Acetals in synthesis

Amide and lactam acetals in synthesis of heterocyclic compounds 92KGS762. 

Formamide acetals in synthesis of heterocycles 79T1675. Heteroannulation with O-aminoaldehydes 80T2359. 

Vert de lilas is useful as an additive in soaps since acetals, unlike aldehydes and ketones, are stable to the alkali in soaps. The main use tor acetals in synthesis is as protecting groups for aldehydes and ketones (see Chapter 9). Cyclic acetals (e.g, 4) are usually used for ketones (Chapter 7) the disconnection is the same once the carbonyl carbon has been discovered. 

Several studies have been reported in which free-energy relationships involving oxidant complexes were observed. The general use of thallium(ni) acetate in synthesis has prompted the evaluation of the reactivity of various acetatothallium(m) species. In the oxidation of hydrazine the rate law is of the form... 

Simple esters cannot be allylated with allyl acetates, but the Schiff base 109 derived from o -amino acid esters such as glycine or alanine is allylated with allyl acetate. In this way. the o-allyl-a-amino acid 110 can be prepared after hydrolysis[34]. The Q-allyl-o-aminophosphonate 112 is prepared by allylation of the Schiff base 111 of diethyl aminomethylphosphonates. [35,36]. Asymmetric synthesis in this reaction using the (+ )-A, jV-dicyclohex-ylsulfamoylisobornyl alcohol ester of glycine and DIOP as a chiral ligand achieved 99% ec[72]. 

An interesting new synthesis of 2,4,5-trisubstituted and 2,4-disubstituted alkylthiazoles has been reported by Dubs (807). Heating the easily obtainable derivatives (276) with ammonium acetate in acetic acid gives thiazoles (10), Rj, Rj = alkyl and R3 = H or alkyl in good yields (Scheme 143). 

Finally, the importance of quinolinium salts to dye chemistry accounts for the long, productive history of their synthesis. The reaction of A/-methylformanihde with ketones, aldehydes, ketone enamines, or enol acetates in phosphoryl chloride leads to high yields of /V-methylquinolinium salts (60). 

Later, a completely different and more convenient synthesis of riboflavin and analogues was developed (34). It consists of the nitrosative cyclization of 6-(A/-D-ribityl-3,4-xyhdino)uracil (18), obtained from the condensation of A/-D-ribityl-3,4-xyhdine (11) and 6-chlorouracil (19), with excess sodium nitrite in acetic acid, or the cyclization of (18) with potassium nitrate in acetic in the presence of sulfuric acid, to give riboflavin-5-oxide (20) in high yield. Reduction with sodium dithionite gives (1). In another synthesis, 5-nitro-6-(A/-D-ribityl-3,4-xyhdino) uracil (21), prepared in situ from the condensation of 6-chloro-5-nitrouracil (22) with A/-D-ribityl-3,4-xyhdine (11), was hydrogenated over palladium on charcoal in acetic acid. The filtrate included 5-amino-6-(A/-D-ribityl-3,4-xyhdino)uracil (23) and was maintained at room temperature to precipitate (1) by autoxidation (35). These two pathways are suitable for the preparation of riboflavin analogues possessing several substituents (Fig. 4). 

Manufacture. The most widely employed method for the commercial synthesis of (H)-cinnamic acid uti1i2es ben2aldehyde, acetic anhydride, and anhydrous sodium or potassium acetate in a condensation reaction commonly referred to as the Perkin reaction (11). 

There are several examples of intramolecular reactions of monocyclic /3-lactams with carbenes or carbenoids most of these involve formation of olivanic acid or clavulanic acid derivatives. Thus treatment of the diazo compound (106) with rhodium(II) acetate in benzene under reflux gives (107), an intermediate in the synthesis of thienamycin (80H(14)1305, 80TL2783). 

Since a few protective groups cannot satisfy all these criteria for elaborate substrates, a large number of mutually complementary protective groups are needed and, indeed, are becoming available. In early syntheses the chemist chose a standard derivative known to be stable to the subsequent reactions. In a synthesis of callistephin chloride the phenolic —OH group in 1 was selectively protected as an acetate. In the presence of silver ion the aliphatic hydroxyl group in 2 displaced... 

The work of Hyatt on cyclotriveratrylene—derived octopus molecules contrasts with this. Of course, these species have the advantage of ligand directionality absent in the benzene-derived octopus molecules. Except for the shortest-armed of the species (i.e., n = 1), all of the complexing agents (i.e., n = 2—4) were capable of complexing alkali metal cations. Synthesis of these species was accomplished as indicated below in Eq. (7.7). These variations of the original octopus molecules were also shown to catalyze the reaction between benzyl chloride and potassium acetate in acetonitrile solution and to effect the Wittig reaction between benzaldehyde and benzyltriphenylphos-phonium chloride. 

The bromination of 4,5-j -dihydrocortisone acetate in buffered acetic acid does not proceed very cleanly (<70%) and, in an attempt to improve this step in the cortisone synthesis, Holysz ° investigated the use of dimethylformamide (DMF) as a solvent for bromination. Improved yields were obtained (although in retrospect the homogeneity and structural assignments of some products seem questionable.) It was also observed that the combination of certain metal halides, particularly lithium chloride and bromide in hot DMF was specially effective in dehydrobromination of 4-bromodihydrocortisone acetate. Other amide solvents such as dimethylacetamide (DMA) and A-formylpiperidine can be used in place of DMF. It became apparent later that this method of dehydrobromination is also prone to produce isomeric unsaturated ketones. When applied to 2,4-dibromo-3-ketones, a substantial amount of the A -isomer is formed. 

Ozonization of A -steroids usually gives complex mixtures (however, see ref. 48). Ozonolysis became a practical step in the general synthesis of B-norsteroids with the discovery that added methanol" (or formaldehyde ) improves yields significantly. Thus, Tanabe and Morisawa prepared 5/ -hydroxy-6/ -formyl-B-norsteroids (74) from cholesterol acetate, dehydroepiandrosterone acetate and pregnenolone acetate in overall yields of 64-74% by the reaction sequence represented below. 

Ring enlargement via an insertion of a carbene generated in the a-position to the ring is an established method and has also been applied to the synthesis of oxepins. The ()3-allylpalladium chloride catalyzed decomposition of substituted ethyl diazo(4/7-pyran-4-yl)acetates in benzene at room temperature gives ethyl oxepin-4-carboxylates 1 in excellent yield.190 The ester function can be replaced by the phosphonate group and other P = 0-functions (see Houben-Weyl,... 

The Ireland-Claisen reaction of ( )-vinylsilanes has been applied to the stereoselective synthesis of syn- and c/nti-2-substituted 3-silyl alkcnoic acids. a R-2-Alkyl-3-silyl acids are prepared by rearrangement of ( )-silyl ketene acetals which are generated in situ from the kinetically formed (Z)-enolate of the corresponding propionate ester40. Chelation directs the stereochemistry of enolization of heteroelement-substituted acetates in such a way that the syn-diastereomers are invariably formed on rearrangement403. 

The synthesis of 2-substituted pyrimidines from 1,3-dicarbonyl compounds and urea derivatives was first described by Evans2 and was later improved by Hunt, McOmie, and Sayer3 for the preparation of 2-mercapto-4,6-dimethylpyrimidine. Burness4 employed 3-ketobutyraldehyde acetal in this procedure to give 2-mercapto-4-methylpyrimidine. 2-Mercaptopyrimidine has been prepared from 1,1,3,3-tetraethoxypropane and thiourea by variations of this basic method 3 6 6 as well as by the reaction of 2-chloropyrimidine with thiourea 1 or sodium hydrosulfide.8... 

A number of microwave-assisted multicomponent methods for the synthesis of imidazoles have been reported [68-71 ]. The irradiation of a 1,2-diketone and aldehyde with ammonium acetate in acetic acid for 5 min at 180 °C in a single-mode reactor provides alkyl-, aryl-, and heteroaryl-substituted imidazoles 39 in excellent yield (Scheme 14) and this method has been used for the rapid and efficient preparation of two biologically active imidazoles, lepidiline B and trifenagrel [68]. 

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