Reactions of C-metallated Pyridines

Lithiation of 2,5-dibromopyridine leads exclusively and efficiently to 2-bromo-5-lithiopyridine in a thermodynamically controlled process it has been suggested that the 2-pyridyl anion is destabilised by electrostatic repulsion between nitrogen lone pair and the adjacent anion this same factor is probably important in the greater difficulty found in generating 2,3-pyridyne (see section 5.3.2). 

The use of halogen to direct lithiation can be combined with the ability to subsequently displace the halogen with a nucleophile.  

Halopyridines take part in palladium-catalysed reactions, for example Heck, carbonylation, and coupling reactions, with, for example, alkynes.  

Lithium derivatives are easily prepared and behave as typical organometallic nucleophiles,thus for example, 3-bromopyridine undergoes efficient exchange with -butyllithium in ether at -78 °C. In the more basic tetrahydrofuran as solvent, and at this temperature, the alkyllithium becomes more nucleophilic and only addition occurs, although the exchange can be carried out in tetrahydrofuran at lower temperatures. Lithiopyridines can also be prepared from halopyridines, including chloropyridines, via exchange with lithium naphthalenide. 2-Bromo-6-methylpyridine can be converted into its lithio derivative without deprotonation of the methyl.  

Direct regioselective a lithiation of pyridine, 2-methoxypyridine, or 2-methylthio-pyridine, can be carried out using a complex base consisting of a mixture of butyllithium and the lithium salt of 2-dimethylaminoethanol. The process may be more complex than simple deprotonation, possibly involving a radical anion intermediate.  

Monolithiation of 2,6-dibromopyridine is best achieved by inverse addition -dibromide to n-butyllithium, or by using dichloromethane as solvent - probably a unique application of this solvent to lithiation. A normal lithiation of 2,5-dibromopyridine, but at -90 °C, produces clean 2-substituted product with a hindered silicon electrophile.  

Lithiation of 2- and 4-t-butoxycarbonylaminopyridines can only take place at C-3 a neat sequence involving first, ring lithiation to allow introduction a methyl group and secondly side-chain lithiation (section 5.11) at the introduced methyl group provided a route to azaindoles (section 17.17.7), as illustrated below for the synthesis of 5-azaindole (pyrrolo[3,2-c]pyridine).  

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Among all the methods of introducing a pyridine moiety into a drug-like molecule, metal-catalyzed carbon-carbon or carbon-nitrogen bond formation reactions of C-metallated pyridines or pyridine halides are the most important and widely used. 

Niobium and tantalum halides form adducts with various nitrogen donor ligands including aliphatic and aromatic amines nitriles, Schiffs bases and imidazoles (Table 5). The reactions of MXS with pyridine and related ligands such as bipy or phen depend critically on the reaction conditions. With py at low temperature MX5 (X = Cl, Br) yielded 1 1 adducts that are rapidly reduced to [MX4(py)2] on increasing the temperature, with formation of l-(4-pyridyl)pyridinium halide. Similarly, bipy and phen reduced the metal in MeCN to oxidation state +IV and formed monoadducts of type [MX bipy)] at room temperature, while at 0°C the same reactions yielded [NbCls(bipy)(MeCN)] and [TaX5(bipy)(MeCN)J (X = C1 or Br). NbBrs and Tals formed [MX5(bipy)2], which were formulated as the eight-coordinate [MX4(bipy)2]X.1 Reduction of the metal can however be prevented, even at room temperature,... 

More recently, reactions of alkali metal acetylides, HC2M (M = Li-Cs), with Aul in liquid NH3 and subsequent heating of the solid product in pyridine (Li-K) or in vacuum (Rb, Cs) gave pale yellow M2AuC2.184,185 They contain [Au C C chains, which interact with the alkali metal cations via the C2 units, and are generally similar to the analogous silver compounds.204... 

Consequently, pyridine has a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. One unique aspect of pyridine is the protonation, alkylation, and acylation of its nitrogen atom. The resultant salts are still aromatic, however, and they are much more polarized. Details for reactivity of pyridine derivatives, in particular, reactions on the pyridine nitrogen and the Zincke reaction, as well as C-metallated pyridines, halogen pyridines, and their uses in the transition metal-catalyzed C-C and C-N cross-coupling reactions in drug synthesis, will be discussed in Section 10.2. 

The C-metallated pyridines can undergo the following types of reactions ... 

Figure 1. Overview of metal-catalyzed C-C and C-N/C-0 cross-coupling reactions of halopyridines or C-metallated pyridines...

Jury JC, Swamy NK, Yazici A, Willis AC, Pyne SG (2009) Metal-catalyzed cycloisomerization reactions of c -4-hydroxy-5-alkynylpyrrolidinones and cii-5-hydroxy-6-alkynylpi-peridinones synthesis of furo[3,2-i)]pyrroles and furo[3,2-b]pyridines. J Org Chem 74 5523-5527... 

Etherification. The reaction of alkyl haUdes with sugar polyols in the presence of aqueous alkaline reagents generally results in partial etherification. Thus, a tetraaHyl ether is formed on reaction of D-mannitol with aHyl bromide in the presence of 20% sodium hydroxide at 75°C (124). Treatment of this partial ether with metallic sodium to form an alcoholate, followed by reaction with additional aHyl bromide, leads to hexaaHyl D-mannitol (125). Complete methylation of D-mannitol occurs, however, by the action of dimethyl sulfate and sodium hydroxide (126). A mixture of tetra- and pentabutyloxymethyl ethers of D-mannitol results from the action of butyl chloromethyl ether (127). Completely substituted trimethylsilyl derivatives of polyols, distillable in vacuo, are prepared by interaction with trim ethyl chi oro s il an e in the presence of pyridine (128). Hexavinylmannitol is obtained from D-mannitol and acetylene at 25.31 MPa (250 atm) and 160°C (129). 

A process for the preparation of functionalized pyridines from diacetylene and the ethyl ester of /3-aminocrotonic acid and acetylacetonimine (72ZOR1328 75DIS) has been described. Owing to the lower nucleophilicity of nitrogen in the initial enamine esters and enamine ketone, the reaction with diacetylene occurs in the presence of sodium metal (80°C, dioxane, 3 h, yield of up to 20%). 

Fast sulphon black F ( C.I.26990). This dyestuff is the sodium salt of 1-hydroxy-8-( 2-hydroxynaphthylazo) -2- (sulphonaphthylazo) -3,6-disulph onic acid. The colour reaction seems virtually specific for copper ions. In ammoniacal solution it forms complexes with only copper and nickel the presence of ammonia or pyridine is required for colour formation. In the direct titration of copper in ammoniacal solution the colour change at the end point is from magenta or [depending upon the concentration of copper(II) ions] pale blue to bright green. The indicator action with nickel is poor. Metal ions, such as those of Cd, Pb, Ni, Zn, Ca, and Ba, may be titrated using this indicator by the prior addition of a reasonable excess of standard copper(II) solution. 

Cycloaddition reactions catalysed by transition metal complexes are an important tool in the construction of a wide range of carbo- and hetero-cyclic systems, such as benzene, pyridines, triazoles, etc. [7]. In general, these reactions are extremely atom-efficient and involve the formation of several C-C bonds in a single step. Among the innumerable possible catalytic systems for the cycloaddition reaction the NHC-metal complexes have received special attention [7c]. 

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. 

Most of the substrates that give both types of cycloaurated complexes are limited to pyridine derivatives, although recently a few exceptions have been reported with thiazoles and imidazoles. The reaction of substituted pyridine ligands such as phpy,1 49,1924 2-benzoyl pyridine,1924 2-anili-nopyridine,1925,1926 l-(2-pyridylamino and 2-pyrimidinylamino)naphthalene, 7 2-phenoxypyri-dine,1811 2-(phenylsulfanyl)pyridine,1925 2-(2-thienyl)pyridine, 8 2-(3-thienyl)pyridine,1928 2-(alkylsulfanyl)pyridine,1929 or papavorine1930 at room temperature yields the nonmetallated compounds which, upon heating, are transformed into the metallated complexes [Au(N,C)Cl2], The process with phpy is illustrated in Scheme 21. 

In the dihapto mode the pyridine ring can be protonated intermolecularly at nitrogen, or even intramolecularly deprotonated at carbon. The first evidence for metal C—N insertion is the reaction of the metallaaziridine complex (111) with homogeneity LiHBEt3 in THF at low temperature that yields (112) (Scheme 49).251-254 Experiments with carbon nucleophiles (RMgCl, MeLi) in place of LiHBEt3 have provided valuable information to allow discrimination between... 

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