Mannich-hydroamination

An asymmetric one-pot sequential Mannich/hydroamination sequence involves a three-catalyst system a chiral organocatalyst, BF3 and a gold complex. It converts an indole-imine into privileged spiro[pyrrolidin-3,2 -oxindole] structures in up to 91/97% yield/ee. 

Later, an enantioselective one-pot tandem Mannich-hydroamination reaction was reported by Liu and co-workers on the basis of a sequential organo- and gold catalysis.The proeess involved propargylated malonitrile and oxindole imine derivatives as substrates and employed a chiral cinchona alkaloid, such as a quinidine phenol derivative, to induce the enantioselective Mannich reaction and a gold catalyst, such as XPhosAuNTfa... 

Scheme 7.64 Tandem nitro-Mannich-hydroamination-isomerisation reaction catalysed by chiral urea catalysis and gold catalysis.

Scheme 7.65 Tandem Mannich-hydroamination reaction catalysed 1 chiral cinchona alkaloid catalysis and gold catalysis.

Enantioselective vanadium and niobium catalysts provide chemists with new and powerful tools for the efficient preparation of optically active molecules. Over the past few decades, the use of vanadium and niobium catalysts has been extended to a variety of different and complementaiy asymmetric reactions. These reactions include cyanide additions, oxidative coupling of 2-naphthols, Friedel-Crafts-type reactions, pinacol couplings, Diels-Alder reactions, Mannich-type reactions, desymmetrisation of epoxides and aziridines, hydroaminations, hydroaminoalkylations, sulfoxida-tions, epoxidations, and oxidation of a-hydroxy carbo) lates Thus, their major applications are in Lewis acid-based chemistiy and redox chemistry. In particular, vanadium is attractive as a metal catalyst in organic synthesis because of its natural abundance as well as its relatively low toxicity and moisture sensitivity compared with other metals. The fact that vanadium is present in nature in equal abundance to zinc (albeit in a more widely distributed form and more difficult to access) is not widely appreciated. Inspired by the activation of substrates in nature [e.g. bromoperoxidase. 

Scheme 15.101 A/.protected 2,5-substituted pyrrole synthesis via a one-pot nitro-Mannich reaction followed by hydroamination.

An enantioselective, one-pot sequence of Mannich reaction and hydroamination, catalysed by a combination of the quinine-derived organocatalyst (185) and gold(I)-... 

Tandem Mannich-type-hydroamination-isomerisation catalysed by chiral thiourea catalysis and gold catalysis. 

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. 

A C=C triple bond of 1,3-diyne 149 was cleaved with 2-aminophenol in the presence of a ruthenium catalyst (Scheme 7.52) [71]. Initially, a ruthenium-catalyzed hydroamination takes place to give alkynyl imine 150. Conjugate addition of 2-aminophenol follows, resulting in the formation of the 1,3-diimine 151, which cyclizes to form the oxazoline 152. Subsequent retro-Mannich reaction cleaves the C-C bond to furnish the oxazole 153 and the imine 154. 

In 2007, Ding and Wn reported a cascade reaction combining enamine and Ag catalysis for the synthesis of 1,2-dihydroisoquinoline derivatives [42]. Initially, the nncleophilic enamine derived from the ketone and proUne attacked the imine that arose from the aldehyde and the amine, forming the Mannich base 140, which then participated in a hydroamination reaction toward pendant alkyne to build the final prodnct (Scheme 9.46). 

In 2010, Monge et al. reported a one-pot tandem reaction by combining bifunctional thiourea and Au complex [77], affording dihydropynole derivatives in moderate yields and high enantioselectivities. The reaction was based on a bifunctional thiourea-catalyzed Mannich-type reaction and a subsequent Au-catalyzed alkyne hydroamination and isomerization of propargylated malononitrile and N-Boc-protected imines (Scheme 9.72). Notably, acidic additive proved cracial to prevent deactivation of the gold catalyst and enhance the reactivity and selectivity. 

Very recently. Barber et al. reported a tandem reaction combining bifunctional urea and Au(I) salt for the asymmetric synthesis of valuable tetrahydropyridine derivatives [80]. This reaction consisted of a urea-promoted nitro-Mannich reaction of an alkyne-tethered secondary nitroalkane to N-Boc-protected imines and an Au(I) complex-catalyzed intramolecular hydroamination and isomerization (Scheme 9.75). Notably, since the inherent Lewis basic tertiary amine-tethered urea would deactivate the Au catalyst, the reaction system was acidified by additional DPP before addition of an Au catalyst to ensure the success of the overall process. 

An example of a cascade reaction combining enamine and silver catalysis for synthesis of 1,2-dihydroisoquinoline derivatives is shown in Fig. 8.26. In the first step, nucleophilic enamine formed from the ketone and proline reacts with the imine, which is generated from the aldehyde and the amine. As a result, the Mannich base is formed, which then undergoes a hydroamination reaction in the presence of silver catalyst. 

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