Bonding enolates

The reaction conditions applied are usually heating the amine with a slight excess of aldehyde and a considerable.excess of 2d-30hydrochloric acid at 100 °C for a few hours, but much milder ( physiological ) conditions can be used with good success. Diols, olefinic double bonds, enol ethers, and glycosidic bonds survive a Pictet-Spengler reaction very well, since phenol and indole systems are much more reactive than any of these acid sensitive functional groups (W.M. Whaley, 1951 J.E.D. Barton, 1965 A.R. Battersby, 1969). 

Keto ester in H bonding enol form ca 1650 Keto from normal chelate-type H bond... 

Also noteworthy is the condensation of dimethyl phthalate (71) with TV.A-bis methoxycar-bonyl)alkyl- and -aryl]amines to give 3F/-3-benzazepines which exist as the intramolecularly hydrogen-bonded enol forms, e.g. 72, rather than the generally more stable benzazepinone tautomers.14... 

The products are in metallotropic equilibrium between the 0-bonded (enol) and C-bonded (keto) isomers, and the topic has been reviewed (194). 

Other bonds that merit attention are those connecting C(7) through C(ll). These could be formed by one of the many methods for the synthesis of ketones. Bond disconnections at carbonyl centers can involve the 0=C-C(a) (acylation, organometallic addition), the C(a)-C((3) bond (enolate alkylation, aldol addition), or C((3)-C(7) bond (conjugate addition to enone). 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. It has been conducted on the pyrazine ring of quinoxaline and the resulting alkynyl- and dialkynyl-quinoxalines were subsequently utilized to synthesize condensed quinoxalines [52-55], Ames et al. prepared unsymmetrical diynes from 2,3-dichloroquinoxalines. Thus, condensation of 2-chloroquinoxaline (93) with an excess of phenylacetylene furnished 2-phenylethynylquinoxaline (94). Displacement of the chloride with the amine also occurred when the condensation was carried out in the presence of diethylamine. Treatment of 94 with a large excess of aqueous dimethylamine led to ketone 95 that exists predominantly in the intramolecularly hydrogen-bonded enol form 96. 

Malonaldehyde, CH2(CHO)2, exists as an intramolecularly hydrogen-bonded enol (86) in the vapour phase. Molecular dynamics calculations suggest that while a short 0—0 distance favours proton transfer to an (identical) tautomer, such proximity is neither a sufficient nor a necessary condition. 

Polar protic solvents also possess a pronounced ability to separate ion pairs but are less favorable as solvents for enolate alkylation reactions because they coordinate to both the metal cation and the enolate ion. Solvation of the enolate anion occurs through hydrogen bonding. The solvated enolate is relatively less reactive because the hydrogen-bonded enolate must be disrupted during alkylation. Enolates generated in polar protic solvents such as water, alcohols, or ammonia are therefore less reactive than the same enolate in a polar aprotic solvent such as DMSO. 

Several chromones such as 2-benzyl-3-benzoylchromone, 39, are photochromic, proceeding to relatively stable hydrogen-bonded enols such as 40.43S... 

In contrast to that of benzyl methyl ketone, deuteriation (or dedeuteriation) of methoxyacetone occurs preferentially at the methyl group in acidic conditions (Bothner-By and Sun, 1967 Hine et al., 1967a Chevallier et al., 1969). The peculiarity of this result has been emphasised by Hine. Indeed, since the methoxy group is expected to stabilise the double bond, enol [501 must be more stable than enol [511. This conclusion is supported by the ab initio calculations of Hehre and Lathan (1972). 

Oximation of the jS-diketone (3) gave the H-bonded enol form of the monooxime (4).8 Its Z-configuration and resistance to further attack by hydroxylamine were attributed to chelation, which is also regarded as responsible for the forced regiospecificity. Cyclization was effected by heating with acetyl chloride, a procedure also claimed for the cyclization of the oxime (5).9... 

Like other compounds with carbon-carbon double bonds, enols are electron rich, so they react as nucleophiles. Enols are even more electron rich than alkenes, though, because the OH group has a powerful electron-donating resonance effect. A second resonance structure can be drawn for the enol that places a negative charge on one of the carbon atoms. As a result, this carbon atom is especially nucleophilic, and it can react with an electrophile to form a new bond to carbon. Loss of a proton then forms a neutral product. 

Lithiumlithium triethylaluminum, sodium triethylboron, sodium triethanolamine borate,- potassium triethylboron and tri-n-butyltin cyclohexanone enolates have been successfully monoalkyl-ated. In Scheme 6 the behavior of the lithium enolate of cyclohexanone (11) and the lithium triethylaluminum enolate upon reaction with methyl iodide is compared. The latter enolate gives better results since no dimethylation products were detected, but clearly the cyclohexanone enolate (11) is much less prone to dialkylation than the cyclopentanone enolate (10). Scheme 6 also provides a comparison of the results of alkylation of the potassium enolate of cyclohexanone, where almost equal amounts of mono- and di-alkylation occurred, with the alkylation of the potassium tiiethylboron enolate where no polyalkylation occurred. The employment of more covalently bonded enolates offers an advantage in cyclohexanone monoalkylations but not nearly as much as in the cyclopentanone case. 

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