6- Methyl-2-bromopyridine

The search for efficient ruthenium catalysts has led to explore the use of the ruthenium(IV) stable system [RuH(cyclooctadienyl)2]BF4. This Ru(lV) precursor is deprotonated into Ru(U) species in the presence of a base. Carboxylate salts KOAc, KOPiv, and potassium pthalimide (KPl) are able to completely promote diarylation of 2-phenylpyridine with chlorobenzene in 1 h at 120°C. The efficiency of the catalytic system was the best in the presence of KPl with chlorobenzene. For 2-chlorotoluene, 2-chlorothiophene, 6-methyl-2-bromopyridine the best yields were obtained with [RuH(cyclooctadienyl)2]BF4. and KOAc in NMP, and from p-Br-C6H4-Cl the dichloro derivatives could be obtained [(Eq. 16)] [83]. 

Bromopyridine has been made by direct bromination of pyridine - from N-methyl-2-pyridone with phosphorus penta-bromide and phosphorus oxybromide from 2-aminopyridine by diazotization with amyl nitrite in 20% hydrobromic acid from sodium 2-pyridinediazotate by solution in concentrated hydrobromic acid and from 2-aminopyridinc by diazotization in the presence of bromine and concentrated hydrobromic acidd The method described here is essentially that of Craig. 

Reaction of 2 equiv of 2-aminopyridines with 2-hydropolyfluoroalk-2-anoates 351 in MeCN in the presence of NEts at 90 °C for 50 h afforded a mixture of the isomeric 2-oxo-2H- and 4-oxo-4//-pyrido[l,2-n]pyrimidines 110 and 111. Reaction of 3 equiv of 2-amino-pyridines and 2-hydropoly-fluoroalk-2-enoates 351 in MeCN in the presence K2CO3 could be accelerated by ultrasonic irradiation (125W). 2-Amino-6-methylpyridine yielded only 2-substituted 6-methyl-4//-pyrido[l,2-n]pyrimidin-4-ones 111 (R = 6-Me), whereas 2-amino-5-bromopyridine gave a mixture of 7-bromo-4//-pyrido[l,2-n]pyrimidin-4-one (111, R = 7-Br, R = CF2C1) and 2-(chlor-o,difluoromethyl)-6-bromoimidazo[l, 2-n]pyrimidine-3-carboxylate in 44 and 8% yields, respectively (97JCS(P 1)981). Reactions in the presence of K2CO3 in MeCN at 90°C for 60h afforded only imidazo[l,2-n]pyrimidine-3-carboxylates. 

Amino group of 7-aminomethyl-2-substituted perhydropyrido[l,2-u]pyr-azines were reacted with 2-bromopyridine and 2-chloropyrimidines to give 7-(hetarylamino)methyl derivatives in the presence of Na2C03 in DMF at 100-120°C for 18h in 13-51% yields (00MIP15). An aminomethyl group of... 

Bromopyridine (193 g, 1.22 mols) is then added dropwise over 20 minutes, the temperature of the reaction mixture being maintained at -50 2°C. The mixture is stirred for 10 minutes at -50°C and p-methyl-cj-pyrrolidinopropiophenone (112.5 g, 0.5 mol) in dry benzene is then added dropwise over ca 30 minutes, at a temperature of -50 2°C. The mixture is stirred for a further 2 hours, the temperature being allowed to rise to -30°C but no higher. 

Although iodides are more reactive than bromides, 2-(trifluoro-methyl)pyridine was obtained in 95% yield from 2-bromopyridine and CF3Br using an undivided electrochemical cell, DMF, and a sacrificial copper anode. CF3Cu was the reactive intermediate (92CC53). Photochem-... 

Poly(methyl 3-(l-oxypyridinyl)siloxane) was synthesized and shown to have catalytic activity in transacylation reactions of carboxylic and phosphoric acid derivatives. 3-(Methyldichlorosilyl)pyridine (1) was made by metallation of 3-bromopyridine with n-BuLi followed by reaction with excess MeSiCl3. 1 was hydrolyzed in aqueous ammonia to give hydroxyl terminated poly(methyl 3-pyridinylsiloxane) (2) which was end-blocked to polymer 3 with (Me3Si)2NH and Me3SiCl. Polymer 3 was N-oxidized with m-ClC6H4C03H to give 4. Species 1-4 were characterized by IR and H NMR spectra. MS of 1 and thermal analysis (DSC and TGA) of 2-4 are discussed. 3-(Trimethylsilyl)-pyridine 1-oxide (6), l,3-dimethyl-l,3-bis-3-(l-oxypyridinyl) disiloxane (7) and 4 were effective catalysts for conversion of benzoyl chloride to benzoic anhydride in CH2Cl2/aqueous NaHCC>3 suspensions and for hydrolysis of diphenyl phosphorochloridate in aqueous NaHCC>3. The latter had a ti/2 of less than 10 min at 23°C. 

This indole C-7 Heck cyclization strategy was employed by Shao and Cai in a synthesis of anhydrolycorine-7-one from the requisite N-aroylindoline [275], by Miki in syntheses of pratosine and hippadine from substrates like 262 [276], and by Rigby to synthesize anhydrodehydrolycorine from an N-benzylhydroindolone [277, 278]. Thai and co-workers constructed examples of the new ring systems, pyrido[2 ,3-d ]pyridazino[2,3-a]indole (264) and pyrido[2 ,3 -Heck cyclizations on the appropriate 2-bromopyridine precursors (e.g., 263) at C-2 or C-7, respectively [279, 280]. Compound 264 undergoes oxidative-addition with methyl acrylate at the C-3 position. This resulting product (not shown) can also be obtained from 263 in a tandem Heck sequence with methyl acrylate (62% yield). 

Both l-ethoxy-2-tributylstannylethene [85, 86] and 1-ethoxy-1-tributylstannylethene [6, 87] are versatile building blocks utilized in Stille couplings. Their Stille adducts can then be hydrolyzed to the corresponding aldehyde and methyl ketone, respectively, as exemplified by the transformation of bromopyridine 98 into methyl ketone 99 [6]. 

Tributylstannyl-2-methylthiopyrimidine (115) was prepared from 5-bromo-2-methyl-thiopyrimidine using either a Pd-catalyzed reaction with hexabutyldistannane in the presence of fluoride or a substitution reaction using a tributylstannyl anion. The subsequent coupling of 115 with 4-bromopyridine delivered the expected pyridylpyrimidine 116 [99]. 

In one case, the intermolecular Heck reaction of 3-pyridyltriflate with ethyl acrylate was accelerated by LiCl to give 159 [127,128], Here, both electronic and steric effects all favored p-substitution. In another case, however, electronic effects prevailed and complete a-substitution was observed. In the presence of an electron-donating substituent (i.e., a protected amine), 3-bromopyridine 160 was coupled with f-butoxyethylene to give 3-pyridyl methyl ketone 162 [126]. The regiochemistry of the Heck reaction was governed by inductive effects, leading to intermediate 161. 

In Rao s total synthesis of niphatesines, a key intermediate 91 was elaborated from an intermolecular Heck reaction of 3-bromopyridine with non-8-en-ol <93TL8329>. In another case, Bracher et al. synthesized a natur ly occurring P-carboline, infractine (93), from p-carboline-l-triflate (92) in a two step process consisting of a Heck reaction with methyl acrylate followed by a hydrogenation <95PHA182>. Their approach provided an expeditious route to infractine, although the Heck reaction was low yielding. 

The synthetic utility of many of the substitution reactions described so far is limited because there are well-established thermal routes to the same products. However, a third group of photochemical nucleophilic substitutions involves aryl halides and nucleophiles based on sulfur, phosphorus or, of particular importance, carbon. Two examples are the reaction of bromobenzene with the anion of t-butyl methyl ketone 13.12), and the replacement of bromine by cyanomethyl in 2-bromopyridine (3.13). This type of reaction offers a clear advantage over lengthy thermal alternatives, and intramolecular versions have been used in the synthesis of indoles (e.g. 3.14) or benzofurans from o-iodoaniline or o-iodoanisole respectively. 

To a solution of the N-methoxy-N-methyl-2,8-bis(trifluoromethyl)-quinoline-4-carboxamide amide (10 g, 28.4 mmol) in anhydrous ether (100 ml) was added a solution of 2-pyridyl lithium (Pinder et al (J. Med. Chem. 1968, 11, 267)) [formed by addition of 2-bromopyridine (3.3 ml, 34.6 mmol) to a solution of butyl lithium (29.7 ml of a commercial 1.6 M solution, diluted with an equal quantity of ether) at -78°C] at -78°C. Analysis of the reaction by TLC after 10 min showed that no starting material remained. The reaction was allowed to warm to room temperature, then poured into aqueous ammonium acetate, and extracted with ether, the combined organic layers washed with brine and dried (MgS04). Filtration through a pad of silica gel using ethyl acetate-hexane (1 1) afforded 9.0 g (84%) of the crude 2,8-bis(trifluoromethyl)-4-quinolinyl-2-pyridinylmethanone. This was recrystallised from isopropyl alcohol to give the product as colourless needles, identical to that described in the literature (Hickmann et al. Pinder et al. Ohnmacht et al. and Adam et al. (Tetrahedron 1991, 36, 7609)). 

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>. 

The reaction of A-methyl-A-acetyl-2-chloro-3-amino tion in THF-hexane (-78 °C) gave azaindole in 83% yield used to prepare the key intermediate for the synthesis of Eupolauramine339. Thus, o-metallation of 3-bromopyridine and treatment with MeNCO gave the anion 319, which reacts with PhCOCH2Br forming the product 320 (equation 191). 

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