Pyridine reaction with organolithiums

Evidence for the formation of an adduct in the reaction of pyridine derivatives with organolithium compounds was also reported by Abramovitch and... 

Reaction with Organolithium Reagents. The fluorination of vinyl lithium derivatives with NFSi has been demonstrated in good yields with complete retention of configuration about the double bond. Phenyl lithium reacts rather poorly with A-fluorobenzenesulfonimide, but more complex phenyl lithium daivatives have been fluorinated to prepare fluoro- and polyfluoro-veratraldehydes as well as complex fluorinated polyaromatic compounds. Organolithium derivatives of heterocycles have been fluorinated by reaction with NFSi at low temperature. In this manner, fluoro-p3aroles and 2-fluoro-5-methylthieno[3,2-b]pyridine are prepared from their corresponding lithio-parent compounds (eq 16). ... 

Finally, Azzena reported on the reductive functionalization of hexahydio-oxazolo[3,4- ] pyridine 193 its reaction with potassium or lithium and naphthalene followed by trapping of the intermediate organolithium derivative allowed for the isolation of piperidine 194 with useful levels of selectivities (Scheme 55) <2002J(P1)360>. 

Strong nucleophiles such as organolithium or organomagnesium derivatives do not react with substituted or unsubstituted phosphabenzene or arsabenzene (39, Y = P or As) by nucleophilic substitution as in the case of pyridines, but by addition to the heteroatom forming intermediate anions 40. These can then be converted into nonaromatic compounds by reaction with water to yield 1-alkyl-1,2-dihydro-derivatives 41, or they can be alkylated by an alkyl halide with the same or a different alkyl group, when two products may result a 1,2-dialkyl-1,2-dihydro 40-derivative 42, or a -derivative 43. The former products are kinetically controlled, whereas the latter compounds are thermodynamically controlled, so that one may favor the desired product by choosing the appropriate reaction conditions. 

The reaction of organolithium compounds with pyridines, discovered initially by Ziegler and Zeiser228 has been investigated much... 

The orientation in the reaction of organolithium compounds with 3-substituted pyridines had not always been unambiguously established. For example, it was reported that 3-picoline and phenyllithium combined to give 5-methyl-2-phenylpyridine (107, R = CH3) exclusively.240 This has been shown to be quite the opposite of what actually happens241 (see Table IV). Similarly, 3-phenylpyridine was said to... 

There is no doubt that in these. reactions the nitrogen atom of the pyridine ring is complexed with either the lithium alkyl or aryl or with the lithium bromide which is usually present in many preparations of organolithium compounds. It has been established that, either in the presence of an excess of lithium bromide or in the total absence of this salt, phenyllithium still gives the same ortho .para ratio on reaction with 3-picoline.229 To account for the predominant formation of the 2,3-isomer in the reaction of CH3Li with 3-alkylpyridines, it was suggested261 that the transition states for these reactions were similar... 

The orientation of the entering nucleophile in the Emmert reaction304,305 presents features which differ from those observed in the reactions of organolithium compounds with pyridines, and deserves further study. When pyridine is heated with acetone in the presence of magnesium and mercuric chloride, 2-pyridyldimethyl-carbinol (127, R = H) is obtained. Unfortunately, the yields in this... 

Organomagnesium compounds usually resemble organolithium compounds in their reactions with nitrogen heterocyclic aromatic compounds [E, G], but they generally give inferior results for preparative purposes. Thus, as in the case of organolithium compounds, addition normally occurs at the 2-position of pyridine, and subsequent elimination or oxidation gives the 2-substituted pyridine [1] ... 

Pyridine is an aromatic 6n electron heterocycle, which is isoelectronic with benzene, but electron deficient. Nucleophiles thus add almost invariably to carbon C2 of the imine-like C=N double bond. Perhaps the best known nucleophilic addition is the Chichibabin reaction with sodium amide in liquid ammonia, giving 2-aminopyr-idine. Reactions of the quinoline moiety of cinchona alkaloids can be more complex. Although expected 2 -addition can be achieved easily with organolithium reagents to yield 13 (Scheme 12.6) [9], LiAlH4, for example, has been shown to attack C4 en route to quincorine and quincoridine (Schemes 12.4 and 12.5). C4 selectivity is due to chelation of aluminum by the C9 OH oxygen. 

Reactions with nucleophiles occur at ring position C-4 (e.g. with Grignard reagents [137]), or at C-3 (with organolithium compounds). They are preparatively not as important as the Chichibabin or Ziegler reaction in pyridine ... 

When a phenyl ring on the backbone of polystyrene (represented by the solid sphere) is reacted with benzoyl chloride and aluminum chloride, the product is the benzoyl derivative 167 (this is a Friedel-Crafts acylation see Chapter 21, Section 21.3.3). If reacted with 168, the product is 169 (an acyl addition reaction of an organolithium reagent see Chapter 18, Section 18.4). When the methyl group of the pyridine unit in 169 is treated with phenyllithium to form the (pyridyllCHgLi derivative, reaction with formaldehyde leads to 170. If 170 is linked to iV-benzoyl 2 -0-isobutyladenosine-3 -monophosphate (171), the product is 172, in which the first nucleotide is bound to the polymer via the 3 position. 

By this reaction, numerous organolithium compounds have been prepared from heterocycles. These heterocyclic lithium compounds can be those of pyridine, quinoline, carbazole, dibenzofuran, dibenzothiophene, etc. With some of these heterocyclic systems, there are made available organolithium compounds wherein the lithium is attached to carbon atoms otherwise inaccessible. We found them to be very helpful in our extensive heterocyclic investigations. 

The reaction of pyridines with organolithium reagents afforded mainly 2-substituted pyridines through alkyl addition to generate a dearomatized hthium complex of dUiydropyridine. From this species, it has been though that ehmination of highly insoluble lithium hydride would yield the final... 

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