Amidation using enolates

In recent years this simple picture has been completely transformed and it is now recognized that the alkali metals have a rich and extremely varied coordination chemistry which frequently transcends even that of the transition metals. The efflorescence is due to several factors such as the emerging molecular chemistry of lithium in particular, the imaginative use of bulky ligands, the burgeoning numbers of metal amides, alkoxides, enolates and organometallic compounds, and the exploitation of multidentate... 

As an alternative, tin enolates are very useful in these additions. Usually they are prepared in situ from the amide using tin(II) trifluoromethanesulfonate and a base. They are subsequently reacted with an enone, catalyzed by a Lewis acid47-48 (see Table 3). With triinethylsilyl trifluoromethanesulfonate as a catalyst, in the presence of proline derived diamines anti-adducts are formed exclusively49 (see Section 1.5.2.4.3.1.). 

TABLE 4-20. Asymmetric Oxidation of Lithium Enolates and Amides Using ( + )-147 as the Oxidant... 

An investigation of keto-enol tautomerism for perfluorinated keto-enol systems was undertaken. N-methylpyrrolidone (NMP) catalyzes equilibration of the keto and enol forms, but if used in more than trace amounts, it drives the equilibrium strongly toward enol because of hydrogen bonding to the amide. The enol is much more thermodynamically stable than its ketone, and it was found that in mildly Lewis basic solvents, such as ether, THE, acetonitrile, and NMP, the enohzation equilibrium lies too far right to allow detection of ketone (Correa et al., 1994). 

ASYMMETRIC OXIDATION OF LITHIUM ENOLATES OF ESTERS AND AMIDES USING (+)-(2R.8aS)-10-(CAMPHORYLSULFONYL)OXAZIRIDINE... 

This result dictated that any alkene-generating elimination process has to proceed via conditions not basic enough to enolize the tertiary amide. Using a procedure developed by Ochiai, the tetraalkylstannane unit of 119 was converted into the chlorotrialkylstannane of 121 in excellent yield. The formation of a halotin species enabled the use of the Tamao-Fleming oxidation36 for formation of the primary alcohol within 122. 

The original system considered by this group involved the lithium enolate and a chiral diether. The results suggest that the presence of an excess of the achiral lithium amide used to deprotonate the ester improves the induction level (Scheme 134)618. Remarkably, employing substoichiometric amounts (20 mol%) of the chiral ligand led to a marginal decrease in the e.e. value. The authors proposed that the formation of an intermediate ternary complex between the enolate, the excess lithium amide and the chiral diether could be responsible for the observed enantiomeric excesses. 

A first set of experiments, the study of the protonation of enolates obtained from benzaldehyde Schiff bases and Lithium Diisopropylamide, showed that the asymmetric induction was not significantly affected by the size of the R moiety of the amino acid (R = Me, Et, i-Pr, n-Bu, f-Bu, Ph ee = 44-56%). The two main factors improving the enantioselection were the Ar substituent of the Schiff base and the lithium amide used for the deprotonation. The following results (Table 1) indicate clearly that the enantioselectivity increases with the electron-donating power of substituents para to the Schiff base (eq 3), leading to 70% ee with the Schiff base of p-methoxybenzaldehyde derived from phenylglycine. ... 

Since most of the synthetically useful enolate anions described in the previous section are prepared by the reactions of enolizable substrates with alkali metal amide bases, it is appropriate to note a few structures of these amide bases. The common bases in synthetic organic chemistry include LDA and LHMDS. The structures of both of these bases are known as the THF solvates.Both of these compounds form bis-solvated dimers corresponding to structure (201). The diethyl ether solvate of LHMDS also forms a bis-solvated dimer (202).Sodium hexamethyldisilazide crystallizes as an unaggregated monomer from benzene solution.Two different cryst line forms of KHMDS are known as the polymeric dioxane solvate (203), ° and the unsolvated dimer (204). ... 

Oppolzer developed this chemistry into an asymmetric synthesis of a-amino acids 110 using enolates of amides 107 derived from his chiral sultam 109. The hydroxylamines 108 are isolated in perfect diastereomeric purity which translates into high ees in the final products14 110. 

Table 3. Enantiosclcctivc Hydrogenation of Enol Acetates and of Itaeonic Acid and Its Esters and Amides Using Rhodium Phosphanc Catalysts...

Scheme 6.22. [2,3]-Wittig rearrangement of amide zirconium enolates using Katsuki s pyrrolidine auxiliary [90].

Aldol reaction of the enolate of lactam 119 and 4-(3-methyl-but-2-enyloxy)-benzaldehyde [70] provided a mixture of two separable alcohols 127. Subsequent elimination of the mesylate of both aldol adducts afforded 128. Finally, reduction of the amide using A1H3 [71] and acid hydrolysis of the acetal provides racemic TAN1251A. 

The modifications of the Gilman-Speeter reaction include the activation of zinc by tri-methylsilyl chloride (TMSCl) and the application of lithium ester enolate" or lithium thioester enolate as the substitute for the traditional Reformatsky reagent. In these modifications, it was found that TMSCl-activated zinc is much more effective in promoting the reaction between ethyl bromoacetate and Schiff bases. In addition, in the presence of a chiral ether ligand, the reaction between lithium ester enolate and imines affords 0-lactams of high enantiomeric excess, probably due to the formation of a ternary complex reagent. " The enantioselectivity and reactivity of the ternary complex depend on the size and nature of the lithium amide used. For example, the lithium amide from 2,2,6,6-tetramethylpiperidine (LTMP) is unfavorable for this reaction." ... 

Enol triflate, which is easily obtained from the keto-carbonyl group regioselectively, can be converted into ester or amide using Pd-catalyzed carbonylation. This means that we can introduce the ester or amide group on the keto-carbonyl carbon to form a,/S-unsaturated ester or amide. 

One of the most attractive options for asymmetric aldol reactions available to the synthetic chemist is to use enolates of carboxylic acid derivatives (inter alia ester, amide, or imide) with an appended chiral auxiliary (alcohol, amine, urethane). An early example of this approach dates back to 1938, when McKenzie reported that benzaldehyde undergoes addition by (-)-menthyl malonate (42) to give propanoic acid derivative 43 in 21 % ee (Equation 4) [43]. The modest selectivity was attributed to the conformational flexibility of ester enolates (cf. 44). 

Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide)... 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Carbonylation of enol triflates derived from ketones and aldehydes affords Q,/)-unsaturated esters[332]. Steroidal esters are produced via their aryl and enol triflates[328]. The enol triflate in 477 is more reactive than the aryl tritlate and the carbonylation proceeds stepwise. First, carbonylation of the enol triflate affords the amide 478 and then the ester 479 is obtained in DMSO using dppp[333]. 

An isolated acetoxyl function would be expected to be converted into the alkoxide of the corresponding steroidal alcohol in the course of a metal-ammonia reduction. Curiously, this conversion is not complete, even in the presence of excess metal. When a completely deacetylated product is desired, the crude reduction product is commonly hydrolyzed with alkali. This incomplete reduction of an acetoxyl function does not appear to interfere with a desired reduction elsewhere in a molecule, but the amount of metal to be consumed by the ester must be known in order to calculate the quantity of reducing agent to be used. In several cases, an isolated acetoxyl group appears to consume approximately 2 g-atoms of lithium, even though a portion of the acetate remains unreduced. Presumably, the unchanged acetate escapes reduction because of precipitation of the steroid from solution or because of conversion of the acetate function to its lithium enolate by lithium amide. 

LDA (Section 21.10) Abbreviation for lithium diisopropyl-amide LiN[CH(CH3)2]. LDA is a strong, sterically hindered base, used to convert esters to their enolates. 

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