Benzamides ortho-lithiated

Secondary amides may direct ortho lithiation, but they must first be deprotonated. This makes them somewhat weaker ortho directors than tertiary amides, but they may still serve the purpose quite well. For example, the lithiation and addition of benzamide (12) to aldehyde (13) was us in a synthesis of 11-deoxycaiminomycinone (Scheme 8). More recently, it has been shown that the amide monoanion may be obtained by addition of a phenylsodium to an isocyanate. ... 

Snieckus, V. Heterocycles via ortho-lithiated benzamides. Heterocycles 980, 14,1649-1676. 

HAUSER-BEAK Ortho Lithiation Ortho-alkylation of benzamides (see 1st edition). 

The X-ray structures of lithiated Af,Af-diisopropylbenzamide and 1-naphthamide revealed for the first time that the oxygen coordination of the lithinm center is maintained in ortho-lithiated aromatic tertiary amides [156] like lV,lV-diisopropyl benzamide and naphthamide, giving species that have been characterized as solid-state dimers (Fig. 26.10). In a (CLi) core, each Li-ion is further stabilized by one solvent molecnle (Et O or THF) and an amide O-center [157]. These solid-state strnctnres are coherent with a CIPE-induced lithiation of benzamides through amide(0)-Li coordination. 

SiBi, M.P., M.A. Miah, and S.V. Jalil Ortho-lithiated Tertiary Benzamides. Magnesium Transmetalation and Synthesis of Phthalides and Isocoumarins including Mel-lein and Kigelin. J. Organ. Chem. (USA) 49, 737 (1984). 

Numerous examples exist in which TMEDA not only facilitates the lithiation of aromatic and heteroaromatic substrates but also controls the regioselectivity of lithiation. While tertiary ben-zamides are susceptible to nucleophilic attack by n-butyllithium to give aryl butyl ketones, the use of s-ButyllithiumnMEDA in THF at —78 °C provides the synthetically useful ortho metalated tertiary benzamide which may be treated with a large variety of electrophiles (eq 4). Even with compounds having a second more acidic site the above conditions allow ortho lithiation to take place under kinetic control. Thus a p-toluamide is ortho lithiated with s-butyllithium/TMEDA in THF at —78 °C, but when Lithium Diisopropylamide is used as the base in THF at 0 °C the thermodynamically favored benzyllithium species is obtained (eq 5). The very marked influence of TMEDA on the lithiation of naphthyl methyl ether in hydrocarbon solvents is dramatically illustrated in the example in eq 6. ... 

Reed, J. N. Snieckus, V. ortho-Amination of lithiated tertiary benzamides. Short route to polysubstituted anthranilamides. Tetrahedron Lett. 1983, 24, 3795-3798. 

The ortho-functionalized ketones 39 are obtained from 2-methyl-N,N -diethyl-benzamides 38 by lithiation in the benzyl position with tBuLi followed by acylation with N, N -dimethylcarboxamides. 

Aromatic amides like 1 (both benzamides and naphthamides) can be dearomatized to yield bi- and polycyclic amides 2 in a stereoselective cyclization reaction triggered by a benzylic lithiation a to the amide nitrogen to form organolithium intermediate 3. The proposed mechanism of the reaction consists of the intramolecular conjugate addition of the benzylic anionic center in 3 into the electron-deficient ortho position of the aromatic ring (Scheme 28.1). In most cases, the addition of l,3-dimethyltetrahydro-2(l//)-pyrimidinone (DMPU) to the reaction medium is required to promote the cyclization step. Considering the proposed mechanism, the high stereoselectivity observed in the cyclization is truly remarkable. 

---