Lithium pyridine derivatives

Those reactions of halogenopyridines with potassium amide and lithium piperidide which proceed via 3,4-pyridyne form the 3- and 4-substituted pyridine derivatives in ratios of 1 2 and 1 1, respectively (see Section II, A, 1). It appears that the ring nitrogen atom has an orienting effect on these additions, but the quantitative divergence of the addition of ammonia and piperidine is not understood at present. 

Reduction of aromatic rings with lithium or calcium " in amines (instead of ammonia—called Benkeser reduction) proceeds further and cyclohexenes are obtained. It is thus possible to reduce a benzene ring, by proper choice of reagent, so that one, two, or all three double bonds are reduced. Lithium triethylborohy-dride (LiBEtsH) has also been used, to reduce pyridine derivatives to piperidine derivatives." ... 

Mixed trialkylstannyl and silyl derivatives have also been used in coupling reactions, with subsequent replacement of the silyl substituent by bromine, leading to species that are capable of undergoing further coupling reactions. This process was amply demonstrated by the recent synthesis of micrococcinic acid 203, which involved four palladium-catalyzed crosscoupling reactions on stannylated substrates, two palladium-catalyzed trimethylstannane replacements of bromine, two trimethylsilyl displacements by bromine, and a total of four bromine-lithium exchange reactions, on three different thiazole derivatives and one pyridine derivative (91-TL4263). 

Pyrrolo[3,4-< ]pyridine derivatives can be synthesized from arylacetonitriles and 5-bromonicotinamide upon reaction with lithium diisopropylamide (LDA). The reaction proceeds in moderate yields (36-54%) <1998T3391>. 

We assume that readers are familiar with facts concerning the similarities and differences between benzene and pyridine derivatives. Pyridine is a base (pKa = 5.19, affording a pH of 8.5 for a 20% aqueous solution. It has a dipole moment of 2.15 D, as seen in Table 3). The fact that the nitrogen heteroatom with a higher electronegativity than carbon causes a depletion of 7i-electrons in y and in a positions leads to regioselective electrophilic substitution in p positions and, conversely, facilitates nucleophilic attack mainly in a positions, e.g., affording a-picoline and lithium hydride from the reaction of pyridine with methyllithium. 

Compound 85 was dehydrogenated at 300° over palladium black under reduced pressure to a pyridine derivative 96 which was independently synthesized by the following route. Anisaldehyde (86) was treated with iodine monochloride in acetic acid to give the 3-iodo derivative 87. The Ullmann reaction of 87 in the presence of copper bronze afforded biphenyldialdehyde (88). The Knoevenagel condensation with malonic acid yielded the unsaturated diacid 91. The methyl ester (92) was also prepared alternatively by a condensation of 3-iodoanisaldehyde with malonic acid to give the iodo-cinnamic acid (89), followed by the Ullmann reaction of its methyl ester (90). The cinnamic diester was catalytically hydrogenated and reduced with lithium aluminium hydride to the diol 94. Reaction with phosphoryl chloride afforded an amorphous dichloro derivative (95) which was condensed with 2,6-lutidine in liquid ammonia in the presence of potassium amide to yield pyridine the derivative 96 in 27% yield (53). 

Dichloro(l, 3-propanediyl)platinum and its bis(pyridine) derivative have been studied by a number of authors. Dichloro(l,3-propanediyl)platinum, and the corresponding substituted 1,3-propanediyl platinum compounds release the parent cyclopropane on treatment with potassium cyanide, potassium iodide, a tertiary phosphine, carbon monoxide, and other ligands.2,6 Reduction by means of hydrogen or lithium aluminum hydride yields chiefly isomeric substituted propanes. Dichlorobis(pyridine)(l,3-propanediyl)platinum in refluxing benzene yields a pyridinium ylid complex, - (CH3CH2CHNC5Hs)-PtpyCla. 

This type of reaction could not be effected using alkyl-lithium or alkyl-Grignard reagents. Also, the products represented by 2.225 and 2.227 with presumed divalent cobalt centers as offered by Johnson and coworkers should be considered as being tentative only no conclusive data were actually given in support of the proposed formulations. There is also a discrepancy between the main textual body and the experimental section of the 1973 paper by Johnson and coworkers as to which Co(III) derivative was actually used in these reactions. In the main body, it is stated that the square planar (implying pyridine-free) Co(III) corrole is used, whereas in the experimental section, it is stated that the pyridine derivatives were used. 

Aromatic nitro compounds are comparable with pyridine derivatives in reactivity and can sometimes be aminated directly. l-(4 -Nitro-l -naphthyl)-piperidine was obtained from 1-nitronaphthalene and sodium piperidide (sodamide and piperidine).396 Nitrobenzene and the alkali derivative of carbazole397 or diphenylamine398 gave the corresponding /7-amino derivative, 9-(/7-nitrophenyl)carbazole (70%) and 4-nitrotriphenylamine (45%). Huisgen and Rist399 record the reaction of nitrobenzene with lithium piperidide. 

Selective bromination of 2-methoxy-6-methylpyridine afforded 5-bromo-2-methoxy-6-methylpyridine <94SC(24)1367). Subsequent deprotonation of the pyridine derivative in the benzilic position, or lithium-bromine exchange, allowed regioselective introduction of various electrophiles. 

Transmetallation of 1-6 or treatment of 1-6 with Lewis acid further broadens the scope of its reaction chemistry. In the presence of CuCl, the reaction of 1-6 with diazo dicarboxylate affords pyridazine derivatives [27]. In the presence of CuCl or nickel complexes, the reaction of 1-6 with alkynes leads to benzene derivatives [28, 29]. Transmetallation of 1-6 with Bids allows further reaction with 2-oxo malonate to give 2/7-pyran derivatives [27]. Transmetallation of 1-6 with CrCls followed by reaction with isocyanates affords pyridine derivatives [30]. Transmetallation of 1-6 with AICI3 followed by reaction with aldehydes affords pentasubstimted cyclo-pentadiene derivatives [31]. Under the similar condition, 1-6 reacts with nitroso compounds to form pyrrole derivatives [32]. Addition of n-butyl lithium activates 1-6 and allows further reaction with carbon monoxide, which leads to carbonylation and affords 2-cyclopentenone upon hydrolysis [33]. 

Methylpyrroles have been converted into pyridines by hydrochloric acid under severe conditions, and also by pyrolysis (p. 109). The formation of a 3-chloropyridine derivative from a pyrrole under Reimer-Tiemann conditions has been mentioned (p. 63). This type of reaction was discovered by Ciamician and Dennstedt treated pyrrole with chloroform in ether and isolated a small yield of 3-chloropyridine. Subsequently, similar reactions were realized with bromoform, carbon tetrachloride, methylene iodide and benzal chloride. Those of several of these reagents with lithium pyrrole in ether and sodium pyrrole under various conditions have been compared. The yields of pyridine derivatives were always low. In submitting 2,5-dimethylpyrrole to the Reimer-Tiemann reaction, Plancher and Ponti23 isolated a pyrrolenine (7). This and its analogues are not intermediates in the conversion of pyrroles into 3-chloropyridines. The idea that dichlorocarbene is the active reagent in reactions using chloroform is supported by recent work 22 ... 

Substituent in pyridine derivative Lithium reagent Conditions Substituents in product References... 

Two features of the reaction of pyridine derivatives with lithium aryls need separate mention. First, when alkyl substituents are present in the pyridine nucleus, metalation of the alkyl group is in competition with nuclear arylation (cf. p. 327). Ziegler and Zeiser found that phenyl lithium in ether converted 2-picoline into picolyl lithium. Sometimes, attempts to metalate... 

In deprotonative functionalization of pyridine derivatives, lithium bases can coordinate to directing groups or nitrogen atom on pyridine ring. With diff erent lithium amide (lithium diisopropylamide versus lithium 2,2,6,6-tetramethylpyperidide) and... 

---