Substitution, electrophilic halogenation, metal

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

Each of these intermediates can be hthiated in the 2-position in good yield. The reactivity toward hthiation is due to the inductive effect of the nitrogen atom and coordination by oxygen from the N-substituent. A wide variety of electrophiles can then carry out substitution at the 2-position. Lithiation at other positions on the ring can be achieved by halogen—metal exchange 3-hthio and 5-hthioindoles have also been used as reactive intermediates. 

The direct lithiation of a 2-substituted 1,2,3-triazole has not been reported. Halogen-metal exchange of 4,5-dibromotriazole with n-butyllithium at — 80 °C occurs smoothly and the subsequent reaction of the lithium intermediate (244) with various electrophiles except aldehydes gives the 4-bromo-5-substituted triazoles (245) (Scheme 46). The corresponding 1-substituted 4,5-dibromo-1,2,3-triazole undergoes a similar reaction at the 5-position . 

The anions generated by proton-metal or halogen-metal exchange (Section 4.1.6.3-4) reacted readily with electrophiles like MeOD, Mel, I2, and A/-formyI morphol i ne (NFM) to give the 5-substituted 1,2,3-triazole 1-oxides 372 (2010UP2) (Scheme 112). 

Substituted 1,2,3-triazole 1-oxides 448 have been reported to undergo electrophilic and nucleophilic aromatic substitution and are subject to debromination, proton-metal exchange, and halogen-metal exchange followed by electrophilic addition. Transmetallation and cross-coupling have not been described. 3-Substituted 1,2,3-triazole 1-oxides 448 can be proton-ated or alkylated at the O-atom and they can be deoxygenated and deal-kylated. The individual reactions are described in Section 4.2.7.1-4.2.7.14. 

The substituted pyrrole 34 has been prepared by halogen-metal exchange in the diene 35, followed by an interesting cyclization induced by TMEDA to provide intermediate 36, which was in turn treated with electrophiles, and oxidized to the final product. Several other similar pyrroles were also prepared in this manner <03EJO771>. 

A good deal of the preparative utility of dihalocyclopropanes arises from the easy halogen-metal exchange. The corresponding carbanion (lithium carbenoid , see Section VLE.l) can be trapped at low temperature by a variety of electrophiles, resulting in substituted or functionalized halocyclopropanes (equation 128). 

When CH3Li or n-BuLi is used in halogen-metal exchange, a rather electrophilic MeX or n-BuX is obtained as a by-product. The alkyl halide can undergo S 2 substitution with the organolithium compound as nucleophile to give the nucleophilic aromatic substitution product. However, Sn2 reactions of organolithium compounds with alkyl... 

A halogen atom in an electrophilic position can be substituted using a metal stannate. Reactions of the 4-iodo derivative (191) with stannyllith-ium, -sodium, or -copper reagents are run at - 78°C to form the 4-stannane (192) (89T993). 

Another method for the regioselective functionalization of indoles is the halogen-metal reaction. The regioselective iodine-copper exchange reaction of 2,3-diiodoindole 203 with dineophylcuprate (neophil = nphyl) provided cuprate 204 which underwent reactions with electrophiles to produce 2-substituted indoles 205 <04OL1665>. A second iodine-copper exchange then afforded a synthesis of 2,3-disubstituted indoles. 

---