Electron deficient organolithium

Addition of Grignard reagents and organolithium compounds to the pyridazine ring proceeds as a nucleophilic attack at one of the electron-deficient positions to give initially... 

Compound 388 is an acylating agent for electron-deficient alkenes, in a Michael addition process. It is formed by treating molybdenum hexacarbonyl with an organolithium compound, followed by quenching the intermediate 387 with boron trifluoride (equation 104). The structure of 388 (R = Ph) can be elucidated by NMR spectroscopy. Other examples of enantioselective and diastereoselective Michael-type additions involving lithium-containing intermediates in the presence of chiral additives can be found elsewhere in the literature . 

The reaction is initiated by the attack of the organolithium at sulfur to produce the pentacoordinate sulfur species. This seems to be the prime reaction of all electron-deficient sulfur compounds with organolithiums (Eq. 45). 

Dimethylpyrimido[4,5-f]pyridazine-5,7-dione 23 and its derivatives undergo attack at both C-3 and C-4. Under conditions of kinetic control, addition occurs preferentially at the more electron-deficient C, whereas thermodynamic control conditions, or the use of bulkier nucleophiles, favor addition at the less hindered position 3. This duality is illustrated by the addition of Grignard and organolithium reagents to C of 3-chloro analogue 24 (Equation 9), whereas stabilized nucleophiles such as the anion of nitromethane add at C-3 (Scheme 10) <2000CHE975>. Displacement of the 3-chloride occurs also upon treatment of 24 with amines (Equation 10) <2000CHE1213>. 

Organolithium compounds occur in solution as dimeric, tetrameric, or hexameric aggregates held together by electron-deficient bridge bonds (14). The actual degree of association depends on the alkyl group involved and the solvent. The nature of the association in these derivatives permits two types of exchange ... 

Lithiation by deprotonation of a C-H bond takes place at a reasonable rate only if the organolithium product displays two features intramolecular coordination of the electron-deficient lithium atom to a heteroatom (hydrocarbons are extremely slow to lithiate under most conditions, even at aromatic or vinylic sites) and stabilisation of the electron-rich C-Li bond by a nearby empty orbital or electron-withdrawing group. These two factors controlling lithiation are of varying importance according to the reaction in question, and the balance between them is a recurring theme of this chapter. 

The ease with which brominated heterocycles may be prepared regioselectively makes the use of these compounds as starting materials for the synthesis of regioselectively lithiated heterocycles extremely attractive. Organolithium derivatives of all the simple heterocycles at all possible positions of substitution have been made by this method.80 The scheme below illustrates some classical methods for forming 2-lithio-,81 3-lithio-,81 and 4-lithiopyridines,82 along with 4-lithioquinoline.83 rc-BuLi works well in these reactions, and indeed may be better than r-BuLi in reactions with electron deficient heterocycles, with which it tends to undergo addition reactions. 

The same reaction happens with 1 HF, but only in much lower yield. Nonetheless, just as cyclic amines are more nucleophilic than acyclic ones, so cyclic ethers are more nucleophilic than acyclic ones. This is one of the reasons why THF is such a good solvent for organolithiums—the nucleophilic lone pair of the oxygen atom stabilizes the electron-deficient lithium atom of the organolithium. 

This amphiphilic conjugate alkylation has been used successfully for nucleophilic alkylation of electron deficient arenes, on the basis of the unprecedented conjugate addition of organolithiums to aromatic aldehydes and ketones by complexation with ATPH [136], Thus, initial complexation of benzaldehyde or acetophenone with ATPH and subsequent addition of organolithiums affords 1,6 adducts with high selectivity, as illustrated in Sch. 99. 

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. 

The products obtained from the reaction of (chloromethyl)trimethylsilane with organolithium reagents depend very much on the structure of the lithium compound. While lithium 2,2,6,6-tetramethylpiperidide initiates an a-elimination as described above, the treatment with sec-butyllithium leads to the formation of chloro(trimethylsilyl)methyllithium (11). This reagent cyclopropanates an electron-deficient alkene through sequential Michael addition and intramolecular ring closure (MIRC reaction), for example, the formation of cyclopropane 12. 

Alcohols, aldehydes, ketones and carboxylic acids can be prepared from Grignard reagents, ArMgBr, and organolithium compounds, ArLi, by reaction with molecules with an electron-deficient site. 

This striking effect of a strong donor base on the catalytic activity of an organolithium compound contrasts with the reverse effect of donor bases on the growth reaction of ethylene with trialkylaluminum compounds. The catalytic activity of the latter is connected with the electron deficient nature of the uncoordinated, monomeric, trialkylaluminum species (10). These facts point to a difference in the mechanism of ethylene addition between the amine-coordinated organolithium catalyst and the trialkylaluminum compounds. 

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