Aminoalkylation intramolecular

The mechanism of palladium-catalyzed intramolecular cyclization of o-bromo(aminoalkyl)benzenes has been discussed earlier (see Scheme 50 in Section IV,A,4). This approach is illustrated by the preparation of 1,2,3,4-tetrahydroisoquinolin-l-ones in Scheme 146,86 and examples of applications in benzazepinone synthesis are given later (see Scheme 173 in Section VI,B). 

Irradiation rraws-2-[3-(7V-methylamino)propyl] stilbene 89 results in the formation of 7V-methyl-l-benzyltetrahydro-2-benzazepine 90 as the only significant primary photoproduct (equation 26), which in turn undergoes secondary photochemical N-demethylation. The final mixture contains 90 (38%) and 91 (25%) at high (>95%) conversion. Intramolecular photoadditions of these (equations 24-26) secondary (aminoalkyl)-stilbenes are highly regioselective processes24. 

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. ... 

Intramolecular cyclization of activated aminoalkyl cyclopropanes to corresponding oxoindolizidines has been achieved.249... 

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. 

Zhao R, Lind J,Merenyi G, EriksonTE(1997) Significance of the intramolecular transformation of glutathione thiyl radicals to a-aminoalkyl radicals. Thermochemical and biological implications. J Chem Soc Perkin Trans 2 569-574... 

Energy profiles for alternative intramolecular cyclizations of 4-(aminoalkyl)-e>-quinones (90) (n = 1-3) have been calculated using the AMI method and ab initio energies of the transition states have been determined. In all the cases, cyclization at position 5 to form (91) occurs via a significantly lower energy transition state... 

Addition of several lithium ester enolates to chiral 1-aminoalkyl choromethyl ketones gave the corresponding chlorohydrins which, when the solvent was completely evaporated to dryness at room temperature, underwent an intramolecular heterocyclization affording 3-hydroxyazetidinium salts 5 <02OL1299>. Azetidinium salts 5 were isolated in enantiomerically pure form, and with total or high diastereoselectivity. The degree of stereoselectivity was only moderately affected by the size of R1 in the a-amino-ketone and the substituents in the ester enolate. 

Substrates containing all the three reactive moieties of Mannich synthesis, that is, substrate, amine, and aldehyde, such as 161 (Fig. 56) also have been subjected to cy-clization. - Two carbonyl functions are present in these molecules, which may produce intramolecular 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. 

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]. 

Recently, Lewis et al. have reported the synthesis of larger rings via the photo-induced intramolecular addition of (aminoalkyl)styrylamides and A -(aminoalkyl)-2-stilbene carboxamides (Scheme 56) [294, 295]. 

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. 

Recently, Leuck et al. [282] have described an acyl-type anchor for the fast and efficient preparation of 3 -aminoalkyl oligonucleotides based on the 2-hydroxy-methyl-6-nitrobenzoyl group (Figure 19.12). The linker is prepared from 6-nitroph-thalide by acylation of the respective aminoalcohol and attachment to LCAA-CPG through the benzylic hydroxyl via the succinyl group. Cleavage is achieved under conditions of basic hydrolysis by the intramolecular attack of the liberated hydroxyl onto the amide carbonyl with the expulsion of the amine. Complete detachment of the oligomer requires 2 h at 55 °C in concentrated ammonia or 30 min at 65 °C in 40% aqueous methylamine-concentrated aqueous ammonia (l lv/v), or can be accomplished at room temperature within 24 h in concentrated ammonia. The new anchor was shown to be superior to the phthalimido support [279] in terms of product yield and deprotection time. 

An example of the intramolecular formation of the S-N bond leading to thiazolidine-1-oxide on the treatment of aminoalkyl disulfides with CBT is presented (90JOC4156) (Scheme 125). 

---