Annular scheme

When a hydroxyazole can tautomerize to a non-aromatic structure, oxidation at an annular sulfur atom becomes easy, e.g. as in Scheme 9 (79AHC 25)83). 

A well-known example of non-prototropic tautomerism is that of azolides (acylotropy). The acyl group migrates between the different heteroatoms and the most stable isomer (annular or functional) is obtained after equilibration. In indazoles both isomers are formed, but 2-acyl derivatives readily isomerize to the 1-substituted isomer. The first order kinetics of this isomerization have been studied by NMR spectroscopy (74TL4421). The same publication described an experiment (Scheme 8) that demonstrated the intermolecular character of the process, which has been called a dissociation-recombination process. 

Annular tautomerism of azoles and benzazoles [the nonaromatic tautomers of imidazole 17, 2H and 4(5)H have been calculated at the MP2/6-31G level to be about 15 kcal mol less stable than the IH tautomer (95JOC2865)]. We present here the case of 4(5)-substituted imidazoles, different from the histamine, histidine, and derivatives already discussed. By analogy with these histamines, 4-methylimidazole 17a is often named distal [N(t)H] and 5-methylimidazole 17b, proximal [N(7t)H] (Scheme 9). 

There was never any doubt that the major tautomer in the case of in-dazole 27 is the IH-one 27a (Scheme 16), and C chemical shifts compared with those of the two V-methyl derivatives confirmed that this is the case in DMSO-dg (770MR716). NMR has been used to determine the equilibrium isomeric composition of N-CHROH, N-C(CH3)20H, N-COCH3 and N-Si(CH3)3 derivatives for azoles and benzazoles, the conclu-sipn being that this composition parallels the annular tautomeric composition [78JCS(P2)99]. The tautomerism of 1-hydroxybenzotriazole was also studied... 

Annular prototropic tautomerism of 1,2,4-triazoles (s-triazoles) involves an equilibrium between three possible forms (26a-26c) (Scheme 13). 

Four pairwise degenerate tautomeric forms referred to as the IH (27a and 27d) and IH (27b and 27c) tautomers are needed to describe the annular prototropic tautomerism of unsubstituted tetrazole 27 (R = H) (Scheme 14). 

Interesting results were also obtained on treatment of 2-amino-4,6,6-trimethyl-dihydropyrimidine 50 and 2,4,6,6-tetramethyldihydropyrimidine 51 with CD3OD in the absence of a base (91TL2057). It was shown that, under these conditions, the 4-methyl protons of 50, the 2,4-dimethyl protons of 51, and H(5) in 50 and 51 undergo H-D exchange. The suggested mechanism involves annular (1,4-dihydro 4,5-dihydro) as well as substituent tautomeric equilibria, as shown in Scheme 20 for H-D exchange in 50. 

Annular tautomerism in tetrahydropyrimidines has also been studied for a few N-unsubstituted tetrahydropyrimidines bearing OH groups at the 6 position. X-Ray analysis of bicyclic 58 (R = H) revealed that its crystals are composed of two independent tautomeric molecules, 58a and 58b (Scheme 24), connected by three hydrogen bonds (86JHC705). According to NMR spectroscopy, the same tautomers 58a/58b (R = H, Me) coexist in solution, their ratios being dependent on the solvent polarity. 

Tautomeric equilibrium in the symmetrical phenoxy-substituted derivative 136 (R = Ph, r = R = OPh) is fast at ambient temperature on the NMR time scale however, at —84°C the proton exchange becomes frozen and both annular tautomers 136a and 136b can be observed (Scheme 40). The similar exchange was also found for P-aryl-substituted 136 (R = Me, Ft, Ph R = R = Ph). In these cases, the equilibrium is very slow, even at ambient temperature, which was attributed to increased steric demands of four phenyl substituents. Unsymmetrically substituted azaphosphorinanes (R R ) provide even more interesting examples. These compounds (R = Ph R = Me, -Pr R = MeO, -PrO) were found to... 

The Diels-Alder reaction of 2-vinylfurans 73 with suitable dienophiles has been used to prepare tetrahydrobenzofurans [73, 74] by an extra-annular addition these are useful precursors of substituted benzofurans (Scheme 2.29). In practice, the cycloadditions with acetylenic dienophiles give fully aromatic benzofurans directly, because the intermediate cycloadducts autoxidize during the reaction or in the isolation procedure. In the case of a reaction with nitro-substituted vinylbenzofuran, the formation of the aromatic products involves the loss of HNO2. 

There is marked competition between intra-annulation and extra-annular addition in the case of 3-vinylfuran as shown by the results of the cycloaddition of 76 with several dienophiles [75] (Scheme 2.30). 

Vinyl- and 3-vinylthiophene (73b and 77) are less reactive than the corresponding furans and show a notable preference for extra-annular addition due to the higher reactivity of the diene system, including the side-chain double bond. 2-Vinylthiophene is less reactive than 3-vinylthiophene. Whereas 2-vinylthiophene (73b) reacted with maleic anhydride and 1,4-benzoquinone to give cycloadducts in reasonable yield, 3-vinylthiophene (77) gave a higher yield of the cycloadduct [76, 77] (Scheme 2.31). 

An /n-geometry can be ensured by appropriate substitution of the building block which carries the acid-base functionality, for instance by using 2,6-disubstituted aromatic compounds like pyridines, 2,6-disubstituted benzoic acids or other 2,6-disubstituted phenyl derivatives (see Scheme 1). The use of 2,6-disubstituted arenes is sometimes called the 1,3-xylyl trick and assures an intra-annular orientation. 

En route to the total synthesis oftashironin (7-114a) and the debenzoylated compound 7-114b, which shows an interesting promotion of neurite growth, Danishefsky and coworkers have developed a domino oxidative dearomatization/trans-annular Diels-Alder reaction [54]. In this line, treatment of 7-115 with phenyl-iodine(III) diacetate (PIDA) led to an intermediate 7-116, which immediately underwent a transannular Diels-Alder reaction to furnish the complex cycloadducts 7-117 in good yields (Scheme 7.31). 

The definition of intra-annular chirality transfer can be best established by the following examples (Scheme 2-1)7 ... 

The examples in Scheme 2-1 show that in intra-annular chirality transfer the resident asymmetric center connects to the enolate through annular covalent bonds. The geometric configuration of the enolate can be either immobile or irrelevant to the sense of asymmetric induction. 

The cases illustrated here are typical examples of extra-annular chirality transfer via the alkylation process (Scheme 2- -9)16 ... 

Scheme 2-9. Extra-annular chirality transfer. Xc stands for the chiral auxiliary.

Scheme 2-10. Two examples of extra-annular chirality transfer.

As a result of the combination of intra- and extra-annular chirality transfer, a productive approach has been developed for the design of chiral enolate systems in which a structurally organized diastereofacial bias is established, as illustrated in the equations in Scheme 2-11. A lithium-coordinated five-membered or six-membered ring fixes the orientation between the inducing asymmetric center and the enolate20 ... 

Scheme 2-11. Chelation-enforced intra-annular chirality transfer.

Martin further mentioned that the scheme he described has already been tried out by Dr. Wadman of the University of Bristol. Wadman, however, never published any results of his very first work on annular chromatography. Martin and Synge won a joint Nobel price in chemistry for their work in partition chromatography, Tiselius won a Nobel price in chemistry for his work in electrophoreses. 

The assistance of some electron-rich groups [94-96], heteroatoms [90, 97, 98] or filled cr-orbitals [99,100] in the oxidation of organic sulfides was studied in a series of papers (Scheme 24). Since the 3p orbitals of sulfur are quite compact compared to those of Se, the mentioned electronic and stereoelectronic effects are rather remarkable. These interactions (discussed in terms of a trans-annular... 

Alkylation of all three triazole annular nitrogens can be effected by trialkyloxonium tetrafluoroborates (Scheme 9) <72JOC2259>. 

The 1,2,5-oxadiazole ring is a stable system and annular-group tautomerism is not favored. Although three tautomeric forms can be drawn for 3-hydroxyfurazans (Scheme 3) IR and NMR data for chloroform solutions show only the presence of the hydroxy compound. Ring-chain tautomerism is an important feature of furoxan chemistry and the equilibration between the isomeric furoxans is discussed in detail later in this chapter (Section 4.05.5.2.1). 

A consequence of the existence of this equilibrium was the formation of a monosulfide (114) in the reaction of the simple dehydrocyclodipeptide (113) with an alanine or phenylalanine residue, as shown in Scheme 36. The reaction could have proceeded by replacement of the OMe by SH, followed by protonation of the exocyclic double bond and intramolecular attack by the thiol group. Alternatively, the m-dithiol could have been in equilibrium with the /rani-dithiol in the latter, a traw.v-annular attack could have generated the monosulfide. 

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