Iodo aniline

In an application of the Suzuki process, 2-chloroquinoline (141) has been converted into the condensed heterocycle 197 (Scheme 58) (89JHC1589). Thus, metalation, trimethyl borate quench, and hydrolysis affords the stable 3-boronic acid 195 which, upon subjection to cross coupling with ortho-iodo aniline in the presence of Pd(0) catalyst and base, affords the 3-arylquinoline 196. Acid catalysis converts this material into the in-dolo[2,3-f ]quinoline (197) in 35% overall yield. 

Although o-bromo, o-chloro, ° and o-iodo anilines give 7-haloisatins, o-fluoroaniline has been reported not to give an isatin. 2,4-Difluoroaniline also fails to give an isatin although cyclization... 

Related to the Heck reaction is the Larock annulation of internal alkynes, which is a general route to heterocyclic and carbocyclic systems. Especially attractive is the construction of the pharmaceutically important indole ring system via palladium-catalyzed coupling of 2-iodo-aniline and the corresponding V-methyl, acetyl, and tosyl derivatives with a wide variety of internal alkynes. The catalytic process appears to involve arylpalladium formation, regioselective addition to the carbon-carbon triple bond, and subsequent intramolecular palladium displacement.- ... 

Iodoaniline 5 03,504 A solution of IC1 (1 mole) is prepared from iodine (127 g) in glacial acetic acid (150 ml) (cf. page 182). When this is dropped, with stirring, into a solution of acetanilide (1 mole) in glacial acetic acid (150 ml) (exothermic reaction ) and the whole is stirred for a further few hours, p-iodoacetanilide is precipitated. After 12 h, the mixture is poured into water (21), and the product is collected and washed with water and dilute sodium hydroxide solution. Recrystallization of this crude material from ethanol gives a 90 % yield of the amide, m.p. 184°, which is hydrolysed by concentrated hydrochloric acid to p-iodo-aniline. 

Pyrroles 531 are formed from the chromium complex 529 and alkynes 530 (R = H, Me or Ph = Me, Ph or NEt2). The dicobaltoctacarbonyl-catalysed reaction of cyanotrimethylsilane with a variety of acetylenes R C=CR (R R = alkyl or Ph) furnishes pyrroles 532, in which the bulkier of the two substituents of unsymmetrical internal acetylenes appears at the position marked with an asterisk . An indole synthesis from o-iodo-aniline and alkynes R C=CR (R R =alkyl or Ph) in the presence of palladium(II) acetate, triphenylphosphine, lithium chloride and potassium carbonate has been described (equation 56). In the case of unsymmetrical alkynes, the bulkier substituent tends to be in position 2 of the indole. ... 

The preparation of indoles by the benzyne route is illustrated by the base-induced cyclization of the amino-alcohols (171 R = H or Me) to indole and 3-methylin-dole, respectively/ The photochemical reaction of o-bromo- or o-iodo-aniline with the enolates (172 R = H, Me, or PrO leads to indoles (173)/ The salt (174), generated by the action of lithium di-isopropylamide on o-tolyl isocyanide, serves as a source of diverse indole derivatives (i) it cyclizes spontaneously to 1-lithioindole, which forms 3-alkyl-indoles on treatment with alkyl halides in the presence of magnesium iodide, (ii) it reacts with allyl esters RC02CH2CH=CH2 (R = alkyl or aryl) to give the ketones (175), which cyclize... 

Other sulfur nucleophiles can be used in the metal-catalyzed C—S bond-forming chemistry. Takagi, Iwachido, and Hayama reported the reaction of aryl halides with thioamide nucleophiles to produce 2-alkylbenzothiazoles, as shown in Eq. 10. ° The presence of CaO base increased the yield significantly, and the use of phosphorus ligands increased the turnover numbers of the catalysts. This chenustry tolerated 2-CH3, 2-CH2OCH3, 2-CH2CN, 4-Br, 5-Cl, 5-CH3, and 5-CF3 substitution of the iodo aniline, bnt not 2-aryl substitution. 

A starting material that is suitable for the direct construction of a heterocycle by an intramolecular Heck-type reaction has to fulfil some simple but fundamental requiranents there has to be the halide function or a triflate for the oxidative addition onto the Pd catalyst, a side chain with an unsaturated functionality such as an alkene or an alkyne in an appropriate distance, and of course the heteroatom in this side chain. Figure 1 presents a substrnctnre typical for very many starting materials, which were transformed to heterocycles by intramolecnlar Heck-type reactions (X = halide, Het = heteroatom). This type of substrnctnre with an allylic side chain is easily accessible by derivatization of 2-bromo- and 2-iodo anilines, phenols, and thiophenols and leads to interesting heterocycles such as indoles and benzofurans, which are related to many natural products and other biological active componnds. 

Scheme 14. Reagents (0 LDA, THF/HMPA, -78°C LDA, THF, -78°C (ii) 2-iodo-aniline, MejAl, PhMe (iii) NaH, BnBr (iv) BClj, -78°C (v) TBDMSCl, imidazole, CH2CI2 (vi) 10% (PhjPfzPdQz, EtjN, DMA, 100°C (vii) HF, MeCN NaBH4, MeOH Pb(OAc)4, PhH NaBH4, MeOH (viii) Red-Al, THF HNj, PhjP, EtOzCN NCOzEt, THF.

Substituents on the terminal alkyne 5 can be varied applying both protocols from aromatic to aliphatic, although method B allows the introduction of a wider variety of substituents on aromatic alkynes ranging from electron donating to electron withdrawing. Substituents on the 2-iodo aniline 6 can also be varied easily, but nitro groups require conditions B. 

Quinazolinones are an important class of fused heterocycles that have been reported with remarkable activities in biology and pharmacology such as anticancer, antiinflammatory, anticonvulsant, antibacterial, antidiabetic, hypolipidemic, and protein tyrosine kinase inhibitors. Alper and Zheng reported a palladium-catalyzed cyclocarbonylation of o-iodoanilines with imidoyl chlorides to produce quinazolin-4(3H)-ones in 2008. A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63-91% yields (Scheme 3.27a). The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones. Later on, a procedure was established based on generating the amidine in situ by a copper-catalyzed reaction of terminal allq nes, sulfonyl azide and o-iodo-anilines. The desired quinazolinones can be produced by carbonylation with Pd(OAc)2-DPPB-NEt3-THF as the reaction system. In the same year, Alper s group developed a procedure for 2,3-dihydro-4(lH)-quinazolinone preparation. The reaction started with the reaction of 2-iodoanilines and N-toluenesulfonyl aldimines followed by palladium-catalyzed intramolecular... 

H20)2 iodine methanol -propanoI krypton 43 PSI krypton 200 PSI K+-acetate 3-iodo-aniline Lil3+2 molecule 1 molecule 2 ... 

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