A facile one-step synthesis of aromatic indolizines by 1,3-dipolar cycloaddition of pyridinium and related heteroaromatic ylides with alkenes in the presence of TPCD Copy4(HCrO4)2

摘要

J. CHEM. soc. PERKIN TRANS. 1 1993 A Facile One-step Synthesis of Aromatic lndolizines by I ,3-Dipolar Cycloaddition of Pyridinium and Related Heteroaromatic Ylides with Alkenes in the Presence of TPCD [Copy,(HCrO,),] Xudong Wei, Yuefei Hu," Tingsheng Li and Hongwen Hu Department of Chemistry, Nanjing University, Nanjing 210008, People's Republic of China A facile and general one-step method is presented for the synthesis of aromatic indolizine compounds 3a-n in moderate to high yields (53-99%) by reaction of the pyridinium N-ylides 1a-e, the quinolinium N-ylide 1f and the isoquinolinium N-ylide 1g with various olefinic dipolarophiles. such as acrylonitrile 2a, methyl acrylate 2b, acrylamide 2c, diethyl maleate 2d and methyl crotonate 2e, respectively, in the presence of a new oxidant TPCD [Copy,(HCrO,),, DM F.For both practical and theoretical reasons, a number of methods have been published for the synthesis of aromatic indolizines,'-3 one of the most important, although usually low yielding, being the 1,3-dipolar cycloaddition of pyridinium and related heteroaromatic ylides with acetylene^.^-' Several modified methods have also been reported to lead to indolizines in relatively low yield or with relatively inaccessible materi- als.l2-I6 The scope of all these procedures, however, have been limited by the acetylenes, few of which are commercially available. However, methods for the preparation of aromatic indolizines by 1,3-dipolar cycloaddition of pyridinium ylides with olefinic dipolarophiles replacing acetylenes are available for certain special cases (e.g. diphenylthiirene S,S-dioxide," a-aminoethylene derivatives, l8 phenyl vinyl sulfoxide,' 2-or 4- vinylpyridines2o and a-methoxyethylene derivatives); 21 also a two-step procedure is possible in which the initially formed tetrahydroindolizines or dihydroindolizines are dehydrogen- ated by treatment with suitable reagent^.',^,'^*^^*^^ All these procedures, however, suffer from drawbacks and limitations.Herein we report a simple and practical one-step method that affords aromatic indolizines in good to high yields starting from 1,3-dipolar cycloaddition of pyridinium ylides with olefinic dipolarophiles in the presence of a new oxidant TPCD [Copy,(HCrO,),, tetrapyridinecobalt(I1) dichromate].Results and Discussion TPCD, a brown crystalline bi-metallic complex with pyridine, prepared easily by adding pyridine (4 equiv.) to aqueous chromium trioxide (2 equiv.) and cobalt@) acetate (1 equiv.), has been found of value in the synthesis of aromatic five- membered ring nitrogen heterocycle^.^^-^^ In continuation of our studies of the chemical behaviour of TPCD, we found that the drawbacks in the synthesis of aromatic indolizines by 1,3- dipolar cycloaddition could be solved easily by its use. N-Phenacylpyridinium bromide la (1 equiv.) and acrylonitrile 2a (4 equiv.), (the same starting materials as used in earlier work),23 were treated with TPCD (0.65 equiv.) in DMF and pyridine at 90 "C under nitrogen for 2 h, after which the reaction mixture was worked up to give yellow crystals, m.p.128-1 30 OC (Scheme 1) identical (IR, 'H NMR and elemental analysis) with authentic 3-benzoyl-1-cyanoindolizines3a (m.p. 128 "C) 23 [cf: 3-benzoyl-1 -cyano- 1,2,3,8a-tetrahydroindolizine4 (lit.,22 m.p. 103-105 "C)]. The 1,3-dipolar cycloaddition and dehydrogen- ative aromatizations in this one-pot reaction gives an extra- ordinarily high yield (93%) not previously reported for similar procedures. tetrapyridinecobalt(i1) dichromate] at 90 "C for 2 h in R F2 1 2 3 1R 2 R' R2 la H 2a H CN lb 2-Me 2b H C02Me lc 4-Me 2c H CONH2 Id 3-CO2Et 2d COpEt COpEt-US le 4-C02Et 2e Me C02Me-trans lf 2,3-Benzo 19 3,6&nZO Weme 1 To demonstrate the scope of the reaction, several other olefinic dipolarophiles, e.g.methyl acrylate 2b, acrylamide 2c, diethyl maleate 2d and methyl trans-crotonate 2e, were allowed to react with N-phenacylpyridinium bromide la under the same conditions to give the corresponding indolizines 3b-e, respectively. It is interesting that the yields of products 3 decrease in the order 3a to 3e (see Table l), the relative activity of the olefinic dipolarophiles changing with a change in the substituents on the ethylene. The monosubstituted ethylene with the strong electron-withdrawing group CN (in 2a) gave the best yield and the 1 ,Zdisubstituted ethylene with electron- withdrawing groups (in 2d) gave a moderate yield. The activity of ethylene with an electron-donating group (2e),was reduced significantly. The substituted pyridinium N-ylides lb-e were allowed to react with acrylonitrile 2a to give 3f-j also in high yield.The reaction between 1 and 2a gave an isomeric mixture of 3h and 3i in a ratio of ca. 1 :1.4 with a total yield of 84%. Results for non- regioselective reactions have already been reported 8*'' and here we observed that the reaction is non-specific with respect to the ratio of isomers. However, the reaction of isoquinolinium N-ylide lg with 2a and 2b gave the 1,2-cycloaddition products 31 and 3m,respectively. Quinolinium N-ylide If gave 3k in a relatively lower yield (79%). Under the same reaction conditions, the reaction of la with 2a without TPCD, or in the presence of just one of the components of TPCD [Cr03, pyridine or cobalt@) acetate], gave none of the desired product 3a.Further, none of the 2,3-dihydro- 2488 Table 1 Indolizines 3 prepared 3R R' R2 Yields ('A) 3a H H CN 93 3b H H C0,Me 88 3c H H CONH, 74 3d H C0,Et C0,Et 70 3e H Me C0,Me 53 3f 5-Me H CN 99 3g 7-Me H CN 88 3h 6-C02Me H CN 35 3i 8-C02Me H CN 49 3j 7-C02Me H CN 95 3k 5,6-Benzo H CN 79 31 7,8-Benzo H CN 98 3m 7,8-Benzo H C0,Me 82 qN TPCWPv/DMF 4 Scheme 2 indolizine 5 or aromatic indolizine 3a was obtained when 3- benzoyl-1 -cyano- 1,2,3,8a-tetrahydroindolizine4 "was warmed with cobalt(I1) acetate at 90 "C in DMF for 2 h. Treatment of compound 4 by TPCD, with or without pyridine, at 90 "C in DMF for 2 h, led to the aromatization of 4 and formation of the indolizine 3a (Scheme 2); the best yield (65%) in this reaction was obtained in only a few experiments.With a freshly prepared sample of 4 and addition of the acrylonitrile 2a to the reaction the yield of 3a increased to 85% (it is likely that the low yield is caused by partial dissociation of 4 at higher reaction temperatures), but it is still significantly lower than that in the one-step reaction (93%). In the light of the above results and the fact that no tetrahydroindolizine or dihydroindolizine could be detected as intermediates in quenched reactions, it seems unlikely that the system involved is a simple one-pot reaction consisting of two components. We suggest that the Co"' component is the 'real' and active entity in the dehydrogenative aromatization and that the CrV1 is actually a reoxidation agent, (Co" + Co"') in which it is converted into Cr"'.The experimental evidence to support such hypotheses is not, however, at present, to hand. Experimental All m.p.s are uncorrected and measured with a Yanaco MP-500 apparatus. IR spectra were recorded on a Nicolet FT-IR 5DX spectrometer with KBr pellets. 'H NMR spectra were recorded on a JEOL JNM-PMX 60SI spectrometer at ambient temperature in CDC1, with TMS as an internal reference and elemental analyses were performed on a Perkin-Elmer 240-C instrument. Preparation of 3-Benzoyl- 1 -cyanoindolizine 3a: Typical Pro-cedure.-A solution of N-phenacylpyridium bromide la (2.78 g, 10 mmol), acrylonitrile 2a (2.12 g, 40 mmol), TPCD (4.0 g, 6.5 mmol) and pyridine (2.0 cm3) in DMF (40 cm3) was stirred at 90 "C for 2 h.The mixture was then cooled to room temperature and poured into 5% aq. HCl (100 cm3). The solution was extracted with diethyl ether (2 x 50 cm3)and the combined extracts were washed with water (2 x 50 an3),dried (Na,SO,) and evaporated to give a solid. This was purified by vacuum chromatography with a short column [silica gel G, 10 pm, 25 x 50 mm, eluted with 25% ethyl acetate in light petroleum (b.p. 60-90 "C)] to give 3a as yellow crystals (2.29 g, 93%), m.p. J. CHEM. SOC. PERKIN TRANS. 1 1993 128-130 "C (from EtOH) (lit.,', 128 "C) (Found: C, 78.1; H, 4.0; N, 12.0. C16H1,N20. Calc. for: C, 78.03; H, 4.09; N, 11.38%); v,,,/cm-' 2200 and 1617; 6, 7.05 (dd, J 1.0, 6.0, 1 H, ArH), 7.27(dd,J1.0,6.0,1H,ArH),7.40-7.90(m,9H,ArH)and9.95 (d, J 6.0, 1 H, ArH).Compounds 3bm were prepared by the same procedure (Table 1). Methyl 3-benzoylindolizine-1 -carboxylate 3b. M.p. 160-162 "C (from EtOH) (lit.,6 161-162 "C) (Found: C, 73.3; H, 4.7; N, 4.8. Calc. for C17H13N03: C, 73.11; H, 4.69; 5.02%); v,,,/cm-' 1615, 169; dH 3.69 (s, 3 H, CH,), 7.05 (dd, J 1.0, 6.0, lH,ArH),7.27(dd,Jl.O,6.0,lH,ArH),7.43-7.95(m,6H, ArH), 8.40 (d, J 8.0, 1 H, ArH) and 9.93 (d, J 6.0, 1 H, ArH). 3-Benzoyl-1 -carbamoylindolizine 3c. M.p. 183-1 84 "C (from EtOH) (lit.,7 193-194 "C) (Found: C, 72.6; H, 4.8; N, 10.5. Calc. for C16H12N,0z: c, 72.72; H, 4.58; N, 10.60%); v,,,/cm-' 3350, 3170, 1670 and 1635; 6, 3.20 (s, 2 H, NH2), 7.00-7.95 (m, 7 H, ArH), 8.55 (d, J9.0, 1 H, ArH) and 9.86 (d, J7.0, 1 H, ArH).Diethyl 3-benzoylindolizine- 1,2-dicarboxylate 3d. M.p. 107- 109°C (from EtOH) (Found: C, 69.1; H, 5.25; N, 3.6. C,,H,,N05 requires C, 69.09; H, 5.24; N, 3.64%); v,,/crn-' 1730, 1695 and 1600; 6, 1.03 (t, J 7.0, 3 H, CH,), 1.33 (t, J 7.0, 3H,CH3), 3.66(q, J7.0,2H,CH2),4.37(q, J7.0,2H,CH2), 7.08 (dd, J2.0, 7.0, 1 H, ArH), 7.30 (dd, J2.0, 7.0, 1 H, ArH), 7.46-7.91 (m, 5 H, ArH), 8.40 (dd, J 1.0,9.0,1 H, ArH) and 9.70 (dd, J 1.0,6.0, 1 H, ArH). Methyl 3-benzoyl-2-methylindolizine-1 -carboxylate 3e. M .p. 116-117°C (from EtOH) (Found: C, 73.7; H, 5.1; N, 4.6. C18H15N03 requires C, 73.71; H, 5.15; N, 4.60%); v,,,/cm-' 1689 and 1602; 6, 2.23 (s, 3 H, CH,), 3.91 (s, 3 H, CH,), 6.97 (m, 1 H,ArH),7.23-7.89(m,6H,ArH),8.37(d,J9.0,1 H,ArH) and 9.55 (d, J 7.0, 1 H, ArH).3-Benzoyl-5methylindolizine-1 -carbonitrile 3f. M.p. 160-162°C (from EtOH) (Found: C, 78.4; H, 4.7; N, 10.6. Cl7H,,N2O requires C, 78.44; H, 4.65; N, 10.76%); v,,,/cm-' 2215and 1625;6,2.59(s,3H,CH3),7.04(d, J8.0, 1 H,ArH), 7.35-7.98 (m, 7 H, ArH) and 8.17 (dd, J2.0,7.0, 1 H, ArH). 3-Benzoyl-7-methylindolizine-1 -carbonitrile 3g. M.p. 17 1- 172°C (from EtOH) (Found: C, 78.4; H, 4.4; N, 10.5. C17H,,N20 requires C, 78.44; H, 4.65; N, 10.76%); v,,,/cm-' 2210 and 1610; 6, 2.67 (s, 3 H, CH,), 7.10 (d, J7.0, 1 H, ArH), 7.30-8.00 (m, 7 H, ArH) and 9.93 (d, J 7.0, 1 H, ArH). Methyl 3-benzoyl- 1 -cyanoindolizine-6-carboxylate3h.M .p. 197-199 "C [EtOAc-light petroleum (60-90 "C)] (Found: C, 71.05; H, 3.8; N, 9.0. C18H12N203 requires C, 71.05; H, 3.97; N, 9.21%); v,,,/cm-' 2215, 1720 and 1618; 6, 4.00 (s, 3 H, CH,), 7.10-8.15 (m, 8 H, ArH) and 10.45 (d, J 7.0, 1 H, ArH). Methyl 3-benzoyl-1-cyanoindolizine-8-carboxylate3i. M.p. 206-209 "C [EtOAc-light petroleum (b.p. 60-90 "C)] (Found: C, 71.1; H, 3.7; N, 9.1. Cl8Hl2N2O3 requires C, 71.05; H, 3.97; N, 9.21%); v,,,/c~-' 2220 and 1725; 6, 4.07 (s, 3 H, CH,), 7.10-8.14 (m, 8 H, ArH) and 10.10 (dd, J 1.0, 7.0, 1 H, ArH). Methyl 3-benzoyl-1-cyanoindolizine-7-carboxylate3j. M.p. 212-214°C (DMF) (Found: C, 71.0; H, 4.05; N, 9.3. Cl8Hl2N2O2 requires C, 71.05; H, 3.97; N, 9.21%); v,,,/cm-' 2220, 1725 and 1625; ~3~4.06 (s, 3 H, CH,), 7.45-7.95 (m, 7 H, ArH), 8.53 (d, J7.0, 1 H, ArH) and 9.93 (d, J7.0, 1 H, ArH).1-Benzoylpyrrolo[ 1,2-a]quinoline-3-carbonitrile 3k. M.p. 180-182°C (EtOAc-acetone) (lit.,,, 177-179 "C) (Found: C, 81.0 H, 3.95; N, 9.3. Calc. for C,,H,,N,O: C, 81.06; H, 4.08; N, 9.45%); v,,,/cm-' 2225 and 1635;6,7.33 (s, 1 H, ArH), 7.35- 7.85 (m, 8 H, ArH), 7.86-8.15 (m, 3 H, ArH). 1 -Benzoylpyrrolo[2,1 -a]isoquinoline-3-carbonitrile31. M.p. 192-193 "C (CHCl,) (lit.,,, 196-197 "C) (Found: C, 80.8; H, 4.0; N, 9.35. Calc. for C,,H,,N,O: C, 81.06; H, 4.08; N, 9.45%); v,,,/c~-' 2225 and 1630; 8, 7.30 (d, J 7.0, 1 H, ArH), 7.40- 7.95 (m, 9 H, ArH), 8.90 (m, 1 H, ArH) and 9.46 (d, J 7.0, 1 H, ArH).J. CHEM. SOC. PERKIN TRANS. 1 1993 Methyl 1 -benzoylpyrrolo[2,1 -a]isoquinoline-3-carboxylate 3m. M.p. 183-1 84 "C(CHC1,-acetone) (Found: C, 76.4;H, 4.35; N, 4.2. C,,H,,NO, requires C, 76.58; H, 4.59; N, 4.25%); v,,/cm-' 1705 and 1620; 6, 3.90 (s, 3 H, CH,),7.22 (d, J 7.0, 1 H,ArH),7.40-7.95(m,9H,ArH),9.60(d,J7.0,1H,ArH)and 9.85 (m, 1 H, ArH). 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