Propionic acid reactions with carbonyl compounds

An early effort to generate a 3-lithiated propionic acid derivative and react it with (external) electrophiles was reported in 1978 [42]. Since simple 3-lithioesters failed to undergo the required reaction, the alkyl carboxylate portion was protected by preceding conversion to the carboxylate anion. Treatment of lithium 3-bromo-propionate with lithium naphthalide generated the desired dilithiated propionic acid, which gave moderate yields of y-hydroxy acid addition products with carbonyl compounds, Eq. (45). 

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

The reaction of nitroarenes with silyl end ethers and ketene silyl acetals in MeCNATiF with 1 equiv. of TASF, followed by in situ oxidation with Br2 or DDQ, provides an easy route to a-nitroaryl carbonyl compounds (Scheme l).12 The use of these compounds as reagents for the synthesis of arylacetic acids, propionic acids, indoles, 2-indolinones and other heterocyclic compounds has recently been described.88... 

Ueda et al. (37) have proposed magnesium oxide catalyst modified with a transition metal ion (M/MgO) for the vinylation of methyl propionate and acetonitrile. Acetonitrile is vinylated to acrylonitrile selectively (94% selectivity at about 10% conversion) over Cr/MgO catalysts at 350 C in the absence of oxygen. The selectivity for the vinylation of methyl propionate over Mn/MgO catalysts is not different from the value obtained with Ti -TSM in the presence of oxygen. The catalyst system, however, is not effective for the reaction of acetic acid. We conducted the reaction of acetonitrile and methanol over Ti -TSM in the presence of oxygen, and found that the vinylation does not take place but the hydrolysis to acetic acid and subsequent esterification with methanol into methyl acetate proceed preferentially. It is likely that Ti -TSM is an appropriate catalyst for the vinylation of carbonyl compounds and M/MgO is appropriate for the vinylation of nitriles. 

Only 4H-4-OXO derivatives of this heterocycle have been prepared. The infrared spectra of these compounds show a characteristic carbonyl absorption at 1780-1790 cm A variety of 2-methyl compounds have been obtained by reaction of the appropriately substituted aminopyrazinecarboxylic acids (9) with acetic anhydride, " an approach which has been described in many patents.Other anhydrides such as propionic and butyric anhydrides react to give the expected products. No reports of 2-unsubstituted compounds have appeared. 

The phenylhydrazones required for the Fischer synthesis are prepared from carbonyl compounds and phenylhydrazine. Alternatively, they can be obtained by a Japp-Klingemann reaction from CH-acidic compounds (y diketones, y -keto esters, etc.) or from enamines by interaction with aryldia-zonium salts. More complex indoles are thus accessible by a simple route. This is demonstrated by the synthesis of 3-(indol-3-yl)propionic acid 40, the starting material of Woodward s lysergic acid synthesis [52]. 

In contrast to facile a-alkylation of carbonyl compounds, a-arylation or alkenylation of carbonyl compounds has been considered to be a difficult reaction. Recently, a big breakthrough has occurred, and methods for the smooth a-arylation or alkenylation of carbonyl compounds have been developed [1]. Active methylene compounds, ketones, aldehydes, esters, amides and nitriles are now a-arylated easily not only with aryl iodides, but also with bromides and even chlorides. These reactions will lead to wide-ranging applications. A typical example of a synthetic application of the innovative reactions is a new preparative method for a-arylated carboxylic acids, such as ibuprofen (1) and naproxen, by direct a-arylation of acetate or propionate. 

This reaction was first reported by Johnson et al. in 1970. It is a highly stereoselective synthesis of y,5-unsaturated esters from the reaction between allylic alcohols and an orthoester in the presence of a trace amount of weak acid, such as propionic acid. Because this reaction is the modification or variant of the Claisen Rearrangement, it is often referred to as the Johnson orthoester Claisen rearrangement. Occasionally, this reaction is also known as the Claisen-Johnson orthoester rearrangement, " or Johnson orthoester protocol. This reaction involves the formation of mixed orthoester from allyl alcohol and the added orthoester, which loses an alcoholic component to form a ketene acetal then migrates to unsaturated carbonyl compounds via the Claisen Rearmagement with high syn selectivity. Posner further extended this reaction to use sulfonyl orthoester. Overall, this reaction has been applied to the synthesis of a variety of complicated natural products, such as squalenes. ... 

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