Intramolecular reactions aminomethylation

Formation, transamination, and mutual transitions of aminomethyl derivatives of phosphines, representing nucleophilic substitution at the carbon atom in the P—C—O(N) fragment, take place under milder conditions than similar reactions of alcohols and amines. The reason is likely the participation of a phosphino group in intramolecular interactions (86MI1). 

In one route, tidopidine (1) was assembled via Sn2 displacement of 2-chlorobenzyl chloride (9) with 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (8). " The nucleophile 8 was synthesized by heating 2-thiophen-2-yl-ethylamine (6) with 1,3-dioxolane in the presence of concentrated hydrochloric acid. 1,3-Dioxolone gave better yields than with formaldehyde, paraformaldehyde and 1,3,5-ttioxane. The interesting transformation 6 —> 8 first involved the formation of the corresponding Mannich base 7, which then underwent a Pictet-Spengler type reaction to afford the ring-closure product 8. It was of interest to note that a possible intramolecular aminomethylation did not take place. 

Pyrrole and indole rings can also be constructed by intramolecular addition of nitrogen to a multiple bond activated by metal ion complexation. Thus, 1-aminomethyl-l-alkynyl carbinols (obtained by reduction of cyanohydrins of acetylenic ketones) are cyclized to pyrroles by palladium(II) salts. In this reaction the palladium(II)-complexed alkyne functions as the electrophile with aromatization involving elimination of palladium(II) and water (Scheme 42) (81TL4277). 

V-Benzyl-/V-(but-3-yny l)aminomethyl]-5-chloro-3-methoxy-1-phenylpyra-zin-2( I //)-one (45) underwent an intramolecular Diels-Alder reaction to afford 2-benzyl-8-chloro-6-methoxy-l,2,3,4-tetrahydro-2,7-naphthyridine (46) (PhBr, reflux 78 %).602... 

Benzimidazole reacts with formaldehyde and secondary amines in a Mannich reaction to give 1-aminomethyl products. Intramolecular Mannich reactions at ring nitrogen can produce bicyclic products, for example, 131 in Scheme 23 <2005JHC173>. 

Except in a few cases,cyclic Mannich ba.scs derived from alkenes arc produced by the reaction of unsaturated amino derivatives with formaldehyde. Intramolecular aminomethylation (Fig. 65) takes place with aminoalkenes (184, X = H path a) or with analogous silyl allyl derivatives (184, X = SiMc , path b) ... 

Aminomcthyl derivatives are usually described as unstable intermediates affording more stable C-aminomethyl products by deaminomethylation (sec above). However, the synthesis of ebumane alkaloids involves as a key step the formation of a mcthylol derivative of the a-dicarboxyester 455 (Fig. 173), which then leads to the tcu-ahydro-pyranc ring 456 by intramolecular 0-aminoalkylation reaction with the immonium ion present in the molecule. 

S02-extrusion affords the electrophilic radical 49 (Scheme 10). Intramolecular homolytic substitution eventually gives tetrahydronaphthalene 50 (92%). Beckwith showed that the A-(o-bromophenyl)amide 51 can be transformed into the corresponding oxindole 54 (70%) at high temperatures using BusSnH via tandem radical translocation of the initially formed aryl radical 52 to form 53 with subsequent intramolecular homolytic substitution [77]. The nucleophilic a-aminomethyl radical 55 reacted in a tandem addition/homolytic aromatic substitution reaction via radical 56 to tetrahydroquinoline 57 [78]. Radical 55 can either be prepared by oxida-... 

In the presence of a nickel(II) catalyst, suUamates can be used as nitrogen sources for the intramolecular vicinal diamination of alkenes 141 (Scheme 16.37). While the mechanism of this oxidative transformation is not fully understood, the reaction bears the advantage that cyclic sulfamates 142 undergo selective deprotection under conventional conditions. Hence, this diamination protocol represents an attractive approach to free aminomethyl pyrrolidines (100). 

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. 

---