Full Functionalization of the Thieno[3,2-b]thiophene Scaffold [Elektronische Ressource] : Benzo[b]thiophenes via Intramolecular Carbomagnesiation of Alkynyl(aryl)thioethers ; Preparation and Reactions of Solid Organozinc Reagents / Thomas Kunz. Betreuer: Paul Knochel

Thomas Kunz

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2011
• Nombre de lectures: 17
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München






Full Functionalization of the Thienbo][t3h,io2-phene Scaffold.
Benzo[b]thiophenes via Intramolecular Carbomagnesiation of
Alkynyl(aryl)thioethers.
Preparation and Reactions of Solid Organozincn tsR eage






von

Thomas Kunz


aus

München


2011
Erklärung

Diese Dissertation wurde im Sinne von § 13z wA.b 4s. d3e br Promotionsordnung vom 29.
Januar 1998 (in der Fassung der sechsten Ändatzeunrugn gvssom 16. August 2010) von
Professor Dr. Paul Knochel betreut.




Ehrenwörtliche Versicherun g

Diese Dissertation wurde selbständig und aouhbnte uHinlfeerl bearbeitet.


München, 28. September 2011




___________________
Thomas Kunz






Dissertation eingereicht am: 30. September 2011

1. Gutachter: Prof. Dr. Paul Knochel
2. Gutachter: Prof. Dr. Manfred Heuschmann

Mündliche Prüfung am: 7. November 2011 This work was carried out from September 200g9u stto 2A0u11 under the guidance of Prof. Dr.
Paul Knochel at the Department of ChemistryL uodfw tihge- Maximilians-Universität Munich.



First of all, I thank Prof. Dr. Paul Knochecel fptoirn gac me as a PhD student in his group,
for his support and advice in the course oafrc hm ayn dre fseor his interest in this work.
I would like to express my appreciation to .P rMoanff.r eDdr Heuschmann for agreeing to
be second reviewer of this thesis and I etmhanbke arlsl mof my defense committee – Prof. Dr.
Konstantin Karaghiosoff, Prof. Dr. Heinz LanPgrhoalfs,. Dr. Thomas Bein and Prof. Dr.
Thomas Klapötke for their interest shown in ntuhsicsr impta by accepting to be referees.

My thanks go to my dear friend and wingman nSe Bbaestrinahardt for the great scientific
cooperation and, distinctly, for everythinge vweed aochuitside of the laboratory. I also express
my gratitude to my soulmate Tobias Blümke fourc ht otoo mbe listed here. Thanks for coping
with me for so long.
I am grateful to Andreas Wagner for the thoroouogfhr eparding of this manuscript. I thank
the former members of the materials resefarc hth ites awmo rokgroup, Dr. Marcel Kienle and Dr.
Silvia Zimdars, for all the fruitful and cvoens trgucetit-togethers. Thanks, also, to Veronika
Werner, Mirjam Dogru, Dr. Dana Medina and Dr. Aansd rSeonnauer for our strong
collaboration.
Also I express my thanks to all past and presemntb emres of this workgroup who are
striving hard to make the work environment panleda spanrtoductive in many ways.
I would like to thank the permanent staff oofu p,th eR egnrate Schröder, Julia Tsvik,
Vladimir Malakhov and Simon Matthe for their henlpd asupport with the every-day business and
everything that comes along unexpectedly.

I express my profound gratitude to my parenrotst,h emr,y Lbottchen, and the close family
for their continuous moral support and patieencier ,a dthvice, and their trust in me.
Parts of this PhD Thesis have been p ublished:

Thomas Kunz, Paul Knochel“:S elective Multiple Magnesiations of the Thieno-[3,2
b]thiophene Scaffold,” Chemistry - A European Jour n20al11,1 7(3, )866-872.

Sebastian Bernhardt, Georg Manolikakes, Thomas K, unPzaul Knoche“l:Pr eparation of Solid
Salt-Stabilized Functionalized Organozincs – Aaptipolnic to Cross-Couplings and
Carbonyl Additions”, Angew. Chem. Int.2 0E1d1,. 5 0, 9205-9208; Angew. Chem2.01 1, 123, 9372-
9375.

Thomas Kunz, Paul Knoche“l:Pr eparation of Functionalized Benbz]oth[iophenes via an
Intramolecular Copper-Catalyzed Carbomagnesiation f o Alkynyl(aryl)thioether,s ”
submitted for publicatio.n




















To my family






















It is better to remain silent
and be thought a fool
than to open one's mouth
and remove all doubt.
- Abraham Lincoln -







A. INTRODUCTION ............................................................ ............1...
1. OVERVIEW....................................................................................................................... 2
2. FUNCTIONALIZATION OF THIENO[3,2-b]THIOPHENE........................................... 4
3. FUNCTIONALIZED BENZO[b]THIOPHENES.............................................................. 7
4. SOLID ORGANOZINC REAGENTS............................................................................. 10
B. RESULTS AND DISCUSSIO.N.......................................................................... .........................12
1. FUNCTIONALIZATION OF THIENO[3,2-b]THIOPHENE......................................... 13
1.1 Precursor Synthesis .................................................................................................... 13
1.2 Preparation of 3,6-Disubstituted 2,5-Dichlorothieno[3,2-b]thiophenes..................... 15
1.3 Preparation of 3,6-Disubstituted Thieno[3,2-b]thiophenes........................................ 17
1.4 Preparation of Fully Functionalized Thieno[3,2-b]thiophenes .................................. 18
1.5 Direct Magnesium Insertion into Substituted 2,5-Dichlorothieno[3,2-b]thiophenes. 20
1.6 Preparation of Fused Pyridazines............................................................................... 21
1.7 Preparation of Thieno[3,2-b]thiophene Oligomers .................................................... 23
2. BENZO[b]THIOPHENES VIA INTRAMOLECULAR CYCLIZATION ..................... 25
2.1 Precursor Synthesis .................................................................................................... 25
2.2 Cyclization of TMS-substituted Alkynyl(aryl)thioethers .......................................... 27
2.3 Transformation of the Silyl Protection Group............................................................ 31
2.4 Further Functionalization of the Benzo[b]thiophene Scaffold................................... 33
2.5 Cyclization of TIPS-protected Alkynyl(aryl)thioethers............................................. 35
2.5 Diversification of Polyfunctional Benzothiophenes to new Heterocyclic Scaffolds . 38
3. PREPARATION AND REACTIONS OF SOLID ORGANOZINC REAGENTS......... 39
3.1 Preparation of Solid Salt-Stabilized Functionalized Organozinc Reagents............... 39
3.2 Application in Negishi Cross-Coupling Reactions .................................................... 40
3.3 Reactivity-Tuning of Organozinc Reagents............................................................... 43
4. SUMMARY ..................................................................................................................... 44
4.1 Functionalization of Thieno[3,2-b]thiophene ............................................................ 44
4.2 Benzo[b]thiophenes via Intramolecular Carbomagnesiation ..................................... 46
4.3 Preparation and Reactions of Solid Functionalized Organozinc Reagents ................ 48
C. EXPERIMENTAL SECTION........................................................................4....9 ..........................
1. GENERAL CONSIDERATIONS.................................................................................... 50
1.1 Solvents ...................................................................................................................... 50
1.2 Reagents ..................................................................................................................... 51
1.3 Content Determination of Organometallic Reagents ................................................. 51
1.4 Analytical data............................................................................................................ 52
2. TYPICAL PROCEDURES.............................................................................................. 53
3. PRODUCT SYNTHESIS AND ANALYTICAL DATA ................................................ 58
3.1 Functionalization of Thieno[3,2-b]thiophene ............................................................ 58
Preparation of 3,6-Disubstituted 2,5-Dichlorothieno[3,2-b]thiophenes....................... 58
Preparation of 3,6-Disubstituted Thieno[3,2-b]thiophenes.......................................... 68
Preparation of Fully Functionalized Thieno[3,2-b]thiophenes .................................... 72
Direct Magnesium Insertion into Substituted 2,5-Dichlorothieno[3,2-b]thiophenes... 81
Preparation of Fused Pyridazines................................................................................. 83
Preparation of Thieno[3,2-b]thiophene Oligomers ...................................................... 88
3.2 Benzo[b]thiophenes via Intramolecular Carbomagnesiation ..................................... 95
Preparation of ortho-Dihaloarenes .................................................................