This dissertation has been 64—7055 microfilmed exactly as received

SINKULA, Anthony Arthur, 1938— I. SYNTHESIS OF A SERIES OF 2,2-CYCLO- ALKYL BENZOTHIAZOLINES. H. A PRELIM­ INARY INVESTIGATION OF SOME SYNTHETIC ROUTES LEADING TO THE FORMATION OF PHENOLIC ARYLPROPANOLAMINES.

The Ohio State University, Ph.D., 1963 Chemistry, pharmaceutical University Microfilms, Inc., Ann Arbor, Michigan I . SYNTHESIS OF A SERIES OF 2,2-CYaOALKYL BENZOTHIAZOLINES

I I . A PRELHaNARY INVESTIGATION OF SOME SYNTHETIC ROUTES LEADING

TO THE FORMATION OF PHENOLIC ARYLPROPANOLAMINES

A DISSERTATION

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School o f The Ohio S tate U niversity

% Anthony Arthur Sinkula, B. S., M. Sc.

The Ohio S tate U niversity 1963

Approved by

Adviser Department of Pharmacy ACKNOWLEDGMENTS

Ify sincere thanks and appreciation are extended to Dr. Jules B,

La Pidus, my adviser, for his suggestions and constructive criticism given during the tenure of this problem, I am grateful to many others, fellow graduate students and faculty members alike, for their excellent suggestions, interest, and moral support. To Betty, for her encourage­ ment and understanding, saying thank you is inadequate. Finally, I would like to thank the Public Health Service who supported this investigation by a PutCLio Health Service Fellowship (MPM-11, 876-02) from the National Institute of Mental Health,

i i CONTENTS

Page ACKNOWLEDGMENTS...... ü

TABLES...... v i PART I . SYNTHESIS OF A SERIES OF 2 ,2-CYCLOALKÏL BENZOTHIAZOLINES

INTRODUCTION AND STATEMENT OF PROBLEM ...... 1

HISTORICAL REVIEW...... •...... ^

Rie Benzothiazoles ...... ^

A old chlorides ...... 4 Carboxyl ! 0 acids ...... 7 E sters ...... 7 A ldehydes ...... 9 Ketones ...... 13

The Benzothiazolines ...... 17

EXPERIMENTAL...... 22

R e a g e n ts ...... 22 Instruments ...... 23 Synthesis of Benzothiazoline Derivatives ...... 23

1. Preparation of 2,2-tetramethylene benzothiazoline .... 23 2. Preparation of 2,2-pentamethylene benzothiazoline .... 26 3. Preparation of 2,2-hexamethylene benzothiazoline .... 27 4. Preparation of 2,2-(2‘-methyl) pentamethylene benzothiazoline ...... 27 5. Preparation of 2,2-(3'-methyl) pentamethylene benzothiazoline ...... 28 6. Preparation of 2,2-(4'-methyl) pentamethylene benzothiazoline ...... 29 7. Preparation of 1,2'-4,2'-cyclohexylidene bis- benzothiazoline ...... 29 8. Preparation of 2,4'-(l*-methyl) piperidyl benzothiazoline ...... 30

Attempted Formation of 2,4‘- (l‘-Methyl) Piperidyl Benzothiazoline Hydrochloride ...... 31 Attenç>ted Formation of 2,4'-(l*-Methyl) Piperidyl Benzothiazoline Methiodide ...... 31

i i i CONTENTS (contd.)

Page Preparation of the Picrate Salt of 2,^ '-(I’-Kethyl) Piperidyl Benzothiazoline ...... 32 9. Preparation of ,5'-henzo-8-methyl-spiro (8-aza-bioyclo- C3.2.1]-octane-3i2'-l',3'~azathiolane) hydrochloride . 32

Formation of ij-',5'-Benzo-8-Methyl-Spiro (8-Aza-Bicyclo- [3.2.1]-0ctane-3,2'-1',3'-Azathiolane) 34 Preparation of 4',5'-Benzo-8-Mothyl-Spiro (8-Aza-Bicyclo- [3.2.1]-0ctane-3,2*-l’,3'-Azathiolane) Picrate ...... 34 Formation of 4 ',5'"Benzo-8-Methyl-Spiro (8-Aza-Bicyclo- [3.2.1]-0ctane-3,2'-1,3-'Azathiolane) M ethiodide ...... 35 Attempted Preparation of a 2,2-Cydoalkyl Benzothiazoline- 1,1-Dioxlde ...... 35 Approach A ...... 35

Preparation of sodivun o-aminobenzenesulfonate ...... 36 Preparation of sodim o-(acetylamino)-benzenesrulfonate . . . 37 Attempted preparation of o-(acetylamino)-benzenesulfonyl c h l o r i d e ...... 37 Phosphorous o x y c h lo rid e ...... 37 Thionyl chloride ...... 38

Approach B ...... 38

Preparation of o-(aminophenyl) methylsulfide hydriodide . . . 39 Preparation of o-(aminophenyl) methylsulfide ...... 39 Preparation of 2-(acetylamino) phenylmethylsulfide .....40 Preparation of 2-(acetylamino) phenylmethyl sulfone ...... 41 Preparation of 2-(aminophei%rl) methyl sulfone hydrochloride . 42 Preparation of 2-(amlnophenyl) methyl sulfone ...... 42

Approach C Attempted oxidation of 2,2-pentamethylene benzothiazoline . . 44 Preparation of 2,2-pentamethylene-3-acetyl benzothiazoline . 44 Attempted oxidation of 2,2-pentamethylene-3-a cetyl benzothiazoline ...... 45

Attempted Reaction of 2,2-Pentamethylene Benzothiazoline w ith Methyl Magnesium I o d i d e ...... 45 D is c u s s io n ...... 4?

SUMMARY AND CONCLUSIONS...... 60

iv CONTENTS (con td .) Page PART I I . A PRELIMINARY INVESTIGATION OF SOME SYNTHETIC ROUTES LEADING TO THE FORMATION OF PHENOLIC ARYLPROPANOLAMINES

INTRODUCTION AND STATEMENT OF PROBLEM...... 63

HISTORICAL REVIEW ...... 65

Phenylpropanolamine ...... 65 l-(o-Hydroxyphenyl)-2-Amino-l-Propanol 69 l-(p-Ifydroxyphenyl)-2-Amino-1-Propanol ...... 70 l-(m-Hydroxyphenyl)-2-Amino-l-Propanol ...... ?2 l-(3 ‘,^’-Dihydroxyphenyl)-2-Amino-l-Propanol ...... ?2

EXPERIMENTAL ...... 78

Preparation of l-(p-%droxyphenyl)-2-Amino-l-Propanol ..... ?8

1. Formation of phenyl propionate ...... ?8 2. Formation of p-hydroxypropiophenone ...... ?8 3 . Formation of p-benzyloxypropiphenone ...... 79 4. Formation of oL -bromo-p-benzyloxypropiophenone ...... 80 5 . Attempted formation of ot--amino-p-benzyloxypropiophenone 81 6. Preparation of iso-butyl nitrite ...... 82 7. Preparation of oC -oximino-p-benzyloxypropiophenone . . . 82 8. Catalytic reduction of p-benzyloxy- 06-oximinopropio- p henone ...... 83

Preparation of l-(m-%droxyphenyl)-2-Amino-1-Propanol ..... 85

1. Formation of m-benzyloxypropiophenone 85 2. Formation of oL -oximino-m-benzyloxypropiophenone .... 85 3 . Catalytic reduction of c/--oximino-m-benzyloxypropio- phenone ...... 86

Preparation of l-(3',4'-Dihydroxyphenyl)-2-Amino-l-Propanol . . 86

1. Formation of 3 ', ^ ' -dihydroxypropiophenone ...... 86 2. Attempted preparation of 3 ',4 ' -dihydroxypropiophenone using boron trifluoride ...... 8? 3 . Attempted formation of 3 ' -dibenzyloxypropiophenone . . 88

Discussion ...... 88 SUMMARY AND CONCLUSIONS...... ’ 92 BIBLIOGRAPHY ...... 93 AUTOBIOGRAPHY...... 103

V TABLES

Table Page 1. Infrared Spectra of Benzothiazolines ...... 36

v i INTRODUCTION AND STATEMENT OF PROBLEM

The search for new and better medicinal agents containing the phenothiazine nucleus is constantly being expanded. The pharmacology of

üiese agents has been extensively investigated (1-4). Increased knowledge of the pharmacology and chemistry of phenothiazines and re la te d compounds has le d to widespread u tiliz a tio n of these drugs.

Currently their major uses are as antihistaminics (5)t pre- and post­ operative antiemetics (6), and sedatives (?). Chlorpromazine (Thorazine), prochlorperazine (Compazine), and trifluoperazine (Stolazine) find wide application as tranquilizers (8-10) and in certain forms of mental illness, particularly schizophrenia (11,12). While the above-mentioned agents serve a useful and vital need in medicine and p sy ch iatry , th ere i s always a demand fo r b e tte r and more effective medicinals of this type and for chemically related compounds. The present problem began with an attempt to find a simple method for synthesizing various phenothiazine derivatives in as few steps as possible, using relatively mild conditions for the reaction. A search of the literature brought to light the work of several German workers

(13-15) who oxidized o-aminophenol using 1,4-benzoquinone to form

3-aminophenoxazone-2 (A), 0

I J 4- H I] ------>

0 Reaction 1 By analogy, i t was thought that oxidation of o-aminothiophenol with 1,4-benzoquinone might lead to the formation of 3-arainophenthiazone-2 (B),

IB

Reaction 2

On refluxing o-aminothiophenol and 1,4-benzoquinone in absolute ethanol for one-half hour, a light yellow precipitate was obtained which was insoluble in all solvents except dioxane and tetrahydrofuran.

Analysis showed this compound to contain 60.53^ carbon, 4.98$ hydrogen,

6,30$ nitrogen, and 19.17$ sulfur. This analysis, however, does not correspond to structure B, It was suggested that in many cases ketones react with o-aminothiophenols to form benzothiazolines or benzothiazines.

If this is true, the following structures (C, D, E) could be postulated as possible products of the reaction:

H H C D E None of these structures, however, could be fitted to the analytical data. The phenothiazines bear an interesting structural resemblance to the c y d o a lk y l benzothiazolines and these l a t t e r compounds have been investigated chemically to a very limited extent. This preliminary work. 3 although fruitless in attempting to assign a structure to the reaction product of o-aminobenzenethiol and 1,4-benzoquinone, suggested other interesting possibilities for further work in this area. After a careful review of the literature concerning the chemistry of benzothiazoles and benzotliiazolines, it was decided at this point to undertake an investi­

gation of the synthesis and properties of some benzothiazolines.

From a pharmacological point of view, the benzothiazoles have

been investigated to a very limited extent (17-23), Their sister

compounds, the benzothiazolines, have been virtually neglected in this

area. It is hoped that the compounds prepared in this investigation may

bo pharmacologically tested at some future time in an attempt to

establish or refute their value as potentially valuable medicinal agents. HISTORICAL REVIEW

Sh.9-fe§.n?igAhia?plQs. Acid chlori.des.T h e first known report concerning a synthesis of an organic compound containing the benzothiazole nucleus can be ascribed to Hofmann (24). He found that treatment of o-aminothiophenol with benzoyl chloride gave 2-phenylbenzothiazole (II).

c=o ir I Reaction 3

He postulated that the reaction proceeded through an intermediate step forming N-benzoylaminothiophenol (l) before cyclizing to the final product (II). Support for this postulation has been eiven by other workers ( 25 ) who noted that when one mole of 2-amino-4-chlorothiophenol was added to two moles of benzoyl chloride and warmed fo r a sh o rt tim e,

2-benzoylamino-4-chlorophenylthiobenzoate was obtained. If, however, the reaction mixture was boiled for one-half hour, only 2-phenylbenzothiazole was obtained. As further proof for the formation of I, 2-benzoylamino-

4-chlorothiophenol was synthesized, and, on heating or recrystallization from ethanol, formed Hofmann's 2-phenylbenzothiazole. This is generalized in the following reaction sequence. Cl

Cl

R- Cl n 1'

Reaction 4

Subsequent publications (26,27) found Hofmann concerned with the synthesis and chemical properties of 2-chloro-2-l%rdroxy-, and 2-aminobenzothiazoles as well as further investigations on 2-alkyl-

benzothiazoles. It has been well established that o-aminothiophenol, on exposure

to air, is quite readily oxidized to the disulfide (24) (III),

&)] ( f ï ”

R eaction 5 The disulfide has been used in benzothiazole thesis (28), but

with correspondingly lower yields than those obtained with pure

o-aminothiophenol. Realizing this, plus the fact that o-aminothiophenol

is easily oxidized, Bogert and Snell (29) sat out to prepare a type of

o-aminothiophenol capable of resisting oxidation yet providing conditions

for obtaining favorable yields of benzothiazoles. This was accomplished

by preparing the zinc salt of o-aminothiophenol (IV) and thence

proceeding to formation of the benzothiazole (Reaction 6), Kflc. 1 W

i l . / ) ■ ^ Reaction 6

These same workers in subsequent publications (30,31) reported on the reactivity of o-aminothiophenol and its disulfide with acid chlorides, acid anhydrides, and esters of oxalic, succinic, glutaric, camphoric, maleic, phthalic, pyromucic, and thiophenic acid, and reported the synthesis of many heretofore unknown benzothiazoles. Substitution of the o-aminothiophenol molecule in various posi­ tions with chlorine, bromide, mothoxy, ethoxy, and methyl substituents and condensation of these with ortho-, meta-, and para-nitrobenzoyl chloride afforded a series of new benzothiazoles for-Hauser (32).

Acid chlorides have been utilized in making quaternary salts of benzothiazole derivatives. Thus, o-methylaminothiophenol has been condensed with acetyl chloride to produce (V) (33):

O CM

I - Cl cMg

2-methylbenzothiazole methochloride

Reaction 7 oL -'unsaturated acid chlorides are known to react with o-aminothiophenol and its salts (3^i35) and, as expected, the product is a 2-substituted benzothiazole (VI),

4- Cl4-îC.H=CM -cC.1 CVA =C.W-CW3 0 C >

2-propenylbenzothiazole

Reaction 8 Carboxvlic acids.—Carboxvlic acids as well as acid chlorides have been utilized to synthesize benzothiazoles (24,26). % again making use of the zinc salt of o-aminothiophenol and carboxylic acids ranging from formic to pentanoic, the respective 2-alkylbenzothiazoles have been produced in good y ie ld . Esters.—Esters have also found use as starting material in the synthesis of benzothiazoles. An interesting case in point is that of diethyl malonate (36),

y CooEt C H i, C o o e t

diethyl malonate dibenzothiazolyl methane

Reaction 9

Another example providing some interesting chemistry in this area is the condensation of-nitroethylacetate and o-aminothiophenol (37)* If the reaction is allowed to proceed for four hours at 100°, a product identified as 2 ,3-dioxodihydrobenzo-l,4-thiazine-2-oxine (VII) is formed yield).

I +• O, n J - CHj.-COOEt- -t- K ,0 OH

Reaction 10

VII was also synthesized in 79?o yield by reacting hydroxylajnine (HONH 2 ) and 2 ,2-d ic h lo r 0- 3-oxodihydrobenz 0-1 ,4-thiazine in ethanol. If, however, o-aminothiophenol and «/--nitroethylacetata are heated ten hours at 100°, the product obtained is 2-methylnitrobenzothiazole (VIII) (38).

vnr Reaction II

Apparently the drastic conditions over an extended period of time cause a cleavage of the sulfur to carbon bond between positions 1 and 2 of the benzothiazine ring (VII) with subsequent cycllzation to VIII, and this is

then obtained as the predominant product. One example is cited in the literature of an c/.-oximino ester

condensing with o-aminothiophenol to yield a 2-substituted benzothiazole

(37). Thus, when ethyl-oA^oximino acetate is added to the required thiophenol, a good yield of benzothiazole-2-carboxamide (IX) is formed. , o O \ " CH - C - o C j.H5- C, — KiU, J_, il G C y Mo" IX

Reaction 12 A reaction somewhat analogous to the above is that reported by

Wheeler (39) in which o-aminothiophenol was heated with benzimino- oL. methyl ether (X) with the evolution of ammonia and methyl alcohol and formation of 2-phenylbenzothiazole (Reaction 13).

tO H II c o c H3

( f ï ” *

X Reaction 13

Aldehyde s.—Aldehvdes have played a major role in the development

of the chemistry of both benzothiazoles and benzothiazolines. Hofmann

(24) is again credited as being the first to use an aldehyde with

o-aminothiophenol to form a benzothiazole. By adding one mole of the

thiophenol to two moles of acetaldehyde, he obtained 2-methylbenzo-

thiazole and theorized that ethanol and water were formed in the course

of the reaction. He did not, however, give any proof of the formation of

these two by-products.

The first synthesis of a benzothiazoline derivative was accom­

plished using o-methylaminothiophenol (XI) and formaldehyde (24)

(Reaction 14), 10

ou H - C -H + H^O

TT 3-ra©thylbenzothiazoline

Reaction 14

Two moles of XI condensed w ith one mole of formaldehyde afforded di-(3~methylbenzothiazolinyl)methane (XII),

o H - c - H ->

Reaction 15

The reaction of o-aminothiophenol and salicylaldéhyde provided the basis for a controversy between two groups of workers concerning the structure of the final product obtained in this reaction. One group

(Hofmann, Bogert, and C o rb itt) (26,40) were of the opinion th a t the benzothiazole was obtained (XIII):

CHO

m r 2-(o-hydroxyphenyl)-benzothiazole

Reaction l6 . 11

Claasz (4l), on the other hand, suggested that the benzothiazoline might be the reaction product and this opinion received support from the work of Lankelma (42)(Reaction 1?).

CHO SH s OH n1' H

2-(o-hydroxyphenyl)-benzothiazoline

Reaction 1?

Bogert and Stull (43), in a refutation of Claasz's postulation concerning the formation of benzothiazolines, stated that neither ketones nor their corresponding dichlorides could be condensed with o-aminothiophenol and argued from these observations that the mechanism of reaction of aldehyde condensation with o-aminothiophenol proceeded by (A) rather than (B) (Reaction 18). SH

SH 11 + A.CHO

Reaction 18

Using the zinc salt o-aminothiophenol, Bogert and Stull attempted to condense acetone, Michlers ketone, and benzophenone chloride, but in all cases only starting material or tarry products were obtained. 12

Lankelma (42), in an attempt to disprove the observations of Bogert,

suggested that benzothiazolines could be converted to benzothiazoles by r e c ry s ta lliz a tio n from various solvents. An example of th is phenomenon is illustrated by the fact that 2-(o-chlorophenyl)-5“Chlorobenzothiazoline is converted to the benzothiazole upon recrystallization from acetone or carbon tetrachloride, A further observation included the fact that

2-alkylbenzothiazolines could be crystallized unchanged from various

solvents, whereas 2-arylbenzothiazolines were converted to the benzo­

thiazole in 2 to 3 recrystallizations from ethanol. A recent reinvesti­

gation of the work of Claasz, Lankelma, and Bogert by Charles and

Freiser (44) has cited evidence in favor of benzothiazoline formation.

Their work is briefly summarized as follows: One-tenth mole of each

starting material was allowed to stand in an Erlenmeyer flask at room.

temperature, thus forming the benzothiazoline. Carbon and hydrogen analytical data correspond quite accurately with the benzothiazoline

structure (see also Claasz, 41 ). Infrared analysis fails to detect any free sulfhydryl group, but a sharp absorption frequency occurred at 3.12 microns indicating an -N-H stretching frequency characteristic of a

benzothiazoline. Ultraviolet spectra illustrated convincing differences

between the benzothiazole and the benzothiazoline.

One other reference appears in the literature concerning reaction

16 (45 ). Using rather vigorous conditions (glacial acetic acid,

ammonium acetate, reflux temperature) a product resulted which, after

recrystallization from ethanol, was identified as 2-(2'-hydroxyphenyl)-

benzothiazole (mixed melting point). 13 In view of the evidence both pro and con, it seems that benzothiazoline formation is entirely possible if mild conditions are used for the reaction. If more drastic conditions are employed to promote the reaction, it seems evident that the reaction proceeds almost entirely to benzothiazole formation.

Ketones.—Ketones have played a major role in the evolution of the chemistry of both the benzothiazoles and benzothiazolines. The general reaction mechanism can be stated in the following reaction sequence :

O - C a -

H + R,H Reaction 19 It has previously been stated that certain workers were of the

impression that the condensation of ketones with o-aminothiophenol was

impossible (4-3). Seven years later, Lankelma and Sharnoff (46)

shattered this illusion when they obtained benzothiazoline derivatives

from the condensations of acetone, acetophenone, cyclohexanone, and

qydopentanone with 4--chloro-2-aminothiophenol hydrochloride. It is

interesting to note here that the authors claim to have obtained highly

colored compounds w ith cyclohexanone and cyclopentanone (R eaction 20). 14

Cl Cl'

DAR.1C BLUE.

2,Z-pentamethylene-5-chloro- benzothiaaoline

Reaction 20

McCLenachan (4?) also noted this observation by proposing a plausible mechanism explaining formation of those colored compounds.

Heating molar amounts of o-aminothiophenol and methyl benzyl ketone at 250° for six hours afforded a low yield of 2-methylbenzo­ thiazole which was identified as its picrate by a mixed melting point

(48). It is very probable that the excessive amount of heat used to promote the reaction formed the benzothiazole by virtue of cleavage of the benzyl group of 2,2-methylbenzylbenzothiazoline with the formation of toluene. This has indeed been shown to be the case in a subsequent investigation (49) (Reaction 21).

o — c •CH, I

Reaction 21

cXÙ -unsaturated ketones have provided some extremely interesting chemistry in this area. The work of Reid and Marx is shown to illustrate this point ( 50 ). 15

(L / d V Uc\ \

KT "XÿJTTT (R.- IT ^ , TTSC (R.C. 0') TYRWIME

Reaction 22

PL xTXxMHi o^c/ CM, R-= CJl , 0 -

k ' &' -- [QL, 0- sSQ l ■5WTT

lO T E ? L , H‘- ( p - \

Reaction 23

Catalyzing molar quantities of o-aminothiophenol and styryl-

[-thienyl-(2)]ketone (XVIII) with HCl, the cyclized product, 2-phenyl-4- [thienyl-(2)]6,?-benzo-l-thia-3-aza-cycloheptadiene-(4,6) is formed (XIX).

If, however, pyridine is used as the catalyst, the reaction proceeds only to the^ -[(o-aminophenyl)-mercapto]-ketone derivative, specifically known as o^-[(-o-aminophenyl)-mercapto]-«^-phenyl-y

H, 0

x x i T Reaction 24 The fact of the matter is that XXII, 4-methyl-6,7-benzo-l- thia-^-aza-oyoloheptadien-(4,6)-one-2, is formed in over 50^ yiold, while no trace of XXI, 2-methyl-6,7-benzo-l-thia-5-aza-cycloheptadiene-(2,6)- one-(4), is seen. Heating equimolar quantities of acetoacetic ethyl ester and o-aminothiophenol, however, provides a facile synthesis of compound XXI,

Analogies to reactions 22, 23. and 24 are found in the literature

(35)• the condensation of o-aminothiophenol with cinnamic acid.

Mills and Whitworth were able to establish keto-2-phenyltetrahydro- heptabenzthiazine (XXIII) as the final product. They found that the preferred course of reaction was that in which the amino group of o-aminothiophenol condensed with the carbonyl group of the acid, while the thiol group had added to the ethylenic double bond (Reaction 25).

I CH = Cl4-CooH CH CH: u >T + II o "jcscrrr Reaction 25 17 It seems plausible from these facts to assume that in the interaction of

negative sulfur atom attacks the slightly electropositive -carbon of the ethylenic double bond and the resulting aminothiopropionyl function passing, \jith loss of a mole of water, to the respective benzthiazine

or benzthione (XIX, XXI, XXII).

One further example of an -unsaturated carbonyl function

condensing with o-aminothiophenol is that provided by Kushkalo and

Bezeraskaya (51).

. s — 1 ---- I CM3 CH3

Reaction 26 Equimolar quantities of o-methylaminothiophenol and a ce tylenedi carboxyli c

acid react to form 3-oxo- 2-(carboxymethylene)- 3 ,4-dihydro-2H-l,4-

benzothiazine (XXIV),

The benzothiazolines

Claasz (52 ) claims the distinction of being the first to report

the synthesis of benzothiazoline (XXV), Utilizing the hydrochloride

salt of o-aminothiophenol and adding 40^ aqueous solution of formaldehyde,

he obtained a yellow oil boiling at 270° (Reaction 27), 18

0 II K - c —H

Réaction 27

Four years later the same worker (4l) reported the synthesis of 2-phenyl- benzothiazoline (Reaction 28).

CKO

+ N.^ I fJ H

Reaction 28

In an attempt to prepare an N-methylbenzothiazoline derivative, Claasz instead found that he had formed 2-phenylbenzothiazole (hi) (Reaction 29).

CI-I3I 100'

Reaction 29 Two further benzothiazolines, 2-o<(-methoxyphenyl benzothiazoline and

2-styrylbenzothiazoline, were reported at this time. Both were synthesized by the above procedure. As stated previously, the mechanism of benzothiazoline formation has been postulated by Bogert and Stull

(page 1 1 ), These same two workers at this time were convinced that ketones would not react with o-aminothiophenol to form benzothiazolines.

After the original work of Claasz, it was not until 1955 that a group of

Russian workers undertook a definitive study of the chemistry of the benzothiazolines (53)» They used o-aminothiophenol. 19 o-raethylaminothiophenol and 2-aralno-5-nitrothiophenol, and succeeded in synthesizing a large number of benzothiazoline derivatives including three cycloalkylenebenzothiazolines which-are of special interest in the present investigation (Reactions 30, 31, 32).

0

l O C v / T s -> N H

Reactions 30, 31, 32

As a means of characterizing these compounds, a silver salt and

N-benzoyl derivative of each was formed. It was claimed by these investigators that the Schotten-Bauraam reaction was used to form the

N-benzoyl compounds. This is in direct contradiction to the results of the present investigation (see experimental). For the N-benzoyl derivative of 2,2-pentamethylenebenzothiazoline, the melting point is given a t 1 1 4 ° . Other workers (54,49) have reported this melting point as that of the parent 2,2-pentamethylenebenzothiazoline (XXVI). No further evidence is cited for proof of an N-benzoyl derivative. Nitrogen analysis, however, confirms an N-benzoyl benzothiazoline. 20

Germany made its contribution to benzothiazoline chemistry in

1958 ■with the published work of Teuber and Waider (5^)» These investi­ gators confirmed the synthesis of compounds XXVI AND XXVII, reported originally ty the Russians. One further cycloalkylbenzothiazoline,

2,2-hexamethylenebenzothiazoline (XXIX) was included in this publication.

Also inoLuded for the first time were ultraviolet spectra for compounds

XXVI, XXVII, and XXIX.

i c x n c

The most comprehensive study of benzothiazoline compounds to date is that of ELderfield and McClenachan (4-9) and is primarily concerned with the thermal decomposition of these compounds. Prior to this investigation only three reports could be found concerning either a thermal or base catalyzed decomposition of benzothiazolines ( 53 *55 t56 ),

The general reaction for benzothiazoline thermal decomposition is illustrated in the following reaction sequence.

.d fOria. 'fl'

1 ^ + R.'H 4 ;------±— IVJ Reaction 33

It was found that the elimination of hydrocarbon in passing from benzothiazoline to benzothiazole was subject to powerful base catalysis

(57)» However, peroxide catalysis had no effect on this transformation. 21

It was, therefore, postulated from these observations that an ionic mechanism predominated whereby the hydrocarbon radical (R*) was eliminated as a carbanion. IVhen R and R' are different, it was noted that the substituent most highly branched at the cZ -carbon was exclusively eliminated. When x = S in reaction 33. the same general pattern was found to hold true as when x = NH. It was further observed that the same trend was operative for thermal decomposition studies.

Two exceptions to the above thermal decompositions were provided by the condensation products of benzil and benzophenone with o-aminothiophenol.

Heating at temperatures of over 300° for 36 to 48 hours failed to thermally decompose the compounds. From the data collected on thermal degradation of benzothiazolines and a base catalyzed degradation of

2-methyl-2-(t-butyl)-benzothiazoline (which yielded isobutane and

2-methylbenzothiazole), i t was concluded that decomposition proceeds via carbanion formation plus the fact that steric factors were also oper­ ative. The base catalyzed degradation was also thought to be a general series of reactions and is represented below.

(1)

+ B H

(2 )

0 ) Reaction 34

f 6H EXPERBENTAL

Reagents

The o-aminothiophenol used in this investigation was technical grade o b ta in ed from Eastman Kodak Company, and was vacuum d i s t i l l e d under nitrogen prior to use. The fraction boiling at 9^98° (5 mm) was

•collected, stored under nitrogen and used within two hours of d istilla ­ t io n .

The cyclic ketones cyclopentanone, cyclohexanone, 2-methyl-,

3-methyl-, and 4-methylcyclohexanone obtained from Eastman Kodak

Company were of analytical reagent grade and were not further purified.

Tropinone, l-methyl-4-piperidone, 1,4-cyclohexanedione, and cydoheptanone were obtained from the A ld rich Chemical Company, Milwaukee,

Wisconsin, and were used as such.

Solvents used for the reactions such as absolute ethyl alcohol

(99.5^) and absolute methyl alcohol (analytical reagent grade) were not further purified. Chloroform used for taking infrared spectra was of analytical reagent grade and was used as such.

Anhydrous calcium oxide was used without further purification.

Potassium bromide used for infrared spectra was analytical reagent grade.

It was micropulverized and dried at 110° for five days. It was then stored in a desiccator until ready for use. .

22 23

Instruments

Infrared spectra were taken on a Pe^kin-Elmer Model 237 infrared spectrophotometer using a fast scan. Solution spectra were taken idLth an infrared microcell utilizing sodium chloride optics.

Attempted optical rotation readings were taken on a Carl Zeiss polarimeter equipped with a double-band interference filter, ^ = 589 m ,

Tubes used to obtain the sample readings were either 50 or 100 ram in length with an internal diameter of 1.6 mm.

All melting points were taken on a Thomas Hoover capillary melting point apparatus and are uncorrected.

Elemental analyses were done by the Alfred Bernhardt Micro- analytical Laboratories, Mulheim, Germany.

Synthesis of benzothiazoline derivatives

1. Preparation of 2.2-tetramethvlene benzothiazoline

A solution of 5*3^ ml. (0.05 mole) of redistilled o-amino-

thiophenol in 75 ml. of absolute ethanol was warmed on a steam bath to

4(^45°. To this solution was added dropwise 4.43 ml, (0.05 mole) of

cyclopentanone, The mixture was refluxed for six hours. If reflux was

continued for periods of longer than six hours, decomposition became increasingly evident as noted by progressive darkening of the solution. 24

After reflux was complete, the reaction mixture was cooled to room temperature and placed in a refrigerator. No crystallization occurred.

The mixture was then placed in a Dry Ice-acetone bath and the side of the flask scratched vigorously to induce crystallization. As soon as crystals began to form, the solution was again placed in a refrigerator and crystallization allowed to proceed to completion. The yield of 2,2-tetramethylene benzothiazoline as crude product was 7.5 g. or 78, 550 . This product was also obtained from the reaction mixture by removing the solvent under reduced pressure and dissolving the residue in absolute other. To the ethereal solution was added petroleum ether

(boiling fraction 30° - 6QO) until the solution remained slightly cloudy.

The resulting ether-petroleum ether mixture was allowed to stand in a refrigerator until crystallization was complete. Two recrystallizations from ethanol yielded white needles melting at 55°-5&°. This melting point agrees satisfactorily with that reported in the literature

(49 ,53 ,54 ).

ANALYTICAL DATA;

Calculated for

C, 69. 09; Found: 69.83 H, 6.85; Found: 6,98 N, 7 .3 3 ; Found: 7 .3 7 25

The following procedure was designed in an attempt to determine what effect water formation had on the course of the reaction. To an alcoholic solution of $.3^ ml. (0.05 mole) of redistilled o-amino- thiophenol contained in a 250 ml. round-bottomed flask was added dropwise 4.2 ml. (0,05 mole) of cyclopentanone. The flask was fitted

1-rith a Sohxlet extraction apparatus containing 20 g. of finely powdered anhydrous calcium oxide in a 33 x 40 mm, extraction thimble. Reflux was started and the azeotropic mixture of ethanol and water (4.4^ by weight of the azeotrope) passed through the extraction thimble for six hours. The yield of 2,2-tetramethylene benzothiazoline as crude product was 3 g. or 31.4% of the theoretical.

An alternative procedure utilizing a water trap was tried. The same molar quantities of o-aminothiophenol and cyclopentanone were used along with 100 ml. of toluene as the solvent. The mixture was refluxed for . six hours. The yield of benzothiazoline was again low

(40%) possibly due to decomposition of the product by heat (toluene boils at 110°).

The fact that calcium oxide in the presence of water produces calcium hydroxide suggested the idea th a t th is l a t t e r in o rg a n ic compound might be carried over into the reaction mixture causing a base-catalyzed decomposition of the benzothiazoline. A Sohxlet apparatus was set up, as previously detailed, containing a mixture of 10 ml. of water and 100 ml, of absolute ethanol. The azeotrope was passed through the extraction 26 thimble (containing 20 g, of calcium oxide) for six hours. Removal of the solvent mixture in the flask failed to yield any resid-ue whatsoever.

Maintaining lower temperatures during the reaction seemed to provide the maximum yield of 2,2-tetramethylene benzothiazoline. Heating an equimolar mixture of o-aminothiophenol and cyclopentanone in absolute ethanol at 40° for 6 hours afforded about 85^ of 2,2-tetramethylene benzothiazoline as crude product.

2. Pret>aration of 2.2-t)entamethvlene benzothiazoline

To 5*34 ml, ( 0,05 mole) of freshly distilled o-aminothiophenol in

75 nil. of absolute ethanol was added 5.17 nil. (O.O 5 mole') of cy clo­ hexanone, The mixture was refluxed for six hours using the Sohxlet

apparatus previously described. Removal of the solvent under reduced pressure afforded 10 g. or 97*5^ of impure 2,2-pentamethylene

benzothiazoline. Two recrystallizations from absolute ethanol produced

shiny white needles melting at 114.5-115°.

The l i t e r a t u r e v alu es f o r the m elting p o in t of t h i s compound

ranged from 111° to 115° (49,53,34). The same yield of this substance was obtained when nitrogen was used as an inert atmosphere in the preceding procedure. The same yield was also obtained when the Sohxlet

apparatus was deleted from the procedure.

. ANALYTICAL DATA:

Calculated for C12H15 NS

c, 70.20 Found: 70.83 H, 7.36 Found: 7.36 N, 6.82 Found: 6,68 27 3. Preparation of 2.2-hexamethvlene benzothiazoline

The method utilizing the Sohxlet apparatus with calcium oxide as the drying agent was repeated in this reaction. Qycloheptanone (5*9 nil,,

0.05 mole) was added dropwise to a warm solution of 5*3^ ml. (O.O 5 mole) of redistilled o-aminothiophenol in 75 ml. of absolute alcohol. The reaction mixture was refluxed for six hours. A light yellow oil was obtained when the solvent was removed under reduced pressure. The oil was dissolved in ether and cooled in a refrigerator. Petroleum ether

(boiling fraction 30°-60°) was added to this cold solution until the mixture became cloudy. The solution was allowed to stand overnight in a refrigerator and resulted in the precipitation of 9 g. or 82.2/o of impure 2,2-hexamethylene benzothiazoline. One recrystallization from

ethanol afforded long, colorless needles melting at 51°-52°, literature melting point 52.5° (llO).

ANALYTICAL DATA:

Calculated for

c, 71.20 Found; 70.68 H, 7.81 Found; 7.64 N, 6 .3 9 Found; 6.07

4. Preparation of 2.2-(2imethvl) pentamethvlene benzothiazoline

Five and n in e -te n th s m l. (O.O5 mole) of 2-methylcyclohexanone was

added dropwise to a warm solution of 5.34 ml. ( 0.05 mole) of freshly

distilled o-aminothiophenol in 100 ml. of absolute ethanol. A Sohxlet

apparatus was assembled and reflux temperature maintained for 24 hours.

The solvent was removed under reduced pressure affording a dark oil.

The oil was vacuum distilled (148°-150° at 1.5 mm. ) yielding 9 g. or 2 8

73^ of 2,2-(2’“methyl) pentamethylene benzothiazoline. This same compound was prepared by Elderfield and McClenachan (49) using o-amino­ thiophenol and an excess of 2-methylcyclohexanone as solvent. They refluxed the mixture for 48 hours and reported a yield of ^0^. The use of calcium oxide in the preparation of this benzothiazoline seems warranted. An increase of 23^ in yield of final product was noted when calcium oxide was used in the procedure. Repeating the procedure of

Elderfield and McClenachan in this investigation afforded the same yield of benzothiazoline as that reported by these workers.

5» Preparation of 2 .2 -(3 * -m eth y l) pentamethvlene benzothiazoline

This compound was also prepared by the conventional procedure. A

solution of 3 .3 4 ml. (0,05 mole) of o-aminothiophenol and 5*9 ml. (O.O 5 mole) of 3-methylcyclohexanone was maintained at reflux temperature for

24 hours. The solvent was removed under reduced pressure and the resulting yellow oil distilled under vacuum. The light yellow oil

obtained from the distillation was placed in a refrigerator overnight.

The oil crystallized completely. 2,2-(3'-Methyl)pentamethylene

benzothiazoline was obtained in 82.2/o yield (9 g.) after two recrystalli­

zations from petroleum ether (boiling fraction 30°~60°), It formed fine white needles melting at 48°-49°.

ANALYTICAL DATA:

Calculated for

C, 71.18; Found; 70.75 H, 7 «81; Found; 7 .6 3 N, 6,38; Found; 6,65 29

6, Preparation of 2.2-(4'-mGthvl) pentamethvlene benzothiazoline

Equimolar quantities of o-aminothiophenol (5*34 ml., O.O 5 mole) and 4-methylqyclohexanone ( 5.6 m l., O.O5 mole) were refluxed for four hours using the conventional Sohxlet apparatus. Removal of the solvent . under reduced pressure yielded a light yellow oil which crystallized on standing overnight in a refrigerator. Tito recrystallizations from absolute ethanol afforded 8 g. or 735° of long white needles melting at

7 4 0 - 7 3 0 . ANALYTICAL DATA:

C alculated fo r (g^^H^gNS

C, 71.18; Found: 71.14 H, 7.81; Found: 7.86 N, 6. 38; Found: 6.40

7. Preparation of 1.2*-4.2'-cyclohexvlidene bis-benzothiazoline

A solution of 5*8 g. (Û .05 mole) of 1,4-cyclohexanedione in 30 ml. of absolute ethanol was added to 10.6 ml. (O.IO mole) of o-aminothio­ phenol and the mixture refluxed for ten hours. Precipitation commenced at this time and the reaction mixture had to be cooled to prevent excessive bumping. The mixture was allowed to stand at room temperature for an additional twelve hours. The resulting white precipitate was filtered off and dried at room temperature. The yield of crude l,2 ‘-4,2'-cyclohexylidene bis-benzothiazoline was 15*5 B. or 78.3^. One recrystallization from dioxane-water (9:1) yielded the pure compound melting at 232®-233° (slight decomposition). The melting point reported in the literature was 233°“234° (53). 30

After standing in a closed container for four months, this compound underwent a change th a t was ra th e r unusual. I t was in so lu b le in all solvents including dioxane and tetrahydrofuran. It also failed to melt at temperatures up to 320°. An infrared spectrogram illustrated striking differences betifeen an old sample and a freshly prepared sample of this compound.

ANALYTICAL DATA;'

Calculated for Cis^lS^Z^E C, 66.24 Found; 66.^ H. 5.56 Found; 5-56 N. 8.58 Found; 8.62

A freshly prepared sample of 1,2'-4,2'-cyclohexylidene bis- benzothiazoline is freely soluble in dioxane and tetrahydrofuran.

Preparation of the monosubstituted ketone derivative was attempted by allowing equimolar quantities of o-aminothiophenol and 1,4-cyclo­ hexanedione to react. An ethanolic solution of 1,4-cyclohexanedione

(5.6 g., 0.05 mole) was added dropwise to 5.34 ml, (0.05 mole) of o-aminothiophenol in 25 ml. of absolute ethanol. The reaction mixture was allowed to sit at room temperature for 12 hours and the resulting white precipitate filtered off and recrystallized-once from dioxane. The compound produced e x c lu siv e ly was 1 , 2 '- 4 , 2 '-cyclonexylidene b is - benzothiazoline (53) as evidenced by a malting point (232°-233°) and an infrared spectrum. ,

8, Preparation of 2«4 '-(l'-methvl) piperidyl_benzothiazoline

The reaction was set up using a Sohxlet apparatus containing 20 g. of anhydrous calcium oxide as the drying agent. A mixture of 5.3^ ml.

(0,05 mole) of re-distilled o-aminothiophenol and 5*65 g* ( 0,05 mole) of 31 l-raethyl-4-piperidone in 75 ml. of absolute ethanol were refluxed for 2 hours. Decomposition became quite pronounced if reflux temperature was maintained for longer periods of time. The reaction mixture was concentrated to about 25 ml. under reduced pressure. The extract crystallized when allowed, to remain in a refrigerator overnight. Excess solvent was removed by suction filtration. Dissolving the crude product in absolute ethanol and decolorizing viith activated charcoal afforded, upon crystallization, 8 g. or 72.?^ of 2,4'-(l'-m ethyl) piperidyl benzothiazoline as long colorless needles. The melting point was 133°-

13^° ifith decomposition. When this substance was exposed to the atmosphere, either in the dry state or under solvent, decomposition resulted in about seven days.

ANALYTICAL DATA:

C alculated fo r C]_2%6^2^

C, 65.41; Found: 65.69 H, 7.31; Found: 7.39 N, 12.71; Found: 12.54

Attempted formation of 2.4*-(l*-methyl) piperidvl benzothiazoline hydrochloride

A solution of 220 mg. (l millimole) of 2,4*-(l'-m ethyl) piperidyl benzothiazoline dissolved in 10 ml. of anhydrous ether was treated tJith anhydrous hydrogen chloride until no further precipitation resulted.

The copious white precipitate, upon filtration, proved to be extremely hygroscopic thus making isolation of this salt impossible.

Attempted formation of 2.4*-(l*-methvl) pjperidvl benzothiazoline methiodide

Two hundred and twenty mg. (l millimole) of 2,4'-(l*-methyl)- piperidyl benzothiazoline was dissolved in 5 ml. of anhydrous ether and 32

.2 ml, of methyl iodide added to this solution. The solution was warmed

for 5 minutes on a steam bath, then allowed to stand at room temperature

for one hour. As the precipitate was filtered, the intense hygroscopic

properties of this salt caused decomposition and no product was isolated.

Preparation of the picrate salt of 2 .4 '- ( 1 *-me th v l^ p ip e rid v l ben z oth ia z olin e

A saturated methanolic solution of picric acid was added dropwise

to 220 mg. (l millimole) of 2,4'-(l'-m ethyl) piperidyl benzothiazoline

dissolved in 5 ml. of absolute ethanol. Picric acid was added until no

further precipitation occurred. The resulting orange-yellow amorphous

precipitate was filtered and washed with 3 ml. of c^bsolute ethanol.

Recrystallization from ethanol afforded yellow platelets melting at

2010-2020 with decomposition.

ANALYTICAL DATA:

Calculated for

C, 48.10; Found: 47.35 H, 4,26; Found: 4.34 N, 15.58; Found: 15.05

9. Preparation of 4*.5*-benzo-8-methvl-spiro (8-aza-bicvclo-r3 .2.1l-octane-3.2 *- I '.3 * - azathiolane) hydrochloride (XXX)

To 2.5 g. (0.02 mole) of o-aminothiophenol in 75 ml. of absolute

alcohol was added 10 ml. of an ethanolic solution containing 2.74 g.

(0,02 mole) of tropinone (free base). The usual Sohxlet apparatus was

assembled and the reaction mixture maintained at reflux temperature for

2 hours. Considerable decomposition was noted. The mixture was placed

in a refrigerator and the wall of the vessel scratched vigorously to

induce crystallization. Crystal formation did not occur, however, even 33 after the solvent was completely removed under reduced pressure. It was suspected that excessive heat in the reaction promoted decomposition.

■ An alternative procedure utilizing room temperature conditions for the reaction was attempted. Tropinone hydro chloride was substituted for tropinone free base and p-toluenesulfonic acid monohydrate used as a catalyst. Tropinone hydrochloride (5 g.» 0.0286 mole) was dissolved in

25 ml. of absolute methanol and added dropwise to a methanolic solution containing 3 ml. of o-aminothiophenol (0.0286 mole). Fifty mg. of p-toluenesulfonic acid monohydrate was finally added to this mixture.

The reaction mixture was allowed to stand at room temperature for 24 hours. The resulting yellow-brown crystals were suction filtered, recrystallized from boiling methanol, and afforded ? g. of a white crystalline compound melting at 218°-219° with decomposition, A small portion of this product was dissolved in water and a freshly pre^red solution of silver nitrate added dropwise. The resulting white precipi­ tate which formed indicated that the hydrochloride salt had indeed been formed (see p. 52 for structure).

ANALYTICAL DATA:

Calculated for

C, 59.45 Found: 59.69 H, 6.77 Found: 6.85 N, 9.90 Found: 10,05

The above data proves that III was indeed the reaction product resulting from the condensation of o-aminothiophenol and tropinone hydrochloride. 3 4

Formation of 4'.5'-benzo-8-^ethvï- spiro(8-a7,a~bicvclo-r3.2.11~octane- 3.2'-l*.3*-azathiolane) (XXXI)

A lO/o solution of sodium hydroxide was added to 590 mg. of XXX dissolved in 20 ml. of distilled water. Addition was continued until no

further precipitation took place. The aqueous suspension of white precipitate was extracted with 2-20 ml. portions of ether and the ether

extracts combined and dried over anhydrous magnesium sulfate. The first

20 ml. of ether was evaporated on a steam bath while the remaining

solvent was removed in a vacuum desiccator. The residue was recrystallized

from absolute alcohol affording fine, white needles of XXXI molting at

1240 - 125 ° w ith decom position. This compound was d rie d a t 56 ° fo r 4

hours (2 mm.) and stored in a vacuum desiccator to prevent decomposition.

ANALYTICAL DATA: '

Calculated for

C, 68.25; ■ Found: 68.34 ■ H, 7.36; Found: 7.43 N, 11.37; Found: 10.93

Preparation of 4'.5'-benzo-8-methvl-soiro (8-aza-bicvclo-r 3.2.11-octane-3.2'-l'.3*- a z a th io la n e ) p ic ra te (XXXII)

One hundred and twenty-three milligrams (0.5 millimole) of XXXI

was dissolved in 5 ml. of absolute ethanol and a saturated methanolic

solution of picric acid added dropwise until precipitation was complete.

Two recrystallizations of the resulting orange-yellow powder from hot

ethanol resulted in fine yellow needles of XXXII melting at 191.5°-

192° with decomposition. 35 ANALYTICAL DATA:

Calculated for C?nH?^N^OyS

c, 50.52 Found: 50.44 H, 4.45 Found; 4.69 N, • 14.73 Found: 14.64

Formation of 4*.5'-bonzo-8-methvl- • sn iro ( 8-a7.a-bicvc1.o--r 3.2 .1 1-octane-» 3.2 *-1.3 *-azathiolane ) methiodide ()IXXIII)

To 50 mg. (0.2 millimole) of XXXI dissolved in 4 ml. of isopropyl alcohol was added O .5 ml. of methyl iodide. l’Ile mixture was heated for

5 minutes on a steam bath. The solution was cooled and the resulting precipitate filtered under suction. Fine, white needles of XXXIII, after drying for 4 hours at $6° and 2 mm. pressure, molted at 179°-

179.5 ° with decomposition.

ANALYTICAL DATA:

Calculated for C]_^H2iN2SI

C, 46.40 Found: 46.36 H, 5.45 Found: 5*63 N, 7.21 Found: 6.78

Attempted preparation of a 2.2-cvcloalkvl benzothiazoline-1.1-dioxide

Approach A

The first method was concerned with the formation of o-acetyl- aminobenzenesulfinic acid from the required sodium sulfonate ifith subsequent condensation of cyclic ketone with the sulfinic acid to produce a 2,2-cycloalkylene benzothiazoline-1,1-dioxide. The reaction sequence is outlined in the discussion folloifing the experimental procedure. 36

TABLE I

INFRARED SPECTRA OF BENZOTHIAZOLINES

Compound -NH -CHg- Phenyl

2,2-Tetramethylene Benzothiazoline 3400 2975.2890 1580,1385 1 ^ 0

2,2-Pentamethylene Benzothiazoline 3380 3000, 2935 . 1585.1400 2850,1460

2,2-Hexamethylene Benzothiazoline 3400 3020,2950 1585.1390 2875.1460

1,2'-4,2'-Cyclohexylidene 3275 3075,2950 1575.1413 Bis-Benzothiazoline 2855.1460

2,2-(2'-Methyl)Pentamethylene No data a v a ila b le Benzothiazoline

2,2-(3'-Methyl)Pentamethylene 3385 3000,2940 1585.1400 Benzothiazoline 2875.1460

2,2-(4'-M ethyl Pentamethylene) 3380 3005 . 2938, 1585.1390 Benzothiazoline 2875.1460

2 ,4 '- ( 1 '-Methyl) Piperidyl 3400 2950 , 2800, 1590,1400 Benzothiazoline 1377 (m ethyl)

4' ,5 '-Benzo-8-Methyl-Spiro-(8-Aza- 3150 2960,2905 1585 Bicyclo[3.2.l]-0ctano-3,2 '-1 ',3 '- 1465 Azathiolane) %drochloride '

Preparation of sodium o-atninobenzenesulfonate

The stoichiometric quantity of sodium hydroxide (2.97 g ., O.O 69 mole) was added to 12 g, ( 0,069 mole) of o-aminobenzenesulfonic acid suspended in 50 ml. of distilled water. VJhen the sodium salt had completely formed, the solution was filtered and the solvent removed under reduced pressure. The resulting white platelets were oven dried at 95° for 10 hours. 37

Preparation of sodium o-(acetvlamino)- benzenesulfonate

Ten grains (0,051 mole) of finely powdered sodium o-aminobenzene- sulfonato was mixed with 6,2 ml, (9.965 mole) of freshly distilled acetic anhydride and the suspension allowed to reflux gently for two hours. The resulting precipitate was filtered off and washed three times with 75 ml, portions of ether. Drying the residue for 20 hours at

^0° in a vacuum oven (10 mm, pressure) afforded 11.04 g, or 91.3^ of

sodium 0-(a ce tylamino)-bonz ene sulfonate ,

Attempted preparation of o-(acetvlamino)- benzenesulfonvl chloride

Three different chlorinating agents were tried in an attempt to

obtain this compound, these being phosphorous pentachloride, phosphorous

oxychloride, and thionyl chloride.

The first reaction was run according to Vogel (60) who used phosphorous pentachloride. To 5 g. (0.026 mole) of sodium o-(acetyl­ amino )-benzenesulfonate in a 100 ml, round-bottom flask was added 5 g* of

finely powdered phosphorous pentachloride. The mixture was refluxed for

14 hours at 175°-l80o. Every three hours the flask was removed from

the oil bath and shaken until the mass became pasty, VJhen heating was

complete, the reaction mixture was cooled to room temperature and poured

over 200 g, of crushed ice. No precipitate formed however, and several

attempts to isolate any product ended in failure.

Phosphorous oxychloride

Two and two-thirds g, (0,0104 mole) of sodium o-(acetylamino)-

benzenesulfonate was placed in a 100 ml, Vfi.dmer flask and 10 g, (6 m l,) 38 of phosphorous oxychloride was added dropwise. The mixture was heated at reflux temperature for 26 hours on a steam bath. At the end of the heating period the suspension was cooled to room temperature and poured over 100 g. of crushed ice. A white precipitate formed along with a slightly brown layer of liquid which settled to the bottom of the beaker.

The mixture was shaken thoroughly to decompose excess phosphorous oxychloride, cooled, and extracted three times with 50 ml. portions of ether. The extracts were collected and washed with water to decompose any phosphorous oxychloride that might have partitioned into the ether.

The combined ether layers were dried vûth calcium chloride. Filtration of this mixture iidth subsequent evaporation of the solvent afforded crystals which rapidly decomposed on standing. Several attempts to isolate and identify these crystals failed in subsequent experiments. *

Thionvl chloride

Thionyl chloride gave the same results as those obtained with phosphorous oxychloride.

It was thought that hydrolysis of the amide was responsible for the decomposition in all three of the above cases.

Approach B

This second method was concerned with the formation of a

2,2-cycloalkyl benzothiazeline-1,1-dioxide by condensation of

2-(aminophenyl) methyl sulfone hydrochloride with a cyclic ketone in the presence of phosphorous oxychloride. The reaction sequence is outlined in the discussion following the experimental procedure. 39

Preparation of o-faminonhenvl) wethvlsnlfide hvdriodide

Methyl iodide (18.? ml., 0,30 mole) was slowly added to 32.4 ml.

( 0.30 mole) of freshly distilled o-aminothiophenol contained in a 25 O ml. round-bottom flask. The ingredients were thoroughly mixed and the flask equipped with a reflux condenser. In a few minutes an exothermic reaction began with subsequent precipitation of o-(aminophenyl) methylsulfide hydricdide. Reaction temperature was not allowed to rise above 40° because at elevated temperatures the formation of o-amino­ thiophenol disulfide in large quantity was noted. As the reaction temperature approached 40°, the flask was submerged in an ice bath and

150 ml. of distilled water added to the reaction mixture. The solid hydriodide salt slowly dissolved in the water layer and o-a.minothiophenol and methyl iodide remaining in the bottom of the flask slowly formed more hydriodide salt. This salt, as it formed, dissolved in the water layer and the reaction continued until both starting materials were expended. A slight excess of methyl iodide (4 ml.) was added at the beginning of the reaction because it is slightly soluble in water (l: 5 0 ).

The mixture was allowed to stand at room temperature for one hour and then filtered. Removal of the solvent under reduced pressure produced essentially a quantitative yield of o-(aminophenyl) me thylsulfide hydriodide.

Preparation of o-(aminophenvl) methylsulfide.

To an aqueous solution of o-(aminophenyl) methylsulfide hydriodide

(pH 3 ) was added 5N potassium hydroxide solution (132 g. KOH per lite r of distilled water) in small portions with constant stirring until the 40 final pH of the solution reached pH 11. The resulting oil which separated from the aqueous phase was removed using a separatory funnel.

The aqueous phase was extracted xcLth 5~50 ®1. portions of ether. The combined ether extracts were added to the oil and this solution dried 12 hours with anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the ether removed under reduced pressure. The resulting light brown oil was vacuum distilled (8?° at 1 mm. 92° a t 3 mm.) and afforded a colorless oil with a characteristic naphthalonic odor. o-( Aninophenyl) methylsulfide has previously been reported to boil at

234 ° with decomposition (2?) and also at 133°~13^° at 15 mm. (64),

Preparation of 2-(acetvlamiho) phenvlme thvlsulfide

Twenty grams (0,144 mole) of o-(3.minophenyl) methylsulfide was warmed on a steam bath for 3 hours vm.th 30 ml. of re-distilled acetic anhydride. The hot mixture was cooled and poured over crushed ice and an additional ‘50 ml, of distilled water added to ensure decomposition of excess acetic anhydride. The aqueous solution ifas then treated vrith sodium bicarbonate until all acetic acid was neutralized. Four-100 ml, p o rtio n s of e th e r were used to e x tra c t the a c e ty l compound from the aqueous layer. The combined ether extracts were then dried over anhydrous magnesium sulfate. The filtered ethereal solution was evaporated and the residue dissolved in 755° ethanol. The yield of pure '

2-(acetylamino) phenylmethylsulfide was rather low (45;^50?) and melted a t 1020-103°, This compares favorably with that melting point reported in the literature (64). The procedure of Vogel ( 6 5 ) was attempted in an e f f o r t to o b ta in th e preceding compound b u t w ith o u t any su ccess. 41

Preparation of 2-(acetvlanAno) phenvlmethvl snlfone

A solution of 7 g. (0.039 mole) of 2-(acetylamino) phenylmethyl

sulfide in 10 ml. of glacial acetic acid was added dropidLse to a mixture

of 10 ml. of 30^ hydrogen peroxide dissolved in 15 ml. of glacial acetic

acid. If the solution of sulfide was added to the peroxide at one time,

the resulting mixture first turned red and then dark broi\Ti. Complete

decomposition occurred i-rithin a few minutes. No sulf one was isolated

from this mixture. The temperature was maintained at 70°-75° for two

hours after the glacial acetic acid solution of sulfide was added drop-

xvise. At the end of this time, the temperature was lowered to 55°“60°

and the solvent evaporated. The resulting pink crystalline mass was

recrystallized from 50 ^ ethanol and yielded 3.2 g. or 26^ of

2-(acetylamino) phenylmethyl sulfone as white needles which melted at

145.5°-146.5°. The literature value for the melting point of this

compound i s given a t 139 °-l4 0 °.

From the variation in melting points obtained in this investiga­

tion and that observed in the literature, it was decided to ascertain

more completely if the sulfone had indeed been produced.

ANALYTICAL DATA:

Calculated for CpHn O^^SN

C, 50.69; Found: 51.05 H, 5.20; Found: 5.12 N, 6. 56 ; Found: 6.49

An infrared spectrum of 2-(acetylamino) phenylmethyl sulfone

taken in chloroform indicated absorption frequencies at 1130, 1150, and

1375 cm”^. All are characteristic of sulfones. The infrared spectrum 42 of 2-(acetylamino) phenylmethyl sulfide taken in the same solvent showed these frequency ansorption bands to be absent.

Preparation of 2-(aminophenvl) methvl sulfone hydrochloride

Three and two-tenths g. (O.OI 5 mole) of 2-(aminophenyl) methyl sulfone was dissolved in 39 ml. of absolute ethanol. Sixteen ml, of concentrated hydrochloric acid was added to this mixture and the solu­ tion maintained at reflux temperature for 4 hours. The solvent (ethyl acetate) was removed under reduced pressure and the resulting mass of light pink needles filtered under suction, dried, and recrystallized from ethanol. The yield of 2-(aminophenyl) methyl sulfone hydrochloride was 2,4 g, or 80$ of the theoretical. The melting point was 149°-159° with slight decomposition.

In fra re d d a ta f o r th is compound gave ab so rp tio n freq u en cies characteristic of a hydrochloride salt and of a sulfone.

Preparation of 2-(aminophenyl) methvl su]-fone

The amine hydrochloride of the above sulfone (2,07 g., 0,01 mole) was dissolved in 10 ml, of distilled water. Enough sodium acetate trihydrato was added to this solution to ensure complete precipitation of the free amine. The yield was quantitative. The melting point of

2-(aminophenyl) methyl sulfone was 83°-84°, Here again the literature is at variance with the molting point obtained in this investigation, A literature melting point of 65°-66° was given for this compound (64),

A sample of impure 2-(aminophenyl) methyl sulfone was dissolved in hot ethanol and decolorized with a small amount of activated charcoal. One 43

gram of free amine crystallized pure from 8 ml. of absolute ethanol.

This sample was dried for 4 hours at 40° (5 mm.) and sent for analysis.

ANALYTICAL DATA:

Calculated for CyH^02SN

C, 49.11 Found: 49.4? H, 5.30 Found: 5*30 N, 8.18 Found: 8.17

In fra re d a n a ly s is of th is compound u sing a potassium bromide pellet afforded tifo medium intensity absorption bands at 3475 cra~^ and

3370 cm“l which are indicative of a primary amine. The sulf one group was detected at Il40 cm”^. If any 2-(acetylamino) phenylmethyl sulfone was present as impurity, this would be detected by the presence of an

amide carbonyl peak between 1640”^ and 1680 cm No such band was

found.

The attempted preparation of the benzothiazoline-1,1-dioxide

using phosphorous oxychloride, 2-(aminophenyl) methyl sulfone hydro­

chloride, and cyclohexanone is sot down in the following procedure. One

gram (0.0048 mole) of 2-(aminophenyl) methyl sulfone hydro chloride was

added in small increments to 4 ml. (0.026 mole) of phosphorous oxy­

chloride. This mixture was placed in an ice bath and 3 ml. (0.03 mole)

of cy clohexanone added dropwise. The mixture was allowed to warm to

room temperature and stand for two hours. A red resinous mass formed

and was thought to be the ketone polymerization product. Column

chromatography, utilizing neutral grade alumina and a variety of solvents

of different polarities, failed to effect the separation of any

identifiable substances. Several further attempts, varying the reaction 44 conditions of the procedure, failed to yield any 2,2-pentamethylene benzothiazoline-1,1-dioxide.

Approach C

The third method was aimed at obtaining a 2,2-cycloalkyl benzothiazoline-1,1-dioxide by direct oxidation of the heterocyclic sulfur atom on the parent benzothiazoline and on its 3-acetyl derivative.

Attempted oxidation of 2.2-pentamethvlene benzothiazoline

A given quantity of 2,2-pentamethylene benzothiazoline was dissolved in glacial acetic acid and an equivalent amount of 30/5 hydrogen peroxide added dropwise. The solution of benzothiazoline turned dark brovm and finally black upon addition of the peroxide solu­ tion and completely decomposed in about 5 minutes.

Preparation of 2.2-pentamethvlene- 3-acetvl benzothiazoline

Four and one-tenth grams (0.02 mole) of 2,2-pentamethylene benzothiazoline was dissolved in 15 wl. of glacial acetic acid and the

so lu tio n warmed to 50°. Ten and tw o -ten th s g. (0 .1 0 mole) of re-distilled acetic anhydride was then added dropwise. Tv;o drops of

concentrated sulfuric acid were finally added. The solution was heated to 90° for three hours. During this time it developed a reddish-brown

color. The solution was cooled to room temperature, poured over crushed ice, and stirred for one hour to decompose excess acetic anhydride. The water layer was decanted and the remaining red oil dissolved in 50 m l. of ether. Sodium bicarbonate was shaken with the ethereal solution until effervescence ceased. The resulting neutralized solution was 45 dried t-iith anhydrous magnesium sulfate, the solvent removed, and the oil distilled (174°-176° at 2.5 mm.). D istillation afforded 4 g. (80^) of a light yellow oil which was identified as 2,2-pentamethylene-3-acetyl benzothiazoline by elemental analysis and. supporting infrared data.

ANALYTICAL DATA:

Calculated for

C, 67. 68; Found: 67.87 H, 6.93; Found: 6.82 N, 5 . 66; Found: 6.34

Attempted oxidation of 2.2-nentamethvlenG- 3-acetvl benzothiazoline

To one equivalent of a solution of the acetylated benzothiazoline in glacial acetic acid was added dropviise 3 equivalents of 30'^ hydrogen solution. The solution was stirred at 70° for four hours. Pouring the cooled solution over crushed ice resulted in the recovery of starting material. Several further attempts, in which heating time, temperature, order of addition of reactants, and variation of reactant ratio were studied still failed to yield any dioxide of tho benzothiazoline.

Attempted oxidations using potassium permanganate and chromic oxide afforded the same results as those obtained with hydrogen peroxide.

Attempted reaction of 2.2-pentamethvlene benzothiazoline td.th methvl magnesium iodide

Commercial magnesium turnings were washed t-Jith sodium dried anhydrous ether to remove any surface grease, dried at 100°, cooled, and stored in desiccator until ready for use. Commercial methyl iodide was distilled and the fraction boiling at 42°-42.5° collected prior to use.

All glassware was dried for three hours at 100° before use. 46

To 0.74 g, (0.03 mole) of magnesium turnings was added 4.28 g.

(0,03 mole) of methyl iodide in $0 ml. of anliydrous ether. The mixture was stirred in a mpisture-free system for 2-3 hours until all of the magnesium disappeared. A solution of 6.15 g* (0.03 mole) of

2,2-pentamethylene benzothiazoline dissolved in 100 ml. of anhydrous ether was added dropwise, from a dropping funnel, to the Grignard reagent solution. The reaction flask was fitted with a reflux condenser contain­ ing a calcium chloride drying tube. The mixture was maintained at reflux temperature for 4 hours and allowed to stand at room temperature for an additional 24 hours. At this time 3 ml. of distilled water was added dropwise id-th stirring. An additional 20 ml. of distilled water was added and stirring continued for an additional 2 hours. The result­ ing flocculent precipitate was allowed to settle for 30 minutes and the e th e r la y e r decanted. The aqueous p o rtio n was e x tra c te d x-Jith 2-50 m l. . portions of ether and the ether washings combined with the decantate.

The ethereal solution was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent afforded a quantitative yield of starting material. To provide higher reflux temperature in the reaction, tetrahydro- furan (b.p. 66°) was also tried as a solvent in an attempt to form the

Grignard addition product. The tetrahydrofuran used in this investiga­ tion was purified by shaking with sodium hydroxide pellets, drying over sodium metal, and finally distilling from lithium aluminum hydride. All quantities of reagents and previous reaction conditions were used ifith

THF. The results, however, were the same as those obtained when ether was used as the solvent. A quantitative yield of starting material was reco v ered . 4?

Discussion

Teuber and Waider (5^)t in an attempt to maintain an oxygen free atmosphere during their benzothiazoline syntheses, flushed out the reaction system -with nitrogen and maintained a flow of nitrogen through­ out the course of the reaction. This evidently was done to prevent formation of any o-aminophenyldisulfide from o-aminothiophenol. It was found in this investigation that the same yields of bensothiazolines could be obtained without the use of nitrogen. It would be reasonable to assume, then, that the formation of benzothiazoline proceeds at a much,faster rate than does formation of the disulfide. The yield of benzothiazoline is not reduced when nitrogen is eliminated from the reaction procedure.

One factor that had not been accounted for in the investigation

of Teuber and Waider was that of water formation during the reaction and its possible inhibitory effect on the progress of the reaction. The law of mass action states that the velocity or rate of the forward reaction is proportional to the concentrations of the reactants. The rate of the reverse reaction is an expression of the re-formation of reactants, VJhen reaction between o-aminothiophenol and cyelopentanone occurs, the products formed are 2«2-tetramethylene benzothiazoline and water. The reverse reaction, however, tends toward the re-formation of

the starting materials. The reverse reaction could possibly be minimized removing one of the products as it is formed. In the above reaction, water would be the easiest product to remove. Water removal should alter the equilibrium in such a way as to have the forvrard reaction predominate thus increasing the yield of benzothiazoline. The results were difficult to interpret since considerable decomposition was evident in the reaction of o-aminothiophenol and cyclopentanone. 48

Décomposition also proved to be a problem in this sjTithesis, .

Decomposition occurred in every case when the reaction temperature remained above 40° for a period of six hours. IVhon the time of reaction was shortened, the yield of benzothiazoline was reduced accordingly. A base catalyzed decomposition of this benzothiazoline could not be credited to either calcium oxide or calcium hydroxide since neither of these substances were found in the reaction mixture when the Sohxlet procedure was used. It was finally concluded that a decrease in yield of 2 , 2-tetramethylene benzothiazoline was due to excessive heat in the re a c tio n .

The dried crystals of this benzothiazoline wore also observed to be unstable. Complete decomposition occurred in about seven days if the substance was stored at room tenporature. Decomposition could be slowed and stability maintained for up to three weeks if the crystals were stored in an inert atmosphere or under vacuum,

Mertes and Gisvold (69) synthesized a series of compounds bearing some resemblance to 2,4'-(l'-m ethyl) piperidyl.oenzothiazoline.

Utilizing l-methyl-4-piperidone hydrochloride and a group of related mercapto propanols as starting materials, they prepared a series of hemithioketals. A representative structure is illustrated below;

H

XXXIV R = H; R' = GH^ XXXVI R = H; R' = C^H.CHg

XXXV R = CH3 ; R« = H XXXVII R = %H^CH2 R* = H 49 Their procedure consisted of refluxing 1-methyl-4—piperidone hydro­ chloride 'With the requisite mercapto propanol in benzene for two hours.

Para-toluenesulfonic acid was used as catalyst. Using these conditions, they obtained hemithioketals in yields of 8.5/^ to 51/°» These low yields were most likely due to the excessive amount of heat which promoted decomposition. Excessive reaction temperatures were found to exert the

same effect in this investigation. This was especially true with

2,2-pentamethylene benzothiazoline, 2,^'-(l*-methyl) piperidyl benzothiazoline and 4 'fj'-benzo-8-methyl-spiro(8-aza-bicyclo-[3.2.11- octane -3 ,2 *-1',3'-azathiolane).

f^drochloride and methiodide salts of the corresponding hemithioketals were prepared by these workers and found to be stable. This was found not to be the case in this investigation for the structurally similar 2,4'-(1'-methyl) piperidyl benzothiazoline. The hydrochloride and m ethiodide s a lt s of th is compound were extrem ely hygroscopic and could not be isolated.

The question of conformation has never been elucidated in the

benzothiazolines, however certain proposals can be made concerning these

compounds ty comparisons to structurally related entities. Kertes and

Gisvold have stated that, due to the size of the sulfur atom and the probability that the ring converts to the least hindered form, the

conformation of their hemithioketals prepared from l-raethyl-4-piperidone would preferentially exist with sulfur in an equatorial position and

oxygen in an axial position. This same reasoning could be seen to hold

true in the case of 2,4-(l'-methyl) piperidyl benzothiazoline. Since

nitrogen is very similar in size to oxygen, this benzothiazoline would * most likely have the sulfur atom in the equatorial position while

retaining nitrogen axial. 5û

Other investigators ( 67, 6 8) working in related areas have similarly noted that the sulfur atom tends to assume an equatorial position when this is possible.

The work of Kertes and Gisvold ( 69) is again credited vjith providing compounds analogous to 4',j'-benzo-8-m ethyl-spiro(8-aza- bicyclo-[3.2.l]-octane-3.2'-l',3'-azathiolane) hydrochloride (XXX) and its derivatives. They reported the preparation of several hemithioketals by condensing the hydrochloride salt of tropinone with a series of substituted thioglycols. A representative structure is shown below along with designations for R and R'.

H

XXXVIII R = H; R* = CH.

XXXIX R = CH3; R' H

XL R = H; R' C6H5 CH2 XLI R = CÆCHg R' = H 51 The low yields of hemithioketals obtained by these workers was most likely due to the relatively vigorous conditions used in the reaction

(reflux temperatures using benzene as the solvent). They reported yields which ranged from 6.9# to 2h#. It was found in the present investigation that if tropinone (free base) and o-aminothiophenol were refluxed for any length of time, extensive decomposition was noted. If the hydrochloride salt of tropinone, o-aminothiophenol, and p-toluene- sulfonic acid were dissolved in absolute ethanol and allowed to stand at room temperature, XXX was obtained in good yield. This fact proved that excessive heat during the reaction greatly decreased the yield of desired product,

Tropinone hydrochloride obtained for use in this investigation was quite impure as evidenced by its dark brown color. Methyl and ethyl alcohol are good crystallisation solvents for this hydrochloride with one reservation: there is a possibility of formation of the ketal of tropinone hydrochloride (XLII), All the essential ingredients are present: a ketone, an alcohol, and a catalyzing acid.

Cl®

Turr

This phenomenon has, in fact, been noted by Brookes and Walker (?l) who obtained the ketal of l-n-butyl-h-piperidone hydrochloride in good yield. The findings in the present investigation have shown that tropinone hydrochloride can be recrystallized unchanged from methanol if 52 the methanol!c solution is not heated. The melting point of recnystallized tropinone hydrochloride was 187°-188° (doc.) while that reported is 188°-189° (dec.) ( 70).

The stereochemistry of the heterocyclic ring of XXX is similar to that of 2,4'-(1'-methyl) piperidyl benzothiazoline. One added feature is evident in XXX, however. The sulfur and nitrogen atoms in this heterocycle are held more firmly in the equatorial and axial positions, respectively, due to increased interaction of these heterocyclic atoms with the methylene bridge of the tropane ring. This same phenomenon is also thought to bo operative in the hemithioketals derived from tropanone. From the stereochemical considerations given 2,4'-(l'-m ethyl) piperidyl benzothiazoline and XXX, the possibility exists that these factors can be generalized to the remaining benzothiazolines synthesized in this investigation, namely, that in the heterocyclic rings of these compounds, the sulfur atom exists in an equatorial position while nitrogen is axial.

Three individual chemical approaches were attempted for formation of 2,2-cycloalkyl benzothiazoline-1,1-dioxides. 53

o'" The proposed reaction (approach A) for the synthesis of these

1,1-dioxides is set forth in the equations below: (See experimental, p . 35) < s > . , ©

O lOH - CO c 1-^3

KJ So%. c 1 Ô G /JHC 0 C.H3

This proposal was lent credence by the work of Evans and Smiles ( 58 ) who used the following reaction sequence to obtain 2,2-dialkyl benaothiazo- line-1,1-dioxides.

^ S O jlCI I rOH-$z5

iclîTi

d l i i ' I 4- K ,0 lOH-0

Y laT ■50WT 54

Using sodiur.i-4-nitrodiphenylamine-2-sulfonate (XLIIl) as the starting material, the corresponding 2-sulfonyl chloride (XLIV) was obtained upon treatment with phosphorous pentachloride, Sodium-4-nitrodiphenylamine-

2-sulfinate (XLV) was obtained when 4-nitrodiphenylamine-2-suifonyl

chloride (XLIV) was shaken with an aqueous solution of sodium sulfite.

Addition of acid and subsequent treatment with ketone or aldehyde afforded the desired 6-nitro-2-alkyl benzothiazoline-1,1-dioxide (XLVI). Thus,

6-nitro-3~phenyl-benzothiazoline-1,1-dioxide was formed by the condensa­

tion of methylal (dimethoxy methane) with the requisite sulfinic acid.

2-methyl-6-nitro-3-phenylbehzothiazoline-l,1-dioxide was sim ilarily made from acetal (l,1-diethoxyethane) and the appropriate sulfinic acid. The

2,2-dimethyl-derivative was also made. No statement was made as to what ketone or acetal was used in this condensation. In all probability, acetone was used. One other benzothiazoline-1,1-dioxide has been reported in the literature (39). Sulfurylindoxyl (2,2-dihydrobenzo- thiazoline-1,1-dioxide) was formed using sulfazon (XLVII) as the starting

compound, daasz proposed the following mechanism for the formation of sulfurylindoxyl (XLIX).

- OH

S Oz, T C vm T O m

T lTT 55

He suggested that ammonia, upon addition to the enolic double bond of sulfazon, formed an amino carbinol (XLVIIl) which lo st ammonium formate in the presence of water and recyclised to form XLIX.

Re-examining the reaction sequence of Evans and Smiles (p. 53). it was concluded in this investigation that the nitro group meta- to the sulfonyl chloride group in 4-nitrodiphenylamine-2-sulfonyl chloride increased the stability of this molecule. This compound is stable due to the fact that the nitro group and the amino group interact meso- merically. This general phenomenon of a nitro group exerting a stabilizing effect on groups in the ortho and para position is well illustrated in the compound picramide (72), This compound, as the name implies, resembles an acid amide raore_ than it does an aromatic amine.

This was not the case in this investigation since decomposition of the suspected o-(acetylamino)-benzenesulfonyl chloride progressed quite rapidly upon exposure to air.

The reaction sequence for approach B is represented by the following equations;

S-CW 3

M Hi"X

S02.CM3

MHC0 CH3

L 56

This reaction scheme provided isolable intermediates that could be easily characterized. The final step, however, caused much difficulty and no identifiable product was isolated from the reaction mixture. A tarry mass formed, possibly a polymerization product of the ketone, when 2-(aminophenyl) methyl sulfone hydrochloride (L) was heated with

cyclohexanone and phosphorous oxychloride.

Evidence exists in the literature concerning the transformation of the hydrochloride of 2-(aminophenyl) methyl sulfone and a carbonyl function into a 2-alkyl- or 2-aryl- benzothiazole-1,1-dioxide (64).

Thus, benzothiazole-1,1-dioxido was formed when 2-(aminophenyl) methyl

sulfone hydrochloride, formic acid, and phosphorous oxychloride were heated together at 130°.

Benzothiazole-1,1-dioxide

The compounds 2-methyl-, and 2-phenylbenzothiazole-l,1-dioxide were also made by cydization of a ce tylaminophenyl methyl sulfone and benzoylamino phenyl methyl sulfone, respectively, in the presence of phosphorous

oxychloride. It would seem reasonable by analogy that formation of 2,2-cydoalkylene benzothiazoline-1,1-dioxides could be effected by this method. 0 57 The reaction conditions, however, were too rigorous even when carried out at room temperature. The desired final product was not realized but various points of chemical interest were noted during this investigation and these, had been discussed in the preceding experimental portion of this thesis.

A report in the literature stated that 2,2-pentamethylene benzothiazoline could be benzoylated at the three position using the

Schotten-Bauman reaction (53).

+•

These workers reported 114° as the melting point for their

2,2-pentamethylene-3-benzoyl benzothiazoline. This seems rather anomolous since the melting point of the parent benzothiazoline obtained in this investigation was observed to be Il4.5°-U 5°. Furthermore, several ■ attempts to obtain the 3-benzoyl derivative by means of the Schotten-

Bauman reaction afforded only starting material for this investigator.

The work of Senkus (66) on the interaction of oxazolidines with

Grignard reagents provided the analogous chemistry for the attempted reaction of benzothiazolines vrLth a Grignard reagent. His results are summarized in the reaction sequence shown on the following page. 58 R-' \ -C {O — c — (^ - c + mq y. l It' 3 -C — C - (L 1 1 %.'

- C - (0 — — f2w K tl.O < - 1 R, - C — O K \

- The carbanion portion (R") of the Grignard reagent probably attacks

olactrophilic carbon 2 of the oxazolidine ring causing a heterolytic

fission of the carbon to oxygen bond. Simultaneously, the electrophilic

inorganic portion (MgX) of the Grignard reagent attacks the electron

rich oxygen atom forming the Grignard addition product. Subsequent

hydrolysis of this addition product with water leads to the substituted

amino alcohol. Bjr analogy, this same generalized and simplified reaction

mechanism could be applied to the reaction of a 2,2-cycloalkylene

benzothiazoline and a Grignard reagent. The reaction mechanism, using 2,2-pentamethylene benzothizaoline, might proceed according to the

following series of reactions:

4- W H 59 The re a c tio n did n o t proceed even a f te r se v e ra l attem p ts to make it do so. This heterocyclic system evidently is quite stable, for no bond cleavage was observed to take place.

The heterocyclic secondary nitrogen group present in all of the benzothiazolines prepared in this investigation is an extremely weak base. These bases, when dissolved in concentrated mineral acids, were immediately precipitated as the free base when water was added. SÜÎ-2-1AJIY AND CONCLUSIONS

1. A series of eight related 2,2-cycloalkyl benzothiazolines were synthesized and various reaction conditions studied in an effort to obtain maxiraura yields of these compounds.

2. An attempt to characterize 2,4-'(1-methyl) piperidyl benzothiazoline by formation of its hydrochloride and methiodide salts failed because these salts are extremely hygroscopic. A picrate salt of this compound was conveniently prepared.

3* The hydrochloride, methiodide, and picrate salts of

4-' ,3'-benzo-8-methyl-spiro ( 8-aza-bicyclo-[3.2.1 ]-octane-3,2'-1 ' ,3'.r azathiolane) were prepared in an effort to characterize this compound.

The hydrochloride salt of 4 ',5*-benzo-8-methyl-spiro ( 8-aza-bicyclo- [3.2.1]-octane-3,2'-l',3'-azathiolane) was sparingly soluble in water.

4". Infrared spectra were taken and an infrared functional group an analysis carried out on all of the benzothiazolines and their derivatives prepared in this investigation.

5. Three different chemical approaches were attempted in an effort to obtain a 2,2-cycloalkyl benzothiazoline-1,1-dioxide. The first method proved impractical when it was determined that o-(acetyl- amino) benzenesulfonyl chloride was unstable and could not be isolated pure from the reaction mixture. Method 2 afforded a series of isolable aminophenyl methyl sulfides and sulfones which were completely characterized by infrared analysis, elemental analysis, and other

60 61 physical data. The attempted reaction of 2-(aminophenyl) methyl sulfone

hydrochloride with cyclohexanone in the presence of phosphorous

oxychloride in the l a s t step of the re a c tio n sequence was doomed to

failure probably due to the rapid decomposition of cyclohexanone. The

third method consisted of an attempted oxidation of 2,2-pentamethylene

b en zo th iazo lin e and i t s 3-a c e ty l analog. The foi-mor compound ra p id ly

decomposed in the presence of such oxidizing agents as hydrogen peroxide,

potassium permanganate, and chromic oxide. Decomposition of the 3-acetyl

derivative was not noted iflth these oxidizing agents and it was apparent

that the heterocyclic sulfur atom present in these benzothiazolines is

completely resistant to oxidation.

6, The attempted reaction of 2,2-pentamethylene benzothiazoline

with methyl magnesium iodide afforded only starting m aterial. This

fact further illustrates the stability of these compounds.

7. The heterocyclic secondary nitrogen atom present in all of

the benzothiazolines prepared in this investigation is an extremely weak

base. These bases, when dissolved in concentrated mineral acids, were

immediately precipitated as the free base when water was added. I I . A PRELIMINARY INVESTIGATION OF SOIIE SYNTHETIC ROUTES

LEADING TO THE FORMATION OF PHENOLIC ARYLPROPANOLAKIIŒS

62 INTRODUCTION AND SIATEIŒNT OF PROBLEM

The class of medicinal compounds known as the sympathomimetic amines has long been recognised as being extremely important in the field of medicine. The general pharmacology of these agents has been extensively investigated (1-34). Detailed discussions of these compounds

complete with references, are also found in several texts (35-40) and review articles (51-53)* In recent years, it has been found that

sympathomimetic aminos produce their characteristic pharmacological

actions either directly, indirectly, or as a combination of both of

these (41-49). Direct and indirect actions refer to the actions of

these drugs on various parameters (heart rate, blood pressure, nictitating membrane, tachyphylactic tendencies) of certain animals

(anesthetized dog, spinal cat) which have been treated vd-th any one of a variety of andrenergic blocking agents (reserpine, cocaine, guanethidine).

Sympathomimetic amines which exhibited a direct action on this membrane were,epinephrine, norphenylepherine, and m-hydroxyphenylpropanolamine.

Indirect acting agents of this class included tyramine, mephentermine, and dextroamphetamine. Sympathomimetic amines showing both direct and

indirect actions were ephedrine, p-hydroxyephedrine, and m-tyramine

(3-hydroxyphenylethylamine). The indirect action was thought to be due

to liberation of norepinephrine (50), All of the compounds tested were

isomeric mixtures.

Patil (48) studied the effects of the four isomers of ephedrine on the heart rate, pressor effect, and tachyphylactic tendencies of the

63 64

anesthetized dog. Ke found that, for all isomers, the heart rate effects

were essentially equal at equipressor doses. However, relative pressor

potencies of the various isomers were different. Tachyphylactic

tendencies were likewise different for each of the four isomers. It was

found that D (-) pseudoephedrine had little pressor effect on the dog

but the pressor effects of the other isomers of ephedrine were blocked

by this isomer. Similar effects were exhibited by this isomer on the

rabbit aortic strip and the cat nictitating membrane. The suggestion

. was put forvrard that these effects were due mainly to competition at

direct receptor sites. D (-) ephedrine pressor effects were reversibly

blocked in reserpine pre-treated animals while those of L (+) ephedrine

and L (+) pseudoephedrine were irreversibly blocked. From these

observations it was concluded that the pressor effects of L (+) ephedrine

and L (+) pseudoephedrine consisted of an indirect action while that of

D (-) ephedrine was both direct and indirect. Finally, Dr. Patil

suggested that the D configuration of these isomers favored a predominant

direct receptor effect while the L configuration favored a predominant

indirect receptor effect.-

It was the purpose of this investigation to study various

synthetic routes leading to the production of hydroxyphenylpropanolaraines

which, on subsequent resolution into their various isomers, could be

tested pharmacologically in an attempt to determine what differences

hydroxylation of the phenyl ring has concerning direct and indirect

actions of these isomers. HISTORICAL REVIEW

Phenvloromnolflmne ( PPA )

This compound was f i r s t prepared in a s e r ie s o f is o la te d re a c tio n s reported by various authors. Propiophenone (5^-58) was used as the starting material in the majority of cases. Thus, treating propiophenone with bromine afforded cZ-bromopropiophenone (59,60),. which was treated with ammonia to yield a small amount of oZ, -aminopropiophenone. This aminoketone was reduced using sodium araalgum and a 25 ^ solution of hydrochloric acid thus producing phenylpropanolamine hydrochloride

(61,62).

Collet (63) prepared the c/--bromoketone in one step by condensing

«xL-bromopropionyl bromide with benzene in the presence of aluminum bromide (Reaction 1).

O + CH3C.U-c-GV-

c - C H - C HJ I I ' O GV R eaction 1

The yield of c/--bromopropiophenone was low. Subsequent treatment ifith ammonia and reduction of the resulting amino ketone afforded a small yield of phenylpropanolamine.

. The oZ, -oximino derivative of propiophenone (64-66) provided a key intermediate which, on reduction, afforded a good yield of

65 66 phenylpropanolamine. Thus, reduction of -oximinopropiophenone with stannous chloride and hydrochloric acid resulted in the formation of phenylpropanolamine (Reaction 2 ).

[H]

C — C - CH3 CW - CM - C 1A3 n u I O Hj,

R eaction 2

PPA was obtained in a low yield however, when the 06, -oximino ketone was reduced using a solution of 1^ palladium chloride, 2^ gum arabic and hydrogen. Hartung ( 66, 67) prepared PPA in almost quantita­ tive yield by hydrogenating an acidified ethanolic solution of the

06-oximino ketone using a palladium on carbon catalyst. If hydrogen chloride was deleted from the ethanolic solution, a mixture of primary and secondary amines was obtained and the reduction proceeded at an extremely slow rate. The primary amine was identified as PPA but the secondary amine was not characterized.

The reaction products of the neutral reduction of o^-oximino- acetophenone have been identified however ( 6 8). Reducing this oximino ketone with two equivalents of hydrogen resulted in the formation of benzylaraine wMch spontaneously condensed to yield diphenyldihydropyra- zine. Subsequent exposure to the atmosphere afforded diphenylpyrazine.

This is illustrated in the following reaction sequence. 67

H;

c

Diphenyldihydropyrazine

M

Diphenylpyrazine

It could be argued that the neutral reduction product (secondary amine) of oZ-oximinopropiophenone might proceed by a mechanism sim ilar to that of the reduction of oZ-oximinoacetophenone.,

w c C. " CA-. ÇM3 c ^ M ■c Co] 1 11 Jj c.

C.I43 The neutral reduction of oZ-oximinopropiophenone produced appreciable amounts of 1-phenyl-2-oximino-l-propanol. It was apparent from this fact that the ketonic function was more rapidly or selectively reduced than the oximino group. This was not the case with the neutral .reduction 68 of cZ-oximinoacetophenone in which the oximino group was more labile to reduction. Preferential reduction of the oximino group was also noted

1-n.th 6-oximinohexanophenone.

An interesting synthetic scheme devised by Kagai for the preparation of PPA utilized benzaldehyde and nitroethano as starting materials (6 9). On condensing these two compounds in the presence of base, 1-phenyl-2-nitro-l-propanol was obtained. Subsequent reduction of this nitro alcohol with zinc dust and acetic acid afforded PPA.

% I

<2.M -CM —C.H3 C,H -CK-CK3 C h o iv iO j. O H n JM j,

Hartung et a l. (?0) prepared a series of arylpropanolaraines substituted in the meta and para positions, and/^ -naphthylpropanol- araine were also prepared. The general reaction sequence leading to these arylpropanolamines is outlined below.

A r- 'i-CHx-CU- A v - C-C- A r - c r t - c H OH IsJ H3^ Cl'O

X XC nr. XT XT x j r Cl 6 CH3

A v =

u r A y =

A series of German and British patents were concerned with the formation of optically-active phenylpropanolamines. Bockmuhl and Gorr 6 9

(73) prepared L-phenylpropanolamine and its L~aminomethyl analog by resolving the corresponding racemic amino ketones with the aid of optically active acids and subsequently reducing the optical isomers obtained by catalytic hydrogenation.

The effect of the catalyst on the production of optically active phenylpropanolamines was the subject of a British patent (7^), The

preparation of a series of L-l-phenyl-2-amino-l-propanols was accomplished in two ways; (l) hydrogenating L-l-phenyl-2-keto-l-propanol ifith

(a) a palladium or platinum c a ta ly s t in th e presence of ammonia or a

primary or secondary amine or (b) an iron, cobalt, nickel, or copper

catalyst in the presence of an ammonium salt or a salt of a primary or

secondary amine. (2) Conversion of L-1-phenyl-2-keto-l-propanol into

its oxime with hydroxylamine (NHgOH) and subsequent reduction to

L-l-phenyl“2-amino-l-propanol.

Two other patents (75,76) were similarly concerned with the

production of analogs of L-1-phenyl-a-amino-1-propanol.

1 -(’o-Hvdroxvnhenvl )-2-am5.no-l-propanol

Bockmuhl et a l. (71) prepared the methylamino derivative of

l-(o-hydroxyphenyl)-2-amino-1-propanol by first treating a methylene

chloride solution of o-benayloxypropiophenone with bromine. This

procedure afforded the oL -broraoketone which was then mixed vjith methyl-

benzyl amine and allowed to stand at room temperature for several hours.

The resulting o-benayloxymethylbenaylaminopropiophenone was hydrogenated

in an ethanolic solution of hydrogen chloride using palladium on carbon

as the catalyst. The resulting 1-(o-hydroxyphenyl)-2-methylamino-1-

propanol which was formed melted at 176°, The reaction sequence is

illustrated below. 70

C — CI42.“ Ûl4-a C — Crt - ctA, u Il ' -) o o BV

r n ------> . r ll k j j C - CM — C.H3 ctM — cH — CM3 ÔH MH-' CH3 CM) l-(p-Hvdroxvphenvl)-2-amno-l-r)roaanol

Hartung and co-workers (?2) are credited xjith the first commercial

synthesis of the para hydroxy derivative of PPA, Forming the -oximino derivative of para-hydroxypropiophenone and reducing this oxime afforded a fair yield of l-(p-hydroxyphenyl)-2-amino-l-propanol. The detailed procedure is contained in a patent (77).

l-(p-Methoxyphenyl)-2-amino-l-propanol has been synthesized using anethol (p-propenylphenyl methyl ether) as the starting product ( 78) .

Addition of bromine to anethol led to the formation of anethol dibromido.

The dibromide was shaken with aqueous acetone to produce anethole

bromohydrin (79). Treatment of the bromohydrin with concentrated

ammonia solution afforded the desired aminopropanol which was character­ iz ed as i t s hydrochloride s a l t . A summary of t h i s s y n th e tic scheme i s presented below,

0C H 3 OCH3 0 C H 3 1. HiO

i. fJH)

CM - CM ç a — CW- CH) ÇH- ÇH- ^‘■‘3 SV* 71

Corrigan et a l. (80) prepared 1-(p-hydroxyphenyl)-2-1sopropylamino-

1-propanol by a series of reactions very similar to those of Hartung

(73). Corrigan and co-workers, in another publication (61), synthesized a series of 1-(p-hydroxyphenyl)-2-aminoethanols. The chemistry utilized in this undertaking can quite readily be applied to that of the

1-(p-hydroxyphenyl)-2-amino-1-propanols. Treatment of ^ -bromo-p- benzoyloxyacetophenone with aqueous methyl amine afforded a $0^ yield of

^-methylamino-p-benzoyloxyacetophenone. No amino derivative was formed if ammonia was used, even under a variety of conditions (82), Reduction of the aminoketone using a palladium catalyst afforded 1-(p-benzoyloxy- phonyl)-2-methylamino-1-ethanol. The formation of l-(p-hydroxyphenyl)-

2-amino-l-ethanol was effected by treatment of b) -bromo-p-benzoyloxy- acetophenone with an acetone solution of sodium iodide. Subsequent addition of hexamethylene tetramine (HMTA) and hydrochloric acid afforded

^-amino-p-benzoyloxyacetophenone hydrochloride. Cleavage of the benzoyl groiç) followed by reduction of the ketonic function yielded

1-(p-hydroxyphenyl)-2-amino-1-e thanol hydro chloride. This series of reactions is presented below. o O - c ■4> o - c,- ■4 y I

C -C rtt-B V * C -C H iI t( o o

CH CJ® OH 72 l-(m-Hvdroxyphenyl)-2-amino-l-propanol

Very few references exist in the literature concerning the

formation of this amino alcohol or its derivatives. Bockmuhl et al. (71) was the first to develop a commercial synthesis for this type of

compound. Forming the -oximino derivative of m-hydroxypropiophenone,

the production of l-(m-hydroxyphenyl)-2-amino-l-propanol was accomplished

by reduction of the oximino ketone using a palladium on carbon catalyst.

Hartung and co-workers also prepared this compound from the corresponding

o^-oximino-m-hydroxyphenylpropiophenone (72,77). Corrigan (80)

synthesized l-(m-hydroxyphenyl)-2-isopropylamino-l-propanol by treating

o<(.-bromo-l-(m-hydroxyphenyl) propan-l-one with isopropyl amine and

subsequently reducing the amino ketone. A British patent provided the

basis for a study concerning the resolution of the optical isomers of

l-(m-hydroxyphepyl)-2-amino-1-propanol and its methylamino analog into

their L- isomers.by the use of D-taratrie acid.

l-(3'.^* -Dihvdroxvnhenvl )-2-amino-1-nr onanol

The majority of the chemical literature concerned with hydroxyl

analogs of phenylpropanolamine is dedicated to the 3,4-dihydroxy-

d e riv a tiv e . This i s probably to be expected sin ce t h i s type of compound

bears such a close resemblance to epinephrine and is therefore quite

important from a medicinal standpoint. The chemical literature on this

subject has been generally reviewed by Anoro (91) up to the year 1933.

One of the earliest syntheses of l-(3 ' ,4'-dihydroxyphenyl)-2-amino-

1-propanol is described in the patent literature (8^,85). Veratrol

(1,2-dimethoxybenzene) and phthalylalanyl chloride were condensed in the 73 presence of aluminum chloride to form 3 ',4 '-dimetho%y- 2-phthalimido- propiophenone. Refluxing this product with concentrated hydrochloric acid solution afforded 3 ',4'-dihydroxy- 2-aminopropiophen-l-one.

Hydrogenating this amino ketone using colloidal platinum yielded l-(3 ',4 '-dihydroxyphenyl)-2-amino-l-propanol. The reaction sequence is presented below.

oCWj 0 C.B3 ch-2 - CK - c - a aca- o s c c —o

oH OH1

L u ------■ <------

CH - (Lrtj OK

Prior to this time, Dzierzgowski ( 86) prepared intermediates by

the Fried 1 “Crafts acylation reaction which are used to the present day

for the production of 1 -( 3 ',^'-dihydroxyphenyl)- 2-am ino- 1 -propanols.

Condensing 0 6-chloropropionic acid with catechol (1,2-dihydroxybenzene)

in the presence of phosphorous oxychloride, a substance was obtained which was identified as 3'-dihydroxy-2-chloropropiophenone. Similarly,

the formation of 3 ',4'-dihydroxy- 2-bromopropiophenone was effected by

the condensation of catechol and c/.-bromopropionic acid in the presence

of zinc chloride or ferric chloride. OH oU

+ CH3-CH-C00H I X. c — C. H — C Hj> u I SV7 Cl o . 74 O tt ( 87) prepared intermediates similar to those of Dzierzgowski.

Using catechol, o^-chloropropionyl chloride, and phosphorous trichloride, he succeeded in forming 3',4'-dihydroxy-&J-chloropropiophenone. By the use of catechol esters, Rosenmund and Lohfert (88) were successful in producing 3 '»4'-dihydroxypropiophenone intermediates which are essential for the formation of dihydroxyphenylpropanolamines. The dihydroxy- propiophenone intermediates in question were made by a Fries rearrange­ ment using aluminum chloride. o coR-

Co (2. A id .

If a molar excess of catechol was added to the reaction mixture, the yield of propiophenone derivative was found to be doubled. OH OH OH ort Ale > 2 ocoR- c - o

Rearrangement of the diacetate and dipropionate esters of catechol with aluminum chloride furnished an 80^ yield of 4-acetylcatechol and a 39^ yield of 4-propionylcatechol. A 2?^ yield of 4-butyrocatechol was similarly obtained from the dibutyrate ester. The acetyl derivative has previously been described (86,100),

Buu-Hoi and Seailles (95) reported the preparation of 4-propionyl- catechol in 95^-98/^ yield by the condensation of propionic acid and catechol in the presence of gaseous boron trifluoride. 75

OH ,OH + CHj CHlOoo H

o This procedure could not be duplicated in the present investigation, however, no matter how the conditions were varied» On the other hand, the condensation of acetic anhydride with catechol in the presence of boron trifluoride has been shoim to proceed ( 9 6). The preparation of l-(3 ' ,^’~dihydroxyphenyl)-2-amino-l-propanol has also been accomplished by Hartung et a l. (72) who obtained it by the. '

catalytic reduction of l-(3 ',4 ' -dihydroxyphenyl)-2-oximinopropan-l-one.

Bockmuhl and Gorr (73) prepared the L- isomer-of l-(3 ',4 '-dihydroxyphenyl)-2-amino-1-propanol by resolving the correspond­ ing aminoketone with the aid of an optically active acid and then

catalytically reducing the pure ketone isomer.

A commercial synthesis of the ethylamino analog of l-(3*,4‘- dihydroxyphenyl)-2-amino-l-propanol (8 9) has been effected by f i r s t brominating 3 ',4 '-dibenzyloxypropiophenone and subsequently treating the brominated ketone with an alcoholic ethylamine solution of 15^

strength. The aminoketone was then catalytically hydrogenated. The

catalytic reduction served a tiro-fold purpose at this point in the

synthesis: (l) cleavage of the benzyl ester was attained and (2) the ketonic function was reduced to a secondary alcohol. The reaction

sequence is presented in the following equations. 76 0(L^T.(f) OCH l® OCrt,0

c - CW - CM] Ç - II > O lOW

OlA .OH 1 4- W ÛH3 CH OH uH- -

A synthesis similar to the preceding example has been realized by

Lespagnol and Cuingnet ($4). The use of secondary amines containing the benzyl group has led to increased yields of dihydroxyphenylpropanolamine analogs as well as providing a moans of easily handling these often volatile amines ( 8 9). Thus, adding benzyl-n-propyl amine to an alcoholic solution of 3',4'-dibenzyloxy-2-bromopropiophen-l-one and allo:d.ng the reaction to proceed for several hours, a good yield of 3‘|4'-dibenzyl- oxy-2-benzylpropylaminopropiophen-l-one was obtained. Catalytic hydro­ genation of the aminoketone in an ethanolic solution containing hydrogen chloride afforded good yields of l-(3 '-4 '-dihydroxyphenyl)-2-propyl- amino-1-propanol. The isopropylamino derivative of this compound has similarly been prepared (80). The benzyl group on the amine was effectively removed by hydrogenolysis to produce the secondary amino- alcohol. The use of alkylbenzyl amines has also been used successfully in the synthesis of dilqidroxyphenylalkylaminobutanols ( 90).

1 -(3 ',4 '-Dihydroxyphenyl)-2-dimethylamino-l-propanol has been synthesized by a rather long and tedious procedure (92). The reaction 77 sequence is outlined in the foUovring series of equations. Yields are given for certain intermediate compounds.

0 CH3 OCM3 OCH3

c It

OH

I - 0 C H 3

CH- — CH - CH3 C — CH — CH i C — C H -— C H3 ' ' . U ' . “ ' , N O H (OH - ( O luH-

The methylamino derivative of this aminoalcohol was prepared in a

similar manner (93). EXPERIMENTAL

Preparation of l-Cp-hvdroxvphorrvl)- 2-amino-l-propanol

1. Formation of phenvl propionate

Thionyi chloride (293 g., 2.46 moles) was added to a mixture of phenol (225 g., 2,4 moles) and propionic acid (1?8 g., 2.4 moles) and the resulting solution cautiously warmed until the evolution of hydrogen

chloride had practically ceased (1-2 hours). The crude phenyl propionate was distilled and the fraction boiling at 200°-210° was collected. The y ie ld was 283 g. or 79^.

2. Formation of p-hvdroxvpropioohenone

A suspension of 221 g. (1.66 moles) of anhydrous aluminum

chloride in 302 ml. of carbon disulfide was placed in a 2-liter, three­

necked round-bottomed flask fitted with a reflux condenser and a dropping

funnel. While the suspension was stirred, 221 g. (1.47 moles) of phenyl

propionate was slowly added. Reaction began immediately with evolution

of hydrogen chloride. When a ll of the phenyl propionate had been added,

the mixture was further heated at gentle reflux for 2 hours or until

evolution of hydrogen chloride ceased. The carbon disulfide was removed

distillation and the mixture remaining in the flask heated for three

hours at 140°-150°. During this time more hydrogen chloride gas evolved.

The mixture thickened and finally congealed to a reddish brown resinous

'mass. Stirring was continued as long as possible. If temperatures 79 above 150° were utilized for any length of time, the yield of p-hydroxypropiophenone was markedly decreased. The solid mass was allowed to cool and the aluminum chloride complex decomposed by slowly adding a mixture of 177 ml. of concentrated hydrochloric acid solution with 177 ml. of water. This was followed by an additional 295 ml. of water. A black oil slowly collected on the surface of the water. The entire flask was allowed to stand in a refrigerator overnight and the solid was then filtered by suction. The yield of crude p-hydroxypropio- phenone was 98 g. or 44.3^, One recrystallization from absolute methanol produced light yellow crystals melting at 146°-147°.

3. Formation' of p~benzvloxvnropir>henone A slightly modified procedure of Suter and Ruddy (90) was used to prepare this compound. To an ethanolic solution of 30 g. (0.20 mole) of p-hydroxypropiophenone contained in a 500 ml. 2-necked, round-bottomed flask was added 28,5 g. (0.224 mole) of benzyl chloride. The ingredients were mixed thoroughly and 18 g. (0.13 mole) of potassium carbonate, along with 1 g. ( 0.007 mole) of sodium iodide, was added to this solu­ tion. The flask was fitted with a reflux condenser and a stirring apparatus and the solution maintained at reflux temperature for 6 hours.

The ethanol was removed under reduced pressure and the resulting mass of potassium carbonate and p-benzyloxypropiophenone washed with 2-50 ml. portions of ÿja sodium hydroxide solution, filtered, and washed id.th water until neutral to litmus. One recrystallization from absolute ethanol afforded 51.7 g. (93.5^) of p-benzyloxypropiophenone melting at 97°-98°. 80

4. Formation of =6 -bromo-p- benzvlQxypropionhenone

The procedure of Bockmuhl, Ehrhart, and Stein (97) was usgd for the preparation of this compound. These workers prepared 3'»4‘- dibenzyloxy--i-bromobutyrophenona but did not isolate it in crystalline form. They used it as the extract after the solvent had been removed.

To 22 g. ( 0,0916 mole) of p-benzyloxypropiophenone in 500 ml. of methylene chloride was added 11 g, (0.11 mole) of calcium carbonate.

Bromine (14,65 g,, 0,0916 mole) was added dropwise to this solution with good stirring. The solution was allowed to stand for an additional hour after all of the bromine had been added (I-II /2 h o u rs). The solvent was removed under reduced pressure and the resulting extract cooled to promote crystallization, A very low yield of the crystalline

catalytic amount (0,003 g ,) of benzoyl peroxide was finally added. The flask was fitted with a mechanical stirring apparatus and a reflux condenser and heated at 60°-70° until the reaction was complete. The reaction was found to be complete when all of the N-bromosuccinimide,

originally on the bottom of the flask, had been converted to succinimide which rose to the top of the carbon tetrachloride. The solution assumed

a li^ t yellow color at the termination of the reaction. The succinimide 81 was filtered off and the solvent removed under reduced pressure. The residue was placed in a refrigerator overnight. The crude product was recrystallized from absolute ethanol to yield 3.5 g. ( 30*7^ ) of -bromo-p-benzyloxypropiophenone. When ethanol was used as the solvent for this reaction, the yield of -bromoketone was appreciably increased. Isolation of the product differed somewhat from the preceding procedure. When the reaction was complete (2-3 hours), the ethanol was removed under reduced pressure.

The residue was shaken with 2-50 ml. portions of carbon tetrachloride

The -bromoketone was soluble in this solvent while succinimide was not.

The solvent was removed by placing the combined carbon tetrachloride extracts in a flash evaporator. The resulting precipitate was recrystallized from 70^ ethanol and a 75^ yield (8.5 g.) of pure p-benzyloxy-o^-bromopropiophenone was obtained.

5. Attempted formation of -amino-n- benzvloxvpropiophe.none

A solution of 5 g. (0.0208 mole) of -bromo-p-benzyloxypropio­ phenone in 20 ml. of absolute ether was placed in a 50 ml. gas washing tube. Ammonia was bubbled through this solution for one hour and the solution was then allowed to stand overnight. A slight precipitate formed which was not identified. Evaporation of the ether, afforded only starting material.

A second approach aimed at obtaining the oL -amino derivative of propiophenone was via reduction of O

Further reduction would then afford the desired amino alcohol. The 8 2 formation of the oL -oxlminoketone was attempted using p-benzyloxypropio­ phenone and methyl, butyl, n-amyl, and iso-butyl nitrite. Iso-butyl nitrite proved to be the best reagent for this purpose.

6. Preparation of Iso-butvl nitrite

The procedure for making n-amyl nitrite was used to prepare this compound (99). A $00 ml. three-necked flask was equipped with a mechanical stirrer, a thermometer, and a separatory funnel with stem extending to the bottom of the flask. A solution of ^7.5 g« of sodium nitrite in 188 ml. of water was placed in the flask and cooled to 0° by means of a Dry loe-acetone bath. A mixture of 70.8 ml. (57*25 g*) of iso-butyl alcohol, 17 ml. (31*25.g.) of concentrated sulfuric acid, and

12.5 ml. of water, previously cooled to 0°, was slowly added to the stirred solution in the flask by means of a separatory funnel. The rate of addition was such that the temperature of the reaction mixture was maintained at ± 1°. The mixture was then allowed to stand for two hours at room temperature. The resulting precipitate of sodium sulfate was filtered off and the yellow layer of iso-butyl nitrite decanted and washed with a 25 ml. aqueous solution containing 0.5 g. of sodium bicarbonate and 6 g, of sodium chloride. The nitrite compound was then dried with anhydrous magnesium sulfate. The yield of iso-butyl nitrite was 67 g. It was distilled prior to use.

7* Preparation of -oxitnino-n- benzvloxvpropiophenone

Para-benzyloxypropiophenone (10 g., 0.04-2 mole) was dissolved in

75 ml. of absolute alcohol and iso-butyl nitrite (7 g., O.O 68 mole) was added in 1 ml, increments. Anhydrous hydrogen chloride was slowly 83 bubbled through the solution and the reaction allowed to proceed for two hours. The reaction mixture was allowed to stand in a refrigerator for an additional four hours. The crude product was filtered off and recrystallized from absolute ethanol. The yield of pure p-benzyloxy-

-oximinopropiophenone, m.p. 13^°-135°, varied between 50 ^ -70^ .

When toluene or benzene were used as the solvents in the above procedure, the yields of «L -oximinoketone were lower (30^-^0^),

Hartung's procedure (??) was attempted for the preparation of c/-oximino-p-benzyloxypropiophenone iTithout any success. Thus, to 5 g.

(0.0208 mole) of p-benzyloxypropiophenone in 50 ml. of absolute ether was added 3.5 g. (0.0327 mole) of iso-butyl nitrite. The solution was slowly saturated with anhydrous hydrogen chloride and reaction allowed to proceed at room temperature for 2-3 hours. The mixture was then allowed to stand for an additional four hours. The other was evaporated and a quantitative yield of starting material was recovered. The same results were obtained when p-hydroxypropiophenone was used as the starting material.' .

8. Catalytic reduction of n-benzvloxv- o^-oximlnopropiophenone

rive and ten per cent palladium on carbon catalysts were prepared according to the method of Vogel (ill). Platinum oxide catalyst was obtained from the Fisher Scientific Company under the name of Platinum

Black.

One gram (0.003? mole) of p-benzyloxy-«/-oximino-propiophenone was dissolved in 40 ml. of absolute ethanol and the solution saturated with anhydrous hydrogen chloride. Fifty milligrams of palladium on 8 4 carbon catalyst was then added to this solution. The mixture was placed in a low pressure-shaker type hydrogenation apparatus (Series 3910» Parr

Instrument Company), Agitation of the solution containing the catalyst was continued until no more hydrogen was absorbed. This usually required 30-60 minutes. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was identified as p-hydroxy- o^-aminopropiophenone hydro chloride, m.p. 225°-226° with decomposition.

The literature value for this compound is 219° (?2). The aminoketone was then dissolved in 30 ml. of water, $0 mg. of fre sh c a ta ly s t added to the solution, and hydrogenation again allowed to proceed. Removal of the solvent under reduced pressure afforded l-(p-hydroxyphenyl)-2- amino-l-propanol, m.p. 210°, The melting point reported in the literature for this compound is 2’b6° (?2). The overall yield of amino alcohol was quantitative.

Reduction of the oxlminoketone was also accomplished in one step.

As it was formed, the aminoketone precipitated from the ethanolic solution. At this point, hydrogenation was stopped, 100 ml. of water added to the solution to dissolve the hydrochloride salt, 50 mg. of fresh catalyst added, and reduction allowed to proceed until no further hydrogen was taken up by the solution. The overall yield of l-(p-hydroxyphenyl-2-amino-l-propanol was in the range of 70^-80^ when p-hydroxy-propiophenone and isobutyl n itrite was taken as the s ta rtin g re a c tio n . H artung' s o v e ra ll y ie ld f o r th is compound was some­ what lower (55^“65/^)« 85 £a:.9paj:ajd.piLi2fJL=.C]a=h3droa^ 8r^PAH9rlr:BCSPanP3..

1. Formation of w-benzyloxypropiophenone Meta-hydroxypropiophenone (Aldrich Chemical Company) was

recrystallized from benzene until a constant melting point was reached

(78^-78. 5 °)• The value reported in the literature for this compound was 79°-82° ( 72).

Ten grams of m-hydroxypropiophenone (O.O? mole) was dissolved in

35 ral. of absolute ethanol and 9 g. of benzyl chloride added dropwise to

this solution. The ingredients were mixed thoroughly. Potassium

carbonate (6 g,, 0.044 mole) was then added followed by a solution of

1 g, ( 0.007 mole) of sodium iodide in 5 ml. of water. Reflux tempera­

ture was maintained for 5 hours. The solvent was removed under reduced

pressure and the resulting oil vacuum distilled. The fraction boiling

a t 1900- 196° (4 mm.) was collected. The oil crystallized completely

when allowed to stand in a refrigerator overnight. The yield of pure

m-benzyloxypropiophenone was 11 g. (65.5#) and i t melted at 31°-31.5°. The melting point reported in the literature was 30*^ (101 ).

2. Formation of c/--oximino-m- benzvloxvproniophenone-

Freshly distilled iso-butyl nitrite (4.8 g., 0.046 mole) was

dissolved in 5 ïoI. of absolute ether and added to an ethanolic solution

of 11 g, ( 0.0458 mole) of m-benzyloxypropiophenone over a period of

thirty minutes. During this time, anhydrous hydrogen chloride was slowly

bubbled through the solution. The solution was placed in a refrigerator

overnight but no precipitate formed. The solvent was then removed under

reduced pressure resulting in a light yellow oil. Ten ml, of water was 8 6 added to this oil and the mixture shaken vigorously for 2-3 minutes. A solid mass formed after thirty minutes. The precipitate was filtered off and the weight of crude c^-oximino-m-benzyloxypropiophenone was

13.5 g. or 83. 4 ^. Recrystallization from ethanol afforded pure oxlminoketone melting at 65 °. A great sacrifice in yield was necessary in order to obtain this compound in the pure state.

3 . Catalytic reduction of -oximlno-m- benzyloxvpropionhenone

The same procedure and reagents were used for this reduction as for that of -oximino-p-benzyloxypropiophenone, A two-step reduction afforded a good yield of 1-(m-hydroxyphenyl)-2-amino-l-propanol hydrochloride, melting point 180°-181°. The literature value was 182°

(72). The overall yield of 1-(m-hydroxyphenyl)-2-amino-l-propanol was in the range of 45?S-50^. Hartung reported yields in the vicinity of

45 ^-50 ^ a lso .

Preparation of l-(3*.4*-dihydroxyphenyl)- 2-amino-l-propanol

1, Formation, of 3 '.4 '-dihvdroxypropiophenone

To 11 g. ( 0.10 mole) of catechol in 50 ml. of dry chlorobenzene was added 19 ml. (0.15 mole) of propionyl chloride and the mixture heated at 50° for thirty minutes. It was then cooled to room temperature and 29.37 g. ( 0.22 mole) of anhydrous aluminum chloride added in small portions. The temperature of the mixture was gradually raised to 1 1 0 ° and held there for three hours. The mixture was then poured over crushed ice and hydrochloric acid to hydrolyze the aluminum chloride complex. Chlorobenzene was removed under reduced pressure. While the 87 mixture was s till warm, 10 ml. of concentrated hydrochloric acid and 50 ml, of toluene were added. After thorough cooling, the product was filtered off and washed well with water and toluene. Recrystallization from 80^ ethanol afforded a 20^ yield of 3 ' , -dihydroxypropiophenone melting at l45°-l46°. The reported malting point for this compound was 146° (88). Since yields were so low using the above procedure, it was decided to attempt various modifications of the above procedure for the purpose of obtaining higher yields of 3 ',4 '-dihydroxypropiophenone.

2. Attempted preparation of 3 '.4 '-dihvdroxv- propiophenona using boron trifluoride

Catechol (13.75 g., 0.125 mole) was suspended in 50 ml. of

carbon tetrachloride and 7.4 g. (0.10 mole) of propionic acid mixed thoroughly into the suspension. Boron trifluoride gas was slowly bubbled through this, suspension and the mixture heated to 60° - 70° fo r three hours. The catechol slowly went into solution and a red layer formed on the surface of the reaction mixture. The flow of boron trifluoride was discontinued and the mixture heated for an additional four hours. The mixture was then poured over 200 g. of crushed ice and the solvent removed under reduced pressure. Only starting material was obtained.

This reaction was also attempted using boron trifluoride etherate and boron trichloride. Both attempts were unsuccessful. 88

3. Attempjbgd.forwatlQn of 3'.4'- dibenavloxvproplo'PhenQne

Préparation' of 1.2-dibeTizvloxvbenzene (dj.benzvlcatechol). —This compotind has previously been prepared, but the yields were quite low

(102), The procedure outlined below afforded a quantitative yield of dibenzylcate chol. To 20 g. (0.182 mole) of catechol dissolved in 75 ml. of absolute alcohol was added 46.2 g. (0.3?0»mole) of benzyl chloride. The ingredi­ ents were well mixed. Fifteen grams (0.109 mole) of potassium carbonate and 1 g. (0.007 mole) of sodium iodide were then added. The mixture was allowed to reflux for four hours, and the solvent was then removed under reduced pressure. The residue was shaken vtLth 2-50 ml. portions of 2^ sodium hydroxide and then washed with water until free from alkali. The yield of dibenzylcatechol, melting point 6l°, was quantitative.

To a solution of 10 g. (0.0345 mole) of dibenzylcate chol in 50 ml. of carbon tetrachloride was added 2.2 g. (O.O 3O mole) of propionic acid. Boron trifluoride gas was slowly bubbled through this solution and the solution heated to 60°-70O for three hours. The flow of boron trifluoride was then stopped and the solution heated for an additional four hours. The complex was decomposed with water and carbon tetra­ chloride removed under reduced pressure. Starting material was the only product obtained,

Pigffwsslga The reaction sequence for the preparation of l-(p-hydroxyphenyl)-

2-amino-l-propanol is presented below. 8 9

OH

c “ c O : OH O ûH i. (b OC.Ht

Cl+ - CM - C,Hx \ % ow Phenyl propionate was obtained in good yield (79^) if care was taken in removing hydrogen chloride formed during the reaction. When temperatures above 70° were employed,, the yield of phenyl propionate was markedly reduced. This was due to the fact that thionyi chloride (b.p. 79°) was evolved in the form of copious white fumes which were easily mistaken for the evolution of hydrogen chloride. Temperatures not exceeding 50° were employed throughout the course of this reaction. Para-hydroxypropiophenone was prepared in yields ranging from

40^ to 505 S by the treatment of phenyl propionate with aluminum chloride. This range of yield is quite satisfactory considering the fact that o-hydroxypropiophenone is also formed in this reaction in yields of

35# to 45 #. Para-benzyloxypropiophenone was prepared in excellent yield in this investigation by using a modified procedure of Suter and Ruddy (90), Attempted preparation of this compound using potassium hydroxide in place of potassium carbonate decreased the yield of p-benzyloxy- propiophenone considerably.

The preparation of c/.-bromo-p-benzyloxypropiophenone, however, using bromine as the brominating agent, was found to be a low-yield 90

reaction (10.3#). Partial cleavage of the benzyl ether was also noted.

When N-br omo succinimide was used as the brominating agent, a 75# yield

of «/.-bromo-p-benzyloxypropiophenone was obtained and no cleavage of

benzyl ether occurred.

Formation of c/.-amino-p-benzyloxypropiophenone from the correspond­

ing bromoketone and ammonia failed to m aterialize. However, this c/--aminoketone could be prepared in good yield from the

and dibenzylamine. Catalytic hydrogenation of -dibenzylamino-p-

benzyloxypropiophenone with sufficient hydrogen afforded the desired

1-(p-hydroxyphenyl)-2-amino-l-propanol.

Formation of -oximino-p-benzyloxypropiophenone or oL -oximino-p-

hydroxypropiophenone by Hartung's method (72) proved unsuccessful in

this investigation. This observation has also been reported by S u te r

and Ruddy (90) concerning the formation of the -oximino derivatives of

3,4-dihydroxybutyrophenone and 3,4-dibenzyloxybutyrophenone. The

reaction mechanism for -oximination of a ketone is postulated to

proceed as follows; (103)

. s : R — CH — C — R + R — 0 — N — 0 — —A R — CH — C — R t + - \ H+ RO <— N - 0 - H

0 " 0 II II >R - CH - C - R > R - C - C - R V <------II N = 0 Nv OH + ROH

This reaction is catalyzed by both acids and bases. Hartung used ether

as the solvent for his oximination reactions. However, the ketone was - 9 1 not soluble in this solvent and the reaction was seen not to proceed.

It seems logical that solution of the ketone would have to be effected in order for the reaction sequence outlined above to proceed. This was accomplished by using ethanol as the solvent.

A 20/S yield of 3 ',4 '-dihydroxypropiophenone was obtained when a mixture of propionyl chloride and catechol was allowed to react in the presence of aluminum chloride. Attempts to increase the yield of this compound by bubbling boron trifluoride gas through a mixture of propionic acid and catechol proved futile in this investigation although

Buu-Hoi and Seailles (95) reported its synthesis in good yield. It has been shown that normal activating effects of groups such as -0R,-NR2, and -OH are nullified to a great extent by complex formation with aluminum chloride (104). Gerrard et a l. (105-110), in a series of pub­ lications concerning the chemistry of boron, reported a compound which formed when boron trichloride and catechol were reacted (o-phenylene chloroboronate), They suggested that the stability of o-pherylene chloroboronate may be due in part to ôTT'-electron resonance. This would explain why ring activation does not occur when boron trichloride and catechol are mixed together. This same phenomenon could also be extended to the use of boron trifluoride. . '

Friedl-Crafts acylation failed to occur when dibenzylcatechol, p ro p io n ic a c id and boron t r i f lu o r id e were mixed to g e th e r. The same forces would also be operative in this case.

o c > - “

o-Phenylene Chloroboronate Resonance Form SUMMARY AND CONCLUSIONS

1, A good overall yield of l-(p-hydroxyphenyl)-2-amino-l-propanol was achieved in this investigation.

a. -Bromo-p-benzyloxypropiophenone was prepared from

p-benzyloxypropiophenone in a 75^ yield by using N-bromosuccini­

mide as the brominating agent. This is a seven-fold increase in

y ie ld o f t h i s compound over the method which u tiliz e d bromide as

the brominating agent. b. Formation of -amino-p-bonzyloxypropiophenone by reaction

of anhydrous ammonia and

unsuccessful, c. Hartung’s method proved unsuitable for the preparation of

c/.-oximino-p-benzyloxypropiophenone. A good yield of this

compound was obtained by a method utilized in this investigation.

d. Catalytic reduction of oZ.-oximino-p-benzyloxypropiophenone

using a palladium on carbon and platinum oxide catalyst afforded

a quantitative yield of l-(p-hydroxyphenyl)-2-araino-l-propanol.

2, l-(m-Hydroxypheryl)-2-araino-l-propanol was prepared in good

yield following a reaction sequence similar to that used for the

preparation of 1-(p-hydroxyphenyl)-2-amino-l-propanol. 3, Low yields of 1 - ( 3 ^dihydroxyphenyl)-2-amino-1-propanol were

produced using a conventional Friedl-Crafts apylation reaction with

aluminum chloride. Attempted formation of this compound using catechol,

propionic acid, and catalysts such as boron trifluoride, boron trifluoride

etherate, and boron^triohloiide was unsuccessful. 92 BIBLIOGRAPHY

9 3 BIBLIOGRAPHY

P a rt I

1. Hutcheon, D. E,, Federation Proc,, %2, 71 (1953)*

2. GLasman, «J., Rauzzino, F., and Seiftor, J., J. Pharmacol. Exptl. Iherap., 122, 25A (1958).

3* Tedeschi, D, H., et a l. . Trifluoperazine, Philadelphia, Lea and Fehiger, 1958, p. 23-33.

4, Domino, E, F ., d in . Pharmacol. Ther., 1 (5), 599 (19^2).

5. Simon, S. W., Ann. Allergy, 1&, 1221 (I 96O),

6, Burton, D, A., Hurter, D., and Jones, C., Anaesthesia, 1 2 , 2?6 (1957 ). 7, Eckerling, B.. Goldman, J., and Cans, B., Obstet. and Gynecol., m , 331 (1959). 8. Combined Staff dinic, Am. J. Med., 2%, 7^7 (1959).

9 . Rudy, L. H., et al.. Am. J. Psychlat., ( 8 ), 7^7 ( I 958 ).

10. LeVann, L, J., Canad. Med. Assoc. J,, 80 (2), 123 (1959).

11. Dierks, M., Am. J. Psychiat., 119 ( 8), 775 (1963).

12. C ap p arell, H, V,, Pennsylvania Med. J . , 65. ( 8), 899 (1962),

13 . Fisher, 0., et_al.. Ber., 22, 2784 (1894).

14. Hepp, F., Ber., 2â. 297 (1895).

15 . Zincke, T., and Hebebrand, A,, Ann,, 226. 6l (1884),

16. Muohkalo, L., Ukr, Chem. J., 12, 193 (1956). Through Chemisches Zentralblatt, 4435 (1956).

1 7. Edelson, E., and Ha skin, A. H., Arch. Dermatol, and ^yphilol,, 6^., 244 (1952 ).

18. Grunberg, E., Soo-Hoo, G,, Htsworth, E., Ressetar, D., and Schintzer, R, J», Trans. M. Y. Acad. Sol., (2) 12, 22 (1950). 94 95 19. Ravits, H. G,, J, Am. Med. Assoo,, lU8, 1005 (1952).

20. R eiss, F ., T rans. N, Y. Acad. Soi., (2) H . 28 (1950).

21. S eale, E. E ,, Can. Med. Assoc. J . , 582 (1 9 5 1 ).

22. Stritzler, G., Fishman, I. M,, and Laureus, S., Trans. N. Y. Acad. Soi., (2) 12. 31 (1950).

23. Gonzalez Ochoa, A ., in T. H. S ternberg and V. D. Newcomer, e d s ., Therapy of Fungus Diseases. L ittle, Brown & Co., Boston, Mass., 1955 . p . 321.

24. Hofmann, A. Ber., 12, 2359 (1879).

25 . Lankelma, H, P., and Knavif, A. E., J. Amor. Chem. Soc., 51, 309, 2654 (1931).

26. Hofinann, A, W, Ber., 12, 8, 1223 (i860).

27. Hofmann, A. W., ibid.. 20, 1798 (1887).

28. Kehrmann, F., and Nossenko, 0., Ber., 2812 (1913).

29. Bogart, M. T., and Snell, F. D., J. Amor, Chem. Soc., Ü6., 1308 (1924).

30. Bogert, M. T., and Stnll, A., Ibjd.. 48, 248 (1926).

31. Bogert, M. T., and Snddth, L., ibid.. 4^, 1315, 3135 (192?).

32. H auser, H., H elv. Chim. A cta, H , I 98 (1928).

33. Kiprianov, A. I,, and Pazenko, Z, N., J. Gen. Chem., 12., 1515 (1949 ). Through Chemical Abstracts, 44, IO 97 (1950).

34 . de Sraet, P., and van Dormaol, A., Bull. soc. Chim. Beiges, 5 8 , 472 (1949 ). Through Chemical Abstracts, 42, 6O7 (1951).

35. Mills, W. H., and Whitworth, J. B., J. Chem. Soc., 1927.. 2738. 36. M ills, w, H., ib ii., 121, 455 (1922). / 37* Kipiranov, A. I., and Snaznaya-H-ina, E. D., Ukrain. Khim. Zhur., 21. 245 (1955 ). Birough Chemical Abstracts, 50, 9387 (1958).

38. Kiprianov, A, I., and Verbovskaya, T, M., J . Gen. Chem., 21., 531 (1961). Birough Chemical Abstracts, 51, 22322 (I 96I),

3 9 . Wheeler, H. L., Am, Chem. J . , 1 2 , 397 (1 8 9 5 ). 96

40. Bogert, M. T., and Corbitt, H,, J. Am. Chem. Soc., 48, 783 (1926).

41. daasz, M., Ber., 4£, U 4l (I916).

42. Lankelma, H. P ., J . Am. Chem. S o c., 52.t 2656 ( l9 3 l ) .

43 . Bogert, M. T., and Stull, A ..'ibid.. 3078 (1925 ) . '

44. Charles, R, G., and Freiser, H., J. Org. Chem., ^ 8, 422 (1953).

45 . Katz, L., J. Am. Chem. Soc., 21» 712 (1953).

46. Lankelma, H. P., and Sharnoff, P. X., J. Am. Chem. Soc., 379 (1932).

47 . McClenachan, E. G., Ph.D. Dissertation, University of Michigan, Ann A rbor, 1959.

48. Kreysa, F. J., J. Amor. Chem. Soc., 21. U55 (1951 ).

49 . Elderfield. R. C., and McClenachan, E. C., J. Am. Chem. Soc., 82, 1982 (1962).

50 . Reid, W., and Marx, ¥., Ber., £0 , 2683 (1957).

51 . Mushkalo, L,, and Bezeraskaya, V., Ukrain. Khim. Zhur., i8, 163 (1952 ). Through Chemical Abstracts, 48, I 3692 (1954).

52 . daasz, M., Ber., 41, 1031 (1912).

13. Kiprianov, A. I., and Portnyagina, V, A,, J, Gen. Chem., 25. 2217 (1955 ). 14. -ffieuber, H, J . , and W aider, H ,, Chem. B e r., g l, 2341 (1918).

11. Kreysa, F. J., et al.. J. Am. Chem. Soc., 21» 1111 (1951).

56 . Leaper, J., IMÈ.» 11» 1891 (l93l).

17. Elderf ield, R. C., and McCarthy, J. R., ibid.. 21» 975 (1951).

18, Evans, W. J., and Smiles, S., J. Chem. Soc,, 1263 (1935).

59 . d a a s z , M., B e r., 42., 616 ( I 916),

60. Vogel, A. I., Eracti-cal_Organic Chemistrv. Longmans, Green and Co., New York, 1956, p. 822.

61. Child, R., and Smiles, S., J. Chem. Soo., 1926 ( 2696).

62. Bare, C. N., and Smiles, S., J. Chem. Soo., 125. 2362 (1924).

63.. Stewart, J., J. Chem. Soc., 121, 21H (1922). 97

64. Zincke, T., and Siebert, G., Ber., M., 1242 (1915).

65 . Vogel, A, I,, Practical Organic Chemistry. Longmans, Green and Co., New York, 1956, p. 576.

66. Senkus, M,, J, Am. Chem. Soc., 1515 (19^5).

67. Djerassi, C.,'Shamma, M., and Kan, T., J, Am. Chem. Soc., 80. 4723 (1958).

68. Fieser, L,, Yuan, C., and Goto, T., ibid.. 82. I 996 ( I 96O).

69. Mertes, M., and Gisvold, 0., J, Pharra. Sol., ^0, 475 (I 96I).

70. Heilbron, I., Dictionary of Orpanic Compounds. Vol. IV, Oxford University Press, New York, 1953, p. 636.

71. Brooks, P., and Walker, J., J. Chem. Soo., 1957. 3173.

72. Royals, E, E., Advanced Orpranic Chemistry.. Prentice-Hall, Inc., Englewood C liffs, 195^, p. 447.

P a rt I I

1. Barger, G., and Dale, H., J. Physiol., 19 (I 9IO).

2. Beyer, K, H ., P hysiol. Rev., 26, I 69 (1946).

3. Lands, A., Pharmacol. Rev., 1, 249 (1949). 4. Lands, A., In the first symposium on chemical biological co-relation pp. 43 - 123. Publ. No. 296 of the Nat. Acad, Sc. N.R.C., Washington, D.C., (1951 ).

5 . Lands, A., Richards, E., Nash. V., and Hooper, K., J. Pharmacol. Exptl. Therap., 294 (1947).

6. Hjort, A,' Randall, !., and Debeer, E., ibid.. 22 , 283 (1948).

7. Harsh, D., m A - . 21. 338 (1948). 8. Marsh, D., ibid.. 2&, 225 (19^8).

9 . Marsh, D., ibid.. 9^, 426 (1948).

10. Lehmann, G., and R andall, L., ib id . . 9 3 . 114 (1948).

11. Graham, B ,, and Kuizenga, M., ib id . . 94. I 50 (1948).

12. Rusinow, I., and Atanasova-Shopava, S., Izvest. Inst. Eksptl. Med. Bulgar. Akad, Nauk., 1, 237 (I 96O): ib id . . 1, 257 (I 96O). Through Chemical Abstracts, 51» ^770 (I961), 9 8

13. Graham, B,, and Kuizenga, M,, J, Pharmacol. Exptl. Therap., Qk, 150 (1948).

14. Astrom, A,, Acta Pharmacol, et Toxicol., 4, 53 (1948).

1 5 . Becker, T., and Warren, M., J. Pharmacol. Exptl. Therap., 21, 289 (1942).

1 6. Walton, R., and Brodie, 0.. ibid.. 96. 343 (1949).

17. Chen, K., and Schmidt, C., ibid.. g4, 339 (1924).

18. Chen, K,, J, Pharmacol. Expor. Med., 22.» 237 (1928).

1 9 . Thienes, C. M., A rch. I n t . Pharmacodyn., 42.,. 453 (1934). .

20. Bum, J. H., J, Pharmacol. E ^tl. Therap., 46, 75 (1932).

21. Graham, J,, and Gurd, M., ibid.. 22., 48 (1941 ).

22. Hayman, C., A rch. I n t . Pharmacodyn., 21, 30? (1929).

23. Stoland, 0., and Ginsberg, A., J. Pharmacol. Exptl. Therap., 42.» 345 (1933). 24. Guddum, J., and Kwiatkowski, H., J., Physiol., g4, 87 (1938).

25 . Brun, G, C., Aata. Pharmacol, et Toxicol., 2., 225 (1947).

26. Pepu, G., Ma si, R., and Gotti, A., Arch. Int. Pharmacodyn, 119. 334 (1929). 27. Blaschko, H., J. Physiol., 21, 7 (1938).

28. Swanson, E., J, Pharmacol. Exptl. Therap., 21, 541 (1929).

29. Swanson, E., and Webster, R. K., ibjd. . 21, 327 (1930).

30. Anderson, R., and Chen, K,, J. Am. Pharm. Assoc., 22.» 290 (1939).

31. DeJo^, D., Acta. Physiol. Pharmacol. Neerl., 2.» 39 (1951).

32. Shimamoto, K., Uchizuim, S., and Kanauchi, 0., Japanese J. Pharm. Chem., 122. 460 (1954).

33. Avaiado, D., Wtiuck, A., and DeBeer, E,, J. Pharmacol. Exptl, Therap., 122, 406 (1958 ).

34 . L ig h t, B ., Whuck, A ., and DeBeer, E ,, Fed, P ro c ,, 12., 415 (1959).

35 . SoUmann, T,, A ^fanual of Pharmacology. W, B, Saunders Company, Philadelphia, 1957» p. 472, 99 36. Grollman, A,, Pharwacolotrv and Therapeutics. Lea and Febiger, Philadelphia, 1962, p. 2?9. 37. Krantz, J,, and Carr, C,, The Pharmacologie Principles of Medical Practice. The Williams and Wilkins Co., Baltimore, 1958, p. 736.

38. Beckman, H ., Pharmacology. W. B. Saunders Company, P h ilad elp h ia, 1 9 6 1 , p . 423. 39. Drill, V., editor. Pharmacology in Medicine. McGraw-Hill Book Co., I n c ., New York, 1958, p. 378.

40. Goodman, L., and Gilman, A. The Pharmacological Basis of Thera­ p e u tic s . The Macmillan Company, New York, I960, p. 476.

41. Fleckenstein, A., and Burn, J, H., Brit. J. Pharmacol., 8, 69 (1953).

42. Fleckenstein, A., and Stockle, D., Arch. exp. Path.'Pharmak., 224. 401 (1955). 43. Burn, J. H., and Rand, M. J., J. Physiol., 144, 314 (1958).

44. Fleming, W. W,, and Trendelenburg, U., J, Pharmacol. Exptl. Therap., 1 3 1 , 4 1 (1961).

45 . Trendelenburg, U., and Weiner, N ., J, Pharmacol. Exptl. Therap., 1 3 â , 152 (1962). 46. Trendelenburg, Ü., Muskus, A., Fleming, W. W., and Gomez Alonso De La Sierra, B., J. Pharmacol. Exptl. Therap., 138. 170 (1962).

47 . Trendelenburg, U., Muskus, A., Fleming, W. W., and Gomez Alonso De La Sierra, B., J. Pharmacol. Exptl. Therap.. 138. 181 ( 1962).

48. Patil, P. N ., Ph. D. Dissertation, Ohio State University (I 963).

49 . Trendelenburg, U., Pharmacol. Rev., 1 5 .t 225 (1963).

50 . Fleckenstein, A., Verh. dtsch. Ges. inn. Med., 17 (1953).

51 . Hartung, W., Chem. Revs., 2., 389 (1931).

52 . Lands, A ., Pharm. Revs, ( l ) 1949» 279.

53 . Lands, A., Richards, E., Nash, V., and Hooper, K., J. Pharmacol. Exptl. Therap., g g ., 297 (1947).

• 54. Thon^son, T., and Stevens, T. S., J. Chem. Soo., 1932. 2 6 1 1 .

5 5 . S h rin er, R.» and Turner, T ., J , Amor. Chem. Soo., 5 2 , I 267 (1930).

56 . Hanser, C., Humphlett, W., and Weiss, M., J. Amer. Chem. Soo., ZO, 426 (1948). 100

57< Strauss, F., and Berkow, A., Ann., 401. 140 (1913).

58. Auwers, K,, Ber., 4it 996 (1912).

59. Pampel, 0., and Sohmidt, G., Ber., 12.» 2897 (1886).

60. Schmidt, C., Ber., 22, 3251 (1889).

61. Calliess, F,, Arch. Pharm., 250. l4l (1912).

62. Eberhard, A., Arch. Pharm., 255. 140 (1917).

63. Collet, A., Chem. Zentr., II, 1898 , 203. '

64. Behr-Bregowski, L., Ber., 10, 1521,(1897).

65. Slater, W. K., J. Chem. Soc., U2. 587 (1920).

66. Hartung, W., and Munch, J., J* Amer, Chem. Soc., 51.» 2262 (1929).

67. Hartung, W,, U, S. Patent 1,989,093.

68. Hartung, W., J. Amer. Chem, Soc., 53.» 2248 (I93l).

69. Nagai, W. N., U. S. Patent 1,356,877..

70. Hartung, W., Munch’, J., and Crossley, F., J. Amer. Chem. Soc., 52» 1091 (1935 ). 71. Bockmiiil, M., Ehrhart, G., and Stein, L., U. S. Patent 1,877,756.

72. Hartung, W., Munch, J., Miller, E., and Crossley, F., J. Amer. Chem. S o c., 51» 4149 (1931).

73. Bockmnhl, M,, and G orr, G., German P a te n t 639,126. Through Chemical Abstracts, 31, 1555 (1937).

74 . I. G. Farbenindustrie A.-G., British Patent 365,535. Through Chemical Abstracts, 22» 1639 (1933).

75 . I. G. Farbenindustrie A.-G., British Patent 365,540. Through Chemical Abstracts, 22» l640 (1933).

76. I. G. Farbenindustrie A.-G., British Patent 365,541. Through Chemical Abstracts, 22» l640 (1933).

77. Hartung, W., Ü. S. Patent 1,995,709.

78. Road, J,, and Reid, W, G., J. Chem. Soc., 1928. 1487.

79. Hearing, P., Ber., 18, 3464 (I 905 ). 101

80. Corrigan, J*, Sullivan, M,, Bishop, H., and Ruddy, A., J, Amer. Chem. S o c., 21, 6258 (1953). 61. Corrigan, J., Langerman, M., and Moore, M., ibid. . 1894 (1945).

82. Tutin, F., Caton, F,, and Hann, A., J. Chem. Soc., 21» 2113 (1909).

83. I. G. Farbenindustrie A.-G., British Patent 396,951» Through Oiemical Abstracts 2â.» 482 (1934).

84. German Patent 216,640. Through Chem. Zentr. I 1910, p. 130.

85 . German P a te n t 254,438. Through Chem. Z en tr. I 1913, p . 351.

86. Dzierzgowski, S. K., J. Russ. Chem.Soc., Zl, 157 (1893). Through Chem. Zentr., II 1893, P« 475.

87. Ott, E., Ber., 51, 1068 (1926).

88. Rosenmund, K., and Lohfert, H., Ber., 61, 2601 (1928).

89. Bockmuhl, M,, Ehrhart, G., and Stein, L., U. S. Patent 2,151,459»

9 0 . Suter, C,, and Ruddy, A,, J. Amer. Chem. Soc., 64, 747 (1944).

91. Anoro, J., Rev. acad. scienc. Madrid, 21, 2l6 (1933). Through Chemical Abstracts, 28, 128 (1234),

92. Iwao, J,, and Samejima, M., J, Pharm. Soc. Japan, 24, 5 ^ (1954). Through Chemical Abstracts, 8174 (1955).

9 3 . French Patent 939,722. To Les Laboratories Dausse. Through Chemical Abstracts, 41, 5186 (1951).

94 . Lespagnol, A., and Cuingnet, E., Ann. pharm. franc., 3,8 , 445 ( 196O). Through Chemical Abstracts, 94. 24903 (I 960).

95 . Buu-Hoi, N., and Seailles, J., J. Org. Chem., 606 (1955).

9 6. Killelea, J., and Lindwall, H,, J. Amer. Chem. Soc., 2Q., 428 (1948).

97. Bockmuhl, M., Ehrhart, G., and Stein, L., U, S. Patent 2,083,001.

9 8. Rothstein, R., Schneck, G., Binovic, K,, and Stoven, 0., Rec. trav. chim., 21, 563 (1954 ).

99. Vogel, A, I., Practical QrganLa Chemistrv. Longmans, Green and Co., . New York, 1956, p. 306.

100, Perkin, A,, and Horsfall, L., J, Chem, Soc., 22, 1314 (I 9OO).

101, British Patent 711,905. Through Chemical Abstracts, 51, 1914 (1956). : 102

102. Schiff, H., and Pellizzari, G., Ann., ggl, 378 (1883).

103. Day, A. R., and Jovillie', M. M., Organic Chemistrv. D. Van Nostrand Company, I n c ., P rin ce to n , New Je rse y , I960, p . 435*

104. Royals, E, E., Advanced Organic Chemistry. Prentice-Hall, Inc., Englewood C liffs, 1954, p. 470.

105 . Gerrard, W., and Macklen, E., Chem. and Ind., 1549 (1959).

106. Gerrard, W.. Mincer, A., and V ^ill, P., J. appl. Chem. (London), 2, 89 (1959). 107. Gerrard, W., and Griffey, P., Chem. and Ind., 55 (1959).

108. Gerrard, W., and Macklen, E., J. appl. Chem. (London), 2.» 85 (1959).

109. Gerrard, W., Hudson, H., and Mooney, E., Chem. and Ind., 432 (1959).

110. Gerrard, W., Lappert, M., and Mountfield, B. A., J. Chem. Soo., 1529 (1959). . 111. Vogel, A. I., Practical Organic Chemistrv. Longmans, Green and Co., New York, 1956, p. 948. AUTOBIOGRAPHY

I, Anthony Arthur Sinkula, was born in Laona, Wisconsin,

January 2, 1938, I received ray secondary education in West DePere,

Wisconsin, graduating from St, Norbert High School in 1955* 1 obtained a Bachelor of Science degree in Pharmacy from the University of Wisconsin in 1959» a.nd a Master of Science degree in Pharmacy at The Ohio State

University in I 96I,

I was granted an assistantship at The Ohio State University for the academic year 1959-1960. At that time I was awarded a pre-doctoral fellowship by the National Institutes of Health (National Institute of

Mental Health), division of Health, Education, and Welfare, I held this fellowship until I received the degree Doctor of Philosophy.

I have accepted a position as research scientist in the

Pharmaceutical Research and Development section of The Upjohn Company.

103