Ketones from orthoesters

B. Suggest a detailed mechanism for the acetal exchange used in this chapter to make an acetal of a ketone from an orthoester. 

Schiff bases (14), which are formed by reaction between DAMN and appropriate carbonyl reagents, are oxidatively cyclized to give a variety of 2-substituted 4,5-dicyanoimidazoles (15) (Scheme 2.1.5). Although dichlorodicyanoquinone (DDQ) or diaminosuccinonitrilc (DISN) have been used frequently to achieve the oxidative cyclization, long reaction times (17 h to 4 days under reflux) are a disadvantage, and N-chlorosuccinimide (NCS) under basic conditions is more convenient in many cases. The Schiff bases are best formed from aromatic aldehydes, but aliphatic aldehydes and ketones, ketoesters, orthoesters, amides, imidates and cyanogen chloride have all been used [15, 41-49J. 

The most commonly used protected derivatives of aldehydes and ketones are 1,3-dioxolanes and 1,3-oxathiolanes. They are obtained from the carbonyl compounds and 1,2-ethanediol or 2-mercaptoethanol, respectively, in aprotic solvents and in the presence of catalysts, e.g. BF, (L.F. Fieser, 1954 G.E. Wilson, Jr., 1968), and water scavengers, e.g. orthoesters (P. Doyle. 1965). Acid-catalyzed exchange dioxolanation with dioxolanes of low boiling ketones, e.g. acetone, which are distilled during the reaction, can also be applied (H. J. Dauben, Jr., 1954). Selective monoketalization of diketones is often used with good success (C. Mercier, 1973). Even from diketones with two keto groups of very similar reactivity monoketals may be obtained by repeated acid-catalyzed equilibration (W.S. Johnson, 1962 A.G. Hortmann, 1969). Most aldehydes are easily converted into acetals. The ketalization of ketones is more difficult for sterical reasons and often requires long reaction times at elevated temperatures. a, -Unsaturated ketones react more slowly than saturated ketones. 2-Mercaptoethanol is more reactive than 1,2-ethanediol (J. Romo, 1951 C. Djerassi, 1952 G.E. Wilson, Jr., 1968). 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitnles arises both from the reactivity of the C=N bond, and from the abiHty of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxyHc acids and esters, aldehydes, ketones, large-ring cycHc ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy pubHshed (10). 

The fact that reaction can be made to go with (25), but not with the simple R OH, is due to the ASe (c/ p. 36) value for the former being more favourable than that for the latter, which involves a decrease in the number of molecules on going from starting material to product. Both aldehydes and ketones that are otherwise difficult to convert into acetals may often be transformed by use of orthoesters, e.g. HC(OEt)3, triethoxymethane ( ethyl orthoformate ), with NH Cl as catalyst. 

All the foregoing syntheses of 0,0,0-orthoesters required at least two steps because 0,0,0-orthoesters cannot usually be prepared directly from esters by reaction with alcohols under add conditions analogous to the preparation of acetals from aldehydes and ketones. There are some exceptions.237 -239 For example. reaction of the racemic mixture of cis- and fraftf-lactones in Scheme 2.115 with (/ ,/ )-butane-2,3-diol in refluxing benzene afforded a mixture of four diastereoisomeric orthoesters (99%) in the ratio 6 6 1 1 that could be sepa-... 

Orthoesters of acrylic acid are converted to y.y-dialkoxyallylzirconocene ethoxides with CpjZr. These latter species serve as 2,2-dialkoxycyclopropyl anion synthon, showing y-addition reactivity toward carbonyl compounds to afford homoallylic alcohols. In the presence of MejSiOTf cyclopropyl carbinols are formed, due to a switch to the -addition mode conjugate addition to enones leads to P-cyclopropyl ketones (e.g., from 2-cyclopen tenone)... 

O-AIkylidene and -arylidene derivatives of D-gluco-, D-allo-, D-manno-, and D-talo-pyranose are difficult to prepare directly. Lem-ieux and Detert59 prepared these from the 1,2-O-ethoxyethylidene orthoester, and were able to recover quantitative yields of 1,2-O-iso-propylidene, 1,2-O-cyclohexylidene, 1,2-O-cyclopentylidene, and diastereoisomeric 1,2-O-benzylidene acetals of D-glucopyranose. In their procedure, the orthoester is allowed to react, with scrupulous exclusion of moisture, with a ketone or aldehyde in the presence of an acid catalyst. 

The biogenetic structural relationships and structure-activity relationships of the diterpenoid skin irritants and co-carcinogens of the Euphorbiaceae and Thymelaceae have been described in a number of reviews.Baliospermum montanum (Euphorbiaceae) contains the orthoester montanin (111) and baliospermin (112) together with some 12-deoxyphorbol-13-esters. A number of new highly irritant 1-alkyl-daphnane orthoester derivatives [(113) and the corresponding 3-ketone] have been obtained from the Thymelaceae. The Chinese... 

Ketones or aldehydes undergo acetal exchange with orthoesters. The mechanism starts off as if the orthoester is going to hydrolyse but the alcohol released adds to the ketone and acetal formation begins. The water produced is taken out of the equilibrium by hydrolysis of the orthoester, and we get two molecules from two entropy is no longer our enemy. 

DIOXANES (SCHEME II). The dioxanes were made from the commercially available (Aldrich) 2,2-bis(hydroxymethyl)propionic acid. This material, condensed with an aldehyde or ketone, gave the desired dioxanecarboxylic acid 7. The carbonyl containing compounds employed were formaldehyde (7a,R, R =H), acetone (7b, R, R =Me), and benzaldehyde ( 7c, R =H, R =Ph). These condensations proceeded smoothly under acid catalysis in good yields (80-95%). In addition to condensation with carbonyls, the diol was also condensed with triethylorthoformate to give a cyclic orthoester (7d, R =H, R =0Et). Condensation with dimethylcarbonate gave the cyclic carbonate (7e, R, R =0). 

Applications Based on Deprotonation of Selenoketals R Se CHB — alkyl) and Seleno-orthoesters. Deprotonation, usually with KDA, of selenoketals (PhSe)2CHR (R = alkyl) gives carbanions that react efficiently with common electrophiles [primary alkyP - and benzyl halides, aldehydes, ketones, and (for R = alkyl or H) epoxides ]. A few of the resulting selenoketals have been hydrolysed under very mild conditions. Carbanions derived from selenoketals undergo intramolecular reactions [e.g. (49)] when appropriately substituted, and can be used in the synthesis of silyl enol ethers, e.g. (50). ... 

Enol ethers are prepared by acid-catalyzed transesterification or transetherification from other enol ethers, orthoesters, ketone acetals and similar precursors with allyl alcohol. The intermediate isopyrocin (the same holds for pyrocin) [48] is cleaved with thionyl chloride to afford the substrate 35 for cyclizing 1,3-elimination (Reaction scheme 21) in the presence of base [49] without significant P-elimination. 

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