Enamine-induced Ring Transformations of 6-Substituted 5-Formyl-1,3-dimethyluracils$ Harjit Singh,* Dolly, Swapandeep Singh Chimni and Subodh Kumar* Department of Chemistry, Guru Nanak Dev University, Amritsar-143 005, India 5-Formyl-1,3,6-trimethyluracil 1 undergoes facile ring transformation with enamines under acidic conditions to provide 1-heteroaroyl-1,3-dimethylurea derivatives. Uracil derivatisation at each of its reactive sites has attained paramount signi®cance in potential medicinal target com- pounds.1 The nucleophile-induced modi®cations of uracil and its derivatives emanating from their reactions at C(5) and/or C(6) or at an electrophilic appendage at C(5) make use of relatively strong nucleophiles, viz.amines, hydrazines, cyanide ion, etc. or of strongly basic reaction conditions (NaOH, NaOEt, BuLi, etc.).2±6 The steric bulk of a methyl group at C(6) of uracil, in general, slows down or com- pletely restricts nucleophilic addition at C(6) and causes alternative reactions due to generation of an anion4b,7 at CCH3.Recently, we have reported8 that 5-formyl-1,3- dimethyluracil reacts with enamines, even under acidic con- ditions, to provide unique annulation products. We envi- saged that in the reactions of enamines with 5-formyl-1,3,6- trimethyluracil under acidic conditions9 the probability of generation of an anion at the 6-CH3 carbon would be low and annulation might constitute the major mode of reaction. Hence, the reactions of 5-formyl-1,3,6-trimethyluracil 1 with enamines have been studied. 5-Formyl-1,3,6-trimethyluracil 1 on reaction with 3-amino- 5,5-dimethylcyclohex-2-enone 2 in re�uxing acetonitrile± TFA solution gives a product (50%), mp 92 8C. The parent ion peak at m/z 303 (Má) in its mass spectrum shows it to be a condensation product of 1 and 2. In its 1H NMR spectrum the appearance of one Me signal as a doublet (d 2.99, J 4.8 Hz) and other Me units as singlets points towards the N(1)0C(6) ring opening of the uracil moiety and a 1 H singlet at d 8.07 shows the presence of the aromatic ring.From these spectral data and the elemental analysis the structure 3 is proposed for this compound. Therefore, 1 undergoes ring transformation with enamines and the 6-Me of 1 does not participate in the reaction (Scheme 1). Similarly, compound 1 reacts with 6-amino-1,3-dimethyl- uracil 4 and 3-aminobut-2-enenitrile 6 in re�uxing acetonitrile±TFA solution to give ring transformation products 5 (80%), mp 180±182 8C, Má at m/z 319 and 7 (8%), mp 120±125 8C, Má at m/z 246, respectively.Therefore, despite the presence of a methyl group, com- pound 1 reacts with enamines through attack at CHO with subsquent annulation at C(6) but the area unit is eliminated and after annulation the uracil ring is opened. We argued that if uracil is substituted at C(6) with Cl, a leaving group, the formation of annulation products with intact uracil units could be facilitated.The reaction of compound 8 with 4 in re�uxing acetonitrile±TFA solution gives annulation product 9, mp 300±310 8C, Má at m/z 303. However, ethyl b-amino/anilino crotonates 10 with 8 provide respective 6-anilino-5-formyl- uracils 11a (70%), mp 222 8C (lit.,10 225 8C) and 11b (45%), mp 180 8C, Má at m/z 259 and corresponding ring- transformed products are not formed (Scheme 2). The formation of compounds 3, 5 and 7 could be rationalised through the initial nucleophilic attack of enamine at CHO to give intermediate 12 which subsequently through intramolecular attack of NH2 at C(6) of uracil provides ring-transformed products6,8 3, 5, 7.The well documented reversibility11 of nucleophilic attack of amines, thiols, alcohols etc. at C(6) of uracil and higher reactivity of formyl than C(6) carbon rule out the possibility of alter- native initial attack of amine nitrogen at C(6) of 1. Also, as J. Chem. Research (S), 1998, 352±353$ Scheme 1 Scheme 2 $This is a Short Paper as de®ned in the Instructions for Authors, Section 5.0 [see J.Chem. Research (S), 1998, Issue 1]; there is there- fore no corresponding material in J. Chem. Research (M). *To receive any correspondence. 352 J. CHEM. RESEARCH (S), 1998the electron-withdrawing ability of the substituent (R1) atthe b position of the enamine increases, the nucleophilicityof enamine NH2 and consequently the yield of the ring-transformation product [CON (80%), CO (50%), CN (8%)]decreases. Further in the case of reactions of 5-formyl-1,3-dimethyluracil with these enamines, the formation ofdihydropyridines through intermediate 14 occurs8 but whenMe is present at C(6), the intermediate 13 does notform dihydropyridine derivatives.It has been found that5-vinyluracil and 6-methyl-5-vinyluracils have cis- and trans-diene congurations, respectively, which the intermediates13 and 14 would respectively acquire. In intermediate 13 thesteric bulk of the Me group probably restricts the attack ofenamine and respective dihydropyridine derivatives are notformed (Scheme 3).Thus, 5-formyl-1,3,6-trimethyluracil 1 undergoes facilering tranformations with enamines under acidic conditionsto provide carbamoylpyridine derivatives, and the methylat C(6) does not contribute 6-CH2£¾ induced annulationreactions and rather restricts the usual Hantszch-typedihydropyridine formation reactions of the 5-formyl group.ExperimentalMelting points were determined in capillaries and are uncorrected.1H and 13C NMR spectra were run on a Bruker AC200 MHzinstrument using TMS as an internal standard. Mass, infraredand UV spectra were recorded on Shimadzu GCMS-QP-2000,Philips Scientic SP3-300 and Shimadzu UV-240 spectrometers,respectively.Elemental analyses of solid samples were performedat the microanalytical laboratory of the Regional SophisticatedInstrumentation Centre, Chandigarh.Reactions of 5-Formyluracils 1, 8 with Enamines: General Procedure.A solution of compound 1 or 8 (1.00 g, 5.95 mmol), enamine(2 equivalent, 12 mmol) in CH3CN (10 ml) containing TFA (0.1 ml)was reuxed.The progress of the reaction was monitored by TLCand after completion (5¡Ó6 h) the solvent was distilled o. Theresidue was chromatographed on a silica gel column using hexane¡Óethyl acetate mixtures as eluents.Compound 3.Yield 50%, mp 92 8C, M+ at m/z 303 (EtOH);1H NMR (CDCl3) 1.14 (s, 6 H, 2CH3), 2.58 (s, 4 H, 2CH2),2.99 (d, J 4.8 Hz, 3 H, NHCH3), 3.02 (s, 3 H, CH3), 3.09 (s,3 H, CH3), 8.07 (s, 1 H, C1CH), 9.03 (br, 1 H, NH); 13C NMR(CDCl3) (Normal/DEPT-135) 22.72 (ve, CH3), 27.04 (ve,CH3), 26.23 (ve, CH3), 34.15 (ve, CH3), 46.22 (£¾ve, CH2), 51.75(£¾ve, CH2), 131.52 (ve, CH), 124.60 (absent), 131.53 (absent),154.60 (absent), 156.42 (absent), 162.55 (absent), 172.15 (absent),196.36 (absent); IR (KBr) ~max 1660 (C1O), 1600 (C1O),1700 cm£¾1 (C1O).(Found: C, 63.5; H, 6.6; N, 13.8.C16H21N3O3requires C, 63.37; H, 6.93; N, 13.86%).Compound 5.Yield 80%, mp 180¡Ó182 8C (EtOH), M at m/z319; 1H NMR (CDCl3) 2.56 (s, 3 H, CH3), 3.10 (s, 3 H, CH3),3.30 (s, 3 H, CH3), 3.47 (s, 3 H, NCH3), 3.71 (d, J 4.63 Hz, 3 H,NHCH3), 8.25 (s, 1 H, 1CH); 13C NMR (CDCl3) (Normal/DEPT-135) 25.10 (ve, CH3), 28.43 (ve, NCH3), 29.49 (ve,NCH3), 34.38 (ve, NCH3), 39.36 (ve, NCH3), 134.93 (ve, CH),106.43 (absent), 107.95 (absent), 127.28 (absent), 134.97 (absent),154.97 (absent), 160.17 (absent), 164.6 (absent), 171.17 (absent);IR (KBr) ~max 1610 (C1O), 1700 cm£¾1 (C1O) (Found: C, 51.9;H, 5.24; N, 21.3.C14H17N5O4 requires C, 52.66; H, 5.37;N, 21.94%).Compound 7.Yield 8%, mp 120¡Ó125 8C (EtOH), M at m/z246; 1H NMR (CDCl3) 2.58 (s, 3 H, CH3), 2.79 (s, 3 H, CH3),2.96 (d, J 4.8 Hz, 3 H, NHCH3), 3.09 (s, 3 H, NCH3), 7.72 (s,1 H, 1CH); 13C NMR (CDCl3) (Normal/DEPT-135) 22.76 (ve,CH3), 23.58 (ve, CH3), 27.12 (ve, NCH3), 34.07 (ve, NCH3),106.74 (absent), 115.99 (absent), 129.59 (absent), 136.67 (ve, CH),154.66 (absent), 157.41 (absent), 162.19 (absent), 171.02 (absent);IR (KBr) ~max 1661 (C1O), 1690 (C1O), 2240 cm£¾1 (C2N).Compound 9.Yield 80%, mp 300¡Ó310 8C (CHCl3¡Óhexane), Mat m/z 303MR (CDCl3) 3.49 (s, 6 H, 2NCH3), 3.75 (s,6 H, 2NCH3), 9.18 (s, 1 H, CH); 13C NMR (CDCl3) 28.71(q NCH3), 30.15 (q, NCH3), 96.20 (s, >C<), 106.52 (s, >C<),139.73 (d, CH), 172.6 (s, C1O), 193 (s, C1O); IR (KBr) ~max 1660(C1O), 1600 cm£¾1 (C1C) (Found: C, 50.74; H, 4.02; N, 24.68%.C13H13N5O4 requires C, 51.48; H, 4.29; N, 23.10%).We thank the University Grants Commission (India) fornancial assistance.Received, 2nd December 1997; Accepted, 9th March 1998Paper E/7/08683KReferences1 H.Wamho, J. Dzenis and K. Hirota, in Adv. Heterocycl.Chem., 1992, 55, 129; D. J. Brown, in ComprehensiveHeterocyclic ChemistryThe Structure, Reactions, Synthesis andUses Of Heterocyclic Compounds, ed. A. R. Katritzky and C.W.Rees, Pergamon Press, Oxford, 1984, vol. 3, pp. 57¡Ó155.2 E. G. Sander, in Bioorganic Chemistry, ed. E. E. Van Tamelen,Academic Press, New York, 1977, vol. 2, pp. 273¡Ó297 and refs.therein; T. K. Bradshaw and D. W. Hutchinson, Chem. Soc.Rev., 1977, 6, 43.3 H. C. van der Plas, Ring Transformations of Heterocycles,Academic Press, New York, 1975, vol. 1¡Ó2; Tetrahedron, 1985,41, 237.4 K. Hirota, Y. Kitade and S. Senda, (a) J. Chem. Soc., PerkinTrans. 1, 1984, 1859 and refs. therein; (b) J. Org. Chem., 1981,46, 3949.5 S. Kumar, S. S. Chimni, D. Cannoo and J. Singh, Bioorg. Med.Chem., 1995, 3, 891 and refs. therein.6 H. Singh, P. Singh, S. S. Chimni and S. Kumar, J. Chem. Soc.,Perkin Trans. 1, 1995, 2363.7 K. Hirota, K. A. Watanabe and J. J. Fox, J. Org. Chem., 1978,43, 1193; K. Hirota, T. Asao, I. Sugiyama and S. Senda,Heterocycles, 1987, 15, 289; M. Noguchi, K. Sakamoto,S. Nagata and S. Kajigaeshi, J. Heterocycl. Chem., 1988, 25,205; N. Yasue, S. Ishikawa and M. Noguchi, Bull. Chem. Soc.Jpn., 1992, 65, 2845; K. Hirota, Y. Kitade, K. Shimada andY. Maki, J. Org. Chem., 1985, 50, 1512.8 H. Singh, Dolly, S. S. Chimni and S. Kumar, Tetrahedron, 1995,51, 12775.9 Under neutral conditions, enamines fail to react with aldehydes.See also K. Hirota, K. Kubo, H. Sajaki, Y. Kitade, M. Sakoand Y. Maki, J. Org. Chem., 1997, 62, 2999.10 A. Sivaprasad, J. S. Sandhu and J. N. Baruah, Indian J. Chem.,Sect. B, 1985, 24, 305.11 I. H. Pitman, M. J. Cho and G. S. Pork, J. Am. Chem. Soc.,1974, 96, 1840; B. A. Otter, E. A. Falco and J. J. Fox, J. Org.Chem., 1968, 33, 3593.Scheme 3J. CHEM. RESEARCH (S), 1998 353