Acid chlorides Reformatsky reaction

Scheme 7.5 gives some examples of the Reformatsky reaction. Zinc enolates prepared from a-haloketones can be used as nucleophiles in mixed aldol condensations (see Section 2.1.3). Entry 7 is an example. This type of reaction can be conducted in the presence of the Lewis acid diethylaluminum chloride, in which case addition occurs at -20° C.171... 

Reaction of p-fluorobenzyl chloride with the anion of diethylmethylmalonate ester followed by saponification and decarboxylation leads to acid 9. Polyphosphoric acid cyclization leads to indanone 10. A Reformatsky reaction with zinc amalgam and bromo-acetic ester leads to carbinol 11 which is then... 

A similar sequence starting with the acylation product (76) from metachlorophenylacetonitrile gives the halogenated tricyclic ketone 83. Condensation of that intermediate with ethyl bromoacetate in the presence of zinc (Reformatsky reaction) gives the hydroxyester 84. This product is then in turn dehydrated under acid conditions (85), saponified to the corresponding acid (86), and converted to the dimethyl-amide (87) by way of the acid chloride. The amide function is then reduced to the amine (88) with lithium aluminum hydride catalytic hydrogenation of the exocyclic double bond completes the synthesis of closiramine (89). This compound also exhibits antihistaminic activity. 

The 3,4-dihydrodiol of BcP was synthesized from 4-oxo-l,2,3,4-tetrahydro-BcP (15) by Method I (66). The ketone L was itself prepared from 4-oxo-l,2,3,4-tetrahydrophenanthrene via a multistep sequence entailing Reformatsky reaction with methyl bromocrotonate, dehydration of the resulting alcohol, isomerization to the aryl-butyric acid, and cyclization of its acid chloride with SnCl - Full... 

An important application of the Reformatsky reaction is the conversion of P-hydroxy esters to a, P-unsaturated esters. Acid-catalyzed dehydration usually leads to a mixture of a, P- and P, y-unsaturated esters. However, conversion of the initially formed p-hydroxy esters to their corresponding acetates by treatment with acetyl chloride, followed by base-catalyzed dehydration with NaOEt, produces conjugated esters in high purity. This sequence of reactions provides an alternative route to the Homer-Wads worth-Emmons olefmation of ketones (see Chapter 8). 

In addition to aldehydes and ketones, organic compounds which are known to react with Reformatsky reagents include esters,nitriles, acid chlorides, organic halides,epoxides, nitrones, azirenes" and imines. This section describes the selectivity reported for Reformatsky reactions with functionally substituted aldehydes or ketones. 

Reactions of Reformatsky reagents with esters or with acid chlorides generally give only low yields of P-keto esters. Hauser reported that ethyl a-bromoisobutyrate could be acylated in reasonable yields with either the acid chlorides or the phenyl esters of aromatic acids, but the reaction fails with acylating... 

Enone synthesis. The Smii-cait aldehydes (Reformatsky-type reaction Cyclic ether cleavage. Smli is a with acid chlorides. It also contributes ai Boronate esters. Hydroboration < by Smlj. 

Palladium is a useful catalyst in several reactions which lead to keto-esters. p-Keto-esters react with allylic carbonates, with catalysis by palladium, in a decarboxylative allylation reaction. y-Keto-esters are prepared, in reasonable yield, by the palladium-catalysed regioselective oxidation of Py-unsaturated esters. y-Keto-esters are obtained in good yield by the palladium-catalysed Reformatsky reaction of ethyl bromoacetate and acid chlorides. Derivatives of y-ketopimelic acid are formed by the rhodium-carbonyl-catalysed reaction of derivatives of acrylic acid with carbon monoxide. A mild method for the conversion of propiolic esters into P-keto-esters via thiol addition has been reported (Scheme 63) it has been used in a formal synthesis of ( )-thienamycin. 

Dehydration of the aldol products of a Refomiatsky reaction does not normally occur under the usual reaction conditions but is often accomplished in a separate step to prepare unsaturated esters. Acid-promoted dehydration of -hydroxy esters can give significant amounts of nonconjugated unsaturated esters by either kinetic or thermodynamic control. Mirrington and cowoikers found that acetates can be prepared directly from Reformatsky reaction mixtures by addition of acetyl chloride. Base-promoted elimination of the acetates produced conjugated esters in high yield. For the reaction shown in Scheme 14, the thermodynamic ratio of products (32) (33) is 40 60 and four different acid-promoted dehydration procedures gave at best a 68 32 ratio of products. ... 

A general route to 3-substituted butenolides (72), which could have considerable potential, is the cyclization of phosphonium salts (71), simply by treatment with triethylamine in methylene chloride. The salts are easily obtained from a-bromo-ketones and bromoacetic acid and, in the examples quoted in this preliminary study, overall yields are high except when 2-bromocyclohexanone was used as the ketonic component (c/. 3, 133). The 3-substituted butenolide group present in naturally occurring cardenolides can be built up from an a-methylthioketone residue by a Reformatsky reaction, followed by acid- and base-catalysed rearrangements. ... 

The reaction of a nitrile with a Reformatsky reagent is known as the Blaise reaction and when applied to (9-trimethylsilyl cyanohydrins leads to the formation of tetronic acids with high ee [79]. By working-up the Blaise reaction with ammonium chloride it is possible to isolate... 

Couplings between Reformatsky reagents and aromatic halides are catalyzed by Ni(PPh3)4 " or Pd(PPh3)4, " " with DMF, NMP or HMPA being used as the essential cosolvents. While the Ni-cata-lyzed reaction can be applied to aromatic chlorides, bromides and iodides, the Pd-catalyzed reaction is useful only for iodides. Compatibility of the free carboxylic acid may especially be noted (equation 109). 

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