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Products from dehydration of dicarboxylic acids derived from anthranilic acid
Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
2003 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 1, no 19, 3396-3403 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2003. Vol. 1, no 19, 3396-3403 p.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:sh:diva-15594DOI: 10.1039/b306032bISI: 000185547400020PubMedID: 14584803Scopus ID: 2-s2.0-0142126224OAI: oai:DiVA.org:sh-15594DiVA: diva2:504982
Available from: 2012-02-22 Created: 2012-02-21 Last updated: 2017-02-15Bibliographically approved
In thesis
1. Synthesis of heterocycles from anthranilic acid and its derivatives
Open this publication in new window or tab >>Synthesis of heterocycles from anthranilic acid and its derivatives
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anthranilic acid (2-aminobenzoic acid, Aa) is the biochemical precursor to the amino acid tryptophan, as well as a catabolic product of tryptophan in animals. It is also integrated into many alkaloids isolated from plants. Aa is produced industrially for production of dyestuffs and pharmaceuticals. The dissertation gives a historical background and a short review on the reactivity of Aa. The synthesis of several types of nitrogen heterocycles from Aa is discussed. Treatment of anthranilonitrile (2-aminobenzonitrile, a derivative of Aa) with organomagnesium compounds gave deprotonation and addition to the nitrile triple bond to form amine-imine complexed dianions. Capture of these intermediate with acyl halides normally gave aromatic quinazolines, a type of heterocyclic compounds that is considered to be highly interesting as scaffolds for development of new drugs. When the acyl halide was a tertiary 2-haloacyl halide, the reaction instead gave 1,4-benzodiazepine-3-ones via rearrangement. These compounds are isomeric to the common benzodiazepine drugs (such as diazepam, Valium®) which are 1,4-benzodiazepine-2-ones. Capture of the dianions with aldehydes or ketones, led to 1,2-dihydroquinazolines. Unsubstituted imine anions could be formed by treatment of anthranilonitrile with diisobutylaluminium hydride. Also in this case capture with aldehydes gave 1,2-dihydroquinazolines. Several different dicarboxylic acid derivatives of Aa were treated with dehydrating reagents, and the resulting products were more or less complex 1,3-benzoxazinones, one of which required X-ray crystallography confirm its structure. During the work on preparation of N-substituted derivatives of Aa, necessary for synthesis of 1,4-benzodiazepine-3,5-diones, it was noted that many of the obtained products were in fact not N-substituted, but O-substituted. This challenged the established notion that Aa reacts nucleophilically at the N-terminal under most conditions. Several grave errors in the recent literature were revealed. In 1976 researchers from the group that originally developed the common benzodiazepine drugs published a retraction of a claim of synthesis of a benzodiazepine by Gärtner in 1904. They found that the method actually gave a 6-membered ring system, not a 7-membered 1,4-benzodiazepine-3,5-dione as originally claimed. Because the 1,4-benzodiazepine skeleton is highly interesting as a scaffold for development of new drugs, a few publications on synthesis of this target has appeared. However, repetition of several of the described syntheses failed to yield the poorly described products. Studies on how to ring close N-carbamoyl derivatives of Aa were undertaken. It became clear that Umpolung of the substrates by N-derivatisation was a necessary prerequisite for ring closure. The introduction of the N-nitroso group was developed to this end, leading to N1-nitroso substituted 1,4-benzodiazepine-3,5-diones. The nitroso group could be removed after ring closure. Heating of one of these compounds induced a ring contraction rearrangement. A proposed mechanism involves elimination of HNO (nitrosyl) and proton mediated loss of CO.

Place, publisher, year, edition, pages
Stockholm: Karolinska Instiutet, 2004. 47 p.
National Category
Organic Chemistry
Identifiers
urn:nbn:se:sh:diva-32065 (URN)91-7349-913-7 (ISBN)
Public defence
2004-05-28, Hörsalen, plan 4, NOVUM, Hälsovägen 7-9, Huddinge, 10:00 (English)
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Available from: 2017-02-15 Created: 2017-02-15 Last updated: 2017-02-15Bibliographically approved

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