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Synthesis of dispiro compounds and derivatives as potential medicinal agents Janis, Ronald Allen Joseph 1968

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S Y N T H E S I S OF D I S P I R O COMPOUNDS AND D E R I V A T I V E S AS P O T E N T I A L M E D I C I N A L A GENTS by RONALD A L L E N J O S E P H J A N I S B.S.P., University of British Columbia, 1966 A T H E S I S S U B M I T T E D I N P A R T I A L F U L F I L M E N T OF THE REQUIREMENTS FOR THE D E G R E E OF MASTER OF S C I E N C E I N PHARMACY in the Division of Pharmaceutical Chemistry of the Faculty of Pharmacy We accept this thesis as conforming to the required standard T H E U N I V E R S I T Y OF B R I T I S H C O L U M B I A October, 1968 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make i t freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his represen-tatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Faculty of Pharmacy The University of British Columbia Vancouver 8, Canada Date October, 1968 ABSTRACT The syntheses of 8-amino-16-azadispiro[6.1.6.2]heptadecan-16-one and its 8-chloroacetyl derivative are reported. The compounds were characterized by their infrared spectra and by elemental analysis of the latter compound. Data is presented for the attempted reaction of dimethylaminoacetic acid with 7-amino-14-azadispiro[5.1.5.2]pentadecan-15-one and 8-amino-16-azadispiro-[6.1.6.2]heptadecan-17-one using dicyclohexylcarbodiimide as the condensing reagent. The reduction of the product obtained from the latter reaction is described. The addition of the 3-dimethylaminoethyl group to the 8-amino dispiro compound named above, in the presence of sodamide was also tried. A 3-dimethylaminoethyl derivative of 7,14-diazadispiro[5.1.5.2]penta-decane was synthesized by the lithium aluminum hydride reduction of the pentadecan-15-one analog. A correct elemental analysis was obtained for the unsaturated compound but the reduced derivative was identified only by its infrared spectrum. It was not determined whether substitution had occurred at the secondary or the lactam nitrogen. The reaction of chloroacetyl chloride with 7,14-diazadispiro[5.1.5.2]pentadecan-15-one using a variety of reaction conditions is described. Data is also presented for the attempted purification of the product obtained from the latter reaction; both thin layer and column chromatography were employed. The condensation reaction of 1-amino-cycloheptanecarbonitrile in the presence of sodium ethoxide and a trace of moisture does not yield the expected 8,16-diazadispiro[6.1.6.2]heptadecan-17-one. Signature of Examiners i i TABLE OF CONTENTS Part Page Abstract i L i s t of Tables v i L i s t of Figures v i i L i s t of Charts v i i i L i s t of Infrared Spectra i x I. INTRODUCTION A. ANTIHISTAMINES 1 1. Pharmacology 1 2. Structure A c t i v i t y Relationships 3 B. LOCAL ANESTHETICS . . 6 1. Pharmacology 6 2. Structure A c t i v i t y Relationships 8 C. ANTIMUSCARINICS 10 1. Pharmacology 10 2. Structure A c t i v i t y Relationships 11 D. PHARMACOLOGICAL ACTIONS OF SOME SPIRO COMPOUNDS 15 II. STATEMENT OF THE PROBLEM 20 II I . CHEMISTRY OF THE PARENT COMPOUNDS A. 7,14-DIAZADISPIR0[5.1.5.2]PENTADECAN-15-0NE 21 B. 14-HYDROXY-14-AZADISPIRO[5.1.5.2]PENTADEC-9-ENE-7,15-DIONE 7-OXIME AND ANALOGS 21 i i i Part Page IV. DISCUSSION OF THE REACTION SEQUENCE A. SYNTHESIS OF DERIVATIVES AND ANALOGS OF 7,14-DIAZADISPIRO[5.1.5.2]PENTADECAN-15-ONE 33 B. SYNTHESIS OF DERIVATIVES AND ANALOGS OF 7-AMINO-14-AZADISPIRO[5.1.5.2]PENTADECAN-15-ONE 43 V. EXPERIMENTAL SECTION ONE SYNTHESIS OF DERIVATIVES AND ANALOGS OF 7,14-DIAZADISPIRO[5.1.5.2]PENTADECAN-15-ONE A. 7,14-DIAZADISPIRO[5.1.5.2]PENTADECAN-15-ONE 49 1. Cyclohexanone Cyanohydrin 49 2. 1-Aminocyclohexanecarbonitrile 50 3. 7,14-Diazadispiro[5.1.5.2]pentadecan-15-one .. 50 B. A 6-DIMETHYLAMINOETHYL DERIVATIVE OF 7,14-DIAZADISPIRO-[5.1.5.2]PENTADECAN-15-ONE 51 1. At Atmospheric Pressure 51 2. At High Temperature and Pressure 52 C. A 6-DIMETHYLAMINOETHYL DERIVATIVE OF 7,14-DIAZADISPIRO-[5.1.5.2]PENTADECANE 52 D. 7-CHLOROACETYL-7,14-DIAZADISPIRO[5.1.5.2]PENTADECAN-15-ONE 53 1. Using DDP as the Hydrochloride Acceptor 53 2. Using Pyridine as the Hydrochloride Acceptor . 57 3. Using DDP and Sodium Acetate as Hydrochloride Acceptors 58 4. Using the Sodium Salt of DDP 58 5. Using Potassium Carbonate as Hydrochloride Acceptor 59 E. PURIFICATION OF 7-CHLOROACETYL-7,14-DIAZADISPIRO-[5.1.5.2] PENTADECAN-15-ONE 59 1. Thin Layer Chromatography on S i l i c a 59 2. Thin Layer Chromatography on Alumina 62 3. "Dry Column"Chromatography on Alumina 62 4. "Dry Column"Chromatography on S i l i c a 64 i v Part Page F. 8,16-DIAZADISPIRO[6.1.6.2]HEPTADECAN-17-ONE (Attempted) 65 1. Cycloheptanone Cyanohydrin 65 2. 1-Aminocycloheptanecarbonitrile 66 3. 8,16-Diazadispiro[6.1.6.2]heptadecan-17-one (attempted) 66 SECTION TWO SYNTHESIS OF DERIVATIVES AND ANALOGS OF 7-AMINO-14-AZADISPIRO[5.1.5.2]PENTADECAN-15-ONE A. 7-AMIN0-14-AZADISPIR0[5.1.5.2]PENTADECAN-15-0NE 68 1. 14-Hydroxy-14-azadispiro[5.1.5.2]pentadec-9-ene-7jl5-dione 7-oxime 68 2. 7-Amino-14-azadispiro[5.1.5.2]pentadecan-15-one 69 B. ' 7-DIMETHYLAMINOACETAMIDO-14-AZADISPIRO[5.1.5.2]-PENTADECAN-15-0NE (Attempted) 69 C. 8-AMINO-16-AZADISPIRO[6.1.6.2]HEPTADECAN-17-ONE 70 1. 16-Hydroxy-16-azadispiro]6.1.6.2]heptadec-10-ene-8,17-dione 8-oxime 70 2. 8-Amino-16-azadispiro[6.1.6.2]heptadecan-17-one 71 D. 8-CHLOROACETAMIDO-16-AZADISPIRO[6.1.6.2]HEPTADECAN-17-ONE 71 E. 8-DIMETHYLAMINOAGETAMIDO-16-AZADISPIRO[6.1.6.2]-HEPTADECAN-17-ONE (Attempted) 72 F. 8-DIMETHYLAMINOETHYLAMINO-16-AZADISPIRO[6.1.6.2]-HEPTADECANE (Attempted) 73 G. 8-DIMETHYLAMIN0ETHYLAMIN0-16-AZADISPIR0[6.1.6.2]-HEPTADECAN-17-ONE (Attempted) 74 H. MISCELLANEOUS 74 1. Raney Nickel Catalyst W-4 74 2. N,N-Dimethylglycine Hydrochloride , 75 3. Chloroacetyl Chloride 75 V Part Page VI. INFRARED SPECTRA 77 VII. SUMMARY 85 VIII. BIBLIOGRAPHY 87 y i LIST OF TABLES Table Page I Maximum Yields of Compounds I with Various Amounts of Catalysts 26 II Reaction Conditions in the Synthesis of the Chloroacetyl Derivative of DDP in which DDP is the Hydrochloride Acceptor 56 III Reaction Conditions in the Synthesis of the Chloroacetyl Derivative of DDP using Potassium Carbonate as the Hydrochloride Acceptor 60 \ v i i LIST OF FIGURES Figure Page 1. Histamine and Representative Antihistamines 5 2. Examples of Synthetic Local Anesthetics 9 3. Acetylcholine and Some Antimuscarinics 14 4. The Structural Relationship Between Spiro Pharmacological Agents Previously Prepared and the Dispiro Derivatives Proposed in this Thesis 19 5. Reduction of C-I to C-II . . 24 6. Structure and Nomenclature of Azadispiro Compounds 27 v i i i LIST OF CHARTS Chart Page 1 22 2 29 29 31 31 34 7 37 47 ix LIST OF INFRARED SPECTRA Infrared Spectrum Page 1. Cycloheptanone Bisulphite Addition Product 78 2. Cycloheptanone Cyanohydrin 78 3. Cyclohexanone Cyanohydrin 78 4. 1-Aminocyclohexanecarbonitrile 79 5. 1-Aminocycloheptanecarbonitrile 79 6. Product from the Attempted Synthesis of 8,16-Diazadispiro-[6.1.6.2]heptadecan-17-one 79 7. 7,14-Diazadispiro[5.1.5.2]pentadecan-15-one Hydrochloride . . 80 8. 7,14-Diazadispiro[5.1.5.2]pentadecan-15-one 80 9. Product from the Attempted Synthesis of 7-chloroacetyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one 80 10. A 3-Dimethylaminoethyl Derivative of 7,14Diazadispiro-[5.1.5.2]pentadecan-15-one 81 11. A 6-Dimethylaminoethyl Derivative of 7,14-Diazadispiro-[5.1.5.2]pentadecane 81 12. 14-Hydroxy-14-azadispiro[5.1.5.2]pentadec-9-ene-7,15-dione 7-oxime 81 13. 7-Amino-14-azadispiro[5.1.5.2]pentadecan-15-one 82 X Infrared Spectrum Page 14. A Product Obtained from the Reaction of N,N-Dimethylglycine, DCC, and 7-Amino-14-azadispiro[5.1.5.2]pentadecan-15-one . . . 82 15. Piperazine Salt of 16-Hydroxy-16-azadispiro-[6.1.6.2]-heptadec-10-ene-8,17-dione 8-oxime 82 16. 16-Hydroxy-16-azadispiro[6.1.6.2]heptadec-10-ene-8,17-dione 8-oxime 83 17. 8-Amino-16-azadispiro[6.1.6.2]heptadecan-17-one 83 18. 8-Chloroacetamido-16-azadispiro[6.1.6.2]heptadecan-17-one . . 83 19. A Product Obtained from the Reaction of Monochloroacetyl Chloride and 8-Amino-16-azadispiro[6.1.6.2]heptadecan-17-one 84 20. Product from the Attempted Synthesis of 8-Dimethylamino-acetamido-16-azadispiro[6.1.6.2]heptadecan-17-one 84 21. Product from the Attempted Synthesis of 8-Dimethylamino-acetamido-16-azadispiro[6.1.6.2]heptadecane 84 ACKNOWLEDGEMENT The writer expresses his sincere appreciation to Dr. T. H. Brown for the guidance and encouragement given during the course of this work and for the suggestion of this research problem. Thanks are also due to Dr. F. S. Abbott for his helpful advice. Financial assistance from the University of British Columbia is gratefully acknowledged. PART I INTRODUCTION The synthesis of derivatives of dispiro compounds was begun in order to make them available for pharmacological testing. These compounds are unique because they contain alicyclic saturated rings that are held perpen-dicular to the side chain. Molecules of this type would provide a particu-larly large blocking area at any receptor to which they might become attached. Pharmacological data on these compounds will help to characterize the steric and electronic requirements of the receptors with which they interact. The side chains proposed for the dispiro compounds are the ones that have been found to produce relatively strong antihistaminic, local anesthetic, or antimuscarinic activity when attached to suitable parent molecules. For good antihistaminic activity, a dimethylaminoethyl group is generally required. Potent local anesthetics often contain a dimethylamino group linked to the parent compound through an amide linkage, and many very active anticholinergics contain the trimethylammonium function. These are the types of side chains that have been proposed for the dispiro compounds. A brief outline of the pharmacology and structure activity relationships of the antihistaminics, local anesthetics, and antimuscarinics follows. Note is also made of the pharmacological results obtained from some related spiro compounds. A. ANTIHISTAMINES 1. Pharmacology Antihistamines may be defined as drugs which diminish or prevent some of the effects of histamine by a mechanism other than the production of pharma-cological responses diametrically opposed to those of histamine. Bronchiolar and intestinal spasm, hypotension, increased capillary permeability, cutaneous 2 wheal and flare, release of epinephrine from the adrenal gland and salivation (but not gastric secretion) are some of the effects of histamine that are diminished by these drugs. Other effects of the antihistamines include, in varying degrees, sedation, local anesthesia, an atropine-like effect that accounts for the drying of mucous membranes, and anti-anaphylactic properties when given in fairly large doses. It is generally believed that an antihistamine exerts its action by competing for the cell receptors of the tissue involved. By attaching itself or covering the receptors in some way, it prevents histamine from exerting its influence on the cell (la) . The greatest beneficial effect of these drugs is in the symptomatic treatment of allergic conditions, notably in mild pollinosis and in acute urticaria. Angioneurotic edema, serum sickness and reactions from certain drugs are usually relieved by the administration of the antihistamines. Atopic dermatitis, contact dermatitis, pruritus ani and vulvae, generalized pruritus and insect bites are some of the itching skin conditions ameliorated by the administration of these drugs (2a). Antihistamines are effective drugs for the prophylaxis of motion sickness (3), but this is probably not a consequence of their antihistaminic activity. Undesirable side effects which vary greatly in severity and incidence with the individual drug are produced by a l l antihistamines. Considerable variation also exists in the sensitivity of individual patients to the toxic as well as the therapeutic actions of these compounds. Sedation ranging from mild drowsiness to deep sleep, is the most common side effect of most of the antihistamines. This effect in turn may give rise to dizziness and disturbed coordination. Lassitude, muscular weakness, dryness of mouth, gastrointestinal 3 upset and anorexia are commonly seen (4). 2. Structure Activity Relationships Most of the antihistaminic substances known can be related to the following general formula: R. X R_ N R. I I R2 R4 When R^  is an ethylene linkage, the compounds can be classified into three broad categories: 1. Ethanolamines, where X = oxygen. 2. Ethylenediamines, where X = nitrogen. 3. Propylamines, where X = carbon. In general, active antihistamines are obtained i f X is 0, N. or C, and it may be incorporated into a suitable heterocyclic ring. For maximum activity, the N-terminal should be tertiary and in particularly, R^  should be methyl groups, or it may be part of a ring without serious loss in activity. R^  and R2 may be aryl, arylmethyl, heterocyclic or heterocyclic methyl. Some representa-tive antihistamines and their structural relation to histamine are shown in Figure 1. The groups present on the N-terminal should be small, symmetrical, and planar. Secondary and primary amine groups in this position result in almost inactive compounds. If a diethylamino or trimethylammonium function is pre-sent, the antihistaminic activity is decreased and the antispasmodic activity is increased (la). The dialkyl amino group may be incorporated into certain ring systems without significant loss in antihistaminic activity. The 4 following groups are in approximate order of decreasing uti l i ty: dimethylamino = pyrrolidino = piperidino > morpholino = thiomorpholino > diethylamino > dibutylamino > secondary amine > primary amine. The group confers the best activity to antihistamines when it is an ethylene function. Except in the phenothiazine series, lengthening or branching of the chain results in a sharp decrease of activity. The addition of an alpha methyl group to the N-terminal of one phenothiazine results in one of the more active antihistamines, promethazine. It is generally believed that the nucleus of these drugs should have at least two aromatic groups or their equivalent in a polycyclic system (la). However, preliminary results obtained on a cyclohexyl analog of diphenhydramine synthesized in this laboratory, indicated that compounds with only one aryl group may s t i l l have considerable antihistaminic activity (5). In the ethanolamine series, the most effective group attached to the 0 atom has been found to be the benzhydryl radical, but replacing one of the phenyl groups with 2-pyridyl or 2-furyl also produces effective com-pounds. Substitution of one of the aromatic rings with a para methyl, methoxy, or halogen is generally advantageous in the non-phenothiazine types of antihistamines. Several different radicals may be used to produce active compounds in the ethylenediamine series. The groups are either isocyclic or heterocyclic aromatic ring systems, one of which may be separated from the nucleus N by a methylene group. Many of the active compounds contain a 2-pyridyl group and a benzyl, substituted benzyl, or one of the isosteres of the benzyl group (la). Unlike the ethanolamines, fusing of the aromatic rings in the Histamine H N" CH, •II J) iphenh ydraraine (an ethanolamine} ,C— 0— CKc P y r i l a r a i n e (an ethylenediamine) Chlorpheniramine (a propylamine) I f — C H 0 CI 1/ \ o K C h l o r c y c l i z i n e (a p i p e r a z i n e ) CI C —N —CH, H CHr Promethazine (a phenothiazine) ff \ \ I T— CH, Figure 1.. Histamine and Representative Antihistamines 6 ethylenediamine series produces phenothiazines that are active antihista-mines. A third type of ethylenediamines is one in which the diamine is part of a piperazine ring. Chlorcyclizine is the most active member of this series; it is four times as active and one-half as toxic as diphenhydramine. In antihistaminic agents that show optical or geometrical isomerism, one isomer is invariably more active than the other. In optical active anti-histamines, the activity generally resides in the dextrorotatory isomer. This isomer specificity, as well as the fact that attempts to relate physical properties such as ionization constants, solubilities, and relative surface activities to antihistamine potency have failed, indicate that steric factors are extremely important in determining activity in this group of drugs. Further information regarding the structure activity relationships of the antihistamines is found in references (la), (6), (7), (8) and (9). B. LOCAL ANESTHETICS 1. Pharmacology Local anesthetics are drugs that block both the generation and con-duction of nerve impulse when applied locally to nerve tissue. The effect of injected local anesthetics varies, depending upon the particular nerve blocked and the concentration of the drug used. The essential features, however, of injection into nerves containing both sensory and motor fibres, are analgesia and muscle relaxation. These drugs may be administered by infiltration of the tissue to bathe fine nerve elements, by injection adjacent to nerves and their branches, by injection into the epidural or subarachnoid spaces, or by topical application. 7 Local anesthetics block conduction by interfering with the large tran-sient increase in the permeability of the membrane to sodium ions that is produced by a slight depolarization of the membrane (2b). Shane suggests that local anesthetics increase the surface pressure of the lipid layer that constitutes the nerve membrane, thereby closing the pores through which the ions move (10). It is known that increasing the external calcium concentra-tion raises the threshold for action potential production, and recently evi-dence has been obtained suggesting that these drugs compete with calcium for membrane sites (11). Further research will be required before the mechanism of action of these drugs is elucidated. Local adverse reactions of these drugs include neurolysis, slough and edema. Systemic effects of local anesthetics are of l i t t le or no therapeutic value. The main serious manifestations of toxicity include depression of the central nervous system and cardiovascular depression. Anaphylactoid shock has occurred after intravenous injection of local anesthetics (12). Lidocaine is of particular interest because it is an aminoacyl amide as are the azadispiro compounds, (the attempted syntheses of which are re-ported in this thesis). Lidocaine produces more prompt, more intense, longer lasting, and more extensive anesthesia than an equal concentration of procaine, which has been used as the standard of comparison for the local anesthetics (2b). Overlapping pharmacological activities are seen in many classes of drugs, including local anesthetics, antihistamines, and antimuscarinics. For example, many local anesthetics, as classified by their chemical structure, possess also varying degrees of antihistaminic, anticholinergic, sedative, antitussive, and convulsive activities. Some examples of synthetic local 8 anesthetics are shown in Figure 2. 2. Structure Activity Relationships The clinically useful local anesthetics may be classified into two groups, the ester and amino compounds, and the non-nitrogenous hydroxy com-pounds. The latter group are used largely for surface anesthesia and even then they are not as effective as the nitrogen containing compounds. Only the structure activity relationships of the nitrogenous compounds will be discussed here. The useful local anesthetics consist of three parts: a lipophilic aromatic group, an intermediate group, and a hydrophilic residue. The general formula for local anesthetics can be stated: Lipophile Intermediate Chain Hydrophile For good activity, a balance between the lipophilic and hydrophilic portions of the molecule is essential (13). The drug must be water soluble enough to be transported through the extracellular fluid and lipid soluble enough to penetrate the cell membrane. The l ipid portion of the molecule is commonly derived from benzoic and para-aminobenzoic acids. In general, the carbonyl group must be conjugated with the aryl group for maximum activity; the introduction of a methylene function between them results in a considerable loss of activity. Substi-tution of a para-amino group on the benzoic acid residue results in an increase of activity; subsequent N-alkylation increases both anesthetic potency and toxicity. Para-alkoxy substitution also increases activity, and the anesthetic activity increases with the molecular weight of the alkyl group. The inter-9 procaine Butethamine D i b u c a i n e L i d o c a i n e Pramoxine Aromatic Residue I n t e r -mediate Chain. Amino Group. C 2 H 5 / H g \ \ / / ° 0 C H 2 C K 2 ^ H 2 N T ^ ^-CO OCHgCHg CS?5 H I C H 2 C K ( C K 3 ) 2 // w -CO !IKCH2CH2-O C 4 H 9 ^ 5 bT \ C 2 H 5 m C O C H , / IT \ C 2 H 5 C 2 H 5 H9C4 0-/ \\ OCErjCHpCHp-ir 0 Figure 2. Examples of Synthetic.Local Anesthetics 10 mediate chain frequently contains an ester linkage, but other groups such as substituted amides, substituted imides, urethanes and ethers are also seen. If the linkage present is stable to hydrolysis in the body, it will result in a compound with a longer duration of' activity. Thus lidocaine (see Figure 2) has a-methyl groups on the phenyl ring that sterically hinder the hydrolysis of the amide bond. The propylene group, as seen in promoxine, appears to be the optinum length for the akyl portion of the intermediate chain, although the ethylene group joined to the ester residue is more commonly seen. The methylene group is reported to make the ester too irritant (lb). The hydrophilic group is usually a secondary or tertiary amino group. Anesthetic potency increases with the size of the alkyl groups as does the toxicity; the maximum increase in activity occurs at to C^. However the diethylamino group is the most commonly seen. No advantage has been observed when the groups on the nitrogen are the same. As was seen in the antihista-mines, the nitrogen may be part of a suitable heterocyclic ring, such as piperidine (lb). C. ANTIMUSCARINICS 1. Pharmacology Antimuscarinics are drugs that inhibit the actions of acetylcholine on structures innervated by postganglionic cholinergic nerves, and on smooth muscle that repond to acetylcholine but lack cholinergic innervation. This class of drugs is also termed atropine-like, anti-cholinergic, antipara-sympathetic, and spasmolytic. In general, small doses of antimuscarinics depress salivary, bronchial, and sweat secretion; larger doses cause mydriasis, 11 cycloplegia, and increase heart rate. S t i l l larger doses inhibit micturation and decrease the tone and motility of the gut. Gastric secretion is inhibited only i f the dose is increased even more. Thus doses of antimuscarinics that are large enough to reduce the tone and motility of the stomach and the duo-denum and depress gastric secretion, usually result in dryness of the mouth, blurred vision, photophobia, and tachycardia (2c). These are the most common side effects seen in the treatment of peptic ulcer with antimuscarinics. Anhydrosis, constipation, urinary retention, and impotence are also encountered. Besides their use in gastrointestinal disorders, these drugs are used in ophthalmology to produce mydriasis and cycloplegia. Some of the drugs in this series have central actions which are important in the treatment of Parkin-son's disease, and the poisoning due to alkyl phosphate compounds and in the treatment of motion sickness (2c). Two antimuscarinics of special interest here are dibutoline and dicyclomine. These compounds both lack aromatic functions that are usually seen in this group of drugs. The azadispiro compounds whose synthesis was attempted in this work also lack aromaticity. Dibutoline (see Figure 3) is used in ophthalmology because of its rapid, relatively brief action after topical application. Dicyclomine reduces the spasm of the gastrointestinal tract, biliary tract, ureter, and uterus without producing the character-ist ic atropinic side effects already mentioned (14). It has been suggested that dicyclomine does not act by competitive antagonism of acetylcholine as do the other anticholinergics, but rather by a local anesthetic action that interrupts local reflexes regulating tone and motility of these muscles (15). 2. Structure Activity Relationships Antimuscarinics vary in chemical structure probably more than do the members of any other single class of pharmacologically active drugs. The relationship between chemical structure and the antimuscarinic activity is enormously complex; consequently, i t will be only briefly outlined here. The general formula for antimuscarinic agents can be represented as: R l R 2 C • — R 4 N R3 + In this formula, R^  is a planar ring, such as phenyl, R£ is a secondary sub-stitution, which may be alkyl, aryl, or hydrogen, and R^  is a hydrogen bonding group. The group linking the terminal C to the cationic head, R^  ^ s 0 £ t e n an ester. The cationic head is a quaternary ammonium group or a tertiary amine with pKa such that a high percentage of the compound is protonated at biological pH (lc). The lipophilic portion of the molecule, R ,^ may vary widely but certain specific volume requirements are usually met. One of the substituents should be a planar ring which is equal or less than a phenyl group in volume, such as the thienyl group. Compounds containing substituted phenyl rings have usually shown a decrease in anticholinergic activity. The phenyl group it-self is not essential for activity (16); for example, high activity has been reported for cyclopentyl-substituted acetic acids (17). The secondary substitution (R2) may be the same as R.^  and it may be incorporated into rings with R ,^ such as in phenothiazines. Or an alkyl group up to normal hexyl or an alicyclic group can represent R^. The assym-13 metric quaternary carbon atom often increases activity (18). This probably indicates a multipoint interaction with an optically active receptor. The group linking the terminal carbon and the cationic head, R ,^ may be varied greatly without markedly altering the inhibitory action. The interatomic distance can vary from 5-9 A. Although many highly active com-pounds contain an ester linkage at R ,^ many other linkages result in active antimuscarinics. Musculotropic activity increases with the length of the linkage. The cationic head is the primary point of attachment of the molecule to the cholinergic site. It is essential for highly active compounds (19), but non-nitrogenous carbocholines have been synthesized that will effectively compete with acetylcholine at the cholinergic receptor (20). Optimal activity appears with substitutions larger than methyl, with isopropyl being the largest useful group before a reduction in activity is seen. Heterocyclic rings also may be used in this position to produce compounds with high anti-muscarinic activity. The structure of acetylcholine and some antimuscarinics are shown in Figure 3. The azadispiro compounds whose syntheses are proposed in this thesis differ most significantly,' from the antihistamines, local anesthetics, and antimuscarinics commonly used, in their lack of aromaticity and their steric configuration. The dispiro compounds contain saturated rings that are per-pendicular to the N-terminal side chain. Most of the clinically useful drugs of a l l three of the groups mentioned contain aromatic rings that may assume a planar conformation with the N-terminal group. Thus far, the requirement for aromaticity in the antihistamines and the local anesthetics has been A c e t y l c h o l i n e CH, ©I CH3COOCJi2CK2- ( . CH, • H — CH 3 A t r o p i n e CHg-OH 2 E C CH CHr 00- — CH KC1U gHC CH CH. p r orjanth e l i n e CH(CH J ©I 5 00CH o CH 9 N — C H , C K ( C H , ) I» i h u t o l i n e CH., ©I (C4H9 ) £ H C 0 0 C H 2 C H — N - C 2 K CH, 1> i c y c l o m i n e Figure 3. Acetylcholine and Some Antimuscarinics 15 found to be very strict. However some active antimuscarinics with no aro-matic character are known, as was mentioned previously. A proposal for future work on the azadispiro compounds is the synthesis of a series of esters. The second group of dispiro compounds used as start-ing material in this thesis, can easily be converted to their secondary alcohol derivatives (21). Thus a series of sterically hindered esters could be prepared. These compounds would contain al icylic rings that are perpendi-cular to the side chain as do the compounds proposed in this thesis, but would differ by the presence of an ester rather than an amide linkage. The ester group is more commonly seen in the local anesthetics and the anticholin-ergics than is the amide group. D. PHARMACOLOGICAL ACTIONS OF SOME SPIRO COMPOUNDS The syntheses of innumerable spiro compounds have been reported. These include compounds with nitrogen, oxygen, silicon and phosphorous incorporated into heterocyclic rings. Spiro compounds composed of three to eight rings, which may or may not be fused to aromatic or steroidal structures, are often seen in the literature. In most cases, only the chemistry of the compounds has been studied, and functional groups characteristic of pharmacological agents are not incorporated into their structures. However, several series of spiro compounds have been synthesized in order to determine structure activity relationships and to provide better therapeutic agents. For example, Capps et al have recently synthesized a large number of triazaspiro compounds, some of which have shown strong anthel-mintic activity (22). Certain sulfamylurea derivatives of l-oxa-8-aza-dispiro[4.5]decane have been found to have hypoglycemic properties in both 16 animals and man (23). In order to further delineate the requirements for psychopharmacological agents, spiro(4-piperidinomethyl-1,3-dioxolane)-2-1'-cyclododecane and related compounds were prepared (24), but no significant biological activity was found. Spirobarbituates were first synthesized as early as 1921 (25). Recently, silicon-substituted derivatives have been pre-pared (26), but these silaalkylspiro analogs did not result in more desirable therapeutic effects. Numerous cycloalkanespiro-5'-hydantoins have been tested for anticonvulsant activity (27), (28), (29), and (30). Analgesic and antiinflammatory activity have been reported with certain cyclohexyl analogs in this series (31). In another series of spirohydantoins, a series of fluorenyl derivatives was synthesized and found to have antitumor activity (32). A large group of spirodihydroperimidines was also tested for anti-neoplastic properties, but only a few of these compounds exhibited any appreciable activity (33). Another series of cytotoxic agents containing spiro rings was prepared as part of a very extensive study of spiro compounds by Rice, Grogan and Geschickter (34). The general structure of the compounds studied by this group is shown below. In the series of compounds prepared for cytotoxic R ( C H 2 ) n activity, ring A was varied from a simple alicyclic ring of five to eight carbon atoms, to substituted carbocyclic rings, and to bicyclic rings such as the tetralins (35), and to heterocyclic rings containing sulphur or oxygen atoms. The value for n varied from one to two and R was a series of dialkyl-17 aminoalkyl groups. Clinical studies of N-dimethylaminopropyl-9-t--butyl-3-azaspiro[5.5]undecane (see Figure 4) on patients with severe carcinomas and sarcomas were very promising (34). Recently Rice extended the A ring to form azatrispirans (36), but less active antitumor activity was seen. When R was substituents such as propargyl, hypnotic and tranquilization effects were seen, while certain a l ly l and dimethylamino derivatives showed CNS stimula-tion and local anesthetic activities, respectively (37). If para-fluoro-aroylalkyl substituents represent the R moiety, potent CNS depressant, hypo-tensive, and antiinflammatory activity were observed in screening tests, and certain of the compounds were clinically active as tranquilizers (38). A series of phenothiazines (39) and butyrophenones (40) linked to the spiro compounds through the endo nitrogen, yielded more compounds with CNS depressant activity. Rice and Grogan also studied permutations of the general formula shown previously, in which the nitrogen in ring B was exo. Pharmacological examinations found that aminospiranes in which the exo-nitrogen atom was sub-stituted \g or y (but not a)) to the spiro carbon atom, displayed potent analgesic, analeptic, and local anesthetic activities (41). A final example of spiro compounds that produced biological activity are the bisdialkylamides of 3,9-dicarboxy-2,4,8,10-tetraoxaspiro[5.5]undecane (42); sedation, muscle relaxation, and tranquilization were seen in the test animals. Considering the structure activity relationships of the local anesthetics discussed previously, it is noteworthy that certain of the spiro compounds such as 3-dimethylamino-3-azaspiro[5.5]undecane-2,4-dione, exhibited local anesthetic activity, although they lack an aromatic function (37). This is consistent with the hypothesis that dicyclomine exerts its antispasmotic effect at least partly through the production of local anesthesia (15). Because of the similarities between the dispiro compounds proposed in this thesis, such 18 as 7-B-dimethylaminoethyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one (-shown in Figure 4 as A), and N-dimethylaminopropyl-9-t-butyl-3-azaspiro-[5.5]undecane, mentioned earlier (34), (and shown in Figure 4 as B), pharmacol-gical screening for anticancer activity on compounds such as A, its dimethylaminopropyl derivative, and the corresponding reduced products, could be profitable. The spiro compounds whose pharmacological activities have just been outlined above, contain N-substituents that can easily assume a planar conformation with either of the spiro rings. These compounds are repre-sented by B, the antitumor agent named in the previous paragraph. As seen in Figure 4 the new dispiro compounds proposed in this thesis, represented by A, differ from the above compounds in that the N-substituents are held approximately at right angles to the terminal cycloalkyl rings, so that such substituents can not assume a planar conformation with the terminal spiro rings. N /\ H 3C CH 3 A (7-3-Dimethylaminoethyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one) B (Nt-Dimethylaminopropyl-9-t-butyl-3-azaspiro[5.5]undecane) Figure 4. The Structural Relationship Between Spiro Pharmacological Agents Previously Prepared and the Dispiro Derivatives Proposed in this Thesis. 20 PART II STATEMENT OF THE PROBLEM The purpose of this investigation was to prepare derivatives of dispiro compounds which contain two cyclohexyl or cycloheptyl rings that are rigidly held perpendicular to the side chain. Molecules of this type would provide a particularly large blocking area at any receptor site to which they might become attached. Pharmacological data on these compounds would give information regarding the steric and electronic requirements of the receptors with which they interact. The side chains proposed for the dispiro compounds are the ones that have been found to produce relatively strong antihistamine, local anesthetic, and antimuscarinic activity when attached to suitable parent molecules. They are B-dimethylaminoethyl, dimethylaminoacetamido, and trimethylammoniumacetamido, respectively. 21 PART III CHEMISTRY OF THE PARENT COMPOUNDS A. 7,14-DIAZADISPIRO[5.1.5.2]PENTADECAN-15-ONE The starting material for the first set of new reactions, 7,14-diazadi-spiro[5.1.5.2]pentadecan-15-one (DDP), was first synthesized by Noland, Sundberg and Michaelson (43) at the University of Minnesota. At that time they were investigating potential synthetic routes to 14-hydroxy-14-azadispiro-[5.1.5.2]pentadec-9-ene-7,14-dione 7-oxime (C-I), one of the starting materials used in the second section of the Experimental. They first obtained DDP in 8% yield in an attempted condensation of 1-aminocyclohexanecarbonitrile with ethyl cyclohexanone-2-carboxylate, catalyzed by sodium ethoxide in absolute ethanol. Repetition of the reaction in the absence of the carboxylate, but in ethanol containing a l i t t l e moisture, gave DDP in 94% yield. The reaction sequence that they propose for the formation of this compound is shown in Chart 1. They believe that the diamine LXVIII could readily cyclize to give the iminoamide LXIX, and this could subsequently be hydrolyzed to LXVII (DDP) by moisture present in the ethanol (43). No n.m.r. data have been reported for DDP and the structure has not been proven unequivo-cally. B. 14-HYDR0XY-14-AZADISPIR0[5.1.5.2]PENTADEC-9-ENE-7,15-DIONE 7-OXIME AND ANALOGS Condensation reactions of aliphatic aldehydes with secondary nitro-paraffins forming nitroalcohols, and of primary nitroparaffins forming nitro-olefins, especially i f the aldehyde is aromatic, are numerous. However there 22 23 have been relatively few reports of similar condensation reactions with ketones. The first report of a condensation reaction between cyclohexanone and nitromethane was made in 1934 when Fraser and Kon prepared 1-nitromethyl-cyclohexanol using sodium ethoxide to catalyze the reaction, and mainly 1-nitromethylcyclohexene using piperidine as catalyst (44). They tried methylamine, ethylamine, concentrated ammonia and aqueous sodium and potassium hydroxide as catalysts, but smaller yields of the 1-nitromethyl compounds were obtained using these bases. The first solid to be isolated from this type of reaction turned out to be C-I. The structure of C-I and its reduced derivative, C-II, are shown in Figure 5. As mentioned in Part III A . , C-I was one of the starting materials used in the second section of the Experimental. This compound was first pre-pared in 1941 by F. B. Erickson in Nightingale's laboratory at the University of Missouri. Cyclohexanone and nitromethane were heated to 105° with piper-idine as the catalyst to yield 8.3 per cent of an unidentified solid with a melting point of 261-262° (dec.) (45). The same solid was obtained i f di-N-propylamine was used as a catalyst (46). Analogous solids were also obtained from 4-methylcyclohexanone and 3-methylcyclohexanone but not from 2-methyl-cyclohexanone (46). In 1947 Lambert and Lowe (47) isolated the same solid using diethylamine as a catalyst. They wrote the formula C j 4 H 2 0 N 2 ° 3 on the basis of carbon, hydrogen, and nitrogen analyses and a molecular weight determination by X-ray methods. They also isolated 1-nitromethylcyclohexene, 1-nitromethylcyclohexanol and 1,1-bis(nitromethyl)-cyclohexane from the same reaction. Nightingale et al (46) obtained C-I in low yields from both 1-nitromethylcyclohexanol and 1-nitromethylcyclohexene in the presence of amine catalysts. Her groups also increased the yield of C-I to 14% by remov-ing the water as it formed by azeotropic distillation from benzene. They 24 OH 0 C-I (il4-Hydroxy-14-azadispiro[5.1.5.2]pentadec-9-ene-7,14-dione 7-oxime) Raney Ni, Hydrogen V 30-60 p . s . i . , R.T. NH-2 H x0 e -n (7-Amino-14-azadispiro[5.1.5.2]pentadecan-15-one) Figure 5. Hydrogenation of C-I to C-II 25 found that no solid was obtained i f nitroethane,1-nitropropane or phenylnitro-iiiethane replaced the nitromethane. And no solid was obtained from the reaction i f sodium ethoxide was used as catalyst. An analogous solid was obtained using cyclopentanone (46). The most thorough investigation into the reaction of alicyclic ketones with nitromethane with respect to the type and quantity of different amine catalyst needed to produce the best yields of solid compound, was carried out by Shozo Miki in 1961 at Nightingale's laboratory (48). At that time the structure of the solid material obtained was not known, but the functional groups present had been determined accurately. Table I summarizes the results of the better catalysts tried. Figure 6 indicates the structure and names of the different compounds. Included are the results from previous studies already referred to as well as subsequent ones (49), (21) and (50) by Nightingale's group. The yield of P-I was the most variable; the yields of two reactions using reagents from the same bottles varied from 12 to 24%. The ketone to catalyst ratio that gave the best yield of P-I was 14:1 and not 4:1 as indicated in Table I of reference (49). The maximum yield reported by Miki was 47.2% for C-I using piperazine as catalyst but a yield of 67.0% was later reported (49). Using piperidine as catalyst, Noland and Sundberg (51) obtained a yield of 29% by adding the amine occasionally during the reaction period and increasing the reflux time to 72 hours. The yield of H-I reported in (49) is 51.5% using piperazine but this result is based on the weight of the piperazine salt obtained, m.p. 208-209° (dec.) but was calculated for the H-I itself (48). Al l the compounds in the table melt with decomposition and some sublimation. The latter causes considerable variation in the melting points reported by different workers. The 3,11-dialkly analogs of C-I have two asymmetric carbons and two centres leading to geometric isomers, making TABLE I MAXIMUM YIELDS OF COMPOUNDS I WITH VARIOUS AMOUNTS OF CATALYSTS I Ketone Catalyst Moles C6H6 Hours Yield Ratio of Ketone M.P. moles D O ml. Reflux % to Catalyst °C P-I a 0. .87 piperidine 0, ,06 115 57 24.3 14: 1 246-247 C-I 0, .93 piperidine 0, .13 115 100 23.7 7: 1 262-263 C-I 0. .55 morpholine 0, .50 100 64 22.3 1: 1 261-263 C-I 1. ,86 piperazine 1, .86 290 30 67.0 1: 1 ' 273-274 M-I b 0. .21 piperazine 0. .10 35 64 40.5 1: 1 272-274 E-1C 0. .80 piperazine 0, .79 150 19 37.0 1: 1 272-276 n-Pr- l° 0. ,28 piperazine 0, .15 75 23 29.0 1.8: 1 270-271 i-Pr-1 0. ,20 piperazine 0, .20 130 71 40.0 1: 1 294-295 t-B-1 0. ,24 piperazine 0. .12 80 63 33.7 2: 1 320-321 s-B-1 0. ,16 piperazine 0. ,08 100 118 23.0 2: 1 285-286 Ch-1 0. ,20 piperazine 0. ,10 100 87 20.3 2: 1 303-304 H-l 0. ,10 piperidine 0. ,10 50 72 48.0 1: 1 250-251 H-I 0. ,21 piperazine 0. ,10 50 80 51.1 2: 1 250-251 0-1 0. ,24 piperazine 0. ,12 57 48 0.9 2: 1 230-231 All data is from reference (49), except (a) , from (48); (b), (50); and (c), (21) • 27 H-I 0-1 P-I 12-Hydroxy-12-azadispiro[4.1.4.2]tridec-8-ene-6,13-dione 6-oxime. C-I 14-Hydroxy-14-azadispi.ro[5.1.5. 2]pentadec-9-ene-7,15-dione 7-oxime. M-I 3,11-Dimethyl- 14-hydroxy-14-azadispiro[5.1.5.2]pentadec-9-ene-7, 15-dione 7-oxime. The other 3,11-dialkyl analogs of C-I are named in an analogous fashion. C-I. R H M-I. R = CH3 E-I. R =• C 2 H 5 n-Pr-I. R = - C 3 H 7 i -Pr-I . R i- C3H7 t-B-I. R t - C 4 H 9 s-B-I. R S--C4H9 Ch-I. R = C6H10 H-I 16-Hydroxy-16-azadispiro[6.1.6.2]heptadec-10-ene-8,17-dione 8-oxime. 0-1 18-Hydroxy-18-azadispiro[7.1.7.2]nonadec-ll-ene-9,19-dione 9-oxime. Figure 6. Structure and Nomenclature of Azadispiro Compounds eight possible racemates. No effort was made by Nightingale's group to deter-mine whether or not these products are single racemates. One sample of t-B-I obtained by Miki (48) had a m.p. of 284-285° and a correct elemental analysis, but subsequent reactions yielded a solid that melted at 320-321° (49)» In the reaction of cyclohexanone catalyzed by morpholine, and in the reaction of cycloheptanone catalyzed by piperidine, hexamethyleneimine and morpholine, no solid separates from the reaction mixture until after acidification with hydrochloric acid (49). The structure of C-I was first elucidated in 1962 by Noland and Sund-berg (51). Nightingale, Reich and Erickson (46) had previously reported an extensive study of the reactions of C-I in 1958, and had proposed the partial structure C. ,H._N0-(C=0)NH0H; they suggested that it contained a C=N group and a -C=C- group, both of which are unconjugated. Noland and Sundberg sub-sequently proved the atomic skeleton by functional group determination experi-ments shown in Chart 2 (51). Acidic hydrolysis of the oximino group in I to Form IV and failure of acid-catalyzed esterification of the latter indicated that a hydroxamic acid' group was not present in I as originally thought. Hydrogenolysis of the acidic hydroxyl group of IV under mild conditions and the position of the amide carbonyl band in the infrared spectrum of XV were consistent with a five-membered ring N-hydroxylactam structure of IV and not a carboxylic acid as would be obtained from a hydroxamic acid structure in I. Conversion of the ketone IV to Ie, the syn or anti stereoisomer of I by oxima-tion, and the subsequent hydrogenation of Ie to II as shown in Chart 3 (51) proved that Ie and I have the same atomic skeleton. Application of Hofmann degradation to lie did not result in the formation of an olefinic elimination product; this suggested that the carbon bearing the trimethylammonium group in He is attached to carbons bearing no hydrogens. This is supported by the Chart 2.* R « ° KOH H2SO4 ' C K 3 I Ii ,R = S02CoHt,(54%) Ij.R-H(13%) 93% From reference (51). 30 fact that the n.m.r. spectrum of XV contains a single large peak at 8.31T attributed to twenty essentially equivalent methylene protons of the two cyclohexane rings. Hofmann degradation was carried out on the trimethylam-monium derivative of V to form an intramolecular displacement product, an epoxide; this reaction is characteristic of 3-hydroxyamine methiodides. Thus the hydoxyl group in V and the amino group in II must be beta to the amine and amide nitrogens, respectively. This set of reactions confirmed the structure of II as shown in Chart 3 and the skeleton of I as an unsaturated five-membered ring ketoxime N-hydroxylactam. House and Magin (52) independently arrived at the same atomic skeleton by a different degradative-route. An independent synthesis of XV and II was performed as synthetic proof of the atomic skeleton of I (C-I) . The scheme used by Nolaiid and Sundberg (51) is shown in Chart 4. Acylation of 1-aminocyclohexanecarbonitrile with ethyl chloroformylacetate and subsequent cyclization with sodium ethoxide ; yielded XXXVI. After alkaline hydrolysis with accompanying decarboxylation and dialkylation with 1,5-dibromopentane, XV was produced. Since XV has been converted to II and the latter is derivable from I ,under conditions of low-pressure hydrogenation, i t was assumed that the atomic skeleton proved to be present in II is also present in I. The double bond was shown to be in the left-hand ring by acid cleavage of the g-ketolactam group with the action of strong alkali at 200° on IV, to yield cyclohexanecarboxylic. The n.m.r. spectrum of the 3,11-dimethyl homolog of IVa clearly showed that the double bond was not in the 10,11-position; the double bond in this position would give a spectrum with only one vinyl proton rather than the two seen to be present. This completed Noland and Sundberg's determination of C-I (51). Chart 4.* CH, ^COCl "COOEt pyridine 42% Kj 6 1 % O - ^ C H 2 C O O E t N — C " s 6 xxxv Q B r - B r X X X V I I a X V c E t O N a 6 8 % B r , 72% H2NOH-HCI .pyridine 7 8 % H 2 ^•^r-coost H A X X X V I KOH 6 7 % OH X X X V I I Br(CH0,Br N n H 2-3% o •6 X V Chart 5.* 2CH3NO, O H O H L X I X -H2Q, 0^9." I T O H C H 2 I N02 L X X I L X X + N-0H I 0" N<£"N=0 N-^C-H 6 e L X X I I I L X X I V B : H L X X V O H L X X V 1 I / L X X V I 32 In Chart 5 is a mechanism for the formation of C-I suggested by Noland and Sundberg (51) . They state that LXXI is the probable intermediate for the link between LXXVI which could readily cyclize to form C-I and the 2:1 conden-sation product LXXI (which has been isolated from the reaction in which C-I is formed), or the 1:2 adduct LXIX. From LXXI would follow a series of steps involving intramolecular oxygen transfer, dehydration, and oxidation-reduction, possibly proceeding in the order shown in the chart. PART IV DISCUSSION OF THE REACTION SEQUENCE A. SYNTHESIS OF DERIVATIVES AND ANALOGS OF 7,14-DIAZADISPIRO[5.1.5. 2] -PENTADECAN-15-ONE The first dispiro compound chosen as starting material for the prepara-tion of compounds with possible biological activity was 7,14-diazadispiro-[5.1.5.2]pentadecan-15-one (DDP). This compound was prepared by the method of Noland and Sundberg (51) from 1-aminocyclohexanecarbonitrile. The latter compound was synthesized by reacting cyclohexanone with sodium bisulfite, followed by potassium cyanide to form the cyanohydrin (66); this in turn was treated with ammonia gas to form the aminocarbonitrile (51). The reaction sequence to DDP is shown in Chart 6. The overall yield of DDP from the ketone was 36%. The maximum yield obtained for the final reaction was only 70% as compared with 94% obtained by Noland and Sundberg (51). This may be due in part to residual benzene present in the 1-aminocyclohexanecarbonitrile, since the yield obtained by them for the latter compound was 61%, but the apparent yield obtained in this laboratory for the same compound was 92%. An attempt was made to form the cycloheptyl analog of DDP; exactly the same procedure (51) was used except that the ketone was cycloheptanone. The cyanohydrin and the 1-aminocycloheptanecarbonitrile were obtained in comparable yields, 47% and 99% respectively. But when the latter compound was reacted with sodium ethoxide, the only solid that separated from the reaction mixture was sodium cyanide. Assuming that the dispiro compound forms by the mechanism suggested by Noland and Sundberg (shown in Chart 1) there appears to be no simple explanation for the lack of formation of at least some 8,16-diazadir-••„. -34 Chart 6. 35 spiro[6.1.6.2]heptadec-17-one. In this laboratory, the cyclopentyl analog, 6,12-diazadispiro[4.1.4.2]tridecan-13-one, had been prepared in low yield from cyclopentanone (53) and (54). A B-dimethylaminoethyl derivative of DDP was prepared by reacting the DDP with sodium hydride and then adding B-dimethylaminoethylbromine hydro-bromide to the reaction mixture (53). Although the structure of this product shown on Infrared Spectra 10 and 11 is the 7-substituted compound, substitu-tion on the amide nitrogen may have occurred. Under neutral conditions, the secondary nitrogen would be considerably more nucleophilic than the amide nitrogen; their pKa values would be about 11 and 0.0 respectively. The adja-cent carbonyl group in the latter exerts an electron-withdrawing effect which decreases the ability of the amide nitrogen to share its unshared pair of electrons. However, in the presence of strong base the carbonyl group would help stabilize the incipient carbanion. Moreover, there appears to be some steric hindrance to attack on the secondary nitrogen, so that i f a di-sodium salt formed in the reaction with sodium hydride, the amide nitrogen may be more easily alkylated. N-alkylation of amide nitrogens in the presence of sodium hydride is known; one example is the reaction of methyl iodide with a NaH treated intermediate in the synthesis of morphine (55). The lack of char-acteristic N-H stretching bands at 3250-3050 cm. * for the lactam also suggests that substitution occurred on the amide nitrogen. The yield of the dimethylaminoethyl derivative of DDP was increased from 11 to 17 per cent by reacting the alkyl halide with DDP at 145° and 120 p . s . i . At s t i l l higher temperature and pressure, 280° and 340 p . s . i . , no product was obtained. Higher yields of the product might be obtained i f the ratio of DDP to alkyl halide was 2 to 1 rather than 1 to 7 (56). The low 36 yields obtained are due at least partly to steric hindrance. In an analogous reaction by F. Leung (57), the condensation of N-cyclohexyl-N-cyclohexane-methylamine with the same alkyl halide, as well as the more reactive iodide derivative, in the presence of sodamide, yielded no product. The B-dimethylaminoethyl derivative of DDP was reduced with LiAlH^ to form the substituted 7,14-diazadispiro[5.1.5.2]pentadecane. As seen from the infrared spectrum 11., the product did not contain the carbonyl function. However, attempts to obtain a correct elemental analysis for the tripicrate derivative of the compound were not successful. The complete reaction sequence ini t ia l ly proposed for DDP is shown in Chart 7. The synthesis of a B-dimethylaminoethyl derivative and its sub-sequent reduction has already been described. As seen in the chart, an alternate reaction sequence to the reduced product might begin with the chloroacetamido derivative of DDP. Chloroacetylation of DDP was attempted under a variety of conditions. The apparatus, solvents, and reactants were thoroughly dried before use. Chloroacetyl chloride was synthesized from the reaction of monochloroacetic acid and benzoyl chloride (70) or thionyl chloride (71), the latter resulting in higher yields. In the first series of reactions, the secondary amine, DDP, was the hydrochloride acceptor. As seen in Table II, Part VI, no significant difference in the yield of product was obtained when the reaction time and the mole ratio of reactants were varied. At temperatures of 190° and 138°, no pro-duct was obtained. In a l l the reactions carried out at the reflux temperature of the solvent, benzene, about 3/4 of the starting material was recovered, either as DDP or as its hydrochloride. 37 Chart 7. :H 0 7-Trimethylammoniumacetyl-7,14-diazadispiro[5.1.5.2]-pentadecan-15-one Iodide 38 In this series of reactions as well as the ones that followed, a gum was obtained. Only after standing for several weeks could the product be obtained as a solid; the addition of acetone allowed the isolation of a white solid by suction fi ltration. In a l l the reactions tried, the solid so obtained had the same infrared spectrum. It did not contain significant quantities of the starting material or DDP HC1. No peaks are seen at 1690 cm. - 1 or 1730 and 1585 cm."1; but i f DDP or DDP HC1 are added to the product in a ratio of 1 to 100, these peaks are easily seen. The infrared spectrum did indicate that a second carbonyl peak had been added to DDP. However, a band was also seen at 1500 cm. "*"; this may be due to the presence of acyclic amide, since Amide II bands are seen in this region. Elemental analysis indicated that chlorine was present but the percent carbon obtained was too low. Thin layer chromatography showed that the product may be composed of three components. It is difficult to explain why the same infrared spectrum is obtained for the product synthesized under varying reaction conditions i f this product is composed of three different compounds. It is probable that at least some acetylation is taking place on the lactam nitrogen, even under neutral conditions. A series of model reactions was carried out to determine the reactivity of the secondary amine and the lactam nitrogen in DDP. Attempts were made to acetylate the compound using acetyl chloride in pyridine and using an excess of acetic anhydride. In both cases no significant yield of product was obtained. However this type of reaction, the acetylation of lactams, are known. For example, a-e-caprolactam is acetylated in acetic anhydride at 110-120° (58). In a similar reaction with DDP, an intractable gum was ob-tained. The results indicate that the secondary nitrogen and possibly the lactam nitrogen, are sterically hindered; at a temperature high enough for the 39 reaction to occur to a s i g n i f i c a n t extent, decomposition occurs. The chloroacetylation of DDP was attempted i n pyridine at 50° and at r e f l u x temperature. An i n t r a c t a b l e t a r was obtained i n both cases. The reaction of chloroacetyl chloride and DDP was also attempted i n g l a c i a l a c e tic acid, according to the method of Grogan et a l (38) they had s u c c e s s f u l l y chloroacetylated d,o'-xylidene by t h i s prodecure. The reaction had been c a r r i e d out by another worker i n t h i s laboratory, and the product obtained gave an i n f r a r e d spectrum s i m i l a r to DDP except that a new peak was present at 1595 cm. * (53). When the reaction was repeated i n t h i s inquiry the compound responsible f o r the 1595 cm. * was separated from DDP by removing the l a t t e r with chloroform. Elemental analysis on the u n i d e n t i f i e d compound indicated that no nitrogen was present. The method of Nagaten et al_ (59) f o r the benzoylation of lactams a f t e r treatment with NaH was applied to the c h l o r o a c e t y l a t i o n of DDP. The i n f r a r e d spectrum of the product contained several peaks i n the carbonyl stretching region i n d i c a t i n g that s u b s t i t u t i o n may have occurred at both nitrogens. Only very small y i e l d s were obtained and the reaction was not investigated further. F i n a l l y , synthesis of 7-chloracetacetyl-7,14-diazadispiro[5.1.5.1]-pentadecan-15-one was attempted using potassium carbonate as the hydrochloride acceptor. This method has been used by several workers to add c h l o r a c e t y l chloride to unhindered primary amines, one example i s the addition of the chloroacetyl group to 2-aminotropone (60). The reaction was f i r s t run i n benzene but the product was obtained i n smaller y i e l d s and contained more impurity than the same reaction i n acetone. Table III i n Part VI shows the d i f f e r e n t reaction conditions t r i e d . The best y i e l d was obtained with a mole 40 ratio of acyl halide to DDP of 2:1. This reaction gave about 5% yield of product with the same infrared spectrum as was obtained from the product of previous reactions run in benzene without potassium carbonate. Over 90% of the starting material was recovered, mostly as DDP, not the hydrochloride, as was seen in reactions without the ^CO^. Attempts were made to purify the product obtained from the reaction of chloracetyl chloride and DDP. First the material was spotted on a 20x20 cm. Eastman K30IR si l ica gel sheet with fluorescent indicator. A total of 1 ml. of a 5 mg./ml. solution of the product in ethanol was spotted along the origin of the sheet forming a line about 2 mm. wide under ultra-violet light. After developing the chromatogram with a hexane, absolute ethanol, diethylamine, 6:1:2 solution, three bands could be seen under short-wave ultra-violet light. The s i l ica was scraped from the dark areas and then extracted with ethanol. The ethanol was evaporated off, and the infrared spectrum of the residue was recorded. The spectra obtained were too weak to be definitely assigned to individual compounds. Two attempts were made to purify the putative chloracetyl derivative of DDP using "dry column" chromatography. The advantage of this technique is that the same conditions found to be suitable for the separation of a mixture by TLC can be directly transferred to the preparative system (61). The mixture to be separated is placed on the top of the column and the chromatogram is developed by allowing the solvent to move down the dry column by capillary action aided by gravity. Furthermore, when the column used is nylon and fluorescent material has been added to the adsorbent, the bands of separating material can, under ideal conditions, be seen i f the chromatogram is developed in the dark and is irradiated with ultra-violet light. The first 41 attempt was made using an alumina adsorbent that had been deactivated with 4% water and had been made fluorescent by the addition of 0.5% duPont No. 609 Luminescent Chemical. The column was prepared and developed according to the method of Loev and Goodman (61). It was loaded by adsorbing the 530 mg. of material to be purified onto alumina and then distributing the alumina onto the column's top. The developing solvent was 80:18:2, acetone reagent:absolute methanol:diethylamine. Before the developing had begun, dark bands were seen under ultra-violet light that were due to the uneven packing of the column. The only band seen under irradiation with ultra-violet light while the column was developing was one that could be seen under ordinary light because i t was coloured. Only a small amount of material was isolated from the first 25 ml. of solvent through the column, and no signifi-cant amount of material was isolated from subsequent fractions. The infrared spectra of the first material isolated was similar to DDP HC1. In order to recover the material from the column, the adsorbent was divided into five portions and these were extracted with hot ethanol, chloroform, and glacial acetic acid, in that order. Only small amounts of materials were extracted and the infrared spectra of these did not indicate the presence of DDP or its derivatives. It is possible that the alkyl halide group chemically reacted with the column. A second column was prepared as before except that silica was used as the adsorbent. The gel was deactivated with 15% water (61) and the fluore-scent material was added as before. The column was loaded by distributing the material to be separated directly on top of the column rather than adsorbing it onto the adsorbent as before. It was thought that denser dark bands might be obtained in this manner. The developing solvent was hexane:absolute ethanol:diethylamine, 6:1:2. Again no dark bands could be seen under short-42 wave ultra-violet light except for the yellow band at the solvent front. As in the previous column, neither the fractions of the developing solvent nor the solvent extractions of the adsorbent yielded material whose infrared spectra indicated that a DDP derivative was present. Because of the difficulties encountered in the purification of the chloroacetyl-DDP and in the synthesis of this compound in good yield, work on an analogous series of dispiro compounds was begun. Relatively l i t t le steric hindrance is present in this series because the nitrogen at which sub-stitution occurs is primary rather than secondary. The reactions of these compounds are discussed in the following section. 43 B. SYNTHESIS OF DERIVATIVES AND ANALOGS OF 7-AMINO-14-AZADISPIRO[5.1.5.2]-PENTADECAN-15-ONE The synthesis and structure determination of C-I, one of the s t a r t i n g materials used i n Section Two of the Experimental, has already been described i n Part III b. In t h i s laboratory C-I (m.p. 272-274° a f t e r r e c r y s t a l l i z a t i o n ) was obtained i n 33.8% and 16.4% y i e l d using piperazine and p y r r o l i d i n e as c a t a l y s t , r e s p e c t i v e l y . The l i t e r a t u r e values are 47.2% (48) (m.p. 263-265.5°, not r e c r y s t a l l i z e d ) and 67% (49), using piperazine, and 23% (49) using pyr-r o l i d i n e . As seen i n Figure 5, i n Part I I I , the reduction of C-I, an unsaturated, five-membered r i n g ketoxime N-hydroxylactam, to C-II a saturated primary aminolactam i s accomplished using n i c k e l as a c a t a l y s t . The reduction was f i r s t accomplished by Nightingale's group at 105-130° and 2900 p . s . i . (46), and then by Noland and Sundberg (51) at room temperature and 30 p . s . i . In t h i s laboratory the l a t t e r method was used; the y i e l d was 45.5%, m.p. 192-193° a f t e r r e c r y s t a l l i z a t i o n s from ethanol, l i t . (51) 95%, m.p. 193-195°, before r e c r y s t a l l i z a t i o n . In some reductions attempted, unreactive s t a r t i n g material and the p a r t i a l l y reduced iminolactam were obtained. The synthesis of 7-dimethyaminoacetamide-14-azadispiro[5.1.5.2]-pentadecan-15-one was attempted by the addition of dimethylaminoacetic acid hydrochloride to C-II previously treated with dicyclohexylcarbodiimide, according to the method of Sheehan and Hess (62) proposed for peptide bond formation. Triethylamine was used as the hydrochloride acceptor (63). The general mechanism for t h i s reaction i s shown below (64). 44 •0 NR' 0- NR' II II ' II II •RC-OH + G > RC-O-C II I NR' HNR' I II III RC-NR' Ii I 0 C-=0 NH^R" -> RCO-NHR* IX NHR' VII VIII V VIII The carboxylic acid (I) reacts with the carbodiimide (II) which, i n turn, could undergo ei t h e r conversion to two act i v e forms (IV and VI) of the o r i g i n a l carboxylic a c i d or rearrangement v i a a c y l transfer to an N-acylurea (VII). The l a t t e r compounds are generally quite stable and exhibit l i t t l e i n c l i n a t i o n to undergo condensation, but t h i s depends on the p a r t i c u l a r peptide d e r i v a t i v e , carbodiimide, and solvent involved. Rearrangement of (III) to (VII) occurs v i a an intramolecular mechanism while the reactions (III) to (IV), (IV) to (VI) and (VIII), and (VI) to (VIII) are bimolecular; therefore, the formation of the desired products should be favored by an increase i n the concentration of the reactants. Hence the amount of solvent employed should be kept to a minimum (64). The dicyclohexylurea (V) i s e a s i l y separable from the product by v i r t u e of the former's general i n s o l u b i l i t y i n most of the solvents employed during the coupling step. Only one attempt was made to condense dimethyaminoacetic acid with C-II. Approximately equimolar quantities of the carboxylic a c i d , C-II, triethylamine, and DCC in dichloromethane were s t i r r e d at room temperature f o r two weeks. No 45-compounds with two carbonyl peaks in the 1750-1650 cm."''' region were isolated from the solvent. The same reaction was also attempted using the cycloheptyl analog of C-II, 8-amino-16-azadispiro[6.1.6.2]heptadecan-17-one. After stirring the reactants at room temperature for two days, the reaction mixture was diluted with hot dichloromethane and filtered to remove the dicyclohexyurea, and triethylamine hydrochloride. This time the filtrate yielded a white solid whose infrared spectrum showed carbonyl peaks at 1705 and 1660 cm. \ an Amide II peak at 1530 cm."1 and peaks at 2825, 2780, and 2725 cm."1 a l l of which are consistent with the desired product. However, the elemental analysis resulted in a carbon value that was too low. An attempted reduction of this compound with LiAlH^ resulted in a liquid whose infrared spectrum indicated that the carbonyl groups had been reduced; however, at least one alcohol group had been formed in the same reaction. The cycloheptyl analog of C-I, H-I, was probably first synthe-sized by Eckstein et al (65) in 1958 in their investigation of the reaction of cycloheptanone, nitromethane, and piperidine. But at that time i t was known only as a crystalline by-product and no physical constants, elemental analyses, or yields were reported by them. The synthesis of this compound had previously been attempted by Nightingale's group but no solid product was obtained (46) . Later her laboratory found that the product had formed but that the addition of acid was necessary to precipitate it from the reaction mixture (49). In this laboratory, H-I was synthesized in 22.5% yield, m.p. 246-249°, l i t . (48) 51.5%, m.p. 208-209°, and l i t . (49) 250-251°, using piperazine as the catalyst, and in 20% yield, m.p. 247-250°, l i t . (49) 46-48%, m.p. 247-249° and 250-251°, using piperidine as the catalyst. 46 Shozo Miki (48) had attempted the hydrogenation of H-I as well as B-I andirP-I (see Figure 6 for structures) but found that none of these was appreciably reduced in the presence of Raney nickel catalyst, unlike C-I, M-I, and P-I, which form C-II, M-II and P-II in good yield under the same conditions. The conditions used for the attempted hydrogenation of H-I were 1,750 p . s . i . and 162°. Miki suggested that steric hindrance may have preven-ted the hydrogenation of these bulkier compounds. The melting point of the H-I used by Miki, 208-209°, suggests that the piperazine salt of H-I (m.p. 225-226°) was actually the compound subjected to hydrogenation conditions. In the present study, H-I was hydrogenated over Raney nickel at room temperature and 30-60 p . s . i . after three days shaking in absolute alcohol. The infrared spectrum showed only one unsaturation peak and the hydroxyl peak at 3200 cm. ^ was no longer present. An elemental analysis was not obtained for H-II itself, but for its chloroacetyl derivative. The correct carbon, hydrogen, nitrogen, and chlorine values were obtained. The chloroacetyl derivative was synthesized by adding monochloro-acetyl chloride to H-II and potassium carbonate in dry benzene and refluxing for 30 minutes. The reaction mixture was filtered hot to remove inorganic salts and the product precipitated from the solvent on cooling. The infrared spectrum showed new peaks at 1665 and 1540 cm. * that were assigned to the Amide I and Amide II bands, respectively, of the acyclic amide. The same reaction also yielded a product with a 1760 cm. * peak; this may be the diacetylated compound, as no Amide II peak was seen. Tertiary and alicylic amides do not exhibit an Amide II band. Chart 8 shows the hydrogenation of H-I, an unsaturated, dispiro compound with a five-membered ring ketoxime N-hydroxylactam j . to H-II, a primary aminolactam; the reactions attempted using H-II are also shown. 8-Dimethylaminoacetamido-16-aza-dispiro[6.1.6.2]heptadecan-17-one 8-Dimethylamino-ethyl-H-II 48 As seen in Chart 8, the synthesis of the 8-B-dimethylaminoethyl derivative of H-II was attempted using sodamide. The reaction was attempted only once and only unreacted H-II could be recovered from the reaction mixture. The next reactions that would have been attempted are the addi-tion of dimethylamine to the chloroacetyl derivative of H-II, and the forma-tion of the methiodide of the product obtained; the analogous reactions with DDP are shown on Chart 7. Time did not permit these reactions to be attempted. PART V EXPERIMENTAL * SECTION ONE SYNTHESIS OF DERIVATIVES AND ANALOGS OF 7,14-DIAZADISPIRO[5.1.5.2]-PENTADECAN-15-ONE A. 7,14-DIAZADISPIRO[5.1.5.2]PENTADECAN-15-ONE 1. Cyclohexanone Cyanohydrin (66) A solution of 150 g, (1.53 moles) of cyclohexanone in 900 mis. of ether was placed in a 3-liter, three-necked flask equipped with reflux condenser, dropping funnel and a mechanical stirrer. To this was added, over a period of six hours, 600 mis. of a saturated solution of sodium bisulfite. The bisulfite addition product was collected by suction filtration and washed thoroughly with solvent ether. The-white solid was added to 600 ml. of water to form a slurry and then placed in the above apparatus. A saturated solution of potassium cyanide (120 g. KCN in 300 mis. water) was added dropwise until a clear solution formed. The two layers were separated and the aqueous layer was extracted twice with 150 ml. of ether. The o i l arid ether layers were combined and then extracted with 300 mis. of water * A l l melting points and boiling points are uncorrected. Unless otherwise stated, the melting points were determined on a Thomas Hoover Unimelt capillary melting point apparatus. For compounds that melted with decomposition, the block was heated to within 20° of the melting point before the tube was inser-ted; the rate of heating was 2° per minute above 200° and 3° per minute above 250° for a l l the compounds. Infrared spectra were recorded on Unicam SP 200 and Beckman IR10 infrared spectrophotometers. Spectra 1-6 in Part VI were recorded on the former instrument. Elemental microanalyses were performed by Dr. Alfred Bernhardt, Hohenberg, Germany. 50 containing 0.75 ml. of concentrated hydrochloric acid, until neutral to red litmus. The ether-oil layer was dried over anhydrous sodium sulfate for 12 hours. The ether was removed by flash evaporation and the residue was disti l led under reduced pressure, b^ 97-98°. The yield was 146 g. (1.17 mole, 56%) of t i t le compound based on cyclohexanone. 2. 1-Aminocyclohexanecarbonitrile (51) Cyclohexanone cyanohydrin (146 g.) was melted and placed in a 200 ml. 3-necked conical flask. Ammonia gas was bubbled through the liquid for 18 hours to form the amino compound. The excess ammonia was then removed by bubbling nitrogen gas through the product. The resulting faint yellow liquid was dissolved in 200 mis. of benzene and extracted with 75 mis. of water. The benzene solution was dried over sodium sulfate for 12 hours. The benzene was removed by flash evaporation but further purification by distillation was not attempted because 1-aminocyclohexanecarbonitrile may be unstable to heat (67). The yield of crude product was 134 g. (1.08 mole, 92%) . 3. 7,14-Diazadispiro[5.1.5.2]pentadecan-15-one (DDP) (43) To a solution of sodium ethoxide (prepared from 31.5 g, of sodium and 900 mis. of 98.4% by weight ethanol) was added 238 g. (1.77 moles).of 1-aminocyclohexanecarbonitrile. The mixture was allowed to stand at room temperature overnight. Crystals started to form after a few minutes and the mixture had solidified after 12 hours. The white solid was collected by suction filtration and recrystallized from chloroform. The yield was 138 g. (0.62 mole; 70% on 1-aminocyclohexanecarbonitrile, 36% on cyclo-hexanone) m.p. 212-217°, l i t . 94%, m.p. 219-222°. After several recrystallizations from CHC1, the m.p. was 218-220°, l i t . 219°. 51 B. A 8-DIMETHYLAMINOETHYL DERIVATIVE OF 7,14-DIAZADISPIRO [:5 .1. 5. 2]-PENTADECAN-15-ONE 1. At Atmospheric Pressure (53) In a 3-necked, 1000 ml. flask equipped with stirrer and reflux con-denser, 8.0 g. (0.036 mole) of DDP and 4.48 g. (0.186) of sodium hydride in 400 mis. of dry xylene were refluxed for two hours. To this was added 19.2 g. (1.34 mole) of B-dimethylaminoethylbromine hydrobromide. The mixture was refluxed with stirring for 48 hours. The resulting red-brown mixture was filtered and the precipitate treated with absolute alcohol to destroy any remaining sodium hydride. The xylene and unreacted B-dimethylaminoethylbromine were removed by distillation at 2-3 mm. from a water bath heated to 80°. The residue in the flask was extracted with anhydrous ether to separate the product from unreacted DDP. The ether was distil led off leaving a viscous light brown liquid. Distillation at 148-174° at 0.7-1.0 mm. (mostly 155-156°.at. 0.9 mm.) yielded 1.17 g. (11%) of clear, colorless liquid. The infrared spectrum showed peaks at 2820 and 2760 cm 1 that are characteristic of the dimethylamino function. 7-'g-Dimethylaminoethyl-7,14-diazadispiro [5 .1.5. .2]pentadecan-17-one  Dipicrate: A solution of 0.3.g. of the product in 10 ml. of 95% ethanol was added to 10 ml. of a saturated solution of picric acid. The mixture was heated to boiling and then allowed to cool slowly. The yellow crystals were filtered and recrystallized from chloroform and petroleum ether (b.p. 60-80°) to a m.p. of 183-184°. Anal. Calcd. for C^H^NgO^: C, 46.34; H, 4.96; N, 16.77; Found: C, 45.83; H, 5.22; N, 16.76. 52 2. At High Pressure and Temperature The sodium salt was prepared in the same quantity and by the same procedure as above. The light orange-brown mixture was poured into an 800 ml. glass liner and the 8-dimethylaminoethylbromine hydrobromide was added in the same quantity as before. The liner was placed inside of the Parr Series 4511 Pressure Reaction Apparatus and the mixture was heated to 145° at which temperature a pressure of 120 p . s . i . was reached. After stirring for 18 hours and then cooling to 20°, a pressure of 80 p . s . i . remained. At this stage the reaction mixture was divided into two portions . (a) One-half of the volume of supernatant (174 ml.) was removed. This was worked-up as before to yield 0.9 g. (17.1%) of very viscous liquid, b.p. 148-161° at 0.7 mm. (on redistillation the b.p. was 164-168° at 1.1-1.3 mm.). The infrared spectrum was identical to that obtained from the reaction at atmospheric pressure. (b) The remainder of the supernatant with most of the solid was exposed to 280° at 340 p . s . i . for 17 hours. A distinct odor of coal-tar was present when the bomb was opened. Distillation of the residue yielded a few drops with a b.p. 155-170° at 0.7 mm. but the infrared spectrum of this fraction showed no peaks characteristic of the dimethylamino function. C. A 8-DIMETHYLAMINOETHYL DERIVATIVE OF 7,14-DIAZADISPIRO [:5 .1. 5.2:]-PENTADECANE In a 100 ml. three necked flask equipped with a mechanical stirrer, reflux condenser, dropping funnel and drying tube was placed 0.18 g. of lithium aluminum hydride in 30 ml. of anhydrous ether; this was refluxed for one hour. A solution of 1.12 g. of 8-dimethylaminoethyl-DDP in 40 ml. 53 of anhydrous tetrahydrofuran was added to the cooled hydride slurry. After the reaction mixture was refluxed for one hour, water was added to the cooled solution until i t just turned white. The mixture was centrifuged, the supernatant poured off, and the precipitate extracted with ether, and the combined oily layers were dried over MgSO .^ The drying agent was filtered off and the solvent was removed by rotary evaporation. Distillation at 138-156° at 4.5 mm. yielded 36% of reduced product. The infrared spectrum showed no carbonyl peak at 1685 cm. 1 and the 2820-2760 cm. * peaks characteristic of the dimethylamino function remained. 7-g-Dimethylaminoethyl-7,14-diazadispiro[5.1.5.2]pentadecane Tripicrate: A solution of 0.3 g. of the product in 10 ml. of 95% ethanol was added to 10 ml. of a saturated solution of picric acid. The mixture was heated to boiling and allowed to cool slowly. The yellow crystals were filtered and then washed with hot ethanol and benzene to remove traces of picric acid. After recrystallization from hot water the feather shaped crystals started to decompose about 212° and melted at 230-231°. Anal. Calcd. for C 3 5 H 4 2 N 1 2 0 2 1 : C> 4 5 A 8 > H> 4 - 3 8 ' N> 17.39; Found: C, 39.85; H, 4.22; N, 19.24 D. 7-CHLOROACETYL-7,14-DIAZADISPIRO[5.1.5.2]PENTADECAN-15-ONE 1. Using DDP as the Hydrochloride Acceptor In a 3-necked 2-liter flask equipped with reflux condenser, dropping funnel, drying tube and stirrer was placed 15 g. (0.0667) of dry DDP in 900 ml. of anhydrous benzene. The chloroacetyl chloride (2.48 g., 0.0222 mole) was added dropwise in 100 ml. of anhydrous benzene to the above solution. No immediate white precipitate formed (if the acyl halide is 54 not carefully redistilled, the dissolved HC1 causes the immediate precipitation of DDP hydrochloride), but after heating a heavy white precipitate was seen. The reaction mixture was refluxed for one hour and then stirred at room temperature for three hours. The mixture was filtered by suction to yield 5.4 g. of white solid whose infrared spectrum indicated that i t was composed mainly of DDP hydrochloride with a trace of unreacted DDP. Hydrogen chloride was bubbled through the clear filtrate to precipitate any dissolved amine. Suction filtration of the milky solution yielded 3 more grams of DDP salt. The s t i l l cloudy filtrate was extracted twice with 500 ml. of water, and the aqueous layer was made basic with 5% NaOH and then filtered to yield 2.7 g. of DDP. The clear, colorless benzene layer was dried over anhydrous MgSO^  for 48 hours. After removal of the drying agent by suction filtration, the drying agent was extracted with hot benzene, acetone and chloroform in succession, to determine i f any product had adsorbed onto i t . The benzene yielded a few mgms. of brown gum from which DDP hydrochloride was isolated. Similarly the acetone and chloroform extractions of the dying agent yielded 40 mg. and 25 mg. of DDP HC1 respectively. A total of the equivalent to about 10 g. of DDP was isolated from the work-up; this is consistent with the 1:3 ratio of acyl halide to amine used. The benzene and HC1 were then removed from the reaction product by rotary evaporation. The viscous liquid that remained (approx. 2 g.) was exposed to a temperature range of -70° to 100° over a period of 48 hours in an attempt to find the best temperature to induce crystallization. Only a few crystals could be seen after this treatment. The semi-solid was kept in the refrigerator for one month. Next the material was dried thoroughly at 100° and 2 mm. The addition of acetone to the gum resulted in a white solid precipitate that could be separated from the brown acetone solution 55 by filtration. This solid was recrystallized from ethanol to yield color-less cubical crystals that decomposed slowly above 180° but more rapidly at 196°, using the Fisher Stage Apparatus. In the capillary apparatus a melting point of 212-213° (dec.) was obtained. The infrared spectrum showed peaks at 1754 and 1645 cm. 1 * The latter could be the Amide I band of a tertiary amide. However a band at 1500 cm. 1 was also present; this may be due to the presence of an acyclic secondary amide. Elemental analysis showed the presence of chlorine. Anal. Calcd. for C H 2 3 N 0 CI: C, 60.29; H, 7.76; N, 9.34; Found: C, 49.39; H, 5.32; N, 9.00 The various reaction conditions that were employed in which DDP was the hydrochloride acceptor are summarized in Table II. Model Reactions-Acetylation of DDP (a) Using Acetyl Chloride and Pyridine In a 50 ml. mini-ware flask equipped with condenser, stirrer, drying tube and dropping funnel were placed 4.4 g. (0.02 mole) of DDP, 0.8 g.(0.02 mole) of freshly distilled pyridine, and 30 ml. of dry chloroform. This was cooled in an ice bath and freshly dis-t i l led acetyl chloride (0.8 g., 0.01 mole) was added dropwise in 10 ml. of dry chloroform. The ice bath was removed and the mixture was stirred for 20 hours at room temperature. The reaction mixture was then divided into two portions. One-half the mixture was removed and filtered, and the filtrate was washed with 5% HCl,, dried over calcium chloride, and evaporated to dryness in vacuo. Only a few milligrams of solid was obtained. After two recrystal-lizations from CHCl^-petroleum ether the infrared spectrum of the solid showed a broad peak centered at 3360 cm. 1 indicating that a hydroxyl group is present. 56 TABLE II REACTION CONDITIONS IN THE SYNTHESIS OF THE CHLOROACETYL DERIVATIVE OF DDP IN WHICH DDP IS THE HYDROCHLORIDE ACCEPTOR LOT GM. DDP REACTION PROCEDURE DDP REMOVER WT. OR QUALITY USED OF PRODUCT I 5 .0 Reflux f o r 3 hours 5% HCl Less than 0. 1 g II 20 .0 Reflux f o r 6 hours 5% HCl Less than 0. 1 S III 25 .8 S t i r f o r 65 hours then r e f l u x 2 hrs 5% HCl Less than 0. 1 g IV 10 .0 Heated with s t i r -r i n g to 190 under 310 p . s . i . f o r 11 hours 5% HCl Intractable t a r V 10 .0 Heated with s t i r -r i n g to 138 under 700 p . s . i . f o r 19 hours 5% HCl and HCl gas DDP, DDP HCl and t a r VI* 15 .0 Reflux f o r 1 hour then s t i r f o r 3 hours HCl gas 0.2 g. * The DDP to chloroacetyl chloride mole r a t i o was 2 to 1 i n each reaction except VI where i t was 3 to 1. The solvent was benzene in a l l the reactions. •57 The second half of the reaction mixture was refluxed for 12 hours. Only DDP hydrochloride was isolated from this portion. (b) Using Acetic Anhydride In 40 ml. of acetic anhydride containing one drop of concentrated H^ SO^  as catalyst, 5 g. of DDP was refluxed for 10 minutes. A small sample was removed and worked-up to yield DDP. The remain-der of the mixture was then refluxed for 30 hours. The acetic anhydride was removed in vacuo. Attempts to decolorize the dark brown gum were unsuccess-ful. Similarly attempts to purify the material by recrystallization from CHCl^-petroleum ether failed. (c) Using Acetic Anhydride at Elevated Pressure In a 100 ml. round bottomed flask with the stopper wired on, 5 g. of DDP in 40 ml. of acetic anhydride was heated under approximately 20 p . s . i . for 5 hours. The mixture was poured into 300 ml. of water and boiled to destroy the anhydride. The solvent was then removed in vacuo to yield a brown solid. Only DDP and uncrystallizable material could be obtained. 2. Using Pyridine as the Hydrochloride Acceptor To a solution of 100 mg. of DDP in 10 ml. of dry pyridine was added dropwise 150 mg. of chloroacetyl chloride. The solution turned purple-brown as the acyl halide was being added. After refluxing for 5 minutes the DDP HCl was filtered off and the pyridine was evaporated in vacuo. The material obtained was an intractable tar. A second reaction was carried out using the above reactants. This time the chloroacetyl chloride was added rapidly enough for the reaction mixture to warm to 50°, but the solution was not refluxed. Again the only water insoluble material was a tar. 58 3. Using DDP and Sodium Acetate as Hydrochloride Acceptors A solution of 3.51 g. of chloroacetyl chloride in 30 mis. of glacial acetic acid was added dropwise with stirring to a solution of 6.0 g. of DDP in 37.5 mis. of glacial acetic acid. After stirring for 10 minutes and cooling to 5° in an ice bath, 9.3 g. of sodium acetate in 37.5 mis. of water was added. The precipitate was removed by suction filtration; it was 4 g. of DDP HC1. The solvent was removed in vacuo to leave approximately 15 g. of solid. This was extracted with chloroform to yield a small amount of DDP and a second compound. An elemental analysis of this unidentified compound (the infrared spectrum of -1 -1 which had no 1700 cm peak but did have a strong peak at 1600 cm ) indicated that nitrogen was absent. 4. Using the Sodium Salt of DDP In a 3-necked flask equipped with stirrer, reflux condenser, drying tube and dropping funnel, a solution of 6 g. of DDP in 300 ml. of xylene was refluxed with 3.4 g. of sodium hydride. The heat was removed and 3.5 g. of chloroacetyl chloride in 50 ml. of dry xylene was added dropwise with stirring to the cool solution. After refluxing for 36 hours the reaction mixture was filtered and the xylene removed in vacuo. The dark brown liquid remaining was disti l led at 2 mm. Three fractions were obtained with b.p. 70-75°, 90=100° and 100-115°; the infrared spectrum of each contained several peaks in the carbonyl region. These fractions were not investigated further because of the small quantities present. The reaction was repeated as before except that excess NaH was removed by filtration through glass wool before the acyl halide was added' and the reflux time was only 20 hours. Again only a few drops of xylene soluble material was obtained; the infrared spectrum was similar to that obtained in the above reaction. 59 5. Using Potassium Carbonate as Hydrochloride Acceptor Chloroacetyl chloride (3.30 ml., 0.042 mole) was added dropwise to a stirred mixture of DDP (4.44 g., 0.020 mole) and anhydrous potassium car-bonate (6.90 g., 0.050 mole) in 500 ml. of dry acetone. The ratio of acyl halide to amine was 2:1. The reaction mixture was refluxed for 24 hours. The 11.01 g. of solid obtained after suction fi ltration, was extracted with acetone to yield 1.18 g. of DDP. The remainder was extracted with hot 95% ethanol to remove 2.05 g. of a mixture of 1.86 g. of DDP and 0.19 g. of DDP HC1. The ethanol insoluble portion was completely water soluble and after being made alkaline very l i t t l e precipitate was seen, indicating that this portion was composed of inorganic salts and not amine. The total amount of DDP recovered was 3.36 g. (76% of the amount used). The acetone was disti l led off in vacuo to yield a viscous liquid that did not crystal-lize after standing in the refrigerator for several days. Attempts to extract solid from the material by the addition of ether and/or acetone in varying proportions was not successful. After standing in a vacuum dissica-tor for two weeks, the addition of acetone to the viscous material caused the precipitation of 450 mg. of white solid. A 1790 cm. 1 peak was present in the infrared spectrum of this material. After ether extraction the solid gave a spectrum identical to that obtained from the product of procedure 1. After recrystallization from ethanol the m.p. was 212-213°. Various reaction conditions were tried in which potassium carbonate was the hydrochloride acceptor; these are summarized in Table III. L\ PURIFICATION OF 7-CHLOROACETYL-7-14-DIAZADISPIRO[5.1.5.2]PENTADECAN-15-ONE (Attempted) 1. Thin Layer Chromatography on Silica A 4x20 cm. Eastman K30IR s i l ica gel sheet with fluorescent indicator 60 TABLE III REACTION CONDITIONS USED IN THE SYNTHESIS OF THE CHLOROACETYL DERIVATIVE OF DDP USING POTASSIUM CARBONATE AS THE HYDROCHLORIDE ACCEPTOR * MOLE RATIO DDP:ACYL HALIDE GM. DDP USED SOLVENT PROCEDURE PRODUCT OBTAINED 1:1 1:1 1:2 4.44 4.44 4.44 benzene acetone acetone Reflux f o r 30 min. Reflux f o r 60 min. Reflux f o r 24 hours Approx. 50 mg. Approx. 200 mg. 450 mg. 1:1 1:2 2.22 20.0 acetone DMF Reflux f o r 8 days S t i r f o r 12 hr. then heat to 130C f o r 5 min. Approx. 20 mg. Trace amounts * In a l l the reactions approximately 75% of the DDP was recovered from the reaction mixture. 61 was activated by heating at 110 for 30 minutes and then spotted with a 5 mg./ml. solution of the product. The following solvents were tried in an attempt to find the one that would give the best separation of the maximum . number of spots: hexane:ethanol, 19:1, 9:1, 8:1, and 6:1; absolute ethanol alone, and the latter with petroleum ether (b.p. 65-110°) , 1:1, 1:6, and 1:10; absolute ethanol:petroleum ether (b.p. 65 -110° ) :g lac ia l acetic acid, 1:6:1, 1:6:2, and 2:6:3; absolute ethanol ."benzene, 1:1 and 1:4; ethanol:glacial acetic acid, 1:2, 1:4 and 1:10; ethanol:water, 1:1, and 1:10; ethanol:acetone, 1:10; hexane:absolute ethanol:diethylamine, 6:1:2, 6:1:1 and 6:1:0.5. The 6:1:2 mixture of this last solvent system was found to give the best separation of the three spots seen. This solvent was then used to develop a 20x20 cm. s i l ica sheet spotted with a total of 1 ml. of the solution; the average spot diameter was about 2 mm. Three bands were seen on the plate under short-wave ultra-violet light. The Rf values were 0.64, 0.75 and 0.8. The 0.64 band appeared to contain about 70% of the solute. The three dark areas and the origin and solvent front were cut from the s i l ica sheet. The s i l ica was scraped off the sheet and the powder was extracted with 3 mis. of hot absolute ethanol. The ethanol was evaporated and the infrared spectra of the solids remaining was determined. The infrared spectrum of pure:silica gel showed bands at 3400 and 1100 cm. ^ (strong and broad) and 2900 and 800 cm. * (medium). The ethanol extract of the gel where no dark band could be seen under ultra-violet light yielded a solid with peaks at 2880 and 2800 cm. ^ also. These latter peaks may be due to the fluorescent indicator or the terephthalate binder. Although some of the spectra showed carbonyl bands in the 1720-1640 cm. ^ region, the peaks were too weak to be assigned to any of the individual dispiro compounds. 62 2. Thin Layer Chromatography on Alumina An activated 4x20 cm. alumina 6063 Eastman thin layer sheet with fluorescent indicator was spotted with a 5 mg./ml. solution of the product. The following solvents were used to develop the sheet: ethyl acetate, ethyl methyl ketone, and each of these containing 10-20% ethanol; acetone, acetone with 10% diethylamine, acetone:diethylamine:methanol, 9:0.5:1.5, 8:0.2:1.8, and 8:1:1; acetone:diethylamine:ethanol, 9:0.5:0.5 and 8:0.25:1.75. It was found that the acetone:diethylamine:methanol, 8:0.2:1.8 gave the best separation. Three spots were seen under short-wave ultra-violet light; the Rf values were 0.22-0.35 (dark), 0.42-0.48 and 0.495-0.54 (light). 3. "Dry Column" Chromatography on Alumina (61) The column material was prepared by mixing 250 g. of Fisher Scientific No. A-540 Absorption Alumina (80-200 mesh) with 10 ml. (4%) distil led water and 1.25 g. (0.5%) E.I . duPont No. 609 Luminescent Chemical (Zinc Silicate: Manganese) on a rotary evaporator unit for 6 hours. The activity of the adsorbent was then determined by the following procedure. A melting point capillary tube was f i l led with the deactivated alumina and a drop of benzene placed on the open end. The tube was inverted and the closed end was snapped off. The damp end was placed into a small test tube containing a few mil l i l i ters of a 0.5% solution of p-aminobenzene in benzene until a drop of the dye solution was absorbed. The capillary was then placed in another test tube containing a few mil l i l i ters of benzene and allowed to develop. The Rf value was found to be between 0.12 and 0.24; this corresponds to an activity of II according to the Brockmann Scale. An activity of II or III is suitable for this type of chromatography. 63 The nylon column was heat sealed at one end and a small pad of glass wool was inserted; two or three holes were made at the bottom for drainage. The adsorbent was added to the 38 inch column in four portions, about 8 inches at a time. After the addition of each portion the column was compacted by allowing the bag to drop through the hand about six inches onto a hard surface two or three times. The tubing was "C" gauge, 1 inch flat diameter nylon made by Walter Coles and Co., Ltd. , Backhouse Works, Eng1and. The column was loaded by depositing the product on the adsorbent. This was done by dissolving 530 mg. of the product in 100 ml. of 100% ethanol and adding the solution to 5 g . o f alumina. The solvent was then evaporated of in vacuo. The material was distributed evenly on the top of the column and then covered with a small layer of sand to prevent distur-bance by the solvent. The column was developed using a solution of 80:18:2 acetone reagent: absolute methanol:diethylamine. A constant head of 3-5 centimeters was present during the developing. The column was run in the dark and watched continuously under short-wave ultra-violet light. Before the developing had begun, dark bands could be seen under uv light; these were due to the uneven packing of the column. After solvent had been added to the column, no new bands could be seen except for one at the solvent front; this band could also be seen under visible light because it was light yellow. The first 25 ml. of solvent to come through the column was evaporated off to yield a few milligrams of viscous yellow liquid. From this was isolated a solid whose infrared spectrum was identical to DDP hydrochloride except for three new peaks at 1760, 1725 and 1640 cm. . No significant amount of material was isolated from the following fractions. 64 Several attempts were made to recover the solid that had been loaded onto the column. This was done by cutting the column into five parts: the loading alumina and four equal portions from the remaining column. Each was extracted with 100 ml. of hot solvent, the alumina filtered off and the solvent removed in vacuo. This procedure was used to extract each portion with ethanol, chloroform and glacial acetic acid, in that order. Infrared spectra were recorded on al l the material obtained. In general, very small amounts of substances were obtained and the infrared spectra of these did not indicate the presence of DDP or its derivatives. Glacial acetic acid extraction yielded 50-70 mg. of white crystalline material from each extraction, but the infrared spectrum of each was very similar and no significant carbon-hydrogen stretching peak could be seen in the 2950-2800 cm. 1 region. An elemental analysis on the solid indicated that no nitrogen was present. Extraction of pure alumina with the same solvent yielded a material with a similar IR spectrum. A final attempt to recover the material from the column was made by soxhlet extraction of each fraction of alumina with ethanol (250 ml.) for several days. More solid like that obtained from the acid extraction was obtained but no other substance was found. 4. "Dry Column" Chromatography on Sil ica (61) The column was prepared as in the above procedure except that the adsorbent was Grace-Davison Chemical Mesh 60-200 Grade 62 Silica Gel. The gel was deactivated with 15% water to give an Rf value of about 0.63 which is equivalent to an activity of III on the Brockmann Scale. In an attempt to obtain denser bands of material on the column, the product (400 mg.) obtained from the attempted chloroacetylation of DDP, was distributed evenly 65 on top of the column and not deposited on the adsorbent as before. The column length was 22 inches and the solvent used was hexane:absolute ethanol:diethylamine, 6:1:2. As in the previous column, no bands could be seen developing except for a visible yellow band that could be seen without ultra-violet light. After the solvent had reached the end of the column, there s t i l l remained about half of the product at the origin. More solvent was run through the column to a total of 180 ml. Five fractions were collected and worked-up as before. No significant amounts of material were obtained. The column was divided into two parts and each was extracted with 300 ml. of hot ethanol. A small amount of material was obtained but the infrared spectrum indicated that i t was not a DDP derivative. F. 8,16-DIAZADISPIRO[6.1.6.2]HEPTADECAN-17-ONE (Attempted) 1. Cycloheptanone Cyanohydrin (66) A solution of 100 g. (0.89 mole) of cycloheptanone in 540 mis of ether was placed in a 2-liter, three-necked flask equipped with a reflux condenser, dropping funnel and a mechanical stirrer. To this was added, over a period of three and one-half hours, 360 mis. of a saturated solution of sodium bisulfite. The bisulfite addition product was collected by suction filtration and washed thoroughly with solvent ether. The white solid was added to 360 mis. of water to form a slurry and then was placed in the above apparatus. A saturated solution of potassium cyanide (72 g. KCN in 180 mis. water) was added dropwise until a clear solution formed. The two layers were separated and the aqueous layer was extracted twice with 100 mis. of ether. The o i l and ether layers were combined and then extracted with 180 mis. of water containing 0.45 ml. of concentrated hydrochloric acid until neutral to red litmus. The ether-oil layer was dried over anhydrous 66 sodium sulfate for 12 hours. The ether was removed by flash evaporation and the residue distilled under reduced pressure, 106-108°. The yield was 58 g., 47% on cycloheptanone. The infrared spectrum showed characteristic hydroxyl and nitri le peaks at 3400 cm. 1 and 2250 cm.-"'', respectively. 2. 1-Aminocycloheptancarbonitrile (51) Cycloheptanone cyanohydrin (58.g.) was melted and placed in a 200 ml. 3-necked conical flask. Ammonia gas was bubbled through the liquid for 18 hours to form the amino compound. The excess ammonia was then removed by bubbling nitrogen gas through the product. The resulting faint yellow liquid was dissolved in 120 mis. of benzene and extracted with 50 mis. of water. After drying over sodium sulfate, the benzene was flashed off. The yield of crude product was 57 g., 99% on the cyanohydrin. The infrared spectrum showed peaks at 3300, 3220, 1600 cm. 1 and 2220 cm. 1 that are characteristic of the primary amino and nitri le groups respectively. 3. 8,16-Diazadispiro[6.1.6.2]heptadecan-17-one (attempted) To a solution of sodium ethoxide (prepared from 7.35 g. of sodium and 210 mis. of 98.4% ethanol) was added 57 g. of 1-aminocycloheptancarbonitrile. The mixture was allowed to stand for one week but the only solid isolated on filtration was sodium cyanide. The alcohol was removed by flash evapo-ration, and the remaining semi-solid was taken-up in benzene, extracted three times with water and dried over sodium sulfate. The resulting semi-solid contained no nitri le peak at 2250 cm. 1 . The peak at 1690-1640 cm. 1 could represent an imino function. Although it has been reported that certain aminonitrile compounds of this type are unstable to heat (67), a distillation was attempted. Most of the product distil led over at b » 60-64°. The I ! 67 infrared spectrum showed peaks at 1690 cm. *(s) and 1620-1560 cm.'^ Cm). It appears that the loss of the n i t r i l e group resulted in the formation of a cyclic imine. SECTION TWO SYNTHESIS OF DERIVATIVES AND ANALOGS OF 7-AMINO-14-AZADISPIRO-[5.1.5.2]PENTADECAN-15-ONE A. 7-AMINO-14-AZADISPIRO[5.1.5.2]PENTADECAN-15-ONE 1. 14 Hydroxy-14-azadispiro[5.1.5.2]pentadec-9-ene-7,15-dione  7-oxime (49) (a) With Piperazine as Catalyst. In a 250 ml. round-bottomed flask equipped with a Stark and Dean trap were placed 24.5 g. (0.25 mole) of cyclohexanone, 30.5 g. (0.25 mole) of nitromethane, 16.5 g. (0.25 mole) of piperazine and 50 ml. of benzene. Crystals began to separate after 15 minutes of refluxing. The reaction mixture was filtered after 30 hours of refluxing and the solid obtained was extracted with hot 1:1 hydrochloric acid for 40 minutes. After recrystallization from ethanol, 11.2 g. (33.8%) of C-I,-ni.p. 272-274° was obtained; l i t . (49) 67%, l i t . (48) m.p. 263-265.5° (not recrystallized), 47.2%. (b) With Pyrrolidine as Catalyst. In a one-litre round-bottomed flask equipped with a Stark and Dean trap were placed 216 g. (2.2 mole) of cyclohexanone, 146.5 g. (2.4 mole) of nitromethane, 36 mis. of pyrrolidine and 328 mis. of benzene. The catalyst was added in three portions; the remainder of the 37.5 g. (0.6 mole) was added in two equal 4 ml. portions after 27 and 43 hours of refluxing. After thoroughly washing with ether, 47 g. (16.4%) of solid (m.p. 270-272°) was obtained; l i t . (48) 23%, m.p. 262-263°; after recrystallization from ethanol the m.p. was 274-275°; l i t . (49) 273-274°; l i t . (51) 275-275°. 69 2. 7-Amino-l4-azadispiro[5.1.5.2]pentadecan-15-one (51) C-I (11 g.) in 200 ml. of absolute ethanol was hydrogenated in the conventional Parr apparatus at 30-60 p . s . i . over 6 g. of Raney nickel. After shaking for 3 days the alcohol was decanted off the catalyst and the catalyst was washed with 100 mis. of hot ethanol. The combined alcohol fractions was filtered through kieselguhr and the alcohol was concentrated; hot water was added to cause the precipitation of fine white needles. After five recrystallizations from ethanol and water the melting point was 192-193°, l i t . 192-193° (40), 195-196° (51). The yield was 45.5% l i t . 95%, m.p. 193-195° (51). In several of the hydrogenation reactions the product was the 14-azadispiro[5.1.5.2]pentadecane-7,15-dione 7-imine as indicated by its infrared spectrum with peaks at 1700 and 1670 cm. \ l i t . 1698 and 1661 cm. 1 (51), and by the melting point 196-208°. Unreacted starting material o 1 and a solid with a melting point of 295-300 were also isolated in some reactions. B. 7-DIMETHYLAMINOACETAMIDO-14-AZADISPIRO[5.1.5.2]PENTADECAN-15-0NE (Attempted) (62) To a suspension of 1.4 g. (0.01 mole) of N,N-dimethylglycine hydro-chloride in 25 ml. of dichloromethane was added 1.01 g. (0.01 mole) of triethylamine, 2.84 g. (0.012 mole) of C- l l and 2.06 g. (0.01 mole) of dicyclohexylcarbodiimide. After being stirred for two weeks at room tempera-ture, the reaction mixture was diluted with 75 ml. of hot dichloromethane and then filtered to remove the dicyclohexylurea, and triethylamine hydro-chloride. The solvent was removed in vacuo to yield a white semi-solid. This was recrystallized from acetone to yield several compounds, none of 70 which had an infrared spectrum with two carbonyl peaks in the 1750-1650 cm." region and peaks in the 2850-2725 cm. * region characteristic of the dimethyl-amino function. C. 8-AMIN0-16-AZADISPIR0[6.1.6.2]HEPTADECAN-17-ONE 1. 16-Hydroxy-16-azadispiro[6.1.6.2]heptadec-10-ene-8,17-dione  8 oxime (49) (a) With Piperazine as Catalyst. Cycloheptanone (71.0 g., 0.63 mole), nitromethane (42.2 g., 0.69 mole), piperazine (25.8 g., 0.3 mole) and 150 ml. of benzene were placed in a 500 ml. round-bottomed flask equipped with a Stark and Dean trap and refluxed for 80 hours. Solid began to separate after 2 hours of refluxing. The solid was collected by suction filtration and washed with ether and then with hot benzene. The yield of piperazine salt of H-I was 32 g., m.p. 223-225°, l i t . 225-226°, after recrystallization from hot ethanol, l i t . (48) 51.1%, m.p. 208-209°, before recrystallization. When the salt was extracted with hot 1:1 hydrochloric acid for 40 minutes it yielded 20.5 g. (22.5%) of H-I, m.p. 246-249°, l i t . (49) m.p. 250-251°. (b) With Piperidine as Catalyst. In a 2000 ml. round-bottomed flask fitted with a Stark and Dean trap were placed 112.17 g. (1.0 mole) of cycloheptanone, 67.14 g. (1.1 mole) of nitromethane, 85.15 g. (1.0 mole) of piperidine, and 500 ml. of benzene, and the solution was refluxed for 90 hours. No solid separated during the reaction time, but after acidifica-tion of the reaction mixture with hydrochloric acid, crystals separated from the solution. They were collected by suction fi ltration, washed with hot water and recrystallized from 95% ethanol to yield 29 g. (20%) of H-I m.p. 71 247-250°, l i t . (49) 46-48%, m.p. 247-249° and 250-251°. 2. 8-Amino-16-azadispiro[6.1.6.2]heptadecan-17-one H-I (20 g.) in 200 ml. of absolute alcohol over 12 g. of Raney nickel was hydrogenated in the conventional Parr apparatus at 30-60 p . s . i . After shaking for three days the alcohol was decanted from the catalyst and the catalyst was washed with 100 mis. of hot ethanol. The combined alcohol fractions was filtered through kieselguhr and the solution was concentrated. The addition of hot water caused the crystallization of a white solid that decomposed above 180°. After several recrystallizations from ethanol and water the material melted at 183-185°d. The yield was 71.6%. The infra-red spectrum showed only one unsaturation peak. This was seen at 1685 -1 cm. A second hydrogenation reaction starting with 27 g. of H-I yielded a small portion (1.3 g.) of unreacted H-I and an unidentified solid (0.5 g.) melting at 290-300°, as well as the solid assumed to be H-II. D. 8-CHLOROACETAMIDO-16-AZADISPIRO[6.1.6.2]HEPTADECAN-17-ONE In a three-necked 100 ml. flask equipped with stirrer, dropping funnel, and reflux condenser was placed 5.29 g. (0.02 mole) of H-II and 3.45 g, (0.025 mole) of potassium carbonate in 50 ml. of dry benzene. To this was added dropwise 1.65 ml. (0.021 mole) of chloroacetyl chloride in 5 mis. of dry benzene. The mixture was refluxed for 30 minutes. A dense white precipitate was seen as soon as the acyl halide was added and its appearance did not change after heating. The reaction mixture was filtered hot to remove the inorganic salts arid any hydrochloride salt that may have formed. On cooling the filtrate yielded 320 mg. of a white solid m.p. 72 210-212 after recrystallization from benzene. The infrared spectrum showed new peaks at 1665 cm. ^ and 1540 cm. * that could represent the Amide I and Amide II bands of acyclic secondary amide. Anal. Calcd. for C 1 8 H 2 9 N 2 0 '2 C 1 : C j 6 3 - 4 2 ' H> 8 - 5 8 > N> 8 - 2 2 J CI, 10.40. Found: C, 63.74; H, 8.70; N, 8.24; CI, 10.26. The benzene from the reaction was evaporated off to yield 700 mg. of a mixture of the compound whose analysis appears above and at least two other compounds. One appears to be the diacetylated product. Its infrared spectrum shows a 1760 cm. peak and no Amide II peak. The latter indicates that no alicyclic monosubstituted amide is present. The melting point of this compound was 176-184°. The third compound had a melting point of 2950300°; this could be the hydrochloride salt of H-II. E. 8-DIMETHYLAMINOACETAMID0-16-AZADISPIR0[6.1.6.2]HEPTADECAN-17-ONE (Attempted) (62) To a suspension of 1.4 g. (0.01 mole) of N,N-dimethylglycine hydro-chloride in 25 ml. of dichloromethane was added 1.01 g. (0.01 mole) of triethylamine, 3.18 g. (0.012 mole) of H-II and 2.06 g. (0.01) of DCC. After being stirred for two days at room temperature, the reaction mixture was diluted with 75 ml. of hot dichloromethane and then filtered to remove the dicyclohexylurea, and the triethyamine hydrochloride. The precipitate was extracted twice with 10% hydrochloric acid and the aqueous solution was made alkaline. A white precipitate .appeared but i t could not be removed by suction fi ltration. The precipitate was removed by ether extraction but the dried ether layer yielded only a few mg. of solid. Hexane extrac-tion of this material yielded a small amount of solid believed to be the desired product. 73 The filtrate obtained from the reaction mixture yielded a semi-solid after the solvent was removed in a rotary evaporator. This material was dissolved in hot acetone and a solid was precipitated from i t by the addition of pet. ether (b.p. 65-110°) . After recrystallization from acetone and further acetone washing a white solid was obtained m.p. 136 .5-137.5° , 700 mg. After several recrystallizations from acetone the m.p. was 138-139.5° . Anal. Calcd. for C ^ H ^ N ^ : C,68.73; H, 10.09; N, 12.02: Found: C, 57.47; H, 9.68; N, 12.34. The infrared spectrum showed 2825 cm. 2780 cm."1, and 2725 cm. 1 peaks characteristic of the dimethylamino function, and carbonyl peaks at -1 -1 -1 1705 cm. and 1660 cm. as well as an Amide II band at 1530 cm. a l l of which are consistent with the t i t le compound. F. 8-DIMETHYLAMIN0ETHYLAMIN0-16-AZADISPIRO[6.1.6.2]HEPTADECANE (Attempted) The material obtained from the previous reaction (0.63 g., 0.0019 mole) was added to a stirred suspension of LiAlH^ (0.15 g., 0.004 mole) in 25 ml. of THF. After refluxing with stirring for 24 hours, the excess hydride was destroyed by the addition of 30% aqueous potassium hydroxide. The mixture was filtered and the coagulated white precipitate was extracted with hot THF. The combined solvent layers were dried over MgSO^  and then the solvent was evaporated off at 50° in vacuo. The product was distilled at 79-81° at 0.4 mm. The two carbonyl peaks were no longer present but a large peak at 3600-3000 cm."1 indicated that an alcohol was present. The strong peak at 1055 cm. 1 indicates that the alcohol could be primary. 74 G. 8-DIMETHYLAMINOETHYLAMINO-16-AZADISPIRO[6.1.6.2]HEPTADECAN-17-ONE (56) (Attempted) A mixture of sodium amide (1.42 g., 0.036 mole) in dry toluene (10 ml.) was stirred and heated to 100° in a 50 ml. 3-necked flask. Then 7.93 g. (0.03 mole) of H-II was added to the amide mixture, and the mixture was refluxed for 3 hours. The bath was removed and 10 ml. of toluene was added to the dark brown paste. The 6-dimethylaminoethylbromine hydrobromide (3.49 g., 0.015 mole) was added and the mixture was refluxed for 48 hours. After the mixture had cooled, 20 ml. of water was added and the toluene layer was separated. The precipitate was washed with ether and the water layer was saturated with potassium carbonate and then extracted twice with 25 ml. of solvent ether. The combined toluene and ether layers were dried over MgSO .^ The drying agent was filtered off and the solvent removed in  vacuo. The semi-solid remaining was diluted with a few mis. of anhydrous ether and filtered to yield 1.8 g. of H-II, m.p. 180-185° after recrystalli-zation from ethanol-water. The very ether soluble portion was disti l led at 1- 2 mm. and 225° to yield a semi-solid with an infrared spectrum essentially the same as the starting material, H-II. H. MISCELLANEOUS 1. Raney Nickel Catalyst W-4 (68) In a 2 l i ter erlenmeyer equipped with a thermometer and a Hershberg stirrer was placed 209 g. of NaOH in 815 ml. of water. The flask was immersed in a cold running water bath and 163 g. of Ni-Al alloy was added in 2- 4 g. portions keeping the temperature at 50°±2° and collapsing the foam with ethanol i f necessary. The cooling bath was then removed and the 75 suspension was digested at 50° for 50 minutes with gentle stirring. The catalyst was washed in the flask by decantation several times with disti l led water and then i t was transferred to a 1 l i ter graduate cylinder. The catalyst was then suspended to a depth of 3/4 the length of the water column in the cylinder by stirring. About 24 1. of water was flushed through the catalyst in a 3-4 hour period, or until the wash water was neutral to litmus. The catalyst was allowed to settle and then the water was decanted. The sludge was transferred to a 250 ml. centrifuge tube and washed three times with stirring not shaking, with 200 ml. of 95% ethanol and then three times with 200 ml. absolute ethanol, centrifuging after each washing. The catalyst was stored under absolute alcohol in a refrigerator. 2. N,N-Dimethylglycine Hydrochloride (69) In a 500 ml. round-bottomed flask equipped with reflux condenser were placed 45 g. (0.6 mole) of glycine, 150 ml. of 90% formic acid and 120 ml. of formalin. The reactants were gently boiled under reflux for 17 hours. On cooling, 60 ml. of concentrated hydrochloric acid was added and the mixture was evaporated to a sirup under reduced pressure. After cooling, the precipitate which formed was removed by suction filtration and then washed thoroughly with acetic acid. The yield was 22.8 g. (27%) m.p. 187-190°, l i t . 64-67%, m.p. 189-190°, after recrystallization from water. The low yield could have been due to the old formalin that was used. 3. Chloroacetyl Chloride (a) Using benzoyl chloride (70) Finely ground, dry monochloro-acetic acid (9.46 g., 0.1 mole) and freshly distilled benzoyl chloride (28.1 g., 0.2 mole) were placed in 50 ml. round-bottomed flask equipped with a heated Vigreux column and distillation collection apparatus. The mixture 76 was heated with an oi l bath at 190 ; the column temperature was 90 . The product was disti l led over as rapidly as possible consistent with good separation. The fraction coming over at 102-110° (12 g.) was collected and stored in a salt-ice bath until used. (b) Using thionyl chloride (71) In a 200 ml. round bottomed flask equipped with a reflux condenser fitted with a drying tube were placed finely ground, dry monochloroacetic acid (84 g., 0.89 mole) and thionyl chloride (115 g., 0.963 mole). The reactants were refluxed gently on a water bath for three hours and then boiled vigorously until the evolution of gas had ceased. The excess thionyl chloride was disti l led off on a steam bath. Distillation yielded 47.5 g. product with no significant infrared peak at 1230 cm. ^ indicating no contamination with thionyl chloride. The fractions that were not pure were added to the unreacted chloroacetic acid in the reaction vessel along with 35 ml. of thionyl chloride and the reaction was run as before. A further 33 g. of product was collected (b.p. 101-109°) to give a total yield of 80.5 g. (80%) based on the acid. PART VI INFRARED SPECTRA Infrared Spectrum 1 . Cycloheptanone Bisulphite Addition Product.. Solid in potassium bromide disk. Infrared Spectrum 2. Cycloheptanone Cyanohydrin Liquid film between sodium chloride plates. Infrared Spectrum 3. Cyclohexanone Cyanohydrin Liquid film between sodium chloride plates. - I • • •' '• t: 'I o BOO 650 Infrared Spectrum 4. 1-Aminocyclohexanecarbonitrile. Liquid film between sodium chloride plates. Infrared Spectrum .5. 1-Aminocycloheptanecarbonitrile. Liquid film between sodium chloride plates. Infrared Spectrum 6. Product from the Attempted Synthesis of 8,16-Diazadispiro[6.1.6.2]hepta-decan-17-one. Liquid film between sodium chloride plates. Infrared Spectrum 7. 7,14-Diazadispiro[5.1.5.2]pentadecan 15-one Hydrochloride. Solid in potassium bromide disk. Jnfrared Spectrum 8. Infrared Spectrum 9. 7,14-Diazadispiro [5.1:5 '. 2]pentadecan 15-one. Solid in potassium bromide disk. Product from the Attempted Synthesis of 7-Chloroacetyl-7,14-diazadispiro-[5.1.5.2]pentadecan-15-one. Solid in potassium bromide disk. Infrared Spectrum 10. Infrared Spectrum 11. A 8-Dimethylaminoethyl Derivative of 7,14-Diazadispiro[5.1.5.2]pentadecan-15-one. . , Liquid film between sodium chloride plates. A 8-Dimethylaminoethyl Derivative of 7,14-Diazadispiro[5.1.5.2]pentadecane Liquid film between sodium chloride plates .• Infrared Spectrum 12. 14-Hydroxy-14-azadispiro[5.1.5.2]-pentadec-9-ene-7.,lS^dione 7-oxime. Solid in potassium bromide disk. WAVtLtNGTH IN MICKONS W A V E N U M B E R C M 1 W A V E I E N G T H IN M I C R O N S « * . . JF 2 5 3 3.5 i i.S 5 5.5 6 4.5 7 73 8 9 10 • 11 12 U 14 WAVENUMBER C M J • ••I ..nr-.. r NO 1'.... Htuuil .N Infrared Spectrum 13. •'. 7-Amino-14-azadispiro[5.1;5.2]penta-, dccan-15-one. Solid, in potassium bromide disk. Infrared Spectrum 14. A Product obtained from.the Reaction of N,N-Dimethylglycine Hydrochloride, DCC, and 7-Amino-14-azadispiro[5.1.5.2]penta decan-15-onc. Solid in potassium bromide disk. Infrared Spectrum 15.? Piperazine Salt of'16-Hydroxy-16-aza-dispiro[6.1.6.2]heptadec-10-ene-8,17-dione 8-oxime. Solid in potassium bromide disk. Infrared Spectrum' 16. 16-Hydroxy-16-azadispiro[6.1.6.2]hep-tadec-10-ene-8,17-dione 8-oxime. Solid in potassium bromide disk. Infrared Spectrum 17. 8-Amino-16-azadispiro[6.1.6.2]hepta-decan-17-one. Solid in potassium bromide disk. Infrared Spectrum 18. 8-Chloroacetamido-16-azadispiro[6.1.6.2]-heptadecan-17-one. , Solid in potassium bromide disk. 84 Infrared Spectrum 19. A Product obtained from the Reaction of Monochloroacetyl Chloride and 8-Amino-16-azadispiro[6.1.6.2]hepta-decan-17-one. , Solid in potassium bromide disk. Infrared Spectrum 20. Product from the Attempted Synthesis of 8-Dimethylaminoacetamido-16-aza-dispiro [6.1.6.2]heptadecan-17-one.. Solid in potassium bromide disk. Infrared Spectrum 21. Product from the Attempted Synthesis of 8-Dimethylaminoacetamido-16-aza-dispiro[6.1.6.2]heptadecane. Liquid film between sodium chloride . plates.. PART VII SUMMARY A B-dimethyaminoethyl derivative of 7,14-diazadispiro[5.1.5. 2]-pentadecan-15-one was synthesized by adding g-dimethyaminoethylbromine hydrobromide to the latter compound after it had been treated with an excess of sodium hydride. This derivative was then reduced using lithium aluminum hydride, as indicated by infrared spectroscopy. A correct elemental analy-sis was obtained for the lactam but not for the reduced analog. It was not determined i f substitution had occurred at the secondary of lactam nitrogen. The synthesis of the chloroacetyl derivative of 7,14-diazadispiro[5.1.5.2]7 pentadecan-15-one was attempted so that it could be used as an intermediate in the synthesis of the dimethyaminoacetyl dispiro compound. The reaction of chloroacetyl chloride with the above-named dispiro compound was attempted using a variety of reaction conditions. The use of potassium carbonate as the hydrochloride acceptor and acetone as the solvent gave the best yields, but even these were very low. Thin layer chromatography indicated that the product obtained from the reaction was a mixture of three components, but attempts to separate these on alumina and on si l ica columns failed. Because of the difficulty experienced in trying to obtain and purify this inter-mediate, and in the failure of 8,16-diazadispiro[6.1.6.2]heptadecan-17-one to form under the same conditions used to synthesize the cyclohexyl analog, attention was turned to the synthesis of analogous dispiro compounds that differed from the first series by the presence of a primary amino group rather than a secondary one. This series of dispiro compounds lack the steric hindrance around the amino group which may be the cause of the low yields of the condensation reactions. 86 The primary amine-lactams used as starting material were obtained by Raney nickel hydrogenation at room temperature of the unsaturated dispiro compounds that contained a five-membered ring ketoxime N-hydroxylactam. The cyloheptyl analog had not been previously reported. The one-step additions of the dimethylaminoacetic acid to 7-amino-14-azadispiro[5.1.5.2]-pentadecan-15-one and 8-amino-16-azadispiro[6.1.6.2]heptadecan-17-one using dicyclohexylcarbodiimide as the condensing agent were attempted. The infrared spectrum of the product obtained from the former reaction indicated that the condensation product did not form. In the case of the latter reaction, the product obtained did not result in a correct elemental analysis although its infrared spectrum was consistent with the desired product. The addition of 8-dimethylaminoethylbromine hydrobromide, to the 8-amino dispiro compoundJ named above after pretreatment with sodamide, was not successful. The inter-mediate for the synthesis of the' 8-dimethyaminoacetyl derivative, 8-chloro-acetamido-16-azadispiro[6.1.6.2]heptadecan-16-one was synthesized by the method found to give the best yields of chloroacetylated product in the first series of dispiro compounds. It was identified by its infrared spectrum and elemental analysis. PART VIII BIBLIOGRAPHY 1. C.O. Wilson, 0. Grisvold, and R.F. Doerge, "Textbook of Organic Medicinal and Pharmaceutical Chemistry", J.B. Lippincott Co., Phila-delphia, fa) pp. 617-638, (b) pp. 591-616, (c) pp. 469-509 (1966). 2. L.S. Goodman and A. Gilman, "The Pharmacological Basis of Therapeutics", The MacMillan Co., New York, (a) pp. 615-640, (b) pp. 367-395, (c) 521-544 (1965). 3. J . J . Brand and W.L.M. Perry, Pharmacol. Rev., 18, 895 (1966). 4. W.M. Heller and M.J. 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