Metallation of pyridineN-oxides and application to synthesis

摘要

J. CHEM. SOC. PERKIN TRANS. I 1995 Metallation of pyridine N-oxides and application to synthesis Olivier Mongin, Patrick Rocca, Laurence Thomas-dit-Dumont, Franqois TrCcourt, Francis Marsais, Alain Godard and Guy QuCguiner * Laboratoire de Chirnie Organique Fine et H&krocyclique de I'IRCOF, URA CNRS 1429,Institut National des Sciences Appliqukes de Rouen, BP 08, F-7613I Mont-Saint-Aignan Cedex, France Regio- and chemi-selective, directed ortho-lithiation of 2-, 2,5-or 3,4-substituted pyridine N-oxides has been achieved with diisopropylamide and butyllithium. Polysubstituted pyridine N-oxides, azaxanthone, and an isomer of orelline have been synthesized by such methods. Compared to the directed ortho-metallation of pyridine, little work on the lithiation of pyridine N-oxides has been reported apart from the pioneering studies of Abramovitch and his group between 1969 and 1972.2-6 In this they both developed the lithiation of pyridine N-oxide as well as various 3-, 4- and 3,4- substituted compounds at low temperature, and proved, that in such compounds, the enhanced acidity of 2-H and the lithium- complexing effect of the oxygen lone pairs makes feasible under strongly basic conditions (treatment with lithium alkyls or lithium dialkylamides) proton abstraction ortho to nitrogen.This work has remained unexploited since these studies mainly because the low selectivity of this reaction often gave mixtures of 2-, 6-and 2,6-functionalized products. Although this original work was later developed by Martin' using an in situ trap technique based on the compatibility between LTMP (lithium 2,2,6,6-tetramethylpiperidide) and such electrophiles as trimethylsilyl chloride or hexafluoroacetone, the problem of regioselectivity remained.Recently, since we developed an interest in preparing 2-or 6-substituted pyridines or pyridine N-oxides for synthetic purposes, we have studied the metallation of pyridine N-oxides, particularly in respect of the 2/6-regioselectivity of such reactions. Two different regioselective pathways are investigated in this paper: the 6-lithiation of 2-substituted pyridine N-oxides 1-3 for which dimetallation cannot occur since the 2 position is blocked. and the 2-lithiation of 3-substituted pyridine N-oxides for which the substituent at C-3 can be an ortho-directing group.The latter example consists of the metallation of 3,4-dimethoxypyridine N-oxide and some applications of this strategy are given with the synthesis of polyaromatic compounds. Results and discussion Metallation of 2-substituted pyridine N-oxides Lithiation of 2-N,N-diisopropylcarboxamidopyridineN-oxide 7 1 and 2-pivaloylaminopyridine N-oxides $2 and 3 with lithium diisopropylamide (LDA) in tetrahydrofuran (THF) at -75 "C (Scheme 1) occurred with total regioselectivity at the C-6 position. No metallation occurred at the C-3 position, although carboxamides and pivaloylamino groups are known to be ortho-directing groups under other conditions.' Reaction of t 2-(N,N-Diisopropylcarboxamido)pyridine N-oxide 1 was prepared from the corresponding pyridinecarboxamide in 70% yield by action of hydrogen peroxide in acetic acid at 80 "C for 12 h.8 Pyridine N-oxides 2 and 3 were prepared respectively from 2- aminopyridine and 5-methyl-2-aminopyridinein a two-step sequence: i, ClCOBu', NEt,, ether, room temp., 2 h; ii, H202, MeCO,H, 80 "C, 12 h.The overall yields were 65% for 2 and 73% for 3. 0- 0- 1 ~=CONP+~.R=H 4-20 2 z = NHCOBU', R = H 3 Z = NHCOBu', R = Me Scheme 1 Reagents and conditions: LDA, THF, -75 "C; ii, electrophile, -75 "C Table 1 Metallation of 2-substituted pyridine N-oxides Yield E Product (%)'Compound Electrophile 1' EtOD D 4 loob 1 PhCHO PhCH(0H) 5 62 1 Ph,CO Ph,CH(OH) 6 60 1 1 C yclohexanone COZ C02Hc-C6H10(0H) 7 8 54 50 1 I2 I 9 77 2d EtOD D 10 80b 2 PhCHO PhCH( OH) 11 80 2 2 Cyclohexanone HC0,Et CHO c-C6HIdoH) 12 13 60 62 2 2 CO, 12 COzH I 14 15 48 73 3' EtOD D 16 loob 3 Me1 Me 17 83 3 HC0,Et CHO 18 62 3 coz CO,H 19 83 3 TsCN CN 20 57 * Isolated yields, unless otherwise indicated. Determined by 'H NMR analysis.Lithiation of 1 was carried out with 1.1 equiv. of LDA for 0.5 h. Lithiation of 2 was carried out with 2.2 equiv. of LDA for 0.5 h. 'Lithiation of 3 was carried out with 2.2 equiv. of LDA for 1.5 h. various electrophiles with the intermediate lithio species provided the corresponding 6-substituted pyridines (Table 1).Metallation of 3,4dimethoxypyridine N-oxide We have previously reported lo that with butyllithium, 3,4- dimethoxypyridine undergoes a regioselective metallation at C-2 without side reactions such as nucleophilic addition. 3,4-Dimethoxypyridine N-oxides 21 was lithiated with butyllithium 0 3,4-Dimethoxypyridine N-oxide 21 was prepared in a three-step sequence from 3-fluoropyridine by a literature procedure' ' (overall yield: 55%). 2504 J. CHEM. SOC. PERKIN TRANS. I 1995 Table 2 Regioselectivity of the metallation of 3,4-dimethoxypyridine N-oxide 21 ~ ~~ ~ ~ ~~ Ratio of 22 :23 :24 Yield of 22, 23 Entry Electrophile" E and 24 (%I 22 23 24 1 DCl D 83 100 -- 2 MeCHO MeCH(0H) 61 100 -- 3 2-MeOC,H4CH0 2-MeOC,H,CH(OH) 60 91d 9d - 4 1, I 80 81' 5' 14' Electrophiles were added and allowed to react at -75 "C. Yields are for isolated products.Determined by 'H NMR analysis. Ratios were determined by 'H NMR analysis. Ratios were determined by isolation of products. Table 3 Regioselectivity of the metallation of 21 when iodine was used as electrophile Yields" (%) Equiv. of Time of reaction Entry BuLi and I, of I,(t/min) 22d 23d 24d 1 2.0 45 60 2 26 2 2.0 5 65 4 11 3 3.3 45 -_ 76 'Yields are for isolated products. in THF, the reaction conditions being determined by quenching of the lithio species with deuterium chloride. With 1.2 equiv. of BuLi at 0 "C deuterium incorporation was poor 7 ( 5%). The best conditions were found to be 2.2 equiv.of BuLi in THF at 0 "C for 45 min, allowing a 83% deuterium incorporation. From these results it seems that the first equivalent of base was entirely chelated by the two methoxy groups to give an intermediate lithio species which on reaction with various electrophiles afforded the corresponding 2-, 6-or 2,6-functionalized products (Scheme 2 and Table 2). OMe OMe 0-0-21 22a-d a; E=D b; E=MCH(OH) OMe OMe 0-0-23c-d 24d C; E = 2-MeOCfiCH(OH) d; E=I Scheme 2 Reagenrs and conditions: i, BuLi, THF, OOC, 45 min; ii, electrophile, -75 "C When DCl was used as electrophile, total regioselectivity at C-2 was observed (Table 2, entry I). The same regioselectivity was observed with acetaldehyde (Table 2, entry 2), but not with 2-methoxybenzaldehyde (Table 2, entry 3) and iodine (Table 2, entry 4).We assume that the action of BuLi on 21 leads to an equilibrium between two lithiated species, the 2-lithio and the 6-lithio derivatives. This equilibrium is in favour of the 2-lithio derivative and the ratios of final products seem to depend on the nature of the electrophile. Nevertheless, a satisfactory regioselectivity of the metallation at C-2 was observed (see ratios in Table 2). The particular case of iodine is more complex because a 2,6- diiodo compound 24 was obtained together with the 2-iodo compound 226 and a very small quantity of the 6-iodo compound 23d (Table 3). However, the 2-iodo derivative 22d could be conveniently obtained using a 5 min reaction time (Table 3, entry 2 :65%).7 Determined by 'H NMR analysis. Moreover, a sufficient excess of both metallating reagent and iodine selectively led to the diiodo derivative 24d (Table 3, entry 3). Application to synthesis Some of the previously prepared pyridine N-oxides were used as key intermediates in the synthesis of polyaromatic compounds. (a) Synthesis of a new 1-azaxanthone. Xanthone derivatives have potential pharmaceutical properties. ' The synthesis of the azaxanthone 25 was achieved in two steps from the alcohol 22c. Thus, oxidation of 22c with manganese dioxide gave the corresponding ketone 26, and this upon treatment with boiling pyridinium chloride (21 5 "C)' cyclized to 25 (Scheme 3). I/ OMeQ 0- OH OMe 0- 0 OMe 22c 26 OH - HO 0 25 Scheme 3 Reagents and conditions: i, MnO,, toluene, reflux, 64%; ii, boiling pyridinium chloride, 20 min, 62% Simultaneous cleavage of the ether moiety and reduction of the N-oxide group are the result of the strongly acidic conditions and the excess of pyridine, respectively.(b) Synthesis of an isomeric analogue of orelline. Orelline 27, a toxin from the poisonous mushrooms Cortinarius orellanus and speciosissimus, ' has previously been synthesised with 2-iodo- 3,4-dimethoxypyridine as a key intermediate. OHYH bH OH 27 (orelline) 28 1) In order to establish unambiguously the structure of the azaxanthone 25, this molecule was synthesized by another route, starting from 3,4- dimethoxypyridine: i, BuLi, THF, -70 OC, 1 h, then 2-MeOC6H,- CHO, -70 OC, 72%; ii, MnO,, toluene, reflux, 90%; iii, boiling pyridinium chloride, 76%.J. CHEM. SOC. PERKIN TRANS. 1 1995 The isomeric analogue of orelline, compound 28, was prepared from 2-iodo-4,5-dimethoxypyridine29, a compound itself synthesized from the corresponding pyridine N-oxide 23d, in very low yield (Table 3, entry 2: 4%), by a metallation- iodination sequence with 3,4-dimethoxypyridine N-oxide 21. An alternative two-step route to compound 29 was via the key intermediate the N-oxide 24d: thus, either reduction of the N-oxide followed by a regioselective iodine-lithium exchange of 30 (61% overall), or by selective deiodination of 24d followed by the reduction of the N-oxide 23d (34% overall).A nickel- phosphine complex-mediated homocoupling 15*10 of 29 gave the 2,2'-bipyridine 31 in good yield (79%). Treatment of 31 in refluxing hydrobromic acid afforded the isomeric analogue of orelline 28 (Scheme 4). OMe OMe 24d iiiI OMe Ifl'1". iv 30I ii OMe IJy 0- 23d 29 ?Me OH OMe 28 31 Scheme 4 Reagents and conditions: i, PCl,, 83%; ii, BuLi, THF, -75 OC, 0.5 h, then HCl, 74%; iii, BuLi, THF, -30 OC, 1 h, then HCl, 77%; iv, PCl,, 44%; v, NiCI,, PPh,, Zn, DMF, 5OoC, 48 h, 79%; vi, conc. aq. HBr, reflux, 20 h, 70% Conclusion 2-Substituted pyridine N-oxides 1-3 and 3,4-dimethoxypyridine N-oxide 21 have been successfully metallated with LDA and BuLi, respectively. Lithiation was ortho directed by the N-oxide group for 2-substituted pyridine N-oxides and by the N-oxide and the methoxy group for 21.The resulting lithiopyridines were obtained in high yields as shown by reaction with various electrophiles. Some of the pyridine N-oxide intermediates thus obtained were used to synthesize a new azaxanthone 25 and an isomeric analogue of orelline 28. This strategy is fully convergent, highly regioselective and allows overall yields, respectively of 40% (2 steps) for 25, and 34% (4 steps) for 28. Experimental General All reactions involving organometallic compounds were carried out under a dry argon atmosphere. Reagents were handled with syringes through septa. Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl.Ether refers to diethyl ether. Column chromatography was performed on silica (0.063-0.200 2505 mm). Mps were determined on a Kofler hot-stage. 'H NMR spectra were recorded on a 60 MHz Varian EM 360L, on a 200 MHz Bruker AC 200 F, or on a 400 MHz Bruker AM 400 spectrometer using CDCI, or deuteriated dimethyl sulfoxide as solvent with chemical shifts being reported as 6 (ppm), respectively, from tetramethylsilane or from hexamethyl-disiloxane; J values are recorded in Hz. 13C NMR spectra were recorded at 50 MHz on a Bruker AC 200 F spectrometer. IR spectra were obtained on a Perkin-Elmer FTIR 1600 spectrophotometer. Mass spectra were recorded on a JEOL JMS-AX 500 instrument. Elemental analyses were performed on a Carlo Erba 1160 instrument.General procedure A: metallation of 2-(N,Ndiisopropyl-carboxamido)pyridine N-oxide 1 2-(N,N-Diisopropylcarboxamido)pyridine N-oxide 1 (1.56 g, 7.0 mmol) in THF (20 cm3) was slowly added to a cold (-75 "C) solution of LDA (7.7 mmol) in THF (100 cm3). The resulting mixture was stirred for 30 min at -75 "C before addition of the required electrophile (15 mmol) in THF (20 cm3). Stirring was continued for 2 h at the same temperature before hydrolysis of the mixture at -75 "C by water (100 cm3) and further dilution with water (50 cm3) at room temperature. The mixture was extracted with dichloromethane (CH,Cl,), and the extract dried (MgSO,) and evaporated to afford a crude product which was purified by flash chromatography on silica.2-(N, N-Diisopropylcarboxamid0)-[6-~H,]pyridine N-oxide 4. General procedure A, using deuteriated ethanol as electrophile, gave the title compound (1 00%).The physical characteristics of this product were found to be identical with those described for 1 ** except for the 'H NMR spectrum where the 6-H signal had disappeared. 2-(N,N-Diisopropylcarboxamido)-6-( 1-hydroxyphenylmethy1)-pyridine N-oxide 5. General procedure A, using benzaldehyde as electrophile, gave the title compound (62%) (eluent: CH,Cl,+ther, 5: 5) as a pale yellow solid, mp 118-120 "C (Found: C, 69.4; H, 7.4; N, 8.4. C19H24NZ03 requires C, 69.5; H, 7.4; N, 8.5%); v,,,(KBr)/cm-' 3340, 3080, 3015, 2970, 2870, 1640, 1495 and 1450; &(60 MHz; CDCl,) 1.00 to 1.85 (12 H, m, 4 CH,), 3.30 to 3.85 (2 H, comp, 2 CH), 6.15 (1 H, s, CH), 6.30 (1 H, s, OH) and 6.70 to 7.70 (8 H, comp, 5 H phenyl + 3 H pyridine).2+V,N-Diisopropylcarboxamido)-6-( 1-hydrox ydiphenyl- methy1)pyridine N-oxide 6. General procedure A, using benzo- phenone as electrophile, gave the title compound (60%) (eluent: cyclohexane-ether, 5:5) as a beige solid, mp 230-232°C (Found: C, 74.2; H, 6.9; N, 6.8. C25H28N203 requires C, 74.2; H, 7.0; N, 6.9%); vma,(KBr)/cm-' 3200, 3080, 2940, 1645, 1610, 1495 and 1445;&(400 MHz; CDCl,) 1.02 (6 H, d, J6.5,2 CH,), 1.47 (6 H, d, J 6.5, 2 CH,), 3.20 (1 H, comp, CH), 3.47 (1 H, comp, CH), 6.69 (1 H, comp, 5-H), 7.24 (12 H, m, 3-H + 4-H + 10 H phenyl) and 8.36 (1 H, s, OH). 2-( N,N-Diisopropylcarboxamido)-&( 1 -h ydrox yc yclohex y1)- pyridine N-oxide 7.General procedure A, using cyclohexanone as electrophile, gave the title compound (54%) (eluent: ether) as a beige solid, mp 78-80°C (Found: C, 66.5; H, 9.0; N, 8.4. Cl8HZ8N20,, 0.3 H,O requires C, 66.35; H, 8.85; N, 8.6%); v,,,(KBr)/cm-' 2935,1637 and 1448; 6,(60 MHz; CDCl,) 1.O& 1.30 (22 H, m, 10 H cyclohexyl + 4 CH,), 3.10-3.90 (3 H, m, 2 CH + OH) and 7.15-7.50 (3 H, m, 3-H + 4-H + 5-H). ** Physical characteristics of compound 1:mp 166168 "C (Found: C, 64.9; H, 8.25; N, 12.6. C1,H,,N,O, requires C, 64.8; H, 8.15; N, 12.6%); v,,,(KBr)/cm-' 3430,3120,3080,2980,2940, 1640, 1610, 1560, 1500, 1480 and 1425;6,(60 MHz; CDCl,) 1.05-1.80 (12 H, m, 4 CH,), 3.2-3.9 (2 H, m, 2 CH), 7.27 (3 H, m, 3-H + 4-H + 5-H)and 8.14 (1 H, comp, 6-H).2-Carboxy-6-(N, N-diisopropy1carboxamido)pyridine N-oxide 8. General procedure A, using solid carbon dioxide as electrophile gave, after acidification by 2 mol dm-, hydrochloric acid (extraction by CH,CI, at pH 2), the title compound (50%) as a white solid, mp 180-182 "C (Found: C, 58.3; H, 6.55; N, 10.2. Cl,H,,N204 requires C, 58.6; H, 6.8; N, 10.5%);vmax(KBr)/cm-'3094,2969, 1651 and 1444; dH(6O MHz; CDCl,) 1.15-1.80 (12 H, m, 4 CH,), 3.20-3.90 (2 H, m, 2 CH), 7.55-7.90 (2 H, m, 4-H + 5-H) and 8.50 (1 H, dd, J2 and 8,3-H). 2-(N,N-Diisopropylcarboxamido)-6-iodopyridine N-oxide 9. General procedure A, using iodine as electrophile, gave the title compound (77%) (eluent: ether) as a pale yellow solid, mp 250"C (Found: C, 41.4; H, 5.1; N, 7.85.C,,H,,N,O, requires C, 41.4; H, 4.9; N, 8.05%); v,,,(KBr)/cm-' 3448,2967, 1624,1508 and 1442; 6,(60 MHz; CDCl,) 0.90-1.70 (12 H, m, 4 CH,), 3.20-3.70 (2 H, m, 2 CH), 6.95 (1 H, t, J 8, 4-H), 7.20 (1 H, dd, J2 and 8,3-H) and 7.85 (1 H, dd, J 2 and 8,5-H). General procedure B: metallation of 2-pivaloylaminopyridine N-oxide 2 Procedure B was identical with general procedure A except that 15.5mmol of LDA and electrophile were used. 2-Pivaloylamin0[6-~H]pyridine N-oxide 10. General pro-cedure B, using deuteriated ethanol as electrophile, gave the title compound (80%). The physical characteristics of this product were found to be identical with those described for 2 tt except for the 'H NMR spectrum where the 6-H signal had disappeared. 2-Pivaloylamino-6-[hydroxy(phenyl)methyl]pyridine N-oxide 11.General procedure B, using benzaldehyde as electrophile, gave the title compound (80%) (eluent: cyclohexane-ether, 7 :3) as a white solid, mp 98 "C (Found: C, 67.8; H, 6.65; N, 9.1. Cl7H,,,N,O3 requires C, 68.0; H, 6.7; N, 9.3%); v,,,(KBr)/cm-' 3000, 1700, 1615, 1570, 1490 and 1450; 6,(60 MHz; CDCl,) 1.30 (9 H, s, Bu'), 6.00 (2 H, m, CH + OH), 6.60 (1 H, dd, J 2 and 8,5-H), 7.30 (6 H, m, 4-H + 5 H phenyl), 8.36 (1 H, dd, J 2 and 8, 3-H) and 10.36 (1 H, s, NH). 6-(1-Hydroxycyclohexyl)-2-pivaloylaminopyridine N-oxide 12. General procedure B, using cyclohexanone as electrophile, gave the title compound (60%) (eluent: cyclohexane-ether, 5 :5) as a pale yellow solid, mp 120 "C (Found: C, 65.6; H, 8.6; N, 9.4.ClGH,,N20, requires C, 65.7; H, 8.3; N, 9.6%); v,,,(KBr)/cm-3260, 2930, 2850, 1690, 1570 and 1485; 6,(400 MHz; CDCI,) 1.41-2.31 (19 H, m, Bur + 10 H cyclohexyl), 3.60 (1 H, s, OH), 7.00 (1 H, dd, J2 and 8, 5-H), 7.31 (1 H, t, J8,4-H), 8.37 (1 H, dd, J2 and 8, 3-H) and 10.51 (1 H, s, NH). 2-Formyl-6-pivaloylaminopyridineN-oxide 13. General pro- cedure B, using ethyl formate as electrophile, gave the title compound (62%) (eluent: cyclohexane-ether, 5 :5) as a yellow solid, mp 102 "C (Found: C, 59.65; H, 6.5; N, 12.5. C,,Hl,N,O, requires C, 59.45; H, 6.35; N, 12.6%); v,,,(KBr)/cm-' 3280, 2960, 1700, 1610, 1530, 1500 and 1460; 6,(60 MHz; CDCl,) 1.33 (9 H, s, Bu'), 7.40 (2 H, m, 4-H + 5-H), 8.70 (1 H, dd, J2 and 8, 3-H), 10.40 (1 H, s, NH) and 10.70 (1 H, s, CHO).2-Carboxy-6-pivaloylaminopyridine N-oxide 14. General pro- cedure B, using solid carbon dioxide as electrophile gave, after acidification by 2 mol dm-, hydrochloric acid (extraction by CH,CI, at pH 2), the title compound (48%) as a pink solid, mp 136 "C (Found: C, 55.3; H, 5.9; N, 11.5. C11H14N204 requires C, 55.45; H, 5.9; N, 11.75%); v,,,(KBr)/cm-' 3350, 3130, 2980, tt Physical characteristics of compound 2: mp 84-85 "C (Found: C, 61.7; H, 7.15; N, 14.6. C,,H,,N,O, requires C, 61.85; H, 7.25; N, 14.4%); v,,,(KBr)/cm-' 3250, 3120, 3050, 2960, 1685, 1600, 1560, 1490 and 1430;6,(60 MHz; CDCl,) 1.36 (9 H, s, Bu'), 7.05 (1 H, ddd, J 2, 6 and 8,5-H), 7.40 (1 H, dt, J2 and 8,4-H), 8.33 (1 H, dd, J2 and 6,6-H), 8.53 (1 H, dd, J2 and 8, 3-H) and 10.50 (1 H, s, NH).J. CHEM. SOC. PERKIN TRANS. I 1995 1710, 1620, 1585 and 1480; 6,(60 MHz; CDCI,) 1.33 (9 H, s, Bu'), 7.73 (1 H, t, J8,4-H), 8.20 (1 H, dd, J2 and 8, 5-H), 8.86 (1 H, dd, J 2 and 8, 3-H) and 10.1 (1 H, s, NH). 2-Todo-6-pivaloylaminopyridineN-oxide 15. General pro-cedure B, using iodine as electrophile, gave the title compound (73%) (eluent: cyclohexane-ether, 5:5) as a pale yellow solid, mp 128°C (Found: C, 37.45; H, 3.95; N, 8.6. Cl,Hl,IN,O, requires C, 37.5; H, 4.1; N, 8.75%); v,,,(KBr)/cm ' 3270, 2960, 1685, 1595, 1550, 1495 and 1475; 6,(400 MHz; CDC1,) 1.26 (9 H,s,Bu'),6.97(1 H,t,J8,4-H),7.49(lH,dd7J2and8,5-H), 8.32 (1 H, dd, J2 and 8, 3-H) and 10.34 (1 H, s, NH).General procedure C: metallation of 5-methyl-2-pivaloylamino-pyridine N-oxide 3 Procedure C was identical with general procedure B except that the metallation time was 1.5 h. 5-Methyl-2-pivaloylamino[6 *H]pyridine N-oxide 16. General procedure C, using deuteriated ethanol as electrophile, gave the title compound (100%). The physical characteristics of this product were identical with those described for 3# except for the 'H NMR spectrum where the 6-H signal has disappeared. 5,6-Dimethyl-2-pivaloylamin0[6-~H]pyridineN-oxide 17. General procedure C, using methyl iodide as electrophile, gave the title compound (83%, 'H NMR integration). It was impossible to separate this product from the starting material and only its 'H NMR spectrum is given: 6H(200 MHz; CDCI,) 1.05(9 H, S, Bu'), 2.01 (3 H, S, 5-CH3), 2.23 (3 H, S, 6-CH3), 6.80 (1 H, d, J9,4-H) and 7.85 (1 H, d, J9, 5-H).2-Formyl-3-methyl-6-pivaloylaminopyridineN-oxide 18. General procedure C, using ethyl formate as electrophile, gave the title compound (62%) (eluent: hexane4ther, 5: 5) as a yellow solid, mp 108-1 10 "C (Found: C, 60.85; H, 7.05; N, 11.85. C,,H,,N,O, requires C, 61.0; H, 6.85; N, 11.85%); v,,,(KBr)/cm ' 3290, 2972, 1771, 1686, 1599, 1506 and 1438; 6,(60 MHz; CDC1,) 1.43 (9 H, s, Bu'), 2.60 (3 H, s, CH,), 7.20 (1 H,d, J8.5,4-H),8.55(1 H,d, J8.5,5-H), 10.30(1 H,s,NH)and 10.80 (I H, s, CHO). 2-Carboxy-3-methyl-6-piva1oylaminopyridine N-oxide 19.General procedure C, using solid carbon dioxide as electrophile gave, after acidification by a 2 mol dm solution of hydrochloric acid (extraction by CH2CI, at pH 2), the title compound as a pale yellow solid, mp 178-180 "C (Found: C, 57.4; H, 6.4; N, 11.2. C,,H,,N,O, requires C, 57.15; H, 6.4; N, 11.1%); v,,,(KBr)/cm-l 3360, 2940, 1710, 1675, 1610, 1580, 1510and 1465;6,(60 MHz; CDCl,) 1.40 (9 H, s, Bu'), 2.75 (3 H, s, CH,), 7.55 (1 H, d, J8.5, 4-H), 8.65 (1 H, d, J8.5, 5-H) and 10.00 (1 H, s, NH). 2-Cyano-3-methyl-6-pivaloylaminopyridineN-oxide 20. Gen-eral procedure C, using tosyl cyanide as electrophile, gave the title compound (57%) (eluent: hexane-ethyl acetate, 4 :6) as a white solid, mp 202-204 "C (Found: C, 61.6; H, 6.4; N, 18.2.C12H15N302requires C, 61.8; H, 6.5; N, 18.0%); v,,,(KBr)/ cm-' 3314, 2970, 2240, 1946, 1692, 1522 and 1478; S,(60 MHz; CDCl,) 1.33 (9 H, s, Bu'), 2.48 (3 H, s, CH,), 7.15 (1 H, d, J9,4-H), 8.44 (1 H, d, J9, 3-H) and 10.10 (1 H, s, NH). General procedure D: metallation of 3,44imethoxypyridine N-oxide 21 Anhydrous 3,4-dimethoxypyridine N-oxide (0.31 g, 2.0 mmol) was added to a cold (-75 "C) solution of butyllithium (4.4 # Physical characteristics of compound 3: mp 80-82 "C (Found: C, 63.15; H, 8.0; N, 13.5. C,,H,,N,O, requires C, 63.45; H, 7.75; N, 13.45%);v,,,(KBr)/cm-' 3280, 2970, 2870, 1680, 1620, 1570, 1535 and 1490; &(60 MHz; CDCl,) 1.20 (9 H, s, Bu'), 2.14 (3 H, s, CH,), 7.02 (1 H, d, J8,4-H), 7.95 (I H, s, 6-H), 8.17 (1 H, d, J8, 3-H) and 10.14 (1 H, s, NH).J. CHEM. SOC. PERKIN TRANS. I 1995 mmol) in THF (50 cm3). The mixture was allowed to warm to 0 "C at which temperature it was stirred for 45 min. It was then cooled to -75 "C and the required electrophile was added to it. Stirring was continued for 2 h at the same temperature before the mixture was hydrolysed at -75 "C by the addition of hydrochloric acid, ethanol and THF (1 :1 :2; 8 cm3). After the solution had been warmed to room temperature, it was diluted with water (1 0 cm3), neutralized with potassium carbonate and then extracted with dichloromethane. The extract was dried (MgSO, j and evaporated to leave the crude product, which was purified by column chromatography on silica (eluent is given in the product description).3,4Dirnetho~y[2-~H]pyridine N-oxide 22a. General procedure D, using deuterium chloride (1 cm3) as electrophile afforded 83% (eluent: CH2C1,-methanol, 9 :1) of the title compound. The physical characteristics of this product were identical with those described for 21' except for the 'H NMR spectrum: 6,(200 MHz; CDCl,) 3.93 (3 H, s, OMe), 4.00 (3 H, s, OMe), 6.73 (1 H, d, J7, 5-H) and 7.93 (1 H, d, J7,6-H). 2-(l-Hydroxyethyl)-3,4-dimethoxypyridine N-oxide 22b. General procedure D, using 2-methoxybenzaldehyde as electrophile afforded 60% (eluent: CH,Cl,-methanol, 95 :5) the title compound as a pale yellow solid (61%) mp 89-90°C (Found: C, 54.6; H, 6.7; N, 6.7. C,H, ,NO, requires C, 54.3; H, 6.7; N, 7.0%); v,,,(KBr)/cm 3500,2980, 1615, 1487 and 1444; 6,(200 MHz; CDCl,) 1.53 (3 H, d, J 6.8, CHCH,), 3.82 (3 H, s, OMe), 3.86 (3 H, s, OMe), 5.20 (1 H, q, J6.8, CHCH,), 6.72 (1 H, d, J 7.3, 5-H), 7.5 (1 H, br s, OH) and 7.89 (1 H, d, J7.3, 6-H).2-[Hydroxy(2-methoxyphenyl)methyl]-3,4dimethoxy-pyridine N-oxide 22c. General procedure D, using 2-methoxy- benzaldehyde as electrophile afforded 60% (eluent: CH,C12- methanol, 97:3) a mixture of the title compound and 2-Chydroxy(2-me thoxypheny1)me thyl] -4,5-dime thoxypyridine N-oxide 23c (ratio: 91 :9). The title compound was obtained in pure form as a white solid by recrystallization from acetone, mp 137 "C (Found: C, 62.0; H, 5.8; N, 4.7. C1,H17N0, requires C, 61.85; H, 5.9; N, 4.8%); v,,,(KBr)/cm 2940, 1600, 1490, 1470 and 1450; dH(200 MHz; CDC1,) 3.76 (3 H, s, OMe), 3.84 (3 H, s, OMe),3.90(3H,s,OMe),6.61[l H,s,CH(OH)],6.78(1 H,d, J 7.3,5-H), 6.87(1 H,d, J7.8,3'-H),6.89(1 H, t, J7.6,5'-H), 7.24 (1 H,dt, J7.8and 1.7,4'-H),7.57(1 H,dd, J7.6and 1.7.6'-H), 7.98 (1 H, d, J7.3, 6-H) and 8.15 (1 H, s, OH).2-Iodo-3,4dimethoxypyridine N-oxide 22d. General procedure D, using iodine in THF (quickly added) at -70 "C, with stirring for 5 min, afforded (eluent: CH,Cl,-methanol, 95: 5) the title compound (65%), mp 167-168 "C (Found: C, 29.6; H, 2.8; N, 4.8. C7H,IN0, requires C, 29.9; H, 2.9; N, 5.0%); vmaX(KBr)/cm-'2940, 1600, 1470 and 1425; dH(200 MHz; C2H,]-DMSO) 3.75 (3 H, s, OMe), 3.88 (3 H, s, OMe), 7.15 (1 H, d, J 7.3, 5-H) and 8.27 (1 H, d, J7.3,6-H).2,6-Diiodo-3,4dimethoxypyridine N-oxide 24d. Anhydrous 3,4-dimethoxypyridine N-oxide (I .25 g, 8.0 mmol) was added to a cold (-75 "C) solution of BuLi (26.5 mmol) in THF (120 cm3). After the mixture had warmed to 0 "C it was stirred for 0.75 h at this temperature before being cooled to -75 "C. A solution of iodine (6.75 g, 26.5 mmol) in THF was then added to the mixture after which it was stirred for 1 h at this temperature. After dilution with ethanol (25 cm3), the solution was warmed to room temperature, diluted with water (40 cm3), treated with sodium thiosulfate to remove the iodine (bleaching) and then extracted with chloroform. The extract was dried (MgSO,) and evaporated to leave the crude product, which was purified by column chromatography on silica gel using CH,Cl,-ethanol (97 : 3) as eluent to afford the title compound as a pale yellow solid (76%), mp 218-219°C (Found: C, 20.9; H, 1.7; N, 3.5.C7H712N0, requires C, 20.65; H, 1.7; N, 3.45%); vmax-(KBr)/cm 2940, 1575, 1470 and 1420; dH(200 MHz; C2H6]- 2507 DMSO) 3.73 (3 H, s, OMe), 3.88 (3 H, s, OMe) and 7.70 (1 H,s, 5-H). 2-Iodo-4,5-dimethoxyyridine N-oxide 23d. 2,6-Diiodo-3,4-dimethoxypyridine N-oxide 24d (0.407 g, 1.O mmol) was added to a cold (-75 "C) solution of BuLi (3.3 mmol) in THF (25 cm3). The mixture was stirred at -30 "C for 1 h and then hydrolysed by addition of hydrochloric acid, ethanol and THF (1 : 1 :2; 4 cm3). It was warmed to room temperature, treated with water (10 cm3) and with potassium carbonate, and then extracted with dichloromethane.The extract was dried (MgSO,) and evaporated to leave the crude product, which was purified by column chromatography on silica gel using CH2C1,-methanol(96: 4) as eluent to afford the title compound as a white solid (7773, mp 171 "C (Found: C, 29.7; H, 2.85; N, 4.8. C,H,TNO, requires C, 29.9; H, 2.85; N, 5.0%); vmax(KBr)/cm-' 2920, 1600, 1510 and 1430; 6,(200 MHz; C2H6]-DMSO) 3.78 (3 H, s, OMe), 3.83 (3 H, s, OMe), 7.50(1 H, s, 5-H) and 8.28 (1 H, s, 2-H). 3,4-Dimethoxy-2-(o-methoxybe11zoyl)pyridineN-oxide 26. A solution of the alcohol 2242(1.10 g, 0.004 mol) in dry toluene (25 cm3) was oxidized by active MnO, (3.48 g, 0.04 mol) at reflux in a Dean-Stark apparatus, the reaction being monitored by TLC.When the reaction was complete, the mixture was filtered through Celite and the filter cake was washed by chloroform. The combined filtrate and washings were dried and evaporated to give a crude product which was purified by chromatography on silica gel using CH,CI,-methanol(95 :5) as eluent to afford the title compound as a beige solid (64%), mp 169 "C (Found: C, 62.3; H, 5.2; N, 4.8. C,SHl,NO, requires C, 62.0; H, 5.3; N, 4.6%); v,,,(KBr)/cm-' 2940, 1670, 1600, 1490, 1465 and 1430; dH(200 MHz; CDCl,) 3.66 (3 H, s, OMe), 3.80 (3 H, s, OMe), 3.95(3H,s,OMe),6.82(1H,d,J7.1,5-H),6.92(1H,d,J7.6, 3'-H), 7.06(1 H, t, J7.7,5'-H), 7.53(1 H,dt, J7.6and 1.5,4'-H), 7.95 (1 H, d, J 7.I, 6-H) and 8.06 (1 H, dd, J 7.7, 6'-H); 6,(50 MHz; CDCl,) 56.2 (OMe), 56.3 (OMe), 61.7 (OMe), 107.8, 112.2, 120.9, 125.0, 131.2, 134.7, 135.5, 143.3, 146.8, 151.7, 160.1 and 184.5 (GO).1H-Benzopyrano[3,2-b] pyridine-4,lO-dione 25. Anhydrous boiling (215 "C) pyridinium chloride (20 g) was added to the ketone 26 (1.5 mmol) and the mixture was heated under reflux for 20 min after which it was poured on ice. The resulting precipitate was filtered off, washed with chloroform and dried. The pure title compound was obtained as a white solid by sublimation at 190 "C/3 mmHg (62%), mp 260 "C (Found: C, 67.4; H, 3.1; N, 6.4. C12H7N03 requires 67.6; H, 3.3; N, 6.6%); v,,,(KBr)/cm-' 3430 (NH), 2920, 1665 (C=O), 161 0, 1560 and 1465; 6,(200 MHz; C2H6]-DMSO) 6.46 (1 H, d, J 7.3, 3-H),7.53(1 H,t,J7.9,8-H),7.75-7.96(3H,m,2-H,&Hand7-H) and 8.18 (1 H, dd, J 7.9 and 1.5, 9-H); d,(50 MHz, ['H6]- DMSO-d6) 116.2, 119.0,131.3, 125.1, 127.9, 136.0, 137.8, 146.9, 155.0, 170.5 and 173.0; m/z (FAB) 214 (M + 1, 100%).2,6-Diiodo-3,4-dimethoxypyridine30.Phosphorus trichloride (1.80 g, 12 mmol, diluted in 8 cm3 of chloroform) was slowly added at 40°C to a stirred solution of 2,6-diiodo-3,4 dimethoxypyridine N-oxide 24 (1.63 g, 4.0 mmol) in chloroform (40 cm'). The mixture was heated under reflux for 1.5 h and then cooled and poured into ice. The crude product was purified by chromatography on silica gel using CH,Cl,- hexane (3 :2) as eluent to afford the title compound as a white solid (83%), mp 97 "C (Found: C, 21.5; H, 1.8; N, 3.65.C7H,12N02 requires C, 21.5; H, 1.8; N, 3.6%); vmax(KBr)/cm-l 2940, 1550, 1525, 1470 and 1415; 6H(200 MHz; CDCl,) 3.80 (3 H, s, OMe), 3.88 (3 H, s, OMe) and 7.13 (1 H, s, 5-H). 2-Iodo-4,5dimethoxypyridine29.Method A:from 2,6-diiodo-3,4-dimethoxypyridine 30.-A solution of compound 30(2.30 g, 5.9 mmol) in THF (25 cm3) was added to a cold (-75 "C) solution of BuLi (1 3.0 mmol) in THF (140 cm3) and the mixture was stirred for 0.5 h at -75 "C.It was then hydrolysed at this temperature by a mixture of hydrochloric acid, ethanol and THF (1 : 1: 1; 15 cm3). After being warmed to room temperature, was diluted with water (20 cm3), treated with sodium carbonate and sodium thiosulfate, and then extracted with CH2C1,. The extract was dried (MgS04) and evaporated to leave the crude product, which was purified by column chromatography on silica gel using CH,Cl, as eluent to afford the title compound as a white solid (7473, mp 103-104 "C (Found: C, 31.9; H, 3.0; N, 5.1.C,H,INO, requires C, 31.7; H, 3.05; N, 5.3%); v,,,(KBr)/cm-' 2970, 1575, 1500 and 1435; 6,(200 MHz; CDCl,) 3.85 (6 H, 2 s, 2 OMe), 7.07 (I H, s, 5-H) and 7.80 (1 H, s, 6-H). Method B:from 2-iodo 4,5-dimethoxypyridine N-oxide 23d.-Phosphorus trichloride (0.5 g, 3.6 mmol, diluted in 5 cm3 of chloroform) was slowly added at 40 "C to a stirred solution of 23d (0.281 g, 1.0mmol) in chloroform (10 cm3). The mixture was heated under reflux for 1.5 h and then cooled and poured into ice. The title compound, obtained as a white solid (44%), was identical with compound 29 prepared by Method A.4,4',5,5'-Tetramethoxy-2,2'-bipyridy131. Zinc powder (0.230 g, 3.5 mmol) was added to a stirred mixture of nickel(I1) chloride hexahydrate (0.832 g, 3.5 mmol) and triphenylphosphine (3.67 g, 14 mmol) in dimethylformamide (20 cm3) under argon at 50 "C. After 1 h, 2-iodo-4,5-dimethoxypyridine29(0.880 g, 3.32 mmol) was added to the stirred mixture and stirring continued for 48 h. The mixture was then treated with ammonia and extracted with hydrochloric acid (2 mol dm-3). The aqueous layer was treated with potassium carbonate and then extracted with CH,C12. The extract was dried (MgSO,) and evaporated to afford the crude product which was purified by chromatography on silica gel using ethyl acetate-methanol (97:3) as eluent to afford the title compound as a white solid (7973, mp 222 "C (Found: C, 60.9; H, 5.8; N, 10.1%; Mf, 276.C,,H,,N,O, requires C, 60.9; H, 5.7; N, 9.9%; M, 276); v,,,(KBr)/cm-' 2920, 1560, 1490 and 1435; 6,(200 MHz; CDCl,) 3.99 (6 H, s, OMe), 4.04 (6 H, s, OMe), 7.96 (2 H, s, 3-H and 3'-H) and 8.15 (2 H, s, 6-H and 6'-H);&(50 MHz; CDCI,) 55.8 (OMe), 56.5 (OMe), 103.2, 132.0, 145.7, 150.8 and 155.5. 2,2'-Bipyridyl-4,4',5,5'-tetraol 28. A solution of 4,4',5,5'- tetramethoxy-2,2'-bipyridyl 31 (0.215 g, 0.78 mmol) in 47% hydrobromic acid (4 cm3) was heated under reflux for 20 h after which the excess of acid was distilled off and the residue was diluted with water and then evaporated.The residue was dissolved in water and the solution adjusted to pH 7 by addition of potassium carbonate. The resulting precipitate was filtered off and washed with distilled water, to afford the title compound (70%), mp 260 "C (Found: C, 54.8; H, 3.4; N, 12.5. Cl,H,N204 requires C, 54.6; H, 3.65; N, 12.7%); v,,,(KBr)/ cm 3312 (OH), 2731, 1630, 1608, 1542, 1480 and 1444; J. CHEM. SOC. PERKIN TRANS. I 1995 6,(200 MHz, [2H,]-DMSO) 7.05 (2 H, s, 3-H and 3'-H) and 7.68 (2 H, s, 6-H and 6'-H);m/z (CI, Bu'H) 221 (M + 1, 100%). AcknowIedgements Dr Marc Mallet is gratefully acknowledged for helpful advice and discussions. We thank the French Ministere de I'Enseignement Superieur et de la Recherche for financial support (grant No 91 26).References 1 G. Queguiner, F. Marsais, V. Snieckus and J. Epsztajn, in Advances in Heterocyclic Chemistry, ed. A. R. Katritzky, Academic Press, San Diego, 1991, vol. 52, p. 187. 2 R. A. Abramovitch and E. E. Knaus, J. Heterocycl. Chem., 1969,6, 989. 3 R. A. Abramovitch, J. Campbell, E. E. Knaus and A. Silhankova, J. Heterocycl. Chem., 1972,9, 1367. 4 R. A. Abramovitch, E. M. Smith, E. E. Knaus and M. Saha, J.Org. Chem., 1972,37, 1690. 5 R. A. Abramovitch, R. T. Coutts and E. M. Smith, J. Org. Chem., 1972,37,3584. 6 R. A. Abramovitch and E. M. Smith, in Pyridine and Its Derivatives, ed. R. A. Abramovitch, Wiley, New York, 1974, part 2, p. 1. 7 S. L. Taylor, D. Y. Lee and J. C. Martin, 1983,48,4158. 8 A. R. Katritzky, J. Chem. SOC.,1957, 191. 9 (a) P. Beak and R. A. Brown, J. Org. Chem., 1977, 42, 1823; (b) J. Epsztajn, Z. Berski, J. Z. Brzezinski and A. Jozwiak, Tetrahedron Lett., 1980,21,4739;(c)J. Epsztajn, J. Z. Brzezinski and A. Jozwiak, J. Chem. Rex, 1986 (S), 18; (d) M. Watanabe and V. Snieckus, J. Am. Chem. Soc., 1980, 102, 1457; (e) W. Fuhrer and H. W. Gschwend,J. Org. Chem., 1979,44,1133;(f)T. Gungor, F. Marsais and G. Queguiner, Synthesis, 1982, 499; (8) J. A. Turner, J. Org. Chem., 1983,48,3401; (h)L. Estel, F. Linard, F. Marsais, A. Godard and G. Qukguiner, J. Heterocycl, Chem., 1989,26, 105. 10 F. Trecourt, M. Mallet, 0.Mongin, B. Gervais and G. Queguiner, Tetrahedron, 1993,49, 8373. 11 T. Talik and Z. Talik, Rocz. Chem., 1964,38,777. 12 F. J. Villani, T. A. Mann, E. A. Weffer, J. Hannon, L. L. Larca, M. J. Landon, W. Spivak, D. Vashi, S. Tozzi, G. Danko, M. Del Prado and R. Lutz, J. Med. Chem., 1975, 18, 1. 13 R. Royer, B. Bodo, P. Demerseman and J. M. Clavel, Bull. SOC. Chim. Fr., 1971, 2929; F. Trecourt, F. Marsais, T. Gungor and G. Queguiner, J. Chem. Soc., Perkin Trans. 1, 1990,2409. 14 W. Z. Antkowiak and W. P. Gessner, Tetrahedron Lett., 1979, 21, 1931; H. A. Hasseberg and H. Gerlach, Helv. Chim. Acta, 1988,71, 957 and references cited therein. 15 M. Tiecco, L. Testaferri, M. Tingoli, D. Chianelli and M. Montanucci, Synthesis, 1984, 736. Paper 5/017 16E Received 17th March 1995 Accepted 18th April 1995