摘要:

Mendeleev Communications Electronic Version, Issue 6, 1998 (pp. 207–248) Synthesis of difluorodithiopyruvic acid derivatives Yurii G. Shermolovich, Vadim M. Timoshenko,* Vitalii V. Listvan and Leonid N. Markovskii† Institute of Organic Chemistry, National Academy of Sciences of the Ukraine, 253660 Kiev, Ukraine. Fax: +38 044 573 2643; e-mail: iochkiev@sovamua.com The reaction of cadmium sulfide with 1,1-dichloro-3,3-difluoro-2-oxo-1-propylthiopropane yields difluorodithiopyruvic propionate.This reacts with morpholine to give difluorodithiopyruvic morpholide; it also undergoes a cycloaddition reaction to the carbon–sulfur double bond with dimethylbutadiene to form 2-difluoroacetyl-4,5-dimethyl-2-propylthio-3H,6H-thiopyran. Previously, when investigating polyfluoroaliphatic thioaldehydes1 and esters of polyfluoroalkanedithiocarboxylic acids,2 we showed that the influence of polyfluoroalkyl substituents results in an increase in the activity of the thiocarbonyl groups in the cycloaddition reactions with dienes.This has allowed us to synthesise new fluoro-containing thiopyran derivatives possessing biological activity.3 In continuing our research into fluoro-containing dithiocarboxylic acid derivatives we have studied the possibility of synthesising oxopolyfluoroalkanedithiocarboxylates.It is known that polyfluoro-containing ketones RFC(O)R [R = various, including sulfur-containing substituents] are effective inhibitors of many enzymes.4 Therefore, it is possible to assume that in the case of oxopolyfluoroalkanedithiocarboxylates with dienes, new fluoro-containing ketones containing a thiopyran ring as the substituent will be formed.They may also be enzyme inhibitors. It is necessary to note that among derivatives of a-oxothiocarboxylic acids, the appropriate amides RC(=O)C(=S)NR2 5,6 have been investigated the most. The first representatives of the a-oxodithiocarboxylates ArC(=O)C(=S)SR were synthesised in 1978,7 and the dithiooxalates ROC(=O)C(=S)SR8 are also known.Among fluoro-containing derivatives of this class only trifluoropyruvic thioamide CF3C(=O)C(=S)NR2 9,10 has been reported. In the present work we report on the synthesis and some properties of the first representative of esters of fluoro-containing a-oxodithiocarboxylic acids, difluorodithiopyruvic propionate 1.For the synthesis of this compound the approach developed by us for the synthesis of polyfluoroalkanedithiocarboxylates,2 consisting of substitution of chlorine atoms in 1,1-dichlorosulfides by sulfur by treatment with zinc or cadmium sulfides, was used. Chlorination of the ketosulfide 211 with sulfuryl chloride gives 1,1-dichloro-3,3-difluoro-2-oxo-1-propylthiopropane 3,‡ which under reflux with cadmium sulfide in acetonitrile results in compound 1 (Scheme 1).The dithioester 1 readily reacts by nucleophilic replacement with secondary amines, in particular with morpholine, forming the difluoropyruvic thioamide 4. Upon interaction of the dithioester 1 with dimethylbutadiene a [2 + 4] cycloaddition reaction on the C=S bond leads to formation of 2-difluoroacetyl-4,5- dimethyl-2-propylthio-2H,6H-thiopyran 5.Under similar conditions thioamide 4 does not react with dimethylbutadiene. Upon reflux of 1 with mercury(II) chloride in acetone dethiylation occurs with formation of 2-difluoroacetyl-4,5-dimethyl-6H-thiopyran 6. This work was financially supported by INTAS (grant no. 95-UA-0005). References 1 Yu. G. Shermolovich, E.I. Slusarenko and L. N. Markovskii, Zh. Org. Khim., 1988, 24, 1931 [J. Org. Chem. USSR (Engl. Transl.), 1988, 24, 1741]. 2 Yu. G. Shermolovich, E. I. Slusarenko, V. M. Timoshenko, A. B. Rozhenko and L. N. Markovskii, J. Fluorine Chem., 1991, 56, 329. 3 Yu. G. Shermolovich, L. N. Markovskii, E. I. Slusarenko and V. M. Timoshenko, Russ. Patent, RU, 2054426, C07D 335/02, 1996 (Chem.Abstr., 1997, 126, 74746q). † Professor Leonid N. Markovskii, a specialist in the field of macromolecular and organoelement chemistry, died on the 3rd February 1998. O HF2C S Prn O HF2C S Prn i Cl Cl ii O HF2C S Prn S iii O HF2C N S O 2 3 1 4 iv O HF2C S S Prn Me Me 5 v O HF2C S Me Me 6 Scheme 1 Reagents and conditions: i, SO2Cl2, CH2Cl2, 20 °C, 8 h, 91%; ii, CdS, MeCN, reflux, 0.5 h, 53%; iii, morpholine, benzene, 20 °C, 12 h, 36%; iv, dimethylbutadiene, diethyl ether, 20 °C, 2 h, 58%; v, HgCl2, CaCO3, acetone, reflux, 3 h, 63%.‡ All compounds obtained were characterised by 1H and 19F NMR and IR spectroscopy and gave satisfactory elemental analysis data. For 1: bp 40–43 °C (0.09 mmHg). 1H NMR (200 MHz, C6D6, TMS) d: 0.57 (t, 3H, Me, J 7.1 Hz), 1.27 (sextet, 2H, CH2, J 7.1 Hz), 2.59 (t, 2H, SCH2, J 7.1 Hz), 6.44 (t, 1H, HCF2, JHF 51.9 Hz). 19F NMR (188 MHz, C6D6, CCl3F) dF: –128.43 (d, 2F, CF2H, JHF 51.9 Hz). IR (film, n/cm–1): 1738 (s, nC=O). Found (%): C 36.84; H 4.34; S 32.56. Calc. for C6H8F2OS2 (%): C 36.35; H 4.07; S 32.34. For 3: bp 110–112 °C (20 mmHg). 1H NMR (200 MHz, CDCl3, TMS) d: 0.41 (t, 3H, Me, J 7.0 Hz), 1.00 (sextet, 2H, CH2, J 7.0 Hz), 2.12 (t, 2H, SCH2, J 7.0 Hz), 5.97 (t, 1H, HCF2, JHF 54.0 Hz). 19F NMR (188 MHz, CDCl3, CCl3F) dF: –121.34 (d, 2F, CF2H, JHF 54.1 Hz).Found (%): C 30.17; H 3.53; Cl 29.63; S 13.43. Calc. for C6H8Cl2F2OS (%): C 30.39; H 3.40; Cl 29.91; S 13.52. For 4: bp 73–75 °C (0.07 mmHg), mp 47–48 °C. 1H NMR (200 MHz, C6D6, TMS) d: 3.15 (m, 4H, 2NCH2), 3.27 (m, 2H, OCH2), 6.57 (t, 1H, HCF2, JHF 51.7 Hz). 19F NMR (188 MHz, C6D6, CCl3F) dF: –130.46 (d, 2F, CF2H, JHF 51.7 Hz). IR (film, n/cm–1): 1740 (s, nC=O). Found (%): C 40.01; H 4.35; N 6.38; S 15.64. Calc. for C7H9F2NO2S (%): C 40.18; H 4.34; N 6.70; S 15.33. For 5: bp 90–95 °C (0.07 mmHg). 1H NMR (200 MHz, C6D6, TMS) d: 0.57 (t, 3H, Me, J 7.0 Hz), 1.18 (sextet, 2H, CH2, J 7.1 Hz), 1.20 (s, 3H, Me), 1.36 (s, 3H, Me), 2.10 (t, 2H, SCH2, J 7.0 Hz), 2.3–2.8 (m, 4H, 2CH2, cyclic), 6.53 (t, 1H, HCF2, JHF 53.1 Hz). 19F NMR (188 MHz, C6D6, CCl3F) dF: –120.01 (d, 2F, CF2H, JHF 52.7 Hz). IR (film, n/cm–1): 1723 (s, nC=O). Found (%): C 50.95; H 6.74; S 22.71. Calc. for C12H18F2OS2 (%): C 51.40; H 6.47; S 22.87. For 7: mp 34–35 °C (diethyl ether–hexane). 1H NMR (200 MHz, C6D6, TMS) d: 1.23 (s, 3H, Me), 1.27 (s, 3H, Me), 2.54 (s, 2H, CH2), 5.56 (t, 1H, HCF2, JHF 52.0 Hz), 6.82 (s, 1H, CH). 19F NMR (188 MHz, C6D6, CCl3F) dF: –121.35 (d, 2F, CF2H, JHF 52.0 Hz). IR (film, n/cm–1): 1682 (s, nC=O). Found (%): C 52.66; H 5.55; S 15.73. Calc. for C9H10F2OS (%): C 52.92; H 4.94; S 15.70.Mendeleev Communications Electronic Version, Issue 6, 1998 (pp. 207–248) 4 R. J. Linderman, in Review of Pesticide Toxicology, eds. R. M. Roe and R. J. Kuhr, Raleigh, NC, 1993, vol. 2, pp. 231–260. 5 W. G. Dauben and J. B. Rogan, J. Am. Chem. Soc., 1956, 78, 4135. 6 E. Marchand and G. Morel, Bull. Soc. Chim. Fr., 1996, 133, 901. 7 R. Mayer, H. Vida and B. Hopt, Z. Chem., 1978, 18, 90. 8 W. Thiel, H. Viola and R. Mayer, Z. Chem., 1977, 17, 366. 9 C. Maliverney and H. G. Viehe, Tetrahedron Lett., 1990, 31, 6339. 10 C. Maliverney, H. G. Viehe, B. Tinant and J. P. Declerq, Bull. Soc. Chim. Fr., 1990, 127, 843. 11 Yu. G. Shermolovich, V. M. Timoshenko, V. V. Listvan and L. N. Markovskii, Zh. Org. Khim., 1998, 34, 1167 (in Russian). Received: Moscow, 24th April 1998 Cambridge, 23rd June 1998; Com. 8/03094D

ISSN:0959-9436     

出版商:RSC    

年代:1998

数据来源: RSC