3- Chloro-4- pyridine preparation

Carbon tetrachloride was also found to react with pyrryl potassium to give 3-chloropyridine, however the mechanism is obscure and would justify further investigation. In a preparatively useful reaction, pyrrole and chloroform in the vapor phase at 500-550° gave 3-chloro-pyridine (33%) and a little 2-chloropyridine (2-5%). No interconversion of the isomers occurred under these conditions, though pyrolytic rearrangement of N-alkylpyrrole to 3-substituted pyridines is considered to involve 2-alkylpyrroles as intermediates. There is some independent evidence that dichlorocarbene is formed in the vapor phase decomposition of chloroform. ... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Cobaloxime(I) is unstable and is best prepared in situ by NaBH4 reduction of chloro(pyridine)cobaloxime(III), a stable complex formed from dimethylglyoxime, CoCl2 -6H20, and pyridine (70% yield).1... 

Bromobis[2,3-butanedione dioximato( 1 -)] (4-terf-butylpyridine)cobalt(lIl) is a tan, microcrystalline solid with greatly enhanced solubility in organic solvents compared to the chloro(pyridine) analogue. It is also the compound of choice in preparing alkylcobaloximes by the subsequent procedure because of the ease of isolation of the resultant products. In addition, the bromo(4-ferf-bupy) species react directly with electron-rich olefins, such as ethyl vinyl ether, in the presence of ethanol to yield, in this case, bis[2,3-butanedione dioximato(l-)]-(2,2-diethoxyethyl)(pyridine)cobalt(III).1J Conversion of the dimethyl sulfide compound to the pyridine derivatives is readily detected by a characteristic infrared absorption at 1600 cm 1 (pyridine stretch). The H nmr spectrum of bromobis[2,3-butanedione dioximato(1 -)] (4-ferf-butylpyridine)cobalt (III) has absorptions in the alkane region in the ratio of 3 4 at 6 1.25 ppm [Py—C (CH3)3 ] and 6 2.43 ppm (dh—CH3) from tetramethylsilane. 

Very mobile nitro groups can be replaced directly by chlorine or bromine, a reaction that has preparative importance for bromo- and chloro-pyridine and -quinoline derivatives. 5-Ethoxy-2-nitropyridine gives 2-bromo-5-ethoxy-pyridine when heated with HBr in glacial acetic acid in a sealed tube for 3 hours at 130°,1260 and 2-bromo-3-ethoxypyridine is obtained from the corresponding nitro compound and boiling 48% HBr.1261 It is particularly easy to introduce Cl or Br in place of a 4-nitro group in pyridine 1-oxide or quino-... 

The SM reactions catalysed by Miyaura s diphenylphosphine-bounded palladium heterogeneous catalyst (342) Preparation of the catalyst and the cross-coupling reaction of 4-tolylboronic acid (271) with 2-chloro pyridine (149) /139I... 

Many 4-alkoxypyridines, e.g. (410), and their corresponding iV-methyl-4-alkoxypyridinium iodides (411) have been prepared and pyrolysed at temperatures less than 185 °C to give olefins derived from the alkyl moiety. The alkoxypyridines are obtained by reaction of the alkoxide with 4-chloro-pyridine. However, synthetically, the reaction suffers from a lack of stereospecificity and carbonium ion rearrangement products may be obtained. ... 

Both BLametani and coworkers 61) and Liao et al. 63) have described synthesis of pyridone (72) which now has the D-ring oxygen functionality differentiated The former research group began with a,P-unsaturated ketone (70) the latter group prepared and utilized diketone (71) (Scheme 8), and described subsequent conversion of product (72) to chloro-pyridine (73). 

A third synthesis which has resulted in the preparation of rieinine and a number of its derivatives is due to Schroeter, Seidler, Sulzbacher and Kanitz,i2 who foimd that cyanoacetyl chloride polymerises spontaneously to 6-chloro-2 4-dihydroxy-3-cyano-pyridine. The di-sodium derivative of this with methyl sulphate produces A -methyl-6-chloro-4-hydroxy-3-cyano-2-pyridone (6-chlororicininic acid), the mono-sodium derivative of which, with methyl bromide or sulphate, is converted into 6-chlororicinine and the latter is reduced by zinc and sulphuric acid to rieinine. A fourth synthesis, starting from 3-nitro-4-pyridone, is due to Reitmann. ... 

Sulfonation with sulfur trioxide, pyridine sulfur trioxide, pyridine bis-sulfur trioxide, and dioxane sulfur trioxide, which are useful sul-fonating agents for acidophobic substances, have been applied to the thiophene seriesd At room temperature the 2-monosulfonic acid (isolated as the barium salt) is obtained in 86% yield. Higher temperatures lead to a disulfonic acid. However, sulfonation with chloro-sulfonic acid appears to be more convenient,as the sulfonyl chloride obtained can be used directly for the preparation of derivatives. 

Ring closure of 2-chloro-l-phenethylpyridinium ion (247) (prepared in situ) to l,2-dihydro-3,4-benzoquinolizium ion involves intramolecular nucleophilic displacement of the chloro group by the phenyl 77-electrons. A related intermolecular reaction involving a more activated pyridine ring and more nucleophilic 7r-electrons is the formation of 4-( -dimethylaminophenyl)pyridine (and benzaldehyde) from dimethylaniline and 1-benzoylpyridinium chloride (cf. Section III,B,4,c). 

An alternate scheme for preparing these compounds starts with a prefabricated pyrimidone ring. Aldol condensation of that compound (95), which contains an eneamide function, with pyridine-3-aldehyde (80), gives the product 96. Catalytic hydrogenation gives the product of 1,4 reduction. The resulting pyrimidinedione, of course exists in the usual tautomeric keto (97a) and enol (97b) forms. Reaction with phosphorus oxyxchloride leads to the chloro derivative 98. Displacement with methoxide gives 99. Reaction of this last intermediate with the furylalkylamine derivative 92 leads to the H-2 blocker lupitidine (100) [22]. 

One route is described in U.S. Patent 3,412,193 as follows. To a mixture of o-(p-chloro-phenoxy)aniline hydrochloride (prepared from 32 g of the base) in 50 ml of pyridine is added gradually while heating under reflux, 25 ml of ethyl chloroformate. After the addition is completed, the mixture is heated under reflux for one hour longer, and then evaporated under reduced pressue to an oily residue. The residue is taken up in 300 ml of water, and extracted with ether (approximately 200 ml). 

Both 5- and 7-amino derivatives of 133 were diazotized and converted into the chloro derivatives using concentrated hydrochloric acid with or without copper(I) chloride (72RTC650 78JHC839). Similarly prepared from 4-aminoimidazo[4,5-c]pyridine was the 4-chloro derivative (65JMC708). A nitro group in the 4-position of 134 was particularly susceptible to nucleophilic displacement by halide (74CHE744). 

Theoretical calculations have predicted that imidazo[l,2-a]pyrimidine (160) should be attacked at C-3 by electrophiles, although reactivity will be lower than in the corresponding imidazo[l,2-a]pyridines (see D,l,e) (74JHC1013). The 3-bromo derivative of 160 was formed when the parent was treated with NBS in chloroform (66JOC809). The usual transformation of oxo to chloro was responsible for the preparation of 5-chloroimidazo[ 1,2-a]pyrimidine [66LA(699) 127]. 

Closely related pyridine adducts were prepared as shown in Scheme 126 by treatment of the corresponding chloro precursor with lithium amidinates. 

Diaminopyridine has been prepared by reduction of 2-amino-3-nitropyridine with iron and aqueous acidified ethanol,3 tin and hydrochloric acid,6 or stannous chloride and hydrochloric acid,6 by catalytic reduction of 3-amino-2-nitropyridine,6 by reduction of 3-amino-2-nitropyridine,7 2-amino-5-chloro-3-nitro-pyridine,8 or 2-amino-5-bromo-3-nitropyridine 4 with sodium hydroxide solution and an aluminum nickel alloy, and by catalytic reduction of 2-amino-5-bromo-3-nitropyridine.4 Animation of... 

By taking advantage of the C(2) activation, 2-allyloxy-3-iodopyridine (173) was prepared by an SNAr displacement of 2-chloro-3-iodopyridine with sodium allyloxide [137]. 2-Chloro-3-iodopyridine was prepared by orrto-lithiation of 2-chloropyridine followed by iodine quench. The intramolecular Heck reaction of allyl ether 173 under Jeffery s ligand-free conditions resulted in 3-methylfuro[2,3-6]pyridine (174). 

Deprotonation readily occurs at C-7, and the resulting anion can further react with various electrophiles. Thus, treatment with BuLi at — 78 °C followed by reaction with diiodoethane was used to prepare the 7-iodo derivatives depicted in Table 2, while the 7-chloro derivatives were prepared by lithiation with lithium diisopropylamide (LDA), followed by reaction with CCI4. The 7-formyl derivative of the parent pyrazolo[l,5- ]pyridine has been prepared in 82% yield by reaction of the BuLi-generated anion with ethyl formate <2001JME2691>. 

Many synthetic routes have been developed to access the saturated oxazolo[3,2- ]pyridine ring system. Among those, the most efficient ones rely on a similar strategy starting from an amino alcohol 360 and a bis-electrophile 361, the latter being either a bis-aldehyde, a keto-ester, a chloro-ketone, or a chloroalkyne (Scheme 96). Among these electrophiles, the first two have demonstrated their utility and generality over the years and have been used for the preparation of many saturated oxazolo[3,2- ]pyridines 362. 

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