3-Sulfolene as an Alternative Reagent for Sulfur Dioxide

NII-Electronic Library Service NII-Electronic Library Service NII-Electronic Library Service 3582 Vol . 26 - (1978) 7: 3, 600 ml). Die mit CHC1,/MeOH (4: 1) ausfliessenden Fraktionen(A) enthielten I und II und die an- schliessenden mit CHC1,/MeOH(7: 3) eluierten (B) Quercitrin. A und B wurden jeweils an Polyamidsaule (10 g, I.D.: 2.5 cm) mit MeOH chrornatographiert. Die gelblichen Fraktionen bei A wurden durch DCCC aufgetrennt. Fraktionen 28—36 ergaben nach Kristallisation aus verdiinntem MeOH 4 mg Von I(Schmp. 167-—175°) und Fraktionen 43-50 ans demselben Losungsmittel 6 mg Von II (Schmp. 170-—177°). Die gelblichen Fraktionen bei B ergaben nach Kristallisation aus verdiinntem MeOH 40 mg Nadeln vom Schmp. 175—179°. (Quercitrin). PMR-Daten von trimethylsilyliertem I und II (CDCI3, 60 MHz) I und II wurden mit Hexamethy1- disilazan und Trirnethylchlorosilan in Pyridin bei Raumtemperatur silyliertfi) TMS-Ather V011 I: 0.77 (3H, d, f=6 Hz, 6”—CI;I3), 2.00 (3H, s, 3”-OCOCH3), 3.17 (1H, qd, ]=1O und 6 Hz, 5”—H), 3.56 (1H, 1:, ]= 10 Hz, 4’’—H), 4.44 (1H,t, [=2 Hz, 2"-H), 4.84 (1H, dd, ]=1O und 2 Hz, 3"-H), 5.11 (1H, d, ]=2 Hz, 1"-H), 6.07 (1H, (1, ]=2 Hz, 6-H), 6.31 (1H, d, ]=2 Hz, 8-H), 6.73 (1H, (1, ]=8 Hz, 3’-H), 7.12 (2H, m, 2’- und 6’-H). TMS-Ather Von II: 0.72 (3H, d, ]=6 Hz, 6”~CH3), 1.89 (3H, s, 4"-OCOCH3), 3.17 (1H, qd, ]=10 und 6 Hz. 5"-H). 3.83 (1H, dd, j=10 und 2 Hz, 3"-H), 4.17 (1H, t, ]=2 Hz, 2”-I-I), 4.80 (1H, t, ]=10 Hz, 4’’—H), 5.11 (1H, d, ]=‘2 Hz, 1"—I-I), 6.07 (1.H, d, ]:2 Hz, 6-H), 6.31 (1H, d, ]=2 Hz, 8-H), 6.73 (1H, d, _/'=8 Hz, 3’—l-I), 7.12 (2H, m, 2’- und 6’-H). 6) T.]. Marby, K.R. Markham und M.B. Thomas, “The Systematic Identification of Flavonoids,” Springer- Verlag, Berlin, Heidelberg, New York, 1970, S. 255. [2C611(%1)1:§,’53E:;1j:f,)§§;l(1i;{l,1$‘})- UDC 547. 732’546. 21. 04 .- 547. 92. 04 3—SuIfolene as an Alternative Reagent for Sulfur Dioxide“ CHIKARA KANEKO, REIKO HAYASHI (née KITAMURA), HARUE FUJII, and ATSUSHI YAMAMOTO Faculty of Pharmaceutical Sciences, Kcmazawa University“). (Received May 20, 1978) The successful use of 3—sulfo1ene as an alternative reagent for sulfur dioxide was demonstrated for the first time by two types of the reactions: i) deoxygenation of aromatic amine N-oxides and ii) isomerization of ergosterol and its derivatives. Keywords deoxygenation; aromatic amine oxides; isomerization; ergosterol and its derivatives; thcrrnolysis of 3—sulfo1ene 3—Sulfolene was synthesized from butadiene and sulfur dioxide in a high yield by heating them together at around 100° in a pressure bottle.3) Backer and Blaas’-'0 noted that this sub- stance can be used in place of 1,3—butadiene in the Die1s—Alder reaction at 100———130°. Sample and Hatch“ demonstrated that the Diels—A1der adduct can be obtained smoothly by heating 3—su1fo1ene with maleic anhydride in refluxing xylene in an open vessel. This fact indicates that there exists an equilibrium between 3—su1folene and its degradation products (the diene and sulfur dioxide) at that ternperaturef” 1) Presented at the 45th Meeting of Hokuriku Branch, Pharmaceutical Society of Japan, Kanazawa, November, 1977. Location: Takaza-machi, Kcmazawa, 920, Japcm. O. Grummitt, A.E. Ardia, and J. Fick, ]. Am. Chem. 500., 72, 5167 (1950). H.]. Backer and T.A.H. Blaas, Ree. Tmv. Chim., 61, 785 (1942). T.E. Sample, Jr. and LF. Hatch, ]. Chem. Edam, 45, 55 (1968). VVhi1e benzyne does not act as a. dienophile with butadiene, the latter genarated from 3-sulfolene (100°) reacts with the former to give 1,4—dihydronaphthalene. The reaction presumably occurs because the butadiene exists in the cisoid conformation in the above equilibrium: L.F. Hatch and D. Peter, ]. Chem. Seen, Chem. Commam, 1968, 1499. C301»-hC.Dl\D \/\/\/x./‘I NII-Electronic Library Service No . 11 3583 While there is no experiment using sulfur dioxide generated from 3—sulfolene, we now demonstrate that 3—sulfolene can be used efficiently as an alternative reagent for sulfur dioxide. The procedure is to heat the reactants (1.1——2 mol equivalents of sulfolene to the respective substrates) in benzene (10 ml for 1 mmol of the substrate) in a sealed tube at 100°. Daniher and Hackley“ found that introduction of a slow stream of sulfur dioxide into a refluxing dioxane solution of pyridine 1-oxide or its derivatives for 3 hr afforded the free base in a moderate yield. We have found that the use of sulfolene (2 mol equivalent) afforded the deoxygenated products in very high yields, if the reaction was continued for longer than 30 hr. The results are summarized in Table I. As expected from inertness of pyridine 1- oxides having an electron withdrawing group towards sulfur dioxide,“ the N-oxides of 2- cyanoquinoline and 6-cyanophenanthridine could not be reduced at all. TABLE I. Deoxygenation of Aromatic Amine Oxides with 3-Sulfolenem /\ __ /\ R-'- IL I + T‘) -—-+ R--'-- IL I \/ N’/ \S/ \/ Ny 1 O2 0 New snhsfinfi’ m V 5 ‘ 20 30 Quinoline -- -— 85 201-—2O2°b3 2-Phenylquinoline 18 63 81 84—~85° Benzo[ f jquinoline 30 72 87 92—93° a) Unreacted N-oxides were also recovered. b) Picrate. The new procedure has then been extended to the isomerization of ergosterol (la) and its acetate (lb). Laubach et al.3) showed that when lb was heated at 100° with a large excess of sulfur dioxide in the presence of its 2/3 volume of pyridine in a sealed tube, ergosta-6,8(14), 22-triene acetate (2b) was formed in 65% yield. Hudgell at al.9> described the isomerization of la under similar conditions but in the absence of pyridine to ergosta—8,14,22—triene (3a) in 85% yield. They explained the formation of 3a by assuming the intermediacy of the triene, (2a) and its subsequent isomerization to 321 and speculated that the isomerization of 2a to 39. might be caused by moisture during the collection of liquid sulfur dioxide into the reaction: vessel. In the present procedure, these transformations proceeded using 1.1 mol equivalent of sulfolene. Thus, when la (2 mmol) and sulfolene (2.2 mmol) were heated in the presence of 6 mmol of pyridine for 20 hr, the triene (2a) was obtained in 80% yield. The same treat- ment of la in the absence of pyridine resulted in the formation of 3a in 65% yield. This and the fact that 2a isomerized to 3a in 85% yield under the same condition as above indicated that the isomerization of 2a to 3a occurred even in the complete absence of moisture. However, ?QH17 A (I:9H17 99H17 W\ K)“. /Y) WY“ to err“ ~* Na: R0’\/\/ R0’\/\/ R0’\/\/ 1 2 3 a: R=H b: R=COCH3 7) RA. Daniher and B.E. Hackley, ]r., J. Org. Chem., 31, 4267 (1966). 1 8) G.D. Laubach, E.C. Schreiber, E.J. Agnello, and K._). Brunings, ]. Am. Chem. 506., 78, 4743 (1956). 9) A.W.D. Hudgell, J.I-I. Turnbull, and W. Wilson, ]. Chem. 500., 1954, S14. * NII-Electronic Library Service 3584 Vol. 26 (1978) since the acetate (lb) by the present procedure (without pyridine: 20 hr) resulted in the formation of 2b and 3b in ca. 1: 1 ratio, it seems reasonable to assume that the free hydroxyl group in the steroids accelerated the isomerization of 2a to 3a. The successful use of sulfolene for sulfur dioxide in the above reactions may indicates that 3-sulfolenem’ offers a useful alternative for sulfur dioxide, whose handling is troublesome by its suffocating odor, highly hygroscopic nature and a low boiling point (~10°). Further- more, since an autogenous pressure during its use is relatively low at around 100° and thus a glass cylinder with a clamped-in stopper can be used, the present procedure is far more su- perior in its easy use than that using liquid sulfur dioxide. The experimental condition was also easily secured in the present procedure, such as a stoichiometric use of the reagent and an expulsion of moisture. Experimental“) General Procedure for the Deoxygenation of guinoline 1-Oxides An N-oxide (1 mmol) and 3-sul- folene (2 mmol) in 10 ml of benzene was heated at 100° for 5—~30 hr in a sealed tube. After the reaction, the solvent was removed under an aspirator pressure. The residue was made alkaline by addition of 20% potassium carbonate solution and the product was extracted with ether. The extract was dried over potas- sium carbonate, filtered, and evaporated to yield the product. The product was purified either by recrystal- lization or column chromatography and the structure was determined by mixed melting point determination with the authentic sample. The results are described in Table I. The other products identified were the re- covered N-oxides and 3-sulfolene. Isomerization of Ergosterol (la) to,Ergosta-6,8(14),22-triene (2a) Ergosterol (la; 792 mg, 2.0 mmol) and 3-sulfolene (260 mg, 2.2 mmol) in 20 ml of benzene in the presence of pyridine (240 mg, 6 mmol) were heated at 100° for 20 hr in a sealed tube. After the reaction, the solvent was removed under an aspirator pressure and the residue was recrystallized from methanol to afford 2a. An additional amount of 2a was furnished by silica gel column chromatography (hexane—ether 2: 1 V /V) of the mother liquor. The combined yield of 2a was 634 mg (80%); mp 111——114°. Mass spectrum m/e 396 (Mt), 271, 253. UV Zfi‘;§H nm (log 8): 252 (4.37). 1H-NMR (CDCl,,) 6: 3.70 (m, 1H, W1,2=25 Hz, H-3); 5.15-5.35 (m, 3H, H-7, 22, and 23), 6.16 (dd, 1H, ]=10 and 3 Hz, H-6). - 13C-NMR (CDCl3) (3: 125.3 (s), 125.7 (d), 129.4 (d), 132.1 (d), 135.4 (d), 147.3 (s) [olefinic carbons]; 71.4 (C1, C-3 carbon). Anal. Calcd. for CZSHMO: C, 84.78; H, 11.18. Found: C, 84.63; ' H, 11.24. Ergosta-8,14,22-triene (3a) -From Ergosta-6,8(14),22-triene (2a): The triene (2a) obtained as above (396 mg, 1.0 mmol) and 3-sulfolene (130 mg, 1.1 mmol) in 10 ml of benzene were heated at 100° for 20 hr in a sealed tube. The residue obtain: d after evaporation of solvent was recrystallized from ethanol to give 3a. An additional amount of 3a was obtained from the mother liquor by column chromatography on silica gel (heXane~ether 2: 1 v/V). The combined yield of 3a was 336 mg (85%); mp 133—135°. Mass spectrum: m/e 396 (M+), 381, 271, 270, 255. UV /'.l,f,°,‘,’§‘ nm (log 5): 252 (4.26). ‘H-NMR (CDCl3) 6: 3.65 (m, 1H, W,,2= 22 Hz, H-3); 5.26 (in, 2H, 1-I-22 and 23); 5.36 (t, 1H, ]==2 Hz, H-15). 13C-NMR (CDCI3) 6: 117.8 (d), 123.2 (5), 132.1 (d), 135.5 (d), 140.7 (s), 150.9 (S) [olefinic carbons]; 71.1 (d, C-3 carbon). Anal. Calcd. for C28H4,,O: C, 84.78; 1-1, 11.18. Found: C, 84.67; H, 11.22. From Ergosterol (la): The compound (3a) was obtained in the same manner as above from la; yield: 65%, mp 133—135°. The identity of this product with 3a obtained as above was assured by the mixed melting point determination and the comparison of spectral data. Isomerization of Ergosterol Acetate (lb) to Ergosta-8,14,22-triene Acetate (3b) and Ergosta-6,8(14),22- triene Acetate (2b) The acetate (lb; 439 mg, 1.0 mmol) and 3-sulfolene (152 mg, 1.29 mmol) in 10 ml of benzene were heated at 100° for 20 hr in a sealed tube. After the reaction, the solvent was removed under an aspirator pressure and the residue was recrystallized from ethanol to give a mixture of 2b and 3b as color- less needles; yield: 357 mg (81%); mp 120-—123°. The proportion of 2b and 3b in the product was deter- mined to be approximately 1: 1 by the inspection of its ‘H-NMR. 1H-NMR (CDCI3) 6: 4.75 (in, 2H (rela- tive intensity), H-3 of 2b and 3b], 5.1-5.4 (m, 6H, olefinic protons of 3b and H-7, -22, and —-23 of 2b), 6.15 (dd, 1H, ]=10 and 3 Hz, H-6 of 2b). Acknowledgement The authors are indebted to Mr. Y. ltatani and Misses, Y. Arano and K. Ohata at Kanazawa University for elemental analyses and Mass and 13C-NMR spectral determinations. 10) 3-Sulfolene is a crystalline solid (mp 64~65°), nonflammable, nontoxic and nonhygroscopic: T.E. Sample, Jr. and LF. Hatch, 07g. 531%., 50, 43 (1970). 11) All melting points are uncorrected. Spectra reported herein were measured with a Hitachi Model 323 UV spectrophotometer, a JEOL-JMS-OISG mass spectrometer, and a JEOL-JNM-60H (for 1H) or -JNM-PS-100 FT-NMR (for 13(3) spectrometer at 23° using tetramethylsilane as an internal standard. NII-Electronic Library Service