Bicyclic aminal

A number of bridged crown ethers have been prepared. Although the Simmons-Park in-out bicyclic amines (see Sect. 1.3.3) are the prototype, Lehn s cryptands (see Chap. 8) are probably better known. Intermediates between the cryptands (which Pedersen referred to as lanterns ) and the simple monoazacrowns are monoazacrowns bridged by a single hydrocarbon strand. Pedersen reports the synthesis of such a structure (see 7, below) which he referred to as a clam compound for the obvious reason . Although Pedersen appears not to have explored the binding properties of his clam in any detail, he did attempt to complex Na and Cs ions. A 0.0001 molar solution of the clam compound is prepared in ethanol. The metal ions Na and Cs are added to the clam-ethanol solutions as salts. Ultraviolet spectra of these solutions indicate that a small amount of the Na is complexed by the clam compound but none of the Cs . 

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. 

In other sections in this chapter, we have referred to a variety of macropolycyclic structures which are more elaborate than the simple three-stranded bicyclic cryptands. This includes bridged double-macrocycles " , in-out bicyclic amines and the macrotricyclic quaternary ammonium salts of Schmidtchen. In addition to these, there are two other types of compounds which deserve special note. The first of these is a stacked twin-ring cryptand, but it is a hybrid molecule rather than a double-cryptand . The species shown below as 20 is a crowned porphyrin, and was designed to provide a pair of metal cation binding sites similar to those which might be available in natural biological systems . 

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... 

Not surprising, the most prevalent synthetic utility is the assembly of the pyrrolidine ring. N-Chloroamine 27 was obtained by treatment of N-methyl-2-cyclopentylethylamine (26) with N-chlorosuccinimide. Under classic Hofmann-Loffler-Freytag reaction conditions, 27 was rearranged either thermally or by UV irradiation in sulfuric acid to bicyclic amine... 

An acid chloride of compound 3 reacts with a bicyclic amine to give compound 227 (88EUP254584) while the zwitterion 228 reacts with a range of alcohols to give esters such as 229 (83BCSJ2974) the 2-isomer reacts similarly... 

The heterocyclic ring may be reduced under very mild conditions after TV-alkylation, giving access to bicyclic amines,7 10 13 or enamines5 Use of 5-bromoisoquinoline in a metalation reaction yielded 6-aminoisoquinoline, a compound otherwise accessed with difficulty.14... 

Aziridinocyclopropanes 163 derived from 2-phenylsulfonyl-l,3-dienes undergo BF3-induced rearrangement to bicyclic amines 165, which feature the skeleton of the tropane alkaloids. The reaction proceeds via cyclopropyl carbinyl cation 164, an intermediate also invoked in the analogous epoxide rearrangements. Trapping by fluoride ion is a competing pathway <96TL3371>. 

The IH of exocyclic alkenes allows the construction of bicyclic amines bearing one methyl group at the ring junction. Although long reaction times (2-7 days) are necessary (Eq. 4.22), amines are obtained in good yield. In contrast, endocyclic aminoalkenes are resistant to cyclization [134]. 

The enantioselectivity of Sn(II) enolate reactions can be controlled by chiral diamine additives. These reagents are particularly effective for silyl thioketene acetals.162 Several diamines derived from proline have been explored and l-methyl-2-(l-piperidinomethyl)pyrrolidine 21 is an example. Even higher enantioselectivity can be achieved by attachment of bicyclic amines to the pyrrolidinomethyl group.163... 

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. 

A similar scaffold for the preparation of peptidomimetics was prepared by Mitsunobu cyclization of the molecule coming from the coupling of 4-benzylprolinol and iV-nosyl(o-nitrobenzensulfonyl) tryptophan 316 (Scheme 41). A Mitsunobu cyclization occurred easily due to the acidity of the NH of the nosyl group that could be further selectively deprotected under very mild conditions. The so-formed bicyclic amine 317 can be further coupled with different amino acids to give compounds 318, employed in the search of a new somatostatin pharmacophore <2005BML4033>. 

BICYCLIC AMINES WITH THREE OR MORE HETEROATOMS... 

Morishima and coworkers30 have studied the CT complexes of iodine with various cyclic and bicyclic amines containing non-adjacent double bonds or aromatic rings. They could show that the iodine-amine CT absorption is a useful means of assigning the ionizations in the PE spectra of amines. 

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-... 

The synthesis and properties of nitramines derived from strained and bicyclic amines are discussed in more detail in Chapter 6. Such compounds often exhibit high performance resulting from high crystal densities and/or high heats of formation due to internal strain. 

Lehn and Sauvage (34) suggest that bicyclic ligands should be better suited than non-cyclic polyethers to selectively complex cations. Their data (Table 8) show this to be valid for the series of bicyclic amines represented by the structures in Fig. 3. 

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