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Aromatic Allylation via Diazotization; Application in synthesis of heterocyclic compounds

Ek, Fredrik LU (2003)
Abstract (Swedish)
Popular Abstract in Swedish

I detta doktorandprojekt har ett antal nya syntesmetoder utvecklats och studerats. En stor del av avhandlingen fokuserar kring införandet av en allylisk grupp i aromatiska föreningar. Allylaromatiska substanser är utmärkta startmaterial i syntesen av föreningar avsedda att användas som kontrastmedel för röntgen. Ett stort antal allylaromatiska substanser med varierande substitutionsmönster har framställts från motsvarande arylaminer via deaminering med tert-butylnitrit och en efterföljande reaktion med allylbromid. Funktionella grupper såsom NO2, CN och CO2Et är många gånger inte kompatibla med de reaktionsbetingelser som råder i alternativa allyleringsmetoder, men tolereras i den studerade... (More)
Popular Abstract in Swedish

I detta doktorandprojekt har ett antal nya syntesmetoder utvecklats och studerats. En stor del av avhandlingen fokuserar kring införandet av en allylisk grupp i aromatiska föreningar. Allylaromatiska substanser är utmärkta startmaterial i syntesen av föreningar avsedda att användas som kontrastmedel för röntgen. Ett stort antal allylaromatiska substanser med varierande substitutionsmönster har framställts från motsvarande arylaminer via deaminering med tert-butylnitrit och en efterföljande reaktion med allylbromid. Funktionella grupper såsom NO2, CN och CO2Et är många gånger inte kompatibla med de reaktionsbetingelser som råder i alternativa allyleringsmetoder, men tolereras i den studerade allyleringsprocessen. Även funktionaliserade allyliska bromider visade sig vara utmärkta reagens i de flesta tillämpningar. Det enkla utförandet har gjort att reaktionen är lämplig för användning i storskaliga processer, vilket också demonstreras i avhandlingen. Under våra studier av allyleringsreaktionen fann vi att en arylamin substituerad med en tetrazolgrupp avvek från tidigare resultat och inte gav den förväntade allylaromatiska föreningen. Istället isolerades en substans som bildats genom att den förväntade allylerade produkten fortsatte att reagera med det brom som bildats under reaktions gång. Detta resultat föranledde fortsatta studier kring denna typ av transformation som påminner om en iodolaktonisering. Ett antal omättade tetrazol- och imidazolderivat gav, motsvarade ringslutna produkter i bra utbyte. Trots likheten med en iodolaktonsering fann vi att ringslutningen av vissa av tetrazol- och imidazolderivaten inte följde Baldwins regler för cyklisering, dvs. de var inte exo-selektiva. Parallellt med ovan beskrivna metod, utvecklades ytterligare en metod för att syntetisera ringslutna tetrazolderivat. Detta var motiverat av dess strukturella likheter med substanser som har farmakologiskt intressanta egenskaper. Allyliska bromider som framställts med allyleringreaktionen användes i denna metod som startmaterial. Via en cykloaddition följt av en intramolekylär N-alkylering kunde sex stycken tetrazolderivat isoleras. Dessa föreningar utnyttjades som startmaterial för parallellsyntes av aminderivat. Tetrazolderivatens strukturella likhet med substansgruppen Bengamider, som visat sig ha cytotoxiska egenskaper, gjorde att vi påbörjade ett projekt som hade som mål att ta fram en analog till Bengamid A. Denna studie har inletts och ett antal viktiga nyckelföreningar har framställts, men den slutgiltiga syntesen av målsubstansen återstår. (Less)
Abstract
A new method for allylation of aromatic systems has been developed. A number of arylamines were converted via diazotization to the corresponding allylaromatic compounds using tert-butyl nitrite and an excess of allylic bromides with complete regioselectivity. Electron-withdrawing groups, in the aromatic moiety, were necessary to obtain good yields. The convenient experimental procedure allowed the synthesis of allyl-3,5-dinitrobenzene at a large scale. In addition, a new allylation-bromocyclization reaction was demonstrated. This result initiated the development of a new method to obtain fused heterocycles via iodocyclization. A number of tetrazoles and imidazole derivatives were prepared in good to excellent yields. The cyclization of... (More)
A new method for allylation of aromatic systems has been developed. A number of arylamines were converted via diazotization to the corresponding allylaromatic compounds using tert-butyl nitrite and an excess of allylic bromides with complete regioselectivity. Electron-withdrawing groups, in the aromatic moiety, were necessary to obtain good yields. The convenient experimental procedure allowed the synthesis of allyl-3,5-dinitrobenzene at a large scale. In addition, a new allylation-bromocyclization reaction was demonstrated. This result initiated the development of a new method to obtain fused heterocycles via iodocyclization. A number of tetrazoles and imidazole derivatives were prepared in good to excellent yields. The cyclization of some of the substrates deviated from Baldwin’s cyclization rules i.e. exo-selectivity. The obtained fused heterocyclic compounds were useful substrates for further derivatization. Furthermore, a method to obtain fused tetrazole derivatives from allylic bromides, generated in the allylation reaction, was developed. This new tandem reaction comprises a cycloaddition between a nitrile and trimethylsilyl azide induced by dibutyltin oxide followed by a intramolecular N-alkylation. These heterocyclic derivatives, incorporating a exomethylene functionality, were used in the parallel synthesis of a small library of amines. The fused tetrazole derivatives have structural similarities with Bengamides, a group of natural products possessing interesting pharmacological properties. This motivated the development of an analogue of Bengamide A, based on a fused tetrazole derivative. Key-intermediates of the analogue have been prepared. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Prof. Renaud, Philippe
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Bengamide analogue., parallel synthesis, trimethylsilyl azide, cycloaddition, imidazole, fused tetrazole derivatives, iodocyclization, benzazepine, tert-butyl nitrite, allylic bromide, aromatic allylation, diazotization, Organic chemistry, Organisk kemi
pages
57 pages
publisher
Organic Chemistry, Lund University
defense location
Kemicentrum sal B
defense date
2003-09-05 10:30
ISBN
91-628-5767-3
language
English
LU publication?
yes
id
71133cf8-0934-47a7-b790-a361b81341d1 (old id 466042)
date added to LUP
2007-10-13 15:33:29
date last changed
2016-09-19 08:45:10
@misc{71133cf8-0934-47a7-b790-a361b81341d1,
  abstract     = {A new method for allylation of aromatic systems has been developed. A number of arylamines were converted via diazotization to the corresponding allylaromatic compounds using tert-butyl nitrite and an excess of allylic bromides with complete regioselectivity. Electron-withdrawing groups, in the aromatic moiety, were necessary to obtain good yields. The convenient experimental procedure allowed the synthesis of allyl-3,5-dinitrobenzene at a large scale. In addition, a new allylation-bromocyclization reaction was demonstrated. This result initiated the development of a new method to obtain fused heterocycles via iodocyclization. A number of tetrazoles and imidazole derivatives were prepared in good to excellent yields. The cyclization of some of the substrates deviated from Baldwin’s cyclization rules i.e. exo-selectivity. The obtained fused heterocyclic compounds were useful substrates for further derivatization. Furthermore, a method to obtain fused tetrazole derivatives from allylic bromides, generated in the allylation reaction, was developed. This new tandem reaction comprises a cycloaddition between a nitrile and trimethylsilyl azide induced by dibutyltin oxide followed by a intramolecular N-alkylation. These heterocyclic derivatives, incorporating a exomethylene functionality, were used in the parallel synthesis of a small library of amines. The fused tetrazole derivatives have structural similarities with Bengamides, a group of natural products possessing interesting pharmacological properties. This motivated the development of an analogue of Bengamide A, based on a fused tetrazole derivative. Key-intermediates of the analogue have been prepared.},
  author       = {Ek, Fredrik},
  isbn         = {91-628-5767-3},
  keyword      = {Bengamide analogue.,parallel synthesis,trimethylsilyl azide,cycloaddition,imidazole,fused tetrazole derivatives,iodocyclization,benzazepine,tert-butyl nitrite,allylic bromide,aromatic allylation,diazotization,Organic chemistry,Organisk kemi},
  language     = {eng},
  pages        = {57},
  publisher    = {ARRAY(0x9a07238)},
  title        = {Aromatic Allylation via Diazotization; Application in synthesis of heterocyclic compounds},
  year         = {2003},
}