Amines bicyclic tertiary

A parallel library of optically active bicyclic tertiary amines 127 bearing N-chiral bridgehead nitrogen atoms was readily prepared by condensation of primary amines, cyclic amino acids 126, and aldehydes. This method gives access to a large variety of substituted hexahydro-l/7-pyrrolo[l,2-/ ]imidazol-l-ones of type 127 (Scheme 16). These... 

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. 

Use has been made of the C-N cleavage in the conversion of the bicyclic tertiary amines, derived from the 4tc + 2tc cycloaddition of pyrroles and isoindoles with benzynes, into aromatic systems, e.g. naphthalen-l,4-imines and anthracen-9,10-imines yield naphthalenes and anthracenes with the extrusion of the nitrogen bridge [24] in yields which are higher than those obtained by standard oxidation procedures. 

Cyclic secondary amines (C7-C9) can be oxidized to bicyclic tertiary amines at a graphite anode in aqueous MeCN with LiBr as electrolyte. It is proposed that a positive species ( Br" ) is formed and is essential for the reaction [84]. 

Pearson, W. H., Walavalkar, R., Schkeryantz, J. M., Fang, W. K., Blickensdorf, J. D. Intramolecular Schmidt reactions of azides with carbocations synthesis of bridged-bicyclic and fused-bicyclic tertiary amines. J. Am. Chem. Soc. 1993,115,10183-10194. 

Coleman and Goheen409 found it better to use iV-chloro amines rather than the A-bromo compounds for synthesis of pyrrolidines and in this way achieved yields of around 75% of substituted pyrrolidines. The method has also proved valuable for synthesis of bicyclic tertiary amines.410"412 Schmitz413 applied it to N,N-dibromo derivatives of primary amines from iV,JV-dibromo-l-propylbutylamine he obtained pyrrolizidine in 35% yield,414 the best yields being obtained here, as in other cases,412 415 416 when the reaction is carried out with irradiation in ultraviolet light. Recently ring closure was also achieved with JV-monochloro derivatives of primary amines 417 pyrrolidine (70%) was obtained from butylamine, 2-methylpyrrolidine (80%) from pentylamine, and 2-propylpyrrolidine (50% and 70%, respectively) from heptylamine or 1-pro-pylbutylamine.417 The mechanism of the Hofmann-Loffler reaction has been discussed by Wawzonek and Culbertson.416... 

Intramolecular Schmidt reactions. Bicyclic tertiary amines are obtained from unsaturated azides. 

Quaternary amonium salts [796], tertiary amines or pyridines [797], bicyclic tertiary amines, cryptants [798] or amphoteric alkylamino sulfonates [799] are suitable as accelerators for this 3-component esterification. Liberation of the aldehyde 280 from its depot form, the bisulphite adduct, may taken place under the reaction conditions in a hydrocarbon [800] or better in ethyl acetate [801]. In order to minimize the occurrence of side products, keeping the aqueous phase more alkaUne for removal of the casually produced small amounts of pyrethroid acid anhydride 305 [802] is recommended. More expedient is the activation of such anhydrides by 4-dimethyl-... 

Bridged bicyclic tertiary allylic amines aza-norbornene and isoquinuclidene have been reported to add to isocyanates, isothiocyanates, and in s/tM-generated carbodiimides to form zwitterionic intermediates that undergo 1,3-diaza-Claisen rearrangements to ureas, thioureas, and guanidines, respectively (Scheme 26) ... 

Epoxides are another viable electrophilic partner for alkyl azides. Baskaran and coworkers found that azido-tethered epoxides afforded bicyclic, tertiary amines bearing a hydroxymethyl substituent upon treatment with a Lewis acid followed by reduction. This one-pot procedure was applicable to bicyclic azido epoxides with varying ring sizes, affording the corresponding bicyclic amines in preparatively useful yields (Table 7.8). These reactions probably involve the initial Lewis acid-assisted formation of a cation followed by azide attack. Migration and concomitant loss of N2 then generates an iminium ion, which persists until stereoselective reduction by hydride (Schane 7.32). 

Scheme 7.16 Enantioselective methanolysis of meso-anhydride catalyzed by bicyclic tertiary amines 77...

In contrast to the alkaloid derived catalyst, some work groups focused their attention on synthetic amino alcohols as desymmetrization catalyst. In 2001, Uozomi et al, reported a series of A -chiral bicyclic tertiary amines 77 for the methanolysis of cyclohexane-1,2-dicarboxylic anhydride [83, 84]. In the presence of a stoichiometric amount of catalyst 77, the desymmetrization of the anhydride proceeds with up to 89% ee (Scheme 7.16). 

The in-out bicyclic amines prepared by Simmons and Park bear a remarkable semblance to the cryptands but lack the binding sites in the bridges. As a result, these molecules interact with electrophiles in a fashion similar to other tertiary amines and generally do not exhibit strong interactions with alkali or alkaline earth metal ions. The in-out bicyclic amines are prepared by reaction of the appropriate acid chlorides and amines in two stages to yield the macrobicyclic amine after reduction of the amidic linkages. A typical amine is shown above as compound 18. 

The bicyclic amine 11-methyl-l l-azabicyclo[5.3.1]hendecanc (71) provided a model system in which the hydrogens on the equivalent a-tertiary-carbon atoms cannot be trans to the nitrogen-mercury bond in the mercur-ated complex and in which epimerization at these a carbons is impossible (77). This bicyclic system is large enough to accommodate a... 

The lithium- -propylamine reducing system has been found capable of reducing julolidine (113) to /d -tetrahydrojulolidine (114, 66% yield) and 1-methyl-1,2,3,4-tctrahydroquinoline to a mixture of enamines (87% yield), l-methyl-J -octahydroquinoline (115) and 1-methyl-al -octahydro-quinoline (116) 102). This route to enamines of bicyclic and tricyclic systems avoids hydroxylation, which occurs during mercuric acetate oxidation of certain bicyclic and tricyclic tertiary amines 62,85 see Section III.A). 

The use of m-CPBA allows the formation of nitrones in the oxidation of tertiary amines. The resulting amines A-oxides are subject to either Cope or Meisenheimer rearrangements, providing formation of nitrones. Thus, the generated corresponding nitrones in the oxidation of bicyclic aziridines give nitrones as a result of a Meisenheimer rearrangement (Scheme 2.14) (93). 

Oxidation of tertiary amines. Early investigations have shown that tertiary amines are oxidized by C102 to iminium ions, and this oxidation can be used to effect cyclization of 2-aminoethanols or 3-aminopropanols to bicyclic oxazolidines or tetrahydro-l,3-oxazines. 

Based on this concept, a large variety of HCLA bases incorporating a vicinal heteroatom (tertiary amine, ether) has been tested for this transformation. These are of two types the proline type, which can be considered as a conformationaUy restricted c/5-fused 5-membered ring bicyclic structure (type A), and the norephedrine- or phenylglycine-type, leading to a more flexible, substituted 5-membered ring structure (type B) (Figure 3). 

Tertiary N-butynylamine 48 when oxidized generates an N-oxide intermediate that is cyclized in situ via gold catalysis to give bicyclic piperidone 49 (09JA8394). As amine 48 can be prepared readily, the overall transformation constitutes a formal [4+2] synthesis. 

The chemical behavior and reactions of pyrrolizidine derivatives were investigated for the most part during structural analysis of naturally occurring pyrrolizidine alkaloids and in the course of the syntheses of their degradation fragments there are several publications concerned specially with this subject. Pyrrolizidine derivatives are typical tertiary amines, and consequently their chemical behavior is a combination of the properties of tertiary amines and of those of the substituent functions. However, some peculiarities of the class can be explained only in terms of the configuration of the bicyclic system. 

Quinuclidine (1) is a saturated bicyclic system with a bridgehead nitrogen atom. It has, in contrast to tertiary aliphatic amines and -substituted piperidines, a rigid structure. The atoms forming the quinuclidine ring are incapable of changing their relative positions by rotation around bond axes. These bond axes are included in the bicyclic system with each ring in the boat form. 

Another formamidine which allows facile removal of hindered tertiary hydrogens has been recently introduced (equation 27). The bridgehead position of a bicyclic amine htu also been alkylated in good yields via the f-butylformamidine. ... 

The tertiary amine can be aliphatic, cycloalkyl, or heterocyclic (including pyridine). The reaction of NaOH with an amine containing two distal alkene units, followed by addition of a neodymium catalyst leads to a bicyclic amine. " ... 

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