Of unsymmetrical ketones

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

The Fischer cyclization has proved to be a very versatile reaction which can tolerate a variety of substituents at the 2- and 3-positions and on the aromatic ring. An extensive review and compilation of examples was published several years ago[3]. From a practical point of view, the crucial reaction parameter is often the choice of the appropriate reaction medium. For hydrazones of unsymmetrical ketones, which can lead to two regioisomeric products, the choice of reaction conditions may determine the product composition. 

The issue of regioselectivity arises with arylhydrazones of unsymmetrical ketones which can form two different enehydrazine intermediates. Under the conditions used most commonly for Fischer cyclizations, e g. ethanolic HCI, the major product is usually the one arising from the more highly substituted enehydrazine. Thus methyl ketones usually give 2-methy indoles and cycliz-ation occurs in a branched chain in preference to a straight chain. This regioselectivity is attributed to the greater stability of the more substituted enhydrazine and its dominance of the reaction path. 

A mixture of methanesulfonic acid and P Oj used either neat or diluted with sulfolane or CH2CI2 is a strongly acidic system. It has been used to control the rcgiosclcctivity in cydization of unsymmetrical ketones. Use of the neal reagent favours reaction into the less substituted branch whereas diluted solutions favour the more substituted branch[3]. 

Reaction of unsymmetrical ketones with strong bases may lead to two different enolates. Whether the eventual product derives from the more stable ( thermodynamie ) enolate, or from the more rapidly formed ( kinetie ) enolate, depends on reaetion conditions. 

We have previously discussed that keto-aldehydes react with anilines first at the aldehyde carbon to form the aldimine. Subsequent condensation with another aniline formed a bis-imine or enamino-imine. The aniline of the ketimine normally cyclizes on the aldimine (24 —> 26). Conversely, cyclization of the aldimine could be forced with minimal aniline migration to the ketimine using PPA (30 —> 31). The use of unsymmetrical ketones has not been thoroughly explored a few examples are cited below. One-pot enamine formation and cyclization occurred when aniline 48 was reacted with dione 49 in the presence of catalytic p-TsOH and heat. Imine formation occurred at the less-hindered ketone, and cyclization with attack on the reactive carbonyl was preferred. ... 

The coupling of unsymmetrical ketones leads to formation of stereoisomeric alkenes the ratio depending on steric demand of substituents R ... 

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). 

In the case of unsymmetrical ketones, the attack usually comes from the less highly substituted side, so that CH3 is more reactive than RCH2, and the R2CH group rarely attacks. As in the case of 10-118, this reaction has been used to effect cycliza-tion, especially to prepare five- and six-membered rings. Nitriles are frequently used instead of ketones, the products being 3-keto nitriles. 

Regioselectivity in the halogenation of unsymmetrical ketones can be attained by treatment of the appropriate enol borinate of the ketone with NBS or NCS. The desired halo ketone is formed in high yield. Another method for achieving the... 

The role of the trimethylsilyl group is to stabilize the enolate formed in the conjugate addition. The silyl group is then removed during the dehydration step. Methyl 1-trimethylsilylvinyl ketone can be used under aprotic conditions that are compatible with regiospecific methods for enolate generation. The direction of annulation of unsymmetrical ketones can therefore be controlled by the method of enolate formation. 

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

The formation of unsymmetrical ketones can also be done starting with IpcBCl2. Sequential reduction and hydroboration are carried out with two different alkenes. The first reduction can be done with (CH3)3SiH, but the second stage requires LiAlH4. 

The method outlined here competes well with the method developed earlier by Danheiser, et al.618 Its superiority is based on the fact that phenyl ester enolates give almost the same results as the S-phenyl thiolester enolates. However, handling the malodorous benzenethiol for the preparation of the active acid derivative and during workup of the p-lactone can be avoided. In addition, phenol is much cheaper than benzenethiol. The method is well suited for the preparation of p-lactones from symmetrical and unsymmetrical ketones. In addition to 3,3-dimethyM-oxaspiro[3.5]nonan-2-one, ( )-3-ethyl-1-oxaspiro[3.5]nonan-2-one and (3R, 4R )- and (3R, 4S )-4-isopropyl-4-methyl-3-octyl-2-oxetanone were prepared by this procedure in high yields (Notes 11 and 12). In the case of unsymmetrical ketones the less sterically crowded diasteroisomer is formed preferentially. With aldehydes as the carbonyl component the yields are unsatisfactory, because of the competitive formation of 1,3-dioxan-4-ones.6... 

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

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). 

Regioselectivity is not a problem in the metalation and alkylation of SAMP-hydrazones derived from aldehydes, symmetrical ketones and unsymmetrical ketones having one substituent without a-hydrogens. On the other hand, SAMP-hydrazones of unsymmetrical ketones react regioselectively at the less substituted carbon, regardless of the E/Z ratio of the starting hydrazone33. 

A series of unsymmetrical ketones was obtained from terminal acetylenes and iodoarenes using dppf as ligand (Equation (25)). ... 

Vinylsilanes (8, 491 492) attylic alcohols (9, 340). Details are available for conversion of a ketone to a vinylsilane in which the C—Si bond has replaced the C -O group (cncsilylation). The reaction affords the less substituted vinylsilane in the case of unsymmetrical ketones. The paper includes details for use of vinylsilanes for cyclopcntenone annelalion by l riedel-Crafts acylation with acryloyl chlorides and subsequent cyclization of pentadienyl cations (9, 498-499).1... 

With thioamides few results are available. Only carbophilic additions have been reported [329, 358]. This mode of addition of organolithiums was used for novel syntheses of unsymmetrical ketones and a-alkylated amines. Although enethiolization of aliphatic thioamides by alkyllithiums limits the scope of these synthetic routes the yields are good and reactions simple to run [358]. 

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