Indoles 6-aminomethyl

Carbocations stabilized by functional groups can also effect 3-alkylation of indoles. From a synthetic point of view the most important are iVJV-dialkyl-methyleneiminium ions which can be generated under Mannich conditions from formaldehyde and secondary amines[13]. The products, 3-(N,AI-dialkyl-aminomethyl)indoles, are useful synthetic intermediates (see Chapter 12). 

Support-bound C-nucleophiles have also been successfully added to imines. Poly-styrene-bound thiol esters can be converted into ketene acetals by O-silylation, and then alkylated with imines in the presence of Lewis acids. Further examples include Mannich reactions of support-bound alkynes and indoles (Table 10.10). Some Man-nich-type products (e.g. 3-(aminomethyl)indoles, 2-(aminomethyl)phenols, (3-amino ketones) are unstable and can decompose upon treatment with acids. 3-(Amino-... 

Gramine (= 3-(Dimethyl-aminomethyl)-indole Donaxine) (indole)... 

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. ... 

Several investigators have uncovered additional copper-catalyzed indole syntheses from 2-ethynylanilines accompanied by in situ indole functionahzation. Yamamoto and colleagues reported the synthesis of Af-(alkoxybenzyl) indoles from the copper-catalyzed tandem reaction between 2-alkynyl-Af-arylideneanihnes and alcohols (Cul, toluene, 100°C, 55%-83%) [26], Ohno, Fujii, and coworkers employed a domino three-component copper-catalyzed process to prepare 2-(aminomethyl)indoles [27, 28] and... 

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). 

SCHEME 3.47 Proposed mechanism for the Cu(I)-catalyzed synthesis of 2-(aminomethyl)indoles. 

Direct Synthesis of 2-(Aminomethyl)indoles through Copper(I)-Catalyzed Domino Three-Component Couphng and Cyclization Reactions Hiroaki Ohno, Yusuke Ohta, Shinya Oishi and Nobutaka Fujii Angew. Chem., Int. Ed. 2007, 46, 2295—2298. Reproduced with permission... 

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 this study, the author examined an atom-economical and diversity-oriented synthesis of 2-(aminomethyl)indoles/isoquinolmes by copper-catalyzed domino multi-component coupling-cyclization. One-pot construction of polycyclic in-doles/isoquinolines bearing an aminomethyl moiety was also investigated. 

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. 

Construction of 2-(Aminomethyl)indoles Through Copper-Catalyzed Domino Three-Component Coupling and Cyclization... 

Synthesis of 2-(Aminomethyl)indoles Using Several Amines and Aldehydes... 

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). ... 

The author expected that a reaction with a chiral ligand which coordinates to a copper atom could produce optically active 2-(aminomethyl)indoles. Knochel recently developed a novel asymmetric synthesis of chiral propargylamines with excellent ee values through a copper-catalyzed asymmetric Mannich-type reaction of alkynes with an aldehyde and a secondary amine using QUINAP as a chiral ligand (up to 98% ee) [1-3]. Carreira reported the similar synthesis of propargylic amine in up to 99% ee with PINAP [4, 5]. The author initially examined the... 

Synthesis of Substituted 2-(Aminomethyl)indoles Using Various Ethynylanilines and Secondary Amines... 

Encouraged by this result, the author investigated the reaction with several 2-(aminomethyl)indoles containing an electron-withdrawing and -donating group to obtain variously substituted tetrahydropyridine-fused indoles 9b-f in moderate to good yields (Table 7). 

The author next examined construction of polycyclic indoles by palladium-catalyzed C-H arylation using 2-(aminomethyl)indole 7x, which was prepared from ethynylaniline la and amine 3h (Table 5, entry 11). By treatment with 20 mol.% of Pd(OAc)2 and 40 mol.% of PPha, dihydrobenzazepine-fused indole 10 was efficiently obtained in 80% yield over 2 steps (Scheme 3). One-pot three-component indole formation/Pd-catalyzed C-H arylation also provided polycyclic indole 10 in 84% yield from la. 

Calindol (13), which contains a 2-(aminomethyl)indole motif, is a positive modulator of the human Ca " receptor showing a calcimimetic activity [1-3]. This compound could be easily synthesized using this domino three-component indole formation (Scheme 4). As the author expected, the reaction of 2-ethynylaniline la with paraformaldehyde 2a and l-(l-naphthyl)ethylamine 11 in presence of CuBr directly produced a protected calindol 12. The allyl and tosyl groups on the nitrogen atoms of 12 were easily removed by successive treatment with Pd(PPh3)4 (2 mol.%)/NDMBA and TBAF [14] to give calindol 13 in 90% yield over 2 steps. 

Table 5 Synthesis of variously substituted 2-(aminomethyl)indoles...

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