Polysubstituted anilines

Synthesis of polysubstituted anilines using the Diels-Alder reaction of methyl-5-aminofuroate [143]... 

Polysubstituted anilines 46JA1232, 46JA1264, 46JA1268 47JA371 ... 

The [4 + 2] cycloaddition reaction of 2- or 2,5-substituted iV-methoxycarbonylpyrroles with dimethyl acetylenedicarboxylate is accelerated tremendously by aluminum chloride (70CJC1472). The Diels-Alder cycloaddition is in fact complete in some cases within 30 min at 0 °C if five molar equivalents of A1C13 are utilized. On warming the reaction mixture to 40 °C, the 7-azabicyclo adduct (199) formed initially undergoes rearrangement to an Af-methoxycarbonyl-3-aminophthalate (200 Scheme 42). The overall scheme constitutes a valuable method for the construction of polysubstituted anilines. 

The oxidation mechanism of polysubstituted anilines with electron-releasing methyl groups is different from that discussed above for polyhaloanilines, because the initially... 

Tert-Butyl Isocyanide Recently, Neo and coworkers have employed Izb in their 3CR for the synthesis of polysubstituted anilines. In the initial step, Izb undergoes a [4jt + lit] hetero Diels-Alder (DA) reaction with the a,p-unsaturated carbonyl compound 382 to afford 384. The polysubstituted furan 384, which then undergoes an in situ [4n + 2%] DA reaction to form intermediate 385, then undergoes dehydration followed by aromatization to provide the desired polysubstituted aniline 388 (Scheme 7.118). Compound 388 then undergoes de-t rl-butylation in the presence of 5% Y(OTf)3 in toluene at 100°C to provide compound 389 [126]. 

Pd-catalyzed cross-benzannulation of diynes 2.231 with aminoenynes 2.230 resulted in polysubstituted anilines 2.232 with yields 40-60% (Scheme 2.78) [3, 132]. 

Saito, S., Uchiyama, N., Gevorgyan, V. and Yamamoto, Y. (2000) Palladium-catalyzed cross-benzannulation of aminoenynes with diynes. Highly regioselective synthesis of polysubstituted anilines. Journal of Organic Chemistry, 65(14), 4338-4341. 

Some time ago, Holliman and co-workers illustrated a method for synthesizing polysubstituted phenazines by reductive cyclization of o-nitrodiphenylamine. However, the yield was poor when competitive cyclizations occurred <70CC1423>. Recently, Kamikawa and co-workers reported a more efficient method to synthesize phenazines using sequential aniline arylation, which was first introduced by Buchwald <97JOC1264>. Regioselective bromination of o-nitrodiphenylamine 226 with bromine in the presence of sodium bicarbonate yielded 227 which was subjected to the Buchwald conditions to provide the desired phenazine 228 and the eliminated product 229 <00TL355>. The former compound is a proposed intermediate for the synthesis of the radical scavenger benthocyanin A. 

Perfluorobenzene undergoes SNAr reactions readily with dimethylanune, aniline, N methylaniline [68], piperidine, W-tnmethylsilyliminotnmcthylphos-phorane [69], and hthium anilide [70], but the reactions are often accompanied by significant amounts of di- or polysubstitution However, with the lithium salt of JV-tnmethylsilylamlme, only one fluorine atomin perfluorobenzeneisreplaced [77] (equation 36)... 

The free amino group strongly activates the aromatic ring towards electrophilic attack and aromatic substitution of amines often results in polysubstitution. For example, the bromination of aniline yields largely 2,4,6-tribromoaniline (Expt 6.59). 

Regioselectivity of the Birch reductive alkylation of polysubstituted biaryls is affected by the electronic nature of substituents on both aromatic rings. The electron-rich 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, whereas phenols and aniline are not dearomatized under these conditions. Biaryls possessing a phenol moiety are alkylated on the second ring, provided that the acidic proton has been removed prior to the Li-NH3 reduction.300... 

Scheme 5.13 Microwave-assisted, one-pot, pseudo-four-com-ponent liquid-phase synthesis of polysubstituted 2,6-dicyano-anilines 62.

In Table 10-3 we have collected experimental S values for adsorption on alumina of 48 polysubstituted benzenes and substituted naphthalenes. These data provide a good collective example of the effects of sample localization on sample adsorption energy. Values of QJ for all the groups i represented in the samples of Table 10-3 can be derived through Eq. (10-1) from experimental S values for the unsubstituted hydrocarbons, benzene and naphthalene, and appropriate monosubstituted benzenes e.g., anisole, nitrobenzene, aniline.t Table 10-2 summarizes these values. This in turn permits the calculation of 2 Ql for each of the compounds of Table 10-3. The latter quantity will be equal to S for the compound in question, if Eq. (10-1) applies and 0 values for a given group i are constant in all compounds of which i is a part. However, the localization of a polyfunctional sample moleculej should be reflected in a value of S which is less than because of the corresponding delocalization of some... 

Halogenation. Just as is true for aniline, the pyrrole ring is reactive toward bromine or chlorine, giving polysubstituted products (Scheme 7.6). No catalyst is required. 

Anilines react rapidly with electrophiles to give polysubstituted products. Their amide derivatives react in a more controlled manner to give para-substituted products. 

The substituents on polysubstituted benzenes are numbered and named alphabetically (Fig. 13.45). Notice that a benzene with a methyl-, a hydroxy-, or an amino-group will have the root word of toluene, phenol, or aniline respectively. Because it is the root word, the carbon attached to that group is automatically C(l). 

Some substituents are so strongly activating that no catalyst is needed, and it is often difficult to stop substitution before more than one new substituent has been added to the ring. For example, many anilines are brominated with Bt2 alone to give 2,4,6-tribromoanilines (Fig. 14.88). Phenols are also highly activated toward further substitution to give polysubstituted products. Mild conditions are needed to restrict the reaction to monosubstitution. 

An amino group is strongly activating and ortho- and para-directing in electrophilic aromatic substitution reactions (Section 16.5). This high reactivity of amino-substituted benzenes can be a drawback at times because it s often difficult to prevent polysubstitution. Reaction of aniline with Bt2, for instance, takes... 

Thiocyanation. Effective thiocyanation of indoles and anilines can also be done with Mn(OAc)3. Thiocyanation occurs specifically on C-3 of indoles and on the para-position of anilines (eq 52). This reaction also works on polysubstituted substrates, except on 3-substituted indoles and para-substituted anilines. 

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