2- Bromo-5-substituted pyridine

Bromine-magnesium exchange offers good chemoselectivity with multiply substituted pyridines. Mono-bromo-substituted pyridines as well as dibromopyridines were easily transformed into the corresponding magnesio-derivatives followed by trapping with electrophiles. For example, 2,5-dibromopyridine produced the corresponding 2-bromo-5-substituted pyridine 66. 

Reaction of -picoline over degassed Raney nickel was found to give 5,5 -dimethyl-2,2 -bipyridine (5), the structure of which was established by its synthesis from 2-bromo-5-methylpyridine. Oxidation of this dimethyl-2,2 -bipyridine, and similar oxidation of the diethyl-2,2 -bipyridine derived from 3-ethylpyridinc, gave the corresponding dicarboxylic acid and the same acid was produced by the action of degassed Raney nickel on sodium nicotinate (in water) or on ethyl nicotinate. These transformations established the 5,5 -substitution pattern for three 2,2 -bipyridines derived from 3-substituted pyridines but such evidence is not available for the biaryls... 

Ethyl substitution at the imidazole 5-position (469) was found to increase potency over the unsubstituted analogue (468), while methyl substitution (470) had a slightly deleterious effect on binding (Table 6.41). Chloro (491), bromo (492), cyano (493) and fluoromethyl (494) substitution at this position were all well tolerated (Table 6.43). Introduction of a chloro-substituted pyridine (475) in place of the more usual / -chlorophenyl group (470) resulted in a slight loss of affinity for the CBi receptor, as did replacement of the p-chloro group of (470) with bromo (471), fluoro (472) and in particular, met-hoxy (473). Trifluoromethyl substitution (474) however, was well tolerated. 

The procedures discussed for aromatics can readily be adopted for the efficient preparation of fluoro-substituted heteroaromatics.141,143,149 150 Fluorodediazoniations of 2-ainino-, 3-amino-, 4-amino- and 2.6-diamino-substituted pyridines and some of the chloro or bromo derivatives have been carried out in liquid hydrogen fluoride with anhydrous sodium nitrite. About 1.2 equivalents of nitrite are used per amino group, and ammonium hydrogen fluoride has also been added. The corresponding fluoropyridines or their hydrochlorides have been obtained in 49-89% yield.150 For example, the reported synthesis150 is suitable for the preparation of larger quantities of 4-fluoropyridine hydrochloride (54% yield mp 100 C) examples are given by the formation of 5-7.150... 

There are several publications devoted to oxidative additions to dihydropyridines [337, 338, 339, 340, 341]. For instance, the addition of stochiometric amounts of iodine in a methanol solution of dihydropyridine 309 gives iodi-nated tetrahydropyrimidine 310 in a stereoselective manner [337]. The same result is obtained when the reaction is performed with AModosuccinimide (NIS) (Scheme 3.107). Interestingly, when the process is carried out in tetra-hydrofuran the incorporation of the succinimide moiety at position 2 yields 3-iodo-2-succinimidotetrahydropyridine 311. Using Af-bromosuccenimide, TV-chlorosuccenimide and 7V-fluoropyridinium trifluoromethanesulfonate produces 3-bromo-, 3-chloro- and 3 flouro-substituted pyridines [337]. 

Bromo-4-Methylpyridine. Solid residue from oxidation of the substituted pyridine with 5% excess of the peracid decomposed violently.3... 

The inter- and intramolecular Heck reactions provide other routes to substituted pyridines . Although electron-deficient 2-bromopyridines are resistant to substitution under Heck conditions, the aminopyridine 142 affords a high yield of the adduct 143 (Equation 68) <1998T6311>. The intermolecular Heck reaction of a 3-pyridyltriflate with ethyl acrylate is accelerated by LiCl <1999SL804>. An efficient Heck vinylation of 3-substituted-2-bromo-6-methylpyridines with methyl acrylate has been developed <2005T4569>. 

In contrast to the well known metal-halogen exchange of bromo and iodo aromatics, commercially available halopyridines are amenable, for all halogens, to DoM chemistry of considerable synthetic value [9d]. Recent results [9d, 41], have pointed to the additional feature of the halogen dance as a tool for the construction of unusually substituted pyridines. Illustrative are the conversion of 69 into 2,3,4-substituted pyridines 70 and, more interestingly, of 71 into the tetrasubstituted 72 bearing all but one of the theoretically possible halogens (Scheme 24) [42]. 

Substitution of two carbons in position 2,3 of the pentadienyl anion (see Section 6.1) creates a type 2,3 system. Such molecules are the dihydropyrazolo-pyridines (DHPP) 42.50 51 The 1,3 dipolar cycloaddition reaction, which is so effective as a method for synthesizing five-membered rings, can also be used to prepare spiroheterocyclic compounds of the 2,3 type. If a suitable bromo-substituted dibenzopentafulvene is reacted with pyridine the pyrazolo-pyridine 42 is formed in 30-90% yields (Scheme 18). 

The procedure can be satisfactorily used to synthesize directly other base-substituted bromo-cobaloximes. Best results for the less volatile bases such as substituted pyridines are obtained by adding the base to the hot solution, subsequently cooling to room temperature, and bubbling air through the solution... 

ESMS has been used to characterize the intermediate Nin-complexes formed in the coupling reaction of 2-bromo-6-methylpyridine in the presence of Raney nickel (Scheme 1) [45]. The composition of the intermediate had already been determined previously by elemental analysis, but the ES mass spectra, showing a strong peak for the ion [Ni2(dmbp)2Br3]+, pointed to a dimeric structure. It was concluded that this ion was formed by the loss of Br from the dimeric structure 1. An alternative explanation is that the intermediate has the more common four-coordinate structure 2, and that the observed peak was due to the ion-paired species [Ni2(dmbp)2Br2]2++Br. The dimeric nature of the intermediate was confirmed by a cross experiment when mixtures of differently substituted pyridines were reacted, mixed ligand dinickel species were observed in the ES mass spectra. 

A regioselective halogenation of pyridinols to provide bromo- and iodohydroxypyridines in excellent yields has been developed. These heterocycles are useful intermediates to other substituted pyridines <03SL1678>. 

Riding et al. [39] interpret their results for the 2- and 3-substituted pyridines in terms of the negative group effect of the nitrogen atom in the ring the distance effect of the substituents is considerable. Extension to some bromonaphthalene, anthracene and phenanthrene compounds has been made [74]. The rate coefficients (at 520°K) obtained are 1-bromo-naphthalene, 5.28 x 10 2-bromonaphthalene, 1.19 x 10 9-bromo-anthracene, 2.15 x 10 9-bromophenanthrene, 4.28 x 10 cm mole sec". ... 

The reaction of 3-bromopyridine with LDA and an electrophile gives both 3-bromo-4-substituted - and 4-bromo-3-substituted-pyridines (the so-called halogen dance reaction).51 Sequential reaction of 2-bromopyridine with LDA and trimethylsilyl chloride gives a mixture of 2-bromo-3-trimethylsilylpyridine (35) and the ring-opened product (36).52... 

Generally, aromatic hydrocarbons or their corresponding substituted derivatives upon interaction with bromine in the absence of light (dark) but in the presence of specific halogen carriers, namely iron, iodine, pyridine or aluminium amalgam invariably result into the formation of appropriate bromo-substituted derivatives. At an initial stage a mono-hromo derivative is formed which on subsequent treatment with bromine ultimately give rise to the formation of the respective polybromo derivative. 

Zinc Derivatives. Zincated and Al-protected 6-iodouracil 155 can be used under Negishi conditions for the preparation of 6-arylated uracil derivatives (Scheme 63). The conversion of the 6-iodouracil derivative is best performed using highly active zinc dust in DMAC.f The oxidative addition of active zinc has also been applied to a number of other iodo- and bromo-substituted 7r-deficient heteroarenes such as pyridine, pyrimidine, and quinoline, giving the corresponding heteroarylzinc halides 156, which are transformed to arylated derivatives by palladium catalysis. ... 

Indeed, a general and facile one-pot procedure has been developed for the synthesis of 2-substituted pyridines from the corresponding pyridine A-oxides and nucleophiles as a good alternative to S Ar chemistry. A variety of nucleophiles and heteroaromatic A-oxides can participate in this reaction, proceeding effectively in the presence of PyBroP (bromo-fra-pyrrolidino-phosphonium hexafluorophosphate), the excellent agent for substrate activation (Scheme 17) [43]. 

The scope of various pyridine derivatives with 1-hexene was examined with L45c-Sc/[Ph3C][B(C6F5)4] as the catalyst (Table 5.8). The asymmetric alkylation of 2-Me, 2-Et, 2- Pr, 2- Bu, and 2-phenyl-substituted pyridines 188 could also be achieved similarly in high yields (83-94%) and enantioselectivity (up to 94 6 er) (entries 1-5). Notably, the C—H bond activation reaction occurred selectively at the pyridine unit rather than at the phenyl group in the case of 2-phenylpyridine, which is in contrast with the reactions catalyzed by late transition metal complexes. The iodo, bromo, and chloro substituents in the picoline substrates are well compatible (entries 6-8). No alkylation reaction was observed with unsubstituted pyridine or quinoline, probably due to the poisoning effect of the N atom of pyridine to the metal center. 

MSubstituted-2-pyridones can be used as substrates for ring closure to a number of polyheterocyclic systems, as an alternate to the Pschorr cycliza-tion Of to the cyclizations of the corresponding At-alkyl-2-halopyridinium halides. 2-Substituted pyridines (MI-625 X =C1, Br, OC Hj) and 3-(2-bromo-ethyl)indole give -[2-(3-indolyl)ethyl]-2-substituted pyridinium bromide... 

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