Aminomethyl derivatives indole

The Mannich reaction is another example of electrophilic aromatic substitution where indole can produce an aminomethyl derivative. 

Like pyrrole, indole readily undergoes the Mannich reaction affording the aminomethyl derivative 7.26. A variety of nucleophiles can displace the amine via an elimination followed by a 1,4-addition reaction, as in the preparation of acetate 7.27. 

Deaminomethylation of Mannich bases may also occur in the presence of electrophilic species, capable of replacing the aminomethyl group linked to the substrate moiety, such as, for example, diazonium salts acting on Mannich bases of phenols and indoles, or alcohols acting on cyclic O-Mannich bases. The deaminomethylation reaction is also prc.sent in. several equilibria afforded by aminomethyl derivatives of benzotriazole (sec 209, Chap. 1, C.6). 

The amidomethylation reaction is suitable for the same purpose, as NH atnide.s, whieh are well-known substrates of Mannich synthesis, can also behave like amine reagents. Thus, the resultant amidomethyl derivative 21 (Fig. 15) can be then subjected to hydrolysis by means of hydrazine to give the primary amine product. - By this method the 6-aminomethyl indole derivative 22 has been obtained. ... 

Typical examples of this class of reaction are the C- or N-aminomcthylations of pynole and indole derivatives, the N- or S-aminomethylation of thioamides, etc. Aminomelhylated products may also easily undergo interconversions, as described below in Sec. C.6. 

Recently, Fujii and Ohno, incorporated a Mannich-type aminomethylation of alkynes 131 in the presence of para-formaldehyde 132 and secondary amines 133 into a cascade cydization leading to 2-aminomethyl indole derivatives 134 (Scheme 9.50) (211]. The proposed mechanism (Scheme 9.51) is similar to that suggested by Kabalka for the analogous benzo(f>]fiiran synthesis (Scheme 9.5). 

During the course of the author s efforts directed toward the development of useful transformations of allenic compounds [66-77], the author found that the reaction of A -tosylated 2-ethynylaniline 1 with paraformaldehyde 2 and diisopropylamine 3 in dioxane in the presence of copper(l) bromide (Crabbe conditions) [78] afforded a 2-(aminomethyl)indole derivative 7 in 92% yield (Scheme 2) without forming the expected [2-(A -tosylamino)phenyl]allene. This reaction can be rationalized by Mannich-type MCR followed by indole formation through intramolecular hydroamination toward the activated alkyne moiety of a plausible intermediate 6. This is the first example of three-component indole formation without producing stoichiometric amount of salts as byproducts. 

In Chap. 2, the author describes a novel synthesis of 2-(aminomethyl)indole by copper-catalyzed domino three-component coupling and cyclization. Two-step construction of polycyclic indoles by combination with palladium-catalyzed C-H functionalization at the indole C-3 position, scope and limitation of the asymmetric three-component indole formation, and synthesis of benzo[e][l, 2]thiazine derivatives and indene-l,l-dicarboxylate, are also presented in this section. 

Next, the author examined the scope of the 2-(aminomethyl)indole formation with various symmetrical secondary amines (Table 2) under the optimized conditions (Table 1, entry 4). The reaction of 2-ethynylaniline la with bulky diisopropylamine 3a (1.1 equiv) and paraformaldehyde 2a (2 equiv) in the presence of CuBr (1 mol.%) gave the expected indole derivatives 7a in 81% yield (entry 1). Pyrrolidine 3c also showed efficient conversion into the corresponding indoles 7c (entry 3). The use of volatile diethylamine 3d successfully afforded 7d, although 2 equiv of Et2NH were needed (entry 4). Secondary amines containing removable allyl and benzyl groups 3e and 3f, respectively, were also acceptable as amine components when the reactions were conducted with a prolonged reaction time (entries 5 and 6). ... 

When Hf(OTf)4 was used in the absence of MesSiCl, the aminomethylation of an indole derivative with a typicalAi,0-acetal preferentially produced kinetically favored iV-aminomethylated indole derivatives instead of thermodynamically favored 3-aminomethylated indoles (eq 3). This method could be successfully extended to the iV-alkylation of pyrroles and other related NH-containing heterocycles. 

Aminomethylation Reaction. The Hf(OTf)4-dopedMe3SiCl system was used as Lewis acid to catalyze the aminomethylation of electron-rich aromatic compounds. Suitable arenes include indoles, furans, pyrroles, thiophenes, and anilines, with new t)q)es of iV,0-acetals having a variety of functional groups, such as cyano, ester, bis(trimethylsilyl)amino, diallylamino, and cyclic amino moieties. This method allowed for the facile synthesis of nonnatural aromatic amino acid derivatives (eq 1). 4 Aminomethylation using a A, 0-acetal with a bis(trimethylsilyl)amino group was particularly successful in the direct preparation of a N-unsubstituted a-indolylglycine derivative, which required only a standard aqueous workup as the deprotective step. ... 

El-Gendy and El-Banna [31] eondueted aminomethylation of Mannieh derivatives of 4-oxopyridazino[4,5-b]indole (Seheme 20). Compounds 152 in the form of quaternary salts showed antihypertensive aetivity. 

A novel three-component coupling reaction for the synthesis of 2-(aminomethyl) indoles and polycyclic indole derivatives from readily available N-protected ethynylanilines, amines, and aldehydes was reported by Ohno, Fujii, and coworkers. This is the first copper catalytic multicomponent construction of an indole ring that produces water as the only by-product. Two C-N bonds and one C-C bond are formed, whereas C(sp)-H bonds of alkynes and C(sp )-H bonds of aldehydes were activated in this reaction [45-48] (Scheme 8.19). 

Scheme 8.19 CuBr catalyzed synthesis of 2-(aminomethyl) indoles and polycyclic indole derivatives from N-protected ethynylanilines, amines, and aldehydes.

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