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Reactions of Carbonyl Compounds in Basic Solutions. Part 30.1The Effect of 2-Formyl, 2,6-Diformyl and 2-Trifluoroacetyl Substituents on the Alkaline and Neutral Hydrolysis of Methyl Benzoate and Phenyl Acetate |
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Journal of Chemical Research, Synopses,
Volume 0,
Issue 11,
1997,
Page 404-405
Keith Bowden,
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摘要:
404 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 404–405† Reactions of Carbonyl Compounds in Basic Solutions. Part 30.1 The Effect of 2-Formyl, 2,6-Diformyl and 2-Trifluoroacetyl Substituents on the Alkaline and Neutral Hydrolysis of Methyl Benzoate and Phenyl Acetate† Keith Bowden,* Jamshid Izadi and Sarah L. Powell Department of Biological and Chemical Sciences, Central Campus, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK Rate coefficients are measured for the alkaline hydrolysis of methyl 2-formyl-, 2,6-diformyl- and 2-trifluoroacetyl-benzoates and for the alkaline and neutral hydrolysis of 2-formyl-, 2,6-diformyl-4-methyl- and 2-trifluoroacetyl-phenyl acetates in water at several temperatures: the relative rates of hydrolysis and activation parameters demonstrate neighbouring group participation by the acyl-carbonyl groups in the ester hydrolysis.Prodrugs have been designed as reversible derivatives of drugs to eliminate undesirable properties of the drug.2 While the linkage employed in forming prodrugs has been various, the formation of esters has been common.3 Esters can be hydrolysed either by enzymes or non-enzymatically to liberate the parent drug.There are clear advantages in using esters whose hydrolysis is facile and can be tuned by comparatively simple structured changes. Neighbouring group participation by suitably situated carbonyl groups in the alkaline hydrolysis of esters has been recently reviewed.4 Criteria have been established for the detection and delineation of this behaviour. For powerful facilitation, the acyl group substituent should be electronwithdrawing and have modest steric ‘bulk’.4,5 Thus, the alkaline hydrolysis of methyl 2-formylbenzoate has been studied at 25.0 °C in water6 and at several temperatures in 70% (v/v) 1,4-dioxane–water7 and the alkaline and neutral hydrolysis of 2-formylphenyl acetate at 25.0 °C in water.8 We describe here the hydrolysis, under alkaline conditions, of model esters.The esters are methyl benzoates and phenyl acetates ortho-substituted with acyl groups designed to achieve high reactivity, i.e. 2-formyl, 2,6-diformyl and 2-tri- fluoroacetyl substituents. Results The prepared model compounds were methyl 2-formyl-, 2,6-diformyl- and 2-trifluoroacetyl-benzoate, 1a–c, and 2-formyl-, 2,6-diformyl- 4-methyl- and 2-trifluoroacetyl-phenyl acetates, 2a–c. The esters 1a and 2a were used as reference compounds.4,7 The alkaline hydrolysis of the methyl benzoates is of first-order both in ester and in hydroxide anion.However, the hydrolysis of the phenyl acetates is of first-order in ester and both zero- and first-order in hydroxide anion. The products of the hydrolysis of all the esters were the corresponding phenol or methanol and the corresponding benzoate or acetate anion. The rate coefficients for the hydrolysis of the esters in water are shown in Table 1 and the activation parameters in Table 2.Discussion Relative Rates.·The rate ratios for the hydrolysis of the esters to that of either methyl benzoate (k2 at 30.0 °C=1.28Å10µ1 dm3 molµ1 sµ1)9 or phenyl acetate [k2 (alkaline) and k1 (neutral) at 27.0 °C=180 dm3 molµ1 sµ1 and 9.0Å10µ8 sµ1, respectively]9 can be calculated to give the values shown in Table 3. Estimates of the rate ratios for unassisted hydrolysis using the known polar and steric effects of 2-substituents on the alkaline hydrolysis of methyl benzoates and phenyl acetates,10,11 as well as the Hammett equation12 and the neutral hydrolysis of phenyl acetates,13 have been made and are shown in Table 3.In all cases, the rate enhancements, re, shown in Table 3, are both significant, i.e. E10, and very large. They all strongly indicate the occurrence of intramolecular catalysis.4 Mechanistic pathways for the alkaline hydrolysis of the methyl 2-acylbenzoates and 2-acylphenyl acetates have been shown as Scheme 1 for the exocyclic and Scheme 2 for the endocyclic intramolecular catalysis in our review.4b A novel pathway for the neutral *To receive any correspondence (e-mail: keithb@essex.ac.uk). †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J.Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). Table 1 Rate coefficients (k2) for the alkaline hydrolysis of substituted methyl benzoates and phenyl acetates in water (at constant ionic strength of 0.1 mol dm–3)a,b 10–2 k2/dm3 mol–1 s–1 Methyl benzoates at 30.0 °C at 60.0 °C l/nmc Subst. 2-CHO 2,6-(CHO)2 2-C(CF3)O 19.1 475 9.30 (1010)d 31.1 617 14.6 (1350)d 302 308 232 10–5 k2/dm3 mol–1 s–1 Phenyl acetates at 27.0 °C at 37.0 °C at 47.0 °C Subst. 2-CHO 2,6-(CHO)2, 4-Me 2-C(CF3)O 1.30 (64.0)e 11.8 (42.8)e 10 600 (7.96)e 1.87 (102)e 14.8 (64.1)e 11 000 (14.3)e 2.68 (165)e 17.4 (89.7)e 11 200 (26.5)e 320 354 268 aRate coefficients are the mean of at least two determinations and were reproducible to within �3%.b1.8% (v/v) 1,4-dioxane–water. cWavelengths used to monitor hydrolysis. d10–2 k3/dm6 mol–2 s–1. e104 k1/s–1 (neutral or water-catalysed reaction). Table 2 Activation parameters for the alkaline hydrolysis of substituted methyl benzoates and phenyl acetates at 20.0 °C in watera,b Methyl benzoates DH‡/kcal mol–1b DS‡/cal mol–1 k–1b Subst. 2-CHO 2,6-(CHO)2 2-C(CF3)O 2.7 1.2 2.4 (1.4)c µ35 µ33 µ37 (µ31)c Phenyl acetates Subst. 2-CHO 2,6-(CHO)2, 4-Me 2-C(CF3)O 6.3 (8.5)d 3.1 (6.5)d µ0.1 (10.9)d µ14 (µ40)d µ20 (µ48)d µ17 (µ36)d aValues of DH‡ and DS‡ are considered to be accurate to �300 cal mol–1 and �2 cal mol–1 K–1, respectively. b1.8 (v/v) 1,4-dioxane–water. cUsing k3/dm6 mol–2 s–1. dNeutral or water-catalysed reaction.R¢ C O O O C R + H2O K1 k1 k-1 R¢ C O O HO C R OH k2 K2 k-2 HO R¢ C O O C OH R K3 k3 k-3 R¢ C O C OH R OH O fast (–H+) O C R + HO R¢ CO– 2 J.CHEM. RESEARCH (S), 1997 405 hydrolysis of the 2-acylphenyl acetates is shown in Scheme 1. The increased rates of the alkaline reaction hydrolysis of the two 2,6-diformyl esters 1b and 2b, relative to those of the 2-formyl esters 1a and 2a, are those expected on the basis of the statistical factor, i.e. Å2, and of the activating effect of a ‘meta’-formyl group on the formyl group undergoing nucleophilic attack. A combination of an electron-withdrawing effect, i.e.s1=0.40,14 and a significant steric ‘bulk’ effect, i.e. Es=µ2.40,12 for the trifluoromethyl substituent would account for the relative rate of the alkaline hydrolysis of 1c, cf. ref. 5. The remarkably rapid rate of reaction for 2c was unexpected. Activation Parameters.·For the alkaline hydrolysis of the more reactive methyl esters employing neighbouring group participation, the enthalpies of activation are exceptionally small and are associated with rather large negative entropies of activation.4 As shown in Table 2, this is true for the methyl esters 1a–c studied here.The same reaction for the phenyl acetates studied here displays very small enthalpies of activation, but the entropies of activation are normal for a bimolecular reaction. The neutral or water-catalysed reactions of the phenyl esters 2a–c also have relatively small enthalpies of activation, with very large negative entropies of activation. The latter are very comparable to those found for the neutral hydrolysis of a number of reactive esters.15 This would appear to be the first observation of intramolecular catalysis by carbonyl groups of neutral or water-catalysis of ester hydrolysis.Experimental Materials.·2,6-Diformylbenzoic acid was obtained by bromination of 2,6-dimethylbenzoic acid and subsequent hydrolysis.16 Oxidation of 4-methyl-2,6-bis(hydroxymethyl)phenol in stages gave 2,6-diformylphenol.17 2-Trifluoroacetylbenzoic acid was prepared by the lithiation ofibromobenzene and reaction with methyl trifluoroacetate and carbon dioxide.18 The Fries rearrangement of phenyl trifluoroacetate gave 2-trifluoroacetylphenol.19 The methyl esters of the acids were prepared from the corresponding acid and diazomethane.7 The phenyl acetates were prepared by treatment of the corresponding phenol in acetic anhydride with concentrated sulfuric acid or pyridine.20 The purity of the acids, phenols and esters was monitored by 1H and 13C NMR and IR spectroscopy, as well as mass spectrometry.The mp values of the acids, phenols and esters, after repeated recrystallization and drying under reduced pressure (P2O5), was in agreement with literature6,16–19 values, as was the boiling point of 2-trifluoroacetylphenyl acetate.21 The following previously unreported esters gave satisfactory elemental analysis. Methyl 2,6-formylbenzoate had mp 65–66 °C and was recrystallised from benzene–hexane. 2,6-Diformyl-4-methylphenyl acetate had mp 110–111 °C and was recrystallised from benzene– hexane.Methyl 2-trifluoroacetylbenzoate had mp 67– 68 °C and was recrystallised from hexane. Measurements.·Rate coefficients for the alkaline and neutral or water-catalysed hydrolysis were determined spectrophotometrically. The reactions were followed at the wavelengths shown in Table 1. The procedure used was that described previously.22 The products of the reactions were found to be either the anions of the corresponding carboxylic acids or the phenols in quantitative yield and were further confirmed spectrophotometrically. Rates were extrapolated to zero buffer concentrations.Hydroxide anion concentrations of 1Å10µ3 to 1Å10µ2 mol dmµ3 were used where required. The hydrolysis of the methyl esters 1a and 1b is of firstorder in both substrate and hydroxide anion. For the methyl ester 1c, the reaction is both first- and second-order in hydroxide anion. The hydrolysis of the acetate esters is of first order in substrate and of both zero and first order in hydroxide anion.Received, 9th May 1997; Accepted, 8th July 1997 Paper E/7/03218H References 1 Part 29, K. Agnihotri and K. Bowden, J. Chem. Res., 1997, (S) 308; (M) 1929. 2 A. A. Sinkula and S. H. Yalkowaky, J. Pharm. Sci., 1975, 64, 181. 3 H. Bundgaard, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, Amsterdam, 1985, ch. 1. 4 (a) K. Bowden, Adv. Phys. Org. Chem., 1993, 28, 171; (b) K.Bowden, Chem. Soc. Rev., 1995, 25, 431. 5 K. Bowden and F. P. Malik, J. Chem. Soc., Perkin Trans. 2, 1992, 5; 1993, 7. 6 M. L. Bender, J. A. Reinstein, M. S. Silver and R. Mikulak, J. Am. Chem. Soc., 1965, 87, 4545. 7 K. Bowden and G. R. Taylor, J. Chem. Soc. B, 1971, 149. 8 J. A. Walder, R. S. Johnson and I. M. Klotz, J. Am. Chem. Soc., 1978, 100, 5156. 9 K. Bowden and R. J. Ranson, unpublished results. 10 N. B. Chapman, J. Shorter and J. H P. Utley, J. Chem. Soc., 1963, 1291; Y.Iskander, R. Tewfik and S. Wasif, J. Chem. Soc. B, 1966, 424; M. Hojo, M. Utaka and Z. Yoshida, Tetrahedron Lett., 1966, 19, 25. 11 T. Nishioka, T. Fujita, K. Kitamura and M. Nakajima, J. Org. Chem., 1975, 40, 2520. 12 C. D. Johnson, The Hammett Equation, Cambridge University Press, Cambridge, 1973. 13 V. Gold, D. G. Oakenfull and T. Riley, J. Chem. Soc. B, 1968, 515. 14 C. Hansch, A. Leo and D. Hoekman, Explaining QSAR Hydrophobic, Electronic and Steric Constants, American Chemical Society, Washington, 1995. 15 A. J. Kirby, in Comprehensive Chemical Kinetics, ed. C. H. Bamford and C. F. H. Tipper, Elsevier, Amsterdam, 1972, vol. 10, ch. 2. 16 J. E. Francis, K. J. Doebel, P. M. Schutte, E. C. Savarese, S. E. Hopkins and E. F. Bachmann, Can. J. Chem., 1979, 57, 3320. 17 Y. Hu and H. Hu, Synthesis, 1991, 325. 18 U. D. G. Prabu, K. C. Eapen and C. Tamborski, J. Org. Chem., 1984, 49, 2792. 19 S. Matsumoto, H. Kobayashi and K. Veno, Bull. Chem. Soc. Jpn., 1969, 42, 960. 20 J. A. S. Cavaleiro, M. de F. P. N. Condesso, M. M. Olmstead, D. E. Oran, K. M. Snow and K. M. Smith, J. Org. Chem., 1988, 53, 5847. 21 D. S. Kemp and F. Vellacio, J. Org. Chem., 1975, 40, 3003. 22 K. Bowden and A. M. Last, J. Chem. Soc., Perkin Trans. 2, 1973, 345. Table 3 Relative rate ratios of the alkaline hydrolysis of the esters in water at 30 °C for 1a–c and 27 °C for 2a–c k/k0 Expected for Ester Observed ‘normal’ hydrolysis Enhanced re 1a 1b 1c 2a 2b 2c 14 900 371 000 7270 722 (7.1Å104)a 6560 (4.8Å104)a 5.89Å106 (8.8Å103)a 5.0 25 5.0 5.0 (5.0)a 25 (25)a 8.0 (8.0)a 3000 15 000 1500 140 (1.4Å104)a 260 (1.9Å103)a 7.4Å105 (1.1Å103)a aNeutral hydrolysis. Scheme 1
ISSN:0308-2342
DOI:10.1039/a703218h
出版商:RSC
年代:1997
数据来源: RSC
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12. |
Reactions of Carbonyl Compounds in Basic Solutions. Part 31.1The Effect of 2-Methylsulfonyl, 2-Methylsulfinyl and 2-Methylsulfanyl Substituents on the Alkaline Hydrolysis of Methyl Benzoate and Phenyl Acetate† |
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Journal of Chemical Research, Synopses,
Volume 0,
Issue 11,
1997,
Page 406-407
Keith Bowden,
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摘要:
C O OMe X O C X O Me a X = SMe b X = SOMe c X = SO2Me d X = H 1 a X = SMe b X = SOMe c X = SO2Me d X = H 2 406 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 406–407† Reactions of Carbonyl Compounds in Basic Solutions. Part 31.1 The Effect of 2-Methylsulfonyl, 2-Methylsulfinyl and 2-Methylsulfanyl Substituents on the Alkaline Hydrolysis of Methyl Benzoate and Phenyl Acetate† Keith Bowden* and Saima Rehman Department of Biological and Chemical Sciences, Central Campus, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK Rate coefficients have been measured for the alkaline hydrolysis of methyl 2-methylsulfonyl-, 2-methylsulfinyl- and 2-methylsulfanyl-benzoates and 2-methylsulfonyl-, 2-methylsulfinyl- and 2-methylsulfanyl-phenyl acetates, as well as of the parent esters, in 30% (v/v) 1,4-dioxane–water at several temperatures: the relative rates of hydrolysis and the activation parameters indicate the importance of both polar and steric effects.Esters are commonly designed as prodrugs of drugs having carboxy or hydroxy functions.2 Such prodrugs can regenerate the drugs by hydrolysis either enzymatically or nonenzymatically. 3 Oxidative metabolism of the methylsulfanyl group to methylsulfinyl and, subsequently, methylsulfonyl is known to occur,4 and has been employed in the design of aspirin prodrugs, methylsulfanylmethyl, methylsulfinylmethyl and methylsulfonylmethyl aspirin.5 The alkaline hydrolysis of ortho-substituted alkyl benzoates6 and phenyl acetates7 has been investigated in some detail; but the methylsulfanyl, methylsulfinyl and methylsulfonyl groups have not been included.ortho-Substituents can exert both polar and steric effects,8 as well as being involved in neighbouring group participation where the capacity exists, cf. ref. 9. As model prodrug esters we have prepared methyl 2-methylsulfanyl-, 2-methylsulfinyl- and 2-methylsulfonylbenzoates, 1a–c, and 2-methylsulfanyl-, 2-methylsulfinyl- and 2-methylsulfonyl-phenyl acetates, 2a–c, and studied their alkaline hydrolysis.Results The alkaline hydrolysis of both the methyl benzoates and phenyl acetates is of first-order in both ester and hydroxide anion. Rate coefficients for the alkaline hydrolysis of the methyl 2-substituted-benzoates and 2-substituted-phenyl acetates at 30.0, 45.0 and 60.0 °C in 30% (v/v) 1,4-dioxane– water are shown in Table 1. The activation parameters are shown in Table 2.Discussion Both polar (electronic) and steric effects will control the reactivity of ortho-substituted systems.6–8 The para-s values of SMe, SOMe and SO2Me are 0.0, 0.49 and 0.73, respectively.10 The Hammett r constants for the alkaline hydrolysis of phenyl acetates in 3% aqueous ethanol at 25 °C, of ethyl benzoates in 3% aqueous ethanol at 25 °C and of methyl benzoates in 40% aqueous 1,4-dioxane at 20 °C are 1.17, 1.33 and 2.07,6,7,11 respectively. Reliable estimates12 can be made for kpara-X/kH in 30% aqueous 1,4-dioxane at 30 °C for SMe, SOMe and SO2Me of 1.0, 7.6 and 21, for the methyl benzoates, and 1.0, 5.4 and 12, for the phenyl acetates.Steric effects are more difficult to estimate for these substituents.8,10 However, estimates of kortho-X/kH in 30% aqueous 1,4-dioxane at 30 °C for SMe, SOMe and SO2Me as 0.4, 0.8 and 0.2, for the methyl benzoates, and as 0.84, 3.8 and 4.8, for the phenyl acetates, can be made. Comparison with the observed values for SMe, SOMe and SO2Me of 0.25, 14 and 0.44, for the methyl benzoates, and of 0.80, 10 and 6.4, for the phenyl acetates, shows reasonable agreement, with the exception of that of methyl 2-methylsulfinylbenzoate. The rate enhancement of ca. 18 for the latter ester could arise from intramolecular catalysis as observed for 2-acylbenzoates9 or, more *To receive any correspondence (e-mail: keithb@essex.ac.uk). †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J.Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). Table 1 Rate coefficients (k2) for the alkaline hydrolysis of methyl 2-substituted benzoates and 2-substituted phenyl acetates in 30% (v/v) 1,4-dioxane–watera 102k2/dm3 molµ1 sµ1 2-Substituent At 30.0 °C At 45.0 °C At 60.0 °C l/nmb Methyl benzoates H SO2Me SOMe SMe 3.28 1.45 45.0 0.813 8.00 4.00 109 2.43 21.1 10.2 216 5.71 230 283 290 323 Phenyl acetates H SO2Me SOMe SMe 120 770 1200 95.5 313 1990 2540 232 700 4500 5070 538 292 319 312 308 aRate coefficients were reproducible to �3%.bWavelength used to monitor alkaline hydrolysis. Table 2 Activation parameters for the alkaline hydrolysis of methyl 2-substituted benzoates and 2-substituted phenyl acetates in 30% (v/v) 1,4-dioxane–water at 30.0 °Ca 2-Substituent DH‡/kcal molµ1 b DS‡/cal molµ1 Kµ1 b Methyl benzoates H SO2Me SOMe SMe 11.8 12.5 9.8 12.4 µ26 µ26 µ27 µ27 Phenyl acetates H SO2Me SOMe SMe 11.3 11.0 9.1 11.0 µ21 µ18 µ24 µ22 aValues of DH‡ and DS‡ are considered accurate to within �500 cal molµ1 and �2 cal molµ1 Kµ1, respectively. b1 cal= 4.184 J.J.CHEM. RESEARCH (S), 1997 407 likely, from a favourable conformation enhancing the electrostatic field effect. The latter would be similar to the finding in the alkaline hydrolysis of the toluene-p-sulfonate salt of methyl 2-dimethylsulfoniophenylacetate.13 The activation parameters, shown in Table 2, are those expected for a bimolecular ester hydrolysis of this type.The significantly reduced enthalpies of activation for the 2-methylsulfinyl substituted esters confirm the facilitation of ester hydrolysis by this group arising from the above effect. Thus, prodrugs employing activation of ester hydrolysis following oxidative metabolism of 2-methylsulfanyl groups have been shown to be possible in model systems; but without the great facility and tuneability of 2-acyl substituents.14 Experimental Benzoic acid, methyl benzoate, phenol, phenyl acetate and thiosalicylic acid were obtained pure commercially. 2-Methylsulfanylbenzoic acid was obtained by methylation of thiosalicyclic acid by methyl iodide in base,15 which gave the corresponding methyl ester by refluxing with methanol–concentrated sulfuric acid.15 Oxidation of the latter acid or methyl ester gave the corresponding methylsul- finyl derivatives, with 1 mol.equivalent of m-chloroperbenzoic acid,5,16 or methylsulfonyl derivatives, with 30% hydrogen peroxide. 17 Phenol reacted with dimethyl disulfide–aluminium trichloride to give 2-methylsulfanylphenol,18 which was acetylated with acetic anhydride–triethylamine to give 2-methylsulfanylphenyl acetate.19 Oxidation of the latter phenol or phenyl acetate gave either the corresponding methylsulfinyl or methylsulfonyl derivatives, with either 1 or 2 mol. equivalents of m-chloroperbenzoic acid, respectively.5,16 The purities of the acids, phenols and esters were monitored by 1H and 13C NMR and IR spectroscopy, as well as by mass spectrometry.The mps of the compounds, after repeated recrystallization and drying under reduced pressure (P2O5), or the bps of the compounds were in agreement with literature values,15,16,18–22 except for those shown below. Methyl 2-methylsulfonylbenzoate, mp 60–61 °C [colourless needles from chloroform–light petroleum (bp 40–60 °C)] (Found: C, 50.3; H, 4.7; S, 14.8.C9H10O4S requires C, 50.5; H, 4.7; S, 15.0%). 2-Methylsulfonylphenyl acetate, mp 102–103 °C [colourless crystalline solid from diethyl ether–light petroleum (bp 40–60 °C)] (Found: C, 54.2; H, 5.1; S, 16.4. C9H10O3S requires C, 54.5; H, 5.1; S, 16.2%). 2-Methylsulfinylphenyl acetate, mp 79–80 °C (colourless crystalline solid from toluene) (Found: C, 50.5; H, 4.6; S, 14.7. C9H10O4S requires C, 50.5; H, 4.7; S, 15.0%). The solvents were purified as described previously.11 Measurements.·Rate coefficients for the alkaline hydrolysis of the esters were determined spectrophotometrically by use of a Perkin-Elmer Lambda 16 UV&ndasspectrophotometer.The reactions were followed at the wavelengths shown in Table 1. The procedure used was that described previously.23 The substrate concentrations were ca. 1Å10µ4 mol dmµ3 and those of hydroxide anion were 2Å10µ3 to 6Å10µ2 mol dmµ3. The products of the reactions were found to be the anion of either the substituted benzoic acids or phenols in quantitative yield and were further confirmed spectrophotometrically by comparison of the spectrum of the acid or phenol in base with that of the reaction product.Received, 19th May 1997; Accepted, 18th August 1997 Paper E/7/03419I References 1 Part 30, K. Bowden, J. Izadi and S. L. Powell, J. Chem. Res. (S), preceding paper. 2 H. Bundgaard, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, Amsterdam, 1985, ch. 1. 3 N. M. Nielsen and H.Bundgaard, J. Med. Chem., 1989, 32, 727. 4 J. Caldwell and S. C. Mitchell, in Comprehensive Medicinal Chemistry, vol. 5, ed. J. B. Taylor, Pergamon, Oxford, 1990, ch. 23.5. 5 T. Loftsson, J. J. Kaminski and N. Bodor, J. Pharm. Sci., 1981, 70, 743; T. Loftsson and N. Bodor, J. Pharm. Sci., 1981, 70, 750, 756. 6 N. B. Chapman, J. Shorter and J. H. P. Utley, J. Chem. Soc., 1963, 1291; Y. Iskander, R. Tewfik and S. Wasif, J. Chem. Soc. B, 1966, 424; M. Hojo, M. Utaka and Z.Yoshida, Tetrahedron Lett., 1966, 19, 25. 7 T. Nishioka, T. Fujita, K. Kitamura and M. Nakajima, J. Org. Chem., 1975, 40, 2520. 8 R. W. Taft, in Steric Effects in Organic Chemistry, ed. M. S. Newman, Wiley, New York, 1956, ch. 13. 9 K. Bowden, Adv. Phys. Org. Chem., 1993, 28, 171; K. Bowden, Chem. Soc. Rev., 1995, 24, 431. 10 C. Hansch, A. Leo and D. Hoekman, Exploring QSAR Hydrophobic, Electronic and Steric Constants, American Chemical Society, Washington, 1995. 11 K. Bowden and M. J. Price, J. Chem. Soc. B, 1971, 1784. 12 K. Bowden, Org. React. (Tartu), 1995, 29, 19. 13 J. Casanova, N. D. Werner and H. R. Kiefer, J. Am. Chem. Soc., 1967, 89, 2411. 14 K. Bowden, A. P. Huntington and S. L. Powell, Eur. J. Med. Chem., in the press; K. Bowden and J. Izadi, Eur. J. Med. Chem., in the press. 15 G. Swarzenbach and E. Rudin, Helv. Chim. Acta, 1939, 22, 360. 16 R. Benassi, U. Folli, D. Iarossi, A. Mucci, L. Schenetti and F. Taddei, J. Chem. Soc., Perkin Trans. 2, 1989, 517. 17 F. G. Bordwell and P. J. Bouton, J. Am. Chem. Soc., 1957, 79, 717. 18 P. F. Ranken and B. G. McKinnie, Synthesis, 1984, 117. 19 D. M. McKinnon, Can. J. Chem., 1980, 58, 2761. 20 T. Durst, K.-C. Tin and M. J. V. Marcil, Can. J. Chem., 1973, 51, 1704. 21 P. Stoss and G. Satzinger, Angew. Chem., Int. Ed. Engl., 1971, 10, 76. 22 K. Andersen, S. Chumpradit and D. J. McIntyre, J. Org. Chem., 1988, 53, 4667. 23 K. Bowden and A. M. Last, J. Chem. Soc., Perkin Trans. 2, 1973, 345.
ISSN:0308-2342
DOI:10.1039/a703419i
出版商:RSC
年代:1997
数据来源: RSC
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13. |
A Clean and High Yield Synthesis of Oligo(butyl methacrylate) with Sulfonate End Groups using Polymer Supported Reagents† |
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Journal of Chemical Research, Synopses,
Volume 0,
Issue 11,
1997,
Page 408-409
John R. Ebdon,
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摘要:
O O O O Bu Bu O Bu O m n p HO OH O O Bu m,n or p step 1 i, ozone ii, Amberlyst A27:BH4 form (48 h, room temp.) O RSX O RO2SO OSO2R O O Bu m,n or p step 2 Amberlyst A27 (24 h, room temp.) R = Ts or Tf X = Cl or O(S02CF3) 408 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 408–409† A Clean and High Yield Synthesis of Oligo(butyl methacrylate) with Sulfonate End Groups using Polymer Supported Reagents† John R. Ebdon and Stephen Rimmer* The Polymer Centre, Lancaster University, Lancaster LA1 4YA, UK Oligo(butyl methacrylate) with sulfonate ester end groups is prepared in a two-step process involving ozonolysis of a poly(butyl methacrylate-co-butadiene) with supported reductive work-up followed by sulfonylation with a supported base.Oligomers with functional end-groups (telechelic oligomers) find uses in many important spheres such as in biomaterials, drug delivery, surface coatings and reactive processing. Clean synthesis of these materials is difficult, firstly because conventional liquid–liquid extraction of reaction mixtures of oligomers often results in the formation of stable emulsions and secondly because other purification procedures used in organic chemistry, such as recrystallization, are not generally useful. Thus, reactions on oligomers may often be extremely time consuming and are usually low-yield processes.Oligomers with sulfonate end groups have been prepared previously by several groups,1 but as far as we are aware sulfonate ester functional oligomers with acrylic or methacrylic backbones have not been reported. We have been seeking ways of synthesizing such materials using clean methodologies. One such method is to use supported reagents.Here we report a clean high-yield method of synthesizing sulfonate ester functional oligomers. The main feature of this synthesis is that the steps involve immobilization of all the reagents and by-products on solid supports, so that simple filtration is the only purification step necessary.The use of a supported strategy also has a second advantage, that is that it is possible to compensate for the low concentration of functional groups (end groups) by using a large excess of the supported reagent. The method is outlined below and represented schematically in Scheme 1. Synthesis of Oligo(butyl methacrylate) with Hydroxy End Groups (OBMA+2OH).—In the first step, an unsaturated polymer was ozonized and then worked up with borohydride supported on Amberlyst A27.The details of this step have been reported previously.2 The number average molecular weight, Mn, of the hydroxy ended oligomer was 1700 g molµ1 (measured by GPC, calibrated against polystyrene standards). Synthesis of Sulfonate Ester Functional Oligo(butyl methacrylate) with Sulfonate Ester End Groups (OBMA+2 Tf and OBMA+2Ts).—The results from the second step are recorded in Table 1. Initially, reactions with the non-supported amine, triethylamine, were attempted.This reaction gave close to a quantitative yield of tosylated oligomer when the reaction was carried out in toluene, but very low yields were obtained in dichloromethane. However, while the majority of the amine hydrochloride precipitated from the toluene solution, a significant amount of salt remained in solution. Also, excess toluene-p-sulfonyl chloride remained in solution. In a small molecule reaction these by-products would be removed by aqueous extraction.When this was attempted with this system, stable emulsions resulted. These emulsions did phase-separate but only after settling for approximately 1 week. The amount of material recovered from this reaction was approximately 50% of that charged and it was still contaminated with large amounts of toluenep- sulfonic acid. This then is clearly an impracticable route. The replacement of the triethylamine with a supported amine solved these problems.Thus tosylated and triflated oligomers were prepared by using Amberlyst A21 as the base. All of the hydrochloride by-product was removed by simply filtering off the resin. Similarly, it was possible to drive the reaction to high yield by using a large excess of sulfonyl derivative/amine reagent. Since the excess reagent is also bound to the resin, removal of this is no longer problematic. *To receive any correspondence (e-mail: s.rimmer@ lancaster.ac.uk). †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J.Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). Table 1 Results of sulfonation ester synthesis Mass yield Yield of sulfonate Solvent R X Amine (mass%) end groups (mol%) Dichloromethane Toluene Toluene Toluene Toluene Toluene Ts Ts Ts Tf Tf Tf Cl Cl Cl OSO2CF3 OSO2CF3 Cl TEA TEA A21 TEA A21 A21 50 50 100 50 100 100 0 99+ 99+ 50 99+ 99+ R and X refer to the structures in Scheme 1, i.e.R=Ts or Tf; X=Cl or O(SO2CF3) Scheme 1 Steps in the synthesis of sulfonate ester functional oligo(butyl methacrylate)J. CHEM. RESEARCH (S), 1997 409 It is noteworthy that the choice of solvent is important in both the supported reaction and the non-supported reaction. At this stage insufficient data are available to determine whether this is an observation of general significance or if it is a feature of oligo(butyl methacrylate) reactions.The FTIR spectrum of a triflated product is shown in Fig. 1. The complete absence of an IR absorption peak associated with hydroxy stretching (at 3200–3000 cmµ1) is clear evidence of the success of these reactions. Also, a new band at 1820 cmµ1, associated with the sulfonate end group, can be seen. The sulfonate end groups could also be observed in the 1H NMR spectrum (CH2 a to the sulfonate group observed at 4.1–4.2 ppm). Fig. 2 shows the 1H NMR spectrum. These spectra also illustrate the high purity of the materials prepared using this methodology, the only impurity being from the remnants of toluene.Thus we have shown that it is possible to prepare, in quantitative yield, oligomers with sulfonyl ester end groups using a supported amine and sulfonyl derivatives. The products are not contaminated with by-products or reagents and are easily recovered. Work is continuing on further nucleophilic substitution reactions on the end groups. Experimental Preparation of Hydroxy Functional Oligo(butyl methacrylate) (OBMA+2OH).—Monomer-starved emulsion polymerization was used to prepare poly(butyl methacrylate-co-butadiene) (PBMAco- BD); the recipe has been previously published.2 The feed contained 17 mol% butadiene while the final polymer contained 12.5 mol% alkene units attributable to butadiene residues (as measured by 1H NMR).The Mn of the polymer was 209 kg molµ1 (GPC calibrated with polystyrene standards). The polymer was isolated from the latex by coagulation in a saturated solution of magnesium sulfate.The polymer was then redissolved in acetone and precipitated into methanol. This was repeated twice. The PBMA-co-BD (20 g) was dissolved in distilled chloroform and ozonized at room temperature for 24 h. Ozone was generated by an electric discharge- type generator and was fed in at a rate of 74 g hµ1. After this time, nitrogen was passed through the vessel for 10 min so that excess ozone could be removed.The solution was then added to a column packed with Amberlyst A27 in the BH4 µ form (10 g). The polymer solution was recirculated through the column, by means of a peristaltic pump, for 48 h. The solvent was then removed to yield a highly viscous colourless oil. Mn=1740 g molµ1 (GPC), dC CH2OH=59.2, 59.7, 60.2. Yield=100%). Preparation of Sulfonate Ester Functional Oligo(butyl methacrylate). ·Reactions with non-supported amine were first attempted as follows: (i) OBMA+2OH (2.5 g) was dissolved in dry dichloromethane (10 ml).Triethylamine (TEA) (1.3 g) was then stirred with tosyl chloride (TsCl) (0.36 g) for 30 min. The dichloromethane solution was then added and the reaction left stirring for 1 week. The solid was filtered off and the product washed with deionized water. This resulted in the production of stable emulsions so that purification took several months to effect. (ii) OBMA+2OH (30 g) was dissolved in toluene (100 ml). TsCl (15.2 g) was mixed with freshly distilled TEA (30 ml) for 30 min. The solution of OBMA+2OH was then added. The reaction was stirred for 5 d at room temperature, after which the precipitate was filtered off and the solution washed with deionized water. Again stable emulsions resulted from this aqueous work-up. Reaction with supported amine Amberlyst A21. OBMA+2OH (2 g) was dissolved in distilled toluene (or chloroform) (80 cm3). Amberlyst A21 that had been thoroughly washed with ethanol and then vacuum dried was added. The sulfonyl derivative was then added (5 g). The beads were agitated by passing dry nitrogen through the vessel for 24 h. Then the beads were filtered off. Received, 3rd June 1997; Accepted, 9th July 1997 Paper E/7/03859C References 1 L. Vandenberge, S. Vandamme, M. J. O. Anteunism and D. Tavernier, Bull. Soc. Chim. Belg., 1991, 100, 115 and references cited therein. 2 S. Rimmer, J. R. Ebdon and M. J. Shepherd, React. Funct. Polym., 1995, 26, 145. Fig. 1 FTIR spectrum of triflated OBMA+2OH Fig. 2 1H NMR spectrum of triflated OBMA+2OH
ISSN:0308-2342
DOI:10.1039/a703859c
出版商:RSC
年代:1997
数据来源: RSC
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14. |
Oxidation of Isothiocyanates to Isocyanates using Dimethyldioxirane; Relevance to Biological Activity of Isothiocyanates† |
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Journal of Chemical Research, Synopses,
Volume 0,
Issue 11,
1997,
Page 410-411
Nicola E. Davidson,
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摘要:
O OH HO HO HO S Ph N OSO3 – K+ Myrosinase PhCH2N C S 1 2 NO2 O P (EtO)2 S 3 NO2 O P (EtO)2 S + [S] Liver Microsomes or CF3CO3H 410 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 410–411† Oxidation of Isothiocyanates to Isocyanates using Dimethyldioxirane; Relevance to Biological Activity of Isothiocyanates† Nicola E. Davidson and Nigel P. Botting* School of Chemistry, University of St. Andrews, St. Andrews, Fife KY16 9ST, UK The reaction of organic isothiocyanates with dimethyldioxirane in acetone produces isocyanates in good yields, trapped out as the ureas by reaction with isopropylamine.Organic isothiocyanates are widely distributed in plants, including cruciferous vegetables1 such as Brussels sprouts, cauliflower and broccoli. They in fact exist as glucosinolates2 1 and are only released by the action of the enzyme myrosinase, when the plant is damaged or cooked. The occurrence of isothiocyanates in the diet means that there is considerable interest in their biological activities. Some, including benzyl isothiocyanate 2 and phenethyl isothiocyanate, two of the most commonly occurring compounds, have anti-carcinogenic properties.Thus administration of benzyl isothiocyanate prior to treatment with the carcinogen N-nitrosodiethylamine inhibited tumour formation in A/J mice,3 while phenethyl isothiocyanate inhibits induction of lung tumourigenesis by NNK [4-(methylnitrosamino)- 1-(3-pyridyl)butan-1-one] in the forestomach and lung of mice.4 Two potential mechanisms for this anti-carcinogenic action have been proposed.Firstly, the isothiocyanates have been shown to induce phase 2 detoxification enzymes.5 Increased levels of these enzymes result in more rapid removal of the carcinogenic species. Secondly, the isothiocyanates have also been found to inhibit metabolic activation of the carcinogen.6 For example, NNK requires a-hydroxylation by cytochrome P-450 enzymes in order to produce the active carcinogen. Phenethyl isothiocyanate specifically inactivates the P-450 enzymes responsible for this hydroxylation thus preventing activation.The relative importance of these two effects is still open to debate. The chemical mechanism of the inhibition of the cytochrome P-450 enzymes by isothiocyanates is not understood. Isothiocyanates are reactive compounds, readily attacked by nucleophiles. Indeed, they are often used to label proteins by reaction with free amino groups, e.g.using fluorescein isothiocyanate. However, cytochrome P-450 enzymes catalyse oxidation reactions and so it is likely that when the isothiocyanates initially interact with the enzyme they undergo an oxidation reaction, producing a more reactive species which is then responsible for the inactivation. This may also explain the specificity observed, in that there is some activation of the isothiocyanate required in order to produce the inhibitor giving an example of suicide (mechanism-based) inhibition.The insecticides parathion 3 and malathion,7 containing a P�S group, undergo oxidative desulfuration by mammalian liver microsomes to give a P�O group and elemental sulfur (Scheme 2). Model studies using trifluoroperacetic acid resulted in the same transformation. Furthermore, analogous conversions of thiocarbonyl groups to carbonyl groups have also been observed.8 If a similar pathway operates for the oxidation of isothiocyanates, a much more reactive isocyanate would be produced at the enzyme active site.This could then acylate an appropriate amino acid side chain causing inactivation of the cytochrome P-450. There is some evidence for the conversion of 2-naphthyl isothiocyanate to 2-naphthyl isocyanate by rat liver microsomes, but only in very low yields (s0.6% conversion).9,10 The chemical oxidation of isothiocyanates has thus been examined as a model for these biological systems. Prior to this work there were only two previous reports of the conversion of isothiocyanates to isocyanates.In 1890 Kuhn and Lieber reported that heating an isothiocyanate with mercuric oxide at 170 °C gave ca. 20% of the corresponding isocyanate.11 More recently,12 the conversion was achieved using palladium(II) chloride in refluxing 1,4-dioxane. Good to excellent yields of isocyanates were obtained using a range of alkyl and aryl derivatives. The other product in this case was thionyl chloride.However to date no nonmetal- catalysed oxidative conversion of isothiocyanates to isocyanates has been reported. The electrophilic nature of isothiocyanates means that the oxidising agent must be carefully chosen to reduce the possibility of competing nucleophilic attack on the central carbon of the heterocumulene system. Dimethyldioxirane (DMD) thus proved to be the most appropriate reagent, as it is a very reactive non-nucleophilic oxidising agent with acetone as its only by-product.13 When benzyl isothiocyanate was reacted with a solution of DMD14 in dry acetone at room temperature analysis by GCMS showed complete consumption of the isothiocyanate after 15 min and only one major product.The product had an identical retention time and mass spectrum to authentic benzyl isocyanate. The identity of the compound was confirmed by addition of isopropylamine to the reaction solution, which resulted in a decrease in the peak due to the isocyanate and the appearance of a new peak, shown to be due to the 1-isopropyl-3-benzylurea by its mass spectrum.The reaction presumably proceeds via an oxathiirane type intermediate 4 (Scheme 3), formed via either initial transfer of oxygen to sulfur and cyclisation, or direct insertion of oxygen into the carbon–sulfur double bond. Similar mechanisms are proposed for the oxidation of other thiocarbonyl compounds. A range of isothiocyanates were then reacted with DMD and the isocyanates isolated as their urea derivatives 5 following trapping with isopropylamine. The optimised yields of the 1-isopropylureas were good to excellent for a range of isothiocyanates (Table 1), including both alkyl and aryl deriva- *To receive any correspondence.†This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). Scheme 1 Scheme 2R N C S DMD Acetone R N C S+ O– R N C O S R N C O + [S] 4 Trapping with isopropylamine N N O R H H 5 J.CHEM. RESEARCH (S), 1997 411 tives. The best yields were obtained using a five-fold excess of DMD. It could be argued that the amine and isothiocyanate initially react to form the thiourea which can then be oxidised to the urea by DMD. However, examination by both GCMS and TLC, against the authentic thiourea, gave no evidence for its formation during the reaction. It was also observed that reaction of the isothiocyanates with isopropylamine was much slower than the observed oxidation of the isothiocyanate to the isocyanate.It thus seemed most likely that the reaction followed the pathway as given in Scheme 3. However, attempts were made to isolate the isocyanates directly from the reaction solution. Unfortunately, these were hampered by both the small scale of the reactions, due to the low concentrations of DMD available, and by competing hydrolysis, illustrated by the recovery of 1,3-diphenylurea in 94% yield from the attempted isolation of phenyl isocyanate.The latter arises from the difficulty observed in obtaining sufficiently dry solutions of DMD in acetone. The presence of the free isocyanate in the reaction solution was finally demonstrated by means of FTIR studies. In acetone solution benzyl isothiocyanate gave peaks at 2169 and 2092 cmµ1. The addition of DMD gave rise to new peaks at 2276 and 2341 cmµ1. The former peak was identical to that produced by authentic benzyl isocyanate.The peak at 2341 cmµ1 was found to be due to dissolved carbon dioxide, presumably arising from hydrolysis of the isocyanate. Indeed the hydrolysis of authentic isocyanate could be monitored in both acetone and the DMD solution. The fate of the sulfur produced in the reaction has not been elucidated. However in some of the GCMS analyses there is evidence for a species similar tmethyl disulfide or dimethyl sulfone.The observation of such oxidised sulfur species accounts for the requirement for excess DMD in order to obtain good yields. A number of other oxidising agents were also examined. m-Chloroperbenzoic acid (MCPBA) and trifluoroperacetic acid will carry out the transformation, although in both cases competing reactions lower the yields. With the MCPBA reactions, competing nucleophilic attack by m-chlorobenzoic acid, a contaminant and by-product, produces the amide following rearrangement and loss of CO2.With trifluoroperacetic acid the aqueous conditions employed for reaction cause hydrolysis of the isocyanate. It was found that using equimolar amounts of both these oxidising agents the yields of benzyl isocyanate from the corresponding isothiocyanate were 25 and 5% respectively, compared to a yield of 58% with equimolar DMD. The ozonolysis of benzyl isothiocyanate was also briefly examined, in dichloromethane at 0–5 °C. In this case most of the isothiocyanate remained unchanged, with only small amounts (ca. 3%) of the isocyanate and some benzaldehyde (ca. 10%). It was not clear whether the latter came from direct reaction of the isothiocyanate or from the isocyanate. In summary these studies have shown that organic isothiocyanates can be efficiently converted to isocyanates via oxidation with DMD. These observations lend credence to the proposal that a similar reaction may be catalysed by cytochrome P-450 enzymes, during their reaction with, and inactivation by, isothiocyanates.The non-nucleophilic nature of DMD makes it a good reagent for this transformation, although it has also been observed to much lesser extents with other oxidising agents. Experimental Dimethyldioxirane (DMD) was synthesised according to the method of Mello et al.14 as a solution in acetone. The concentration was determined by NMR analysis of the oxidation of methyl phenyl sulfide in CDCl3.14 The GCMS analyses were carried out using a Hewlett-Packard 5890A gas chromatograph, with SGE BP1 column and a linear temperature gradient from 30 to 300 °C, attached to a Finnigan MAT Incos mass spectrometer. 1H and 13C NMR spectra were obtained using a Varian 2000 FT spectrometer (1H, 300 MHz; 13C, 75.42 MHz) and a Varian Gemini FT spectrometer (1H, 200 MHz; 13C, 50.31 MHz). FTIR spectra were recorded on a Perkin Elmer 1710 spectrophotometer. General Procedure.·In a typical reaction phenyl isothiocyanate (150 mg, 1.11 mmol) was added to a solution of DMD (440 mg, 6.0 mmol) in dry acetone (180 ml) and stirred under nitrogen at room temperature for 15 min.Analysis by GCMS indicated the reaction was complete and isopropylamine (1.12 g, 18.9 mmol) was added at 0 °C. This mixture was then stirred under nitrogen for 1.5 h prior to filtration and concentration under reduced pressure. The crude product was purified by column chromatography on silica, eluting with ethyl acetate–light petroleum (bp 40–60 °C) (30:70).This afforded the product as a white solid (200 mg, 89%), mp 160 °C (lit.,15 156 °C); vmax (nujol)/cmµ1 3350 (NH), 1650 (CO), 700, 750 (Ph); dH (200 MHz; CDCl3) 1.23 [6 H, d, J 7 Hz, CH(CH3)2], 3.97 [1 H, m, CH(CH3)2], 5.53 (1 H, d, J 7 Hz, NHCH), 6.97–7.32 (5 H, m, ArH), 7.54 (1 H, br s, ArNH); dC (50.31 MHz; CDCl3) 23.68 [CH(CH3)2], 42.47 [CH(CH3)2], 120.59, 123.42, 129.54 (aromatics), 139.63 (quat. aromatic), 156.38 (CO); m/z (EI) 178 (M+, 13%), 119 (2, PhNCO+), 93 (100, PhNH2 +), 77 (4, Ph+).N. P. B. is currently a RSE/SOED Research Fellow. N. E. D. wishes to thank St. Leonard’s College and the University of St. Andrews for funding. Received, 20th June 1997; Accepted, 22nd July 1997 Paper E/7/04356B References 1 M.-T. Huang, T. Osawa, C.-T. Ho and R. T. Rosen, Food Phytochemicals for Cancer Prevention (Fruits and Vegetables), ACS Symposium Series 546, American Chemical Society, Washington, 1994. 2 Y. S. Zhang and P.Talalay, Cancer Res., 1994, 54, 1976. 3 G. R. Fenwick, R. K. Heaney and W. J. Mullin, CRC Rev. Food Sci. Nutr., 1983, 18, 123. 4 L. W. Wattenberg, J. Natl. Cancer Inst., 1977, 58, 395. 5 L. W. Wattenberg, Cancer Res., 1992, 52, 2085. 6 C. S. Yang, T. J. Smith and H.-Y. Hong, Cancer Res., 1994, 54, 1982. 7 K. A. Ptashne and R. A. Neal, Biochemistry, 1972, 11, 3224. 8 B. Testa and P. Jenner, Drug Metabolism Rev., 1981, 12, 1. 9 M.-S. Lee, Chem. Res. Toxicol., 1992, 5, 791. 10 M.-S. Lee, Environ. Health Perspect., 1994, 102, 115. 11 B. Kuhn and M. Lieber, Chem. Ber., 1890, 23, 1536. 12 S. M. Parashewas and A. A. Danopoulos, Synthesis, 1983, 8, 638. 13 W. Adam, R. Curci and J. O. Edwards, Acc. Chem. Res., 1989, 22, 205. 14 R. Mello, M. Fiorentino, C. Fusco and R. Curci, J. Am. Chem. Soc., 1989, 111, 6749. 15 J. W. Boehmer, Recl. Trav. Chim. Pays-Bas, 1936, 55, 379. Scheme 3 Table 1 Optimised yields of 1-isopropylureas obtained from the oxidation of organic isothiocyanates with DMD and trapping with isopropylamine. Reaction carried out in acetone at room temperature, with a 5-fold excess of DMD, using 1 mmol of isothiocyanate (see General Procedure) Isothiocyanate Isolated yield of (R·N�C�S) ureaa 5 (%) Benzyl Phenethyl Phenyl Butyl 84 67 89 71 aAll the products gave satisfactory spectral d
ISSN:0308-2342
DOI:10.1039/a704356b
出版商:RSC
年代:1997
数据来源: RSC
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15. |
Chromone Studies. Part 9.1Dynamic NMR Analysis of Rotational Isomerism in 2-(N,N-Dialkylamino)chromones |
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Journal of Chemical Research, Synopses,
Volume 0,
Issue 11,
1997,
Page 414-415
Perry T.Kaye Kaye,
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摘要:
R2 R3 OH O R2 R3 O OH S R2 R3 OH OMe O R2 R3 O O O2N O O NMe2 R1 iv i,ii,iii v,vi,vii viii,ix,x xi (For 1a) 1a–k 4a,i 1l 2a,c,f–h 3a,b,j–k R3 OH 5a,b,d,e CO2Et CH2 COR1 6 xii a bc def NMe2 NEt2 NMe2 NMe2 NEt2 NMe2 NMe2 NMe2 NMe2 HH OMe HHHHH Cl HHH OMe OMe F Cl Br H R1 R2 R3 N[CH2]3CH2 N[CH2]4CH2 NMe2 j k l H H H H NO2 H g hi 414 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 414–415† Chromone Studies. Part 9.1 Dynamic NMR Analysis of Rotational Isomerism in 2-(N,N-Dialkylamino)chromones† Perry T.Kaye* and Isaiah D. I. Ramaite Department of Chemistry, Rhodes University, P.O. Box 94, Grahamstown, 6140, South Africa Dynamic 1H NMR spectroscopy has been used to explore the influence of substituents on the internal rotation of the amino group in a series of twelve 2-(N,N-dialkylamino)chromones; the rotational barriers (DG‡) in CDCl3 and CD2Cl2 were found to range from 38 to 52 kJ molµ1. In previous dynamic NMR studies of chromone derivatives we have investigated internal rotation in chromone-2-carboxamides2 and chromone-derived acrylamides.1 In these studies it became apparent that A-ring substituents have little effect on the somewhat remote carboxamide and enamine rotors.In the 2-amino derivatives examined here, however, it was anticipated that substituent effects on the electron density at C(2) would be clearly reflected in the relative magnitudes of the C(2)·N rotational barriers. The title compounds 1a–l were synthesised using the established routes outlined in Scheme 1.3–7 The A-ring substituents were chosen to elucidate the influence of electronreleasing and electron-withdrawing substituents on the C(2)·N rotational barriers and, hence, the electron-density at C(2), while symmetrically disubstituted 2-amino groups were selected to facilitate interpretation of the dynamic NMR data.For each of the compounds studied, splitting of the N-alkyl signals was observed (see Fig. 1), coalescence occurring in the temperature range 194–267 K (Table 1).The splitting is attributed to hindered rotation of the dialkylamino moiety about the C(2)·N bond, arising from the delocalisation effects illustrated in Fig. 2(a). Examination of the data in Table 1 reveals several interesting trends. (i) While the variation in the DG‡ values is typically small (DG‡=44.9�1.2 kJ molµ1 for compounds 1a–i,l) relative to the estimated error, the electronic effects of the A-ring substituents are, in fact, discernible.Electron-withdrawing groups enhance nitrogen lone pair delocalisation [Fig. 2(a)] and thus increase the rotational barrier, while electron-releasing groups have the opposite effect [DG‡ for 1l (R2=NO2)a1i (R2=Cl)a1a (R2=H)a1c (R2=OMe) and for 1f (R3=Cl)a1g (R3=F), 1a (R3=H)a1d (R3=OMe).‡ (ii) Changing the N-alkyl substituents from methyl to ethyl is accompanied by an increase in DG‡ (cf. compounds 1a and 1b, and 1d and 1e), reflecting the greater electron-releasing inductive effect of ethyl relative to methyl.(iii) Compared to the ‘parent’ system 1a, the pyrrolidinyl derivative 1j exhibits a significantly higher rotational barrier, while the piperidinyl analogue 1k has a correspondingly lower value for DG‡. In our investigation of N,N-disubstituted chromone-2-carboxamides,2 the N·CO rotational barrier for the pyrrolidinyl derivative was also significantly higher than for the piperidinyl analogue · an observation attributed to the greater ease with which the pyrrolidine nitrogen assumes the planar sp2 arrangement necessary for effective lone-pair delocalisation.The insolubility of the piperidinyl analogue (1k) in CDCl3 necessitated a solvent change (to CD2Cl2); however, this is considered unlikely to affect the magnitude of DG‡ significantly, given the similarity of the data obtained for the pyrrolidinyl analogue 1j in both solvents (DG‡ 52.3�0.1 kJ molµ1). (iv) The rotational barriers measured for the 2-(dimethylamino)chro- *To receive any correspondence (e-mail: chpk@hippo.ru.ac.za).†This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). ‡Both 6- and 7-substituents (i.e. R2 and R3) are capable of mesomeric interaction with C-2 (see ref. 8). Scheme 1 Reagents and conditions: i, BF3.OEt2, Et2O; ii, Cl2C=N+Me2Clµ, Cl[CH2]2Cl2; iii, MeOH, 50 °C; iv, ButOK, CS2, C6H6; v, K2CO3, EtI, (MeCO)2O; vi, MCPBA, Cl[CH2]2Cl; vii, R2NH (R=Me, Et); viii, LDA, THF; ix, MeCONMe2; x, Tf2O, CH2Cl2; xi, conc.H2SO4–conc. HNO3; xii, EtO2CCH2CONR2 (R=Me, Et), POCl3 Fig. 1 Partial 1H NMR spectra of compound 1i in CDCl3 at selected temperaturesO O N R¢ R¢ R •• O O– N R¢ R¢ R + ( a) O H O R O O N R¢ R¢ R ( b) NMe2 CONMe2 •• ( c) •• J. CHEM. RESEARCH (S), 1997 415 mones (DG‡ ca. 44 kJ molµ1) lie between those determined for 1-(dimethylamino)cyclohexene (24.9 kJ molµ1)9 and for the conjugated enamine, 4-(dimethylamino)but-3-en-2-one (55.9 kJ molµ1).10 The influence of conjugation is particularly evident in the chromone-derived enamines examined previously [see Fig. 2(b)],1 which exhibit unusually high rotational barriers (ca. 67 kJ molµ1). Although the enamine moiety in the title compounds 1 is conjugated with the carbonyl group, nitrogen lone-pair delocalisation is presumably inhibited by competitive delocalisation involving the chromone ether oxygen [see Fig. 2(c)], thus accounting for the somewhat lower rotational barriers observed for these compounds. Experimental The 2-aminochromones required for this study were obtained following the literature methods3–7 outlined in Scheme 1. Compounds 1a, 1b, 1d, 1e, 1h and 1k are known; analytical data for the remaining compounds, which are new and which gave satisfactory NMR (1H and 13C) and MS data, are summarised in Table 2.Variable-temperature 1H NMR spectra were recorded for solutions of the 2-aminochromones 1a–l in CDCl3 or CD2Cl2 on a Bruker AMX 400 NMR spectrometer, equipped with a variable temperature unit, which has been calibrated using 80% ethylene glycol in (CD3)2SO. Temperature stability was judged to be �0.1 K and the overall error in coalescence temperatures (Tc) estimated to be �2 K. Frequency separations at coalescence (Dvc) were obtained by extrapolation as described by Lai and Chen.12 We thank the Deutscher Akademischer Austauschdienst (DAAD) and the Foundation for Research Development (FRD) for bursaries (to I.D. I. R.), and Rhodes University and the FRD for generous financial support. Received, 24th April 1997; Accepted, 23rd July 1997 Paper E/7/02801F References 1 Part 8, P. T. Kaye and I. D. I. Ramaite, J. Chem. Res. (S), 1995, 78. 2 D. N. Davidson and P. T. Kaye, J. Chem. Soc., Perkin Trans. 2, 1991, 927. 3 J. Morris, D. G. Wishkia and Y.Fang, J. Org. Chem., 1992, 57, 6502. 4 J. R. Bantick and J. L. Suschitzky, J. Heterocycl. Chem., 1981, 18, 679. 5 J. A. Morris, G. Donn and Y. Fang, Synth. Commun., 1994, 24, 849. 6 A. Balbi, G. Roma, M. Mazzei and A. Ermili, Farmaco, Ed. Sci., 1983, 38, 784; A. Ermili, A. Balbi, M. Di Braccio and G. Roma, Farmaco, Ed. Sci., 1977, 32, 713. 7 A. Balbi, G. Roma, M. Mazzei and A. Ermili, Farmaco, Ed. Sci., 1983, 38, 784. 8 D. N. Davidson, P. T. Kaye and I. D. I. Ramaite, J. Chem.Res. (S), 1993, 462. 9 J. E. Anderson, D. Casarini and L. Lunazzi, Tetrahedron Lett., 1988, 29, 3141 (Chem. Abstr., 1989, 10, 134396g). 10 J. Dabrowski and L. Kozerski, Org. Magn. Reson., 1973, 5, 469. 11 R. J. Smith, D. H. Williams and K. James, J. Chem. Soc., Chem. Commun., 1989, 682. 12 Y. H. Lai and P. Chen, J. Chem. Soc., Perkin Trans. 2, 1989, 1665. Table 1 Dynamic 1H NMR data for internal rotation of the N,N-dialkylamino moiety in compounds 1a–l Tc/ DvC/ DG‡c/ Compd.R1 R2 R3 Ka Hzb kJ molµ1 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l NMe 2 NEt2 NMe2 NMe2 NEt2 NMe2 NMe2 NMe2 NMe2 l l N[CH2]3CH2 l l N[CH2]4CH2 NMe2 HH OMe H H NO2 HHH OMe OMe Cl F Br HH HH 222 226 219 213 219 223 221 222 225 267 264e 194e 233 81.8 78.3 65.6 43.2 72.0 72.4 73.5 77.7 83.0 142.4d 115.9d 120.3d 95.0 44.2 45.1 44.0 43.5 43.8 44.7 44.2 44.3 44.8 52.4 52.2 37.8 46.1 aCoalescence temperature (�2 K) in CDCl3. bFrequency separation of bands at coalescence; estimated errors R�2.0 Hz.cFree energy of activation for rotation, DG‡=RTc (22.96+ln Tc/Dvc) (see ref. 11); estimated errors �0.5 kJ molµ1. dFor NCH2 signals. eVariable temperature spectra recorded in CD2Cl2. Table 2 Analytical data for new 2-aminochromones 1 Compd. R1 R2 R3 Mp/°C Found Mol. formula Required 1c 1f 1g 1h 1i 1j 1l NMe2 NMe2 NMe2 NMe2 NMe2 l l N[CH2]3CH2 NMe2 OMe HHH Cl NO2 H Cl F Br HHH 150–152a 185a 138–140a 203b 158–160a 148–150c 216–218d C, 65.2; H, 6.05; N, 6.3% M+, 219.0886 C, 58.5; H, 4.5; N, 6.1% M+, 223.0408 M+, 207.0679 M+, 266.9884 C, 58.6; H, 4.5; N, 6.3% M+, 223.0398 C, 72.6; H, 6.2; N, 6.3% M+, 234.0632 C12H13NO3 C11H10ClNO2 C11H10FNO2 C11H10BrNO2 C11H10ClNO2 C13H13NO2 C11H10N2O4 C, 65.7; H, 5.9; N, 6.4% M, 219.0895 C, 59.2; H, 4.5; N, 6.3% M, 223.0400 M, 207.0696 M, 266.9895 C, 59.1; H, 4.5; N, 6.3% M, 223.0400 C, 72.6; H, 6.05; N, 6.5% M, 234.0641 aFrom EtOAc. bFrom MeOH–CH2Cl2. cFrom ligroin. dFrom EtOH. Fig. 2 (a) Nitrogen lone-pair delocalisation inhibiting rotation about the N·C(O) bond in 2-aminochromones; (b) conjugative effects in chromone-derived acrylamides; and (c) competitive delocalisation involving the chromone ether
ISSN:0308-2342
DOI:10.1039/a702801f
出版商:RSC
年代:1997
数据来源: RSC
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16. |
Unusual Trifluoroacetic Anhydride Promoted Fragmentation of aγ,γ,γ-Trifluoro-β-(p-methoxyphenyl-amino) Sulfoxide† |
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Journal of Chemical Research, Synopses,
Volume 0,
Issue 11,
1997,
Page 416-417
Alberto Arnone,
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摘要:
NH MeO p-TolS CF3 p-Tol S CF3 O NHPMP 1 p-Tol S CF3 O NH2 PMP A CF3CO2 – + TFA TFAA MeO CF3CO2 S NH2 + CF3 p-Tol + CF3CO2 – B S NH MeO CF3 p-Tol •CF3CO2H CF3CO2 – 2 –CF3CO2H CF3CO2 – + S NH MeO CF3 p-Tol •CF3CO2H CF3CO2 – + 2 1 2 S NH MeO CF3 p-Tol CF3CO2 S -p-Tol MeO NH2 3 S -p-Tol MeO N 4 CF3 Me CH2Cl2 reflux NEt3 (2 equiv) HCl 1M 5 S NH MeO CF3 p-Tol •CF3CO2H + CF3CO2 – H 2 1 S H2C NH MeO CF3 p-Tol + 2 CF3CO2H heat or NEt3 C S Me N MeO CF3 p-Tol 4 2 CF3CO2H + + CF3COMe S NH2 MeO p-Tol H2O 3 416 J.CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 416–417† Unusual Trifluoroacetic Anhydride Promoted Fragmentation of a g,g,g-Trifluoro-b-(p-methoxyphenylamino) Sulfoxide† Alberto Arnone,a Pierfrancesco Bravo,*b Luca Bruch�e,b Marcello Crucianelli,b Matteo Zanda*b and Carmela Zappal`aa aC.N.R. - Centro di Studio sulle Sostanze Organiche Naturali, via Mancinelli 7, 20131 Milano, Italy bDipartimento di Chimica, Politecnico, via Mancinelli 7, 20131 Milano, Italy The reaction of a g,g,g-trifluoro-b-(p-methoxyphenylamino) sulfoxide with trifluoroacetic anhydride under Pummerer conditions occurs in an abnormal fashion, providing an excellent yield of the cyclic six-membered sulfonium salt arising from intramolecular interception of the usual trifluoroacetoxy-sulfonium intermediate by the electron rich p-methoxyphenyl group.The Pummerer reaction (PR) of N-monoprotected b-aminosulfoxides has been rarely investigated so far.1 We have recently reported that g-fluoro-b-(N-Z-amino) sulfoxides undergo an unusual ‘non-oxidative’ PR promoted by tri- fluoroacetic anhydride (TFAA) and sym-collidine.2 By this reaction the sulfinyl group can be efficiently and stereoselectively displaced one-pot by a trifluoroacetoxy group in an SN2 fashion.As an extension to our work on the synthesis of chiral fluoro-organic molecules we devised a stereoselective preparation of the 2-trifluoromethyl substituted indoline ring.Based on encouraging results reported in literature, 3 we expected to obtain the target framework via a Pummerer cyclization of the g,g,g-trifluoro-b-(p-methoxyphenylamino) sulfoxide 1. The sulfoxide 1 is readily and stereoselectively available through reduction of the corresponding g-fluoro-b-imino sulfoxide4 or condensation of lithiated methyl p-tolyl sulfoxide with the N-p-methoxyphenyl imine of trifluoroacetaldehyde. 2b Disappointingly, addition of TFAA (1.2 equiv.) to a THF solution of 1 (Scheme 1) resulted in the formation of unidentified by-products (TLC).None of the expected indoline products could be detected by careful examination of the crude reaction mixture. However, a polar compound was isolated which proved to be the cyclic sulfonium trifluoroacetate 2 (50% yield).5 Next, we found that preliminary treatment of 1 with trifluoroacetic acid (TFA), followed by TFAA, produced an almost quantitative yield of the salt 2. The presence of two trifluoroacetoxy groups for each molecule was shown by 19F and 13C NMR analysis.Clearly, the sulfonium trifluoroacetate 2 is produced via trapping of the trifluoroacetoxy-sulfonium cation B by the electron rich p-methoxyphenyl group. The improvement obtained by using TFA suggests that 2 could arise from the ammonium trifluoroacetate A, while the direct reaction of 1 with TFAA should follow other pathways, producing the observed by-products. The chemical behaviour of the sulfonium salt 2 has been investigated (Scheme 2).Surprisingly, upon refluxing the salt 2 in methylene chloride for 4 h the amine 3 was obtained in 46% yield, together with small amounts of the imine 4. The same reaction, though at a much slower rate, was found to occur spontaneously upon storage of neat 2 at 4 °C. Formation of compound 5, expected on the basis of literature reports,5a,b arising from intramolecular nucleophilic attack of the trifluoroacetoxy anion onto the C-1 sp3 carbon and C·S bond breaking, was not observed. On the other hand, treatment of 2 with triethylamine (2 equiv.) resulted in the formation of the trifluoroacetone imine 4 in 90% yield.A reasonable pathway for the formation of 3 and 4 from 2 is shown in Scheme 3. *To receive any correspondence. †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem.Research (M). Scheme 1 (PMP=p-methoxyphenyl) Scheme 2 Scheme 3J. CHEM. RESEARCH (S), 1997 417 The trifluoroacetoxy counterion of compound 2 or triethylamine might promote the b-elimination, triggered by the removal of H-2, unusually acidic for the presence of the strongly electron withdrawing CF3 group. This should lead to the enamine C, which is expected to tautomerize readily to the imine 4. In the absence of a base, the resulting imine 4 can be hydrolysed to the amine 3 and trifluoroacetone (which is highly volatile and could not be isolated) by the 2 equiv.of TFA formed in the process. We checked the relationship existing between 3 and 4 by treating the latter with TFA or with a 1 M aqueous HCl solution overnight: the expected amine 3 was formed in 80% yield, confirming its proposed origin. Experimental The instrumentation and general experimental and analytical procedures have been recently described in detail.6 g,g,g-Trifluoro- b-(p-methoxyphenylamino) sulfoxide 1 was prepared according to literature procedures.2b,4 Sulfonium Trifluoroacetate 2.·A methylene chloride solution (3 ml) of 1 (1 mmol), cooled at 0 °C was treated with 0.22 ml of neat TFA (3 mmol) and then with 0.17 ml of neat TFAA (1.2 mmol) at the same temperature.The reaction mixture immediately turned dark brown. After 5 min the solvent was gently removed under reduced pressure, and the crude mixture submitted to flash chromatography (FC) with CHCl3–methanol (9:1 to 8:2) as eluent.Pure 2 was obtained in nearly quantitative yield as a yellow foam. Compound 2: Rf 0.02 (6:4, hexane:AcOEt); dH (CD3COCD3) 7.84 and 7.54 (4 H, m), 7.59 (1 H, d, J 3.3 Hz), 7.38 (1 H, d, J 9.1 Hz), 7.20 (1 H, dd, J 9.1 and 2.7 Hz), 7.05 (1 H, d, J 2.7 Hz), 5.06 (1 H, dddq, J 6.8, 4.8, 3.3 and 7.7 Hz), 4.86 (1 H, dd, J 13.7 and 4.8 Hz), 4.32 (1 H, dd, J 13.7 and 6.8 Hz), 3.70 (3 H, s), 2.45 (3 H, br s); dF (CD3COCD3) µ71.25 (3 F, d, J 7.7 Hz), µ71.88 (6 F, s); dC (CD3COCD3) 162.16 (q, JCF 34.5 Hz), 154.43, 146.93, 140.20, 132.60, 131.51, 130.10, 124.94 (q, JCF 282 Hz), 124.36, 123.17, 121.60, 117.46 (q, JCF 294 Hz), 113.69, 56.37, 51.46 (q, JCF 32.7 Hz), 39.54, 21.51.Amine 3.·A methylene chloride solution (5 ml) of 2 (0.6 mmol) was refluxed for 4 h. The solvent was removed under reduced pressure and the crude mixture was submitted to FC (hexane– AcOEt, 5:1), affording the amine 3 as main product (46%) together with a minor amount of imine 4 (6%).Amine 3: Rf 0.43 (hexane–AcOEt, 4:1); dH (CDCl3) 7.03 (4 H, s), 7.00 (1 H, d, J 2.8 Hz), 6.83 (1 H, dd, J 8.5 and 2.8 Hz), 6.72 (1 H, d, J 8.5 Hz), 3.72 (3 H, s), 3.50 (2 H, br signal), 2.28 (3 H, br s); dC (CDCl3) 152.33, 142.36, 135.65, 132.64, 129.85, 127.35, 120.62, 117.65, 116.64, 116.42, 55.84, 20.93 (Found: C, 68.48; H, 6.49; N, 5.40%. C14H15NOS requires C, 68.54; H, 6.16; N, 5.71%). The same amine 3 was obtained in 80% yield upon treatment of a solution of the imine 4 (0.2 mmol) in THF (4 ml) with 2 ml of 1 M aqueous HCl or neat trifluoroacetic acid (2 equiv.) at room temperature overnight.Imine 4.·A methylene chloride solution (5 ml) of 2 (0.4 mmol) was treated with 2 equiv. of neat triethylamine and stirred for 2 h at room temperature. The solvent was removed under reduced pressure and the crude mixture was submitted to FC (hexane–AcOEt, 4:1), affording the imine 4 in 90% yield. Rf 0.61 (hexane–AcOEt, 4:1); dH (CDCl3) 7.29 and 7.13 (4 H, m), 6.72 (1 H, dd, J 8.5 and 2.7 Hz), 6.67 (1 H, d, J 2.7 Hz), 6.58 (1 H, d, J 8.5 Hz), 3.69 (3 H, s), 2.33 (3 H, s), 1.92 (3 H, br s).dF (CDCl3) µ75.50 (3 F, br s). dC (CDCl3) 158.21 (q, JCF 33.8 Hz), 157.44, 139.01, 138.23, 133.20, 132.00, 130.16, 119.66 (q, JCF 278 Hz), 119.47, 116.89, 114.90112.18, 55.39, 21.13, 14.68. Received, 2nd June 1997; Accepted, 22nd July 1997 Paper E/7/03814C References 1 (a) S. Wolfe, R. J. Bowers, S.K. Hasan and P. M. Kazmaier, Can. J. Chem., 1981, 59, 406 and references cited therein; (b) K. Yamamoto, S. Yamazaki, I. Murata and Y. Fukuzawa, J. Org. Chem., 1987, 52, 5239; (c) J. E. McCormick and R. S. McElhinney, J. Chem. Soc., Perkin Trans. 1, 1985, 93. 2 (a) P. Bravo, M. Zanda and C. Zappal`a, Tetrahedron Lett., 1996, 37, 6005; (b) P. Bravo, A. Farina, V. P. Kukhar, A. L. Markovsky, S. V. Meille, V. A. Soloshonok, A. E. Sorochinsky, F. Viani, M. Zanda and C. Zappal`a, J. Org. Chem., 1997, 62, 3424. 3 O. De Lucchi, U. Miotti and G. Modena, Organic Reactions, ed. L. A. Paquette, Wiley, New York, 1991, vol. 40. 4 P. Bravo, G. Cavicchio, M. Crucianelli, A. OL. Markovsky, A. Volonterio and M. Zanda, Synlett., 1996, 887. 5 For recent reports on stable sulfonium salts formed under Pummerer conditions see: (a) M. Amat, S. Hadida, G. Pshenichnyi and J. Bosch, J. Org. Chem., 1997, 62, 3158; (b) M. Amat. M.-L. Bennasar, S. Hadida, B. A. Sufi, E. Zulaica and J. Bosch, Tetrahedron Lett., 1996, 37, 5217. We thank Professor J. Bosch for providing us with unpublished experimental data. For unusual Pummerer cyclizations see also: (c) S. G. Pyne and A. R. Hajipour, Tetrahedron, 1994, 50, 13 501. For an overview on the chemistry of sulfonium salts see: (d) The Chemistry of the Sulphonium Group, Parts 1 and 2, ed. C. J. M. Stirling and S. Patai, Wiley, New York, 1981. 6 A. Arnone, P. Bravo, S. Capelli, G. Fronza, S. V. Meille, M. Zanda, G. Cavicchio and M. Crucianelli, J. Org. Chem., 1996, 61, 3375.
ISSN:0308-2342
DOI:10.1039/a703814c
出版商:RSC
年代:1997
数据来源: RSC
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17. |
Synthesis of Cathasterone and its Related Putative Intermediates in Brassinolide Biosynthesis† |
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Journal of Chemical Research, Synopses,
Volume 0,
Issue 11,
1997,
Page 418-419
Suguru Takatsuto,
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摘要:
OH HO OH HO H OH HO OH HO H OH H O 1 2 3 4 OH OMe OMe OMe OMe O OH OR OH O RO H H OR RO 5 6 (22 R,23 R) 7 (22 S,23 S) 8 9 i ii + R = Et3Si R = H 10 3 vii R = Et3Si R = H 11 4 vii viii v,vi 1 iv 2 iii 418 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 418–419† Synthesis of Cathasterone and its Related Putative Intermediates in Brassinolide Biosynthesis† Suguru Takatsuto,*a Hiroki Kuriyama,b Takahiro Noguchi,b Hiroyuki Suganuma,b Shozo Fujiokac and Akira Sakuraic aDepartment of Chemistry, Joetsu University of Education, Joetsu-shi, Niigata 943, Japan bTama Biochemical Co.Ltd., 2-7-1 Nishishinjuku Shinjuku-ku, Tokyo 163, Japan cThe Institute of Physical and Chemical Research (RIKEN), Wako-shi, Saitama 351-01, Japan The putative intermediates in brassinolide biosynthesis, 22a-hydroxycampesterol 1, 6-deoxocathasterone and its 6a-hydroxylated compound 3, as well as cathasterone 4, are synthesized from a known (22E,24S)-6b-methoxy-3a,5-cyclo- 5a-ergost-22-ene 5.Using the cultured cells of Catharanthus roseus, we have previously demonstrated the occurrence of two biosynthetic pathways to brassinolide, namely the early C6-oxidation pathway (the sequence: campesterolh6a-hydroxycampestanolh6- oxocampestanol, and the sequence: cathasteroneh t e a s t e r o n e h3 - d e h y d r o t e a s t e r o n e ht y p h a s t e r o l hc a s t a s t e r - onehbrassinolide) and the late C6-oxidation pathway (the sequence: 6-deoxoteasteroneh3-dehydro-6-deoxoteastero n e h6 - d e o x o t y p h a s t e r o l h6 - d e o x o c a s t a s t e r o n e hc a s t a s t e r - onehbrassinolide.1,2 However, the step of campestanol to 6-deoxoteasterone and the step of 6-oxocampestanol to cathasterone 4 remain to be elucidated.In the former step, it is reasonably suggested that 6-deoxocathasterone 2 should be an intermediate, inferred from the natural occurrence of 4 and its conversion to teasterone.3 In addition, by analogy to the conversion of campesterol into 6-oxocampestanol via campestanol and 6a-hydroxycampestanol,4 there is the possibility that 4 would be biosynthesized via 2 and its 6a-hydroxylated compound 3 from 22a-hydroxycampesterol 1, which would be derived from campesterol by 22a-hydroxylation.In order to investigate these possibilities, we have now synthesized these putative intermediates 1–3. Our synthesis is described here along with our alternative synthesis of 4. We have previously synthesized 4 from (22R,23R,24S)- 3b-acetoxy-22,23-epoxy-5a-ergostan-6-one in four steps with epoxide opening by HBr as a key reaction.3 However, in this reaction, the desired 22-hydroxy-23-bromide and the undesired 23-hydroxy-22-bromide were obtained in a ratio of ca. 1:3. Thus, we have now taken an alternative short cut to the 22S-hydroxy-24R-methyl side chain of the target steroids. A known 22-ene compound 55 was epoxidized with m-chloroperbenzoic acid to provide the (22R,23R)-epoxide 6 (70%) and its (22S,23S)-isomer 7 (25%).The epoxide 6 was reduced with AlH3 to afford 22-ol 8 (42%) and 23-ol 9 (49%). When compared with the epoxide opening with HBr, the selectivity for 8 was increased and the desired side chain was completed in one step from 6. The AlH3 reduction of each (22R,23R)-epoxide derived from stigmasterol and brassicasterol has been reported to give a ratio of (26:74) and (66:34) of the corresponding 22-ol and 23-ol, respectively.6 Our present data and the reported data indicate that, possibly because of the steric hindrance, the hydride attacks the C-23 position in the descending order of the (22R,23R)- epoxides derived from brassicasterol, crinosterol and stigmasterol.The 22-ol 8 was subjected to acid treatment to give 1 in 96% yield. Catalytic hydrogenation of 1 provided 2 in 70% yield. After protecting two hydroxy groups as triethylsilyl ethers, the resulting compound was hydroborated and oxi- *To receive any correspondence.†This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). Fig. 1 Structures of cathasterone and its related compounds Scheme 1 Reagent and conditions: i, mCPBA, CH2Cl2, room temp., 5 h; ii, LiAlH4–AlCl3, THF, reflux, 2 h; iii, p-TsOH, 1,4-dioxane–H2O, reflux, 4 h; iv, H2, 10% Pd-C, EtOH, 40 °C, 3 h; v, Et3SiCl, pyridine, room temp., 2 h; vi, BH3–THF, THF, room temp., 5 h, then 2 M NaOH, 30% H2O2; vii, (Bu)4NH, THF, room temp., 6 h; viii, Collins reagent, CH2Cl2, room temp., 5 hJ.CHEM. RESEARCH (S), 1997 419 dized with alkaline H2O2 to give 10 in 86% yield. Deprotection of 10 provided 3 in 81% yield. Oxidation of 10 with Collins reagent and deprotection afforded 4 in 55% yield. Identification of the possible biosynthetic intermediates 1–3 from plants and their biological evaluation are now in progress. Experimental Mps are uncorrected. 1H NMR spectra were recorded at 400 MHz on a JEOL a-400 spectrometer in a CDCl3 solution with Me4Si as internal standard. HR-MS were recorded on a HITACHI M-80 or a JEOL HX-110 mass spectrometer. ( 2 2 R , 2 3 R , 2 4 S ) - 2 2 , 2 3 - E p o x y - 6 b- m e t h o x y - 3 a, 5 - c y c l o - 5 a- e r g o s t a n e 6 and its (22S,23S)-Isomer 7.·A known compound 55 (249 mg) in CH2Cl2 (15 cm3) was treated with m-chloroperbenzoic acid (296 mg) at room temp.in the dark for 5 h and then with Ca(OH)2 (380 mg) for 30 min. Work-up and chromatography on silica gel (100 g) with hexane–EtOAc (20:1) as eluent provided 6 (180 mg, 70%) as an oil, dH 1.05 (3 H, d, J 6.1 Hz, 21-H3), 2.50 (1 H, dd, J 7.0 and 2.4 Hz, 22-H), 2.72 (1 H, dd, J 6.4 and 2.4 Hz, 23-H). HR-MS (EI) (Found M+, 428.3645. C29H48O2 requires Mr 428.3651). Further elution gave 7 (64 mg, 25%), mp 81–82 °C (hexane–EtOAc), dH 0.97 (3 H, d, J 4.6 Hz, 21-H3), 2.40–2.50 (2 H, m, 22-H and 23-H).HR-MS (EI) (Found M+, 428.3658. C29H48O2 requires Mr 428.3651). (22S,24R)-6b-Methoxy-3a,5-cyclo-5a-ergostan-22-ol 8 and (23S, 24S)-6b-Methoxy-3a,5-cyclo-5a-ergostan-23-ol 9.·The epoxide 6 (152 mg) in THF (15 cm3) was treated with LiALH4 (160 mg) and AlCl3 (213 mg) at reflux under Ar for 2 h. Work-up (diethyl ether) and chromatography on silica gel (25 g) with toluene–EtOAc (50:1) afforded 8 (64 mg, 42%), mp 43.5–45 °C (toluene–EtOAc), dH 0.88 (3 H, d, J 6.8 Hz, 28-H3), 0.89 (3 H, d, J 6.3 Hz, 21-H3), 3.78 (1 H, t, J 6.4 Hz, 22-H).HR-MS (EI) (Found M+, 430.3818. C29H50O2 requires Mr 430.3808). Further elution gave 9 (75 mg, 49%), mp 90.5–91 °C (toluene–EtOAc), dH 0.96 (3 H, d, J 6.7 Hz, 28-H3), 0.97 (3 H, d, J 6.4 Hz, 21-H3), 3.89 (1 H, m, 23-H). HR-MS (EI) (Found M+, 430.3799. C29H50O2 requires Mr 430.3808). (22S,24R)-3b,22-Dihdyroxyergost-5-ene 1.·The 22-ol 8 (250 mg) in 1,4-dioxane (5 cm3) and H2O (0.75 cm3) was refluxed with p-TsOH (5 mg) for 4 h.Work-up (EtOAc) and chromatography on silica gel (20 g) with toluene–EtOAc (4:1) as eluent gave 1 (233 mg, 96%), mp 193–195 °C (toluene–EtOAc), dH 0.70 (3 H, s, 18-H3), 0.81 (3 H, d, J 6.7 Hz, 26-H3), 0.83 (3 H, d, J 6.7 Hz, 27-H3), 0.88 (3 H, d, J 6.7 Hz, 28-H3), 0.89 (3 H, d, J 6.7 Hz, 21-H3), 1.01 (3 H, s, 19-H3), 3.52 (1 H, m, 3a-H), 3.78 (1 H, t, J 6.6 Hz, 22-H), 5.35 (1 H, m, 6-H). HR-MS (EI) (Found M+, 416.3655. C28H48O2 requires Mr 416.3652).(22S,24R)-3b,22-Dihydroxy-5a-ergostane 2.·The 5-ene 1 (30 mg) in EtOH (3 cm3) was treated with 10% Pd–C (70 mg) under H2 at 40 °C overnight. Work-up and chromatography on silica gel (20 g) with toluene–EtOAc (5:1) as eluent gave 2 (21 mg, 70%), mp 200–202 °C (toluene–EtOAc), dH 0.67 (3 H, s, 18-H3), 0.81 (3 H, s, 19-H3), 0.81 (3 H, d, J 6.7 Hz, 26-H3), 0.83 (3 H, d, J 6.7 Hz, 27-H3), 0.88 (6 H, dÅ2, J 7.0 Hz, 21-H3 and 28-H3), 3.59 (1 H, ddd, J 15.9, 10.8 and 4.9 Hz, 3a-H), 3.77 ( H, t, J 6.4 Hz, 22-H).HR-MS (EI) (Found M+, 418.3812. C28H50O2 requires Mr 418.3808). (22S,24R)-3b-22Bis(triethylsiloxy)-5a-ergostan-6a-ol 11.·The 5-ene 1 (230 mg) in pyridine (5 cm3) was treated with Et3SiCl (0.58 cm3) at room temp. for 2 h. Work-up (diethyl ether) and chromatography on silica gel (25 g) with hexane–EtOAc (25:1) as eluent gave the corresponding silyl ether (322 mg, 90%), mp 126–127 °C (hexane–EtOAc), dH 0.96 (18 H, tÅ6, J 7.9 Hz, CH2CH3), 3.47 (1 H, ddd, J 15.6, 10.7 and 4.7 Hz, 3a-H), 3.76 (1 H, dd, J 9.8 and 4.7 Hz, 22-H), 5.32 (1 H, m, 6-H).HR-MS (EI) (Found M+, 644.5399. C40H76O2Si2 requires Mr 644.5380). This compound (236 mg) in THF (6 cm3) was reacted with 1 M BH3–THF complex in THF (1.2 cm3) at room temp. for 5 h. After treating with H2O (0.5 cm3), the mixture was treated with 2 M NaOH (0.4 cm3) and 30% H2O2 (0.4 cm3) for 30 min. Work-up (diethyl ether) and chromatography on silica gel (25 g) with toluene–EtOAc (100:1) provided 10 (231 mg, 95%), mp 64–65 °C (toluene–EtOAc), dH 0.96 (9 H, tÅ3, J 7.9 Hz, CH2CH3), 0.96 (9 H, tÅ3, J 7.9 Hz, CH2CH3), 3.40 (1 H, ddd, J 10.4, 10.4 and 4.3 Hz, 3a-H), 3.53 (1 H, ddd, J 15.6, 10.7 and 4.7 Hz, 6b-H), 3.76 (1 H, dd, J 9.5 and 4.3 Hz, 22-H).HR-MS (EI) (Found M+, 662.5511. C40H78O3Si2 requires Mr 662.5485). (22S,24R)-5a-Ergostan-3b,6a,22-triol 3.·Compound 10 (30 mg) in THF (2 cm3) was treated with 1 M (Bu)4NF in THF (0.3 cm3) at room temp.for 6 h. Work-up (EtOAc) and chromatography on silica gel (25 g) with hexane–EtOAc (1:3) as eluent gave 3 (16 mg, 81%), mp 225-226.5 °C (hexane–EtOAc), dH 0.67 (3 H, s, 18-H3), 0.81 (3 H, d, J 7.8 Hz, 26-H3), 0.82 (3 H, s, 18-H3), 0.83 (3 H, d, J 6.8 Hz, 27-H3), 0.88 (3 H, d, J 6.8 Hz, 28-H3), 0.88 (3 H, d, J 6.3 Hz, 21-H3), 3.42 (1 H, ddd, J 10.7, 10.7 and 4.4 Hz, 6b-H), 3.59 (1 H, ddd, J 16.1, 11.2 and 4.9 Hz, 3a-H), 3.77 (1 H, t, J 6.6 HJz, 22-H). HR-MS (negative-FAB) (Found [MµH]µ, 433.3698.C28H49O3 requires Mr 433.3684). (22S,24R)-3b,22-Dihydroxy-5a-ergostan-6-one 4.·The 6a-ol 10 (114 mg) in CH2Cl2 (5 cm3) was treated with Collins reagent (598 mg) at room temp. for 5 h. Work-up (diethyl ether) and chromatography on silica gel (25 g) with toluene–EtOAc (150:1) as eluent gave the cathasterone bis-triethylsilyl ether 11 (75 mg, 66%), mp 188–190 °C (toluene–EtAOc), dH 0.95 (9 H, t, J 7.9 Hz, CH2CH3), 0.97 (9 H, t, J 7.9 Hz, CH2CH3), 3.51 (1 H, m, 3a-H), 3.76 (1 H, dd, J 9.8 and 4.6 Hz, 22-H).HR-MS (EI) (Found M+, 660.5333. C40H76O3Si2 requires Mr 660.5329). The ether 11 (73 mg) was deprotected as described above and a crude product was purified by chromatography on silica gel (25 g) with hexane–EtOAc (1:2) as eluent to provide 4 (40 mg, 83%), mp 183.5–185 °C (MeOH) (lit.,3 mp 176–177 °C), dC (CDCl3) 11.18, 11.19, 13.13, 15.77, 17.81, 19.95, 21.52, 23.90, 27.64, 30.02, 30.68, 32.01, 35.32, 36.62, 37.94, 39.29, 39.44, 39.48, 40.93, 42.87, 46.68, 52.48, 53.85, 56.65, 56.73, 70.67, 71,59, 210.84. HR-MS (EI) (Found M+, 432.3610. C28H48O3 requires Mr 432.3601). Its 1H NMR and EI-MS spectral data are in good agreement with the reported data.3 We thank Mr Tetsu-ichiro Morita of The Institute of Physical and Chemical Research (RIKEN) for the measurement of NMR spectra. Received, 7th July 1997; Accepted, 31st July 1997 Paper E/7/04788F References 1 S. Fujioka and A. Sakurai, Nat. Prod. Rep., 1997, 1. 2 A. Sakurai and S. Fujioka, Biosci. Biotechnol. Biochem., 1997, 61, 757 3 S. Fujioka, T. Inoue, S. Takatsuto, T. Yanagisawa, T. Yokota and S. Sakurai, Biosci. Biotechnol. Biochem., 1995, 59, 1543. 4 H. Suzuki, T. Inoue, S. Fujioka, T. Saito, S. Takatsuto, T. Yokota, N. Murofushi, T. Yanagisawa and S. Sakurai, Phytochemistry, 1995, 40, 1391. 5 S. Takatsuto, T. Watanabe, S. Fujioka and A. Sakurai, J. Chem. Res., 1997, (S) 134; (M) 0901. 6 J.-L. Giner, C. Margot and C. Djerssai, J. Org. Chem., 1989, 54, 369.
ISSN:0308-2342
DOI:10.1039/a704788f
出版商:RSC
年代:1997
数据来源: RSC
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18. |
Reaction of Isoeugenol with Formaldehyde in Basic Medium: Formation oftrans-4-(4-Hydroxy-3-hydroxymethyl-5-methoxy)-5-methyl-1,3-dioxane and its Transformation into the Tricyclo[5.2.2.02,6]undecane System† |
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Journal of Chemical Research, Synopses,
Volume 0,
Issue 11,
1997,
Page 422-423
Vishwakarma Singh,
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摘要:
HO MeO 1 HO MeO 3 OH O O H H HCHO NaOH O O H H O O OMe 4 O MeO O O H H O MeO OH OH MeCN–H2O Na I O4 2 422 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 422–423† Reaction of Isoeugenol with Formaldehyde in Basic Medium: Formation of trans-4-(4-Hydroxy- 3-hydroxymethyl-5-methoxy)-5-methyl-1,3-dioxane and its Transformation into the Tricyclo[5.2.2.02,6]undecane System† Vishwakarma Singh* and S. Prathap Department of Chemistry, Indian Institute of Technology, Powai, Bombay 400 076, India Formation of the title compound 3, via an unusual Prins-type reaction on isoeugenol with formaldehyde in alkaline medium, and its conversion into a tricyclo[5.2.2.02,6]undecane system 4 is described. In the context of a synthetic endeavour we needed to prepare the phenol 2 which was thought to be obtainable via hydroxymethylation of isoeugenol 1.However, the hydroxymethylation of 1 with formaldehyde in basic medium furnished a highly unusual product 3 as a result of the hydroxymethylation being followed by a Prins reaction across the double bond.The Prins reaction generally occurs under acidic conditions1–3 and such type of reaction in alkali has not, to the best of our knowledge, been reported earlier. We now report the structure of the compound 3 and its transformation to the tricyclic system 4. Treatment of isoeugenol with an excess of formaldehyde (aqueous, ca. 30%) in basic medium for ca. 7 h followed by acidification gave a product in good yield (60%) to which we assigned the structure 3 based on high-field 1H NMR (500 MHz), 13C NMR and other data.A plausible mechanism for the formation of the product 3 it outlined in Scheme 2. The conjugation of the phenolic group with the double bond of the side chain via the aromatic ring appears to be responsible for the Prins-type reactions. The product 3 may be obtained either from isoeugenol 1 or its hydroxymethylated derivative 2 via a quinonoid species of type 5 and/or 6 respectively.Thus, the quinonoid species 6 may undergo hydroxymethylation to give 7 which upon addition of one more mole of formaldehyde either directly or via the oxetane intermediate 8, leads to the formation of 9. Intramolecular cyclisation of the species 9 finally gives the product 3 as shown in Scheme 1. Alternatively, the species 5 may also undergo hydroxymethylation4 in an analogous fashion to give the intermediate 10 which upon subsequent hydroxymethylation at the ortho position of the aromatic ring finally gives the product 3.In this context, it may be mentioned that the intermediacy of oxetanes has been proposed during the acidcatalysed Prins reaction of alkenes.5 It may also be noted that the hydroxymethylation of eugenol 11, wherein the double bond in the side chain is not conjugated, smoothly furnished the usual compound 12 (Scheme 3) upon treatment with formaldehyde and base. In order to synthesize the tricyclic system 4, a solution of the compound 3 in acetonitrile was oxidized with aqueous sodium metaperiodate and the resulting spiroepoxycyclohexa- 2,4-dienone was trapped with cyclopentadiene.6 Usual work-up and chromatography of the crude product furnished the adduct 4 as a solid (mp 132 °C) in very good yield (72%).The structure of the adduct 4 was deduced from its spectral and analytical data.7 The IR spectrum showed a strong absorption band at 1742 cmµ1 for the carbonyl group.The 1H NMR spectrum exhibited characteristic signals at d 5.93 (br s, 1 H, b-proton of b,g-enone moiety) and 5.77 (m, 1 H), 5.6 (m, 1 H) olefinic protons. It further exhibited signals at d 5.02 (d, J 6 Hz, 1 H), and 4.64 (d, J 6 Hz, 1 H) due to the equatorial and axial protons of the O·CH2·O group. In addition it showed signals at d 4.06 (dd, J1 11 Hz, J224 Hz, 1 H), 3.72 (d, J 10 Hz, 1 H), corresponding to the equatorial proton of the O·CH2·C group and the methine proton of the O·CH·C�C group.The methoxy signal appeared at d 3.60 (s, 3 H). Furthermore, signals were observed at d 3.5 (br d, J26 Hz, 1 H, methine proton) and at 3.28 (superimposed dd, J1=J2=11 Hz, 1 H, axial proton of O·CH2·C group). Other resonances were observed at d 3.06 (d overlapped with other signal, total 2 H, methine and 1 H of O·CH2 of oxirane group), 2.88 (d, 1 H, J26.5 Hz, 1 H, OCH2 of oxirane moiety), 2.72 (s, 1 H, methine H at the bridgehead), 2.69 (m, 1 H, allylic methylene of cyclopentene ring), 2.05 (d, J 18 Hz, 1 H, of allylic methylene) and 1.95 (m, 1 H, methine proton of the H·C·CH3 group).The methyl signal appeared at d 0.67 (d, J 3.5 Hz, 3 H). Comparison of the above spectral features with that of the compound 3 and other adducts of type 4 clearly revealed the structure of the adduct which was also supported by its 13C NMR spectrum. Thus, the 13C NMR spectrum of 4 displayed characteristic resonances at d 204.9 for the carbonyl carbon and at 141.2, 135.0, 128.3, 127.4 for the four olefinic carbons.It further exhibited signals at d 93.7, 88.2, 84.2, 72.5, 59.0, 53.9, 53.7, 53.0, 44.1, 38.8, 36.7, 32.4 and 12.8 for the other quaternary, methine, methylene and methyl carbons. The transformation of compound 3 into the tricyclic system 4 provided further mutual chemical support for their structures. We have thus described an unusual Prins-type reaction of potential use in functionalisation–homologation across a *To receive any correspondence.†This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). Scheme 1HO MeO 1 O MeO 2 HO H • • • • O MeO 6 HO – NaOH base HCHO HO MeO 5 O MeO 8 HO O MeO 7 HO OR – – O O – O MeO 9 OH O O – 10 O O H HO MeO 3 O O H MeO HO OH H hydroxymethylation HCHO HCHO HCHO OH MeO 11 OH MeO 12 OH HCHO base J. CHEM. RESEARCH (S), 1997 423 double bond and also described the transformation of the Prins-type product into a tricyclic system having a b,g-enone chromophore of synthetic utility.Experimental IR spectra were recorded on a Nicolet Impact 400 FT-IR instrument. Mass spectra were recorded on a Hewlett Packard GCD 1800-A instrument. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on a Varian VXR 300S instrument. Some 13C NMR (125 MHz) spectra were also taken on a GE NMR Omega instrument.All the samples were dilute solutions in CDCl3 with SiMe4 as internal standard. Melting points were taken on a Buchi-type apparatus and are uncorrected. All the organic extracts were dried over anhydrous Na2SO4. Reactions were monitored with TLC and spots visualized with iodine vapour. Chromatographic separations were performed on silica gel–light petroleum. t r a n s - 4 - ( 4 - H y d r o x y - 3 - h y d r o x y m e t h y l - 5 - m e t h o x y ) - 5 - m e t h y l - 1 , 3 - d i - oxane (3).·To a solution of compound 2 (3 g, 18.3 mmol) in water (15 ml) and formaldehyde [aqueous 37–41%; 10 ml (excess)] was added NaOH (0.6 g) and the mixture was stirred at room temperature. After stirring had continued for 7 h, the reaction mixture was acidified with HCl (50%) and extracted with diethyl ether (3Å30 ml).The combined ether layer was washed with brine (15 ml) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue was chromatographed.Elution with light petroleum–ethyl acetate (60:40) gave the dioxane 3 (2.8 g, 60%) as a solid which was recrystallized from light petroleum– ethyl acetate (65:35), mp 108 °C; vmax/cmµ1 (KBr) 3418, 1611; dH (500 MHz) 6.86 (s, 1 H, aromatic), 6.81 (s, 1 H, aromatic), 6.35 (s, 1 H, OH), 5.16 (d, J 6.30 Hz, 1 H, equatorial proton of O·CH2·O), 4.80 (d, J 6.3 Hz, 1 H, axial proton of O·CH2·O), 4.70 (s, 2 H, CH2OH), 4.10 (dd, J1 10 Hz, J224 Hz, 1 H, equatorial proton of ·CH2·O), 4.02 (d, J 10 Hz, 1 H, benzylic methine), 3.88 (s, 3 H, OCH3), 3.40 (superimposed dd, J1=J2210 Hz, 1 H, axial proton of CH2O), 2.65 (s, 1 H, OH), 2.08 (m, 1 H, methine H), 0.60 (d, J 7 Hz, 3 H, CH3); dC (125 MHz) 146.9143.9, 131.2, 126.2, 120.1, 109.3 (aromatic carbons), 94.3, 86.3, 73.2, 61.9, 56.3, 36.5 and 12.8; m/z 254 (M+) (Found: C, 61.46; H, 7.48.C13H18O5 requires C, 61.41; H, 7.08%). 7 p- M e t h o x y - 1 0 p- ( 5 - m e t h o x y - 1 , 3 - d i o x a n - 4 - y l )s p i r o [ o x i r a n e - 2 , 9 pendo- tricyclo[5.2.2.02,6]undeca-4p,10p-dien]-8p-one 4.·To a solution of compound 3 (2 g, 7.87 mmol) in acetonitrile (30 ml) was added freshly cracked cyclopentadiene (8 ml, excess) and the reaction mixture was cooled in an ice bath (10 °C).A solution of NaIO4 (6 g, 28.1 mmol) in water (50 ml) was then added dropwise to the reaction mixture with stirring. After stirring for 8 h, the reaction mixture was filtered and extracted with diethyl ether (3Å25 ml).The organic layer was washed with brine (10 ml) and dried over anhydrous sodium sulfate. Removal of solvent followed by chromatography [light petroleum–ethyl acetate (85:15)] of the residue on silica gel furnished spiro compound 4 (1.8 g, 72%) as a solid, which was recrystallised from light petroleum–ethyl acetate (80:20), mp 132 °C. vmax/cmµ1 (KBr) 3063, 2939, 2849, 1743; dH (500 MHz) 5.93 (br s, 1 H, b-proton of b,g-enone), 5.77 (m, 1 H, olefinic H), 5.6 (m, 1 H, olefinic H), 5.02 (d, J 6 Hz, 1 H, equatorial proton of O·CH2·O), 4.64 (d, J 6 Hz, 1 H, axial proton of O·CH2·O), 4.06 (dd, J1 11 Hz, J224 Hz, 1 H, equatorial proton of OCH2), 3.72 (d, J 10 Hz, 1 H, methine H), 3.6 (s, 3 H, OCH3), 3.5 (br d, J26 Hz, 1 H, methine H), 3.28 (superimposed dd, J1=J2=11 Hz, 1 H, axial proton of OCH2·C), 3.06 (d, overlapped with other signal, total 2 H, methine and 1 H, OCH2 of oxirane), 2.88 (d, 1 H, J26.5 Hz, O·CH2 of oxirane group), 2.72 (s, 1 H, methine H at the bridgehead), 2.69 (m, 1 H, allylic methylene of cyclopentene ring), 2.05 (d, J 18 Hz, 1 H, allylic methylene), 1.95 (m, 1 H, methine H) and 0.67 (d, J 3.5 Hz, 3 H, CH3); dC (125 MHz) 204.9 (CO), 141.2, 135.0, 128.3, 127.4 (olefinic carbons), 93.7, 88.2, 84.2, 72.5, 59.0, 53.9, 53.7, 53.0, 44.1, 38.8, 36.7, 32.4 and 12.8; m/z 318 (M+) (Found: C, 68.37; H, 7.15.C18H22O5 requires C, 67.91; H, 6.97%). 5-Allyl-2-hydroxy-3-methoxybenzyl Alcohol (12).·To a solution of eugenol 11 (1 g, 6.1 mmol) in water (5 ml) and formalin (37–41%; 3 ml) was added NaOH (0.2 g) with stirring at room temperature.After stirring for 5 h, the reaction mixture was acidified with HCl (50%) and extracted with diethyl ether (3Å20 ml). The ether layer was washed with brine (10 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with light petroleum–ethyl acetate (70:30) furnished the alcohol 12 (0.98 g, 83%) as a liquid; vmax/cmµ1 (KBr) 3400, 1640, 1615; dH 1H NMR (300 MHz) 6.66 (m, 2 H, aromatic protons), 6.03 (br s, 1 H, ArOH), 5.94 (m, 1 H, olefinic H), 5.07 (m, 2 H, olefinic H), 4.66 (br s, 2 H, ArCH2), 3.87 (s, 3 H, OCH3), 3.30 (d, J27 Hz, 2 H, Ar·CH2·O·), 2.44 (s, 1 H, Ar·CH2·OH); m/z 194 (M+).We thank R.S.I.C., I.I.T. Bombay, and T.I.F.R., Bombay, for spectral facilities. P. S. is thankful to CSIR New Delhi for a senior fellowship. Financial support to V. S. from DST New Delhi is gratefully acknowledged. Received, 19th May 1997; Accepted, 31st July 1997 Paper E/7/03410E References 1 B. B. Snider, in Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 2, pp. 527–561. 2 (a D. R. Adams and S. P. Bhatnagar, Synthesis, 1977, 661; (b) C. W. Roberts, in Friedel–Crafts and Related Reactions, G. A. Olah, Wiley, New York, 1974, vol. 2, part 2, p. 1175. 3 E. Arundale and L. A. Mikesa, Chem. Rev., 1952, 51, 505. 4 A. A. R. Sayigh, H. Ulrich and M. Green, J. Chem. Soc., 1964, 3482. 5 O. Meresz, K. P. Leung and A. S. Denes, Tetrahedron Lett., 1972, 2797. 6 (a) V. Singh and B. Thomas, J. Chem. Soc., Chem. Commun., 1992, 1211; (b) V. Singh and S. Prathap, Synlett., 1994, 542. 7 (a) A. P. Marchand, Stereochemical Applications of NMR Studies in Rigid Bicyclic Systems, Verlag Chemie International, Florida, 1982; (b) G. C. Levy and G. L. Nelson, Carbon-13 Nuclear Magnetic Resonance for Organic Chemists, Wiley, New York, vols 1 and 2, 1977. Scheme 2 Scheme 3
ISSN:0308-2342
DOI:10.1039/a703410e
出版商:RSC
年代:1997
数据来源: RSC
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19. |
Montmorillonite Clay-catalysed Synthesis of Bis(indol-3-yl)-methanes and 1,2-Bis(indol-3-yl)ethanes† |
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Journal of Chemical Research, Synopses,
Volume 0,
Issue 11,
1997,
Page 424-425
Amiya Krishna Maiti,
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摘要:
NH Me MeO OMe CHO NH NH OMe OMe Me Me NH Me O2N CHO NH NH NO2 Me Me NH Me O NH O O O NH NH NH Ph O NH NH NH Ph O Me Me Me 1b 1c 2b 2c 3b 3c 1a 1a 1a 4b 4c 2a 4b 5c 1a Products Substrates 424 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 424–425† Montmorillonite Clay-catalysed Synthesis of Bis(indol-3-yl)- methanes and 1,2-Bis(indol-3-yl)ethanes† Amiya Krishna Maiti and Prantosh Bhattacharyya* Department of Chemistry, Bose Institute, 93/1, A.P.C. Road, Calcutta 700009, India Condensation of indoles with carbonyl compounds in the presence of montmorillonite clay produces bis(indol- 3-yl)methanes in good yield; an extension of this procedure, involving nucleophilic ring opening of oxiranes, produces 1,2-bis(indol-3-yl)ethanes.During the past few years a large number of natural products containing bis(indolyl)methanes,1 and bis(indolyl)ethanes2 have been isolated from marine sources. Some of these have been found to have biological activity. We are, therefore, interested in developing a new and efficient method for the preparation of these moieties by condensation of carbonyl compounds and nucleophilic ring opening of oxiranes with indole respectively, in the presence of montmorillonite clay K-10.Many applications of montmorillonite clay K-10 in organic synthesis are found in the literature.3 Traditionally, condensation reactions of indoles with carbonyl compounds involve use of BF3–Et2O, AcOH, heat, etc.4,5 However, acidic clay is inexpensive, stable and noncorrosive, and moreover work-up procedures are very simple: just by filtering, the clay can be separated from the reaction mixtures.Thus we become interested in exploring the use of clays in the synthesis of the bis(indolyl)methane and bis(indolyl)ethane moieties. We have found that the condensation and ring opening proceed smoothly in the presence of montmorillonite clay under mild conditions. Montmorillonite clay has a high specific area and its Lewis acidity is as efficient as that of AlCl3.6 This increases the electrophilicity of the carbonyl carbon as well as of the oxirane carbon and welcomes the participation of indole in the cleavage.The results are reported in Table 1. Experimental Melting points are uncorrected and were determined on a Toshniwal apparatus. IR spectra were recorded on a Shimadzu model IR-408 spectrometer. 1H NMR spectra were recorded on a JEOL 100 MHz instrument using [2H6]DMSO as solvent and Me4Si as internal standard.Column chromatography was performed on silica gel (60–120 mesh, Merck). Montmorillonite clay K-10 was purchased from Aldrich. General Procedure.·To a solution of indole (0.02 mol) and the carbonyl compound/oxirane (0.01 mol) in chloroform (254 ml) *To receive any correspondence. †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J.Chem. Research (M).J. CHEM. RESEARCH (S), 1997 425 montmorillonite K-10 clay (1 g) was added and the mixture stirred at room temperature. After completion of the reaction, the whole mixture was filtered and the clay-free material, after chromatography over silica gel, gave the pure bis(indol-3-yl)methane and 1,2-bis(indol-3-yl)ethane. Received, 26th February 1997; Accepted, 31st July 1997 Paper E/7/01355H References 1 S. A. Morris and R. J. Anderson, Tetrahedron, 1990, 46, 715. 2 G. Bifulco, I. Bruno, R. Riccio, J. Lavayre and G. Bourdy, J. Nat. Prod., 1995, 58, 1254. 3 P. Laszlo, Science, 1987, 235, 1472 and references cited therein. 4 R. J. Sundberg, The Chemistry of Indoles, Academic Press, New York, London, 1970. 5 E. Leete, J. Am. Chem. Soc., 1959, 6023. Table 1 Condensations on clay surface Reaction Found (required) (%) time Yield Mp Molecular Substrate (t/min) Product (%)a (T/°C) formula C H dH b 1a, 1b 30 1c 70 150 C27H26N2O2 79.00 (79.02) 6.30 (6.34) 2.0 (6 H, s), 3.64 (3 H, s), 3.84 (3 H, s), 5.96 (1 H, s), 6.72 (1 H, s), 6.84–7.20 (10 H, m), 7.68 (2 H, s, D2O exch.) 1a, 2b 25 2c 85 254 C25H21N3O2 75.92 (75.95) 5.29 (5.31) 2.0 (6 H, s), 6.0 (1 H, s), 6.68–7.64 (10 H, m), 8.04 (2 H, d), 9.96 (2 H, s, D2O exch.) 1a, 3b 30 3c 80 116 C19H13NO2 79.38 (79.44) 4.45 (4.53) 2.42 (3 H, s), 7.10–8.28 (9 H, m), 8.44 (2 H, br s, D2O exch.) 2a, 4b 135 4c 55 140 C24H20N2 85.65 (85.71) 5.82 (5.95) 3.50 (2 H, d), 4.76 (1 H, t), 6.82–7.32 (13 H, m), 7.56 (2 H, d), 7.70 (2 H, br s, D2O exch.) 1a, 4b 120 5c 60 232 C26H24N2 85.24 (85.31) 6.55 (6.59) 2.06 (6 H, s), 3.72 (2 H, d), 4.52 (1 H, t), 6.80–7.40 (11 h, m), 7.58 (2 H, d), 8.82 (2 H, br s, D2O exch.) aYields refer to pure isolated products. bIn [2H6]DMSO at 100 MHz.
ISSN:0308-2342
DOI:10.1039/a701355h
出版商:RSC
年代:1997
数据来源: RSC
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Regioselective Halogenation and Dimerization of Alkoxynaphthalenes with Alumina- or Kieselguhr-supported Copper(II) Halides† |
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Journal of Chemical Research, Synopses,
Volume 0,
Issue 11,
1997,
Page 426-427
Yoshitada Suzuki,
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摘要:
OR Br 2 OR OR CuBr2–Kieselguhr benzene 30 °C, 3 h 3 CuBr2–Al2O3 benzene 30 °C, 3 h 1 OR a R = Me b R = Et c R = Bun d R = C6H13 CuCl2–Al2O3 or Kieselguhr benzene, 30 °C, 1 h 1 3 426 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 426–427† Regioselective Halogenation and Dimerization of Alkoxynaphthalenes with Alumina- or Kieselguhrsupported Copper(II) Halides† Yoshitada Suzuki, Kiyoshi Takeuchi and Mitsuo Kodomari* Department of Industrial Chemistry, Faculty of Engineering, Shibaura Institute of Technology, Shibaura, Minato-ku, Tokyo 108, Japan The reaction of 1-alkoxynaphthalenes 1 with alumina-supported copper(II) bromide or copper(II) chloride gave dimers, 4,4p-dialkoxy-1,1p-binaphthyls 3, as major products, and with Kieselguhr-supported copper(II) bromide afforded 1-bromo- 4-alkoxynaphthalenes 2, while the reaction of 2-alkoxynaphthalenes 4 with alumina- or Kieselguhr-supported copper(II) bromide gave preferentially 1-bromo-2-alkoxynaphthalenes 5.Copper(II) bromide and chloride have been used as halogenating agents under homogeneous conditions for compounds containing active hydrogen atoms such as ketones,1 and under heterogeneous conditions in non-polar solvents for aromatic hydrocarbons.2 In the latter case, the reaction is carried out by heating the reagents in a high-boiling solvent under drastic conditions, when rather complex mixtures of halogenated compounds, are obtained. We have reported that copper(II) halides can be activated remarkably by supporting onto neutral alumina, and that polymethylbenzenes are brominated selectively to give the nuclear-brominated products by use of alumina-supported copper(II) bromide.3 Alkoxybenzenes are regioselectively chlorinated by aluminasupported copper(II) chloride to give 4-chloro-1-alkoxybenzenes in high yield.4 In this paper, we describe the halogenation and the dimerization of alkoxynaphthalenes with inorganic-supported copper(II) halides.The reaction of 1 with copper(II) bromide in refluxing benzene afforded a mixture of 2 and 3. In contrast, similar reaction using Kieselguhr-supported copper(II) bromide proceeded smoothly at 30 °C to give 2 in high yields, and the yield of 3 was negligible. For instance, when 1a was treated with Kieselguhr-supported copper(II) bromide in benzene at 30 °C for 3 h, 2a was obtained in 92% yield. Non-polar solvents such as benzene were better than polar solvents. In polar solvents such as chloroform and tetrahydrofuran, the yield was decreased.The reaction in ethanol did not proceed because of the elution of copper(II) bromide from the Kieselguhr into the solution. These results suggest that the reaction occurs on the surface of the supported reagent and not in solution.5 When alumina-supported copper(II) bromide was employed, bromination did not proceed but dimerization of alkoxynaphthalenes occurred. The reaction of 1a with alumina- supported copper(II) bromide was performed in benzene at 30 °C for 1 h to give 3a in 87% yield and the brominated compounds were formed only in trace quantities. Silica gel and graphite were also effective as supports to give the binaphthyl as a main product along with brominated products.Alumina was most effective and showed the highest selectivity among the supports tested (Table 1). In the reaction of 1 with copper(II) chloride, both Kieselguhr and alumina gave 3 preferentially, and chlorinated products were formed in low yield (Table 2). The yield of 3 in the reaction using the reagent supported on alumina was slightly higher than that in the reaction using the same reagent supported on Kieselguhr. The reaction of 1a with copper(II) chloride in refluxing benzene gives a mixture of 3a and 4-chloro- and 8-chloro-1-methoxynaphthalene,6 whereas a similar reaction with alumina- or Kieselguhr-supported copper(II) chloride proceeded smoothly, even at 30 °C, to give selectively 3a in high yield, no 8-chloro-1-methoxynaphthalene being formed.For instance, the reaction fo 1a with alumina-supported copper(II) chloride in benzene at 30 °C for 1 h afforded 3a in 85% yield and 4-chloro- 1-methoxynaphthalene in 8% yield. *To receive any correspondence. †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M).Table 1 Reaction of 1-methoxynaphthalene (1a) with CuBr2–supporta Yield (%) CuBr2/1a Time Support Molar ratio (t/h) 2ab 3ac Noned Kieselguhr Alumina Silica gel Graphite 2.0 1.5 3.0 1.5 1.5 1.5 413111 47 40 92 tr 18 17 45 tre tr 87 69 76 aAll reactions were carried out at 30 °C in benzene. bBy GLC. cIsolated yield. dReflux. etr indicates a yield of less than 1%. Table 2 Reaction of 1-alkoxynaphthalenes (1) with CuX2–supporta Yield (%) Time 1 CuX2 Support (t/h) 2b 3c 1b 1c 1d 1b 1b 1b 1d CuBr2 CuBr2 CuBr2 CuCl2 CuBr2 CuCl2 CuCl2 Kieselguhr Kieselguhr Kieselguhr Kieselguhr alumina alumina alumina 3331311 93 93 95 15 15 13 10 trd tr tr 73 80 80 85 aAll reactions were carried out at 30 °C in benzene.bBy GLC. cIsolated yield. dtr indicates a yield of less than 1%.OR 4 OR 5 CuX2–Support benzene 50 °C, 2 h OR RO 6 X SMe SMe CuX2–Al2O3 X a 1-MeSb 2-MeS- 7 a 4-X-1-MeSb 1-X-2-MeS- 8 J. CHEM. RESEARCH (S), 1997 427 2-Alkoxynaphthalenes 4 were easily brominated under mild conditions by use of Kieselguhr- or alumina-supported copper(II) bromide to give 5 (X=Br) in high yields.Although the reaction with alumina-supported copper(II) bromide proceeded even at 10 °C, dibrominated compounds and 6 were produced along with 5 (X=Br). In contrast, with Kieselguhr-supported copper(II) bromide, only 5 (X=Br) were obtained in high yields (Table 3). For example, while the reaction of 4c with copper(II) bromide in benzene at 50 °C for 2 h produced only a 6% yield of 5c (X=Br), a similar reaction with Kieselguhr-supported copper(II) bromide gave an 86% yield of 5c (X=Br).On the other hand, with alumina-supported copper(II) bromide, the reaction proceeded completely at 10 °C in 1 h to give, in addition to 5c (X=Br) (77%), the dibromide (21%) and 6c (2%). In contrast to the bromination, chlorination of 4 with alumina-supported copper(II) chloride proceeded at 50 °C to give 5 (X=Cl) in high yields. When the reagent supported on Kieselguhr was employed, a mixture of 5 (X=Cl) and 6 was obtained. 4a was chlorinated with alumina-supported copper(II) chloride in benzene at 50 °C for 2 h to give 5 (C=Cl) in 83% yield, whereas a similar reaction with copper( II) chloride under the same conditions did not take place. These reactions are postulated to proceed by electron transfer to give the radical cation of the alkoxynaphthalene, which either undergoes reaction with the copper(II) halide or dimerizes.9 1- and 2-methylsulfanylnaphthalene 7 reacted with alumina- supported copper(II) halides to give the halogenated compounds 8 in high yields, and dimerization of 7 did not occur.The reaction of 7b with copper(II) bromide in benzene at 50 °C yielded no detectable products after 5 h. In contrast, with alumina-supported copper(II) bromide, 8b (X=Br) was obtained in 92% yield from a reaction run at 50 °C for 1 h. These results are shown in Table 4. Copper(II) chloride was less reactive than copper(II) bromide towards 7.Chlorination required a higher temperature than bromination. Experimental Preparation of Supported Copper(II) Halides.·The reagents were prepared by a method previously reported.3a Kieselguhr-supported copper(II) halides were also prepared by similar method. Reagents having 9% (w/w) copper(II) halide on a support were used. 1-Bromo-4-methoxynaphthalene 2a: General Procedure for Bromination of 1-Alkoxynaphthalenes.·A mixture of 1a (1.90 g, 12 mmol) and Kieselguhr-supported copper(II) bromide (24 g, 36 mmol) in benzene (150 ml) was stirred at 30 °C for 3 h.The mixture was filtered, and the spent reagent was washed with benzene. The combined filtrates were evaporated, and the residue was distilled under vacuum to give 2.3 g (85%) of 1-bromo-4-methoxynaphthalene 2a bp 155–157 °C at 5 Torr (lit.,6 159–160 °C at 4 Torr). 4,4p-Dimethoxy-1,1p-binaphthyl 3a.·A mixture of 1a (0.95 g, 6 mmol) and alumina-supported copper(II) chloride (5.56 g, 12 mmol) in benzene was stirred at 30 °C for 1 h.The mixture was filtered and the spent reagent was washed several times with hot benzene. Hexane was added to the combined filtrates, which were concentrated, to precipitate 4,4p-dimethoxy-1,1p-binaphthyl 3a (0.8 g, 85%) mp 254–255 °C (from hexane–benzene) (lit.,6 252–254 °C). GLC analysis of the filtrate after removal of the material showed the presence of 1-chloro-4-methoxynaphthalene. 1-Chloro-2-methoxynaphthalene 5a: General Procedure for Chlorination of 2-Alkoxynaphthalenes.·A mixture of 4a (0.95 g, 6 mmol) and alumina-supported copper(II) chloride (8.34 g, 18 mmol) in benzene (30 ml) was stirred at 50 °C for 2 h.The mixture was worked up as above and 2,2p-dimethoxy-1,1p-binaphthyl 6a (0.09 g, 10%), mp 193–195 °C (lit.,7 190–195 °C), separated out from the cold filtrate. The filtrate after removal of 6a was shown by GLC to contain 4a (3%) and 1-chloro-2-methoxynaphthalene 5a (83%).This filtrate was evaporated and the residue was chromatographed on silica gel. Elution with hexane gave 5a (X=Cl), mp 66–67 °C (lit.,8 68 °C). 1-Chloro-2-methylsulfanylnaphthalene 8b.·The reaction was carried out as above using 2-methoxysulfanylnaphthalene (0.52 g, 3 mmol) and alumina-supported copper(II) chloride (6.95 g, 15 mmol) in benzene (30 ml) at 80 °C for 1.5 h. The mixture was filtered and the spent reagent was washed with benzene. The combined filtrates were evaporated and the residue was recrystallized from ethanol to give 8b (X=Cl) (0.58 g, 93%), mp 77–78 °C.Received, 24th June 1997; Accepted, 31st July 1997 Paper E/7/04445C References 1 (a) A. W. Fort, J. Org. Chem., 1961, 26, 765; (b) L. C. King and G. K. Dstrum, J. Org. Chem., 1964, 29, 3459. 2 (a) J. C. Ware and E. E. Brochert, J. Org. Chem., 1961, 26, 2267; (b) D. C. Nonhebel, J. Chem. Soc., 1963, 1216. 3 M. Kodomari, H. Satoh and S. Yoshitomi, (a) J. Org. Chem., 1988, 53, 2093; (b) Bull. Chem. Soc. Jpn., 1988, 61, 4149. 4 M. Kodomari, S. Takahashi and S. Yoshitomi, Chem. Lett., 1987, 1901. 5 I. Tanimoto, K. Kushioka, T. Kitagawa and K. Maruyama, Bull. Chem. Soc. Jpn., 1979, 52, 3258. 6 S. R. Bansal, D. C. Nonhebel and J. M. Mancilla, Tetrahedron, 1973, 29, 993. 7 A. McKillop, A. G. Turrell, D. W. Young and E. C. Taylor, J. Am. Chem. Soc., 1980, 102, 6504. 8 Beilstein, 6 (EII), 648. Table 3 Reaction of 2-alkoxynaphthalenes (4) with CuX2–supporta Yield (%) 4 CuX2 Support 5b 6c 4a 4b 4c 4d 4ad 4a 4b 4c 4d CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuCl2 CuCl2 CuCl2 CuCl2 Kieselguhr Kieselguhr Kieselguhr Kieselguhr alumina alumina alumina alumina alumina 89 90 86 90 72 83 84 85 82 0010 20 10 10 10 15 aSolvent: benzene, CuX2:4=3, 50 °C, 2 h. bBy GLC. cIsolated yield. d10 °C, 1 h. Table 4 Halogenation of methylsulfanylnaphthalenes (7) with CuX2–Al2O3 a Conditions Yield (%)b 7 CuX2 T/°C t/h 8a 8b 7a 7b 7a 7b CuBr2 CuBr2 Cucl2 CuCl2 50 50 80 80 2211 80 81 92 90 aSolvent: benzene, CuX2/7=5. bBy GLC.
ISSN:0308-2342
DOI:10.1039/a704445c
出版商:RSC
年代:1997
数据来源: RSC
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