Deuteriation enolates

Besides its use as a mechanistic probe, deuteriation of anions under kinetically controlled conditions is a potentially promising way to access deuteriated molecules in a regio- and stereo- controlled manner, in opposition to the thermodynamic equilibration in the presence of an excess of deuterium donor. Thus, treatment of the lithium anion of 2-methyltetralone (p E = 7.31, pfsfEa = 10.8, pKkr = 18.1 in water)335, by one equivalent of a solution of deuterium chloride in deuterium oxide, generates the intermediate O-deuteriated enol whose reaction with water or with an excess of deuterium chloride in deuterium oxide conducts to, respectively, the tetralone or the deuteriated tetralone (Scheme 69)336. 

The synthesis of camphor (80% optical purity) by heating optically pure di-hydrocarvone at 400 °C for 20 h is reminiscent of Money s racemic camphor synthesis (Vol. 1, p. 39) in that both correspond to a biogenetic-type synthesis via enol formation. Further synthetic work on deuteriated camphors (see references therein and Vol. 3, p. 67 Vol. 4, p. 48 Vol. 7, p. 38 for earlier work) includes syntheses of optically pure [8- Hi]-, [8- H2]-, and [8- H3]-(—)-camphor (204) by modification of known reactions (Scheme 5) and the use of an improved Zn-Cu... 

All prepared magnesium enolates 17 are stable in refluxing diethyl ether. Deuteriation, and reactions with various electrophiles confirm their structure (see section HI). It is noteworthy that the lithiated carbanion-enolate analogue, directly obtained by deprotonation of an a-ketoester 18 with lithiated bases (LDA, for example), is not stable and immediately degrades in the medium, whatever the temperature. Comparatively, the magnesium chelate 17 shows a higher stability, which allows its preparation and synthetic applications. 

X,Y=0,S,Se,Te], has been undertaken.628 The stabilities of different tautomeric forms of 4-hydroxycoumarins have been evaluated629 by MNDO calculations, and the four lowest-energy oxo-hydroxy tautomers of 5-fluorouracil have been studied630 using density functional methods. Semiempirical calculations have been carried out on the keto-enol tautomerism of triazolopyrimidines.631 A base-catalysed keto-enol tautomer-ism has been proposed632 to be responsible for the observed deuterium exchange of the hydrogens at the 3-position of diazepam when the molecule is treated with alkaline deuteriated methanol. 

The Clemmensen reduction was accompanied by D/H exchange via acid-catalysed enolization of the carbonyl group, resulting in the production of deuteriated compounds 57 and 58 with various numbers of deuterium atoms. The mixture of the compound 59 obtained by the Wolf-Kishner reduction was predominantly labelled at position 2. This has been proved by the 13C-NMR spectrum. Isotope shift and loss intensivity on substituted C(2) carbon signals have been observed54,55. 

D20, 70 and 30% respectively of the axial [23] and equatorial [24] deuteriated ketone were formed. If it is assumed that protonation of the enolate oxygen atom is faster than that of C(c), this result corresponds to the stereoselectivity of axial and equatorial attachment of D+ to the enol (27). The higher selectivity between axial and equatorial deuteriated ketones observed for hydrolysis of the corresponding ethyl enol ether (90 10) and pyrrolidine enamine (>90 10) means that the stereoselectivity is probably smaller for the enol than for the related compounds. 

In acidic conditions, deuteriation at the methylene group of benzyl methyl ketone is also preferred with a ratio kJk xOA (Roques, 1972) which corresponds to a difference of about 1.3 kcal mol-1 between the two transition states. This result can be ascribed to the conjugative stabilisation of the /l2,3-enol [481 compared with the zll,2-enol [49]. Since the difference... 

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). 

Garbisch (1965) explained predominant bromination (67%) on the methylene site of 2-methylcyclohexanone 1681 (6-position) in methanol (as opposed to 4% in ether) as due to easier formation of the more stable /F,6-enol ether from the acetal. Similar peculiar regioselectivities for acid-catalysed bromination, chlorination and deuteriation of [691-1731 have been reported... 

However there are aspects of Leipert s work that can be taken more seriously especially his observation of the effect of deuteriation on the chemical shift Ad(1H, 2H). This isotopic shift has been instrumental in solving the problem of the hydrogen bond in AA cis enol tautomer - see Sect. III. 

A careful study of the C-deuteriation of a series of preformed endocyclic337 and acyclic or exocyclic lithium enolates has recently been carried out by Eames and coworkers338, extending their previous observations on protonation339. 

In certain cases, seemingly simple enolates can have a chiral memory effect . For example, treatment of a-imino lactam (5)-88 with f-BuOK in CD3OD for 6-13 days at 25°C gave the corresponding enantiomerically deuteriated a-imino lactam l-d-(S)-89 in quantitative yield with 98% D incorporation and ee 97% (equation 15) , via a conformationally chiral enolate. This methodology has been extended towards enan-tioselective alkylation of enolates. Excellent levels of enantioselectivity (ee 88%) were achieved for a-imino lactam (S)-SS using KHMDS as Brpnsted base and benzyl iodide as the electrophile . Interestingly, to prevent unwanted racemization of the intermediate enolate, the reaction time for deprotonation was lowered to 10 seconds, and to ensure rapid alkylation, 20 equivalents of Bnl were used . 

The irradiation of phenylcyclohexenyl ketone (146) under argon in methanol results in its conversion to the cyclic ketone (147) by the well known Nazarov reaction. A careful study of this reaction by n.m.r. spectroscopy in deuteriated solvent shows that the enol (148), a long suspected intermediate, is the initial photochemical product. This is transformed readily by a thermal reaction into the final product (147). If non-protic solvents are used for the irradiation two new products (149) and (150) are formed. The structure of the stable compound (149) was determined by X—ray crystallography. The formation of the compound (149) is... 

Further chemically induced dynamic nuclear polarization (CIDNP) studies have appeared concerning the photoreduction of acetone by propan-2-ol, including the use of a variety of deuteriated components.19 The enol of acetone has been detected by such methods,20 and Bargon and Seifert21 have now observed by CIDNP spectroscopy the ends from acetaldehyde (giving vinyl alcohol) and several aliphatic aldehydes. Vinyl alcohol, for example, is generated in a spin-polarized state by photoreduction of [2He]acetone with ethanol in DaO (Scheme 3). 

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