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Synthesis of heterocycles from anthranilic acid and its derivatives
Södertörn University, School of Chemistry, Biology, Geography and Environmental Science. Karolinska Institutet.
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: urn:nbn:se:sh:diva-32065ISBN: 91-7349-913-7 (print)OAI: oai:DiVA.org:sh-32065DiVA: diva2:1074554
Public defence
2004-05-28, Hörsalen, plan 4, NOVUM, Hälsovägen 7-9, Huddinge, 10:00 (English)
Opponent
Supervisors
Available from: 2017-02-15 Created: 2017-02-15 Last updated: 2017-02-15Bibliographically approved
List of papers
1. Ring forming reactions of imines of 2-aminobenzaldehyde and related compounds
Open this publication in new window or tab >>Ring forming reactions of imines of 2-aminobenzaldehyde and related compounds
2003 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 1, no 2, 367-372 p.Article in journal (Refereed) Published
National Category
Organic Chemistry
Identifiers
urn:nbn:se:sh:diva-15590 (URN)10.1039/b209505j (DOI)000181557300019 ()12929432 (PubMedID)2-s2.0-0041317250 (Scopus ID)
Available from: 2012-02-22 Created: 2012-02-21 Last updated: 2017-12-07Bibliographically approved
2. Products from dehydration of dicarboxylic acids derived from anthranilic acid
Open this publication in new window or tab >>Products from dehydration of dicarboxylic acids derived from anthranilic acid
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
National Category
Organic Chemistry
Identifiers
urn:nbn:se:sh:diva-15594 (URN)10.1039/b306032b (DOI)000185547400020 ()14584803 (PubMedID)2-s2.0-0142126224 (Scopus ID)
Available from: 2012-02-22 Created: 2012-02-21 Last updated: 2017-12-07Bibliographically approved
3. Alkylation and acylation of basic salts of anthranilic acid
Open this publication in new window or tab >>Alkylation and acylation of basic salts of anthranilic acid
2004 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 45, no 5, 969-972 p.Article in journal (Refereed) Published
Abstract [en]

The O-nucleophilicity of basic anthranilic acid salts was documented, analyzed, and utilized in synthesis. Specifically substitutions leading to esters instead of secondary amines, and formation of anthranilic acid anhydrides were studied.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:sh:diva-15497 (URN)10.1016/j.tetlet.2003.11.111 (DOI)000188380400018 ()2-s2.0-0346392216 (Scopus ID)
Available from: 2012-02-20 Created: 2012-02-20 Last updated: 2017-12-07Bibliographically approved
4. Synthesis of 1,4-benzodiazepine-3,5-diones
Open this publication in new window or tab >>Synthesis of 1,4-benzodiazepine-3,5-diones
2004 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, no 19, 6371-6376 p.Article in journal (Refereed) Published
Abstract [en]

Even though benzodiazepines have a strong position in medicinal chemistry, very few synthetic routes to 1H-1,4-benzodiazepine-3,5(2H,4H)-diones have ever been published and the claimed products have often been poorly characterized. Through the present work several 1H-1,4-benzodiazepine-3,5(2H,4H)-diones have become available from N-carbamoylmethylanthranilic acids. The required ring closures were achieved only when the amino groups of the starting materials were substituted with electron withdrawing groups such as acetyl, alkyloxycarbonyl, or nitroso. During the synthetic work a novel ring contraction rearrangement from a 1-nitroso-1H-1,4-benzodiazepine-3,5(2H,4H)-dione to a 3H-quinazoline-4-one was observed. The proposed mechanism involves elimination of HNO followed by a proton-mediated loss of CO. The 1-nitrosated 1,4-benzodiazepinediones could be separately denitrosated to the corresponding amino compounds.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:sh:diva-15466 (URN)10.1021/jo049169b (DOI)000223897700025 ()
Note

Som manuskript i avhandling. As manuscript in dissertation.

Available from: 2012-02-21 Created: 2012-02-20 Last updated: 2017-12-07Bibliographically approved

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