is called a Grob as well as a Wharton fragmentation [1] [2]. 

Since the mid 1950s Grob has investigated these fragmentations in detail, and provided very much experimental material for the scope, mechanism and stereochemistry of this reaction type, summarized in some reviews.Therefore, the term Grob fragmentation is justified. 

The addition of strongly polarized carbon-carbon double bonds (enols) to simple iminium ions, known as the Mannich reaction (equation 1), is a fundamentally important route to amines, especially in biosynthetic processes. 2 This reaction type is less synthetically useful if weakly polarized or unpolarized carbon-carbon iT-bonds are used as nucleophiles (equation 2). Because of the low electrophilic reactivity of the iminium moiety, the reverse reaction, known as the Grob fragmentation (equation 2), is often the more important process. However, if the iminium moiety has a carbonyl substituent on nitrogen, its... 

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