New synthetic methodologies for natural products by William Gerard Bornmann A thesis submitted in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE in Chemistry Montana State University © Copyright by William Gerard Bornmann (1978) Abstract: The orbital symmetry allowed [3.3] sigmatropic rearrangement of enamines derived from 2-acetyl-6-methyl-3,4-dihydro-2H-pyran has allowed for facile entry into highly functionalized cyclohexanone derivatives. This new synthetic methodology offers promise for entry into sesquiterpene natural products. A by-product of this research has led to a symple synthesis of brevicomin, the aggregating sex pheromone of the pine bark beetle, Dendroctonus brevicomis.  /t' ' STATEMENT OF PERMISSION TO COPY In p resen ting t h is th e s is in p a r t ia l f u l f i l lm e n t o f the requirements ■for an advanced degree a t Montana S ta te U n iv e r s i t y , I agree t h a t the L ib ra ry sha l l make i t f r e e ly a v a i la b le f o r in s p e c t io n . I f u r t h e r agree th a t perm ission f o r ex tens ive copying o f t h is th e s is f o r s c h o la r ly purposes may be granted by my major p ro fe sso r , o r , in h is absence, by the D ire c to r o f L ib r a r ie s . I t is understood th a t any copying o r p u b l ic a t io n o f t h is th e s is f o r f in a n c ia l ga in s h a l l not be a llowed w i th o u t my w r i t t e n perm iss ion . S igna ture Date / <77F To my w i fe . Daria NEW SYNTHETIC METHODOLOGIES FOR NATURAL PRODUCTS by . WILLIAM GERARD BORNMANN A th e s is subm itted in p a r t ia l f u l f i l lm e n t o f the requirements f o r the degree • o f MASTER OF SCIENCE in Chemistry Approved: Chairpersonon, Graduate Committee XVvvi Head, Major Department Graduate Dean MONTANA STATE UNIVERSITY Bozeman, Montana December, 1978 -V • iv ACKNOWLEDGMENTS Several people have had a major r o le in. making t h is research study poss ib le and I would l i k e to take t h is o p p o r tu n i ty to thank them. I would e s p e c ia l ly l i k e to thank my parents w i th o u t whose help the comple tion o f t h is th e s is would no t have been made poss ib le . I would l i k e to thank Mr. Chris Evans f o r the expe rt g lass b low ing , and Mrs. K je s t in e Carey o f the L ib ra ry f o r always g e t t in g a much needed book. Special thanks are a lso extended to Mr. Gordon W ill iamson o f Mechanical Engineering f o r lend ing me prec ious equipment and g iv in g h e lp fu l adv ice . I would a lso l i k e to thank my fe l lo w researchers . My spec ia l thanks to Dr. Bradford P. Mundy f o r h is guidance and unending patience w i th my many tangen ts . And, most im p o r ta n t ly , I would l i k e thank my w i fe , D a r ia , f o r her pa t ience , understand ing and u n s e l f is h s a c r i f ic e s which have enable me to achieve. TABLE OF CONTENTS. Page DEDICATION...................... ............................................................................................... i VITA................................... ..................... '............................................................■ . . . i i i ACKNOWLEDGMENTS.................................. i v TABLE OF CONTENTS................................... ................................................... : • v LIST OF TABLES..................................................................■......................................... v i LIST OF FIGURES ......................................................................................................... V i i ABSTRACT. . ........................ x PART I A NEW SYNTHETIC APPROACH TO SESQUITERPENE INTERMEDIATES Chapter 1. HISTORICAL.................................................................................. ..................... I 2. RESULTS AND DISCUSSION. . . ......................................................... .... . H 3. APPLICATION OF THE ENAMINE COPE REARRANGEMENT .......................... 33 ■ 4. FUTURE RESEARCH ...................................................................... 36 5. EXPERIMENTAL. . ...........................■ ....................................38 REFERENCES. , .......................... .............................. . . . . . . . . . . . . 64 PART I I A NEW SYNTHESIS OF BREVICOMIN 1. HISTORICAL........................................... 70 2. RESULTS AND DISCUSSION...................... .............................. ' ....................... 84 3. EXPERIMENTAL........................................... .... . ....................................... 90 REFERENCES. . .............................................................................................................. 102 LIST OF TABLES Table Page vi 1. P r in c ip le Spectroscop ic C h a ra c te r is t ic s o f Reactant and Products .......................................................................... 13 2. Temperature Study o f the P y ro ly s is Cond itions o f The Methyl Imine o f 2 -A ce ty l-6 -M e th y l- 3 ,4 -D ihyd ro -2H -Pyran. . 14 3. P r in c ip le Spectroscop ic C h a ra c te r is t ic s o f Reactants and P roduc ts .......................................................................... 24 4 4. Temperature Study o f . t h e P y ro ly s is Conditions o f the P y r ro l id in e Enamine o f 2 -A ce ty l-6 -M e th y l- 3 ,4-D i hydro-2H-Pyran.............................................................................. 26 v i i LIST OF FIGURES Fi gure ' Page 1. [ 3 ,3 ] S igmatrop ic Rearrangement o f 2 - fo rm y l-2 ,5 - d ih y d ro -4H -p y ra n . . ................................................................................... 2 2. Biichi Synthesis o f S ubs t i tu ted 4 -Ace ty l cyclohexenes . . . . 3 3. L ipkow itz Synthesis o f 2 -A ce ty l-6 -M e th y l-3 ,4 -D ih yd ro - 2H-Thipyran ....................................... 4 4. Proposed Synthesis o f 1 ,2 -D im e thy l-6 - A c e t y l - P ip e r i d i n e ....................................... . . . ........................... 4 5. [ 3 ,3 ] S igmatrop ic Rearrangement o f O -a lT y lhexanolac t im . . . 5 5. Amino [3 ,3 ] S igmatrop ic Rearrangement o f H i l l and Newkom. . 6 7. Thermal S igmatrop ic Rearrangement o f 4 - A l l y l IsopyrazoTe to a P y razo I . . .......................................... 7 8. Eschenmoser1s Synthesis o f y ,s -Unsa tu ra ted Amides .................. 3 9. H i l l and Gilman Synthesis o f N-Methyl- 2 ,2-D imethyl P en t-4 -E nam ine . ....................................... 9 10. [ 3 ,3 ] S igmatrop ic Rearrangement o f the PyrroT id ino Enamine o f Acety l Furan to O-Amino Phenol . . . . . . . . 10 11. P repara tion o f 4 -Ace ty l Cyclohexene and 3 -Acety l Cyclohexanone By the Enamine Cope Rearrangement . . . . . 12 12. Thermal Isome riza t ion o f the Imine to the Corresponding Enamin e . ................................... .... . . . . 16 13. Proposed [ 1 ,3 ] S igmatrop ic Hydrogen S h i f t ............................... . 16 14. Klopman's Proposed Keto-Enol Tau tom er iza t ion ............................... 17 15. Proposed [ 3 ,3 ] S igmatrop ic M ig ra t io n ...............................' . . . . 18 16. Boat T ra n s i t io n S ta te Geometry....................................... 19 17. Geometry o f S -A c e ty l - I - ( I -M e th y l ) Amino Cyclohexene . . . . 20 18. Proposed Hydrogen Bonding . . . . '............................. 21 v i i i 19. Proposed Supraannular E f f e c t ...................................................................... 21 20. P repara tion o f 5 -A ce ty l - I - ( I - P y r r o l i d i n y l ) Cyclohexene by the Enamine Cope Rearrangement Proceeded by Ether A lk y la t io n o r Acid H yd ro ly s is .......................... .... . . 25 21. Proposed [3 ,3 ] S igmatrop ic Rearrangement o f the P y r ro l id in o Enamine o f 2 -Ace ty l-6 -M e thy l-3 ,4 -D ihyd ro -2H -Pyran . . . . 28 22. Geometry o f 5 -A ce ty l - I - ( I -P y r ro l id in y l )C y c lo h e xe n e ................. 29 23. Proposed Synthesis o f 3 -Acety l cyclohexanone by D ie ls -A ld e r Reaction and the Formation o f the Corresponding P y r ro l id in o Enamines....................................... 31 24. Proposed Cope Rearrangement o f the Ace ty l Enol o f 2 -Acety l -6-Methyl - 3 ,4-D i hydro-2H-Pyran............................................ 32 25. Proposed Synthesis o f a-Cyperone......................................................... 34 26. Proposed Synthesis o f 7g,10g Se lin a -4 ,1 1 -D iene ........................... 35 27. General S u b s t i tu t io n Pa tte rn o f Reactants and Products in the Enamine Cope Rearrangement................................... 37 28. Vacuum P y ro ly s is Apparatus...................................................................... 40 29. S i l v e r s t e i n ' s Brevicomin S yn thes is .................................................... 73 30. S i l v e r s t e in 1 s A l te rn a te Scheme.................................................... .... . 74 31. Wasserman Synthesis o f Brevicomin .................................................... 75 32. Improved S i lv e r s te in Synthesis o f B rev icom in ............................... 76 33. Kocienski Synthesis o f Brevicomin .................................................... 77 34. Coke Synthesis o f B rev icom in .............................. 78 35. Mundy Synthesis o f Brevicomin ............................................................. 80 36. Kassanye Synthesis o f B rev icom in .......................................................... 81 37. Sharpless Synthesis o f C yc l ic E the rs ................................................ 82 F igure Page F igure - Page 38. N ico laou Synthesis o f B ic y c l i c Ethers ................................... 83 39. Synthesis o f 2 -P rop iony l-5 -M e thy l-3 ,4 -D ihyd ro -2H -Pyran . . . 85 40. Novel S yn the t ic Approach to B re v ic om in . - ....................................... 87 41. Reaction Mechanism f o r the Formation o f 5 -Me thy l-7 - E th y l -6 ,8 -D io xa b ic y c lo [3 .2 .1 ]o c t -3 -e n e ....................................... 88 42. Reaction Mechanism f o r the Formation o f 5 -Me thy l-7 - Ethyl - 6 ,8-D i oxabi cyc l o [ 3 .2.1 ]o c t -4 -o n e ....................................... 89 IX XABSTRACT The o r b i t a l symmetry a llowed [ 3 .3 ] s igma trop ic rearrangement o f enamines de r ived from 2 -a ce 'ty l-6 -m e th y l- 3 ,4 -d ihyd ro -2H -pyran has allowed f o r f a c i l e e n t ry in to h ig h ly fu n c t io n a l iz e d cyclohexanone d e r iv a t iv e s . This new s y n th e t ic methodology o f fe rs promise, f o r en try in to sesqu iterpene na tu ra l p roduc ts . A by-p roduc t o f t h is research has led to a symple syn thes is o f b rev icom in , the aggregating sex pheromone o f the p ine bark b e e t le , Dendrootonus brevioomis. x i Experimental ideas are o f te n born by chance, w i th the help o f some casual obse rva t ion . Nothing is more common; and th is i s r e a l l y the s im p les t way o f beg inn ing a piece o f s c i e n t i f i c work. We take a w a lk , so to speak, in the realm o f sc ience , and we pursue what happens to p resen t i t s e l f to our eyes. "S e rend ip i ty " Claude Bernard 1865 Part I : A NEW SYNTHETIC APPROACH TO SESQUITERPENE • INTERMEDIATES CHAPTER I HISTORICAL In recen t yea rs , two concepts have emerged in s y n th e t ic method­ o logy ; t h a t o f la t e n t f u n c t io n a l i t y and the use o f h e te ro c y c l ic con- I pounds in o rgan ic s y n th e s is . D. Ledn icer in 1972 q u i te a p t ly v e r b a l iz ­ ed the concept o f l a t e n t f u n c t io n a l i t y as: "One c a r r ie s some necessary fu n c t io n through one o r more steps o f a syn thes is in a precursor form; and a t the proper stage the p recu rso r is converted to the needed g roup ." One could say th a t t h is concept is a more soph is t ic a te d use o f p r o te c t ­ ing groups. The second and the most im po rtan t concept was discussed by A. I . Meyers, and invo lves the use o f h e te ro c y c l ic compounds in o rgan ic syn thes is . By d i r e c t l y app ly ing t h e .p r in c ip le o f la t e n t f u n c t io n a l i t y in a h e te ro c y c l ic s yn the s is , one cou ld , in e f f e c t , design a he te rocyc le which could a l low f o r the in t r o d u c t io n o f a v a r ie t y o f fu n c t io n a l groups o r carbon ske le tons . Thus in s h o r t , Meyers' concept was th a t o f using a he te rocyc le as a p recu rso r o r v e h ic le f o r the syn thes is o f a more complex molecu le. These concepts were r e f le c te d in the s y n th e t ic approach to sub­ s t i t u t e d cyclohexenes taken by Buchi3 ' 4 which was based on the previous work by J. D. Roberts5 and Lu tz t h a t deu te r ium -labe led 2 - fo rm y l- 2 , 5 - d i ­ methyl - 2 , 3 -d ihydro-4H-pyran [1 ] could the rm a l ly isomerize by means o f a [ 3 ,3 ] s igma trop ic rearrangement. A se r ie s o f we ll-p lanned NMR s tud ies c o n c lu s iv e ly demonstrated th a t the a ldehyd ic deuterium CDO labe l ex- 2changed w i th H-6. I t was a lso noted th a t the o p t ic a l a c t i v i t y due to the asymmetric cen te r ( * ) was not l o s t . F igure I . [ 3 ,3 ] S igmatrop ic Rearrangement o f 2 - fo rm y l-2 ,5 - d i hydro-4H-Pyran By d im e r iz ing a ,B -unsa tu ra ted compounds [ 4 ] , Biichi was able to ob ta in acyl d ihydropyrans [ 5 ] which, when fo llowed by a W i t t ig condensa­ t i o n , gave 3 ,4 -d ih yd ro -2H -py rane th y lenes [ 5 ] , These compounds were, in essence, a l l y ! v in y l e thers whose thermal oxy-Cope rearrangement had been p re v io u s ly we ll documented in the l i t e r a t u r e . Jus t as had been expected, these s u b s t i tu te d 3 ,4 -d ihyd ro -2H -pyran e t h y lenes underwent oxy-Cope rearrangements to y ie ld s u b s t i tu te d cyclohexene [7 ] compounds. Such su b s t i tu te d acyl cyclohexenes are not r e a d i ly ob ta inab le from mixed D ie ls -A ld e r reac t ions and, in f a c t , are on ly minor products from these H 2 3 r e a c t io n s . 3R Il 4 0 5 0 6 R 0 7 Figure 2. Biichi Synthesis o f Subs t i tu ted 4 -Ace ty l cyclohexenes Now, in a con t in u in g e f f o r t in t h is la bo ra to ry to r e a l iz e the f u l l im p l ic a t io n s o f t h is work, i t was conceived to s u b s t i tu te d i f f e r e n t heteroatoms f o r the carbonyl oxygen and rearrange them in to the r in g . Thus K. L ip kow itz 7 ' 8 f i r s t made the th ioca rbony l by r e f lu x in g 2 -a c e ty l - 6 -m e thy l- 3 , 4 -d ihydro -2H -pyran in p y r id in e and phosphorous p e n ta su l f id e . Sealed tube p y ro ly s is o f the th io a c e ty l pyran [9 ] y ie ld e d the th ia p y - rany l system [1 0 ] . 4Figure 3. L ipkow itz Synthesis o f 2-A ce ty l-6 -M e th y l-3 ,4 - D ihydro-ZH-Thiapyran Thus, my o b je c t iv e was to a ttempt the next heteroatom, n it rogen The methyl im ine o f 2 -a c e ty l -6 -m e th y l- 3 , 4 -d ihydro -2H -pyran [11 ] was pre pared and was sub jected to cond it io n s o f the Cope rearrangement. The expected product from the p y ro ly s is was the su b s t i tu te d I ,2 -d im e thy -6 - a c e t y l - p ip e r id in e [1 2 ] . O N O I l ^ 12 Figure 4. Proposed Synthesis o f 1 ,2 -D im e th y l-6 -A ce ty l-P ip e r ­ id in e However, t h is was not observed, and ca re fu l ana lys is o f the spec tra l data from the product led to our assignment f o r the s t ru c tu re o f the 5observed compound as 5 -a c e ty l - I - ( I -m e th y l) amino cyclohexene [1 3 ] . A f te r cons ide ra t io n o f a mechanism f o r the re a c t io n , i t became apparent th a t an imine-enamine ta u tom e r iza t ion had f i r s t taken p lace , fo l lowed by a [3 ,3 ] s igmatrop ic s h i f t o r Cope rearrangement. This would account f o r the carbon ske le ton o f the r in g . Thermal isom e r iza t io n o f im ine to enamines have been thorough ly discussed in the l i t e r a t u r e 9 f o r many years . However, the a p p l ic a t io n o f such isom e r iza t io n p r io r to a [ 3 ,3 ] s igmatrop ic s h i f t has received very l i t t l e a t te n t io n . Some in te r e s t in g examples can be poin ted to , however. P y ro ly s is o f 0 - a l I y l hexanolac t im 10 [14 ] gave the 3 - a l l y l - hexanolactam [16 ] in b e t te r than 60% y ie ld . F igure 5. [ 3 ,3 ] S igmatrop ic Rearrangement o f 0 -a l ly lh e xa no la c t im 6R a t io n a l iz a t io n o f t h is re a c t io n sequence was th a t the imine [14 ] had r e a d i ly isomerized to the enamine [1 5 ] . This in te rm ed ia te was then se t up f o r a the rm a l ly -a l low ed [3 ,3 ] s igmatrop ic s h i f t . H i l l and Newkom11 demonstrated th a t when qua te rna ry ammonium s a l ts o f i mines w i th an a lk y l group in the 2 p o s i t io n were converted to the anhydro base (enam ine)[T8 ],they could be then the rm a l ly rearranged to [ 1 9 ] , presumably by a [3 ,3 ] s igmatrop ic s h i f t . F igure 6. Amino [3 ,3 ] S igmatrop ic Rearrangement o f H i l l and Newkom Based on t h i s w o rk ,12 Bramley and Grigg demonstrated th a t 4 , 4 - d ia l I y l - 3 , 5 -d im e thy lpy razo le f i r s t isomerized to the enamine [21 ] and then r e ­ arranged by way o f a [ 3 ,3 ] s igmatrop ic s h i f t to [2 2 ] . 7N - N HN - N HN - N 20 21 22 Figure 7. Thermal S igmatrop ic Rearrangement o f 4 -A l l y l Isopyra - zo le to a Pyrazol Another system in ve s t ig a te d by the same authors was th a t o f 3 - a l l y l i n - doIem ime ketemine [23 ] which f i r s t th e rm a l ly isomerized to the enamine [24 ] and then rearranged to [25 ] by means o f a [ 3 ,3 ] s igmatrop ic s h i f t . To su bs tan t ia te t h is conc lus ion , the enamine [26 ] was prepared (CH3I / NaOH), and thermal rearrangement gave the expected product [2 7 ] . 827 Eschenmoser has employed the method o f t ra n s v in y l e t h e r i f i c a t i o n o f 1- d imethylam ino-1-methoxy-ethene and the d imethyl ace ta l o f N,IVd im e thy l- acetamide as a v i n y la t in g agent. Again note the enamine in te rmed ia te [31 ] which then p a r t ic ip a te s in the ac tua l [ 3 ,3 ] s igmatrop ic s h i f t . + 28 N(CH3)2 OCH3 CH2— ( / \ / (OCH3)2 CH3- C \ N(CH3)2 N(CH3)2 N(CH3)2 31 32 Figure 8. Eschenmoser' s Synthesis o f Y ,6-Unsaturated Amides 9H i l l and Gilman have demonstrated th a t the enamine [33 ] prepared from N-methyl a l ly lam in e and a -d is u b s t i tu te d aldehydes pyro lyzed q u a n t i ta ­ t i v e l y to [34 ] v ia a [ 3 ,3 ] s igmatrop ic s h i f t a t 250° C. M ild h yd ro ly s is o f [34 ] gave the aldehyde [3 5 ] . F igure 9. H i l l and Gilman Synthesis o f N-Methyl-2 ,2 Dimethyl Pent-4-Enamine We now could view our enamine s igmatrop ic rearrangement in terms o f E. J . Co rey 's15 r e t r o - s y n th e t ic ana lys is as: From such ana lys is o f the s y n th e t ic t r e e , i t seems obvious th a t the en­ amine trans fo rm is the key in te rm ed ia te . Thus, the d i r e c t p repa ra t ion and rearrangement o f the enamine was undertaken. The p y r r o l id in e en- 10 amine o f 2 -a c e ty l -6 -m e th y l- 3 , 4 -d ih yd ro pyran rearranged q u i te e a s i ly under the p y ro ly s is c o nd it io n s as be fo re . R e trosyn the t ic ana lys is y ie ld s the obvious conc lus ion th a t the new enamine [41 ] is a lso q u i te a usefu l s y n th e t ic in te rm ed ia te : 40 41 The on ly l i t e r a t u r e analogy to our system was reported by B i r - k o f fe r 16 and Daum in 1962. Here the p y r ro l id in e enamine o f ace ty l fu ran [43 ] was prepared and Cope rearranged to the corresponding o-amino phenol [4 4 ] . F igure 10. [ 3 ,3 ] S igmatrop ic Rearrangement o f the P y r ro l id in e Enamine o f Acety l Furan to o -Amino Phenol CHAPTER 2 RESULTS AND DISCUSSION The N-methyl im ine o f 2 -ace ty l-6 -m e thy l-3 ,4 -d ih yd ro -2H -py ran was prepared by passing methyl amine in to a co ld s o lu t io n o f e the r c o n ta in ­ ing 2 -a c e ty l -6 -m e th y l- 3 , 4 -d ihydro -2H -pyran and mo lecu lar s ieves . F o l­ low ing i s o la t io n and p u r i f i c a t i o n , the methyl im ine [11 ] was vacuum pyro lyzed a t 250° C to y ie ld [15 ] in 66% y ie ld a f t e r d i s t i l l a t i o n . The product o f the p y ro ly s is was assigned the s t ru c tu re [13 ] based on the fo l lo w in g spec troscop ic evidence (Table 1 ) : The in f r a re d spectra shows -I -I the imine C=N s t re tc h 1667 cm and the e the r C-O-C s t re tc h 105.3 cm f o r [ 1 1 ] ; however, the product does no t e x h ib i t a C-O-C s t re tc h nor a “ IC=N s t r e t c h ; however an N-H s t re tc h 3413 cm was observed as we ll as a C=C s t re tc h 1645 cm~^ which is a lso c h a r a c te r is t ic o f a ca rbony l. Sec­ ondary enamines C=C s t re tc h a t 1695 cm~^ was observed. The u l t r a v i o l e t abso rp t ion spectra shows the d i s t i n c t n // S band 231 nm f o r the im ine [ 1 1 ] ; however, the p y ro ly s is p roduct has an abso rp t ion a t 220 nm as w e l l .a s 284 nm. This is in d ic a t i v e o f both a secondary enamine and a carbonyl group presen t as w e l l . NMR spectroscopy confirmed the s t r u c ­ tu re as t h a t o f [1 3 ] by the obse rva tion o f the v in y l hydrogen as a t r i p l e t a t 4.486 which is in e x c e l le n t agreement w i th the observed chemical s h i f t o f the v in y l h yd ro ly s is o f 1 -N -p ip e r id in o cyc lo hex - l-e ne a t 4 .56s , which is a lso observed as a t r i p l e t . Also the methyl group ad jacen t to the carbonyl was observed a t 2.166. Fu r the r s t ru c tu ra l 12 ana lys is was done by chemical deg radation as fo l lo w s . Simple c a t a ly t i c hydrogenation o f [13 ] w i th Pd/C produces the sa tu ra ted amine [45 ] in 82% y ie ld . The qua ternary ammonium s a l t o f [4 5 ] was prepared in e the r and excess methyl io d id e , and t h i s , when fo l lowed by a Hoffman e l im in a t io n w ith potassium te r t - b u to x id e 17 gave 4 -a ce ty l cyclohexene [47 ] in 62% y ie ld . Acid h yd ro ly s is o f [13 ] gave 3 -ace ty l cyclohexanone [36 ] in 72% y ie ld . A temperature versus product study (Table 2) was then c a r r ie d ou t w i th the re s u l ts th a t 250° C was the optimum p y ro ly s is temperature. Temperatures any h igher u sua l ly gave ex tens ive po lym e r iza t ion and a marked decrease in product y ie ld . F igure 11. P repara tion o f 4 -Ace ty l Cyclohexene and 3 -Acety l Cyclohexanone By the Enamine Cope Rearrangement Table I . P r in c ip le Spectroscop ic C h a ra c te r is t ic s o f Reactant and Products In f ra re d Spectroscopy NMR Spectroscopy 11 13 11 13 1667 cm"^ C=N s t re tc h o f im ine 3.076 r n O Il Z \ E oJ 1053 cm ^ C-O-C s t re tc h o f the e the r CH- C 4.486 x N N-H s t re tc h o f secondary enamine 3413 cm '1 CH3-NH 2.686 C=C s t re tc h o f secondary enamine 1645 cm 1 CH3 i " 0 2.166 C=O s t re tc h 1695 cm 1 14 Table 2. Temperature Study o f The P y ro ly s is Cond itions o f The Methyl !mine o f 2 -A ce ty l-6 -M e th y l- 3 , 4-Dihydro-2H-Pyran 11 T ( 0C) % 11* % 13* 5.0 grams 150° C 100% ------ 5.0 grams 175° C 100% 5.0 grams 200° C 81 .6% ,18.4% 5.0 grams 225° C 29.0% 71.0% 5.0 grams 250° C 100% 5.0 grams 275° C — 73.0%** 5.0 grams 300° C ------ 48.2%** *R e la t iv e g lc peak areas o f m a te r ia l is o la te d , ana lys is was done on 10% SE-30 Chromosorb W a t 160° C and peak areas were measured by t r i - angu la t io n . * *Ex tens ive po lym e r iza t ion was observed in the p y ro ly s is tube. 15 In cons ide r ing the re a c t io n mechanism f o r our plan i t was o f i n ­ te re s t to e s ta b l is h the c o n f ig u ra t io n o f the N-methyl im ine as syn or a n t i . Carefu l e va lua t io n o f the NMR18 data es tab l ished the C-methyl group was observed a t a h ighe r f i e l d f o r the a n t i isomer than f o r the syn . This is a lso observed f o r the N-methyl group f o r the a n t i as w e l l ; however, the C-H proton is observed a t a lower f i e l d f o r the an t i isomer than f o r the syn . The coup ling cons tan t f o r the C-methyl group and the N-methyl group is sm a lle r (J = 8.9 Hertz ) f o r the a n t i isomer than f o r the S^ m isomer (J = 1.5 H e r tz ) . The coup ling cons tan t between CH and N-methyl is la rg e r f o r the an t i (J = 8 .9 Hertz) than f o r the Sjm (J = 0.5 H e r tz ) . We can conclude th a t our N-methyl im ine is 92% a n t i and 8% syn . The f i r s t c r i t i c a l step in the rearrangement is the thermal i s o ­ m e r iz a t io n 19 o f the N-methyl ke t im ine [11 ] to the N-methyl enamine [ I IA ] . 16 Figure 12. Thermal Isome riza t ion o f the Imine to the Corres­ ponding Enamine The mechanism f o r t h is is om e r iza t io n can be pos tu la ted to be a [1 ,3 ] s igmatrop ic hydrogen s h i f t . For such a s h i f t to be therma lIy a llowed an a n ta ra fa c ia l m ig ra t io n 203-0 o f the hydrogen on C-j, would have to be accomplished (F igu re 13). F igure 13. Proposed [1 ,3 ] S igmatrop ic Hydrogen S h i f t From the o r b i t a l topo logy diagram, we can see th a t as the n i - p O trogen atom reh yb r id ize s from sp to sp there is a simultaneous rehy- 17 o 2 b r id i z a t io n o f C-I from an sp c o n f ig u ra t io n to sp . Thus as the hydro­ gen is being t ra n s fe r re d from carbon to the n it rogen there is a syn­ chronous isom e r iza t ion o f the double bond from C^=N to Thus the non-bonding p a i r o f e le c tron s on the n i t rogen now becomes a v a i la b le f o r ove r lap w i th the n-system o f the double bond, and could be the d r iv in g fo rce f o r the re a c t io n . Klopman20f has suggested th a t ke to-eno l tautom- erism could p o ss ib ly be a [1 ,3 ] s igmatrop ic s h i f t system in v o lv in g a heteroatom (oxygen) possessing an occupied p - o r b i t a l pe rpend icu la r to the p - ir -p lane . Figure 14. Klopman's Proposed Keto-Enol Tau tomeriza tion 18 One can note th a t in the geometry o f IA severe s t e r i c in te r a c ­ t io n s between the enamine and the methyl group are a t a minimum and th a t c o p la n a r i ty has been mainta ined between the n it rogen and the carbon o f the double bond. The second step o f the rearrangement is a concerted [3 ,3 ] sigma- t r o p ic m ig ra t io n .20' 22 For t h is rearrangement to be th e rm a l ly a l lowed , the re must be a s u p ra fa c ia l - s u p ra fa c ia l over lap o f the p - o r b i t a l lobes (F igu re 15). An o r b i t a l topo logy diagram c le a r ly shows t h is in the cy ­ c l i c six-membered t r a n s i t io n s ta te [ I I B ] . F igure 15. Proposed [3 ,3 ] S igmatrop ic M ig ra t ion We w i l l a lso note th a t in both [ I I A ] and [ I I B ] th a t the ove r lap between the unpaired e le c tron s on the n it rogen and the ir-system o f the double bond are a t a maximum due to the c o p la n a r i ty o f the N and carbon atoms. Thus in a concerted fa sh io n , as the carbons 3 and 3' are rehy- Il-BIl-A 19 b r id iz in g to form the a-bond, carbon I ' and are a lso re h y b r id iz in g o O from sp to sp which w i l l form the ir-system between I ' and 2 1. The in te ra c t io n o f the cen tra l p-lobes o f C -21 and oxygen s l i g h t l y des tab i- 22I i z e the system and c o n t r ib u te to the extreme p y ro ly s is c o nd it io n s . F igure 16. Boat T ra n s i t io n S ta te Geometry Even though the c h a i r - l i k e t r a n s i t io n s ta te geometry is lower in energy due to the quas i-p la na r arrangement o f the s ix p - lobes , i t is a lso s t e r i c a l I y imposs ib le to be a t t a in e d .22,3 Thus the on ly a ccess i­ b le t r a n s i t io n s ta te geometry is th a t o f the boat. 20 Figure 17. Geometry o f 5 -A ce ty l - I - ( I -M e th y l) Amino Cyclohexene Again in the p roduc t, 5 - a c e ty l - I - ( I -m e th y l) amino cyclohexene c o p la n a r i ­ t y has been mainta ined between the n i t rogen atom and the carbons, hence, the ove r lap between the unpaired e le c trons o f the n i t rogen and the / T 23 system o f the double atom is a t a maximum. One would expect th a t the product [13 ] would isomerize again from the enamine to the imine [4 8 ] . However, NMR data does not show [48 ] to be present in app rec iab le amounts ( le ss than 1%). One may be able to r a t io n a l iz e t h is by the fa c t th a t in c e r ta in systems hydrogen bonding may s t a b i l i z e the enamine tautomer24 through in t e r - 21 molecu lar che la te fo rm a tion between the carbonyl oxygen and the NH p ro ­ ton (F igu re 18). This could a lso account f o r the high b o i l i n g p o in t o f the rearranged product [4 8 ] . F igure 18. Proposed Hydrogen Bonding An a l t e r n a t i v e exp lana tion could be a t t r ib u te d to the supraannu- I a r e f f e c t . 25 In our system, the w -e lec trons o f the enamine double bond could in te r a c t w i th the carbonyl group. Thus we would not see the r e ­ ve rs ion back to the methyl imine but ra th e r the s ta b i l i z e d enamine form. 3 F igure 19. Proposed Supraannular E f fe c t 22 To te s t the v a l i d i t y o f t h is rearrangement, o the r examples were examined. The e thy l [51A ], propyl [51B ], and bu ty l [51C] i mines were prepared in the manner p re v io u s ly described and pyro lyzed under the same cond it io n s to y ie ld the corresponding a l k y l amin o -5 -a ce ty lcyclohexene in every case. Acid h yd ro ly s is a lso y ie ld e d the 5 -ace ty I cyclohexanone. The severe disadvantage o f s y n th e t ic a l l y using these compounds would be th a t a l l the a l k y l amin o -5 -a ce ty lcyclohexenes are extremely a i r s e n s i t iv e and have to be s to red under n i t ro gen . Based on the data a lready d iscussed, the s p e c i f i c i t y o f p y ro ly ­ s is could be fu r th e re d by the d i r e c t p repa ra t ion o f the enamine, thus e l im in a t in g the i n i t i a l imine-enamine ta u tom e r iza t io n . A lso , i t would unambiguously e s ta b l is h th a t the fo rm a tion o f the enamine is the key step in the thermal rearrangement. The p y r ro l id in e enamine o f 2 -a c e ty l - 6-m e thy l- 3 , 4-dehydro-2H-pyran [53 ] was formed by gen t ly warming a m ix­ tu re o f the pyran and p y r ro l id in e over molecu lar s ieves . The vacuum p y r ro ly s is o f the re s u l t in g enamines [53 ] under the same cond it ion s p re ­ v io u s ly described provided an e x c e l le n t y ie ld o f the des ired product 23 [4 1 ] . Ins trumenta l ana lys is again v e r i f i e d the s t ru c tu re (Table 3 ) . The in f ra re d spectra o f the i n i t i a l enamine [ 8 ] e xh ib i te d a C=C s t re tc h o f enamine a t 1672 cnf^ and an e the r C-O-C s t re tc h a t 1070 cm \ The rearranged product [4 1 ] d id not e x h ib i t the e the r C-O-C s t r e tc h , however the C=C s t re tc h o f enamine was observed a t 1639 cm" 1 as we ll as the C=O s t re tc h o f carbonyl a t 1698 cm"1 . The u l t r a v i o l e t absorp tion spectra showed an abso rp t ion a t 228 nm f o r [ 8] , however the rearranged product [41 ] g ives two: 227 nm ( c h a ra c te r i s t i c o f enamine) and 281 nm ( c h a ra c te r i s t i c o f the t r a n s i t io n o f a ca rbon y l) . The nuc lea r magnetic resonance spectrum confirmed the s t re tc h as [41 ] by the obse rva tion o f the methyl group ad jacen t to the carbonyl a t 2.146 and a lso the v in y l hydrogen as a t r i p l e t a t 4.286. Simple ac id h yd ro ly s is o f [4 1 ] gave a c e ty lc y c lohexanene [36 ] in 73% y i e l d . A lk y la t io n o f [4 1 ] w i th methyl - iod ide fo l lowed by ac id h yd ro ly s is y ie ld 2 -methy l-5 -acety lcyc lohexanone [40 ] in 76% y ie ld . Note: *Both isomers were observed. Table 3. P r in c ip le Spectroscop ic C h a ra c te r is t ic s o f Reactants and Products In f ra re d Spectroscopy NMR Spectroscopy 53 41 53 41 1070 cm' 1 C-O-C s t re tc h o f the e the r 3.645 CH2— CXN_ 1672 cm" 1 C=C s t re tc h o f the enamine 1639 cm" 1 XcH=cv I 4.285 C=O s t re tc h o f the carbonyl 1598 cm' 1 CHo— C — 3 Ii 2.145 25 Figure 20. P repara tion o f 5 -A ce ty l - I - ( I - P y r r o l i d i n y l )Cyc1o- hexene by the Enamine Cope Rearrangement Proceeded by Ether A lk y la t io n or Acid H yd ro lys is Again, a temperature versus product study (Table 4) was under­ taken w ith the re s u l ts th a t 250° C was the optimum p y ro ly s is temperature which concurs w ith th a t o f the imine rearrangement. Temperatures any h igher gave ex tens ive po lym e r iza t ion and a marked decrease in product j u s t as we observed in the prev ious imine p y ro ly s is (Table I , p. 13). The i n i t i a l fo rma tion o f the p y r ro d id ino enamine cou ld , in theo ry , y ie ld two isomers [53A] and [5 3B ] ; however, on ly [53A] was observed. ,N * 8 O 53-A 53 -B 26 Table 4. Temperature Study o f the P y ro ly s is Cond it ions o f the P y r ro l id in e Enamine o f 2 -A c e ty l - 6-Methy l-3 ,4 -D ihydro -2H -Pyran 53 T ( 0C) % 53* % 41* 5.0 grams 150° C 100% ' ' - - - - 5 .0 grams 175° C 100% — 5.0 grams 200° C 79.0% 21. 0% 5.0 grams 225° C 31.0% 69.0% 5.0 grams 250° C — . 100% 5.0 grams 275° C — 70.0%** 5.0 grams 300° C — 55.0%** *R e la t iv e g lc peak areas o f m a te r ia l is o la te d ; ana lys is was done on 10% SE-30 Chromosorb W a t 160° C peak areas were measured by t r ia n g u la t io n . **Ex tens ive po lym e r iza t ion was observed in the p y ro ly s is tube. 27 This could be r a t io n a l iz e d by the severe s t e r i c in te ra c t io n s between the methylene groups ( * ) ad jacen t to the n i t rogen atom and the coplanar pyran r in g in [5 3B ] . Such in te ra c t io n s are minimized in [53A] wh ile over lap o f the e le c t ro n p a i r on the n i t rogen and the m -e lectrons o f the double bond are maximized by the requ ired c o p la n a r i ty o f the n it rogen o f the n i t rogen and carbon atoms. 23,28 Thus, severe d e s ta b i l i z in g non- bonded repu ls ion a r ise s from the more su b s t i tu te d isomer. This can be f u r t h e r subs tan t ia ted by the reported p repa ra t ion o f the p y r ro l id in e enamine o f ace ty l cyclopentane [53 ] [54 ] e x c lu s iv e ly in the less s u b s t i ­ tu ted isomer [55A] . 29 The mechanism f o r the thermal rearrangement o f the p y r ro l id in e enamine o f 2 - a c e ty l - 6-m e thy l- 3 , 4-d ihyd ro -2H -pyran to 5 -a c e ty l - I - ( I - p y r r o l i d i n y l ) cyclohexene was again env is ioned as a concerted [3 ,3 ] s ig - matrop ic s h i f t o f oxy-Cope rearrangement. 20' 22 For such a rearrangement to be th e rm a l ly a l lowed , the re must be a s u p ra fa c ia l - s u p re fa c ia l over lap o f the in te r a c t in g p -o r b i t a l lobes which can be seen from the o r b i t a l topo logy o f [5 3C ]. 28 Figure 21. Proposed [3 ,3 ] S igmatrop ic Rearrangement o f the P y r ro l id in o Enamine o f 2 -A c e ty l - 6-M e thy l- 3 ,4-D ihydro-2H-Pyran Again , even though the c h a i r - l i k e t r a n s i t io n s ta te geome- t r y 22' 3a' b is c le a r l y favored over the boa t, i t is a lso c le a r once again th a t the c h a i r t r a n s i t io n s ta te is s t e r i c a l l y imposs ib le to be a t ta in ed in [53C ], hence the boat t r a n s i t io n s ta te represents the on ly access ib le pathway. One must note th a t in the rearranged product [ 4 1 ] , the over lap between the e le c t ro n p a i r on the n i t rogen and the e le c tron s o f the ir- system are a t a maximum due to the c o p la n a r i ty o f the n it rogen and the 23 ,28Cyclohexene carbons. S te r ic h indrance between the methylene hydro- 29 gens ad jacen t to the n it rogen ( * ) and the 4 ace ty l cyclohexene r in g are a t a minimum, which s ig n i f i c a n t l y c o n t r ib u te s to the s t a b i l i t y o f the molecule. F igure 22. Geometry o f S -A c e ty l - I - ( I -P y r ro l id in y l )C y c lo h e x e n e In conc lus ion , o f the two systems in ve s t ig a te d , the imine and enamine; the 5- a c e t y l - I - ( I - p y r r o l i d i n y l jcyclohexene is eas ie r to work w i th , a i r s tab le f o r sho r t periods o f time and the y ie ld s are much b e t te r . In s y n th e t ic s t ra te g ie s t h is would be the in te rm ed ia te compound o f cho ice . Another p la u s ib le s y n th e t ic s t ra te g y would be the D ie ls -A ld e r re a c t io n between 2-methoxy bu tad iene -5 ,6 and methy l-3 -bu tene-2-one [5 7 ] ; however, the re would be two products from th is re a c t io n [58A] and [58B] and whether o r not one could separate these is unknown. However, i f one could separate these two components, m ild ac id h yd ro ly s is o f [58A] would g ive the 5 -ace ty l cyclohexanone [5 9 ] . Now the p repa ra t ion o f the p y r r o l - id in o enamine o f 5-a ce ty l cyclohexanone w i l l y ie ld f i v e compounds 41 30 [OOA9B ] , o f which on ly one w i l l be the ta rg e t compound [60A ]. Therefore one can conclude th a t the enamine-Cope rearrangement would be the method o f choice f o r p repa ring compounds o f the na ture because o f the f a c t th a t the enamine f u n c t io n a l i t y w i l l be in the c o r re c t c o n f ig u ra t io n f o r a d d i t io n a l work". I t has been a lso suggested th a t the ace ty l enol [61 ] d e r iv a t iv e could a lso p o ss ib ly be Cope rearranged to g ive [6 2 ] , which then could be a lk y la te d in the 2 p o s i t io n . The shortcomings to t h is could be the f a c t t h a t upon ac id h yd ro ly s is to the ketone [6 3 ] , enamine fo rm a tion w i l l be in d is c r im in a te and y ie ld 6 compounds [64A-F ]. 31 Figure 23. Proposed Synthesis o f 3 -Acety l cyclohexanone By D ie ls -A ld e r Reaction And the Formation o f the Corresponding P y r ro l id in e Enamines 32 Figure 24. Proposed Cope Rearrangement o f the Acety l Enol o f 2 -A c e ty l - 6-Methy l-3 ,4 -D ihydro -2H -Pyran CHAPTER 3 APPLICATION OF THE ENAMINE COPE REARRANGEMENT Re trosyn the t ic a n a ly s is 15 o f the b i c y c l i c sesquiterpenes ske le - to n s30a,b o f the eudesmanes [6 5 ] , eremophilanes [ 66] , and valeranes [67 ] reveal one key in te rm ed ia te [ 68] which m ight serve as a common p recu rso r . For eudesmanes (R = CH3) , and f o r eremophilane (R = H), Robinson anne la t ion o f [ 68] w i th e thy l v in y l ketone w i l l a l low f o r the cons truc ­ t io n o f the basic o c t a lene ske le ton essen t ia l f o r the t o ta l syn thes is31 o f compounds re la te d to the abovementioned carbon ske le tons . Thus, a p p l ic a t io n o f the enamine Cope rearrangement can best be demonstrated 34 by the proposed syn thes is o f a-cyperone [7 4 ] . Robinson anne la t io n 32a,b o f the r e s u l t in g enamine [71 ] would g ive [7 2 ] . S e le c t iv e k e ta l i z a t io n o f oc,0-unsa tu ra ted ketones such as [72 ] w i th o the r ketones present is well-known. Thus the product [73 ] fo l lowed by a W i t t ig condensation would conve rt the ace ty l carbonyl to a methylene group. Hyd ro lys is o f the ke ta l would once again regenerate our a ,B -unsa tu ra ted ketone and thus complete the t o ta l syn thes is o f a-cyperone [7 4 ] . Note th a t the syn thes is is accomplished in f i v e h ig h -y ie ld steps as compared to the syn thes is developed by P iers which was accomplished in e ig h t s teps. Another syn thes is o f a-cyperone by J. K. Roy34 cons is ted o f the Robinson annexation o f dehydrocarvone which gave a reported 3% y ie ld . 74 Figure 25. Proposed Synthesis o f a-Cyperone 35 Another demonstration o f the enamine Cope rearrangement as a usefu l s y n th e t ic too l could be in the proposed syn thes is o f 7AE106 s e l in a -4 ,1 1-d iene . Again Robinson a nn e la t io n 32 o f [7 1 ] w i th e thy l v in y l ketone would g ive [7 2 ] . P re fe re n t ia l k e t a l iz a t io n w i th e th a n e d i th io l33 o f the a ,B -unsa tu ra ted ketone in [ 7 2 ] , fo l lowed by Raney n icke l desu l­ f u r i z a t io n , would y ie ld the unsa tura ted compound [7 5 ] . Subsequent W i t t ig condensation o f [76 ] would g ive [7 7 ] . F igure 26. Proposed Synthesis o f 7AEMNA Se lin a -4 ,1 1-Diene CHAPTER 4 FUTURE RESEARCH Future research in the area o f the enamine-oxy-Cope rearrange­ ment w i l l have to depend on the syn thes is o f va r ious s u b s t i tu te d 2- a c e t y l - 3 ,4 -d ihyd ro -2H -py rans . 36-39 We can e a s i ly see th a t a s p e c i f i ­ c a l l y s u b s t i tu te d pyran p recu rso r w i l l g ive a s p e c i f i c a l l y su b s t i tu te d 5 -a c e ty l - I - ( I - p y r r o l i d i n y l )cyclohexene. Thus we could gene ra l ize the s u b s t i t u t io n pa t te rn in both s ta r t in g pyran [81 ] and rearranged enamine [83 ] as: 37 81 Ra Figure 27. General S u b s t i tu t io n Pa tte rn o f Reactants and Products in the Enamine Cope Rearrangement The re fo re , one could syn thes ize a s p e c i f i c a l l y s u b s t i tu te d pyran which would in tu rn g ive a s p e c i f i c enamine [8 5 ] . Several e x c e l le n t rev iews36,37 have been pub lished which deal w i th the D ie ls -A ld e r reac t ions o f a ,g -unsa tu ra ted carbonyl compound g i v ­ ing 3 ,4-d ih y d ro -2H-pyrans and va r ious o the r fu n c t io n a l groups in the 2- p o s i t io n as ace ty l o r carbomethoxy. One must keep in mind th a t an ace ty l group (methyl ketone) in the 2- p o s i t io n is a p re re q u is i te f o r p y r r o l id in o enamine fo rm a tion and subsequent rearranged p roduct. As we can see, the f u l l p o te n t ia l o f t h is s yn th e t ic technique can on ly be re a l iz e d by the proper development o f the i n i t i a l pyran r in g p recu rso r. CHAPTER 5 EXPERIMENTAL Proton nuc lea r magnetic resonance spectra were recorded on Varian A-60 o r Varian T-60 nuc lea r magnetic resonance Spectrometers. Peak p o s i t io n s are g iven in pa r ts per m i l l i o n downfie ld from t e t r a - methy ls i la n e as an in te rn a l s tandard . Mass spectra f o r both l i q u id and s o l id compounds were ob ta ined from a Varian Model CH-5 mass spec­ trome te r . Glc analyses were c a r r ie d ou t using a Varian Aerograph se r ies 2700 ins trumen t and a l l work was done using a 10' x 3 /8 ' copper column packed w i th 1.5% 0V-101 on Chromosorb G. Gas f low was mainta ined a t 18 m l/sec . In f ra re d spectra were ob ta ined w ith Beckman IR 5A o r IR20 i n ­ f ra re d spectrophotometers. UV spectra were recorded on a Cary 14 r e ­ cord ing spectrophotometer o r on a Varian se r ies 634 U V -v is ib le spec tro ­ photometer. M e lt ing po in ts were performed on a Fisher-Johns hot stage m e lt ­ ing p o in t apparatus and are uncorrec ted . B o i l in g po in ts are uncorrected and reported in mm o f mercury (b .p . 75° C in d ica te s the b o i l in g p o in t was 75° C a t 10 mm o f mercury). Solvents were gene ra l ly removed under reduced pressure v ia Buchi r o ta to r y evapora to r. General Procedure f o r the P y ro ly s is o f !mines and Enamines The vacuum p y ro ly s is cond it io n s f o r e i th e r the imines o r ena- mines were the same. A 15 ml round bottom f la s k was charged w ith the 3 9 i mine o r examine to be pyro lyzed and was placed on the Pyrex p y ro ly s is : 1 ' ■ * - 1 - tube ( Pyrex h e l ic e s ) and the e n t i r e system was evacuated (0 .3 mm o f mercury). The hea ting element (18 fe e t o f r e s is ta n t mi chrome w ire ) f o r I the p y ro ly s is tube was c o n t ro l le d by a Va r iab le Powerstat Transformer. The in te rn a l temperature o f the column was monitored w i th an i ro n -con - s tan tan thermocouple fused in to the wa ll o f the column and the tempera­ tu re was recorded w i th an Omega Type 2809 D ig i ta l Thermometer. When the in te rn a l temperature reached 250° C the hea ting mantle was a c t iv a te d and the imine o r enamine was a llowed to r e f l u x . The crude pyro lyzed product was c o l le c te d in a pyrex U-tube f i l l e d w i th pyrex he l ice s and e x te r n a l ly cooled in a Dewar f la s k con­ ta in in g e i th e r isopropy l a lc o h o l /d ry ice o r i c e / s a l t m ix tu re s . When e i th e r the im ine o r enamine was no longe r present in the 15 ml round bottom f la s k , both trans fo rmers were shut o f f and the system was a llowed to cool down to room temperature. At t h is p o in t the vacuum was broken, and the contents o f the U-tube were removed by f lu s h in g w i th dry hexane. Removal o f t h is so lven t under reduced pressure y ie ld s the p roduct. (Re­ f e r to diagram on fo l lo w in g page .) Prepa ra t io n o f 2 -A c e ty l - 6-M e thy l- 3 , 4-Dihydro-2H-Pyran [ 8 ] As described in the l i t e r a t u r e , 40 methy l-3 -bu tene-2-one 100 grams (1.42 moles) was placed in a s tee l pressure vessel and d imerized a t 185° C f o r fo u r hours. A f te r c o o l in g , the contents were removed and vacuum d i s t i l l e d (water a s p i ra to r ) to g ive a c o lo r le s s l i q u i d , b .p . 40 HOSE TO VACCUUM GLASS WOOL WITH ALUMINUM b FO IL WRAPPING IUND GLASS JOINT TO VAR IABLE POWER TRANSFORMER2 c m D IAMETER PYREX TUB ING TEMPERTURE BATH NICROME WIRE PYREX HELICES 2 cm. X 3 0 cm. PYREX TUBINGASBESTOS TAPE W RAPP ING ' DEWAR FLASK PYREX HELICES TO D IGITAL THERMOMETER TO VARIABLE POWER TRANSFORMER POINTED STOPPER GROUND GLASS JO INT 15 m l. ROUND ' BOTTOM FLASK TO VAR IAB LE POWER TRANSFORMER HEATING MANTLE Figure 28. Vacuum P y ro ly s is Apparatus 41 74° C, 42.5 grams (85% y i e l d ) . nmr data ' Il O 8 Chemical S h i f t ( 6) Number o f Protons Nature o f Peaks 2 4.17 I broad t r i p l e t 3,4 2 .03-1 .56 4 m u l t ip le t 5 4.48 1(7 cps ) m u lt i pi e t 7 1 .73 3 s in g le t 8 2.17 3 s in g le t I . R. ( f i lm ) cm 2874 (C-H s t r e t c h ) ; 1712 (C=O s t r e t c h ) ; 1675 (C=C s t r e t c h ) ; 1429; 1385; 1351; 1279; 1232 (C-O-C s t r e t c h ) ; 1163; 1103; 1070 (C-O-C s t r e t c h ) ; 917.4 ; 894 .5 ; 758.7 (CH==CH s t r e t c h ) . U. V. (hexane) 208 nm (e3.32) 281 ( e l .59) 42 Mass Spectrum m/e ( r e la t i v e in t e n s i t y ■ 140 (37%); 97 (100%); 79 (5.3%); 69 (9.0%); 55 (7.5%); 53 (4.5%); 43 (2.5%); 41 (15.1%). General P repa ra tion o f N -A lky l !mines o f 2 -A c e ty l - 6-M e thy l- 3 , 4-Dihydro Pyrans For the sake o f b r e v i t y we w i l l on ly cons ider in d e ta i l the p repa ra t ion o f the N-methyl im ine o f 2 - a c e ty l - 6-m e thy l- 3 ,4-dehydro pyran [1 1 ] . A l l o the r i mines were prepared in the same manner w i th the id e n t ic a l r e s u l t s . Only t h e i r spec tra l c h a ra c te r is t ic s w i l l be g iven. A s o lu t io n o f 2 - a c e ty l - 6-m e thy l- 3 , 4 -d ihyd ro pyran (19 grams, 0.071 mole) and 100 ml o f d ie th y l e the r con ta in ing 15 grams o f Linde 4 A mo lecu la r41 sieves was cooled to O0 C in an i c e / s a l t ba th . In to t h is s o lu t io n was bubbled 2.48 grams (8.085 moles) o f methyl amine (a 20% excess). The r e s u l t in g s o lu t io n was a llowed to come to room temperature and s t i r o v e rn ig h t , a t the end o f which time the mo lecu la r sieves were f i l t e r e d from the re a c t io n m ix tu re and washed tw ice w i th 25 ml po r t io n s o f anhydrous d ie th y l e th e r . The so lven t was then removed from the com­ bined e the r f r a c t io n s under reduced pressure and the remaining res idue was vacuum d i s t i l l e d (water a sp ira te d ) to g ive 9.72 grams (0.068 mole) 97% b .p . 25) 37° C, a 97% y ie ld , component. Ana lys is by g lc in d ica te d on ly one 4 3 4 Chemical Number Nature S h i f t ( 6) o f Protons o f Peaks 2 4.18 I m u lt i p i e t 3,4 1 .44-2.23 4 muI t i p l e t 5 4.42 I muI t i p l e t 7 I .74 3 s in g le t 8 1 .87 3 s in g le t 9 3.07 3 s in g le t ( f i lm ) cm" 1 1667 (C=N s t r e t c h ) ; 1429; 1379; 1299; 1282; 1235 (C-O-C s t r e t c h ) ; 1163; 1053 (C-O-C s t r e t c h ) ; 917.4; 873.4; 754.7 U.V. (hexane) 231 nm XVvi2R6 Amax. Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 153 (28.2%); 124 (13.6%); 97 (100%); 70 (16.1%); 56 (32.1%); 29 44 (12.4%) N-Ethyl !mine o f 5 -M e th y l-2 -A ce ty l- 3 , 4-D ihydro-2H-Pyran [51 A] 9 Chemical S h i f t ( 6 ) Number o f Protons Nature o f Peaks 2 4.16 I m u l t i p le t 3,4 I .29-2.26 4 m u lt i p i e t 5 4.37 I m u l t i p le t 7 1 .70 3 s in g le t 8 2.15 3 s in g le t 9 3.09 2 qua r te t 10 0.91 3 t r i p l e t I . R. ( f i lm ) cm 2902; 1678 (C=N s t r e t c h ) ; 1660 (C=C s t r e t c h ) ; 1440; 1386; 1238 45 1170 (C-O-C s t r e t c h ) ; 1072 (C-O-C s t r e t c h ) ; 923; 754 U.V. (hexane) 230 nm (e3.47) Xmas. Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 167 (29.3%); 124 (16.1%); 97 (100%); 70 (56.1%); 43 (16.2%) N-Propyl !mine o f 5 -M e th .y l- 2 -A c e ty l - 3 , 4-Dihydro-2H-Pyran [51B] 4 IO 9 46 . Chemical S h i f t ( 6 ) 2 4.14 3 ,4 ,10 I .32-2 .24 5 4.39 7 1 .71 8 2.14 9 2.15 11 0.93 Number o f Protons Nature o f Peaks I m u l t i pi e t 6 m u lt i pi e t I m u lt i p i e t 3 s in g le t 3 s in g le t 3 broad t r i p l e t 3 t r i p l e t I .R . ( f i lm ) cm 2899; 1675 (C=N s t r e t c h ) ; 1664 (C=C s t r e t c h ) ; 1440; 1383; 1236; 1168 (C-O-C s t r e t c h ) ; 1070 (C-O-C s t r e t c h ) ; 920.8 ; 753.0 U.V. (hexane) 232 nm (e3.44) Xmax. Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 181 (31.1%); 124 (14.6%); 97 (100%); 84 (40.1%); 57 (18.8%) N-Butyl !mine o f 2-A c e t y l - 6-M e thy l- 3 , 4-Dih.ydro-2H-P,yran [51C] b - p * (0 .25) 67° C 47 4 7 9 11 12 Chemical S h i f t ( 6 ) Number o f Protons Nature o f Peaks 2 4.12 I m u lt i p i e t 3,4,10,11 I .30-2.25 8 muI t i p l e t 5 4.36 I m u lt i p i e t 7 1 .76 3 s in g le t 8 2.18 3 s i n g le t 9 3.19 2 t r i p l e t 12 0.96 3 t r i p l e t ( f i lm ) cm ^ 2892; 1674 (C-N s t r e t c h ) ; 1665 (C=C s t r e t c h ) ; 1446; 1380; 1167 ( C-O-C s t r e t c h ) ; 1070 (C-O-C s t r e t c h ) ; 921; 756 U.V. (hexane) 236 ntn (e3.40) Xmax. 1236 48 Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 195 (28.6%); 98 (51.2%); 97 (100%); 71 (26.1%) General P repara tion o f S -A c e ty I - I - ( I -A lk y I )A m in o Cyclohexene Again we w i l l on ly descr ibe in d e ta i l the p repa ra t ion o f 5- a c e t y l - I - ( I -methyl Jamino cyclohexene [1 3 ] . The o the r imines which were a lso in ve s t ig a te d (e th y l [5 2 8 ] , propyl [528] and bu ty l [52C]) were ac­ complished in e xa c t ly the same manner, on ly the spec tra l data w i l l be g iven f o r these compounds. Using the general p y ro ly s is procedure, 5.0 grams (0.035 mole) o f [ 11] were placed in the 15 ml round bottom f la s k and fo l low in g the cond it io n s p re v io u s ly descr ibed , p y ro ly s is was i n i t i a t e d . A f te r th ree hours, the apparatus was cooled and the crude p y ro ly s is product was removed, y ie ld in g 4.7 grams o f an a i r - s e n s i t i v e compound which had to be s to red under n i t ro g e n . Ana lys is by g lc suggested on ly one compound p resen t. D i s t i l l a t i o n under high vacuum gave 3.3 grams (9.023 mole) o f [ 1 3 ] , b .p . (Q g) 125° C, 66% y ie ld . (Note: 1.4 grams o f polymerized res idue remained in the d i s t i l l a t i o n f l a s k . ) 9 O 4 9 Chemical S h i f t ( 6 ) Number o f Protons Nature o f Peaks 3 ,4 , 5 ,6 0.84-2.41 7 unresolved m u lt i p i e t 2 4.48 I t r i p l e t 7 2.16 3 s in g le t 8 3.40 I broad m u l t i pi e t 9 2.68 3 doub le t I . R. ( f i lm ) cm 3413 (NH s t r e t c h ) ; 2857; 3268; 1645 (C=C s t r e t c h ) ; 1563; 3086 (C=C-H s t r e t c h ) ; 1695 (C=O s t r e t c h ) ; 1429; 1342; 840 .3 ; 751.9 (C=C) U.V. (hexane) 220 nm (e3.79) 284 nm (el .77) Xmax. Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 153 (28.6%); 123 (16.3%); 110 (100%); 83 (12.6%); 80 (98.2%); 70 (11.8%); 43 (26.8%) 5-A c e ty l - I - ( I - E t h y l )Amino Cyclohexene [52A] b-p- (0 .8) 132° C 50 3 =If T B ^ 8 N H , o > 6 O Chemical S h i f t ( 6) Number o f Protons Nature o f Peaks 3 ,4 , 5 ,6 I .02-2.50 7 mu I t i p l e t 2 4.44 I t r i p l e t 7 2.14 3 s in g le t 8 3.44 I mult i p l e t 9 2.74 2 m u lt i pi e t 10 0.87 3 t r i p l e t I . R. ( f i lm ) cm 3421 (N-H s t r e t c h ) ; 3254; 2850; 1697 (C=0 s t r e t c h ) ; 1637 (C=C s t re tc h o f enamine); 1558; 1428; 134; 844.6 ; 750.1 U.V. (hexane) 222 nm (c3.80) 283 nm ( e l . 71) Xmax. 51 Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 167 (41.6%); 123 (27%); 80 (100%); 70 (21.7%); 44 (33.4%) 5 -A ce ty l - I - ( I -P ro p y l)Ami no Cyclohexene [52B] b‘ p* (0.8) 140° C 3 2 If I4 8 ^ 8 N H IO 6 Il O Chemical S h i f t ( 6 ) Number o f Protons Nature o f Peaks 3 ,4 ,5 ,6 ,1 0 I .08-2.56 9 m u lt i p i e t 9 2.70 2 m u l t ip le t 2 4.45 I mu I t i p l e t 7 2.16 3 s in g le t 8 3.38 I mult i p l e t 11 0.91 3 t r i p l e t I .R . ( f i lm ) cm 3405 (N-H s t r e t c h ) ; 3259; 3094 (=Cx^ s t r e t c h ) ; 2890; 1704 (C=0 52 s t r e t c h ) ; 1643 (enamine C=C); 1408; 1351; 986; 892; 740.9 U.V. (hexene) 223 nm (e3 .77 ) ; 2.81 nm ( e l . 6 8 ) , Xmax. Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 181 (30.6%); 138 (172%); 123 (22%); 80 (100%); 70 (15%); 58 (21.2%); 43 (39.1%) 5-A c e ty l - I - ( I - B u t y l )Ami no Cyclohexene [52C] b-p-(0.8) 146° C 12 IO 5 3 Chemical S h i f t (S) Number o f Protons Nature o f Peaks 3 ,4 ,5 ,6 ,10 ,11 1 .1-2.51 11 mul t i pi e t 2 4.42 I m u l t ip le t 7 2.15 3 s in g le t 8 3.31 I m u l t ip le t 9 2.67 2 m u l t ip le t 12 0.92 3 t r i p l e t I .R . ( f i lm ) cm 3400 (NH s t r e t c h ) ; 3261; 3089 (=Cs ^ s t r e t c h ) ; 1649 (C=C s t re tc h o f enamine); 1562; 1423; 1353; 852; 746.1 U.V. (hexane) 229 nm XVvi2O6N 282 nm ( e l . 8 8 ) , Xmax. Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 195 (36.4%); 152 (16.9%); 123 (21.3%); 80 (100%); 72 (20.6%); 70 (14.2%); 43 (33.2%) Hydroqenolysls o f S -A ce ty l - I - ( I -M e th y l)Am in o Cyclohexene [45 ] 3.0 grams (0.021 mole) o f 5 - a c e ty l - I - ( I -methyl)am ino cyclohexene were d isso lved in a 50 ml o f d ry e th a n o l , to which was added '1 .5 grams o f 10% Pd/C. This e n t i r e m ix tu re was placed in a Parr C a ta ly t ic Hydro­ genation apparatus under a hydrogen atmosphere o f 25 I b s . w i th shaking a t room tempera ture . A t the end o f 24 hours, the contents were removed. 5 4 and the Pd/C was f i l t e r e d and washed tw ice w ith 25 ml p o r t io n s o f dry e th a n o l. The ethanol f r a c t io n s were combined and the so lven t removed under reduced pressure. The remaining res idue was vacuum d i s t i l l e d (water a s p i ra to r ) to g ive 2.46 grams (0.017 mole), b .p . ^23 C (82% y i e l d ) ; g lc a na lys is on 10% SE-30 150° C in d ica ted on ly one component. 3 Chemical Number Nature S h i f t (6) 7 2.16 o f Protons o f Peaks 3 s in g le t 1 , 2 ,3 ,4 ,5 ,6 0 .84-2 .14 10 unresolved m u l t ip le t 9 2.42 3 s in g le t LR . ( f i lm ) cm™1 3333 (NB s t re tc h ) ; 2857; 1701 (C=0 s t r e t c h ) ; 1445; 1346 U.V. (hexane) 284 nm ( e l . 92 ); 201 nm XVv i - 6 , xmax. 55 Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 155 (22.4%); 140 (12.3%); 125 (9.6%); 112 (100%); 97 (14%); 82 (13.3%); 43 (26.1%) Prepara tion o f 4 -Ace ty l cyclohexene [47 ] 2.0 grams (0.013 mole) o f [45 ] was added to a s o lu t io n o f 50 ml o f anhydrous d ie th y l e the r and 2.3 grams (0.016 mole) o f 25% excess methyl io d id e . The s o lu t io n was a llowed to s t i r under N2 atmosphere f o r fo u r hours a t room tempera ture , a t the end o f which time the quaternary ammonia s a l t was c o l le c te d by vacuum f i l t r a t i o n and washed th ree times w ith 25 ml po r t io n s o f anhydrous e th e r . The s a l ts were then added to a s o lu t io n o f 1.45 grams (0.013 mole) o f potassium te r t - b u to x id e in 50 ml o f t e r t - b u t y l a lcoho l a t 80° C w i th s t i r r i n g . A f te r f i v e hours, the s o lu t io n was cooled and e x tra c ted w i th 50 ml po r t io n s o f anhydrous e th e r , d r ie d over anhydrous magnesium s u l fa te , and the so lven t removed under reduced pressure. The remaining res idue was vacuum d i s t i l l e d (water a s p i ra to r ) to g ive a c le a r l i q u i d 1.0 grams, b .p . 75° C, a y ie ld o f 62%. Ana lys is by g lc in d ica te d on ly one compound presen t. 3 O 5 6 Chemical Number Nature S h i f t (6) o f Protons o f Peaks 3 ,4 ,5 ;6 I .12-2.84 7 unresolved m u lt i p i e t L 2 5.64 2 broadened s in g le t 8 2.14 3 s in g le t s trong peaks a t 2.19 and 2.06. I .R . ( f i lm ) cm~^ 2857; 1724; 1429; 1351; 1220; 716 .3 ; 651.6 U.V. (hexane) 180 nm ( VH.0 3 ) ; 284 nm XVviv-R6 , Xmax. Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 124 (22.6%); 81 (59.3%); 70 (33.8%); 54 (29.2%); 43 (100%) General P repa ra tion o f 3 -Ace ty l cyclohexanone [36 ] Since a l l o f the 5- a c e t y l - I - ( I - a l k y l ) ami no cyclohexenes were ac id hydro lyzed to the same p roduc t, 3 -ace ty l cyclohexanone [3 6 ] , on ly the ac id h yd ro ly s is o f 5 - a c e ty l - I - ( I -m e th y l) ami no cyclohexene w i l l be described in f u l l d e t a i l . The p repa ra t io n o f 3 -a ce ty l cyclohexanone was achieved in the fo l lo w in g manner. 3.0 grams (0.019 mole) o f f r e s h ly d i s t i l l e d [13 ] were d isso lved in 50 ml o f a 5% aqueous s u l f u r i c a c id . This e n t i r e s o lu t io n was re f lu xed under a n i t rogen atmosphere f o r 24 hours and the re s u l t in g orange-co lored s o lu t io n was cooled and the benzene la ye r 57 separated. The aqueous la y e r was e x tra c ted tw ice w ith 25 ml po r t ions o f benzene. The combined benzene po r t io n s were washed th ree times w i th 50 ml po r t io n s o f sa tu ra ted sodium b icarbonate and d r ie d over anhydrous magnesium s u l fa te . Removal o f the so lven t under reduced pressure l e f t a res idue which was vacuum d i s t i l l e d (water a s p i r a to r ) , b .p . 124° C, to y ie ld 1.97 grams o f a c o lo r le s s l i q u i d , a y ie ld o f 72%. Ana lys is by g lc showed on ly one compound p resen t. 5 6 4 O 6 O 8 Chemical S h i f t (6) 2.16 Number o f Protons 3 Nature o f Peaks s in g le t 2,3,4,5,6 1 .16-2.48 9 m u lt i p i e t I . R. ( f i lm ) cm 2857; 1701 (CK) s t r e t c h ) ; 1721; 1429; 1351; 1255; 1220; 1163 LI. V. (hexane) 288 nm (e3.70) 58 Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 140 (10%); 97 (61.25%); 69 (37.5%); 55 (40%); 43 (100%); 41 (71.25%); 39 (33.5%) General P repara tion o f P y r ro l id in o Enamine o f 2 -A ce ty l-6 -M e th y l-3 ,4 - D ihydro-^H-Pyran [53 ] 10 grams (0.071 mole) o f 2 -a c e ty l -6 -m e th y l- 3 ,4 -d ihyd ro -2H - pyran were added to 5.5 grams (0.077 mole) o f p y r r o l id in e and 15 grams o f Linde 4A molecu lar s ieves . This m ix tu re was then warmed to 35° C and mainta ined a t t h is tempera ture , w h i le s t i r r i n g under a n i trogen atmosphere f o r 24 hours. A f te r t h i s t ime the re a c t io n m ix tu re was coo led , the molecu lar sieves were f i l t e r e d from the m ix tu re and were washed tw ice w ith 25 ml p o r t io n s o f anhydrous e th e r . The e the r was combined w i th the f i l t r a t e and removed under reduced pressure . The res idue was vacuum d i s t i l l e d to g ive a c o lo r le s s l i q u i d , b .p . 83° C, 12.45 grams, a y ie ld o f 91%. Glc ana lys is suggested th a t on ly one compound was p resen t. nmr data 8 5 9 Chemical S h i f t (<5) Number o f Protons Nature o f Peaks 6 1 .82 3 s in g le t 2,3,10,11 I .42-2.26 8 unresolved m u lt i p i e t 4 4.49 I mu I t i p l e t I 4.24 I m u lt i pi e t 8 2.64 2 doub le t 9,12 2.94 4 unresolved mult i p l e t I .R . ( f i lm ) cm~^ 3078 ((X^ s t r e t c h ) ; 2857; 1672 (C=C s t re tc h o f enamine); 1613; 1287; 1250; 1235; 1166; 1070 (C-O-C s t r e t c h ) ; 950.6; 754.7 (C=C s t re tc h ) U.V. (hexane) 228 n'm (e3.78) Amax. Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 193 (32.3%);. 123 (22.1%); 122 (32%); 97 (100%); 96 (51.2%); 70 (23%) Ana l: Ca lc 'd f o r C-j9H-|gON; C 74.56; H 9.90. Found: C 76.90; H 10.26. P repara tion o f S -A c e ty l - I - ( I -P y r ro l id in y l )C y c lo h e x e n e [41 ] Using the general p y ro ly s is procedure, 5.0 grams (0.025 mole) o f p y r r o l id in e enamine was placed in the 15 ml round bottom f la s k and f o l ­ low ing the cond it io n s p re v io u s ly descr ibed , p y ro ly s is was i n i t i a t e d . 60 A f te r th ree hours the apparatus was cooled and the crude p y ro ly s is product was removed, y ie ld in g 5 grams o f an a i r s e n s i t iv e product which had to be s to red under n i t ro g e n . Glc ana lys is in d ica te d a homogeneous compound, and high vacuum d i s t i l l a t i o n gave 4.3 grams o f a c le a r ye l low l i q u i d , b .p . ^ 135° C, a y ie ld o f 86% a f t e r d i s t i l l a ­ t io n . (Note: 0.61 grams o f polymerized residues remained in the d i s ­ t i l l a t i o n f l a s k . ) 3 Chemical S h i f t (6) Number o f Protons Nature o f Peaks 3 ,4 ,5 ,6 ,9 ,1 0 I .08-2.46 11 m u l t ip le t 2 4.28 I mu I t i p l e t 7 2.14 3 s in g le t 8,11 2.89 4 mu I t i p l e t I . R. ( f i lm ) cm 2890; 1698 (CO s t r e t c h ) ; 1639 (DO s t r e t c h ) ; 1 395; 1351; 1163; 61 754.7; 2082 C==Cxu s t re tc h ) . ’ ; ' . ■ 11 ^ U.V. (hexane) 227 nm (e3.81); 281 nm (el .62), Xmax. Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 193 (21%); 1 7 8 (8 .2% ) ; 150(100% ); 1 08 (6 .3% ) ; 123 (42.6%); 80 (8.9%); 70 (44%); 43 (57.6%) Anal: Ca lc 'd f o r CpH^gNO; C 74.58; H, 9 .90. Found: C 74.68; H5 9.68 Prepara tion o f 3 -Ace ty l cyclohexanone [36 ] 4 .0 grams (0.020 mole) o f f r e s h l y - d i s t i l l e d 5 -a c e ty l - I - p y r r o l i - d ine-rl-cyc lohexene were d isso lved in 50 ml o f dry benzene. The r e s u l t ­ ing s o lu t io n was placed under a n i t rogen atmosphere to which was added 10 ml o f a 5% aqueous s u l f u r i c ac id and re f lu xed f o r a per iod o f 24 hours, a f t e r which the s o lu t io n was cooled and ex tra c ted th ree times w ith 100 ml p o r t io n s o f e th e r . The combined e the r e x t ra c ts were washed th ree times w i th 100 ml p o r t io n s o f sa tu ra ted sodium b ica rbona te , d r ie d over anhydrous magnesium s u l fa te and the so lven t removed under reduced pressure. The remaining res idue was vacuum d i s t i l l e d (water a s p i ra to r ) to g ive a c o lo r le s s l i q u i d , b .p . 124° C, 2.11 grams, a y ie ld o f 73%. Spectra was id e n t ic a l to th a t p re v io u s ly d iscussed. 62 Prepara tion o f 2 -Methy l-5 -Acety lcyc lohexanone [40 ] 3 .0 grams (0.015 mole) o f 5 - a c e ty l - I -p y r ro l id in e -1 -c yc lo hexene were d isso lved in 50 ml o f d ry benzene, and the e n t i r e s o lu t io n was placed under a n i t rogen atmosphere. While s t i r r i n g , 2.12 grams (0.015 mole) o f methyl io d ide were in je c te d over a period o f 1/2 hour. The re s u l t in g m ix tu re was then allowed to r e f lu x fo r 24 hours, a t the end o f which time 10 ml o f aqueous 5% s u l f u r i c ac id was added. The r e s u l t in g s o lu t io n was f u r t h e r re f lu xed f o r an a d d i t io n a l f i v e hours to a f f e c t h y d ro ly s is . The re s u l t in g orange-co lored s o lu t io n was cooled and e x tra c ted th ree times w i th 100 ml p o r t io n s o f e the r . The combined e the r e x t ra c ts were washed th ree times w i th 100 ml p o r t io n s o f sa tu ra ted sodium b ica rbona te , d r ie d over anhydrous magnesium s u l fa te and the e the r removed under reduced pressure . The r e s u l t in g residue was vacuum d i s t i l l e d to y ie ld a c o lo r le s s l i q u i d , b .p . ^ 131-132° C, 1.81 grams (76%). Glc ana lys is in d ic a te s on ly one compound presen t. n ^ \ / 5\ 7 / 8 U 6 Il O 63 \ Chemical Number . Nature S h i f t (6) o f Protons o f Peaks 8 2.18 3 s in g le t 9 0.92 3 m u lt i pi e t (both isomers present) 3 ,4 ,5 ,6 ,2 1 .12-2.55 8 m u lt i pi e t ( f i lm ) , cm""^ 2924; 1712-1689 (C=O s t r e t c h ) ; 1456; 1429; 1359; 1266; . 1176; 965.3 U.V. (hexane) 290 nm (s3 .72) Xtnax. Mass Spectrum m/e ( r e la t i v e in te n s i t y ) 43 (100%); 55 (72%); 96 (65.6%); 111 (57.8%); 139 (15.6%); 154 (19.6%) Ana l: Ca lc 'd f o r CgH-j^Og; C, 70.10; H, 9 .14 . Found: C, 69.-82; H, 8.53 N REFERENCES REFERENCES K • D. Ledn ice r , "La ten t F u n c t io n a l i t y in Organic S y n t h e s i s Advances in Organic Chem is try , V o l . 8 , E. C. Tay lo r (E d . ) , W iley I n te r - sc ience , New York (1972), p. 179. 2. A. I . Meyers, Heterocycles in Organic S yn thes is , J. W iley , 1974. 3. G. Buchi and J. E. Powe ll, J r . , OFP Am. Chem. Soc. , 89 , 4559 (1967). 4. G. Buchi and J. E. Powe ll, J r . , J^ Am. Chem. Soc. , 92 , 3126 (1970). 5. R. P. Lutz and J . D. Roberts, J^ Am. Chem. Soc. , 83 , 2198 (1961 ) . 6. D. L. Dalrymple, I . L. Kruger and W. N. White, The Chemistry o f the Ether L inkage, S. Patai (E d . ) , W iley In te rs c ie n ce , New York (1967), p. 644. 7. K. B. L ip kow itz , Ph.D. Thes is , Montana Sta te U n iv e r s i t y , 1975. 8. K. B. L ipkow itz and B. P. Mundy, T e t . L e t t . , in press. 9. a. R. W. Layer, "The Chemistry o f !m ines ," Chem. Rev. , 63 , 489 (1963). b. J. P. Ans lerne. The Chemistry o f the Carbon-Nitrogen Double Bond, S. Patai (E d . ) , W iley In te rs c ie n ce , New York (1969). c. R. A. C lark and D. C. Parker, J. Amer. Chem. Soc. , 93 , 7257 (1971). d. H. Ah lb rech t and S. F ische r , T e t . , 29, 659 (1973). e. H. Ah lb rech t and G. Papke, T e t ., L e t t . , 4443 (1972). f . H. Ah lb rech t and S. F ische r , T e ix , 2&_, 2836 (1970). g. H. Ah lb rech t and S. F ische r , T e t . , 30, 2571 (1974) h. H. Qust and A. Heuble in , Chem. B e r . , 108, 2574 (1974). 10. D. S. Black and A. M. Wade, Chem. Comm., 871 (1970). 11. R. K. H i l l and G. R. Newhom, T e t . L e t t . , 5059 (1968) 12. R. K. Bramley and G. G rigg , Chem. Comm. , 99 (1969). 6 6 13. D. F e l ix , K. Gschwend-Steen, A. E. Wick and A. Eschenmeser, Helv. Chim. A c ta , 52^ , 1030 (1969). 14. R. K. H i l l and N. W. Gilman, l e t . L e t t . , 1421 (1967). 15. a. E. J. Corey, R. D. Cramer and W. Howl, J . Amer. Chem. Soc., 94, 440 (1972). b. E. J. Corey, R. D. Cramer and W. Howl, J. Amer. Chem. Soc., 94, 431 (1972). 16. L. B i r k o f f e r and D. Daum, Chem. Be r. , 95 , 183 (1962). 17. D. E. Pearson and C. A. Bueh le r , "Potassium Te r t-B u to x ide in S yn thes is ," Chem. Rev. , 74, 45 (1974). 18. D. Y. C u r t in , E. J. Grubbs, C. G. McCarty, Amer. Chem. Soc. , 88, 2775 (1966). 19. W. B. Jenninqs and D. R. Boyd, J . Amer. Chem. Soc., 94, 7187 (1971). 20. a. R. B. Woodward and R. Hoffman, The Conservation o f O rb i ta l Symmetry, Academic Press, New York (1971). b. T. L. G i l c h r i s t and R. C. S to r , Organic Reactions and O rb i ta l Symmetry, Cambridge U n iv e rs i t y Press, New York (1972). c. I . Fleming, F ro n t ie r O rb i ta ls and Organic Chemical Reactions, John W iley , New York (1976). d. K. F u k i , Theory o f O r ie n ta t io n and S te re o -S e le c t io n , Sp r inger- Ve r lag , New York (1975). e. J. E. Baldwin and R. H. Fleming, J_. Amer. Chem. Soc. , 94, 2140 (1972). f . G. K. Klopman (E d . ) , Chemical R e a c t iv i t y and Reaction Paths, John W iley and Sons, New York (1974), p. 129. 21. W. J. LeNoble, H ig h l ig h ts o f Organic Chemistry , Marcel Dekker, New York (1974). 22. a. S. J. Rhoads and N. R. Raul in s , Org. Reactions, 22_, I (1975). 6 7 22. b. M. J. S. Dewar and L. E. Wade, J r . , J. Amer. Chem. Soc., 95, 290 (1973). •c. ■ M. J. S. Dewar and L. E. Wade, J r . , J. Amer. Chem. Soc., 99, 4417 (1977). 23. W. D. Gurowitz and M. A. Joseph, J_. Org. Chem. , 32, 3289 (1967). 24. a. G. 0. Dudek and R. H. Holm, Amer. Chem. Soc. , 83 , 2099 (1963). b. G. 0. Dudek and R. H. Holm, J_. Amer. Chem. Soc. , 83 , 2914 (1963). 25. a. Y. A. Ovchinnkov and G. P. Kugatwa-Shemyakina, J e t . , 23, 697 (1962). b. G. M. N iko laev and G. P. Kugatwa-Shemyakina, l e t . , 23, 2987 ' (1967). c . G. M. N iko laev and G. P. Kugatwa-Shemyakina, T e t . , 23^ , 2721 ■ (1967). 26. A. DeSavignac and A. L a t , Comptes Rendus, Series C, 277, 1367 (1973). 27. E. F. Mooney (E d . ) , Annual Review o f MMR Spectroscopy, V o l . I , Academic Press, New York (1970). 28. a. A. G. Cook, Enamines: Syn thes is , S tru c tu re and Reactions, Marcel Dekker, New York (1969). b. S. F. Dyke, The Chemistry o f Enamines, Cambridge U n iv e rs i ty Press, New York (1973). 29. D. J. Dunham and R. G. Lawton, J_. Amer. Chem. Soc. , 93 , 2074 (1971). 30. a. T. K. Devon and A. I . S c o t t , Handbook o f N a tu ra l ly Occurring Compounds, V o l . I I , Academic Press, New York (1972). b. Ko ji Nakanishi and T is h io Goto, Natural Products Chemistry , . V o l . I , Academic Press, New York (1974). 31. J. ApSimon, The Tota l Synthesis o f Natural P roduc ts , V o l . I I , W iley In te rs c ie n ce , New York (1973). 68 32. R. M. Coates and J. E. Shaw, J_. Orq. Chem., 35, 2597 (1970). 33. E. P iers and K. F. Cheng, Can. Chem., 46, 377 (1968). 34. J. K. Roy, Chem. and In d . , 1393 (1954). 35. K. K le in and W. Rojahn, l e t . L e t t . , 279 (1970). 36. G. Desemoni and G. Taccon i, "Heterodiene Synthesis w i th a,B- Unsaturated Compounds," Chem. Rev. , 75, 651 (1975). 37. "a,B-Unsaturated Carbonyl Compounds as D ienes," J. Colonge and G. Descotes, 1 ,4 -C yc loadd it io n Reactions, Jan. Hamer (E d .) , Academic Press, New York (1967). 38. B. P. Mundy, K. B. L ipkow itz and G. W. D irk s , H e te rocyc les , 6_, 51 (1977). 39. B. P. Mundy, K. B. L ipkow itz and G. W. D irk s , "C yc loadd it ion Reactions Leading to Pyran D e r iv a t iv e s , " (subm it ted ) . 40. K. A ld e r , H. Offermanns and E. Ruder, Chem. B e r . , 74^ , 905 (1941 ) . 41. K. Taguchi and F. H. Westheimer, J_. Org. Chem. , 36, 1570 (1971 ) . A MEW SYNTHESIS OF BREVICOMIN Chapter I HISTORICAL The western pine bark b e e t le , Dendvoaotonus b ve v ia om is , has been respons ib le f o r mass d e s t ru c t io n o f the ponderosa pine in both the United States and Canada. The invas ion and eventual d e s tru c t io n o f the t ree by D. bvev iaom is occurs in two phases. In the f i r s t , an i n i t i a l a t ta ck is made by a few bee tles which bore in to the t ree and cons t ru c t a n up t ia l chamber. In t h is per iod o f a c t i v i t y , they expel f r a s s , a m ix tu re o f feca l p e l le ts and wood fragments . The frass con­ ta in s a t h i r d component, a sex pheromone^ which in tu rn t r ig g e rs the secondary massive invas ion which undoubtedly k i l l s the t re e . In 1968, S i l v e r s t e in 2 and coworkers is o la te d 2 mg o f the aggre­ ga t ing sex pheromone o f D. bvev iaom is from 1.6 kg. o f f ra ss and reported the s t ru c tu re as e x o -7 -e th y l -5 -m e thy l- 6 ,8 -d io x a b ic y c lo [3 .2.1 ) - octane ( I ) o r exo-brev icom in . 71 Because one could a c tu a l ly use exo -b rev icom in f o r the mani­ p u la t io n o f the mating hab its o f D. bvev ioom is one could p o te n t ia l l y p rov ide the Forest Serv ice w ith an e c o lo g ic a l ly advantageous means o f popu la t ion c on t ro l f o r t h is s p e c i f i c in s e c t . I t is in te r e s t in g to note th a t there are no e f fe c t i v e means o f c o n t r o l l in g D. b re v ioom is up to t h is p o in t . Thus, a t te n t io n was then turned toward the to ta l syn thes is o f brevicomin because o f the obvious i s o la t io n problems, e s p e c ia l ly in la rge q u a n t i t ie s . 3 As Mundy has po in ted ou t in a recen t rev iew , r e t r o - s y n th e t ic ana lys is o f the 7 -e th y l -5 -m e th y l -6 ,8 -d io x a b ic y c lo [ 3 .2 .1 ] octane r in g ske le ton revea ls two poss ib le routes f o r the cons tru c t io n o f the ke ta l moiety o f t h is molecule. In rou te [ a ] , the s y n th e t ic s t ra te g y demands the cons tru c t io n 72 i o f a molecule w i th ketone and g lyco l f u n c t io n a l i t y , w h i le rou te [b ] cons is ts o f the cons tru c t io n o f a d ihydropyran c a rb in o l . 4In 1969, S i lv e r s te in pub lished the f i r s t syn thes is o f b re v i- comin in which the s y n th e t ic s t ra te g y cons is ted o f the p repa ra t ion Of the e thy lene ke ta l (3J o f 6^bromohexane-2-one ( 2 ) , fo l low ed by t r e a t ­ ment w i th t r ip h e n y l phosphine to y ie ld the phosphomiurn s a l t (4 ) . Con­ densation o f (4) w i th p ro p inonaldehyde y ie ld e d a m ix tu re o f c is and trans non-6-ene-2-one e thy lene ke ta l (5^), which upon t rea tmen t w ith m-chloroperbenzoic ac id gave the c is and trans epoxides (6) which were separated by g lc . H yd ro lys is gave the in te rm ed ia te d io l (7) which c losed to the b i c y c l i c k e ta l . 73 o ^ r - \ r ~ \Q CH3-C-(CH2)4-Br H° ° H' H% CH3-C-(CH2)4-Br CH3-C^(CH2)4-P +O3 r n o -----------> CH03-C-(CH2)3-CH-CH-CH2(C3 3 m-C'C6H4C0?- ^ CH3-C-(CH2)3CH-CH-CH2(C3 3 2 . ) CH 3 - C H 2 -C H O 3 ^ 3 H 2 SO4 Z H 2O ----------------> CH3-C -(C H2)3-CH-CH-CH2(C 3 3 A c e t o n e L I OH » 1 Figure 29. S i l v e r s t e in 's Brevicomin Syn thes is . An a l t e r n a t i v e approach taken by S i lv e r s te in invo lved the ac id h yd ro ly s is o f 2 -ace ty l bu ty ro la c tone ( 8 ) , which when fo l lowed by k e t a l - iz a t io n gave 5-bromopentan-2-one, e thy lene ke ta l (9) in 60% y ie ld . Treatment o f 9 w i th NaZNH3 and 1-butyne gave the non-6-yn-2-one e t h y l ­ ene ke ta l in 16.7% y ie ld . This was reduced w i th n ic ke l t e t r a ­ aceta te and sodium borohydride to g ive c is -non -6 -ene-2 -one ethylene ke ta l (2) in 80% y ie ld . 7 4 o \\ x o y ^o 8 1. ) HBr1 H2O 2 . ) H (T l)H , H+ o H , CH3-C -C H2-C H2-CH2-Br No, NH3 CH3CH2C=CH^ 9 ^ r\ Ox O H2 l Ni-(OAc)4 ° x ^ CH3-C -(CH 2)3-C = C -C H2-CH3 — ------> CH3(C (XC ) —6v(C) / C)(C 3 2-CH3 IO Figure 30. S i l v e r s t e in 's A l te rn a te Scheme. 5 Working along the same l i n e s , Wasserman and coworkers a l k y l ­ ated ace toace t ic e s te r w ith c is - 1 -bromo-3-hexene (TJJ wh ich, fo l lowed by s a p o n i f ic a t io n and deca rboxy la t io n , gave c is -non -6 -ene-2 -one (12). The ketone ( I jH was t re a ted w i th m-chloroperbenzoic ac id to g ive the c is -epox ide ( U ) which upon sealed tube p y ro ly s is a t 210°C gave b re v i - comin in a 95% y ie ld : w i th an exo/endo r a t i o o f 90:10. + CH3-^ - C H 2-H -O C H 2CH3 Br I l 75 -> ( I ) 90% Exo I 0 % Endo Figure 31. Wasserman Synthesis o f B re v icomin. S i lv e r s te in 6 and coworkers, in 1971, were able to g re a t ly improve t h e i r o r ig in a l syn thes is by the conversion o f c i s -3 -hexene - l-o l (14) to i t s to s y la te e s te r (15J , which was used to a lk y la te e thy l ace toace ta te . Th is , fo l lowed by ac id h yd ro ly s is and deca rboxy la t ion y ie ld e d (1 2 ) , c is -6 -n o n e n e -2 -o l , in 37% y ie ld . Treatment o f 12 w i th m -ch loroperbenzo ic ac id in benzene a t 15°C gave c i s-6,7-oxedononan-2- one, which in tu rn was re f lu xed in benzene to g ive I a 55% y ie ld (95% o f which was exo and 5% endo). 7 6 C3 3-C H 2-CH = CH-(CH2)2-OH 14 TtC I 8 0% CH3-CH2-CH=CH-(CH2)2 OTs 15 C H 3 - C - C H 2 - C - O E l IN NoOH 3 7 % OH , r e f l u x OIl 12 Figure 32. Improved S i lv e r s te in Synthesis o f Brevicomin. In 1976, P. L. Kocienski and R. W. Ostrow7 pub lished ye t another syn thes is o f brevicomin based on the ketone d io l synthon developed by S i ! v e rs te in . The Eschenmoser fragmen ta t ion o f the epoxy ketone (15) y ie ld e d R I K e ta lyza t ion o f 1_5 gave the S i lv e r s te in in te rm ed ia te , 6-nonyn-2-one e thy lene k e t a l , (10 ) . Reduction o f the a ce ty le n ic ke ta l (10) by BH3 -Me2S fo l lowed by p ro tona t io n gave the S i lv e r s te in i n t e r ­ mediate, c is -non -6 -ene -2 -one , ( 5 ) . S te re o spe c i f ic ac id cleavage o f the c is epoxide (6) w i th concomitant h yd ro ly s is o f the ke ta l gave the keto d io l in te rm ed ia te , (7 ) . 77 O Ii :o 15 P-Ts-NHNH2 ----------------- > CH2CI2 , HO-Ac CH3-C(CH2)3-C iC -C H2 -CH3 0 16 Figure 33. Kocienski Synthesis o f B re v icomin. The S i lv e r s te in in te rm ed ia te was s t i l l to be used in another 78 syn thes is o f brevicomin in 1977 by Coke^, which cons is ted o f the a l k y la ­ t io n o f 1 ,3-cyclohexanedione w ith e thy l iod ide to g ive 2 - e th y l - 1 ,3- cyclohexanedione, which when fo llowed by trea tment w i th phosphorous t r i c h lo r i d e y ie ld e d the c h lo r id e (17 ) . Treatment o f YJ_ w i th methyl- l i t h iu m , fo l lowed by p y ro ly s is , g ives 16. This a ce ty le n ic ketone was reduced to the c is o le f i n w i th 10% pa llad ium on barium s u l fa te . T re a t ­ ment o f 12 w i th m-chloroperbenzoic ac id y ie ld e d the S i lv e r s te in i n t e r ­ mediate, (13 ) ; wh ich, when heated a t 21O0C gave both exo and endo brevicomin in a 9:1 r a t i o . O Il CH % - C - (CHg)^-CEC-CHg-CH^ 16 _Ha______ Pd(BaSO4) O CH3 -H -(C H g)3-CH = C H -C H g -C H 3 12 Fn-ClC6H4CO3H CH2CI2 ( I ) Figure 34. Coke Synthesis o f Brevicomin. 7 9 Now tu rn in g our a t te n t io n to the second r e t r o s y n th e t ic rou te , b, H. C. Brown^ provided the i n i t i a l s y n th e t ic impetus in a paper pub­ l is h e d in 1970, in which c y c l i c e thers were cons truc ted from unsatu­ ra ted a lcoho ls v ia o rgmercu ra t ion /demercu ra t ion . 1. ) Hg(OAc)2 > 2 . ) OH- ZNoBH4 r n 3 The mechanism f o r t h is re a c t io n was thought to proceed along the l in e s o f f i r s t e l e c t r o p h i l i c a t ta c k by the mercu riace ta te ca t ion to form the in te rm ed ia te c y c l i c mercurinium ion which then undergoes subsequent in t ram o le cu la r n u c le o p h i l ic a t ta ck o f the hydroxyl group. Demercuration and dep ro tona tion gave a f i ve-membered c y c l i c e the r . In a se r ie s o f papers f i r s t pub lished in 1971 Mundy^ demon­ s t ra te d a th re e -s te p syn thes is o f brev icom in . The s y n th e t ic s t ra tegy developed from the -n j*s + Trg2 c y c lo a d d i t io n o f methyl v in y l ketone and a c ro le in to y ie ld 2 - fo rm y l-6 -m e th y l- 2 , 3 -d ih yd ro -2H -py ran , (19 ). The Grignard re a c t io n o f e thy lmagnesiurn bromide w ith l j ) gave both isomers o f 2 - (2 -h yd ro xye th y l) -6 -m e th y l-2 ,3 -d ih yd ro -2H -p y ran , ( 2 0 j . C y c l iz a t io n o f the pyranyl c a r b in o l , (20 ) , v ia the oxymercura tion /demercura tion 80 method o f Brown gave exo/endo brevicomin in a 1:1 r a t i o . EtMgBr I . IHg(OAc) 2.) HO- ZNa BH Figure 35. Mundy Synthesis o f Brevicomin. Mundy has a lso demonstrated th a t t rea tment o f 20 w i th p - to luene - s u l fo n ic ac id in benzene gives brevicomin in 87% y ie ld w i th a 64:36 r a t i o o f exo to endo isomers. I t is a lso wo rthwh ile to mention th a t u n l ik e any o f the be fo re - mentioned syntheses, Kossanye11 reported a q u i te novel syn thes is o f brevicomin in 1977. Here the s e le c t iv e i r r a d ia t i o n o f 2 -p ro p io n y l-6 - methyl - 2 ,3 -d ih yd ro -4H -py ran , (21_), by s in g le t s e n s i t i z a t io n and t r i p l e t quenching by I -m e thy lnap tha !ene gave the s te re o se le c t iv e exo-isomers o f I -m e th y l -6 -e xo -e th y l- 7 ,8 -d io x a b ic y c l i c [ 3 . 2 . I ]o c t -2 -e n e , (22 ) , in 23% y ie ld . C a ta ly t ic hydrogenation o f 22 gave exo b r e v ic o m in , ( I j , in 95% y ie ld . 81 X> 3 00 mm vycor filter Pentane > H 2 Pd/C • P * - 22 I Figure 36. Kassanye Synthesis o f B re v icomin. Thus, in a con t in u in g e f f o r t in our la bo ra to ry to improve the o r ig in a l Mundy syn thes is o f b rev icom in , a search fo r a b e t te r e le c t r o ­ p h i l i c reagent was begun. Careful in v e s t ig a t io n o f the l i t e r a t u r e revealed such an e le c t r o p h i le in phenylse leny l c h lo r id e . In 1974, K. B. Sharpless reported a new rou te f o r the syn thes is o f a l l y l i c e thers by the e le c t r o p h i l i c a d d i t io n o f va r ious *Sex reagents (where x = c l , Br o r oAc) to a lkenes. These reagents always undergo trans-1 ,2 add it io n s to g ive the adduct, (23 ) , which is q u i te s tab le when x = oAc, but is both the rm a l ly and s o l v o l y t i c a l I y unstab le when x = c l o r Br. A dd it io n o f an a lcoho l gave the phenylse lenoe the r, (24 ) , which when ox id ized w i th 30% H2O2 in THF a t room temperature gave 25. This underwent syn e l im i ­ na t ion v ia 26 to g ive the a l l y l i c e th e r , (27 ) , in 93% y ie ld . 82 Figure 37. Sharpless Synthesis o f C yc l ic E thers. Based on t h is work o f Vemura^, N ic o la o u ^ reported in 1977 th a t trea tmen t o f unsatura ted a lcoho ls such as 28 w i th phenylselenyI c h lo r id e in methylene c h lo r id e a t -78°C a f fo rded the phenylseleno e the rs , (30 ) . Ox ida tion o f 30 w i th 30% H2O9ZTHF gave the a l l y l i c e th e r , (3 2 ) , in 87% y ie ld . Treatment o f the phenylse leno e the r w ith Raney n ic ke l in THF a t 25°C re d u c t iv e ly removed the phenylseleno group to g ive the b i c y c l i c e th e r , (31_), in 95% y ie ld . 53 Figure 38. N icolaou Synthesis o f B ic y c l ic E thers. The mechanism f o r t h is re a c t io n was again pos tu la ted to proceed v ia an i n i t i a l a t ta ck o f the h ig h ly e le c t r o p h i l i c Secl on the double bond fo llowed by the in tram o le cu la r n u c le o p h i l ic a t ta ck by the hydroxyl group, v ia 29. R ea l iz ing the importance o f these experimenta l f in d in g s , the question we addressed ourse lves to was, can the a d d i t io n o f Secl to d ihydropyran ca rb in o ls produce a b i c y c l i c k e t a l , and, i f so, can we in f a c t syn thes ize brev icom in . Chapter 2 RESULTS AND DISCUSSION I c The D ie ls -A ld e r re a c t io n 0 o f I -butene-3-one gave 2 -a c e ty l -6 - m e thy l-3 ,4 -d ihyd ro -2H -pyran in 85% y ie ld . The ac tua l p repa ra t ion o f 2- 21p ro p io n y l-6 -m e th y l- 3 ,4 -d ihyd ro -2H -pyran was accomplished in two ways w ith approx imate ly equal e f f i c ie n c y . The f i r s t method was th a t o f S tork 17and Doud which cons is ted o f the fo rm a tion o f the c y c lo he xy l i mine o f 23, fo l lowed by the a d d i t io n o f e th y l magnesium bromide which y ie ld s the enamine, ( 23a) . A lk y la t io n o f 23a w i th methyl iod ide a t 0°C, fo l lowed by h yd ro ly s is w i th one equ iva len t o f 5% aqueous a ce t ic ac id gave 21_ in 81% y ie ld . The second method in vo lved the d i r e c t a lk y la t io n o f the p y r r o l id in e enamine, (24J , a t O0C w i th methyl io d id e , again fo l lowed by ca re fu l h yd ro ly s is w i th one equ iva le n t o f 5% aqueous a c e t ic ac id to g ive 21_ in 88% y ie ld . One must be ca re fu l in the ac id h y d ro ly s is , o therw ise I g the 2 -p ro p io n y l-6 -m e thy l- 3 , 4 -d ihyd ro -2H -pyran , (21_), r in g w i l l open. 85 / Figure 39. Synthesis o f 2-Propionyl-5 -M e thy l- 3 , 4-D ihydro-2H- Pyran. 19The n on -s te reo spe c i f ic reduc t ion o f 2 -p rop io n y l-6 -m e th y l-3 ,4 - d ihydro-2H-pyran, (21J , by sodium borohydride in isop ropy l a lcohol a t O0C gave both isomers 2- ( 2-h yd ro xye th y l) -6 -m e thy l-3 ,4 -d ih yd ro -2H -py ra n , (20 ) , in a 1:1 r a t i o ; determined by g lc on 15% 0V-101 a t I lO 0C. T re a t ­ ment o f 20 w i th I e qu iva len t o f pheny lse leny l c h lo r id e a t -78°C in 86 methylene c h lo r id e con ta in in g two equ iva len ts o f potassium carbonate gave 4 -pheny lse leno -5 -me thy l- 7 - e th y l - 6 ,8 -d io x a b ic y c lo [3 .2 .1 ]octane ( 38) in q u a n t i ta t iv e y i e ld . K e ta l iz a t io n was evidenced by the appearance o f fo u r in f r a re d absorp tions in the 1200-1050 cm ^ re g io n s , c h a ra c te r is t ic o f c y c l i c k e ta ls . Both nuc lea r magnetic resonance and mass spec tra l data supported t h is conc lus ion . Treatment o f 38^ w i th a c t iv a te d Raney Nickel in THF a t room temperature gave both endo and exo isomers o f 7 -e th y l -5 -m e th y l- 6 , 8 - d io x a b ic y c lo [3 .2 . 1]oc tane , ( Tj , in 92% y ie ld . The exo and endo isomer r a t i o was determined to be in I :1 by g lc ana lys is on 5% SE-30. Ox ida tion o f 38 w i th 30% hydrogen perox ide in THF a t room temperature w i th p e r io d ic coo l in g gave the expected p roduc t, 5-methyl - 7 - e th y l - 6 ,8 -d io x a b ic y c lo [ 3 . 2 . 1]o c t - 3 -e n e , (22 ) , in on ly 29% y ie ld . The major p ro d u c t .o f the re a c t io n was 5 -m e th y l -7 -e th y l - 6 , 8 -d io x a b ic y c lo - [3 .2 .1 ]o c ta ne -4 -one , (39 ) , in 71% y ie ld . C a ta ly t ic hydrogenation o f .22 w ith 10% Pd/C in e thy l ace ta te gave a 91% y ie ld o f I w i th a 1:1 isomer r a t i o . 87 Figure 40. Navel S yn the tic Approach to B re v icomin. Ox ida tion o f 38 w i th m -chloroperbenzoic ac id in methylene c h lo r id e a t 25°C gave 2^2 in 86% y ie ld w ith an exo/endo isomer r a t i o o f I : I . In the o x id a t io n reac t io n o f 4 -pheny ls e leno-5 -methy l- 7 - e th y l - 6 ,8 -d io x a b ic y c lo [3 .2 .1 ]o c ta n e w ith 30% hydrogen pe rox ide , we can r a t i o n ­ a l iz e the fo rmation o f 5 -m e th y l -7 -e th y l - 6 , 3 -d io x a b ic y c lo [3 .2 .1 ]oc t-3 -ene by the syn e l im in a t io n o f the se lenox ide , (40 ) , in the same fash ion as those reported by Reich w ith concomitant fo rma tion o f phenylse len ic ac id . 88 ■> / 0 n + 0SeOH Tl Figure 41. Reaction Mechanism f o r the Formation o f 5 -Me thy l-7 - E th y l -6 ,3 -D io x a b ic y c lo [3 .2 .1 ]o c t -3 -e n e . The fo rmation o f the major p roduct o f the re a c t io n 39^ was 20pos tu la ted to be der ived from a Pummer-Iike ' rearrangement. Protona­ t io n o f the se lenoxide g iv in g 41 which upon e l im in a t io n o f water gives the Pummer in te rm ed ia te (43 ). H yd ro lys is o f t h is in te rm ed ia te , fo l lowed by a hydrogen t ra n s fe r to the phenylse len ide gives a species which e ven tua l ly leads to H 20 39 o Ii OH - H 2O 4 l 7 | n n Figure 42. Reaction Mechanism f o r the Formation o f 5 -Methy l-7 - E th y l - 6 ,8 -D io x a b ic y c lo [3 .2 . I ]o c t-4 -one . The ro le o f the water h yd ro ly s is in the Rummer rearrangement was confirmed w i th the o x id a t io n o f 38 w i th one equ iva len t o f m -ch loroper- benzoic ac id which on ly gave one p roduc t, 22, in 36% y ie ld . Chapter 3 EXPERIMENTAL ■ - ‘ ■ Prepara tion o f 2 -p ro p io n y l-5 -m e th y l- 3 ,4-di.hydro-2H-pyran This compound was prepared by two methods o u t l in e d below. Method A 15.0 grams (0.077 mole) o f the p y r r o l id in e enamine o f 2 -ace ty l - 6 -me thy l- 3 ,4 -d ihyd ro -2H -pyran was placed in dry benzene and cooled to 0°C. While the m ix tu re was s t i r r i n g under a n i t rogen atmosphere, 11.00 grams (0.077 mole) o f methyl io d ide were added over a pe r iod o f t h i r t y m inutes. A f te r s t i r r i n g f o r one hour a t O0C, the m ix tu re was re f lu xed f o r tw en ty - fo u r hours ; a t the end o f which time the s o lu t io n was cooled to O0C and hydro lyzed by one equ iva le n t o f a 5% aqueous s o lu t io n o f a ce t ic ac id (4.62 grams o f a c e t ic ac id in 87.9 ml o f w a te r . ) This m ix tu re was then a llowed to s t i r f o r 45 minutes a t the end o f which time the s o lu t io n was ex tra c ted w ith fo u r 100 ml po r t ion s o f e the r which was washed w i th two 15 ml p o r t io n s o f sodium b ica rbona te , d r ie d over anhy­ drous magnesium s u l f a t e , f i l t e r e d and the e the r removed under vacuum v ia a r o ta to r y evapora to r. The res idue was vacuum d i s t i l l e d to g ive 10.44 grams o f a c o lo r le s s l i q u i d , b .p . 84°C, 88% y ie ld . > Method B 20 grams (0.142 mole) o f 2 -ace ty l-6 -m e thy l-3 ,4 rd ih yd ro -2H -py ran and 14.1 grams (0.142 mole) o f cyc lohexy l amine was placed in 200 ml o f 91 dry benzene and re f lu xed w ith a Dean-Stark water sepa ra to r f o r twenty- fo u r hours a t the end o f which time the benzene was removed under reduced pressure v ia r o ta to r y evapora to r and the res idue was vacuum d i s ­ t i l l e d to y ie ld 29.2 g o f a c le a r l i q u i d , b . p . ^ 95-96°C. 14 grams (0.063 mole) o f the c y c lo he xy l i mine o f 2 -a c e ty l -6 - methy l-3 ,4 -d ihyd ro -2H -py ran were added to a s o lu t io n o f 150 ml o f dry THF and 9.23 grams (0.069 moles) o f ethylmagnesium bromide. This s o lu ­ t io n was re f lu xed f o r f i v e hours, a t the end o f which time the s o lu t io n was cooled to O0C and 8.94 grams (0.063 moles) o f methyl iod ide were added over a per iod o f one hour. This m ix tu re was then allowed to s t i r a t room temperature f o r tw en ty - fo u r hou rs . The m ix tu re was then cooled to 0°C and hydro lyzed w i th I e qu iva le n t o f 5% aqueous a c e t ic ac id (3.78 grams, in 71.87 ml) f o r t h i r t y m inu tes . The m ix tu re was e x tra c ted w i th fo u r 100 ml po r t io n s o f e th e r , washed tw ice w ith 50 ml po r t io n s o f 5% sodium b icarbonate d r ie d over magnesium s u l fa te f i l t e r and the e the r was removed under vacuum v ia r o ta to r y evapora to r. The res idue was vacuum d i s t i l l e d to y ie ld 81% o f a c o lo r le s s l i q u i d , b .p . 84°C. Products from both reac t ions were id e n t i f i e d by IR, NMR, UV and mass spectra data . Ana lys is by g lc on 15% SE-30 a t I 30°C showed the compounds to be id e n t i c a l . NMR Data , 9 2 Chemical S h i f t (