摘要:

Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) Mild elimination of a glycosidically linked –OCH2CH2CH2NH2 spacer-arm Ekaterina V. Shipova and Nicolai V. Bovin* M. M. Shemyakin–A. Yu. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117871 Moscow, Russian Federation. E-mail: bovin@carb.siobc.ras.ru DOI: 10.1070/MC2000v010n02ABEH001222 The spacer-arm –OCH2CH2CH2NH2 of complex oligosaccharides can be removed by oxidative deamination followed by alkaline b-elimination.The application of oligosaccharides to various chemical and biochemical studies often requires that these were prepared with the free 1-OH group or as spacered glycosides, i.e., as glycosides of alcohols whose second function may serve for conjugation with macromolecules or labels.Spacering is one of the key problems of oligosaccharide synthesis strategy. The introduction of a spacer or prespacer group can be performed (i) at the final stage of the synthesis (by glycosidation of the oligosaccharide with a spacer alcohol) or (ii) at the initial stage when the spacer also serves as a 1-O-protecting group. Both approaches have advantages and drawbacks.The former makes it possible to obtain both free and spacered oligosaccharides; however, spacering at the final stage usually leads to a loss of yield, especially when a microscale synthesis is performed. The second approach is more economical; however, only the spacered product can be obtained. Here we describe a methodology based on the second approach, namely, the removal of the spacer group –OCH2CH2– CH2NH2, which was often employed in our studies.1,† A simple one-stage removal of the spacer-arm by acid hydrolysis or acid acetolysis in oligosaccharides 1a and 1b was unsuccessful because of cleavage of the acid-labile Fuca1-2Gal bond.‡ In searching for a mild despacering procedure, we examined the applicability of the following two-stage approach.The spacerarm –OCH2CH2CH2NH2 in compound 3a or 3b was subjected sequentially to the Corey method3 and alkaline b-elimination by treatment of the compounds with 3,5-di-tert-butyl-1,2-benzoquinone in methanol and acidification of intermediate azomethines † As a rule, this spacer is used as the trifluoroacetamidopropyl group –OCH2CH2CH2NHCOCF3, which can be quantitatively deblocked by an alkali.2 ‡ No cleavage of the glycosidic bond Galb-sp leading to desired peracetate 2a or 2b was observed when acid acetolysis of the corresponding trifluoroacetamidopropyl glycosides of trisaccharides 1a or 1b (AcOH/ Ac2O/H2SO4, 100:100:1, 0–20 °C) was carried out.More severe conditions (an increase in the amount of sulfuric acid or a higher temperature) led to the cleavage of the Fuca1-2Gal bond. Analogous results were obtained upon acid acetolysis (AcOH/Ac2O/H2SO4, 100:100:1, 5 °C) of A trisaccharide acetamidopropyl glycoside 4a.However, under the same conditions, the similar B trisaccharide glycoside 4b was converted into peracetate 2b, 90%. 5 with oxalic acid. The final acetylation with acetic anhydride in pyridine simplified the chromatographic purification (see Scheme 1). In this way, the azomethine obtained from the spacered blood group trisaccharide B gave rise to 41% aldehyde 6§ and 39% –OCH2CH2CH2NHAc derivative 4b.The azomethine obtained from spacered blood group trisaccharide A under the same conditions gave rise to benzoxazole 7§ (70%). Although according to Corey and Achiva3 primary amines can be converted into either carbonyl compounds or benzoxazole depending on carbon chain branching, it is surprising that trisaccharides having only minor differences in the sites distant from the reaction centre behaved in such a different fashion under the same conditions‡,¶.The next stage of the proposed method has to be alkaline b-elimination of the free trisaccharide from derivatives 6 and 7.However, the treatment with aqueous alkali solutions would result in splitting off the monosaccharide from the position O-3 of the despacered Gal moiety due to additional b-elimination, where the deprotected 1-OH group plays a role of the aldehyde group. To avoid the secondary b-elimination (so-called peeling), we used the conditions of base-catalysed acetolysis/acetylation (AcOH + AcONa + Ac2O) described earlier for the elimination of complex oligosaccharides from the protein core:4 acetic anhydride converts 1-OH into 1-OAc and thus blocks it.Thus, the treatment of compounds 6 and 7 with an AcOH–AcONa–Ac2O mixture at 110 °C for 48 h†† gave despacered derivative 2b or 2a in 68 or 93% yield, respectively. Note that we did not optimise the conditions of either the Corey reaction or b-elimination and did not perform a one-pot process, which can increase the yields of final oligosaccharides. Thus, we have demonstrated that 3-aminopropyl glycosides of complex oligosaccharides can be converted into despacered forms in non-acidic conditions.§ A solution of amine 3 (0.34 mmol) and 3,5-di-tert-butyl-1,2-benzoquinone (83 mg, 0.37 mmol) in 30 ml of MeOH was stirred under argon at room temperature.The colour of the reaction mixture changed from dark brown to green in 1 h. The stirring was continued for 24 h; next, oxalic acid dihydrate was added to pH 2, the reaction mixture was evaporated to dryness in vacuo, and the solid residue was washed with a 2:1 ethyl acetate–benzene mixture to remove the remaining benzoquinone. The residue was conventionally acetylated with Ac2O in Py for 24 h, and product 6 or 7 was separated by column chromatography.Selected spectral data: 6: 1H NMR (CDCl3) d: 1.19 (d, 3H, Me''), 1.9–2.18 (27H, 9OAc), 3.37 (m, 2H, CH2CHO), 3.67 dd (1H, H2, J2,1 7.5 Hz, J2,3 10 Hz), 3.78 (m, 1H, H5), 3.98, 4.08 (2H, H6), 4.09, 4.30 (2H, H6'), 4.10 (m, 1H, OCHCH2), 4.41 (1H, H5''), 4.45 (m, 1H, OCH'CH2), 4.46 (d, 1H, H1), 4.51 (m, 1H, H5' ), 5.12 (1H, H3''), 5.18 (1H, H2'' ), 5.23 (1H, H4''), 5.34 (dd, 1H, H2', J2',1' 3 Hz, J2',3' 10 Hz), 5.37 (d, 1H, H1'), 5.39 (d, 1H, H4, J4,3 3.5 Hz), 5.46 (dd, 1H, H3' ), 5.52 (d, 1H, H1'', J1'',2'' 3.5 Hz), 5.61 (dd, 1H, H4').FAB MS, m/z: 922 (M+). 7: 1H NMR (CDCl3) d: 1.07 (d, 3H, Me''), 1.35 (s, 9H, 3Me-q), 1.5 (s, 9H, 3Me-q), 3.30 (t, 2H, CH2C=), 3.81 (dd, 1H, H2, J2,1 7 Hz, J2,3 9 Hz), 3.89 (dd, 1H, H3, J3,4 3 Hz), 4.13 (m, 1H, OCHCH2), 4.26 (1H, H5' ), 4.43 (m, 1H, OCH'CH2), 4.5 (1H, H2' ), 4.51 (d, 1H, H1), 5.02 (dd, 1H, H3', J3',2' 11 Hz, J3',4' 3 Hz), 5.2 (1H, H5'' ), 5.24 (d, 1H, H1', J1',2' 3 Hz), 5.25 (1H, H3''), 5.32 (dd, 1H, H2'', J2'',3'' 11 Hz, J2'',1'' 3.5 Hz), 5.37 (dd, 1H, H4), 5.46 (dd, 1H, H4'), 5.51 (d, 1H, H1''), 6.17 (d, 1H, NHAc, JNH,2' 9 Hz), 7.54 (d, 1H, H-q), 7.55 (d, 1H, H-q).FAB MS, m/z: 1123 (M+). ¶ Corey and Achiva3 also described the formation of a benzoxazole product without an explanation of the over-oxidation. O OR O O Y RO OR OR O RO OR OR O OR sp Me 1a sp = OCH2CH2CH2NHCOCF3, R = H, Y = NHAc 1b sp = OCH2CH2CH2NHCOCF3, R = H, Y = OH 2a sp = OAc, R = Ac, Y = NHAc 2b sp = OAc, R = Ac, Y = OAc 3a sp = OCH2CH2CH2NH2, R = H, Y = NHAc 3b sp = OCH2CH2CH2NH2, R = H, Y = OH 4a sp = OCH2CH2CH2NHAc, R = Ac, Y = NHAc 4b sp = OCH2CH2CH2NHAc, R = Ac, Y = OAcMendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) †† Base-catalysed acetolysis of 7. A mixture of 7 (100 mg, 89 mmol), 500 mg of anhydrous sodium acetate, 2 ml of acetic anhydride and 2 ml of acetic acid was kept in a 5 ml sealed tube for 48 h at 110 °C.The reaction mixture was poured onto ice and extracted with chloroform. The organic layer was washed with water, a saturated aqueous solution of NaHCO3 and water, dried and concentrated in vacuo. Column chromatography using an acetone–hexane eluent gave 75 mg (93%) of peracetate 2a, FAB MS, m/z: 908 (M+). Pure b- and a-acetates were isolated by HPLC.a-2a: 1H NMR (CDCl3) d: 1.13 (d, 3H, Me''), 1.9–2.1 (30H, 10OAc), 4.05 (dd, 1H, H3), 4.11 (1H, H6), 4.06 (1H, H6), 4.2 (dd, 1H, H2), 4.51 (ddd, 1H, H2', J2',1' 3 Hz, J2',3' 7.5 Hz, J2',NH 9.5 Hz), 4.8 (dd, 1H, H3' ), 5.18 (1H, H3'' ), 5.23 (1H, H4''), 5.25 (d, 1H, H1'), 5.30 (1H, H1''), 5.35 (1H, H2''), 5.46 (dd, 1H, H4, J4,3 3 Hz, J4,5 1 Hz), 6.06 (d, 1H, NHAc), 6.33 (d, 1H, H1, J1,2 3 Hz).b-2a: 1H NMR (CDCl3) d: 1.08 (d, 3H, Me''), 1.9–2.1 (30H, 10OAc), 3.86 (dd, 1H, H2, J2,1 7 Hz, J2,3 9 Hz), 3.9 (dd, 1H, H5, J5,6 7 Hz, J5,4 1 Hz), 4.2 (dd, 1H, H3), 4.27 (dd, 1H, H5'' ), 4.38 (1H, H5'), 4.61 (ddd, 1H, H2', J2',1' 3.5 Hz, J2',3' 11 Hz, J2',NH 11 Hz), 5.1 (dd, 1H, H3' ), 5.25 (d, 1H, H1'), 5.35 (1H, H4''), 5.42 (1H, H4), 5.54 (1H, H4' ), 5.56 (d, 1H, NHAc), 5.62 (d, 1H, H1, J1,2 7 Hz). References 1 N.V.Bovin, Glycoconjugate J., 1998, 15, 431. 2 E. Yu. Korchagina and N. V. Bovin, Bioorg. Khim., 1992, 18, 283 (Russ. J. Bioorg. Chem., 1992, 18, 153). 3 E. J. Corey and K. Achiva, J. Am. Chem. Soc., 1969, 91, 1429. 4 N.V. Bovin and A.Ya. Khorlin, Bioorg. Khim., 1985, 11, 420 (in Russian). O OAc O O AcO AcO OAc OAc O AcO OAc OAc O OAc OCH2CH2CHO Me O OCH2CH2CH2NH2 O O O OCH2CH2CH2N O O OCH2CH2CH HO N 5 O OAc O O AcHN AcO OAc OAc O AcO OAc OAc O OAc OCH2CH2 Me O N i, H+ ii, Ac2O, Py 6 7 Scheme 1 Received: 3rd November 1999; Com. 99/1550

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年代:2000

数据来源: RSC

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Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) Convenient synthesis of cationic glycerolipids via methylthiomethyl ethers Mikhail A. Maslov,* Nina G. Morozova and Galina A. Serebrennikova M. V. Lomonosov Moscow State Academy of Fine Chemical Technology, 117571 Moscow, Russian Federation. Fax: +7 095 434 8711; e-mail: maslov@httos.mitht.msk.ru DOI: 10.1070/MC2000v010n02ABEH001211 Glycerol ether lipids containing various positively charged groups have been prepared via corresponding methylthiomethyl ethers.The biological activity of positively charged non-phosphorus glycerolipids, which contain both various aliphatic residues in the hydrophobic domain and polar groups, is well known.1 Cationic lipids exhibit antitumor activity due to the inhibition of protein kinase C and diacylglycerokinase;1 they inhibit replication of the HIV-1 virus1 and are effective antagonists of the platelet activating factor.1,2 In the last decade different cationic lipids have been synthesised for the purpose of gene therapy.3,4 The genetic modification of somatic cells with cationic lipids is an alternative route to viral-mediated gene therapy and has some advantages such as safety and simplicity.Therefore, the preparation of new types of cationic lipids and the investigation of structure–activity relationships seems to be promising for bioorganic chemistry. Although several approaches to the introduction of positively charged heads to lipids, which are based on the alkylation of either tertiary amines with 3-bromo-3-deoxy-,5–7 3-O-methanesulfonyl- 7 and 3-O-toluenesulfonyl-substituted7 1,2-dialkylglycerols or O-substituted 3-(dimethylamino)-1,2-propanediol with short-chain alkyl halides,4,8 are widely used, the yields of desirable products are low.This fact can be explained by the elimination of outgoing groups and by steric hindrances. In early reports,9,10 metylthiomethyl (MTM) ethers have been recommended as protective groups for the hydroxyl function because of their stability and selective cleavage under certain conditions.More recently, MTM ethers were employed in nucleoside11 and lipid12 chemistry. To increase the yields, we propose herein a convenient procedure for the preparation of positively charged glycerolipids via corresponding MTM ethers (Scheme 1).In the synthesis of compounds 2, initial 1,2-dialkylglycerols 1 were treated with a mixture of DMSO, acetic anhydride and acetic acid (the molar ratio 6.5:3.4:1) as described previously,9,12 and the mixture was kept from two to five days. MTM ethers were purified using chromatography on silica gel. The yields were generally equal to 50–61%. The 1H NMR spectra exhibited characteristic signals of MTM groups, viz., singlets at 2.12–2.15 and 4.64–4.68 ppm for SMe and OCH2S, respectively.The treatment of MTM ethers (highly reactive asymmetric O,S-acetals) with bromine gives a-bromo ethers, which can be easily displaced with various nucleophiles. The reaction of MTM derivatives 2 with different secondary (XH) or tertiary (X) heterocyclic amines (Table 1) in the presence of bromine afforded cationic lipids 3–5 in 90–98% yields.The limitation of the proposed method was demonstrated with lipid 2c, whose allylic group can interact with bromine. The yields of compounds 3c and 4c were no higher than 45%. In a typical procedure, to a solution of MTM ether 2a–d (0.1 mmol) in 1 ml of anhydrous dichloroethane, a corresponding amine (0.5 mmol) and, after 5 min, an excess of bromine (0.12– 0.15 mmol) were added at room temperature.The reaction mixture was stirred for 10–30 min. After the removal of the organic solvent in a vacuum, volatile amine traces were additionally removed at a reduced pressure (0.5 Torr). The resulting lipid was purified by chromatography on silica gel. 1H NMR spectroscopy, mass spectrometry and elemental analysis data for all of the novel compounds are in accordance with the assigned structures.† † 3a: 1H NMR (Bruker MSL-200, 200 MHz, CDCl3, SiMe4 as an internal standard) d: 0.85 [t, 3H, (CH2)15CH3, J 6.8 Hz], 1.22 [br.s, 30H, (CH2)15Me], 1.50 (m, 2H, OCH2CH2), 3.35–3.49 (m, 8H, OCH2CH2, CH2OC18H37, CHOMe, OMe), 3.68 (dd, 1H, J 5.1 and 10.7 Hz) and 3.83 (dd, 1H, CH2O, J 3.0 and 10.7 Hz), 4.10 (s, 3H, N+Me), 5.81 (dd, 2H, OCH2N+, J 10.2 and 13.2 Hz), 7.29 and 7.44 (m, 2H, –CH=CH), 10.59 (m, 1H, –CH=N).MS (Vision 2000 time-of-flight mass spectrometer with matrix-assisted laser desortion ionization), m/z: 452.6, [M – Br]+. 3b: 1H NMR, d: 0.84 [t, 3H, (CH2)15CH3, J 6.8 Hz], 1.14 (t, 3H, OCH2CH3, J 7.0 Hz), 1.21 [br. s, 30H, (CH2)15Me], 1.49 (m, 2H, OCH2CH2), 3.32–3.43 (m, 4H, OCH2CH2, CH2OC18H37), 3.49–3.61 (m, 3H, CHOEt, OCH2Me), 3.68 (dd, 1H, J 5.1 and 10.7 Hz) and 3.83 (dd, 1H, CH2O, J 3.0 and 10.7 Hz), 4.10 (s, 3H, N+Me), 5.79 (dd, 2H, OCH2N+, J 10.3 and 12.6 Hz), 7.36 and 7.46 (m, 2H, –CH=CH), 10.49 (m, 1H, –CH=N).MS, m/z: 466.4 [M – Br]+. 3c: 1H NMR, d: 0.85 [t, 3H, (CH2)15CH3, J 6.8 Hz], 1.22 [br. s, 30H, (CH2)15Me], 1.50 (m, 2H, OCH2CH2), 3.35–3.50 (m, 5H, OCH2CH2, CH2OC18H37, CHOAll), 3.63–3.81 (m, 2H, CH2O), 4.00 (m, 2H, OCH2– CH=CH2), 4.08 (s, 3H, N+Me), 5.19 (m, 2H, OCH2–CH=CH2), 5.80 (m, 3H, OCH2N+, OCH2CH=CH2), 7.26 and 7.44 (m, 2H, –CH=CH), 10.61 (m, 1H, –CH=N).MS, m/z: 479.6 [M – Br]+. 3d: 1H NMR, d: 0.85 [t, 6H, 2(CH2)15CH3, J 6.4 Hz], 1.23 [br. s, 60H, 2(CH2)15Me], 1.50 (m, 4H, 2OCH2CH2), 3.34–3.57 (m, 7H, 2OCH2CH2, CH2OC18H37, CHOC18H37), 3.68 (dd, 1H, CH2O, J 5.2 and 10.0 Hz) and 3.79 (dd, 1H, CH2O, J 3.2 and 10.0 Hz), 4.09 (s, 3H, N+Me), 5.79 (dd, 2H, OCH2N+, J 10.2 and 14.5 Hz), 7.27 and 7.42 (m, 2H, –CH=CH), 10.69 (m, 1H, –CH=N).MS, m/z: 693.1 [M – Br]+. 4a: 1H NMR, d: 0.84 [t, 3H, (CH2)15CH3, J 6.8 Hz], 1.22 [br. s, 30H, (CH2)15Me], 1.51 (m, 2H, OCH2CH2), 3.35–3.48 (m, 8H, OCH2CH2, CH2OC18H37, CHOMe, OMe), 3.52 (s, 3H, N+Me), 3.70 (m, 4H, 2NCH2CH2O), 4.00 (m, 5H, 2NCH2CH2O, CH2O), 4.15 (dd, 1H, CH2O, J 2.6 and 11.1 Hz), 5.35 (dd, 2H, OCH2N+, J 7.9 and 20.7 Hz).MS, m/z: 471.8 [M – Br]+. Scheme 1 Reagents and conditions: i, DMSO–Ac2O–AcOH, benzene, 24 °C, 2–5 days; ii, XH or X, dichloroethane, 24 °C, 10–30 min. OC18H37 OR OH OC18H37 OR OCH2SMe OC18H37 OR OCH2X Y 1a–d 2a–d 3a–d 4a–c 5a,b: R = C18H37 a R = Me b R = Et c R = CH2CH=CH2 d R = C18H37 i ii 1–4: Table 1 Synthesised compounds.CompoundR X YYield (%) 3a 3b 3c 3d Me Et CH2CH=CH2 C18H37 Br– 97 97 45 96 4a 4b 4c Me Et CH2CH=CH2 Br– 92 91 35 5a 5b C18H37 92 80 N N Me O N Me N N N NMendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) This work was partially supported by the Russian Foundation for Basic Research (grant no. 96-03-33383a). References 1 I. D. Konstantinova and G. A Serebrennikova, Usp. Khim., 1996, 65, 581 (Russ. Chem. Rev., 1996, 65, 537). 2 M. Koltai and P. G. Braquet, Clin. Rev. Allergy, 1994, 12, 361. 3 D.D.Lasic, Liposomes in Gene Delivery, CRC Press, New York, 1997. 4 A. D. Miller, Angew.Chem., Int. Ed. Engl., 1998, 37, 1768. 5 S. L. Morris-Natschke, F. Gumus, C. J. Marasco, K. L. Meyer, M. Marx, C. Piantadosi, M. D. Layne and E. J. Modest, J. Med. Chem., 1993, 36, 2018. 6 T. Ren and D. Liu, Tetrahedron Lett., 1999, 40, 209. 7 M. A. Maslov, E. V. Siycheva, N. G. Morozova and G. A. Serebrennikova, Izv. Akad. Nauk, Ser. Khim., 1999, 1381 (Russ. Chem. Bull., 1999, 48, 1369). 8 J. H. Felgner, R. Kumar, C. N. Sridhar, C. J. Wheeler, Y. J. Tsai, R. Border, P. Ramsey, M. Martin and P. L. Felgner, J. Biol. Chem., 1994, 269, 2550. 9 P. M. Pojer and S. J. Angyal, Aust. J. Chem., 1978, 31, 1031. 10 K. Suzuki, J. Inanaga and M. Yamaguchi, Chem. Lett., 1979, 1277. 11 S. Zavgorodny, M. Polianski, E. Besidsky, V. Kriukov, A. Sanin, M. Pokrovskaya, G. Gurskaya, H.Lonnberg and A. Azhaev, Tetrahedron Lett., 1991, 32, 7593. 12 I. D. Konstantinova, S. G. Zavgorodny, A. I. Miroshnikov, I. P. Ushakova and G. A. Serebrennikova, Bioorg. Khim., 1995, 21, 66 (Russ. J. Bioorg. Chem., 1995, 21, 58). 4b: 1H NMR, d: 0.84 [t, 3H, (CH2)15CH3, J 6.4 Hz], 1.16 (t, 3H, OCH2CH3, J 6.8 Hz), 1.22 [br. s, 30H, (CH2)15Me], 1.50 (m, 2H, OCH2CH2), 3.34–3.51 (m, 4H, OCH2CH2, CH2OC18H37), 3.53 (s, 3H, N+Me), 3.58 (q, 1H, OCH2Me, J 6.8 Hz), 3.60 (m, 1H, CHOEt), 3.62 (q, 1H, OCH2Me, J 6.8 Hz), 3.71 (m, 4H, 2NCH2CH2O), 4.00 (m, 5H, 2NCH2CH2O, CH2O), 4.13 (dd, 1H, CH2O, J 3.0 and 10.7 Hz), 5.35 (dd, 2H, OCH2N+, J 8.1 and 20.9 Hz).MS, m/z: 485.8 [M – Br]+. 4c: 1H NMR, d: 0.86 [t, 3H, (CH2)15CH3, J 6.5 Hz], 1.22 [br. s, 30H, (CH2)15Me], 1.50 (m, 2H, OCH2CH2), 3.35–3.53 (m, 8H, OCH2CH2, CH2OC18H37, CHOAll, N+Me), 3.71 (m, 4H, 2NCH2CH2O), 3.92–4.17 (m, 8H, 2NCH2CH2O, OCH2CH=CH2, CH2O), 5.20–5.49 (m, 3H, OCH2N+, OCH2CH=CH2), 5.80 (m, 1H, OCH2CH=CH2). MS, m/z: 497.8 [M – Br]+. 5a: 1H NMR, d: 0.85 [t, 6H, 2(CH2)15CH3, J 6.8 Hz], 1.23 [br. s, 60H, 2(CH2)15Me], 1.51 (m, 4H, 2OCH2CH2), 3.34–3.56 (m, 9H, 2OCH2– CH2, CH2OC18H37, CHOC18H37, CH2O), 5.34 (br. s, 2H, OCH2N), 7.06 and 7.11 (m, 2H, –CH=CH), 7.74 (m, 1H, –CH=N). MS, m/z: 678.0 [M]+, 699.8 [M + Na]+. 5b: 1H NMR, d: 0.86 [t, 6H, 2(CH2)15CH3, J 6.8 Hz], 1.23 [br. s, 60H, 2(CH2)15Me], 1.52 (m, 4H, 2OCH2CH2), 3.28 (br. t, 4H, 2OCH2CH2, J 6.8 Hz), 3.35–3.55 (m, 5H, CH2OC18H37, CHOC18H37, CH2O), 5.59 (br. s, 2H, OCH2N), 7.29 (m, 2H), 7.53 (m, 2H) and 7.99 (m, 1H, benzimidazole). MS, m/z: 726.9 [M]+, 748.9 [M + Na]+. Received: 6th October 1999; Com. 99/1539

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出版商:RSC    

年代:2000

数据来源: RSC

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Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) Reactions of alkali metal acetylides with red phosphorus Svetlana N. Arbuzova,*a Lambert Brandsma,b Nina K. Gusarova,a Mikhail V. Nikitina and Boris A. Trofimova a Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russian Federation. Fax: +7 3952 39 6046; e-mail: gusarova@irioch.irk.ru b Department of Organic Chemistry, University of Utrecht, 3584 CH, Utrecht, The Netherlands DOI: 10.1070/MC2000v010n02ABEH001245 The two-step cleavage of red phosphorus with an alkali metal and an alkali metal acetylide (an alkyl halide was added at each step) gives b-substituted acetylenic phosphines. Acetylenic phosphines are usually synthesised by the reaction of alk-1-ynyllithium with dialkylphosphinous chlorides.1 Recently,2 we found the Csp–P bond formation by direct cleavage of the yellow phosphorus molecule (P4) with but-1-ynyllithium.Here we report that less reactive red phosphorus† also reacts with an alkali metal acetylide‡ (but-1-ynylsodium) in liquid ammonia (Scheme 1) to give, upon alkylation of the reaction mixture, acetylenic phosphines 1 and 2 in low yields (5%).§ To improve the yields of acetylenic phosphines (up to 10– 12%), a two-step cleavage of the red phosphorus macromolecule in liquid ammonia was used (Scheme 2).One equivalent of potassium metal and an excess of sodium acetylide were used at the first and second steps, respectively. An alkyl halide was added to the reaction mixture at each step.According to published data,3 polyphosphide anions A are formed at the first step; these ions give corresponding polyalkylphosphines 3 after alkylation. The treatment of the latter with alkali metal acetylides followed by the alkylation of intermediate alkyl(organoethynyl)phosphide anions B yields dialkyl- (organoethynyl)phosphines 1 and 4.¶ A search for optimum conditions of the synthesis of acetylenic phosphines by direct reactions of red phosphorus with alkali metal acetylides is in progress.† Red phosphorus was successively washed with an aqueous sodium carbonate solution, acetone and diethyl ether and dried in a vacuum. ‡ Alkali metal acetylides were prepared from alkali metal amides and corresponding acetylenes in liquid ammonia.4 § Reaction of red phosphorus with but-1-ynylsodium and ethyl bromide: 0.4 mol of but-1-ynylsodium was added to a suspension of 0.1 mol of red phosphorus in 1 dm3 of liquid ammonia, and the mixture was stirred for 0.5 h.Next, 0.5 mol of ethyl bromide was added dropwise for 1 h, and the reaction mixture was stirred for 3 h until the evaporation of liquid ammonia. Diethyl ether (200 ml) and water (250 ml) were successively added to the residue.After vigorous stirring, the layers were separated followed by triple extraction with diethyl ether. The organic solution was dried with K2CO3; the solvent and the by-product (hex-3-yne) were removed in vacuo. Distillation of the remaining liquid at a low pressure gave 0.79 g of a product with bp 40–70 °C (0.3 Torr). This product contained (according to GLC) 29% phosphine 1 (yield 2%) and 71% phosphine 2 (yield 3%).All operations were carried out under a nitrogen atmosphere. Spectroscopic data for the mixture are identical to those for the sample obtained previously.2 This work was supported by the Russian Foundation for Basic Research (grant no. 98-03-32925a). References 1 W. Voskuil and J. F. Arens, Recl.Trav. Chim. Pays-Bas, 1962, 81, 993. 2 (a) B. A. Trofimov, L. Brandsma, S. N. Arbuzova and N. K. Gusarova, Zh. Obshch. Khim., 1997, 67, 343 (Russ. J. Gen. Chem., 1997, 67, 322); (b) B. A. Trofimov, L. Brandsma, S. N. Arbuzova and N. K. Gusarova, Izv. Akad. Nauk, Ser. Khim., 1997, 884 (Russ. Chem. Bull., 1997, 46, 849). 3 G. M. Bogolyubov and A. A. Petrov, Dokl. Akad. Nauk SSSR, 1967, 173, 1076 [Dokl.Chem. (Engl. Transl.), 1967, 173, 329]. 4 L. Brandsma and H. D. Verkruijsse, Synthesis of Acetylenes, Allenes and Cumulenes, Elsevier, Amsterdam, 1981, p. 17. 5 A. M. Aguiar, J. R. S. Irelan, C. J. Morrow, J. P. John and G. W. Prejean, J. Org. Chem., 1969, 34, 2684. ¶ General method for the synthesis of 1 and 4: 0.2 mol of potassium metal was added to a suspension of 0.2 mol of red phosphorus in 1 dm3 of liquid ammonia, and the mixture was stirred until a blue colour disappeared, and a yellow-brown suspension was formed.Thereafter, 0.2 mol of ethyl bromide was added for 5 min. A suspension of 0.3 mol of an alkali metal acetylide in liquid ammonia was introduced into the reaction mixture. The reaction mixture was stirred for 0.5 h; next, 0.3 mol of ethyl bromide was added dropwise for 1 h.After 0.5 h, the ammonia was evaporated at ~40 °C. Diethyl ether (200 ml) and water (250 ml) were successively added to the residue. After vigorous stirring, the layers were separated followed by triple extraction with diethyl ether. The organic solution was dried with K2CO3; the solvent and the by-product (an alkylated acetylide) were removed in vacuo.Distillation of the remaining liquid at a low pressure gave phosphines 1 and 4. All operations were carried out under a nitrogen atmosphere. The residues contained small amounts of di(but-1-ynyl)ethylphosphine 2 and ethyl[bis(phenylethynyl)]- phosphine (GLC, GC–MS and 31P NMR data), respectively, among other high-boiling compounds. But-1-ynyl(diethyl)phosphine 1: yield 10%, bp 40–45 °C (0.3 Torr).Spectroscopic data are identical to those for the sample obtained previously. 2 Diethyl(phenylethynyl)phosphine 4: yield 12%, bp 100–105 °C (0.3 Torr) [lit.,5 105–107 °C (0.7 Torr)]. 1H NMR (CDCl3) d: 1.05–1.35 (m, 6H, Me), 1.6–1.8 (m, 4H, CH2P), 7.2–7.6 (m, 5H, Ph). 13C NMR (CDCl3) d: 9.93 (Me, 2JCP 10.65 Hz), 19.29 (CH2, 1JCP 6.90 Hz), 88.23 (ºCP, 2JCP 24.0 Hz), 104.52 (PhCº), 123.35 (Carom), 128.28 (CHarom), 128.33 (CHarom), 131.66 (CHarom). 31P NMR (CDCl3) d: –38.5. MS, m/z: 190 [M+]. IR (n/cm–1): 2173 (CºC). Pn EtCºCPEt2 + (EtCºC)2PEt i, EtCºCNa, NH3 (liquid) ii, EtBr 1 2 Scheme 1 n[RCºCPEt] nRCºCPEt2 Pn [Pn –] [(PEt)n ] nK NH3 (liquid) nEtBr an excess of RCºCNa an excess of EtBr – A 3 B 1R = Et 4 R = Ph Scheme 2 Received: 6th December 1999; Com. 99/1571

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Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) Synthesis of chlorofurazans from nitrofurazans Aleksei B. Sheremetev,* Natal’ya S. Aleksandrova, Elena V. Mantseva and Dmitrii E. Dmitriev N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow, Russian Federation. E-mail: sab@cacr.ioc.ac.ru DOI: 10.1070/MC2000v010n02ABEH001250 Furazans bearing one and two chlorine atoms can be easily prepared by nucleophilic displacement of a nitro group at a furazan ring upon treatment with the Vilsmeier reagent.Although the synthesis of simple furazan building blocks, which can be employed in the preparation of more complex derivatives, is of considerable current interest the chemistry of chlorofurazans (chloro-1,2,5-oxadiazoles) has not been adequately explored.The reported examples of this class of compounds include 3-chloro-4-phenylfurazan,1,2 isomeric 3-chloro-4-(nitrophenyl)- furazans3 and 3-chloro-4-(pyrid-3-yl)furazan.4 However, these starting materials are difficult to obtain. In the context of the use of nucleophilic substitution reactions in the synthesis of furazans,5–11 we have sought a straightforward and, if possible, general method for the synthesis of halogen derivatives. A classical procedure for the replacement of a hydroxy group with a chlorine atom at a (hetero)aromatic ring is the treatment of a hydroxy compound by a mixture of phosphorus oxychloride with DMF (the Vilsmeier reagent) or another catalyst.This method was successfully used for the preparation of chloronitrobenzenes12 and applied to hydroxy-1,3,4-oxadiazoles.13,14 However, note that our attempts to prepare chlorofurazans by the treatment of available hydroxyfurazans9,10 with the Vilsmeier reagent were unsuccessful.We found that a nitro group at a furazan ring15 underwent displacement by chlorine when heated with the Vilsmeier reagent.† A variety of chlorofurazans can be produced in moderateto- good yields only from 3-nitro-4-R-furazans bearing an electronwithdrawing group R.Thus, when 3,4-dinitrofurazan 116 was treated with the reagent at 30 °C for 24 h, 3-chloro-4-nitrofurazan 2‡ was obtained in 62% yield (Scheme 1) and isolated by column chromatography on silica gel, using 30% CH2Cl2 in pentane as an eluent. The starting furazan 1 was also recovered in 29% yield.Note that no traces of compound 3 were detected. Our attempts to improve the yield of 2 by changing the reaction time and temperature were unsuccessful. Treatment of 1 with POCl3 in the absence of DMF did not afford chloro products; only the starting compound was detected. † General procedure. Dimethylformamide (0.02 mol for one nitro group) was added dropwise to a solution of a nitrofurazan (0.01 mol) in POCl3 (15 ml).The reaction mixture was heated with stirring for 6–24 h. After cooling, the mixture was poured into ice water and extracted with pentane–CH2Cl2. The extracts were washed with water and dried. The crude products were separated by chromatography. ‡ All chloro compounds gave satisfactory elemental analyses and mass spectra.The structures were also confirmed by IR and NMR spectroscopy. For 2: oil, Rf 0.79 (pentane–CH2Cl2, 1:1). 13C NMR (CDCl3) d: 141.9 (C–Cl), 157.2 (C–NO2). 14N NMR (CDCl3) d: –45.5 (NO2, Dn1/2 10 Hz). IR (n/cm–1): 1570, 1330 (NO2), 1610, 1180, 860 (furazan ring). MS, m/z: 151, 149 (M+), 105, 103 (M+ – NO2), 75, 73, 68. For 5: oil. 13C NMR (CDCl3) d: 137.2 (C–CNO2), 140.5 (C–Cl), 146.2 (C–CCl), 158.7 (C–NO2). 14NNMR (CDCl3) d: –40.0 (NO2, Dn1/2 7 Hz). MS, m/z: 218, 216 (M+). For 6: mp 59–61 °C. MS, m/z: 208, 206, 204 (M+). For 8: oil. 13C NMR (CDCl3) d: 136.5 (C–Cl), 148.8 (C–NO2), 151.4, 154.9. 14N NMR (CDCl3) d: –39.0 (NO2, Dn1/2 9.5 Hz). IR (n/cm–1): 1540, 1360 (NO2). MS, m/z: 247, 245 (M+). For 9: mp 25–26 °C. 13C NMR (CDCl3) d: 139.7 (C–Cl), 158.5. MS, m/z: 234, 235, 236 (M+).For 11: mp 26–27 °C. 13C NMR (CDCl3) d: 142.1 (C–Cl), 148.0 (C– CNO2), 155.0 (C–NO2), 156.1 [CN(O)N]. 14N NMR (CDCl3) d: –38.4 (NO2, Dn1/2 13 Hz), –65.2 (N®O, Dn1/2 28 Hz). IR (n/cm–1): 1550, 1350 (NO2), 1580, 1170, 1105, 915, 870 (furazan ring). MS, m/z: 263, 261 (M+). For 13: mp 55–56 °C. MS, m/z: 185 (M+), 139 (M+ – NO2). Compound 2 is a highly volatile liquid soluble in all organic solvents.It can be purified by freezing from pentane at –78 °C. Treatment of 4,4'-dinitrobifurazan 416 with the Vilsmeier reagent at 60 °C for 6 h led to the nucleophilic displacement of nitro groups to yield a mixture of starting compound 4 and chloro derivatives (Scheme 2). The mixture was chromatographed on a column to give compound 4 as the major product (74%) with small amounts of monochlorofurazan 5 (13%) and 4,4'-dichlorobifurazan 6 (2%).Compound 5 was obtained in 37% yield by a similar reaction carried out in the presence of PCl5. The same reaction gave a higher yield (45%) at 80 °C. Pure product 6 was only obtained in 3% yield by flash chromatography. The low yield is probably due to a substantial loss of volatile compound 6 (evaporation of 6 with CH2Cl2 was observed) in the course of separation. When a mixture of 4,4'-dinitroazofurazan 716 and the Vilsmeier reagent with an excess of POCl3 was heated at 80 °C for 6 h, halofurazans 8 and 9 in a ratio of 2:1, respectively, were the only products isolated (89%) (Scheme 3).Monochloro and dichloro compounds 8 and 9 were then separated and purified by chromatography on silica gel.The same reaction in the presence of three equivalents of PCl5 gave 4,4'-dichloroazofurazan 9 as the sole product in 84% yield. The nucleophilic substitution reactions in 4,4'-dinitroazoxyfurazan 1016 proceed at the carbon atom bonded to the nitro group proximate to the N-oxide of the azoxy group and at the carbon atom bonded to the N(O) atom of the azoxy group.11 Indeed, treatment of compound 10 with the Vilsmeier reagent N O N O2N NO2 N O N O2 N Cl N O N Cl Cl i i 1 2 3 Scheme 1 Reagents and conditions: i, POCl3/ DMF, 30–60 °C, 24–72 h.N O N O2 N N O N NO2N O N O2 N N O N Cl N O N Cl N O N Cl i 4 5 6 Scheme 2 Reagents and conditions: i, POCl3/PCl5/DMF, 80 °C, 6 h. N O N O2 N N N O N O2 N N N O N O2 N N N O N Cl N N O N Cl N N O N Cl N i 7 8 9 Scheme 3 Reagents and conditions: i, POCl3/DMF, 80 °C, 6 h.Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) in the above manner afforded 4-chloro-4'-nitroazoxyfurazan 11§ and 3-chloro-4-nitrofurazan 2, which resulted from the nucleophilic displacement of an azoxyfurazanyl moiety (Scheme 4), in ~50% yields. The reaction mixture contained none dichloro derivatives such as 4,4'-dichloroazoxyfurazan¶ and 3,4-dichlorofurazan 3. 3-Methyl-4-nitrofurazan remained unaffected under treatment with the Vilsmeier reagent in an excess of POCl3 at 80 °C for 36 h. Under similar conditions, the nitro group of 3-amino-4- nitrofurazan 12 was also unchanged; at the same time, the amino group was transformed to a formamidine moiety (as was observed in nitroanilines12) to give compound 13 in quantitative yield (Scheme 5).In conclusion, a simple method for chlorofurazan synthesis has been developed. As a result, key precursors such as 3-chloro-4- nitrofurazan, 4-chloro-4'-nitrobifurazan and 4,4'-dichloroazofurazan can be easily prepared. This work was supported by the Russian Foundation for Basic Research (grant no. 98-03-33024a). § The identification of the N-oxide position was made using selective 13C–{14N} double heteronuclear resonance and by comparison with the published data.7 ¶ 4,4'-Dichloroazoxyfurazan was prepared by oxidation of azo compound 9 with Caro’s acid in 67% yield, mp 75–77 °C. References 1 B. W. Nash, R. A. Newberry, R. Pickles and W. K.Warburton, J. Chem. Soc. (C), 1969, 2794. 2 R. Calvino, R. Fruttero, A. Gasco, V. Mortarini and S. Aime, J. Heterocycl. Chem., 1982, 19, 427. 3 R. Calvino, A. Serafino, B. Ferrarotti, A. Gasco and A. Sanfilippo, Arch. Pharm. (Weinheim, Ger.), 1984, 317, 695. 4 P. Sauerberg, P. H. Olesen, S. Nielsen, S. Treppendahl, M. J. Sheardown, T. Honore, C. H. Mitch, J. S. Ward, A. J. Pike, F. P. Bymaster, B. D. Sawyer and H. E. Shannon, J.Med. Chem., 1992, 35, 2274. 5 A. B. Sheremetev, E. V. Mantseva, N. S. Aleksandrova, V. S. Kuzmin and L. I. Khmel’nitskii, Mendeleev Commun., 1995, 25. 6 A. B. Sheremetev, O. V. Kharitonova, T. M. Melnikova, T. S. Novikova, V. S. Kuzmin and L. I. Khmel’nitskii, Mendeleev Commun., 1996, 141. 7 A. B. Sheremetev, V. O. Kulagina, N. S. Aleksandrova, D. E. Dmitriev, Yu. A. Strelenko, V.P. Lebedev and Yu. N. Matyushin, Propellants, Explosives, Pyrotechnics, 1998, 23, 142. 8 A. B. Sheremetev, S. E. Semenov, V. S. Kuzmin, Yu. A. Strelenko and S. L. Ioffe, Chemistry-European Journal, 1998, 4, 1023. 9 A. B. Sheremetev and N. S. Aleksandrova, Mendeleev Commun., 1998, 238. 10 A. B. Sheremetev, O. V. Kharitonova, E. V. Mantseva, V. O. Kulagina, E. V. Shatunova, N.S. Aleksandrova, T. M. Melnikova, E. A. Ivanova, D. E. Dmitriev, V. A. Eman, I. L. Yudin, V. S. Kuzmin, Yu. A. Strelenko, T. S. Novikova, O. V. Lebedev and L. I. Khmel’nitskii, Zh. Org. Khim., 1999, 35, 1555 (in Russian). 11 A. B. Sheremetev, N. S. Aleksandrova, T. M.Melnikova, T. S. Novikova, Y. A. Strelenko and D. E. Dmitriev, Heteroatom Chem., 2000, 11, 48. 12 V. L. Zbarskii, G.M. Shutov, B. F. Zhilin, R. G. Chirkova and E. Yu. Orlova, Zh. Org. Khim., 1971, 7, 310 [J. Org. Chem. USSR (Engl. Transl.), 1971, 7, 303] and references therein. 13 H. Singh, L. D. S. Yadav and B. K. Bhattacharya, J. Indian Chem. Soc., 1984, 61, 436. 14 M. M. Hamad, Arch. Pharm. (Weinheim, Ger.), 1990, 323, 595. 15 For review on the nitrofurazan chemistry, see: A. B. Sheremetev, Ross. Khim. Zh. (Zh. Ross. Khim. Ob-va im. D. I. Mendeleeva), 1997, 41 (2), 43 [Mendeleev Chem. J., 1997, 41 (2), 62]. 16 T. S. Novikova, T. M. Melnikova, O. V. Kharitonova, V. O. Kulagina, N. S. Aleksandrova, A. B. Sheremetev, T. S. Pivina, L. I. Khmel’nitskii and S. S. Novikov, Mendeleev Commun., 1994, 138. N O N O2N N N O N NO2 N O N O N O2N N N O N Cl N O N O N Cl NO2 i 10 11 2 Scheme 4 Reagents and conditions: i, POCl3/DMF, 80 °C, 6 h. Scheme 5 Reagents and conditions: i, POCl3/DMF, 80 °C, 6 h. N O N O2N NH2 12 N O N O2N N 13 i NMe2 Received: 15th December 1999; Com. 99/1576

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年代:2000

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Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) Formation of cyclic ketene N-hydroxyaminals, 2-acylmethylene-1-hydroxyimidazolidines, in the reaction of 1,2-bishydroxylamines with 1,3-ketoaldehydes Dmitrii G. Mazhukin,* Aleksei Ya. Tikhonov, Vladimir A. Reznikov and Leonid B. Volodarsky N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation.Fax: +7 383 234 4752; e-mail: dimm@mail.nsk.ru DOI: 10.1070/MC2000v010n02ABEH001231 The reaction of aliphatic 1,2-bishydroxylamines with 1,3-ketoaldehydes generated in situ in acidic media leads to 2-acylmethylene- 1-hydroxyimidazolidines, a new class of cyclic ketene N-hydroxyaminals. Aliphatic 1,2-diamines react with 1,3-dicarbonyl compounds in the presence of acids with the formation of 2,3-dihydro-1,4-diazepinium salts.1 The best yields of 1,4-diazepines were observed at pH 2–5 when the formation of accompanying enaminoketones was minimised because the equilibrium was shifted towards the thermodynamically more favourable diazepinium cation.2 The reaction of another type of N-centered binucleophiles, aliphatic 1,2-bishydroxylamines,3 with 1,3-dicarbonyl compounds has not so far been investigated.It is tempting to suppose that 1,3-ketoaldehydes may react with 1,2-bishydroxylamines to form 1,4-diazepine N-oxides or their tautomeric N-hydroxy derivatives. Because 1,3-ketoaldehydes are unstable compounds, we used their synthetic equivalents, viz., the 1,3-ketoacetal 2a, sodium salt 2b or enol ether 2c, in the reaction with 1,2-bishydroxylamines 1a–c.Free 1,3-ketoaldehydes 2 were generated in the reaction mixture by acidification or acid-catalysed hydrolysis (pH 2–5). We found that the reaction of cis-1,2-bis(hydroxylamino) cyclohexane 1a with the sodium salt of 3-oxo-3-phenylprop- 1-enol 2b in glacial acetic acid was complete within 30 h at room temperature to afford a compound in 63% yield.The elemental analytical data for this compound formally corresponded to a product of condensation of the ketoaldehyde with the bishydroxylamine with elimination of two water molecules. However, the product was neither of the 1,4-diazepines 3 or 4. As judged from the spectroscopic characteristics of this compound, it has the structure of a cyclic ketene N-hydroxyaminal, viz., 2-benzoylmethylene-1-hydroxyimidazolidine 5a.Thus, the 1H NMR spectrum of 5a exhibits a characteristic signal (5.62 ppm) of the methyne proton at an (electron-rich) sp2 carbon atom. The 13C NMR spectrum of 5a shows the presence of a carbonyl group (184.2 ppm) and an enamine fragment (a doublet at 75.4 ppm and a singlet at 166.9 ppm).A number of intense broad bands typical of enaminoketones4 were observed in the IR spectrum of 5a at 1525–1615 cm–1. Ketene aminals, including cyclic examples of the imidazolidine series, are reactive species, and convenient starting compounds for the synthesis of fused heterocycles. The chemistry of these compounds has been reviewed in refs. 5, 6. However, only one R2 NHOH R1 NHOH R3 R4 O R5 O O O R5 OX 1a–c 2a 2b,c or N NH R2 R1 R3 R4 OH R5 O N NH R3 R4 R2 R1 OH R5 O AcOH or HCl pH 2–5 N N R3 R4 R2 R1 OH R5 O H N N R2 R1 R3 R4 OH R5 O H+ – H2O HCl N NH R2 R1 R3 R4 OH R5 O · 2HCl 6 7 8d 5a,bA,c–g 5bB H+ 2a–c AcOH Na2CO3 N N O R5 O R2 R3 R1 R4 N N O R5 OH R2 R3 R1 R4 NH NH R2 R1 R3 R4 CF3 O 9f,g 4 3 OH 1a, 5a R1 + R3 = (CH2)4, R2 = R4 = H, R5 = Ph 1b, 5b R1 = R3 = R4 = Me, R2 = H, R5 = Ph 1c, 5c R1 = R2 = R3 = R4 = Me, R5 = Ph 5d, 8d R1 + R3 = (CH2)4, R2 = R4 = H, R5 = Me 5e R1 = R2 = R3 = R4 = R5 = Me 5f, 9f R1 + R3 = (CH2)4, R2 = R4 = H, R5 = CF3 5g, 9g R1 = R2 = R3 = R4 = Me, R5 = CF3 2a R5 = Me 2b R5 = Ph, X = Na 2c R5 = CF3, X = Et Scheme 1Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) example of the synthesis of a cyclic ketene N-hydroxyaminal, by the reaction of 4,5-dihydro-1-hydroxy-2-methylimidazole with ethyl benzoate in the presence of lithium diisopropylamide (LDA), has been reported earlier.7 The reaction of 1,2-bishydroxylamines 1b,c with 1,3-ketoaldehyde 2b also leads to 2-benzoylmethylene-1-hydroxyimidazolidines 5.Thus, a mixture of two isomeric imidazolidines 5bA and 5bB was obtained in the reaction of unsymmetrical 1,2-bishydroxylamine 1b with the sodium salt of enol 2b.In this reaction, the sterically hindered 1,2-bishydroxylamine 1c gave the cyclic ketene N-hydroxyaminal 5c in high yield. The formation of 5 could be rationalised as a result of dehydration of intermediate imidazolidines 6 (cf. ref. 8) to 4,5-dihydroimidazoles 7, which are obviously more stable as tautomeric enaminoketones 5A,B.When 1,2-bishydroxylamine 1a reacted with acetoacetaldehyde diethyl acetal 2a in anhydrous methanol saturated with HCl, the dihydrochloride 8d was quantitatively precipitated from the reaction mixture. The free enaminoketone base 5d was prepared by careful alkalination of a solution of 8d (Scheme 1). The reaction of 1,2-bishydroxylamines 1a,c with trans-b- ethoxyvinyl trifluoromethyl ketone 2c9 in a water–methanol solution of HCl gave cyclic ketene N-hydroxyaminals 5f and 5g, respectively.† In the case of 1,2-bishydroxylamine 1c, the cyclic ketene aminal 9g was formed in the reaction mixture along with compound 5g in almost equal amount.The 1H NMR spectrum of crude compound 5f exhibits low-intensity signals of a by-product that can be identified as the ketene aminal 9f. The 13C NMR spectroscopy data for 2-acylmethylene-1-hydroxyimidazolidines 5‡ indicate that these compounds exist in solution as enaminoketone EK rather than ketoamidine KA forms.The observed signals are likely due to fast proton transfer (on an NMR scale) with the formation of enol–amidine species EA§ and, as a consequence, with the presence of tautomeric mixture EK EA in the solution. The evident difference between the positions of long-wave maxima in the UV spectra of parent enaminoketones11,12 (lmax = 325–330 nm) and enhydroxylaminoketones13 (lmax = 350 nm), as compared with the positions of maxima for 5a–c (lmax = 330–333 nm) motivated us to reject alternative tautomeric form EK'.Because of the presence of carbonyl signals in the 13C NMR spectra, the bicyclic tautomers, enamine EB and imine IB (Scheme 2), can be ruled out as significant contributors. In the above reaction with 1,3-ketoaldehyde 2b, 1,2-hydroxyaminooxime 10,16 a precursor of 1,2-bishydroxylamines, afforded 2,5-dihydroimidazole derivative 11.The 1H and 13C NMR spectra of 11 in [2H6]DMSO indicated that this compound is a mixture of two tautomers 11A and 11B in the ratio ~10:1 (Scheme 3).The conjugation in a diazadiene fragment of 4H-imidazole 11B seems to be less favourable than the formation of tautomer 11A possessing an exocyclic double bond. Sterically hindered 2-acylmethylene-1-hydroxyimidazolidines 5c,e,g are of interest as possible chelating ligands for the preparation of transition metal complexes with abnormal magnetic properties.We have found that the oxidation of 5c by PbO2 leads to an unstable paramagnetic compound. According to the † Typical condensation procedure: a solution of 15 mmol of 1,3-ketoaldehyde 2a–c in 10 ml of glacial AcOH (for 2b) or in 10 ml of methanol (for 2a,c) was added dropwise to a solution of 10 mmol of 1,2-bishydroxylamine 1a,b,3(a)c3(b) in 10 ml AcOH or 10 ml MeOH containing ~25 mmol of HCl (2.08 ml of a concentrated aqueous HCl solution) for 15 min with stirring.The reaction mixture was kept at room temperature for 30–72 h or refluxed for 3–7 h up to the disappearance of starting 1,2-bishydroxylamine and intermediate 1,3-dihydroxyimidazolidine 6 (the reaction was monitored using TLC plates treated by I2 vapour).The solvent was removed in vacuo, the residue was treated with 10 ml of water, and a saturated sodium carbonate solution was carefully added to adjust pH ~8. The mixture was extracted with EtOAc (3×15 ml), and the combined organic layers were dried with anhydrous MgSO4. Evaporation of the EtOAc solution gave a crude product, which was purified by silica gel chromatography (chloroform was the eluent) to yield 2-acylmethylene- 1-hydroxyimidazolidines 5 (30–68% yields). EPR spectrum, this compound has an iminonitroxide moiety (aN1 = 9.2 G, aN2 = 4.6 G), i.e., it is an oxidation product of corresponding tautomeric species KA.At the same time, the reaction of 5g with Ni, Co, Cu and Pd salts followed by oxidation of the resulting chelates with PbO2 yielded stable paramagnetic complexes, in which the energy of exchange interactions between unpaired electrons was ~100 cm–1.17 This study was supported by INTAS (grant no. 94-3508) and the Russian Foundation for Basic Research (grant no. 99-03- 33113). ‡ All new compounds gave satisfactory elemental analysis data and were characterised by UV, IR, 1H NMR and 13C NMR spectroscopy. 5a: 63% yield, mp 198–201 °C (EtOH). 13C NMR (50.32 MHz, [2H6]DMSO) d: 20.2, 21.3, 23.5, 28.9 (4t, CH2), 51.6 (d, C-4), 61.7 (d, C-5), 75.4 (d, CH=), 126.4 (d, Cmeta, Ph), 128.1 (d, Cortho, Ph), 129.9 (d, Cpara, Ph), 140.9 (s, Cipso, Ph), 166.9 (s, C-2), 184.2 (s, C=O). UV [EtOH, lmax/nm (lg e)]: 243 (4.13), 333 (4.44). 5g: 33% yield, mp 208–211 °C (EtOAc–hexane). 13C NMR (50.32 MHz, [2H6]DMSO) d: 17.8 (q, Me), 22.2 (q, Me), 61.2 (s, C-4), 68.7 (s, C-5), 71.5 (d, CH=), 118.2 (q, CF3, 2JC–F ª 280 Hz), 163.8 (s, C-2), 171.0 (q, C=O, 3JC–F ª 30 Hz). 9g: 34% yield, mp 193–194 °C (CHCl3). 13C NMR (50.32 MHz, [2H6]DMSO) d: 22.4 (q, Me), 62.3 (s, C-4 and C-5), 71.5 (d, CH=), 117.5 (q, CF3, 2JC–F ª 280 Hz), 161.9 (s, C-2), 169.4 (q, C=O, 3JC–F ª ª 30 Hz). 11: 32% yield, mp 145–147 °C (EtOAc–hexane). 1H NMR (200.13 MHz, [2H6]DMSO) d; 11A: 1.75 (s, 6H, Me), 6.57 (s, 1H, CH=), 7.49–7.61, 7.93–8.01, 8.56–8.63 (3m, 10H, Ph); 11B, 1.59 (s, 6H, Me), 4.60 (s, 2H, CH2), 7.42–7.63, 8.01–8.08, 8.57–8.62 (3m, 10H, Ph). 13C NMR (50.32 MHz, [2H6]DMSO) d; 11A: 26.1 (q, Me), 64.5 (s, C-5), 77.3 (d, CH=), 125.9 (s, Cipso, Ph), 126.8, 127.7, 128.5, 128.8, 131.4 (5d, Cortho, Cmeta, Cpara, Ph and PhC=O), 139.1 (s, Cipso, PhC=O), 148.5 (s, C-4), 158.2 (s, C-2), 187.4 (s, C=O); 11B: 24.8 (q, Me), 36.4 (t, CH2), 73.8 (s, C-4), 126.2 (s, Cipso, Ph), 126.7, 128.3, 131.0, 133.7 (4d, Cortho, Cmeta, Cpara, Ph and PhC=O), 135.9 (s, Cipso, PhC=O), 153.5 (s, C-5), 162.4 (s, C-2), 193.5 (s, C=O).The assignment of signals due to carbon atoms in the imidazole ring for tautomers 11A and 11B was performed on the basis of literature analogues.10 All spectroscopic data for compounds 5, 8, 9 and 11 will be published elsewhere.§ This species was postulated previously14,15 for 2-acylmethyleneimidazolidines. N N R2 R1 R3 R4 OH R5 O N N R2 R1 R3 R4 OH R5 O H N N R2 R1 R3 R4 OH R5 O H N N R2 R1 R3 R4 O R5 O H H N N R2 R1 R3 R4 H O R5 OH N N R2 R1 R3 R4 O R5 OH KA EK EA EK' EB IB Scheme 2 Ph NOH NHOH O Ph ONa 2b AcOH, room temperature, 72 h NH N Ph O Ph O N N Ph O Ph O Scheme 3 11A 11B 10Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) References 1 D.Lloyd and H. McNab, Adv. Heterocycl. Chem., 1993, 56, 1. 2 C. Barnett, D. R. Marshall and D. Lloyd, J. Chem. Soc. (B), 1968, 1536. 3 (a) D.G.Mazhukin, A. Ya. Tikhonov, L. B. Volodarsky, E. P. Konovalova, L. A. Tikhonova, I. Yu. Bagryanskaya and Yu. V. Gatilov, Izv. Akad. Nauk, Ser. Khim., 1993, 896 (Russ. Chem. Bull., 1993, 42, 851); (b) M. Lamchen and T. W. Mittag, J. Chem. Soc. (C), 1966, 2300. 4 Ya. F. Freimanis, Khimiya enaminoketonov, enaminoiminov, enaminotionov (Chemistry of Enaminoketones, Enaminoimines and Enaminothiones), Zinatne, Riga, 1974, p. 111 (in Russian). 5 Z.-T. Huang and M.-X. Wang, Heterocycles, 1994, 37, 1233. 6 V. A. Makarov and V. G. Granik, Usp. Khim., 1998, 67, 1013 (Russ. Chem. Rev., 1998, 67, 923). 7 V. A. Reznikov and L. B. Volodarsky, Izv. Akad. Nauk, Ser. Khim., 1996, 1789 (Russ. Chem. Bull., 1996, 45, 1699). 8 L. N. Grigor’eva, A. Ya. Tikhonov, V. V. Martin and L. B.Volodarsky, Khim. Geterotsikl. Soedin., 1990, 765 [Chem. Heterocycl. Compd. (Engl. Transl.), 1990, 637]. 9 M. Hojo, R. Masuda, Y. Kokuryo, H. Shioda and S. Matsuo, Chem. Lett., 1976, 499. 10 (a) I. A. Grigor’ev, V. V. Martin, G. I. Schukin, V. I. Mamatyuk and L. B. Volodarsky, Khim. Geterotsikl. Soedin., 1985, 247 [Chem. Heterocycl. Compd. (Engl. Transl.), 1985, 205]; (b) I. A.Grigor’ev, I. A. Kirilyuk and L. B. Volodarsky, Khim. Geterotsikl. Soedin., 1988, 1640 [Chem. Heterocycl. Compd. (Engl. Transl.), 1988, 1355]. 11 L. B. Volodarsky, V. A. Reznikov and V. S. Kobrin, Zh. Org. Khim., 1979, 15, 415 (Russ. J. Org. Chem., 1979, 15, 364). 12 V. A. Reznikov, T. I. Reznikova and L. B. Volodarsky, Zh. Org. Khim., 1982, 18, 2135 (Russ. J. Org. Chem., 1982, 18, 1881). 13 V. V. Martin and L. B. Volodarsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1336 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1980, 29, 956). 14 M. W. Anderson, M. J. Begley, R. C. F. Jones and J. Saunders, J. Chem. Soc., Perkin Trans. 1, 1984, 2599. 15 I. G. Ostroumov, A. E. Tsyl’ko, I. A. Maretina and A. A. Petrov, Zh. Org. Khim., 1988, 24, 1165 (Russ. J. Org. Chem., 1988, 24, 1049). 16 L. B. Volodarsky and A. Ya. Tikhonov, Synthesis, 1986, 704. 17 V. Ovcharenko, I. Korobkov, S. Fokin, A. Burdukov, G. Romanenko, V. Ikorskii, N. Pervukhina, D. Mazhukin and V. Reznikov, Mol. Cryst. Liq. Cryst., 1997, 505, 311. Received: 18th November 1999; Com. 99/1558

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Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) Simple synthesis of anions of closo-monocarbon carborane-substituted alcohols Leonid I. Zakharkin,a Valentina A. Ol’shevskaya,*a Pavel V. Petrovskiia and John H. Morrisb a A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 117813 Moscow, Russian Federation. Fax: + 7 095 135 5085; e-mail: olshevsk@ineos.ac.ru b Department of Pure and Applied Chemistry, Strathclyde University, Glasgow G1 1XL, UK DOI: 10.1070/MC2000v010n02ABEH001242 The anions of closo-monocarbon carborane-substituted alcohols were synthesised in reactions of the caesium salt of the closo- 1-lithium monocarbon carborane anion with aldehydes and propylene oxide.The synthesis of the closo-monocarbon carborane anion HCB11H11 – , which is isoelectronic to the closo-carborane C2B10H12, was reported by Knoth.1 He also demonstrated that HCB11H11 – is readily metallated with BuLi analogously to C2B10H12 in LiCB11H11 – and assumed the existence of the chemistry of C-derivatives of closo-monocarbon carborane anions, which is analogous to the chemistry of neutral C2B10H12 derivatives.This hypothesis was confirmed only in studies2,3 of reactions of LiCB11H11 – with CO2 and S2 and with EtBr, Ph3SiCl, CF3Br, Ph2PCl and PhCH2Cl, resulting in the anions of C-substituted monocarbon carboranes.However, unlike these reagents, in the reaction of LiCB11H11 – with C6F5Br in THF, perfluoroarylation proceeded at boron atoms in the 12- and 7-positions rather than at the carbon atom.3 No explanation for such a ‘dual’ reactivity of LiCB11H11 – was given; in addition, it was never observed for neutral closo-LiCB10H10CH.We studied the reactions of the caesium salt of LiCB11H11 – 1 with other electrophilic reagents (aldehydes and propylene oxide). We found that only previously unknown C-substituted anions of closo-monocarbon carborane alcohols are readily formed in this case according to Scheme 1.† Previously,2,3 C-substituted closo-monocarbon carborane anions were synthesised using only the trimethylammonium salt of closomonocarbon carborane.The reaction of this salt with 2 mol of BuLi in THF resulted in the soluble lithium salt of closo-1- lithium monocarbon carborane LiCB11H11 – Li+. However, this procedure is inconvenient because (i) 2 mol of BuLi is required to obtain LiCB11H11 – Li+ and (ii) Me3N should be removed from † General procedure for the synthesis of alcohols 2a–e and 3.A benzene solution of BuLi (5.25 mmol, 1.18 M) was added to a solution of HCB11H11 – Cs+ (5 mmol) in 15 ml of THF under argon at 10–15 °C with stirring. Compound 1 was immediately formed as a white precipitate. After addition of BuLi, the reaction mixture was stirred for 0.5 h at 20 °C, and a solution of the corresponding aldehyde or propylene oxide (5.25 mmol) in THF (4 ml) was added.The precipitate was dissolved at a temperatrure of no higher than 30 °C. After cessation of the exothermic reaction, the reaction mixture was additionally stirred for 4–5 h at 20 °C. THF was removed in vacuo, water (4 ml) was added to the residue, and the precipitated crystals were filtered off.the reaction mixture after the addition of 1 mol of BuLi and before the addition the second mole of BuLi. The reaction suggested can be considered as a general method for preparation of primary and secondary alcohols of closomonocarbon carborane-substituted anions from aldehydes. Unlike the published data,2,3 the readily available caesium salt of monocarbon carborane (HCB11H11 – Cs+)4 is readily metallated with one mole of BuLi in THF.Though the caesium salt of closo-1- lithium monocarbon carborane is poorly soluble in THF, it easily reacts with aldehydes and propylene oxide to give lithium alcoholates readily soluble in THF. In most cases, treatment of the reaction mixture with water results in crystalline caesium salts of closo-monocarbon carborane-substituted alcohols, which are formed in high yields.If the caesium salt of the reaction product is obtained as viscous oil (2c), its treatment with Me4NBr results in the corresponding crystalline tetramethylammonium salt of the closo-monocarbon carborane-substituted alcohol. The simple preparation method and high yields of the closo-monocarbon carborane alcohols open new possibilities for the use as initial compounds for the synthesis of other functionalised closomonocarbon carborane anions.‡ This work was supported by INTAS (grant no. 96-1114). ‡ All new compounds exhibited satisfactory elemental analysis data, and their structures were confirmed by NMR and IR spectroscopy. 1H NMR spectra were mearsured on a Bruker AMX 400 instrument (400.13 MHz) in (CD3)2CO, standard TMS.IR spectra were mearsured in KBr pellets on a UR-20 spectrometer. [1-Hydroxymethyl-closo-monocarbon carborane]caesium 2a: yield 72%. 1H NMR, d: 3.25 (t, 1H, OH, 3J 6.8 Hz), 3.58 (d, 2H, CH2, 3J 6.8 Hz). IR (n/cm–1): 3461 (OH), 2532 (BH). Found (%): C, 7.96; H, 4.56; B, 38.47. Calc. for C2H14B11CsO (%): C, 7.84; H, 4.57; B, 38.85.[1-(1'-Hydroxy-2'-methyl)propyl]-closo-monocarbon carborane]caesium 2b: yield 78%. 1H NMR, d: 0.83 (d, 3H, Me, 3J 6.8 Hz), 0.87 (d, 3H, Me, 3J 6.8 Hz), 1.91 (m, 1H, CHMe2, 3J 6.8 Hz, 3J 6.8 Hz, 3J 1.6 Hz), 2.56 (d, 1H, OH, 3J 5.2 Hz), 3.56 (dd, 1H, CHOH, 3J 5.2 Hz, 3J 1.6 Hz). IR (n/cm–1): 3459 (OH), 2534 (BH). Found (%): C, 17.51; H, 5.86; B, 33.98.Calc. for C5H20B11CsO (%): C, 17.25; H, 5.75; B, 34.16. [1-(1'-Hydroxybut-2'-enyl)-closo-monocarbon carborane]tetramethylammonium: yield 81%. 1H NMR, d: 1.60 (d, 3H, Me, 3J 4.4 Hz), 2.88 (d, 1H, OH, 3J 3.6 Hz), 3.42 (s, 12H, Me4N), 4.03 (m, 1H, CH), 5.34, 5.39 (m, 2H, CH=CH, 3J 14.4 Hz). IR (n/cm–1): 3457 (OH), 2533 (BH), 1585 (C=C). Found (%): C, 37.49; H, 10.35; N, 4.95.Calc. for C9H30B11NO (%): C, 37.66; H, 10.46; N, 4.88. {1-[1'-Hydroxy(phenyl)methyl]-closo-monocarbon carborane}caesium 2d: yield 77%. 1H NMR, d: 3.62 (d, 1H, OH, 3J 3.6 Hz), 4.80 (d, 1H, CH, 3J 3.6 Hz), 7.14–7.26 (m, 5H, Ph). IR (n/cm–1): 3458 (OH), 2532 (BH). Found (%): C, 25.06; H, 4.90. Calc. for C8H18B11CsO (%): C, 25.14; H, 4.71. {1-[1'-Hydroxy(2-furyl)methyl]-closo-monocarbon carborane}caesium 2e: yield 68%. 1H NMR, d: 3.71 (br. s, 1H, OH), 4.77 (s, 1H, CH), 6.10 (dd, 1H, Hb, 3J 3.2 Hz, 4J 1.2 Hz), 6.76 (dd, 1H, Hb', 3J 3.2 Hz, 3J 2.0 Hz), 7.33 (dd, 1H, Ha', 3J 2.0 Hz, 4J 1.2 Hz). Found (%): C, 19.80; H, 4.48; B, 31.71. Calc. for C6H16B11CsO2 (%): C, 19.36; H, 4.30; B, 31.92. [1-(2'-Hydroxypropyl)-closo-monocarbon carborane]caesium 3: yield 78%. 1H NMR, d: 1.51 (d, 3H, Me, 3J 6.0 Hz), 1.87 (dd, 1H, CHH, 2J 14.8 Hz, 3J 4.4 Hz), 1.94 (dd, 1H, CHH, 2J 14.8 Hz, 3J 6.8 Hz), 2.92 (d, 1H, OH, 3J 3.6 Hz), 3.72 (m, 1H, CH, 3J 6.8 Hz, 3J 6.0 Hz, 3J 4.4 Hz, 3J 3.6 Hz).IR (n/cm–1): 3556 (OH), 2537 (BH). Found (%): C, 14.35; H, 5.31; B, 35.38. Calc. for C4H18B11CsO (%): C, 14.58; H, 5.39; B, 35.59. HCB11H11 – Cs+ + BuLi LiCB11H11 – Cs+ 2a–e a R = H b R = Pri c R =MeCH=CH d R = Ph e R = O THF i, RCHO ii, H2O 1 1 + H2C CH–Me MeCHCH2CB11H11 – Cs+ O OH 3 THF C RCH HO Cs+ Scheme 1Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) References 1 W. H. Knoth, J. Am. Chem. Soc., 1967, 89, 1274. 2 T. Jelínek, J. Ple ek, S. Hermánek and B. tíbr, Collect. Czech. Chem. Commun., 1986, 51, 819. 3 T. Jelínek, P. Baldwin, W. R. Sheidt and C. A. Reed, Inorg. Chem., 1993, 32, 1982. 4 K. Shelly, D. C. Finster, J. Ya. Lee, W. R. Scheidt and C. A. Reed, J. Am. Chem. Soc., 1985, 107, 5955. s S Received: 2nd December 1999; Com. 99/1568

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Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) Regioselectivity of the substitution for the nitro group in 2,4,6-trinitrobenzonitrile under the action of thiols. The synthesis of 4,6-dinitro derivatives of benzoannelated sulfur-containing heterocycles Igor L. Dalinger, Tat’yana I. Cherkasova, Valerian M. Khutoretskii and Svyatoslav A. Shevelev* N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow, Russian Federation.Fax: +7 095 135 5328; e-mail: shevelev@cacr.ioc.ac.ru DOI: 10.1070/MC2000v010n02ABEH001220 Conditions for the regioselective substitution for a nitro group in the ortho-position in 2,4,6-trinitrobenzonitrile under the action of thiols (PhCH2SH, HSCH2CO2Et or PhSH) in the presence of K2CO3 or KOH were found, and the intramolecular cyclization of the ortho-fragments –SX and –CN (X = Cl or CH2CO2Et) was performed to afford 3-chloro-4,6-dinitrobenzo[d]isothiazole and 3-amino- 2-ethoxycarbonyl-4,6-dinitrobenzo[b]thiophene, respectively. We are concerned with the chemistry of primary conversion products of 2,4,6-trinitrotoluene (TNT) in the context of the utilisation of this explosive.1 These products include 2,4,6-trinitrobenzonitrile (TNBN), which can be easily prepared from TNT by the treatment with nitrosyl chloride.2 One of the promising synthetic applications of TNBN is the production of benzo-annelated heterocycles, which can be performed, in particular, by the selective replacement of a nitro group in the orthoposition with a unit capable of intramolecular cyclization with the nitrile group.We found that in the reaction of TNBN with PhCH2SH in the presence of K2CO3 both ortho and para nitro groups were replaced with the PhCH2S unit: an isomer mixture of ortho and para sulfides 1a and 1b was formed, the ratio between which depends on the polarity of the solvent (Scheme 1, i). It can be seen that the fraction of ortho substitution considerably increased with decreasing polarity of solvents in the order aqueous DMF, MeCN and PhMe (Scheme 1, i, i1–i3).We used a mixture (5:1) of ortho and para isomers 1a and 1b prepared in a medium of PhMe for the intramolecular cyclization starting from 1a (via 2a). It is well known that the ArS– CH2Ph bond is easily cleaved under the action of chlorinating agents to form ArSCl.3 It is also known that spontaneous intramolecular cyclization with the formation of 3-chlorobenzo[d]- isothiazoles proceeds in the presence of CN and SCl units in the ortho position.4 Indeed, 3-chloro-4,6-dinitrobenzo[d]isothiazole 3 (Scheme 1, ii) was prepared by the treatment of the above mixture of sulfides 1a and 1b with SO2Cl2.The substitution for the para nitro group was not observed in the reaction of HSCH2CO2Et with TNBN (in the presence of KOH in aqueous acetonitrile); 3-amino-2-ethoxycarbonyl-4,6- dinitrobenzo[b]thiophene 5, a representative of previously unknown 4,6-dinitrobenzo[b]thiophenes (Scheme 1, iii), was the only reaction product.According to published data,5 benzothiophene 5 is formed by base-catalysed intramolecular cyclization of ortho-substitution product 4a (Scheme 1, iii).A representative of aromatic thiols, PhSH, reacting with TNBN (in the presence of K2CO3) in aqueous DMF gives a mixture of isomer ortho and para sulfides 6a and 6b (Scheme 1, iv, iv1). However, the reaction proceeds regiospecifically in a toluene medium: only a nitro group in the ortho position of TNBN is replaced, and the only product, ortho-sulfide 6a, is formed in high yield (Scheme 1, iv, iv2).The identity of the individual products or isomer mixtures obtained was supported by 1H and 13C NMR spectroscopy, mass spectrometry, IR spectroscopy and elemental analysis. The yields in Scheme 1 are specified for isolated individual products or purified isomer mixtures. At the same time, the ratio between ortho and para isomers (1H NMR data) is given for isolated crude reaction products.In all cases, the reaction was performed until the complete conversion of TNBN.† † 1H NMR spectra were recorded on a Bruker AM-300 spectrometer, solvent [2H6]DMSO. 3: mp 200–202 °C (PriOH). 1H NMR, d: 8.9 (s, 1H, H7), 9.1 (s, 1H, H5). 13C NMR, d: 112.18, 112.73, 120.21, 129.30, 144.95, 149.42, 150.37. 5: mp 200 °C (PriOH). 1H NMR, d: 1.3 (t, 3H, OEt), 4.3 (qw, 2H, OEt), 6.6 (br. s, 2H, NH2), 8.7 (s, 1H, H7), 9.4 (s, 1H, H5). 13C NMR, d: 14.22, 61.25, 105.79, 116.89, 124.06, 124.93, 125.45, 141.62, 144.90, 145.89, 163.65. 6a: mp 110–112 °C (PriOH). 1H NMR, d: 7.7 (m, 5H, Ph), 8.0 (s, 1H, H3), 8.7 (s, 1H, H5). Scheme 1 Reagents, conditions and results: i, 1 equiv. PhCH2SH + 1.8 equiv.K2CO3; i1, DMF/H2O (4:1, v/v; 0.42 M PhCH2SH), 0–2 °C, 3 h, 91% yield of 1a + 1b, 1a:1b = 2:1; i2, MeCN (0.42 M PhCH2SH), 80 °C (boiling), 3 h, 90% yield of 1a + 1b, 1a:1b = 3:1; i3, toluene (0.25 M PhCH2SH), 110 °C (boiling), 8 h, 40% yield of 1a + 1b, 1a:1b = 5:1; ii, 1a:1b = 5:1, 7 equiv. SO2Cl2/DCE, boiling, 8 h, 50% yield of 3 (in terms of 1a); iii, 1 equiv. HSCH2CO2Et + 1.8 equiv.KOH, MeCN/H2O (4:1, v/v, 0.42 M HSCH2CO2Et), 0 °C, 0.5 h, 20 °C, 3 h, 54% yield of 5; iv, 1 equiv. PhSH + 1.8 equiv. K2CO3; iv1, DMF/H2O (4:1, v/v; 0.42 M PhSH) 0–2 °C, 3 h, 76% yield of 6a + 6b, 6a:6b = 2:1; iv2, toluene, (0.25 M PhSH), 110 °C (boiling), 4 h, 80% yield of 6a. O2N NO2 NO2 CN TNBN O2N SCH2Ph NO2 CN 1a O2N NO2 SCH2Ph CN 1b i O2N SCl NO2 CN 2a 1a ii NO2 O2N S N 3 O2N SCH2 CO2Et NO2 CN 4a Cl NO2 O2N S 5 NH2 CO2Et O2N SPh NO2 CN 6a O2N NO2 SPh CN 6b TNBN iv iiiMendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) This work was supported by the International Science and Technology Centre (ISTC) (grant no. 419). References 1 V. A. Tartakovsky, S. A. Shevelev, M. D. Dutov, A. Kh. Shakhnes, A. L. Rusanov, L. G. Komarova and A. M. Andrievsky, in Conversion Concepts for Commercial Applications and Disposal Technologies of Energetic Systems, ed. H. Krause, Kluwer Academic Publishers, Dordrecht, 1997, p. 137. 2 M. E. Sitzman and J. C. Dacons, J. Org. Chem., 1973, 38, 4363. 3 (a) D. M. Tink and J. T. Strupczewski, Tetrahedron Lett., 1993, 34, 6525; (b) N. Kharasch and R. B. Langford, J. Org. Chem., 1963, 28, 1903. 4 J. R. Beck and J. A. Yahner, J. Org. Chem., 1978, 43, 1604. 5 J. R. Beck, J. Org. Chem., 1972, 37, 3224. Received: 2nd November 1999; Com. 99/1548

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Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) The benzylidenefluorene dianion Dmitrii M. Roitershtein,*a,b Mikhail E. Minyaev,b Pavel A. Belyakovb and Eduard S. Petrova a L. Ya. Karpov Institute of Physical Chemistry, 103064 Moscow, Russian Federation. Fax: +7 095 975 2450 b Higher Chemical College, Russian Academy of Sciences, 125047 Moscow, Russian Federation. Fax: +7 095 135 5343; e-mail: roiter@hcc.keldysh.ru DOI: 10.1070/MC2000v010n02ABEH001099 The interaction of benzylidenefluorene with alkali metals in THF solutions results in the formation of the benzylidenefluorene dianion or the 1,2-bis(9-fluorenyl)-1,2-diphenylethane dianion depending on the nature of the alkali metal.Aryl-substituted olefins and polycyclic aromatic hydrocarbons undergo reduction to form dianions1–3 or even tri- and tetraanions. 2–5 The studies in this field were primarily concerned with symmetrically substituted olefins;6–11 little information is availaible about unsymmetrically substituted vinylarenes.12 Earlier, we have reported on the synthesis of organolanthanide complexes using hydrocarbon dianions as ligands.13–15 To extend the range of dianions, we have examined the two-electron reduction of benzylidenefluorene, a trisubstituted vinylarene, which can be synthesised from fluorene and benzaldehyde.16,17 However, the possibility of selective reduction of benzylidenefluorene to its dianion under the treatment with alkali metals is questionable because of the well-known ability of unsymmetrically substituted vinylarenes to form dimers under the action of alkali metals.1 Moreover, Schlenk and Bergmann18 found that the interaction of benzylidenefluorene with sodium in diethyl ether followed by hydrolysis of the reaction mixture leads to 1,2-bis- (9-fluorenyl)-1,2-diphenylethane. Therefore, the treatment of benzylidenefluorene by sodium in diethyl ether leads to dimerization of the benzylidenefluorene radical ion instead of formation of the dianion.We report here on the reaction of benzylidenefluorene 1 with alkali metals in THF solutions resulting in formation of the benzylidenefluorene dianion or the 1,2-bis(9-fluorenyl)-1,2-diphenylethane dianion depending on the nature of the alkali metal. The behaviour of the benzylidenefluorene dianion in a THF solution was examined by NMR spectroscopy.The reaction of 1 with potassium in a THF solution leads to the formation of the benzilydenefluorene dianion. A colourless solution of benzilydenefluorene placed in the Schlenk vessel† containing a potassium mirror immediately turned orange-brown (lmax = 428 nm). The keeping of the solution over the potassium surface at ambient temperature for 48 h with occasional stirring resulted in the quantitative formation of dipotassium benzylidenefluorene 2.The quenching of the dianion solution by H2O or D2O resulted in the formation of 9-benzylfluorene 319 or 9,10-dideuterio- 9-benzylfluorene 4.‡ Therefore, the use of potassium/THF instead of sodium/diethyl ether allowed us to obtain the benzylidenefluorene dianion and to avoid dimerization of the initially formed radical ion.Nevertheless, the reduction of benzylidenefluorene by sodium or lithium metal in a THF solution (using a † All experiments were carried out in evacuated and sealed vessels like the Schlenk tubes. In the typical experiment, 1.053 g (4.14 mmol) of 1 was dissolved in 70 ml of absolute THF and allowed to react with a potassium mirror prepared from 0.500 g (12.8 mmol, 3-fold excess) of potassium. To prepare NMR samples, 7 mg scale experiments were performed in 0.5 ml of [2H8]THF.sodium mirror or a lithium suspension) led to another result. A slightly coloured precipitate and an intensely coloured solution were formed in both cases. The subsequent hydrolysis of the reaction mixture resulted in the formation of 1,2-bis(9-fluorenyl)- 1,2-diphenylethane 5 in 86 (sodium) or 64% (lithium) isolated yield.§ The 1H NMR spectrum of 2 exhibits nine resonance signals due to aromatic protons (Figure 1).¶ The 2D 1H–1H correlation and NOE between H10–H16 and H10–H1 allowed us to assign the 1H NMR signals.The 3JHH constants were calculated using the ‡ 3: mp 130–131 °C (lit.,19 130–131 °C). 1H NMR (250 MHz, CDCl3) d: 3.13 (d, 2H), 4.25 (t, 1H), 7.15–7.40 (mm, 11H), 7.75 (m, 2H). 4: mp 131–133 °C. 1H NMR (250 MHz, CDCl3) d: 3.13 (br. s, 1H, n1/2 12 Hz), 7.15–7.40 (mm, 11H), 7.78 (m, 2H). 13C {1H} NMR (75 MHz, CDCl3) d: 39.7 (t), 48.7 (t), 119.9, 124.9, 126.4, 126.7, 127.2, 128.3, 129.6, 139.8, 140.9, 146.8. MS (EI, 70 eV, 250 °C) m/z (%): 259 (11) [M + 1], 258 (59) [M], 257 (44) [M – 1], 167 (47), 166 (100), 165 (70), 164 (17), 92 (42), 91 (8), 44 (18), 43 (68), 40 (30), 39 (11).§ A solution of 0.226 g (0.89 mmol) of 1 in 20 ml of THF was stirred over a sodium mirror for 36 h. A reddish orange precipitate was formed. The precipitate was hydrolysed with 4 ml of degassed water. The reaction with lithium powder was carried out in a similar way. The standard procedure gave 0.196 g (86%) of 5, mp 336–337 °C (lit.,18 mp 321 °C). 1H NMR (500 MHz, CD2Cl2) d: 4.03 (br. s, 2H, n1/2 3.8 Hz), 4.66 (br. s, 2H, n1/2 3.8Hz), 6.88–6.975 (m, 10H), 7.21 (t, 2H), 7.28–7.38 (m, 6H), 7.40 (d, 2H), 7.47 (d, 2H), 7.70 (d, 2H), 7.87 (d, 2H). 13C {1H} NMR (75.5 MHz, CD2Cl2) d: 50.0, 52.7, 119.7, 120.1, 124.7, 126.3, 126.6, 126.8, 127.0, 127.2, 127.5, 127.6, 138.2, 141.2, 142.5, 144.6, 147.2.MS (EI, 70 eV, 250 °C) m/z (%): 510 (1.4) [M+], 345 (4), 331 (8), 330 (23), 253 (6), 180 (26), 179 (7), 178 (5), 167 (6), 166 (54), 165 (100), 164 (11), 163 (6), 115 (4), 91 (10), 57 (6). ¶ 2: 1H NMR (500 MHz, [2H8]THF) d: 4.40 (H10), 4.82 (H14, 3JH14H15 7.1 Hz), 5.29 (H12, 3JH12H13 7.9 Hz), 6.11 (H15, 3JH15H16 8.1 Hz), 6.15 (H16), 6.30 (H13, 3JH13H14 7.1 Hz), 6.41 (H3, H6, 3JH3H4 7.4 Hz), 6.94 (H2, H7, 3JH2H3 7.2 Hz), 7.04 (H1, H8, 3JH1H2 8.1 Hz), 8.00 (H4, H5). 13C {1H} NMR (100 MHz, [2H8]THF) d: 31.8 (C9), 66.5 (C10, JC10H10 142.8 Hz), 97.2 (C14, JC14H14 158.4 Hz), 100.1 (Cquatern), 108.5 (C3), 108.8 (C12, JC12H12 149.7 Hz), 117.3 (C1), 117.9 (C15), 120.5 (C2, C4, JC4H4 149.1 Hz), 124.4 (Cquatern), 129.6 (C16), 132.0 (C13), 132.9 (Cquatern), 146.1 (Cquatern) (the assignments were made using DEPT and CW-decoupling experiments). 2– K THF X2O X X 1 2 3 X = H 4 X = D K2 + M+ M THF M+2 H2O M = Li, Na 5Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) CALM program. A comparison between the simulated and experimental spectra (Figure 1) confirm the rigidity of the dianion in a THF solution. Because all protons of the phenyl group in 2 are nonequivalent on the NMR time scale, we have to suppose that this phenomenon resulted from the inability of a phenyl ring to rotate at room temperature; thus, the ortho- and meta-protons are distinguishable. The 13C NMR spectrum of 2¶ is also consistent with this hypothesis; there are 14 separated resonance signals in the spectrum.Six resonance signals correspond to the phenyl group.A comparison of the 13C NMR data for 2¶ with the corresponding data for 1†† (all spectra were recorded in the same solvent to exclude the influence of specific solvatation on the chemical shifts) indicates that the most significant difference between the chemical shifts of the resonance signals of corresponding carbon atoms in 1 and 2 was observed for C-9 and C-10 carbon atoms.This observation allowed us to suppose that an excessive electron density is significantly localised at the ‘former double bond’ carbon atoms that is rather common for the dianions of vinylarenes.1,2 A significant difference in the chemical shifts of ortho-, meta- and para-carbons and protons of the phenyl group should be mentioned. At the same time, the chemical shifts of protons of the fluorenyl moiety of the dianion are in a good agreement with those found for fluorenyl derivatives of alkali metals.20,21 The strong upfield shift of C(H)-14 in both 13C and 1H NMR spectra is of most interest. A significant impact of a quinoid resonance structure of the benzyl fragment of the dianion can be an explanation for this phenomenon.This speculation is also consistent with the absence of free rotation of the phenyl ring and with a considerable difference in the 13C chemical shifts of C-9 and C-10 carbons.The latter is downfield shifted by more than 30 ppm in comparison with the †† 1: 1H NMR (300 MHz, [2H8]THF) d: 7.09 (t, 1H), 7.20–7.55 (mm, 6H), 7.65 (m, 3H), 7.82 (m, 3H), 7.91 (d, 1H). 13C {1H} NMR (75 MHz, [2H8]THF) d: 120.2, 120.4, 121.1, 125.1, 127.3, 127.7, 128.09, 128.11, 128.8, 128.9, 129.3, 130.0, 137.4, 137.5, 138.1, 140.2, 140.5, 142.3.C-9 signal; this can be interpreted as the consequence of a significant impact of the quinoid resonance structure. To investigate the dynamics of this system, we performed high-temperature NMR experiments. Suprisingly, no changes in the 1H NMR spectrum of 2 were found up to 333 K.This fact indicates that the rigid structure of 2 in a [2H8]THF solution remains unchanged even at elevated temperatures; therefore, no rotation of the phenyl ring can be observed. This observation is inconsistent with the behaviour of the more sterically hindered tetraphenylethylene dianion in solution, where equivalent phenyl protons were detected even at room temperature.15 Similar phenomena were observed earlier in dilithium 1-phenyl-1,2,2-tris- (trimethylsilyl)ethylene, where the rotation of phenyl group was also frozen at room temperature.12 Unfortunately, high-temperature NMR spectra were not measured for this compound.We thank Dr. Yu. A. Strelenko for helpful discussions of the NMR data. This work was supported by the Russian Foundation for Basic Research (grant nos. 96-03-34237 and 96-03-33313). References 1 M. Szwarc, Carbanions. Living Polymer and Electron Transfer Processes, Interscience, New York, 1968. 2 R. B. Bates, in Studies in Organic Chemistry, eds. E. Buncel and T. Durst, Elsevier, Amsterdam, 1980, vol. 5, p. 1. 3 H. Bock, K. Ruppert, C. Nather, Z. Havlas, H.-F. Herrmann, C.Arad, I. Gobel, A. John, J. Meuret, S. Nick, A. Rauschenbach, W. Seitz, T. Vaupel and B. Solouki, Angew. Chem., Int. Ed. Engl., 1992, 31, 550. 4 H. Bock, K. Gharagozloo-Hubmann, C. Nather, N. Nagel and Z. Havlas, Angew. Chem., Int. Ed. Engl., 1996, 35, 631. 5 H. Bock, Z. Havlas, D. Hess and C. Nather, Angew. Chem., Int. Ed. Engl., 1998, 37, 502. 6 A. Sekiguchi, M. Ichinohe, M. Takahashi, C.Kabuto and H. Sakurai, Angew. Chem., Int. Ed. Engl., 1997, 36, 1533. 7 M. Walczak and G. Stucky, J. Am. Chem. Soc., 1976, 98, 5531. 8 A. Sekiguchi, T. Nakanishi, Ch. Kabuto and H. Sakurai, J. Am. Chem. Soc., 1989, 111, 3748. 9 Yu. Yokoyama, O. Kikuchi, T. Koizumi and K. Takahashi, Chem. Lett., 1994, 411. 10 H. Bock, K. Ruppert and D. Fenske, Angew. Chem., Int. Ed. Engl., 1989, 28, 1685. 11 H. Bock, T. Hauck and C. Nather, Organometallics, 1996, 15, 1527. 12 A. Sekiguchi, M. Ichinohe, T. Nakanishi, C. Kabuto and H. Sakurai, Bull. Chem. Soc. Jpn., 1995, 68, 3215. 13 D. M. Roitershtein, A. M. Ellern, M. Yu. Antipin, L. F. Rybakova, Yu. T. Struchkov and E. S. Petrov, Mendeleev Commun., 1992, 118. 14 D. M. Roitershtein, L. F. Rybakova, E. S. Petrov, A. M. Ellern, M. Yu. Antipin and Yu. T. Struchkov, J. Organomet. Chem., 1993, 460, 39. 15 D. M. Roitershtein, J. W. Ziller and W. J. Evans, J. Am. Chem. Soc., 1998, 120, 11342. 16 J. Thiele and F. Henle, Liebigs Ann. Chem., 1906, 347, 290. 17 J. Thiele, Chem. Ber., 1900, 33, 851. 18 W. Schlenk and E. Bergmann, Liebigs Ann. Chem., 1928, 463, 1. 19 D. Lavie and E. D. Bergmann, Bull. Soc. Chim. Fr., 1951, 18, 250. 20 J. A. Dixon, P. A. Gwinner and D. C. Lini, J. Am. Chem. Soc., 1965, 87, 1379. 21 J. J. Brooks, W. Rhine and G. D. Stucky, J. Am. Chem. Soc., 1972, 94, 7339. 8.0 7.0 6.0 5.0 d/ppm 4 1 2 3 13 16 15 12 14 10 16 2– 1 2 3 4 4a 4b 5 6 7 8 8a 9 9a 10 11 12 13 14 15 16 Figure 1 Calculated (top) and experimental (bottom) 1H NMR (500 MHz) spectra of 2. Received: 15th January 1999; Com. 99/1427

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Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) Reaction between phthalonitrile and phenylacetonitrile Vladimir Yu. Orlov,* Alexander D. Kotov and Nikolay A. Budanov Department of Biology and Ecology, P. G. Demidov Yaroslavl State University, 150000 Yaroslavl, Russian Federation. E-mail: orl@bio.uniyar.ac.ru DOI: 10.1070/MC2000v010n02ABEH001213 The title reaction performed in the DMSO–NaOH system resulted in the formation of 2,3-diphenyl-2,3-(2'-cyanophenyl)butanedioic acid diamide, which was selectively hydrolysed to 2,3-diphenyl-2,3-(2'-cyanophenyl)butanedioic acid.Aromatic nitriles are widely used as synthetic intermediates and monomers for preparing polymer materials, organic dyes, etc. Nucleophilic substitution is an effective method for the functionalization of arenes containing electron-withdrawing substituents. 1 The CN-activated aromatic nucleophilic substitution for halogens or a nitro group2–4 and nucleophilic substitution for hydrogen in highly activated arenes5,6 are well known. However, little is known about this type of functionalization in cyanoarenes. Vicarious nucleophilic substitution for hydrogen in dicyanonaphthalene was reported.7 Previously,8 we performed the oxidative nucleophilic substitution of the phenylacetonitrile carbanion for hydrogen in benzonitrile in the DMSO–NaOH system to form a,a-bis(2-cyanophenyl)phenylacetamide.Roze et al.9 examined nucleophilic substitution in 4-nitrophthalonitrile by dimedone and reported the uncommon replacement of the CN group. The interaction of phthalonitrile with phenylacetonitrile in DMSO–NaOH resulted in the formation of a compound that decomposed at about 200 °C.The IR spectrum of this compound exhibited absorption bands due to nitrile and amido groups (nCºN 2202 cm–1, nN–H 3350 cm–1 and nC=O 1620 cm–1). In the region 2000–1700 cm–1, the absorption pattern corresponds to overlapping bands of mono- and disubstituted benzene rings. Figure 1 demonstrates the 1H NMR spectrum of the isolated compound.The 13C NMR spectrum exhibits signals due to a quaternary carbon atom (50 ppm) and carbon atoms of nitrile (121.36 ppm) and amido (170 ppm) groups and an aromatic ring (122.2–140.56 ppm). The mass spectrum of the compound exhibits peaks with m/z of 246, 219, 190 and 122. An analysis of the spectroscopic data allowed us to propose the following reaction scheme:† The reaction can be explained as nucleophilic substitution for a CN group in phthalonitrile, dimerization of the intermediate and formation of 2,3-diphenyl-2,3-bis(2'-cyanophenyl)butanedioic acid diamide 1.The above diamide was selectively hydrolysed to 2,3-diphenyl- 2,3-bis(2'-cyanophenyl)butanedioic acid 2 (Figure 2) by boiling in acetic acid according to the following reaction:‡ References 1 F.Terrier, Nucleophilic Aromatic Displacement: The Influence of the Nitro Group, VCH, New York, 1991, ch. 1 and 3. 2 P. S. Kaninskii, I. G. Abramov, O. A. Yasinskii, G. S. Mironov and V. V. Plahtinskii, Zh. Org. Khim., 1992, 28, 1232 (Russ. J. Org. Chem., 1992, 28, 964). † 1H NMR spectra were recorded on a Bruker AM-300 spectrometer at 300 MHz in [2H6]DMSO, 13C NMR spectra were recorded on a BS567 spectrometer at 25 MHz in [2H6]DMSO, IR spectra were measured on a Specord M-80 instrument in Vaseline oil.Synthesis of 1: sodium hydroxide, phenylacetonitrile and phthalonitrile (in the ratio 10:2:1.5) were added to DMSO, and the mixture was intensely stirred at 80–85 °C for 6 h.On completion of the reaction, the reaction mixture was transferred into cold water, and the precipitate was filtered off and washed with water, ethanol and diethyl ether. Yield 80% after recrystallization from toluene–ethanol (1:1), mp 200 °C (decomp.). IR (n/cm–1): 2202 (CºN) and 3345 (N–H). MS, m/z (%): 246 (100), 219 (40), 190 (45), 122 (55). Found (%): C, 76.36; H, 4.84; N, 12.23.Calc. for C30H22N4O2 (%): C, 76.58; H, 4.71; N, 11.91. ‡ Synthesis of 2: a solution of 1 was boiled in acetic acid for 6 h. The precipitate formed after cooling the reaction mixture was filtered off, washed with ethanol and dried. Yield 50%, mp 230–232 °C. IR (n/cm–1): 3220 (O–H), 1724 (C=O), 2208 (CºN). Found (%): C, 76.39; H, 4.43; N, 6.11. Calc. for C30H20N2O4 (%): C, 76.26; H, 4.27; N, 5.93. 8.0 7.0 6.0 5.0 4.0 3.0 8.5 8.0 7.5 d/ppm d/ppm Figure 1 1H NMR spectrum of 1. CN CN N N C C Ph O H2N Ph N O NH2 DMSO NaOH 1 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 d/ppm Figure 2 1H NMR spectrum of 2. N C C Ph O H2N Ph N O NH2 N C C Ph O HO Ph N O OH AcOH 1 2Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) 3 V. V. Plahtinskii, I.G. Abramov, P. S. Kaninskii, O. A. Yasinskii and G. S. Mironov, Kinet. Katal., 1993, 34, 993 [Kinet. Catal. (Engl. Transl.), 1993, 34, 890]. 4 V. V. Bardin, O. N. Logunova and G. G. Furin, Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, 1988, 2, 77 (in Russian). 5 M. Makosza and J. Winiarski, Acc. Chem. Res., 1987, 8, 282. 6 O. N. Chupakhin, V. N. Charushin and H. C. van der Plas, Nucleophilic Aromatic Substitution of Hydrogen, Academic Press, San Diego, 1994, ch. 2. 7 M.Makosza, Chem. Lett., 1987, 1, 61. 8 V. V. Kopeykin, V. Yu. Orlov and A. D. Kotov, Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 1992, 11–12, 27 (in Russian). 9 M. Roze, E. Berzinsh and O. Neiland, Zh. Org. Khim., 1987, 23, 2629 [J. Org. Chem. USSR (Engl. Transl.), 1987, 23, 2322]. Received: 18th October 1999; Com. 99/1541

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Mendeleev Communications Electronic Version, Issue 2, 2000 (pp. 43–82) A new method for synthesis of 6-aryl-2H-thiopyran-2-thiones Denis V. Kozhinov, Sergei A. Woznesensky, Arkadii A. Dudinov* and Mikhail M. Krayushkin N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow, Russian Federation. Fax: +7 095 135 5328; e-mail: mkray@cacr.ioc.ac.ru DOI: 10.1070/MC2000v010n02ABEH001256 A simple and convenient method for the synthesis of 6-aryl-2H-thiopyran-2-thiones by the interaction of 1-aryl-5,5-dichloropenta- 2,4-dienones with thiourea in acidic media is reported.Thiopyranthiones 1 can be used as intermediates for the synthesis of polynitrogen-containing heterocyclic systems.1 Several methods for the preparation of 2H-thiopyran-2-thiones are described in the literature but most of them involve the use of difficultly available or toxic starting materials.Thus, a method for the preparation of 6-substituted or 3,6-disubstituted 2H-thiopyran- 2-thiones from aryl aminovinyl thioketones and ketenes followed by treatment of the resulting thiopyrans with phosphorus pentasulfide has been reported.2 3,5-Disubstituted 2Hthiopyran- 2-thiones have been obtained by reaction of enamines bearing aliphatic or aromatic substituents with carbon disulfide.3 3-Acyl- or 3,6-diaryl-2H-thiopyran-2-thiones have been obtained by the action of dithiol-1,2-ylium salts on methyl 2-aroyl (or 2-acyl) dithioacetates.4 In this paper, we report a simple and convenient method for the synthesis of 6-aryl-2H-thiopyran-2-thiones 1 by the interaction of 1-aryl-5,5-dichloropenta-2,4-dienones 2† with thiourea in acidic media.‡ This method facilitates significantly the synthesis of the target compounds as the starting compounds have been obtained from readily available methyl aryl ketones and dichloroacrolein (or its monochloroacetals).The latter are formed by the radical addition of CCl4 to vinyl ethers.5–6 Compounds 1 are formed on heating compounds 2 and thiourea in ethanol in the presence of hydrochloric acid. 5,6-Dihydro- 2H-benzo[h]thiochromen-2-thione 3 was prepared in the same manner from 2-(3,3-dichloro-2-propenylidene)-1,2,3,4-tetrahydronaphthalen- 1-one. The structures of the obtained com- † 1-(3,4-Methylenedioxyphenyl)-5,5-dichloropenta-2,4-dienone 2f was obtained as described previously;5 mp 134–135 °C, yield 56%.Found (%): C, 53.11; H, 2.83; Cl, 26.00. Calc. for C12H8Cl2O3 (%): C, 53.17; H, 2.97; Cl, 26.15. ‡ General procedure for the preparation of 6-aryl-2H-thiopyrane-2- thiones 1. A mixture of compound 2 (4 mmol), thiourea (10–20 mmol) and conc. HCl (0.4 ml) in 10 ml of ethanol was refluxed for 6–7 h. The resulting solution was kept overnight and the residue was filtered off and recrystallised from ethanol.In some cases, the mother liquor was evaporated, and the residue was chromatographed (silica gel; eluent: ethyl acetate–hexane, 1:1). pounds were confirmed by 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis data.§ The probable pathway of the reaction involves the replacement of one or two chlorine atoms of the dichlorovinyl moiety giving mercapto derivatives or isothiuronium salts.Next, cyclization proceeds in a similar manner as in the formation of 6-aryl-2H-pyran-2-ones from compounds 2.6 References 1 M. Alajarin, R. Molina and A. Soler, An. Quim., Ser. C, 1980, 76 (3), 207 (Chem. Abstr., 1981, 94, 192239v). 2 J. C. Meslin, Y. T. N’Guessan, H. Quiniou and F.Tonnard, Tetrahedron, 1975, 31, 2679. 3 R. Mayer, G. Laban and M. Wirth, Liebigs Ann. Chem., 1967, 703, 140. 4 F. Clesse, J.-P. Pradere and H. Quiniou, Bull. Soc. Chim. Fr., 1973, 2, 586. 5 L. P. Sorokina and L. I. Zakharkin, Izv. Akad. Nauk SSSR, Ser. Khim., 1964, 73 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1964, 13, 62). 6 L. P. Sorokina and L. I. Zakharkin, Izv. Akad. Nauk SSSR, Otd.Khim. Nauk, 1958, 1445 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1958, 7, 1393). § The NMR spectra were recorded on Bruker WM-250 and Bruker AM-300 instruments in [2H6]DMSO solutions. 1a: mp 66–67 °C (lit.,2 mp 66–68 °C), yield 27%. 1H NMR, d: 7.5 (m, 5H), 7.7 (m, 3H). 1b: mp 111–112 °C (lit.,2 mp 110–111 °C), yield 35%. 1H NMR, d: 7.1 (d, 2H), 7.42 (dd, 2H), 7.62 (dd, 3H). 13C NMR, d: 121.6 [C(3)], 128 (CAr-meta), 129.3 (CAr-ortho), 133 (CAr-ipso), 135.6 [C(4)], 135.7 (CAr-para), 136.5 [C(5)], 154.8 [C(6)], 203.9 [C(2), C=S]. MS, m/z: 238 [M+]. 1c: mp 78–79 °C (lit.,2 mp 79–81 °C), yield 27%. 1H NMR, d: 2.4 (s, 3H, Me), 7.17 (dd, 1H), 7.27 (dd, 3H), 7.45 (dd, 3H). 1d: mp 68–69 °C (lit.,2 mp 67–68 °C), yield 32%. 1H NMR, d: 3.8 (s, 3H, OMe), 7.1 (d, 2H), 7.45 (m, 2H), 7.6 (d, 1H), 7.75 (d, 2H). 13C NMR, d: 114.1 (CAr-meta), 120.3 [C(3)], 127 (CAr-ipso), 128.1 (CAr-ortho), 135.7 [C(4)], 136.5 [C(5)], 157.2 [C(6)], 161.7 (CAr-para), 203.6 [C(2), C=S]. MS, m/z: 234 [M+]. 1e: mp 106–108 °C, yield 12%. 1H NMR, d: 7.5 (m, 3H), 7.75 (m, 3H), 7.95 (s, 1H). MS, m/z: 282, 284 [M+]. 1f: mp 185–186 °C, yield 38%. 1H NMR, d: 6.1 (s, 2H, CH2), 7.05 (d, 1H), 7.2 (d, 1H), 7.3 (s, 1H), 7.4 (dd, 2H), 7.6 (d, 1H). MS, m/z: 248 [M+]. 3: mp 110–111 °C, yield 71%. 1H NMR, d: 2.85 (m, 4H), 7.4 (m, 5H), 7.65 (d, 1H). Found (%): C, 67.70; H, 4.39; S, 27.28. Calc. for C13H10S2 (%): C, 67.79; H, 4.38; S, 27.84. OAlk OAlk Cl Cl3C OAlk Cl Cl2C – AlkCl H O Cl2C COMe R CCl2 O R (H2N)2C=S H+ 2a–f R S S 1a–f a R = H b R = p-Cl c R = p-Me d R = p-OMe e R = m-Br f R = 3,4-OCH2O CCl4 Received: 27th December 1999; Com. 99/1582

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