Synthesis of functionalized benzophenones and terphenyls based on site-selective Suzuki-Miyaura reactions of bis(triflates) of various hydroxylated benzophenones and benzoates [Elektronische Ressource] / vorgelegt von Muhammad Nawaz

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• Publié par: universitat_rostock
• Publié le: 01 janvier 2010
• Nombre de lectures: 191
• Poids de l'ouvrage: 3 Mo

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UNIVERSITÄT

ROSTOCK

Synthesis of Functionalized Benzophenones and Terphenyls based on Site-Selective

Suzuki-Miyaura Reactions of Bis(triflates) of various Hydroxylated Benzophenones

and Benzoates

DISSERTATION

zur

Erlangung des Doktorgrades

doctor rerum naturalium (Dr. rer. nat.)

der Mathematisch-Naturwissenschaftlichen Fakultät

der Universität Rostock

vorgelegt von

Muhammad Nawaz geb. am 12 April 1981, Paharpur, Dera Ismail Khan, Pakistan.

Rostock, October, 2010.

urn:nbn:de:gbv:28-diss2011-0067-4

Die vorliegende Arbeit entstand in der Zeit von Oktober2008bis Oktober2010am

Institut für Chemie der Universität Rostock.

Erinreichung der Dissertation:

1. Gutachter: Prof. Dr. Peter Langer, Universität Rostock, Institut für Chemie

2. Gutachter: Prof. Dr. Jürgen Voss, Universität Hamburg, Inst. für Organische Chemie

Tag der Abgabe: 26th October, 2010

Prüfer Hauptfach:

Prof. Dr. Peter Langer

th Wissenschaftliches Kolloquium: 12 April, 2011

Anyone who has never made a mistake has never tried anything new. Albert Einstein

Dedication

I dedicate this humble effort and fruit of my study to my dearest elder Brother

Malik Muhammad Mushtaq

Who always supported my morally and financially, prayed continuously for my success

and sacrificed his precious today for my better tomorrow.

Acknowledgement BythegraceofAllah,theAlmighty,thecreatorofuniverse,whograntedHidayahtothe mankindandpeaceandblessingsbeuponhisprophet,HazratMuhammad(Peacebeupon Him),whoexhortedhisfollowerstoseekknowledgefromcradletograve,I'vebeenableto completethisacademicenterprise. Thelastdayofajourneyisalwaysveryclosetothefirstday.Somanypeoplehave helpedandsupportedmeduringthelasttwoyearsofmystayhereatRostock.Iwilltryto thankallofthemhere,butitisalmostinevitablethatIwillforgetsomeone,soifyouarethat someone,pleaserememberthatitwasnotintentionalandItrulyappreciateeverythingwhat youdidforme. Itismyfirstandforemostobligationtoexpressmysinceregratitudefromthecoreofmy hearttoProfessorDr.PeterLangermysupervisor.Hispropersupervision,experience,time devotionandkeeninterestenablemetoaccumulatethishumblework. IacknowledgethesupportandhelpofMuhammadAdeelduringtheearlydaysofmy PhDhereatRostock.I’mgratefultoMuhammadFarooqIbadforbeinganicelabfellowand providingmeaniceworkingatmosphereinthelaboratory.I’mthankfultoQamarBhaiatHEJ, KarachiUniversity,forpursuingmetotravelAbroadformyPhDstudies. ItwasamemorableandanunforgettabletimehereatRostock,tobewithKamranAli, IhsanullahandImranMalik.Wecelebratedmanygatheringstogether.ManythankstoKamran forhelpingmeinvariousmatters.IamthankfultoallmypastandpresentcolleaguesMunawar Hussain,Obaid‐Ur‐Rahamn,RasheedKhera,MuhammadZeeshan,AsadAli,AneelaMaalik, HumeraRafique,Baraa,ZahidHasan,IftikharAli,TariqBabar,SajidAli,MuhammadShareef, RasheedAhmed,Shkoor,Dhafer,Ghazwan,AhmedMahalandOmerAkrawifortheirsupport encouragementandhelptopursuethisworkandallotherswhomIhavemissedheredo deserveequalcredit. IwouldalsoliketothankLindaSupe,FriedrichErben,SebastainRiemann,Alina Bunescue,Dennis,Ingo,Franziska,Satenik,PeterEhlersandalltheotherGermancolleagues. TheyalwayswerewillingtohelpmewheneverIwasneedofthem.

I’dliketoexpressmyspecialgratitudetoDr.MartinHeinfornotonlyhistimeforproof‐ readingofmythesisbutalsoforhishelpforinterpretationofvariouscomplicatedNMR‐ Spectra,toDr.DirkMichalikforseveralnicediscussionabout2D‐NMRspectra,toDr.Holger Feistforhisenthusiasmtoteachaboutsecurityinstruction,toDr.AlexanderVillinger,for measuringX‐Raycrystallographicanalysisofmycompounds.I’dalsoliketoacknowledgethe membersofIR,UV,MS,andE.AlaboratoriesoftheInstituteofChemistry,Universityof Rostock. Last,butnotleastI’dliketothanktechnical&non‐technicalstaffoftheInstituteof Chemistry,especiallyAnnaHallmannandClaudiaVinkefortheirtremendoussupportduring mystay. Finally,Iwouldliketothankmyentirefamily,especiallymymother,foralltheirpray, divinelove,patienceandencouragementevenwhentheydidn’treallyunderstandwhatIwas doing.Idon’thaveenoughwordstopaythankstomybrotherforhisconstanthelpandsupport throughoutmylife,particularlyafterthedeathofmyfather,whenIwasjust12yearold.Since thenheguidedmesonicely,holdmyfingerandtoldmehowtowalkinthedifficultandtough waysoflife.I’veagreatdebtonmylifeofhim,duetoenormoussacrificesmadebyhim,formy betterfuture.MayAllahgivemethecourage,strengthandopportunitythatIcansupporthim back,evenifpartially.Lastly,onemorebunchofthankstoeveryonethatIhaven’tbeenableto mentionbynamehere.Icouldn’thavedoneitwithoutyou. MuhammadNawaz UniversityofRostock October,2010

Table of Contents Abbreviations ……………………………………………………………………….... 1 Summary ……………………………………………………………………………… 2 1.Introduction…………………………...……………………………………………… 6 1.1 General Introduction ...………………………………………………………… 6 1.2 Palladium-catalyzed reactions …...…………………………….……………… 6 1.3 Palladium-catalyzed Suzuki-Miyaura reactions ……………….……………… 9  1.4 Palladium-catalyzed reactions of Bis(triflates) ………………...……………… 11 2. Synthesis of functionalized 2′,4-diarylbenzophenones, 2′,4′-diarylbenzophenones, 3,4- diarylbenzophenones based on site-selective Suzuki-Miyaura cross-coupling reactions of bis(triflates) of various Hydroxylated Benzophenones………............................... 17  2.1 General introduction to benzophenones … …………………………………… 17 2.2Synthesis of functionalized 2′19,4-diarylbenzophenones ……………………….. 2.3 Synthesis of functionalized 2′,4′27-diarylbenzophenones . …………….……….  2.4 Synthesis of 3,4-Diarylbenzophenones ……………………………………… 31  2.5 Sonogashira reaction of the bis(triflate) of 3,4-dihydroxybenzophenone …… 35  2.6 Conclusion …………………………………………………… …….……… 37 3. Synthesis of functionalizedp-terphenyls andm-terphenyls based on site-selective Suzuki cross-coupling reactions of bis(triflates) of 2,5- and 2,4-dihydroxybenzoate ………………..………………………………………………………….…………….38  3.1 Introduction ………………………………………………….……………… 38 3.1.1 Introduction top38-terphenyls ………………………………………….. 3.1.2 Introduction tom40-terphenyls …………………………………………. 3.2 Synthesis of functionalizedp40-terphenyls ………………………………………..  3.3 Synthesis of functionalizedm-terphenyls …………………………………...... 47  3.4 Conclusion ……………………………………………………………………… 51

4. 5.

Abstract………………………………………………...…………..……………...…..52

Experimental Section ………………………………………………………….54 5.1 General: Equipment, chemicals and work techniques ...……….………………. 54 5.2 Procedures and spectroscopic data ………………………….…………………. 56 References……………………………………………………..………….. …………..121 Data for X-Ray Crystal Structures………………………….….………..…………..127 Declaration / Erklärung…………………………..………….………………………140

Abbreviations Ar Aromatic APT Attached Proton Test ATCCType Culture Collection American nBuLin-Butylithium DEPT Distortionless Enhancement by Polarisation Transfer EI Electronic Impact ESI Electrospray Ionization EtOAc Ethylacetate HRMS High Resolution Mass Spectroscopy IR Infrared Spectroscopy LDA Lithium Diisopropylamide MS Mass Spectrometry Ph Phenyl NEt 3  Triethylamine NMR Nuclear Magnetic Resonance HMQC Heteronuclear Multiple Quantum Coherence HMBCMultiple Bond Correlation Heteronuclear COSY Correlated Spectroscopy NOESY Nuclear Overhauser and Exchange Spectroscopy Me 3 SiOTf Trimethylsilyl-trifluoromethanesulfonate Me 3 SiCl Trimethylsilylchloride RCM Ring Closing Metathesis TBAI Tetrabutyl Amonium Iodide TBAF Tetrabutyl Amonium Fluoride TFA Trifluoroacetic Acid Tf 2 AnhydrideO Trifluoromethanesulfonic THF Tetrahydrofurane TLC Thin Layer Chromatography TMS Trimethylsilane UV Ultraviolet Spectroscopy

1

“Summary and Task of the Thesis”

Most of the work mentioned here has already been published in reputed journals. This thesis can be summarized as follows: The task of my thesis was to study palladium(0)-catalyzed Suzuki cross-coupling reactions of various types of bis(triflates) of benzophenones and benzoates. The triflates are readily available from the corresponding hydroxy compounds. The issue of site-selectivity plays an important role in

my thesis. In this context, steric and electronic parameters have been investigated. The palladium(0)-catalyzed Suzuki cross-coupling reaction of the bis(triflates) of 2′,4- dihydroxybenzophenones afforded 2′,4-diarylbenzophenones. The reactions proceeded with very good site-selectivity. The first attack takes place at carbon atom C-4. The site-selectivity of palladium(0)-catalyzed reactions of bis(triflates) is controlled by electronic and steric parameters. The oxidative addition of palladium usually occurs first at the most electron deficient and sterically less hindered carbon atom. Therefore, the site-selective formation of mono-adducts can be explained by the fact that carbon atom C-4 is more electrons deficient and less sterically hindered than C-2′. One electron-withdrawing benzoyl group is locatedorthoC-2 to ′. In contrast, both an electron-withdrawing benzoyl group and an electron-withdrawing ester group are locatedparaand

orthoto C-4, respectively.

Me SiO 3

O

O

OSiMe 3

OMe

O

OH O

O

OMe

O H

2 Ar O

O

OMe

1 Ar 1 1.0 e q Ar B(OH) 2 2 1.0 e q Ar B(OH) 2 OT f O O OT f O ArB(O H) 2 O Me

Ar

2

O

OTf

2 .0 e q ArB(OH ) 2

O

Ar

OMe

O

Ar

O Me

The Suzuki-Miyaura cross-coupling reaction of the bis(triflate) of 2,4′-dihydroxy benzophenone afforded 2,4′-diarylbenzophenones. The reactions again proceeded with very good site-selectivity in favour of carbon atom C-4′which is less sterically hindered than C-2.

2 Ar O

1 1.0 eq Ar B(OH ) 2

1 2 Ar 1.0 eq Ar B(OH ) 2

OTf O

Ar

1 .0 e q ArB( OH ) 2 OTf O 2.0 eq ArB(OH) 2

O Tf

Ar

O

Ar

The Suzuki-Miyaura reaction of the bis(triflate) of 3,4-dihydroxybenzophenone with two equivalents of boronic acids gave 3,4-diarylbenzophenones. When one equivalent of boronic acid was used, the reaction proceeded with site-selective attack at carbon atom C-4. 3,4- diarylbenzophenones containing two different aryl groups were prepared by sequential addition of two different boronic acids. The site-selective formation of the mono-adducts can be explained by the fact that carbon atom C-4 (locatedparato the keto group) is more electron-deficient than C-3 (locatedmetathe keto group). Steric parameters have no role to play, due to the similar steric to environment of carbon atoms C-3 and C-4. The Sonogashira cross-coupling reactions of the bis(triflate) of 3,4-dihydroxybenzophenone with terminal alkynes display remarkable compatibility with regard to the formation of symmetrical and unsymmetrical alkyne-substitution and the reaction proceeded with the same site-selectivity as was observed in case of Suzuki-Miyaura

reaction of the same substrate.

3