Studies on ketene and its derivatives—XIII

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STUDIES ON KETENE AND ITS DERIVATIVES--XIII* SYNTHESIS OF @#MlNOCROTONAMIDE AND THE STRUCTURF OF ITS PYROLYSED PRODUCT PWtical

T. KATO, H. YAMANAKAand T. SHIBATA Institute, Toboko University School of Medicine, Kitad, Send&

Japan

(Receioed fn Jopan 1 J&y 1966; ucce~ted~r F~~i~t~on 15 Noocnrbct1966) Abawt-R&on of diketene with an exces of ammonia gives &aminocrotonamide (I), wbicb on b&ng is transformed into ~~~to~y~o~oto~de (IIb) wbicb bad been incomctly assigned tbe smxturc ~~3,~y~~,adimetlH-~p~do~~~de (I&I).*,’ Hydnlysis of Sib w&balkali gave ~~y~3~4p~idone cv) in a good yield. Structural assignmcnts of XIbare described. CHICK and

WILSMORE~ reported in 1910the reaction of diketene with ammonia to give acetoacetamide. When this reaction was carried out with an excess of ammonia, a white precipitate of acetoacetamide was converted into a yellow oil, which on heating was ~sfo~~ to a crystalline substance, m.p. 197’, CsHBO,Ns (IQ They proposed the structure 4-amino-3,4-dihydro-4,6-dimethyi-lX-2-pyridone-5-carbamide (Ha) based on the following: (a) the elemental analysis and the mol. wt. determination, (b) hydrolysis of II with aq. alkali to give Camino3,4dihydro-4,6-dimethyl-2p~done-~bo~~~ acid (Hr)t accompanied by the evolution of ~~rnol~~o~a. The authors quoted the self condensation reaction of acetoacetamides to give 4,6~me~yl-lH-2-p~done-5~b~de (IVa) as shown in Chart 1. Although the yellow oil could not be purified, they described it as consisting mainly of the nonisolated amide of @mGnocrotonic acid, CHsC(NHs):CHCONHs (I), from the analogy to the Claisen reaction .$ The structure 1;Iawas assigned to this compound (II). Recently, L.&n* r+investigated this reaction and reported the same structure Ha. In a previous pape# we reported that the structure of Claisen compound is not 4,6~e~yI-lH-Z-p~don~5~~de (I’Va)but 3-acetyl-4-amino-f-lH-2pyridone (IVb) and that in addition a good yield of 2,~e~yl4py~~done (V) was obtained. Accordingly, we re-investigated the structure II, because in part the structural assignment was incorrectly reported. In our present paper the preferred structure for II is shown to be ~~-a~~otony~o~roton~de (I&) and not the cyclic structure Ha proposed by Chick et o&l** According to the literature, 1 diketene was treated with excess ammonia to give a~toa~~de, which was ~~sfo~~ into a yellow oil. Heating of the yellow oil gave colorless crystals. Elemental analysis and mol. wt. determination established its * Part XII: T. Kate, H. Ytunanaka and T. Sbibata, C/fern.Pkrm. Buff, Jopm, to be published. t Tbe free acid III could not be isolated, but trcatmcnt of tbe reaction mixture with HNO, and

AgNOs gavea ppt which WBSassumed to be tbe Ag salt of III.

’ F. Chick andN. Wiknox-e, J. Chem. &c. 97,1982 (1910). * L. Ckisen and K, Meyer, Bet. Dtsch. Chem. Ces. 35,584 (1902). ’ P. Levin, Zh. Obshei Khbn. 30,134O (1960). 4 T. I&to, H. Yamanaka and T. Sbibata, Chem. Charm. &II. Juprm, to be published. 2.965

T. KATO, H. YAMANAKAand T.

2966

%IIBATA

CHART 1.

CH*=C-0 I I CHrC=O

a

MUNH,

-?%

[Yehw Oil]

J A

HO

-H,o

H,N

IIa

2

VI7 NH,

--NH,

C,H&,N,

(II)

0

IVa CHART 2.

IIb

Studies on ketone and its derivatives--XIII

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empirical formula as CaH,O,N, (II). Properties such as the m.p., solubilities and chemical behavior are similar to those describcd.rs5 Before making the structural study, an attempt was made to isolate the yellow oil as a pure substance, and by treating the oil with chloroform and potassium carbonate a good yield of crystals, C4H,0N2, was obtained. This compound was characterized as @-aminocrotonamide (I) by elemental analysis, mol. wt. determination, IR and NMR spectra. Because of the ready transformation to compound II, it is clear that the yellow oil is crude I. Chick and Wilsmore’ reported that the hydrolysis of II with aq. alkali gave ammonia and 4-amino-3,4-dihydro+-dimethyl-I H-2-pyridone-S-carboxylicacid (III) which, however, could not be isolated. When this reaction was re-examined, III was not detected, but 2,fSdimethyl-3H4pyrimidone (V) was obtained in good yield (73 %). If the cyclic structure IIa is correct, the formation of the pyrimidone structure V from the pyridone structure IIa is unlikely, and structure IIb offers a very reasonable explanation (Pathway B in Chart 3). When II was hydrolyzed with hydrochloric acid, the yield of V decreased, and acetone, carbon dioxide and ammonium chloride were formed, and no pyridine derivatives could be obtained. These data contradict structure IIa. The acidic hydrolysis seems to proceed mainly along pathway A and the alkaline hydrolysis chiefly along pathway B. In pathway A the products of the first stage appeared to be /Saminocrotonic acid and /?-aminocrotonamide (I) instead of I and acetoacetamide. In order to con&m this a comparison with the acidic hydrolysis of a model compound such as p-acylaminocrotonamide was made. Thus, /I-aminocrotonamide (I) was reacted with isobutyric anhydride giving j3-isobutyroylaminocrotonamide (VI). And when VI was hydrolysed with dilute hydrochloric acid, the formation of isobutyramide was confirmed. This observation supports structure IIb. Levii? reported that II with nitrous acid evolves two moles of nitrogen. This reaction Seemed to support structure IIa. We re-tested this diazotization reaction, and found that no hetcrocyclic compounds such as 2,6-dimethyl-lH-Zpyridone-f carboxylic acid could be isolated from the reaction mixture from which nitrogen had been evolved. Therefore, we doubted structure IIa and preferred structure IIb. Actually, ethyl p-aminocrotonate does not evolve nitrogen, and the evolution of one mole and two moles of nitrogen was confirmed from @rminocrotonamide (I) and /?-isobutyroylaminocrotonamide (VI) respectively. This fact shows that the diazotization reaction proceeds simultaneously with acidic hydrolysis to give two moles of amide (Pathway A in Chart 3), and although the /Samino function does not react with nitrous acid the amido group does, evolving two equivalent moles of nitrogen. Upon catalytic reduction with PtOa, II absorbed only one mole of hydrogen to give its dihydro compound. Elemental analysis and mol. wt. determination provided the empirical formula C8Hi600Ns (VII). Hydrolysis of VII gave @minobutyric acid (VIII). The UV spectrum of VII suggested the elimination of a double bond (IIb: 295 rnp, VII: 285 mp), and the NMR spectrum of VII indicated the absence of an olefinic proton. From these data we assigned the structure of /I-@‘-iminobutyrolyamino) butanamide (VII) to the dihydro product. Both /?-aminocrotonamide (I) and ethyl ,f3-aminocrotonate did not absorb hydrogen under similar conditions, but /?acylaminocrotonamide (VI) absorbed one mole of hydrogen to give a dihydro compound (IX), which was hydrolysed, giving /?-aminobutyric acid (VIII). These results

T. KATO,H. YAMNUU and T. !%BATA CHART 3.

HN ==fMe IIb

2 M&O

f 2COa + 3NHa

vr

Me

\

CH.CO~NH, + Me-coai,*coNH,

/ Me

support the structure IIb, since, if VII were the cyclic structure it could not be hydrolysed to give /hminobutyric acid (WI). The UV and IR spectra do not help to differentiate between IIa or IIb, but the NMR spectrum of II in DMSO indicates the existence of the olelinic proton at 4.25 ppm. This fact also supports structure IIb. Although ketoenol tautomerism is possible, the data mentioned above strongly support the correctness of structure 1% As f3-aminocrotonamide (I) could be used as a starting material for pyrimidine derivatives, we are presently investigating this problem. EXPERIMENTAL @-Aminocrotonamide 0)

Asolnofdiketent(&Ig)inEt,O(25Oml)wascookdinani~bath,dryNt4waspasl#dthraugh for 2 hr. Initially an exothermic reaction took place and white crystals were prccipi~ted,

the soln

Studica on kctcnc and its dcrivati-XIII CHART 4.

+ 0

Me

2moleN,

0

VI CHART 5

OH

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T. KATO, H YAMANAKAand T. SHIBATA

which upon reacting with an excess of dry NH,, turned into an Et*0 insoluble oil. After adding liq. NH, (50 ml), the reaction mixture was allowed to stand overnight at room temp. To the resulting residue was added anhyd K&OS (140 g), and the residue was extracted with hot CHCla. From the CHCl, extract white crystals (m.p. 98-lOO”, 96 g) were obtained. Recrystallization from CHClt gave colorless prisms, m.p. lWlOl”, yield, 96%. (Found: C, 48.17; H, 8.13; N, 28.26. Mol. wt. by Rast method, 95.4. CIHBONI (l) requires: C, 47.98; H, 8.05; N, 27.98%. Mol. wt. 100.1.) NMR (CD(&); 1.84 ppm (singlet, 3H, Me protons), 44 ppm (singlet, H-I., ole6nlc proton). /%~obutyroyhminocrotonamkie

(vr)

A soln. of I (2 g) and isobutyric anhydride (35 g) in CHC& (10 ml) was refluxed for 1 hr. The soln. was condensed to give a crystalline residue, which was puritied by recrystallization from benzene to give colorless needles, m.p. 148-149”, yield, 2.1 g (62”d. (Found: C, 56.48; H, 8.09; N, 16.95. GHt,O,N, (VI) requires: C, 56.45; H, 8.29; N, 1646x.) #I-(B’-Aminocrotonyhmino)crotonamide (ITb) (1) According to the lit.,i diketene (10 & was reacted with NH, to give a yellow oil, which upon heating in a current of H, was transformed to a pale yellow crystalline substance (8 g). Recrystallization from EtOH gave colorless small prisms, rap. 195-196” (lit.’ m.p. 197”) . (Found: C, 52.63; H, 7.07; N, 2260. Mol. wt. (vapor pressure osmometer), 178. C,H,,O,N, (II) requires: C, 5244; H, 7.15; N, 22.94% Mol. wt. 183.) UV spectrum (EtOH): 295 m,u (log e 3.72). (2) I (40 g) was heated at 125” under reduced pressure for 4 hr. The reaction product was recrystallixed from EtOH to give colorless prisms, m.p. 195”. undepressed on admixture with a specimen obtained in the above run and its IR spectrum was identical in every respect with that of Hb, yield, 12 g (33 %). Hydrolysis of IIb (1) With uq. alkali. A soln. of IIb (O-55 g) in 8 % NaOH (20 ml) was refluxed for 2.5 hr. NH, gas which was evolved was identitied by its characteristic odor and by Nessler’s reagent. The reaction mixture was passed through a column of Amberlite IRC-50, and the etlluent was condensed to give a crystalline solid, Recrystallization from Me&O gave colorless prisms, rap. 192-193”, undepmased on admixture with an authentic specimen of 2,6-dimethyl-3H4pyrimidone,~ yield, @27 g (73 %). (Found: C, 58.05; H, 6.62; N, 2266. C&ON, (V) requires: C, 58.05; H, 6.50; N, 22057x.) When this reaction was carried out with cont. NaOHaq, the yield of V increased; that is, IIb (5 g) was hydrolysed with 40% NaOHaq (50 ml) for 2 hr, and neutralized with Ac0I-L After evaporation, the residue was extra&d with benzene to give V, mp. 192”, yield, 3 g (88”A. (2) With 15% HCI. A soln of IIb (1.1 g) in 15% HCl(30 ml) was mfluxed. The gas, which was evolved, when absorbed into a Ba(OH& soln gave a white ppt of BaCO,. After 2 hr, the reaction mixture was condensed, and to the distillate 2,4dinitrophenylhydrazine was added to give yellow crystals, mp. 124”, undepressed on admixture with an authentic sample of acetone 2&dinitrophenylhydrazone. The residue was neutraked with 28 % NH,OH (2 ml), and extra&d with hot benzene. From the benzene extract a small amount of 2&dimethyl-3H4pyrimidone (V) was obtained. Dikuotizdon

reaction

(1) /%@‘-Aminocrotonyhm&w)crotonumih (IIb). To a soln of IIb (@SS g) in 3N HCl (10 ml), was added dropwise a soln of NaNO, (062 g in 2 ml of H,O) under icecooling. After allowing to stand at room temp. for 2 hr, the reaction mixture was warmed in a water bath at 40”. The N, gas evolved was measured with a volumetric cylinder containing 50% KOH (Found: N,, 149 ml at 26.5”. Theoretical volume (2 equlmolar) : 147 ml.) (2) /I-Amhocrotonamide (I). In the manner described above, I (@2 g) was reacted with NaNO, (@4 g in 10 ml of 3N HCl) to evolve 43 ml of N, at 15.5”. Theoretical volume (1 equimolar). 47 ml. (3) j%Zsobutyroyhm&&?crotomzmide(VI). Using the procedure described above, VI (O-85 g) and NaNO, (1.4 g) in 3N HCl (20 ml) gave 236 ml of N, at 16”. (Theoretical volume (2 equlmolar amount), 237 ml.) 6 A. Pinner, Ber. Dtsch. Chem. Ges. 22,1616 (1889).

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Catalytic reduction

(1) B-(B’-Aminorrotonylamino)croto~m~ (Ilb). To a soh~. of IIb (O-55 g) in MeOH (50 ml), was added PtO, (O-5 Q, and the mixture was shaken in H, until the absorption ceased. The reduction proceeded gradually and the time required was about 9 hr. The catalyst was filtered off and the solvent was removed from the filtrate by evaporation under reduced press., from which a white crystalline residue was obtained. Recrystallization from MeOH gave colorless prisms, m.p. 1765-177”. yield, 0.5 g. (Found: C, 52.00; H, 824; N, 2254. C,HI5O,N, (VU) requires C, 51.87; H, 8.16; N, 22.69 %.) UV spectrum (EtOH): 285 m,u (log e 2.55). A soln. of VII (0.25 g) in 15 % HCl(l0 ml) was refluxed for 4 hr. The gas which was evolved was characterized as CO,. The reaction mixture was condensed, and from the distillate Me&O was identified. The residue was dissolved in MeOH, and passed through a column of Amberlite IR-4B. The effluent was evaporated in uacuo, and the residue was extracted with abs. EtOH, from which a small amount of /3-aminobutyric acid (VW) was obtained, mp. 187.5”. colorless prisms from MeOH and Me&O (lit: rap. 186187”). (Found: C, 46.33; H, 8.77; N, 13.39. C,H+O,N (VIII) requires: C, 46.59; H, 8.80; N, 13-58x.) (2) /?-Isobutyroykaminocrotonamide (VI). A mixture of VI (0.68 g) and PtO, (O-5 @ in MeOH (50 ml) was shaken in HI. After 5 hr, about 100 ml of H, was absorbed at 15”. The catalyst was filtered off, and the filtrate was treated as above to give colorless needles, m.p. 196196.5” @OH), yield, 0.69 g (96”%). (Found: 55.91; H, 9-U; N, 16.11. CBH1,O,Ns (IX) requires: C, 55.79; H, 9.36; N, 16-27x.) Compound IX was hydrolysed with HCI as above and gave VIII. ’ R. Stoermer und E. Rovert, Ber. Dtsch. Chem. Ges. 55,1038 (1922).