The synthesis of some lactones related to podophyllotoxin

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THE SYUTliESIS OV SOME Lj»CTOHE£ EELaTED TO PODOPH^eLOTOXIH

by Artiiur Ellis Brown

Thesis submitted to the Faculty of the Graduate School of the University of Maryland in partial fulfillment of the requirements for the degree of Doctor of Philosophy Id 50

UMI Number: DP70280

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The author wishes to express his sincere appreciation of the interest and guidance of Professor Kathan a. Drake, which made this work possible.

TABuE OF CONT-..NTS INTRODUCTION............................................... I DISCUSSION FXPDi -1MiiiNTA

............................................ 3 ( •t

......i

#!)4

Dthyl Benzylm&lonate......................... ......... 34 Ethyl Benzylacetoacetate.................... *......... 35 Phenacyl Bromide...................................

35

Ethyl Denzy Iphenacylmalonate........................... 36 Ethyl Benzylphenncyl&eetoacetate...................... .38 Ethyl Benzylphenacylcy&noacetate....................... 39 Hydrazone of /3-benzoyl- oc-benzylpropionitrlie (XXI)...40 3,4-Dinitrophenylhydrazone of Ethyl BenzylphenacylciCtto acetate. •< •• •* ••.. ..... .... •• .• .* •• .. ...... •.. .40 BenzylphenacylmsIonic acid............................. 41 Benzylpnenaeylacetic acid (XIII)....................... 42 Ethyl o.enzy 1paenacy 1acetate............................ 43 p -Phony Ip h ena cy1 Benzylphene eylzcetate................. 45 Benzyl- f3 -hydroxy- o,-phenethylmalonie acidlactone (Xl).44 Ethyl Benzyl- 'i-lroinophenacyimoIonate (XXIII)......

.45

ilydriodic Acid Reduction of Ethyl Benzyl- QL-bromophenacylmalonate.................................... .4 Aluminum Isopropoxide Reduction of Ethyl Benzyl- cLhr om oph ena cy lina1on ate............................... 46 Catalytic Reduction of EthylBenzyiphenacylmalonate....47 CA-Benzyl-

phenyl- ^-butyrolactone (XII)............. 47

Attempted Addition of Formaldehyde to Ethyl Benzyi­ phenacylmalonate .................................... 48 Attempted Addition of Formaldehyde to Benzylphen&cylmalonic acid...........

49

ii Attempted Addition of Formaldehyde to Benzylphenacylacetic acid,.......

49

£-Chloroethyl Triphenylmethyl Ether...........

49

f-Bromoethyl Triphenylmethyl EtherT....................50 E-Cyanoethyl Triphenylmethyl Ether. ........

51

Attempted Hydrogenolysis of n-Butyl Triphenylmethyl Ether............

51

Attempted ilydrogenolysis of Ethyl Triphenylmethyl Ether. 51 Reaction of Benzyl Alcohol with Methyl Acrylate....... 5£ Reaction of Sodium Benzylate with j3 -Bromopropiophenona5£ Reaction of gC,/3 -Dibromopropiophenone with Benzyl Alcohol and Potassium Iodide........................53 Attempted Tr&nsetherification of /3 -EthoxypropiophenoneJ54 Reaction of Ethyl Benzyl- CL-bromophenacylmalonate with Potassium Cyanide.............................. 54 A.ttempted Reformatsky Reaction with Ethyl Benzyl- CLbromophenacylmalonate...............

55

Reaction of Ethyl Formate with Ethyl Benzylphenacylm&lonzte............................................ 55 Attempted Alkylation of Formylation Product........... 56 Attempted Reduction of Alkylated Forcnylzted Product.... 56 Saponification of Reduced Product..................... 5 7 Copper Derivative of Formyluted Product................57 hydrogenation of Copper Derivative.....................59 Attempted Benzyl&tion of Formyl&ted Compound.......... 59 Attempted Benzyiation of Copper Derivative............. 60 Reaction of /3-N aphthy Famine with FormyIs ted Product...60 Reaction of Alkali with Ethyl Bensylphenacylmalonate...61 (3 -Benzoyl- QL-benzylpropionic acid enol lectone (XXIV).6£ Saponification of /3 -Benzoyl- a-benzylpropionie acid enol lactone........................................ 63

iii cL - or /3-/ldehydo-/^-be'tioyl- CL -benzylpropionic acid enol lactone diethylecetal.......................... 63 LITERATURE CITED.......................................... o5

INTRODUCTION

Podophyllotoxin is one of tne compounds obtained from the rhizome extract of Podophyllum peltatum, and has been ‘ has reviewed found damaging to cancerous cells. L Sterling*0 the evidence on which Borsche and Spaeth based their sug­ gestion that podophyllotoxin has the structure I, and picropodophyllin, an isomer occurring with it, and into which it is easily converted, the structure II. Hartwell and Schrecker

Recently

have suggested that both substances

have the structure II, the difference between podophyl­ lotoxin and picropodophyllin being that of stereochemical arrangement.

They also admit the possibility of III.

In

an effort to find similar compounds for cancer therapy, this investigation was undertaken to find a synthetic route to compounds of structure IV, the stripped open-chain analogue of I.

Other synthetic work leading to compounds

related to podophyllotoxin and to other naturally occurring phenolic compounds of the 1-phenyltetralin and 1,4-diphenylbutane series has been reported by Sterling^ and 4 Price . Since there has been no previous approach to un­ substituted compounds similar to IV, reference will be made during the course of the discussion to the reactions which were deemed similar to those chosen for study.

2

OH CHoOH

0 c

II

CHpOH 0=

0 IV

III

OCH

CHgOH

^0V: RiR2 = CHS ^0 VI: RjR2 z H, H VII:

V, VI, VII

II

;

= CHo ; ^0-

vs

OCIfc = OCH■3

DISCUSSION An attempt was made to find a synthetic route to IV which would also apply to the preparation of V, VI, end VII.

This entailed the avoidance of reactions which in­

volved acid conditions suitable to the cleavage of tne ether groups.

With this in mind, the following reaction series

was undertaken: CKgBr UaOCgHfi

^COOCgHk OH v C00C2H5

HCHO K2C03

0

0 CHoOH

'CIIo OC (CpHg )3

.COOCgHg ■COOOgllg

;coocoi:^ G0000H5

C10(C6H5 )3

1. Al(OGH(CH3 )p)c; O U o n r v V i A -P A U 3 aponi fi cat ion

4

heat

pa

IV

Ethyl benzylmalonate was prepared according to the proa cedure in Organic Syntheses^ and tne yields were found to be as reported (52-57J4) .

However, it was found that the

use of sodium hydride instead of sodium ethoxide as a base, in excess ethyl malonate instead of absolute ethanol as a solvent, cut down the time necessary for the reaction and increased the yield to 85$.

The time spent preparing abso

lute ethanol and cutting sodium under oil was saved when sodium hydride was used, since the base is commercially available in a form suitable for use, an easily poured powder, and the reaction could be run at higher temperatures than those obtainable when ethanol was used.

5 The preparation of phenacyl bromide was also modifiedG Published directions suggest that the crude product of the bromination, after being evaporated at low pressure to re­ move hydrogen bromide and the etner used as solvent, be washed with a mixture of petroleum ether ana water, a puri­ fication process which leads to a strongly lachrymatory product that holds a large amount of water, making its use in the laboratory unpleasant and its suitability for malonic ester condensations questionable.

If the crude

brominated product is freed of solvent by lengthy (l to 6 hours) evaporation under the diminisned pressure obtainable with a v/ater-pump, while a slight current of air is intro­ duced by means of a capillary tube, arid then washed thoroughly with water, it may be recrystallized from petroleum ether to yield hard flat plates that dry in air to a stable, almost non-lachrymatory product.

The water that was held after the

washing can be easily removed by decantation during the re­ crystallization. The attempted preparation of ethyl benzylphenacylmalonate under the us util conditions, i.e. by the use of sodium ethoxide in alcohol solution, led to tarry products. Since ethyl phenacylm&lonate can be easily made using the above conditions, it was decided that the lack of success involved the greater difficulty of introducing the second group onto the central carbon. Homeyer

Wallingford, Thorpe and

reported success in the use of ethyl carbonate as

solvent for the introduction of the second alkyl group. By using this solvent, and distilling out the ethanol formed

6 by the reaction of t .e sodium etaoxide with the ethyl benzylmalonate, the desired ethyl benzylphenacylmalonate was pre­ pared.

Hov/ever, the difficulty in removing all of the sol­

vent, a necessity before crystallization could be accomplished led to experiments involving the replacement of the ethyl carbonate with benzene.

It was found that the sodio deriv­

ative of the benzylmalonic ester was soluble in benzene containing a slight excess of the ester.

When the prepara­

tion was run using these solvents, the alcohol formed was easily removed as the benzene-aleohol azeotrope in a good fractionating column, and the benzene by fast steam distil­ lation after the phenacylation.

The resulting product

could sometimes be crystallized directly, and sometimes had to be distilled in a molecular still before crystallization. The distillation was smooth, removing first the remaining excess benzylmalonic ester, and then the product as a clear, light yellow, viscous liquid thcit required only two or three crystallizations to be obtained pure.

There remained a

heavy red tarry residue which could not be purified. The use of sodium hydride proved beneficial in this reaction also.

The use of large volumes of benzene (about

7 - 8 liters per mole) was obviated by using excess ethyl benzylmalonate, in which the sodio derivative was much more soluble.

In this case, in place of steam distillation,

which was as expected very s3_ow, the crude reaction mixture was extracted with water to remove inorganic and basic substances, and then subjected to rapid distillation under tne pressure obtainable in ordinary distillation apparatus

7 with an oil diffusion pump.

When the rate of distillation

started to fall, the resicue was transferred to a molecular still and distilled as above.

One important difference

was noted in the molecular distillation of the product obtained wnen the preparation was performed using sodium hydride instead of sodium ethoxide.

If the heavy red res­

idue in this reaction was subjected to slow molecular distillation, the desired product continued to distill, raising the yield from about 35# to about 55#. Sodium hydride was used for the preparation of ethyl benzylacetoacetate also.

When a procedure identical to that

used to prepare ethyl benzylmalonate was used, ethyl benzylacetoacetate was obtained in 83# yield.

Various workers

have reported results in which they obtained this compound in yields of about 60# of the theoretical amount when the usual bases were used. An attempt was made to make ethyl benzylcyanoacetate by the same method, but unlike the malonic end acetoacetic esters, ethyl cyanoacetate did not form a sodio derivative which was soluble in excess of the ester.

The slurry became

very viscous, and had to be diluted with absolute ethanol. After the ethanol had been added, no more sodium hydride could be added, since in the presence of alcohol sodium hydride is a good reducing agent for nitriles and esters. Unless a suitable solvent is found for this reaction, there is no advantage in using sodium hydride in place of sodium ethoxide. In the preparations of ethyl benzylphenacylacetoacetate

8 end ethyl benzylphenacylcyanoacetate, sodium nydride was used in a procedure identical to that in waich ethyl benzylphenacylmalonate was prepared.

As a condensing agent

for this type of reaction, sodium hydride seemed to nave general application, giving higher yields, and facili­ tating manipulation in the laboratory through the use of smaller volumes; the preparation of large quantities of absolute alcohol was also unnecessary. In the earlier preparations of ethyl benzylphenacylmalonate, it was noted that a large amount of ethyl benzylmalonate was recovered.

lienee a preparation was attempted

using a large excess of phenacyl bromide.

After the

strongly lachrymatory product was worked up, there were obtained only traces of the desired product, and most of the phenacyl bromide was recovered.

It was discovered at

this time that phenacyl bromide distills smoothly under pressures around one-half micron. An attempted preparation of ethyl benzylphenacylm&lonate from benzyl chloride and ethyl phenacylmalonate resulted only in the formation of tarry substances, pre­ sumably because there was more than one center of active hydrogens In the ethyl phenacylmalonate. The preparation of derivatives of the carbonyl group of ethyl benzylphenacylm&lonate proved to be difficult. The action of £,4-dinitrophenylhydrazine yielded dark red resinous products, and semicarbazide did not react with the compound in aqueous alcohol or pyridine either at 3 room temperature or when heated. Kues and Paal reported

9

the action of hydrazine and hydroxylamine on diphenacylmalonic ester, and found either no reaction or, under stren­ uous reaction conditions, tars from which no pure substances could be obtained.

Hydrazine with no solvent produced an

immediate and vigorous reaction, but no products could be isolated from the tarry reaction mixture. Ethyl benzylphenacylmalonate (VIII) reacted rapidly with bromine in boiling carbon tetrachloride solution, and

Br ID 10

COOCoH ‘COOCgH HI

or Al(0CH(CHfe)s)3 XXXII

VTII

sapon

■COOII CQOH

IX

10

more slowly at room temperature after a snort induction period. The product of this quantitative reaction contained one bromine atom whose lability was demonst c.ted by the reaction with hydriodic acid

9

to produce the original ester in quantita­

tive yield, and by the reaction with aluminum isopropoxide, wherein the bromine was replaced with hydrogen to the exclusion of any carbonyl reduction.

The final evidence for the

structure was the reduction to ethyl benzylphenethylmalonate by hydrogen.

Leuchs and Reinhart‘S prepared benzylphen-

ethylmalonic acid (IX) by saponification of the ester pro­ duced by the reaction of ethyl malonate, phenethyl bromide and benzyl chloride.

The catalytic reduction of ethyl

benzylphen&eylmalonate proceeded directly to the formation of ethyl benzylphenethylmalonate with no break in the rate of absorption of hydrogen at a point corresponding to the preparation of the sucstituted benzyl alcohol.

Furthermore,

when a reduction stopped because of insufficient catalyst, that part of the reaction mixture which was not the phen­ ethyl compound was identified as starting compound. Although the keto group of ethyl benzylphenacylmalonate was reduced directly to a methylene group by catalytic hydrogenation, aluminum isopropoxide reduced the carbonyl with simultaneous lactonization, as is generally the case with gamma keto esters.^

The product of this reaction (X)

could not be crystallized, presumably because there was a mixture of esters from the partial transesterification, but saponification and subsequent acidification produced a crys­ talline compound, the malonic acid lactone (XI).

Decarbox­

ylation was readily accomplished by heating, and the resulting

11 lactone (XII) was easily recrystallized.

If the original ethyl

benzylphenacylmalonate was saponified, and the free acid heat­ ed, the monobasic keto acid (XIII) thus obtained yielded the same lactone (XII) when reduced with aluminum isopropoxide in isopropyl alcohol.

A l ( 0011(0115)2)3

GOOR

heat

X II

‘CO OH

COOH

X III

XI A1(0CH(CH3)2 )3

heat

12

The possibility of the desired reaction of ethyl benzylphenacylmalonate with formaldehyde seemed questionable, since the review of Walker^ reports experiments in which aryl alkyl ketones form methylol derivatives only with difficulty.

The

ease of reversal of the reaction and the fact that the use of other than very mild reaction conditions produce only complex products, were cited by Walker as the cause of the failure of the reaction; strong alkalies and heat can not be used. The optimum conditions, according to Walker, require shaking the ketone with anhydrous potassium carbonate and paraform­ aldehyde in anhydrous methanol.

Under these conditions ethyl

benzylphenacylmslonate failed to react. Haworth and Sheldrick 13 , however, succeeded in adding formaldehyde to a compound similar to ethyl benzylphenacylmalonate.

When formalin and aoueous sodium hydroxide were

allowed to react with 6,7-dimethoxy-l-(3,4-dimethoxyphenyl)4-keto-l,2 ,5,4-tetrahydronaphthalene-f-carboxyIic acid (XIV), two methylol groups entered in the three-position, one of them forming a lactone.

SaponifIcation removed one methylol

group and dehydrated the other, producing a methylene compound, 6 ,7-dimethoxy-l-(3,4-dimethoxy-phenyl)-4-keto-5-met.hylene-l, 2,3,4-tetrahydronaphthalene-£-c&rboxylic acid (XV).

In the

hope of obtaining a compound similar to XVI and blocking the free hydroxyl with the trityl group before removing the other methylol group, ethyl benzylphenacylmalonate was saponified, and tne resulting acid subjected to the same reaction conditions as those used by Haworth and Sheldrick.

Although their re­

action went in good yield in a few hours, the malonic acid

15

COOH

XIV

ECHO

NaOH

XVI OCI3S

saponification Clio

COOH

XV

3L4 yielded only starting materials on standing as much as a week. On standing a month, the formaldehyde underwent a Cannizzaro reaction, removing sufficient alkali from the reaction mix­ ture to precipitate the starting acid.

The malonic acid was

heated to decarboxylate it in order to start with an acid more nearly approximating that of Haworth and Sheldrick, hut the same result was obtained with the monobasic acid. Since this route seemed to offer difficulties, it was thought that it might be possible to obtain a compound such as

oxide in iso ropyl alcohol (G.C5 mole) and heated under reflux: for 2 hours.

The solution was cooled, 2 ml. of concentrated sul­

furic acid in 20 ml. of 'water was added, and the alcohol was distilled out, tope t :or r;ith the acetone forned, through an efficient fractionating column.

The distillate was caught

in 50 oil. of 2 1 hydrochloric acid containing 0.001 mole of 2 ,4-dinitroo’ienTrlhyfrazin©•

The precipitate was filtered into

a Gooch crucible, washed with 2 N hydrochloric acid, and then with water until free of chloride ion. dried at 100° and weighed.

The crucible was

The proc \-nitate weighed 0.211C g*

(0.CuOOOO mole), showing that this aeount of reducing agent had reacted. The aqueous acid solution from which the acetone and al­ cohol wore distilled was washed with chloroform until colorless (o ml.)*

The resulting solution "./as then t i t r a t e d wi th s ta n d a rd O Q

silver nitrate solution, us ing a 'modified

Mohr method. The

titration required 0.000902 mole, indicating that 90*2g of th© bromine orig5np.li y oresent had been removed by reduction. The agreement, 3 parts nor thousand, be tv/eon the amount of bromine rey oved and the amount of reducing agent oxidized, indicated that there was no ce.rbon;rl reduction.

47

C a ta ly tic

R e d u c tio n o f E t h y l B e n z y lp h e n a c y lm a lo n a te

A s o lu tio n o f 0 .

37 g .

(0 * 0 0 1 m o le)

o f e t h y l b e n z y lp h e n -

a c y lm a lo n a te i n 80 m l. o f 9o$ e th a n o l was shaken w it h h y d ro ­ gen w it h v a r io u s c a t a l y s t s . c a ta ly s t

wasalw ays f i r s t

B o th p la tin u m

When p la tin u m o x id e was u s e d ,

th e

red u ced by s h a k in g w ith h y d ro g e n .

o x id e and Raney n ic k e l w ere used a t room tem ­

p e r a t u r e and p re s s u re ,

b u t th e b a riu m -c o p p e r-c h ro m iu m -o x id e

was used as i n d i c a t e d .

The p ro d u c ts w ere e i t h e r e t h y l b e n z y l-

p h e n a c y lm a lo n a te (A ) o r e t h y l b e n z y lp h e n e th y lm a lo n a te

(B ),

e x c e p t Run N o. 7 w h ic h pro du ced a brown o i l fro m w hich no p ure su b stan ces c o u ld be i s o l a t e d . Hun g . C a t . No. 1 2 3 4 5 6 7

0 .1 0 .4 £ £ £ 1 1

e q u iv . Hg P ro d u c ts absorbed

PtOg 1 .5 P t0 2 £ H i(R ) £ H i(R ) £ N i(R ) £ BaCuCrO — BaCuCrO —

Remarks

1 p a rt A, 3 p a rts B B 10 m in u te in d u c tio n p e r io d . B A added i n s o lu t io n B A added s o l id . B 3 m l. (CgH 5 ) 3N ad d ed . S lo w . A 1500 p . s . i . , 1 2 5 ° , £ h r s . £000 p . s . i . , 1 3 5 0 , 3 h r s .

The e t h y l b e n z y l- {3 -p h e n e th y lm a lo n a te was i d e n t i f i e d s a p o n if i c a t i o n and a c i d i f i c a t i o n a c id , w h ic h m e lte d a t 15£ a m e ltin g

by

to g iv e b e n z y l - /3 - p h e n e t h y i-

1 5 3 .2 ° .

The l i t e r a t u r e

r e p o r te d

p o in t o f 1 5 3 ° .

d - B e n z y l - %- p h e n y l- 3 f-b u ty r o la c to n e Method A .

B e n z y lp h e n a c y la c e t i c

(X IX ) a c id

(2 .6 8 g . ,

0 .0 1 m o le)

was d is s o lv e d i n 20 m l. o f 1 M alum inum is o p ro p o x id e i n i s o p r o p y l a lc o h o l and h e a te d under r e f l u x f o r £ days w it h occa­ s i o n a l slow d i s t i l l a t i o n o f th is D ilu te

o f th e a c e to n e fo rm ed .

A t th e end

t im e , no more ac e to n e was p re s e n t i n th e d i s t i l l a t e . h y d r o c h lo r ic a c id was added and th e a lc o h o l was removed

48 by d i s t i l l a t i o n .

The r e s u l t i n g

was e x t r a c t e d w it h c h lo r o fo r m ,

su sp en sio n o f o i l i n w a te r th e e x t r a c t d r ie d w it h magnesium

s u l f a t e and e v a p o ra te d a t th e w a te r pump. was d i s t i l l e d

The syrup r e s u l t i n g

i n a m o le c u la r s t i l l under a p re s s u re o f 0 , 1

m ic ro n w it h a b a th te m p e ra tu re o f 1 0 0 ° , g iv in g d is tilla te . ta lliz a tio n m e lte d a t

When seeded,

th e d i s t i l l a t e

fro m e th a n o l gave £ .3 g .

(7 9 .1 )

mg. sample mg. HpO mg. COg

(9 1 $ )

C17H16Q2 6 .3 9 $ H 6 .6 6 6 .4 8

R e e ry s -

o f la c to n e w h ich

8 0 . 92% C 8 1 .2 2 8 1 .0 6

6 . £6£ 7 .1 4 3 3 .7 3 2 4 .1 2 7 1 8 .6 3 7 2 1 .2 1 8

A s m a ll sam ple o f th e la c t o n e a c id

h e a te d i n a t e s t t u b e a t 1 5 0 ° ; a l c o h o l , and c r y s t a l l i z e d r e c r y s ta lliz e d

c r y s ta lliz e d .

7 9 .6 - 8 0 . 6 ° .

C a lc u la te d f o r Found

M ethod B .

a c le a r w h ite

( X I ) was

th e p ro d u c t was d is s o lv e d i n hot

by s c r a tc h in g and c o o lin g .

fro m a lc o h o l,

When

th e substance p ro v e d to be I d e n t i c a l

w it h th e la c t o n e fro m th e above r e d u c tio n . A tte m p te d A d d it io n o f Form ald eh yd e to E t h y l B e n z y lp h e n a c y lm a lo n a te E t h y l b e n z y lp h e n a c y lm a lo n a te

( 7 .4 0 g . ,

0 . 0 2 m o le ), 0 . 6 0 g .

( 0 . 0 2 mole monomer) o f p a ra fo rm a ld e h y d e , and 0 .3 0 g .

(0 .0 0 2 1

m o le ) o f anhydrous p o ta ss iu m c a rb o n a te w ere p la c e d i n an E r l e n m eyer f l a s k w i t h 15 m l. o f d r y m e th a n o l and a m a g n e tic s t i r r e r . The f l a s k was c lo s e d

w it h a s to p p e r and s t i r r e d f o r

A t th e end o f t h i s tim e th e in to

100 m l.

o f th e f l a s k w ere

o f 2 N h y d r o c h lo r ic a c id .

fo rm e d was f i l t e r e d , fro m e t h a n o l.

c o n te n ts

It

14 d a y s . poured

The w h ite p r e c i p i t a t e

washed w it h w a te r , and r e c r y s t a l l i z e d

p roved to be s t a r t i n g m a t e r i a l .

49

A tte m p te d A d d it io n o f Form aldehyde to B e n zy lp h en ac yim a io rxic a c id An aqueous s o l u t i o n o f 3 .1 £ g . a c y lm a lo n ic a c id , and 8 m l.

o f b e n z y lp h e n -

10 m l. o f £ . 5 N sodium h y d ro x id e

( 0 . 1 m o le ) o f 37p f o r m a lin was a llo w e d

room te m p e ra tu re f o r 40 h o u rs . in e s s

( 0 .0 1 m o le)

s o lu t io n ,

to

stand a t

A c i d i f i c a t i o n pro du ced & c lo u d ­

t h a t l a t e r d e p o s ite d as c r y s t a l s .

F u rth e r a c id if ic a t io n

p r e c i p i t a t e d more c r y s t a l s , w h ich when f i l t e r e d

and d r ie d i n

u n t i l th e s m e ll o f fo rm a ld e h y d e was no lo n g e r a p p a r e n t, 3 .0

g.

g iv in g

a ir

weigher

They m e lte d w it h v ig o ro u s e v o lu t io n o f gas a t 1 6 0 ° a s o lid

t h a t m e lte d a t 173 - 1 7 4 ° .

A m ixed m e ltin g

p o i n t w it h th e o r i g i n a l m a lo n ic a c id d em o n strated p ro d u c t was s t a r t i n g

m a te r ia l,

t h a t th e

re c o v e re d i n good y i e l d .

A tte m p te d A d d it io n o f Form aldehyde t o B e n z y lp h e n a c y la c e tlc a c id A s o lu t io n o f £ .7 g . a c id ,

10 m l.

( 0 .0 1 m o le ) o f b e n s y lp h e n a c y lfc e t ic

o f £ . 5 N sodium h y d ro x id e s o lu t io n ,

and Q m l.

of

5 7 $ f o r m a lin was a llo w e d to sta n d s to p p e re d f o r 5 weeks a t room te m p e r a tu r e .

A h e a v ie r l i q u i d

t a k e n up i n e t h e r , s u re .

phase was o b s e rv e d .

as

was

d r ie d ana e v a p o ra te d under d im in is h e d p r e s ­

b u t co u ld n o t be c r y s t a l l i z e d .

m a in e d

It

W ith no s o lv e n t i t

a h a rd c l e a r alm o st c o lo r le s s g la s s .

w it h £ , 4 - d in it r o p h e n y lh y d r a z in e

i n a lc o h o lic

re ­

T re a tm e n t

s o l u t i o n y ie ld e d

o n ly a t r a c e o f th e £ ,4 -d in itr o p h e n y lh y d r a z o n e o f fo rm a ld e h y d e , id e n tifie d

by m e ltin g

p o in t , m ixed m a ltin g p o in t and a n a ly s is .

A t e s t o f th e o r i g i n a l aqueous phase l e f t a f t e r w it h

e t h e r showed i t

th e e x t r a c t i o n

t o be o n ly s l i g h t l y a l k a l i n e ,

a b o u t pH 8 .

g - C h lo r o e t h y l T r ip h e n y lm e th y l E th e r A s o lu t io n o f 8 . 0 5 g .

( 0 . 1 m o le ) o f e th y le n e

c h lo r o h y a r in ,

50 2 6 ,0

g.

( 0 . 1 m ole) o f t r i p h e n y l c a r b i n o l and 0 .0 5 g .

t o lu e n e s u lf o n ic a c id

in

o f p-

75 m l, o f benzene was h e a te d under r e ­

f l u x w it h a D e a n -S ta r k t r a p u n t i l no more w a te r was b e in g c o lle c te d .

The t h e o r e t i c a l amount o f w a te r was o b ta in e d .

s o l u t i o n was co o led w h ile b ein g s t i r r e d . not s tir r e d ,

th e s o lu t io n was

th e c r y s t a l s adhered v e r y s tr o n g ly to th e w e lls

o f th e f l a s k .

The c r y s t a l s were f i l t e r e d

fro m p e tro le u m e t h e r .

and r e c r y s t a l l i z e d

The p ro d u c t w eigh ed ;

m e lte d a t 1 3 1 .1 - 1 3 1 . 8 ° . p r o d u c t,

If

The

.7 g .

The benzene f i l t r a t e

(7 0 $ ) and

c o n ta in e d more

b u t was n o t w orked up.

C a lc u la t e d Found

f o r C g iH ig O C l

mg. sample mg. HgO mg. C0„ mg. AgCl

7 .3 3 1 3 .9 5 8 2 1 .0 4 8

5 .9 3 & 6 .0 4 5 .9 5 6 .7 3 2 3 .5 8 2 1 9 .2 9 8

H

7 8 .1 3 4 C 7 8 .3 5 7 8 .2 4

1 0 .9 8 4 C l 1 0 .7 9 1 0 .9 8

4 .9 1 8

7 .0 0 4

2 .1 4 4

3 .0 9 1

S in c e t h is work was done th e p r e p a r a t io n o f t h i s

compound

fro m t r ip h e n y lm e t h y l c h lo r id e and th e c h lo r o h y d r in i n p y r id in e , £3 w it h a m e ltin g p o in t o f 130 - 1 3 1 ° , has been r e p o r t e d . 2 -B ro m o e th y l T r ip h e n y lm e th y l E th e r T h is compound was made as d e s c rib e d above f o r r a tio n

o f th e 2 - c h lo r o

t h e o r e t ic a l y ie ld

compound.

It

mg. mg. Bag. mg.

was o b ta in e d i n n e a r ly

a lth o u g h e x a c t m easurem ents were n o t made.

The w h it e c r y s t a l s m e lte d a t 1 2 7 .0 C a lc u la te d Found

th e p re p a ­

f o r CgxHxgOBr

sample HgO COg AgBr

1 2 7 .8 ° .

5 .2 1 $ 5 .4 3 5 .5 8

6 .3 8 7 4 5 .9 540 3 .1 0 2 2 2 .9 7 2 1 1 5 .1 5 4 3 1 5 .0 4 1 2

H

6 3 .6 7 $ C 6 9 .0 2 6 8 .9 4

7 .9 8 0 4 .1 5 6

5 .0 9 8 2 .6 8 0

2 1 .7 6 % Br 2 2 .2 2 2 2 .3 4

51 2 -C y s n o e th y l T r ip h e n y lm e th y l E th e r T h is compound was made as d e s c rib e d above f o r

th e 2 - c h lo r o

compound, e x c e p t t h a t to lu e n e was used in s te a d o f benzene f o r th e r e a c t i o n medium, and to lu e n e was used in p la c e o f p e tro le u m e t h e r f o r th e r e c r y s t a l l i z a t i o n . 1 6 9 .2 -

The compound m e lte d a t

( 1 6 7 .2 )

1 7 0 .5 ° .

C a lc u la t e d f o r C£2 H i 90N Found mg. sample 6 .1 7 2 4 mg. Hg0 5 .4 3 3 mg. C0£ 1 9 .0 7 0 2 m l. N£ 0 .2 0 3 p re s s u re te m p e ra tu re OC. A tte m p te d H y d ro g e n o ly s is

6 .1 1 # H 5 .2 2 6 .4 9 6 .3 7 8 3 3 .6 1 5 5 1 9 .7 6 7 7 0 .1 6 2

3 4 .3 1 h C 3 4 .5 1 8 4 .5 7

4.4-7 ‘ h N 4 .9 3 5 .0 5

4 .4 8 0

3 .4 6 7

0 .2 0 3 766 34

0 .1 6 2 765 35

o f n - B u t y l T r ip h e n y lm e th y l E th e r

Two grams o f n - b u t y l t r i t y l

e th e r i n 100 m l.

o f a b s o lu te

e t h a n o l w ere shaken w it h 0 .0 5 g . o f p a lla d iu m o x id e f o r 5 h o u rs u n d er

hydrogen a t 35 p . s . i . The c a t a l y s t was f i l t e r e d

o f f and th e

f i l t r a t e t r e a t e d w ith w a te r u n t i l c lo u d y .

s ta n d in g

f o r 5 d ay s,

th e s o lu t io n d e p o s ite d c r y s t a l s .

b e in g r e c r y s t a l l i z e d

fro m a lc o h o l,

8 1 .6 0 and w eighed 0 . 6 n o t be c r y s t a l l i z e d , and b u t a n o l.

g.

th e p ro d u c t m e lte d a t 8 0 .7 -

The re m a in d e r was an o i l

t h a t could

A m ixed m e ltin g p o in t w i t h an a u t h e n t ic

material specim en

showed no d e p r e s s io n .

A tte m p te d Hydrogen o l y s i s A s o lu t io n o f 20 g .

o f E t h y l T r ip h e n y lm e th y l E th e r ( 0 .0 6 9 m o le)

o f e t h y l t r ip h e n y lm e t h y l

cy c lo h e x a n e was shaken v /ith h ydrogen a t room tem p er­

a t u r e and 20 p . s . i . o x id e ,

A fte r

and was c o n s id e re d to be s t a r t i n g

o f e t h y l t r i t y l e th e r

e th e r in

A fte r

p r e s s u r e , u s in g s u c c e s s iv e ly p a lla d iu m

p la tin u m o x id e ,

and p la tin u m o x id e t h a t had f i r s t

been

52 re d u c e d w it h h yd ro g e n .

No a b s o r p tio n o f hydrogen to o k p la c e .

The same s o lu t io n was shaken w it h reduced p la tin u m o x id e a t room te m p e ra tu r e u n d er 1500 p . s . i .

No r e a c t io n to o k p la c e .

When Raney n i c k e l was used a t a te m p e ra tu re o f 1 1 5 ° and u n d er a p re s s u re o f £300 p . s . i . ,

no r e a c t io n to o k p la c e ,

and s t a r t ­

in g m a t e r i a l was re c o v e re d i n good y i e l d . R e a c tio n o f B e n z y l A lc o h o l w it h M e th y l A c r y la t e A s o lu tio n o f 0 .1 g .

(0 .0 0 4 3 5 atom ) o f sodium i n 10 m l.

o f b e n z y l a lc o h o l was added w it h s t i r r i n g lu tio n o f 8 ,8

g,

( 0 . 1 m o le )

and c o o lin g

to a so­

o f m e th y l a c r y l a t e and 3 m l.

of

b e n z y l a lc o h o l so t h a t th e te m p e ra tu re d id n o t r i s e above 4 0 ° . The r e a c t io n m ix tu r e was a llo w e d to s ta n d f o r £ d ays. la tio n

u n d e r reduced p re s s u re gave 1 1 .4 g .

whose b o i l i n g

p o in t,

o f a c le a r d i s t i l l a t e

even w it h c a r e f u l f r a c t i o n a t i o n ,

u a l l y and s t e a d i l y fro m 56 -

D is til­

ro s e g ra d ­

1 3 7 ° under 100 m icrons p r e s s u r e .

R epeated f r a c t i o n a t i o n d id n o t a c h ie v e any s e p a r a tio n . ific a tio n

a t room te m p e ra tu re w it h a l c o h o l i c

Sapon­

sodium h y d ro x id e

y i e ld e d a s u b sta n c e s o lu b le i n aqueous a l k a l i and p r e c i p i t a t e d by m in e r a l a c id s .

The p ro d u c t was in s o lu b le

m e lte d o v e r 5 0 0 ° .

R e p r e c i p i t a t i o n c o n tin u e d to g iv e th e same

gummy m a t e r i a l w hich c o u ld n o t be p u r i f i e d

i n c h lo ro fo rm and

s u ffic ie n tly

fo r

id e n t i f i ca t i o n . R e a c tio n o f Sodium B e n z y la te w ith P -B rom opropiophenone A benzene s o lu t io n o f 4 .£ 5 g . p ro p io p h en o n e was added to 0 .4 5 g .

(0 .0 £

(0 .0 S m o le ) o f ft -b ro m o -

15 m l. o f b e n z y l a lc o h o l i n w h ich

atom ) o f sodium had been d is s o lv e d .

m ix tu r e was s t i r r e d

f o r 4 h o u rs , f i l t e r e d ,

The r e a c t io n

and d i s t i l l e d

u n d er

53

re d u c ed p r e s s u r e .

A f t e r th e benzene was rem oved,

th e b e n z y l

a lc o h o l was removed a t room te m p e ra tu re a t a p re s s u re o f . 5 m ic ro n .

The re s id u e was d is s o lv e d

p r e c ip ita te d

a w h ite s o l i d .

in a lc o h o l,

The p r e c i p i t a t e

s o lu b le i n a f r e s h p o r t io n o f a lc o h o l, o b ta in e d d e p o s ite d a p r e c i p i t a t e r e p e a te d ,

each tim e p ro d u c in g

m e lte d to a v is c o u s l i q u i d c o n s is t e n t w it h R e a c tio n o f

q l.

To 35 m l.

and th e s o lu t io n th u s

on c o o lin g .

a t 115 - 1 3 0 ° .

T h is p ro ce ss was

T h is b e h a v io r was

t h a t o f p h e n y l v i n y l k e to n e . 0 -D ib ro m o p ro p io p h en o n e w it h B e n z y l A lc o h o l and P o ta s s ium Xo d id e o f b e n z y l a lc o h o l a t 1 0 0 ° c o n ta in in g 8 . 3 g .

The r e a c t io n m ix tu re was s t i r r e d

h o u rs ,

th e n c o o le d and poured i n t o

and k e p t a t 1 0 0 ° f o r 2

excess t h i o s u l f a t e

The o rg a n ic l a y e r was e x t r a c t e d w ith e t h e r ,

o v e r n ig h t ,

was h e a te d to 9 0 ° t o e x p e l th e e t h e r . d is c h a rg e d by s t i r r i n g

w it h

g a n ic la y e r was s e p a ra te d .

th io s u lfa te

th e r e a c t io n m ix tu r e The io d in e c o lo r was s o lu tio n ,

ana th e o r ­ 15 m l.

presum ably o f b e n z y l a lc o h o l and p ro d u c ts .

d is tillin g in

the b o i l i n g

p h e n y l v i n y l k e to n e .

p o t,

A fte r

p o in t ro s e g r a d ­

a s m a ll amount o f m a t e r i a l and le a v in g th e s t i l l

It

u n d er d im in is h e d p re s s u re .

th e b e n z y l a lc o h o l was c o l .e c te d ,

t a r r y r e s id u e

a c id had

The o rg a n ic l a y e r amounted to

was s u b je c te d to d i s t i l l a t i o n

u a lly ,

s o lu tio n .

d r ie d and r e t u r n e d

t o th e r e a c t i o n f l a s k t o w h ic h 2 drops o f s u l f u r i c A f t e r s ta n d in g

( 0 .0 2 m o le )

An im m ed iate re d c o lo r d e v e l­

oped.

and c o n s is te d

and c o o lin g

le s s o f a w h ite s o lid w h ich

cA, ( -d ib ro m o p ro p io p h e n o n e .

been added.

-

was o n ly p a r t i a l l y

( 0 . 0 5 m o le) o f p o tassiu m io d id e was added 5 .8 4 g . of

.1

p ro b a b ly th e polym er fro m

a

54 A tte m p te d T r a n s e t h e r i f i c a t i o n A s o lu t io n o f £ .5 5 g , phenone, 3 . 1 g .

o f [5 -B th o x y p ro p io p h e n o n e

( 0 . 0 1 4 m ole) o f (3 -e th o x y p r o p io -

( 0 .0 2 8 m o le) o f b e n z y l a l c o h o l ,

and 0 .0 7 7

g.

(0 .0 0 0 4 5 m o le ) o f p -r to lu e n e s u lfo n ic a c id i n benzene to make 11 2 m l. was h e a te d under r e f l u x

f o r 4 h o u rs .

c o u ld be d e t e c t e d , and th e s t a r t i n g by d i s t i l l a t i o n

Ho e th a n o l fo rm ed

p ro d u c ts w ere re c o v e re d

und er d im in is h e d p re s s u re .

R e a c tio n o f E t h y l B e n zy l-c x-b ro m o p h e n a cy lm alo n a te w it h P o ta s ­ sium C yanide A s o l u t i o n o f 4 .4 6 g .

( 0 . 0 1 m ole) o f e t h y l b e n z y l- d -

b ro m o p h en acylm alo n ate was h e a te d under r e f l u x w it h 1 .0 g . ( 0 .0 1 5 m o le) 1Z h o u rs .

o f d ry p o ta s s iu m c y a n id e i n a b s o lu te a lc o h o l f o r

A t th e end o f t h i s

s o lid was f i l t e r e d th e f i l t r a t e

h o t to remove th e p o ta s s iu m b ro m id e , and

c h ille d

in ic e .

was removed by f i l t r a t i o n ta lliz e d

tim e th e s u s p e n s io n o f w h ite

fro m 60$ e t h a n o l,

A p r e c ip ita te

and w eighed 0 .7 5 it

m e lte d a t

form ed s lo w ly ;

it

g . Yfhen r e c r y s ­

( 6 9 . 8 ) 7 0 .£ -

7 1 .£ ° .

When th e r e a c t io n was c a r r ie d o u t i n 95 $ e th a n o l, a l a r ­ g e r y ie ld

o f m a t e r i a l was o b ta in e d , w hich when r e c r y s t a l l i z e d

as above m e lte d a t

(7 5 .0 )

7 5 .2

-

76. 20.

The use o f 75$ e th a n o l as s o lv e n t and

th e d i r e c t

f u s io n

a t 1 3 5 ° o f th e r e a c t a n t s w it h o u t any s o lv e n t r e s u lt e d i n th e fo r m a tio n o f t a r s

fro m w hich t r a c e s o f s t a r t i n g

c o u ld be i s o l a t e d , t a in e d a b o ve .

alo ng w it h tr a c e s o f th e

m a t e r ia ls

same compound ob­

When g ly c e r o l o r d io x a n e was used as s o lv e n t ,

most o f th e s t a r t i n g C a lc u la te d f o r Found

m a t e r i a l was re c o v e re d unchanged. C44H460 n

6 .1 8 $ H 6 .4 3 6 .5 0

7 0 .3 8 $ C 7 0 .5 3 7 0 .3 5

£ 4 .0 0 $ 0C2 H5 2 3 .7 5 2 3 .6 9

55

mg. sam ple 7 .8 7 4 mg. HgO 4 .5 1 4 a g . COg 2 0 .3 5 1 m l. t h i o s u l f a t e N o f th io s u lfa te

7 .5 5 1 4 .5 7 6 1 9 .4 1 4

4 .9 0 6

5 .1 1 5

1 2 .6 8 1 2 .0 6 0 .0 1 2 2 4 0 .0 1 3 3 8

A tte m p te d R e fo rm a ts k y R e a c tio n w ith E t h y l Ben z y l - qL-bromophena c y la a lo n a t e U sing th o r o u g h ly d ry a p p a r a tu s , a s o l u t i o n o f 4 .4 7 g . ( 0 . 0 1 m o le) lu te

o f e t h y l b e n z y l- o L-b rom ophenacylm alonate i n abso­

e t h e r was s t i r r e d

and h e a te d under r e f l u x w it h 7 . 1 g .

( 0 . 1 m o le) o f z in c a l l o y r e a c t io n a f t e r

(8 $ c o p p e r ).

12 h o u rs .

T h e re was no a p p a re n t

The e th e r was r e p la c e d by to lu e n e

and th e h e a tin g was c o n tin u e d f o r 36 h o u rs . no r e a c t io n .

The a d d it io n

T h e re was a g a in

o f p a ra fo rm a ld e h y d e caused no ch ang e,

and th e p o ly m e r su b lim ed i n t o

th e co n d en ser.

R e a c tio n o f E t h y l Form ate w it h E t h y l B e n z y lp h e n a c y lm a lo n a te A s u s p e n s io n o f d ry a l c o h o l - f r e e p are d by d is s o lv in g 4 .6 g . e v a p o ra tin g

(0 .2

sodium methoxide was p r e ­

atom) o f sodium in d ry m e th a n o l,

th e s o lu t io n to d ry n e s s , h e a tin g

f o r 2 h o u rs a t

lo w p re s s u re i n an o i l b a th a t 2 0 0 ° , and th e n d i s t i l l i n g 25 0 m l. o f d ry b en zen e.

E t h y l b e n z y lp h e n a c y lm a lo n a te

0 .0 4 7 5 m o le ) and ab o u t 18 g .

in

(1 7 .5 g .,

o f d ry e t h y l fo rm a te were ad d ed .

The s u s p e n s io n , w hich a c q u ir e d a y e llo w c o lo r when th e k e to n e was added, was s t i r r e d

a t a b o u t 4 0 ° f o r 44 h o u rs , a t th e end

o f w hich tim e th e r e a c t io n m ix tu r e was a c l e a r re d s o l u t i o n . The s o l u t i o n was c o o le d to 1 0 ° , f u n n e l, and t r e a t e d w it h 60 m l.

tra n s fe rre d

o f ic e w a t e r .

w it h a s tre a m o f n it r o g e n and a llo w e d to w ere fo rm ed : la y e r ,

th e lo w e r aqueous l a y e r ,

and th e u pp er benzene l a y e r .

It

s e ttle .

to a s e p a r a to r y was a g i t a t e d T h re e la y e r s

a m id d le d a rk red o i l y The two lo w e r phases w ere

56 s e p a ra te d fro m th e u p p e r l a y e r ,

and th e benzene l a y e r was

washed t h r e e tim e s w it h c o ld 0.1 H sodium h y d ro x id e s o lu t io n w h ic h had been sw ept w it h n i t r o g e n . com bined, washed w it h e t h e r , ic e

The aqueous e x t r a c t s w ere

and poured s lo w ly i n t o a s lu s h o f

and c o n c e n tr a te d h y d r o c h lo r ic a c id .

fo rm e d was ta k e n up i n e t h e r . c ip ita te

tu rn e d p a r t i a l l y

The gummy p r e c i p i t a t e

On one o c c a s io n th e gummy p r e ­

c r y s t a l l i n e when t r e a t e d w it h e t h e r ,

b u t th e su b sta n c e c o u ld n o t be r e p r e c i p i t a t e d s o lu tio n .

when once i n

When th e s o lv e n t was e v a p o ra te d c a r e f u l l y a f t e r b e in g

d r i e d w it h an h yd ro u s sodium s u l f a t e ,

th e r e s i d u a l o i l had a

s h a rp s m e ll s i m i l a r t o t h a t o b s erve d a f t e r a p a r a l l e l p re p a ra ­ tio n

o f £ -h y d r o x y m e th y le n e -l-d e c a lo n e .

A tte m p te d A l k y l a t i o n

o f F o r m y la tio n P ro d u c t

The o i l o b ta in e d above was h e a te d under r e f l u x w ith s t i r ­ r in g

w ith 250 m l.

o f d ry a c e to n e ,

14 g .

d ro u s p o ta ss iu m c a rb o n a te and 17 g . io d id e f o r 15 h o u r s .

( 0 . 1 m o le ) o f anhy­

( 0 . 1 m o le)

o f is o p r o p y l

The r e a c t io n m ix tu re was e v a p o ra te d to

d ry n e s s under d im in is h e d p re s s u re and th e r e s id u e was ta k e n up i n e th e r and w a t e r .

The e t h e r phase was washed tw ic e w it h

sodium h y d ro x id e s o l u t i o n , p e ra tu re ,

le a v in g

d r ie d ,

and e v a p o ra te d a t room tem ­

a p p ro x im a te ly 1 m l. o f a re d o i l .

The o i l

was s t i r r e d and s c ra tc h e d w it h 60 m l. o f 5 0 - 6 0 ° l i g r o i n , s to r e d under n it r o g e n i n th e r e f r i g e r a t o r f o r

1 days.

T h ere

was no a p p a re n t r e a c t i o n o r ch an g e, and o th e r a tte m p ts to in d u c e c r y s t a l l i z a t i o n met w it h f a i l u r e . A tte m p ted R e d u c tio n o f A lk y la t e d F o rm y la te d p ro d u c t The l i g r o i n

s o l u t i o n fro m th e above e x p e rim e n t was

and

57 e v a p o ra te d under re d u c ed p re s s u re and th e r e s i d u a l o i l was d is s o lv e d i n is o p r o p y l a lc o h o l c o n ta in in g excess alum inum i s o p r o p o x id e .

Slow d i s t i l l a t i o n

some a c e to n e .

A f t e r 40 hours no more ac eto n e was fo rm e d .

s o l u t i o n was c o o le d , s o lu tio n .

th ro u g h a good colum n y ie ld e d

and poured i n t o

The

ic e and sodium h y d ro x id e

The o rg a n ic l a y e r was washed tv /ic e w it h 10$ sodium

h y d r o x id e s o lu t io n and th e n e v a p o ra te d .

The a l k a l i n e

on a c i d i f i c a t i o n

The o r g a n ic re s id u e

showed no p r e c i p i t a t e .

e x tra c ts

c o u ld n o t be p u r i f i e d . S a p o n i f i c a t io n o f Reduced P ro d u c t The o rg a n ic r e s id u e d i r e c t l y above was d is s o lv e d i n a lc o ­ h o lic

sodium h y d r o x id e , and on s ta n d in g a t room te m p e ra tu re

a fe w h o u rs d e p o s ite d a la r g e mass o f s o f t s o l i d , s a p o n i f i c a t i o n o f e t h y l b e n z y lp h e n a c y lm a lo n a te .

as i n th e Benzene was

a d d e d , and c a r e f u l f r a c t i o n a t i o n removed th e a lc o h o l as th e a z e o tr o p e .

The b enzene s u s p e n s io n was e x tr a c te d

w it h w a t e r ,

and th e aqueous e x t r a c t a c i d i f i e d .

o i l was e x t r a c t e d w it h e t h e r ,

t h r e e tim e s The r e s u l t in g

b u t th e h ard c l e a r g la s s o b ta in e d

on e v a p o r a tio n c o u ld n o t be c r y s t a l l i z e d ,

and no p u re p ro d u c ts

c o u ld be i s o l a t e d . C opper D e r i v a t i v e

o f F o rm y la te d P ro d u c t

An aqueous s o l u t i o n o f th e s o d io d e r i v a t i v e

o f th e f o r m y l­

a te d p ro d u c t was t r e a t e d w ith a s a t u r a te d aqueous s o lu t io n o f c u p r ic

a c e ta te .

A g re e n p r e c i p i t a t e was fo rm e d ;

o f f w it h d i f f i c u l t y ,

s in c e i t

c o u ld be r e p r e c i p i t a t e d ta llin e .

it

was f i l t e r e d

was g e la tin o u s and s o f t .

fro m aqueous e th a n o l,

A fte r r e p r e c ip ita tio n

th e f i l t r a t i o n

It

b u t was n o t c r y s ­ was e a s i e r ,

and

58

the product was solid.

Various samples from different prepar­

ations melted gradually over a five to ten degree range from 140° to 175°. A solution of the formyluted product in ether was shaken with a saturated aqueous solution of cupric acetate.

The ether

phase took on the characteristic green color of the copper derivative, which could be obtained from it on evaporation. To a solution of the formylsted product in either methyl or ethyl alcohol was added dropwise a saturated solution of cupric acetate in water.

Although filtration left most of the

product in the filtrate, a fine precipitate was separated which melted at (145) 152 - 156° with decomposition. Analysis:

5.01 4 H

35.85 Jo C

14.97 Jo CuO

A solution of the copper derivative in carbon tetrachlo­

ride was passed through a chromatographic column packed with activated alumina.

A yellow-brown area at the top remained

while the green remained lower in the column.

P

Ct

S

wi C*-

e of more

carbon tetrachloride made the separation of the two colors le s s distinct, but chloroform made the separation sharp again,

and eluted the green color, leaving the yellow-brown band at the top of the column.

Evaporation of the filtrate yielded

a hard dark green glass which melted from 167 - 175° with

decomposition. Analysis:

5.IE h H 5.08

65.59 h C 63.56

15,6 5 A CuO 13.63

A solution of the copper derivative in absolute ether was passed through an alumina column.

The copper was completely

removed, and the filtrate contained aluminum.

59

Hydrogenation of Copper Derivative A solution of 8 g. of copper derivative in 150 ml. of 95^ ethanol was shaken with platinum oxide and hydrogen at room temperature and pressure. charged.

The green color was dis­

Since the catalyst apparently became poisoned

and fresh platinum oxide had to be added, the volume of hydro­ gen absorbed by the compound could not be determined.

The

catalyst was removed by filtration, and the slightly yellow filtrate was evaporated under diminished pressure.

The residue

was taken up in ether and washed with 0.1 N sodium hydroxide, an amount of alkali approximately equivalent to the amount of copper derivative being required.

Addition of cupric acetate

solution to this slightly alkaline extract produced the orig­ inal copper derivative. Attempted Benzylation of Farmylated Compound A solution of 1.2 g. of copper derivative in 30 ml. of ether was shaken with 30 ml. of 2,b% sulfuric acid.

The blue

aqueous layer was drawn off, and the yellow-brown ether layer was dried with anhydrous sodium sulfate and evaporated, leaving 0.8 g. of oil.

Tliis oil was dissolved in 8 ml. of ethanol

containing 0.1 g. of sodium hydroxide, and 0.3 g. (0.0024 mole) of benzyl chloride was added.

There being no apparent reaction,

the solution was warmed briefly on a steam cone and let stand for 24 hours.

Dilution with water, followed by extraction with

ether and evaporation under diminished pressure, yielded 0.7 g. of a red oil from which no pure substance could be obtained.

60

A tte m p te d B e n z y la t io n o f Copper D e r i v a t iv e A s o l u t i o n i n d ry benzene o f 0 ,8 3 g . and 0 ,3 0 g .

( 0 .0 0 2 5 m o le)

s ta n d o v e r n ig h t . te re d o f f ,

o f b e n z y l c h lo r id e was a llo w e d

A s m a ll amount o f brown p r e c i p i t a t e

and th e s o lu t io n

exam ined f o r p ro d u c ts .

to

was f i l ­

was h ea te d u n d e r r e f l u x f o r 2 0 h o u rs .

A w a te r in s o lu b le p r e c i p i t a t e

o n ly d a rk t a r r y

o f copper d e r i v a t i v e

was f i l t e r e d

o ff,

and th e f i l t r a t e

When th e b e n z y l c h lo r id e was rem oved,

p ro d u c ts re m a in e d , fro m w h ic h no pure s u b sta n c es

c o u ld be i s o l a t e d . R e a c tio n o f

/ 3 -N a p h th y la m in e w it h F o rm y la te d P ro d u c t

An a l k a l i n e

s o lu t io n o f th e fo r m y la te d compound fro m

0 .0 2 5 m ole o f e t h y l b e n z y lp h e n a c y lm a lo n a te was poured i n t o s o lu t io n o f 5 g . of

( 0 .0 3 5 m o le )

o f /J -n a p h th y la m in e and 17 m l.

c o n c e n tr a te d h y d r o c h lo r ic a c id in 150

was added u n t i l th e

a

m l.

s o lu t io n became c lo u d y .

o f e t h a n o l.

W ater

A f t e r s ta n d in g

f o r 90 m in u te s th e y e llo w p r e c i p i t a t e w h ich had form ed was f i l ­ te re d .

R e c r y s ta lliz a tio n

t h a t m e lte d g r a d u a lly i n

tw ic e from 95,4 e th a n o l gave a p ro d u c t th e neigh b orho od o f 220 ° w ith decom­

p o s it i o n . C a lc u la t e d f o r C33 H 31 O5N Found mg. sample mg. HgO mg. CO8

5 .9 9 % H 5 .7 7

7 5 .9 8 .4 C 7 2 .3 6

7 .2 4 9 3 .7 4 0 1 9 ,2 2 0

A sam ple o f t h i s p ro d u c t was b o ile d w i t h 100 m l. zen e c o n ta in in g 6 m l. o f a b s o lu te e th a n o l. filte r e d

h o t,

p r e c ip ita te .

b u t when th e

filtr a te

The c le a r y e llo w

in g and e v a p o ra te d p a r t i a l l y

o f ben­

The su s p e n s io n was

was c o o le d ,

th e r e was no

s o lu tio n was re h e a te d to b o i l ­

a t th e b o i l i n g

p o in t,

p ro d u c in g

61

a precipitate which was collected and dried. Analysis m g . sample m g . HgO mg. COg

5.55 fo H

75.39 & C

4.068 2.019 10.940

A sample of the product from alcohol above was dissolved in absolute ethanol (0.1 g. in 500 ml.) and passed through a column of Activated alumina.

Cautious evaporation of the fil­

trate yielded yellow needles.

When sublimed at a bath temper­

ature of 140° and under a pressure of 0.2 micron, the product melted at (176.6) 177.5 - 178.4°.

The literature lists the

melting point of dl-/3-naphthylformamidine as i860. Calculated for CB1H15N^ Found m g . sample mg . H£0 mg. C0£

5.44 ,6 H

85.10 > C 85. 92 36 .06

6.077 7 6.1621 3.0960 3.19 28 19.1557 19.4514

Other attempts of purify the compound resulted is oils, tars, or low melting solids. Reaction of Alkali with Ethyl Benzylphenacylmaionate Ethyl benzylphenacylmaIonate (5.68 g., 0.01 mole) v.as dissolved in 250 ml. of thiophene-free benzene and treated with 0.25 g. (9.01 mole) of sodium hydride.

The suspension -was

heated under reflux for 5 hours, cooled, and poured into ice water.

Hydrogen was evolved.

The benzene layer was washed with

water until the washings were no longer alkaline, dried with anhydrous sodium sulfate and evaporated on a steam cone.

The

flask containing the residue was evacuated briefly to remove the last traces of benzene, and the i*esidue was then boiled

62

w it h 6 0 - 8 0 ° l i g r o i n , ta ls .

w h ic h c o n v e rte d th e o i l y r e s id u e

The su sp en sio n was f i l t e r e d

h o t,

w eighed 2.2 g . , was r e c r y s t a l l i z e d

(20 m l . )

d ilu te

(1 5 4 )

1 5 5 .0 -

c r y s ta ls

a more s lu s h .

o f m e ltin g

1 5 6 .0 ° .

C a lc u la t e d f o r Cx 7 H140 £ Found mg. mg. .

s o lu tio n )

form ed an a lm o s t s o l id

R e c r y s t a l l i z a t i o n f o u r tim e s y ie ld e d w h ite p o in t

w hich

fro m 80 m l. o f 95/4 e th a n o l.

P r e c i p i t a t i o n was v e r y slow from t h i s c o n c e n tr a te d s o lu t io n

end th e s o l i d ,

to c r y s ­

sample H£0 C0 £

7 .6 2 9 3 .9 5 2 2 2 .6 3 9

5 .6 4 $ H 5 .8 0 5 .9 0

8 1 .5 8 >4 C 8 0 .9 9 8 0 .9 9

7 .9 1 2 4 .1 7 0 2 3 .4 3 0

/7-Benzoyl-X-benzylpropionic acid enol lactone (XXIV) Dry, a l c o h o l - f r e e

in

sodium m e th o x id e

d r y b en zen e, and 1 8 .4 g .

m a l o n a t e and 16 m l. sion was s t i r r e d

( 0 . 2 m o le ) was suspended,

( 0 . 0 5 m o le) o f e t h y l b e n z y lp h e n a c y l-

o f d ry e t h y l fo rm a te were a d d e d .

f o r 22 hours at room te m p e r a tu r e . w it h d i l u t e

sodium h y d ro x id e

The suspen­

It

was th e n

c h ille d

and e x t r a c t e d

water.

S in c e th e e t h y l fo rm a te d id n o t r e a c t a t room te m p e ra tu r e ,

the e x t r a c t i o n rem oved o n ly a v e r y The benzene s o l u t i o n s t e a m cone.

s m a ll amount o f m a t e r i a l .

re m a in in g was e v a p o ra te d to an o i l on a

The r e s id u e was b o ile d w ith 6 0 - 8 0 ° l i g r o i n ,

ment w h i c h c o n v e rte d was filtered h o t ,

th e re s id u e t o c r y s t a l s .

and th e f i l t r a t e

small amounts of an o i l y m a t e r i a l . f r o m th e h o t f i l t r a t i o n

was r e c r y s t a l l i z e d

1 5 9 .5 ° .

C^H^O s

5 .6 4 $ H 6 .0 3 6 .1 3

o b ta in e d

t h r e e tim e s from

ed at

Calculated f o r Found

The suspensio n

The p r e c i p i t a t e

8 . 5 g . o f w h ite f l u f f y

1 5 9 .1 -

a tre a t­

on c o o lin g d e p o s ite d o n ly

9 5 $ ethanol, y i e l d i n g ( 1 5 3 .7 )

s o lu t io n and

n e e d le s w hich m e lt ­

8 1 .5 8 $ C 8 1 ,6 5 8 1 .5 7

63

mg. mg. mg.

sample HgO COg

6 .3 1 9 5 3 .4 0 4 6 1 8 .9 0 7 7

5 .9 9 1 8 3 .7 8 4 1 1 7 .9 0 8 8

S a p o n i f i c a t io n o f / 3 - B e n z o y l- Q t-b e n z y Ip ro p io n ic a c id e n d

la c to n e

The e n o l la c to n e o f /3 - b e n z o y l - d - b e n z y lp r o p io n ic a c id ( 0 . 2 5 g. , 0 .0 0 1 m o le ),w a s h e a te d w it h 15 m l. o f 0 . 1 If sodium h y d r o x id e s o lu t io n an h o u r. It

( 0 .0 0 1 5 m ole) and 15 m l. o f 9 6 $ e th a n o l f o r

The s o lu t io n was a llo w e d to

s ta n d and c o o l o v e r n ig h t .

was th e n e v a p o ra te d u n d er reduced p re s s u re to d ry n e s s .

15 m l. A fte r

o f w a te r was ad d ed , a s l i g h t l y

t u r b id s o lu t io n was fo rm e d .

th e t u r b i d i t y was removed by f i l t r a t i o n ,

was a c i d i f i e d of 0 . 1

s lo w ly w it h s t i r r i n g

N h y d r o c h lo r ic

a c id .

w it h an a u t h e n t ic

1 7 2 .6 -

s l u r r y was c h i l l e d

F i l t r a t i o n and d r y in g

u n d er re d u c e d p re s s u re y ie ld e d 0 .2 5 g . w h ic h m e lte d a t ( 1 7 1 . 0 )

th e s o l u t i o n

by ad d in g d ro p w is e £0 m l.

The c r y s t a l l i n e

o v e r n ig h t I n th e r e f r i g e r a t o r .

When

1 7 3 .3 ° .

a t 60©

(9 4 $ ) o f w h ite c r y s t a ls A mixed m e ltin g p o in t

specim en o f b e n z y lp h e n a c y l& c e tic a c id

(X III)

m e lte d a t 1 7 2 .8 - 1 7 4 . 3 ° . q -

or

-A ld e h y d o - /^ - b e n z o y l- a - b e n z y lp r o p io n lc a c id e n o l l a c ­ to n e d i e t h y l a c e t a l

E t h y l b e n z y lp h e n a c y lm a lo n a te ( 0 . 0 5 m o le ) o f e t h y l o r th o fo r r a a te ,

(1 8 .4 g . ,

0 .0 5 m o le ) ,

and 1 .2 5 g .

7 .4 g.

( 0 . 0 5 m o le) o f

sodium h y d r id e were p la c e d i n a f l a s k w it h 250 m l.

o f d ry t h i o -

p h e n e - f r e e benzene and h e a te d und er r e f l u x f o r 12 h o u rs .

The

m ix tu r e was co o le d and e x t r a c t e d w it h w a te r u n t i l n e u t r a l ,

and

th e benzene s o lu t io n was d r ie d and e v a p o ra te d on a steam cone. The r e s id u e l e f t a f t e r

th e e v a p o r a tio n , when b o ile d w it h 6 0 - 8 0 °

lig r o in ,

changed to c r y s t a l s o f /3 - b e n z o y l -