Bicyclic amines, basicity

Electronic factors also influenced the outcomes of these cyclization reactions cyclization of pyrrole 84 to bicyclic amine 85 is catalyzed by the sterically open complex 79a. In this reaction, initial insertion into the Y - H bond occurred in a Markovnikov fashion at the more hindered olefin (Scheme 19) [48]. The authors proposed that the Lewis basic aromatic ring stabilizes the electrophilic catalyst during the hydrometallation step, overriding steric factors. In the case of pyrroles and indenes, the less Lewis basic nitrogen contained in the aromatic systems allowed for the cyclization of 1,1-disubstituted alkenes. 

However, in more complicated amines, this straight correlation is violated. The bicyclic tertiary amine l-azabicyclo[4.4.4]tetradecane (22) and the acyclic tertiary amine n-Bu3N have nearly the same first IP (7.84 and 7.90 eV, respectively), but the proton affinity of the bicyclic amine is 20 kcal mol 1 lower than that of the acyclic52. On the other hand, for other bridge-head tertiary amines like l-azabicyclo[2.2.2]octane (quinuclidine, 20) and l-azabicyclo[3.3.3]undecane (manxine, 21) the expected relation between proton affinities and IP values is observed. The extraordinary properties of l-azabicyclo[4.4.4]tetradecane (22) are caused by its unusual conformation the nitrogen lone-pair is directed inward into the bicycle where protonation is not possible. In the protonated form, the strained out-conformation is adopted. This makes it the least basic known tertiary amine with purely saturated alkyl substituents. Its pKa, measured in ethanol/water, is only +0.693. Strain effects on amine basicities have been reviewed by Alder88. 

The properties of natural macrocycles, the cyclodextrins, has stimulated interest in the preparation of synthetic macrocycles. Three basic types have been made macrocyclic amines, cyclophanes, and cyclic peptides. Hersh-field and Bender (33) prepared a bicyclic amine with hydroxamate sub-... 

Scheme 2.11. Basicity of bicyclic amines substituted with electron-withdrawing groups [39],...

Fig. 14.6 3 -Amino-, 3-aminomethyl-, 3-hydroxy- and 3-hydroxymethylpyrrolidine basic structures for novel bicyclic amines.

NMR, 7, 409 Thietane, 2-thioxo-rearrangements, 7, 422 Thietane, triimino-cycloadducts, 7, 433 synthesis, 7, 41 Thietane-2,4-diones synthesis, 7, 435 Thietanes, 7, 403-447 5-amination, 7, 444 basicity, 7, 424 bicyclic... 

Cyclization to six-membered rings (Eq. 15) provided modest diastereoselectivity and required the use of bulkier PhMeSiH2 to prevent olefin hy-drosilylation. Propargyl and homopropargyl amines 94 afforded a variety of heterocycles (Scheme 21), if the catalyst was added slowly over the reaction course to diminish side reactions resulting from metal coordination to the basic amine [56]. The reaction procedure was extended to the diastereoselect-ive bicyclization of dienyne substrate 95, giving 96 as product in a cascade fashion (Eq. 16) [57]. 

The most dramatic rate retardations of proton transfers have been observed when the acidic or basic site is contained within a molecular cavity. The first kinetic and equilibrium studies of the protonation of such a basic site were made with large ring bicyclic diamines [72] (Simmons and Park, 1968 Park and Simmons, 1968a). It was also observed (Park and Simmons, 1968b) that chloride ion could be trapped inside the diprotonated amines. The binding of metal ions and small molecules by macrocyclic compounds is now a well-known phenomenon (Pedersen, 1967, 1978 Lehn, 1978). In the first studies of proton encapsulation, equilibrium and kinetic measurements were made with several macrobicyclic diamines [72] using an nmr technique. 

In a study of the synthesis of marine 2-aminoimidazole alkaloids, the aminal C-N bond of bicyclic 898 was cleaved regioselectively to form the allylic amine 899. Deuterium exchange results in H-1, H-2, and H-5, but not H-7 exchange, although the C(6)-C(7) double bond underwent isomerization 901. This is atributed to the assistance of the carbamoyl group that formed the oxazoline 900. Hydrolysis of the carbamate group of 899 under basic conditions affords either pyrrole 902 or pyridine 903 (Scheme 218) <2004OL3933>. 

The exo-succinimido moiety in l-(morpholinobicyclo[n.l.0]alkyl)pyrrolidine-2,5-diones is readily displaced by strongly basic amines such as morpholine. Heating the starting material in morpholine gave 4,4 -bicyclo[n.l.0]alkanediyldimorpholines 5. No cisitrans isomerization of the bicyclic system was observed. 

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