SOME REACTIONS OF ACETYLENIC ALCOHOLS A ·thesis presented for the degree of Doctor of Philosophy in Chemistry in the University of Canterbury by R. W. Vannoort Christchurch, New Zealand 1983 TABLE OF CONTENTS CHAPTER PAGE ABSTRACT . • • . • • . . . • • • • • . • . . 1 . . . . . . . . 1 GENERAL INTRODUCTION 2 . . . . . . . . . . . 1.1 Background 2 1.2 Allenic Compounds from Propargyl . . . . . . . . . . . . . . . . Alcohols 2 1.3 Allylic Alcohols from Propargyl . . . . . . . . . . . . . . Alcohols 11 1.4 Reduction of Propargyl Alcohols to give both Allenes and Alkenols 19 -Solvent Effects • • 2 LITHIUM ALUMINIUM HYDRIDE REDUCTION OF 2,2-DI-(METHOXYMETHYL)-3-PHENYLHEX-4-YN- 3-0L (98) AND 1-METHOXY-2,2-DIMETHYL-3- . . . . . . . . . . . PHENYLHEX-4-YN-3-0L (90b). 35 . . . . . . . . . . . . 2.1 Introduction 35 . . . . . . . 2.2 Synthesis of Alkynol ( 98) . 36 . . . . . 2.3 Reactions of Alkynol ( 9 8) . 38 2.4 Discussion of Alkynol (98) Reactions 45 . . . . . . . 2.5 Synthesis of Alkynol (90b) 49 . . . . . . . 2.6 Reactions of Alkynol ( 90b) 49 . 2.7 Discussion of Alkynol ( 90b) Reactions. 53 CHAPTER PAGE 3 LITHIUM ALUMINIUM HYDRIDE REDUCTIONS OF 1-METHOXY-2-PHENYLPENT-3-YN-2-0L (136), 1-METHOXY-3-PHENYLHEX-4-YN-3-0L (137), . . . AND 7-METHOXY-4-PHENYLHEPT-2-YN-4-0L ( 138) 57 . . . . . . . . 3.1 Introduction 57 . . . 3.2 Synthesis of Alkynol (136) 58 . . . . . 3.3 Reactions of Alkyno1 ( 136) 58 . 3.4 Discussion of Alkynol ( 13~) Reactions. 62 . . . 3.5 Purification of Alkynol (137). 64 . . . . . 3.6 Reactions of Alkynol ( 137) 64 . 3.7 Discussion of Alkynol (137) Reactions. 69 . . . 3.8 Synthesis of Alkynol ( 13 8) 71 . . . 3.9 Reactions of Alkyno1 ( 138) 72 . 3.10 Discussion of Alkynol ( 138) Reactions. 75 4 LITHIUM. ALUMINIUM HYDRIDE REDUCTION OF . . . PROPARGYL ALCOHOLS IN BENZENE SOLVENT. 76 . . . . . . . . . . . . 4.1 Introduction 76 . . . . . . . 4.2 Synthesis of Alkynol (90a) 77 4.3 Reactions of Alkynols ( 9 Oa) , (90b) . . . . . . . . . . . . . . . . and (98) 77 4.4 Discussion of Alkynol ( 9 Oa) , ( 90b) . . . . . . . . . . . and (98) Reactions 78 4.5 Reactions of Alkynols ( 18) , (136)' . . . . . . . . . . . . (137) and (138). 79 4.6 Discussion of Alkynol ( 18) , (136), . . . . . . . (137) and ( 138) Reactions. 82 CHAPTER .PAGE 5 EXPERIMENTAL . 5.1 Apparatus, Materials and Instrumentation 83 . . . . 5.2 Experimental Relating to Chapter 2 85 5.3 Experimental Relating to Chapter 3 110 . . . . 5.4 Experimental Relating to Chapter 4 140 APPENDIX 149 REFERENCES 152 ACKNOWLEDGEMENTS 177 TABLE OF ILLUSTRATIONS Page Page Scheme 1,3 24 Table 1 168 Scheme 2 25 Table 2 169 Scheme 4,5 26 Table 3 170 Scheme 6,7 27 Table 4 171 Scheme 8 28 Table 5 172 Scheme 9 29 Table 6 173 Scheme 10 30 Table 7 174 Scheme 11,14 31 Scheme 12 32 Scheme 13 33 Table A 34 Scheme 15,16 159 Block A 175 Scheme 17,18 160 Block B 176 Scheme 19,20 161 Scheme 21,22 162 Scheme 23,24,25 163 Scheme 26 164 Scheme 27,28,29 165 Scheme 30 166 Scheme 31,32,33 167 1 ABSTRACT The lithium aluminium hydride (deuteride) reduction of 2,2-di-(methoxymethyl)-3-phenylhex-4-yn-3-ol (98), in a range of ether solvents has been examined. Intramolecular solvation of the aluminium atom during the reduction process has been identified and the mode of formation of the reaction products discussed. Isolation and identification of the unexpected cyclopropane derivatives (115) and (116) resulted in extending studies to encompass the reaction of 1-methoxy- 2,2-dimethyl-3-phenylhex-4-yn-3-ol (90b) with lithium aluminium hydride (deuteride). Cyclopropane derivatives were also isolated and the mode of formation of propenyl-cyclopropane (125) established. In an attempt to determine the effect of ring size in intramolecular solvation, 1-methoxy-2-phenylpent-3-yn-2-ol (136), 1-methoxy-3-phenylhex-4-yn-3-ol (137) and 7-methoxy-4-phenylhept- 2-yn-4-ol (138), were synthesized and their reactions with lithium aluminium hydride (deuteride) in diethyl ether, tetra hydrofuran or 2,5-dimethyltetrahydrofuran were studied. It was observed that intramolecular solvation occurs for methoxy compounds (136) and (137) but not for (138); these results are discussed. A semi-quantita·tive rate comparison was made for the reactions of 2,2-dimethyl-3-phenylhex-4-yn-3-ol (90a), its 1-methoxy-(90b) and 1,1-dimethoxy-(98) derivatives, when reduced by lithium aluminium hydride (deuteride) in benzene solvent. Similar work was undertaken on 2-phenylpent-3-yn-2-ol (18), its 1-methoxy derivative (136), and methoxy alkynols (137) and (138). Rate enhancement was only observed when the alkynols contained an internal ether moiety. 2 CHAPTER 1 GENERAL INTRODUCTION 1.1 BACKGROUND The field of complex metal hydride reductions has grown at a phenomenal rate since the appearance in 1947 of the first papers concerning the preparation and properties 1 of lithium aluminium hydride and its ability to reduce a 2 range of organic functional groups. Although other complex metal hydrides have since been reported, by far the greater number of applications in organic synthesis utilize lithium aluminium hydride, LiAlH . Its frequent use is undoubtedly 4 related to its relative stability, ease of handling and availability. The basis of this Ph.D. research is one such current area of interest and involves the study of propargyl alcohol reductions with lithium aluminium hydride in a variety of ether solvents. Two reaction paths may be followed in reactions of this type. The first, infrequently observed, type of reaction yields an allenic compound, while the second, more frequently observed reaction path, leads to the formation of allylic alcohols, in which the double bond may have the cis or trans stereochemistry. 1.2 ALLENIC COMPOUNDS FROM PROPARGYL ALCOHOLS Allenes are compounds which contain the'C=C=C/grouping. ' / The earliest authentic synthesis of an allenic compound 3 was reported in 1888 and involved debromination of 2,3- dibromopropene with zinc, essentially the same technique as 3 4 is used today to create the pare~t, "allene" The fact that early allenic preparations involved numerous and often tedious experimental procedures, together with the mistaken belief that the cumulated double-bond system would prove to be relatively unstable, meant that interest in allenic syntheses diminished dramatically. Allenes came to be regarded as chemical curiosities mainly of interest for the chirality which van't Hoff had successfully predicted 5 as long ago as 1875 . The presence of an optically active allene in nature 6 was first shown in 1952, when Celmer and Solomons characterized the fungal metabolite myomycin (1). It was c t HC=cc::CCH~C=CCH=CHCH=CHCH2co2H ( 1) later recognised that many other optically active allenes occur in natural products, including other fungal Rc:::cc::ccH=C=CR' (la) metabolites (all of which contain the characteristic diyne-allene grouping ( la)); the carotenoid pigments ~I HO (2) (a) R=Ac (b) R=H OR 7 8 of brown algae (fucoxanthin (2a) , neoxanthin (2b) ); 4 ( 3) 9 labellenic acid (3) from the seed oil of Leonotis nepetaefolia , and an a11enic sesquiterpenoid (4) from the grasshopper H CH3 CH3 J '.}.::: ~C-c- CH ~c~ II 3 a/ 0 ,- •uOH HO CH 3 ( 4 ) R oma1v ea M. t· era 10 . The search for new allenic syntheses ~crop was thus rekindled. One such technique developed, involved the reduction of propargyl alcohols of type (5) with lithium aluminium hydride. Common structural features are summarised in Scheme 1.* In the reduction process, the initial hydride attack on the hydroxyl group of alkynol (5) results in the formation of an oxygen-aluminium bond with the concommittant evolution of hydrogen. The alkynyloxyaluminium hydride group (6) then functions as a hydride donor, donating a hydride ion intramolecularly to the near carbon of the acetylenic triple bond, coupled with a concerted shift of an electron pair and the departure of the group X. The group X may be a 11 12 chlorine group (leaving as Cl- • ), a hydroxyl group 13 14 (leaving as -OA1H • ), a tetrahydropyranyloxy group 2 15 16 17 (leaving as (9) • • ), a tertiary alkyiammonium group 18 19 (leaving as Me N or PhCH(CH )NMe ) , an alkoxy group 3 3 2 (leaving as OR, R=n-C3H7, t-C4H9 , c~2CH=CH2 , or 20 . (C H )N(CH ) ) or an oxiran oxygen atom which leaves as 2 5 2 2 21 an alkoxide . The stereochemistry of the reaction allows * Schemes 1-14 as foldouts at end of General Introduction. 5 the approaching hydride ion to attack either syn or anti to the displaced group X, resulting in the diastereomeric allenes (7) and (8) respectively. It continues to be a matter of debate whether the allene-forming reaction .is synchronous SNi' as implied in Scheme 1, or whether the alternative SN2' mechanism involving an addition-elimination process is in fact occurring. The SN2' mechanism, analogous to the SN2' reaction in allylic systems, is given in Scheme 2. The first step of the reduction involves the formation of the oxygen-aluminium bond with the resultant hydrogen evolution, and is identical with the first step of Scheme 1. The aluminium bound to the oxygen then serves to donate a hydride ion intramolecularly to the near carbon of the acetylenic function resulting in the formation of two carbanions (a) and (b) which are stabilized by the counterions in the reaction medium. Subsequent attack by the electron pair on C4 followed by the elimination of the group X yields the diastereomeric allenes (7) and (8). It is also possible for carbanion (a) to gain extra stabilization by the formation of the five-membered cyclic organoaluminium species (10) and (11); geometric constraints (trans double bond in five-membered ring) do not permit this stabilization to occur for carbanion (b). Anti elimination of (10) then results in the formation of allene (7) (overall syn displacement),while syn elimination of (11) gives allene (8) (overall anti displacement). Evidence for the existence of the alanate intermediates (10) 22 23 24 and (11) has only recently been reported • r r In an analogous manner to the aforementioned a-allenic alcohol production (Scheme 1) , the reaction of propargyl