Diels-Alder reactions of 2(1H)-quinolones having an electron-withdrawing group at the 4-position with 1,3-butadiene derivatives were carried out to give the phenanthridones richly functionalized under the conditions of atmospheric and high pressure. Furthermore, the reactivities of 4-substituted 2(1H)-quinolones acting as a dienophile were examined using MO calculation.

2(1H)-Quinolones are aromatic and there are many reports of substitution reactions.1) Recently, Nakagawa and co-workers reported the first example of a Diels-Alder (DA) reaction of 1-methoxycarbonyl-3-phenylthio-2(1H)-quinolone with 2-silyloxydiene in the presence of Lewis acid gave the intermediate for the Dynemisine A core (a marine alkaloid) in 60-70% yield. The above thermal reactions with 2-silyloxydiene or Danishefsky diene were unsuccessful.2) The phenanthridone skeleton aromatized or hydrogenated is commonly found in many alkaloids 3) of Amarylidaceae. Therefore, phenanthridones richly functionalized would be expected to be potentially valuable synthetic intermediates, and to possess interesting biological activities.3) We have also reported the synthesis of phenanthridones richly functionalized using DA cycloadditions of 2(1H)-quinolones having an electronwithdrawing group at the 4-position.4) It is considered that cycloadditions of 3-substituted 2(1H)-quinolones, a moiety acting as a dienophile give phenanthridones functionalized at different positions from those resulting from the DA cycloaddition of 4-substituted 2(1H)-quinolones. In this paper, we wish to report the synthesis of phenanthridones by uncatalyzed and thermal DA cycloadditions of 1-methyl-2(1H)-quinolones having an electron-withdrawing group at the 3-position with alkyl-and silyloxy-1,3-butadienes under atmospheric and high pressure (AP and HP 5) ) conditions. DA Cycloaddition Firstly, DA cycloadditions of 1-methyl-2(1H)-quinolones having an electron-withdrawing group [such as methoxycarbonyl-(1a), 6) cyano-(1b), 7) acetyl-(1c), benzoyl-(1d), 1d,e) formyl-(1e), 8) and nitro-(1f, g), 9) ] at the 3-position with 2,3-dimethyl-1,3-butadiene (2a) were examined under AP conditions as shown in Table 1 and Chart 1. The reactions of 1a-d with a symmetric diene (2a) gave stereoselectively functionalized phenanthridones (3a-c, e, entries 1, 3, 5, 7) at 180°C in moderate yields, but that of 1d afforded the adduct (3d, entry 6) in poor yield. Upon treatment with diisobutylaluminum hydride (DIBAL), the ester carbonyl group in 3a was reduced to the hydroxymethyl group i.e. 4. The same reactions of 1f at 160°C produced the cis-adduct (3f, entry 8) in 46% yield stereoselectively, and at 180°C gave a new product (5a, entry 9) aromatized by elimination of HNO 2 and dehydrogenation in 95% yield. Similarly, the reaction of 1g at 180°C (neat) afforded the cis-adduct (3g, entry 10) in 94% yield and additional heating of 3g at 180°C for 2 d in o-xylene gave the aromatized product (5b) in 64% yield. HP-DA cycloadditions 5) of 1a, b with 2a at 120°C for 2 d afforded stereoselectively the cis-adducts [3a (51%), entry 2; 3b (7%), entry 4] with the recovery of the starting material.Furthermore, cycloadditions of 1a, b, e, f with Danishefsky's diene (2b) were attempted under AP and HP conditions (Table 2, Chart 2). The reaction of 1a with unsymmetric 2b was carried out at 180°C for 4 d, followed by trifluoroacetic acid (TFA) work-up to give the cis-enone adduct ...

2(1H)-Quinolones are aromatic and many substitution reactions have been reported. 1) Nakagawa and co-workers. reported the first example, a Diels-Alder (DA) reaction of 1-methoxy-carbonyl-3-phenylthio-2(1H)-quinolone with 2-silyloxy-1,3-butadiene to give the intermediate (phenanthridone derivative) for a marine alkaloid (Dynemisine A).2) In addition, an aromatized or hydrogenated phenanthridone skeleton is a feature of many Amarylidaceae alkaloids. 3)Therefore, richly functionalized phenanthridones shoud be valuable synthetic intermediates. We recently reported the synthesis of phenanthridones richly functionalized using the DA reaction of 2(1H)-quinolones having an electron-withdrawing group at the 4-position with Danishefsky's diene, as well as 2-trimethylsilyloxy-, dimethyl-, and dimethoxy-1,3-butadienes.4) DA reactions of cyclic 1,3-butadiene and the unsynmetric alkyldiene with 2(1H)-quinolones have not yet been described. A phenanthridone in which the ene part at the 8,9-positions lack substituent groups would be useful. Here, we describe the synthesis of phenanthridones by the uncatalyzed and thermal DA reaction of 1-methyl-2(1H)-quinolones having an electron-withdrawing group at the 4-position with isoprene, butadiene sulfone, and cyclohexadiene at atmospheric and high pressure (AP and HP 5) ). Furthermore, we investigated the regioselectivety of isoprene and stabilization energies for the reaction of cyclohexadiene with 2(1H)-quinolones using the MO calculation .DA Reaction Firstly, DA reactions of 1-methyl-2(1H)-quinolones having an electron-withdrawing group [such as methoxycarbonyl-(1a), 6) cyano-(1b), 7) acetyl-(1c), 4) and benzoyl-(1d), 8) ] at the 4-position with a unsymmetric diene (2a) were examined under AP shown in Table 1 and Chart 1. The reactions of 1a-d with isoprene (2a) stereoselectively yielded the main adducts [5,8-dimethylphenanthridones (3a-d), entries 1, 3, 5, 7] and the minor adducts [5,9-dimethylphenanthridones (3e, f), entries 3, 5] at 180°C. The formation of the 9-methylphenanthridone (3g) in the DA reaction of 1d with 2a was identified by 1 H-NMR spectral analysis, but 3g was not separated from the reaction mixture. Also, DA reactions of 1a-d with 2a were attempted under HP as shown in Table 1. However, these reactions did not yield the satisfactory results.Furthermore, DA reactions of 1a-c with 2b at AP stereoselectively afforded 4a-c in 29-37% yields (Table 1 and Chart 1). However, reaction of 1d with 2b did not give 4d and 1d was recovered. Reaction of 1a with cyclic diene (2c) at AP yielded cis-[5a (15%)] and trans-adducts [5b (6%)]. The same reaction under HP gave only the cis-adduct [5a (18%)]. Also, isomerization of 5a with lithium diisopropylamide (LDA) at Ϫ78°C gave 5b (5%) with recovery of the starting material.We confirmed the stereochemistry of the ring juncture in 3a-f, 4a-c, and 5a, b as follows. We confirmed that in the DA reactions of 2(1H)-quinolones with 2,3-dimethyl-1,3-butadiene, the stereochemistries of the ring juncture in the 6(5H)-phenanthridone de...

Cycloadditions of 1,3-butadiene derivatives having an electron-rich group at the 1-position with 4- or 3-substituted 2(1H)-quinolones were carried out to give the richly functionalized phenanthridines under both atmospheric and high pressure conditions. Furthermore, the reactivity of 4- or 3-substituted 2(1H)-quinolones acting as a dienophile with 1-substituted dienes was examined using MO calculation.

2(1H)-Quinolones are classified as aromatic heterocycles.With regard to reactions of 2(1H)-quinolones, substitution reactions [1][2][3][4][5][6][7][8] have been widely reported, but little attention has been focused on addition reactions. Diels-Alder (DA) reaction of 2(1H)-quinolones with diene afforded the phenanthridones in one pot. Recently, Weltin verified the ability of the 6(5H)-phenanthridones to inhibit poly(ADP-ribose)-polymerase (PARP) activity in lymphoma cells. [9][10][11][12] Furthermore, Cheng reported that 8,9-dimethoxyphenanthridinium salts (A, Chart 1) possess activity against leukemias P388. 13)We reported the synthesis of functionalized phenanthridones by novel DA reaction of 1-methyl-2(1H)-quinolones having an electron-withdrawing group (such as methoxycarbonyl, acetyl, cyano) at the 4-or 3-position that acts as a dienophlie.14-17) It is well known that the nitro group function as a leaving group and a strong electron-withdrawing group. Herein, we report the synthesis of 6(5H)-phenanthridones by DA reaction of 3-nitro-2(1H)-quinolones under atmospheric and high pressure (AP and HP) conditions, and we investigate of the reactivity of the 2(1H)-quinolones using molecular orbital (MO) calculation.DA Reaction Firstly, DA reactions of 3-nitro-(1a) and 3,6-dinitro-1-methyl-2(1H)-quinolones (1b) 18,19) with 1,3-butadienes (2a, b) were investigated under AP and HP conditions, as shown in Table 1 and Chart 1. DA reactions of 1a, b with 1-methoxy-1,3-butadiene (2a) were carried out at 180°C for 5 d in o-xylene (entries 1, 4), and gave 6(5H)-phenanthridones (3a, 20) 83%; 3b, 68%), respectively. The same reaction of 3a at 160°C for 3 d (entry 2), also afforded 3a (63%). On the other hand, DA reaction of 1a with 2a was performed under HP conditions (10 kbar) at 90°C for 2 d (entry 3), and gave endo-DA adduct (4a, 57%) and exo-DA adduct (4b, 20%), respectively. Heating of 4a, b at 180°C in sealed tube produced 3a (67%, 64%, respetively) aromatized by elimination of hydrogen and nitrogen dioxide (HNO 2 ), followed by release of MeOH. These facts indicated that 3a, b resulted from release of HNO 2 and MeOH of corresponding DA adducts (such as 4a) under AP conditions. Furthermore, DA reactions of 1a with 2,3-dimethoxy-1,3-butadiene (2b) at 180°C under AP condition gave 1-methyl-8,9-dimethoxy-6(5H)-phenanthridone (6a 3) ; 31%, 45%, entries 5, 6) which was the synthetic intermediate for A possessing a bioactivity. DA reactions of 1b with 2b at 180°C afforded 1-methyl-8,9-dimethoxy-2-nitro-6(5H)-phenanthridone (6b; 17%, 13%, entries 7, 8) in poor yields. But, DA reactions of 1a, b with 2b under HP condition (10 kbar) at 90°C for 2 d afforded DA adducts (5a, 57%; 5b, 55%, entries 9, 10) in reasonable yields. Heating of 5a, b at 180°C produced 6a (48%) and 6b (40%) aromatized by release of HNO 2 , followed by dehydrogenation, respectively. The stereochemistries of the group at C-7 in 4a, b were determined by nuclear Overhauser effect (NOE) measurement of 1 H-NMR spectra. The spectrum of 4a indicated a correlatio...

Cycloaddition of 1 methyl 2(1H ) quinolones with electron-withdrawing groups such as methoxycarbonyl, cyano, and acetyl groups, at the 3 or 4 position with 2,3 dimethoxyand 2 (trimethylsilyloxy) 1,3 butadienes aŠorded stereoselectively phenanthridone derivatives under atmospheric and high pressures. Furthermore, regioselectivities of the cycloaddition of 3or 4 substituted 2(1H ) quinolones with 2 (trimethylsilyloxy) 1,3 butadiene were examined using MO calculation.Key words-4 cyano 2(1H ) quinolone; 2,3 dimethoxy 1,3 butadiene; cycloaddition; regioselectivity; stereoselectivity180°C で 3 日間加熱すると，立体選択的に cis 付加 体（3a, 25％; 3b, 30％;

Synthesis of 5(6H)-Phenanthridones Using Diels-Alder Reaction of 3-Nitro--2(1H)-quinolones Acting as Dienophiles. -The Diels-Alder reaction of quinolones of type (I) or (IX) yielding phenanthridone derivatives is studied. -(FUJITA*, R.; YOSHISUJI, T.; WAKAYANAGI, S.; WAKAMATSU, H.; MATSUZAKI, H.; Chem. Pharm. Bull. 54 (2006) 2, 204-208; Tohoku Pharm. Univ., Aoba, Sendai 981, Japan; Eng.) -M. Bohle 28-136

Diels-Alder Cycloadditions of 2(1H)-Quinolones Having an Electron-Withdrawing Group at the 3-Position Acting as Dienophiles withDienes.-The title reaction is investigated under different conditions and the results are discussed on the basis of MO calculations. The structure of (VI) is determined by X-ray analysis. -(FUJITA, REIKO; WATANABE,