Chemistry of tetra-alkoxyethenes. Part VI. Cycloadditions with alpha;beta;-unsaturated carbonyl compounds and chemistry of the resulting tetra-alkoxydihydropyrans

摘要

1976 1533Chemistry of Tetra-alkoxyethenes. Part V1.l Cycloadditions with ag-Unsaturated Carbonyl Compounds and Chemistry of the Resulting Tetra-a I koxyd i hyd ropyransBy Pieter H. J. Ooms, Leon P. C. Delbressine, Hans W. Scheeren, and Rutger J. F. Nivard," Departmentof Organic Chemistry, Catholic University, Toernooiveld, Nijmegen, The NetherlandsHeating tetra-alkoxyethenes (1) at 100 "C with a-cyano-orp-unsaturated carbonyl compounds (2) gives 4 + 21cycloaddition products in high yields. Mild acidic hydrolysis of the resulting 2.2.3.3-tetra-alkoxy-5-cyano-3.4-dihydro-2H-pyrans (4) gives separable mixtures containing a 6-oxo-ester (1 I ) , formed by ring opening, and an a-pyrone (1 2). which arises by recyclization of the 8-oxo-ester after hydrolysis of its acetal function.In concentratedsulphuric acid, compounds (4) are converted either into 3.3-dialkoxy-5-cyano-3.4-dihydro-2-pyrones (1 3) orinto 3-alkoxy-5-cyano-2-pyrones (1 4). depending on the reaction temperature. Treatment of (4) with baseyields 2.2.3-trialkoxy-5-cyan0-2H-pyrans (1 5) by elimination of alcohol.WE have reported that cycloadditions between electron-rich tctra-alkoxyethenes (1) and electron-poor cyano-ethenes (2), activated by a second electron-withdrawingR'O .#:R1 OR' OR'R'O OR'R'd 'OR''amp; / c R 2 + )=c,H XR'O 0 R'( 4 )action with an a@-unsaturated carbonyl compound.Only the extremely nucleophilic tetra-aminoethene (5)has been shown to react in a different way. It yields lo afive-membered ring compound, probably as a conse-quence of elimination of the highly stabilized diamino-carbene 11s12 (7) from an initially formed dipolar adduct(6) (Scheme 2).Recently Bdlanger and Brassard l3 succeeded in con-verting the cycloaddition products (9) from p-chloro-keten acetals and ap-unsaturated carbonyl compoundsinto a-pyrones (lo), by elimination of hydrochloric acidand hydrolysis of the orthoester function (Scheme 3).Inview of the wide occurrence of pyran and pyrone de-rivatives in nature,14 and the applications of a-pyrones 15in synthetic organic chemistry, such simple preparationsof dihydropyrans and a-pyrones may be of value. Wenow give a more extensive report on the synthesis of di-hydropyran derivatives from tetra-alkoxyethenes andap-unsaturated carbonyl compounds, and discuss thepossibility of selective removal of the orthoester andacetal functions in these products.SCHEME 1RESULTSa-substituent (X), yield cyclobutane derivatives,3 whenX = CN, SO,Ph, or C0,R.However, when X is an acylgroup, 4 + 21 cycloadditions take place, yielding di-hydropyran derivatives (4) (Scheme 1). Similar six-membered ring compounds have been obtained previouslyfrom several other types of electron-rich olefins, such asenol ethers,3-5 enamines,697 and keten acetal~,*~~ by re-Tetramethoxyethene did not react with cinnamdde-hyde or crotonaldehyde at 100 "C. With acrylddehydeand methyl vinyl ketone at the Same temperature onlysmall ~*ounts of a dihYdroPYran derivative wereformed, together with large m-~~ounts of PolymericProducts.Higher temperatures, as used in CYClO-additions of enol ethers 334 (150-200 "C) and ketenPart v. P. H. J. Ooms, J. W. Scheeren, and R. J. F. Nivard,P. 13. J. Ooms, J. W. Scheeren, and R. J. F. Nivard, Syn-13. I. Longley, jun., and W. S. Emerson, J . Amer. Chem.C. W. Smith, D. G. Norton, and S. A. Ballard, J . Amer.L. . Tietze, Chem. Ber., 1974, 107, 2491.amp;I. von Strandtmann, M. P. Cohen, and J. Shavel, jun.,' I. Fleming and M. H. Karger, J . Chem. SOC. ( C ) , 1967, 226. * S. M. McElvain, E. R. Degginger, and J. D. Behun, J . Amer.J.C.S. Perkin I , 1976, 1048.thesis, 1975, 860.SOL, 1950, 72, 3079.CIbem. SOG.. 1951, 73, 6267.Tetvahedvon Letters, 1965, 3103.Chem. SOC., 1954, 76, 5736.A.B6langer and P. Brassard, J.C.S. Chem. Comm., 1972,10 H. W. Wanzlick and H. J. Kleiner, Chem. Ber., 1965, 98,11 H. Wiberg, Angew. Chem., 1968, 80, 809; Angew. Chem.l2 R. W. Hoffmann, Angew. Chew., 1968, 80, 823; Angew.13 A. BClanger and P. Brassard, Canad. J . Clzem., 1975, 55,14 See, e.g., F. M. Dean, ' Naturally Occurring Oxygen Ring15 N. P. Shusherina, N. D. Dmitrieva, E. A. Luk'yanets. and863.3024.Internat. Edn., 1968, 7, 766.Ckem. Ifltemat. Edn., 1968, 7, 754.195, 201.Compounds,' Buttenvorths, London, 1963, ch. 4.R. Y a . Levina, Russ. Chem. Rev., 1967. 36, 1751534 J.C.S. Perkin Iacetals (150 "C) cannot be applied in reactions of tetra-methoxyethene, since it decomposes l6 homolytically atabout 150deg;C.Faster cycloadditions were found with aP-unsaturatedcarbonyl compounds, R2CH = CY*COR3, having anelectron-withdrawing a-substituent. The reactivity at100 "C towards tetra-alkoxyethenes was apparently stilltoo low for practical use with Y = S02Ph, Bz, or C0,R.the mixture under reflux for about 1 h (Table 2).Sul-phuric acid and toluene-9-sulphonic acid are less effectivecatalysts for the conversion (4) _+ (11). In these casesthe reaction mixture contained many more side-products,which were not identified.1.r. data revealed that the side-products (12) exist inthe enol (3-hydroxypyrone) form (12b) , after crystalliz-ation (Table 3). Normally treatment of compounds (4)Ph PhPh Ph I PhI II I q N . c " ,. N H PhPh 2 2(8)SCHEME 2However, the cyano-derivatives (Y = CN) reacted with concentrated sulphuric acid gave only products con-smoothly, giving 2,2,3,3-tetra-alkoxy-5-cyano-3,4-dihy- taining the a-pyrone ring (Scheme 5).Below 0 "C 3,3-dro-2H-pyrans (4). In this way several ring-substituted dialkoxy-5-cyano-3,4-dihydropyrones (13) were obtained(Table 4). At higher temperatures these compoundsapparently eliminate alcohol in the acidic medium; at25 "C 3-alkoxy-5-cyano-2-pyrones (14) were isolated(Table 5). The same products were obtained when thepure compounds (13) were treated with concentratedsulphuric acid at 25 "C. These reactions failed withcompounds (4; R2 = a-furyl); in this case a complexmixture arose, perhaps owing to acidolytic cleavage of the@?+ pi;: - PoR H R R2(9) (10)SCHEME 3a-cyano-cinnamaldehydes and -benzylideneacetophen-ones could be converted into dihydropyran derivatives inyields of 80-95 (Table 1).Extension of the reactionto the preparation of compounds (4; R2 = H or alkyl)was not studied, since useful syntheses of the necessarystarting compounds are not available.Hydrolysis of 2,2,3,3- Tetra-alko;~.y-5-cyano-3,4-dihydro-2H-pyrans (4) in the Presence of Acids.-Acidic hydro-lysis of compounds (4) yields different products accordingto the reaction conditions. Refluxing in dioxan-waterwith hydrogen chloride as catalyst yielded substituted8-oxo-esters (11) as the main products. In all casesa-pyrone derivatives (12) were formed as principal side-products, in 20-250/, yields (Scheme 4). The oxo-esters could be separated easily from the side-products,because of the low solubility of the latter.In generalhighest yields of oxo-esters (1 1) were obtained on heatingCN R31' CN R3HO' 0(12b)SCHEME 4fury1 group.in reactions with (4; R3 = H).Unsatisfactory results were also obtainedl6 R. W. Hoffmann, J. Schneider, and H. Hauser, Chem. Ber., Reactivity of 2,2,3,3-Tetra-alkoxy-5-cyano-3,4-dihydro-2H-pyrans (4) towards Bases.-Treatment of compounds 1966, 99, 18921976 1535(4) with sodium methoxide in 1 ,Z-dimethoxyethaneusually caused elimination of alcohol, yielding 2,2,3-tri-alkoxy-5-cyano-2H-pyrans (1 5) (Table 6). CompoundsCN R30 conc. H2SOL , :2c: conc.H2S0~, 25 O C-10 t o oocRrsquo;0Rrsquo; 0(13 1 11L)SCHEME 5(4; R3 = H) did not react with methoxide.Use of astronger base (t-butoxide) resulted in complex mixtures,independent of the nature of R3. Hydrolysis of theCN R 3(15)SCHEME 6products (15) with sulphuric acid again yielded thea-pyrone derivatives (14) (Scheme 6).DISCUSSIONComparison of the reactivity of tetra-alkoxyetheneswith that of other electron-rich olefins reveals thatenamines add much faster to ap-unsaturated carbonylcompounds. In general, enamines give six-memberedcycloaddition products at room temperature, even withless activated ap-unsaturated ketones6. 7 The reactivityof enol ethers and keten acetals seems not very differentfrom that of tetra-alkoxyethenes. Ethyl vinyl ether and1,l-dialkoxyisobutene add smoothly to 2-benzylidene-2-cyanoacetophenone. They both even add to lessactivated carbonyl compounds, e.g.cinnamaldehyde andacrylaldehyde, although at higher temperatures. How-ever, the presence of the acetal function in the cyclo-addition products (4) from tetra-alkoxyethenes providesthese compounds with a much more varied reactivitythan the related dihydropyrans without this group. Ingeneral 2,2-dialkoxydihydropyrans give only open-chainproducts, viz. 8-oxo-esters, on acidic hydrolysis,**13 with-out formation of side-products corresponding to (12).The formation of the compounds (12) on acidic hydrolysisof 2,2,3,3-tetra-alkoxydihydropyrans may be ascribed tohydrolysis of the acetal function in the primarily formedl7 A. Roedig and H. A. Renk, Chem. Bey., 1973, 106, 3877.l* P.Schiess and H. L. Chia, Helv. Chim. Actu, 1970, 53, 486.l9 P. H. J. Ooms, J. W. Scheeren, and R. J. F. Nivard, Syn-thesis, 1975, 263.6-0x0-ester (1 1). The resulting product (16) will enolize (16a) (lGb), favouring recyclization by intra-molecular transesterification (Scheme 7).CN R 3HO(16b)SCHEME 7The hydrolysis of the acetal function in (11) is slow incomparison with the hydrolysis of the orthoester functionin (4). The products (11) can be obtained in higheryields when compounds (4) are subjected to brief treat-ment with dilute hydrochloric acid; compounds (12) areobtained only after longer reaction times. The cycliz-ation of (16), giving (12) in acidic medium is apparentlycomplete. The occurrence of the a-oxo-ester (16a) or itstautomer (16b) in the reaction mixture has never beenobserved. Similarly, acidic hydrolysis of (15) yields onlythe cyclic product (14) ; the a-alkoxy-analogue of (l6b),which must be an intermediate in this reaction, could notbe detected.An alternative route for the conversion of (15) into (14)may be via valence isomerization of (15) into the di-enones (17), as described for several other a-pyran de-rivatives,9J7J* However, compounds (15), dissolved inORrsquo; Rrsquo; 0phenyl cyanide, are apparently completely stable at200 ldquo;C, whereas the isomerization products (17), beingketen acetals, should decompose at this tempera-ture.16J9ym The thermal stability of (15) may beexplained by arguments similar to those used for 4,6,6-t rialkylpyrans.al20 S.M. McElvain and C. L. Stevens, J . Azner. Chem. Soc.,z1 A. F. Kluge and C . P. Lillija, J . Org. Chem., 1971, 36, 1977.1946, 68, 19171536 J.C.S. Perkin ITABLE 12,2,3,3-Tetra-alkoxy-5-cyano-3,4dihydro-2H-pyrans (4; Rf = Me) (Scheme 1)Yield M.p.() ("C) W e87 158 426 (M), 411 (M - CH,),90 134 416/414 (Ad), 401/399395 (M - OCH,)(M - OCH,)(M - CH,), 385138395 120 411 (M), 396 (M - CH,),88 81 371 (M), 356 (M - CH,),380 (M - OCHJ340 (M - OCH,)80 122 335 (M), 320 (M - CH,),304 (M - OCH,)Analyses ("/)7 N6.556.553.353.43.43.43.753.84.24.21 x6.86.73.53.43.53.83.53.63.94.03.43.4vrnax.(KBr)/cm--l2 212 ( E N ) ,2 210 ( E N ) .1620 ( e C - 0 )1625 (C=C-0)CC,,H,,N,O, Reqd. 61.95H5.35.35.355.46.16.25.76.96.36.4Found 62.1Found 63.7C,,H,,ClNO, Rcqd.63.65C,,H,,NOB Reqd. 67.15Found 66.9C2,H,,N0, Reqd. 64.7Found 65.02 208 (CZN),2 218 ( E N ) ,1 618 (C=C-0)164011 632(c-0)2 212 (CZN),1646 ( e C - 0 )C,,H2,N06 Reqd. 60.9Found 61.0TABLE 2act-Dialkoxyy-cyano-8-oxo-esters (1 1 ; R3 = Ph) (Scheme 4)Yield75(70)7070804585M.p.67("C12012512210983Analyses (yo)rC,,H,,N20, Reqd. 61.15amp;CFound 60.5R1 RSMe p-N02C6H4Me p-C1Camp;,Me PhMe p-MeO0C6H4Me 2-Fury1Et Ph___.-amp;I4.94.96.04.95.755.85.855.95.355.46.656.7mle381 (M - OCHJ, 363(M - COOCHJ4031401 (M), 3721370 (M -OCH,), 3441342 (M -CO-OCH,)367 (M).336 (M - OCH,),397 (M). 366 (M - OCH,),357 (M), 326 (M - OCH,),308 (M - COOCH,)338 (M - COOCH,)298 (M - COOCH,)409 (M), 364 (M - OCZH,),336 (M - COOC2H5)v,,,.(KBr) Icn1-l2 235 (CZN),1735 (C=O),1692 ( e 0 )1 735(C=O),1 693 (C=O)1 760 ( e O ) ,1696 (C=O)1761 (C=O),1690 (C=O)1731 (C=O),1692 (C=O)1731 (C=O),1692 ( G O )2 237 ( E N ) ,2 240 (CZN) ,2 239 ( E N ) ,2 240 (CZN),2 239 (CZN),C2,H,,C1N05 Reqd. 62.76Found 63.0C,,H,,N05 Reqd. 68.65Found 68.8C,,H,,TU'O, Reqd. 66.5Found 66.7CIQH,,NO, Reqd. 63.85Found 63.8C,,H,,NO, Reqd. 70.4Found 70.1TABLE 35-Cyano-3-hydroxy-2-pyrones ( 12b) (Scheme 4)Analyses ()Yield M.p.R2 () ("C) mleP-NO,.C,H, 25 216 334 (M), 306 (M - CO),277 (M - CO - COH)p-ClC6H, 22 226 3251323 ( M ) , 297/295(M - CO), 2681266(M - CO - COH)Ph 20 197 289 (M), 261 (M - CO),232 (M - CO - COH)Lsx.(CHC13) I ,v,,.(KBr) 1crn-l nm2 222 ( C 3 ) , 345 Cl*Hl,N,O51 710 (GO),1 625 (GC-0)2 230 ( E N ) ,1710 (C=O),1627 (CkC-0)2 225 ( E N ) ,1710 fC=O).3 362 (OH), 33 1 C,,H,,ClNO,3 350 (OH), 33 1 C,,H,,NO,7 N8.48.2C HReqd. 64.65 3.0Found 63.05 3.1Reqd. 66.8 3.1Found 66.7 3.14.354.15Reqd. 74.75 3.85Found 74.1 3.94.854.81620 ( G C a )3 355 (OH), 342 C,9H,,N0, Reqd. 71.45 4.12 22s (CZN), Found 71.3 4.04.44.35p-MeOC,H, 25 228 319 (M), 304 (M - CH,),288 ( M - OCH,), 291(M -l CO), 262 -'(M - CO - COH)1 710 (C=O),1620 (GC-0)EXPERIMENTALand i.r.data (KBr pellets).~-Cyano-a~-unsatuyated CaybovGyl Compounds R2CH:C(CN)*COR3.-The compounds with R3 = Ph were pre-pared by Knoevenagel condensations between an appro-priate aldehyde and cyanoacetophenone, with piperidine aswas isolated. New compounds are those with R2 =fi-C1C6H4 (m.p- 87" ; yield 80) and R2 = a-furyl (m.p-1 1 7 O ; yield 75).All products were characterized by m.p.s, mass spectra, In cases Only One probably the22 H. Kaufflnann, BEY., 1917, 50, 5271976TABLE 43,3-Dialkoxy-5-cyano-3,4dihydro-2-pyrones ( 13 ; R3 = Ph) (Scheme 5)1537Yield M.p.R' R2 () ("C) mleMe fi-02W.Camp;4 95 163 380 (M), 349 (M - OCH,),Me P-C1C6H, 90 125 370/368 (M), 339/337 (M334 (M - H,COCH,)- OCII,), 324/322 (M - H,COCHamp;Me 1'11 90 154 335 (M), 304 (M - OCH,),289 (M - H,COCH,)Me p-AlcOC,II, 90 164 365 ( M ) , 334 (M - OCH,),319 (M - H,COCH,)Bt 1'11 88 121 363 (M), 318 (M - OC,H,),259 (A - H5C20C2H,)vniax.( KBr) /cm-'2 212 (CEN),1745 (C=O),2 210 (CEN),1 745 (M),1 757 (C=O),1753 (C=O),1 630 (C=C-0)1630 (GC-0)2 216 ( E N ) ,1635 (GC-0)2 202 (CEN),1631 ( e C - 0 )1751 (C=O),2 210 (CEN),1636 (GC-0)Yield M.p.("C)Analyses ()rC20Hl,N206 Reqd.63.15 4.25Found 63.0 4.25C HC2,Hl,C1N0, Reqd. 64.95 4.3Found 65.2 4.3C2,Hl,N0, Reqd. 71.65 5.1Found 71.4 5.1C2,HlDN0, Reqd. 69.05 5.25Found 68.9 5.2C22H,1N0, Reqd. 72.7 5.8Found 72.5 6.8TABLE 53-Alkoxy-5-cyano-2-pyrones (14; R3 = Ph) (Scheme 5 )228 348 ( A l ) , 333 (144 - CH,),152 339/337 (M), 3241322 (M317 ( M - OCHJ- CH,), 305/306 (A4303 (M), 288 (A4 - CH,),- OCH,)272 ( M - OCH,)153194 333 (M), 318 (M - CHJ,302 ( M - OCH,)124 317 (M), 288 (A1 - C2H5),272 (M - OCZH,)-N77.357.33.83.84.24.13.853.83.853.9Analyses ()Amax.(CHC1,) I, avmaX. (KBr) /cm-l nm C H N2 229 (CEN),1732 (C=O),1606 (GC-0)1731 (C=O),1611 (C=C-0)2 232 (CEN),2 225 ( E N ) ,S 220 (CZN),1735 (C=O),1611 (GC-0)1732 (GO),1 609 (C=C-0)1726 (GO),1610 (c---c-O)2 230 (CEN),295 C19H12N205 Reqd. 66.5 3.45 8.05300 Cl9H,,C1NO, Reqd. 67.55 3.6 4.15Found 67.2 3.6 4.2301 ClgHl,NO, Reqd. 75.25 4.3 4.6Found 75.1 4.36 4.7294 C20Hl,N0, Reqd. 72.05 4.55 4.2Found 71.9 4.5 4.2303 C2,H15N03 Reqd.75.7 4.75 4.4Found 75.7 4.85 4.4Found 65.7 3.45 8.1TABLE 62,2,3-Trialkoxy-5-cyano-2H-pyrans (16) (Scheme 6)Me p-ClC6H4 73 96 385/383 ( M ) , 2 218 (CEN),370/368 (A1 1639 (C=C-0)- CH,), 354/352( A l - OCHJ- CHJ, 318 (MMe 1'11 92 102 349 (M), 334 (M 2 210 (CZN),Me SIeO*C,H, 90 152 379 (M), 2 210 ( E N ) ,1636 (M-0)- OCH,)364 (M - CHJ,348 (M - OCH,)324 (M - CH,),308 (M - OCH,)362 (M - C,H,),346 (M - OC2H5)1639 (GC-0)Me 2-Fury1 90 95 339 (M), 2 210 ( E N ) ,1638 (C=C-0)Et PI1 75 Oil 391 (M), 2 215 ( E N ) ,1 635 (GC-0)332 C21H,,ClN0, Reqd. 65.7 4.75 3.65 25 "C/Found 65.9 4.8 3.7 8 h332 C2,H1,NO4 Reqd. 72.2 5.5 4.0 Reflux/Found 72.4 5.6 3.9 3 h336 C2,H2,N0, Reqd. 69.65 5.6 3.7 Reflux1Found 69.3 5.5 3.6 8 h331342Reqd.67.25 5.05 4.15 Reflux/Found 67.6 5.1 4.1 3 hReflux/3 1538 J.C.S. Perkin Ip-Cyanocinnamaldehydes ( R3 = H) were prepared asdescribed by Wa~serman.~~ The p-methoxy-compound(R2 = fi-MeO*C,H,) was obtained in 33 yield and hadm.p. 137".(4)(Table 1) .-A mixture of a tetra-alkoxyethene (0.02 mol)and a @-acyl-@-cyanostyrene (0.01 mol) was heated withoutsolvent a t 100 "C. After 1 h the excess of tetra-alkoxy-ethene was evaporated off and the residual oil crystallizedfrom methanol.aa-Dialkoxyy-cyano-8-oxo-esters (1 1) (Table 2) .-Theproduct (4) from the previous preparation (3 mmol), dis-solved in dioxan (35 ml) and water (35 ml) , was treated withconcentrated hydrochloric acid (0.3 ml) and refluxed for 1 h.Evaporation left a residue which was dissolved in chloro-form.The solution was washed three times with a satur-ated sodium chloride solution (until neutral), dried (Na,-SO,), filtered, and evaporated. The residue was crystallizedfrom methanol.5-Cyano-3-l~ydroxy-2-pyromx (1 2b) (Table 3) .-The sameprocedure was used as in the foregoing preparation, but re-fluxing was continued for 24 h. The solvent was thenremoved, and on addition of chloroform to the oily residuethe crystalline product (12b) was precipitated.3,3-Dialko~y-5-cyano-3,4-dihydro-2-j1yrones ( 13) (Table 4).-Finely divided tetra-alkoxycyanodihydropyran (4) ( 1mmol) was dissolved in concentrated sulphuric acid (5 ml)at 0 "C with ctirring. After 1 h the solution was poured on2 , 2,3,3- Tetra-alk oxy- 5-cyan o- 3,4-dihydro - 2H-pyransto crushed ice. The mixture was then extracted three timeswith chloroform, and the combined extracts were washedthree times with saturated sodium chloride solution (untilneutral), dried (Na,SO,), filtered, and evaporated. Theresidual oil was crystallized from methanol.3-A lkoxy-5-cyano-2-pyrones (14) (Table 5) .-The pro-cedure was the same as the foregoing, but the reaction mix-ture was stirred for 1 h a t 25 "C.2,2,3-Trialkoxy-5-cyano-SH-pyrans (16) (Table 6) .-Sod-ium methoxide (2 mmol) was added to a solution of thetetra-alkoxycyanodihydropyran (4) (1 mmol) in dry 1,2-di-methoxyethane (10 ml). The mixture was stirred for thetime and a t the temperature indicated in Table 6. Thesolution was then evaporated and the residue dissolved inwater. This solution was extracted three times with chloro-form and the combined extracts were washed three timeswith saturated sodium chloride solution, dried (Na2S04),filtered, and evaporated. The residue was crystallized frommethanol.The investigation was carried out under the auspices ofthe Netherlands Foundation for Chemical Research (S.O.N.)with financial support from the Netherlands Organizationfor Advancement of Pure Research (Z.W.O.).5/2518 Received, 23rd December, 1978123 H. H. Wasserman, B. Suryanarayana, and D. D. Grassetti,J . Amer. Cham. SOC., 1956, 78, 2808