2-Aminobuta-1,3-dienes as annulation reagents for 4-quinolones and benzothiopyran-4-ones: an attractive route for the highly diastereoselective synthesis of acridine- and thioxanthene-derivatives

摘要

J. Chem. Soc. Perkin Trans. 1 1997 2807 2-Aminobuta-1,3-dienes as annulation reagents for 4-quinolones and benzothiopyran-4-ones an attractive route for the highly diastereoselective synthesis of acridine- and thioxanthene-derivatives Uwe Beifuss * and Michael Taraschewski Institut fuuml;r Organische Chemie der Georgndash;Augustndash;Universitauml;t Gouml;ttingen Tammannstrasse 2 D-37077 Gouml;ttingen Germany Enamines regioselectively add to the C N1-bond of 4-silyloxyquinolinium triflates with high yields and the BF3?Et2O mediated annulations of 4-quinolones with 2-aminobuta- 1,3-dienes proceed with high diastereoselectivity to give substituted 1,2,3,4,4a,9,9a,10-octahydroacridine-3,9-dione derivatives; 4-silyloxy-1-benzothiopyrylium triflates and benzothiopyran-4-ones behave analogously. Over the last few years there has been a considerable interest in reactions with 2-aminobuta-1,3-dienes,1 since it was shown that they can be employed as dienes in intermolecular Dielsndash;Alder reactions 2 to yield the corresponding cyclization products with high diastereo- and enantio-selectivity.In most examples reported so far the 2-aminobuta-1,3-dienes have been used in hetero Dielsndash;Alder reactions with C S C O C N and N N dienophiles 3 and in homo Dielsndash;Alder reactions with nitroolefins as dienophiles.3c,4 Here we report on the first examples of the highly diastereoselective annulation of 4-quinolones and benzothiopyran-4-ones with 2-aminobuta-1,3-dienes. Recently we have found that nucleophiles like silyl enol ethers and organometallic reagents undergo regioselective 1,2- additions to the C N1-bond of 4-silyloxyquinolinium triflates 2 (X = NR)5a and the C S1-bond of 4-silyloxy-1-benzothiopyrylium triflates 2 (X = S) (Scheme 1).5b Furthermore it was demonstrated that these positively charged heteroaromatic systems can be annulated in a highly regio- and diastereoselective manner employing unsubstituted as well as 3-monoand 3,4-disubstituted 2-silyloxybuta-1,3-dienes.6 To further explore the reactivity of 4-quinolones 1 (X = NR) and the corresponding 4-silyloxyquinolinium triflates 2 (X = NR) their reactions with enamines and 2-aminobuta-1,3- Scheme 1 Reagents and conditions i 1 (1.0 equiv.) TIPSOTf (1.1 equiv.) room temp.1 h; ii CH2Cl2 3 (2.0 equiv.) room temp. 30ndash;60 min; iii camphorsulfonic acid (1.0 equiv.) CH2Cl2 room temp. 2ndash;3 h 89 (5a); 76 (5b); 93 (5c) X O X OTIPS + TfOndash; NR2 + i 1 2 3 X O O X OTIPS O 2cent; ii iii 1,2,4,5 a X = NCO2Et b X = NCbz c X = S 3 a NR2 = morpholino b NR2 = piperidino c NR2 = pyrrolidino 5 4 dienes were investigated.It was found that reaction of the Nprotected 4-silyloxyquinolinium triflates 2a,b with the enamines 3andash;c proceeds via 1,2-addition to the C N1 bond to give exclusively adducts 4a,b in high yields (Scheme 1 Table 1).dagger; The products were isolated as mixtures of their syn- and antidiastereomers with ratios varying from 1.7 1.0 to 3.4 1.0 but so far the relative stereochemistry of the diastereomeric 1,2- addition products 4a,b has not been established beyond any doubt. By performing the reaction of the benzothiopyrylium triflate 2c with 3a which yields syn-4c and anti-4c in a 1.0 2.1 ratio (Scheme 1 Table 1) it was demonstrated that the 1,2- additions with enamines are not restricted to quinolinium salts.It is remarkable however that in order to obtain high yields of the 1,2-adducts it is necessary (a) to run the reactions in the absence of any bases like 2,6-lutidine and (b) to avoid aqueous work up. The hydrolysis of the silyl enol ethers 4 could easily be achieved by using camphorsulfonic acid (CSA) (Scheme 1). In addition the diastereomeric keto silyl enol ethers syn-4a and anti-4a were hydrolyzed separately and it was found that under these conditions no isomerization occurred at C-29. Surprisingly no reaction was observed when the 4-silyloxyquinolinium triflates 2 and the 2-aminobuta-1,3-dienes 6 were reacted under the conditions that had been established for the 1,2-addition process (Scheme 2).After some experimentation it was discovered that the annulation could be achieved Scheme 2 Reagents and conditions i 1 (1.0 equiv.) CH2Cl2 BF3?Et2O (1.0 equiv.) then 6 (1.5 equiv.) room temp. 60 min 1 a X = NCO2Et b X = NCbz c X = S 6 a R = Pri b R = But c R = c-C6H11 N R X N O H R H X O O H R H 1 + i 6 7 8 7,8 a R = Pri X = NCO2Et b R = But X = NCO2Et c R = c-C6H11 X = NCO2Et d R = Pri X = NCbz f R = c-C6H11 X = NCbz g R = Pri X = S dagger; Satisfactory analytical (combustion and/or high-resolution mass) and spectral (UV IR NMR and MS) data were obtained for all compounds. 2808 J. Chem. Soc. Perkin Trans. 1 1997 when 4-quinolones 1 instead of the 4-silyloxyquinolinium tri- flates 2 were reacted with the 2-aminobuta-1,3-dienes 6 and BF3?Et2O as a Lewis acid.Best results were obtained with 1.1 equiv. of BF3?Et2O in CH2Cl2 at room temperature. Under these conditions the reaction of the N-ethoxycarbonylprotected 4-quinolone 1a with the 4-isopropyl-substituted 2- aminobuta-1,3-diene 6a yielded the cis,cis-1,2,3,4,4a,9,9a,10- octahydroacridine-3,9-dione 8a with three stereogenic centers exclusively in 74 yield.Dagger; The reaction of 1a with the 4-tertbutyl- and the 4-cyclohexyl-substituted 2-aminobuta-1,3-dienes 6b and 6c gave the corresponding annulation products 8b and 8c in diastereomeric pure form (Table 2 entries 1ndash;3; Scheme 2). Similar results were obtained in the annulation of 6a and 6c with the N-benzyloxycarbonyl (Cbz)-protected 4-quinolone 1b (Table 2 entries 4 6; Scheme 2). No product though was formed in the reaction of 1b with the 4-tert-butyl-substituted 2- aminobuta-1,3-diene 6b (Table 2 entry 5; Scheme 2).It is interesting to note that the transformations cannot be performed with the N-methyl- and the unprotected 4-quinolones. This type of annulation process is not restricted to quinolones but can also be used for the synthesis of thioxanthene-3,9-dione derivatives as was demonstrated by the reaction of 1c with 6a. Here the diastereomerically pure cis,cis-annulation product 8g was isolated in 72 yield (Table 2 entry 7; Scheme 2). The structural elucidation of the cyclization products was mainly based on NMR studies. For example 1H NMR- and 2D-COSY-experiments allowed an unambiguous configurational assignment of 8a.sect; In addition an X-ray crystal structure analysis could be obtained for 8a.para; The transformations may either proceed as more or less concerted intermolecular Dielsndash;Alder reactions with normal electron demand or as anionic Domino processes,6,7 where in the first step an inter- Table 1 Formation of 4 by 1,2-addition of enamines 3 to positively charged aromatic heterocyclic systems 2 Entry 1 2 3 4 5 1 2 a a a b c X NCO2Et NCO2Et NCO2Et NCbz S 3 a b c a a NR2 morpholino piperidino pyrrolidino morpholino morpholino 4 a a a b c Yield a 4 () 81 86 84 87 93 a After column chromatography.Table 2 Diastereoselective formation of annulation products 8 by reaction of 1 with 2-aminobuta-1,3-dienes 6 Entry 1 2 3 4 5 6 7 1 a a a b b b c X NCO2Et NCO2Et NCO2Et NCbz NCbz NCbz S 6 a b c a b c a R Pri But c-C6H11 Pri But c-C6H11 Pri 8 a b c d e f g Yield a 8 () 74 31 65 54 mdash; 63 72 a After column chromatography.Dagger; General procedure for the synthesis of 8 boron trifluoridendash;diethyl ether (1.1 mmol) and a 2-aminobuta-1,3-diene 6 (1.5 mmol) were successively added to a stirred solution of 1 (1.0 mmol) in dry dichloromethane (15 cm3) under argon at room temperature. The reaction mixture was stirred for 1 h at room temperature. After quenching the reaction by addition of saturated aq. sodium hydrogen carbonate (5 cm3) and further stirring for 10 min at room temperature the aqueous phase was extracted twice with dichloromethane (2 times; 5 cm3). The combined organic layers were dried over sodium sulfate the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel with ethyl acetatendash;light petroleum (bp 40ndash;60 8C) (1 4) as eluent to yield the annulation product 8.In addition starting material 1 and unidentified decomposition products could be isolated as side products. No diastereomeric annulation products 8 were found. molecular 1,4-addition of the enamine to the vinylogous amide takes place. This is followed by an intramolecular 1,4-addition of the enolate to the conjugated iminium ionmdash;both newly formed in the first addition step. Apart from the high diastereoselectivity of the process it is clearly an advantage that the hydrolysis of the enamines 7 which are believed to occur as intermediates needs no extra step but simply takes place under aqueous work-up conditions.Dagger; The 2-aminobuta-1,3-dienes 6 were prepared in accordance with the procedures published by Enders et al.3a and Barluenga et al.,8 and the N-protected 4- quinolones 1a,b were obtained by standard procedures.9 For further transformations it was necessary to know whether the two keto groups formed during the annulation process could easily by discriminated.For this purpose the acetalization of 8a and 9 (9 could be obtained by hydrogenolytic cleavage of the Cbz group in 8d) (H2 Pd/C 80) was investigated. It was found that acetalization of both 8a and 9 proceeded exclusively at C-3 to yield 10a,b (Scheme 3). These results demonstrate the different reactivity of the two keto functions. Under these reaction conditions no isomerization took place at C-9a. Further work is now directed to the synthesis of enantiomerically pure annulation products using 2-aminobuta- 1,3-dienes of C2-chiral amines.10 In summary we have established that substituted 2-amino- Scheme 3 Reagents and conditions i CSA (2.0ndash;5.0 equiv.) R2OH room temp.30ndash;60 min N O O H H R1 N O H H R1 OR2 OR2 9a i 8a R1 = CO2Et 9 R1 = H 10a R1 = CO2Et R2 = Et 10b R1 = H R2 = Me 78 80 sect; Selected data for 8a dH(300 MHz; C6D6; Me4Si; J in Hz) 0.66 d 3JCH3 CH 6.5 6H CH(CH3)2 0.83 (ddt 3J1-H CH 10.0 3J1-H 2-Hax 14.0 3J1-H 2-Heq 3.5 3J1-H 9a-H 3.5 1H 1-H) 0.96 (t 3JCH2 CH3 7.0 3H CO2CH2CH3) 2.13 (dd 2J4-Hax 4-Heq 15.0 3J4-Hax 4a-H 13.0 1H 4-Hax) 2.18 (dd 2J2-Hax 2-Heq 16.5 3J2-Hax 1-H 14.0 1H 2-Hax) 2.36ndash;2.49 (m 2H 2-Heq 4-Heq) 2.57 (dseptet 3JCH 1-H 10.0 3JCH CH3 6.5 1H 29-H) 2.98 (m 1H 9a-H) 3.96ndash;4.08 (m 2H CO2CH2CH3) 4.90 (dt 3J4a-H 4-Hax 13.0 3J4a-H 4-Heq 5.0 3J4a-H 9a-H 5.0 1H 4a-H) 6.78 (dt 3J7-H 6-H 7.5 3J7-H 8-H 7.5 4J7-H 5-H 1.0 1H 7-H) 7.25 (ddd 3J6-H 5-H 7.5 3J6-H 7-H 8.5 4J6-H 8-H 2.0 1H 6-H) 8.11 (d 3J5-H 6-H 9.0 1H 5-H) 8.14 (dd 3J8-H 7-H 7.5 4J8-H 6-H 1.5 1H 8-H); dC(75 MHz; C6D6; Me4Si) 14.31 (CO2CH2- CH3) 21.13 CH(CH3)2 21.66 CH(CH3)2 30.04 CH(CH3)2 41.80 (C-2) 41.88 (C-4) 44.91 (C-1) 47.30 (C-9a) 56.26 (C-4a) 62.72 (CO2CH2CH3) 123.33 (C-5) 123.70 (C-7) 124.24 (C-8a) 127.39 (C-8) 134.64 (C-6) 140.65 (C-10a) 153.30 (CO2CH2CH3) 193.51 (C-9) 204.99 (C-3).para; Crystal structure solution and refinement diffraction data were collected on a Siemensndash;Stoe AED four-circle diffractometer at 183 K with Mo-Ka radiation (l = 0.710 73 Aring;). The structure was solved by direct methods with SHELX-86 and refined by full-matrix least-squares on F2 (SHELX-93). Non-hydrogen atoms were refined anisotropically and hydrogen atoms inserted in calculated positions.Crystal data C19H23NO4 M = 329.38 triclinic space group P1� a = 932.3(10) b = 1189.7(10) c = 1668(2) pm a = 107.42(10) b = 91.05(5) g = 95.61(6)8 V = 1.754(3) nm3 Z = 4 Dc = 1.247 Mg m23 mcalc = 0.087 mm21 F(000) = 704 crystal size 1.0 times; 1.0 times; 1.0 mm 5533 collected reflections 4022 independent reflection goodness of fit 1.068 refinement converged for all data with R = 0.0542 and Rw = 0.1360. Atomic coordinates bond lengths bond angles and displacement parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC). See Instructions for Authors J. Chem. Soc. Perkin Trans. 1 1997 Issue 1. Any request to the CCDC for this material should quote the full literature citation and the reference number 207/140. The single X-ray analysis of 8a was performed by Dr M.Noltemeyer and H.-G. Schmidt (Institut fuuml;r Anorganische Chemie Tammannstr. 4 D-37077 Gouml;ttingen Germany). J. Chem. Soc. Perkin Trans. 1 1997 2809 buta-1,3-dienes can be used for the highly diastereoselective annulation of 4-quinolones and benzothiopyran-4-ones. Furthermore it was demonstrated that enamines serve as nucleophiles for the regioselective 1,2-addition to 4-silyloxyquinolinium triflates and 4-silyloxybenzothiopyrylium triflates. Acknowledgements This work was supported by the Georgndash;Augustndash;Universitauml;t Gouml;ttingen and the Fonds der Chemischen Industrie Frankfurt am Main. We thank 3M Neuss and Huuml;ls AG Marl for chemicals. References 1 Reviews D. Enders and O. Meyer Liebigs Ann. Chem. 1996 1023; K. Krohn Angew. Chem. 1993 105 1651; Angew. Chem. Int. Ed.Engl. 1993 32 1582. 2 W. Carruthers Cycloaddition Reactions in Organic Synthesis Pergamon Oxford 1990; F. Fringuelli and A. Taticchi Dienes in the Diels-Alder Reaction Wiley New York 1990. 3 (a) D. Enders O. Meyer G. Raabe and J. Runsink Synthesis 1994 66; (b) J. Barluenga F. Aznar C. Ribas C. Valdeacute;s M. Fernaacute;ndez M.-P. Caball and J. Trujillo Chem. Eur. J. 1996 2 805; (c) J. Barluenga F. Aznar C. Valdeacute;s A. Martiacute;n S. Garciacute;a-Granda and E. Martiacute;n J. Am. Chem. Soc. 1993 115 4403; (d ) J. Barluenga F. Aznar C. Valdeacute;s and M.-P. Cabal J. Org. Chem. 1993 58 3391; (e) J. Barluenga F. Aznar and C. Valdeacute;s Synlett 1991 487; ( f ) J. Barluenga F. Aznar M.-P. Cabal and C. Valdeacute;s J. Chem. Soc. Perkin Trans. 1 1990 633; (g) J. Barluenga F. Aznar C. Valdeacute;s and F. L. Ortiz Tetrahedron Lett. 1990 31 5237; (h) J.Barluenga F. Aznar M.-P. Cabal F. H. Cano and M. D. L. C. Foces-Foces J. Chem. Soc. Chem. Commun. 1988 1247; (i) J. Barluenga Bull. Soc. Chim. Belg. 1988 97 545. 4 (a) D. Enders O. Meyer and G. Raabe Synthesis 1992 1242; (b) A. Mezzetti P. Nitti G. Pitacco and E. Valentin Tetrahedron 1985 41 1415; (c) F. Benedetti G. Pitacco and E. Valentin Tetrahedron 1979 35 2293; (d) R. A. Ferri G. Pitacco and E. Valentin Tetrahedron 1978 34 2537; (e) G. Pitacco A. Risaliti M. L. Trevisan and E. Valentin Tetrahedron 1977 33 3145. 5 (a) U. Beifuss and S. Ledderhose Synlett 1997 313; (b) U. Beifuss M. Tietze and H. Gehm Synlett 1996 182. 6 (a) U. Beifuss and S. Ledderhose Synlett 1995 938; (b) U. Beifuss H. Gehm M. Noltemeyer and H.-G. Schmidt Angew. Chem. 1995 107 705; Angew. Chem. Int.Ed. Engl. 1995 34 647; (c) U. Beifuss and H. Gehm Phosphorus Sulfur Silicon Relat. Elem. 1994 95 and 96 339. 7 Reviews L. F. Tietze Chem. Rev. 1996 96 115; L. F. Tietze and U. Beifuss Angew. Chem. 1993 105 137; Angew. Chem. Int. Ed. Engl. 1993 32 131. 8 J. Barluenga I. Merino and F. Palacios Tetrahedron Lett. 1990 31 6713. 9 P. J. Kocienski Protecting Groups Thieme Stuttgart 1994. 10 Reviews J. K. Whitesell Chem. Rev. 1989 89 1581; H. Waldmann Nachr. Chem. Tech. Lab. 1991 39 1142. Paper 7/04289B Received 18th June 1997 Accepted 21st July 1997 J. Chem. Soc. Perkin Trans. 1 1997 2807 2-Aminobuta-1,3-dienes as annulation reagents for 4-quinolones and benzothiopyran-4-ones an attractive route for the highly diastereoselective synthesis of acridine- and thioxanthene-derivatives Uwe Beifuss * and Michael Taraschewski Institut fuuml;r Organische Chemie der Georgndash;Augustndash;Universitauml;t Gouml;ttingen Tammannstrasse 2 D-37077 Gouml;ttingen Germany Enamines regioselectively add to the C N1-bond of 4-silyloxyquinolinium triflates with high yields and the BF3?Et2O mediated annulations of 4-quinolones with 2-aminobuta- 1,3-dienes proceed with high diastereoselectivity to give substituted 1,2,3,4,4a,9,9a,10-octahydroacridine-3,9-dione derivatives; 4-silyloxy-1-benzothiopyrylium triflates and benzothiopyran-4-ones behave analogously.Over the last few years there has been a considerable interest in reactions with 2-aminobuta-1,3-dienes,1 since it was shown that they can be employed as dienes in intermolecular Dielsndash;Alder reactions 2 to yield the corresponding cyclization products with high diastereo- and enantio-selectivity.In most examples reported so far the 2-aminobuta-1,3-dienes have been used in hetero Dielsndash;Alder reactions with C S C O CN and N N dienophiles 3 and in homo Dielsndash;Alder reactions with nitroolefins as dienophiles.3c,4 Here we report on the first examples of the highly diastereoselective annulation of 4-quinolones and benzothiopyran-4-ones with 2-aminobuta-1,3-dienes. Recently we have found that nucleophiles like silyl enol ethers and organometallic reagents undergo regioselective 1,2- additions to the C N1-bond of 4-silyloxyquinolinium triflates 2 (X = NR)5a and the C S1-bond of 4-silyloxy-1-benzothiopyrylium triflates 2 (X = S) (Scheme 1).5b Furthermore it was demonstrated that these positively charged heteroaromatic systems can be annulated in a highly regio- and diastereoselective manner employing unsubstituted as well as 3-monoand 3,4-disubstituted 2-silyloxybuta-1,3-dienes.6 To further explore the reactivity of 4-quinolones 1 (X = NR) and the corresponding 4-silyloxyquinolinium triflates 2 (X = NR) their reactions with enamines and 2-aminobuta-1,3- Scheme 1 Reagents and conditions i 1 (1.0 equiv.) TIPSOTf (1.1 equiv.) room temp.1 h; ii CH2Cl2 3 (2.0 equiv.) room temp. 30ndash;60 min; iii camphorsulfonic acid (1.0 equiv.) CH2Cl2 room temp. 2ndash;3 h 89 (5a); 76 (5b); 93 (5c) X O X OTIPS + TfOndash; NR2 + i 1 2 3 X O O X OTIPS O 2cent; ii iii 1,2,4,5 a X = NCO2Et b X = NCbz c X = S 3 a NR2 = morpholino b NR2 = piperidino c NR2 = pyrrolidino 5 4 dienes were investigated. It was found that reaction of the Nprotected 4-silyloxyquinolinium triflates 2a,b with the enamines 3andash;c proceeds via 1,2-addition to the C N1 bond to give exclusively adducts 4a,b in high yields (Scheme 1 Table 1).dagger; The products were isolated as mixtures of their syn- and antidiastereomers with ratios varying from 1.7 1.0 to 3.4 1.0 but so far the relative stereochemistry of the diastereomeric 1,2- addition products 4a,b has not been established beyond any doubt.By performing the reaction of the benzothiopyrylium triflate 2c with 3a which yields syn-4c and anti-4c in a 1.0 2.1 ratio (Scheme 1 Table 1) it was demonstrated that the 1,2- additions with enamines are not restricted to quinolinium salts. It is remarkable however that in order to obtain high yields of the 1,2-adducts it is necessary (a) to run the reactions in the absence of any bases like 2,6-lutidine and (b) to avoid aqueous work up.The hydrolysis of the silyl enol ethers 4 could easily be achieved by using camphorsulfonic acid (CSA) (Scheme 1). In addition the diastereomeric keto silyl enol ethers syn-4a and anti-4a were hydrolyzed separately and it was found that under these conditions no isomerization occurred at C-29. Surprisingly no reaction was observed when the 4-silyloxyquinolinium triflates 2 and the 2-aminobuta-1,3-dienes 6 were reacted under the conditions that had been established for the 1,2-addition process (Scheme 2). After some experimentation it was discovered that the annulation could be achieved Scheme 2 Reagents and conditions i 1 (1.0 equiv.) CH2Cl2 BF3?Et2O (1.0 equiv.) then 6 (1.5 equiv.) room temp. 60 min 1 a X = NCO2Et b X = NCbz c X = S 6 a R = Pri b R = But c R = c-C6H11 N R X N O H R H X O O H R H 1 + i 6 7 8 7,8 a R = Pri X = NCO2Et b R = But X = NCO2Et c R = c-C6H11 X = NCO2Et d R = Pri X = NCbz f R = c-C6H11 X = NCbz g R = Pri X = S dagger; Satisfactory analytical (combustion and/or high-resolution mass) and spectral (UV IR NMR and MS) data were obtained for all compounds.2808 J. Chem. Soc. Perkin Trans. 1 1997 when 4-quinolones 1 instead of the 4-silyloxyquinolinium tri- flates 2 were reacted with the 2-aminobuta-1,3-dienes 6 and BF3?Et2O as a Lewis acid. Best results were obtained with 1.1 equiv. of BF3?Et2O in CH2Cl2 at room temperature. Under these conditions the reaction of the N-ethoxycarbonylprotected 4-quinolone 1a with the 4-isopropyl-substituted 2- aminobuta-1,3-diene 6a yielded the cis,cis-1,2,3,4,4a,9,9a,10- octahydroacridine-3,9-dione 8a with three stereogenic centers exclusively in 74 yield.Dagger; The reaction of 1a with the 4-tertbutyl- and the 4-cyclohexyl-substituted 2-aminobuta-1,3-dienes 6b and 6c gave the corresponding annulation products 8b and 8c in diastereomeric pure form (Table 2 entries 1ndash;3; Scheme 2).Similar results were obtained in the annulation of 6a and 6c with the N-benzyloxycarbonyl (Cbz)-protected 4-quinolone 1b (Table 2 entries 4 6; Scheme 2). No product though was formed in the reaction of 1b with the 4-tert-butyl-substituted 2- aminobuta-1,3-diene 6b (Table 2 entry 5; Scheme 2). It is interesting to note that the transformations cannot be performed with the N-methyl- and the unprotected 4-quinolones. This type of annulation process is not restricted to quinolones but can also be used for the synthesis of thioxanthene-3,9-dione derivatives as was demonstrated by the reaction of 1c with 6a.Here the diastereomerically pure cis,cis-annulation product 8g was isolated in 72 yield (Table 2 entry 7; Scheme 2). The structural elucidation of the cyclization products was mainly based on NMR studies. For example 1H NMR- and 2D-COSY-experiments allowed an unambiguous configurational assignment of 8a.sect; In addition an X-ray crystal structure analysis could be obtained for 8a.para; The transformations may either proceed as more or less concerted intermolecular Dielsndash;Alder reactions with normal electron demand or as anionic Domino processes,6,7 where in the first step an inter- Table 1 Formation of 4 by 1,2-addition of enamines 3 to positively charged aromatic heterocyclic systems 2 Entry 1 2 3 4 5 1 2 a a a b c X NCO2Et NCO2Et NCO2Et NCbz S 3 a b c a a NR2 morpholino piperidino pyrrolidino morpholino morpholino 4 a a a b c Yield a 4 () 81 86 84 87 93 a After column chromatography.Table 2 Diastereoselective formation of annulation products 8 by reaction of 1 with 2-aminobuta-1,3-dienes 6 Entry 1 2 3 4 5 6 7 1 a a a b b b c X NCO2Et NCO2Et NCO2Et NCbz NCbz NCbz S 6 a b c a b c a R Pri But c-C6H11 Pri But c-C6H11 Pri 8 a b c d e f g Yield a 8 () 74 31 65 54 mdash; 63 72 a After column chromatography. Dagger; General procedure for the synthesis of 8 boron trifluoridendash;diethyl ether (1.1 mmol) and a 2-aminobuta-1,3-diene 6 (1.5 mmol) were successively added to a stirred solution of 1 (1.0 mmol) in dry dichloromethane (15 cm3) under argon at room temperature.The reaction mixture was stirred for 1 h at room temperature. After quenching the reaction by addition of saturated aq. sodium hydrogen carbonate (5 cm3) and further stirring for 10 min at room temperature the aqueous phase was extracted twice with dichloromethane (2 times; 5 cm3). The combined organic layers were dried over sodium sulfate the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel with ethyl acetatendash;light petroleum (bp 40ndash;60 8C) (1 4) as eluent to yield the annulation product 8. In addition starting material 1 and unidentified decomposition products could be isolated as side products. No diastereomeric annulation products 8 were found. molecular 1,4-addition of the enamine to the vinylogous amide takes place.This is followed by an intramolecular 1,4-addition of the enolate to the conjugated iminium ionmdash;both newly formed in the first addition step. Apart from the high diastereoselectivity of the process it is clearly an advantage that the hydrolysis of the enamines 7 which are believed to occur as intermediates needs no extra step but simply takes place under aqueous work-up conditions.Dagger; The 2-aminobuta-1,3-dienes 6 were prepared in accordance with the procedures published by Enders et al.3a and Barluenga et al.,8 and the N-protected 4- quinolones 1a,b were obtained by standard procedures.9 For further transformations it was necessary to know whether the two keto groups formed during the annulation process could easily by discriminated. For this purpose the acetalization of 8a and 9 (9 could be obtained by hydrogenolytic cleavage of the Cbz group in 8d) (H2 Pd/C 80) was investigated.It was found that acetalization of both 8a and 9 proceeded exclusively at C-3 to yield 10a,b (Scheme 3). These results demonstrate the different reactivity of the two keto functions. Under these reaction conditions no isomerization took place at C-9a. Further work is now directed to the synthesis of enantiomerically pure annulation products using 2-aminobuta- 1,3-dienes of C2-chiral amines.10 In summary we have established that substituted 2-amino- Scheme 3 Reagents and conditions i CSA (2.0ndash;5.0 equiv.) R2OH room temp. 30ndash;60 min N O O H H R1 N O H H R1 OR2 OR2 9a i 8a R1 = CO2Et 9 R1 = H 10a R1 = CO2Et R2 = Et 10b R1 = H R2 = Me 78 80 sect; Selected data for 8a dH(300 MHz; C6D6; Me4Si; J in Hz) 0.66 d 3JCH3 CH 6.5 6H CH(CH3)2 0.83 (ddt 3J1-H CH 10.0 3J1-H 2-Hax 14.0 3J1-H 2-Heq 3.5 3J1-H 9a-H 3.5 1H 1-H) 0.96 (t 3JCH2 CH3 7.0 3H CO2CH2CH3) 2.13 (dd 2J4-Hax 4-Heq 15.0 3J4-Hax 4a-H 13.0 1H 4-Hax) 2.18 (dd 2J2-Hax 2-Heq 16.5 3J2-Hax 1-H 14.0 1H 2-Hax) 2.36ndash;2.49 (m 2H 2-Heq 4-Heq) 2.57 (dseptet 3JCH 1-H 10.0 3JCH CH3 6.5 1H 29-H) 2.98 (m 1H 9a-H) 3.96ndash;4.08 (m 2H CO2CH2CH3) 4.90 (dt 3J4a-H 4-Hax 13.0 3J4a-H 4-Heq 5.0 3J4a-H 9a-H 5.0 1H 4a-H) 6.78 (dt 3J7-H 6-H 7.5 3J7-H 8-H 7.5 4J7-H 5-H 1.0 1H 7-H) 7.25 (ddd 3J6-H 5-H 7.5 3J6-H 7-H 8.5 4J6-H 8-H 2.0 1H 6-H) 8.11 (d 3J5-H 6-H 9.0 1H 5-H) 8.14 (dd 3J8-H 7-H 7.5 4J8-H 6-H 1.5 1H 8-H); dC(75 MHz; C6D6; Me4Si) 14.31 (CO2CH2- CH3) 21.13 CH(CH3)2 21.66 CH(CH3)2 30.04 CH(CH3)2 41.80 (C-2) 41.88 (C-4) 44.91 (C-1) 47.30 (C-9a) 56.26 (C-4a) 62.72 (CO2CH2CH3) 123.33 (C-5) 123.70 (C-7) 124.24 (C-8a) 127.39 (C-8) 134.64 (C-6) 140.65 (C-10a) 153.30 (CO2CH2CH3) 193.51 (C-9) 204.99 (C-3).para; Crystal structure solution and refinement diffraction data were collected on a Siemensndash;Stoe AED four-circle diffractometer at 183 K with Mo-Ka radiation (l = 0.710 73 Aring;). The structure was solved by direct methods with SHELX-86 and refined by full-matrix least-squares on F2 (SHELX-93). Non-hydrogen atoms were refined anisotropically and hydrogen atoms inserted in calculated positions. Crystal data C19H23NO4 M = 329.38 triclinic space group P1� a = 932.3(10) b = 1189.7(10) c = 1668(2) pm a = 107.42(10) b = 91.05(5) g = 95.61(6)8 V = 1.754(3) nm3 Z = 4 Dc = 1.247 Mg m23 mcalc = 0.087 mm21 F(000) = 704 crystal size 1.0 times; 1.0 times; 1.0 mm 5533 collected reflections 4022 independent reflection goodness of fit 1.068 refinement converged for all data with R = 0.0542 and Rw = 0.1360.Atomic coordinates bond lengths bond angles and displacement parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC). See Instructions for Authors J. Chem. Soc. Perkin Trans. 1 1997 Issue 1. Any request to the CCDC for this material should quote the full literature citation and the reference number 207/140. The single X-ray analysis of 8a was performed by Dr M. Noltemeyer and H.-G. Schmidt (Institut fuuml;r Anorganische Chemie Tammannstr. 4 D-37077 Gouml;ttingen Germany). J. Chem. Soc. Perkin Trans. 1 1997 2809 buta-1,3-dienes can be used for the highly diastereoselective annulation of 4-quinolones and benzothiopyran-4-ones.Furthermore it was demonstrated that enamines serve as nucleophiles for the regioselective 1,2-addition to 4-silyloxyquinolinium triflates and 4-silyloxybenzothiopyrylium triflates. Acknowledgements This work was supported by the Georgndash;Augustndash;Universitauml;t Gouml;ttingen and the Fonds der Chemischen Industrie Frankfurt am Main. We thank 3M Neuss and Huuml;ls AG Marl for chemicals. References 1 Reviews D. Enders and O. Meyer Liebigs Ann. Chem. 1996 1023; K. Krohn Angew. Chem. 1993 105 1651; Angew. Chem. Int. Ed. Engl. 1993 32 1582. 2 W. Carruthers Cycloaddition Reactions in Organic Synthesis Pergamon Oxford 1990; F. Fringuelli and A. Taticchi Dienes in the Diels-Alder Reaction Wiley New York 1990. 3 (a) D. Enders O. Meyer G. Raabe and J.Runsink Synthesis 1994 66; (b) J. Barluenga F. Aznar C. Ribas C. Valdeacute;s M. Fernaacute;ndez M.-P. Caball and J. Trujillo Chem. Eur. J. 1996 2 805; (c) J. Barluenga F. Aznar C. Valdeacute;s A. Martiacute;n S. Garciacute;a-Granda and E. Martiacute;n J. Am. Chem. Soc. 1993 115 4403; (d ) J. Barluenga F. Aznar C. Valdeacute;s and M.-P. Cabal J. Org. Chem. 1993 58 3391; (e) J. Barluenga F. Aznar and C. Valdeacute;s Synlett 1991 487; ( f ) J. Barluenga F. Aznar M.-P. Cabal and C. Valdeacute;s J. Chem. Soc. Perkin Trans. 1 1990 633; (g) J. Barluenga F. Aznar C. Valdeacute;s and F. L. Ortiz Tetrahedron Lett. 1990 31 5237; (h) J. Barluenga F. Aznar M.-P. Cabal F. H. Cano and M. D. L. C. Foces-Foces J. Chem. Soc. Chem. Commun. 1988 1247; (i) J. Barluenga Bull. Soc. Chim. Belg. 1988 97 545. 4 (a) D. Enders O. Meyer and G. Raabe Synthesis 1992 1242; (b) A.Mezzetti P. Nitti G. Pitacco and E. Valentin Tetrahedron 1985 41 1415; (c) F. Benedetti G. Pitacco and E. Valentin Tetrahedron 1979 35 2293; (d) R. A. Ferri G. Pitacco and E. Valentin Tetrahedron 1978 34 2537; (e) G. Pitacco A. Risaliti M. L. Trevisan and E. Valentin Tetrahedron 1977 33 3145. 5 (a) U. Beifuss and S. Ledderhose Synlett 1997 313; (b) U. Beifuss M. Tietze and H. Gehm Synlett 1996 182. 6 (a) U. Beifuss and S. Ledderhose Synlett 1995 938; (b) U. Beifuss H. Gehm M. Noltemeyer and H.-G. Schmidt Angew. Chem. 1995 107 705; Angew. Chem. Int. Ed. Engl. 1995 34 647; (c) U. Beifuss and H. Gehm Phosphorus Sulfur Silicon Relat. Elem. 1994 95 and 96 339. 7 Reviews L. F. Tietze Chem. Rev. 1996 96 115; L. F. Tietze and U. Beifuss Angew. Chem. 1993 105 137; Angew. Chem.Int. Ed. Engl. 1993 32 131. 8 J. Barluenga I. Merino and F. Palacios Tetrahedron Lett. 1990 31 6713. 9 P. J. Kocienski Protecting Groups Thieme Stuttgart 1994. 10 Reviews J. K. Whitesell Chem. Rev. 1989 89 1581; H. Waldmann Nachr. Chem. Tech. Lab. 1991 39 1142. Paper 7/04289B Received 18th June 1997 Accepted 21st July 1997 J. Chem. Soc. Perkin Trans. 1 1997 2807 2-Aminobuta-1,3-dienes as annulation reagents for 4-quinolones and benzothiopyran-4-ones an attractive route for the highly diastereoselective synthesis of acridine- and thioxanthene-derivatives Uwe Beifuss * and Michael Taraschewski Institut fuuml;r Organische Chemie der Georgndash;Augustndash;Universitauml;t Gouml;ttingen Tammannstrasse 2 D-37077 Gouml;ttingen Germany Enamines regioselectively add to the C N1-bond of 4-silyloxyquinolinium triflates with high yields and the BF3?Et2O mediated annulations of 4-quinolones with 2-aminobuta- 1,3-dienes proceed with high diastereoselectivity to give substituted 1,2,3,4,4a,9,9a,10-octahydroacridine-3,9-dione derivatives; 4-silyloxy-1-benzothiopyrylium triflates and benzothiopyran-4-ones behave analogously.Over the last few years there has been a considerable interest in reactions with 2-aminobuta-1,3-dienes,1 since it was shown that they can be employed as dienes in intermolecular Dielsndash;Alder reactions 2 to yield the corresponding cyclization products with high diastereo- and enantio-selectivity. In most examples reported so far the 2-aminobuta-1,3-dienes have been used in hetero Dielsndash;Alder reactions with C S C O C N and N N dienophiles 3 and in homo Dielsndash;Alder reactions with nitroolefins as dienophiles.3c,4 Here we report on the first examples of the highly diastereoselective annulation of 4-quinolones and benzothiopyran-4-ones with 2-aminobuta-1,3-dienes.Recently we have found that nucleophiles like silyl enol ethers and organometallic reagents undergo regioselective 1,2- additions to the C N1-bond of 4-silyloxyquinolinium triflates 2 (X = NR)5a and the C S1-bond of 4-silyloxy-1-benzothiopyrylium triflates 2 (X = S) (Scheme 1).5b Furthermore it was demonstrated that these positively charged heteroaromatic systems can be annulated in a highly regio- and diastereoselective manner employing unsubstituted as well as 3-monoand 3,4-disubstituted 2-silyloxybuta-1,3-dienes.6 To further explore the reactivity of 4-quinolones 1 (X = NR) and the corresponding 4-silyloxyquinolinium triflates 2 (X = NR) their reactions with enamines and 2-aminobuta-1,3- Scheme 1 Reagents and conditions i 1 (1.0 equiv.) TIPSOTf (1.1 equiv.) room temp.1 h; ii CH2Cl2 3 (2.0 equiv.) room temp. 30ndash;60 min; iii camphorsulfonic acid (1.0 equiv.) CH2Cl2 room temp. 2ndash;3 h 89 (5a); 76 (5b); 93 (5c) X O X OTIPS + TfOndash; NR2 + i 1 2 3 X O O X OPS O 2cent; ii iii 1,2,4,5 a X = NCO2Et b X = NCbz c X = S 3 a NR2 = morpholino b NR2 = piperidino c NR2 = pyrrolidino 5 4 dienes were investigated. It was found that reaction of the Nprotected 4-silyloxyquinolinium triflates 2a,b with the enamines 3andash;c proceeds via 1,2-addition to the C N1 bond to give exclusively adducts 4a,b in high yields (Scheme 1 Table 1).dagger; The products were isolated as mixtures of their syn- and antidiastereomers with ratios varying from 1.7 1.0 to 3.4 1.0 but so far the relative stereochemistry of the diastereomeric 1,2- addition products 4a,b has not been established beyond any doubt.By performing the reaction of the benzothiopyrylium triflate 2c with 3a which yields syn-4c and anti-4c in a 1.0 2.1 ratio (Scheme 1 Table 1) it was demonstrated that the 1,2- additions with enamines are not restricted to quinolinium salts. It is remarkable however that in order to obtain high yields of the 1,2-adducts it is necessary (a) to run the reactions in the absence of any bases like 2,6-lutidine and (b) to avoid aqueous work up. The hydrolysis of the silyl enol ethers 4 could easily be achieved by using camphorsulfonic acid (CSA) (Scheme 1). In addition the diastereomeric keto silyl enol ethers syn-4a and anti-4a were hydrolyzed separately and it was found that under these conditions no isomerization occurred at C-29.Surprisingly no reaction was observed when the 4-silyloxyquinolinium triflates 2 and the 2-aminobuta-1,3-dienes 6 were reacted under the conditions that had been established for the 1,2-addition process (Scheme 2). After some experimentation it was discovered that the annulation could be achieved Scheme 2 Reagents and conditions i 1 (1.0 equiv.) CH2Cl2 BF3?Et2O (1.0 equiv.) then 6 (1.5 equiv.) room temp. 60 min 1 a X = NCO2Et b X = NCbz c X = S 6 a R = Pri b R = But c R = c-C6H11 N R X N O H R H X O O H R H 1 + i 6 7 8 7,8 a R = Pri X = NCO2Et b R = But X = NCO2Et c R = c-C6H11 X = NCO2Et d R = Pri X = NCbz f R = c-C6H11 X = NCbz g R = Pri X = S dagger; Satisfactory analytical (combustion and/or high-resolution mass) and spectral (UV IR NMR and MS) data were obtained for all compounds.2808 J. Chem. Soc. Perkin Trans. 1 1997 when 4-quinolones 1 instead of the 4-silyloxyquinolinium tri- flates 2 were reacted with the 2-aminobuta-1,3-dienes 6 and BF3?Et2O as a Lewis acid. Best results were obtained with 1.1 equiv. of BF3?Et2O in CH2Cl2 at room temperature. Under these conditions the reaction of the N-ethoxycarbonylprotected 4-quinolone 1a with the 4-isopropyl-substituted 2- aminobuta-1,3-diene 6a yielded the cis,cis-1,2,3,4,4a,9,9a,10- octahydroacridine-3,9-dione 8a with three stereogenic centers exclusively in 74 yield.Dagger; The reaction of 1a with the 4-tertbutyl- and the 4-cyclohexyl-substituted 2-aminobuta-1,3-dienes 6b and 6c gave the corresponding annulation products 8b and 8c in diastereomeric pure form (Table 2 entries 1ndash;3; Scheme 2).Similar results were obtained in the annulation of 6a and 6c with the N-benzyloxycarbonyl (Cbz)-protected 4-quinolone 1b (Table 2 entries 4 6; Scheme 2). No product though was formed in the reaction of 1b with the 4-tert-butyl-substituted 2- aminobuta-1,3-diene 6b (Table 2 entry 5; Scheme 2). It is interesting to note that the transformations cannot be performed with the N-methyl- and the unprotected 4-quinolones. This type of annulation process is not restricted to quinolones but can also be used for the synthesis of thioxanthene-3,9-dione derivatives as was demonstrated by the reaction of 1c with 6a. Here the diastereomerically pure cis,cis-annulation product 8g was isolated in 72 yield (Table 2 entry 7; Scheme 2).The structural elucidation of the cyclization products was mainly based on NMR studies. For example 1H NMR- and 2D-COSY-experiments allowed an unambiguous configurational assignment of 8a.sect; In addition an X-ray crystal structure analysis could be obtained for 8a.para; The transformations may either proceed as more or less concerted intermolecular Dielsndash;Alder reactions with normal electron demand or as anionic Domino processes,6,7 where in the first step an inter- Table 1 Formation of 4 by 1,2-addition of enamines 3 to positively charged aromatic heterocyclic systems 2 Entry 1 2 3 4 5 1 2 a a a b c X NCO2Et NCO2Et NCO2Et NCbz S 3 a b c a a NR2 morpholino piperidino pyrrolidino morpholino morpholino 4 a a a b c Yield a 4 () 81 86 84 87 93 a After column chromatography.Table 2 Diastereoselective formation of annulation products 8 by reaction of 1 with 2-aminobuta-1,3-dienes 6 Entry 1 2 3 4 5 6 7 1 a a a b b b c X NCO2Et NCO2Et NCO2Et NCbz NCbz NCbz S 6 a b c a b c a R Pri But c-C6H11 Pri But c-C6H11 Pri 8 a b c d e f g Yield a 8 () 74 31 65 54 mdash; 63 72 a After column chromatography. Dagger; General procedure for the synthesis of 8 boron trifluoridendash;diethyl ether (1.1 mmol) and a 2-aminobuta-1,3-diene 6 (1.5 mmol) were successively added to a stirred solution of 1 (1.0 mmol) in dry dichloromethane (15 cm3) under argon at room temperature. The reaction mixture was stirred for 1 h at room temperature. After quenching the reaction by addition of saturated aq. sodium hydrogen carbonate (5 cm3) and further stirring for 10 min at room temperature the aqueous phase was extracted twice with dichloromethane (2 times; 5 cm3).The combined organic layers were dried over sodium sulfate the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel with ethyl acetatendash;light petroleum (bp 40ndash;60 8C) (1 4) as eluent to yield the annulation product 8. In addition starting material 1 and unidentified decomposition products could be isolated as side products. No diastereomeric annulation products 8 were found. molecular 1,4-addition of the enamine to the vinylogous amide takes place. This is followed by an intramolecular 1,4-addition of the enolate to the conjugated iminium ionmdash;both newly formed in the first addition step. Apart from the high diastereoselectivity of the process it is clearly an advantage that the hydrolysis of the enamines 7 which are believed to occur as intermediates needs no extra step but simply takes place under aqueous work-up conditions.Dagger; The 2-aminobuta-1,3-dienes 6 were prepared in accordance with the procedures published by Enders et al.3a and Barluenga et al.,8 and the N-protected 4- quinolones 1a,b were obtained by standard procedures.9 For further transformations it was necessary to know whether the two keto groups formed during the annulation process could easily by discriminated.For this purpose the acetalization of 8a and 9 (9 could be obtained by hydrogenolytic cleavage of the Cbz group in 8d) (H2 Pd/C 80) was investigated. It was found that acetalization of both 8a and 9 proceeded exclusively at C-3 to yield 10a,b (Scheme 3).These results demonstrate the different reactivity of the two keto functions. Under these reaction conditions no isomerization took place at C-9a. Further work is now directed to the synthesis of enantiomerically pure annulation products using 2-aminobuta- 1,3-dienes of C2-chiral amines.10 In summary we have established that substituted 2-amino- Scheme 3 Reagents and conditions i CSA (2.0ndash;5.0 equiv.) R2OH room temp. 30ndash;60 min N O O H H R1 N O H H R1 OR2 OR2 9a i 8a R1 = CO2Et 9 R1 = H 10a R1 = CO2Et R2 = Et 10b R1 = H R2 = Me 78 80 sect; Selected data for 8a dH(300 MHz; C6D6; Me4Si; J in Hz) 0.66 d 3JCH3 CH 6.5 6H CH(CH3)2 0.83 (ddt 3J1-H CH 10.0 3J1-H 2-Hax 14.0 3J1-H 2-Heq 3.5 3J1-H 9a-H 3.5 1H 1-H) 0.96 (t 3JCH2 CH3 7.0 3H CO2CH2CH3) 2.13 (dd 2J4-Hax 4-Heq 15.0 3J4-Hax 4a-H 13.0 1H 4-Hax) 2.18 (dd 2J2-Hax 2-Heq 16.5 3J2-Hax 1-H 14.0 1H 2-Hax) 2.36ndash;2.49 (m 2H 2-Heq 4-Heq) 2.57 (dseptet 3JCH 1-H 10.0 3JCH CH3 6.5 1H 29-H) 2.98 (m 1H 9a-H) 3.96ndash;4.08 (m 2H CO2CH2CH3) 4.90 (dt 3J4a-H 4-Hax 13.0 3J4a-H 4-Heq 5.0 3J4a-H 9a-H 5.0 1H 4a-H) 6.78 (dt 3J7-H 6-H 7.5 3J7-H 8-H 7.5 4J7-H 5-H 1.0 1H 7-H) 7.25 (ddd 3J6-H 5-H 7.5 3J6-H 7-H 8.5 4J6-H 8-H 2.0 1H 6-H) 8.11 (d 3J5-H 6-H 9.0 1H 5-H) 8.14 (dd 3J8-H 7-H 7.5 4J8-H 6-H 1.5 1H 8-H); dC(75 MHz; C6D6; Me4Si) 14.31 (CO2CH2- CH3) 21.13 CH(CH3)2 21.66 CH(CH3)2 30.04 CH(CH3)2 41.80 (C-2) 41.88 (C-4) 44.91 (C-1) 47.30 (C-9a) 56.26 (C-4a) 62.72 (CO2CH2CH3) 123.33 (C-5) 123.70 (C-7) 124.24 (C-8a) 127.39 (C-8) 134.64 (C-6) 140.65 (C-10a) 153.30 (CO2CH2CH3) 193.51 (C-9) 204.99 (C-3).para; Crystal structure solution and refinement diffraction data were collected on a Siemensndash;Stoe AED four-circle diffractometer at 183 K with Mo-Ka radiation (l = 0.710 73 Aring;).The structure was solved by direct methods with SHELX-86 and refined by full-matrix least-squares on F2 (SHELX-93). Non-hydrogen atoms were refined anisotropically and hydrogen atoms inserted in calculated positions. Crystal data C19H23NO4 M = 329.38 triclinic space group P1� a = 932.3(10) b = 1189.7(10) c = 1668(2) pm a = 107.42(10) b = 91.05(5) g = 95.61(6)8 V = 1.754(3) nm3 Z = 4 Dc = 1.247 Mg m23 mcalc = 0.087 mm21 F(000) = 704 crystal size 1.0 times; 1.0 times; 1.0 mm 5533 collected reflections 4022 independent reflection goodness of fit 1.068 refinement converged for all data with R = 0.0542 and Rw = 0.1360. Atomic coordinates bond lengths bond angles and displacement parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC).See Instructions for Authors J. Chem. Soc. Perkin Trans. 1 1997 Issue 1. Any request to the CCDC for this material should quote the full literature citation and the reference number 207/140. The single X-ray analysis of 8a was performed by Dr M. Noltemeyer and H.-G. Schmidt (Institut fuuml;r Anorganische Chemie Tammannstr. 4 D-37077 Gouml;ttingen Germany). J. Chem. Soc. Perkin Trans. 1 1997 2809 buta-1,3-dienes can be used for the highly diastereoselective annulation of 4-quinolones and benzothiopyran-4-ones. Furthermore it was demonstrated that enamines serve as nucleophiles for the regioselective 1,2-addition to 4-silyloxyquinolinium triflates and 4-silyloxybenzothiopyrylium triflates.Acknowledgements This work was supported by the Georgndash;Augustndash;Universitauml;t Gouml;ttingen and the Fonds der Chemischen Industrie Frankfurt am Main. We thank 3M Neuss and Huuml;ls AG Marl for chemicals. References 1 Reviews D. Enders and O. Meyer Liebigs Ann. Chem. 1996 1023; K. Krohn Angew. Chem. 1993 105 1651; Angew. Chem. Int. Ed. Engl. 1993 32 1582. 2 W. Carruthers Cycloaddition Reactions in Organic Synthesis Pergamon Oxford 1990; F. Fringuelli and A. Taticchi Dienes in the Diels-Alder Reaction Wiley New York 1990. 3 (a) D. Enders O. Meyer G. Raabe and J. Runsink Synthesis 1994 66; (b) J. Barluenga F. Aznar C. Ribas C. Valdeacute;s M. Fernaacute;ndez M.-P. Caball and J. Trujillo Chem. Eur. J. 1996 2 805; (c) J. Barluenga F. Aznar C. Valdeacute;s A. Martiacute;n S. Garciacute;a-Granda and E. Martiacute;n J. Am.Chem. Soc. 1993 115 4403; (d ) J. Barluenga F. Aznar C. Valdeacute;s and M.-P. Cabal J. Org. Chem. 1993 58 3391; (e) J. Barluenga F. Aznar and C. Valdeacute;s Synlett 1991 487; ( f ) J. Barluenga F. Aznar M.-P. Cabal and C. Valdeacute;s J. Chem. Soc. Perkin Trans. 1 1990 633; (g) J. Barluenga F. Aznar C. Valdeacute;s and F. L. Ortiz Tetrahedron Lett. 1990 31 5237; (h) J. Barluenga F. Aznar M.-P. Cabal F. H. Cano and M. D. L. C. Foces-Foces J. Chem. Soc. Chem. Commun. 1988 1247; (i) J. Barluenga Bull. Soc. Chim. Belg. 1988 97 545. 4 (a) D. Enders O. Meyer and G. Raabe Synthesis 1992 1242; (b) A. Mezzetti P. Nitti G. Pitacco and E. Valentin Tetrahedron 1985 41 1415; (c) F. Benedetti G. Pitacco and E. Valentin Tetrahedron 1979 35 2293; (d) R. A. Ferri G. Pitacco and E. Valentin Tetrahedron 1978 34 2537; (e) G.Pitacco A. Risaliti M. L. Trevisan and E. Valentin Tetrahedron 1977 33 3145. 5 (a) U. Beifuss and S. Ledderhose Synlett 1997 313; (b) U. Beifuss M. Tietze and H. Gehm Synlett 1996 182. 6 (a) U. Beifuss and S. Ledderhose Synlett 1995 938; (b) U. Beifuss H. Gehm M. Noltemeyer and H.-G. Schmidt Angew. Chem. 1995 107 705; Angew. Chem. Int. Ed. Engl. 1995 34 647; (c) U. Beifuss and H. Gehm Phosphorus Sulfur Silicon Relat. Elem. 1994 95 and 96 339. 7 Reviews L. F. Tietze Chem. Rev. 1996 96 115; L. F. Tietze and U. Beifuss Angew. Chem. 1993 105 137; Angew. Chem. Int. Ed. Engl. 1993 32 131. 8 J. Barluenga I. Merino and F. Palacios Tetrahedron Lett. 1990 31 6713. 9 P. J. Kocienski Protecting Groups Thieme Stuttgart 1994. 10 Reviews J. K. Whitesell Chem. Rev. 1989 89 1581; H. Waldmann Nachr.Chem. Tech. Lab. 1991 39 1142. Paper 7/04289B Received 18th June 1997 Accepted 21st July 1997 J. Chem. Soc. Perkin Trans. 1 1997 2807 2-Aminobuta-1,3-dienes as annulation reagents for 4-quinolones and benzothiopyran-4-ones an attractive route for the highly diastereoselective synthesis of acridine- and thioxanthene-derivatives Uwe Beifuss * and Michael Taraschewski Institut fuuml;r Organische Chemie der Georgndash;Augustndash;Universitauml;t Gouml;ttingen Tammannstrasse 2 D-37077 Gouml;ttingen Germany Enamines regioselectively add to the C N1-bond of 4-silyloxyquinolinium triflates with high yields and the BF3?Et2O mediated annulations of 4-quinolones with 2-aminobuta- 1,3-dienes proceed with high diastereoselectivity to give substituted 1,2,3,4,4a,9,9a,10-octahydroacridine-3,9-dione derivatives; 4-silyloxy-1-benzothiopyrylium triflates and benzothiopyran-4-ones behave analogously.Over the last few years there has been a considerable interest in reactions with 2-aminobuta-1,3-dienes,1 since it was shown that they can be employed as dienes in intermolecular Dielsndash;Alder reactions 2 to yield the corresponding cyclization products with high diastereo- and enantio-selectivity. In most examples reported so far the 2-aminobuta-1,3-dienes have been used in hetero Dielsndash;Alder reactions with C S C O C N and N N dienophiles 3 and in homo Dielsndash;Alder reactions with nitroolefins as dienophiles.3c,4 Here we report on the first examples of the highly diastereoselective annulation of 4-quinolones and benzothiopyran-4-ones with 2-aminobuta-1,3-dienes. Recently we have found that nucleophiles like silyl enol ethers and organometallic reagents undergo regioselective 1,2- additions to the C N1-bond of 4-silyloxyquinolinium triflates 2 (X = NR)5a and the C S1-bond of 4-silyloxy-1-benzothiopyrylium triflates 2 (X = S) (Scheme 1).5b Furthermore it was demonstrated that these positively charged heteroaromatic systems can be annulated in a highly regio- and diastereoselective manner employing unsubstituted as well as 3-monoand 3,4-disubstituted 2-silyloxybuta-1,3-dienes.6 To further explore the reactivity of 4-quinolones 1 (X = NR) and the corresponding 4-silyloxyquinolinium triflates 2 (X = NR) their reactions with enamines and 2-aminobuta-1,3- Scheme 1 Reagents and conditions i 1 (1.0 equiv.) TIPSOTf (1.1 equiv.) room temp.1 h; ii CH2Cl2 3 (2.0 equiv.) room temp.30ndash;60 min; iii camphorsulfonic acid (1.0 equiv.) CH2Cl2 room temp. 2ndash;3 h 89 (5a); 76 (5b); 93 (5c) X O X OTIPS + TfOndash; NR2 + i 1 2 3 X O O X OTIPS O 2cent; ii iii 1,2,4,5 a X = NCO2Et b X = NCbz c X = S 3 a NR2 = morpholino b NR2 = piperidino c NR2 = pyrrolidino 5 4 dienes were investigated. It was found that reaction of the Nprotected 4-silyloxyquinolinium triflates 2a,b with the enamines 3andash;c proceeds via 1,2-addition to the C N1 bond to give exclusively adducts 4a,b in high yields (Scheme 1 Table 1).dagger; The products were isolated as mixtures of their syn- and antidiastereomers with ratios varying from 1.7 1.0 to 3.4 1.0 but so far the relative stereochemistry of the diastereomeric 1,2- addition products 4a,b has not been established beyond any doubt. By performing the reaction of the benzothiopyrylium triflate 2c with 3a which yields syn-4c and anti-4c in a 1.0 2.1 ratio (Scheme 1 Table 1) it was demonstrated that the 1,2- additions with enamines are not restricted to quinolinium salts.It is remarkable however that in order to obtain high yields of the 1,2-adducts it is necessary (a) to run the reactions in the absence of any bases like 2,6-lutidine and (b) to avoid aqueous work up. The hydrolysis of the silyl enol ethers 4 could easily be achieved by using camphorsulfonic acid (CSA) (Scheme 1). In addition the diastereomeric keto silyl enol ethersyn-4a and anti-4a were hydrolyzed separately and it was found that under these conditions no isomerization occurred at C-29. Surprisingly no reaction was observed when the 4-silyloxyquinolinium triflates 2 and the 2-aminobuta-1,3-dienes 6 were reacted under the conditions that had been established for the 1,2-addition process (Scheme 2).After some experimentation it was discovered that the annulation could be achieved Scheme 2 Reagents and conditions i 1 (1.0 equiv.) CH2Cl2 BF3?Et2O (1.0 equiv.) then 6 (1.5 equiv.) room temp. 60 min 1 a X = NCO2Et b X = NCbz c X = S 6 a R = Pri b R = But c R = c-C6H11 N R X N O H R H X O O H R H 1 + i 6 7 8 7,8 a R = Pri X = NCO2Et b R = But X = NCO2Et c R = c-C6H11 X = NCO2Et d R = Pri X = NCbz f R = c-C6H11 X = NCbz g R = Pri X = S dagger; Satisfactory analytical (combustion and/or high-resolution mass) and spectral (UV IR NMR and MS) data were obtained for all compounds. 2808 J. Chem. Soc. Perkin Trans. 1 1997 when 4-quinolones 1 instead of the 4-silyloxyquinolinium tri- flates 2 were reacted with the 2-aminobuta-1,3-dienes 6 and BF3?Et2O as a Lewis acid.Best results were obtained with 1.1 equiv. of BF3?Et2O in CH2Cl2 at room temperature. Under these conditions the reaction of the N-ethoxycarbonylprotected 4-quinolone 1a with the 4-isopropyl-substituted 2- aminobuta-1,3-diene 6a yielded the cis,cis-1,2,3,4,4a,9,9a,10- octahydroacridine-3,9-dione 8a with three stereogenic centers exclusively in 74 yield.Dagger; The reaction of 1a with the 4-tertbutyl- and the 4-cyclohexyl-substituted 2-aminobuta-1,3-dienes 6b and 6c gave the corresponding annulation products 8b and 8c in diastereomeric pure form (Table 2 entries 1ndash;3; Scheme 2). Similar results were obtained in the annulation of 6a and 6c with the N-benzyloxycarbonyl (Cbz)-protected 4-quinolone 1b (Table 2 entries 4 6; Scheme 2).No product though was formed in the reaction of 1b with the 4-tert-butyl-substituted 2- aminobuta-1,3-diene 6b (Table 2 entry 5; Scheme 2). It is interesting to note that the transformations cannot be performed with the N-methyl- and the unprotected 4-quinolones. This type of annulation process is not restricted to quinolones but can also be used for the synthesis of thioxanthene-3,9-dione derivatives as was demonstrated by the reaction of 1c with 6a. Here the diastereomerically pure cis,cis-annulation product 8g was isolated in 72 yield (Table 2 entry 7; Scheme 2). The structural elucidation of the cyclization products was mainly based on NMR studies. For example 1H NMR- and 2D-COSY-experiments allowed an unambiguous configurational assignment of 8a.sect; In addition an X-ray crystal structure analysis could be obtained for 8a.para; The transformations may either proceed as more or less concerted intermolecular Dielsndash;Alder reactions with normal electron demand or as anionic Domino processes,6,7 where in the first step an inter- Table 1 Formation of 4 by 1,2-addition of enamines 3 to positively charged aromatic heterocyclic systems 2 Entry 1 2 3 4 5 1 2 a a a b c X NCO2Et NCO2Et NCO2Et NCbz S 3 a b c a a NR2 morpholino piperidino pyrrolidino morpholino morpholino 4 a a a b c Yield a 4 () 81 86 84 87 93 a After column chromatography.Table 2 Diastereoselective formation of annulation products 8 by reaction of 1 with 2-aminobuta-1,3-dienes 6 Entry 1 2 3 4 5 6 7 1 a a a b b b c X NCO2Et NCO2Et NCO2Et NCbz NCbz NCbz S 6 a b c a b c a R Pri But c-C6H11 Pri But c-C6H11 Pri 8 a b c d e f g Yield a 8 () 74 31 65 54 mdash; 63 72 a After column chromatography.Dagger; General procedure for the synthesis of 8 boron trifluoridendash;diethyl ether (1.1 mmol) and a 2-aminobuta-1,3-diene 6 (1.5 mmol) were successively added to a stirred solution of 1 (1.0 mmol) in dry dichloromethane (15 cm3) under argon at room temperature. The reaction mixture was stirred for 1 h at room temperature. After quenching the reaction by addition of saturated aq. sodium hydrogen carbonate (5 cm3) and further stirring for 10 min at room temperature the aqueous phase was extracted twice with dichloromethane (2 times; 5 cm3). The combined organic layers were dried over sodium sulfate the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel with ethyl acetatendash;light petroleum (bp 40ndash;60 8C) (1 4) as eluent to yield the annulation product 8.In addition starting material 1 and unidentified decomposition products could be isolated as side products. No diastereomeric annulation products 8 were found. molecular 1,4-addition of the enamine to the vinylogous amide takes place. This is followed by an intramolecular 1,4-addition of the enolate to the conjugated iminium ionmdash;both newly formed in the first addition step. Apart from the high diastereoselectivity of the process it is clearly an advantage that the hydrolysis of the enamines 7 which are believed to occur as intermediates needs no extra step but simply takes place under aqueous work-up conditions.Dagger; The 2-aminobuta-1,3-dienes 6 were prepared in accordance with the procedures published by Enders et al.3a and Barluenga et al.,8 and the N-protected 4- quinolones 1a,b were obtained by standard procedures.9 For further transformations it was necessary to know whether the two keto groups formed during the annulation process could easily by discriminated.For this purpose the acetalization of 8a and 9 (9 could be obtained by hydrogenolytic cleavage of the Cbz group in 8d) (H2 Pd/C 80) was investigated. It was found that acetalization of both 8a and 9 proceeded exclusively at C-3 to yield 10a,b (Scheme 3). These results demonstrate the different reactivity of the two keto functions. Under these reaction conditions no isomerization took place at C-9a. Further work is now directed to the synthesis of enantiomerically pure annulation products using 2-aminobuta- 1,3-dienes of C2-chiral amines.10 In summary we have established that substituted 2-amino- Scheme 3 Reagents and conditions i CSA (2.0ndash;5.0 equiv.) R2OH room temp.30ndash;60 min N O O H H R1 N O H H R1 OR2 OR2 9a i 8a R1 = CO2Et 9 R1 = H 10a R1 = CO2Et R2 = Et 10b R1 = H R2 = Me 78 80 sect; Selected data for 8a dH(300 MHz; C6D6; Me4Si; J in Hz) 0.66 d 3JCH3 CH 6.5 6H CH(CH3)2 0.83 (ddt 3J1-H CH 10.0 3J1-H 2-Hax 14.0 3J1-H 2-Heq 3.5 3J1-H 9a-H 3.5 1H 1-H) 0.96 (t 3JCH2 CH3 7.0 3H CO2CH2CH3) 2.13 (dd 2J4-Hax 4-Heq 15.0 3J4-Hax 4a-H 13.0 1H 4-Hax) 2.18 (dd 2J2-Hax 2-Heq 16.5 3J2-Hax 1-H 14.0 1H 2-Hax) 2.36ndash;2.49 (m 2H 2-Heq 4-Heq) 2.57 (dseptet 3JCH 1-H 10.0 3JCH CH3 6.5 1H 29-H) 2.98 (m 1H 9a-H) 3.96ndash;4.08 (m 2H CO2CH2CH3) 4.90 (dt 3J4a-H 4-Hax 13.0 3J4a-H 4-Heq 5.0 3J4a-H 9a-H 5.0 1H 4a-H) 6.78 (dt 3J7-H 6-H 7.5 3J7-H 8-H 7.5 4J7-H 5-H 1.0 1H 7-H) 7.25 (ddd 3J6-H 5-H 7.5 3J6-H 7-H 8.5 4J6-H 8-H 2.0 1H 6-H) 8.11 (d 3J5-H 6-H 9.0 1H 5-H) 8.14 (dd 3J8-H 7-H 7.5 4J8-H 6-H 1.5 1H 8-H); dC(75 MHz; C6D6; Me4Si) 14.31 (CO2CH2- CH3) 21.13 CH(CH3)2 21.66 CH(CH3)2 30.04 CH(CH3)2 41.80 (C-2) 41.88 (C-4) 44.91 (C-1) 47.30 (C-9a) 56.26 (C-4a) 62.72 (CO2CH2CH3) 123.33 (C-5) 123.70 (C-7) 124.24 (C-8a) 127.39 (C-8) 134.64 (C-6) 140.65 (C-10a) 153.30 (CO2CH2CH3) 193.51 (C-9) 204.99 (C-3).para; Crystal structure solution and refinement diffraction data were collected on a Siemensndash;Stoe AED four-circle diffractometer at 183 K with Mo-Ka radiation (l = 0.710 73 Aring;). The structure was solved by direct methods with SHELX-86 and refined by full-matrix least-squares on F2 (SHELX-93).Non-hydrogen atoms were refined anisotropically and hydrogen atoms inserted in calculated positions. Crystal data C19H23NO4 M = 329.38 triclinic space group P1� a = 932.3(10) b = 1189.7(10) c = 1668(2) pm a = 107.42(10) b = 91.05(5) g = 95.61(6)8 V = 1.754(3) nm3 Z = 4 Dc = 1.247 Mg m23 mcalc = 0.087 mm21 F(000) = 704 crystal size 1.0 times; 1.0 times; 1.0 mm 5533 collected reflections 4022 independent reflection goodness of fit 1.068 refinement converged for all data with R = 0.0542 and Rw = 0.1360. Atomic coordinates bond lengths bond angles and displacement parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC). See Instructions for Authors J. Chem. Soc. Pein Trans. 1 1997 Issue 1. Any request to the CCDC for this material should quote the full literature citation and the reference number 207/140.The single X-ray analysis of 8a was performed by Dr M. Noltemeyer and H.-G. Schmidt (Institut fuuml;r Anorganische Chemie Tammannstr. 4 D-37077 Gouml;ttingen Germany). J. Chem. Soc. Perkin Trans. 1 1997 2809 buta-1,3-dienes can be used for the highly diastereoselective annulation of 4-quinolones and benzothiopyran-4-ones. Furthermore it was demonstrated that enamines serve as nucleophiles for the regioselective 1,2-addition to 4-silyloxyquinolinium triflates and 4-silyloxybenzothiopyrylium triflates. Acknowledgements This work was supported by the Georgndash;Augustndash;Universitauml;t Gouml;ttingen and the Fonds der Chemischen Industrie Frankfurt am Main. We thank 3M Neuss and Huuml;ls AG Marl for chemicals. References 1 Reviews D.Enders and O. Meyer Liebigs Ann. Chem. 1996 1023; K. Krohn Angew. Chem. 1993 105 1651; Angew. Chem. Int. Ed. Engl. 1993 32 1582. 2 W. Carruthers Cycloaddition Reactions in Organic Synthesis Pergamon Oxford 1990; F. Fringuelli and A. Taticchi Dienes in the Diels-Alder Reaction Wiley New York 1990. 3 (a) D. Enders O. Meyer G. Raabe and J. Runsink Synthesis 1994 66; (b) J. Barluenga F. Aznar C. Ribas C. Valdeacute;s M. Fernaacute;ndez M.-P. Caball and J. Trujillo Chem. Eur. J. 1996 2 805; (c) J. Barluenga F. Aznar C. Valdeacute;s A. Martiacute;n S. Garciacute;a-Granda and E. Martiacute;n J. Am. Chem. Soc. 1993 115 4403; (d ) J. Barluenga F. Aznar C. Valdeacute;s and M.-P. Cabal J. Org. Chem. 1993 58 3391; (e) J. Barluenga F. Aznar and C. Valdeacute;s Synlett 1991 487; ( f ) J. Barluenga F. Aznar M.-P. Cabal and C. Valdeacute;s J. Chem.Soc. Perkin Trans. 1 1990 633; (g) J. Barluenga F. Aznar C. Valdeacute;s and F. L. Ortiz Tetrahedron Lett. 1990 31 5237; (h) J. Barluenga F. Aznar M.-P. Cabal F. H. Cano and M. D. L. C. Foces-Foces J. Chem. Soc. Chem. Commun. 1988 1247; (i) J. Barluenga Bull. Soc. Chim. Belg. 1988 97 545. 4 (a) D. Enders O. Meyer and G. Raabe Synthesis 1992 1242; (b) A. Mezzetti P. Nitti G. Pitacco and E. Valentin Tetrahedron 1985 41 1415; (c) F. Benedetti G. Pitacco and E. Valentin Tetrahedron 1979 35 2293; (d) R. A. Ferri G. Pitacco and E. Valentin Tetrahedron 1978 34 2537; (e) G. Pitacco A. Risaliti M. L. Trevisan and E. Valentin Tetrahedron 1977 33 3145. 5 (a) U. Beifuss and S. Ledderhose Synlett 1997 313; (b) U. Beifuss M. Tietze and H. Gehm Synlett 1996 182. 6 (a) U. Beifuss and S. Ledderhose Synlett 1995 938; (b) U.Beifuss H. Gehm M. Noltemeyer and H.-G. Schmidt Angew. Chem. 1995 107 705; Angew. Chem. Int. Ed. Engl. 1995 34 647; (c) U. Beifuss and H. Gehm Phosphorus Sulfur Silicon Relat. Elem. 1994 95 and 96 339. 7 Reviews L. F. Tietze Chem. Rev. 1996 96 115; L. F. Tietze and U. Beifuss Angew. Chem. 1993 105 137; Angew. Chem. Int. Ed. Engl. 1993 32 131. 8 J. Barluenga I. Merino and F. Palacios Tetrahedron Lett. 1990 31 6713. 9 P. J. Kocienski Protecting Groups Thieme Stuttgart 1994. 10 Reviews J. K. Whitesell Chem. Rev. 1989 89 1581; H. Waldmann Nachr. Chem. Tech. Lab. 1991 39 1142. Paper 7/04289B Received 18th June 1997 Accepted 21st July 1997