Disubstituted-pyridines

51] and directly linked aryl systems (3.1) [46, 51, 52] the bicyclo[2.2.2]octane core has also been compared with phenyl, cyclohexyl and a range of related cores [53, 54]. 

5-Disubstituted-1,3,2-dioxaborinanes, 4.5, are structurally similar to 2,5-disubsti-tuted-1,3-dioxanes but without the complication of cis-/fra s-isomerism the creation of the dioxaborinane ring is achieved by esterification of a 2-substituted-propan-1,3-diol with an arylboronic acid [62, 63]. For compounds of this type with a 5-aryl substituent, 2-arylpropan-l,3-diols are required and are prepared by coupling the ethyl cyanoacetate anion and a 4-substitut-ed-phenyl bromide or iodide [62] and the 5-alkyl-substituted-1,3,2-dioxaborinanes [63] are obtained from 2-alkylpropan-1,3-diols (4.1). 

Pyridine rings are not particularly common as nematogenic cores partly because they are usually not superior to the pyrimidine analogues and partly because they are less easy to synthesize. Several different syntheses of pyridines have been reported [64-71] 

---

Pyridine undergoes 2- and 4-alkylation with Grignard reagents, depending on whether free metal is present (19). Free metal gives mixtures or exclusive 4-alkylation. Substituent-directed metaHation (eq. 5) has become an important approach to the synthesis of disubstituted pyridines (12). For example, 2- uoro-pyridine [372-48-5] reacts with butyUithium and acetaldehyde to give a 93% yield of alcohol [79527-61-1]. 

Substituent-directed metallations are being used for the synthesis of disubstituted pyridines. A 2-substituent directs to the 3-position, and a 3-substituent usually directs to the 4-position however, in the presence of A/ A/ A[7V -tetratnethylethylenediatnine (TMEDA), 2-metallation may be achieved (12). 

There are no natural sources of pyridine compounds that are either a single pyridine isomer or just one compound. For instance, coal tar contains a mixture of bases, mosdy aLkylpyridines, in low concentrations. Few commercial synthetic methods produce a single pyridine compound, either most produce a mixture of aLkylpyridines, usually with some pyridine (1). Those that produce mono- or disubstituted pyridines as principal components also usually make a mixture of isomeric compounds along with the desired material. 

Using the processes described above, complex products are obtained if a monosubstituted phenol is used instead of a 2,6-substituted material. However, by using as the amine" a 2-disubstituted pyridine such as 2-amylpyridine, more linear and, subsequently, useful polymers may be obtained. 

This chemoselectivity stands in contrast to that of 2,6-disubstituted pyridines. For example, 2,6-dimethylpyridine 35 was reacted with hydrogen peroxide and acetic anhydride to produce the expected acetoxy derivative 36. A second iteration of the previous reaction conditions did not afford an aldehyde, as in the previous example, but 2,6-bis-acetoxy derivative 37. 

This is the least investigated system and the few known derivatives have been synthesized from 3,4-disubstituted pyridines (routes i or ii). The first recorded pyridopyrimidine of any system was pyrido[3,4-d]-... 

Scheme 35 Formation of 2,5-disubstituted pyridines 162 from a,/ -unsaturated complexes with a primary 3-amino group 160 and alkynes 90 [36,88]...

Disubstituted pyridines [86] 87 have been prepared by catalyzed cycloaddition of 4-methyl-1,2,3-triazine 85 with aldehyde enamines 86 (Equation 3.29). The best yields were obtained when ZnBr2 was used as catalyst. 

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

Another class of bimacrocyclic 2,6-disubstituted pyridines is the bissul-fonamides [18]. They were synthesized in an analogous manner to the concave pyridines [13] and their basicities were also measured relative to thymol blue in ethanol (Liining et al., 1991a). The data are listed in Table 9. 

Steric factors and especially hindered rotations may change the pATa of an acid by up to two pAfa units as has been found for 2,6-disubstituted pyridines 2,6-di-t-butylpyridine [70k] is an unusual (Kanner, 1982) non-nucleophilic base which has a surprisingly low pKa value. When [70k] is compared to other 2,6-dialkylsubstituted pyridines [70] it is found to be the only disubstituted pyridine with a smaller pKa than pyridine itself (see Table 29). The exceptional behaviour of [70k] has been investigated intensively... 

Table 18 The secondary a-deuterium KIEs for the Menshutkin reaction between 3,5-disubstituted pyridines and methyl iodide in 2-nitropropane at 25°C.a...

In a more recent study, Harris and co-workers (Harris et al., 1981) found that the secondary a-deuterium KIEs (Table 18) were larger (more inverse) when a poorer nucleophile was used in the SN2 reactions (22) between 3,5-disubstituted pyridines and methyl iodide in 2-nitropropane at 25°C. 

Large (near the theoretical maximum) a-carbon KIEs for the Menshutkin reactions between 3,5-disubstituted pyridines and methyl iodide [reaction (22) Table 20] have also been reported by Yamataka and co-workers (Ando et al., 1987). Although the a-carbon KIEs increase slightly as more electron-withdrawing substituents are added to the nucleophile, they are all large and... 

Fluoropyridines form valuable starting materials for a range of disubstituted pyridines because, after lithiation, nucleophilic substitution of fluoride (sometimes via the N-oxide) can be used to introduce, say, N or O substituents as in 191 and 192 (Scheme 96). Subsequent annelations can allow complex polycyclic heteroaromatics to be constructed. ... 

Direct metalation of 2,6-disubstituted pyridines has also been reported to occur at the 4-position under certain conditions. Thus the 2,6-bistrimeth-ylsilyl chromium tricarbonyl compound 96 gave the 4-lithio derivative 102 [91JCS(P1)501], and 2,6-dichloropyridine gave mainly the 4-lithio derivative 103 under kinetic deprotonation conditions, in contrast to the thermodynamic situation where 3-lithiation was preferred (91JOC4793). 

The question of additivity of SCS is difficult to probe, because ortho interactions, notoriously difficult to account for, are bound to arise in even disubstituted pyridine rings, apart from those with the 3,5-disposition. To test this, proton chemical shifts have been measured for six series of substituted methyl pyridinecarboxylates (71), (72), (73), (74), (75) and (76) <750MR(7)4l), and SCS ortho and para can be accounted for by assuming additive substituent, ester, and nitrogen effects. However, for protons meta to the substituent, particularly for the case where both the proton and the substituent are adjacent to N, the additivity breaks down, and there is evidence of substituent-nitrogen interactions. 

A variety of thienopyridine isomers can be generated in low to moderate yields from the reaction of disubstituted pyridines and phenyl isothiocyanate. The pyridine derivatives contain a halogen at position 2 or 3 of the ring, and the other substituent is either a cyanomethyl substituent (CH2CN) or an ester (CH2C02Et) <19978949, 1998S1095>. 

The /V-acyl compounds are very suitable for the synthesis of pyrrolo[3,4-b]pyridines (10). As a rule, these compounds are synthesized starting from 2,3-disubstituted pyridines (69BCJ2996 75CB1003 77CCC283). Only a... 

Methoxy-3-isobutylpyrazine 176 (Structure 4.53) is found in galbanum oil obtained from Ferula galbaniflua. 2,4-disubstituted pyridines 177, N,N-dimeth-ylated amino compounds 178, alkyl pyrazines 179, quinoline 180 and methyl quinolines 181 were isolated from fig leaf absolute [64]. 

---