Bromopyridines, reduction

Cyclization of the side chain onto the nitrogen atom leads to compounds with sedative and tranquilizing activity. The lack of structural specificity, that is, the fact that both positional isomers (41,43) show the same activity, is notable. Thus, condensation of the Grignard reagent from 2-bromopyridine with ben-zophenone affords the tertiary carbinol, 40. Catalytic reduction... 

Homolytic aromatic substitution often requires high temperatures, high concentrations of initiator, long reaction times and typically occurs in moderate yields.Such reactions are often conducted under reducing conditions with (TMSlsSiH, even though the reactions are not reductions and often finish with oxidative rearomatization. Reaction (68) shows an example where a solution containing silane (2 equiv) and AIBN (2 equiv) is slowly added (8h) in heated pyridine containing 2-bromopyridine (1 equiv) The synthesis of 2,3 -bipyridine 75 presumably occurs via the formation of cyclohexadienyl radicals 74 and its rearomatization by disproportionation with the alkyl radical from AIBN. ... 

The intermolecular Heck reaction of halopyridines provides an alternative route to functionalized pyridines, circumventing the functional group compatibility problems encountered in other methods. 3-Bromopyridine has often been used as a substrate for the Heck reaction [124-126]. For example, ketone 155 was obtained from the Heck reaction of 3-bromo-2-methoxy-5-chloropyridine (153) with allylic alcohol 154 [125]. The mechanism for such a synthetically useful coupling warrants additional comments oxidative addition of 3-bromopyridine 153 to Pd(0) proceeds as usual to give the palladium intermediate 156. Subsequent insertion of allylic alcohol 154 to 156 gives intermediate 157. Reductive elimination of 157 gives enol 158, which then isomerizes to afford ketone 155 as the ultimate product This tactic is frequently used in the synthesis of ketones from allylic alcohols. 

Aminopyridine has been prepared by heating nicotinamide in an alkaline potassium hypobromite solution at 70° by hydrolysis of 8-pyridylurethan with oleum by heating 3-amino-pyridine-2-carboxylic acid at 250° by reduction of 3-nitro-pyridine with zinc and hydrochloric acid and by heating 3-bromopyridine with ammonia and copper sulfate in a sealed tube. ... 

Acetylene can be made to react with aryl iodides in the presence of [PdCl2(PPh3)2] and Cul as catalyst (equation 180) 631 The potential intermediate, phenylacetylene, was not observed. (E) - 2-Bromostyrene and 2-bromopyridine also underwent the reaction. The initial reduction of palladium(II) to palladium(O) is believed to involve the coupling of two moles of acetylene. The precise mechanism is not known, but the reaction is thought to proceed according to Scheme 68. 

An example of the overall strategy is the coupling of bromopyridine and a secondary amine across 1,3-butadiene (equation 64). The conditions employ Pd and rely on in situ reduction to the effective catalyst, a version ofPd . 

The more flexible tether embodied in bispyridocarbazoles 321 and 322 was synthesized by Roques and colleagues (779) as shown in Scheme 50. The bischloro tether 319 was prepared from 4-bromopyridine (316) by halogen-metal exchange, condensation with 4-cyanopyridine, and Wolff-Kishner reduction of the resulting ketone 317. Catalytic hydrogenation, chlorination, and then alkylation of 320 with 319 gave the desired bispyridocarbazoles (321, 322). An important discovery in this research is that the methosulfate salts impart excellent water solubility to the bispyridocarbazoles. 

In later studies. Hall et al. (71) employed the same method as above to study the intracellular distribution of platinum complexes that carry bromine labels (2, 3) or anthraquinones (1). Again, after 24 hours, all complexes were found to be localized within the nucleus, with little platinum being in the cytosol. In the case of the platinum(II)-3-bromopyridine complex (2), the bromine was also observed to colocalize with the platinum. This finding is consistent with the amine moieties that remain bound to platinum(II) complexes inside cells. In another case of the platinum(IV)-bromoacetate complex (3), the distribution of the bromine was much more diffuse when compared with that of the platinum, which is consistent with the reduction of the platinum(IV) complex. However, whether the reduction occurred before or after cell entry is still unclear (see Fig. 4) (71). Hence, by this method of labeling, the bio-transformation of platinum(IV) agents can be monitored via SRIXE. 

ArOPPr2 system allows for a reduction of the catalyst loading to 3 mol% Rh without a significant reduction in yields, and the use of less expensive K3P04 as a base in certain cases. An extended survey of the substrate scope identified that a number of 2,6-disubstituted bromoarenes and heteroaryl halides including pyridines and thiophenes are reactive substrates. 2-Bromopyridine and 2-bromothiophene are poor substrates however, possibly due to the formation of catalytically inactive stable metal chelates. Finally, additional functional groups including anilines, alkenes, and chloroarenes are tolerated. 

Reduction. Alkyl iodides are reduced in water hy exposure to air and BusB. N-Heteroarylation. In the Pd-catalyzed substitution of heteroaryl halides (e.g., bromopyridines) with amides and sulfonamides the yields are greatly increased in the presence of Et3B. Coordination of the Lewis acid by the nuclear nitrogen atom accelerates the reductive elimination step. 

Recently, Nadin and Harrison [70] made a similar observation with pyridones, employing a rare example of a pyridine radical. Reaction of the 3-bromopyridine derivative 278 with BusSnH and AIBN furnished the 1-exo trig cyclized product 279 along with 10% of uncyclized reduction product. It is worth noting that the same reaction failed under the Heck conditions. 

The product is a useful intermediate in the synthesis of the analgesic epibatidine. Selective reduction of the non-conjugated double bond is followed by addition of a pyridine nucleophile (a lithium derivative can be prepared from a bromopyridine) to the vinyl sulfone. 

The preparation and reactions of 3-bromo-4,S-diaminopyridine have been studied. The nitration of 4-amino-3-bromopyridine (IX-182) and the subsequent rearrangement of the nitramino derivative IX-183 give 4-amino-3-bromo-S-nitro-pyridine (IX-184). The reduction of IX-184 with iron and acetic acid produces... 

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