Phenylacetic acid, enolate

Lithium enolates of carboxylic acids such as phenylacetic acid or of amides such as N-methyl-N-phenylvaleric acid amide 1974 are oxidized by BTSP 1949 to a-hydroxy acids, which are isolated after esterification, e.g., to 1973, or to a-hydroxyamides such as 1975 [155] (Scheme 12.43) (cf. also the formation of 3-hydroxybutyrolactam 1962). 

Inclusion of basic nitrogen in the p-position is also compatible with antiinflammatory activity in this series. Nitration of phenylacetic acid (27) affords 28. Methyl iodide alkylation of the enolate prepared from 28 using two equivalents of sodium hydride gives 29. This appears to involve an Ivanov intermediate (28a). Catalytic reduction of the... 

Base-catalyzed condensation between phenylacetic acid and phthalic acid produces enol lactone 78, which is reduced to benzoate 79 with HI and phosphorous. Friedel-Crafts cyclization by polyphosphoric acid followed by reduction produces alcohol 80. This alcohol forms ethers exceedingly easily, probably via the carbonium ion. Treatment with N-methyl-4— piperidinol in the presence 6f acid leads to the antidepressant hepzidine (81). 

Other studies have provided additional data on the relative stabilities of the lithium aldolates 14 and 15 derived from the condensation of dilithium enediolates 13 (Rj = alkyl, aryl) with representative aldehydes (eq. [ 10]) (16). Kinetic aldol ratios were also obtained for comparison in this and related studies (16,17). As summarized in Table 4, the diastereomeric aldol chelates 14a and ISa, derived from the enolate of phenylacetic acid 13 (R = Ph), reach equilibrium after 3 days at 25° C (entries A-D). The percentage of threo diastere-omer 15 increases with the increasing steric bulk of the aldehyde ligand R3 as expected. It is noteworthy that the diastereomeric aldol chelates 14a and 15a (Rj = CH3, C2HS, i-C3H7) do not equilibrate at room temperature over the 3 day period (16). In a related study directed at delineating the stereochemical control elements of the Reformatsky reaction, Kurtev examined the equilibration of both... 

Optically active a -hydroxy acids The enolate of the amide (2) derived from phenylacetic acid and L-prolinol (10,332) is oxidized by 2-(phenylsulfonyl)-3-phen-yloxaziridine (1) to give optically active a-hydroxy amides (3). Significantly, the configuration of 3 depends upon the base. The lithio enolate (LDA) is converted to the (S)-isomer in >95% de, whereas the sodio enolate, generated with NaN[Si(CH3)3]2, is converted into the (R)-isomer in 93% de. 

The halogens in o-bromo- or o-iodo-veratric acids are replaced by ketone enolates to give primary products which on lactonization or lactamization lead to benzazepines or benzoxepines respectively.126 There would appear to be no reason why this reaction could not be extended to reactions of o-halo-phenylacetic acids in general. 

SCHEME 129. Enantioselective condensation of phenylacetic acid lithium enolate with benzalde-hyde and the proposed transition state model603... 

The procedure is based upon the standard method of Wis-licenus.1 Ethyl phenylmalonate has also been obtained from benzyl cyanide and ethyl carbonate. Phenylmalonic acid has been prepared by carbonation of the enolate of phenylacetic acid. ... 

Another important example of the importance of chirality, related to rheumatology, is that shown by some members of the NSAID family of aryl acids. Certain molecules which inhibit prostaglandin synthetase in vitro show in vivo antiinflammatory actions. Such compounds include several families of acidic NSAIDs, particularly the aryl acids salicylates, indomethacin analogs, phenylacetic acids, fenamic acids and enolic compounds. With respect to the indomethacin analogs, an important characteristic has emerged, namely, the requirement for a sinister absolute configuration (the S form, which happens to be -t-) at the chiral centre. For these drugs the (5)-(-l-) enantiomers show dominant, if not exclusive, activity. ... 

Sodium enolates of ketones and disodium enediolates of substituted phenylacetic acids reacted with activated aziridines to afford 7-amido ketones and 7-amidobutyric acids, respectively (Scheme 72). Aziridine-2-carboxylic acid esters can be utilized as versatile precursors for amino acid derivatives. Although the product distribution resulting from the reaction of activated aziridine-2-carboxylates with amines depends on the structure of the reactants, the reactions with alcohols or thiols in the presence of acidic cabilysts generally gave the a-amino acid derivatives (Scheme 73). ° On the other hand, free 3-methyl-2-aziridinecarboxylic acids (168) reacted with thiophenol, cysteine and glutathione to afford P-amino acid derivatives with sulfur substituents at the a-position as the main product (Scheme 73). ... 

The Ivanov reaction is the preparation of a 3-hydroxy acid by reaction of the magnesium dianion of a carboxylic acid with an aldehyde or ketone." In a seminal paper, Zimmerman and Traxler investigated the Ivanov reaction of phenylacetic acid and benzaldehyde and obtained anti and syn 3-hydroxy acids (127) and (128) in 69% and 22% yields, respectively (equation 85). The observed stereochemistry was rationalized with a cyclic, chair-like transition state in which a magnesium cation is chelated by one oxygen each of the carboxylate enolate and the aldehyde (the Zimmerman-Traxler transition state ). 

As a nucleophile, a carbanion can react readily with a carbon atom bearing a good leaving group, which is a useful method for forming new carbon-carbon bonds. The aldol reaction and the Claisen condensation are familiar examples of carbanions (tis enolates) undergoing nucleophilic addition to carbon-oxygen double bonds. Carbanions may also act as nucleophiles in Sn2 reactions. The reaction of phenylacetic acid (90) with sodium in liquid ammonia leads to a carbanion (91) that reacts with benzyl chloride to produce 23-diphenylpropionic acid (92, equation 5.66). ... 

The enolate ions react with phosphorochloridites to give enolphosphites (106, 107). However, the dianion of phenylacetic acid is alkylated at the a carbon (108). It appears that these processes are subject to symbiotic control. 

The most widely accepted transition state model of the aldol addition is the Zimmerman-Traxler model [72]. Originally postulated in a seminal paper dating from 1957 for the addition of Ivanov reagents [73] - dianions of phenylacetic acid with MgX as counterions (cf. Section 2.1) - to benzaldehyde, the model postulates a sbc-membered chair-like transition state. This hypothesis was adapted to a numerous aldol additions performed with a large variety of enolates of hthium, boron, and other metals. The strength of this model is a convincing explanation for the cis-syn, trans-anti correlation, as outlined in Scheme 4.30. 

A cyclic transition state model, that differs from the Zimmerman-Traxler and the related cyclic models inasmuch as it does not incorporate the metal in a chelate, has been proposed by Mulzer and coworkers [78] It has been developed as a rationale for the observation that, in the aldol addition of the dianion of phenylacetic acid 152, the high ti-selectivity is reached with naked enolate anions (e.g., with the additive 18-crown-6). Thus, it was postulated that the approach of the enolate to the aldehyde is dominated by an interaction of the enolate HOMO and the n orbital of the aldehyde that functions as the LUMO (Scheme 4.31), the phenyl substituents of the enolate (phenyl) and the residue R of the aldehyde being oriented in anti position at the forming carbon bond, so that the steric repulsion in the transition state 153 is minimized. Mulzer s frontier molecular orbital-inspired approach reminds of a 1,3-dipolar cycloaddition. However, the corresponding cycloadduct 154 does not form, because of the weakness of the oxygen-oxygen bond. Instead, the doubly metallated aldol adduct 155 results. Anh and coworkers also emphasized the frontier orbital interactions as being essential for the stereochemical outcome of the aldol reaction [79]. 

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