Peri lithiation

Fig. 13.6. Nickel-catalyzed arylation of Grignard compounds. The Grignard compound can be prepared via a substituent-directed peri-lithiation of a substituted naphthalene (see Section...

TTie lithiation of a l,6-methano[10]annulenamide occurs selectively at the peri position, but the lithiation of fused ring aromatics t es place preferentially at the ortho (rather than peri) position,as shown by the examples in Scheme 12. Subsequent transformations of the phthalides obtained in the naphthalene example also illustrate the usefulness of this method for the annelation of aromatic rings. The preference for ortho over peri lithiation holds true for phenanthrenes as well. The selective metd-ation of trimethoxyphenanthrenamide (15) followed by phthalide synthesis as above constitute the key steps in the synthesis of the phenanthroquinolizidine alkaloid cryptopleurine and the phenanthroindoli-zidine alkaloid antofme (Scheme 13). ... 

The peri lithiation reaction, in which a DMG at position Cl directs deprotonation at C8 position of a naphthalene derivative, has received so far less attention (Scheme 26.11) [136]. The best DMGs for peri metalation are those which coordinate to the base and do not acidify—hence activate the ortho (C2) position [137]. Naphthalenes carrying F, Cl, CF, CF O, CONR at position 1 arekinet-ically and thermodynamically deprotonated by organometaUic reagents at position 2. In contrast, peri lithiation is favored if the DMG is OLi, NLi, NLiMe, NMe, and CH NMe. ... 

Methoxynaphthalenes may be lithiated in their ortho or peri positions according to conditions (see Table 1 in Section LA). 1,4-Dimethoxynaphthalene, for example, perilithi-ates cleanly with f-BuLi (Scheme 67) ... 

In aromatic compounds, potent but frustrated (their ortho positions blocked) directing groups may lead to lithiations at positions other than ortho. For example, when the carbamate 610 is treated with LDA in refluxing THE, lithiation occurs at a remote position (not peri, note) and an anionic Fries rearrangement ensues to give 611 (see Section I.B.l.d). Lactonization gives 612 (Scheme 239). ... 

Regioselective lithiation on the benzene moiety of 4-substituted quinazolines occurs at position peri to the N1 ring nitrogen. Thus, treatment of 4-methoxyquinazolines 8 with an excess of lithium 2,2,6,6-tetramethylpiperidide (LTMP) at — 78 to 0 X followed by reaction with various electrophiles affords 8-substituted quinazoline derivatives 9. This regioselective lithiation provides easy access to a large range of substituted quinazolines which are not easily synthesized by other routes. ... 

The predominant lithiation at 3-position in 2-methoxynaphthalene may be due to steric factors. When one compares the two transition states corresponding to lithiation at 1-position and at 3-position, one may note that the alkyl group of the lithiating agent is hindered by the peri-H in 63, while no such hindrance is present in 64. 

Direct lithiation, i.e. C-deprotonation of quinolines requires an adjacent substituent, such as chlorine, fluorine or alkoxy. Historically, what is probably the first ever strong base C-lithiation of a six-membered heterocycle was the 3-lithiation of 2-ethoxyquinoline. Both 4- and 2-dimethylaminocarbonyloxyquinolines lithiate at C-3 4-pivaloylaminoquinoline lithiates at the peri position, C-5. Quinolines with an ortfto-directing... 

Lithiation, by direct analogy with imidazole, involves the 3-proton, bnt 5-lithiation occurs on comparable treatment of its 3-ethylthio derivative, the substituent both blocking attack at C-3 and assisting lithiation at the peri-position the ethylthio group can, of course, be subsequently easily removed. ... 

We have tried to summarize in this chapter the basic tendencies and mechanisms of directed metalation. DoM in presence of DMG(s) allows for the regioexhaustive functionalization of aromatics. DreM, frequently combined with migration of the DMG or rearrangement, gives a powerful tool for the synthesis of natural products. Peri and lateral lithiations have shown to further enable functionalization for aromatic scaffolds, and last but not least, when coordinated to and thus activated by a metal complex, aromatic ring systems can be subjected to enantiose-lective metalation reactions. Although such a chapter cannot cover the topic in an exhaustive manner, we hope to have found a compromise between scholarly presentation and citation of relevant literature. 

The presence of an orf/to-directing group, such as Cl or OMe, on the benzene ring of benzodiazines (quinazolinones, quinoxalines, phthalazines) favours lithiation of that ring at the peri position to a ring nitrogen." ... 

---