Acylated heterocycles

Isoquinoline alkaloids. The regioselective allylation of N-acyl heterocycles (13, 10) can be used for synthesis of isoquinoline alkaloids. Thus simultaneous reaction of the dihydroisoquinoline (1) with a diunsaturated acyl chloride (2) and allyltributyltin affords the 1,2-adduct (3), which undergoes a Diels-Alder cyclization... 

The syntheses of simple 1,3-oxazines (74AG596 86G361) from acylated amino acids (86G361) by treatment with dihalotriphenylphosphorane and of heterocondensed l,3-oxazin-4-ones from several N-acylated heterocyclic /3-enamino esters (81CB3188) have been implemented by aza-Wittig reactions of heterocyclic 2-(triphenylphosphoranylidenamino)esters with acid halides. 

Instruments that can be employed to measure energy barriers in acyl heterocycles should thus be able to follow these interconversion processes that occur in the energy range between 4 and 80 kJ mol". Furthermore, detection of separate conformers in equilibrium is an important intrinsic feature of experimental methods for quantitative population analysis while its sensitivity limits accuracy in measuring biased equilibria. 

CD and ORD have also been employed to detect conformational properties of acyl heterocycles in optically active molecules especially in biological systems. These techniques have been employed, for example, in the conformational study of proline derivatives (70MI2 70M13 73BCJ3894), and as complementary approaches to NMR measurements. 

Measurements of dipole moments, Kerr constants, and dielectric absorption have been employed (81RCR336) widely to obtain information on the conformational equilibrium in acyl heterocycles. Details on conformer structures and populations depend on the choice of additive scheme, group moments, or polarizability tensor in the case of Kerr constants. Several early conclusions, especially for furan- and thiophene-2-carboxaldehyde, appeared contradictory, owing to the choice of these quantities. A more precise definition of polarizability tensors for several heterocycles and a choice of group moments and additive schemes tested on a large amount of available experimental results and supported by accurate theoretical calculations have led to more confidence in the use of experimental dipole moments and Kerr constants in conformational analysis. A limitation of the method is that the... 

The results obtained on C-acyl heterocycles will be reviewed according to classifications 1-3 mentioned in Section I,A. Occasional reference will also be made to results from theoretical calculations (classical and quantum mechanical) and to solvent effects, when necessary for a better understanding of experimental behavior. The last section of this article offers a comprehensive criticism of these topics in the study of conformational equilibria. 

A. Conjugated Acyl Heterocycles 1. Five-Membered Heteroaromatic Derivatives... 

The conformational properties of the amide system in N-acyl heterocyclic derivatives may nevertheless be characterized by further peculiarities. Differences must be anticipated between N-acyl derivatives of conjugated and nonconjugated heterocycles. 

For N-acyl heterocycles we have preferred to employ, for a more immediate reading of the conformers, the N,0-cis and N,0-trans symbolism commonly employed in the original papers, in place of standard , Z terms. The superscript refers to the position of the nitrogen atom in the ring. 

CONFORMER Populations and Free Energy of Activation in Representative N-Acyl Heterocycles... 

Conformational isomers were detected (68JCS(B)1241 85JOC2080) in other N-acyl azabicyclic derivatives. However, owing principally to their molecular complexity, they do not represent molecular systems of particular interest for understanding the factors influencing the conformational properties of acyl heterocycles. 

The semiempirical valence electron methods have been widely employed for calculating total energies as a function of the conformational degrees of freedom the relative stability of conformers and energy barriers are obtained in the different acyl heterocyclic derivatives. The degree of reliability of the different approaches varies, depending only on the molecular structure ... 

A generally better agreement with experimental results appears to be obtained with the more sophisticated PNDO, NDDO, and MINDO/3 methods (76CPL(37)608 76TCA(42)311 81JHC1055 84ZC303 84ZOB674), yet they have only been used on a limited number of acyl heterocycles. 

The considerable number of results reported for acyl heterocycles enable a number of conclusions to be tentatively drawn, indicating the presence both of common behaviors and of differentiating trends in the classes of compounds examined. 

A great deal of experimental and theoretical work has been done on acyl heterocycles, as will also appear from the account given in this article. Nevertheless, we believe that a number of points are worth deeper investigation, and attention has not yet been given to aspects of more than marginal importance. We offer the following suggestions for further work in this area. 

Few conformational studies have been carried out on saturated or partially unsaturated C-acyl heterocycles. Quantitative thermodynamic data on conformer stabilities and barriers are seldom available. 

Several other points perhaps need better definition and several questions await answers. We hope that many of them will emerge from the arguments gathered in the previous sections. Nevertheless, in view of the conclusions so far reached and of the new problems arising out of these results, we feel that all the experimental responses and the attempts to interpret them in the study of conformational properties of organic molecules in general, and of acyl heterocycles in particular, represent a powerful test for the models of electronic structure of molecules and for the behavior they exhibit under different conditions. 

Aryl and alkyl nitriles also react with pyrrolyl and indolyl anions to yield the acylated heterocycles (see Section 3.05.1.2.9). 

The C-acyl heterocycles do not generally form hydrates under acidic or alkaline conditions unless the five-membered ring is also substituted with a second electron-withdrawing group or, as with the trifluoroacetyl and trichloroacetyl derivatives, the carbonyl group is activated to nucleophilic attack. Such activated substituents also undergo the normal reactions with aqueous sodium hydroxide, sodium alkoxide and with amines to give the appropriate... 

These highly promising results were further modified and applied to the chemistry of heterocyclic compounds167-169 as it is an easy pathway to prepare acylated heterocycles in a one-pot reaction which consists of the employment of a carbonyl... 

The anion generated by deprotonation of thiazole at C-2 with -butyllithium reacts with an aldehyde, which, followed by oxidation with Mn02, provides access to the acylated heterocycle as shown in Scheme 18 <2005BML5241>. 

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