1975 3494-Acetyl-3- benzyl idenepiperazine-2,5-d ionesBy Srinivasachari Rajappa and Bhagwan G. Advani, CIBA-GEIGY Research Centre, Goregaon, BombayCyclisation of (N-acetyldidehydrophenylalany1)sarcosine with acetic anhydride at 75' has furnished thehitherto unknown 4-acetyl-3-trans- benzylidene-1 -methylpiperazine-2,5-dione (IV), which readily undergoesdeacetylation on treatment with morpholine.400063, IndiaEVIDENCE in the literature suggests that a 4-acetylgroup in a 3-benzylidenepiperazine-2,5-dione may besubject to so much steric strain that deacetylation isextremely easy, and that, as a result, the 4-acetylderivative may not even be isolable. We describe herethe synthesis and properties of 4-acetyl-3-benzylidene-l-methylpiperazine-2,5-dione (IV).In 1969, Dominy and Lawtonl reported the cyclis-ation of (N-acetyldidehydrophenylalany1)glycine (I)with acetic anhydride at 100" to give a product withjust one acetyl group; they assumed that this was theexpected 4-a~etyl-3-benzylidenepiperazine-2~5-dione(111). However, in 1970, Porter and Sammes provedthat this product was in fact the 1-acetyl isomer (V).The same monoacetyl compound was subsequentlyobtained by Gallina and Liberatori3 from the diacetyl-1 B.W. Dominy and R. G. Lawton, J . Org. Chem., 1969, 84,201 3.piperazinedione (VIII) by base-catalysed condensationwith benzaldehyde; n.m.r. studies by these authorsindicated that it was the 4-acetyl group that was lostduring the reaction. There was no evidence for theformation of the diacetyl derivative (VII).During their model studies, Porter and Sammescyclised (N-acetyldidehydrophenylalany1)sarcosine (11)with acetic anhydride at 100" and obtained the product(VI), m.p.142-143", lacking an acetyl group. Theysuggested that ' the loss of the N-acetyl group fromposition 4, either during the reaction or during isolation 'may be a consequence of steric strain. We have nowdiscovered that if less drastic conditions are employedduring this cyclisation (75"; 8 h under nitrogen), theA. E. A. Porter and P. G. Sammes, J . Chem. SOC. ( C ) , 1970,2530.C. Gallina and A. Liberatori, Tetrahedron Letters, 1973, 1135;Tetrahedron, 1974, 80, 667350 J.C.S. Perkin Iexpected 4-acetyl derivative (IV) is obtained in goodyield.The identification rests on analytical and spectraldata, and smooth deacetylation to give compound (VI).R'AcAc AC( Y r n 1 (1x1The mass spectrum shows the molecular ion at nz/e 258(ca. 5) and the base peak at mle 216 (M - CH,:C:O).The lH n.m.r. spectra of the acetyl (IV) and deacetyl(VI) derivatives (see Table) show only one significantlH N.m.r. bands of compounds (IV) and (VI) in CDCI,(6 values)C=CH 7-43 70.6 NMe 3.03 3.08(IV) (W2 (IV) (VI)*P 7.35 7.38 Ac 2-38CH, 4.13 4.14 NH 8-0difference apart from the acetyl proton signal: thesignal due to the olefinic proton is further downfieldin the spectrum of the acetyl derivative (IV) by ca.0.35 p.p.m. The i.r. spectrum (Nujol) of the 4-acetylderivative (IV) exhibits bands at 1742, 1715, 1665,and 1642 cm-l.These values may be compared withthose of the l-acetyl-3-benzylidene derivative (IX) 4at 1700, 1690, 1680, and 1635 cm-l. The unusuallyhigh carbonyl frequency in the 4-acetyl-3-benzylidenederivative (IV) may perhaps be due to inefficientoverlap between the lone pair on N-4 and the adjoiningcarbonyl groups, as a result of steric crowding. TheU.V. spectrum of 4-acetyl-3-benzylidene-l-rnethylpiper-azine-2,5-dione (IV) Amx. 247.5br and 282.5br nm(E 12,400 and 13,300) also seems to suggest someconformational change due to overcrowding ; it showsa flattened appearance in comparison with that of thedeacetyl derivative (VI).Compound (IV) is reasonably stable to heat; it isrecovered unchanged after being refluxed in toluene for6 h.As expected, it is easily attacked by nucleophiles.Treatment with aqueous potassium hydroxide at roomtemperature results in ring opening to give the startingacid (11). However, smooth deacetylation to 3-benzylidene-l-methylpiperazine-2,5-dione (VI) isachieved by treatment with morpholine in benzene atroom temperature. Porter and Sammes have alreadyestablished that this deacetyl derivative (VI) possessesthe trans-configuration about the double bond. Webelieve, therefore, that our 4-acetyl derivative (IV) hasthe same configuration. The downfield shift of theolefinic proton signal already mentioned is perhaps to beascribed to the decreased electron density at the olefiniccarbon atom in the NN-diacyl enamine (IV) as opposedto the N-monoacyl enamine (VI).In the hope of obtaining the 1,4-diacetyl derivative(VII) , we heated (N-acetyldidehydrophenylalany1)-glycine (I) in acetic anhydride at 70" for 10 h undernitrogen and obtained a product melting at ca.160-155" the previously reported monoacetyl compound(V) melts at 200-202". However, the lH n.m.r.spectrum (CDCI,) showed that the product was probablya ca. 1 : 1 mixture of the diacetyl (VII) and monoacetyl(V) derivatives 6 : 8-13br (NH), 7.55 (s, C:CH), 7.17(s, CXH), 7-37 (s, Ph), 7-42 (s, Ph), 4.62 (s, CH,), 4.47(s, CH,), 2.62 (s, Ac), 2-58 (s, Ac), and 2.47 (s, Ac). Wehave so far been unable to obtain the pure diacetylderivative (VII) from this mixture by crystallisation.A series of 4-acetyl-3-arylidene derivatives of glycyl-L-proline anhydride has been reported recently; nospectral data were provided.EXPERIMENTALN.m.r. spectra were taken with a Varian A-60 instru-ment, with Me,Si as internal standard.4-A cetyl-3-trans-benzyldene- l-methylpipemsine- 2,s-dione(IV) .-((N-Acetyldidehydrophenylalany1)sarcosine ( 16 g ) inacetic anhydride (80 m1) was heated on an oil-bath a t 76"under nitrogen, with stirring, for 8 h.The acetic anhydridewas then distilled off under vacuum and the residue digestedwith benzene. The solid was filtered off and recrystallisedfrom benzene-hexane to give the product (IV) (7.5 g ) ,m.p. 160-163" (Found: C, 65.5; H, 5.7; N, 10.65.C1,HI,N2O8 requires C, 65.1; H, 6.45; N, 10.85).Deacetylation of Compound (IV) .-A solution of com-pound (IV) (3a3 g ) in benzene (100 ml) was treated withmorpholine (1.1 g ) , left a t room temperature for 24 h,then evaporated in vacuo.The residue crystallised fromethyl acetate-hexane to give 3-trans-benzylidene- l-methyl-piperazine-2,5-dione (VI) (2-2 g ) , m.p. and mixed m.p.2140-143" (Found: C, 66-65; H, 5.9; N, 12.7. Calc. forCl2HI2N2O2: C, 66-65; H, 5.6; N, 12.95).Riing-opening of Compound (IV) .-A solution of com-pound (IV) (0.3 g) in methanol (5 ml) was treated withpotassium hydroxide (0.1 g ) in water (2 ml), left a t roomtemperature for 3 h, and then evaporated in vacuo. Theresidue was treated with water (5 ml) and the mixturefiltered. The filtrate was acidified and the solid filteredoff. Recrystallisation from methanol-propan-2-01 gavethe dipeptide (11) (0.15 g), m.p. and mixed m.p. 216-218",identical (i.r. spectrum) with authentic material (Found :C, 60-75; H, 6.25; N, 10-05. Calc. for Cl,Hl,N20,: C ,60.85; H, 5.85; N, 10.15).We thank Professor T. R. Govindachari for his interestin this work, and Dr. S. Selvavinayakam and his associatesfor the microanalytical and spectral data.4/1883 Recsived, 16th September, 197434 K. W. RlakeandP. G. Sammes, J . Chem. SOC. ( C ) , 1970, 980.5 H. Poise1 and U. Schmidt, Chem. Ber., 1973, 106, 3408
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