Enolates also aminations

Aldehydes enolize very readily but also self-condense rather easily. Lithium enolates can t be made cleanly, because the self-condensation reaction happens even at -78 °C and is as fast as the enoliza-tion by LDA. Silyl enol ethers are a much better choice. They clearly must not be made via the lithium enolate, and amine bases are usually used. As each molecule of enolate is produced in the equilibrium, it is efficiently trapped by the silylating agent. 

Instead of alkyl halides other electrophiles, such as imines or iminium ions, are also used for the nucleophilic attack of enolates. Primary amines react with aldehydes and ketones to produce imines °. For example, the reaction of acetophenone with methyl amine gives... 

Although stereoselective formation of enolates from acyclic ketones with bases such as LDA is rather difficult, stereodefined boron enolates are more readily accessible. In the Mukaiyama method, an ethyl ketone is treated with a dialkylboron triflate and a tertiary amine, usually i-Pr2NEt. The resultant Z-(0) boron enolates (also known as enol borinates) are believed to be formed under kinetic control by deprotonation of the Lewis acid-complexed substrate. Brown and co-workers have shown that E- 0) boron enolates may be prepared by treatment of ethyl ketones with dicyclohexylboron chloride in the presence of Et3N. ... 

The Michael addition of secondary amines to a,)S-unsaturated carbonyl compounds under MWI essentially required the presence of water to drive the amine addition to completion and the presence of at least 10 mole equivalents of the amine. Besides increasing the polarity and possibly some micellar effect, water facilitates protonation of the resulted enolate from amine addition. In a typical procedure, benzalacetophenone was mixed with morpholine (469) and water in a teflon flask and subjected to MWI for 2 min to yield 93% of the 1,4-adduct 471 (Scheme 92). The method was also extended to other morpholine derivatives 472 and 473 in 30% and 100% yields, respectively (00SC643). 

Ethylphenol and 1 eq. KOBu-r in benzene kept at 25° for 1 h, 2-acetoxymethyl-phenol added, and the mixture kept at 25° for 3 h product. Y 63%. F.e. and nucleophiles (MeOH, amines, NaNj, (3-dicarbonyl enolates), also syntheses via p-quinone methids and vinylogs thereof, s. B. Loubinoux et al.. Tetrahedron Letters 30, 1939-42 (1989). 

Studies of the amination of ring-substituted phenylketenes showed different behavior between their reactions with -butylamine and with diethylamine. Each amine reacted by an initial addition forming an intermediate amide enol which then was converted to the product amide in a second step that was also amine catalyzed. n-Butylamine was however more reactive in conversion of the amide enols to the product amides than was diethylamine, and this permitted elucidation of the second step... 

Three-component Mannich-type reactions of aldehydes, amines, and silicon enolates also proceeded smoothly using PS-SO3H in water (Scheme 3.37). In general, ketene silyl acetals are known to be easily hydrolyzed in the presence of water however, such water-labile compounds could be successfully used in this reaction. Moreover, a remarkable effect of the loading levels of the polystyrene-supported sulfonic acid on yields was observed. It was suggested that the hydrophobic environment created by the catalyst might suppress hydrolysis of ketene silyl acetals. 

Indeed, remarkable enantioselectivity was observed with the enolates of cyclohexanone, a-tetralone, lactams, and lactones upon treatment with benzylic and allylic bromides or iodides but also methyl iodide. As the presence of lithium bromide was found to have a beneficial effect on the stereoselectivity, it was concluded that a complex between the lithium enolate, the amine 2, and lithium bromide was crucial for high enantioselectivity some illustrative examples are shown in Scheme 5.2 [2]. 

Also noteworthy is the condensation of dimethyl phthalate (71) with TV.A-bis methoxycar-bonyl)alkyl- and -aryl]amines to give 3F/-3-benzazepines which exist as the intramolecularly hydrogen-bonded enol forms, e.g. 72, rather than the generally more stable benzazepinone tautomers.14... 

The (3-elimination of epoxides to allylic alcohols on treatment with strong base is a well studied reaction [la]. Metalated epoxides can also rearrange to allylic alcohols via (3-C-H insertion, but this is not a synthetically useful process since it is usually accompanied by competing a-C-H insertion, resulting in ketone enolates. In contrast, aziridine 277 gave allylic amine 279 on treatment with s-BuLi/(-)-spar-teine (Scheme 5.71) [97]. By analogy with what is known about reactions of epoxides with organolithiums, this presumably proceeds via the a-metalated aziridine 278 [101]. 

The different reactivity mentioned above also proves the validity of inequality ki, k3> >k4 used in the simplification of our model. On the contrary, in the presence of CHA less than one equivalent the signals of both the la and Ih appear, a large extent of deuteration at C-3 is observed both in the cis and tram isomers and in the product flavone (2). Using an excess of amine both isomer gave 2 deuterated at C-3 to an extent ca. 80-85 %. Considering the kinetic profile of the interconversion we conclude that it takes place via an enolate where the rate determining step is the deprotonation at C-3. 

This can also be done at room temperamre by treatment with trimethylsilyl triflate and a tertiary amine or with MesSil in the presence of hexamethyldisilazane. Enol ethers can be pyrolyzed to alkenes and aldehydes in a manner similar to that of 17-3 ... 

In Section 5.1.3 the conversion of aldehydes 491 and 494 into N-silylated Schiff bases and their in-situ reaction with allylmagnesium bromide into unsaturated secondary amines 493 and 495 is described. Likewise, reactions of the N-silylated Schiff bases such as 489 with the lithium enolate of methyl isobutyrate 498 to give yS-lactams such as 499 are also discussed in Section 5.1.3. 

The DKR processes for secondary alcohols and primary amines can be slightly modified for applications in the asymmetric transformations of ketones, enol esters, and ketoximes. The key point here is that racemization catalysts used in the DKR can also catalyze the hydrogenation of ketones, enol esters, and ketoximes. Thus, the DKR procedures need a reducing agent as additional additive to enable asymmetric transformations. 

Scheldt and co-workers have also accessed enolate equivalents from enals to furnish cyclopentanes 236 asymmetrically. Formation of the enolate equivalent from enals 235 with the NHC, followed by an intramolecular Michael reaction and 0-acylation, gives the lactone products 236, which are readily opened by either alcohols or amines to generate functionalised cyclopentane derivatives 237 in excellent ee. 

Tin enolates are also used in aldol reactions.27 Both the Sn(II) and Sn(IV) oxidation states are reactive. Tin(II) enolates can be generated from ketones and Sn(II)(03SCF3)2 in the presence of tertiary amines.28 The subsequent aldol addition is syn selective and independent of enolate configuration.29 This preference arises from avoidance of gauche interaction of the aldehyde group and the enolate P-substituent. The syn stereoselectivity indicates that reaction occurs through an open TS. 

Ketones can also be reduced to alkenes via enol triflates. The use of Pd(OAc)2 and triphenylphosphine as the catalyst and tertiary amines as the hydrogen donors is effective.226... 

The silyl ketene acetal rearrangement can also be carried out by reaction of the ester with a silyl triflate and tertiary amine, without formation of the ester enolate. Optimum results are obtained with bulky silyl triflates and amines, e.g., f-butyldimethylsilyl triflate and (V-methyl-Af, /V-dicyclohcxylaminc. Under these conditions the reaction is stereoselective for the Z-silyl ketene acetal and the stereochemistry of the allylic double bond determines the syn or anti configuration of the product.243... 

Imidate esters can also be generated by reaction of imidoyl chlorides and allylic alcohols. The lithium anions of these imidates, prepared using lithium diethylamide, rearrange at around 0°C. When a chiral amine is used, this reaction can give rise to enantioselective formation of 7, 8-unsaturated amides. Good results were obtained with a chiral binaphthylamine.265 The methoxy substituent is believed to play a role as a Li+ ligand in the reactive enolate. 

The oxidation of silyl enol ethers with the osmium tetroxide-amine oxide combination also leads to a-hydroxyketones in generally good yields.147... 

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