The organometallic approach to the functionalization of five- and six-membered nitrogen heterocycles

The present thesis work concerns the preparation and optionally site selective functionalization of five- and six-membered nitrogen heterocycles and the investigation of atropisomerism of α,o-bis(methoxymethyl)-1-phenylindole. Mono- and disubstituted 2-bromo-3-fluoroquinolines can be converted into the 3-fluoroquinoline-2-carboxylic acids by consecutive halogen/metal permutation and into the 2-bromo-3-fluoroquinoline-4-carboxylic acids by consecutive deprotonation and carboxylation. These latter compounds can be reduced to afford the 3-fluoroquinoline-4-carboxylic acids. Rather than to introduce one functional group alternatively at the 2- and 4-position, one may also attach two different functional groups sequentially to both sites. An expedient route to all three monobrominated and all three dibrominated isomers of 4-(trifluoromethyl)pyrimidine, and several other halogenated pyrimidines, is described. Pyrimid-5-yllithium species are fairly stable when the metal is flanked by two electron-withdrawing substituents such as trifluoromethyl and chlorine or bromine. Thus, introduction of a carboxy group into the 5-position of 4(6)-(trifluoromethyl)pyrimidine can be achieved by carboxylation of the corresponding lithio species. This later compound can readily obtained by either butyllithium mediated permutational halogen/metal interconversion of 5-bromo-6-chloro-4(trifluoromethyl)pyrimidine or by reaction of 2,4-dibromo- or 2,4-dichloro-6-(trifluoromethyl)pyrimidine with an amide type base. In contrast, functionalization of 4(6)-(trifluoromethyl) pyrimidine at the 2- or 4-position is hampered by the low stability of the lithium species and by a permanently menacing side reaction which results bipyrimidine. Functionalization of 1-phenylindole selectively at the α- and ortho-position as well as simultaneously at both sites is accomplished by application of organometallic reagents. The analog bearing diastereotopic α,o-bis(methoxymethyl) group, prepared from the α,o-diformyl derivative, can serve as a "probe" for the evaluation of the activation barrier for free rotation by means dynamic 1H-NMR technique. When 1-(4-methoxybenzyl)pyrazole is treated with either butyllithium or lithium diisopropylamide, the substrate undergoes metalation at the exocyclic α-position but mutates to the 5-lithio species in the course of few minutes or hours. Trapping the intermediate with a rapidly reacting electrophile such as chlorotrimethylsilane or carbon dioxide offers a selective access to either of the two possible regioisomers. On the other hand, the relatively inert 1-iodobutane and butyl trifluoromethanesulfonate ("triflate") inevitably give rise to product mixture as the 5-lithio species is more slowly intercepted than it can revert to the α-metallomer by rapid dynamic equilibration process.

Schlosser, Manfred
Lausanne, EPFL
Other identifiers:
urn: urn:nbn:ch:bel-epfl-thesis3273-2

Note: The status of this file is: EPFL only

 Record created 2005-05-18, last modified 2018-01-27

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