THE I”TER4CTION OF ETHYL ACETOACETATE, ETC. PART II. 2159

CCXC1.-The Interaction of Ethyl Acetoaceiute and 0-Hydroxydistyryl Ketones. Part I I .

By ISIDOR M o m s HEILBRON, THOU ALFRED FORSTER, and

THE condensation of ethyl acetoacetate with o-hydroxydistyryl ketones was shown by Heilbron and Forster (J., 19%, 125, 2064) to lead to the formation of cyhhexenones and not, as in the c88e

,4BRAEAM BRUCE W H I T W O R ~ .

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2160 HEILBRON, FORSTER, AXD WKITWOBTPI:

of the o-hydroxymonostyryl derivatives, to pyrones. Further, it was found that the position taken up by the p-ketonic ester in the conjugated system can be arrived a t owing to the fact that when it attaches itself to the styryl residue containing the o-hydroxyl the resulting cycbhexenone is free of the carbethoxy-group. Thus, the interaction of 2'-methoxy-2-hydroxydistyryl ketone with ethyl acetoacetate leads to the formation of two cyclohexenones the struc- tures of which have been proved to be in accord with the following formulae :

7H2* CO $H (1.) HO -c ,H,*CH-CH,*C*CH:CH*C ,H,*OMe

MeO~C,H,~CHwCH,~C~CH:~H~C,H4~OH ('I.) C0,Et -7H-COTH

In order to test whether cyclohexenone formation is an invariable result of such condensations, the study of this reaction has now been extended to the case of the extremely reactive unsymmetrical 4'- dimethylamino-2-hydroxydistyryl ketone (XIII) , in which the greater amount of the free affinity is almost certainly concentrated at C(l) (Heilbron and Buck, J., 1921,119, 1500). In consequence of this it was anticipated that ethyl acetoacetate would enter the molecule a t positions 1-2 (formula XIIIj, giving rise to the cyclo- hexenone (111), if this type of compound were actually formed.

The result obtained was anomalous, for although a cyclohexenone resulted when the reactants were condensed in presence of concen- trated aqueous potassium hydroxide, the cyclohesenone contained the original carbethoxy-group, and consequently if the deductions previonsly arrived a t are correct, must represent the compound of structure IV. Now Borsche (AnnuZen, 1910, 375, 145) has shown that whereas distyryl ketone readily reacts with ethyl acetoacetate in presence of piperidine, pp'-tetramethyldiaminodktyryl ketone is unreactive under these conditions. It has now been ascertained that condensation can be brought about under similar conditions to those used in the above experiment, resulting in the formation of the cycbhexenone (V).

C O , E t * F H - C v

CO,Et.VH-CqH Me8.C 6H,*CH*CH,-C C H :C€€*C ,H,*OH (Iv.

Me~C,H,*CH=C~C*CH:CH*C,H,*NMe, Similarly, .by employing 50% potassium hydroxide, 4-dimethyl-

aminostyryl methyl ketone also reacts with ethyl acetoacetate,

W-)

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TIFE INTERACTION OF ETHYL ACETOACETATE, ETC. PART n. 2161

giving in the first place the saturated cydohexane derivative (W), from which water can easily be removed with formation of (VII).

It is thus apparent that the p-dimethylamino-group, although normally acting as a retardmg factor, does not necessarily rule out the structure given in (IV). That this truly represents the constitu- tion of the ketone under consideration was finally proved by oxidisjng the cyclohexenone with potassium permanganate in acetone solution, when salicylic acid was isolated from the decomposition products. That the anomalous behaviour is closely connected with the peculiar activity of the ketone is evident, for, as shown below, it disappea s on methylation of the free hydroxyl group, which reaction destroys the activity of the compound (Heilbron and Buck, loc. cit.). Further, with 4’-dimethylamino-4-methoxy-2-hydroxy- distyrpl ketone, in which the “ active ” properties of the parent ketone are also entirely suppressed (compare Heilbron and Whit- worth, J., 1923,123,238), ethyl acetoacetate yields a cydohexenone with the carbethoxyl eliminated and which consequently must possess the structure (VIII).

y&*CO*$H- (VIII. ) MeO*( HO) C6H,.CH0C~.C*CH:CHoC6H,*NMe,

On the other hand, the isomeric 4’-dimethylamino-3-methoxy- 2-hydroqdistyryl ketone and also the 5-methoxy-compound, both of which are “ active ” (Heilbron and Whitworth, Zoc. tit-), yield as main products of the condensatioln cycbhexenones similady constituted to that obtained from 4’-dimethylamino-Z-hydroxy- distyryl ketone itself.

(=.I Me0 =c ,H,*CHeCH,*C*CH:CH*C 6H4-me, me^---------------__-------_-----_____--------. OMe (X-1

*CO,Et*$!H-CO%H

yH(COm2 (XI.) HO *c 6H4-CHmCH,oCO*CH :CH-C 6H40NMe2 OH (m-) &a ________ _ _ _ _ _ _ _ _______ _ _ _ _ _ _ _ _ _ _ _ _ ________ ---

With 4‘-dimethylamino-2-rnethox-ydistyryl ketone, two isomeric compounds of empirical formula C,,H&04N were isolated. The higher-melting cyclohexenone (m. p. l64”), which is only formed in minute amount, was shown to be identical with the methyl ether of (IT) and consequently must possess the structure (X). The isomeride

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2162 HEILBRON, FORSTER, AND WHITWOBTH:

of m. p. 114' must accordingly have the constitution (IX), the reaction in this case having followed the normal course.

The primary object of the investigation has been achieved in definitely proving that, in all the cases examined, cyclohexenones alone are formed aa products of the condensation, and the facts harmonise well with the mechanism previously suggested to account for the elimination of carbethoxyl during the condensation (Heilbron and Forster, loc. cit.).

As regards the point a t which ethyl acetoacetate enters the molecule, this must certainly depend largely on the polar character of the substituent groups and their total effect upon the doubly- conjugated system. The authors feel, however, that the question is too complex to allow of an immediate explanation and t'hat no good purpose would be served by attempting this until the e%ect of polar influences in less complicated molecules is more thoroughly under- stood. It is also possible that other factors have to be taken into account and that steric duences play a part in determining the position taken up by the entering group. Thus in the case of 4'- dimetjhylamino - 2 - hy drox ydist yryl ketone it is conceivable that ethyl acetoacetate, probably through the intermediate formation of a labile addition product, brings about a transformation of the co-ordinated cis-form of the ketone (SIII) into a tram-isomeride ( X I V ) , a rearrangement which must necessarily modify the dis- tribution of residual af6nity effects.

1 ,H

(XIII. ) \/ M e a - - -

This suggestion is supported to some extent by the observation recorded by Heilbron and Buck (Zoc. cit.) that, whereas 4'-dimethyl- amino-2-hydroxydistpyl ketone is characterised by the ease with which it forms molecular addition compounds and is indeed exceed- ingly diilicult to isolate free from solvate addenda, this may be readily accomplished by crystallisation from ethyl acetoacetate. Again the profound effect which this ester exerts on the conhguration of unsaturated ketones is exemplified in the yellow form of o-hydroxy- styryl methyl ketone, which is readily transformed into ita colourless isomeride by crystallisation from this substance (McGOogin and Heilbron, J., 1924, 125, 2099). On the other hand, ethyl cyano- acetate does not induce isomerism of this type (unpublished work)

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THE IXTEXACTION OF ETHYL ACETOACETATE, ETC. PUT II. 2163

and it might consequently be expected that in this ctwe addition would take place a t the usually reactive unsaturated centire. In presence of 50% sodium hydroxide a condensation product of empiri- cal formula C,H&O,N was isolated to which either formula (XI) or (XII) could be ascribed. That the former correctly represents the structure of the compound was shown by treatment of the dicarboxylic acid with concentrated potassium hydroxide solution, when h i o n of the molecule occurred with production of p-dimethyl- aminobenzaldehyde. In considering the formation of this aldehyde, it has to be borne in mind that the effect of the strong alkali might possibly produce a type of reversed Michael reaction, in which m e the presence of the p-dimethylamhobemaldehyde would simply result through disintegration of the distyryl ketone, h i o n occurring at the double bonds. That this, however, was not the case waa evident from the fact that no trace of mlicylaldehyde was found in the reaction mixture.

E X P E R I M E N T A L.

Ethyl 3 -p-Dimt?thyluminopheny1-5- 0- h ydmxystyr yl- A=- c yclokene - l -one-2-cu~~Zute (IV) .-A solution containing 4'-dimethylamino- 2-hydroxydistyryl ketone (4 g.), ethyl acetoacetate (8 c.c.), absolute alcohol (20 c.c.), and potassium hydroxide solution (3 C.C. of 20%) was allowed to stand at room temperature for 24 hours. The precipitated product (2 g.) was collected and crystallised from either absolute alcohol or benzene. It separates in orange-yellow prisms (m. p. 196") containing 1 mol. of solvent, from which it ca,n be freed by heating in the steam-oven. It dissolves in concentrated sulphuric acid, giving the deep red solution characteristic of this type of cyclohexenone (Found in material crystallised from alcohol: C, 72.0; H, 7.4; N, 3.1. C25~704N,C2H60 requires c, 71.9; H, 7-3; N, 3.1%. Found in material crystallised from benzene : C, 76-8; H, 6.9; N, 2.9. C,,H2,O4N,C6H6 requires c, 77.0; H, 6.9; N, 2.9%. Found in anhydrous compound : C, 73.9 ; H, 6.7 ; N, 3-1. C,,H,,O,N requires C, 74.1 ; H, 6.7 ; N, 3.4%).

Oxidation.-About 1 g. of the substance dissolved in acetone was treated a t room temperature with hely-powdered potassium permanganate, added in very small portions at a time. When the oxidation was complete, the mixture mas filtered and the residue suspended in wafer and treated with sulphur dioxide until the manganese dioxide had dissolved. As no solid separated, the solution was made strongly acid with hydrochloric acid and ether-extracted. On removal of solvent, colourless needles were obtained and ident%ed as salicylic acid by mixed m. p. with an authentic specimen of the acid and also by the characteristic ferric chloride coloration.

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2164 HEILBRON, FORSTER, AND WHJTWORTH :

3-p-Dimeth ylamino phen yl-5 - 0- h ydrox ystyry 1 - A5-cyclohexene - 1 - one- 8 - ~ a r b o ~ y Z i ~ Acid-The previous ester was saponified by heating for 3 hours on the steam-bath with sodium hydroxide solution. The red, pasty mass mas dissolved in water, and the acid precipitated by addition of dilute acetic acid. The pure compound crystallised from alcohol in yellow plates, m. p. 225" (Found : C, 73.3; H, 6.0. C,H,O,N requires C , 73.3 ; H, 6.1%).

3-p-D~methylamino-5-o-hyd~oxy~ty~yl-A~-cyclohexene - 1 - one. -The free acid was dissolved in glacial acetic acid and boiled for 1 hour with 20% sulphuric acid. After cooling, the green liquid was carefully neutralised with dilute alkali, and the precipitated cycb- hexenone crystallised from methyl alcohol, from which it separated in yellow, felted needles, m. p. 23%" (Found : C , 78.9; H, 6-9. C,H,Oa requires C , 79.3; H, 6.9%).

Ethyl 3 -p - Dimeth ylamino-5 - o -methoxyst yryl- A5-c yclohexene- 1 -one - 2-carboxylate (X).-By direct methylation of the corresponding hydroxy-compound by the usual methods, only uncrystallisable products were obtained. The pure methyl ether was readily pro- duced, however, by methylation in acetone solution according to Heilbron and Buck's method (Zoc. cit .) . It separates from high- boiling ligroin in lemon-yellow prisms, m. p. 164", and dissolves in alcoholic potash to a yellow, and in concentrated sulphuric acid to a red solution (Found : C, $4-4; H, 7-0. C,,H,,O,N requires C, 74.5; H, 6.9%).

Ethyl 3-0 -Methoxyph en yl-5-p-dimethy~minostyryl- A5-cycloheze ne- 1-one-Z-carboxylate (IX).-A solution of 4'-dimethylamino-% methoxydistyryl ketone (3 g.) and 3 C.C. of ethyl acetoacetate in 10 C.C. of alcohol was heated for 3 hours on the steam-bath with potass- ium hydroxide solution (3 C.C. of 2073, the colour changing from deep red to orange. On gradual dilution with water a semi-solid mass was deposited which proved exceedingly dSicult to crystallise, but this was Snally accomplished by means of alcohol in presence of animal charcoal. Microscopic examination of the crystals revealed the presence of two substances, which were separated by repeated fractionation from carbon disulphide into a main fraction of the above ester (m. p. 112") and a small quantity of a substance, m. p. 160°, which was identical with the methyl ether obtained by methylation of the hydroxy-cyclohexenone (IV) .

3-o-methxypheny l -5-p-dimeth ylamimst yryl- A5-c yclohexene- l-one-2-carboxyZute can be conveniently prepared in good yield free from the higher-melting isomeride by treating an alcoholic solution of the ketone (6 g.) and ethyl acetoacetate (8 c.c.) at room temperature with potassium hydroxide solution (6 C.C. of 20%). After a few hours the red solution was inoculated witlh a crystal of the lower-

Ethyl

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THE INTERACTION OF ETHYL ACETOACETATE, ETC. PART II. 2165

melting ether and kept for 2 days. The crude product (5 g.) crptalhes from ether in orange needles (m. p. 114") which are extremely hygroscopic and change colour to brick-red on standing in moist air (Found : C, 74-2; H, 7.2. C2,&04N requires c, 74.5 ; H, 6.9%).

- Eth y 1 1 -Nethoxy - 3 - o -me,thx yphen y 1 - 5 - p-dimeth y laminost yr y 1 - A1 = =- c y c l o h ~ i e n e - 2 - ~ r ~ x ~ ~ . - ~ substance was prepared by dissolving the corresponding cyclohexenone (m. p. 114') in sodium ethoxide solution and heating under reflux with methyl iodide for 3 hours. It separates from ether in pale yellow needles, m. p. 148" (Found : C, 74.2; H, 7-4. C,,H3,O4N requires C, 74-8; H, 7.2%).

Ethyl 3-p-Dimethylaminop~yl-5-p-dimethy~m~~y~l-As-cyclo- hexene-l-one-2-carboxylate (V).-A solution containing 3.2 g. of 4 : 4f-tetramethyldiamindistyryl ketone (Sachs and Lewin, Ber., 1902, 35, 2576), ethyl acetoacetate (5 c.c.), and alcohol (10 c.c.) was heated under reflux for 1 hour with sodium hydroxide solution (1 C.C. of 50%). The clear red liquid was filtered from deposited sodium carbonate, and the cyclohexenone, which separated on cooling, repeatedly crystallised from absolute alcohol. It forms orange- yellow needles, m. p. 174-175" ; the phenylhydrazone melts at 239" (Found : C, 7443; H, 7.5; N, 6.7. C,,H,,O8, requires C, 75.0;

Ethyl 3 - p- Dirneth y luminophen y 1 - b - m t h y lc yclohe.xune - 5-01 - 1 -one - 2 - curboxylate (VI) .-A hot alcoholic solution of 4-dimethylamino- styryl methyl ketone (4 g.) and ethyl acetoacetate (6 c.c.) was treated with sodium hydroxide (1 C.C. of SOYo), and the resulting red solution kept for 12 hours at room temperature. The cycb- hexane crystallises from high-boding ligroin in colourless needles, m. p. 149" (Found : C, 67.7; H, 8.1; N, 4.4. Cl,&,O,N requires C, 67-8; H, 7.9; N, 4.3%). The phenylhydrazone separates from absolute alcohol in colourless crystals, m. p. 179" (Found : N, 10.3. C,H,,0,X3 requires N, 10.37-J.

3- p-dimeth y lurninopheny 1-5 -methyl - As-c y clohexene- 1 -one-2 - curboxylute (VII) is formed on heating an alcoholic solution of the above compound with excess of 10% sodium hydroxide solution, when an oily mass is produced which slowly solidSes. The cyclo- hexenone crystallises from methyl alcohol after treatment with charcoal in glistening plates, m. p. 66" (Found : N, 4.8. C,,GO,N requires N, 4.7%).

Ethyl 3-p-dirnethylami~~ny1-5-(3'-met?wxy-2'-hydroxy)styry1- A=- cyclohezene-l-one-2-carbozylate waa prepared by boiling an alcoholic solution of 4'-dimethylamino-3-methoxy-2-hydroxydistyryl ketone (5 g. ) and ethyl acetoacetate (2 mols.) for 3 hours under reflux with sodium hydroxide solution (3 C.C. of 44%). After removal of inor-

R, '7.4; N, 6.5%).

Ethul

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2166 THE INTERACTION OF ETHYL ACETOACETATE, ETC. PART 11.

ganic material by filtration, the crude cyclohexenone was purified by repeated crystaht ion h t from absolute alcohol and finally from high-boiling ligroin. It forms yellow crystals, m. p. 197- 198", r e d y soluble in chloroform and benzene, sparingly soluble in alcohol (Found : C, 71.6; H, 6.5. C,,H,O,N requires C, 71.8; H, 6.7%).

3-( 4'- Methozy -2'- hydroxy)phnyl-5-p-dddykcminostyryl-A5-cyclo - hexem - 1 -om .-An alcoholic solution containing 4'- dime thylamino-4 - methoxy-2-hydroxydistyryl ketone (6 g.) and ethyl acetoacetate (8 g . ) waa heated for 4 hour on the steam-bath with 6 C.C. of 50% sodium hydroxide. After cooling, the solution was filtered from a small quantity of material which could not be further purified, and the filtrate diluted with water. The red, amorphous solid thus obtained was dried and repeatedly crystallised from benzene. The pure cyclohexenone forms orange-red crystals, m. p. 218" (Found : C , 75.8 ; H, 6.9. C,H,,03N requires C, 76-0 ; H, 6.9%).

Ethyl 3-p-Dimethylumiqhen yl-5- (5'-methox y -2 - h ydroxy )st y yl- As- cyclokxm-l-om-2-carboxylate.-4'-Dimethylamino - 5 - methoxy - 2 - hydroxydistyryl ketone (4 g.) and ethyl acetoacetate (8 g.) were treated in alcoholic solution with aqueous sodium hydroxide (8 C.C. of 20%). After 3 days, the solution was filtered from a small quantity of solid, and the filtrate slowly diluted with water, when the cyclohexenone ester was precipitated. It crystallises from benzene wi th 1 mol. of solvent of crystallisation in yellow crysfah m. p. 196-197" (Found: C, 74.9; H, i - 2 . C,,H,O,N,C,H_ requires C, 74-8; H, 6.8%). The residue was washed with water to remove inorganic material and crystallised from aqueous pyridine. It separated in orange crystals, m. p. 250". Analysis of this com- pound shows that the carbethoxyl has been split off, from which it follows that its structure corresponds to 3-(5'-methoxy-2'-hydroxy)- phenyl-5-p-dimethylaminostyryl-A5-cyclohexene- 1 -one (Found : C , 75.9 ; H, 6.9. C,H2,03N requires C, 76.0 ; H, 6.9%).

y-p-Dimethyhminocinnalraoyl- $-o-h@roxyphenylpropane-aa'-d icarb - oxylic Acid (XI).-A mixture containing 4'-dimethylamino-2- hydroxydistyryl ketone (8.2 g. of chloroform addition product) and 8 C.C. of ethyl cyanoacetate in 25 C.C. of hot alcohol was treated with sodium hydroxide solution (8 C.C. of 50yo), when a deep*red coloration rapidly developed and ammonia was evolved. After 16 hours the reaction mixture was filtered from tarry and inorganic material. dilutd to 2000 c.c., and the clear orange-red solution rendered acid with dilute acetic acid. A s an examination of the precipitated product after crystallisation from benzene indicated that two sub- stances were present, the whole was boiled with sodium hydroxide solution until all evolution of ammonia had ceased. After again

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ammcfi ~ ~ d c ~ ~ v r r p AND CON~OATION. PABT II. 2167

rendering acid, the precipitated product WM purihd by r e p t e d txytdhation from nitrobenzene, when glistening, orange needles, m. p. 220°, were obtained (Found : C, 66-3; H, 5.8. -0,N requirea C, 66.6; H, 543'70). That the ethyl cyanacetate had entered the molecule a't positions 1 and 2 (XIII) wiu proved by slowly running a concentrated alkaline solution of the acid from a dropping-funnel on to b o h g potassium hydroxide solution (50 C.C.

of 70%) contained in a distillation flaak, fitted with a condenser. Pale green crystals (m. p. 66") separated from the collected sfearn distillate and were identified as p-dimethybminobenzaldehyde by mixed m. p. determinations with an authentic specimen and by the formation of the phenylhydrazone. The residue left in the flask was carefully examined for the presence of dcylddehyde, but no trace either of this or of salicylic acid could be found.

The authors desire to thank the Council of the Department of Scientific and Industrial Research for a grant in aid to one of them (T. A. P.) which has enabled this work to be carried out.

TEE CXIVERSITS, LIVERPOOL. [Received, July loth, 1925.1

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