Tetrahydro Derivatives

These show marked similarities to their acyclic counterparts, e.g. tetrahydrofuran closely resembles diethyl ether. Minor differences arise due to the less sterically hindered nature of the heteroatoms in the cyclic compounds. The basicities are tetrahydropyrrole (pKa 10.4), tetrahydrofuran (— 2.1) and tetrahydrothiophene (thiolane) ( — 4.5). 

Reactivity of Five-membered Rings with One Heteroatom 

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In a series of detailed studies, Armand and coworkers have examined the electrochemical reduction of pyrazines (72CR(C)(275)279). The first step results in the formation of 1,4-dihydropyrazines (85), but the reaction is not electrochemically reproducible. The 1,4-dihydropyrazine is pH sensitive and isomerizes at a pH dependent rate to the 1,2-dihydro compound (83). The 1,2-dihydropyrazine then appears to undergo further reduction to 1,2,3,4-tetrahydropyrazine (88) which is again not electrochemically reproducible. Compound (88) then appears to undergo isomerization to another tetrahydro derivative, presumably (8, prior to complete reduction to piperazine (89). These results have been confirmed (72JA7295). 

V-Benzoylation of a 1,2,3,4-tetrahydro derivative is reported, whilst related 1,4-dialkyl derivatives resulted from borohydride reduction of the parent [2,3-f ] compound in the presence of carboxylic acids (79JHC973). 

In a related reaction the amino alcohol (413) was cyclized with HBr to the 3-methyl-1,2,3,4-tetrahydro derivative (414) <65JCS1558), whilst the Isay reaction itself has been shown (Section 2.15.15.6.1) to probably occur, at least in some cases, via a [6 + 0( )] cyclization of intermediate anils. 

Oxidations in the pteridine series comprise (i) replacement of hydrogen by hydroxyl, (ii) glycol formation at the central C=C bond (iii) the removal of hydrogen atoms from dihydro and tetrahydro derivatives. 

Discussion of these compounds is divided into isomers of aromatic compounds, and dihydro and tetrahydro derivatives. The isomers of aromatic azoles are a relatively little-studied class of compounds. Dihydro and tetrahydro derivatives with two heteroatoms are quite well-studied, but such compounds become more obscure and elusive as the number of heteroatoms increases. Thus dihydrotriazoles are rare dihydrotetrazoles and tetrahydro-triazoles and -tetrazoles are unknown unless they contain doubly bonded exocyclic substituents. 

Reduction of dihyro compounds to the tetrahydro derivatives is sometimes possible. For example, thiazolines are reduced to thiazolidines by aluminum amalgam. 

Just as selective oxidation can be carried out on these systems, reduction also occurs with considerable selectively. Hydrogenation of binaphthol (Pd catalyst) in glacial acetic acid at room temperature for seven days affords the octahydro (bis-tetrahydro) derivative in 92% yield with no apparent loss of optical activity when the reaction is conducted on optically pure material. The binaphthol may then be converted into the bis-binaphthyl crown in the usual fashion. 

This tetrahydro-derivative, on demethylation by boiling in acetic acid containing hydrogen bromide, yields 6-acetyltetrahydro-a-morphimethine, m.p. 240-2° (vac.), which is hydrolysed by boiling normal soda solution to tetrahydro-a-morphimethine (II. MeO HO), m.p. 206-8° vac.) B. HCl, m.p. 243-9° vac ), — 29-6° (HjO) (Mosettig... 

The y- and 8-methylmorphimethines on catalytic hydrogenation both yield a tetrahydro-derivative, m.p. 115°, [a] f° — 29-2° (dilute acetic acid), which may be a stereoisomeride of tetrahydro-a-methylmorphimethine (II). 

Berberine is probably the most widely distributed alkaloid. It and the allied alkaloids palmatine, jatrorrhizine, columbamine and coptisine occur somewhat frequently in the Rhcnadales (list, p. 169) as the tetrahydro-derivatives, but, in the botanical families referred to in the distribution list below, the tetrahydro-derivatives are exceptional and the unreduced alkaloids usual. The associated alkaloids include two members of the aporphine group, domesticine and t odomesticine (p. 315), one member of the cryptopine group, y-homochelidonine (p. 294) and two members of the double woquinoline type, viz., berbamine and oxyacanthine (p. 346). 

Constitution. Comparison of the empirical formula of the three alkaloids, and the fact that jatrorrhizine and columbamine each stands to palmatine in the relation of a monohydric phenol to its methyl ether, makes it clear that the only difference between jatrorrhizine and columbamine must be in the position of the free hydroxyl group. The method by which this point was settled is described in dealing with the two tetrahydro-derivatives of these alkaloids (p. 291). The constitution of palmatine (XXV R = R = Me) is dealt with under tetrahydropalmatine, but it is still necessary to describe the complete synthesis of this alkaloid via oxypalmatine (XXVII) and tetrahydropalmatine. 

For dirnethyldesweostrychnidine the Achmatowicz formula has been slightly modified to (XIX) by Holmes and Robinson. The third substance, dimethyWesstrychnidine-D yields both a dihydro- and a tetrahydro-derivative and, unlike des-base-D, from which it is derived, does not undergo internal alkylation when subjected to the hydrogenation process in acid solution it is represented by (XX). 

Under similar conditions, but with palladised charcoal as catalyst, solasodine forms a dihydro-derivative, C27H45O2N, m.p. 208-5-210-5°, [a] ° — 63-5° (CHCI3), and in presence of platinic oxide, a tetrahydro-derivative, C27H4,02N, which is dimorphic, m.p. 292-5°, and 285-291°, [air - 4-94° (CHCI3). 

Berberine, 162, 169, 170, 171, 287, 328, 329, 331, 344, 345, 631 Berberine, quaternary ammonium bases from tetrahydro-derivative, 337 Berberine and related bases, pharmacological action, 345 syntheses, 334 Berberineacetone, 333 cptBerberine, 297 profoBerberine, 336 4-Berberines, 335 Berberinium hydroxide, 333 Berberinol, 333 Berberis spp., 328, 331, 346 Berberoline, 332 Berberonic acid, 507 Berberrubine, 329, 343 Berbine, 336 Betaine, 518 Bicucine, 170, 209... 

In this connection the possibility of oxidation of these substances to the tetrahydro derivatives should be mentioned. It was made use of by Thiele and Bailey for the preparation of 6-methyl-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine (6-azathymine) (46) and only recently by Grundman et al. for that of 6-azauracil (42). 

Oxidation of the hexahydro to tetrahydro derivatives was mentioned in connection with the synthesis of 3,5-dioxo-l,2,4-triazines (e.g., Section II,B,2,a). The reverse procedure, hydrogenation of the tetrahydro derivatives, was used with 6-azauracil, 6-azathymine, and their iV-methyl derivatives. With all these compounds hydrogenation proceeds smoothly in the presence of Adams catalyst. Only the hydrogenation of l-methyl-6-azathymine was not successful. ... 

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