588 J.C.S. Perkin IReduction of Enaminones in the Preparation of 3-Aminocyclohexanols ;a Novel Preparation of Tetronic AcidBy John V. Greenhill,' Mohamed Ramli, and Therezinha Tomassini, School of Pharmacy, University ofReduction of enaminones derived from cyclohexane-1.3-dione gives the corresponding 3-aminocyclohexa nols.In the case of the N-unsubstituted derivative the major product is the trans-isomer. The position of attack ofammonia on 2-acetylcyclopentanone and 2-acetylcyclohexanone has been elucidated by reduction of the derivedenaminones. In the former case the base attacks the side-chain carbonyl group, but in the latter the ring carbonylgroup. Reduction of 2- (substituted amino)fumaric esters gave enaminone analogues of tetronic acid, hydrolysisof which afforded tetronic acid [4-hydroxyfuran-2(5H) -one] itself.Bradford, Bradford BD7 1 DPHYDROGENATION of 3-acetamidophenol over Raney nickelat high temperature and pressure has been reported 192R.R. Burford, F. R. Hewgill, and P. R. Jefferies, J. Chem.yield) with a cis : trans ratio of about 4 : 1.preparation of enaminones from cyclohexane-l,3-dione1813.The readyto @ve, after hYdrolYsis~ 3-aminocYc10hexano1 (56%2 V. J. Trapelis and J . D. Dadura, J . oyg. Chem., 1961, 26,SOC., 1967, 2937. 3 J. V. Greenhill, J . Chem. SOC. (C), 1971, 26991975 589suggested a possible alternative route to S-aminocyclo-hexanol and to the corresponding secondary and tertiaryamines .In a preliminary study, enaminones derived frompiperidine and phenethylamine were treated with a rangeof reducing agents.With metal hydrides there was noreduction. Hydrogenation over palladium producedeither N-C bond fission to give the parent amine or O-Cbond fission to produce the N-cyclohexyl derivative ofthe parent amine. Best results were obtained withRaney nickel in ethanolic sodium hydroxide at 70" and20 atm pressure: the required amino-alcohols were pro-duced in high yields.Application of these conditions to 3-aminocyclohex-2-enone gave, after distillation, a 75% yield of the amino-alcohol. This was converted into the benzamide, whichafter fractional crystallisation gave 59% of the trans-and 31% of the cis-isomer. This technique offers analternative route to the 3-aminocyclohexanols, requiresmilder conditions and, at least in the case investigated,gives considerably more of the trans-isomer.In the course of some synthetic work the reactionbetween ammonia and 2-acetylcyclopentanone was in-vestigated.Only one enaminone (t.1.c. ; column chrom-atography) was obtained in high yield and it was neces-sary to seek an unequivocal proof of structure to dis-tinguish between the two possibilities (1) and (2). Thecompound was resistant to metal hydride reducing agentsbut was converted into the amino-alcohol by hydrogen-ation over palladium-charcoal in glacial acetic acid.Oxidation of the benzoyl derivative (3) to the oxo-amide(4) gave a product which showed a doublet methyl signalin the n.m.r. spectrum ( T 8.78; J 7 Hz). The enaminonemust therefore have had structure (l), since the alterna-tive (2) would produce an amido-ketone in which themethyl group would give a singlet at about T 7-90.Thei.r. spectrum of compound (4) showed a carbonyl band at1725 cm-l, presumably indicating intramolecular hydro-gen bonding as shown.The corresponding reaction of 2-acetylcyclohexanonehas previously been reported4 to give compound (5),identified on the basis of U.V. and n.m.r. spectra. SinceD. L. Ostercamp, J. Org. Chem., 1970, 85, 1632.K. Dixon and J. V. Greenhill, J.C.S. Perkin 11, 1974, 164.K. J. Boosen, Swiss Pat., 529,128/1972.neither of these techniques could give an unequivocalproof of structure, we applied our method. Reductionof the only enaminone isolated (86%) to the amino-alcohol with lithium aluminium hydride was successful.Benzoylation followed by oxidation gave compound (6) ,which showed a singlet methyl absorption in the n.m.r.spectrum ( T 7433).The i.r. spectrum showed a carbonylpeak at 1700 cm-l.It is evident that ammonia attacks 2-acetylcyclo-pentanone at the side-chain carbonyl carbon atom but itshornologue at the ring site. In both cases the productwould be stabilised by intramolecular hydrogen bondingand by a vinylogous amide electronic interaction betweenthe nitrogen lone pair and the carbonyl group. Thedifference in reaction site probably reflects the greaterthermodynamic stability of exocyclic double bonds infive-membered rings and of endocyclic double bonds insix-membered rings.Me I( 5 )iOPh( 6 1The need to prepare enaminone analogues of tetronicacid led us to repeat a number of the published routes tothe parent compound.The most recent work on tetronicacid synthesis involves modifications 6s to previousmethods and was repeated carefully. In our hands thesemethods proved difficult and gave variable results. Ourexperience with enaminone reduction led us to investigatethe route outlined in the Scheme. The addition ofF02Met-IC02MeSCHEMEammonia and amines to the acetylenic diester (7) hasbeen carefully studied.8 Although the reaction proceeds' T. P. C. Mulholland, R. Foster, and D. B. Haydock, J.C.S.Perkin I, 1972, 1226. * R. Huigsen, K. Herbig, A. Siegl, and H. Huber, Chem. Ber.,1966, 99, 2526; K.Herbig, R. Huigsen, and H. Huber, ibid., p.2646590 J.C.S. Perkin Iin high yield, the isomer ratio of the product dependsupon the amine used.In compound (8) one carbonyl group is part of anenaminone system whereas the other would be expectedto react as a simple ester. We hoped that the lattermight be more readily reduced by lithium aluminiumhydride to give the alcohol (9) which might be induced toring close to the enaminone (10).Reactions were carried out with a series of diesters (8)and several solvents. We were unable to reduce tertiaryenaminones ( 8 ; R1 = R2 = alkyl) or primary enamin-ones ( 8 ; R1= R2 = H). In all cases starting materialwas recovered, although after prolonged refluxing (24 h)this was sometimes accompanied by a small quantity ofan intractable product. With the secondary enaminonesinvestigated (8; R1 = H, R2 = Me, But, or Ph) reactionoccurred during 3 h in refluxing tetrahydrofuran.Inno case was any alcohol (9) isolated, the product alwaysproving to be the enaminone (10). Hydrolysis of thiscompound (followed by U.V. spectroscopy) was completein 12 h at room temperature. Removal of the liberatedamine by ion-exchange and careful evaporation of theaqueous solution below 50" avoided the formation ofanhydrotetronic acid and gave an essentially pureproduct.The addition of secondary amines to the acetylenicdiester (7) has been shown * to give exclusively the cis-product (8). Failure to reduce these compounds evenwith prolonged refluxing is probably due to steric hind-rance by the enaminone methoxycarbonyl group.Thecorresponding primary and secondary enaminones (8)were shown to exist mainly in the trans-form, and onwarming the proportion of the hydrogen-bonded,thermodynamically more stable, trans-isomer was furtherincreased. Steric hindrance to the reduction of theester group [see (12)] would then be less and it seems thatOMeIR( 12 1R( 13 1the primary alcohol (13) is first formed. Inversion of theconfiguration would be facilitated by the partial single-bond character of the C=C link [see (13)] and ring closurecould thus occur spontaneously under the reaction con-ditions. In view of the previously recorded experiencewith the reduction of enaminones it is not surprising thatthe product (10) is resistant to further reduction. Thatthe primary enaminone (8; R1 = R2 = H) is not reducedis more difficult to explain, but probably reaction is pre-vented by complex formation between the NH, groupand the reagent.Enaminones have considerable potential as startingmaterials in synthesis.The present work has given usnew routes to 3-amino-alcohols and to tetronic acid.Although overall yields of tetronic acid are no better thanthose achieved by other workers, we have found this theeasiest way to make the compound and the route ispotentially capable of further improvement.EXPERIMENTALReduction of 3-Aminocyclohex-2-enone.-A mixture of theenaminone (1 mol), aqueous 20% sodium hydroxide (20 ml),and Raney nickel (W7) 10 in ethanol (500 ml) was hydro-genated at 70" and 20 atm until uptake ceased (ca.8 h).After filtration, the solution was evaporated and most of theresidual water removed by azeotropic distillation withbenzene. The residue was shaken with chloroform (1 1) andthe solution dried (MgSO,) and evaporated; the residual oilwas distilled to give 3-aminocyclohexanol (75y0), b.p. 130-134" at 20 mmHg (lit.,, 118-122" at 13 mmHg). Similarlywere prepared (a) 3-methylaminocyclohexanol (52%), b.p.130-132" at 20 mmHg (lit.,I1 68" at 0.05 mmHg), i.r.,n.m.r., and mass spectra consistent with structure; (b) 3-pifieridinocyclohexanol (50%), b.p. 146-148' at 20 mmHg,m.p. 104-105" [from light petroleum (b.p. 80-lOO')](Found: C, 72.0; H, 11.4; N, 7.8; 0, 8.6.C,,H,,NOrequires C , 72.1; H, 11.6; N, 7.6; 0, 8.7%) [hydrochloride,m.p. 216-217" (from ethanol-ether) (Found: C, 59.9; H,10.1; N, 6.4; 0, 7.2. C,,H,,ClNO requires: C, 60.2; H,10.0 ; N, 6.4; 0, 7.3%)] ; (c) 3-phenethylaminocyclohexanol(74y0), m.p. 109" [from light petroleum (b.p. 80-100')](Found: C , 76.7; H, 9.5; N, 6.4. C14H,,N0 requires C ,76.7; H, 9.65; N, 6.4%) [hydrochloride, m.p. 220" (fromethanol) (Found: C, 65.6; H, 8.5; N, 5.3. C,,H,,ClNOrequires: C , 65.7; H, 8.6; N, 5-5y0)].cis : trans Ratio of 3-AminocyclohexanoE.-The distilledproduct of the above reaction was completely melted andstirred. To a sample (2.4 g) were added water (30 ml),aqueous 20% sodium hydroxide (12 ml), and benzoylchloride (6 g), and the mixture was shaken for 10 min in astoppered flask.The product was extracted with warmchloroform (6 x 50 ml) and the extracts were rapidlywashed with water (10 ml) and evaporated. The residuewas dissolved in the minimum of chloroform and kept at 0"overnight to yield trans-3-benzamidocyclohexanol (2.7 g,59%), m.p. 170-171" (raised t o 172-5-173.5' withoutsignificant loss on further recrystallisation) (lit.,I 169").Addition of petroleum (b.p. 40-60') to the filtrate gave cis-3-benzamidocyclohexanol (1.4 g, 31%), m.p. 149-151"(raised to 153-1 54" on recrystallisation from ethyl acetate)(lit.], 155").2-( l-A minoethy1idene)cyclopentanone ( 1) .-Ammonia waspassed into a solution of 2-acetylcyclopentanone (47 g)(purified by way of its copper chelate, m.p.240") in ethanol(100 nil) for 2$ h and the product was set aside overnight.The solvent was evaporated off, the residue taken up inmethylene chloride, and the solution washed with 5% sodiumhydroxide and water (2 x 20 ml), dried (Na,SO,), andevaporated. The residue was chromatographed on a silicacolumn (ethyl acetate) to give a single Product (3.7 g, 79y0),m.p. 83-84' (unchanged on recrystallisation from benzene-light petroleum) (Found: C, 67-0; H, 8.5; N, 11.5.C,Hl,NO requires C, 67.2; H, 8.8; N, 11.2~0)1 Am= (EtOH)319 nm (c 13,600); vm= (KBr) 1520 and 1630 cm-' (enamin-one), T (CDCl,) 7.60 (m, [CH2I3) and 8-10 (s, Me).2-( l-Aminoethy1)cyclopentanoZ.-A solution of 2-( l-amino-9 L. Wolff and C. Schwabe, Annulen, 1896, 291, 226.10 H.Adkins and H. R. Billica, J . Amer. Chem. Soc., 1948, 70,11 T. D. Perrine, J . Ovg. Chem., 1961, 16, 1303.6951975 591ethy1idene)cyclopentanone (0.55 g) in glacial acetic acid(50 ml) was hydrogenated for 8 h at normal temperature andpressure over 10% palladium-charcoal (1 g). The solventwas removed and the residue dissolved in ether; the solutionwas washed with aqueous sodium hydroxide, dried, andevaporated t o give the crude amino-alcohol (0.5 g). Benz-oylation (PhCOC1) in 10% sodium hydroxide gave 2-(1-benzamidoethy1)cyclopentanol (3) (0.8 g), vms. (film) 1640(amide C=O) and 3400 cm-1 (OH).2-( l-BenzamidoethyZ)cycZopentanone (4) .-A solution of theforegoing alcohol (0-5 g) in acetone was oxidised with Jonesreagent (0.5 ml) to give the oxo-amide (0.4 g), m.p.91" [frompetroleum (b.p. 80-100°)] (Found: C, 72.9; H, 7.4; N, 6.1.C,,H,,NO, requires C, 72.7; H, 7.4; N, 6.1y0), vmx. (CHCl,)1650 (amide G O ) and 1725 cm-l (ketone GO), m/e 231, T(CDCI,) 2.40 (5H, m, aromatic) 7-90br (8H, m, aliphatic),and 8-79 (3H, d, J 7 Hz, Me).1-(2-AminocycZohexyZ)ethanoZ.-A solution of l-acetyl-2-aminocyclohexene 4 [m.p. 107-108"; Am, (EtOH) 317 nm(& 12,700)] (15 g) in tetrahydrofuran (150 ml) was added tolithium aluminium hydride (5 g) in tetrahydrofuran (200 ml)over 1 h, and the mixture was refluxed (1 h). The productobtained after work-up with 20% sodium hydroxide andextraction with ether was distilled to give the amino-alcohol(7 g, 46%), b.p. 135-137" at 0.1 mmHg. The N-benzoyZderivative had m.p.97-98" (from benzene-light petroleum)(Found: C, 72.8; H, 8-4; N, 5.4. C,,H,lNO, requires C,72.9; H, 8.5; N, 5.7y0), v,, (KBr) 1620 (amide G O ) and3300 cm-l (OH), T (CDCl,) 8.90 (3H, d, Me).l-Acetyl-2-benzaunidocyclohexane.-A solution of the fore-going alcohol (1 g) in acetone (10 ml) was treated with Jonesreagent (1.2 ml) to give the oxo-amide (0.9 g, goyo), m.p.158-159" [from light petroleum (b.p. 40--60")] (Found:C, 73.8; H, 7.6; N, 5-8. C,,H,,NO, requires C, 73.5; H,7.8; N, 5-7%), v,, (KBr) 1630 (amide G O ) and 1700 cm-'(ketone G O ) , T (CDC1,) 7.83 (s, Ac).General Method for 4-(Substitzcted amino) furan-2( 5H)-ones.--A solution of the dimethyl 2-(substituted amino)maleate(0.01 mol) in tetrahydrofuran (€00 ml) was added dropwiseto lithium aluminium hydride (0.01 mol) in tetrahydrofuran(80 ml) and the mixture was refluxed for 3 h.The cooledproduct was treated with just enough water to decomposethe reagent, dried (MgSO,) , and evaporated. Recrystallis-ation gave (a) 4-methyZaminofuran-2(5H)-one (48y0), m.p.149-150" (from ethyl acetate-light petroleum) (Found :C, 53.1; H, 6-2; N, 12.4. C,H,NO, requires C, 53.1; H,6.2; N, 12.4%), m/e 113, vmx. (KBr) 1610 and 1705 cm-l,T (CDC1,) 5.28 (2H, s, CH,), 5-36 (IH, s, =CH), and 7-18(3H, s, NHMe), A,, (H,O) 258 nm ( E 18,700); (b) 4-t-butyl-aminofuran-2(5H)-one (72%), m.p. 121-122" (from ben-zene-light petroleum) (Found: C, 61.8; H, 8.3; N, 9-0.C,H,,NO, requires C, 61.9; H, 8.4; N, 9.0yo), m/e 155, vmxa(KBr) 1610 and 1725 cm-l, 7 (CDCI,) 5.29 (lH, s, =CH), 5.37(2H, s, CH,), and 8.68 (9H, s, NHBul), A,x. (H,O) 262 nm(E 21,000) ; (c) 4-aniZznofuran-2(5H)-one (40y0), m.p. 219-220" (from ethyl acetate) (Found: C, 68.6; H, 5.2; N, 8-0.C1,H,NO2 requires C, 68.5; H, 5.15; N, 8.0yo), m/e 175,v,, (KBr) 1595, 1610, and 1690 cm-l, 7 [(CD,),CO] 2-72(5H, aromatic), 4.75 (lH, s, =CH), and 5-18 (2H, s, CH,),A,x. (H,O) 285 nm ( E 18,500).Tetronic Acid.-A solution of 4-t-butylaminofuran-2(5H)-one (0.05 mol) in ~ N - H C ~ (100 m.1) was stirred for 12 h, thenpassed through a column containing Zeo-Karb 225 to removet-butylamine. The column was washed with water untilthe washings gave no reaction with iron(I1r) chloride solu-tion. The aqueous solution was evaporated to dryness at50". Drying h vacuo (KOH) gave essentially pure tetronicacid [4-hydroxyfuran-2(5H)-one] (50y0), m.p. 140' (lit.,l'?140-142"), m/e 100, v- (KBr) 1595 and 1695 cm'l, 7(CD,OD) 5.05 (2H, s, CH,) and 5.31 (IH, s, =CH), A,,(H,O) 225 nm (E 13,500).We thank Mr. R. Smith for technical assistance.[4/2103 Received, 10th October, 19741l2 E. Benary, Ber., 1907,40, 1079
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