Part I: Novel Reactions with Triphenylphosphine

Home , Silver bromide, Triphenylphosphine, Triphenylphosphine oxide

Part I, Novel reactions with triphenylphosphine dibromide ; Part II, Synthetic routes to substituted α-Dialkylaminomethyl-4-quinolinemethanols

Item Type text; Dissertation-Reproduction (electronic)

Authors Higgins, Jerry Gene, 1936-

Publisher The University of Arizona.

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Link to Item http://hdl.handle.net/10150/565128 PART I: NOVEL REACTIONS WITH

TRIPHENYLPHOSPHINE DIBROMIDE

PART II: SYNTHETIC ROUTES TO SUBSTITUTED

at -DIALKYLAMINOMETHYL-4-QUINOLINEMETHANOLS

Jerry Q tf' Higgins

A Dissertation Submitted to the Faculty of the

DEPARTMENT OF CHEMISTRY

In Partial Fulfillment of the Requirements For the Degree of

DOCTOR OF PHILOSOPHY

In the Graduate College

THE UNIVERSITY OF ARIZONA

1 9 6 6

/ THE UNIVERSITY OF ARIZONA

GRADUATE COLLEGE

I hereby recommend that this dissertation prepared under my

direction by \ J e r f ~ y G . ______

entitled f l i r t £ , hJo\I&i f £ 4 C f ,0 /J s 77-/ t/Uy/phd*?Vf. /7> \?f OMtO ParTIZ* SyA/rhehc toafe*> to ‘Pubzt, fa te d u e th /l- H -4 UtAJoi/AjiMethuto /$ be accepted as fulfilling the dissertation requirement of the degree of PL P.______

Dissertation Director

After inspection of the dissertation, the following members

of the Final Examination Committee concur in its approval and

recommend its acceptance:*

XAJc’XJUp'' X % )n/u f / s r / u

H / l 1/ f ^ L j l K .

*This approval and acceptance is contingent on the candidate's adequate performance and defense of this dissertation at the final oral examination. The inclusion of this sheet bound into the library copy of the dissertation is evidence of satisfactory performance at the final examination. STATEMENT BY AUTHOR

This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the Univer sity Library to be made available to borrowers under rules of the Library.

Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author.

SIGNED: ACKNOWLEDGMENTS

The author wishes to express his thanks to

Dr. John P, Schaefer for his contributions and advice during the course of this research.

ill To Cynthia Higgins, John Higgins., and Jim and Marie Owen

iv TABLE OF CONTENTS

Page

LIST OF ILLUSTRATIONS 0 0 0 0 0*0 © x

LIST OF TABLES oooooeooeooo xi

LIST OF SPECTRA. ooooooooooooooooooooeoooo xii

ABSTRACT.. oooooooooooooooooo o o o o o o o xv

PART I

INTRODUCTION... 2

RESULTS AND DISCUSSION...... 5

1. Preparation of trans_-l-Bromo-3-vinyl- oyolopontano 5

2. Reaction of Triphenylphosphine Dibromide with Phenols...... 16

3. Reaction of Triphenylphosphine Dibromide with Ketones...... 18

4. Reaction of Lithium Aluminum Hydride with the Triphenylphosphine. Dibromide-Alcohol Complex...... 20

EXPERIMENTAL...... e...... 21

1. General... OO 0 O ©OO ©OOOO ©OOOOOOOOOOO ©©OOO < 21

2 . Purification of Reagents and Solvents. 22

3. Oxidation of Norcamphor.0000000000900 o oo 22

4. N,N-Dimethyl cis-3-Hydroxycyclopentyl- acetamide.....e. 23

v vi

TABLE OP CONTENTS— Continued

Page

5. N,N-Dlmethyl-cls-3-hydroxyoyclopentyl- ethyleneamlne. OOOOOOOOOOOOOOOOOOOOOOO 23

6. cls-3-Vlnylcyclopentanol o, oooooooooooooo 24

7 o cls-(3-Vlnylcyclopentyl)-3, 5-dlnltro- benzoate,■OOOOOOOOOOOOOOOOOOOOOOOOOOOO 25

8. trans-1-Bromo-3-vlnylcyc1opentane 25

9. cls-3-Vlnylcyclopentyl Tosylate.. e o o o o o 26 10. Aoetolysis of els-3-Vlnylcyclopentyl Tosylate©...... ©..... 0 0-0 0 00000900 26

11. Solvolysis of trans-1-Bromo-3-vinylcyclopentane,>0000000000000000000000000 27 12. Solvolysis of trans-1-Bromo-3-vinylcyclopentane in 50-50 Ethanol-Water, 28

13. Solvolysis of trans-l-Bromo-3-vinylcyclopentane in Aqueous Silver Nitrate...... o.*.. 28

14. 2-Bromonaphthalene,•ooeoeoooooooooo 0 09900 29

15. 2-Bromotoluene...o.©...... 31

16. 3 —Bromopyndme...... o...... 32

17. Cmnamy 1 Bromide ...... o...... 33 18. 1—Bromonaphthalene...... o...... 34

19. 2 -Bromopy r id m e ....e...... ©...... 35 20. 8-Bromoqumoline ...... e...... 36 21. Toluene from Benzyl Alcohol...... 37 vii

TABLE OF CONTENTS--Continued

Page

22. n-Octane from n-Octanol...... 37

23. Reaction of 2-Methylcyclohexanol- Triphenylphosphine Dibromide Complex with Lithium Aluminum ■

Hydride 060000-000 00000 0 00 0 00-60000 38

24. 1-Bromocyclopentene...... 39

25. trans-Stilbene from Desoxybenzoin...... 40

26. Desoxybenzoin-dg...... 40

27. Reaction of Desoxybengoin-dg with Triphenylphosphine Dibromide...... 41.

PART II

INTRODUCTION...... a...... 44

1. History of the Cinchona Alkaloids...... 44

2. Important Cirichona Alkaloids...... 45

3. Suggested Biogenetic Relationships In the Cinchona Alkaloids...... 46'

4. Synthetic Sequences...... 49

5 . Syntheses of Substituted 4-Qulndllhe- methano1s...... 49

RESULTS AND DISCUSSION...... o 59

1. Synthetic Routos...... o...... 59

EXPERIMENTAL...... oo.. 72 viii

TABLE OF CONTENTS--Continued

Page

1 o Gr O Z IG 3? 3.- loooooooocoooooooooooooooooooooeoo 72

2„ 2-(2-Thienyl)cinchoninic Acid 00900000000 72

3» 2-(2-Thienyl)-4-quinolinecarbonol o o o o e o e 73

4„ 2-(2-Thienyl) -4-quinolinealdehyde. 74

5. 2-(2-Thienyl)-4-quinolinealdehyde

S 3 T I1 Z L O S - X 1 " b O Z O T l - O OO&OOOOOOOOOOOOOOOO&OO&OO 76

6 . 2-(2-Thienyl)-4-quinolinealdehyde Bisulfite Adduct 76

7. 2-(2-Thienyl)-4-quinolinecyanohydrin.... 77

8. 2-(2-Thienyl)cinchoninoyl Chloride 77

2-(2-Thienyl)-4-(N,N-dimethyl-l, 3-propylenediamine)quinoline-

carboxamide.... oooooooooooooooooooo 78

10 , 2-(2-Thienyl)-4-p-anisidinequinoline-

carboxamide,'OOOOOOOOOOOOOOOOOOOOOOOO OOO 78

11, 2-(2-Thienyl)cinchoninoylphenyl- Z'3- d.6 ooooooooooooooooooooooooo oooo 79 .

12 2-(2-Thienyl)cinchoninoyl-N,N-diethyl- 0 "tiny lono di&iniLnG ooooooo»ooooooooooooooo 79

13. Hydrolysis of 2-(2-Thienyl)-4-quino linecyanohydrin. . . 0090000000000000000 80

14. 2-Acetylthiophene.. ooooooooooooo 81

3. ^ o Et/lnyi Bromomalonate * 00000000000000060000 81

16. Diethyl N,N-Diethylaminomalonate...... 82

17. Ethyl N #N-Diethylaminoaeetate...... 83. lx

TABLE OF CONTENTS— Continued

Page

18. Ethyl 2-(2-Thienyl)cinchoninafce < o o o o o o o 83

19. 6-Chloro-2-(2-thienyl)cinchoninic Acid.LOOOOOOOOO oooooooooooooooeooooo 84

20 „ Methyl 6-Chloro-2-(2-fchienyl)cinchoni- I T l d r i v O OOOOOGOOOOOOOOOOOOOOOOOOOOOOOOOOO 85 21. Ethyl 6-ChlorO“2-(2-thienyl)cinchdni- 3 f X 3 i i s 6 OOOOOOOOOOQOOOOOOOOOOOOOOOOOOOOOO 85 22. 2-(2-Thienyl)cinchoninoyloctadecyl- d i l l i H 2 D . 0 OOOOOGOOOGOOOOOOOOOOOOOOOOO. OOOOO 86

23. Ethyl N- 2-(2-Thienyl)cinchoninoyl

Glycinate,■OOOO OOOGOOOOOOOOOOOOOOOOOOOO 86

24. Ethyl -£2-(2-Thienyl)cinchoninoyl]' -

N,N-diethyl Glycine,ooooooooogoooogo 87

25. Reduction of Ethyl -£2-(2-Thienyl) cinchoninoyl] -N,N-diethyl Glycine with Sodium Borohydride to Give the

!D 3. 01 OOOOOOOOOOOOOOOOOOOOOOOOQOOOOOOOO 88

26. Ethyl @V-(2-Thienyl)-6-chlorocinchoni- noy1-N,N-die thy1 Glycine...... 88

APPENDIX I. IR and NMR Spectra from Part I ooooooeo 90

APPENDIX II. IR and NMR Spectra from Part II o o o o o e o 100

LIST OP REPERENOES oooooooooooooooooooooooeoooooooooe 110

P I^eoooooeoooooooeoooooooooooooooooooooo 110

P Ctr’fc II o ©©©ooooooeooooooeoooeoooo 00000000 112 LIST OF ILLUSTRATIONS

PART I

Figure Page

Kinetic Plots of Cyclopentyl Bromide as Compared to trans-1-Bromd-3-vinyl-

cyclopentane, OQOOOOOOOOOOOOOO 14

PART II

Figure Page

lo Hypothetical Relations of the cinchona

Alkaloids Q 0 & O G 060000000 00000060000 48

2. Synthetic Routes to 4-Quinolinemethanols0„0„ 58

3- Attempted Synthetic Route to 4-Amino- ' " qu mo 1m e m e thano1seooeoeoooooooooooooooooo 60

4. Synthses of 4-Quinolinecarboxamides.„„„6 e „„ 62

. 5: IR Spectrum of ^ -Substituted~N,N-diethyl . Glycine Ethyl Ester...... 65 6. NMR Spectrum of -Substituted-N#N-diethyl Glycine Ethyl Ester...... o...... 66

7. NMR Spectrum of p^-Substituted-N*N-diethyl Glycme Ethyl Ester...... o...... 70 8. IR Spectrum of '=^-Substituted-N,N-diethyl Glycme Ethyl Ester.....e... 71

x LIST OF TABLES

PART II

Table

1 Anfcimalarial Compounds.„ LIST OF SPECTRA

PART I

Page

Baeyer-Vi11iger Oxidation Product of Norcamphor,„. ooooooooooooooooooooooooooooo 91 NfN-Dimethyl cis-3-Hydroxyeyelopentyl- acetamide,OOOOOOOOOOOOOOO OOOOOOOOOOO0OOOCOO 91 N ,N-Dime thy1-2-(3-cyclopentanolyl)-ethylene-

a m i n e ooooooo ooooooooeooooooooooooooooooooo 91 cis-3-Vinylcyelopentanol „ „„„„ 0 0 „ „ 92

trans-3-Vinyleyc1openty1 Bromide’ O 0O OOOOOOOO 92

3-Vinyl.cyclopentyl Acetate'O O O O o 0 0.0 O o O o o o o o o o 92 3-Vlnylcyclopentanol from Solvolysis with

AgNO^0000000000600000060000000060000000 93

3-Vinyleyclopentyl Nitrate Ester G OOOOOOOOOOO 93 3-Vinylcyclopentanol from Solvolysis with AgGlO^000060000000000000000000000000000000 93

8-Bromoquinoline

Page

N,N-Dimethyl els-3-Hydroxyeyelopentyl- acetamideooooooooooooooooooooooooooooooooo 95 N,N-Dimethyl-2-(3-0yclopentanolyl)-ethylene-

amine 000000000000 0 0 0 0 0 0 * 0 000000000000000000 95 xiii

LIST OF SPECTRA— Continued

NMR Page

3. cis-3-Vinylcyclopentanol„ 96

4. cis-3-VinyIcyclopenfcy1 Tosylate...... 96

5° 3-Vinylcyclopentyl Acetate...... 97

6c 8 “33x^oino cjiji IL ©o©oo©ooo©oqo©oooooooo

7. 1-Bromoeyelopentene...... 98

8. * U X * 3 .1 fX S *“"S 1 b o x i . 6 O00©0000000©00000000©0000©0000 98

9. Do s o xy I d o 3 fi z o i in (3. ^ qo©ooo©©©©o©q©p©o©©©©o©oo©oo 99

10. trans-Stilbene Containing Deuterium...... 99

PART II

IR Page

1. 2-(2-Thienyl)cinchoninic Acid...... 101

2. 2-(2-Thienyl)-4-quinoliriemethanol...... 101

3. 2-(2-Thienyl)-4-quinolinealdehyde...... 101

4. 2 - ( 2-Thienyl) -4-quinolinecyanohy'drin...... 102

5. 2-(2-Thienyl)-4-quln6liriemethandl Hydro- CinH-O I^ILCl© OOOO©OOO©POOO©O0OOOP© O©0©OOO©OOOOO - 102

6 . 2-(2-Thienyl)-4-quinolinemethanol...... 102

7. 2-(2-Thienyl)clnchoninoyl Chloride Hydro- chloride©o©©©©©©©©©©©©©©©©©©©©©©©©©©©©©©©© 103

8. 2-(2-Thienyl)-4-p-anisidinequinollhe- carboxamide ©©©©©©©©©©‘©©©©©©©©©©©©©©©o©©©©© 103 xiv

LIST OF SPECTRA— Continued

Page

9« 2 -(2 -Thienyl)cinchoninoylphenylhydrazide„,,„ 103

10. Ethyl N-2-(2-Thienyl)cinchoninoyl Glycinate. 104

11. 2-( 2-Thienyl )cinchoninoyl-N j.N-dle thy 1- etIiylene d-Lamme 104

12. 2-(2-Thienyl)cinchoninoyl-N-sulfanilamide... 104

13= 2-(2-Thienyl)cinchoninoyloctadecylamine=.„.. 105

14= 2-(2-Thienyl)-4-quinolinealdehyde Bisuirite A d d U Cte.ooooeoooeooooo.oooe.oeeoo.oeooooooe 105

15= Ethyl c^-^2-(2-Thienyl)-6-chlorocirichdrii-.. noyiJ^N,N-diethyl Glycine...... 105

16. Ethyl 2-(2-Thienyl)-6-chloroclnchoninate..== 106

17= 2-(2-Thienyl)-6-chlorocinchoninic Acid..»..= 106

18= Methyl 2-(2-Thienyl)-6-chloroclnchoninate=== 106

19= 2-(2-Thienyl)-4-quinolinealdehyde Serni-

cauhazone o@=o==0====o===@o0==oo======oo=o= 107

NMR Page

1 = 2-(2-Thienyl)-4-quinolinealdehyde. oooooooooo 108

2 = N-2-(2-Thienyl)cinchoninoyl-N,Nidlmethyl-

propylenediamine,’ O 0 O O O O G 00000 0 00 0 0 0 0 0 0 0 0 6 0 0 108

3 = 2-(2-Thienyl)cinchoninoyl-N,N-diethyl- O dlL3#in3-lflO Oooeooooooooooooooooeooooo© 109

4. Ethyl o X - £2-(2-Thienyl)-6-chlorocinchdni- " noyl]-N,N-diethyl Glycine,‘OOOOOOOOOOOOOOOOO 109 ABSTRACT

Part I

The preparation of trans-l-bromo-3-vinylcyclo-.

pentane from norcamphor in five steps is described,

Solvolyses of this compound proceeds without rate enhance ment or .rearrangement to the norbornyl skeleton and the

explanation for these observations is suggested.

The reactions of triphenylphosphine dibromide with phenols and ketones are also described.

Part II

Basic condensation of isatin and 5-chloroisatin with 2-acetylthiophene gave the 2-(2-thienyl) substituted

cinchoninic acids which were converted to their ethyl

esters. The condensation of these esters with ethyl N,N-

diethylaminoacetate to the /^-keto esters proceeded in

70-95$ yields. These substituted /^-keto esters did not

easily undergo decarboxylation but gave mostly degradation products.

The 2-(2-thienyl)-4-quinolinecyanohydrin was

synthesized and upon hydrolysis with dilute acid the

2-(2-thienyl)-4-quinolinemethanol was obtained.

xv xvi

Selected derivatives of these compounds were tested for anfcimalarial activity Part I

Novel Reactions with Triphenylphosphine Dibromide INTRODUCTION

Triphenylphosphine dihalides can be prepared by the addition of the desired halogen to triphenylphos- 1 I P phine under anhydrous conditions. ' The reaction is exothermic and the triphenylphosphine dihalide adduct can be isolated as a stable crystalline solid. Triphenyl phosphine dichloride can alternatively be prepared by heating triphenylphosphine oxide with phosphorous penta- chloride,*^^

The choice of solvents depends on the reaction condition and the reactants.Some common solvents used are N,N-dimethylformamide, acetonitrile5 diglyme, triglyme, and softie hydrocarbons. The tertiary phosphine dihalides react readily with carboxylic acids to give the acid halides and with aldehydes and ketones to give the gem-dihalogen com- 7 pounds.1

% (C6H5)3PX2 + R-COgH ---- ^ (C6H5)3P=0 + R-C-X

(C6H5)3PX2 + R 1RC=0 --- (C6H5)3P=0 + R'RCXg

2 Carboxamides do not form stable acylphosphine imides, but go directly to the nitriles and phosphine oxides„^ 0 y---- > (C6H5)3P=0 + RCN 2HX (C6H ) PX + R-C-NH - Y W/ -- > (C6H5)3P=N-C-R + 2HX

Active methylene groups react with triphenylphosphine dihalide in the presence of triethylamine to give phospho-ylides: 8

(c 6h 5)3p x 2 + h 2c r 2 + 2(c 2h 5)3n ------(c6h 5)3p=c r 2

+ 2(C2H5)3N-HX R= -0N,-002R, >0=0

The reaction of triphenylphosphine dihalides ■ ' ' - Q with alkyl halide gives the phosphonium perhalides:^

(c 6h 5)3p x 2 + r x ------(c 6h 5)3e x -x 2

The phosphine dihalides hydrolyze readily to give hydrogen halide and the phosphine oxide. They react similarly with hydrogen sulfide to give the 7 corresponding phosphine sulfides:

,R3PX2 + H20(S) -- :------R3P=Q(S) + 2HX 4

In 1959* Horner, Oediger, and Hoffmann^ found

that if (-)-menthol is reacted with trialkyIphosphine

dichloride the product is the (+)-neomenthyl chloride.

This means that the reaction was accompanied by a

Walden inversion. Further study of this mechanism by

Wiley^ and Schaefer^*^ showed that inversion was the

general stereochemical course of reaction for all alco

hols with the exception of those sterically hindered,

such as exo-norborneol. For example, Schaefer and

Weinberg^ found that if triphenyIphosphine dibromide was reacted with endo-norborneol in DMF, the product was 98 + 2$ exo-norbornyl bromide. This led them to

postulate the following mechanism:

Fast (1.) (C6H 5 )3P + B i-2 ------> (C6H 5 )3PBr2

(2.)

Br+HBr

o (3 .) + (g 6h 5 )3p o

^OP(CrH.) 6 5 '3 RESULTS AND DISCUSSION lo Preparation and Reactions of ,trans-l-Bromo-3-Vinyl-

cyclopentane

17 -21 Bartlett and his associates ' have recently carried out a comprehensive study of the solvolysis of

1-(A -cyclopentenyl)-2-ethyl arenesulfonates and some related derivatives. It was found that during the sol ve lyses of these compounds not only was there a rate enhancement but that in certain instances the reactants closed to the bicyclic system, A factor which compli cates the interpretation of their data is that in the reaction of l-(A^-cyclopentenyl)-2-ethyl tosylate, con siderable driving force for both participation and cyclization must occur from the conversion Of a primary to a secondary cation. This necessarily weakens any arguments which can be made which ascribe the interesting behavior of this system to the unusual properties of the norbornyl cation,

A system which would avoid this latter compli cation is represented by trans-l-bromo-3-.vinylcyclopentane (l). It was thought at first that a convenient method to prepare this compound would be a 1,4-addition ■

5 6 reaction of vinylmagnesium bromide with 2-cyclopentenone to obtain the 3-vinylcyclopentanone, and subsequent reduction with sodium borohydride to give the cis-trans mixture of isomers of the alcohol. This method proved unsatisfactory due to very low yields and random stereo chemistry.

The next approach proved satisfactory and gave the desired stereochemistry. The preparation of trans- l-bromo-3-vinylcyclopentane is outlined below.

LiAlH

P • Br

150-200

(1) (6) (5) The Baeyer-Villiger oxidation of norcamphor was accomplished by a procedure similar to that described by Meinwald and Frauenglass,This reaction was exo

thermic upon addition of 40$ peracetic acid but proceeded

smoothly to give a 77$ yield of purified product (app„ I,

IR-1).

It was not necessary to purify the former lactone before reacting with dimethylamine, but the yields were about 10-20$ higher when purified lactone was used. It was necessary to seal the dimethylamine and lactone in a stainless steel autoclave and heat for 2 days at

190-200° to obtain complete reaction (when the reaction was run in thick-walled sealed glass tubes, the tubes exploded under the high pressure). After distilling through a short fractionating column there was obtained an 88$ yield of N,N-dimethyl cis-3-hydroxycyclopentylacetamide (4) (app. I, IR-2, NMR-l).

The reduction of the amide proceeded smoothly but a slightly better yield of product was obtained when the reaction mixture was stirred overnight at room temperature. The work-up of this reaction was also changed. Normally, when a lithium aluminum hydride reduction is worked up, an excess of water is.added and the aqueous layer is then extracted with the desired solvent. This introduces two problems„ First, the product may be slightly soluble in a strong basic solu tion, and second, it usually takes more time than desired to completely dissolve the salts in the water and, if filtered before dissolving, the salts form a gel which is very difficult to filter free. To avoid these complications it was found that one could add '

2N ml, (where N represents grams of lithium aluminum hydride) of water and stir vigorously until the.excess lithium aluminum hydride and salts are decomposed (this is apparent when the salts become, white), Then 2N grams of 50$ sodium hydroxide is added and the solution stirred until all the salts have coagulated to small dry pellets which can easily be filtered. Using this procedure a

90$ yield of N,N-dimethyl cis-3-hydroxyeye1opentylethy- leneamine (5) was obtained (app, I, IR-3> MR-2),

The reaction of hydrogen peroxide with 3 in methanol to give the N-oxide was exothermic and quanti tative, It was necessary to heat the N-oxide at 80° in a vacuum to obtain crystillization. The N-oxide decomposed to the olefin (6) at

130-200° in 68$ yield. The NMR and IR spectra were consistent with the formulated structure (app, I, IR-4, MR-3), The yield of olefin (6) was cut almost to half If the N-oxlde was not crystallized before decom position.

The 3,5-dinitrobenzoate and the tosylate of 6

(app. I, NMR-4) of 6 formed readily in pyridine to give

solid derivatives (see experimental) for characteriza

tion.

The cis-alcohol (6) gave the trans-bromo compound

(l) (app. I, IR-5) when reacted with triphenylphosphine dibromide. The inversion was assumed from previous

studies^"^ with this reagent (also see introduction).

The stereochemistry of 4,5 and 6 follows from

the method of synthesis, and therefore the tosylate (?) has the cis configuration.

( 0 ^ ) 3 ? Br

CH=CH

CH=CH 2 0S0oC/:H,lCH CH^Cz-HnSCUCl

(7) 22 17 Lawton and Bartlett ' found that the solvoly-

O sis of 1-(A -cyclopentenyl)-2-ethyl tosylate gave exo-

norbornyl derivatives. They also found that the reaction

proceeded with rate enhancement as compared to the satu

rated derivative. They concluded from these data that

the driving force fp'r ring closure must be related to

the favorable electronic structure of the bridged cation,

because the strain energy of the bicyclic system was

almost as great as the calculated standard heat of cycli-

zation of an olefin. In subsequent papers by Bartlett

and his associates^ ~ it was shown that in all solvents

tested the double bond increases the rate of solvolysis

and decreases the importance of nucleophilicity in the

solvent as compared to the saturated derivatives.. In

other words, the double bond participates in the solvoly-

ses in such a way as to make the developing cation in the

transition state more self sufficient.

As mentioned earlier in this work, a factor which complicates the interpretation of their data is

that in the reaction of l-(A^-cyclopentenyl)-2-ethyl

tosylate, considerable driving force for both partici

pation and cyclization must occur from the conversion of

a primary to a secondary cation. A system which would

avoid the conversion of a primary cation to a secondary cation in the transition state would be trans-l-bromo-

3-vinylcyclopentane (l). Solvelytic studies with 1 were carried out in water and formic acid in the presence of silver nitrate or silver perchlorate to give 3-vinylcyelo pentanol and the rate constants for 1 as compared to cyclopentyl bromide were determined conductimetrically in 50$ water-ethanol. The acetolysis of the cis-tosylate

(7) was carried out in glacial acetic acid buffered with sodium acetate and the only produdt obtained was the

3-vinylcyclopentyl acetate as determined by comparison of its VPC retention time and infrared spectrum (app. I,

IR-6) with those of an authentic sample. The MMR spec trum of the authentic sample (app, I, NMR-6) was compared and supported by the correct elemental analysis (see experimental).

Further evidence concerning the failure of ring closure to occur lies in the product studies which showed in all cases that the 3-vinylcyelopentanol was recovered, When silver nitrate was reacted with 1 in water the main product was the alcohol (app, I, IR-7), accompanied by a small amount of the nitrate ester

(10-50$, depending upon the concentration of the react-* ants). The nitrate ester structure was deduced from its infrared spectrum (app, I, IR-8) and its conversion 12 back to the 3-vinylcyclopentanol by basic hydrolysis and reduction with lithium aluminum hydride„ Solvolysis in water with silver perchlorate gave almost all 3-vinyl cyclopentanol (app,. I; IR-9) „

All the above experiments indicate that the 3-vinylcyclopentyl cation does not cyclize to the norbornyl cation. Several factors> both steric and elec tronic in origin, may be responsible for these results. First, it appears that no participation from the double bond is present. When the rate constant of 1 as compared to cyclopentyl bromide was determined in

$0$ water ^-ethanol at 69.64 + 0.01° (temperature calibrated with National Bureau of Standards thermometer and the deviation averaged over a period of three days), the presence of the double bond showed a rate decrease of approximately two (Fig. l).

Second, it must be considered whether the carbon atoms which are hypothetically involved in the "cyclization" process are capable of approaching sufficiently close for interaction between the p- and v-orbitals to

occur. An examination of Dreiding models of 3-vinyl

cyclopentyl cation (8) and l-(A^-cyclopentenyl)-2-ethyl

cation (9) indicates that the geometry of these ions is

such that the distance of approach is 0.4A closer in 13

Bartlett's Ion (9) than in ours (8) if no compression

strain is introduced, but, more seriously, since the vinyl groups cannot line up for maximum overlap with the empty p-orbital there is introduced considerable

steric hindrance by the vinylic hydrogen in 8; however,

if the product ion is very stable, these objectives could probably be overcome at small expenditure of energy by

introducing a degree of torsional strain into the system.

A third factor which must be considered is the

contrasting types of orbital overlap in the two systems.

Favorable overlap in 9 is evident from the rate enhance

ment and the formation of cyclized products. This type

of p-7r interaction is also encountered in the formation

of stable metal ion-olefin complexes and is evidently

quite favorable. 14

+ • * * 4 ♦ « • ♦ ♦ * ...... O ■ B !i 1 III # #itrtl niili o" ’ a i-...... t 4 , ..It t ♦ ♦ ♦- f ? • ‘ t O 5» *o zse lo» 2$e joe r

Fig. 1. Kinetic Plots of Cyclopentyl Bromide as Compared to trans-l-Bromo-3-vinylcyclopentane. 15 A system which is similar to 8 from an elec tronic viewpoint is the 7-bicyclo £ 2.2.1] heptenyl cation

(10). Although the p- and ir-orbitals are nearly lined up, overlap is sufficiently important to cause an

p"2 enormous rate increase J (in comparison to the saturated analog) of the tosylate leading to 10. The prognosis for overlap is less favorable for 8 however, since, at best, interaction between only a portion of the T-bond and the p-orbital can occur.

In view of the complexities involved it is not possible to draw any firm conclusions regarding which of the above mentioned factors are ultimately respon sible for the failure to observe the conversion of 1 to the norbornyl system. 16

2. Reaction of Trlphenylphosphine Dibromide With Phenols

Although bimolecular displacement reactions on aromatic rings are relatively uncommon, they are feasible when the substituent is activated by an election with drawing group or when the leaving group is exceptionally stable (e.g. N^)„ Since the formation of triphenylphosphine oxide is an energetically favorable process, tri- ph phenylphosphine dihalides and similar reagents such as the triphenylphosphite dihalides, can be used to convert phenols to aryl halides. Me have found that this reaction is general and is capable of producing aryl halides in high yields.

When a solution of trlphenylphosphine in aceto nitrile is reacted with bromine at 25-30°, triphenylphosphine dibromide is formed rapidly and quantitatively.

Addition of an equimolar quantity of a phenol results in the formation of a complex which is readily decomposed at 200-350° to the aryl halide, trlphenylphosphine oxide, and hydrogen bromide. Due to the solubility of alkyl and aryl bromides and the insolubility of triphenylphosphine oxide in pentane, pentane extraction provides a convenient method for isolation of the product. The pentane extracts can then be passed through a short "alumina" column to remove any last traces of hydrogen bromide or triphenylphosphine oxide. This method of isolation gives a product.that is at least 98-99$ pure

(see experimerital procedure for 2-bromonaphthalene) „

Utilizing this procedure, 2-bromonaphthalene was obtained in yields of 82-86$ from y^-naphthol. The reaction is also suitable for large scale preparations and is cur rently the best method for preparing this compound, which is normally tedious to synthesize. Using similar condi tions, <=<-naphthol was converted to 1-bromonaphthalene in 72$ yield.

The reaction is also applicable to heterocyclic systems. In this case it is necessary to neutralize the amine hydrobromide salts before extraction with pentane, but otherwise, the work-up is the same. Treat ment of 3-hydroxypyridine with triphenylphosphine dibromide gave 3-bromopyridine in 76$ yield. Similarly,

2-bromopyridine could be isolated in 6l$ yield from 2- hydroxypyridine and 8-hydroxyquinoline (app, I, IR-10,

HMR-6 ) was converted to the corresponding bromide in

48$ yield.

Although many simple aryl halides are readily available through direct halogenation of the aromatic nucleus, cases frequently arise when isomer formation 18 makes this route Impractical« In these cases and those \ - In which heterocycles are normally inert to direct halogenation, reaction of the appropriate phenols with triphenylphosphine dihalide presents a practical alter native. For example, from o-cresol, o-bromotoluene was isolated in 72$ yield.

3. Reaction of Triphenylphosphine Dibromide With Ketones

The phosphine dihalides resemble the phosphorus pentahalides in their behavior toward carbonyl compounds.

From aldehydes and ketones, gem-dihalogen compounds are obtained.^ As expected when cyclopentanone was reacted with triphenylphosphine dibromide in acetonitrile and refluxed overnight the major product was the 1-bromocyclopentene obtained by first forming the gem-dibromide; under the reaction conditions hydrogen bromide was elimi nated (app. I, NMR-7)c This gave approximately a 50$ yield of the bromoalkene.

From the above information it was predicted that desoxybenzoin would give gL-bromostilbene. Instead it was found that under the reaction conditions used

(see experimental) the major product was trans-stilbene

(app. I, NMR-8). 19 In order to ascertain a reasonable mechanism for this unexpected reaction, desoxybenzoin-dg was syn thesized by exchange with deuterium oxide in diglyme„

After the third exchange no hydrogen was detected on the o<-carbon in desoxybenzoin by NMR (app. I, NMR-9)0 •

The desoxybenzoin-dg was reacted with triphenylphosphine dibromide in both acetonitrile and pentane and the results were the same. It was found that the trans- stilbene formed contained 1.35 deuterium atoms per mole.

The triphenylphosphine oxide was isolated and purified to give no deuterium atoms per mole and the hydrogen bromide evolved was trapped with N,N-dimethylaniline as a salt and analyzed for 0.144 deuterium atoms per mole. From the NMR (app. I, NMR 8 and 10) of the non- deuterated and deuterated trans-stilbene it is apparent that the areas of the olefinic peaks are quite different.

Also it can be said that a source of hydrogen is present that does not come from the cK-methylene group. This could be due to cracking of the compounds at the reactions conditions. It was not determined if deuterium was pre sent on the aromatic ring of the stilbene.

Due to the complexity of this reaction and the conditions used for the reaction (e.g. 280°) it is im practical at this point to draw any firm conclusions regarding the reaction course. 20

4, Reaction of Lithium Aluminum Hydride With the

Triphenylphosphine Dibromide and Alcohol Complex

Due to the lability of the triphenylphosphine' oxide as a leaving group and its ability to be displaced by other nucleophiles (e„g„ Br), it was apparent that it should also be displaced by hydride ions. This was proven to be the case when the complex of triphenylphos phine dibromide and benzyl alcohol was added to lithium aluminum hydride in dry triglyme to give toluene.

LiAlHj, (C6H5)3P^O-CH2C6H5-HBr --- — ^ ( C g H ^ P + CgHjCHj

The toluene was isolated by distilling from the triglyme solution without decomposing the excess lithium aluminum hydride„ The triphenylphosphine was isolated by adding the decomposed solution to an excess of water and filtering. The same procedure was used with n-octanol to n-octane. •

When 2-methylcyclohexanol was used the products consisted mainly of 1-methylcyclohexene (90$) and methylcyclohexane (10$) through elimination and displacement. EXPERIMENTAL lo General

Boiling points and melting points are uncor rected.

The analytical vapor chromatograms were taken using a 5 ft. or 10 ft. 20$ Carbowax 20M-on-firebrick column in a Wilkins Instrument and Research, Inc.,

Areograph gas chromatographic instrument or on a similar column in an F and M Scientific Corporation Model 609

Flame Ionization gas chromatograph; the preparative gas chromatographic separations were made on an Areograph using a 5 ft. 20$ Carbowax 20M-on-firebrick column.

Infrared spectra were recorded with a Perkin-

Elmer Infracord Spectrophotometer and the instrument calibrated with a polystyrene film.

Nuclear magnetic resonance spectra were measured on a Varian A-60 Spectrometer.

Microanalyses were performed by C. F._Geiger,

Ontario, California, and deuterium analyses by Josef

Nemeth, Urbana, Illinois.

21 2. Purification of Reagents and Solvents

Triglyme, diglyme, and tetrahydrofuran were cautiously distilled from lithium aluminum hydride„ BMP was distilled through an efficient fractionating column*

Pyridine (employed in the synthesis, of p-nitrobenzoates) was distilled from sodium hydroxide when necessary but usually the analytical reagent pyridine was satisfactory.

Acetonitrile was distilled once from phosphorus pentoxide

Hydrocarbon solvents were dried by distilling to two- thirds of their initial volume.

3. Oxidation of Norcamphor

The Baeyer-Villiger oxidation of norcamphor was accomplished by a procedure similar to that described by Meinwald and Frauenglass.2^ Peracetic acid (40$,

70 cc.) was added dropwise to 20 g. (0.18 mole) of nor camphor in 100 cc. acetic acid buffered with 10 g. of sodium acetate while the temperature was kept at 30°.

The reaction was then stirred 5 days in the dark. The solution was neutralized by pouring into a 2 molar excess of sodium carbonate in one liter of water and then extracting 7-8 times with 200-300 cc. portions of ethyl ether. The ether was dried, concentrated, and the 23

product distilled at 0.05 mm. to give 17.5 g. (0 „l4 mole,

77$) of product boiling at 73-75°.

4. NjN-Dimethyifrcis-B-Hydroxycyclopentylacetamide

Excess dime thylamine, 122 g. (0.9 mole) of lac

tone, and 1 g. of dime thylamine hydrochloride were sealed

in an autoclave and heated at 200° for 48 hr. The excess

amine was distilled off using an aspirator and the product was then collected at 111-113° at 0.05 mm. to give 145 g. 26 (88$) of amide, n^ , 1.4950.

5. N, N -Dime thy 1 -ci_s-3 -hydroxy eye lopentyle thy leneamine

N ,N-Dimethy1-els-3-hydroxyeye1opentylace tamide

(145 g., 0.74 mole) in 500 cc. of dry ethyl ether was

added dropwise to 34 g. of lithium aluminum hydride in

1200 cc. of dry ethyl ether and the reaction stirred

overnight at room temperature.. The suspension was decom

posed by adding 90 cc. of water followed by 50 cc. of

50$ sodium hydroxide solution and the reaction stirred

vigorously until the salts coagulated. The solution was

filtered by suction, dried over magnesium sulfate, and

concentrated. The product was distilled and collected

in the range 74-76° at 0.05 mm. to give 120 g. (90$) of

amine. 6 . cis-3-Vlnylcyclopentanol

Hydrogen peroxide (30^, 80 cc„) was added dropwise to 20 g.,, (0.11 mole) of N,N~dimethyl-cis-3-hydroxy- cyclopentylethyleneamine in 50 cc„ of methanol,at a rate to maintain gentle reflux without external heating* The reaction was stirred at room temperature for 24 hr* and then the excess hydrogen peroxide was decomposed with activated platinum until acidic ferrous sulfate gave a negative test for peroxides* The methanol-water was distilled off at 50° and 25-30 mm* until a thick oil remained. The oil was heated 80-90° at 0*05 mm. until the N-oxide crystallized. The N-oxide melted with decom position to the olefin at 170-180°. The N-oxide was then pyrolyzed at 160-200° at 26 mm. while the olefin and hydroxylamine were collected in a receiving flask cooled in ice water. The distillate was washed with an excess of 3 N hydrochloric acid to remove the hydroxylamine.

The cis-3-vinylcyclopentanol was extracted 3 times with

50 cc.# 30 cc*, and 30 cc* portions of ether. The extracts were combined, dried over magnesium sulfate, and concentrated. The product was collected at 87-89° 28 and 26 mm. to give 9*3 g» (68$) olefin, nD , 1*4665*

Anal. Calcd. for C^H-^gO: C, 74*95J H, 10.78.

Found: c, 74*47; H, 11,03= 25

To cis-3-Vinylcyclopentyl 3,5-Dinitrobenzoate

cls-3-Vinylcyclopentanol (l g„) was dissolved in 3 cc. of anhydrous pyridine and an equmolar quantity of 3,5-dinitrobenzoyl chloride was added. The reaction was heated to reflux and then stirred at room tempera ture for 30 minutes. Sufficient ice was added to preci pitate the ester which was filtered, washed with 10$ sodium carbonate solution, and recrystallized twice from

95$ ethanol to give 0.51 g« of product melting at 8l.O-

81.7°.

Anal. Caicd. for c i 4H]_4^2°6: 54.94; H, 4.6l;

N, 9.15. Found: C, 54.69; H, 4.67; N, 9.37.

8. trans-1-Bromo-3-vinylcyclopentane

To 14.1 g. (0.054 mole) of triphenylphosphine in

50 cc. of dry dimethylformamide was added dropwise with cooling 8.7 g. (0.054 mole) of bromine. To this solution was added 6.0 g. (0.053 mole) of cis-3-vinylcyclopentanol.

The solution was heated at 80-130° and dimethylformamide and product were collected at 26 mm. The distillate was diluted with 500 cc. of water, neutralized with sodium carbonate, extracted twice with 100 cc. and 50 cc. of ethyl ether, dried over magnesium sulfate and concentrated. The product was collected at 66„0-67„5° and .26 mm„ to 26 give after two distillations 6.8 g. (730), nD , 1 .4958.

Anal. Calcd. for C, 48.02; H, 6 .29.

Found: 0, 48.11; H, 6.57.

9. cls-3-Vlnylcyclopentyl Tosylate

To 1 g. of cis-3-vinylcyclopentanol In 5 cc. of pyridine was added 1.7 of p-toluenesulfonyl chloride.

The solution was warmed for 5 minutes and then allowed to stand 10 hr. at room temperature. The solution was diluted with 25 cc. of cold water and a thick oil separated. The oil was extracted with ethyl ether, dried over magnesium sulfate, and concentrated to give

O .95 g. of product which crystallized by boiling in hexane and then copied in ice water. The product melted at 40,8-41.4° and decomposed at elevated temperatures.

Anal, Calcd. for C^H^gO^S: C, 63.14; H, 6 ,8l.

Found: C, 63,46; H, 6.94.

10, Acetolysis of cis-3-Vinylcyclopentyl Tosylate

To 10 cc. of glacial acetic acid containing

0.2 g, of potassium acetate was added 0.55 g. of tosy late and the reaction heated at 100° for 8 hr. The reaction solution was then added to 75 cc. of ice water. 27 extracted with ethyl ether, dried over magnesium sulfate, and concentrated to give a light brown oil. The 3-vinyl-

cyclopentyl acetate (stereochemistry not determined) was isolated and purified only for analytical purposes by gas chromatography (Aerograph, Wilkens Instrument and Research

Inc,) using a 5 ft, 1/4 in, Carbowax column. No detect able norbornyl acetate was present as compared with the retention time of an authentic sample.

Anal, Calcd, for C^H-^Ogj C, 70,10; H, 9,15,

Found: C, 70,42; H, 9,38,

11, Solvolysis of trans-1-Bromo-3-vinyIcyclopentane

To 1,3 g. of silver perchlorate in 15 cc, of formic acid (97-100$) buffered with an equmolar quantity of sodium formate was added 0,8 g, of trans-1-bromo-3- vinylcyclopentane and the reaction stirred 10 minutes,

A 10$ molar excess of 20$ sodium hydroxide solution was added and the solution stirred for 2 hr. The product was extracted with ethyl ether, dried over magnesium sulfate, and concentrated to give 0.29 g« of brown oil.

The product was isolated and purified by analytical VPC to give 3-vinylcyclopentanol (stereochemistry not deter mined) as the major product using a 5 ft. 1/4 in. Carbowax column. The product was identified by comparison of its VPC retention time and infrared spectrum with that of an authentic sample.

12, Solvolysis of trans-l-Bromo-3-vinylcyclopentane in

50-50 Ethanol-Mater

The solvolysis was carried out at + 0,01°

(temperature calibrated with National Bureau of Standards thermometer and the deviation averaged over a period of three days) utilizing the eonductimetrie technique to give absolute rate constants for cyclopentyl bromide of

1„4 + 0.2 X 10"^ sec.""1, and for trans-l-bromo-3-vinyl-

h ^,"1 cyclopentane of 6.2 + 0.2 X 10" sec.- .

13. Solvolysis of trans^l-Bromo-3-vinylcyclopentane

in Aqueous Silver Nitrate

trans-l-Bromo-3-vinylcyclopentane (4 g.) was added dropwise to 6 g. of silver nitrate in 100 cc. of water and the solution stirred 30-45 minutes and then the silver bromide filtered. The reaction mixture was extracted twice with 50 cc, portions of ethyl ether, dried over magnesium sulfate, and concentrated to give

1.4 g. of crude product. The 3-vinylcyclopentanol was isolated and purified by analytical VPC and identified by its infrared spectrum with that of an authentic sample and Its VPC retention time with that of an authen

tic sample. The 3,5-dinitrobenzoate prepared by the previous procedure melted at 74.8-75.4° (low melting probably due to cis-trans isomers) and the mixed melting point with authentic sample was 76.1-78.8°.

Anal. Calcd. for C ^ H ^ N g O g : C, 54.94; H, 4.6l;

N, 9.15. Pound: c, 55-07; H, 4.49; N, 8.83.

14. 2-Bromonaphthalene

A 500 Co. three-necked round bottom flask was equipped with a Trubore stirrer, a pressure compensating dropping funnel, and a reflux condenser with drying tube. The flask was charged with 144 g. of triphenylphosphine (0.55 mole) and 125 cc. of acetonitrile. With stirring, the solution was cooled in an ice bath and

88 g. (0.55 mole) of bromine was added dropwise over a period of 20-30 minutes. After the addition of the bromine, the ice bath was removed and J2 g. (0.50 mole) of y^-naphthol in 100 cc. of acetonitrile was added in one portion and the reaction mixture heated to 60-70° for at least 30 minutes. The flask was then fitted for a simple distillation and the acetonitrile distilled off under water aspirator pressure until the oil bath

temperature reached 110°. ' After all the acetonitrile 30

had been removed, the condenser was replaced with a

short, large glass tube connected to a 500 cc. flask

half filled with water and the oil bath was replaced

with a Wood's metal bath. The bath temperature was

raised to 200-220° and kept at this temperature until

all the solid had melted. Stirring was continued and

.the bath temperature raised to 340° and held there until

evolution of hydrogen bromide ceased (approximately

20-30 minutes). The Wood's metal bath was removed and

the reaction mixture cooled to approximately 100° and

then poured into a 800 cc. beaker and cooled to room

temperature. Pentane (300 cc.) was added and the solid

broken into a fine precipitate and filtered off by sue- -- tion and washed thoroughly twice more with 300 cc. portions

of pentane. The pentane filtrates were combined, washed

with 200 cc. of 20$ sodium hydroxide, and dried over

anhydrous magnesium sulfate. The pentane extract was

then passed through a 25 mm. diameter column filled to

35 cm. in depth with alumina; distillation of the pentane

gave 87 g. (82-86$) of 2-bromonaphthalene, a white solid

melting at 45-50° (lit.^ b.p. 146-7; m.p. 59°). 31 1 5 o 2-Bromotoluene

A 500 cc„ three-necked round bottom flask equipped with a mechanical stirrer, a pressure compen

sation dropping funnel, and a reflux condenser was charged with 144.1 g. (0.55 mole) of triphenylphosphine and 200 cc. of dry acetonitrile. With cooling and stirring

88 g. bromine was added dropwise over a period of 20-30 minutes. After the addition of the bromine 54 g. (0.5 mole) of o-cresol in 30 cc. of acetonitrile was added in one por tion and the solution warmed until all the solid dissolved.

The acetonitrile was removed under aspirator pressure

(25-30 mm.) until only the solid complex remained. The flask was placed in a Wood's metal bath and heated gradu ally until the temperature reached 350°. The 2-bromotoluene began to distill as it was formed. The reaction was complete when the evolution of hydrogen bromide ceased.

The crude product was then washed with a 20$ sodium hydrox ide solution to remove any remaining cresol. The product was then taken up in pentane and passed through an alumina column and the removal of the pentane gave 53 g. of pure product, b.p. 177-180°. A slightly better yield was

obtained when the tripenylphosphine oxide residue was washed with pentane. This afforded only 2-4 g. more product and was thus not worthwhile„ The purity (97-99$) of the product was checked by analytical VPC and NMR

(lit,27 b.p. 178-181°),

16, 3-Bromopyridlne

A three-necked round bottom flask equipped with a mechanical stirrer, a pressure compensation dropping funnel, and a reflux condenser was charged with 27 g,

(0,1 mole) of triphenylphosphine and 75 cc, of dry acetonitrile. With stirring and cooling 16 g, (0,1 mole) of bromine was added dropwise. After the addition of the bromine, 9,5 go (0,1 mole) of 3-hydroxypyridine was added in one portion and the solution heated to the boiling point of acetonitrile. The acetonitrile was distilled until the oil bath reached 100-110°„ The oil bath was replaced with a Wood's metal bath and the tem perature gradually taken up to 300° and kept there until the evolution of hydrogen bromide ceased (care was taken to prevent excess foaming). When the reaction solution had cooled to approximately 60-90°, 15 cc. of 50$ sodium hydroxide was added and the solution stirred vigorously until all the salts dissolved. The 3-bromopyridine was extracted with pentane, dried over magnesium sulfate, and the pentane removed by distillation. The product 33 distilled at 169° to give 10.5 g. (76^) of product.

(lit.28 b.p. 752 172-3°).

17. Cinnamyl Bromide

A 500 cc. three-necked round bottom flask equipped with a Trubore stirrer, a pressure compensation dropping funnel, and a reflux condenser with drying tube was charged with 350 cc. of acetonitrile and 106.4 g. (0.4 mole) of triphenylphosphine. The flask was cooled in an ice-water bath and 64 g. (0.4 mole) of bromine was added dropwise over a period of approximately 15-20 minutes.

With continued stirring the ice-water bath was removed and 54 g. (0.4 mole) of cinnamyl alcohol in 50 cc. of acetonitrile added in portions over a period of 5-10 minutes. The solvent was removed by distillation using a water aspirator (30-40 mm.) and an oil bath until the bath temperature reached 120°. The water aspirator was replaced with a vacuum pump, the water cooled condenser with an air condenser, and with rapid stirring the dis tillation continued. The majority of the product dis tilled at 91-98° at 2-4 mm. and about 59 S- of product crystallized in the receiving flask (7 2 - 7 5 $). The product was dissolved in 200 cc. of ethyl ether, washed with

75 cc. of saturated sodium carbonate solution, dried over 34 magnesium sulfate, and distilled to give 56 g. of product distilling at 66-68° (0.07 mm.) or 84-86° (0.8 mm.)2^ and melting at 29°. l8. 1-Bromonaphttlalene

A three-necked round bottom flask equipped with a mechanical stirrer, a pressure compensation dropping funnel, and a reflux condenser was charged with 27 g.

(0.1 mole) of triphenylphosphine and 100 cc„ of aceto nitrile. With stirring and cooling 16 g. (0.1 mole) of. bromine was added dropwise. After the addition of the bromine, 14 g. (0.1 mole) -naphthol dissolved in 50 cc. of acetonitrile was added in one portion and the solution heated to the boiling point and kept there for 15-20 minutes. The acetonitrile was distilled until the oil bath reached 100-110°. The oil bath was replaced with a Wood’s metal bath and the bath temperature raised to

200-220° and kept at this temperature until all the solid; had melted. The bath temperature was then raised to 340° and held there until evolution of hydrogen bromide ceased.

The Wood's metal bath was removed and the reaction mixture cooled to approximately 100° and poured into a 600 cc. beaker and cooled to room temperature. Pentane (100 cc.) was added and the solid broken into a fine precipitate and filtered by suction and washed thoroughly twice more with 100 cc, portions of pentane. The pentane extracts were combined, washed with 20 cc, of 20$ sodium hydroxide and dried. The pentane was passed through an alumina column and then removed to give 14 g, (72$) of 1-bromo- 30 naphthalene,

19, 2 -BromopyrMine

A three-necked round bottom flask equipped with a mechanical stirrer, a pressure compensation dropping funnel, and a reflux condenser was charged with 27 g,

(0,1 mole) of triphenylphosphine and 75 cc. of dry acetonitrile. With stirring and cooling, 16 g. (0.1 mole) of bromine was added dropwise. After the addition of the bromine, 9„5 g, (0.1 mole) of 2-hydroxypyridine was added in one portion and the solution heated to the boiling point of acetonitrile. The acetonitrile was distilled until the oil bath reached 100-110°,. The oil bath was replaced with, a Wood's metal bath and the tem perature gradually taken up to 240-280° and kept in this range until the evolution of hydrogen bromide ceased

(care was taken to prevent excess foaming). When the reaction solution had cooled to approximately 80-90°,

15 cc. of 50$ sodium hydroxide was added and the solution 36 stirred vigorously until all the salts dissolved. The

2-bromopyridine was extracted with pentane, dried over magnesium sulfate, and the pentane removed by distilla tion. The product distilled at 74° (12 mm.) to give

9-6 g. (61^) (lit.31 b . p .13 74-75°)-

20, 8-Bromoquinoline

Bromine (l6 g., 0.1 mole) was added dropwise to

27 g. (0.1 mole) of triphenylphosphine in 100 cc„ of dry acetonitrile. 8-Hydroxyquinoline (14 g., 0.1 mole) was added and the solution warmed to the boiling point of acetonitrile. The acetonitrile was then distilled at

30 mm. until only the solid complex remained. The com plex was slowly heated to 300° and kept at this tempera ture for 2-3 minutes, and then allowed, to cool to 200°.

This procedure was repeated three times. The solution was allowed to cool to approximately 100° and 10 cc. of

50$ sodium hydroxide was added with stirring after which

5 cc. of water was added. The reaction was stirred vigorously for 15 minutes and then poured into 400 cc. of pentane. After boiling the pentane for 10 minutes, the pentane extract was decanted and this procedure repeated once more. The pentane extracts were combined and filtered to remove a small amount of tripenylphosphine oxide„ The solution was concentrated and distilled to give 10 g. (48^) of 8-bromoquinoline distilling at 117° and O.T. mm. (lit0^2 b.p. 302°)«,

21. Toluene from Benzyl Alcohol •

Triphenylphosphine (53 ; 0.2 mole) and 100 cc. of dry triglyme were, placed in a 500 cc. round bottom flask and with stirring, 32 g. (0.2 mole) of bromine was added dropwise at a sufficient rate to keep the tempera ture below 40°. After the addition of the bromine, 21 g.

(0.2 mole) of benzyl alcohol was added in portions over a period of 5-10 minutes and the solution stirred for at least 30 minutes. The slurry was then transferred to a pressure compensating dropping funnel and added dropwise to 15.2 g. of LiAlH^ in 200 cc. dry triglyme at a rate sufficient to keep the solution between 50° and

80°. The toluene was distilled from the triglyme until only triglyme distilled. The distillate was diluted with 200 cc. of water and the toluene separated, dried and distilled to give 14 g. (76$) of product collected at 110° (lit.33 b.p. 110°).

22. n-Octane■from n-Octanol

Triphenylphosphine (27 g., 0.1 mole) and 50 cc. of dry triglyme were placed in a 250 cc. round bottom 38 flask and with stirring 16 g. (0.1 mole) of bromine was added dropwise at a rate to keep the temperature below

40°„ After the addition of the bromine, 13 g. (0,1 mole) of n-octanol was added in portions over a period of 5-10 minutes and the solution stirred for at least 30 minutes.

The slurry was then transferred to a pressure compensating dropping funnel and added dropwise to 8 g, of LiAlH^ in

75 cc. of dry triglyme at a rate sufficient to keep the solution between 50° and 80°, The n-octane was distilled from the triglyme until only triglyme distilled. The distillate was diluted with 200 cc, of water and the n-octane separated, dried, and distilled to give 9 g°

(79$) of product collected at 123-125°,

23. Reaction of 2-Methylcyclohexanol-Triphenylphosphine

Dibromide Complex With Lithium Aluminum Hydride

Triphenylphosphine (27 g,. Oil mole) and 50 cc, of dry diglyme were placed in a 250 cc, round bottom flask and with stirring 16 g, (0,1 mole) of bromine was added dropwise at a rate sufficient to keep the tempera ture below 40°, After the addition of the bromine, 11 g,

(0,1 mole) of 2-methylcyclohexanol was added in portions over a period of 5-10 minutes and the solution stirred at room temperature for 5 hr. The slurry was then 39 transferred to a pressure compensating dropping funnel and added dropwise to 5 g° of LiAlH^ in 75 cc. of dry diglyme at a rate sufficient to keep the solution between

50° and 80°o The mixture of products was distilled from the diglyme until only diglyme distilled. The distillate was diluted with 200 cc. of water and the.products sepa rated and dried over magnesium sulfate to give 7.3 g.

(74$) of crude product. Analysis showed a mixture of products of which approximately 10$ was methylcyclohexane and approximately 90$ 1-methyIcyc1ohexene.

24. 1-Bromocyclopentene

TriphenyIphosphine (79 g., 0.3 mole) was dis solved in 200 cc. of dry acetonitrile and with stirring and cooling 48 g. (0.3 mole) of bromine was added dropwise over a period of 30 minutes. After the addition of the bromine, 30 g. (0.36 mole) of cyclopentanone was added in one portion and the reaction refluxed overnight.

The acetonitrile was distilled off until a thick oil remained. The oil bath was gradually taken up to 16O-I8O 0 and the product collected at 30 mm. pressure. The dis tillate was diluted with 300 cc. of water and the lower layer separated and distilled to give 22 g. (51$) of pro duct boiling at 12.4° (lit.^ b.p. 126°). 40

25® trans-Stilbene from Desoxybenzoin

Triphenylphosphine (27 g®„ 0.1 mole) was dis solved in 100 oc. of dry acetonitrile and 16 g. (0.1 mole) of bromine was added dropwise at a rate sufficient to keep the temperature under 40°. After the addition of the bromine, 15 g, (0.076 mole) of desoxybenzoin was added and the acetonitrile distilled at 30 mm. pressure. The solid residue was heated at 270-280° until evolution of hydrogen bromide ceased. The dark oil was allowed to . cool to approximately 100° and poured into 100 be. of 95$ ethyl alcohol. Water (20 cc.) was added to the ethanol solution and with stirring the product crystallized at

0°. The dark brown precipitate was dissolved in 125 cc. of methanol and while hot water was added dropwise until small flaky crystals began to appear. Upon cooling and filtration 10.4 g. (32$) of crude trans-stilbene was obtained. Recrystallization from pentane gave a white flaky solid melting at 124° (lit.^ myp. 124)»

26. Desoxybenzoin-dg

Desoxybenzoin (19.5 g., 0.1 mole), 20 g. of deuterium oxide (99.5$)> 0.5 g. of potassium carbonate, and 100 cc. of dry diglyme were refluxed for 48 hr. The 41 solution was concentrated at 30 mm„ to approximately half its volume and then 20 g, of fresh deuterium oxide and 50 cc. of dry diglyme were added. After refluxing

72 hr., the solvents were removed at 30 mm. and the product dissolved in dry ether. The potassium carbonate was filtered and the dther removed by aspirator until the product crystallized. The product showed 1.96 deuterium atoms per mole.

27. Reaction of Desoxybenzoin-dg With Triphenylphosphine

Dibromide

Bromine (3.2 g., 0.02 mole) was added dropwise with stirring and cooling to 5.4 g. (0.02 mole) of tri phenylphosphine in 25 cc. dry pentane. After the addi tion of the bromine, 4 g. of desoxybenzoin-dg was added and the pentane removed at 30 mm. The solid residue was heated to 270-290° until the evolution of hydrogen bromide ceased. The dark oil was cooled to approximately

100° and poured into 60-40 ethanol-water solution. After cooling the pentane solution, some triphenylphosphine oxide crystallized and was filtered. The pentane extract was passed through a small alumina column and then the pentane removed. After two recrystallizations from dry carbon tetrachloride the product melted at 124.5-125.5°« Deuterium analysis gave 1„35 deuterium atoms per mole of trans-stilbene,

Triphenylphosphine oxide from this reaction was purified by recrystallization from pentane to give pro duct melting at 158-159° an-d deuterium analysis gave no detectable deuterium.

The hydrogen bromide evolved was reacted with

N,N-dimethylaniline in dry ethyl ether to give white solid which gave 0.144 deuterium atoms per mole of N,N- dimethylaniline hydrobromide. Part II

Synthetic Routes to Substituted

©<-Dialkylaminomethyl-4-quinolinemethanols INTRODUCTION

1, History of the Cinchona Alkaloids

The cinchona alkaloids, named as such because of their existence in the bark of the Cinchona and

Remijla. species, have been known since the early seven teenth century. Their subsequent introduction into medical use has led to extensive and successful culti vation and breeding of the trees in India, Ceylon, and 1 the Dutch East Indies. Their popularity in medicine began through the efforts of the wife of the then Spanish

Viceroy of Peru, the Countess of Chinchon, who in 1638 was successfully treated for malaria through administra tion of these crude alkaloids.

Almost two hundred years later, one of the most intensive chemical investigations of the nineteenth cen tury began, with the isolation of a crude mixture of crystalline alkaloids from the bark by Gomes in Portugal in l8l0, and of pure quinine and cinchonine by Pelletier and Coventou in 1820. Since this stimulating work others have isolated over two dozen more bases from the same genera.

44 45 2. Important Cinchona Alkaloids

Of these more than twenty bases only five of primary Importance will be mentioned here. These are substituted derivatives of Ruban (l) as illustrated in the following diagram:

(i)

Rl = R 2 r 3 Ruban------H -H -H

Quinine, Quinidine------CH=CH2 -OH -OCH

Cinchonine, Cinchonidine— ———————CH==CH2 -OH -H

From the numbering system in the above diagram one could name quinine and quinidine as 6 ’-methoxy-3-vinylruban-9-ol 46 and cinchonine and cinchonidine as 3-vinylruban-9-ol.

Quinine (levorotatory) and quinidine (dextrorotatory) are C^-epimers and cinchonine (dextrorotatory) and cin chonidine (levorotatory) are C^-epimers.

As mentioned earlier, these compounds are import ant in treating diseases such as malaria, but in recent years they have become somewhat unsatisfactory due to the ease of metabolism in the human tissue. This has stimu lated much work on the synthesis of similar substituted compounds that are more stable to metabolic oxidation.

3. Suggested Biogenetic Relationships in the Cinchona

Alkaloids

It has been suggested that cinchonamine is an important precursor to many alkaloids including the cinchona, yohimbe, and strychnos groups. In order to go from the cinchonamine (2) to the normal cinchona skeleton (3 ), one can visualize the cleavage of the

N-l bond and formation of a new bond between N-l and

0-2*. This may also suggest that cinchonamine represents

2 ' CHo-CHo -0H

■>

(2) (3) 47

a relatively early stage, or an offshoot, in the bio

genesis of the cinchona alkaloids, and provides strong

support for the view that the quinoline rings of the major bases are derived from tryptophan (4). Although much room remains for speculation as to the exact pathways, it is probably safe and justified to say that

the three classes of alkaloids mentioned earlier have

common precursors (fig. 1) .

NH.

CH2-CH-C02H

------r

(4)

4-7 Dihydroxyphenylalanine and glycine have been

shown to be the precursors of rings D and E of yohimbine.

The cooperation of tryptophane, dihydroxyphenylalanine,

and glycine is also involved in the biosynthesis of the Q alkaloids of the strychnos group, and it is noteworthy

that a special feature of this latter case, namely, the 48 NH,

CHq -CH-C0oH CHg-CHg-NHg

ECHO f— H 2NCH2C02H

NH,

HO ^ ^ CH2-CH-C02H *(HO) _/ CH^CHO

Strychnine

> H a ^ c i r " ^ OH

Cinchonine Figure 1. Hypothetical Relations of the Cinchona Alkaloids 49

cleavage of the bond of the dlhydroxyphenyl ring, is

entirely analogous to the change required for the con

version of the yohimbine D, E ring system to the quinu-

clidine array of the cinchona group.^

4. Synthetic Sequences

Much work has been done on the cinchona alkaloids, but the outstanding contributions of Rabe to the study of the cinchona alkaloids and the total synthesis of dihydroquinine®* in 1931 combined many of the methods used in the synthetic schemes.

In 1944, Woodward * completed the total syn thesis of quinine. This was an outstanding accomplishment.

Starting with 7-hydrOxyisoquinoline they were able to synthesize dl-quinotoxine. This compound was proven iden tical in all respects with the natural material. This synthesis, together with the previously established con- 13 version of d-quinotoxine into quinine, completed the total synthesis of quinine.

5 . Synthesis of Substituted 4-Quinolinemethanols

Since World War II, many compounds have been syn thesized and tested for their antimalarial activity.

Although many of these compounds showed some antimalarial activity, the substituted 4-quinolinemethanols seemed most promising. These compounds are related closely to the cinchona alkaloids mentioned earlier in that they are readily oxidized in the o<-position on the quinoline ring causing a deactivating effect against malaria.

It has been shown that animal tissues contain an enzyme capable of catalyzing the oxidation of l6 17 quinine, other cinchona alkaloids, ' quinoline and T Q some of its derivatives, and N-methylnicotinamide.

The product resulting from the oxidation of quinine through the intervention of this enzyme, derived from rabbit liver, has been isolated"*^ and identified^ as a

2 1-hydroxy derivative of quinine, 1-2 '-hydroxy-6 '-metho^y

3-vinylruban-9~ol (see compound (l) for nomenclature).

The 6 '-desmethoxy. analogue of this substance, as well as a more highly oxidized derivative, has been isolated from human urine following ingestion of quinidine and cinchonidine. The precise structures of these compounds have not been determined.

The isolation of quinine oxidase from rabbit liver was accomplished in approximately 5$ purity by 18 Knox. The enzyme has properties similar to and is associated with the flayoprotein, liver aldehyde oxidase.

All the flavoprotein present is accounted for by the 51 aldehyde oxidase. Anaerobically It is reduced by cin

chonine, while under aerobic conditions hydrogen peroxide

is formed as the oxidation of the substrate proceeds. In

the presence of this enzyme and of 2 '-hydroxyquinine,

the anaerobic oxidation of an aldehyde is accompanied by a reduction of the former to quinine. 21 2 1-Hydroxyquinine is only 0.05 to 0.25 as potent against malaria as quinine. Thus, it appears unlikely that the antimalarial action of quinine is predicated

..upon its conversion to this substance. Consideration of the nature of the metabolic products of the cinchona alkaloids as shown above has resulted in the suggestion that the potency of these drugs might be enhanced by the introduction of substituents into the 2 '-position of

their component quinoline nuclei, thus blocking the point

of attack of quinine oxidase. This was proven to be the 22 case when 2 ’-phenyldihydrocinchonine was synthesized and tested.*

Since this time many newer and more potent 2^ ”26 4-quinoline methanols have been synthesized and tested. D~

Some of these compounds are listed in the following pages

(Table I).

*Antimalarial drugs are characterized by SN

proceeding the number. 52 OH I c h 3o CH MTD = 0.449 PTD = 0.326 METD= 0.016 TI = 28.0

(1) SN 359 -2 Quinine

CH.

(c h 2)2-c h -c h .

HO^ / ^ 2 \ CH (

CH. MTD = 0.465 PTD = O .279 METD= 0.002 TI = 232.5

(2) SN 15356

/ G4H9 HC^ / G^ 2 ~ \ c h 3o PIT \ C4H 4

MTD = 0.371 PTD = 0.186 METD= 0.001 TI = 371.0

(3) SN 14883

Table I. Antimalarial Compounds 53 / V g

MTD = 0.185 FTD = 0.138 METD= 0.0018 TI = 102.7

(4) SN 14270

MTD = 0.372 FTD = 0.279 METD= 0.0037 TI = 100.5

(5) SN 15031

/ c UH9

MTD = 0.369 FTD = 0.277 METD= 0.0037 TI = 100.0

(6) SN 14273

Table I. Antimalarial Compounds (continued) 54

MTD = 0.186 FTD = 0.093 METD= 0.0018 TI = 101.6

(7) SN 14062

C4H9

MTD = 0.373 FTD = 0.280 METD= 0.002 TI = 186.5

(8) SN 15068

N- HO

Gallinaceum Malaria, Chick Q=2 Lophurae Malaria, duck Q-20 Cathemerium Malaria, duck Q=80

(9) SN 10275

Table I. Antimalarial Compounds (continued) 55

Gallinaceum Malaria, chick Q=3 Lophurae Malaria, duck Q=8

Not studied in humans

(10) SN 12673

/ c 6h 13

c 6h i 3 Gallinaceum Malaria, chick Q=6 Lophurae Malaria, duck Q=8

Not studied in humans

(11) SN 12674

Gallinaceum Malaria, chick Q=8 Lophurae Malaria, duck Q=8

Not studied in humans (12) SN 12678 Table I. Antimalarial Compounds (continued) The general preparation schemes of these 4-quino

linemethanols are outlined below, where X is any substi

tuent.

The starting point for these syntheses is the condensation of a substituted isatin with the desired methyl ketone or the Doebner-Miller condensation2^ to give the cinchoninic acids (12) which can easily be converted to the esters (6) through the acid chlorides

(13), by simple esterification, or by the procedure developed in this laboratory using triethyl orthoformate catalyzed with p-toluenesulfonic acid. The condensation of 6 with ethyl acetate in benzene using sodium ethoxide as the base proceeds smoothly to give 70-85$ yields of

the y^-keto ester. Without isolating the y^-keto ester,

it is decarboxylated to 7, brominated using various

techniques2^""2^ to 8, reduced to 9, and converted to 11 without isolating 10„ An alternative route is conversion of 12 to the acid chloride (13), then to 14,^ which can easily be converted to 8.

. These procedures provide convenient routes to the ethanol-amino structure at the 4-position on the quinoline nucleus, but problems are encountered when functional groups are present that are labile to the 26 reaction conditions, 26 The previous synthetic routes have proved unsatisfactory when substituents are present which are labile under the reaction conditions. For example, when methoxy or ethoxy groups were present on the quinoline nucleus, they were cleaved to the hydroxy derivative on attempted decarboxylation in acid media. Due to these undesirable side reactions, new routes to the ethanol amine structure were explored. 58

1) CH3C02C2H5

NaOC2H 5 X3C9H3NC02C2H5 X3C9H3NCOGH3 C6H6 2) H+, H o0 (6) (7) H W [H] X 3CgH 3NCH (OH) CH2Br X3CgH3NCOCH2Br

(9) (8)

w . HNR, [3CgH 3N^HOpH2 ^ X3CgH3NCH(OH)-CH2NR2

(10) (11)

S0C1, X3CgH3NCOOH X3CgH3NCOCl

(12) (13)

V (8) ■X3CgH3NCOCHN2

(14)

Figure 2, Synthetic Routes to 4-Quinolinemethanols„ RESULTS AND DISCUSSION

1„ Synthetic Routes

Since little work has been done on the thiophene substituted cinchoninic acids, we decided to make several derivatives of this type and have them tested for antimalarial activity. The first reaction scheme (fig, 3) to the ethanol amine structure proved unsatisfactory because of low yields and unexpected products.

The reaction of 15 and 16 to give IT (app, II,

IR-l) proceeded smoothly with yields of 80-85$, Reduction of 17 with lithium aluminum hydride in ethyl ether-THF gave 18 (app, II, IR-2) in 80-90$ yields. The selenium dioxide oxidation of 18 in dioxane gave 19 (app. II, IR-3,

NMR-l) in good yields but the heating period was increased from one half hour to one or two hours. The reaction of

19 with sodium bisulfite gave a quantitative yield of

20 (app. II, IR-14) and reaction of the latter with potassium cyanide in water-ether mixture gave good yields of 21 (app. II, IR-4)j this reaction was complete when all of the solid (20) disappeared into the ether layer.

Recrystallization of 21 from chloroform gave a stable white crystalline material.

59 60

(15)

HO .ON X / CH

NagCO^ 4-

(18) Figure 3. Attempted Synthetic Route to 4-Ami no-quinoline-

methanols. 61

Unexpectedly, when 21 was subjected to hydrolysis in acid media, the product was not the ot-hydroxy acid but the hydrochloride of the alcohol (22) (app. II, IR-5) which was neutralized with aqueous sodium carbonate to the alcohol (l8) (app. II, IR-6). A reasonable mechanism may be written in which the first step is the hydrolysis of the cyano group to the acid (23), which is unstable at the reaction conditions, decarboxylating to 24 which may

HO, CH

(23) (24)

(22) 62

The acid (17) was converted to the acid chloride hydrochloride (25) (app. II, IR-7) by refluxing in excess thionyl chloride for two hours to give 70-80$ yields.

The acid chloride hydrochloride (25) was reacted with a variety of amines to give the amides. The following amides were synthesized, where R represents the 2-(2-thienyl)quinoline hydrochloride portions (app. II, IR-8 to 13, NMR-2 and 3).

R-C-NH \

Figure 4. Syntheses of 4-Quinolinecarboxamides.

Compounds 26-32, including the semicarbazone of compound

19 (app. II, IR-19), were sent to test their antimalarial activity. A second approach which seemed promising was the

reaction of the sodium salt of diethyl N,N-diethylamino-

malonate with the acid chloride (25) to give the g-keto

diester. This reaction proceeded smoothly but when the

decarboxylation was attempted using acid and basic condi

tions, it was found that acyl cleavage occurred to give

the 2-(2-thienyl)cinchoninic acid (17) back. This pro

cedure proved unsatisfactory and was abandoned.

A third approach was a basic condensation of

ethyl N,N-diethylaminoacetate with the substituted

cinchoninate esters. The condensation proved satisfac

tory to give 75-950 yields of 37 and 38 using sodium

N(C

(39) (35) R=H (37) R=H

(36) R=C1 (38) R=C1

hydride as the base, benzene or toluene as the solvent,

and heating from 36 to 48 hr. 64

The attempted decarboxylation of 37 did not proceed as expected but gave mostly acyl cleavage in dilute potassium hydroxide and degradation products in dilute sulfuric or hydrochloric acid. The IR and NMR spectra suggested that the ester group may be forced into the Tr-clouds of the quinoline moiety. Partial reduction with sodium borohydride also suggested this possibility although the enol-form of 37 and 38 could also cause the abnormality in the spectra and chemical data.

The model compounds, synthesized by condensing ethyl benzoate with 39, gave upon reduction with sodium borohydride the ^-hydroxy ester. These reactions were normal; the products had the expected spectral features

(fig. 5 and 6).

(42) 65

Figure 5. IR Spectrum of ^-Substituted-N,N-diethyl

Glycine Ethyl aster. 66

'WMWW,*** MW,*,

Figure 6. NMR Spectrum of o<-Substituted-N,N-diethyl

Glycine Ethyl Ester. 67 The.condensation of 35 with 39 in toluene with sodium hydride as the condensing agent gave after 48 hr. a 93$ yield of product. The NMR (fig. 7) showed three . protons at 9.8 T and 6 protons at 8.75 T and, instead ; ... of showing a simple splitting pattern for the methylene groups, gave a multiplet located at approximately 6.57%

From the model compounds (fig. 5 and 6) it is evident that the resonance of the methylene hydrogens of the ethyl group on 37, connected to the nitrogen atom, were lowered from 7.4 T to 6„5*T and the resonance of the oxygen methylene hydrogens are raised from 5°9 Y to

6.51%

The IR spectrum (fig. 8) of compound 37 did not give a carbonyl band expected for the ethyl ester but instead only one carbonyl band with a small shoulder was present at 1650 cm . Upon partial reduction for one hour using excess sodium borohydride it was found that the carbonyl band at 1650 cm-'*' diminished and a normal ester carbonyl band began to appear at 1735 cm- . The loss of the enol-form and the change in geometry of the

^-keto ester group as the ketone carbon was changed p Q from sp to sp bonding could easily explain this pheno menon. Furthermore, when compound 37 was stirred overnight at room temperature with excess sodium borohydride, both 68 carbonyl bands disappeared (fig. 8), giving the diol 43 which gave correct elemental analysis and NMR (fig. 7).

n (c 2h 5)2 0HV /CH-CH20H

From these data one may rationalize that as the ketone carbon was changed from sp 2 to sp 3 bonding by reduction, the ester group was able to move out of the T-clouds of the aromatic nuclei, causing the normal ester carbonyl band to appear on the IR spectrum, and/or the loss of the enol-structure could also give similar results. It was found that the triplet at 9.8 T completely disappeared upon reduction of the ester group, thus giving more evidence that the ester group was the ethyl group pre sent in an abnormal region of the NMR. The reduction of the ester group with sodium borohydride remains unexplained unless one rationalizes in terms of the y^-keto ester. As the ketone group is reduced, the hydroxyl group forms an ionic complex with an additional

BHg, thus situating the reducing agent in a position to effect maximal reducing power. It is also known that as the hydrides are removed from the reducing agent the remaining hydrides are far more reactive. Further work on the reduction of y^-keto esters would probably explain these results, but at present no information is available to justify this reasoning.

The condensation of 36 (app. II, IR-16) with 39 gave the exact spectra data as compound 37 as related to its NMR (app. II, NMR-4) and IR (app. II, IR-15).

Although some interesting data were obtained from these compounds, the problem of finding a new and better synthetic route to the 4-quinolinemethanols remains. 70

Figure 7. NMR Spectrum of

Glycine Ethyl Ester. 71

Glycine Ethyl Ester. EXPERIMENTAL

1. General

Boiling points and melting points are uncorrected.

Infrared spectra were taken on a Perkin-Elmer

Infracord Spectrophotometer and the instrument calibrated with a polystyrene film.

Nuclear magnetic resonance spectra were taken on a Varian A-60 Spectrometer. I Microanalyses were performed by C. F, Gieger,

Ontario, California.

2. 2-(2-Thienyl)cinchoninic Acid

Ethanol (50 cc., 95$)* 290 00. of water, 51 g.

(1.27 mole) of sodium hydroxide (100$), and 51 g. (0.35 mole) of isatin were placed in a 500 cc. round bottom three-necked flask and with mechanical stirring 46 g.

(O.36 mole) of acetylthiophene was added and the solution refluxed .16-20 hr. After the heating period the stirring was stopped and the solution poured into a 600 cc. beaker and allowed to sit in an ice-water bath until the entire solution set to a solid (4-5 hr.). The solid sodium salt

72 73 was vacuum filtered and the last traces of solvent removed by pressing with a large rubber stopper. The damp sodium salt was transferred to a 2 1. beaker and

1000 cc. water added and the solution stirred until all the solid dissolves. The solution was slowly poured into 200 g. ice containing a 2 molar excess glacial acetic acid (manual stirring was required during the, addition). After the neutralization the yellow solid was vacuum filtered and pressed free of water. The damp product was dissolved in a minimum quantity of hot iso propyl alcohol (approximately 200 cc.) and cooled in the refrigerator overnight. Upon vacuum filtration and drying there was obtained 73 g. (830 yield) acid melting at 209-211° (lit.27 ffi.pv 211°).

3. 2-(2-Thienyl)-4-quinolinecarbonol

Lithium aluminum hydride (6 g . ) and 250 cc. dry ether were placed in a 1 1. three-necked flask and with mechanical stirring 36 g. (0.014 mole) of 2-(2-thienyl)cinchoninic acid in 200 cc. dry tetrahydrofuran was added dropwise. The suspension was stirred 12 hr. at room temperature and then decomposed by adding dropwise 12 cc. water followed by 12 cc. 500 sodium hydroxide solution.

The suspension was stirred vigorously until the salts coagulated. The solution was vacuum filtered and the

filtrate concentrated at 30 mm, to give 30 g, (88$)

brown oil which set to a glassy solid. An analytical

sample was recrystallized from chloroform to give a white powder melting at 124-125°,

Anal, Calcd, for C^H^NOS: C, 69,67; H, 4,59;

N, 5.81. Found: C, 69,42; H, 4,63; N, 5 .62,

4. 2-(2-Thienyl)-4-quinofinealdehyde

Selenium dioxide (17 g., 0.153 mole) was added

in portions over a period of 30 minutes to a stirred

solution of 75 g. (0.31 mo l e ) 2-(2-thienyl)-4-quinoline-

carbonol in 300 cc. dioxane while the temperature was,

raised from 60-100°. The solution was refluxed for

2-3 hr. and the selenium metal filtered. The dioxane was distilled at 30 mm. to give 66 g. (89$) crude product which crystallized overnight. The aldehyde was recrystal

lized from chloroform to give yellow crystals melting at

111.1-112.0°.

Anal. Calcd. for C^H^NOS: C, 70.29; H, 3.79;

N, 5 .85. Found: C, 70,34; H, 3,92; N, 5 .88. The preparation of 2-(2-thienyl)-4-quinolinealdehyde was also prepared by using equmolar amount

of selenium dioxide with 2-(2-thienyl)-4-quinolinemethanol.

Selenium dioxide (34 g., 0.30 mole) was added in portions over a period of 30-40 minutes to a stirred

solution of .75 g. (0<,31 mole) of 2-(2-thienyl) -4-quinolinemethanol in 300 cc. dioxane while the temperature was raised from 60-100°. The solution was refluxed for

2 hr. and the selenium metal filtered. The dioxane was distilled at 30 mm. to give a dark brown residue.

This residue was mostly the selenium dioxide adduct of 2-(2-thienyl)-4-quinolinealdehyde. This adduct was converted directly to the bisulfite adduct by bubbling

sulfur dioxide into an aqueous solution of the sele nium adduct. The bisulfite adduct was decomposed by addition of saturated sodium carbonate solution. The dark brown aldehyde was filtered and recrystallized from chloroform to give 34 g. (45$) yellow crystalline needles.

Although this method gives a direct synthesis to the bisulfite adduct, it is more practical to use equmolar quantities of selenium dioxide. 76

5» 2-(2-Thienyl)-4-qulnollnealdehyde Semicarbozone

Semiearbozide hydrochloride (2 g.) and 1.6 g. sodium acetate were dissolved in a 10$ aqueous ethanol solution-and 3 g. aldehyde, dissolved in a minimum amount of ethanol, was added in one portion. The solution was warmed to the boiling point of ethanol and the solution stirred for an additional 30 minutes at room temperature.

The semicarbozone was filtered, washed thoroughly with ethanol, and dried to give a quantitative yield of product melting at 252-253°.

, Anal. Calcd. for C-^H-^N^OS: C, 60.77; H, 4.08;

N, 18.91. Found: C, 60.37; H, 4.28; N, I8 .60.

6 . 2-(2-Thlenyl)-4-quinolinealdehyde Bisulfite Adduct

Ethanol (22 cc.), 7 g. (0.029 mole) 2-(2-thienyl)-

4-quinolinealdehyde, and 90 cc. saturated sodium bisulfite solution were stirred for 4 hr. at 40-60°. After the reaction time 30 g. ice was added to the suspension and stirred an additional 1 hr. The product was filtered, washed thoroughly with ethanol and dried to give 9.6 g.

(94$). 77

7. 2-(2-Thienyl)-4-quinoIlnecyanohydrin

Ethyl ether (100 cc,) and 17 g„ (0.05 mole) bisul fite adduct were placed in a 250 cc. Erlenmeyer flask and with stirring 4 g, (0.114 mole) of potassium cyanide in 25 cc. water was added in one portion and the solution stirred until all the solid dissolved. The ether layer was separated, dried over magnesium sulfate, and concen trated to give 11.8 g. (86$) crude product. Recrystalli zation from chloroform gave white crystalline needles melting at 133-134°.

Anal. Calcd. for C^H^NgOS: C, 67.65; H, 3.78;

N, 10.52. Found: C, 68.32;" H, 3.68; N, 10.35.

8. 2-(2-Thienyl)cinchoninoyl Chloride

2-(2-Thienyl),cinchoninoyl acid (17 g . , 0.067 mole) was added to 100 cc. thionyl chloride and the solu tion refluxed 2 hr. The thionyl chloride was removed by distillation at 30 mm. After the removal of the thionyl

chloride 50 cc. toluene was added and then distilled to remove last traces of thionyl chloride. This procedure was repeated twice. The solid residue was then stirred

in 200 cc. dry ethyl ether containing a trace of hydrogen

chloride gas at 0° for 2 hr. and then filtered to give 78

16 go ( 78$). of acid chloride hydrochloride melting at

138-141°o

9. 2-(2-Thienyl)-4-(N,N-dimethyl-l, 3-propylenediamine)-

quinolinecarboxamide

2-(2-Thienyl)cinchoninoyl chloride hydrochloride

(4 g«,, 0.013 mole) was added to 50 cc. dry tetrahydrofuran

and with stirring 2 g. (0.02 mole). N,N-dimethyl-l,3-pro-

pylenediamine was added dropwise. The solution was warmed

(50-60°) for 10 minutes and then 15-20 cc. 10$ potassium

carbonate was added and the solution stirred for 20-30 minutes. Ice (approximately 50-60 g,) was added and the

solution stirred until the product became a solid. The

product is filtered, dried, and recrystallized from cyclo

hexane to give 3.5 g. (80$) melting at 138.8-139..5°.

Anal. Calcd. for C ^ H g ^ O S : C, 67.23; H, 6.24;

N, 12.38. Found: 0, 67.25; H, 6.27; N, 12.68.

10. 2-(2-Thienyl)-4-p-anisldinequinolinecarboxamide

p-Anisidine (2 g., 0.016 mole) was added in one

portion to 4 g. (0.013 mole) 2-(2-thienyl)cinchoninoyl

chloride hydrochloride in 50 cc. dry tetrahydrofuran and o'- the solution stirred at 40-50 for 30 minutes. The solu

tion was neutralized with 20-25 cc. 10$ potassium carbonate 79 and then 50-60 g, ice was added and the solution stirred for an additional, 30 minutes. The product was filtered, dried, and recrystallized from tetrahydrofuran-ethanol solution to give 4 g. (88$) melting at 259.5-261.0°.

Anal. Calcd. for C2iHi6N2°2S: C> 69°98; H, 4.4?; N, 7.77. Pound: C, 70.13; H, 4.82; N, 7.55.

11. 2-(2-Thienyl)cinchonlnoylphenylhydrazide

Phenylhydrazide (l.l g., 0.0081 mole) was added in one.portion to a stirred solution of 2.4 g. (0.0077 mole)

2-(2-thienyl)cinchoninoyl chloride hydrochloride in

50 cc. dry tetrahydrofuran and the solution stirred at reflux for an additional 10 minutes. The tetrahydrofuran was distilled at 30 mm. to give a yellow solid. The residue was stirred for 30-40 minutes in 25 cc. 20$ aqueous potassium carbonate and the solid vacuum filtered.

The residue was suspended in boiling ethanol (50 cc.) for

2-3 minutes, cooled to room temperature, and filtered to give 2.8 g. (97$) white powder melting at 240-241°.

Anal. Calcd. for C21H15N3°2S: G> 67 ° 5 4 j H, 4.05;

N, 11.25. Found: G, 67,36; H, 4.16; N, 11.12.

12. 2-(2-Thienyl)cinehoninoyl-N,N-diethylethylenediamine

N,N-Diethylethylenediamine (1.15 g.* 0.01 mole) was added dropwise to a stirred solution of 3 g. (0.0097 80 mole) 2-(2-fchienyl)clnchonlnoyl chloride hydrochloride

In 25 cc„ dry tetrahydrofuran„ The reaction was warmed to 50° for 10 minutes and then after cooling to room temperature, the solution was neutralized with 25 cc„

20$ aqueous potassium carbonate. The product was extracted twice with 50 cc, portions of ethyl ether. The ether was removed by distillation at 30 mm, to give a l$ght gray solid which, upon recrystallization from cyclohexane, gave

2,4 g, (72$) white powder melting at 106,8-108,0°,

Anal, Calcd. for C^Hg^N^OS: C, 67,96; H, 6 .56;

N, 11,89, Found: C, 67,74; H, 6 ,89; N, 12,13.

•13. Hydrolysis of 2-(2-Thlenyl)-4-quinolinecranohydrin

The cyanohydrin derivative (4 g.) was added to

40 cc. 6 N, hydrochloric acid and the solution refluxed

12 hr. The reaction suspension was cooled and filtered to give 3.4 g. (8l$) yellow powder. After two recrystal lizations from glacial acetic acid there.was obtained a golden crystalline product melting at 261-264°. Neutrali zation with aqueous sodium carbonate gave a light gray powder melting at 121-123°. Recrystallization from chloroform gave a white powder melting at 123.5-125° which was 2-(2-thienyl)-4-quinolinemethanol and the former compound being the hydrochloride salt. Anal. Calcd. for HC1: C, 60.53;

H, 4.36; Nj, 5.04. Found: C, 60.44; H, 4.37; N, 5.05.

Anal... Calcd. for C^H^NOS: C, 69.67; H, 4.59;

N, 5.81. Found: 0, 70.02; H, 4.60; N., 5 .81.

14. -2-Acetylthiophene

28 Using the procedure of Kasak and Hartough

168 g. (2 mole) of thiophene and 107 g. (1 mole) of 97$

acetic anhydride were heated to 70-75°, the source of

heat removed, and 10 g. (6 cc„) of 85$ phosphoric acid was added. After 2-3 minutes the reaction became exo

thermic and occasional cooling was required. The boiling

subsided in a few minutes and the solution was refluxed

2 hr. The cooled solution was washed with 250 cc. water

followed by two washings with 100 cc. portions of 5$

sodium carbonate. The orange-red liquid (lower layer) was distilled through a short fractionating column after

removing 75-80 cc. of unchanged thiophene (b.p. 83-84°)

at atmosphere pressure. The product was distilled at

10 mm. to give 94 g. of clear liquid boiling at 89-90°.

15. Ethyl Bromomalonate

Using the procedure of Palmer and McWherter^

160 g. (l mole) of diethyl malonate and 150 cc. carbon tetrachloride were placed in a 1 1. three-necked flask fitted with a mechanical stirrer, a reflux condenser, and a dropping funnel with the stem reaching almost to the blades of the stirrer. The. bromine reaction was initiated with a large electric bulb and after the reaction started the rest of the bromine was added at such a rate to keep the liquid boiling gently. It was then refluxed until no more hydrogen bromide came off

(1 hr.). The solution was cooled and washed five times with 50 cc. portions of 5$ sodium carbonate solution.

The product was fractionated once through an efficient column to give 160 g. (67$) clear liquid boiling at

122-125° at 16 mm.

16. Diethyl N,N-Diethylaminomalonate

Diethyl, amine (73 g., 1.0 mole) was added dropwise to 100 g. (0.42 mole) diethyl bromomalonate in

200 cc. 1000 ethanol over a period of 2 hr. The solution was stirred for 2 hr. at room temperature and then heated to 50-00° fop 15-20 minutes. Dry ethyl ether (500 cc.) was added and the solution stirred at 0° for 1 hr. The diethyl amine hydrobromide was filtered and the filtrate concentrated at 30 mm. After filtering again the product was distilled at 1 mm. with the oil bath temperature 83 ranging 110-120°. About 10 cc. forerun was discarded and the product collected at 85-90° to give 43 g. (44$) water clear product (lit^° b.p.g, 110-113°).

17i Ethyl NjN-Dietbylamlnoacetate

The ethyl bromoacetate (167 g., 1.0 mole) was added dropwise over a period of 2 hr. to 146 g. (2.0 mole) diethyl amine in 500 cc. dry ethanol. After the solution had stirred for 12 hr. at room temperature, it was stirred at 0° for 2 hr. and filtered. Ethyl ether (500 cc.) was added and the solution stirred an additional 2 hr. at

0° and again filtered. This procedure removed most of the diethyl amine hydrobromide. The solvents were removed through a fractionating column at 30 mm. After another filtration the product was distilled at 28 mm. to give

133 g. (83$) water clear product boiling at 84-86° (lit.^ b*P°i2> 68°).

18. Ethyl 2-(2-Thienyl)cinchoninate

2-(2-Thienyl)cinchoninic acid (30 g., 0.117 mole),

55 cc. triethyl orthoformate, and 0.3 g.■ p-toluenesulfonic acid were refluxed until all the acid dissolved (approxi mately 6 hr.). The ethyl formate and ethanol were col lected during the refluxing period. After the reaction was complete (6-7 hr.) the excess triethy1 orthoformate was removed at 30 mm. to give a dark brown residual oil which readily crystallized. Recrystallization from iso propyl alcohol gave 25 g. (74$) crystalline product melting at 81.0-82;.5° (lit.2^ m.p. 83°).

19. 6-Chloro-r2-(2-Thienyl)cinchonlnic Acid

Chloroisatin (99«7 g. , 0.53 mole), 76 cc. 95$ ethanol, 444 cc. water, 78.4 g. 100$ NaOH, and 70.7 g»

(O.56 mole) acetylthiophene were refluxed together for

18 hr. After the heating period the hot solution was poured into all. beaker and cooled in ice water for

5 hr. The product wafe vacuum filtered and the excess solvent was pressed out with large rubber stopper. The damp sodium salt was dissolved in 1500 cc. warm water and then poured slowly into 2 moles glacial acetic acid in 300-400 g. ice. The product was vacuum filtered and dried to give 84 g. (55$) of light yellow powder. An analytical sample recrystallized from ethanol melted at

257-258°.

Anal. Calcd. for C^HgClNOgS: C, 58.03; H, 2 .78;

N, 4.83. Found: C, 57.85; H, 2 .80; N, 5.05. 85 20. Methyl 6-ChIoro-2-(,2-Thienyl)cinchonlnate

5-Chloro-2-(2-thlenyl)cinchdnihic acid (1.3 g.,

0.0045 mole) was added to an excess of diazomethane in ethyl ether at 0°. The solution was stirred for 30 minutes and then the ether was evaporated with an aspirator to give a quantitative yield of product. Recrystallization from methanol gave a light yellow crystalline product - melting at 148.5-149,5°.

Anal, Calcd. for G15H1oclN02S: G> "59.31; H, 3.31;

Nj 4.61. Found: 0, 59.13; H, 3.19; N, 4.58.

21. Ethyl 6-Chloro-2-(2-Thienyl)cinchoninate

5-Chloro-2-(2-thienyl)cinchoninic acid (35 g.,

0.12 mole), 54 g. triethyl orthoformate, and 0.5 g. p-toluenesulfonic acid were refluxed together until all the acid dissolved (approximately 30 hr.). The solution was then cooled to room temperature arid allowed to sit overnight. The product was then stirred with ethanol and filtered. Recrystallization from ethanol gave 31 g. (82$) light yellow needles melting at l40,0-

141.0°.

Anal. Calcd. for C16H 12C1N02S: C> 6 o ^ 7 ; H, 3.80;

N, 4.92. Found: C, 60.76; H, 3.52; N, 4.45. 22„ 2-(2-Thienyl)cinchoninoyloctadecylamine

Armene 18 (3.3 g=) was added in portions to 4 g.

(0.0129 mole) 2-(2-thienyl)oinchoninoyl chloride hydro chloride in 20 cc. dry tetrahydrofuran and the solution stirred for 30 minutes. Ice (20 g„) and 20 cc. 5$ aqueous sodium carbonate solution were added and the solution stirred until the product crystallized. Upon filtration and recrystallization from acetone there was obtained 4.7 g. (93$) of cream colored product melting at 110-112°.

Anal. Calcd. for C32H46N2OS: C} 75.84; H, 9.15;

N, 5.53. Pound: C, 76.01; H, 9.43; N, 5.84.

23. Ethyl M-2-(2-Thienyl)oinchoninoyl Crlycinate

Ethyl glycinate (3 g.) was added to 20 cc. dry tetrahydrofuran containing 5 cc. dry pyridine. With stirring 5 g. 2-(2-thienyl)oinchoninoyl chloride hydro chloride was added in portions and the reaction mixture stirred for 30-40 minutes. Ice (20 g.) and 20 cc. 5$ aqueous sodium carbonate solution were added and the solution stirred until the product crystallized. The product was filtered and recrystallized from cyclohexane to give 4 g. (74$) melting at 151-153°. Anal. Calcd, for c18Hl6N203S: c* 63.51; H, 4.74

N, 8.23. Found: C, 63.99; H, 4.69; N, 7.88.

24. Ethylo<-^2-(2-Thienyl)cinchoninoyl] -N,N-dlethyl

Glycine

Ethyl 2-(2-thienyl)cinohoninate (26 g., 0.092 mole), 25 g. (0.157 mole) ethyl diethylaminoacetate,

8.0 g. sodium hydride (containing 58.6$ mineral oil), and 60 cc. dry toluene were placed In a 200 cc. round bottom flask with condenser and drying tube and with stirring the solution was heated 90-100° for 36 hr.

After the heating period 5-10 cc. ethanol was added to decompose the excess sodium hydride and the solution was slowly poured into 400 cc. ice water containing

15 cc. glacial acetic acid. The solution was stirred vigorously for one hr. or until the product crystallized

The solution was filtered to give 31 g. product. After filtration the toluene layer was separated and concen trated to give 3 g. more product. The total yield of product was 34 g. (0.086 mole, 93$). Recrystallization from isopropyl alcohol gave light gray crystals melting at 172-174°.

Anal. Calcd. for C!22H24^203^: 66.64; H, 6.10

N, 7 .06. Found: C, 66.82; H, 6.11; N, 7.33. 88

25 o Reduction of Ethyl c< - [2-(2-Thienyl)cinchpninoyl ]] -

N^N-diethyl Glycine With Sodium Borohydride to Give

the Diol

The y^-keto ester (4 g,) was added to 100 cc 100$ ethanol and 4 g„ sodium borohydride added in portions and the solution stirred for one hour. Upon work-up it was found that the reduction was incomplete. The same pro cedure as before was used and the solution stirred 5 hr.

Sodium borohydride (4 g.) was again added and the solution stirred an additional 12 hr. Upon work-up it was found that no carbonyl band was present in the IR and the NMR showed no ester group remaining. Identification of the compound showed it to be the diol by reduction of the keto group and subsequent reduction of the ester. The product melted at 134-136° and amounted to 3 g.

Anal. Calcd. for C20H24N2°2®: 67.38; H, 6 .78;

N, 7.86. Pound: • C, 67.891 H, 6 .6l; N, 7.95.

26. Ethyl ~~d- [2-(2-Thienyl)-6-ChlorocinchoninoylJ -N,N-~~

~~diethyl Glycine~~

~~Ethyl 6-chloro-2-(2-thienyl)cinchoninate (13 g.,~~

~~O. 041 mole), 13 g. (0.082 mole) ethyl diethylaminoacetate,~~

~~4.5 g. sodium hydride (containing 58.6$ mineral oil), and 89~~

30 ec,, dry benzene were placed In a 200 cc. round bottom flask with condenser and drying tube and the solution refluxed 48 hr. After the refluxing period 10 cc, ethanol was added dropwise to decompose the excess sodium hydride.

The solution was then slowly poured into 400 cc, ice water and the solution stirred vigorously until the pro duct crystallized (1-2 hr,). The product was filtered, washed with 50 cc, ethyl ether, and dried to give 13.5 g.

~~(0.031 mole, 7 7 $ ) product melting at 187,5-190,0°,~~

~~Anal. Calcd, for C22H23C'LN203S: 61,03; H, 5.38;~~

~~N, 6 .49. Found: C, 61,20; H, 5.21; N, 6.53. APPENDIX I~~

~~IR and NMR Spectra from Part I~~

~~90 91~~

~~WAVELENGTH MICRONS 7 8 9 1 0 11~~

~~WAVELENGTH (MICRONS) 6 7 8 9 1 0 11~~

~~WAVELENGTH (MICRONS)~~

~~fJ.N'DiMzrtyl 3r0><-ydo c -'tJfQA /yfjetkylevz- 4 0 0 0 3 0 0 0 2000 iMin/e. 92~~

~~WAVELENGTH 'MICRONS)~~

~~I f l - 4~~

~~C l s -^AJlnylcyc /opevtoAro I 4 0 0 0 3 0 0 0 2000 1500 1200 1000 90( CM'~~

~~4 0 0 0 3 0 0 0 2000 1 5 0 0 C M ' 1000 900 800~~

~~L R -b frass-3-^iuylcydopei/fy/~~

~~11 ftroA-i fWe * WAVELENGTH (MICRONS)~~

~~4 0 0 0 3 0 0 0~~

~~--- - l-SJifiiylcyclopewty I 11 fic e tQ tc WAVELENGTH (MICRONS) 93~~

~~4000 3000 2000 1500 CM ' 1000 900 800 700~~

~~5-V~~

~~■frOtA solv tyS'S AjHOj WAVELENGTH (MICRONS)~~

~~4000 3000 2000 1500 CM ' 1000 900 800 700~~

~~WAVELENGTH (MICRONS/~~

~~4000 3000 2000 1500 CM ' 1000 900 800 700~~

~~j/lcydopr/. ‘ u c l ftcM 5 UdyS/5 'Vi'th AyC/Oy. WAVELENGTH (MICRONS) 94~~

~~4 0 Q P 3 0 0 0 2000 1 5 0 0 CM' 1000 900 800 7 0 0~~

~~i z BronOauiNoliNe 7 8 9 1 0~~

~~WAVELENGTH (MICRONS) 95~~

~~— MMK-l — j V'hJ-D.uerty, iti-34JUy- cyciap tjjryhK ? r»A, y~~

~~NMK-3 —~~

~~c/5 -3- 'Jt/lylc.ydoptUtuAol~~

~~- - A/MH'4- — ^dl-i~Vi>yl<-yclopeutyl Toiylate.~~

~~5/ 3rw’ 97~~

~~10 r i-s-i 98 99~~

~~1:0 rfMlr) *' NMB- 9 — DesoytybeNZOM'd).~~

~~J if Jf L~~

~~■ : 1 1 ■11 HSmITT APPENDIX II~~

~~IR and NMR Spectra from Part II~~

~~100 101~~

~~WAVELENGTH MICRONS)~~

~~100~~

~~■5 4 0~~

~~lk -1 1 2-(l Thienyl)citKhov;A/fC.~~

~~4 0 0 0 3 0 0 0~~

~~WAVELENGTH (MICRONS)~~

~~4 0 0 0 3 0 0 0 1 0 0 0 9 0 < nlJcfiy / * 102~~

~~. WAVELENGTH MICRONS)~~

~~4000 3000 1 0 0 0 9 0 i cyavohjdriN~~

~~4000 3000 2000 1500 CM1 1000 900 800 700~~

~~2 -(2-7"'hicHyfyy- Mertb*uo! HyJrochionJc~~

~~WAVELENGTH (MICRONS)~~

~~4 0 0 0 3 0 0 0~~

~~2<2-T/);evvy/)-V-^v»>o//we- 7 8 9 1 0 11 fAttklHol WAVELENGTH (MICRONS) 103~~

~~WAVELENGTH MICRONS)~~

~~4 0 0 0 3 0 0 0 1000 90( Chlcrl de HyJrochlor; Je~~

~~WAVELENGTH MICRONS)~~

~~_____ 2-(z-Thie*/yl)-4-p-aN(s~~

~~4 0 0 0 3 0 0 0 1 0 0 0 9 0 < dine £>JiNolinecarbotQM\tie 104~~

~~WAVELENGTH MICRONS)~~

~~_E thyl ^-2~C2-Th!e,vyI) — 4 0 0 0 3 0 0 0 90< c i a/c hoHi'Noy I <]lyc.; Hate~~

~~WAVELENGTH (MICRONS) 6 7 8 9 10 11 100~~

~~______L J_-(z-Thie»yl)ciNcho»;x>yl-~~

~~4 0 0 0 3 0 0 0 2000 1 5 0 0 120%, 1000 90. yV-su/fcA/Z/dM.Ve 105~~

~~4 0 0 0 3 0 0 0 0.0~~

~~_ 2~(2-Th.: uifjo - 7 8 9 10 ii liMeoldd^yJe bisulfite. WAVELENGTH (MICRONS) A U *-t~~

~~WAVELENGTH (MICRONS) 5 61,1,1 7 8 %9 10 11 100~~

~~IR -1 5 Ethyl °<-[2<2-TA/~~

4 0 0 0 3 0 0 0 i o o o 9 o < chlorociHcho*iHoyl]-A/)llf- Jiethyl 6/yc/ve RANSMITTANCE (%) _ TRANSMITTANCE (%) _ TRANS 4000 3000 4000 3000 WAVELENGTH WAVELENGTH /MICRONS) (MICRONS) 90( C/'/vc 90( otoci ' e t a /'M A O f d iv c o t lo b c £-ch - o r o l h c - £ - ) l y J t e i h T - l ( - l rAii. d d A IroAJinic. 7 1 - R I -20 106

~~ABSORBANCE 0.0 0 4 0 0 0 3 0 0 0 4 0 1 9 8 7 W A V E L E N G T H ( M I C R O N S ) 11 _ 'zTi//y- i /He- o/iH uiN 2'(z-Thie/J/Iy^-Q StA'ic irbozoNt StA'ic 107 108~~

~~— WMR-l — aldehyde~~

~~5vvec/> /351 i~~

~~I I >; Wu V VviW^^Vrif^V^^V1 W W vf "'Wwwy M~~

~~' : - '-1 •■•-;^--t-- !.. t ■ 1 ;■• t ••■;■■ jmu >~~

~~— NKR-3 — 2/2-7/- evyl)ciMC *<>»' «ey'- V,A/- dientylen/KAiry.Mwe~~

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