Synthesis of some derivatives of acetonylbarbituric acid

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U n p u b l i s h e d t h e s e s s u b m i t t e d f or the M a s t e r ’s and D o c t o r ’ s d e g r e e s a n d d e p o s i t e d in t h e N o r t h w e s t e r n U n i v e r s i t y L i b r a r y a r e o p e n f o r i n s p e c t i o n , b u t a r e to be u s e d o n l y w i t h d u o r e g a r d to t h e r i g h t s o f t h e a u t h o r s . Bibliographical r e f e r e n c e s m a y be n o t e d , b u t p a s s a g e s m a y be c o p i e d o n l y w i t h t h e p e r m i s s i o n o f t h e a u t h o r , a n d p r o p e r c r e d i t m u s t be g i v e n in s u b s e q u e n t w r i t t e n o r p u b l i s h e d w o r k . E x t e n s i v e c o p y i n g or p u b l i c a t i o n o f t h e t h e s e s in w h o l e o r in p a r t r e q u i r e s a l s o the c o n s e n t of the D e a n of the G r a d u a t e S c h o o l of N o r t h w e s t e r n Uni versi t y . This thesis h a s b e e n u s e d b y t h e f o llowiJ ^g a t t e s t t h e i r a c c e p t a n c e of rne




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ACKNOWLEDGMENT The author wishes to express her appreciation to Dr. C. D. Hurd for his constant guidance and encouragement in carrying out these investigations.

TABLE OF CONTENTS INTRODUCTION ........................................


Barbituric Acid Derivatives .....................


Dioxolanes and 1,3-Dioxanes ........

. . . . . .


Dxazolidines and 1,3-Oxazines ...................


Condensation of Aldehydes with Acetonylbarbituric Acids .


Reduction of Ethylacetonylbarbituric Acid. . . .

23 26

Preparation of 5-Ethyl-5-(2-aminopropyl)barbituric Acid.......................................


Oxidation of Ethylacetonylbarbituric Acid with H y p o h a l i t e s .............................. E X P E R I M E N T A L ...................................

32 34

Starting Materials. . ...........................


Preparation of 5-Alkyl-5-acetonylbarbituric Acids


Preparation of Dioxolanes and 1,3-Dioxanes. . . .


Attempted Preparation of Oxazolidines ..........


Condensation of Aldehydes with Acetonylbarbituric A c i d s .....................................


Reduction of Ethylacetonylbarbituric Acid. . . .


Attempted Preparation of 5-Ethyl-5-(2-aminopropyl)barbituric Acid................... .


Oxidation of Ethylacetonylbarbituric Acid with Hypohalites




V I T A ...........................................






!; !|

Since 1903, when Fischer and v. Mering1 discovered that

is simple barbituric acid derivatives possess narcotic activity, !ihundreds of harhituric acid derivatives have been prepared. S; ji Nearly all of them have substituents in the 5-position, and ; many have substituents in the 1-position or the 1- and 3| positions*

Of the derivatives substituted only in the 5-


!; position, 5,5-diethylbarbituric acid (Barbital) was found1 j! to be a powerful narcotic.

If smaller groups are present,

; the compound has little or no activity, while if the groups are larger the activity reaches a maximum with dipropylbarbituric acid.

However, if one of the groups is ethyl,

: maximum hypnotic activity is reached where the other is amyl, isoamyl (Amytal), or hexyl.

Unsaturated radicals have been

employed to advantage \ diallylbarbituric acid (Dial) is slightly better as an hypnotic than dipropylbarbituric acid, and 5-(l-cyclohexenyl)-5-ethylbarbituric acid (Phanodorm) and 5 - (l-cyclohexenyl)-l, 5-dimethylbarbituric acid (Epivan) are in clinical use. have been prepared.

Derivatives containing aromatic groups Ethylphenylbarbituric acid (Phenobarbital)

is an excellent narcotic. Substitution of the 1-position by alkyl groups gives more powerful and shorter-acting drugs $ 5-ethyl-l-methyl-5phenyl-barbituric acid (Prominal) and l-(3L,3-dibromopropyl)-

C l)

E. Fischer and v. Mering, Therap. d. Gegen. March (1903)$ Chem. Zentr. (5]2* 1155 (1903).

;j5,5-diethylbarbituric acid (Diogenal) are examples. S i i Many derivatives of thiobarbituric acid are known. Their j1 |lhypnotic action is generally shorter: and their stability is |i

jless than that of the oxygen analogs.


butyl)-2-thiobarbituric acid (Pentothal) is an example.2 ■ j Ij During the last few years the interest has turned to !barbituric acid derivatives containing oxygen, nitrogen, halo:gen, and sulfur in the substituents at the 1-, 3-, and 5!positions.

The oxygen-containing radicals include acetonyl,3 ’4

* £ -hydroxyethyl,5 pinacolyl,6 alkoxyalkyl,7 alkoxyalkoxyalkyl,8 9 Xo furfuryl, and tetrahydrofurfuryl. The nitrogen-containing 2.1 acetanilido, 12 piperidyl, 1 radicals include dialkylaminoalkyl,


(2) G. M. Dyson, The Chemistry of Chemotherapy, Bouverie House, London, 1928; A. L. Tatum, Physiological Review, iS, 472 (1939). (3) A. W. Dox and B. Houston, J. Am. Chem. Soc., 46, 252 (5-924). (4) A. V. Kirsanov and Y* N. Ivashchenko, J. Gen. Chem. (USSR), 8, 1576 (1938). (5) G. S. Skinner, J. Am. Chem. Soc., 59, 322 (1937)* G. S. Skinner and A. P. Stuart, ibid., 6£, 2993 (1941). (6) S. M. McElvain and R. F. Taylor, ibid., 63, 2513 (1941). (7) F. F. Blicke and M. F. Zienty, ibid., 63, 2991 (1941)* F. C. Whitmore and M. A. Thorpe, U. S. Patent, 2,161,212 C. A., 33, 7493 (1939). (8) Y. Prelog and V. Hahn, Coll. Trav. chim. Tch^coslovaquie, 8, 219 (1936)* Chem. Zentr. II, 1544 (1936). (9) W. R. Kirner and G. H. Richter, J. Am. Chem. Soc., 51, 3131 (1929)* L. Rosenthaler, Pharm. Acta Helv., 13. 359 (1938)* C. A., 33, 9551 (1939). (10) A. W. Dox and E. G. Jones, J. Am. Chem. Soc., 50, 2033 (1928). (11) A. W. Dox and L. Yoder, ibid., 45. 1757 (1923). (12) J. A. Timm, ibid., 52, 1943 (1935;. (13) I. Y. Zbarskii, Ukrain. Gosudarst. Inst. Eksptl. Farm. (Kharkov) Konsul1tatsionnye Materialy, 265 (1939)* C. A., 36, 3160 (1942).

3. i,

! | ||p>-picolyl,14 imidazolemethyl,15 and antipyryl.16 Several jj j!nitrogen-containing dyes have been prepared*17 Among the P !lsulfur-containing radicals are p-toluenesulfonyl,18 thienyl,19 !! 20 land thiazolemethyl. Some of the halogen-containing barbiI*turic acid derivatives in particular have been useful as •! 5 21 |idrugs. A few of the radicals used are 0 -bromoethyl, 9


•2-chloro(or bromo)-2-propenyl,22 and bromoisobutenyl.23


In the present work it was considered of interest to

jiprepare barbituric acid derivatives with groups in the 5jlposition containing oxygen and nitrogen, which could be pre­ p a r e d from 5-alkyl-5-acetonylbarbituric acids.

The approach

to these compounds was through the reactivity of the acetonyl 'group. The first problem was the preparation of the alkyl3

!acetonylbarbituric acids.

The method of Dox and Houston


tried, but the yields of alkylacetonylbarbituric acids obtained were much less than they had reported.

The method of

' (14) C. S. Kuhn and G. H. Richter, J. Am. Chem. Soc., 57. 1927 (1935). (15) M. S. Taggert and G. H. Richter, ibid. 55, 1110 (1933). (16) A. Sonn and W. Litten, Ber. 66, 1512 (1933). (IV) A. E. Pierce and M. M. Rising, J. Am. Chem. Soc., 58, 1361 (1936) $ A. Mossini, Ann. chim. farm., Dec. 47 (1939)$ C. A., 34, 2175 (1940). E. L. D ’Ouville, F. J. Myers, and R. Connor, J. Am. (18) Chem. Soc., 61, 2033 (1939). (19) F. F. Blieke and M. F. Zienty, ibid., 63, 2945 (1941). (20) F. E. Hopper and T. B. Johnson, ibid. 56, 484 (1934). : (21) G. S. Skinner, ibid., 59, 322 (1937)$ H. R. Henze and J. J. SpurlocK, ibid., 63, 3360 (1941). F. Boedecker and H. Gruber, U.S. Patent 2,080,071$ i; (2 2 ) Chem. Zentr., II, 1047 (1937)$ Y. 0. Gabel, I. Y. Zbarskii, and R. P. Gvirtsman, Ukrain. Gosudarst. Inst. Eksptl. Farm. (Kharkov), Konsul1tatsionnve Materialy, No. 4, 106 (1939); C. A., 36. 3787 (1942). (23) G. Heilner, Ger. Patent 629,373$ Chem. Zentr. II, 819 (1936).

|Kirsanov and Ivashchenko4 was reported to give satisfactory i

yields but required the preparation of bromoacetone.


chloroacetone is commercially available, it was considered preferable to develop a method using that compound. The usual method of preparing 5-alkylbarbituric acids is by treating ethyl malonate with an alkyl halide in the presence of sodium ethoxide


or magnesium ethoxide,

condensing the ethyl alkylmalonate with urea.36 !was tried.



This approach

Reaction of ethyl malonate and chloroacetone in

ether solution with sodium ethoxide in the presence of a trace of sodium iodide gave 64 per cent of ethyl acetonylmalonate.

Gault and Salomon

using bromoacetone.


obtained a 70 per cent yield

Attempts to prepare ethyl ethylacetonyl-

malonate from ethyl acetonylmalonate and ethyl iodide, how­ ever, were unsuccessful. Accordingly, the plans were modified to attach the groups in the reverse order.

With ethyl ethylmalonate and sodium

ethoxide, chloroacetone gave tarry materials from which no pure compounds were isolated. similar results.

Dox and Houston3 obtained

A tarry product w^s also obtained when

ethyl butylmalonate was used.

Since the tar resulted by de­

composition of chloroacetone in anhydrous alkaline solution, an experiment was tried with a derivative of chloroacetone (24) (25)

R. Adams and R. M. Kamm, Organic Syntheses, 4, 11 (1925). H. Lund, Kong, dansk. Vidensk. Selsk., mat-Fysiske Medd, 13. No. 13 (1935)$ Chem. Zentr., I, 2096 (1936). (26) E. Fischer and A. Dilthey, Ann. 355. 334 (1908). (27) H. Gault and T. Salomon, Compt. rend. 174, 754 (1922)$ Ann. chi*., 2, 133 (1924).

|iwhich was stable under those conditions* *

methyldioxolane is such a compound*

2-Chloromethyl-228 It was prepared by

distillation of benzene and water from a mixture of benzene, chloroacetone, and ethylene glycol with a trace of acid as a icatalyst.

Once obtained, however,' 2-chlor omethyl-2-methyl-

:dioxolane failed to react either with ethyl butylmalonate and sodium ethoxide in alcohol solution, or with ethyl butylmalonate and sodium in dry ether solution.

This inactivity

aligns itself with the findings of Ktthn28 that 2-chloromethyl2-phenyldioxolane does not react with alcoholic sodium hy­ droxide on boiling for several hours, nor with the sodium derivative of ethyl acetoacetate, nor with the sodium deriva­ tive of 3,6-dioxaheptanol.

However, 2-chloro(or bromo)methyl-

2-phenyldioxolane reacts with metallic magnesium to give & Grignard reagent. '

Since malonic esters gave trouble, attention was turned

to the alternative approach, namely, to start with barbituric acid.

Substitution into the 5-position has been reported

for allyl halides,29 for chloroacetanilide,12:and for chloro-3 and bromoacetone.4 5-Acetonylbarbituric acid is readily prepared by the action of chloroacetone on barbituric acid.3

The reaction of acetonyl­

barbi turic acid with ethyl iodide, however, could not be (28) M. KOhn, J. prakt. Chem., 156, 103 (1940). (29) F. Hoffmann-LaRoche and Co., A. -G., Ger. Patent 526,854$ C. A., 25 , 4893 (1931).

Icarried out either by heating the acid with ethyl iodide and i jjsodium ethoxide in absolute alcohol, or by refluxing an aqueous l ! ||alcohol solution of the acid and sodium hydroxide with ethyl ij

J iodide* The reaction of ethylbarbituric acid with chloro­ u s jjacetone in neutral, aqueous alcohol solution was more satisj|factory*

The yield increased with increasing times of reflux

i;to 32 per cent at two and a half hours $ but when a small !jamount of sodium iodide was added, a maximum of 74*6 per cent II j !came at a reflux time of only half an hour. The yield was jjless with both shorter and longer reflux periods. This is 12 30 j! shown graphically in Figure 1 (P.43). Timm and Perletz observed a similar catalytic effect of potassium iodide in other syntheses of a somewhat related nature* Dioxolanes and 1,3-Dioxanes ;!

The first dioxolane derivative to be prepared was 2-


It was synthesized in 1861 by Wurtz.31

t;Since that time a surprisingly large number of dioxolane and ij 1,3-dioxane derivatives have been prepared.

Piperonal and

related compounds have been extensively studied.


cyclic acetals or ketals have been prepared from sugars. 32 , jThese are dioxolanes also. Bergmann and others have pre­ pared dioxolane and 1,3-dioxane derivatives in the study of ‘ glycerides.

More recently, dioxolanes and 1,3-dioxanes have

(30) P. Perletz, Ph.D. Thesis, 1940, Northwestern University. ' (31) A. Wurtz, Compt. rend., 53, 378 (1861)$ Chem. Zentr., 3£, 222 (1862). (32) M. Bergmann, A. Miekeley, and E. v. Lippmann, Ber., 62, 1467 (1929).

been used as local anesthetics, as antiseptics, as perfumes, and as solvents. A number of methods for the preparation of these compounds have been developed.

Most of them involve reaction of a

polyhydroxy compound with a ketone or aldehyde in the presence of an acidic catalyst.

In some cases no catalyst is used,

and in others a neutral dehydrating agent is employed.


methods include the reaction of acetylenes with polyhydroxy compounds, and the reaction of alkylene oxides with aldehydes or ketones.

There are a number of less general methods.

The first workers simply heated the reactants together. Wurtz31 prepared 2-methyldioxolane by heating acetaldehyde with an excess of ethylene glycol at 100° for eight days. Lochert


prepared 2-ethyldioxolane similarly.

acted with glycerol


Acrolein re-

at 50-60° during several weeks to give

10 to 15 per cent of 4-hydroxymethyl-2-vinyldioxolane. Self condensation of l,2-dihydroxy-2-isopropyl-5-hexanone s§ gives rise to 2,4-endoethylene-2-methyl-4-isopropyldioxolane, " on distillation: ,o -c h 2 c h 3c o c h 2c h 2c h o h c h 2 o h


c h (c h 3 )2 c h 2-c h 2

Hydrogen chloride has been used extensively as a catalyst. (33) H. Lochert, Ann. chim., (6) 16, 30 (1889). (34) H. Hibbert and M. S. Whelan, J. Am. Chem. Soc. Slj..;,3115 (1929). (35) F. Tiemann and F. W. Semmler, Ber., 30, 442 (1897).

Del^pine36 obtained dioxolane by heating ethylene glycol and paraformaldehyde with 1 per cent of hydrogen chloride at 100° for eight hours.

Emil Fischer37 prepared a mixture of 4-

hydroxymethyl-2,2-dime thyldioxolane and 2,2-dimethyl-5hydroxy-l,3-dioxane by shaking glycerol and three molar proportions of acetone with 1 per cent of dry hydrogen chlor­ ide at room temperature for twenty hours.


reacts with excess acetone under the influence of 1 per cent of dry hydrogen chloride during two days at room temperature to give 3,3,9,9-tetramethyl-2,4,8,10-tetraoxaspiro[5,5]undecane.38 h o c h 2sv

^c h 2 o h

a hoch2


+ 2 CH3COCH3 nc h 2 o h



jh c h 3^

x c h 2- o v

o -c h /



.c c h 2- o x


Franke and Gigerl39 found that benzaldehyde reacted with simple glycols such as isobutylene glycol or 1,3-butanediol when dry hydrogen chloride was bubbled into the cooled mixture for an hour, or when the mixture was refluxed for an hour with a 1 per cent solution of dry hydrogen chloride in alcohol. The products reported were 4,4-dimethyl-2-phenyldioxolane or 4-me thyl-2-phenyl-1,3 -dioxane. decanediol did not react.

1,4-Pentanediol and 1,10-

Cis-9,10-dihydroxystearic acid

(36) M. Delepine, Compt. rend., 131. 744 (1900). (37) E. Fischer, Ber., 28, 1167 (1895). (38) J. Bbeseken, G. Schaefer, and P. Hermans, Rec. trav. chim., 4i, 722 (1922). (39) A. Franke and B. Gigerl, Monatsh., 42, 8 (1928).

reacts with acetone containing 2 per cent of dry hydrogen chloride by standing twelve days at room temperature.40 The trans form failed to react.

In a few cases dry sodium

sulfate has been added to remove the water formed in the re­ action.41

Hydrogen chloride is a reactant as well as a

catalyst in its reaction with acrolein and ethylene glycol at 0° to give 2(j^ -chloroethyl)dioxolane.34

Hydrogen bromide

undergoes the same reaction.42 Sulfuric acid has been used both as a catalyst and as a dehydrating agent in the reaction of polyhydroxy compounds with aldehydes and ketones.

Bbeseken43 found that chloral

condensed with ethylene glycol when heated with half the volume of concentrated sulfuric acid for several hours. Usually, however, only a trace of sulfuric acid is used. Read, Lathrop, and Chandler44 prepared 2,4-dimethyl-5-phenyldioxolane by refluxing equal molar quantities of acetaldehyde and 1-phenyl-l,2-propanediol with a trace of 40 per cent sul­ furic acid for six hours.

Compounds of this type are used in

perfumes. (40) V. I. Esafov, J. Gen. Chem. (USSR), 6, 1818 (1936); C. A., 4268 (1937), 31. (41) E. Fischer and E. Pffihler, Ber., 53, 1606 (1920)$ R. Dworzak and K. Hermann, Monatsh., 52, 83 (1929)$ M. Bergmann and N. M. Carter, Z. physiol. Chem., 191, 211 (1930). (42) H. S. Hill and G. J. C. Potter, J. Am. Chem. Soc. 51. 1509 (1929). (43) J. BBeseken, Verlag. Akad. Wetenschappen Amsterdam, 35. 1084 (1926)j C. A., 21, 1962 (1927). (44) R. R. Read, H. Lathrop, and H. L. Chandler, J. Am. Chem. Soc., 4g, 3116 tl927).

Phosphoric acid also has been used both in relatively large amounts and in traces in this type of condensation. Verley45 obtained dioxolane by heating together 100 g. of ethylene glycol, 50 g. of 40 per cent aqueous formaldehyde, and 50 g. of phosphoric acid for a short time at 100°. Hibbert and coworkers found that ethylene glycol reacts with -chlorocinnamaldehyde under the influence of a trace of phosphoric acid.46 In one of the most successful ways of carrying out the reaction the water is distilled off as an azeotropic mixture with benzene or 1,1,2-trichloroethane or even an excess of the aldehyde or ketone, if it is of suitable boiling point. An acid catalyst, preferably benzenesulfonic acid or ptoluene sulfonic acid, is used.



used the apparatus

of Meyer48 which returned the dried solvent to the distilla­ tion flask continuously, to prepare dioxolanes and 1,3-dioxanes from simple glycols and ethyl acetoacetate, furfural, cyclohexanone, eyclopentanone, etc. 90 per cent.

-^he yields were from 70 to

Similarly Kuhn28 prepared a series of dioxolanes

and 1,3-dioxanes from camphor, chloroacetone, amino ketones, (45) A. Verley, Bull. soc. chim., (j3) 21, 275 (1899)$ Chem. Zentr., (5) 3, 919 (1899). (46) H. Hibbert, E. 0. Houghton, and K. A. Taylor, J. Am. Chem. Soc., 51, 611 (1929). (47) E. J. Salmi, Ber., 71, 1803 (1938)$ E. J. Salmi and V. Rannikko, Ber., 600 (1939)$ E. J. Salmi and A. Pofcgolainen, Ber., 72, 798 (1939) $ E. J. Salmi and I. J. Jansson, Suomen Kemistilehti, 12B, 28 (1939)$ C.A., M * 423 (1940). (48) H. Meyer, Ann., 433 . 327 (1923).


etc., and simple glycols.

Senkus49 has obtained substituted

1,3-dioxanes by condensation of simple aldehydes or ketones with the polyhydroxy compounds obtained by condensation of jjformaldehyde with nitroparaffins.


| j

CH3CH2 N02 + 2 HCHO

? H 2 ° H r CH3CN02 CH2 OH





Matthes, Ber., 34, 3484 (1901). and V. N. Belov, J. Gen. Chem. (USSR), C. A., 30, 3792 (1936). Radt, and E. Brand, Ber., £4, 1645 S. Malkowa, Compt. rend., 190T 495 and B. A. Rashkoven, J. Gen. Chem. (1937)* C. A., 2i, 5356 (1937).

2-Arylaminooxazolidines were prepared


by the action

of phenyl isocyanate on amino alcohols, and cyclization of the product with dry hydrogen chloride. CH 3 CHOHCH 2 N H —/

CH 3


CHs-< ’ ' V - NCO


ch 3

A \/




Oxazolidine derivatives have been prepared by the action of mercuric oxide on thiourea derivatives


Some oxazolidine derivatives have been shown to have useful pharmacological activity; 2 -aryl derivatives have local 81 anesthetic activity, and some 5,5-dialkyl-2,4-oxazolidine 89 diones are powerful hypnotics. In view of these facts attempts were made to prepare oxazolidine derivatives from ethylacetonylbarbituric acid and amino alcohols.

No such compounds were obtained, however.

With 2 -amino-l-ethanol, ethylacetonylbarbituric acid gave (87) F. B. Dains, E. J. Joss, and F. E. Stubbs, Univ. Kansas Sci. Bull., 20, 161 (1931); C. A., 26, 2717 (1932). (8 8 ) F. B. Dains, R. £§. Brewster, J. S. Blair, and W. C. Thompson, J. Am. Chem. Soc., 44 , 2637 (1922); I. B. Douglass and F. B. Dains, ibid., 56, 719 (1934); B. Schmidt, F. Hitzler, E. Lahde. R. Herbech, and M. Pezzati, Ber., 71, 1933 (1938); R. Gebauer, Ger. Patent 694,133; C. A., 35, 5259 (1941). (89) H. Erlenmeyer, Helv. Chim. Acta, 21, 1013 (1938); R. W. Stoughton, J. Am. Chem. Soc., 63, 2376 (1941).

only a salt.

When sodium hydroxide was added, sodium ethyl-

acetonylbarbiturate was formed and no further reaction occurred in boiling ether at 35°.

^his was probably due at least partly

to the insolubility of the salt in ether. 1


,3-propanediol gave tarry materials when heated at 190°

with ethylacetonylbarbituric acid and a small amount of the 2 -amino- 2 -methyl- 1

,3-propanediol salt of p-toluenesulfonic

acid. Condensation of Aldehydes with Acetonvlbarbituric Acids It is well known that aldehydes and ketones condense with active methylene groups, such as those adjoining carbonyl, eyano, or nitro groups.

Where more than one methylene group

is available it has been possible in some cases to direct condensation to one or the other position by a suitable choice of catalyst.

This has been done with methyl ethyl ketone.

Alkaline condensing agents lead to mixtures of 5-methyl-4heptene-3-one and 5-methyl-5-heptene-3-one, while sulfuric acid gives principally 3,4-dimethyl-4-hexene-2-one and hy9o drochloric acid gives mainly 3,4-dimethyl-3-hexene-2-one. It has also been done in the more complex case of levulinic acid. to the

Condensation in this instance was directed

ok-position by reacting benzaldehyde with levulinic

lactone under the influence of such bases as ammonia, piperi­ dine, diethylamine, aniline, or potassium carbonate. Tischbein, and Lossow




0.1 g. of sodium acetate, and 3 cc. of acetic anhydride was heated together on the steam bath for four hours. poured onto an equal volume of ice.

It was

The solid was filtered

soff, washed with water, and recrystallized from methanol. It melted at 226-229°, and mixed with starting material at 229-231°.

Apparently no reaction occurred.

Attempted Preparation of Oxazolidines Reaction of Ethylacetonylbarbituric Acid with 2-Amino1 -ethanol.

(1) Toluene (100 cc.) was distilled slowly from

a mixture of 5.00 g. of ethylacetonylbarbituric acid and

56. il jj 1.45 cc. of 2-amino-l-ethanol.

| j; that

The apparatus was so arranged

the distillate separated into two layers by gravity and

1 _ jj the toluene was returned continuously to the distillation |l |j flask. After seven hours, return of toluene was stopped, j!

j| and the solvent was removed on the steam bath. A slightly I j yellow, viscous glass remained. It failed to crystallize


on standing for two weeks. It was probably simply the salt j j of ethylacetonylbarbituric acid and 2-amino-l-ethanol. jj 1 (2) Ethylacetonylbarbituric acid (4.94 g.), 1.40 cc. of i jj 2-amino-l-ethanol, 0.93 g. of sodium hydroxide, and 1 cc. of ji water were ground together in a mortar and then refluxed with ij jj 35 cc. of ether for five and a half hours. The pasty mass li

ij quickly became a finely divided white solid. The solid was i j jj filtered off, suspended in dilute hydrochloric acid, and i l !i washed with water. It melted at 235-237°, and mixed with a ( I ! j known sample of ethylacetonylbarbituric acid at 235-237°. tl

ji The amount recovered (2.19 g.) was 44 per cent of the amount jl taken.

No oxazolidine derivative was isolated,

j i Reaction of ethylacetonylbarbituric Acid with 2-Aminoi ! Ij ,! 2 -methvl-lT3-propanediol. Ethylacetonylbarbituric acid (5.00 g.), 1 2.98 g. of 2-amino-2-methyl-1,3-propanediol, and 0.81 g. of

| i p-toluenesulf onic acid were ground together in a mortar and i then heated gradually to 190° and kept at that temperature j for eleven hours.

The black, glassy material was dissolved

in hot alcohol and filtered from a trace of brittle, black solid.

To the solution was added benzene, and the mixture was

57. j i (j

|extracted with dilute hydrochloric acid.

The aqueous extract

jwas made neutral to litmus.

The brown semisolid which

Jseparated was filtered off.

Attempts to crystallize it were


The filtrate was concentrated to small volume.

ijA black tar separated.

Attempts to obtain a crystalline


|solid from it were unsuccessful.

No oxazolidine derivative

was isolated. jjCondensation of Aldehydes with Ace tonylbarbituric Acids j

Ethylacetonylbarbituric Acid and Benzaldehvde.

(l) Ethyl-

jace tonylbarbituric acid (5.00 g.) was refluxed with 2.5 g. of |jfreshly distilled benzaldehyde and 1.94 g. of fused potassium jjacetate for one and three-quarters hours. The black reaction i jimixture was distilled with steam. From the distillate separated ij j|about 0.5 g. of oil smelling of benzaldehyde. The residue was

ij | jbroken up, stirred with 60 cc. of water, and filtered. 1 solid, dry, weighed 4.2 g.


Attempts to crystallize it failed.

j!From the filtrate on acidification separated a brown solid I* |:which, dry, weighed 0.7 g. Attempts to crystallize it failed i»

if a lS O . !! jj (2) Dry hydrogen chloride was bubbled into a mixture of jj 5.14 g. of ethylacetonylbarbituric acid and 2.40 cc. of ii

;i freshly distilled benzaldehyde in 30 cc. of benzene until ? no more was absorbed.

The mixture was allowed to stand for


i! eight days at room temperature with occasional shaking.



Ij solid was filtered off and washed with benzene.

The product

j; was 4.91 g. (96 per cent recovery) of ethylacetonylbarbituric

j| acid melting at 237-239°.

! l

|| (3) To a solution of 4.00 g. of ethylacetonylbarbituric i ij j acid in 40 cc. of glacial acetic acid was added 1.94 cc. of i 5) ; || benzaldehyde. The mixture was heated to 100° and hydrogen | chloride was bubbled through it intermittently during seven

s>| hours.

The product was cooled and filtered.

The residue,


| dry, weighed 2.52 g. and melted at 239-240°$ this is a 63 per |f

I; cent recovery of ethylacetonylbarbituric acid. \ ij

Ace tonylbarbituric Acid and Vanillin.

(1) A mixture of

I ■j 4.00 g. of ace tonylbarbituric acid, 3.5 g. of vanillin, 0.02- g | i jj of zinc chloride, and 30 cc. of glacial acetic acid was re1 !| fluxed for thirty hours. It was cooled and filtered. The i!

j solid was purified by solution in alkali and reprecipitation i i }J with acid. The product was 1 g. of ace tonylbarbituric acid ii ij melting at 246° with decomposition $ this is 25 per cent of Ij the amount taken.

The solution was concentrated under 20 mm.

pressure^ the residue was a viscous, black tar.

It dissolved

ij in dilute sodium hydroxid.e, and on acidification a brown solid ji

s| separated.

Attempts to crystallize this material were un­

successful. (2) A mixture of 4.0 g. of acetonylbarbituric acid, 3.3 g Si of vanillin, and 15 cc. of anhydrous pyridine was refluxed i for thirteen and a half hours.

The black, viscous material


| was mixed with 70 cc. of hot water and acidified with 4 M ii hydrochloric acid, whereupon a brown precipitate formed.


1 was filtered off and purified by solution in sodium hydroxide i ; and repreeipitation by acid.

The product was 3.1 g. (77 per

cent recovery) of acetonylbarbituric acid melting at 229-234°. Reduction of Ethylacetonylbarbituric Acid Reaction of Ethylacetonylbarbituric Acid with Hydrogen. A mixture of 5.45 g. of ethylacetonylbarbituric acid, 20 cc. of dioxane, and 1.5 g. of nickel deposited on kieselguhr* was placed in a bomb of 75 cc. free volume and hydrogen was added to a pressure of 103 atmospheres.

It was shaken con­

tinuously and heated to 80°, at which temperature it was kept for two hours.

On cooling the bomb, the pressure was

87 atmospheres $ this corresponds to absorption of one mole of hydrogen per mole of ethylacetonylbarbituric acid as cal­ culated from the gas law. bomb was opened.

Ammonia was given off when the

The solution was filtered to remove the

catalyst, and concentrated to small volume* -

A solid crystal­

lized with difficulty from the viscous solution$ recrystal­ lization from alcohol gave 1.8 g. of ethylacetonylbarbituric acid melting at 235-237° (mixed with an authentic sample it melted at 234-235°).

About 1 g. more of solid adhered to the

walls of the flasks and beakers used.

On account of the small

amount of material and the sticky nature of it, it was not possible to isolate any other products.


propyl)barbituric acid probably was not formed in appreciable amount. •*We are indebted to Dr. V. N. Ipatieff for a sample of this • catalyst, and for the use of his facilities in carrying out this experiment.


Reaction of Ethviacetonylbarbituric Acid with Aluminum


during twenty hours from a mixture of 5.24 g. of ethylacetonyl-

jj barbituric acid and 4.45 g. of aluminum isopropoxide. The j jj distillate gave a precipitate with saturated sodium bisulfite jj jj solution. The residue was made just sufficiently acid with

i| dilute

sulfuric acid to prevent precipitation of aluminum

jj hydroxide, and the solution was evaporated to dryness under |j i! reduced pressure. The residual solid was extracted with I II hot alcohol. The alcohol solution on cooling deposited 3.5 g. I jj of ethylacetonylbarbituric acid melting at 234-237° (mixed j| with an authentic sample of ethylacetonylbarbituric acid it i! I melted at 234-238°)• This is a 67 per cent recovery of I! jj starting material. jj


(2) Toluene (50 cc.) was refluxed for two days with 5.00 g.

\ of ethylacetonylbarbituric acid and 1.6 g. of aluminum isoji j propoxide, and then distilled off. Another portion of 50 cc. Ii ji of toluene was added, refluxed for two days, and distilled I i; off. The residue was made just sufficiently acid with sulji

Ii furic acid to prevent precipitation of aluminum hydroxide. h

j: The solid was filtered off and recrystallized from alcohol ii to give 1.0 g. of ethylacetonylbarbituric acid melting at ji 236-237°.

! i jj

The toluene distillate was analyzed for acetone by the

ji method of Marasco1 °° as modified by Hurd and Blunck.101 ji

| A mixture of 10 cc. of the distillate, 50 cc. of 2 per cent : hydroxylammonium chloride, and four drops of methyl orange

was titrated with 0*1126 M sodium hydroxide $ 1*83 and 1*72 cc ijwere required for two samples.


A blank was run omitting the

chloride solution^ 3.00 cc. of 0.1014 M

jjhydrochloric acid and 2.52 cc. of 0.1126 M sodium hydroxide jjwere required for neutralization. Calculation gives 0.00211 !( jland 0*00198 mole of acetone in the 91 cc. of distillate. The i j jjaverage, 0.00204 mole, is 8.6 per cent of the theoretical jlamount, 0.0236 mole. ji Ij As a check on the method, a solution of 3.00 cc. of acej t Ijtone in 250 cc. of toluene was analyzed. The samples rei jiquired 15.34 and 15.45 cc. of 0.1126 M sodium hydroxide, and ji

jjthe blank omitting the hydroxylammonium chloride solution rejjquired 2.00 cc. of 0.1014 M hydrochloric acid and 1.61 cc. i ! of 0.1126 M sodium hydroxide. By calculation the samples are j|found to contain 0.00175 and 0.00176 mole of acetone, rei j spectively.

These values differ from the true value, 0.00183

|j mole, by 3.8 per cent.

The yield of acetone, and of 5-ethyl-


!j 5- (2-hydroxypropyl)barbituric acid, is probably less than 12 I per cent in this reaction. i IAttempted Preparation of 5-Ethvl-5-(2-aminopropyl)barbituric 'iAcid i |

Reaction of Ethylacetonylbarbituric Acid Oxime with

|Aluminum Amalgam and Water. Water was added gradually to a i , Iwell-stirred mixture of 2.00 g. of ethylacetonylbarbituric acid oxime and 0.4 g. of amalgamated granulated aluminum in 100 cc. of ether.

Reaction ceased after one and a half hours

The aluminum and aluminum hydroxide were filtered off and the

I;filtrate was evaporated to dryness.

The solid on recrystal-


lization from alcohol gave 1.0 g. of ethylace tony lbarbituric I;

i|acid oxime (50 per cent recovery) melting at 232-234° (mixed ||with an authentic sample it melted at 226-232°).

No 5-ethyl-

| 5-(2-aminopro pylD barbituric acid was isolated. it

Keaction of Ethylacetonylbarbituric Acid with Hydrogen

j and Ammonia. A mixture of 5.48 g. of ethylacetonylbarbituric ti ;! acid, 2.0 g. of nickel deposited on kieselguhr (supplied by Dr. V. N. Ipatieff),- 20 cc. of purified dioxane, and about |! 3 cc. of liquid ammonia was placed in a bomb of 75 cc. free ‘i

|| volume, and hydrogen was added -until the total pressure was ■ 90 atmospheres. The temperature was raised gradually to 60° i ; and kept there for two and a half hours. The pressure did not drop during the last hour.

i ! pressure was 84 atmospheres.

On cooling the bomb the This corresponds to absorption

of 0.71 mole of gas per mole of ethylacetonylbarbituric acid. : The reaction product was filtered from the catalyst and conj centrated to small volume. soluble in water. of it.

The residue was a glassy material

Benzene was added to a dioxane solution

The oil which separated reacted with acetyl chloride

i; to give a glass which could not be induced to crystallize. i l ii The material which remained dissolved in the benzene solu! tion did not react with acetyl chloride. :: which could not be induced to crystallize. 5 -ethyl-5-(2-amino pro pyl) barbituric

It also was a glass None of the expected

acid was isolated.

Oxidation of Ethylacetonylbarbituric Acid with Hvuohalites Reaction of Ethylacetonylbarbituric Acid with Iodine and Sodium Hydroxide.

A solution of 3.35 g. of iodine and 6.8 g.

of sodium iodide in 25 cc. of water was added to a solution of 0.93 g. of ethylacetonylbarbituric acid in 10 cc. of 10 per cent sodium hydroxide solution. immediately.

Iodoform separated

After standing overnight the iodoform was fil­

tered off and the excess iodine was removed by means of sodium thiosulfate solution.

The solution was acidified and con­

centrated to about 20 cc., and sodium thiosulfate was again added.

The hot solution was filtered, and the filtrate on

cooling deposited crystals which, after recrystallization from water, weighed 0.35 g. and melted at 231-234° (mixed with an authentic sample of ethylacetonylbarbituric acid it melted at 233-235°).

^his is a 37.6 per cent recovery of

ethylacetonylbarbituric acid.

The iodoform weighed 0.55 g.,

32 per cent of the theoretical amount, and melted at 120-122°. The small amounts of materials used prevented the isolation of other products. Reaction of Ethylacetonylbarbituric Acid with Calcium Hypochlorite.

A solution of 13.5 g. of calcium hypochlorite

(HTH) in 40 cc. of water was added to a solution of 5.00 g. of ethylacetonylbarbituric acid in 9.5 cc. of 10 per cent sodium hydroxide solution.

A vigorous reaction occurred.

The mixture was distilled.

The distillate consisted of 30 cc.

of water and about 0.5 cc. of oily liquid.

The residue on

acidification deposited a brown gummy material which was only very slightly soluble in alkali. components were unsuccessful. barbituric acid was isolated.

Attempts to separate the

No 5-ethyl-5-(carboxymethy1)

SUMMARY An improved method of preparation of aIkylacetonylbar­ bituric acids from aIkylbarbituric acids and chloroacetone was found.

Sodium iodide is important as a catalyst in the

reaction. Several products of reaction of ethylacetonylbarbituric acid with glycols were prepared.

They are 5-ethyl-5-(l-

methyl-2,5-dioxacyclopentyl)methylbarbituric acid, 5-ethyl5 - (l-methyl-2,6-dioxacyclohexyl)methylbarbituric acid, 5e thyl - 5- (1,3 -d ime thyl-2,5 -d ioxa cyc lopentyl)me thylba rb itur i c acid, 5-e thyl-5- (1-me thyl-4-nitro-4-hydr oxyme thyl-2,6-dioxa­ cyclohexyl) me thvlbarbituric acid, and 5-ethyl-5-(1-methyl-4amino -4-hydr o x ^ thyl -2,6-d i oxac yclohexy 1) me thylbarbi tur i c acid*

2-Nitro-2-methyl-1,3-propanediol failed to react with

ethylacetonylbarbituric acid. 5-E thyl-5- (1-me thyl -4 -ami no-4 -hyd r oxyme thyl-2,6-d i oxa cyclohexyDmethylbarbituric acid was prepared by hydrogena­ tion of 5-e thyl-5-(1-me thyl-4-nitro-4-hydr oxyme thyl-2,6dioxacyclohexyl)methylbarbituric acid in the presence of Raney nicke 1 •

5-E thyl-5- (1-me thyl-4-ace tamino-4-hydr oxyme thyl-2,6-

dioxacyclohexyl)methylbarbituric acid was prepared from the amine by the action of ketene in aqueous solution. Attempts to obtain 5-ethyl-5-(1-methyl-2-aza-5-oxacyclopentyl)methylbarbituric acid by reaction of 2-amino-l-ethanol with ethylacetonylbarbituric acid, and 5-ethyl-5-(1,3-dimethyl-


3-hydroxymethyl-2-aza-5-oxacyclopentyl)me thy lbarbituric acid by reaction of 2-amino-2-methyl-l, 3 -propanediol with ethyl­ acetonylbarbituric acid failed. negative:

These reactions also were

condensation of aromatic aldehydes with acetonyl-

barbituric acid and ethylacetonylbarbituric acid, reduction of ethylacetonylbarbituric acid to 5-ethyl-5-(2-hydroxypropyl) barbituric acid, preparation of 5-ethyl-5-(2-aminopropyl)barbituric acid either by reduction of ethylacetonylbarbituric acid oxime or by reaction of ethylacetonylbarbituric acid with ammonia and hydrogen, and preparation of 5-e thyl-5-' (carboxymethyl)barbituric acid by oxidation of ethylacetonyl­ barbituric acid with hypohalites.



Margaret Louise McAuley


March 14, 1918, Huntingdon, Pa.


Graduated from Lakeland High School, Lakeland, Florida, 1934 B. S. degree from Florida Southern College 1937 M. S. degree from Northwestern University 1940

Or gani za ti o n s :

Mu Omega Xi, Sigma Xi, American Chemical Society


Assistant in l\fethematics and Physics, Florida Southern College, 1936-1937 Research Assistant, Northwestern University Dental School, 1938-1940 Assistant in Chemistry, Northwestern University, 1940-1941 Tutor and Assistant in Chemistry, Northwestern University, 1941-1942