Mendeleev Communications Electronic Version, Issue 1, 2001 (pp. 1.42) Intermolecular and intramolecular cycloaddition reactions of 1-ethyl-1,2,4-triazinium salts with alkynes Nataliya N. Mochulskaya, Anatoly A. Andreiko, Valery N. Charushin,* Boris V. Shulgin, Dmitry V. Raikov and Vladimir I. Solomonov Department of Organic Chemistry, Urals State Technical University, 620002 Ekaterinburg, Russian Federation.Fax: +7 3432 74 0458; e-mail: charushin@prm.uran.ru 10.1070/MC2001v011n01ABEH001370 Azomethyne ylides generated from 3-alkylthio substituted 1-alkyl-5-aryl-1,2,4-triazinium salts 4a.c on treatment with triethylamine undergo 1,3-dipolar cycloaddition with dimethyl acetylenedicarboxylate to give pyrrolo[2,1-f ][1,2,4]triazines, while 1-ethyl-5- phenyl-1,2,4-triazinium salts 1a,b bearing the C��C bond in the side-chain 3-alkynylthio substituent react with acetylenes to undergo either intermolecular 1,3-dipolar cycloaddition or intramolecular inverse electron demand Diels.Alder reactions.Inverse electron demand Diels.Alder reactions of ¥�-deficient azaaromatics is a powerful synthetic methodology.1 N-Alkyl-1,2,4- triazinium salts are appropriate substrates to be used in these (4 + 2) cycloaddition reactions.Indeed, we found that 1-ethyl- 5-phenyl-l,2,4-triazinium salts bearing acetylenic 3-butynylthio (compound 1a) or 4-pentynylthio (compound 1b) substituents at C-3 can undergo intramolecular (4 + 2) cycloaddition reaction under very mild conditions, thus being transformed into thieno- [2,3-b]- 3a or thiopyrano[2,3-b]pyridines 3b (Scheme 1).2 On the other hand, N-alkylpyridinium and other azinium salts, especially those bearing the CH2W fragment at the quaternary nitrogen (W is an electron-withdrawing group) are precursors of N-heterocyclic ylides, which can undergo 1,3-dipolar (3 + 2) cycloaddition reactions with both alkenes and acetylenes. The feature of N-alkyl-1,2,4-triazinium salts is that electron-withdrawing groups W in the N-alkyl fragment are not necessary to generate ylides, as found by the dimerisation into 4a,4b,9,10- tetrahydro-1,3,6,8,8a,10a-hexaazaphenanthrenes.3,4 In continuation of our studies on the behaviour of 1-alkyl-1,2,4-triazinium salts,5.7 we report that deprotonation of 1-ethyl-3-alkylthio-5- aryl-l,2,4-triazinium salts 4a.c with triethylamine (TEA) results in azomethine ylides 5a.c (non-stabilised species), which react in situ with dimethyl acetylenedicarboxylate (DMAD) to form pyrrolo[2,1-f ][1,2,4]triazines 6a.c in good yields (Scheme 2).¢Ó Attempts to use other alkynes, such as phenylacetylene, di(4-nitrophenyl) acetylene and di(pyridin-2-yl)acetylene, as dipolarophiles in the reaction with 4c were unsuccessful.When irradiated with UV light or pulsed electron beams, pyrrolo[2,1-f ][1,2,4]triazines 6a.c were found to exhibit intense luminescence giving emission in the region 450.650 nm with maxima at 500 nm and the light output comparable with that of stilbene.¢Ô It was interesting to examine the chemical behaviour of 3-alkynylthio-1,2,4-triazinium salts 1a,b on treatment with DMAD, i.e., when both types of cycloaddition reactions [(4 + 2) and (3 + 2)] can compete with each other.We found that, in case of a 4-pentynylthio substituent (n = 2), the intermolecular 1,3-dipolar cycloaddition reaction of 1b with DMAD leading to pyrrolotriazine 7 (47% yield) proceeds much faster than the intramolecular Diels.Alder reaction, while 3-butynylthio substituted 1-ethyl-1,2,4-triazinium salt 1a (n = l) undergoes predominantly the intramolecular ring transformation into thieno- [2,3-b]pyridine 3a in 44% yield (Scheme 3).Both reactions were carried out under identical conditions with triethylamine in absolute ethanol at room temperature. Although in both reactions we cannot exclude the formation of minor quantities of alternative products, moderate yields of 3a and 7 can be N N N Ph S (CH2)n BF4 N N N S (CH2)n H Ph BF4 .N2, CH2=CH2 . HBF4 N S (CH2)n Ph 1a,b a n = 1 b n = 2 2a,b 3a,b Scheme 1 ¢Ó All new compounds gave expected 1H NMR spectra, mass spectra and satisfactory elemental analyses. 3a: Dimethyl acetylenedicarboxylate (0.08 g, 0.56 mmol) was added to a suspension of 1-ethyl-3-(3-butynylthio)-5-phenyl-1,2,4-triazinium tetrafluoroborate 1a (0.18 g, 0.50 mmol) in 4 ml of absolute ethanol, and then triethylamine (0.06 g, 0.55 mmol) was added dropwise with stirring. The reaction mixture was stirred at room temperature for 36 h.After filtration, the solvent was removed in vacuo. Flash dry-column chromatography on silica gel (hexane.acetone, 4:1) gave 6-phenyl-2,3- dihydrothieno[2,3-b]pyridine (0.047 g, 44% yield) as white crystals, mp 82.83 ¡ÆC (lit.,2 mp 83 ¡ÆC). 6a: Dimethyl acetylenedicarboxylate (0.21 g, 1.46 mmol) was added to a suspension of 5-(4-bromophenyl)-1-ethyl-3-propylthio-1,2,4-triazinium tetrafluoroborate (0.52 g, 1.22 mmol) in 4 ml of absolute ethanol, and then triethylamine (0.14 g, 1.34 mmol) was added dropwise with stirring. The reaction mixture was stirred at room temperature for 72 h to precipitate a yellow crystalline product, which was collected by filtration and recrystallised from ethanol to yield 0.23 g (40%) of 4-(4-bromophenyl)- 5,6-dimethoxycarbonyl-7-methyl-2-propylthiopyrrolo[2,1- f ]- 1,2,4-triazine as a yellow product, mp 126.128 ¡ÆC. 1H NMR (CDCl3) d: 1.09 (t, 3H, SCH2CH2Me), 1.85 (m, 2H, SCH2CH2Me), 2.79 (s, 3H, Me), 3.20 (t, 2H, SCH2CH2Me), 3.47 (s, 3H, COOMe), 3.88 (s, 3H, COOMe), 7.54 (d, 2H, BrC6H4), 7.62 (d, 2H, BrC6H4).MS, m/z (%): 479 (58, [M + 1]+), 478 (16, M+), 477 (55), 464 (27), 462 (26), 446 (48), 444 (35), 438 (20), 437 (100), 436 (23), 435 (93). Compounds 6b and 6c were obtained analogously to 6a. 6b: yield 65%, yellow crystals, mp 108.110 ¡ÆC. 1H NMR (CDCl3) d: 1.48 (t, 3H, SCH2Me), 2.80 (s, 3H, Me), 3.21 (q, 2H, SCH2Me), 3.39 (s, 3H, COOMe), 3.87 (s, 3H, COOMe), 7.4.7.6 (m, 3H, Ph), 7.6.7.7 (m, 2H, Ph).MS, m/z (%): 386 (23, [M + 1]+), 385 (100, M+), 357 (21), 352 (41), 294 (32), 262 (20). 6c: yield 40%, yellow crystals, mp 165.167 ¡ÆC. 1HNMR ([2H6]DMSO) d: 2.61 (s, 3H, SMe), 2.76 (s, 3H, Me), 3.35 (s, 3H, COOMe), 3.82 (s, 3H, COOMe), 7.4.7.6 (m, 5H, Ph). MS, m/z (%): 372 (34, [M + 1]+), 371 (100, M+), 340 (22), 339 (35), 280 (35), 252 (22), 239 (21). 7: Dimethyl acetylenedicarboxylate (0.18 g, 1.26 mmol) was added to a suspension of 1-ethyl-3-(4-pentenylthio)-5-phenyl-1,2,4-triazinium tetrafluoroborate 1b (0.39 g, 1.05 mmol) in 5 ml of absolute ethanol, and then triethylamine (0.12 g, 1.16 mmol) was added dropwise with stirring.The reaction mixture was allowed to stand at room temperarure for 24 h.The solvent was removed in vacuo. Flash dry-column chromatography on silica gel (hexane.ethyl acetate, 4:1) gave 5,6-dimethoxycarbonyl-7-methyl- 2-(4-pentenylthio)-4-phenylpyrrolo[2,1-f ][1,2,4]triazine (0.208 g, 47%): yellow solid, mp 80.82 ¡ÆC. 1H NMR (CDCl3) d: 1.99 (t, 1H, C��CH, J 2.8 Hz), 2.07 (m, 2H, SCH2CH2, J 7.0 Hz), 2.42 (td, 2H, CH2C��CH, J 2.8 Hz, J 7.0 Hz), 2.80 (s, 3H, Me), 3.32 (t, 2H, SCH2, J 7.0 Hz), 3.39 (s, 3H, COOMe), 3.87 (s, 3H, COOMe), 7.4.7.6 (m, 3H, Ph), 7.6.7.7 (m, 2H, Ph).MS, m/z (%): 423 (24, M+), 396 (24), 395 (100), 384 (78), 371 (25), 364 (38), 357 (41), 267 (23).Mendeleev Communications Electronic Version, Issue 1, 2001 (pp. 1–42) explained by side reactions of starting 1,2,4-triazinium salts 1a,b, such as dequaternisation5 and dimerisation,3,4 as experimentally found by TLC.Thus, the conversion of 1-ethyl-3- alkynylthio-1,2,4-trazinium salts 1a,b into thieno[2,3-b]- pyridine 3a or pyrrolo[2,1-f ][1,2,4]triazine 7 depends on the length of the side chain bearing the acetylenic fragment. The found phenomenon is consistent with well-known features of the intramolecular Diels–Alder reactions of alkynyl-substituted pyrazines, pyrimidines and 1,2,4-triazines.2,8–11 In these ring transformations, the formation of bridged intermediates like 2 (Scheme 1) with an annelated five-membered ring is more favourable as compared to cycloadducts 2 condensed with a sixmembered ring.2,8–11 As a consequence, intramolecuh; Alder reactions leading to azines condensed with five-membered rings proceed much faster and require milder conditions. 2,8–11 The above results demonstrate a new interesting property of 1,2,4-triazinium salts to undergo two modes of cycloaddition reactions with alkynes. Evidence for the structures of 3a, 6a–c and 7 is provided by 1H NMR spectroscopy and mass spectrometry.† This work was supported by the US Civilian Research and Development Foundation (grant no.REC-005) and the Russian Foundation for Basic Research (grant nos. 00-03-32785a and 00-15-97390). References 1 D. L. Boger and S. M. Weinreb, Hetero Diels–Alder Methodology in Organic Syntheses, Academic Press, New York, 1987. 2 V. N. Charushin, A. van Veldhuizen, H. C. van der Plas and C.H. Stam, Tetrahedron, 1989, 45, 6499. 3 O. N. Chupakhin, B. V. Rudakov, S. G. Alexeev, V. N. Charushin and V. A. Chertkov, Tetrahedron Lett., 1990, 31, 7665. 4 B. V. Rudakov, S. G. Alexeev, V. N. Charushin, O. N. Chupakhin, V. A. Chertkov, G. G. Alexandrov and E. S. Klimov, Zh. Org. Khim., 1992, 28, 589 (Russ. J. Org. Chem., 1992, 28, 479). 5 O. N. Chupakhin, B. V. Rudakov, S. G.Alexeev, S. V. Shorshnev and V. N. Charushin, Mendeleev Commun., 1992, 85. 6 V. N. Charushin, S. G. Alexeev, O. N. Chupakhin and H. C. van der Plas, Adv. Heterocycl. Chem., 1989, 46, 73. 7 O. N. Chupakhin, S. G. Alexeev, B. V. Rudakov and V. N. Charushin, Heterocycles, 1992, 33, 931. 8 A. E. Frissen, Intramolecular Inverse Electron Demand Diels–Alder Reaction of Pyrimidines, Thesis, Wageningen, 1990, p. 117. 9 A. E. Frissen, A. T. M. Marcelis and H. C. van der Plas, Tetrahedron, 1987, 43, 1589. 10 A. E. Frissen, A. T. M. Marcelis and H. C. van der Plas, Tetrahedron, 1989, 45, 803. 11 A. E. Frissen, G. Geurtsen, A. T. M. Marcelis and H. C. van der Plas, Tetrahedron, 1990, 46, 595. ‡ For measuring the photoluminiscence spectra, compounds 6a–c and 7 were irradiated with monochromatic UV light at a wavelength of 310 nm followed by measuring emission with the second monochromator equipped with a photoelectric multiplier (1050 V) and an automatic potentiometer.The radioluminiscence and scintillation characteristics of compounds 6a–c and 7 were obtained using special nanosecond techniques. The test materials were excited by irradiation with pulsed electron beams at a high current density (pulse duration of 2 ns, electron energy of 100–200 keV, current density of 100–700 A cm–2) using a Radan electron accelerator. The spectra in the range 300–800 nm were measured by a charge-connecting detector (CCD) equipped with a computer. N N N Ar S R1 BF4 4a–c N N N Ar S R1 5a–c TEA DMAD N N N S R1 Ar Me MeOOC MeOOC 6a–c a R1 = Et, Ar = 4-BrC6H4 b R1 = Me, Ar = Ph c R1 = H, Ar = Ph Scheme 2 N N N Ph S (CH2)n BF4 1a,b N N N S Ph Me MeOOC MeOOC 7 COOMe COOMe n = 2 n = 1 3a Scheme 3 Received: 1st September 2000; Com. 00/1696