Functionalisation of Carbonyl Compounds

The reaction of cyclohexanone with nitrosobenzene catalysed by N-sulfonyl prolinamides 15b or 15g yields the a-ojygenated cyclohexanone  

---

The reductive lithiation of dioxolanes requires the formation of an allylic or benzylic organolithium, and represents a valuable umpolung method for the functionalisation of carbonyl compounds. 

Scheme 6.4 a-Functionalisation of carbonyl compounds promoted by prolinamides. 

We used this strategy in chapter 6 under two-group C-X disconnections where bromination of ketones was the usual functionalisation. More relevant here are conversions of carbonyl compounds into 1,2-dicarbonyl compounds by reaction with selenium dioxide SeC>2 or by nitrosation. So acetophenone 57 gives the ketoaldehyde10 58 with SeC>2. These 1,2-dicarbonyl compounds are unstable but the crystalline hydrate 59 is stable and 58 can be reformed on heating. Since aromatic ketones such as 57 would certainly be made by a Friedel-Crafts reaction the disconnection 58a is not between the two carbonyl groups and offers an alternative strategy. 

The sixth chapter of the book was devoted to advances in enantioselective nickel-catalysed a-functionalisation, and to a-alkylation/arylation reactions of carbonyl compounds. A prochiral carbonyl compound can be activated toward electrophilic substitution via the formation of an enol or enolate intermediate, generating a tertiary or quaternary centre at the a-carbon. The use of a non-carbon electrophile leads to heterofunctionalised products, while that of carbon electrophiles affords a-arylated/alkylated carbonyl compounds, and the generation of a new stereogenic centre in these reactions... 

The required nitrite esters 1 can easily be obtained by reaction of an appropriate alcohol with nitrosyl chloride (NOCl). The 3-nitroso alcohols 2 formed by the Barton reaction are useful intermediates for further synthetic transformations, and might for example be converted into carbonyl compounds or amines. The most important application for the Barton reaction is its use for the transformation of a non-activated C-H group into a functional group. This has for example been applied for the functionalisation of the non-activated methyl groups C-18 and C-19 in the synthesis of certain steroids. ... 

In recent years, the variety of useful diazo substrates for asymmetric intramolecular cyclopropanation processes has really expanded. As another example, Charette and Wurz have reported the first example of an intramolecular cyclopropanation involving a-nitro-a-diazo carbonyl compounds.This reaction, catalysed by Rh2[(S)-DOSP]4, led to the formation of nine-membered nitrocyclopropyl lactones in good yields and enantioselectivities with extremely high diastereoselectivities (Scheme 6.17). This novel methodology constituted an efficient entry into chiral functionalised macrocyclic-fused cyclopropane oc-amino acids. 

This chapter deals with target molecules of two main types hydroxyketones 1 and 1,3- or P-diketones 4. Both have a 1,3-relationship between the two functionalised carbons. Both can be disconnected at one of the C-C bonds between the functional groups to reveal the enolate 2 of one carbonyl compound reacting with either an aldehyde 3 or acid derivative 5 such as an ester. 

The direct functionalisation of ketones is not limited to simple sulfonates. The a-(+)-10-camphorsulfonyloxy group has been also introduced into various types of ketones or carbonyl compounds bearing an active methylene group by using the HTIB analog, [a-(+)-10-camphorsulfonyl-oxy]hydroxyiodobenzene (147).250... 

The electrophile (E in -146) can be an alkyl halide, acid chloride, conjugated carbonyl compound and so on. A simple example illustrating the use of a functionalised alkyl halide, produces the Z-alkene 148 as the larger group is added by carbocupration.36 Addition in the reverse order would have given -148. 

Ring expansion of homophthalic anhydride 114 on reaction with N-i- r-N-methylhydrazine in acetic acid resulted in the 2,3-benzodiazepinedione derivative 115 in moderate yield. The combination of the less hindered nitrogen (NCH3) and the more reactive carbonyl group in 114 may explain the regioselectivity observed. Functionalisation of C5 by the azido group then led ultimately via the amine 116 and the peptide 117 to the 2,3-benzodiazepine-1,4-diones 118. These final compounds were designed to act as peptidomimetics at the carboxy terminus of hydroxyamides one such compound 118 (R =... 

FGA of a triple bond gives a simple strategy for assembling a 1,4-di-functionalised skeleton. Diadducts (36) of acetylene and carbonyl compounds can be hydrogenated (no catalyst poison) to remove the triple bond. 

---