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Studies related to the insect control potential of thujone derivatives Balsevich, J. 1975

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STUDIES RELATED TO THE INSECT CONTROL POTENTIAL OF THUJONE DERIVATIVES by J . BALSEVICH B . S c , Univers i ty of B r i t i s h Columbia, 1972 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF T(HE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in the Department of Chemistry We accept th is thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA A p r i l , 1975 In presenting t h i s t h e s i s in p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I f u r t h e r agree that permission for extensive copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s r e p r e s e n t a t i v e s . It i s understood that copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gain s h a l l not be allowed without my w r i t t e n permission. The U n i v e r s i t y of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date 3 ! A t t < ? /o J47i Depa rtment i i ABSTRACT Treatment of cedar leaf oil with aqueous potassium permanganate resulted in the oxidative ring opening of thujone (VI), the major component of the leaf oil, to yield the crystalline a-thujaketonic acid (VII). This material because of its availability and interesting structure represented an attractive starting material for the synthesis of some novel analogs of possible insect controlling agents. Therefore, to achieve this goal the functionalization of the ketonic carbonyl of a-thujaketonic acid was studied. Treatment of the sodium salt of a-thujaketonic acid in dimethyl sulfoxide with the phosphorane produced from either methyltriphenylphosphoniurn bromide or isopropyl-triphenylphosphoniurn iodide yielded the methylene and isopropylidene derivatives of a-thujaketonic acid (XIII, XIV). These two compounds represented two novel analogs of chrysanthemic acid, a naturally occurring material of which numerous derivatives are known which possess insecticidal activity. With the establishment of the conditions for the Wittig reaction of a-thujaketonic acid with a phosphonium salt, two routes for the synthesis of phosphonium salts which when coupled to a - or 3-thujaketonic acid (XI, XII) would lead to insect hormone analogs, were studied. Thus, Horner reaction of 2-butanone with trimethylphos-- i i i -phonoacetate resulted in the preparation of cis and trans methyl 3-methyl-2-pentenoates (XX, XXI), which were separated by means of spinning band distillation. In the first sequence studied the separate isomers were elaborated via standard means to yield the cis and trans 7-methyl-6-nonene-3-ols (XXVI and XXXII) which possessed the desired carbon skeleton. However, upon conversion of the trans secondary alcohol (XXXII) to the iodide (XXXIII), and treatment of this iodide with triphenylphosphine, none of the desired trans 7-methyl-6-nonene-3-triphenyl-phosphonium iodide (XIX) was isolated. Therefore, the study of an alternate route for the synthesis of the desired cis and trans 7-methyl-6-nonene-3-triphen.y1phosphonium iodides (XVIII and XIX) was undertaken. Elaboration of cis methyl 3-methyl-2-pentenoate to cis 5-methyl-4-heptenetriphen,ylphosphonium iodide (XLVI) was achieved by standard means. Treatment of this phosphonium salt with n-butyllithium and ethyl iodide then yielded the desired cis 7-methyl-6-nonene-3-triphenylphosphonium iodide (XVIII). - iv -TABLE OF CONTENTS Page ABSTRACT i i LIST OF ILLUSTRATIONS v i i LIST OF TABLES i x 1. INTRODUCTION 1 1.1 General Background 1 1.2 Hormonal Control of Insect Metamorphosis 2 1.3 Insect Control Potent ia l 4 1.4 Spec i f i c Juvenile Hormone Analogs 11 1.5 Pheremones 12 1.6 Pyrethroids 19 2. SCOPE OF PRESENT-WORK 25 3. DISCUSSION 27 3.1 a-Thujaketonic Acid 27 3.2 Synthetic Objectives 29 3.3 The Witt ig Reaction 30 3.4 Attempted Preparation of Appropriate Phosphonium 41 Intermediates XVIII and XIX 3.5 Alternate Routes for the Synthesis of the Desired 53 Phosphonium Salts XVIII and XIX 3.6 Prel iminary Investigation of an Alternate Route for 56 the Synthesis of the Desired Phosphonium Salts XVIII and XIX 3.7 Overall Results 59 - v -Page 4. EXPERIMENTAL Ci_s and Trans Methyl 3-Methyl-2-Pentenoates (XX and XXI) 61 Trans 3-Methyl-2-Pentene-l-ol (XXVIII) 63 Cis 3-Methyl-2-Pentene-l-ol (XXII) 64 Trans 3-0xo-4-Carboethoxy-7-Methyl-6-Nonene (XXX) 64 Cis 3-0xo-4-Carboethoxy-7-Methyl-6-Nonene (XXIV) 65 Trans 3-0xo-7-Meth,y1-6-Nonene (XXXI) 66 Cis_ 3-0xo-7-Methyl-6-Nonene (XXV) 67 Trans 7-Methyl-6-Nonene-3-o1 (XXXII) 67 Cis 7-Methyl-6-Nonene-3-ol (XXVI) 68 Trans 3-1 odo-7-Meth,yl-6-Nonene (XXXIII) 68 7-Methyl-3-Nonanol (XXXV) 69 3-lodo-7-Methyl-Nonane (XXVI) 70 Methylene Derivative of a-Thujaketonic Acid (XIII) 70 Isopropylidene Derivative of a-Thujaketonic Acid (XIV) 71 Methyl Ester of the Methylene Derivative of a-Thujaketonic 71 acid (XVII) n-Butyl Ester of the Methylene Derivative of a-Thujaketonic 72 acid (X) (R = n-butyl, R'=R"=H) 1-Pentenyl Ester of the Methylene Derivative of 73 a-Thujaketonic acid (X) (R = CH2CH2CH2CH=CH2, R'=R"=H) Methyl Ester of the Isopropylidene Derivative of 73 a-Thujaketonic Acid (X, R'=R"=R=CH3) n-Butyl Ester of the Isopropylidene Derivative of 74 a-Thujaketonic Acid (X, R = n-butyl, R'=R"=CH3) Cis 5-Methyl-4-Heptene-l,3-Dioicacid (XLIIIa) 74 - v i -Page Cis 5-Methyl-4-Heptenoic Acid (XLIV) 76 Cis_ 5-Methyl-4-Heptene-1-o1 (XLV) 76 Cis_ 1-lodo-5-Methyl-4-Heptene (XXXVIII) (X = I) 77 Cis 5-Methyl-4-Heptenetriphenylphosphoniurn Iodide (XLVI) 77 Cis 7-Methyl-6-Nonene-3-Tripheny1phosphonium Iodide (XVIII) 78 REFERENCES 79 - v i i -L i s t of I l l u s t r a t i on s F ig. Page 1 Endocrine Regulation of L i f e Cycle of Yellow 3 Mealworm 2 Comparison of Electronegative Centers of Juveni le 9 Hormone (I) with Ecdysone (I I) 3 P.M.R. Spectrum of a-Thujaketonic Acid 28 4 Scheme for Elaboration of a-Thujaketonic Acid to 31 Derivatives of g-Thujaketonic Acid 5 Proposed Mechanism for Ring Opening of a-Thujaketonic 34 Acid Under Basic Conditions 6 Proposed Mechanism for Ring Opening of a-Thujaketonic 34 Acid Under Ac id ic Conditions 7a P.M.R. Spectrum of Methyl Ester of Ring Opened 36 Material Obtained from Sodium Methoxide Reaction (z-g-Thujaketonic Acid) 7b P.M.R. Spectrum of Methyl Ester of Ring Opened 37 Material Obtained from Aqueous Acid Treatment of a-Thujaketonic Acid (E-3-Thujaketonic Acid) 8 Scheme for the Synthesis of the Desired Phosphonium 45 Salts XVIII and XIX 9 Gas Chromatographic Traces of Cis and Trans Methyl 47 3-Methyl-2-Pentenoates 10a P.M.R. Spectrum of Cis Methyl 3-Methyl-2-Pentenoate 48 (XX) I Ob P.M.R. Spectrum of Trans Methyl 3-Methyl-2-Pentenoate 49 (XXI) II Possible Side Reactions Competing with Phosphonium 52 Sa l t Formation 12 Scheme for the Preparation of Phosphonium Salt 53 XXXVII - v i i i -Fig. Page 13 Alternate Routes for Synthesis of the Desired 54 Phosphonium Salts XVIII and XIX 14 Proposed Scheme for Synthesis of O l e f i n i c Halide 54 XXXVIII 15 Outline of Corey's Synthesis of 1-Bromo-4-Methyl- 55 3-Hexane (XXXIX) 16 Products Obtained From the Lithium Aluminum Hydride 58 Reduction of the Decarboxylation Reaction Mixture Obtained from the Cis Diacid XLIIIa - ix -L i s t of Tables Table Page 1 JH A c t i v i t y of Various Compounds with Terpenoid 6 Backbones on T. Mol i tor 2 Ef fect of Modifying Methyl Juvenate Unsaturation 7 on JH A c t i v i t y in T. Mol i tor 3 Ef fect on JH A c t i v i t y in T. Mol i tor of Modif icat ion 8 of the Epoxide End of Methyl Juvenate 4 Juveni le Hormone A c t i v i t y on Rhodnium prol ixus 10 5 Ef fects of Chrysanthemic Acid Esters and Standard 13 Compounds on D. fasc iatus 6 Effects of Structural Modif icat ion on At t rac t ion of 15 the Male Red-Banded Leaf Ro l le r (Argyrotaenia velutinona) 7 Structures of Some Insect Pheremones 16 8 Attractants Found by Volume Screening of Chemicals 18 9 Structures of the Natural ly Occurring Pyrethroids 20 10 Tox i c i t y of Natural Pyrethronyl Esters to the 22 German Cockroach ( B l a t t e l l a germanica L.) 11 Insect ic ida l A c t i v i t i e s of (±)-Allethronyl Esters 23 12 In sect ic ida l A c t i v i t y of Imidomethyl Chrysanthemates 24 13 Structural Comparison of Methylene and Isopropylidene 32 Derivatives of a-Thujaketonic Acid to Chrysanthemic Acid 14 Chemical Sh i f t s for Compounds of the Type 38 kVcH-C(H):CH-C0 2Et (XV and XVI) 15 Overall Results for the Conversion of a-Thujaketonic 42 Acid to Some Simple O l e f i n i c Ester Derivatives - X -Table Page 16 Structural Comparison of Juveni le Hormone with 43 Possible Analogs Avai lab le from Thujaketonic Acid 17 Comparison of Some P.M.R. Data for Compounds of the 51 Type XL and XLI - xi -ACKNOWLEDGEMENTS I wish to express my appreciat ion to Dr. James P. Kutney for his help and encouragement throughout t h i s work. A l s o , I am grateful to Dr. A. Markus for his help in the experimental aspects, s p e c i f i c a l l y with the work done i n studying the react ion condit ions for the W i t t i g reac t ion . - 1 -1. INTRODUCTION 1.1 GENERAL BACKGROUND j Insectic ides have long been in use and have been invaluable in suppressing damage to ag r i cu l tu ra l products and to the health of man and animals. Concern over environmental aspects, and the a b i l i t y of many insects to become immune to the various insect ic ides has created a general in teres t in developing a l te rnat i ve methods to ex i s t ing chemical control agents. I t was in the mid-1930's that S i r Vincent Wigglesworth^ showed that the molting and metamorphosis of Rhodnius prol ixus nymphs were regulated by hormones. Since that time great s t r ides have been made in deducing the hormonal aspects of a n i n sec t ' s l i f e cyc le. In 1956, Professor Carro l l Williams at Harvard discovered that the abdomen of the adult male of Hyalophora cecropia was a r i ch source of juven i le hormone. With th i s discovery also came the r ea l i z a t i on that u t i l i z a t i o n of hormonal agents might be an e f fec t i ve way for con t ro l l i ng insect populations. In 1967, a 3 major breakthrough occurred when Professor H. Rol ler and co-workers at the Univers ity of Wisconsin elucidated the structure of the major cecropia juven i le hormone as methyl trans , t rans,c i s -10, - 2 -1 1 - e p o x y - 7 - e t h y l - 3 , 1 1 - d i m e t h y l 2 , 6 - t r i d e c a d i e n o a t e ( I ) . S i n c e t h i s time i n t e r e s t i n t h e f i e l d o f i n s e c t c h e m i s t r y i n g e n e r a l has been growing a t a r a p i d r a t e , as can be a t t e s t e d t o by t h e i n c r e a s i n g number o f p u b l i c a t i o n s . 1.2 HORMONAL CONTROL OF INSECT METAMORPHOSIS Hormonal c o n t r o l o v e r t h e development and m a t u r a t i o n o f the i n s e c t can be c o n s i d e r e d as r e g u l a t e d by t h r e e main groups o f hormones ( F i g . 1 ) ^ . The b r a i n hormones ( b e l i e v e d t o be p o l y p e p t i d e s ) a r e s e c r e t e d by n e u r o s e c r e t o r y c e l l s i n the p r o t o c e r e b r u m and a c t i v a t e t h e p r o t h o r a c i c g l a n d s . The a c t i v a t e d p r o t h o r a c i c g l a n d s a r e then b e l i e v e d t o s e c r e t e one o r s e v e r a l c l o s e l y r e l a t e d s t e r o i d s , t h e e c dysones ( I I ) . - 3 -F i g . 1. Endocrine Regulation of L i f e Cycle of Yellow Mealworm. - 4 -OH II These ecdysones, or t he i r metabolic products then cause the insect to molt. The kind of c u t i c l e secreted by the epidermal c e l l s at each molt i s then affected by a th i rd group of hormones secreted by the corpora a l l a t a , the juven i le hormones ( I ) . In the presence of juven i le hormone, the immature insect w i l l remain in the same state. Thus, i n the presence of both juven i le and molting hormones, the insect w i l l molt, however the new c u t i c l e secreted w i l l be the same as the old one. At the end of a stage, for example, at the l a s t l a rva l i n s ta r , the concentration of juven i le hormone drops, and in the presence of molting hormone the insect w i l l now molt into the next stage, e i ther the pupa or adult. In the adu l t , juven i le hormone then plays a ro le in the development of the ovaries. 1.3 INSECT CONTROL POTENTIAL Being able to disrupt the development and maturation cycle - 5 -o f an i n s e c t l e a d s t o a p o s s i b l e means o f c o n t r o l l i n g i n s e c t p o p u l a t i o n s . J u v e n i l e hormone must be p r e s e n t a t c e r t a i n t i m e s d u r i n g the i n s e c t l i f e c y c l e , and a b s e n t a t o t h e r s . The p o t e n t i a l u t i l i z a t i o n o f j u v e n i l e hormone compounds as i n s e c t c o n t r o l l i n g a g e n t s , r e s t s i n t h e i r a p p l i c a t i o n to t h e i n s e c t a t an u n f a v o u r a b l e t i m e . | i J u v e n i l e hormones a f f e c t v i r t u a l l y a l l i n s e c t s upon which t h e y have been t e s t e d . In immature i n s e c t s t h e y p r o d u c e a v a r i e t y o f m o r p h o g e n e t i c e f f e c t s . As w e l l as d e t e r m i n i n g t h e t y p e o f c u t i c l e t h a t the e p i d e r m a l c e l l s s e c r e t e i n r e s p o n s e t o e c d y s o n e s , j u v e n i l e hormones a l s o a f f e c t the d e velopment o f i n t e r n a l o r g ans such as the c e n t r a l n e r v o u s system, t h e g l a n d s , 5 and t h e m idgut, where t h e y p r e v e n t m a t u r a t i o n and m e t a m o r p h o s i s . The use o f n a t u r a l j u v e n i l e hormones as i n s e c t c o n t r o l l i n g a g e n t s , however, h a s some drawbacks such as l a c k o f s p e c i e s s p e -c i f i c i t y and environmental i n s t a b i l i t y . To overcome t h e s e problems and i n o r d e r t o t r y and d e f i n e a s t r u c t u r e - r e a c t i v i t y c o r r e l a t i o n , a number o f a n a l o g s have been p r e p a r e d . J a c o b s o n e t a l p r e p a r e d a number o f compounds w i t h t e r p e n o i d backbones t o which v a r i o u s f u n c t i o n a l g roups were a t t a c h e d ( T a b l e 1 ) . The i n t e r e s t i n g f i n d i n g was t h e h i g h a c t i v i t y o f compounds 9 - 1 1 . But a l s o o f i n t e r e s t was the wide d i v e r s i t y o f compounds which e x h i b i t e d a c t i v i t y . J a c o b s o n e t a l ^ a l s o s t u d i e d the e f f e c t s o f m o d i f y i n g u n s a t u r a t i o n ( T a b l e 2) and t h e - 6 -Table 1 JH A c t i v i t y of Various Compounds with Terpenoid Backbones on T_. molitor Dose required to give a c t i v i t y rat ing 1.0 - 7 -epoxide f u n c t i o n a l i t y in a series of unsaturated esters (Table 3) . Table 2 Ef fect of Modifying Methyl Juvenate Unsaturation on JH A c t i v i t y in T. molitor j Compound A c t i v i t y (yg) a Methyl laurate > 10 Methyl 10,11-epoxyundecanoate . > 10 Methyl 10,11-epoxy-11-methyl - > 10 tridecanoate Methyl 10,11-epoxy-11-methyl - > 10 dodecanoate Methyl 3,7,11-trimethyldodecanoate > 10 Methyl 1 0 , l l - e p o x y - 3 , 7 , l l - t r i m e t h y l - > 10 dodecanoate Methyl 1 0 , l l - e p o x y - 3 , 7 , l l - t r i m e t h y l - > 10 2-dodecanoate Methyl 1 0 , l l - e p o x y - 3 , 7 , l l - t r i m e t h y l - > 10 6-dodecanoate Methyl farnesate 10,11-epoxide 0.031 Cecropia JH (mixed isomers) 0.01 Dose required to give a c t i v i t y rat ing 1.0. - 8 -Table 3 Ef fec t on JH A c t i v i t y i n T. mol i tor of Modi f i ca t ion of the Epoxide End of Methyl Juvenate Compound A c t i v i t y (ug) aDose required to give a c t i v i t y r a t i n g 1.0 Previous c y c l i z a t i o n of juveni le hormone and methyl farnesate 10,11-epoxide under ac id conditions had given both mono- and b i c y c l i c acids whose esters were devoid of a c t i v i t y in T. m o l i t o r . Coupled with the resul ts from Tables 2 and 3, i t seems that unsaturation and the epoxide f u n c t i o n a l i t y are necessary for high a c t i v i t y . Recently, White et a l ^ have proposed an i n t e r e s t i n g hypothesis i n attempting to r a t i o n a l i z e s t r u c t u r e - r e a c t i v i t y e f f e c t s . On comparing molecular models i t was revealed that the conf igurat ion - 9 -of compound I ( F i g . 2) was such that the electronegative centres could be made to coincide with the d i s t r i b u t i o n of s i m i l a r groups in ecdysone ( I I ) , the hormone responsible for the i n i t i a t i o n of molting in insec ts . F i g . 2 . Comparison of Electronegative Centers of Juveni le Hormone (I) with Ecdysone ( I I ) . Since many juveni le hormone mimics can be made to f i t on the ecdysone skeleton, and possess a s i m i l a r d i s t r i b u t i o n of e l e c t r o -negative groups, the p o s s i b i l i t y of these two insect hormones having some common receptor s i t es might seem reasonable. In order to test t h e i r hypothesis, White et a l ^ synthesized a number of compounds which would f i t t h e i r hypothesis. The resul t s are summarized in Table 4. The resu l t s from th i s study were quite promising. In agreement with other work i t was noted that the epoxidized compounds were much more act ive than those lacking t h i s f u n c t i o n a l i t y and also the trans o l e f i n s were more ac t ive than the c i s . A l l the compounds were quite a c t i v e , with the high a c t i v i t y of compound 4 being espec ia l ly noteworthy as up u n t i l now - 10 -Table 4 Dose in pg required to give a score of 10, i . e . h a l f - j u v e n a l i s e d ; Dose in ug required to give a score of 19, i . e . complete supernumerary larva - 11 -the C18 cecropia juveni le hormone had exhibi ted the highest a c t i v i t y i n Rhodnius p r o l i x u s . Possible explanations for the high a c t i v i t y include i t s f a c i l i t y for c u t i c l e penetrat ion, i t s metabolic s t a b i l i t y , i t s a b i l i t y to in ter fe re with the metabolic degradation of the natural hormone, or the s t ruc tura l s i m i l a r i t y of compound 4 with the natural hormone. 1.4 SPECIFIC JUVENILE HORMONE ANALOGS As mentioned e a r l i e r i t was noted that one drawback of the natural cecropia j u v e n i l e hormone was i t s r e l a t i v e lack of species s p e c i f i t y . Analogs were hoped to provide a so lut ion to t h i s problem, and examples of species s p e c i f i c analogs are o now known. Bowers et a l i n 1967 i so la ted from the wood of the balsam f i r (Abies balsamea 1.) a compound (juvabione, III) which possessed a high degree of j u v e n i l e hormone a c t i v i t y against the species Pyrrhocoris apterus. Consequently dehydrojuvabione (IV) g was i so la ted by Cerny et al and also found to possess high - 12 -a c t i v i t y i n Py_r. apterus. The i n t e r e s t i n g f i n d i n g here was t h a t these two natural products d i d not e x h i b i t n o t i c e a b l e a c t i v i t y a g a i n s t other species t e s t e d . A s i m i l a r r e s u l t was noted by Treadgold et a l ^ who studied some e s t e r s of chrysanthemic a c i d (the a c i d p o r t i o n of some n a t u r a l l y o c c u r r i n g p y r e t h r o i d s ) . The r e s u l t s as t e s t e d on Dysdercus f a s c i a t u s are shown i n t a b l e 5. These compounds were a l s o t e s t e d on the f o l l o w i n g i n s e c t s : Rhodnius p r o l i x u s and Cimex l e n t i c u i u s (Hemiptera Reduvidae and C i m i c i d a e ) , P l u t e l l a x y l o s t e l l a ( L e p i d o p t e r a ) , Phaedon c o c h l e a r i r e and Tenebrio m o l i t o r ( C o l e o p t e r a ) , Aedes aegypti ( D i p t e r a ) , and B l a t e l l a germanica (Orthoptera). However, only i n the case of _D_. f a s c i a t u s (Hemiptera Pyrrhocoridae) was j u v e n i l e hormone a c t i v i t y noted. 1 .5 PHEROMONES Although j u v e n i l e hormone analogs appear to have a b r i g h t f u t u r e i n the area o f i n s e c t c o n t r o l , a number of other p o s s i b i l i -t i e s are a l s o being explored and are of c u r r e n t i n t e r e s t . The use of i n s e c t pheromones i s one of these areas. Pheromones can be c l a s s e d as substances which are secreted to the o u t s i d e environment by an animal and r e c e i v e d by a second i n d i v i d u a l of the same species i n which they r e l e a s e a s p e c i f i c r e a c t i o n . Insect pheromones then, are compounds by which i n s e c t s convey s p e c i f i c i n f o r mation. The e f f e c t s o f i n s e c t pheromones range widely from LEAF 13 OMITTED IN PAGE NUMBERING. - 14 -such appl icat ions as marking t r a i l s , exh ib i t ing alarm, or for the purpose of at tractancy. In contrast to insect hormones, pheromones are mostly species s p e c i f i c , as well as structure s p e c i f i c , with a s l i g h t s t ruc tura l modif icat ion often negating the a c t i v i t y of the compound (Table 6 ) . ^ Because of t h e i r high s p e c i e s - s p e c i f i c i t y and t h e i r high potencies ( for example, the compound nematatabiol which i s the at t ractant pheromone of Chrysopa japana and Chrysopa septem- punctata i s ac t ive in the amount of 10" yg.) pheromones are a t t r a c t i v e candidates for use i n c o n t r o l l i n g insect populations. The possible use of these compounds would l i k e l y have to be resolved for each s p e c i f i c insect problem. V, nematatabiol For example, a congregating pheromone could be used to a t t r a c t a cer ta in species of insects to a trap baited with a le tha l compound or adhesive material which would prevent the insect from l e a v i n g , or a l t e r n a t i v e l y , a sex at t ractant pheromone could be released into an infested area, thus masking the pheromone released by the insect and thus keeping the males and females from locat ing each - 15 -Table 6 Effects of Structural Modi f i ca t ion on A t t r a c t i o n of the Male Red-Banded Leaf Ro l l e r (Argyrotaenia velutinana) natural pheromone o inac t ive (both c i s & trans) - 16 -other for purposes of mating. Furthermore, because of the high potency of these compounds, th i s type of a p p l i c a t i o n would be t e c h n i c a l l y f e a s i b l e . At present, chemically i d e n t i f i e d pheromones are known from only seven of the twenty-seven insect orders , but i t would seem l i k e l y that i n t r a s p e c i f i c chemical communication may 13 eventually be detected in every order. The structures of pheromones are quite d iverse , but often they are der ivat ives of long chain s l i g h t l y branched 13 hydrocarbons (Table 7 ) . \ Table 7 Structures of Some Insect Pheromones Female Sex Attractant of the Bo l l Weevil (Anthonomus grandis) o Sex A t t r a c t a n t of the Black Carpet Beetle (Attagenus megatoma) - 17 -Table 7 continued o Female Sex Pheromone of the Pink Bollworm Moth (Pectinophora gossypiel la) Sex a t t ractant of the Female Gypsy Moth (Porthetr ia  dispor) Sex Pheromone of the Female Pine Emperor Moth (Nudaurelia cytherea) V° Sex Pheromone of the Bean Beetle (Acanthoscelides obtectus) - 18 -Besides these natura l ly occurring insect pheromones which have been i so la ted from i n s e c t s , a number of synthetic compounds are known which possess pheromonal a c t i v i t y (Table 8 ) . ^ Table 8 Attractants Found by Volume Screening of Chemicals Formula Common or chemical name Species a t t racted Cue-lure Melon f l y Dacus  cucurbitae Coq. OCH, Methyl eugenol Oriental f r u i t f l y Dacus dorsal i s (Hendel) Heptyl butyrate Yellow jackets Vespula spp. Amiure European chafer Amphimallon majal is (RazTJ Ethyl dihydrochry- Rhinoceros beetle octHs santhemumate Oryctes rhinoceros (L. ) The compounds l i s t e d in th i s table were found by mass tes t ing of samples by the U.S .D.A. against various insect pests. - 19 -1.6 PYRETHROIDS As was noted e a r l i e r , cer ta in esters of chrysanthemic ac id were noted to possess high juveni le hormone a c t i v i t y against D_. fasciatus (Table 5) , while the ethyl ester of dihydrochrysanthemic ac id (compound 9, Table 8) was noted as a synthetic a t t rac tant of the rhinoceros beet le , Oryctes rhinoceros. I t i s also in teres t ing to note that na tura l ly occurring esters of chrysanthemic ac id (pyrethroids) found i n various plant sources are very tox ic to insec ts . Pyrethrum, which represents the dr ied flowers of Chrysan-themum c i n e r a r i a e f o l i u m , has been used as an i n s e c t i c i d e from ancient times. The ^ insect ic idal a c t i v i t y of pyrethrum has been a t t r ibuted to the act ion of the s ix const i tuents : pyrethrum I , pyrethrum I I , c i n e r i n I , c i n e r i n I I , jasmolin I , and jasmolin II (Table 9 ) . 1 5 The i n s e c t i c i d a l act ion of pyrethrins i s due to t h e i r a b i l i t y to paralyze insec ts . Knockdown occurs almost instantaneously at very low doses, with higher doses being required to k i l l the insec t . A number of analogs have been prepared by e i ther modifying the acid moeity and using the natural alcohol for e s t e r i f i c a t i o n purposes (Table 10 and 11), or by using the natural acid p o r t i o n , and using various alcohols to prepare the ester der ivat ives (Table 12)' The use of benzyl a l c o h o l , phthal imidocarbinol , and f u r y l c a r b i n o l were found to have good i n s e c t i c i d a l a c t i v i t i e s . With - 20 -the natural a lcohols , none of the esters of the modified acids were found to have i n sec t i c i da l a c t i v i t i e s with comparable t o x i c i t y to that of pyrethrins un t i l the discovery of 2,2,3,3-tetramethylcyclopropane-carboxyl ic acid by Matusi and K i t a h a r a , ^ who synthesized various esters of th i s acid and found them to be nearly equal to chrysan-themates in the i r t o x i c i t y to insects. Table 9 Structures of the Natural ly Occurring Pyrethroids H,C C H , H 3 C \ / C H , \ yM V H H \ C = C V A / \ A c — c c H 3 C H" c-o H 2 H H \ / il o Pyrethrin I H ,C C H 3 H 3 C H - - C \ K ^ C . H H C - O ^ ^ ° O Cincrin I H,C H jC H,C C H , CH, II \ =c: A y y ; c * c ^ c = c , C H 2 C H , c — c , H-' o c - o H 2 Jasmolin 1 H H , C 0 2 C H,C H,C C H , - H V H H \ H H / C = C V A / " \ > C - C > = C / N H C C C I / \ H - \ . , - ' V C s N " H H, O C - O o Pyrethrin II H , C 0 2 C C H , \ CH, / H,C H V H 11 \ C C H ' C - O o Cincrin II C Hi Hi >\ / C C = C I / \ C H H C H 3 O H , C 0 2 C H,C H,C C H , J A / =cv. A / c — c . H " 'c o C H , H H N -o 12 C H 2 C H , / \ H H H 2 Jasmolin II O - 21 -Table 9 continued: CH, H V * /> L I H H O H H ( + ) -P> rc t l i r o l one CH 3 H V / xrr.s H 2 4. v HO"' I C-C CH 2CH 3 H Jasmolonc I I y H 3 C C H j H O O C \ / H .C C C II C O O H ( + )-fruii .s-Chrysanthemum dicarboxvlic acid - V * J * -C H , H , HO-'T " C - C * C H , C = C O H ' \ l ( + )-Cinerolone , \2' C = / H , C H 3 C C H , H C O O H (+ )-fra/is-Chrysanthemic acid , C H , H 3 C O O C \ / C=C^ C1 , / V / \ / H 3 C C C H J 1 •. H C O O H ( + )-fran5-Pyre!hric acid - 22 T A B L E 1 0 Toxicity of Natural Pyrethronyl Esters to the German Cockroach {Bhitlclla germanica L.) Acid Activity" H 3 C X n / C = C \ <-> H 3 C C O j H * \ I C-CH C H (-) H C 3 C H 2 C 0 2 H H 3 C \ , C = C H C 0 2 H H 3 c ' \\\2-CU {-i C H / \ H,C C H , I I H 3 C C C H \ / \ / \ C / C C 0 2 H • (± ) H 3 C H 3 C C H 3 H 3 C x / C H w C H \ • c V co>H ( + + ) H,C H 3 C \ C - -CH / \ / \ H 3 C - C C H 2 C O , H ( + ) H,C cf. Resynthesized pyrcthrin I (5 + ) ' Exposure by contact - 23 -TABLE j 1 Insecticidal Activities of (+)-AI!cthronyl Esters Acid I12C H 2 C CI ICO, H Relative activity" LC 5 0(nig/IOO ml) - (-) H j C - M C C H C O , H > 1000 (-) H j C - H C H ,C—HC C H C O , H > 1000 (-) H 3 C \ ( / H 2 C C H C O , H 920 ( + ) H 3 C H 3 C \ ( / H 3 C HC C H C O , H 500 (+) \ C C H C 0 2 H / \ / H 3 C C / \ H 3 C CI I 3 135 (4 + ) H 3 C \ C C H C H 2 C O , H / \ / H 3 C C / \ H 3 C C H 3 >!000 (-) - 24 T A B L E 1 2 Insecticidal Activity of Imidometliyl Chrysanthemates C H 3 C H 3 X \ / 11 C H 3 C C \ / \ / \ - . C = C H - C H C H - C - O - C l l j - N A 3 / . il \ / C H 3 O C II y Relative toxicity (LC 5 0 ) Chrysanthemate to Musca dbmestica' Phthalimidomethyl (±)-cis, trans- 33 Monothiophthalimidomethyl (±)-cis, irans- 100 Dithiophthalimidoinethyl (±)-cis, trans- 42 3,4,5,6-Tctrahydrophthalimidomethyl (±)-cis, 80 trans- (Phthalthrin) ( + )-fraHS-Phthalthrin 170 l,2,3,4LTetrahydrophthalimidometliyl (±)-c/s, 20 trans-a,x'-Dimethylmaleimidomethyl (±)-cis, iraiu- 75 a-Mctliyl-a'-ctliylmaleimidomethyl (±)-<7s, trans- 38 a-Mcthyl-a'-phcnylmaleimidomethyl (±)-cis. 23' trans-2,4-DichIorophthalimidomethyl {±)-cis, trans- 34 Pyrethrins 100 Allellirin 50 2.6-Dimethyl-4-allyl-bcnzyl ( + )-<•«. trans- 188 'Campbell turntable method - 25 -2.. SCOPE OF PRESENT WORK The previous discussion has provided a b r i e f summary of the various areas of insect chemistry which have received some at tent ion i n the recent l i t e r a t u r e . Thus, i t i s c lear that c e r t a i n s t ruc tura l types provide b i o l o g i c a l a c t i v i t i e s of the juveni le hormone type, others possess insect repellency or attractancy propert ies , while s t i l l others reveal toxic properties reminiscent of the pyrethroid f a m i l y . In many of these areas addi t ional researches essential to provide a better understanding of s t r u c t u r e - a c t i v i t y re la t ionships and hopeful ly , to develop useful appl icat ions of such chemicals in insect c o n t r o l . With these various objectives in mind, i t was decided to i n i t i a t e a synthetic program leading to various novel analogs of compounds within the above mentioned fami l ies and to subsequently evaluate t h e i r potent ia l usefulness. I t seemed p a r t i c u l a r l y a t t r a c t i v e to u t i l i z e , as s ta r t ing materials for the synthetic program, some organic compounds which are presently regarded as waste byproducts in the pulp and paper industry . In t h i s manner successful developments of the chemistry v/ould stimulate useful appl icat ions of such waste products. { \ - 26 -Of the various trees which are important in the forest industry of B r i t i s h Columbia, three species, the western red cedar, the douglas f i r , and the western hemlock have been studied in regard to t he i r chemical composition." ' ' Of pa r t i cu l a r in teres t to us was the western red cedar tree of which the main component in the leaves and branches is the monoterpene thujone (VI). Currently, branches and leaves of trees are waste byproducts of the forest industry, and generally disposed of by burning or dumping methods, thus const i tut ing a po l lu t ion hazard, as well as wasting a large portion of the t ree. VI Since thujone can be obtained from the leaves and branches by an economically v iable steam d i s t i l l a t i o n and f rac t ionat ion process, and because of the a t t r ac t i ve f unc t i ona l i t i e s of thujone i t was decided to study the possible usage of th i s material as a precursor to insect cont ro l l i ng agents. - 27 -3. DISCUSSION 3.1 . cx-THUJAKETONIC ACID ! I The treatment of cedar leaf o i l with aqueous potassium I o permanganate i s a known reaction which resu l t s in the ox idat ive r ing opening of thujone to a - thujaketonic acid (VI -> V I I ) . C O O H During the o x i d a t i o n , the c h i r a l centre adjacent to the methyl group i s l o s t , while the rest of the stereochemistry i s f i x e d . Thus, only one product i s obtained, with the stereochemistry about the cyclopropane r ing established as having the iso-propyl group and hydrogen c i s to each other. Due to the central ro le that th i s material occupied i n regards to some of the synthetic invest igat ions i t s p .m.r . spectrum was recorded and analyzed for future reference. The spectrum contained * Cedar leaf o i l was obtained through the courtesy of MacMillan Bloedel Research L t d . , and consisted of approximately 35% thujone and 12% terpenoid impur i t i e s . - 28 -F i g . 3. P.M.R. Spectrum of a-Thujaketonic A c i d . - 29 -a three proton s ing let at 6 2.22 which could be at t r ibuted to the methyl group adjacent to the ketonic carbonyl while at 6 0.94 occurred a s ix proton doublet (J = 5 Hz) which was assigned to the methyl protons of the iso-propyl group. The four l i n e resonance centered at 6 2.49 was assigned to the methylene protons adjacent to the carboxylate group. These two protons were adjacent to a ch i r a l centre and thus gave r i s e to the observed AB pattern (J = 17 Hz). Centered at 6 1.91 was a one proton doublet of doublets which was assigned to the proton on the cyclopropane r ing adjacent to the ketonic carbonyl. This proton along with the methylene protons of the cyclopropane r ing formed an ABX system. One of the cyclopropyl methylene protons gave r i s e to the doublet of doublets centered at 6 0.88. The other cyclopropyl proton and the methine proton of the isopropyl group then accounted for the mul t ip le t which spanned the region 6 1.5 to 6 1.1. 3.2 SYNTHETIC OBJECTIVES As was shown in the int roduct ion, a number of insect cont ro l l i ng agents are der ivat ives of chrysanthemic ac id , have a terpenoid backbone, or are branched long chain hydrocarbons. I t was therefore hoped to f ind some general procedures for the elaboration of a -thujaketonic acid to produce a ser ies of der ivat ives which would s t r uc tu ra l l y resemble some of these act ive compounds. P r e v i o u s l y ^ , work had been done in th i s area to produce der ivat ives of the type (VIII + IX). - 30 -COOR The work described i n t h i s thesis was aimed a t : 1.) the transformation of the ketonic carbonyl of a- thujaketonic acid to an o l e f i n i c l inkage to produce der iva t ies of the type (X) , and 2.) synthesis of sui table substances for subsequent coupling to a- thujaketonic acid at the ketonic carbonyl . I f the above object ives could be achieved with a - thujaketonic a c i d , then i t would seem possible to produce an analogous series of der ivat ives with e-thujaketonic acid (XI , X I I ) . 3.3 THE WITTIG REACTION The Wi t t ig reaction was deemed as the method of choice for the elaboration of the ketonic carbonyl of a- thujaketonic a c i d . With - 31 -F i g . 4. Scheme for Elaboration of a-Thujaketonic Acid to Derivatives of (3-Thujaketonic A c i d . - 32 -the Witt ig reaction there i s no ambiguity about the pos it ioning of the double bond, and by use of su itable phosphonium sa l t s a wide var iety of side chains can be introduced. Therefore, a var iety of conditions were studied in order to ef fect the desired transformation. The phosphonium sa l t s used for the study were the commercially ava i lab le methyltriphenylphosphoniurn bromide and the eas i l y prepared i sopropy l -triphenylphosphonium iodide. Successful appl icat ion of the Wit t ig reaction with these phosphonium sa l t s would then y i e l d chrysanthemic a c i d - l i k e compounds (Table 13). Table 13 ' Structural Comparison of Methylene and Isopropylidene Derivatives of a-Thujaketonic Acid to Chrysanthemic Ac id . H COOH trans-Chrysanthemic Acid C O O H XII I, Methylene Derivative of a -thujaketonic Acid - 33 -COOH XIV, Isopropylidene Derivat ive of a - thujaketonic Acid The f i r s t attempts at the W i t t i g react ion were done on an ethereal mixture of a - thujaketonic acid and methyltriphenylphosphonium bromide using two equivalents of n - b u t y l l i t h i u r n . These react ion conditions however, led only to t a r r y decomposition products, perhaps obtained by indiscr iminant attack of the base on the cyclopropyl ketone d e r i v a t i v e . I t was therefore decided to invest igate the use of the methyl ester of a - thujaketonic ac id as the s t a r t i n g material for the W i t t i g reac t ion . Using methanol as the solvent , and sodium methoxide as the base however gave back only s t a r t i n g material and r ing opened material ( X H I a ) . The mechanism ( F i g . 5) being v i s u a l i z e d for th i s react ion involves attack of the base at the protons alpha to the carbomethoxy group, followed by r ing opening to form the enolate of the methyl ester of B-thujaketonic a c i d . - 34 -o XII la " " " ^ F ig . 5. Proposed Mechanism for Ring Opening of a-Thujaketonic Acid under Basic Conditions. Although the desired product was not obtained, the resu l t was an interest ing one. The ester thus obtained was believed to be the Z isomer due to the occurrence of a one proton septet (J = 7 Hz) at 5 4.0 (see below). Previously, the ring-opened acid havi the E configuration (XI), was prepared in th i s laboratory by the 20 treatment of a-thujaketonic acid with aqueous mineral ac id . The proposed mechanism is out l ined below (Fig. 6 ) . F ig . 6. Proposed Mechanism for Ring Opening of a-Thujaketonic Acid under Ac id ic Conditions. - 35 -For a more d i rec t comparison, the ring-opened acid obtained from the aqueous acid treatment was converted to the methyl ester. The p.m.r. spectra of the two methyl esters (Fig. 7a, 7b) were then compared. The spectra were quite s im i la r except for two noticeable d i f ferences. In the case of the material obtained from the sodium methoxide reaction there was a one proton septet (J = 7 Hz) at 6 4.0 and the signal for the v i n y l i c proton occurred at 6 5.4. In the case of the methyl ester of the material obtained from the aqueous acid treatment, there was no septet at 6 4.0, and the signal of the v i n y l i c proton came at 6 5.6. These observations 21 corresponded to the resu lts obtained by Pizzey et al who studied the proton magnetic resonance spectra of a number of crotonic acid der ivat ives of the type XV + XVI. pJ H(4) R1 H(4) \ / H(2) \ / ,C , K ' C C0 2Et R OC C=C / \ / \ X C0 2Et X H(2) trans c i s XV XVI Their overal l resu l t s (Table 14) indicated that in th i s type of a system the resonance of the proton(s) on C-4 which was c i s to the carboethoxy group would occur at lower f i e l d than would the resonance of the proton(s) at C-4 i f th i s group and the carboethoxy F i g . 7 a . P.M.R. Spectrum of Methyl Ester of Ring Opened Material obtained from Sodium Methoxide Reaction (contains some a-thujaketonic acid).(Z-3-Thujaketonic Acid Methyl Ester) I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I ! I I ! ' ? I T T T I I I I I I | I I V I | I l' I I | l' I I I |' I I I I | I I I I | I I I I | I I I I | | I | I | | i | | | | i | i | , ; i ; | — i i i i i i i i i i i i i i i i i i I i I i i I i i i i I i t i i I i F i g . 7b. P.M.R. Spectrum of Methyl Ester of g-Thujaketonic Acid obtained from Aqueous Acid Treatment of a-Thujaketonic A c i d . (E-3-Thujaketonic Acid Methyl Ester) - 38 -were trans. A l s o , i t was noted that the resonance of the v i n y l i c proton at C-2 occurred at lower f i e l d in the case of the trans ester as compared with c i s . Table 14 Chemical S h i f t s for Compounds of the Type R 1 R 2 CH-C(X):CH-C0 2 Et CIS trans H H H H Cl Cl C:C-H(2) 6 5.99 6 6.04 C:C-C-H(4) 6 2.51 6 2.23 c i s trans H H H H S-Ph S-Ph 6 5.33 6 5.86 6 2.42 <5 1.75 CIS trans H H H H S-mesityl S-mesityl 6 4.81 6 5.82 6 2.42 5 1.61 CIS trans H H H H Cl Cl 6 6.03 6 6.55 From these resul t s i t thus appeared that the r ing opening of a - thujaketonic acid could be accomplished s te reose lec t ive ly to provide e i ther isomer. This was a pleasing r e s u l t , however i t was not invest igated f u r t h e r , as the goal at t h i s time was the study of the Wit t ig reac t ion . - 39 -Therefore, in considering more vigorous reaction condi t ions , i t was decided to use the anion of dimethyl sul foxide as the base and dimethylsulfoxide as the solvent. Under these conditions (room temperature, 24 hours) only a poor recovery of the s t a r t i n g methyl ester contaminated with a small amount of ring-opened material was obtained. At elevated temperatures (100 C , 24 hours), no material soluble in the ether extract was recovered. Limited success was f i n a l l y achieved by using sodium hydride in 1,2-dimethoxyethane, i n which the methylene der iva t ive (XVII) of the methyl ester of a - thujaketonic ac id was obtained in 21% y i e l d . ^ ^ ^ . ^ ^ N ^ ^ C O z C H 3 XVII Under the same conditions employing isopropyltr iphenylphos-phonium i o d i d e , no Wi t t ig product could be detected and a 40% recovery of s t a r t i n g material was achieved. From the resul t s of these studies i t seemed l i k e l y that the hindered nature of the ketonic carbonyl of a - thujaketonic acid was r e s u l t i n g in preferent ia l nuc leophi l i c attack by the phosphorane at the carbomethoxy group. A l s o , the hindered nature of the ketonic carbonyl was l i k e l y responsible for the basic removal of the protons adjacent to the carbomethoxy group thus r e s u l t i n g in the formation of ring-opened m a t e r i a l . Therefore, to overcome these problems and eliminate the unwanted side reactions i t would be necessary to decrease the a c i d i t y of the protons adjacent to the carbomethoxy group, - 40 -and also make the carbonyl of th i s function less e l e c t r o p h i l i c . I t was therefore decided to work with the sodium sa l t of a-thujaketonic ac id. Since, the in s i t u preparation of the l i th ium sa l t with n-buty l -l i th ium was not successful , i t was decided to prepare the sodium sa l t by the action of methanolic sodium hydroxide, and then i so l a te th i s mater ia l . Due to s o l u b i l i t y considerations and because of the claimed 22 s e l e c t i v i t y , dimethyl sulfoxide was chosen as solvent. Following the 22 procedure of Corey et al , reaction of the dry sodium sa l t with methyltriphenylphosphoniurn bromide gave the desired methylene der ivat ive (XIII) in about 90% y i e l d . With isopropyltr iphenylphos-phonium iodide the corresponding isopropylidene der ivat ive (XIV) was obtained in about 85% y i e l d . The high y i e l d of the isopropylidene der ivat ive was espec ia l l y noteworthy, as general ly the y ie ld s of 23 tetrasubst i tuted o le f i n s from the Witt ig reaction are not very good. Thus, the f i r s t object ive had now been rea l i zed . With the achievement of the desired funct iona l i za t ion of the ketonic carbonyl of a-thujaketonic acid i t was now desired to f ind a general procedure for the e s t e r i f i c a t i o n of the obtained o l e f i n i c acids. 24 Recently, Shaw et al reported a simple convenient procedure for the quant i tat ive e s t e r i f i c a t i o n of carboxyl ic acids. Their method consisted of t reat ing the acid in hexamethylphosphoramide with sodium hydroxide and an a lky l hal ide. This procedure was modified s l i g h t l y in that the sodium s a l t of the o l e f i n i c acid was formed f i r s t by the action of methanolic sodium hydroxide. The s a l t was i s o l a ted , - 41 -washed with petroleum ether; dried in vacuo; and then treated with an a l k y l halide in hexamethylphosphoramide. Use of t h i s procedure resulted in good y i e l d s of some simple ester d e r i v a t i v e s . The resul t s along with some spectroscopic data are summarized in Table 15. 3.4 ATTEMPTED PREPARATION OF APPROPRIATE PHOSPHONIUM INTERMEDIATES XVIII AND XIX. With procedures for the W i t t i g reaction and subsequent e s t e r i f i c a t i o n having been established there remained the f i n a l ob jec t ive , which was the synthesis of sui table synthetic intermediates for the subsequent coupling with thujaketonic acid v ia the Wi t t ig reac t ion . I t was hoped that t h i s approach would al low the preparation of a series of j u v e n i l e hormone analogs. To be s p e c i f i c , the target molecules were the phosphonium s a l t s XVIII and XIX. The subsequent react ion of the phosphoranes. derived from XVIII and XIX with ct- and B-thujaketonic acids would then lead to materials which are s t r u c t u r a l l y s i m i l a r to the cecropia juveni le hormone (Table 16). XVIII XIX - 42 -Table 15 Overall Results for the Conversion of a-Thujaketonic Acid to Some Simple O l e f i n i c Ester Der ivat ives . Compound A l k y l a t i n g Agent % Y i e l d I .R. Data P.M.R. data used for E s t e r i - v (C = 0) [cm - 1 ] Chemical S h i f t R1 R" f i c a t i o n of C = C-CH-, H H Mel 74 1741 6 1 .75 H H n-BuBr*3 70 1735 6 1 .74 H H H2C = CN(CH 2 ) 2 CH 2 OTs b 68 1735 6 1 .76 Me Me Mel 67 1740 6 1 .53, 6 1.62, 6 1 .69 Me Me n-BuI c 65 1735 6 1 .52, 6 1.61, 6 1 .70 a refers to i so la ted y i e l d of o l e f i n i c ester (X) based on a-thujaketonic a c i d . b c a t a l y t i c amount of sodium iodide used in e s t e r i f i c a t i o n r e a c t i o n , c prepared by Dr. A. Markus. - 43 -Table 16 Structural Comparison of Juvenile Hormone with Possible Analogs Avai lab le from Thujaketonic A c i d . I , Juvenile Hormone - 44 -The s y n t h e t i c scheme f o r the preparat ion of these phosphonium s a l t s was based on a sequence used by T r o s t et al i n t h e i r synthesis 25 of the cecropia j u v e n i l e hormone. The o v e r a l l s y n t h e t i c plan i s shown i n F i g . 8. X V I I I ( X = I ) 45 -XIX (X = I) F i g . 8. Scheme for the Synthesis of the Desired Phosphonium Salts XVIII and XIX. 1 - 46 -The f i r s t step in the sequence involved the react ion of trimethylphosphonacetate with methyl ethyl ketone. C i s - and trans-methyl 3-methyl-2-pentenoates (XX, XXI) were obtained in 18% and 37% y i e l d s respec t ive ly . These esters were separated from each other by spinning band d i s t i l l a t i o n which general ly resulted in the i s o l a t i o n of products which were 90-98% i somer ica l ly pure, as determined by gas chromatography (F ig . 9) . The only complication during the separation of the two isomers was the'thermal isomerizat ion of the c i s isomer to the 3^-unsaturated product (XXXIV). This isomerizat ion was more serious i f larger quant i t ies were separated so that longer time periods were necessary for the d i s t i l l a t i o n . However, under normal separation conditions t h i s isomerizat ion was OCHj XX XXXIV i n s i g n i f i c a n t . With the separate isomers now ava i lab le ( F i g . 10a, 10b), the stereochemical i n t e g r i t y of the double bond in each isomer was assured, as the condit ions for the fo l lowing transformations would not l i k e l y r e s u l t in any isomerizat ion. Therefore, the separated isomers were subjected to a l i t h i u m aluminum hydride reduct ion, which resulted in the i s o l a t i o n of the desired a l l y l i c alcohols (XXII, XXVIII) in y i e l d s of 83% to 94%. The next step in the sequence was the conversion of the a l l y l i c alcohols to the corresponding a l l y l i c ha l ides . O r i g i n a l l y , Trost et al had used - 47 -c i s (XX) trans (XXI) F i g . 9. Gas Chromatographic Traces of Cis and Trans Methyl 3-Methyl-2-Pentenoates. F i g . 10a. P.M.R. Spectrum of Cis_ Methyl 3-Methyl-2-Pentenoate (XX). - p i VD F i g . 10b. P.M.R. Spectrum of Trans Methyl-3-Methyl-2-Pentenoate (XXI). - 50 -phosphorus tribromide for th i s conversion, however, th i s procedure was abandoned in favor of a procedure used by Stork et al to form a l l y l i c chlor ides which were not contaminated with rearrangement products. Since the desired a l l y l i c chlor ides were found to be unstable as well as d i f f i c u l t to handle because of the i r v o l a t i l i t y , they were not i so l a ted , but rather they were treated d i r e c t l y with 27 the anion of ethyl 3-oxo-pentanoate. The desired monoalkylated B-ketoesters (XXIV, XXX) were then i so lated in 39% to 44% y i e l d by means of f r ac t i ona l d i s t i l l a t i o n . Subsequent saponi f icat ion and decarboxylation of the 3-ketoesters gave the resultant ketones (XXV, XXXI) in about 80% to 90% y i e l d . The ketones were then smoothly reduced with sodium borohydride in ethanol to afford the c i s and trans alcohols (XXVI^ XXXII) in 90% to 95% y i e l d . A comparison of the p.m.r. spectra of the products obtained to th i s point confirmed that the i n t eg r i t y of the double bond in the two isomers had been retained (Table 17). At th i s point, due to i t s greater a v a i l a b i l i t y , only the trans isomer was used. Thus, the trans o l e f i n i c alcohol (XXXII) was converted to the o l e f i n i c iodide (XXXIII) by the action of pQ triphenylphosphite di iodide in ether. However, on treatment of the iodide with triphenylphosphine none of the desired phosphonium sa l t (XIX) was obtained. This conclusion was reached on the basis of the p.m.r. spectrum of the polar products obtained from the react ion. The p.m.r. spectrum of the desired phosphonium sa l t (XIX) would be expected to exh ib i t resonances at approximately 6 7.5 (15 H, $~P+-), 5 5.0 (2 H, - 51 -Table 17 Comparison of Some P.M.R. Data for Compounds of the Type XL and XLI. 3 X C H 4 (2) 3 CH, (2) (1) H3C H 0) LHa* XL, c i s XLI , trans chemical s h i f t s , 6 C = C-CH 3(1) C = C-CH 2(2) C = C-H(3) c i s trans c i s trans c i s trans •OH 0 1.70 1.68 1.62 1.61 1.63 1.58 2.05 2.04 2.02 1.95 2.03 1.94 5.31 5.37 4.89 4.97 5.00 4.97 CIS trans OH 1.62 1.60 2.01 1.98 5.01 5.09 - 52 -C=CV^ | and yC ^ ) and 6 2.5 to 6 0.8 (17 H). The p.m.r . spectrum of the obtained polar material had no resonance around the region 6 4.0 to 6 6.0 and although resonances occurred in the 6 7.5 and 6 1.0 to <5 2.5 regions, the r a t i o of the i n t e n s i t i e s of these resonances was about 2.5:1 respec t ive ly . As a further check to ascertain whether any of the desired phosphonium s a l t was present, the polar products from the reaction were used i n a W i t t i g reaction with the sodium s a l t of a - thujaketonic a c i d . From t h i s react ion however only a quant i ta t ive recovery of a - thujaketonic acid was obtained. From these resul t s i t seemed that perhaps e l iminat ion and/or c y c l i z a t i o n reactions ( F i g . 11) might be occurring p r e f e r e n t i a l l y to the desired subs t i tu t ion reac t ion . and/or rearrangement products cyc\'\ zation products F i g . 11. Possible Side Reactions Competing with Phosphonium Sal t Formation. I f the double bond of the o l e f i n i c iodide (XXXIII) was i n t e r f e r i n g with the formation of the desired phosphonium s a l t then perhaps the desired phosphonium s a l t (XIX) could be obtained by protect ing the double bond p r i o r to the react ion of the iodide with triphenylphosphine. In order to check whether t h i s might be a v iable - 53 -pathway to the desired product i t was decided to hydrogenate the o l e f i n i c alcohol (XXXII), convert t h i s saturated alcohol (XXXV) to the saturated iodide (XXXVI) and then treat t h i s iodide with tr iphenyl phosphine (F ig . 12). To t h i s end, the unsaturated decanol (XXXII) was reduced with hydrogen in the presence of a palladium c a t a l y s t . The saturated alcohol (XXXV) was then converted to the saturated iodide (XXXVI) in the manner previously described. Treatment of t h i s iodide with triphenylphosphine however d id not give any detectable amount of the desired phosphonium s a l t (XXXVII). XXXV XXXVI XXXVII F i g . 12. Scheme fo (r the Preparation of Phosphonium Sa l t XXXVII. From these resul t s i t could not be ascertained whether the double bond in the unsaturated iodide (XXXIII) was responsible for the formation of unwanted s ide-products , however, i t did appear as though e l iminat ion was probably much more favorable than s u b s t i t u t i o n . Because of these resul t s i t was decided that the o r i g i n a l synthetic scheme would not be p r a c t i c a l and was abandoned. 3.5 ALTERNATE ROUTES FOR THE SYNTHESIS OF THE DESIRED PHOSPHONIUM SALTS XVIII AND XIX. The formation of phosphonium sa l t s from primary halides 29 proceeds much more r e a d i l y than from secondary ha l ides . Therefore - 54 -i t would seem reasonable to form the desired phosphonium s a l t s v ia reaction with the sui table primary halide followed by a l k y l a t i o n with another primary hal ide . This type of strategy i s revealed in the two routes shown in F i g . 13. /. base XXXVIII (X = Br , I) XLVI XVIII + XXXIX (X = Br , I) •base F i g . 13. Al ternate Routes for Synthesis of the Desired Phosphonium Salts XVIII and XIX. In the f i r s t method, the o l e f i n i c halide (XXXVIII) could be prepared by modifying the previous scheme as shown in F i g . 14. XXXVIII F i g . 14. Proposed Scheme for Synthesis of O l e f i n i c Halide XXXVIII. - 55 -In the second route the o l e f i n i c halide (XXXIX) used for a l k y l a t i n g the n-propylphosphonium s a l t i s a known compound which 30 has been prepared by Corey et al , as out l ined in F i g . 15. XXXIX F i g . 15. Outl ine of Corey's Synthesis of 1-Bromo-4-Methyl-3-Hexene (XXXIX). - 56 -3.6 PRELIMINARY INVESTIGATION OF AN ALTERNATE ROUTE FOR THE SYNTHESIS OF THE DESIRED PHOSPHONIUM SALTS XVIII AND XIX Due to the a v a i l a b i l i t y of the a l l y l i c alcohol XXII i t was decided to test the f e a s i b i l i t y of the f i r s t proposed al ternate route for the synthesis of the desired phosphonium s a l t s XVIII and XIX. Since an important step of the a l ternate route was the a l k y l a t i o n of a primary phosphonium s a l t (XLVI) with a primary a l k y l h a l i d e , a model react ion involv ing ethyltriphenylphosphonium bromide was studied in th i s laboratory by Dr. S. Morehead. I t was found that sec-butyltriphenylphosphonium bromide (XLVIII) could be obtained by t reat ing the ethyltriphenylphosphonium bromide with n-butyl1i thium and ethyl bromide i n die thyl ether (XLVII -»• XLVII I ) . n- 8 u L i +- — pep ^ e+s, — ^ P V » BU ' 3 — 1 rz XLVII XLVIII This r e s u l t was encouraging and also noteworthy in that 31 Tr ippet t and co-workers had reported that the act ion of triphenylphos-phine on sec-butyl bromide y ie lded only e l iminat ion products. Therefore, to achieve the desired goa l , the c i s a l l y l i c 32 alcohol XXII ( F i g . 14) was converted to the known a l l y l i c bromide XLII by the act ion of phosphorous tribromide in ether. This a l l y l i c bromide was then used in the a l k y l a t i o n of diethylmalonate to y i e l d t h i s c i s d ies ter XLI11. Saponif icat ion of the dies ter with aqueous potassium hydroxide gave the c i s d i a c i d XL 11 la as a white c r y s t a l l i n e - 57 -C O O H COOH XLIIIa s o l i d . The y i e l d of th i s d iac id based upon the a l l y l i c alcohol XX was 52%. Upon heating the d iac id XLIIIa or upon ref lux ing i t d i l u t e sulphuric acid a mixture of products was obtained which analyzed for an emperical formula of Cg^-j^^- The mass spectrum obtained on th i s mixture further substantiated the analysis by having 142(10%) as the highest molecular ion recorded. From the proton magnetic resonance spectrum i t could be ascertained that the desired c i s o l e f i n i c acid XLIV was present as well as a side product which contained no o l e f i n i c or acid proton. Since the infrared spectrum contained two carbonyl stretches (1725 cm \ 1700 cm ^) i t appeared as i f the side product was a lactone. Reduction of the decarboxylation reaction mixture with l i th ium aluminum hydride y ie lded a mixture of alcohols which were separated by vacuum d i s t i l l a t i o n . The lower bo i l i ng alcohol (100°C at 12 tor r ) was found to be the desired o l e f i n i c alcohol XLV, while the higher bo i l i ng alcohol (140°C at 12 tor r ) was determined to be a saturated d io l by means of i t s proton magnetic resonance spectrum, infrared spectrum, and mass spectrum. Also, since the proton magnetic resonance spectrum indicated the presence of a primary alcohol (3.63, 2H, mult . ) , but no secondary alcohol i t there seemed l i k e l y that the decarboxylation of the c i s d iac id XLIIIa y ie lded the 6-lactone XLVII (Fig. 16) as a major side-product which would then account for the observed products obtained from the l i th ium aluminum hydride reduction. - 58 -COOH -C0 2 XLIV C O O H O XLIIIa XLVII OH + OH XLV XLVIII F i g . 16. Products Obtained From the Lithium Aluminum Hydride Reduction of the Decarboxylation Reaction Mixture Obtained From the Cis Diacid XLII Ia . substantial lowering of the y i e l d of the synthetic sequence, the desired c i s alcohol XLV was obtainable i n pure form and was car r ied fur ther . Treatment of t h i s alcohol with tr iphenylphosphite d i i o d i d e resulted i n the formation of the o l e f i n i c iodide XXXVIII (X = I) which was then converted to the desired primary phosphonium s a l t XLVI by the act ion of t r i p h e n y l p h o s p h i n e i n r e f l u x i n g ethyl acetate. The structure of t h i s phosphonium s a l t was d e f i n i t e l y establ ished from the combustion analysis (C^gH^QPI), proton magnetic resonance spectrum (6 3.62, 2H, H H + m u l t i p l e t , ^ C C j U )» a n d t n e m a s s spectrum (373, 11%, M - I ) . remaining task of elaborating the carbon skeleton to produce the desired phosphonium s a l t XVIII was then achieved by treatment of the primary phosphonium s a l t with n - b u t y l l i t h i u m and ethyl iodide i n ethyl ether. Although the above mentioned side react ion resulted in a With the desired f u n c t i o n a l i t y having been introduced, the - 59 -3.7 OVERALL RESULTS In summary, the work done towards t h i s thesis has resulted in the determination of the reaction conditions for the successful Wit t ig reaction of a - thujaketonic acid (VI I ) , thus providing a means for the possible elaboration of a - thujaketonic acid to novel analogues i of known insect c o n t r o l l i n g agents. A l s o , i t was determined that a - thujaketonic acid could be ring-opened s tereose lec t ive ly to af ford e i ther (E)- or (Z)-3-thujaketonic ac id which in turn could be used as s t a r t i n g materials f o r the preparation of a complementary ser ies of analogues. F i n a l l y , two routes for the.synthesis of the desired phosphonium sa l t s XVIII and XIX, which when coupled with thujaketonic acid v i a the W i t t i g react ion would lead to juveni le hormone analogs, were studied. . In the f i r s t route the desired carbon skeleton was obtained, however, attempted f u n c t i o n a l i z a t i o n s to produce the desired phos-phonium s a l t f a i l e d . In the second route a primary phosphonium s a l t (XLVI) was formed and the carbon skeleton was elaborated to provide one of the target phosphonium sa l t s (XVIII ) . - 60 -4. EXPERIMENTAL The separation of the c i s and trans methyl 3-methyl-2-pente-i noates (XX, XXI) was achieved on a Nester-Faust auto-annular spinning band s t i l l . The s t i l l was equipped with a 90 cm t e f l o n shaf t , and the separation was achieved at atmospheric pressure by using a bo i l up rate of about 12 drops/min. and a takeoff r a t i o of about 30:1. The progress of the d i s t i l l a t i o n was monitored by means of gas chromatography, using a Carle model 8000 gas chromatograph. The column used was a 1/8" x 6' s ta in less steel column which was packed with 3.1 g of 5% by weight Ethofat 60/25 on 90-100 mesh Anakrom ABS. Helium was used as the c a r r i e r gas. With a column temperature of about 111°C and a flow rate of about 25 ml/min. the c i s isomer had a retention time of about 3.20 m i n . , while the trans isomer had a retention time of about 3.68 min. The a - thujaketonic acid (VI) used was prepared from cedar 20 leaf o i l by using the method of Thompson . The cedar leaf o i l used was supplied by MacMillan Bloedel Research L t d . , and general ly consisted of approximately 88% thujone and 12% terpenoid impuri ty . Products obtained were general ly characterized by the b o i l i n g point (B.P.) in f rared spectrum ( I . R . ) , proton magnetic resonance spectrum ( P . M . R . ) , mass spectrum (M.S . ) , and a n a l y s i s . Except for the c i s and trans methyl 3-methyl-2-pentanoates and the ci_s 1-bromo-3-methyl-2-pentene, no physical or spectral data for any of the compounds prepared had been published. - 61 -B o i l i n g points were general ly determined during d i s t i l l a t i o n or by using the micro -bo i l ing point method ( S i w o l o b o f f s method) as 33 described in Vogel Infrared spectra were recorded on the Perkin-Elmer model 710 spectrophotometer. Polystyrene was used as the c a l i b r a n t and the samples were run as neat l i q u i d s between s a l t s . The pos i t ion of the desorption was recorded in wavenumbers (cm~^). Proton magnetic resonance spectra were obtained from e i ther the Varian model XL-100 or HA-100 spectrometer. Tetramethylsi lane was used as the internal standard, and carbon te t rach lor ide was used as the solvent . Peaks obtained from the spectra were recorded i n the delta (6) scale . Mass spectra obtained were a l l low reso lu t io n and were run on the Van"an/MAT model CH4B spectrometer. The electron energy general ly used was 70 eV. Combustion analyses obtained were performed by Mr. P. Borda. The adsorbent general ly used for column chromatographic purposes was Shawinigan Alumina (adsorption: 0.550-0.750 mg./gm. of ortho-ni t r o a n i l i n e ) . Cis and Trans Methyl 3-Methyl-2-Pentenoates (XX and XXI) To a s l u r r y of sodium hydride (29.4 g of.50% suspension, 0.60 moles) i n dry 1,2-dimethoxyethane (1.2&) at 0°C - 5°C (ice-water bath) was added trimethylphosphonoacetate (109.3 g , 0.60 moles). At - 62 -the end of the addi t ion (ca. 30 min) the resul tant thick s l u r r y was s t i r r e d (Hershberg s t i r r e r ) at room temperature for a further hour. At t h i s point a so lut ion of 2-butanone (43.6 g, 0.60 moles) in 1,2-dimethoxy-ethane (100 ml) was added at a dropwise ra te . At the end of t h i s addi t ion (ca. 20 min.) the react ion mixture was allowed to s t i r at room temperature for 20 hours at which point water (300 ml) was added. The i aqueous port ion was separated and extracted with ether (3 x 100 m l ) . The organic portions were combined and washed with brine (2 x 100 m l ) , dr ied over sodium sulphate, and the solvents were removed by simple atmospheric d i s t i l l a t i o n . The crude esters were then p u r i f i e d by vacuum d i s t i l l a t i o n (15 torr ) and separated by spinning bond d i s t i l l a t i o n to give the crs ester (XX) (11.6g) i n about 95% isomeric p u r i t y , the trans ester (XXI) (21.0 g) in about 97% isomeric p u r i t y , and a 25:75 mixture of the c i s and trans esters (10.7 g ) . The y i e l d for t h i s reaction was 43.3 g or 56%. The c i s esteg had a b o i l i n g point of 148°C at atmospheric pressure. IR: 1718 (C0CH 3), 1642 ( O C ) . PMR: 1.07 (3H, t r i p l e t , J - 7.5 Hz, C H 3 C H 2 ) , 1.87 (3H, doublet , J = 1.4 Hz, CH 3-C=C), 2.64 (2H, quartet , J = 7.5 Hz, CH 3 CH 2 ) , 3.67 (3H, s i n g l e t , C-0CH 3 ) , 5.64 (IH, m u l t i p l e t , C=C-H). MS: M + 128 (50%), 97 (71%), 28 (100%). A n a l y s i s : ca lculated for ^ H ^ : C, 65.58; H, 9.44; found: C, 65.38; H, 9.37. The trans es^er had a b o i l i n g point of 155°C at atmospheric pressure. IR: 1719 (C-0CH 3 ) , 1646 (C=C). PMR: 1.07 (3H, t r i p l e t , J = 7.5 Hz, CH 3 CH 2 ) , 2.16 (3H, doublet , J = 1.3 Hz, CH3~C=C), 2.18 (2H, quartet , J = 7.5 Hz, C H 3 C H 2 ) , 3.68 (3H, s i n g l e t , C-0CH 3 ) , 5.68 (IH, - 63 -quartet , J = 1.3 Hz, C=C-H). MS: M + 128 (18%), 97 (28%), 43 (100%). A n a l y s i s : ca lculated for C ^ ^ : C, 65.58, H, 9.44; found: C, 65.61; H, 9.41. Trans. 3-Methyl-2-Pentene-l -ol (XXVIII) i ! To a s l u r r y of l i t h i u m aluminum hydride (16.7 g , 0.43 moles) i n anhydrous ether (300 ml) at 0-5°C (ice-water bath) was added a solut ion of the trans ester (XXI) (36.6 g , 0.29 moles) i n anhydrous ether (50 ml) . At the end of the addi t ion (ca. 30 min) the react ion mixture was allowed to s t i r at room temperature for a fur ther 5 hours, at which point the excess l i t h i u m aluminum hydride was decomposed by the cautious addi t ion of water (15 ml) followed by aqueous 10% NaOH (20 ml) and a further port ion of water (50 ml) . The react ion mixture was then f i l t e r e d (Buchner funnel) and the white granular s a l t s were washed thoroughly with ether (200 ml) . The f i l t r a t e was then dried over potash, the solvent was removed by f l a s h evaporation and the crude product was d i s t i l l e d under vacuum (12-20 torr ) to give the p u r i f i e d material (XXVII) as a co lor less l i q u i d . The b o i l i n g point of the alcohol was 160°C at atmospheric pressure. IR: 3356 (OH), 1666 (C=C). PMR: 1.02 (3H, t r i p l e t , J = 7.5 Hz, C H 3 C H 2 ) , 1.68 (3H, broad s i n g l e t , CH 3-C=C), 2.04 (2H, quartet , J = 7.5 Hz, C H 3 C H 2 ) , 4.16 (2H, doublet , J = 7.0 Hz, CH 20H), 5.37 (IH, t r i p l e t of quartets , J = 7.0 & 1.4 Hz, C=C-H). MS: M + 100 (19%), 71 (100%). A n a l y s i s : ca lculated for C 6 H 1 2 0 : C, 71.95; H, 12.08; found: C, 72.20; H, 12.20. - 64 -Cis 3-Methyl-2-Pentene-l-ol (XXII) Treatment of the c i s ester (XX) (36.0 g , 0.28 moles) i n anhydrous ether (300 ml) with l i t h i u m aluminum hydride (16.7 g , 0.43 moles) as above gave the desired c i s a l l y l i c alcohol (XXII) (24.3 g, 0.25 moles) as a co lor less l i q u i d . The b o i l i n g ; p o i n t at atmospheric pressure was 153°C. IR: 3370 (OH), 1667 (C=C). PMR: 1.02 (3H, t r i p l e t , J - 7.5 Hz, CH 3 CH 2 ) , 1.70 (3H, broad s i n g l e t , CH 3-C=C), 2.05 (2H, quartet , J = 7.5 Hz, CH 3 CH 2 ) , 4.01 (2H, doublet , J = 7.0 Hz, CHgOH), 5.31 (IH, t r i p l e t , J = 7.0 Hz, C=C-H). MS: M + 100 (8%), 71 (39%), 31 (100%). A n a l y s i s : ca lculated for CgH^O: C, 71.95; H, 12.08; found: C, 72.15; H, 11.94. Trans 3-0xo-4-Carboethoxy-7-Methyl-6-Nonene (XXX) To a so lut ion of the trans a l l y l i c alcohol (XXVIII) (20.0 g , 0.20 moles) i n anhydrous ether (30 ml) and dry hexamethylphosphoramide (50 ml) under nitrogen was added an ethereal so lut ion of methyl 1ithium (115 ml of a 1.8 M s o l u t i o n , 0.21 mole). This resul tant so lut ion was then added to a cooled mixture (ice-water bath) of methanesulphony! chlor ide (28.6 g, 0.25 moles) and anhydrous l i t h i u m chlor ide (17.0 g , 0.40 moles) in anhydrous ether (200 ml) under ni trogen. At the end of the addi t ion (ca. 35 min) the react ion was s t i r r e d at room temperature for a further 6 hours, at which point the anion of ethyl 3-oxo-pentanoate 27 (prepared from 27.3 g (0.19 moles) of ethyl-3-oxo-pentanoate , 4.37 g - 65 -(0.19 moles) of sodium) in absolute ethanol (150 ml) was added. At the end of the addit ion (ca. 5 min.) the react ion mixture was allowed to s t i r at room temperature for 24 hours. At t h i s point the react ion mixture was concentrated i n vacuo and taken up in water (300 ml) and extracted with l i g r o i n (3 x 125 mis) . The organic portions were combined, washed with water (3 x 40 m l ) , and dried over sodium sulphate. A f t e r removal of the solvents by f l a s h evaporation the remaining mixture was subjected to a vacuum d i s t i l l a t i o n and f i l t r a t i o n through alumina (ca. 300 g) using petroleum ether (65-100) as the eluent . The desired trans g-ketoester (XXX) (20.0 g, 89. mmoles) was obtained as a^colorless l i q u i d . The b o i l i n g point at 30 t o r r was 159°C. IR: 1736 (C-OEt), 1716 ( c = o ) , 1666 (C=C). PMR: 0.95 (3H, t r i p l e t , J = 7.5 Hz, C H 3 C H 2 ) , 161 (3H, broad s i n g l e t , CH 3-C=C), 1.95 (2H, quartet , J = 7.5 Hz, CH 3 CH 2 ) , H 3.28 (IH, t r i p l e t , J = 7.5 Hz, io^Et ^ ' 4 , 9 7 ^ 1 H ' m u 1 t i P l e t > C=C-H). MS: M + 226 {7%), 169 (36%), 123 (100%). A n a l y s i s : calculated for C 1 3 H 2 2 ° 3 : C ' 6 8 - 9 9 ' H> 9-8 0'> f o u n d : c> 68.92; H, 9.82. Cis 3-0xo-4-Carboethoxy-7-Methyl-6-Nonene (XXIV) Treatment of the ci_s a l l y l i c alcohol (XXII) (24 g , 0.24 moles) as above gave the desired c i s (3-ketoester (XXIV) (21.0 g, 93 mmoles) as a co lor less l i q u i d . The b o i l i n g point at atmospheric pressure was li 258°C. IR: 1740 (C-OEt), 1708 ( 0 0 ) . PMR: 0.94 (3H, t r i p l e t , J = 7.5 Hz, CH 3 CH 2 ) , 1.62 (3H, broad s i n g l e t , CH3~C=C), 2.02 (2H, quartet , ' - 66 -J = 7.5 Hz, CH 3 CH 2 ) , 3.23 (IH, t r i p l e t , J = 7.1 Hz) , 4.89 (IH, t r i p l e t , J = 7.1 Hz, C=C-H). MS: M + 226 (15%), 169 (43%), 123 (100%). A n a l y s i s : ca lculated for C ] 3 H 2 2 0 3 : C, 68.99; H, 9.80; found: C, 69.09; H, 9.80. Trans 3-0xo-7-Methy1-6-Nonene (XXXI) j — — — — — — — — — — — — — — — — — — — — — — — — — — — i A mixture of the trans g-ketoester (XXX) (20.0 g, 89 mmoles) and 5% aqueous NaOH (150 ml , 0.19 moles) were s t i r r e d at room temperature for a period of 26 hours. At the end of t h i s time the react ion mixture was washed with l i g r o i n (1 x 30 ml) and made jus t a c i d i c (RH paper) with 3M H 2 S0^. Steam d i s t i l l a t i o n of t h i s mixture was followed by extract ion of the d i s t i l l a t e with l i g r o i n (3 x 100 ml ) . The organic portions were combined, dr ied over sodium sulphate, and the solvents removed by f l a s h evaporation. Subsequent vacuum d i s t i l l a t i o n (12-20 torr ) gave the desired trans ketone (XXXI) (12.0 g , 78 mmoles) as a co lor less l i q u i d . The b o i l i n g point at atmospheric pressure was 206°C. IR: 1712 ( o o ) , 1668 ( O C ) . PMR: 0.94 (3H, t r i p l e t , J = 7.3 Hz, CH 3 CH 2 ) , 1.58 (3H, broad s i n g l e t , CH 3-C=C), 1.94 (2H, quartet , J = 7.3 Hz, CH 3CH 2 ) , 4.97 (IH, m u l t i p l e t , C=C-H). MS: M + 154 (14%), 82 (69%), 55 (100%). A n a l y s i s : calculated for C ^ H ^ O : C, 77.87; H, 11.97; found: C, 77.77; H, 11.60. - 67 -Cis 3-0xo-7-Methyl-6-Nonene (XXV) Treatment of the c i s 3-ketoester (XXIV) (20.0 g, 89 mmoles) as above gave the desired c i s ketone (XXV) (11.8 g, 77 mmmoles) as a co l o r -less l i q u i d . The bo i l ing point at atmospheric pressure was 202°C. IR: 1709 (c*o), 1670 (C=C). PMR: 0.96 (3H, t r i p l e t , J = 7.5 Hz, CH 3CH 2), 1.63 (3H, broad s i ng le t , CH3~C=C), 2.03 (2H, quartet, J = 7.5 Hz, CH 3CH 2), 5.00 (IH, mu l t i p l e t , C=C-H). MS: M + 154 (27%), 82 (93%), 57 (100%). Analys i s : calculated for C 1 f J H 1 8 0 : C, 77.87; H, 11.76; found: C, 78.12, H, 11.52. Trans 7-Methyl-6-Nonene-3-ol (XXXII) To a s lu r ry of sodium borohydride (4.0 g, 105 mmoles) in 95% ethanol (350 ml) was added the trans ketone (XXXI) (16.2 g, 105 mmoles) in 95% ethanol (30 ml). At the end of the addit ion (ca. 20 min.) the reaction was allowed to s t i r at room temperature for a further 3 hours, at which point the ethanol was removed by f la sh evaporation and the resultant residue was taken up in water (100 ml). This resu ltant mixture was then extracted with ether (3 x 75 ml). The combined organic extracts were then washed with brine (2 x 20 ml) and dried over potash. The ether was then removed by f la sh evaporation and the crude product was d i s t i l l e d i n vacuo (23 to r r ) to give the desired trans alcohol (XXXII) (15.7 g, 100 mmoles) as a co lor less l i q u i d . The bo i l i ng point at 23 to r r - 68 -was 114°C. IR: 3360 (OH), 1666 (C=C). PMR: 0.97 (3H, t r i p l e t , J = 7.0 Hz, CH 3 CH 2 ) , 1.60 (3H, broad s i n g l e t , CH 3-C=C), 1.98 (2H, quartet , J = 7.0 Hz, C H 3 C H 2 ) , 3.43 (IH, m u l t i p l e t ,,C(Q H) . 5.09 (IH, t r i p l e t of quartets , J = 7.0 & 1.3 Hz). MS: M + 156 (13%), 138 (19%), 109 (100%). A n a l y s i s : ca lculated for C 1 Q H 2 0 0 : C, 76.86; H, 12.90; found: C, 76.60; H, 12.98. Cis 7-Methy1-6-Nonene-3-o1 (XXVI) Treatment of the c i s ketone (XXV) (4.0 g , 26 mmoles) as above gave the desired c i s alcohol (XXVI) (3.7 g , 24 mmoles) as a co lor less l i q u i d . The b o i l i n g point at atmospheric pressure was 210°C. IR: 3400 (OH). PMR: 0.94 (3H, t r i p l e t , J = 7.2 Hz, CH C H 2 ) , 1.62 (3H, broad s i n g l e t , CH 3-C=C), 2.01 (2H, quartet , J = 7.2 Hz, C H 3 C H 2 ) , 3.44 (IH, m u l t i p l e t , 'cC[jH), 5.01 (IH, t r i p l e t , J = 7.0 Hz, C=C-H). MS: M + 156 (8%), 138 (15%), 109 (100%). A n a l y s i s : ca lculated for C 1 0 H 2 Q 0 : C, 76.86; H, 12.90; found: C, 76.56; H, 12.85. Trans 3-Iodo-7-Methyl-6-Nonene (XXXIII) To a cooled (ice-water bath) so lut ion of iodine (12.7 g , 50 mmoles) i n anhydrous ether (250 ml) under nitrogen was added t r i p h e n y l -phosphite (15.5 g, 50 mmoles) i n anhydrous ether (50 mis ) . At the end of the addit ion (ca. 30 min.) the react ion mixture was allowed to s t i r at room temperature for a further 17 hours. At t h i s point the trans - 69 -alcohol (XXXII) (7.50 g , 48 mmoles) i n ether (25 ml) was added, (ca. 10 min.) and the mixture was allowed to s t i r for a further hour at room temperature at which point the reaction mixture was concentrated i n vacuo to about 1/4 of i t s volume, and eluted through neutral alumina (200 g) using petroleum ether (65-110) as the eluent . Af ter removal of the solvent by f l a s h evaporation the desired trans iodide (XXXIII) (10.2 g, 38 mmoles) was obtained as a co lor less l i q u i d . The b o i l i n g point at atmospheric pressure was 230°C (d). IR: 1668 (C=C). PMR: 0.95 (3H, t r i p l e t , J = 7 Hz, C H 3 C H 2 ) , 1.60 (3H, broad s i n g l e t , CH 3-C=C), 3.96 (IH, mult iplet , ' c^K 5.02 (IH, m u l t i p l e t , C=C-H). MS: M + 266 (26%), 138 (32%), 55 (100%). A n a l y s i s : ca lculated for C 1 Q H l g I : C, 45.13; H, 7.20; found: C, 45.50; H, 7.20. 7-Methyl-3-Nonanol (XXXV ) A solut ion of the trans alcohol (XXXIII) (1.56 g , 10 mmoles) in absolute ethanol (130 ml) was hydrogenated (360 ml H^) at atmospheric pressure in the presence of palladium (10% Pd/C). Af ter f i l t r a t i o n through c e l i t e and removal of the solvent by f l a s h evaporation the residue was eluted through neutral alumina (10 g) using petroleum ether (65-110) as the solvent . Removal of the solvent by f l a s h evaporation y ie lded the desired saturated alcohol (XXXV ) (1.0 g , 63 mmoles as a co lor less l i q u i d . The b o i l i n g point at atmospheric pressure was 206°C. IR: 3400 (OH). PMR: 3.38 (IH, m u l t i p l e t , ,a*j]H). MS: M + 158(0%), 140 (7%), 129 (31%), 59 (100%). A n a l y s i s : ca lculated for C ^ H ^ O : C, 75.88; H, 14.01; found: C, 75.60; H, 13.85. - 70 -3-lodo-7-Methy1-Nonane (XXXVI) The saturated alcohol (XXXV) (600 mg., 3.8 mmoles) was treated with tr iphenylphosphite d i iod ide as before (compound XXXIII) . From th is react ion was obtained the saturated iodide (XXXVI) (804 mg., 3.0 mmoles) as a co lor less l i q u i d . The b o i l i n g point at atmospheric pressure was 224°C. ( d e c ) . P . M . R . : 1.01 (3H, t r i p l e t , J = 7.0 Hz, CH 3 CH 2 ) , 3.97 (IH, m u l t i p l e t , C \ ' J ) . M . S . : M + 268 (2%), 141 (100%). A n a l y s i s : ca lculated for c - | 0 H 2 i 1 : C ' 4 4 - 7 9 ; H, 7.89; found: C, 47.88; H, 8.25. Methylene Derivat ive of a-Thujaketonic Acid (XIII) A mixture of sodium hydride (1.6 g. of a 50% suspension i n mineral o i l , 53 mmoles) and dry dimethylsulfoxide (60 ml) were heated (under nitrogen atmosphere) at 70-80°C. for 45 min. At the end of t h i s time the react ion mixture was allowed to cool to room temperature at which point a so lut ion of methyltriphenylphosphonium bromide (10.5 g . , 29 mmoles) in dry dimethylsulfoxide (50 ml) was added. This mixture was s t i r r e d for a further 10 min. at room temperature and then cooled to near 0°C. (ice-water bath) at which point the sodium s a l t of a - thujaketonic acid (VII) (5.9 g . , 29 mmoles) was added. The resul tant s l u r r y was allowed to s t i r at room temperature for 20 hours at which point i t was taken up i n water (200 ml) and washed with methylene chlor ide (2 x 30 ml ) . The aqueous port ion was then made j u s t a c i d i c with 3M H^SO^ and was extracted with l i g r o i n (3 x 100 ml) . The organic portions were combined - 71 -and washed with water (3 x 30 m l ) , dried over sodium sulphate, and the solvent was then removed by f l a s h evaporation to give the methylene der iva t ive of a-thujaketonic ac id as a pale yel low o i l . The b o i l i n g point at atmospheric pressure was 250°C. IR: 1613 (C=C). PMR: 1.73 (3H, s i n g l e t , CH 3-C=C), 4.54 (IH, broad s i n g l e t , C=C-H), 4.81 (IH, broad s i n g l e t , O C - H ) . MS: M + 182 (48%), 139 (82%), 69 (100%). A n a l y s i s : ca lculated for C ^ H^Og: C, 72.49; H, 9.95; found: C, 72.20; H, 9.91. Isopropylidene Derivat ive of a-Thujaketonic Acid (XIV) Treatment of the sodium s a l t of a- thujaketonic acid (1.9 g . , 9.2 mmoles) with the phosphorane formed from isopropyltr iphenylphos-phonium iodide (3.1 g . , 9.3 mmoles) as described above gave the desired isopropylidene der iva t ive (1.7 g . , 8.1 mmoles) as a l i g h t yel low l i q u i d . IR: 1703 (C=0). PMR: 0.96 (6H, doublet , J = 7.0 Hz) , 1.57 (3H, broad s i n g l e t , C=C-CH 3), 1.64 (3H, broad s i n g l e t , C=C-CH 3), 1.71 (3H, broad s i n g l e t , C=C-CH3). MS: M + 210 (68%), 167 (85%), 121 (100%). A n a l y s i s : ca lculated f o r C 1 3 H 2 2 0 2 : C, 74.24; H, 10.54; found: C, 74.04; H, 10.29. Methyl Ester of the Methylene Derivat ive of a-Thujaketonic Acid (XVII) A mixture of the sodium s a l t of the methylene der iva t ive of a-thujaketonic acid (XIII) (4.5 g . , 22 mmoles) and methyl iodide (3.8 g . , - 72 -27 mmoles) i n hexamethylphosphoramide (40 ml) was s t i r r e d f o r 27 hours a t room t e m p e r a t u r e . A t the end o f t h i s time t h e r e a c t i o n m i x t u r e was poured i n t o w a ter (120 ml) and e x t r a c t e d w i t h l i g r o i n (3 x 60 m l ) . The o r g a n i c p o r t i o n s were combined and washed w i t h a s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n (1 x 25 ml) and w a t e r (3 x 25 m l ) . A f t e r d r y i n g o v e r sodium s u l f a t e and removal o f the s o l v e n t by f l a s h e v a p o r a t i o n , the d e s i r e d methyl e s t e r was o b t a i n e d as a c o l o r l e s s l i q u i d (4.0 g., 20 mmoles). The b o i l i n g p o i n t a t a t m o s p h e r i c p r e s s u r e was 212°C. IR: 1741 ( C - 0 ) , 1645 (C=C). PMR: 1.84 (3H, s i n g l e t , C=C-CH 3), 3.62 (3H, s i n g l e t , 0 C H 3 ) . MS: M + 196 ( 1 1 % ) , 107 ( 6 7 % ) , 69 ( 1 0 0 % ) . A n a l y s i s : c a l c u l a t e d f o r C 1 2 H 2 Q 0 2 : C, 73.47; H, 10.20; f o u n d : C, 73.28; H, 10.20. n - B u t y l E s t e r o f t h e M e t h y l e n e D e r i v a t i v e o f a - T h u j a k e t o n i c A c i d (X)  (R = n - b u t y l , R'=R"=H^ A m i x t u r e o f the sodium s a l t o f the m e t h y l e n e d e r i v a t i v e o f a - t h u j a k e t o n i c a c i d ( X I I I ) (4.4 g., 24 mmoles), n - b u t y l bromide (13.7 g., 100 mmoles), and a c a t a l y t i c amount o f sodium i o d i d e i n h e x a m e t h y l -phosphoromide was s t i r r e d a t room t e m p e r a t u r e f o r 48 h o u r s . A t t h e end o f t h i s t i m e t h e r e a c t i o n m i x t u r e was t r e a t e d as above t o g i v e the d e s i r e d n - b u t y l e s t e r (5.1 g., 21 mmoles) as a c o l o r l e s s l i q u i d . The b o i l i n g p o i n t a t a t m o s p h e r i c p r e s s u r e was 268°C. IR: 1735 (C=0), 1644 (C=C). PMR: 1.74 (3H, s i n g l e t , C=C-CH 3), 3.94 (2H, t r i p l e t , J = 7.0 Hz, 0CH 2- ). MS: M + 238 ( 3 2 % ) , 121 ( 8 3 % ) , 41 ( 1 0 0 % ) . A n a l y s i s : c a l c u l a t e d - 73 -for C 1 5 H 2 6 0 2 : C, 75.58; H, 10.99; found: C, 75.41; H, 10.97. 1-Pentenyl Ester of the Methylene Derivative of a-Thujaketonic Acid (X)  (R = -CH2CH2CH2CM=Crl77 R'=R"=H) ~ A mixture of the sodium sa l t of the methylene der ivat ive of a-thujaketonic acid (4.4 g., 24 mmoles), 5-0-tosyl-1-pentene (5.0 g., 21 mmoles), and a c a t a l y t i c amount of sodium iodide in hexamethylphos-phoramide were s t i r r ed at room temperature for a period of 48 hours. At the end of th i s time the reaction mixture was treated as above to give the desired 1-pentenyl ester (4.6 g., 19 mmoles) as a l i g h t yellow l i q u i d . The bo i l i ng point at atmospheric pressure was 277°C. IR: 1735 (C=0), 1613 (C=C). PMR: 1.76 (3H, s i ng le t , C=C-CH3), 3.97 (2H, t r i p l e t , J = 6.5 Hz, OChy). MS: M + 250 (27%), 121 (82%), 41 (100%). Analys is: calculated for C 1 6 H 2 6 0 2 : C, 76.75: H, 10.47; found: C, 76.48; H, 10.46. Methyl Ester of the Isopropylidene Derivative of a-Thujaketonic Acid (X) (R = R'=R"=CH7P ~~ — — A mixture of the sodium sa l t of the isopropylidene der ivat ive of a-thujaketonic acid (XIV) (4.5 g., 19 mmoles) and methyl iodide (3.27 g., 23 mmoles) in hexamethylphosphoromide (40 ml) were s t i r r ed at room temperature for a period of 24 hours. At the end of t h i s time the reaction mixture was worked up as before giving the desired methyl ester (3.8 g., 17 mmoles) as a co lor less l i q u i d . The bo i l i ng point - 74 -at 0.1 t o r r was 62°C. IR: 1740 (C=0). PMR: 1.53 (3H, broad s i n g l e t , C=C-CH 3), 1.62 (3H, broad s i n g l e t , C=C-CH 3), 1.69 (3H, broad s i n g l e t , C=C-CH 3), 3.72 (3H, s i n g l e t , 0CH 3 ) . MS: M + 224 (37%), 121 (100%), 107 (93%). A n a l y s i s : calculated for C 1 4 H 2 4 0 2 : C, 74.95; H, 10.78; found: C, 74.68; H, 10.72. n-Butyl Ester of the Isopropylidene Derivat ive of a-Thujaketonic Acid  R - n - b u t y l , R'=R"=CHT) ' A mixture of the sodium s a l t of the isopropylidene d e r i v a -t i v e of a - thujaketonic acid (XIV) 4.5 g . , 19 mmoles) and n-butyl iodide (4.2 g . , 23 mmoles) in hexamethylphosphoramide (40 ml) was s t i r r e d at room temperature for a period of 48 hours. At the end of t h i s time the react ion mixture was worked up as before g iv ing the desired n-butyl ester (4.3 g . , 16 mmoles) as a pale yel low l i q u i d . The b o i l i n g point at 0.1 t o r r was 70°C. IR: 1735 (C=0). PMR: 1.52 (3H, broad s i n g l e t , C=C-CH 3), 1.61 (3H, broad s i n g l e t , C=C-CH 3), 1.70 (3H, broad s i n g l e t , C=C-CH 3), 3.92 (2H, t r i p l e t , J = 6.5 H z , ~ C H 2 0 - ) . MS: M + 266 (27%), 121 (62%), 43 (100%). A n a l y s i s : ca lculated for C 1 7 H 3 Q 0 2 : C, 76.64; H, 11.35; found: C, 76.35: H, 11.29. Cis 5-Methyl-4-Heptene- l ,3 -Dioicacid (XLIIIa) To a f resh ly prepared solut ion of sodium ethoxide in ethanol (1.90 g. of sodium, 83 mmoles, in 300 ml of absolute ethanol) - 75 -was added d ie thy l malonate (13.9 g . , 87 mmoles). To th i s s t i r r e d 32 mixture was added a so lut ion of the cis . a l l y l i c bromide (XL 11) (13.5 g . , 83 mmoles) in anhydrous ether (30 ml) . This resul tant mixture was then allowed to s t i r at room temperature for a period of two hours. At th is point the solvents were removed by f l a s h evaporation and the resul tant s l u r r y was taken up in water (100 ml) and extracted with ether (3 x 100 ml) . The ethereal port ion was dried (sodium sul fa te) and the solvent was removed by f l a s h evaporation. The remaining o i l was then treated with an aqueous potassium hydroxide solut ion (180 ml of a 10% s o l u t i o n , 0.33 moles). This mixture was s t i r r e d at room temperature for a period of 20 hours at which point i t was washed with ether (1 x 40 m l ) , made j u s t a c i d i c with sulphuric a c i d , and extracted with methylene ch lor ide (3 x 75 ml) . The organic portions were combined and dr ied (sodium s u l f a t e ) . The solvent was then removed by f l a s h evaporation y i e l d i n g an o i l which c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from 1igroin/benzene gave the c i s d i a c i d (10.2 g . , 55 mmoles) as a white c r y s t a l l i n e s o l i d . The melting point of the d i a c i d was 92-94°C. PMR: 0.97 (3H, t r i p l e t , J = 7.5 H z . , C H 3 C H 2 ) , 1.70 (3H, broad s i n g l e t , C=C-CH 3), 2.08 (2H, quartet , J = 7.5 Hz, CH 3 CH 2 ) , 3.45 (IH, t r i p l e t , J = 7.5 Hz. U - C ^ Q ^ ) , 5.09 (IH, broad t r i p l e t , J = 7.5 H z . , C=C-H). MS: M + 186 (11%), 82 (100%), 55 (53%). A n a l y s i s : ca lculated for C g H ^ O ^ C, 58.05; H, 7.58; found: C, 57.78, H, 7.39. - 76 -Cis 5-Methyl-4-Heptenoic Acid (XLIV) The c i s d iac id (XLI I la) (10.2 g . , 55 mmoles) was placed in a c la i sen f l ask and heated to 140°C in vacuo (12 t o r r ) . A mixture of the monoacid (XLIV) and an isomeric lactone (XLVII) (6.2 g . , 44 mmoles) were co l lec ted as they d i s t i l l e d over (116°C. at 12 t o r r ) . IR (of mixture) : 1725 (C=0 of lac tone) , 1700 (C=0 of a c i d ) . PMR: 1.67 (3H, broad s i n g l e t , C=C-CH 3), 5.09 (IH, m u l t i p l e t , O C - H ) . MS: M + 142 (11%). A n a l y s i s : ca lculated for C g H 1 4 0 2 : C, 67.57; H, 9.92; found: C, 67.32; H, 10.00. Cis 5-Methyl-4-Hepten-l-o1 (XLV) The decarboxylation react ion mixture from above (4.3 g . , 30 mmoles) was treated with l i t h i u m aluminum hydride (1.7 g . , 45 mmoles) in anhydrous ether (50 ml) . This mixture was s t i r r e d at room temperature for a period of 18 hours at which point the excess l i t h i u m aluminum hydride was destroyed by the cautious addi t ion of a 5% aqueous sodium hydroxide so lut ion (4 ml) and water (8 ml ) . The react ion mixture was f i l t e r e d (Buchner funnel) and the white granular p r e c i p i t a t e was washed with ether (3 x 20 ml) . The ethereal portion was dried (potash) and the solvent removed by f l a s h evaporation. The remaining o i l was subjected to a vacuum d i s t i l l a t i o n from which was obtained the desired o l e f i n i c alcohol (XLV) (B.P. 100°C. at 12 t o r r ) (0.96 g . , 7.5 mmoles) - 77 -and a saturated d io l (XLVIII) (B.P. 140°C at 12 tor r ) (2.6 g., 18 mmoles). IR: 3400 cm" 1 (OH). PMR: 0.96 (3H, t r i p l e t , J = 7.5 Hz., CH 3CH 2), 1.66 (3H, broad s ing le t , C=C-CH3), 3.51 (2H, t r i p l e t , J = 7.0 Hz., CH20H), 5.03 (IH, mu l t i p l e t , OC-H). MS: M + 128 (43%), 81 (50%), 55 (100%). Analys i s : calculated for CgH^O: C, 74.94; H, 12.58; found: C, 74.93; H, 12.75. Cis, 1-lodo-5-Methyl-4-Heptene (XXXVIII) (X = I ) . Treatment of the c i s o l e f i n i c alcohol (XLV) (294 mg., 2.3 mmoles) with triphenylphosphite d i iod ide (2.4 mmoles) as before (compound XXXIII) gave the desired c i s o l e f i n i c iodide (328 mg., 1.4 mmoles) as a co lor less l i q u i d . PMR: 0.98 (3H, t r i p l e t , J = 7.5 Hz, CH 3CH 2), 2.64 (3H, broad s ing le t , C=C-CH3), 3.16 (2H, t r i p l e t , J = 6.5 Hz, CH 2 I ) , 5.00 (IH, mu l t i p l e t , C=C-H). Analys is : calculated for C g H 1 5 I : C, 40.35; H, 6.35; found: C, 37.54; H, 5.93. Cis 5-Methyl-4-Heptenetriphenylphosphonium Iodide (XLVI) A solut ion of the o l e f i n i c iodide (XXXVIII) (750 mg. , 3.2 mmoles) and triphenylphosphine (865 mg., 3.3 mmoles) in ethyl acetate (5 ml) was heated at re f lux for 17 hours. At the end of th i s time the reaction mixture was allowed to cool to room temperature, at which point 10 ml of anhydrous ether was added. Decanting o f f of the solvent l e f t behind an amber syrup which c r y s t a l l i z e d as needles - 78 -(940 mg., 1.9 mmoles) upon standing with ethyl acetate. The melting point of the phosphonium s a l t was 148-155°C. PMR: 1.60 (3H, broad s i n g l e t , C=C-CH 3), 3.62 (2H, m u l t i p l e t , ^ C ^ . ) , 5.09 (IH, m u l t i p l e t , C=C-H), 7.85 (15H, m u l t i p l e t , - p * 3 ) . MS: 373 (11%), 372 (10%), 262 (100%). A n a l y s i s : calculated for C 2 6 H 3 Q P I : C, 62.41; H, 6.04; I , 25.36; found: C, 62.65; H, 6.12; I . 25.20. Cis 7-Methyl-6-Nonene-3-Tripheny1phosphonium Iodide (XVIII) To a s l u r r y of c i s 5-methyl-4-heptenetriphenylphosphonium iodide (XLVI) 100 mg., 0.2 mmoles) in anhydrous ether (1 ml) was added (nitrogen atmosphere) a 0.2 M solut ion of n - b u t y l l i t h i u m in ether (1 m l , 0.2 mmoles). This mixture was allowed to s t i r at room temperature for 15 min. at which point a so lut ion of ethyl iodide (31.2 mg., 0.2 mmoles) i n anhydrous ether (1 ml) was added. This mixture was then s t i r r e d for 15 hours at room temperature at which point the solvent was removed in vacuo. The resul tant semisolid material was taken up i n methylene chlor ide (10 ml) and f i l t e r e d . The methylene chlor ide was removed in vacuo and the resul tant syrop was allowed to stand with ethyl acetate (1 ml) from which was obtained the desired phosphonium s a l t (XVIII) as a white c r y s t a l l i n e powder (64 mg., 0.12 mmoles). The melting point of the s a l t was 108-112°C. PMR: 0.94 (3H, t r i p l e t , J = 7.5 Hz, C H 2 C H 3 ) , 1.22 (3H, t r i p l e t , J = 7.0 Hz, CH 2 CH 3 ) , 1.53 (3H, broad s i n g l e t , C=C-CH 3), 4.58 (IH, m u l t i p l e t , ^ C C ^ 3 ) > 5.00 ( IH, m u l t i p l e t , C=C-H). MS: 401 (1.5%), 400 (2%), 262 (100%). References. - 79 -1. V. B. Wigglesworth, Quart. J . Micro S c i . , 77, 191 (1934). 2. C. M. Wi l l i ams , Nature, 178, 212 (1956). 3. H. R o l l e r , K. H. Dahm, C. C. Sweeley, and B. M. Tros t , Angew. Chemie  Intern. E d . , E n g l . , 6, 179 (1969). 4. C. E. Berkoff , Intra-Science Chemistry Reports, 4 , 241 (1970). 5. H. A. Schneiderman, Insect Juvenile Hormones, edited by J . J . Menn and M. Beroza, P .4 , Academic Press, New York, 1972. 6. M. Jacobson, M. Beroza, D. L . B u l l , H. R. Bul lock , W. F. Chamberlain, T . P. McGovern, R. E. Redfern, R. Sarmiento, M. Schwarz, P. E. Sonnet, N. Wakabayashi, R. M. Walters , and J . E. Wright, i b i d . , P. 249. 7. J . F. Grove, R. C. Jennings, A. W. Johnson,and A. F. White, Chem. and  I n d . , 346 (1974). 8. W. S. Bowers, H. M. Fales , M. J . Thompson,and E. C. Uebel, Science, 154, 1020 (1966). 9. V. Cerny, L . Dole j s , L . Lab ler , F. Storm, and K. Slama, Tetrahedron  L e t t . , 1053 (1967). 10. N. Punja, C. N. E. Ruscoe, and C. Treadgold, Nature, 242, 94 (1973). 11. W. L . Roelofs , and A. Comeau, J . Insect P h y s i o l . , 1_7, 435 (1971 ) . 12. S. B. Hyeon, S. Isoe, and T. Sakan, Tetrahedron L e t t . , 5325 (1968). 13. J . G. MacConnell and R. M. S i l v e r s t e i n , Angew. Chem. Internat . E d i t . , 1_2, 644 (1973). 14. M. Beroza, Chemicals C o n t r o l l i n g Insect Behavior, edited by M. Beroza, P. 148, Academic Press, 1970. 15. M. Matsui and I . Yamamoto, Natura l ly Occurring Insec t i c ides , edited by M. Jacobson, and D. G. Crosby, P. 3 , Marcel Dekker, I n c . , New York, 1971 References continued - 80 -16. M. Matsui and T. Ki tahara , Agr. B i o l . Chem., 31_, 1143 (1967). 17. Pr ivate communication with V. Hach. 18. Werner and Bogert, J . Org. Chem., _3, 578 (1939). 19. W. Lee, B.Sc. Thesis , Studies Related to Insect Control Potent ia l of  Thujone Der iva t ives , 1973. 20. J . Thompson, B.Sc. Thesis , Studies Related to Insect Control Potent ia l  of Thujone Der iva t ives , 1972. 21. J . S. Pizey and W. E. Truce, J . Chem. S o c , 865 (1964). 22. R. Greenwald, M. Chaykonsky, and E. J . Corey, J . Org. Chem., 28, 1128 (1962). 23. Pr ivate communication with A. Markus. 24.. J . E. Shaw, D. C. Kunerth, and J . J . Sherry, Tetrahedron L e t t . , 689, (1973). 25. K. H. Dahm, B. M. T r o s t , and H. R o l l e r , J . Amer. Chem. S o c , 89, 5292 (1967). 26. G. S t o r t , P. A. Grieco , and M. Gregson, Tetrahedron L e t t . , 1393 (1969). 27. C. W. Anderson, I. F. Halverstadt , W. H. M i l l e r and R. 0. R o b l i n , J r . , J . Amer. Chem. S o c , 67, 2197 (1945). 28. D. G. Coe, S. R. Landauer, and H. N. Rydon, J . Chem. S o c , 2281 (1954). 29. A. Maercker, Org. Reactions, 14-, 270 (1965). 30. E. J . Corey, J . A. Katzenellenboyen, N. W. Gilman, S. A. Roman, and B. W. Er ickson, J . Amer. Chem. Soc . , 90, 5618 (1968). 31. S. T r i p p e t t , Quart. Rev. , 17.. 406 (1964). 32. K. M o r i , M. Ohki , A. Sato, and M. Matsui , Tetrahedron, 28, 3739 (1972). 33. A. I . Vogel , A Textbook of P r a c t i c a l Organic Chemistry, 3rd e d i t i o n , P. 85, Longmans, London, 1956. 

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