- Email: [email protected]
Reactions of fluorine-containing 3-oxo esters with aldehydes
Journal of Fluorine Chemistry 117 (2002) 1±7
Reactions of ¯uorine-containing 3-oxo esters with aldehydes M.V. Pryadeinaa, O.G. Kuzuevaa, Ya.V. Burgarta, V.I. Saloutina,*, K.A. Lyssenkob, M.Yu. Antipinb a
Institute of Organic Synthesis, Urals Division, Russian Academy of Sciences, S. Kovalevskoy Str. 20 GSP-147, Ekaterinburg 620219, Russia b Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Str. B-334, Moscow 119991, Russia Received 4 March 2002; received in revised form 15 May 2002; accepted 26 June 2002
Abstract Fluoroalkylcontaining 3-oxo esters react with aldehydes to form 2-benzylidene-3-¯uoroacyl-esters or 4-aryl(alkyl)-3,5-dialkoxycarbonyl2,6-dihydroxy-2,6-di(¯uoroalkyl)tetrahydropyranes depending on the conditions. Ethyl penta¯uorobenzoylacetoacetate with benzaldehyde affords 3,5-diethoxy-carbonyl-4-phenyl-2-penta¯uorophenyl-7,8,9,10-tetra¯uoro-4,5-dihydrobenzo[b]oxacin-6-one. # 2002 Elsevier Science B.V. All rights reserved. Keywords: 3-Oxo ester; Aldehyde; Condensation; Tetrahydropyranes
1. Introduction The reactions of 1,3-dicarbonyl compounds with aldehydes, known as the Knoevenagel condensation, are used widely for synthesis of various products [1]. Interaction of non-¯uorinated 3-oxo esters with aldehydes, depending on the conditions and structure of starting reagents, can result in 2-alkyl(aryl)methylene-3-oxoesters, 2-alkyl(aryl)methylenedi(3-oxoesters) or cyclohexanones [1±3]. Data on the condensation of ¯uorine-containing 3-oxo esters with aldehydes are available only for ethyl tri¯uoroacetoacetate leading to 2-arylmethylene-substituted tri¯uoroacetoacetic esters [4] or 4-aryl-2,6-dihydroxy-3,5-diethoxycarbonyl2,6-di(tri¯uoromethyl)tetrahydropyranes [5]. In this paper, the interaction of ¯uorine-containing 3-oxo esters with aldehydes, usually benzaldehyde, in different conditions are described. 2. Results and discussion 2.1. Synthesis of 2-benzylidene-2-flluoroacyl esters In the present work, it has been found that ¯uoroalkylcontaining 3-oxo esters 1a±g react with an equimolar amount of benzaldehyde in re¯uxing toluene in the presence of piperidine with azeotropic removal of water to form * Corresponding author. Fax: 7-3432-745954. E-mail address: [email protected] (V.I. Saloutin).
2-benzylidene-2-¯uoroacyl esters 2a±g in moderate yields (Scheme 1). Compounds 2a±g may exist in two isomeric forms (Z- and E-isomers regarding the C=C bond). Two sets of identical resonance signals in the 1 H and 19 F NMR spectra of products 2a±g indicate their existence as an equilibrium mixture of Zand E-isomers in all cases. In the IR spectra of esters 2a±g, most absorption bands corresponding to the vibration of carbonyl groups have broad or doublet character that con®rms the presence of two isomers in all cases. The distinction between E- and Z-isomers was made on the basis of the character of the methine proton signals in the 1 H NMR spectra. In each case one of the methine protons signals appeared as a broad singlet, possibly, because of interaction with ¯uorine atoms of the ¯uoroalkyl substituent. It is possible in the case of the Z-isomer only. The 19 F NMR spectrum of 2-benzylidene-substituted tri¯uoroacetoacetate 2b, recorded in CDCl3 with the digital resolution 0.122 Hz, con®rms the existence of such interaction as the tri¯uoromethyl group of the E-isomer is observed as a singlet at 85.99 ppm while that of the Z-isomer is exhibited as a doublet at 90.42 ppm (JF±H 1 Hz). 2.2. Synthesis of 4-alkyl(aryl)-3,5-dialkoxycarbonyl2,6-dihydroxy-2,6-di(fluoroalkyl)tetrahydropyranes When the reactions of ¯uoroalkyl-containing 3-oxo esters 1a±c,e,f,h with aldehydes were carried out in re¯uxing ethanol in the presence of a base (KF or piperidine), the substituted tetrahydropyranes 3a±h were obtained
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 1 4 9 - 5
2
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
Scheme 1.
Scheme 2.
(Scheme 2). Benz-, p-hydroxybenz- and aceticaldehydes were used as aldehyde components. However, two isomeric structures, namely the tetrahydropyrane of type A or the acyclic substituted dialkyl glutarate of type B, are equally probable for these condensation products.
A earlier report on the condensation of ethyl tri¯uoroacetoacetate with benzaldehyde postulated the formation of the corresponding tetrahydropyrane A (Rf CF3 , R1 OEt, R2 Ph) based on elemental analysis and IR spectra only [5]. In the present paper, the hexahydropyrane structure of products 3 was established by NMR spectroscopy and X-ray analysis.
One set of resonance signals for equivalent ester and ¯uoroalkyl groups in the 1 H and 19 F NMR spectra corresponded to the symmetrical structure of tetrahydropyrane 3. In the 1 H NMR spectra appeared resonance signals of protons H4 and H3, H5 as a triplet and a doublet, respectively. That can be explained by the tetrahydropyrane structure only, when two protons H3, H5 are magnetically equivalent and interact with the third non-equivalent proton H4. In the 19 F NMR spectra, signals of ¯uorine atoms at the a-carbon of the ¯uoroalkyl substituent are an AB system that is typical for a ¯uoroalkyl group attached to an asymmetric center. Since the tetrahydropyrane structure 3 contains ®ve contiguous stereocenters (including one pseudochiral center) 16 possible stereoisomers can a priori be envisaged. Examination of the 1 H NMR spectra of 3a±h shows that these products are formed as a single diastereomer (racemic). The observed coupling constants (3 JH4 H3 H5 12:2± 12.5 Hz) corresponding to the trans-axial methine protons (H3, H4, H5), indicate that the phenyl and alkoxycarbonyl groups in tetrahydropyrane 3 occupy the equatorial positions. From literature data, it can be proposed that the ¯uoroalkyl substituent occupies preferentially the equatorial
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
3
Fig. 1. The general view of 3e. The principal bond lengths: O(1)±C(5) 1.406(2), O(1)±C(1) 1.425(2), O(2)±C(1) 1.372(2), O(7)±C(5) 1.394(2), C(1)±C(2) 1.551(3), C(4)±C(5) 1.551(3), C(3)±C(4) 1.539(3), C(2)±C(3) 1.545(3), C(1)±C(6) 1.552(3), C(5)±C(18) 1.545(3), C(2)±C(8) 1.521(3), C(4)±C(16) 1.520(3), Ê ; bond angles: C(5)±O(1)±C(1) 118.3(2), O(2)±C(1)±O(1) 113.0(1), O(2)±C(1)±C(2) C(3)±C(10) 1.530(3), O(5)±C(16) 1.206(3), O(3)±C(8) 1.200(2) A 115.0(2), O(1)±C(1)±C(2) 109.1(2), O(2)±C(1)±C(6) 104.4(2), O(1)±C(1)±C(6) 101.9(1), C(2)±C(1)±C(6) 112.5(2), C(3)±C(2)±C(1) 110.7(2), C(4)±C(3)± C(2) 109.0(1), C(3)±C(4)±C(5) 110.2(1), O(7)±C(5)±O(1) 110.0(2), O(7)±C(5)±C(4) 113.3(2), O(1)±C(5)±C(4) 111.2(2)8.
position [6]. Thus, the above cyclocondensation occurs stereoselectively. Final con®rmation of the relative stereochemistry in hexahydropyrane 3e was obtained by a single-crystal X-ray analysis (Figs. 1 and 2; for details see Section 3). The X-ray investigation of 3e has revealed that tetrahydropyrane is characterized by the chair conformation with the phenyl, methoxycarbonyl and C2F4H groups in equatorial positions and hydroxy groups axial (Fig. 1).
Fig. 2. The scheme illustrating the formation of the H-bonded dimers in Ê, crystal of 3e. The parameters of H-bonds are: H(2O)O(30 ) 2.02 A Ê ; H(7O)O(5) 1.96 A Ê, O(2)H(2O)O(30 ) 1698, O(2)O(30 ) 2.808(2) A Ê. O(7)H(7O)O(5) 1498, O(7)O(5) 2.716(2) A
In spite of the fact that 3e possesses formal Cs symmetry, the analysis of bond lengths and angles has shown signi®cant distortions around the O(1) atom. While the n(O(1))±s(C± OH) interactions must be formally the same for O(2) and O(7) atoms the corresponding C(1)±O(1) and O(1)±C(5) Ê ) are signi®cantly different as bonds (1.425(2), 1.406(2) A well as C(1)±O(2) and C(5)±O(7) bonds (1.372(2), Ê ). It is worth noting that a such difference in 1.394(2) A the bond lengths can not be directly explained by the crystal packing effect because both hydroxy groups participate in the intramolecular (O(7)H(7O)O(5)) and intermolecular (O(2)H(2O)O(30 )) H-bonds of comparable strengths (Figs. 1 and 2). The latter H-bond assembles molecules in centrosymmetric dimers. Thus, the above distortions of the tetrahydropyrane cycle can not be explained in terms of n(O(1))±s(C±OH) interactions. On the other hand, the different types of the H-bonds lead to the different mutual orientation of the OH groups in respect to the endo-cyclic C±O bonds and thus to the distinctions in the interactions of the hydroxy groups lone pairs with the antibonding s-orbitals of C±O(1) bonds. The torsion angles H(2O)O(2)C(1)O(1) and H(7O)O(7)C(5)O(1) (83, 1458) indicate that such interactions with endo-cyclic C±O bonds can occur only in the case of an O(2)H(2O) group which is consistent with the observed shortening of the O(2)±C(1) bond and the elongation of the C(1)±O(1) bond in comparison with the O(7)±C(5) and C(5)±O(1) bonds, respectively. The attempts to dehydrate tetrahydropyranes 3a±h upon re¯uxing in toluene with azeotropic removal of water in the presence of p-toluenesulfonic acid were unsuccessful. Evidently, the tetrahydropyrane structure of these heterocycles is stable due to the presence of the electron-withdrawing
4
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
Scheme 3.
¯uoroalkyl substituents. In addition, the participation of hydroxyl groups in the formation of intra- or intermolecular hydrogen bonds with the ester substituent prevents dehydration. 2.3. Reaction of ethyl pentafluorobenzoylacetoacetate with benzaldehyde The ethyl ester of penta¯uorobenzoylacetic acid 1i with benzaldehyde in re¯uxing ethanol in the presence of KF affords compound 4. In contrast to the spectra of tetrahydropyranes 3, the IR spectrum of 4 is characterized by the absence of an absorption band corresponding to the vibration of an hydroxyl group, while the absorption band at 1625 cm 1 due to the C=C bond vibration is present. The 19 F NMR spectrum has resonance signals of ¯uorine atoms of C6F5 and C6F4 groups in a ratio of 1:1. The 1 H NMR spectrum exhibits doubled resonance signals of non-equivalent ester groups and resonance signals of two methine protons as an AB system (J 11:3 Hz). From these spectral and analytical data, structures of 5,6,7,8-tetra¯uoro-4,2-(1,3-diethoxycarbonyl-2-phenyl-1,3-propylendiyl)-2-penta¯uorophenylbenzo[d]dioxane E or 3,5-diethoxycarbonyl-2-penta¯uorophenyl-4-phenyl-7,8, 9,10-tetra¯uoro-4,5-dihydrobenzo[b]oxacin-6-one D may be proposed for product 4. A possible mechanism of the formation of compoundsD, E is shown in Scheme 3. Evidently, glutarate B is formed as an intermediate for each case. Under reaction conditions, the latter undergoes intramolecular cyclization to afford heterocycle C (path A) or product E (via pyrane A, path
B). The cyclization occurs through intramolecular substitution of the ortho-¯uorine atom in the penta¯uorophenyl substituent byhydroxylgroupandisaccomplishedbyeliminationofHFand H2O (Scheme 3). The distinction between structures D and E was made on the basis of 13 C NMR spectroscopic data. The spectrum exhibited a signal at 190.0 ppm which is typical for a carbonyl atom in structure D. So, the reaction of pentaluorophenylacetylacetate 1i with benzaldehyde occurs via path A to form the substituted benzo[b]oxacinone 4 (D). Thus, in contrast to non-¯uorinated analogues, the ¯uorine-containing 3-oxo esters in the reaction with aldehydes can produce both acyclic non-saturated ketones and heterocyclic products depending on the conditions. 3. Experimental Melting points were measured in open capillaries and are reported uncorrected. Infrared spectra were measured on a Specord 75 IR spectrometer. 1 H and 13 C NMR spectra were recorded on a Bruker DRX-400 instrument (1 H: 400 MHz, using TMS as an internal standard; 13 C: 100 MHz, using TMS as an internal standard). 19 F NMR spectra were recorded on a Tesla BS-587A instrument (75 MHz, using C6F6 as an internal standard). Microanalyses were performed with a Carlo Erba CHNS-O EA 1108 elemental analyzer. Thin-layer chromatography was performed on `Silufol-UV 254' plates.
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
Crystallographic data for 3e: at 110 K C19H18F8O7 Ê, b are triclinic, space group P 1, a 10:131(4) A Ê Ê 10:781(4) A, c 11:522(4) A, a 65:067(8)8, b Ê 3, Z 2, 78:594(8)8, g 63:697(8)8, V 1022:8(6) A 3 M 510:33, dcalc 1:657 g cm , m Mo Ka 1:70 cm 1, F 000 520. Intensities of 7968 re¯ections were measured with a Smart 1000 CCD diffractometer at 110 K Ê , o-scans with 0.38 step in o (l Mo Ka 0:71073 A and 10 s per frame exposure, 2y < 58 ), and 5360 (R int 0:0211) independent re¯ections were used in further re®nement. The structure was solved by direct methods and re®ned by the full-matrix least-squares technique against F2 in the anisotropic±isotropic approximation. The analysis of the Fourier electron density synthesis revealed that two CF2H groups are disordered by two positions with equal occupancies for C(7)F(3)F(4) and with 0.3 and 0.7 occupancies for C(19)F(7)F(8). The hydrogen atoms in the ordered part of the molecule were located from the Fourier density synthesis and were re®ned in isotropic approximation. The re®nement converged to wR2 0:1676 and GOF 1:067 for all independent re¯ections (R1 0:0587 was calculated against F for 3696 observed re¯ections with I > 2 s I. All calculations were performed using SHELXTL PLUS 5.1 on IBM PC AT. Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 179146.1 3.1. Synthesis of 2-benzylidene-3-fluoroacylesters 2a±g A mixture of benzaldehyde (0.21 g, 2.0 mmol), 3-oxo ester 1a±g (2.0 mmol) (Scheme 1) and 1 ml of pyperidine was re¯uxed in toluene for 6 h with azeotropic removal of water. Toluene was removed under reduced pressure. Column chromatography on silicagel (eluantÐbenzene) gave products 2a±g as oils. 3.1.1. Ethyl-2-benzylidene-3-oxo-4, 4-difluorobutanoate (2a) Yield, 52%. 1 H NMR (CDCl3, (Z): E 1:1) Z: d 1.26 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:2 Hz, OCH2 CH3), 6.24 (1H, t, JH F 53:4 Hz, HCF2), 7.42 (5H, m, C6H5), 7.89 (1H, ws, CH); E: d 1.29 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:2 Hz, OCH2 CH3), 6.08 (1H, t, JH F 53:4 Hz, HCF2), 7.45 (5H, m, C6H5), 7.96 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 1:1) Z: d 37.04 (2F, d, JH F 53:4, HCF2); E: d 34.23 (2F, d, JH F 53:4, HCF2) ppm. IR: 3040 (CH), 1720 (C=O), 1690 (CO2Et), 1600±1595 (C=C), 1250±1010 (C±F) cm 1. Analysis: Found: C, 61.27; H, 4.71; F, 15.22. Calc. for C13H12F2O3: C, 61.42; H, 4.76; F, 14.94%. 1
Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: 44-1223/336033; E-mail: [email protected]).
5
3.1.2. Ethyl-2-benzylidene-3-oxo-4,4, 4-trifluorobutanoate (2b) Yield, 54%. 1 H NMR (CDCl3, (Z): E 1:1) Z: d 1.29 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:2 Hz, OCH2 CH3), 7.47 (5H, m, C6H5), 7.81 (1H, ws, CH); E: d 1.32 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.33 (2H, q, J 7:2 Hz, OCH2 CH3); 7.38 (5H, m, C6H5), 7.99 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 1:1) Z: d 85.97 (3F, s); E: d 90.38 (3F, s, CF3) ppm. IR: 3050 (CH), 1730 (C=O), 1700 (CO2Et), 1615±1570 (C=C), 1300±1070 (C±F) cm 1. Analysis: Found: C, 57.11; H, 4.00; F, 20.83. Calc. for C13H11F3O3: C, 57.36; H, 4.07; F, 20.94%. 3.1.3. Ethyl-2-benzylidene-3-oxo-4,4,5, 5-tetrafluoropentanoate (2c) Yield, 53%. 1 H NMR (CDCl3, (Z): E 2:3) Z: d 1.28 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:2 Hz, OCH2 CH3), 6.23 (1H, tt, 2 JH F 52:0, 3 JH F 5:5 Hz, H(CF2)2), 7.39 (5H, m, C6H5), 7.92 (1H, ws, CH); E: d 1.35 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.33 (2H, q, J H H 7:2 Hz, OCH2 CH3), 6.11 (1H, tt, 2 JH F 52:0, 3 JH F 5:5 Hz, H(CF2)2), 7.39 (5H, m, C6H5), 8.01 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 2:3) Z: d 23.04 (2F, m, 2 JH F 52, 3 JH F 5:5 Hz, HCF2 CF2), 41.99 (2F, m, HCF2CF2 ); E: d 23.8 (2F, m, 2 JH F 52:0, 3 JH F 5:5 Hz, HCF2 CF2), 39.40 (2F, m, HCF2CF2 ) ppm. IR: 3045 (CH), 1720 (C=O), 1690 (CO2Et), 1600±1570 (C=C), 1300±1070 (C±F) cm 1. Analysis: Found: C, 55.29; H, 4.19; F, 24.88. Calc. for C14H12F4O3: C, 55.27; H, 3.98; F, 24.98%. 3.1.4. Ethyl-2-benzylidene-3-oxo-4,4,5,5,6,6,7, 7-octafluoroheptanoate (2d) Yield, 40%. 1 H NMR (CDCl3, (Z): E 1:3) Z: d 1.29 (3H, t, J 7:06 Hz, OCH2CH3 ,), 4.33 (2H, q, J 7:06 Hz, OCH2 CH3), 6.28 (1H, tt, 2 JH F 52:0, 3 JH F 5:5 Hz, H(CF2)4), 7.47 (5H, m, C6H5), 7.99 (1H, ws, CH); E: d 1.32 (3H, t, J 7:06 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:06 Hz, OCH2 CH3), 5.99 (1H, tt, 2 JH F 52:0, 3 JH F 5:5 Hz, H(CF2)2), 7.38 (5H, m, C6H5), 7.81 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 1:3) Z: d 48.21 (2F, m, CF2), 40.74 (2F, m, CF2), 33.11 (2F, m, CF2), 24.66 (2F, dm, JH F 52 Hz, HCF2); E: d 45.80 (2F, m, CF2), 38.73 (2F, m, CF2), 32.51 (2F, m, CF2), 24.66 (2F, dm, JH F 52 Hz, HCF2,) ppm. IR: 3045 (CH), 1720 (C=O), 1690 (CO2Et), 1600±1570 (C=C), 1300±1070 (C±F) cm 1. Analysis: Found: C, 47.32; H, 3.31; F, 38.00. Calc. for C16H12F8O3: C, 47.53; H, 2.99; F, 37.60%. 3.1.5. Ethyl-2-benzylidene-3-oxo4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononoate (2e) Yield, 45%. 1 H NMR (CDCl3, (Z): E 3:7) Z: d 1.29 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:2 Hz, OCH2 CH3), 7.54 (5H, m, C6H5), 7.88 (1H, ws, CH); E: d 1.31 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.33 (2H, q, J 7:2 Hz, OCH2 CH3), 7.40 (5H, m, C6H5), 8.60 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 3:7) Z: d 35.05 (2F,
6
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
m, CF2), 39.05 (2F, m, CF2), 40.64 (2F, m, CF2), 40.94 (2F, m, CF2), 48.52 (2F, m, CF2), 81.03 (3F, m, CF3); E: d 35.68 (m, 2F, CF2), 39.05 (2F, m, CF2), 40.23 (2F, m, CF2), 40.63 (2F, m, CF2), 45.76 (2F, m, CF2), 81.03 (3F, m, CF3) ppm. IR: 3030 (CH), 1730 (C=O), 1700 (CO2Et), 1610±1560 (C=C), 1210±1090 (C±F) cm 1. Analysis: Found: C, 41.73; H, 2.05; F, 47.00. Calc. for C18H11F13O3: C, 41.71; H, 2.11; F, 47.02%. 3.1.6. Methyl-2-benzylidene-3-oxo-4,4,5, 5-tetrafluoropentanoate (2f) Yield, 46%. 1 H NMR (CDCl3, (Z): E 1:2) Z: d 3.85 (3H, s, OCH3 ), 6.28 (1H, tt, 2 JH F 52:65, 3 JH F 5:5 Hz, H(CF2)2), 7.46 (5H, m, C6H5), 7.90 (1H, ws, CH); E: d 3.85 (3H, s, OCH3 ), 6.09 (1H, tt, 2 JH F 52:65, 3 JH F 5:5 Hz, H(CF2)2), 7.39 (5H, m, C6H5), 8.0 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 1:2) Z: d 23.08 (2F, m, 2 JH F 52:65, 3 JH F 5:5 Hz, HCF2 CF2), 41.83 (2F, m, HCF2CF2 ); E: d 23.77 (2F, m, 2 JH F 52:65, 3 JH F 5:5 Hz, HCF2 CF2), 39.35 (2F, m, HCF2CF2 ) ppm. IR: 3075 (CH), 1720 (C=O), 1690 (CO2Me), 1600±1535 (C=C), 1230±1100 (C±F) cm 1. Analysis: Found: C, 54.13; H, 3.17; F, 26.59. Calc. for C13H10O3F4: C, 53.80; H, 3.47; F, 26.19%. 3.1.7. Methyl-2-benzylidene-3-oxo-4,4,5,5,6,6,7,7, 7-nonafluoroheptanoate (2g) Yield, 40%. 1 H NMR (CDCl3, (Z): E 2:3) Z: d 3.87 (3H, s, OCH3 ), 7.48 (5H, m, C6H5), 7.84 (1H, ws, CH); E: d 3.87 (3H, s, OCH3 ), 7.41 (5H, m, C6H5), 8.08 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 2:3) Z: d 36.56 (2F, m, CF2), 39.96 (2F, m, CF2), 48.25 (2F, m, CF2), 80.88 (2F, m, CF3); E: d 36.05 (2F, m, CF2), 39.49 (2F, m, CF2), 45.69 (2F, m, CF2), 80.88 (2F, m, CF3) ppm. IR: 3050 (CH), 1740 (C=O), 1710 (CO2Me), 1615±1565 (C=C), 1290±1130 (C±F) cm 1. Analysis: Found: C, 44.44; H, 2.37; F, 41.90. Calc. for C15H9F9O3: C, 44.13; H, 2.22; F, 41.89%. 3.2. Synthesis of 4-aryl-3,5-dialkoxycarbonyl-2,6dihydroxy-2,6-di(fluoroalkyl)tetrahydropyranes (3a±f) A mixture of 3-oxo ester 1a±c,e,f,h (10 mmol), arylaldehyde (5 mmol) and anhydrous KF (1.57 g, 2.7 mmol) in 50 ml of ethanol (Scheme 2) was re¯uxed for 6±8 h. The reaction mixture was poured into 100 ml of water and extracted with diethyl ether (2 30 ml). The extract was washed with aqueous solution of NaHSO3 (40%), water and dried under MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from aqueous ethanol (40%) to give product 3a±f as white powders. 3.2.1. 2,6-Di(difluoromethyl)-3,5-diethoxycarbonyl2,6-dihydroxy-4-phenyltetrahydropyrane (3a) Yield, 40%; mp, 128±130 8C. 1 H NMR (DMSO-d6): d 0.85 (6H, t, J 7:1 Hz, 2 OCH2CH3 ), 3.07 (3H, m, H3, H4, H5), 3.77 (4H, q, J 7:1 Hz, 2 OCH2 CH3), 5.70 (2H, t,
JH F 54:7 Hz, 2 HCF2), 7.33 (5H, s, C6H5) ppm. 19 F NMR (DMSO-d6): d 27.11 (2F, m, AB-system, Dn 126:5, 2 JF F 282:6, 2 JF H 54:7 Hz, HCF2) ppm. IR: 3380 (OH), 1750 (CO2Et), 1240±1090 (CF) cm 1. Analysis: Found: C, 52.03; H, 5.29; F, 17.69. Calc. for C19H22F4O7: C, 52.05; H, 5.06; F, 17.34%. 3.2.2. 3,5-Diethoxycarbonyl-2,6-dihydroxy-2, 6-di(trifluoromethyl)-4-phenyltetrahydropyrane (3b) Yield, 43%; mp, 115±117 8C (lit. mp 116±118 8C [5]). 1 H NMR (DMSO-d6): d 0.75 (6H, t, J 7:1 Hz, 2 OCH2CH3 ), 3.29±4.37 (3H, m, H3, H4, H5), 3.74 (4H, q, J 7:1 Hz, 2 OCH2 CH3), 7.29 (5H, s, C6H5), 7.92 (2H, ws, 2OH) ppm. 19 F NMR (DMSO-d6): d 79.54 (3H, s, CF3) ppm. IR: 3340 (OH), 1710 (CO2Et), 1220±1020 (CF) cm 1. Analysis: Found: C, 48.13; H, 4.27; F, 24.25. Calc. for C19H20F6O7: C, 48.11; H, 4.25; F, 24.03%. 3.2.3. 3,5-Diethoxycarbonyl-2,6-dihydroxy-2,6-di (1,1,2,2-tetrafluoroethyl)-4-phenyltetrahydropyrane (3c) Yield, 35%; mp, 135±137 8C. 1 H NMR (DMSO-d6): d 0.72 (6H, t, J 7:1 Hz, 2 OCH2CH3 ), 3.36 (2H, d, 3 JH H 12:3 Hz, H3, H5), 4.08 (1H, t, 3 JH H 12:3 Hz, H4), 3.71 (4H, q, J 7:1 Hz, 2 OCH2 CH3), 6.52 (2H, tt, 2 JH F 51:8, 3 JH F 6:6 Hz, 2H(CF2)2), 7.28 (5H, s, C6H5), 7.47 (2H, ws, 2OH) ppm. 19 F NMR (DMSO-d6): d 25.09 (2F, dt, 2 JH F 51:8, 3 JH F 6:6 Hz, HCF2 CF2), 33.41 (2F, ABsystem, Dn 165, 2 JF F 265:4, 3 JH F 6:6 Hz, HCF2CF2 ) ppm. IR: 3400 (OH), 1710 (CO2Et), 1200± 1105 (CF) cm 1. Analysis: Found: C, 46.82; H, 4.05; F, 28.30. Calc. for C21H22F8O7: C, 46.85; H, 4.12; F, 28.23%. 3.2.4. 3,5-Diethoxycarbonyl-2,6-dihydroxy-2,6-di (nonafluorobuthyl)-4-phenyltetrahydropyrane (3d) Yield, 34%; mp, 125±127 8C. 1 H NMR (CDCl3): d 0.76 (6H, t, J 7:2 Hz, 2 OCH2CH3 ), 3.22±4.03 (3H, m, H3, H4, H5), 3.84 (4H, q, J 7:2 Hz, 2 OCH2 CH3), 6.17 (2H, ws, 2OH), 7.30 (5H, s, C6H5) ppm. 19 F NMR (CDCl3): d 35.50 (2F, m, CF2), 41.29 (4F, m, 2CF2), 81.03 (3F, m, CF3) ppm. IR: 3360 (OH), 1710 (CO2Et), 1270±1100 (CF) cm 1. Analysis: Found: C, 38.83; H, 2.62; F, 44.33. Calc. for C25H20F18O7: C, 38.77; H, 2.60; F, 44.03%. 3.2.5. 3,5-Dimethoxycarbonyl-2,6-dihydroxy-2,6-di (1,1,2,2-tetrafluoroethyl)-4-phenyltetrahydro-pyrane (3e) Yield, 40%; mp, 143±144 8C. 1 H NMR (CDCl3): d 3.36 (6H, s, OCH3); 3.50 (3H, AB2-system, H3, H4, H5, nAB 37:9, JAB 12:5 Hz); 5.93 (2H, ws, 2OH); 6.13 (2H, t.t, 2H(CF2)2, 2 J H F 52, 3 J H F 6:6 Hz); 7.30 (5H, s, C6H5) ppm. 19 F NMR (CDCl3): d 27.02 (2F, d.t, HCF2 CF2, 2 J H F 52, 3 J H F 6:6 Hz); 33.44 (2F, ABsystem, Dn 179, HCF2CF2 , 2 J F F 265:9, 3 J H F 6:6 Hz) ppm. IR: 3490, 3320 (OH); 1715, 1700 (CO2Me); 1270±1115 (CF) cm 1. Analysis: Found: C, 44.98; H, 3.60; F, 30.00. Calc. for C19H18F8O7: C, 44.72; H, 3.56; F, 29.78%.
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
3.2.6. 3,5-Diethoxycarbonyl-2,6-dihydroxy-2,6di(perfluorohexyl)-4-(4-hydroxyphenyl)tetrahydropyrane (3f) Yield, 24%; mp, 118±120 8C. 1 H NMR (DMSO-d6/CCl4): d 0.84 (6H, t, J 7:1 Hz, 2OCH2CH3 ), 3.27 (2H, d, 3 JH H 12:2 Hz, H3, H5), 3.79 (1H, t, 3 JH H 12:2 Hz, H4), 3.87 (4H, q, J 7:1 Hz, 2 OCH2 CH3), 6.19, 6.79 (4H, 2s, C6H4), 6.95 (2H, ws, 2OH) ppm. 19 F NMR (DMSO-d6/ CCl4): d 35.62 (2F, m, CF2), 39.39 (4F, m, 2CF2), 41.14± 42.33 (4F, m, 2CF2), 80.95 (3F, m, CF3) ppm. IR: 3370 (OH), 1700 (CO2Et), 1220±1060 (C±F) cm 1. Analysis: Found: C, 35.66; H, 1.99; F, 49.58. Calc. for C29H20F26O8: C, 35.14; H, 2.04; F, 49.89%. 3.3. Synthesis of 3,5-dialkoxycarbonyl-2,6-dihydroxy2,6-di(fluoroalkyl)-4-methyltetrahydropyranes (3g,h) A mixture of 3-oxoester 1b,f (10 mmol), acetic aldehyde (2.2 g, 5 mmol) and anhydrous KF (1.57 g, 2.7 mmol) in 50 ml of ethanol (Scheme 2) was heated in a sealed tube in boiling water bath for 6 h. After cooling ( 70 8C), the tube was opened. The reaction mixture was poured into cooled water. The resulting precipitate was ®ltered off and washed with boiling hexane to give products 3g,h. 3.3.1. 3,5-Diethoxycarbonyl-2,6-dihydroxy-2,6di(trifluoromethyl)-4-methyltetrahydropyrane (3g) Yield, 58%; mp, 106±108 8C. 1 H NMR (DMSO-d6/CCl4): d 0.88 (3H, d, JH CH3 6:4 Hz, CH3), 1.23 (6H, t, 2 OCH2CH3 ), 2.67 (2H, d, 3 JH H 11:9 Hz, H3, H5), 2.87 (1H, m, H4), 4.11 (4H, q, 2 OCH2 CH3). 7.40 (2H, ws, 2OH) ppm. 19 F NMR (DMSO-d6/CCl4): d 78.61 (3F, s, CF3) ppm. IR: 3440±3200 (OH), 1720 (CO2Et), 1200±1040 (C±F) cm 1. Analysis: Found: C, 40.68; H, 4.36; F, 27.82. Calc. for C14H18F6O7: C, 40.79; H, 4.40; F, 27.65%. 3.3.2. 2,6-Dihydroxy-3,5-dimethoxycarbonyl-2,6di(1,1,2,2-tetrafluoroethyl)-4-methyltetrahydro-pyrane (3h) Yield, 45%; mp, 103±105 8C. 1 H NMR (DMSO-d6/CCl4): d 0.87 (3H, d, JH H 6:8 Hz, CH3); 2.79±2.94 (3H, m, H3, H4, H5), 3.67 (6H, s, 2 OCH3), 6.31 (2H, tt, 2 JH F 52:3, 3 JH F 6:8 Hz, 2H(CF2)2), 7.12 (2H, ws, 2 OH) ppm. 19 F NMR (DMSO-d6/CCl4): d 26.34 (2F, dt, 2 JH F 52:5, 3 JH F 6:1 Hz, HCF2 CF2), 32.27 (2F, m, HCF2CF2 ) ppm. IR: 3370 (OH), 1700 (CO2Me), 1220±1060 (C±F) cm 1. Analysis: Found: C, 37.36; H, 3.53; F, 34.57. Calc. for C14H16F8O7: C, 37.51; H, 3.60; F, 33.91%.
7
3.4. Synthesis of 3,5-diethoxy-carbonyl-4-phenyl-2pentafluorophenyl-7,8,9,10-tetrafluoro-4,5dihydrobenzo[b]oxacin-6-one (4) A mixture of 3-oxo ester 1i (28.22 g, 10 mmol), benzaldehyde (5.31 g, 5 mmol) and anhydrous KF (1.57 g, 2.7 mmol) in 50 ml of ethanol (Scheme 3) was re¯uxed for 6±8 h. The resulting mixture was poured into 100 ml of water and extracted with diethyl ether (2 30 ml). The extract was washed with aqueous solution of NaHCO3, water and dried under MgSO4. The solvent was removed under reduced pressure. Column chromatography on silicagel (eluantÐchloroform) gave product 4 (12.01 g, 38%) as a white powder (mp, 105±106 8C). 1 H NMR (DMSO-d6/ CCl4): d 1.09, 0.96 (6H, 2 t, J 7:2 Hz, 2 OCH2CH3 ); 4.14±3.88 (4H, 2 q, J 7:2 Hz, 2 OCH2 CH3); 5.05 (2H, AB-system, 2H, Dn 29:56, JH3 H4 11:33 Hz, H3, H4), 7.6±7.28 (5H, m, C6H5) ppm. 13 C NMR (DMSO-d6/CCl4): d 146.22 (C-1), 131.83 (C-2), 60.83 (C-3), 45.54 (C-4), 190.0 (C-5), 163.72 (C-6), 61.49 (C-7), 13.11 (C-8), 166.75 (C-9), 62.11 (C-10), 13.63 (C-11), 138.17 (C-12), 128.99 (C-13, C17), 128.53 (C-14, C-16) ppm. 19 F NMR (DMSO-d6/CCl4): d 23.98±20.64 (2F, m), 19.83±19.31 (1F, m), 16.48±15.83 (1F, m), 12.78±12.13 (1F, m), 8.04±7.50 (1F, m), 5.75±5.16 (1F, m), 0.34±1.78 (2F, m) ppm. IR: 1745 (CO2Et), 1710 (CO2Et, C=O), 1625 (C=C), 970 (CF) cm 1. Analysis: Found: C, 55.16; H, 2.81; F, 27.35. Calc. for C29H17F9O6: C, 55.07; H, 2.71; F, 27.04%. Acknowledgements The authors wish to thank the Russian Foundation of Fundamental Researches (grant no. 00-03-32767a, 00-0332807a) and INTAS (grant no. 00-711) for ®nancial support of this work.
References [1] [2] [3] [4]
E. Knoevenagel, Chem. Ber. 37 (1904) 4461. P.D. Gardner, R.L. Brandon, J. Org. Chem. 22 (1957) 1704. C. Gnanadickam, Ann. Chim. 7 (1962) 826. I. Katsuyama, K. Funabiki, M. Matsui, H. Muramatsu, K. Shibata, Chem. Lett. 2 (1996) 179. [5] A.S. Dey, M.M. Joullie, J. Org. Chem. 30 (1965) 3237. [6] V.M. Potapov, Stereokhimiya (Stereochemistry), Khimia, Moscow, 1988, p. 464 (in Russian).
Reactions of ¯uorine-containing 3-oxo esters with aldehydes M.V. Pryadeinaa, O.G. Kuzuevaa, Ya.V. Burgarta, V.I. Saloutina,*, K.A. Lyssenkob, M.Yu. Antipinb a
Institute of Organic Synthesis, Urals Division, Russian Academy of Sciences, S. Kovalevskoy Str. 20 GSP-147, Ekaterinburg 620219, Russia b Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Str. B-334, Moscow 119991, Russia Received 4 March 2002; received in revised form 15 May 2002; accepted 26 June 2002
Abstract Fluoroalkylcontaining 3-oxo esters react with aldehydes to form 2-benzylidene-3-¯uoroacyl-esters or 4-aryl(alkyl)-3,5-dialkoxycarbonyl2,6-dihydroxy-2,6-di(¯uoroalkyl)tetrahydropyranes depending on the conditions. Ethyl penta¯uorobenzoylacetoacetate with benzaldehyde affords 3,5-diethoxy-carbonyl-4-phenyl-2-penta¯uorophenyl-7,8,9,10-tetra¯uoro-4,5-dihydrobenzo[b]oxacin-6-one. # 2002 Elsevier Science B.V. All rights reserved. Keywords: 3-Oxo ester; Aldehyde; Condensation; Tetrahydropyranes
1. Introduction The reactions of 1,3-dicarbonyl compounds with aldehydes, known as the Knoevenagel condensation, are used widely for synthesis of various products [1]. Interaction of non-¯uorinated 3-oxo esters with aldehydes, depending on the conditions and structure of starting reagents, can result in 2-alkyl(aryl)methylene-3-oxoesters, 2-alkyl(aryl)methylenedi(3-oxoesters) or cyclohexanones [1±3]. Data on the condensation of ¯uorine-containing 3-oxo esters with aldehydes are available only for ethyl tri¯uoroacetoacetate leading to 2-arylmethylene-substituted tri¯uoroacetoacetic esters [4] or 4-aryl-2,6-dihydroxy-3,5-diethoxycarbonyl2,6-di(tri¯uoromethyl)tetrahydropyranes [5]. In this paper, the interaction of ¯uorine-containing 3-oxo esters with aldehydes, usually benzaldehyde, in different conditions are described. 2. Results and discussion 2.1. Synthesis of 2-benzylidene-2-flluoroacyl esters In the present work, it has been found that ¯uoroalkylcontaining 3-oxo esters 1a±g react with an equimolar amount of benzaldehyde in re¯uxing toluene in the presence of piperidine with azeotropic removal of water to form * Corresponding author. Fax: 7-3432-745954. E-mail address: [email protected] (V.I. Saloutin).
2-benzylidene-2-¯uoroacyl esters 2a±g in moderate yields (Scheme 1). Compounds 2a±g may exist in two isomeric forms (Z- and E-isomers regarding the C=C bond). Two sets of identical resonance signals in the 1 H and 19 F NMR spectra of products 2a±g indicate their existence as an equilibrium mixture of Zand E-isomers in all cases. In the IR spectra of esters 2a±g, most absorption bands corresponding to the vibration of carbonyl groups have broad or doublet character that con®rms the presence of two isomers in all cases. The distinction between E- and Z-isomers was made on the basis of the character of the methine proton signals in the 1 H NMR spectra. In each case one of the methine protons signals appeared as a broad singlet, possibly, because of interaction with ¯uorine atoms of the ¯uoroalkyl substituent. It is possible in the case of the Z-isomer only. The 19 F NMR spectrum of 2-benzylidene-substituted tri¯uoroacetoacetate 2b, recorded in CDCl3 with the digital resolution 0.122 Hz, con®rms the existence of such interaction as the tri¯uoromethyl group of the E-isomer is observed as a singlet at 85.99 ppm while that of the Z-isomer is exhibited as a doublet at 90.42 ppm (JF±H 1 Hz). 2.2. Synthesis of 4-alkyl(aryl)-3,5-dialkoxycarbonyl2,6-dihydroxy-2,6-di(fluoroalkyl)tetrahydropyranes When the reactions of ¯uoroalkyl-containing 3-oxo esters 1a±c,e,f,h with aldehydes were carried out in re¯uxing ethanol in the presence of a base (KF or piperidine), the substituted tetrahydropyranes 3a±h were obtained
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 1 4 9 - 5
2
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
Scheme 1.
Scheme 2.
(Scheme 2). Benz-, p-hydroxybenz- and aceticaldehydes were used as aldehyde components. However, two isomeric structures, namely the tetrahydropyrane of type A or the acyclic substituted dialkyl glutarate of type B, are equally probable for these condensation products.
A earlier report on the condensation of ethyl tri¯uoroacetoacetate with benzaldehyde postulated the formation of the corresponding tetrahydropyrane A (Rf CF3 , R1 OEt, R2 Ph) based on elemental analysis and IR spectra only [5]. In the present paper, the hexahydropyrane structure of products 3 was established by NMR spectroscopy and X-ray analysis.
One set of resonance signals for equivalent ester and ¯uoroalkyl groups in the 1 H and 19 F NMR spectra corresponded to the symmetrical structure of tetrahydropyrane 3. In the 1 H NMR spectra appeared resonance signals of protons H4 and H3, H5 as a triplet and a doublet, respectively. That can be explained by the tetrahydropyrane structure only, when two protons H3, H5 are magnetically equivalent and interact with the third non-equivalent proton H4. In the 19 F NMR spectra, signals of ¯uorine atoms at the a-carbon of the ¯uoroalkyl substituent are an AB system that is typical for a ¯uoroalkyl group attached to an asymmetric center. Since the tetrahydropyrane structure 3 contains ®ve contiguous stereocenters (including one pseudochiral center) 16 possible stereoisomers can a priori be envisaged. Examination of the 1 H NMR spectra of 3a±h shows that these products are formed as a single diastereomer (racemic). The observed coupling constants (3 JH4 H3 H5 12:2± 12.5 Hz) corresponding to the trans-axial methine protons (H3, H4, H5), indicate that the phenyl and alkoxycarbonyl groups in tetrahydropyrane 3 occupy the equatorial positions. From literature data, it can be proposed that the ¯uoroalkyl substituent occupies preferentially the equatorial
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
3
Fig. 1. The general view of 3e. The principal bond lengths: O(1)±C(5) 1.406(2), O(1)±C(1) 1.425(2), O(2)±C(1) 1.372(2), O(7)±C(5) 1.394(2), C(1)±C(2) 1.551(3), C(4)±C(5) 1.551(3), C(3)±C(4) 1.539(3), C(2)±C(3) 1.545(3), C(1)±C(6) 1.552(3), C(5)±C(18) 1.545(3), C(2)±C(8) 1.521(3), C(4)±C(16) 1.520(3), Ê ; bond angles: C(5)±O(1)±C(1) 118.3(2), O(2)±C(1)±O(1) 113.0(1), O(2)±C(1)±C(2) C(3)±C(10) 1.530(3), O(5)±C(16) 1.206(3), O(3)±C(8) 1.200(2) A 115.0(2), O(1)±C(1)±C(2) 109.1(2), O(2)±C(1)±C(6) 104.4(2), O(1)±C(1)±C(6) 101.9(1), C(2)±C(1)±C(6) 112.5(2), C(3)±C(2)±C(1) 110.7(2), C(4)±C(3)± C(2) 109.0(1), C(3)±C(4)±C(5) 110.2(1), O(7)±C(5)±O(1) 110.0(2), O(7)±C(5)±C(4) 113.3(2), O(1)±C(5)±C(4) 111.2(2)8.
position [6]. Thus, the above cyclocondensation occurs stereoselectively. Final con®rmation of the relative stereochemistry in hexahydropyrane 3e was obtained by a single-crystal X-ray analysis (Figs. 1 and 2; for details see Section 3). The X-ray investigation of 3e has revealed that tetrahydropyrane is characterized by the chair conformation with the phenyl, methoxycarbonyl and C2F4H groups in equatorial positions and hydroxy groups axial (Fig. 1).
Fig. 2. The scheme illustrating the formation of the H-bonded dimers in Ê, crystal of 3e. The parameters of H-bonds are: H(2O)O(30 ) 2.02 A Ê ; H(7O)O(5) 1.96 A Ê, O(2)H(2O)O(30 ) 1698, O(2)O(30 ) 2.808(2) A Ê. O(7)H(7O)O(5) 1498, O(7)O(5) 2.716(2) A
In spite of the fact that 3e possesses formal Cs symmetry, the analysis of bond lengths and angles has shown signi®cant distortions around the O(1) atom. While the n(O(1))±s(C± OH) interactions must be formally the same for O(2) and O(7) atoms the corresponding C(1)±O(1) and O(1)±C(5) Ê ) are signi®cantly different as bonds (1.425(2), 1.406(2) A well as C(1)±O(2) and C(5)±O(7) bonds (1.372(2), Ê ). It is worth noting that a such difference in 1.394(2) A the bond lengths can not be directly explained by the crystal packing effect because both hydroxy groups participate in the intramolecular (O(7)H(7O)O(5)) and intermolecular (O(2)H(2O)O(30 )) H-bonds of comparable strengths (Figs. 1 and 2). The latter H-bond assembles molecules in centrosymmetric dimers. Thus, the above distortions of the tetrahydropyrane cycle can not be explained in terms of n(O(1))±s(C±OH) interactions. On the other hand, the different types of the H-bonds lead to the different mutual orientation of the OH groups in respect to the endo-cyclic C±O bonds and thus to the distinctions in the interactions of the hydroxy groups lone pairs with the antibonding s-orbitals of C±O(1) bonds. The torsion angles H(2O)O(2)C(1)O(1) and H(7O)O(7)C(5)O(1) (83, 1458) indicate that such interactions with endo-cyclic C±O bonds can occur only in the case of an O(2)H(2O) group which is consistent with the observed shortening of the O(2)±C(1) bond and the elongation of the C(1)±O(1) bond in comparison with the O(7)±C(5) and C(5)±O(1) bonds, respectively. The attempts to dehydrate tetrahydropyranes 3a±h upon re¯uxing in toluene with azeotropic removal of water in the presence of p-toluenesulfonic acid were unsuccessful. Evidently, the tetrahydropyrane structure of these heterocycles is stable due to the presence of the electron-withdrawing
4
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
Scheme 3.
¯uoroalkyl substituents. In addition, the participation of hydroxyl groups in the formation of intra- or intermolecular hydrogen bonds with the ester substituent prevents dehydration. 2.3. Reaction of ethyl pentafluorobenzoylacetoacetate with benzaldehyde The ethyl ester of penta¯uorobenzoylacetic acid 1i with benzaldehyde in re¯uxing ethanol in the presence of KF affords compound 4. In contrast to the spectra of tetrahydropyranes 3, the IR spectrum of 4 is characterized by the absence of an absorption band corresponding to the vibration of an hydroxyl group, while the absorption band at 1625 cm 1 due to the C=C bond vibration is present. The 19 F NMR spectrum has resonance signals of ¯uorine atoms of C6F5 and C6F4 groups in a ratio of 1:1. The 1 H NMR spectrum exhibits doubled resonance signals of non-equivalent ester groups and resonance signals of two methine protons as an AB system (J 11:3 Hz). From these spectral and analytical data, structures of 5,6,7,8-tetra¯uoro-4,2-(1,3-diethoxycarbonyl-2-phenyl-1,3-propylendiyl)-2-penta¯uorophenylbenzo[d]dioxane E or 3,5-diethoxycarbonyl-2-penta¯uorophenyl-4-phenyl-7,8, 9,10-tetra¯uoro-4,5-dihydrobenzo[b]oxacin-6-one D may be proposed for product 4. A possible mechanism of the formation of compoundsD, E is shown in Scheme 3. Evidently, glutarate B is formed as an intermediate for each case. Under reaction conditions, the latter undergoes intramolecular cyclization to afford heterocycle C (path A) or product E (via pyrane A, path
B). The cyclization occurs through intramolecular substitution of the ortho-¯uorine atom in the penta¯uorophenyl substituent byhydroxylgroupandisaccomplishedbyeliminationofHFand H2O (Scheme 3). The distinction between structures D and E was made on the basis of 13 C NMR spectroscopic data. The spectrum exhibited a signal at 190.0 ppm which is typical for a carbonyl atom in structure D. So, the reaction of pentaluorophenylacetylacetate 1i with benzaldehyde occurs via path A to form the substituted benzo[b]oxacinone 4 (D). Thus, in contrast to non-¯uorinated analogues, the ¯uorine-containing 3-oxo esters in the reaction with aldehydes can produce both acyclic non-saturated ketones and heterocyclic products depending on the conditions. 3. Experimental Melting points were measured in open capillaries and are reported uncorrected. Infrared spectra were measured on a Specord 75 IR spectrometer. 1 H and 13 C NMR spectra were recorded on a Bruker DRX-400 instrument (1 H: 400 MHz, using TMS as an internal standard; 13 C: 100 MHz, using TMS as an internal standard). 19 F NMR spectra were recorded on a Tesla BS-587A instrument (75 MHz, using C6F6 as an internal standard). Microanalyses were performed with a Carlo Erba CHNS-O EA 1108 elemental analyzer. Thin-layer chromatography was performed on `Silufol-UV 254' plates.
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
Crystallographic data for 3e: at 110 K C19H18F8O7 Ê, b are triclinic, space group P 1, a 10:131(4) A Ê Ê 10:781(4) A, c 11:522(4) A, a 65:067(8)8, b Ê 3, Z 2, 78:594(8)8, g 63:697(8)8, V 1022:8(6) A 3 M 510:33, dcalc 1:657 g cm , m Mo Ka 1:70 cm 1, F 000 520. Intensities of 7968 re¯ections were measured with a Smart 1000 CCD diffractometer at 110 K Ê , o-scans with 0.38 step in o (l Mo Ka 0:71073 A and 10 s per frame exposure, 2y < 58 ), and 5360 (R int 0:0211) independent re¯ections were used in further re®nement. The structure was solved by direct methods and re®ned by the full-matrix least-squares technique against F2 in the anisotropic±isotropic approximation. The analysis of the Fourier electron density synthesis revealed that two CF2H groups are disordered by two positions with equal occupancies for C(7)F(3)F(4) and with 0.3 and 0.7 occupancies for C(19)F(7)F(8). The hydrogen atoms in the ordered part of the molecule were located from the Fourier density synthesis and were re®ned in isotropic approximation. The re®nement converged to wR2 0:1676 and GOF 1:067 for all independent re¯ections (R1 0:0587 was calculated against F for 3696 observed re¯ections with I > 2 s I. All calculations were performed using SHELXTL PLUS 5.1 on IBM PC AT. Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 179146.1 3.1. Synthesis of 2-benzylidene-3-fluoroacylesters 2a±g A mixture of benzaldehyde (0.21 g, 2.0 mmol), 3-oxo ester 1a±g (2.0 mmol) (Scheme 1) and 1 ml of pyperidine was re¯uxed in toluene for 6 h with azeotropic removal of water. Toluene was removed under reduced pressure. Column chromatography on silicagel (eluantÐbenzene) gave products 2a±g as oils. 3.1.1. Ethyl-2-benzylidene-3-oxo-4, 4-difluorobutanoate (2a) Yield, 52%. 1 H NMR (CDCl3, (Z): E 1:1) Z: d 1.26 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:2 Hz, OCH2 CH3), 6.24 (1H, t, JH F 53:4 Hz, HCF2), 7.42 (5H, m, C6H5), 7.89 (1H, ws, CH); E: d 1.29 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:2 Hz, OCH2 CH3), 6.08 (1H, t, JH F 53:4 Hz, HCF2), 7.45 (5H, m, C6H5), 7.96 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 1:1) Z: d 37.04 (2F, d, JH F 53:4, HCF2); E: d 34.23 (2F, d, JH F 53:4, HCF2) ppm. IR: 3040 (CH), 1720 (C=O), 1690 (CO2Et), 1600±1595 (C=C), 1250±1010 (C±F) cm 1. Analysis: Found: C, 61.27; H, 4.71; F, 15.22. Calc. for C13H12F2O3: C, 61.42; H, 4.76; F, 14.94%. 1
Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: 44-1223/336033; E-mail: [email protected]).
5
3.1.2. Ethyl-2-benzylidene-3-oxo-4,4, 4-trifluorobutanoate (2b) Yield, 54%. 1 H NMR (CDCl3, (Z): E 1:1) Z: d 1.29 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:2 Hz, OCH2 CH3), 7.47 (5H, m, C6H5), 7.81 (1H, ws, CH); E: d 1.32 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.33 (2H, q, J 7:2 Hz, OCH2 CH3); 7.38 (5H, m, C6H5), 7.99 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 1:1) Z: d 85.97 (3F, s); E: d 90.38 (3F, s, CF3) ppm. IR: 3050 (CH), 1730 (C=O), 1700 (CO2Et), 1615±1570 (C=C), 1300±1070 (C±F) cm 1. Analysis: Found: C, 57.11; H, 4.00; F, 20.83. Calc. for C13H11F3O3: C, 57.36; H, 4.07; F, 20.94%. 3.1.3. Ethyl-2-benzylidene-3-oxo-4,4,5, 5-tetrafluoropentanoate (2c) Yield, 53%. 1 H NMR (CDCl3, (Z): E 2:3) Z: d 1.28 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:2 Hz, OCH2 CH3), 6.23 (1H, tt, 2 JH F 52:0, 3 JH F 5:5 Hz, H(CF2)2), 7.39 (5H, m, C6H5), 7.92 (1H, ws, CH); E: d 1.35 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.33 (2H, q, J H H 7:2 Hz, OCH2 CH3), 6.11 (1H, tt, 2 JH F 52:0, 3 JH F 5:5 Hz, H(CF2)2), 7.39 (5H, m, C6H5), 8.01 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 2:3) Z: d 23.04 (2F, m, 2 JH F 52, 3 JH F 5:5 Hz, HCF2 CF2), 41.99 (2F, m, HCF2CF2 ); E: d 23.8 (2F, m, 2 JH F 52:0, 3 JH F 5:5 Hz, HCF2 CF2), 39.40 (2F, m, HCF2CF2 ) ppm. IR: 3045 (CH), 1720 (C=O), 1690 (CO2Et), 1600±1570 (C=C), 1300±1070 (C±F) cm 1. Analysis: Found: C, 55.29; H, 4.19; F, 24.88. Calc. for C14H12F4O3: C, 55.27; H, 3.98; F, 24.98%. 3.1.4. Ethyl-2-benzylidene-3-oxo-4,4,5,5,6,6,7, 7-octafluoroheptanoate (2d) Yield, 40%. 1 H NMR (CDCl3, (Z): E 1:3) Z: d 1.29 (3H, t, J 7:06 Hz, OCH2CH3 ,), 4.33 (2H, q, J 7:06 Hz, OCH2 CH3), 6.28 (1H, tt, 2 JH F 52:0, 3 JH F 5:5 Hz, H(CF2)4), 7.47 (5H, m, C6H5), 7.99 (1H, ws, CH); E: d 1.32 (3H, t, J 7:06 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:06 Hz, OCH2 CH3), 5.99 (1H, tt, 2 JH F 52:0, 3 JH F 5:5 Hz, H(CF2)2), 7.38 (5H, m, C6H5), 7.81 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 1:3) Z: d 48.21 (2F, m, CF2), 40.74 (2F, m, CF2), 33.11 (2F, m, CF2), 24.66 (2F, dm, JH F 52 Hz, HCF2); E: d 45.80 (2F, m, CF2), 38.73 (2F, m, CF2), 32.51 (2F, m, CF2), 24.66 (2F, dm, JH F 52 Hz, HCF2,) ppm. IR: 3045 (CH), 1720 (C=O), 1690 (CO2Et), 1600±1570 (C=C), 1300±1070 (C±F) cm 1. Analysis: Found: C, 47.32; H, 3.31; F, 38.00. Calc. for C16H12F8O3: C, 47.53; H, 2.99; F, 37.60%. 3.1.5. Ethyl-2-benzylidene-3-oxo4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononoate (2e) Yield, 45%. 1 H NMR (CDCl3, (Z): E 3:7) Z: d 1.29 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.35 (2H, q, J 7:2 Hz, OCH2 CH3), 7.54 (5H, m, C6H5), 7.88 (1H, ws, CH); E: d 1.31 (3H, t, J 7:2 Hz, OCH2CH3 ), 4.33 (2H, q, J 7:2 Hz, OCH2 CH3), 7.40 (5H, m, C6H5), 8.60 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 3:7) Z: d 35.05 (2F,
6
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
m, CF2), 39.05 (2F, m, CF2), 40.64 (2F, m, CF2), 40.94 (2F, m, CF2), 48.52 (2F, m, CF2), 81.03 (3F, m, CF3); E: d 35.68 (m, 2F, CF2), 39.05 (2F, m, CF2), 40.23 (2F, m, CF2), 40.63 (2F, m, CF2), 45.76 (2F, m, CF2), 81.03 (3F, m, CF3) ppm. IR: 3030 (CH), 1730 (C=O), 1700 (CO2Et), 1610±1560 (C=C), 1210±1090 (C±F) cm 1. Analysis: Found: C, 41.73; H, 2.05; F, 47.00. Calc. for C18H11F13O3: C, 41.71; H, 2.11; F, 47.02%. 3.1.6. Methyl-2-benzylidene-3-oxo-4,4,5, 5-tetrafluoropentanoate (2f) Yield, 46%. 1 H NMR (CDCl3, (Z): E 1:2) Z: d 3.85 (3H, s, OCH3 ), 6.28 (1H, tt, 2 JH F 52:65, 3 JH F 5:5 Hz, H(CF2)2), 7.46 (5H, m, C6H5), 7.90 (1H, ws, CH); E: d 3.85 (3H, s, OCH3 ), 6.09 (1H, tt, 2 JH F 52:65, 3 JH F 5:5 Hz, H(CF2)2), 7.39 (5H, m, C6H5), 8.0 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 1:2) Z: d 23.08 (2F, m, 2 JH F 52:65, 3 JH F 5:5 Hz, HCF2 CF2), 41.83 (2F, m, HCF2CF2 ); E: d 23.77 (2F, m, 2 JH F 52:65, 3 JH F 5:5 Hz, HCF2 CF2), 39.35 (2F, m, HCF2CF2 ) ppm. IR: 3075 (CH), 1720 (C=O), 1690 (CO2Me), 1600±1535 (C=C), 1230±1100 (C±F) cm 1. Analysis: Found: C, 54.13; H, 3.17; F, 26.59. Calc. for C13H10O3F4: C, 53.80; H, 3.47; F, 26.19%. 3.1.7. Methyl-2-benzylidene-3-oxo-4,4,5,5,6,6,7,7, 7-nonafluoroheptanoate (2g) Yield, 40%. 1 H NMR (CDCl3, (Z): E 2:3) Z: d 3.87 (3H, s, OCH3 ), 7.48 (5H, m, C6H5), 7.84 (1H, ws, CH); E: d 3.87 (3H, s, OCH3 ), 7.41 (5H, m, C6H5), 8.08 (1H, s, CH) ppm. 19 F NMR (CDCl3, (Z): E 2:3) Z: d 36.56 (2F, m, CF2), 39.96 (2F, m, CF2), 48.25 (2F, m, CF2), 80.88 (2F, m, CF3); E: d 36.05 (2F, m, CF2), 39.49 (2F, m, CF2), 45.69 (2F, m, CF2), 80.88 (2F, m, CF3) ppm. IR: 3050 (CH), 1740 (C=O), 1710 (CO2Me), 1615±1565 (C=C), 1290±1130 (C±F) cm 1. Analysis: Found: C, 44.44; H, 2.37; F, 41.90. Calc. for C15H9F9O3: C, 44.13; H, 2.22; F, 41.89%. 3.2. Synthesis of 4-aryl-3,5-dialkoxycarbonyl-2,6dihydroxy-2,6-di(fluoroalkyl)tetrahydropyranes (3a±f) A mixture of 3-oxo ester 1a±c,e,f,h (10 mmol), arylaldehyde (5 mmol) and anhydrous KF (1.57 g, 2.7 mmol) in 50 ml of ethanol (Scheme 2) was re¯uxed for 6±8 h. The reaction mixture was poured into 100 ml of water and extracted with diethyl ether (2 30 ml). The extract was washed with aqueous solution of NaHSO3 (40%), water and dried under MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from aqueous ethanol (40%) to give product 3a±f as white powders. 3.2.1. 2,6-Di(difluoromethyl)-3,5-diethoxycarbonyl2,6-dihydroxy-4-phenyltetrahydropyrane (3a) Yield, 40%; mp, 128±130 8C. 1 H NMR (DMSO-d6): d 0.85 (6H, t, J 7:1 Hz, 2 OCH2CH3 ), 3.07 (3H, m, H3, H4, H5), 3.77 (4H, q, J 7:1 Hz, 2 OCH2 CH3), 5.70 (2H, t,
JH F 54:7 Hz, 2 HCF2), 7.33 (5H, s, C6H5) ppm. 19 F NMR (DMSO-d6): d 27.11 (2F, m, AB-system, Dn 126:5, 2 JF F 282:6, 2 JF H 54:7 Hz, HCF2) ppm. IR: 3380 (OH), 1750 (CO2Et), 1240±1090 (CF) cm 1. Analysis: Found: C, 52.03; H, 5.29; F, 17.69. Calc. for C19H22F4O7: C, 52.05; H, 5.06; F, 17.34%. 3.2.2. 3,5-Diethoxycarbonyl-2,6-dihydroxy-2, 6-di(trifluoromethyl)-4-phenyltetrahydropyrane (3b) Yield, 43%; mp, 115±117 8C (lit. mp 116±118 8C [5]). 1 H NMR (DMSO-d6): d 0.75 (6H, t, J 7:1 Hz, 2 OCH2CH3 ), 3.29±4.37 (3H, m, H3, H4, H5), 3.74 (4H, q, J 7:1 Hz, 2 OCH2 CH3), 7.29 (5H, s, C6H5), 7.92 (2H, ws, 2OH) ppm. 19 F NMR (DMSO-d6): d 79.54 (3H, s, CF3) ppm. IR: 3340 (OH), 1710 (CO2Et), 1220±1020 (CF) cm 1. Analysis: Found: C, 48.13; H, 4.27; F, 24.25. Calc. for C19H20F6O7: C, 48.11; H, 4.25; F, 24.03%. 3.2.3. 3,5-Diethoxycarbonyl-2,6-dihydroxy-2,6-di (1,1,2,2-tetrafluoroethyl)-4-phenyltetrahydropyrane (3c) Yield, 35%; mp, 135±137 8C. 1 H NMR (DMSO-d6): d 0.72 (6H, t, J 7:1 Hz, 2 OCH2CH3 ), 3.36 (2H, d, 3 JH H 12:3 Hz, H3, H5), 4.08 (1H, t, 3 JH H 12:3 Hz, H4), 3.71 (4H, q, J 7:1 Hz, 2 OCH2 CH3), 6.52 (2H, tt, 2 JH F 51:8, 3 JH F 6:6 Hz, 2H(CF2)2), 7.28 (5H, s, C6H5), 7.47 (2H, ws, 2OH) ppm. 19 F NMR (DMSO-d6): d 25.09 (2F, dt, 2 JH F 51:8, 3 JH F 6:6 Hz, HCF2 CF2), 33.41 (2F, ABsystem, Dn 165, 2 JF F 265:4, 3 JH F 6:6 Hz, HCF2CF2 ) ppm. IR: 3400 (OH), 1710 (CO2Et), 1200± 1105 (CF) cm 1. Analysis: Found: C, 46.82; H, 4.05; F, 28.30. Calc. for C21H22F8O7: C, 46.85; H, 4.12; F, 28.23%. 3.2.4. 3,5-Diethoxycarbonyl-2,6-dihydroxy-2,6-di (nonafluorobuthyl)-4-phenyltetrahydropyrane (3d) Yield, 34%; mp, 125±127 8C. 1 H NMR (CDCl3): d 0.76 (6H, t, J 7:2 Hz, 2 OCH2CH3 ), 3.22±4.03 (3H, m, H3, H4, H5), 3.84 (4H, q, J 7:2 Hz, 2 OCH2 CH3), 6.17 (2H, ws, 2OH), 7.30 (5H, s, C6H5) ppm. 19 F NMR (CDCl3): d 35.50 (2F, m, CF2), 41.29 (4F, m, 2CF2), 81.03 (3F, m, CF3) ppm. IR: 3360 (OH), 1710 (CO2Et), 1270±1100 (CF) cm 1. Analysis: Found: C, 38.83; H, 2.62; F, 44.33. Calc. for C25H20F18O7: C, 38.77; H, 2.60; F, 44.03%. 3.2.5. 3,5-Dimethoxycarbonyl-2,6-dihydroxy-2,6-di (1,1,2,2-tetrafluoroethyl)-4-phenyltetrahydro-pyrane (3e) Yield, 40%; mp, 143±144 8C. 1 H NMR (CDCl3): d 3.36 (6H, s, OCH3); 3.50 (3H, AB2-system, H3, H4, H5, nAB 37:9, JAB 12:5 Hz); 5.93 (2H, ws, 2OH); 6.13 (2H, t.t, 2H(CF2)2, 2 J H F 52, 3 J H F 6:6 Hz); 7.30 (5H, s, C6H5) ppm. 19 F NMR (CDCl3): d 27.02 (2F, d.t, HCF2 CF2, 2 J H F 52, 3 J H F 6:6 Hz); 33.44 (2F, ABsystem, Dn 179, HCF2CF2 , 2 J F F 265:9, 3 J H F 6:6 Hz) ppm. IR: 3490, 3320 (OH); 1715, 1700 (CO2Me); 1270±1115 (CF) cm 1. Analysis: Found: C, 44.98; H, 3.60; F, 30.00. Calc. for C19H18F8O7: C, 44.72; H, 3.56; F, 29.78%.
M.V. Pryadeina et al. / Journal of Fluorine Chemistry 117 (2002) 1±7
3.2.6. 3,5-Diethoxycarbonyl-2,6-dihydroxy-2,6di(perfluorohexyl)-4-(4-hydroxyphenyl)tetrahydropyrane (3f) Yield, 24%; mp, 118±120 8C. 1 H NMR (DMSO-d6/CCl4): d 0.84 (6H, t, J 7:1 Hz, 2OCH2CH3 ), 3.27 (2H, d, 3 JH H 12:2 Hz, H3, H5), 3.79 (1H, t, 3 JH H 12:2 Hz, H4), 3.87 (4H, q, J 7:1 Hz, 2 OCH2 CH3), 6.19, 6.79 (4H, 2s, C6H4), 6.95 (2H, ws, 2OH) ppm. 19 F NMR (DMSO-d6/ CCl4): d 35.62 (2F, m, CF2), 39.39 (4F, m, 2CF2), 41.14± 42.33 (4F, m, 2CF2), 80.95 (3F, m, CF3) ppm. IR: 3370 (OH), 1700 (CO2Et), 1220±1060 (C±F) cm 1. Analysis: Found: C, 35.66; H, 1.99; F, 49.58. Calc. for C29H20F26O8: C, 35.14; H, 2.04; F, 49.89%. 3.3. Synthesis of 3,5-dialkoxycarbonyl-2,6-dihydroxy2,6-di(fluoroalkyl)-4-methyltetrahydropyranes (3g,h) A mixture of 3-oxoester 1b,f (10 mmol), acetic aldehyde (2.2 g, 5 mmol) and anhydrous KF (1.57 g, 2.7 mmol) in 50 ml of ethanol (Scheme 2) was heated in a sealed tube in boiling water bath for 6 h. After cooling ( 70 8C), the tube was opened. The reaction mixture was poured into cooled water. The resulting precipitate was ®ltered off and washed with boiling hexane to give products 3g,h. 3.3.1. 3,5-Diethoxycarbonyl-2,6-dihydroxy-2,6di(trifluoromethyl)-4-methyltetrahydropyrane (3g) Yield, 58%; mp, 106±108 8C. 1 H NMR (DMSO-d6/CCl4): d 0.88 (3H, d, JH CH3 6:4 Hz, CH3), 1.23 (6H, t, 2 OCH2CH3 ), 2.67 (2H, d, 3 JH H 11:9 Hz, H3, H5), 2.87 (1H, m, H4), 4.11 (4H, q, 2 OCH2 CH3). 7.40 (2H, ws, 2OH) ppm. 19 F NMR (DMSO-d6/CCl4): d 78.61 (3F, s, CF3) ppm. IR: 3440±3200 (OH), 1720 (CO2Et), 1200±1040 (C±F) cm 1. Analysis: Found: C, 40.68; H, 4.36; F, 27.82. Calc. for C14H18F6O7: C, 40.79; H, 4.40; F, 27.65%. 3.3.2. 2,6-Dihydroxy-3,5-dimethoxycarbonyl-2,6di(1,1,2,2-tetrafluoroethyl)-4-methyltetrahydro-pyrane (3h) Yield, 45%; mp, 103±105 8C. 1 H NMR (DMSO-d6/CCl4): d 0.87 (3H, d, JH H 6:8 Hz, CH3); 2.79±2.94 (3H, m, H3, H4, H5), 3.67 (6H, s, 2 OCH3), 6.31 (2H, tt, 2 JH F 52:3, 3 JH F 6:8 Hz, 2H(CF2)2), 7.12 (2H, ws, 2 OH) ppm. 19 F NMR (DMSO-d6/CCl4): d 26.34 (2F, dt, 2 JH F 52:5, 3 JH F 6:1 Hz, HCF2 CF2), 32.27 (2F, m, HCF2CF2 ) ppm. IR: 3370 (OH), 1700 (CO2Me), 1220±1060 (C±F) cm 1. Analysis: Found: C, 37.36; H, 3.53; F, 34.57. Calc. for C14H16F8O7: C, 37.51; H, 3.60; F, 33.91%.
7
3.4. Synthesis of 3,5-diethoxy-carbonyl-4-phenyl-2pentafluorophenyl-7,8,9,10-tetrafluoro-4,5dihydrobenzo[b]oxacin-6-one (4) A mixture of 3-oxo ester 1i (28.22 g, 10 mmol), benzaldehyde (5.31 g, 5 mmol) and anhydrous KF (1.57 g, 2.7 mmol) in 50 ml of ethanol (Scheme 3) was re¯uxed for 6±8 h. The resulting mixture was poured into 100 ml of water and extracted with diethyl ether (2 30 ml). The extract was washed with aqueous solution of NaHCO3, water and dried under MgSO4. The solvent was removed under reduced pressure. Column chromatography on silicagel (eluantÐchloroform) gave product 4 (12.01 g, 38%) as a white powder (mp, 105±106 8C). 1 H NMR (DMSO-d6/ CCl4): d 1.09, 0.96 (6H, 2 t, J 7:2 Hz, 2 OCH2CH3 ); 4.14±3.88 (4H, 2 q, J 7:2 Hz, 2 OCH2 CH3); 5.05 (2H, AB-system, 2H, Dn 29:56, JH3 H4 11:33 Hz, H3, H4), 7.6±7.28 (5H, m, C6H5) ppm. 13 C NMR (DMSO-d6/CCl4): d 146.22 (C-1), 131.83 (C-2), 60.83 (C-3), 45.54 (C-4), 190.0 (C-5), 163.72 (C-6), 61.49 (C-7), 13.11 (C-8), 166.75 (C-9), 62.11 (C-10), 13.63 (C-11), 138.17 (C-12), 128.99 (C-13, C17), 128.53 (C-14, C-16) ppm. 19 F NMR (DMSO-d6/CCl4): d 23.98±20.64 (2F, m), 19.83±19.31 (1F, m), 16.48±15.83 (1F, m), 12.78±12.13 (1F, m), 8.04±7.50 (1F, m), 5.75±5.16 (1F, m), 0.34±1.78 (2F, m) ppm. IR: 1745 (CO2Et), 1710 (CO2Et, C=O), 1625 (C=C), 970 (CF) cm 1. Analysis: Found: C, 55.16; H, 2.81; F, 27.35. Calc. for C29H17F9O6: C, 55.07; H, 2.71; F, 27.04%. Acknowledgements The authors wish to thank the Russian Foundation of Fundamental Researches (grant no. 00-03-32767a, 00-0332807a) and INTAS (grant no. 00-711) for ®nancial support of this work.
References [1] [2] [3] [4]
E. Knoevenagel, Chem. Ber. 37 (1904) 4461. P.D. Gardner, R.L. Brandon, J. Org. Chem. 22 (1957) 1704. C. Gnanadickam, Ann. Chim. 7 (1962) 826. I. Katsuyama, K. Funabiki, M. Matsui, H. Muramatsu, K. Shibata, Chem. Lett. 2 (1996) 179. [5] A.S. Dey, M.M. Joullie, J. Org. Chem. 30 (1965) 3237. [6] V.M. Potapov, Stereokhimiya (Stereochemistry), Khimia, Moscow, 1988, p. 464 (in Russian).