Page  145 Issue in Honor of Prof. Charles Rees ARKIVOC 2002 (vi) 145-151 Triazolopyridines 21.1 The stereochemistry of 1-[1,2,3]triazolo [1,5-a] pyridin-7-yl-4-(2H-[1,2,3]triazol-4-yl)-1,3-butadienes and triazolo ring opening derivatives Belén Abarca*, Rafael Ballesteros, and Mostafá Elmasnaouy Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Valencia Avda. Vicente Andrés Estellés s/n, 46100, Burjassot, (Valencia), Spain E-mail: [email protected] Dedicated to Professor Charles W. Rees on his 75th birthday (received 24 Jun 02; accepted 18 Aug 02; published on the web 26 Aug 02) Abstract The synthesis and NMR study of the geometry of 1-[1,2,3]triazolo[1,5-a]pyridin-7-yl-4-(2H[ 1,2,3]triazol-4-yl)-1,3-butadienes 1a, 1b, 5 and of new 1-(6-substituted-2-pyridyl)-4-(2H[ 1,2,3]triazol-4-yl)-1,3-butadienes 8-10 is reported. The stereochemistry of all butadienes studied is 1E, 3E except for compound 5 that is the 1Z, 3Z stereoisomer of 1a. Keywords: Triazolopyridines, alkenes, stereochemistry determination Introduction Previously, we have reported that 1-[1,2,3]triazolo[1,5-a]pyridin-7-yl-4-(2H-[1,2,3]triazol-4-yl)1,3- butadienes 1 can be synthesized together with bitriazolopyridines 2 in the lithiation reaction of [1,2,3]triazolo[1,5-a]pyridines 3, when reactions are carried out at –70 ºC in THF as solvent, and the mixture allowed to rise room temperature before hydrolysis,2,3 (Scheme 1). We had nmr evidence that the intermediate 4 was formed, and this may undergo six-membered ring opening to give 1 or loss of hydride to give 2. A similar intermediate has been reported in the reactions of ring opening of triazolopyridinium salts by nucleophiles.4-6 In those cases azolyldiene derivatives with different geometry were found depending on nucleophile size and electronegativity. We now wish to report a study of the geometry of azolyldienes 1a,b and of new 1-(6-substituted-2pyridyl)- 4-(2H-[1,2,3]triazol-4-yl)-1,3-butadienes 8-10, obtained from compounds 1 and sulfuric acid, acetic acid, or selenium dioxide. ISSN 1424-6376 Page 145 ©ARKAT USA, Inc

Page  146 Issue in Honor of Prof. Charles Rees ARKIVOC 2002 (vi) 145-151 R R N NN LDA Z H N N N THF, -70oC NN N 3a, R=H R 4, Z= Li b, R=CH3 7, Z= COOLi Scheme 1 Results and Discussion When compound 1b was described,2 we assumed that the geometry of the butadiene was 1E, 3Z. It was known,5 that similar azolyldiene derivatives were formed when [1,2,3]-triazolopyridinium salts reacted with nucleophiles. In all the reported cases the double bond of the diene attached to the triazole retained its original cis geometry. When we described compound 1a we did not pay attention to its stereochemistry.3 We realized later that coupling constant data do not fit for a E, Z configuration. A careful 1H nmr study of compounds 1a,b (Table 1) leads us now to propose the 1E, 3E configuration for both. Table 1. 1H NMR data of compounds 1a, 1b, 5, 6: dH (ppm) and coupling constants J (Hz) R R N NNN + H NNNN NN NN RR 12 H4 H5 H6 Hd Hc Hb Ha Other 1a 7.98 7.587.457.08 (d) 7.37 (dd) 8.07(dd) 7.45 (d) 8.37 (s, DMSO (dd) 7.50 7.35 (m) Jd,c=15,60 Jc,d=15,60 Jb,a=15,60 Ja,b=15,60 1H3); 300MHz J4,5=8,28 (m) Jc,b=10,90 Jb,c=10,90 8.22(s, 1b 7.56 (d) 7.23 7.09 (d) 6.88 (d) 7.24 (dd) 7.99 (dd) 7.28 (d) 2.65 (s, CDCl3 J4,5=8,61 (dd) J6,5=6,90 Jd,c=15,70 Jc,d=15,70 Jb,a=15,58 Ja,b=15,58 3H); 500MHz J5,4=8,61 Jc,b=10,89 Jb,c=10.89 2.49 (s, 5 7.95 (d) 7.46 7.28 (d) 6.70 (d) 6.83 (dd) 7.76 (dd) 7.25 (d) 8.29 (s, DMSO J4,5=8,50 (dd) J6,5=7,00 Jd,c=11,50 Jc,d=11,50 Jb,c=11,50 Ja,b=11,04 1H) 400MHz J5,4=8,50 Jc,b=11,50 Jb,a=11,04 8.15(sa, 6 7.85 (d) 7.36 7.02 (d) 3.25 1,90-1,84 1.81-1.68 2.72 7.60 (s, DMSO J4,5=8,80 (dd) J6,5=6,90 (t, 2H) (m, 2H) (m, 2H) (t, 2H) 1H) 250MHz J5,4=8,80 J= 6,90 J= 6,90 A 500 MHz (CDCl3) spectrum of 1b shows four different signals for the dienic protons at d 6.88 (d, J=15.70 Hz), 7.24 (dd, J1=15.70, J2=10.89 Hz), 7.28 (d, J=15.58 Hz) and, 7.99 (dd, J1=15.58, J2=10.89 Hz) that indicate two trans coupling constants. Also in a 300 MHz (DMSO) spectrum of 1a it is possible to distinguish the four dienic protons at d 7.08 (J=15.6 Hz), 7.37 (J1=15.6, J2=10.9 Hz), 7.45 (d, J=15.6 Hz) and, 8.07 (dd, J1=15.6, J2=10.9 Hz), with two trans ISSN 1424-6376 Page 146 ©ARKAT USA, Inc

Page  147 Issue in Honor of Prof. Charles Rees ARKIVOC 2002 (vi) 145-151 coupling constants. To confirm the assignment of the double bond proton shifts, we did NOEexperiments. Irradiation of the singlet due to the H3' in compound 1a (d 8.22) produced DIFNOE signals at d 7.08 (Hd) and 7.37 (Hc); irradiation of the singlet at d 8.37 (H3) did not produce appreciable DIFNOE signals. Interestingly, we obtained compound 5, the Z, Z isomer of compound 1a (Figure 1), when we treated 7-lithiotriazolopyridine in ether with a large excess of solid CO2. The coupling constants in this case J1=11.5 and J2=11.04 Hz fit perfectly for that configuration (see Table 1). Both compounds, 1a and 5, gave the same tetrahydro derivative 6 by hydrogenation.1 1a,b 56 Figure 1 Experimental conditions used to obtain the two different isomers are very similar, with low temperatures, and similar reaction times (no differences in thermodynamic, or kinetic control). The change of solvent from THF to ether, known to coordinate differently with Li+ ions, could be one reason for the observed outcome. Another possibility is shown in scheme 2. According to Messmer et al.5,6 the proposed intermediate 4 must have the triazolopyridine group in an axial position and undergo ring opening by disrotation that should proceed in the sense portrayed in the scheme, since the lone pair of the bridge-head nitrogen can turn only inward with respect to the bond-breaking because it should get into the plane of the five membered ring. It implies that 4 can be opened only via route a leading to the 1E, 3Z compound, then a facile isomerization occurred to give 1E, 3E diene 1a. The presence of CO2 in the reaction medium may produce a lithium carbamate intermediate 7. The stereoelectronic effect between the nitrogen lone pair and the carbamate ion produced nitrogen inversion and the triazolopyridine group in now in the pseudo ecuatorial position, ring opening of 7 may be only via the opposite sense of disrotation (route b) affording 1Z, 3Z diene 5. N N NR N N N R H N N N N N N H 4 5 a b c d 6 N N N (CH2)4 N N N H N N N Li H Ar type a N N N H Ar 1a 1E, 3Z 1E, 3E 4 Ar= 7-triazolopyridinyl N N N H Ar COOLitype b 5 1Z, 3Z 7 Ar= 7-triazolopyridinyl Scheme 2 ISSN 1424-6376 Page 147 ©ARKAT USA, Inc

Page  148 Issue in Honor of Prof. Charles Rees ARKIVOC 2002 (vi) 145-151 The utility of azolylbutadienes in cycloaddition reactions7-9 led us to look for new compounds of this type. We have synthesized compounds 8-10 using the known reaction of triazolopyridines with electrophiles that undergo triazole ring opening.10 Thus, reaction of 1a,b with sulfuric acid gave disubstituted pyridines 8a,b, with acetic acid 9a,b and with selenium dioxide 10b (compound 10a was not isolated) (Scheme 3), all of them with the E, E configuration (see Table 2). HN H N iii i N N 1a,b NN or ii RR NN OR R'OR 10a R= H 8a R= R'= H 10b R= CH3 8b R= CH3, R'= H 9a R= H, R'= Ac 9b R= CH3, R'= Ac i) H2SO4, H2O, reflux, ii) AcOH, reflux, iii) SeO2,dioxane/reflux Scheme 3 Table 2. 1H NMR data of compounds 8a,b, 9a,b, 10b: dH (ppm) and coupling constants J (Hz) H H H H H H H Other 7. o o o o 8.03 (s, 1H) 8 7 7. 4 H H H H 4.80 (s, 2H) a . 8 3 a b c d C 4 3 (d7. o o o o 4.86 (q, 8 7 7. 0 H H H H J=6,20, 1H) b . 5 3 a b c d 2.36 (s, 3H) Cl 1 8 (d1.46 (d, 7. o o o o 7.80 (s, 1H) 9 7 7. 2 H H H H 5.25 (s, 2H) a . 7 1 a b c d 2.18 (s, 3H) 3 0 (d7. o o o o 5.93 (q, 9 7 7. 1 H H H H J=6,60, 1H) b . 6 7 a b c d 2.41 (s, 3H) 2 2 (d2.14 (s, 3H) 7. o o 2.69 (s, 3H) 1 7 7. 3 6. H H 6. 2.37 (s, 3H) 0 . 6 2 7 b c 7 b 7 4 (d 0 0 ISSN 1424-6376 Page 148 ©ARKAT USA, Inc

Page  149 Issue in Honor of Prof. Charles Rees ARKIVOC 2002 (vi) 145-151 Experimental Section General Procedures. Melting points were determined on a heated stage and are uncorrected. Nmr spectra were recorded on a Bruker AC250MHz, an Avance 300MHz Bruker DPX or an Avance 500MHz DRX instruments. DIFNOE experiments on an Unity 400MHz Varian. HRMS (EI) determinations were made using a VG Autospec Trio 1000 (Fisons). (1E,3E)-1-[1,2,3]Triazolo[1,5-a]pyridin-7-yl-4-(2H-[1,2,3]triazol-4-yl)-1,3-butadiene 1a and (1E,3E)-1-(3-Methyl-[1,2,3]triazolo[1,5-a]pyridin-7-yl)-4-(5-methyl-2H-[1,2,3]triazol-4-yl)1,3- butadiene (1b). Prepared as described.3,2 (1Z,3Z)-1-([1,2,3]Triazolo[1,5-a]pyridin-7-yl)-4-(2H-[1,2,3]triazol-4-yl)-1,3-butadiene (5). A solution of n-butyllithium in hexane (17mL, 1.6M) was added to diisopropylamine, freshly distilled from KOH (3.8 ml, 27.28 mmols), at -40ºC under argon. Equimolar amount of a solution of [1,2,3]triazolo[1,5-a]pyridine 1a (3.25g, 27.28mmol) in anhydrous ether (130 mL) was added with stirring. A deep red colour developed. The mixture was kept at -40ºC (6h), and then a large excess of solid carbon dioxide was added (the temperature was reduced) and then left at room temperature overnight. The mixture was hydrolysed with a saturated solution of ammonium chloride. Extraction with dichloromethane gave, after drying and evaporation of the organic solvent, a residue which was purified by chromatography giving starting material 1a (1,5g). The aqueous layer was acidified with HCl (10%), a precipitate was formed, filtered and purified by alumina chromatography. Elution with ethyl acetate/hexane (3:1) gave a yellow solid identified as 5 (0.71 g, 41%). mp 273-274ºC (methanol). Exact mass calcd. for (C12H10N6): 238.0967; found 238.0969. MS (EI) m/z 238 (74); 210 (50); 209 (52); 181 (61); 154 (100); 140 (21); 127 (27); 115 (11); 77 (15). 13C NMR d (DMSO) 142.90 (C); 134.03 (C); 133.14 (C); 132.21 (CH); 126.40 (CH); 125.72 (2 CH); 125.02 (CH); 122.58 (CH); 121.07 (CH); 117.25 (CH); 116.83 (CH). Hydrogenation of compound 5 in ethanol with Pd/C catalyst gave the tetrahydro derivative 6. mp 123-125ºC (methanol). Exact mass calcd. for (C12H14N6): 242.1280; found 242.1281. MS (EI) m/z 242 (64); 214 (100); 185 (69); 172 (47); 157 (44); 144 (25); 107 (24); 105 (84); 78 (27). 13C NMR d (DMSO) 144.39 (C); 138.88 (C); 133.97 (CH); 129.37 (C); 126.01 (2 CH); 115.93 (CH); 113.72 (CH); 30.04 (CH2); 28.73 (CH2); 25.50 (CH2); 24.10 (CH2). General procedure for ring opening reactions of triazolopyridines 1a,b with H2SO4 A solution of the triazolopyridine 1a (0.2g, 0.84mmol) or 1b (0.2g, 0.75mmol) in aqueous sulfuric acid (10mL, 2.5M) was heated to reflux for 5h with 1a and 12h with 1b. The solution was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic solvent was dried, and evaporated. The residue was purified by silica chromatography. ISSN 1424-6376 Page 149 ©ARKAT USA, Inc

Page  150 Issue in Honor of Prof. Charles Rees ARKIVOC 2002 (vi) 145-151 6-[(1E,3E)-4-(2H-[1,2,3]-Triazol-4-yl)-1,3-butadienyl]-2-pyridylmethanol (8a). Elution with CH2Cl2/AcOEt (1:1) gave a yellow oil characterized as 8a (153mg; 80%). Exact mass calcd. for (C12H12N4O): 228.1011; found 228.1010. MS (EI) m/z (%) 228 (34); 227 (6); 199 (17); 181 (20); 160 (14); 146 (100); 130 (7); 117 (10); 91 (7). 13C NMR d (CD3OD) 162.15 (C); 156.02 (C); 138.84 (CH); 138.60 (C); 134.16 (2CH); 133.81 (CH); 132.73 (CH); 124.37 (CH); 121.34 (CH); 120.26 (CH); 65.60 (CH2). 1-{6-[(1E,3E)-4-(5-Methyl)-2H-[1,2,3]triazol-4-yl]-1,3-butadienyl]-2-pyridyl}-1-ethanol (8b). Elution with AcOEt/hexane (2:1) gave a white solid characterized as 8b, (102mg; 53%), mp 117-119ºC (methanol). Exact mass calcd. for C14H16N4O: 256.1325; found 256.1333. MS (EI) m/z (%) 256 (27); 241 (6); 209 (18); 193 (10); 175 (3); 160 (100); 154 (10); 106 (9) 77 (5). 13C NMR d (CDCl3) 162.31 (C); 153.50 (C); 137.61 (CH); 137.40 (C); 135.10 (C); 133.30 (CH); 131.87 (CH); 130.75 (CH); 122.09 (CH); 120.75 (CH); 118.33 (CH); 68.41 (CH); 24.13 (CH3); 10.11 (CH3). General procedure for ring opening reactions of triazolopyridines 1a,b with AcOH A solution of the triazolopyridine 1a (0.2g, 0.84mmol) or 1b (0.2g, 0.75mmol) in glacial acetic acid (10mL) was heated to reflux for 10h with 1a and 12h with 1b. The solution was neutralized with saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic solvent was dried, and evaporated. The residue was purified by silica chromatography. 6-[(1E,3E)-4-(2H-[1,2,3]triazol-4-yl)-1,3-butadienyl]-2-pyridylmethyl acetate (9a). Elution with AcOEt/ hexane (3:1) gave a white solid characterized as 9a, (147mg; 65%), mp 125-128ºC (ethyl acetate). Exact mass calcd. for C14H14N4O2: 270.1116; found 270.1114. MS (EI) m/z (%) 270 (54); 241 (6); 227 (100); 199 (29); 181 (36); 146 (36); 130 (13); 92 (10). 13C NMR d (CDCl3) 170.86 (CO); 155.51 (C); 155.10 (C); 144.38 (C); 137.31 (CH); 132.90 (CH); 132.83 (CH); 131.64 (CH); 129.75 (CH); 122.23 (CH); 120.96 (CH); 120.18 (CH); 66.79 (CH2); 20.94 (CH3). 1-{6-[(1E,3E)-4-(5-methyl-2H-[1,2,3]triazol-4-yl)-1,3-butadienyl]-2-pyridyl}ethyl acetate (9b). Elution with AcOEt/ hexane (1:1) gave a white solid characterized as 9b, (163mg; 73%), mp 108-110ºC (ethyl acetate). Exact mass calcd. for C16H18N4O2: 298.1429; found 298.1419. MS (EI) m/z (%) 298 (25); 256 (20); 255 (100); 239 (29); 213 (29); 192 (20); 176 (39); 150 (47); 134 (37); 104 (35); 78 (17). 13C NMR d (CDCl3) 170.58 (CO); 160.14 (C); 154.95 (C); 140.82 (C); 137.80 (C); 137.20 (CH); 133.08 (CH); 132.75 (CH); 130.85 (CH); 121.60 (CH); 120.69 (CH); 118.14 (CH); 73.31 (CH); 21.28 (CH3); 20.77 (CH3); 9.99 (CH3). Ring opening reaction of triazolopyridine 1b with SeO2 A suspension of triazolopyridine 1b (0.2g, 0.75mmol) and selenium dioxide (2 equivalents) in dioxane (10mL) was heated at 80ºC for 7h. The mixture was filtered and the filtrate neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic solvent was dried, and evaporated. The residue was purified by silica chromatography. Elution with AcOEt/ hexane (2:1) gave a white solid characterized as 1- ISSN 1424-6376 Page 150 ©ARKAT USA, Inc

Page  151 Issue in Honor of Prof. Charles Rees ARKIVOC 2002 (vi) 145-151 {6-[(1E,3E)-4-(5-Methyl-2H-[1,2,3]triazol-4-yl)-1,3-butadienyl]-2-pyridyl}-1-ethanone (10b). (41mg; 21%). mp. 138-140ºC (ethanol). Exact mass calcd. for C14H14N4O: 254.1167; found 254.1166. MS (EI) m/z (%) 254 (59); 226 (10); 211 (100); 184 (7); 172 (23); 142 (12); 106 (13); 78 (7). 13C NMR d (CDCl3) 200.61 (CO); 171.09 (C); 154.74 (C); 153.37 (C); 141.99 (C); 137.32 (CH); 133.56 (CH); 132.16 (CH); 130.90 (CH); 125.38 (CH); 122.50 (CH); 119.79 (CH); 25.73 (CH3); 10.29 (CH3). Acknowledgements Our thanks are due to Comisión Interministerial de Ciencia y Tecnología (CICYT, project PB981422) for financial support, and SCSIE, mass spectrometry section, for technique assistance. References 1. For Part 20 see: Abarca, B.; Ballesteros, R.; Elmasnaouy, M. Tetrahedron 1999, 55, 12881. 2. Jones, G.; Pitman, M. A.; Lunt, E.; Lythgoe, D. J.; Abarca, B.; Ballesteros, R.; Elmasnaouy, M. Tetrahedron 1997, 53, 8257. 3. Abarca, B.; Ballesteros, R.; Elmasnaouy, M. Tetrahedron 1998, 54, 15287. 4. Gelleri, A.; Messmer, A. Tetrahedron Lett. 1973, 4295. 5. Gelleri, A.; Messmer, A.; Nagy, S.; Radics, L. Tetrahedron Lett. 1980, 21, 663. 6. Messmer, A.; Hajós, G.; Tímári, G. Tetrahedron 1992, 48, 8451. 7. Messmer, A.; Hajós, G.; Timári, G. Monastsh. Chem. 1988, 119, 1113. 8. Messmer, A.; Hajós, G.; Timári, G.; Gelléri, A. Monastsh. Chem. 1988, 119, 1121. 9. Kotschy, A.; Hajós, G.; Messmer, A. J. Org. Chem. 1995, 60, 4919. 10. Abarca, B.; Ballesteros, R.; Jones, G.; Rodrigo, G.; Veciana, J.; Vidal-Gancedo, J. Tetrahedron 1998, 54, 9785 and references cited here in. ISSN 1424-6376 Page 151 ©ARKAT USA, Inc