Unsymmetrical ketones, synthesis

V K. Singh, Practical and Useful Methods for the Enantioselective Reduction of Unsymmetrical Ketones, Synthesis 1992, 607-617. 

Singh, V. K. Practical and useful methods for the enantioselective reduction of unsymmetrical ketones. Synthesis 1992, 607-617. 

Unsymmetrical ketone synthesis is performed by the carbonylative coupling reaction of aryl iodides and alkyl iodides in the presence of a stoichiometric amount of zinc-copper couple and 1% of Pd(PPh3)4 under 1 atm of CO (Scheme The reaction may... 

TABLE 1. Unsymmetrical Ketone Synthesis from Aryl Iodide and Alkyl Halide... 

Asymmetric Reduction of Unsymmetrical Ketones Using Chiral Boron Reagents Review Synthesis 1992, 605. 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

Tripylborane is an interesting reagent which resembles thexylborane. One of the important uses of thexylborane lies in the synthesis of unsymmetrical thexyldialkylboranes which can then be used in the synthesis of unsymmetrical ketones. However, the reaction is only successful if the alkene used in the first hydroboration step is an internal alkene. Simple terminal alkenes such as 1-hexene react too rapidly with the initially formed thexylmonoalkylborane to allow the reaction to be stopped at that stage. Therefore, mixtures of products result (ref. 27). 

Example Compound (27) was needed for synthesis of analogues of vernolepin, an anti-tumour compound. Robinson disconnection suggests unsymmetrical ketone (28)... 

The synthesis of unsymmetrical ketones can be carried out in a tandem one-pot process by successive addition of two different alkyllithium reagents.115... 

Section B of the Scheme 9.1 shows several procedures for the synthesis of ketones. Entry 6 is the synthesis of a symmetrical ketone by carbonylation. Entry 7 illustrates the synthesis of an unsymmetrical ketone by the thexylborane method and also demonstrates the use of a functionalized olefin. Entries 8 to 10 illustrate synthesis of ketones by the cyanide-TFAA method. Entry 11 shows the synthesis of a bicyclic ketone involving intramolecular hydroboration of 1,5-cyclooctadiene. Entry 12 is another ring closure, generating a potential steroid precursor. 

TABLE 8.14 Selected examples of the synthesis of unsymmetrical ketones ... 

Zeolites have been employed in the preferential synthesis of optically active sites and in determining the particular products formed from certain reactions. In looking at the products formed from the decomposition and reformations involving an unsymmetrical ketone, the major products are a combination of products listed below ... 

The metalation chemistry of the imidazoline system has received attention only recently, with the lithiation of l-benzyl-2-imidazoline being found to occur at the 2-position (90TL1767). Although the reactivity of the lithi-ated species with alkyl halides was poor, better results were achieved with disulfide and carbonyl electrophiles (90TL1767,90TL1771). The products formed by reaction with ketones were found to be unstable with respect to fragmentation, and this result was utilized to provide a new route for the synthesis of unsymmetric ketones (Scheme 138). 

Hydrazones can also be deprotonated to give lithium salts which are reactive toward alkylation at the j> carbon. Hydrazones are more stable than alkylimines and therefore have some advantages in synthesis.79 The / A Alimcthy I hydrazones of methyl ketones are kinetically deprotonated at the methyl group. This regioselectivity is independent of the stereochemistry of the hydrazone.80 Two successive alkylations of the A A -dimethylby-drazone of acetone can provide unsymmetrical ketones. 

The reduction of an unsymmetrical ketone creates a new stereo center. Because of the importance of hydroxy groups both in synthesis and in relation to the properties of molecules, including biological activity, there has been a great deal of effort directed toward enantioselective reduction of ketones. One approach is to use chiral borohydride reagents.92 Boranes derived from chiral alkenes can be converted to borohydrides, and there has been much study of the enantioselectivity of these reagents. Several of the reagents are commercially available. 

Fischer indole synthesis Cyclization of arylhydrazones by heating with an acid or Lewis acid catalyst yields an indole system. The most commonly used catalyst is ZnCl2- The disadvantage of this reaction is that unsymmetrical ketones give mixtures of indoles if R also has an a-methylene group. 

Unsymmetrical ketones can yield two different enolates, and in some cases the one that is the less stable thermodynamically is formed faster.148 Scheme 24 illustrates the example of 2-methylcyclopentanone. When this ketone is added slowly to excess f-butyllithium, the proton is removed preferentially from the less substituted carbon. If excess ketone is added, it can serve as a proton donor to allow equilibrium to be established, and nearly all the enolate is then the more highly substituted one.149 It may be possible in some cases to take advantage of such a selective formation of one of two possible enolates in synthesis. A more general procedure is to use a compound in which the desired position is activated... 

The method has been extended to include the synthesis of aldehydes or of unsymmetrical ketones by using appropriate mixtures of carboxylate salts. 

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