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Synthesis of 2:3-benzo-1, 1-dimethyl-1-silacyclohex-2-ene and derivatives Lo, Daniel Ching-Shun 1966

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SYNTHESIS OF 2:3-BENZO-l, 1-DIMETHYL-l-SILACYC10HEX-2-ENE AND DERIVATIVES by DANIEL CHING-SHUN LO B.S., OREGON STATE UNIVERSITY, 1963 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENT FOR THE DEGREE OF MASTER OF SCIENCE IN PHARMACY in the Department of Pharmaceutical Chemistry of the Faculty of Pharmacy We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA October, 1966 I n p r e s e n t i n g t h i s t h e s i s i n 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 a t the U n i v e r s i t y of B r i t i s h Columbia, I agree t h a t 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 able f o r reference and study, I f u r t h e r agree t h a t p e r m i s s i o n - f o r 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 . I t i s understood t h a t 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 g a i n s h a l l not be allowed without my •written p e r m i s s i o n . Daniel C. Lo Department of P f f A B M A Q Y The U n i v e r s i t y of B r i t i s h Columbia Vancouver 8, Canada D a t e„_S^gEM3M _ g j a > . 1966 ABSTRACT The synthesis of 2:3-benzo-l,l-dimethyl-l-silacyclo-hex-2-ene has been reported. This compound was prepared by the simultaneous addition of 3-(o-bromophenyl)-propyl bromide and dichlorodimethylsilane to excess magnesium i n t e t r a -hydrofuran. The six-membered rin g organosilicon compound was readily brominated by N-bromosuccinimide to give the 4-derivative. Attempts were then made to synthesize the 4-cyano and the 4-carboxylate derivatives from th i s bromina-t i o n product. Experimental data are also given for an attempted preparation of 2:3-benzo-4-(2-dimethylaminoethoxy) -1,l-dimethyl-l-silacyclohex-2-ene. Signature of Examiners i ACKNOWLEDGEMENT The author expresses his very sincere thanks to Dr. T.H. Brown f o r the guidance, advice and encourage-ment given to him throughout the course of this work. i i TABLE OF CONTENTS Part Page Abstract i L i s t of Figures . . v I. INTRODUCTION 1 A. Some Biochemical Aspects of S i l i c o n 1 B. B i o i s o s t e r i c Properties of S i l i c o n and Carbon Compounds 2 C. A Review of Local Anesthetics 5 Chemistry and Structure-Activity Relation-ship 5 Mode of Action 9 Metabolism 12 The Overlapping Properties of Local Anesthetics 13 I I . STATEMENT OF PROBLEM 15 II I . CHEMISTRY OF CYCLIC ORGANOSILICON COMPOUNDS . . . 16 A. Chemical Behavior of S i l i c o n .16 B. Ring Size and Reactivity 17 C. Synthesis of Cyc l i c Organosilicon Compounds . 21 Grignard Synthesis 21 Wurtz-Fittig Synthesis 23 Lithium Synthesis 24 I i i Part Page IV. DISCUSSION 26 V. EXPERIMENTAL 38 o-Bromotoluene ( 9 0 ) 38 o-Bromobenzyl Bromide 39 S-(o-bromobenzyl)-is©thiourea picrate 40 3-(o-Bromophenyl)-propan-l-ol 40 3-(o-Bromophenyl)-propyl-/-naphthylearbamide . . 41 3-(o-Bromophenyl)-propyl Bromide 42 S-(3-(o-bromophenyl)-propyl)-isothiourea picrate 42 Synthesis of 2:3-Benzo-l,l-dimethyl-l-silacyclo-hex-2-ene 43 Synthesis of 2:3-Benzo-4-bromo-l,l-dimethyl-l-silacyclo-hex-2-ene 44 Synthesis of 2:3-Benzo-l,l-dimethyl-l-sila-cyclohex-2-ene by an alternate procedure (attempted) .45 2:3-Benzo-4-(2-dimethylaminoethoxy)-l,1-di-methyl-l-silacyclo-hex-2-ene (attempted) . . . 46 2:3-Benzo-4-cycano-l,1-dimethyl-l-silacyclohex-2-ene (attempted) 47 Synthesis of 2:3-benzo-l,l-dimethyl-l-silacyclo-hex-2-ene-4-carboxylic acid (attempted) . . . 48 VI. INFRARED SPECTRA 50 Part Page V I I . SUMMARY 55 V I I I . BIBLIOGRAPHY 57 V LIST OP FIGURES Figures - Infrared Spectrum of... Page 1. o-Bromotoluene 50 2. o-Bromobenzyl Bromide 50 3. S-(o-Bromobenzyl)-isothiourea picrate . . . . 50 4. 3-(o-Bromophenyl)-propan-l-ol 51 5. 3- (o-Bromophenyl) -propyl- <k -naphthylcarbamide 51 6. 3- (o-Bromophenyl) -propyl Bromide 51 7. S-(3-(o-Bromophenyl)-propyl)-is othiourea picrate 52 8. F r a c t i o n ( l ) from Reaction of 3-(o-Bromophenyl)-propyl magnesium Bromide and dichlorodimethyl-silane 52 9. Fraction(2) from Reaction of 3-(o-Bromophenyl)-propyl magnesium Bromide and dichlorodimethyl-silane 52 10. 2:3-Benzo-l,l-dimethyl-l-silacyclohex-2-ene . 53 11. 2:3-Benzo-4-bromo-l,l-dimethyl-l-silacyclohex-2-ene 53 12. The l i q u i d f r a c t i o n from the reaction of 2:3-Benzo-4-bromo-l,1-dimethyl-l-silaeyclohex-2-ene and potassium cyanide/2-dimethylamino ethanol 53 13. 4,4'-Bi(2:3-benzo-l,1-dimethyl-l-silaeyelohex-2-ene 54 PART I INTRODUCTION Many s i l i c o n containing medicinal agents have been prepared ( 1 , 2 , 3 , 4 ) but none possess l o c a l anesthetic a c t i v -i t y . The purpose of this research was an attempt to prepare an acid from an organosilicon compound, i n the hope that t h i s acid would serve as a potential intermediate f o r the synthesis of various types of ester and amide derivatives with possible l o c a l anesthetic a c t i v i t i e s . In the follow-ing introduction, some of the biochemical and medicinal aspects of s i l i c o n compounds w i l l be discussed, and the pharmacology of l o c a l anesthetics w i l l also be reviewed. A. SOME BIOCHEMICAL ASPECTS OP SILICON It i s of interest to note that s i l i c o n , i n spite of i t s abundance on earth as s i l i c a t e s , plays only a very i n -s i g n i f i c a n t role i n mammalian biochemistry. It i s found as a trace element i n a l l l i v i n g matter and occurs i n a l l tissues. There are wide variations i n the d i f f e r e n t organs: the kidney and the pancreas contain the most s i l i c o n , and the brain the least (5). The s i l i c o n i n skin may have to do with i t s e l a s t i c properties. Rollhauser (6) reported that the s i l i c o n content and the e l a s t i c i t y of mammalian skin both decrease with an increase i n age. 2 The l i t e r a t u r e indicates that s i l i c o n content of the brain tissues has been the subject of a number of investiga-tions (7,8,9). The metabolism of s i l i c o n i n d i f f e r e n t organs has also become the interest f o r some workers (10.11,12). In the investigation of trace element metabolism by the kidney, Soroka (13) reported that the rate of elimination of s i l i c o n by the kidney when the central nervous system (CNS) i s i n the excited state i s much faster than f o r other trace elements and i s the slowest along with aluminum, when the CHS i s inhibited by a depressant. S i l i c o n occurs i n a l l plants, where presumably i t plays an important role s t r u c t u r a l l y and chemically. The incorporation of s i l i c o n i s also important i n plant, and improved growth from the additions of s i l i c a t e s has been demonstrated with r i c e and m i l l e t (14). Mitsui and Takato (15) showed that s i l i c o n was an essential element fo r the growth of r i c e plants: necrosis of leaves resulted as a symptom of s i l i c o n dioxide deficiency. It i s believed that s i l i c o n i s involved i n the general metabolism i n plants. L i t t l e or nothing, however, i s known of the mode of action of s i l i c o n i n plant growth. B. BIOISOSTERIC PROPERTIES OP SILICON AND CARBON COMPOUNDS To many organic medicinal chemists, every physio-l o g i c a l l y active compound of known structure i s a challenge.... a challenge either to better i t , or perhaps to equal i t . 3 There are many ways to attack such a problem. One of the methods which has been frequently used i s that of i s o s t e r i c replacement. The concept of isosterism was f i r s t introduced by Langmuir (16) who pointed out the remarkably s i m i l a r physical properties of carbon dioxide and nitrous oxide. He deduced from the octet theory that the number and arrangement of electrons i n these molecules are the same. Compounds show-ing such a relationship to one another were termed i s o -s t e r i c compounds or isosteres. Many years l a t e r , t h i s con-cept had been broadened even further, and i n 1946, Mentzer (17) was able to demonstrate the relationship between some i s o s t e r i c compounds and t h e i r b i o l o g i c a l a c t i v i t y . The term 'bio-isostere' was introduced by Freidman (18) to denote compounds which f i t the d e f i n i t i o n f o r isosteres and have the same type of b i o l o g i c a l a c t i v i t y . Many available s i l i c o n compounds contain t e t r a -valent, tetrahedron s i l i c o n . Inorganic compounds of s i l i c o n i n which d i r e c t l y attached atoms make a tetrahedral angle with the central s i l i c o n atom are SiH^, SiF^, S i C l ^ , etc., and the organosilicon compounds which have the same geometry are ( C H ^ S i , ( C H ^ S i C l , ( C H ^ S i C l , etc. These data taken with a consideration of the r e l a t i v e energies of the 3s, 3p» and 3d o r b i t a l s lead to the con-elusion that s i l i c o n , l i k e carbon, prefers to use sp (f-bonding i n most of i t s compounds. Consequently, there exists a wide-ranging s t r u c t u r a l s i m i l a r i t y between the 4 compounds of s i l i c o n and of carbon, at least with regard to bonding type i n cr-bonding and molecular geometry. The l i t e r a t u r e and investigations are suggestive that s i l i c o n compounds can be used as bioisosteres of carbon compounds. Many silicon-substituted medicinal agents have been prepared to show the b i o i s o s t e r i c relationship with the o r i g i n a l carbon compounds. Fessenden and Coon (1) prepared 12 pairs of compounds, each pair d i f f e r i n g only by one a;tom ( s i l i c o n i n place of carbon). The drug system chosen was the alkanediol dicarbamates and* related monocarbamates. The most prominent of t h i s series i s the mild t r a n q u i l i z e r and muscle relaxant, meprobamate. O C M 3 O U 2 N - C - 0 - C H 2 - Z - C H 2 - 0 - C - N H ^ Z = Si, c The carbamates tested were found to have no s i g n i f i c a n t t o x i c i t y and b i o l o g i c a l a c t i v i t i e s between the bioisosteres were similar, except, i n some pairs, silacarbamates were shorter acting. The allergenic nature of dimethyl-di-(4-hydroxyphenyl) - s i l a n e ( l ) (19) was investigated since the carbon compound, 2,2-bis-(4-hydroxylphenyl)- propane (Bisphenol A)(II) has been demonstrated as an allergen by Fregert and Rosman (20). 5 I t was found t h a t subjec ts w i t h h y p e r s e n s i t i v i t y t o ( I I ) a l s o show a p o s i t i v e r e a c t i o n to ( I ) (21). A s i l i c o n analog of a p r e v i o u s l y s t u d i e d sympathomimetic amine was a l s o prepared by Pessenden and Coon (2), and i t was s i g n i f i c a n t t h a t the p h a r m a c o l o g i c a l e v a l u a t i o n r e v e a l e d no gross d i f f e r e n c e i n the a c t i v i t y of b o t h compounds. Even t h e i r t o x i c i t i e s were found t o be e q u i v a l e n t . Many other s i l i c o n - s u b s t i t u t e d m e d i c i n a l agents have a l s o been prepared i n recent y e a r s . For examples, "the s i l i c o n - s u b s t i t u t e d s p i r o b a r b i t u r a t e s (4) and the p h e n y l -s u b s t i t u t e d s i lacarbamates ( 3 ) have been s y n t h e s i z e d and t h e i r b i o l o g i c a l a c t i v i t i e s i n v e s t i g a t e d . The d a t a obtained i n d i c a t e t h a t a s i l i c o n atom can be used as a n o n - i o n i c t e t r a v a l e n t b i o i s o s t e r e of a carbon i n a drug system. These s t u d i e s , which c o r r e l a t e the chemica l and p h y s i c a l p r o p e r t i e s o f p a i r s of compounds w i t h p h a r m a c o l o g i c a l and b i o c h e m i c a l d i f f e r e n c e s and s i m i l a r i t i e s , p r o v i d e a u s e f u l t o o l f o r the e l u c i d a t i o n of the p r o p e r t i e s of a drug system. 0. A REVIEW OP LOCAL ANESTHETICS Chemistry and S t r u c t u r e - A c t i v i t y R e l a t i o n s h i p Hundreds of compounds have been prepared that , possess l o c a l a n e s t h e t i c a c t i v i t y . Many have been d i s c a r d e d because they are l o c a l l y d e s t r u c t i v e to t i s s u e , t o x i c s y s t e m i c a l l y , or u n s a t i s f a c t o r y from the s tandpoint o f 6 potency. A l l the useful l o c a l anesthetics consist of three parts. There i s a hydrophilic amino group which i s connected by an intermediate group to a l i p o p h i l i c aromatic residue. Broadly speaking, the structure of a l o c a l anesthetic may be defined by the general formula (22): Lipophile Intermediate chain Hydrophile The l i p o p h i l i c center usually consists of an aromatic or heterocyclic nucleus, but i t may be exchanged for an a r a l k y l or an a l k y l group. The hydrophilic center, i n nearly a l l anesthetic agents, consists of a secondary or t e r t i a r y amino group. This amino group i s of importance because most of the c l i n i c a l l y suitable injectable l o c a l anesthetics need to be dependent on t h i s group f o r t h e i r a c t i v i t i e s . The intermediate chain consists of a hydro-carbon bridge attached to the hydrophilic center. The l i n k between the intermediate group and the aromatic l i p o p h i l i c center i s frequently an ester linkage, as i n procaine and cocaine. The ester linkage i s important because i t i s this bond which i s hydrolyzed during metabolic degradation and inactivation i n the body (23,24). The various types of l o c a l anesthetics then d i f f e r only i n so f a r as the ester linkage, -COgR, or has been exchanged f o r groups such as -NHCO-, HHCP2-, -NHC0NH-, -CONH-, -CO-, or -0-. Some of the commonly used l o c a l anesthetics are shown i n Figure I. Figure I . STRUCTURAL FORMULAS OF LOCAL ANESTHETICS Aromatic 1 I Inter-i Amino i Aromatic Inter-I 'Amino Residue 1 mediate | Group Residue mediate J Group 1 I Chain Chain C H , -ColOCH zCW 2- -co ! / O C H i C H ^ H j , - N Procaine J Piperocaine 'J ^n-Co'oCHCHi Cocaine C H V C M j C H C H ( C O O C H , ) -I I I I I COI O C H i C H 2 — /CH 3 I HqC N -CO - O C H 2 C H 2 . - ' N /CH 3 Tetracaine C H , * C H . C H 3 i N .CO-C H 2 C H ( C H 3 ) . Butethamine Mepivacaine COrOCHCH2-Hexylcaine •CO Benoxinate 1 1 / c*^ -OCH2CH*—N I N H — C O C H z . / C 2 H 5 \ w«c4o-C , H 2.M5-Lidocaine Pramoxine / " A O C H i C H z C M j J ^ o 8 There are several theories concerning the structure-a c t i v i t y relationship of l o c a l anesthetics. The most common one, as pointed out by Quevauviller (25), i s a balance between the l i p o p h i l i c and the hydrophilic parts of the molecule. This balance i s essential because, i f the hydrophilic part dominates, the l o c a l anesthetic a c t i v i t y i s l o s t ; i f on the other hand, the l i p o p h i l i c character i s unduly marked, the compound i s not readi l y soluble. There-fore, the hydrophilic-lipophilic-balance(HLB) f o r these agents i s important because i t determines the behavior of the molecule at the interfaces, as for instance the c e l l membrane. When the anesthetic a c t i v i t i e s of d i f f e r e n t compounds are considered with s p e c i a l respects to the molecular structure, the above factors become more complex. The complexity l a r g e l y attributes to the fact that the structural formula of a compound does not adequately indicate the form, s i z e , nor s t e r i c structure, nor the physical properties associated with the pharmacological action. Buchi and P e r l i a (26) emphasized the importance of those aspects of l o c a l anesthetics which implicate electron theory. Later, Perkow (27) call e d attention the the fact that i n a l l active anesthetics of ester type and amide type, the carbonyl group i s activated by a lower electron density at the carbon atom. The electron d i s t r i b u t i o n within the molecule i s i n turn responsible f o r those forces such as 9 the van der Waal's, dipole-dipole, hydrogen and ionic bonds, which modify greatly the behavior of the molecule at the interfaces. Mode of Action The current theory about the propagation of nerve impulses, that changes i n the c e l l membrane permeability to ions determine the action potential, gives support to the view that nerve block i s produced by alterations of the permeability (28,29,30,31). It i s believed that the l i p i d s adsorbed on the membrane are organized and, together with inorganic ions, are responsible f o r the transmission of impulses. On administration of a l o c a l anesthetic agent, the adsorption equilibrium i s disturbed, r e s u l t i n g i n the disorganization of the conduction layer, and consequently, the cessation of the propagation of impulses. The exact mechanism, whereby a l o c a l anesthetic influences the permeability of the membrane i s s t i l l at present unknown. It i s , however, interesting to note that the r e l a t i v e anesthetic potency of a series of compounds exactly parallels, t h e i r effectiveness i n increasing the surface pressure of monomolecular films of l i p i d s (32). On the basis of t h i s work, Shanes (31,33) suggested that the l o c a l anesthetics achieve block by increasing the sur-face pressure of the l i p i d layer that constitutes the nerve membrane, thereby closing the pores through which ions 10 move. This would, consequently, cause a general decrease i n the resting permeability and would also l i m i t the increase i n sodium permeability, the fundamental change necessary f o r the generation of the action p o t e n t i a l . Since the molecular structure of l o c a l anesthetics invariably conforms to the l i p o p h i l i e - h y d r o p h i l i c p r i n c i p l e , generally with an amino group as the hydrophilic center, Lofgren (34) considers i t probable that the amino group comes into contact with an appropriate polar hydrophilic group i n the membrane to form a complex, by vi r t u e 1 of the van der Waal's forces, whereby penetration occurs to exert, l o c a l anesthetic a c t i v i t y . The physical properties of the l o c a l anesthetics containing amino groups and the a b i l i t y of these bases to penetrate the c e l l membrane has been the subject of a number of investigations. As pointed out by Goodman and Gilman (35), the l o c a l anesthetics act, i n t r a -e e l l u l a r l y , i n the form of the p o s i t i v e l y charged ammonium cation. This phenomenon was recently supported by the findings of Ritchie and Greengard (36). They reported that conduction of impulses i s blocked by these l o c a l anesthetics only when the pH i s s l i g h t l y on the ac i d i c side; that i s , they must be i n t h e i r cationic form. A l l these findings seem to indicate that the cation i s the molecular form that combines with some receptor i n the membrane to prevent i t s generation of an action p o t e n t i a l . This theory i s also 11 supported by Ariens and Simonis (37). Another interesting contribution to the question of the mechanism of l o c a l anesthetic action was recently made by Eckert (38). He demonstrated that many l o c a l anesthetics form I T-electron complexes with thiamine, the l o c a l anesthetic acting as doner and thiamine as acceptor. He thus believed that l o c a l anesthetics act by blocking thiamine which i s essential to the nerve functions. In connection with these findings, i t i s interesting to note that thiamine does have an antagonistic action upon l o c a l anesthetics such as procaine, cocaine, and lidocaine i n t o p i c a l and i n f i l t r a t i o n anesthesia, as well as i n nerve block (39). There are, however, several objections to t h i s interesting suggestion. F i r s t , thiamine, i f involved i n nerve conduction at a l l , i s most l i k e l y to be involved i n the form of coenzyme, thiamine pyrophosphate, which can serve as an acceptor i n a charge-transfer complex with l o c a l anesthetics. Secondly, i t i s by no means certain that l o c a l anesthetics would form charge-transfer complexes with thiamine, either i n the free or i n coenzyme form (40). Nevertheless, Agin (41) has reported the formation of a 'charge-transfer complex' between procaine and ri b o -nucleic acid, and i t was then suggested that ribose, the c e l l surface mucopolysaccharides, may play an important part i n the action of certain anesthetics. The experiments 12 of Agin then emphasize the interesting fact that the l o c a l anesthetics may owe t h e i r possible blocking effects to t h e i r a b i l i t y to form charge-transfer complexes with constituents of the nerve membrane. Metabolism The metabolic fate of l o c a l anesthetics i s of great p r a c t i c a l importance because t h e i r t o x i c i t y depends larg e l y on the balance between t h e i r rate of absorption and t h e i r rate of elimination. The rate at which they are destroyed varies greatly, and t h i s i s a major factor i n determining the safety of a p a r t i c u l a r anesthetic agent. Since most of the commonly used l o e a l anesthetics are esters, hydrolysis that occurs frequently i n both the l i v e r and plasma seems to be the major degradation of these agents. There i s , however, a great v a r i a t i o n i n the way that the d i f f e r e n t individual agents are metabolized. For example, procaine i s destroyed mainly i n the plasma, whereas cocaine i s destroyed i n the l i v e r (42), both by the enzymatic a c t i v i t y of esterases. To show the varying degree of enzymatic a c t i v i t y of esterases, Becker ( 4 3 )» i n comparative experiments with human serum, reported that metabutethamine was hydrolyzed 3 0 - 3 5 times, meprycaine 15-21 times, and piperocaine 5-8 times, as rapidly as procaine. Using paper electrophoresis of human serum, Becker ( 4 4 ) was then able to l o c a l i z e the 13 esterase a c t i v i t y against these l o c a l anesthetics, and suggested that there are several serum esterases with vary-ing degree of hydrolytic action upon dif f e r e n t l o c a l anesthetics of the ester type. Inasmuch as these esterases are involved quite intimately i n various "bodily functions, the relationship of the l o c a l anesthetics to these enzymes i s important both from the standpoint of anesthetic potency and from that of t o x i c i t y . The l i v e r seems to be the chief s i t e of destruction of the non-ester type of l o c a l anesthetics. Hollunger (45) showed that i n rabbit l i v e r , lidocaine i s metabolized oxidatively by an enzyme system known as the amidases. e x i s t -ing i n the microsomes, and t h i s requires the presence of both oxygen and reduced triphosphopyridine nucleotide (TPN). There i s also a species difference i n the disposal of l o c a l anesthetics. Blaschko (46) reported that rabbit serum rapidly hydrolyzed cocaine whereas horse serum does not. Kalow (47) also call e d attention to species d i f f e r -ences i n the metabolism of ester-type l o c a l anesthetics due to v a r i a b i l i t y of plasma esterases. For example, procaine i s hydrolyzed i n man, but i s excreted intact i n the horse. The Overlapping Properties of Local Anesthetics Based upon t h e i r chemical structure, many of the l o c a l anesthetic agents, i n addition to t h e i r nerve blocking properties, have been found to have s i g n i f i c a n t sedative, 1 analgesic, and antitussive a c t i v i t i e s . The central analgesic 14 property i s noted with lidocaine, which on administration intravenously or intramuscularly, has been c l i n i c a l l y adopted as a central analgesic f o r intensively painful conditions (48,49.50). Steinhaus and Howland (51,52), i n t h e i r studies of lidocaine, observed depression of the pharyngeal and laryngeal reflexed. In experiments on rabbits and dogs, lidocaine was found to suppress the cough reflexes attending i severe mechanical i r r i t a t i o n , without producing respiratory arrest (53,54). Benzobutamine (55) was also found to have the most interesting antitussive a c t i v i t y among a series of many other related compounds, and r e s u l t s also show that benzobutamine produces i n s i g n i f i c a n t respiratory depression. Local anesthetics are generally regarded as con-vulsive drijgs. Recent findings, however, show that the anticonvulsive properties of such drugs have been reported (56,57). The anticonvulsive a c t i v i t i e s of l o c a l anesthetics, lidocaine, butamine, tetracaine have been compared with those of phenobarbitals and dipheiiylhydantoin (58). It was found that they showed a c t i v i t i e s of the same order of magnitude as those of reference compounds but of much shorter duration. Zipf (59) i n his reviews of the general, pharmaco-dynamic actions of l o c a l anesthetics, i l l u s t r a t e d many other overlapping properties". These properties include parasym-pathetic blocking action, spasmolytic action, anticholinergic action, and l a s t of a l l antihistaminic and a n t i a l l e r g i c actions. PART II STATEMENT OP PROBLEM The purpose of t h i s investigation was to attempt to prepare 2:3-benzo-l,l-dimethyl-l-silacyelohex-2-ene and i t s 4-functional derivatives. It was also thought of interest to attempt to prepare the 4-carboxylate derivative i n order to make t h i s compound available f o r the synthesis of various types of ester and amide derivatives with possible l o c a l anesthetic a c t i v i t i e s . Because of the successful synthesis of t e t r a l i n derivatives as l o c a l anesthetic agents by Senda and Izumi (103)» and because of the str u c t u r a l s i m i l a r i t y between t e t r a l i n and 2:3-benzo-l,l-dimethyl-l-silaeyclohex-2-ene, i t was f e l t that the appropriate derivatives of the l a t t e r compound should be b i o i s o s t e r i c with those of the former compound. That i s to say, the organosilicon analogs should possess s i m i l a r l o c a l anesthetic a c t i v i t i e s to the t e t r a l i n derivatives. PART III CHEMISTRY OP CYCLIC ORGANOSILICON COMPOUNDS A. CHEMICAL BEHAVIOR OF SILICON In i t s chemical behavior, s i l i c o n i s usually tetravalent but i s capable of a maximum covalency of six i n combination with atoms of relative-small volume and high nuclear charge, as i n the f l u o r o s i l i c a t e ion S i F g = and i n s i l i c o n acetylacetonate (61). In t h i s respect, i t d i f f e r s markedly from carbon. In most of i t s organic compounds s i l i c o n remains tetravalent l i k e carbon, but i t must be borne i n mind that the electropositive nature and the hexacovalency of s i l i c o n may become evident under a variety of conditions and may cause vigorous reactions unknown to the analogous carbon compounds. In terms of electronegativity, s i l i c o n i s assigned a value of 1.8 compared with 2.5 f o r carbon (60). This results i n approximately 12 per cent ionic character i n the silicon-carbon bond. Also, the larger size of the s i l i c o n atom, with correspondingly greater screening of i t s nuclear charge may well be considered as a marked difference from the carbon atom. With a l l these fundamental differences, therefore, i f the chemical behavior of s i l i c o n i s to be predicted by an absolute analogy with the carbon atom, th i s 17 attempt i s l i k e l y to f a i l . Another dominant chemical c h a r a c t e r i s t i c of s i l i c o n i s i t s tendancy to oxidize. The high molar heat of oxida-t i o n of s i l i c o n (198 Kcal compared with 94 Kcal of carbon) w i l l enable any oxidizable compounds to revert to s i l i c a r e a d i l y and rapi d l y i f s u f f i c i e n t oxygen and a c t i v a t i o n energy are provided. However, combustion i s not the only mechanism f o r such oxidation; the s i l i c o n may seek combina-t i o n with oxygen through hydrolysis, alcoholysis, and other s i m i l a r reactions with oxygen containing substances. In any case, the various covalent s i l i c o n compounds d i f f e r greatly i n the ease and rate which they undergo various form of oxidation, but the thermodynamic p o s s i b i l i t y i s always present. B. RING SIZE AND REACTIVITY There has not been any successful synthesis of a three-ring compound with r i n g s i l i c o n reported. S i l a c y c l o -propanes appear to undergo rearrangement to v i n y l s i l a n e s , analogous to the rearrangement of cyclopropane to propylene. S k e l l and Goldstein (65) attempted to prepare s i l a c y c l o -propane by d i f f e r e n t synthetic pathways; however, only v i n y l s i l a n e was obtained. It was then believed that these reactions involved s k e l e t a l rearrangement with the assump-t i o n of a silacyclopropane intermediate (65). Unsuccessful e f f o r t s were made to trap t h i s intermediate. 18 Many silicon-containing 4-membered rings have been prepared with much success (66,67,73,74). This series of compounds has shown chemical interest because the s i l a c y c l o -butane r i n g system i s extremely susceptible to cleavage by polar reagents. F a c i l e r i n g opening was f i r s t observed by Sommer and Baum (73) with ethanolic base and s u l f u r i c acid, and by Lindsey and Knoth (67) with bromine and ethanolic s i l v e r n i t r a t e . In addition to these polar reagents, Gilman and Atwell (66,69) recently reported that the s i l i c o n -containing 4-membered r i n g also undergo ri n g cleavage with lithium aluminum hydride (LAH) as well as a basic alumina column. In attempt to explain the f a c i l e r i n g opening of silacyclobutanes, e a r l i e r workers have proposed several theories. Sommer and Baum (73) attributed the r e a c t i v i t y of the silacyclobutanes to angular strains present i n the rin g on assumption that the silacyclobutane r i n g i s planar and that the C-C-C angle i s tetrahedral. West (74) reported that since the tetrahedral angle of s i l i c o n i s e a s i l y deformed the angular strains i n silacyclobutane are no greater than cyclobutane. Another th e o r e t i c a l consideration concerning the high r e a c t i v i t y of silacyclobutanes has been previously reported by Sommer and others ( 7 5 ) . He has explained the high r e a c t i v i t y of methyl-l-silacyclobutane i n hydrolysis reactions by a consideration of the s t r u c t u r e - a c t i v i t y r e l a -tions r e s u l t i n g from s t e r i e factors. By analogy, the 19 geometry of silacyclobutanes with other polar reagents would i d e a l l y approximate a structure of the type I, with r i n g opening being the predominant reaction. c cb b Gilman and Atwell (66) i n supporting t h i s theory have prepared two dif f e r e n t compounds, a silacyclobutane II and a silacyclopentane I I I . Comparison of the r e a c t i v i t i e s of these two compounds were then made. Ph -St (II) (III) The five-membered r i n g III was found to be quite non-reactive under conditions where II was readily cleaved. That i s , III did not react with any polar reagents which cleaved the r i n g i n I I . To explain the difference i n r e a c t i v i t e s , Gilman and Atwell (5) postulated the follow-ings: 1. Since the r i n g substituents i n II are 'pulled back' (re l a t i v e to III) away from the path of the attacking reagent, the formation of IV should be greatly f a c i l i t a t e d ; 20 2. The C-Si-C angle i n IV would be expected to be about 90; and since the r i n g angle i n II should be closed to t h i s value, much less i n t e r n a l s t r a i n (I-strains) should be introduced during the formation of the five-membered ring homolog III; 3. Due to an increased crowding of the r i n g substituents i n IV r e l a t i v e to I I , an increased s t e r i c s t r a i n should re s u l t during the formation of IV. A l l these points are i n support of Sommer's theory which indicates that the formation of IV from II would be more energetically favorable than the Since the five-membered r i n g has been found to be non-reactive toward polar reagents, i t seems reasonable that s i m i l a r considerations should hold f o r compounds with larger r i n g s i z e . As the tetrahedral bond angles at s i l i c o n are reported to be more e a s i l y deformed than those of carbon (76), t h i s may lead to some r e l i e f of i n t e r n a l s t r a i n when s i l i c o n i s present as a heteroatom i n the s i x - and seven-membered rings. The silacyclohexane does have st r a i n l e s s conforma-tions available and the geometrical calculations were made assuming that a l l bond angles are tetrahedral; the C-C (iv) c a = b : C : d : P l l formation of a s i m i l a r complex from I I I . o distance was taken as 1.54 A and the C-Si distance as 21 C. SYNTHESIS OP CYCLIC ORGANOSILICON COMPOUNDS A survey of l i t e r a t u r e indicates that the following methods are the ones that are most frequently used for the preparation of c y c l i c organosilicon compounds. Q-rignard Synthesis It i s the most v e r s a t i l e of a l l methods i n use since i t makes i t possible to substitute halogen and alkoxysilanes with the most varied organie groups, subject p r a c t i c a l l y only to s t e r i c l i m i t a t i o n s . The method proceeds most often from chlorosilanes since these are most re a d i l y available. Diethyl ether usually i s the solvent of choice since the reaction i n t h i s solvent proceeds with highest y i e l d . However, work with ether i s somewhat r i s k y p a r t i c u l a r l y i f greater amounts are used because of i t s self-inflammatory nature i n a i r as soon as i t evaporates. Much endeavor was therefore devoted to the replacement of ether by other solvents. The solvent of choice then appears to be tetrahydrofuran (THP). The 22 pronounced solvent effects of THF have been demonstrated by Ramsden (78) i n the preparation of Grignard reagents from normally unreactive halides. The effect of the more polar THP i n the reactions of Grignard reagents with s i l i c o n halides must be to increase the r e a c t i v i t y of the Grignard reagents or vice versa. With the aid of Grignard reagents prepared from organic dihalides one can prepare compounds of the follow-ing c y c l i c derivatives: 1. Br(CHj ) 4 B^ + S i C l 4 M g 3. _BT(CHx)sBr + S\Cl 4 Mem), fa > ( 7 9 ) - ( 7 3 ) • ( 1 9 ) The highest y i e l d s are obtained i n the case of s i x -membered rings while seven-membered rings are formed i n very low y i e l d s . The r i n g closure i s favored by increased number of chlorine atoms on s i l i c o n causing the strong dipole (79) and by d i l u t i o n of reaction mixture. B i c y e l i c and t r i c y c l i c silanes can also be prepared: 23 The mechanism of the G-rignard synthesis of organo-s i l i c o n compounds has not been established. It i s believed that the reaction proceeds by an i n i t i a l nuclebphilic attack at the s i l i c o n atom (80) by the negative organic moiety of the complex, under simultaneous coordination of magnesium with halogen. This results i n a c y c l i c synchronous process with a t r a n s i t i o n state of the following type where X represents the halogen (81): 1 Si - - X Wurtz-Fittig Synthesis The reaction of an organic halide with a s . i l y l halide i n the presence of metallic sodium, which i s analogous to the Wurtz-Fittig reaction, i s one of the oldest methods of preparing organosilicon compounds. The reaction has been carried out i n ether or more recently, i n higher b o i l i n g solvents such as xylene and toluene; the l a t t e r has the advantage that sodium i s more reactive i n the fused state. 24 The method i s most suitable f o r the preparation of t e t r a -organo-substituted compounds, especially i n the aromatic se r i e s . To prepare c y c l i c organosilieon compounds, this method has been demonstrated with good y i e l d s . Some of the examples showing intramolecular a l k y l a t i o n are given below: The mechanism of the Wurtz-Fittig reaction has not been s a t i s f a c t o r i l y explained; one can, however, postulate a transitory formation of an organic sodium compound and the alk y l a t i o n by an ionic mechanism or else by a r a d i c a l mechanism (84). Lithium Synthesis The lithium synthesis of organosilieon compounds has been greatly developed. In many respects the lithium synthesis has become a r i v a l to the Grignard reaction. The chief advantage of the lithium synthesis i s indicated i n syntheses of tetraorgano-substituted derivatives, p a r t i c -u l a r l y i n introducing more bulky groups. In other respects, 25 including experimental procedure, the lithium synthesis i s very similar to that of the Grignard reaction. In the formation of s i l i c o n rings, the lithium synthesis i s frequently employed. Some of the reactions are shown as follows: 1. P K 2 S i C l 2 + U ( C H J 4 L > P h 2 S i (8-0 —* phisC^  ~ (8e) 3. PK 3 S i C l + U ( C H O S U > ?bzs(~y ( 8 8 ) * A number of c y c l i c organosilicon derivatives have also been prepared from aromatic d i l i t h i u m compound, for example: *Silacyclohexane i s produced by the reaction i n only 0.65% y i e l d . PART IV DISCUSSION The preparation of o-bromotoluene was used as a s t a r t i n g point f o r the reaction sequence to obtain the desired c y c l i c organosilieon compound, 2:3-benzo-l,l-dimethyl-l-silacyclohex-2-ene. This preparation employed the Gattermann reaction (90) i n which the o-toluidine was diazotized i n ice-cold solution i n 40$ hydrobromic acid with sodium n i t r i t e , and then the replacement of the diazonium s a l t group by bromine was catalyzed markedly by copper turn-ings. The reaction can be represented by the following equations: 3? CI) -v 2.HBr + KaMOi. <ZVL N i t To ensure a smooth reaction, 40% HBr had to be used (91) instead of the commercially available 48% reagent, otherwise the d i a z o t i z a t i o n i s very d i f f i c u l t to control, and the reaction may become very vigorous and force out the stopper. An alternate procedure f o r obtaining the o-bromotoluene i s by using the Sandmeyer reaction which i s 27 shown as follows: This procedure i s es s e n t i a l l y the same as the Gattermann method, except that i n the c a t a l y t i c reaction i n the replacement of the diazonium s a l t group by bromine, one molecular equivalent of the cuprous s a l t component i s required instead of the copper turnings, apparently because of the formation of the intermediate molecular complex. The structure of the complex i s not known but the reaction i s considered to follow a fr e e - r a d i c a l mechanism (92). Gattermann's procedure i s the simpler of the two. I f a cuprous s a l t i s not available, the copper-catalyzed reaction of Gattermann i s always applicable. In the second stage of the reaction sequence, the o-bromotoluene was brominated to give the corresponding o-bromobenzyl bromide. This preparation was achieved by using Holliman and Mann's modification (93) of Kenner and Wilson's method (94). The bromination took place at 150°C. by adding 85% of the calculated quantity of bromine without vigorous agitation of the reaction mixture. The preparation of o-bromobenzyl bromide i n 80% y i e l d from o-bromtoluene has been reported by Kenner and Wilson (94)» but i n the preparation 28 described i n this thesis, only 65% y i e l d was obtained, show-ing possibly that the optimum reaction conditions were not met. However, since a detailed procedure was not given by Kenner and Wilson, a comparison was not possible. An alternate procedure f o r the preparation of o-bromobenzyl bromide from o-bromotoluene was described by Gorsich ( 9 7 ) . In t h i s procedure, N-bromosuccinimide (NBS) was used instead of molecular bromine, and the reaction was i n i t i a t e d by u l t r a v i o l e t l i g h t . Since the y i e l d obtained was 64%, t h i s procedure was s a t i s f a c t o r y . Based on the procedures described for the prepara-t i o n of o-bromobenzyl bromide, a f r e e - r a d i c a l reaction mechanism has been proposed for these reactions. Because of the electron withdrawing effect of the phenyl r i n g and electronegativity of the o-bromo-substituent i n the molecule, the proton i n the a l k y l side chain can be e a s i l y extracted. This favors the free Br. r a d i c a l attack. A chain reaction i n i t i a t e d by the free bromine atom proceeds slowly and i s l i k e l y to terminate when most of the molecules have become brominated. Since i t i s believed that the k i n e t i c chains i n bromination are short, many acts of i n i t i a t i o n are there-fore needed; i n t h i s case, constant heat application to the reaction mixture i s e s s e n t i a l . I. Initiation B r : B r 1 > B r * + Br • 2 9 3 . T i e r r n n a o . ' t ton B r - -v B r H + HBr H + 8 r : B r > + • Br ^ ^ 6 " + B r Br B r , ( r e c o m b m e d ) OC H z l 6 r Free-radical halogenations may also be carried out using reagents other than the molecular halogens. The most fa m i l i a r of these 'halo-carriers' i s N-bromosuccinimide (NBS), the N-Br bond of which i s e a s i l y broken ( 9 5 ) . NBS i s often considered a brominating agent s p e c i f i c a l l y f o r a l l y l i c carbon, and i n keeping with i t s homolytic character, the bromination with NBS may be accelerated photochemically. The method described by Gorsich, then, i s a t y p i c a l example of photochemical substitution by free r a d i c a l s . Very probably, the i n i t i a l attack on the substrate (o-bromotoulene) i n the bromination i s by the succinimido r a d i c a l , a f t e r which the resulting carbon r a d i c a l attacks a second molecule of NBS. As the bromine r a d i c a l can re-combine with the succinimido r a d i c a l , i n order to ensure 30 maximum e f f i c i e n c y i n t h i s photochemical process, continued i r r a d i a t i o n i s required to maintain an adequate supply of-i n i t i a t i n g r a d i c a l s . This chain reaction mechanism i s i l l u s t r a t e d as follows: o o Th^ e bromide obtained was a l i q u i d at reduced pressure (93-96/1 mm Hg) and was a s o l i d (m.p. 30°C.) i n the pure form. Due to the discrepancy between the observed b o i l i n g point and the di f f e r e n t l i t e r a t u r e values (136/16 mm Hg) (97); 129/19 mm Hg (93); 66-69/0.2 mm Hg) (97), the S-alkylisothiourea picrate derivative (98) was prepared for analysis. The o-bromobenzyl bromide, when suitably treated with one atomic proportion of magnesium, gave o-bromobenzyl-magnesium bromide, which then reacted with ethylene oxide to give 3-(o-bromophenyl)-propan-l-ol(X). U3T) e Z ) 31 OH B y The reaction of the Grignard reagent with ethylene oxide showed a t y p i c a l preparation of various primary alcohols i n which the chain i s lengthened by two carbon atoms. The key reaction can be regarded as a nucleophilic addition i n i t i a t i n g i n attack of the p o s i t i v e l y polarized carbon i n ethylene oxide by a potential carbanion present i n the Grignard reagent (99). The successful preparation and manipulation of t h i s Grignard reagent required considerable care. The entire preparation had to be carried out under an atmosphere of dry nitrogen, otherwise oxidation r e a d i l y occurred with the subsequent formation of o-bromobenzyl alcohol. Moreover a number of side reactions occurred, and among the by-products were a low b o i l i n g f r a c t i o n of ethylene bromo-hydrin ( i d e n t i f i e d by infrared spectrum, b o i l i n g point, and r e f r a c t i v e index) and possibly 2:2'-dibromodibenzyl (94), colorless c r y s t a l s , m.p. 84-84.5. 32 Side Reaction: Br-CHtCrti-OH The 3-(o-bromophenyl )0-propan-l-ol obtained was a colorless l i q u i d , b.p. 120-123/2 mm Hg. The infrared spectrum of thi s propanol showed a characteristic-OH absorption band at 3300 cm*""1". In the next stage of the synthesis, the prepared propanol was converted by phosphorus tribromide into the corresponding bromide. A sim i l a r reaction was i l l u s t r a t e d by G-ilman and Marrs (86) i n the preparation of 2-(o-chloro-phenyl)-ethyl bromide from the appropriate ethanol. This preparation was achieved successfully with 75-80% y i e l d . When 3-(o-bromophenyl)-propyl bromide was allowed to react with magnesium i n tetrahydrofuran, the r i n g closure product of 2:3-benzo-l,l-dimethyl-l-silacyclohex-2-ene(XI) was obtained. This compound was i d e n t i f i e d by elemental analysis and by i t s infrared spectrum which showed absorp-t i o n bands at 1080 cm""1" 1125 cm""1' and 1140 cm-"1".... a char a c t e r i s t i c proposed for the silacycloalkene nucleus (86). In investigating the reaction mechanism f o r this synthesis, a di-G-rignard reagent (VIII) has been proposed 33 for the organomagnesium compound (100). However, on addition of the dichlorodimethylsilane to the possibly formed * d i -Grignard reagent 1, three d i f f e r e n t fractions of l i q u i d s were obtained which, by elemental analysis and infrared studies, were not characterized to be the expected ri n g product. The synthesis was achieved successfully by the simultaneous addition of the bromide and dichlorodimethyl-silane to magnesium i n THP, the completion of the reaction being detected by the negative test of Color Test I (101). It seems l i k e l y that t h i s reaction consists of two steps: the formation of 3-(o-bromophenyl)-propyldimethylsilane (X), and with excess magnesium, the s i l a c y c l i c compound. CXI) 34 Since the synthesis of 2:3-benzo-l,l-dimethyl-l-silacyelohex-2-ene had proved successful, attempts were made to prepare more functional derivatives from the non-functional r i n g compound. Treatment of the r i n g product (XI) with N-bromosucccinamide (NBS) gave 2:3-benzo-4-bromo-l, l-dimethyl-l-silaeyclohex-2-ene (XII). The structure of the bromination product was based upon elemental analysis, i n f r a -red spectrum, and i t s reactions. The infrared spectrum of t h i s compound s t i l l showed absorption bands at 1082 cm - 1, 1135 cm"1, and 1150 cm , which are apparently c h a r a c t e r i s t i c of the six-membered benzosilacyeloalkene nucleus (86). Because of i t s r e a c t i v i t y toward s i l v e r n i t r a t e , a test c h a r a c t e r i s t i c of benzylic halide, the bromination of (XI) with NBS at the 5- or 6- position was also excluded. The bromination product was then allowed to react with 2-dimethylaminoethanol i n the presence of sodium amide, an attempt to prepare a derivative with a possible l o c a l anesthetic side-chain. A colorless l i q u i d , b.p. 65-69/1 mm Hg, was obtained. The infrared spectrum of t h i s liquid-Mid not show the c h a r a c t e r i s t i c t e r t i a r y amine absorption bands, and instead, showed possible C=C absorption bands at 1640 cm" and 3000 cm - 1. The presence of C=C bond i n t h i s compound was further characterized by i t s r e a c t i v i t y toward bromine i n carbon tetrachloride. 35 Proposed Reaction: C H 3 CW. The unsuccessful synthesis of the aminoalkylether d e r i v a t i v e then l e d to the next attempt i n which the bromo compound was to be converted t o the n i t r i l e by the a c t i o n of potassium cyanide i n aqueous ethanol. I t was thought that i f the 4 - n i t r i l e were s u c c e s s f u l l y made, subsequent h y d r o l y s i s would y i e l d the a c i d . This a c i d , then, could serve as a p o t e n t i a l intermediate f o r the synthesis of a number of e s t e r and amide d e r i v a t i v e s which might possess l o c a l a n e s t h e t i c a c t i v i t i e s . The attempt, however, f a i l e d when the only i s o l a b l e product, a c o l o r l e s s l i q u i d , was i d e n t i f i e d t o be the same compound obtained i n the previous experiment. The same r e a c t i o n was attempted by r e p l a c i n g the h i g h l y p o l a r solvent of aqueous ethanol w i t h absolute methanol and dimethyl s u l f o x i d e , a l e s s p o l a r s o l v e n t . The r e s u l t s obtained were i d e n t i c a l . The r e s u l t s obtained from these attempts suggest t h a t e l i m i n a t i o n i s o c c u r r i n g . Since the y i e l d of o l e f i n i n 36 a preparation w i l l depend l a r g e l y on how e f f e c t i v e l y the e l i m i n a t i o n r e a c t i o n competes w i t h the Sn r e a c t i o n (s) that g e n e r a l l y accompany i t , c a r e f u l considerations have to be put i n the E/Sn r a t i o which may be e i t h e r r a i s e d or lowered, depending on the base involved (102). I f the base i s weak but i s s t r o n g l y n u c l e o p h i l i c toward carbon ( f o r example, PhS~ and CN"), i t w i l l be very e f f e c t i v e i n b r i n g i n g about bimolecular s u b s t i t u t i o n (where a t t a c k on carbon i s required) but f a r l e s s e f f e c t i v e i n b r i n g i n g about b i -molecular e l i m i n a t i o n (where e x t r a c t i o n of a proton i s r e q u i r e d ) . Hence, when such base i s added to a s o l u t i o n of the s u b s t r a t e , bimolecular s u b s t i t u t i o n i s expected to take place. Consequently, i f KCN was allowed t o react w i t h the 4-bromo compound, s u b s t i t u t i o n should take place w i t h the cyano group r e a d i l y r e p l a c i n g the bromo group. Since, however, the same o l e f i n was obtained i n a l l the previous attempted r e a c t i o n s ( e i t h e r i n the s t r o n g l y b a s i c medium such as the sodium amide, or i n the weakly b a s i c medium, the potassium cyanide), the r a t e of these r e a c t i o n s seemed not to be a f f e c t e d by the a d d i t i o n of bases. Assumption was then made that these r e a c t i o n s proceeded w i t h a E l or unimolecular e l i m i n a t i o n mechanism. 37 The f i n a l synthesis was an attempt to prepare the G-rignard reagent of 2:3-benzo-4-bromo-l,l-dimethyl-l-silacyclohex-2-ene, which should serve as a useful synthetic intermediate to obtain the corresponding acid (by carbona-tion) and other derivatives. Carbonation of the reaction mixture with Dry Ice followed by acid hydrolysis obtained colorless c r y s t a l s , m.p. 170-171GC. On the basis of elemental analysis and infrared studies, t h i s i s o l a b l e compound i s believed to be 4,4'-bi-(2:3-benzo-l,l-dimethyl-l-silacyclohex-2-ene)(XVI). I t i s possible that the formation of (XVI) results from a Wurtz-type coupling reaction enhanced by tetrahydrofuran. C H * CX21) PART V EXPERIMENTAL A l l melting points and b o i l i n g points are uncorrected. Elemental microanalyses were performed by Dr. G. Weiler and his associates, Oxford, England, and Dr. Alfred Bernhardt, Hohenweg, West Germany. Infrared spectra were recorded on a Unicam Sp. 200 Infrared Spectrophotometer. o-Bromotoluene (90) A solution of o-toluidine (162 gm., 1.5 mol.) i n 880 ml. (6 mol.) of 40% hydrobromic acid i n a three l i t e r f l a s k was cooled to 5°0 and diazotized with 116 gm. (1.7 mol.) of powdered sodium n i t r i t e added about 10 gm. at a time. A f t e r each addition the f l a s k was stoppered and s t i r r e d vigorously u n t i l the red fumes were absorbed with the temperature kept below 10°C. When the diazotization was complete, about 5 gm. of copper turnings were added, and the fl a s k was attached to a condenser and heated very cautiously. As soon as the f i r s t sign of reaction was observed, the f l a s k was cooled with i c e . Nitrogen was evolved vigorously. When the reaction subsided, the fl a s k was heated on a steam bath f o r one-half hour. One l i t e r of water was added and the mixture was d i s t i l l e d with steam u n t i l about 1.5 l i t e r passed over. The 39 d i s t i l l a t e was made alk a l i n e with 10% sodium hydroxide and the organic layer separated. The crude d-bromotoluene was washed twice with cone, s u l f u r i c acid, and then three times with water. The washings removed most of the color. The organic layer was dried over sodium sulfate overnight, f i l t e r -ed, and d i s t i l l e d at atmospheric pressure. The pure product, 110-120 gm (43-47% y i e l d ) , b o i l s at 178-181 C. ( l i t . (90) b.p. 179-1810). The infrared spectrum showed the ch a r a c t e r i s t i c o-substitution absorption band at 760 em"1, and the absorp-t i o n band at 1380 cm"*1 was assigned to the methyl bending mode. The band at 2990 was assigned to the ch a r a c t e r i s t i c methyl C-H absorption. o-Bromobenzyl Bromide A o n e - l i t e r three necked f l a s k was equipped with a mechanical s t i r r e r , condenser, and dropping funnel, o-Bromotoluene (171 gm., 1 mol.) was heated i n the f l a s k (to approximately 140°C.) and s t i r r e d at a very slow rate. Bromine (128 gm., 0.8 mol.) was added dropwise with the temperature kept between 140-150°C. The addition of bromine was finished i n three hours, and s t i r r i n g continued for an additional hour; during that time, most of the HBr formed escaped through the condenser. The solution was cooled and d i s t i l l e d under reduced pressure. The pure product came of f at 93-96° 1 mm Hg i n 75$ y i e l d (160 grams), ( l i t . (94) b.p. 129/19 mm Hg; (97) 66-69/0.3 mm Hg.) 40 The infrared spectrum showed absence of methyl bending absorption. The bands at 2990 cm"1 and 3060 cm"1 were assigned to stretching mode of methylene group and aromatic C-H respectively. S-(o-bromobenzyl)-isothiourea picrate Finely powdered thiourea (1 gm.), o-bromobenzyl bromide ( l gm.), and ethyl alcohol (10 ml.) were refluxed for a period of 5 minutes. P i c r i c acid (1 gm.) was then added, and the mixture was heated u n t i l a clear solution was obtained and cooled. The crystals were removed by f i l t r a t i o n and r e c r y s t a l l i z e d from ethanol to give yellow needles, m.p. 227-228 C. Anal. Calcd. f o r C ^ H ^ O ^ B r S : C, 35.45; H, 2.51; N, 14.76; S, 6.76 Found: C, 35.77; H, 2.54; N, 15.51; S, 6.96 L 5-(o-Bromophenyl)-propan-l-ol This preparation was performed throughout i n an atmosphere of dry nitrogen. o-Bromobenzyl bromide (160 gm., 0.64 mol.) i n ether (500 ml.) was added dropwise to a s t i r r e d mixture of magnesium (16 gm., 0.66 gm-atom.) and ether (50 ml.). The reaction was i n i t i a t e d by the addition of an iodine c r y s t a l . When the formation of the Grignard reagent had been formed by three hours' s t i r r i n g , i t was cooled i n an ice bath, and a cold solution of ethylene oxide (63 ml., 1.25 mol.) i n ether (100 ml.) was slowly added. 41 A sticky semisolid slowly separated. The mixture, a f t e r standing overnight, was hydrolyzed by d i l . s u l f u r i c acid. The ethereal layer, was dried over magnesium sulfate and d i s t i l l e d under reduced pressure to give the following fracti o n s : a. 39.41/3 mm Hg; b. 120-123/2 mm Hg; c. 123.145/2 mm Hg. Fraction (b) was the colorless propanol (64 grams, 47% y i e l d ) , n^° 1.5699. Fraction (a) was i d e n t i f i e d to be ethylene bromohydrin. The infrared spectrum showed the cha r a c t e r i s t i c 0-H absorption band at 3300 cm - 1. The strong absorption bands at 1470 cm - 1, 2850 em"1 and 2900 cm"1 were assigned to methylene stretching. The o-substitution absorption band was shown at 760 cm"1. 3-(o-Bromophenyl)-propyl-i-naphthylcarbamide 0.5 gm. of the anhydrous 3-(o-Bromophenyl)-propanol-l was placed i n a test tube, and 0.5 gm. of the <A-naphthyli-soeyanate. was added. The mixture was heated gently for 2 minutes and was then cooled i n a beaker of i c e . The side of the test tube was scratched to induce c r y s t a l l i z a t i o n . When the crystals had been formed, 5 m. of petroleum ether (b.p. 66-75 C.) was added, and the mixture was warmed and f i l t e r e d . The f i l t r a t e was cooled i n a beaker of ice, and the urethan crystals slowly precipitated. The crystals were r e c r y s t a l l i z e d from petroleum ether, m.p. 112-113 C» Anal. Caled. f o r C ^ H ^ O ^ r : C, 62.51; H, 4.72; N, 3.56 42 Found: C, 62.65; H, 4.66; TS-, 4.26 5-(o-Bromophenyl)-propyl Bromide A 500-ml three necked f l a s k was equipped with a mechanical s t i r r e r , a condenser, and dropping funnel. 3-(o-Bromophenyl)-propan-l-ol (100 gm., 0.46 mol.) was placed i n the f l a s k and cooled to ice bath temperature; then, phosphorus tribromide (63 gm.» 0.23 mol.) was slowly added with s t i r r i n g . When the addition was completed, the mixture was warmed to room temperature and s t i r r e d for 2.5 hours; followed by heating on a steam bath f o r 1.5 hours. On cooling and hydrolysis with water, ether was added and the organic layer was separated. The organic layer was dried over magnesium sulfate and the solvent was d i s t i l l e d . The pure product was a colorless l i q u i d , b.p. 114-115/2 20 mm Hg., n* = 1.5830. The y i e l d was 97.5 grams (75%). The bands at 1465 cm"1, 2830 cm"1 and 2910 cm"1 were assigned to the methylene stretching. Methylene bending absorption was shown at 1438 cm - 1. Aromatic C-H absorption and o-substitution were shown at 3010 cm"1 and 750 em"1 respectively. S-(5-(o-bromophenyl)-propyl)-isothiourea picrate Finely powdered thiourea (0.5 gm.), 3-(o-bromo-phenyl)-propyl bromide (0.5 gm.), and ethyl alcohol (5 ml.) were refluxed f o r a period of 15 minutes. P i c r i c acide (0.5 gm.) was added and the mixture was heated for an additional 43 5 minutes. A clear solution was obtained and cooled; the picrate crystals were slowly precipitated by adding a few drops of water. The crystals were removed by f i l t r a t i o n and r e c r y s t a l l i z e d from ethanol to give yellow prisms, m.p. 182-182.5 C. Anal. Calcd. f o r C ^ H ^ O ^ B r S : C, 38.57; H, 2.43; N, 14.10; S, 6.44 Pound: C, 38.45; H, 2.27; N, 14.80; S, 6.74 Synthesis of 2:3-Benzo-l,l-dimethyl-l-silacyclo- hex-2-ene 3-(o-Bromophenyl)-propyl bromide (27.8 gm., 0.1 mol.) diluted to 100 ml. with tetrahydrofuran was slowly added to 5.0 gm. (0.22 gm-atom.) of magnesium i n 20 ml. of the same solvent. When the formation of di-Grignard reagent was i n i t i a t e d , the simultaneous addition of 13.0 gm (0.1 mol.) of dichlorodimethylsilane was begun. The reaction mixture was refluxed during the addition of the chlorosilane (2 hours) and then for an additional four hours. At t h i s time the mixture gave a negative test f o r organomagnesium compound using Michler's ketone (Color Test I) (101). The mixture was cooled and f i l t e r e d through glass wool and was hydrolyzed with d i l . ammonium chloride solu-t i o n . The organic layer was separated, and the aqueous layer was dried over magnesium sulfate and was concentrated by using a f l a s h evaporator. The concentrated o i l was then taken up by petroleum ether (b.p. 66-75 C.) and passed through a column of alumina. The petroleum ether eluate was 44 d i s t i l l e d to give 8.5 gm. (48%) of product, b.p. 57-59/1 mm Hg. The infrared spectrum of the compound showed bands at 1082 cm*"1, 1125 em""1 and 1141 cm"1 which constitute the characteristics of a benzosilacyeloalkene nucleus. Methylene bending absorption was shown at 1438 em"1, and the bands at 2830 cm"1 and 2950 cm"1 were assigned to methylene stretching, whereas the bands at 2880 cm"1 was assigned to stretching of methyl group. The a l k y l - s i l i c o n absorption was shown at 1250 cm"1, 850 cm"1 and 800 cm"1. Anal. Calcd. f o r C^jH-^Si: C, 74.94; H, 9.15, S i , 15.92. Pound: C, 74.93; H, 8.92; S i , 14.55. Synthesis of 2:3-Benzo-4-bromo-l tl-dimethyl-l- silac.vclo-hex-2-ene A mixture of N-Bromosuccinamide (4.8 gm., 0.027 mol.), 2:3-benzo-l,l-dimethyl-l-silacyelo-hex-2-ene(4«8 gm., 0.027 mol.), and benzoyl peroxide (0.05 gm.) i n 100 ml. of carbon tetrachloride was heated at reflux temperature for 3.5 hours. The suspension was cooled i n ice bath; f i l t r a t i o n of the cold suspension gave 3.5 gm. of succinimide, m.p. 125-126°C. The f i l t r a t e was concentrated on a f l a s h evaporator and the r e s u l t i n g o i l d i s t i l l e d under reduced pressure to give 3.5 gm. (47% y i e l d ) , of the product, b.p. 115-119/3 mm Hg. The product had to be kept from exposure to l i g h t as de-composition might take place r e a d i l y . 45 The infrared spectrum showed the c h a r a c t e r i s t i c benzosilacycloalkene nucleus absorptions at 1082 cm - 1, 1135 cm"1 and 1150 cm"1 (86). The a l k y l - s i l i c o n absorp-t i o n was shown at 1250 cm"1, 858 cm"1, and 798 em"1. Anal. Calcd. f o r C ^ H ^ S i B r : C, 51.73; H, 5.88; Br, 31.38; S i , 10.98. Pound: C, 51.73; H, 6.02; Br, 31.21. Synthesis of 2:3-Benzo-l.l-dimethyl-l-sila-cyclohex-2-ene by an alternate procedure (attempted) A solution of 3-(o-Bromophenyl)-propyl bromide (27.8 gm., 0.1 mol.) i n 250 ml. of tetrahydrofuran (THF) was added dropwise to a s t i r r e d mixture of magnesium (4.8 gm., 0.2 mol.) i n 20 ml. of the same solvent. The di-G-rignard reagent was formed i n 80$ y i e l d a f t e r s t i r r i n g the mixture for 22 hours at room temperature, followed by 2 hours at reflux. The f i l t e r e d organomagnesium compound was placed i n a clean 500-ml three necked f l a s k equipped with a mechanical s t i r r e r , a condenser, and a dropping funnel. Then a solution of dichlorodimethylsilane (13.0 gm., 0.1 mol.) i n 20 ml. of THF was added slowly to the Grignard reagent. Color Test I (101) was negative a f t e r 5 hours at reflux. Hydrolysis was effected by pouring into an aqueous solution of ammonium chloride. Ether was added and the organic layer separated. The aqueous layer was extracted thoroughly with ether and discarded. The combined organic layer was dried over magnesium sulfate overnight. The f i l t e r e d solution was 46 concentrated on a f l a s h evaporator and the residue was taken up by petroleum ether (b.p. 66-75 C.) and passed through a column of alumina. The petroleum ether eluate was d i s t i l l e d to give the following fract i o n s : (a) b.p. 43r44/2 mm Hg., (b) 59-62/1 mm Hg, (c) 85-93/1 mm Hg with decomposition. The infrared spectra and elemental analysis showed that none of these fractions contained the silacycloalkene nucleus. The infrared spectrum of f r a c t i o n (a) showed the char a c t e r i s t i c CH^ s i l i c o n absorption at 1250 cm"-1, but other a l k y l - e i l i c o n absorption bands were absent at 850 cm"1, and 800 cm"1, The infrared spectrum of fr a c t i o n (b) did not show absorption band at 3060 cm"1 indicating that aromatic cha r a c t e r i s t i c was absent. The broad band at 3300 em"1 was assigned to 0-H absorption. 2t 5-Benzo-4-(2-dimethylaminoethoxy)-l t1-dimethyl- l - s i l a c y clo-hex- 2- ene (at t emp t ed) To a suspension of sodium amide (0.92 gm., 0.036 mol.) i n 20 ml. of dry benzene was added a solution of 2-dimethyl-aminoethanol (0.95 gm., 0.018 mol.) i n 30 ml. of dry benzene. The mixture was warmed f o r 8 hours and then refluxed f o r an additional hour. When cooled, a solution of 2:3-benzo-4-bromo-l,l-dimethyl-l-silaeyclohex-2-ene (2.8 gm., 0.018 mol.) i n 20 ml. of dry benzene was added. S t i r r i n g and refluxi n g was continued f o r 72 hours; a dark brown precipitate plus a dark red l i q u i d resulted. The mixture was poured into 100 ml. of water and the organic layer was separated. The aqueous 47 l a y e r was extracted w i t h two 20 ml. po r t i o n s of ether and added to the organic l a y e r . Benzene solvent was removed by usin g a f l a s h evaporator. The residue was d i s t i l l e d under pressure to give a c l e a r l i q u i d , b.p. 65-69/1 mm Hg* This l i q u i d d e c o l o r i z e d bromine i n carbon t e t r a c h l o r i d e , and the i n f r a r e d spectrum d i d not i n d i c a t e the presence of the t e r t i a r y amino group. 2:5-Benzo-4-cycano-l.l-dimethyl-l-silacyclohex-2-ene  (attempted) Run 1 - A mixture of 2:3-benzo-4-bromo-l,l-dimethyl-l-silacyelohex-2-ene (5 gm., 0.0194 mol.) and potassium cyanide (1.25 gm., 0.0193 mol.) i n a 50% alcohol-water mixture and r e f l u x e d f o r one hour. The a l c o h o l was d i s t i l l e d o f f and the residue was extracted thoroughly with ether. The organic l a y e r was d r i e d over magnesium s u l f a t e overnight and was then concentrated w i t h the a i d of a f l a s h evaporator. The organic concentrated was d i s t i l l e d under pressure to give a c l e a r l i q u i d , b.p. 65-69/1 mm Hg. This l i q u i d d e c o l o r i z e d bromine i n carbon t e t r a c h l o r i d e , and f a i l e d t o react w i t h e t h a n o l i c s i l v e r n i t r a t e IR spectrum d i d not show the presence of the n i t r i l e absorption band. Elemental a n a l y s i s was suggestive that a p o s s i b l e o l e f i n had been formed i n the s i l i c o n r i n g . Run 2 - The same experiment was performed according to the procedure as described above w i t h absolute methanol r e p l a c i n g the aqueous a l c o h o l as s o l v e n t . The same c l e a r l i q u i d , b.p. 65-69/1 mm Hg. was obtained. 48 Run 3 - The same experiment was performed according to the procedure as described i n Run 1 with dimethyl sulfoxide replacing the aqueous alcohol as solvent. No is o l a b l e product was obtained. The infrared spectra of the l i q u i d s obtained from Runs 1 and 2 showed a l k y l - s i l i e o n absorptions at 1250 cm - 1, 860 cm"1, and 800 cm"1. The bands at 1640 cm"1 and 3000 em"1 were assigned to possible C=G absorptions. Synthesis of 2:3-benzo-l.l-dimethyl-l-silacyclohex- 2-ene-4-carboxylic acid (attempted) A solution of 2:3-benzo-4-bromo-l,l-dimethyl-l-silacyelohex-2-ene (5 gm., 0.0194 mol.) i n 30 ml. of t e t r a -hydrofuran (THF) was added slowly to a s t i r r e d mixture of magnesium (0.47 gm., 0.0195 mol.) and THF (20 ml.). The reaction was i n i t i a t e d by the addition of a c r y s t a l of iodine. S t i r r i n g was continued f o r 24 hours at room temperature followed by 6 hours at r e f l u x . The mixture, when cooled, was poured slowly and steadily with s t i r r i n g into a 100 ml. f l a s k containing 20 gm. of Dry Ice i n the form of small lumps. S t i r r i n g was continued u n t i l a l l the Dry Ice had evaporated, "then 50 gm. of crushed ice was added to the s t i f f mass, and the mixture was a c i d i f i e d with 10 ml. of d i l u t e hydrochloric acid (1:1 by volume) and vwas-; s t i r r e d u n t i l most of the s o l i d had decomposed. The mixture was transferred to a separatory funnel and washed with 20 ml. of ether. The ether portion was extracted twice with 20 ml. portions of 5% sodium 49 hydroxide, and the aqueous layer was run into a clean beaker. On a c i d i f y i n g the f i l t r a t e with hydrochloric acid, no crystals were obtained. The ethereal portion, on standing overnight, gave a s o l i d , m.p. 170-171°. The infrared spectrum of t h i s s o l i d did not show absorption bands of the carbonyl group and- the hydroxyl group indicating" that i t was not an acid; instead, the infrared spectrum of which was s i m i l a r to that of 2:3-benzo-l,-l-dimethyl-l-silacyclohex-2-ene, showing absorption bands at 1080 cm"1, 1125 cm"1 and 1145 cm"1 indicating that the benzosilacyclohexene nucleus was s t i l l present. With the information obtained from elemental analysis, t h i s compound has been assigned the structure 4,4'-bi(2:3-benzo-l,l-dimethyl -l-silacyclohex-2-ene) OSI). Anal. Calcd. for C 2 2 H 5 0 S i 2 : C, 75.42; H, 8.57. Found: C, 75.41; H, 8.52. PART VI INPRARED SPECTRA 50 F i g u r e 1. I n f r a r e d Spectrum of o-Bromotoluene. l i q u i d f i l m between sodium c h l o r i d e p l a t e s . F i g u r e 2 . I n f r a r e d Spectrum of o-Bromobenzyl Bromide. L i q u i d f i l m between sodium c h l o r i d e p l a t e s . F i g u r e 3. I n f r a r e d Spectrum of S-(o-Bromobenzyl)-i s o t h i o u r e a p i c r a t e . S o l i d i n potassium bromide d i s k . 51 Figure 4. Infrared Spectrum of 3-(o-Bromophenyl)-propan-l-ol. Liquid f i l m between sodium chloride plates. Figure 5. Infrared Spectrum of 3-(o-Bromophenyl)-propyl-o*--naphthylcarbamide. So l i d i n potassium bromide disk. Figure 6 Infrared Spectrum of 3-(o-Bromophenyl)-propyl Bromide. Liquid f i l m between sodium chloride plates. 52 Figure 7. Infrared Spectrum of S-(3-(o-Bromophenyl)-propyl)- isothiourea p i c r a t e . Soli d i n potassium bromide disk. Figure 8. Infrared Spectrum of F r a c t i o n ( l ) from Reaction of 3-(o-Bromophenyl)-propyl magnesium Bromide and diehlorodimethyl silane. Liquid f i l m between sodium chloride plates. Figure 9. Infrared Spectrum of Fraction(2) from Reaction of 3-(o-Bromophenyl)-propyl magnesium Bromide and dichlorodimethylsilane. Liquid f i l m between sodium chloride plates. 53 Figure 10. Infrared Spectrum of 2;3-Benzo-l,l-dimethyl-l-s ilacyclohex-2-ene. Liquid f i l m between sodium chloride plates. Figure 11. Infrared Spectrum of 2:3-Benzo-4-bromo-l,l-dimethyl-l-silacyelohex-2-ene. Liquid f i l m between sodium chloride places. Figure 12. Infrared Spectrum of the l i q u i d f r a c t i o n from the reaction of 2:3-Benzo-4-bromo-l,l-dimethyl-l-silacyclohex-2-ene and potassium cyanide/2-dimethylamino ethanol. Liquid f i l m between sodium chloride plates. t r a r e m i t t a n c e 5 8 8 8 54 Figure 13. Infrared Spectrum of 4,4'-Bi(2:3-benzo-l, l-dimethyl-l-silacyclohex-2-ene). Solid i n potassium bromide disk. i PART VII SUMMARY The synthesis of 2:3-benzo-l,l-dimethyl-l-silacyclohex-2-ene and i t s 4-bromo derivative have been reported. These compounds have been characterized by means of t h e i r infrared spectra and by elemental analyses of t h e i r pure samples. The reaction scheme used to prepare these compounds was as follows: o-bromotoluene was brominated with free bromine to give o-bromobenzyl bromide which, on treatment with metallic magnesium, gave the Grignard reagent rea d i l y . The Grignard reagent, under specified conditions, was allowed to react with ethylene oxide to give 3-(o-bromophenyl)-propan-l-ol. This propanol was converted to the appropriate bromide with phosphorus tribromide. Prom 3-(o-bromophenyl) -propyl bromide, a Grignard reagent was again prepared. But as soon as the Grignard reaction was i n i t i a t e d , a simultaneous addition of dichlorodimethylsilane was effected. The product obtained was 2:3-benzo-l,l-dimethyl-l-silacyclohex-2-ene i n 48% y i e l d . The organosilieon r i n g compound was then allowed to react with U-bromosuccinimide to obtain the 4-bromo derivative:. Attempts were then made to prepare the 4-cyano and the 4-(2-dimethyl-aminoethoxy) derivatives, from 2:3-benzo-56 4-bromo-l,l-dimethyl-silacyGlohex-2-ene, but results indicated that elimination was occurring. Attempt was also made to prepare the 4-carboxylate derivative by carbonation reac-t i o n , but i t was believed that dimerization was taking place r e s u l t i n g from a Wurtz-type coupling reaction enhanced by THF. PART VIII BIBLIOGRAPHY 1. R.J. Pessenden and M.D. Coon, J . Med. Chem., 8, 604 (1965). 2. R.J. Pessenden and M.D. Coon, J . Med. Chem., 7, 561 (1964) . 3. R.J. Pessenden and M.D. Coon, J . Med. Chem., % 262 (1965) . 4. R.J. Pessenden and M.D. Coon, J . Med. Chem., 7, 695 (1964). 5. M. Kochmann and L. Maier, I I I , Bioehem. Z. 223., 243 (1930). 6. H. Rollhauser, Gegenbaurs morphol. Jahrb., j9_0, 249 (1950). 7. A.O. Voiner and A.K. Ruaanov, Biokhimiya. 11, 102 (1949), through Chem. Abstr. 42, 6719 (1949). 8. S.I. Dorfman and S.A. Shipitsyn, Biokimiya, 20, 139 (1955), through Chem. Abstr., 42, 12651 (19557. 9 . M. Kimitsuki, Pukuoka Acta Med., 4 6 , 998 (1965), through Chem. Abstr., £0, 12252~H96T7. 10. A. Wlodzimierz, Kosmos Warsaw) Ser. A., 12, 497 (1963). 11. V.R. Soroka, Probl. Endokinol. i Gormonterap. 10, 76 (1964). 12. V.R. Soroka, Khoz. i . Med. 1965. p. 600-602. 13. V.R. Soroka, Ukr. Biokhim. Zh., 4, 35 (1963), through Chem. Abstr.. £2, 1 5 6 9 8 ( 1 9 6 3 ) . 14. A.L. Sommer, U. of C a l i f , publications, A g r i c u l . Science, 5(2). 57 (1925). 15. S. Mitsui and H. Takato, Nippon Dojo-Hirykako Zasshi, $0, 535 (I960), through Chem. Abstr.. 56, 725 (1962"7T 58 16. I . langmuir, J . Am. Chem. Soc., 4JL, 1543 (1919). 17. C Mentzer, P. Grey, D. Molho, and B. B i l l e t , B u l l . Soc. Chim. 1946. p. 271. 18. H.L. Preidman, " F i r s t Symposium on Chemical-Biological Correlation", Nat'l Research Council publication #206, Washington, D.C, 1951. 19. J.L. Speier, J . Am. Chem. Soc.. 24, 1003 (1952). 20. S. Fergert and H. Rosman, Acta Dermat. Venereol., 40, 206 (I960). 21. S. Fergert and H. Rosman, Nature, 1£2, 989 (1963). 22. N. Lofgren, Arkiv. Kemi. Mineral Geol., A22, #18, 1946. 23. C.E. Becker, J . Dent. Research, 4.0, 190 (1961). 24. C.E. Becker, J . Dent. Research. 4J>, 195 (1961). 25. A. Quevauviller, Prod• Pharm.. 2» 533, 585 (1952). 26. J . Buchi and X. P e r l i a , Arzneimitt. Forseh., 11, 62 (1961). 27. W. Perkow, Arzneimitt. Forseh., 10, 1020 (I960). 28. R.E. Taylor, Am. J . Physiol.. 196, 1071 (1959). 29. A.L. Bennett and E.G. Chinburg, J . Pharmacol. Exp. Therap.. 88, 72 (1946). 30. R. Straub, Experientia, 12, 182 (1956). 31. A.M. Shanes, Pharm. Rev., 10, 59 (1958). 32. J.C. Skou, J . Pharm. and Pharmacol.. 13_, 204 (1961). 33. A.M. Shanes, Ann. Rev. Pharm., 2 , 185 (1963). 34. L.E. Tammelin and N.M. Lofgren, Acta Chem. Scand., 1, 871 (1947), through Chem. Abstr., ^2, 7443g (1948). 35. L. Goodman and A. Gilman, "The Pharmacological Basis of Therapeutics", 2nd Ed., Macmillan, N.Y. 1955. 36. J.M. Ritchie and P. Greengard, J . Pharmacol., 155, 241 (1963). 59 37. E.J. Ariens and A.M. Simonis, Archs. i n t . Pharmacodynam. Ther. 141. 309 (1963). 38. Erkert, Arzneimitt. Forseh.. 12, 8 (1962). 39. R. Hazard, J . of Physiol. Paris. 52, 116 (i960), through Chem. Abstr.. j>4_, 21457 (I960). 40. <J.M. Ritchie and P. Greengard, Ann. Rev. Pharm., 6, 405 (1966). 41. D. Agin, Nature. 205. 805 (1965). 42. B.B. Brodie et a l , J . Pharm. Exp. Therap., 94. 359 (1948). 43. C.E. Becker, J . Dent. Research. 40. 190 (1961). 44. C.E. Becker, J . Dent. Research. 4J), 195 (1961). 45. G. Hollunger, Acta Pharmacol. Toxicol.. 17, 356 (I960), through Chem. Abstr.. 14711e (1961). 46. H. Blaschko, et a l , B r i t . J . Pharm. Chemotherap., 10, 442 (1955). 47. W. Kalow, Biochem. Pharmacol.. 8, 111 (1961). 48. O.C. P h i l l i p s , et a l , Anesth. Analg. (Cleveland), £9, 317 (I960). 49. F.W. Wagers, and CM. Smith, J . Pharmacol., 150. 317 (I960). 50. E. B a r t l e t t and 0. Hutaserani, Anesth. Analg. (Cleveland), 40, 296-304 (1961). 51. J.E. Steinhaus and D.E. Howland, J . of Pharmacol.. 119, 186 (1957). 52. J.E. Steinhaus and D.E. Howland, Anesth. Analg. (Cleveland), 21, 40 (1958). 53. W. Smith, E. Frommel and C. Morris, J . of Pharmacol. (Lond.), 11, 600 (1959). 54. M.O.Maykut and W. Kalow, Canad. Anesth. Soc. J., 2, 109 (1955). 55. A.C Vecehi, Melone and G. M a f f i i , Farmaco (Sc. Ed.), 1±> 697 (1959). 56. K. Tanaka, Proc. Soc. exp. B i o l . , (N.Y.), jK), 192 (1952). 60 57. K. Kapila and R.B. Arora, J . Pharmacol. (Lond.) 14, 253 (1962) . 58. H.H. Prey, Acta Pharmaco. Toxicol., 19_, 205 (1962). 59. H.F. Zipf, Arzneimitt. Forseh., 7, 529 (1957). 60. L. Pauling, "The Nature of the Chemical Bend", Cornell Univ. Press, Ithaca, N.Y. (1942). 61. S. Sidgwick, "The Electronic Theory of Valency", Oxford Univ. Press, London, p. 115 (1932). 62. F.S. Kipping and J.E. Sands, J . Chem. Soc. 119. 830 (1921). 63. H. Gilman et a l , J . Am. Chem. Soc. 82, 2076 (I960). 64. R. West and R.E. Bailey, J . Am. Chem. Soc. 85, 2871 (1963) . ~~ ~~ 65. P.S. S k e l l and J.E. Goldstein, J . Am. Chem. Soc. 86, 1442 (1964). 66. H. Gilman and W.H. Atwell, J . Am. Chem. Soc. 86, 2687 (1964) . 67. W.H. Knoth and R.V. Lindsey, J r . J . Org. Chem. 2J5, 1392 (1958). 68. G.R. Chainani, S. Cooper, and H. Gilman, J . Org. Chem. 28, 2146 (1963). 69. H. Gilman and W.H. Atwell, J . Am. Chem. Soc. 86, 5589 (1964). 70. R.A. Benkeser et a l , J . Am. Chem. Soc. 84_, 4723 (1962). 71. R. Fessenden and F.J. Freenor, J . Org. Chem. 26, 2003 (1961). " ' ~ 72. R.A. Benkeser et a l , J . Am. Chem. Soc. 86, 2446 (1964). 73. L.H. Sommer and G.A. Baum, J . Am. Chem. Soc. 76, 5002 (1954). 74. R. West, J . Am. Chem. Soc. 77, 2338 (1955). 75. L. Sommer, et a l , J . Am. Chem. Soc. 79_, 3295 (1957). 76. M.K. Wilson and S.M. Polo, Unpublished infrared studies. 61 77. R. West, J . Am. Chem. Soc., 76, 6015 (1954). 78. R. Ramsden, et a l , J . Org. Chem.. 22, 1202 (1957). 79. R. West, J . Am. Chem. S o c . 76, 6012 (1954). 80.. A.F. Reid and C.J. Wilkins, J . Chem. Soc.. 4029 (1955). 81. C. Eaborn, "Organosilicon Compounds", Buttermorth Scient. Pubis. London, I960. 82. L.H. Sommer and O.F. Bennett, J . Am. Chem. Soc., 79, 1008 (1957). 83. H. G-ilman and O.L. Marrs, J . Org. Chem.. ^ O, 325 (1965). 84. H.G-. Emblem, et a l , Chem. and Ind. (London), 905 (1955). 85. D.R. Weyenberg, et a l , Chem. Eng. News, 23. (#37), 67 86. H. Oilman and O.L. Marrs, J . Org. Chem., 29, 3175 (1964). 87. B. Wittenberg and H. ailman, J . Am. Chem. Soc., 80, 2677 (1958) . 88. H. G-ilman and R. Tomasi, J . Am. Chem. Soc., 81, 137 (1959) . 89. H. Gilman and E.A. Zuech, Chem. and Ind. (London), 120 (1960) . 90. A.I. Vogel, " P r a c t i c a l Organic Chemistry", 3rd Ed., Longmans, Green & Co., London, pp. 606 (1964). 91. H. Gilman, "Organic Syntheses" C o l l . v o l . I, John Wiley & Sons, New York, pp. 130 (1932). 92. E.S. Gould, "Mechanism & Structure i n Organic Chemistry", Holt, Rinehart & Winston, Inc. N.Y., pp. 729 (1959). 93. F.G. Holliman and F.G. Mann, J . Chem. S o c , 547 (1943). 94. J . Kenner and J . Wilson, J . Chem. Soc., 1110 (1927). 95. C. Djerassi, Chem. Rev.. £3_, 271 (1948). 96. L. Fieser and M. Fieser, "Advanced Organic Chemistry", Reinhold Publ. Corp., New York, pp. 121 (1961). 97. R.D. Gorsich, Ph. D. Thesis Dessertation, Library, Iowa State Univ. Ames, Iowa (1957). 62 98. W.J. Levy and N. Campbell, J . Chem. Soc.. 1442 (1939). 99. E.S. Gould, "Mechanism and Structure i n Organic Chemistry", Holt, Rinehart, and Winston, Inc., N.Y., pp. 400 (1957). 100. R.E. Dessy and G-.S. Handler, J . Am. Chem. Soc.. 80, 5824 (1958). 101. H. Gilman and F. Schulze, J . Am. Chem. Soc. 47, 2002 (1925). 102. E.S. Gould, "Mechanism and Structure i n Organic Chemistry", Holt, Reinhart, and Winstron, Inc., New York, pp. 487 (1957). 103. S. Senda and H. Izumi, Yakugaku Zasshi, £1, 964 (1961). 

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