W&M ScholarWorks Dissertations, Theses, and Masters Projects Theses, Dissertations, & Master Projects 2008 Organotitanium-Aluminum Promoted Carbometalations of Alkynols: Substituent Effects Nikola A. Nikolic College of William & Mary - Arts & Sciences Follow this and additional works at: https://scholarworks.wm.edu/etd Part of the Inorganic Chemistry Commons, and the Organic Chemistry Commons Recommended Citation Nikolic, Nikola A., "Organotitanium-Aluminum Promoted Carbometalations of Alkynols: Substituent Effects" (2008). Dissertations, Theses, and Masters Projects. Paper 1539626876. https://dx.doi.org/doi:10.21220/s2-jn77-gm95 This Thesis is brought to you for free and open access by the Theses, Dissertations, & Master Projects at W&M ScholarWorks. It has been accepted for inclusion in Dissertations, Theses, and Masters Projects by an authorized administrator of W&M ScholarWorks. For more information, please contact [email protected]. ORGANOTITANIUM-ALUMINUM PROMOTED CARBOMETALATIONS OF ALKYNOLS: SUBSTITUENT EFFECTS Nikola A. Nikolic Princeton, New Jersey Bachelor of Science, College of William and Mary in Virginia, 1986 A Thesis presented to the Graduate Faculty of the College of William and Mary in Candidacy for the Degree of Master of Science Department of Chemistry The College of William and Mary May 2008 APPROVAL PAGE This thesis is submitted in partial fulfillment of the requirements for the degree of Master of Science Nikola A. Nikolic Approved by the Committee, January 2008 Committee Chair Professor David W. Thompson College of William and Mary Professor ©riristophrer JVAbelt College of William Mary Professor Randolph A. Coleman College of William and Mary TABLE OF CONTENTS DEDICATION...:................................................................... v ACKNOWLEGDEMENTS. .......... vi LIST OF TABLES..................................................................................................vii LIST OF FIGURES........................................................ viii ABSTRACT.............................................................................................................2 INTRODUCTION................................................................................................. 3 LITERATURE REVIEW Description of Carbometalation Systems ............................................. 9 Carbom etalation of Term inal Alkynes...................................................11 Carbometalation of Internal Acetylenes ...................................... 25 Synthetic Utility of Carbometalated Products ................................... 37 The Mechanism of Carbometalation ......................................................44 EXPERIMENTAL Carbometalation System: Alkynol + R 3 AI + (r|5-C5H5-mMem)2TiCl2........................................................................... 48 Carbometalation of 3-Butyn-l-ol ................................................ 50 Carbometalation of 3-Pentyn-l-ol. ..........................................................51 Carbometalation of 4-Pentyn-2-ol ...........................................................51 Carbometalation of 4,0-Dideutero-3-butyn-l-ol ................................. 52 Carbometalation of 3-Butyn-l-ol Quenched With CH 3 OD/D2 O 52 EXPERIMENTAL (cont'd) Synthesis of Bis-(r]5-lJ2>4-trimetliylcyclopentadienyl) Titanium (TV) chloride ......................... 53 Synthesis of Bis-(rj5-l,2,3>435-pentamethylcycIopentadienyI) Titanium(IV) chloride . ......... 60 RESULTS AND DISCUSSION Carbometalation of 3-Butyn-l-ol--Stereoselectivity ..........................62 Carbometalation of 3-pentyn-l-ol ...........................................................69 Effects of Ring Substituents .................................................................... 72 Discussion of the Mechanism. .........................................................74 REFERENCES ............................... 77 iv DEDICATION This thesis is dedicated to my father and teacher, Dr. Nikola M. Nikolic v ACKNOWLEDGEMENTS I would like to thank Dr. David W. Thompson for his outstanding guidance and support throughout the course of this project. I would also like to thank C. P. Desmond Longford for the helpful comments and suggestions which he contributed. Miss Susan D. Parker deserves a special thanks for the patience and understanding she exhibited during this endeavor. LIST OF TABLES 1. Carbometalation of Terminal Alkynes with Organoalanes 15 2. Conversion of Terminal Acetylenes to Alkenylmercuric Chlorides via an AlMe 3 / Cl2 ZrCp2 Carbom etalation 23 3. Carbometalation of Terminal Alkynes with Organozincs 24 4. Carbometalation of Internal Alkynes with Organoalanes 27 5. Carbometalation of Internal Alkynes with Organozincs 37 6. Carbometalation of Alkynols with Orgaoalanes 74 vii LIST OF FIGURES 1. Methylation of Alkynols with Trimethylahiminum / Titanocene Dichlorides 4 2. Ethylation of Alkynols with Titanocene Dichlorides and Diethylaluminum Chloride 5 3. An Approach to Controlled Carbometalation with Ziegler-Natta Catalyst System 6 4. Carbometalation Reaction Vessel 50 5. 2H NMR Spectrum of Bis(p5-1,2,4- trim ethylcyclop entadienyl)tit anium(TV) Dichloride 60 6. 13C NMR Spectrum of Bis(rj5-1,2,4- trimethylcyclopentadienyl)titanium(IV) dichloride 61 7. An Approach to Controlled Carbometalation with Ziegler-Natta Catalyst System 65 8. 2H NMR Spectrum of 4-0-Dideutro-3-butyn-l-ol Methylmetalation Products 67 9. 1H NMR Spectrum of 3-Butyn-l-ol Methylmetalation products Quenched w ith CH3 OD / D 2 O 69 10. 2H NMR Spectrum of 3-Pentyn-l-ol Methylmetalation Products 73 11. 2H NMR Spectrum of 6-Methyl-5-hepten-3-ol 74 12. Modified Carbometalation Pathway 78 viii ORGANOTITANIUM-ALUMINUM PROMOTED CARBOMETALATIONS OF ALKYNOLS: SUBSTITUENT EFFECTS 2 ABSTRACT Homoallylic alcohols are useful intermediates in natural product synthesis, particularly in the construction of terpenoid carbon skeletons. Until recently, however, the synthesis of such alkenols has been somewhat cumbersome. In this investigation, homoallylic alcohols were synthesized in one pot via methylmethylation of homopropargyl alcohols with trimethylaluminum. A series of ring-substituted titanocene dichlorides were used as promoters of this process. The major focus of this study was to examine the effects of ring substitution on the regiochemistry of the methyl addition. Three ring-substituted titanocene promoters: (MeCp) 2 TiCl2 , (Me3 Cp)2 TiCl2 , and (Me 5 Cp)2 Ti2 Cl2 were investigated. Each of these promoters was used to methylate both an internal hompropargylic alcohol (i.e. 3-pentyn-l-ol) and a terminal hompropargyl alcohol (i.e. 3-butyn-l-ol). In these studies, an increase in the number of ring substituents on the titanocene promoter afforded an increase in regioselectivity of methylation of the substrates. Unfortunately, increased ring substitution also led to decreased yields of the methylated substrates. The addition of the methyl group occurred predominantly on the terminal acetylenic carbon of the 3- pentyn-l-ol substrate. Conversely, the methyl addition was predominantly internal for 3-butyn-l-ol. In both cases, the addition of the methyl-metal bond occurs in a syn fashion. 3 INTRODUCTION TO THE RESEARCH GOALS The focus of this investigation is the adaptation of typical Ziegler- Natta catalyst systems to effect single-stage carbometallation reactions on the acetylenic functionality of alkynols. Since the early 1950’s, it has been well known that Ziegler-Natta catalyst systems are powerful, repetitive carbometalating reagents for the production of polyolefins. However, only during the past decade has progress been made in utilizing the Ziegler-Natta chemistry in a manner of interest to non-macromolecular synthesis. Since the stereoselective construction of carbon skeletons is fundamental to organic synthesis, it is surprising that so little effort had been made in adapting the discoveries of Ziegler to these ends. In the late 1970’s, Thompson et at. published the results on the controlled single-stage carbometallations of homopropargyl alcohols using bis(r|5 -cyclopentadienyl)titanium dichloride-organoalane reagents, which are active Ziegler catalysts for the polymerization of ethylene. Representative results from these studies which are germane to the investigation reported herein are shown in Figures 1 and 2. Figure 3 illustrates a proposed pathway for these carbometalation reactions. in ' 03 S' ^H 5 2 ,® w Ph 5 S S o ~ > rH rH o ^ —>o w o H O rH O CD T ? fi ^ g P H 05 i 05 i "g •+J C CD 3 CD "5 Si 0) f t - 9 g 9 P CO CO CD CO <D CO CD r —H Products ^ Ph ^ P h 1 “ CO j s ^ oo (Relative (Relative Rati( CD 4H> 05 S) ® S i § ^ CO CO CO o * rH a rH rH i-H T—H P h f-< 03 CM CM <N cq O £ o cq 1 2 0 1 2 0 1 2 0 rH CD 5-1 P +3 cti o o o o <D5-1 aft CD Eh O O cq CO r H c3 O • pH e S Hoq CsJ s S' a c ? CD O Dichloride ffl Titanocene ■M Figure 1. Methylation of alkynols with trrmetylalummum/titanocene dichlorides. rH • o O o r— ( o . r-H t—i rH £ 1 1 i I P p a<D 1 PP ffl CP Ph CO co CO co S' S' n—• o <—1 lO r—( 1-0 o v~' 9 T T P ^ p ^ -u05 PA ^ PA a <x> a ^ 8 P r o d u c t s ° ? f f i r-—l * r—< • >» c o 5>i CO (Relative Ratio)rP A £ s H * 5 (E)-3-Hexen-l-ol (57) 3-Ethyl-3-penten-l-ol (7) 3-Ethyl-3-penten-l-ol (5) c o CO 3-Ethyl-3-buten-l-ol (43) 4-M ethyl-3-hexen-l-ol (95) 4-M ethyl-3-hexen-l-ol (93) o +3 cti i—i 1—1 rH i—I rH P h u CM CM rHcti CM <M CM o . S O O O o o <M <M (M i—i ▼H rH CM CM Tim e (m in ) e . 02 Jh P Cti O O o OO fH a> t 02 E-> <N CT 0 N o rA ? rA? 1 o o o e S3 & S3 S3 d02 5 * $ <5* m D ic h lo r id e T it a n o c e n e p— Figure 2. Methylation of alkynols wiith dietylaluminum chloride/titanocene dichlorides. r o 9 i—t ro H i -4-3 1 P CP f q P h 3-Butyn-l-ol 3-Butyn-l-ol CO c b 3-Pentyn-l-ol 6 Inspection of Figures 1 and 2 demonstrates that both bis(rj 5 - cyclopentadienyl)titanium dichloride and bis(r| 5 -methylcyclopentadienyl) titanium dichloride give carbometalated products in good yields with a Me I al-Me tl O al Alkyne Activation M \ / O Carbometalation, al Carbometalation Me M Me h o r O O al al Terminal Terminal Internal Addtion Addtion Addtion (anti) (syn) H© Me Me H0^ (Z)-3-penten-1-ol (E)-3-penten-1-ol Me 3-methyl-3-buten-1 -ol Figure 3.