Azines substituent reactivity

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

Greater reactivity gamma to an azine-nitrogen would be expected on the basis of the greater ara-quinoid than orf/io-quinoid interactions between various substituents and azine-nitrogens in ground states and excited states. Such a difference in interaction is supported by several kinds of data spectral,basicity, dipole moment, and chlorine quadrupole resonance of halo, methoxy,... 

Alkylthio, arylthio, and thioxo. The thioxo group in pyrimidine-2,4-dithione can be displaced by amines, ammonia, and amine acetates, and this amination is specific for the 4-position in pyrimidines and quinazolines. 2-Substitution fails even when a 5-substituent (cf. 134) sterically prevents reaction of a secondary amine at the 4-position. Acid hydrolysis of pyrimidine-2,4-dithione is selective at the 4-position. 2-Amination of 2-thiobarbituric acid and its /S-methyl derivative has been reported. Under more basic conditions, anionization of thioxo compounds decreases the reactivity 2-thiouracil is less reactive toward hot alkali than is the iS-methyl analog. Hydrazine has been reported to replace (95°, 6 hr, 65% 3deld) the 2-thioxo group in 5-hexyl-6-methyl-2-thiouracil. Ortho and para mercapto- or thio- azines are actually in the thione form. ... 

The effects of the nucleophile on aromatic substitution which are pertinent to our main theme of relative reactivity of azine rings and of ring-positions are brought together here. The influence of a nucleophile on relative positional reactivity can arise from its characteristics alone or from its interaction with the ring or with ring-substituents. The effect of different nucleophiles on the rates of reaction of a single substrate has been discussed in terms of polarizability, basicity, alpha effect (lone-pair on the atom adjacent to the nucleophilic atom), and solvation in several reviews and papers. ... 

The effect of hydrogen bonding to nuclear substituents in transition states is reviewed in Sections I,D, 2,b, and II, E. Relative reactivity at different ring-positions is postulated to be alterable by hydrogen bonding of an azine-nitrogen to the solvent or to the reagent (Section II, B, 3 and III,B). However, there appears to be no kinetic data relevant to this postulate. 

Relative reactivity of ring-positions based on positional selectivity of polychloro-azines must be regarded with caution because of the unequal activating effects of the chlorine substituents on each other. Also, it should be emphasized that one cannot use the positional selectivity in di- and tri-substitutions to assess relative reactivity of different positions. In such substitutions, the reactivity is determined by a complex combination of activating and deactivating effects which are unequal at the ring-positions (cf. Sections II, E, 1, II, E, 2,c, and II,E,2,e). 

The relation of the activation by a nitro group to that by an azine-nitrogen in various bicyclic positions provides information in support of that available from studies of azines and forms the basis for certain predictions of azine reactivity. The data tabulated in Section IV, A, 2 also provide a few comparisons of leaving groups, nucleophiles, and deactivating and activating substituents (cf. Sections II, E and III, A, 2). 

The relations 4- > 2-position in rate and 4- < 2-position in will apparently apply to reactions with anions, but the reverse relation is observed in piperidination, presumably due to 2-substitution being favored by hydrogen bonding in the zwitterionic transition state (cf. 47, 59, and 277) or by solvent-assisted proton removal from the intermediate complex (235). Substitutions of polychloroquino-lines (in which there is a combined effect of azine-nitrogen and unequal mutual activation of the chlorine substituents) also show 4- > 2-position in reactivity contrary statements are documented by these same references. Examples are cited below of the relation 2- > 4-position when a protonated substrate or a cyclic transition state is involved. 

The initial step in Scheme 91 presumably involves deprotonation of the phenacyl substituent to give a pyridinium ylide. Such ylides may be generated as reactive (unstable) intermediates in the synthesis of cycl[3.2.2]azines from iV-(trimethylsilylmethyl)-2-pyridones (Scheme 92) in the presence of an excess of DMAD, the cyclazine is the major product <2003S1398>. 

In the diazines, triazines and tetrazines, the effects of the additional nitrogen atom(s) are roughly additive. In Table 4 the positions of substituents in the common azine ring systems are listed in order of increasing reactivity. The limit is reached in 2-, 4- or 6-substituted 1,3,5-triazines for which the reactivity approximates to that in the corresponding carbonyl compound (559). 

Table 4 Substituent Environments in Azines Listed in Order of Increasing Reactivity...

As explained in Chapter 3.2, the reactivity of six-membered rings containing two heteroatoms bears the same relationship to six-membered rings containing one heteroatom as do the latter to benzene. Hence many of the methods listed for the preparation of pyridines by substituent introduction and modification in Table 1 of Section 4.2.4.1 are also applicable to the preparation of analogous azines. 

The thiadiazoles are 7r-electron deficient. This enhances the reactivity of substituents in the azine ring, and this is most pronounced in the orthoquinonoid systems. But the electron deficiencies of these systems make them vulnerable for nucleophilic ring opening reactions. Sometimes the preferred reaction pathway may be difficult to predict. The nucleophilic ring opening reactions are treated in a separate section. 

All of the azines are weak bases, in which the natures and positions of substituents alter the ease and orientation of N-protonation. This review does not aim to provide a comprehensive survey of basic characteristics within the series, but merely highlights the reactivities of particular ring nitrogen atoms with proton acids, since these reactivities are frequently related to trends observed in N-alkylation, N-acylation, and N-oxidation. 

The fact that none of these reports has emphasized the physical aspects of electrophilic substitution in the series reflects the paucity of quantitative studies, and the low reactivity of these compounds in the presence of electrophiles. Few kinetic studies have been reported and the regio-chemical effects of substituents have seldom been quoted in quantitative form. The present chapter brings together those quantitative results that are available, and collates data on substituent effects. One worthwhile field of study would appear to be the application to the azines of Taylor s method involving thermolysis of esters [75JCS(P2)277, 75JCS(P2) 1783]. 

Pyridines and azines. An -substituent in pyridine 597 is in an electronic environment approaching that of a substituent in the imino compound 598. Since the reactions of the carbonyl compounds 599 are better known than those of the imino compounds 598, the reactions of -substituted pyridines are compared with those of the analogous carbonyl compounds (see preceding section 3.2.3.1.1). However, the electron pull is much greater in carbonyl compounds than in pyridine -substituents on pyridine accordingly show reactivities intermediate between those of substituents on benzene and those attached to carbonyl groups. 

Table 4 Substituent environments in azines listed in order of increasing reactivity...

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