Arenechromium Tricarbonyl Complexes: Conformational

Home , Anisole, Chromium hexacarbonyl, Organochromium chemistry, Trimethylsilyl, Vicinal (chemistry)

η6 – ARENECHROMIUM TRICARBONYL COMPLEXES: CONFORMATIONAL

ANALYSIS, STEREOCONTROL IN NUCLEOPHILIC ADDITION AND

APPLICATIONS IN ORGANIC SYNTHESIS

HARINANDINI PARAMAHAMSAN

Submitted in partial fulfillment of the requirements for the degree of

Doctor of Philosophy

Thesis Advisor: Prof. Anthony J. Pearson

Department of Chemistry

CASE WESTERN RESERVE UNIVERSITY

May 2005 CASE WESTERN RESERVE UNIVERSITY

SCHOOL OF GRADUATE STUDIES

We hereby approve the dissertation of

Harinandini Paramahamsan candidate for the Ph.D. degree*.

(signed) Prof. Philip P. Garner (Chair of the Committee, Department of

Chemistry, CWRU)

Prof. Anthony J. Pearson (Department of Chemistry, CWRU)

Prof. Fred L. Urbach (Department of Chemistry, CWRU)

Dr. Zwong-Wu Guo (Department of Chemistry, CWRU)

Dr. Stuart J. Rowan (Department of Macromolecular Science and

Engineering, CWRU)

Date: 14th January 2005

*We also certify that written approval has been obtained for any propriety material contained therein.

To Amma, Naina & all my Teachers

Table of Contents

List of Tables………………………………………………………………………..……iv

List of Figures…………………………………………………………………….…...... vi

List of Schemes…………………………………………………………………….….….ix

List of Equations………………………………………………………...……….……….xi

Acknowledgements………………………………………………………….…..……….xii

List of Abbreviations……………………………………………………………………xiv

Abstract………………………………………………………………………………….xvi

CHAPTER I...... 1

I.1 Structure and Bonding ...... 2

I.2 General Methods of Preparation ...... 3

I.3 Reactivity and Chemistry...... 4

I.4 Illustrations of Applications in Organic Synthesis ...... 5

References………………………………………………………………………..10

CHAPTER II...... 14

II.1 Conformational Features of Arenechromium Tricarbonyl Complexes – General

and Background ...... 15

II.2 X-ray Crystal Structure Analysis of Chiral Alkoxyarenechromium Tricarbonyl

Complexes...... 24

II.3 Conformational Analysis of Chiral Arenechromium Tricarbonyl Complexes in

Solution: Correlation to Solid State Structure and Conformation ...... 29

i II.4 Variable Temperature NMR Studies ...... 48

II.5 Conclusions...... 51

Experimental………………...…………………………………………………...54

Appendix to Chapter II…………………………………………………………..73

References………………………………………………………………………117

CHAPTER III ...... 125

III.1 Conformational Analysis of Arene Chromium Tricarbonyl Complexes...... 126

III.2 13C NMR Chemical Shifts in Conformational Analysis...... 131

III.3 13C NMR Complexation Shifts, Conformation and Regioselectivity of

Nucleophilic Addition...... 135

III.4 CCS in Chiral Arene Chromium Tricarbonyl Complexes...... 140

III.5 Conclusions...... 142

References…………………………………………………………………...….144

CHAPTER IV ...... 151

IV.1 Nucleophilic Addition to Arene Chromium Tricarbonyl Complexes – General and

Background...... 152

IV.2 Camphor Derived Chiral Isoborneol Directed Nucleophilic Addition to

Arenechromium Tricarbonyl Complexes ...... 165

IV.3 Results and Discussion...... 177

IV.4 Efforts towards Synthesis of FK-506 sub-unit...... 184

ii IV.5 Conclusions...... 186

Experimental……………………………………………………..……………..188

References…………………………………………………………………..…..213

CHAPTER V ...... 224

V.1 Studies in Vicinal Stereocontrol in Nucleophilic Addition to Arenechromium

Tricarbonyl Complexes...... 225

V.2 Formal Synthesis of (±)Juvabione ...... 234

V.3 Miscellaneous Results During Stereocontrol Study ...... 234

V.4 Vicinal Stereocontrol and Asymmetry During Nucleophilic Addition ...... 236

V.5 Conclusions...... 239

Experimental…………………………………………………………...……….240

References…………………………………………………………..…………..253

APPENDIX……………………………………………………………………………..257

BIBLIOGRAPHY………………………………………………………………………324

iii List of Tables

Table II.1 Torsion Angles of Tripod Rotation for the Four Complexes II.1-II.4 ...... 27 Table II.2 Arene Carbon-carbon Bond Lengths from the Crystal Structures of Complexes II.1 – II.4 ...... 28 Table II.3 13C NMR Carbon Chemical Shifts at the Four Diastereotopic Arene Complexed Carbons with 13C NMR Chemical Shift Pattern and Correlation to Tripod Orientation (For explanation of A edge and B edge see Figure II.24) ...... 46

Table III.1 Θ–Values and Populations of conformation III.B (PB) in C6H5RCr(CO)3 at 33±5 ºC ...... 127 Table III.2 Complexation Shifts d1-d4 for Complexes III.1-III.6 (Cn and C’n represent the CCS of the arene and the corresponding complex respectively) ...... 136

Table III.3 Population Pmeta (%) Compared to Regioselectivity of Nucleophilic Addition. t Nucleophile: (a) – LiCH(Me)CO2Bu (b) LiC(OR)MeCN...... 138 Table III.4 ∆ Values for Complexes III.1 – III.6 ...... 138 Table IV.1 Regioselectivity on Nucleophilic Addition of Anions to (tert-Butylbenzene)-

Cr(CO)3 ...... 156 Table IV.2 Diastereoselectivity During Isobutyronitrile Anion Addition to Arenechromium Tricarbonyl Complexes with PIB-OH, MIB-OH and DOIB-OH Chiral Auxiliaries...... 166 Table IV.3 Chiral C2-substituted Isoborneols Prepared from D(+) Camphor and their Yields ...... 171 Table IV.4 Synthesis of Chiral Alkoxyarenechromium Tricarbonyl Complexes IV.12 by

SNAr Reaction of Complex IV.11...... 174 Table IV.5 Ratio of Diastereoselectivity on Nucleophilic Addition to Chiral Arenechromium Tricarbonyl Complexes (* Major isomer presumed)...... 178 Table IV.6 13C NMR Chemical Shifts Correlated (*Tripod orientation from X-ray crystal structures #Major isomer on tert-butyl lithio acetate addition)...... 187 Table V.1 Ratio of Regio- and Stereoisomeric Cyclohexadienol Ether Products from Addition of tert-Butyl Lithiopropionate to Anisole Chromium Tricarbonyl Complexes V.1- V.3 ...... 227

iv Table V.2 Ratio of Regio- and Stereoselectivity in Propionitrile Anion Addition to Complexes V.1 – V.3...... 231

v List of Figures

Figure I.1 Metal-Carbonyl Bonding ...... 2 6 Figure I.2 Molecular orbital interaction diagram of η -benzene-Cr(CO)3 complex. Reprinted with permission from (Albright, T. A.; Carpenter, B. K. Inorg. Chem. 1980, 19, 3092-3097) Copyright (1980) American Chemical Society...... 3

Figure I.3 Change in Arene Reactivity on Coordination with Cr(CO)3 and Planar Chirality ...... 4 Figure II.1 Conformations anti-Eclipsed and syn-Eclipsed Due to Electronic Effect of Substituents...... 16 Figure II.2 Illustration of Conformational Change Due to Steric Effect of Arene Substituent...... 17 Figure II.3 Classic Illustration of Steric Complementarity in Arenechromium Tricarbonyls ...... 17

Figure II.4 Resolving a Misunderstanding in Orientation of the Cr(CO)3 Tripod...... 18

Figure II.5 CO- πarene interaction...... 19 Figure II.6 Examples of Tripod Orientation Angles for a Variety of Arene Substituents 19 Figure II.7 Relative Energies of Tripod Conformations by EHT Calculations ...... 20 Figure II.8 Illustration of Kinetically and Thermodynamically Restricted Rotation...... 21 Figure II.9 X-ray Crystal Structure of Complex II.1 (Complex prepared by Dr. James D. Dudones and X-ray Structure Determined by Dr. Alan Pinkerton et al)...... 25 Figure II.10 X-ray Crystal Structure of Complex II.2 (X-ray Structure Determined by Dr. Alan Pinkerton et al)...... 25 Figure II.11 X-ray Crystal Structure of Complex II.3(a) and II.3(b) (X-ray Structure Determined by Dr. Alan Pinkerton et al)...... 26 Figure II.12 X-ray Crystal Structure of Complex II.4 ...... 26 Figure II.13 Possible Conformations for Chiral Alkoxyarene Complexes...... 29 Figure II.14 Double-bond Complexed to Chromium (0) Compounds ...... 32 Figure II.15 Two Reactants Exercising their Inherent Topological Selectivity ...... 33 Figure II.16 Difference in Energy of the cis-endo and trans-endo Conformers of Complex II.5 by MM2 Calculations...... 34

vi Figure II.17 Double Bond Character Induced by π-acceptance and π-donation of the Substituents...... 35 Figure II.18 Complexes Whose NOEs at Room Temperature Were Studied...... 36 1 Figure II.19 H NMR Spectrum of Complex II.13 (600 MHz, THF-d8)...... 37 Figure II.20 NOE Signal Enhancements Shown for Two Irradiations in Complex II.13. 40 Figure II.21 Two Diastereotopic A and B Edge Faces of the Complex ...... 43 Figure II.22 1H-13C HMQC Spectra of Complex II.13 Expanded Showing the Arene Complex Region ...... 44 Figure II.23 1H-1H COSY Spectrum of Complex II.13 Expanded Showing the Arene Complex Region ...... 45 Figure II.24 Final Assignment of CCS For the Arene Carbons of Complex II.13...... 45 Figure II.25 Plot of Variation of 1H Chemical Shift of Arene Protons of Complex PIB-

TMS II.1 in THF-d8 Solution with Temperature (Series 1- δH1, Series 2- δH2, Series 3-

δH4, Series 4- δH3)...... 49 Figure II.26 Plot of 13C Chemical Shift of Diastereomeric Arene Carbons of Complex

II.16 in THF-d8 Solution (Series 1- δC1, Series 2- δC2, Series 3- δC3, Series 4- δC4) ..... 50 Figure III.1 Anti- and syn-eclipsed conformers III.A and III.B...... 126 Figure III.2 Anisotropic Shielding Cones for Common Organic Bonds ...... 132 Figure III.3 Proposed Anisotropy of the Chromium-Carbonyl Bond on the Arene ...... 133 Figure III.4 Shielding and Deshielding of Arene Nuclei Due to Anisotropy of the

Cr(CO)3 Tripod ...... 133 Figure III.5 Superposition of the Three Donor and Acceptor Orbitals Based on the Electronic Property of the Substituent Inducing Further Charge Distribution and Polarization ...... 134 Figure III.6 Tripod Orientation and 13C Chemical Shift Pattern in Chiral Arene Complexes...... 141 Figure III.7 Unexplainable Shielding in Chiral Arene Chromium Tricarbonyl Complexes ...... 141 Figure IV.1 Four Possible Cyclohexadienyl Anion Intermediate for Nucleophilic Addition to a Mono-Substituted Arenechromium Tricarbonyl Complex...... 155

Figure IV.2 Polarization of the Arene due to Conformation of the Cr(CO)3 ...... 158

vii Figure IV.3 Representation of the Arene HOMO and LUMO Coefficients...... 159 Figure IV.4 Chiral Auxiliaries Proposed for the Study ...... 169 Figure IV.5 Illustrative Example of Determination of Ratio of Diastereoselectivity of Diastereomeric Cyclohexadienol Ether Mixture ...... 175 Figure IV.6 CD Spectrum of Major R isomer of IV.19...... 176 Figure IV.7 CD Spectrum of Major S isomer of IV.19 ...... 177 Figure IV.8 Conformation of the Tripod in Solid State and Major Isomer on Nucleophilic Addition ...... 180 Figure IV.9 13C NMR Carbon Chemical Shifts at the meta Carbons of the Seven Arene Complexes with Corresponding Major Isomer on Nucleophilic Addition...... 181 Figure IV.10 Plot of Ratio of Diastereoselectivity on Nucleophilic Addition to Sum of 13 C NMR Chemical Shift (CDCl3) Difference at the meta Arene Carbons and ortho Arene Carbons ...... 182 Figure IV.11 Plot of Ratio of Diastereoselectivity on Nucleophilic Addition to Sum of 13 C NMR Chemical Shift (CDCl3) Difference at the meta Arene Carbons...... 183 Figure IV.12 Approach Towards Synthesis of FK-506 Sub-unit ...... 184 Figure V.1 Examples of Natural Products with Vicinal Stereocenters Involving Ring Position ...... 225 Figure V.2 Possible Open Transition States of the Intermediate (The π cloud and the Complexed Chromium Tricarbonyl on the Top Face are Omitted for Clarity)...... 232 Figure V.3 Calculated Molecular Mechanics Strain Energy of the Possible erythro and threo η5-Cyclohexadienyl Tricarbonyl Chromium Conformers on tert-Butyl Lithiopropionate and Lithiopropionitrile Anion Addition. (The Complexed Chromium Tricarbonyl on the Bottom Face is Omitted for Clarity) ...... 233

viii List of Schemes

Scheme I.1 Illustration of natural product synthesis utilizing activation at the benzylic position and the arene ring...... 6 Scheme I.2 Illustration of application in the asymmetric synthesis of axially chiral (-)- steganone and vancomycin A-B ring system...... 6 Scheme I.3 Carbocycles from dearomatization of arene chromium tricarbonyl complexes applied in the synthesis of (±)-acorenone, (+)-ptilocaulin and (-)-acetoxytubipofuran...... 7 Scheme II.1 Unexpected Modification of C=C bond in vinyl Isobornyloxyarene Chromium Tricarbonyl Complex II.5...... 31 Scheme II.2 Nucleophilic Addition Followed by Protonation and Decomplexation of Simple Allyloxyarene ChromiumTricarbonyl Complexes II.9 and II.10...... 32 Scheme IV.1 Nucleophilic Addition to Arenechromium Tricarbonyl Complexes...... 153 Scheme IV.2 Steps in Dearomatization by Nucleophilic Addition Protonation Sequence to the Arenechromium Tricarbonyl Complex...... 154 Scheme IV.3 Conversion of Anisolechromium Tricarbonyl to 5-Substituted Cyclohexenones ...... 159 Scheme IV.4 Formal Synthesis of (+)-Juvabione by Chiral Evans Enolate Addition to Arenemanganese Complex ...... 160 Scheme IV.5 Planar Chiral Arene Chromium Tricarbonyl Complexes – Illustration of Synthesis, Resolution and Application in Organic Synthesis...... 161 Scheme IV.6 Asymmetric Nucleophilic Addition/Protonation Sequence Using Chiral Phosphine and Phosphite Ligands ...... 162 Scheme IV.7 Chiral Oxazolines and SAMP-Hydrazones in Nucleophilic Addition to Arenechromium Tricarbonyl Complexes ...... 163 Scheme IV.8 Enantio-enriched Cyclohexenes from Chiral Pentaammineosmium(II) Anisole Derivatives...... 164 Scheme IV.9 Semmelhack’s Menthol Derived Chiral Auxiliaries in Asymmetric Nucleophilic Addition and Proposed Origin of Diastereoselection...... 165 Scheme IV.10 Reaction Scheme for the Proposed Study...... 170 Scheme IV.11 Preparation of DOIB-OH IV.6c Chiral Auxiliary from D(+)-Camphor. 172

ix Scheme IV.12 Preparation of Starting Fluoroarene Complex IV.11 by Method A and Method B ...... 173 Scheme IV.13 Determination of the Stereochemistry of Addition from Cyclohexenone IV.19 ...... 176

Scheme IV.14 Reversal in Selectivity in MIB Chiral Auxiliary with –Si(CH3)3 para Substituent...... 179 Scheme IV.15 Diastereoselective Nucleophilic Addition to Arenemanganese Tricarbonyl Complexes...... 183 Scheme IV.16 Lithio Methylphenylsulfone Addition to Complex IV.24 ...... 185 Scheme IV.17 Chiral Auxiliary Directed Methylphenylsulfone Anion Addition – Asymmetric Approach Towards FK-506 Sub-unit...... 186 Scheme V.1 Use of Prochiral Nucleophile in Nucleophilic Addition Generating Vicinal Stereocenters...... 226 Scheme V.2 Nucleophilic Addition and Protonation-Decomplexation/Oxidation Sequence for Complexes V.1-V.3 ...... 227 Scheme V.3 Determination of the Major Stereoisomer from Complex V.3 on tert-Butyl Lithiopropionate Addition ...... 230 Scheme V.4 Determination of the Major Stereoisomer from Complex V.3 on Propionitrile Anion Addition ...... 231 Scheme V.5 Synthesis of Intermediate V.14 in a Formal Synthesis of (±)-Juvabione... 234 Scheme V.6 One Step Reduction of the Enone Double Bond and Ketalization of the Carbonyl in V.10...... 235 Scheme V.7 Chiral Auxiliary Directed Nucleophilic Addition of tert-Butyl Lithiopropionate to Complex V.24 and V.25 ...... 237 Scheme V.8 Unsuccessful Evans enolate Addition to Arenechromium Tricarbonyl Complex V.3...... 239

x List of Equations

Equation I.1 General Equation Representing the Nucleophilic Addition Reaction Studied ...... 8

Equation III.1 Empirical Equation for Calculation of Pmeta...... 137 Equation IV.1 Preparation of Chiral 2-isoborneols from D(+) Camphor...... 171 Equation V.1 Self-Nucleophilic Addition in the Absence of Carbon Nucleophile ...... 235 Equation V.2 Proposed Chiral Evans Enolate Addition to Complex V.3 ...... 238 Equation V.3 Preparation of N-acylated Oxazolidinone – Symmetrical Anhydride Method ...... 238

xi Acknowledgement

My thanks are foremost due to my advisor Prof. Anthony J. Pearson for his patient guidance, support and encouragement during these years and for providing a congenial atmosphere of learning. There is more education I received than I can articulate here which is due to him. I thank my Masters advisor Prof. K. K. Balasubramaniam for his continued encouragement during my doctorate work and being a source of inspiration.

I thank Dr. James D. Dudones for guiding me with experimental arenechromium chemistry as I started work afresh in the lab. My thanks are due to Dr. Namasivayam

Palani from whom I learnt my basic experimental skills.

I thank Dr. Alan Pinkerton, University of Toledo for performing the key X-ray crystal structures used in the work. My sincere thanks are due to Dr. Dale Ray for his kind and patient assistance with the NMR experiments. I thank Dr. James Faulk for the mass spectral measurements, John Hays, Chuck, Victor Morasanu and Carolyn

Simmonds for their assistance. I thank Dr. Michael Zagorski, Dr. Rekha Srinivasan and

Mihaela Apetri for help with the CD spectrometer measurements and Dr. Suman

Chakravarthy for useful discussions about theoretical calculations. I thank Prof. Philip P.

Garner, Prof. Fred L. Urbach, Dr. Zwong-Wu Guo and Dr. Stuart J. Rowan for their time serving in my graduate committee.

My heartfelt thanks are due to previous graduate students in our lab, Dr. Seema

Katiyar, Dr. Eugene F. Mesaros, Dr. Jin Bum Kim, Dr. Sheng Cui, Dr. Xiaolong Wang,

xii Dr. Jiunn-Jye Hwang, Dr. Wenjing Xiao, Dr. Ismet Dorange, Dr. Sarunas Zigmantus, Dr.

Victor P. Ghidu and the present members, Dr. Avdhoot Velankar, Brian Servé,

Yoonhyun Kwak, Diana V. Ciurea, Shubhamita Basu, Jimmy Zhang, Penny Neisen

Roufs, Huikai Sun and Yan Zhou for sharing their knowledge and for their support and help. I am indebted to fellow graduate student Kutralanathan Ranganathan for recovering

the data files from my crashed computer’s hard disk in the final year, saving months of work. My thanks are also due to Pat Eland, Prof. John Stuehr, Mary Eileen Fogarty and

Zedeara Diaz for their care and support.

I profusely thank the Department of Chemistry and Case Western Reserve

University for giving me an opportunity for doctoral work and the National Institute of

Health for funding.

My thanks are due to Vidhya Chakrapani, Amita C. Patil, Sunita Warrier, Aruna

N. Tata, Dr. Sukhvarsha Mehra and Gayathri Krishnamoorthy, my roommates over the

years and all my friends in Cleveland who have been my family away from home; friends

in other geographical locations who were part of my life; my brother Hari and my

extended family of grandmothers, uncles, aunts, brothers and sisters. I thank them all,

without whose unflagging love, support and prayers, I would not have accomplished

much. Most of all I thank my parents Samyuktha and Paramahamsan, who have stood by

me always whatever I did and whatever I am, I owe it to them.

xiii List of Abbreviations

T [α]D Specific Rotation at Temperature T (K) AIB Anisyl isoborneol BIB benzyl isoborneol BINOL 2,2'-Dihydroxy-1,1'-dinaphthyl BNIB β-naphthyl isoborneol BPIB biphenyl isoborneol CCS 13C NMR Chemical Shift CD Circular Dichroism (spectroscopy) CHIB cyclohexyl isoborneol COSY Correlation Spectroscopy CPMAS Cross Polarized Magic Angle Spinning d doublet dd doublet of a doublet de diastereomeric excess DMAP dimethyl amino pyridine DMF dimethyl formamide DOIB Spiro[(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptane-3,2’-[1,3]dioxolan]-2- ol ee enantiomeric excess EHT Extended Hückel Theory EI HRMS electron impact high resolution mass spectrometry EIB ethyl isoborneol FAB HRMS Fast atom bombardment high resolution mass spectrometry FTIR Fourier transform infra-red (spectroscopy) GC gas chromatography GC-MS gas chromatography HMPA Hexa methyldiphosphoramide HMQC Hetero Molecular Quantum Correlation (spectroscopy) HOMO Highest Occupied Molecular Orbital

xiv HSQC Hetero Quantum Correlation (spectroscopy) IPIB isopropyl isoborneol IPRIB isopropenyl isoborneol LDA lithium di-isopropyl amine LUMO Lowest Unoccupied Molecular Orbital m multiplet Me methyl MIB methyl isoborneol MM2 Molecular Mechanics MO Molecular Orbital NIB α-naphthyl isoborneol NMR Nuclear Magnetic Spectroscopy NOE Nuclear Overhauser Effect ORTEP Oak Ridge Thermal Ellipsoid Plot PIB phenyl isoborneol ppm parts per million q Quadruplet r.t. room temperature

Rf Retention factor t triplet Tert tertiary THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilane (NMR standard) or trimethylsilyl (substituent) TS transition state UV ultra violet (light) V/V volume ratio VIIB vinyl isoborneol XIB xylyl isoborneol

xv η6 – ARENECHROMIUM TRICARBONYL COMPLEXES: CONFORMATIONAL

ANALYSIS, STEREOCONTROL IN NUCLEOPHILIC ADDITION AND

APPLICATIONS IN ORGANIC SYNTHESIS

Abstract

HARINANDINI PARAMAHAMSAN

Dearomatization of arenechromium tricarbonyl complexes provides a mild and rapid entry into functionalized carbocycles. Chiral auxiliary directed nucleophilic addition provides synthetically useful enantio enriched substituted cyclohexenones. The present studies were aimed at understanding the origin of diastereoselection and develop systems giving both enantiomers. Chiral auxiliaries derived from camphor attached to arenes with trimethylsilyl group as the para substituent gave both enantiomers in very high diastereoselectivity with lithio tert-butyl acetate nucleophile. The chiral auxiliaries are retrievable in most of the cases. The origin of diastereoselectivity is proposed to be due to charge control as reflected in the orientation of the Cr(CO)3 tripod with respect to

the chiral auxiliary.

H OR* OR* OR* O H O O O t-BuO t-BuO (OC)3Cr protonation/decomplexation Si(CH Si(CH ) Si(CH3)3 3 3 3 )3 R* = -NIB (1:31 (R major isomer)) -PIB (21:1 (S major isomer))

xvi The chiral auxiliary directed lithio methyl phenyl sulphone addition was performed in an effort to asymmetrically synthesize, the cyclohexyl sub-unit of the

immunosuppressant FK-506. Preliminary results indicate a moderate diastereoselectivity

with the lithio methyl phenyl sulphone nucleophile.

X-ray crystal structure analysis and conformational analysis of the chiral

arenechromium tricarbonyl complexes by NOE studies revealed a cis-endo conformation

of the Cr(CO)3 tripod with respect to the camphyl framework. A possible preference of

tripod orientation in solution was also proposed from the 13C NMR chemical shifts. In

this context, conformational analysis of the chromium tricarbonyl tripod rotamers was

thoroughly reinvestigated and the proposition that 13C NMR chemical shifts of the arene

manifesting its electron charge densities is presented.

Addition of the pro-chiral nucleophiles to arenechromium tricarbonyl complexes

was performed to study the vicinal stereocontrol during nucleophilic addition. The

excellent erythro vicinal stereocontrol obtained on lithio tert-butyl propionate addition to

para trimethylsilylanisolechromium tricarbonyl has been applied to a racemic formal

synthesis of the sex pheromone Juvabione.

OCH3 OCH3 O O nucleophilic addition O Cr(CO)3 protonation & O decomplexation H OH TMS TMS H > 99:1 erythro Juvabione intermediate

xvii

CHAPTER I

Introduction to Arenechromium Tricarbonyl Chemistry

1 6 Arene chromium tricarbonyl complexes (η -arene-Cr(CO)3) belong to a class of

polyene(ML3) compounds with interesting and fascinating reactivity. Like many other

classes of organometallic compounds, their chemistry has proven to be useful in asymmetric synthesis,1 in catalysis as chiral ligands2 and as catalysts3 themselves. The

application of transition metal arene π-complexes in organic synthesis and catalysis has

recently been reviewed.4 An introduction to bonding, preparation, reactivity, chemistry

and an illustration of applications in organic synthesis will be briefly enumerated in this

chapter.

I.1 Structure and Bonding

6 In η -arene-Cr(CO)3 complexes, the zero-valent chromium atom is coordinatively

bonded to three CO ligands by a metal-carbonyl bond. (Figure I.1).

lone pair on carbonyl carbon

Cr C = O

filled chromium empty CO p* orbital d orbital

Figure I.1 Metal-Carbonyl Bonding

This is characterized by delocalization of the lone pair of electrons on the

carbonyl to the metal by a σ bond and by back-bonding constituting electron delocalization from chromium to the vacant anti-bonding orbital of the carbonyl ligand.5

The structures of these complexes are often compared to that of ‘a piano stool’ with the arene regarded as the seat and the three chromium carbonyl bonds as the legs. The η6-

2 arene provides the six other electrons that are needed for d6 chromium to satisfy the 18

6 electron rule. The molecular orbital interaction diagram for (benzene)Cr(CO)3 is shown in Figure I.2.

6 Figure I.2 Molecular orbital interaction diagram of η -benzene-Cr(CO)3 complex. Reprinted with permission from (Albright, T. A.; Carpenter, B. K. Inorg. Chem. 1980, 19, 3092-3097) Copyright (1980) American Chemical Society.

I.2 General Methods of Preparation

Among the numerous available methods,7 there are two that are most commonly used for the preparation of arene-Cr(CO)3 complexes. One is the convenient and general

Mahaffy and Pauson procedure,8 which involves thermal reaction of chromium

3 hexacarbonyl with the corresponding arene in di-n-butyl ether and THF solvent mixture.

There are a variety of solvent systems which can be used. The second method is the arene

exchange reaction of labile arene complexes by heating in a sealed tube with ether-THF

mixture.9

I.3 Reactivity and Chemistry

Much of the reactivity associated with these complexes is due to the dramatic

change in properties of the arene on complexation (Figure I.3).

Reduced electron density - Enhanced nucleophilic attack Stabilized anion Facilitated oxidative and cation X H addition of Pd(0) HX X X X Enhanced HHH H solvolysis Y H Enhanced acidity HCC HYCr Cr Enhanced OC CO OC CO Cr H H OC CO OC CO acidity OC Planar chirality - non-superimposable mirror images Steric effect - Effective shielding of the complexed face

Figure I.3 Change in Arene Reactivity on Coordination with Cr(CO)3 and Planar Chirality

The electron accepting nature of the Cr(CO)3 group decreases the electron density

on the arene, making not only the ring, but also the benzylic and homo-benzylic positions

more prone to nucleophilic attack. The ring and benzylic protons also show enhanced acidity. Solvolysis at the benzylic and homo-benzylic positions is also enhanced compared to the uncomplexed arene due to neighboring group participation by Cr(CO)3.

The other important effect of the Cr(CO)3 is its steric effect, shielding one face of the arene, which forces nucleophiles to add on the arene face opposite to that of Cr(CO)3

4 complexation. Stereochemically, planar chirality arises from the facial differentiation by

Cr(CO)3 in 1,2-disubstituted and 1,3-disubstituted arenes.

More than any other reaction, nucleophilic additions to η6-arene complexes have been extensively studied and have provided insights into the reactivity of the complexes.10 Depending on the nature of the workup following the nucleophilic attack,

the arene yields either dearomatized addition product or a substituted arene. Nucleophiles

add to the arene, consistent with the MO structure of the complexes, where the LUMO is

concentrated more on the arene than on the Cr(CO)3. Electrophiles adding to the arene

are thought to add, first to the chromium due to the HOMO (1e+π*) being concentrated

on the Cr(CO)3. A more detailed background on nucleophilic addition to these complexes, which is the focus of this work, is presented in Chapter IV. The arene

complexes also undergo electrophilic substitution by Friedel-Crafts acylation though

slower than the arenes themselves.11 Due to activation of the benzylic and homo-benzylic

centers on complexation, the arene-Cr(CO)3 complexes undergo carbo-cyclization,

diastereoselective radical cyclization,12 cycloaddition and cross-coupling reactions.13

I.4 Illustrations of Applications in Organic Synthesis

Arene-Cr(CO)3 complexes have found numerous applications in organic

synthesis14 and have been used in the synthesis of sesquiterpenes, diterpenes, alkaloids

and some important axially chiral compounds. Much of their utility in synthesis is due to

increased reactivity of the arene and at the benzylic position and also due to planar

chirality.

5 O OCONH2 OH H2N OCH H 3 Mitomycin C N NNH OH N H3C O O

TMS TMS N OTMS cycloaddition Br NR N MeO + Alkaloid MeO Cr(CO) MeO OMe 3 Cr(CO)3 (-)-lasubine(I) OMe OMe OMe H OMe i) sec-BuLi, H (OC)3Cr OMe i) BuLi, O OMe THF Cr(CO)3 TMSCl OMe ii) BuLi, O OMe ii) a, -65 °C TMS MeI (OC)3Cr OMe TMS OTf a = Diterpene Helioporin D

Scheme I.1 Illustration of natural product synthesis utilizing activation at the benzylic position and the arene ring

Br O O MeO O O OH

MeO Cr(CO) cat. Pd(PPh ) CHO 3 O 3 4 MeO O OMe Na CO , MeOH, MeO O + O 2 3 OH H2O MeO MeO O OHC OMe OMe B(OH) 2 (dr >99%) (-) - steganone H H Boc N COOMe

OHC Br BnO Cr(CO)3 OMe OHC Br MeO N3 OMe OMe Cr(CO)3 OMe MeO MeO

Cr(CO)3 Intermediate for vancomycin A-B ring system

Scheme I.2 Illustration of application in the asymmetric synthesis of axially chiral (-)-steganone and vancomycin A-B ring system

An illustration of applications in synthesis of the natural products mitomycin C15,

(-)-lasubine(I)16 and helioporin D17 that utilize the reactivity of the arene is shown in

6 Scheme I.1. One of the key steps involved in these syntheses is obtaining enantiomerically pure starting arene chromium complex either by resolution or diastereoselective preparation. Planar chirality18 in the arene complexes has been utilized

asymmetric synthesis of (-) -steganone19 and a subunit of the vancomycin A-B ring

system20 (Scheme I.2).

Dearomatization of the η6-arene, though a synthetically useful reaction in building

multi-functionalized carbocycle building blocks, has so far been applied to the synthesis

of only three natural products ((+)-ptilocaulin,21 racemic acorenone22 and (-)-

acetoxytubipofuran23) Scheme I.3).

O NC O OMe CN dearomatization Sesquiterpene rac acorenone

(OC)3Cr rac

NH2 NO3 OMe Enantioselective OMe HN NH TMS H protonation/silylation Me Cr(CO)3 Cr(CO)3 Alkaloid (+)-ptilocaulin H i) Li OEt CHO AcO Ph Ph H OEt H N MeO OMe O ii) MeI, CO, THF/HMPA O Cr(CO)3 iii) NaOEt (2M), MeI, rt (+)-(5R,6S) (-)- acetoxytubipofuran 42%, 76% ee

Scheme I.3 Carbocycles from dearomatization of arene chromium tricarbonyl complexes applied in the synthesis of (±)-acorenone, (+)-ptilocaulin and (-)-acetoxytubipofuran

In the same context it is worth mentioning that dearomatization of η2-arene

complexes of osmium, to give cyclohexadiene and cyclohexenone derivatives, is also an

7 emerging area of research.24 Though the first η6-arene chromium complexes were discovered as early at 195725 and in the past decade or so the chemistry has been further explored to allow their use as intermediates in organic synthesis, more understanding26 needs to be gained on the chemistry of these complexes.

This document presents our investigations in understanding chiral arene chromium tricarbonyl complexes, their selectivity in reacting with nucleophiles in particular and their potential application in organic synthesis. Our group has been interested in understanding the origin of diastereoselectivity in nucleophilic additions to chiral alkoxyarene chromium tricarbonyls27 (The chiral group is a camphor derived isoborneol) (Equation I.1).

i) LDA, THF, t-butyl acetate -78 °C O O O ii) HMPA, 2h, -60 °C Cr(CO)3 O R iii) CF3COOH, -60 °C, 0.5h Si iv) NH4OH, rt, 0.5h R Si R = alkyl or aryl substituent

Equation I.1 General Equation Representing the Nucleophilic Addition Reaction Studied

A conformational study of these chiral arene chromium tricarbonyls was performed to determine if there are any conformational preferences in solution. In an effort to understand the complexation shifts in the NMR spectra of the chiral complexes, a thorough study of the NMR analysis of the tripod orientation with respect to substituents on the arene was performed (Chapter II). This study revealed grey areas raising dispute and arguments for a new understanding of complexation shifts in NMR of these complexes which will be documented in Chapter III. This thesis also presents a

8 study of vicinal stereocontrol that is possible when a pro-chiral enolate nucleophile is used. In addition in Chapter IV, I have attempted to develop an understanding of the stereodirecting effects of a chiral ether substituent during asymmetric nucleophile additions to alkoxyarene-Cr(CO)3 complexes. An application of this chemistry is a formal synthesis of the natural product juvabione that is detailed in Chapter V. A more detailed introduction is presented for each chapter that is directly relevant to the subject matter of that chapter.

9 References

1 (a) Semmelhack, M. F. “Organoiron and Organochromium Chemistry” In

Organometallics in Synthesis: A Manual. Schlosser, M. Ed.; Wiley: Chichester, West

Sussex, England; New York, 2002, pp 1081-1121. (b) Hegedus, L. S. Transition Metals

in the Synthesis of Complex Organic Molecules; University Science Books: Mill Valley,

California, 1994, pp 307-333.

2 (a) Muniz, K. “Planar chiral arene chromium(0) complexes as ligands for asymmetric

catalysis.” Top. Organomet. Chem. 2004, 7, 205-224. (b) Gibson, S. E.; Ibrahim, H.

“Asymmetric catalysis using planar chiral arene chromium complexes.” Chem. Commun.

2002, 2465-2473. (c) Koide, H.; Uemura, M. “Synthesis of axially chiral benzamides

utilizing tricarbonyl(arene)chromium complexes.” Chirality 2000, 12, 352-359.

3 Rigby, J. H.; Kondratenko, M. A. “Arene complexes as catalysts.” Top. Organomet.

Chem. 2004, 7, 181-204.

4 Kündig, E. P.; Editor Transition Metal Arene π-Complexes in Organic Synthesis and

Catalysis. [In: Top. Organomet. Chem.; 2004, 7], 2004.

5 Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principles and Applications of Organotransition Metal Chemistry, University Science Books: Mill Valley, California,

1987.

6 Albright, T. A.; Carpenter, B. K. “Conformational effects of nucleophilic and

electrophilic attack on (arene)chromium tricarbonyl complexes.” Inorg. Chem. 1980, 19,

3092-3097.

7 Kündig, E. P. “Synthesis of transition metal η6-arene complexes.” Top. Organomet.

Chem. 2004, 7, 3-20.

8 Mahaffy, C. A. L.; Pauson, P. L. “(η6-Arene)tricarbonylchromium complexes.” Inorg.

Syn. 1979, 19, 154-158.

9 Kündig, E. P.; Perret, C.; Spichiger, S.; Bernardinelli, G. “Naphthalene complexes. V.

Arene exchange reactions in naphthalenechromium complexes.” J. Organomet. Chem.

1985, 286, 183-200.

10 (a) Semmelhack, M. F. “Nucleophilic addition to arene-metal complexes.” In

Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,

1991; Vol. 4, 517-549. (b) Morris, M. J. In Comprehensive Organometallic Chemistry II;

Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995, Vol. 5, 471-

549. (c) Semmelhack, M. F. “Transition metal arene complexes: Nucleophilic addition.”

In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson,

G., Eds.; Pergamon: Oxford, 1995; Vol. 12, 979-1016.

11 Von Rosenberg, J. L.; Pinder, A. R. “Electrophilic substitution in

(arene)tricarbonylchromium complexes. Part 1.” J. Chem. Soc., Perkin Trans. 1 1987,

747-752.

12 Merlic, C. A.; Walsh, J. C. “Completely diastereoselective radical reactions using

arenechromium tricarbonyl complexes.” Tetrahedron Lett. 1998, 39, 2083-2086.

13 Uemura, M. “(Arene)Cr(CO)3 complexes: Cyclization-, cycloaddition- and cross-

coupling-reactions.” Top. Organomet. Chem. 2004, 7, 129-156.

14 Schmalz, H.-G.; Gotov, B.; Boettcher, A. “Natural products synthesis.” Top.

Organomet. Chem. 2004, 7, 157-179.

15 Jones, G. B.; Guzel, M.; Mathews, J. E. “Stereoselective route to mitosanes via

tricarbonyl η6 arene chromium complexes.” Tetrahedron Lett. 2000, 41, 1123-1126.

16 Ratni, H.; Kündig, E. P. “Synthesis of (-)-lasubine(I) via a planar chiral [(η6-

arene)Cr(CO)3] complex.” Org. Lett. 1999, 1, 1997-1999.

17 (a) Geller, T.; Schmalz, H.-G.; Bats, J. W. “Chiral arene-Cr(CO)3 complexes in organic

synthesis: a short enantioselective total synthesis of putative helioporin D.” Tetrahedron

Lett. 1998, 39, 1537-1540. (b) Geller, T.; Jakupovic, J.; Schmalz, H.-G. “Preparation of

helioporin D from the seco-pseudopterosin aglycon: revision of the stereostructure of

helioporin D.” Tetrahedron Lett. 1998, 39, 1541-1544.

18 For more recent example, Polunin, K. E.; Schmalz, H. G. “Application of chromium-

arene complexes in the organic synthesis. Efficient synthesis of stilbene phytoalexins.”

Russ. J. Coord. Chem. (Translation of Koordinatsionnaya Khimiya) 2004, 30, 252-261.

19 (a) Uemura, M.; Daimon, A.; Hayashi, Y. “An asymmetric synthesis of an axially

chiral biaryl via an (arene)chromium complex: formal synthesis of (-)-steganone.” J.

Chem. Soc., Chem. Commun. 1995, 1943-1944. (b) Kamikawa, K.; Watanabe, T.;

Daimon, A.; Uemura, M. “Stereoselective synthesis of axially chiral natural products, (-)-

Steganone and O,O'-Dimethylkorupensamine A, utilizing planar chiral (arene)chromium

complexes.” Tetrahedron 2000, 56, 2325-2337.

20 Kamikawa, K.; Tachibana, A.; Sugimoto, S.; Uemura, M. “Stereoselective synthesis of

the axially chiral A-B ring system of vancomycin utilizing a planar chiral arene

chromium complex.” Org. Lett. 2001, 3, 2033-2036.

21 6 Schellhaas, K.; Schmalz, H.-G.; Bats, J. W. “Chiral [η -arene-Cr(CO)3] complexes as

synthetic building blocks: a short enantioselective total synthesis of (+)-ptilocaulin.”

Chem. - Eur. J. 1998, 4, 57-66.

22 Semmelhack, M. F.; Yamashita, A. “Arene-metal complexes in organic synthesis: synthesis of acorenone and acorenone B.” J. Am. Chem. Soc. 1980, 102, 5924-5926.

23 Kündig, E. P.; Cannas, R.; Laxmisha, M.; Liu, R.; Tchertchian, S. “Chromium-

mediated asymmetric synthesis of both enantiomers of acetoxytubipofuran.” J. Am.

Chem. Soc. 2003, 125, 5642-5643.

24 Harman, W. D. “The dearomatization of arenes by dihapto-coordination.” Top.

Organomet. Chem. 2004, 7, 95-127.

25 Fischer E. O.; Öfele, K. “Aromatic complexes of metals. XIII.

Benzenechromiumtricarbonyl.” Chem. Ber. 1957, 90, 2532-2535.

26 (a) Merlic, C. A.; Walsh, J. C.; Tantillo, D. J.; Houk, K. N. “Chemical

Hermaphroditism: The potential of the Cr(CO)3 moiety to stabilize transition states and intermediates with anionic, cationic, or radical character at the benzylic position.” J. Am.

Chem. Soc. 1999, 121, 3596-3606. (b) Merlic, C. A.; Zechman, A. L.; Miller, M. M.

“Reactivity of (η6-Arene)tricarbonylchromium complexes with carbenoids: Arene

activation or protection?” J. Am. Chem. Soc. 2001, 123, 11101-11102.

27 (a) Pearson, A. J.; Gontcharov, A. V. “Asymmetric conversion of arenechromium

complexes to functionalized cyclohexenones: Progress toward defining an optimum

chiral auxiliary.” J. Org. Chem. 1998, 63, 152-162. (b) Dudones, J. D.; Pearson, A. J.

“The first examples of ester enolate addition across a chiral (alkoxybenzene)-chromium

complex π-bond with a remarkable degree of 1,5-asymmetric induction.” Tetrahedron

Lett. 2000, 41, 8037-8040.

CHAPTER II

Confirming Conformational Preference and Deriving Tripod Orientation in Chiral

Alkoxy Arene Chromium Tricarbonyl Complexes

14 II.1 Conformational Features of Arenechromium Tricarbonyl Complexes –

General and Background

The conformation of the Cr(CO)3 tripod with respect to the substituents on the arene is a key feature in the chemistry of arene chromium tricarbonyls as regioselectivity of nucleophilic addition and electrophilic addition is known to depend on it. An understanding of the factors influencing the tripod orientation1 and knowledge of barriers to rotation2 would help us appreciate the interesting chemistry of these complexes.3

II.1.1 Factors Influencing Tripod Orientation

The following three factors influence the tripod orientation in solid state and solution.

a) Electronic effect of arene substituents

b) Steric effect of arene substituents and steric complementarity

between the Cr(CO)3 tripod and arene substituents

c) π- carbonyl stabilizing interaction

a) Electronic effect of arene substituents: In the absence of steric effects, the Cr-CO bond vector eclipses the arene carbon-substituent bond (syn-eclipsed) in the case of an electron donating substituent. In the case of electron accepting substituent, the Cr-CO bond vector eclipses the arene carbon para to the carbon (anti-eclipsed or staggered) to which the substituent is attached (Figure II.1). In the case of more than one substituent on the arene, the combination of electronic and steric effects determines the conformation of the arene.

15 A D

A = Electron accepting substituent D = Electron donating substituent anti eclipsed conformation syn eclipsed conformation Example: Examples: A = -TMS, -CO2CH3 D = -CH3, -OCH3, -NH2, -N(CH3)2

Figure II.1 Conformations anti-Eclipsed and syn-Eclipsed Due to Electronic Effect of Substituents

The conformation adopted is due to preference of the three empty molecular

orbitals of chromium which are orthogonal to the orbitals of Cr(CO)3, to overlap with

electron rich centers of the arene, i.e., ortho and para carbons in case of electron donating and meta and ipso in case of electron accepting substituents on the arene. The AHH

4 (Albright Hofmann Hoffmann) model for orientation of Cr(CO)3 significantly depends

upon the positional relationship between the substituents which determine the electronic perturbation on the arene and hence the conformation of the Cr(CO)3 tripod.

b) Steric effect of the arene substituents and steric complementarity between the Cr(CO)3

tripod and arene substituents: Bulky substituents on the arene force the Cr(CO)3 to adopt the staggered orientation. The classic example is the completely anti-eclipsed orientation of the tripod in the case of tert-butyl arene chromium tricarbonyl. Though the electron donating effect of the tert-butyl group should orient the tripod in a syn-eclipsed conformation, the solid state structure shows an anti-eclipsed orientation (Figure II.2).

Another example illustrated is the 1,3,5-trisubstituted methyl and 1,3,5-trisubstituted tert- butyl benzene chromium tricarbonyl.

16 CH H C 3 CH 3 3 CH3 CH3

H3CCH3 anti-eclipsed syn-eclipsed

Figure II.2 Illustration of Conformational Change Due to Steric Effect of Arene Substituent

An important and sometimes overlooked factor is the ability of the Cr(CO)3 tripod and the arene substituents to accommodate each other leading to steric complementarity.

A wide variety of cases with steric complementarity5 between arene susbstituents and the

Cr(CO)3 tripod are known. Figure II.3 shows the ethyl groups accommodating the

Cr(CO)3 to a syn-eclipsed orientation, while the greater steric influence of the methyl

groups in the corresponding methyl complex orients the tripod in a staggered fashion.6

The cog-wheel orientation of alternating the methyl groups in the ethyl substituent orients the Cr(CO)3 to the syn-eclipsed arrangement with the chromium carbonyl bonds eclipsing

the arene carbon attached to the ethyl substituent with the methyl group in the opposite

face to that of complexation.

cog-wheel orientation staggered orientation of the ethyl groups and syn-eclipsed orientation of the Cr(CO)3 tripod

Less sterically bulky hexamethyl arene has a staggered orientation while the supposedly more bulky ethyl group orients in a syn-eclipsed fashion!

Figure II.3 Classic Illustration of Steric Complementarity in Arenechromium Tricarbonyls

There have been misunderstandings in explaining conformational preferences in

the solid state by not taking into account steric complementarity possible in some of these

17 complexes.7 Considering the steric effect of the substituents in isolation, while not giving

enough credit to the stereo dynamics of the Cr(CO)3 tripod with respect to the arene

substituent and vice versa has given rise to unsatisfactory explanations of conformational

orientation. In explaining the staggered and syn-eclipsed orientations of the tricarbonyl in

para-substituted dimethylacetal and diethylacetal benzaldehyde chromium tricarbonyl

respectively, the steric bulk of the acetal groups were taken as a whole, instead of taking

into account the steric complementarity present in these complexes and this has led to

misunderstanding the factor behind the unexpected tripod orientation (Figure II.4). Both

the dialkylacetal complexes probably would prefer conformation A, in order to minimize

the steric interactions with the superimposed carbonyl bond. It is the diethylacetal group

by its higher steric bulk that can force itself in this conformation more than the

dimethylacetal group and this accommodation explains the supposedly anomalous

orientations of the Cr(CO)3 tripod in this series of complexes.

H C-H CO OCH -CH OC H3CO OCH3 3 2 2 3 OC Cr CO H O R R' O R'

R R Conformation A R = -CF , -Si(CH ) 3 3 3 R' = -CH3 , -CH2CH3

Figure II.4 Resolving a Misunderstanding in Orientation of the Cr(CO)3 Tripod

c) Carbonyl – πarene interaction: More recently a subtle intra- and intermolecular CO-

πarene interaction has been substantiated by X-ray diffraction studies and ab initio

8 calculations. An attractive interaction between the carbonyl group of a Cr(CO)3 moiety, whose axis is almost parallel to a neighboring arene plane (complexed and uncomplexed

18 arenes) has been proposed to explain certain disfavored conformations in certain complexes (Figure II.5).9

O CO C CO Cr

π - carbonyl interation

Figure II.5 CO- πarene interaction

Often, the influence of subtle crystal packing effects is used to explain the anomalous crystal structures. It should be emphasized that crystal packing effects are not usually important as determined by extended Hückel calculations, showing that the preferred gas phase conformation is similar to that in solid state.10 Figure II.6 collects examples of arene complexes with the torsional angle of tripod orientation from X-ray crystal structures. Even for symmetrically substituted arene complexes, the tripod is rotated at different angles.

torsion angle NH2 CH3 OCH3 R

0 2.2 8.8 44.4

MeO2C CO2Me H3CO OCH3 (H3C)2N N(CH3)2

23.8 18.4 23.7

Figure II.6 Examples of Tripod Orientation Angles for a Variety of Arene Substituents

19 II.1.2 Barriers to Rotation of the Cr(CO)3 Tripod

11,12 Rotational barriers for polyene-ML3 transition metal complexes, and in

particular conformational preferences of arene-Cr(CO)3 complexes, have been studied

theoretically and experimentally, and the chromium-arene bond is known to have a very

small barrier to rotation. The energy difference between the staggered and eclipsed

-1 conformation in benzene-Cr(CO)3 is only 0.3 kcal mol from electron diffraction

studies.13 Localization of the double bonds in benzene has been proposed to considerably increase the barrier, as determined from extended Hückel theory (EHT) calculations

(Figure II.7).

0.0 9.3 19.4 kcal/mol

NH2 NH2 BH2 BH2

0.0 1.3 0.0 1.7 kcal/mol

Figure II.7 Relative Energies of Tripod Conformations by EHT Calculations

Barriers to rotation have been viewed in terms of kinetic and thermodynamic

restriction to tripod rotation as shown in Figure II.8. Jackson et al, who have done

pioneering work in analyzing the stereochemistry of organometallic compounds,14 have

shown that ‘in the case of slowed tripodal rotation, there involves a barrier to interchange

between two conformers and this is quantitatively expressed as free energy of activation

for that conformational interchange’, and termed it ‘kinetically restricted rotation’. The

other ‘thermodynamically restricted rotation’ is ‘the situation when the equilibrium

favors a single rotamer, even if the conformational change is rapid enough on the NMR

20 time scale to provide signal averaging, the conformational change is still restricted in the sense that the conformer populations are not equal’, as stated by Mislow and Raban.15

R Energy Energy Intermediate R

R R R

Kinetically restricted rotation Thermodynamically restricted rotation

Figure II.8 Illustration of Kinetically and Thermodynamically Restricted Rotation

There seems to be a misconception in studying rotational barriers by low temperature NMR. Often authors look for a 2:1 pattern in 13C chemical shifts for the carbonyls as an indication for slowed tripod rotation, when it is should be considered that even if there is slowed tripod rotation on the NMR time scale, it might not be obvious because the magnetic environment of the three carbonyls can be even then indistinguishable.

II.1.3 NMR Spectroscopic Analysis of Arenechromium Tricarbonyl Complexes

Complexation of Cr(CO)3 markedly alters the NMR spectrum of the arene.

Traditionally, the syn-eclipsed and anti-eclipsed orientation of the tripod with respect to the substituents has been studied by 1H and 13C NMR, a thorough discussion of which is presented in the next chapter. Since this chapter also details NMR conformational

21 analysis, though specifically for chiral arene-Cr(CO)3, the background on this topic is

presented here.

The NMR spectrum of an arene-Cr(CO)3 complex is marked by a significant

upfield shift of the complexed arene protons (2 ppm) and arene carbons (15 to 40 ppm).

From benzene to benzene chromium tricarbonyl, the 13C chemical shift difference is 35

ppm (128.5 ppm – 93.5 ppm). Shielding of the aromatic protons in the 1H NMR spectra

has been ‘attributed to two factors: (i) a large reduction of the paramagnetic ring current

produced by the involvement of the π electrons in the carbon metal bonds; (ii) an

important diamagnetic anisotropy of the Cr(CO)3 moiety increasing the resonance of all the aromatic protons. These two factors are large enough to reverse the deshielding effect resulting from the reduction of the π electron density on the ring protons due to the complex formation.’ It is generally accepted that the proton eclipsed by a Cr-CO bond is deshielded compared to those that are not, though the mechanism is still uncertain. In fact changes in chemical shifts are observed at α, β and even γ position of the arene alkyl substituents, though progressively less.

The situation is slightly different in the case of the 13C NMR spectra. Unlike

aromatic ring currents that make up for the deshielding in proton nuclei of the arene, the

ring carbons are practically not influenced by ring current as noted by the similarity

between alkene and benzene 13C chemical shifts. There is some controversy surrounding the shifts as these are not understood completely. The upfield shift observed in the 13C

22 spectra of the complex might be entirely due to the diamagnetic anisotropy of the

Cr(CO)3 moiety increasing the resonance of all the complexed arene carbons.

In general the conformational preference for simple arene-Cr(CO)3 is less

pronounced in NMR spectra since the barrier to Cr(CO)3 rotation is very low and hence

the observed chemical shifts are averaged on the NMR time scale. The required energy

calculated from HMO studies to enforce a totally eclipsed conformation is 29 KCal/mol.

Nevertheless low temperature NMR analysis and CPMAS analysis of certain complexes

have led to detection of restricted rotation. The 1H NMR chemical shifts are also solvent and concentration dependent16 while that of CCS due to intermolecular solvent effects are

considered very little. The chemical shifts of the arene protons in benzene solution are

shifted less (1.0 ppm) than the corresponding spectrum in CDCl3 and CCl4 (1.0-1.5 ppm).

In acetone solution, the shift is even smaller (0.35 – 0.45 ppm) which has been attributed

to the proton-acceptor properties of the solvent. The anisotropic ring carbon chemical

shifts have been deliberated, but have not lead to any conclusions.17 More work has to

done in this area for complete understanding. The 1H and 13C NMR of chiral arene

chromium tricarbonyl complexes present an even more interesting problem and no studies on the chemical shifts of diastereotopic arene protons and carbons have been reported so far.

As part of a study to understand the origin of diastereoselectivity during nucleophilic addition to chiral alkoxy arene chromium tricarbonyl complexes, we were interested in determining the conformation of the complexes in solution. We proposed to

23 analyze the NMR spectra of the chiral complexes to determine if they answer questions to

conformational preferences and sought to address the deficiency in NMR studies on

chiral complexes as well. In general in arene chromium tricarbonyl complexes the

conformation found in the solid state is the one found predominantly in solution.18 The complexes in question are the isoborneol derived alkoxyarene chromium tricarbonyl complexes with differing substituents (R = methyl, vinyl, 1-naphthyl, phenyl, benzyl, xylyl, etc) at the C2 position of the camphyl framework. We undertook to determine the solid state structures of some of the complexes and also find any evidence for a conformational preference in solution.

II.2 X-ray Crystal Structure Analysis of Chiral Alkoxyarenechromium

Tricarbonyl Complexes

X-ray crystal structures were determined for complexes II.1-II.4 and the ORTEP representations are given in Figures II.9 - II.12. The complexes were prepared by SNAr addition of the corresponding potassium alkoxide to a fluoroarenechromium tricarbonyl complex (either para-fluorotoluene or para-trimethylsilylfluoroarenechromium tricarbonyl). Single crystals were grown by cooling a solution of these complexes in either hexane/methylene chloride mixture or hexane/ethyl acetate mixture.

O O O O Cr(CO)3 R H Cr(CO) Si 3 R' R = Phenyl (II.1) R' = -TMS (II.3) R= Methyl (II.2) R' = -CH3 (II.4)

Figure II.9 X-ray Crystal Structure of Complex II.1 (Complex prepared by Dr. James D. Dudones and X- ray Structure Determined by Dr. Alan Pinkerton et al)

Figure II.10 X-ray Crystal Structure of Complex II.2 (X-ray Structure Determined by Dr. Alan Pinkerton et al)

Figure II.11 X-ray Crystal Structure of Complex II.3(a) and II.3(b) (X-ray Structure Determined by Dr. Alan Pinkerton et al)

Figure II.12 X-ray Crystal Structure of Complex II.4

26 While complexes II.1, II.2 and II.4 showed a single structure, complex II.3

existed in two forms, both cis-endo, but different in the directional orientation of the

tripod. One striking and common feature in all the structures is the face of the arene to

which Cr(CO)3 is complexed, i.e., all the complexes have the tripod on the cis-endo face with respect to the camphor framework. The tripod rotational features of the complexes can be derived from the torsion angle of each of the Cr-CO bonds from the fully syn-

eclipsed conformation, from the center of the arene, and are summarized in Table II.1.

The direction of rotation of the tripod with respect to the chiral auxiliary is indicated by

the notations Ir (right) and Il (left).

O OR* O OR* C C O Cr C O O C Cr Si R C Cr C C C Si Si O OCO O O I Il r

Averaged torsional Direction Complex θ θ θ angle θ of rotation II.1 30.1 27.4 33.4 30.3 Ir II.2 13.0 10.9 13.3 12.4 Ir II.3(a) 17.0 20.6 16.6 18.1 Il II.3(b) 4.6 0.1 5.4 3.4 Ir II.4 25.5 25.9 24.1 25.2 Il

Table II.1 Torsion Angles of Tripod Rotation for the Four Complexes II.1-II.4

A few interesting features are observable from the structures. In the simple

anisole chromium tricarbonyl complex, the tripod is rotated 8.8º from the syn-eclipsed orientation. The crystal structure of the simple 4-methoxytrimethylsilylbenzene chromium tricarbonyl has not been determined. But one would expect that the tripod is

27 syn-eclipsed to the methoxy group with possible displacement similar to the anisole

complex. The nearly staggered orientation found in complex II.1 and a significant

deviation from the syn-eclipsed conformation found in complexes II.2 and II.3(a)

indicates that the chiral auxiliary does influence the directional orientation of the tripod.

Arene carbon-carbon bond distances vary depending on whether the Cr-CO bond

vector eclipses the bond or not. This can be seen in Table II.2.

6 O 1 Cr(CO)3 *R 5 2 3 4 R

Complex C1-C2 C2-C3 C3-C4 C4-C5 C5-C6 C6-C1 II.1 1.430 1.407 1.424 1.406 1.424 1.389 II.2 1.420 1.407 1.425 1.402 1.435 1.406 II.3(a) 1.405 1.408 1.412 1.410 1.409 1.420 II.3(b) 1.416 1.394 1.412 1.411 1.404 1.400 II.4 1.405 1.415 1.403 1.417 1.407 1.416

Table II.2 Arene Carbon-carbon Bond Lengths from the Crystal Structures of Complexes II.1 – II.4

Structural parameters have previously been correlated with the electronegativity and Hammett constants of arene substituents for varying arene substituents.19 The relative

positions of the arene substituents and the individual steric and electronic effects in

unison are known to be reflected in the structural parameters of the arene and in the

Cr(CO)3 tripod orientation. With all other factors constant, asymmetric effects of a chiral

moiety as a neighboring group (in this case the chiral camphyl moiety), have not been reported. We proceeded to conformationally analyze a set of complexes with trimethylsilyl para substituent, in solution and determine whether correlation with the solid state structure is plausible.

28 II.3 Conformational Analysis of Chiral Arenechromium Tricarbonyl Complexes

in Solution: Correlation to Solid State Structure and Conformation

Camphor has a rigid bicyclic framework and the only conformations possible for

these chiral alkoxy trimethylsilylarenechromium tricarbonyl complexes should arise from

three bond rotations as shown in Figure II.13.

OSi

R Cr CO OC CO

Tripod directional Tripod conformation with respect orientation to the exo and endo face with respect to of camphor framework arene CO OR* OR* OC CO Cr OC CO OSi Cr CO OC Cr Vs OSi OC Vs CO R Cr CO OC CO R Si Si cis-endo trans-endo Il Ir

Figure II.13 Possible Conformations for Chiral Alkoxyarene Complexes

The two bond rotations about the ether oxygen (the bonds C2(of camphyl)-O and

O-arene carbon) would both lead to two conformations which would determine face

selectivity of the chromium tricarbonyl. The rotation about the C2 carbon of camphyl

group and oxygen would bring the arene ring very close to one of gem dimethyl groups and hence is likely to be disfavored. The other bond rotation about the arene carbon-

oxygen bond would place the Cr(CO)3 group syn to the endo face of camphyl moiety or

trans (opposite face) to the endo face of camphyl resulting in two possible conformations

29 cis-endo or trans-endo respectively. The electronic effects of the alkoxy group and the trimethylsilyl group would force the Cr(CO)3 tripod to a syn-eclipsed conformation with respect to the alkoxy group. In the case of an arene with a simple methoxy group and para-trimethylsilyl group, there is no facial orientation of the tripod. But in the presence of the chiral centers on the auxiliary, the two faces of the arene are differentiated. Hence the rotation about the chromium – η6 arene bond, which determines the orientation of the tripod with respect to the chiral auxiliary, i.e., either oriented left (Il) or right (Ir), leads to four conformations combining these two bond rotations. The left-right notations are taken from Albright’s note on the left-right asymmetry in polyene-ML3 complexes. Evidence for a preferred conformation is explained below.

II.3.1 Evidence for cis-endo Conformational Preference of the Arene-Cr(CO)3 with

Respect to the Camphyl Framework

It should be noted that in the solid state the cis-endo conformation is specifically preferred for all four complexes whose structures have been determined by X-ray analysis. The face selectivity of Cr(CO)3 in this series of complexes in solution, i.e., either cis-endo or trans-endo was evidenced rather serendipitously as noted below.

II.3.1.1 Unexpected Modification of an Alkene Double Bond!

The one pot dearomatization procedure of nucleophilic addition, protonation and decomplexation of arene complex II.5, during the study of chiral auxiliary directed nucleophilic addition provided evidence for the cis-endo preference noted above. Lithio propionitrile was added to complex II.5 in THF at -60 ºC, followed by addition of

30 HMPA, followed by protonation using trifluoroacetic acid and decomplexation with

aqueous ammonia. The expected substituted cyclohexadienol ether II.7 was not obtained.

The product II.8 (See Appendix for 1H NMR and 1H-1H COSY spectra) with two alkenic

protons not adjacent to each other was not completely characterised (Scheme II.1).

A O Si O X Cr(CO)3 Si A CN II.8

II.7 II.5 Reaction condition A: i) LDA, THF,propionitrile, -78 °C (ii) HMPA, 2 h, -60 °C (iii) CF3COOH, -60 °C, 0.5 h (iv) NH4OH, rt, 0.5 h

Scheme II.1 Unexpected Modification of C=C bond in vinyl Isobornyloxyarene Chromium Tricarbonyl Complex II.5

There is a modification of the vinyl substituent at C2 of the camphyl group.

It is known that chromium(II) reagents reduce double bonds under aqueous

conditions at room temperature in very high yields.20 Chromium(II) reduces alkynes,

alkyl halides and epoxides by reductive elimination to alkenes and reduces allyl chlorides

to less substituted olefins in aqueous DMF.21 Most notably relevant to our observation,

5 22 chromium hydrides such as (η -C5Ph5)-Cr(CO)3H are known to reduce olefins.

Nucleophilic addition to η6-arene chromium tricarbonyl involves the formation of a η5- cyclohexadienyl tricarbonyl chromium anion intermediate, with chromium in -1 formal oxidation state. The observed modification of the vinyl double bond can only be explained by complexation of the chromium tricarbonyl to the alkene double bond in an intermediate step.

31 To our knowledge modification of an allyloxyarene – Cr(CO)3 complex of this

type during nucleophilic addition and decomplexation has not been previously observed.

To test whether this is a general reaction for allyloxyarene chromium tricarbonyl

complexes, the dearomatization procedure was carried out for two simple allyl oxy arene

complexes II.9 and II.10. Both complexes furnished only the simple nucleophilic

addition products II.11 and II.12 respectively (Scheme II.2).

R R R R O i) LDA, THF, O tert-butyl acetate, -78 °C ii) HMPA, 2 h, -60 °C O Cr(CO)3 iii) CF3COOH, -60 °C, 0.5 h O iv) NH OH, rt, 0.5 h Si 4 Si

R = -H (II.9) R = -H (II.11) -CH3 (II.10) -CH3 (II.12)

Scheme II.2 Nucleophilic Addition Followed by Protonation and Decomplexation of Simple Allyloxyarene ChromiumTricarbonyl Complexes II.9 and II.10

Chelate alkenylarenedicarbonyl chromium complexes of the kind shown in Figure

II.14 are well characterized.23

Cr OC CO

Figure II.14 Double-bond Complexed to Chromium (0) Compounds

The lack of reactivity of the carbon-carbon double bond in complexes II.9 and

II.10 and modification in the case of complex II.5 implies that the Cr(CO)3 in complex

II.5 is closer to the vinyl double bond, and coordination occurs readily, i.e., Cr(CO)3 is indeed cis-endo to the camphor framework! In general electrophiles add to the cyclohexadienyl anion intermediate, by prior attachment to chromium and then, by

32 reductive elimination, transfer to the η5-cyclohexadienyl arene moiety to yield the diene.

This result provides evidence for the preference of cis-endo conformation in solution.

II.3.1.2 Topological Bias in the Camphyl Framework

The observations noted above suggest a preferred cis-endo orientation of Cr(CO)3 with reference to the camphor moiety, in the case of complex II.3. Whether it holds good for the series of complexes of type II.1 and II.2 in solution is the critical question. In hindsight, when we analyze the SNAr reaction, forming the chiral complexes, it is evident

that both reactants possess a bias in the manner in which reactants approach them. It is

well known that nucleophiles attack the chromium tricarbonyl complexed arene, anti to

its complexed face. The alkoxide nucleophile in this case also has face selectivity in that,

the chiral isobornyloxide would attack the fluoroarene from its sterically less hindered

endo face and add to the anti face of the chromium complex (Figure II.15).

anti face of arene complex Si

exo face of alkoxide CO syn face of arene complex Cr CO O CO F endo face of alkoxideR attack from endo face of the alkoxide on the anti face of the arene complex

OSi

R Cr CO OC CO

Figure II.15 Two Reactants Exercising their Inherent Topological Selectivity

33 This two way selective addition can arguably happen irrespective of the

substituent at C2 and C3 of the camphyl group. The topological bias in favor of the endo face in the camphor framework for a multitude of reactions and derivatives is well precedented24 and this can be possibly extended to the observation of cis-endo

conformational preference exhibited in this case as well.

II.3.1.3 Significant Barrier to Arene-oxygen Bond Rotation

In the presence of a significant rotational barrier for the Ar-C-O bond, the face

selective coordination of Cr(CO)3 for the series of complexes in solution would be fixed.

MM2 calculations25 performed on the energy minimized cis-endo conformer of complex

II.5 and the corresponding conformer with the C(ar)-O bond rotated by 180º i.e., the

trans-endo, reveal a 2.2 kcal/mole energy difference in favor of the cis-endo conformer

for complex II.5 (Figure II.16).

Ecis-endo = 0 kcal/mole Etrans-endo = 2.2 kcal/mole

Figure II.16 Difference in Energy of the cis-endo and trans-endo Conformers of Complex II.5 by MM2 Calculations

34 While π-symmetry interactions between the arene and the substituent are known even in uncomplexed arenes, systematic studies of substituent effects in arene chromium tricarbonyl complexes indicate significant double bond character for the arene carbon- oxygen bond.26 Π - Electron donating and electron withdrawing substituents on the arene complex interact with the chromium tricarbonyl to form zwitterionic resonance structures

(Figure II.17).

A π acceptance A CO Cr CO Cr OC CO OC CO OSi

R Cr CO D π donation D OC CO

Cr CO Cr CO OC CO OC CO

Figure II.17 Double Bond Character Induced by π-acceptance and π-donation of the Substituents

Steric strain energy calculations from MM2 force field for a series of complexes with differing substitution at C2 of the camphyl group did not show any consistent preference for the cis-endo conformation. But existence of the aforementioned double bond character would increase the barrier to rotation about this bond. The MM2 calculations on the zwitterionic forms would give a much larger rotational energy barrier, but were not done because of the inability to draw such structures in conventional molecular modeling software such as Spartan. From the X-ray crystal structures, the C2-

O-arene carbon bond angle is measured to be 120.07°, 124.32°, 120.18°, 120.19° and

118.26° for the complexes II.1, II.2, II.3(a), II.3(b) and II.4 respectively. These angles are close to 120° which would result from the sp2 hybridisation of oxygen and support the double bond nature of the bond. Further support for the double bond character can be

35 6 derived from the fact that the fluxional process in [Cr(CO)2(PPh3)(η -C6H3OMe-2,6-

t Bu 2)] is assigned as restricted rotation about the O-Me bond, especially as a similar

t process occurs in the complex of C6H2OMe-2,6-Bu 2-4-CH2OPPh2, which acts as a σ - π

– chelate, thus ruling out arene rotation.27

II.3.1.4 Evidence for Single Conformational Preference from NOE

Conformational Analysis

NOE as a tool in conformational analysis has the elegant capability to answer questions such as whether or not a compound has a conformational preference in solution! And if there is a preferred conformation, what is it and to what extent is it preferred quantitatively?28 NOE studies were done for the complexes with trimethylsilyl group in the para position shown in Figure II.18.

O O O Si O Si R Cr H Cr OC CO OC CO OC OC II.3

-R = -CH3 O II.2 II.1II.16 II.14 II.15 II.13

Figure II.18 Complexes Whose NOEs at Room Temperature Were Studied

Before proceeding to the NOE analysis we shall analyze a typical 1H NMR spectrum of these complexes. Figure II.19 shows the 1H NMR spectrum of complex II.13 in THF-d8.

1 Figure II.19 H NMR Spectrum of Complex II.13 (600 MHz, THF-d8)

The 1H NMR spectrum of II.13 shows two sets of diastereotopic protons for the arene complex, and this is also the case with the 13C NMR spectrum. While the two meta protons appear as simple doublets (assigned by NOE with the –TMS group), the ortho protons each appear as a doublet of doublets, the smaller coupling resulting from a mutual W coupling. Even in uncomplexed benzene derivatives, meta coupling between non-equivalent protons is commonly observed. In all the complexes studied, the four

13 protons and C peaks appear as separate signals in CDCl3, C6D6 and THF-d8. In the case of uncomplexed arenes with the chiral auxiliaries, both the 1H and 13C NMR showed only one set of signals each for the ortho and meta nuclei, as expected. This has been found for the arenes (II.1a, II.2a and II.15a) prepared by decomplexation of the corresponding arene complexes II.1, II.2 and II.15 respectively. This can be expected to be the case in all similar arenes. The ortho and meta protons’ signals in these arenes appear as simple doublets and carbon signals as a single peak. This is possible only if rotation about the

37 arene carbon-oxygen bond is facile. Non-equivalence of proton chemical shifts for the ortho protons in achiral (1’-tert-butyl-2’2’-dimethylpropyl)benzenechromium tricarbonyl has been attributed to restricted rotation about the carbon-carbon(arene) bond rotation.29

Each of the four proton signals in these alkoxy arene chromium tricarbonyl complexes could be due to a single rotational isomer about the arene carbon-oxygen bond or could be the time averaged signal due to rapid interconversion of the cis-endo and trans-endo rotamers on the NMR time scale. Preference for a single rotamer in this case will be indicated by signal enhancement of just one of the two diastereotopic protons on irradiation of a proton signal on the chiral camphyl moiety.

HA and HB are Positive NOE diastereomeric protons enhancement

No NOE Single conformational Chiral H preference group HA HB

One essential condition for the NOE difference experiment to be applied is that the signals of the protons to be irradiated, should be well resolved, i.e., sufficiently separated from their nearest signals. It should be emphasized at this point that while signal enhancement of only one of the two diastereotopic protons confirms a single rotamer preference, an asymmetry in the enhancement of the two protons could be due to structural properties as well. An asymmetry in signal enhancement of the diastereotopic protons could be because they are structurally close to the proton being irradiated albeit in different proportions due to differences in distance. The second case for asymmetry is when the two diastereotopic protons are interconverting rapidly and there exists a

38 preference for one of the rotamers. In essence the structural effects should be delineated from the conformational effects in the NOE studies, though this is difficult.

NOE difference experiments were performed on the complexes shown in Figure

II.18 in THF-d8, for complexes II.14 and II.16 in C6D6 and CDCl3 respectively, while for complex II.3, it was carried out both in THF-d8 and C6D6. Assignment of the proton signals key to the NOE studies was done by analysing the COSY and HMQC correlations. For NOE studies, the two ortho protons are the ones that would be affected because of their proximity to the chiral auxiliary. And indeed this is shown to be the case from the NOE studies, as we observed no signal enhancement for the meta protons by irradiation of any proton peak on the chiral moiety. The protons ortho to the –TMS group were easily assigned by irradiation of the TMS methyl protons. If rotation about the arene-oxygen bond is facile then on irradiation of a proton within the chiral auxiliary, the signals of both the ortho protons (to alkoxy substituent) should be enhanced equally, which wasn’t observed in any of the complexes studied. An illustrative example of NOEs is presented for complex II.13. Irradiation of each of the two signals on the camphyl moiety led to enhancement of only one of the diastereotopic ortho proton resonances, indicating a conformational preference, i.e., a preferential rotamer about the arene- oxygen bond (Figure II.20).

Figure II.20 NOE Signal Enhancements Shown for Two Irradiations in Complex II.13

A conformational preference was clearly indicated in case of complexes II.1, II.2,

II.3 (in both THF-d8 and C6D6 solvent), II.13, II.14 and II.16. The assignment of signals and analysis of the NOEs are presented in the end of the chapter. The NOE results of complex II.15 with its benzyl isobornyloxy substituent showed an asymmetry in the signal enhancements, but the analysis is slightly complicated as the benzyl methylene protons are themselves diastereotopic! Since even in complex II.3, the methyl isobornyloxy substituent is shown to exist in a single conformation, it would not be unreasonable to state that complex II.15 too exists as a single conformer and the difference in signal enhancements are due to structural effects and not conformational preferences!

40 Conformational study of 10,11-Dihydro-5H-dibenzo[a,d]cycloheptene derivatives using NMR Lanthanide shift reagents have determined that the chromium tricarbonyl tripod is predominantly in the concave face (endo) of the arene even in solution.30 The

NOE studies indicating a single conformation even at room temperature along with the alkene reduction in complex II.4 provide evidence for the exclusive presence of the cis- endo rotamer in solution for the complexes studied. MM2 calculations of the rotamers and the double bond character of the C(ar)-O bond providing a significant rotational energy barrier in these complexes lend further support this argument. The cis-endo rotamer is the preferred conformation in the solid state (X-ray analysis) too and it seems only reasonable to assign this as the preferred solution conformation.

II.3.2 13C NMR Chemical Shifts as an Aid in Conformational Analysis: Predicting

the Directional Orientation of the Cr(CO)3 Tripod

13C NMR chemical shifts (CCS) have been used to determine the conformational and configurational preference of organic compounds. NMR spectroscopy has been successfully applied to problems of stereochemistry in organic molecules ranging from polymers to complex proteins and medium- to large- ring natural products. 13C NMR chemical shifts have also been used to provide answers to stereochemical problems.31

CCS and coupling constants in organometallic compounds have been analysed to determine the fluxionality and conformations of σ- and π- bonded complexes.32 In arene chromium chemistry CCS data has so far been applied to determine the syn-eclipsed or anti-eclipsed conformational ratio of Cr(CO)3 with respect to substituents on the arene, which will be discussed in detail in a succeeding chapter. The CCS of naphthalene

41 chromium complexes with varied ligands have been correlated with reactivity toward nucleophilic addition.33 The application of CCS analysis to the conformer population problem has been so far unsuccessful largely due to failure to take into account all factors contributing to the observed chemical shift.34 Even 1H NMR analysis has some errors because of the failure to account for the localization of the Cr-CO bond. A thorough investigation will be presented in the succeeding chapter.

II.3.2.1 Hypothesis

Taking note of the generally agreed argument that arene carbons eclipsed by a Cr-

CO bond are relatively deshielded compared to those that are not, preferential orientation of the tripod in the complexes under study (either Il and Ir) should be characterized by their 13C chemical shifts. In the absence of anisotropy from the chiral auxiliary and the presence of a preferred cis-endo conformation (which is the case as evidenced from the previous section), one can expect in similarly substituted arene chromium tricarbonyls, that there exists a pattern in the CCS of complexes that prefer, say, conformational orientation Il due to preferred orientation of the tripod. This can be expected irrespective of the barrier to rotation about the arene and the Cr(CO)3 tripod. This should arguably be different in Ir. Instances of preferred tripod rotation should show an edge facial differentiation, assuming the tripod is a significant contributor to diastereotopicity of the arene carbons and protons (Figure II.21).

42 B edgeface OR* OR* HH H O H Si A face B face A face B face Cr(CO)3 HHA edge face TMS TMS Il Ir In case of conformation preference of the tripod, the NMR chemical shifts should show a consistent pattern

Figure II.21 Two Diastereotopic A and B Edge Faces of the Complex

As determined from the solid state structures of three complexes II.1, II.2 and

II.3 which are similarly substituted at the para position with a –TMS group, complexes

II.1 and II.2 have a Il conformation while one of the two solid state structures of complex

II.3 displays the Ir orientation of the tripod. If the hypothesis on the reflection of the orientation of the tripod on the CCS pattern holds good, the CCS of the arene carbons of complexes II.1 and II.2 should have the same pattern and complex II.3 should show a pattern different (more of a reversal in pattern) from that of the former. We undertook to determine if such a pattern exists and proceeded to assign the CCS of the arene carbons of all the complexes whose NOE was studied.

II.3.2.2 An Illustration of Assigning 13C Chemical Shift For a Chiral

Arenechromium Tricarbonyl Complex

A combination of NMR methods35 leading to precisely assign the 13C NMR chemical shifts of these complexes is illustrated with the NMR of complex II.13. The 1H

NMR, 13C NMR, HMQC and COSY spectra along with the conformation determined by

NOE difference experiments lead to assigning the CCS of the arene carbons. A differentiation of diastereomers of chromium tricarbonyl complexes of methyl O-

43 methylpodocarpate by assigning the CCS of the arene carbons has been reported.36 The

1H NMR, NOE representation, 1H-13C correlation, 1H-1H COSY spectra of complex II.13 are depicted in Figures II.21 - II.23. The protons and carbon signals on the spectra are arbitrarily numbered from δH1 to δH4 and δC1 to δC4 respectively, with δH1 and δC1 representing the most deshielded nuclei and δH4 and δC4 the most shielded nuclei.

Assigning 13C chemical shifts of arene carbons of the complex

• From COSY, δH1-δH3 and δH2-δH4 are coupled. There is also significant meta

coupling between δH1-δH2 and δH3-δH4.

• From HMQC, δC1-δH1, δC2-δH3, δC3-δH2 and δC4-δH4 are correlated

• From NOE, δH1 and δH3 are ortho to –TMS group; δH2 is on the same face as

naphthyl substituent; δH4 is close to two methylene protons of C3 of camphyl

moiety. The final assignment of CCS for the arene carbons of complex II.13 is

shown in Figure II.24.

Figure II.22 1H-13C HMQC Spectra of Complex II.13 Expanded Showing the Arene Complex Region

Figure II.23 1H-1H COSY Spectrum of Complex II.13 Expanded Showing the Arene Complex Region

CH B edge face H3C 3 H H δC H 4 δC2 CH3 H O Si H CH3 H δC δC CH3 H 3 Cr 1 OC CO OC A edge face

Figure II.24 Final Assignment of CCS For the Arene Carbons of Complex II.13

II.3.2.3 Correlating CCS of Arene Carbons with Tripod Orientation

The CCS of the diastereotopic arene carbons thus determined for the selected complexes and their assignments are tabulated in Table II.3. The CCS of the most deshielded of the ortho and meta carbons are italicized and underlined.

45 OR* OR* OR* OR* Cr(CO) Cr(CO)3 3 δC CO δC4 δC3 OC 3 δC4 CO OC δC δC δC1 δC2 2 1 OC CO TMS TMS TMS TMS

R* = -PIB (1), -MIB (2), XIB (14), AIB (16) R* = -NIB (13), -DOIB (3), BIB(15)

Complex Solvent A face δC A face δC B face δC B face δC ortho to -TMS meta to -TMS ortho to -TMS meta to -TMS

PIB (II.1) THF-d8 101.1 83.7 102.3 84.5

MIB (II.2) THF-d8 101.4 83.0 102.2 83.0

DOIB (II.3) THF-d8 102.2 82.4 101.1 79.7

DOIB(II.3) C6D6 100.7 81.1 99.3 78.3

NIB (II.13) THF-d8 102.1 84.0 100.7 83.1

AIB (II.16) CDCl3 98.8 82.7 99.4 84.3

XIB (II.14) C6D6 98.3 83.0 98.7 85.6

BIB (II.15) THF-d8 100.9 84.9 100.1 84.7

Table II.II.3 13C NMR Carbon Chemical Shifts at the Four Diastereotopic Arene Complexed Carbons with 13C NMR Chemical Shift Pattern and Correlation to Tripod Orientation (For explanation of A edge and B edge see Figure II.24)

One edge face of the arene is more deshielded than the other. In complexes II.1, II.2, II.14 and II.16 it is the B edge face while in complexes II.3, II.13 and II.15 it is the A edge face. As expected, complexes II.1 and II.2 showed the same pattern in their CCS while the complex II.3 showed the arrangement of the CCS reversed. Complexes II.14 and II.16 showed a pattern similar to that of complexes II.1 and II.2 implying an Il orientation of the tripod. Complex II.13 and II.15 showed a pattern similar to complex II.3 and hence can be assigned to have the Ir tripod orientation. The effect of the solvent seems to be invariant as complex II.3 revealed the same pattern in both THF-d8 and C6D6 solvents. Generally the arene carbon eclipsed by

46 the Cr-CO bond is deshielded more than the one that is not. This argument is invoked when comparing the Cr-CO bond eclipsing among the ortho, meta and para positions. In this case wherein two non-equivalent ortho and meta arene carbons are involved and the edge face of the arene bearing two carbonyl groups is more deshielded than the other, it is difficult to pronounce the same here.

The question now is whether we can say that this correlation reflects the preferred directional orientation of the tripod in solution. One might argue that the observed CCS differences observed must be largely due to the asymmetry of the chiral auxiliary in spite of the intermittent ether bond. This argument is acceptable for explaining the differences in the arene carbons ortho to the auxiliary. In case of the meta carbons, what seems to be the contributing factor is the anisotropy of the two carbonyl ligands close to these positions.

The hypothesis correlating the CCS of the arene carbons to the tripod orientation fits in this small sample set of seven complexes. The complexes with methyl para substitution like complex II.4 would show a different pattern for the Il and Ir orientations.

The presence of such a pattern and a reversal points to the fact that the orientation of the tripod is the major contributor to the 13C NMR shielding of the arene. The pattern of the

13 C chemical shifts in conjunction with the cis-endo preference of Cr(CO)3 though points to conformational preference in this series of chiral arene chromium tricarbonyl complexes, needs further understanding and study for general application as a method to determine tripod orientation in solution.

47 II.4 Variable Temperature NMR Studies

The motivation to carry out variable temperature NMR studies initially was to determine whether there is a slowed tripod rotation at low temperature indicated by a split

(or broadening) in the carbonyl signal in the 13C NMR spectrum. Even at the lowest temperature of -90 °C, at which a proper NMR was obtainable, the carbonyl peaks were still coincident. Hence this experiment was inconclusive. Nevertheless, both 1H and 13C

NMR spectra were recorded at various temperatures at 600 MHz and 175 MHz, respectively, for complex II.1, to determine whether any noteworthy effects could be derived from either of them. The 1H chemical shifts of the two pairs of diastereotopic protons were plotted as a function of temperature (Figure II.26)

48 CH H3C 3 δH δH 4 2 CH3 Si O CH3 H C δH3 δH1 CH3 3 Cr OC CO OC 1

Temperature dependent proton chemical shift of complex 1

5.8

5.6

5.4 Series1 Series2 Series3 5.2 Series4 Proton Chemical Shift Chemical Proton 5

4.8

4.6 - 80 °C - 70 °C - 60 °C - 50 °C - 40 °C - 30 °C - 20 °C - 10 °C 0 °C Temperature

1 Figure II.25 Plot of Variation of H Chemical Shift of Arene Protons of Complex PIB-TMS II.1 in THF-d8 Solution with Temperature (Series 1- δH1, Series 2- δH2, Series 3- δH4, Series 4- δH3)

The variation of chemical shift with increasing temperature was similar for the pair of protons adjacent to each other (H1 & H4 and H2 & H3), i.e., their slopes were similar and all the protons were shielded on increasing the temperature. The 13C chemical shift variation of the complex II.16 with temperature was also studied and is very small in the temperature range 25 °C to -35 °C as shown in Figure II.27.

49 CH H3C 3 δC3 δC1 CH3 Si O CH3 H C δC4 δC CH3 3 Cr 2 OC CO OC

Temperatue Dependent Variation of CCS of complex 16

105

100

95 Series1 Series2 Series3 90 Series4 Carbon Chemical Shift

80 - 35 °C - 25 °C - 15 °C - 5 °C 5 °C 15 °C 25 °C Temperature

13 Figure II.26 Plot of C Chemical Shift of Diastereomeric Arene Carbons of Complex II.16 in THF-d8 Solution (Series 1- δC1, Series 2- δC2, Series 3- δC3, Series 4- δC4)

Low temperature 13C chemical shifts of simple complexes of anisole, toluene and ethyl benzene, tert-butylbenzene and acetophenone have been compared and contrasted.37

In the complexes with electron donating subsituents (-OCH3, -CH3 and –C2H5), the meta carbons are shifted downfield with increasing temperature while the ortho and para carbons are shifted upfield with increasing temperature and this trend is reversed for electron withdrawing substituents.

50 Both the meta carbons of complex II.16 are shifted upfield on increasing the temperature, and the difference in chemical shift in going from -35 °C to 25 °C is 0.8 ppm. This observation is consistent with the electronic properties of the alkoxy substituent and the trimethylsilyl group. One of the ortho carbons (δC3) is shielded by 0.2 ppm while the other (δC4) is deshielded by 0.03 ppm on increasing the temperature. The electronic properties of the substituents should actually lead to deshielding of the ortho carbons on increasing the temperature. The anomaly in this case warrants further study as it is at this point inexplicable.

II.5 Conclusions

In conclusion 1,4-disubstituted arene chromium tricarbonyl complexes with the chiral camphyl moiety as the neighboring group were studied for their conformational behavior and certain trends are apparent. The camphyl moiety seems to force the Cr(CO)3 into the cis-endo conformation as evidenced from the solid state structures, NOE studies favoring a single conformation and double bond modification in complex II.5 on nucleophilic addition/protonation/decomplexation sequence. The influence of the –TMS group in the para position, while pivotal in obtaining well resolved NMR spectra of the complexes in the arene complex region, its effect is indeterminant in forms on the conformational behavior. The –TMS group would, due to its electron withdrawing effect, force the orientation of the Cr(CO)3 tripod to be syn-eclipsed to the alkoxy substituent, but steric effect of the camphyl group plays a significant role as shown in the crystal structures of complexes II.1 and II.3 which have nearly staggered tripod orientations.

The sample set for studying the directional orientation of the Cr(CO)3 tripod based on the

51 CCS of the arene carbon, though limited owing to the inability to obtain well resolved 1H

NMR spectra for NOE analysis, fits well with the solid state structure and hypothesis. It illustrates an application of the 13C chemical shifts in gaining stereochemical information and in this case orientation of the Cr(CO)3 tripod. Subtle steric effects such as interaction of the carbonyl ligands with the C2 substituents seem to be the influencing factor. An understanding needs to be gained on what forces the tripod to be in the Il orientation for complex II.1 and II.2 (and complexes II.14 and II.16) or Ir orientation for complex II.3 and II.4 (and complex II.13 and II.15). In the complexes whose π–carbonyl interaction was studied the distance between the carbonyl oxygen and the nearest and furthest arene carbon is reported to be 3.43 and 3.80 A° respectively. From the crystal structure of II.1, these distances were found to be 3.65 and 4.65 A° respectively. The distance between the corresponding carbonyl oxygen with the C2 methyl carbon in II.2 is much higher (5.10

A°). It is reasonable to speculate that a π–carbonyl interaction between one of the carbonyl ligands and the aromatic substituents at C2 of the camphyl group might direct tripod orientation which apparently is different for simple phenyl derivatives and the naphthyl substituent.

This study represents the first report of conformational preferences in chiral 1,4- disubstituted arene chromium tricarbonyls. These observations so far have led to further understanding of the stereodynamics of these types of alkoxy arene chromium tricarbonyl complexes, knowledge of which is important in understanding their reaction pathways.

The NMR analysis of these chiral arene chromium complexes may lend more support to theoretical studies carried out to understand the complexation shifts, though some of the

52 arguments presented need further theoretical understanding. Determination of conformation of similar complexes in solution is plausible by the NMR analysis presented here. They are consistent with the X-ray crystal structures and that should allow us to make a reasonable proposal for explaining the origin of diastereoselectivity in nucleophilic addition to these complexes, details of which are presented in a later chapter.

53 Experimental

General procedures. All reactions involving chromium tricarbonyl complexes were performed using oven-dried (125 ºC) glassware under anhydrous, oxygen free argon atmosphere. All reactions were performed in freshly distilled (under nitrogen) solvents and monitored by TLC on silica gel. Thin layer chromatography was performed on

E.Merck silica gel 60 F254 0.25 mm plates, and the plates were visualized with UV light and/or with phosphomolybdic acid solution in ethanol or iodine. Reactions performed at -

60 ºC were maintained at that temperature using ethanol bath and Neslab Cryotrol. Flash chromatography was performed on silica gel with mesh 170-400 under nitrogen pressure and the elutin solvents are reported as V/V percent mixtures. NMR spectra were recorded on a Varian XL200 (200 MHz) or Varian Gemini-300 (300 MHz) or Varian Inova 600

(600 MHz) or a Varian Unity 400 (400 MHz) spectrometer. FTIR spectra were recorded as neat oils or KBr pellet on a Nicolet Impact 400 FTIR spectrometer. Optical rotations were recorded on a Perkin-Elmer 241 polarimeter. High resolution mass spectra (HRMS) of compounds were recorded in-house using a Kratos MS25A instrument by either EI

(Electron Ionization) or FAB (Fast Ion Bombardment). Capillary GC was performed on a

Hewlett Packard 5890 Series II Gas Chromatograph equipped with an HP-5 30 m x 0.32 mm capillary column and a flame ionization detector. The melting points were measured on a Thomas Hoover apparatus and are uncorrected. The purity of new compounds was assessed from their 1H and 13C NMR spectra. Preparation of chiral auxiliaries is detailed in Chapter III.

54 NMR experiments - General. The NOE 1H NMR experiments were carried out in

Varian 600 MHz spectrometer at room temperature 23-25 ºC in NMR tube in THF-d8 as solvent (Aldrich). The solvents of the 1H and 13C NMR were referenced respectively as follows, CDCl3-7.26 ppm & 77.0 ppm, C6D6-7.17 ppm & 128.0 ppm, THF-d8-3.61 ppm

& 67.4 ppm. Low temperature NMR experiments were done by cooling the probe externally with liquid nitrogen. The nomenclature followed in the NMR studies for labeling the arene complexed protons and carbons is shown below. The four protons and carbon signals are labeled from most the deshielded to shielded nuclei as δH1 thro’ δH4 and δC1 thro’ δC4 respectively.

1H NMR 13C NMR

δH1 δH2 δH3 δH4 δC1 δC2 δC2 δC4

ppm ppm

General procedure for synthesizing chiral chromium complexes:

To a heterogeneous mixture of potassium hydride (20% dispersion in mineral oil; 4.5 mmol, 1.5 equiv, washed thrice with freshly distilled diethyl ether to remove the mineral oil), in anhydrous diethyl ether (12 mL) at 0 ºC under argon, was added dropwise, a solution of the chiral isoborneol (3.3 mmol, 1.1 equiv), in diethyl ether (6 mL), so that the hydrogen gas effervescence is not too vigorous. One hour after hydrogen gas evolution had stopped, a solution of the fluoroarene chromium tricarbonyl complex (η6-(4- fluoro(trimethylsilyl)benzene)chromium tricarbonyl or η6-4-fluoro(toluene)chromium tricarbonyl) (3 mmol, 1 equiv) in ether (9 mL) was added dropwise. The SNAr reaction

55 was complete after 4 hours as indicated by complete disappearance of starting fluoro complex on the TLC plate. The dark brown mixture was carefully quenched by slow addition of 5% aqueous hydrochloric acid or an aqueous solution of ammonium chloride.

The aqueous phase was then extracted with ether (3 x 25 mL) and the combined ether extracts were washed with water, dried (MgSO4), then filtered and concentrated in vacuo to give a yellow oil or solid. The crude product was purified either by recrystallization from 1:1 mixture of hexane/dichloromethane which usually gave yellow crystals which was washed with cold hexane or purified by flash chromatography on silica gel (hexanes- ethyl acetate or hexanes-ether as eluent system).

η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-phenyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (II.1) was prepared from phenyl isoborneol and η6-(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl (Preparation and data given in Chapter IV). Recrystallization with 1:1 hexane/methylene chloride gave rhombic yellow crystals.

8 7 9 4 5 3 6 O 1 2 10 Cr(CO)3 Si

+ Yield:86%; Rf: 0.31 (20:1 hexane/ether); FAB HRMS m/z 514.1629 (M ), calcd for

1 C28H34O4SiCr 514.1631; H NMR (600 MHz, THF-d8) δ 7.58 (1H, d, J = 7.8 Hz), 7.50

(1H, d, J = 7.8 Hz), 7.41 (1H, t, J = 7.5 Hz), 7.36 – 7.30 (2H, m), 5.55 (1H, d, J = 6.6

Hz), 5.48 (1H, d, J = 7.2 Hz), 4.95 (1H, dd, J = 6.9, 1.5 Hz), 4.87 (1H, dd, J = 6.9 Hz),

1.5 Hz), 2.53 (1H, d, J = 14.4 Hz), 2.45 (1H, d, J = 14.4 Hz), 1.96 (1H, t, J = 4.2 Hz),

56 1.80 – 1.77 (1H, m), 1.40 – 1.35 (1H, m), 1.23 (3H, s), 1.03 (3H, s), 0.99 (3H, s), 1.25 –

13 1.20 (1H, m), 0.85 – 0.80 (1H, m), 0.21 (9H, s, -Si(CH3)3); C NMR (150 MHz, THF-d8)

δ 235.0 (CO), 143.0 (C(arene complex)-O-), 140.8 (C(phenyl)-C2), 129.0, 128.9, 128.8,

128.6, 126.6 (preceding five signals correspond to five C-H carbons of the phenyl group),

102.3 (C-ortho to TMS), 101.1 (C-ortho to TMS), 93.9 (C-TMS or C2), 93.7 (C-TMS or

C2), 84.5 (C-meta to TMS), 83.7 (C-meta to TMS), 55.8 (C1), 51.1 (C7), 46.4 (C4), 39.9

(C3), 31.1 (C6), 26.4 (C5), 22.0 (C8 or C9), 21.9 (C8 or C9), 10.2 (C10), -1.3 (-

1 1 1 13 Si(CH3)3); H- H COSY (600 MHz, THF-d8) δ δH1-δH4, δH2-δH3; H- C HMQC (600

MHz, THF-d8) δ δH1-δC1, δH2-δC2, δH3-δC4, δH4-δC3; NOE (600 MHz, THF-d8) δ δH1 and δH2 ortho to -Si(CH3)3, δH4 close to equatorial proton attached to C3 of camphor;

-1 FTIR (KBr) νmax 2934 (C-H stretch), 1966, 1885 (carbonyl stretch) cm .

η6-{4-[[(1R,2R)-1,2,7,7-Tetramethylbicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (II.2) was prepared from methyl isoborneol and η6-(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl as a greenish yellow solid.

8 7 9 4 5 3 6 O 1 2 10 Cr(CO)3 11 Si

+ Yield: 97%; Rf: 0.75 (4:1 hexane/ethyl acetate); FAB HRMS m/z 452.1467 (M ), calcd

1 for C23H32O4SiCr 452.1475; H NMR (600 MHz, THF-d8) δ 5.73 (2H, m), 5.27 (1H, dd,

J = 6.9, 2.1 Hz), 5.13 (1H, dd, J = 6.9, 2.1 Hz), 2.51 ( 1H, dt, J = 13.2, 3.6 Hz), 1.60 (3H, s), 1.55 (1H, t, J = 6.6 Hz), 1.51 – 1.46 (1H, m), 1.32 (3H, s), 1.16 – 1.11 (1H, m), 0.99

57 13 (3H, s), 0.97 – 0.88 (3H), 0.94 (3H, s), 0.28 (9H, s); C NMR & APT (50 MHz, THF-d8)

δ 235.1 (CO), 141.8 (C(arene complex)-O-), 102.2 (C-ortho to TMS), 101.4 (C-ortho to

TMS), 93.2 (C-TMS or C2), 91.0 (C-TMS or C2), 83.0 (corresponds to two C-meta to

TMS), 55.0 (C1), 49.5 (C7), 46.8 (C4), 44.4 (C3), 31.2 (C6), 26.9 (C5), 21.3 (C8 or C9 or

1 C11), 21.2 (C8 or C9 or C11), 20.9 (C8 or C9 or C11), 10.4 (C10), -1.2 (-Si(CH3)3); H-

1 1 13 H COSY (600 MHz, THF-d8) δ δH1-δH3, δH2-δH4; H- C HMQC (600 MHz, THF-d8) δ

δH1-δC1, δH2-δC2, δH3-δC3, δH4-δC4; NOE (600 MHz, THF-d8) δ δH1 and δH2 ortho to -

Si(CH3)3, δH3 close to equatorial proton attached to C3 of camphor, δH4 methyl protons of C9 of camphyl group; FTIR (KBr) νmax 2947, 2888 (C-H stretch), 1960, 1865

(carbonyl stretch) cm-1.

η6-{4-[[[Spiro[(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptane-3,2’-[1,3]dioxalan]-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (II.3) was prepared from

Spiro[(1R, 2S)-1,7,7-trimethylbicyclo[2.2.1]heptane-3,2’-[1,3]dioxalan]-2-ol38 and η6-(4- fluoro(trimethylsilyl)benzene)chromium tricarbonyl as a yellow solid.

8 7 9 O 5 4 3 O O 6 1 2 Cr(CO) 10 H 3 Si

+ Yield: 79%; Rf: 0.64 (4:1 hexane/ethylacetate); FAB HRMS m/z 496.1370 (M ), calcd for

1 C24H32O6SiCr 496.1373; H NMR (600 MHz, C6D6) δ 5.16 (1H, dd, J = 6.9 Hz, 0.9 Hz),

5.12 (1H, dd, J = 6.9 Hz, 2.1 Hz), 5.02 (1H, dd, J = 6.9 Hz, 0.9 Hz), 4.85 (1H, dd, J = 6.9

Hz, 2.1 Hz), 4.01 (1H, s), 3.47 – 3.44 (1H, m), 3.29 – 3.26 (1H, m), 3.25 – 3.17 (2H),

1.73 -1.69 (1H, m), 1.49 – 1.44 (1H, m), 1.41 – 1.35 (2H), 1.35 (3H, s), 1.31 – 1.26 (1H,

58 13 m), 1.15 (3H, s), 0.75 (3H, s), 0.12 (9H, s, -Si(CH3)3); C NMR and APT (50 MHz,

C6D6) δ 234.4 (CO), 144.8 (C(arene complex)-O-), 115.3 (C3),100.7 (C-ortho to TMS),

99.3 (C-ortho to TMS), 92.3 (C(arene complex)-TMS), 89.7 (C2), 81.1 (C-meta to TMS),

78.3 (C-meta to TMS), 64.2 (-O-(CH2)2-O-), 63.7 (-O-(CH2)2-O-), 51.9 (C4), 49.8 (C1 or

C7), 48.1 (C1 or C7), 33.9 (C6), 21.0 (C8 or C9), 20.9 (C8 or C9), 20.3 (C5), 11.2 (C10),

1 1 1 13 -1.4 (-Si(CH3)3); H- H COSY (400 MHz, C6D6) δ δH1-δH2, δH3-δH4; H- C HSQC

(400 MHz, C6D6) δ δH1-δC2, δH2-δC4, δH3-δC1, δH4-δC3; NOE (600 MHz, C6D6) δ δH1 and δH3 ortho to -Si(CH3)3, δH2 close to endo proton attached to C2 of camphyl and one

1 dioxalane methylene protons, δH4 is close to C9 methyl protons; H NMR (600 MHz,

THF-d8) δ 5.77 (1H, d, J = 6.6 Hz), 5.73 (1H, d, J = 6.6 Hz), 5.32 (1H, dd, J = 7.2 Hz, 1.8

Hz), 5.29 (1H, dd, J = 7.2 Hz, 1.8 Hz), 4.07 – 4.02 (1H, m), 3.92 (1H, s), 3.90 – 3.73

(3H), 1.68 – 1.64 (1H, m), 1.61 – 1.56 (1H, m), 1.42 – 1.29 (2H), 1.16 (3H, s), 1.01 (3H,

13 s), 0.95 – 0.83 (1H, s), 0.89 (3H, s), 0.28 (9H, s, -Si(CH3)3); C NMR and APT (50

MHz, THF-d8) δ 235.2 (CO), 145.9 (C(arene complex)-O-), 115.6 (C3),102.2 (C-ortho to

TMS), 101.2 (C-ortho to TMS), 93.6 (C(arene complex)-TMS), 90.7 (C2), 82.4 (C-meta to TMS), 79.7 (C-meta to TMS), 65.3 (-O-(CH2)2-O-), 64.8 (-O-(CH2)2-O-), 52.8 (C4),

50.4 (C1 or C7), 48.7 (C1 or C7), 34.5 (C6), 30.5 (C5), 21.4 (C8 or C9), 20.8 (C8 or C9),

1 1 1 11.5 (C10), -1.1 (-Si(CH3)3); H- H COSY (600 MHz, THF-d8) δ δH1-δH4, δH2-δH3; H-

13 C HMQC (600 MHz, THF-d8) δ δH1-δC1, δH2-δC2, δH3-δC4, δH4-δC3; NOE (600 MHz,

THF-d8) δ δH1 and δH2 ortho to -Si(CH3)3, δH3 close to endo proton attached to C2 of camphyl group; FTIR (KBr) νmax 2954 (C-H stretch), 1966, 1885, 1874 (carbonyl stretch) cm-1.

59 η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-(1-naphthyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (II.13) was prepared from naphthyl isoborneol and η6-(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl as a yellow solid which on recrystallization from 1:1 methylene chloride/hexane mixture gave yellow rhombic crystals.

8 7 9 4 5 3 6 O 1 2 10 10' Cr(CO)3 Si 5'

+ Yield: 77%; Rf: 0.39 (20:1 hexane/ether); FAB HRMS m/z 564.1788 (M ), calculated for

1 C32H36O4SiCr 564.1782; H NMR (600 MHz, THF-d8) δ 8.57 – 8.55 (1H, m), 7.94 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz), 7.79 – 7.77 (1H, m), 7.51 (1H, t, J = 7.8 Hz),

7.35 – 7.31 (2H), 5.56 (1H, d, J = 6.6 Hz), 5.37 (1H, dd, J = 6.6 Hz, 2.4 Hz), 5.16 (1H, dd, J = 7.2 Hz, 1.2 Hz), 4.91 (1H, dd, J = 7.2 Hz, 2.4 Hz), 3.03 (1H, dt, J = 14.4 Hz, 3.6

Hz), 2.82 (1H, d, J = 15.0 Hz), 2.11 (1H, t, J = 4.2 Hz), 1.84 – 1.76 (1H, m), 1.54 – 1.50

(1H, m), 1.45 (3H, s), 1.23 (1H, dt, J = 12.6 Hz, 4.8 Hz), 1.18 (3H, s), 1.02 (3H, s), 0.87

13 (1H, m), 0.09 (9H, s, -Si(CH3)3); C NMR & APT (50 MHz, THF-d8) δ 235.5 (CO),

143.2 (C(arene complex)-O-), 137.7 (C5’ or C10’), 136.7 (C5’ or C10’), 133.3 (C1’),

131.4, 130.3, 130.2, 128.1, 126.8, 126.6, 125.8 (preceding seven signals correspond to seven C-H carbons of the naphthyl group), 102.1 (C-ortho to TMS), 100.7 (C-ortho to

TMS), 99.1 (C-TMS or C2), 94.8 (C-TMS or C2), 84.0 (C-meta to TMS), 83.1 (C-meta to TMS), 58.1 (C1), 52.7 (C7), 47.5 (C4), 42.9 (C3), 32.6 (C6), 27.1 (C5), 22.9 (C8 or

1 1 C9), 25.5 (C8 or C9), 15.0 (C10), -1.0 (-Si(CH3)3); H- H COSY (600 MHz, THF-d8) δ

1 13 δH1-δH2, δH3-δH4; H- C HMQC (600 MHz, THF-d8) δ δH1-δC1, δH2-δC3, δH3-δC2,

60 δH4-δC4; NOE (600 MHz, THF-d8) δ δH1 and δH3 ortho to -Si(CH3)3, δH4 close to protons attached to C3 of camphyl and β-hydrogen of naphthyl group & δH2 close to

-1 peri-hydrogen of the naphthyl group; FTIR (KBr) νmax 1961, 1869 cm .

η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-(3’,5’-dimethylphenyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (II.14) was prepared from xylyl isoborneol and η6-(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl as a yellow solid which on recrystallization from 1:1 hexane/methylene chloride mixture gave yellow rhombic crystals.

8 7 9 4 5 3 6 O 1 2 10 Cr(CO)3 6' 2' Si

+ Yield: 73%; Rf: 0.60 (20:1 hexane/ether); FAB HRMS m/z 524.1947 (M ), calcd for

1 C30H38O4SiCr 524.1944; H NMR (600 MHz, C6D6) δ 7.54 (1H, s), 7.00 (1H, s), 6.84

(1H, s), 4.83 (1H, ddd, J = 6.6 Hz, 2.4 Hz, 0.6 Hz), 4.65 (1H, ddd, J = 7.2 Hz, 2.4 Hz, 1.2

Hz), 4.50 (2H, AB quartet x d, J = 7.2 Hz, 1.8 Hz), 2.39 (3H, s), 2.26 (3H, s), 2.16 (1H, dt, J = 14.4 Hz, 3.6 Hz), 2.06 (1H, d, J = 14.4 Hz), 1.67 (1H, t, J = 4.5 Hz), 1.59 – 1.54

(1H, m), 1.18 (3H, s), 1.13 (3H, s), 1.15 – 1.06 (2H), 1.02 – 0.96 (1H, m), 0.85 (3H, s),

13 0.04 (9H, s, -Si(CH3)3); C NMR and APT (50 MHz, C6D6) δ 234.4 (CO), 140.5

(C(arene complex)-O-), 140.0 (C(phenyl)-C2), 139.0 (C-(aromatic)-CH3), 137.1 (C-

(aromatic)-CH3), 129.9 (C2’ or C6’), 127.2 (C2’ or C6’), 122.8 (C4’), 98.7 (C-ortho to

TMS), 98.3 (C-ortho to TMS), 94.3 (C-TMS or C2), 93.5 (C-TMS or C2), 85.6 (C-meta

61 to TMS), 83.0 (C-meta to TMS), 55.7 (C1), 50.6 (C7), 45.7 (C4), 39.9 (C3), 30.4 (C6),

26.2 (C5), 21.6 (C8 or C9 or two aromatic –CH3s), 21.6 (C8 or C9 or two (aromatic)C–

1 1 CH3s), 21.2 (C8 or C9 or two (aromatic) C–CH3s), 9.9 (C10), -1.5 (-Si(CH3)3); H- H

1 13 COSY (400 MHz, C6D6) δ δH1-δH2, δH3-δH4; H- C HMQC (400 MHz, C6D6) δ δH1-

δC2, δH2-δC4, δH3-δC1, δH4-δC3; NOE (600 MHz, C6D6) δ δH1 and δH3 ortho to -

Si(CH3)3, δH2 close to protons attached to C9 methyl group of camphyl and δH4 is close to the exo proton at C3 of camphyl; FTIR (KBr) νmax 3013, 2967, 2921, 2894 (C-H stretch), 1960, 1887 (carbonyl stretch) cm-1.

η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-(4-methoxyphenyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (II.16) was prepared from anisyl isoborneol and η6-(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl as a yellow oil and purified by flash column chromatography (9:1 hexanes/ethyl acetate) and solvent evaporated to yield a yellow powder.

8 7 9 4 5 3 6 O 1 2 10 Cr(CO)3 6' 2' Si 5' 3'

+ Yield: 87%; Rf: 0.29 (20:1 hexane/ether); FAB HRMS m/z 543.1663 (M -H), calcd for

1 C29H36O5SiCr 544.1737; H NMR (600 MHz, CDCl3) δ 7.40 (1H, dd, J = 8.1, 2.1 Hz),

7.30 (1H, dd, J = 8.1, 2.1 Hz), 6.90 (2H, dt, J = 11.4, 3.0 Hz), 5.29 (2H, dd, J = 6.0, 3.6

Hz), 4.83 (1H, dd, J = 7.2, 2.4 Hz), 4.70 (1H, dd, J = 7.5, 2.7 Hz), 2.43 (1H, dt, J = 13.8,

3.0 Hz), 2.24 (1H, d, J = 7.2 Hz), 1.94 (1H, t, J = 4.2 Hz), 1.76 – 1.72 (1H, m), 1.26 –

62 1.12 (2H), 1.15 (3H, s), 0.98 (3H, s), 0.94 (3H, s), 0.83 – 0.79 (1H, m), 0.20 (9H, s, -

13 Si(CH3)3; C NMR & APT (50 MHz, CDCl3) δ 234.1 (CO), 159.1 (C4’), 141.0

(C(arene complex)-O-), 132.1 (C2’ or C6’), 129.9 (C2’ or C6’), 126.2 (C1’), 113.7 (C3’ or C5’), 113.3 (C3’ or C5’), 99.4 (C-ortho to TMS), 98.8 (C-ortho to TMS), 93.9 (C-

TMS or C2), 93.3 (C-TMS or C2), 84.3 (C-meta to TMS), 82.7 (C-meta to TMS), 55.1

(C1), 55.2 (-O-CH3), 50.1 (C7), 45.5 (C4), 39.8 (C3), 30.3 (C6), 26.1 (C5), 21.6 (C8 or

1 1 C9), 21.0 (C8 or C9), 9.7 (C10), -1.3 (-Si(CH3)3); H- H COSY (600 MHz, CDCl3) δ

1 13 δH1-δH4, δH2-δH3; H- C HMQC (600 MHz, CDCl3) δ δH1-δC1, δH2-δC2, δH3-δC4, δH4-

C3; NOE (600 MHz, CDCl3) δ δH1 and δH2 ortho to -Si(CH3)3, δH3 close to protons of

C9 methyl group of camphyl; FTIR (KBr) νmax 3011, 2954, 2898 (C-H stretch), 1956,

1895, 1859 (carbonyl stretch)cm-1.

η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-benzylbicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (II.15) was prepared from benzyl isoborneol and η6-(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl as a yellow solid which on recrystallization from 1:1 hexane/methylene chloride yielded yellow rhombic crystals.

8 7 9 4 5 3 6 O 1 2 10 Cr(CO)3 Si 4' 2' 3'

+ Yield: 73%; Rf: 0.45 (20:1 hexane/ether); FAB HRMS m/z 528.1786 (M ), calcd for

1 C29H36O4SiCr 528.1788; H NMR (600 MHz, THF-d8) δ 7.25 (2H, d, J = 7.2 Hz), 7.20

63 (2H, d, J = 7.2 Hz), 7.17 (1H, d, J = 7.2 Hz), 5.74 (1H, d, J = 7.2 Hz), 5.67 (1H, d, J = 7.2

Hz), 5.51 (1H, d, J = 7.2 Hz), 5.36 (1H, d, J = 6.6 Hz), 3.92 ( 1H, d, J = 16.2 Hz), 2.90

(1H, d, J = 15.6 Hz), 2.00 (1H, t, J = 9.9 Hz), 1.81 (1H, d, J = 13.2 Hz), 1.69 (1H, d, J =

13.2 Hz), 1.49 – 1.40 (1H, m), 1.24 – 1.19 (1H, m), 1.07 (3H, s), 0.87 (3H, s), 0.59 (3H,

13 s), 0.31 (9H, s, -Si(CH3)3); C NMR & APT (50 MHz, THF-d8) δ 235.0 (CO), 142.9

(C(arene complex)-O-), 139.0 (C(aromatic)-CH2-), 131.6 (C3’), 128.8 (C2’), 127.2 (C4’),

100.9 (C-ortho to TMS), 100.1 (C-ortho to TMS), 95.5 (C-TMS or C2), 94.1 (C-TMS or

C2), 84.9 (C-meta to TMS), 84.7 (C-meta to TMS), 55.6 (C1), 50.8 (C7), 46.2 (C4), 43.9

(-CH2-Ph), 40.8 (C3), 31.1 (C6), 27.0 (C5), 22.0 (C8 or C9), 21.1 (C8 or C9), 11.8 (C10),

1 1 1 13 -1.3 (-Si(CH3)3); H- H COSY (600 MHz, THF-d8) δ δH1-δH4, δH2-δH3; H- C HMQC

(600 MHz, THF-d8) δ δH1-δC1, δH2-δC2, δH3-δC4, δH4-δC3; NOE (600 MHz, THF-d8) δ

δH1 and δH2 ortho to -Si(CH3)3, δH3 close to one –CH2-Ph proton and endo proton at C3 of camphyl, δH4 is close to C10 of camphyl; FTIR (KBr) νmax 2967, 2921 (C-H stretch),

1966, 1885 (carbonyl) cm-1.

η6-{4-[[[Spiro[(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptane-3,2’-[1,3]dioxalan]-2- yl]oxy]methyl}chromium tricarbonyl (II.4) was prepared from Spiro[(1R, 2S)-1,7,7- trimethylbicyclo[2.2.1]heptane-3,2’-[1,3]dioxalan]-2-ol and η6-(4- fluorotoluene)chromium tricarbonyl as a yellow solid and purified by flash chromatography (4:1 hexane/ethyl acetate).

8 7 9 O 5 4 3 O O 6 1 2 Cr(CO) 10 H 3

64 + Yield: 82%; Rf: 0.34 (4:1 hexane/ethyl acetate); FAB HRMS m/z 438.1133 (M ), calcd

1 for C22H26O6Cr 438.1135; H NMR (600 MHz, THF-d8) δ 5.64 (1H, d, J = 7.2 Hz), 5.58

(1H, d, J = 7.2 Hz), 5.39 (1H, dd, J = 6.9 Hz), 2.1 Hz), 5.34 (1H, dd, J = 7.2 Hz, 2.4 Hz),

4.05 – 4.01 (1H, m), 3.89 – 3.81 (3H, m), 3.80 (1H, s), 2.06 (3H, s), 1.76 – 1.74 (2H, m),

1.66 (1H, dt, J = 12.6 Hz, 3.6 Hz), 1.61 – 1.56 (1H, m), 1.39 – 1.34 (1H, m), 1.16 (3H, s),

13 0.99 (3H, s), 0.89 (3H, s); C NMR (50 MHz, THF-d8) δ 235.4 (CO), 142.4 (C(arene complex)-O-), 115.6 (C3), 102.6 (C(arene complex)-CH3), 97.7 (C-ortho to –CH3), 96.3

(C-ortho to -CH3), 91.1 (C2), 83.4 (C-meta to –CH3), 80.5 (C-meta to –CH3), 53.0 (C4),

50.4 (C1 or C7), 48.7 (C1 or C7), 34.6 (C6), 21.4 (C8 or C9), 21.3 (C8 or C9), 20.9 (C5),

19.6 (Arene-CH3), 11.4 (C10); FTIR (KBr) νmax 2961, 2892 (C-H stretch), 1960, 1876

(carbonyl stretch) 1546, 1486 cm-1.

η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-vinylbicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (II.5) was prepared from vinyl isoborneol and η6-(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl greenish oil which on recrystallization from 2:1 hexane/methylene chloride solvent gave II.5 as greenish yellow crystals.

8 7 9 4 5 3 6 O 1 2 Cr(CO)3 10 1' 2' Si

+ Yield: 73%; Rf: 0.61 (15:1 hexane/ether); FAB HRMS m/z 464.1463 (M ), calcd for

1 C24H32O4SiCr 464.1475; H NMR (400 MHz, CDCl3) δ 6.03 (1H, J = 17.7, 11.1 Hz),

5.49-5.41 (3H, m), 5.35 (1H, dd, J = 12.8, 0.8 Hz), 2.27 (1H, dt, J = 13.0, 3.7 Hz), 1.86

65 (1H, d, J = 13.5 Hz), 1.83 (1H, t, J = 4.4 Hz), 1.79-1.62 (1H, m), 1.52-1.30 (2H), 1.09-

13 0.80 (1H, m), 1.01 (3H, s), 0.95 (3H, s), 0.91 (3H, s), 0.25 (9H, s, -Si(CH3)3); C NMR

& APT (50 MHz, CDCl3) δ 234.3 (CO), 141.5 (C(arene complex)-O-), 138.9 (C1’),

116.6 (C2’), 99.9 (C-ortho to TMS), 99.6 (C-ortho to TMS), 93.1 (C-TMS or C2), 92.0

(C-TMS or C2), 82.9 (C-meta to TMS), 82.2 (C-meta to TMS), 54.2 (C1), 49.6 (C7),

45.5 (C4), 38.6 (C3), 30.4 (C6), 26.0 (C5), 21.1 (C8 or C9), 20.8 (C8 or C9), 10.1 (C10),

-1 -1.3 (-Si(CH3)3); FTIR (KBr) νmax cm .

General Procedure for Nucleophilic Addition/Electrophilic Addition/Demetallation

Sequence:

After an additional 30 minutes a solution of the arene tricarbonyl chromium complex (2.5 mmol, 1 equiv) in 12.5 mL of THF was added, followed immediately by the addition of anhydrous HMPA (5.4 mL, 31 mmol, 12.5 equiv). The resulting heterogeneous, yellow reaction mixture was warmed to -60 ºC and maintained at this temperature for the duration of the reaction. After 4 hours trifluoroacetic acid (5.2 mL, 67.5 mmol, 27 equiv) was added in one portion and the reaction mixture immediately turned to a deep red color. After 0.5 hours the reaction mixture was removed from the cooling bath and diluted with aqueous concentrated ammonia (5 mL). Finally, after an additional 0.5 hours the now heterogeneous green reaction mixture was diluted with additional aqueous

66 concentrated ammonia and extracted with ether. The combined ether extracts were washed with water, dried (MgSO4), then filtered and concentrated in vacuo and usually gave a green colored oil. The product was then purified by column chromatography using hexane/ethyl ether eluent system.

η6-{4-[Allyloxy]trimethylsilylbenzene}chromium tricarbonyl (II.9)

Cr(CO)3

Si(CH3)3

Complex II.9 was prepared from allyl alcohol and η6-(4- fluoro(trimethylsilyl)benzene)chromium tricarbonyl as a yellow solid. Yield: 86%; Rf:

+ 0.31 (20:1 hexane/ether); FAB HRMS m/z 342.0381 (M ), calcd for C15H18O4SiCr

1 342.0379; H NMR (300 MHz, CDCl3) δ 6.00 (1H, tdd, J = 17.3, 10.4 Hz, -CH2-

CH=CH2), 5.55 (2H, d, J = 6.9 Hz, arene H’s meta to TMS), 5.10 (2H, d, J = 6.9 Hz, arene H’s ortho to TMS), 5.42 (1H, dq, J = 17.3, 1.5 Hz, trans H), 5.36 (1H, dq, J = 10.4,

13 1.3 Hz, cis H), 4.44 (2H, dt, J = 5.5, 1.4 Hz,-O-CH2-CH=CH2), 0.27 (9H, s); C NMR and APT (50 MHz, CDCl3) δ 233.7 (CO), 143.4 (arene C-O-CH2-), 131.7 (-O-CH2-

CH=CH2), 119.1 (-O-CH2-CH=CH2), 113.0 (arene C-TMS), 99.9 (arene carbons meta to

TMS), 78.6 (arene carbons ortho to TMS), 69.3 (-O-CH2-CH=CH2), -1.2 (-Si(CH3)3);

FTIR (KBr) νmax 2934 (C-H stretch), 1966, 1885 (carbonyl), 1536, 1470 (substituted aromatic) cm-1.

67 η6-{4-[[2-(2-Methyl-3-butene)]oxy]trimethylsilylbenzene}chromium tricarbonyl

(II.10)

Cr(CO)3

Si(CH3)3 Complex II.10 was prepared from 3-hydroxy-3-methyl-butene and η6-(4- fluoro(trimethylsilyl)benzene)chromium tricarbonyl as a yellow solid. Yield: 90%; Rf:

+ 0.53 (20:1 hexane/ether); FAB HRMS m/z 370.0689 (M ), calcd for C17H22O4SiCr

1 370.0692; H NMR (200 MHz, CDCl3) δ 6.16 (1H, dd, J = 17.7 Hz, 10.9 Hz, -

C(CH3)2CH=CH2), 5.48 (2H, d, J = 7.1 Hz, arene H’s meta to TMS), 5.26 (1H, d, J =

17.1 Hz, cis H), 5.25 (1H, dd, J = 10.9 Hz, 0.6 Hz, trans H), 5.17 (2H, d, J = 7.1 Hz,

13 arene H’s ortho to TMS), 1.52 (2x3H = 6H, s), 0.25 (9H, s, -Si(CH3)3); C NMR and

APT (50 MHz, CDCl3) δ 234.2 (CO), 143.1 (-O-C(CH3)2-CH=CH2), 142.2 (arene C-O-

C(CH3)2-), 114.8 (-O-C(CH3)2-CH=CH2), 99.8 (arene carbons meta to TMS), 93.3 (arene

C-TMS), 82.5 (arene carbons ortho to TMS), 82.0 (-O-C(CH3)2-CH=CH2), 26.7 (-O-

C(CH3)2-CH=CH2) (-1.2 (-Si(CH3)3); FTIR (KBr) νmax 2971 (C-H stretch), 1956, 1868

(carbonyl), 1530, 1470 (substituted aromatic), 1262 cm-1.

tert-Butyl (2-trimethylsilyl-5-allyloxycyclohexa-2,4-dien-1-yl)acetate (II.11)

8 9 7 O 1 O 6 2 3 O 11 5 10 4 Si(CH3)3

68 Nucleophilic addition of tert-butyl lithio acetate to chromium complex II.9 followed by

1 protonation and decomplexation yielded II.11.Yield: 62%; Rf: (hexane/ether); H NMR

(200 MHz, CDCl3) δ 6.14 ( 1H, d, J = 5.9 Hz), 6.08 – 5.89 (1H, m), 5.40 – 5.20 (2H),

5.01 (1H, dd, J = 5.9 Hz, 2.2 Hz), 4.41 – 4.20 (2H), 2.85 – 2.73 (2H), 2.56 – 2.43 (1H, m), 2.44 – 2.31 (1H, m), 2.16 (1H, dd, J = 16.8 Hz, 2.0 Hz), 2.01 (1H, ddd, J = 14.9 Hz,

13 3.2 Hz, 0.8 Hz), 1.46 (9H, s, -COOC(CH3)3), 0.10 (9H, s, -Si(CH3)3); C NMR and APT

(50 MHz, CDCl3) δ 172.2 (C11), 157.5 (C1), 133.1 (C8 or C3), 133.0 (C8 or C3), 132.3

(C4), 117.4 (C9), 93.8 (C2), 80.3 (C6), 68.0 (C7), 36.8 (C10), 32.4 (C5), 31.5 (-

COOC(CH3)3), 28.2 (-COOC(CH3)3), -1.2 (-Si(CH3)3).

General procedure for decomplexing the chromium tricarbonyl to yield the arene:

The corresponding chromium tricarbonyl complex was taken and a solution in chloroform was made in a vial and the sample left in sunlight. After a week, the yellow solution turned completely colorless with green sediments at the bottom of the vial. To the solid green precipitate (with all the chloroform evaporated) was added about 2 mL of chloroform and the heterogeneous solution was passed through a short alumina pad. The filtrate was evaporated to yield white colored solid or colorless oil.

4-[[(1R,2S)-1,7,7-Trimethyl-2-phenyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene (II.1a) was prepared by decomplexation of II.1. The colorless filtrate was evaporated which revealed a white solid on cooling.

69 8 7 9 4 5 3 6 O 1 2 10 2' Si 3' 4'

1 Yield: 90%; Rf: (20:1 hexane/ether); H NMR (200 MHz, CDCl3) δ 7.52 – 7.25 (5H, m),

7.21 (2H, d, J = 8.6 Hz), 6.49 (2H, d, J = 8.6 Hz), 2.38 – 2.35 (1H, m), 1.90 – 1.58 (2H),

1.40 -1.08 (3H), 0.95 – 0.84 (1H, m), 1.18 (3H, s), 1.03 (3H, s), 0.97 (3H, s), 0.17 (9H, s,

13 -Si(CH3)3); C NMR & APT (50 MHz, CDCl3) δ 154.7 (C(aromatic)-O-), 140.8

(C(phenyl)-C2), 134.1 (two carbons C-ortho to TMS), 129.9 (C(aromatic)-TMS), 128.2,

128.1, 127.3, 126.7, 125.4 (preceding five signals correspond to five C-H carbons of the phenyl group), 117.7 (two carbons C-meta to TMS), 89.5 (C2), 55.1 (C1), 50.6 (C7), 45.8

(C4), 40.7 (C3), 30.5 (C6), 26.6 (C5), 21.8 (C8 or C9), 21.4 (C8 or C9), 10.2 (C10), -0.8

(-Si(CH3)3).

4-[[(1R,2R)-1,2,7,7-Tetramethylbicyclo[2.2.1]hept-2-yl]oxy]trimethylsilylbenzene

(II.2a) was prepared by decomplexation of II.2 and the colorless filtrate was evaporated to a colorless oil.

8 7 9 4 5 3 6 O 1 2 10 11 Si

1 Yield: 90%; H NMR (300 MHz, CDCl3) δ 7.35 (2H, d, J = 8.5 Hz), 6.78 (2H, d, J = 8.6

Hz), 2.48 (1H, dt, J = 14.0, 4.0 Hz), 2.04 – 1.40 (3H), 1.42 – 0.80 (3H), 1.27 (3H, s), 1.15

13 (3H, s), 0.84 (3H, s), 0.73 (3H, s), 0.24 (9H, s, -Si(CH3)3); C NMR (75 MHz, CDCl3) δ

70 156.4 (C(aromatic)-O-), 134.0 (C(aromatic)-ortho to TMS), 129.4 (C(aromatic)-TMS),

118.3 (C(aromatic)-meta to TMS), 55.8 (C1), 50.0 (C7), 45.32 (C4), 45.31 (C3), 29.8

(C6), 26.5 (C5), 21.3 (C8 or C9 or C11), 21.26 (C8 or C9 or C11), 21.20 (C8 or C9 or

C11), 13.2 (C10), -0.8 (-Si(CH3)3).

4-[[(1R,2S)-1,7,7-Trimethyl-2-benzyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene (II.15a) was prepared by decomplexation of complex

II.15 and solvent evaporation yielded a while solid.

8 7 9 4 5 3 6 O 1 10 2 Si

1 13 Yield: 90%; H NMR (400 MHz, C6D6) δ 0.27 (9H, s); C NMR (100 MHz, C6D6) δ

155.5 (C(arene complex)-O-), 138.8 (C(aromatic)-CH2-), 135.1 (C-ortho to TMS), 130.8

(C(aromatic)-TMS), 129.7, 127.6, 126.4 (preceding three signals correspond to C-H of the benzyl aromatic ring carbons), 118.2 (C(aromatic)-meta to TMS), 88.9 (C2), 54.8

(C1), 50.3 (C7), 45.3 (C4), 44.0 (-CH2-Ph), 41.4 (C3), 30.6 (C6), 27.1 (C5), 21.2 (C8 or

C9), 20.9 (C8 or C9), 12.1 (C10), -0.8 (-Si(CH3)3).

Temperature Dependent Chemical Shift variation studies:

13C NMR chemical shift variation with temperature of complex II.16 (150 MHz, THF- d8): Temperature = -35 °C: δ 235.3, 160.2, 143.0, 132.6, 130.2, 127.8, 114.2, 113.8,

102.1, 101.3, 94.00, 93.97, 84.8, 83.9, 56.0, 55.3, 50.9, 46.5, 40.0, 31.1, 26.5, 22.1, 21.8,

10.2, -1.3; Temperature = -25 °C: δ 235.3, 160.3, 142.9, 132.7, 130.3, 127.8, 114.2,

71 113.8, 101.9, 101.1, 94.1, 94.0, 84.9, 83.9, 56.0, 55.3, 50.9, 46.5, 40.1, 31.2, 26.5, 22.0,

21.8, 10.2, -1.3; Temperature = -15 °C: δ 235.2, 160.4, 142.7, 132.8, 130.4, 127.7, 114.2,

113.9, 101.7, 100.9, 94.2, 94.1, 85.0, 83.9, 56.0, 55.3, 50.9, 46.5, 40.1, 31.2, 26.5, 22.0,

21.8, 10.2, -1.3; Temperature = -5 °C: δ 235.2, 160.4, 142.7, 132.8, 130.4, 127.7, 114.2,

113.9, 101.5, 100.8, 94.3, 94.1, 85.0, 83.9, 56.1, 55.3, 50.9, 46.6, 40.1, 31.2, 26.5, 22.0,

21.8, 10.2, -1.3; Temperature = 5 °C: δ 235.2, 160.4, 142.6, 132.8, 130.6, 128.6, 127.6,

114.2, 113.9, 101.4, 100.6, 94.4, 94.1, 85.1, 83.9, 56.1, 55.4, 50.9, 46.6, 40.2, 31.2, 26.5,

22.0, 21.7, 10.2, -1.3; Temperature = 15 °C: δ 235.1, 160.5, 142.5, 132.9, 130.5, 128.6,

127.6, 114.3, 114.0, 101.3, 100.5, 94.5, 94.2, 85.2, 83.9, 56.1, 55.4, 50.9, 46.7, 40.2, 31.2,

26.5, 22.0, 21.7, 10.2, -1.3; Temperature = 25 °C: δ 235.1, 160.5, 142.4, 132.9, 130.6,

128.6, 127.6, 114.3, 114.0, 101.1, 100.4, 94.6, 94.2, 56.1, 55.4, 50.9, 46.7, 40.2, 32.6,

31.3, 26.6, 22.0, 21.7, 10.2, -1.3.

1H NMR chemical shift variation (of the complexed arene protons) with temperature of complex II.1 (600 MHz, THF-d8):

Temperature δH1 δH2 δH3 δH4 (°C) (ppm) (ppm) (ppm) (ppm) 25 5.55 5.48 4.95 4.87 0 5.5735 5.4900 4.9275 4.8610 -11 5.6055 5.5120 4.9335 4.8775 -20 5.6335 5.5305 4.9385 4.8920 -30 5.6630 5.5485 4.9430 4.9065 -40 5.6950 5.5675 4.9470 4.9260 -50 5.7290 5.5850 4.9470 4.9470 -60 5.7620 5.6045 4.9610 4.9610 -70 5.8065 5.6225 4.9575 4.9980 -80 5.8465 5.6365 4.9565 5.0220

APPENDIX TO CHAPTER II

1H NMR, 13C NMR , 1H-1H COSY, 1H-13C HMQC, NOE & 13C NMR assignments

Of Complexes II.1 – II.3, II.13 – II.16 &

1H NMR and 13C NMR of II.1a, II.2a, II.15a

73 1 13 H NMR (600 MHz, THF-d8) & C NMR (150 MHz, THF-d8) of II.1

74 1 1 H- H COSY (600 MHz, THF-d8) of II.1

75 1 13 H- C HMQC (600 MHz, THF-d8) of II.1

76 1 H NOE (600 MHz, THF-d8) of II.1

77 Representation of NOEs of complex II.1 (600 MHz, THF-d8) and final assignment of arene carbons:

O Si

Cr OC CO OC II.1

δH3 (4.95 ppm)

δH2 δC4

δC2

δC2 δC1

δH4 Cr δH1 (4.87 ppm) OC OC CO

OR*

COSY: δH1-δH4, δH2-δH3 δC4 δC3 HMQC: δH1-δC1, δH2-δC2, δH3-δC4, δH4-δC3 A edge B edge NOE: δH & δH are ortho to -TMS face face 1 2 δC 2 δC1

78 1 13 H NMR (600 MHz, THF-d8) & C NMR (50 MHz, THF-d8) of II.2

79 1 1 H- H COSY (600 MHz, THF-d8) of II.2

80 1 13 H- C HMQC (600 MHz, THF-d8) of II.2

81 1 H NOE (600 MHz, THF-d8) of II.2

82 Representation of NOEs of complex II.2 (600 MHz, THF-d8) and final assignment of arene carbons:

O Si

Cr OC CO OC II.2

δH4 (5.13 ppm)

δH2 δC4

δC2 δC δC3 1

δH 3 δH1 Cr (5.27 ppm) CO OC CO

OR*

COSY: δH1-δH3, δH2-δH4 δC4 δC3 HMQC: δH1-δC1, δH2-δC2, δH3-δC3, δH4-δC4 A edge B edge NOE: δH & δH are ortho to -TMS face face 1 2 δC 2 δC1

83 1 13 H NMR (600 MHz, THF-d8) & C NMR (50 MHz, THF-d8) of II.3

84 1 1 H- H COSY (600 MHz, THF-d8) of II.3

85 1 13 H- C HMQC (600 MHz, THF-d8) of II.3

86 1 H NOE (600 MHz, THF-d8) of II.3

87 Representation of NOEs of complex II.3 (600 MHz, THF-d8) and final assignment of arene carbons:

O O Si

H Cr OC CO OC II.3

δH4 (5.29 ppm) δH1

δC3

δC1

CO Cr δC 2 CO δC4 CO

δH2 δH3 (5.32 ppm)

OR*

COSY: δH1-δH4, δH2-δH3 δC3 δC4 HMQC: δH1-δC1, δH2-δC2, δH3-δC4, δH4-δC3 A edge B edge face face NOE: δH1 & δH2 are ortho to -TMS δC 1 δC2

88 1 13 H NMR (600 MHz, C6D6) & C NMR (50 MHz, C6D6) of II.3

89 1 1 H- H COSY (400 MHz, C6D6) of II.3

90 1 13 H- C HSQC (400 MHz, C6D6) of II.3

91 1 H NOE (600 MHz, C6D6) of II.3

92 Representation of NOEs of complex II.3 (600 MHz,C6D6) and final assignment of arene carbons:

O O Si

H Cr OC CO OC II.3

δH4 (4.85 ppm) δH3

δC3

δC1

CO Cr δC 2 CO δC4 CO

δH1 δH2 (5.12 ppm)

OR*

COSY: δH1-δH2, δH3-δH4 δC3 δC4 HMQC: δH1-δC2, δH2-δC4, δH3-δC1, δH4-δC3 A edge B edge face face NOE: δH1 & δH3 are ortho to -TMS δC 1 δC2

93 1 13 H NMR (600 MHz, THF-d8) & C NMR (50 MHz, THF-d8) of II.13

1 1 H- H COSY (600 MHz, THF-d8) of II.13

95 1 13 H- C HMQC (600 MHz, THF-d8) of II.13

96 1 H NOE (600 MHz, THF-d8) of II.13

97 Representation of NOEs of complex II.13 (600 MHz, THF-d8)and final assignment of arene carbons:

O Si

Cr OC CO OC II.13

δH4 (4.91 ppm)

δC4

δC2 δH3 δC3

δH2 (5.37 ppm) δC OC Cr 1

OC CO δH1

OR*

COSY: δH -δH , δH -δH δC δC4 1 2 3 4 3 B edge HMQC: δH -δC , δH -δC , δH -δC , δH -δC A edge 1 1 2 3 3 2 4 4 face face NOE: δH1 & δH3are ortho to -TMS δC1 δC2

98 1 13 H NMR (600 MHz, C6D6) & C NMR (150 MHz, C6D6) of II.14

99 1 1 H- H COSY (600 MHz, C6D6) of II.14

100 1 13 H- C HMQC (400 MHz, C6D6) of II.14

101 1 H NOE (600 MHz, C6D6) of II.14

102 NOEs of complex II.14 (600 MHz, C6D6) and final assignment of arene carbons:

O Si

Cr OC CO OC II.14

δH4 (4.50 ppm) δH δC3 3

δC1 δC4

δC2 δH2 (4.65 ppm) Cr δH1 OC OC CO

OR*

COSY: δH1-δH2, δH3-δH4 δC4 δC3 HMQC: δH1-δC2, δH2-δC4, δH3-δC1, δH4-δC3 A edge B edge NOE: δH & δH are ortho to -TMS face face 1 3 δC 2 δC1

103 1 13 H NMR (600 MHz, THF-d8) & C NMR (50 MHz, THF-d8) of II.15

104 1 1 H- H COSY (600 MHz, THF-d8) of II.15

105 1 13 H- C HMQC (600 MHz, THF-d8) of II.15

106 1 H NOE (600 MHz, THF-d8) of II.15

107 Representation of NOEs of complex II.15 (600 MHz, THF-d8)and final assignment of arene carbons:

O Si

Cr OC CO OC II.15

δH4 (5.36 ppm) δH1 δC3

δC1

δC4

δC2

δH3 (5.51 ppm) Cr δH2 OC CO OC

OR*

COSY: δH -δH , δH -δH δC δC4 1 4 2 3 3 B edge HMQC: δH -δC , δH -δC , δH -δC , δH -δC A edge 1 1 2 2 3 4 4 3 face face δC NOE: δH1 & δH2 are ortho to -TMS 1 δC2

108 1 13 H NMR (600 MHz, CDCl3) & C NMR (50 MHz, CDCl3) of II.16

109 1 1 H- H COSY (600 MHz, CDCl3) of II.16

110 1 13 H- C HMQC (600 MHz, CDCl3) of II.16

111 1 H NOE (600 MHz, CDCl3) of II.16

112 Representation of NOEs of complex II.16 NOE (600 MHz, CDCl3)and final assignment of arene carbons:

O Si

Cr OC CO OC II.16

δH3 (4.83 ppm) δC δH 4δC2 2

δC3 δH4 δC1 (4.70 ppm) δH1 Cr OC OC CO

OR*

COSY: δH1-δH4, δH2-δH3 δC4 δC3 HMQC: δH1-δC1, δH2-δC2, δH3-δC4, δH4-δC3 A edge B edge NOE: δH & δH are ortho to -TMS face face 1 2 δC 2 δC1

113 1 1 13 H NMR (200 MHz, CDCl3) & C NMR (50 MHz, CDCl3) of II.1a

114

1 13 H NMR (300 MHz, CDCl3) & C NMR (75 MHz, CDCl3) of II.2a

115 13 H NMR (400 MHz, C6D6) & C NMR (100 MHz, C6D6) of II.15a

116 References

1 Solladié-Cavallo, A. “Arene-chromium tricarbonyl complexes: bonding and behavior.”

Polyhedron, 1985, 4, 901-927 and references sited therein.

2 McGlinchey, M. J. “Slowed tripodal rotation in arene-chromium complexes: steric and electronic barriers.” Adv. Organomet. Chem. 1992, 34, 285-325 and references sited therein.

3 (a) Semmelhack, M. F. “Nucleophilic addition to arene-metal complexes.” In

Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,

1991; Vol. 4, 517-549. (b) Morris, M. J. “Arene and heteroarene complexes of chromium, molybdenum and tungsten.” In Comprehensive Organometallic Chemistry II; Abel, E.

W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995, Vol. 5, 471-549. (c)

Semmelhack, M. F. “Transition metal arene complexes: Nucleophilic addition.” In

Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson,

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4 Albright, T. A.; Hofmann, P.; Hoffmann, R. “Conformational preferences and rotational barriers in polyene-ML3 transition metal complexes.” J. Am. Chem. Soc. 1977, 99, 7546.

5 Kilway, K. V.; Siegel, J. S. “Effect of transition-metal complexation on the stereodynamics of persubstituted arenes. Evidence for steric complementarity between arene and metal tripod.” J. Am. Chem. Soc. 1992, 114, 255-261.

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6 Kilway, K. V.; Siegel, J. S. “Evidence for gated stereodynamics in [1,4-bis(4,4- dimethyl-3-oxopentyl)-2,3,5,6-tetraethylbenzene]chromium tricarbonyl.” J. Am. Chem.

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7 Gilbert, T. M.; Bond, A. H.; Rogers, R. D. “Structures of (η5-benzene dimethylacetal)- and (η6-benzene diethylacetal)chromium tricarbonyl: structural evidence for the near- electroneutrality of the dialkylacetal substituent.” J. Organomet. Chem., 1994, 479, 73-

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8 Gambaro, A.; Ganis, P.; Manoli, F.; Polimeno, A.; Santi, S.; Venzo, A. “Experimental evidence at atomic resolution of intra- and intermolecular CO...π(arene) bond interactions.” J. Organomet. Chem., 1999, 583, 126-130.

9 (a) Ceccon, A.; Gambaro, A.; Manoli, F.; Venzo, A.; Ganis, P.; Valle, G.; Kuck, D.

“Synthesis and structural investigation of tricarbonylchromium mono-, bis-, and tris- complexes of triptindan.” Chem. Ber. 1993, 126, 2053-2060. (b) Ceccon, A.; Gambaro,

A.; Manoli, F.; Venzo, A.; Kuck, D.; Bitterwolf, T. E.; Ganis, P.; Valle, G. “Synthesis and structure of tricarbonylchromium mono-, bis- and tris- complexes of 10- methyltribenzotriquinacene.” J. Chem. Soc., Perkin Trans. 2, 1991, 233-241. (c)

Bitterwolf, T. E.; Ceccon, A.; Gambaro, A.; Ganis, P.; Kuck, D.; Manoli, F.; Rheingold,

R. L.; Valle, G.; Venzo, A. “Tricarbonylchromium complexes of centropolyindans. Part

4. Physicochemical and structural characterization of anti-Cr(CO)3-4b,9,9a,10- tetrahydroindeno[1,2-a]indene, syn-Cr(CO)3-4b,9,9a,10-tetrahydroindeno[1,2-a]indene and syn,anti-[Cr(CO)3]2-4b,9,9a,10-tetrahydroindeno[1,2-a]indene.” J. Chem. Soc.,

Perkin Trans 2, 1997, 735-741. (d) Ceccon, A.; Gambaro, A.; Manoli, F.; Venzo, A.;

Ganis, P.; Kuck, D.; Valle, G. “Tricarbonylchromium complexes of centro-polyindans.

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Part 2. Synthesis and structure of tricarbonylchromium mono- and bis-complexes of

4b,5,9b,10-tetrahydroindeno[2,1-a]indene.” J. Chem. Soc., Perkin Trans 2, 1992, 1111-

1117.

10 Saillard, J. Y.; Lissillour, R.; Grandjean, D. “Molecular conformation and crystalline stacking: example of substituted derivatives benzenechromium tricarbonyl. I. Theoretical determination of molecular conformations. Comparison with crystal conformations.” J.

Organomet. Chem., 1981, 210, 365-376.

11 Albright, T. A. “Rotational barriers and conformations in transition metal complexes.”

Acc. Chem. Res. 1982, 15, 149-155.

12 Muetterties, E. L.; Bleeke, J. R.; Wucherer, E. J.; Albright, T. A. “Structural, stereochemical, and electronic features of arene-metal complexes.” Chem. Rev. 1982, 82,

499-525.

13 Chiu, N. S.; Schäfer, L.; Seys, R. “Internal rotation in gaseous benzenechromium tricarbonyl.” J. Organomet. Chem. 1975, 101, 331-346.

14 Jackson, W. R.; Jennings, W. B.; Spratt, R. “Restricted rotation in tricarbonyl(arene)chromiums.” J. Chem. Soc. D, 1970, 593.

15 Mislow, K.; Raban, M. “Stereoisomeric relations of groups in molecules.” Top.

Stereochem. 1967, 1, 1.

16 Mangini, A.; Taddei, F. “Proton magnetic resonance spectra and solvent effect of some benzenechromium tricarbonyls.” Inorg. Chim. Acta, 1968, 2, 8-11.

17 Maricq, M. M.; Waugh, J. S.; Fletcher, J. L.; McGlinchey, M. J. “Anisotropic ring- carbon chemical shifts in arene chromium tricarbonyl complexes.” J. Am. Chem. Soc.

1978, 100, 6902-6904.

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18 For illustrative examples of solution state conformation shown to be same as solid state conformation: (a) Rose-Munch, F.; Khourzom, R.; Djukic, J.-P.; Rose, E.; Langlois, B.;

Vaisserman, J. “Conformational study of η6-[4-(trifluoromethoxy)aniline]tricarbonyl chromium.” J. Organomet. Chem. 1994, 470, 131-135. (b) Stewart, K. R.; Levine, S. G.;

McPhail, A. T. “Induced conformational preference via metal carbonyl complexation: proton NMR and x-ray crystallographic studies of 4-chromanonechromium(0) tricarbonyl.” J. Organomet. Chem. 1984, 263, 45-53. (c) Prim, D.; Tranchier, J.-P.; Rose-

Munch, F.; Rose, E.; Vaissermann, J. “Tricarbonyl-η6-[(2-thiophenyl)arene]- and - η6-

[(2-thiophenyl)carbonylarene]-chromium complexes: preparation and conformational study.” Eur. J. Inorg. Chem. 2000, 901-905. (d) Mailvaganam, B.; Perrier, R. E.; Sayer,

B. G.; McCarry, B. E.; Bell, R. A.; McGlinchey, M. J. “Chromium tricarbonyl complexes of methyl O-methylpodocarpate: differentiation of diastereomers by high-field NMR spectroscopy.” J. Organomet. Chem. 1988, 354, 325-340. (e) Levisalles, J.; Rose-Munch,

F.; Rose, E.; Semra, A.; Garcia Oricain, J.; Jeannin, Y.; Robert, F. “Conformation of tricarbonyl[2,3-dimethyl-1-(triisopropylsiloxy)benzene]chromium and regioselectivity of its lithiation.” J. Organomet. Chem. 1987, 328, 109-122. (f) Rose-Munch, F.; Rose, E.;

Semra, A.; Filoche, M. “Nucleophilic aromatic substitutions SNAr on 2,6- dimethylchlorobenzenechromium tricarbonyl.” J. Organomet. Chem. 1989, 363, 123-130.

19 Djukic, J. –P.; Rose-Munch, R.; Rose, E.; Vaissermann, J. “"Distorted" (η6- arene)tricarbonylchromium complexes: Correlation of structural parameters with the electronegativity cG and Hammett constants σ of arene substituents.” Eur. J. Inorg.

Chem., 2000, 1295-1306.

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20 Castro, C. E.; Stephens, R. D.; Moje, S. “The reduction of multiple bonds by low- valent transition metal ions. The homogeneous reduction of olefins by chromous sulfate.”

J. Am. Chem. Soc. 1966, 88, 4964-4969.

21 (a) Crandall, J. K.; Heitmann, W. R. “Reduction of acetylenes by chromium(II)-amine complexes.” J. Org. Chem. 1979, 44, 3471-4. (b) Kochi, J. K.; Singleton, D. M.;

Andrews, L. J. “Alkenes from halides and epoxides by reductive eliminations with chromium(II) complexes.” Tetrahedron 1968, 24, 3503-15. (c) Omoto, M.; Kato, N.;

Sogon, T.; Mori, A. “Revisit to the reduction of allylic chlorides to less substituted olefins by a low-valent chromium species in the presence of a proton source.”

Tetrahedron Lett. 2001, 42, 939-941.

22 Tang, L.; Papish E. T.; Abramo G., P.; Norton J. R.; Baik, M.-H.; Friesner R. A.;

Rappe, A. J. Am. Chem. Soc. 2003, 125, 10093-10102.

23 (a) Kündig, E. P.; Pache, S. H. “Product class 4: arene organometallic complexes of chromium, molybdenum, and tungsten.” Sci. Syn. 2003, 2, 153-228. (b) Nesmeyanov, A.

N.; Krivykh, V. V.; Il'minskaya, E. S.; Rybinskaya, M. I. “Cationic areneallyldicarbonylchromium complexes.” J. Organomet. Chem., 1981, 209, 309-321.

Rybinskaya, M. I. “Synthesis and spectral study of chelate alkenylarenedicarbonyl complexes of chromium, molybdenum and tungsten.” J. Organomet. Chem., 1978, 162,

323-342. (d) Donnini, G. P.; Shaver, A. “Arene-chromium complexes: photochemical substitution of phosphine and phosphite ligands by olefin.” Can. J. Chem. 1978, 56,

1477-1481. (e) Trahanovsky, W. S.; Hall, R. A. “Arene-metal complexes. 11. Conversion of (η8-allyl phenyl ether)dicarbonylchromium to (π-allyl)(6-

121 oxocyclohexadienyl)dicarbonylchromium.” J. Am. Chem. Soc., 1977, 99, 4850-4851. (f)

Trahanovsky, W. S.; Hall, R. A. “Arene-metal complexes. VIII. Preparation of η8- alkenylbenzene)dicarbonylchromium complexes.” J. Organomet. Chem., 1975, 96, 71-

82. (g) Nesmeyanov, A. N.; Rybinskaya, M. I.; Krivykh, V. V.; Kaganovich, V. S.

“Chelate areneolefindicarbonylchromium complexes.” J. Organomet. Chem., 1975, 93,

C8-C10.

24 (a) Uang, B.-J.; Po, S.-Y.; Hung, S.-C.; Liu, H.-H.; Hsu, C.-Y.; Lin, Y.-S.; Chang, J.-

W. “Asymmetric synthesis employing chiral ketones as templates.” Pure App. Chem.

1997, 69, 615-620. (b) Oppolzer, W. “Camphor as a natural source of chirality in asymmetric synthesis.” Pure App. Chem. 1990, 62, 1241-50. (c) Oppolzer, W. “Camphor derivatives as chiral auxiliaries in asymmetric synthesis.” Tetrahedron 1987, 43, 1969-

2004.

25 Spartan'02 Wavefunction, Inc. Irvine, CA.

26 Hunter, A. D.; Shilliday, L.; Furey, W. S.; Zaworotko, M. J. “Substituent interactions in η6-arene complexes. 1. Systematic x-ray crystallographic study of the structural manifestations of π-donor and π-acceptor substituent effects in substituted chromium (η6- arene)Cr(CO)3 complexes.” Organometallics 1992, 11, 1550-1560.

27 Campi, E. M.; Gatehouse, B. M. K.; Jackson, W. R.; Rae, I. D.; Wong, M. G.

“Restricted rotation about arene-oxygen bonds in some 1,3-di-tert-butyl-2- methoxyarenedicarbonylphosphorus(III)chromium compounds.” Can. J. Chem. 1984, 62,

2566-

28 Neuhaus, D.; Williamson, M. P. The Nuclear Overhauser Effect in Stereochemical and

Conformational Analysis, VCH Publishers, Weinheim, 1990.

122

29 Van Meurs, F.; Van der Toorn, J. M.; Van Bekkum, H. “Substituent effects in p-

(tricarbonylchromium)arenes. I. Proton NMR spectroscopy of alkyl-substituted p-

(tricarbonylchromium)benzenes.” J. Organomet. Chem. 1976, 113, 341-351.

30 Weissensteiner, W.; Hofer, O.; Wagner, U. G. “Conformation and internal mobility of

10,11-dihydro-5H-dibenzo[α,δ]cycloheptene derivatives in solution. Conformational analysis of highly flexible structures.” J. Org. Chem. 1988, 53, 3988-3996.

31 Pihlaja, K.; Kleinpeter, E. Carbon-13 NMR Chemical Shifts in Structural and

Stereochemical Analysis, VCH Publishers, Winheim, 1994.

32 (a) Mann, B. E. “Carbon-13 NMR chemical shifts and coupling constants of organometallic compounds.” Adv. Organomet. Chem., 1974, 12, 135- 213. (b) Jolly, P.

W.; Mynott, R. “The application of carbon-13 NMR spectroscopy to organo-transition metal complexes.” Adv. Organomet. Chem., 1981, 19, 257-304.

33 Desobry, V.; Kundig, E. P. “Naphthalene complexes. Part 2. A carbon-13 NMR study of naphthalene chromium complexes. Correlation with reactivity: nucleophilic aromatic substitution reactions.” Helv. Chim. Acta, 1981, 64, 1288-1297.

34 For a few other reports of conformer population calculation using Jackson’s equation see: (a) Szczecinski, P. “Application of scalar carbon-13/fluorine-19 spin-spin couplings between carbonyl carbons and aromatic fluorine to investigations of conformation of tricarbonylchromium complexes of fluorobenzenes.” J. Organomet. Chem. 1992, 423,

23-29. (b) Boutonnet, J. C.; Mordenti, L.; Rose, E.; Le Martret, O.; Precigoux, G.

“Organometallic chemistry. XXII. Synthesis of substituted arenes by the addition of a nucleophile to an arenechromium tricarbonyl and then oxidative decomplexation of the metal.” J. Organomet. Chem., 1981, 221, 147-156. (c) Rose-Munch, F.; Aniss, K.;

123

Roses, E.; Vaisserman, J. “Synthesis and conformation of complexes obtained by reaction of carbanions of α-imino esters or nitriles with

(halobenzene)tricarbonylchromium.” J. Organomet. Chem. 1991, 415, 223-255.

35 (a) Martin, G. E.; Zetzker, A. S. 2D NMR Methods for Establishing Molecular

Connectivity; A Chemist’s Guide to Experimental Section, Performance, and

Interpretation, VCH Publishers, Weinheim, 1988. (b) Croasmun, W. R.; Carlson, R. M.

K. 2D NMR Spectroscopy; Applications for Chemists and Biochemists, VCH Publishers,

Weinheim, 1987.

36 Mailvaganam, B.; Perrier, R. E.; Sayer, B. G.; McCarry, B. E.; Bell, R. A.;

McGlinchey, M. J. “Chromium tricarbonyl complexes of methyl O-methylpodocarpate: differentiation of diastereomers by high-field NMR spectroscopy.” J. Organomet. Chem.

1988, 354, 325-340.

37 Roques, B. P.; Segard, C.; Combrisson, S.; Wehrli, F. “Carbon-13 NMR low temperature study of the rotation around the chromium-arene bond.” J. Organomet.

Chem. 1974, 73, 327-330.

1289-1291.

124

CHAPTER III

13C NMR Chemical Shifts of Arene Chromium Tricarbonyl Complexes

125 III.1 Conformational Analysis of Arene Chromium Tricarbonyl Complexes

Conformational analysis of arene chromium tricarbonyl complexes, more precisely the orientation of the chromium tricarbonyl tripod with respect to the arene substituents has been extensively studied by X-ray crystallography analysis and NMR spectroscopy1 and less extensively by dipole moment and electric bireferengence.2 The conformational analysis under question is the equilibrium in solution between the two rotamers, anti-eclipsed rotamer III.A and syn-eclipsed rotamer III.B (Figure III.1).

R R

anti-eclipsed III.A syn-eclipsed III.B

Figure III.1 Anti- and syn-eclipsed conformers III.A and III.B

The solid state Cr(CO)3 tripod orientation has always been found to exist in solution state too.3 The factors affecting the conformation of the tripod were discussed in detail in Chapter II. In the absence of steric effects, the conformation of the tricarbonyl is syn-eclipsed with electron donating groups and anti-eclipsed to electron withdrawing groups on the arene, i.e., one of the chromium carbonyl bonds is eclipsed with the arene and substituent bond (Carter and Hofmann models).4 It is generally accepted that regioselectivity of nucleophilic addition to arene chromium tricarbonyls is related to the orientation of the chromium tricarbonyl tripod with respect to the arene substituents,5 which has inspired studies to correlate conformer populations with regioselectivity.

Determination of the population distribution of conformers III.A and III.B by 1H and 13C

NMR analysis has not provided any conclusive analysis, though numerous papers have appeared since 1971.6

126 III.1.1 Reports on NMR Conformational Analysis and Correlation with

Regioselectivity of Nucleophilic Addition

All the reported conformational analyses have considered the aforementioned equilibrium to exist and the chemical shifts, both proton and carbon, to be affected significantly by the population distribution along with other factors. Jackson et al7 proposed the conformer population equation based on temperature dependent NMR chemical shift with certain assumptions. The population PB was calculated using the relation PB = (θmax – θ)/2θmax, where θmax is the signal separation between meta and ortho and para protons, in the individual conformers and θ is the signal separation at the temperature of the experiment.

For mono-substituted benzene chromium tricarbonyl complexes, van Meurs et al8 have determined the syn-elipsed conformer III.B population using the Jackson equation.

PB = (0.5 – Θ/ Θmax) x 100 where Θ = θmeta – θpara with Θmax = 1.21 ppm and θ values are the differences in proton chemical shift between the arene and the complex at the corresponding position (Table III.1).

-R Θ (ppm) PB (%) -Methyl +0.20 67 -Ethyl +0.06 55 -neo Pentyl +0.14 62 -iso propyl -0.10 42 -tert-Butyl -0.29 26 -tert-Ethyl -0.43 15 -CH(tert-Butyl)2 -0.60 -

Table III.1 Θ–Values and Populations of conformation III.B (PB) in C6H5RCr(CO)3 at 33±5 ºC

127 Solladie-Cavallo et al9 have determined conformer populations using 1H chemical shifts by taking into account substituent effects at each arene position, considering them to vary from free arene to complex. The PB values obtained are better than those of van

Meurs et al. A treatment similar to that of 1H chemical shift for 13C chemical shift was reported to be unsuitable for determination of conformer population.

Roques et al10 have reported a method similar to van Meurs et al. In addition to using 1H chemical shift, the 13C chemical shift at the para carbon of the complex has been used to determine the population using the following equation, claiming that complexation does not significantly change the transmission of electronic substituent effects to the para position:

δ(C)obs = δ(C)PIc + ∆(Rfree) + θ where δ(C)PIc is the carbon chemical shift in benzene-Cr(CO)3, ∆(Rfree) is the substituent parameter (δ(C)para – δ(C) of benzene) and θ is the localization of the Cr-CO bond, which is zero for benzene. In general the PB (%) values do not match well with the regioselectivity of nucleophilic addition. While credit must be accorded for taking into account the effect in chemical shift due to localization of the Cr-CO bond, the sole consideration of the chemical shift of just the para carbon has arguably led to errors.

Brocard et al11 have reported conformer populations for mono-, 1,4-disubstituted and 1,3-disubstituted arene chromium tricarbonyl complexes with 1H chemical shifts, calculated and used substituent effects in the complex, and obtained values that correlate reasonably with regioselectivity of nucleophilic addition.

128 III.1.2 Drawbacks in the NMR Analysis

Earlier reports on conformer population do not correlate well with the regioselectivities of nucleophilic addition to arene chromium tricarbonyls, though there have been claims of the same.12 The following are what we perceive as the drawbacks in the earlier analyses.

(i) Anisotropy of the Chromium-Carbonyl bond: The anisotropy of the

chromium-carbonyl bond which is thought to affect the chemical shifts is not

well studied. While a carbon or proton that eclipses the metal-carbonyl bond

is thought to be more deshielded, the shielding or deshielding influence on

other carbonsor protons is not considered at all and the combined influence of

all three chromium-carbonyl bonds is not taken into account. Moreover there

is confusion whether to invoke the anisotropy of the metal-carbon bond or the

carbon-oxygen bond.

(ii) Localization of the Cr-CO Bond: Except for the report by Roques et al, there

is a complete disregard for a predominance of a conformation which is

intermediate between syn-eclipsed and anti-eclipsed in solution as in the solid

sate, wherein the conformation of the Cr(CO)3 tripod is not perfectly syn-

eclipsed or anti-eclipsed. This factor corresponds to the localization term θ

introduced by Roques et al and conformer populations disregarding this term

might prove to be erroneous.

(iii) Reference Chemical Shift: Some analyses have involved a reference chemical

shift of tert-butylbenzene chromium tricarbonyl which is known to be

completely anti-eclipsed. The extent to which the shielding occurs depends on

129 the electron richness of the arene, which in turn depends on the substituents.

Therefore, to base the conformer population calculations for arene complexes

of varied electron density, on a single standard reference chemical shift of

tert-butylbenzene chromium tricarbonyl, would obviously involve some

errors.

(iv) Substituent Effect: One invokes transmission of substituent effects in aromatic

systems. There has been controversy regarding whether the arene on

complexation is still aromatic13 or changed to anti-aromatic. Recently

researchers reported evidence for the anti-aromatic nature of the arene on

14 15 16 complexation with Cr(CO)3. Jackson et al and a few others also support

the non-transmission of π–substituent effects (non-aromatic) by the chromium

tricarbonyl, while a majority of groups who have attempted to determine

conformer populations have invoked the substituent effect term. This issue is

still not resolved and presents a contradictory picture on the influence of

substituents on the chemical shifts of arene chromium tricarbonyl complexes.

Considering all this, it can be postulated that the chemical shift of the complexed carbons are affected mainly by two factors: (i) the chemical shift averaging due to relative population of the two conformations A and B and (ii) the extent of localization of the Cr-CO bond with respect to the arene-substituent bond, assuming substituent effects to be invariant in going from arene to the complex. Even if this is the case, the question is whether there is a way to delineate the effect of the conformer population from the anisotropy due to localization of the carbonyl ligand. The complexation shift (d)

130 represents the difference in the 13C chemical shifts between the complexed arene (C’n) and the arene (Cn) and conceptually it is difficult to differentiate the former two contributing factors in the d values.

III.2 13C NMR Chemical Shifts in Conformational Analysis

We revisited the subject in view of the inconsistencies in the NMR conformational analysis reported so far and due to our interest in understanding selectivity in nucleophilic addition to arene chromium tricarbonyls as they present a simple entry into complex organic molecules. In the stereochemical analysis of medium to large ring natural products, 13C chemical shifts have been considered the most sensitive and are successfully applied to such problems.17 Even in arene chromium chemistry, the

13C chemical shifts of naphthalene chromium complexes with varied ligands have been correlated with the reactivity toward nucleophilic addition.18 The application of 13C chemical shift analysis (and also 1H NMR analyses) to this conformer population problem has so far been largely unsuccessful.19 We wish to present our findings relating to understanding the conformation problem in terms of the 13C NMR chemical shifts

(CCS) and its relation to regioselectivity of nucleophilic addition.

The shielding of the arene carbons on complexation with chromium tricarbonyl can be viewed as a combination of various different factors.20 Simply stated the 13C chemical shifts can be viewed as due to two interrelated effects, one being the electron charge density perturbations due to molecular orbital overlap, and the second is the anisotropic shielding by the chromium-carbonyl tripod. Interestingly, in all the

131 conformational analysis so far the first question which arose was whether 13C chemical shifts indeed represent the time averaged chemical shift values of the possible conformations, or whether they simply represent the electron densities of the carbon atoms, as with simple arenes.

III.2.1 13C Chemical Shift and Anisotropy of the Chromium Tricarbonyl Tripod

The diamagnetic anisotropy of the chromium-carbonyl covalent bond has not been specifically studied so far, while that of common bonds in organic molecules have been elaborated in terms of magnetic shielding cones (Figure III.2). These shielding and deshielding zones are induced by the magnetic field of the bonding electrons.

- shielded above and below the arene ring - + - - Shielding - +

- + zones + CC + O - + + Deshielding + - + zones - -- carbon-carbon carbonyl double carbon-carbon aromatic benzene single bond bond triple bond

Figure III.2 Anisotropic Shielding Cones for Common Organic Bonds

Recently a shielding model for the carbonyl bond, in non-conformity with the conventional shielding cones of the carbonyl bond, has been described based on semi- empirical calculations.21 The authors proposed anisotropic shielding of nuclei above and beyond the carbon atom and deshielding for nuclei above and beyond the oxygen atom from the center of the carbonyl bond. We propose a shielding cone for the chromium- carbonyl bond (Figure III.3) similar to the carbon-carbon triple bond.

132 - Shielding zones + Deshielding zones + - - Cr C O - + + C O Only this part of the - cone is affecting the arene carbon chemical shift

Figure III.3 Proposed Anisotropy of the Chromium-Carbonyl Bond on the Arene

From Figure III.3 one can infer that only part of the anisotropic cone influences the magnetic environment of the arene nuclei. The total shielding effect will be a vector sum of all shielding and deshielding effects of the tripod. According to this model, the arene carbon opposite to the arene carbon eclipsed by the chromium-carbonyl bond is shielded. Conversely, this argument is in concurrence with the widely accepted argument that the arene carbons eclipsed by the bond are deshielded with respect to those that are not. The shielding effect due to the magnetic anisotropy of the Cr(CO)3 tripod can be conveniently derived from the complexation shift value d. The complexation shift dn at a particular carbon (n) of the arene complex, represents the difference in CCS of the arene

(Cn) and the corresponding complex (C’n).

D - Electron Donor substituent (syn-eclipsed) A - Electron Accepting substituent (anti-eclipsed) Shielded A D Deshielded Deshielded Deshielded Shielded Shielded

Shielded Shielded Deshielded Deshielded Deshielded Shielded

Figure III.4 Shielding and Deshielding of Arene Nuclei Due to Anisotropy of the Cr(CO)3 Tripod

133 The shielding and deshielding of the arene nuclei due to the anisotropy of the

Cr(CO)3 tripod for the syn- and anti-eclipsed conformation in symmetric complexes is shown in Figure III.4. All shielding effects observed in complexes can be explained by this shielding model. This will be illustrated with examples later in the chapter.

III.2.2 13C Chemical Shifts and Electronic Perturbation of the Arene Complex

It is well known that conformation depends on the electronic properties of the arene. The syn-eclipsed and anti-eclipsed conformations of the Cr(CO)3 tripod have much to do with effective overlap of the Cr(CO)3 MOs.

A D 1 1 donor 2 2 1 orbitals 3 3 acceptor 2 4 4 orbital 3 A - electron accepting substituent 4 D - electron donating substiutent

Figure III.5 Superposition of the Three Donor and Acceptor Orbitals Based on the Electronic Property of the Substituent Inducing Further Charge Distribution and Polarization

The Cr(CO)3 fragment further polarizes the electron density on the arene by complexation. Figure III.5 shows the top view of the hybrid orbitals. The three donor orbitals are coordinated to three carbonyl ligands and the three acceptor orbitals are syn or anti eclipsed based on the charge distribution on the arene which is based on the electronic and steric properties of the substituents.

Existence of a correlation between the CCS and electronic charge on the arene complex was deduced in view of an interesting observation. Albright et al had reported a net 0.397 electron transferred from benzene on complexation with Cr(CO)3. Carbon-13

134 NMR text books elaborate a linear correlation between 13C chemical shifts and local π electron densities in aromatic systems.22 Theoretical calculations by Karplus and Pople23 predict 86.7 ppm shift per π electron on these systems. The difference in chemical shift on going from benzene to the complexed benzene is 35 ppm, which matches with 34.4 ppm obtained as a result of the electron transfer effect on the chemical shift from theoretical predictions (0.397 x 86.7 ppm = 34.4 ppm). It should also be noted that experimentally 160 ppm is the chemical shift per π electron.24 In view of this chemical shift match, it would not be incorrect to correlate the 13C chemical shifts of arenes with electron charge densities of the arene complexes. One could consider the Cr(CO)3 moiety similar to an arene substituent σ bonded to the arene. An arene substituent has electronic effects on the ortho, meta and para carbons, likewise the tripod has effects on the carbons which are seemingly manifested in the conformation of the tripod with respect to the arene substituents. The CCS of mono-substituted and 1,4-disubstituted arene chromium tricarbonyl complexes are chosen for study due to the simplicity of analysis of their spectra because of their molecular symmetry present. Interestingly, the non-additive CCS in 1,4-disubstituted benzenes relating to nonlinear resonance and shift-charge ratio effects has been investigated.25 Our interest with arenechromium tricarbonyl is also with the same substitution pattern.

III.3 13C NMR Complexation Shifts, Conformation and Regioselectivity of

Nucleophilic Addition

The 13C chemical shifts of six arene complexes III.1 - III.6 were analyzed, with substituents chosen to offer a modest range of electronic and steric properties.

135 Calculation of the corresponding 13C chemical shifts26 complexation shifts dn is shown in

Table III.2.

OCH3 R' 1 R = -H (III.1) 1 R' = -CH3 (III.4) 2 = -CH(CH ) (III.5) = -CH3 (III.2) 2 3 2 Cr(CO)3 Cr(CO)3 = -C(CH3)3 (III.6) 3 = -Si(CH3)3 (III.3) 4 4 R

III.1 III.2 III.3 III.4 III.5 III.6 C1 159.7 157.5 160.3 137.7 148.7 151.1 C2 114.0 113.8 113.6 129.1 126.3 125.3 C3 129.6 129.9 134.8 128.3 128.2 128.1 C4 120.8 130.0 131.4 125.1 125.7 125.4 C’1 143.4 141.4 144.4 109.9 120.2 123.1 C’2 78.1 78.9 77.9 93.0 92.0 92.6 C’3 95.0 95.4 100.0 94.5 93.0 91.0 C’4 85.3 101.9 93.6 89.8 91.8 93.6 d1 16.3 16.1 15.9 27.8 28.5 28.0 d2 35.9 34.9 35.7 36.1 34.3 32.7 d3 34.6 34.5 34.8 33.8 35.2 37.1 d4 35.5 28.1 37.8 35.3 33.9 31.8

Table III.2 Complexation Shifts d1-d4 for Complexes III.1-III.6 (Cn and C’n represent the CCS of the arene and the corresponding complex respectively)

CCS and Conformation of the Cr(CO)3 Tripod

A greater complexation shift (d value) indicates that the corresponding arene carbon is shielded more on complexation. Certain patterns are quite apparent from Table

III.2. The value d1 is similar for similarly substituted arene carbons. The value d1 for each of the complexes III.1-III.3 (~ 16 ppm) is less than the other values which average at 35 ppm. This deshielding at C1 can be explained by a partial exocyclic double bond formation leading to shielding of the C’1 carbon (Figure II.17). Though this π-symmetry resonance interaction is present even in the free arene, the complexed chromium tricarbonyl offers further stabilization, structural manifestations of which have been

136 studied.27 The large deshielding at the methoxy carbon as compared to the methyl bonded arene carbon can also be viewed in terms of a greater preponderance of a syn-eclipsed conformation for complex III.1, than for III.4. Barriers to rotation reported so far have been for the simple complexes. If they were indeed to exist in such a manner, the barriers to tripod rotation would be much higher and substantial, though Cr(CO)3 is generally considered a free rotor.

The crystal structures of complexes III.4-III.6 indicate that the conformation of the tripod changes from syn-eclipsed to anti-eclipsed gradually due to steric effects. The progressive deshielding at C’2 and C’4 and shielding at C’3 can be explained by the present shielding model for arenes with donor substituents. In complex III.2 with two donor substituents (-OCH3 and –CH3) it can be expected that ∆23 would be less than that in complex III.1.

CCS and Regioselectivity of Nucleophilic Addition

In an effort to correlate these conformational effects implied by the CCS of the complexes, with regioselectivity, an equation to fit the ratio of regioisomers to the CCS was attempted. By an ad hoc approach, an empirical equation (Equation III.1) for percentage of meta addition Pmeta from the d values was arrived at, where, ∆nm represents the absolute difference between complexation shifts dn and dm.

Pmeta (%) = 100∆14/(∆13 + ∆24)

Equation III.1 Empirical Equation for Calculation of Pmeta

137 Complex Pmeta (%) % of o:m:p addn. from literature III.1 94 4:96:0 (a) III.2 48 25:75:0 (a) III.3 96 4:96:0 (a) III.4 77 28:72:0 (b) III.5 76 0:80:20 (b) III.6 38 0:35:65 (b)

Table III.3 Population Pmeta (%) Compared to Regioselectivity of Nucleophilic Addition. Nucleophile: (a) t – LiCH(Me)CO2Bu (b) LiC(OR)MeCN

Table III.3 shows the calculated Pmeta (%) from Equation 1 and experimental ratios obtained for lithio tert-butyl propionate and an alkoxy substituted lithio propionitrile anion. The percent of meta additions obtained from the equation are strikingly close to observed percentage of meta addition. This is more precise than any of the former conformational results from NMR analysis! Equation III.1 does not concur with the results in the case of complex III.2, where two donor substituents (-OCH3 and –

CH3) are arranged para to each other. This substitution pattern leads to competing substituent effects on tripod orientation. The significance of ∆12 and ∆34 are not apparent.

All possible ∆ values were derived as absolute difference of each of the four d values as shown in Table III.4. Similar to d values, certain patterns can be noted from the ∆ values as well though the exact significance of the values is again unclear.

Complex ∆12 ∆13 ∆14 ∆23 ∆24 ∆34 III.1 19.6 18.3 19.2 1.3 0.4 0.9 III.2 18.8 18.4 12.0 0.5 6.8 6.4 III.3 19.8 18.9 21.9 0.9 2.1 3.0 III.4 8.3 6.0 7.5 2.9 0.8 1.5 III.5 5.8 6.7 5.4 0.9 0.4 1.3 III.6 4.7 9.1 3.8 4.4 0.9 5.3

Table III.4 ∆ Values for Complexes III.1 – III.6

138 Regioselectivity of nucleophilic addition to arene chromium tricarbonyls has generally been explained in terms of charge control and orbital control for the arene complex, taken in combination and individually.28,29 A frontier orbital correlation is based on the LUMO of the free arenes as well.30 More recently Schmalz et al investigated the meta selectivity in nucleophilic addition to anisole chromium tricarbonyl complex

III.1 by a density functional study and rationalized it based on charge control.31 None of the studies have tried to quantitatively analyze the regioselectivities, even though nucleophilic additions were reported more than three decades ago. Since the regioselectivities depend on the nature of the nucleophiles as well, it can be assumed that for certain nucleophiles orbital control plays a greater role than the charge control. This stands verified in this analysis that the regioselectivity for a particular nucleophile correlates well with the electron charge density perturbations in the complex.

In a way the dn values represent the decrease in positive charge at the corresponding arene carbons on complexation with Cr(CO)3 and represent the degree of perturbation of electron densities (En) of the arene carbons on complexation. The net electron density removed from the arene would be the difference of the total charge density given to the acceptor orbitals by the arene and the total charge donated by the donor orbitals to the arene. Consider that E represents the charge perturbation on complexation, then the net charge transferred from arene to Cr(CO)3 would be |E1-

E4|+|E3-E6|+|E5-E2|. For mono- and 1,4-disubstituted arenes this would be equal to |E1-

E4|+2|E3-E2|. This seems to be related to the derived empirical equation and further understanding is needed in this context.

139 The current discussion quantifies the regioselectivities based on charge control (as reflected in the CCS of arene carbons) for the complexes III.1 and III.3 - III.6 in which electronic effects of the substituents orient the Cr(CO)3 tripod in the same direction invoking Equation III.1. Only complex III.2, which has two donor substituents para to each other, and conflict in the orientation of Cr(CO)3 albeit in different capacities, shows an anomaly in the series. The discrepancy indicates that not all contributions have been considered in arriving at Equation III.1 and a more detailed theoretical analysis is needed. Nevertheless, it provides a starting point for further analysis. This can possibly be applied to other complexes taking into account the electronic effects of the substituents.

CCS and Calculation of Torsional Angle of Cr(CO)3 orientation

There is a correlation between the conformation of the Cr(CO)3 tripod i.e., the torsional angle and regioselectivity of nucleophilic addition. In fact 13C NMR chemical shifts have been used to determine the torsional angles in biphenyl, ketoximes, carbohydrates32 and binaphthyl derivatives with a high degree of precision.33 It is quite possible that the equation for meta addition might be related to determining the torsional angle which in turn is known to determine the regioselectivity!

III.4 CCS in Chiral Arene Chromium Tricarbonyl Complexes

In Chapter II, in an effort to determine conformational preferences in chiral arene chromium tricarbonyl complexes, we had proposed that a pattern in CCS of the complexes in solution might indicate a preferred orientation of the tripod with respect to

140 the substituents. For two sets of chiral auxiliaries (-OR1* & -OR2*) two opposite patterns were observed, with the diastereotopic arene carbon chemical shifts differentiating the two edges of the arene (Figure III.6).

OR * OR1* OR1* 2 OR2* Cr(CO)3 Cr(CO)3 C3 CO C4 C3 OC C4 CO OC C C C1 C2 2 1 OC CO TMS TMS TMS TMS

Figure III.6 Tripod Orientation and 13C Chemical Shift Pattern in Chiral Arene Complexes

We sought to explain the difference in chemical shifts of the diastereotopic carbons based on the shielding model of the Cr(CO)3 tripod proposed here. In the case of the chiral complexes with, say about 30° rotation of the tripod from the syn-eclipsed conformation, the shielding cones of the chromium carbonyl bonds differentiate the two edges of the arene complex as represented in III.C in Figure III.7. The two edges of III.C are magnetic anisotropically different, but the actual NMR shielding effects that go into explaining this phenomenon is beyond our expertise and should present an interesting problem to NMR spectroscopists and theoretical chemists.

OR1* OR1* + OR1* - - Cr C O- Cr(CO)3 + shielded C4 C3 deshielded - edge C2 C edge - Shielding zones 1 Si - + Deshielding zones TMS TMS III.C

Figure III.7 Unexplainable Shielding in Chiral Arene Chromium Tricarbonyl Complexes

An explanation on the observed shielding and deshielding is arguably possible based on the electronic perturbations in the arene complexes themselves. It should be

141 possible to determine charge densities of the arenechromium tricarbonyl from semi- empirical calculations and determine if the conformation of the tripod differentiates two meta (and/or the two ortho) positions electronically. Calculations are underway to determine the charge densities for different orientations of the tripod for complexes III.1-

III.3.

III.5 Conclusions

Analysis of the CCS of arenechromium tricarbonyls is presented in a new light here. We have proposed a new diamagnetic shielding model for explaining the shielding and deshielding effects in the 13C NMR of the complexes. The scientific basis to this in terms of calculating the magnetic tensors of the tripod should be studied to accept this model. On the other hand, instead of treating the chemical shifts as due to the equilibrium of syn-eclipsed and anti-eclipsed conformations, we have considered them to be simply electronic perturbations due to Cr(CO)3 complexation. We proposed an empirical equation based on complexation shifts d from 13C chemical shift data, which quantifies selectivity in nucleophile addition and is by far the most consistent with percentage of meta addition products reported. The previous arguments on regioselectivity based on a balance of charge and/or orbital control should probably be seen in light of the charge distribution inferred herein. More analysis of the data is required to predict whether the additions other than at the meta position are predominantly ortho or para or at the ipso carbon of the complex. While this report details mono- and 1,4-disubstituted arene chromium tricarbonyl complexes, it would be of great interest to study 1,2- and 1,3- substituted complexes which possess axial chirality and are of considerable interest in

142 asymmetric synthesis. The precise physical significance of the ∆ values, the phenomenon of charge distribution and their reflection in the 13C chemical shifts is an inviting field of study both by theoretical analysis and interpretation of the 13C NMR spectroscopy. The derivation of torsional angle of orientation of the Cr(CO)3 tripod with respect to the arene substituents from the CCS of arene chromium tricarbonyl complexes another interesting phenomenon, also remains to be investigated. Another interesting phenomenon is the pattern exhibited in the CCS of chiral arenechromium tricarbonyls, diastereotopicity of which is worth further investigation. Much of the information presented here should be inviting to NMR spectroscopists and theoretical chemists to further investigate the 13C chemical shifts of arenechromium tricarbonyl in new light.

143 References

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2 Aroney, M. J.; Cooper, M. K.; Englert, A.; Pierens, R. K. “The conformations of some mono-substituted derivatives of (η6-benzene)tricarbonylchromium(0) from dipole moment and electric birefringence studies.” J. Mol. Struc. 1981, 77, 99-108.

3 For illustrative examples of solution state conformation shown to be same as solid state conformation: (a) Rose-Munch, F.; Khourzom, R.; Djukic, J.-P.; Rose, E.; Langlois, B.;

Vaisserman, J. “Conformational study of η6-[4-(trifluoromethoxy)aniline]tricarbonyl chromium.” J. Organomet. Chem. 1994, 470, 131-135. (b) Stewart, K. R.; Levine, S. G.;

Munch, F.; Rose, E.; Vaissermann, J. “Tricarbonyl- η6-[(2-thiophenyl)arene]- and - η6-

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F.; Rose, E.; Semra, A.; Garcia Oricain, J.; Jeannin, Y.; Robert, F. “Conformation of tricarbonyl[2,3-dimethyl-1-(triisopropylsiloxy)benzene]chromium and regioselectivity of

144 its lithiation.” J. Organomet. Chem. 1987, 328, 109-122. (f) Rose-Munch, F.; Rose, E.;

Semra, A.; Filoche, M. “Nucleophilic aromatic substitutions SNAr on 2,6- dimethylchlorobenzenechromium tricarbonyl.” J. Organomet. Chem. 1989, 363, 123-130.

4 (a) Carter, O. L.; McPhail, A. T.; Sim, G. A. “Configurations of arenechromium tricarbonyls.” Chem. Commun. 1966, 212-213. (b) Albright, T. A.; Hofmann, P.;

Hoffmann, R. “Conformational preferences and rotational barriers in polyene-ML3 transition metal complexes.” J. Am. Chem. Soc. 1977, 99, 7546-7557 (c) Albright, T. A.

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5 Albright, T. A.; Carpenter, B. K. “Conformational effects of nucleophilic and electrophilic attack on (arene)chromium tricarbonyl complexes.” Inorg. Chem. 1980, 19,

3092-3097.

6 Segard, C.; Roques, B.; Pommier, C.; Guiochon, G. “Studies of arenetricarbonylchromium derivatives by gas-liquid chromatography and nuclear magnetic resonance.” Anal. Chem. 1971, 43, 1146-1151.

7 Jackson, W. R.; Jennings, W. B.; Rennison, S. C.; Spratt, R. “Stereochemistry of organometallic compounds. VI. Electronic and steric effects in tricarbonyl(alkylbenzene)chromiums.” J. Chem. Soc. B: Phys. Org., 1969, 9, 1214-1221.

8 Van Meurs, F.; Van der Toorn, J. M.; Van Bekkum, H. “Substituent effects in π-

(tricarbonylchromium)arenes. I. Proton NMR spectroscopy of alkyl-substituted π-

(tricarbonylchromium)benzenes.” J. Organomet. Chem. 1976, 113, 341-351.

145

9 Solladie-Cavallo, A.; Suffert, J. “Proton and carbon-13 NMR of substituted chromium tricarbonyl complexes; substituent effects and chromium tricarbonyl conformation.” J.

Org. Mag. Res. 1980, 14, 426-430.

10 Roques, B. P.; Segard, C.; Combrisson, S.; Wehrli, F. “Carbon-13 NMR low temperature study of the rotation around the chromium-arene bond.” J. Organomet.

Chem. 1974, 73, 327-330.

11 Brocard, J.; Laconi, A.; Couturier, D. “Proton NMR conformational analysis of disubstituted arene tricarbonyl chromium complexes.” J. Org. Mag. Res. 1984, 22, 369-

371.

12 Solladie-Cavallo, A.; Wipff, G. “Importance of the conformation of XC6H5Cr(CO)3 complexes in the regioselectivity of nucleophilic additions to the aromatic ring.”

Tetrahedron Lett. 1980, 21, 3047-3050.

13 (a) Mitchell, R. H.; Brkic, Z.; Berg, D. J.; Barclay, T. M. “Effective aromaticity of tricarbonylchromiumbenzene, about 25% enhanced over that of benzene: Structural evidence from a complexed benzannulene.” J. Am. Chem. Soc. 2002, 124, 11983-11988.

(b) Mitchell, R. H.; Chen, Y.; Khalifa, N.; Zhou, P. “The synthesis, aromaticity, and

NMR properties of [14]annulene fused organometallics. Determination of the effective bond localizing ability ("Relative aromaticity") and diamagnetic anisotropy of several organometallic moieties.” J. Am. Chem. Soc. 1998, 120, 1785-1794.

14 (a) Simion, D. V.; Sorensen, T. S. “A theoretical computation of the aromaticity of

146

Simion, D. V.; Sorensen, T. S. “Does Cr(CO)3 complexation reduce the aromaticity of benzene?” J. Am. Chem. Soc. 2000, 122, 510-513.

15 Jackson, W. R.; Pincombe, C. F.; Rae, E. D.; Thapebinkarn, S. “Stereochemistry of organometallic compounds. XIII. Carbon-13 NMR spectra of some tricarbonyl(arene)chromium compounds.” Aust. J. Chem., 1975, 28, 1535-1539.

16 (a) Brown, D. A.; Raju, R. R. “Infrared and proton magnetic resonance spectra of π- complexes of substituted condensed hydrocarbons.” J. Chem. Soc. A, 1966, 1617-1621.

(b) Wu, A.; Biehl, E. R.; Reeves, P. C. “Transmission of substituent effects in anilinetricarbonylchromium compounds.” J. Organomet. Chem., 1971, 33, 53-57 (c) Wu,

A.; Biehl, E. R.; Reeves, P. C. “Transmission of substituent effects in

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451.

17 Pihlaja, K.; Kleinpeter, E. Carbon-13 NMR Chemical Shifts in Structural and

Stereochemical Analysis, VCH Publishers, Weinheim, 1994.

18 Desobry, V.; Kündig, E. P. “Naphthalene complexes. Part 2. A carbon-13 NMR study of naphthalene chromium complexes. Correlation with reactivity: nucleophilic aromatic substitution reactions.” Helv. Chim. Acta, 1981, 64, 1288-1297.

19 For a few other reports of conformer population calculation using Jackson’s equation see: (a) Szczecinski, P. “Application of scalar carbon-13/fluorine-19 spin-spin couplings between carbonyl carbons and aromatic fluorine to investigations of conformation of tricarbonylchromium complexes of fluorobenzenes.” J. Organomet. Chem. 1992, 423,

23-29. (b) Boutonnet, J. C.; Mordenti, L.; Rose, E.; Le Martret, O.; Precigoux, G.

“Organometallic chemistry. XXII. Synthesis of substituted arenes by the addition of a

147 nucleophile to an arenechromium tricarbonyl and then oxidative decomplexation of the metal.” J. Organomet. Chem., 1981, 221, 147-156. (c) Rose-Munch, F.; Aniss, K.; Roses,

E.; Vaisserman, J. “Synthesis and conformation of complexes obtained by reaction of carbanions of α-imino esters or nitriles with (halobenzene)tricarbonylchromium.” J.

Organomet. Chem. 1991, 415, 223-255.

20 Maricq, M. M.; Waugh, J. S.; Fletcher, J. L.; McGlinchey, M. J. “Anisotropic ring- carbon chemical shifts in arene chromium tricarbonyl complexes.” J. Am. Chem. Soc.

1978, 100, 6902-6904.

21 Martin, N. H.; Allen, N. W.; Brown, J. D.; Kmiec, D. M.; Vo, L. “An NMR shielding model for protons above the plane of a carbonyl group.” J. Mol. Graph. & Mod. 2003,

22, 127-131.

22 Spiesecke, H.; Schneider, W. G. “Determination of π-electron densities in azulene from

C13 and H1 nuclear resonance shifts.” Tetrahedron Lett. 1961, 468-472.

23 Karplus, M.; Pople, J. A. “Carbon N.M.R. [nuclear magnetic resonance] chemical shifts in conjugated molecules.” J. Chem. Phys. 1963, 38, 2803-2807.

24 Alger, T. D.; Grant, D. M.; Paul, E. G. “Carbon-13 magnetic resonance. VI. Theory of carbon-13 magnetic resonance shifts in aromatic molecules.” J. Am. Chem. Soc. 1966, 88,

5397-5406.

25 Bromilow, J.; Brownlee, R. T. C.; Craik, D. J.; Sadek, M.; Taft, R. W. “Nonadditive carbon-13 nuclear magnetic resonance substituent shifts in 1,4-disubstituted benzenes.

Nonlinear resonance and shift-charge ratio effects.” J. Org. Chem. 1980, 45, 2429-2438.

26 (a) 13C Chemical shifts for the alkyl substituted arenes was used from a comprehensive table given in Breitmaier, E.; Voelter, W. Carbon-13 NMR spectroscopy, VCH

148

Publishers, Weinheim, 1987. (b) The carbon spectra of the anisole complexes (III.1 -

III.3) and free arenes were determined at room temperature in CDCl3 solvent with 0.5%

TMS as internal standard. (c) The chemical shifts of the III.4 – III.6 were reported in

Jackson, W. R.; Pincombe, C. F.; Rae, E. D.; Thapebinkarn, S. Aust. J. Chem., 1975, 28,

1535-1539.

27 (a) Hunter, A. D.; Shilliday, L.; Furey, W. S.; Zaworotko, M. J. “Substituent interactions in η6-arene complexes. 1. Systematic x-ray crystallographic study of the structural manifestations of π-donor and π-acceptor substituent effects in substituted

6 chromium (η -arene)Cr(CO)3 complexes.” Organometallics 1992, 11, 1550-1560. (b)

Hunter, A. D.; Mozol, V.; Tsai, S. D. “Nonlinear substituent interactions and the electron

6 richness of substituted (η -arene)Cr(CO)3 complexes as measured by IR and carbon-13

NMR spectroscopy and cyclic voltammetry: role of π-donor and π-acceptor interactions.”

Organometallics 1992, 11, 2251-2262.

28 (a) Semmelhack, M. F. “Nucleophilic addition to arene-metal complexes.” In

Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,

1991; Vol. 4, 517-549. (b) Morris, M. J. In Comprehensive Organometallic Chemistry II;

Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995, Vol. 5, 471-

549. (c) Semmelhack, M. F. “Transition metal arene complexes: Nucleophilic addition.”

In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson,

G., Eds.; Pergamon: Oxford, 1995; Vol. 12, 979-1016.

29 Semmelhack, M. F.; Garcia, J. L.; Cortes, D.; Farina, R.; Hong, R.; Carpenter, B. K.

6 “Nucleophilic addition to (η -(alkylbenzene)Cr(CO)3) complexes. Dependence of

149 regioselectivity on the size of the alkyl group and the reactivity of the nucleophile.”

Organometallics 1983, 2, 467-469.

30 Semmelhack, M. F.; Clark, G. R.; Farina, R.; Saeman, M. “Substituent effects in addition of carbanions to arenechromium tricarbonyl complexes: correlation with arene

LUMO.” J. Am. Chem. Soc. 1979, 101, 217-218.

31 Pfletschinger, A.; Koch, W.; Schmalz, H.-G. “On the regioselectivity of nucleophilic additions to anisole-Cr(CO)3 and related complexes: a density functional study.” New J.

Chem. 2001, 25, 446-450.

32 Bock, K.; Brignole, A.; Sigurskjold, B. W. “Conformational dependence of carbon-13 nuclear magnetic resonance chemical shifts in oligosaccharides.” J. Chem. Soc., Perkin

Trans. 2, 1986, 1711-1713.

33 A section in Reference 16 titled “Conformational Analysis of Conjugated Compounds:

Dihedral Angle Subject to Steric Hindrance” pp 242-251 and references cited therein.

150

CHAPTER IV

Chiral Auxiliary Directed Nucleophilic Addition to Arenechromium Tricarbonyl

Complexes: Understanding Origin of Diastereoselection & Applications in Organic

Synthesis

151 IV.1 Nucleophilic Addition to Arene Chromium Tricarbonyl Complexes –

General and Background

Nucleophilic addition reactions to arene chromium tricarbonyl complexes,1,2,3 very briefly introduced earlier, will be further elaborated here. The emphasis is on carbon nucleophile addition, factors governing regioselectivity of addition and asymmetric nucleophilic addition, as a background to our study in understanding the diastereoselectivity during chiral auxiliary directed nucleophilic additions. Compared to other known arene-metal complexes, the reactivity of arene-Cr(CO)3 complexes towards

4 +2 +2 + nucleophiles is the least ((C6H6)Fe(C6H6) > ((C6H6)Ru(C6H6) > ((C6H6)Mn(CO)3 >

+ + (C6H6)Mn(CO)2PPh3 > (C6H6)FeCp > (C6H6)Cr(CO)3). Nevertheless the electron deficiency of the arene is enough for nucleophiles to add to it.

IV.1.1 Chemistry of Nucleophilic Addition to Arene-Cr(CO)3 Complexes

Carbon nucleophile addition to arene-Cr(CO)3 complexes was first reported by

Semmelhack et al in 1974 as a method of phenylation of the nucleophile.5 Addition of a nucleophile to the arene complex (IV.1) forms η5-substituted cyclohexadienyl anion

IV.2, and depending on the subsequent procedure results in modification of the arene- complex (Scheme IV.1). Cyclohexadienyl complex IV.2 on treatment with an electrophile adds with or without CO insertion to yield substituted 1,3-cyclohexadienes of type IV.3, while oxidation with, example, iodine yields the substituted arene IV.5.When the added electrophile is a proton IV.2 yields the simple cyclohexadiene without CO insertion. In certain cases a substituted arene-Cr(CO)3 complex IV.4 is obtained. An irreversible loss of a leaving group (using fluoride or chloride) on nucleophilic addition

152 leads to these arene substitution products. Another mode of nucleophilic substitution in these complexes referred to as cine- and tele- substitutions, is characteristic of reactive nucleophiles which add irreversibly to the arene ring.

"R X IV.1

Cr(CO)3 Nu

Nu R'' H IV.2 X Cr(CO)3

η5-cyclohexadienyl anion

E -X X=H

Nu "R Nu Nu "R "R E Cr(CO)3 IV.3 O IV.4 IV.5 Nucleophilic addition Nucleophilic Nucleophilic addition followed by electrophilic substitution followed by oxidation addition

Scheme IV.1 Nucleophilic Addition to Arenechromium Tricarbonyl Complexes

Treatment of the arene-Cr(CO)3 complex with a lithium base leads to lithiation of the complex which on treatment with a suitable electrophile yields substituted arene complexes. A general methodology for preparing enantiomerically enriched planar chiral arene-Cr(CO)3 complexes is by asymmetric deprotonation of the complexed arene by chiral bases followed by electrophilic addition. Recovery of the Cr(CO)3 as Cr(CO)6 after nucleophile attack is possible by performing the addition in carbon monoxide atmosphere.6 The focus of our work is on the one pot procedure applied in the

153 dearomatization of the arene by nucleophilic addition/protonation/decomplexation sequence (Scheme IV.2).7

Nu H k1 oxidative Nu H addition Nu Cr(CO) (OC) Cr k-1 (OC)3Cr 3 3 Cr H H OC OC CO

Scheme IV.2 Steps in Dearomatization by Nucleophilic Addition Protonation Sequence to the Arenechromium Tricarbonyl Complex

The nucleophilic addition step is usually reversible (very few nucleophiles add irreversibly) yielding the cyclohexadienyl anion.8 In the second step, electrophiles add to the chromium metal and then transfer to the arene which is formally a reduction followed by elimination. The regioselectivity of nucleophilic addition depends on many factors.

IV.1.2 Factors Influencing Regioselectivity of Nucleophilic Addition

There is considerable literature regarding the regioselectivity of nucleophilic addition to arene chromium tricarbonyl complexes and a qualitative understanding of the factors governing this selectivity. It is worth mentioning though that so far the observed selectivities have not been quantitatively rationalized. Simply stated regioselectivity of nucleophilic addition could be under kinetic or thermodynamic control. Instances of different regioselectivity under kinetic and thermodynamic control have been reported.9

Very few mechanistic investigations have been carried out related to this problem.

154 Thermodynamic Control

Thermodynamically controlled reactions depend simply on the relative stabilities of competing cyclohexadienyl anion intermediates.10 For a mono-substituted arene-

Cr(CO)3 complex the four possible cyclohexadienyl intermediates are shown in Figure

IV.1. The tripod in the intermediate has a high barrier to rotation (9-13 kcal/mol) and one of the chromium-carbonyl bonds eclipses the sp3 carbon where the nucleophile has attacked. Hence bulky substituents on the position meta to nucleophilic addition destabilize the anion.

Nu Nu Nu Nu

R H H H R Cr Cr R R Cr Cr OC CO OC CO OC CO CO OC CO OC CO CO ipso addition ortho addition meta addition para addition

Figure IV.1 Four Possible Cyclohexadienyl Anion Intermediate for Nucleophilic Addition to a Mono- Substituted Arenechromium Tricarbonyl Complex

Kinetic Control

Kinetically controlled reactions depend on the properties of the reactants and the reaction conditions, which are: (a) The electronic and steric effect of the carbon nucleophile; (b) the reaction conditions (temperature, reaction time, solvent and co- solvents); (c) the nature of the arene ligand. a) The Nature of the Carbon Nucleophiles

11 Semmelhack has classified carbon nucleophiles reacting with arene-Cr(CO)3, based on their reactivity and the pKa of their corresponding carbon acids, into three classes: (a)

Stabilized carbanions (carbon acids with pKa < 18) Example: Enolate of diethyl malonate.

(b) More reactive carbanions (pKa >20) which yield cyclohexadienyl addition products

155 prior to slow equilibration via reversible anion addition. Example: Nitrile stabilized

t anions and ester enolates (LiCH2COOBu ). (c) More reactive carbanions (pKa > 20) which give irreversible addition to the arene complex. Example: Very reactive nucleophiles such as dithianyl anions and phenyllithium. Some of the nucleophiles do not favor an electrophile addition after nucleophilic addition (ester enolates fall into this category). The role played by the reactivity of the nucleophile in regioselectivity has been studied very elegantly by Semmelhack.12 (Table IV.1).

S Nu = X S

Cr(CO)3 Nu Nu meta para

Anion Ratio Combined σp X meta:para Yield (%) for X O- 73.27 84 NMe2 63:37 80 -0.83 NMe2 57:43 78 -0.83 OMe 54:46 71 -0.27 Me 43:57 75 -0.17 H 28:72 75 0 H 23:77 85 0 Cl 21:79 80 +0.23

Table IV.1 Regioselectivity on Nucleophilic Addition of Anions to (tert-Butylbenzene)-Cr(CO)3

A direct correlation has been drawn between σp and the reactivity of the dithianyl carbanion toward the tert-butylbenzenechromium tricarbonyl, from the straight line obtained on plotting ln(paraX/paraH) versus σp of the substituent X.

156 b) The Reaction Conditions

The nucleophilic addition is many times driven in the forward direction by addition of coordinating solvents such as crown-ethers or HMPA. HMPA (and crown-ethers) stabilizes the intermediate cyclohexadienyl anion, or rather decreases the rate of the reverse reaction (k1 >> k-1), and increases the nucleophilicity of the carbon nucleophile by coordinating to Li+ more strongly than does THF. HMPA is known to alter the course of some chemical reactions,13 but it does not influence the regioselectivity of nucleophilic addition to arenechromium tricarbonyl complexes in kinetically controlled reactions. c) The Nature of the Arene Ligand

The nature of the arene ligand is the most widely studied in its influence on regioselectivity. In kinetically controlled reactions, the selectivity is analyzed based on charge control and/or orbital control.

Charge Control

Charge control includes charge polarization on the arene due to the resonance effects of the substituents and the further polarization induced by the conformation of the

Cr(CO)3. Certain things should be kept in mind when considering charge control. Firstly, the charge densities on the arene due to resonance effects of the substituents are such that with electron donating substituents, the ortho and para positions are electron rich and the meta positions are electron deficient. This is reversed for electron withdrawing arene substituents. So even without the Cr(CO)3 if nucleophiles were to add to the arene with an electron donating substituent, the regioselectivity would also be predominantly meta

(Figure IV.2).

157 A D δ+ + + δ δ+ δ δ+

D = electron-donating A = electron-withdrawing group group

Figure IV.2 Polarization of the Arene due to Conformation of the Cr(CO)3

The chromium-carbonyl bond is known to eclipse the carbon attached to electron- donating substituents and the carbon para to an electron-withdrawing substituent. Hence in the absence of major steric effects, the tripod is oriented syn-eclipsed to electron- donating substituents and anti-eclipsed to electron-withdrawing substituents, polarizing the arene in a manner parallel to the electronic perturbation by the substituent. The polarization induced by the conformational preference of the Cr(CO)3 is best evaluated when the electronic effects of the substituents are same, but the steric effect of the substituent forces the tripod to be oriented in a particular manner. The classic example is the series of the alkyl substituted arene chromium tricarbonyls, where increasing the size of the alkyl substituent gave more of para addition at the expense of the meta addition.

This extra polarization due to the conformation of the Cr(CO)3 tripod has been observed from 1H NMR studies.

Orbital Control

Orbital control invokes the matching of arene centered LUMO to the HOMO of the nucleophile. Early discussions of orbital control took into consideration the LUMO of the uncomplexed arene. This did not explain the difference in regioselectivity between anisole- and toluene chromium tricarbonyl, since they have similar LUMO coefficients.

158 Later studies invoked the MO coefficients derived from Extended Hückel Molecular

Orbital (EHMO) calculations performed on the arene complexes themselves, taking into

14 consideration the conformation of the Cr(CO)3. The conformation of the Cr(CO)3 tripod affects both the electron charge densities on the arene carbons as well the coefficients of the MOs (both HOMOs and LUMOs).

D A D - electron donor substituent A - electron acceptor substituent

Figure IV.3 Representation of the Arene HOMO and LUMO Coefficients

Simply stated, regioselectivity of nucleophilic attack depends on just many factors, the nature of the arene ligand (electronic and steric effect) and the nature of the nucleophile (electronic and steric effect). The nature of arene ligand depends on the substituents on the arene and the conformation of the Cr(CO)3 (factors which affect the conformation of the tripod were elaborated earlier in Chapter II).

A particularly useful dearomatization reaction converting anisole chromium tricarbonyl to 5-substituted cyclohexenones is shown in Scheme IV.3. The nucleophilic addition is predominantly meta (meta/ortho ratio 97:3) for a variety of nucleophiles and a qualitative understanding of the regioselectivity has been discussed in a density functional study of the intermediate anionic complexes.15

OCH OCH3 3 OCH3 I) Demetallation O Nu H 5-substituted Cr(CO)3 II) Hydrolysis Cr(CO)3 Cr(CO)3 cyclohexenone Nu Nu Nu

Scheme IV.3 Conversion of Anisolechromium Tricarbonyl to 5-Substituted Cyclohexenones

159 Though the dearomatization procedure presents a viable methodology for a mild and rapid synthesis of functionalized carbocycles from suitable arenes, it is yet to be fully exploited in organic synthesis. Much of its utility depends on the possibility of asymmetric induction during the reaction.

IV.1.3 Asymmetric Nucleophilic Addition to Arene Transition Metal Complexes

Leading to Chiral Carbocycles

Chiral carbocycles have been prepared by the dearomatization of complexes16 of

6 6 + 2 2+ η -arene–Cr(CO)3, η -arene–Mn(CO)3 and η -Os(NH3)5 . Asymmetric induction during nucleophilic addition reaction to arene transition metal complexes in general is possible by one of the following methods:

a) Chiral Nucleophile

Miles and Brinkman reported successful addition of the chiral Evans enolate to phenoxybenzene manganese tricarbonyl complex and observed modest diastereoselectivity (55% de)17 (Scheme IV.4).

O O O OPh O BF 4 THF ON ON + Mn(CO) H H 3 -78 °C O Mn(CO)3 + O Mn(CO)3 OPh OPh ON 3.5:1

HO + HO H H30 H

OPh O

Scheme IV.4 Formal Synthesis of (+)-Juvabione by Chiral Evans Enolate Addition to Arenemanganese Complex

160 This has been successfully applied to an asymmetric formal synthesis of the insect sex-pheromone Juvabione. This is the only known example of a chiral nucleophile added to an arene transition metal complex.

b) Using Planar Chiral Arene Chromium Complexes

OMe

Cr(CO)3

Enantioselective protonation/silylation

Ph N Ph Li TMS-Cl, THF, -100 °C followed by recrystallization

H CO (H3C)3Si (+) 70%, 90% ee 3 (-) 70%, 99% ee H3CO (H3C)3Si Cr(CO)3 Cr(CO)3 i) Li i) n-BuLi ii) TMS ii) CuCl Br iii) Br O iii) p-TsOH.H2O

OCH3 Si(CH3)3 Si

Cr(CO)3 40%

i) Co (CO) Si(CH3)3 2 8 NH2 NO3 ii) NMO HN NH HH H (H3C)3Si Me O O H H Si(CH3)3 Alkaloid (+)-ptilocaulin 88%, 100% de, 90% ee

Scheme IV.5 Planar Chiral Arene Chromium Tricarbonyl Complexes – Illustration of Synthesis, Resolution and Application in Organic Synthesis

161 As previously mentioned in the introduction chapter, the planar chirality possible in arene chromium tricarbonyl complexes has been exploited in asymmetric synthesis.

They are generally prepared either by complexation of the arene followed by resolution of the two isomers, or by substituting a group on the arene complex by asymmetric deprotonation followed by nucleophilic addition. An asymmetric synthesis of ptilocaulin and tricyclic dienone18 was accomplished using this methodology (Scheme IV.5).

c) Chiral Ligand in Place of One of the Carbonyl Ligands

Chiral phosphine and phosphite ligands in place of one carbonyl ligand have been used in asymmetric induction (Scheme IV.6). Both yields and diastereoselectivities are shown to be only modest. The reactivity of the arene to nucleophilic addition is reduced with the decrease in the electron withdrawing effect due to loss of one carbonyl ligand.

Li S S SS H i) RX, CO S OC ii) decomplexation OC Cr 40% de Cr O OC L* OC L* Li L* = P PPh2 OPPh2 O 3

Scheme IV.6 Asymmetric Nucleophilic Addition/Protonation Sequence Using Chiral Phosphine and Phosphite Ligands

Use of external chiral ligands along with organolithium nucleophiles has also led to high enantioselectivities and possibly can be used in catalytic quantities as well.

d) Chiral Auxiliary Directed Nucleophilic Addition

162 There are only a handful of nucleophilic addition reactions known that are chiral auxiliary directed. Two kinds of chiral auxiliaries that direct nucleophiles to the ortho and meta position of the arene chromium complexes have been studied. Chiral oxazolines, imines and SAMP-hydrazones yield diastereomerically enriched addition products (ratio as high as 99%) on organolithium/electrophile addition with reactions done in carbonmonoxide atmosphere (Scheme IV.7). Diastereoselectivity in the case of oxazoline derivatives is thought to originate from coordination controlled nucleophilic addition.

R R' O N R Li R N O N H Cr(CO)3 O R' 81-99% de Cr(CO)3 R'Li Disfavored transition R R"X, HMPA R" state R O N O O N R' R' N R' Cr(CO) Cr(CO)3 3 Li i) R"X, CO, HMPA O ii) NaH, R"X Favored transition R" state R" 95-99% de

Scheme IV.7 Chiral Oxazolines and SAMP-Hydrazones in Nucleophilic Addition to Arenechromium Tricarbonyl Complexes

163

O O O O O O O i) Electrophile O + ii) Nucleophile i) H O [Os] [Os] ii) H- [Os] Nu1 Nu1 si face E E binding O Oxidation O i) H+ H O Yields: 41 - 46% ii) Nucleophile iii) Oxidation H3C O NH ee: 97% 3 Nu1 H CO H3N Nu 3 O Os E 2 H3N NH3 NH Yields: 19 - 33% 3 ee: 81 - 93% Nu Favored coordination 1 E

Scheme IV.8 Enantio-enriched Cyclohexenes from Chiral Pentaammineosmium(II) Anisole Derivatives

In nucleophilic additions to pentaammineosmium η2-arene complexes involving chiral anisole derivative, several asymmetrically functionalized cyclohexenes have been prepared with various electrophile and nucleophile combination in moderate yields and high diastereoselectivity (Scheme IV.8). The chiral lactate moiety supposedly interacts with the osmium metal and exists as a coordination diastereomer bound on the si face of the arene and the diastereoselectivity has been attributed to thermodynamic control.

Nucleophilic addition to chiral alkoxy arene chromium tricarbonyls have been reported from our laboratories and by Semmelhack. While Semmelhack et al have reported a modest diastereoselectivity using chiral monocyclic alcohols (Scheme IV.9), results from the Pearson laboratory employing bicyclic isoborneols derived from camphor as chiral auxiliaries showed a higher diastereoselection on isobutyronitrile anion addition.

164 -78 °C O O O 0 °C (OC) Cr 3 (OC)3Cr Cr(CO)3 CN NC favored intermediate disfavored intermediate

O O

CN CN

Scheme IV.9 Semmelhack’s Menthol Derived Chiral Auxiliaries in Asymmetric Nucleophilic Addition and Proposed Origin of Diastereoselection

Diastereoselectivity has been explained by formation of the favored intermediate cyclohexadienyl anion with least steric interaction with the chiral ether.

IV.2 Camphor Derived Chiral Isoborneol Directed Nucleophilic Addition to

Arenechromium Tricarbonyl Complexes

As mentioned above, we are interested in understanding nucleophilic additions to chiral alkoxy arenechromium tricarbonyl complexes as a methodology to prepare chiral non-racemic carbocycles.

IV.2.1 Motivation

Our motivation to further study chiral auxiliary directed nucleophilic addition reactions rested on two intriguing results (Table IV.2) with camphor derived isoborneols

(PIB-OH IV.6a, MIB-OH IV.6b and DOIB-OH IV.6c) as chiral auxiliaries. One is the high diastereoselectivity obtained during the addition of isobutyronitrile anion to complex

165 IV.8a with methyl para substituent, which yielded diastereomers in the ratio 24:1. This high selectivity is to be viewed in light of the fact that the two meta centers are sterically similar. The steric similarity of the two meta positions is indicated clearly in the X-ray crystal structures of the complexes studied (viewed three dimensionally using the software Mercury 1.1.1). The other result is that the chiral auxiliaries with differing substitution at C2 of the camphyl moiety, on going from phenyl to methyl yielded different isomers as the major components, i.e., there was a reversal in selectivity due to the change in substituents at C2 of the camphyl group. In explaining the results, the arguments invoked a steric approach control during nucleophilic attack on conformations from MMX calculations, but there are some doubts as to the orientation of the tricarbonyl moiety with respect to the arene substituents, and this was not taken into account.19 This is an interesting case of high 1,5-asymmetric induction, and the observed reversal of selectivity prompted us to investigate this reaction further.

OR* OR* R* = PIB, MIB, DOIB i) (Me)2(CN)CLi, Cr(CO)3 THF, -78 °C O CN ii) CF3COOH, -78 °C OH OH O R OH R Ph H R = H (IV.7), -CH3 ( IV.8) R = H (IV.9), IV.6a IV.6b IV.6c -CH3 ( IV.10)

Complex Chiral auxiliary -R % de Combined Major Isomer yield % (of the cyclohexnone) IV.7a PIB-OH -H ca 60 95 S IV.8a PIB-OH -CH3 92 63 S IV.7b MIB-OH -H 28 89 R IV.8b MIB-OH -CH3 80 81 R IV.7c DOIB-OH -H 88 86 R IV.8c DOIB-OH -CH3 94 65 R

Table IV.2 Diastereoselectivity During Isobutyronitrile Anion Addition to Arenechromium Tricarbonyl Complexes with PIB-OH, MIB-OH and DOIB-OH Chiral Auxiliaries

166 Reactions exhibiting 1,5-asymmetric induction20 are rare in chemical literature which provided the impetus to understand the origin of diastereoselectivity in the chiral auxiliary directed nucleophilic addition reactions. This exercise was expected to throw some light on the reactivity of the arene complexes themselves. In the process of studying the origin of diastereoselectivity we also sought to tailor the reaction to a synthetically more useful methodology to obtain functionalized chiral carbocycles.

IV.2.2 Proposed Study

The previous study used the sterically hindered isobutyronitrile anion as the nucleophile in determining the influence of the chiral auxiliary. The nucleophile, itself sterically demanding, was probably contributing in the observed diastereoselectivities.

For the proposed study, it was sought to proceed with a more synthetically useful nucleophile. tert-Butyl lithio acetate was chosen for the study because of the ease in modification of the ester functionality in a synthetic sequence, if necessary (though a reduction in the selectivity is expected as it is not as sterically demanding as the isobutyronitrile anion). The nucleophile tert-butyl lithio acetate enolate is not activated enough to add to the arene as such and requires HMPA as a co-solvent to force the reaction forward.

The steric and electronic properties of the para substituent is key to the nucleophile addition, as seen by the greater selectivity when the methyl substituent is present as compared to unsubstituted arene. The methyl substituent, though yielding greater diastereoselectivity in diastereoselection also gives considerable ortho addition,

167 due to the electron donating property of the methyl group. Also synthetic modifications after nucleophilic addition are limited with a methyl substituent due to isomerization and further diastereomer formation. It was sought to modify this substituent to a sterically demanding group but having opposite electronic effect so that the ortho product is suppressed. The –Si(CH3)3 group emerged as a simple and ideal solution as it is a sterically demanding group and also, due to its electron accepting nature, would promote addition meta to the chiral alkoxy substituent.

In order to understand the role of the chiral auxiliary in this stereoselective reaction, several other chiral auxiliaries were proposed for study along with DOIB-OH,

MIB-OH and PIB-OH. The proposed chiral auxiliaries to be studied are shown in Figure

IV.4. Camphor derived auxiliaries have been a source of high stereoinduction in a multitude of reactions.21 It seemed appropriate that these bicyclic isoborneols should be used in the study of the nucleophilic addition reactions, as the monocyclic alcohols had given only moderate selectivity as studied both in our laboratory and as noted by Schmalz et al.22 The idea was to increase the sample set while trying to determine factors that the chiral auxiliary might bring to bear in the stereoselection, and design auxiliaries that would give either enantiomer selectively. Chiral auxiliaries IPIB-OH (IV.6e), CHIB-OH

(IV.6f), IBIB-OH (IV.6g), and EIB-OH (IV.6d) were suggested as extensions of MIB-

OH (IV.6b) with increasing steric bulk at C2 of the camphyl moiety. A progressive increase of steric bulk at C2 from methyl, ethyl and isopropyl groups would obviously lead to the tert-butyl group. But the inability to prepare such a sterically hindered alcohol is known. The VIIB-OH (IV.6h) and IPRIB-OH (IV.6o) were included to determine if

168 there is any π-stacking interaction, as such interactions have been noted in other reactions in arene chromium tricarbonyl complexes.23

O O OH OH OH OH OH

Ph H IV.6a IV.6b IV.6c IV.6d IV.6e Phenyl Methyl Ethylenedioxy Ethyl Isopropyl isoborneol isoborneol isoborneol isoborneol isoborneol PIB-OH MIB-OH DOIB-OH EIB-OH IPIB-OH

OH OH OH OH OH

IV.6j Anisyl isoborneol IV.6f IV.6g IV.6h IV.6i O AIB-OH Cyclohexyl Isobutyl Vinyl Benzyl isoborneol isoborneol borneol isoborneol CHIB-OH IBIB-OH VIIB-OH BIB-OH

OH OH OH OH OH

IV.6k Ph Biphenyl isoborneol IV.6n IV.6o BPIB-OH Phenethyl Isopropenyl Ph IV.6l IV.6m isoborneol isoborneol Xylyl α-Naphthyl PEIB-OH IPRIB-OH isoborneol isoborneol XIB-OH NIB-OH OH OH IV.6q IV.6r IV.6p OH Diphenylmethyl Mesityl β-Naphthyl isoborneol isoborneol isobornel DPIB-OH MSIB-OH BNIB-OH

Figure IV.4 Chiral Auxiliaries Proposed for the Study

The aryl substituents at C2 of the camphyl moiety, having different steric and electronic effects properties, such as XIB-OH (IV.6l), BPIB-OH (IV.6k), DPIB-OH

(IV.6q), AIB-OH (IV.6j), NIB-OH (IV.6m), BNIB-OH (IV.6p) and MSIB-OH (IV.6r)

169 were also included. BIB-OH (IV.6i), DPIB-OH (IV.6q) and PEIB-OH (IV.6n) were included to determine the influence of variation in the proximity of the aryl group to the camphyl group and the arene chromium complex group.

The chiral complexes were prepared by SNAr addition of the chiral alkoxides to the fluoroarene complex. While chloroarene complexes also undergo SNAr substitution reactions with alkoxide anion to give alkoxy arene chromium tricarbonyl complexes, the corresponding fluoro complexes react about 2000 times faster24 and hence were chosen as starting material. The entire scheme for the proposed study is shown in Scheme IV.10.

F i) LDA, THF, t-butyl acetate -78 °C OR* OR* R* ii) HMPA, 2h, -60 °C O K iii) CF3COOH, -60 °C, 0.5h (OC) Cr O Cr(CO)3 R' 3 iv) NH4OH, rt, 0.5h Si(CH3)3 t-BuO Et O, 0 °C rt one-pot 2 Si(CH3)3 Si(CH3)3 IV.11 IV.12 IV.13

Scheme IV.10 Reaction Scheme for the Proposed Study

IV.2.3 Preparation of Chiral Auxiliaries and Chiral Complexes

Preparation of Chiral Alcohols

Grignard reagents add quantitatively to camphor in the presence of anhydrous cerium chloride25 (either catalytic or stoichiometric) at room temperature to yield the exo- alcohols (isoborneols) in good yields (Equation IV.1).26 Methyl isoborneol (MIB-OH

IV.6b), phenyl isoborneol (PIB-OH IV.6a) and vinyl isoborneol (VIIB-OH IV.6h) have been prepared by this method from D(+) camphor.

170 i) anhyd.CeCl3, THF ii) R'MgX, THF, r.t. OH O R' D(+) Camphor 2-substituted isoborneols IV.6

Equation IV.1 Preparation of Chiral 2-isoborneols from D(+) Camphor

The chiral alcohols BIB-OH27 (IV.6i), EIB-OH28 (IV.6d), NIB-OH29 (IV.6m),

BNIB-OH30 (IV.6p), PEIB-OH31 (IV.6n) and AIB-OH32 (IV.6j) are known in the literature to be prepared under various conditions but are not completely characterized.

These auxiliaries along with the other new auxiliaries were prepared using the same procedure. The yields of preparations are collected in Table IV.3.

Chiral isoborneol Grignard reagent Yield (%) IV.6a Phenyl isoborneol (PIB-OH) Phenyl magnesium chloride 82 IV.6b Methyl isoborneol (MIB-OH) Methyl magnesium bromide 74 IV.6d Ethyl isoborneol (EIB-OH) Ethyl bromide/Mg 79 IV.6e Isopropyl isoborneol (IPIB-OH) Isopropyl bromide/Mg 41 IV.6f Cyclohexyl isoborneol (CHIB-OH) Cyclohexyl bromide/Mg 43 IV.6g Isobutyl isoborneol (IBIB-OH) Isobutyl bromide/Mg 74 IV.6h Vinyl isoborneol (VIIB-OH) Vinyl bromide 78 IV.6i Benzyl isoborneol (BIB-OH) Benzyl magnesium chloride 79 IV.6j Anisyl isoborneol (AIB-OH) Anisyl bromide/Mg 91 IV.6k Biphenyl isoborneol (BPIB-OH) Biphenyl bromide/Mg 86 IV.6l Xylyl isoborneol (XIB-OH) Xylyl bromide/Mg 75 IV.6m Naphthyl isoborneol (NIB-OH) Naphthyl bromide/Mg 86 IV.6n Phenethyl isoborneol (PEIB-OH) Phenethyl bromide/Mg 45 IV.6o Isopropenyl isoborneol (IPRIB-OH) Isopropenyl magnesium bromide 55 IV.6p β-Naphthyl isoborneol (BNIB-OH) 3-bromonaphthalene/Mg 81

Table IV.3 Chiral C2-substituted Isoborneols Prepared from D(+) Camphor and their Yields

In general the Grignard reagents were prepared by stirring the appropriate bromide with magnesium pellets in THF and the cooled solution was transferred dropwise to the slurry of camphor and cerium chloride by a canula at room temperature.

171 Preparation of the naphthyl Grignard reagent33 required the addition of benzene to prevent the Grignard reagent from solidifying on cooling. The diphenylmethyl bromide was extremely hygroscopic and efforts to make the corresponding Grignard reagent were fruitless, while mesitylmagnesium bromide did not add to camphor, possibly due to the steric bulk of the mesityl group. Hence chiral auxiliaries MSIB-OH (IV.6r) and DPIB-

OH (IV.6q) were not prepared. Only the DOIB-OH (IV.6c) chiral auxiliary was prepared differently by the known three step procedure34 as shown in Scheme IV.11.

O p-TSA, O SeO2 O L-selectride O benzene + O O O diethyl ether OH O O O O IV.14 HO OH H minor major reflux IV.15a IV.15b IV.6c

+ H /H2O

Scheme IV.11 Preparation of DOIB-OH IV.6c Chiral Auxiliary from D(+)-Camphor

Solid chiral auxiliaries were purified by recrystallization and oils were purified by flash column chromatography. The purity of each alcohol was determined from its 1H and

13C NMR spectra and by GC-MS analysis.

Preparation of Chiral Alkoxyarenechromium Tricarbonyl Complexes

The (para-fluoro-trimethylsilylbenzene)Cr(CO)3 complex IV.11 was prepared by both methods A and B (Scheme IV.12). In preparing the complex, previous results from our laboratory had noted a possible instability of the TMS group during complexation and hence a mild complexation strategy following Method A35 was followed. The starting fluoro complex was thence prepared by refluxing naphthalene chromium tricarbonyl

(itself prepared by refluxing naphthalene and chromium hexacarbonyl in decalin and

172 ethyl formate)36 and the corresponding arene in diethyl ether-THF mixture in a sealed tube (Method A). The para-fluorotrimethylsilylbenzene37 IV.17 was prepared by the known method of refluxing para-fluorophenylmagnesium bromide IV.18 and trimethylsilyl chloride in diethyl ether. The general Pauson and Mahaffy procedure38 of refluxing the arene with chromium hexacarbonyl and di-n-butyl ether-THF mixture

(Method B) yielded the complex in 71%.

Cr(CO)3

+ Diethyl ether/ 3 eq THF, heat in a sealed tube, 48h, Mg pellets, diethyl 33% in two steps F F F ether, TMSCl, reflux, Method A 3h, 84%

Method B (OC)3Cr Si(CH ) Si(CH3)3 Br 3 3 Cr(CO)6, Bu2O, THF, reflux, 65h, IV.18 IV.17 IV.11 71 %

Scheme IV.12 Preparation of Starting Fluoroarene Complex IV.11 by Method A and Method B

The chiral alkoxy groups were attached to the arene complex by SNAr reaction of the corresponding potassium alkoxide (by treating with potassium hydride), yields of which are noted in Table IV.4. The compounds were obtained as yellow to greenish- yellow solids in good to moderate yields and were easily purified by recrystallization from dichloromethane-hexane mixture. The complexes with aryl substituent in the chiral auxiliary recrystallized as rhombic yellow crystals.

O IV.11O K IV.12 R' R' (OC)3Cr Si Si(CH ) (OC)3Cr 3 3 Et2O, 0 °C to rt

173 Complex Chiral auxiliary Yield (%) IV.12a Phenyl isoborneol 86 IV.12b Methyl isoborneol 97 IV. 12c DOIB-OH 79 IV. 12d Ethyl isoborneol 72 IV. 12e Isopropyl isoborneol 56 IV. 12f Cyclohexyl isoborneol 39 IV. 12h Vinyl isoborneol 73 IV. 12i Benzyl isoborneol 73 IV. 12j Anisyl isoborneol 87 IV. 12k Biphenyl isoborneol 89 IV. 12l Xylyl isoborneol 73 IV. 12m Naphthyl isoborneol 77 IV. 12o Isopropenyl isoborneol 83 IV. 12p β-Naphthyl isoborneol 65

Table IV.4 Synthesis of Chiral Alkoxyarenechromium Tricarbonyl Complexes IV.12 by SNAr Reaction of Complex IV.11

The IPIB-TMS IV.12e and CHIB-TMS IV.12f complexes decomposed within 3-4 days of preparation even on storing with the exclusion of light and under refrigeration.

The 1H NMR spectrum of the decomposed material in the case of CHIB-TMS IV.12f revealed the presence of decomplexed arene. The bulky cyclohexyl group possibly promotes loss of the chromium tricarbonyl. The complexes of PEIB-OH IV.6g and IBIB-

OH IV.6n were not prepared. All other complexes were stable as solids at room temperature when stored away from light.

IV.2.4 Nucleophilic Addition to Chiral Alkoxyarenechromium Tricarbonyl

Complexes

The complexes thus prepared were added to the enolate solution followed by

HMPA as co-solvent at -60 °C. The mixture was stirred for 2 hours and trifluoroacetic acid was added, followed by decomplexation with ammonium hydroxide solution. After

174 workup the solution of the reaction mixture in the NMR solvent was passed through a plug of alumina to remove chromium compounds. The diastereoselectivity during nucleophilic addition was determined by integrating proton signals that were sufficiently separated (usually the cyclohexadiene protons) in the 1H NMR spectrum of the mixture of cyclohexadienol ethers IV.13. An illustrative example of 1H NMR of a diastereomeric mixture is shown in Figure IV.5.

Figure IV.5 Illustrative Example of Determination of Ratio of Diastereoselectivity of Diastereomeric Cyclohexadienol Ether Mixture

Determination of Major Isomer of Nucleophilic Addition

The major isomer from diastereoselective nucleophilic addition was determined from the sign of optical rotation, in chloroform solution, of the corresponding cyclohexenone IV.19 obtained by hydrolysis of the dienol ether mixture. The hydrolysis was carried out with para-toluenesulfonic acid at room temperature (Scheme IV.14). The

175 S isomer is dextrorotatory. The stereoisomer was further confirmed by recording the CD spectrum in hexane. The S isomer shows negative Cotton effect (n-π*) at λmax 338 nm

(Figure IV.6 & IV.7). This assignment was made from comparison of the previously published CD spectrum of a related enone39 and can be explained using the Octant

Rule.40

O O O OR* [α]589 = +37.2° TsOH.H2O 20 °C, CHCl , O H S or R S 3 c = 10 t-BuO THF,rt, 4h CO2t-Bu CO2t-Bu CO2t-Bu Si(CH3)3 IV.13 + rotation - rotation IV.19

Scheme IV.13 Determination of the Stereochemistry of Addition from Cyclohexenone IV.19

CD spectrum of Cyclohexenone 30 from BIB-TMS complex (R isomer)

10 Absorbance 0 320 325 330 335 340 345 350 355 360 365 370

-10

-20

-30 Wavelength (nm)

Figure IV.6 CD Spectrum of Major R isomer of IV.19

176 CD spectra of Cyclohexenone from AIB-TMS complex

0 320 325 330 335 340 345 350 355 360 365 370 -10 Absorbance

-20

-30

-40

-50 Wavelength (nm)

Figure IV.7 CD Spectrum of Major S isomer of IV.19

IV.3 Results and Discussion

The results of tert-butyl lithioacetate additions to the chiral arene chromium tricarbonyl complexes IV.12 for all successful reactions are collected in Table IV.5 with the ratio of their diastereomeric cyclohexadienol ethers IV.12 and the corresponding major isomer. No ortho addition was detected in the cyclohexadiene products. In some cases traces of decomplexed arene was observed in the 1H NMR spectrum of the crude reaction mixture. The results of diastereoselectivity from Table IV.5 show that aryl chiral auxiliaries give better stereoselection than the alkyl substituents at C2 of camphor. This greater selectivity by aryl substituted chiral auxiliaries over alkyl substituted auxiliaries has also been noted in other reactions.41 The complexes IV.12c, IV.12i and IV.12m gave

R as the major isomer while the remaining complexes give the opposite isomer as the major one. From a synthetic view point, the results are very encouraging with the S and R isomers of the cyclohexenone IV.19 obtained from the PIB-OH (IV.6a) and NIB-OH

(IV.6m) auxiliaries, respectively, with diastereoselectivity as high as 97%.

177 OR* OR* OR* i) LDA, THF, t-butyl acetate -78 °C ii) HMPA, 2h, -60 °C O O iii) CF COOH, -60 °C, 0.5h 3 t-BuO t-BuO (OC)3Cr iv) NH4OH, rt, 0.5h Si(CH ) Si(CH3)3 3 3 Si(CH3)3 IV.13 IV.12

Ratio of Major Chiral auxiliary/Complex Cyclohexadienol isomer IV.12 Ethers (IV.13) Phenyl isoborneol (PIB) IV.12a 96:4 S Methyl isoborneol (MIB) IV.12b 55:45 S 3,3-Ethylenedioxyisoborneol (DOIB) IV.12c 30:70 R Benzyl isoborneol (BIB) IV.12i 38:62 R Xylyl isoborneol (XIB) IV.12l 96:4 S* p-Methoxy isoborneol (AIB) IV.12j 90:10 S α-Naphthyl isoborneol (NIB) IV.12m 3:97 R Biphenyl isoborneol (BPIB) IV.12k 90:10 S Ethyl isoborneol (EIB) IV.12d 80:20 S

Table IV.5 Ratio of Diastereoselectivity on Nucleophilic Addition to Chiral Arenechromium Tricarbonyl Complexes (* Major isomer presumed)

Interestingly, the MIB-TMS (IV.12b) complex gave the same major S isomer as the PIB-TMS IV.12a complex, opposite to the R isomer obtained in both MIB-H IV.7b and MIB-CH3 IV.8b complex during isobutyronitrile addition. It was necessary to know whether a change of nucleophile also leads to a difference in stereoselection. tert-Butyl lithio acetate with HMPA as co-solvent was added to MIB-H (IV.7b) complex and R was obtained as the major isomer (Scheme IV.15). It was deduced that the –Si(CH3)3 in

IV.12b is the reason for the change in stereoselection and indeed plays a role.

178 O OR* i) LDA, THF, t-butyl acetate -78 °C O ii) HMPA, 2h, -60 °C O O iii) CF COOH, -60 °C, 0.5h 3 t-BuO iv) NH4OH, rt, 0.5h t-BuO R R = H major isomer R (OC)3Cr R R = TMS major isomer S R= -H IV.7b R= -H IV.20b IV.19 R= -TMS IV.12b R= -TMS IV.13b

Scheme IV.14 Reversal in Selectivity in MIB Chiral Auxiliary with –Si(CH3)3 para Substituent

The BNIB-TMS IV.12p complex exists as rotational isomers, as observed in the

1H NMR spectrum, in solution even at room temperature, and nucleophilic addition to the complex was not performed. The IPRIB-TMS IV.12o complex gave a complex mixture of products which probably includes the nucleophilic addition product and reaction of the double bond at C2 of the camphyl group. Attempts to separate the mixture were unsuccessful. The VIIB-TMS complex IV.12o gave a product with the double bond of the vinyl group modified, which has been discussed in Chapter II.

Understanding Origin of Diastereoselectivity and Reversal of Selectivity

Over the years there has been a consistent exploitation of the asymmetric sense of the camphyl group in a multitude of diastereoselective reactions.42 The camphyl group has been modified to yield better selectivities based on the reactions.43 Also a reversal in asymmetric induction is noted in a few reactions with camphor based auxiliaries.44

Interesting cases of reversal in selectivity by simple modification of the chiral auxiliary have been reported.45

179 The nucleophilic addition reactions studied here are considered to be kinetically controlled. Both nitrile anions and ester enolates add reversibly to arene chromium tricarbonyl complexes, but addition of HMPA retards the backward reaction (k1 >> k-1).

With all other reaction parameters fixed (tert-butyl lithioacetate as nucleophile and same reaction conditions), the diastereoselectivity must solely be dependent on the properties of the starting chiral complex and the asymmetric induction is thought to occur at the nucleophilic addition step. Similar to explaining regioselectivity of addition, we viewed the diastereoselectivity in this kinetically controlled reaction in terms of charge and orbital control arguments of the chiral arene chromium tricarbonyl complex.

In our studies on the conformational analysis of these chiral complexes and from

X-ray crystal structures we have confirmed the preference for a cis-endo conformation of the tripod with respect to the camphyl group. With respect to the directional orientation of the chromium tricarbonyl tripod, the X-ray crystal structure analysis shows that complexes IV.12a and IV.12b have Il conformer, while IV.12c exists in both Il and Ir conformations in the solid state the latter albeit with different torsional angles (Figure

IV.8).

OPIB OMIB ODOIB ODOIB

TMS TMS TMS TMS IV.12a IV.12b IV.12c Torsional angle: 33.0 13.1 17.9 3.2

Orientation: Il Il Ir Il Major isomer on nucleophilic addition: S S R

Figure IV.8 Conformation of the Tripod in Solid State and Major Isomer on Nucleophilic Addition

180 Further, from NMR studies we determined the most deshielded meta arene carbon for seven complexes IV.12a, IV.12b, IV.12c, IV.12i, IV.12l, IV.12m and IV.12j and we argued that the pattern of 13C NMR chemical shifts might reflect the preferred orientation

13 of the Cr(CO)3 tripod. It was argued that from the pattern of C NMR chemical shifts, the complexes IV.12a, IV.12b, IV.12l and IV.12j have Il conformation and the complexes IV.12c, IV.12i and IV.12m exist in Ir conformation in solution. That argument apart, from the NMR studies we could at least determine which of the two meta

13 carbons has less electron density i.e., the one most deshielded (C1) in the C NMR spectra.

O S isomer OR* OR* Cr(CO)3 Cr(CO)3 R isomer O O O C C C C2 O 2 1 1 Nu TMS TMS O C C 1 2 C1 C2 R* = -PIB (IV.12a) 102.3 101.1 R* = -DOIB (IV.12a) 100.7 99.3 -MIB (IV.12b) 102.2 101.4 -BIB (IV.12b) 100.9 100.1 -XIB (IV.12l) 98.7 98.3 -NIB (IV.12l) 102.1 100.7 -AIB (IV.12j) 99.4 98.8 (C1 more deshielded than C2)

Figure IV.9 13C NMR Carbon Chemical Shifts at the meta Carbons of the Seven Arene Complexes with Corresponding Major Isomer on Nucleophilic Addition

Figure IV.9 shows the 13C NMR chemical shifts of the arene meta carbons and the major isomer obtained from nucleophilic addition on the corresponding complexes. There is a striking correlation of the results of selectivity that we observed with nucleophilic attack at the most deshielded meta carbon. From just this information it is difficult to deduce whether the reaction is under charge or orbital control. Plots of diastereoselectivity with differences in 13C NMR chemical shift of the meta arene carbons

181 do not correlate well but with the sum of the difference of ortho and meta carbons they do correlate (Figure IV.10 & IV.11). Though the significance of this trend is not apparent at this point, it underscores the role of charge density of the arene on diastereoselection.

Chiral complexes PIB AIB BPIB NIB MIB BIB EIB Selectivity as a factor of 10 9.6 9.6 9.1 9.7 5.5 3.7 3.4 Sum of the difference of ortho/meta 2.2 2.2 2.3 2.7 1.3 1.0 0.6 carbons Sum of the difference of meta carbons 0.6 0.6 0.6 1.3 0.9 0.2 0.3

Correlation of Selectivity Vs Sum of difference of ortho and meta CCS of Chiral Arene Chromium Tricarbonyl Complexes

2.5

1.5 Chemical Shift 1

0.5 Sum of difference of ortho and meta Carbon-13 Carbon-13 meta and ortho of Sum difference of 0 024681012 Selectivity as a factor of 10

Figure IV.10 Plot of Ratio of Diastereoselectivity on Nucleophilic Addition to Sum of 13C NMR Chemical Shift (CDCl3) Difference at the meta Arene Carbons and ortho Arene Carbons

182 Correlation of Selectivity Vs Difference of Carbon-13 Chemical Shift of Meta Carbons

6 Carbons

2 Difference of Carbon-13 Chemical Shift of meta meta of Shift Chemical Carbon-13 of Difference 0 0 0.2 0.4 0.6 0.8 1 1.2 1.4 Selectivity as a factor of 10

Figure IV.11 Plot of Ratio of Diastereoselectivity on Nucleophilic Addition to Sum of 13C NMR Chemical Shift (CDCl3) Difference at the meta Arene Carbons

Reversal of selectivity along with high enantioselectivity was obtained in rhodium catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carbonyl compounds when using chiral diphosphosphonites prepared from (R)-BINOL, with a difference in the structure of the chiral backbone, which yields substituted cyclohexanones.46 Reversal of diastereoselectivity was reported from our laboratory in studies of hydride addition to chiral arene-manganese tricarbonyl complexes47 (Scheme IV.17).

Mn(CO) CH 3 Mn(CO)3 CH3 3 CH3 Nu Nucleophile N N N

Mn PF6 CH Nu CH3 3 CH3

Scheme IV.15 Diastereoselective Nucleophilic Addition to Arenemanganese Tricarbonyl Complexes

183 The effect of direction of Mn(CO)3 tripod orientation on the MO coefficients of the arene was determined and the arene meta carbon with larger coefficient was attacked by the nucleophile. The same factor explains the selectivities observed in the arenechromium tricarbonyl complexes studied here.

IV.4 Efforts towards Synthesis of FK-506 sub-unit

FK-50648 (IV.21) has been shown to have potent activity as an immunosuppressant from recent clinical trials. Since its activity was reported in the late

1980s a number of synthetic studies were carried out. Earlier work from our laboratory involved a racemic synthesis of IV.22 from the cyclohexenone IV.23 derived by nucleophilic addition to 3-methoxycyclohexadienyliron tricarbonyl complex.49

H3CO Ph OCH3 H CO O S 3 O H OH O O OTBDMS O O IV.22 O H OH O O Ph OCH3 O S O O FK-506 IV.21 OH IV.23

Figure IV.12 Approach Towards Synthesis of FK-506 Sub-unit

We recognized that non-racemic IV.23 might also be accessible by nucleophilic addition of the corresponding methylphenylsulfone anion to a suitable chiral arene chromium tricarbonyl complex (Figure IV.13). The anion of methylphenylsulphone has been reported to undergo SNAr reactions with chlorotoluenetricarbonyl chromium

50 complexes. Since the pKa of the carbanion is 29 in DMSO, addition is expected to be

184 facile. The nucleophile was first tested with the simple racemic complex IV.24 under the same reaction conditions as tert-butyl lithioacetate addition done previously (Scheme

IV.18).

i) LDA, THF, -78 °C OCH3 OCH3 p-TsOH, O methylphenylsulfone diethyl ether, ii) HMPA, 2h, -60 °C Ph rt, 1h OO O S S iii) CF COOH, -60 °C, 0.5h (OC)3Cr 3 O 45% Ph Si iv) NH4OH, rt, 0.5h Si(CH3)3 61% IV.25 IV.23 IV.24

Scheme IV.16 Lithio Methylphenylsulfone Addition to Complex IV.24

The reaction in the absence of HMPA did not yield any diene and the starting complex was recovered. While the 1H NMR of the crude reaction mixture after workup showed only the presence of the diene IV.25, purification led to some decomposition of the diene. Hydrolysis of this diene IV.25 yielded the cyclohexenone IV.23 in 45% yield.

The BPIB-TMS IV.12k complex was chosen for the asymmetric reaction, as it is known to give the same isomer (S) at the ring junction as in the natural product. Lithio methyl phenyl sulfone addition to BPIB-TMS IV.12k gave a modest selectivity of 1:3.5.

The reaction with NIB-TMS IV.12k complex also gave a (reversed) diastereoselectivity of 3.5:1 (Scheme IV.17). The isomers are presumed to be S and R respectively from the earlier studies and were not determined in this addition.

185 OR* i) LDA, THF, -78 °C OR* methylphenylsulfone ii) HMPA, 2h, -60 °C Ph O S (OC)3Cr iii) CF3COOH, -60 °C, 0.5h O Si(CH ) TMS iv) NH4OH, rt, 0.5h 3 3 R* = -NIB IV.12m R* = -NIB (dr - 1:3.5) IV.26m -BPIB IV.12k -BPIB (dr - 3.5:1) IV.26k

Scheme IV.17 Chiral Auxiliary Directed Methylphenylsulfone Anion Addition – Asymmetric Approach Towards FK-506 Sub-unit

Separation of the diastereomers followed by hydrolysis of the major isomer should yield the enantiomerically pure cyclohexenone.

IV.5 Conclusions

The present study has primarily led to two chiral auxiliaries (phenyl isoborneol IV.6a and naphthyl isoborneol IV.6m) which yield opposite enantiomers in very high ee from tert-butyl lithioacetate enolate addition. Aryl chiral auxiliaries are better than simple alkyl substituted ones. This high diastereoselection on nucleophilic addition at the meta carbons of the alkoxy arenechromium tricarbonyls represents a case of conformational transmission of chirality from the C2 of the camphyl group through the Cr(CO)3 tripod to the site of nucleophilic attack. A few cases of 1,5 asymmetric diastereocontrol by conformational restrictions are reported.51 From NMR studies it appears that the nucleophile adds predominantly to the more electron deficient carbon (Table V.6). The selectivity also correlates with the arene LUMO coefficients from earlier studies on arene manganese tricarbonyl complexes, which was based on the orientation of the tripod affecting the LUMO coefficients of the arene. With the orientation of the Cr(CO)3 tripod affecting both charge (as seen from 13C NMR chemical shifts of the meta carbons) and

186 LUMO coefficients of the arene it is directly responsible for results of diastereoselection observed irrespective of the substituent para to the chiral alkoxy group.

Complex Solvent A edge A edge B edge B edge Tripod* Major# ortho to meta to ortho to meta to (Il or Ir) isomer -TMS -TMS -TMS -TMS -PIB (IV.12a) THF-d8 102.1 83.7 102.3 84.5 Il S -MIB (IV.12b) THF-d8 101.4 83.0 102.2 83.1 Il S -AIB (IV.12j) CDCl3 98.8 82.7 99.4 84.3 - S -DOIB (IV.12c) THF-d8 102.2 82.4 101.1 79.7 Ir & Il R -DOIB (IV.12c) C6D6 100.7 81.1 99.3 78.3 Ir & Il R -NIB (IV.12m) THF-d8 102.1 84.0 100.7 83.1 - R -BIB (IV.12i) THF-d8 100.9 84.9 100.1 84.7 - R

Table IV.6 13C NMR Chemical Shifts Correlated (*Tripod orientation from X-ray crystal structures #Major isomer on tert-butyl lithio acetate addition)

As an application of this methodology, an asymmetric approach to the cyclohexyl subunit of FK-506 was attempted yielding moderate diastereoselection with the methylphenylsulfone anion. Its application in a formal synthesis of Juvabione, a more compelling example in natural product synthesis is described in Chapter V. Finally considering all the data that we have obtained with regard to conformational preferences,

NMR studies, solid state structure and selectivity of nucleophilic addition all point at the orientation of the tripod as a structural element in determining the diastereoselectivity.

The tripod orientation itself is controlled by stereoelectronic effects of the substituents with emphasis on the π-carbonyl interaction between the C2 aryl substituents and one of the carbonyl ligands.

187 Experimental

General procedures: All reactions involving chromium tricarbonyl complexes were performed using oven-dried (125 ºC) glassware under anhydrous, oxygen free argon atmosphere. All reactions were performed in freshly distilled (under nitrogen) solvents and monitored by TLC on silica gel. The TLC plates were visualized with UV light and/or with phosphomolybdic acid solution in ethanol. Reactions performed at -60 ºC were maintained at that temperature using ethanol bath and Neslab Cryotrol. Flash chromatography was performed on silica gel with mesh 170-400 under nitrogen pressure.

NMR spectra were recorded on a Varian Gemini 200 (200 MHz) or Varian Gemini 300

(300 MHz) or Varian Inova 600 (600 MHz) spectrometer. FTIR spectra were recorded as neat oils or KBr pellet on a Nicolet Impact 400 FTIR spectrometer. High resolution mass spectra (HRMS) of compounds were recorded in-house using a Kratos MS25A instrument by either EI (Electron Ionization) or FAB (Fast Ion Bombardment). Capillary

GC was carried out using HP5890 Series II Gas Chromatograph. The melting points were measured on a Thomas Hoover apparatus and are uncorrected. The purity of new compounds was assessed from their 1H and 13C NMR spectra.

General Procedure for Preparation of C2 substituted chiral isoborneols:

In an oven dried round bottomed flask with stirrer anhydrous cerium chloride and

D (+) Camphor (99.5% from Acros) were mixed. Freshly distilled and cooled THF was added and the slurry was stirred at room temperature. After approximately 2 hours the corresponding Grignard reagent was added drop-wise via a syringe or through a canula

188 under nitrogen atmosphere. Usually there is a slight color change from white to yellow or grey slurry. The progress of reaction was checked with tlc and GC. The workup involves very slow drop-wise addition of saturated ammonium chloride solution until the grey/yellow slurry separates as a solid and a clear organic solution. The supernatant was removed and the solid precipitate washed thrice with diethyl ether. The washings were combined and dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The isoborneols were obtained as sweet smelling white solids or colorless oils. Solids were purified by recrystallization and oils were purified by flash column chromatography.

(1R, 2S)-1,7,7-Trimethyl-2-phenylbicyclo[2.2.1]heptan-2-ol (IV.6a)

8 7 9 4 5 3 6 OH 1 2 10 1' 2' 3' 4'

22 Colorless oil. Yield: 82%; [α] D = -33.8 (c = 1.00g/100 mL, CHCl3); Rf: 0.37 (9:1

+ hexane/ethyl acetate); EI HRMS m/z 230.1678 (M ), 230.1671 calculated for C16H22O;

1 H NMR (400 MHz, CDCl3) δ 7.53 (2H, d, J = 7.6 Hz), 7.33 (2H, t, J = 7.6 Hz), 7.27 –

7.24 (1H, m), 2.33 (1H, d, J = 14.0 Hz), 2.19 (1H, dt, J = 14.0, 3.7 Hz), 1.90 (1H, t, J =

4.0 Hz), 1.84 (1H, s), 1.77 – 1.61 (1H, m), 1.27 (3H, s), 1.26 – 1.15 (2H), 0.91 (2x3H, s),

13 0.87 – 0.80 (1H, m); C NMR and APT (50 MHz, CDCl3) δ 146.2 (C1’), 127.6, 126.9,

126.8 (preceding 3 signals are aromatic C-H carbons), 83.6 (C2), 53.5 (C1), 50.5 (C7),

189 45.7 (C3), 45.5 (C4), 31.3 (C6), 26.6 (C5), 21.7 (C8 and C9), 9.9 (C10); FTIR (KBr) νmax

3554 (O-H stretch), cm-1.

(1R, 2S)-1,7,7-Trimethyl-2-ethylbicyclo[2.2.1]heptan-2-ol (IV.6d)

8 7 9 4 5 3 6 OH 1 10 1' 2'

25 Colorless Oil. Yield: 79%; [α] D = - 6.91 (c = 5.4 g/100 mL, ethanol) [Literature: -7.09

+ (c = 5.4 g/100 mL]; Rf: 0.36 (9:1 hexane/ethyl acetate); FAB HRMS m/z 182.1682 (M ),

1 13 calcd for C12H22O 182.1671; H NMR (200 MHz, CDCl3) δ; C NMR and APT (50

MHz, CDCl3) δ 81.4 (C2), 52.4 (C1) 49.6 (C7), 45.4 (C3), 45.2 (C4), 31.9 (C6), 30.6

(C5), 27.2 (C1’), 21.7 (C8 or C9), 21.2 (C8 or C9), 10.8 (C10), 8.8 (C2’); FTIR (KBr)

-1 3535 (O-H stretch) νmax cm .

(1R, 2S)- 2-Isopropyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (IV.6e)

8 7 9 4 5 3 6 OH 1 2 10 3' 1' 2'

+ Colorless Oil. Yield: 41%; Rf: 0.31 (14:1 hexane/ether); EI HRMS m/z 196.1835 (M ),

1 calcd for C13H24O 196.1827; H NMR (200 MHz, CDCl3) δ 1.93 (1H, ddd, J = 13.1, 3.6,

4.0 Hz), 1.84 – 1.61 (3H), 1.52 – 1.33 (2H), 1.29 (1H, s), 1.09 – 0.98 (1H, m), 1.08 (3H, s), 0.95 (3H, d, J = 3.5 Hz), 0.91 (3H, d, J = 3.5 Hz), 0.93 (3H, s), 0.83 (3H, s); 13C NMR and APT (50 MHz, CDCl3) δ 82.3 (C2), 52.4 (C1), 50.5 (C7), 47.0 (C3), 44.6 (C4), 37.3

190 (C1’), 29.5 (C6), 27.7 (C5), 21.5 (C8 or C9), 21.1 (C8 or C9), 18.5 (C2’ or C3’), 18.2

-1 (C2’ or C3’), 12.2 (C10) ; FTIR (KBr) νmax 3533 (O-H stretch), 2947(C-H stretch) cm .

(1R, 2S)- 2-Cyclohexyl 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (IV.6f)

8 7 9 4 5 3 6 OH 1 10 1'

White solid. Yield: 43%; Rf: 0.51 (9:1 hexane/ethylacetate); FAB HRMS m/z 236.2141

+ 1 (MH ), calcd for C16H27O 236.2140; H NMR (300 MHz, CDCl3) δ 1.94 – 1.84 (1H, m),

1.87 – 1.70 (4H), 1.68 – 1.63), 1.56 (1H, s), 1.55 – 1.34 (3H), 1.32 (1H, s), 1.26 – 1.14

(5H), 1.10 – 1.04 (1H, m), 1.07 (3H, s), 0.94 (3H, s), 0.83 (3H, s); 13C NMR and APT (50

MHz, CDCl3) δ 82.4 (C2), 52.3 (C1), 50.4 (C7), 48.4 (C1’), 46.5 (C3), 44.4 (C4), 29.3

(C6), 28.5 (C5), 27.8, 27.7, 27.0, 26.6, 26.5 (preceding five signals correspond to CH2 carbons of the cyclohexyl group), 21.4 (C8 or C9), 21.0 (C8 or C9), 12.5 (C10); FTIR

-1 (KBr pellet) νmax 3529 (O-H stretch), 2944 (C-H stretch) cm .

(1R, 2S)-1,7,7-Trimethyl-2-benzylbicyclo[2.2.1]heptan-2-ol (IV.6i)

8 7 9 4 5 3 6 OH 1 10 1'

2' 4' 3'

Colorless oil. Yield: 79%; Rf: 0.45 (9:1 hexane/ethylacetate); EI HRMS m/z 244.1825

+ 1 (M ), calcd for C17H24O 244.1827; H NMR (400 MHz, CDCl3) δ 7.32 – 7.22 (5H), 2.81

191 (2H, JAB = 13.2 Hz), 1.82 – 1.75 (3H), 1.68 – 1.62 (2H), 1.52 – 1.44 (1H, m), 1.41 (1H, s), 1.19 – 1.12 (1H, m), 1.08 (3H, s), 0.88 (3H, s), 0.82 (3H, s); 13C NMR and APT (50

MHz, CDCl3) δ 138.1 (C1’), 130.7 (C2’ and C6’), 128.3 (C3’ and C5’), 126.5 (C4’),

80.2 (C2), 52.7 (C1), 49.3 (C7), 46.2 (C3), 45.2 (C4), 44.7 (-CH2-Ph), 30.5 (C6), 27.2

(C5), 21.6 (C8 or C9), 21.1 (C8 or C9), 10.4 (C10); FTIR (KBr) νmax 3585(O-H stretch),

3033, 2954, 2875 (C-H stretch), 1499, 1460, 1124cm-1.

(1R, 2S)-1,7,7-Trimethyl-2-[4-methoxyphenyl]bicyclo[2.2.1]heptan-2-ol (IV.6j)

8 7 9 4 5 3 6 OH 1 2 10 1' 2' 3' 4' O

22 White crystalline solid. Yield: 91%; [α] D = -20.62 ° (c = 2.42 g/100 mL , CHCl3); Rf:

+ 1 0.22 (10:1 hexane/ether); FAB HRMS m/z 260.1726 (M ), calcd for C17H24O2; H NMR

(200 MHz, CDCl3) δ 7.45 (2H, d, J = 8.8 Hz), 6.87 (2H, d, J = 8.8 Hz), 3.82 (3H, s, -O-

CH3), 2.29 (1H, d, J = 13.8 Hz), 2.18 (1H, dt, J = 14.2, 3.1 Hz), 1.90 (1H, t, J = 4.2 Hz),

1.84 (1H, s), 1.82 – 1.66 (1H, m), 1.28 (3H, s), 1.25 – 1.12 (2H), 0.92 (3H, s), 0.91 (3H,

13 s), 0.87 – 0.79 (1H, m); C NMR and APT (50 MHz, CDCl3) δ 158.5 (C4’), 138.4

(C1’), 127.9 (C2’ & C6’), 112.9 (C3’ & C5’), 83.4 (C2), 55.3 (-O-CH3), 53.6 (C1), 50.4

(C7), 45.68 (C4), 45.66 (C3), 31.4 (C6), 26.7 (C5), 21.8 (C8 or C9), 21.7 (C8 or C9), 9.9

-1 (C10); FTIR (KBr) νmax 2934 (C-H stretch), 1966, 1885 (carbonyl stretch) cm .

192 (1R, 2S)-1,7,7-Trimethyl-2-[4-biphenyl]bicyclo[2.2.1]heptan-2-ol (IV.6k)

8 7 9 4 5 3 6 OH 1 2 10 1' 2' 3' 4' 7' 8' 9' 10'

25 White crystalline solid. Yield: 86%; mp = 120 – 121 °C; [α] D = - 22.12 (c = 2.31 g/100

+ mL, CHCl3); Rf: 0.31 (10:1 hexane/ether); FAB HRMS m/z 305.1939 (M -H), calcd for

1 C22H16O 305.1905; H NMR (200 MHz, CDCl3) δ 7.66 – 7.32 (9H, m), 2.38 (1H, d, J =

14.0 Hz), 2.24 (1H, ddd, J = 14.0, 4.1, 3.1 Hz), 1.95 (1H, dd = t, J = 4.2 Hz), 1.88 (1H, s),

1.85 – 1.69 (1H, m), 1.37 – 1.17 (2H), 1.03 – 0.87 (1H, m), 1.31 (3H, s), 0.97 (3H, s),

13 0.95 (3H, s); C NMR and APT (50 MHz, CDCl3) δ 145.3 (C1’), 140.8 (C4’), 139.6

(C7’), 128.8, 127.3, 127.1, 126.3 (preceding 4 signals aromatic C-H carbons), 83.6 (C2),

53.6 (C1), 50.5 (C7), 45.71 (C3), 45.70 (C4), 31.4 (C6), 26.7 (C5), 21.74 (C8 or C9),

21.72 (C8 or C9), 10.0 (C10) ; FTIR (KBr) νmax 3489 (O-H stretch), 2951, 2880 (C-H stretch) cm-1.

(1R, 2S)-1,7,7-Trimethyl-2-[3’,5’-dimethylphenyl]bicyclo[2.2.1]heptan-2-ol (IV.6l)

8 7 9 4 5 3 6 OH 1 2 10 1' 3' 4'

193 25 White crystalline solid. Yield: 75%; M. Pt. = 95 - 97 °C; [α] D = - 33.37° (c = 2.08 g/100

+ mL, CHCl3); Rf: 0.38 (14:1 hexane/ether); FAB HRMS m/z 258.1958 (M ), calcd for

1 C18H26O 258.1984; H NMR (200 MHz, CDCl3) δ 7.14 (2H, s), 6.92 (1H, s, H4’), 2.35

(6H, s), 2.34 (1H, d, J = 13.9 Hz), 2.17 (1H, ddd, J = 13.9, 4.0, 3.2 Hz), 1.90 (1H, dd = t,

J = 4.2 Hz), 1.81 (1H, s), 1.79 – 1.64 (1H, m), 1.32 – 1.07 (2H), 1.27 (3H, s), 0.96 – 0.82

13 (1H, m), 0.93 (3H, s), 0.92 (3H, s); C NMR and APT (50 MHz, CDCl3) δ 146.3 (C11’),

137.0 (C3’ & C5’), 128.4 (C4’), 124.7 (C2’ & C6’), 83.6 (C2), 53.4 (C1), 50.4 (C7), 45.6

(C3), 45.4 (C4), 31.3 (C6), 26.6 (C5), 21.7 (C8 or C9 or arene-CH3), 21.6 (C8 or C9 or

-1 arene-CH3), 10.0 (C10); FTIR (KBr) νmax 3605(O-H stretch), 3033 (C-H stretch) cm .

(1R, 2S)-1,7,7-Trimethyl-2-[1-naphthyl]bicyclo[2.2.1]heptan-2-ol (IV.6m)

8 7 9 4 5 3 6 OH 1 2 10 20 11 18 19 12 17 13 15 16 14

25 White crystalline solid. Yield: 86%; M. Pt. = 121-122 °C; [α] D = - 38.1 ° (c = 0.31 g/100 mL, benzene) [Literature: -38.0 ° (c = 0.3 g/100 mL, benzene); Rf: 0.46 (9:1

+ 1 hexane/ethylacetate); FAB HRMS m/z 280.1811 (M ), calcd for C20H24O 280.1827; H

13 NMR (200 MHz, CDCl3) δ; C NMR and APT (50 MHz, CDCl3) δ; FTIR (KBr) νmax

3457 (O-H stretch), 3054, 2951(C-H stretch) cm-1.

194 (1R, 2S)-1,7,7-Trimethyl-2-[2’-propenyl]bicyclo[2.2.1]heptan-2-ol (IV.6o)

8 7 9 4 5 3 6 OH 1 2 10 2' 1' 3'

+ Colorless oil. Yield: 55%; Rf: 0.21 (14:1 hexane/ether); EI HRMS m/z 193.1596 (M -H),

1 calcd for C13H22O 193.1671; H NMR (300 MHz, CDCl3) δ 5.06 (1H, s), 4.90 (1H, t, J =

13.2 Hz), 2.09 (1H, d, J = 13.5 Hz), 1.91 (1H, dt, J = 13.5, 3.7 Hz), 1.88 (3H, d, J = 1.2

Hz), 1.74 (1H, t, J = 4.4 Hz), 1.71 – 1.59 (1H, m), 1.55 (1H, s), 1.40 – 1.19 (2H), 1.15

(3H, s), 1.09 – 0.99 (1H, m), 0.99 (3H, s), 0.86 (3H, s); 13C NMR and APT (50 MHz,

CDCl3) δ 149.8 (C1’), 112.1 (C2’), 83.9 (C2), 52.3 (C1), 50.1 (C7), 45.1 (C3), 42.9 (C4),

30.8 (C6), 27.1 (C5), 21.8 (C8, C9 or C3’), 21.5 (C8, C9 or C3’), 21.4 (C8, C9 or C3’),

11.6 (C10) ; FTIR (Neat on NaCl plate) νmax 3487 (O-H stretching), 2967, 2881 (C-H stretch), 1631 (C=C stretch) cm-1.

η6-(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl (IV.11)

Cr(CO)3

Si(CH3)3

η6-(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl was prepared from the corresponding arene by Pauson and Mahaffy procedure of refluxing the arene with chromium hexacarbonyl in dibutyl ether and THF mixture. The yellow crystalline solid was purified by recrystallization from 1:1 hexane/dichloromethane mixture and washed with ice cooled hexane. Yield: 71%; Rf: 0.48 (20:1 hexane/ether); FAB HRMS m/z

195 + 1 304.0025 (M ), calcd for C12H13O4FSiCr 304.0023; H NMR (200 MHz, CDCl3) δ 5.52

(2H, dd, J = 3.6, 6.3 Hz, H meta to fluoro), 5.29 (2H, dd = t, J = 5.7 Hz, H ortho to

13 fluoro), 0.28 (9H, s, -Si(CH3)3); C NMR and APT (50 MHz, CDCl3) δ 232.5 (CO),

148.0 (d, JC-F = 266.2 Hz), 98.5 (d, J = 6.6 Hz), 95.3 (arene(C)-Si(CH3)3, 79.0 (d, J =

-1 18.3 Hz), -1.2 (-Si(CH3)3); FTIR (KBr) νmax 3105, 1968, 1914, 1867 cm .

General procedure for synthesizing chiral chromium complexes:

To a heterogeneous mixture of potassium hydride (20 % dispersion in mineral oil; 4.5 mmol, 1.5 equiv, washed thrice with freshly distilled diethyl ether to remove the mineral oil), in anhydrous diethyl ether (12 mL) at 0 ºC under argon, was added a solution of the chiral isoborneol (3.3 mmol, 1.1 equiv), in diethyl ether (6 mL), dropwise so that the hydrogen gas effervescence is not too vigorous. One hour after the hydrogen gas evolution had stopped, a solution of the fluoro arene chromium tricarbonyl complex (η6-

(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl or η6-4-fluoro(toluene)chromium tricarbonyl or η6-anisolechromium tricarbonyl) (3 mmol, 1 equiv) in ether (9 mL) was added dropwise. The SNAr reaction was complete after 4 hours as indicated by complete disappearance of starting fluoro complex on the TLC plate. The dark brown mixture was carefully quenched by slow addition of 5% aqueous hydrochloric acid or an aqueous solution of ammonium chloride. The aqueous phase was then extracted with ether (3 x 25 mL) and the combined ether extracts were washed with water, dried (MgSO4), then filtered and concentrated in vacuo to give a yellow oil or solid. The crude product was purified either by recrystallization from 1:1 mixture of hexane/dichloromethane which

196 usually gave yellow crystals which was washed with cold hexane or purified by flash chromatography on silica gel (hexanes-ethyl acetate or hexanes-ether as eluent system).

η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-ethylbicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (IV.12d) was prepared from ethyl isoborneol IV.6d and η6-(4-fluoro(trimethylsilyl)benzene)chromium tricarbonyl IV.11 as a greenish yellow solid.

8 7 9 4 5 3 O 6 1 2 Cr(CO) 10 3 1' 2' Si

+ Yield: 72%; Rf: 0.55 (9:1 hexane/ethyl acetate); EI HRMS m/z 466.1622 (M ), calcd for

1 C24H34O4SiCr 466.1631; H NMR (400 MHz, CDCl3) δ 5.48 (2H, d, J = 6.8 Hz), 5.14

(1H, dd, J = 7.0, 2.2 Hz), 5.09 (1H, dd, J = 7.0, 2.2 Hz), 2.51 (1H, dt, J = 12.8, 3.7 Hz),

2.37 – 2.27 (1H, m), 1.76 – 1.58 (3H), 1.51 – 1.48 (2H), 1.35 (1H, d, J = 12.8 Hz), 1.11 –

1.06 (1H, m), 1.03 (3H, s), 1.00 (3H, t, J = 7.6 Hz), 0.92 (3H, s), 0.86 (3H, s), 0.26 (9H,

13 s, -Si(CH3)3); C NMR & APT (50 MHz, CDCl3) δ 234.1 (CO), 141.8 (C(arene complex)-O-), 99.7 (C-ortho to TMS), 99.4 (C-ortho to TMS), 93.6 (C-TMS), 92.9 (C2),

83.1 (C-meta to TMS), 82.8 (C-meta to TMS), 54.1 (C1), 50.2 (C7), 45.0 (C4), 43.5 (C3),

30.0 (C6), 29.6 (C1’), 26.6 (C5), 20.9 (C8 or C9), 20.7 (C8 or C9), 12.1 (C2’), 10.5

-1 (C10), -1.2 (-Si(CH3)3); FTIR (KBr) νmax cm .

197 η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-(isopropyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (IV.12e)

8 7 9 4 5 3 6 O 1 2 10 Cr(CO)3 1' 2' 3' Si

IV.12e was prepared from isopropyl isoborneol IV.6e and η6-(4-fluoro (trimethylsilyl) benzene) chromium tricarbonyl IV.11 as a green solid. Yield: 56%; Rf: 0.56 (14:1

1 hexane/ether); H NMR (600 MHz, THF-d8) δ 5.44 (1H, dd, J = 1.2, 6.6 Hz), 5.42 (1H, dd, J = 1.8, 6.6 Hz), 5.00 (1H, dd, J = 2.4, 6.6 Hz), 4.97 (1H, dd, J = 2.4, 6.6 Hz), 2.28 –

2.24 (1H, m), 1.83 (1H, septet, J = 6.9 Hz), 1.51 – 1.46 (2H), 1.43 – 1.35 (2H), 1.29 –

1.23 (1H, m), 0.96 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 0.91 – 0.88 (1H, m), 0.87

13 (3H, s), 0.59 (3H, s), 0.46 (3H, s), 0.0 (9H, s, -Si(CH3)3); C NMR & APT (50 MHz,

THF-d8) δ 235.2 (CO), 144.0 (C(arene complex)-O-), 101.5 (C-ortho to TMS), 101.0 (C- ortho to TMS), 97.8 (C-TMS), 94.2 (C2), 87.1 (C-meta to TMS), 85.3 (C-meta to TMS),

56.5 (C1), 50.9 (C7), 45.8 (C4), 39.4 (C3), 38.3 (C1’), 30.9 (C6), 27.1 (C5), 21.8, 21.6,

21.3, 19.2 (preceding four signals correspond to methyl C8/C9/C2’/C3’), 13.5 (C10), -

-1 1.2 (-Si(CH3)3); FTIR (KBr) νmax 2960, 1947, 1874, 1525 cm .

198 η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-(cyclohexyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (IV.12f)

8 7 9 4 5 3 6 O 1 2 10 Cr(CO)3 1' 6' Si 3' 4'

IV.12f was prepared from cyclohexyl isoborneol IV.6f and η6-(4-fluoro (trimethylsilyl) benzene) chromium tricarbonyl IV.11 as a green solid. Yield: 39%; Rf: 0.47 (20:1

1 hexane/diethyl ether); H NMR (300 MHz, CDCl3) δ 5.51 – 5.47 (2H), 5.06 – 5.03 (2H),

2.39 – 2.33 (1H, m), 1.89 – 1.45 (11H), 1.26 – 1.14 (4H), 1.10 (3H, s), 1.07 – 0.98 (1H, m), 0.83 (3H, s), 0.79 – 0.73 (1H, m), 0.65 (3H, s), 0.26 (9H, s, -Si(CH3)3); FTIR (KBr)

-1 νmax 2947, 1978, 1874, 1525, 1473 cm . The complex is not stable even on refrigeration and decomposed in 2-3 days.

η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-(4-biphenyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (IV.12k)

8 7 9 3 4 2 5 O 6 1 10 Cr(CO)3 1' 2' Si

4' 7'

IV.12k was prepared from biphenyl isoborneol IV.6k and η6-(4-fluoro (trimethylsilyl) benzene) chromium tricarbonyl IV.11 as a yellow crystalline solid. Yield: 89%; Rf: 0.13

199 + 1 (20:1 hexane/ether); FAB HRMS m/z 590.1974 (M ), calcd for C34H38O4SiCr; H NMR

(400 MHz, CDCl3) δ 7.66 – 7.53 (5H), 7.50 – 7.31 (4H), 5.30 (2H, d, J = 7.0 Hz), 4.80

(1H, dd, J = 34.1, 1.9 Hz), 4.80 (1H, dd, J = 20.2, 2.6 Hz), 2.50 (1H, ddd, J = 14.2, 2.9,

4.1 Hz), 2.32 (1H, d, J = 14.3 Hz), 1.99 (1H, t, J = 4.2 Hz), 1.87 – 1.55 (1H, m), 1.38 –

1.23 (2H), 1.08 – 0.82 (1H, m), 1.19 (3H, s), 1.04 (3H, s), 0.97 (3H, s), 0.20 (9H, s, -

13 Si(CH3)3); C NMR and APT (50 MHz, CDCl3) δ 234.0 (CO), 140.7 (C(arene complex)-O-), 140.5, 140.4, 139.2 (preceding three signal correspond to C1’, C4’ & C7’),

129.2, 128.9, 127.5, 127.2, 127.1, 126.4, 125.5 (preceding 7 signals belong to biphenyl

C-H carbons), 99.3 (C-ortho to TMS), 98.7 (C-ortho to TMS), 94.1 (C-TMS), 93.1 (C2),

84.4 (C-meta to TMS), 82.7 (C-meta to TMS), 55.5 (C1), 50.4 (C7), 45.6 (C4), 39.9 (C3),

30.4 (C6), 26.1 (C5), 21.6 (C8 or C9), 21.1 (C8 or C9), 9.8 (C10), -1.3 (-Si(CH3)3); FTIR

-1 (KBr) νmax 2959 (C-H stretch), 1972, 1895, 1874 (carbonyl stretch) cm .

η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-(2’-propenyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (IV.12o)

8 7 9 4 5 3 6 O 1 2 10 Cr(CO)3 2' 1' 3' Si

IV.12o was prepared from biphenyl isoborneol IV.6o and η6-(4-fluoro (trimethylsilyl) benzene) chromium tricarbonyl IV.11 as a greenish yellow crystalline solid. Yield: 83%;

+ Rf: 0.59 (20:1 hexane/ether); FAB HRMS m/z 478.1640 (M ), calcd for C25H34O4SiCr

478.1631; 1H NMR spectrum indicated two complexes in the ratio 3:1: 1H NMR (400

MHz, CDCl3) Major isomer: δ 5.48 – 5.40 (2H), 5.30 (1H, dd, J = 2.0, 6.8 Hz), 5.26 (1H,

200 s), 5.18 – 5.13 (2H), 2.31 (1H, dt, J = 3.5, 14.0 Hz), 2.05 (1H, d, J = 14.0 Hz), 1.86 –

1.80 (1H, m), 1.78 (3H, s), 1.73 – 1.62 (1H, m), 1.42 – 1.30 (2H), 1.25 – 1.01 (1H, m),

1.07 (3H, s), 1.05 (3H, s), 0.90 (3H, s), 0.25 (9H, s, -Si(CH3)3); Data for the minor isomer: δ 5.07 (1H, s), 4.88 (1H, dd, J = 2.0, 6.8 Hz), 4.81 (1H, dd, J = 2.0, 6.8 Hz), 2.21

13 – 2.17 (1H, m); C NMR and APT (50 MHz, CDCl3) δ 234.1 (CO), 146.4, 144.1,

142.3, 118.6, 115.1, 99.6, 98.9, 94.8, 94.1, 82.8, 82.2, 53.9, 50.4, 45.1, 38.3, 37.9, 30.4,

25.9, 21.6, 21.0, 21.0, 20.9, 20.8, 12.1, -1.3 (-Si(CH3)3) (Note: More carbon peaks were observed than present in the empirical formula, not certain whether it is due to rotational isomers (about the C2-C1’ bond) or coordination of the chromium to the vinylic double bond; FTIR (KBr) νmax 2975, 2867 (C-H stretch), 1966, 1879 (carbonyl stretch), 1526,

1460 cm-1

η6-{4-[[(1R,2S)-1,7,7-Trimethyl-2-(2-naphthyl)bicyclo[2.2.1]hept-2- yl]oxy]trimethylsilylbenzene}chromium tricarbonyl (IV.12p)

8 7 9 4 5 3 6 O 1 2 10 Cr(CO)3 1' 3' Si 4' 9' 6' 8' 7'

IV.12p was prepared from biphenyl isoborneol IV.6p and η6-(4-fluoro (trimethylsilyl) benzene) chromium tricarbonyl IV.11 as a dark yellow oily solid. Yield: 65%; Rf: 0.29

1 (20:1 hexane/ether); H NMR (200 MHz, CDCl3) revealed a mixture of isomers.

Chemical shifts not listed here. FTIR (KBr) νmax 2965, 2867 (C-H stretch), 1966, 1890,

1859 (carbonyl stretch), 1526, 1465 cm-1.

201 General Procedure for Nucleophilic Addition/Electrophilic Addition/Demetallation

Sequence:

202 tert-Butyl [5-[[(1R,2S)-1,7,7-trimethyl-2-phenylbicyclo[2.2.1]hept-2-yl]oxy]2- trimethylsilylcyclohexa-2,4-dien-1-yl] acetate1 (IV.13a)

8 7 9 O O 5 4 3 H 6 O 1 2 10 Si

1 Yield: 72%; Rf: 0.48 (20:1 hexane/ether); Data for major diastereomer: H NMR (300

MHz, CDCl3) δ 7.51 – 7.49 (1H, m), 7.40 – 7.20 (4H), 5.91 (1H, d, J = 5.7 Hz), 4.17 (1H, dd, J = 5.7, 2.2 Hz), 2.75 – 2.64 (1H, m), 2.48 (1H, dt, J = 14.4, 3.6 Hz), 2.37 (1H, dd, J

= 16.6, 6.7 Hz), 2.24 (1H, dd, J = 14.5, 12.0 Hz), 2.17 (1H, d, J = 14.3 Hz), 2.07 (1H, d, J

= 16.6 Hz), 1.92 – 1.82 (2H), 1.83 – 1.67 (1H, m), 1.56 (9H, s), 1.56 – 1.42 (1H, m), 1.36

13 – 1.08 (2H), 1.07 (3H, s), 0.92 (2x3H, s), 0.01 (9H, s, -Si(CH3)3); C NMR (75 MHz,

CDCl3) δ 172.6 (-COOC(CH3)3), 150.7 (C1’), 141.6 (C1”), 133.6 (C3’), 130.3 (C4’),

128.4, 127.7, 127.1, 126.7, 125.6 (preceding five signals correspond to C-H aromatic carbons), 99.9 (C2’), 89.8 (C2), 80.3 (C6’), 54.6 (C1), 50.4 (C7), 45.5 (C4), 40.4 (C3),

36.1 (C5’-CH2-COO-), 32.5 (C5), 31.7 (C5’), 30.2 (C6), 28.3 (-COOC(CH3)3), 26.4 (-

COOC(CH3)3), 21.6 (C8 or C9), 21.2 (C8 or C9), 10.1 (C10), -1.4 (-Si(CH3)3); The diastereomer ratio from 1H NMR = 21:1; The major isomer was determined to be S from optical rotation and CD spectrum of the cyclohexenone.

tert-Butyl [5-[[(1R,2S)-1,2,7,7-tetramethylbicyclo[2.2.1]hept-2-yl]oxy]2- trimethylsilylcyclohexa-2,4-dien-1-yl] acetate (IV.13b)

1 Cyclohexadienol ether IV.13a made by Dr. James Dudones

203 8 7 9 O O 5 4 3 H 6 O 1 10 2 Si

1 Yield: 85%; Rf: 0.58 (20:1 hexane/ether); Partial Data for major diastereomer: H NMR

(300 MHz, CDCl3) δ 6.18 (1H, d, J = 5.8 Hz), 4.89 (1H, dd, J = 2.0, 5.8 Hz), 2.80 – 2.25

(1H, m), 2.05 – 1.94 (3H), 1.80 – 1.60 (3H), 1.46 (9H, s), 0.09 (9H, s, -Si(CH3)3); Partial data for minor diastereomer: δ 6.17 (1H, d, J = 6.0 Hz), 1.44 (9H, s); The diastereomer ratio from 1H NMR = 1.2:1;The major isomer was determined to be S from optical rotation and CD spectrum of the cyclohexenone.

tert-Butyl [5-[[[Spiro[(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptane-3,2’-

[1,3]dioxalan]-2-yl]oxy]2-trimethylsilylcyclohexa-2,4-dien-1-yl] acetate (IV.13c)

8 7 9 O O O 5 4 3 O 6 O 1 2 10 H Si

1 Yield: 65%; Rf: 0.71 (20:1 hexane/ether); H NMR (300 MHz, CDCl3) Partial data for

Major diastereomer δ 6.18 (1H, d, J = 5.8 Hz), 4.89 (1H, dd, J = 5.8, 2.0 Hz), 4.02 – 3.71

(4H), 3.79 (1H, s), 2.80 – 2.73 (1H, m), 1.45 (9H, s), 0.88 (3H, s), 0.84 (3H, s), 0.09 (9H, s, (-Si(CH3)3); Partial data for Minor diastereomer: δ 6.18 (1H, d, J = 6.0 Hz), 1.47 (9H, s); The diastereomer ratio from 1H NMR = 70:30;The major isomer was determined to be

R from optical rotation of the corresponding cyclohexenone.

204 tert-Butyl [5-[[(1R,2S)-1,7,7-trimethyl-2-(1-ethyl)bicyclo[2.2.1]hept-2-yl]oxy]2- trimethylsilylcyclohexa-2,4-dien-1-yl] acetate (IV.13d)

8 7 9 4 O 5 3 O 6 O 1' 5' 1 2 10 1'' 2' Si 2'' 3'

Nucleophilic addition to ethyl isobornyl oxy complexes followed by protonation and decomplexation following the general procedure and purified by flash column chromatography (20:1 hexane/ethylacetate). Yield: 81%; Rf: 0.49 (20:1 hexane/ether);

1 Data for major diastereomer: H NMR (400 MHz, C6D6) δ 6.25 (1H, d, J = 6.0 Hz), 4.96

(1H, dd, J = 5.6, 2.0 Hz), 3.08 (1H, tt, J = 9.4, 2.4 Hz), 2.78 – 2.71 (2H), 2.65 – 2.60 (1H, m), 2.55 – 2.40 (1H, m), 2.39 – 2.20 (2H), 1.70 – 1.51 (2H), 1.60 – 1.28 (4H), 1.42 (9H, s, -COOC(CH3)3), 1.16 (3H, s), 1.10 – 1.01 (2H), 1.08 (3H, s), 0.95 – 0.81 (2H), 0.84

13 (3H, s), 0.15 (9H,s, -Si(CH3)3)); C NMR & APT (50 MHz, C6D6) δ 171.7 (-

COOC(CH3)3), 151.9 (C1’), 134.3 (C3’), 130.2 (C4’), 98.2 (C2’), 89.1 (C2), 79.5 (C6’),

53.6 (C1), 50.5 (C7), 45.5 (C4), 43.7 (C3), 36.3 (C5’-CH2-COO-), 32.6 (C1’’), 32.6

(C5’), 30.5 (C6), 28.2 (-COOC(CH3)3), 27.8 (-COOC(CH3)3), 27.2 (C5), 21.7 (C8 or C9),

21.0 (C8 or C9), 12.8 (C2’’), 10.3 (C10), -1.0 (-Si(CH3)3); The diastereomer ratio from

1H NMR = 2:1;The major isomer was determined to be S from the optical rotation of the corresponding cyclohexenone.

tert-Butyl [5-[[(1R,2S)-1,7,7-trimethyl-2-benzylbicyclo[2.2.1]hept-2-yl]oxy]2- trimethylsilylcyclohexa-2,4-dien-1-yl] acetate (IV.13i)

205 8 7 9 O O 5 4 3 H 6 O 1 10 2 Si

1 Yield: 72%; Rf: 0.48 (20:1 hexane/ether); H NMR (200 MHz, CDCl3) Partial data for major diastereomer: δ 6.21 (1H, d, J = 5.9 Hz), 5.14 (1H, dd, J = 2.1, 5.9 Hz), 3.90 (1H, d, J = 15.0 Hz), 0.94 (3H, s), 0.80 (3H, s), 0.34 (3H, s), 1.44 (9H, s), 0.13 (9H, s, -

Si(CH3)3); Partial data for minor diastereomer: δ 6.20 (1H, d, J = 6.0 Hz), 5.07 (1H, dd, J

= 2.0, 6.0 Hz), 3.84 (1H, d, J = 14.8 Hz), 1.50 (9H, s), 0.83 (3H, s), 0.79 (3H, s), 0.40

1 (3H, s), 0.12 (9H, s, -Si(CH3)3); The diastereomer ratio from H NMR = 38:62;The major isomer was determined to be R from optical rotation and CD spectrum of the corresponding cyclohexenone.

tert-Butyl [5-[[(1R,2S)-1,7,7-trimethyl-2-[3’,5’-dimethylphenyl]bicyclo[2.2.1]hept-2- yl]oxy]2-trimethylsilylcyclohexa-2,4-dien-1-yl] acetate (IV.13l)

8 7 9 O O 5 4 3 H 6 O 1 2 10 Si

1 Yield: 62% (83% borsm); Rf: 0.51 (20:1 hexane/ether); Data for major diastereomer: H

NMR (200 MHz, CDCl3) δ 7.12 (1H, s), 6.96 (1H, s), 6.89 (1H, s), 5.94 (1H, d, J = 5.9

Hz), 4.17 (1H, dd, J = 2.2, 6.0 Hz), 2.78 – 2.65 (1H, m), 2.48 – 2.30 (2H), 2.34 (2x3H, s),

2.20 – 2.05 (2H), 1.90 – 1.78 (2H), 1.56 (9H, s, -COOC(CH3)3), 1.57 – 1.44 (1H, m),

206 1.36 – 1.07 (2H), 1.14 – 1.00 (2H), 1.07 (3H, s ), 0.93 (3H, s), 0.92 (3H, s), 0.03 (9H, s, -

1 Si(CH3)3); The diastereomer ratio from H NMR = 21:1;The major isomer was not determined.

tert-Butyl [5-[[(1R,2S)-1,7,7-trimethyl-[4-methoxyphenyl]bicyclo[2.2.1]hept-2- yl]oxy]2-trimethylsilylcyclohexa-2,4-dien-1-yl] acetate (IV.13j)

8 7 9 O O 5 4 3 H 6 O 1 2 10 Si

1 Yield: 87%; Rf: 0.20 (20:1 hexane/ether); Data for major diastereomer: H NMR (300

MHz, CDCl3) Major isomer: δ 7.34 – 7.30 (1H, m), 7.23 – 7.18 (1H, m), 6.88 – 6.77

(2H), 6.00 (1H, d, J = 6.3 Hz), 4.12 (1H, dd, J = 2.3, 6.2 Hz), 3.79 (3H, s), 2.94 – 2.90

(1H, m), 2.45 – 2.30 (3H), 2.17 – 2.07 (2H), 1.83 (1H, t, J = 4.1 Hz), 1.78 – 1.62 (1H, m),

1.47 (9H, s), 1.26 – 1.09 (4H), 1.05 (3H, s), 0.92 (3H, s), 0.90 (3H, s), 0.04 (9H, s, -

Si(CH3)3); Partial Data for Minor Diastereomer: δ 5.95 (1H, d, J = 6.3 Hz), 3.80 (3H, s);

The diastereomer ratio from 1H NMR = 90:10;The major isomer was determined to be S from optical rotation and CD spectrum of the corresponding cyclohexenone.

tert-Butyl [5-[[(1R,2S)-1,7,7-trimethyl-2-(1-naphthyl)bicyclo[2.2.1]hept-2-yl]oxy]2- trimethylsilylcyclohexa-2,4-dien-1-yl] acetate (IV.13m)

207 8 7 9 O 4 O 5 3 6 O 1 2 10 10' Si 5'

+ Yield: 86%; Rf: 0.56 (20:1 hexane/ether); EI HRMS m/z (M ), calculated for; Data for

1 major diastereomer: H NMR (400 MHz, C6D6) δ 9.25 (1H, d, J = 8.8 Hz), 7.85 (1H, m),

7.66 (1H, dd, J = 8.2, 1.4 Hz), 7.63 (1H, d, J = 8.0 Hz), 7.53 (1H, d, J = 6.8 Hz), 7.36

(1H, dt, J = 0.8, 6.6 Hz), 7.26 (1H, t, J = 8.0 Hz), 5.75 (1H, d, J = 5.6 Hz), 4.61 (1H, dd, J

= 5.8, 2.2 Hz), 2.97 – 2.92 (1H, m), 2.71 (1H, dd, J = 16.8, 2.0 Hz), 2.60 (1H, ddd, J =

16.4, 6.8, 2.0 Hz), 2.50 (1H, dt, J = 3.4, 11.2 Hz), 2.45 – 2.38 (2H), 1.83 (1H, dd, J =

15.0, 1.8 Hz), 1.78 (1H, t, J = 4.0 Hz), 1.66 – 1.60 (1H, m), 1.53 – 1.45 (1H, m), 1.50

(9H, s, -COOC(CH3)3), 1.26 (3H, s), 1.20 (3H, s), 1.17 – 1.07 (2H), 0.86 (3H, s), 0.02

13 (9H,s, -Si(CH3)3)); C NMR & APT (50 MHz, C6D6) δ 172.4 (-COOC(CH3)3), 151.1

(C1’), 138.6 (C10” or C5”), 135.5 (C10” or C5”), 134.2 (C3’), 133.7 (C1”), 130.2 (C4’),

129.7, 129.6, 129.5, 126.3, 125.71, 125.66, 124.4 (preceding seven signals correspond to

C-H aromatic carbons), 99.9 (C2’), 94.4 (C2), 79.6 (C6’), 56.5 (C1), 51.5 (C7), 46.2

(C4), 43.3 (C3), 36.4 (C5’-CH2-COO-), 33.2 (C5’), 33.1 (C5), 31.0 (C6), 28.4 (-

COOC(CH3)3), 26.3 (-COOC(CH3)3), 22.3 (C8 or C9), 21.8 (C8 or C9), 14.0 (C10), -1.1

1 (-Si(CH3)3); The diastereomer ratio from H NMR = 31:1;The major isomer was determined to be R from the optical rotation of the corresponding cyclohexenone.

tert-Butyl [5-[[(1R,2S)-1,7,7-trimethyl-2-(1-biphenyl)bicyclo[2.2.1]hept-2-yl]oxy]2- trimethylsilylcyclohexa-2,4-dien-1-yl] acetate (IV.13k)

208 8 7 9 O O 5 4 3 H 6 O 1 2 10 Si

1 Yield: 82%; Rf: 0.53 (14:1 hexane/ether); H NMR (600 MHz, CDCl3) Major diastereomer: δ 7.64 – 7.55 (5H), 7.47 – 7.40 (3H), 7.33 (1H, t, J = 7.5 Hz), 5.93 (1H, d,

J = 6.0 Hz), 4.23 (1H, dd, J = 5.7, 2.1 Hz), 2.72 – 2.69 (1H, m), 2.52 (1H, dt, J = 13.8,

3.9 Hz), 2.41 – 2.37 (1H, m), 2.29 – 2.24 (1H, m), 2.20 (1H, d, J = 14.4 Hz), 2.09 (1H, dd, J = 16.5, 1.5 Hz), 1.90 – 1.86 (2H), 1.80 – 1.75 (1H, m), 1.58 (9H, s), 1.35 – 1.31

(1H, m), 1.23 – 1.14 (1H, m), 1.09 (3H, s), 1.02 – 0.98 (1H, m), 0.96 (3H, s), 0.94 (3H, s), 0.02 (9H, s, -Si(CH3)3); Minor diastereomer: δ 5.86 (1H, d, J = 6.0 Hz), 4.26 (1H, dd,

J = 6.3 Hz, 2.1 Hz); The diastereomer ratio from 1H NMR = 90:10;The major isomer was determined to be S from optical rotation of the corresponding cyclohexenone.

tert-Butyl [5-[[(1R,2S)-1,2,7,7-tetramethyl bicyclo[2.2.1]hept-2-yl]oxy]2-cyclohexa-

2,4-dien-1-yl] acetate (IV.20b)

8 7 9 O O 5 4 3 H 6 O 1 10 2

209 Yield: 72%; Rf: 0.65 (4:1 hexane/ethyl acetate); δ Chemical shifts not assigned.

Diastereomer ratio not determined. The major isomer was determined to be R from optical rotation and CD spectrum of the corresponding cyclohexenone.

tert-Butyl (5-oxo-cyclohex-3-enyl) acetate (IV.19)

O 5 O

3 1 O

A solution of the cyclohexadienol ethers IV.13 (1 equiv) and para-toluenesulfonic acid monohydrate (2 equiv) in diethyl ether was stirred at room temperature until the tlc indicates complete disappearance of the dienol ether (approximately after 4 hours). The reaction mixture was then diluted with saturated aqueous sodium bicarbonate solution and extracted three times with diethyl ether. The combined ether extracts were washed with brine, dried (sodium sulfate), and solvent removed in vacuo to produce an oil.

Purification by preparatibr tlc afforded the enone as a colorless oil. The chiral auxiliaries were retrievable without changes in most cases. Rf: 0.34 (3:1 hexane/ethylacetate);

25 1 [Literature: [α] D = +37.2 ° (c = 10, CHCl3) for the S isomer]; H NMR (300 MHz,

CDCl3) δ 6.97 (1H, ddd, J = 2.7, 5.3, 10.1 Hz), 6.04 (1H, d, J = 10.1 Hz), 2.62 – 2.46

13 (3H), 2.33 – 2.07 (4H), 1.46 (9H, s, -COOC(CH3)3); C NMR (75 MHz, CDCl3) δ 198.8

(C5), 170.9 (-COOC(CH3)3), 149.3 (C3), 129.7 (C4), 80.5 (-COOC(CH3)3), 43.8 (-CH2-

COO-), 41.2 (C6), 32.0 (C5), 31.5 (C2), 28.1 (-COOC(CH3)3); FTIR (KBr, cm-1) 3039,

2980, 2934, 1729, 1690, 1624 cm-1.

210 2-(2-trimethylsilyl-5-methoxycyclohexa-2,4-dien-1-yl)methylsulfonylbenzene (IV.25)

OCH3

O O S Ph Si

+ Yield: 61%; Rf: 0.71 (1:1 hexane/ethyl acetate); EI HRMS m/z 336.1201 (M ), calculated for C17H24O3SiS 336.1216. Attempted purification by preparative tlc led to partial decomposition (possibly hydrolysis of the enol ether).

[5-[[(1R,2S)-1,7,7-trimethyl-2-(1-naphthyl)bicyclo[2.2.1]hept-2-yl]oxy]2- trimethylsilylcyclohexa-2,4-dien-1-yl] methylsulfonylbenzene (IV.26m)

8 7 9 O Ph 4 5 3 O S 6 O 1 2 10 10' Si 5'

Yield: (not determined); Rf: 0.50 (3:1 hexane/ethyl acetate); EI HRMS m/z 584.2781

+ 1 (M ), calculated for C36H44O3SiS 584.2780; Ratio of diastereoselectivity from the H

NMR of the crude material showed a ratio of 3.5:1

211 tert-Butyl [5-[[(1R,2S)-1,7,7-trimethyl-2-(1-biphenyl)bicyclo[2.2.1]hept-2-yl]oxy]2-

trimethylsilylcyclohexa-2,4-dien-1-yl] methylsulfonylbenzene (IV.26k)

8 7 9 O Ph 4 5 3 O S 6 O 1 10 2 Si

Yield: (not determined); Rf: 0.40 (3:1 hexane/ethyl acetate); Ratio of diastereoselectivity from the 1H NMR of the crude material showed a ratio of 3.5:1

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“A switch of enantiofacial selectivities using designed similar chiral Ligands in zirconium-catalyzed asymmetric aza Diels-Alder reactions.” J. Org. Chem. 1999, 64,

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Kreidler, B.; Oertling, H.; Unger, S.; Frey, W. “Regioselective formation of endo- and

221 exo-cyclic enamines: both enantiomeric products accessible by the same chiral auxiliary.”

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4083-4085.

47 Pearson, A. J.; Milletti, M. C.; Zhu, P. Y. “Observations on selectivity reversal during chiral auxiliary-directed asymmetric nucleophile additions to arene-manganese tricarbonyl complexes.” J. Chem. Soc., Chem. Commun. 1995, 853-854.

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1994, 35, 4891-4894.

223

CHAPTER V

Vicinal Stereocontrol in Nucleophilic Addition to Arene Chromium Tricarbonyl

Complexes

224 V.1 Studies in Vicinal Stereocontrol in Nucleophilic Addition to Arenechromium

Tricarbonyl Complexes

One interesting problem in organic synthesis is the control of stereochemistry of two adjacent stereocenters, one at a ring position and the other at the carbon proximal to this juncture.1 Many natural products belonging to the class of steroids and terpenes have this functionality (Figure V.1). The classic way to control the vicinal stereochemistry is by stereocontrolled reduction of the substituted exo-cyclic double bond. We herein present our results addressing this stereocontrol through our study on vicinal stereocontrol during nucleophilic addition to certain η6-arene chromium tricarbonyl complexes.2

CO2CH3 H H H H OHC H O H O H H R1 R2 HO OH erythro-juvabione (R1=H, R2=CH3) Steroids Terpenes threo-juvabione (R1=CH3, R2=H)

Figure V.1 Examples of Natural Products with Vicinal Stereocenters Involving Ring Position

The one-pot dearomatization procedure of nucleophilic addition, electrophilic addition and decomplexation of η6–anisole tricarbonylchromium leads selectively to 5- substituted methoxycyclohexadienes and thereby to synthetically useful 5-substituted cyclohexenones.3 The use of prochiral nucleophiles in the dearomatization procedure leads to formation of two new adjacent stereocenters (Scheme V.1). Though prochiral nucleophiles such as tert-butyl lithiopropionate and propionitrile are known to attack selectively the meta position of η6–anisole tricarbonylchromium,4 no systematic study has been reported on the degree of vicinal stereocontrol during this reaction.5

225 Y Y Y i) X H2CX X ii) protonation X Cr(CO)3 H followed by CH3 decomplexation

Scheme V.1 Use of Prochiral Nucleophile in Nucleophilic Addition Generating Vicinal Stereocenters

4-Substituted η6-anisole tricarbonyl chromium complexes V.1 (R = H), V.2 (R =

CH3) and V.3 (R = Si(CH3)3), with varying steric bulk at the 4-position of the anisole were chosen for the study. The presence of a substituent at the position para to the methoxy group was expected to influence the vicinal stereoselectivity of the reaction, considering addition would be selectively meta to the methoxy substituent. The complexes V.1-V.3 were prepared by the standard procedure of refluxing the corresponding arenes with chromium hexacarbonyl in dibutyl ether and THF mixture.6

While the arenes, anisole and para-methylanisole are commercially available, 4- trimethylsilylanisole was prepared by refluxing trimethylsilyl chloride with the Grignard reagent prepared from 4-bromomethoxy benzene.7 The one-pot dearomatization procedure for the complexes V.1-V.3 was performed with tert-butyl lithiopropionate at -

60 ºC with HMPA as co-solvent, which is required for ester enolates to add to arene chromium tricarbonyl complexes. Nucleophilic addition followed by oxidation of the cyclohexadienyl anion complex to yield aromatic products V.4-V.6 was carried out to determine the extent of regioselectivity of addition (Scheme V.2).

226 H C 3 O O O iii) I2 -60 °C to rt, 3 h OCH3 i) LDA, THF, -78 °C R (OC) Cr tert-butyl propionate 3 (V.4-V.6) ii) HMPA, 2 h, -60 °C OCH R 3 O R = -H (V.1) -CH3 (V.2) iii) CF3COOH, -60 °C, O 0.5 h H -Si(CH3)3 (V.3) R iv) NH4OH, rt, 0.5 h (V.7-V.9)

Scheme V.2 Nucleophilic Addition and Protonation-Decomplexation/Oxidation Sequence for Complexes V.1-V.3

V.1.1 Results and Discussion

The regioselectivity in the nucleophilic addition step was determined by GC-MS analysis and integration of 1H NMR spectra of the crude aromatized products (V.4- V.6) obtained from oxidation with iodine (Table V.1).

-R meta:ortho meta isomers ortho isomers Combined ratio ratio ratio Yield (%) -H (V.1) 96:4 -d -d 74 b b -CH3 (V.2) 75:25 2:1 2:3 55 c -Si(CH3)3 (V.3) 96:4 >99:1 - 92

a Ratios from 1H NMR analysis of aromatized products from oxidation reaction. bMajor stereoisomer not assigned. c >99:1 means only one isomer was detected by 1H NMR. dRatios of stereoisomers could not be determined (see text).

Table V.1 Ratio of Regio- and Stereoisomeric Cyclohexadienol Ether Products from Addition of tert-Butyl Lithiopropionate to Anisole Chromium Tricarbonyl Complexes V.1- V.3

The ratios of regio- and stereoisomers of cyclohexadienol ethers (V.7- V.9) obtained for the three complexes on reaction with the enolate of tert-butyl propionate

227 were determined by integrating suitably separated 1H NMR signals. The regioselectivity results obtained from capillary GC and 1H NMR spectra were comparable (<3% error).

The regioselectivity of nucleophilic addition has often been explained in terms of charge and/or orbital control.8 More recently regioselectivity of nucleophilic addition to anisole chromium tricarbonyl complexes was correlated with stability of the η5 – cyclohexadienyl anionic intermediate.9 In general the arene carbon atom eclipsed by a carbonyl ligand is attacked by the nucleophile. In the absence of steric effects, the conformation of the tricarbonyl is syn-eclipsed to the electron donating groups (one of the carbonyl ligands eclipses the arene carbon bonded to electron donating groups such as -

OCH3 and –CH3) and anti-eclipsed to electron withdrawing groups (one of the carbonyl ligands eclipses the arene carbon para to the electron withdrawing group such as -

10 Si(CH3)3) on the arene.

Substituents para to the methoxy group were initially chosen with regard to their anticipated steric effect on the reaction, thereby influencing vicinal stereocontrol during meta addition, but their electronic properties, which determine the conformation of the tricarbonyl chromium, also play a significant role as reflected in the regioselectivity of the reactions. In the case of complex V.3, with electron donating and electron accepting substituent at the 1- and 4- positions respectively, the tricarbonyl would adopt a conformation that is electronically favored with respect to both substituents. This is not the case with complex V.2, which has two electron donating substituents, albeit with different capacities, and both 2- and 3- positions on the arene might compete for the

228 incoming nucleophile. This results in addition to both positions, but with a preponderance of meta addition, due to the greater directing effect of the methoxy group versus the methyl group. The significant ortho addition can also be rationalized by the stability of the corresponding η5 –cyclohexadienyl anion with the carbonyl ligands eclipsing the methyl group and the carbon attacked by the nucleophile. The regioselectivity of addition to anisole chromium tricarbonyl complex V.1 was as reported in literature.5 Both the complexes V.1 and V.3 interestingly gave similar regioselectivities.

Addition of tert-butyl lithiopropionate to 4-trimethylsilylanisole chromium tricarbonyl (V.3) followed by protonation gave diene V.9 not only in excellent regioselectivity (96:4 – meta/ortho) but also vicinal stereocontrol (>99:1)! In the case of complex V.2, the diastereoselectivity observed for each of the regioisomers was not appreciable. Complex V.1 gave a mixture of several isomeric products. While it is known to produce the 1,3-cyclohexadiene selectively, under the stated reaction conditions, diene isomerisation occurs, annihilating any stereochemistry induced at the ring carbon during the nucleophilic addition step.

The stereochemistry of the single stereoisomer V.9 (erythro or threo) was determined by converting it to the known keto carboxylic acid V.12 (Scheme V.3). Thus, hydrolysis of cyclohexadiene V.9 afforded cyclohexenone V.10 which on catalytic hydrogenation yielded keto-ester V.11. The mixture of isomeric dienes V.7 from complex

V.1 when converted to the corresponding keto-ester afforded an equimolar mixture of erythro and threo stereoisomers.The tert-butyl group was removed by treating V.11 with

229 formic acid11 resulting in the known keto-acid V.12. A few reaction conditions were tried before the formic acid treatment was found to be successful in removing the tert-butyl ester group. Only starting material was recovered or decomposition of the starting keto ester V.11 occurred when it was treated with trifluoroacetic acid or HCl-dioxane mixture.

Pd-C, H O p-TSA O 2 diethyl ether ethyl acetate rt, 2 h rt, 2 h COOtBu V.9 t 94% COO Bu 78% V.10 V.11

100% formic acid 72% rt, 3 h O

OH H

V.12 erythro

Scheme V.3 Determination of the Major Stereoisomer from Complex V.3 on tert-Butyl Lithiopropionate Addition

Comparison of 1H and 13C NMR spectra of V.12 with literature data confirmed the isomer to be erythro.12 The erythro isomer possesses two 13C NMR chemical shifts distinct from the threo isomer. These signals correspond to two methylene carbons which for the erythro and threo are δ 44.6 and 29.1, and δ 45.6 and 27.9 respectively. Moreover the 1H NMR spectrum of the keto-carboxylic acid V.12 revealed a doublet at δ 1.17 corresponding to the erythro isomer (The 1H chemical shift for the threo isomer is at δ

1 13 1.21 in CDCl3). While compounds V.9, V.10 and V.11 showed only one set of H and C

NMR signals, the 13C NMR spectrum of keto-acid V.12 revealed very small signals corresponding to the V.12-threo keto- acid, suggesting that some epimerization occurs during the conversion of V.11 to V.12.

230 Stereoselectivity Results on Propionitrile Anion Addition

The nucleophilic addition reaction was also studied with propionitrile anion and the stereoselectivity is tabulated in Table V.2

OCH3 i) LDA, THF, -78 °C OCH3 propionitrile (OC) Cr ii) HMPA, 2 h, -60 °C 3 CN iii) CF3COOH, -60 °C, H R 0.5 h R R = -H (V.1) iv) NH4OH, rt, 0.5 h V.13-V.14 -CH3 (V.2) -Si(CH3)3 (V.3)

Complex meta/ortho Yield meta:erythro/threo Ratio % V.1 95:5 74 50:50 V.2 75:25 81 - V.3 85:15 92 90:10

Table V.2 Ratio of Regio- and Stereoselectivity in Propionitrile Anion Addition to Complexes V.1 – V.3

OCH Pd-C, H2 3 p-TSA O O O ethyl acetate 20% aq. H SO / diethyl ether 2 4 rt, 2 h CH COOH O rt, 2 h 3 CN CN CN 100 °C, 24h OH H H TMS V.15 V.16 V.17 V.12 erythro

Scheme V.4 Determination of the Major Stereoisomer from Complex V.3 on Propionitrile Anion Addition

The stereoselectivity of propionitrile anion addition to complex V.3 is not as good as with tert-butyl lithiopropionate enolate. The reaction without HMPA resulted in the same selectivity for the complex V.3. The major stereoisomer (erythro or threo) was determined similar to tert-butyl lithioacetate by hydrolysis to enone V.16 and hygrogenation to keto propionitrile V.17 (Scheme V.4). Conversion of the nitrile to

231 carboxylic acid was carried out by the known method of hydrolysis by refluxing in sulfuric acid/acetic acid mixture to afford the known keto-carboxylic acid V.12. The isomer was determined to erythro in this case too by NMR analysis.

V.1.2 Understanding Vicinal Stereocontrol in Nucleophilic Addition to

Arenechromium Tricarbonyl Complexes

Stereoselective formation of the erythro isomer from complex V.3 in both tert- butyl lithiopropionate and propionitrile anion addition can be reasoned by considering two possible open transition states (Figure V.2). In the open transition states TS-1 and

TS-2 during tert-butyllithiopropionate addition, the gauche interaction of the trimethylsilyl group with the methyl group of enolate in TS-1 appears to be responsible for favoring transition state TS-2 and ensuring the formation of a single erythro isomer.

OCH3 OCH3 OCH3 O O O R = -TMS H O O H H O H R R H TMS TS-1 TS-2 Erythro isomer

Figure V.2 Possible Open Transition States of the Intermediate (The π cloud and the Complexed Chromium Tricarbonyl on the Top Face are Omitted for Clarity).

Molecular mechanics strain energy calculations performed using PC Spartan13 for the corresponding three η5-cyclohexadienyl complex conformations in both cases supports this proposition (Figure V.3). The energy of the erythro conformer with the least strain is 0.5 kcal/mol lower than the threo conformer with the least strain. Though this energy difference does not account for the very high selectivity observed, it leads us to favor TS-2. In both cases the conformation with the highest strain is the one with the

232 methyl group of the enolate gauche to the –TMS group. The trimethylsilyl group serves a number of roles in this stereoselective addition reaction. Its electron accepting ability prevents the 1,3-diene from isomerising and its steric effect promotes selective formation of the erythro isomer.

Erythro conformers Threo conformers

H3CO H3CO CH3 Z CH3 Si Si Z H CH3 CH CH3 H 3 H H CH3 +4.6 kcal/mol +5.1 kcal/mol H CO -28.3kcal/mol -28.0 kcal/mol 3 H3CO H CH3 CH Si 3 CH Si Z CH 3 H Z CH3 H 3 H CH3 +9.0 kcal/mol +8.8 kcal/mol -24.2 kcal/mol -25.4 kcal/mol H3CO H3CO Z CH3 Si H CH3 CH Si H CH 3 CH H 3 Z CH 3 +10.8 kcal/mol H 3 +10.2 kcal/mol -25.5 kcal/mol -25.0 kcal/mol Z = -COOt-Bu, -CN

Figure V.3 Calculated Molecular Mechanics Strain Energy of the Possible erythro and threo η5- Cyclohexadienyl Tricarbonyl Chromium Conformers on tert-Butyl Lithiopropionate and Lithiopropionitrile Anion Addition. (The Complexed Chromium Tricarbonyl on the Bottom Face is Omitted for Clarity)

The steric effect of the tert-butyl ester group in the stereoselection cannot be ignored considering that there is less erythro/threo stereoselectivity in the case of propionitrile anion. Also worth noting is that the cyclohexadienyl complex obtained on propionitrile addition is markedly lower in energy than the corresponding tert-butyl lithiopropionate enolate complex conformers.

233 V.2 Formal Synthesis of (±)Juvabione

The sesquiterpene Juvabione, an insect sex pheromone, is an illustrative example of numerous natural products such as steroids and terpenoids that possess a structural moiety with stereocenters at a ring position and at the proximal exocyclic carbon.

Ketalization of keto-ester V.11 by ethylene glycol14 to yield V.18, followed by reduction of the ester carbonyl by lithium aluminum hydride yielded ketal alcohol V.19, a known intermediate for the synthesis of (±)-erythro Juvabione V.20 (Scheme V.5).15

O p-TSA, ethylene glycol O O benzene, reflux, 4 h O O

O 88% O H H V.11 V.18 CO CH 2 3 52% LiAlH4, THF 0 °C, 1 h

O O O H V.19 H V.20 six steps OH H erythro (±) Juvabione

Scheme V.5 Synthesis of Intermediate V.14 in a Formal Synthesis of (±)-Juvabione

V.3 Miscellaneous Results During Stereocontrol Study

During the catalytic hydrogenation of the enone double bond of cyclohexenone

V.10 in ethyl acetate solvent, the required keto ester V.11 was obtained (Scheme V.3).

The same reaction in methanol yielded the dimethyl ketal V.21 in 62% yield. Such ketal formation of during hydrogenation of enones is known.16 In place of the two steps to prepare the intermediate V.18 from cyclohexenones V.10, the hydrogenation with Pd-

C/H2 was performed with ethylene glycol as solvent. But only the starting material was recovered even after stirring the reaction mixture for a day. The cyclohexenone V.10 was

234 not soluble in ethylene glycol which arguably is the reason for ketalization/reduction not proceeding (Scheme V.6).

Pd-C, H2 O Pd-C, H ethylene glycol 2 OO O O methanol rt, 24 h O rt, 2 h O O X O 62% O O V.18 V.10 V.21

Scheme V.6 One Step Reduction of the Enone Double Bond and Ketalization of the Carbonyl in V.10

An interesting reaction was observed during the nucleophilic addition of the ester enolate to complex V.3 (Equation V.1).

TMS TMS OCH3 i) 5 equiv. n-BuLi, THF, -78 °C TMS TMS ii) 4h, -60 °C (OC)3Cr

iii) CF3COOH, -60 °C, 0.5h + OCH3 (OC)3Cr iv) NH4OH, rt, 0.5h OCH3 TMS V.22 one-pot OCH V.23 V.3 3 OCH3

Equation V.1 Self-Nucleophilic Addition in the Absence of Carbon Nucleophile

During one attempt of tert-butyl lithioacetate addition to arene complex V.3 diene

V.22 was obtained as product. This is formed by deprotonation of the proton ortho to methoxy group which acts as a carbon nucleophile and adds to the unreacted complex

V.3 to give a single nucleophilic addition product diene V.22 and the corresponding decomplexed arene V.23. The same result was obtained when the reaction was carried out using n-butyllithium as the base reproduced this result. This methodology could be useful in preparing substituted biaryl compounds. But the diene V.23 proved to be extremely unstable and rearomatized to give the simple 4-trimethylsilylmethoxybenzene

(possibly due to the presence of a trace of H+). Reaction of n-butyllithium with

235 complexes V.1 and V.2 did not yield the corresponding self-nucleophilic addition products similar to complex V.3. The acidity of the proton ortho to the methoxy group is possibly high enough for deprotonation with n-butyllithium because of the electron accepting trimethylsilylgroup in the meta position, which is not the case with complexes

V.1 and V.2.

V.4 Vicinal Stereocontrol and Asymmetry During Nucleophilic Addition

With the possibility of asymmetric induction by both chiral auxiliary directed nucleophilic addition and by adding a suitable chiral nucleophile we proceeded to investigate these avenues.

V.4.1 Chiral Auxiliary Directed Double Stereoinduction During Nucleophilic

Addition

Asymmetric nucleophilic additions directed by suitable chiral auxiliaries substituted on the alkoxyarene for related complexes have been reported, and the absolute stereochemistries of the cyclohexenones that are obtained by enol ether hydrolysis have been established.17 We have obtained diastereoselectivity of 33:1 from tert-butyl lithioacetate reaction with V.24 to give V.25a, with R stereochemistry at the newly formed stereogenic center. Addition of tert-butyl lithiopropionate to the complex V.24 followed by protonation and decomplexation furnished cyclohexadienol ether V.25b in good diastereoselectivity (>80% de) (Scheme V.7).

236 OR* i) LDA, THF, tert-butyl acetate or O tert-butyl propionate, -78 °C O ii) HMPA, 2 h, -60 °C Cr(CO)3 O R' H TMS R iii) CF3COOH, -60 °C, 0.5 h TMS iv) NH OH, rt, 0.5 h R'= NIB R'= AIB 4 V.26a R = H, R'= NIB (dr > 33:1) V.26b R = Me, R'= NIB (de > 80%) (R,R) V.27a R = H, R'= AIB (dr > 24:1) V.27b R = Me, R'= AIB (de > 80%) (S,S) V.25 V.24 O

Scheme V.7 Chiral Auxiliary Directed Nucleophilic Addition of tert-Butyl Lithiopropionate to Complex V.24 and V.25

The major diastereomer is assigned as (R, R) based on our earlier work (Chapter

IV) and the present study. Of the four stereoisomers of Juvabione, the isomer with most potent biological activity is the (4R,1’R) isomer and this indeed is obtained from the present study.21 We have shown here that with the naphthylisoborneol chiral auxiliary, it is possible to obtain the R isomer in high diastereoselectivity.

V.4.2 Chiral Nucleophile Addition: Unsuccessful Attempt to Add Evans’ Enolate to

Arenechromium Tricarbonyl Complex

Miles et al have reported addition of a chiral Evans enolate to arene manganese tricarbonyl complexes with modest 3.5:1 selectivity.18 The addition of these enolates to arenechromium tricarbonyl complexes has not been reported in the literature and we proceeded to study the addition of these chiral Evans enolates to complex V.3. We expected to obtain good stereoselectivity considering the results from the manganese complexes and the erythro selectivity that is obtained on tert-butyl lithiopropionate addition to complex V.3 (Equation V.2).

237 O O OCH3 OCH3 ON O O + Cr(CO)3 Ph Li N O H TMS TMS Ph V.3

Equation V.2 Proposed Chiral Evans Enolate Addition to Complex V.3

The simple N-propionyl oxazolidinone V.29 was first used to test the feasibility of the reaction. Oxazolidinone V.29 was prepared by the standard method of treating the commercially available oxazolidinone V.28 with propionic anhydride in the presence of

DMAP and triethylamine (Equation V.3).19

Propionic O anhydride O O O NH DMAP, Et3N O N THF, rt, 2h V.28 V.29

Equation V.3 Preparation of N-acylated Oxazolidinone – Symmetrical Anhydride Method

Efforts to add the enolate of the oxazolidinone under various conditions did not yield the diene (Scheme V.8). The pKa of the corresponding carbon acid of the N- propionyl oxazolidinone is 17. Successful additions have been reported for carbon nucleophiles with pKa greater than 21, which explains the non addition of these enolate nucleophiles to arenechromium tricarbonyl complexes. The starting material was recovered in all the reactions.

238 O O

OCH3 OCH3 ON O O + Cr(CO) Li 3 N O X H TMS TMS Reaction conditions: i) LDA, THF,Nu, -78 °C ii) HMPA, 2 h, -60 °C iii) CF3COOH, -60 °C, 0.5 h iv) NH4OH, rt, 0.5 h i) LDA, THF,Nu, -60 °C ii) CF3COOH, -60 °C, 0.5 h iii) NH4OH, rt, 0.5 h i) LDA, THF,Nu, -78 °C ii) twice amount of HMPA, 2 h, -60 °C iii) CF3COOH, -60 °C, 0.5 h iv) NH4OH, rt, 0.5 h i) LDA, THF,Nu, -78 °C ii) HMPA, 2 h, 0 °C iii) CF3COOH, 0 °C, 0.5 h iv) NH4OH, rt, 0.5 h i) KHMDS in toluene, THF, -78 °C ii) HMPA, 2 h, -60 °C iii) CF3COOH, -60 °C, 0.5 h iv) NH4OH, rt, 0.5 h

No diene with methyl doublet was observed in the 1H NMR of the crude reaction mixture

Scheme V.8 Unsuccessful Evans enolate Addition to Arenechromium Tricarbonyl Complex V.3

V.5 Conclusions

This study on vicinal stereocontrol during nucleophilic addition to arene-Cr(CO)3 complexes has provided a solution to the problem of vicinal erythro stereocontrol in the context of six-membered carbocycles. The results have been applied to a five step synthesis of the known Juvabione intermediate V.14 from complex V.3. It is now established that by having substituents that prevent diene isomerisation, the nucleophilic addition, protonation, decomplexation sequence can be utilized to obtain diastereomeric addition products selectively as shown here. tert-Butyl lithiopropionate gave better stereoselection than lithiopropionitrile. Efforts to add the enolates of N-acylated oxazolidinones were fruitless, arguably due to the lower pKa of the corresponding carbon acid. It would be interesting to investigate the addition of chiral esters prepared from chiral alcohols, considering that ester enolates add fairly selectively to arene chromium tricarbonyl complexes. The chiral auxiliary directed nucleophilic addition has been shown to yield modest selectivities of 80% diastereomeric excess.

239 Experimental

NMR spectra were recorded on a Varian Gemini 200 (200 MHz) or Varian Gemini 300

(300 MHz) or Varian 600 (600 MHz) spectrometer. FTIR spectra were recorded as neat oils or KBr pellet on a Nicolet Impact 400 FTIR spectrometer. High resolution mass spectra (HRMS) of compounds were recorded in-house using a Kratos MS25A instrument by either EI (Electron Ionization) or FAB (Fast Ion Bombardment). Capillary

GC was carried out using HP5890 Series II Gas Chromatograph. Melting points were measured on a Thomas Hoover apparatus and are uncorrected. The purity of new compounds was assessed from their 1H and 13C NMR spectra.

Experimental parameters for Capillary GC on HP5890 Series II Gas Chromatograph:

Column: 25 m HP 5MS capillary column

Carrier gas: Helium at 45 psi

Injector temperature: 200 ºC

Detector temperature: 300 ºC

Run time: 26 minutes

240 η6-(Anisole)chromium tricarbonyl (V.1)

Cr(CO)3

1 Yield: 82%; Rf: 0.55 (4:1 hexane/ethyl acetate); H NMR (300 MHz, CDCl3) δ 5.55 (2H, d, J = 6.2 Hz), 5.12 (2H, d, J = 6.8 Hz), 4.88 (1H, t, J = 6.2 Hz), 3.72 (3H, s) ; 13C NMR and APT (50 MHz, CDCl3) δ 233.4 (CO), 143.4 (C(aromatic)-OCH3), 95.0 (ortho to –

OCH3), 85.3 (C(aromatic) para to –OCH3), 78.1 (meta to –OCH3), 55.5 (-Ar-OCH3).

η6-(4-methyl(methoxy)benzene)chromium tricarbonyl (V.2)

Cr(CO)3

CH3

1 Yield: 77%; Rf: 0.40 (4:1 hexane/ethyl acetate); H NMR (200 MHz, CDCl3) δ 5.42 (2H, d, J = 6.9 Hz, ortho to –OCH3), 5.15 (2H, d, J = 6.9 Hz, meta to –OCH3), 3.67 (3H, s, -

13 OCH3), 2.08 (3H, s, -Ar-CH3); C NMR and APT (50 MHz, CDCl3) δ 233.9 (CO),

141.4 (C(aromatic)-OCH3), 101.9 (C(aromatic)- CH3), 95.4 (ortho to –OCH3), 78.9 (meta to –OCH3), 55.7 (-Ar-OCH3), 19.7 (-Ar-CH3).

η6-(4-methoxytrimethylsilylbenzene)chromium tricarbonyl (V.3)

Cr(CO)3

241 + Yield: 92%; Rf: 0.44 (4:1 hexane/ethyl acetate); FAB HRMS m/z 316.0218 (M ),

1 calculated for C13H16O4SiCr 316.0223; H NMR (300 MHz, CDCl3) δ 5.55 (2H, d, J =

6.4 Hz, meta to –OCH3), 5.09 (2H, d, J = 6.4 Hz, ortho to –OCH3), 3.73 (3H, s, -Ar-

13 OCH3), 0.27 (9H, s, -Si(CH3)3); C NMR and APT (50 MHz, CDCl3) δ 233.7(CO),

144.4 (C(aromatic)-OCH3), 100.0 (meta to –OCH3), 93.6 (C(aromatic)-Si(CH3)3), 77.9

-1 (ortho to –OCH3), 55.3 (-Ar-OCH3), -1.3 (-Si(CH3)3); FTIR (KBr) νmax 1961, 1869 cm .

General Procedure for Nucleophilic Addition/Electrophilic Addition/Demetallation

Sequence:

To a solution of diisopropylamine (1.7 mL, 12.5 mmol, 5 equiv) in anhydrous THF (12.5 mL) at 0 ºC was added dropwise n-butyllithium (1.6M in hexanes; 5.0 mL, 12.5 mmol, 5 equiv). After 15 minutes, the resulting LDA solution was cooled to -78 ºC and a solution of tert-butyl propionate (1.9 mL, 2.5 mmol, 5 equiv) in THF (12.5 mL) was added dropwise. After an additional 30 minutes a solution of the arene tricarbonyl chromium complex (2.5 mmol, 1 equiv) in 12.5 mL of THF was added, followed immediately by the addition of anhydrous HMPA (5.4 mL, 31 mmol, 12.5 equiv). The resulting heterogeneous, yellow reaction mixture was warmed to -60 ºC and maintained at this temperature for the duration of the reaction. After 4 hours trifluoroacetic acid (5.2 mL,

67.5 mmol, 27 equiv) was added in one portion and the reaction mixture immediately turned to a deep red color. After 0.5 hours the reaction mixture was removed from the cooling bath and diluted with concentrated aqueous ammonia (5 mL). Finally, after an additional 0.5 hours the now heterogeneous green reaction mixture was diluted with additional concentrated aqueous ammonia and extracted with ether. The combined ether

242 extracts were washed with water, dried (MgSO4), then filtered and concentrated in vacuo to give a green oil. Integration of the 1H NMR spectrum of the crude product indicated the diastereomer ratio. The product was then purified by column chromatography.

General Procedure for Nucleophilic Addition/Oxidation Sequence:

The reaction was performed as described above with the following procedural change.

After 4 hours of reaction time after the arene complex has been added, a solution of iodine (4 equiv) in THF was added and the red solution was stirred at room temperature for 3 hours. The solution was diluted with diethyl ether and washed with 5% aqueous sodium bisulfite, brine and water, then dried (MgSO4), and solvent was evaporated. The crude product was analyzed by 1H NMR spectroscopy and capillary GC to determine the ratio of the ortho and meta regioisomers.

tert-Butyl 2-(5-methoxy-2-methylphenyl)propionate + tert-Butyl 2-(2-methoxy-5- methylphenyl)propionate (V.5)

O O O O + O O

+ Combined yield: (0.42 g, 67%); Rf: 0.31 (95:5 hexane/ethyl acetate); EI HRMS m/z (M )

250.1574, calculated for C15H22O3 250.1569; Ratio of regioisomers from capillary GC:

76:24; Retention times: Ortho isomer tR = 15.64 min, Meta isomer tR = 16.01 min

1 Data for major meta isomer H NMR (300 MHz, C6D6) δ 7.14 (1H, d, J = 2.6 Hz), 6.93

(1H, d, J = 8.3 Hz), 6.64 (1H, dd, J = 8.3, 2.7 Hz), 3.78 (1H, q, J = 7.1 Hz), 3.35 (3H, s),

243 13 2.18 (3H, s), 1.39 (3H, d, J = 7.0 Hz), 1.29 (9H, s); C NMR (75 MHz, CDCl3) δ 174.1,

158.2, 140.9, 131.2, 127.9, 112.2, 112.1, 80.6, 55.4, 42.6, 28.1, 18.8, 17.9

Data for minor isomer tert-Butyl 2-(2-methoxy-5-methylphenyl) propionate (V.5) 1H

NMR (300 MHz, C6D6) δ 7.20 (1H, s), 6.88 (1H, d, J = 8.1 Hz), 6.48 (1H, d, J = 8.1 Hz),

4.19 (1H, q, J = 7.3 Hz), 3.31 (3H, s), 2.14 (3H, s), 1.55 (3H, d, J = 7.1 Hz), 1.35 (9H, s);

13 C NMR (75 MHz, C6D6) δ 174.0, 155.1, 130.6, 129.8, 129.0, 128.3, 110.7, 79.4, 55.0,

40.5, 28.0, 20.7, 18.0.

tert-Butyl 2-(5-methoxy-2-trimethylsilylphenyl)propionate + tert-Butyl 2-(2- methoxy-5-trimethylsilylphenyl)propionate (V.6) 96:4

O O O O + O O Si Si

+ Combined yield: (0.59 g, 76%); Rf: 0.42 (95:5 hexane/ethyl acetate); EI HRMS m/z (M )

308.1789, calculated for C17H28O3Si 308.1808; Ratio of regioisomers from capillary GC:

93:7; Retention times: Ortho isomer tR = 17.52 min Meta isomer tR = 18.17 min

1 Data for major meta isomer H NMR (300 MHz, C6D6) δ 7.39 (1H, d, J = 8.3 Hz), 7.29

(1H, d, J = 2.3 Hz), 6.72 (1H, dd, J = 8.3, 2.6 Hz), 3.93 (1H, q, J = 7.0 Hz), 3.36 (3H, s),

13 1.47 (3H, d, J = 6.9 Hz), 1.28 (9H, s) 0.36 (9H, s); C NMR (50 MHz, C6D6) δ 173.6,

161.7, 149.9, 136.5, 129.1, 112.5, 112.4, 80.0, 54.6, 46.3, 27.9, 20.5, 0.7

1 Data for minor ortho isomer H NMR (300 MHz, C6D6) δ 7.64 (1H, s), 7.36 (1H, dd, J =

8.0, 1.7 Hz), 6.59 (1H, d, J = 8.2 Hz), 4.23 (1H, q, J = 7.0 Hz), 3.33 (3H, s), 1.55 (3H, d,

244 13 J = 6.9 Hz), 1.25 (9H, s) 0.27 (9H, s); C NMR (50 MHz, C6D6) δ 173.6, 161.7, 149.9,

133.5, 133.1, 127.9, 110.5, 79.5, 54.8, 40.7, 28.1, 18.2, -0.7.

tert-Butyl 2-(5-methoxycyclohexa-2,4-dien-1-yl)propanoate + 1,3-isomeric diene mixture (V.7)

OCH3 O

Pale yellow oil. Combined yield: (0.56 g, 72%); Rf: 0.73 (4:1 hexane/ethyl acetate); FAB

+ HRMS m/z 310.1966 (M ), calculated for C17H30O3Si 310.1964.

tert-Butyl 2-(2-methyl-5-methoxycyclohexa-2,4-dien-1-yl)propanoate + isomeric dienes (V.8)

OCH3 O

Pale yellow oil. Combined yield: (0.35 g, 55%); Rf: 0.46 (9:1 hexane/ethyl acetate); EI

+ HRMS m/z (M ) 252.1723, calculated for C15H24O3 252.1725.

tert-Butyl 2-(2-trimethylsilyl-5-methoxycyclohexa-2,4-dien-1-yl)propanoate (V.9)

H3CO Si(CH3)3

O O

245 Pale yellow oil. Yield: (0.70 g, 90%); Rf: 0.73 (4:1 hexane/ethyl acetate); FAB HRMS

+ 1 m/z 310.1966 (M ), calculated for C17H30O3Si 310.1964; H NMR (300 MHz, CDCl3)

δ6.30 (1H, d, J = 6.1 Hz), 4.91 (1H, dd, J = 6.1, 2.2 Hz), 3.57 (3H, s), 3.02-2.97 (1H, m),

2.52-2.36 (2H), 2.13 (1H, dd, J = 2.3, 17.5 Hz), 1.46 (9H, s), 0.98 (3H, d, J = 7.1 Hz),

13 0.12 (9H, s); C NMR and APT (50 MHz, CDCl3) δ 174.6, 159.5, 134.6, 129.6, 93.0,

80.0, 54.7, 44.9, 37.2, 28.0, 27.8, 10.1, -0.6; FTIR (Neat on NaCl plate) νmax 1726, 1645 cm-1.

tert-Butyl 2-(5-oxocyclohex-2-en-1-yl)propanoate (V.10-erythro)

A solution of the cyclohexadiene V.9 (1.5 g, 5.4 mmol, 1 equiv) in 10 mL of diethyl ether, and para-toluenesulfonic acid monohydrate (1.54 g, 8.1 mmol, 1.5 equiv) was stirred at room temperature until all the starting diene had been consumed, according to

TLC (3h). The reaction mixture was then diluted with aqueous saturated NaHCO3 (5 mL) and extracted with diethyl ether. The combined ether extracts were washed with brine, dried (Na2SO4), and the solvent was removed in vacuo. Purification by column chromatography (4:1 hexane/ethyl acetate) afforded the title compound as a pale yellow

+ oil (1.10 g, 94%); Rf: 0.34 (4:1 hexane/ethyl acetate); FAB HRMS m/z (MH ) 225.1487,

1 calculated for C17H30O3Si 225.1491; H NMR (200 MHz, CDCl3) δ 6.98 (1H, ddd, J =

6.7, 3.8, 1.6 Hz), 6.04 (1H, dd, J = 6.7, 0.7 Hz), 2.55 (1H, dd, J = 10.3, 0.6 Hz), 2.45-2.13

13 (5H), 1.46 (9H, s), 1.14 (3H, d, J = 3.3 Hz); C NMR (50 MHz, CDCl3) δ 199.2, 174.2,

246 149.7, 129.7, 80.8, 44.9, 41.6, 37.9, 29.9, 28.2, 14.4; FTIR (Neat on NaCl plate) νmax

1683 cm-1.

tert-Butyl 2-(3-oxocyclohexyl)propanoate (V.11-erythro)

V.10-erythro (0.45 g, 2 mmol) was hydrogenated in 10 mL ethyl acetate solution over

10% Pd-C (0.02g, 0.2 mmol) at room temperature under 1 atm. H2 for 4 hours. After removal of the catalyst by filtration through a Celite pad, the solvent was distilled in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate (3:1)) to afford the title compound V.11-erythro as a colorless oil (0.35 g, 78%); Rf: 0.50 (3:1

+ hexane/ethyl acetate); EI HRMS m/z (MH ) 227.1651, calculated for C13H22O3 227.1647;

1 H NMR (300 MHz, CDCl3) δ 2.40-2.29 (2H), 2.26-2.15 (2H), 2.10-1.90 (3H), 1.87-1.76

(1H, br m), 1.63-1.52 (2H), 1.41 (9H, s), 1.05 (3H, d, J = 7.2 Hz); 13C NMR (50 MHz,

CDCl3) δ 211.1, 174.6, 80.5, 45.5, 44.9, 41.6, 41.3, 29.2, 28.1, 25.1, 14.0; FTIR (Neat on

-1 NaCl) νmax 1723 cm .

2-(3-Oxocyclohexyl)propanoic acid (V.12-erythro)

O H O

Keto-ester V.11-erythro (0.32 g, 1.41 mmol) was dissolved in 3 mL of 100% formic acid and the solution was stirred at room temperature for 3 hours. The solution was then

247 concentrated in vacuo to give an oil, which was chromatographed on silica gel

(methylene chloride/methanol (98:2)). The combined fractions after evaporation of solvent yielded a white crystalline solid (0.17 g, 72%); Rf: 0.30 (98:2 methylene

+ chloride/methanol); Mp: 75-77 ºC; EI HRMS m/z (M ) 170.0943, calculated for C9H14O3

1 170.0943; H NMR (200 MHz, CDCl3) δ 9.43 (1H, br s), 2.45-2.21 (4H), 2.20-2.01 (3H),

13 2.00-1.83 (2H), 1.18 ( 3H, d, J = 7.0 Hz) ; C NMR (50 MHz, CDCl3) δ 211.6, 180.9,

44.6, 44.4, 41.2, 41.1, 29.1, 25.2, 13.6; Three small signals corresponding to the V.12- threo keto acid were observed at δ 45.6, 27.9, 13.8; FTIR (Neat on NaCl plate) νmax

3452, 1720 cm-1.

2-(2-trimethylsilyl-5-methoxycyclohexa-2,4-dien-1-yl)propaneitrile (V.13)

2 3 1 4 H3CO 5 6 CN

Red oil. Yield: (0. g, 74%); Rf: 0.38 (8:1 hexane/ethyl acetate); EI HRMS m/z 163.0997

+ (M ), calculated for C10H13ON 163.1001; Ratio of meta/ortho-95:5; erythro/threo ratio

1 for meta isomer ~ 50:50; Data for the erythro/threo mixture: H NMR (200 MHz, CDCl3)

δ 6.09 – 5.98 (1H, m), 5.45 – 5.23 (1H, m), 4.96 (1H, d, J = 6.0 Hz), 3.60 (s, 3H), 2.80 –

2.55 (2H), 2.53 – 2.21 (2H), 1.32 (3H, d, J = 6.9 Hz), One doublet corresponding to the methyl of the other stereoisomer: 1.32 (3H, d, J = 6.9 Hz), One doublet corresponding to

13 the ortho isomer: 1.43 (3H, d, J = 7.3 Hz) C NMR and APT (50 MHz, CDCl3) δ 158.0

& 157.6 (C1), 126.7 (C4), 122.1 (-CN), 117.6 & 117.2 (C3), 54.9 (-OCH3), 37.9 & 37.7

(C6), 30.9 &30.5 (C5) 29.2 & 29.1 (–C(H)CN), 15.5 & 15.2 (NC-C(H)CH3); FTIR (Neat

-1 on NaCl plate) νmax cm

248 2-(2-trimethylsilyl-5-methoxycyclohexa-2,4-dien-1-yl)propaneitrile (V.15)

2 3 1 4 H3CO Si(CH3)3 5 6 CN

Red oil. Yield: (0.70 g, 92%); Rf: 0.56 (7:1 hexane/ethyl acetate); EI HRMS m/z

+ 1 235.1400 (M ), calculated for C13H21ON 235.1392; H NMR (200 MHz, CDCl3) δ 6.39

(1H, d, J = 6.0 Hz), 5.01 (1H, dd, J = 6.0, 2.0 Hz), 3.60 (3H, s), 2.79 – 2.28 (4H), 1.21

13 (3H, d, J = 7 Hz), 0.14 (9H, s, -Si(CH3)3); C NMR and APT (50 MHz, CDCl3) δ 159.0

(C1), 136.5 (C3), 128.3 (C4), 123.0 (-CN), 93.6 (C2), 54.9 (-OCH3), 37.4 (C6), 29.1 (C5 or –C(H)CN), 28.8 (C5 or –C(H)CN), 13.6 (NC-C(H)CH3), -0.6 (-Si(CH3)3); FTIR (Neat

-1 1 on NaCl plate) νmax 3076, 1989, 1644 cm ; Partial data for minor isomer: H NMR (200

MHz, CDCl3) δ6.38 (d, J = 5.5 Hz), 5.07 (dd, J = 5.6 Hz, 2.0 Hz), 3.62 (s), 1.29 (d, J =

7.2 Hz), 0.12 (s).

tert-Butyl 2-(1,4-dioxaspiro[4.5]dec-7-yl)propanoate (V.18-erythro)

O O O

O H

To keto-ester V.11 (0.23g, 1 mmol, 1 equiv) was added ethylene glycol (0.08 g, 1.2 mmol, 1.2 equiv), 20 mL of dry benzene and a few crystals of para-toluenesulfonic acid.

The mixture was refluxed with azeotropic removal of water (Dean-Stark trap) for 3 hours, after which the cooled reaction mixture was washed with half-saturated NaHCO3, dried

(MgSO4) and concentrated in vacuo to afford V.18-erythro. The crude material was purified by column chromatography (4:1 hexane/ethyl acetate) to afford a colorless oil

249 + (0.23 g, 88%); Rf: 0.46 (4:1 hexane/ethyl acetate); EI HRMS m/z (M ) 270.1831,

1 calculated for C15H26O4 270.1827; H NMR (200 MHz, CDCl3) δ 3.90 (4H, s), 2.21-2.07

(1H, m), 1.96-1.51 (4H, m), 1.41 (9H, s), 1.36-0.88 (5H, m), 1.04 (3H, d, J = 7.0 Hz); 13C

NMR (50 MHz, CDCl3) δ 175.3, 109.3), 79.9, 64.3, 64.2, 45.8, 38.5, 38.3, 34.8, 29.4,

-1 28.2, 23.1, 14.1; FTIR (Film on NaCl plate) νmax 1727 cm .

2-(1,4-dioxaspiro[4.5]dec-7-yl)propan-1-ol (V.19-erythro)

O O

OH H

In a 10 mL round bottom flask under nitrogen atmosphere was placed 0.015g (0.4 mmol,

2 equiv) of lithium aluminium hydride in 0.5 mL of freshly distilled THF, and the reaction flask was cooled in an ice bath. V.18-erythro (0.053g, 0.2 mmol, 1 equiv) in 0.6 mL of THF was added dropwise to the reaction vessel and the mixture was stirred for 1 hour, after which 2.5 mL of ethyl acetate was added dropwise at 0 ºC. The solution was diluted with 3 mL of diethyl ether, washed with brine, dried (Na2SO4), and the solvent was removed in vacuo. Column chromatography (1:1 hexane/ethyl acetate) gave V.19- erythro as a colorless liquid (0.02 g, 52%); Rf: 0.5 (1:1 hexane/ethyl acetate); EI HRMS

+ 1 m/z (M ) 200.1413, calculated for C11H20O3 200.1412; H NMR (200 MHz, CDCl3) δ

3.94 (4H, s), 3.60 (1H, dd, JAB = 10.7, Jvic = 5.8 Hz), 3.44 (1H, dd, JAB = 10.6, Jvic = 6.7

Hz), 1.77-1.52 (7H), 1.50-1.20 (3H), 1.10-0.99 (1H, m), 0.88 (3H, d, J = 6.8 Hz); 13C

NMR (50 MHz, CDCl3) δ 109.7, 66.2, 64.4, 64.2, 40.4, 37.6, 37.0, 34.9, 29.6, 23.5, 13.4;

-1 FTIR (Thin film on NaCl plate) νmax 3563 (broad) cm .

250 tert-Butyl 2-(3,3-dimethoxycyclohexyl)propanoate (V.21)

O O O

O H

V.10-erythro (0.45 g, 2 mmol) was hydrogenated in 10 mL methanol solution over 10%

Pd-C (0.02g, 0.2 mmol) at room temperature under atmospheric pressure for 4 hours.

After removal of the catalyst by filtration through a celite pad, the solvent was distilled in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate (3:1)) to afford the title compound V.11-erythro as a colorless oil (0.23 g, 62%); Rf: 0.79 (3:1

+ hexane/ethyl acetate); EI HRMS m/z (M ) 272.1984, calculated for C15H28O4 272.1988;

1 H NMR (200 MHz, CDCl3) δ 3.18 (3H, s), 3.13 (3H, s), 2.15 (1H, q, J = 7.0 Hz), 2.06 –

1.94 (2H), 1.80 – 1.57 (3H), 1.50 – 1.30 (3H), 1.43 (9H, s), 1.25 – 1.16 (1H, m), 1.06

13 (3H, d, J = 7.0 Hz); C NMR (50 MHz, CDCl3) δ 175.4 (-COOC(CH3)3), 100.4 (CH3-O-

C-O-CH3) ), 80.0 (-COOC(CH3)3), 47.5 (=C(OCH3)2), 47.4 (=C(OCH3)2), 45.7, 37.2,

35.6, 32.6, 20.4, 28.2 (-COOC(CH3)3), 22.2, 14.0 (-C(H)-CH3); FTIR (Film on NaCl

-1 plate) νmax 2940, 1727, 1459 cm .

tert-Butyl [5-[[(1R,2S)-1,7,7-trimethyl-2-(1-naphthyl)bicyclo[2.2.1]hept-2-yl]oxy]2- trimethylsilylcyclohexa-2,4-dien-1-yl] propionate (V.26b)

O O

251 Nucleophilic addition to complex V.24 followed by protonation and decomplexation followed the general procedure. Yield: 76% (based on recovered starting complex V.24);

+ Rf: 0.30 (20:1 hexane/ether); EI HRMS m/z 558.3498 (M ), calculated for C36H50O3Si

1 558.3529; Data for major diastereomer: H NMR (600 MHz, C6D6) δ 9.21 (1H, d, J = 9.0

Hz), 7.65-7.58 (3H), 7.50 (1H, d, J = 7.2 Hz), 7.27 (1H, t, J = 8.1 Hz), 7.21 (1H, t, J = 7.8

Hz), 5.87 (1H, d, J = 6.6 Hz), 4.57 (1H, dd, J = 2.1, 6.3 Hz), 3.22 (1H, dt, J = 10.8, 3.0

Hz), 2.65 (1H, dd, J = 3.6, 18.0 Hz), 2.59-2.47 (2H), 2.40 (1H, d, J = 15.0 Hz), 1.73 (1H, t, J = 3.9 Hz), 1.46-1.37 (1H, m), 1.41 (9H, s), 1.26-1.18 (1H, m), 1.23 (3H, s), 1.17 (3H, s), 1.05-0.95 (3H), 0.88 (3H, d, J = 7.2 Hz), 0.81 (3H, s), 0.07 (9H, s); 13C NMR (50

MHz, C6D6) δ 174.5, 152.2, 139.0, 135.7, 135.4, 133.3, 129.7, 129.5, 129.1, 128.3,

126.0, 125.7, 125.2, 124.2, 100.3, 94.3, 79.3, 56.5, 51.3, 46.0, 44.9, 42.8, 38.7, 31.0, 29.1,

28.1, 26.0, 22.1, 21.5, 14.3, 10.8, -0.5; FTIR (Thin film on NaCl plate) νmax 1725, 1644,

1563 cm-1.

252 References

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Nakayama, M. “Stereoselective syntheses of steroid side chains. Efficient syntheses of

(2RS,3RS)-2-methyl-3-[(1RS)-1,5-dimethylhexyl]cyclopentanone and (2RS)-2-[(1RS)-3- oxocyclohexyl]propanoic acid.” Chem. Lett. 1986, 763-766. (c) Evans, D. A.; Nelson, J.

V. “Stereochemical study of the [3,3] sigmatropic rearrangement of 1,5-diene-3- alkoxides. Application to the stereoselective synthesis of (±)-juvabione.” J. Am. Chem.

Soc. 1980, 102, 774-782.

13 Spartan'02 Wavefunction, Inc. Irvine, CA.

14 Crimmins, M. T.; DeLoach, J. A. “Intramolecular photocycloadditions-cyclobutane fragmentation: total synthesis of (±)-pentalenene, (±)-pentalenic acid, and (±)- deoxypentalenic acid.” J. Am. Chem. Soc. 1986, 108, 800-806.

15 For recent syntheses of Juvabione (a) Soldermann, N.; Velker, J.; Vallat, O.; Stoeckli-

Evans, H.; Neier, R. “Application of the novel tandem process Diels-Alder

255 reaction/Ireland-Claisen rearrangement to the synthesis of rac-juvabione and rac- epijuvabione.” Helv. Chim. Acta 2000, 83, 2266-2276. (b) Kawamura, M.; Ogasawara, K.

“Stereo- and enantiocontrolled synthesis of (+)-juvabione and (+)-epijuvabione from (+)- norcamphor.” J. Chem. Soc., Chem. Commun. 1995, 2403-2404. (c) Watanabe, H.;

Shimizu, H.; Mori, K. “Synthesis of compounds with juvenile hormone activity. XXXI.

Stereocontrolled synthesis of (+)-juvabione from a chiral sulfoxide.” Synthesis 1994,

1249-1254.

16 Hudson, P.; Parsons, P. J. “Acetal formation during the catalytic hydrogenation of cyclic α,β-unsaturated ketones.” Synlett 1992, 867-868.

17 (a) Pearson, A. J.; Gontcharov, A. V. “Asymmetric conversion of arenechromium complexes to functionalized cyclohexenones: Progress toward defining an optimum chiral auxiliary.” J. Org. Chem. 1998, 63, 152-162. (b) Dudones, J. D.; Pearson, A. J.

“The first examples of ester enolate addition across a chiral (alkoxybenzene)-chromium complex π-bond with a remarkable degree of 1,5-asymmetric induction.” Tetrahedron

Lett. 2000, 41, 8037-8040. (c) Semmelhack, M. F.; Schmalz, H.-G. “Asymmetric induction in the nucleophile addition to η6-arene-tricarbonyl-chromium(0) complexes.”

Tetrahedron Lett. 1996, 37, 3089-3092.

18 Miles, W. H.; Brinkman, H. R. “A formal synthesis of (+)-juvabione.” Tetrahedron

Lett. 1992, 33, 589-592.

19 Ager, D. J.; Allen, D. R.; Schaad, D. R. “Simple and efficient N-acylation reactions of chiral oxazolidinone auxiliaries.” Synthesis 1996, 1283-1285.

256

APPENDIX

SPECTRA OF COMPOUNDS & X-RAY CRYSTAL STRUCTURE DATA

257

1 13 H NMR (600 MHz, THF-d8) and C NMR (50 MHz, THF-d8) of II.4

258 1 13 H NMR (400 MHz, CDCl3) and C APT NMR (50 MHz, CDCl3) of II.5

259 1 1 1 H NMR (200 MHz, CDCl3) and H- H COSY (300 MHz, CDCl3) of II.8

260 1 13 H NMR (300 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of II.9

261 1 13 H NMR (200 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of II.10

262 1 13 H NMR (200 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of II.11

263 1 13 H NMR (200 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of IV.6j

264 1 13 H NMR (200 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of IV.6l

265 1 13 H NMR (200 MHz, CDCl3) and C APT NMR (50 MHz, CDCl3) of IV.6k

266 1 13 H NMR (300 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of IV.6f

267 1 13 H NMR (200 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of IV.6e

268 1 13 H NMR (300 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of IV.6o

269 1 13 H NMR (400 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of IV.6i

270 1 13 H NMR (400 MHz, CDCl3) and C APT NMR (50 MHz, CDCl3) of IV.6a

271 1 13 H NMR (200 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of IV.11

272 1 13 H NMR (400 MHz, CDCl3) and C NMR (50 MHz, CDCl3) of IV.12d

273 1 13 H NMR (400 MHz, CDCl3) and C NMR (100 MHz, CDCl3) of IV.12d

274 1 13 H NMR (600 MHz, THF-d8) and C NMR (50 MHz, THF-d8) of IV.12e

275 1 13 H NMR (300 MHz, CDCl3) and C NMR (75 MHz, CDCl3) of IV.13a

276 1 1 1 H NMR (300 MHz, CDCl3) and H- H COSY (300 MHz, CDCl3) of IV.13b

277 1 13 H NMR (400 MHz, C6D6) and C APT NMR (50 MHz, C6D6) of IV.13d

278 1 H NMR (300 MHz, CDCl3) of IV.13j

1 H NMR (600 MHz, CDCl3) of IV.13k

279 1 H NMR (200 MHz, CDCl3) of IV.13i

280 1 H NMR (300 MHz, CDCl3) of IV.13c

281 1 13 H NMR (400 MHz, C6D6) and C APT NMR (50 MHz, C6D6) of IV.13m

282 1 13 H NMR (300 MHz, CDCl3) and C NMR (75MHz, CDCl3) of IV.19

283 1 13 H NMR (200 MHz, CDCl3) and C APT NMR (50MHz, CDCl3) of V.1

284 1 13 H NMR (200 MHz, CDCl3) and C APT NMR (50MHz, CDCl3) of V.2

285 1 13 H NMR (200 MHz, CDCl3) and C APT NMR (50MHz, CDCl3) of V.3

286 1 H NMR (300 MHz, CDCl3) of V.7

1 H NMR (300 MHz, CDCl3) of V.8

287 1 13 H NMR (200 MHz, CDCl3) and C NMR (50MHz, CDCl3) of V.9

288 1 13 H NMR (200 MHz, CDCl3) and C NMR (50MHz, CDCl3) of V.10-erythro

289 1 13 H NMR (200 MHz, CDCl3) and C APT NMR (50MHz, CDCl3) of V.11-erythro

290 1 13 H NMR (200 MHz, CDCl3) and C APT NMR (50MHz, CDCl3) of V.21

291 1 13 H NMR (200 MHz, CDCl3) and C APT NMR (50MHz, CDCl3) of V.18-erythro

292 1 13 H NMR (200 MHz, CDCl3) and C APT NMR (50MHz, CDCl3) of V.19-erythro

293

1 13 H NMR (200 MHz, CDCl3) and C APT NMR (50MHz, CDCl3) of V.12-erythro

294 1 13 H NMR (200 MHz, CDCl3) and C NMR (50MHz, CDCl3) of V.13

295 1 13 H NMR (200 MHz, CDCl3) and C NMR (50MHz, CDCl3) of V.15

296 1 13 H NMR (600 MHz, C6D6) and C APT NMR (50MHz, C6D6) of V.26b

297 1 H NMR (600 MHz, CDCl3) and 1H-1H COSY (200MHz, CDCl3) of V.22

298 Table A 1: Summary of X-ray Data Collection and Structural Analysis of Complex II.1

O Cr(CO)3 Si

Empirical formula C28 H34 Cr O4 Si Color/ Habit Yellow Rectangle Formula weight 514.64 Temperature (K) 150(1) Radiation wavelength MoK\a (λ = 0.71073 A°) Crystal system/Space group Orthorhombic, P2(1)2(1)2(1) Unit cell dimensions a = 10.7012(14) A° α = 90.00° b = 10.8019(14) A° β = 90.00° c = 22.171(3) A° γ = 90.00° Cell volume 2562.8(6) A°3 Z, Density (exp) 4, 1.334 mg/m3 Absorption coefficient 0.525 mm-1 F (000) 1088 Crystal size 0.3 x 0.2 x 0.2 mm Theta range for data collection 2.10 to 29.95° Limiting indices -15 ≤ h ≤ 12, -15 ≤ k ≤15, -31 ≤ l ≤ 26 Monochromator Highly oriented graphite crystal

Reflections collected/unique 6827/4856 [Rint = 0.0554] Absorption correction method Empirical: Multipole Expansion (Blessing, 1995) Refinement method Full-matrix least-squares on F2 Data/Restraints/Parameters 6827/0/410 Goodness-of-fit on F2 0.898 Final R indices [I>2sigma(I)] R1 = 0.0707 wR2 = 0.0392 R indices (all data) R1 = 0.0632 wR2 = 0.0579

299 Table A 2: Hydrogen Atom Coordinates (x104) and Isotropic Displacement Coefficients (A°2x104) of II.1

x y z U

Cr Cr 5675(3) 9531 (3) 9340 (15) 181(9) Si Si 5415(6) 12443 (6) 10308(3) 213(15) O1 O 2995(14) 8367(12) 8797(6) 186(4) O2 O 6188(18) 6835(15) 9145(8) 435(5) O3 O 7289(17) 10132(16) 8273(8) 369(5) O4 O 7934(16) 9351(17) 10136(7) 364(5) C1 C 5955(3) 13729(2) 9821(13) 322(7) C2 C 6697(3) 11897(3) 10803 (12) 320(7) C3 C 4083(3) 12942(3) 10785(12) 351(7) C4 C 3612(2) 9290(2) 9086(9) 163(5) C5 C 3813(2) 9082(2) 9715 (10) 194(5) C6 C 4371(2) 10009 (19) 10070(10) 201(5) C7 C 4801(2) 11145(19) 9818(9) 171(5) C8 C 4665(2) 11278(2) 9190 (10) 187(5) C9 C 4082(2) 10362(2) 8824 (10) 179(5) C10 C 2482(2) 8575 (19) 8189(9) 165(5) C11 C 3579(2) 8593(2) 7748 (10) 191(5) C12 C 3620(3) 9352(2) 7238 (11) 268(6) C13 C 4652(3) 9351(2) 6860 (12) 358(7) C14 C 5647(3) 8590(3) 6977(12) 388(7) C15 C 5617(3) 7815(2) 7470(12) 329(6) C16 C 4591(2) 7813(2) 7851(11) 247(6) C17 C 1547(2) 7475(2) 8092(9) 175(5) C18 C 1160(2) 7535(2) 7420(0) 244(6) C19 C 321(3) 8713(2) 7385(12) 291(6) C20 C 306(2) 9162(2) 8046(11) 258(6) C21 C 1598(2) 9718(2) 8184(12) 207(5) C22 C 323(2) 7948(2) 8407(10) 223(5) C23 C 376(3) 8125(3) 9096(11) 309(7) C24 C -820(3) 7120(2) 8291(14) 326(6) C25 C 2027(3) 6206(2) 8277(12) 243(6) C26 C 5978(2) 7878(2) 9210 (10) 265(6) C27 C 7045(2) 9452(2) 9839(10) 238(5) C28 C 6688(2) 9903(2) 8694 (11) 237(6)

300 Table A 3: Hydrogen Atom Coordinates and Isotropic Displacement Parameters (x10-3 A°) for II.1

x y z U

H1A H 0.635(3) 1.436(3) 1.0064(11) 50 H1B H 0.521(3) 1.410(2) 0.9639(11) 50 H1C H 0.649(3) 1.352(2) 0.9511(12) 50 H2A H 0.687(2) 1.250(3) 1.1124(12) 50 H2B H 0.750(3) 1.180(2) 1.0586(12) 50 H2C H 0.653(3) 1.119(3) 1.1021(12) 50 H3A H 0.423(3) 1.356(2) 1.1030(11) 50 H3B H 0.381(2) 1.224(2) 1.1044(12) 50 H3C H 0.339(3) 1.320(2) 1.0561(12) 50 H5A H 0.353(3) 0.829(2) 0.9900(11) 50 H6A H 0.447(3) 0.986(2) 1.0502(10) 50 H8A H 0.498(2) 1.198(2) 0.8968(11) 50 H9A H 0.404(2) 1.050(2) 0.8400(11) 50 H12A H 0.291(3) 0.984(2) 0.7148(12) 50 H13A H 0.462(3) 0.987(2) 0.6532(11) 50 H14A H 0.637(3) 0.862(2) 0.6777(12) 50 H15A H 0.630(3) 0.730(2) 0.7516(12) 50 H16A H 0.460(2) 0.729(2) 0.8187(11) 50 H18A H 0.187(3) 0.762(2) 0.7118(11) 50 H18B H 0.067(3) 0.680(2) 0.7277(10) 50 H19A H -0.043(3) 0.855(2) 0.7262(11) 50 H19B H 0.063(3) 0.935(2) 0.7104(10) 50 H20A H -0.033(3) 0.967(2) 0.8172(11) 50 H21A H 0.162(3) 1.012(2) 0.8579(12) 50 H21B H 0.183(2) 1.036(2) 0.7891(11) 50 H23A H -0.039(3) 0.839(2) 0.9229(11) 50 H23B H 0.100(3) 0.870(2) 0.9224(12) 50 H23C H 0.058(2) 0.735(2) 0.9321(11) 50 H24A H -0.158(3) 0.757(2) 0.8426(11) 50 H24B H -0.080(3) 0.630(2) 0.8530(10) 50 H24C H -0.092(3) 0.694(2) 0.7861(12) 50 H25A H 0.273(3) 0.604(2) 0.8042(12) 50 H25B H 0.137(3) 0.561(3) 0.8213(11) 50 H25C H 0.232(2) 0.621(2) 0.8721(12) 50

301 Table A 4: Anisotropic Displacement Parameters (A°2x104) for II.1

U11 U22 U33 U23 U13 U12

Cr 193.9(19) 165 (17) 183.8(18) -1 (16) -6 (18) 3.3(17) Si 259(4) 183(3) 197(3) -36(3) -40(3) 4(3) O1 249(9) 162(8) 147(8) -9(6) -39(7) -30(7) O2 547(13) 179(10) 578(13) -45(9) -35(10) 86(9) O3 329(12) 468(12) 309(11) 29(9) 110(9) -29(9) O4 269(10) 495(12) 329(10) 14(9) -89(9) 65(10) C1 394(19) 233(14) 338(17) -2(12) -33(14) -80(13) C2 375(17) 267(14) 318(17) -57(12) -120(14) -10(13) C3 406(19) 366(17) 281(16) -110(12) -1(14) 52(14) C4 157(12) 163(13) 171(11) -28(9) -2(9) 17(9) C5 217(13) 204(12) 160(12) 16(10) 16(11) 4(10) C6 205(13) 245(12) 154(11) 5(9) -3(12) -12(11) C7 176(13) 161(12) 175(12) -29(9) 5(10) 18(10) C8 184(13) 165(11) 212(13) -9(9) 5(10) 12(10) C9 229(13) 163(11) 147(11) 17(10) -8(10) 40(11) C10 225(13) 148(11) 123(12) 1(9) -34(10) 21(10) C11 237(14) 161(11) 174(12) -44(9) -19(10) -31(10) C12 377(16) 207(14) 219(13) -29(11) 27(12) -3(12) C13 56(2) 269(15) 248(14) -54(11) 120(14) -142(15) C14 379(18) 393(16) 394(17) -212(13) 194(16) -158(17) C15 303(16) 295(15) 388(16) -137(12) 28(15) -11(14) C16 285(16) 216(13) 240(13) -66(10) 14(12) 7(12) C17 217(13) 135(11) 173(12) -21(10) -28(10) 2(10) C18 304(15) 211(12) 218(13) -37(11) -89(11) -4(12) C19 301(17) 244(14) 329(16) 9(11) -139(13) -13(13) C20 238(15) 200(13) 336(15) 2(10) -30(12) 39(10) C21 267(14) 136(12) 218(13) -7(10) -34(11) 25(11) C22 182(13) 177(12) 311(14) -27(10) -14(11) -6(10) C23 346(18) 306(15) 273(15) -53(11) 97(13) -35(13) C24 262(15) 272(14) 444(17) -44(12) -2(15) -39(13) C25 276(16) 152(13) 301(15) 14(11) -32(12) -8(11) C26 235(14) 274(14) 285(14) 13(11) 1(11) -11(11) C27 258(14) 224(13) 233(13) 14(11) 50(11) -3(12) C28 231(14) 209(13) 270(14) -24(11) -61(12) -5(11)

302 Table A 5: Bond Lengths (A°) for II.4

Cr C4 2.293(2) Cr C5 2.213(2) Cr C6 2.198(2) Cr C7 2.244(2) Cr C8 2.201(2) Cr C9 2.241(2) Cr C26 1.837(2) Cr C27 1.837(3) Cr C28 1.840(3) Si C1 1.852(3) Si C2 1.854(3) Si C3 1.855(3) Si C7 1.893(2) O1 C4 1.356(2) O1 C10 1.473(2) O2 C26 1.158(3) O3 C28 1.160(3) O4 C27 1.163(3) C4 C5 1.430(3) C4 C9 1.389(3) C5 C6 1.407(3) C6 C7 1.424(3) C7 C8 1.406(3) C8 C9 1.424(3) C10 C11 1.527(3) C10 C17 1.568(3) C10 C21 1.556(3) C11 C12 1.397(3) C11 C16 1.392(3) C12 C13 1.386(4) C13 C14 1.370(4) C14 C15 1.377(4) C15 C16 1.385(4) C17 C18 1.549(3) C17 C22 1.569(3) C17 C25 1.520(3) C18 C19 1.559(3) C19 C20 1.544(3) C20 C21 1.539(3) C20 C22 1.536(3) C22 C23 1.539(3) C22 C24 1.538(4)

Table A 6: Bond Angles (°) for II.4

C4 Cr C5 36.96(8) C4 Cr C6 66.21(8) C4 Cr C7 78.62(8) C4 Cr C8 65.60(8) C4 Cr C9 35.66(8) C4 Cr C26 91.20(9) C4 Cr C27 155.58(9) C4 Cr C28 113.58(9) C5 Cr C6 37.19(8) C5 Cr C7 67.52(8) C5 Cr C8 78.59(9) C5 Cr C9 66.09(8) C5 Cr C26 90.27(10) C5 Cr C27 118.82(9) C5 Cr C28 150.51(10) C6 Cr C7 37.38(7) C6 Cr C8 66.25(8) C6 Cr C9 78.37(9) C6 Cr C26 117.14(9) C6 Cr C27 94.29(10) C6 Cr C28 153.52(9) C7 Cr C8 36.86(7) C7 Cr C9 67.19(8) C7 Cr C26 154.50(9) C7 Cr C27 94.87(9) C7 Cr C28 116.28(9) C8 Cr C9 37.38(8) C8 Cr C26 153.68(9) C8 Cr C27 121.50(10) C8 Cr C28 89.11(9) C9 Cr C26 116.31(9) C9 Cr C27 158.81(10) C9 Cr C28 87.88(9) C26 Cr C27 84.77(11) C26 Cr C28 89.21(10) C27 Cr C28 90.49(10) C1 Si C2 110.71(14) C3 Si C1 110.77(14) C3 Si C2 108.88(13) C3 Si C7 106.00(12)

303 C7 Si C1 109.20(11) C7 Si C2 111.18(11) C4 O1 C10 120.06(15) Cr C4 O1 131.96(15) Cr C4 C5 68.47(13) Cr C4 C9 70.11(13) O1 C4 C5 114.67(19) O1 C4 C9 126.32(18) C5 C4 C9 119.0(2) Cr C5 C4 74.57(13) Cr C5 C6 70.81(14) C4 C5 C6 119.8(2) Cr C6 C5 72.00(13) Cr C6 C7 73.06(13) C5 C6 C7 122.1(2) Cr C7 Si 134.59(12) Cr C7 C6 69.56(12) Cr C7 C8 69.91(12) Si C7 C6 121.67(16) Si C7 C8 121.89(16) C6 C7 C8 16.31(19) Cr C8 C7 73.23(12) Cr C8 C9 72.85(13) C7 C8 C9 122.6(2) Cr C9 C4 74.23(13) Cr C9 C8 69.78(12) C4 C9 C8 119.98(19) O1 C10 C11 107.58(17) O1 C10 C17 104.30(16) O1 C10 C21 110.69(17) C11 C10 C17 114.41(17) C11 C10 C21 116.92(19) C17 C10 C21 102.24(18) C10 C11 C12 123.3(2) C10 C11 C16 119.1(2) C12 C11 C16 117.6(2) C11 C12 C13 120.9(3) C12 C13 C14 120.4(3) C13 C14 C15 119.7(3) C14 C15 C16 120.2(3) C11 C16 C15 121.1(2) C10 C17 C18 105.70(18) C10 C17 C22 103.02(16) C10 C17 C25 115.51(19) C18 C17 C22 101.06(18) C18 C17 C25 112.76(19) C22 C17 C25 117.1(2) C17 C18 C19 103.60(18) C18 C19 C20 102.47(19) C19 C20 C21 107.6(2) C19 C20 C22 103.10(19) C21 C20 C22 102.61(19) C10 C21 C20 103.77(18) C17 C22 C20 93.22(18) C17 C22 C23 116.8(2) C17 C22 C24 113.57(18) C20 C22 C23 114.32(19) C20 C22 C24 113.5(2) C23 C22 C24 105.5(2) Cr C26 O2 177.9(2) Cr C27 O4 176.4(2) Cr C28 O3 177.5(2)

304 Table A 7: Summary of X-ray Data Collection and Structural Analysis of Complex II.2

O Cr(CO)3 Si

Empirical formula C23 H32 Cr O4 Si Color/ Habit Yellow Rectangle Formula weight 452.58 Temperature (K) 150(1) Radiation wavelength MoK\a (λ = 0.71073 A°) Crystal system/Space group Monoclinic, P2(1) Unit cell dimensions a = 7.7412(14) A° α = 90.00° b = 10.9198(14) A° β = 103.90° c = 14.3413(3) A° γ = 90.00° Cell volume 1176.82(15) A°3 Z, Density (exp) 2, 1.277 mg/m3 Absorption coefficient 0.562 mm-1 F (000) 480 Crystal size 0.44 x 0.22 x 0.20 mm Theta range for data collection 4.39 to 27.65° Limiting indices -10 ≤ h ≤ 9, -14 ≤ k ≤13, -18 ≤ l ≤ 18 Monochromator Highly oriented graphite crystal

Reflections collected/unique 4724/4723 [Rint = 0.0155] Absorption correction method Empirical: Multipole Expansion (Blessing, 1995) Refinement method Full-matrix least-squares on F2 Data/Restraints/Parameters 4724/1/358 Goodness-of-fit on F2 1.398 Final R indices [I>2sigma(I)] R1 = 0.0508 wR2 = 0.1123 R indices (all data) R1 = 0.0508 wR2 = 0.1123

305 Table A 8: Atom Coordinates (x104) and Isotropic Displacement Coefficients (A°2x104) of II.2

x y z U

Cr Cr 2426(8) 2753 (5) 2970 (4) 131(14) Si Si -512 (15) 3226 (11) 4588(8) 194(2) O4 O 5448(4) 2836(4) 1999(2) 317(7) O3 O 4259(5) 4762(3) 4265(2) 330(8) C28 C 3535(6) 3991(4) 3760(3) 205(9) O2 O 397(6) 4656(4) 1637(3) 463(11) C18 C 3947(7) -1789(5) 153(3) 288(10) H18B H 3550(6) -1110(4) -350(3) 200 H18A H 5110(6) -2130(5) 10(3) 200 C27 C 4271(5) 2814(5) 2358(3) 216(8) O1 O 3444(4) -1(3) 2297 (19) 189(6) C26 C 1199(6) 3919(4) 2143(3) 246(10) C1 C -1360(7) 4599(4) 3846(4) 297(10) H1C H -2060(6) 5120(5) 4170(3) 200 H1B H -1930(6) 4360(5) 3250(4) 200 H1A H -340(7) 5030(5) 3790(3) 200 C25 C 6217(7) -987(5) 1647(4) 313(11) H25C H 6420(6) -230(5) 1360(3) 200 H25B H 6980(7) -1580(5) 1660(3) 200 H25A H 6470(6) -770(4) 2340(4) 200 C6 C 2381(5) 1689(4) 4263(3) 157(8) H6 H 2960(6) 1860(4) 4880(3) 20 C11 C 2737(7) 625(4) 622(3) 234(9) H11C H 4020(7) 950(4) 640(3) 200 H11B H 2070(6) 1250(5) 790(3) 200 H11A H 2230(6) 380(4) 30(4) 200 C8 C -149(5) 1881(4) 2917(3) 168(8) H8 H -1260(7) 2130(4) 2640(3) 200 C3 C -2397(6) 2389(5) 4872(4) 312(11) H3C H -310(6) 297(4) 528(3) 200 H3B H -2180(6) 1680(5) 5170(3) 200 H3A H -3250(6) 2080(4) 4320(3) 200 C21 C 1148(6) -1259(4) 1166(4) 240(9) H21B H 680(6) -1180(4) 1710(4) 200 H21A H 180(6) -990(4) 650(3) 200 C9 C 711(6) 1135(4) 2338(3) 186(8) H9 H 370(7) 1110(5) 1770(4) 200 C2 C 1095(7) 3669(6) 5722(4) 353(12) H2C H 570(6) 4190(5) 6090(3) 200 H2B H 2080(7) 4080(5) 5620(3) 200 H2A H 1560(6) 2900(5) 6110(3) 200

306 C20 C 1808(7) -2563(4) 987(4) 277(11) H20 H 1110(7) -3060(5) 1040(4) 200 C7 C 641(5) 2163(4) 3878(3) 172(8) C5 C 3248(6) 958(4) 3707(3) 179(8) H5 H 4340(7) 690(5) 3970(4) 200 C4 C 2425(5) 680(3) 2739(3) 149(8) C23 C 3662(7) -2551(4) 2743(3) 284(11) H23C H 3260(6) -3280(5) 2860(3) 200 H23B H 2870(6) -2050(5) 2940(3) 200 H23A H 4890(6) -2400(5) 3180(3) 200 C10 C 2857(5) -467(4) 1305(3) 166(8) C17 C 4316(6) -1415(4) 1234(3) 222(9) C24 C 4753(9) -3752(5) 1558(4) 389(13) H24C H 4360(7) -4410(5) 1680(4) 200 H24B H 5780(7) -3720(5) 1970(4) 200 H24A H 5000(6) -3970(4) 890(4) 200 C19 C 2235(8) -2542(4) -1(4) 383(13) H19B H 2370(6) -3260(5) -230(3) 200 H19A H 1190(6) -2250(5) -480(3) 200 C22 C 3666(6) -2593(4) 1683(3) 233(9)

Table A 9: Anisotropic Displacement Parameters (A°2x104) for II.2

U11 U22 U33 U23 U13 U12

Cr 148(3) 119(3) 118(3) 4(3) 17(2) -2(3) Si 181(6) 237(6) 167(5) -34(4) 48(4) 1(4) O4 293(16) 364(18) 329(16) -57(17) 144(13) -32(17) O3 350(19) 286(19) 327(19) -86(15) 28(15) -49(15) C28 220(2) 200(2) 170(2) 4(17) -8(16) 19(17) O2 500(2) 300(2) 480(2) 167(18) -119(18) -16(17) C18 470(3) 320(2) 48(17) -48(17) 15(17) 80(2) C27 260(2) 157(18) 213(18) -9(19) 34(15) 30(2) O1 220(15) 188(15) 147(13) -30(11) 22(11) 33(12) C26 230(2) 180(2) 260(2) 52(18) -61(18) -41(17) C1 350(3) 180(2) 370(3) -50(2) 110(2) 0(2) C25 280(3) 300(3) 400(3) 20(2) 150(2) 40(2) C6 200(2) 157(19) 125(18) 12(15) 60(15) -28(15) C11 320(3) 180(2) 200(2) 15(17) 45(18) 6(18) C8 124(19) 170(2) 210(2) -6(15) 39(15) -13(15) C3 190(2) 420(3) 340(3) 80(2) 93(19) -3(19) C21 220(2) 200(2) 280(2) -43(17) 35(18) -6(17) C9 210(2) 140(2) 210(2) 0(16) 43(17) -33(16) C2 260(3) 450(3) 320(3) -160(2) 20(2) 0(2) C20 330(3) 150(2) 350(3) -16(17) 70(2) -69(17) C7 220(2) 112(18) 200(2) -15(15) 94(16) -22(16)

307 C5 240(2) 100(19) 210(2) 28(15) 68(17) -21(16) C4 180(2) 106(18) 179(19) 8(14) 80(15) -7(14) C23 400(3) 210(3) 270(2) 77(17) 130(2) 85(19) C10 200(2) 170(2) 142(18) -17(15) 57(15) -15(16) C17 240(2) 190(2) 230(2) -23(17) 71(17) 34(17) C24 560(4) 240(3) 370(3) 20(2) 140(3) 120(3) C19 600(4) 200(3) 300(3) -116(19) 10(2) 20(2) C22 260(2) 120(2) 330(2) 21(16) 104(18) 57(15)

Table A 10: Bond Lengths for II.2

Cr C28 1.838(4) Cr C26 1.840(4) Cr C27 1.849(4) Cr C8 2.194(4) Cr C6 2.196(4) Cr C7 2.210(4) Cr C5 2.246(4) Cr C9 2.264(4) Cr C4 2.288(4) Si C3 1.848(5) Si C2 1.859(5) Si C1 1.864(5) Si C7 1.902(4) O4 C27 1.150(5) O3 C28 1.164(5) O2 C26 1.159(6) C18 C19 1.530(8) C18 C17 1.562(6) O1 C4 1.348(5) O1 C10 1.476(5) C25 C17 1.522(7) C6 C5 1.408(6) C6 C7 1.425(6) C11 C10 1.531(6) C8 C7 1.401(6) C8 C9 1.436(6) C21 C10 1.553(6) C21 C20 1.555(6) C9 C4 1.404(6) C20 C19 1.530(7) C20 C22 1.542(7) C5 C4 1.414(6) C23 C22 1.522(6) C10 C17 1.553(6) C17 C22 1.575(6) C24 C22 1.553(6)

Table A 11: Bond Angles (°) for II.2

C28 Cr C26 88.90(19) C28 Cr C27 88.1(2) C26 Cr C27 90.4(2) C28 Cr C8 128.82(18) C26 Cr C8 87.36(18) C27 Cr C8 142.96(17) C28 Cr C6 88.21(17) C26 Cr C6 143.1(2) C27 Cr C6 126.21(17) C8 Cr C6 66.49(15) C28 Cr C7 96.74(18) C26 Cr C7 106.41(19) C27 Cr C7 162.54(18) C8 Cr C7 37.10(15) C6 Cr C7 37.74(15) C28 Cr C5 108.33(18) C26 Cr C5 162.00(18) C27 Cr C5 95.20(19) C8 Cr C5 7.86(16) C6 Cr C5 36.95(15) C7 Cr C5 67.35(16) C28 Cr C9 164.27(18) C26 Cr C9 96.86(17) C27 Cr C9 106.45(18) C8 Cr C9 37.54(15) C6 Cr C9 78.38(16)

308 C7 Cr C9 67.60(15) C5 Cr C9 65.15(16) C28 Cr C4 143.17(17) C26 Cr C4 127.51(18) C27 Cr C4 86.57(19) C8 Cr C4 66.21(15) C6 Cr C4 66.35(14) C7 Cr C4 79.51(14) C5 Cr C4 36.32(15) C9 Cr C4 35.93(15) C3 Si C2 109.5(3) C3 Si C1 109.6(2) C2 Si C1 111.1(3) C3 Si C7 108.3(2) C2 Si C7 109.0(2) C1 Si C7 109.4(2) O3 C28 Cr 179.0(4) C19 C18 C17 103.3(4) O4 C27 Cr 178.1(4) C4 O1 C10 124.3(3) O2 C26 Cr 178.3(5) C5 C6 C7 121.4(4) C5 C6 Cr 73.4(2) C7 C6 Cr 71.7(2) C7 C8 C9 122.7(4) C7 C8 Cr 72.1(2) C9 C8 Cr 73.9(2) C10 C21 C20 103.2(4) C4 C9 C8 119.2(4) C4 C9 Cr 73.0(2) C8 C9 Cr 68.6(2) C19 C20 C22 103.0(4) C19 C20 C21 107.0(4) C22 C20 C21 101.8(3) C8 C7 C6 116.8(4) C8 C7 Si 120.7(3) C6 C7 Si 122.4(3) C8 C7 Cr 70.8(2) C6 C7 Cr 70.6(2) Si C7 Cr 125.3(2) C6 C5 C4 120.9(4) C6 C5 Cr 69.6(2) C4 C5 Cr 73.5(2) O1 C4 C9 127.2(4) O1 C4 C5 113.8(4) C9 C4 C5 119.0(4) O1 C4 Cr 129.3(3) C9 C4 Cr 71.1(2) C5 C4 Cr 70.2(2) O1 C10 C11 107.8(3) O1 C10 C17 103.5(3) C11 C10 C17 114.2(3) O1 C10 C21 111.8(3) C11 C10 C21 115.6(4) C17 C10 C21 103.3(3) C25 C17 C10 114.9(4) C25 C17 C18 113.3(4) C10 C17 C18 106.1(3) C25 C17 C22 117.7(4) C10 C17 C22 102.1(3) C18 C17 C22 101.0(4) C18 C19 C20 104.3(4) C23 C22 C20 114.9(4) C23 C22 C24 105.7(4) C20 C22 C24 112.9(4) C23 C22 C17 117.4(4) C20 C22 C17 93.3(3) C24 C22 C17 112.5(4)

309 Table A 12: Summary of X-ray Data Collection and Structural Analysis of Complex II.3

O O O Cr(CO)3 H Si

Empirical formula C24 H32 Cr O6 Si Color/ Habit Yellow Plate Formula weight 496.59 Temperature (K) 150(1) Radiation wavelength MoK\a (λ = 0.71073 A°) Crystal system/Space group Monoclinic, P2(1) Unit cell dimensions a = 9.0373(14) A° α = 90.00° b = 10.5947(14) A° β = 96.08° c = 25.708(3) A° γ = 90.00° Cell volume 2447.6(6) A°3 Z, Density (exp) 4, 1.348 mg/m3 Absorption coefficient 0.553 mm-1 F (000) 1048 Crystal size 0.22 x 0.14 x 0.06 mm Theta range for data collection 3.14 to 26.56° Limiting indices -11 ≤ h ≤ 11, -13 ≤ k ≤13, -32 ≤ l ≤ 31 Monochromator Highly oriented graphite crystal

Reflections collected/unique 9263/8142 [Rint = 0.0519] Absorption correction method Empirical: Multipole Expansion (Blessing, 1995) Refinement method Full-matrix least-squares on F2 Data/Restraints/Parameters 9263/1/770 Goodness-of-fit on F2 1.077 Final R indices [I>2sigma(I)] R1 = 0.0631 wR2 = 0.1130 R indices (all data) R1 = 0.0743 wR2 = 0.1173

310 Table A 13: Hydrogen Atom Coordinates (x104) and Isotropic Displacement Coefficients (A°2x104) of II.3

x y z U

Cr1 Cr -2427(8) -4477(8) -890(3) 132(18) Cr1' Cr 3310(9) -8303 (8) -4039(3) 150(19) Si1 Si -5951(15) -4379(16) -237(5) 186(3) Si1' Si -509(16) -8783(14) -4696(6) 184(3) O1 O -1049(4) -7272(4) -1187(13) 189(8) O1' O 4616(4) -5379(4) -3854(13) 206(9) O2 O -3722(5) -1990(4) -1252(17) 422(12) O2' O 2732(5) -10305(4) -3264(19) 410(12) O3 O -522(5) -3139(5) -39(17) 441(12) O3' O 4113(5) -10251(5) -4802(18) 437(12) O4 O -064(5) -4049(5) -1602 (18) 461(13) O4' O 6511(4) -8377(5) -3609(15) 410(11) O5 O -3139(4) -7981(3) -2362(13) 187(8) O5' O 3508(5) -4700(4) -2632 (16) 345(11) O6 O -3014(4) -8991(3) -1586 (13) 183(8) O6' O 2925(4) -3721(4) -3407(17) 340(11) C1 C -6782(7) -3124(7) -678(2) 293(14) C1' C 14(7) -9358(7) -5336(2) 317(15) C2 C -5093(8) -3770(7) 401(2) 341(16) C2' C -761(8) -1.0091(7) -4237(3) 325(15) C3 C -7407(8) -5549(7) -118(3) 348(16) C3' C -2226(7) -7825(7) -4815(3) 354(16) C4 C -2171(6) -6592(5) -10225(19) 147(11) C4' C 3456(6) -6152(5) -3990(2) 156(11) C5 C -2025(6) -6317(5) -485(2) 176(12) C5' C 3342(6) -6550(5) -4518(2) 167(11) C6 C -3150(6) -5646(5) -263(2) 152(11) C6' C 2160(6) -7323(5) -4711(2) 190(12) C7 C -4449(6) -5215(5) -565(19) 139(11) C7' C 1055(6) -7746(5) -4402(2) 168(11) C8 C -4525(6) -5449(5) -1107(2) 152(11) C8' C 1267(6) -7372(5) -3873(2) 181(12) C9 C -3428(5) -6122(5) -1342(19) 123(11) C9' C 2432(6) -6591(5) -3660(2) 173(11) C10 C -1003(6) -7511(5) -1735(2) 180(12) C10' C 5089(6) -5142(5) -3312(19) 159(11) C17 C 524(5) -8059(5) -1820(2) 197(12) C17' C 6646(5) -4532(6) -3269(19) 203(11) C18 C 599(7) -7989(6) -2414(2) 273(14) C18' C 7195(7) -4591(7) -2682(2) 276(13) C19 C -492(6) -9022(6) -2652(2) 275(14)

311 C19' C 6302(7) -3558(6) -2433(2) 272(14) C20 C -1110(6) -9550(6) -2166(2) 210(12) C20' C 5263(6) -3075(6) -2903(2) 248(13) C21 C -2128(5) -8520(5) -1964(19) 176(12) C21' C 4138(6) -4128(5) -3059(2) 213(12) C22 C 262(5) -9519(6) -1750(2) 201(11) C22' C 6297(6) -3098(6) -3347(2) 235(13) C23 C -013(8) -9936(7) -1199(2) 315(15) C23' C 5549(9) -2724(7) -3891(3) 390(17) C24 C 1558(8) -10318(7) -1907(3) 358(17) C24' C 7677(8) -2252(7) -3245(3) 318(15) C25 C 1814(6) -7455(7) -1495(3) 342(16) C25' C 7681(8) -5160(8) -3618(3) 380(17) C26 C -3243(6) -2955(5) -1117(19) 178(12) C26' C 2945(6) -9548(6) -3567(2) 257(12) C27 C -972(6) -4220(5) -1330(2) 263(14) C27' C 5272(6) -8349(6) -3773(19) 225(12) C28 C -1252(6) -3641(5) -377(2) 232(13) C28' C 3791(6) -9507(7) -4505(2) 268(13) C46 C -4468(9) -8683(9) -2360(3) 500(2) C46' C 2245(10) -3937(9) -2550(4) 690(3) C48 C -4404(7) -9333(7) -1859(2) 289(14) C48' C 1747(8) -3433(9) -3102(4) 640(3)

Table A 14: Hydrogen Atom Displacement and Anisotropic Displacement Coefficients II.3 x y z U

H1A H -0.711(7) -0.339(7) -0.100(3) 0.050 H1B H -0.618(8) -0.246(7) -0.073(3) 0.050 H1C H -0.764(8) -0.272(7) -0.058(3) 0.050 H1D H -0.060(8) -0.990(7) -0.549(3) 0.050 H1E H 0.115(8) -0.990(6) -0.531(3) 0.050 H1F H 0.008(7) -0.862(7) -0.557(3) 0.050 H2A H -0.444(8) -0.324(8) 0.038(3) 0.050 H2B H -0.472(8) -0.433(8) 0.059(3) 0.050 H2C H -0.577(7) -0.337(7) 0.059(2) 0.050 H2D H -0.162(8) -1.059(7) -0.431(3) 0.050 H2E H -0.084(7) -0.975(7) -0.392(3) 0.050 H2F H -0.005(8) -1.074(7) -0.425(3) 0.050 H3A H -0.800(8) -0.597(7) -0.038(3) 0.050 H3B H -0.813(8) -0.517(7) 0.009(3) 0.050 H3C H -0.700(8) -0.619(7) 0.006(3) 0.050 H3D H -0.309(7) -0.833(7) -0.502(2) 0.050 H3E H -0.217(8) -0.729(7) -0.508(3) 0.050 H3F H -0.239(8) -0.751(7) -0.455(3) 0.050

312 H5A H -0.117(6) -0.646(5) -0.027(2) 0.020 H5D H 0.406(6) -0.623(5) -0.472(2) 0.020 H6A H -0.301(6) -0.545(5) 0.010(2) 0.020 H6D H 0.210(6) -0.753(5) -0.504(2) 0.020 H8A H -0.527(6) -0.515(5) -0.130(2) 0.020 H8D H 0.060(6) -0.772(5) -0.368(2) 0.020 H9A H -0.345(6) -0.625(5) -0.171(2) 0.020 H9D H 0.251(6) -0.645(5) -0.330(2) 0.020 H10A H -0.117(6) -0.687(6) -0.192(2) 0.020 H10D H 0.509(6) -0.600(5) -0.312(2) 0.020 H18A H 0.040(6) -0.715(6) -0.253(2) 0.020 H18B H 0.156(6) -0.804(5) -0.2515(19) 0.020 H18D H 0.697(6) -0.528(6) -0.253(2) 0.020 H18E H 0.832(6) -0.454(6) -0.2574(19) 0.020 H19A H -0.130(6) -0.860(5) -0.2914(19) 0.020 H19B H -0.005(6) -0.969(5) -0.282(2) 0.020 H19D H 0.563(6) -0.370(5) -0.220(2) 0.020 H19E H 0.692(6) -0.292(5) -0.227(2) 0.020 H20A H -0.164(6) -1.028(6) -0.220(2) 0.020 H20D H 0.475(6) -0.212(5) -0.287(2) 0.020 H23A H 0.080(8) -1.004(7) -0.099(3) 0.050 H23B H -0.027(8) -1.084(8) -0.113(3) 0.050 H23C H -0.074(8) -0.954(7) -0.104(3) 0.050 H23D H 0.524(8) -0.169(7) -0.386(3) 0.050 H23E H 0.456(8) -0.315(7) -0.399(2) 0.050 H23F H 0.621(8) -0.296(7) -0.415(3) 0.050 H24A H 0.245(8) -1.021(7) -0.161(3) 0.050 H24B H 0.193(7) -1.009(6) -0.228(3) 0.050 H24C H 0.141(8) -1.111(7) -0.188(3) 0.050 H24D H 0.748(8) -0.134(7) -0.321(3) 0.050 H24E H 0.834(8) -0.219(7) -0.360(3) 0.050 H24F H 0.827(8) -0.239(7) -0.294(3) 0.050 H25D H 0.794(8) -0.598(8) -0.351(3) 0.050 H25D H 0.183(7) -0.647(7) -0.153(3) 0.050 H25E H 0.854(8) 0.475(7) -0.353(3) 0.050 H25E H 0.267(8) -0.771(7) -0.160(3) 0.050 H25F H 0.737(8) -0.512(7) -0.398(3) 0.050 H25F H 0.174(7) -0.748(7) -0.111(3) 0.050 H46A H -0.446(7) -0.908(6) -0.263(2) 0.020 H46B H -0.519(6) -0.842(6) -0.253(2) 0.020 H46D H 0.284(6) -0.298(5) -0.239(2) 0.020 H46E H 0.163(6) -0.456(6) -0.230(2) 0.020 H48A H -0.506(6) -0.895(5) -0.163(2) 0.020 H48B H -0.440(6) -1.015(6) -0.196(2) 0.020 H48D H 0.104(6) -0.406(6) -0.325(2) 0.020 H48E H 0.174(6) -0.261(6) -0.303(2) 0.020

313 Table A 15: Anisotropic Displacement Parameters for II.3

U11 U22 U33 U23 U13 U12

Cr1 145(4) 116(4) 136(4) -15(4) 16(3) -8(4) Cr1' 159(4) 160(4) 135(4) -1(4) 37(3) 13(4) Si1 196(7) 185(8) 183(7) -39(7) 54(6) 23(7) Si1' 184(8) 185(8) 183(7) -26(6) 28(6) -40(6) O1 155(19) 230(2) 176(18) -19(16) 1(15) 100(16) O1' 230(2) 250(2) 136(19) -13(16) 52(15) -131(17) O2 640(3) 230(3) 400(3) 80(2) 50(2) 20(2) O2' 490(3) 300(3) 470(3) 220(2) 170(2) 60(2) O3 380(3) 460(3) 450(3) -170(2) -110(2) -140(2) O3' 380(3) 490(3) 440(3) -200(2) 80(2) 110(2) O4 390(3) 560(3) 480(3) -100(2) 260(2) -160(2) O4' 220(2) 620(3) 360(2) -30(2) -118(18) 50(2) O5 159(19) 250(2) 152(18) 12(15) -6(14) 2(16) O5' 410(3) 330(3) 350(2) -90(2) 280(2) -130(2) O6 143(18) 220(2) 204(19) 42(15) 76(15) -14(15) O6' 160(2) 300(3) 550(3) -90(2) -25(19) 47(18) C1 320(4) 340(4) 220(3) -70(3) -20(3) 100(3) C1' 400(4) 350(4) 220(3) -170(3) 140(3) -120(3) C2 470(4) 330(4) 230(3) -140(3) 10(3) 100(3) C2' 440(4) 220(4) 320(4) 20(3) 70(3) -110(3) C3 280(4) 300(4) 500(5) -80(3) 200(3) -90(3) C3' 180(3) 410(4) 470(4) -70(3) -20(3) 10(3) C4 180(3) 140(3) 140(3) 0(2) 40(2) -20(2) C4' 200(3) 130(3) 140(3) 0(2) 30(2) 0(2) C5 160(3) 120(3) 250(3) 20(2) 20(2) 20(2) C5' 150(3) 180(3) 180(3) 0(2) 70(2) -10(2) C6 190(3) 180(3) 90(3) 30(2) 70(2) 20(2) C6' 220(3) 200(3) 150(3) 10(2) -20(2) 0(2) C7 220(3) 40(3) 160(3) -30(2) 50(2) 10(2) C7' 140(3) 140(3) 220(3) -20(2) 10(2) 30(2) C8 120(3) 150(3) 190(3) 0(2) 10(2) 10(2) C8' 140(3) 160(3) 250(3) 70(2) 50(2) 10(2) C9 120(3) 180(3) 70(2) -50(2) 0(19) 10(2) C9' 180(3) 210(3) 140(3) -30(2) 50(2) 10(2) C10 190(3) 200(3) 150(3) 0(2) 20(2) 20(2) C10' 180(3) 190(3) 110(3) 10(2) 0(2) -50(2) C17 130(3) 210(3) 250(3) -60(2) 10(2) 10(2) C17' 150(3) 230(3) 230(3) 40(3) 30(2) -40(3) C18 190(3) 360(4) 290(3) -30(3) 130(2) 10(3) C18' 270(3) 300(4) 230(3) 70(3) -70(2) -80(3) C19 240(3) 410(4) 180(3) -50(3) 80(2) 120(3) C19' 350(3) 290(4) 170(3) -40(2) 30(2) -50(3) C20 180(3) 190(3) 250(3) -120(3) 0(2) -40(3)

314 C20' 280(3) 190(3) 280(3) -80(2) 80(2) -10(3) C21 180(3) 190(3) 150(3) -30(2) 10(2) 10(2) C21' 260(3) 170(3) 210(3) -50(2) 40(2) -40(2) C22 140(2) 230(3) 240(3) -50(3) 30(2) 50(3) C22' 300(3) 220(3) 170(3) 70(2) -20(2) -70(3) C23 390(4) 310(4) 240(3) 80(3) 20(3) 170(3) C23' 520(5) 350(4) 270(4) 160(3) -90(3) -170(4) C24 280(4) 380(4) 410(4) -80(3) 40(3) 170(3) C24' 360(4) 270(4) 320(4) 60(3) 30(3) -170(3) C25 40(3) 510(5) 470(4) -170(3) 10(3) -40(3) C25' 200(3) 500(5) 460(4) -120(4) 110(3) -90(3) C26 280(3) 100(3) 150(3) 20(2) 20(2) -10(2) C26' 260(3) 260(3) 270(3) -60(3) 110(2) 70(3) C27 260(3) 260(4) 270(3) -70(3) 40(3) -130(3) C27' 300(3) 210(3) 170(3) 60(2) 50(2) 70(3) C28 230(3) 150(3) 310(3) 10(2) -20(2) 30(2) C28' 200(3) 290(3) 320(3) -120(3) 30(2) -10(3) C46 340(4) 730(6) 390(4) 40(4) -160(3) -280(4) C46' 700(6) 520(6) 950(7) -250(5) 550(6) -30(5) C48 250(3) 300(4) 320(3) 0(3) 30(3) -110(3) C48' 250(4) 330(5) 137(9) -170(6) 240(5) -70(4)

Table A 16: Bond Lengths (A°) for II.3

Cr1 C4 2.283(5) Cr1 C5 2.222(5) Cr1 C6 2.187(5) Cr1 C7 2.231(5) Cr1 C8 2.178(5) Cr1 C9 2.233(5) Cr1 C26 1.841(5) Cr1 C27 1.843(6) Cr1 C28 1.832(6) Cr1' C4' 2.286(5) Cr1' C5' 2.232(5) Cr1' C6' 2.183(5) Cr1' C7' 2.229(5) Cr1' C8' 2.174(5) Cr1' C9' 2.243(5) Cr1' C26' 1.845(6) Cr1' C27' 1.832(6) Cr1' C28' 1.835(6) Si1 C1 1.853(7) Si1 C2 1.855(6) Si1 C3 1.856(7) Si1 C7 1.892(5) Si1' C1' 1.862(5) Si1' C2' 1.850(7) Si1' C3' 1.852(7) Si1' C7' 1.884(5) O1 C4 1.348(6) O1 C10 1.437(6) O1' C4' 1.347(6) O1' C10' 1.434(6) O2 C26 1.150(6) O2' C26' 1.149(7) O3 C28 1.162(6) O3' C28' 1.155(7) O4 C27 1.147(6) O4' C27' 1.155(6) O5 C21 1.417(6) O5 C46 1.413(8) O5' C21' 1.424(7) O5' C46' 1.432(9) O6 C21 1.413(6) O6 C48 1.419(7) O6' C21' 1.407(7) O6' C48' 1.421(9)

315 C4' C5' 1.416(7) C4' C9' 1.400(7) C5 C4 1.405(7) C5 C6 1.408(7) C5' C6' 1.394(8) C6 C7 1.412(7) C6' C7' 1.412(7) C7 C8 1.410(7) C7' C8' 1.411(7) C8 C9 1.409(7) C8' C9' 1.404(8) C9 C4 1.420(7) C10 C17 1.534(7) C10 C21 1.548(7) C10' C17' 1.542(7) C10' C21' 1.561(7) C17 C18 1.537(8) C17 C22 1.577(8) C17 C25 1.504(8) C17' C18' 1.538(7) C17' C22' 1.561(8) C17' C25' 1.517(9) C18 C19 1.554(9) C18' C19' 1.539(9) C19 C20 1.526(8) C19' C20' 1.536(8) C20 C21 1.552(7) C20 C22 1.549(7) C20' C21' 1.533(8) C20' C22' 1.550(7) C22 C23 1.531(8) C22 C24 1.533(8) C22' C23' 1.540(8) C22' C24' 1.536(8) C46 C48 1.454(10) C46' C48' 1.538(14)

Table A 17: Bond Angles (°) for II.3

C5 Cr1 C4 36.32(18) C5 Cr1 C6 37.25(19) C5 Cr1 C7 67.41(19) C5 Cr1 C8 78.4(2) C5 Cr1 C9 66.2(2) C5 Cr1 C26 163.0(2) C5 Cr1 C27 109.0(2) C5 Cr1 C28 91.9(2) C6 Cr1 C4 66.17(18) C6 Cr1 C7 37.26(18) C6 Cr1 C8 66.4(2) C6 Cr1 C9 78.7(2) C6 Cr1 C26 126.0(2) C6 Cr1 C27 145.5(2) C6 Cr1 C28 86.5(2) C7 Cr1 C4 79.11(18) C7 Cr1 C8 37 27(19) C7 Cr1 C9 67.55(18) C7 Cr1 C26 96.3(2) C7 Cr1 C27 161.4(2) C7 Cr1 C28 109.5(2) C8 Cr1 C4 66.21(19) C8 Cr1 C9 37.24(19) C8 Cr1 C26 91.4(2) C8 Cr1 C27 124.8(2) C8 Cr1 C28 146.6(2) C9 Cr1 C4 36.62(18) C9 Cr1 C26 113.1(2) C9 Cr1 C27 94.1(2) C9 Cr1 C28 157.5(2) C26 Cr1 C4 148.9(2) C26 Cr1 C27 88.0(2) C26 Cr1 C28 89.2(2) C27 Cr1 C4 87.9(2) C27 Cr1 C28 88.5(2) C28 Cr1 C4 121.5(2) C4' Cr1' C5' 36.50(18) C4' Cr1' C6' 65.7(2) C4' Cr1' C7' 78.68(19) C4' Cr1' C8' 65.3(2) C4' Cr1' C9' 36.00(19) C4' Cr1' C26' 133.7(2) C4' Cr1' C27' 87.6(2) C4' Cr1' C28' 135.4(2) C5' Cr1' C6' 36.8(2) C5' Cr1' C7' 67.20(19) C5' Cr1' C8' 78.0(2) C5' Cr1' C9' 65.98(19) C5' Cr1' C26' 166.4(2) C5' Cr1' C27' 99.2(2)

316 C5' Cr1' C28' 101.5(2) C6' Cr1' C7' 37.32(19) C6' Cr1' C8' 66.2(2) C6' Cr1' C9' 78.4(2) C6' Cr1' C26' 139.2(2) C6' Cr1' C27' 131.9(2) C6' Cr1' C28' 86.5(2) C7' Cr1' C8' 37.34(19) C7' Cr1' C9' 67.57(19) C7' Cr1' C26' 104.2(2) C7' Cr1' C27' 165.6(2) C7' Cr1' C28' 100.3(2) C8' Cr1' C9' 37.0(2) C8' Cr1' C26' 88.9(2) C8' Cr1' C27' 138.4(2) C8' Cr1' C28' 135.1(2) C9' Cr1' C26' 101.3(2) C9' Cr1' C27' 103.5(2) C9' Cr1' C28' 164.9(2) C26' Cr1' C27' 88.3(2) C26' Cr1' C28' 90.2(3) C27' Cr1' C28' 86.4(2) C1 Si1 C2 113.3(3) C3 Si1 C1 109.4(3) C3 Si1 C2 108.8(4) C3 Si1 C7 108.4(3) C7 Si1 C1 109.1(3) C7 Si1 C2 107.7(3) C1' Si1' C2' 112.2(3) C1' Si1' C3' 108.7(3) C1' Si1' C7' 107.1(3) C2' Si1' C3' 111.0(3) C2' Si1' C7' 108.6(3) C3' Si1' C7' 109.1(3) C10 O1 C4 120.2(4) C4' O1' C10' 120.2(4) C21 O5 C46 105.5(5) C21' O5' C46' 105.3(6) C21 O6 C48 106.7(4) C21' O6' C48' 107.1(6) Cr1 C4 O1 131.5(4) Cr1 C4 C5 69.5(3) Cr1 C4 C9 69.8(3) O1 C4 C5 115.1(4) O1 C4 C9 126.1(4) C5 C4 C9 118.8(5) Cr1' C4' O1' 131.2(4) Cr1' C4' C5' 69.7(3) Cr1' C4' C9' 70.3(3) O1' C4' C5' 114.0(4) O1' C4' C9' 126.2(5) C5' C4' C9' 119.8(5) Cr1 C5 C4 74.2(3) Cr1 C5 C6 70.0(3) C6 C5 C4 120.4(5) Cr1' C5' C4' 73.8(3) Cr1' C5' C6' 69.7(3) C4' C5' C6' 119.4(5) Cr1 C6 C5 72.7(3) Cr1 C6 C7 73.1(3) C5 C6 C7 122.4(5) Cr1' C6' C5' 73.5(3) Cr1' C6' C7' 73.1(3) C5' C6' C7' 123.2(5) Cr1 C7 Si1 131.1(3) Cr1 C7 C6 69.7(3) Cr1 C7 C8 69.3(3) Si1 C7 C6 120.1(4) Si1 C7 C8 124.0(4) C6 C7 C8 115.9(5) Cr1' C7' Si1' 128.8(3) Cr1' C7' C6' 69.5(3) Cr1' C7' C8' 69.2(3) Si1' C7' C6' 120.4(4) Si1' C7' C8' 124.7(4) C6' C7' C8' 114.9(5) Cr1 C8 C7 73.4(3) Cr1 C8 C9 73.5(3) C7 C8 C9 123.4(5) Cr1' C8' C7' 73.5(3) Cr1' C8' C9' 74.2(3) C7' C8' C9' 124.2(5) Cr1 C9 C4 73.6(3) Cr1 C9 C8 69.3(3) C8 C9 C4 119.1(5) Cr1' C9' C4' 73.7(3) Cr1' C9' C8' 68.8(3) C4' C9' C8' 118.4(5) O1 C10 C17 109.0(4) O1 C10 C21 114.1(4) C17 C10 C21 104.5(4) O1' C10' C17' 108.7(4)

317 O1' C10' C21' 113.9(4) C17' C10' C21' 102.7(4) C10 C17 C18 105.0(4) C10 C17 C22 101.9(4) C10 C17 C25 114.6(5) C18 C17 C22 100.6(4) C18 C17 C25 114.7(5) C22 C17 C25 118.1(5) C10' C17' C18' 104.5(4) C10' C17' C22' 103.2(4) C10' C17' C25' 112.8(5) C18' C17' C22' 101.9(5) C18' C17' C25' 114.0(5) C22' C17' C25' 118.7(5) C17 C18 C19 105.3(5) C17' C18' C19' 104.4(5) C18 C19 C20 102.0(5) C18' C19' C20' 102.4(4) C19 C20 C21 107.3(5) C19 C20 C22 102.8(4) C21 C20 C22 102.3(4) C19' C20' C21' 107.2(5) C19' C20' C22' 102.0(4) C21' C20' C22' 103.3(4) O5 C21 O6 105.6(4) O5 C21 C10 110.1(4) O5 C21 C20 113.7(4) O6 C21 C10 112.3(4) O6 C21 C20 112.4(4) C10 C21 C20 102.9(4) O5' C21' O6' 105.8(4) O5' C21' C10' 108.1(4) O5' C21' C20' 114.7(5) O6' C21' C10' 111.8(4) O6' C21' C20' 113.2(5) C10' C21' C20' 103.3(4) C17 C22 C20 93.5(4) C17 C22 C23 115.5(5) C17 C22 C24 112.6(5) C20 C22 C23 115.9(5) C20 C22 C24 112.6(5) C23 C22 C24 106.7(5) C17' C22' C20' 92.8(4) C17' C22' C23' 115.6(5) C17' C22' C24' 113.4(5) C20' C22' C23' 115.1(5) C20' C22' C24' 114.0(5) C23' C22' C24' 105.9(5) Cr1 C26 O2 178.3(5) Cr1' C26' O2' 178.4(6) Cr1 C27 O4 179.4(5) Cr1' C27' O4' 179.6(5) Cr1 C28 O3 177.7(5) Cr1' C28' O3' 178.8(6) O5 C46 C48 107.4(5) O5' C46' C48' 102.7(6) O6 C48 C46 105.5(5) O6' C48' C46' 105.7(6)

318 Table A 18: Summary of X-ray Data Collection and Structural Analysis of Complex II.4

O O O Cr(CO)3 H

Empirical formula C22 H26 Cr O6 Color/ Habit Orange Plate Formula weight 438.43 Temperature (K) 120(1) Radiation wavelength MoK\a (λ = 0.71073 A°) Crystal system/Space group ?, P2(1) Unit cell dimensions a = 7.9484(7)(14) A° α = 90.00° b = 13.6135 (11) A° β = 93.03° c = 9.5596 (8) A° γ = 90.00° Cell volume 1032.96(15) A°3 Z, Density (exp) 2, 1.410 mg/m3 Absorption coefficient 0.589 mm-1 F (000) 460 Crystal size 0.25 x 0.15 x 0.05 mm Theta range for data collection 3.42 to 29.35° Limiting indices -8 ≤ h ≤ 10, -18 ≤ k ≤18, -12 ≤ l ≤ 12 Monochromator Highly oriented graphite crystal

Reflections collected/unique 4556/4224 [Rint = 0.0261] Absorption correction method Empirical: Multipole Expansion (Blessing, 1995) Refinement method Full-matrix least-squares on F2 Data/Restraints/Parameters 4556/1/262 Goodness-of-fit on F2 1.081 Final R indices [I>2sigma(I)] R1 = 0.0405 wR2 = 0.0895 R indices (all data) R1 = 0.0451 wR2 = 0.0909

319 Table A 19: Hydrogen Atom Coordinates and Isotropic Displacement Coefficients (A°2x103) of II.4 x y z U

Cr1 Cr 0.13081(5) 0.88233(3) 0.81395(4) 0.01406(10) O1 O 0.3027(2) 1.00830(13) 1.31745(19) 0.0199(4) O2 O 0.5089(2) 1.07351(13) 1.19129(18) 0.0191(4) O3 O 0.4793(2) 0.92634(14) 1.01161(17) 0.017.0(4) O4 O 0.1581(4) 0.71594(19) 1.0177(3) 0.051.5(7) O5 O -0.2383(3) 0.84938(15) 0.7649(2) 0.029.2(5) O6 O 0.1787(3) 0.73514(18) 0.5859(2) 0.037.7(6) C1 C 0.5952(4) 0.9499(2) 1.3697(3) 0.021.2(6) H1A H 0.6456 1.0011 1.4306 0.025 C2 C 0.4624(3) 0.98688(19) 1.2590(3) 0.016.1(5) C3 C 0.4484(3) 0.89895(18) 1.1530(2) 0.015.9(5) H3A H 0.3369 0.8685 1.1560 0.019 C4 C 0.5851(4) 0.82614(19) 1.2093(3) 0.020.3(6) C5 C 0.5078(4) 0.7804(2) 1.3390(3) 0.024.8(6) H5A H 0.3929 0.7591 1.3171 0.030 H5B H 0.5737 0.7246 1.3733 0.030 C6 C 0.5127(4) 0.8641(2) 1.4480(3) 0.027.7(7) H6A H 0.5801 0.8459 1.5316 0.033 H6B H 0.4002 0.8813 1.4740 0.033 C7 C 0.7218(3) 0.8950(2) 1.2783(3) 0.022.3(6) C8 C 0.2749(4) 1.1128(2) 1.3091(3) 0.024.2(6) H8A H 0.2416 1.1389 1.3979 0.029 H8B H 0.1891 1.1288 1.2367 0.029 C9 C 0.4457(4) 1.1517(2) 1.2727(3) 0.025.5(6) H9A H 0.4351 1.2119 1.2187 0.031 H9B H 0.5175 1.1635 1.3563 0.031 C10 C 0.6380(4) 0.7516(2) 1.1028(3) 0.027.1(6) H10A H 0.5415 0.7144 1.0692 0.041 H10B H 0.7204 0.7081 1.1458 0.041 H10C H 0.6856 0.7850 1.0257 0.041 C11 C 0.8145(4) 0.9587(2) 1.1737(3) 0.025.8(6) H11A H 0.8967 0.9989 1.2237 0.039 H11B H 0.7348 0.9999 1.1226 0.039 H11C H 0.8699 0.9170 1.1094 0.039 C12 C 0.8591(4) 0.8405(3) 1.3673(3) 0.0345(7) H12A H 0.9392 0.8871 1.4064 0.052 H12B H 0.9155 0.7947 1.3094 0.052 H12C H 0.8084 0.8058 1.4416 0.052 C13 C 0.3492(3) 0.96225(17) 0.9299(3) 0.0146(5) C14 C 0.1935(3) 0.99345(19) 0.9801(3) 0.0143(5) H14A H 0.1676 0.9797 1.0773 0.017

320 C15 C 0.0669(3) 1.03019(19) 0.8859(3) 0.0177(5) H15A H -0.0457 1.0420 0.9195 0.021 C16 C 0.0904(3) 1.03620(19) 0.7403(3) 0.0196(5) C17 C 0.2435(3) 1.00178(19) 0.6923(3) 0.0186(5) H17A H 0.2533 0.9927 0.5914 0.022 C18 C 0.3721(3) 0.96409(18) 0.7852(3) 0.0168(5) H18A H 0.4683 0.9297 0.7477 0.020 C19 C -0.0477(4) 1.0766(2) 0.6423(3) 0.0260(6) H19A H -0.0312 1.1459 0.6302 0.039 H19B H -0.1550 1.0654 0.6812 0.039 H19C H -0.0449 1.0443 0.5532 0.039 C20 C 0.1477(4) 0.7793(2) 0.9390(3) 0.0266(7) C21 C -0.0950(3) 0.85944(17) 0.7862(3) 0.0194(6) C22 C 0.1635(4) 0.7923(2) 0.6736(3) 0.0219(6)

Table A 20: Anisotropic Displacement Coefficients (A°2x104) of II.4

U11 U22 U33 U23 U13 U12

Cr1 152.4(17) 106.2(16) 161.1(17) -5.8(18) -12.4(12) -6.6(18) O1 177(9) 188(9) 235(9) -19(8) 44(7) 34(7) O2 220(10) 142(8) 212(9) 6(7) 39(7) 15(7) O3 144(8) 239(9) 125(8) 8(7) -9(7) 19(7) O4 699(19) 305(13) 514(15) 200(12) -225(13) -192(13) O5 201(10) 303(11) 369(11) 11(9) -6(8) -48(8) O6 328(12) 375(13) 423(13) -221(11) -27(10) 42(10) C1 255(14) 242(14) 136(12) -20(10) -25(10) 49(11) C2 181(12) 158(12) 144(11) -18(10) 19(9) 4(10) C3 173(11) 172(15) 132(10) -4(9) 18(8) 2(10) C4 270(14) 168(13) 171(12) 26(10) 5(11) 47(11) C5 322(16) 229(14) 195(13) 45(12) 27(12) 82(13) C6 372(15) 275(18) 185(12) 40(11) 25(11) 114(12) C7 225(12) 236(16) 203(11) -41(12) -33(9) 55(12) C8 289(15) 185(13) 254(14) -34(11) 26(12) 53(11) C9 274(15) 165(13) 323(15) -41(12) -7(12) 31(11) C10 339(16) 238(14) 235(13) 18(11) 14(12) 104(12) C11 144(13) 303(15) 325(15) -31(12) -9(11) 11(11) C12 301(17) 374(17) 346(16) -6(14) -126(13) 136(14) C13 177(12) 109(11) 150(11) -8(9) -12(9) -5(9) C14 156(13) 138(12) 134(12) -8(10) -5(9) -19(10) C15 140(12) 127(11) 262(13) -34(10) -12(10) -2(9) C16 220(13) 112(11) 248(13) 15(10) -55(11) -3(10) C17 213(13) 172(12) 174(12) 10(10) 20(10) -31(11) C18 173(13) 153(12) 178(12) 6(10) 21(10) 3(10) C19 283(15) 195(13) 291(14) 35(12) -95(12) 49(12) C20 325(17) 216(15) 247(15) 41(13) -74(13) -74(13) C21 207(13) 154(14) 221(12) -4(9) 13(10) -1(9) C22 173(13) 188(13) 295(14) -66(12) -5(11) -9(11)

321 Table A 21: Bond Lengths (A°) of II.4

Cr1 C21 1.827(3) Cr1 C20 1.843(3) Cr1 C22 1.845(3) Cr1 C15 2.196(3) Cr1 C17 2.216(3) Cr1 C16 2.228(3) Cr1 C14 2.231(3) Cr1 C18 2.247(3) Cr1 C13 2.285(3) O1 C8 1.441(3) O1 C2 1.443(3) O2 C2 1.404(3) O2 C9 1.426(3) O3 C13 1.354(3) O3 C3 1.436(3) O4 C20 1.144(4) O5 C21 1.154(3) O6 C22 1.155(3) C1 C2 1.540(4) C1 C6 1.551(4) C1 C7 1.558(4) C2 C3 1.568(3) C3 C4 1.546(4) C4 C10 1.513(4) C4 C5 1.544(4) C4 C7 1.556(4) C5 C6 1.543(4) C7 C12 1.538(4) C7 C11 1.541(4) C8 C9 1.515(4) C13 C18 1.405(3) C13 C14 1.416(4) C14 C15 1.407(4) C15 C16 1.417(4) C16 C17 1.403(4) C16 C19 1.509(4) C17 C18 1.415(4)

Table A 22: Bond Angles (°) of II.4

C21-Cr1-C20 90.09(13) C21 Cr1 C22 87.48(12) C20 Cr1 C22 87.60(14) C21 Cr1 C15 87.70(10) C20 Cr1 C15 120.30(12) C22 Cr1 C15 151.68(12) C21 Cr1 C17 118.05(11) C20 Cr1 C17 151.80(13) C22 Cr1 C17 91.68(11) C15 Cr1 C17 66.32(10) C21 Cr1 C16 89.45(10) C20 Cr1 C16 157.64(12) C22 Cr1 C16 114.71(12) C15 Cr1 C16 37.35(10) C17 Cr1 C16 36.82(10) C21 Cr1 C14 113.56(10) C20 Cr1 C14 92.76(11) C22 Cr1 C14 158.94(11) C15 Cr1 C14 37.05(10) C17 Cr1 C14 78.16(9) C16 Cr1 C14 67.08(9) C21 Cr1 C18 154.83(10) C20 Cr1 C18 115.02(12) C22 Cr1 C18 94.94(11) C15 Cr1 C18 78.32(9) C17 Cr1 C18 36.95(10) C16 Cr1 C18 66.75(10) C14 Cr1 C18 65.88(9) C21 Cr1 C13 150.09(10) C20 Cr1 C13 91.17(11) C22 Cr1 C13 122.43(11) C15 Cr1 C13 66.05(9) C17 Cr1 C13 65.63(9) C16 Cr1 C13 78.39(9) C14 Cr1 C13 36.53(9) C18 Cr1 C13 36.11(9) C8 O1 C2 108.3(2) C2 O2 C9 105.45(19) C13 O3 C3 118.24(18) C2 C1 C6 106.6(2) C2 C1 C7 102.2(2) C6 C1 C7 102.2(2) O2 C2 O1 105.5(2) O2 C2 C1 113.8(2)

322 O1 C2 C1 112.6(2) O2 C2 C3 110.79(19) O1 C2 C3 111.7(2) C1 C2 C3 102.5(2) O3 C3 C4 109.96(19) O3 C3 C2 113.6(2) C4 C3 C2 103.90(19) C10 C4 C5 114.0(2) C10 C4 C3 114.3(2) C5 C4 C3 103.6(2) C10 C4 C7 118.5(2) C5 C4 C7 101.6(2) C3 C4 C7 102.9(2) C6 C5 C4 104.4(2) C5 C6 C1 103.1(2) C12 C7 C11 106.3(2) C12 C7 C4 113.8(3) C11 C7 C4 114.3(2) C12 C7 C1 112.4(2) C11 C7 C1 116.1(2) C4 C7 C1 94.0(2) O1 C8 C9 102.8(2) O2 C9 C8 102.1(2) O3 C13 C18 116.1(2) O3 C13 C14 124.5(2)

323

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