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Transition metal catalysed generation and application of dihydroaromatic compounds for the synthesis of dibenzoazepine derivatives and polysubstituted benzenes [Elektronische Ressource] / vorgelegt von Fabrizio Galbiati

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Transition metal-catalysed generation and application of dihydroaromatic compounds for the synthesis of dibenzo-azepine derivatives and polysubstituted benzenes Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) dem Fachbereich Chemie der Philipps-Universität Marburg vorgelegt von Fabrizio Galbiati aus Mailand Marburg/Lahn 2006 Vom Fachbereich Chemie der Philipps-Universität Marburg als Dissertation am 28.04.2006 angenommen. Erstgutachter: Prof. Dr. Gerhard Hilt Zweitgutachter: Prof. Dr. Armin Geyer Tag der mündlicher Prüfung am 22.05.2006 II To my family and in memory of my brother Marco IIIAcknowledgements After three years it is now time for me to take farewell and I want to express my gratitude and thank to the following people. My supervisor, Prof. Dr. Gerhard Hilt, for accepting me as a Ph.D. student and for the really interesting research topic. Prof. Dr. Armin Geyer, Prof. Dr. Werner Massa and Prof. Dr. Wolfgang Ensinger for being part of the Ph.D. examinating academy board. My Ph.D. collegues Steffen Lüers, Patrick Bolze, Wilfried Hess and Christoph Hengst for the fruitful collaboration in the research and for the help in the first months of my stay in Marburg. A special thank to Markus Pfitzenmaier (AK Prof.

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Published 01 January 2006
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Transition metal-catalysed generation and application of dihydroaromatic
compounds for the synthesis of dibenzo-azepine derivatives and
polysubstituted benzenes





Dissertation
zur Erlangung des Doktorgrades
der Naturwissenschaften
(Dr. rer. nat.)





dem Fachbereich Chemie
der Philipps-Universität Marburg
vorgelegt von




Fabrizio Galbiati
aus
Mailand


Marburg/Lahn 2006




Vom Fachbereich Chemie
der Philipps-Universität Marburg als Dissertation am 28.04.2006 angenommen.

Erstgutachter: Prof. Dr. Gerhard Hilt
Zweitgutachter: Prof. Dr. Armin Geyer

Tag der mündlicher Prüfung am 22.05.2006




















II










To my family and in memory
of my brother Marco













IIIAcknowledgements
After three years it is now time for me to take farewell and I want to express my gratitude and
thank to the following people.

My supervisor, Prof. Dr. Gerhard Hilt, for accepting me as a Ph.D. student and for the really
interesting research topic.
Prof. Dr. Armin Geyer, Prof. Dr. Werner Massa and Prof. Dr. Wolfgang Ensinger for being
part of the Ph.D. examinating academy board.
My Ph.D. collegues Steffen Lüers, Patrick Bolze, Wilfried Hess and Christoph Hengst for the
fruitful collaboration in the research and for the help in the first months of my stay in
Marburg. A special thank to Markus Pfitzenmaier (AK Prof. Geyer) for the profitable
discussion over two dimensional NMR and for the “emergency samples measurements” on
late evenings.
The graduate students Frank Schmidt, Phillip Schorr, Iris Kieltsch, Thomas Vogler, Sebastian
Würtz, Yvonne Gnas, Maja Heitbaum, Christian Walter, Katrin Hasse, Jonas Treutwein,
Johannes Teichert and Judith Janikowski for the time we shared together.
The chemistry laboratory trainee Sabrina Morneweg for the synthesis of most of my starting
materials and Tina Krieg (AK Dehnen) for the generous support of “extra dry solvents”.
All the personal of the Philipps Universität Chemistry Department for the preciuos
collaboration.
Prof. Carlos Cativiela, Prof. José Antonio Gálvez, Prof. María D. Díaz-de-Villavegas, Ramón
Badorrey and Roberto Díez (Organic Chemistry Department of the University of Zaragoza –
Spain) for the sincerity and friendship.
All my friends and flatmates, especially Christian Hasse and Valeria Bertini for the continuos
encouragements during the writing of my Ph.D. thesis.
My parents for always believing in me and supporting me in whatever I have done during my
life.

And last but not the least,
my girlfriend (and future wife) Francesca for all the support and help in difficult moments.
IV










Every time you are tempted to react in the same old way,
ask if you want to be a prisoner of the past or a pioneer of the future.

Deepak Chopra












VIndex

A Introduction 2
1 Cycloaddition reactions 2
1.1 [4+2+2]-Cycloadditions 3
1.2 [2+2+2]-Cycloadditions 5
1.2.1 Homo Diels-Alder with alkenes 6
1.2.2. alkynes 7
1.3 [6+2]-Cycloadditions 8
1.4 The Hilt catlyst 9
1.4.1 Cycloaddition reactions 9
1.4.1.a [2+2+2]-Cycloadditions 9
1.4.1.b [4+2]-Cycloadditions 10
1.4.1.c Proposed mechanism 11
1.4.2 Hydrovinylation reactions 11
1.4.2.a Proposed mechanism 12
1.4.3 [2+2+2]-Cyclotrimerisation 12
2 C-H activation reactions and cyclopropanations 15
2.1 Synthesis of α-diazocarbonyl compounds 15
2.1.1 Acylation of diazoalkanes 15
2.1.2 Diazo-transfer reactions
2.1.3 Other reactions 16
2.2 Diazocarbonyl in synthesis 17
2.2.1 C-H and N-H activation reactions 18
2.2.1.a Acceptor substituted carbenoids 19
2.2.1.b Acceptor/acceptor substituted carbenoids 19
2.2.1.c Donor/acceptor substituted carbenoids 20
VI 2.2.2 Cyclopropanation reactions 22
2.2.2.a Synthesis of cyclopropane-containing
products 22
2.2.2.b Cyclopropanation and subsequent reactions 23
3 Research topic 25

B Results and discussion 27
1 Cobalt(I)-catalysed neutral Diels-Alder of nitrogen
functionalised alkynes 28
2 Synthesis of heterocyclic compounds via cobalt(I)-catalysed
Diels-Alder reactions 44
2.1 Dihydropyridine derivatives 44
2.2 Piperidone and thiopiperidone derivatives 44
3 Synthesis of dibenzo-azepine derivatives 46
4 Catalytic C-H activation by means of metal-carbenoid
induced C-H insertion 64
4.1 Rhodium(II)-catalysed C-H activation 64
4.2 Copper(II)-catalysed C-H activation 84
5 Sumary 89

C Experimental prt 94
1 Genral 95
1.1 Solvents 95
1.2 Materials 95
1.3 Chromatography 96
2 Instrumental analysis 96
3 General procedures 97

VII4 Cobalt(I)-catalysed neutral Diels-Alder of nitrogen
functionalised alkynes 99
5 Synthesis of dibenzo-azepine derivatives 126
6 Catalytic C-H activation by means of metal-carbenoid
induced C-H insertion 146

D Apendix 164
1 Abbreviations 165
2 Crystallographic data 167
2.1 Crystallographic data for 1,2-dimethyl-4-phenyl-
5,6,8,12b-tetrahydroisoindolo [1,2-a]isoquinolin-
8-one (250)
2.2 Crystallographic data for 1,2,3-trimethoxy-6,7-dimethyl-
-9,10,12,16b-tetrahydrodibenzo[3,4:5,6]-azocino[2,1-a]-
isoindol-12-one (251) 170
2.3 Crystallographic data for 3-methoxy-6,7,9-trimethyl-
11,15b-dihydro-9H-dibenzo [3,4:5,6]azepino[2,1-a]-
isoindol-11-one (249) 173
2.4 Crystallographic data for 18-azaoctacyclo
2,7 8,16 9,14 10,12 11,15 20,25[16.7.0.0 .0 .0 .0 .0 .0 ]-pentacosa-
2,4,6,8(16),20(25),21,23-heptaen-19-one (252) 176
2.5 Crystallographic data for 6,7-dimethyl-11,15b-dihydro-
9H-benzo[5,6]naphtha-[2',1':3,4]azepino[2,1-a]isoindol-
11-one (246) 179
2.6 Crystallographic data for 7-methoxy-11,15b-dihydro-
-9H-dibenzo[3,4:5,6]azepino [2,1-a]isoindol-
11-one (247) 182
2.7 Crystallographic data for [2-(1,3-dioxo-1,3-dihydro-
isoindol-2-ylmethyl)-5,6-dimethyl-3-phenyl-cyclohexa
-2,5-dienyl]-phenyl-acetic acid methyl ester (287) 185

3 Refrences 188
VIII













A Introduction














A Introduction
Introduction

From practical, economical and environmental standpoints, transition-metal catalysed
streactions are set to dominate the chemical industry in the 21 century. These reactions will
have an impact on the production of fine chemicals, pharmaceuticals, agrochemicals,
polymers, etc. It is not therefore surprising that the field of transition metal catalysis has been,
and will remain, one of the top priorities of academic and industrial research. Transition metal
catalysis continues to have a major impact in the area of carbon-carbon bond forming
processes. Furthermore, carbon-carbon bond formation has the added potential of enabling the
stereoselective assembly of the carbon skeleton of the target molecule rather than mere
functionalisation.

1 Cycloaddition reactions
Cycloadditions, and the Diels-Alder reactions in particular, are only one example of the
countless class of reactions which largely benefited from the spectacular advances that have
been made in catalysis during the last decades. The synthetic utility of the Diels-Alder
1reaction for the synthesis of complex structures is well documented . The vast majority of
2reports relate to thermal or Lewis acid catalysed applications on substrates with normal and
inverse electron demand. A variety of Lewis acids are effective catalysts, including SnCl , 4
ZnCl , AlCl and its derivatives such as Et AlCl. This type of reactions are governed by the 2 3 2
principle of conservation of orbital symmetry. The orbital-symmetry rules (also called
Woodward-Hoffman rules) apply only to concerted reactions, i.e., where two σ-bonds are
formed (or broken) at about the same time. Thermal Diels-Alder reactions of non activated
starting materials such as olefines and alkynes, are limited to few examples. Because of the
harsh reaction conditions, yields are generally lower and accompanied by side products. Low-
valent transition metal complexes can instead catalyse such reactions under mild conditions
3 4 5 6 7and in higher yields . These catalysts are mostly based on iron , nickel , titanium , palladium ,
8 9rhodium and cobalt complexes. When a transition metal catalyst is involved the reaction
proceeds through a multistep mechanism within the ligand sphere of the metal and is not any
more governed by the Woodward-Hoffman rules.
10Nicolaou recently reported the total synthesis of the terpenoid (–)-Colombiasin A (6). The
core structure of the product (3) was generated by means of a selective asymmetric Diels-
Alder reaction between the Danishefsky-type diene (1) and the quinone (2). After conversion
of (3) to the precursor (4), thermal extrusion of SO followed by an intramolecular Diels-2
Alder reaction completed the skeleton of the target molecule (6) (Scheme 1).
2