Pyridines as Substrates

Thermolytic conversions of aromatic pyridines into pyrazines have been reported, albeit in minute yield. Thus vacuum pyrolysis of 4-dichloroamino-2,3,5,6-tetraduoropyridinc (69) at 550°C gave at least 12 products in which 2,3,5,6-tetrafluoropyrazine (70) could be identified and flow thermolysis of 

4-azido-2,3,5,6-tetrafluoropyridine in nitrogen at 300°C gave l,2-difluoro-l,2-bis(3,5,6-trifluoropyrazin-2-yl)ethylene (71), isolated in 0.1% yield.  

Primary Syntheses from Other Heterocyclic Systems 

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In 1987, Popp et al. described the first Reissert reaction with pyridine as substrate using TMS-CN (14), in the presence of a catalytic amount of aluminum chloride [39]. Further modifications included the use of diethylaluminiumcyanide and tri-n-butyltin cyanide as alternative cyanide sources (Scheme 4d) [29, 40, 41]. 

The yield of 17 is 50 62% in the reactions involving butyl- or. vw-butyllithium due to competitive transfer of the butyl or sec-butyl group. Yields of 17 are improved by using pyridine as the additive, but diastereoselectivity is not as high as when the alkyllithiums are employed. Without any additive, a complex mixture of syn- and anti-diastereomers plus products resulting from addition of the a-carbon of the substrate borane to the aldehyde are obtained. 

Chiral pyridine-based ligands were, among various Ar,AT-coordinating ligands, more efficient associated to palladium for asymmetric nucleophilic allylic substitution. Asymmetric molybdenum-catalyzed alkylations, especially of non-symmetric allylic derivatives as substrates, have been very efficiently performed with bis(pyridylamide) ligands. 

Various methylenetetrahydrofurans were accessible by a combination of a Zn-promoted Michael addition and a cyclization using alkylidenemalonates and pro-pargyl alcohol as substrates, as reported by Nakamura and coworkers [108]. Tetrasubstituted pyridines of type 2-189 have been obtained through a solvent-free InCl3-promoted domino process of 2-187 and 2-188 (Scheme 2.44) [109]. 

Recently, a method for synthesizing substituted pyridines incorporating 3-azadienynes as substrates in ruthenium-catalyzed cycloisomerizations was described <06JA4592>. This route is a two-step process that first converts readily available JV-vinyl or JV-arylamides (e.g., 26) to the corresponding C-silyl alkynyl imines (e.g., 27) and subsequent ruthenium-catalyzed protodesilylation and cycloisomerization results in the formation of the corresponding substituted pyridines (e.g., 28). 

Pro-chiral pyridine A-oxides have also been used as substrates in asymmetric processes. Jprgensen and co-workers explored the catalytic asymmetric Mukaiyama aldol reaction between ketene silyl acetals 61 and pyridine A-oxide carboxaldehydes 62 <06CEJ3472>. The process is catalyzed by a copper(II)-bis(oxazoline) complex 63 which gave good yields and diastereoselectivities with up to 99% enantiomeric excess. 

It is interesting to note that another reaction pathway is observed when the pyridine adduct of HBF4 is used as substrate instead of the ether adduct. In this case exclusively oxidative addition of HF takes place to give compound 15.32... 

The intramolecular displacement of the pyrimidine chloride by a tethered pyridine, as in substrate 42 or various other nitrogen-containing heterocycles, was reported by Vdovenko and co-worker to produce a variety of condensed pyridopyrimidines such as compound 43 <00T5185>. 

The ALDs are a subset of the superfamily of medium-chain dehydrogenases/reductases (MDR). They are widely distributed, cytosolic, zinc-containing enzymes that utilize the pyridine nucleotide [NAD(P)+] as the catalytic cofactor to reversibly catalyze the oxidation of alcohols to aldehydes in a variety of substrates. Both endobiotic and xenobiotic alcohols can serve as substrates. Examples include (72) ethanol, retinol, other aliphatic alcohols, lipid peroxidation products, and hydroxysteroids (73). 

Both diorganotellurium(IV) and diorganoselenium(IV) dibromides are known, stable compounds, which permits a direct comparison of the selenium(IV) and tellurium(IV) compounds. Di-4-chlorophenyltellurium(IV) dibromide (36) and one equivalent of pyridine were essentially unreactive with respect to bromination of either 4-pentenoic acid or 4-pentenol. With either substrate, 36 gives only 2-3% conversion to brominated products after several days of reaction (Fig. 17). In contrast, diphenylselenium(IV) dibromide (1, Fig. 1) and 2-(dimethylaminomethyl)-phenyl phenyl bromoselenonium bromide (37) gave essentially complete bromination of either 4-pentenoic acid or 4-pentenol in 1 h in the presence of one equivalent of pyridine as shown in Fig. 17. 

This enzyme [EC 1.1.1.50], also referred to as hydroxy-prostaglandin dehydrogenase, catalyzes the reaction of androsterone with NAD(P)+ to produce 5a-androstane-3,17-dione and NAD(P)H. Other 3a-hydroxysteroids can act as substrates as well as 9-, 11- and 15-hydroxy-prostaglandins. The stereochemistry is B-specific with respect to the pyridine coenzymes. 

This enzyme [EC 1.6.1.1] (also known as NAD(P)+ trans-hydrogenase (B-specific), pyridine nucleotide transhy-drogenase, and nicotinamide nucleotide transhydro-genase) catalyzes the reversible reaction of NADPH with NAD+ to produce NADP+ and NADH. This FAD-dependent enzyme is B-specific with respect to both pyridine coenzymes. In addition, deamino coenzymes will also serve as substrates. 

Regioselactive g-metallation of ir-excessive five ring heterocycles is not a novel reaction. Oxazoline and pyridine as well as carboxylate- and carboxamide -substituted heterocycles have been lithiated. From the point of synthetic utility thiophenes have been shown to be useful substrates after careful optimization of reaction conditions furans have been of less utility. 

Indeed, where reactions at a ring carbon take place under relatively mild conditions, special circumstances are at work. For example, 2,6-tert-butylpyridine combines with sulfur trioxide in liquid sulfur dioxide at -10 C to give the corresponding 3-sulfonic acid (Scheme 2.3). An explanation is that the bulky tert-butyl groups prevent access of the large electrophile to N-1. Steric hindrance is much less at C-3 and sulfonation is diverted to this site using the free pyridine as the substrate. 

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