A new synthesis of ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate (Hagemann's ester) and its methyl and t-butyl analogues

摘要

602 J.C.S. Perkin IA New Synthesis of Ethyl 2-Methyl-4-oxocyclohex-2-enecarboxylate(Hagernannlsquo;s Ester) and its Methyl and t-Butyl AnaloguesBy A. L. Begbie and B. T. Golding,rdquo; School of Molecular Sciences, University of Warwick, Coventry CV4 7ALRegioselective cyclisations of esters of 2-acetyl-5-oxohexanoic acid led to (i) alkyl 2-methyl-4-oxocyclohex-2-enecarboxylates (alkyl = But, Et, or Me) (catalysed by pyrrolidinium acetate), (ii) esters of 4-pyrrolidino-2-methyl-cyclohexa-1.3-dienecarboxylic acid (in the presence of pyrrolidine), and (iii) alkyl 4-methyl-2-oxocyclohex-3-enecarboxylates (catalysed by hydrogen chloride).ETHYL 2-METHYL-4-OXOCYCLOHEX-2-ENECARBOXYLATE(la) (Hagemannrsquo;s ester l) is a versatile synthetic inter-mediate.2 It is commonly made via the condensation of2 equiv.of ethyl acetoacetate with 1 equiv. of formalde-hyde in the presence of a catalytic amount of piperid-ine.3-5 The ethoxycarbonyl group ct to the ketone isselectively removed from the intermediate (2) by heatingwith sodium ethoxide in ethan01,~ whence Hagemannrsquo;sester is obtained in ca. 50 overall yield. Other lesssatisfactory methods for its preparation have been re-corded.6 The investigation described here was promptedby our need in other synthetic work for a convenientlarge-scale synthesis of the t-butyl analogue (lb).As a possible approach to the t-butyl ester (lb) and animproved route to the esters (la) and (lc), we investi-gated the cyclisation of esters (3a-c) of 2-acetyl-5-oxohexanoic acid. In general, dioxo-esters of type(3) can undergo aldol cyclisation in two ways, givingeither the 8-keto-ester (1) or its structural isomer, thep-keto-ester (4).rsquo; The relative amounts of these isomersformed will be determined by kinetic and/or equilibriumfactors depending on the conditions used.Much pre-vious work8 indicated that this cyclisation led, underacidic or basic conditions, to mainly the P-keto-ester (4).It has been claimed9 that compound (3a) gives Hage-mannrsquo;s ester (la) in low yield, by catalysis with sodiumethoxide, but the insufficient characterisation of theproduct does not rule out the possibility that it was com-pound (4a) or a mixture of the esters (la) and (4a).However, it has been conclusively demonstrated,l0S l1that whereas acid-catalysed cyclisation of (3d) gives theester (4d) as expected, the use of piperidinium acetate ascatalyst effects cyclisation to give mainly the ester (Id).The dioxo-esters (3a-c) were prepared by base-catalysed Michael addition of the appropriate ester ofacetoacetic acid to but-3-en-2-0ne.l~ We have foundthat cyclisation of these dioxo-esters proceeds rapidly inthe presence of catalytic quantities of pyrrolidine andacetic acid, and gives the esters (la), (lb), or (lc), re-C.T. L. Hagemann, Ber., 1893, 26, 876.2 R. E. Ireland, lsquo; Organic Synthesis,rsquo; Prentice-Hall, NewYork, 1969, p. 75; D. Nasipuri, G. Sarkar, R. Roy, and M.Guha, J . Indian Chem. SOG., 1966, 43, 383, and references therein;W. S. Johnson, Accounts Chem. Res., 1968, 1, 1; M.Ohashi,Chem. Comm., 1969, 893; 0. R. Ghatak and N. R. Chatterjee,J . Chem. Soc. ( C ) , 1971, 190.P. Rabe and D. Spence, Annalen, 1905, 342, 328; P. Rabeand F. Rahm, Ber., 1905, 38, 969.L. I. Smith and G. F. Rouault, J . Amer. Chem. SOC., 1943,65, 631.5 M-M. Claudon, R. Cornubert, H. Lemoine, and R. Malzieu,Bull. SOC. chim. France, 1958, 843.spectively, uncontaminated by isomers no signals fromthe isomer (4a) are observed in the 100 MHz lH n.m.r.spectrum of the ester (la). The overall yield of this2 3 a;Rrsquo;= Et , R = H, R = Hb; R1= But, amp;H, R3= HC; R1= Me, $= H, R3= Hd;R1= E-t,RZ=H, R3= Mee;Rrsquo;= Et,+=various ,R3= Hf ; Rrsquo;= But,RfCH2Ph,d.Ha;Rrsquo;= Et, R Ht 2 c;R = Me,R = H2 d;Rrsquo;= Et,R =Me1 2 a;R =Et, R =Hb;Rrsquo;= Eulsquo;, R2= HqRrsquo;= Me, R2= HdiRrsquo;= Et , R2= Mesimple two-step procedure is 70-75 for (la), ca.50 for(lb), and 55 for (lc).To assess the purity of the synthetic esters (la) and(lc) we followed Heneckitrsquo;s procedure l2 (i.e. catalysis ofcyclisation by hydrogen chloride) to prepare (4a) from(3a) and (4c) from (3c). Their lH n.m.r. spectra agreewith the assigned structures and also show that eachcompound is initially contaminated with ca. 15 of theisomers (la) and (lc), respectively. Pure P-keto-ester(4c) can be obtained by crystallisation of a once-distilled6 E. C. Horning, M. G. Horning, and E. J. Platt, J . Amer.Chem. SOC., 1949, 71, 1771; M. S. Newman and H. A. Lloyd,J . Org. Chem., 1952: 17, 577.7 H. Henecka, Chemie der Beta-dicarbonylverbindungen,rsquo;Springer-Verlag, Berlin, 1950, p.263.8 R. N. Lacey, J . Chem. SOC., 1960, 1625, and referencestherein.0 H. M. E. Cardwell and F. J. McQuillin, J . Chem. Soc., 1949,708; C. Mannich and J-P. Fourneau, Ber., 1938, 71, 2090.10 H. Plieninger and T. Suehiro, Chem. Ber., 1956, 89, 2789;for further examples of such piperidine acetate-catalysedcyclisations see H. Plieninger, L. Arnold, and W. Hoffmann,1965, 98, 1399.l1 R. Brettle and D. Seddon, J . Chem. SOG. ( C ) , 1970, 1320.l2 H. Henecka, Chem. Ber., 1948, 81, 1791972 603sample of the product. The main difference between the1H n.m.r. spectra of the esters (la) and (4a) c '-.c) and(4c)l is in the appearance of the l-H signal a, - triplet(7 6-79) in the case of the 8-isomer (la), but as a quartet(T 6.86) for the p-isomer (4a).When a small excess of neat pyrrolidine is added to anyof the esters (la-c) or (3a-c), rapid exothermic re-actions occur and the yellow crystalline dienamines(Sa-c) are formed almost quantitatively.Though un-stable in air, they may be used to characterise the esters(la-c) . Under similar conditions, a crystalline productcould not be obtained from the isomeric ester (4a). Thestructures (5a-c) follow unambiguously from spectro-scopic and analytical data (see Experimental section).In particular, their formulation as conjugated dien-amines (5) rather than unconjugated dienamines (6) isconsistent with a strong absorption in the visible spec-trum for (Sa) a, 386 nm (E 31,600) and a singlet forthe olefinic proton in the n.m.r. spectrum T 5-53 for(Sa).The dienamines are resistant to hydrolysis onthe evidence of n.m.r. spectra, there was an 83 re-covery of (5a) from refluxing in B~-hydrochloric acid forCO,RP e OH1 h and 98 recovery on subjecting it to conditions (inaqueous methanol) used for the preparation of the ester(la) and they are not therefore intermediates in thecyclisation of the esters (3a-c) to (la-c) when pyr-rolidinium acetate is used as catalyst.* However, there is no explicit evidence for an enamine inter-mediate. The reaction between the ester (3c) and pyrrolidinein 2H4methanol was followed by IH n.m.r. spectroscopy.During the rapid formation (ca. 5 min a t 33') of the dienamine(k), no resonances were detected which could be ascribed to anintermediate such as the enamine (7a).t Product equilibration does not occur.Under conditions otherwise identical to those used withpyrrolidinium acetate, triethylammonium acetate fails tocyclise the ester (3a). Furthermore, product equilibra-tion does not occur in the pyrrolidinium acetate-catalysedcyclisation of compound (3a), since the @-isomer (4a) isrecovered unchanged from conditions used to preparecompound (la). It is therefore likely (cf. refs. 13 and 14)that with pyrrolidinium acetate as catalyst the cyclisingstep involves the intramolecular condensation of anenamine * with a ketone carbonyl group, followed byelimination of water and hydrolysis of an intermediateimmonium ion.Of four possible enamines, two (7a)and (7b)l can cyclise to six-membered rings. The pre-ferred formation of the ester (la) may be due to (7a)undergoing cyclisation faster than (7b), as the latter hasa much greater degree of steric crowding in the transitionstate required for a cyclisation cf. (7A) and (7B), withmaximal orbital overlap of the double bond x-electronswith the lone-pair electrons on nitrogen. Cyclisation ofthe enamine (7a) gives the intermediate (8). In theabsence of acid this is dehydrated and deprotonated(or deprotonated and dehydrated) to the dienamine (5).Although an immonium ion such as (8) could be attackedby water to yield the amino-alcohol (9), under non-acidicconditions further conversion of the N-C-OH system of(9) into a carbonyl group may not occur, as this wouldnecessitate loss of the pyrrolidino-anion, a poor leavinggroup, even if solvent-assisted by proton transfer.How-ever, in the presence of acetic acid the ion (8) can betrapped by attack of water, protonation on nitrogen, andloss of pyrrolidine to give, after dehydration, Hagemann'sester (la).The alternative direction of cyclisation of the dioxo-esters (3a) and (3c) under acidic catalysis probably goesthrough enols as intermediates (cf. pp. 9-11 of ref. 13).The preferred formation of the ester (4a) 7 may be due tothe faster cyclisation of enol (loa) compared with (lob),CO,ROHHfor the following reasons: (i) the carbonyl group in (loa)is less hindered than that in (lob) ; (ii) the preferred con-formations for cyclisation, (10A) and (10B) can be13 A. T.Nielson and W. J. Houlihan in Org. Reactions, 1968,34 T. A. Spencer, H. S. Neel, T. W. Flechtner, and R. A. Zayle,16, 7-9, 50-53, and references therein.Tetrahedron Letters, 1965, 3889stabilised by an intramolecular hydrogen-bond only inthe case of (10A) ; and (iii) the carbonylgroup of the estercan act as a general base catalyst, thereby increasing thenucleophilicity of the enolic double bond of (loa).Several synthetic uses of Hagemann's ester have in-volved the preparation of 2-substituted S-methylcyclo-hex-2-enones through alkylation of its anion and re-moval with alkali of the ethoxycarbonyl group from theintermediate (le) .2 Poor yields ha ~~ - been experiencedin this latter rea~ti0n.l~ We have ez ined the potentialof the t-butyl analogue (Ib) as a starting material insuch syntheses since the t-butoxycarbonyl group islabile to mild acid.Benzylation of the ester (lb) tocompound (If) was effected smoothly on treating itspotassium salt with benzyl bromide in acetonitrile.The t-butoxycarbonyl group was removed from theester (If) on heating in benzene containing a catalyticamount of toluene-p-sulphonic acid and gave 2-benzyl-3-methylcyclohex-2-enone in 72 overall yield.EXPERIMENTALMaterials.-Methyl acetoacetate (B.D.H.) , ethyl aceto-J.C.S. Perkin IEsters (la), t-Butyl2-Methyl-4-oxocyclohex-2-enecarboxylate(lb), and (lc).-The ester (3a) (100 g, 0.5 mol), glacialacetic acid (4-5 g, 0.075 mol), and pyrrolidine (4.0 g,0.055 mol) in 9 : 1 methanol-water (100 ml) wererefluxed for 1 h.The solvent was distilled off and the residuewas dissolved in ether (250 ml). After being washed withsmall portions of M-hydrochloric acid and dilute aqueoussodium hydrogen carbonate, the solution was dried andevaporated. The resulting red oil was distilled, giving theester (la) as a pale yellow oil (76.5 g, 84), b.p. 105' at 0.2mmHg (lit.,4 142-144'/15 mmHg); t 4-19 (4, J ca. 1.41-H), 7.4-8.0 (m, CH,,), 8.01 (d, J ca. 1 Hz, CH,C=),and 8.72 (t, J 7.1 Hz, CH,*CH,) identical with a spectrumof (la) prepared by Rabe's method 3~4-j : vmX. 1728s, 1672s,and 1633m cm-1; Amx 234 nm (E 13,500) ; semicarbazone,m.p. 156' (lit.,3 169'). The esters (lb) and (lc) were pre-pared in the manner described for (la) except that solventwas omitted, the reaction mixture was heated for 30 minat 80" (bath), and the quantities of catalysts were 0.2 mol.equiv.(pyrrolidine) and 0.25 mol. equiv. (acetic acid) :(lb) (76; ca. 90 pure by g.l.c.), b.p. 94" at 0.1 mmHg;7 4.21 (lH, q), 6.85 (lH, t, wi ca. 8 Hz), 74-7-9 (4H, m),8.00 (3H, d, J ca. 0-5 Hz), and 8.52 (9H, s); vmX. 1724s,Hz, 3-H), 5.83 (9, J 7.2 Hz, CH,*CH,), 6.79 (t, Z U ~ 9 Hz,1674s, and 1632m cm-l; A,, 234.5 nm (E 15,700); m/eacetate (B.D.H.), t-butyl acetoacetate (Aldrich), pyrrolidine ......"..LQ(~), 154(22), 137(20), 110(23), 109(30), and 57(100)(B.D.H.), and potassium t-butoxide (Kodak) were of '**"'"**'#**und: M+, 210.1247. C,,H~,~, requires M , 210.1255) ;satisfactory purity for direct use.AnalaR solvents wereused in all reactions. But-3-en-one (Koch-Light) wasstabilised with 10 water and was dried and distilled 16immediately before use. 1H N.m.r. spectra were taken forca. 10 solutions in carbon tetrachloride at 60 MHz (Perkin-Elmer R12) or a t 100 MHz (Varian HA100) using tetra-methylsilane as internal standard, i.r. spectra for ca. 3solutions in carbon tetrachloride using 0.25 mm NaCl cells(Perkin-Elmer 257), and U.V. spectra for methanolic solu-tions in quartz cells (Unicam SP 800). Mass spectra wererun on an A.E.I. MS 902 machine (University of Hullservice). Full spectroscopic data have not been includedfor compounds (3a--c), (4c), (5b), and (5c). In the case of(3a-c), the n.m.r., i.r., and mass spectra were unexcep-tional, whilst for compounds (4c), (5b), and (5c) the spectraldata paralleled those for (4a) or (5a).A Honeywell F andM instrument with an SE 30 column (2 f t ) a t 175' was usedfor g.1.c.Ethyl (3a), t-Butyl (3b), and Methyl (3c) 2-A cetyl-5-oxo-hexanoate.-Genera2 procedure. But-3-en-Zone (ca. 1mol) was added dropwise to a stirred mixture of anester of acetoacetic acid (1 mol. equiv.) and methanolicsodium methoxide (0.015 mol. equiv.), keeping the tem-perature of the reaction below 20". After 18 h at 20"(3a) and (3c)l or 35" (3b) g.1.c. showed the reactions to becomplete. Dichloromethane was added and the mixturewas washed with small portions of M-hydrochloric acid.The organic layer was dried and evaporated and the residuewas fractionally distilled giving the ester (3a), (3b), or (3c)as an oil: (3a) (88), b.p.110-121" at 0.1-0.3 mmHg(lit.,1z 127-129" at 4.5 mmHg), A,, 249 nm (e 325);(3b) (71y0), b.p. 110-116deg; at 0.1 mmHg, kz 258 nm(E 246) (Found: M+, 228.1359. C,,H,,O, requires M ,228-1361); and (3c) (75), b.p. 112-120" at 0-2 mmHg,Lax. 257 nm (E 253) (Found: MC, 186.0890. CgH#4 re-quires M , 186.0892).16 R. A. Barnes and M. Sedlak, J . Org. Chem., 1962, 27, 4562;see however ref. 18.(lc) (73y0), b.p. 86-90' at 0.2 mmHg (lit.,17 135' at2 mmHg).Ester (4a) and Methyl 4-Methyl-2-oxocyclohex-3-enecar-boxylate (4c).-Treatment of esters (3a) or (3c) with hydro-gen chloride in benzene followed by NN-dimethylaniline(140"/2 h) essentially as described,12 gave the esters (4a)or (4c) as pale yellow oils (40): (4a), b.p.90" a t 0-1mmHg (1it.,l2 119-120' at 3-5 mmHg); T 4-23 (9, J ca.1-H), 7.6-8.0 (ni, CHJ,), 8.05 (s, CH,CH=), and 8-75 (t,J 7.1 Hz, CH3*CH2) ; v- 1740s, 1680s, and 1636mw cm-l;236 nm (E 13,700); semicarbazone, m.p. 163" (fromethanol) (Found: C, 55.3; H, 7-15; N, 17-75. CllH1,N,03requires C, 55-2; H, 7.15; N, 17.55); and (4c), b.p.85-90' at 0.1 mmHg, needles, m.p. 52-53" (from acetone-hexane) (Found: C, 64.2; H, 6-9. CgH1203 requiresC, 64.25; H, 7.2).Ethyl (5a), t-Butyl (5b), and Methyl (5c) Esters of 2-Methyl-4-pyrrolidinocyclohexa- 1,3-dienecarboxylic A cid.-General procedure (0.01-0-1 molar scale). The ester (1) or(3) was mixed with pyrrolidine (4 excess).An exo-thermic reaction occurred ; the mixture became yellow,and finally solidified. The solid was taken up in M-hydro-chloric acid and after washing with ether, the aqueousextract was basified. The precipitated solid was filteredoff, washed with water, and dried (yield ca. 2Tb). Alter-natively, the ester (1) or (3) was refluxed (Fo 1 min with1 equiv. of pyrrolidine in methanol. Evapor988n gave thecrystalline product (5). Recrystallisation of these crudeproducts (3 x from hexane) gave analytical samples: (5a)yellow plates which darkened in air, m.p. 71-71.5'; 75.53 (lH, s, H-3), 5-92 (2H, q, CH,*CH,), 6.72 (4H, m,CH,*N*CH,), 7-5-8.2 (8H, m, 2 x CHJ2), 7.86 (3H, s,CH3C=), and 8.73 (3H, t, CH3CH2) ; vmX.1683s and 1615m16 L. F. Fieser and M. Fieser, ' Reagents for Organic Syn-thesis,' Wiley, New York, 1967, p. 697.l7 E. Schwenk and E. Bloch, J . Amer. Chem. Soc., 1942, 64,3050.1 Hz, 3-H), 5.88 (q, J 7.1 Hz, CH2CH3), 6.86 (9, ~4 13 Hz1972cm-1; Am=. 386 nm (E 31,600); m / e 235(98), 206(1190(54), and 162(100) (Found: M , 235.1561. C,4H,,Nu2requires 235.1572) ; (5b) yellow needles, m.p. 79-80"(Found: C, 72.85; H, 9.45; N, 5-45. C1,H25N02 requiresC, 72.95; H, 9.55; N, 5.3); and (5c) yellow crystals,m.p. 85" (Found: C, 70.55; H, 8.6; N, 6.3. C1,H,,NO2requires C, 70.55; H, 8.65; N, 6.35).t-Butyl 3-BenzyZ-2-methyl-4-oxocyclohex-2-enecarboxyZate(If) and 2-BenzyZ-3-methyZcycZohex-2-enone (with M. R.ADAMS).-Ester (lb) (5.92 g, 0.028 mol) in dry acetonitrile(40 ml) was added dropwise to potassium t-butoxide(3.26 g, 0.029 mol) under nitrogen at 0".After stirringfor 10 min, benzyl bromide (5-0 g, 0.029 mol) in acetonitrile(10 ml) was added dropwise. The mixture was allowed towarm to room temperature and after 2 h was filtered andevaporated. The residue was distilled giving the ester(If) (6.95 g, 83) as an oil, b.p. 128-130" a t 0.01 mmHg;(4H, m), 8.09 (3H, s), and 8.60 (9H, s); v,, 1730s, 1675s,and 1630mw cm-l; A,, 243 nm (e 9850); m / e 300 (M')T 2.88 (5H, s), 6.33 (ZH, s), 6.85 (lH, t, W+ 8 Hz), 7.5-8.0and 229 (100) (Found: C, 75.2; H, 7.95. C19H2403requires C, 75-95; H, 8-05y0).The ester (If) (6.1 g, 0.020 mol) and toluene-fi-sulphonicacid (0-2 g) in dry benzene (80 ml) were refluxed for 24 hunder nitrogen. The solution was washed with aqueoussodium hydrogen carbonate and, after drying, the benzenewas removed. 2-Benzyl-3-methylcyclohex-2-enone 3-5 g,87; overall yield from (lb) 72 was obtained as apale yellow oil, b.p. 90" at 0.05 mmHg (lit.,15 123-126" at0.3 mmHg). 1.r. and U.V. spectra were in agreement withpreviously reported l8 data.We thank Professor J. W. Cornforth for suggesting thisinvestigation and for discussions, Dr. W. R. Bowman fordiscussions on the mechanism of the pyrrolidine-catalysedreactions, and the S.R.C. for a research studentship (toA. L. B.).1/1006 Received, June 18th, 197110. R. Ghatak, J. J. Chrakraiarty, and A. K. Banerjii, Tetra-hedron, 1968, 24, 1677