On the reaction ofN-vinyliminophosphoranes. Part 16. A new synthesis of 5H-indeno1,2-bpyridines and 5H-indeno1,2-bpyridin-5-ones

摘要

J. CHEM. SOC. PERKIN TRANS. I 1991 On the Reaction of N-Vinyliminophosphoranes. Part 16.' A New Synthesis of 5H-Ind e n o1,2-61pyr i d i nes and 5N-Ind e no1,2-61py r i d in-5-ones Makoto Nitta," Manami Ohnuma and Yukio lino Department of Chemistry, School of Science and Engineering, Waseda University, Shinjuku-ku, Tokyo 7 69, Japan Thermal react ion of tri bu tyl (inden-3-ylimino) p hosp hora ne with ~l,p-unsaturated ketones and aIde hydes led to a Michael-type C-C bond formation and subsequent aza-Wittig reaction to give 5H-indeno(l,2- b)pyridines in good to modest yield. The products were oxidized conveniently by chromium trioxide and t-butyl hydroperoxide to give 5H-indenol,2-b pyridin-5-ones, including the 4-azafluorenone alkaloid onyc h ine.The 4-azafluorenone (5H-indeno 1,2-bpyridin-5-one) alkal- oids isolated from Annonaceae species comprise a small but biologically intriguing group of alkaloids. This class of alkaloids has been postulated to be derived from aporphine precursors.2 Subsequent to the initial isolation and structural misassignment of onychine (4-methyl-SH-indeno 1,2-bpyridin-5-one)," the structure of this alkaloid was confirmed by ~ynthesis,~-~ and the isolation '-and synthesis of other 4-azafluorenones '-lo have been explored. Several approaches have been developed for the synthesis of the 5H-indeno 1,2-bpyridin-5-ones: oxidative thermal rearrangement of 2-indanone oxime O-ally1 ethers, albeit in low yields;499*1 ' direct cyclization of 2-aryl-3-methylpyridines to give 5H-indeno 1,2-bpyridines followed by oxidation; 5*1 cyclization of 2-aryl-3-nicotinic acids by use of polyphosphoric Several other approaches have been studied.l2 We have recently demonstrated the simple preparation of N-vinyliminophosphoranes, which were found to react with X-bromo ketones, x,P-unsaturated ketones, and activated tropones in an enamine-type alkylation (Michael addition) followed by aza-Wittig reaction to provide convenient routes to pyrroles, ' pyridines, l4 n(2,4)pyridinophanes,' and l-azaazu- lenes.I6 As an extension of our studies on the synthetic utility of N-vinyliminophosphoranes,we have examined the reaction of tributyl(inden-3-y1imino)phosphorane 2b l7 with cx,p-unsatu- rated ketones and aldehydes to provide a convenient route to 5H-indeno 1,2-bpyridines, which were conveniently oxidized to 5H-indeno 1,2-bpyridin-5-ones, including the 4-azafluorenone alkaloid onychine 12e.We describe here our results in detail. Results and Discussion The (inden-3-y1imino)triphenylphosphorane2a and tributyl- (inden-3-y1imino)phosphorane2b ' were easily prepared by Staudinger reaction of readily available 3-azidoindene 1 'with triphenylphosphine and tributylphosphine, respectively, in anhydrous solvent. The phosphoranes 2a and 2b were easily hydrolysed in acidic media to give indan-l-one 3 (Scheme 1). 2a; R = Ph 3 b;R=Bu Scheme 1 The phosphorane 2a is stable under work-up conditions and satisfactory physical data were obtained.On the other hand, the phosphorane 2b was not stable under work-up conditions Table 1 Reaction of the phosphorane 2b with +unsaturated ketones 4ad and aldehydes 4e and f Reaction Product (5) Entry Substrate Solvent time (f/h) yield () 1 4a Ph Me 17 5a (80) 2 3 4b 4c PhH PhMe 4 20 5b (78) (85) 4 4d PhH 22 5d (84) 5 6 4e 4f PhMe PhH 18 9 5e (49) 51 (lo),5b (30) and satisfactory analytical data were not obtained. However, the acid hydrolysis and comparison of the assigned 'H NMR data of compound 2b with those of the triphenyl analogue 2a clearly support the structure of compound 2b. Since the phosphorane 2a seemed to be less reactive as compared with the butyl analogue 2b, the synthetic reactions were examined conveniently by using in situ butyl derivative 2b in a one-pot procedure without isolation.' When a solution of 3-azidoindene 1 and tributylphosphine in anhydrous benzene or toluene was stirred at 0 "C,the reaction proceeded easily with complete disappearance of 1 within 30 min. To this reaction mixture were added an a$-unsaturated ketone 4a-d or an aldehyde 4e or 4f and 5 mol of Pd-C, and the mixture was heated under reflux to give a 5H-indeno1,2- blpyridine derivative 5a-f and tributylphosphine oxide (Scheme 2). The results are summarized in Table 1. In the case 4a-f 5a-f of ketones 4a-d (entries 14), products 5a-d were obtained in good yield. In the case of aldehyde 4e, on the other hand, 4- methyl-5H-indeno 1,2-bpyridine 5e, which is a precursor of onychine, was obtained in modest yield (entry 5).In contrast, the reaction with cinnamaldehyde 4f resulted in the formation of two products, the expected 4-phenyl compound 5f and unexpected 2-phenyl isomer 5b in a modest combined yield (entry 6). The structure of each of the known compounds 5a-e, but not that of compound 5f, has been characterized by comparison of their physical data with those reported in the literature (see Experimental section). The structure of compound 5f was assigned on the basis of elemental analyses of the picrate, and high-resolution mass, IR and 'H NMR spectra. Comparison of the assigned 'H NMR spectrum of compound 5f with those of compounds 5a-e easily revealed the structure of the former.The formation of compounds 5a-f is explained by the mechanism shown in Scheme 3. The initial step is the enamine- 6a-f 9 -OPBu3 -OPBuj t i R' H lph 8a-f 11 lPdiC IPdiC Sa-f Sb Scheme 3 type alkylation (Michael addition) of substrate 2b onto the p-carbon atom of enones 4a-f to give intermediates 6a-f, which undergo hydrogen migration to generate iminophosphoranes 7a-f. Intramolecular aza-Wittig reaction then gives the dihydropyridines 8a-f, which are dehydrogenated with Pd-C to give the 5H-indeno172-bpyridines 5a-f. In the case of cinnamaldehyde 4f, addition of the P-carbon atom of the phosphoranimine 2b to the carbonyl carbon of aldehyde 4f leading to the cyclic intermediate 9 occurs in addition to the Michael addition.We propose that the intermediate 9 then undergoes hydrogen migration and N-P bond cleavage to give the internal salt 10, cyclization of which occurs to generate the dihydropyridine 11, which is dehydrogenated with Pd-C to give compound 5b. The Michael addition is frontier orbital c~ntrolled,'~and is favoured with the ketones 4a4 and aldehyde 4e. In the case of cinnamaldehyde 4f, however, the charge-controlled reaction or the lower steric hindrance of the formyl group in 4f might cause the formation of the additional product 5b. Results similar to the present case have been reported previo~sly.'~,~~ J. CHEM. SOC. PERKIN TRANS. 1 1991 Treatment of compounds 5a+ with 10 moly; of CrO, and 7-fold excess of Bu'OOH2' in CH,Cl, afforded 5H-indenoc 172-bpyridin-5-ones 12a-e (Scheme 4, Table 2).In the R' '0 a; R' = Me, I?= H b; R' = Ph, R2= H c;R1=Ph,R2=Ph d;R'=Me, R2=Ph 12a-e 8; R' = H, R2 = Me Scheme 4 Reugenfs:CrO,, Bu'OOH case of substrate 5e, however, a modest yield of onychine 12e was obtained. Even prolonged heating did not result in a high yield of onychine. Structural assignment of products 12a-e was based on comparison of the physical data with those reported in the literature (see Experimental section). Indene derivatives are widely available, hence the present methodolbgy using tributyl(inden-3-ylimino)phosphorane can serve as a novel and convenient route to 5H-indeno172-blpyridine and SH-indeno 1,2-bpyridin-5-one derivatives. Experimental IR spectra were recorded on a Shimadzu IR-400 spectrometer. 'H and 13C NMR spectra were recorded on Hitachi R-24 and Hitachi R-90H spectrometers and the chemical shifts are given relative to internal SiMe, standard.J-Values are given in Hz. High-resolution mass spectra were run on a JEOL DX-300 spectrometer. Microanalyses were performed at the Science and Engineering Research Laboratory of Waseda University. M.p.s were measured on a Buchi apparatus and are uncorrected. Preparation of Phosphoranes 2a and 2b.-A solution of azidoindene 1 l8 (391 mg, 2.5 mmol) and triphenylphosphine (622 mg, 2.5 mmol) in anhydrous benzene (7 cm3) was stirred at room temperature for 1 h. After the benzene was evaporated off, the residue was crystallized from benzene-hexane to give compound 2a as crystals, m.p.126127 "C; G,(CDCI,; 90 MHz) 3.10 (2 H, br s, 1-H), 4.79 (1 H, d, J 1.8, 2-H) and 7.00-7.90 (19 H, m, 4-, 5-,6- and 7-H and Ph); GC(CDCl3; 22.6 MHz) 35.3 1 (1 C, s, C-1), 105.13 (1 C, d, Jpc9.7, C-2), 118.94 (1 C, tert-C), 122.78 (1 C, d, Jpc1.4, C-4), 123.76 (1 C, tert-C), 125.34 (1 C, tert-C), 128.21 (6 C, d, Jpc12.4, Ph), 130.65 (3 C, d, Jpc98.1, Ph), 131.35 (3 C, d, Jpc2.8, Ph), 132.48 (6 C, d, Jpc9.7, Ph), 143.42 (1 C, d, Jpc1.4, C-7a), 147.14 (1 C, d, Jpc23.5, C-3a) and 149.29 (1 C, d, Jpc2.1, C-3); v,,,(CHCl,)/cm-' 3060,3002, 1597, 1562,1446,1349,1309,1266,1141,1108 and 980; m/z 392 (M + 1, 21), 391 (M', 75) and 183 (100) (Found: M', 391.1485. C,,H,,NP requires M, 391.1492). A solution of the phosphorane 2b l7 in CDC1, was prepared in a 'H NMR tube and exhibited the following spectral data: G,(CDCl,; 60 MHz) 0.65-1.85 (27 H, m, Bu'), 3.35 (2 H, br s, 1-H), 4.97 (1 H, br s, 2-H), 6.7C7.50 (3 H, m, 4-, 5-and 6-H), 7.72-7.98 (1 H, m, 7-H) (Found: M', 331.2421.Calc. for C,,H,,NP: M, 331.2421). Hydrolysis of Phosphoranes 2a and 2b.-(A) A solution of compound 2a (78 mg, 0.2 mmol) in ethanolic H2S04 C0.5 mol drn-,; water-EtOH (1 :9) (3 cm3) was heated under reflux for 7 h. The reaction mixture was then neutralized with aq. NaHCO, and extracted with CH,Cl,. After the extract was dried over MgSO,, CH2CI, was evaporated off and the resulting residue was separated by TLC on silica gel with hexane-AcOEt (3:l) as a developer to give indan-1-one 3 (16 mg, 61) and triphenylphosphine oxide (50 mg, 95).(B) To a solution of the phosphorane 2b, which was prepared J. CHEM. SOC. PERKIN TRANS. 1 1991 1117 Table 2 Oxidation of compounds 5a- with Cr0,-Bu'OOH Reaction Product Recovery of Entry Substrate Solvent time (r/h) yield () substrate 5 () 1 5a CHzClCHzCl 3 62 13 2 5b CH,CI, 3 89 6 3 5c CH2C12 22 88 8 4 5d CH2C12 5 5e CH2Cl, by reaction of the azide 1 (32 mg, 0.2 mmol) and tributylphosphine (40 mg, 0.2 mmol) in benzene (2 cm3) at room temperature, was added hydrochloric acid (2 mol dm-,; 0.2 cm3). Then the mixture was heated under reflux for 1 h. The reaction mixture was neutralized with aq. NaHCO,, extracted with benzene, and the extract was dried over Na2S04.After the benzene was evaporated off, the residue was separated by TLC on silica gel with hexane-AcOEt (3 :1) as a developer to give the ketone 3 (17 mg, 65) and tributylphosphine oxide (19 mg, 44). General Procedure for the Reaction of Phosphorane 2b with z,p-Unsarurated Ketones 4a4 and Aldehydes 4e and 4f.--To a solution of 3-azidoindene l9 (188 mg, 1.2 mmol) in dry benzene or toluene (5 cm3) was added tributylphosphine (202 mg, 1 mmol) and the mixture was stirred for 30 min at 0 "C to give compound 2b. To this solution were added a ketone 4a-d or aldehyde 4e or 4f (0.5 mmol) and 10 Pd/C (25 mg, 0.025 mmol of Pd) was added and the mixture was refluxed under nitrogen for the period indicated in Table 1.The reaction mixture was concentrated and the resulting residue was separated by TLC on silica gel with hexane-AcOEt (10: 1) as developer to give the corresponding tricycle 5a-f, along with tributylphosphine oxide (60-90). The results are summarized in Table 1. For 2-rnethyl-SH-indeno 1,2-bpyridine 5a: oil (lit.,' m.p. 27- 30 "C); amp;(CDC13; 60 MHz) 2.56 (3 H, S, Me), 3.55 (2 H, S, 5-H), 6.81 (1 H, d, J8.0, 3-H), 7.12-7.58 (3 H, m, 6-, 7- and 8-H), 7.80 (1 H, d, J8.0,4-H) and 8.17-8.37 (1 H, m, 9-H); v,,,(CHCl,)/cm-' 3051,2930, 1710, 1601,1575,1445,1264 and 740. For 2-phenyl-SH-indeno 1,2-bpyridine 5b m.p. 1 19.4- 120.5 "C(from EtOH) (lit.,,, 126128 "C); 6,(CDCI,; 60 MHz) 3.80 (2 H, s, 5-H2), 7.12-7.82 (8 H, m, 3-, 4-, 6-, 7- and 8-H and Ph) and 7.98-8.23 (3 H, m, 9-H and Ph); v,,,(CHCl,)/cm-' 3012,1601,1570,1475,1424,1415,1189 and 1072.For 2,4-diphenyI-SH-indeno 1,2-bpyridine 5c: m.p. 15 1.2- 152.5 "c (from EtOH) (lit.," 157.5-158 "c); 8,(CDC1,; 60 MHz) 3.81 (2 H, s, 5-H,), 7.067.64 (12 H, m, 3-, 6-, 7- and 8-H and Ph) and 7.92-8.24 (3 H, m, 9-H and Ph); v,,,(CHCl,)/cm-' 2691, 1437, 1426, 1341,1217 and 1028. For 2-methyl-4-phenyl-5H-indenol,2-bpyridine 5d: m.p. 216217.5 "c(from EtOH) (lit.,23 217-218 "c); 6,(CDCI,; 60 MHz) 2.59 (3 H, s, Me), 3.68 (2 H, s, 5-H), 6.90 (1 H, s, 3-H), 7.10-7.57 (8 H, m, 6-, 7- and 8-H and Ph) and 7.95-8.19 (1 H, m, 9-H); v,,,(CHCI,)/crn-' 2941, 1593, 1563, 1501, 1452, 1381, 1263,1189,1072 and 869. For 4-methyl-SH-indeno 1,2-bpyridine 5e: m.p.90.5-96 "C (from EtOH) (lit.,5 97-99 "C); G,(CDCl,; 60 MHz) 2.21 (3 H, s, Me), 3.47 (2 H, s, 5-H), 6.70 (1 H, d, J5.6, 3-H), 7.167.48 (3 H, m, 6-, 7- and 8-H), 7.80-8.05 (1 H, m, 9-H) and 8.21 (1 H, d, J 5.6, 2-H); v,,,(CHCl,)/cm-' 2954, 1601, 1455, 1384 and 1072. For 4-phenyl-SH-indeno 1,2-bpyridine 5f 6,(CDCl3; 90 MHz) 3.79 (2 H, br s, 5-H), 7.01 (1 H, d, J 5.1, 3-H), 7.267.64 (8 H, m, 6-, 7- and 8-H and Ph), 8.05-8.15 (1 H, m, 9-H) and 8.47 (1 H, d, J 5.1, 1-H); v,,,(CHCl,)/cm-' 2892, 1566, 1445, 1334, 1157, 1075 and 823 (Found: M', 243.1046. Cl8HI3N requires M, 243.1049). Picrate: m.p.207-208 "C (Found: C, 61.1; H, 3.75; N, 11.95. C24Hl,N,0, requires C, 61.0; H, 3.4; N, 11.92;). 5 73 14 8 33 36 General Procedure for the Oxidation of Indenop~~ridines5a-with CrO,-Bu'OOH.-A solution of indenopyridine (0.5 mmol), Cr03 (5 mg, 0.05 mmol) and Bu'OOH (3.5 mmol) in anhydrous CH,CI, or CH,CICH2Cl(3 cm3) was stirred under reflux for the period indicated in Table 2.After the reaction mixture had been washed with water, the extract was dried over Na2S04 and then concentrated. The residue was separated by TLC on silica gel with hexane-AcOEt (2:l) or CH2C12 as developer to give SH-indenoC 1,2-bpyridin-5-ones 12ae The results are summarized in Table 2. For 2-methyl-SH-indeno 1,2-bpyridin-5-one 12a: m.p. 1 16 118 "C (from EtOH) (lit.,5 104-105 "C); GH(CDCI3; 60 MHz) 2.55 (3 H, s, Me), 7.06 (1 H, d, J 7.4, 3-H) and 7.23-7.91 (5 H, m, 4-, 6,7-, 8-and 9-H); v,,,(CHCl,)/cm-' 2972, 1716, 1580, 1419,1257,1174 and 1099.For 2-Phenyl-SH-indeno 1,2-bpyridin-5-one 12b:m.p. 146- 147.5 "C (from EtOH) (lit.,24 146-147 "C); 6,(CDC13; 60 MHz) 7.09-8.19 (11 H, m); vm,,(CHCl,)/cm-' 2993, 1716, 1575, 1416, 1263,1101 and 917. For 2,4-diphenyl-SH-indeno 1,2-bpyridin-5-one 12c: m.p. 162.5-163.5 "C (from EtOH) (lit.," 163-164.5 "C); GH(CDCI3; 60 MHz) 7.19-7.71 (12 H, m, 3-, 7-, 8-and 9-H and Ph) and 7.79-8.24 (3 H, m, 6-H and Ph); v,,,(CHCl,)/cm-' 3002, 1708, 1550,1363,1270 and 928. For 2-methyl-4-phenyl-SH-indeno1,2-bpyridin-5-one 12d: m.p. 115.5-1 16.7 "C (from EtOH) (lit.,,, 119-120 "C); 6,- (CDC1,; 60 MHz) 2.59 (3 H, s, Me), 6.89 (1 H, s, 3-H) and 7.20- 7.94 (9 H, m, 6-, 7-, 8-and 9-H and Ph); v,,,(CHCI,)/cm-' 3001, 1715,1593,1550,1378,1273,1172 and 891.For 4-methyl-SH-indeno 1,2-bpyridin-5-one 12e:m.p. 125- 127 "c(from EtOH) (lit.,5 134-135 "c); G,(CDCI,; 60 MHz) 2.53 (3 H, s, Me), 6.70 (1 H, d, J 5.8, 3-H), 6.99-7.91 (4 H, m, 6-, 7-, 8-and 9-H) and 8.29 (1 H, d, J 5.8, 2-H); v,,,(CHCI,)/ cm-' 2933, 1703, 1601, 1566 and 918. Acknowledgements Financial support by the Science and Engineering Research Laboratory of Waseda University is greatly acknowledged. References 1 Part 15:N.Kanomataand M. Nitta, Tetrahedron Lett., 1990,31,1291. 2 A. Cave, M. Leboeuf and P. G. Waterman, Alkaloids: Chemical and Biological Perspective, ed. S. W. Pelletier, Wiley, London, 1987, vol. 5, 245; G. J. Arango, D.Cortes, B. K. Cassels, A. Cave and C. Merienne, Phytochemisrry, 1987,26,2093;M. 0.F. Goulart, A. E. G. Sant'ana, A. B. de Oliveira, G. G. de Oliveira and J. G. S. Maia, Phytochemistry, 1986,25, 1691. 3 M. E. F. de Almeida, R. Braz, M. V. von Bulow, 0.R. Gottlieb and J. G. S. Mata, Phytochemisrry, 1976, 15, 1186. 4 J. Koyama, T. Sugita, Y. Suzuta and H. hie, Heterocycles, 1979, 12, 1017. 5 N. S. Prostakov, A. T. Soldatenkov, P. K. Radzhan, V. 0.Fedorov, A. A. Fomichev and V. A. Rezakov, Chem. Heterocycl. Compd. (Engl. Transl.), 1982, 390. 6 T. Alves, A. B. de Oliveira and V. Snieckus, Tetrahedron Lett., 1988, 29,2 135. 7 0.Laprevote, F. Roblot, R. Hocqemiller and A. Cave, J. Nut. Prod., 1118 J. CHEM. SOC. PERKIN TRANS. I 1991 1988,51, 555; P.G. Waterman and I. Muhammad, Phytochemistry, 1985,24, 523. 8 J. Zhang, A.-R. 0.el-Shabrawy, M. A. el-Shanawany, P. L. Schiff, Jr. and D. J. Slatkin, J. Nat. Prod., 1987,50,800. 9 D. Tadic B. K. Cassels, A. Cave, M. P. F. Goulart and A. B. de Oliveira, Phytochemistry, 1987, 26, 155 1. 10 J. Koyama, T. Okatani, K. Tagahara and K. Irie, Heterocycles, 1989,29, 1649. 11 N. S. Prostakov, G. A. Vasilrsquo;ev, V. P. Zvolinskii, A. V. Varlamov, A. A. Savina, 0.I. Sorokin and N. D. Lopatina, Chem. Heterocyclo. Compd. (Engl. Transl.), 1975, 971. 12 M. T. DuPriest, C. L. Schmidt, D. Kuzmich and S. B. Williams, J. Org. Chem., 1986, 51, 2021 and references cited therein. cited therein. 13 Y. Iino, T. Kobayashi and M. Nitta, Heterocycles, 1986, 24, 2437.14 M. Nitta and Y. Iino, J. Chem. SOC., Perkin Trans. I, 1990, 435 and references cited therein. 15 N. Kanomata and M.Nitta, J. Chem. Soc., Perkin Trans. I, 1990, 11 19 and references cited therein. 16 M. Nitta, Y. Iino, E. Hara and T. Kobayashi, J. Chem. Soc., Perkin Trans. 1, 1989,51. 17 M. Nitta, Y. Iino and K. Kamata, Heterocycles, 1989,29, 1655. 18 A. Hassner and F. W. Fowler, J. Org. Chem., 1968,33,2686. 19 I. Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley, London, 1976; T.-L. Ho, Hard and Soft Acids and Bases Principle in Organic Chemistry, Academic, New York, 1977. 20 T. Kobayashi and M. Nitta, Chem. Lett., 1986, 1549. 21 J. Muzart, Tetrahedron Lett., 1987,28,2131. 22 G. R. Newkome and D. L. Fishel, J. Org. Chem., 1972,37, 1329. 23 N. S. Prostakov, A. V. Varlamov, G. A. Vasilrsquo;ev, 0. G. Kesarev and G. A. Urbina, Chem. Heterocycl. Compd. (Engl. Transl.), 1977, 105. 24 P. I. Zakharov, V. P. Zvolinksii, V. K. Shevtsov, V. G. Pleshalov, T. S. Seitembetov, A. V. Varlamov, G. A. Vasilrsquo;ev and N. S. Prosta-kov, Chem. Heterocycl. Compd. (Engl. Transl.), 1979, 78. Paper 0/03421 E Received 26th July 1990 Accepted 31st October 1990