Synthons carbonyl cation

The problem of an unnatural (illogical) synthon arises here too (cf. Chapter 23). A 1,4-diketone (1) can be disconnected at its central bond into the natural enolate (2) but that requires also an unnatural synthon, the a-carbonyl cation (3). We shall need reagents for this synthon as well as for related synthons at different oxidation levels. We met some of these reagents—a-halo carbonyl compounds and epoxides—in Chapter 6. 

While we must use polarity inversion to add the a-carbonyl cation synthon (1) to an enolate ion, no such tricks are needed to add synthon (3) allyl halides are easily made (Chapter 24) and are reactive in 8 2 reactions. The conversion of... 

Ai a higher oxidation level (31), the electrophfiic synthon would be the -carbonyl cation (32), a very unstable species. The best reagents for this synthon are the -halo carbonyl compounds, easily made (see Chapter 7) and readily attacked by nucleophiles. 

Because of their high reactivity, these complex salts react rapidly and regiospecifically, at low temperature, with a number of carbon and heteroatomic nucleophiles, including thiols, amines, and alcohols. Finally, exposure of the double bond takes place under particularly mild conditions so that isomerization of the (3,Y-unsaturated carbonyl system may be avoided. The present scope of reactions with these vinyl cation synthons is summarized in [able I. 

The corresponding reactions are mostly ionic involving nucleophilic displacement by SnI, Sn2 or carbonyl substitution with amines, alcohols and thiols on carbon electrophiles. The normal polarity of the disconnection 1 will be a cationic carbon synthon 2 and an anionic heteroatom synthon 3 represented by acyl or alkyl halides 4 as electrophiles and amines, alcohol or thiols 5 as nucleophiles. 

The corresponding disconnection is of the newly formed C-C bond 8a. The synthons are the acyl cation and a nucleophilic carbon species that might be a metal derivative RM (chapter 13) but will generally be an enolate in the next 10 chapters. And that is how carbonyl compounds are nucleophilic. 

Treatment of methyl phenyl sulfoxide with diethylaminosulfur trifluoride (DAST), in the presence of antimony trichloride provides 159 in quantitative yield (66). The reaction proceeds in good yield with dialkyl sulfoxides and alkyl aryl sulfoxides (163). Reoxidation of the a-fluorosulfide (165) to the corresponding sulfoxide (161), followed by pyrolysis, provides a direct synthesis of fluoroolefins (65). The reaction is believed to proceed by a Pummerer-type mechanism (l.e., a fluoro-Pummerer reaction, Scheme 48). Similarly, Umemoto (67) reported that N-fluorocollidine (167) converted sulfides to ot-fluorosulfides (170) presumably via an S-fluorosulfonium cation species 168 (Scheme 49). The synthetically challenging fluorovinyl ether nucleosides (175) and (176) were prepared using the fluoro-Pummerer reaction (Scheme 50) (60) the (E)-isomer (175) could be isomerized to 176 under photolytic conditions. Finch and co-workers (69) converted 160 to the sulfoximine 178 and demonstrated the utility of this compound as a mild fluoromethylene synthon (Scheme 51). Base-catalyzed condensation 178 with a carbonyl compound gave 179 which afforded... 

This example shows how retrosynthetic consideration of the next generation target molecules is sometimes more demanding than the choice in the first step. The logical first retrosynthetic step of TM 2.12 is the disconnection of the C-C bond in the P position to the carbonyl group generating two stable synthons, carbanion on the a-C atom to the carbonyl group and carbocation on the a-C atom to the double bond, known as the allylic cation (Scheme 2.27). 

On the other hand, the carbethoxy cation, a seemingly illogical synthon, has an available synthetic equivalent in diethyl carbonate. Diethyl carbonate is produced by oxidative carbonylation of ethanol, promoted by various heterogeneous catalysts one of the most effective is the mixed catalyst CuCl2/PdCl2 deposited on charcoal (Scheme 4.20). 

The decision to first disconnect the 1,4-dicarbonyl pattern is challenging. It results with in a carbanion of ethyl acetoacetate and cationic synthon charged on the a-C atom to the carbonyl group (Scheme 5.39). We therefore propose a-bromo ketone TM 5.17a as a new target molecule. 

Disconnection a is feasible only if protection of carbonyl group in carbanionic synthon is completed before the preparation of the Grignard reagent as a S5mthetic equivalent. Disconnection b indicates the synthetic route that starts with alkylation of the stabilized a-carbanion. Disconnection c does not offer any good solution for the synthon where the carbanion appears on the 3-C atom. For the cationic synthon, instead, enone RCOCH=CH2 is a convenient reagent. 

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