Three-component aminomethylation

Three-component aminomethylation from amine, formaldehyde and a compound with an acidic methylene moiety. 

The Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde, and a primary or secondary amine. The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions to give mixtures of isomeric 3-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone, and the more highly branched (3-amino ketone usually predominates. 

The original Mannich reaction is the acid-catalyzed aminomethylation of enohz-able ketones with non-enolizable aldehydes and ammonia, primary amines, or secondary amines, which involves nucleophilic addition of ketone enols to iminium salts generated in situ from the aldehydes and the nitrogen compounds [183]. This three-component coupling reaction provides a powerful tool for carbon-carbon bond formation and introduction of nitrogen functionality. The classical Mannich reaction has some drawbacks in reaction efficiency, regioselectivity, and appli-... 

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... 

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... 

Construction of Nitrogen Heterocycles Bearing an Aminomethyl Group by Copper-Catalyzed Domino Three-Component Coupling-Cyclization Yusuke Ohta, Hiroaki Chiba, Shinya Oishi, Nobutaka Fujii and Hiroaki Ohno J. Org. Chem. 2009, 74, 7052-7058. 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 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... 

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. 

In relation to the three-component indole formation, a novel four-component synthesis of 3-(aminomethyl)isoquinoline was developed. The reaction of 2-ethynylbenzaldehyde with (HCHO) , secondary amine, and t-BuNH2 proceeds through Mannich-type reaction, cycUzation, and elimination of t-butyl group. By the use of alkane diamine instead of r-BuNH2, 3-(aminomethyl)isoquino-line-fused polycyclic compounds were also synthesized by cascade cycUzation and oxidation. Changing the carbon tether of the diamine component led to the synthesis of isoquinoUnes fused with various heterocycles. 

It should be noted that the examples of E-type formation of bonds in imidazo[l,5-a] quinoxalines are limited to variant EIq. The three-component reaction of 3-benzoylquinoxalin-2(l//)-one 34a with aromatic aldehydes and NHjOAc in boiling methanol is the only example of Eg-lype synthesis of the imidazo[l,5-a] quinoxaline system (Mamedov et al. 2011). This reaction leads not only to imidazo [l,5-fl]quinoxaline derivatives 12a and 67a-g but also to 2,4,5-trisubstituted imidazoles 68a-h, sometimes as major products. It should be noted that the reaction of A-alkylated 3-benzoylquinoxalin-2(lfl)-one 34i yields only imidazo[l,5-a] quinoxaline 67g. As distinct from variant CIq of synthesis of imidazo[l,5-a] quinoxalines where aminomethyl derivatives are used to introduce the C(l)-N(2) fragment into 3-benzoylquinoxalin-2(lfl)-one, in this case the reaction involves... 

By use of the versatile reactivity of the copper catalysts, the Ohno group expanded their three-component indole formation (Scheme 19.78) to a one-pot synthesis of diazepine-fused indoles [152]. After formation of 2-(aminomethyl)indoles 307 using 2-ethynyl-At-mesylanilines 305, formaldehyde, and 2-bromobenzylamines 288b, addition of NaOMe furnishes removal of Ms group and spontaneous copper-catalyzed N-arylation to produce indole-fused 1,4-diazepines 308 (Scheme 19.82). 

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). 

More complex cascade processes involving this type of three-component couphng include the Cu(I)-catalyzed cascade coupling/cyclization reaction for the synthesis of 2-(aminomethyl) indoles 104 (Scheme 5.69) [72] and 105 (Scheme 5.70) [73], and the Cu(I)-catalyzed domino three-component coupling/cyclization/N-arylation reaction, which provided a concise synthesis of indole-fused 1,4-diazepines 106 (Scheme 5.71) [74]. 

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