摘要:

Mendeleev Communications Electronic Version, Issue 2, 2002 1 Nucleophilic addition of secondary nitro compounds to acetylene Boris F. Kukharev,* Valery K. Stankevich and Galina R. Klimenko A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russian Federation. Fax: +7 3952 39 6046; e-mail: admin@irioch.irk.ru 10.1070/MC2002v012n02ABEH001541 The products of C-vinylation were prepared in 52.65% yield by the reaction of secondary nitroalkanes with acetylene in DMSO.KOH. Mono- and polynitroalkanes can add to an activated triple carbon. carbon bond under conditions of basic catalysis, for example, to the esters of propiolic acid.1 It is well known that nucleophilic addition to acetylene is facilitated in a ¡®super-base¡� DMSO.KOH medium.2 We found that 2-nitropropane 1a and nitrocyclohexane 1b added to acetylene in DMSO.KOH to give corresponding Cvinylation products 2a,b.The process proceeded at an initial acetylene pressure of 14 atm and at 100 ¡ÆC. The full conversion of compounds 1a,b was reached in 4 h.¢Ó The 1H NMR spectra of the reaction mixtures exhibited no signals that could be assigned to the vinylation products of either the acy-forms of nitro compounds 3a,b or oxymes 4a,b.The formation of the above compounds results from the splitting of nitro esters. Thus, under the given conditions, the process of O-vinylation did not proceed. Our attempts to carry out the C-vinylation of nitro compounds 1a,b using benzene as a solvent were unsuccessful. In the reactions of acetylene with nitromethane, nitroethane and 1-nitropropane in DMSO.KOH, only resin-like products were isolated.Probably, this was due to the ability of primary nitroalkanes to cause autocondensation under alkaline conditions, for example, to methazonic acid and isooxazole derivatives.1(b),3 Terminal acetylenes, as well as acetylene, can successfully react with secondary nitroalkane derivatives in DMSO.KOH.Thus, the E- and Z-isomers of 1-(3-methyl-3-nitro-1-butenyl)- benzene 5a,b were obtained by the reaction of 2-nitropropane and phenylacetylene.¢Ô According to 1H NMR data, the amount of the E-isomer was higher than that of the Z-isomer by a factor of 4.2. Moreover, the 1H NMR spectra of the reaction products exhibited no signals due to 1-[1-(1-methyl-1-nitroethyl)vinyl]benzene 5c, which is the product of the addition of 2-nitropropane to ¥á-phenylacetylene. The predominant formation of isomer 5a and the absence of isomer 5c in the reaction mixture suggest that the reaction proceeds by a coordinated trans-nucleophilic addition mechanism.4 The nitronate ion3 [Me2C..N+(=O)O.¡ìMe2C=N+O2 2.] served as a nucleophile; it was formed by the alkaline deprotonation of the nitroalkane.References 1 (a) V. V. Perecalin and A. S. Sopova, Nenasyshchennye nitrosoedineniya (Unsaturated Nitro Compounds), Nauka, Moscow, 1966 (in Russian); (b) S. S. Novikov, G. A. Shwekhgeimer, V. V. Sevostyanova and V. A. Shlyapochnikov, Khimiya alifaticheskikh i alitsiklicheskikh nitrosoedinenii (Chemistry of Aliphatic and Aliciclyc Nitro Compounds), Khimiya, Moscow, 1974 (in Russian); (c) V.Grakauskas and K. Baum, J. Org. Chem., 1969, 34, 3927. 2 B.A.Trofimov, Zh. Org. Khim., 1986, 22, 1991 [J. Org. Chem. USSR (Engl. Transl.), 1986, 22, 1788]. 3 P. G. Coombes, in Comprehensive Organic Chemistry. The Synthesis and Reactions of Organic Compounds, eds. D. Barton and W. D. Ollis, ¢Ó A mixture of compound 1a or 1b (10 g), powdered potassium hydroxide (5 g) and DMSO (100 ml) was placed in a stainless steel 250 ml rotary autoclave. The mixture was saturated with acetylene at 14 atm and heated at 100 ¡ÆC for 4 h.After cooling, the mixture was poured into 1 dm3 of cold water and extracted with diethyl ether (3¡¿100 ml). The combined extracts were dried with anhydrous potassium carbonate, and the ether was distilled in a vacuum to give nitroalkenes 2a,b. 2a: yield 52%, bp 71.72 ¡ÆC (61 torr), nD 20 1.4335, d4 20 0.9576. 1HNMR (400 MHz, CDCl3) d: 1.68 (s, 6H, Me), 5.31 (d, 1H, cis-CH=C, 3Jcis 10.7 Hz), 5.35 (d, 1H, trans-CH=C, 3Jtrans 17.3 Hz), 6.18 (dd, 1H, C.CH=C, 3Jcis 10.7 Hz, 3Jtrans 17.3 Hz). 13C NMR (100 MHz, CDCl3) d: 25.37 (Me), 87.78 (NC), 116.56 (=CH2), 138.12 (=CH).IR (neat, n/cm.1): 1530 (NO2), 1630 (C=C), 3085 (=CH2). Found (%): C, 52.24; H, 7.98; N, 12.02. Calc. for C5H9NO2 (%): C, 52.16; H, 7.88; N, 12.17. 2b: yield 65%, bp 77.78 ¡ÆC (4 torr), nD 20 1.4818, d4 20 1.0336. 1H NMR (400 MHz, CDCl3) d: 1.36.1.60 (m, 6H, C6H10), 1.84 (m, 2H, C6H10), 2.44 (m, 2H, C6H10), 5.32 (d, 1H, cis-CH=C, 3Jcis 10.7 Hz), 5.36 (d, 1H, trans-CH=C, 3Jtrans 17.4 Hz), 5.93 (dd, 1H, C.CH=C, 3Jcis 10.7 Hz, 3Jtrans 17.4 Hz). 13C NMR (100 MHz, CDCl3) d: 22.48 (C-3, C-5), 24.75 (C-4), 34.05 (C-2, C-6), 91.19 (NC), 117.96 (=CH2), 138.38 (=CH). IR (neat, n/cm.1): 1530 (NO2), 1635 (C=C), 3090 (=CH2). Found (%): C, 61.83; H, 8.56; N, 9.14. Calc. for C8H13NO2 (%): C, 61.91; H, 8.44; N, 9.03. CH R R NO2 C R R NO2 1a,b 2a, b C2H2 a R = Me b R + R = (CH2)5 Scheme 1 1a,b C R R N O OH C R R N 3a,b O O C2H2 C R R NOH 4a,b Scheme 2 ¢Ô A mixture of compound 1a (18.8 g), phenylacetylene (14 g), melted potassium hydroxide (7.5 g) and 150 ml of DMSO was stirred at 100 ¡ÆC for 6 h.After cooling, the mixture was treated as described above; a mixture of two nitro compounds 5a,b was isolated. 5a,b: yield 41%, bp 106.110 ¡ÆC (3 torr), nD 20 1.5346, d4 20 1.0578. 1H NMR (400 MHz, CDCl3) d: 5a (Z-isomer): 1.60 (s, 6H, Me), 5.96 (d, 1H, NCCH=C, 3J 12.5 Hz), 6.78 (d, 1H, CH=C, 3J 12.5 Hz), 7.12.7.45 (m, 5H, Ph); 5b (E-isomer): 1.43 (s, 6H, Me), 6.37 (d, 1H, NCCH=C, 3J 16.1 Hz), 6.60 (d, 1H, NCC=CH, 3J 16.1 Hz), 7.12.7.45 (m, 5H, Ph). IR (neat, n/cm.1): 1535 (NO2), 1595, 1605, 1655 (C=C), 3020, 3055, 3080 (=CH). Found (%): C, 69.21; H, 6.77; N, 7.08. Calc. for C11H13NO2 (%): C, 69.09; H, 6.85; N, 7.32. PhC CH H H Ph NO2 1a H Ph H NO2 1a Ph H H NO2 Scheme 3 5c 5a 5b Ph NO2 H NO2 Scheme 4Mendeleev Communications Electronic Version, Issue 2, 2002 2 vol. 2: Nitrogen Compounds, ed. I. O. Sutherland, Pergamon Press, Oxford, 1979, part 8. 4 (a) E. Winterfeld, in Chemistry of Acetylenes, ed. N. G. Viehe, Marsel Dekker, New York, 1969; (b) J. I. Dickstein and S. I. Miller, in The Chemistry of the Carbon–Carbon Triple Bond, ed. S. Patai, John Wiley & Sons, Chichester, 1978, part 2, pp. 813–955. Received: 13th December 2001; Com. 01/18

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Mendeleev Communications Electronic Version, Issue 2, 2002 1 Cyclization of allenyl phosphonates to 3-chloro-4-(diethylphosphono)- 2,5-dihydrofurans induced by CuCl2 Valery K. Brel* and Evgeny V. Abramkin Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russian Federation. Fax: +7 095 785 7024; e-mail: brel@ipac.ac.ru 10.1070/MC2002v012n02ABEH001574 3-Chloro-4-(diethylphosphono)-2,5-dihydrofurans 5a–f were synthesised by the reaction of 1-(hydroxymethyl)allenyl phosphonates with CuCl2.Phosphorylated alkadienes are frequently used as building blocks in organic synthesis.1 These compounds react with halogens,2 proton acids,3 sulfenyl chlorides,4(a) selenyl chlorides,4(b)–(e) potassium dichloroiodate (KICl2)5 and N,N-diethylbenzeneselenylamide (in the presence of Py/SO3)6 with the formation of 1,2- oxaphosphol-3-enes 2 due to the participation of the phosphoryl oxygen atom as an internal nucleophile at the final step of addition (Scheme 1).In continuation of earlier works in the synthesis of 1,2- and 1,3-alkadienes and in connection with our interest in developing new synthetic strategies for the construction of heterocyclic phosphonates,7 we report here an unusual halogenation of 1-(hydroxymethyl)allenyl phosphonates 1 by copper(II) halides to new chlorinated 2,5-dihydrofuryl phosphonates.The application of copper(II) halides to the transformation of organic compounds is documented. They were used for the halogenation of aromatic molecules,8 compounds with double and triple bonds,9 ketones,10,11 esters,12 enolates, phosphorus ilydes,13 2-sulfonyl and phosphinoxy anions.14 The lactonization of allenic carboxylic acids by the action of CuCl2 and CuBr2 was published.15 In addition to the previously reported preparation of 4-unsubstituted 2,5-dihydrofuryl phosphonates through cyclization of allenes 1 by AgNO3,3(c) we carried out the halogenation of 1-(hydroxymethyl)allenyl phosphonates 1a–f with CuCl2.Allenes 1a–f were prepared7(c) starting from propargyl alcohols 3a–f. Halogenation was carried out by adding two equivalents of copper(II) chloride hydrate to a solution of allenyl phosphonate 1a–f in acetonitrile at room temperature. The progress of reaction was controlled by TLC. When the conversion was complete (12– 24 h), the products were separated from CuCl and isolated as yellowish oils by column chromatography on silica gel (Scheme 2).The following mechanism can be proposed for this reaction (Scheme 3): the coordination of CuCl2 with 2,3-�-bonds causes a distortion and polarization of allenic system and increases the contribution of resonance structure 8 with a ó-coordinated Cu atom.The intermolecular nucleophilic attack of the hydroxyl group allows us to ‘catch’ this structure, and resulting intermediate 9 rapidly transforms to 5 by the oxidative coupling of ligands. The structures of 5a–f were clearly assigned by 1H, 13C and 31P NMR spectroscopy.† The NMR spectra of 5a–f were in good agreement with published data for 2,5-dihydrofuryl phosphonates. 7(c),7(f) Thus, we developed an easy and convenient synthesis of 3-chloro-4-(diethyphosphono)-2,5-dihydrofurans 5a–f, which are building blocks for the synthesis of biologically and pharmaceutically interesting molecules. References 1 (a) I. V. Alabugin and V. K. Brel, Usp. Khim., 1997, 66, 225 (Russ. Chem. Rev., 1997, 66, 205); (b) N. G. Khusainova and A. N. Pudovik, Usp. Khim., 1987, 56, 975 (Russ.Chem. Rev., 1987, 56, 564); (c) Ch. Angelov, Phosphorus Sulfur Relat. Elem., 1983, 15, 177. C R R'' (EtO)2P R' O P O R' X EtO O R R'' XY – EtY 1 2 Scheme 1 Scheme 2 Reagents and conditions: i, (EtO)2PCl, Et3N, Et2O, –20 °C; ii, room temperature, 24 h; iii, p-TolSO3H, MeOH, room temperature, 1 h; iv, 2CuCl2, MeCN, room temperature, 24 h. R'' R OH ZO i, ii C R'' R ZO (OEt)2(O)P 3a–f 4a–f Z = CH(Me)OEt iii C R'' R HO (OEt)2(O)P 1a–f iv O Cl (EtO)2(O)P R'' R 5a–f a R = R'' =Me b R = Me, R'' = CH2Cl c R = Me, R'' = CH2OH d R = Me, R'' = CH=CH2 e R + R'' = f R + R'' = C R R'' (EtO)2P OH O C R R'' (EtO)2P OH O Cu Cl Cl + CuCl2 C R R'' (EtO)2P OH O Cu Cl Cl (EtO)2P O O H CuCl R R'' Cl 1 6 8 7 O R R'' CuCl (OEt)2(O)P 9 CuCl2 O R R'' Cl (OEt)2(O)P 5 2CuCl + Scheme 3Mendeleev Communications Electronic Version, Issue 2, 2002 2 2 (a) V.M. Ignat’ev, Ch. Angelov, B. I. Ionin and A. A. Petrov, Zh. Obshch. Khim., 1975, 45, 2342 [J. Gen. Chem. USSR (Engl. Transl.), 1975, 45, 2299]; (b) Ch. Angelov, M. Kirilov, I. B. Ionin and A. A. Petrov, Zh. Obshch. Khim., 1979, 49, 2225 [J. Gen. Chem. USSR (Engl. Transl.), 1979, 49, 1955]. 3 R. S. Macomber, J. Org. Chem., 1977, 42, 3297. 4 (a) Ch. Angelov and K. Vachkov, Phosphorus Sulfur Relat. Elem., 1984, 21, 237; (b) Ch. Angelov, D. D. Enchev and M. Kirilov, Phosphorus Sulfur Relat. Elem., 1988, 20, 35; (c) Ch. Angelov and Ch. Christov, Phosphorus Sulfur Relat. Elem., 1983, 15, 373; (d) Ch. Angelov and C. Tancheva, Zh. Obshch. Khim., 1985, 55, 53 [J. Gen. Chem. USSR (Engl.Transl.), 1985, 55, 45]; (e) C. Tancheva, Ch. Angelov and D. Mondeshka, Heterocycles, 1985, 23, 843. 5 I. V. Alabugin, G. A. Sereda, E. V. Abramkin, V. K. Brel, N. V. Zyk and N. S. Zefirov, Dokl. Akad. Nauk, 1995, 345, 487 [Dokl. Chem. (Engl. Transl.), 1995, 345, 301]. 6 I. V. Alabugin, V. K. Brel, N. V. Zyk and N. S. Zefirov, Izv. Akad. Nauk, Ser. Khim., 1996, 779 (Russ. Chem. Bull., 1996, 45, 739). 7 (a) V. K. Brel, Synthesis, 2001, 1539; (b) V. K. Brel, Synth. Commun., 1999, 29, 3869; (c) V. K. Brel, Synthesis, 1999, 463; (d) V. K. Brel, Synthesis, 1998, 710; (e) I. V. Alabugin and V. K. Brel, Phosphorus Sulfur Silicon Relat. Elem., 1996, 1, 61; (f) N. S. Zefirov, A. S. Koz’min, T. M. Kasumov, K. A. Potekhin, V. D. Sorokin, V. K. Brel, E. V. Abramkin, Yu. T.Struchkov, V. V. Zhdankin and P. J. Stang, J. Org. Chem., 1992, 57, 2433. 8 P. Kovcic and K. E. Davis, J. Am. Chem. Soc., 1964, 86, 427 and references therein. 9 (a) C. E. Castro, J. G. Gaughan and D. C. Owsley, J. Org. Chem., 1965, 30, 587; (b) W. C. Baird, Jr, J. H. Surridge and M. Busa, J. Org. Chem., 1971, 36, 3324; (c) S. Uemura, A. Onoe and M. Okano, J. Chem. Soc., Chem. Commun., 1975, 925; (d) S.Uemura, H. Okazaki, A. Onoe and M. Okano, J. Chem. Soc., Perkin Trans. 1, 1978, 1278; (e) R. Rodebaugh, J. C. Debenhan, B. Freiser-Reid and J. P. Synder, J. Org. Chem., 1999, 64, 1758. 10 J. K. Kochi, J. Am. Chem. Soc., 1955, 77, 5274. 11 J. Ito, T. Konoike, T. Harada and T. Saegua, J. Am. Chem. Soc., 1977, 99, 1487. 12 M. W. Rathke and A. Lindert, J. Am.Chem. Soc., 1971, 93, 4605. 13 H. Schmidbaur, C. Doerzbach and G. A. Bowmaker, German Patent no. 3,415,037 (Chem. Abstr., 1986, 105, 60757y). 14 C. A. Maryanoff, B. F. Maryanoff, R. Tang and K. Mislow, J. Am. Chem. Soc., 1973, 95, 5839. 15 S. Ma and S. Wu, Tetrahedron Lett., 2001, 42, 4075. † 3-Chloro-4-(diethylphosphono)-2,2-dimethyl-2,5-dihydrofuran 5a. Typical procedure: a solution of 1a (0.12 g, 0.52 mmol) in 3 ml of anhydrous MeCN was introduced into a 30 ml round-bottom flask containing 5 ml of anhydrous MeCN and CuCl2·H2O (0.178 g, 1.04 mmol). The resulting brown solution was kept at room temperature for 24 h.Reactions were monitored by TLC on silica gel and 1H NMR spectroscopy. MeCN was removed in a vacuum, and the black residue was extracted several times with warm methylene chloride.The solvent was evaporated, and the crude product was chromatographed on a silica gel column with light petroleum–ethyl acetate (2:1 to 1:3) as an eluent to give 5a (0.106 g, 76%). Rf 0.68 (CHCl3–MeOH, 10:0.3). 1H NMR (CDCl3) d: 1.34 (dt, 6H, 2Me, J 1.0 and 7.2 Hz), 1.40 (s, 6H, 2Me), 4.17 (dq, 4H, 2CH2OP, J 8.0 and 7.2 Hz), 4.80 (dd, 2H, OCH2, J 1.9 Hz). 13C NMR (CDCl3) d: 16.07 (d, Me, JC–P 6.8 Hz), 16.13 (d, Me, JC–P 6.4 Hz), 25.13 (d, Me, JC–P 1.5 Hz), 62.22 (d, POCH2, JC–P 5 Hz), 73.28 (d, COCH2, JC–P 16.3 Hz), 89.51 (d, OCMe2, JC–P 14.8 Hz), 121.33 (d, PC=, JC–P 200.0 Hz), 147.22 (d, ClC=, JC–P 3.1 Hz). 31P NMR (CDCl3) d: 9.80. IR (film, n/cm–1): 1243 (P=O), 1619 (C=C). Found (%): C, 44.82; H, 6.71; P, 11.65. Calc.for C10H18ClPO4 (%): C, 44.70; H, 6.75; P, 11.53. 3-Chloro-4-(diethylphosphono)-2-chloromethyl-2-methyl-2,5-dihydrofuran 5b was prepared from allene 1b (0.14 g, 0.52 mmol), anhydrous MeCN (8 ml) and CuCl2·H2O (0.178 g, 1.04 mmol). Yield 76%. Rf 0.66 (CHCl3–MeOH, 10:0.3). 1H NMR (CDCl3) d: 1.37 (dt, 6H, 2Me, J 1.0 and 7.2 Hz), 1.44 (s, 3H, Me), 3.67 (m, 2H, ClCH2), 4.12 (dq, 4H, 2CH2OP, J 8.0 and 7.2 Hz), 4.84 (dd, 2H, OCH2, J 2.0 Hz). 13C NMR (CDCl3) d: 16.06 (d, Me, JC–P 6.5 Hz), 22.39 (s, Me), 49.11 (s, CH2Cl), 62.27 (d, POCH2, JC–P 5.0 Hz), 62.52 (d, POCH2, JC–P 5.5 Hz), 73.75 (d, COCH2, JC–P 16.2 Hz), 91.46 [d, OC(Me)CH2Cl, JC–P 15.1 Hz], 124.91 (d, PC=, JC–P 198.2 Hz), 141.56 (d, ClC=, JC–P 4.0 Hz). 31P NMR (CDCl3) d: 7.47. IR (film, n/cm–1): 1241 (P=O), 1612 (C=C).Found (%): C, 39.57; H, 5.72; P, 10.06. Calc. for C10H17Cl2PO4 (%): C, 39.62; H, 5.65; P, 10.22. 3-Chloro-4-(diethylphosphono)-2-(hydroxymethyl)-2-methyl-2,5-dihydrofuran 5c was prepared from allene 1c (0.13 g, 0.52 mmol), anhydrous MeCN (8 ml) and CuCl2·H2O (0.178 g, 1.04 mmol). Yield 56%. Rf 0.28 (CHCl3–MeOH, 10:0.3). 1H NMR (CDCl3) d: 1.31 (s, 3H, Me), 1.39 (dt, 6H, 2Me, J 1.0 and 7.8 Hz), 3.50 (br.s, 1H, OH), 3.61 (m, 2H, CH2OH), 4.13 (dq, 4H, CH2OP, J 8.0 and 7.8 Hz), 4.81 (dd, 2H, OCH2, J 2.0 Hz). 13CNMR (CDCl3) d: 16.14 (d, Me, JC–P 6.4 Hz), 20.08 (d, Me, JC–P 1.4 Hz), 62.53 (d, POCH2, JC–P 5.6 Hz), 62.58 (d, POCH2, JC–P 5.7 Hz), 66.02 (s, HOCH2), 74.97 (d, COCH2, JC–P 16.9 Hz), 92.97 [d, OC(Me)CH2OH, JC–P 14.5 Hz], 123.72 (d, PC=, JC–P 198.8 Hz), 143.51 (d, ClC=, JC–P 3.5 Hz). 31P NMR (CDCl3) d: 9.19. IR (film, n/cm–1): 1242 (P=O), 1608 (C=C), 3674, 3602 (OH). Found (%): C, 42.30; H, 6.52; P, 10.71. Calc. for C10H18ClPO5 (%): C, 42.19; H, 6.37; P, 10.88. 3-Chloro-4-(diethylphosphono)-2-ethenyl-2-methyl-2,5-dihydrofuran 5d was prepared from allene 1d (0.128 g, 0.52 mmol), anhydrous MeCN (8 ml) and CuCl2·H2O (0.178 g, 1.04 mmol).Yield 70%. Rf 0.67 (CHCl3– MeOH, 10:0.3). 1H NMR (CDCl3) d: 1.34 (dt, 6H, 2Me, J 0.8 and 7.0 Hz), 1.48 (s, 3H, Me), 4.14 (dq, 4H, 2CH2OP, J 8.0 and 7.0 Hz), 4.80 (dd, 2H, OCH2, J 1.9 Hz), 5.21 (dd, 1H, HHC=, J 10.6 and 1.1 Hz), 5.3 (dd, 1H, HHC=, J 17.2 and 10.6 Hz), 5.93 (dd, 1H, HC=CH2). 13C NMR (CDCl3) d: 16.17 (d, Me, JC–P 6.4 Hz), 23.42 (d, Me, JC–P 1.4 Hz), 62.33 (d, POCH2, JC–P 5.7 Hz), 62.38 (d, POCH2, JC–P 5.7 Hz), 73.94 (d, COCH2, JC–P 16.4 Hz), 90.97 [d, OC(Me)CH=, JC–P 14.8 Hz], 115.10 (s, =CH2), 122.05 (d, HC=, JC-P 199.4 Hz), 137.54 (d, PC=, J 1.7 Hz), 145.25 (d, ClC=, JC–P 3.2 Hz). 31P NMR (CDCl3) d: 9.53. IR (film, n/cm–1): 1240 (P=O), 1613, 1643 (C=C). Found (%): C, 47.04; H, 6.50; P, 11.09. Calc. for C11H18ClPO4 (%): C, 47.07; H, 6.46; P, 11.04. 3-Chloro-4-(diethylphosphono)-2-(2-norbornylidene)-2,5-dihydrofuran 5e was prepared from allene 1e (0.149 g, 0.52 mmol), anhydrous MeCN (8 ml) and CuCl2·H2O (0.178 g, 1.04 mmol). Yield 67%. Rf 0.68 (CHCl3– MeOH, 10:0.3). 1H NMR (CDCl3) d: 1.16–1.90, 2.36 (m, 10H, CH2, CH), 1.34 (dt, 6H, 2Me, J 0.9 and 8.0 Hz), 4.14 (dq, 4H, 2CH2OP, J 8.0 and 8.0 Hz), 4.53 (m, 2H, OCH2). 13C NMR (CDCl3) d: 16.11 (d, Me, JC–P 5.5 Hz), 21.90 (s, CH2), 27.27 (s, CH2), 35.74 (s, CH2), 39.19 (s, CH), 43.13 (s, CH2), 46.69 (s, CH), 62.33 (d, POCH2, JC–P 5.5 Hz), 62.25 (d, POCH2, JC–P 5.5 Hz), 72.25 (d, COCH2, JC–P 16.1 Hz), 96.64 (d, OC, JC–P 15.1 Hz), 125.13 (d, PC=, JC–P 200.7 Hz), 145.78 (d, ClC=, JC–P 3.0 Hz). 31P NMR (CDCl3) d: 9.13. IR (film, n/cm–1): 1245 (P=O), 1605 (C=C). Found (%): C, 52.61; H, 7.06; P, 9.81.Calc. for C14H22ClPO4 (%): C, 52.42; H, 6.91; P, 9.66. Received: 4th March 2002; Com. 02/1900 3-Chloro-4-(diethylphosphono)-2-(2-cyclohexenylidene)-2,5-dihydrofuran 5f was prepared from allene 1f (0.142 g, 0.52 mmol), anhydrous MeCN (8 ml), and CuCl2·H2O (0.178 g, 1.04 mmol). Yield 73%. Rf 0.67 (CHCl3–MeOH, 10:0.3). 1H NMR (CDCl3) d: 1.33 (m, 2H, CH2), 1.34 (dt, 6H, 2Me, J 0.9 and 8.0 Hz), 1.78 (m, 2H, CH2), 2.10 (m, 2H, CH2), 4.12 (dq, 4H, 2CH2OP, J 8.0 and 8.0 Hz), 4.81 (m, 2H, OCH2), 5.61 (br. d, 1H, HC=CH, J 11.0 Hz), 5.97 (dt, 1H, HC=CH, J 11.0 and 2.7 Hz). 13C NMR (CDCl3) d: 16.11 (d, Me, JC–P 5.7 Hz), 18.30 (s, CH2), 24.15 (s, CH2), 31.71 (s, CH2), 61.39 (d, POCH2, JC–P 5.0 Hz), 72.61 (d, COCH2, JC–P 16.5 Hz), 89.31 (d, OC, JC–P 14.8 Hz), 126.30 (s, HC=), 123.11 (d, PC=, JC–P 198.8 Hz), 130.01 (s, HC=), 146.03 (d, ClC=, JC–P 3.8 Hz). 31P NMR (CDCl3) d: 9.14. IR (film, n/cm–1): 1241 (P=O), 1612, 1639 (C=C). Found (%): C, 50.78; H, 6.50; P, 10.20. Calc. for C13H20ClPO4 (%): C, 50.91; H, 6.57; P, 10.10.

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摘要:

Mendeleev Communications Electronic Version, Issue 2, 2002 1 Unusual oxidation of 4-amino-4H,8H-bisfurazano[3,4-b:3',4'-e]pyrazines Aleksei B. Sheremetev* and Igor L. Yudin N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 135 5328; e-mail: sab@ioc.ac.ru 10.1070/MC2002v012n02ABEH001528 The oxidation of 4,8-diamino-4H,8H-bisfurazano[3,4-b:3',4'-e]pyrazine 1 with positive halogen reagents and related oxidants afforded a stable nitrogen-centered radical, bisfurazano[3,4-b:3',4'-e]pyrazine biradical 4; tetrazene 2 was a probable intermediate.Previously, high-nitrogen furazan derivatives that are attractive ingredients for gas-generating pyrotechnic compositions were described.1.3 We recently reported the synthesis of a new high-nitrogen macrocycle incorporating the 4H,8H-bisfurazano[3,4-b:3',4'-e]- pyrazine moiety by the oxidative cyclization of a linear precursor with terminal amino groups at a furazan ring using dibromoisocyanurate. 4 To extend the study, we investigated the similar oxidation of an N-aminopiperazine, viz., 4,8-diamino-4H,8Hbisfurazano[ 3,4-b:3',4'-e]pyrazine 1.5 The oxidation of N-aminoheterocycles by tert-butyl hypochlorite, (diacetoxyiodo)benzene, or lead tetraacetate (LTA) usually leads to the formation of three types of products: (i) a transtetrazene, (ii) a new heterocycle from the ring expansion of the starting heterocycle by N-nitrene intermediate rearrangement, and (iii) the parent NH-heterocycle.6.8 The methods of synthesis and the chemistry of N-aminoheterocycles were reviewed previously. 9 When N-amine 1 was treated with an excess of dibromoisocyanurate in MeCN at room temperature, the product was neither desired tetrazene 2 nor tetrazocine 310 (Scheme 1). The structure of the dark violet product was identified as the biradical 4¢Ó by comparison with the mp and spectral data for an authentic sample.5,11,12 Other oxidants {tert-butyl hypochlorite, (diacetoxyiodo)benzene, [bis(trifluoroacetoxy)iodo]benzene (BTI), perchloryl fluoride, xenon difluoride, and LTA} also reacted with N-amine 1 in a similar fashion.This type of reactions has not been observed previously in other N-aminoheterocycles.13 A probable mechanism involving initial tetrazene intermediate formation (e.g., of type 2) followed by the loss of nitrogen and the generation of biradical 4 can be suggested.In fact, it was found that the oxidation of N,N'-diamine 1 with LTA in CH2Cl2/CF3CO2H at .40 to .30 ¡ÆC did not lead to the loss of nitrogen, and an extremely explosive solid, probably tetrazane 2,¢Ô was formed. The solid gave biradical 4 with the loss of nitrogen on heating to room temperature. The oxidation of the monoamine 55 by treatment with dibromoisocyanurate led to the same biradical 4.An initial tetrazene was evidently intermediate in this case. The result of reaction of amine 5 with tert-butyl hypochlorite in acidic conditions confirmed this assumption (Scheme 2). The mixture produced a dark coloured solution, presumably due to the formation of a radical. Proton rich conditions favoured hydrogen abstraction from the solvent by the radical.The dark violet colour was substantially discharged rapidly upon heating to room temperature. The resulting brown solid was purified by flash column chromatography (SiO2; PriOH.diethyl ether, 7:1) to afford tetrazene 6.¡× Compound 6 is an extremely labile yellow solid, which can explode when heated or scratched.On recrystallization from isopropanol, it was converted into dihydro compound 7.11,14 We prepared other mono-N-aminopiperazines 8a.c by the N-amination of monosubstituted 4H,8H-bisfurazano[3,4-b:3',4'-e]- pyrazines 7a.c12 with hydroxylamine-O-sulfonic acid according to the published procedure5 (Scheme 3). When amines 8a and 8b were subjected to the same oxidation conditions as in Scheme 2, the corresponding tetrazenes were not detected in the reaction mixture; the mixture was observed to turn dark ¢Ó Biradical 4 was found to be stable as a solid in storage at room temperature (more than 3 years).It is soluble in common organic solvents; however, it rapidly decomposed in solution (as the result of hydrogen abstraction from the solvent). Biradical 4 is an explosive of moderate sensitivity and should be handled with care.¢Ô Warning! It is a dangerous primary explosive. In a solid form at .70 ¡ÆC it was subject to spontaneous explosion. N N N N N O N N O N N N N O N N O N H2N NH2 i 3 1 N N N O N N O N N N N N N O N N O N . N2 2 4 Scheme 1 Reagents and conditions: i, dibromoisocyanurate, MeCN, 20 ¡ÆC, 5 min, 94%. ¡× Compounds described in this communication are explosives and should be handled with appropriate precautions.All new compounds gave satisfactory spectroscopic and analytical results. Selected data for 6: mp 159.164 ¡ÆC (explosion!). 1HNMR ([2H6]DMSO) d: 11.8 (NH). 13CNMR ([2H6]DMSO) d: 145.0 (C.NH), 152.8 (C.NN=N). MS (EI), m/z: 358 (M+), 330 (M+ . N2), 328 (M+ . N2 . H2), 300 (M+ . . N2 . NO).Calc. for C8H2N14O4: 358.20. IR, n/cm.1: 3240.3260, 1640, 1580, 1110, 985, 860. For 8a: mp 210.213 ¡ÆC. 1HNMR ([2H6]DMSO) d: 3.41 (3H, Me), 5.7 (2H, NH2). For 8b: mp 171.174 ¡ÆC (decomp.). 1H NMR ([2H6]DMSO) d: 6.7 (NH2). MS (EI), m/z: 303 (M+). For 8c: mp 208.210 ¡ÆC (decomp.). 1H NMR ([2H6]DMSO) d: 6.3 (NH2), 8.9 (CH). MS (EI) m/z: 285 (M+). For 9: the compound exploded when tested for melting point.IR (KBr, n/cm.1): 1640, 1597, 1575, 1430, 1350, 1305, 1190, 1150, 1085, 965. Found (%): C, 22.46; N, 41.74. Calc. for C5N8O6 (268.11) (%): C, 22.40; N, 41.79. Scheme 2 Reagents and conditions: i, dibromoisocyanurate, MeCN/CH2Cl2, 20 ¡ÆC, 56%; ii, ButOCl, CF3CO2H/CHCl3, .5.0 ¡ÆC, 38%; iii, PriOH/.. N N N O N N O N 4 N HN N O N N O N 5 NH2 i . N2 N HN N O N N O N 6 N ii N NH N O N N O N N NH HN N O N N O N 7 iiiMendeleev Communications Electronic Version, Issue 2, 2002 2 blue in 10 min, but no detectable product was formed.Similar results were obtained with (diacetoxyiodo)benzene, BTI, and Na2S2O8–CF3CO2H as oxidants. On the other hand, the oxidation of amine 8c with Na2S2O8–CF3CO2H gave an unusual poorly soluble light yellow product that precipitated from the reaction mixture (Scheme 3).The light yellow solid darkened on heating above 75 °C. At about 110 °C, it decomposed with the release of nitrogen oxides. IR spectra of the solid show the presence of the nitro group at 1350 and 1575 cm–1. The 1H NMR spectrum ([2H6]DMSO) confirmed the absence of any hydrogen atoms in the compound, but low solubility prevented the collection of 13C NMR data.The 14N NMR spectrum is comparable with that of starting compound 7c (a singlet). However, the 14N NMR spectrum of the compound shows a downfield resonance at –42.1 ppm (NO2) as compared to –35.6 ppm for the same nitrogen atom in 7c. This observation can be accounted for only if the hydrogen atom at the dinitromethyl group was replaced by an electronwithdrawing substituent as in oligomer 9.§ Microanalysis gave the molecular formula C5N8O6, indicating the same structure of 9.Mass spectrometric analysis was impossible due to the instability of compound 9 under the ionization conditions; only small fragments were observed in the spectrum. In conclusion, the difference in behaviour of these N-amino compounds clearly shows the importance of a substituent at the second piperazine nitrogen atom.The oxidation of 4,8-diamino- 4H,8H-bisfurazano[3,4-b:3',4'-e]pyrazine represents the first example of formation of a stable aminyl radical by the oxidative deamination of an N-amino heterocycle. This work was supported by the NATO Collaborative Linkage Grant (SSS.CLG.977566) and the International Science and Technology Centre (project no. 1882). References 1 A. B. Sheremetev, I. L. Yudin, N. S. Aleksandrova, V. G. Andrianov and I. B. Starchenkov, in Proc. 23rd International Pyrotechnics Seminar, 1997, Tsukuba, Japan, 377. 2 R. L. Willer, R. S. Day, D. J. Park, US Patent 5460669, 1995 (Chem. Abstr., 1996, 124, 33168). 3 C. Perotto and D. Duvacquier, Fr. Demande FR 2757119, 1998 (Chem. Abstrs., 1998, 129, 138166). 4 A. B. Sheremetev, V. O. Kulagina, I. L. Yudin and N. E. Kuzmina, Mendeleev Commun., 2001, 112. 5 I. B. Starchenkov, V. G. Andrianov and A. F. Mishnev, Khim. Geterotsikl. Soedin., 1997, 250 [Chem. Heterocycl. Compd. (Engl. Transl.), 1997, 33, 216]. 6 D. M. Lemal, in Nitrenes, ed. W. Lwowski, Interscience, New York, 1970, pp. 345–403. 7 B. V. Ioffe, M. A. Kuznetsov and A.A. Potekhin, Khimiya organicheskikh proizvodnykh gidrazina (Chemistry of Organic Hydrazine Derivatives), Khimiya, Leningrad, 1979, p. 95 (in Russian). 8 V. N. Belov, in Sovremennye problemy organicheskoi khimii (Modern Problems of Organic Chemistry), ed. K. A. Ogloblin, Leningrad, 1986, vol. 8, p. 4 (in Russian). 9 V. V. Kuz’menko and A. F. Pozharskii, Adv. Heterocycl.Chem., 1992, 53, 85. 10 L. V. Batog, L. S. Konstantinova, O. V. Lebedev and L. I. Khmel’nitskii, Mendeleev Commun., 1996, 193. 11 A. B. Sheremetev and I. L. Yudin, Mendeleev Commun., 1996, 247. 12 I. V. Tselinskii, S. F. Mel’nikova, T. V. Romanova, S. V. Pirogov, G. Kh. Khisamutdinov, T. A. Mratkhuzina, V. L. Korolev, I. Z. Kondyukov, I. Sh. Abdrakhmanov and S. P. Smirnov, Zh. Org. Khim., 1997, 33, 1739 (Russ. J. Org. Chem., 1997, 33, 1656). 13 S. F. Nelsen, in Free Radicals, ed. J. K. Kochi, Interscience, New York, 1973, vol. 2, pp. 527-593. 14 I. B. Starchenkov and V. G. Andrianov, Khim. Geterotsikl. Soedin., 1996, 717 [Chem. Heterocycl. Compd. (Engl. Transl.), 1996, 32, 618]. Scheme 3 Reagents and conditions: i, Na2CO3–H2NOSO3H–H2O–dioxane, 60–75 °C, 37–62%; ii, Na2S2O8–CF3CO2H–glyme, room temperature, 24%. NH N N O N N O N 7a–c R NN N O N N O N 8a–c R NN N O N N O N 9 NH2 NO2 NO2 i ii 8c a R = Me b R = C(NO2)2F c R = CH(NO2)2 n Received: 31st October 2001; Com. 01/1854

ISSN:0959-9436     

出版商:RSC    

年代:2002

数据来源: RSC

摘要:

Mendeleev Communications Electronic Version, Issue 2, 2002 1 Synthesis of fused quinoxalines Michail G. Ponizovsky,a Artem M. Boguslavsky,a Mikhail I. Kodess,b Valery N. Charushin*a and Oleg N. Chupakhinb a Department of Organic Chemistry, Urals State Technical University, 620002 Ekaterinburg, Russian Federation. Fax: +7 3432 74 5191; e-mail: charushin@prm.uran.ru b Institute of Organic Synthesis, Urals Branch of the Russian Academy of Sciences, 620219 Ekaterinburg, Russian Federation 10.1070/MC2002v012n02ABEH001560 The intramolecular cyclization of NH and N-alkyl quaternary salts of 2-quinoxaline-2-carboxaldehyde hydrazones affords pyrazolo- [3,4-b]quinoxalines in good yields.The idea to use tandem nucleophilic addition reactions at two neighbouring C=N bonds of an azine ring for construction of condensed aza heterocycles has been successfully applied to pyrazines and their aza and benzo analogues.1–5 Indeed, the orthocyclization of 1-alkyl-1,4-diazinium salts with bifunctional nucleophiles is an efficient synthetic approach to condensed pyrazines, quinoxalines, pyrido[2,3-b]pyrazines and pteridines in which the pyrazine ring is fused with five- and six-membered heterocycles (Scheme 1).1,2 Another approach to condensed aza heterocycles is based on a nucleophilic reaction at the C=N bond of an azine ring in combination with a nucleophilic attack at the exo-cyclic electrophilic centre (Scheme 2).This approach was illustrated by the reaction of 6-carbonyl-substituted 1,2,4-triazines with hydrazines.6 In this paper, we report on a new methodology for the synthesis of fused quinoxalines from quinoxaline-2-carboxaldehyde. Attempts to perform a cyclization reaction between quinoxaline- 2-carboxaldehyde and hydrazines without activation of the quinoxaline moiety were unsuccessful.We also failed to obtain N-alkyl quaternary salts by reacting quinoxaline-2-carboxaldehyde with methyl iodide or triethyloxonium tetrafluoroborate (the Meerwein reagent).Therefore, it was suggested to obtain fused quinoxalines in two steps: (i) condensation of quinoxaline- 2-carboxaldehyde with hydrazines resulting in corresponding hydrazones 1a–g; (ii) quarternization of quinoxalines 1a–g with methyl iodide followed by an intramolecular nucleophilic attack of NH of the side-chain hydrazone moiety at the activated C=N bond of the pyrazinium cation (Scheme 3).Hydrazones 1a–g prepared according to standard procedures† were subjected to N-alkylation with methyl iodide. It was expected that both nitrogen atoms of the pyrazine ring, N-1 and N-4, might be alkylated with methyl iodide. Indeed, the quaternization‡ of quinoxaline-2-carboxaldehyde N,N-dimethylhydrazone 1a (a model compound incapable of a further intramolecular cyclization) gave a mixture of two quaternary salts 2a and 3a in N N R HX HY N N R X Y H H H Scheme 1 N N HX HY N N E Y Scheme 2 E X N N COH N N CH N NHR NH2–NHR N N COH N N CH N NHR MeI 1a–g Me I Scheme 3 R † A common synthetic procedure for quinoxalin-2-carboxaldehyde hydrazones 1a–g.A solution of 1.0 g (6.2 mmol) of quinoxaline-2-carboxaldehyde in 15 ml of ethanol was added gradually to a solution of 6.2 mmol of hydrazine (or hydrazine hydrochloride) in 10 ml of water for 3–5 min with stirring at 60–70 °C.After stirring for additional 3–5 min, the reaction mixture was cooled to room temperature to give a hydrazone precipitate, which was filtered off and recrystallised. 1a: 66% (from water), mp 78–79 °C. 1H NMR ([2H6]DMSO) d: 3.18 (s, 6H, NMe2), 7.33 (s, 1H, CH=N), 7.6–7.8 (m, 2H, H-6, H-7), 7.9–8.0 (m, 2H, H-5, H-8), 9.28 (s, 1H, H-3). 13C NMR ([2H6]DMSO) d: 41.90 (qq, Me, 1JC,H 137.0 Hz, 3JC,Me 3.03 Hz), 126.95 (dm, CH=N, 1JC,H 166.0 Hz), 127.94, 128.51, 129.66 (m, C-5, C-6, C-7, C-8), 140.09 (ddd, C-4a, 3JC,CH 10.6 Hz, 3JC,CH 10.3 Hz, 2JC,CH 5.4 Hz), 141.37 (dd, C-8a, 3JC,CH 9.0 Hz, 2JC,CH 5.8 Hz), 142.56 (dd, C-3, 1JC,H 185.0 Hz, 3JC,CH 3.5 Hz), 153.33 (dd, C-2, 2JC,CH 9.4 Hz, 2JC,CH 6.2 Hz).Found (%): C, 51.9; H, 4.2; N, 30.0. Calc. for C11H12N4 (%): C, 51.95; H, 3.89; N, 30.28. 1b: 75% (from aqueous ethanol), mp 210–212 °C. 1HNMR ([2H6]DMSO) d: 6.85–7.35 (m, 5H, Ph), 7.70–7.90 (m, 2H, H-6, H-7), 7.90–8.10 (m, 2H, H-5, H-8), 8.01 (s, 1H, CH=N), 9.51 (s, 1H, H-3), 11.91 (s, 1H, NH). 13C NMR ([2H6]DMSO) d: 112.78 (d, C-3', 1JC,H 160.6 Hz), 120.32 (dm, C-5', 1JC,H 160.7 Hz, 3JC,CH 7.4 Hz), 128.36, 128.74, 128.94 and 130.14 (C-5, C-6, C-7, C-8), 129.13 (ddd, C-4', 1JC,H 158.9 Hz, 3JC,CH 8.0 Hz, 2JC,CH 1.7 Hz), 134.38 (dd, CH=N, 1JC,H 166.4 Hz, 3JC,CH 3.7 Hz), 140.64 (ddd, C-4a, 3JC,CH-3 9.4, 2JC,CH-6 5.8 Hz, 3JC,CH-5 5.8 Hz), 141.37 (dd, C-8a, 3JC,CH-7 8.7 Hz, 2JC,CH-8 5.7 Hz), 142.90 (dd, C-3, 1JC,H 186.3 Hz, 3JC,CH 4.0 Hz), 143.91 (m, C-1'), 149.68 (dd, C-2, 2JC,CH 9.4 Hz, 2JC,CH 6.6 Hz).Found (%): C, 72.5; H, 4.7; N, 22.5. Calc. for C15H12N4 (%): C, 72.56; H, 4.87; N, 22.57. 1c: 75% (from aqueous ethanol), mp 220–221 °C. 1HNMR ([2H6]DMSO) d: 2.37 (s, 3H, Me), 7.04–7.22 (m, 4H, p-C6H4), 7.60–7.81 (m, 2H, H-6, H-7), 7.88–8.01 (m, 2H, H-5, H-8), 7.92 (s, 1H, CH=N), 9.45 (s, 1H, H-3), 11.09 (s, 1H, NH).Found (%): C, 73.5; H, 5.1; N, 21.1. Calc. for C16H14N4 (%): C, 73.26; H, 5.38; N, 21.36. 1d: 87% (from acetic acid), mp 338–340 °C. 1H NMR ([2H6]DMSO) d: 3.30–4.60 (br. s, 1H, COOH), 7.30 (d, 2H, H-2', H-6'), 7.72–7.87 (m, 2H, H-6, H-7), 7.80 (d, 2H, H-3', H-5'), 7.98–8.11 (m, 2H, H-5, H-8), 8.10 (s, 1H, CH=N), 9.50 (s, 1H, H-3), 11.5 (s, 1H, NH).Found (%): C, 65.8; H, 4.1; N, 19.1. Calc. for C16H12N4O2 (%): C, 65.70; H, 4.14; N, 19.17. 1e: 63% (from acetic acid), mp 255–256 °C. 1H NMR ([2H6]DMSO) d: 7.35 (d, 2H, H-2', H-6'), 7.76–7.89 (m, 2H, H-6, H-7), 8.00–8.12 (m, 2H, H-5, H-8), 8.16 (d, 2H, H-3', H-5'), 8.20 (s, 1H, CH=N), 9.50 (s, 1H, H-3), 11.80 (s, 1H, NH). Found (%): C, 61.3; H, 3.7; N, 23.7.Calc. for C15H11N5O2 (%): C, 61.43; H, 3.78; N, 23.88. 1f: 70% (from aqueous ethanol), mp 96–98 °C. 1HNMR ([2H6]DMSO) d: 3.00 (d, 3H, NMe), 7.40 (s, 1H, H-3), 7.58–7.75 (m, 2H, H-6, H-7), 7.81–8.99 (m, 2H, H-5, H-8), 8.40 (d, 1H, NH), 9.20 (s, 1H, CH=N). Found (%): C, 64.8; H, 5.2; N, 29.6. Calc. for C10H10N4 (%): C, 64.50; H, 5.41; N, 30.09. 1g: 72% (from aqueous ethanol), mp 91–92 °C. 1HNMR ([2H6]DMSO) d: 4.50 (d, 2H, CH2Ph), 7.20–7.40 (m, 5H, Ph), 7.60 (s, 1H, H-3), 7.65– 7.79 (m, 2H, H-6, H-7), 7.87–8.02 (m, 2H, H-5, H-8), 8.90 (t, 1H, NH), 9.20 (s, 1H, CH=N). Found (%): C, 73.1; H, 5.4; N, 20.9. Calc. for C16H14N4 (%): C, 73.26; H, 5.38; N, 21.36.Mendeleev Communications Electronic Version, Issue 2, 2002 2 the ratio 4:1 (1H NMR data).The quaternization of quinoxalines 1b,c with methyl iodide in DMSO proceeds more selectively to result in the formation of N(4)-quaternary salts 2b,c. Salts 2b,c undergo a spontaneous intramolecular nucleophilic attack leading to ¥òH-adducts 4a,b followed by their oxidation into pyrazolo[3,4-b]quinoxalines 5b,c. This two-step reaction can be regarded as intramolecular nucleophilic substitution of hydrogen (SN H ).7 Indeed, the elimination of hydrogen is facilitated by atmospheric oxygen, as it takes place in many other SN H reactions.7 In case of phenylhydrazones 1d,e bearing electron-withdrawing groups (COOH, NO2) at the paraposition, the nucleophilic character of NH of the hydrazone moiety is insufficient to cause the SN H process; therefore, only the N4-methylation reaction takes place affording quaternary salts 2d,e (Scheme 5).Evidence for the structure of pyrazoloquinoxalines 5b,c is provided by 1H and 13C NMR data.¡× The X-ray diffraction analysis of compound 5b revealed that the pyrazoloquinoxaline system is planar and the methyl group is attached to the quaternary nitrogen, while the phenyl group is not coplanar with the tricyclic system due to hindrance caused by the N-methyl substituent (Figure 1).¢Ò In N-alkyl-substituted quinoxalin-2-carboxaldehyde hydrazones 1f,g the nucleophilic character of NH is enhanced, and the intramolecular reaction can be carried out on reflux in aqueous ethanol in the presence of a few drops of sulfuric acid to afford ¢Ô Quaternization of quinoxalin-2-carboxaldehyde phenylhydrazones 1a.e with methyl iodide.A solution of the corresponding quinoxalin-2-carboxaldehyde phenylhydrazone (2 mmol) in 2 ml of DMSO and 2 ml of methyl iodide was heated in water bath at 40.50 ¡ÆC and refluxed for 3 h. The precipitate obtained after cooling the reaction mixture to room temperature was filtered off, washed with diethyl ether, dried in air and recrystallised to give either quinoxalinium salts 2d,e or pyrazolo[3,4-b]- quinoxalinium salts 5b,c.Attempts to isolate individual salts 2a and 3a derived from quaternization of quinoxaline 1a with methyl iodide by recrystallization were unsuccessful. 2d: 65% (from AcOH.DMSO), mp 360.362 ¡ÆC. 1HNMR ([2H6]DMSO) d: 4.0 (br. s, 1H, COOH), 4.70 (s, 3H, N+Me), 7.48 (d, 2H) and 7.93 (d, 2H, p-C6H4), 8.11.8.59 (m, 4H, H-5, H-6, H-7, H-8), 8.23 (s, 1H, CH=N), 10.0 (s, 1H, H-3), 11.98 (s, 1H, NH).Found (%): C, 46.7; H, 3.4; N, 12.6. Calc. for C17H15N4O2I (%): C, 47.02; H, 3.47; N, 12.90. 2e: 67% (from AcOH.DMSO), mp 314.315 ¡ÆC. 1HNMR ([2H6]DMSO) d: 4.79 (s, 3H, N+Me) 7.56 (d, 2H, H-2', H-6'), 8.16.8.28 (m, 2H, H-3', H-5'), 8.16.8.59 (m, 4H, H-5, H-6, H-7, H-8), 8.31 (s, 1H, CH=N), 10.13 (s, 1H, H-2), 12.26 (s, 1H, NH). 13C NMR ([2H6]DMSO) d: 45.60 (dd, N+Me, 1JC,H 146.1 Hz, 3JC,CH 4.6 Hz), 113.25 (ddd, C-2', C-6', 1JC,H 166.4 Hz, 3JC,CH 5.7 Hz, 2JC,CH 2.4 Hz), 119.53, 133.79, 134.03 and 136.79 (C-5, C-6, C-7, C-8), 125.83 (dd, C-3', C-5', 1JC,H 167.6 Hz, 3JC,CH 4.6 Hz), 129.73 (m, C-8a), 130.15 (dd, CH=N, 1JC,H 171.3 Hz, 3JC,CH 5.1 Hz), 141.16 (dm, C-2, 1JC,H 197.7 Hz), 140.73 (tt, C-4', 2JC,H 9.6 Hz, 3JC,CH 3.4 Hz), 144.01 (m, C-4a), 148.82 (m, C-1'), 151.46 (dd, C-3, 3JC,CH 7.5 Hz, 2JC,CH 4.3 Hz).Found (%): C, 44.1; H, 3.3; N, 16,4. Calc. for C16H14N5O2I (%): C, 44.16; H, 3.24; N, 16.09. ¡× 5b: 62% (from water), mp 206.208 ¡ÆC. 1HNMR ([2H6]DMSO) d: 4.19 (s, 3H, N+Me), 7.70.7.88 (m, 5H, Ph), 8.20.8.78 (m, 4H, H-5, H-6, H-7, H-8), 9.61 (s, 1H, CH=N). 13C NMR ([2H6]DMSO) d: 38.65 (q, N+Me, 1JC,H 146.3 Hz), 117.77, 130.32, 132.59 and 137.83 (C-5, C-6, C-7, C-8), 127.86 (dm, 1JC,H 166.1, C-2', C-6'), 129.7 (m, C-8a), 130.06 (ddd, C-3', C-5', 1JC,H 165.4 Hz, 3JC,CH 6.1 Hz, 2JC,CH 3.1 Hz), 131.26 (dm, C-4', 1JC,H 163.5 Hz, 3JC,CH 7.2 Hz), 132.97 (m, C-9a), 137.59 (m, C-1'), 140.31 (dd, C-4a, 2JC,CH 5.4 Hz, 3JC,CH 9.7 Hz), 140.34 (d, C-3, 1JC,H 204.8 Hz), 145.79 (d, C-3a, 2JC,CH 11.0 Hz).Found (%): C, 49.4; H, 3.4; N, 14.2. Calc. for C16H14N4I (%): C, 49.38; H, 3.62; N, 14.20. 5c: 71% (from water), mp 304.305 ¡ÆC. 1HNMR ([2H6]DMSO) d: 1.83. 1.92 (m, 3H, MePh), 4.18 (s, 3H, N+Me), 7.58 (d, 2H), and 7.74 (d, 2H, p-C6H4), 8.17.8.78 (m, 4H, H-5, H-6, H-7, H-8), 9.6 (s, 1H, CH=N). Found (%): C, 50.8; H, 3.5; N, 14.0.Calc. for C17H15N4I (%): C, 50.77; H, 3.76; N, 13.93. N N N NMe2 1a N N N NMe2 2a N N N NMe2 3a Me Me Scheme 4 ¢Ò Crystallographic data for 5b: crystals of C16H13N4I are monoclinic at 293 K, space group Cc, a = 6.689(3), b = 33.689(15), c = 7.224(3) A, b = 112.416(10)¡Æ, V = 1504.9(12) A3, Z = 4, M= 389.21, dcalc = 1.713 g cm.3, m(MoK¥á) = 2.126 cm.1, F(000) = 760.Intensities of 3863 reflections were measured with a Smart 1000 CCD diffractometer at 293 K [l(MoK¥á) = = 0.71072 A, w-scans, 2q < 62¡Æ], and 2476 independent reflections (Rint = = 0.0260) were used in further refinement. The absorption correction was carried out semiempirically from equivalents. The structure was solved by the heavy atom method and refined by the full-matrix leastsquares technique against F2 in the anisotropic-isotropic approximation. The positions of the hydrogen atoms were calculated geometrically and refined in a ridding model.The refinement converged to wR2 = 0.0899 and GOF = 0.984 for all independent reflections [R1 = 0.0395 was calculated against F for 1912 observed reflections with I > 2s(I)]. All calculations were performed using SHELXTL PLUS 5.0.Atomic coordinates, bond lengths, bond angles and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC). For details, see ¡®Notice to Authors¡�, Mendeleev Commun., Issue 1, 2002. Any request to the CCDC for data should quote the full literature citation and the reference number 1135/106. N N N N 1b.e H R1 MeI N N N N 2b.e H R1 Me N N N N Me H R1 4b,c N N N N Me H R1 5b,c [O] Scheme 5 b R1 = H c R1 = Me d R1 = COOH e R1 = NO2 Figure 1 Molecular structure of pyrazolo[3,4-b]quinoxalinium iodide 5b.C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) N(1) N(2) N(3) N(4)Mendeleev Communications Electronic Version, Issue 2, 2002 3 pyrazolo[3,4-b]quinoxalines 6a,b in good yields (Scheme 6).†† In this case, the pyrazine ring is activated by N-protonation; indeed, no reaction was observed without an acid.Although several approaches to the synthesis of pyrazolo- [3,4-b]quinoxalines have been described in the literature,8–10 we believe that the above two-steps procedure involving condensation of the carbonyl group ring with hydrazines (to introduce a nucleophilic fragment into a side-chain of pyrazines) followed by intramolecular SN H reaction at the activated C=N bond is a promising methodology for the synthesis of fused 1,4-diazines.This work was supported by the US Civilian Research and Development Foundation (award no. REC-005) and the Russian Foundation for Basic Research (grant no. 01-03-96456a).References 1 V. N. Charushin, O. N. Chupakhin and H. C. van der Plas, Adv. Heterocycl. Chem., 1988, 43, 301. 2 V. N. Charushin, G. A. Mokrushina, G. M. Petrova, G. G. Alexandrov and O. N. Chupakhin, Mendeleev Commun., 1998, 133. 3 V. N. Charushin, S. G. Alexeev, O. N. Chupakhin and H. C. van der Plas, Adv. Heterocycl. Chem., 1989, 46, 73. 4 O. N. Chupakhin, B. V. Rudakov, S.G. Alexeev and V. N. Charushin, Heterocycles, 1992, 33, 931. 5 O. N. Chupakhin, G. L. Rusinov, D. G. Beresnev, V. N. Charushin and H. Neunhoeffer, J. Heterocycl. Chem., 2001, 38, 901. 6 A. Rykowski, M. Mojzych and Z. Karczmarzyk, Heterocycles, 2000, 53. 7 O. N. Chupakhin, V. N. Charushin and H. C. van der Plas, Nucleophilic Aromatic Substitution of Hydrogen, Academic Press, New York, 1994. 8 P. Madhavan Pillai and P. Ramabhadran, Indian J. Chem., 1986, 25B, 901. 9 M. von Saltza, J. D. Dutcher, J. Reid and O. Wintersteiner, J. Org. Chem., 1963, 28, 999. 10 G. Henseke and C. Bauer, Chem. Ber., 1959, 92, 509. †† Intramolecular cyclization of quinoxalin-2-carboxaldehyde alkylhydrazones 1f,g into pyrazolo[3,4-b]quinoxalines 6a,b. A few drops of sulfuric acid were added to a solution of quinoxalin-2-carboxaldehyde alkylhydrazone (2 mmol) in 10 ml of ethanol and 10 ml of water to adjust pH 2, and the reaction mixture was refluxed for 4 h.The precipitate obtained after cooling and neutralization of the reaction mixture was filtered off and recrystallised to give pyrazolo[3,4-b]quinoxalines 6a,b. 6a: 75% (from aqueous ethanol), mp 129–130 °C. 1HNMR ([2H6]DMSO) d: 4.18 (s, 3H, NHMe), 7.80 (tm, 2H), 7.91 (tm, 2H, H-6, H-7), 8.11 and 8.20 (2dd, 2×2H, H-5, H-8), 8.66 (s, 1H, CH=N). 13CNMR ([2H6]DMSO) d: 33.76 (q, Me, 1JC,H 140.4 Hz), 127.55, 128.05, 129.65 and 130.64 (C-5, C-6, C-7, C-8), 132.71 (d, C-3, 1JC,H 197.0 Hz), 136.34 (d, C-3a, 1JC,H 10.11 Hz), 140.33 (ddd, C-4a, 1JC,H 9.88 Hz, 2JC,CH 5.52 Hz, 2JC,CH 1.23 Hz), 140.61 (dd, C-8a, 1JC,H 10.11 Hz, 2JC,CH 5.52 Hz), 141.45 (m, C-9a). Found (%): C, 65.3; H, 4.5; N, 30.4. Calc. for C10H8N4 (%): C, 65.21; H, 4.38; N, 30.42. 6b: 80% (from aqueous ethanol), mp 113–114 °C. 1HNMR ([2H6]DMSO) d: 5.80 (s, 2H, CH2Ph), 7.25–7.35 (m, 5H, Ph), 7.80–8.00 (m, 2H, H-6, H-7), 8.15–8.31 (m, 2H, H-5, H-8), 8.82 (s, 1H, CH=N). Found (%): C, 73.7; H, 4.3; N21.2. Calc. for C16H12N4 (%): C, 73.83; H, 4.65; N, 21.52. N N N NHR 1f R = Me 1g R = CH2Ph H+ N N N NHR H [O] N N 6a R = Me 6b R = CH2Ph N N R Scheme 6 Received: 28th January 2002; Com. 02/1886

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Mendeleev Communications Electronic Version, Issue 2, 2002 1 Interaction of diazoimidazoles and their diazonium salts with primary and secondary amines Elena V. Sadtchikova* and Vladimir S. Mokrushin Department of Technology of Organic Synthesis, Urals State Technical University, 620002 Ekaterinburg, Russian Federation. Fax: +7 3432 74 0458; e-mail: seb@htf.ustu.ru 10.1070/MC2002v012n02ABEH001570 A number of 2- and 5-triazenoimidazoles were prepared by the coupling of diazo compounds with aliphatic amines; however, 4,5-dicyanoimidazole- 2-diazonium chloride was transformed into 2-amino-1-methylimidazole-4,5-dicarbonitrile. It is well known that dacarbazine [5-(3,3-dimethyl-1-triazeno)- imidazole-5-carboxamide, DTIC] is one of the most active anticancer drugs for the treatment of malignant melanomas and Hodgkin tumors.1 In in vivo experiments, dacarbazine generates the corresponding monomethyltriazene derivative, which undergoes proteolytic decomposition into 5-aminoimidazole-4-carboxamide (AIC) and a reactive methanediazonium species.The cytotoxic effect of the latter is due to the methylation of guanine residues in DNA.2 Here, we report on the interaction of diazotised 2- and 5-aminoimidazoles3–5 with primary and secondary amines, which was carried out to prepare more stable structural analogues of dacarbazine and its N-demethylated derivative. 5-(3,3-Dialkyl- 1-triazeno)imidazoles bearing nitro, cyano, aminocarbonyl and ethoxy groups at the 4-position were prepared earlier.4–7 We applied a similar procedure to obtain dialkyltriazenoimidazoles 3a–c and 4a–d† on the basis of 4,5-dicyanoimidazole-2-diazonium chloride3 1a, 5-diazoimidazol-4-morpholylcarboxamide 2a, 5-diazoimidazol-4-N-(p-tolyl)carboxamide 2b and its diazonium salt as diazo components.8 The reactions of diazo imidazoles with primary amines are of considerable interest.Since it is well known that monoalkyltriazeno derivatives are photosensitive and unstable substances, their reactions were carried out in the dark at low temperature. Monomethyltriazenoimidazoles 4e,f† were obtained by the reactions of 5-diazoimidazol-4-morpholylcarboxamide 2a and 5-diazoimidazol-4-N-methylcarboxamide 2c with methylamine.Similar conversions of diazo compound 2b and its diazonium salt allowed us to obtain 3-p-tolyl-3,7-dihydroimidazo[4,5-d]- [1,2,3]triazine-4-one 5a in almost quantitative yield as the only product, thus indicating that the intramolecular coupling reaction proceeds faster than the intermolecular one.Ethyl 5-diazoimidazole- 4-carboxylate 2d reacted with methylamine in a similar way to give imidazotriazinone derivative 5b. Unexpectedly, the reaction of diazonium salt 1a with methylamine resulted in the formation of 2-amino-1-methylimidazole- 4,5-dicarbonitrile 6 in 78% yield.We believe that unstable triazene 3d initially formed under the reaction conditions affords diazomethane. It generates a carbene species, which is capable of alkylating at NH of the imidazole ring. The structure of amine 6 was confirmed by 1H NMR spectroscopy, as well as by chemical conversions.‡ Thus, under diazotization conditions (NaNO2/HCl) compound 6 is transformed into 4,5-dicyano- 1-methylimidazole-2-diazonium chloride 1b, which affords N N COR N N R1 N N COR N2 H N N N N HN O R2 MeNH2 HR1 2a–c 2d 4a–f 2a– d 5a, b 2a R = morpholyl 2b R = NHC6H4-Me-p 2c R = NHMe 2d R = OEt 5a R2 = C6H4-Me-p 5b R2 = Me 4a R = morpholyl, R1 = NMe2 4b R = morpholyl, R1 = piperidinyl 4c R = NHC6H4-Me-p, R1 = piperidinyl 4d R = NHC6H4-Me-p, R1 = morpholyl 4e R = R1 = NHMe 4f R = morpholyl, R1 = NHMe Scheme 1 † All melting points are uncorrected.IR spectra were recorded on a Specord M-75 instrument in KBr pellets. 1H NMR spectra were recorded on a Bruker WR-250 instrument (250 MHz) in ([2H6]DMSO + CCl4) using TMS as an internal standard. General procedure for the synthesis of the triazeneimidazoles 3a–c and 4a–f. To a mixture of 1 mmol of 2- or 5-diazoimidazole (1a or 2a–d) in 3 ml of dry acetonitrile was added 10 mmol of a corresponding amine at –5 to 0 °C.The reaction mixture was kept in the dark at low temperature until the diazo compound disappeared (10–30 min). Crude products were collected by filtration. The precipitates were either crystallised from ethanol–chloroform or washed with diethyl ether. 3a: yield 62%, mp 136 °C. 1H NMR, d: 13.26 (br. s, 1H, NH), 3.64 (s, 3H, Me), 3.28 (s, 3H, Me). IR, n/cm–1: 3400, 2970, 2925, 2245, 1570. Found (%): C, 44.15; H, 3.77; N, 51.91. Calc. for C7H7N7 (%): C, 44.44; H, 3.73; N, 51.83. 3b: yield 98%, mp 143 °C. 1H NMR, d: 13.44 (br. s, 1H, NH), 3.67 (m, 2H, CH2), 3.05 (m, 2H, CH2), 1.70 (m, 6H, 3CH2).IR, n/cm–1: 3450, 2970, 2945, 2860, 2210, 1610. Found (%): C, 52.28; H, 4.79; N, 42.83. Calc. for C10H11N7 (%): C, 52.39; H, 4.84; N, 42.77. 3c: yield 96%, mp 157 °C. 1H NMR, d: 13.28 (br. s, 1H, NH), 3.73 (m, 6H, 2CH + 2CH2), 3.11 (m, 2H, 2CH). IR, n/cm–1: 3470, 2990, 2915, 2870, 2210, 1625. Found (%): C, 46.66; H, 3.88; N, 42.47. Calc. for C9H9N7O (%): C, 46.75; H, 3.92; N, 42.40. 4a: yield 74%, mp 152 °C. 1H NMR, d: 12.32 (br. s, 1H, NH), 7.45 (s, 1H, 2-H), 3.57 (s, 3H, Me), 3.53 (s, 3H, Me), 3.43 (m, 6H, 2CH + 2CH2), 3.16 (m, 2H, 2CH). IR, n/cm–1: 3415, 2955, 2900, 2860, 1610. Found (%): C, 47.64; H, 6.41; N, 33.21. Calc. for C10H16N6O2 (%): C, 47.61; H, 6.39; N, 33.31. 4b: yield 89%, mp 114 °C. 1H NMR, d: 12.17 (br. s, 1H, NH), 7.38 (s, 1H, 2-H), 3.73 (m, 4H, 2CH2), 3.57 (m, 8H, 4CH2), 1.69 (m, 6H, 3CH2).IR, n/cm–1: 3390, 2965, 2935, 2910, 2850, 1590. Found (%): C, 53.35; H, 6.93; N, 28.67. Calc. for C13H20N6O2 (%): C, 53.41; H, 6.90; N, 28.75. 4c: yield 85%, mp 216 °C. 1H NMR, d: 12.29 (br. s, 1H, NH), 7.84 (s, 1H, 2-H), 7.38 (d, 2H, 2',6'-H, J 8.24 Hz), 7.31 (d, 2H, 3',5'-H, J 8.24 Hz), 3.01 (m, 4H, 2CH2), 2.39 (s, 3H, Me), 1.63 (m, 6H, 3CH2).IR, n/cm–1: 3435, 3350, 2985, 2940, 2925, 2860, 1690, 1620. Found (%): C, 61.44; H, 6.45; N, 26.93. Calc. for C16H20N6O (%): C, 61.52; H, 6.45; N, 26.90. 4d: yield 83%, mp 237 °C. 1H NMR, d: 12.42 (br. s, 1H, NH), 8.03 (s, 1H, 2-H), 7.41 (d, 2H, 2',6'-H, J 8.24 Hz), 7.33 (d, 2H, 3',5'-H, J 8.24 Hz), 3.65 (m, 4H, 2CH2), 2.93 (m, 4H, 2CH2), 2.40 (s, 3H, Me).IR, n/cm–1: 3430, 3350, 3075, 2980, 2930, 2875, 1680, 1615. Found (%): C, 57.22; H, 5.74; N, 26.46. Calc. for C15H18N6O2 (%): C, 57.31; H, 5.77; N, 26.73. 4e: yield 55%, mp 168 °C. 1H NMR, d: 12.65 (br. s, 1H, NH), 10.70 (q, 1H, NHMe, J 3.66 Hz), 7.78 (q, 1H, CONHMe, J 4.58 Hz), 7.52 (s, 1H, 2-H), 3.03 (d, 3H, NHMe, J 3.66 Hz), 2.85 (d, 1H, CONHMe, J 4.58 Hz).IR, n/cm–1: 3290, 3090, 1640, 1570. Found (%): C, 39.67; H, 5.42; N, 46.22. Calc. for C6H10N6O (%): C, 39.56; H, 5.53; N, 46.13. 4f: yield 61%, mp 139 °C. 1H NMR, d: 12.24 (br. s, 1H, NH), 10.45 (m, 1H, NHMe), 7.34 (s, 1H, 2-H), 3.59 (m, 8H, 4CH2), 3.01 (d, 3H, J 3.60 Hz, NHMe). IR, n/cm–1: 3320, 3070, 2955, 2900, 2860, 1585. Found (%): C, 45.34; H, 5.84; N, 35.23. Calc. for C9H14N6O2 (%): C, 45.37; H, 5.92; N, 35.27.‡ 2-Amino-1-methylimidazole-4,5-dicarbonitrile 6. To a solution of 0.2 g (1.11 mmol) of diazonium salt 1a in 5 ml of acetonitrile a solution of 0.05 ml (1.11 mmol) of methylamine in 5 ml of acetonitrile was added at 0 °C. The mixture was kept in the dark for 5 min. The removal of the solvent under a reduced pressure gave amine 6, which was crystallised from ethanol (0.12 g, 75%).Mp 165 °C. 1H NMR, d: 6.83 (br. s, 2H, NH2), 3.46 (s, 3H, Me). IR (KBr, nmax/cm–1): 3250, 3170, 2910, 2240, 2220, 1630, 1580. Found (%): C, 49.04; H, 3.42; N, 47.69. Calc. for C6H5N5 (%): C, 48.98; H, 3.43; N, 47.60.Mendeleev Communications Electronic Version, Issue 2, 2002 2 2-(4-dimethylaminophenylazo)-1-methylimidazole-4,5-dicarbonitrile 7§ upon coupling with N,N-dimethylaniline. Thus, we found that the reactions of diazoimidazoles with aliphatic amines result in a variety of compounds, one of which is N-methylated imidazole derivative 6.This work was supported by the Russian Foundation for Basic Research (grant no. 01-03-96433a) and the US Civilian Research and Development Foundation (project no. RC1-2393-EK-02).References 1 Registr lekarstvennykh sredstv Rossii. Entsiklopediya lekarstv (Register of Medicinal Means of Russia. Encyclopædia of Medicine), 8th edn., ed. Yu. F. Krylov, Registr Lekarstvennykh Sredstv, Moscow, 2001, p. 251 (in Russian). 2 B. J. Denny, R. T. Wheelhouse, M. F. G. Stevens, L. L. H. Tsang and J. A. Slack, Biochemistry, 1994, 33, 9045. 3 W. A. Sheppard and O.W. Webster, J. Am. Chem. Soc., 1973, 95, 2695. 4 V. S. Mokrushin, I. S. Selezneva, T. A. Pospelova, V. K. Usova, S. M. Malinskaya, G. M. Anoshina and Z. V. Pushkareva, Khim.-Farm. Zh., 1982, 3, 303 (in Russian). 5 Y. E. Shealy, C. A. Krauth and J. A. Montgomery, J. Org. Chem., 1962, 27, 2150. 6 Y. E. Shealy, J. Pharm. Sci., 1970, 59, 1533. 7 T. A. Pospelova, Yu. M. Shafran, V. S.Mokrushin, Z. V. Pushkareva and G. M. Anoshina, Khim.-Farm. Zh., 1982, 5, 543 (in Russian). 8 E. V. Sadtchikova and V. S. Mokrushin, Khim. Geterotsikl. Soedin., in press. § 2-(4-Dimethylaminophenylazo)-1-methylimidazole-4,5-dicarbonitrile 7. A suspension of 0.1 g (0.68 mmol) of amine 6 in 5 ml of 2 N HCl was cooled to –5 °C with stirring. Then, 0.06 g (0.82 mmol) of sodium nitrite in 1 ml of water was added dropwise to the reaction mixture. The resulting mixture was stirred for 15 min. After diazotization, 0.1 ml (0.82 mmol) of N,N-dimethylaniline was added. The resulting suspension was filtered, and the product was recrystallised from ethanol (0.15 g, 79%). Mp 202 °C. 1HNMR, d: 7.82 (d, 2H, 2',6'-H, J 9.16 Hz), 6.83 (d, 2H, 3',5'-H, J 9.16 Hz), 3.42 (s, 3H, Me), 3.17 (s, 6H, 2Me). IR (KBr, nmax/cm–1): 3160, 3050, 2910, 2230, 2220, 1595. Found (%): C, 60.13; H, 4.61; N, 35.19. Calc. for C14H13N7 (%): C, 60.20; H, 4.69; N, 35.10. N N NC NC H N N R1 3a–c N N NC NC H N2Cl 1a R1–H MeNH2 N N NC NC H N N NH 3d Me N N NC NC NH2 6 Me N N NC NC N2Cl 1b Me N N NC NC N 7 Me PhNMe2 N NMe2 3a R1 = NMe2 3b R1 = piperidinyl 3c R1 = morpholyl Scheme 2 Received: 28th February 2002; Com. 02/1896

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Mendeleev Communications Electronic Version, Issue 2, 2002 1 4-(1-Benzotriazolyl)-5-nitrophthalonitrile as a highly active substrate in aromatic nucleophilic substitution reactions Alexey V. Smirnov, Igor G. Abramov,* Vladimir V. Plakhtinskii and Galina G. Krasovskaya Department of Organic Chemistry, Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation. Fax: +7 0852 44 0729; e-mail: abramov.orgchem@staff.ystu.yar.ru 10.1070/MC2002v012n02ABEH001538 The title compound was synthesised, and its derivatives were prepared in high yields using the selective substitution of O-, S- and N-nucleophiles for the nitro group; an activating effect of the benzotriazolyl moiety on the above reactions was found.Previously,1–6 we studied the activated aromatic nucleophilic substitution for the nitro group in 4-nitrophthalonitrile and for the bromine atom and the nitro group in 4-bromo-5-nitrophthalonitrile using various O-, S- and N-nucleophiles.Benzotriazole is widely used in SNAr reactions as a nitrogen-containing nucleophile.7–9 The procedure for preparing 4-(1-benzotriazolyl)- 5-nitrophthalonitrile 1 in 48% yield was reported earlier.3 The yield of the mono-substituted product was increased up to 59% by decreasing reaction temperature and using another alkaline agent.However, we failed to prevent the formation of disubstituted products 2a,b (Scheme 1). Therefore, we developed a two-step procedure (Scheme 2) to prepare chromatographically pure compound 1. This procedure allowed us to synthesise the target product in 83% yield on a basis of starting 4-bromo-5-nitrophthalonitrile.† At the first step, 4-bromo-5-nitrophthalonitrile readily reacted with o-phenylenediamine in boiling isopropanol in the presence of triethylamine to form 4-(2-aminoanilino)-5-nitrophthalonitrile.2 The second step consisted in the diazotisation of the isolated product on heating in acetic acid to result in the target compound.The synthesised substrate is of interest because a benzene ring bears four electron-acceptor substituents: two cyano groups and a benzotriazole moiety in the ortho position with respect to the nitro group. Although the reactions of substitution for the nitro group were studied in detail,10 reactions with the participation of the above compound were not described in the literature.Substitution for the benzotriazole moiety was described for only aliphatic systems. We found that the presence of a comparatively strong electronacceptor benzotriazole substituent increases the probability of a nucleophilic attack on the carbon atom bound to the nitro group. Moreover, this carbon atom is activated by two cyano groups; thus, the nitro group becomes more labile.Because of this, only the nitro group in compound 1 can be readily replaced by various O-, S- and N-nucleophiles under mild reaction conditions. Thus, compound 1 reacted with substituted phenols (Scheme 3) in a 75% aqueous DMF solution in the presence of potassium carbonate within 30 min even at room temperature (20 °C). Reaction products 3a–l‡,†† precipitated from the reaction mixture and did not require further purification.The reaction of 1 with bisphenols occurred under analogous conditions with the formation of, for example, compound 4§,†† (Scheme 4). The above nucleophiles can replace the nitro group1 in 4-nitrophthalonitrile only at 60 °C, whereas substitution for the heterocyclic moiety in 4-benzotriazolylphthalonitrile did not occur at a higher temperature.3 We † 4-(1-Benzotriazolyl)-5-nitrophthalonitrile 1. 4-(2-Aminoanilino)-5-nitrophthalonitrile (31.00 g, 0.11 mol) was dissolved in 300 ml of acetic acid. A solution of 7.60 g (0.11 mol) of NaNO2 in 50 ml of water was added to the resulting solution. The reaction mixture was stirred at 70 °C for 3 h. The precipitate formed after cooling was filtered off, washed with 20 ml of acetic acid, and dried at 70 °C.N Br N N O O N N N H K2CO3 DMF, 20 °C N N N N O O N N N N N N N N N N N N N N N N N N BNPN 1 2a 2b Scheme 1 Et3N PriOH N NH N N O O NH2 BNPN 1 Scheme 2 H2N H2N NaNO2 MeCOOH 1 OH R O N N N N N 3a–l K2CO3 75% aq. DMF R a R = H b R = 3,4-Me c R = 4-Cl d R = 4-Br e R = 4-(4-MeC6H4) f R = 4-Ph g R = 4-cyclohexyl h R = 4-COMe i R = 4-F j R = 4-Cl-3,5-Me k R = 4-Cl-3-Me l R = 3-COMe Scheme 3Mendeleev Communications Electronic Version, Issue 2, 2002 2 partially replaced the benzotriazole unit by phenoxide (according to LC data) only in compound 2 upon refluxing the corresponding parent compounds in anhydrous DMF for a long time.Under the specified conditions (20 °C, 75% aqueous DMF), the reaction with S-nucleophiles such as 4-bromothiophenol occurred more readily (Scheme 5). The product of selective substitution for the nitro group precipitated from the reaction mixture 1 to 2 min after mixing the reactant solutions.If benzotriazole was used as an N-nucleophile in the considered reaction with compound 1 under the specified conditions, the substitution of the benzotriazole ring for the nitro group primarily took place at the second nitrogen atom.In this case, the yield of compound 2a was as high as 76%. According to 1H NMR data, compound 2a precipitated from the reaction mixture exhibited a non-symmetrical structure identical to that described previously.4 Compound 2b was not precipitated from the reaction mixture, and it was detected in a mixture with 2a in the analysis of the product obtained after diluting the filtrate with water.For comparison, note that the nitro group in 4-nitrophthalonitrile can be replaced3 with benzotriazole only at 70 °C in anhydrous DMF to result in a mixture of 1- and 2-substituted derivatives in the ratio 1.4:1. The substrate under consideration can also react with ambident nucleophiles such as thiourea and the nitrite ion.The reaction of 1 with thiourea began with the formation of an isothiuronium salt, which was rearranged into a mercapto derivative in the presence of a base (triethylamine). The resulting thiophenoxide is reactive, and it attacked substrate 1 in the presence of triethylamine to afford 4-(1-benzotriazolyl)- 5-[2-(1-benzotriazolyl)-4,5-dicyanophenylsulfanyl]phthalonitrile 6‡,†† (Scheme 6).Compound 1 can react with alkali metal nitrites in the presence of potassium carbonate at elevated temperatures (Scheme 7). Compound 7¶,†† was formed by the replacement of the nitro group on an O-attack of the nitrite ion.11 In contrast to thiophenoxide, the resulting compound is inactive in nucleophilic substitution reactions, and it can be easily separated from the reaction mixture.Thus, the above results are indicative of a higher reactivity of 4-(1-benzotriazolyl)-5-nitrophthalonitrile in nucleophilic substitution reactions than that of 4-nitrophthalonitrile. It is believed that the benzotriazole unit has a considerable activating effect on the test reaction of selective substitution for the nitro group. Both donor and acceptor substituents are simultaneously present in the prepared compounds, and this fact is responsible for their unique properties.On this basis, new promising materials with special photophysical properties, for example, phthalocyanines12 and hexazocyclanes,13 can be synthesised. References 1 I. G. Abramov, V. V. Plachtinsky, G. S. Mironov and O. A. Yasinsky, Izv. Vyssh. Uchebn. Zaved., Khim.Khim. Tekhnol., 1997, 2, 31 (in Russian). 2 I. G. Abramov, M. V. Dorogov, S. A. Ivanovskii, A. V. Smirnov and M. B. Abramova, Mendeleev Commun., 2000, 78. ‡ 4-(1-Benzotriazolyl)-5-phenoxyphthalonitrile 3a. Compound 1 (2.00 g, 0.07 mol), phenol (0.66 g, 0.07 mol) and K2CO3 (0.97 g, 0.07 mol) dissolved in 5 ml of water were added to 15 ml of DMF. The resulting mixture was intensely stirred at room temperature for 0.5 h.The formed precipitate was filtered off, washed with 20 ml of ethanol and then 100 ml of water, and dried at 70 °C. Compounds 3b–l, 5 and 6 were prepared in a similar manner with the use of equimolar amounts of other phenols, 4-bromothiophenol and thioacetamide as reactants. § 4-(1-Benzotriazolyl)-5-{4-[2-(1-benzotriazolyl)-4,5-dicyanophenoxy]- phenoxy}phthalonitrile 4.Compound 1 (2.00 g, 0.07 mol), a bisphenol (0.04 mol) and K2CO3 (0.97 g, 0.07 mol) dissolved in 5 ml of water were added to 15 ml of DMF. The resulting mixture was intensely stirred at room temperature for 1 h. The formed precipitate was filtered off, washed with 20 ml of ethanol and then 100 ml of water, and dried at 70 °C. N N N N O O N N 1 OH OH 2 K2CO3 75% aq.DMF O N N N N N O N N N N N 4 Scheme 4 Scheme 5 1 S N N N N N K2CO3 75% aq. DMF Br 5 SH Br ¶ 4-(1-Benzotriazolyl)-5-hydroxyphthalonitrile 7. Compound 1 (2.00 g, 0.07 mol), NaNO2 (0.69 g, 0.07 mol) and K2CO3 (0.97 g, 0.07 mol) dissolved in 5 ml of water were added to 15 ml of DMF. The resulting mixture was heated to 70 °C and intensely stirred at this temperature for 0.5 h.After cooling to room temperature, HCl was added to the reaction mixture to pH 1. The formed precipitate was filtered off, washed with 20 ml of ethanol and dried at 70 °C. N N N N O O N N 1 2 PriOH 6 Scheme 6 S H2N NH2 Et3N N N N N N S N N N N N OH N N N N N 1 7 NaNO2, K2CO3 75% aq. DMF Scheme 7Mendeleev Communications Electronic Version, Issue 2, 2002 3 3 I.G. Abramov, V. V. Plachtinsky, M. B. Abramova, A. V. Smirnov and G. G. Krasovskaya, Khim. Geterotsikl. Soedin., 1999, 1537 [Chem. Heterocycl. Compd. (Engl. Transl.), 1999, 35, 1342]. 4 I. G. Abramov, A. V. Smirnov, S. A. Ivanovskii, M. B. Abramova and V. V. Plachtinsky, Khim. Geterotsikl. Soedin., 2000, 1219 [Chem. Heterocycl. Compd. (Engl. Transl.), 2000, 36, 1062]. 5 I. G. Abramov, S.A. Ivanovskii, A. V. Smirnov and M. V. Dorogov, Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 2000, 1, 120 (in Russian). 6 I. G. Abramov, A. V. Smirnov, S. A. Ivanovskii, M. B. Abramova and V. V. Plachtinsky, Heterocycles, 2001, 6, 1161. 7 A. R. Katritzky, T. Kurz, S. Zhang and M. Voronkov, Heterocycles, 2001, 9, 1703. 8 A. R. Katritzky, A. V. Ignatchenko and H. Lang, Heterocycles, 1995, 41, 131. 9 A. R. Katritzky and J. Wu, Synthesis, 1994, 597. 10 F. Terrier, Nucleophilic Aromatic Displacement: The Influence of the Nitro Group, VSH Publishers, New York, 1991. 11 T. J. Broxton, D. M. Muir and A. J. Parker, J. Org. Chem., 1975, 14, 2037. 12 O. V. Shishkina, V. E. Mayzlish and G. P. Shaposhnikov, Zh. Obshch. Khim., 2001, 2, 271 (Russ. J. Gen. Chem., 2001, 2, 1712). 13 S. A. Siling, S. V. Shamshin, A. B. Grachev, O. Yu. Tsiganova, V. I. Yuzhakov, I. G. Abramov, A. V. Smirnov, S. A. Ivanovskii, A. G. Vitukhnovsky, A. S. Averjushkin and Bui Chi Lap, Oxidation Commun., 2000, 4, 481. †† The 1H NMR spectra of 5% sample solutions in [2H6]DMSO were measured on a Bruker DRX-500 instrument using TMS as an internal standard. 3a: yield 89%, mp 188–191 °C. 1H NMR, d: 8.62 (s, 1H), 7.13 (d, 1H, J 8.2 Hz), 7.80 (d, 1H, J 8.2 Hz), 7.75 (s, 1H), 7.64 (t, 1H), 7.50 (t, 1H), 7.42 (t, 2H), 7.27 (t, 1H), 7.18 (d, 2H, J 8.81 Hz). Found (%): C, 71.09; H, 3.30; N, 20.80. Calc. for C20H11N5O (%): C, 71.21; H, 3.29; N, 20.76. 3b: yield 94%, mp 236–238 °C. 1H NMR, d: 8.62 (s, 1H), 8.14 (d, 1H, J 8.1 Hz), 7.80 (d, 1H, J 8.1 Hz), 7.72 (s, 1H), 7.63 (t, 1H), 7.50 (t, 1H), 6.90 (s, 1H), 6.75 (s, 2H), 2.25 (s, 6H).Found (%): C, 72.15; H, 4.14; N, 19.25. Calc. for C22H15N5O (%): C, 72.32; H, 4.14; N, 18.17. 3c: yield 92%, mp 237–239 °C. 1H NMR, d: 8.62 (s, 1H), 8.15 (d, 1H, J 8.2 Hz), 7.90 (s, 1H), 7.80 (d, 1H, J 8.0 Hz), 7.63 (t, 1H), 7.50 (t, 1H), 7.40 (d, 2H, J 8.4 Hz), 7.15 (d, 2H, J 8.1 Hz). Found (%): C, 64.51; H, 2.72; N, 18.90. Calc.for C20H10ClN5O (%): C, 64.61; H, 2.71; N, 18.84. 3d: yield 96%, mp 251–253 °C. 1H NMR, d: 8.65 (s, 1H), 8.14 (d, 1H, J 8.2 Hz), 7.90 (s, 1H), 7.80 (d, 1H, J 8.1 Hz), 7.64 (t, 1H), 7.56 (d, 2H, J 8.0 Hz), 7.50 (t, 1H), 7.15 (d, 2H, J 8.1 Hz). Found (%): C, 57.60; H, 2.43; N, 16.78. Calc. for C20H10BrN5O (%): C, 57.71; H, 2.42; N, 16.83. 3e: yield 84%, mp 215–217 °C. 1H NMR, d: 8.67 (s, 1H), 8.17 (d, 1H, J 8.3 Hz), 7.87 (d, 1H, J 8.0 Hz), 7.83 (s, 1H), 7.67 (m, 3H), 7.50 (t, 3H), 7.25 (d, 4H, J 7.9 Hz), 2.33 (s, 3H). Found (%): C, 75.68; H, 4.01; N, 16.45. Calc. for C27H17N5O (%): C, 75.86; H, 4.01; N, 16.38. 3f: yield 87%, mp 208–210 °C. 1H NMR, d: 8.66 (s, 1H), 8.16 (d, 1H, J 8.3 Hz), 7.88 (s, 1H), 7.83 (d, 1H, J 8.0 Hz), 7.67 (m, 3H), 7.60 (d, 2H, J 7.9 Hz), 7.50 (t, 1H), 7.45 (t, 2H), 7.35 (t, 1H), 2.27 (d, 2H, J 8.1 Hz).Found (%): C, 75.38; H, 3.67; N, 17.01. Calc. for C26H15N5O (%): C, 75.53; H, 3.66; N, 16.94. 3g: yield 82%, mp 204–206 °C. 1H NMR, d: 8.62 (s, 1H), 8.14 (d, 1H, J 8.2 Hz), 7.80 (d, 2H, J 8.2 Hz), 7.70 (s, 1H), 7.65 (t, 1H), 7.50 (t, 1H), 7.25 (d, 2H, J 8.1 Hz), 7.10 (d, 2H, J 8.0 Hz), 2.55 (s, 1H), 1.80 (d, 4H, J 7.8 Hz), 1.60 (d, 1H, J 8.5 Hz), 1.35 (m, 4H), 1.25 (m, 1H).Found (%): C, 74.31; H, 5.05; N, 14.64. Calc. for C26H21N5O (%): C, 74.44; H, 5.05; N, 16.70. 3h: yield 91%, mp 215–217 °C. 1H NMR, d: 8.70 (s, 1H), 8.12 (d, 1H, J 8.3 Hz), 8.00 (s, 1H), 7.93 (d, 2H, J 8.3 Hz), 7.80 (d, 1H, J 8.0 Hz), 7.65 (t, 1H), 7.50 (t, 1H), 7.20 (d, 2H, J 8.2 Hz). Found (%): C, 69.52; H, 3.46; N, 18.50.Calc. for C22H13N5O2 (%): C, 69.65; H, 3.45; N, 18.46. 3i: yield 83%, mp 209–211 °C. 1H NMR, d: 8.65 (s, 1H), 8.15 (d, 1H, J 8.1 Hz), 7.84 (d, 1H, J 8.3 Hz), 7.78 (s, 1H), 7.65 (t, 1H), 7.50 (t, 1H), 7.25 (m, 4H). Found (%): C, 67.49; H, 2.85; N, 19.70. Calc. for C20H10FN5O (%): C, 67.60; H, 2.84; N, 19.71. 3j: yield 96%, mp 225–227 °C. 1H NMR, d: 8.60 (s, 1H), 8.13 (d, 1H, J 8.2 Hz), 7.87 (s, 1H), 7.80 (d, 1H, J 7.9 Hz), 7.65 (t, 1H), 7.50 (t, 1H), 7.00 (s, 2H), 2.30 (s, 6H). Found (%): C, 65.93; H, 3.53; N, 17.49.Calc. for C22H14ClN5O (%): C, 66.09; H, 3.53; N, 17.43. 3k: yield 94%, mp 213–215 °C. 1H NMR, d: 8.60 (s, 1H), 7.12 (d, 1H, J 8.0 Hz), 7.90 (s, 1H), 7.80 (d, 1H, J 8.3 Hz), 7.62 (t, 1H), 7.50 (t, 1H), 7.40 (d, 1H, J 8.0 Hz), 7.15 (s, 1H), 7.0 (d, 1H, J 7.9 Hz), 2.30 (s, 3H).Found (%): C, 65.20; H, 3.14; N, 18.20. Calc. for C21H12ClN5O (%): C, 65.38; H, 3.14; N, 18.15. 3l: yield 89%, mp 186–188 °C. 1H NMR, d: 8.67 (s, 1H), 8.12 (d, 1H, J 8.0 Hz), 7.90 (s, 1H), 7.83 (d, 2H, J 8.4 Hz), 7.70 (s, 1H), 7.65 (t, 1H), 7.56 (t, 1H), 7.50 (t, 1H), 7.45 (d, 1H, J 8.1 Hz). Found (%): C, 69.57; H, 3.46; N, 18.41.Calc. for C22H13N5O2 (%): C, 69.65; H, 3.45; N, 18.46. 4: yield 77%, mp > 300 °C. 1H NMR, d: 8.60 (s, 2H), 8.15 (d, 2H, J 8.2 Hz), 7.90 (s, 2H, J 8.1 Hz), 7.80 (d, 2H, J 7.9 Hz), 7.65 (t, 2H), 7.50 (t, 2H), 7.20 (s, 4H). Found (%): C, 68.33; H, 2.71; N, 23.54. Calc. for C34H16N10O2 (%): C, 68.45; H, 2.70; N, 23.48. 5: yield 97%, mp 181–183 °C. 1H NMR, d: 8.40 (s, 1H), 7.15 (d, 1H, J 8.2 Hz), 7.70 (d, 2H, J 8.5 Hz), 7.65 (t, 1H), 7.57 (d, 1H, J 7.9 Hz), 7.50 (t, 1H), 7.40 (d, 1H, J 8.0 Hz). Found (%): C, 55.45; H, 2.33; N, 16.25; S, 7.43. Calc. for C20H10BrN5S (%): C, 55.57; H, 2.33; N, 16.20; S, 7.42. 6: yield 86%, mp 285–287 °C. 1H NMR, d: 8.45 (s, 2H), 8.35 (s, 2H), 8.13 (d, 2H, J 8.5 Hz), 7.60 (m, 4H), 7.50 (d, 2H, J 8.3 Hz). Found (%): C, 64.47; H, 2.33; N, 27.01; S, 6.17. Calc. for C28H12N10S (%): C, 64.61; H, 2.32; N, 26.91; S, 6.16. 7: yield 90%, mp > 300 °C. 1H NMR, d: 12.60 (s, 1H), 8.40 (s, 1H), 8.15 (d, 1H, J 8.0 Hz), 7.70 (s, 1H), 7.63 (t, 1H), 7.57 (t, 1H), 7.48 (d, 1H, J 8.1 Hz). Found (%): C, 64.20; H, 2.70; N, 26.70. Calc. for C14H7N5O (%): C, 64.37; H, 2.70; N, 26.81. Received: 6th December 2001; Com. 01/1864

ISSN:0959-9436     

出版商:RSC    

年代:2002

数据来源: RSC

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Mendeleev Communications Electronic Version, Issue 2, 2002 1 A convenient synthesis of 4(5)-(2-hydroxyaroyl)-5(4)-trifluoromethyl-1,2,3-triazoles from 2-trifluoromethylchromones and chromen-4-imines Vyacheslav Ya. Sosnovskikh* and Boris I. Usachev Department of Chemistry, A. M. Gor’ky Urals State University, 620083 Ekaterinburg, Russian Federation. Fax: +7 3432 61 5978; e-mail: Vyacheslav.Sosnovskikh@usu.ru 10.1070/MC2002v012n02ABEH001562 The reactions of 2-trifluoromethylchromones and 2-trifluoromethyl-4H-chromen-4-imines with sodium azide in the presence of acetic acid give the ketone and imine derivatives of 5(4)-trifluoromethyl-1,2,3-triazole in high yields.Vicinal triazoles belong to well-studied heterocyclic systems formed by the reactions of organic and inorganic azides with activated acetylenes1–4 and alkenes.5–8 However, data on 1,2,3- triazoles with CF3 groups are scanty, although CF3-containing heterocycles are widely used in medicine and agriculture.9 They are primarily prepared by the cycloaddition reactions of organic azides to CF3-containing acetylenes10–13 and by the oxidation of polyfluorinated aliphatic á-diketone bishydrazones.14 To continue our studies15–18 on the chemical properties of 2-trifluoromethylchromones, we examined the reactions of chromones 1a–d with sodium azide.We found that this is a simple and effective method for the synthesis of previously unknown salicyloyltriazoles 2a–d.† It is most likely that the reaction occurs via intermediate 3, which results from 1,3-dipolar cycloaddition or the initial attack of the azide anion on the C(2) atom followed by cyclization to 3.Ring opening in intermediate 3 results in aryl triazolyl ketones 2 in 50–86% yields; thus, chromones 1 can be considered as synthetic equivalents of inaccessible trifluoropropynyl ketones 4. The reaction of chromones 1 with NaN3 occurred in AcOH– EtOH at 80 °C within 4–10 h. However, it was found that this reaction is typical of only 2-trifluoromethylchromones, and it did not take place on the replacement of CF3 by H, CF2H, (CF2)2H and CCl3 groups, as well as with 3-chloro-2-trifluoromethylchromone. Moreover, in the absence of an electron-acceptor substituent at the 6-position of the chromone system, the reaction was slow so that 2-trifluoromethylchromone remained unconverted after contact with NaN3 under the above conditions for 10 h.We found that the replacement of C=O with the C=N–R group enhanced the reactivity of the double bond of a pyrone ring towards sodium azide. Thus, chromen-4-imines 5, which were synthesised by the condensation of the Schiff bases of 2-hydroxy- and 2-hydroxy-5-methylacetophenones with CF3CO2Et followed by the cyclisation of resulting aminoenones 6 to cations 5' under the action of HCl and the treatment of the latter with an aqueous ammonia solution,19 readily react with NaN3 in the presence of AcOH to form aryl triazolyl ketone imines 7.‡ This result can be explained by the fact that compounds 5, which are † General preparation procedure for triazoles 2.A mixture of chromone 1 (1.0 mmol) and NaN3 (0.10 g, 1.5 mmol) in 2 ml of AcOH–EtOH (1:1) was heated at 80 °C for 4 h for 1a,c or 10 h for 1b,d.Next, the reaction mixture was mixed with 10 ml of water; the product was filtered off, washed with water, dried and recrystallised. 4(5)-(2-Hydroxy-5-nitrobenzoyl)-5(4)-trifluoromethyl-1,2,3-triazole 2a: yield 86%, mp 177–178 °C (CCl4). 1H NMR (400 MHz, [2H6]DMSO) d: 7.16 [d, 1H, H(3), oJ 9.1 Hz], 8.35 [dd, 1H, H(4), oJ 9.1 Hz, mJ 2.9 Hz], 8.52 [d, 1H, H(6), mJ 2.9 Hz], 11.9 (br.s, 1H, NH or OH). IR (Vaseline oil, n/cm–1): 3270, 1680, 1640, 1615, 1570, 1515. Found (%): C, 39.65; H, 1.79; N, 18.58. Calc. for C10H5F3N4O4 (%): C, 39.75; H, 1.67; N, 18.54. 4(5)-(5-Chloro-2-hydroxybenzoyl)-5(4)-trifluoromethyl-1,2,3-triazole 2b: yield 68%, mp 148–149 °C (hexane–toluene). 1HNMR (400MHz, CDCl3) d: 7.05 [d, 1H, H(3), oJ 9.0 Hz], 7.52 [dd, 1H, H(4), oJ 9.0 Hz, mJ 2.6 Hz], 8.27 [d, 1H, H(6), mJ 2.6 Hz], 11.80 (s, 1H, NH or OH). IR (Vaseline oil, n/cm–1): 3350, 1625, 1605, 1560, 1525, 1495. Found (%): C, 41.14; H, 1.72; N, 14.68. Calc. for C10H5ClF3N3O2 (%): C, 41.19; H, 1.73; N, 14.41. 4(5)-(3,5-Dibromo-2-hydroxybenzoyl)-5(4)-trifluoromethyl-1,2,3-triazole 2c: yield 50%, mp 175–176 °C (hexane–toluene). 1H NMR (400 MHz, CDCl3) d: 7.96 [d, 1H, H(4), mJ 2.3 Hz], 8.43 [d, 1H, H(6), mJ 2.3 Hz], 12.44 (s, 1H, NH or OH).IR (Vaseline oil, n/cm–1): 3190, 1635, 1585. Found (%): C, 29.25; H, 1.18; N, 10.41. Calc. for C10H4Br2F3N3O2 (%): C, 28.94; H, 0.97; N, 10.13. 4(5)-(4,6-Dimethyl-3,5-dinitro-2-hydroxybenzoyl)-5(4)-trifluoromethyl- 1,2,3-triazole 2d: yield 66%, mp 160–161 °C (hexane–CCl4). 1H NMR (400 MHz, [2H6]DMSO) d: 2.06 (s, 3H, Me), 2.22 (s, 3H, Me), 6.2 (br. s, 2H, OH, NH).IR (Vaseline oil, n/cm–1): 3280, 1695, 1590, 1535. Found (%): C, 38.43; H, 2.06; N, 18.61. Calc. for C12H8F3N5O6 (%): C, 38.41; H, 2.15; N, 18.67. ‡ 2-[Benzylimino-(1,2,3-triazol-4-yl)methyl]phenol 7a was prepared from compound 5a according to a procedure analogous to that for 2; however, the heating was performed for 10 min.Yield 57%, mp 146–147 °C (ethanol–H2O, 1:1). 1H NMR (400 MHz, CDCl3) d: 4.50 (s, 2H, CH2), 6.64 [dd, 1H, H(6), oJ 8.0 Hz, mJ 1.6 Hz], 6.74 [ddd, 1H, H(5), oJ 8.0, 7.3 Hz, mJ 1.1 Hz], 7.06 [dd, 1H, H(3), oJ 8.4 Hz, mJ 1.0 Hz], 7.24–7.33 (m, 5H, Ph), 7.35 [ddd, 1H, H(4), oJ 8.4, 7.3 Hz, mJ 1.7 Hz], 11.3 (br.s, 1H, NH). 1H NMR (400 MHz, CDCl3 + CF3CO2H) d: 4.72 (s, 2H, CH2), 6.81 [dd, 1H, H(6), oJ 8.3 Hz, mJ 1.5 Hz], 6.96 [t, 1H, H(5), oJ 8.1 Hz], 7.31 [d, 1H, H(3), oJ 8.5 Hz], 7.15–7.17 [m, 2H, H(3'), H(5')], 7.36–7.39 [m, 3H, H(2'), H(4'), H(6')], 7.67 [ddd, 1H, H(4), oJ 8.5, 7.3 Hz, mJ 1.6 Hz], 8.2 (br. s, 2H, NH, OH). 1H NMR (400MHz, [2H6]DMSO) d: 4.52 (s, 2H, CH2), 6.71 [dd, 1H, H(6), oJ 8.0 Hz, mJ 1.6 Hz], 6.81 [ddd, 1H, H(5), oJ 8.0, 7.4 Hz, mJ 1.1 Hz], 6.97 [dd, 1H, H(3), oJ 8.3 Hz, mJ 0.9 Hz], 7.26–7.39 (m, 5H, Ph), 7.39 [ddd, 1H, H(4), oJ 8.3, 7.4 Hz, mJ 1.6 Hz], 14.22 (s, 1H, NH), 16.7 (br.s, 1H, OH). IR (Vaseline oil, n/cm–1): 1675, 1610. Found (%): C, 58.98; H, 3.78; N, 16.13. Calc. for C17H13F3N4O (%): C, 58.96; H, 3.78; N, 16.18. 2-[Benzylimino-(1,2,3-triazol-4-yl)methyl]-4-methylphenol 7b was prepared from compound 5b analogously to 7a.Yield 55%, mp 215–216 °C (ethanol–H2O, 2:1). 1H NMR (400 MHz, CDCl3) d: 2.15 (s, 3H, Me), 4.47 (br. s, 2H, CH2), 6.38 [br. d, 1H, H(6), mJ 1.5 Hz], 6.93 [d, 1H, H(3), oJ 8.4 Hz], 7.15 [dd, 1H, H(4), oJ 8.4 Hz, mJ 1.9 Hz], 7.24–7.36 (m, 5H, Ph), 13.8 (br.s, 1H, NH). IR (Vaseline oil, n/cm–1): 1675, 1615, 1580, 1535. Found (%): C, 60.14; H, 4.18; N, 15.49. Calc. for C18H15F3N4O (%): C, 60.00; H, 4.20; N, 15.55. O O R1 CF3 R4 R3 R2 1a–d O O R1 R4 R3 R2 3 N N N H NaN3 AcOH, EtOH R1 R2 O R4 R3 O H NH N N CF3 2a–d OH O R1 R4 R3 R2 4 CF3 a R1 = R3 = R4 = H, R2 = NO2 b R1 = R3 = R4 = H, R2 = Cl c R1 = R3 = H, R2 = R4 = Br d R1 = R3 = Me, R2 = R4 = NO2 Scheme 1 CF3Mendeleev Communications Electronic Version, Issue 2, 2002 2 strong bases, undergo protonation at the imine nitrogen atom20 in the presence of AcOH and generate iminium cations 5', which participate in the reaction.This hypothesis was supported by the fact that compounds 5 did not react with NaN3 in ethanol without adding AcOH. Salicyloyltriazoles 8a,b,§ which cannot be synthesised from corresponding chromones 1, were isolated upon the hydrolysis of imines 7a,b under the action of an aqueous-ethanol solution of HCl.These compounds can be more conveniently prepared from chromenimines 5c,d without the stage of the separation of easily hydrolysable imines 7c,d with 2-hydroxyethyl groups. Because the transformations 6 ® 5 and 5 ® 7 occur via common intermediate 5', it is reasonable to suggest that compounds 6 would give ketones 8 upon the treatment with NaN3 and AcOH.Indeed, we found that aminoenones 6c,d, as well as chromenimines 5c,d, give salicyloyltriazoles 8a,b under analogous conditions.¶ Thus, we developed a simple and efficient synthetic procedure for 4(5)-salicyloyl-5(4)-trifluoromethyl-1,2,3-triazoles and their imines.These compounds are of considerable interest because the biological activity of triazole ketones is well known.4 This work was supported by the Russian Foundation for Basic Research (grant no. 99-03-32960) and, in part, by the US Civilian Research and Development Foundation (grant no. REC-005). References 1 A. N. Nesmeyanov and M. I. Rybinskaya, Dokl.Akad. Nauk SSSR, 1964, 158, 408 [Dokl. Chem. (Engl. Transl.), 1964, 158, 902]. 2 F. P. Woerner and H. Reimlinger, Chem. Ber., 1970, 103, 1908. 3 Y. Tanaka, S. R. Velen and S. I. Miller, Tetrahedron, 1973, 29, 3271. 4 L. I. Vereshchagin, L. G. Tikhonova, A. V. Maksikova, L. D. Gavrilov and G. A. Gareev, Zh. Org. Khim., 1979, 15, 612 [J. Org. Chem. USSR (Engl. Transl.), 1979, 15, 544]. 5 A. N. Nesmeyanov and M. I. Rybinskaya, Dokl. Akad. Nauk SSSR, 1966, 167, 109 [Dokl. Chem. (Engl. Transl.), 1966, 167, 301]. 6 G. Beck and D. Günther, Chem. Ber., 1973, 106, 2758. 7 Y. Tanaka and S. I. Miller, J. Org. Chem., 1972, 37, 3370. 8 A. I. Sitkin, V. I. Klimenko and G. Kh. Khisamutdinov, Ukr. Khim. Zh., 1979, 45, 180 (in Russian). 9 Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, eds.R. Filler, Y. Kobayashi and L. M. Yagupolskii, Elsevier, Amsterdam, 1993. 10 W. Carpenter, A. Haymaker and D. W. Moore, J. Org. Chem., 1966, 31, 789. 11 W. P. Norris and W. G. Finnegan, J. Org. Chem., 1966, 31, 3292. 12 N. P. Stepanova, N. A. Orlova, V. A. Galishev, E. S. Turbanova and A. A. Petrov, Zh. Org. Khim., 1985, 21, 979 [J. Org.Chem. USSR (Engl. Transl.), 1985, 21, 889]. 13 N. P. Stepanova, V. A. Galishev, E. S. Turbanova, A. V. Maleev, K. A. Potekhin, E. N. Kurkutova, Yu. T. Struchkov and A. A. Petrov, Zh. Org. Khim., 1989, 25, 1613 [J. Org. Chem. USSR (Engl. Transl.), 1989, 25, 1456]. 14 G. G. Bargamov, K. A. Lysenko, M. D. Bargamova and Yu. T. Struchkov, Izv. Akad. Nauk, Ser. Khim., 1995, 2465 (Russ. Chem.Bull., 1995, 44, 2361). 15 V. Ya. Sosnovskikh, V. A. Kutsenko and D. S. Yachevskii, Mendeleev Commun., 1999, 204. 16 V. Ya. Sosnovskikh, B. I. Usachev, D. V. Sevenard, E. Lork and G.-V. Röschenthaler, Tetrahedron Lett., 2001, 42, 5117. 17 V. Ya. Sosnovskikh and V. A. Kutsenko, Izv. Akad. Nauk, Ser. Khim., 1999, 817 (Russ. Chem. Bull., 1999, 48, 812). 18 V. Ya. Sosnovskikh, I.I. Vorontsov and V. A. Kutsenko, Izv. Akad. Nauk, Ser. Khim., 2001, 1360 (Russ. Chem. Bull., Int. Ed., 2001, 50, 1430). 19 V. Ya. Sosnovskikh and B. I. Usachev, Tetrahedron Lett., in press. 20 V. Ya. Sosnovskikh and B. I. Usachev, Mendeleev Commun., 2000, 240. § 4(5)-Salicyloyl-5(4)-trifluoromethyl-1,2,3-triazole 8a. A mixture of aminoenone 6c (0.50 g, 1.8 mmol) and NaN3 (0.24 g, 3.7 mmol) in 2 ml of AcOH–EtOH (1:1) was heated at 80 °C for 2 h.Next, 1 ml of 50% ethanol and five drops of concentrated HCl were added to the reaction mixture. The resulting solution was refluxed for 5 min; thereafter, the mixture was stirred with 10 ml of water. The precipitate was filtered off, washed with water, dried and recrystallised. Yield 73%, mp 150–151 °C (hexane–toluene, 1:2).Ketone 8a in 77% yield was prepared by a similar procedure from compound 5c on heating for 10 min. 1HNMR (400MHz, CDCl3) d: 6.96 [ddd, 1H, H(5), oJ 8.2, 7.2 Hz, mJ 1.1 Hz], 7.09 [dd, 1H, H(3), oJ 8.6 Hz, mJ 1.1 Hz], 7.58 [ddd, 1H, H(4), oJ 8.6, 7.2 Hz, mJ 1.7 Hz], 8.11 [dd, 1H, H(6), oJ 8.2 Hz, mJ 1.7 Hz], 11.84 (s, 1H, NH), 12.5 (br. s, 1H, OH). IR (Vaseline oil, n/cm–1): 3350, 1635, 1605, 1565, 1520.Found (%): C, 46.67; H, 2.21; N, 16.29. Calc. for C10H6F3N3O2 (%): C, 46.70; H, 2.35; N, 16.29. 4(5)-(2-Hydroxy-5-methylbenzoyl)-5(4)-trifluoromethyl-1,2,3-triazole 8b was prepared from aminoenone 6d analogously to 8a; however, the heating was performed for 6 h. Yield 79%, mp 125–126 °C (hexane– toluene, 2:1). 1H NMR (400 MHz, CDCl3) d: 2.30 (s, 3H, Me), 7.00 [dd, 1H, H(3), oJ 8.5 Hz], 7.40 [dd, 1H, H(4), oJ 8.5 Hz, mJ 2.0 Hz], 7.83 [br.d, 1H, H(6), mJ 1.2 Hz], 11.68 (s, 1H, NH), 12.5 (br. s, 1H, OH). IR (Vaseline oil, n/cm–1): 3365, 3340, 1675, 1630, 1600, 1580, 1530. Found (%): C, 48.99; H, 3.05; N, 15.58. Calc. for C11H8F3N3O2 (%): C, 48.72; H, 2.97; N, 15.49. R OH N CF3 O R' H 6a–d HCl O R N H R' CF3 Cl NH3 5' O R N R' CF3 5a–d R O O H NH N N CF3 AcOH NaN3 8a,b O R N H R' AcOH NaN3 NH N N CF3 R O N H NH N N CF3 7a–d HCl R' 5–7: a R = H, R' = CH2Ph b R = Me, R' = CH2Ph c R = H, R' = (CH2)2OH d R = Me, R' = (CH2)2OH 8: a R = H b R = Me Scheme 2 ¶ Note that the 1H NMR spectra of imines 7a,b showed that all aromatic protons are shielded in both CDCl3 and [2H6]DMSO solutions, as compared with ketones 8a,b. The signal of the H(6) proton was most significantly upfield shifted (by almost 1.5 ppm); this is likely due to the arrangement of a triazole ring out of the molecular plane because of unfavourable steric interactions with the benzyl group. In this case, the 2-hydroxyaryl substituent and the imino group lie in the same plane because of a strong intramolecular hydrogen bond between the phenol proton and imine nitrogen (dOH 16.7 ppm in [2H6]DMSO). Received: 31st January 2002; Com. 02/1888

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Mendeleev Communications Electronic Version, Issue 2, 2002 1 Synthesis of chlorin e6 amide derivatives Dmitrii V. Belykh, Lyudmila P. Karmanova, Leonid V. Spirikhin and Aleksandr V. Kutchin* Institute of Chemistry, Komi Scientific Centre, Urals Branch of the Russian Academy of Sciences, 167982 Syktyvkar, Russian Federation. Fax: +7 8212 43 6677; e-mail: chemi@mail.komisc.ru 10.1070/MC2002v012n02ABEH001536 The reactions of methylpheophorbide a with primary and secondary amines have been investigated as a means for the synthesis of sensitizers used in the photodynamic therapy of tumors.It was found earlier that the exo cycle E of methylpheophorbide a 1 can be easily opened by simple primary amines (methylamine1 and ethylamine2) with the formation of amides 2 and 3 (Figure 1), respectively.The analogous interaction of 1 with secondary amines has not been reported, although it is interesting for the synthesis of sensitizers for the photodynamic therapy of tumors.3,4 It is well known that the insertion of a hydroxyl group increases the hydrophilicity of porphyrin and the selectivity of its accumulation in tumors.3 Nucleophilic substitution with ethanolamine at C-13(1) in the exo cycle E of 1 may be a convenient method for the insertion of a hydroxyl group into the porphyrin molecule.In this work, secondary and tertiary chlorin e6 amides 4–6 (Figure 1) were synthesised using the reaction of nucleophilic substitution at C-13(1) in the exo cycle E of 1.† Chlorin e6 13(1)-N-(2-hydroxyethyl)amide-15(2),17(3)-dimethyl ester 4‡ was prepared by the treatment of 1 with ethanolamine in chloroform at room temperature.Valency vibration band of C=O 13(1) keto group is absent from the IR spectrum of the substance obtained and bands ‘amide-I’ (at 1638 cm–1), ‘amide-II’ (at 1526 cm–1), valency vibration band of amide N–H (weak band at 3100 cm–1) are present in this spectrum. The 1H NMR spectrum shows a triplet of amide group NH proton (at 6.88 ppm) and doublets of 15(1)-methylene group protons [5.58 (d, 1H, J 18.4 Hz) and 5.31 (d, 1H, 18.4 Hz)].The singlets of 5-, 10- and 20-protons in the amide spectrum are downfield shifted with respect to analogous signals of methylpheophorbide a spectrum, and a difference between their chemical shifts is smaller. The downfield shifts of 5-, 10- and 20-proton signals and a decrease of the chemical shift difference between 5- and 10-protons may be explained by an increase in ‘ring current’ and the leveling of this proton shielding caused by exo ring opening.The interaction of 1 with secondary amines (dimethylamine, morpholine) was carried out by the same way. The structures of tertiary amides 5§ and 6¶ were determined by IR and NMR spectroscopy.The ‘amide-I’ bond in IR spectra of compounds obtained and 15(1)-methylene group signals in 1H NMR spectra show that exo cycle E recovering and amide formation occur. An NMR and HPLC study of compounds 5 and 6 shows that each of these substances exists as two isomers in the ratio 2:1. We suppose that the 13(1)-amide group and a chlorin ring are in different planes, and tertiary amide isomers differ in the 13(1)-amide group position relatively to a chlorin ring.The 1H and 13C NMR spectra of the tertiary amides should be interpreted as a superposition of the spectra of two isomers (‘double set of signals’). Each of superposed spectra has the same amount of signals (for 1H and 13C NMR spectra) of the same multiplicity (for 1H NMR spectra).The intensity ratio between isomer signals in 1H NMR spectra of both tertiary amides is 2:1. HPLC data are consistent with NMR data. The HPLC of 5 shows two peaks in a ratio of 2:1 (by intensity). † 1H and 13C NMR spectra were obtained in deuterochloroform solutions at 300 and 75 MHz using a Bruker AM-300 spectrometer. Signals were assigned by a comparison with the spectra of chlorin e6 13(1)-N-ethylamide- 15(2),17(3)-dimethyl ester 3.2 IR spectra were obtained in KBr pellets on a Specord M80 spectrometer.UV-VIS spectra were obtained in chloroform solutions using a Lambda 20 spectrometer (Perkin–Elmer) in a range of 350–750 nm. HPLC analysis was carried out on a ‘Milikhrom 1’ chromatograph (column 2×64 mm; Silasorb 600, 5.0 µm). Benzene–ethyl acetate in a ratio of 7:5 was used as an eluent for the analysis of amide 5.Silica gel (La Chema, 40–100 mesh) was used for column chromatography. General procedure for the synthesis of chlorin e6 13(1)-amides- 15(2),17(3)-dimethyl ester. A solution of 1 in chloroform (3 ml) was stirred with an amine (0.3 ml; for dimethylamine, 0.5 ml of a 33% aqueous solution) at room temperature until the absence of the starting material (TLC).The reaction mixture was diluted with chloroform (50 ml), washed with water (3×100 ml), dried (Na2SO4) and evaporated to dryness at 30– 40 °C under reduced pressure. The product was purified by column chromatography on silica gel (eluent: tetrachloromethane–acetone) and reprecipitated from chloroform–pentane. ‡ Chlorin e6 13(1)-N-(2-hydroxyethyl)amide-15(2),17(3)-dimethyl ester.Compound 4 (222 mg, 63%) was obtained from 322 mg of 1. Amide 4 was eluted with CCl4–acetone (3:1, v/v). 1H NMR, d: 9.69 (s, 1H, 10-H), 9.64 (s, 1H, 5-H), 8.81 (s, 1H, 20-H), 8.10 [dd, 1H, 3(1)-H, J 17.7 and 11.6 Hz], 6.37 [dd, 1H, 3(2)-H (trans) J 17.7 and 1.4 Hz], 6.15 [dd, 1H, 3(2)-H (cis), J 11.6 and 1.4 Hz], 6.88 [br. t, 1H, 13(1)-NH (amide), J 5.7 Hz], 5.58 [d, 1H, 15(1)-CH2(B), J 18.4 Hz], 5.31 [d, 1H, 15(1)- CH2(A), J 18.4 Hz], 4.47 (m, 1H, 18-H), 4.40 (m, 1H, 17-H), 3.75 [s, 3H, 15(3)-Me], 3.61 [s, 3H, 17(4)-Me], 3.57 [s, 3H, 12(1)-Me], 3.50 [s, 3H, 1(1)-Me], 3.31 [s, 3H, 7(1)-Me], 3.81 [q, 2H, 8(1)-CH2, J 7.5 Hz], 2.2– 2.6 [m, 4H, 17(1)-CH2, 17(2)-CH2], 1.71 [d, 3H, 18(1)-Me, J 7.0 Hz], 1.72 [t, 3H, 8(2)-Me, J 7.5 Hz], 3.80–3.95 [m, 2H, 13(2)-CH2], 4.02 [t, 2H, 13(3)-CH2, J 5 Hz]. 13C NMR, d: 174.37, 173.53, 170.48, 168.94, 166.63, 154.34, 149.06, 144.82, 138.99, 136.10, 134.92, 134.61, 130.26, 129.77, 129.43, 127.72, 121.68, 102.02, 101.47, 98.84, 93.65, 62.09, 53.03, 52.27, 51.59, 49.18, 43.55, 37.98, 31.06, 29.72, 17.68, 12.13, 11.99, 11.32. IR (KBr, n/cm–1): 1740 (ester nC=O), 1638 (‘amide-I’), 1610 (‘chlorin band’), 1526 (‘amide-II’).UV-VIS [CHCl3, l/nm (lg e)]: 663.7 (4.76), 608.1 (3.76), 557.9 (3.34), 529.0 (3.69), 500.5 (4.21), 401.6 (5.13). 1 Methylpheophorbide a 2 Chlorin e6 13(1)-N-methylamide-15(2),17(3)-dimethyl ester: R = NHMe 3 Chlorin e6 13(1)-N-ethylamide-15(2),17(3)-dimethyl ester: R=NHEt 4 Chlorin e6 13(1)-N-(2-hydroxyethyl)amide-15(2),17(3)-dimethyl ester: R=NHCH2CH2OH 5 Chlorin e6 13(1)-N,N-dimethylamide-15(2),17(3)-dimethyl ester: R=NMe2 6 Chlorin e6 13(1)-morpholinoamide-15(2),17(3)-dimethyl ester, numbering: Figure 1 Chlorophyll derivatives. 2 1 5 N NH HN N O MeO2C MeO2C 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 A B C D E 3(1) 3(2) 2(1) 7(1) 8(1) 8(2) 12(1) 13(1) 13(4) 13(3) 13(2) 17(1) 17(2) 17(3) 18(1) 17(4) N NH HN N MeO2C MeO2C 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 A B C D E 3(1) 3(2) 2(1) 7(1) 8(1) 8(2) 12(1) 13(1) 15(2) 15(3) 15(1) 17(1) 17(2) 17(3) 18(1) 17(4) O R 1 2–6Mendeleev Communications Electronic Version, Issue 2, 2002 2 It is possible that different positions of the 13(1)-amide group relatively to the chlorin ring influence the electronic surrounding of nearest protons and, therefore, the chemical shifts of their signals.For example, the greatest chemical shift difference of proton signals between isomers is observed for 15(1)-CH2 protons. It indicates different influences of the amide group on the electronic surroundings of these protons at different positions relatively to the chlorin ring. Longwave bonds in the electron spectra of all amides are in the range 663–664 nm.Thus, these compounds should be interesting as potential sensitizers for the photodynamic therapy. References. 1 P. A. Ellsworth and C. B. Storm, J. Org. Chem., 1978, 43, 281. 2 L. Ma and D. Dolphin, Tetrahedron, 1996, 52, 849. 3 A. F. Mironov, Ross. Khim. Zh., 1998, no. 5, 23 (in Russian). 4 A. F. Mironov, SPIE Proceedings CIS Selected Papers ‘Laser Use in Oncology’, 1996, vol. 2728, pp. 150–164. § Chlorin e6 13(1)-N,N-dimethylamide-15(2),17(3)-dimethyl ester. Compound 5 (35 mg, 54%) was obtained from 60 mg of 1. The amide was eluted with CCl4–acetone (10:1, v/v). 1H NMR, d: major isomer: 9.75 (s, 1H, 10-H), 9.71 (s, 1H, 5-H), 8.88 (s, 1H, 20-H), 8.15 (dd, 1H, J 17.9 and 11.5 Hz), 6.40 [dd, 1H, 3(2)-H (trans), J 1.8 and 19.6 Hz], 6.18 [dd, 1H, 3(2)-H (cis), J 1.6 and 11.5 Hz], 5.88 [d, 1H, 15(1)-CH(B), J 19 Hz], 5.08 [d, 1H, 15(1)-CH(A), J 18.9 Hz], 4.4–4.6 (m, 2H, 18-H, 17-H), 3.84 [s, 3H, 15(3)-Me], 3.68 [s, 3H, 17(4)-Me], 2.78 [s, 3H, 13(1)- NMe2], 3.4–4.0 [m, 14H, 12(1)-Me, 1(1)-Me, 7(1)-Me, 13(1)-NMe2, 8(1)-CH2], 2.1–2.7 [m, 4H, 17(1)-CH2, 17(2)-CH2], 1.75 [m, 6H, 18(1)- Me, 8(2)-Me]; minor isomer: 9.73 (s, 1H, 10-H), 9.68 (s, 1H, 5-H), 8.83 (s, 1H, 20-H), 8.13 (dd, 1H, J 17.7 and 11.5 Hz), 6.40 [dd, 1H, 3(2)-H (trans), J 1.8 and 19.6 Hz], 6.18 [dd, 1H, 3(2)-H (cis), J 1.6 and 11.5 Hz], 5.73 [d, 1H, 15(1)-CH(B), J 19.3 Hz], 5.16 [d, 1H, 15(1)- CH(A), J 19.2 Hz], 4.4–4.6 (m, 2H, 18-H, 17-H), 3.80 [s, 3H, 15(3)- Me], 3.70 [s, 3H, 17(4)-Me], 3.13 [s, 3H, 13(1)-NMe2], 3.4–4.0 [m, 14H, 12(1)-Me, 1(1)-Me, 7(1)-Me, 13(1)-NMe2, 8(1)-CH2], 2.1–2.7 [m, 4H, 17(1)-CH2, 17(2)-CH2], 1.75 [m, 6H, 18(1)-Me, 8(2)-Me]. 13C NMR, d: major isomer: 173.45, 173.29, 170.64, 168.70, 167.28, 154.20, 149.32, 144.74, 138.79, 136.27, 134.76, 134.62, 133.77, 130.42, 130.09, 129.66, 127.09, 121.60, 102.46, 101.01, 98.91, 93.88, 52.96, 49.18, 51.92, 51.77, 37.04, 35.31, 31.36, 29.87, 23.10, 19.80, 17.58, 12.24, 11.86, 11.35; minor isomer: 173.45, 173.29, 170.19, 168.96, 166.53, 154.20, 149.08, 144.74, 138.79, 136.18, 135.19, 134.52, 133.77, 130.42, 130.20, 129.66, 127.09, 121.60, 102.77, 101.01, 98.91, 93.65, 53.75, 49.53, 52.08, 51.77, 37.73, 35.27, 31.93, 29.87, 23.19, 19.80, 17.58, 12.24, 12.00, 11.35.IR (KBr, n/cm–1): 1746 (ester nC=O), 1632 (‘amide-I’), 1613 (‘chlorin band’).UV-VIS [CHCl3, l/nm (lg e)]: 663.7 (4.70), 608.0 (3.62), 559.7 (2.98), 528.7 (3.47), 500.6 (4.13), 402.1 (5.19). ¶ Chlorin e6 13(1)-morpholinoamide-15(2),17(3)-dimethyl ester. Compound 6 (24 mg, 42%) was obtained from 50 mg of 1. The amide was eluted with CCl4–acetone (4:1, v/v). 1H NMR, d: major isomer: 9.72 (s, 1H, 10-H), 9.67 (s, 1H, 5-H), 8.86 (s, 1H, 20-H), 8.11 (dd, 1H, J 17.0 and 11.6 Hz), 6.38 [dd, 1H, 3(2)-H (trans), J 17.9 and 1.5 Hz], 6.16 [dd, 1H, 3(2)-H (cis), J 11.6 and 1.6 Hz], 5.81 [d, 1H, 15(1)-CH(B), J 19.0 Hz], 5.09 [d, 1H, 15(1)-CH(A), J 19.0 Hz], 4.42–4.65 (m, 2H, 18-H, 17-H), 3.57 [s, 3H, 15(3)-Me], 3.66 [s, 3H, 17(4)-Me], 3.88 [s, 3H, 12(1)-Me], 3.51 [s, 3H, 1(1)-Me], 3.34 [s, 3H, 7(1)-Me], 3.7–4.2 [m, 10H, 8(1)-CH2, 13(2)-CH2, 13(3)-CH2], 2.2–2.7 (m, 4H), 1.6–1.8 [m, 6H, 18(1)-Me, 8(2)-Me]; minor isomer: 9.69 (s, 1H, 10-H), 9.64 (s, 1H, 5-H), 8.81 (s, 1H, 20-H), 8.11 [dd, 1H, 3(2)-H], 6.38 [dd, 1H, 3(2)-H (trans), J 17.9 and 1.5 Hz], 6.16 [dd, 1H, 3(2)-H (cis), J 11.6 and 1.6 Hz], 5.52 [d, 1H, 15(1)-CH(B), J 19.0 Hz], 5.25 [d, 1H, 15(1)-CH(A), J 19.0 Hz], 4.42– 4.65 (m, 2H, 18-H, 17-H), 3.54 [s, 3H, 15(3)-Me], 3.62 [s, 3H, 17(4)- Me], 3.83 [s, 3H, 12(1)-Me], 3.50 [s, 3H, 1(1)-Me], 3.33 [s, 3H, 7(1)- Me], 3.7–4.2 [m, 10H, 8(1)-CH2, 13(2)-CH2, 13(3)-CH2], 2.2–2.7 [m, 4H, 17(1)-CH2, 17(2)-CH2], 1.6–1.8 [m, 6H, 18(1)-Me, 8(2)-Me]. 13C NMR, d: major isomer: 173.45, 173.29, 169.24, 168.78, 167.16, 154.39, 149.00, 144.73, 138.86, 136.15, 134.89, 134.55, 134.40, 133.60, 130.22, 130.03, 129.47, 125.54, 121.64, 102.23, 101.01, 98.78, 93.87, 67.00, 52.10, 51.59, 49.43, 42.51, 37.08, 31.19, 30.87, 29.65, 19.67, 17.67, 12.14, 12.11, 11.33; minor isomer: 173.61, 173.04, 169.00, 168.68, 166.55, 154.39, 149.19, 144.78, 138.93, 136.22, 134.97, 135.12, 134.61, 133.43, 130.28, 129.83, 129.47, 125.74, 121.64, 102.29, 101.22, 98.78, 93.65, 66.84, 52.24, 51.59, 49.13, 42.43, 37.79, 31.19, 30.87, 29.76, 19.67, 17.67, 12.22, 12.11, 11.33. IR (KBr, n/cm–1): 1742 (ester nC=O), 1636 (‘amide-I’), 1608 (‘chlorin band’). UV-VIS [CHCl3, l/nm (lg e)]: 663 (4.73), 608.7 (3.74), 557.1 (3.41), 528.5 (3.68), 500.5 (4.19), 402.2 (5.21). Received: 4th December 2001; Com. 01/1862

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年代:2002

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摘要:

Mendeleev Communications Electronic Version, Issue 2, 2002 1 Vapour deposition for the refinement, separation and production of high-purity ammonium thiocyanate and thiourea Farit Kh. Urakaev,*a,b Yurii P. Savintsev,a Vyacheslav S. Shevchenko,a Aleksei P. Chupakhin,b Vera I. Gordeevaa and Lev Sh. Bazarova a Institute of Mineralogy and Petrography, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation.Fax: +7 3832 33 2792; e-mail: urakaev@uiggm.nsc.ru b Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russian Federation 10.1070/MC2002v012n02ABEH001565 Based on the high volatility and difference in the vapour pressures of ammonium thiocyanate and thiocarbamide and the reaction of mutual isomerization, new methods were developed for refining, separating and producing the pure isomers from commercial ammonium thiocyanate.Commercial or coke-chemical ammonium thiocyanate NH4NCS is the product of recovery of prussic acid by ammonium polysulfides from a coke-oven gas.1 The NH4NCS content of commercial ammonium thiocyanate is 60–93%. Ammonium thiocyanate is a pseudohalide2 with the melting point Tm = 150 °C and a unique property to change3 into its organic isomer, thiourea (NH2)2CS, a molecular crystal with Tm » 180 °C.The mutual isomerization NH4NCS (NH2)2CS can be used for producing thiourea.4–6 It is well known6,7 that this reaction proceeds in a solid phase, a melt and a solution at 140–180 °C at a noticeable rate as a kinetically reversible first-order reaction.The forward and reverse reactions lead to the formation of an equilibrium eutectic fusion containing ~75% ammonium thiocyanate and ~25% thiourea (melting point of ~104 °C). We have developed a ‘dry’ method for the separation and production of pure ammonium thiocyanate and thiourea from coke-chemical ammonium thiocyanate. The kinetics of interconversion and the purity of separated isomers were observed by measuring the conductivity of aqueous solutions.8,9 An ammonium thiocyanate solution is an electrolyte, whereas thiourea solutions do not exhibit conductivity.To measure the vapour pressures of isomers and to refine, separate and produce pure ammonium thiocyanate and thiourea, we used a set-up shown in Figure 1. The set-up is based on a glass double-neck round-bottom 1 l flask 1 with turning device 2 and desublimator cells 3–6, pressure gauge 7 (vacuum, oil, membrane and thermal-conduction manometers), nitrogen trap 8, backing pump 9, and valves (Ä).Items 1–6 were joined via ground glass sections with Teflon gaskets (0.2 mm thick). The temperature of the inner walls of glass articles 1–6 was controlled by thermostats 10–14 with water (10, 11; up to 100 °C) or silicon oil (12–14; up to 230°C) to within ~0.5 °C.Flask 1 was filled with an inert gas from cylinder 15. The vapour pressure of ammonium thiocyanate is 0.3–0.4 Pa (~2×10–3 torr) at 313.13 K (~40 °C).10 To estimate the vapour pressures of ammonium thiocyanate and thiourea at high temperatures, we used the published method.11 The accuracy of this method is ±0.5 torr.Owing to the isomerization NH4NCS (NH2)2CS, the pressures of the isomers can be reliably measured only at the melting point of thiourea. The measurements were conducted on a simplified device without cells 3–6. Flask 1 was filled with finely ground and pure ammonium thiocyanate or 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Ar or N2 Figure 1 Schematic diagram of the set-up for measuring vapour pressures, refining, separating and preparing ammonium thiocyanate and thiocarbamide (see the text).Table 1 Refinement of commercial ammonium thiocyanate. Impurities in commercial ammonium thiocyanate and the parameters of refinement Purity of ammonium thiocyanate, NH4CNS Temperature of cells 1–2/K (°C), yield of NH4CNS (%) and impurity contents of sublimates 3–6 Temperatures of cells 3–6/K (°C) at a temperature of 14 equal to 180 °C and NH4CNS purity (%) Initial commercial ammonium thiocyanate from Donetsk (wt%) Certified by All-Union State Standard 3768-64 for pure ammonium thiocyanate (wt%) 403 (130) 423 (150) 443 (170) 463 (190) 483 (210) 503 (230) Cell 3 363 (90) Cell 4 343 (70) Cell 5 323 (50) Cell 6 293 (20) NH4CNS, no less than 92.5 99 99.8 99.5 99.5 99 94 89 99.8 99.6 99.0 97–99 Nonvolatile substances, no more than 0.13 0.01 no no no no no no no no no no Water-insoluble substances, no more than 0.6 0.005 — — — — — — — — — — Sulfates, no more than 0.7 0.0025 no no no no no no no no no no Heavy metals, no more than — 0.0003 10–5% Chlorides, no more than 0.9 0.002 10–3% Iron, no more than 0.9 0.001 10–5% Substances oxidesed by iodine (in terms of sulfides), no more than — 0.002 10–3% Absorbance of alcohol solutions — 0.05 — — — — — — — — — — Thiourea — — no no no traces 1% 3% traces no no noMendeleev Communications Electronic Version, Issue 2, 2002 2 thiourea.The system was pumped out and filled with argon to atmospheric pressure at room temperature. Flask 1 was placed in thermostat 14.Synchronously with the termination of sample melting by a needle-like valve located between 7 and 8, the rate of pumping was determined, which allowed us to measure vapour pressures, typically, within 1 min. The melting point was registered visually and using a thermocouple, and it was compared at that moment with the reading of gauge 7. The averaged data for vapour pressures at 180 °C are 3–4 torr for thiourea and ~35 torr for ammonium thiocyanate.The initial coke-chemical ammonium thiocyanate (mp 130°C; NH4NCS content, ~90 wt%) was obtained from Kemerovo byproduct coke plants. Table 1 lists its average technical characteristics compared with those of pure ammonium thiocyanate. The method for cleaning ammonium thiocyanate involves sublimation- desublimation process at specified sublimation temperatures (1–2: 130–230 °C, see columns 4–9 in Table 1) and the desublimation of substrates (3–6: 90–20 °C, columns 10–13) at reduced pressures (10–1–10–3 torr).The resulting melt boils and transforms into a gas phase. The ammonium thiocyanate vapour desublimates on substrates 3–6. The end of the process is determined by the disappearance of boiling.Nonvolatile impurities remained in flask 1. A specific feature of this method is that, on heating the starting substance in a vacuum, only a portion of the substance melts and evaporates, which is in contact with the heated surface. Thus, in spite of rather high temperatures in unit 14, their absolute value does not affect the quality of cleaned ammonium thiocyanate (cf. columns 3 and 10–12 in Table 1).The chosen range of temperatures in units 1 and 2 has an optimum at 150– 180 °C. The equilibrium isomers mixture was produced due to the known kinetics of isomerization.5–9 Flask 1 was filled with cleaned ammonium thiocyanate under argon and kept for a given time in unit 14 heated to 150 °C. Then, the obtained fusion was poured from flask 1 into a vessel with liquid nitrogen.The resulting porous ingot was powdered. After analysing the composition of fusion powders, optimal temperatures (155–170 °C) for making a fusion and the corresponding holding times after the complete melting of ammonium thiocyanate have been determined (1–3 h). The colourless fusions contained 20–30% thiourea, 80–70% ammonium thiocyanate and less than 1% decomposition products.To separate ammonium thiocyanate and thiourea, we placed the powdered fusion in flask 1, evacuated the system and specified some parameters for the separation of isomers. In preliminary experiments, the optimal weight of the charge was found to be 1 g. This yielded the highest indices of purity of ammonium thiocyanate and thiourea.In the alternate evacuation and filling of the system with an inert gas, up to 20 g of a powder can be consumed (in Table 2, we spent only 5 g). Table 2 shows the results of 10 runs for separation of isomers. We can state that in this method on the substrate with a temperature higher than 120 °C no ammonium thiocyanate can be desublimated, and 150 °C is too high for producing pure thiourea owing to its isomerization into ammonium thiocyanate.The optimal conditions for desublimating thiourea are created at 120–140 °C, and for ammonium thiocyanate at < 100 °C. Using optical analysis, we found that ammonium thiocyanate and thiourea crystals produced by known solution methods have plenty of faults including vacuoles filled with crystallization medium and gas.In ammonium thiocyanate (fine acicular shape, 98.4–99.5% purity) and thiourea (fine tabular, 98.0–99.8%) crystals produced by this method, no gas–liquid inclusions have been found. The refinement and separation of isomers is performed in one stage, it does not require other chemicals, and is an ecologically clean process with minor and easily trapped byproducts. This work was supported by the Russian Foundation for Basic Research (grant nos. 01-03-32834, 01-05-65048 and 02-03-32109) and the programme “Universities of Russia” (no. UR.06.01.001). References 1 A. A. Popov, I. I. Rozhnyatovskii and V. M. Zaichenko, Koks Khim., 1973, 10, 43 (in Russian). 2 A. M. Golub, H. Kohler, V. V. Skopenko, H. Boland, T. P Lishko, V. M. Samoilenko and G. V. Tsintsadze, in Chemie der Pseudohalogenide, eds.A. M. Golub, H. Kohler and V. V. Skopenko, VEB Deutschher Verlag der Wissenschaften, Berlin, 1979 (in German). 3 J. E. Reinolds and E. A.Werner, J. Chem. Soc. Trans., 1903, 83, 1. 4 G. H. Burrows, J. Am. Chem. Soc., 1924, 46, 1623. 5 A. N. Kappanna, Quarterly J. Indian Chem. Soc., 1927, 4, 217. 6 Hsu Hai-Han and Wang Han-Chang, Acta Chim. Sinica, 1964, 30, 363 (in Chinese). 7 Yu. Ya. Kharitonov, Zh. Fiz. Khim., 2000, 74, 1039 (Russ. J. Phys. Chem., 2000, 74, 924). 8 F. Kh. Urakaev and L. Sh. Bazarov, Zh. Neorg. Khim., 2001, 46, 54 (Russ. J. Inorg. Chem., 2001, 46, 47). 9 V. L. Moskalevich and N. A. Lebedinskii, in Voprosy Khimii i Khim. Tekhnologii, KhGU, Khar’kov, 1984, vol. 74, p. 23 (in Russian). 10 C. G. De Kruif, J. Chem.Phys., 1982, 77, 6247. 11 A. V. Suvorov, Termodinamicheskaya khimiya paroobraznogo sostoyaniya (Thermodynamic Chemistry of Vapour State), Khimiya, Leningrad, 1986 (in Russian). Table 2 Separation of ammonium thiocyanate and thiourea by a gas-phase method. Run no. Temperature of cells 1–6/°C Yield of products by cells 3–6 (%) Content of basic substance by cells 3–5 (%) Melting point/°C (±1 °C) Presure/ torr Thiourea Mixture thiourea– ammonium thiocyanate Ammonium thiocyanate 1–2 3 4 5 6 3 4 5 6 Total3 4 5 Thiourea Ammonium cyanate 1 150 145 100 70 20 19 19 50 6 94.0 99.1 17.2/82.4 98.4 180 148 5×10–3 2 160 130 130 80 20 26 5 63 3 97.0 99.7 — 99.5 182 149 5×10–3 3 170 140 90 70 20 20 30 45 2 97.0 99.5 16.8/83.0 99.5 181 149 5×10–2 4 180 130 110 80 20 23 11 63 2 98.0 99.8 — 99.5 182 149 5×10–2 5 180 130 110 80 20 26 7 63 2 98.0 99.7 — 99.5 182 149 5×10–3 6 180 135 110 50 20 26 4 68 0.6 98.6 99.6 — 91.6 182 142 ~5 7 180 150 110 80 20 5 22 68 2 97.0 — 18.7/80.7 99.5 172 149 5×10–3 8 180 120 110 80 20 20 10 65 2 97.0 99.8 — 99.5 182 149 5×10–1 9 190 130 130 80 20 26 4.3 66 0.3 96.6 99.7 — 99.5 182 149 5×10–1 10 200 130 110 80 20 21 2 62 8 93.0 98.0 — 99.2 178 147 5×10–3 Received: 14th February 2002; Com. 02/1891

ISSN:0959-9436     

出版商:RSC    

年代:2002

数据来源: RSC

摘要:

Mendeleev Communications Electronic Version, Issue 2, 2002 1 Thermodynamics of intermolecular interactions between saccharides and 18-crown-6 in water Elena V. Parfenyuk,* Olga I. Davydova, Nataliya Sh. Lebedeva and Alexander V. Agafonov Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, Russian Federation. Fax: + 7 0932 237 8509; e-mail: ava@ihnr.polytech.ivanovo.su 10.1070/MC2002v012n02ABEH001540 The intermolecular complexes of D-galactose, D-maltose, sucrose and raffinose with 18-crown-6 were found to be entropy stabilised.Crown ethers are analogues of enzymes and cyclic antibiotics.1 The carbohydrate components of cell membranes are the receptors of biologically active compounds (enzymes, drugs, etc.).2 Therefore, the interactions between crown ethers and carbohydrates are of particular interest.We used 18-crown-6 and saccharides (D-galactose, D-maltose, sucrose and raffinose)¢Ó as model compounds. The heats of interactions were measured on an automatic titration differential calorimeter3 at 298.15 K. An aqueous solution of the crown ether [(2.7)¡¿10.3 mol dm.3] was titrated with aqueous saccharide solutions (~0.2 mol dm.3).Corrections for the heats of dilution of the crown ether were made. The stoichiometry of complexes was determined from titration curves. The stability constant K and the enthalpy change .H were calculated on a computer by varying Ki and .Hi to minimise U(Hi, Ki) = ¥Ò(Qexpt . Qcalc).2 Assuming the 1:1 complex stoichiometry, the U value was minimised to give an optimised set of K and .H for 1:1 complexation.Table 1 summarises the stability constants and the thermodynamic parameters of interactions between the saccharides and 18-crown-6. It can be seen that the intermolecular complexes are stable in water. The complex of D-galactose with 18-crown-6 is most stable complex. The complex of sucrose with 18-crown-6 exhibited the lowest stability.The interactions between the saccharides and the crown ether are accompanied by exothermic effects. However, the entropy changes mainly contributed to the .G values. The saccharide and crown ether molecules are strongly hydrated in aqueous solutions. The hydration shells of saccharide molecules are formed by the interactions of OH groups with water and by hydrophobic hydration.D-Maltose molecules have stronger and more compact hydration shells than those of sucrose molecules.4 Therefore, the interactions between D-maltose and 18-crown-6 are accompanied by much greater entropy changes and become less favourable in terms of enthalpy as compared with sucrose. Moreover, the disaccharide and crown ether molecules are conformationally flexible.1,5,6 This factor may contribute to .S and .H values, especially in the case of raffinose.Thus, the studied complexes are entropy stabilised. The contribution from the entropy of dehydration processes is the major factor affecting intermolecular interactions in the test systems. References 1 M. Hiraoka, Crown Compounds. Their Characteristics and Applications, Elsevier, Amsterdam, 1982, p. 27. 2 D. E. Metzler, Biochemistry. The Chemical Reactions of Living Cells, Academic Press, New York, 1977, p. 341. 3 N. Sh. Lebedeva, K. V. Mikhailovskii and A. I. Vyugin, Zh. Fiz. Khim., 2001, 75, 1147 (Russ. J. Phys. Chem., 2001, 75, 1031). 4 S. A. Galema and H. Hoiland, J. Phys. Chem., 1991, 95, 5321. 5 S. B. Engelsen and S. Perez, Carbohydr. Res., 1996, 292, 21. 6 D. E. Dorman and J. D.Roberts, J. Am. Chem. Soc., 1971, 93, 4463. ¢Ó 18-Crown-6 (Sigma) and D-galactose (Sigma) were dried in a vacuum at 308 and 353 K, respectively. D-Maltose (monohydrate) and raffinose (pentahydrate) (Serva, analytical reagent grade) were used without further purification. Sucrose (pure) was recrystallised from ethanol and dried in a vacuum at 353 K. Solutions were prepared using double-distilled degassed water. Table 1 Stability constants and thermodynamic parameters of interactions between the saccharides and 18-crown-6 in water at 298.15 K. Saccharide log K .G/kJ mol.1 .H/kJ mol.1 T.S/kJ mol.1 D-Galactose 3.60¡¾0.12 .20.55 .1.45¡¾0.05 19.08 D-Maltose 3.35¡¾0.45 .19.12 .0.87¡¾0.11 18.25 Sucrose 2.53¡¾0.06 .14.45 .4.85¡¾0.04 9.60 Raffinose 2.77¡¾0.06 .15.82 .2.26¡¾0.05 13.66 Received: 13th December 2001; Com. 01/1866

ISSN:0959-9436     

出版商:RSC    

年代:2002

数据来源: RSC