Directed metalation organolithiums

We recently demonstrated that organolithium reagents formed by directed metallation of pivaloylanilines would react rapidly with carbon monoxide at 0°C or room temperature to form high yields of dioxindoles (Fig. 16) (ref. 30). This... 

Germyl, Stannyl, and Plumbyl Anions The preparative methods for the synthesis of the germyl, stannyl, and plumbyl anions are essentially the same as those mentioned above for the silyl anions. The most widely used methods are (1) reduction of halides R3EX (R = alkyl, aryl E = Ge, Sn, Pb X = Cl, Br) with alkali metals and (2) reductive cleavage of the E-E bond of R3E-ER3 (R = alkyl, aryl E = Ge, Sn, Pb) with alkali metals or organolithium reagents. Due to the favorable polarization of the (E = Ge, Sn, Pb) bond, the direct metalation... 

An excellent example of the application of pyridine lithiation is the synthesis of the fully substituted pyridine atpenin B 255, an antibiotic produced by Penicillium. Its first synthesis, in 1994, was achieved by a series of directed metallations (Scheme 126) which started with 2-chloropyridine 256 and introduced the substituents stepwise around the ring. 2-Chloropyridine can be lithiated ortho-directed by the chlorine) by either LDA or by PhLi, and the organolithium 257 was oxidized to 258 with trimethylborate and then peracetic acid. 0-Methylation and substitution of chloride by methoxide gave 2,3-dimethoxypyridine 259 (Scheme 127). 

Thiophene is sufficiently acidic to be directly metallated upon treatment with n-BuLi (see Figure 4.1). This direct lithiation can also be realized with polystyrene-bound 3-(alkoxymethyl)thiophene [96]. The resulting organolithium compounds react as expected with several electrophiles, such as amides (to yield ketones), alkyl halides, aldehydes, and Me3SiCl [96]. 

Reaction with even harder nucleophiles such as organolithiums and Grignard reagents is substantially limited by virtue of the fact that these carbon nucleophiles add by direct attack at the metal center, as opposed to the softer carbon nucleophiles which add by attack on the allyl ligand. Direct metal addition can lead to the opening of alternative reaction pathways, e.g. 3-H elimination, in competition with reductive elimination which accomplishes nucleophile allylation (equation 40). 

When the a-position is allylic, metalation is easier, and the resulting organolithium is not prone to oxidation y-substitution then predominates over a-substitution, as shown by the example in Scheme 11 The stereoelectronic preference of dipole-stabilized organolithiums for the nodal plane of the amide or amidine ir-system makes possible the directed metalation of bridgehead positions. Two examples are il-... 

Metalation and Halogen-Metal Exchange.—The direct metalation of thiophens with organolithium compounds and the halogen-metal exchange reaction between halogenothiophens and organolithium derivatives have... 

Keywords Configurational stability Deep eutectic solvents Direct metalation group Epoxides Natural products Organolithiums Oxetanes Oxygen heterocycles Stereoselective synthesis Tetrahydrofurans... 

DIRECTED METALATION OF ARENES WITH ORGANOLITHIUMS, LITHIUM AMIDES, AND SUPERBASES... 

Clayden, J. (2004) Directed Metallation of Aromatic Compounds, in The Chemistry of Organolithium Compounds the Chemistry of Functional Groups, (eds. Rappoport, Z., Marek, I.), John Wiley Sons, Ltd, Chichester, pp. 495-646. 

The role of organolithium aggregates and mixed aggregates in organolithium mechanisms has been reviewed. The synthetic utility of the regio- and stereo-selective lithiation of aziridines has been highlighted. " The latest developments on the direct metallation (mainly lithiation chemistry) of various 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles, and 1,3,4-oxadiazoles have been presented. ... 

Carbocyclic substitution can also be achieved by first introdueing a reactive organomelallic substituent. Preparation of organolithium reagents can be done by one of the conventional melhods. especially halogen-metal exchange or directed lithiation. Table 14.2 gives examples. 

Organolithium compounds can readily be prepared from metallic Li and this is one of the major uses of the metal. Because of the great reactivity both of the reactants and the products, air and moisture must be rigorously excluded by use of an inert atmosphere. Lithium can be reacted directly with alkyl halides in light petroleum, cyclohexane, benzene or ether, the chlorides generally being preferred ... 

This type of metallic exchange is used much less often than 12-32 and 12-33. It is an equilibrium reaction and is useful only if the equilibrium lies in the desired direction. Usually the goal is to prepare a lithium compound that is not prepared easily in other ways, for example, a vinylic or an allylic lithium, most commonly from an organotin substrate. Examples are the preparation of vinyllithium from phenyl-lithium and tetravinyltin and the formation of a-dialkylamino organolithium compounds from the corresponding organotin compounds ... 

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