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V .5: . ¢fifl$$¢wn “ :1_ J ‘5 11...: rrg‘i .in 5.4% 1,5 r 'V x .v , o. _ .5 ‘1‘!" 1? . 3&1‘53; " :5 x!’ 1% ' ‘§§$%$ &w%@n 5‘ 1.33233“: “I; ‘§ HIGANS TSATE me“:1!”le ”“1“!!!leUHIVNIIIIUHIW J 301589 6610 t \‘l 515,-.) o . 9t This is to certify that the dissertation entitled Nuances In Intramolecular Cycloadditions Of Double Bonds To Triplet Benzene Rings presented by Robert Paul Smart has been accepted towards fulfillment of the requirements for Ph.D. Chemistry degree in (PXYég/i sznu~ 9'ij profeQ or Date November 16, 1994 MS U i: an Ajfirmau‘w Action/Equal Opportunity Institution 0-12771 NUANCES IN INTRAMOLECULAR CYCLOADDITIONS OF DOUBLE BONDS TO TRIPLET BENZENE RINGS By Robert Paul Smart A DISSERTATION Submitted to Michigan State University In partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1994 ABSTRACT NUANCES IN INTRAMOLECULAR CYCLOADDITION S OF DOUBLE BONDS TO TRIPLET BENZENE RINGS By Robert Paul Smart The regioselectivity with which ortho-substituted p-butenoxyacetophenones undergo intramolecular triplet [2+2] photocycloaddition to tricycloundeca-2,lO-dienes was investigated. Both electron donating and withdrawing groups produce the same absolute selectivity: addition of the remote double bond exclusively toward the ortho ring substituent. It is likely that the observed regioselectivity is associated with differentiating effects on both the initial triplet-state cycloaddition and the subsequent electrocyclic reactions. Steric interactions between meta-ring substituents and the approaching double bond can effectively alter the regiochemical course of the reaction. Conformational restrictions imposed by the tether connecting the arene and alkene attenuate the directing influence exerted by the ortho substituents. The regioselectivity associated with the ortho [2+2] photocycloaddition process involving an ortho alkyl group may be due solely (or in part) to the formation of a triplet dienol. Independent studies have shown that the triplet biradical of the photoenol lives for microseconds. There should be sufficient spin density at the para carbon to produce some hexenyl radical cyclization prior to decay to the ground state enol. Such a process would occur exclusively from the syn biradical, effectively bypassing the direct interaction of the triplet benzene and the double bond. Photosensitization techniques have been performed on cyano and carboxy analogs of p-butenoxyacetophenones that do not absorb in the near UV range or do not efficiently form excited triplet states. Triplet-triplet energy transfer from the solvent acetone results in efficient [2+2] photocycloadditon to form cyano and ester substituted tricycloundeca—ZJO- dienes and tricyclododeca-2,1 l-dienes in 50-75% isolated yields. *In most but not all cases, the same products were formed by direct irradiation at 254 nm. Although the main thrust of this project has been mechanistic, the ultimate goal is to incorporate the findings in the synthesis of natural products. Many natural products have 8/5 fused and 4/5/6 ring systems as their skeletal framework; one such class is the ophiobolins. The knowledge of the factors which control regioselectivity of [2+2] cycloaddition and efficiency of triplet sensitization of non-keto aromatics provides a firm foundation toward use of this reaction for the synthesis of natural products. Copyright by ROBERT PAUL SMART 1994 «.3! vii ‘7 ;J ‘1‘ Acknowledgments Sincere thanks are given to Professor Peter J. Wagner. His knowledge of chemistry and his ability to express abstract ideas precisely were invaluable in the completion of my research. Appreciation is also given to the National Institutes of Health and Michigan State University for the generous financial support and use of its excellent research facilities. The author is very much indebted to my close friends at Michigan State University both past and present. In particular, Kevin, Ali, Marty and Kung-Lung, who proved me with sanity and normality during my stay. Our luncheon journeys sparked many stimulating discussions regarding the finer things in life. I also thank the professors at the liberal arts colleges with which I am affiliated for their positive role models. Their enthusiasm for teaching and respect toward their pupils has prompted me to pursue a career in teaching. Last but not least, I would like thank the ones I love for their patience and their ability to forgive for my mood swings when I thought I'd never finish. To answer their reoccurring question, "When are you finally getting done...its been forever?"---Now. Table of Contents LIST OF TABLES LIST OF FIGURES INTRODUCTION Research Objectives Background Mechanistic Considerations Predicting the Mode of Photocycloaddition Arene-Alkene Ortho Photocycloaddition Arene-Alkene Meta Photocycloaddition Arene-Alkene Para Photocycloaddition Equilbrium Between Cyclooctatriene and Cyclohexadiene Triplet Sensitization Techniques Triplet Sensitization-«Representative Examples Quantum Yield Determination RESULTS Preparation of Reactants Characterization of Products Photochemistry of 20Me-4T2Me-K Photochemistry of 2Me-4T2H-K Photochemistry of 2Me-4T2Me-K Photochemistry of 2CD3-4T2Me-K Photochemistry of 2,5Me-4T2H-K Photochemistry of 2,5Me-4T2Me-K Photochemistry of 2Me-4T211-SI-K Photochemistry of 2Me-4T2Me-SI-K Photochemistry of 2,6Me-4T2Me-K Photochemistry of 2CN-4T2Me-K Photochemistry of Indanone-3Me-5T2Me Photochemistry of 2F-4T2Me-K Photochemistry of 2CF3-4T2Me-K Photochemistry of 21-4T2Me-K 25 28 33 35 38 41 43 47 47 51 51 52 53 54 57 58 Photochemistry of lCN-4T2H 59 Photochemistry of lCN-4T2H-COT 60 Photochemistry of 1CN-4T3H 64 Photochemistry of lCN-2T2H 67 Photochemistry of 1CN-2T3H 68 Photochemistry of 1EC-4T3H ' 70 Photochemistry of lEC-4T21-1 71 Photochemistry of 1EC-2T3H 72 Photochemistry of 4T2H-K 74 Photochemisz of4T3H-K 75 Photochemistry of 4T2N(CN)-K 76 Photochemistry of cis-4T2N(Et)-K 78 Photochemistry of 4T2N(F)-K 81 Computational Studies 81 Kinetic Results 84 DISCUSSION 86 Regioselectivity 86 Overall Mechanism 87 Exciplex Formation 88 Biradical Formation 93 Photoenolization of o-alkylphenyl ketones 94 Differential Rates of Electrocyclizations 97 Quantum Yields 99 Thermal Ring Opening of Non-Ketone Substituted Cyclobutenes 100 Photolysis of 4- and 6-X-12-oxabicyclo[6.4.0]dodeca-1,3,5-trienes 102 Photolysis of 3-cyano-9-oxatricyclo[82.0.05,10]dodeca-2,1l-diene 105 Photochemistry of lCN-4T2H-COT 106 Stereoselectivty 1 10 Future Work 1 12 EXPERIMENTAL 1 16 Instrumentation 1 16 Chemicals 116 Solvents 1 16 Chromatography Material 118 Internal Standards 118 Preparation of Reactants 119 Identification of Photoproducts 161 Photokinetic Data 208 Photochemical Glassware 208 Sample Preparation ‘ 208 Degassing Procedure 208 Irradiation Chambers 209 Calculation of Quantum Yields 209 Computational Parameters 211 APPENDIX 213 Crystal Structure of 1CN-4T3H-CB 213 Quantum Yields 217 AMI Calculation of the Rotational Barrier in 2Me-4Tzn-SI-K 230 NMR Spectra 231 REFERENCES 240 Table 1: Table 2: Table 3: Table 4: Table 5: Table 6: Table 7: Table 8: Table 9: Table 10: Table 11: Table 12: Table 13: Table 14: LIST OF TABLES Relative Ratios for Meta Photocycloaddition Products in the Interaction of Cylopentene and Meta Substituted Anisoles Kinetic Parameters for Electrocyclic Equilibrium between Several Substituted Cyclooctatrienes and Bicyclo[4.2.0] octa-2,4-dienes Chemical and Quantum Yields for Products Arising from Photolysis of 8-cyano-2,3-benzobicyclo[4.2.0] octa-2,4,7-triene Isolated Yields of Various Cyclobutenes Arising from Triplet Sensitization Isolated Yields of Various Ortho Substituted Cyclobutenes and Cyclooctatrienes Quantum Yields of Various Cyclooctatrienes or Cyclobutenes Quantum Yields of Cyclobutene Formation 0R and 0'1 Values for Ortho Substituents in 4—Butenoxyacetophenone Electronic Charge Distributions for the Excited Singlet of lR-4T2H-COT Selected Dihedral Angles for 1CN-4T2H-COT and 1CN-4T3H-COT Bond Distances for lCN-4T3H-CB Bond Angles for 1CN-4T3H-CB Quantum Yield Determination of lCN-4T3H-CB at 313 nm Quantum Yield Determination of 2,5Me-4T2H-CB at 313 nm page# 14 19 23 83 83 84 85 90 110 112 215 216 218 219 Table 15: Table 16: Table 17: Table 18: Table 19: Table 20: Table 21: Table 22: Table 23: Table 24: Quantum Yield Determination of 2,5Me-4T2H-COT at 313 nm Quantum Yield Determination of 2Me-4T2H-SI-CB-t at 313 nm Quantum Yield Determination of 2Me-4T2H-SI-CB-a at 313 nm Quantum Yield Determination of 2Me-4T2H-SI-COT-t at 313 nm Quantum Yield Determination of lCN-2T3H-CB at 313 nm Quantum Yield Determination of 1EC-2T3H-CB at 313 nm Quantum Yield Determination of 2F-4T2Me-COT at 313 nm Quantum Yield Determination of lCN-2T2H-LCB at 313 nm Quantum Yield Determination of 1CN-4T2H-LCB at 313 nm Quantum Yield Determination of 2Me-4T2Me-CB at 313 nm 220 221 222 223 224 225 226 227 228 229 Figure 1: Figure 2: Figure 3: Figure 4: Figure 5: Figure 6: Figure 7: Figure 8: Figure 9: Figure 10: Figure 11: LIST OF FIGURES Stabilization of the Singlet Excited State by Benzene-Ethylene Orbital Interactions Crystal Structure of 1CN-4T3H-CB 1H NMR of 2,5Me-4T2H-CB-t in CDC13 1H NMR of 2Me-4T2H-COT in CDC13 1H NMR of an Equilibrium Mixture of 20Me-4T2Me-COT and 20Me-4T2Me-CH in CDC13 1H NMR of an Equilibrium Mixture of 2F-4T2Me-COT and 2F-4T2Me-CH in CDC13 1H NMR of 2Me-4T2H-SI-CB-t in CDC13 1H NMR of 2Me-4T2H-SI-CB-a in CDC13 1H NMR of 2Me-4T2H-SI-COT-t in CDC13 1H NMR of 2Me-4T2H-SI-COT-a in CDC13 1H NMR of 1CN-4T3H-CB (bottom) and 1CN-4T3H-COPE (top) in toluene-d8 page# 213 231 232 233 234 235 236 237 238 239 INTRODUCTION Research Objective The overall goal of this research was to gain a clearer understanding of the mechanism and synthetic potential of photochemical cycloadditions of excited triplet aromatic substrates to olet'ms. This study focused on two separate but related aspects: 1) to determine the regioselectivity of the initial [2+2] ortho addition onto more highly substituted benzene rings and 2) to examine the effects of triplet sensitization techniques on related aromatic substrates that do not absorb in the near UV range or do not efficiently form excited triplet states when irradiated. The results presented, in conjunction with previous work, will hopefully allow this reaction to be exploited in the synthesis of natural products. 0 Background The onset of modern arene photochemistry arose from a landmark discovery of the photoisomerization of benzene to fulvene (1).1 254nm ———-> 50°C This finding undermined the established belief that benzene was photochemically inert. 1 Much of the subsequent arene photochemical research has been centered around the interactions of benzene with alkenes. 2 During the past few decades, arene-alkene photocycloaddition has profoundly affected organic synthesis as demonstrated by the many successful synthetic approaches that currently utilize this reaction as a key step.2’ 3’ 4’ 5 Use of mild photochemical activation in construction of complex polycyclic molecules allows for control of the chemo- , regio-, and Stereoselectivity that is not fully accessible by more traditional synthetic procedures. Irradiation of benzene at 254 nm in the presence of an alkene can lead to formation of 1,2-(0rtho), 1,3-(meta), and 1,4-(para) cycloadducts depending on the substitution pattern of the arene and olefin. For example, intermolecular photoaddition of benzene to 1,2-disubstituted ethylene leads to bicyclo[4.2.0]octa-2,4-diene 2, tricyclo[3.3.0.04’6]oct- 2—enes 3, or bicyclo[2.2.2] octa-2,5-dienes 4 depending upon the electronic nature of the ethylene substituents. For all modes of cycloaddition, the stereochemistry of the alkene is preserved in the products.6 Generally, para cycloaddition is very inefficient and rarely observed. In contrast, both ortho and meta photocycloadditions are facile and occur with a wide variety of substituted double bonds and aromatic rings. 1) + 1:3. 5+ :4: «5' 2 Mechanistic Considerations Since the initial discovery of photocycloaddition of excited benzenes to alkenes,7 the factors which influence the mode of addition have been investigated. Several groups have focused intensely on the mechanism behind this synthetically useful reactions: 8 The reaction is believed to occur from the singlet manifold of the arene. Morrison and co- workers studied sensitization of the photocycloaddition of 6-phenylhex-2-ene.9’ 10 Benzene-sensitization of the cis-isomer produced both cis-trans isomerization and cyclization at approximately equal rates. Alternatively, triplet sensitization using 3 benzophenone or acetone produced no cycloaddition products. Quenching studies using cis-piperylene provided additional information. Cis-piperylene was ineffective at quenching both cycloaddition and cis-trans isomerization of 6-phenylhex-2-ene. Mattay1 1 provided additional evidence for singlet state cycloaddition. The quantum yields for ortho, meta, or para cycloaddition of benzene to 15,3-dioxoles were reduced up to 70% when irradiated in the presence of xenon compared to argon purged samples; xenon is known to accelerate singlet-triplet intersystem crossing. Thus, Mattay concluded that the photocycloaddition of 1,3-dioxoles and benzene involve exclusively the singlet excited state. Bryce-Smith12,Gilbertl3’ 14 and Sheridanls, 16 have suggested the possible presence of a biradical intermediary with the bicyclo[3.2.l] octenyl skeletons, 5 and 6, in the meta photocycloaddition process. Based on the high degree of regioselectivity associated with this reaction, it is believed that biradical formation must be superseded by an interaction of the excited benzene and alkene. The excited complex is highly polarized due to the differing behavior of electron donating and electron withdrawing substituents on the arene ring. Scheme: Meta Photocycloaddition via the Bicyclo[3.2.1]octenyl Biradical R R h /R R OMB 1 —+V -> 0 R \ 5 R Me I“ ':“—“ HR” NC 6 R '.R 4 Reedich and Sheridan16 generated the proposed bicyclo[3.2. 1] octenyl biradical by photochemical explusion of nitrogen. The chemistry of this biradical mirrors that involved in the meta cycloaddition process. These radicals couple to form a cyclopropyl ring and, more importantly, if asymmetrically substituted molecules are used from which two different meta cycloadducts are formed, these products are produced in the same ratio as in the meta cycloaddition case. 254nm + 254nm Meta cycloaddition 1 : 1 254nm Azo compound (7) l : 1.04 Azo compound (8) l : 1.01 Exciplex formation was first proposed as an intermediate in meta photocycloaddition by Morrison and Ferree in their paper on intrarnolecular reactions of 6- phenylhex-2-ene.10 No experimental evidence corraborating its involvement was presented. Mattay, Scharf and Leismann17’ 18 provided the first direct evidence for an exciplex intermediate in 1977. They observed an emmision (ca. 400 nm) during photocycloaddition of benzene to substituted 1,3-dioxoles and 1,4-dioxenes in acetonitrile, but not in cyclohexane. They also found that triethylamine effectively quenches exciplex 5 emmision with a rate constant of ksv=11.6i0.4 L mol‘l. This is nearly identical to that for quenching of meta cycloaddition (ksv=11.7i1.5 L mol'l). Houk19 provided a qualititative picture based on frontier orbital theory to rationalize regioselectivity associated with cycloaddition of benzene to alkenes. The HOMO's and LUMO's of benzene are labelled S, A, S*, and A* according to their symmetries with respect to a plane perpendicular to the benzene ring and passing through the position of attachment Actual frontier orbitals of benzene are combinations of lowest excited singlet Bzu (SA*-AS*) and lowest triplet B1u (SS*+AA*). In an ortho approach, stabilization can be achieved by mixing of the alkene's HOMO (1:) with the benzene A orbital. In a meta approach, stabilization is afforded by interaction of the alkene's HOMO with the S orbital of benzene. These interactions are depicted below. Slight stabilization for both meta and ortho addition can be accomplished through interactions of the IV“ orbital of the alkene and the A* orbital of benzene. Para-approach is only weakly stabilized by an interaction of benzene S and alkene rt orbitals. Thus, it is predicted that meta complexation is stabilized by the S-A* transition, whereas, ortho complexation is stabilized by the A-S* transition. Frontier Orbital Theory accurately describes partitioning between modes of cyclization when substituents are placed on the arene ring or ethylene unit. Addition of a substituent, whether it be electron donating or withdrawing, effectively removes the degeneracy of the HOMO and LUMO molecular orbitals. Interaction of ethylene with donor substituted benzene promotes meta addition at positions 2 and 6. This selectivity is due to preferential stabilization of the S-A* transition. Alternatively, benzene rings bearing an electron withdrawing substituent promote ortho cycloaddition due to increased charge transfer interactions. B2u (SA*-AS*) lowest excited singlet state ‘\_:\ B1u (SS* +AA*) lowest triplet state 3* E1u(SS*-AA*; SA* + AS*) degenerate states rth ° 0 1t* (LUMO) . meta 0 Art meta Q \ rom=1395A . rm, = 2.416131 S rpalm = 2.790A ortho . 7t (HOMO) O A Benzene FMO's Aikene FMO's Figure 1: Stabilization of the Singlet Excited State by Benzene-Ethylene Orbital Interactions Predicting The Mode Of Photocycloaddition Several investigators have attempted to formulate factors which affect the regioselectivity of arene-olefin photocycloaddition. Bryce-Smith postulated that the mode of cyclization can be predicted based on differences in ionization potentials (AIP) between the benzene ring and the alkene.20 Reactions of benzene (IP=9.24eV) with alkenes having IP's ranging from 9.6 eV to 8.65 eV proceed along a meta pathway. Ortho cycloaddition is preferred with strong donor and acceptor alkenes (9.6eV < [P < 8.65eV). Generally, this rule provides temendous predictive value. Mattay21’ 22 has also derived a general rule for predicting the mode of photocycloaddition of benzene to alkenes, based on the Rehm-Weller theory of electron transfer . According to this equation, the Gibbs free energy (AG) of electron transfer can be accurately calculated from redox potentials of starting materials and excitation energy of the excited species. This rule allows correlations to be made for a wide variety of substituted arenes and alkenes. In general: 1. The mode of cycloadditon changes from meta to ortho when AG< 1.4-1.6 eV indicating an increasing degree of charge transfer developing in the excited state complex. 2. Electron transfer predominates when AG 5 0. Arene-Alkene Ortho Photocycloaddition Ortho photocycloaddition is greatly favored and in many cases is the sole pathway in bichromophoric pairs which have a strong electron donor-acceptor relationship. Gilbert demonstrated this principle in photoreactions of arenes having both electron donor and electron acceptor substituents. Irradiation of 4-methoxybenzonitrile with electron rich ethyl vinyl ether produces a 2:1 mixture of ortho cycloaddition products, 1-cyano-8-ethoxy-4- 8 methoxy[4.2.01r6] octa -2,4-diene (9) and 4-cyano-7-ethoxy-1-methoxy[4.2.01’6] octa -2,4-diene (10) respectively. Alternatively, irradiation of 4-methoxybenzonitrile and cis- cyclooctene produces the endo meta cycloadduct, 11, in 65% isolated yield.23 CN M 0 pH— /—0Et ' CN OEt 0M0 . .. I. I I I I I ..‘—_ 254nm 254nm —-—_>M‘° NC CB 9 10 11 Gilbert also reported that direct photocycloaddition of electron rich alkenes to 2- methoxybenzonitriles proceeds in high yields.24 Initially formed l-cyano-8-ethoxy-6- methoxy[4.2.0196] octa -2,4-diene (12) rapidly opens to l-cyano-8-ethoxy- methoxycycloocta-1,3,5-triene (13). The resulting cyclooctatriene undergoes photochemical diene to cyclobutene ring closure to form l-cyano-8-ethoxy-6- methoxybicyclo[4.2.0] octa-2,5-diene (14). Similar reactions were observed with methyl- 2-methoxybenzoate and 2-methoxyacetophenone, however, the yields were appreciably lower. CN : OMer OEt TNO: 2541““ mom 254nm :IZGOE 0M9 12 14 Intramolecular variants of this reaction have also been investigated. Cyano and methoxycarbonyl substituted 4-phenoxybut-1—enes undergo efficient intramolecular cycloaddition to give good yields of 4-oxatricyclo[7.2.0.03t7] undeca-2,10-dienes 9 (15125: 26 The formation of intermediate cyclooctatriene was efficiently quenched by 1,3-dienes, but its rapid photochemical ring closure was uneffected by triplet quenchers. R2 R1 hv R1 R: ”1 hV R2 _—_> __‘ —> 1:1 — C .— LCD 0 ' 15 R1: CN, COOMe ; R2: 11 R‘: H ; R2: CN, COOMe McCullough27 observed similar results for naphthonitrile systems. For example, irradiation of 2,3-dimethyl-2-butenyl(1-cyano-2-naphthyl) methyl ether in benzene provided a 20:1 mixture of two ortho cycloaddition products, 16 and 17, respectively. Prolonged irradiation produced only one cycloadduct, 17 (initially the minor isomer). Ring opening to cyclooctatriene was not observed. 16 17 In an attempt to measure the degree of intramolecular quenching of rt,1t* triplets of ketones substituted with unsaturated tethers, Wagner and Nahm discovered the first reported 1,2-photocyclization of a triplet benzene to a remote olefin.28t 29 Upon irradiation, the remote double bond underwent an intramolecular [2+2] cycloaddition with the benzene ring of the o-alkoxyphenyl alkyl ketone. The resulting intermediate, bicyclo[4.2.0] octa-2,4-diene 18, was thermally converted to cyclooctatriene 19. Additional irradiation of the cyclooctatriene effected a photochemical diene-to-cyclobutene interconversion to give bicyclo[4.2.0] octa-2,7-diene 20. The stereochemistry of 10 photostable bicyclo[4.2.0] octa-2,7-dienes was determined by nOe studies. In all cases, disrotatory photoclosure of the cyclooctatriene resulted in formation of a cis 4/6 ring fusion. In fact, closure occurred only in one direction to form a cis 5/6 ring fusion. 5:}Lfijj420 *0» £ri:;t,> 18 19 20 Recently, it has been demonstrated that this reaction proceeds with a high degree of regioselectivity”: 31 Electron withdrawing groups and alkyl groups ortho to the olefin tether direct cyclization toward the substituent, while strong electron donating groups drive the remote double bond away. Selectivity appears to reflect inductive effects both on the nature of initial triplet state cycloaddition and the competing thermal and photochemical electrocyclization reactions of the resultant photoproducts. X0 0 O . hv .. ©- --—- 0.:- 4’ x Ax° X=OMe, SMe x ' 0 hv 15* A _. o ‘— 0 A0 x X=CN, CONHz, CH3, COzR 1 l Triplet napthalenes have also been also shown to undergo ortho photocycloaddition with simple alkenes.30 Irradiation of 1-butenoxy-2-acetonaphthones and 2-butenoxy-1- acetonaphthones in benzene results in formation of ortho [2+2] cycloadducts in high chemical yield. The quantum yields for l-butenoxy-2-acetonapthones were substanially higher than for 2-butenoxy-l-acetonapthones. Presumably this difference is due to 1- butenoxy-2-acetonapthone's ability to stabilize the radical character in the rate determining step. R1 \ J/RR Bl O o 2 :3 R2 hv 300.3 o R1=R2=H =0.23 R1=Me, R2=H o=0.17 R1=H, R2=Et =0.31 0 32 CO 0 m “30’ 50 R1=R2=H o=0.01 R1:Me, R2=H ¢=0.04 R1=H, R2=Et ......... Ortho photocycloaddition occurs readily in systems involving alkynes. In nearly all cases, the initially formed cyclobutene adduct opens to the all cis cyclooctatetraene. Wender and Fisher have shown that when benzene and dirnethyl acetylenedicarboxylate are irradiated, cyclooctatetrene 21 is obtained in good yield.32 COQMG hV 002MB 21 While intermolecular cycloaddition between an alkyne and benzene is facile, the intramolecular variant of this reaction is inefficient.33 Pirrung has overcome this problem by incorporating a trialkylsilyl group on the alkyne.34 OH I OH I I \ - SIMe3 . OH ' SIM93 46% Arene-Alkene Meta Photocycloaddition Intermolecular meta photocycloaddition was discovered simultanously by two independent reseach groups in 1966. Wilzbach and Kaplan reported the formation of 1:1 adducts upon irradation (254 nm) of 10% solutions of cyclopentene, cis-2-butene and 2,3- dimethylbut-2—ene in benzene. 13 254nm fig? 254nm O.‘ 0“" , 254nm >_—_< D, Bryce-Smith, Gilbert and Orger reported addition of cis-cyclooctene to benzene to form a 1:1 adduct in 85% isolated yield. On the basis of spectroscopic and chemical evidence the adduct was identified as tetracyclo[6.6002,4037]tetradec-S-ene 22. 254nm Regioselectivity of meta cycloaddition is influenced considerably by steric interactions”: 36 As depicted above, intermolecular meta photocycloaddition generally proceeds with the double bond moiety adding to the 2- and 6- positions of the arene, relative to the electron donor group. As the steric bulk of donor groups increases, regioselectivity migrates to the 3- and 5-position relative to the ring substituent. l4 01 9 .0 . l T ‘ (3.5) .5 .............. 2. 26.99---- methyl only 2,6 iso-propyl 2: 1 t-butyl Substituents on the arene ring profoundly effect the regioselectivity of intermolecular meta photocycloaddition”: 38’ 39’ 40 Donor ring substituents orient preferently to position 3, while acceptor ring substitutents prefer positions 4 and 6. Table 1: Relative Ratios For The Possible Meta Photoproducts CN 13 7 13 67 CF3 5 16 36 43 F 0 0 51 49 O 0 43 57 H 13 87 15 Regioselectivity is also observed in intramolecular photocycloaddition. There are two principal modes of cycloaddition available to 5-phenylpent-1-ene and its derivatives: 1,3-addition and 2,6-addition. Gilbert and Taylor41 reported that 5-phenylpent-1-ene undergoes 2,6 as well as 1,3 addition in a ratio of 72:28. 254 nm V / _> “. 2,6-addition 1,3-addition 72 : 28 The usefulness of meta arene-alkene cycloaddition in polycyclopentanoid synthesis is exemplified by the total synthesis of the sesquiterpene (i)-cedrene.42 The key photochemical reaction is photolysis of the anisole, yielding cycloadducts 23 and 24 in 65% isolated yield. Rapid increase in molecular complexity due to meta photocycloaddition dramatically shortens the total synthesis of (i)-cedrene to four steps. The observed regioselectivity is dictated by the presence of the ortho methoxy group. Recently, Wender reported the stereocontrolled synthesis of (i)-1aurenene, a naturally occuning fenestrane.3 The synthesis was based on the most complex example of an arene-olefin meta photoaddition to date, and provided a novel strategy for the preparation of other rosettane analogs. The successful cycloaddition of the lactol indicates that the key cycloaddition step can be extended to more highly congested substrates. (i)-laurenene Arene—Alkene Para Photocycloaddition While ortho and meta photocycloadditions have been throughly investigated, little effort has been spent to determine the factors which control para cycloaddition. As 17 previously mentioned, para cycloadditon is very inefficient and is the major mode of addition in only a few isolated cases: addition of dienes and allenes to benzene.43 When benzene was irradiated in the presence of isoprene, the para cycloadduct 25 was isolated as the major product by prepative glc, along with a minor amount of the 1,3- adduct 26. Similarly, photolysis of cyclonona-1,2-diene afforded the 1,4-adduct 27 as the major product. The aforementioned reactions were the first reported examples in which hydrocarbon olefms underwent unsensitized 1,4-cycloaddition to benzene as the major process“: 45 G + V hv(254nm)> W & 25 26 e O e. £9 + > ‘0 27 4 : 1 Thermal Rearrangements Equilbrium between Cyclooctatriene and Cyclohexadiene Cope first observed the near unity thermal equilibrium between cycloocta-1,3,5- triene 29 and its valence isomer bicyclo[4.2.0] octa-2,4-diene 28.46 This interconversion is an orbital topology-allowed, six electron, disrotatory process. 18 C A C In the case of hexatriene, the electrocyclic equilibrium favors its tautomer, cyclohexadiene, due to the energetically favored formation of a o-bond relative to a rt-bond. Incorporating the hexatriene system in a ring dramatically alters this equilibrium.47 For large rings, greater than eight carbons, the equilibrium lies in favor of bicyclohexadienes. In contrast, equilibrium greatly favors cyclohepta—1,3,5-tliene, where the ends of the triene are linked by one methylene unit. This is due to the severe ring strain in norcaradiene. — ___ A | (orbit. .\/CHa>n ”=1 Keq<<1 n: Kequ ”23 Keq>>1 Kinetic parameters for electrocyclic equilibrium between several substituted cyclooctatrienes and their tautomers, bicyclo[4.2.0] octa-2,4-dienes, were reported by Huisgen.48 l9 Table 2: Kinetic parameters for Electrocyclic Equilbrium between Several Substituted Cyclooctatrienes and Bicyclo[4.2.0] octa-2,4-dienes Since the free energies of 1,3,5-cyclooctatriene and bicyclo[4.2.0] octa-2,4-diene differ only slightly, electronic and steric effects will ultimately alter the equilibrium between valence isomers. Substitution in the 7- or 8- positions stabilizes the bicyclo [4.2.0] octa- 2,4-diene skelton relative to the unsubstituted cyclooctatriene. Roth and Peltzer reported the independent gas phase photochemistry of 1,3,5- cyclooctatriene 29 and its valence tautomer 28 in 1965.49 Irradiation of 29 produced two major products, 28 and 30, in a ratio of 2:1. A minor amount of "unzipped" product, octa-1,3,5,7-tetrene, was also present. hV / v —> 1 Gas \ + a. + \ \ \ \ Phase 29 28 30 2 : 1 Irradiation of bicyclo[4.2.0] octa-2,4-diene 28 produces its isomer 29, along with benzene and ethylene.49t 50 Photofragmentation has been seen in other fused ring systems. Phase 20 / hv \ r... + + n 29 28 Huisgen and Dahmen51 reported the presence of two 1,3,5-cyclooctatriene isomers, 32 and 33, arising from the thermolysis (171°C) of trans, cis, cis, trans- decatetra-2,4,6,8-ene (31). trans-7,8-Dimethyl-1,3,5-cyclooctatriene (32) comprised 99.68% of the products. The amount of cis-7,8-dimethyl-1,3,5-cyclooctatriene (33) increased to 0.71% of products when the temperature of reaction was increased to 205°C. In both cases, cyclooctatrienes were in thermal equilibrium with their corresponding bicyclo [4.2.0] octa-2,4-dienes. The equilibrium constant favored the bicyclic isomer for both the trans-system (Keq=4.25) and cis-system (Keq=15.7).48 / \ CH3 emf-0t CH3 .:ACH3 \ / T "'CHa ‘— CH3 CH3 31 .‘ 32 trans-system I “‘x \ CH3 CH / H3C ._ O 3 .:ACH3 \ / oonrot. CH3 ‘CH3 33 cis-system Triplet Sensitization Techniques 52 Energy transfer permits population of electronic states of a molecule in a different manner than by absorption of light. The chemistry arising from sensitization often differs 21 dramatically from the direct process. The most common types of energy transfer are triplet- triplet and singlet-singlet, both allowed by spin conservation.53 The efficiency of triplet-triplet energy transfer is dependent on a number of factors.54 First and foremost, the acceptor's S0-T1 energy gap must be smaller than, or equivalent to, the donor's S0-T1 energy gap for energy transfer to take place. Next, the sensitizer (donor) must be chemically inert and absorb wavelengths that are not absorbed or weakly absorbed by the acceptor molecule. Finally, the rate of intersystem crossing of sensitizer must be high. Triplet Sensitization---Representative Examples Direct photolysis of 3,5-cycloheptadienone, 34, led to efficient formation of carbon monoxide and 1,3,5-hexatriene through photofragmentation.55 This reaction could not be quenched by either piperylene or napthalene. Schuster later found that triplet sensitization of 34 produced another reaction, leading to the valence tautomer bicyclo[3.2.0] hept-6-en- 3-onediene (35) via a diene to cyclobutene ring closure.56 These observations indicated that photodecarbonylation occurs via the singlet manifold and prevents intersystem crossing to the uiplet state. LW +co Direct 0 O Triplet 35 Sensitized Similar results were found in the direct and sensitized photochemistry of bicyclo[4.2.1] nona-2,4-dien-9-one (36). Schuster found that direct photoylsis of 36 in diethyl ether or cyclohexane produced 1,3,5-cyclooctatliene (28) by decarboxylation and 22 endo-tricyclo[4.2.1.02r5] non-3-en-9-one (37) in a ratio of 5:1.57 Alternatively, irradiation of 36 in the presence of a triplet sensitizer (acetone, Michler's ketone, benzophenone, or triphenylene) gave dihydrobarbaralone (38) as the major product in all cases. Small amounts of products 28 and 37 were also present when acetone was used as a sensitizer. o h \ V O C o + C + Direct 28 37 36 hv 4 Triplet ” O Sensitized 38 Direct irradiation of 6-cyanobenzocyclooctatetrene, 39, in cyclohexane afforded 5- and 8-cyano—2,3-benzobicyclo[4.2.0] octa-2,4,7-triene, 41 and 40, in 21 and 63% yields respectively.58 NC CN 6 00 -—~”” 0‘ «Q + cyclohexane CN 39 40 41 Triplet-sensitized irradiation of 40 using Michler's ketone provided 1- and 6- cyanobenzosemibullvalenes, (43) and (44) (=0.88 and 0.006 respectively) and naphthalene (45) (<1>=0.012). Direct irradiation of 40 in cyclohexane led to formation of ' -.. W 23 five products, the major being 44. The cyclooctatetrenes 39 and 42 were observed only by direct irradiation. Deuterium labeling studies suggested that 39 and 42 were not formed by electrocyclic ring opening of 40. The major product by both methods arose from a di- lt-methane rearrangement of 40. CN CN hv CN CN r-Wtfio 42 43 44 45 46 , Table 3: Chemical and Quantum Yields for Products Arising from Photolysis of 40 7 Conditions I39 I42 I43 I44 I45 I46 I Direct(a) >290nm 8%(.007) 8%(.007) 55%(.05) 15%(.015) 5%(.004) Sensit.(b) 334nm ---- 7%(.006) 78%(.088) 11%(.012) Quantum Yield Determination The quantum yield of formation of a given species is given by the ratio of molecules formed to the number of photons absorbed (equation 1). Quantum Yield ( 1) moles of photons of irradation absorbed Knowledge of the amount of light absorbed by the reacting species is determined independently by chemical actinometry. Most actinometry, however, only determines the amount of incident light upon the sample. Fortunately, Beer's Law relates the amount of incident light to the amount of light absorbed by the reacting species (equation 2). I3 = Ion-10‘8“) (2) where: 1,,t = light absorbed I0 = incident light 8 = molar extinction coefficient 1 = path length c = concentration of actinometer(absorbing species) 24 According to this equation, the amount of absorbed light will equal the amount of incident light when the optical density of the absorbing species is 2 2. RESULTS Ring Substitution Several ortho substituents have been prepared to examine regioselectivity in the photocycloaddition of p-butenoxyacetophenones. Their- structures and corresponding thesis notations are listed below. para-Alkenoxyacetophenones and derivatives O 4TnH where : 4T=position of the tether on the ring 11: #of carbons between oxygen and olefin H: indicates an internal hydrogen on the olefin Rin Substituents T815. R2, R3, R5, & R6=H; n=3 4T3H- K R2, R3, R5, & R6=H; n=2 4T2H- K R2=Me; R3, R5, & R6=H; n: 2Me-4T2H- K R2—Me; R5=Me; R3 & R6=H; n=2 2 ,5Me-4T2H-K R2=Me; R5=isopropyl; R3 & R6=H n2: 2Me-4T2H-51-K 25 26 4T2Me where : 4T=position of the tether on the ring 2: #of carbons between oxygen and olefin Me: indicates an internal methyl substituent Rin Substituents I Thesis Notation R2=Me; R3,5R, R6_H 2e4T2Me-K R2=CF3; R3,R5, & R6=H 2CF3-4T2Me-K - R 1 -R2=3-methylcyclopent- 1 -one Indanone-3Me-5T2Me-K 27 Several 0- or p-butenoxybenzonitliles and benzoate esters were prepared which do not absorb strongly in the near UV (>300 nm). They are listed below. Comparisons will be made between their direct and triplet sensitized photoreactivity. Triplet-triplet energy transfer from acetone was used to produce 100% triplet reaction. Non-ketone Reactants xTnl'l where : xT =position of the tether on the ring n = #of carbons between oxygen and olefin (2 or 3) H = indicates an internal hydrogen on the olefin Rin Substituents Thesi Notation R=CN; n=3; x=4 f lCN-4T3H R=CN; n=2; x=4 1CN-4T2H R=COOEt; n=3; x=4 lEC-4T3H R=COOEt; n=2; x=4 .. lEC-4T2H R=COOEt; n=3; x=2 3 _ lEC_2TH R=CN; n=3; x=2 7 1CN'23H ,l R=CN; n=2; x=2 lCN-2T2H 28 Several p-butenoxyacetophenones were prepared which have substitution along the tether. Their structures and corresponding thesis notations are listed below. Tether Substitution Tether Substituents Thesis Notation R=Me; R1, R2=H; R3=CN 4T2N(CN)-K _ 2 RR], R3=H; R2=Et 4T2N(Et)-K R=H;R1, R2. R3=F 4T2N(F)-K Preparation of Reactants The majority of para-alkenoxyacetophenone derivatives were prepared by Fries rearrangement of their corresponding acetates in nitrobenzene at, or below, room temperature, followed by etherification in acetone or DMF. 2Me-4T2Me-K, 2Me- 4T2H-K, 20Me-4T2Me-K, 2F-4T2Me-K, 2,5Me-4T2Me-K, 2,5Me-4T2H-K, 2Me-4T2Me-SI-K and 2Me-4T2H-51-K were synthesized as shown below. 29 X 0 X Acetyl Chloride. Pyridine fl Aluminium Chloridpe x D o H © , 0°C--room temp. 0 20K Nitrobenzene O H 0 tether o ‘ Potassium Carbonate X R 2CD3-4T2Me-K was prepared by alkylation of 3-bromoanisole using n- butyllithium and iodomethane-d3. The resulting anisole was acylated using a Friedel-Craft reaction followed by deprotection using sodium cyanide in DMSO. 2-Methyl(d3)-4- hydroxyacetophenone was finally converted into 2CD3-4T2Me-K by etherification. 0 Br CD3 CDJ 1. n-BuLi g 1' A103 : 2. CD31 2. Acetic Anhyn'de OMe 0M9 OMe O NaCN CD CD 0 3 i tether 3 DMSO ‘potassium carbonate OH 203-4T2uo-K 2CN-4T2Me-K was prepared by acylating m-anisidine using boron trichloride and acetyl cloride, followed by deprotection of the hydroxy group using aluminium chloride. The resulting 2-amino—4—hydroxyacetophenone was then converted to 2—amino-4— 30 (3'—methyl-3'-buten-1'-oxy)acetophenone by an etherification. Finally, the amino group was transformed to a nitrile by a Sandmeyer reaction. 0 o NH2 ’ NH2 1. BC13 A103 NH? > ——> 2. Acetyl Chloride OMe OH 0M9 3.A1Cl3 tether O 1. HCl 0 K2C03 <——— )..C. 2. NaNOz 3. CuCN, NaCN 2cu-4rm-K 2CF3-4T2Me-K was prepared by bromination of 3-trifluoromethylphenol in carbon disulfide at 0°C, followed by etherification. The resulting compound, 1-bromo-2- trifluoromethyl-4—(3'-methyl-3'-buten-l'-oxy)benzene was lithiated and quenched with acetic anhydride to give 2CF3-4T2Me-K. Br Br CF3 CF3 CF3 tether ll BIZ : C52 Potassium Carbonate OH 2,6Me-4T2Me-K was prepared by several steps as shown below. 3,5- dimethylphenol was protected and then brominated para to the methoxy group by NBS. 31 The resulting compound was converted to 2,6-dimethyl-4-hydroxyacetophenone by lithium-halogen exchange, nucleophilic substitution, and deprotection. Finally, coupling of the phenol with 4-tosyl-2-methyl-l-butene provided 2,6Me-4T2Me-K. Iodomethane : NBS — Potassium Carbonate CC14 ' OH 0M8 0M8 n-BuLi 21-4T2Me-K was prepared in the same manner as 2CF3-4T2Me-K. This is accomplished by bromination, etherification, and acylation by way of a lithium-halogen exchange. Bf Br Br2 tether k cs; Potassium CarbonaTe 0:4 0H 03’ ll 32 4T2N(CN)-K was prepared in several steps as shown below. Etherification of 4- hydroxyacetophenone with 3-bromo-2,2-dimethylpropan-l-ol provided 3-(4'- acetylphenoxy)-2,2-dimethylpropan-l-ol, which was then oxidized to an aldehyde using PCC. The resulting compound, 3-(4'-acetylphenoxy)-2,2-dimethylpropanal was ultimately converted to 4T2N(CN)-K via a modified Wittig reaction. 0 o o 6 Br 0 H 6 FCC ______.>. ——> o H o 0 >04, A n-BuLi fl. diethyl cyanomethylphosphoate 4T2N(Et)-K and 4T2N(F)-K were prepared by coupling 4- NC hydroxyacetophenone with cis-6—bromo-3-hexene and 4-bromo-1,1,2-trifluoro-l-butene respectively. Potassium carbonate was used as a base in both cases to deprotonate the phenoL F O 0 Br / O F F ‘———-’ ——> / K2C03 K2C03 F 0 H / F 33 Characterization of Products Derivatives of para-alkenoxyacetophenones (0.01-0.02 M solutions in deuterated methanol or benzene) were irradiated in NMR tubes with a medium pressure mercury arc filtered through Pyrex. Generally, the majority of the starting ketone disappeared after five hours of irradiation, and analogs of 1-acetyl-8-oxau'icyclo[7.2.0.05’9] undeca-2,10-diene were formed. Products arising from y—hydrogen abstraction were also observed with reactants bearing an ortho alkyl group.59’ 60 Large scale irradiations were performed using 0.2-0.3 g of ketone in argon-bubbled methanol or benzene. The photoproducts were isolated by column chromatography or preparative TLC using hexane/ethyl acetate as the eluent. All reactants and photoproducts were characterized by 1H NMR (300MHz), 13C NMR (75MHz), FTIR, mass spectrometry and UV-visible spectroscopy depending upon their thermal stability. The regioselectivity of addition was determined by the relative ratios of the cyclobutene photoproducts or the relative ratios of the corresponding thermal products. There are four cyclobutene structures possible from this two photon process. Each cyclobutene has an unique vinyl resonance--having distinct coupling constants and chemical shifts. Predicted chemical shifts and coupling constants for each possible product are shown in the scheme below. Cyclobutenes CB-t and LCB-t arise from cyclization of the double bond toward the ortho substituent CB-t has three vinyl protons: two doublets at ~6.2 and ~6.4 ppm and a doublet of doublets at ~5.8 ppm. The two doublets are weakly coupled to one another (3 Hz), which is characteristic of vinyl coupling in cyclobutene.61 Alternatively, LCB-t has only one vinyl proton which is shifted upfield due to its enol-ether character. It has two allylic couplings of ~6.3 and ~2.5 Hz. Thermal ring opening of either LCB-t and CB-t results in the formation of the cyclooctatriene isomer, COT-t. COT-t has three vinyl protons: a downfield doublet at ~6.9 ppm , a doublet of doublets at ~5.8 ppm and an 34 upfield doublet at ~S.3 ppm. Two of the vinyl protons are coupled to one another with a ~7 Hz coupling constant. 0 O 0 o 0 “V \ \ 0 w = H +— / A a o . R H hv// CH-t (XJT-t CB-t LCB-t 8~5.3, d, J~7Hz 5~6.2, d, J~3Hz 6~5.2.dd. J~6.3 & 2.5Hz 8~6.9, d, J~7Hz MA. (1, J~3Hz )‘tg/s 8~5.8, dd, J~7.8 & 5H2 8~5.8, dd, J~6 & 3H2 m\\ m—‘fing—‘fi/S: ..\ CH-a C0T~a CB-a LCB-a 8~5.3, bs 86.3, bs 8~7,bs 8~5.8, d, J~13Hz 8~5.8, dd, J~10 & 3Hz 6~5.2,d, J~2.5Hz 8~5.9,ddd, J~13, 8 & 5H2 5~5.9, ddd, J~10, 6 & 3Hz CB-a and LCB-a arise from cyclization of the remote olefin away from the ortho ring substituent. CB-a has three vinyl protons: a broad singlet at ~6.3 ppm, a doublet of doublets of doublets at 5.9 ppm and a doublet of doublets at ~5.8 ppm. The two multiplets are coupled to one another with roughly a 10 Hz coupling, characteristic of vinyl coupling in a cyclohexene ring.61 LCB-a has two vinyl protons positioned at opposite ends of the olefin region: a downfield singlet (~7 ppm) due to its conjugation with the acetyl group and an upfield doublet at ~5.2 ppm. This vinyl proton is coupled allylically to the six-five bridge-head proton. Thermal ring opening of CB-a and LCB-a produces its valence tautomer, COT-a. COT-a has three vinyl protons similar to COT-t, however, their chemical shifts and couplings are dramatically different. The three vinyl protons in COT-a are grouped closely together between 6.0 and 5.0 ppm. The two multiplets, the doublet at date tcsu dim 35 ~5.8 ppm and the doublet of a doublet of doublets at ~5.9 ppm are coupled together with a large 13 Hz coupling constant. This coupling is characteristic of vinyl coupling in cis- cyclooctatriene.61 The stereochemistry of the photostable tricyclo[7.2.0.05v9] octa-2,10-diene was determined by nOe studies. In all cases, disrotatory photoclosure of the cyclooctatriene resulted in formation of a cis 4/6 ring fusion. In fact, closure occurred in only one direction to form a cis 5/6 ring fusion. In some instances, rapid thermal ring opening of the cyclobutenes prevented stereochemical elucidation by nOe. The stereochemistry of these compounds was determined by comparing their chemical shifts and coupling constants to cyclobutenes previously characterized by nOe. Photochemistry of 20Me-4T2Me-K in methanol Methanol A ‘ O O hv (pyrex) r 10 0 M60 20Me-4T2Me-K 20Me-4T2Me-CB A solution of 20Me-4T2Me-K (2.6 mg in 1 mL solvent) in methanol-d4 was purged with argon and irradiated with a medium pressure mercury are filtered through Pyrex. A single photoproduct was observed by 1H NMR after eight hours of irradiation at room temperature. The product was characterized as l-acetyl-5-methyl-2-methoxy-8- oxatricyclo[7.2.0.05v9] undeca-2,10—diene, 20Me-4T2Me-CB. Preparatory scale photolysis (850 mg in 300 mL solvent) was carried out through Pyrex to isolate 20Me- 4T2Me-CB. After 28 hours of irradiation, the reaction mixture was concentrated under 36 reduced pressure. 1H NMR showed the presence of the starting ketone and its photoproduct, 20Me-4T2Me-CB. Purification of the reaction mixture by silica gel chromatography afforded a mixture of products arising from the decomposition of 20Me- 4T2Me-CB. The decomposition products were determined to be 20Me-4T2Me-CH and 20Me-4T2Me-COT. * Photoproduct 20Me-4T2Me-CB was identified by its characteristic 1H NMR. It showed signals corresponding to three vinyl protons: a doublet at 6.35 ppm(H-lO), a doublet at 6.23 ppm(H-l 1) and a doublet of doublets at 4.75 ppm(H-3). Peaks at 6.35 and 6.23 ppm are coupled to one another with a 3 Hz coupling constant. This AB quartet pattern uniquely identifies angular cyclobutenes arising from cyclization toward the ring substitutent. The signal at 4.75 ppm is assigned to a proton on an enol ether based on its upfield shift. Homonuclear decoupling experiments indicate that proton (H-3) is coupled to vicinal protons H~40t and H-4B with 6.1 and 3.2 Hz coupling constants. Due to the thermal instability of 20Me-4T2Me-CB, nOe studies could not be profonned. The stereochemistry of 20Me-4T2Me-CB was determined by comparison of chemical shifts and coupling constants to those obtained through nOe characterizations of other cyclobutenes. Thermal Chemistry of 20Me-4T2Me-CB The crude photolysis mixture of 20Me-4T2Me-K and 20Me-4T2Me-CB was dissolved in methanol, purged with argon and heated at 50°C in a constant temperature bath. After complete disappearance of 20Me-4T2Me-CB as determined by TLC, the reaction mixture was purified by column chromatography. Two products were isolated as an equilibrium mixture; a 1:1 ratio was determined by integration of the vinyl protons in the 1H NMR spectra. The thermal products were identified as 4-acetyl-5-methoxy-8- methyl-1l-oxatricyclo[6.3.0.0196]undeca-2,4-diene, 20Me-4T2Me-CH and 4-acetyl-5- methoxy-8-methyl-l l-oxabicyclo[6.3.0] undeca- l ,3,5-triene, 20Me-4T2Me-COT. 37 O OMe6 20MC-4T2Me'CB 20M0'4T2M2'COT 20Me'4T2Me'CH 1] Their structures were identified based on characteristic chemical shifts and couplings in their 1H NMR spectra. The fact that the cyclohexadiene and cyclooctatriene are in a 1:1 equilibrium made proton assignment difficult especially for the methylenes in the five membered ring. 1H NMR of the equilibrium mixture showed five signals corresponding to vinyl protons: a doublet at 7.2 ppm(H-3COT), a doublet at 6.7 ppm (H- 3CH), a doublet of doublets at 5.24 ppm(H-ZCH), a doublet of doublets at 5.24 ppm (H- 6c()'1‘) and a doublet at 5.1 ppm(H-ZCQT). Homonuclear decoupling experiments indicate that the peak frequencies at 6.7 ppm(H-3CH) and 5.24 ppm(H-ZCH) are coupled to each other (10 Hz). This coupling uniquely identifies a cyclohexadiene arising from thermal ring opening of cyclobutene (CB-t). The two vinyl protons at opposite ends of the vinyl region, H-3C()T and H-ZCOT. are coupled to one another (5.3 Hz). The large upfield shift of proton H-ZCOT is indicative of an enol ether proton. The other remaining signal for vinyl proton H-6COT is coupled to two vicinal allylic protons H—70tand H-7B with 9.3 and 7.1Hz coupling constants. id: 41 4T 51.1 at 4T 38 Photochemistry of 2Me-4Tzfl-K Irradiation of 2Me-4T2H-K (~0.01 M) in argon-purged methanol through a Pyrex filter provided a single photoproduct after three hours (50% completion). This was identified as 1-acetyl-2-methyl-8-oxatricyclo[7.2.0.09’5] undeca-2,10-diene, 2Me- 4T2H-CB, based on its 1H NMR spectrum. Large scale photolysis (0.5 g per 300 mL solvent) of 2Me-4T2H-K in argon-purged methanol was carried out to isolate 2Me- 4T2H-CB. The reaction was monitored by gas chromatography. At near depletion of the starting material, the reaction mixture was concentrated in vacuo. 1H NMR analysis of the reaction mixture showed the presence of 2Me-4T2H-K and its photoproduct, 2Me- 4T2H-CB. 2Me-4Tzfi-CB was converted to its thermal product, 2Me-4T2H-COT, before isolation (see below). / Methanol y ‘ O O hv (pyrex) r 10 . O 2Me' 4T2H-K 2Me'4T2H'CB The photoproduct, 2Me-4T2H-CB was identified based on its 1H NMR spectrum. It showed signals corresponding to three vinyl protons: a doublet at 6.5 ppm(H- 10), a doublet at 6.3 ppm(H-l 1), and a quartet of doublets of doublets at 5.6 ppm (H-3). Frequencies at 6.5 and 6.3 ppm are coupled to one another (3 Hz). This AB quartet pattern was seen in 20Me-4T2H-CB and uniquely identifies angular cyclobutene arising from cycloaddition toward the ortho substituent. Homonuclear decoupling experiments on the peak frequency at 5.62 ppm indicate that this proton is coupled to two adjacent vicinal protons (II-4a and H-4B) with J=4.4 and 4.4 Hz respectively. It is also coupled allylically 39 to protons of the vinylic methyl (J=1.6 Hz). This vinyl pattern was also seen in 2Me- 4T2Me-CB, 2,5Me-4T2H-CB, and 2Me-4T2H-SI-CB-t. Thermal Chemistry of 2Me-4T2H-CB A crude photolysis mixture of 2Me-4T2H-CB and 2Me-4T2H-K was dissolved in methanol (300 mL), purged with argon, and heated in a constant temperature bath at 50°C. The reaction progress was monitored by thin layer chromatography. After complete conversion of 2Me-4T2H-CB (4 hours), the reaction mixture was purified by column chromatography (hexanes: ethyl acetate, 85:15). A single product was identified as 4—acetyl-5-methyl-l1-oxabicyclo[6.3.0]undeca-1,3,5-tn'ene, 2Me-4T2H-COT (134 mg, 27% yield based on starting ketone). Methanol fl The product was characterized by MS, UV—Vis and by NMR spectroscopy. 2Me- 4T2H-COT has the same molecular ion peak as the starting ketone, 2Me-4T2H-K. Six signals were observed in the vinyl region (165.7, 138.7, 137.7, 136.7, 127.3, and 94.7 ppm) in the 13C N MR spectrum. A peak frequency corresponding to the acetyl group at 198.5 ppm was also observed. 1H NMR of 2Me-4Tzn-COT showed the presence of three signals corresponding to vinyl protons: a doublet of doublets at 6.94 ppm (H-3), a quartet of doublets of doublets at 5.94 ppm (H-6) and a doublet of doublets at 5.25 ppm 40 (H—2). The downfield shift of proton H-3 is indicative of a proton that is conjugated to an electron withdrawing group. Homonuclear decoupling experiments indicate that the vinylic hydrogen H-6 is coupled to both vicinal protons H-70t and H-7B with a 9.3 and 6.6 Hz couplings. It is further coupled allylically to the protons of the vinylic methyl group with a 1.5 Hz coupling. The upfield shift of H-2 is indicative of a proton of an enol ether. It is coupled to the upfield proton H-3 (5.6 Hz) and allylically to the eight/five bridgehead proton H-9 (2.1Hz). The UV-Vis spectrum showed a lmax at 320 nm (e~1760) indicative of a highly conjugated system. The excitition coefficient was low in comparison to other cyclooctatrienes isolated in this study. This is due to decomposition of the cyclooctatriene. Photochemistry of 2Me-4T2Me-K in Benzene NMR scale irradiation of 2Me-4T2Me-K (2.1 mg in 1 mL solvent) was carried out in argon-purged benzene-d6 through a Pyrex filter. After three hours of irradiation, 2Me-4T2Me-K was partially converted(~60%) into a single photoproduct. The newly formed product was believed to be 1,2,3,4-tetrahydro-1-methyl-6-(3'-methyl-3'—buten-1'- oxy)-2,3-dioxa-l-naphthol, 2Me-4T2Me-II, arising from hydrogen atom abstraction from the ortho methyl group. Purification of 2Me-4T2Me-II by column chromatography was unsuccessful. No observable 2+2 photocycloaddition products where formed under these conditions. 41 Identification of 2Me-4T2Me-II was accomplished by analysis of the 1H NMR spectrum. Structural comparisions were made with the starting ketone, 2Me-4T2Me-K and previously reported benzocyclobutenols.6’ 62 The 1H NMR spectrum of 2Me- 4T2Me-II showed several diagnostic protons: a downfield AB quartet at 5.1 and 4.3 ppm (J AB=15-5 Hz ) and a methyl singlet at 1.57 ppm. The aromatic protons in 2Me- 4T2Me-Il are shifted upfield compared to 2Me-4T2Me-K. The aromatic protons appear at 6.68(d), 6.67(dd), and 6.2 ppm(d). All other peak resonances in 2Me- 4T2Me-II mirrored the starting ketone having nearly identical chemical shifts for the protons on the tether. Typically, the chemical shifts of methylene protons in benzocyclobuteneols are 2.9 and 3.1 ppm.61’ 62 The dramatic downfield chemical shift of the methylene protons in 2Me-4T2Me-II is due to the proximity of a heteroatom. Photochemistry of 2Me-4T2Me-K in methanol 2Me-4TM-K Irradiation of a 0.01 M solution of 2Me-4T2Me-K in argon-purged methanol resulted in the formation of a single photoproduct after three hours. The product was determined as 1-acetyl-2,5-dimethyl-8-oxatricyclo[7.2.0.09’5] undeca-2,10-diene, 2Me- 4T2Me-CB. Deuterium incorporation was also observed by the rapid depletion of the peak frequency corresponding to the ortho methyl group at 2.5 ppm. Prolonged irradiation caused decomposition of 2Me-4T2Me-K and 2Me-4T2Me-CB. 42 The photoproduct, 2Me-4T2Me-CB was identified based on its 1H NMR spectrum. It showed signals corresponding to three vinyl protons: a doublet at 6.5 ppm, a doublet at 6.3 ppm, and a broad triplet at 5.54 ppm. Frequencies at 6.5 and 6.3 ppm are coupled to one another (3 Hz). This AB quartet pattern has been seen in previous cases and is characteristic of cyclobutenes arising from cyclization toward the substituent.61 Homonuclear decoupling experiments on the peak frequency at 5.54 ppm indicate that this proton is coupled to two adjacent vicinal protons (H-40t and H-4B) with J =4.6 and 4.5 Hz respectively. It is also coupled allylically to protons of the vinylic methyl (J =1.5 Hz). Thermal Chemistry of 2Me-4T2Me-CB Preparatory scale photolysis (245 mg per 75 mL) in purged methanol was carried out to isolate 2Me-4T2Me-CB. At 50% conversion the photolysis was stopped and the solvent removed. 1H NMR analysis of the reaction mixture showed the presence of 2Me- 4T2Me-CB. The photolysis mixture was redissolved in methanol(~0.01 M) and heated at 50°C for two hours. Purification of the mixture by silica gel chromatography provided an equilibrium mixture of 4-acetyl-5,8-dimethyl-1 1-oxatricyclo[6.3.0.01’6]undeca-2,4-diene, 2Me-4T2Me-CH and 4-acety1-5,8-dimethyl-1l-oxabicyclo[6.3.0] undeca-1,3,5-triene, 2Me-4T2Me-COT in 1:7 ratio as determined by integration of the vinyl protons. 2Me'4T2Me'CB 2Me'4T2Me'COT 2Me'4T2Me'CH 1] 43 The thermal product, 2Me-4T2Me-COT, was fully characterized by 1H NMR, 13C NMR, IR, MS and UV-Vis spectroscopy. 2Me-4T2Me-COT has the same molecular ion peak as 2Me-4T2Me-K. 1H NMR showed the presence of three vinyl protons: a doublet at 6.95 ppm (H-3), a quartet of doublets of doublets at 5.9 ppm (H-6), and a doublet at 5.1 ppm (H—2). Homonuclear decoupling experiments show that protons H-3 and H-2 are coupled (5.1 Hz). Again, chemical shifts of these two protons are diagnostic. The large downfield shift of proton H-3 indicates conjugation with the acetyl group. Likewise, the upfield shift of the vinyl proton H-2 is indicative of a proton of a enol ether. The chemical shifts and couplings of these two protons uniquely identifies cyclooctatrienes arising from cyclization toward the ring substituents. The signal corresponding to proton H-6 (5.9 ppm) is coupled to two vicinal protons H-70t and H-7B (J=9.5 and 6.3 Hz). Weak allylic coupling (1.6 Hz) afforded by the adjacent methyl is also observed for proton H-6. 13C NMR further confirmed the structural assignment. Six peak signals were observed in the vinylic region, one of which is shifted considerable upfield (93 ppm). A peak corresponding to the acetyl group (198 ppm) was also observed. UV-Visible spectroscopy showed a Kmax at 321 nm (e~5300) and the IR showed a carbonyl stretch at l672cm‘1 both of which are indicative of a highly conjugated system. The structure of the minor thermal product, 2Me-4T2Me-CH, was assigned, based on it 1H NMR. The spectrum showed two signals corresponding to vinyl protons: a doublet at 6.3 Hz (H-3) and a doublet at 5.3 Hz (H-2). The two protons are coupled to one another (10 Hz), characteristic of vinyl protons in a cis cyclohexene.61 Photochemistry of 2CD3-4T2Me-K Similiar photochemistry was observed for 2CD3-4T2Me-K as for 2Me- 4T2Me-K. Irradiation of 2CD3-4T2Me-K (0.015 M) in benzene through a Pyrex filter resulted in the partial formation (~40%) of 2CD3-4T2Me-II after three hours. Products arising from ortho 2+2 cycloaddition were not observed. Benzene O hv (pyrex) O 030 zoos-“max Irradiation of 2CD3-4T2Me-K (~0.01 M) in argon purged methanol provided a single photoproduct in the same fashion as 2Me-4T2Me-K . The product was indentified as 2CD3-4T2Me-CB based on comparison to the 1H NMR spectrum of 2Me-4T2Me- CB. The chemical shifts and couplings observed in the 1H NMR of 2CD3-4T2Me-CB and 2Me-4T2Me-CB are similar. Photochemistry of 2,5Me-4T2H-K in methanol Compound 2,5Me-4T211-K provided a model compound to determine the relative effects of alkyl substituents at the ortho and meta positions. Photolysis of 2,5Me- 4T2H-K (0.0098 M) in argon-purged methanol through a Pyrex filter provided a single photoproduct after eight hours. This was identified as l-acetyl-2,10—dimethy1-8- oxatricyclo[7.2.0.09t5] undeca-2,10-diene, 2,5Me-4T2H-CB. Thus, a methyl group ortho to the acetyl suppressed the selectivity associated with a methyl ortho to the tether.31 Large scale photolysis (1 g per 500 mL solvent) of 2,5Me-4T2H-K in argon-purged methanol afforded 2,5Me-4T2H-CB (365 mg, 37%) after purification by dry column flash chromatography (hexaneszethyl acetate, 80:20). Sr: ‘ I Ch; 45 2,5MC'4T2H-K 2,5Me-4T2H-CB Characterization of 2,5Me-4T2H-CB was accomplished by 1H NMR and 13C NMR. A structural comparison can be made between 2Me-4T2H-SI-CB-t and 2,5Me- 4Tzfi-CB. 1H NMR showed signals corresponding to two vinyl protons: a quartet at 6.1 ppm (H-ll) and a quartet of doublets of doublets at 5.6 ppm (H-3). Homonuclear decoupling experiments on the peak frequency at 5.6 ppm(H-3) indicate that it is coupled to two adjacent vicinal protons (HM and H-4B) with a 5.8 (2.2 ppm) and 4.0 Hz (1.9 ppm). It is also coupled allylically to protons of the vinylic methyl (1.6 ppm). A similar coupling pattern was observed in the spectra for 2Me-4T2H-CB and 2Me-4T2H-SI-CB-t. Proton (H-1 1) is found to be coupled allyically to the vinylic methyl group. Five signals were observed in the vinyl region (151, 137, 131, 124, and 123 ppm) in the 13C NMR spectrum. A peak frequency corresponding to the acetyl group at 212 ppm was also observed. The stereochemistry of 2,5Me-4T2H-CB was determined by nOe experiments. Irradiation of the methyl group on C-10 afforded enhancements at H-11(1.75%), H-7 (1.36%), and the bridgehead proton H-5 (2.85%). Thus indicating that the cyclobutene ring is cis to bridgehead proton H-5. 01“ C01 [I'll 46 Thermal Chemistry of 2,5Me-4T2H-CB A solution of 2,5Me-4T2H-CB (30 mg per 50 mL solvent) in argon-purged methanol was heated at 50°C for 48 hours. 1H NMR analysis showed little thermal ring opening. Addition of a catalytic amount of para- toluenesulfonic acid caused rapid conversion of 2,5Me-4T2H-CB to 2,5Me-4Tzn-COT. Purification of the reaction mixture by thin layer chromatography provided 2,5Me-4T2H-COT (26 mg, 88%). O C .Ha / 0 CH3 2,5MC'4T2Me'CB 2,5Me-4T2Me-COT The structure was characterized by MS, IR, UV-Vis and by NMR spectroscopy. 2,5Me-4T2H-COT has the same molecular ion peak as the starting ketone, 2,5Me- 4T2H-K in the mass spectrum. The 1H NMR of 2,5Me-4Tzfi-COT showed signals corresponding to two vinyl protons: a broad singlet at 6.9 ppm (H-3) and a quartet of doublets of doublets at 5.9 ppm (H6). The downfield shift of proton H-3 is indicative of a proton that is conjugated to an electron withdrawing group. Homonuclear decoupling experiments indicate that the vinylic proton H-6 is coupled to both vicinal protons (H-70t and H-7B) with a 9.3 and 6.7 Hz coupling. It is further coupled allylically to the vinylic methyl group. Six signals were observed in the vinyl region (158, 142, 139, 137, 126, and 102 ppm) in the 13C NMR spectrum. A frequency corresponding to the acetyl group at 199 ppm was also observed. UV-Vis spectroscopy showed a Kmax at 329 nm (e~5400) indicative of a highly conjugated system. The presence of an acetyl group was further confirmed by a carbonyl stretch at 1660 cm‘1 by IR. 47 Photochemistry of 2,5Me-4T2Me-K Photolysis of 2,5Me-4T2Me-K (~0.01 M) in argon-purged benzene or methanol resulted in no observable photoproducts by 1H NMR at extended periods (>20 hours). The methyl group on the double bond of 2,5Me-4T2Me-K appears to suppress the photocycloaddition process. Similar results have been seen elsewhere in an analogous system.3 1 0 >290nm O ——-> No Reaction solvent 2,5MC'4T2Me-K Photochemistry of 2Me-4T2H-SI-K in methanol A solution of 2Me-4T2H-SI-K (2.6mg per lmL solvent) in CD3OD was degassed with argon and irradiated through Pyrex. Reaction progress was monitored by time resolved 1H NMR. 1H NMR analysis showed the presence of two photoproducts in a ratio of 1.25:1 after four hours of irradiation. The cyclobutene photoproducts were identified as 1-acetyl-3-isopropyl-l1-methyl-8-oxatlicyclo[7.2.0.09’5] undeca-2,10—diene, 2Me-4T2H-SI-CB-a and l-acetyl-10—isopropyl-2-methyl-8-oxatricyclo[7.2.0.09’5] undeca-2,10-diene, 2Me-4T2H-SI-CB-t respectively. In this case, there is a slight preference for cyclization away from the ortho substituent. Preparatory scale photoylsis (1.2g per 500mL) in argon-purged methanol afforded 2Me-4T2H-SI-CB-t (0.218g) and 2Me-4T2H-SI-CB-a (0.273g) in 41% yield overall after purification by silca gel chromatography. .4» O O Methanol 2 O hv (pyrex) . 4 1t ,. F H O E H 8 \———.6 ' 8 \—_.:6 2Me-4Tzn-SI-K 2Me-4T2H-51-CB-t 2Me-4Tzn-51-CB-a 1.00 2 1.25 Characterization of 2Me-4T2H-SI-CB-t was accomplished by 1H NMR, IR and Mass spectroscopy. A structural comparison can be made between 2Me-4T2H-SI-CB-t and 2,5Me-4T2H-CB. The IR spectrum had a strong absorbance at 1700cm'1 indicative of a nonconjugated carbonyl compound. An identical molecular ion peak to the starting ketone was found in the mass spectrum. 1H NMR showed signals corresponding to two vinyl protons: a doublet at 6 ppm (H-1 1) and a quartet of doublets of doublets at 5.3 ppm (H-3). Homonuclear decoupling experiments on the peak frequency at 5.3 ppm(H-3) indicate that it is coupled to two adjacent vicinal protons (H-40t and H-4[3) with a 4.2 (1.8 ppm) and 4.0 Hz (1.6 ppm). It is also coupled allylically to protons of the vinylic methyl (1.6 ppm). A similar coupling pattern was observed in the spectra for 2,5Me-4T2H-CB and 2Me-4T2H-CB. Proton (H-1 1) is found to be coupled allyically to the methine proton of the adjacent isopropyl group. The 1H NMR of lAP-2Me-4T2H-SIPr-CB-a showed signals corresponding to two vinyl protons: a doublet of a quartet at 5.8 ppm (H-10) and a broad singlet at 5.6 ppm (H-2). Homonuclear decoupling experiments suggest that proton H-3 is coupled allylically to the five/six bridgehead proton (H-5), and to the vinylic methyl at 1.5 ppm. 2Me- 4T2H-SI-CB-a has the same molecular ion peak as the starting ketone, 2Me-4T2H-SI- K. 49 Thermal Chemistry of 2Me-4Tzn-SI-CB-a A solution of 2Me-4T23-SI-CB-a (270mg per 100mL solvent) in argon-purged benzene was heated 50°C in a constant temperature water bath. After 48 hours, NMR analysis showed little thermal ring opening. Addition of a catalytic amount of para- toluenesulfonic acid caused the rapid conversion of 2Me-4T2H-SI-CB-a to 2Me- 4Tzfl-SI-COT-a. Purification of the reaction mixture by thin layer chromatography provided 2Me-4T2H-SI-COT-a (170.6mg, 63%). \ Benzene I __. 0.. . 50 C \ .. H 2Me-4Tzrl-SI-CB-a 2Me-4T2n-51-COT-a The structure was identified based on its MS, UV-Vis, and 1H-NMR spectra. 2Me-4T2H-SI-COT-a has the same molecular ion peak as the starting ketone,2Me- 4T2H-SI-K and 2Me-4T2H-SI-CB-a by mass spectroscopy. The UV-Vis spectrum showed a Kmax at 313.5 nm (8~4810) indicative of a highly conjugated system. The 1H NMR of 2Me-4T2H-51-COT-a showed signals corresponding to two vinyl protons: a broad singlet at 6 ppm (H-5) and a singlet at 5.4 ppm (H-2). The upfield chemical shift of H-2 is indicative of an enol ether proton. Proton H-5 is weakly coupled to allylic protons H-70t and H-7B. There are distinct differences in the spectra for 2Me-4T2H-SI-COT-a and its regioisomer 2Me-4T2H-SI-COT-t discribed below. 50 Thermal Chemistry of 2Me-4Tzn-51-CB-t The thermal ring opening of 2Me-4T2H-SI-CB-t to 2Me-4T2H-SI-COT-t was sluggish at 50°C in benzene. After 24 hours of heating only a small amount (<25%) of 2Me-4T2H-SI-COT-t was present by 1H NMR analysis. However, addition of a catalytic amount of para-toluenesulfonic acid caused rapid ring opening to 2Me-4T2H- SI-COT-t. Purification of the reaction by silica gel column chromatography gave 2Me- 4T2H-51-COT-t in 79% yield. 2Me—4Tzn-SI-CB-t 2Me-4Tzn-SI-COT-t The structure was characterized by MS, IR, UV-Vis and by NMR spectroscopy. A direct structural comparison can be made with 2,5Me-4Tzn-COT. 2Me-4T2H-SI- COT-t has the same molecular ion peak as the starting ketone, 2Me-4T2H-SI-K. Six signals were observed in the vinyl region (156.2, 141.2, 139.2, 136.3, 126.1, and 112.6 ppm) in the 13C NMR spectrum. A signal corresponding to the acetyl group at 199 ppm was also observed. 1H NMR of 2Me-4T2H-SI-COT-t showed signals corresponding to two vinyl protons: a broad singlet at 7 ppm (H-3) and a quartet of doublets of doublets at 5.7 ppm (I-l-6). The downfield shift of proton H-3 is indicative of a proton that is conjugated to an electron withdrawing group. Homonuclear decoupling experiments suggest that the vinylic hydrogen H-6 is coupled to both vicinal protons H—70t (6.3 Hz) and H—7B (5.1 Hz). It is further coupled allylically to the protons of the vinylic methyl group with a 1.6 Hz coupling. The UV-Vis spectrum showed a Xmax at 330.5 nm (e~5750) 51 indicative of a highly conjugated system. An acetyl group was further confirmed by a carbonyl stretch at 1670cm'1. Photochemistry of 2Me-4T2Me-SI-K Photolysis of 2Me-4T2Me-SI-K (~0.015M) in argon-purged benzene or methanol resulted in no observable photoproducts by 1H NMR at extended periods (>20 hours). The methyl group on the double bond of 2Me-4T2Me-SI-K appears to suppress the photocycloaddition process, as seen previously seen for 2,5Me-4T2Me-K. 2Me-4T2Me-SI-K Photochemistry of 2,6Me-4T2Me-K Irradiation of a 0.01M solution of 2,6Me-4T2Me-K in argon-purged benzene resulted in the formation of a single photoproduct after five hours. A single product was determined to be 2'-methyl-4'-(3'-methyl-3'-buten-1'-oxy)-1-methylbenzocyclobutenol, 2,6Me-4T2Me-II, arising from hydrogen abstraction from an ortho methyl group. No observable 2+2 photocycloaddition products where formed under these conditions. Similarly, NMR scale photolysis of 2,6Me-4T2Me-K (2.1mg in lmL solvent) was carried out in argon-purged methanol-d4 through a Pyrex filter. Deuterium incorporation was observed by the depletion of the peak resonance corresponding to the ortho methyl group. No photoproducts arising from ortho 2+2 cyloaddition were observed by 1H NMR after ten hours. 52 Benzene _ H . Q 0 hv (pyrexY ‘6 0 O 2,6Me'4T2Me' K 2’6Me‘4T2Me'II Photoproduct 2,6Me-4T2Me-II was identified by its characteristic 1H NMR. A direct structural comparison can be made with 2'-methyl-4'-methoxy-1- methylbenzocyclobutenol, obtained from photolysis of 2,6-dimethyl-4- methoxyacetophenone.62 The 1H NMR of 2,6Me-4T2Me-II showed several diagnostic protons: an AB quartet of 13.8 Hz at 3.0 and 2.9 ppm and a methyl singlet at 1.56 ppm. All other peak resonances in 2,6Me-4T2Me-II mirrored the starting ketone. Typically, the chemical shifts for the methylene protons in benzocyclobutenols are 2.9 and 3.1 ppmcl, 62 Photochemistry of 2CN-4T2Me-K NMR scale photolysis of 2CN-4T2Me-K (2mg ketone per 0.75mL solvent) was carried out in argon-purged methanol or benzene at 313 nm or through Pyrex. The progress of the reactions was monitored by 1H NMR. At either of the four reaction conditions, no photocycloaddition was observed. 2CN-4T2Me-K remained photostable after long periods of irradiation (>20 hours). 53 Solvent . HO hv (pyrex) r No Reaction 0 Photochemistry of Indanone-3Me-5T2Me A solution of Indanone-3Me-5T2Me (1.9mg per 0.75mL solvent) in CD3OD was degassed with argon and irradiated at 300 nm in a Rayonet. The reaction was monitored by time resolved 1H NMR. Analysis showed the presence of two photproducts in ratio of 1:1 after sixteen hours. The cyclooctatriene photoproducts were identified as trans-4,1 l-dimethyl-14—oxatricyclo[9.3.0.03v7]tetradecatri-1,3,8-ene-6-one, Indanone- COT-trans, and cis-4,11-dimethy1-14-oxatricyclo [9.3.0.017] tetradecatri-1,3,8-ene-6- one, Indanone-COT-cis. Attempts to separate the diastereomers were unsuccessful by either alumina or silica gel column chromatography. l4 2 O 14 ,' 4 p Methanol ‘ 12 .0 O hv (300an a 10 15 O 8 hndanone-3Me-5T2M. Indanone-COT-cis Indanone-COT-trans 1 : 1 The 1H NMR of the diastereomeric mixture shows distinct vinyl signal pairs: two doublets of triplets at 6.4 and 6.2 ppm (H-8cis and H-Suans), two overlapping doublet of 54 doublets of doublets at 5.9 ppm (H-9cis and H-9trans) and two singlets at 5.6 and 5.5 ppm (H-zcis and Hams). The chemical shifts of the two singlet protons are diagnostic. The upfield shift of these protons are indicative of vinyl protons of enol ethers. Homonuclear decoupling of the vinyl pairs indicates that H-8 and H-9 are strongly coupled to each other with a coupling of 12 Hz. This coupling constant is characteristic of vinyl protons of cis- cyclooctene and uniquely identifies cyclooctatriene arising from cyclization away from the ortho substituent. The adjacent methylene protons, H-100t and H-lOB, are coupled allylically to H-8 and vinylically to H-9. The methyl protons for cis- and trans- cyclooctatriene also have distinct signals. The signals for the eight/five bridgehead methyls are at 1.20 and 1.17 ppm. The cyclopentanone methyls in cis- and trans-Indanone-COT appear as doublets (7 Hz coupling) at 1.21 and 1.23 ppm. Photochemistry of 2F-4T2Me-K Irradiation of a solution of 2F-4T2Me-K (2.2mg) in argon-purged methanol (lmL) provided two products in a ratio of 10:1 after three hours. The products were identified as 1-acetyl-2-fluoro-5-methy1-8-oxatricyclo[7.2.0.05t9]undeca-2,10-diene , 2F-4T2Me-CB-t, and its regioisomer 1-acety1-1 1-f1uoro-5-methyl-8- oxatlicyclo[7.2.0.05t9]undeca-2,10-diene, 2F-4T2Me-CB-a respectively. Methanol _ ‘ O O hv (pyrexr 10‘ O 2F'4T2Me'K 2F-4T2Me-CB-t ZF- 4T2Me-CB-a 10 : 1 55 Difficultly arose in characterizing the minor cyclobutene regioisomer, 2F-4T2Me- CB-a, due to extensive overlap of the peak frequencies in the 1H NMR's aliphatic region by the major isomer. The two regioisomers can be distinguished based on the couplings of the vinyl protons. The major isomer, 2F-4T2Me-CB-t, has three signals in the vinyl region: an AB quartet at 6.5 (H-10) and 6.35 ppm (H-ll) with a 2.9 Hz coupling and a doublet of doublets of doublets at 5.3 ppm. The AB quartet coupling is characteristic of vinyl protons of a cyclobutene ring. The multiplet at 5.3 ppm (H-2) is coupled to the vicinal protons, H-401 and H-4B with a 6.5 and 2.8 Hz coupling. A strong fluorine coupling of 15.6 Hz is also observed in H3. The minor regioisomer, 2F-4T2Me-CB-a, has a characteristic coupling between two vinyl protons (H-2 and H-3) of 10 Hz. This coupling is indicative of vinyl protons in a cis-cyclohexene ring.61 Proton H-2 (5.65 ppm) is coupled allyically to only one of the methylene protons at C-4. Proton H-3 is coupled to both vicinal protons H-40t and H-4B (6.7 and 2.4 Hz). The coupling between H-10 and fluorine was not determined. Thermal Chemistry of 2F-4T2Me-CB-t A dry methanol solution of 2F-4T2Me-K (700mg per 300mL solvent) was bubbled with argon and irradiated through a Pyrex filter until ~90% conversion (by GC). 1H NMR analysis of the reation showed the presence of the starting ketone and 2F- 4T2Me-CB-t. The reaction mixture was then heated at 50°C in argon-purged methanol (200mL) for five hours. Purification of the crude reaction mixture by dry column flash chromatography (ethyl acetatezhexanes, 5:95) gave a 1:1 ratio of 4-acetyl-5-fluoro-8- methyl-11-oxatricyclo[6.3.0.01’6]undeca-2,4-diene, 2F-4T2Me-CH and 4-acetyl-5- fluoro-8-methy1-l1-oxabicyclo[6.3.0] undeca-1,3,5-triene, 2F-4T2Me-COT in 36% yield (254mg). 56 2F-4T2Me-COT 2F-4T2Me-CH The thermal products 2F-4T2Me-COT and 2F-4T2Me-CH were identified based on their characteristic chemical shifts and couplings in the 1H NMR. The fact that the cyclohexadiene and cyclooctatriene are in a 1:1 equilibrium made proton assignment difficult especially for the methylenes in the five membered ring. 1H NMR of the equilibrium mixture showed the presence of five vinyl protons: a doublet of doublets at 7.3 ppm(H-3CQT), a doublet of doublets at 6.5 ppm(H-3CH), a doublet of doublets of doublets at 5.85 ppm (H-6COT), a doublet of doublets at 5.3 ppm(H-ZCH), and a doublet of doublets of doublets at 5.1 ppm(H-ZCOT). Homonuclear decoupling experiments suggest that frequencies at 6.5 ppm(H-3CH) and 5.3 ppm(H-ZCH) are strongly coupled to each other with a coupling of 10 Hz. This coupling is characteristic of vinyl protons on cis—cyclohexene. The two vinyl protons at opposite ends of the vinyl region, H-3CQT and H-ZCOT are coupled to one another (6 Hz). The large upfield shift of proton H-2CQT is indicative of a proton of an enol ether. The other remaining vinyl proton, H-6C()T is coupled to two vicinal protons H-7occ0T and H-7BCOT with a 9.6 and 7.5 Hz coupling. Flourine coupling is observed for all vinyl protons in both 2F-4T2Me-COT and 2F- 4T2Me-CH. A large flourine vinyl coupling of 17 Hz is observed in H-6COT. The 13C NMR provided additional information. Two singlets were observed in the carbonyl region 57 196 (doublet, 3 Hz) and 193 ppm (doublet, 3 Hz). Two C=O stretches were observed in the IR at 1682 and 1678cm-1. Photochemistry of 2CF3-4T2Me-K A solution of 2CF3-4T2Me-K (1.7mg per 0.75mL sclvent) in methanol-d4 was purged with argon and irradiated through a Pyrex filter. A single photoproduct was observed by 1H NMR after twenty-three hours of irradiation at room temperature. The product was characterized as 4-acetyl-5-trifluoromethyl-8-methyl-11-oxabicyclo[6.3.0] undeca-1,3,5-triene, 2CF3-4T2Me-COT. Preparatory scale photolysis (180mg per 60mL solvent) was carried out to isolate 2CF3-4T2Me-COT. Purification of the photolysis mixture by silica gel column chromatography caused decomposition of 2CF3- 4T2Me-COT. The structure of 2CF3-4T2Me-COT was determined from the 1H NMR of the photolysis mixture. F C 3 6 O O Methanol : O 4 hv (pyrex) O 2 F C 3 0 1o lAP-ZCF3-4T2Me lAP-ZCF3-4T2Me-COT Photoproduct 2CF3-4T2Me-COT was identified based on its characteristic 1H NMR. It showed signals corresponding to three vinyl protons: a doublet at 7.2 ppm(H-3), a quartet of doublets of doublets at 6.8 ppm(H-6) and a doublet at 6.23 ppm(H-2). Peak resonances at 7.2 and 5.2 are coupled to one another with a 4.8 Hz coupling constant . This AB quartet pattern uniquely identifies cyclooctatrienes arising from cyclization toward l iti I can, indi Phi wit “it phi wa die 58 the ortho ring substituents. Proton (H-2) is assigned as a proton on an enol ether based on its upfield shift. The downfield shift of proton (H-3) is indicative of a proton that is conjugated to an electron withdrawing group. Homonuclear decoupling experiments indicate that proton (H-6) is coupled to both vicinal protons H-7a and H713 with 9.2 and 6.5 Hz coupling constants. Photochemistry of 21-4T2Me-K A solution of 21-4T2Me-K (2.6mg per 0.75mL solvent) in CD3OD was degassed with argon for fifteen minutes and irradiated using a medium pressure mercury lamp fitted with a Pyrex filter. 1H NMR analysis of the reaction mixture showed only minimal product formation (~10% conversion) after nine hours of irradiation. The major product was identified as 1-acetyl-2-isopropyl-5-methyl-8-oxatricyclo[72.0.095] undeca-2,10- diene, 21-4T2Me-CB. The structure was identified based on its characteristic chemical shifts and coupling constants in the 1H NMR spectrum. The fact that the reaction was so inefficient made proton assignment difficult especially for the methylenes in the five membered ring. 1H NMR showed signals corresponding to three vinyl protons: a doublet at 6.49 ppm(H-10), a doublet at 6.24 ppm(H-ll), and a doublet of doublets of doublets at 5.65 ppm(H-3). Peaks at 6.40 and 6.24 ppm are coupled to one another with a 3 Hz coupling constant. 59 This AB quartet pattern uniquely identifies angular cyclobutenes arising from cyclization toward the ring substituent. Photochemistry of lCN-4T2H in Acetone ‘ NMR scale photolysis of lCN-4T21-1 (2mg benzonitrile per 0.75mL solvent) was carried out in argon-purged acetone-d6 at 313 nm. The reaction progress was monitored by 1H NMR. Analysis showed the presence of two products. The ratio of these products were time dependent. At 20% conversion, the ratio of products was approximately 1:1. Upon prolonged irradiation only one product was present. Attempts were made to isolate both products. Large scale irradiation of 1CN-4T2H (420mg per 160mL solvent) in acetone at 313 nm led to the formation of two products at 25% depletion of the benzonitrile by GC analysis. The reaction mixture was stopped at this point, concentrated, and separated by silica gel colunm chromatography Two products, 1-cyano-8- oxatricyclo[7.2.0.0599]undeca-2,10-diene, 1CN-4Tzn-CB and 4-cyano—1 1- oxabicyclo[6.3.0] undeca-1,3,5-triene, lCN-4T2H-COT, were isolated along with the starting benzonitrile. lCN-4T2H-CB was isolated in 51.5 % when‘lCN-4T2H is irradiated to near completion. / /:I 313nm Acetone N C 1-CN-4T2H l-CN-4T2H-COT l-CN-4T2H-CB 60 Photochemistry of CN-4T2H-COT The fate of CN-4Tzfl-COT was determined by irradiating pure samples in acetone-d6. At low concentrations of 1CN-4T2H-COT (~0.001M), a condition where nearly all incidental light is absorbed by the solvent, 1CN-4T2H-COT underwent diene to cyclobutene ring closure to form 1CN-4T2H-CB at 313 nm irradiation. However, at higher concentrations of 1CN-4T2H-COT (~0.015M), 1CN-4T2H-COT formed lCN-4Tzn-LCB. O 10 C_N 2 8 6 2 ’. 10 . ...m\ 313nm 313nm I > A t O A to 10‘ 4 / ceone ce ne ,. NC 0 NC 4 O _: 4 (0.015M) 6 (0.001M) a y , H 2 6 l-CN-4T2H-LCB l-CN-4T2H-COT 1-CN-4Tm-CB Photoproducts 1CN-4T2H-CB and 1CN-4T2H-COT were characterized using mass spectroscopy and 1H NMR. 1CN-4T2H-CB has the same molecular ion peak as both lCN-4T2f1-COT and lCN-4T2H. 1H NMR of 1CN-4T2H-CB showed the presence of four signals corresponding to vinyl protons: a doublet at 6.26 ppm(H-10), a doublet at 6.11 ppm(H-l 1), a doublet of doublets of doublets at 5.8 ppm(H-3), and a doublet of doublets at 5.75 ppm(H-2). The signals at 6.26 and 6.11 are coupled to one another (2.8 Hz) and characteristic of vinyl protons in a cyclobutene. Likewise, frequencies at 5.8 and 5.75 ppm are coupled (10 Hz). This value is in accord with vinyl coupling in cyclohexene. These two coupling constants uniquely identifes the angular cyclobutene photoproduct. It is interesting to note that H-40t is coupled to the allylic (H-2) in this tricyclic system, whereas H-4B is not. 61 The stereochemistry of 1CN-4T211-CB was elucidated by nOe experiments Irradiation at the resonance corresponding to the six/five bridgehead proton, H-5, produces enhancements at H-40t(0.46%), H-6(2.17%), and the vinyl proton of cyclobutene, H- 11(1.07%). These results indicate that the cyclobutene ring is cis to the bridgehead proton H-S, which further suggests that the six/five ring juncture is cis-fused. The 1H NMR of 1CN-4T2H-COT showed the presence of four vinyl protons: a doublet at 6.6 ppm (H-3), a doublet of doublets of doublets at 5.9 ppm (H-6), a doublet at 5.85 ppm (H-5) and a doublet at 5.3 ppm (H-2). Homonuclear decoupling of these protons indicate that H-6 and H-5 are coupled to each other (12.7 Hz). The magnitude of this coupling is characteristic of vinyl protons of cis-cyclooctene.61 Protons H-3 and H-2 are also shown to be coupled (6.9 Hz). The proton H-2 appears to be a proton of an enol ether based on its chemical shift. The upfield shift of proton H-3 indicates a high degree of deshielding offered by an adjacent electron-withdrawing group. 13C NMR further confirmed this structural assignment. Six singlets were observed in the vinylic region, two of which were shifted considerable upfield (104.34 and 95.72 ppm). A frequency corresponding to the cyano(~121 ppm) was also observed. The UV-Visible spectrum showed a Xmax at 326 nm (e~7500) indicative of a highly conjugated system. Characterization of lCN-4T2H-LCB is presented below. Thermal Chemistry of lCN-4T2H-CB Heating lCN-4T2H-CB in toluene-d8 (2.0mg in lmL solvent) provided a minor amount of lCN-4T2H-COT as well as a considerable amount of an unidentified decomposition product. This result is surprising since cyclobutene ring opening to cyclooctatriene has been reported by Wagner to readily occur in substituted l-acetyl-8- oxatricyclo[7.2.0.05t9]undeca-2,10-dienes.28 62 + decomposition NC 4 product 1-CN-4T2H-CB 1-CN-4T2H-COT Photolysis of 1CN-4T2H at 254 nm in Acetonitrile Irradiation of lCN-4T2H in argon-purged acetonitrile at 254 nm in a quartz vessel (126mg reactant in 45mL solvent) gave two products in a 1:1 ratio after complete disappearance of starting material (2 hours). Purification of the reaction mixture by silica gel column chromatography gave 11-cyano-4-oxatricyclo[7.2.0.03t7]undeca-2,10-diene, lCN-4T2H-LCB and 4-cyano-11-oxabicyclo[6.3.0] undeca-l,3,5—triene, lCN-4T2H- COT. The ratio of these two photoproducts was time dependent. Prolonged irradiation produced only 1CN-4T2H-LCB. The fate of 1CN-4T2H-COT was determined by independent irradiation. Photolysis of 1CN-4T2H-COT in argon-purged acetonitrile-d3 gave 1CN-4T2H-LCB as the only observable photoproduct at 254 nm. Gilbert has reported sirniliar results.25 Thermal Chemistry of 1CN-4T2H-LCB Heating a solution of 1CN-4T2H-LCB in argon-purged toluene-d8 gave no observable thermal reananged products after 12 hours. lCN-4T2H-LCB decomposed upon heating at 100°C for extended periods. 63 8 H / O 19 w‘" 6 254nm , | CH3CN NC NC 2 4 l-CN-4Tm 1-CN-4T2H-COT l-CN-4T2H-LCB I IN 1 Photoproduct 1CN-4T2H-LCB showed the same molecular ion peak as the starting benzonitrile, lCN-4T2H, by mass spectroscopy. 1H NMR showed signals coresponding to two vinyl protons: a broad singlet at 5.9 ppm (H-10) and a doublet of doublets at 4.9 ppm(H-2). Homonuclear decoupling experiments indicate that the vinyl proton (H-2) is coupled to the four-six bridgehead proton, H-1(6.3 Hz) and allylically to the six-five bridgehead proton, H-7(2.4 Hz). The vinylic proton (H-10) is coupled to the four-six bridgehead proton, H-9, which is further coupled to the methylene group, H- 8a,B (5.9 and 1.5 Hz) and H-1 (4.3 Hz). The stereochemistry of 1CN-4T21-1-LCB was determined by nOe analysis. Irradiation of the peak frequency corresponding to the cyclobutene proton, H-10, afforded enhancements at H-9 (2%), H-8(l%) and the five-six bridge-head, H-7 (1%). Structural elucidatation for 1CN-4T2H-LCB was assisted by its reported crystal structure and 1H NMR. Proton coupling and chemical shift comparisions were made between Gilbert's published 1H NMR data and those reported in this work. The stereochemistry of 1CN-4T2H-LCB, determined by nOe, was in accord with the published crystal structure.25 Photochemistry of 1CN-4T3H The photochemistry of lEC-4T3H is nearly identical to that of 1CN-4T3H. A solution of lCN-4T3H (2mg per lmL) in acetone-d6 was degassed and irradiated through a 313 nm filter solution. The reaction was monitored by time resolved 1H NMR. Product formation was slow (>15hours). A single photoproduct was indentified as 1- cyano-9-oxatricyclo[8.2.0.05i10]dodeca-2,11-diene,1CN-4T3H-CB by 1H NMR. An attempt was made to isolate this by large scale photolysis (450mg per 160ml) in argon- purged acetone. This afforded 263mg (58.4%) of 1CN-4T3H-CB after purification by silica gel column chromatography. The expected intermediate, 1CN-4T3H-COT could not be isolated, however its possible presence was detected by UV-Visible spectroscopy; A lmax at ~300 nm was observed during photolysis, indicative of a highly conjugated system. \ 313nm CN 0 O Acetone 1CN-4T3H 1CN-4T3H-CB Photoproduct 1CN-4T3H-CB was characterized using mass spectroscopy, IR, 13C and 1H NMR. lCN-4T3H-CB has the same molecular ion peak as 1CN-4T3H. 1H NMR of 1CN-4T2H-CB showed signals corresponding to four vinyl protons: a doublet at 6.75 ppm(H-ll), a doublet at 6.19 ppm(H-12), a doublet of doublets of doublets at 5.95 ppm(H-3), and a doublet of doublets at 5.75 ppm(H-2). The peak frequencies at 6.75 and 6.19 ppm are characteristic of vinyl protons in cyclobutene. Likewise, peak frequencies at 5.8 and 5.75 ppm are coupled to one another (10 Hz). This 65 vinyl pattern uniquely identifies the angular cyclobutene photoproduct. Homonuclear decoupling experiments confirmed all proton interactions. The 13C NMR provided additional information. Four singlets were observed in the vinyl region (137.5, 136.3, 131.1, and 119.0 ppm). The presence of a cyano group was confirmed by a carbon- nitrogen stretch of 2240cm'1 in the IR, and a singlet at 123 ppm in the 13C NMR spectrum. The stereochemistry of 1CN-4T3H-CB was elucidated by nOe experiments. Irradiation of the cyclobutene proton H-ll afforded enhancements at H-6(2.52%), H-8 (2.8%), and H-12(3.66%). The bridgehead proton H5 was uneffected by irradiation at H- 11. X-ray crystallography provided clear evidence of the stereochemistry of 1CN- 4T3H-CB. The cyclobutene ring of lCN-4T3H-CB is trans to the bridgehead proton H-5. Photolysis of 1CN-4T3H in acetonitrile at 254 nm Irradiation of 1CN-4T3H in aceonitrile at 254 run provided similar results as that carried out in acetone at 313 nm. A quartz test tube containing 1CN-4T3H(126mg) in argon-purged acetonitrile (45mL) was irradiated at 254 nm in an ice bath. The solution rapidly turned yellow and the reaction was complete after three hours as determined by GC analysis. A single photoproduct was isolated by column chromatography and recrystallized in ethyl aceate and hexane. The product was determined to be lCN-4T3H-CB based on its identical melting point. Thermal Chemistry of lCN-4T3H-CB Time resolved 1H NMR was used to investigate the thermal ring opening of 1CN- 4T3H-CB. In a NMR tube, a solution of 1CN-4T3H-CB in toluene-d3(0.015M) was heated at 100°C. After five hours analysis showed quantative conversion of 1CN-4T3H- CB to 12-cyano-4-oxatricyclo[8.2.0.0398]dodeca-2,1l-diene, lCN-4T3H-COPE, via a 66 Cope rearrangement. Ring opening to the cyclooctatriene did not occur even with the addition of a catalytic amount of para toulenesulfonic acid to 1CN-4T3H-CB in toluene. 1CN-4T3H-CB 1CN-4T3H-COPE Thermal product 1CN-4T3H-COPE was characterized 1H NMR. It showed signals corresponding to two vinyl protons: a broad singlet at 5.93 ppm(H-ll) and a doublet of doublets at 5.05 ppm(H-2). Homonuclear decoupling experiments were used to confirmed all proton connections. Proton H-2 is adjacent to an enol ether based on its upfield chemical shift. It is coupled allyically to bridgehead proton H-8 (2.5 Hz). Further coupling (5.9 Hz) to the adjacent four-six bridgehead (H-l) was also observed. Vinylic proton (H-ll) is coupled to the four-six bridge-head proton, H-10, which in turn is coupled to the methylene, group H-90t,[3 (6.0 and 4.3 Hz). A structural comparision can be made to lCN-2T2H-LCB. A sirniliar thermal rearrangement was observed in the chemistry of 1-trifluoroacety1- 7-oxa[7.2.01,9.05i9]undeca-2,lO-diene, structural analog to lCN-4T3H-CB.63 The stereochemistry is opposite to that found for 1CN-4T3H-CB. The six-six bridgehead proton H-8 is cis to the cis-fused cyclobutene ring. 67 Photochemistry of lCN-2T2H Irradiation of lCN-2T2H (0.01M) in argon-purged acetone through a 313 nm filter solution produced a single product after four hours. At roughly 70% conversion, the photochemistry was stopped and the yellow reaction mixture was concentrated. Purification of the mixture by silica gel chromatography gave lCN-2T2H-LCB in 74% isolated yield based on consumed starting material. A similar result was obtained for the photochemistry of 1CN-2T2H in acetonitrile at 254 nm in a quartz reaction vessel. However, the conversion of lCN-2T2H to 1CN-2T2H-LCB was more rapid (< 2 hours in an ice bath) under these conditions. / C.N 8 H 6 Acetone/313nm 10* o - II C N Acetonitrile/254nm 2 O 4 rem-2T,H 1CN-2T2H-LCB Photoproduct 1CN-2T2H-LCB was characterized by MS, 1H NMR and 13C N MR. lCN-2T2H-LCB showed the same molecular ion peak as the starting benzonitrile, lCN-4T2H, by mass spectroscopy. 1H NMR showed signals corresponding to three vinyl protons: a doublet of doublets at 6.1 ppm (H-1 1) a doublet at 6 ppm (H-10), and a doublet of doublets at 4.8 ppm (H-2). The AB quartet at 6.1 and 6 ppm represents the protons on a cyclobutene ring. Homonuclear decoupling experiments suggest that the cyclobutene proton (H-1 1) is further coupled allylically to the four-six bridgehead proton,H-1(1 Hz). The upfield chemical shift of H-2 at 4.8 ppm is indicative of a enol ether proton. Proton (H-2) is coupled to the four-six bridgehead, H-l (6.5 Hz) and allylically to the six-five bridgehead H-7. 13c NMR provides additional structural 68 evidence. Four peak frequencies were observed in the vinyl region (160.6, 142.2, 131.9 and 88.6). A peak frequency corresponding to a cyano group was also observed at 122 Photochemistry of 1CN-2T3H in acetone A 0.015M argon-purged acetone-d6 solution of 5-(2'-cyanophenoxy)pent—1-ene was photolyzed in a NMR tube through a 313 nm monochromic solution. The reaction was monitored by 1H NMR. Reaction was 50% complete after eight hours. A single photoproduct was indentified as 3-cyano—9-oxatlicyclo[8.2.0.05910]dodeca-2,1l-diene, lCN-2T3H-CB. Preparatory scale photolysis (950mg per 400mL acetone) was carried out to isolate the single photoproduct, 1CN-2T3H-CB, which was isolated by silica gel column chromatography as a pale yellow liquid in 49% yield. I hv (254nm) 1CN-2T3H 1CN-2T3H-CB 1CN-2T3H-CB-di-1t Photochemistry of 1CN-2T3H in acetonitrile at 254 nm Similar results were obtained when 1CN-2T3H was irradiated in acetonitrile at 254 nm. Photolysis of 1CN-2T3H in argon-purged acetonitrile at 254 nm in a quartz vessel (126mg reactant in 45mL solvent) gave two products in a 2:1 ratio after complete depletion of the starting material. The products were determined to be lCN-2T3H-CB 69 and a di-rt-methane rearranged isomer, 1-cyano-7-oxatetracyclo[7.4.1008,3] dodeca-9- ene respectively, lCN-2T3H-CB-di-rt. Prolonged irradiation of 1CN-2T3H-CB at 254 nm resulted in complete conversion to lCN-2T3H-CB-di-n. Photoproduct lCN-2T3H-CB was characterized by MS and 1H NMR. 1CN- 2T3H-CB showed the same molecular ion peak as the starting benzonitrile, 1CN-2T3H, by mass spectroscopy. 1H NMR showed signals corresponding to three vinyl protons: a doublet of doublets at 6.7 ppm (H-2), a doublet at 6.6 ppm (H-ll), and a doublet of doublets at 6.2 ppm (H-12). An AB quartet at 6.6 and 6.2 ppm represents the protons on the cyclobutene with a characteristic coupling of 3 Hz. Homonuclear decoupling experiments indicate that the cyclobutene proton (H-12) is further coupled to the four/six bridgehead proton, H-1(0.8 Hz). H-1 is further coupled to the adjacent vinyl proton (H-2) with a 5.5 Hz coupling. H-2 is allylically coupled only to H-40t (3 Hz) as seen previously for 1CN-4T2H-CB. The stereochemistry of lCN-2T3H-CB was elucidated by nOe experiments. Irradiation of the cyclobutene proton H-ll afforded enhancements at H-8 (2.8%), and H- 12(1.5%). Bridgehead proton H5 was uneffected by irradiation at H] 1. The cyclobutene ring of 1CN-4T3H-CB is therefore trans to the bridgehead proton H-S. The di-n-methane rearranged photoproduct, lCN-2T3H-CB-di-rt was fully characterized spectroscopically. 1CN-2T3H-CB-di-1t showed the same molecular ion peak as 1CN-2T3H-CB by mass spectroscopy. Several diagnostic protons are observed in the 1H NMR spectrum. It showed signals coresponding to two vinyl protons: a doublet at 6.1 ppm (H—9) and a doublet of doublets at 5.9 ppm (H-10). These protons are coupled to each another (6 Hz) and are characteristic of vinyl protons in a cyclopentene ring.61 Homonuclear decoupling experiments indicate that the cyclopentene proton (H-10) is further coupled to a tertiary cyclopropyl proton, H-ll (2.4 Hz). H-ll is further coupled to the other tertiary cyclopropyl proton H-12 at 3.1 ppm (6.6 Hz). Substantial downfield shifts of protons H-ll and H-12 have been reported previously by Comellisse. 13C NMR 70 provides additional structural evidence. Two singlets were observed in the vinyl region (129.5 and 127.9 ppm). A peak frequency corresponding to a cyano group was also observed at 121.6 ppm. Cyclopropyl carbons are shifted downfield >20 ppm in 1CN- 2T3H-CB-di-1t. This uncharacteristic chemical shift for cyclopropyl carbons have been observed in other strained fused ring systems. The presence of a cyano group was further confirmed by a carbon-nitrogen stretch at 2231cm'1 by IR. Photochemistry of 1EC-4T3H in acetone \ 313nm EtOOC Q 0 ———> Acetone 1EC-4T3H 1EC-4T3H-CB In a NMR tube, 1EC-4T3H (0.0154M) in acetone-d6 was degassed with argon and irradiated by a mercury arc lamp through a 313 nm monochromic filter. Time resolved NMR analysis of the photolysis mixture showed the reaction 50% complete after four hours. A single photoproduct was identified as 1-ethoxycarbonyl-9- oxatricyclo[8.2.0.05t10]dodeca-2,1l-diene, 1EC-4T3H-CB. Large scale photolysis (500mg per 160mL acetone) was carried out to isolate the single photoproduct. lEC- 4T3H-CB was isolated by silica gel column chromatography as a pale yellow liquid in 51.2% yield. 71 Photochemistry of 1EC-4T3H in acetonitrile at 254 nm Irradiation of lEC-4T3H in aceonitrile at 254 nm provided a similar result as that in acetone at 313 nm. A quartz test tube containing lEC-4T3H (140mg) in argon-purged acetonitrile (50mL) was irradiated at 254 nm in an ice bath. The solution rapidly turned yellow. GC analysis showed formation of two products in a 6:1 ratio after 2.5 hours. These were determined to be 1-ethoxycarbonyl-9—oxatricyclo[82.0.05,10]dodeca-2,1 1- diene and its C-5 epimer. Photoproduct lEC-4T3H-CB was characterized by 1H NMR . A direct structural comparison can be made with 1CN-4T3H-CB spectrum. 1H NMR spectroscopy showed four vinyl protons: a doublet at 6.7 ppm (H-1 1), a doublet at 6.3 ppm (H-12), a doublet of doublets of doublets at 5.9(H-3), and a doublet of doublets at 5.7 ppm (H-2). The AB quartet at 6.7 and 6.3 ppm (3 Hz), as well as the 10 Hz coupling observed between H-2 and H-3, uniquely identifies the angular cyclobutene photoproduct. Homonuclear decoupling experiments confirmed all proton interactions. Photochemistry of 1EC-4T2H Photolysis (254nm or 313nm) of lEC-4T2H (~0.015M) in argon-purged acetoniuile or acetone resulted in no observable photoproducts by 1H NMR at extended periods (>10 hours). Instead, 1EC-4T2H was rapidly converted to polymeric material. Gilbert reported similar results for the methyl benzoate derivative when irradiated at 254nm in acetonitrile.25 72 \ \/> hv EtOOC—.—-O No Reaction Solvent mic-4T,H Photochemistry of lEC-2T3H The photochemistry arising from 1EC-2T3H is similar to that of 1CN-2T3H. A 0.014M argon-purged acetone-d6 solution of 1EC-2T3H was photolyzed in a NMR tube through a 313 nm monochromic solution. Two products was observed by time resolved NMR. The major was characterized as 3-ethoxycarbonyl-9- oxatricyclo[8.2.0.05rl0]dodeca-2,1l-diene, 1EC-2T3H-CB, which undergoes secondary photolysis to 1EC-2T3H-CB-di-rt. Preparatory scale photolysis (500mg 1EC-2T3H per 160mL acetone) was carried out to isolate lEC-2T3H-CB. Upon completion, the crude reaction mixture was purified by silica gel chromatography. lEC- 2T3H-CB was obtained in 43% yield. \ \7 v Q—O Solvent COOEl 254nm 1 IEC'2T3H 1EC’2T3H'CB lEC-2T3H-CB-di-1t 73 Photolysis of 1EC-2T3H in acetonitrile at 254 nm Irradiation of lEC-2T3H in argon-purged acetonitrile at 254 nm in a quartz reaction vessel resulted in the formation of two products in a 8:1 ratio after 3.25 hours. The two products were determined to be 1EC-2T3H-CB and l-ethoxycarbonyl-7- oxatetracyc1o[7.4.1.0.083] dodeca-9-ene, lEC-2T3H-CB-di-1t, a di-rt-methane rearranged product. Irradiation of 1EC-2T3H-CB (0.015M) in acetonitrile at 254 nm resulted in formation of lEC-2T3H-CB-di-1t. Photoproduct 1EC-2T3H-CB was characterized by MS and 1H NMR. lEC- 2T3H-CB showed the same molecular ion peak as the starting ethyl ester, 1EC-2T3H, by mass spectroscopy. 1H NMR showed signals corresponding to three vinyl protons: a doublet of doublets at 7 ppm (H-2), a doublet at 6.6 ppm (H-1 1), and a doublet of doublets at 6.15 ppm (H-12). The two upfield protons (H-ll and H-12) are coupled to each other (3 Hz), characteristic of vinyl protons of a cyclobutene ring. Homonuclear decoupling experiments indicate that the downfield vinyl proton (H-2) is coupled to the four-six bridgehead (H-l) with a 5.5 Hz coupling. The bridgehead proton (H-l) is futher coupled to the vinyllic proton (H-12) (1 Hz). The secondary photoproduct, 1EC-2T3H-CB-di-1t was characterized using MS, IR and 1H NMR spectroscopy. A direct structural comparison can be made with 1CN- 2T3H-CB-di-1t. 1EC-2T3H-CB-di-n showed the same molecular ion peak as lEC- 2T3H-CB, by mass spectroscopy. The ester group was confirmed by a carbonyl stretch at 1711cm'1 by IR. 1H NMR showed signals corresponding to two vinyl protons: a doublet at 6.1 ppm (H-9) and a doublet of doublets at 5.9 ppm (H-10). The two vinyl protons are coupled to each other (5.8 Hz), characteristic of vinyl protons of a cis -cyclopentene.61 Proton (I-I-10) is further coupled to a tertiary cyclopropyl proton, H-ll (2.4 Hz); this in turn is further coupled to the other tertiary cyclopropyl proton H-12 at 2.6 ppm (6.8 Hz). 74 Photochemistry of 4-(3'-buten-1'-oxy)acet0phenone (4T2H-K)- Nahm's Compound A solution of 4T2H-K (2.1 mg in 0.75 mL solvent) in methanol-d4 was purged with argon and irradiated with a medium pressure mercury are filtered through Pyrex. A single photoproduct was observed by 1H NMR after 1.5 hOurs of irradiation at room temperature. The product was characterized as 1-acety1-8-oxatricyclo[7.2.0.095] undeca- 2,10—diene, 4Tzu-CB. Preparatory scale photolysis (300 mg 4TZH-K in 200 mL solvent) was carried out through Pyrex to isolate 4T2H-CB. The reaction progress was monitored by thin layer chromatography. After complete disappearance of the starting ketone (13 hours), the reaction mixture was heated at 50°C for six hours. During this time the reaction solution turned bright yellow. Purification of the reaction mixture by silica gel column chromatography (hexaneszethyl acetate, 90:10) provided 4-acetyl-11- oxabicyclo[6.3.0] undeca-1,3,5-triene as a yellow solid, 4T2H-COT ( 0.198 g, 66%). Irradiation of 4T2H-COT (~0.012M) in argon-purged methanol provided complete reversion to 4Tzn-CB. / Methanol _ ‘ @0 hv (pyrex)' 10 , O Photoproduct 4Tzn-CB was identified by its characteristic 1H NMR. It showed signals corresponding to four vinyl protons: a doublet of doublets at 6.34 ppm(H-10), a doublet at 6.27 ppm(H-l 1), a doublet of doublets of doublets at 5.84 ppm(H-3) and a doublet of doublets at 5.72 ppm(H-2). Homonuclear decoupling experiments indicate that 75 the peaks at 6.34 and 6.27 ppm are coupled to one another with a 3 Hz coupling constant. The vinyl proton signal at 5.72 ppm is coupled strongly (10 Hz) to the vinyl proton at 5.84 ppm and allyically to the proton resonance at 2.2 ppm(H—4). The stereochemistry of the photostable tricyclo[7.2.0.0.5t9]octa-2,lO-diene, 4T2H-CB, was determined by nOe studies.64 Irradiation of the 5/6 bridgehead proton, H5 (2.38 ppm), afforded an enhancement at the cyclobutene proton H-10. The thermal product, 4T2H-COT, was identified based on its characteristic chemical shifts and coupling constants in the 1H NMR spectrum. It showed signals corresponding to four vinyl protons: a doublet at 7.03 ppm (H-3), a triplet of doublets at 6.31 ppm (H-5), a doublet of doublets of doublets at 5.95 ppm (H-6), and a doublet at 5.42 ppm (H-2). Homonuclear decoupling of the vinyl pairs indicates that H-5 and H-6 are strongly coupled to each other with a coupling of 12.3 Hz. This coupling constant is characteristic of vinyl protons of cis-cyclooctene. The chemical shifts of the two doublet protons are also diagnostic. The upfield shift of H-2 is indicative of a vinyl proton of an enol ether and the downfield shift of H3 is indicative of a proton that is conjugated to an electron withdrawing group. Photochemistry of 4-(4'-penten-1'-oxy)acetophenone (4T3H-K) In a NMR tube, 4T3H-K was dissloved in argon-purged deuterated benzene (2.3 mg per 0.75 mL solvent) and irradiated through a Pyrex filter sleeve. Reaction progress was monitored by time resolved 1H NMR. After 16 hours of irradiation, 4T3H-K was only partially converted (<30%) into a single photoproduct, 1-acety1-9- oxatricyclo[8.2.0.010r5] undeca-2,11-diene, 4T3H-CB. Preparatory scale photolysis (400 mg per 250 mL benzene) was carried out to isolate 4T3H-CB. After 68 hours of irradiation through Pyrex, the reaction was ceased and concentrated in vacuo. The reaction mixture was redissolved in 60 mL of methanol and heated for five hours at 50°C. 76 Purification of the reaction mixture by silica gel column chromatography (hexanes:ethyl acetate, 90: 10) provided 4-acety1- 12-oxabicyclo[6.4.0] undeca-1,3,5-triene as a yellow oil. hv A v 50°C Methanol The thermal product, 4T3H-COT, was identified based on its characteristic chemical shifts and coupling constants in the 1H NMR spectrum. A structural comparsion can be made with 4T2H-COT. The 1H NMR spectra showed signals corresponding to four vinyl protons: a doublet at 6.9 ppm (H-3), a triplet of doublets at 6.35 ppm (H-5), a doublet of doublets of doublets at 6.1 ppm (H-6), and a doublet at 5.95 ppm (H-2). Homonuclear decoupling of the vinyl pairs indicates that H-5 and H—6 are strongly coupled to each other with a coupling of 11.4 Hz. This coupling constant is characteristic of vinyl protons of cis-cyclooctene. The chemical shifts of the two doublet protons are also diagnostic. The upfield shift of H-2 is indicative of a vinyl proton of an enol ether and the downfield shift of H-3 is indicative of a proton that is conjugated to an electron withdrawing group. It is interesting to note that the downfield chemical shift of proton H-2 is less pronounce in 4T3H-COT than in 4Tzfi-COT. This would suggest that the triene unit of the 8-6 fused system is less conjugated with the oxygen than in the 8-5 fused ring system. Photochemistry of 4T2N(CN)-K Irradiation of a 1:9 cis/trans mixture of 5-(4'-Acetylphenoxy)-4,4-dimethyl-2- pentenenitrile (2.1mg) in argon-purged methanol (0.75mL) provided rapid isomerization of the double bond (122.5 cis/trans) after 15 minutes as determined by integration of the vinyl 77 protons. Prolonged irradiation of the reaction mixture produced two products in a 121.3 ratio as determined by integration of peak resonances corresponding to the acetyl groups at ~2.1 ppm. The photoproducts were determined to be (4—endo)-1-acetyl-4-cyano-6,6- dimethyl-8-oxatricyclo[72.0.095] undeca-2,10-diene and (4-exo)-1-acetyl-4-cyano-6,6— dimethyl-8-oxatricyclo[72.0.095] undeca-2,10—diene. Preparatory scale photolysis was carried out to isolated the photoproducts. cis-and trans-5-(4'-Acetylphenoxy)-4,4- dimethyl-Z-pentenenitrile (0.06g) was dissolved in freshly distilled methanol (25mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitored by thin layer chromatography. Purification of the crude reaction mixture by thin layer chromatography (hexaneszethyl acetate, 80:20) gave 1-acetyl-4—cyano-6,6-dimethyl-8- oxatricyclo[7.2.0.09t5] undeca~2,10-diene and its thermal rearranged isomer 1-acetyl-4- cyano-6,6-dimethyl-8-oxatricyclo[7.2.0.09v5] undeca-3,10-diene. The exact stereochemistry of the latter could not be determined due to its thermal instability. Characterization of 1-acetyl-4-cyano-6,6-dimethyl-8-oxatricyclo[72.0.095] undeca-2,10-diene was accomplished by 1H NMR. It showed the presence of four vinyl protons: a doublet at 6.6 ppm (H-10), a doublet at 6.5 ppm(H-l 1), a doublet of doublets at 6.1 ppm(H-2), and a doublet of doublets at 5.8 ppm (H3). The AB quartet pattern at 6.6 and 6.5ppm (3 Hz), as well as the 10.2 Hz coupling observed between H-2 and H-3, uniquely identifies the angular cyclobutene photoproduct. Homonuclear decoupling 78 experiments on the peak frequencies at 5.8 ppm(H-3) and 6.1 ppm(H-2) indicate that they are further coupled to the peak resonace at 3.5 ppm (4.8 and 1.5 Hz respectively). The thermal product, 1-acetyl-4-cyano-6,6-dimethyl-8-oxatricyclo[72.0.095] undeca-3,10-diene, was characterized by 1H NMR. It showed signals corresponding to three vinyl protons: a broad doublet of doublets at 6.85 ppm(H-3), a doublet at 6.3 ppm (H-lO), and a doublet at 6.2 ppm (H-1 1). The AB quartet pattern at 6.3 and 6.2 ppm (3 Hz) is characteristic of vinyl protons in cyclobutene.61 The downfield shift of proton H-3 is indicative of a proton that is conjugated to an electron withdrawing group. Homonuclear decoupling of proton (I-I-3) indicates that it is coupled to two vicinal protons at 3.12 ppm and 2.05 ppm (2.7 and 6.3 Hz respectively). Photochemistry of cis-4T2N(Et)-K Irradiation of a solution of cis-6-(4'-acetylphenoxy)-3-hexene (3.2 mg) in argon- purged methanol (0.8 mL) provided two products in a 20:1 ratio as determined by integration of peak resonances corresponding to the cyclobutene proton (H-1 1) at 6.3 and 6.2 ppm. The two photoproducts were determined to be (4-endo)-1-acetyl-4-ethyl-8- oxatricyclo[7.2.0.09’5]undeca-2,-10-diene, (4-endo)-Et-CB, and (4-exo)-1-acetyl-4- ethyl-8-oxatricyclo[7.2.0.09’5] undeca-2,-10-diene, (4-exo)-Et-CB, respectively. Cisltrans isomerization of the double bond was also observed during the photoreaction as determined by the observation new double bond resonances (J =16Hz). 79 Characterization of (4-endo)-1-acetyl-4-ethyl-8-oxatricyclo[7.2.0.09t5]undeca-2,- 10—diene was accomplished by 1H NMR. It showed the presence of four vinyl protons: a doublet at 6.4 ppm (H-10), a doublet at 6.3 ppm (H-1 1), a doublet of doublets at 5.9 ppm (H-2), and a doublet of doublets at 5.7 ppm (H-3). The AB quartet pattern at 6.4 and 6.3ppm (3 Hz), as well as the 10.2 Hz coupling observed between H-2 and H-3, uniquely identifies the angular cyclobutene photoproduct. Nearly identical chemical shifts and coupling constants were observed for (4-exo)-1—acetyl-4-ethyl-8—oxatricyclo[7 2.0.095] undeca-2,-10-diene. The stereochemistries of these compounds were determined by comparing their chemical shifts and coupling constants to (4-endo)-1-acetyl-4-methyl-8- oxauicyclo[7.2.0.09t5]undeca-2,-10-diene previously characterized by nOe.64 Thermal Ring Opening of endo and exo-4T2N(Et)-CB cis-6-(4'-Acetylphenoxy)—3-hexene (0.2 g) was dissolved in freshly distilled methanol (250mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitored by thin layer chromatography. After complete disappearance of the starting ketone (28 hours), the reaction mixture was heated at 50°C for six hours. The reaction mixture turned yellow during this time. Attempts to separate the crude reaction mixture were unsuccessful by thin layer chromatography (hexaneszethyl acetate, 80:20). NMR analysis of the photoproducts showed a diastereomeric mixture of (endo and exo)-4— acetyl-7-ethyl-11-oxabicyclo[6.3.0]undeca-1,3,5-triene and (endo and exo)-4-acetyl-7- ethyl-11-oxatricyclo[6.3.0.0.1’6]undeca-2,4-diene. The overall ratio of products was 3 (7-endo)-Et-COT : 1.5 (7-endo)-Et-CH : 1 (7-exo)-Et-COT : 1 (7-exo)-Et- CH as determined by integration of their vinyl protons. Exp 3.110 PM! 0017 divul Print 80 Thermal ring opening of (4-endo)-Et—CB provided a 2:1 equilibrium mixture of 4- acetyl-7-ethyl-1 1-oxabicyclo[6.3.0]undeca-1,3,5—triene, (7-endo)-Et-COT and 4-acetyl- 7-ethyl-1 1-oxatricyclo[6.3.0.0.1r6] undeca-2,4-diene, (7-endo)-Et-CH. The structures of these compounds were determined by their characteristic vinyl regions in the 1H NMR. The 1H NMR of (7-endo)-Et-COT showed signals corresponding to four vinyl protons: a doubletat 6.96 ppm (H-3), a doublet at 6.29 ppm (H-5), a doublet of doublets at 5.65 ppm (H-6), and a doublet of doublets at 5.54 ppm (H-2). Homonuclear decoupling experiments indicate that the peak frequencies at 5.65 and 6.29 ppm are coupled to one another with a coupling constant of 12.1 Hz. This coupling is characteristic of vinyl protons in cis cyclooctene.61 The 1H NMR of (7-endo)-Et-HX showed signals corresponding to three vinyl protons: a broad doublet at 6.78 ppm (H-5), a doublet of doublets at 6.52 ppm (H-2), and a doublet of doublets at 5.72 ppm (H-3). The two upfield protons (H-2 and H-3) are coupled to each other (10.1 Hz), characteristic of vinyl protons of a cyclohexene ring.61 Thermal ring opening of (4-exo)-Et-CB provided a 1:1 equilibrium mixture of 4-acetyl-7-ethyl-11-oxabicyclo[6.3.0]undeca-1,3,5-triene, (7-exo)-Et-COT and 4- 81 acetyl-7-ethyl-11-oxatricyclo[6.3.0.0.1’6] undeca-2,4-diene, (7-exo)-Et-CH, as determined by integration of the vinyl protons. The structures of these compounds were determined by their characteristic vinyl regions in the 1H NMR. Nearly identical chemical shifts and coupling constants were observed between the diastereomers. Photochemistry of 4T2N(F)-K A solution of 4-(3',4',4'-trifluoro-3'-buten-l'-oxy)acetophenone (3 mg per 1 mL solvent) in CD3OD was degassed with argon and irradiated through Pyrex. Reaction progress was monitored by time resolved 1H NMR. After 30 minutes of irradiation, much of the starting ketone disappeared and only a trace amount of photoproduct was observed. The photoproduct was determined to be l-acetyl-4,4,5-uifluoro—8-oxatricyclo[7.2.0.09’5] undeca-2,-10-diene based on its characteristic vinyl region in 1H NMR. F trace amounts Computational Studies Semi-empirical studies of the excited and ground state were carried to provide additional insight into the factors which control the regio- and stereoselectivity associated with ortho [2+2] photocycloaddition. iii 0 Rotational Barriers in 2Me-4T2H-SI 82 5-Isopropyl-4-methoxy-2-methylacetophenone was used as the model compound to determine the energies of rotation around the methoxy bond. Nonbonded interactions between the protons of the homoallylic carbon and the isopropyl group on the benzene ring result in a calculated ~7kcal/mol preference in exciplex formation toward the isopropyl group rather than away from it (see Appendix) 0 Optimized Geometries for lCN-2T2H-COT, lCN-2T3H-COT, 1AP-4T2H- COT“, and 1CN-4T2H-COT* Semi-empirical calculations of the ground state minima of lCN-ZTZH-COT and 1CN- 2T3H-COT were carried out to determine the degree of triene conjugation in the fused cyclooctatrienes. Calculations indicated that the triene unit in the 8-5 fused ring system was nearly planar in the ground state. However, in the case of the 8-6 fused ring system, one of the double bonds is nearly orthogonal to the adjacent diene in the cyclooctatriene. Ring closure will occur exclusively from this highly conjugated diene unit. AMI calculations on the excited singlet of lAP-4Tzn-COT and lCN-4T2H- COT were canied out to determine electric charge distribution in the excited cyclooctatriene unit. The partitioning of charge in the excited state shows definite cationic (C1-C3) and anionic regions (C4-C6). The results suggest that ring closure to cyclobutene should occur from either diene unit (see Discussion). 83 Table 4: Isolated Yields of Various Cyclobutenes Arising From Tiplet Sensitization C clobutene Isolated yield21 1CN-4T3H-CB CNflTZH-CB 52% 1EC-4T3H-CB 53% ._1C__2T2H_________ ______________._;4‘7 __ ___ _ 1EC-2T3H-CB 43% a: irradiation in acetone Table 5: Isolated Yields of Various Ortho Substituted Cyclobutenes and Cyclooctatrienes Products 7 , Isolated ield ., # l - 2,5Me-4T2H-CB-t - 37%a W 2Me-4T2H-SI-CB-t r 18%a 2Me-4T2H-SI-CB-a 2Me-4T2H-SI-COT-t ‘ - ‘- [2Me-4T2H-SI-COT-a I 63%b a: from starting ketone b: from cyclobutene 84 V. Quantum Yields Quantum yields for cyclobutene formation were measured at moderate conversion (30-60 %) by the means of UV-Vis spectroscopy. Methanol solutions of cyclooctatrienes(10'5 M), which could be detected by UV-Vis, were degassed by the freeze-and-thaw method and irradiated at 313 nm in parallel with valerophenone actinometer (tbAp = 0.33) in a merry-go-round apparatus at room temperature. Quantum yields of 2+2 cycloadduct formation were analyzed at low conversion (5- 15 %) by the means of gas chromatography. Methanol solutions of starting ketones (0.01M) were degassed by the freeze-and-thaw method and mediated at 313 nm in parallel with valerophenone actinometer (<1) Ap = 0.33) in a merry-go-round apparatus at room temperature. Table 6: Quantum Yields of Various Cyclooctatrienes or Cyclobutenes Reactant Product f Quantum yield (1) 2,5Me-4T2H-COT 2,5Me-4T2H-CB 2M84T2Me-COT 2Me-4T2Me-CB 2Me-4T2H-SI-COT-t 2Me-4T2H-SI-CB-t 2Me-4T2H-I-COT-a 2Me-4T2H-SI-CB-a 2,5Me-4T2H- K 2,5Me-4T2H-COT 2Me-4T2H-SI-K 2Me-4T2H-SI-COT-t 2F-4T2Me-K 2F-4T2Me-COT 0.0025b a: CB determined by UV-Vis b: COT determined by GC 85 Quantum Yields for cyclobutene formation were measured at low conversion (<10%) by gas chromatography. Acetone solutions of the starting nitrile or ester (~0.01M) were degassed by the freeze-thaw method and irradiated at 313 nm in parallel with valerophenone actinometer. The quantum yield for cyclooctatriene ring closure to cyclobutene was determined in the same fashion as ortho substituted cyclooctatrienes for comparison purposes. Table 7: Quantum Yields of Cyclobutene Formation Quantum yield (I) rReactants lCN-4T2H-COT a: in acetone b: in methanol DISCUSSION The results presented, in conjunction with previous studies, have provided numerous clues into this unique photocycloaddition reaction. At the same time, these results spur a myriad of new questions that will be addressed in future studies. Regioselectivity The high degree of regioselectivity observed in photocycloaddition of ortho substituted p-butenoxyacetophenones is quite remarkable. In nearly all cases studied, the initial [2+2] ortho cycloaddition of the remote double bond is directed exclusively toward the ortho ring substituent. R R o O O hv O hv O Methanol Methanol 9 Fl = F(9%) Fl = CF3, Me, OMe, and F(91°/o) Similar strong regioselectivity was observed with substituents meta to the acetyl group.31 This selectivity was attributed in large part to inductive effects of the meta ring substituents on the nature of initial triplet state cycloaddition reaction. Alkyl and electron withdrawing groups ortho to the olefin tether (meta to the acetyl) direct cyclization toward themselves, while only strong electron donating groups drive the remote double bond away. 86 87 , X +— 0 —-> X x X=COONH2, CN, alkyl X=OMe, SMe The major question that must be answered is why the observed regioselectivty is nearly absolute. Clearly, this reaction is subject to very powerful differentiating effects. The fact that both electron withdrawing and electron donating groups foster the same absolute regioselectivity suggests that the inductive effect of the ortho substituent is not solely responsible for the majority of the observed selectivity as was shown for meta substituents. It is believed that the observed ortho substituent regioselectivity is associated with differentiating effects on both the initial triplet—state cycloaddition and the subsequent electrocyclic reactions. Overall Mechanism The mechanism of this reaction is assumed to be analogous to that for addition of olefins to cyclohexenones.65’ 66 Irradiation of p-butenoxyacetophenone derivatives generates a charge transfer complex (exciplex) that subsequently collapses to a biradical BR, which can either revert back to starting material or couple to form cyclohexadiene CH as shown below. 88 Subtle differences in electronics or sterics at any stage during this triplet—state cycloaddition reaction could potentially have profound effects on the observed regioselectivity. The significance of these factors on each step of the reaction scheme will be discussed. Exciplex Formation Exciplex orientation has been shown to greatly effect regioselectivity in meta photocycloaddition.8’ 21’ 22’ 67 Olefins preferentially add 2,6- to electron rich benzenes, placing the donor at position 3, whereas electron deficient benzenes direct addition 2,4- as shown in the scheme below. F30 0,0. + at. E> a . ’ F3C (I) El (endo +exo) (endo +exo) (endo +exo) 89 This selectivity has been rationalized by the substituent's ability to stabilize the developing charge upon addition of the olefin. O). W = electron withdrawing D = electron donating Inductive and resonance effects of ortho substituents also may play a critical role in establishing the regiochemistry of the initially formed cycloadduct. The approach and reactivity of the donor double bond is affected by the degree of electron density present at carbon centers ortho to the tether. Charge transfer interactions will be strongest with the more positive adjacent center. Donor ring substituents (OMe, F, and Me) supply electron density to positions ortho and para by resonance. More electron density is afforded to the para position than the ortho positions. No resonance stabilizing effect is possible for the electronwithdrawing substituent CF3. Inductively, all ortho ring substituents deplete electron density to varying degree at adjacent carbon centers. Inductive effects diminish the further the substituent is from the charge center. 90 The OR and 0'1 values for the ortho ring substituents are presented below and used in this study to describe both the resonance and inductive effects of the substituents in relative terms. I Table 8: OR and 0'1 values68 for Ortho Substituents in 4-Butenoxyacetophenone I Ortho Substituent _ In 2CF3-4T2Me-K, exciplex formation occurs in the direction of the ortho substituent due to induction (61:0.42). The ortho trifluoromethyl group removes the electron density from the adjacent carbon center making the interaction between the donor double bond and the acceptor benzene ring strong. Similarly, the ortho substituents in 20Me-4T2Me-K and 2F-4T2Me-K will orientate the exciplex toward themselves. Both fluorine (61:05) and methoxy (01:0.27) inductively create positive charge at the carbon next to the one it is attached. These substituents also generate electron density on para and ortho carbon atoms through resonance. Thus, the carbon atom ortho to both the tether and substituents will be the more positive carbon center. Exciplex formation will be orientated toward this center as shown below. 91 Q :7 t. ‘ in uctive ‘—-— , 8+ ls“0’ / X: F, OMB, and CF3 The directing ability of the ortho substituents was pitted against those of meta substituents in order to determine which factors effect regioselectivity. Compound 2,5Me-4T2H-K provided a model compound to determine the relative effects of alkyl substituents at the ortho and meta positions. Irradiation of 2,5Me-4T211-K in methanol provided a single photoproduct, 2,5Me-4T2H-CB-t, resulting from cyclization toward the ortho alkyl group. The ortho substituent completely surpresses the directing prowess of the meta alkyl substituent.31 The regioselectivity associated with ortho alkyl substituents will be discussed later, but in short, is due to the formation of a triplet dienol via hydrogen abstraction by the acetophenone group. Steric interactions between ring substituents and the approaching double bond can effectively alter the regiochemical course of the reaction. The constraint of the tether 92 connecting the arene and alkene limits the possibilities for substituents on the arene ring to exert their directing influenece. This effect is seen in the photochemistry of 2Me-4T2H- SI-K. In all cases studied, addition of the double bond is toward the ortho ring substituent. The introduction of an isopropyl group ortho to the tether causes reversal of regioselectivity, favoring addition away from the ortho substituent in a ratio of 1:1.25. During exciplex formation, the tether will orientate the double bond over the benzene ring. The homoallyic carbon-oxygen bond will twist away from the side of the ring in which complexation will occur. This is illustrated in the scheme below. 2Me-4T2H-SI-K Semi-empirical (AMI) calculations on the rotational barrier of the tether provided insights into the observed selectivity. 5-Isopropyl-4-methoxy-2-methylacetophenone was used as the model compound. N onbonded interactions between the protons of the homoallylic carbon and the isopropyl group on the ring result in a calculated ~7kcal/mol preference in exciplex formation toward the iSOpropyl group rather than away from it (see Appendix). Similarly, steric interactions can surpress the otherwise preferred syn addition of 2,5Me-4T2H-K. The lack of reactivity of 2,5Me-4T2Me-K results from nonbonded interactions between the meta methyl on the ring and the methyl on the double bond during exciplex formation, which are enhanced during biradical formation. 93 Identical observations have been reported before in the photochemistry of 4-(3'—buten-l'- oxy)-3-methoxyacetophenone, 3OMe-4T2H-K.31 Irradiation of 30Me-4T2H-K in benzene through Pyrex produces a 4:1 ratio of cyclobutene photoproducts, 3OMe-4T2H- CB-a and 3OMe-4T2H-CB-t respectively. However the regioselectivity is completely reversed by a methyl group on the double bond as in 30Me-4T2Me-K. R o o OMe o é L + 0 M60 0 OMe Fl R 20Me-4T2H-K : R=H 20% 80% 20Me—4T2Me-K : R=Me 100% Possibilities Arising From Biradical Formation Addition of a ring substitutent in 4-(3-buten-1-oxy)acetophenone allows for the formation of two separate noninterconverting biradicals due to the spirocyclic bonding in the intially formed cyclohexadiene. These biradicals can subsequently couple to form either syn or anti products or decay to ground state acetophenone. 94 It is possible that kpsatkpa; but for the observed selectivity of ortho substituent to be derived solely from differential biradical partitioning, kps>>kpa must hold since there can be little difference in biradical decay to the ground state (kds=kda)- The two biradicals must have essentially the same stability relative to the ground state acetophenone, since the ring substituent should not accelerate cyclopentyl ring opening in either biradical. The ring substituent X, however, will cause a slight puckering in the ring at the ortho carbon which might enhance coupling between these two radical centers. It is unlikely that is the sole reason for the absolute regioselectivity observed in these reactions. Photoenolization of o-alkylphenyl ketones Phenyl ketones containing an ortho alkyl group are known to have two different conformers, anti and syn, which interconvert via a bond rotation about the C-C bond connecting the carbonyl to the aromatic ring. The geometries of both conformers were described by Wagner and Chen60 as rotational minima in which the carbonyl oxygen and ortho alkyl group are on the same or opposite side of the plane perpendicular to the benzene ring bisecting the para carbon and carbonyl carbon. 95 bond 0 rotation O R anti triplet syn triplet Photokinetic studies have shown that photoenolization of o-alkyl phenyl ketones effeciently competes with other photochemical processes common to these compounds. Wagner and Chen reported the substantial decrease(by a factor of 20) in quantum yield for Norrish type H cleavage of valerophenone when the parent compound is altered by an ortho-methyl group.60 The rate of hydrogen abstraction from a smortho alkyl group was determined to be on the order of 5x109s‘1 by measuring the triplet lifetime of 8-methyl-1- tetralone.6O The regioselectivity associated in the [2+2] photocycloaddition of ortho alkyl substituted p-butenoxyacetophenones may be due solely (or in part) to the formation of a triplet dienol. Studies have shown that the triplet biradical of the photoenol lives for microseconds.69' 70 There should be sufficient spin density at the para carbon to produce some hexenyl radical cyclization before decay to the ground state enol occurs. Such a process would occur exclusively from the syn biradical effectively bypassing the direct interaction of the triplet benzene and the double bond. 96 Evidence for the existence of a triplet dienol was determined experimentally. Irradiation of 2Me-4T2Me-K in deuterated methanol (0.015M) resulted in the rapid depletion of the resonance corresponding to the ortho methyl group (2.50 ppm) in the starting material. Deuterium incorporation was also observed in the photoproduct, 2Me-4T2Me-CB. It is quite possible that the trace amount of acid present in methanol71 quenches the enol and that both efficient benzylic H-D exchange and cycloaddition are faster than cyclobutenol formation under this condition. Photolysis of 2Me-4T2Me-K in deuterated benzene results in the formation of cyclobutenol. Based on the chemical shift of the benzylic protons in the cyclobutenol photoproduct and comparison with previously reported 62, 72 adducts, it is believed that the triplet enol was trapped by oxygen. Similar results were seen in the photochemistry of 2CD3-4T2Me-K. OMe 2Me'4T2Me-II 5.1 & 4.3 AB Quartet, 5.07 & 4.3 AB Quartet, 3.05 & 2.9 AB Quartet, 15.5Hz 14Hz, reference62 14Hz, reference62 3Me-5T2Me-Indanone was synthesized to determine the importance of a triplet dienol in the regioselectivity of ortho alkyl substituents. A structural analogy can be made between the indanone and ortho methyl acetopheneone in the anti conformation. The fused system prevents bond rotation of the ketone to form the perferred syn conformer. 97 Irradiation of 3Me-ST2Me-Indanone in methanol provides a 1:1 ratio of cyclooctatriene diastereomers, Indanone-COT-trans and Indanone-COT-cis. The two cyclooctatrienes arise from ortho [2+2] cycloaddition away from the alkyl portion of the cyclopentanone ring. Thus, 3Me-5T2Me-Indanone provides the opposite regioselectivity from that shown for other alkyl substituents. No photoproducts were observed when 3Me-5T2Me-Indanone was irradiated in benzene or acetonitrile. fl Methanol °O°m I Indanone-3Me-ST2Me Indanone-COT-cis Indanone-COT-trans 1 : 1 Differential Rates of Electrocyclizations The thermal equilibrium between the initially formed cyclohexadiene (CH) and its valance tautomer cyclooctatriene (COT) may be crucial in determining the overall regioselectivity of this reaction due to the differing photochemistries of these two isomers. 98 It has been shown experimentally that cyclobutene (CB) formation occurs from disrotatory ring closure of cyclooctatriene. The quantum efficiency of this process is low (5-10%). In contrast, cyclohexadiene rapidly reverts photochemically to starting ketone with a quantum efficiency of ~70%.73 Thus, the direction in which the thermal equilibrium lies could potentially determine the observed photoproduct. Perhaps only the cyclohexadiene that opens quickest to cyclooctatriene produces the photostable cyclobutene as shown in the scheme above. The rates of thermal ring opening of the regioisomeric cyclobutenes may also be a major factor in the observed regioselectivity of this reaction. Quite possibly, the minor cyclobutene (CB-a), obtained from cyclization away from the ortho substituent, opens faster to a equilibrium mixture of cyclooctatriene and cyclohexadiene than the major cyclobutene, CB-t. The position and chemical nature of the substituent will alter ring Opening of cyclobutene. In CB-t, the substituents are at a node in the it system and will not offer any stabilization of the zwiterionic intermediate believed to be involved ring Opening process.28 In contrast, substituents in CB-a are conjugated with the acceptor 1: system and should facilitate ring opening if the substituent is electron withdrawing. 99 X=e|ectron withdrawing Quantum Yields Quantum yields for the initial 2+2 photocycloaddition of ortho substituted phenyl ketones to cyclohexadienes (cyclooctatrienes) are roughly a factor of 10 lower than for phenyl ketones without ortho substitution.64 This substantial difference may be due in part to low population of the 1t,rt* triplet state of the phenyl ketone upon excitation. Steric bulk of the ortho substituent prevents complete conjugation of the acetyl with the benzene ring which is necessary for 1t,1t* state population. Population of other energetically similar states (i.e. n,1r*) can then occur. This is seen in the photochemistry of 2Me-4T2Me-K, 2Me-4T2Me-K, and 2,6Me-4T2Me-K. ‘ Quantum yield studies indicate that photoreversion of cyclohexadiene to starting ketone proceeds efficiently (70%).64 This would account in part for the low quantum and chemical yields observed for the overall process from starting ketone to cyclobutene. In general, reversion of the biradical is a major source of inefficiency in the cycloaddition reaction. Agosta has determined that the quantum yields for reversion are much higher than for product formation in intramolecular 2+2 photocycloadditions of carbonyl-substituted l,5-hexadienes.74r 75 Photoreversions of biradicals have also been shown to be highly efficient in cycloadditions of triplet enones to double bonds.76t 77’ 78 100 Differences in the Thermal Chemistry Between Acetyl and Cyano Substituted Cyclobutenes Heating derivatives of 4-Acetyltricyclo[7.2.0.05’9]undeca-2,10—dienes in methanol at 50°C rapidly causes ring opening of cyclobutenes to all-cis cyclooctatrienes. This transformation presumably involves the formation of a biradical followed by an electron u'ansfer to form an intermediate with a high degree of zwiterionic character.28 ——> —-> —> , ’ R j A n _ O n R R o R O n=1 or 2 In contrast, cyano and ethoxycarbonyl substituted 9-oxatricyclo[8.2.0.05r10]dodeca—2,1 1- dienes and 8-oxatricyclo [7.2.0.05 .9] undeca-2,10-dienes do not thermally open to cyclooctatrienes. The differences in thermal chemistry hinges on the ability of the acetyl or cyano substituent to stabilize the developing zwiterionic character in the ring opening transition state. A good judge of their stabilizing prowess can be obtained from their pKa's. The difference in pKa's between acetone and acetonitrile (20 and 25 respectively) suggests that acetyl substituted cyclobutene is ~7 kcals/mol more likely to open to the all cis cyclooctatriene than its cyano substituted counterpart. It must be stressed that this is only a relative number since the zwiterionic intermediate is a developing dipole, not a solvated ion as in the pKa measurements. The sluggish ring opening of 1-cyano-9-oxatricyclo[8.2.0.05r10]dodeca-2,11- diene to cyclooctatriene allows for Cope rearrangement to compete. Thermal transformation through Cope rearrangement is symmetry allowed. The transition state for 101 this rearrangement resembles a chair configuration. The stereochemistry at the six-six ring junction is reversed in the Cope product. Toluene 100°C, 5Hrs I ' “‘"j Similiar results were observed in the thermal chemistry of 1-trifluoroacetyl-7- oxa[7.2.01v9.05’9]undeca-2,10-diene,TFA-CB. Warming a solution of TFA-CB in toluene at 100°C resulted in the formation of TFA-CB-COPE via a Cope rearrangement.63 Ring opening to cis-cyclooctatriene, TFA-COT was not observed. The formation of the eight membered ring is favored when there is an electron donating or withdrawing group conjugated with the bridge-bond of cyclobutene. Stabilization of the developing zwitterionic intermediate is necessary for cyclooctatriene formation. 0‘ H c. I "I “r" \ o H s“ I I 0 F3 l 3' I "In his H O 1’ ‘\ O TFA-COT TF A-C B-COP E 102 Photolysis of 4- and 6-substituted-12-oxabicyclo[6.4.0]dodeca-1,3,5- trienes Ring closure of cyclooctatriene to cyclobutene is'highly regioselective. This selectivity appears to be dependent on the size of the accompanying ring. [radiation of 4- or 6-cyano-lZ-oxabicyclo[6.4.0] dodeca-1,3,5-triene at 313 nm results in the formation of l- or 3-cyano-9-oxatlicyclo[8.2.0.05t10]dodeca-2,1 l-diene respectively. Photochemical ring closure produced only the angular cyclobutene irrespective of the cyclooctatriene isomer. R1=H, R2=CN Of COOEt R1=CN or COOEt, R2=H In contrast, irradiation of the corresponding fused eight-five ring system produced different cyclobutene regioisomers. Photolysis of 4-R-11-oxabicyclo[6.3.0]undeca—1,3,5-triene (where R=acety1, cyano, ethoxycarbonyl) at 313 nm gave 1-R-8-oxatricyclo[72.0.0599] undeca-2,10-diene. Irradiation of 6-R-11-oxabicyclo[6.3.0]undeca-1,3,5-triene (where R=acetyl, cyano) at 313 nm produced the linear cyclobutene, 9-R-4- oxatricyclo[7.2.0.03v7]undeca-2, 10-diene. 103 or [IO "“5 . R1=CN. C0051, Ol’ COCH3 R1=H R2=CN or COCH3 R2=H Semi-empirical calculations(AM1) of the ground state minima of 6-cyano-11— o xabicyclo[6.3.0]undeca-1,3,5-triene 1CN-2T2H-COT and 6-cyano-12- oxabicyclo[6.4.0]dodeca-1,3,5-tliene 1CN-2T3H-COT are presented below. The triene unit in the 8-5 fused ring system was nearly planar in the ground state. Both diene units am thus able to close to form either the angular or linear cyclobutene. However, in the case of the 8-6 fused ring system, one of the double bonds is nearly orthogonal to the adjacent (1 ie ne in the cyclooctatriene. Ring closure will occur exclusively from this highly conjugated diene unit. The lack of triene conjugation for the 8-6 fused ring system was noted in the ultraviolet-visible spectroscopy of these compounds. A Xmax of 305 nm was recorded for 6-cyano—12-oxabicyclo[6.4.0]dodeca-1,3,5-tliene compared to a Xmax of 335 mm for 6-cyano- l 1-oxabicyclo[6.3.0]undeca-1,3,5-triene. 104 ion-zrafl-cor 105 Photolysis of 3-cyano-9-oxatricyclo[8.2.0.05’10]dodeca-2,ll-diene Direct irradiation of 3-cyano-9-oxatricyclo[8.2.0.05,10]dodeca-2,1l-diene, 1CN- 2T3H-CB in acetonitrile produced 1-cyano-7-oxatetracyclo[7.4.1.0.08’3] dodeca-9-ene via a di-rt-methane rearrangement. Photosensitized irradiation of 1CN-2T3H-CB in acetone gave only a minor amount of di-rt-methane product, indicating that the reactive state in this system is most likely S1. The mechanism for this photochemical transformation is presumably stepwise in nature due to the rigid framework of 1CN-2T3H-CB. The overall process can formally be considered as a 1,2-shift of one 1: unit to the other it unit with concomitant ring closure to form the cyclopropane ring between the methylene group and the other end of the nonmigrating 1t moiety.79 The observed regioselectivity can be rationalized by considering the stabilities of the developing biradicals produced on cleavage of the first formed cyclopropane ring as shown in the scheme below. The product arises exclusively from cleavage of the three-four bridge bond to give the biradical stabilized by nitrile delocalization. The alternative biradical formed from cleavage of the three-six bridged bond has only minor stabilization afforded by a secondary carbon center and would revert to 1CN-2T3H-CB via a 1,2-alkyl shift followed by recombination of the biradical. 106 Similar results have been obtained in the photochemistry of 4-(3'-buten-1'-oxy)-3- methylacetophenone, 3Me-4T2H-K at 313 nm in benzene—d6.31 Irradiation of 3Me- 4Tzn-K produced mainly 3Me-4T2H-CB plus a minor amount of a di-rt-methane rearrangement product. Irradiation at >334 nm produced only 3Me-4T2H-CB, thus indicating that the di-rt—methane rearrangement arose from 3Me-4T2H-CB. O 0 M9 313nm / A M6 0 Benzene= O ' sue-412w K Photochemistry of lCN-4T2H-COT Possibly the most intriguing finding to stem from the photosensitization of benzonitriles is the observation that different cyclobutene photoproducts arise when irradiation conditions are changed in the case of lCN-4T2H-COT. 107 O~\ 254nm 313nm NC“; at Acetonitrile N C Acetone 1CN-4T2H-LCB 1CN-4T2H-COT . lCN-4T2H-CB These observations are open to a number of possible explanations. One such explanation suggests that chemistry arising from the singlet and triplet electronic states of 1CN- 4T2H-COT are remarkably different and thus different photoproducts are obtained. Gilbert has shown that 1,3-dienes (0.50 M‘l) quenched the formation of lCN-4T2H- COT by approximately 50% in cyclohexane solution.25 The photocyclization of 1CN- 4T2H-COT (at 320 nm) was uneffected by the presence of the 1,3-dienes. Thus it is concluded that the latter process results from the singlet state. Another plausible explanation suggests a strong wavelength dependency of the photoproduct distribution in the photochemistry of lCN-4T2H-COT. Numerous investigations have shown that product distributions are affected by slight changes in the source of excitation. For example, Dauben has shown wavelength dependency in the photochemistry of cis-bicyclo [4.3.0] nona-2,4-diene.80 Irradiation of cis-bicyclo [4.3.0] nona-2,4-diene with >300 nm light generates cis-tricyclo [4,401,637.10] deca-8-ene, the 11:4 product. Alternatively, irradiation at shorter wavelengths(254 nm) produces nona— l,3,5-triene via a 1:6 process. Dauben has suggested that conformational factors may dictate these wavelength dependent reactions. 108 Experiments were performed to distinguish between the two possible explanations. Irradiation of lCN-4T2H-COT in acetonitrile at either 313 nm or 254 nm provided only the linear cyclobutene adduct. This indicates that its photochemistry is not wavelength dependent. lCN-4T2H-LCB must be arising from the excited singlet of 1CN-4T2H- COT. Further evidence in favor of state dependency was obtained by irradiation of 1CN- 4T2H-COT in acetone at longer wavelengths(313 nm). At low concentrations of 1CN- 4T2H-COT, a condition present in the photochemistry of 1CN-4T2H, all the light is absorbed by acetone. Triplet-triplet energy transfer from acetone to lCN-4T2H-COT will occur. This process should be highly exothermic due to the large triplet energy of acetone (ET~ 78 kcal/mole79). However, at higher concentrations (0.015M in acetone), lCN-4T2H-COT will compete with acetone for the light due to the substantial absorption of the cyclooctatriene (e~7500 at 325 nm). Thus ample amounts of 1CN-4T2H-LCB should be formed by 313 nm irradiation. This has been confirmed by experiment. Regioselective triplet ring closure of cyclooctatriene to cyclobutene can be rationalized in terms of biradical stability. Excitation of 1CN-4T2H-COT in acetone will afford its excited triplet via triplet-triplet energy transfer from the solvent. Twisting of the double bond of acrylonitrile will generate a 1,2 diradical. Both radicals are effectively allylic and stabilized through resonance as shown in the scheme below. 109 0 R R n In all cases previously studied, para-substituted 1-(3'-buten-1'-oxy)benzene L R=nitrile or acetyl efficiently cyclized to form the photostable angular cyclobutene via a two photon process. AMl calculations on the excited singlet of 1CN-4T2H-COT and lAP-4T2H-COT were carried out to determine the plausible explanation for diene ring closure of 1CN- 4T2H-COT to 1CN-4T2H-LCB. Electric charge distribution (presented below) indicates that cyclooctatriene ring closure to cyclobutene is likely to occur at either diene unit to give both the angular or linear cyclobutene. The partitioning of charge in the excited state shows definite cationic (Cl-C3) and anionic regions (C4-C6). The minimized geometry of the excited singlet of lCN-4T2H-COT showed that both diene units are slightly twisted but neither more than the other. R4 5 6 lR-4Tm-COT 110 Table 9: Electronic Charge Distributions for the excited singlet of lR-4T2H-COT Carbon Number R=Acety1 R=Cyano Cl 0.33 0.22 02 -0. 15 +0.1 1 G3 0.32 0 G4 -0.61 -0.18 C-5 -0. 10 -0. 10 06 -0.36 -0.35 The regioselective cyclooctatriene ring closure of 1CN-4T2H-COT to lCN-4T2H- LCB is perplexing. AMl calculations suggest that either diene unit can close to form a mixture of cyclobutenes. Possibly, steric interactions between the acetyl group and the diene protons during ring closure may prevent formation of the linear cyclobutene. The linearity of the nitrile will preclude this interaction. Further research on the regioselectivity of cyclooctatriene ring closure should be canied out. Stereoselectivty The exact stereochemistry of the tricyclic photoproducts has been established by nOe and in the case of 1CN-4T3H-CB by x—ray crystallography (see appendix). Clear stereochemical trends are present. Photoproducts with a four-five-six skeletal framework have the bridgehead substitutent (H or CH3) cis to the cyclobutene ring. Presumably, the stereochemistry arises from disrotatory photochemical ring closure of the all-cis cyclooctatriene in only one direction to produce a cis 5/6 and a cis 4/6 ring fusion. The five membered ring must constrain the eight membered ring in a particular puckered geometry. 111 \“v “w I“) mY r Y “r o A R O R = Acetyl or Cyano Surprisingly, the stereochemistry of the four-six-six skeletal framework is opposite that of the four—five-six framework. In the former case the bridgehead proton is trans to the cyclobutene ring. Woodward-Hoffman rules dictate photochemical diene ring closure to occur in a disrotatory fashion to produce a cis fused cyclobutene ring. Quite possibly the six membered ring may pucker the cyclooctatriene in a opposite manner to that of the five membered ring. AMl calculations on the ground states of 1CN-4T2H-COT and 1CN-4T3H-COT were performed. The minimized structures are presented. The cyclic ether is puckered in the opposite manner for the 8/5 ring system than in the 8/6 ring system. Disrotatory ring 112 closure of the cyclooctatriene will provide cyclobutenes with opposite stereochemistries at the bridgehead. lCN-4Tm-COT 1CN-4T2H-COT Table 10: Selected Dihedral Angles for 1CN-4T2H-COT and lCN-4T3H-COT Atom Connections lCN-4T2H-C0T(°) 1CN'4T3H'COT(°) C1-C2-C3-C4 3.305 -4.016 0-C2-C3-C4 -170.763 175.788 Future Work Stereoselectivity It would be instructive to determine the stereoselectivity of singlet state ortho cyclization as a function of substitution along the tether. Wagner and Cheng81 have shown a high degree selectivity associated with the corresponding triplet ortho cyclization of substituted phenyl ketones. In theory, singlet state cyclization should be substantially more selective than the triplet due in large part to differences in their electronic nature. A variety 113 of mono-, di-, and trisubstituted tethers will be synthesized to determine the stereo— and diastereoselectivity of this reaction. X R1 n2 x “1 MY hv Y X R2 ——> ——" —> CH3CN O. ' 31 R2 X Y R2 R1 X=OMe, SiMe3, SMe; Y=CN, CO0Me, CF3 X=CN, CO0Me, CF3; X=OMe, SiMeg, Me Regioselectivity The determination of which carbons of a polysubstituted benzene are attacked by an alkene is of fundamental importance both mechanistically and synthetically. We have demonstrated that the conesponding triplet intramolecular ortho cyclization proceeds with a high degree of regioselectivity when electron donating or withdrawing groups are ortho or meta to the alkene tether.30’ 31 The regioselectivity is partially suppressed in the intramolecular process due to the propensity of the tether to form a five membered ring system. The bimolecular variant should provide a clearer understanding of the initial ortho 2+2 cycloaddition reaction. It is anticipated that electron donor and electron acceptor substituents on the benzene ring will have opposite directing natures depending on the electronic character of the reacting alkene or alkyne. An analogy can be drawn with the intermolecular cyclization of substituted alkenes to cyclohexenones.66’ 82 A representative group of olefins with either electron donating or withdrawing substituents, symmetrically or unsymmetrically disposed will be used to test the relative reactivity as a function of electron richness and regioselectivity as a function of inductive effects of the substituents. A variety of substituted alkynes will also be used since they are known to add ortho to singlet benzenes. 114 waxed CECE =,CN CO0Me, COMe, COOH =OMe, Me =\ = a a a =\ {HO—E CN—E —E}R2 = x—E X { OM. CF, on F} Another important structural question that must be addressed is the regiochemlstry of the cyclooctatriene-bicyclo[4.2.0] octa-2,7-diene closure. In all cases studred 8 10 12 ring closure of the cyclooctatrienes was regioselective, involving only one of the two diene subumts This tendency must be due to a subtle mixture of steric and electromc effects 0‘ R1 R: 0 R1 92 R‘ 92 G 231/KC?) aeogfiQ/i 0 R1, R2: CO0Me, CF3, CH3, OMe, and H R‘ O O O .0 std» R 0 R1: CN, F, OMe, and H Natural Product Synthesis Although the main thrust of this project to date is mechanistic the ultimate goal would be to incorporate the findings into natural product synthesis. Many natural products have 8/5 fused rlng systems as their skeletal framework; one such class is the ophrobolrns 115 Recently, Dauben reported the stereocontrolled route to the ceroplastin nucleus via a McMurry coupling of a dicyclopentane system.83 Alternatively, one could incorporate ortho photocycloaddition as the key step in formation of this natural product. This is illustrated in the retrosynthetic scheme below. 0H \ H 3’ 3’ =>éQc=>/%E:Y o Ortho photocyclization provides an unprecedented opportunity for the construction of a variety of fused 5/6/4 tricyclic systems. Abel] and Leech have recently isolated and characterized the sterpurene metabolite, 7,12-Dihydroxysterpurene, from the fungus Stereum purpureum.84 A plausible synthesis to this sterpurene is presented below. All bicyclo [4.2.0] octa-2,7-dienes so far isolated by Gilbert and Wagner have the 6/5 bridgehead proton cis to the cyclobutene ring. Reduction of the cyclobutene is generally preferred over cyclohexene reduction due to ring strain. on cc on me H NC :3 ocrr3 => => 2? ”'30 cu ergo \ 0H OCH3 OCHa 7, 12-Dihyrdoxysterpurene I . Instrumentation EXPERIMENTAL This section describes the instrumentation used to characterize all substrates presented in this work. 1H and 13C NMR: FTIR: UV: GC: HPLC: MS: Melting Points: 11. Chemicals Varian Gemini 300, Varian VXR-300, and Varian VXR-500 Nicolet 42/Infrared Spectrophotometer with a 0.025mm 212308-0 Aldrich IR cell Shimadzu UV-160 Recording UV-VIS Varian 1400 and 3400 Gas Chromatographs with Hewlett Packard HP3393A, HP3392A, and HP3395 Integrators Rainin Dynamax HPLC interfaced with a dual wavelength programmable detector and fraction collector Joel JMS-HXl 10 Mass Spectrometer and VG Trio-1 Benchtop GC-MS with a Hewlett Packard 5890 Gas Chromatogrph Thomas Hoover Capillary Melting Point Apparatus. Melting points are not corrected. This section describes the preparation, purification, and identification of all chemicals used in this work. All substrates used in the preparation of the photoprecursors were the highest purity commerially available. The purity of such compounds was checked by gas chromatOgraphy or 1H NMR prior to use. A. Solvents Benzene85 116 1 17 Reagent-grade benzene (3.5L) was stirred over cone. H2804 (0.5L) until the acid washing remained colorless (usually three portions of 0.5L of cone. H2804). The benzene layer was subsequently separated, washed with distilled water (3 x150mL), saturated NaHC03 (3 x200mL), saturated NaCl (2x100mL), and then dried over MgSO4. The filtered benzene was then refluxed for 24 hours over P205‘(150 g). After the stated period, the benzene was distilled through a meter column packed with stainless steel helices. The first and last 10% were discarded. The middle fraction distilled between at 78-80°C. Methanol86 Reagent-grade absolute methanol was refluxed over Mg metal (2.5 g/ 1200 mL) overnight, then distilled through a half meter column packed with glass helices. The middle fraction (80%) which distilled between 64-65°C was saved. Acetone85 Capillary GC/GC-MS grade acetone (2L) was treated successively with small amounts of KMn04 (0.5 gram portions) until a violet color persists. Anhydrous K2C03 (8 g) was added and the mixture was refluxed for 12 hours. The solvent was then fractionally distilled through a one foot column packed with glass helices. The middle fraction (90%) which distilled between at 56-57°C was saved and stored over type 4A Linde molecular sieves. Acetonitrile” Reagent-grade acetonitrile (2L) was refluxed over P205 (2 g) for four hours, then distilled through a one foot column packed with glass helices. The solvent was then refluxed over CaH2 for 24 hours and then fractionally distilled through a half meter column 118 packed with glass helices. The middle fraction (80%) which boiled at 81-82°C was saved and stored over type 4A Linde molecular sieves. B. Chromatography Material The majority of the photoprecursors and photoproducts Were purified by silica gel chromatography. Preparative thin layer chromatography (Analtech Uniplate silica gel plates of 20x20cm, 1000 microm) was utilized for samples up to 150millig. Flash chromatography (Aldrich [cat#22,719-6] Silica gel, Merck, grade 60, 230-400 mesh, 60A.) was used for larger samples up to five g. The column diameter was selected according to the size of the sample. "Dry column flash chromatography" (Aldrich [cat. #28,850—0] TLC standard grade silica gel without binder ) was utilized for samples larger than five g and for samples that decompose on silica gel while being eluted. C. Internal Standards Ethyl phenyl acetate: Ethyl phenyl acetate was purified by fractional distillation. Dodecane(Cl2): Dodecane was washed with sulfuric acid and distilled by Dr. Peter J. Wagner. Valerophenone: Valerophenone was prepared from the acylation of benzene with valeryl chloride by Dr. Bong-Ser Park. Methyl benzoate: Methyl benzoate was purified by fractional distillation. n-Pentyl benzoate: n-Pentyl benzoate was purified by fractional distillation. n-Heptyl benzoate: n-Heptyl benzoate was purified by fractional distillation. n-0ctyl benzoate: n-0ctyl benzoate was purified by fractional distillation. 119 D. Preparations O X C (1 d1 x x A l hl ' , ' ' ' ' ' g cet)’ on e M I: Y/g Aluminium Chlogg Y Y i on O H © , 0°C--noom temperamre 0 1a: =CH3, y=H 2a-e 3a-e 1b: x=CH3, y=CH3 lc: x=F, y=H 1d: X=OMe, y=H Y 1e: x=CH3, y=CH(CH3)2 o Tether 0 e , Potassium Carbonate 9 Ex R 2Me-4T2Me-K: X=CH3, y=H, R=CH3 2Me-4T2H-K: X=CH3, y=H, R=H 2,5Me-4T2Me-KZ X=CH3, y=CH3, R=CH3 2,5Me-4T2H-K: x=CH3, y=CH3, R=H 2F-4T2Me-K: x=F, y=H, R=CH3 ZOMe-4T2Me-K: x=0Me, y=H, R=CH3 2Me-4T2Me-SI-KI X=CH3, y=CH(CH3)2, R=CH3 2Me-4T2H-51-K: X=CH3, y=CH(CH3)2, R=H 3-Methylphenyl acetate (23) Acetyl chloride (21.78 g, 0.2775 mol) was added in a dropwise manner to a solution of m-cresol In (20.0 g, 0.185 mol) and pyridine (29.26 g, 0.3699 mol) in 75mL of dry benzene at 0°C. The mixture was stirred under argon at room temperature for 24 hours. The reaction mixture was hydrolyzed with 5% HCl (25 mL) and separated. The organic layer was extracted four times with 30 mL portions of 2N NaOH and dried over magnesium sulfate. The extract was concentrated in vacuo to give a crude yellow oil. 120 Purification of the crude product by vacuum distillation gave 3-methylphenyl acetate 2a as a colorless liquid (27.1 g, 98%). 1H NMR (300MHz; CDCI3) : 6 2.27(s, 3H), 2.34(s, 3H), 6.86( m, 2H), 7.02(broad d, J=7.8 Hz, 1H), 7.24(dd, J=8.4 Hz and 7.2 Hz, 1H). 130 NMR(75MHz; CDC13) : 21.05, 21.22, 118.44, 122.10, 126.57, 129.07, 139.53, 150.56 and 169.54. IR(CCI4): 1208, 1370, 1489, 1590, 1615, 1769, 2924 and 3036 cm-1. 2,5-Dimethylphenyl acetate (2b) The acetate was prepared in the same manner as 3-methylphenyl acetate 2a by reacting 2,5-dimethylphenol lb (25.0 g, 0.2046 mol), pyridine (32.37 g, 0.4092 mol) and acetyl chloride (24.09 g, 0.3069 mol) in benzene at 0°C. The product was obtained as a colorless liquid in 93% yield [Chem. Abstracts Registry # 877-48-5]. 1H NMR (300MHz; CDC13) : 8 2.13(s, 3H), 2.30(s, 3H), 2.31(s, 3H), 6.82( s, 1H), 6.94(broad d, J=7.83 Hz, 1H), 7.10(d, J=7.71 Hz, 1H). . 13C NMR(75MHz; c003): 15.63, 20.72, 20.79, 122.29, 126.70, 126.77, 130.75, 136.81, 149.07 and 169.29. IR(CCI4): 1208, 1441, 1458, 1510, 1580, 1773, 2867 and 2955 cm-1. 3-Fluorophenyl acetate (2c) The acetate was prepared in the same manner as 3-methylphenyl acetate 2a by reacting 3-fluorophenol 1c (10.0 g, 0.089 mol), pyridine (14.08 g, 0.178 mol) and acetyl chloride (10.50 g, 0.1340 mol) in benzene at 0°C. The reaction was completed in 24 hours at room temperature. Purification by vacuum distillation gave 3-fluorophenyl acetate 2c( 11.20 g, 82%) as a colorless liquid [Chem. Abstracts Registry # 701-83-7]. 121 1H NMR (300MHz; (20013) : 8 2.28(s, 3H), 6.82( dd, J=2.5 & 2.3 Hz, 1H), 6.92(ddd, J=8.5, 2.5 & 0.9 Hz, 1H), 7.25(m, 2H). 3-Methoxyphenyl acetate (2d) The acetate was prepared in the same manner as 3-methy1phenyl acetate 2a by reacting 3-methoxyphenol 1d (15.0 g, 0.121 mol), pyridine (19.14 g, 0.242 mol) and acetyl chloride (14.23 g, 0.1815 mol) in benzene at 0°C. The reaction was completed in 24 hours at room temperature. Purification by vacuum distillation gave 3-methoxyphenyl acetate 2d ( 19.09 g, 95%) as a pale yellow liquid [Chem. Abstracts Registry # 5451-83- 2]. 1H NMR (300MHz; CDC13) : 8 2.27(s, 3H), 3.77(s, 3H), 6.63( dd, J=2.31 Hz and 2.28 Hz, 2H), 6.67(ddd, J=8.01 Hz, 2.19 Hz and 0.87 Hz, 1H), 6.76(ddd, J=8.4 Hz. 2.49 Hz and 0.81 Hz, 1H), 7.26(dd, J=8.16 Hz and 8.13 Hz, 1H). 13C NMR(300MHz; CDCI3) : 21.04, 55.29, 107.54, 111.56, 113.70, 129.74, 151.55 160.40 and 169.31. IR(CCI4) : 1468, 1491, 1609, 1789, 2838, 2959 and 3005 cm'l. 2-Isopropyl-5-methylphenyl acetate (2e) The acetate was prepared in the same manner as 3-methylphenyl acetate 23 by reacting thymol 1e (15.0 g, 0.1 mol), pyridine (15.8 g, 0.2 mol) and acetyl chloride (11.75 g, 0.15 mol) in benzene at 0°C. The reaction was completed in 24 hours at room temperature. Purification by vacuum distillation gave 2-isopropyl—5-methylphenyl acetate 2e ( 17.1 g, 89%) as a colorless liquid [Chem. Abstracts Registry # 6380-28-5]. 4-Hydroxy-Z-methylacetophenone (3a) A solution of 3-methylphenyl acetate 2a (15.0 g, 0.1 mol) in nitrobenzene (50 mL) was added dropwise to a solution of aluminum chloride (26.67 g, 0.2 mol) in nitrobenzene 122 (200 mL) at 0°C under argon. The reaction mixture was warmed to room temperature and stirred for 96 hours. After the stated period, the mixture was hydrolyzed with 5% HCl (200 mL). The nitrobenzene layer was diluted with ether (200 mL) and extracted with 50 mL portions of 2N N a0H. The combined aqueous washings were acidified with HCl to a pH of 3-5 and extracted with ether (6 x 100 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by vacuum distillation gave 4—hydroxy-2-methylacetophenone 3a as a white solid (7 .5 g, 50%), m.p(129-131°C). 1H NMR (300MHz; CDCI3) : 6 2.53(s, 6H), 6.67( broad s, 1H), 6.70(d, J=2.55 Hz, 1H) and 7.69(d, J=8.64 Hz, 1H). 13C NMR(75MHz; CDCI3) : 22.54, 29.05, 112.38, 118.96, 133.05, 148.21, 158.77, and 200.16. 4-Hydroxy-2,5-dimethylacetophenone (3b) 2,5—Dimethylphenyl acetate 2b was converted to the ketone by Fries rearrangement in the same manner as 3-methylphenyl acetate. A solution of 2,5-dimethylphenyl acetate 2b (20.0 g, 0.122 mol) in nitrobenzene was added to a solution of aluminum chloride (40.65 g, 0.3049 mol) in nitrobenzene at 0°C. The reaction was completed in 96 hours at room temperature with a 49.1% yield. The product was recrystallzed twice from hexane:ether (40:60) [Chem. Abstracts Registry # 26216-10-4]. 1H NMR (300MHz; CDCI3) : 5 2.13(s, 3H), 2.51(s, 3H), 2.52(s, 3H), 6.6( s, 1H), 6.65(s, 1H) and 7.5(s, 1H). 2-Fluoro-4-hydroxyacetophenone (3c) 3-Fluorophenyl acetate 2c (11.20 g, 0.0727 mol) was added dropwise to a cooled solution (5°C) of aluminium chloride (14.54 g, 0.10905 mol) dissolved in dichloroethane (30mL). Upon complete addition of the acetate, the ice bath was removed and the reaction mixture was refluxed for four days under an argon atmosphere. The reaction mixture was 123 then poured over 200 g of ice and extracted with ether (5x50mL). The combined extracts were washed twice with 25mL portions of brime, dried over magnesium sulfate and concentrated in vacuo. Purification of the crude product by dry column flash chromatography on silica gel (hexane:ethyl acetate, 90:10) gave 2.4 g of 2-fluoro-4— hydroxyacetOphenone and 4.8 g of 4—fluoro-2-hydroxyacetophenone. 4-fluoro-2-hydroxyacetophenone [Chem. Abstracts Registry # 98619—07-9] 1H NMR (300MHz; CDC13) : 8 2.58(d, J=5.2 Hz,3H), 6.02(s, 1H), 6.58(dd, J=12.6 & 2.4 Hz, 1H), 6.72(dd, J=8.8 & 2.5 Hz, 1H), 7.845(t, J=8.7 Hz, 1H). 4-Hydroxy-2-methoxyacetophenone (3d) 3-Methoxyphenyl acetate 2d was converted to the ketone by a Fries rearrangement in the same manner as 3-methylphenyl acetate 2a. To a solution of aluminum chloride (19.27 g, 0.1445 mol) in nitrobenzene was added a solution of 3-methoxyphenyl acetate 2d (12.0 g, 0.073 mol) in nitrobenzene in a dropwise manner at 0°C under argon. The reaction was completed in 96 hours at room temperature with a 40% yield. The product was recrystallized from ethanol:water(50:50) (mp 138-139°C, 111.87 138°C). 1H NMR (300MHz; CDCI3) : 6 2.7(s, 3H), 3.9(s, 3H), 6.45(m, 2H), and 7.75(d, J=8.8 Hz, 1H). 4-Hydroxy-5-isopropyl-2-methyIacetophenone (3e) 2-Isopropyl-5-methylphenyl acetate 2e was converted to the ketone in the same manner as 3-fluorophenyl acetate 2c, using a 1.2 molar excess of aluminum chloride in respect to the acetate 2e. Purification of the crude reaction mixture by dry column flash chromatography, followed by recrystallization in wet ethanol gave 4—hydroxy-5-isopropyl- 2-methylacetophenone as a off-white powder in 81% yield (mp 123-125°C) [Chem. Abstracts Registry # 37847-35-1]. 124 1H NMR (300MHz; CDCI3) : 8 1.25(d, J=6.9 Hz, 6H), 2.17(s, 3H),2.54(s,3H), 3.l7(sept., J=6.9 Hz, 1H), 5.21(br s, 1H), 6.57(s, 1H), 7.60(s, 1H). 4-(3'-Methyl-3'-buten-1'-oxy)-2-methylacetophenone (2Me-4T2Me-K) 4-Hydroxy-2-methylacetophenone 3a (4.0 g, 0.0266 mol), 4-tosyl-2-methyl-1- butene (4.60 g, 0.019 mol) and anhydrous potassium carbonate (11.03 g, 0.078 mol) in dry acetone (50 mL) were refluxed under argon for 40 hours. The cooled mixture was gravity filtered to remove the salt formed during the reaction and concentrated in vacuo. The resulting yellow oil was diluted with ether (50 mL) and extracted with 2N Na0H (4x25mL). The organic layer was dried over magnesium sulfate, gravity filtered and concentrated in vacuo to give a crude yellow liquid. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 95:5) gave 4-(3'-methyl-3'- buten-1'-oxy)-2-methylacetophenone 2Me-4T2Me-K in 68% yield. 1H NMR (300MHz; CDCI3) : 5 1.78(3, 3H), 2.48(t, J=6.87 Hz, 2H3), 2.52(s, 3H), 2.53(s, 3H), 4.09(t, J=6.87 Hz, 2H7), 4.78(br s[allylic coupling], 1H1()), 4.83(br s[allylic coupling], 1H1()), 6.73(m, 2H3,5) and 7.72(m[second order],lH6). 13C NMR(75MHz; CDCI3): 22.6, 22.7, 29.0, 37.0, 66.4, 111.0, 112.2, 118.03, 129.8, 132.5, 141.8, 142.1, 161.2 andl99.3. IR(CC|4): 1138.2, 1240.4, 1317.6, 1566.4, 1603.0, 1680.2, 2930.2, 2972.7, and 3080.7 cm-l. MS(m/z):4l.1, 43.1, 69.1, 135.1(Base), 150.1, 218.1 and 219.2(M+1). HRMS: calculated 218.1307 and found 218.1300 125 4-(3'-Buten-l'-oxy)-2-methylacetophenone (2Me-4zn-K) 4-Hydroxy-2-methylacetophenone 3a (5.40 g, 0.036 mol), 4—bromo-1-butene (7.28 g, 0.054 mol) and anhydrous potassium carbonate (14.93 g, 0.108 mol) in 50 mL of dry acetone were refluxed under an argon atmosphere for 90 hours. The cooled mixture was gravity filtered to remove potassium bromide formed during the reaction and concentrated in vacuo. The resulting yellow oil was diluted with ether (50mL) and extracted with 2N NaOH (4x25mL). The organic layer was dried over magnesium sulfate, gravity filtered and concentrated in vacuo to give a crude yellow liquid. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 90: 10) gave 4—(3'-buten-l'-oxy)-2-methylacetophenone 2Me-42H-K in 57.9% yield. 1H NMR (300MHz; CDCI3) : 5 2.52(s, 3H), 2.57-2.50(m, 2H3), 4.040, J=6.72 Hz, 2H7), 5.20-5.08(m, 2H10), 5.88(ddt, J: 17.1 Hz, 10.23 Hz, and 6.69 Hz, 1H9), 6.73(m, 2H3,5) and 7.72(d, J=9.39 Hz, 2H6). 13c NMR(75MHz; CDCI3): 22.54, 28.99, 33.39, 67.09, 110.93, 117.20, 117.96, 129.80, 132.46, 134.00, 142.10, 161.21 and 199.30. IR(CC|4): 1138.15, 1240.39, 1317.55, 1566.40, 1603.05, 1680.21, 2928.32, and 3082.64 cm-l. MS(m/z):43, 55.1, 77.1, 135.(Base), 189.1, 204.1 and 205.1(M+1). HRMS: calculated 204.1151 and found 204.1138 126 4-(3'-Methyl-3'-buten-l'-oxy)-2,5-dimethylacetophenone (lAP-2Me-4T2Me-5Me) The ketone was prepared from 4-hydroxy-2,5-dimethylacetophenone 3b (3.0 g, 0.0183 mol), 4-tosyl-2-methyl-l—butene (6.58 g, 0.0274 mol) and potassium carbonate (7.59 g, 0.0549 mol) in the same fashion as that of 4-(3'-methyl-3'-buten-1'-oxy)-2- methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 95:5) gave 4-(3'-methyl-3'-buten-l'-oxy)-2,5- dirnethylacetophenone 1AP-2Me-4T2Me-5Me in 71% yield. 1H NMR (300MHz; CDCI3) : 5 1.80(s,3H), 2.18(s, 3H), 2.510, J=6.5 Hz, 2H8), 2.52(s, 3H), 2.53(s,3H), 4.100, J=6.6 Hz, 2H7), 4.79(d, J=0.93 Hz, 1H1()), 4.83(d, 1.53 Hz, 1H1()), 6.62(s, 1H3) and 7.54(s, 1H6). 13C NMR(75MHz; CDCI3): 15.6, 22.3, 22.6, 29.0, 37.1, 66.4, 112.1, 113.9, 123.5, 128.9, 132.9, 141.9, 159.3, and 199.4. IR(CC|4): 11059.0, 1142, 1257.8, 1321.4, 1562.5, 1678.3, 2928.3 and 2972.7 cm-l. 4-(3'-Buten-1'-oxy)-2,5-dimethylacetophenone (2,5Me-4T211-K) The ketone was prepared from 4-hydroxy-2,5-dimethylacetophenone (3.0 g, 0.0183 mol), 4-bromo-l-butene (3.71 g, 0.0274 mol) and potassium carbonate (7.59 g, 0.0549 mol) in the same fashion as that of 4-(3'-buten-1'-oxy)-2-methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl 127 acetate, 93:7) gave 4-(3'-buten-1'-oxy)-2,5-dimethylacetophenone, 2,5Me-4T2H-K in 62% yield. 1H NMR (300MHz; CDCI3) : 5 2.17(s, 3H), 2.49(d, J=0.72 Hz, 3H), 2.52(s, 3H), 2.54(br t, J=6.57 Hz, 2H3), 4.010, J=6.57 Hz, 2H7), 5.10-5.06(br d, 1:10.26 Hz, 1H1()), 5.17-5.11(br d, 1:17.22, 1H1()), 5.95-5.81(ddt, 17.1, 10.32 & 6.7 Hz, 1H9), 6.59(s, 1H3) and 7.52(s, 1H6). 13C NMR(75MHz; CDCI3): 15.55, 22.30, 28.92. 33.49, 67.06, 114.02, 116.98. 123.47, 128.99, 132.88, 134.15, 139.37, 159.25 and 199.39. IR(CC|4): 2928.3, 1678.3, 1610.8, 1564.5, 1356.1, 1321.4, 1257.8, 1142.0, 804.4 MS(m/z): 41.1, 43.1, 69.1, 135.1(Base), 150.2, 218.2 and 219.2(M+1). HRMS: calculated 218.1307 and found 218.1301 4-(3'-Methyl-3'-buten-1'-oxy)-2-fluoroacetophenone (2F-4T2Me-K) The ketone was prepared from 4-hydroxy-2-fluoroacetophenone 3c (2.40 g, 0.0156 mol), 4-tosyl-2—methyl-1-butene (4.49 g, 0.0187 mol) and potassium carbonate (6.468 g, 0.0468 mol) in the same fashion as that of 4-(3’-methyl-3'-buten-1'-oxy)-2- methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 95:5) gave 4-(3'—methyl-3'-buten-1'-oxy)-2- fluoroacetophenone 2F-4T2Me-K in 71.5% yield. 1H NMR (300MHz; CDCI3) : 5 1.78(3, 3H), 2.500, 1:6.84 Hz, 2H3), 2.57(d, 1:5.22 Hz, 3H), 4.100, 1:6.81 Hz, 2H7), 4.7705: s, 1H1()), 4.84(br s, 1H1()), 6.58(dd, 1:13.14 & 2.4 Hz, 1H3), 6.72(dd, 1:8.79 & 2.49 Hz, 1H5), 7.85(t, J=8.79 Hz, 1H6). 13C NMR(75MHz; CDCI3): 22.7, 31.2, 36.8, 67.0, 102.0(d), 111.0(d), 112.4, 118.0(d), 132.0(d), 141.4, 164.1(d), 165.5 and 194.4. IR(CC|4): 1116.9, 11128.5, 1265.5, 1361.9, 1616.6, 1684.1, 2938 and 3080.7 cm-l. MS(m/z):41.1(Base), 43.1, 69.1, 139.1, 155.1, 222.2 and 223.2. HRMS: calculated 222.1056 and found 222.1021 4-(3'-Methyl-3'-buten-1'-oxy)-2-methoxyacetophenone (20Me-4T2Me-K) The ketone was prepared from 4-hydroxy-2-methoxyacetophenone 3d (2.25 g, 0.0136 mol), 4-tosyl-2-methyl-l-butene (4.878 g, 0.0203 mol) and potassium carbonate (5.64 g, 0.041 mol) in the same fashion as that of 4-(3'-methyl-3'-buten-1'-oxy)-2- methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 95:5) gave 4-(3'-methyl-3'-buten-1'-oxy)-2- methoxyacetophenone 20Me-4T2Me-K. ca 0X 0n 2-1 1H NMR (300MHz; CDCI3) : a l.79(s, 3H), 2.490, J=6.8 Hz, 2H3), 2.55(s, 3H), 3.87(s, 3H), 4.110, 1:6.8, 2H7), 4.78(br s, 1H1()), 4.84(br s, 1H1()), 6.44(d, 1:2.2 Hz, 1H3), 6.50(dd, 1:8.73 & 2.3 Hz, 1H5) and 7.79(d, J=8.7 Hz, 1H6). 13C NMR(75MHz; CDCI3): 22.6, 31.7, 36.9, 55.4, 66.5, 98.7, 105.4, 112.2. 120.9, 132.5, 141.6, 160.9, 163.8 and 1975.. IR(CC|4): 1035.9, 1140.1, 1167.1, 1203.8. 1265.5, 1358.1, 1603.1, 1672.5 and 2939.9 cm-l. MS(m/z): 39, 41, 43. 69, 151(base), 166, 219, 234 and 235(M+1) HRMS: calculated 234.1256 and found 234.1250. S-Isopropyl-4-(3'-methyl-3'-buten-1'-oxy)-2-methylacetophenone (2Me-4T2Me-SI-K) The ketone was prepared from 4-hydroxy-5-isopropyl-2-methylacetophenone 3e (2.25 g, 0.0136 mol), 4-tosyl-2-methyl-1-butene (4.878 g, 0.0203 mol) and potassium carbonate (5.64 g, 0.041 mol) in the same fashion as that of 4-(3'-methyl-3'-buten-1'- oxy)-2-methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 95:5) gave 5-isopropyl-4-(3'-methyl-3'-buten-1'-oxy)- 2-methylacetophenone, 2Me-4T2Me-SI-K in 75% yield. me sill me 130 1H NMR (300MHz; CDCI3) : 6 1.20(d, J=6.93 Hz, 6H), 1.79(s, 3H), 2.52(br t, J=6.57 Hz, 2H8), 2.53(s, 3H), 2.54(s, 3H), 3.25(septet, J=6.9 Hz, 1H11), 4.11(t, J=6.6 Hz, 2H7), 4.80(m, 2H 10), 6.64(s, 1H3) and 7.59(s, 1H6). 13C NMR(75MHz; CDCI3): 22.36, 22.45, 22.63, 26.82, 29.19, 37.27, 66.36, 112.282, 114.35, 128.68, 129.47, 133.97, 139.20, 141.96, 158.58 and 199.96. 5-Isopropyl-4-(3'-buten-1'-oxy)-2-methylacetophenone (2Me-4T2H-SI-K) The ketone was prepared from 4—hydroxy-5-isopropyl-2-methylacetophenone 3e (2.25 g, 0.0136 mol), 4-bromo-1-butene (4.878 g, 0.0203 mol) and potassium carbonate (5.64 g, 0.041 mol) in the same fashion as that of 4-(3'-methyl-3'-buten-1'-oxy)-2- methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 95:5) gave 5-isopropyl-4-(3'-buten-1'-oxy)-2- methylacetophenone, 2Me-4T2H-SI-K in 61% yield. 131 1H NMR (300MHz; CDCI3) :5 l.21(d, J=6.9 Hz, 6H), 2.53(s, 3H), 2.54(s,3H), 2.56(dddt, 1:6.54, 6.54, 1.32 & 1.29 Hz, 2H3), 3.26(septet, J=6.87 Hz, 1H11), 4.050, 1:6.5 Hz, 2H7), 5.10(ddt, 1:10.23, 1.83 & 1.17 Hz, 1H1()), 5.l6(ddt, 1:17.19, 1.67 & 1.59 Hz, 11110), 5.90(ddt, 1:17.07, 10.26 & 6.78 Hz, 1H9), 6.63(s, 1H3) and 7.59(s, 1H6). 13c NMR(75MHz; CDCI3): 22.31, 22.38. 26.83, 29.11, 33.62, 67.13, 114.32, 117.10, 128.62, 129.40, 133.83, 134.32, 139.14, 158.49 and 199.80. IR(CC|4): 1055.2, 1072.6, 1165.1, 1240.1, 1356.1, 1558.7, 1608.8, 1678.3 and 2964.9cm-1. MS(m/z): 55, 91, 149, 177(base), 189, 231,246 and 247(M+1). HRMS: calculated 246.1620 and found 246.1624. 132 Br CD3 CD3 1. n-BuLi A 1- A103 2 2. CD31 2. Acetic Anhyride OM OMe e OMe O NaCN CD CD 0 ‘potassium carbonate 3-Methyl(d3)anisole A solution of 3-bromoanisole (2.0 g, 0.0107 mol) in tetrahydrofuran (25mL) was cooled to -78°C. n-BuLi (5.88 mL, 2.0M) in hexanes was added dropwise to the stirred mixture. The mixture was stirred at -78°C for 1.5 hours and then transferred via a double- ended needle (using argon pressure) to a -78°C solution of iodomethane-d3 (1.55 g, 0.0107 mol) in tetrahydrofuran (15 mL). The mixture was stirred at -78°C for thirty minutes and was slowly warmed to 0°C. The mixture was quenched with saturated NH4C1 solution (20mL) at 0°C. The mixture was tranferred to a separatory funnel with ether (100mL) and the organic phase was washed with 50 mL portions of water and saturated NaCl solution. The organic phase was dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification of the crude product by dry column chromatography on silica gel (hexane:ethyl acetate=95:5) gave 3-methyl(d3)anisole (1.10 g, 82%) [Chem. Abstracts Registry # 20369-34—0]. 133 4-Methoxy-2-methy|(d3)acetophenone A solution of 3-methyl(d3)anisole (1.10 g, 0.0088 mol) in dry carbon disulphide (25 mL) was cooled to 5°C. Finely powdered anhydrous aluminium chloride (2.58 g, 0.01936 mol) was added to the stirred mixture. Freshly distilled acetic anhydride (0.0898 g, 0.0088 mol) was then slowly added via a syringe over a 10 minute period. The mixture was allowed to warm to room temperature and refluxed for 24 hours. The mixture was cooled to room temperature and poured over ice (50 g). The mixture was transferred to a separatory funnel with ether (100mL) and the organic phase was washed with 50 mL portions of 10% HCl, water, and saturated NaCl solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated at reduced pressure. Purification of the crude product by dry column flash chromatography on silica gel (hexane:ethyl acetate=90: 10) gave 4—methoxy-2-methyl(d3)acetophenone in 66% yield. 4-Hydroxy-2-methyl(d3)acetophenone 4-Methoxy-2-methyl(d3)acetophenone (1.0 g, 0.006 mol) and sodium cyanide (1.47 g, 0.03 mol) were suspended in DMSO (30 mL) and heated at 165°C (bath temperature) under argon. After 16 hours, the reaction mixture was poured over ice and acidified with 6N HCl (caution : HCN evolution). The mixture was tranferred to a separatory funnel with ether (100 mL) and extracted with 25 mL portions of 2N Na0H. The combined aqueous washings were acidified with HCl to a pH of 3-5 and extracted with ether(3x100 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification of the crude product by silica gel column chromatography (hexane:ethyl acetate=90: 10) gave 4-hydroxy-2-methyl(d3)acetophenone in 33% yield. 134 2-Methy|(d3)-4-(3'-methyl-3'-buten-1'-oxy)acetophenone (2D3-4T2Me-K) The ketone was prepared from 4-hydroxy-2-methyl(d3)acetophenone (0.03 g, 0.00196 mol), 4—tosyl-2-methyl-1-butene (0.471 g, 0.00294 mol) and potassium carbonate (0.948 g, 0.0069 mol) in the same fashion as that used for 4-(3'-methyl-3'—buten-1'-oxy)- 2—methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 95:5) gave 2-methy1(d3)-4-(3'-methyl-3'-buten-1'- oxy)acetophenone 2D3-4T2Me-K in 74% yield. 10 NMR (300MHz; 00013) :5 1.790» s, 3H), 2.490, J=6.84 Hz, 2H3), 2.53(s, 3H), 4.100, J=6.81 Hz, 2H7), 4.78011, 1H10), 4.83(m, 1H1()), 6.72(d, 1:2.7 Hz, 1H3), 6.73(dd, J=6.81 & 2.64 Hz, 1H5) and 7.74(m[second order], 1H6). 130 NMR(75MHz; 00013): 22.75, 29.01. 36.98, 66.37. 110.99, 112.19, 118.0. 129.84, 132.51, 141.81, 142.07. 161.27 and 199.39. MS(m/z):4l.2, 43.1, 69.1. 137.2, 138.2(Base), 1532,2212 and 222.3(M+1). HRMS: calculated 221.1496 and found 221.1511 no ma. P10 g3 V1 135 0 o NH2 NH2 NH2 1. BCl3 4 AlCl3 ‘ 2. Acetyl Chloride O M e o H CN "”2 0mm 0 A 1. H01 0 K2C03 7. NaNOz 3. CuCN, NaCN ZCN-4Tm-K 2-Amino-4-methoxyacetophenone A solution of m-anisidine (6.4 g, 0.052 mol) in CH2C12 (30mL) maintained at -50°C was slowly treated with a solution of BC13 in CH2C12 (50 mL, 1M, 0.05 mol) to give a slurry, which was stirred for 30 minutes at -50°C. Freshly distilled acetyl chloride (3.925 g, 0.05 mol) and aluminium chloride (6.67 g, 0.05 mol) were added sequentially. The mixture was stirred at -50°C for one hour , at ambient temperature for18 hours, and at 40°C for three hours. The mixture was cooled to room temperature and then poured over ice (100 g). The aqueous mixture was made alkaline with 10% NaOH, transferred to a separatory funnel with ethyl acetate (200 mL) and extracted with ethyl acetate (4x100mL). The combined organic phases were washed with 100 mL of saturated NaCl, dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification of the crude product (black oil) by column chromatography (diethyl etherzmethylene chloride, 20:80) gave 2-amino—4-methoxyacetophenone (2.64 g, 32%) [Chem. Abstracts Registry # 42465- 53-2]. 2-Amino-4-hydroxyacetophenone 11101 ) 1 Ha [1 SOIUUO 136 A solution of 2-amino-4-methoxyacetophenone (1.5 g, 0.0091 mol) in CH2C12 (25 mL) was treated with aluminium chloride (2.44 g, 0.0182 mol) in five portions. The mixture was stirred for 18 hours, then additional aluminium chloride (1.22 g, 0.0091 mol) was added. The mixture was stirred vigorously for four hours, poured over ice (100 g) and extracted with ethyl acetate (3x100 mL). The combined organic phases were exu'acted with 25 mL portions of 2N Na0H. The combined aqueous washings were acidified with HCl to a pH of 3-5 and extracted with ethyl acetate (3x100 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated at reduced pressure to give 2- amino-4-hydroxyacetophenone as a pale yellow solid (80% yield, mpl63-165°C) [Chem. Abstracts Registry # 90033-64-0]. 2-Amino-4-(3'-methyl-3'-buten-1'-oxy)acetophenone The ketone was prepared from 2-amino-4-hydroxyacetophenone (1.10 g, 0.0073 mol), 4-tosyl-2-methyl-l-butene (1.92 g, 0.008 mol), and potassium carbonate (3.027 g, 0.0219 mol) in the same fashion as that of 4-(3'-methyl-3'-buten-1'-oxy)—2- methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 95:5) gave 2-amino-4-(3'-methyl-3'-buten-1'- oxy)acetophenone in 77.5% yield. 1H NMR (300MHz; 00013) :5 1.78(3, 3H), 2.470, J=6.84 Hz, 2H), 2.490, 3H), 4.05(t, J=6.94 Hz, 2H), 4.77(br s, 1H), 4.83(br s, 1H), 6.09(d, J=2.42 Hz, 1H), 6.23(dd, J=9.0 & 2.46 Hz, 1H), 6.5(br s, 2H) and 7.61(d, J=9.0 Hz, 1H). 5-(3'-Methyl-3'-buten-1'-oxy)-2-acetylbenzonitrile (2CN-4T2Me-K) A solution of 2-amino-4-(3’-methyl-3'-buten-1'-oxy)acetophenone (0.4 g, 0.00183 mol) in water (3 mL) maintained at 5°C was slowly treated with 1.5 mL of concentrated HCl to give the amino salt. The salt solution was subsequently treated with a cooled solution (5°C) of sodium nitrite (0.152 g, 0.002196 mol) in water (2 mL). The diazonium 3131 HR‘ 137 salt was immediately added to a cooled solution (5°C) of sodium cyanide (0.269 g, 0.055 mol) and cuprous cyanide (0.197 g, 0.0027 mol) in water (25 mL). The reaction mixture was stirred for six hours at room temperature. The mixture was filtered through a cotton plug and transferred to a separatory funnel with ether (100 mL). The organic phase was washed with 50 mL portions of water, saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated at reduced pressure. Purification of the crude product by silica gel column chromatography (hexane:ethyl acetate, 95:5) gave 5-(3'- methyl-3'-buten-1'-oxy)-2-acetylbenzonitrile, 2CN-4T2Me-K in 38.5% yield (mp 71- 72°C). 1H NMR (300MHz; CDCI3) : 8 1.79(s, 3H), 2.52(t, J=6.75 Hz, 2H8), 2.63(s, 3H), 4.l4(t, J=6.75 Hz, 2H7), 4.78(br s, 1H1()), 4.86(br s, 1H1()), 7.11(dd, J=8.79 & 2.6 Hz, 1H5), 7.26(d, J=2.6 Hz, 1H3) and 7.87(d, J=8.79 Hz, 1H6). 13C NMR(75MHz; CDCI3): 22.64, 27.38, 36.66, 67.20, 112.60, 112.78, 118.02, 121.18, 131.92, 132.22, 141.13, 161.69 and 194.58. IR(CCI4) : 737, 909, 1260, 1319, 1360, 1597, 1688, 1742, 2180 and 2940 cm'l. MS(m/z):39, 41, 69(Base), 146, 229 and 230(M+1). HRMS: calculated 229.1103 and found 229.1107. 138 Br Br CF3 CF3 01:3 V 0H Br tether 2 = C32 Potassium Carbonate 4-Bromo-3-trifluoromethylphenol A solution of 3-trifluoromethylphenol (5.0 g, 0.03086 mol) in carbon disulfide (10 mL) maintained at 0°C was slowly treated with a solution of bromine (5.0 g, 0.0313 mol) in carbon disulfide (10 mL) over a 10 minute period. The mixture was stirred at 0°C for one hour, follwed by three hours at room temperature. The resulting reaction mixture was added to water (25 mL) and then subjected to repeated extraction with methylene chloride (150 mL). The methylene chloride layer was washed with aqueous sodium bicarbonate, water, and saturated sodium chloride. The organic layer was dried over sodium sulfide, gravity filtered and concentrated at reduced pressure. Purification of the crude product by dry column flash chromatography on silica gel (hexane:ethyl acetate, 90: 10) gave 4-bromo- 3-trifluoromethylphenol (3.1 g, 42%). 1H NMR (300MHz; 00013) : 5 5.65(s, 1H), 6.84(dd, J=8.6 & 2.9 Hz, 1H), 7.15(d, J=2.9 Hz, 1H) and 7.51(d, J=8.6 Hz, 1H). 1-Bromo-2-trifluoromethyl-4-(3'-methyl-3'-buten-1'-oxy)benzene The bromobenzene was prepared from 4-bromo-3-trifluoromethylphenol (2.0 g, 0.0083 mol) , 4-tosyl-2-methyl-1-butene (2.39g, 0.00996 mol) and potassium carbonate 139 (3.44 g, 0.0249 mol) in the same fashion as that for 4-(3'-methyl-3'-buten-1'-oxy)-2- methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 95:5) gave 1-bromo-2—trifluoromethyl-4-(3'-methyl-3'- buten-1'-oxy)benzene in 64% yield. 1H NMR (300MHz; CDCI3) : 8 1.78(s, 3H), 2.49(t, J=6.7 Hz, 2H), 4.06(t, J=6.7 Hz, 2H), 4.78(br s, 1H), 4.84(br s, 1H), 6.89(dd, J=8.8 & 3.0 Hz, 1H), 7.20(d, J=3.0 Hz, 1H) and 7.55(d, J=8.8 Hz, 1H). 2-Trifluoromethyl-4-(3'-methyI-3'-buten-1'-oxy)acetophenone (2CF3-4T2Me-K) A solution of l-bromo-2-trifluoromethyl-4-(3'-methyl—3'-buten-1'-oxy)benzene (0.5 g, 0.0016 mol) in tetrahyrofuran (10mL) was cooled to -78°C. n-BuLi (1.0 mL of 2.0M) in hexanes was added dropwise to the stirred mixture. The mixture was stirred at -78°C for 1.5 hours and then transferred via a double-ended needle (using argon pressure) to a -7 8°C solution of acetic anhydride (0.408 g,0.004 mol) in tetrahydrofuran (15 mL). The mixture was stirred at -78°C for thirty minutes and was slowly warmed to 0°C. The mixture was stirred for 2 hours at 0°C and then quenched with saturated NH4C1 solution (20mL). The mixture was tranferred to a separatory funnel with ether (100mL) and the organic phase was washed with 50 mL portions of water and saturated NaCl solution. The organic phase was dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate=95:5) gave 2-trifluoromethyl-4-(3'-methyl-3'-buten-l'- oxy)acetophenone 1AP-2CF3-4T2Me in 32% yield. 10 NMR (300MHz; 00013) :5 1.79(s, 3H), 2.50011 t, J=6.7 Hz, 2H3), 2.54(s, 3H), 4.120, 1:6.72 Hz, 2H7), 4.78(br s, 1H1()), 4.85(br 8,1H10), 7.03(dd, 1:8.60 & 2.50,1H5), 7.2(d, J=2.49 Hz, 1H3) and 7.50(d, J=8.7 Hz, 1H6). 130 NMR(75MHz; 00013): 22.71, 30.8, 36.85, 66.93, 112.49, 113.69(q, 1:5.6 Hz), 116.50, 123.29(q, 1:272 Hz), 130.31, 141.48, 160.36, and 200.11. IR(CCI4) : cm-l. MS(m/z):41.1, 43.1, 69.1(base), 189.0, 205.1, 272.2 and 273.2(M+1). HRMS: calculated 272.1024 and found 272.1013. Br OM e n-BuLi o o Acetic Anhyd. O I < tether NaCN ‘_ Potassitnn Carbonate DMSO 2,6Me-4Tm-K 141 3,5-Dimethylanisole 3,5-Dimethylphenol (20 g, 0.164 mol), iodomethane (27.9 g, 0.196 mol) and anhydrous potassium carbonate (45.3 g, 0.328 mol) in dry acetone (200 mL) were refluxed for 24 hours under argon. The cooled mixture was filtered and concentrated at reduced pressure. The resulting oil was diluted with ether (100mL) and extracted with 2N Na0H (4x25mL). The ether layer was dried over magnesium sulfate, gravity filtered and concentrated. Purification of the crude product by fractional distillation gave 3,5- dimethylanisole (bp 193-195°C) in 72% yield. 111 NMR(300MHz;CDCI3) : 56.590, 1H), 6.53(s, 2H), 3.76(s, 3H) and 2.28(s, 6H). 4-Bromo-3,5-dimethylanisole To a solution of 3,5-dimethylanisole (5.0 g, 0.0373 mol) in carbon tetrachloride (80 mL) were added N-bromosuccinimide (7.96 g, 0.0447 mol) and Merck 60 silica gel (20 grrnas). The mixture was vigorously stirred at room temperature for 22 hours. The insoluble material was removed by filteration. The organic layer was then washed with aqueous sodium thiosulfate and dried over magnesium sulfate. The solution was gravity filtered and concentrated at reduced pressure. Purification of the crude product by kugelrohr distillation gave 7.33 g (92%) of 4-bromo-3,5-dimethylanisole. IH NMR(300MHz;CDCl3) : 86.63(s, 2H), 3.75(s, 3H) and 2.340, 6H). MS(M/Z): 39, 40, 51, 65, 77, 91, 92, 105, 135, 171, 173, 214 and 216(Base and M+1). 2,6-Dimethyl-4-methoxyacetophenone A solution of 4-bromo-3,5-dimethylanisole (3.0 g, 0.0141 mol) in dry ether (25mL) was cooled to -78°C and 14 mL of 2.0M n-BuLi in hexanes was added dropwise to the stirred mixture. The mixture was stirred at -78°C for one hour and then transferred via 142 a double-ended needle (using argon pressure) to a —78°C solution of acetic anhydride (5.75 g, 0.0564 mol) in ether (20 mL). The mixture was stirred at -78°C for one hour and was slowly warmed to room temperature. The mixture was quenched with saturated NH4C1 solution (25mL). The mixture was tranferred to a separatory funnel with ether (100mL) and the organic phase was washed with 50 mL portions of water and saturated NaCl solution. The organic phase was dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification of the crude product by dry column flash chromatography on silica gel (hexane:ethyl acetate=90: 10) gave 2,6-dimethyl-4-methoxyacetophenone (0.44 g, 18%) [Chem. Abstracts Registry # 104174-28-9]. 1H NMR(300MHz;CDCI3) : 86.53(s, 2H), 3.76(s, 3H), 2.43 (s, 3H) and 2.22(s, 6H). 2,6-Dimethyl-4-hydroxyacetophenone 2,6-Dirnethyl-4-methoxyacetophenone (0.44 g, 0.00247 mol) and sodium cyanide (0.605 g, 0.01235 mol) were suspended in DMSO (15 mL) and heated at 145°C (bath temperature) under argon. After 20 hours, the reaction mixture was poured over ice and acidified with 6N HCl (caution : HCN evolution). The mixture was tranferred to a separatory funnel with ether (50 mL) and extracted with 25 mL portions of 2N Na0H. The combined aqueous washings were acidified with HCl to a pH of 3—5 and extracted with ether (3x50 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification of the crude product by silica gel column chromatography (hexane:ethyl acetate, 90:10) gave 2,6-dimethyl-4:hydroxyacetophenone (0.0759 g) [Chem. Abstracts Registry # 91060-92-3]. 143 2,6-Dimethyl-4-(3'-methyl-3'-buten-1'-oxy)acetophenone (2,6Me-4T2Me-K) The ketone was prepared from 2,6-dimethyl-4-hydroxyacetophenone (0.0759 g, 0.0046 mol), 4-tosyl-2-methyl-l-butene (0.1333 g, 0.0056 mol) and potassium carbonate (0.3174 g, 0.0023 mol) in dry acetone in the same fashion’as that of 4-(3'-methyl-3'- buten-1'-oxy)-2-methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate. 95:5) gave 2,6-dimethyl-4-(3'-methyl- 3'—buten-1'-oxy)acetophenone. 1H NMR (300MHz; 00013) :5 1.78(br s, 3H), 2.21(s, 6H), 2.43(s, 3H), 2.460, J=6.87 Hz, 2H3), 4.030, 1:6.81 Hz, 2H7) and 6.54(s, 2H3,5). 130 NMR(75MHz; 00013): 19.61, 22.77, 32.41. 37.12, 66.27, 111.99, 113.76. 134.45, 135.44, 142.10, 158.72 and 208.01. MS(m/z): 69, 77, 91, 121, 149(base), 164, 217. 232, and 233(M+1). HRMS: calculated 232.1464 and found 232.1462. 144 Br Br Br tether —2—> ——> 032 K2C03 4-Bromo-3-isopropylphenol Bromination of 3-isopropylphenol was carried out in the same manner as 4-bromo- 3—trifluorophenol. A solution of 3-isoproylphenol (5.0 g, 0.0367 mol) in carbon disulfide was slowly treated with a solution of bromine (7.33 g, 0.0459 mol) in carbon disulfide at 0°C. The reaction was completed in three hours at room temperature. Purification of the crude product by dry flash column chromatography (hexane:ethyl acetate, 90: 10) gave 4- bromo-3-isopropylphenol (2.90 g, 37%). i 1H NMR (300MHz; CDCI3) : 8 1.20(d, J=6.84 Hz, 6H0, 3.27(sept., J=6.87 Hz, 1H), 5.03(br s, 1H), 6.53(dd, J=8.6 & 3.0 Hz, 1H), 6.75(d, J=3.0 Hz, 1H) and 7.35(d, J=8.6 Hz, 1H). 4-Bromo-1-(3'-methyl-3'-buten-l'-oxy)-3-isopropylbenzene The coupled product was prepared in the same fashion as that of 4—(3'-methyl-3'- buten-1'-oxy)-2-methylacetophenone by reacting 4-bromo-3-isopropylphenol (2.90 g, 0.0135 mol), 4-tosyl-2-methyl-butene (3.89 g, 0.0162 mol) and potassium carbonate (5.60 g, 0.0405 mol) in acetone. Purification of the crude product by silica gel column 145 chromatography (hexane:ethyl acetate, 90:10) gave 4-bromo-1-(3'-methyl-3'-buten-1'- oxy)-3-isopropylbenzene (2.6 g, 68%). 1H NMR (300MHz; 00013) :5 1.20(d, J=6.87 Hz, 6H), 1.79(s, 3H), 2.47011 1, J=6.86 Hz, 2H), 3.29(sept., J=6.87 Hz, 1H), 4.02(t, J=6.87 Hz, 2H), 4.78(m, 1H), 4.83(m, 1H), 6.59(dd, J=8.73 & 3.03 Hz, 1H), 6.81(d, J--'3.03 Hz, 1H) and 7.37(d, J=8.73 Hz, 1H). 2-IsopropyI-4-(3'-methyl-3'-buten-1'-oxy)acetophenone (21-4T2Me-K) A solution of 4-bromo-l-(3'-methyl-3'-buten-1'-oxy)-3-isopropylbenzene (1.5 g, 0.0053 mol) in dry tetrahydrofuran (25mL) was cooled to -7 8°C and 4 mL of 2.0M n-BuLi in hexanes was added dropwise to the stirred mixture. The mixture was stirred at -78°C for two hours and then transferred via a double-ended needle (using argon pressure) to a -78°C solution of freshly distilled acetic anhydride (2.16 g, 0.0212 mol) in tetrahydrofuran (20 mL). The mixture was stirred at -78°C for one hour and was slowly warmed to room temperature, followed by refluxing for four hours. The mixture was quenched with saturated NH4C1 solution (25mL). The mixture was tranferred to a separatory funnel with 100mL ether and the organic phase was washed with 50 mL portions of water and saturated NaCl solution. The organic phase was dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification of the crude product by dry flash column chromatography on silica gel (hexane:ethyl acetate, 95:05) gave 2-isopropyl-4-(3'-methyl- 3'-buten-1'-oxy)acetophenone 21-4T2Me-K (0.40 g, 31%). 146 1H NMR (300MHz; 00013) : 5 1.20(d, J=6.81 Hz, 6H), 1.80(s, 3H), 2.500. J=6.87 Hz, 2H3), 2.53(s, 3H), 3.730ch 1:6.85 Hz, 1H11), 4.100, J=6.86 Hz, 2H7), 4.80(m, 2H10), 6.70(dd, 1:8.61 & 2.61.1H5), 6.91(d, 1:2.64 Hz, 1H3) and 7.58(d, 1:8.61 Hz, 1H6). 130 NMR(75MHz; 00013): 22.80, 23.96, 29.02, 30.03, 37.08, 66.40, 110.25, 112.23, 130.48, 131.48, 141.88, 152.03, 161.38 and 201.03. IR(CC|4): 1055.2, 1190.2, 1232.7, 1249.1, 1307.9, 1354.2, 1566.4, 1603.1, 1680.2 and 2968.8 cm‘l. MS(m/z): 69, 91, 45, 163(base), 246 and 247(M+1). HRMS: calculated 246.1620 and found 246.1594. [ndanone-3Me-5T2M, Phenyl 4-chlorobutyroate The ester was prepared in the same manner as 3-methylphenyl acetate 2a by reacting phenol (6.0 g, 0.064 mol), pyridine (15.1 g, 0.191 mol) and 4-chlorobutyryl 147 chloride (13.5 g, 0.096 mol) in benzene at 0°C. The reaction was completed in 24 hours at room temperature. Purification by fractional vacuum distillation gave Phenyl 4- chlorobutyroate ( 11.32 g, 89%, bp 107°C at 1.2 torr) as a pale yellow liquid. 1H NMR (300MHz; 00013) : 5 2.220t, 1:7.2 & 6.24hz, 2H), 2.790, 1:7.2 Hz, 2H), 3.69(t, J=6.24 Hz, 2H), 7.1(m, 2H), 7.24(m, 1H), and 7.39(m, 2H). 5-Hydroxy-3-methyl-l-indanone In a argon-purged 100mL round bottom flask, aluminum chloride (8.46 g, 0.063mol) was slowly added via a solid addition funnel to neat Phenyl 4-chlorobutyroate (5.6 g, 0.028mol). The addition was highly exothermic. Upon complete addition of AlCl3, the reaction mixture was heated to 150°C for five hours. The reaction mixture was allowed to cool to 50°C and quenched with 10% HCl and ice. The mixture was taken up into ether (100mL) and extracted with 2N Na0H (6x30mL). The base washings were combined and acidified to a pH~3 with concentrated HCl. The resulting solution was extracted with ether (4x40mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystalization from 15% ethanol/water gave 5- hydroxy-3-methyl-1-indanone (0.4g, 9%, mp I45-146°C). 1H NMR (300MHz; CDCI3) :8 7.65(d, J=8.3 Hz, 1H), 6.88(br s, 1H), 6.85(dd, J=8.2 & 1.6 Hz, 1H), 3.5(ddq, J=3.5, 7.5 & 7.14 Hz, 1H), 2.9(dd, J=18.9 & 7.5 Hz, 1H), 2.25(dd, J=18.9 & 3.5 Hz, 1H) and 1.35(d, J=7.14 Hz, 3H). 3-Methyl-5-(3'-methyI-3'-buten-1'-oxy)indan-1-one The indanone was prepared from 5-hydroxy-3-methy1—l-indanone (0.4 g, 0.0025 mol), 4-tosyl-2-methyl-1-butene (0.889 g, 0.0037 mol) and potassium carbonate (1.025 g, 0.0074 mol) in the same fashion as that of 4-(3'-methyl-3'-buten-1'-oxy)-2- methylacetophenone. Purification of the crude product by column chromatography on 148 silica gel (hexane:ethyl acetate, 90: 10) gave 3-methyl-5-(3'-methyl-3'—buten—1'-oxy)indan- l-one in 76% yield. 1H NMR (300MHz; CDCI3) :8 7.63(d, J=9.3 Hz, 1H7), 6.89(br s, 1H4), 6.86(dd, J=9.3 & 2.1 Hz, 1H6), 4.85(br s, 1H11), 4.79(br s, 1H11), 4.14(t, J=6.8 Hz, 2H8), 3.35(ddq, J=3.5, 7.6, & 7.1 Hz, 1H3), 2.89(dd, J=18.9 & 7.6 Hz, 1H2), 2.52(br t, =6.8 Hz, 2H9), 2.24(dd, J=18.9 & 3.5 Hz, 1H2), 1.80(s, 3H12) and 1.36(d, J=7.1 Hz, 3H13). 13C NMR(75MHz; CDCI3): 204.6, 164.7, 162.9, 141.7, 129.7, 125.2, 115.4, 112.3, 109.2, 66.8, 45.5, 37.0, 32.7, 22.8 and 21.3. IR(CC|4): 2965, 1711, 1601, 1296 and 1254. MS(m/z): 41, 69, 147(base), 162, 163, 230 and 231(M+1). HRMS: calculated 230.1307 and found 230.1280. 5-bromo-1-pentene A three-necked flask equipped with a stillhead/condenser, dropping funnel and a magnetic stir bar was charged with 1,5-dibromopentane (100g, 0.435mol). The 1,5- dibromopentane was heated to 195-200°C on an oil bath. HMPA (70.62g, 0.394mol) was then added dropwise at a rate of 1-2 drops/second. Distillation of the crude 5-bromo-1- pentene began upon the addition of HMPA. Purification by fractional distillation gave 5- bromo—l-pentene(bp 125- 127°C) as a clear liquid (41.6g, 71%yield.). 149 10 NMR (300MHz; 00013) : 5 1,93(q. J=6.93 Hz, 2H), 2.16-2.23(dt, J=6.81and 6.84 Hz, 2H), 3.400. J=6.78 Hz, 2H), 4.9-5.0(dq, 1:10.69 and 1.35 Hz. 1H). 5.0- 5.1(dq, 1:17.22 and 1.65 Hz, 1H), 5.75(ddt, 1:17.07, 10.23 and 6.75 Hz, 1H). 130 NMR(75MHz; 00013): 31.73, 32.01, 33.11. 115.87, and 136.71. 5-(4'-Ethoxycarbonylphenoxy)pent-l-ene 4-Hydroxybenzoic acid was converted into ethyl 4-hydroxybenzoate by Fischer esterification. In a 100mL round bottom flask equipped with a reflux condenser, 4- hydroxybenzoic acid (10 g, 0.0725 mol) was dissolved in ethyl alcohol (50mL, approx. 20 fold excess). The reaction was acid catalyzed by the addition of 2 mL of H2804 to the solution. The reaction was refluxed until complete conversion (24 hours). The reaction mixture was neutralized with aqueous sodium bicarbonate, tranferred to a separatory funnel with ether (100mL). The organic phase was washed with 50 mL portions of water and saturated NaCl solution. The organic phase was dried over magnesium sulfate, filtered and concentrated at reduced pressure. Ethyl 4—hydroxybenzoate was obtained in 88% yield as a white powder. Ethyl 4-hydroxybenzoate (4.0 g, 0.024 mol), 5-bromo-1-butene (4.3 g, 0.0288 mol) and anhydrous potassium carbonate (8.4 g, 0.0608mol) was suspended in dry acetone (50mL). The stirred reaction mixture was refluxed under argon until thin layer chromatography showed the disappearance of starting material. Upon completion, the mixture was gravity filtered to remove potassium bromide, formed during the reaction, and concentrated. The resulting oil was diluted with diethyl ether (50mL) and extracted with 2N Na0H (4x20mL). The ether solution was dried over magnesium sulfate, gravity filtered and concentrated. Purification of the crude product by silica gel chromatography (32 cm x 2.0 cm)(hexane: ethyl acetate, 90: 10) gave 5-(4'—Ethoxycarbonylphenoxy) pent- l-ene as a colorless liquid in 53% yield. 150 5-(4'-Ethoxycarbonylphenoxy) pent-l-ene (1EC-4T3H) 1H NMR(300MHz;CDCl3) : 87.96(d, J=8.7 Hz, 2H2,6), 6.88(d, J=8.7 Hz, 2H3,5), 5.82(ddt, J=l6.9, 10.2 & 6.6 Hz, 1H1()), 5.05(dq, 1:17.1 & 1.8 Hz, 1H11), 4.99(dq, 1:102 & 1.8 Hz, 1H11), 4.32(q, 1:7.2 Hz, 2H12), 4.00, 1:6.45 Hz, 2H7), 2.22(dt, 1:6.9 &6.6 Hz, 2H9), 1.89(tt, J=6.4 & 6.9 Hz, 2H8) and 1.360, 1:7.1 Hz, 3H13). 130 NMR(75MHz; 00013): 14.40, 28.27, 30.03. 60.61, 67.32, 114.02, 115.39. 122.79. 131.52, 137.59, 162.78 and 166.44. MS(m/z): 39, 41(Base) 68, 69, 121, 138 and 235(M+1) HRMS: calculated 234.1256 and found 234.1250 4-(4'-Ethoxycarbonylphenoxy)but-l-ene The ester was prepared from ethyl 4-hydroxybenzoate (4.0g, 0.024mol), 4-bromo- l-butene (3.9g, 0.0288mol) and anhydrous potassium carbonate (8.4g, 0.0608mol) in the same fashion as 1EC-4T3H. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 95:5) gave 4-(4’- ethoxycarbonylphenoxy) but-l-ene in 61% yield. 151 4-(4'-Ethoxycarbonylphenoxy) but-l-ene (1EC-4T2H) 1H NMR(300MHz;CDCI3) :5 7.96(d, J=8.7 Hz, 2H2,6), 6.89(d, J=8.7 Hz, 2H3,5), 5.89(ddt, 1:17.1, 10.4 & 6.9 Hz, 1H9), 5.15(dq, 1:17.1 & 1.6 Hz, 1H1()), S.ll(dq, 1:103 & 1.2 Hz, 1H1()), 4.32(q. J=7.2 Hz, 2H13), 4.040, J=6.8 Hz, 2H7) 2.55 (qt. J=6.9 & 1.5 Hz, 2H3), and 1.36(t, J=7.2 Hz, 3H12). 130 NMR(75MHz; 00013): 14.35, 33.44, 60.57. 67.28, 114.01, 117.27, 122.87, 131.48, 134.03, 162.57, and 166.36. MS(m/z): 39, 53, 54, 55(Base), 65, 93, 103, 121, 138, 192, 220 and 221(M+1). HRMS: calculated and found 5-(2'-Ethoxycarbonylphenoxy)pent-l-ene The ortho ester was prepared by acid catalyzed Fischer esterification in the same fashion as 1EC-4T3H by reacting 2-hydroxybenzoic acid ( 10 g, 0.725 mol) in ethyl alcohol (50 mL). After work-up, ethyl 2-hydroxybenzoate was obtained asa white solid (9.8 g, 81.7%). Williamson etherification of ethyl 2-hydroxybenzoate (4.0 g, 0.024 mol) with 5-bromo-1-butene (4.3g, 0.0288 mol) and anhydrous potassium carbonate (8.4 g, 0.0608 mol) gave 5-(2'-ethoxycarbonylphenoxy) pent-l-ene (2.75 g, 49%) as a colorless liquid. 5-(2'-Ethoxycarbonylphenoxy) pent-l-ene (1EC-2T3H) lH NMR(300MHz;CDCI3) : 87.74(dd, J=7.5 & 1.9 Hz, 1H6), 7.4(ddd, J=8.4, 7.5 & 1.9 Hz, 1H4), 6.94(m, 2H3,5), 5.83(ddt, J=l7.0, 10.20 & 6.70 Hz, 1H10), 5.08- 5.0(dq, 1:17.10 & 1.7 Hz, 1H11), 5.0-4.95(dm, J=10.2 Hz, 1H11), 4.33(q, J=7.2 Hz, 2H12), 4.02(t, J=6.3 Hz, 2H7), 2.26(br dt, J=6.9 & 6.6 Hz, 2H9), 1.90(tt, J=6.9 & 6.36 Hz, 2H8) and 1.36 (t, J=7.13 Hz, 3H13). 130 NMR(75MHz; 00013): 14.27, 28.31, 29.98. 60.69, 67.92, 113.06, 115.13, 119.99, 120.88, 131.43, 133.07, 137.73, 158.34 and 166.63. HRMS: calculated 234.1256 and found 234.1255. 5-(4'-Cyanophenoxy)pent-l-ene The benzonitrile was prepared by coupling 4-cyanophenol (4.15 g, 0.035 mol), 5- bromo-l-butene (4.3 g, 0.0288 mol) and anhydrous potassium carbonate (14.5 g, 0.105 mol) in the same fashion as 1EC-4T3H. Purification of the crude reaction mixture using dry column flash chromatography (hexane:ethyl acetate, 90: 10) gave 5-(4'- cyanophenoxy)pent-l-ene (3.3 g). 153 5-(4'-Cyanophenoxy)pent-l-ene (1CN-4T3H) 111 NMR(300MHz;CDCI3) : 87.55(d, 1:8.91 Hz, 2H2,6), 6.92(d, J=8.91 Hz, 2H3,5). 5.88-5.75(ddt, J=17.07, 10.35 & 6.66 Hz, 1H1()), 5.08-5.01(dq, 1:17.07 & 1.67 Hz, 1H11), 5.02-4.97(dq, J=10.3 & 1.42 Hz, 1H11), 3.99(t, J=6.41 Hz, 2H7) 2.24-2.18(dt, J=6.66 & 6.87 Hz, 2H9) and 1.93-1.84 (tt, J=6.45 & 6.81 Hz, 2H3). 13C NMR(75MHz; CDCI3): 28.02, 29.85, 67.45, 103.66, 115.11, 115.48, 119.23, 133.88, 137.29 and 162.29. IR(CCI4) : 1170.9, 1257.8, 1510.5, 1608.8, 2228.1, 2947.6 and 3082.6 cm‘l. MS(m/z): 39, 41(base), 67, 68, 69, 187 and 189(M+2). HRMS: calculated 187.0997 and found 187.1001. 4-(4'-Cyanophenoxy)but-l-ene The benzonitrile was prepared by refluxing 4-cyanophenol (3 g, 0.025 mol), 4- bromo-l-butene (3 g, 0.022 mol), and potassium carbonate (10.4 g, 0.075 mol) in acetone for 48 hours in the same fashion as 1EC-4T2H. Purification of the crude reaction mixture by dry column flash chromatography, followed by distillation under reduced pressure gave 4-(4'-cyanophenoxy)but- l-ene as a colorless liquid (1.6 g, 42%). 4-(4'-cyanophenoxy)but-l-ene (1CN-4T211) IH NMR(300MHz;CDCI3) : 87.55(d, 1:9 Hz, 2H2,6). 6.92(d, 1:8.97 Hz, 2H3,5). 5.93-5.79(ddt, 1:17.16, 10.38 & 6.69 Hz, 1H9). 5.20-5.13(dq, 1:172 & 1.58 Hz, 154 1H10),5.15-5.09(dq.1=10.9 & 1.36 Hz, 1H1()), 4.040. J=6.69 Hz, 2H7) and 2.58-2.51 (dddt, J=6.66, 6.63, 1.34 & 1.34 Hz, 2H3). 130 NMR(75MHz; 00013): 33.25, 67.48, 103.83, 115.17, 117.50, 119.20, 133.69, 133.91 and 162.14. IR(CC|4): 835.3, 1172.9, 1255.8 1508.6, 1608.8, 2230.0, 2934.1 and 3084.6 cm-l. HRMS: calculated 173.0841 and found 173.0840 S-(2'-Cyanophenoxy)pent-l-ene The ortho alkenoxybenzonitrile was synthesized in the same manner as lEC- 2T3H by refluxing 2-cyanophenol (5g. 0.042mol), 5-bromo-1-pentene (5.4g, 0.036mol) and potassium carbonate (16.5g, 0.12mol) in acetone. Dry column flash chromatography gave 5-(2'-cyanophenoxy) pent-l-ene as a colorless liquid. S-(2'-Cyanophenoxy)pent-l-ene (lCN-2T3H) IH NMR(300MHz;CDCl3) : 87.50(ddd, J=8.0, 7.6 &1.7 Hz. 1H4), 7.4(dd, 1:7.56 &1.7 Hz, 1H6), 6.96(ddd, J=7.56, 7.6 & 0.87 Hz, 1H5), 6.92(br d, 1:8.1 Hz, 1H3),5.9-5.75(ddt, 1:170, 10.2,& 6.69 Hz, 1H1()), 5.09-5.01(dq, 1:17.1 & 1.65 Hz, 1H11), 5.02-4.97(dm, 1:10.17 Hz, 1H11), 4.06(t, J=6.36 Hz, 2H7), 2.27(dt, J=6.93 &6.7 Hz, 2H9) and 1.93-1.84 01. J=6.93 & 6.36 Hz, 2H3). 130 NMR(75MHz; 00013): 27.97, 29.84, 68.07, 112.19. 115.53, 116.45, 120.59. 133.75, 134.22, 137.38 and 160.70. 58411 5.13.: L572 13C . 120.71. IR(CC "Rug 155 IR(CC|4): 918.2, 1111.1, 1261.6, 1288.6, 1495.0, 1601.1, 2231.9, 2945.7 and 3082.6cm'1. HRMS: calculated 187.0997 and found 187.0997. 4-(2’-Cyanophenoxy)but-l-ene 4-(2'-Cyanophenoxy)but-l-ene was prepared by coupling 2-cyanophenol (5.0 g,0.042 mol) and 4—bromo-1-butene (5.7 g, 0.42 mol) using potassium carbonate (14.5 g, 0.105 mol) as the base. Work-up and purification was similar to lEC-4T3H. 4-(2'- cyanophenoxy)but- l-ene was isolated in 51% (3.7 g). 4-(2'-Cyanophenoxy)but-l-ene (lCN-2T2H) 1H NMR(300MHz;CDCl3) : 87.5(ddd, J=7.5, 7.2 &1.7 Hz, 1H4), 7.4(dd, J=7.6 & 1.7 Hz, 1H6),6.96(ddd, J=7.5, 7.3 & 0.96 Hz, 1H5), 6.94(br d, J=7.7 Hz, 1H3), 5.97- 5.84(ddt, 1:17.13, 10.30 & 6.75 Hz, 1H9), 5.21-5.15(dq, 1:17.13 & 1.57 Hz, 1H1()), 5.13-5.10(dm, J=10.9 Hz, 1H1()), 4.09(t, J=6.66 Hz, 2H7) and 2.58-2.51 (dddt, J=6.72, 6.69, 1.30 & 1.30 Hz, 2H3). 130 NMR(75MHz; 00013) : 33.27, 68.24, 102.14, 112.23, 116.36. 117.69, 120.71, 133.55, 133.77, 134.22,and 160.53. IR(CCI4) : 742.7, 1111.1, 1261.6, 1288.6, 1495.0, 1601.1 and 2231.9 cm'l. HRMS: calculated 173.0841 and found 173.0836. 5.0 bro 156 5-(4'-Acetylphenoxy) pent-l-ene The ketone was prepared from 4-hydroxyacetophenone ( 2.0 g, 0.015 mol), 5- bromo-l-pentene ( 2.25 g, 0.015 mol) and potassium carbonate (7.6 g, 0.055 mol) in the same fashion as that of 4-(3'-methyl-3'-buten-1'-oxy)—2-methy1acetophenone. Purification of the crude product by column chromatography on silica gel (hexane/ethyl acetate 95:5) gave 5-(4'-acetylphenoxy) pent-l-ene (1AP-4T3H) in 68% yield. 5-(4'-Acety|phenoxy) pent-l-ene (1AP-4T3H) 1H NMR(300MHz;CDCI3) : 87.90(d, J=8.94 Hz, 2H2,6), 6.89(d, J=8.97 Hz, 2H3,5), 5.89-5.76(ddt, J=17.0, 10.2 & 6.7 Hz, 1H1()), 5.04(dq, J=17.0 & 1.62 Hz, 1H11), 4.98(dm, J=10.2 Hz, 1H11), 4.01(t, J=6.40 Hz, 2H7), 2.53(s, 3H), 2.23(br dt, J=6.9 & 6.6 Hz, 2H9) and 1.88 (tt, J=6.5 & 6.9 Hz, 2H3). 13C NMR(75MHz; CDCI3): 26.22, 28.12, 29.9, 67.28, 114.05, 115.32, 130.6, 130.5, 137.42, 162.94 and 196.77. IR(CC|4): 2947.6, 1682.1, 1603.0, 1255.8, 1170.9, 800.6, and 711.6. 157 4-(4'-Acetylphenoxy) but-l-ene 4-(4'-Acetylphenoxy) but-l-ene was prepared by Nahm. The sample was purified by silica column chromatography using a mixture of hexanes and ethyl acetate (90: 10) as the eludent. 4-(4'-Acetylphenoxy) but-l-ene (1AP-4T2H) 1H NMR(300MH2;CDCI3) : 87.90(d, 1:8.9 Hz, 2H2,6).6.90(d,1:8.9 Hz, 2H3,5), 5.87(ddt, 1:17.10, 10.20 & 6.7 Hz, 1H9), 5.16(dq, 1:172 & 1.65 Hz, 1H1()), 5.10(dq, J=10.2 & 1.14 Hz, 1H1()), 4.060, J=6.7 Hz, 2H7) and 2.58-2.51 (tdt, 1:1.23, 6.7 & 6.7 Hz, 2H3), 2.53(s, 3H). 130 NMR(75MHz; 00013): 26.28, 33.40, 67.34, 114.13, 117.32, 130.25, 130.53. 133.94, 162.79 and 196.71. 11110014) : 2930.2, 1682.1, 1603.0, 1253.9, 1170.9, 800.6, 771.6. &\X,0H PCC fl fl K2003 :OH Alumina ’: o O @O A n-BuLi fi diethyl cyanomethylphosphoate (A) 31 158 3-(4'-Acetylphenoxy)-2,2-dimethylpropan-l-ol 4-Hydroxyacetophenone (3 g, 0.022 mol), 3-bromo-2,2-dimethylpropanol (3.68 g, 0.022 mol) and anhydrous potassium carbonate (9.12 g, 0.066 mol) in 50 mL of dry acetone were refluxed under an argon atmosphere for 72 hours. The cooled mixture was gravity filtered to remove potassium bromide formed during the reaction and concentrated in vacuo. The resulting yellow oil was diluted with ether (50mL) and extracted with 2N Na0H (3x25mL). The organic layer was dried over magnesium sulfate, gravity filtered and concentrated in vacuo to give a crude yellow liquid. Unreacted 3-bromo-2,2— dimethylpropanol was removed from the raction mixture by fractional distillation (bp 185°C). Purification of the crude product by recrystallization (ethanolzwater) gave 3-(4'- Acetylphenoxy)-2,2-dimethylpropan-l-ol as a white solid in 44% yield (mp 31-33°C ). 1H NMR (300MHz; CDCI3) : 5 7.9(d, J=9 Hz, 1H), 6.92(d, J=9 Hz, 1H), 3.9(s, 2H), 3.5(s, 2H), 2.5(8, 3H), 0.92(s, 6H). 3-(4'-Acetylphenoxy)-2,2-dimethylpropanal Oxidation of 3—(4'-Acetylphenoxy)-2,2-dimethylpropan-1-ol to the aldehyde was accomplished by treatment with PCC. A suspension of 3-(4'-Acetylphenoxy)-2,2- dimethylpropan-l-ol (4 g, 0.018 mol), PCC (8 g , 0.036) and basic alumina (50 grams) in dichloromethane (75mL) was stirred under argon at room temperature. The reaction progress was monitored by thin layer chromatography. After complete conversion of the alcohol (20 hours), the mixture was gravity filtered. The organic filtrate was concentrated in vacuo. The resulting brown oil was purfied by column chromatography (hexane:ethyl acetate, 80:20) to give 3-(4'-Acetylphenoxy)-2,2-dimethylpropanal, which was used immediately. 159 1H NMR(300MHz;CDCl3) : 5 9.9(s, 1H), 7.9(d, J=9 Hz, 2H), 6.89(d, J=9 Hz, 2H), 3.8(s, 2H), 2.54(s, 3H), 1.2(s,6H). 5-(4'-Acetylphenoxy)-4,4-dimethyl-2-pentenenitrile A solution of diethyl cyanomethylphosphonate (2.25. g, 0.0127 mol) in dry THF (50mL) was cooled to -23°C and 8 mL of 1.6M n-BuLi in hexanes was added dropwise to the stirred mixture. The mixture was stirred at -23°C for one hour and 3-(4'- acetylphenoxy)-2,2-dimethylpropanal (3.5 g, 0.16 mol) in THF (10mL) was added via a gas-tight syringe. The mixture was stirred at -23°C for one hour and was slowly warmed to room temperature. The mixture was quenched with saturated NH4C1 solution (25mL). The mixture was tranferred to a separatory funnel with ether (90mL) and the organic phase was washed with 50 mL portions of water and saturated NaCl solution. The organic phase was dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification of the crude product by dry column flash chromatography on silica gel (hexane:ethyl acetate=95:5) gave trans- and cis-5-(4'-Acetylphenoxy)-4,4-dimethyl-2- pentenenitrile (~9:1) in 23% yield as a white solid(mp. 60-61°C). 1H NMR(300MHz;00013) : 87.93(d, 1:9 Hz, 2H2,6). 6.89(d, 1:9 Hz, 2H3,5), 6.80(d, J=16.7, 1H9trans), 6.48(d, J=12.4, 1H9cis), 5.38(d, J=16.7, 1H10trans), 5.38(d, 1:124, 1H10cis). 3.89(s, 2H7cis). 3.78(s, 2H7trans), 2.54(s, 3Htrans), 160 2.53(s,3Hcis), l.54(s, 3H11trans)1 1.39(s, 3Hllcis). 1.2(s, 3H12trans). and 1.2(s, 3H12cis)- 130 NMR(75MHz; 00013): 196.7, 162.4, 160.7, 130.8, 117.5, 114.1 98.7, 75.1, 39.0, 26.3, and 23.3. IR(CC14) : 2255, 1675, 1601, 1173, 920, and 750cm-1. MS(m/z): 43(32%), 65(l6%), 81(16%), 107(22%), 119(18%), 121(90%), 149(base), 243(24%), and 244(M+1). cis-5-(4'-Acetylphenoxy)-3-pentene The ketone was prepared from 4-hydroxyacetophenone (3 g, 0.022 mol), cis-1-bromo-3— hexene (3.6 g, 0.022 mol) and potassium carbonate (9.1 g, 0.066 mol) in the same fashion as that used for 4-(3'-buten-1'-oxy)-2-methylacetophenone. Purification of the crude product by column chromatography on silica gel (hexane:ethyl acetate, 90: 10) gave cis-5- (4'-Acetylphenoxy)-3-pentene in 77% yield. 130 NMR(75MHz; 00013): 196.5, 162.8, 134.5, 130.4, 130.0, 123.5. 114.0. 67.6, 27.0, 26.15, 20.5, and 14.1. IR(CCI4) : 2966, 1682, 1603, 1254, 1171 and 750cm-1. MS(m/z): 39(16%), 41(62%), 43(42%), 55(base), 67(46%), 82(57%), 83(77%), 121(99%), 136(23%), 137(26%), 218(36%), and 219(M+1). 161 III. Identification of Photoproducts Photolysis of 5-(4'-cyanophenoxy)pent-l-ene (lCN-4T3H) In a NMR tube, 5-(4'-cyanophenoxy)pent-l-ene (2.0mg) was dissloved in deuterated acetone (0.75mL, 1.5 x 10'2M). The sample was purged with argon for 15 minutes and then irradiated through a 313 nm filter solution. The reaction was monitored by time resolved NMR. Product formation was slow (>15 hours). It is believed that an impurity in the deuterated acetone was impeding the photoreaction. A single photoproduct was indentified as 1-cyano-9-oxatricyclo[82.0.05110]dodeca-2,ll-diene. Large scale photolysis was carried out to isolated the photoproduct. 5-(4'-Cyanophenoxy)pent-1-ene (450mg) was dissolved in freshly distilled acetone (160mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitiored by gas chromatography. The reaction mixture was concentrated at reduced pressure and separated using silica gel chromatography (hexaneszethyl acetate, 85: 15). 1-Cyano-9-oxatricyclo[8.2.0.05t10] dodeca-2,11-diene.was obtained as clear needles in 58% yield (263mg). Similar results were obtained when (1CN-4T3H) was irradiated in acetonitrile at 254 nm. In a quartz test tube, 5-(4'-cyanophenoxy)pent—l-ene (126mg) was dissloved in acetonitrile (45mL), purged with argon for twenty minutes and irradiated at 254 nm using a Rayonet The reaction progress was monitored by gas chromatography. The reaction solution rapidly turned yellow and by GC analysis showed the formation of one major product after three hours of irradiation. Purification of the crude product by silica gel column chromatography (ethyl acetate/hexanes 10:90) gave 1-cyano-9- oxatricyclo[8.2.0.05110]dodeca-2,11-diene. The melting points of the products obtained from direct and sensitized irradiation were identical (mp.70-71°C). 162 313nm : C N‘ Acetone 1-cyano—9-oxatricyclo[8.2.0.051 101dodcca-2,1 1-diene 1H NMR(300MHz;CDCl3) : 86.75(d, 1:2.94 Hz, 1H11), 6.19(d, 1:2.97 Hz, 1H12), 5.95(ddd, 1:9.9, 7.4 & 2.0 Hz, 1H3), 5.75(dd, 1:9.9 & 2.9 Hz, 1H2), 4.04(dddd, J=11.8, 4.8, 1.65 & 1.35 Hz, 1H3), 3.61(ddd, J:14.6, 11.8 & 2.7 Hz, 1H3), 2.03(ddd, J=15.6, 7.4 & 2.8 Hz, 1H4), 1.2-1.74011, 2H7,6), 1.6-1.5(m, 3H7,6,5), and 1.5(dddd, J=15.6, 2.9 &20 Hz, 1H4) l30 NMR(75MHz; 00013): 137.53, 136.29, 131.31, 123.71, 119.03, 84.74, 65.38, 47.29,38.62, 28.27, 26.24, and 26.09. IR(CC|4): 2936.0, 2856.6, 2239.6, 1286.7, 1091.9, 947.2, 706.0cm-1. MS(m/z) : 39(90%), 41(94%), 51(56%), 55(97%), 69(51%), 77(100%), 91(82%), 103(54%), 104(82%), 130.1(61%), 160.1(54%), 161.1(73%), 187.1, 188.1(M-1-1) Nuclear Overhauser Enhancement (n0e) experiments were carried out on the photoproduct to determine the stereochemistry. Irradiation of the cyclobutene proton H11 afforded enhancements at H6(2.52%),H3 (2.80%), and H12(3.66%). The bridgehead proton H5 was uneffected by irradiation at H11. 163 Thermal Rearrangement of 1-cyano-9-oxatricyclo[82.0.05110]dodeca—2,1l-diene. In a NMR tube, 1-cyano-9—oxatricyclo[82.0.05t10]dodeca—2,1l-diene (25mg) was dissolved in toluene-d3 (0.7 5mL). The reaction mixture was purged with argon and heated for five hours at 100°C. NMR analysis of the reaction mixture showed quantitative conversion of l-cyano-9-oxatricyclo[82.0.05110]dodeca—2,ll-diene to 12-cyano-4— oxatricyclo[8.2.0.0318]dodeca-2,1l-diene, via a cope rearrangement in which C-8 is inverted. 100°C, 5Hrs V Toluene 12-cyano-4-oxatricyclo[8.2.0.0318] dodeca-2, 1 l-diene 1H NMR(300MHz;Tquene-d8) :8 5.93(br s, 1H1()), 5.05(dd, J=5.85 & 2.55 Hz, 1H2). 3.70(dddd, J=10.8. 4.1. 2.3 & 2.3 Hz, 1H5). 3.22(ddd, 1211.8, 10.8 & 2.8 Hz, 164 1H5). 3.08(ddd, J=5.8, 4.2 & 1.4 Hz, 1H1)2.47(dddd, J=6.0, 4.3, 1.8 & 1.38 Hz, 1H10), 1.60(m, 1H8). 1.50-1.30(m, 3H), 1.26(ddd, J=13.35. 4.45 & 1.95 Hz, 1H9), O.85(ddd, J=13.4, 11.5 & 5.9 Hz, 1H9) and 0.75(ddd, 1212.7, 11.8 & 3.9 Hz, 1H). Photolysis of 4-(4'-cyanophenoxy)but-l-ene (lCN-4T2H) In a NMR tube, 1.95mg of 4-(4'-cyanophenoxy)but-1-ene was dissloved in acetone-d6 (0.75mL), purged with argon for ten minutes, and irradiated using a medium pressure mercury are filtered with a solution consisting of 0.002M K2Cr04 in 1% aqueous K2C03 (313 nm). The reaction solution rapidly turned yellow and NMR analysis showed the formation of two isomers. The ratio of the product isomers were time dependent. At low conversion of lCN-4T2H (<20%), two products were present in a 1:1 ratio, but upon high conversion of the starting material only one product was present. Preparatory scale photolysis allowed for the isolation of the two photoproducts. 4-(4'- Cyanophenoxy)but- 1-ene (420mg) was dissolved in freshly distilled acetone (160mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitiored by gas chromatography. The photolysis was stopped after25% conversion. Purification of the crude mixture by silica gel chromatography (ethyl acetate/hexane, 15:85) afforded pure samples of two photoproducts, 1-cyano—8-oxatricyclo[7.2.0.0519]undeca- 2,10-diene, l-CN-4T211-CB and 4-cyano-1l-oxabicyclo[6.3.0] undeca-1,3,5-triene,l- C N - 4 T 2 H - C 0 T . Prolonged irradiation produced only 1-cyano-8- oxatricyclo[7.2.0.0519]undeca-2,10-diene (51.5%). l-Cyano-8-oxatricyclo [7.2.0.0519]undeca-2,lO-diene decomposed upon heating in toluene at 100°C for an extended period of time; only a minor amount of ring opening to cyclooctatriene,1-CN- 4T2H-COT, was present. There was no evidence of any cope-rearranged product. 165 / 313nm Acetone NC 4 4-cyano-1 1-oxabicyclo[6.3.0] undeca-l,3,5-tn'ene 1H NMR(300MHz;CDCl3) : 86.6(d, J=6.9 Hz, 1H3), 5.9(ddd, J=12.6, 7.7 & 5.1 Hz, 1H6), 5.85(d, J=12.9 Hz, 1H5), 5.3(d, J=6.6 Hz, 1H2), 4.3(ddd, J=8.7, 6.9 & 6.9 Hz, 1H1()), 4.2(ddd, J=8.7, 7.8 & 4.8 Hz, 1H1()), 3.15(m, 1H8), 2.47(m, 2H9), 2.2(ddd, J=15.6, 12.6 & 7.8 Hz, 1H7) and 1.8(ddd, 12.3, 6.6 & 5.1 Hz, 1H7) l3C NMR(75MHz;CDCl3) : 8171.74, 141.01, 133.89, 123.21, 121.69, 104.34, 95.72, 69.63, 39.74, 32.28, and 31.24. UV-Vis (Methanol) : 4max (326 nm) 7425, (313 nm) 6579. MS(m/z): 39(25%), 55(Base), 77(28%), 104(24%), 117(27%), 145(25%), 173(55%) and 174(M+1). 1-cyano-8-oxatricyclo[72.0.0519]undeca-2, 10-diene 1H NMR(300MHz;CDCl3) : 86.26(d, J=2.8 Hz, 1H), 6.ll(d, J=2.8 Hz, 1H), 5.83(ddd, J=9.9, 6.0 & 2.2 Hz, 1H), 5.75(dd, J=10.0 & 2.7 Hz, 1H), 4.11(ddd, J=8.3, 8.3 & 4.65 Hz, 1H), 3.93(ddd, J=9.15, 8.3 & 7.6 Hz, 1H), 2.45 (dddd, J=13, 8.3, 5.9 & 2.4 Hz, 1H), 2.31(ddd, J=17.5, 6.1 & 2.4 Hz, 1H), 2.18(dddd, J=17.4, 5.9, 2.6 & 2.3 Hz, 1H) and 1.96(m, 2H). MS(m/z) : 39(100%), 41(40%), 51(37%), 55(99%), 63(27%), 77(41%), 91(27%), 104(26%), 117(28%), 173(23%) and 174(M+1). 166 The stereochemistry of 1-cyano-8-oxatricyclo[7.2.0.0519]undeca-Z,10-diene was determined by nOe experiments. Irradiation of the six-five bridgehead proton H5 afforded enhancements at H4(0.46%), H6 (2.17%), and the cyclobutene proton, H11(1.07%). In a quartz vessel, 4-(4'-cyanophenoxy)but-l-ene (119mg) was dissloved in acetonitrile(45mL), purged with argon for twenty minutes and irradiated at 254 nm using a Rayonet in an ice bath. The reaction progress was monitored by gas chromatography. The reaction solution rapidly turned yellow. GC analysis showed the formation of two products after two hours of irradiation. Purification of the crude product by preparative thin layer chromatography (ethyl acetate/hexanes 5:95) gave ll-cyano-4- oxatricyclo[7.2.0.03t7]undeca-2,10-diene, 1-CN-4T2H-LCB and 4-cyano-11- oxabicyclo[6.3.0] undeca-1,3,5-triene, 1-CN-4T2H-COT in a 1:1 ratio. Irradiation of l-CN-4T2H-COT in acetonitrile-d3 (2.4mg in lmL solvent) at 254 1110 gave l-CN- 4T2H-LCB. Nearly identical results were obtained by Gilbert. In a NMR tube, l-CN-4T2H-COT (2.9mg) was dissolved in deuterated acetonitrile (0.8 mL), flushed with argon for 10 minutes to remove oxygen and irradiated at 167 313 nm. The reaction progress was monitored by 1H NMR analysis. After one hour, 1- CN-4T2H-COT was completely converted to 1-CN-4T2H-LCB. Thermal Chemistry of l-CN-4T2H-LCB Heating a sample of 1-CN-4T2H-LCB in an argon-purged toluene-d3 gave no observable thermal rearranged products by 1H NMR analysis. l-CN-4T2H-LCB readily decomposed upon heating at 100°C. Gilbert reported a high degree of polymerization with a minor amount of lt-CN-4T2H-COT upon heating. 8 / O 10 ”11“" 6 e7 o - 1:00 CH3CN NC NC 2 4 1-0N-4T2H 1-CN-4T2H-C0T l-CN-4T2H-LCB l hv J 1 1-cyano-4—oxatricyclo[7.2.0.0317]undeca-2,10-diene 1H NMR(300MHz;C6D6) : 55.87011 s, 1H1()), 4.89(dd, 1:6.3 & 2.4 Hz, 1H2), 3.70(dd, J=8.3 & 8.5 Hz, 1H5), 3.45(ddd, J=11.8, 8.5& 5.5 Hz, 1H5), 3.12(ddd, J=6.3, 4.35 & 0.87 Hz, 1H1), 2.46(dddd, J=5.9, 4.3, 1.5 & 1.5 Hz, 1H9), 1.65(m, 1H7), 1.43(ddd, J=13.2, 5.2 & 1.6 Hz, 1H8), 1.34(m, 1H6), 1.0(m, J=11.6 & 8.5 Hz, 1H6) and 0.59(dddd, J=13.2, 11.8 & 5.9 Hz, 1H8) MS(m/z) : 39(100%), 51(45%), 53(24%), 55(70%), 63(26%), 66(26%), 77.1(33.7%), 117(24%), 121(23%), 122(37%), 173(17%) and 174(M+1). The stereochemistry of 11-cyano-4-oxatricyclo[7.2.0.0317]undeca-2,10-diene was determined by nOe experiments. Irradiation of the cyclobutene proton H10 afforded enhancements at H9(2%), H3 (1%), and the six-five bridgehead proton, H7(l%). 168 Photolysis of 5-(4'-Ethoxycarbonylphenoxy) pent-l-ene (lEC-4T3H) In a NMR tube, 5-(4'-Ethoxycarbonylphenoxy) pent- 1-ene (2.7mg) was dissloved in 0.75mL acetone-d6 (1.54 x 10-2M). The sample was purged with argon for 20 minutes and irradiated through a 313 nm filter solution. NMR analysis of the reaction mixture showed that reaction was 50% complete after four hours. The single photoproduct was identified as 1-ethoxycarbonyl-9-oxatricyclo[8.2.0.05110]dodeca-2,1l-diene. Preparatory scale photolysis was carried out to isolate the photoproduct. 5-(4'- Ethyoxycarbonylphenoxy)pent-l-ene (500mg) was dissolved in freshly distilled acetone (160mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitiored by gas chromatography. Purification of the crude reaction mixture by silica gel column chromatography (ehtyl acetatezhexanes, 10:90) gave 1-ethoxycarbonyl-9- oxatricyclo[8.2.0.05110]dodeca-2,1l-diene in 51% (256mg) as a pale yellow liquid. Similar photolysis was carried out at 254 nm. In a quartz vessel, 5-(4'- ethyoxycarbonylphenoxy)pent- l-ene (140mg) was dissloved in acetonitrile(SOmL), purged with argon, and irradiated in a Rayonet reaction chamber at 254 nm. The reaction was completed after 2.5 hours. Two products were identified as 1-ethoxycarbonyl—9- oxatricyclo[8.2.0.05110]dodeca-2,1l-diene and its C-5 epirner in a 6:1 ratio. 169 1-Ethoxycarbonyl-9-oxat1icyclo[8.2.0.051 10]dodeca-2,1 l-diene 1H NMR(300MHz;CDCl3) : 86.74(d, 1:3.06 Hz, 1H11), 6.27(d, J=3.06 Hz, 1H12), 5.90(ddd, J=9.9, 7.3 & 2.0 Hz, 1H3), 5.71(dd, 1:9.9 & 2.85 Hz, 1H2), 4.20(bq, 1:7.0 Hz, 2H), 3.85(dddd, 1:117, 4.65, 1.65 & 1.4 Hz, 1H3), 3.59(ddd, J=12.8, 11.8 & 2.6 Hz, 1H3), 2.01(ddd, 1:152, 7.3 & 2.6 Hz, 1H4), 1.8(m, 2H7,6),1.6(m, 3H7,6,5), 1.5(dddd, 15.2, 2.85 & 2.0 Hz, 1H4), and 1.260, 1:7.0 Hz, 3H). Photochemistry of 1EC-4T2H Photolysis (254nm or 313nm) of 1EC-4T2H (~0.015M) in argon-purged acetonitrile or acetone resulted in no observable photoproducts by 1H NMR at extended periods (>10 hours). Instead, 1EC-4T2H was rapidly converted to polymeric material. Gilbert reported similar results for the methyl benzoate derivative when irradiated at 254m in acetonitrile.25 170 \ \fi hv EtOOC—-.—O No Reaction Solvent 1120-4'12H Photolysis of 5-(2'-cyanophenoxy) pent-l-ene (lCN-2T3H) In a NMR tube, 5-(2'-cyanophenoxy)pent~l-ene (2.1mg) was dissolved in 0.75mL deuterated acetone (1.5 x 10’2M). The sample was purged with argon for 20 minutes and then irradiated through a 313 nm filter solution (0.002M K2Cr04 in 1% aqueous K2C03). The reaction was monitored by time resolved NMR. The reaction was 50% complete after eight hours. A single photoproduct was indentified as 3-cyano-9- oxatricyclo[8.2.0.05110]dodeca-2,l1-diene. Large scale photolysis was carried out to isolate the photoproduct. 5-(2'—Cyanophenoxy)pent-l-ene (950mg) was dissolved in freshly distilled acetone (400mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitiored by gas chromatography. The reaction mixture was concentrated at reduced pressure and separated using silica gel chromatography (ethyl acetate/hexane 5:95). 3-Cyano-9-oxatricyclo[8.2.0.05110]dodeca-2,l1-diene was obtained as a pale yellow liquid Similar results were obtained when 1CN-2T3H was irradiated in acetonitrile at 254 nm. In a quartz vessel, 5-(2'-cyanophenoxy)pent-1-ene (141mg) was dissloved in acetonitrile (50mL), purged with argon to remove oxygen, and irradiated in a Rayonet reaction chamber at 254 nm. The reaction was complete in 2.0 hours of irradiation. Two products, 3-cyano-9-oxatricyclo[8.2.0.05110]dodeca-2,1l-diene, 1CN-2T3H-CB and its di-n-methane rearranged isomer, 1~cyano-7-oxatetracyclo[7.4.1.0.0813] dodeca-9-ene, 171 were obtained in a 2:1 ratio. Prolonged irradiation of 1CN-2T3H-CB resulted in complete conversion to l-cyano-7-oxatetracyclo[7.4.1.0.0813] dodeca—9-ene. \ \_j 313nm 12 O o Acetone CN | hv(254nm)1 3-Cyano-9-oxatricyclo[8.20.051 1O]dodeca-2,l l-diene 1H NMR(300MHz;CDCl3) :5 6.66(dd, 1:5.5 81 3.0 Hz, 1H2), 6.65(d, 1:3.0 Hz, 1H11), 6.16(dd, 1:2.97 & 0.84 Hz, 1H12), 3.88(tdd, 1:1.7, 11.7 & 5.2 Hz, 1H8), 3.56(ddd, 1:121, 11.7 & 3.0 Hz, 1H3), 3.l9(dd, J=5.6 81 0.8 Hz, 1H1), 2.18(dd, J=16.1 81 3.8 Hz, 1H4), 1.80(dddd, J=16.1, 12.45, 3.0 81 1.6 Hz, 1H4) 1.7-1.3(m, 5H). MS(m/z) : 39(83%), 41(100%), 55(66%), 77(94%), 91(88%), 103(67%), 104(75%), 135(77%), l6l(92%), 187(66%), and 188(M+1). 1-Cyano-7-oxatetlacyclo[7.4. 1.0.0813] dodeca-9-ene: 1H NMR(300MHz;CDCl3) :8 6.11(d, 1:6.0 Hz, 1H9), 5.91(dd, 1:6.0 81 2.4 Hz, 1H1()), 3.86(dddd, J=11.7, 5.2, 1.7 & 1.7 Hz, 1H6), 3.71(ddd, J=12.1, 11.7 & 3.9 Hz, 1H6), 3.12(d, J=6.6 Hz, 1H12), 2.59(dd, J=6.6 & 2.4 Hz, 1H11), 2.37(m, 1H3), 2.05(dd, J=13.2 & 7.5 Hz, 1H2), 1.8-1.5(m, 3H4,5,5), 1.28(dd, J=13.2 & 12.4 Hz, 1H2), and 1.26(dq, 1:39 81 12.5, 1H4). 172 130 NMR(75MHz;CDCl3) : 5129.5, 127.9, 121.6, 84.6, 64.3, 55.9, 48.0, 38.2, 28.6. 25.8, 25.7 and 24.1. IR(CC|4) : 2938.0, 2868.5, 2231.9, 1356.1, 1082.2, 908.6 and 733cm'1. MS(m/z): 39, 41, 51, 77, 116, 117, 130, 143.1(base), 187, and 188(M-1-1). Nuclear Overhauser Enhancement (nOe) experiments were carried out on the photoproduct to determine the stereochemistry. Irradiation of the cyclobutene proton H11 afforded enhancements at H3 (2.80%) and H12(1.5%). The bridgehead proton H5 was uneffected by irradiation at H11. Photolysis of 4-(2‘-cyanophenoxy)but-1—ene (lCN-2T2H) In a N MR tube, 4-(2'-cyanophenoxy)but—l-ene (2.1mg) was dissloved in acetone- d6 (0.75mL), purged with argon for twenty minutes, and irradiated using a medium pressure mercury are filtered with a 313 nm solution. The reaction solution rapidly turned yellow, and by NMR analysis showed the formation of one product after four hours of irradiation. Large scale photolysis allowed for the isolation of the photoproduct. 4-(2'- Cyanophenoxy)but- l-ene (900mg) was dissolved in freshly distilled acetone(400mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitiored by gas chromatography. At 70% conversion, the photolysis was stopped and the reaction mixture was concentrated at reduced pressure. Purification of the crude 173 mixture by silica gel chromatography (ethyl acetate/hexane 10:90) gave 9-cyano-4— oxatricyclo[7.2.0.0317]undeca-2,10-diene was a pale yellow liquid (460mg, 74%, based on 70% conversion of 1CN-2T211.) . 6 ¢j 313nm 10 =' 00 - E1 ‘ Acetone / O 4 CN 9-Cyano-4-oxatricyclo[72.0.0317]undeca-2,10—diene IH NMR(300MHz;CDC13) : 56.06(dd, 1:27 81 0.9 Hz, 1H), 5.98(d, J=2.8 Hz, 1H), 4.84(dd, J=6.5 81 2.2 Hz, 1H), 4.21(ddd, 1:8.6, 8.6 81 0.9 Hz, 1H), 3.94(ddd, J=11.8, 8.6 81 5.6 Hz, 1H), 3.72011 dd, 1:65 81 0.8 Hz, 1H), 2.45(m, 2H), 2.21(m, J=5.6 81 0.9 Hz, 1H), 1.72(m, 1:1 1.8 81 8.6 Hz, 1H) and 1.47011, 1H). 130 NMR(75MHz;CDCl3) : 5160.58, 142.17, 131.86, 122.08, 88.53, 69.59, 47.70. 42.09, 35.86, 32.83, and 30.61. Photolysis of 5-(2'-Ethoxycarbonylphenoxy) pent-l-ene (1EC-2T3H) In a NMR tube, 5-(2'-Ethoxycarbonylphenoxy) pent-l-ene (2.5mg) was dissloved in 0.75mL acetone-d6 (1.42 x 10'2M). The sample was purged with argon for 20 minutes and then irradiated through a 313 nm filter solution. NMR analysis of the reaction mixture showed the presence of two photoproducts. The major photoproduct was identified as 3- ethoxycarbonyl-9-oxatricyclo[8.2.0.05110]dodeca-2,11-diene. The minor photoproduct arose from secondary photolysis of 3-ethoxycarbony1—9-oxatricyclo[8.2.0.05110]dodeca— 2,11-diene. Preparatory scale photolysis was carried out to isolated the major photoproduct. 5-(2'-Ethyoxycarbonylphenoxy)pent-l-ene (500mg)was dissolved in 174 freshly distilled acetone (160mL ) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitiored by gas chromatography. Purification of the crude reaction mixture by silica gel column chromatography gave 3-ethoxycarbonyl-9- oxatricyclo[8.2.0.05110]dodeca-2,1l-diene, lEC-2T3H-CB, in 42.6 % (213mg) as a pale yellow liquid. Similar photolysis was carried out at 254 nm. In a quartz vessel, 5-(2'- ethyoxycarbonylphenoxy)pent-l-ene (150mg) was dissloved in acetonitrile (50mL), purged with argon to remove oxygen, and irradiated in a Rayonet reaction chamber at 254 nm. The reaction was complete in 3.25 hours of irradiation. Two products were obtained in a 8:1 ratio. The products was determined to be lEC-2T3H-CB and its di-rt-methane rearranged isomer, 1-ethoxycarbonyl-7-oxatetracyclo[7.4.1.0.0813] dodeca-9-ene. Prolonged irradiation of produced complete conversion to 1-ethoxycarbonyl-7- oxatetracyclo[7.4.1.0.0813] dodeca-9-ene. 254nm Solvent 3-ethoxycarbonyl-9-oxatricyclo[8.2.0.05-10]dodeca-2,1 l-diene 1H NMR(300MHz;CDCl3) :5 6.96(dd, 1:5.5 & 2.8 Hz, 1H2), 6.64(d, 1:3.0 Hz, 1H11), 6.15(dd, 1:3.0 81 0.9 Hz, 1H12), 4.15(q, 1:7.1 Hz, 2H), 3.89(dddd, J=11.6, 5.0, 1.6 81 1.6 Hz, 1H3), 3.56(ddd. 1:120, 11.7 & 2.9 Hz, 1H3), 3.20(dd. 1:56 81 0.9 Hz, 1H1), 2.56(dd, 1:160 & 3.1 Hz, 1H), l.79-1.57(m, 4H), 1.5-1.4(m, 2H), and 1.260,1:7.1 Hz, 3H). 175 MS(m/z) : 39(59%), 41(59%), 51(43%), 55(54%), 65(36%), 77(63%), 91(52%), 135(44%), 159(32%), 161(100%), 208(40%), 234(3%), and 235(M+1). 1ethoxycarbonyl-7-oxatetracyclo[7.4.1.0.0813] dodeca-9-ene lH NMR(300MHz;CDCl3) :8 6.07(d, J=5.8 Hz, 1H9), 5.93(dd, J=5.8 & 2.4 Hz, 1H1()), 4.08(q, J=7.1 Hz, 2H), 3.85(dddd, J=11.6, 4.8, 1.7 & 1.3 Hz, 1H6), 3.73(ddd. J=11.8, 11.6 & 4.1 Hz, 1H6), 3.01(d, J=6.8 Hz, 1H12), 2.65(dd, J=6.8 & 2.4 Hz, 1H11), 2.39(dd, 12.9 & 7.7 Hz, 1H2), 2.25(m, 12.4, 7.7 & 3.3 Hz, 1H3), 1.6- 1.3(complex, 4H), 1.21(t, J=7.1 Hz, 3H) and 1.06(dd, J=12.9 & 12.4 Hz, 1H2). IR(CC|4): 2932.2, 1711.1, 1256.5 and 1076.4cm-1. MS(m/z) : 39(35%), 41(66%), 77(33%), 91(47%), 121(34%), 138(32%), 161.1(base), 234(10%) and 235(M+1) Nuclear Overhauser Enhancement (nOe) experiments were carried out on the photoproduct to determine the stereochemistry. Irradiation of the cyclobutene proton H11 afforded enhancements at H3 (4.0%) and H12(4.6%). The bridgehead proton H5 was uneffected by irradiation at H11. 176 Photolysis of 4-(3'-buten-l'-oxy)acetophenone (4T2H-K) In a NMR tube, 4T211-K was dissloved in argon-purged deuterated methanol (2.1 mg per 0.75 mL solvent) and irradiated through a Pyrex filter sleeve. Reaction progress was monitored by time resolved 1H NMR. After 1.5 hours of irradiation, 4T2H-K was converted into a single photoproduct, 1-acetyl-8—oxatricyclo[7.2.0.0915] undeca-2,10- diene, 4T2H-CB. / Methanol .. 0 1-acetyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene 1H NMR(300MHz;CD30D) :86.34(dd, 1:3.03 81 0.6 Hz, 1H1()), 6.27(d, 1:2.9 Hz, 1H11), 5.84(ddd, J=10, 5.7, & 2.9 Hz, 1H3), 5.72 (dd, J=10 & 2.3 Hz, 1H2), 3.77(dd, J=8.6 & 5.6 Hz, 2H7), 2.38 (m, 1H5), 2.26(ddd, J=16.7, 5.8 & 4.6 Hz, 1H4), 2.20(dddd, J=16.7, 6.1, 3.0, & 2.3 Hz, 1H4), 2.16 (s, 3Hacetyl)1 and 2.0-1.8 (m, 2116). Thermal Chemistry of 4T2H-CB 4-(3'-buten-1'-oxy)acetophenone (0.3 g) was dissolved in freshly distilled methanol (200mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitored by thin layer chromatography. After complete disappearance of the starting ketone (13 hours), the reaction mixture was heated at 50°C for six hours. 177 During this time the reaction solution turned bright yellow. Purification of the reaction mixture by silica gel column chromatography (hexaneszethyl acetate, 90:10) provided 4- acetyl-1l-oxabicyclo[6.3.0] undeca-1,3,5-triene as a yellow solid ( 0.198 g, 66%). 4-acetyl-1 1-oxabicyclo[6.3.0] undeca- 1,3,5-triene 1H NMR(300MHz;00013) : 87.03(d, J=6.7 Hz, 1H3), 6.310d, 1:1.5 81 12.4 Hz, 1H5), 5.95(ddd, 1:123, 6.3, 81 5.8 Hz, 1H6), 5.42(d, J=6.8 Hz, 1H2), 4.28(ddd, 1:8.7, 6.9 81 6.5 Hz, 1H1()), 4.16(ddd, J=8.7, 7.5, 81 6.0 Hz, 1H1()), 3.1(m, 1H3), 2.5(dddd, J=16.0, 5.6, 3.7, 81 1.6 Hz, 1H7), 2.35(dddd, J=16.0, 9.6, 6.0, 81 1.5 Hz, 1H7),2.34 (s, 3Hacety1), 2.15(dddd, 1:121, 7.4 &6.9Hz, 1H9) and 1.83 (dddd, J=12.9, 12.1, 6.5, 81 6.0Hz, 1H9). Photolysis of 4:(4'-penten—1'-oxy)acetophenone (4T3H-K) In a NMR tube, 4T3H-K was dissloved in argon-purged deuterated benzene (2.3 mg per 0.75 mL solvent) and irradiated through a Pyrex filter sleeve. Reaction progress was monitored by time resolved 1H NMR. After 16 hours of irradiation, 4T3H-K was only partially converted (<30%) into a single photoproduct, l-acety1-9- oxatricyclo[8.2.0.01015] undeca-2,11-diene, 4T3H-CB. Preparatory scale photolysis (400 mg per 250 mL benzene) was carried out to isolate 4T3H-CB. After 68 hours of irradiation through Pyrex, the reaction was ceased and concentrated in vacuo. The reaction 178 mixture was redissolved in 60 mL of methanol and heated for five hours at 50°C. Purification of the reaction mixture by silica gel column chromatography (hexaneszethyl acetate, 90: 10) provided 4-acetyl-12-oxabicyclo[6.4.0] undeca-l,3,5-triene as a yellow oil. 4-acetyl-12-oxabicyclo[6.4.0] undeca— 1,3,5-triene 1H NMR(300MHz;CDCI3) 1 86.9(d, J=7.2 Hz, 1H3), 6.35(td, 1:1.2 81 11.4 Hz, 1H5), 6.1(ddd, 1:114, 7.5, & 7.2 Hz, 1H6), 5.95011 (1, J=7.2 Hz, 1H2), 4.09(ddd, 1:8.4, 8.1 81 5.7 Hz, 1H11), 3.76(ddd, 1:11.1, 8.1, 81 3.9 Hz, 1H11), 2.72(m, 1H3), 2.4(dddd,1:13.8,7.5, 81 0.9 Hz, 1H7), 2.33(s, 3Hacety1), 2.24(dddd, J=13.8, 7.5, 3.6, 81 1.2 Hz, 1H7), 1.9-1.7(m, 2H) and 1.6-1.4 (m, 2H). Photolysis of 4-(3'-methyl-3'-buten-1'-oxy)-2-methylacetophenone (2Me-4T2Me-K) ---In Methanol In a NMR tube, 4-(3'—methyl-3'-buten-1'-oxy)-2—methylacetophenone (1.5mg) was dissolved in 0.75mL of deuterated methanol (0.0092M). The sample was purged with argon for fifteen minutes and irradiated using an medium pressure mercury arc lamp fitted with a Pyrex filter. The reaction progress was followed closely by time resolved NMR. After three hours of irradiation, the reaction was 50% complete and only one cycloadduct was observed by proton NMR. The product was determined to be 1-acetyl-2,5-dimethyl- 8-oxatricyclo[72.0.0915] undeca-2,10-diene, 2Me-4T2Me-CB. Deuterium incorporation was also observed by 1H NMR by the rapid depletion of the peak frequency 179 corresponding to the ortho methyl group. Prolonged irradiation produced polymerization of the reaction mixture. Methanol A O 0 hv (pyrex) ' 10 4 0 80 .5 \——-' 6 2Me-4T2Me-K 2Me'4T2Me-CB 1-acetyl-2,5-dimethyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene 1H NMR(300MHz;CD30D) :86.50(d, J=3.03 Hz, 1H1()), 6.28(d, J=3.03 Hz, 1H11), 5.54(br t, J=4.4 Hz, 1H3), 3.80(m, 2H7), 2.28(dd, J=16.8 & 4.6 Hz, 1H4), 2.14 (s, 3Hacetyl)1 2.1 (m, 1H6), 1.92(ddd, J=16.6, 4.5 & 2.0 Hz, 1H4), 1.7(ddd, J=12.5, 6.9 & 5.3 Hz, 1H6), 1.58(q, J=1.65 Hz, 3H) and l.01(s, 3H). ---In Benzene 4-(3'-methyl-3'-buten-1'-oxy)-2-methylacetophenone was dissolved in benzene (2.1mg in lmL solvent), purged with argon, and irradiated through a Pyrex filter. The reaction progress was monitored by 1H NMR. After three hours of irradiation, the starting material was partially converted into a single photoproduct. The product was believed to be 1,2,3,4-tetrahydro-1-methyl-6-(3'-methyl-3'-buten-1'-oxy)-2,3-dioxa-1-naphthol. This type of oxygen trapped product has been observed by Matsuura72 and Yate888. 180 Benzene _ O ZMC- 4T2Me' K 2Me'4T2Me-II 1,2,3,4-tetrahydro-1-methyl-6-(3'-methyl-3‘-buten-1'—oxy)-2,3-dioxa-1-naphthol 1H NMR(300MHz;C6D6) : 86.68(d, J=7.95 Hz, 1H), 6.67(dd, J=7.95 & 2.85 Hz, 1H), 6.20(d, J=2.6 Hz, 1H), 5.1 & 4.3(AB Quartet, J=15.5 Hz, 2H),4.85(br s, 1H), 4.81(br s, 1H), 3.70(dt, J=6.84 & 1.5 Hz, 2H), 2.3(br t, J=6.84 Hz, 2H), 1.62(br s, 3H), l.57(s, 3H). Thermal Chemistry of 2Me-4T2Me-CB Warming an argon-purged sample of in methanol at 50°C results in the formation of two thermal products after two hours of heating. Purification of the reaction mixture by silica gel column chromatography (hexaneszethyl acetate 95:5) gave a equilibrium mixture of 4-acetyl-5,8-dimethyl-l 1-oxatricyclo[6.3.0.0116]undeca-2,4-diene and 4-acetyl-5,8- dimethyl-l1-oxabicyclo[6.3.0] undeca- 1,3,5-triene in 1:7 ratio. 181 4-acetyl—5,8-dimethyl- 1 1-oxabicyclo[6.3.0] undeca-1,3,5-triene 1H NMR(300MHz;CDCl3) : 8 6.95(d, 125.1 Hz, 1H3), 5.92(qdd, 121.6, 9.5 & 6.3 Hz, 1H6), 5.1(d, 125.1 Hz, 1H2), 4.15(br t, J=8.7 Hz, 1H1()), 4.07(ddd, 1211.6, 8.6 & 5.5 Hz, 1H1()), 2.31(s, 3H), 2.24(dd, 1213.7 & 9.4 Hz, 1H7), 2.2(ddd, 1211.9, 11.6 and 8.9 Hz, 1H9), 2.05(dd, 1213.7 & 6.3 Hz, 1H7), 1.74(br s, 3H), 1.63(br dd, 1211.9 & 5.5 Hz, 1H9), 1.12(s, 3H). 13C NMR(75MHz; CDCI3) : 8 198.5, 169.4, 141.0, 137.9, 137.6, 126.9, 93.3. 67.5, 46.9, 37.7, 37.0, 27.2, 26.5, and 22.1. UV-Vis (Methanol) : 4max (321 nm) 5311, (313 1110) 5074. IR(CCI4) : 2966.9, 1672.5, 1651.3, 1354.2, 1176.7, 1147.8, 1124.6, 1068.7 cm‘l. MS(m/z): 41(40.2%), 43(37.9%), 69(43%), 135(Base), 150(30.5%), 218(16.4%) and 219.2(M+1). 4-acetyl-5,8-dimethyl-l 1-oxatricyclo[6.3.0.0116]undeca-2,4-diene 1H NMR(300MHz;CDCl3) (partial) : 86.27(d, 1:10 Hz, 1H3). 5.31(d, 1:10 Hz, 1H2). 4.2-4.0(m, 2H10), 2.88(dd, 1210.5 & 7.7 Hz, 1H6). 2.26(s, 3H) and 1.13(s, 3H) 182 Photolysis of 4—(3'-buten-1'-oxy)-2-methylacetophenone (2Me-4T211-K) In a NMR tube, 4-(3'—buten-1'-oxy)-2-methylacetophenone (1.5mg) was dissolved in 0.75mL methanol-d4 (~0.01M). The sample was purged with argon for 15 minutes and then irradiated through a Pyrex filter. NMR analysis of the'reaction mixture showed that the reaction was 50% complete after three hours of irradiation. A single photoproduct was identified as 1-acetyl-2-methyl-8-oxatricyclo[7.2.0.0915] undeca-2,10-diene, 2Me- 4T23-CB. Preparatory scale photolysis was carried out to isolated the photoproduct. 2Me-4T2H-K (0.5g) was dissolved in freshly distilled methanol (300mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitored by gas chromatography. At near depletion of the starting material, the reaction was stopped and then concentrated under reduced pressure at room temperature. A proton NMR was immediately taken and showed a mixture of starting ketone and its photoproduct, 2Me- 4T2H-CB. / Methanol A ‘ O O hv(pyreX) ’ 10* . 0 ZMC' 4T2H-K 2Me'4T2H'CB l-acetyl-2-methyl-8-oxatricyclo[7.2.0.0915] undeca-2,10-diene 1H NMR(300MHz;CD30D) :86.47(d, 1:3 Hz, 1H1()), 6.29(d, 1:3 Hz, 1H11), 5.62(qdd, 1:16.44, 81 4.4 Hz, 1H3), 3.86(ddd, 128.1, 7.5 81 6.1 Hz, 1H7), 3.72(ddd. 128.1, 7.9 815.3 Hz, 1H7), 2.29(ddd, 1:159, 5.1 81 4.3 Hz, 1H4), 2.2(m, 1H5), 183 2.09(s, 3H), 2.06(ddd,1=12, 7.5, 81 6.4 Hz, 1116). 1.92(m, 1H4). 1.84(ddd, 1:12, 7.5. 815.3 Hz, 1H6). and 1.59(q, 1:1.7 Hz, 3H) Thermal Chemistry of 2Me-4T2H-CB A crude photolysis mixture of 2Me-4T2H-CB and 2Me-4T2H-K was dissolved in methanol (300mL), purged with argon, and heated in a constant temperature bath at 50°C. The reaction progress was monitored by thin layer chromatography. After complete conversion of 2Me-4T2H-CB (4 hours), the reaction mixture was purified by column chromatography (hexanes: ethyl acetate, 85:15). A single product was identified as 4-acetyl-5-methy1-1l-oxabicyclo [6.3.0] undeca-1,3,5—triene, 2Me-4T2H-COT (134mg, 27% yield based on starting ketone). 4—acetyl-5—methyl-l 1-oxabicyclo[6.3.0] undeca-1,3,5-triene 1H NMR(300MHz;CDCl3):86.94(dd,125.6 & 1.6 Hz, 1H3), 5.94(qdd,1=1.5, 9.3 & 6.6 Hz, 1H6), 5.25(dd. 1:56 81 2.1 Hz, 1H2), 4.19(ddd, 1:8.85, 5.34 81 3.7 Hz, 1H1()), 3.95(ddd, 128.85, 8.55 & 6.6 Hz, 1H10), 3.03(m, 1H3), 2.5 (ddd, 1:137, 9.25 81 4.43 Hz, 1H7), 2.30 (s, 3H), 2.29 (m,1H9), 2.10(ddd,1=13.7, 6.5 81 3.03 Hz, 1H7), l.98(dddd, 11.0, 8.6, 4.95, 813.7 Hz, 1H9) 1.58(q,121.65 Hz, 3H), and 1.7011 s, 3H). 184 13C NMR(75MHz; CDCI3):8198.5, 165.7, 138.7, 137.7, 136.7, 127.3, 94.7, 68.8, 42.6, 31.6, 27.6, 25.6, and 22.3. UV-Vis (Methanol) : 4max (320 run) 1760 **low value may be due to rapid decomposition of the cyclooctatriene. MS(m/z): 43(75%), 55(base), 77(33%), 91(40%), 105(33%), 119(26%), 133(24.5%), 135(82%), 16l(41%), 204(83%) and 205(11%). Photolysis of 4-(3'-buten-1'—oxy)-2,S-dimethylacetophenone (2,5Me-4T2H-K) In a NMR tube, 4-(3'-buten-1'—oxy)-2,5—dimethylacetophenone (1.6mg) was dissolved in 0.75mL methanol-d4 (9.8 x 10'3M). The sample was purged with argon for 20 minutes and then irradiated through a Pyrex filter. NMR analysis of the reaction mixture showed that the reaction was 100% complete after eight hours of irradiation. A single photoproduct was identified as 1-acetyl-2,10-dimethyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene, 2,5Me-4Tzfi-CB. Preparatory scale photolysis was carried out to isolated the photoproduct. 4-(3'—Buten-1'-oxy)-2,5-dimethylacetophenone (1.0g) was dissolved in freshly distilled methanol ( 500mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitored by gas chromatography. Purification of the crude reaction mixture by dry column flash chromatography (hexaneszethyl acetate, 80:20) gave 2,5Me-4T2H-CB (365mg, 37%). / O Methanol y 0 hv( rex) ' O PY H C 295M94T2H'K 2,5Me-4T2H-CB 185 1-acety1-2,10-dimethyl-8—oxatricyclo[72.0.0915] undeca-2,10-diene 111 NMR(300MHz;CD30D) :86.08(q, 1:1.6 Hz, 1H11), 5.59(qdd, 1:1.6. 5.8 & 4.0 Hz, 1H3), 3.91(dd, 127.8 & 5.9 Hz, 2H7), 2.18(ddd, 1215.9, 5.7, & 2.2 Hz, 1H4), 2.1(m, 1H5), 2.06(s, 3Hacetyl). l.88(ddd, 126, 10.1, & '12 Hz, 1H6), l.87(m, 1H4), 1.76(ddd, 1212, 7.5, 4.7 Hz, 1H6), l.66(d, 121.6 Hz, 3H), and 1.56(q, 1.6 Hz, 3H) 130 NMR(75MHz, 00300): 5 212, 151, 137, 131, 124, 123, 92, 68, 40. 32, 28, 27, 19, and 11. The stereochemistry of 1-acetyl-2,10-dimethyl-8-oxatricyclo[72.0.0915] undeca- 2,10-diene was determined by nOe experiments. Irradiation of the methyl group on c-10 afforded enhancements at H11 (1.75%), H7 (1.36%), and the bridgehead proton H5 (2.85%). Thus indicating that the cyclobutene ring is cis to the bridgehead proton H5. Thermal Chemistry of 2,5Me-4T2H-CB In a large Pyrex test tube, 2,5Me-4T2H-CB (30mg) was dissolved in methanol (50mL), purged with argon, and heated in a constant temperature water bath (50°C). The reaction progess was monitored by thin layer chromatography. After 48 hours of heating, para-toluenesulfonic acid (2mg) was added to the reaction solution to help facilitate 186 rearrangement. NMR analysis of the reaction mixture showed quantitative conversion of l- acetyl-2,10-dimethyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene to its ring opened isomer, 4-acetyl-2,5-dimethyl-11-oxabicyclo[6.3.0] undeca-1,3,5-triene. Purification of the crude reaction mixture was accomplished by preparative thin layer chromatography (ethyl acetatezhexanes, 5:95). Methanol 50°C 4-acetyl-2,5-dimethyl-l l-oxabicyclo[6.3.0] undeca-1,3,5-triene (26mg, 88%) 1H NMR(300MHz;CDCl3) : 56.88011 s, 1H3), 5.88(qdd, 1:1.5, 9.3 81 6.7 Hz, 1H6), 4.22(ddd.1:8.9, 8.3 81 3.3 Hz, 1H1()), 3.97(ddd, 1:120, 8.9 81 6.7 Hz, 1H1()), 3.03(m, 1H3), 2.45 (ddd, 1213.8, 9.3 81 4.0 Hz, 1H7), 2.43 (s, 3HAcety1), 2.09(ddd, 1213.8, 6.7 81 4.26 Hz, 1H7), l.98(m, 2H9), 1.76011 s, 3HMe) 1.70(d, 1:1.60 Hz, 3HMe)- 130 NMR(75MHz, CDCL3): 5 198.74, 158.41, 142.28, 138.65, 136.23, 126.44, 101.75, 68.06, 41.58, 31.90. 29.07, 26.41, 23.04, and 15.89. 111(0014) 1 2974.6, 1657.6, 1354.2, 1167.1, 1151.7, 1109.21, 908.6 cm-l. UV-Vis (Methanol) : 4max (329 nm) 5420 M8 : 39(25%), 41(27%), 43(87%), 53(22%), 55(base), 77(37%). 91(43%), 149(42%), 218(55%), and 219(M+1). 187 Photolysis of 4-(3'-methyl-3'-buten-1'-oxy)-2,5-dimethylacet0phenone (2,5Me-4T2Me-K) In a NMR tube, 4-(3'-methyl-3'-buten-1'-oxy)-2,5-dimethylacetophenone (1.8mg) was dissolved in 0.75mL methanol-d4 (1.0 x 10'2M). The sample was purged with argon for 20 minutes and then irradiated through a Pyrex filter. 1H NMR analysis of the reaction mixture showed no observable photoproducts after 20 hours of irradiation. Similar results were obtained using benzene as the solvent. The methyl group on the double bond of 2,5Me-4T2Me-K appears to suppress the photocycloaddition process. 2,5MC‘4T2Me-K Photolysis of 5-isopropyl-4-(3'-buten-1’-oxy)-2-methylacetophenone(2Me-4T21-1-SI-K) In a NMR tube, 2Me-4T2H-SI-K (2.6mg) was dissolved deuterated methanol (lmL), purged with argon, and irradiated through a Pyrex filter. The reaction progress was monitored proton NMR spectroscopy. The reaction was nearly complete after four hours of irradiation. 2Me-4T2H-SI-K was converted into two cyclobutene photoproducts, 1-acetyl-3-isopropyl-11-methyl-8-oxatricyclo[7.2.0.0915] undeca-2,10— diene and 1-acetyl-3-isopropyl-11-methyl-8-oxatricyclo[7.2.0.0915] undeca-2,10-diene in a 1.25:1 ratio respectively. Preparatory scale photolysis was carried out to isolate the cyclobutene photoproducts. 2Me-4T2H-SI-K (1.2g) was dissolved in methanol (500mL), purged with argon and irradiated in an immersion well through a Pyrex sleeve. The reaction progress was monitored by gas chromatography. Purification of the crude reaction mixture by silica gel column chromatography gave 1-acetyl-3-isopropyl-11- 188 methyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene (0.273g) and 1-acetyl-10-isopropyl- 2-methy1-8-oxatricyclo172.0.0915] undeca-2,10—diene (0.218g) (overall yield 41%). fl Methanol \ k r 10 O hv (pyrex) . 1-acetyl-3-isopropyl-1 l-methyl-8-oxatricyclo[7.2.0.0915] undeca-2,10-diene lH NMR(300MHz;C6D6) :8 5.83(dq, 120.6 &1.5 Hz, 1H1()), 5.62(br s, 1H2), 3.65(ddd, 128.4, 7.9 &3.0 Hz, 1H7), 3.57(ddd, 129.3, 8.4 & 6.9 Hz, 1H7), 2.18(s, 3Hacetyl), 2.14(br qq, J=6.9 & 6.9 Hz, 1H1pr), 2.08(d, 1211.1 Hz, 1H4), 1.96(dddd, 1212.0, 9.3, 7.9 & 6.3 Hz, 1H6), 1.7(m, 2H5,4), 1.49(d, 121.5 Hz, 3HMe), 1.4(dddd, 1212.0, 6.7, 4.3 & 3.0 Hz, 1H6), 0.93-0.91(d, J=6.9 Hz, 3H1pr) and 0.92-0.90(d, J=6.9 Hz, 3H1pr). l-acetyl-10-isopropyl-2—methyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene 1H NMR(300MHz;C6D6):85.97(d,121.5 Hz, 1H11), 5.34(qdd, 1:1.5, 4.2 81 4.0 Hz, 1H3), 3.72(ddd,1=9.3, 8.2 81 6.5 Hz, 1H7), 3.62(ddd,1=8.2, 7.0 81 5.8 Hz, 1H7), 2.14(s, 3Hacetyl), 2.18(dqq,1=1.5, 6.9 81 6.9 Hz, 1H11),), 1.96(dddd, 1212.8, 9.4, 7.0 81 0.96 Hz, 1H6), 1.8(m, 2H4,5), 1.61(dddd, 1212.8, 6.5, 5.8 81 4.3 Hz,1H6), 1.59(m, 1H4), 1.58(d, 1:1.5 Hz, 3HMe), 1.03(d, J=6.9 Hz, 3H1pr) and 0.96(d, J=6.9 Hz, 3HIPr)- IR(CC|4): 2963.0, 2930.2, 1699.5, 1458.4, and 1250.0cm-1. 189 Thermal Chemistry of 2Me-4T2H-51-CB-t In a large test tube, 2Me-4T2H-SI-CB-t (218mg) was dissolved in freshly distilled benzene (100mL), purged with argon, and heated in a constant temperature bath at 50°C. The reaction progress was monitored by thin layer chromatography. After 24 hours, a crystal of para-toluenesulfonic acid was added to the reaction mixture. 2Me- 4T2H-SI-CB-t opened rapidly after the addition of acid. Purification of the crude reaction mixture by silica gel column chromatography (hexaneszethyl acetatezdichloromethane, 80:5:15) gave 2Me-4T2H-SI-COT-t (173mg, ~79%). Benzene __, H 50°C 6 0 CH3 2Me'4T2H'SI'CB't 2Me'4T2H'51'COT't 4-acetyl-2-isopropyl-5-methyl-1 1-oxabicyclo[6.3.0] undeca- 1,3,5-triene 1H NMR(300MHz;C6D6) : 86.98(d, 121.5 Hz, 1H3), 5.68(qdd, 121.6, 6.3, & 5.1 Hz, 1H6), 3.74(ddd, 128.2, 6.9 & 4.2 Hz, 1H10), 3.51(ddd, 129.5, 8.2 & 6.6 Hz, 1H1()), 3.30(dqq, 121.5,6.9 & 6.9 Hz, 1H), 2.66(m, 1H8), 2.28 (ddd, 1214.5, 6.0 & 5.1 Hz, 1H7), 2.09 (s, 3Hacetyl), l.88(s, 3Hmethyl)1 1.71(ddd, 1214.5, 6.3 & 4.5 Hz, 1H7), 1.38(overlapping dddd's, 1211.9, 9.5, 6.9, 6.6 & 4.2 Hz, 2H9), 1.10(d, J=6.9 Hz, 3Hiso), and 0.92(d, J=6.9 Hz, lHiso). 130 NMR(75MHz, CDCL3): 5 198.63, 156.23, 141.16, 139.15, 136.30, 126.13, 112.59, 67.97, 41.13, 31.89, 29.55, 27.84, 26.57, 23.07. 22.03. and 20.58. IR(CCI4) : 2963.0, 1668.6. 1649.4, 1145.9, 1022.4 cm'l. 190 UV-Vis (Methanol) : Xmax (330.5 1110) 5747 Thermal Chemistry of 2Me-4T2H-SI-CB-a In a large Pyrex test tube, 2Me-4T2H-SI-CB-a (270mg) was dissolved in benzene (100mL), purged with argon, and heated in a water bath at 50°C. After 24 hours of heating, a crystal of para-toluenesulfonic acid was added to the reaction mixture to accelerate ring opening. 1H NMR and thin layer chromatography showed the complete conversion of 2Me-4T2H-SI-CB-a to a single product. Purification of the reaction mixture by silica gel column chromatography gave 2Me-4T2H-5I-COT-a in 63% yield (170.6mg). 2MC'4T2H'SI'CB‘3 2Me'4T2H'SI'COT-a 4-acetyl-6-isopropyl-3-methyl-1 l-oxabicyclo[6.3.0] undeca- 1,3,5-triene 1H NMR(300MHz;C6D6) : 55.92011 s, 1H5), 5.36(s, 1H2), 3.68(dt, 1:8.3 81 7.1 Hz, 1H1()), 3.52(ddd, 128.3, 8.3 & 5.0 Hz, 1H1()), 2.81(dddd, 129.0, 7.3, 5.6 & 1.7 Hz, 1H8), 2.06(ddd, 1215.9, 5.5 & 1.9 Hz, 1H7), l.97(s, 3HAcetyl)1 l.97(s, 3HMe), 1.96(m, 1H), 1.67(dd,1=15.9 & 9.0 Hz, 1H7), 1.32(m, 1212.0 & 7.4 Hz, 1H9), 1.09(m, 1212.0 & 5.1 Hz, 1H9), 0.85(d, J=6.9 Hz, 3Hiso), and 0.83(d, J=6.9 Hz, 1Hiso)- 191 13C NMR(75MHz;CDCl3) : 205.8, 156.3, 141.3, 139.2, 136.4. 126.2, 112.7, 68.1, 41.2, 32.0, 29.7, 28.0, 23.2, 22.1, and 20.7. UV-Vis (Methanol) : Xmax (313.5 mm) 4813. Photolysis of 4-(3'-methyl-3'-buten-1'-oxy)-5-isopropyl-2-methy1acetophenone (2Me-4T2Me-SI-K) In a NMR tube, 4-(3'-methyl-3'-buten-1'-oxy)-5-isopropyl-2-methylacetophenone (2mg) was dissolved in 0.75mL methanol-d4 (1.0 x 10-2M). The sample was purged with argon for 20 minutes and then irradiated through a Pyrex filter. 1H NMR analysis of the reaction mixture showed no observable photoproducts after 20 hours of irradiation. Similar results were obtained using benzene as the solvent. The methyl group on the double bond of 2Me-4T2Me-SI-K appears to suppress the photocycloaddition process, as seen previously seen for 2,5Me-4T2Me-K. 2Me-4T2Me-51-K Photolysis of 2-isopropyl-4-(3'-methyl-3'-buten-1'-oxy)acetophenone(21-4T2Me-K) A solution of 21-4T2Me-K (2.6mg per 0.7 5mL solvent) in CD30D was degassed with argon for fifteen minutes and irradiated using a medium pressure mercury lamp fitted with a Pyrex filter. 1H NMR analysis of the reaction mixture showed only minimal product formation (~10% conversion) after nine hours of irradiation. The major product 192 was identified as l-acety1-2-isopropyl-5—methyl—8-oxatricyclo[72.0.0915] undeca-2.10- diene. Methanol A 00 W a 0 l-acetyl-2-isopropyl-5-methyl-8-oxatricyclo[72.0.0519] undeca-2,10-diene 1H NMR(300MHz;CD30D)(Partial):86.49(d,123.1 Hz, 1H1()), 6.24(d,123.0 Hz, 1H 1 1), 5.65(ddd, 125.0, 4.1 & 0.8 Hz, 1H3), 3.8(m, 2H7), 2.12 (s, 3H), 1.04(s, 3H), 1.0(d, 127 Hz, 3Hiso) and 0.98(d, 127Hz, 3Hiso) Photolysis of 4-(3'-methyl-3'-buten-l'-oxy)-2-methoxyacetophenone(20Me-4T2Me-K) In a NMR tube, 20Me-4T2Me-K was dissloved in argon-purged deuterated methanol (2.6mg per lmL solvent) and irradiated through a Pyrex filter sleeve. Reaction progress was monitored by time resolved 1H NMR. After eight hours of irradiation, 20Me-4T2Me-K was converted into a single photoproduct, 1-acetyl-5-methyl-2- methoxy-8-oxatricyclo[7 2.0.0519] undeca-2,10-diene, 20Me-4T2Me-CB. 193 1-acetyl-5-methyl-2-methoxy-8-oxatricyclo[72.0.0519] undeca-2,10-diene 1H NMR(300MHz;CD30D) : 86.35(d, 1:2.97 Hz, 1H1()), 6.23(d, 1:2.97 Hz, 1H11), 4.75(dd, 126.1 &3.2 Hz, 1H3), 3.87(m, 2H7), 3.49(s, 3H), 2.35(dd, 1216.4 & 6.09 Hz, 1H4), 2.16(m, 1H6), 2.09 (s, 3H), 2.04(dd, 1216.4 & 3.15 Hz, 1H4), 1.65(ddd, 1212.3, 5.8 & 4.5 Hz, 1H6) & 1.04(s, 3H). Large scale photolysis was carried out to isolate 20Me-4T2Me-CB. 20Me-4T2Me-K (850mg) was dissloved in methanol (300mL), purged with argon and irradiated in an immersion well through Pyrex. The reaction was monitored by thin layer chromatography. At near depletion of the starting material, the reaction was stopped and then concentrated under reduced pressure at room temperature. A proton NMR was immediately taken and showed a mixture of starting ketone and its photoproduct, 20Me-4T2Me-CB. Thermal Chemistry of 20Me-4T2Me-CB A crude photolysis mixture of 20Me-4T2Me-CB and 20Me-4T2Me-K was dissolved in methanol (200mL), purged with argon, and heated in a constant temperature bath at 50°C. The reaction progress was monitored by thin layer chromatography. After complete conversion of 20Me-4T2Me-CB, the reaction mixture was purified by column chromatography. Two products were isolated in equilibrium (1:1 ratio). They are determined to be the thermal products of lAP-20Me-4T2Me-CB, 4-acetyl-5-methoxy- 8-methyl-l1-oxatricyclo[6.3.0.0116]undeca-2,4-diene and 4-acetyl-5-methoxy-8-methyl- l 1-oxabicyclo[6.3.0] undeca-1,3,5-triene. 194 4-acetyl-5-methoxy-8—methyl-l l-oxatricyclo[6.3.0.0116]undeca-2,4:diene 1H NMR(300MHz;CDCl3) : 86.7(d, 1210.1 Hz, 1H3), 5.1(d, 1210 Hz, 1H2), 4.1- 4.1(m, 2H10), 3.58(s, 3H), 3.27(dd, 1210.1 & 7.95 Hz, 1H6), 2.25(s, 3H), 2.26(dd, 1212 & 10.1 Hz, 1H7), l.89(ddd, 1212.6, 5.6 & 4.1 Hz, 1H9), 1.81(dd, 12.5 & 7.9 Hz, 1H9),1.78(ddd, 1211.9, 8.0 & 0.9 Hz, 1H7) and 1.14(s, 3H). 4-acetyl-5-methoxy-8-methyl-1 1-oxabicyclo[6.3.0] undeca- 1,3,5-triene 1H NMR(300MHz;CDCl3) : 57.19(d, 1:5.34 Hz, 1H3), 5.24(dd, 129.3 81 7.1 Hz, 1H6), 5.l4(dd, 125.34 & 0.5 Hz, 1H2) 4.1-4.2(m, 2H10), 3.69(s, 3H), 2.35(s, 3H), 2.27(dd, 1214.1 & 9.3 Hz, 1H7), 2.10(dd, 1214.1 &7.2 Hz, 1H7), 1.76(ddd, 1211.8, 8.0 & 0.9 Hz, 1H9), 1.65(dd, 1211.7 & 5.6 Hz, 1H9) and 1.59(s, 3H). 130 NMR(75MHz;CDCI3)(equilibrium-partial) : 200, 196, 160, 154, 139, 130. 127, 123, 114, 99, 93, 61, 57, 47, 44, 41,32 and 24. 195 Photolysis of 2-trifluoromethyl-4~(3'-methyl-3'—buten-1'-oxy)acetophenone (2CF3-4T2Me-K) ---In Methanol In a NMR tube, 2-trifluoromethyl-4-(3'-methyl-3'-buten-l'-oxy)acetophenone (1.7mg) was dissolved in 0.75mL of deuterated methanol (0.008M). The sample was purged with argon for fifteen minutes and irradiated using an medium pressure mercury arc lamp fitted with a Pyrex filter. The reaction progress was followed closely by time resolved 1H NMR. After twenty-three hours of irradiation, the reaction was 50% complete and only one cycloadduct was observed by proton NMR. The product was determined to be 2CF3-4T2Me-COT. Large scale photolysis of 2CF3-4T2Me-K (180mg) in argon-purged methanol (60mL) provided 2CF3-4T2Me-COT. Purification of the photolysis mixture by silica gel column chromatography caused decomposition of 2CF3- 4T2Me-COT. The structure of 2CF3-4T2Me-COT was determined from the 1H NMR of the photolysis mixture. F C 3 6 Methanol ; O O 0 hv (pyrex) 4 OF C 2 3 0 10 2CF3-4T2Me- K 2CF3-4T2Me-C0T 4-acetyl-5-trifluoromethyl-8-methyl-1 l-oxabicyclo[6.3.0] undeca-1,3,5-triene 1H NMR(300MHz;CDCl3) : 57.2(d, 1:4.8 Hz, 1H3). 6.8(qdd, 121.6, 9.2 81 6.5 Hz, 1H6). 5.2(d,1=4.8 Hz, 1H2), 4.2011 dd, 1:9.0 81 8.7, 1H1()), 4.12(ddd, 1:114, 196 9.0 & 5.4 Hz, 1H1()), 2.4(dd, 1212.4 & 9.2 Hz, 1H7). 2.3(s, 3H), 2.2(m, 1H9), 1.76(dd, 1212.4 & 6.3 Hz, 1H7). l.6(m, 1H9), and 1.21(s, 3H). Photolysis of 4—(3’-methyl-3'—buten-1'-oxy)-2-fluoroacetophenone (2F-4T2Me-K) In a NMR tube, 4—(3'-methyl-3'-buten-1'-oxy)-2-fluoroacetophenone (2.2mg) was dissloved in lmL deuterated methanol (1 x 10'2M). The sample was purged with argon for 20 minutes and then irradiated through a Pyrex filter. The reaction was monitored by time resolved NMR. After three hours, the reaction was nearly complete. Two photoproducts were indentified by 1H NMR in a ratio of ~10:1 as 1-acetyl-2-fluoro-5- methyl-8-oxatricyclo[7.2.0.0519]undeca-2,10-diene, 2F-4T2Me-CB-t and its regioisomer, l-acetyl-l 1-fluoro-S-methyl-8-oxatricyclo[7.2.0.0519]undeca-2, lO-diene, 2F-4T2Me-CB-a respectively. Indentification of the minor product was difficult due to extensive overlap of the structurely similar major photoproduct. A partial 1H NMR for 1- acetyl-11-fluoro-5-methyl-8-oxatricyclo[7.2.0.0519]undeca-2,10-diene is presented, stressing the characteristic olefin region. 1-acetyl-2-fluoro-5-methyl-8-oxatricyclo[72.0.0519] undeca-2,10-diene IH NMR(300MHz;CD3OD):86.5(d,1=2.94 Hz, 1H 10), 6.35(d, 1:2.90 Hz, 1H11), 5.31(ddd, 1215.6, 6.5 & 2.8 Hz, 1H3), 3.85(ddd, 129.6, 8.25 & 6.9 Hz, 1H7), 3.79(ddd, 129.4, 8.25 & 2.9 Hz, 1H7), 2.32(ddd, 1216.9, 6.6 & 3.9 Hz, 1H4), 197 2.25(ddd, 1212.2, 9.6, & 9.4 Hz, 1H6), 2.17(d, 120.63 Hz, 3HAcetyl). 2.02(ddd, 1216.9, 6.0 & 2.8 Hz, 1H4). l.64(ddd, 1212.2, 6.8 & 2.9 Hz, 1H6) & l.07(s, 3H). l—acetyl-l 1-fluoro-5-methyl-8-oxatricyclo[7.2.0.0519]undeca-2,10—diene 1H NMR(300MHz;CD30D) : 85.92(ddd, 1210.1, 6.7 ’& 2.4 Hz, 1H3), and 5.65(dd, 1210.1 & 3.2 Hz, 1H2). Preparatory scale photolysis was carried out to isolate 2F-4T2Me-CB. 2F- 4T2Me-K (700mg) was dissolved in freshly distilled methanol (300mL), purged with argon and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitiored by thin layer chromatography and stopped at near depletion of 2F- 4T2Me-K. The reaction mixture was concentrated under reduced pressure and its 1H NMR was taken. Purification of the reaction mixture by coloumn chromatography gave a mixture of three products, 2F-4T2Me-CB and two thermal rearranged isomers. Thermal Chemistry of 2F-4T2Me-CB . In a large Pyrex test tube, crude 2F-4T2Me-CB (250mg) was dissolved in methanol (100mL), purged with argon, and heated in a constant temperature water bath (50°C). The reaction progess was monitored by thin layer chromatography. After 5 hours of heating, 2F-4T2Me-CB was completely converted. Purification of the crude reaction mixture by preparative thin layer chromatography (ethyl acetatezhexanes, 5:95) gave a 1:1 ratio of 4-acetyl-5-fluoro-8-methyl-1l-oxatricyclo[6.3.0.01s6]undeca-2,4-diene and 4- acetyl-S-fluoro-8-methyl-l 1-oxabicyclo[6.3.0] undeca- l ,3,5-triene. 198 Methanol ‘ 50°C , 4-acetyl-5-fluoro-8-methyl-l 1-oxatricyclo[6.3.0.01v6]undeca-2,4-diene 1H NMR(300MHz;CDCl3) : 86.53(dd, 1210 & 7.6 Hz, 1H3), 5.3(dd, 1210 & 2.34 Hz, 1H2), 4.12(dd, J=8.6 & 4.5 Hz, 2H10), 3.25(ddd, 1210, 9.8 & 7.4 Hz, 1H6), 2.4(d, 125.7 Hz, 3H), 2.23(dd, 1212.4 &10 Hz, 1H7), l.87(dd, 1212.4 & 7.4 Hz, 1H7), 1.9-1.7(complex, 2H9) and1.17(s, 3H). 4-acetyl-5-fluoro-8-methyl-1 l-oxabicyclo[6.3.0] undeca-1,3,5-lriene IH NMR(300MHz;CDCl3):87.3(dd,126.03 81 0.75 Hz, 1H3), 5.85(ddd. 1:17.1, 9.6 81 7.5 Hz, 1H6), 5.23(ddd, 126.03, 3.1, & 0.75 Hz, 1H2) 4.25011 t, 1:8.9 Hz,1H1()), 4.18(ddd,1=11.3, 8.7 81 5.7 Hz, 1H1()), 2.3(d,1=2.0 Hz, 3H), 2.25(ddd, 1:143, 10, 81 2.0 Hz, 1H7), 2.12(ddd,1=14.3, 7.5, 81 1.5 Hz, 1H7), 1.9-1.7(complex, 2H9), and 1.13(s, 3H). 130 NMR(75MHz, 000L3) (equilibrium): 5 195.60. 1:3 Hz, carbonyl) and 193(d,1=3 Hz, carbonyl), 172.8(d), 172.5, 168.7, 158.1, 154.8, 142.5(d), 129.1(d), 123.4, 120.8, 112.5(d), 108.6, 93.8, 87.5(d), 67.7, 67.1, 54.8, 47.4, 40.4, 37.7, 37.2, 36.9, 33.0(d), 31.3(d), 27.4, 27.0, and 21.9. IR(CCI4) (equilibrium) : 2965,2667, 1682, 1678. 1377, 1069, and 908.6cm-1. 199 Photolysis of 4-(3'-methyl-3'-buten-1'-oxy)-2-methyl(d3)acetophenone (2CD3-4T2Me-K) ---In Benzene 4-(3'-methyl-3'-buten-1'-oxy)-2-methyl(d3)acetophenone was dissolved in benzene (2.0mg in lmL solvent), purged with argon, and irradiated through a Pyrex filter. The reaction progress was monitored by 1H NMR. After three hours of irradiation, the starting material was partially converted into a single photoproduct (~40%). Purification of 2CD3-4T2Me-II by preparative thin layer chromatography (hexanes:ethyl acetate, 90: 10) was unsuccessful. No observable 2+2 photocycloaddition products were formed under these conditions. Benzene ~ O 0 hv (pyrex) ' 0 030 2003-4T2M,-K 200,-4T2M,-11 2CD3-4T2Me-II 1H NMR(300MHz;C6D6) : 86.94(dd, 128.1 & 0.7 Hz, 1H), 6.76(dd, 128.1 & 2.0 Hz, 1H), 6.65(dd, 122.1 & 0.7 Hz, 1H), 4.85(br s, 1H), 4.79(br s, 1H), 3.78(t, J=6.84 Hz, 2H), 2.3(t, J=6.84 Hz, 2H), 1.59(br s, 3H), 1.54(s, 3H). ---In Methanol In a NMR tube, 4-(3'-methyl-3'-buten-l'-oxy)-2-methyl(d3)acetophenone (1.5mg) was dissolved in 0.75mL of deuterated methanol (~0.01M). The sample was purged with 200 1 argon for fifteen minutes and irradiated using an medium pressure mercury arc lamp fitted with a Pyrex filter. The reaction progress was followed closely by time resolved NMR. After eleven hours of irradiation, 2CD 3-4T2Me-K was converted into a single photoproduct, 1-acetyl-2-methyl (d3)—5-methyl-8-oxatricyclo[7.2.0.0519] undeca-2,10— diene, 2CD3-4T2Me-CB. Methanol A 00 1...... , . 4 0 8O .5 D3C '6 2003-4T2M,.K 200,-4T2M,-00 1-acetyl-2-methyl (d3)-5-methyl-8-oxatricyclo[72.0.0519] undeca-2,10—diene 1H NMR(300MHz;CD30D):86.50(d,123.03 Hz, 1H1()),6.28(d,1=3.0 Hz, 1H11), 5.54(dd. 1:4.8 814.14 Hz, 1H3), 3.80(m, 2H9), 2.26(dd, 16.8 & 4.8 Hz, 1H4), 2.12 (s, 3H), 2.1 (m, 1H6), 1.94(dd,1=16.8 81 4.14 Hz, 1H4), 1.69(ddd,1:12.8, 7.23 81 5.61 Hz, 1H6), and l.01(s, 3H). Photolysis of 2,6-dimethyl-4—(3'-methyl-3'-buten-1'-oxy)acetophenone (2,6Me-4T2Me-K) : In a NMR tube, 2,6Me-4T2Me-K (1.7mg) was dissolved in 0.75mL of deuterated benzene (~0.01M). The sample was purged with argon for fifteen minutes and irradiated using an medium pressure mercury arc lamp fitted with a Pyrex filter. The reaction progress was followed closely by time resolved 1H NMR. Five hours of irradiation resulted in the formation of a single photoproduct. The photoproduct was 201 determined to be 2'-methyl-4'-(3'-methyl-3'-buten-1'—oxy)-1-methylbenzocyclobutenol, 2,6Me-4T2Me-II, arising from hydrogen abstraction from an ortho methyl group. Similarly, NMR scale photolysis of 2,6Me-4T2Me-K (2.1mg in lmL solvent) was carried out in argon-purged methanol-d4 through a Pyrex filter. No photoproducts arising from ortho 2+2 cyloaddition were observed by 1H NMR after ten hours. Benzene 4 H O 0 hv (pyrex)fi O 0 2,6MC'4T2Me'K 2,6M64T2Me'n 2'-methyl-4'—(3'—methyl-3'-buten- 1'-oxy)- l-methylbenzocyclobutenol 1H NMR(300MHz;C6D6) : 86.63(br s, 1H), 6.53(br s, 1H), 4.82(m, 2H), 3.82(t, J=6.6 Hz, 2H), 3.02 & 2.88(AB Quartet, 1213.8 Hz, 2H), 2.34(t, J=6.6 Hz, 2H), 2.12(s, 3H), 1.62(br s, 3H) and 1.56(s, 3H). Photolysis of 3-Methyl-5-(3'-methyl-3'-buten-l'-oxy)indan-1-one (Indanone-3Me-5T2Me) A solution of Indanone-3Me-5T2Me (1.9mg per 0.75mL solvent) in CD30D was degassed with argon and irradiated at 300 nm in a Rayonet. The reaction was monitored by time resolved 1H NMR. Analysis showed the presence of two photproducts in ratio of 1:1 after sixteen hours. The cyclobutene photoproducts were identified as trans- 4,1 l-dimethyl-14-oxatricyclo[9.3.0.0317]tetradecatri-1,3,8-ene-6-one, Indanone-COT- trans, and cis-4,1 l-dimethyl-14-oxatricyclo[9.3.0.03a7]tetradecatri—1,3,8-ene-6-one, Indanone-COT-cis. Attempts to separate the diastereomers were unsuccessful by either alumina or silica gel column chromatography. 202 2 O 6 2 O 4 '2 4 0 Methanol _ 12 Q 0 hv (300nm)’ a a . 10 O 8 . O 8 Indanone-3Me-5T2Me Indanone-COT-cis Indanone-COT-trans 1 : 1 cis- and trans-4,1l-dimethyl-14-oxatricyclo[9.3.0.0317]tetradecatri-1,3,8—ene-6-one lH NMR(300MHz;CD30D) (mixture of diastereomers) : 8 6.36(dt, 1211.8 & 1.4 Hz, 1H8), 6.23(br dt, 12.1, 1.35 Hz, 1H3), 5.99(tdd, 1212.0, 8.5 & 7.5 Hz, 2H9), 5.62(s, 1H2), 5.47(s, 1H2), 4.28(ddd, 1210.3, 9.0 & 6.0 Hz, 1H13), 4.8-4.19(m, 3H13), 2.88(bq, J=7.2 Hz, 2H4), 2.69-2.62(dd, 1218.8 & 7.0 Hz, 1H5), 2.69-2.62(dd, 1218.8 & 7.0 Hz, 1H5), 2.46(dd, 1214.4 & 8.5 Hz, 2H10), 2.04-1.98(dd, 1218.8 & 2.05 Hz, 2H5), 1.23(d, 127.1 Hz, 3HMe). 1.21(d, 127.1 Hz, 3HMe). 1.20(s, 3HMe). l.17(1s, 3HMe). ’ Photolysis of 5-(3'-methyl-3'—buten-1'-oxy)-2-acetylbenzonitrile (2CN-4T2Me-K) NMR scale photolysis of 2CN-4T2Me-K (2mg ketone per 0.75mL solvent) was carried out in argon-purged methanol or benzene at 313 nm or through Pyrex. The progress of the reactions was monitored by 1H NMR. At either of the four reaction conditions, no photocycloaddition was observed. 2CN-4T2Me-K remained photostable after long periods of irradiation (>20 hours). 203 Solvent . we hv (pyrex) : No Reactlon 0 NC 2CN'4T2Me' K Photolysis of cis-and trans-5-(4'-Acetylphenoxy)-4,4-dimethyl-2-pentenenitrile (4T2N(CN)-K) In a NMR tube, cis-and trans-5-(4'-Acetylphenoxy)-4,4-dimethyl-2-pentenenitrile (2.1mg) was dissolved in 0.75mL methanol-d4 (1.15 x 10’2M). The sample was purged with argon for 20 minutes and then irradiated through a Pyrex filter. NMR analysis of the reaction mixture showed rapid cis-trans isomerization of the double bond after 15 minutes (9:1 trans-cis to 2.5:1 trans-cis). Continued irration of the reaction mixture produced two products in a 1:1.3 ratio as determined by integration of peak resonances corresponding to the acetyl groups (~2.1 ppm). The photoproducts were determined to be (4R)-1-acety1—4- cyano-6,6-dimethyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene and (4S)-l-acetyl-4~ cyano-6,6-dimethyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene. Preparatory scale photolysis was carried out to isolated the photoproducts. cis-and trans-5-(4'- Acetylphenoxy)-4,4-dimethyl-2-pentenenitrile (0.06g) was dissolved in freshly distilled methanol (25mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitored by thin layer chromatography. Purification of the crude reaction mixture by thin layer chromatography (hexaneszethyl acetate, 80:20) gave 1-acetyl-4-cyano- 6,6-dimethyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene and its thermal rearranged isomer 1-acety1-4-cyano-6,6-dimethyl-8-oxatricyclo[72.0.0915] undeca—3,10-diene. The exact stereochemistry of the isolated l-acety1-4-cyano-6,6-dimethy1-8- 204 oxatricyclo[7.2.0.0915] undeca-2,10-diene could not be determined due to its thermal instability. l~acetyl-4-cyano—6,6-dimethyl-8-oxatricyclo[7.2.0.0915] undeca-2,10-diene 1H NMR(300MHz;CDCl3) :8 6.56(d, 123 Hz, 1H1()), 6.47(d, 123 Hz, 1H11), 6.09(dd, J=10.2 & 1.5 Hz, 1H2), 5.83(dd, 1210.2 & 4.8 Hz, 1H3), 3.60(AB Quartet, J=8.7 Hz, 2H7), 3.49(ddd, 124.8, 4.2 & 1.5 Hz, 1H4), 2.37(d, 124.2 Hz, 1H5), 2.21(s, 3Hacetyl) , 1.11(s, 3H), and 0.98(s, 3H). 1-acetyl-4—cyano-6,6-dimethyl-8-oxatricyclo[7.2.0.0915] undeca-3,10-diene 1H NMR(300MHz;CDCl3) : 8 6.85(br dd, 126.3 & 2.7 Hz, 1H3), 6.33(d, 123 Hz, 1H1()), 6.23(d, 123 Hz, 1H11), 3.64(AB Quartet, J=8.4 Hz, 2H7), 3.12(ddd, 1219.5. 2.7, & 2.4 Hz, 1H2), 2.6(br s, 1H5), 2.24(s, 3Hacetyl) , 2.05(ddd, 1219.5, 6.3, & 1.5 Hz, 1H2), 1.2(s, 3H), and 0.9(s, 3H). Photochemistry of 4T2N(Et)-K Irradiation of a solution of cis-6-(4'-acetylphenoxy)-3-hexene (3.2 mg) in argon- purged methanol (0.8 mL) provided two products in a 20:1 ratio as determined by integration of peak resonances corresponding to the cyclobutene proton (H-1 1) at 6.3 and 6.2 ppm. The two photoproducts were determined to be (4-endo)-l-acetyl-4-ethyl-8- oxatricyclo[7.2.0.0915]undeca-2,-lO-diene, (4-endo)-Et-CB, and (4-exo)-1-acetyl-4— ethyl-8-oxatricyclo[72.0.0915] undeca-2,—10-diene, (4-exo)-Et-CB, respectively. 205 Cis/trans isomerization of the double bond was also observed during the photoreaction as determined by the observation new double bond resonances (1216Hz). 0 0 O 2 8.0 _.~ \ 10 -.4 + 10 4 CHsOH 01‘ , "Et 01‘ , ‘a / 3 \ 65 3 \ 6: El End0'4T2H(Et) EXO-4TZH(Et) endo-1-acety1-4-ethyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene 1H NMR(300MHz;CD30D) :5 6.43(d,1=2.9 Hz, 1H1()), 6.31(d,1=2.9 Hz, 1H11), 5.92(dd, J=10.2 & 4.7 Hz, 1H3), 5.73(dd, J=10.2 & 1.4 Hz, 1H2), 3.81(dd, 127.75 & 6.15 Hz, 2H7), 2.2(m, 1H5), 2.13(s, 3Hacetyl) , 2.0(dddt, 124.7, 1.4, & 3.7Hz, 1H4), 1.5(m, 2H6), 1.0(dq, 127.4 & 3.7Hz, 2H), and 0.97(t, 127.4 Hz, 3H). exo—1-acetyl-4-ethyl-8-oxatricyclo[72.0.0915] undeca-2,10-diene 1H NMR(300MHz;CD3OD) :8 6.35(d, 1:3 Hz, 1H10), 6.22(d, 1:3 Hz, 1H11), 5.92(dd, 1210.2 & 4.7 Hz, 1H3), 5.8-5.6(m, 2H2,3). 3.7(AB Quartet, 2H7). 2.14(s, 3Hacetyl)- Therrnal Ring Opening of endo and exo-4T2N(Et)-CB cis-6-(4'-Acetylphenoxy)-3-hexene (0.2 g) was dissolved in freshly distilled methanol (250mL) and irradiated in an immersion well through a Pyrex filter. The reaction progress was monitored by thin layer chromatography. After complete disappearance of the starting ketone (28 hours), the reaction mixture was heated at 50°C for six hours. Attempts to separate the crude reaction mixture were unsuccessful by thin layer chromatography (hexaneszethyl acetate, 80:20). NMR analysis of the photoproducts showed a diastereomeric mixture of (endo and exo)-4-acetyl-7-ethyl-1l- "I? 11 206 oxabicyclo[6.3.0]undeca-1,3,5-triene and (endo and exo)-4-acetyl-7—ethyl-11- oxatricyclo[6.3.0.0.116]undeca-2,4-diene. The overall product ratio was 3 (7-endo)-Et- COT : 1.5 (7-endo)-Et-CH : 1 (7-exo)-Et-COT : 1 (7-exo)-Et-CH as determined by integration of their vinyl protons. 0 0 % Methanol 45% Ca 5 E1 50 C 0 10 L: 2 Endo and Exo endo-4-acetyl-7-ethyl-l1-oxabicyclo[6.3.0] undeca-1,3,5-triene lH NMR(300MHz;CDCl3) : 86.97(d, 127.75 Hz, 1H3), 6.29(d, 1212.1 Hz, 1H5), 5.64(dd, 1212.1 & 7.14 Hz, 1H6), 5.44(dd, 127.8 & 1.4 Hz, 1H2), 4.3-4.0(m, 2H10), 3.1(m, 1H3), 2.31(s, 3H), 0.9(t, 127.4 Hz, 3H) endo-4-acetyl-7-ethyl-1 1-oxatricyclo[6.3.0.0116]undeca-2,4-diene 1H NMR(300MHz;CDCl3) : 86.78(br d, 126.1 Hz, 1H5), 6.62(dd, 1210.1 & 1.5 Hz, 1H2), 5.72(dd, 1210.1 & 1.0 Hz, 1H3), 4.3-4.0(m, 2H10), 2.8(m, 1H6), 2.29(s, 3H), 0.9(t, 127.4 Hz, 3H) 207 exo-4-acetyl-7-ethyl- 1 1-oxabicyclo[6.3.0] undeca-1,3,5-triene 1H NMR(300MHz;CDCl3) : 57.03(dd. 126.15 81 1.4 Hz, 1H3), 6.31(d, 1:109 Hz, 1H5), 5.84(dd, 1:109 81 6.75 Hz, 1H6), 5.31(dd, 1:6.12 81 1.4 Hz, 1H2), 4.3-4.0(m, 2H10), 3.1(m, 1H3), 2.30(s, 3H),0.9(t,1=7.4 Hz, 3H) exo-4wacetyl-7-ethyl-1 l-oxatricyclo[6.3.0.01v6]undeca-2,4-diene 1H NMR(300MHz;CDCl3) : 86.67(td, 1:1.2 81 5.94 Hz, 1H5), 6.51(dd,1=10 81 1.5 Hz, 1H2), 5.680d,1:1.1 81 10 Hz, 1H3), 4.3-4.0(m, 2H10), 2.8(m, 1H6), 2.29(s, 3H), 0.90, 1:7.4 Hz, 3H). Photochemistry of 4T2N(F)-K A solution of 4—(3',4',4'-trifluoro-3'-buten-1‘-oxy)acetophenone (3 mg per 1 mL solvent) in CD30D was degassed with argon and irradiated through Pyrex. Reaction progress was monitored by time resolved 1H NMR. After 30 minutes of irradiation, much of the starting ketone disappeared and only a trace amount of photoproduct was observed. The photoproduct was determined to be 1-acetyl-4,4,5-trifluoro-8-oxatricyclo[7.2.0.0915] undeca-2,-10-diene based on its characteristic vinyl region in 1H NMR. t: trace amounts 208 IV . Photokinetic Data A. Photochemical Glassware The glassware used for quantum yield studies was class A volumetric except for the polyethylene syringes used to fill irradiation test tubes The glassware was cleaned in the following fashion: 1) rinsed with acetone, 2) boiled in a bath of distilled water/alconox at a boil for 24 hours, 3) rinsed five times with distilled water, 4) boiled in a bath of distilled water at a boil for 24 hours, 5) rinsed five times with distilled water, and finally 6) dried in an oven overnight at 180°C. The irradiation ampoules were made by streching 13x100mm Pyrex culture tubes just below the telfon label to an uniform length of 150m. It is essential that the tubes are uniform in both length and thickness so that an accurate measure of the quantum yield can be determined. B. Sample Preparation All weighings were done on a Mettler AE163 top loading digital analytical balance, which is accurate to within 0.00001 g. Equal volumes of sample (2.8mL) were placed via a Rainin Precision Microliter Pipette into each ampoule. C. Degassing Procedure The filled irradiation tubes were fitted onto a 12-port degassing cow with #00 one hole rubber stoppers. The samples were then frozen to liquid nitrogen temperature and evacuated with a diffusion pump for 15 minutes. The stopcocks were closed and the samples were allowed to warm to room temperature. This freeze-pump—thaw cycle was repeated four times. The samples were finally sealed in vacuo with an oxygen-natural gas torch. 209 D. Irradiation Chambers All samples for kinetic studies were irradiated in parallel with actinometer solutions in a merry-go-round apparatus having 7mm slits. A Hanovia 450W medium pressure mercury lamp cooled in a quartz immersion well was used as the light source. The whole apparatus was immersed inside a 10 gallon crock filled with distilled water. The 313 nm chamber used a lcm filter solution consisting of 0.002M K2Cr04 in 1% aqueous K2C03. A Coming C8-7-37 filter was used to isolate the 365 nm emission band. E.Calculation of Quantum Yields Quantum yields were measured utilizing the following equation, <1>=[Prod]/I where I is the intensity of light absorbed by the reactant and [P] is the concentration of the photoproduct measured by analytical techniques. Light intensity absorbed was determined by irradiating the reactant in parallel with either valerophenone(VP) or 2-methylvalerophenone(2-MeVP) actinometer which have well defined quantum yields. The quantum yields of Norish-type II cleavage ((1)11) for VP and 2-MeVP at 0.1M in benzene are 0.3389 and 0.01690 respectively. I 2 [AP] / 0.33 orI 2 [2-MeVP] / 0.16 The actinometers and photoproducts observed were analyzed using gas Chromatographs equipped with flame ionization detectors. Retention times of the observed photoproducts and the internal standards were compared with authentic samples of each. Response factors for the various photoproducts and their corresponding internal standards are listed below. 210 Gas Chromatograph Response Factors for Various Photoproducts Photo roduct / Internal standard Calc'd Ex' 1 -- m 142 1.08 _oo 1AP-2Me-4T2H-SIP-COT-t/n-heptyl benzoate lCN- 2T3H-CB/n-heptyl benzoate 1. 315 _____15_ 1EC-2T3H-CB/n- -hepty1 benzoate W- 0. 942 2T2H-LCB/n-1CN- pe-ntyl benzoate - 1AP-2F-4T2Me/n—heptyl benzoate 1 lAP-2Me-4T2Me-COT/n-heptyl benzoate I131.334 _ Rflproduct)exp 2 ([prod.]/[int.std.]) x (Areaim std/Areaprod) { # of carbons + 1/2 (# of C-0 bonds)} Std Rt(product)calcod = { # of carbons + 1/2 (# of C-0 bonds)}pmd The concentration of phot0products and the products resulting from the Type II cleavage of the actinometer were determined using the following equations: 21 1 [prod] 2 Rf(prod) x [int std.) x Area prod I Area int. std. [AP] 2 Rf(AP) x [int std.] x Area Ap/ Area int. std- where, [prod] and [AP] are the concentration of the photoproduct and acetophenone respectively, Rf is the instrument response factor( see above), [int std] is the concentration of the internal standard, and Area x is the integrated area for that particular compound. Computational Parameters Semi-empirical studies of the excited and ground state were canied to provide additional insight into the factors which control the regio- and stereoselectivity associated with ortho [2+2] photocycloaddition. General Procedures for Calculations: 0 The structure was constructed in the Editor Program in CAChe system 0 The structure was then minimized using molecular mechanics (MM2) ° MM2 Options 1. Cut-off distances for Van der Waals interactionS-- 9A 2. Optimization relaxation factors-- 1.00 3. Convergence-- 0.001kcals/mol 0 Finally, the MM2 output structure was further minimized using AM]91 3 To distinguish between a local minima and the global minima, the MOPAC92 output structure was altered by varying bond angles or distances and then resubmitted to MOPAC. If similar energies were obtained then it is assumed to be the global minima. Specific Procedure for Calculations: 9 Rotational Barriers in 2Me-4T2H-SI 212 5-Isopropyl-4-methoxy-2-methylacetophenone was used as the model compound to determine the energies of rotation around the methoxy bond. The compound was constructed and minimized as described above. The resulting compound was then submitted to MOPAC using the following parameters: 0 Calculation Type: Optimized Search 0 Search Type: Reaction Coordinate 0 Multiplicity : Triplet using UHF - Parameters: AMl 0 Key Words: noanci 0 Optimized Geometries for 1CN-2T2H-COT, 1CN-2T3H-COT, 1AP-4T2H- COT*, and lCN-4T2H-COT“ These compounds were constructed and minimized as described above and then submitted to MOPAC using the following parameters: 0 Calculation Type: Optimized Geometry ' Multiplicity: Singlet and Excited Singlet* - Parameters: AMI 0 Key Words: NONE Electronic charge distributions calculated for 1AP-4T2H-COT and 1CN-4T2H-COT were obtained from the MOPAC output file, which can be opened in Microsoft Word. APPENDIX 3! H78 Figure 2: Crystal Structure of 1CN-4T3H-CB93 213 214 Crystal Data For 1CN-4T3H-CB Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions (1110) Crystal System # of Reflections Used for Unit Cell Det. Omega Scan Peak Width at Half-height Lattice Parameters Space Group 2 value Dcalc I3000 11(M0K01) C12H130N 187.24 colorless, plate 0.04 x 0.20 x 0.28 monoclinic 5 (20.1-21.0°) 0.34 a : 6.442A b 2 10.653A c : 14.974}. [3 2 95.18° v : 1023713 P21/c 4 1.215 g/cm3 400 0.72 cm'1 215 Table 11: Bond Distances for 1CN-4T3H-CB atom atom . distance 01 1 C2 , 1.50 01 010 1 1.59 01 i 012 - ‘ 1.54 01 . 013 l 1.46 02 03 1.31 02 ‘ H2 0.95 03 ‘ C4 ‘ 1.50 03 } H3 ‘ 0.95 04 ; 05 1.50 C4 ‘ H4A ' 0.95 C4 5 H4B ‘ 0.95 05 j 06 1 1.53 05 l 010 ‘ 1.52 06 1 H6A ‘ 0.95 06 H6B . 0.95 07 . 08 * 1.52 07 H7A 7 0.95 C7 ' H7B ‘ 0.95 08 .' 09 1.438 C8 . H8A 0.95 08 1 H8B ; 0.95 09 . 010 ‘ 1.415 010 l 011 l 1.51 011 - 012 * 1.30 C11 ‘ H11 0.95 012 H12 , 0.95 013 1 N14 ' 1.14 216 Table 12: Bond Angles for 1CN-4T3H-CB atom atom atom ang“ 02 01 010 113.9 02 01 012 . 111.8 02 01 013 ~ 111.7 010 01 012 § 82.7 010 01 013 115.2 012 01 013 ' 118.8 01 02 03 123.1 01 02 H2 . 118.46 03 02 H2 118.46 02 03 04 123.5 02 03 H3 118.26 04 03 H3 118.26 03 04 05 110.4 03 04 H4A 109.25 03 04 H4B 109.25 05 04 H4A 109.25 05 04 H4B 109.25 H43 04 H4B 109.46 04 05 06 , 115.5 04 05 010 112.3 04 05 H5 106.36 06 05 010 109.4 06 05 H5 , 106.36 05 06 H6A 109.39 Table 12 (cont'd): Bond Angles for 1CN-4T3H-CB atom atom atom angle(°) C5 C6 H6B 109.39 C7 C6 H6A 109.39 C7 C6 H6B 109.39 H6A C6 H6B 109.46 C6 C7 C8 111.2 C6 C7 H7A 109.04 C6 C7 H7B 109.04 C8 C7 H7A 109.05 C8 C7 H7B 109.05 H7A C7 H7B 109.46 C7 C8 09 111.1 C7 C8 H8A 109.07 C7 C8 H8B 109.07 09 C8 H8A 109.07 09 C8 H8B 109.07 H8A C8 H8B 109.46 C8 09 C10 111.2 01 010 05 114.5 C1 C10 09 110.9 C1 C10 C11 86.4 C5 C10 09 110.2 C5 C10 C11 117.9 09 C10 C11 114.9 C10 C11 C12 94.4 C10 C11 H11 132.8 C12 C11 H11 132.8 C 1 C12 C11 96.3 C1 C12 H12 131.87 C11 C12 H12 131.86 C1 C13 N14 177 l _.._.1 h...._ *‘_J 218 Table 13: Quantum Yield Determination of 1CN-4T3H-CB at 313 nm in acetone GC Conditions for 1CN-4T3H-CB GC Conditions for Valerophenone Act. Before Irradiation After Irradiation Quantum Yield 1CN-4T3H-CB 1400 Varian GC, He = 25 mUmin DB-1+ Megabore Column (15 meters) Column=135°C, Injector=230°C, Detector=230°C. 3400 Varian GC, He = 25 mL/min DB-210 Megabore Column (15 meters) Column=100°C, Injector=200°C, Detector=220°C. [1CN-4T3H]=0.0102M in acetone [n-pentyl benzoate]=0.0008958M in acetone [Valerophenone]=0.09909M in benzene [Ethyl phenylacetate]=0.01044M in benzene [1CN-4T3H-CB]=0.000652M [Acetophenone]=0.01145M; 1:0.0347 0.019 219 Table 14: Quantum Yield Determination of 2,5Me-4T2H-CB at 313 nm in methanol GC Conditions for Valerophenone Act. Before Irradiation After Irradiation Quantum Yield *** 3400 Varian GC, He = 25 mL/min DB—210 Megabore Column (15 meters) Column=95°C, Injector=200°C, Detect012220°C. [2,5Me-4T2H-COT]=O.000312M [Valerophenone]=0.1021M in benzene [Ethyl phenylacetate]=0.00993M in benzene [2,5Me-4T2H-CB]=0.0000927M u... [Acetophenone]=0.0008053M; 1:0,00244 0.038 Determined by UV Spectroscopy by AOD 220 Table 15: Quantum Yield Determination of 2,5Me-4T2H-COT at 313 nm in methanol GC Conditions for Cyclooctatriene GC Conditions for Valerophenone Act. Before Irradiation After Irradiation Quantum Yield 0 CH3 2,5Me-4Tm-COT 3400 Varian GC, He = 25 mL/min DB-210 Megabore Column (15 meters) Column=145°C, Injector=200°C, Detector=220°C. 3400 Varian GC, He = 25 mIJmin DB-210 Megabore Column (15 meters) Column=100°C, Injector=200°C, Detector=220°C. [2,5Me-4T2H-K]=0.0103M in methanol [n-heptyl benzoate]=0.00102M in methanol [Valerophenone]=0.0996M in benzene [Ethyl phenylacetate]=0.0108M in benzene [2,5Me-4T2H-COT]=0.000708M [Acetophenone]=0.00593M; I=0.01796 0.039 221 Table 16: Quantum Yield Determination of 2Me-4T2H-SI-CB-t at 313 nm in methanol GC Conditions for Valerophenone Act. Before Irradiation After Irradiation Quantum Yield *** _r . 2Me-4Tm-51-03-t 3400 Varian GC, He = 25 mL/min DB-210 Megabore Column (15 meters) Column=95°C, Injector=200°C, Detector=220°C. [2Me-4T2H-SI-COT-t]=0.00039M [Valerophenone]=0. 1019M in benzene [Ethyl phenylacetate]=0.01105M in benzene [2Me-4T2H-SI-CB-t ]=0.0000718M Ma: [Acetophenone]=0.0015934M; I=0.00483 0.015 Determined by UV Speetroscopy by AOD 222 Table 17 : Quantum Yield Determination of 2Me-4T2H-51-CB-a at 313 nm in methanol 2Me-4Tm-51-03-a GC Conditions for 3400 Varian GC, He 2 25 mUmin Valerophenone Act. DB-210 Megabore Column (15 meters) Column=95°C, Injector=200°C, Detector=220°C. Before Irradiation [2Me-4T2H-SI-COT-a]=0.000393M [Valerophenone]=0.0997M in benzene [Ethyl phenylacetate]=0.0095M in benzene After Irradiation [2Me-4T2H-SI-CB-a]=0.000289M *** [Acetophenone]=0.000986M; I=0.00299 Quantum Yield 0.0967 *** Determined by UV Spectroscopy by AOD 223 Table 18: Quantum Yield Determination of 2Me-4T2H-SI-COT-t at 313 nm in methanol GC Conditions for Cyclooctatriene GC Conditions for Valerophenone Act. Before Irradiation After Irradiation Quantum Yield 0 CH3 2Me-4Tm-51-COT-t 3400 Varian GC, He = 25 mL/min DB-210 Megabore Column (15 meters) Column=l35°C, Injector=200°C, Detector=220°C. 3400 Varian GC, He = 25 mL/min DB—210 Megabore Column (15 meters) Column=95°C, Injector=200°C, Detector=220°C. [2Me-4T2H-SI-K]=0.00993M in methanol [n-heptyl benzoate]=0.00104M in methanol [Valerophenone]=0.0991M in benzene [Ethyl phenylacetate]=0.00915M in benzene [2Me-4T2H-SI-COT-t]=0.0002 1 8M [Acetophenone]=0.00168M; I=0.00509 0.0428 224 Table 19: Quantum Yield Determination of 1CN-2T3H-CB at 313 nm in acetone 1CN-2T3H-CB GC Conditions for 3400 Varian GC, He = 25 mIJmin 1CN-2T3H-CB DB-210 Megabore Column (15 meters) Column=140°C, Injector=200°C, Detector=220°C. GC Conditions for 3400 Varian GC, He = 25 mL/min Valerophenone Act. DB-210 Megabore Column (15 meters) Column=100°C, Injector=200°C, Detector=220°C. Before Irradiation [1CN-2T3H]=0.01007M in acetone [n—heptyl benzoate]=0.001309M in acetone [Valerophenone]=0.1013M in benzene [Ethyl phenylacetate]=0.0108M in benzene After Irradiation [1CN-2T3H-CB] =0.000528M [Acetophenone]=0.0204M; I=0.061 8 Quantum Yield 0.00854 225 Table 20: Quantum Yield Determination of 1EC-2T3H-CB at 313 nm in acetone GC Conditions for 1EC-2T3H-CB GC Conditions for Valerophenone Act. Before Irradiation After Irradiation Quantum Yield 1EC-2T3H-CB 3400 Varian GC, He = 25 mL/min DB-210 Megabore Column (15 meters) Column=140°C, Injector=200°C, Detector=220°C. 3400 Varian GC, He = 25 mUmin DB-210 Megabore Column (15 meters) Column=100°C, Injector=200°C, Detector=220°C. [1EC-2T3H]=0.0082M in acetone [n—heptyl benzoate]=0.00104M in acetone [Valerophenone]=0. 1013M in benzene [Ethyl phenylacetate]=0.0108M in benzene [1EC-2T3H-CB]=0.000696M [Acetophenone]=0.0204M; I=0.0618 0.0113 226 Table 21: Quantum Yield Determination of 2F-4T2Me-COT at 313 nm in methanol GC Conditions for Cyclooctatriene GC Conditions for Valerophenone Act. Before Irradiation After Irradiation Quanmm Yield 0 F 2F-4T2Me-COT 3400 Varian GC, He 2 25 mUmin DB-210 Megabore Column (15 meters) Column=140°C, Injector=200°C, Detector=220°C. 3400 Varian GC, He = 25 mL/min DB-210 Megabore Column (15 meters) Injector=200°C, Detector=220°C,Column=ramped {70°C(9min)— l40°C(10°C/min)-185°C} [2F-4T2Me-K]=0.0104M in methanol [n-heptyl benzoate]=0.001127M in methanol [Valerophenone]=0. 10M in benzene [Dodecane]=0.0096M in benzene [2F-4T2Me-COT ]=0.0008372M [Acetophenone]=0.0109M; I=0.033 0.0025 227 Table 22: Quantum Yield Determination of lCN-2T2H-LCB at 313 nm in acetone GC Conditions for 1CN-2T2H-LCB GC Conditions for Valerophenone Act. Before Irradiation After Irradiation Quantum Yield 0“ > z E..“O O 1CN-2TZH-LCB 3400 Varian GC, He = 25 mL/min DB-210 Megabore Column (15 meters) Column=135°C, Injector=200°C, Detector=220°C. 3400 Varian GC, He = 25 mL/min DB-210 Megabore Column (15 meters) Injector=200°C, Detector=220°C,Column=ramped {70°C(5min)—100°C(10°C/min)-185°C} [1CN-2T2H]=0.01064M in acetone ' [n-pentyl benzoate]=0.001146M in acetone [Valerophenone]=0.09988M in benzene [Dodecane]=0.009624M in benzene [1CN-2T2H-LCB]=0.0007934M [Acetophenone]=0.01644M; I=0.0498 0.0159 228 Table 23: Quantum Yield Determination of 1CN-4T2H-LCB at 313 nm in methanol GC Conditions for Valerophenone Act. Before Irradiation After Irradiation Quantum Yield lCN-4Tm-LCB 3400 Varian GC, He = 25 mUmin DB-210 Megabore Column (15 meters) Injector=200°C, Detector=220°C,Column=ramped {70°C(5min)— 100°C(10°C/min)-185°C} [lCN-4T2H-COT]=0.000267M [Valerophenone]=0. 1008M in benzene [Dodecane]=0.00285M in benzene [1CN-4T2H-LCB]=0.0000957M *** [Acetophenone]=0.000579M; I=0.001755 0.0545 *** Determined by UV Spectroscopy by AOD 229 Table 24: Quantum Yield Determination of 2Me-4T2Me-CB at 313 nm in methanol GC Conditions for Valerophenone Act. Before Irradiation After Irradiation Quantum Yield *** 3400 Varian GC, He = 25 mL/min DB-210 Megabore Column (15 meters) Injectom200°C, Detector=220°C,Column=ramped {70°C(5min)-100°C(10°C/min)-185°C} [2Me-4T2Me-COT]=0.000336M [Valerophenone]=0.0994M in benzene [Dodecane]=0.00939M in benzene [2Me-4T2Me-CB]=0.0001044M *** [Acetophenone]=0.00124M; I=0.00377 0.0277 Determined by UV Spectroscopy by AOD 230 AM] Calculation of the Rotational Barrier in 5-isopropyl-2-methyl-4-methoxyacetophenone calc_energy 414.15 to -27.39 kcol/ mole dihedralO 0.00 to 360.00 degree -34.15 Kcals/mo] '27'4 KcaIs’mol 231 3. 333 . 3 \L \» 333.333 ‘14-‘1‘4‘1‘11‘1C‘11—1“4d1d‘1.1“4“1‘11111fidIIddq4dddd141-‘1q‘iq4‘4‘d u u N .3... o ans: 9 3m 225 a whatfiumhu; 33. moms 2 3 2 S N O ? 4“dfldd‘qJ‘i-‘ddd-d‘1‘qddfl11midddd1d‘d4 a m 39:... 9 3: 225 a Nzahawmhoa 5 805 11 1 p31 -dddiqd44