Enolates regioselective alkylation

The reduction of a,/ -unsaturated ketones, e.g., 7, by lithium in ammonia is another possibility for generation of enolates19. This method has been mainly used in the preparation of enolates for stereo- and regioselective alkylations in the steroid and terpenoid fields (see... 

Regioselective alkylation of a methyl ketone Even though the kinetic enolate of 2-heptanone consists of a mixture of terminal and internal enolates in the ratio 87 13, benzylation in DME results in preferential internal alkylation. Regioselective benzylation at the terminal position can be enhanced by addition of various ligands such as benzo-14-crown-4 and DMF, but HMPT is the most effective ligand, resulting in a ratio of terminal to internal benzylation of 11 1. The three ligands also increase the rate of alkylation. The same effect, but less marked, is observed in alkylation with the less reactive electrophile butyl iodide. 

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at — 72°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioselectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2B0S02CF3, at low temperatures (D A. Evans, 1979). Both types of fraiu-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

The direct a-alkylation of monoketones normally employs reaction of an alkyl halide or sulfonate with the enolate anion produced using a strong base. This method can be satisfactorily used with symmetrical ketones, which are to be dialkylated with a dihalide, and with intramolecular cyclization reactions, where the formation of five- and six-membered rings is often favored over the formation of three-, four-, seven-, and eight-membered rings (M. Mous-seron, 1937 W.S. Johnson, 1963). Regioselective alkylation of dianions according to Hauser s rule (see p. 9f.) is usually also a satisfactory procedure (F.W. Sum, 1979). 

A new method of kinetically controlled generation of the more substituted enolate from an unsymmetrical ketone involves precomplexation of the ketone with aluminium tris(2,6-diphenylphenoxide) (ATPH) at —78°C in toluene, followed by deprotonation with diisopropylamide (LDA) highly regioselective alkylations can then be performed.22 ATPH has also been used, through complexation, as a carbonyl protector of y./)-unsaturated carbonyl substrates during regioselective Michael addition of lithium enolates (including dianions of /i-di carbonyl compounds).23... 

Damoun, S. Van de Woude, G. Choho, K. Geerlings, P. Influence of alkylating reagent softness on the regioselectivity in enolate ion alkylation a theoretical local hard and soft acids and bases study. J. Phys. Chem. A 1999, 303, 7861-7866. 

The enolate is stable to further reduction, and protonation during the work-up will give a ketone.] But reaction with an alkyl halide is more fruitful because the enolate forms only where the double] bond of the enone was, regioselective alkylation becomes possible. 

The more reactive ft -carbon atom of ketone a,/ -dianions can be regiospecifically coupled with alkyl halides to give first lithium enolates, which are then trapped by more reactive carbon electrophiles such as allylic halides. The first example shown in Table 8 deals with the sequential /1-alkylation and ce-allylation of a ketone a,/1-dianion1 13. Thus, the dianion underwent regioselective alkylation at the ft carbon with //-pentyl bromide and then allylation with allyl bromide at the a carbon. When an excess of allyl bromide is reacted with the a, ft -dianion, the diallylated product is obtained in a good yield, whereas a threefold excess of pentyl bromide only resulted in the formation of the ft-alkylation product. Similar consecutive alkyl/allyl-type reactions are also possible for ketone a,5-dianions14. 

A systematic study of the reductive alkylation of acetophenones revealed that the desired transformation (Scheme 30) required a careful selection of reagents and conditions. The best results were obtained from reduction by potassium in ammonia at -78 °C, with t-butyl alcohol as the proton source. Exchange of the potassium counterion of the enolate (152 M = K) for lithium then ensured regioselective alkylation at C-1 to give (153) in 80-90% yields (Scheme 30). Metals other than potassium as the reductant led to undesirable side reactions with the carbonyl group, which included simple reduction to the methylcar-binol and ethylbenzene (lithium or sodium), while the absence of a proton source or presence of a strong... 

Regioselective alkylations at C-6 of 2-methylcyclohexanone have been accomplished via the alkylation of thermodynamically unstable trisubstituted lithium, lithium triethanolamine borate, potassium triethylboron, tri- -butyltin and benzyltrimethylammonium enolates (c/. 2). Alkylation is faster than equilibration for the more reactive alkylating agents. Although enolate equilibration has been shown to compete with butylation using n-butyl iodide under certain conditions, butylation of the enolate (2 M = Li) in liquid ammonia-THF gave a mixture of cis- and /ra/ij-2-methyl-6-butylcyclohexanone along with 2-methylcyclohexanone in an 83 17 ratio in 90% yield no 2,2-dialkylcyclohexanone was obtained in this reaction (Scheme 8). ... 

The regioselectivity of the reductive cleavage of alkyl vinyl ethers with Cp /Sm(TI11 ) , that is, competition (Scheme 318) between (i) sp2 C-O fission () leading to vinyl species and alkoxides and (ii) sp3 C-O fission to enolates and alkyl complexes has been studied. Interestingly, it was found that the selectivity depends on the substituent R3. The path (i) was observed for R3 = Me (R1 =Ph, R2 = H), while (ii) was found for R3 = benzyl. The reactions were detected by H NMR spectroscopy. Hydrolysis, deuterolysis, and electrophilic trapping of the intermediates were used to prove the kind of bond cleavage.1110... 

Enolates are generated from a-cyanoketones. Such species undergo regioselective alkylation. ... 

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