Towards a new synthesis of benzodiazines based on C(sp2)-H activation: direct oxidative amination versus rearrangement

Date: 15 December 2016

Venue: UAntwerpen, Campus Middelheim, G0.10 - Middelheimlaan 1 - 2020 Antwerpen (route: UAntwerpen, Campus Middelheim)

Time: 3:30 PM

Organization / co-organization: Department of Chemistry

PhD candidate: Mattijs Baeten

Principal investigator: Bert Maes

Short description: PhD defence Mattijs Baeten - Faculty of Science - Department of Chemistry


The original aim of this work was to develop a new approach for the synthesis of benzodiazines featuring a nitrogen atom next to the bridgehead (and aza analogues) via C(sp2)-H amination. Therefore, the first chapter reviews existing methods for the formation of carbon-nitrogen bonds involving a direct oxidative amination reaction. Considering that cross dehydrogenative coupling reactions represent the state of the art in carbon-nitrogen bond formation and have the potential to deliver sustainable synthesis methods, such methodology was put forward to develop new synthesis methods for benzodiazines (and aza analogues) based on intramolecular oxidative C-H amination.

In Chapter 2, the synthesis of quinoxalines from N-substituted-N-phenylethanediamides via oxidative Pd catalysis is described as first ring system. Although catalyst deactivation caused incomplete conversions in some cases and therefore no unique set of reaction conditions with broad scope could be identified, the reaction protocol developed already possesses a great potential in comparison to the classical quinoxaline synthesis methods. This was demonstrated with an alternative synthesis of the API Ataquimast.

The next chapter deals with our attempts to synthesize a second ring system, quinazolines, via cross dehydrogenative catalysis involving oxidative C(sp2)-H amination of N-benzylamidines. Amidines are on itself interesting substrates as they can be easily synthesized via a Pinner reaction starting from a nitrile and an amine, requiring only HCl and an alcohol as solvent. Although no method for the synthesis of quinazolines based on oxidative amination could be found, another interesting reaction was observed when N-benzylamidines were treated with hypervalent iodine compounds as oxidants.  Instead of quinazolines, secondary amides were obtained from the N-substituted amidines via oxidative rearrangement and isocyanate elimination. The N substituent does not need to be a benzyl. To show that the synthesis method is applicable for more complex examples featuring functionality of relevance to concrete applications, the pesticide Boscalid was synthesized in high yield starting from N-tert-butyl -4’-chlorobiphenyl-2-carboximidamide. Interestingly, the reaction proved to be general and very useful for the preparation of sterically hindered secondary amides which are not, or only in low yields, accessible through classical amide synthesis approaches.

At the same time it was found that isourea could be synthesized from the same N-substituted amidines when the reaction with the hypervalent iodine compound was executed in the presence of an alcohol. This is described in the final chapter of the PhD thesis. Subsequently, it was tested whether the same technique could be used for the synthesis of guanidines, when amines are added instead of alcohols as nucleophiles. After all, isourea have limited applications but guanidines on the other hand are very interesting compounds. However, the synthesis of guanidines proved more difficult. Competitive oxidation of the amines by the hypervalent iodine compounds was the major challenge and it was only after the correct hypervalent iodine compound was identified, that a good, selective high-yielding synthesis method could be developed. To emphasize the advantages of the new guanidine synthesis, we synthesized the API Pinacidil in an alternative manner. To demonstrate the effectiveness of the new protocol with respect to sustainability, the PMI (Process Mass Intensity) of the Pinacidil synthesis was calculated and compared with the classical approach used. The new process has a PMI which was significantly lower than the classical synthesis. Both for the synthesis of amides, as for the synthesis of guanidines, the formed iodoarene by-product formed (originating from the hypervalent iodine reagent) could be recovered using a simple extraction protocol with heptane. Reoxidation of the iodoarene gives again the hypervalent iodine reagent which could be reused. Considering this was not taken into account with the PMI calculation performed, the alternative protocol will score in reality even better in this respect. If a catalytic amount of iodoarene could be used in combination with a cheap oxidant, an even more sustainable protocol could be established. The main challenge to achieve this will be again the compatibility of this oxidant with the oxidation sensitive amine functionalities.

Although some benzodiazine scaffolds could be synthesized via CDCs, this proved to be a bigger challenge than originally anticipated. Several interesting competitive oxidative side reactions were identified, optimized and subsequently further developed. The biggest future challenge in the field of bicyclic azaheterocycle synthesis based on intramolecular C-N bond formation via CDC will therefore be the identification of sustainable oxidants that avoid these competitive side reactions.