Bicyclic alkylation

Berglund BA, Fleming PR, Rice KC, Shim JY, Welsh WJ, Howlett AC (2000) Development of a novel class of monocyclic and bicyclic alkyl amides that exhibit CBI and CB2 cannabinoid receptor affinity and receptor activation. Drug Des Discov 16 281-294... 

When the reaction of c/s-cyclohexyl carboxylates 101 and 107 was conducted in the presence of maleic anhydride (1 equiv) in toluene, a cycloisomerization affording c/s-fused bicyclic alkyl carboxylates 106 and 108 was observed (Scheme 50) [31]. 

Reaction of 57 with dihalogenoalkanes is reported to give not only the expected dithioether (58) but also the bicyclic salt (59) (Scheme 26) (118). This reaction should depend on the alkyl chain length. 

Selective biomination at the mote substituted position makes possible connection of two different alkyl groups. The use of dialkylthexylboranes and dialkyUialoboranes allows fuU utilization of alkyl groups (370,371). Bicyclic and more complex boracycles can be transformed into carbon stmetures not readily available by other methods (372). 

Similar alkylations may be effected on oxygen. l-(2-Chloroethyl)imidazolidin-2-one (312) when treated with potassium hydroxide or sodium hydride underwent ring closure to the tetrahydroimidazo[2,l-6]oxazole (313) (57JA5276). This approach can be used for the preparation of bicyclic hydantoins and the corresponding dihydro derivatives of (313) using the mesylate of (312) and NaH (77JHC5U, 79JMC1030). 

Azetidines, 7, 237-284, 238-246 addition compounds with trimethylboron, 7, 240 AT-alkylation, 7, 240 applications, 7, 246 AT-arylation, 7, 240 azetidin-2-ones from, 7, 263 bicyclic... 

Pyrylium salts alkyl groups reactivity, 3, 662 aromaticity, 3, 640 arylammes from, 3, 657 benzenoid compounds from, 3, 656, 658 benzisoxazol-3-yl-synthesis, 6, 124 bicyclic... 

Alkylation of 28 with acrolein gives the bicyclic ketone (65), which can be converted to 4-cyclooctene-l-carboxylic acid by the action of base on its methiodide (55a). 

The formation of bicyclic imines (263,264) from piperidine enamines and y-bromopropyl amines may appear at first sight to be a simple extension of the reactions of enamines with alkyl halides. However, evidence has been found that the products are formed by an initial enamine exchange, followed by an intramolecular enamine alkylation. Thus y-bromodiethylamino-propane does not react with piperidinocyclohexene under conditions suitable for the corresponding primary amine. Furthermore, the enamine of cyclopentanone, but not that of cyclohexanone, requires a secondary rather than primary y-bromopropylamine, presumably because of the less favorable imine to enamine conversion in this instance. 

The chiral bicyclic imidazolidine 74 is deprotonated at the 2 position by s-BuLi and the resulting anion adds to alkyl halides, acid chlorides, chlorofor-mates, phenyl isocyanate, and aldehydes. The use of this compound as a chiral formyl anion equivalent seems to be limited, however, since the diastereoselectiv-ity in the addition to aldehydes is poor and hydrolysis of the products 75 to give aldehydes also produces cyclohexane-1,2-diamine, necessitating isolation of the aldehyde as its 2,4-dinitrophenylhydrazone (96SL1109 98T14255). 

In one of their solutions to the problem, Corey and his coworkers solved the first problem by starting with a preconstructed cyclopentane the stereochemistry was steered by deriving the oxygen atoms from a rigid bicyclic molecule. Alkylation of... 

Antidepressant activity is retained when the two carbon bridge in imipramine is replaced by a larger, more complex, function. Nucleophilic aromatic substitution on chloropyridine 31 by means of p-aminobenzophenone (32) gives the bicyclic intermediate 33. Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 35. Alkylation of the anion from 35 with l-dimethylamino-3-chloropropane leads to tampramine 36 [8]. 

However, steric factors are also important.74 Ruchardt and coworkers showed, for a series of acyclic alkyl derivatives, that a good correlation exists between kd and ground state strain.75,76 Additional factors are important for bicyclic and other conformationally constrained azo-compounds.49 51 77 Wolf78 has described a scheme for calculating kd based on radical stability (HOMO Jt-deloealization energies) and ground state strain (stcric parameters). 

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