Xerox University Microfilms 300 North Zeeb Road Ann Arbor, Michigan 48106 I I 77-2418 HSU, Fu-Lian, 1944- STEREOCHEMICAL STUDIES of ADRENERGIC DRUGS: I

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Xerox University Microfilms 300 North Zeeb Road Ann Arbor, Michigan 48106 I I 77-2418 HSU, Fu-Lian, 1944- STEREOCHEMICAL STUDIES OF ADRENERGIC DRUGS: I. CONFORMATIONALLY RESTRICTED ANALOGS OF NOREPHEDRINE AND METARAMINOL. II. OPTICALLY ACTIVE 2,4(5)-DISUBSTITUTED 2-IMIDAZOLINES. The Ohio State University, Ph.D., 1976 Chemistry, organic

Xerox University microfilms, Ann Arbor, Michigan 48106

0 1976

FU-LIAN HSU

I. CONFORMATIONALLY RESTRICTED ANALOGS

OF NOREPHEDRINE AND METARAMINOL

II. OPTICALLY ACTIVE 2,4(5)-

DISUBSTITUTED-2-

IMIDAZOLINES

Dissertation

Presented in Partial Fulfillment of the Requirements for

the Degree Doctor of Philosophy in the Graduate

School of The Ohio State University

Fu-Lian Hsu, B.S., Pharmacy

* * * * *

The Ohio State University 1976

Reading Committee: Approved By

Duane D. Miller Neil J. Lewis Popat N. Patil Adviser College of Pharmacy ACKNOWLEDGEMENTS

I would like to express my sincere gratitude and appreciation to my adviser, Professor Duane D. Miller, for his guidance, encouragement, and understanding throughout my graduate career, making this dissertation possible.

I am indebted and thankful to Professor Popat N.

Patil for his interest, suggestions and encouragement during the course of this study.

I am thankful to graduate students and postdoctoral fellows for their wonderful friendship, suggestions, and discussions.

Finally, I wish to acknowledge my grandmother, mother, and my wife for their love, inspiration, and encouragement. Without them this study may have never been accomplished. VITA

March 15, 1944 Born, Hsichih, Taiwan Republic of China

1962-1966 B.S., Pharmacy Taipei Medical College, Taipei, Taiwan

1966-1967 Second Lieutenant Marines, Medical Supplies Officer Republic of China

1967-1970 Research and Teaching Assistant, Department of Chemistry, Taipei Medical College, Taipei, Taiwan

1970-1972 Teaching Assistant, Depart ment of Pharmaceutical Chemistry, Wayne State University, Detroit, Michigan

1972-1976 Research Assistant, Depart ment of Medicinal Chemistry, The Ohio State University, Columbus, Ohio

PUBLICATIONS

Duane D. Miller, Fu-Lian Hsu, Kadhim N. Salman, and Popat N. Patil, "Stereochemical Studies of Adrenergic Drugs: Diastereomeric 2-Amino-l-Phenylcyclobutanols," J . Med. Chem., 19, 180 (1976).

Duane D. Miller, Fu-Lian Hsu, Robert R. Ruffolo, Jr., and Popat N. Patil, "Stereochemical Studies of Adrenergic Drugs. Optically Active Derivatives of Imidazolines," J . Med. Chem., in press.

T. J. Hsu, W. H. Hsu, Z. Z. Wang, Fu-Lian Hsu, S. J. Lai, and S. G. Lai, "Study of Contamination in Water Sources of the Hsin-Tien River," J. Formosan Med. Assoc., 71, 467 (1972).

FIELD OF STUDY: Medicinal Chemistry iii TABLE OF CONTENTS

Page ACKNOWLEDGEMENTS...... ii

VITA ...... iii

LIST OF TABLES ...... V

LIST OF FIGURES ...... vi

INTRODUCTION...... 1

STATEMENT OF PROBLEM...... 31

RESULTS AND DISCUSSION

I. Cyclobutane Analogs of Norephedrine and Metaraminol...... 37

II. Optically Active 2,4(5)-Disubstituted- 2-Imidazolines 64

SUMMARY...... 91

EXPERIMENTAL ...... 94

BIBLIOGRAPHY ...... 127 LIST OF TABLES

Table Page

1. The chemical shifts of acetyl derivatives (

2. Physical properties of alanine derivatives...... 72

3. Physical properties of phenylalanine derivatives...... 74

4. The physical properties of optically active 2-imidazolines...... 81

v LIST OF FIGURES

Figure Page

1. Biosynthesis of NE and epinephrine...... 3

2. Three conformations of (-)-NE...... 12

3. Structural comparison of NE, tolazoline and histamine...... 22

4. Nuclear magnetic resonance spectra of trans-acetamido ester 69 ...... 41

5. Nuclear magnetic resonance spectra of cis-acetamido ester 79 ...... 51

6. Nuclear magnetic resonance spectra of cis-acetamido alcohol 82 ...... 54

7. Nuclear magnetic resonance spectra of trans-acetamido alcohol 84 ...... 55

8. Illustrates the responses to (-)- norepinephrine 3 X 1 0 ~ i n the presence of various concentrations of 55*HC1 and 56 • HC 1 ...... 63

9. Circular dichroism curves of the methyl derivatives of naphazoline 60a and 60b ...... 82

10. Circular dichroism curves of the methyl derivatives of tolazoline 62a and 62b ...... 83

11. Circular dichroism curves of the methyl derivatives of clonidine 63a and 63b...... 84

12. Illustrates the dose response curves of two imidazolines on rabbit aortic strips prepared according to Furchgott and B hadrakom ...... 86

vi Page

13. Cumulative log dose-response curves for phenylephrine in the absence and presence of various concentrations of R(+)- and S (-)-methylnaphazoline (compounds 60a and 60b respectively)...... T T 7 ...... 88

14. Schild plot for the data presented in Figure 1 3 ...... 89

15. Cumulative log dose-response curve for histamine in the presence of 10“^M concentration of R{ + )~ and S (— )— methylnaphazoline...... 90

vii INTRODUCTION

The nervous system is conceptually divided into the

central nervous system (CNS) and the peripheral nervous

system (PNS). The PNS is further divided into the autonomic

and somatic nervous systems. The autonomic nervous system which constitutes sympathetic and parasympathetic systems

regulates the function of smooth muscles, heart and glands

in the body (in other terms, sympathetic and parasympathetic nervous systems, respectively). A drug which acts at the adrenergic neuroeffector junction is considered an adrener gic d r u g .

There is a similarity between the effect of drugs and those of nerve stimulation. For example, when muscarine

is applied to the heart, it slows it in a manner similar

to vagal stimulation. In 1895, Oliver and Schaffer"*" showed that the adrenal extract mimicked the effects of sympathetic stimulation. Therefore they suggested the sympathetic nerves may act by releasing a chemical substance. However, evidence of chemical transmission in the autonomic nervous 2 system was not demonstrated by Lowei until 1921. On the basis of these results, Lowei suggested a substance which showed the heart rate was released from the nerve endings and was called "vagusstoff." Using similar experiments, he was also able to show that stimulation of the nervous accelerans caused the release of an accelerator substance called "acceleranstoff." Subsequent work established the fact that the "acceleranstoff" was (-)-epinephrine (1) or

(-)-norepinephrine (NE, 2) and the "vagusstoff" was acetyl- 3 choline (3). Dale called the nerve fibers that release acetylcholine as "cholinergic" and those that release NE or epinephrine as "adrenergic."

X, R = OH, R*= CH3 2, R- 0H» R= H 4, R = H, R= H

Although NE is the main catecholamine in all 4 sympathetically innervated organs, epinephrine and 5 dopamine 4 are also found in small amounts.

It has been shown that a number of processes in the adrenergic nervous system are sensitive to stereo chemical parameters. The biosynthesis of NE and epineph rine has been extensively studied and a number of these 6-9 biosynthetic processes are stereoselective (Figure 1). L (-)-Tyrosine is taken up by nerve terminals from which

D(-)-NE is synthesized. The conversion of L (-)-tyrosine to L (-)-3,4-dihydroxyphenylalanine (dopa) by hydroxylase is highly stereoselective. Aromatic-L-amino acid decarboxy lase is stereospecific in that only aromatic amino acids with the L-configuration are decarboxylated. The intro duction of a 3-OH group in dopa is stereospecific in which only one enantiomer is formed. Phenethanolamine N-methyl- transferase is less stereoselective, both isomers of NE can be methylated; however the (-)-isomer is the better substrate.

H HOv__ H HO Ch 2- c - c o o h Tyrosine Hydroxylase ^ HO-^J)-CH2~-C-COOH

n h 2 n h 2 L-Dopa L-Tyrosine

B J / S Dopa )__ Dopamine “Decarboxylase ^ _HO-n^j\-CH2 CH2 NH2 3 -Hydroxylase

Dopamine

H °.__ O H H O QH r Phenethanolamine HO- N-Methyl-transferase -CHa NH H H CH3 D-NE D-Epinephrine

Figure 1. Biosynthesis of NE and epinephrine 4

The uptake of exogenous NE by adrenergic nerve granules from the cytoplasm has been shown to be stereoselective^'^ at low concentration for the R configuration of NE and no stereoselectivity is observed at high concen tration. The uptake process appears to require ATP and

It is fairly well accepted that a large portion of

NE either synthesized from dopamine or taken up from the cytoplasm is stored in a physiologically inert form within 12 vesicles in the adrenergic nerve ending. Norepinephrine is stored in vesicles in combination with ATP in a molar 13 ratio 4:1. The storage site is highly stereoselective , so that R optical isomers and the erythro diastereomeric compounds possess greater affinity than S-isomers and the threo diastereoisomers respectively. Unnatural amines such as a-methyldopamine (5) which is converted to a-methylnorepinephrine enzymatically, and metaraminol (6) are called "false neurotransmitters." The uptake of NE by nerve endings and the release process from granules are also stereoselective for the R configuration of NE and related compo u n d s .^ ^

HO HO

5 6A/ It is generally accepted that a nerve impulse passes down the sympathetic postganglionic fiber making the membrane of the fiber permeable to Ca of the extracellular 15 16 ++ fluid. ' This entry of Ca causes, by some unknown mechanism, the release of NE. Several investigators 17-20 reported that the release of NE is regulated by the prejunctional adrenoceptors. It was proposed that the released NE could activate prejunctional a-adrenoceptor and

"turn off" the release of additional transmitter via a 21 negative feedback control mechanism. The inhibitory control of the adrenoceptor on the release of NE appears to 22 be stereoselective for NE isomers.

After being released from the adrenergic nerve ending either by nerve stimulation or by indirect acting drug, the transmitter, norepinephrine, produces a character istic effect on the effector cell. This specific response is thought to be brought about by the combination of the chemical transmitter with the receptor on the effector cell. 23 In 1905, Langley proposed that there were two types of tissue receptors, excitatory and inhibitory, and the response to NE depends on the types of receptor with which it reacts. Dale, in support of this hypothesis, demon strated the vasoconstrictor action of epinephrine was antagonized by ergotoxin, while the cardiac stimulatory 24 effect was not. These results suggested that there were at least two sites at which epinephrine could act, one of which was blocked by ergotoxin. 25 Ahlquist in 1948 defined the concept of alpha and beta adrenergic receptors to separate the various pharmaco logical actions of adrenergic drugs. Essentially, the combination of adrenergic agonist with a-receptor elicits an excitatory response (contraction), with the exception of intestinal relaxation. On the other hand, the 8-receptor is associated with inhibitory functions with the exception of myocardial stimulation. Further proof in support of this classification came from studies of adrenergic antag onists. Alpha-adrenergic blocking agents, such as dibena- mine (7) and phentolamine (8) block excitatory responses.

In contrast, dichloroisoproterenol (9) and pronethalol(10) rst AS'*-'* block the 8-receptors producing inhibitory responses.

In general the relative potency on the a-adrenoceptor is epinephrine> N E > isoproterenol (11), and for the 8-receptor, isoproterenol> epinephrine> NE. On the basis of further studies of the 8-receptor, it has been suggested that oon 8-receptors can be classified into two subtypes. ' The

8-^-receptors include those receptors in heart which cause an increase in the rate and force of contraction, whereas

82_receptors include those receptors in the peripheral nervous system which are responsible for vasodilation, bronchodilation and uterine relaxation. Evidence in 7

CH. H3 C" @ \

HO 8

OH NCH(CH3)2 OH NCH(CH3)2 H H 9, X* Cl 10 11, X = OH

support of this sub-division was the use of selective ? fi agonist and the development of selective (3-blocking . 28-31 agents.

The pAx scale as a quantitative measurement of drug antagonism:pAx is the negative logarithm of the molar con centration of an antagonist required to reduce the effect of a multiple dose (x) of an agonist to that of a single 32 dose. The relative potencies of adrenergic antagonist are generally recorded as pA£ value. If the adrenoceptors in different tissues are the same the pA£ value of an 33 antagonist should be the same in these tissues. Patil developed a very valuable method for distinguishing adreno ceptors in different tissues. He found the isomeric activity differences of a given pair of optical isomers in

different tissues to be the same in all a-adrenergic 11 12 tissues. Based on this study, Patil et ad. * revealed

that a-adrenoceptors are homogeneous in different tissues

while a variety of adrenergic tissues displayed different

isomeric activity differences indicating that more than one

3-adrenergic receptor exists.

Epinephrine and NE not only induce pharmacological

responses but also cause biochemical changes on glyco- 8 genolysis and lipolysis in_ vivo. Both events are mediated

through NE- or epinephrine-induced formation of adenosine

3',5*-cyclic phosphoric acid (cyclic AMP). It is thought g that lipolysis is a 3-receptor-med.iated process. However,

it is unlikely the lipolytic 3-adrenoceptors are identical

in all respect with the 3-receptors mediating glycogen- olysis, cardioacceleration, etc.'*~’/^

Based on the site of action, NE and other sympatho mimetic amines have been further classified into three groups: direct acting on adrenoceptor, indirect acting and 37 38 mixed acting. ' The indirect acting drugs are ineffec

tive when adrenergic tissue catecholamines are depleted.

The inhibition of uptake potentiates the action of NE released by sympathetic nerve stimulation. Active trans port is involved in the uptake of norepinephrine and the uptake pump is thought to be located on the axonal membrane and can be inhibited by cocaine. The inhibition of uptake by sympathomimetic amines is stereoselective. Thus, in phenolic amines 3-hydroxylated R-isomers are more potent than the corresponding S-isomers and S-(+)-amphetamine (12) 35 is 20 times more potent than R-(-)-amphetamine.

nh2 oh nh - ch3 12 13

The early syntheses giving rise to racemic compounds and the pharmacological evaluation of the racemates indicat ed that stereoselectivity was involved since the racemates were less active than the optically active natural compounds. The natural NE is levorotatory with an R configuration. Due to the stereoselectivity of (-)-epineph- 39 rine in adrenergic tissues Easson and Stedman proposed three points of binding: the basic nitrogen, the aromatic group, and the alcoholic hydroxyl group of a drug with 40 41 adrenoceptors. Patil and coworkers ' have investigated the relationship between absolute configuration and potency of a variety of a-agonists in an effort to test the Easson-

Stedman hypothesis. It was concluded that the Easson-

Stedman hypothesis is of predictive value for direct-acting 10 a-agonists but not for indirect effects. This study suggested that compounds that produce adrenergic effects by release of endogenous NE are generally less stereo selective than those acting directly on adrenoceptors.

The structure activity relationships (SAR) of sympathetic amines at different sites has been studied 42 extensively since the investigations of Barger and Dale. 35 Several generalizations can be made as presented. The phenolic OH at the 3 and 4 positions are important for optimal a- and 3-adrenergic activity but more critical for

3-receptor activation. The m-OH group is more important in the activation of a-adrenoreceptors than is the g-OH group. Noncatecholamines such as amphetamine and ephedrine

(13) generally produce greater CNS stimulation than the corresponding catecholamines. The optical isomer with R configuration on C-l and/or S configuration on C-2 has a higher potency than its racemate or diastereoisomer. The affinity for uptake sites increases with the removal of the

3-OH. An a-methyl group on sympathomimetic amines with the

S configuration increase affinity for uptake sites and also increase resistance to metabolic inactivation by monoamine oxidase (MAO). The 3-adrenergic activity increases with an increase in the size of the N-alkyl substituent. 11

It is known that the biological action of drugs

depends greatly on their size, shape and electronic distri- 43-47 bution. Any modificatxon of the molecule will indeed

change one or another of these parameters. It is known

that adrenoceptors are very sensitive to the stereochemical

changes in a variety of adrenergic agonist and antagonist.

Almost all of the optical isomers of the potent

adrenergic drugs studied thus far are conformationally

flexible molecules (Figure 2). One may speculate as to

the conformational requirements of a drug when it forms a

complex with the adrenergic receptor. In an attempt to

define the preferred conformations of phenethylamine

derivatives at adrenoceptor sites, a variety of physical methods have been used. In an aqueous solution, using NMR 48-49 techniques, it has been shown D (-)-ephedrine, ampheta- 50 51 mine, and dopamine prefer an extended-trans conforma

tion (trans refers to the relationship of phenyl and amino

group) with the side chain almost perpendicular to the

phenyl ring. In the solid state using X-ray methods, the 52 53 preferred conformation of ephedrine, NE, lsoproter- 54 55 56 enol, phenethylamine and dopamine is the extended 57 form. Forrest et al. using NMR analysis examined sixteen

trimethylsilyl ethers of phenethylamine derivatives in

CCl^. He noted both extended and folded conformations are

important for these compounds. 12

OH OH OH OH OH OH

HO HO HO'

a b c

Figure 2. Three conformations of (-)-NE

Kier^'~^'^8 employing Extended Hiickel Theory

(EHT) has calculated that the preferred conformation of ephedrine, NE, and isoproterenol is extended-trans and for dopamine the gauche conformation. Conformational analyses, using theoretical methods such as CNDO, INDO, PCILO has led 61"*63 many research groups to observe similar results in which the phenethylamines have two or three favored conformations, namely, trans and gauche. Although one conformation may be slightly favored over the others in each compound, the energy barriers separating these conform ations are relatively low.

It seems inappropriate to ascribe biological importance to a single conformation of a conformationally flexible compound since the functional groups may adopt a different orientation during interaction with the receptor. Thus, rigid molecules in which the key functional groups are fixed become the most acceptable approach to study the conformational requirements of drug-receptor interactions.

As a general rule, the rigid molecule should resemble as closely as possible the prototype conformationally flexible 64 drug.

Smissman et ad.^ ^ have prepared a number of trans-decalin analogs of phenethylamines. For norephedrine 6 5 analogs, they found that all four diastereoisomers

(14a-d) are equipotent on vas deferens. However, among the N-isopropyl derivatives of norephedrine^ only 15a and

15b, possessing a gauche phenyl and amino relationship, showed a potentiation of the contractile response of vas deferens to NE without a direct action on the a-adreno ceptor.

R 1 R 2 R 3 R 4

14a OH Ph H NH b Ph OHHNH

c Ph OH n h 2 H d OH Ph N H 2 H

15a OH Ph H NHiPr b OH Ph NHiPr H c Ph OH NHiPr H d Ph OH H NHiPr 67 68 Smissman and coworkers ' have also examined the diastereoisomers of 2-amino-3(3,4-dihydroxyphenyl)-3-trans- decalol in order to gain a better understanding of the conformational requirements for the inhibition of NE and dopamine uptake. It was found that 16, in which the 3-OH and amino group have a dihedral angle of 180°, was the most potent competitive inhibitor of NE and dopamine uptake.

A study of the preferred conformation for the active site of COMT has also been carried out with these compounds.

The results indicated 16 fits the active site best, while

17, possessing a trans relationship between the phenyl and amino groups, is the best substrate for COMT among the possible diastereoisomers. Since a variety of conforma tionally restricted compounds can serve as a substrate for

COMT it would appear that the enzyme itself can undergo conformational change."^ Smissman and Pazdernik^^ also studied the amphetamine analogs in the trans-decalin series and found that behavioral effects were produced only in compound 18 in which the amino and phenyl groups are in a trans-conformation 1 2 3 4 R R R R 16 OH H NH R’ 2 HO

17 HH NH 2

i* © • H H NH 15

70 71 Nelson et ajL. ' utilized a similar approach and synthesized octahydrophenanthrene analogs of norephedrine

19 and amphetamine (20). The diastereoisomers of 19 were tested in vas deferens preparations. Only 19d exhibited a potentiation effect while 19a and 19c showed adrenergic blocking activity. The rigid amphetamines, 20a and 20b, both failed to produce amphetamine-like behavioral effects.

R 1 R 2 R 3 R 4

19a H OH n h 2 H

b OH H n h 2 H

c OH H H n h 2

d H OH H n h 2

20a H H n h 2 H

b H HH n h 2

Because of the low biological activity and uncon- clusive results of the isomeric trans-decalin and octahydro phenanthrene analogs of phenethylamine, it appears that the hydrocarbon moiety employed to confer rigidity to the pharmacophoric groups is too bulky and appears to prevent the pharmacophoric groups from access to the receptor sites.

Conformationally rigid or semirigid phenethylamines with minimal modifications have been synthesized by several 72 researchers with greater success. Horn and Snyder 16 examined the ability of amphetamine analogs, cis- and trans-phenylcyclopropylamine (21 and 22) and of 2-aminoindan (23) to inhibit catecholamine uptake by synaptosomes.

It was found that tranylcypromine (22) is more potent than the cis-isomer, 21 and 2-aminoindan is far more potent than 'r 1-aminoindan (24). Thus it appears that a phenyl ring and amino group in a trans conformation gives optimum inhibi- 17 73 tion of uptake. '

21 22

NH,

NH2

23 24

Racemates cis- and trans-3-phenyl-2-methylazetidin-

3-ol (25 and 26) and the desmethylazetidine analog were prepared to study the inhibition of NE uptake in rat vas 73 deferens. The result indicates that the orientation of the a-methyl relative to the phenyl or hydroxyl groups in the azetidine series plays a significant role in the 17 prevention of NE uptake.

H c6 H5 CH

H' '''H H

25 26

Several norephedrine analogs have also been reported and these include cis- and trans-2-amino-l-indanol 74 (27 and 28) , cis- and trans-2-amino-l-tetralol (29 and 75 76 30), ' and cis- and trans-2-amino-l-benzocycloheptanol 77 78 (31 and 32). ' The pharmacological evaluations were carried out on different a-adrenoceptor tissues and re vealed that the erythro isomers in general were more potent than the corresponding threo isomers. This work in general indicates that the erythro form in a set of diastereomeric phenylpropanolamine compounds will give optimum activity in an a-adrenergic receptor system. 79 Gray et al. have synthesized 6,7-dihydroxy-l,2,3,

4-tetrahydroisoquinoline 34, a rigid cisoid conformation of epinine (33) and compound 35, a rigid transoid confor- ■vw mation of a-methyldopamine (5). This study indicates that a transoid conformation is more suited than cisoid for inducing a-adrenergic activity. 18

OH OH

NH2

27 28

OH NH2

29 30

OH MB

31 32

HO HO NH HO H HO CH

33 34

HO HO NH2 NH; 0 HO HO

35 37 19

Compound 34 was also able to displace NE in cardiac nerve •wv 8 0 endings. However the introduction of a methyl group

either at the 2 and/or 4 position of the parent molecule

34 resulted in compounds which were unable to release NE

from cardiac sites. These findings appear to be consistent 81 with earlier observations of Dale et al. that a methyl

substituent at benzylic position of p-tyramine significant

ly decreases its pressor activity. An unexpected observa

tion is that the quaternary ammonium iodide 36 is more 8 0 active as a depleter of NE than the parent compound 34.

Norsalsolinol (34) can also be viewed as a rigid dopamine analog, thus 34 was examined as an inhibitor of dopamine uptake in synaptosome rich homogenates of rat 79 corpus striatum along with the transoid analog, 37.

The preferred conformation for inhibition of dopamine is extended-trans isomer. Although 37 was found to act 8 3 directly on dopamine receptor in an in vitro study, a comparative study with the cisoid compound 34 is.not available.

In addition to the phenethylamines an important group of drugs capable of interacting with the a-adrenergic 84"-87 receptor are the imidazoline derivatives. The discovery of naphazoline (38) and tolazoline (39) with the opposite effects on circulatory system, the former acting as an a-adrenergic agonist and the latter serving as an 20 8 8 a-blocking agent, stimulated considerable interest in 89 the pharmacology of 2-imidazolines. In 1949 Meier et: al. demonstrated the specific a-blocking activity of phentolamine which later became a useful a-adrenergic antagonist for classification of sympathomimetic amines. Urech and 90 coworkers have investigated a variety of 2-substituted aminomethylimidazolines and have found that the adreno lytic effect caused by these drugs are similar to those found in phentolamine. Since the discovery of naphazoline and tolazoline a large number of 2-aralkyl-2-imidazolines have been prepared and their pharmacological effects 91 examined. Certain 2-aralky1-2-imidazolines are highly 8 5 potent a-adrenergic agonists, e.g., naphazoline and oxymetazoline (40) , whose action can be abolished by classical a-adrenergic antagonists such as phentolamine.

Xylometazoline (41) and tetrahydrozoline (42) also exhibit similar pharmacological effects on the adrenergic nervous system. The imidazoline derivatives unlike their counter parts, the phenethylamines, do not possess any S-adrenergic effects, thus indicating that they are highly selective a-adrenergic agonists.^ ^ The specific adrenergic effects exhibited by the sympathomimetic imidazolines are primarily vasoconstriction in the peripheral adrenergic nervous systems. 21

R -ON- H

R R R

38 □ 42

□ HO CH3 ch3

39 ch2-

ch3

In 1966/ a 2-aminoimidazoline derivative, 2-[(2,6- 93 94 dichlorophenyl)imino]imidazolidine (clonidine, 43) '

was synthesized and showed a promising antihypertensive

action. Like naphazoline, clonidine is an a-adrenergic

agonist. One postulation is that the antihypertensive

effect is believed to be mediated through stimulation of a-adrenergic receptors in vasomotor centers of the CNS,

resulting in a feedback linked depression of vasofunc- 22

The structural features of 2-aralkyl-2-imidazolines

such as tolazoline are not only related to NE by containing

a phenethylamine portion but also to histamine (44) (see

Figure 3). This specific feature has generated complex

jSJE 39 44

Figure 3. Structural comparison of NE, tolazoline and histamine.

pharmacological activities derived in major part from a

combination of adrenergic and histaminergic effects. As

early as 19 44 the potent vasoconstricting effect of

imidazolines, sensitive to a-adrenoceptor blocking agents, 99 100 was recognized. ' Along with these observations,

additional effects such as an increase in gastric secretion and cardiac stimulation produced by some imidazolines such

as tolazoline were noted .101 The cardiac stimulation

produced by the imidazolines could have occurred from

either adrenergic or histaminergic action.10^ l0^ The use

of histamine 2 receptor antagonists ,1 0 0 '100 along with the

well known histamine, and adrenergic antagonists, provided

valuable tools in distinguishing the relative adrenergic

and histaminergic effects of imidazolines. There are a

number of potent imidazoline derivatives which have been

reinvestigated in order to interpret their pharmacological

effects based on the site of action. A number of new

pharmacological effects have been observed with certain

imidazolines. Patil and associates 00 have found

naphazoline, tetrahydrozoline and tolazoline are direct .

acting agents on the a-adrenoceptor and act at a common

site in rabbit aorta. Similar observations have also been

found in producing contractions in isolated rat vas deferens 92 and relaxing the isolated rabbit intestine. Furthermore,

tetrahydrozoline and tolazoline were found capable of 8 5 stimulating histamine H 2 receptors. More recently 107 Kappanen et al. have found clonidine also stimulates

histamine H 2 receptors in CNS as well as in the PNS .100,100

This observation led to the suggestion that stimulation of central histamine H 2 receptors brings about a depression of the cardiovascular system and may be the mechanism 24 by which clonidine produces its antihypertensive action.

The a-stimulation by sympathomimetic imidazolines also performs an action similar to direct acting sympatho mimetic amines by activating the prejunctional a-receptors and thereby decreasing NE release by nerve stimulation.'*"'*'^

On the other hand the a-blocker, phentolamine enhances the release of NE elicited by nerve stimulation.

The 2-substituted imidazolines have a wide range of pharmacological actions, including adrenergic blocking, sympathomimetic, antihistaminic, histaminergic, and para sympathomimetic activities; slight changes in structure may 111 make one or another of these properties dominant. The imidazolines which have been found to be pharmacologically active are those derivatives which in general have an alkyl, 91 . . . aralkyl and ammo substitution at 2 -position.

The alkyl groups with less than five carbons have 88 112 been studied pharmacologically. ' Replacement of alkyl with phenylmethyl, i.e. tolazoline, greatly enhances its vasodilatory ability.

Tolazoline, a potent a-adrenolytic and vasodilator is about 100 times more active than the corresponding alkyl derivatives. The substitution of an alkyl group at the methylene bridge such as 45a and 45b has little influence on the blood pressure as compared to the parent compound 39.

Increased blood pressure effects have been reported with a 25

91 methyl substitution on nitrogen, compound 45c. The

addition of substituents to the phenyl ring gives very

interesting results. An alkyl substituent, compound 45d

does not change the type of action. However, if the para

position is substituted by a hydroxyl, compound 45e, the

action on the circulation is reversed and it becomes a vasoconstrictor. The introduction of second and third

hydroxyl group, 45f and 45g, enhances this activity.

Methylation of phenolic OH groups, compound 45h, gives a

compound that produces vasodilation.

\5 R 1 R 2 R 3 R 4

a H HH C 2H 5 b H H A* C 2H 5 C 2H 5 c HH c h 3 H

d H H H 4-CH3

RJ e H H H 4-OH R: f H H H 3,4-di-OH

g H H H 3,4,5-tri-OH

h HH H 3,4-di-OCH3

depressor■ activity in cats due 8 8 to peripheral vasodilation while 2-benzyl -1,4 ,5,6-tetra- hydropyrimidine (46a) is reported to produce pressor effects 113 in the same animal. The a-alkoxy analogs (46b-d) of tolazoline and 46a produced no effects on blood pressure in 26

114 renal hypertensive rats. The introduction of a chlorine atom on the aryl ring of tolazoline molecule enhances the adrenolytic effect.Faust et al.reported a series of chlorinated derivatives of 2-imidazolines and 2-substituted-1 ,4,5,6-tetrahydropyrimidines and examined the cardiovascular effects on blood pressure as tested in the anesthetized dog. The results showed that the optimum adrenolytic activity was exhibited by the ortho-chloro derivative, (46e), of tolazoline. Further modification on

46e indicates that substitution at the methylene bridge with hydroxyl or a methyl group, or the substitution at nitrogen with a methyl, or the enlargement of the hetero cyclic ring all decrease the adrenolytic activity.

1 2 3 46 R R R R n

a H H H H 3

e 2-C1 H H H 2

An interesting pharmacological result is observed when the phenyl group is replaced by naphthyl group.

Naphazoline and other derivatives, 4 7a-c, are powerful vasoconstrictors while naphazoline is the most potent of this series. 27 47a. X = 4-OH CH2~x I b x = 4-OCH- H ^ J X c, X = 2-OCH3

The structures possessing a guanidine moiety have shown cardiovascular effects. The initial work of guanethidine (48) , an effective antihypertensive agent acting by preventing the release of sympathetic transmitter 117 led to many structural variations of guanethidine. 118 Hughes and coworkers have synthesized phenylguanidine derivatives and examined the cardiovascular effects in anesthetized dogs. Unlike guanethidine, phenylguanidine

(49a) is a moderate vasoconstrictor. As in the 2-aralkyl

2-imidazoline series, hydroxyl substitution of the phenyl ring leads to enhanced pressor action. The 3,4-dihydroxy derivative, 49b, was one of the most selective and potent vasoconstrictor agents with a slight effect on heart rate.

4 8 28

1 49 X R

a HH H H

b 3,4-di-OH H H H X c 3,4-di-OH H CH H ^ 3 d 3,4-di-OH CH 3 H H

e 3,4-di-OH H H H

f 2, 6-di-Cl H CH 3 H

Methylation of the amino group (49c and d) maintained the pressor activity, but caused cardiac stimulation. Chlorina tion of the phenyl ring at the 3 and 4 position is almost as effective in increasing vasoconstrictor activity as is hydroxylation. However, the 2,6-dichlorophenyl derivative,

49f has an a-adrenolytic and a-sympatholytic effect with no effect in the CNS. The a-adrenergic stimulant activity of phenylguanidines is qualitatively similar to that of the phenethylamine series.

The antihypertensive drug clonidine (43) not only belongs chemically to the class of the imidazoline derivatives, but can also be viewed as containing a guani dine moiety. Infrared"^H and NMR spectra^^^ have revealed that in solution the resonance structure with exocyclic double bond is preferred. The a-sympathetic effect of clonidine has been discussed previously and suggested to be mediated via central a-adrenergic ; 95-98,121,122 receptors 29

A number of clonidine-like 2-arylaminoimadazolines have properties very similar to those of clonidine. The potency of these compounds in the central nervous system is correlated with their peripheral a-adrenergic stimulating 8 6 activity in conjunction with their lipid solubility.

Naphazoline/ oxymetazoline/ xylometazoline, and tetrahydro zoline have pharmacological properties similar to clonidine and activate directly the a-adrenergic receptors without

B-adrenergic effects. However, unlike clonidine these

2-arylmethyl- 2-imidazolines only activate peripheral a-adrenoceptors. The ability of imidazolines to bind with 8 6 the central or peripheral a-adrenoceptors led Boudier to study the SAR of imidazolines on peripheral and central a-adrenergic receptors. The observed affinity correlated primarily with pKa, whereas molar volume was also found to be a factor in determining the a-agonist activity with the peripheral a-receptors. Since physicochemcial para meters could not be correlated with central a-adrenergic activity, they implied that the structural requirement for central a-adrenoceptors were different from those in the periphery.

Unlike phenethanolamines, stereochemical studies of sympathomimetic imidazolines have received only limited attention. Pullman et al_* ^ have applied quantum-mechani cal methods, PCILO (perturbative configuration interaction using localized orbitals), to study the conformation of

naphazoline. The most stable conformation is found to have

a perpendicular orientation of the two rings: naphthylene 120 and imidazoline. NMR studies of clonidine indicate that

the perpendicular conformation of the phenyl group and

heterocyclic ring is preferred over the planar conformation. 123 Recently Meeman-Van Benthem et al. using CNDO/2

(complete neglect of differential overlap) calculated that

the angle between both rings is about 34° which is not in

agreement with the result observed from NMR analysis. To

test the requirement of perpendicular conformation of

clonidine for its antihypertensive activity, Jen and 124 125 coworkers ' have synthesized a series of tricyclic

compounds 50-53>s

antihypertensive effects without any stimulation of CNS a-adrenoceptors as seen with clonidine. STATEMENT OF PROBLEM

I. Cyclobutane analogs of norephedrine and metaraminol

The investigation of the conformational require ments of phenethanolamines in their interaction with adrenergic nerve terminals and adrenoceptors has triggered a great deal of interest in rigid and semirigid analogs in which the key pharmacophoric groups, phenyl, 3-alcoholic

OH and a-amino, are placed in a relatively fixed position.

Earlier works carried out by Smissman and coworkers,^ ^ and Nelson and Miller^ gave encouraging results. However, the low biological activity and some unexpected results indicated a necessity for further investigation. A major criticism of past work is the introduction of bulky hydro carbon portion to fix the functional groups in a desired stereochemical orientation for pharmacological evaluation.

This bulky hydrocarbon skeleton may be in some manner either preventing the drug from gaining access to the receptor site or diminishing the optimum interaction between drug and receptor due to the steric hindrance caused by this hydrocarbon moiety. The preparation of a rigid molecule as close as possible to the parent compound may provide a solution to this problem. Utilization of the

31 32

cyclopropyl and cyclobutyl groups to confer the restricted

carbon skeleton of parent drug molecules has been sucess- 72 73 fully applied in the study of adrenergic ' and choliner- 126,127 gic systems.

The purpose of this research was to synthesize the

conformationally restricted analogs of norephedrine (54) 84 and metaraminol (6). Norephedrine, a mixed acting

sympathomimetic amine, directly has been employed as a

nasal decongestant. Unlike norephedrine, metaraminol acts mainly on a-adrenergic receptors. Both compounds have a

similar resistance to inactivation by the enzymes, MAO and

COMT. One methylene unit is inserted between the a-CH^ and

8-carbon in norephedrine and metaraminol to give a semi

rigid cyclobutane analog. The two sets of isomers synthe

sized are the norephedrine analogs, cis- and trans- 2-amino-

1-phenylcyclobutanol (55 and 56), and the metaraminol vvv analogs, cis- and trans-2-amino-l-(3-hydroxyphenyl)cyclobutanol (57 and 5 8 ). The synthesis of these compounds

should allow us to investigate the conformational require ments for the interaction of agonists and/or antagonists with adrenergic receptors, uptake sites, and release sites of the adrenergic nervous system. They may also provide more insight into the conformational changes that occur during the course of a drug-receptor interaction. 33

CH3

( 0 ) - C H - C H — |" " N H 2 OH NH2 HO NH2 HO H

54 55 56

HO pi_i_ HO HO

NH2 ■ OH NH2 HO

57 58

II. Optical isomers of 2, 4-disubstituted 2-imidazolines

In general there are two types of drugs phenethanol-

amines and 2-imidazolines that are widely known for their

ability to interact with the adrenergic nervous system.

Norepinephrine is the prototype of phenethanolamine and

possesses one asymmetric carbon. The stereoselectivity

involved in the pharmacological responses in the phenethyl-

amine series is well documented.^ ^ Several reports

have recently appeared on the SAR study of imidazoline

derivatives. However 2-imidazoline derivatives

have received little attention with respect to the stereo

chemical features involved in producing pharmacological

effects. The major reason imidazolines have been shadowed

by phenethanolamines in stereochemical studies is apparently 34 due to the lack of an asymmetric center in the molecule or resolution of imidazoline possessing an asymmetric center.

It is speculated that phenethanolamines and imidazolines 8 5 act at a common site on the adrenoceptor, and thus optical isomers of 2-imidazolines should show different biological activities.

The general structure of sympathomimetic imidazol ines can be viewed as being comprised of three major portions, the aromatic moiety, the bridge X between two rings, and the imidazoline nucleus. The bridge X can be a carbon or nitrogen atom.

,N' A r X ' "N*

The purpose of this research is to introduce an asymmetric center at either the bridge or on the hetero cyclic nucleus to give a pair of optical isomers and to evaluate their pharmacological effects on isolated tissues.

Five sets of isomers are obtained in this manner. They are

R- and S-2-(1-methyl-l,2,3,4-tetrahydro-l-naphthyl)-2- imidazoline (59a and 59b), 4R- and 4S-2-(1-naphthylmethyl)-

4-methyl-2-imidazoline (60a and 60b), 4R- and 4S-2-(l- naphthylmethyl)-4-benzyl-2-imidazoline (61a and 61b),

4R- and 4S-2-benzyl-4-methyl-2-imidazoline (62a and 62b), 35

4R- and 4S-2-[(2,6-dichlorophenyl)imino]4-methylimidazol-

idine (63a and 6 3b) corresponding to the parent compounds,

tetrahydrozoline, naphazoline, tolazoline, and clonidine.

These imidazolines represent compounds with different

modes of action in the adrenergic nervous system. Tetra

hydrozoline and naphazoline mainly activate the peripheral

a-adrenoceptor while tolazoline is an a-blocker and also

possesses histaminergic effects. Clonidine is a potent

a-agonist mainly acting on the CNS adrenergic nervous and

histaminergic systems. The preparation of optically

active imidazolines should provide new knowledge as the

configurational requirements of imidazoline derivatives

for both agonist and antagonist activity at a-adrenergic receptors,. These compounds should also provide a better

understanding of the stereochemical features required for

action on the central and peripheral adrenergic as well

as histaminergic receptors. N ^r/ 60a, R=CH 3 , R'=H \ J R 60b, R= H, R'=CH3 H 60c, R = R'=H,CH 3 61a, R= C 0 H5 CH2 s R'= H §ib, RSH, R'=C6 H5 CH2 RESULTS AND DISCUSSION

The synthetic aspects will be divided into parts based on the structural feature of the molecules synthe sized. The first part involves the syntheses of conformationally restricted cyclobutane analogs of phenethanolamines and the second portion is concerned with the preparation of optically active 2 ,4 (5)-disubstituted

2-imidazolines. Pharmacological results obtained thus far will be discussed at the end of each group of compounds.

I. Cyclobutane Analogs of Norephedrine and Metaraminol.

A. trans-2-Amino-l-phenylcyclobutanol (56).

The preparation of trans-amino alcohol (56) via a regio- and stereo-specific route relied on the synthesis of the key intermediate, 1-phenylcyclobutene-l,2 -oxide

(67). The starting material 1-phenylcyclobutene (6 6 ) has 129 been previously reported by Burger and Bennett.

1-Phenylcyclobutanol (65) was prepared by treatment of cyclobutanone (64) with the Grignard reagent, phenylmagnesium bromide in 85% yield. The infrared spectrum showed an hydroxyl absorption at 3350 cm ^ and the NMR spectrum gave a single peak at 6 2.75 integrated for one

37 38 proton and was exchanged using deuterium oxide. The dehydration of 65 was carried out by distillation in the presence of a catalytic amount of p-toluensulfonic acid through a short column to yield 6 6 . The NMR spectrum indicated the olefinic proton at 6 6.25 as a multiplet.

The treatment of 66 with peracetic acid using anhydrous sodium carbonate as a buffer according to the procedure 130 of Korach et al. gave an excellent yield of epoxide

67. In the NMR spectrum of 67 the olefinic proton was absent but a new signal appeared as a broad quartet at

5 4.1 which was assigned the methine proton. The isola tion of the resulting epoxide was very critical. Only water was employed in washing the reaction mixture instead of the normal work-up procedure.Epoxide 67 using the normal work up procedure of washing with 5% sodium bicarbonate, sodium iodide solution, sodium bisulfite solution, water, and saturated sodium chloride or upon standing would rearrange to 1 -phenyl.cyclopropanecarboxyl- 131 aldehyde. The Lewis acid-catalyzed rearrangement of cyclobutene epoxide to the corresponding aldehyde has been 132 reported by Garin. The NMR spectrum of 1-phenylcyclo- propanecarboxylaldehyde showed an AA'BB' pattern of cyclopropyl protons at 6 1.26 and 1.63, integrating for two protons respectively, an aldehyde group H at 6 9.3, integrating for one proton. The aldehyde group absorbed 39 Scheme 1

U p-TsOH OH

64 65

CH3 CO3 H ■> NQ 2 CO 3

66 67

Na N3 1) B2 H6—THF N 3 > d m f- h2o 2)HCI HO H

Ac20 56-HCI (■•••I •NHAc pyridine 1 AcO H

69 /-V 40

at 1715 and 2800 cm ^ in ir spectrum. The epoxide was

used immediately for the next reaction without any further

purification.

The reaction of 67 with sodium azide in N,N-

dimethylformamide and water gave a stereo-specific trans-

azido alcohol 68 which was chromatographed on silica gel

using ether-n-pentane (3:7) as the solvent to afford a

solid product. The trans-azido alcohol 68 was then

reduced with diborane in tetrahydrofuran followed by

treatment of dry hydrogen chloride to yield the desired

trans-2-amino-l-phenylcyclobutanol hydrochloride (56*HC1). . . . - i .... —.

The N,O-diacetyl derivative 69 was prepared by treatment

with acetic anhydride and pyridine (Scheme 1).

The NMR spectrum of 69 (Figure 4) was consistent

with the proposed structure. The amide proton of 69 gave

a broad doublet at 6 5.30 (J.-,rT = 8.0 Hz) while the Nil / Url methine proton gave a broad quartet at 64.80 (J = 8.0 Hz).

The quartet signal for the methine proton collapsed to a

triplet (J = 8.5 Hz) after deuterium exchange of the amide

proton indicating the amide group is attached directly to

the methine carbon. This confirmed the structural assign ment of the azido alcohol 6 8 and confirmed that the azide

ion opened the epoxide ring at the less hindered carbon. 133 The known'trans opening of the epoxide with sodium azide

and the NMR data of acetate amide 69 in contrast to that I U-T-J H i! O \ V c - c h 3

CH3-C-O H

5.0 PPM ( 0 ) 4.0

Figure 4. Nuclear magnetic resonance spectra of trans-acetamido ester 69. 42 obtained for the isomeric acetate amide 7JL lec^ to the functional group and stereochemical assignment of 56.

B. cis-2-Amino-l-phenylcyclobutanol (55).

The preparation of cis-amino alcohol 55 was attempted initially from the corresponding trans-isomer

56 analogous to the procedure utilized by Nelson and 70 Miller. Accordingly, trans-amino alcohol 56 was treated with benzoyl chloride and sodium hydroxide to afford amide 70. The infrared spectrum showed the amide carbonyl at 1630 c m ” '*' and hydroxyl group at 3350 cm Reaction of

70 with methane sulfonyl chloride gave oxazoline 71. The crude oxazoline was not purified at this stage, but was converted into oxazolinium salt 71a with methyl iodide in nitromethane. It was thought that the oxazolinium salt

71a would precipitate if an equal volume of ether was 134 added. However, no precipitation occurred after the addition of ether, even though the reaction mixture was kept at low temperature. Therefore it was suspected that the cyclization to oxazoline might not have taken place

(Scheme 2).

A second attempt at the synthesis of cis-amino alcohol 55 was to study the addition of nitrosyl formate to 1-phenylcyclobutene (66, Scheme 3). This type of 135 addition has been studied by Hamann and Swern. 43

Scheme 2

HO C6 H5 COCI HO

NaOH

56-HCI 70

71a 44

Nitrosyl formate which was generated in situ from isoamyl nitrite and formic acid was allowed to react with a number of acyclic, alicyclic, and aryl-substituted unsaturated

compounds and generally proceeds by a trans-addition, but with norbornene it yields the exo-cis adduct. Since cis addition had been detected it was thought that the reaction of 66 with nitrosyl formate would possibly yield a mixture of cis- and trans-nitroso formoxy compounds 72 which would be separated by column chromatography followed by reduction with lithium aluminum hydride to yield the cis - and trans amino alcohol 55 and 56. The reaction of formic acid, 66 and isoamyl nitrite was carried out at 5°C. The crude mixture was chromatographed on silica gel, eluted with

50% chloroform in benzene. However, none of the expected products could be isolated.

Another method of approaching the synthesis of cis-amino alcohol 55 is the addition of N,N-dichlorourethan

(DCU) to 1-phenylcyclobutene, a reaction which was dis- 136 137 covered by Swern. ' DCU adds to double bonds to yield 3-chloro N-chlorocarbamates which when washed with aqueous sodium bisulfite gives 3-chlorocarbamates in excellent yields. With terminal olefins and vinyl monomers, addition proceeds in antimarkovnikov fashion. However, with internal olefins allylic chlorination competes with double bond addition and the yields of adducts are usually 45

Scheme 3

i-AmO-NO 4- HCOOH fi-Am-0-N0]e HCO® H '

& H CO2 ■» i-AmOH + [NO]

HCOO-NO

i-AmONO NO HCOOH O-C-H

66 72

1) UAIH4 5 5 -HCI 4- 5 6 - HCI 2) HCI 46 low, and mixture of erythro and threo adduct are formed.

For instance, the addition of DCU to cyclohexene gives a mixture in which the major component is the trans-g-chloro- 136 carbamate (37%). Thus far no report had dealt with the addition of DCU to the strained cyclobutene ring system.

Our interest in this type of reaction is due to the fact that pyrolysis of B-chlorocarbamates give rise to 2-oxazol- idones as illustrated with the formation of 74 in Scheme 4 which can serve as the precursor for the cis-amino alcohol through base hydrolysis.

Reaction of DCU with 66 was carried out in benzene at 5° and only one crystalline product was isolated in

27% yield. The presence of chlorine was detected by

Beilstein test. The NMR spectrum was in agreement with the proposed structure. A triplet at 6 1.2 (3H) was assigned to the CH^ group, a quartet at 6 4.1 (2H) was assigned to the methylene of the ethyl group, a broad doublet at 6 4.4 (1H) was assigned to NH group, and was exchangeable with D20. A multiplet at 5 4.8 (1H) was assigned to the methine proton which collapsed to a narrower multiplet after D 2O exchange. It has been found that pyrolysis of the (3-chlorocarbamate gives 2-oxazoli- 136 done with the elimination of C2H^C1. The pyrolysis of

73 at 120° in acetic acid or 150° without any solvent gave a complicated mixture in which the desired product 47 Scheme 4

o ii 1) ci2 n -c -o c 2 h5 Q 2) NqHS03

66 73

oxazolidone _74 could not be detected even though ethyl chloride was trapped as a quaternary salt in an ether solution of triethylamine.

The successful synthesis of cis-amino alcohol 55 involved the formation of an intermediate a-aminoketone

76. Two methods of preparing 2-N,N-dibenzylaminocyclobutanone (76) were carried out (Scheme 5) . The first method involved a series of reactions analogous to those 138 of Burger and Ong. Bromination of cyclobutanone with bromine in carbon tetrachloride afforded the 2-bromocyclo- 139 140 butanone (75) ' along with other brommated products. 48 Scheme 5

Bzl2NH ± >

I) No/toluene ^ Q

COOC2 H5 2) Cl Si (CHs )3 (Cb^^SiO 0 Si(CH3)3

The 2-bromoketone was then allowed to react with excess dibenzylamine in ether. Chromatography on silica gel gave

2-dibenzylaminoketone 76. A less expensive and more convenient route to 76 was through the acyloin condensa- 141 tion using the conditions of Ruhlman et al. and 142 Bloomfield. The reaction of diethyl succinate and chlorotrimethylsilane in toluene with sodium sand afforded

1,2-bistrimethylsiloxycyclobutene-l (77). The 2-hydroxy- 141 cyclobutanone was generated dibenzylamine at 20° to give 2-dibenzylaminocyclobutanone (76) in better yield

(Scheme 5). 49

The NMR spectrum of 76 showed the benzylic protons to be unequivalent with J,. _ = -14 Hz. This AB pattern of A / i3 benzylic protons was seen throughout the entire series of compounds containing the dibenzylamino group.

The preparation of cis-2-N,N-dibenzylamino-l- phenylcyclobutanol hydrochloride (78) , a protected derivative of cis-amino alcohol 55 was accomplished by a Grignard reaction of the 2-aminoketone 76 and phenylmagnesium iwv bromide in tetrahydrofuran. Removal of the benzyl protect ing groups was accomplished by hydrogenolysis using 10%

Pd-C as a catalyst to give cis-2-amino-l-phenylcyclobutanol

(55). It was converted to the N,0-diacetyl derivative 79 using acetic anhydride and pyridine (Scheme 6).

The NMR spectrum was consistent with a cis disposition of groups in 79 (Figure 5). The amide proton of 79 showed as a broad doublet at 5 6.60 (J.,TT = 8.0 Hz) ■ w v N x i f U i l which was further down-field than the amide proton of 69

( 6 5.30). In 69 the amide proton is cis to the phenyl ring and would be expected to be upfield in comparison to the amide proton of 79. Since the shielding effect of a phenyl ring has been observed on groups cis to such a phenyl substituent in other four-membered ring 73 143-145 systems. ' The methine proton in 79 gave a quartet at 5 4.60, which collapsed to a triplet (J„T = L n / 2 8.5 Hz) after deuterium exchange. Again it is consistent 50 that the methine proton in 79 occurs at a higher field than that of 69 since it is cis to the phenyl ring in 79.

This work indicates that the Grignard addition to the tertiary aminoketone 76 occurred in a stereospecific manner and indicates that the phenylmagnesium bromide attacked the carbonyl group from the least hindered side. This is analogous to the hydride reduction of cyclic tertiary 146 aminoketones to the cis-ammo alcohols.

Scheme 6

1) C6H5MgBr 2) NH4CI

NBzl, 3) HCI HO NHBzl2

76 78

10% Pd-C Ac20 - m,H 55-HCI m ' Ho Pyridine i AcO NHAc

79 2.0 3.0 4.0 5.0 PPM ( T ) 6.0 7.0 8.0 9.0

350

! l. - 1 . J

8.07.0 6.0 4.0 3.0 2.0

Figure 5. Nuclear magnetic resonance spectra of cis-acetamido ester 79. 52

For further verification of the stereochemistry of cis- and trans-amino alcohol 55 and 56 chemical trans- 147 formations were used. Testa has prepared 2,2-dimethyl- oxazolidine derivatives of phenethanolamine using acetone

in the presence of glacial acetic acid. It was ration alized that an oxazolidine could be produced from the cis-amino alcohol 55 but not trans isomer 56. Therefore,

55 was treated with acetone along with a catalytic amount of glacial acetic acid at room temperature for 10 hr under anhydrous conditions. The NMR spectrum of the crude reaction mixture did not indicate the presence of gem- dimethyls which would have been present if formation had taken place. The reaction mixture was chromatographed on silica gel, eluting with ether-isopropylalcohol (1:4) to give only the starting material (Scheme 7). Under the same conditions trans-amino alcohol 56 gave a product more likely to be the imirie hydrochloride salt 81. The infrared spectrum clearly indicated the presence of C=N at 1640 cm ^ and the alcoholic OH at 3420 cm Due to the limited amount of 81 further characterization became impossible.

The N-K) acyl migration of 3-amino alcohols has been studied extensively. It was found that the amide derivative of cis- 2 -aminocyclopropanol was converted to amino ester in alcoholic hydrogen chloride solution without 148 changing its configuration. An oxazolidine was proposed to be the intermediate for this transformation. To test the ability of N + 0 acetyl migration for cis-amino alcohol

55 but not for trans isomer 56 the preparation of cis- and trans-acetamido alcohol 82 and 84 was attempted. The reaction of 55 with 1 molar ratio of acetic anhydride in pyridine afforded 82. Under the same conditions 56 was converted to 84. The NMR spectra of 82 and 84 (Figure 6 and 7) are summarized in Table 1 along with the N,0-acetyl derivatives of cyclobutane analogs of norephedrine and metaraminol. It was found that the methyl signal of acetamido group that is cis to the phenyl group appears at higher field than the corresponding isomer due to the shielding effect of the phenyl group. A similar effect has also been observed in the case of NH and methine p r o t o n s .

Scheme 7

8 0 55 1) Acetone HOAc 2) HCI

n=c(ch3)2 2.0 3.0 4.0 5.0 PPM (T ) 6.0 7.0 8.0 9.0

<90 300 ICO

130

H-0 .N-C-CH

S.O 7.0 6.0 5.0 ppm (a) 3.0 2.0 1.0

Figure 6 . Nuclear magnetic resonance spectra of cis-acetamido alcohol 82. 2.0 3.0 4.0 5.0 PPM (Tt 6.0 7.0 8.0 9.0

3 0 0 100

100

H - 0

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0

Figure 7. Nuclear magnetic resonance spectra of trans-acetamido alcohol 84. 1 _ " 56

Scheme 8

55- HCI /V» HO MHAc X X * 82 83 Ac20 Pyridine HCI / ------X ------Si M"NH Ac N' R* 56-HCI HO H 84

Thus the chemical shifts of the amide proton in trans acetate amide series appear at higher field than cis- isomers, and the methine proton of trans-isomers appear down-field from those of cis-acetate amide isomers.

A solution of each acetamido alcohol 82 and 84 in 1 0 % hydrogen chloride in absolute ethanol was refluxed for 2 hr. A hydrochloride salt was isolated from cis- acetamido alcohol 82 while the starting material was recovered from the trans-isomer under the same conditions.

The cis-2-amino-l-phenyl-1-acetoxycyclobutane hydro chloride (83) was characterized by ir spectrum in which the ester carbonyl group absorbed at 1730 cm The limited amount of 83 did not allow further characterization. 57

Table 1. The chemical shifts of acetyl derivatives (6 )*

compds CH 3c o n h CH NH methine 3C 0 2

84 S, 1.7 bd, 5.33 q* 4.6

82 s, 1.85 bd, 6.67 q# 4.6

69 s, 1.65 S/ 1.95 bd, 5.30 q> 4.8

79 s, 2.0 s, 2.0 bd, 6.60 q* 4.65

** S, 1.7 s, 1.95 m, 4.8-5.0 m, 4.7-5.0

93 S, 2.03 s, 2.03 bd, 6.43 m, 4.43-4.90

* Solvent : CDCl^

** trans-2-acetamido-1-(3-benzyloxyphenyl)-1-acetoxycyclo- , , 152 butane.

C. trans-2-Amino-1-(3-hydroxyphenyl)cyclobutanol (58).

The synthesis of trans-amino alcohol 58 is analogous to the preparation of trans- 2-amino- 1 -phenylcyclobutanol (56)• The initial step was the preparation of 3-benzyloxybromobenzene (8 6 ) from 3-bromophenol accord- 153 ing to the procedure of Pmer et ai. Reaction of 3- bromophenol with benzyl chloride and potassium carbonate in acetone gave 86 in 9 7% yield. Grignard reaction of cyclobutanone and 3-benzyloxyphenylmagnesium bromide afforded alcohol 87. Dehydration of 87 using catalytic 58 amount of p-toluenesulfonic acid in benzene yielded an olefinic product 8 8 . The epoxidation of 1-(3-benzyloxyphenyl) cyclobutene (8 8 ) using peracetic acid and anhydrous sodium carbonate gave the epoxide 89. The unstable epoxide was then treated immediately with sodium azide in

N,N-dimethylformamide and water at 80-85°. The reaction mixture was chromatographed on silica gel, eluted with ether-petroleum ether (65-110°) (3:7) to give trans-azido alcohol 90 as a white crystalline solid in 48% yield.

The reduction of 90 was carried out using diborane in tetrahydrofuran to give the protected trans-amino alcohol

91 in excellent yield. trans-2-Amino-1-(3-hydroxyphenyl)- cyclobutanol (58) was then obtained by removing the benzyl protecting group through catalytic hydrogenation using 1 0 %

Pd-C at atmospheric pressure and at room temperature

(Scheme 9). Compound 58®HC1 was hygroscopic and unstable.

D. cis-2-Amino-1-(3-hydroxyphenyl)cyclobutanol (57).

The cis-amino alcohol 57 was prepared following the previous method for norephedrine analog. The reaction of Grignard reagent, 3-benzyloxyphenylmagnesium bromide, and 2-N,N-dibenzylaminocyclobutanone (76) in tetrahydro furan afforded N, 0 -protected cis-amino alcohol 92. The benzyl groups were removed by hydrogenolysis to give a hygroscopic cis-amino alcohol 57 which was converted to 59

Scheme 9

HO BzIO A-'-'A C6 H5 CH2 C1 Br O er —K2 C 0 3 * 7 85 86

THF BzIO

0 OH 64 87

p-TsOH- CH3 CO3 H BzIO NQ2 C0g

BzIO 1) B2 H6-THF © 10% Pd-C 1 >1 ""NHg -> ^ 58HCI ,© 2) HCI HO H Cl H 2

91 the triacetyl derivative 93 using acetic anhydride and pyridine.

The NMR spectrum of 9 3 is summarized in Table 1 and the results were consistent with other acetyl amide derivatives.

Scheme 10

BzIO BzIO MgBr ii" V H c P NBzIp 2) HCI 0 HO NHBzl2

76 92

AcO AcoO 10 % Pd - C in' - "" H 57- HCI Pyridine AcO NHAc H 2 61

E. Biological Results and Discussion

E-l. Cyclobutane Analogs of Norephedrine, 55 and 56

The norephedrine analogs 55 and 56 were examined for their ability to potentiate the action of (-)-norepin ephrine. The dense adrenergically-innervated rat vas deferens provides a good system for the study of the potentiation of the effects of (-)-norepinephrine by various drugs. The potentiation of the response of (-)- norepinephrine by drugs provides an indirect method for the study of the drug's ability to inhibit uptake of . . 70,154 norepinephrine.

The mean contraction of the reserpine-pretreated tissue to low concentrations of (-)-norepinephrine was -5 10 ± 2% (n = 6 ). In the presence of either low (3 X 10 M) or high (3 X 10 ^M) concentrations of 56, the response to

(-)-norepinephrine was not affected. On the other hand

55 in a concentration dependent fashion, potentiated the responses of (-)-norepinephrine. Results of this potentia^ tion of (-)-norepinephrine are illustrated for 55 and 56 in Figure 8 . Neither 55 nor 56 produced any intrinsic effects on the tissue alone during the incubation periods.

Since these experimental drugs are analogs of norephedrine (54) the potentiation by (~)~54 was also examined. The drug is mixed acting, hence as expected -5 it produced some intrinsic effects at 1 X 10 M and 62

- 5 3 X 10 M. The intrinsic effects of (-)-54 could complicate the potentiation experiments. When the con-

” 6 centration of (-)-54 was lowered to 3 X 10 M, there was less than 5% intrinsic effect produced; however, the potentiation of (-)-norepinephrine produced by (—)—54 :/ was 66 ± 8 % (n = 3). The potentiation of (-)-norepinephrine -4 by 55 at 3 X 10 M was 55 ± 3% (n = 4). Approximately equal potentiation of (-)-norepinephrine ioy the drugs, 55 and (-)-54, at two equal concentrations indicates that 55 has approximately l/1 0 0 th the potency of (-)-norepineph rine. This work appears to be in agreement with previous studies on the inhibition of (-)-norepinephrine uptake by 72 73 conformationally restricted phenethylamine analogs, '

It was shown with the cis- and trans-2-phenylcyclopropyl- amines that the trans compound was considerably more effective in inhibiting the uptake of (-)-norepinephrine 73 72 in both peripheral and central nervous system tissues.

In the more effective norephedrine analog, 55, there is a trans-relationship between the phenyl ring and the amino function; thus this would appear to lend some credence to the thought that compounds may bind and inhibit the amine uptake pump in an anticlinal or anti- . . , 72,155,156 periplanar conformation. 60

Rat vas deferens n=4

40 Q>Ql Q. HO ®NH o 2 NI

^ 20 o. with HO n=2

.-5 -4 10 10

Experimental drug (M )

Figure &. Illustrates the responses to (-)-norepineph rine (NE) 3 X 10"7M in the presence of various concen trations of 55*HC1 and 56*HCI. The tissues were obtained frorrTreserpine^reated rats (5 mg/kg, i.p./ 16 to 22 hr). (-)-Norepinephrine, 3 X 10“ 7M, without any drug produced a mean (n = 6 ) contraction of 10 ± 2%. On every tissue the maximal effects of (±)- methoxamine were considered 1 0 0 %. 64

E-2. Cyclobutane Analogs of Metaraminol, 57 and 58.

The a-adrenoceptor stimulant activity of metaraminol analogs 57 and 58 were compared on the rabbit -4 aortic strips. When tested up to 10 M, both analogs did not produce any contraction of the tissue; however at -4 3 X 10 M 57 produced a small contraction of the tissue, while 58 did not. The ED,-n of the metaraminol was ****** D U -7 8 X 10 M and relative to the maximum contraction pro duced by (-)-metaraminol, the contraction produced by -4 57 (at 3 X 10 M) was approximately 7%. Although both analogs are weaker than metaraminol, the slightly higher activity of 57 over 58 indicates that the trans relation ship between phenyl ring and amino group is favored for the a-adrenoceptor stimulation.

II. Optically Active 2,4(5)-Disubstituted-2-Imidazolines.

The general procedures for preparing 2-substituted 157 2-imidazolines have been well-documented. The mildest conditions for this synthesis involves the condensation of the imidate ester hydrochlorides and the 1 ,2 -diamines in methanol.4-u i 158

There are several methods that have been employed for the synthesis of the imidate ester hydrochloride 159 using a variety of starting materials. The Pinner synthesis is an old but effective method in which the synthesis consists of condensing a nitrile and alcohol

under anhydrous conditions in the presence of hydrogen

chloride or hydrogen bromide. The formation of the

imidate ester hydrochloride is markedly affected by two

factors: moisture and temperature. The hydrolysis of

an imidate by moisture forms an ester and this hydrolysis

is accelerated by hydrogen ions. The unsubstituted

imidate hydrohalides normally decompose to the corres ponding amides and alkyl halides when heated. Thus, the preparation of imidate ester hydrochloride is achieved at

low temperature under anhydrous conditions.

A. 2-(1-Methyl-l,2,3,4-tetrahydro-l-naphthyl)-2-

imidazoline (59).

The synthesis of the methyl substituted tetrahydrozoline 59 was initiated with the preparation of the precursor

1 -cyano-l-methyl-l,2 ,3,4-tetrahydronaphthalene (103) via

che Pinner synthesis. The preparation of the cyano compound 96_ was first attempted from the reaction sequence as shown in Scheme 11. Tetralone (94) was reduced with

NaBH^ to yield tetralol (95)^^ in 83% yield. A variety of methods have been used to convert the alcohol to the X 61 nitrile. The most direct transformation of the alcohol to the nitrile in high yield has been reported by Brett ICO et al. and can be accomplished in one pot by treatment 66 of the alcohol with triphenylphosphine and carbon tetra chloride followed by addition of sodium cyanide and dimethyl sulfoxide. However, under these same conditions

1-tetralol could not be converted to the nitrile 96. An alternative route to nitrile 96 was attempted via inter mediate chloride 98. The treatment of 1-tetralol with thionyl chloride afforded the chloride 98 along with a side product 1,2-dihydronaphthalene (97). Compound 97 and 9 8 were produced in a relative ratio of 1:1. The purification of 98 was made difficult due to the close boiling points of 97 and 98. The conversion of the chloride 98 to the nitrile 96 was attempted initially in ethyl methyl ketone according to the procedure of Carlsson 163 et al. However, only the elimination product 97 was isolated under these conditons. When dimethyl sulfoxide was employed as the solvent, substitution of the chloride by cyanide became predominant (Scheme 11).

The reaction sequence reported by Protiva and 164 coworkers was found to be a better route to compound 96

(Scheme 12). The reduction of 1-naphthoic acid (99) in sodium carbonate solution using 4% sodium amalgam afforded

1 ,2 ,3,4-tetrahydro-l-naphthoic acid (1 0 0 ) in high yield.

The carboxylic acid 100 was then treated with thionyl chloride to give the acid chloride 101 followed by treat ment with concentrated ammonium hydroxide to yield the 67 crystalline amide 102. The dehydration of 102 was accomplished by a direct distillation from a mixture of the amide 102 and phosphorous pentoxide to afford 96 in

71% yield starting from 99.

Scheme 11

NaBH4 l)Ph3p /c C I4 2) NaCN,DMS0

' NaCN DMSO

The methylation of the nitrile 96 was originally carried out by treating 96 with sodium amide and methyl iodide in benzene according to the procedure of Protiva 16 5 et al. Compound 10 3 was obtained in fair yield along with some byproducts which were not characterized.

However, methylation in high yield was accomplished when , 164 ether was used as a solvent. 68

Scheme 12

COOH COOH 1) Ma-Hg S0CI2

N 02 CO 3 2) H2S04 99 100

COCI

NH4 0 H P 2 O 5

101 102

CN NC

Na NH 2

CH3 I

96 103

As mentioned previously we expected to obtain the imidazoline 59 via the imidate ester 104 intermediate.

Reaction of 103 with absolute alcohol and anhydrous hydrogen chloride was undertaken at 0 ° and then kept at 167 4° for two weeks. However, only starting material 103 was recovered from the reaction mixture. Failure of this transformation was attributed to the steric hindrance of 159 the alkyl portion adjacent to the nitrile group of 103.

A more direct method in the formation of imidazolines involving the reaction between a nitrile and diamine monotosylate at 210° had been reported by Oxley and 168 Short. Under these conditions the final product 59 was obtained from the nitrile 103 and 2-aminoethylammonium p-toluenesulfonate in 96% yield (Scheme 13).

Scheme 13

H Cl 103 104

B. R- and S-l,2-Diaminopropane Dihydrochloride (108a

and 1 0 8 b ) .

The optically active 1,2-diaminopropane will be prepared and serve as one of the starting materials for the synthesis of the imidazolines. The optical isomers

108a and 108b were prepared by the synthetic route outlined in Scheme 14 rather than by conventional resolution.

Thus, the R-isomer of 1,2-diaminopropane (108a) was obtained from R-alanine (105) with retention of configura tion and the S-isomer 108b was formed from S-alanine.

R-alanine was first converted to the methyl ester 106a by treatment with 2 ,2-dimethoxypropane and concentrated hydrochloric acid at room temperature using the procedure 171 of Rachele. The free base of 106a was then treated with methanol saturated with ammonia in a manner analogous 172 to the method of Yang and Rinng to yxeld the optxcally active alanine amide 107a. Diborane reduction of 107a in 173 tetrahydrofuran followed by the addition of methanol and dry hydrogen chloride gave the desired optically active 1,2-diaminopropane dihydrochloride 108a. Under the same conditions, S-alanine ethyl ester- hydrochloride (106b) was converted into S-l,2-diaminopropane (108b). Scheme 14

NH2 NH3 Cl CH30^.0C H 3 I H ^ C\ , CHg COOH HCI ^ ‘S o o r "

106a, R=R=CH3 , R'=H .105 I06b, R=H, R'=CH3 , R" =

1) NaOH/ CHCI3 2) NH3/ C H 30H © e © e nh3 ci nh3 ci nh2 i i 1) B2H6 -THF R'""f °Hz 2) HCI R R^_N C0NH2 R Table 2. Physical Properties of Alanine Derivatives.

[a] . Final Temp. mp c o n c . (%) omp s* crystn. solv. N a 589 H g 578 • (°C) 1—1 o o

106a Me0H-Et20 109-111° -7.7174 24 • MeOH

106b 62° (dec.) + 3.8 +4.01 24 1.82/ MeOH ■—i 0 1 • CO 107a CHC 1 3-Et 20 74-76®172 -10.9 28 o • (D MeOH

107b CHC 1 3 -Et20 74-76° +10.4 -1 1 . 1 28 0.96, MeOH

108a Me0H-Et20 236-8° + 3.96 +4.04 28 0.96, H 2°

108b Me0H-Et20 236-8° -4.0 -4.12 28 0.85, h 2° 73

C. R- and S-l,2-Diamino-3-phenylpropane (112a and 112b).

Described earlier was the preparation of the

optically active 1 ,2 -diamines via a stereospecific synthe

sis from amino acids of known absolute configuration.

Thus, in a similar manner R-phenylalanine (109) was

converted to the R-isomer 112a and the commercially

available intermediate S-phenylalanine amide (111b) was

transformed to the S-isomer 112b (Scheme 15).

Scheme 15

(B © nh3 ci NHp CH3 Q-OCH 3 I 13

\ H X C00H HCI COOCH3 C 6 H 5 CH 2 c6 h5ch 2

109 10

1) NaOH/CHCI 3

2) NH3/ CH3OH Cl0 Cl0

e NH3 0 NH3 nh2 b2h6 - t h f p ' , 1 1 1 i ^ C CHc \ HCI conh2 R

IJ2a, R=C 6H5CH2 , R'=H INa, R=C 6H5CH2 , R' = h

112b, R = H, R = C6H5CH2 III b, R = H, R/=C6H5 CH2 Table 3. Physical Properties of Phenylalanine Derivatives.

[ctj^ Final Compd mp C o n e . (%) crystn. solv. N a 589 H g 578

110 3 Me0H-Et20 159-161° -16.5 -17.4 1.00, MeOH

1 1 1 a benzene 91-93° -13.41 -14.08 1.13, MeOH

1 1 1 b 91-93° +13.46 +14.15 1.03, MeOH

1 1 2 a 95% Et0H-Et20 2 0 0 - 2 0 1 ° + 32 +33.3 1.1, H20

1 1 2 b 95% Et0H-Eto0 2 0 0 - 2 0 1 ° -31.43 -32.67 1.05, H 20

-vl 75

D. 1- and 4(5)-Methyl-2(1-naphthylmethyl)-2-imidazoline

(60a, 60b, 60c, 115). AA/WV

It has been discussed previously that the imidazol

ine nucleus can be obtained by the condensation of the

imidate ester hydrochloride and diamine at low temperature 158 as reported by King and Acheson. They also noted that

the condensation of the diamine dihydrochloride and the

imidate ester hydrochloride resulted in diminished yield

of imidazolines. However, it was found that if one uses

two equivalents of triethylamine to help generate the

free base of the diamine dihydrochloride, the condensation

occurs as effectively as when one uses the free diamine

initially.

1-Naphthylacetonitrile (113) was converted to the

114 imidate ester •Vvwv according to the procedure of McElvain 167 and Stevens. The imidate was then allowed to react with optically active 108a and 108b via a modification 158 of the procedure of King and Acheson to give the optical isomers 60a and 60b, respectively. The racemic mixture 60c was prepared from 114 and racemic 1,2-diamino

propane in MeOH. Under the same conditions compound 115 was obtained from N-methylethylenediamine and 114

(Scheme 16) 76

Schem e 16

® © nh2 ct CH2CN CHo-C. I OC2Hg c 2h5oh CHg H2N n hc h3

113

CH3 HH, CH3 CH3 HH,

H2 N NH2 H2 N 1 h2 -2 HCI X X zN NHz • 2 HCI . Et3 N / 1 60c 60a 60b

E. R- and S-4-Benzyl-2(1-naphthylmethyl)-2-imidazoline

(61a and 61b)

The synthesis of optical isomers 61a and 61b was

carried out in a manner analogous to the preparation of optically active compound 60a and 60b. Thus, the conden

sation of 114 with R- and S-l,2-diamino-3-phenylpropane dihydrochloride (1 1 2 a and 1 1 2 b) afforded the optically active 61a and 61b, respectively (Scheme 17). 77

Schem e 17

H CH2C6H5 r Y 61a © © H2N NH2 • 2 HCI ^ N H 2 Cl 112a _ CHo-C OC2.H5 Et3N

114

61b

•2 HCI 112b

F. 2-Benzyl-4-methyl-2-imidazoline (62a, 62b, and 62c).

Under the same conditions used in the naphazoline series the optically active tolazoline derivatives 62a and 62b as well as the racemic 62c were prepared from the imide ester 117 and the corresponding 1,2-diarnino- propane in methanol (Scheme 18). 78

Scheme 18

0 e HI CM C2H50H ^ MHo Ci c h 2 c n — — ----» C H 2 c f 0 C 2H 5

116

G. 2-[(2,6 -Dichlorophenyl)imino]-4-methyl-2-imidazolidine

(63a, 63b, and 63c).

The syntheses of optically active 63a, 63b, and the

racemic 63c were carried out via the key intermediate

thiourea, 120. Compound 120 which has been reported by 176 Kinochita et ad. was prepared starting from 2,6-dichlor-

oaniline (118). The reaction of ammonium thiocyanate and

benzoyl chloride followed by treatment with 118 afforded

the benzoyl thiourea 119. Saponification of 119 in sodium hydroxide gave the thiourea 1 2 0 which was then converted

to the hydroiodide salt 1 2 1 by treating with methyl iodide 177 177 178 in methanol. Using a known procedure ' the 79 condensation of 121 with racemic 1 ,2-diaminopropane at

140° gave the racemic compound 63c. The optical isomers

63a and 63b could also be obtained by a modification of ' M V W V ' W W V 175 176 the procedure for the synthesis of clonidine. '

A solution of the hydroiodide salt 121, optically active

R- or S-l,2-diaminopropane (108a or 108b), and a two molar ratio of triethylamine in a sealed tube using 1 -propanol as solvent was heated at 140° for 8 hr to afford the desired optically active product 63a and 6 3b, respectively

(Scheme 19).

The circular dichroism (CD) curves of the opti-^ cally active naphazoline derivatives (6'WWW 0a and 60b, Figure 9) and tolazoline derivatives (62a and 62b,

Figure 10) show that the R-isomers produce a positive

Cotton effect while the S-isomers give a negative Cotton effect. However, in the clonidine series just the opposite is observed; the R-isomer 63a produces a negative >www Cotton effect and the S-isomer produces a positive Cotton effect (Figure 11). 80

Scheme 19

n h 4s c n NH-C-NHCCcH CgHgCOCI Cl Cl

118 119

NaOH CH31 NH-C-NH CH3OH

120

63a

108a Et3N» 140 ^NH -HI NH-C 108b XS-CH3 63b 140

121

63 c H2 N nh 2 Table 4. The Physical Properties of Optically Active 2-Imidazolines

Final [a]28 Compd crystn. Solv. mp(°C) bp(°C/mm) Cone. (%) N a 589 H g 578

60a 163-6/0.18 +47.6 +50.0 1.06/ CHCl

60b 152-4/0.12 -49.4 -52.4 1.14, CHCl

60a HCI abs. EtOH-Et20 187-188.5 + 53.4 +56.13 1.06, MeOH

60b HCI abs. EtOH-Et20 187-188.5 -52.58 -55.38 0.93, MeOH

61a HCI MeOH-Et20 189-191.5 +79.84 +83.87 1.24, MeOH

61b HCI MeOH-Et20 189-191.5 -79.32 -83.16 0.95, MeOH

62a 111-4/0.15 + 57.1 + 60.1 1 .1 2 , CHCl

62b 106-7/0.13 -58.0 -61.0 1.03, CHCl

62a picrate 95% EtOH 112-4 + 29.0 + 30.4 1 .1 2 , MeOH

62b picrate 95% EtOH 112-4 -30.1 -31.43 0.91, MeOH

63a HCI Me0H-Et20 260-2 (dec) +17.92 +19.01 1 .0 1 , MeOH

63b HCI MeOH-Et20 260-2 (dec) -18.87 -19.65 1.15, MeOH

00 H 82

20 R isom er

- io

S isomer -20

-30 ------1------1------1------1------1______1______I______I 210 220 230 240 X (yn-M)

Figure 9. Circular dichroism curves of the methyl derivatives of naphazoline 60a and 60b. 83

H /N y^ c h 3 CH 2 -picrate H

R isomer

'o x ciT

- 1 0

S isomer

-20

J i 1 i L 210 220 230 240

a (m m )

Figure 10. Circular dichroism curves of the methyl derivatives of tolazoline 62a and 62b. 84

S isomer

R isomer

-20

t______220 230 240 250 A (WA)

Figure 11. Circular dichroism curves of the methyl derivatives of clonidine 63a and 63b. 85

H. Biological Results and Discussion

H-l. 2-(1-Methyl-l,2,3,4-tetrahydro-l-naphthyl)-2-

imidazoline (59).

In vitro, the pharmacological activity of the compound 42 and a methyl derivative of tetrahydrozoline,

5 9 , was compared on two separate strips obtained from one rabbit aorta. Relative to phenylephrine, the maximum contraction of the tissue produced by 42 and 59 were 61 and 49% respectively. When compared at the a-adrenoceptor stimulant activity of 59 was l/100th that of 42. Results are illustrated in Figure 12 . Thus methyl substitution appears to decrease the a-adrenoceptor stimulant effect of tetrahydrozoline.

H-2. Methyl Derivatives of Naphazoline, 60a and 60b.

Neither compound 60a or 60b possessed agonist activity on the rabbit aorta when examined in concentra- _3 tions as high as 10 M. Conversely, the parent compound,

38, was a potent agonist on a-adrenoceptors with an

— 8 of 6 X 10 M. Both compounds 60a and 60b possess moderate a-adrenoceptor blocking activity as evidenced by parallel shifts in the dose-response curve to the agonist, phenyl- X 8 0 ephrine (Figure 13). Figure 14 is a Schild plot for compounds 60a and 60b. The intercept along the abcissa is the P A 2 / which is a measure of antagonist activity. The

PA 2 values of 5.60 and 5.76 for compounds 60a and 60b , Contraction (Phenylephrine = 100% ) too 20 40 aiu cnrcin o hnlprn a obtained. was phenylephrine to contraction maximum h cnrcin rdcd y hnlprn a con n o c was phenylephrine by produced contraction The iue 2 Ilsrts h ds rsos cre of curves response dose the Illustrates 12. Figure codn t Frhot n Barkm19 n a On Bhadrakom.1'9 and Furchgott to according rgws osrce. h tsu a wse and washed as was given sidered tissue the of The curve response constructed. dose prepared the was strips drug strip, aortic separate rabbit on imidazolines two 60 80 10 -7 abt Aorta Rabbit 0 0 1 . 10 ocnrto ( ) M ( Concentration 10 -3 ch 10 . -4

86 10 -3 87 respectively, indicate an apparent lack of stereoselec tivity. The slopes on the Schild plot are very close to the theoretical value of one indicating that blockade is competitive.

Since compounds 60a and 60b each possess an imidazoline ring, their ability to block the response to histamine was examined. As shown in Figure 15, both compounds possess weak antihistamine activity in the rabbit aorta. The PA 2 values for compounds 60a and 60b are 4.3 and 4.5, respectively, indicating an appropriate

2 0 -fold higher affinity for a-adrenoceptors than for the

H^-histaminergic receptor. As with the a-adrenoceptor, no apparent stereoselectivity could be detected with the histamine receptors. CONTRACTION (X OF MAXIMUM) hnlprn. ah on i tema o 4 observa 4 of mean the is point Each phenylephrine. error of the mean. the of error various of presence and absence the in phenylephrine in ad h vria br rpeet h standard the represent to bars vertical contraction the and maximum the tions as~percent~of for (-)-methylnaphazoline S curves and expressed R(+)- of dose-response log concentrations Cumulative 13. Figure 100 cmons 0 ad 0 rsetvl) Te aa are data The respectively). 60b and 60a (compounds 40 20 60 to -8 to -T 10 •* 3*10~® 10 4[R(+)*malhynophatolinc]j to 6 10 -J [ e n i r h p e l y n e h p 10 'CH to -8 ] m to •7 O5 3x10"® IO'5 to -6 10 10 J [s(-) 4 ' -methylnophoioltne]M to •«

CH. I ©

Slope = 0.99 Slope =0.99 & (A O a

-Log [MethylnaphazolineJ

Figure 14. Schild plot for the data presented in figure 13. The dose ratios were calculated by dividing the ED 50 of a dose-response curve to phenylephrine in the presence of R(+)- or S(-)- methylnaphazoline (60a or 60b respectively) by the ED 50 of the control dose-response curve to phenyl ephrine. The intercept along the abscissa is the PA 2 which is the negative log of the molar concen tration of antagonist that causes a two-fold shift to the right in the dose-response curve to an agonist. Each point is the mean of 4 observations and the vertical bars are the standard error of the m e a n . Contraction (% of Maximum) f osrain ad h vria br represent bars mean the is vertical the point and Each observations 3 1]). - of ratio / [dose naphazoline] pA The histamine. itmn i te rsne f 04 ocnrtos of for curve concentrations 10~4m of dose-response log presence the in Cumulative histamine 15. Figure ais n te olwn euto: A p to equation: following contraction the are and data maximum the The ratios of percent as expressed S (-)-methylnaphazoline. and R(+)- standard error of the mean. the of error standard 100r 60 20 80 40 — — — — — — Cont l o tr n o C — —

2 106 aus ee band rm h dose- the from obtained were values

10"4 10 " A 4 W ft fJi | © n i m a t s 2 H [ 1 1 -- et naphazolne PA P , e lin o z a h p a ( ln R y th !e V (-)-E S 4 naphazolne , p , e lin o z a h p a ln y h t e M - ) 10 5

2 -log([methyl g o l - = JL A

104 2 &

s 4.3 3

4 .S

SUMMARY

It has been proposed that complexation of key functional groups in drug molecules with spatial chemical groups on receptors initiates biological actions. A number of conformationally flexible phenethanolamines have been investigated for their effects in the adrenergic nervous system. To investigate the conformational require ment of phenethanolamines for their interaction with adren ergic receptors the preparation of conformationally restricted analog of phenethanolamines has been carried out.

A major criticism of past work carried out by Smissman's group^^ ^ and Nelson and Miller^ is the introduction of a bulky hydrocarbon portion to confer the rigidity of phenethanolamines. Conformationally restricted analogs of phenethylamine drugs have been synthesized using cyclo- 72 73 72 79 propyl, azetidine, indan, and isoquinoline ring systems. In this study one methylene unit is inserted between the a-CH^ and g-carbon in norephedrine and metaraminol to give a conformationally restricted cyclobutane analog.

The preparations of norephedrine analogs, cis- and trans-2-amino-l-phenylcyclobutanol (55 and 56), and cis- and trans-2-amino-l-(3-hydroxyphenyl)cyclobutanol (57 and 91 92

58) are described. The biological result indicated that the

cis-amino alcohol 55, possessing a trans phenyl ring and the

amino function, is more effective in inhibiting the uptake

of (-)-norepinephrine than the trans-isomer 56 on rat vas

deferens. The a-stimulant activity of metaraminol analogs

57 and 58 were compared on the rabbit aorta strips. The -4 higher activity of 57 over 58 at the concentration 10 M

suggested that the trans relationship between phenyl ring

and amino group was favored for a-adrenoceptor stimulation.

A series of sympathetic 2,4-disubstituted 2-imidazo

lines were prepared. They are 2-(1-methyl-l,2,3,4-tetra- .

hydro-l-naphthyl)-2-imidazoline (59), 4R- and 4S-2-(l-

naphthylmethyl)-4-methyl-2-imidazoline (60a and 60b), 4R-

and 4S-2-(1-naphthylmethyl)-4-benzyl-2-imidazoline (61a and

61b), 4R- and 4S-2-benzyl-4-methyl-2-imidazoline (62a and

62b), 4R- and 4S-2-[(2,6-dichlorophenyl)imino]-4-methyl-

imidazolidine (63a and 63b) corresponding to the parent

compounds, tetrahydrozoline, naphazoline, tolazoline, and clonidine. The synthesis of optically active 2,4-disubsti

tuted 2-imidazoline involves the preparation of R- and

S-l,2-diaminopropane and R- and S-l,2-diamino-3-phenylpropane from the corresponding amino acid and then allowing

the optically active diamino dihydrochloride to react with

the appropriate imidate' ester hydrochloride in the presence of triethylamine. 93

The pharmacological activity of tetrahydrozoline

and the methyl derivative 59 was compared on rabbit aorta.

At EDCrt the a-stimulant activity of 59 was l/100th that of J (J MAfW tetrahydrozoline. Thus methyl substitution appears to

decrease the a-adrenoceptor stimulant effect of tetra hydrozoline.

Naphazoline is a potent a-adrenoceptor agonist

(-log ED^q = 7.22) whereas the methyl derivative 60a and

60b were moderately potent antagonists(P^ = 5.6 and 5.8, respectively) of the a-adrenoceptor on rabbit aorta.

Compounds 60a and 60b also produced blockade of the res ponse to histamine on rabbit aorta with PA 2 = 4.3 and 4.5 respectively. Methyl substitution on the imidazoline ring of naphazoline reversed the pharmacological effect of parent compound. No stereoselectivity could be detected in a-adrenergic or histamine receptor systems. EXPERIMENTAL

Melting points (uncorrected) were determined on a Thomas-Hoover melting point apparatus. Infrared spectra were recorded on a Perkin-Elmer 257, Beckman IR-33, and

Beckman 4230 infrared spectrophotometers. Nuclear

Magnetic Resonance spectra were obtained using a Varian

A-60A Spectrophotometer. The optical rotations were recorded by using a Perkin Elmer 240 polarimeter. Circular dichroism were measured with a Jasco Model ORD/UV-5 optical rotation recorder. Gas-liquid partition chroma tography was performed using the P and M Scientific Model

402 high efficiency gas chromatograph. Analyses were obtained by Galbraith Laboratories, Inc., Knoxville, Tenn.

Analytical results for elements indicates were within

± 0.4% of the theoretical values.

1-phenylcyclobutanol (65) . a solution of bromobenzene

(53 g, 0.34 mol) in 130 ml of Et 20 was added dropwise with stirring to Mg turnings (8.0 g, 0.33 mol) with a crystal of in 30 ml of Et 20 under argon. The mixture was warmed with hot water until the reaction started.

The reaction mixture was then allowed to cool to room temperature with the slow addition of the remainder of

94 95 bromobenzene and maintained the reaction at a mild reflux.

The final solution was refluxed for 3 hr and then cooled in an ice bath followed by the addition of cyclobutanone

(20 g, 0.29 mol). The reaction mixture was refluxed for

2 hr and treated with aqueous NH^Cl. The organic layer was separated and the aqueous layer was extracted with

E t 20 . T^e combined organic layer was washed with 1^ 0 , dried (MgSO^), and evaporated to give an oil which was distilled to yield 40 g of 65(85%): bp 76-80°/0.8 mm 1 -1 (lit 92-98°/l mm); ir (neat) 3350 cm x (broad, OH);

NMR (CDC13) 6 1.50-2.71 (m, 6H, -CH 2CH 2CH2-), 2.81

(s, 1H, OH, exchangeable with ' 7.16-7.57 (m, 5H, aromatic).

1-Phenylcyclobutene (6 6 ). A mixture of 1-phenylcyclo- ■ i — i. ■ —, ■ .. -ffd&.O.l...— butanol (65) (13.5 g, 91 mmol) and p-TsOH (ca. 10 mg) was placed into a pre-heated oil bath at 1 1 0 °, and the product was allowed to distill from the flask through a short column. The olefin (6 6 ) was collected as an oil (10.6 g, 89%): bp 74-80°/3 mm (lit y 74-75°/3.5 mm); ir (neat) 730, 1450, 1490 (aromatic), 3030-3080 cm ^

(olefin); NMR (CDC13) 2.37-2.83 (m, 4H, -CH 2C H 2- ) ,

6.18(m, 1H, vinylic), 7.08-7.53 (m, 5H, aromatic). 96

trans-2-Azido-l-phenylcyclobutanol (6 8 )- To an ice-cooled

mixture of 1-phenylcyclobutene (6 6 )(7.8 g, 0.06 mol) and

15 g anhydrous sodium carbonate (0.14 mol) in 50 ml of

CH 2C 1 2 was added 13 g of 40% peracetic acid (0.07 mol) in

acetic acid (a trace of sodium acetate was added to the

peracetic acid to neutralize any sulfuric acid present).

The reaction mixture was then allowed to rise to room

temperature and stirred for an additional hr. The reaction mixture was then filtered and sodium carbonate was washed with several protions of CH 2C12. The CH 2 C1 2 layers were

combined and washed with water, dried (Na2 S0 ^) and evap

orated to give a light yellow liquid 67 (8.7 g, 97%):

NMR (CDClg) 6 7.58 (s, 5H, aromatic), 4.07 (m, 1H, CH)

and 1 . 7-2 .6 (m, 4 H ,-CH2CH2“). Upon standing at room

temperature this material underwent rearrangement to a 131 mixture of 1 -phenylcyclopropanecarboxaldehyde and ] 38 trace amount of 2 -phenylcyclobutanone.

The crude epoxide 67 (12.1 g, 0.083 mol) and

sodium azide (40 g, 0.06 mol) in 100 ml of H20 was added

to 800 ml of DMF. The reaction mixture was stirred for

7 hr at 80-90°. The dark brown solution was cooled with

the aid of an ice bath and then extracted with three

200 ml portions of ether. The ether layers were combined and washed with saturated NaCl solution, dried (MgSO^) and the solvent was evaporated to yield 1 1 . 6 g of light 97 brown oil. Column chromatography using silica gel with

30% ether in n-pentane afforded 4.8 g of 68(52%). A portion was recrystallized from n-pentane-ether to give a white solid: mp 64-65°; ir (neat) 2120 (N^) / 3380 cm ^

(OH); NMR (CDCl3) 6 1.45-2.80(m, 4H, CH 2CH2), 2.7(s,

1H, OH), 3.9 (br.t/ 1H, me t h i n e ) , 7.45 (m, 5H, aromatic).

Anal. Calcd for ^^oH11^3^: ^3.48; 5.86; N, 22.21.

Found: C, 63.43; H, 6.05; N, 21.98.

trans-2-Amino-l-phenylcyclobutanol (56) . The azide 68

(4 g, 21 mmol) was added to 250 ml of B^H^ (1 molar in

THF). The mixture was stirred at 50° for 48 hr. Alcohol saturated with HCl was added until no further reaction occurred. The solvent was removed and the remaining white residue was taken up in water and the pH was adjusted to 9 with 2N NaOH. The basic solution was extracted with

CHCl^. The CHCl^ extract was dried (Na2 SO^) and evapor ated to give 2.6 g of an oil (76%). The oil was crystal lized from benzene-hexane to give a white solid 56: mp

88.5-90°.

A small amount of the oil was converted to the HCl salt of

56. The HCl salt of 56 was recrystallized from MeOH-Et^O •WV MA/V M to give a white solid: mp 223-224° (decomp); ir (KBr)

3380 cm -1 (OH); NMR (CD3OD) 6 1.5-3.0 (m, 4H, -CH^CH.,-) ,

3.95 (br.t, 1H, methine), 7.4-7.78 (m, 5H, aromatic). 98

Anal. Calcd for C^ q H ^ N O C I ; C, 60.15; H, 7.07; N, 7.01.

Found: C, 60.01; H, 7.04; M. 6.98.

trans-2-Acetamido-l-phenyl-l-acetoxycyclobutane (69).

To a solution of 10 ml of pyridine and 10 ml of acetic

anhydride was added 300 mg of the HCl salt of 56. After

sitting at room temperature overnight the solution was

evaporated to give an oil, to which was added 10 ml of

3% HCl for 30 min. The mixture was then taken up in

CHCl^ and washed with 10% aqueous HCl, saturated solution

of NaHCO^/ and H 20. The CHCl^ layer was then dried

(Na^SO^) and evaporated to yield a solid residue that was

recrystallized from CHCl 3 ~Et20 to yield 292 mg solid (94%):

mp 159.5-161°; ir (KBr) 1660 (amide), 1745 (ester),

3250 cm " 1 (NH); NMR (CDC13) 5 1.65 (s, 3H, CH^CONH), 1.95

(s, 3 H , C H 3C02)/ 2.2-3.0 (m, 4H,-CH2CH2-), 4.80 (q, 1H,

CH, JC H / C H 2 = 8.5 Hz), 5.30 (br, d, NH, JNRfCH = 8 H z > and

7.34 (s, 5H, aromatic);exchange NH with D 20 , 5 4.80 (t, 1H,

CH) . Anal. Calcd for C 1 4 H 17 NC>3; C, 68.00; H, 6.93; N, 5.66.

Found: C, 67.84; H, 7.05; N, 5.54.

Ethyl (N-2-chloro-2-phenylcyclobutyl)carbamate (73).

1-Phenylcyclobutene (6.6 g, 0.06 mol) in 25 ml of benzene was placed in a 100 ml three-neck flask equipped with a thermometer, N 2 inlet tube with dropping funnel and drying tube. DCU (9.5 g, 0.06 mol) was then added dropwise at a rate to maintain the reaction temperature at 5-10°. After

the addition was complete the reaction mixture was allowed

to come to room temperature and stirred until complete

disappearance of olefin monitored by gas chromatography

(10% Carbowax, column temperature 160°). A 20% aqueous

solution of NaHS0 3 (50 ml) was then added to the mixture

at 5-10°. The organic layer was separated and the

aqueous layer was extracted with Et 2 0 . The organic

solution was washed with 1^0, saturated NaCl and dried

(Na2 SO^). The crude mixture was first crystallized from

hexane then recrystallized from Et 20 at low temperature

to yield 73 (5.6 g, 37%): mp 96-97.5°; ir (KBr) 1520,

1670 (amide), 3280 cm - 1 (NH); NMR (CDC13)6 1.2 (t, 3H,

CH 3 -CH2 , J = 7 Hz) , 1.6-3.2 (m, 4H, CH2CH2), 4.1 (q, 2H,

CH 2 -CH3, J = 7 Hz), 4.4 (br.s, 1H, NH), 4.8 (m, 1H, methine) , 7.4 (m, 5H, aromatic). Anal. Calcd for C-^H^g

N 0 2C1: C, 61.54; H, 6.36; N, 5.52. Found: C, 61.82;

H, 6.22; N, 5.60

2-Bromocyclobutanone (75). A solution of B r 2 (9.1 g,

0.057 mol) in 96 ml of CCl^ was added slowly to a stirred

solution of cyclobutanone (4 g, 0.057 mol) in 40 ml of

CCl^ at -5°C over 3 hr period. The final solution was

then allowed to come to room temperature and stirred for

another 3 hr. The solvent was removed to give an oil which 100 was distilled to yield 75 (3.6 g, 43%): bp 36-38°/0.4 mm)

(lit1 4 0 70-71°/14 m m ) ; ir (neat) 1790 (C=0); NMR (CDC13)

6 1.87-3.64 (m, 5H, -CH 2CH 2C H - ) , 5.08 (br.t, 1H, methine, j c h , c h 2 9 H z ) '

1,2-Bistrimethylsiloxycyclobutene-l (77). Sodium (50 g,

1.13 mol) in 300 ml of toluene was refluxed with rapid stirring for 3 hr under N2- To this stirred solution was added chlorotrimethylsilane (126 g, 1.16 mol) and diethyl succinate (50 g, 0.287 mol) at about 60° over 1 hr. The filtrate was evaporated under vacuum to remove toluene to give an oil which was distilled to afford 78 (51 g, 78.3%); 1 41 • bp 59-61°/2.3 mm (lit 75°/10 mm): NMR (CDCl-j) 6 0.18

(s, 18H, 2 OSi(CH3)3), 2.13 (s, 4H, allylic).

2-Dibenzylaminocyclobutanone (76). Method A . To a solution of 2-bromocyclobutanone 75 (950 mg, 6.4 mmol) in

20 ml of anhydrous Et 20 was added dibenzylamine (11 g,

55.76 mmol). The solid material that formed was removed and washed with Et 20. The Et20 layer was evaporated and the resultant oil was placed on a silica gel column and eluted with CHCl-j-CgHg-MeOH (5:1:1) to give 846 mg of an oil, 76 (53%).

Method B . Compound 77 (6.9 g, 30 mmol) was added dropwise'to a solution of dibenzylamine (5.92 g, 30 mmol) in 15 ml of MeOH at 20° under N 2 atmosphere. The reaction 101 mixture was stirred an additional 2 hr after the addition was complete. The MeOH was removed by evaporation and the resulting brown oil (7.9 g) was treated with a saturated solution of HCl in ether and the resulting dibenzylamine hydrochloride solid was separated by fractional crystallization from MeOH-Et 2 0 . The remaining aminoketone hydrochloride residue was then treated with aqueous 10% NaOH and extracted several times with ether.

The ether layers were combined and washed with an aqueous saturated solution of NaCl, dried (MgSO^), and evaporated to give a crude oil that was chromatographed on silica gel and eluted with CHCl 3 :Et20 (4:1) to give 6.2 g of

76 (78%): ir (neat) 1775 cm" 1 (C=0); NMR (CDC13) 5 1.7-2.78

(m, 4H, -CH 2C H 2-) , 3.53 (d, 2H, 2 C H ^ -ph, = -14 Hz),

3.78 (d, 2H,2 CH H -ph, J =-14 Hz), 7.72 (m, 10H, aromatic). A— d Aij A small amount of 76 was further purified by passing it over a silica gel column. The column was eluted with CHCl^ to give a light yellow oil which was taken up in ether. Dry HCl gas was added to the ether solution to give a yellow gummy residue which crystallized after considerable effort from MeOH-Et 20 to give a white solid HCl salt of 76: mp 80-81°. Anal. Calcd for

C18H20NOC1: C ' 71*63; H ' 6*68'* N <- 4.64. Found: C, 71.55;

H, 6.61; N, 4.79. 102

cis-2-Dibenzylamino-l-phenylcyclobutanol hydrochloride

(78). To a solution of phenylmagnesium bromide/ prepared

by adding a solution of bromobenzene (2.4 g, 15.2 mmol) in

10 ml of THF to Mg turnings (350 mg, 15.2 mmol) in 20 ml

of THF, was added slowly with stirring a solution of 76

(2 g, 7.05 mmol) in 20 ml of THF. The mixture was refluxed

with stirring under N 2 for 4 hr and then quenched with

aqueous NH^Cl. The THF layer was separated and the

aqueous layer was extracted with ether and the organic

layers were combined, washed with aqueous NaCl, dried

(Na2 S0^), and evaporated to give 2.5 g of brown residue.

The residue was placed on a silica gel column and eluted

with CHCl^ to yield 1.6 g of the free base of 78 (6 6 %)..

A small portion of the solid was recrystallized from MeOH

mp 82-83.5°; ir (neat) 3350 cm - 1 (OH); NMR (CDCl-j) 6 2.15

(m, 4 H , -CH 2C H 2-) , 3.3 (d, 2H, 2 C I ^ H -ph, J^B = -14 Hz),

3.57 (d, 2 H , 2 CH_H -ph, JAtJ = -14 Hz), 4.78 (br.s, 1H, A.—jj A d OH), 7.25 (m, 10H, aromatic). The free base was converted

to a hydrochloride salt 7 8 yielding a white solid:

mp 186-188° (decomp). Anal. Calcd for C^H^NOCl: C,

75.87; H, 6.90; N, 3.69. Found: C, 75.90; H, 7.04;

N, 3.56.

cis-2-Amino-1-phenylcyclobutanol (55). To 100 mg of 10%

Pd-C in 2 ml of 95% EtOH, saturated with H 2 at atmospheric

pressure for 10 hr, was added the hydrochloride salt 7 8 (210 mg, 0.55 mmol) in 6 ml of 95% EtOH. The mixture was stirred for 20 hr in which time 1.14 mmol of H 2 was consumed. The catalyst was removed by filtration and the ethanol filtrate was evaporated to give an oil which crystallized from MeOH-Et2OH to give 114 mg of a hydro scopic solid which was dried under vacuum at 80° to yield a white solid, HCl salt of 55: mp 123-124.5°; ir (KBr)

3250, 3450 cm" 1 (OH); NMR (D20) 6 2.4 (m, 4H, -CH 2C H 2~ ) ,

4.15 (m, 1H, methine), 7.45 (s, 5H, aromatic). Anal.

Calcd for C^qH^NOCI: C, 60.15; H, 7.07; N, 7.01. Found:

C, 60.01; H, 7.04; N, 6.98.

The HCl salt of 55 was converted to the free base by treating the salt with IN NaOH and extracting the free base into CHCl^. The CHCl^ layer was dried (Na^O^) and evaporated to give a solid residue which was crystallized from benzene-hexane to give white solid 55: mp 78-79°. cis-2-Acetamido-l-pheny1-1-acetoxycyclobutane (79). A solution of 90 mg (0.45 mmol) of HCl salt of 55, 4 ml of acetic anhydride and 5 ml of pyridine was stirred at room temperature overnight. The excess pyridine and acetic anhydride was evaporated to give a yellow oil which was treated with 6 ml of 3% HCl for 30 min. The mixture was then extracted with CHCl^. The CHCl^ solution was washed with 10% aqueous HCl, saturated NaHCO^, saturated NaCl, dried (Na2 SO^) and evaporated to give a solid which was 104 recrystallized from petroleum ether (60-110°)-benzene to give 101 mg of 79 (91%): mp 128.5-130°; ir (KBr) 1650

(amide), 1750 (ester), 3250 cm - 1 (NH); NMR (CDC13) 6 2.0

(s, 6H, amide and ester CH^), 1.80-2.70 (m, 4H, -CH 2CH 2 -),

4.65 (q, 1H, CH, ^ = 8.5 Hz), 6.60 (br.d, 1H, NH, Ori j on 2

nu ~ 8 Hz) and 7.30 (s, 5H, aromatic); exchange NH N H / OH with D20 64.65 (t, 1H, CH) . Anal. Calcd for ci 4H i 7N 0 3 :

C, 68.00; H, 6.93; N, 5.66. Found: C, 67.84; H, 7.05;

N, 5.54. trans-2-Acetamido-l-phenylcyclobutanol (84) . To a solution of acetic anhydride (52.9 mg, 0.51 mmol) and

2 ml of pyridine was added 150 mg of 56 HCl (0.75 mmol).

The solution was stirred overnight at room temperature and then evaporated to give an oil, to which was treated with 5 ml of 3% HCl for 30 min. The mixture was then extracted with CHCl^. The combined CHCl^ layers were washed with NaHCO^ solution, H 2O, dried (Na2S0 ^) and evaporated to give a residue which was recrystallized from benzene-hexane to yield 67 mg of 84 (6 6 %): mp 103-104.5°; ir (KBr) 1670 (amide), 3350 (NH), 3400 cm " 1 (OH); NMR

(CDC13 ) 6 1.3-2.78 (m, 4H -CH 2CH 2- ) , 1.7 (s, 3H, C H 3) ,

4.09 (br. s, 1H, OH), 4.6 (br. q, 1H, methine, J_,.T = Lrl / 2 8 Hz), 5.33 (br. d, 1H, NH, JNH/CH = 8 H z ) , 7.4 (m, 5H, aromatic); exchange NH with D 30, 6 4.6 (br. t, 1H, methine, 105

r>-u ~ ® Hz). Anal. Calcd for CloHlc.N0o: C, 70.22; CH / ^ 2 H, 7.37; N, 6.82. Found: C, 70.29; H, 7.41; N, 6.78.

cis -2-Acetamido-l-phenylcyclobutanol (§J2) . It was

prepared according to the procedure for 84: yield 65%; mp 130-131°; ir (KBr) 1635 (amide), 3250 (NH), 3300 cm- 1

(OH); NMR (CDC13 ) 6 1.85 (s, 3H, C H 3) , 2.12-2.4 (m, 4H,

-CH 2CH2-), 3.63 (br. s, 1H, OH), 4.38-4.88 (m, 1H, methine) 8

6.67 (br. d, 1H, NH, JNR CH = 8.5 Hz), 7.28 (m, 5H, aromatic). Anal. Calcd for C, .H, ,-NO.: C, 70.22; H, 7.37; ±z I d Z

N, 6.82. Found: C , 70.36; H, 7.31; N, 6 .80 .

3-Benzyloxybromobenzene (8 6 ). To a solution of m-bromophenol (50 g, 0.29 mol) in 125 ml of dried acetone was added dropwise with mechanical stirring benzylchloride

(40 g, 0.316 mol) under argon. Anhydrous K 2C 0 3 (45 g,

0.32 mol) was then added in small portions into the reaction mixture which was then allowed to reflux for

4 days. K 2C0 3 was filtered and the filtrate was evapo rated to give a solid which was taken into benzene. The benzene solution was washed with 1 N NaOH, saturated

NaCl, dried (Na2SO^) and evaporated to ca. 250 ml to which was added petroleum ether (30-60°) until turbid

solution was formed. The crystalline precipitate which

formed on cooling was recrystallized from benzene- petroleum ether (30-60°) to yield 73.45 g (97%) of 8 6 : 106

mp 58-59.5° {lit1 5 3 59-63°); NMR (CDC13) 5.0 (s, 2H,

benzylic), 6.73-7.2 (m, 4H, disubstituted aromatic),

7.35 (s, 5H, monosubstituted aromatic).

trans-2-Azido-l-(3-benzyloxyphenyl)cyclobutanol (90)* To

a solution of epoxide 89 (10 g, 39.6 mmol) and NaN 3 (19 g,

2 77 mmol) in 25 ml of 1^0 was added 200 ml of DMF. The

reaction mixture was stirred for 8 hr at 80-85°. The

solution was cooled and then extracted with Et 2 0 . The

E t 20 layers were combined and washed with saturated NaCl,

dried (MgSO^) and evaporated to give a dark brown oil which was chromatographed on silica gel, eluted with

E t 2 0 : petroleum ether (65-110°) (3 : 7). One fraction

(Rf = 0.2, silica gel plate, ether/petroleum ether =

3: 7, indicator iodine) was collected as a solid which was

recrystallized from ether-petroleum ether (65-110°) to afford trans-azido alcohol 90 (5.3 g, 48%): mp 69-71°;

ir (KBr) 2100 (N3 ) , 3450 cm - 1 (OH); NMR (CDC13) 6 1.4-

2.77 (m, 4H, -CH 2 CH 2 -)/ 2.78 (s, 1H, OH, exchangeable with D 20 ) , 3.81 (m, 1H, methine), 5.03 (s, 2H, benzylic),

6.82-7.5 (m, 9H, aromatic). Anal. Calcd for ci7Hi7N3^2:

C, 69.14; H, 5.80; N, 14.23. Found: C, 69.01; H, 6.00;

N , 1 4 .1 0 . 107

trans-2-Amino-1-(3-benzyloxyphenyl)cyclobutanol hydro

chloride (91). To a cold solution of trans-azido alcohol

90 (3.2 g, 10.83 mmol) in 30 ml of THF under Nn was added ■Wv /

dropwise a solution of E^Hg (6 5 ml, 1 molar). The

resulting mixture was stirred another hour at room

temperature and then refluxed for 48 hr. Alcohol sat

urated with HCl was added until the decomposition of

borane was completed. The solution was evaporated and

the remaining white solid was dissolved in H 2O and washed

with E t 2 0 . The aqueous solution was then made basic with

2N NaOH and extracted with Et 2 0 . The E t 20 extract was

washed with saturated NaCl, dried (MgSO^), and evaporated

to give an oil which was converted to a hydrochloride salt.

The crude salt was recrystallized from Me0 H- E t 20 to yield

3.1 g of 91 (94%): mp 206-9° (decomp): ir (KBr) 3420 cm ^

(OH); NMR (D20) 61.6-3.16 (m, 4H, - O ^ O E ^ - ) , 4.18 (br. t,

1H, methine, JCH CH = 8 Hz), 5.19 (s, 2H, benzylic),

7.02-7.75 (m, 9H, aromatic).

cis-2-Dibenzylamino-l-(3-benzyloxyphenyl)cyclobutanol

hydrochloride (92). A mixture of ?-benzyloxybromobenzene

(15.78 g, 60 mmol) and Mg turnings (1.53 g, 62.85 mmol)

in 85 ml of THF was refluxed under Ar until most of Mg

had passed into the solution. The mixture was then

refluxed for another 3 hr. To the 3-benzyloxyphenylmagnesium bromide cooled in an ice bath was added slowly a solution of 76 (6.67 g, 25.14 mmol) in 30 ml of THF.

The mixture was then refluxed for 4 hr and then quenched with NH^Cl solution. The organic layer was separated and

the aqueous layer was extracted with Et 2 0 . The organic

layers were combined and washed with saturated NaCl, dried

(MgSO^), and evaporated to give a brown oil. The residue was placed in a silica gel column and eluted with CHCl^

to yield a free base of 92 (6.9 g, 65%): ir (neat) 3350

cm" 1 (OH); NMR (CDC13) 6 2.05-2.3 (m, 4H, - C H 2CH2“), 3.25

(d, 2H, 2CH H -C,H(., J_ _ = -15 Hz), 3.53 (d, 2H, A ij o j A g o 2 CH..H -CcH , J = -15 Hz), 5.0 (s, 2H, O-benzylic) , A J3 d o A. g o

5.02 (s, 1H, OH, exchangeable with D 20), 6.62-7.48 (m, 19H aromatic). Anal. Calcd for C 3 ^ H 32N 0 2C1: C, 76.61; H, 6.64

N, 2.88. Found: C, 76.54; H, 6 .6 6 ; N, 2.88. cis-2-Amino-1-(3-hydroxyphenyl)cyclobutanol (57). To a

H 2 saturated suspension of 500 mg of 10% Pd-C in 6 ml of

95% EtOH was added a solution of 92 (1 g, 2.06 mmol) in I 10 ml of EtOH-MeOH (1:1). The mixture was stirred under

H 2 at atmospheric pressure for 20 hr. The catalyst was removed and the filtrate was evaporated to give an oil which was then recrystallized from Me0H-Et20 with charcoal to afford a white hygroscopic hydrochloride salt of 57

(410 mg, 92.4%): ir (neat) 3300 cm-1 (OH); NMR (C030D)

6 2.22-2.55 (m, 4H, -CH2CH2~ ) , 3.78-4.08 (m, 1H, methine),

6.65-7.35 (m, 4H, aromatic). Anal. Calcd for C 3 1 H 32N 0 2 C1: 109

C, 55.69; H, 6.54; N, 6.49. Found: C, 55.36; H, 6.36;

N, 6.24.

cis-2-Acetamido-l-(3-acetoxyphenyl)-1-acetoxycyclobutane

(93). A mixture of 57*HC1 (100 mg, 0.556 mmol), 4 ml of

acetic anhydride and 4 ml of pyridine was stirred for

24 hr at room temperature. The workup procedure as

described for 79 was carried out to yield an oil which

was chromatographed on silica gel and eluted with 1 0 %

CHCl^ in EtOAc to yield 38 mg of 93 (27%); bp 195°/0.025 mm; ir (neat) 1665 (amide), 1750, 1770 (diester), 3300

cm" 1 (NH); NMR (CDC13) 6 1.77-2.73 (m, 4H, -CH 2CH2~), 2.03

(s, 6H , CH_£-NH and CH--£-0-), 2.27 (s, 3H, CH-,-£-0-C,H -) , J0 O 0 4. 43-4.90 (m, 1H, methine), 6.43 (br. d, 1H, NH, =

8 Hz), which was exchangeable with D 20, 6.82-7.36 (m, 4H,

aromatic). Anal. Calcd for C-^gH^gNO^: C, 62.94; H, 6.27;

N, 4.59. Found: C, 62.74; H, 6.44; N, 4.31. 110

1-Tetralol (95). To a solution of a-tetralone (20 g, 0.137 mol) in 1 1 of 95% EtOH was added dropwise a solution of

NaBH^ (2.65 g, 0.07 mol) in 30 ml of K 20 * T^e raixture was

stirred for 20 hr at room temperature following the addition of 10 ml of IN NaOH. The solvent was evaporated to give an oil which was dissolved in ether. The ether solution was washed with saturated NaCl, dried (MgSO^), and evaporated to yield an oil, which was distilled to afford 95 (16.6 g, 83%): bp 100-101/1 mm (lit1 6 0 102-

104°/2 mm); ir (neat) 3350 cm ” 1 (OH); NMR (CDC13 ) 6 1.27-

2.05 (m, 4H, -CH2CH 2 - / 2.59 (m, 2H, benzylic), 3.63 (s,

1H, OH, exchangeable with ' m e thine),

6.8-7.45 (m, 4H, aromatic).

1-Chlorotetralin (98). To a stirring solution of a-tetralol

(5.22 g, 35.2 mmol) in 20 ml of ether in an ice-bath was added slowly a solution of SOCI 2 (7.3 g, 61.3 mmol) in

5 ml of ether. The solution was stirred overnight at room temperature. The excess SOCI 2 and solvent was evaporated to give a residue which was taken into CHCl^. The organic solution was washed with F^O, dried (Na2SO^) , and evaporated to give an oil which was distilled to afford chloride 9 8 and olefin 97 in a 5:4 ratio , respectively.

98 (2.34 g, 40%): bp 78-80°/0.4 mm (lit1 6 5 bp 115-118°/

15 mm); NMR (CDC13) 5 1.5-2.42 (m, 4H, - C F ^ C H ^ ) , Ill

2.55-2.9 (m, 2H, benzylic), 5.18 (br. t, 1H, methine,

J„,_T = 3.5 Hz), 6.83-7.45 (m, 4H, aromatic). 97 : 48- C^XA g V / il A 1 0*1 50°/0.4 mm (lit 89°/16 mm) NMR (CDC13) 6 1.95-2.83

(m, 2H, allylic), 2.52-2.88 (m, 2H, benzylic), 5.72-6.02

(m, 1H, vinylic), 6.37 (dt, 1H, vinylic, J = 10, 1.5 Hz),

7.00 (m, 4H, aromatic).

I,2,3,4-Tetrahydronaphthalene-l-carboxylic acid (100) .

Sodium amalgam (4%) was prepared with caution by grinding a small piece of sodium in Hg in a mortar. 4% Na-Hg

(100 g, 174 mmol of Na) was added in a small portion to a solution of a-naphthoic acid (5 g, 29.1 mmol) and Na 2C 0 3

(8.5 g, 80 mmol) in 50 ml of H 20. The mixture was refluxed for 2 hr and then cooled to room temperature. Hg was separated and the aqueous solution was acidified with concentrated to pH 5. The acidic solution was extracted with Et 20. The Et20 layers were washed with saturated NaCl, dried (MgSO^), and evaporated to give a solid which was recrystallized from EtOAc to afford 4.42 g of 100 (86.4%): mp 82-84° (lit1 8 2 85°); ir (KBr) 1700

(COOH), 2400-3400 cm " 1 (COOH); NMR (CDC13) 5 1.5-2.3

(m, 4H, —CH 2CH2_), 2.75 (br. t, 2H, benzylic, J = 6 Hz),

3.80 (br. t, 1H, methine, J = 6 Hz), 7.14 (m, 4H, aromatic),

II.8 (s, 1H, COOH). 112

1.2.3.4-Tetrahydro-l-naphthoyl chloride (101). A solution

of acid 100 (3 g, 17.04 mmol) and SOCl 2 (6.1 g, 51.12 mmol)

in 25 ml of benzene was refluxed for 12 hr. The mixture

was evaporated to give a residue which was distilled to

yield 3.25 g of acid chloride 100 (98%): bp 86-88°/0.12 mm 1 64 (lit 108-110°/1.5 mm); ir (neat) 1795 (C=0); NMR (CDC13)

6 1.57-2.33 (m, 4H, -CH2CH2~) 2.71 (br. t, 2H, benzylic,

J = 6 Hz), 4.14 (br. t, 1H, methine, J = 6 Hz), 7.07 (s,

4H, aromatic).

1.2.3.4-Tetrahydronaphthalene-l-carboxamide (102). Acid

chloride 101 (2.5 g, 12.85 mmol) was added dropwise to a

well stirred concentrated NH^OH (58%) (3.8 g, 64.25 mmol)

cooled in an ice-salt bath. To the mixture was added

25 ml of benzene and the mixture was allowed to stir for

5 hr at room temperature. Benzene was evaporated and

aqueous layer was extracted with CHCl^. The CHCl^ layers were combined and washed with H 20 , evaporated to give a

crude solid product which was recrystallized from 80% EtOH 1 64 to yield amide 102 (2.15 g, 95%): mp 166-167° (lit

161-162°); ir (KBr) 1500, 1655 (amide), 3180, 3360 cm " 1

(NH2); NMR (CD3OD) 6 1.67-2.25 (m, 4H, -CH 2C H 2“ ) , 2.8

(br. t, 2H, benzylic, J = 6 Hz), 3.73 (br. t, 1H, methine,

J = 6 Hz), 7.12 (s, 4H, aromatic). 113

1-Cyano-l,2,3,4-tetrahydronaphthalene (96). Method A.

A solution of 98 (5.3 g, 31.8 mmol), NaCN (2.8 g, 57 mmol), and Nal (350 mg) in 30 ml of DMSO was stirred for 15 hr at 95-100°. The dark reaction mixture was mixed with

200 ml of CHCl^. Organic layer was separated and washed with H 20 , dried (Na2SC>4) and evaporated to give an oil which was distilled to yield 96 (3.0 g, 60%): bp 90°/0.18 "AAI mm.

Method B . A mixture of amide 102 (43.8 g, 0.25 mol) and ^ 2 ^ 5 (71 g, 0.5 mol) was heated with a naked flame under vacuum to give a crude product which was redistilled to afford 96 (31.3 g, 80%): bp 84-87°/0.2 mm

(lit164 142°/8 m m ) ; ir (neat) 2280 cm " 1 (CN); NMR (CDCl3)

6 1.58-2.23 (m, 4H, -CH 2CH2~), 2.74 (br. t, 2H, benzylic,

J_„ = 6 Hz), 3.88 (br. t, 1H, methine, J_„ = 6.5 Hz),

7.13 (m, 4H, aromatic).

1-Cyano-l-methyl-l,2,3,4-tetrahydronaphthalene (103). To a suspension of NaNH 2 (8 . 1 g, 0.207 mol) in 130 ml of Et20 was added dropwise with stirring a solution of 96 (21.75 g,

0.14 mol) in 35 ml of Et20 at room temperature. The mix ture was stirred at reflux for 3 hr and then cooled in an ice-bath. To this suspension was added slowly a solution of CH^I (25.53 g, 0.18 mol) in 50 ml of Et 20. The re sulting mixture was stirred overnight at room temperature.

To the reaction was added 80 ml of H20 and the organic layer was separated. Aqueous solution was extracted with 114

E t 20. The organic solution was combined and washed with 5% HCl, N a 2 S0 3 solution, saturated NaCl, dried

(MgSO^), and evaporated to afford a residue oil which was distilled to give 103 (17.65 g, 74.5%): bp 88-89°/0.07 mm

(lit1 6 5 108°/ 0.7 mm); ir (neat) 2250 cm " 1 (CN); NMR

(CDC13) 5 1.67-2.37 (m, 4H, -CH 2C H 2~ ) , 1.65 (s, 3H, C H 3) ,

2.75 (br. t, 2H, benzylic, J = 6 Hz), 7.0-7.53 (m, 4H, aromatic).

2-(1-Methyl-l,2,3,4-tetrahydro-l-naphthyl)-2-imidazoline

(59). A mixture of 103 (13.96 g, 81.52 mmol) and 2-aminoethylammonium p-toluene sulfonate (19 g, 81.85 mmol) was heated at 210-215° for 8 hr. The solid crude product was dissolved in 50 ml of 2N HCl and washed with Et20 in which

2 g of 103 was recovered. The acidic solution was made basic with NaOH and extracted with Et 20. The E t 20 solution was washed with saturated NaCl until a colorless solution was obtained. The Et20 layer was then dried (MgSO^) and evaporated to give light yellow solid which was recrystal lized from n-heptane to yield 59 (14.35 g, 96%): mp 102.5-

103.5°; ir (KBr) 1380 (CH3), 3150 cm " 1 (NH); NMR (CDC13)

6 1.60 (s, 3H, CH3), 1.69-2.27 (m, 4H, -CH 2CH2-), 2.82

(m, 2H, benzylic), 3.57 (br. s, 4H, N C H 2 CH 2N), 7.15 (m,

4H, aromatic). 115

A small portion of free base 59 was converted to

hydrochloride which was recrystallized from absolute

EtOH-Et 20 to yield a white solid: mp 2 2 0 - 2 2 1 .5 °.

Anal. Calcd for C 1 4 H 1 9 N 2C1: C, 67.06; H, 7.64;

N , 11.17. Found: C, 66.96; H, 7.64; N, 11.04.

R-Alanine methyl ester hydrochloride (106a). To a

suspension of R-alanine (2 g, 22.5 mmol) in 230 ml of 2,2-

dimethoxypropane was added 23 ml of HCl (37%) . The

mixture was stirred for 18 hr at room temperature. The

solvent was evaporated and the resulting residue was dried

under high vacuum to give a solid which was recrystallized

from Me0H-Et20 to yield the hydrochloride salt, 2.9 g 174 -l (92%): mp 109-111° (lit ^ mp 109-110°); ir (KBr) 1740 cm X

(C=0); NMR (CD3OD) 1.58 (d, 3H, CH^-CH, J = 7.5 Hz), 3.85

(s, 3H, 0CH3). 4.15 (q, 1H, CH^CH, J = 7.5 Hz); ta] ^ 4

-7.7° (c, 1%, M e O H ) .

R-Alanine amide (107a). To the free base of 106a (16.59 g,

0.1416 mol) was added a solution of 25 ml MeOH saturated with N H 3 at 0°. The mixture was allowed to stand at room

temperature and monitored by TLC (silica gel plate, MeOH:

C H C 1 3 = 1:1, R^=0.3). After 4 days the reaction was com pleted and the MeOH and excess NH 3 were evaporated to give a yellow oil, (8 . 6 6 g, 69.4%) which solidified upon stand- 172 mg: mp 74-76° (lit mp 72-74°); ir (neat) 1675 (C=0), 116

3290, 3375 cm" 1 (NH2); NMR (CD3OD) 6 1.29 (d, 3H, CH^-CH-,

J = 7 Hz) , 3.45 (q, 1H, Cf^-CH-, J = 7 Hz) .

S-Alanine amide (107b). It was prepared from L-alanine ethyl ester hydrochloride according to the previous method for 107a: yield 61%; mp 74-76°; ir (KBr) 1660 (C=0), 3150,

3350 cm " 1 (NH2); NMR (CD 3 OD) 1.28 (d, 3H, CH^-CH-,

J = 7 Hz), 3.44 (q, 1H, C^CH-, J = 7 Hz).

R-l,2-diaminopropane dihydrochloride (108a). A 250 ml three neck flask equipped with a magnetic stirring bar, dropping funnel, thermometer, and reflux condenser was flushed with dried N 2 and maintained under a slight positive N 2 pressure. To a solution of 107a (1 g, 11.35 mmol) in 2 5 ml THF was added dropwise 57 ml of B2Hg (1 molar in THF) at 20-25° over a 1 hr period. The solution was stirred for another 1 hr at 20-25°, and was then refluxed for 6 hr. The solution was cooled to 20-25° and

MeOH (15 ml) was added dropwise at a rate such that the reaction temperature did not exceed 30°. The resulting clear solution was allowed to stand overnight at room temperature. After cooling to below 10° in an ice-bath, dry HCl was bubbled slowly into the solution with stirring until the solution reached pH 2. The white solid was collected, washed with ether and recrystallized from MeOH-

E t 20 to give 108a (1.13 g, 6 8 %), mp 236-238° (lit1^ mp

238.5°); NMR (D20) 6 1.44 (d, 3H, C H 3 -CH-, J = 6.5 Hz), Anal. Calcd for C 3H 1 2 N 2C12: C, 24.50; H, 8.23; N, 19.05

Found: C, 24.44; H, 8.17; N, 19.01.

S-l,2-diaminopropane dihydrochloride (108b). The prepara

tion was identical to that for the preparation of 108a: mp 236-238°; NMR (D20) 6 1.44 (d, 3H, C H 3 -CH, J = 6.5 Hz),

3.28 (m, 2H, -CH-CH2-), 3.72 (m, 1H, CH^CH-) . Anal. Calcd

for C 3H ^ 2N 2 C12: C, 24.50; H, 8.23; N, 19.05. Found: C,

24.47; H, 8.25; N, 18.96.

R-phenylalanine methyl ester hydrochloride (110)- A solu tion of R-phenylalanine (5 g, 30.27 mmol) and 31 ml of HCL

(36%) in 300 ml of 2,2-dimethoxypropane was stirred at room temperature for 18 hr. The resulting mixture was evapor ated to about 50 ml to which was added Et20 until a turbid solution was formed. The crystalline product was collected and recrystallized from Me0H-Et20 to give 110 (6.1 g, 94%), 17? -1 mp 159-161° (lit 159-161°) ir (KBr) 1750 cm (C=0) :

NMR (D20) 6 3.35 (d, benzylic, J = 6.5 Hz) 3.89 (s, 3H,

0CH3), 4.51 (t, 1H, CH-CH2, J = 6.5 Hz), 7.44 (m, 5H, aromatic).

R-phenylalanine amide (111a). By a procedure similar to that for the preparation of 107, 111a was prepared from the free base of 110: yield 84%; mp 91-93°; ir (KBr) 1660

(amide), 3315, 3380 cm " 1 (NH, NH2): NMR (CDC13) 6 1.42 118

(br. s, 2 H , NH2), 2.48-3.72 (m, 3H, -CH2 ~ C H - ) , 6.00

(br. s, 2H, CONH2 ) , 7.23 (s, 5H, aromatic).

S-l,2-Diamino-3-phenylpropane dihydrochloride (112b). The

reduction of 1 1 1 b was carried out similar to the diborane

procedure used in the alanine series. The final reaction

mixture after treatment with dry HC1 was evaporated to

give a crude product which was dissolved in MeOH. The

MeOH solution was refluxed for 10 min and then evaporated

to give a solid which was recrystallized from 95% EtOH-

Ether to afford optically active diamine 112b (72%):

mp 200-201°; NMR (CD3OD) 5 3.08-3.43 (m, 4H, benzylic and

-CH-CH2~). 3.65-4.17 (m, 1H, -CH-CH2-), 7.37 (s, 5H,

aromatic). Anal. Calcd. for CgH.^N 2Cl 2 • 2/3 H 20: C, 45.92;

H, 7.43; N, 11.91. Found: C, 45.79; H , 7.64; N, 11.71.

R-l/2-Diamino-3-phenylpropane dihydrochloride (112a). ' The

preparation was identical to that for the preparation of

112b; mp 200-201°; NMR (D20) 5 3.03-3.45 (m, 4H, benzylic

and —CH—CH2~), 3.74-4.17 (m, 1H, methine), 7.4 (s, 5H,

aromatic. Anal. Calcd. for cgH26N2C^2*H2°: C '

H, 7.53; N, 11.62. Found: C, 44.90; H , 7.40; N / 11.57. 119

General Procedure for the preparation of Imidate Ester

Hydrochloride. A mixture of nitrile (0.1 mol) and absolute EtOH (0.12 mol) was cooled in ice-bath and treated with dry-HCl (0.115 mol). The mixture was then kept at 4° for 4 days. The resultant viscous liquid was treated with an equal volume of Et 2 0 . The hydrochloride salt which precipitated was filtered off and washed with Et 2 0 .

Ethyl phenyliminoacetate hydrochloride (117) : yield 98%; 1 q I _ I mp 105-106° (lit soften at 60°); ir (KBr) 1640 cm

(C=N) ; NMR (CD3OD) 6 1.42 (t, 3H, C H^ J = 7 Hz), 4.02

(s, 2H, benzylic), 4.47 (q, 2H, CH 3-CH 2~/ J = 7 Hz), 7.37

(s, 5H, aromatic).

Ethyl 1-naphthyliminoacetate hydrochloride (114): was found to be a highly viscous oil and was used without further purification.

General Procedure for optically active 2-arylmethyl-4- methyl-2-imidazolines. The optically active imidazolines were prepared via a modification of the procedure of King 158 and Acheson. To a cold solution of optically active

1 ,2-diamine dihydrochloride (1 0 . 2 mmol) and Et^N (2.28 g,

22.5 mmol) in 8 ml of MeOH was added a cold solution of iminoester hydrochloride (10.57 mmol) in 5 ml of MeOH.

The reaction mixture was refluxed for 1 hr and evaporated to give an oil. This crude product was treated with 25 ml 120 of IN NaOH and extracted with CHCl^. The combined CHCl^ solution was washed with 1^ 0 , dried (Na2S0 ^ ) , and evaporated to afford an oil product for each of the imidazoline optical isomers.

R-(+)-4-Methyl-2(1-naphthylmethyl)-2-imidazoline (60a): yield 95.7%; ir (neat) 3150 cm -1 (NH); NMR (CDC13) 5 1.03

(d, 3H, C H 3 -CH-, J = 6 Hz), 2.87-4.03 (m, 3H, -NCH-CH2 “N - ) ,

3.93 (s, 2H, benzylic), 4.37 (br. s, 1H, NH), 7.20-8.18

(m, 7H, aromatic).

60a•HC1: CD, tQ] 216 + 2 2 3 7 0 (0.102%, MeOH). Anal. Calcd for C. ,-H, _N 0C1: C, 69.09; H, 6.57; N, 10.74. Found: C, J.D 1 / Z 69.08; H, 6.64; N, 10.77.

S-(-)-4-Methyl-2(1-naphthylmethyl)-2-imidazoline (60b): yield 87.4%: ir (neat) 3160 cm -1 (NH); NMR (CDC13) 6 1.07

(d, 3H, C H 3 -CH-, J = 6 Hz), 2.92-4.1 (m, 3H, -N-CH^CH-N-),

3.98 (s, 2H, benzylic), 4.19 (br. s, 1H, NH), 7.3-8.2 (m, 7H, aromatic).

6 0 b •H C l : CD, C 9 3 216 “ 2 1 7 3 0 (0.114%, MeOH). Anal. Calcd for ClcH._N 0Cl: C, 69.09; H, 6.57; N, 10.74. Found: C, J-D 1 / Z 68.87; H, 6.60; N, 10.62.

61a*HCl: yield 58%; mp 189-191°; NMR (CD^OD) 6 2.85 (d,

2 H , C cH cC H 0- , J = 6 Hz), 3.40-4.55 (m, 3H, N-CH-CH--N), d —Z — — z 4.3 (s, 2H, naph-CH^-)/ 7.13-7.97 (m, 12H, aromatic). 121

Anal. Calcd for C21**'?1N2<“'^2: ^ . 8 8 ; 6.28; N# 8.32.

Found: C, 74.84; H, 6.12; N, 8.19.

61b*HC1: yield 6 6 %; mp 189-191.5°; NMR (CD3OD) 2.9 (d,

2H, ph CH2-/ J = 6 H z ) / 3.45-4.60 (m, 3H, -NCH 2 ~CH-N)

4.33 (s, 2H, naph CH^-), 7.05-8.04 (m, 12H, aromatic).

Anal. Calcd for C 2 1H 21H 2C 1 2 : C, 74.88; H, 6.28; N, 8.32.

Found: C, 75.06; H, 6.11; N, 8.44.

R-2~Benzyl-4-methyl-2-imidazoline (62a): yield 70%: ir (neat) 3150 cm" 1 (NH): NMR (CDC13) 6 1.12 (d, 3H, C H 3

-CH-, J = 6 Hz), 3.49 (s, 2H, benzylic), 2.92-4.07 (m, 3H,

-N—CH—CH 2 —N — ) , 4.98 (s, 1H, N H ) , 7.22 (s, 5H, aromatic).

62a*picrate: CD, 191224 + ^4670 (0.11%, MeOH).

Anal. Calcd for C.^H.„NcO_: C, 50.62; H, 4.25; N, 17.36. LI LI d / Found: C, 50.55; H, 4.34; N, 17.12.

S-2-Benzyl-4-methylimidazoline (62b): yield 76%; ir (neat)

3150 cm- 1 (NH); NMR (CDCl3) 6 1.12 (d, 3H, CH^-CH-,

J = 6 Hz), 3.51 (s, 2H, benzylic), 2.92-4.08 (m, 3H, -N-CH-

CH 2 ~N-), 4.72 (br. s, 1H, NH), 7.23 (s, 5H, aromatic).

62b*picrate: CD, [0 ]00/1 “ 15510 (0.156%, MeOH).

Anal. Calcd for C ^ H ^ N ^ : C, 50.62; H, 4.25; N, 17.36.

Found: C, 50.70; H, 4.46; N, 17.19. 122

Preparation of racemate imidazolines. A cold solution of imidate ester hydrochloride (15.1 mmol) in 8 ml of MeOH was added to the diamino compound (15.1 mmol) in 4 ml of

MeOH and the resulting mixture was refluxed for 1 hr. The mixture was evaporated to give a residue which was taken into 10 ml of H 2O and extracted with CHCl^. The combined

CHCl^ solution was washed with H 2O, dried (Na2 S O ^ ) , and evaporated to afford the free base of imidazolines.

4-Methyl-2(1-naphthylmethyl)-2-imidazoline (60c); yield

56.4%; ir (neat) 3150 cm” 1 ; NMR (CDCl.^) 6 1.03 (d, 3H,

CH 3-CH-, J = 6 Hz), 2.87-3.92 (m, 3H, -N-CH-CH^-N-), 3.95

(s, 2H, benzylic), 4.45 (s, 1H, NH), 7.28-8.20 (m, 7H, aromatic).

60c•HC1; mp 163-164.5° (absolute Et0 H-Et 2 0 ) ; ir (KBr)

3150 cm- 1 (NH) ; NMR (CDC13) 6 1.03 (d, 3H, CH-^-CH-,

J = 6 Hz) , 2.87-3.92 (m, 3H, -N-CH-CH 2 ~ N - ) , 3.95 (s, 2H, benzylic), 7.13-8.15 (m, 7H, aromatic), 10.57 (br. s, 2H,

2NH) . Anal. Calcd for C ^ H ^ ^ C l : C, 69. 09 ; H, 6.57;

N, 10.74. Found: C, 69.29; H, 6.32; N, 10.57.

2-Benzyl-4-methyl-2-imidazoline (62c): yield 79.5%; ir

(neat) 3150 cm " 1 (NH); NMR (CDC13) 6 1.10 (d, 3H, C H 3 -CH-,

J = 6 Hz), 3.47 (s, 2H, benzylic), 2.9-4.15 (m, 3H,

-N-CH-CH2-N-), 5.24 (s, 1H, NH), 7.20 (m, 5H, aromatic). 123 62c*picrate: mp 112-114° (95% EtOH). Anal. Calcd for

H^N^O.,:± / b / C, 50.62; H , 4.25; N, 17.36. Found: C, 50.71; H, 4.20; N, 17.45.

l-Methyl-2(1-naphthylmethyl)-2-imidazoline (115): yield

76%; bp 168-170°/0.4 mm; ir (neat) 1380 (CH^)/ 1610 cm ^

(C=N); NMR (CDC13) 6 2.61 (s, 3H, NCH3), 3.01-3.92 (m,

4 H , -N-CH 2 -CH 2 -N-), 3.99 (s, 2H, benzylic), 7.23-8.17

(m, 7H, aromatic).

115.HC1: mp 238.5-240° (decomp): ir (KBr) 1620 cm ^ (C=N);

NMR (D20 6 3.25 (s, 3 H , N C H 3 ) , 3.94 (t, 2H, N-CH_2-CH 2-N,

J = 8 H z ) , 4.0 (t, 2H, N- C H 2 -CH 2 -N, J = 8 Hz), 4.27 (br. s,

2H, benzylic), 7.55-8.15 (m, 7H, aromatic). Anal. Calcd

for C,CH,_N 0C1: C, 69.09; H, 6.57; N, 10.74. Found: C, I d X / 2 68.90; H, 6.51; N, 10.82.

N - (2,6 -dichlorophenyl)thiourea (120). To a hot solution of NH^SCN (5.35 g, 70.3 mmol) in 125 ml of dry acetone was added PhCOCl (8.75 g, 6 2.2 mmol) with stirring to give suspension. To this resulting hot reaction mixture was added a solution of 118 (10 g, 61.72 mmol) in 85 ml of acetone. The yellow reaction mixture was refluxed for

1 hr and the solvent evaporated to half the original volume.

The mixture was then mixed with 850 ml of H20 and the yellow solid was collected and washed with H 20 to yield

N - (2,6 -dichlorophenyl)-N 1-benzoyl-thiourea (119) [ir (KBr), 1680 (C = O), C = S), 3320 cm ^ (NH)] which was saponified with 10% NaOH (103 ml) for 4 hr. The solution was 124 acidified with concentrated HCl to precipitate both benzoic acid and thiourea 120 which were dissolved in NH.OH (58%). fx Compound 120 was collected from NH^OH solution and recrys tallized from CHC1 3 “95% Et0H-Et20 to yield 7.5 g (55%) of 1 74 white solid: mp 156-158° (lit. 156-158°); ir (KBr)

1620 (0=3), 3260, 3480 (NH, NH2): NMR (CD30D) 5 4.59 (br. s,

3H, NH and NH2) , 7.38 (m, 3H, aromatic).

S-Methyl-(2,6-dichlorophenyl)isothiouronium iodide (121).

A solution of 120 (10 g, 45.23 mmol) and CH^I (10 g, 70.45 mmol) in 100 ml of MeOH was refluxed for 3 hr. The mixture was evaporated to afford the yellow solid 121 (15.04 g, 1 77 -1 92%): mp 184-188° (lit ' 170°) ir (KBr) 3250 cm (NH);

NMR (CD3OD) 5 2.83 (s, 3H, SCH3), 4.82 (br. s, 3H, NH and

NH2), 7.6 (s, 3H, aromatic).

A small portion of 121 was treated with 33% K2C03 followed the extraction with Et 20 to give the free base of

121: mp 125-127°; ir (KBr) 3290, 3480 cm -1 (NH2); NMR

(CDC13) 5 2.51 (s, 3H, SCH3), 6.73-7.37 (m, 3H, aromatic).

R - (+)-2[ (2,6 -Dichlorophenyl)imino]-4-methylimidazolidine

(63a). A solution of 121 (1.48 g, 4.08 mmol), 108a

(800 mg, 5.04 mmol), and Et3N (1.15 g, 11.36 mmol) in 8 ml of n-PrOH was heated in a sealed tube at 140° for 12 hr.

The resulting yellow solution was evaporated and then taken into 15 ml of IN NaOH and then extracted with CHCl3*

The CHC1 3 layer was washed with H 20, dried (MgSO^), and 125 evaporated to yield a yellow oil 63a (887 mg, 89%) which was converted to a hydrochloride salt. The hydrochloride

salt of 63a was washed with CHCl^ and recrystallized from

Me0H-Et20 to yield a white solid: mp 260-262° (decomp);

ir (KBr) 1655 (C=N), 3250, 3310 cm” 1 (NH); NMR (CD3OD)

5 1.35 (d, 3 H , CH-j-CH-, J = 6 Hz) , 3.20-4.45 (m, 3H,

-N-CH-CH 2 -N-), 7.55 (m, 3H, aromatic); CD [0]23O - 12630

(1.00% MeOH). Anal. Calcd for C ^ H ^ N ^ d ^ : C, 42.81;

H, 4.31; N, 14.98. Found: C, 42.76; H, 4.29; N, 14.89.

S- (-) -2 [ (2, 6 -Dichlorophenyl) imino] -4-methylimi'dazolidine

(63b). The hydrochloride salt of 63b was prepared in a manner similar to the procedure used in preparing 63a: yield 89%; mp 260-262° (decomp); ir (KBr) 1650 (C=N), 3250,

3310 cm- 1 (NH; NMR (D20) 6 1.34 (d, 3H, C H 3 -CH-, J = 6 H z ) ,

3.27-4.46 (m, 3H, -N-CH-Oi^-N-), 7.55 (m, 3H, aromatic);

CD, J 230 + 1 2 7 0 6 (0.106%, MeOH). Anal. Calcd for C1Q

H 1 2 N 3C 1 3 : C, 42.81; H, 4.31; N, 14.98. Found: C, 42.72;

H, 4.29; N, 14.84.

2-[(2, 6 -Dichlorophenyl)imino]-4-methylimidazolidine (63c).

A mixture of 121 (2.5 g, 6.9 mmol) and 1,2-diaminopropane was heated at 140° for 2 hr. The resulting yellow oil was taken into 10 ml of 5N NaOH and extracted with CHC13- The

C H C 1 3 solution was washed with H 20, dried and evaporated to yield 1.36 g, (81%) of 63c which was converted to the 126 hydrochloride salt: mp 276-278° (decomp); ir (KBr) 1660

(C=N)/ 3240, 3320 cm " 1 (NH); NMR (CD-OD) <5 1.33 (d, 3 H , c h 3- c h - , J = 6 Hz), 3.22-4.40 (m, 3H, -N-CH-CH 2 ~ M - ) ,

7.53 (m, 3H, aromatic. A n a l . Calcd for ciqh 12N 3C ^ 3 :

C, 42.81; H, 4.31; N, 14.98. Found: C, 42.63; H, 4.15;

N, 15.02. BIBLIOGRAPHY

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