Intramolecular reactions aminoalkylation

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. 

The insertion approach is very successful in the hydroamination of alkynes and alkenes catalyzed by lanthanide complexes developed by Marks et al. [220]. Thorough mechanistic studies have been undertaken for the intramolecular reaction (hydroamination-cyclization of aminoalkenes), although the intermolecular version of the process is also efficient [222]. The mechanism of the reaction can be represented in a simplified way by Scheme 6.68. The insertion step is almost thermoneutral, but the protonolysis of the M-aminoalkyl bond that follows is exothermic and provides the necessary driving force. The insertion of the alkene into the Ln-N bond is irreversible and rate determining and it goes through a... 

Aoyama and co-workers have also investigated the intramolecular photoamination reactions of several tertiary (aminoal-kyl)styrenes. Irradiation of the (dibcnzylaminoalkyl)styrenes 28 and 29 results, respectively, in the formation of the pyrrolidine 30 and the piperidine 31 as mixtures of diastereomeric adducts. Irradiation of the (aminoalkyl)styrene 32 provides the bicyclic adduct 33 in good yield. Unlike the highly regioselective intramolecular addition of 22 and intermolecular addition reaction of stiibene with W,AI-dimethylisopropylamine (Scheme 3), the intramolecular reaction of the A/-methyl-Af-isopropylamine 34 yields a mixture of adducts 35 and 36 which result from N-methyl and Al-isopropyl hydrogen abstraction, respectively. 

The 9-(aminoalkyl)anthracenes 67 and 68 also undergo intramolecular addition upon irradiation in benzene solution to yield the 1.4-adducts 69 and 70, respectively. The formation of these adducts is proposed to occur via photoinduced electron transfer followed by N-H proton transfer to yield 10-anthryI-aniIino biradical intermediates (Scheme 9). In the case of the biradical from 68, C-N bond formation affords adduct 70. The biradical from 67 undergoes C-C bond formation at the ortho position of the anilino radical, followed by hydrogen transfer to yield 69, rather than C-N bond formation to form the highly strained lower homolog of 70. The formation of 62 from the intramolecular reaction of 58 and of 5 from the iniermolecular reaction of anthracene and dimethylaniline may also occur via C-C bond formation in the biradical or radical pair intermediates. 

Data on photophysics and photochemistry of intramolecular stilbene-amine exciplexes and reactions have been reported [34]. The obtained data indicated that the photophysical and photochemical behavior of a series of traws-(aminoalkyl) stilbenes in which a primary, secondary, or tertiary amine is appended to the stUbene ortho position with a Me, Et, or Pr linker. The tertiary (aminoalkyl) stilbenes formed fluorescent exciplexes and underwent trans cis isomerization but failed to undergo intramolecular N—H addition. The secondary (aminoalkyl)stilbenes did not form fluorescent exciplexes but underwent the addition to the stilbene double bond. Intramolecular reactions were highly selective, providing an efficient method for the synthesis oftetrahydrobenzazepines. Direct irradiation of the primary (aminoalkyl) stilbenes resulted only in trans-cis isomerization, while irradiation in the presence of the electron acceptor p-dicyanobenzene resulted in regioselective intramolecular N—H addition to the stilbene double bond. 

The intramolecular reactions of the secondary a-(aminoalkyl)styrenes and P-(aminoalkyl)styrenes are dependent upon both the alkyl chain length and its point of attachment. The products of direct irradiation of the a-(aminoalkyl)styrenes 19-21 are shown in Scheme 13 along with their putative... 

Although the intramolecular aminocarbonylation described above is an extension of the standard amide-forming reaction, a different type of intramolecular aminocarbonylation has been studied, wherein the amine moiety adds across the olefin moiety activated by a Pd catalyst to generate /3-aminoalkyl-Pd species, followed by CO insertion and alcoholysis, forming a lactone or an ester. ... 

Carbon monoxide has been used to scavenge OH fonned from the ozonolysis of alkenes. The CO2 tints generated was detected by FTIR spectroscopy and the "OH yields for individual reactions were calculated.239 The significance of the OH-induced intramolecular transformation of glutathione thiyl radicals to a-aminoalkyl radicals has been discussed with respect to its biological implications.240 The kinetics and mechanism of the process indicated that it could be a significant pathway for the selfremoval of glutathione thiyl radicals in vivo. 

Trichlorotitanium enolates are directly prepared from a ketone, TiCU, and a tertiary amine [122,123] and undergo aldol reactions with aldehydes [124-129], ketones [129], and imines [130,131], Intramolecular condensation with esters is also known [132-137], Although these reactions, based on a titanium enolate [16], which often results in high diastereoselectivity in aldol and related reactions [122], will not be discussed in detail in this article, the success of the alkylation of this titanium enolate with SNl-active electrophiles should be discussed owing to the high Lewis acidity of the metal center [123], Equation (37) shows stereoselective alkylation with an orthoacetate, which is usually inert to alkali metal enolates [138], Aminoalkylation of trichlorotitanium enolates with (a-chloroalkyl)amine has been performed analogously [139,140],... 

Aoyama and coworkers have synthesized several pyrrolidine and piperidine derivatives via intramolecular photoaddition reactions of tertiary (aminoalkyl) styrene (Scheme 52) [282, 283]. 

Intramolecular PET cyclizations of aminoalkyl-substituted phthalimides were investigated by the groups of Kanaoka and Coyle [168-171]. Because of the relatively low oxidation potentials of tertiary amines, these electron-transfer reactions are highly exergonic [172, 173]. The regioselectivity of the CH-activation step was remarkably high for the A -methyl, A -phenyl substituted substrates (Scheme 43). 

Nitrogen heterocycles continue to be valuable reagents and provide new synthetic approaches such as NITRONES FOR INTRAMOLECULAR -1,3 - DIPOLAR CYCLOADDITIONS HEX AH YDRO-1,3,3,6-TETR AMETHYL-2,1 -BENZISOX AZOLINE. Substituting on a pyrrolidine can be accomplished by using NUCLEOPHILIC a-sec-AMINOALKYLATION 2-(DI-PHENYLHYDROXYMETHYL)PYRROLIDINE. Arene oxides have considerable importance for cancer studies, and the example ARENE OXIDE SYNTHESIS PHENANTHRENE 9,10-OXIDE has been included. An aromatic reaction illustrates RADICAL ANION ARYLATION DIETHYL PHENYLPHOSPHONATE. 

Although the tryptamine-to-p-carboline transformation is the most prevalent example of the Pictet-Spengler intramolecular aminoalkylation reaction in the indole series, it is by no means the only pattern. For example, Kundu and coworkers used 1- and 2-(2-aminophenyl)indoles to form tetracyclic systems by cyclization at C-2 and C-3, respectively [356]. 

Several other syntheses of the lif-azepino[5,4,3-c,c/ indole ring system have been reported, including the Mitsunobo reaction <85TL4043>, an intramolecular, acid-catalyzed aminoalkylation <88JOC5128> and intramolecular imine formation <87H(26)1197> leading to total synthesis of clavicipitic acid. Palladium-catalyzed ring closure of (127) afforded the cyclized derivative (128) (Equa-... 

The photochemical behavior of the orr/to-(aminoalkyl)slil-benes 92—94 is also dependent upon the polymethylene linker (Scheme II). Irradiation of 93 and 94 results in formation of the benzazepines 96 and 97. These adducts are presumably formed by regioselective N—H transfer to the proximal end of the stilbene double bond in 93 and the distal end in 94, in both cases resulting in the formation of a 1,7-biradical intermediate. Since intramolecular stilbene-amine addition reactions are non-regioselective, the regioselectivily of N-H transfer must be subject to exciplex conformational control. The biradical inter-... 

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