Photochemistry of cyclopentenones : Beyond [2+2] photocycloaddition reactions Hendrik Eijsberg To cite this version: Hendrik Eijsberg. Photochemistry of cyclopentenones : Beyond [2+2] photocycloaddition reactions. Other. Université Paris Sud - Paris XI; Università degli studi (Cagliari, Italie). Facoltà di scienze matematiche, fisiche e naturali. Dipartimento di scienze chimiche (Cagliari, Italie), 2012. English. NNT : 2012PA112075. tel-00820031 HAL Id: tel-00820031 https://tel.archives-ouvertes.fr/tel-00820031 Submitted on 3 May 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. N° ORDRE UNIVERSITE PARIS-SUD 11 UFR SCIENTIFIQUE D’ORSAY UNIVERSITA DEGLI STUDI DI CAGLIARI FACOLTA DI SCIENZE MATEMATICHE, FISICHE E NATURALI. THESIS Submitted in fulfillment of the requirements for the degrees of: LE GRADE DE DOCTEUR EN SCIENCES DE L’UNIVERSITE PARIS-SUD 11 ORSAY IL TITOLO DI DOTTORE DI RICERCA DELL UNIVERSITA DI CAGLIARI By Hendrik EIJSBERG Subject: Photochemistry of cyclopentenones: Beyond [2+2] photocycloaddition reactions Presented the 2nd of May 2012 before the review board: Prof. M. Thérisod President Prof R. Ballini Reviewer Prof O. Piva Reviewer Prof D. J. Aitken Thesis supervisor Prof P.-P. Piras Thesis supervisor 1 Summary The aim of this project was to explore the scope and limitations of a tandem photochemical process, consisting of a [2+2] cycloaddition between cyclopentenones and alkenes followed by a Norrish I/γ- hydrogen transfer reaction of the initial bicyclic adduct is formed. Using standard synthetic procedures, a small library of cyclopentenone substrates was prepared. The development of new methods to access substituted cyclopentenones, using organocatalyzed aldolisation conditions, was considered; however, these efforts were unfruitful. The photochemical studies showed that a selection of cyclopentenones and alkenes could react together to furnish cyclobutene aldehydes with average to good yields. The reaction conditions were optimized for the formation of this specific compound type, and some of the limitations as regards substrate diversity were determined. In some cases, control of the regioselectivity of the Norrish-I process was problematic. In course of the study, it was discovered that some of these cyclobutene aldehydes could themselves react photochemically, via an intramolecular Paternò–Büchi reaction, to form hitherto unknown tricyclic oxetanes. This constitutes a one-pot triple photochemical reaction sequence between the starting cyclopenenones and alkenes. Conditions were optimized for this transformation and several examples prepared. The tricyclic core structure was studied in detail, in both solution and the solid state, revealing that the formation had been highly diastereoselective in some examples. Some limitations, arising from steric hindrance and/or use of electron rich alkenes, constituted a limitation of the scope of the process. 2 Résumé L’objectif de ce projet a été d’explorer les limites et les possibilités d’une réaction tandem photochimique, composée d’une cycloaddition [2+2] entre des cyclopentenones et des alcènes, suivie d’une Norrish I/transfert du γ-hydrogen si l’adduit bicyclique se forme.En utilisant des procédures de la littérature, une petite bibliothèque de cyclopentenones fut préparée. Le developpement de méthodes permettant l’accès à des cyclopentenones substituées, par des réactions d’aldolisation organocatalysées, fut explorée sans succès. Des études photochimiques menées sur une selection de cyclopentenones et d’alcènes ont montré qu’ils pouvaient réagir ensemble pour fournir des cyclobutène aldehydes avec des moyens à bons rendements. Les conditions réactionnelles furent optimisées pour la formation de ce composé et quelques unes des limites en termes de susbtrat furent déterminées. Dans certains cas, un problème de régiosélectivité de la réaction de Norrish I furent constatés. Durant le cette étude, il fut découvert que certains de ces cyclobutène aldéhydes pouvaient eux- mêmes réagir photochimiquement par une réaction de Paternò–Büchi intramoléculaire pour mener à des oxétanes tricycliques totalement inédits. Ceci représente une séquence one-pot de trois réactions photochimiques entre la cyclopentenone de départ et l’alcène. Les conditions opératoires furent optimisées pour cette transformation et plusieurs exemples furent préparés. La structure centrale tricyclique fut étudiée en détail, en solution et dans l’état solide, montrant que la formation de ces oxétanes était hautement diastéréoselective dans certains exemples. Certaines limitations, découlant de gène stérique et/ou l’utilisation d’alcènes électroniquement riches, constituent une limite à la portée de cette réaction. 3 Riassunto Questo progetto ѐ nato con l’obiettivo di sviluppare un processo tandem fotochimico, costituito da una cicloaddizione [2+2] tra olefine e substrati ciclopentenonici, seguita da una reazione di Norrish-I / trasferimento di γ-idrogeno sul prodotto biciclico ottenuto. Usando procedure standard, ѐ stata preparata una libreria di substrati ciclopentenonici da testare in questo processo. Lo studio di nuove metodologie organocatalitiche per la sintesi di tali substrati ѐ stato inoltre intrapreso, sfortunatamente senza buoni risultati. Lo studio di questo processo ha mostrato come una serie di ciclopentenoni sia effettivamente in grado di reagire con doppi legami olefinici, portando alla formazione di derivati aldeidici ciclobutenici, con discrete o buone rese. Le condizioni di reazione sono state ottimizzate per la formazione di questa classe di composti, e alcune limitazioni relative alla struttura del substrato sono emerse da questi studi. In alcuni casi, infatti, il controllo della regioselettività della reazione di Norrish-I si ѐ rivelato problematico. Durante tale studio, ѐ apparso che alcune delle aldeidi ciclobuteniche ottenute si sono rivelate in grado di reagire ulteriormente in condizioni fotochimiche, attraverso una reazione di Paternò–Büchi intramolecolare, portando alla formazione di ossetani triciclici finora sconosciuti. Ciò costituisce in ultima analisi un triplo processo fotochimico one-pot a partire da ciclopentenoni e alcheni. Anche le condizioni di reazione per questa sequenza sono state ottimizzate e alcuni esempi sono stati preparati e isolati. La struttura triciclica di questi nuovi composti e stata caratterizzata nel dettaglio, sia in soluzione che allo stato solido, rivelando un’elevata diastereoselettività in diversi casi. La presenza di gruppi stericamente ingombranti, o l’uso di olefine elettronricche, si sono dimostrati tuttavia una limitazione alla sintesi di queste interessanti strutture. 4 General introduction ............................................................................................................................. 11 The basics of organic photochemistry ........................................................................................... 13 Basic transformations through organic photochemistry .............................................................. 17 [2+2] photocycloaddition. ......................................................................................................... 17 Carbonyl photochemistry .......................................................................................................... 19 Other photochemical transformations ..................................................................................... 23 Chapter 1 Presentation of research project ...................................................................................... 25 Chapter 2 Preparation of cyclopentenones ...................................................................................... 33 Reactivity of cyclopentenones ...................................................................................................... 33 Methods for the synthesis of cyclopentenones ............................................................................ 35 Total ring construction .............................................................................................................. 35 Cyclization.................................................................................................................................. 40 Rearrangements of small carbocycles ....................................................................................... 45 Rearrangements and transformations of larger sized rings. .................................................... 45 Misc. transformations ............................................................................................................... 51 Cyclopentenones prepared in this work ....................................................................................... 52 4-substituted cyclopentenones ................................................................................................. 52 2-substituted cyclopentenones ................................................................................................. 55 5-substituted cyclopentenones ................................................................................................