Tetrahedron 2005, 61, 4099-4113

New synthetic approach to substituted isoindolo[2,1-a]quinolinecarboxylic acids via intramolecular Diels–Alder reaction of4-(N-furyl-2)-4-arylaminobutenes-1 with maleic anhydride

Fedor I. Zubkov,a,* Ekaterina V. Boltukhina,a Konstantin F. Turchin,b Roman S. Borisova

and Alexey V. Varlamova

aOrganic Chemistry Department, Russian Peoples Friendship University, 6 Miklukho-Maklayia St., 117198 Moscow, Russian FederationbCenter of Drugs Chemistry, All-Russian Institute for Chemical and Pharmaceutical Research, 7 Zubovskaya St.,

119815 Moscow, Russian Federation

Received 18 October 2004; revised 24 January 2005; accepted 10 February 2005

Available online 16 March 2005

Abstract—Acylation of substituted 4-(furyl-2)-4-arylaminobut-1-enes with maleic anhydride provided 2-allyl-6-carboxy-4-oxo-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-enes in high yield under mild reaction conditions. The Diels–Alder adducts are formed via an initial amideformation followed by a stereoselective intramolecular [4C2] exo-cycloaddition reaction. Treatment of the tricyclic compounds withphosphoric acid at high temperatures (70–120 8C) promoted cyclic ether opening, intramolecular cyclization and aromatization to give thecorresponding tetracyclic compounds, 5,6,6a,11-tetrahydro-10-carboxyisoindolo[2,1-a]quinolines, in moderate yields. The influence of theacid and the reaction temperature on the cyclization reactions are also discussed.q 2005 Elsevier Ltd. All rights reserved.

1. Introduction

Polycyclic nitrogen heterocycles with an isoindolo[2,1-a]-quinoline motif (1) have been shown to possess importantbiological properties. For example, compounds 2 and 3(Scheme 1), analogs of berberine alkaloids, have beenshown to have effect against N2-induced hypoxia and inhibithuman topoisomerase II, respectively.1,2

Considering the important pharmacological propertiesdisplayed by compounds with isoindolo[2,1-a]quinoline

0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2005.02.017

Scheme 1.

Keywords: Homoallylamines (4-(furyl-2)-4-N-arylaminobut-1-enes); Intramolecul10-oxatricyclo[5.2.1.01,5]decenes; Intramolecular Friedel–Crafts alkylation.* Corresponding author. Tel.: C7 95 3355798; fax: C7 95 9550779; e-mail: fzu

cores, several synthetic approaches have been reported1–11

and reviewed.8 Phthalimides,1,11 derivatives ofanthranilic acid,2,4,6,10 benzanilide3 and quinoline deriva-tives5,7 have been used to prepare isoindolo[2,1-a]quinolinecores.

Most of these approaches were reported in the last 10 years.One of the earliest and shortest routes7 for the preparation ofthe nitro substituted isoindolo[2,1-a]quinoline was theinteraction between quinoline salt and picryl chloride inthe presence of a base.

Tetrahedron 61 (2005) 4099–4113

ar furan Diels–Alder reaction (IMDAF); Isoindolo[2,1-a]quinolines; 3-Aza-

[email protected]

Scheme 2.

F. I. Zubkov et al. / Tetrahedron 61 (2005) 4099–41134100

As part of our research program directed towards thepreparation of polycyclic nitrogen heterocycles usinghomoallylamines as starting compounds, we were interestedin developing a route to isoindolo[2,1-a]quinoline via anintramolecular Diels–Alder cycloaddition/cyclic etheropening–aromatization/cyclization sequence. Herein wedisclose our initial results on this study.

We recently reported the preparation of 1,2,3,4-tetrahydro-quinolines12 from 4-alkyl- and 4-pyridylsubstituted 4-(N-aryl)aminobut-1-enes via an acid promoted intramolecularcyclization. It was established that Friedel–Crafts alkylationproceeded only under strong mineral acids (H3PO4 orH2SO4) treatment at 65–85 8C. An initial attempt to utilizethis route to prepare 2-furyl substituted tetrahydroquino-lines, a potential precursor to isoindolo[2,1-a]quinolines 1,from 4-(2 0-furyl)-4-(N-aryl)aminobut-1-enes failed due tothe acid lability of the furfuryl moiety and the deactivatinginfluence of the ammonium cation formed upon protonation.

Scheme 3.

Scheme 4.

Acylation of the secondary amine would be expected toavoid decomposition of the furan ring under acidicconditions and to yield the desired cyclized product.

To study the influence of the acetyl group on the cyclizationreaction, amide 4 was chosen as the substrate (Scheme 2). Itwas then subjected to various reaction conditions to promotethe intramolecular cyclization reaction. Heating the amide 4with BF3$OEt2 in ether or AlCl3 in boiling hexane promotedpolymerization and no tetrahydroquinoline 5 formation wasobserved. Heating compound 4 in 85% ortho-phosphoricacid at 30 8C promoted decomposition of amide 4 andprovided N-acetyltoluidine 6, alcohol 7 and diol 8 as thefragmentation products. N-Acetyltoluidine 6 and thehydration product 7 were isolated from the reaction mixture;the formation of compound 8 was confirmed by LCMS. Wewould like to note that isolation of N-alkyl substitutedacetanilide as the fragmentation product under harshconditions has been described in the previous publication.13

F. I. Zubkov et al. / Tetrahedron 61 (2005) 4099–4113 4101

It is also known that under acidic conditions (H3PO4 orH2SO4, 65–85 8C) 3a,6-epoxyisoindolones 9 undergoescyclic ether opening and aromatization reaction sequenceto give isoindolones 10 (Scheme 3).14

In this paper an alternative way of synthesizing tetracycles 1from homoallylamines based on the acid catalyzed3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-enes15 cyclization ispresented.

2. Results and discussion

The required precursors for our study 11a–i and 12a–e werereadily synthesized via a two-step process.16 Condensationof the aniline and furfural gave the imine, which was thentreated with the Grignard reagent to give amines 11, 12 inmoderate to good yields (Scheme 4).

The reaction of homoallylamines 11a–i, 12a–e with maleicanhydride14a,b,17–23 was carried out at room temperature(2–4 days) and the products 13 and 14 were isolated in highyields. In the case of amines with an ortho-substituent(11b,d,e,h and 12b,c,e) the reaction rate was slow (3–4days) compared to the unsubstituted amines. The 2-benzyl

Scheme 5.

Scheme 6.

derivative 11g required longer reaction time (O7 days) todrive the reaction to complete (Scheme 5).

The cycloaddition reaction was highly stereoselective andonly the exo-adducts 13, 14 were formed as confirmed bythe 1H NMR spectra of the crude reaction mixtures (in thecase of endo-orientation of carboxyl group in the 6-positionin the tricycles 13, 14 J6-exo,7 would be around 5.0 Hz).14b

The possible formation of cycloaddition products 16 hasbeen proposed in the literature.24 The preparation ofmonoesters 15, from adducts 14a,b unambiguously con-firms that no intermediate anhydride 16 was isolated(Scheme 5).

Exo-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-enes 13 and 14were isolated as mixtures of isomers (A and B) based on theorientation of the methallyl (for 13) or allyl (for 14) groupsrelative to the 1,7-epoxy-bridge (Scheme 6). The isomerratio varied from 2.5:1 to 1:3 depending on the position andnature of the substituent. Isomers of compounds 13 and 14could not be separated due to poor solubility in commonlyused organic solvents (chloroform, alcohol, ethyl acetate).However, we were able to separate isomers of compound14d using fractional crystallization from i-PrOH–DMF.

Scheme 7.


The relative configuration of the isomers 14dA and 14dBwas established basing on 1H NMR NOE values indicatingthe increase of Hi intensity when the Hj signal was saturated(hHi{Hj}). The comparison of the NOE values for 2-H, 5-H,and 2 0-H in two isomers of 14d (h5-H{2 0-H}, h3 0-H{5-H}z3% in 14dA, and !1% in 14dB; h2-H{5-H}zh5-H{2-H} !1% in 14dA, and z2.5% in 14dB) demonstrated that theallyl substituent was cis to 5-H in 14dA, and trans to 5-H in14dB.

Acylation of furfurylamines 11 and 12 with maleicanhydride initially gave the maleinamide intermediate 17,which immediately underwent [4C2] cycloaddition to givecycloadducts 13 and 14. Treatment of N-acetylallylamines 4and 18 with maleic anhydride did not produce any of theaddition products 19 even in boiling o-xylene (Scheme 6).That is why the alternative reaction, when an anhydridesimilar to 16 could be initially formed (Scheme 5), is hardlypossible. It is notable that the adducts 13 and 14 did notundergo thermal exo-endo-isomerisation in boiling xyleneas described for similar compounds types.14b

The rate of the intramolecular cyclization of 2-methallyl-substituted 3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-enes13c,d (possessing an electron rich aromatic ring) was very

Scheme 8.

fast and the reaction proceeded even at 10 8C in the presenceof ortho-phosphoric acid. The products—6b,9-epoxyiso-indolo[2,1-a]quinolines 20a,b were isolated in 37 and 63%yields, respectively (Scheme 7).

According to NMR spectroscopic data, the crude product20a exists in the form of two isomers with relative ratiow93:7. In the predominant isomer 20a (isolated byrecrystallization) 6a-H and 10a-H were in the same cis-orientation as 2-H and 5-H in the isomer 14dB of compound14d (see above). The conclusion followed from comparisonof the NOE values for 6a-H and 10a-H in this isomer of 20a(h6a-H{10a-H}Z2.4%, h10a-H{6a-H}Z4%) with the NOEvalues for 2-H and 5-H in both isomers of 14d. Thestereochemistry of product 20b was established by analogywith 20a.

Heating compounds 13 at 70–85 8C in the presence ofphosphoric acid promoted cyclization, cyclic ether openingfollowed by aromatization to give isoindolo[2,1-a]quino-lines 21a–i in 31–72% yields (Scheme 7). Heatingpentacyclic compounds 20a,b at 65 8C in the presenceof PPA readily initiated the cyclic ether opening andaromatization reaction sequence to give the isoindolo-quinolines 21d,c in good yields.


Intramolecular cyclization of 2-allylsubstituted 3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-enes 14a–e required moresevere reaction conditions compared to their methallylsubstituted analogs 13 (Scheme 8). It can be explained bypoor stability of the intermediate secondary carbocationformed by protonation of the allyl fragment, compared tothe tertiary one formed from the methallyl fragment.Accordingly, heating compounds 14a,b in phosphoric acidat 65 8C initiated the cyclic ether opening and aromatizationreaction sequence to give 3-allylisoindolones 22a,b.However heating 3-allylisoindolones 22a–e in the presenceof phosphoric acid at 130–150 8C, polyphosphoric acid ormixture of H3PO4/H2SO4 (3:1, in volume) at 100–120 8Cpromoted cyclization to give compounds 23a–e. The bestresults were obtained by using the latter conditions to yieldcompounds 23a–e in 31–55%.

In contrast to the 5,5-dimethylisoindolo[2,1-a]quinolines21, their 5-monosubstituted homologues 23 are formed as amixture of two diastereomeres 23A and 23B according tothe orientation of the hydrogen atoms at the C5 and C6a

positions (Scheme 8). The ratio of the isomers 23A/23Bvaries from 3.5:1 to 12:1. Isomer 23A with the 5-methylgroup in a pseudo-equatorial orientation (and with a cis-orientation of the protons 5-H and 6a-H) predominates in allcases.

The relative stereochemistry of 23A a–e and 23B a–e wasdetermined based on the J values between protons 5-H and6-H. Thus, for the major isomer 23A with an axialorientation of the proton 5-H, the coupling constants wereJ5ax,6axZ11.0–13.5 and J5ax,6eqZ5.8–6.6 Hz, while for theminor isomer 23B with an equatorial orientation of theproton 5-H, the constants were much smaller: J5eq,6axZ5.8and J5eq,6eqZ1.2 Hz. In both isomers of the tetracyclic acids23 and also in their 5,5-dimethylanalogues 20, 21 the proton6a-H has the axial orientation confirmed by the valuesof the spin–spin coupling constants (J6a-ax,6axZ9.7–12.9,J6a-ax,6eqZ2.0–4.9 Hz).

In conclusion, this work demonstrates a new two-stepapproach to 10-carboxy-11-oxa-5,6,6a,11-tetrahydroiso-indolo[2,1-a]-quinolines from readily available 4-(furyl-2)-4-N-arylaminobut-1-enes which generates the final productsin up to 60% overall yield.

3. Experimental

All reagents were purchased from Acros Chemical Co. Allsolvents were used without further purification. Meltingpoints were determined using a Fisher–Johns melting pointapparatus and are uncorrected. IR spectra were obtained inKBr pellets for solids or in thin film for oils. NMR spectra1H (200 or 400 MHz) and 13C (100.6 MHz) were recordedfor solutions (2–5%) in deuteriochloroform or DMSO-d6 at30 8C and traces of chloroform (1H NMR d 7.26 ppm)or DMSO-d5H (1H NMR d 2.49 ppm and 13C NMR39.43 ppm) were used as the internal standard. Mass spectrawere obtained by electron ionization at 70 eV on a VarianMAT-112 spectrometer or Finnegan MAT95XL chromato-mass spectrometer. The purity of the obtained substancesand the composition of the reaction mixtures were

controlled by TLC silufol UV254 plates. The separation ofthe final products was carried out by column chroma-tography on Al2O3 (activated, neutral, 50–200 mm) or byfractional crystallization.

3.1. 4-(2 0-Furyl)-4-N-arylaminobutenes-1 (11a–i, 12a–e).Typical procedure

The corresponding aldimine (0.30 mol) was slowly addeddrop-wise at reflux to a stirred solution of allylmagnesiumbromide, prepared from allyl bromide (39 mL, 0.45 mol)and magnesium turnings (22.0 g, 0.90 mol) in ether(300 mL) (for amines 12), or to a solution of methallyl-magnesium chloride, prepared from methallyl chloride(41 mL, 0.45 mol) and magnesium turnings (22.0 g,0.90 mol) in mixture THF–ether (1:1, 300 mL) (for amines11). After the addition of the Schiff base, the reactionmixture was stirred for 1 h at room temperature. The cooledreaction mixture was poured into saturated aqueous NH4Clsolution (300 mL) under ice cooling and extracted withether (3!100 mL). The organic layer was dried overMgSO4 and concentrated. The residue was distilled in vacuoto give the products 11a–i or 12a–e as colourless oils.

3.1.1. 2-Methyl-4-N-phenylamino-4-(2 0-furyl)butene-1(11a). Yield 51.76 g (76%); bp 130–133 8C/3 mmHg; nD

25

1.5578; IR 3390 (NH), and 1645 (C]C) cmK1; 1H NMR(CDCl3, 200 MHz) d 1.74 (br s, 3H, Me-2), 2.54 (dd, 1H,JZ14.0, 8.2 Hz, H-3A), 2.66 (dd, 1H, JZ14.0, 6.1 Hz,H-3B), 3.95 (br s, 1H, NH), 4.58 (dd, 1H, JZ8.2, 6.1 Hz,H-4), 4.81 (br s, 1H, H-1A), 4.87 (br s, 1H, H-1B), 6.16 (dd,1H, JZ3.2, 0.9 Hz, H-3 0), 6.27 (dd, 1H, JZ3.2, 1.8 Hz,H-4 0), 6.60 (m, 2H, H-Ph), 6.69 (m, 1H, H-Ph), 7.13 (m, 2H,H-Ph), 7.33 (dd, 1H, JZ1.8, 0.9 Hz, H-5 0). Anal. Calcd forC15H17NO: C, 79.29; H, 7.49; N, 6.17. Found: C, 79.27; H,7.48; N, 6.16.

3.1.2. 2-Methyl-4-N-(2 00-methylphenyl)amino-4-(2 0-furyl)butene-1 (11b). Yield 47.72 g (66%); bp 131–134 8C/1.5 mmHg; nD

23 1.5521; IR 3421 (NH), and 1641(C]C) cmK1; 1H NMR (CDCl3, 400 MHz) d 1.68 (br s,3H, Me-2), 2.15 (s, 3H, Me-2 00), 2.60 (dd, 1H, JZ13.9,8.6 Hz, H-3A), 2.69 (dd, 1H, JZ13.9, 5.4 Hz, H-3B), 3.93(br s, 1H, NH), 4.58 (dd, 1H, JZ8.6, 5.4 Hz, H-4), 4.85 (brs, 1H, H-1A), 4.89 (br s, 1H, H-1B), 6.16 (dd, 1H, JZ3.2,0.8 Hz, H-3 0), 6.27 (dd, 1H, JZ3.2, 1.8 Hz, H-4 0), 6.53 (d,1H, JZ7.7 Hz, H-Ph), 6.64 (dt, 1H, JZ7.7, 1.0 Hz, H-Ph),7.04–7.02 (m, 2H, H-Ph), 7.34 (dd, 1H, JZ1.8, 0.8 Hz,H-5 0). Anal. Calcd for C16H19NO: C, 79.67; H, 7.88; N,5.81. Found: C, 79.65; H, 7.88; N, 5.84.

3.1.3. 2-Methyl-4-N-(4 00-methylphenyl)amino-4-(2 0-furyl)butene-1 (11c). Yield 54.23 g (75%); bp 138–140 8C/2.5 mmHg; nD

22 1.5536; IR 3393 (NH), and 1650(C]C) cmK1; 1H NMR (CDCl3, 200 MHz) d 1.71 (br s,3H, Me-2), 2.30 (s, 3H, Me-4 00), 2.63 (dd, 1H, JZ14.3,8.1 Hz, H-3A), 2.74 (dd, 1H, JZ14.3, 6.1, H-3B), 3.90 (br s,1H, NH), 4.64 (dd, 1H, JZ8.1, 6.1 Hz, H-4), 4.89 (br s, 1H,H-1A), 4.95 (br s, 1H, H-1B), 6.24 (dd, 1H, JZ3.2, 0.5 Hz,H-3 0), 6.35 (dd, 1H, JZ3.2, 1.8 Hz, H-4 0), 6.61 (m, 2H,H-Ph), 7.03 (m, 2H, H-Ph), 7.41 (dd, 1H, JZ1.8, 0.5 Hz,H-5 0). Anal. Calcd for C16H19NO: C, 79.67; H, 7.88; N,5.81. Found: C, 79.69; H, 7.85; N, 5.83.


3.1.4. 2-Methyl-4-N-(2 00-ethylphenyl)amino-4-(2 0-furyl)-butene-1 (11d). Yield 65.03 g (85%); bp 141–143 8C/4 mmHg; nD

22 1.5502; IR 3417 (NH), and 1651 (C]C) cmK1;1H NMR (CDCl3, 400 MHz) d 1.36 (t, 3H, JZ7.5 Hz,CH2Me), 1.80 (br s, 3H, Me-2), 2.63 (q, 2H, JZ7.5 Hz,CH2Me), 2.72 (dd, 1H, JZ13.9, 8.7 Hz, H-3A), 2.82 (dd,1H, JZ13.9, 5.2 Hz, H-3B), 4.14 (br s, 1H, NH), 4.73 (dd,1H, JZ8.7, 5.2 Hz, H-4), 4.98 (br s, 1H, H-1A), 5.01 (br s,1H, H-1B), 6.26 (dd, 1H, JZ3.2, 0.8 Hz, H-3 0), 6.38 (dd,1H, JZ3.2, 1.7 Hz, H-4 0), 6.66 (d, 1H, JZ7.8 Hz, H-Ph),6.80 (t, 1H, JZ7.8 Hz, H-Ph), 7.15 (t, 1H, JZ7.8 Hz,H-Ph), 7.17 (d, 1H, JZ7.8 Hz, H-Ph), 7.44 (dd, 1H, JZ1.7,0.8 Hz, H-5 0). Anal. Calcd for C17H21NO: C, 80.00; H, 8.23;N, 5.49. Found: C, 80.21; H, 8.25; N, 5.39.

3.1.5. 2-Methyl-4-N-(2 00-methoxyphenyl)amino-4-(2 0-furyl)butene-1 (11e). Yield 35.47 g (46%); bp 153–154 8C/3 mmHg; nD

22 1.5578; IR 3411 (NH), and 1640(C]C) cmK1; 1H NMR (CDCl3, 400 MHz) d 1.75 (br s,3H, Me-2), 2.66 (dd, 1H, JZ14.0, 8.0 Hz, H-3A), 2.73 (dd,1H, JZ14.0, 5.9 Hz, H-3B), 3.88 (s, 3H, OMe), 4.63 (dd,1H, JZ8.0, 5.9 Hz, H-4), 4.68 (br s, 1H, NH), 4.87 (br s, 1H,H-1A), 4.91 (br s, 1H, H-1B), 6.22 (d, 1H, JZ3.1 Hz, H-3 0),6.32 (dd, 1H, JZ3.1, 1.7 Hz, H-4 0), 6.61 (dd, 1H, JZ7.8,1.4 Hz, H-Ph), 6.71 (dt, 1H, JZ7.8, 1.4 Hz, H-Ph), 6.81 (dd,1H, JZ7.8, 1.4 Hz, H-Ph), 6.84 (dt, 1H, JZ7.8, 1.4 Hz,H-Ph), 7.38 (d, 1H, JZ1.7 Hz, H-5 0). Anal. Calcd forC16H19NO2: C, 74.71; H, 7.39; N, 5.45. Found: C, 74.75; H,7.36; N, 5.42.

3.1.6. 2-Methyl-4-N-(4 00-methoxyphenyl)amino-4-(2 0-furyl)butene-1 (11f). Yield 57.83 g (75%); bp 156–158 8C/2 mmHg; nD

23 1.5566; IR 3374 (NH), and 1640(C]C) cmK1; 1H NMR (CDCl3, 200 MHz) d 1.71 (br s,3H, Me-2), 2.56 (dd, 1H, JZ13.8, 8.1 Hz, H-3A), 2.66 (dd,1H, JZ13.8, 6.0 Hz, H-3B), 3.74 (s, 3H, OMe), 4.51 (dd,1H, JZ8.1, 6.0 Hz, H-4), 4.83 (br s, 1H, H-1A), 4.89 (br s,1H, H-1B), 6.18 (d, 1H, JZ3.2 Hz, H-3 0), 6.30 (dd, 1H, JZ3.2, 1.8 Hz, H-4 0), 6.59 (m, 2H, H-Ph), 6.76 (m, 2H, H-Ph),7.36 (d, 1H, JZ1.8 Hz, H-5 0). Anal. Calcd for C16H19NO2:C, 74.71; H, 7.39; N, 5.45. Found: C, 74.73; H, 7.39; N,5.46.

3.1.7. 2-Methyl-4-N-(2 00-benzylphenyl)amino-4-(2 0-furyl)butene-1 (11g). Yield 75.13 g (79%); bp 185–195 8C/2.5 mmHg; nD

20 1.5833; IR 3398 (NH), and 1650(C]C) cmK1; 1H NMR (CDCl3, 400 MHz) d 1.64 (br s,3H, Me-2), 2.50 (dd, 1H, JZ13.9, 8.4 Hz, H-3A), 2.64 (dd,1H, JZ13.9, 5.4 Hz, H-3B), 4.01 (br s, 2H, CH2Ph), 4.66(dd, 1H, JZ8.4, 5.4 Hz, H-4), 4.72 (br s, 1H, H-1A), 4.75(m, 1H, H-1B), 5.99 (d, 1H, JZ3.2 Hz, H-3 0), 6.30 (dd, 1H,JZ3.2, 1.8 Hz, H-4 0), 6.66 (dd, 1H, JZ7.5, 1.2 Hz, H-Ph),6.81 (dt, 1H, JZ7.5, 1.2 Hz, H-Ph), 7.15 (dd, 1H, JZ7.5,1.2 Hz, H-Ph), 7.19 (dt, 1H, JZ7.5, 1.2 Hz, H-Ph), 7.37 (d,1H, JZ1.8 Hz Hz, H-5 0), 7.25–7.39 (m, 5H, H-Ph). Anal.Calcd for C22H23NO: C, 83.28; H, 7.26; N, 4.42. Found: C,83.29; H, 7.30; N, 4.45.

3.1.8. 2-Methyl-4-N-(2 0,4 0-dimethylphenyl)amino-4-(2 0-furyl)butene-1 (11h). Yield 38.25 g (50%); bp 142–145 8C/3 mmHg; nD

21 1.5500; IR 3417 (NH), and 1620(C]C) cmK1; 1H NMR (CDCl3, 400 MHz) d 1.67 (br s,3H, Me-2), 2.12 (s, 3H, Me-Ar), 2.19 (s, 3H, Me-Ar), 2.58

(dd, 1H, JZ13.8, 8.7 Hz, H-3A), 2.67 (dd, 1H, JZ13.8,5.3 Hz, H-3B), 3.78 (br s, 1H, NH), 4.54 (dd, 1H, JZ8.7,5.3 Hz, H-4), 4.84 (br s, 1H, H-1A), 4.88 (br s, 1H, H-1B),6.15 (d, 1H, JZ3.1 Hz, H-3 0), 6.26 (dd, 1H, JZ3.1, 1.8 Hz,H-4 0), 6.43 (d, 1H, JZ7.9 Hz, H-6 00), 6.83 (br d, 1H, JZ7.9 Hz, H-5 00), 6.86 (br s, 1H, H-3 00), 7.33 (d, 1H, JZ1.8 Hz,H-5 0). Anal. Calcd for C17H21NO: C, 80.00; H, 8.23; N,5.49. Found: C, 80.20; H, 8.27; N, 5.52.

3.1.9. 2-Methyl-4-N-(4 00-isopropylphenyl)amino-4-(2 0-furyl)butene-1 (11i). Yield 45.99 g (57%); bp 150–151 8C/1 mmHg; nD

22 1.5435; IR 3390 (NH), and 1635(C]C) cmK1; 1H NMR (CDCl3, 400 MHz) d 1.23 (d, 6H,JZ7.0 Hz, CHMe2), 1.73 (br s, 3H Hz, Me-2), 2.58 (dd, 1H,JZ14.1, 8.7 Hz, H-3A), 2.68 (dd, 1H, JZ14.1, 5.7 Hz,H-3B), 2.82 (sept, 1H, JZ7.0 Hz, CHMe2), 2.92 (br s, 1H,NH), 4.58 (dd, 1H, JZ8.7, 5.7 Hz, H-4), 4.85 (br d, 1H, JZ0.7 Hz, H-1A), 4.90 (br d, 1H, JZ0.7 Hz, H-1B), 6.22 (dd,1H, JZ3.0, 0.7 Hz, H-3 0), 6.32 (dd, 1H, JZ3.0, 1.7 Hz,H-4 0), 6.59 (BB 0, 2H, H-Ph), 7.04 (AA 0, 2H, H-Ph), 7.37(dd, 1H, JZ1.7, 0.7 Hz, H-5 0). Anal. Calcd for C18H23NO:C, 80.30; H, 8.55; N, 5.20. Found: C, 80.32; H, 8.66; N,5.42.

3.1.10. 4-N-Phenylamino-4-(2 0-furyl)butene-1 (12a).Yield 48.56 g (76%); bp 155–156 8C/7 mmHg; nD

20 1.5640;IR 3398 (NH), and 1630 (C]C) cmK1; 1H NMR (CDCl3,200 MHz) d 2.75 (t, 2H, JZ6.4 Hz, H-3), 4.04 (br s, 1H,NH), 4.65 (t, 1H, JZ6.4 Hz, H-4), 5.24 (dd, 1H, JZ17.4,1.2 Hz, H-1trans), 5.26 (dd, 1H, JZ10.0, 1.2 Hz, H-1cis),5.85 (ddt, 1H, JZ17.4, 10.0, 6.4 Hz, H-2), 6.24 (dd, 1H, JZ3.1, 0.8 Hz, H-3 0), 6.35 (dd, 1H, JZ3.1, 1.8 Hz, H-4 0), 6.69(d, 2H, JZ7.5 Hz, H-Ph), 6.78 (t, 1H, JZ7.5 Hz, H-Ph),7.23 (t, 2H, JZ7.5 Hz, H-Ph), 7.41 (dd, 1H, JZ1.8, 0.8 Hz,H-5 0). Anal. Calcd for C14H15NO: C, 78.87; H, 7.04; N,6.57. Found: C, 78.89; H, 7.06; N, 6.57.

3.1.11. 4-N-(2 00-Methylphenyl)amino-4-(2 0-furyl)butene-1 (12b). Yield 53.12 g (78%); bp 140–142 8C/4 mmHg; nD

20

1.5576; IR 3419 (NH), and 1628 (C]C) cmK1; 1H NMR(CDCl3, 400 MHz) d 2.21 (s, 3H, Me-2 00), 2.71 (dd, 2H, JZ7.1, 6.1 Hz, H-3), 3.95 (br s, 1H, NH), 4.62 (t, 1H, JZ6.1 Hz, H-4), 5.20 (dd, 1H, JZ10.4, 1.8 Hz, H-1cis), 5.24(dd, 1H, JZ17.1, 1.8 Hz, H-1trans), 5.82 (ddt, 1H, JZ17.1,10.4, 7.1 Hz, H-2), 6.19 (d, 1H, JZ3.1 Hz, H-3 0), 6.33 (dd,1H, JZ3.1, 1.8 Hz, H-4 0), 6.60 (d, 1H, JZ8.4 Hz, H-Ph),6.70 (t, 1H, JZ8.4 Hz, H-Ph), 7.09 (d, 1H, JZ8.4 Hz,H-Ph), 7.10 (t, 1H, JZ8.4 Hz, H-Ph), 7.39 (d, 1H, JZ1.8 Hz, H-5 0). Anal. Calcd for C15H17NO: C, 79.30; H, 7.49;N, 6.17. Found: C, 79.30; H, 7.51; N, 6.19.

3.1.12. 4-N-(2 00-Methoxyphenyl)amino-4-(2 0-furyl)-butene-1 (12c). Yield 45.93 g (63%); bp 156–158 8C/2 mmHg; nD

23 1.5636; IR 3407 (NH), and 1640(C]C) cmK1; 1H NMR (CDCl3, 400 MHz) d 2.72 (t, 2H,JZ7.0 Hz, H-3), 3.88 (s, 3H, OMe), 4.58 (t, 1H, JZ7.0 Hz,H-4), 4.66 (br s, 1H, NH), 5.15 (dd, 1H, JZ10.1, 1.3 Hz,H-1cis), 5.20 (dd, 1H, JZ17.1, 1.3 Hz, H-1trans), 5.81 (ddt,1H, JZ17.1, 10.1, 7.0 Hz, H-2), 6.20 (br d, 1H, JZ3.0 Hz,H-3 0), 6.31 (dd, 1H, JZ3.0, 1.7 Hz, H-4 0), 6.60 (dd, 1H, JZ7.7, 1.5 Hz, H-Ph), 6.70 (dt, 1H, JZ7.7, 1.5 Hz, H-Ph), 6.80(dd, 1H, JZ7.7, 1.5 Hz, H-Ph), 6.84 (dt, 1H, JZ7.7, 1.5 Hz,H-Ph), 7.37 (dd, 1H, JZ1.7, 0.7 Hz, H-5 0). Anal. Calcd for


C15H17NO2: C, 74.07; H, 6.99; N, 5.76. Found: C, 74.09; H,7.00; N, 5.76.

3.1.13. 4-N-(4 00-Methoxyphenyl)amino-4-(2 0-furyl)-butene-1 (12d). Yield 48.11 g (66%); bp 158–160 8C/4 mmHg; nD

23 1.6210; IR 3391 (NH), and 1619 (C]C) cmK1;1H NMR (CDCl3, 200 MHz) d 2.62 (t, 2H, JZ6.7 Hz, H-3),3.68 (s, 3H, OMe), 3.71 (br s, 1H, NH), 4.45 (t, 1H, JZ6.7 Hz, H-4), 5.10 (dd, 1H, JZ17.1, 1.9 Hz, H-1trans), 5.13(dd, 1H, JZ10.1, 1.9 Hz, H-1cis), 5.74 (ddt, 1H, JZ17.1,10.1, 6.7 Hz, H-2), 6.12 (dd, JZ3.4, 0.9 Hz, H-3 0), 6.25 (dd,1H, JZ3.4, 1.8 Hz, H-4 0), 6.55 (m, 2H, H-Ph), 6.72 (m, 2H,H-Ph), 7.31 (dd, 1H, JZ1.8, 0.9 Hz, H-5 0). Anal. Calcd forC15H17NO2: C, 74.07; H, 6.99; N, 5.76. Found: C, 74.11; H,6.97; N, 5.75.

3.1.14. 4-N-(2 00,3 00-Dimethylphenyl)amino-4-(2 0-furyl)-butene-1 (12e). Yield 54.95 g (76%); bp 168–171 8C/4 mmHg; nD

23 1.5571; IR 3421 (NH), and 1629(C]C) cmK1; 1H NMR (CDCl3, 200 MHz) d 2.17 (s, 3H,Me-Ar), 2.37 (s, 3H, Me-Ar), 2.79 (t, 2H, JZ6.3 Hz, H-3),4.66 (t, 1H, JZ6.3 Hz, H-4), 5.23 (dd, 1H, JZ10.0, 2.0 Hz,H-1cis), 5.29 (dd, 1H, JZ17.1, 2.0 Hz, H-1trans), 5.88 (ddt,1H, JZ17.1, 10.0, 6.2 Hz, H-2), 6.23 (d, 1H, JZ3.2 Hz,H-3 0), 6.36 (dd, 1H, JZ3.2, 1.8 Hz, H-4 0), 6.55 (d, 1H, JZ8.1 Hz, H-Ph), 6.67 (d, 1H, JZ7.5 Hz, H-Ph), 7.04 (dd, 1H,JZ8.1, 7.5 Hz, H-Ph), 7.43 (d, 1H, JZ1.8 Hz, H-5 0). Anal.Calcd for C16H19NO: C, 79.67; N, 7.88; H, 5.81. Found: C,79.69; N, 7.90; H, 5.80.

3.2.N-Acetyl-4-N-arylamino-4-(2 0-furyl)butene-1 (4, 18).Typical procedure

Homoallylamine 11c or 12d (0.10 mol) was refluxed in10-fold molar excess of acetic anhydride (w100 mL) for1 h. An excess of the anhydride was removed in vacuo. Theresidue was diluted with water (200 mL), and the solutionwas basified with sodium carbonate to pH 9–10. Themixture was extracted with ether (3!70 mL), and driedover MgSO4. After solvent distillation, the residue waspurified on Al2O3 (3!10 cm, ethyl acetate–hexane) in caseof 4 or by recrystallization in case of 18.

3.2.1. N-Acetyl-2-methyl-4-N-(4 00-methylphenyl)amino-4-(2 0-furyl)butene-1 (4). Colorless oil; yield 25.19 g(89%); Rf (20% ethyl acetate–hexane) 0.58; nD

24 1.5400;IR 1656 (N–C]O, and C]C) cmK1; EI-MS (70 eV) m/z(rel intensity): MC 323 (100), 306 (26), 279 (85), 249 (23),234 (19), 220 (14), 204 (13), 191 (9), 165 (5), 153 (6), 132(5), 103 (5), 77 (9), 36 (6), 28 (10); 1H NMR (CDCl3,200 MHz) d 1.77 (s, 3H, Me), 1.78 (s, 3H, Me), 2.34 (s, 3H,Me-4 00), 2.40 (dd, 1H, JZ15.0, 7.7 Hz, H-3A), 2.51 (dd, 1H,JZ15.0, 7.7 Hz, H-3B), 4.81 (br s, 1H, H-1A), 4.86 (br s,1H, H-1B), 6.07 (d, 1H, JZ3.2 Hz, H-3 0), 6.25 (dd, 1H, JZ3.2, 1.9 Hz, H-4 0), 6.36 (t, 1H, JZ7.7 Hz, H-4), 6.67 (m,2H, H-Ph), 7.08 (m, 2H, H-Ph), 7.33 (d, 1H, JZ1.9 Hz,H-5 0). Anal. Calcd for C18H21NO2: C, 76.32; H, 7.42; N,4.95. Found: C, 76.30; H, 7.42; N, 4.98.

3.2.2. N-Acetyl-4-N-(4 00-methoxyphenyl)amino-4-(2 0-furyl)butene-1 (18). Colorless needle like crystals; yield22.19 g (87%); mp 40.5–41.5 8C; IR 1656 (N–C]O, andC]C) cmK1; EI-MS (70 eV) m/z (rel intensity): MC 283

(11), 228 (39), 186 (100), 135 (24), 117 (12), 107 (14), 91(21), 79 (7), 65 (6), 55 (6), 43 (9), 39 (5); 1H NMR (CDCl3,200 MHz) d 1.77 (s, 3H, Ac), 2.42–2.58 (m, 2H, H-3), 3.79(s, 3H, OMe); 5.10 (dq, 1H, JZ10.3, 1.5 Hz, H-1cis), 5.14(dq, 1H, JZ17.3, 1.7 Hz, H-1trans), 5.83 (dddd, 1H, JZ17.3, 10.3, 7.1, 5.9 Hz, H-2), 6.02 (dd, 1H, JZ3.1, 0.8 Hz,H-3 0), 6.20 (t, 1H, JZ7.9 Hz, H-4); 6.24 (dd, 1H, JZ3.1,1.8 Hz, H-4 0), 6.79 (br s, 4H, H-Ph), 7.33 (dd, 1H, JZ1.8,0.8 Hz, H-5 0). Anal. Calcd for C16H17NO2: C, 75.29; H,6.67; N, 5.49. Found: C, 75.31; H, 6.69; N, 5.52.

3.3. N-p-Tolylacetamide (6) and N-acetyl-2-methyl-4-N-(4 00-methylphenyl)amino-4-(2 0-furyl)butanol-2 (7)

A mixture of 3.30 g (11.66 mmol) of N-acetyl derivative 4and 15 mL of 85% H3PO4 was stirred at 30 8C for 1 h. Thenit was diluted with water (200 mL) and basified with 25%aqueous ammonia to pH 9–10. The mixture was extractedwith ethyl acetate (3!50 mL) and the extract was driedover Na2SO4. The crude crystalline product obtained afterevaporation of the solvent was chromatographed on Al2O3

(1.5!10 cm, hexane–ether–ethyl acetate) to give com-pounds 6 and 7 as white crystals.

3.3.1. Compound 6. Yield 37%; mp 149 8C.

3.3.2. Compound 7. White crystals; yield 0.60 g (17%); Rf

(20% ethyl acetate–hexane) 0.42; IR 3320 (OH), and 1700(N–C]O) cmK1; 1H NMR (CDCl3, 200 MHz) d 1.49 (s,3H, Me), 1.51 (s, 3H, Me), 1.90 (s, 3H, Me), 2.20 (s, 3H,Me-4 00), 2.28 (dd, 1H, JZ14.8, 7.5 Hz, H-3A), 2.34 (dd, 1H,JZ14.8, 5.5 Hz, H-3B), 4.00 (br s, 1H, OH), 4.61 (dd, 1H,JZ7.5, 5.5 Hz, H-4), 6.13 (d, 1H, JZ3.2 Hz, H-3 0), 6.25(dd, 1H, JZ3.2, 1.8 Hz, H-4 0), 6.50 (m, 2H, H-Ph), 6.94 (m,2H, H-Ph), 7.31 (d, 1H, JZ1.8 Hz, H-5 0). Anal. Calcd forC18H23NO3: C, 71.76; H, 7.64; N, 4.65. Found: C, 71.78; H,7.69; N, 4.65.

3.4. 4-Oxo-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acids 13a–i and 14a–e. Typical procedure

Corresponding amine 11, 12 (0.10 mol) was dissolved in250 mL of benzene. Then an equimolar amount of maleicanhydride (0.10 mol, 9.80 g) was added in one portion to thesolution. The reaction mixture was stirred for 1–7 days atroom temperature. Then the crystalline product was filteredoff, washed with benzene (2!100 mL) and ether (2!80 mL) and dried at 100 8C to give desired products 13, 14as white solids.

3.4.1. 4-Oxo-3-phenyl-2-methallyl-3-aza-10-oxatri-cyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (13a). Ratioof isomers A/Bw1/1; yield 31.20 g (96%); mp 185.5 8C; IR1738 (COOH), and 1672 (N–C]O) cmK1; EI-MS (70 eV)m/z (rel intensity): MC 325 (4), 270 (18), 240 (3), 226 (11),172 (100), 170 (12), 135 (10), 117 (9), 99 (9), 91 (10), 77(17), 44 (6); 1H NMR (DMSO-d6, 200 MHz) isomer A d1.71 (br s, 3H), 2.18–2.23 (m, 2H), 2.56 (d, 1H, JZ9.2 Hz),2.94 (d, 1H, JZ9.2 Hz), 4.78 (br s, 1H), 4.85 (br s, 1H), 5.01(dd, 1H, JZ8.4, 6.0 Hz), 5.08 (d, 1H, JZ1.5 Hz), 6.37 (dd,1H, JZ5.8, 1.5 Hz), 6.59 (d, JZ5.8 Hz), 7.05–7.60 (m,5H), 11.50 (br s, 1H); isomer B d 1.70 (br s, 3H), 2.18–2.23(m, 2H), 2.57 (d, 1H, JZ9.2 Hz), 3.20 (d, 1H, JZ9.2 Hz),


4.75 (br d, 1H, JZ4.4 Hz), 4.78 (br s, 1H), 4.85 (br s, 1H),5.01 (d, 1H, JZ1.5 Hz), 6.48 (dd, 1H, JZ5.8, 1.5 Hz), 6.54(d, JZ5.8 Hz), 7.05–7.60 (m, 5H), 11.50 (br s, 1H). Anal.Calcd for C19H19NO4: C, 70.15; H, 5.85; N, 4.31. Found: C,70.16; H, 5.83; N, 4.29.

3.4.2. 4-Oxo-3-(2 00-methylphenyl)-2-methallyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (13b).Ratio of isomers A/Bw1.7/1; yield 27.46 g (81%); mp231–234 8C (decomp.); IR 1744 (COOH), and 1672(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

339 (2), 284 (24), 254 (2), 240 (7), 224 (4), 187 (14), 186(100), 184 (8), 156 (98), 135 (8), 130 (12), 118 (14), 107 (6),91 (19), 79 (5), 65 (7); 1H NMR (DMSO-d6, 400 MHz)isomer A d 1.64 (s, 3H); 1.88 (dd, 1H, JZ14.2, 3.6 Hz), 2.10(s, 3H), 2.55 (d, 1H, JZ9.1 Hz), 2.69 (dd, 1H, JZ14.2,10.2 Hz), 2.92 (d, 1H, JZ9.1 Hz), 4.66 (br s, 1H), 4.70 (br s,1H), 4.95 (dd, 1H, JZ10.2, 3.6 Hz), 5.09 (d, 1H, JZ0.9 Hz), 6.37 (dd, 1H, JZ5.7, 0.9 Hz), 6.54 (d, 1H, JZ5.7 Hz), 7.16–7.31 (m, 4H), 12.18 (br s, 1H); isomer B d1.57 (s, 3H), 2.16 (s, 3H), 2.24 (m, 1H), 2.41 (m, 1H), 2.53(d, 1H, JZ8.7 Hz), 3.19 (br d, 1H, JZ8.7 Hz), 4.75 (t, 1H,JZ5.5 Hz), 4.76 (br s, 1H), 4.77 (br s, 1H), 5.04 (d, 1H, JZ1.0 Hz), 6.46 (dd, 1H, JZ5.7, 1.0 Hz), 6.57 (d, 1H, JZ5.7 Hz), 7.16–7.31 (m, 4H) 12.18 (br s, 1H). Anal. Calcd forC20H21NO4: C, 70.80; H, 6.19; N, 4.13. Found: C, 70.85; H,6.17; N, 4.10.

3.4.3. 4-Oxo-3-(4 00-methylphenyl)-2-methallyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (13c).Ratio of isomers A/Bw1/2; yield 32.21 g (95%); mp 191.5–192.5 8C; IR 1747 (COOH), and 1680 (N–C]O) cmK1;EI-MS (70 eV) m/z (rel intensity): MC 339 (6), 323 (5), 282(12), 254 (2), 240 (6), 186 (100), 160 (3), 145 (5), 135 (8),118 (15), 99 (13), 91 (37), 77 (16), 71 (5), 65 (9), 55 (9); 1HNMR (DMSO-d6, 200 MHz) isomer B d 1.72 (br s, 3H),2.15–2.24 (m, 2H), 2.31 (s, 3H), 2.56 (d, 1H, JZ9.2 Hz),2.92 (d, 1H, JZ9.2 Hz), 4.76 (br s, 1H), 4.85 (br s, 1H), 4.97(dd, 1H, JZ8.1, 5.8 Hz), 5.07 (d, 1H, JZ1.5 Hz), 6.36 (dd,1H, JZ5.8, 1.5 Hz), 6.53 (d, 1H, JZ5.8 Hz), 7.14 (BB 0,2H), 7.23 (AA 0, 2H), 11.50 (br s, 1H); isomer A d 1.70 (br s,3H), 2.15–2.24 (m, 2H), 2.29 (s, 3H) 2.55 (d, 1H, JZ9.2 Hz), 3.17 (d, 1H, JZ9.2 Hz), 4.69 (dd, 1H, JZ9.5,3.9 Hz), 4.76 (br s, 2H), 5.00 (d, 1H, JZ1.5 Hz), 6.47 (dd,1H, JZ5.8, 1.5 Hz), 6.58 (d, 1H, JZ5.8 Hz), 7.19 (BB 0,2H), 7.40 (AA 0, 2H), 11.50 (br s, 1H). Anal. Calcd forC20H21NO4: C, 70.80; H, 6.19; N, 4.13. Found; C, 70.78; H,6.16; N, 4.13.

3.4.4. 4-Oxo-3-(2 00-ethylphenyl)-2-methallyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (13d).Ratio of isomers A/Bw1.5/1; yield 22.59 (64%); mp225 8C; IR 1737 (COOH, and N–C]O) cmK1; EI-MS(70 eV) m/z (rel intensity): MC 353 (1), 218 (20), 182 (7),172 (7), 144 (30), 132 (18), 120 (15), 105 (8), 99 (24), 91(20), 77 (20), 65 (7); 1H NMR (DMSO-d6, 200 MHz)isomer A d 1.11 (t, 3H, JZ7.6 Hz), 1.58 (s, 3H), 1.87 (dd,1H, JZ12.5, 4.0 Hz), 2.28 (dd, 1H, JZ12.5, 10.4 Hz), 2.50(d, 1H, JZ9.2 Hz), 2.54 (q, 2H, JZ7.6 Hz), 2.91 (d, 1H,JZ9.2 Hz), 4.77 (br s, 2H), 4.91 (dd, 1H, JZ10.4, 4.0 Hz),5.06 (d, 1H, JZ1.8 Hz), 6.46 (dd, 1H, JZ5.8, 1.8 Hz), 6.58(d, 1H, JZ5.8 Hz), 7.15–7.35 (m, 4H); isomer B d 1.09 (t,3H, JZ7.6 Hz), 1.63 (br s, 3H), 2.45–2.60 (m, 5H), 3.16 (d,

1H, JZ9.5 Hz), 4.65 (br s, 1H), 4.70 (br s, 1H), 5.08 (dd,1H, JZ6.0, 8.7 Hz), 5.10 (d, 1H, JZ1.8 Hz), 6.37 (dd, 1H,JZ5.8, 1.8 Hz), 6.54 (d, 1H, JZ5.8 Hz), 7.15–7.35 (m,4H). Anal. Calcd for C21H23NO4: C, 71.39; H, 6.51; N, 3.97.Found: C, 71.37; H, 6.55; N, 3.95.

3.4.5. 4-Oxo-3-(2 00-methoxyphenyl)-2-methallyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid(13e). Ratio of isomers A/Bw1.6/1; yield 23.78(67%); mp 172–174 8C; IR 1742 (COOH), and 1658(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

355 (7), 301 (5), 300 (27), 270 (2), 256 (8), 221 (5), 203(14), 202 (100), 187 (4), 135 (13), 134 (11), 123 (6), 117 (9),107 (5), 94 (6), 91 (12), 79 (7), 77 (9); 1H NMR (CDCl3,400 MHz) isomer A d 1.69 (s, 3H), 2.03 (dd, 1H, JZ13.2,3.8 Hz), 2.39 (dd, 1H, JZ13.2, 10.9 Hz), 2.84 (d, 1H, JZ9.1 Hz), 3.07 (d, 1H, JZ9.1 Hz), 3.86 (s, 3H), 4.70 (br s,1H), 4.76 (br s, 1H), 4.92 (dd, 1H, JZ10.9, 3.8 Hz), 5.25 (d,1H, JZ1.6 Hz), 6.33 (dd, 1H, JZ5.7, 1.6 Hz), 6.47 (d, 1H,JZ5.7 Hz), 6.90–7.00 (m, 2H), 7.20–7.35 (m, 2H); isomerB d 1.64 (s, 3H), 2.44 (m, 2H, JZ9.2, 5.6 Hz), 2.84 (d, 1H,JZ9.1 Hz), 3.17 (d, 1H, JZ9.1 Hz), 3.81 (s, 3H), 4.64 (dd,1H, JZ9.2, 5.6 Hz), 4.76 (br s, 1H), 4.81 (br s, 1H), 5.27 (d,1H, JZ1.7 Hz), 6.40 (dd, 1H, JZ5.7, 1.7 Hz), 6.57 (d, 1H,JZ5.7 Hz), 6.90–7.00 (m, 2H), 7.20–7.35 (m, 2H). Anal.Calcd for C20H21NO5: C, 67.60; H, 5.92; N, 3.94. Found: C,67.60; H, 5.95; N, 3.93.

3.4.6. 4-Oxo-3-(4 00-methoxyphenyl)-2-methallyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid(13f). Ratio of isomers A/Bw1.3/1; yield 29.11 g(82%); mp 187–188.5 8C; IR 1745 (COOH), and 1672(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

355 (12), 337 (5), 311 (2), 300 (26), 256 (11), 221 (39), 202(100), 186 (21), 161 (9), 149 (5), 135 (37), 117 (19), 107(10), 91 (16), 77 (12), 55 (14), 44 (9); 1H NMR (CDCl3,400 MHz) isomer A d 1.71 (br s, 3H), 2.25 (dd, 1H, JZ13.5,3.7 Hz), 2.43 (dd, 1H, JZ13.5, 10.8 Hz), 2.85 (d, 1H, JZ9.0 Hz), 3.02 (d, 1H, JZ9.0 Hz), 3.81 (s, 3H), 4.69 (dd, 1H,JZ10.8, 3.7 Hz), 4.77 (br s, 1H), 4.82 (br s, 1H), 5.31 (d,1H, JZ1.7 Hz), 5.35 (dd, 1H, JZ5.7, 1.7 Hz), 6.44 (d, 1H,JZ5.7 Hz), 6.92 (BB 0, 2H), 7.15 (AA 0, 2H), 11.50 (br s,1H); isomer B d 1.71 (br s, 3H), 2.37 (dd, 1H, JZ15.9,10.4 Hz), 2.56 (dd, 1H, JZ15.9, 3.7 Hz), 2.85 (d, 1H, JZ9.0 Hz), 3.15 (d, 1H, JZ9.0 Hz), 3.80 (s, 3H), 4.61 (dd, 1H,JZ10.4, 3.7 Hz), 4.81 (br s, 1H), 4.90 (br s, 1H), 5.26 (d,1H, JZ1.7 Hz), 6.42 (dd, 1H, JZ5.7, 1.7 Hz), 6.57 (d, 1H,JZ5.7 Hz), 6.90 (BB 0, 2H), 7.31 (AA 0, 2H), 11.50 (br s,1H). Anal. Calcd for C20H21NO5: C, 67.60; H, 5.92; N, 3.94.Found: C, 67.60; H, 5.90; N, 3.98.

3.4.7. 4-Oxo-3-(2 00-benzylphenyl)-2-methallyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (13g).Ratio of isomers A/Bw1/4; yield 34.44 g (83%); mp 202–203 8C; IR 1738 (COOH), and 1675 (N–C]O) cmK1;EI-MS (70 eV) m/z (rel intensity): MC 415 (11), 360 (30),316 (8), 280 (35), 262 (100), 206 (9), 194 (15), 184 (8), 180(17), 165 (18), 135 (11), 117 (10), 105 (5), 99 (11), 91 (29),77 (6); 1H NMR (DMSO-d6, 400 MHz) isomer B d 1.58 (brs, 3H), 1.75 (dd, 1H, JZ13.3, 3.3 Hz), 2.05 (dd, 1H, JZ13.3, 10.8 Hz), 2.59 (d, 1H, JZ9.1 Hz), 2.94 (d, 1H, JZ9.1 Hz), 3.71 (d, 1H, JZ15.5 Hz), 3.92 (d, 1H, JZ15.5 Hz),4.58 (br s, 1H), 4.67 (br s, 1H), 4.98 (dd, 1H, JZ10.8,


3.3 Hz), 5.11 (s, 1H), 6.36 (d, 1H, JZ5.7 Hz), 6.53 (d, 1H,JZ5.7 Hz), 7.05 (d, 1H, JZ7.6 Hz), 7.13–7.34 (m, 8H),12.26 (br s, 1H); isomer A d 1.46 (br s, 3H), 1.79 (dd, 1H,JZ13.2, 4.0 Hz), 2.24 (dd, 1H, JZ13.2, 11.1 Hz), 2.51 (d,1H, JZ9.1 Hz), 2.94 (d, 1H, JZ9.1 Hz), 3.90 (m, 2H), 4.16(dd, 1H, JZ11.1, 4.0 Hz), 4.48 (br s, 1H), 4.63 (br s, 1H),5.05 (br s, 1H), 6.32 (dd, 1H, JZ6.0, 1.6 Hz), 6.36 (d, 1H,JZ6.0 Hz), 6.94 (d, 1H, JZ7.9 Hz), 7.13–7.34 (m, 8H),12.26 (br s, 1H). Anal. Calcd for C26H25NO4: C, 75.18; H,6.02; N, 3.37. Found: C, 75.20; H, 6.00; N, 3.38.

3.4.8. 4-Oxo-3-(2 00,4 00-dimethylphenyl)-2-methallyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylicacid (13h). Ratio of isomers A/Bw1/1; yield 25.42 g(72%); mp 235–236 8C; IR 1720 (COOH), and 1674(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

353 (2), 335 (2), 321 (7), 298 (10), 254 (5), 238 (5), 200(100), 170 (9), 144 (22), 132 (12), 117 (10), 99 (12), 91 (14),77 (9); 1H NMR (DMSO-d6, 200 MHz) isomer A d 1.62 (brs, 3H), 1.89 (dd, 1H, JZ12.8, 4.0 Hz), 2.05 (s, 3H), 2.27(s, 3H), 2.45 (dd, 1H, JZ12.8, 10.7 Hz), 2.52 (d, 1H, JZ9.2 Hz), 2.89 (d, 1H, JZ9.2 Hz), 4.70 (br s, 1H), 4.77 (br s,1H), 4.87 (dd, 1H, JZ10.7, 4.0 Hz), 5.08 (d, 1H, JZ1.5 Hz), 6.36 (dd, 1H, JZ5.8, 1.5 Hz), 6.53 (d, 1H, JZ5.8 Hz), 7.02–7.15 (m, 3H); isomer B d 1.60 (br s, 3H),2.12 (s, 3H), 2.27 (br s, 3H), 2.50 (m, 2H), 2.55 (d, 1H, JZ9.2 Hz), 3.13 (d, 1H, JZ9.2 Hz), 4.24 (dd, 1H, JZ9.2,4.3 Hz), 4.66 (br s, 1H), 4.77 (br s, 1H), 5.03 (d, 1H, JZ1.5 Hz), 6.44 (dd, 1H, JZ5.8, 1.5 Hz), 6.57 (d, 1H, JZ5.8 Hz), 7.02–7.15 (m, 3H). Anal. Calcd for C21H23NO4: C,71.39; H, 6.51; N, 3.97. Found: C, 71.39; H, 6.52; N, 4.00.

3.4.9. 4-Oxo-3-(4 00-isopropylphenyl)-2-methallyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid(13i). Ratio of isomers A/Bw1/2.5; yield 30.09 g(82%); mp 174–174.5 8C; IR 1725 (COOH), and 1675(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

367 (22), 312 (21), 268 (8), 214 (100), 198 (11), 172 (11),146 (12), 135 (29), 117 (21), 99 (18), 91 (22), 77 (15), 65(9), 55 (22), 19 (41); 1H NMR (DMSO-d6, 200 MHz)isomer B d 1.19 (d, 6H, JZ6.7 Hz), 1.70 (s, 3H), 2.17 (d,2H, JZ7.9 Hz), 2.55 (d, 1H, JZ9.2 Hz), 2.88 (sept, 1H, JZ6.7 Hz), 2.93 (d, 1H, JZ9.2 Hz), 4.67 (m, 1H), 4.74 (m,2H), 4.99 (m, 1H), 5.05 (d, 1H, JZ1.6 Hz), 6.35 (dd, 1H,JZ5.6, 1.6 Hz), 6.51 (d, 1H, JZ5.6 Hz), 7.16 (BB 0, 2H),7.28 (AA 0, 2H); isomer A d 1.18 (d, 6H, JZ6.6 Hz), 1.70 (s,3H), 2.37 (m, 1H), 2.51 (m, 1H), 2.53 (d, 1H, JZ9.2 Hz),2.88 (sept, 1H, JZ6.6 Hz), 3.20 (d, 1H, JZ9.2 Hz), 4.85(m, 1H), 4.99 (m, 2H), 4.99 (d, 1H, JZ1.6 Hz), 6.45 (dd,1H, JZ5.8, 1.6 Hz), 6.55 (d, 1H, JZ5.8 Hz), 7.24 (BB 0,2H), 7. 43 (AA 0, 2H). Anal. Calcd for C22H25NO4: C, 71.94;H, 6.81; N, 3.82. Found: C, 71.96; H, 6.80; N, 3.84.

3.4.10. 4-Oxo-3-phenyl-2-allyl-3-aza-10-oxatricyclo-[5.2.1.01,5]dec-8-ene-6-carboxylic acid (14a). Ratio ofisomers A/Bw1/1; yield 27.06 g (87%); mp 180–182 8C;IR 1749 (COOH), and 1670 (N–C]O) cmK1; EI-MS(70 eV) m/z (rel intensity): MC 311 (8), 293 (5), 270 (20),226 (12), 212 (23), 173 (15), 172 (100) 170 (16) 145 (6), 121(13), 104 (13), 103 (16), 99 (12), 93 (13), 91 (21), 77 (36);1H NMR (CDCl3, 400 MHz) isomer A d 2.41 (m, 2H), 2.84(d, 1H, JZ9.2 Hz), 3.02 (d, 1H, JZ9.2 Hz), 4.59 (dd, 1H,JZ9.8, 5.2 Hz), 5.07 (dd, 1H, JZ18.5, 1.3 Hz), 5.09 (dd,

1H, JZ10.4, 1.3 Hz), 5.27 (d, 1H, JZ1.8 Hz), 5.71 (dd, 1H,JZ18.5, 10.4 Hz), 6.39 (dd, 1H, JZ5.8, 1.8 Hz), 6.47 (d,1H, JZ5.8 Hz), 7.20–7.45 (m, 5H), 10.06 (br s, 1H); isomerB d 2.62 (m, 2H), 2.86 (d, 1H, JZ9.2 Hz), 3.10 (d, 1H, JZ9.2 Hz), 4.63 (t, 1H, JZ4.8 Hz), 5.17 (dd, 1H, JZ18.0,1.3 Hz), 5.19 (dd, 1H, JZ9.3, 1.3 Hz), 5.33 (d, 1H, JZ1.8 Hz), 5.77 (dd, 1H, JZ18.0, 9.3 Hz), 6.49 (dd, 1H, JZ5.8, 1.8 Hz), 6.62 (d, 1H, JZ5.8 Hz), 7.20–7.45 (m, 5H),10.06 (br s, 1H). Anal. Calcd for C18H17NO4: C, 69.45; H,5.47; N, 4.50. Found: C, 69.49; H, 5.46; N, 4.54.

3.4.11. 4-Oxo-3-(2 00-methylphenyl)-2-allyl-3-aza-10-oxa-tricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (14b).Ratio of isomers A/Bw2/1; yield 27.30 g (84%);mp 211.5–212 8C; IR 1744 (COOH), and 1673(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

325 (2), 307 (2), 284 (7), 253 (3), 226 (6), 195 (7), 186(100), 118 (24), 99 (13), 91 (47), 77 (24), 65 (32), 55 (22);1H NMR (DMSO-d6, 400 MHz) isomer A d 1.99 (m, 1H),2.14 (s, 3H), 2.55 (d, 1H, JZ9.1 Hz), 2.59 (m, 1H), 2.94 (d,1H, JZ9.1 Hz), 4.75 (dd, 1H, JZ10.6, 4.4 Hz), 4.93 (dd,1H, JZ10.1, 1.7 Hz), 4.96 (dd, 1H, JZ17.0, 1.7 Hz), 5.04(d, 1H, JZ1.7 Hz), 5.63 (ddt, 1H, JZ17.0, 10.1, 7.1 Hz),6.41 (dd, 1H, JZ5.7, 1.7 Hz), 6.56 (d, 1H, JZ5.7 Hz),7.20–7.29 (m, 4H). Anal. Calcd for C19H19NO4: C, 70.14;H, 5.89; N, 4.30. Found: C, 70.41; H, 5.96; N, 4.24.

3.4.12. 4-Oxo-3-(2 00-methoxyphenyl)-2-allyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (14c).Ratio of isomers A/Bw1.5/1; yield 19.10 g (56%); mp 152–153 8C; IR 1755 (COOH), 1684 (N–C]O) cmK1; EI-MS(70 eV) m/z (rel intensity): MC 341 (12), 300 (16), 282 (4),256 (5), 242 (7), 202 (100), 186 (8), 134 (9), 121 (16), 99(12), 91 (21), 81 (12), 77 (30), 65 (15); 1H NMR (CDCl3,200 MHz) isomer A d 2.18 (m, 1H), 2.57 (m, 1H), 2.91 (d,1H, JZ9.2 Hz), 3.03 (d, 1H, JZ9.2 Hz), 3.84 (s, 3H), 4.70(dd, 1H, JZ10.4, 4.6 Hz), 5.00 (br d, 1H, JZ10.4 Hz), 5.02(br d, 1H, JZ17.1 Hz), 5.41 (d, 1H, JZ1.5 Hz), 5.68 (m,1H), 6.45 (dd, 1H, JZ5.8, 1.5 Hz), 6.47 (d, 1H, JZ5.8 Hz),6.95–7.05 (m, 2H), 7.20–7.40 (m, 2H); isomer B d 2.40 (m,1H), 2.57 (m, 1H), 2.91 (d, 1H, JZ9.2 Hz), 3.02 (d, 1H, JZ9.2 Hz), 3.87 (s, 3H), 4.53 (t, 1H, JZ5.2 Hz), 5.19 (br d, 1H,JZ9.2 Hz), 5.21 (br d, 1H, JZ18.0 Hz), 5.41 (d, 1H, JZ1.5 Hz), 5.89 (m, 1H), 6.52 (dd, 1H, JZ6.1, 1.5 Hz), 6.63(d, 1H, JZ6.1 Hz), 6.95–7.05 (m, 2H), 7.20–7.40 (m, 2H).Anal. Calcd for C19H19NO5: C, 66.86; H, 5.57; N, 4.10.Found: C, 66.86; H, 5.56; N, 4.10.

3.4.13. 4-Oxo-3-(4 00-methoxyphenyl)-2-allyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (14d).Ratio of isomers A/Bw1/1; yield 32.05 g (94%).

Isomer A mp 67.5–69.5 8C; IR 1720 (COOH), and 1685(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

341 (22), 300 (24), 256 (12), 242 (12), 221 (63), 202 (100),186 (17), 161 (7), 134 (11), 123 (20), 121 (37), 103 (23); 93(14), 77 (20), 55 (11). 1H NMR (DMSO-d6, 200 MHz) d2.24 (ddd, 2H, JZ9.2, 6.8, 5.5 Hz), 2.57 (d, 1H, JZ9.2 Hz),2.93 (d, 1H, JZ9.2 Hz), 3.77 (s, 3H), 4.73 (dd, 1H, JZ9.2,5.5 Hz), 4.98 (dd, 1H, JZ10.1, 1.5 Hz), 5.03 (dd, 1H, JZ18.0, 1.5 Hz), 5.08 (d, 1H, JZ1.5 Hz), 5.72 (ddt, 1H, JZ18.0, 10.1, 6.8 Hz), 6.41 (dd, 1H, JZ5.8, 1.5 Hz), 6.55(d, 1H, JZ5.8 Hz), 6.96 (BB 0, 2H), 7.17 (AA 0, 2H), 11.50


(br s, 1H); 1H NMR (CDCl3, 400 MHz) d 1.99 (m, 2H,CH2-3 0), 2.79 (d, 1H, JZ9.2 Hz, H-6), 3.02 (d, 1H, JZ9.2 Hz, H-5), 3.04 (s, 3H, MeO-4 00), 4.47 (t, 1H, JZ5.0 Hz,H-2), 5.15 (m, 1H, H-1 0A), 5.17 (m, 1H, H-1 0B), 5.23 (d,1H, JZ1.8 Hz, H-7), 5.74 (ddt, 1H, JZ16.8, 10.5, 7.0 Hz,H-2 0), 6.45 (dd, 1H, JZ5.9, 1.8 Hz, H-8), 6.57 (d, 1H, JZ5.9 Hz, H-9), 6.88 (m, 2H, H-3 00 and H-5 00), 7.27 (m, 2H,H-2 00 and H-6 00); 13C NMR (CDCl3, 100.6 MHz) d 33.6(t, JZ128.0 Hz, C3 0), 46.2 (d, JZ138.2 Hz, C6), 50.5 (d,JZ139.3 Hz, C5), 55.3 (q, JZ144.2 Hz, MeO), 61.6 (d, JZ146.3 Hz, C2), 81.5 (d, JZ169.0 Hz, C7), 91.3 (s, C1), 114.3(d, JZ160.8 Hz, C3 00 and C5 00), 119.9 (dd, JZ154.0,159.5 Hz, C1 0), 126.1 (d, JZ161.0 Hz, C2 00 and C6 00), 129.3(s, C1 00), 131.4 (d, JZ152.8 Hz, C2 0), 133.4 (d, JZ178.0 Hz,C9), 137.2 (d, JZ177.5 Hz, C8), 158.0 (s, C4 00), 171.5 (s,COOH), 173.5 (s, C4). Anal. Calcd for C19H19NO5: C,66.86; H, 5.57; N, 4.10. Found: C, 66.88; H, 5.60; N, 4.10.

Isomer B mp 117.5–118 8C; IR 1740 (COOH), and 1675(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

341 (29), 300 (30), 256 (15), 242 (14), 221 (78), 202 (100),186 (22), 161 (10), 134 (14), 123 (27), 121 (46), 108 (11),103 (29); 93 (18), 77 (26), 55 (14). 1H NMR (DMSO-d6,200 MHz) d 2.48–2.59 (m, 2H), 2.55 (d, 1H, JZ9.2 Hz),3.01 (d, 1H, JZ9.2 Hz), 3.76 (s, 3H), 4.57 (t, 1H, JZ5.5 Hz), 5.01 (d, 1H, JZ1.5 Hz), 5.12 (br dd, 1H, JZ9.2,1.5 Hz), 5.14 (dd, 1H, JZ18.3, 1.5 Hz), 5.82 (ddt, 1H, JZ18.3, 9.2, 6.7 Hz), 6.52 (dd, 1H, JZ5.8, 1.5 Hz), 6.73(d, 1H, JZ5.8 Hz), 6.95 (BB 0, 2H), 7.41 (AA 0, 2H), 11.57(br s, 1H); 1H NMR (CDCl3, 400 MHz) d 2.30 (dddt, 1H,JZ13.4, 7.7, 1.1 Hz, H-3 0A), 2.41 (dddt, 1H, JZ13.4, 10.8,6.6, 1.1 Hz, H-3 0B), 2.82 (d, 1H, JZ9.1 Hz, H-6), 3.00 (d,1H, JZ9.1 Hz, H-5), 3.11 (s, 3H, MeO-4 00), 4.50 (dd, 1H,JZ10.8, 4.5 Hz, H-2), 5.01 (m, 1H, H-1 0A), 5.04 (m, 1H,H-1 0B), 5.27 (d, 1H, JZ1.8 Hz, H-7), 5.68 (dddd, 1H, JZ17.0, 10.2, 7.7, 6.6 Hz, H-2 0), 6.38 (dd, 1H, JZ5.7, 1.8 Hz,H-8), 6.46 (d, 1H, JZ5.7 Hz, H-9), 6.89 (m, 2H, H-3 00 andH-5 00), 7.14 (m, 2H, H-2 00 and H-6 00); 13C NMR (CDCl3,100.6 MHz) d 32.6 (t, JZ131.5 Hz, C3 0), 46.1 (d, JZ140.0 Hz, C6), 50.6 (d, JZ140.0 Hz, C5), 55.3 (q, JZ144.2 Hz, MeO), 60.1 (d, JZ141.7 Hz, C2), 81.6 (d, JZ169.0 Hz, C7), 90.4 (s, C1), 114.2 (d, JZ160.0 Hz, C3 00 andC5 00), 118.8 (dd, JZ154.5, 158.5 Hz, C1 0), 127.3 (d, JZ160.5 Hz, C2 00 and C6 00), 128.6 (s, C1 00), 132.3 (d, JZ154.8 Hz, C2 0), 135.6 (d, JZ177.8 Hz, C8), 135.8 (d, JZ177.8 Hz, C9), 158.4 (s, C4 00), 172.2 (s, COOH), 173.4 (s,C4). Anal. Calcd for C19H19NO5: C, 66.86; H, 5.57; N, 4.10.Found: C, 66.86; H, 5.58; N, 4.12.

3.4.14. 4-Oxo-3-(2 00,3 00-dimethylphenyl)-2-allyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (14e).Ratio of isomers A/Bw2.5/1; yield 25.76 g (76%); mp227 8C; IR 1747 (COOH), and 1672 (N–C]O) cmK1;EI-MS (70 eV) m/z (rel intensity): MC 339 (4), 321 (2), 299(5), 298 (27), 254 (9), 240 (14), 201 (16), 200 (100), 198(11), 170 (6), 159 (7), 132 (13), 130 (10), 121 (16), 120 (8),105 (8), 103 (14), 99 (9), 91 (16), 77 (17); 1H NMR (DMSO-d6, 200 MHz) isomer A d 2.12 (s, 3H), 2.29 (s, 3H), 2.65 (m,2H), 2.85 (d, 1H, JZ10.0 Hz), 3.03 (d, 1H, JZ10.0 Hz),4.49 (dd, 1H, JZ8.9, 5.0 Hz), 5.25 (dd, 2H, JZ16.8,10.1 Hz), 5.33 (d, 1H, JZ1.5 Hz), 5.89 (dd, 1H, JZ16.8,10.1 Hz), 6.50 (dd, 1H, JZ5.5, 1.5 Hz), 6.70 (br d, 1H, JZ5.5 Hz), 6.95–7.00 (m, 1H), 7.05–7.25 (m, 2H), 12.00 (br s,

1H); isomer B d 2.12 (s, 3H), 2.29 (s, 3H), 2.65 (m, 2H),2.84 (d, 1H, JZ10.0 Hz), 2.98 (d, 1H, JZ10.0 Hz), 4.13(dd, 1H, JZ5.8, 4.6 Hz), 5.01 (m, 1H, JZ10.7 Hz), 5.03 (m,1H, JZ17.1 Hz), 5.38 (d, 1H, JZ1.5 Hz), 5.65 (m, 1H, JZ16.8, 10.1 Hz), 6.39 (dd, 1H, JZ5.5, 1.5 Hz), 6.57 (br d, 1H,JZ5.5 Hz), 6.95–7.00 (m, 1H), 7.05–7.25 (m, 2H), 12.00(br s, 1H). Anal. Calcd for C20H21NO4: C, 70.80; H, 6.19; N,4.13. Found: C, 70.83; H, 6.17; N, 4.13.

3.5. 6-Ethoxycarbonyl-4-oxo-3-aza-10-oxatricyclo-[5.2.1.01,5]dec-8-enes (15a,b). Typical procedure

Adduct 14a,b (0.01 mol) was refluxed in ethanol (20 mL)for 2 h in the presence of catalytic amounts of H2SO4

(concd). Then the reaction mixture was poured into 150 mLof water and extracted with ethyl acetate (4!60 mL). Theextract was dried over MgSO4 and concentrated in vacuo.The crude product was recrystallized from mixture ofhexane–ethyl acetate to give esters 15a,b as white solids.

3.5.1. 6-Ethoxycarbonyl-4-oxo-3-phenyl-2-allyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene (15a). Ratio of isomersA/Bw1.2/1; yield 2.37 g (70%); mp 74.5–76 8C; IR 1786(COOEt), 1695 (N–C]O) cmK1; EI-MS (70 eV) m/z (relintensity): MC 339 (23), 298 (31), 270 (1), 212 (26), 200(5), 172 (100), 127 (80), 121 (27), 104 (15), 99 (80), 91 (14),77 (37), 65 (8); 1H NMR (DMSO-d6, 200 MHz) isomer A d1.22 (t, 3H, JZ7.2 Hz), 2.25 (m, 2H), 2.68 (d, 1H, JZ9.2 Hz), 3.02 (d, 1H, JZ9.2 Hz), 4.10 (d, 2H, JZ7.2 Hz),4.85 (dd, 1H, JZ10.1, 4.6 Hz), 4.95–5.20 (m, 2H), 5.13 (d,1H, JZ1.5 Hz), 5.78 (m, 1H), 6.42 (dd, 1H, JZ5.8, 1.5 Hz),6.57 (d, 1H, JZ5.8 Hz), 7.10–7.60 (m, 5H); isomer B d 1.17(t, 3H, JZ7.2 Hz), 2.59 (m, 2H), 2.68 (d, 1H, JZ9.2 Hz),3.13 (d, 1H, JZ9.2 Hz), 4.02 (q, 2H, JZ7.2 Hz), 4.71 (dd,1H, JZ5.5, 4.6 Hz), 4.95–5.20 (m, 2H), 5.05 (d, 1H, JZ1.5 Hz), 5.78 (m, 1H), 6.52 (dd, 1H, JZ5.8, 1.5 Hz), 6.75(d, 1H, JZ5.8 Hz), 7.10–7.60 (m, 5H). Anal. Calcd forC20H21NO4: C, 70.80; H, 6.19; N, 4.13. Found: C, 70.83; H,6.17; N, 4.12.

3.5.2. 6-Ethoxycarbonyl-4-oxo-3-(2 0-methylphenyl)-2-allyl-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene (15b).Ratio of isomers A/Bw3/1; yield 3.07 g (87%); mp 115–116.5 8C; IR 1724 (COOEt), and 1697 (N–C]O) cmK1;EI-MS (70 eV) m/z (rel intensity): MC 353 (10), 312 (34),307 (7), 232 (9), 226 (43), 210 (11), 186 (100), 156 (15), 144(11), 127 (57), 121 (28), 99 (80), 91 (38), 65 (15), 39 (11);1H NMR (CDCl3, 400 MHz) isomer A d 1.30 (t, 3H, JZ7.1 Hz), 2.05–2.19 (m, 1H), 2.24 (s, 3H), 2.44–2.57 (m, 1H),2.78 (d, 1H, JZ9.1 Hz), 2.93 (d, 1H, JZ9.1 Hz), 4.15–4.37(m, 2H), 4.51 (dd, 1H, JZ10.8, 4.5 Hz), 5.01 (dd, 1H, JZ10.0, 7.0 Hz), 5.04 (dd, 1H, JZ17.0, 7.0 Hz), 5.25 (d, 1H,JZ1.6 Hz), 5.60–5.74 (m, 1H), 6.41 (dd, 1H, JZ5.7,1.7 Hz), 6.52 (dd, 1H, JZ5.7, 1.3 Hz), 7.20–7.28 (m, 4H).Anal. Calcd for C21H23NO4: C, 71.39; H, 6.51; N, 3.97.Found: C, 71.42; H, 6.50; N, 3.40.

3.6. 11-Oxo-6,6a,9,10,10a,11-hexahydro-5H-6b,9-epoxy-isoindolo[2,1-a]quinoline-10-carboxylic acids (20a,b).Typical procedure

A mixture of the corresponding adduct 13c,d (0.01 mol) and85% H3PO4 (30 mL) was stirred at 10–15 8C for 1.5 h


(monitoring by TLC). At the end of the reaction, the mixturewas diluted with water (150 mL). The obtained precipitatewas filtered off, washed with cold water (5!80 mL) anddried in air. Then the crude product was recrystallized togive the desired product 20 as colorless crystals.

3.6.1. 3,5,5-Trimethyl-11-oxo-6,6a,9,10,10a,11-hexa-hydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline-10-carb-oxylic acid (20a). Major isomer. Yield 1.25 g (37%); mp215.5–217 8C decomp. (chloroform); IR 1746 (COOH), and1672 (N–C]O, and C]C) cmK1; EI-MS (70 eV) m/z (relintensity): MC 339 (11), 321 (4), 294 (3), 240 (100), 224(18), 196 (8), 181 (7), 158 (13), 144 (8), 115 (7), 91 (7), 81(4); 1H NMR (DMSO-d6, 400 MHz) d 1.29 (s, 3H, Me-5),1.35 (s, 3H, Me-5), 1.77 (dd, 1H, JZ13.5, 3.4 Hz, H-6A),1.83 (dd, 1H, JZ13.5, 11.8 Hz, H-6B), 2.25 (s, 3H, Me-3),2.56 (d, 1H, JZ9.1 Hz, H-10), 3.06 (d, 1H, JZ9.1 Hz,H-10a), 4.62 (dd, 1H, JZ11.8, 3.4 Hz, H-6a), 5.02 (d, 1H,JZ1.7 Hz, H-9), 6.49 (dd, 1H, JZ5.7, 1.7 Hz, H-8), 6.61 (d,1H, JZ5.7 Hz, H-7), 6.95 (dd, 1H, JZ8.5, 2.0 Hz, H-2),7.24 (d, 1H, JZ2.0 Hz, H-4), 8.47 (d, 1H, JZ8.5 Hz, H-1),12.19 (br s, 1H, COOH); 13C NMR (DMSO-d6, 100.6 MHz)d 173.2 (s), and 169.5 (s) (COOH, and C12), 137.6 (d, JZ177.5 Hz, C8), 134.7 (d, JZ178.5 Hz, C7), 134.4, 133.1, and132.1 (s, C4a, C3, C12a), 127.2 (d, JZ154.0 Hz, C4), 126.9(d, JZ157.5 Hz, C2), 118.0 (d, JZ163.5 Hz, C1), 89.8 (s,C6b), 81.0 (d, JZ168.5 Hz, C9), 52.5 (d, JZ142.5 Hz, C6a),51.0 (d, JZ141.0 Hz, C10a), 45.1 (d, JZ138.5 Hz, C10),37.1 (t, JZ131.5 Hz, C6), 32.6 (s, C5), 32.2 (q, JZ126.0 Hz,Me-5), 30.5 (q, JZ126.0 Hz, Me-5), 20.7 (q, JZ126.5 Hz,Me-3). Anal. Calcd for C20H21NO4: C, 70.80; H, 6.19; N,4.13. Found: C, 70.82; H, 6.23; N, 4.17. Minor isomer (hasnot been isolated). 1H NMR (DMSO-d6, 400 MHz) d 1.33(s, 3H, Me-5), 1.37 (s, 3H, Me-5), 1.95 (t, 1H, JZ13.1 Hz,H-6A), 2.12 (dd, 1H, JZ13.1, 2.1 Hz, H-6B), 2.25 (s, 3H,Me-3), 2.57 (d, 1H, JZ9.1 Hz, H-10), 3.02 (d, 1H, JZ9.1 Hz, H-10a), 4.05 (dd, 1H, JZ13.1, 2.1 Hz, H-6a), 5.08(d, 1H, JZ1.7 Hz, H-9), 6.50 (dd, 1H, JZ5.7, 1.7 Hz, H-8),6.71 (d, 1H, JZ5.7 Hz, H-7), 6.97 (dd, 1H, JZ8.2, 2.0 Hz,H-2), 7.27 (d, 1H, JZ2.0 Hz, H-4), 7.61 (d, 1H, JZ8.2 Hz,H-1), 12.19 (br s, 1H, COOH).

3.6.2. 1-Ethyl-5,5-dimethyl-11-oxo-6,6a,9,10,10a,11-hexahydro-5H-6b,9-epoxyisoindolo[2,1-a]quinoline-10-carboxylic acid (20b). Yield 2.22 g (63%); mp 150–151 8C(heptane–chloroform); IR 1700 (COOH), and 1617(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

353 (4), 309 (2), 280 (4), 254 (100), 240 (16), 212 (12), 186(13), 172 (13), 160 (16), 144 (12), 130 (10), 115 (11), 99(20), 91 (7), 77 (4); 1H NMR (CDCl3, 400 MHz) d 1.17 (t,3H, JZ7.7 Hz), 1.36 (s, 3H), 1.44 (s, 3H), 1.91 (t, 1H, JZ12.8 Hz), 2.13 (dd, 1H, JZ12.9, 2.7 Hz), 2.75 (d, 2H, JZ7.7 Hz), 2.83 (d, 1H, JZ8.8 Hz), 2.92 (d, 1H, JZ8.8 Hz),4.23 (dd, 1H, JZ12.7, 2.7 Hz), 5.28 (d, 1H, JZ1.5 Hz),6.49 (dd, 1H, JZ6.0, 1.5 Hz), 6.62 (d, 1H, JZ6.0 Hz), 7.12(dd, 1H, JZ7.4, 2.4 Hz), 7.15 (t, 1H, JZ7.4 Hz), 7.19 (dd,1H, JZ7.4, 2.4 Hz), 7.40 (br s, 1H); 13C NMR (DMSO-d6,100.6 MHz) d 172.8 (s); 169.1 (s) (COOH and N–C]O);139.0 (s); 138.8 (s); 132.4 (s); 136.8 (d) and 134.4 (d) (C7

and C8); 126.3 (d); 125.8 (d); 124.1 (d); 90.6 (s, C6b); 81.7(d, C9); 55.2 (d, C6a); 49.4 (d, C10a); 45.1 (d, C10); 40.6 (t,C6); 34.0 (s, C5); 33.2 (q) and 31.6 (q) (Me-5); 24.5 (t,CH2CH3); 14.3 (q, CH2CH3). Anal. Calcd for C21H23NO4:

C, 75.22; H, 6.27; N, 4.18. Found: C, 75.20; H, 6.29; N,4.15.

3.7. 5,5-Dimethyl-10-carboxyisoindolo[2,1-a]quinoline-11-ones (21a–i). Typical procedure

A mixture of corresponding adduct 13 (0.01 mol) and 85%H3PO4 (40 mL) was stirred at 70–85 8C for 45 min(monitoring by TLC). At the end of the reaction, themixture was diluted with water (200 mL). The obtainedprecipitate was filtered off, washed with cold water (5!80 mL) and dried in air. Then the crude product wasrecrystallized to give desired isoindoloquinolines 21 ascolorless crystals.

3.7.1. 5,5-Dimethyl-5,6,6a,11-tetrahydro-11-oxoiso-indolo[2,1-a]quinoline-10-carboxylic acid (21a). Yield2.09 g (68%); mp 237.5–240 8C (heptane–chloroform); IR1727 (COOH), and 1617 (N–C]O) cmK1; EI-MS (70 eV)m/z (rel intensity): MC 307 (92), 292 (65), 264 (21), 263(100), 248 (18), 232 (11), 218 (15), 204 (12), 115 (9), 102(7), 91 (6); 1H NMR (CDCl3, 400 MHz) d 1.47 (s, 3H,Me-5), 1.54 (s, 3H, Me-5), 1.72 (t, 1H, JZ12.7 Hz, H-6ax),2.41 (dd, 1H, JZ12.7, 2.6 Hz, H-6eq), 4.97 (dd, 1H, JZ12.7, 2.6 Hz, H-6a), 7.23–7.39 (m, 2H, H-Ar), 7.48 (dd, 1H,JZ7.3, 1.8 Hz, H-Ar), 7.76–7.86 (m, 2H, H-Ar), 8.38 (dd,1H, JZ7.9, 1.5 Hz, H-1), 8.50 (dd, 1H, JZ7.9, 1.5 Hz,H-9); 13C NMR (DMSO-d6, 100.6 MHz) d 166.2 (s), and165.3 (s) (COOH, and N–C]O), 146.4 (s), 136.6 (s), 133.1(s), 129.5 (s), 128.9 (s), 132.9 (d, C8), 131.7 (d, C9), 127.4(d), 126.6 (d), 126.5 (d), 125.6 (d), 120.4 (d), 56.5 (d, C6a),41.9 (t, C6), 33.6 (s, C5), 31.7 (q), and 30.6 (q) (Me-5). Anal.Calcd for C19H17NO3: C, 74.27; H, 5.54; N, 4.56. Found: C,74.22; H, 5.57; N, 4.59.

3.7.2. 1,5,5-Trimethyl-5,6,6a,11-tetrahydro-11-oxoiso-indolo[2,1-a]quinoline-10-carboxylic acid (21b). Yield1.00 g (31%); mp 209.5–210 8C (i-PrOH–DMF); IR 1728(COOH), and 1619 (N–C]O) cmK1; EI-MS (70 eV) m/z(rel intensity): MC 321 (79), 306 (12), 288 (13), 275 (100),262 (12), 245 (4), 221 (12), 130 (14), 115 (25), 91 (15), 77(18), 65 (12), 51 (13); 1H NMR (CDCl3, 400 MHz) d 1.30(s, 3H, Me-5), 1.44 (s, 3H, Me-5), 1.72 (dd, 1H, JZ13.4,10.3 Hz, H-6ax), 2.39 (s, 3H, Me-1), 2.42 (dd, 1H, JZ13.4,4.7 Hz, H-6eq), 4.98 (dd, 1H, JZ10.3, 4.7 Hz, H-6a), 7.20–7.30 (m, 3H, H-Ar), 7.77–7.79 (m, 2H, H-Ar), 8.45 (dd, 1H,JZ5.8, 2.1, H-9); 13C NMR (DMSO-d6, 100.6 MHz) d165.6 (s), and 165.4 (s) (COOH, and N–C]O), 148.7 (s),139.5 (s), 132.7 (s), 131.7 (s), 129.8 (s), 128.5 (s), 133.0 (d,C8), 131.4 (d, C9), 129.2 (d), 126.81 (d), 126.80 (d), 124.1(d), 57.3 (d, C6a), 45.2 (t, C6), 33.2 (s, C5), 32.2 (q), and 30.2(q) (Me-5), 20.0 (q, Me-1). Anal. Calcd for C20H19NO3: C,74.77; N, 5.92; H, 4.36. Found: C, 74.80; N, 5.96; H, 4.32.

3.7.3. 3,5,5-Trimethyl-5,6,6a,11-tetrahydro-11-oxoiso-indolo[2,1-a]quinoline-10-carboxylic acid (21c). Yield1.61 g (50%); mp 222–230 8C decomposition (heptane–chloroform); IR 1708 (COOH, and N–C]O) cmK1; EI-MS(70 eV) m/z (rel intensity): MC 321 (1), 277 (66), 262 (100),246 (14), 232 (17), 218 (3), 124 (6), 115 (9), 91 (4), 77 (7);1H NMR (CDCl3, 400 MHz) d 1.45 (s, 3H, Me-5), 1.52 (s,3H, Me-5), 1.69 (t, 1H, JZ13.0 Hz, H-6ax), 2.38 (s, 3H,Me-3), 2.38 (dd, 1H, JZ13.0, 2.7 Hz, H-6eq), 4.92 (dd, 1H,


JZ13.0, 2.7 Hz, H-6a), 7.13 (dd, 1H, JZ8.5, 1.5 Hz, H-2),7.25 (d, 1H, JZ1.5 Hz, H-4), 7.74 (d, 1H, JZ8.5 Hz, H-1),7.78 (t, 1H, JZ7.4 Hz, H-8), 8.25 (dd, 1H, JZ7.4, 1.1 Hz,H-7), 8.47 (dd, 1H, JZ7.4, 1.1 Hz, H-9), 15.80 (br s, 1H,COOH), 13C NMR (DMSO-d6, 100.6 MHz) d 166.1 (s), and164.8 (s) (COOH, and N–C]O), 146.3 (s), 136.5 (s), 134.8(s), 130.7 (s), 129.5 (s), 129.1 (s), 132.6 (d, C8), 131.8 (d,C9), 127.5 (d), 127.0 (d), 126.4 (d), 120.2 (d), 56.6 (d, C6a),42.4 (t, C6), 33.4 (s, C5), 31.6 (q), and 30.6 (q) (Me-5), 20.6(q, Me-3). Anal. Calcd for C20H19NO3: C, 74.77; H, 5.92; N,4.36. Found: C, 74.75; H, 5.92; N, 4.40.

3.7.4. 1-Ethyl-5,5-dimethyl-5,6,6a,11-tetrahydro-11-oxoisoindolo[2,1-a]quinoline-10-carboxylic acid (21d).Yield 1.51 g (45%); mp 199.5–200.5 8C (i-PrOH–DMF);IR 1744 (COOH), and 1639 (N–C]O) cmK1; EI-MS(70 eV) m/z (rel intensity): MC 335 (98), 318 (15), 302(6), 289 (100), 232 (7), 204 (9), 128 (9), 115 (19), 102 (10),91 (11), 77 (12), 65 (9), 51 (9); 1H NMR (DMSO-d6,400 MHz) d 1.16 (s, 3H, Me-5), 1.18 (t, 3H, JZ7.5 Hz,CH2Me), 1.41 (s, 3H, Me-5), 1.74 (dd, 1H, JZ13.4, 8.8 Hz,H-6ax), 2.46 (dd, 1H, JZ13.4, 5.8 Hz, H-6eq), 2.74 (m, 2H,CH2Me), 5.21 (dd, 1H, JZ8.8, 5.8 Hz, H-6a), 7.28 (d, 1H,JZ7.4 Hz, H-Ar), 7.33 (t, 1H, JZ7.4 Hz, H-3), 7.38 (d, 1H,JZ7.4 Hz, H-Ar), 7.88 (t, 1H, JZ7.5 Hz, H-8), 8.00 (d, 1H,JZ7.5 Hz, H-7), 8.14 (d, 1H, JZ7.5 Hz, H-9); 13C NMR(DMSO-d6, 100.6 MHz) d 166.1 (s), and 165.3 (s) (COOH,and N–C]O), 149.0 (s), 140.0 (s), 138.6 (s), 131.1 (s),129.7 (s), 128.2 (s), 133.0 (d, C8), 131.4 (d, C9), 127.2 (d),126.9 (d), 126.8 (d), 123.8 (d), 57.5 (d, C6a), 44.7 (t, C6),34.3 (s, C5), 31.8 (q), and 29.9 (q) (Me-5), 24.8 (t, CH2CH3),14.1 (q, CH2CH3). Anal. Calcd for C21H21NO3: C, 75.22; H,6.27; N, 4.18. Found: C, 75.26; H, 6.28; N, 4.19.

3.7.5. 1-Methoxy-5,5-dimethyl-5,6,6a,11-tetrahydro-11-oxoisoindolo[2,1-a]quinoline-10-carboxylic acid (21e).Yield 1.15 g (34%); mp 248–250 8C (i-PrOH–DMF); IR1723 (COOH), and 1628 (N–C]O) cmK1; EI-MS (70 eV)m/z (rel intensity): MC 337 (100), 302 (25), 304 (12), 293(82), 278 (9), 263 (20), 248 (18), 135 (16), 220 (9), 204 (13),152 (9), 139 (20), 102 (25), 91 (27), 73 (30), 65 (19); 1HNMR (DMSO-d6, 400 MHz) d 1.29 (s, 3H, Me-5), 1.38 (s,3H, Me-5), 1.50 (dd, 1H, JZ13.1, 11.7 Hz, H-6ax), 2.45(dd, 1H, JZ13.1, 3.3 Hz, H-6eq), 3.84 (s, 3H, OMe), 5.16(dd, 1H, JZ11.7, 3.3 Hz,-6a), 7.04 (d, 1H, JZ7.7 Hz,H-Ar), 7.13 (d, 1H, JZ7.7 Hz,-Ar), 7.29 (t, 1H, JZ7.7 Hz,H-3), 7.85 (t, 1H, JZ7.7 Hz, H-8), 8.01 (d, 1H, JZ7.7 Hz,H-7), 8.13 (d, 1H, JZ7.7 Hz, H-9); 13C NMR (DMSO-d6,100.6 MHz) d 165.2 (s), and 165.1 (s) (COOH, andN–C]O), 152.7 (s), 148.2 (s), 140.2 (s), 129.4 (s), 128.8(s), 121.8 (s), 132.8 (d, C8), 131.9 (d, C9), 127.6 (d), 127.1(d), 118.5 (d), 110.7 (d), 56.8 (OMe-1), 56.0 (d, C6a), 45.2 (t,C6), 34.1 (s, C5), 32.3 (q), and 30.1 (q) (Me-5). Anal. Calcdfor C20H19NO4: C, 71.22; H, 5.64; N, 4.15. Found: C, 71.18;H, 5.69; N, 4.15.

3.7.6. 3-Methoxy-5,5-dimethyl-5,6,6a,11-tetrahydro-11-oxoisoindolo[2,1-a]quinoline-10-carboxylic acid (21f).Yield 2.43 g (72%); mp 228–229.5 8C (i-PrOH–DMF); IR1732 (COOH), and 1627 (N–C]O) cmK1; EI-MS (70 eV)m/z (rel intensity): MC 337 (100), 322 (30), 304 (7), 293(24), 278 (18), 262 (4), 205 (4), 191 (3), 139 (3), 115 (2),102 (2), 91 (2); 1H NMR (CDCl3, 400 MHz) d 1.44 (s, 3H,

Me-5), 1.51 (s, 3H, Me-5), 1.68 (dd, 1H, JZ12.8, 13.4 Hz,H-6ax), 2.36 (dd, 1H, JZ13.4, 2.8 Hz, H-6eq), 3.84 (s, 3H,OMe), 4.91 (dd, 1H, JZ12.8, 2.8 Hz, H-6a), 6.88 (dd, 1H,JZ8.9, 2.8 Hz, H-2), 6.97 (d, 1H, JZ2.8 Hz, H-4), 7.73 (dd,1H, JZ7.5, 1.5 Hz, H-Ar), 7.79 (t, 1H, JZ7.5 Hz, H-8),8.32 (d, 1H, JZ8.9 Hz, H-1), 8.48 (dd, 1H, JZ7.3, 1.5 Hz,H-Ar); 13C NMR (DMSO-d6, 100.6 MHz) d 165.8 (s), and165.2 (s) (COOH, and N–C]O), 157.0 (s), 146.3 (s), 138.5(s), 129.23 (s), 129.16 (s), 126.4 (s), 132.8 (d), 132.0 (d),126.8 (d), 121.6 (d), 112.7 (d), 112.0 (d), 56.6 (d, C6a), 55.4(q, OMe), 42.0 (t, C6), 33.9 (s, C5), 31.6 (q), and 30.6 (q)(Me-5). Anal. Calcd for C20H19NO4: C, 71.22; H, 5.64; N,4.15. Found: C, 71.22; H, 5.62; N, 4.18.

3.7.7. 1-Benzyl-5,5-dimethyl-5,6,6a,11-tetrahydro-11-oxoisoindolo[2,1-a]quinoline-10-carboxylic acid (21g).Yield 1.28 g (32%); mp 168–169 8C (i-PrOH–DMF); IR1726 (COOH), and 1617 (N–C]O) cmK1; EI-MS (70 eV)m/z (rel intensity): 399 (4), 398 (22), 397 (MC, 72), 380 (2),354 (4), 353 (16), 352 (31), 351 (100), 338 (5), 336 (6), 322(5), 308 (4), 306 (6), 292 (5), 204 (4), 165 (5), 91 (11); 1HNMR (DMSO-d6, 400 MHz) d 1.16 (s, 3H, Me-5), 1.37 (s,3H, Me-5), 1.67 (dd, 1H, JZ13.4, 9.4 Hz, H-6ax), 2.41 (dd,1H, JZ13.4, 5.4 Hz, H-6eq), 4.07 and 4.16 (AB, 2H, JZ15.9 Hz, CH2Ph), 4.91 (dd, 1H, JZ9.4, 5.4 Hz, H-6a), 7.04–7.09 (m, 4H, H-Ar), 7.16 (t, 2H, JZ7.4 Hz, H-Ar), 7.25(t, 1H, JZ7.6 Hz, H-Ar), 7.39 (br d, 1H, JZ7.5 Hz, H-Ar),7.83 (t, 1H, JZ7.6 Hz, H-Ar), 7.94 (d, 1H, JZ7.6 Hz,H-Ar), 8.06 (d, 1H, JZ7.6 Hz, H-9); 13C NMR (DMSO-d6,100.6 MHz) d 166.0 (s), and 165.7 (s) (COOH, andN–C]O), 148.8 (s), 140.8 (s), 140.4 (s), 136.6 (s), 133.0(d), 131.5 (s), 131.3 (d), 130.1 (s), 128.9 (2C, d), 128.8 (d),128.4 (2C, d), 128.2 (s), 127.1 (d), 126.7 (d), 126.1 (d),124.4 (d), 57.4 (d, C6a), 34.4 (s, C5), 38.6 (t, CH2Ph), 44.6(t, C6), 31.8 (q), and 30.0 (q) (Me-5). Anal. Calcd forC26H23NO3: C, 78.59; H, 5.79; N, 3.53. Found: C, 78.63; H,5.78; N, 3.56.

3.7.8. 1,3,5,5-Tetramethyl-5,6,6a,11-tetrahydro-11-oxo-isoindolo[2,1-a]quinoline-10-carboxylic acid (21h).Yield 2.04 g (61%); mp 220–221 8C (i-PrOH–DMF); IR1718 (COOH, and N–C]O) cmK1; EI-MS (70 eV) m/z (relintensity): MC 335 (100), 320 (18), 302 (16), 289 (76), 276(11), 246 (11), 235 (13), 218 (3), 204 (3), 172 (4), 137 (5),128 (7), 115 (10), 91 (5); 1H NMR (CDCl3, 400 MHz) d1.29 (s, 3H, Me-5), 1.44 (s, 3H, Me-5), 1.73 (dd, 1H, JZ13.3, 10.1 Hz, H-6ax), 2.36 (s, 3H, Me-Ar), 2.38 (s, 3H,Me-Ar), 2.40 (dd, 1H, JZ13.3, 4.7 Hz, H-6eq), 4.94 (dd,1H, JZ10.1, 4.7 Hz, H-6a), 7.03 (br s, 1H, H-Ar), 7.09 (br s,1H, H-Ar), 7.75–7.80 (m, 2H, H-Ar), 8.45 (dd, JZ6.1, 2.5,H-Ar), 15.65 (br s, 1H, COOH); 13C NMR (DMSO-d6,100.6 MHz) d 165.6 (s), and 165.3 (s) (COOH, andN–C]O), 148.6 (s), 139.2 (s), 136.0 (s), 132.4 (s), 129.6(s), 129.2 (s), 128.6 (s), 132.8 (d, C8), 131.6 (d, C9), 129.7(d), 126.8 (d), 124.5 (d), 57.4 (d, C6a), 45.2 (t, C6), 34.0 (s,C5), 32.1 (q), and 30.1 (q) (Me-5), 20.8 (q), and 19.8 (q)(Me-1 and Me-3). Anal. Calcd for C21H21NO3: C, 75.22; H,6.27; N, 4.18. Found: C, 75.24; H, 6.23; N, 4.20.

3.7.9. 3-Isopropyl-5,5-dimethyl-5,6,6a,11-tetrahydro-11-oxoisoindolo[2,1-a]quinoline-10-carboxylic acid (21i).Yield 2.34 g (67%); mp 223.5–224.5 8C (i-PrOH–DMF);IR 1708 (COOH, and N–C]O) cmK1; EI-MS (70 eV) m/z


(rel intensity): MC 349 (92), 334 (100), 316 (8), 305 (40),290 (11), 273 (5), 115 (6), 43 (11); 1H NMR (CDCl3,400 MHz) d 1.20 (d, 6H, JZ6.9 Hz, CHMe2), 1.37 (s, 3H,Me-5), 1.45 (s, 3H, Me-5), 1.57 (t, 1H, JZ12.9 Hz, H-6ax),2.49 (dd, 1H, JZ13.1, 2.6 Hz, H-6eq), 2.90 (sept, 1H, JZ6.9 Hz, CHMe2), 5.15 (dd, 1H, JZ12.7, 2.2 Hz, H-6a), 7.19(dd, 1H, JZ8.5, 1.8 Hz, H-2), 7.40 (d, 1H, JZ1.8 Hz, H-4),7.85 (t, 1H, JZ7.6 Hz, H-8), 8.01 (br d, 1H, JZ7.6 Hz,H-7), 8.11 (br d, 1H, JZ7.6 Hz, H-9), 8.16 (d, 1H, JZ8.5 Hz, H-1); 13C NMR (DMSO-d6, 100.6 MHz) d 166.1 (s),and 165.3 (s) (COOH, and N–C]O), 146.3 (s), 146.0 (s),136.6 (s), 133.0 (d), 131.9 (d), 131.1 (s), 129.4 (s), 129.2 (s),126.8 (d), 125.4 (d), 124.3 (d), 120.5 (d), 56.6 (d, C6a), 33.7(s, C5), 42.2 (t, C6), 33.4 (d, CHMe2), 31.8 (q), and 30.8 (q)(Me-5), 24.1 (q), and 24.0 (q) (CHMe2). Anal. Calcd forC22H23NO3: C, 75.65; H, 6.59; N, 4.01. Found: C, 75.68; H,6.62; N, 4.03.

3.8. 1-Allyl-3-oxo-2-arylisoindolo-7-carboxylic acids(22a,b). Typical procedure

A mixture of corresponding adduct 14a,d (0.01 mol) and85% H3PO4 (40 mL) was stirred at 65 8C for 1.5 h(monitoring by TLC). At the end of the reaction, themixture was diluted with water (200 mL). The obtainedprecipitate was filtered off, washed with cold water (5!80 mL) and dried in air. Then the crude product was purifiedby recrystallization to give desired products 22a,b ascolorless crystals.

3.8.1. 1-Allyl-3-oxo-2-phenyl-2,3-dihydro-1H-isoindole-4-carboxylic acid (22a). Yield 1.52 g (52%); mp 123–124 8C (ethyl acetate–hexane); IR 1782 (COOH), and 1652(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

293 (4), 252 (100), 209 (20), 180 (23), 152 (14), 104 (14), 89(5), 77 (68), 57 (8), 51 (21), 40 (33); 1H NMR (CDCl3,400 MHz) d 2.61 (ddd, 1H, JZ14.3, 7.8, 6.2 Hz, H-3 0A),2.80 (ddd, 1H, JZ14.8, 7.8, 3.3 Hz, H-3 0B), 4.85 (dd, 1H,JZ16.9, 1.0 Hz, H-1 0trans), 5.00 (br d, 1H, JZ10.1 Hz,H-1 0cis), 5.26 (ddd, 1H, JZ16.9, 10.1, 7.8 Hz, H-2 0), 5.40(dd, 1H, JZ6.2, 3.3 Hz, H-3), 7.39 (m, 1H, H-Ar), 7.50–7.55 (m, 4H, H-Ar), 7.76–7.81 (m, 2H, H-Ar), 8.47 (dd, JZ6.7, 2.0 Hz, H-Ar); 13C NMR (DMSO-d6, 100.6 MHz) d167.8 (s), and 165.2 (s) (C]O), 146.0 (s), 135.4 (s), 133.1(d), 131.8 (d), 130.5 (d), 129.27 (2C, d), 129.24 (s), 128.7(s), 127.2 (d), 127.1 (d), 124.8 (2C, d), 119.9 (t, CH2]),61.2 (d, C3), 34.0 (t, –CH2–). Anal. Calcd for C18H15NO3:C, 73.72; H, 5.12; N, 4.78. Found: C, 73.75; H, 5.16;N, 4.81.

3.8.2. 1-Allyl-3-oxo-2-(4 0-methoxyphenyl)-2,3-dihydro-1H-isoindole-4-carboxylic acid (22b). Yield 1.97 g(61%); mp 124.5–126 8C (ethyl acetate–chloroform); IR1723 (COOH, and N–C]O) cmK1; EI-MS (70 eV) m/z (relintensity): MC 323 (23), 282 (100), 264 (2), 238 (12), 210(14), 195 (3), 167 (10), 141 (3), 128 (4), 92 (10), 77 (16); 1HNMR (CDCl3, 400 MHz) d 2.56 (ddd, 1H, JZ14.4, 8.0,5.9 Hz, H-3 0A), 2.77 (ddd, 1H, JZ14.4, 6.0, 3.5 Hz, H-3 0B),3.84 (s, 3H, OMe), 4.85 (dd, 1H, JZ16.8, 1.2 Hz,H-1 0trans), 4.97 (br d, 1H, JZ10.0 Hz, H-1 0cis), 5.32(dddd, 1H, JZ16.8, 10.0, 8.0, 6.0 Hz, H-2 0), 5.31 (dd, 1H,JZ5.9, 3.5 Hz, H-3), 6.99 (d, 2H, JZ8.9 Hz, H-Ar), 7.38(d, 2H, JZ8.9 Hz, H-Ar), 7.71–7.76 (m, 2H, H-Ar), 8.38

(dd, 1H, JZ5.9, 2.7 Hz, H-Ar); 13C NMR (DMSO-d6,100.6 MHz) d 167.9 (s), and 165.1 (s) (C]O), 158.2 (s),146.0 (s), 132.9 (d), 132.1 (d), 130.6 (d), 129.0 (s), 128.8 (s),127.9 (s), 127.4 (d), 126.5 (2C, d), 119.9 (t, CH2]), 114.5(2C, d), 61.7 (d, C3), 55.5 (q, OMe), 34.0 (t, –CH2–). Anal.Calcd for C19H17NO4: C, 70.59; H, 5.26; N, 4.33. Found: C,70.62; H, 5.24; N, 4.30.

3.9. 5-Methyl-5,6-dihydro-10-carboxyisoindolo[2,1-a]-quinoline-11-ones (23a–e). Typical procedure

Corresponding adduct 14 (0.01 mol), the mixture of 85%H3PO4 and 96% H2SO4 (45 mL, 3:1 in volume) were stirredat 100–120 8C for 1 h (monitoring by TLC). At the end ofthe reaction, the mixture was diluted with water (200 mL).The obtained precipitate was filtered off, washed with coldwater (5!80 mL) and dried in air. Then the crude productwas purified by recrystallization to give desired isoindolo-quinolines 23 as colorless crystals.

3.9.1. 5-Methyl-5,6,6a,11-tetrahydro-11-oxoisoindolo-[2,1-a]quinoline-10-carboxylic acid (23a). Ratio ofisomers A/Bw4/1; yield 1.52 g (52%); mp 185.5–186 8C(i-PrOH–DMF); IR 1728 (COOH), and 1623 (N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC 293(54), 278 (11), 264 (5), 250 (24), 249 (100), 234 (26), 232(12), 220 (8), 234 (26), 232 (12), 217 (7), 204 (20), 131 (6),117 (7), 102 (8), 91 (7), 77 (14); 1H NMR (CDCl3,200 MHz) isomer A d 1.53 (d, 3H, JZ7.0 Hz, Me-5), 1.89(dt, 1H, JZ12.8, 5.8 Hz, H-6ax), 2.41 (ddd, 1H, JZ12.8,2.8, 1.2 Hz, H-6eq), 3.32 (ddd, 1H, JZ7.0, 5.8, 1.2 Hz,H-5), 4.93 (dd, 1H, JZ12.8, 2.8 Hz, H-6a), 7.15–7.50 (m,3H, H-Ar), 7.70–7.85 (m, 2H, H-Ar), 8.35–8.55 (m, 2H,H-Ar); 13C NMR (DMSO-d6, 100.6 MHz) d 166.2 (s), and165.4 (s) (COOH, and N–C]O), 146.1 (s), 134.2 (s), 132.3(s), 129.5 (s), 128.8 (s), 133.0 (d, C8), 131.6 (d, C9), 127.8(d), 126.6 (d), 126.5 (d), 125.4 (d), 120.2 (d), 59.4 (d, C6a),36.0 (t, C6), 30.8 (d, C5), 20.7 (q, Me-5); 1H NMR (CDCl3,200 MHz) isomer B d 1.47 (d, 3H, JZ6.7 Hz, Me-5), 1.48(ddd, 1H, JZ13.2, 12.8, 11.0 Hz, H-6A), 2.73 (ddd, 1H, JZ13.2, 5.8, 2.8 Hz, H-6B), 3.32 (ddd, 1H, JZ11.0, 6.7,5.8 Hz, H-5), 4.84 (dd, 1H, JZ12.8, 2.8 Hz, H-6a), 7.15–7.50 (m, 3H, H-Ar), 7.70–7.85 (m, 2H, H-Ar), 8.35–8.55 (m,2H, H-Ar); 13C NMR (DMSO-d6, 100.6 MHz) d 166.4 (s),and 165.4 (s) (COOH, and N–C]O), 146.5 (s), 134.0 (s),132.9 (s), 129.5 (s), 128.9 (s), 133.0 (d, C8), 131.5 (d, C9),129.8 (d), 126.6 (d), 126.5 (d), 125.3 (d), 120.1 (d), 55.2 (d,C6a), 33.5 (t, C6), 30.3 (d, C5), 24.0 (q, Me-5). Anal. Calcdfor C18H15NO3: C, 73.72; H, 4.78; N, 4.78. Found: C, 73.53;H, 5.00; N, 4.75.

3.9.2. 1,5-Dimethyl-5,6,6a,11-tetrahydro-11-oxoiso-indolo[2,1-a]quinoline-10-carboxylic acid (23b). Ratioof isomers A/Bw4.5/1; yield 1.50 g (49%); mp 142.5–143 8C (i-PrOH–DMF); IR 1723 (COOH, andN–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

307 (29), 289 (7), 278 (4), 266 (100), 261 (59), 222 (8), 165(8), 128 (6), 118 (15), 91 (47), 77 (19), 65 (41); 1H NMR(CDCl3, 200 MHz) isomer A d 1.31 (d, 3H, JZ6.9 Hz,Me-5), 1.59 (dt, 1H, JZ13.5, 9.9 Hz, H-6ax), 2.41 (s, 3H,Me-1), 2.77 (ddd, 1H, JZ13.5, 6.6, 4.9 Hz, H-6eq), 3.28(ddd, 1H, JZ13.5, 6.9, 6.6 Hz, H-5), 4.94 (dd, 1H, JZ9.9,4.9 Hz, H-6a), 7.19–7.30 (m, 3H, H-Ar), 7.75–7.85 (m, 2H,


H-7 and H-8), 8.48 (m, 1H, H-9); 13C NMR (DMSO-d6,100.6 MHz) d 167.5 (s), and 167.0 (s) (COOH, andN–C]O), 149.9 (s), 137.0 (s), 134.2 (d), 134.0 (s), 133.2(s), 132.7 (d), 130.4 (s), 130.4 (d), 128.9 (s), 128.2 (d), 128.0(d), 126.2 (d), 60.6 (d, C6a), 38.2 (t, C6), 32.1 (d, C5), 22.5(q, Me-5), 20.5 (q, Me-1). Anal. Calcd for C19H17NO3: C,74.26; H, 4.56; N, 5.54. Found: C, 74.05; H, 5.63; N, 4.43.

3.9.3. 1-Methoxy-5-methyl-5,6,6a,11-tetrahydro-11-oxoisoindolo[2,1-a]quinoline-10-carboxylic acid (23c).Ratio of isomers A/Bw3.5/1; yield 1.03 g (32%); mp207–209 8C (heptane–chloroform); IR 1723 (COOH), and1628 (N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity):MC 323 (100), 306 (26), 279 (85), 249 (23), 234 (19), 220(14), 204 (13), 191 (9), 165 (5), 153 (6), 132 (5), 103 (5), 77(9), 36 (6), 28 (10); 1H NMR (CDCl3, 400 MHz) isomer A d1.37 (d, 3H, JZ6.9 Hz, Me-5), 1.44 (td, 1H, JZ13.4,11.3 Hz, H-6ax), 2.73 (ddd, 1H, JZ13.4, 6.5, 3.8 Hz,H-6eq), 3.27 (ddq, 1H, JZ11.3, 6.9, 6.5 Hz, H-5), 3.95 (s,3H, OMe), 4.84 (dd, 1H, JZ11.3, 3.8 Hz, H-6a), 6.96 (br d,1H, JZ8.0 Hz, H-2), 7.01 (dd, 1H, JZ8.0, 1.0 Hz, H-4),7.29 (t, 1H, JZ8.0 Hz, H-3), 7.70–7.80 (m, 2H, H-Ar), 8.45(dd, 1H, JZ7.2, 1.5 Hz, H-9); 13C NMR (DMSO-d6,100.6 MHz) d 165.3 (s), and 165.2 (s) (COOH, andN–C]O), 152.9 (s), 148.2 (s), 136.2 (s), 132.94 (d),132.08 (d), 129.39 (s), 128.67 (s), 127.6 (d), 127.1 (d), 122.8(s), 119.4 (d), 111.0 (d), 59.2 (d, C6a), 56.1 (OMe), 38.8 (t,C6), 30.8 (d, C5), 21.3 (q, Me-5); 1H NMR (CDCl3,400 MHz) isomer B d 1.42 (d, 3H, JZ7.0 Hz, Me-5), 2.04(ddd, 1H, JZ13.5, 8.4, 6.0 Hz, H6A), 2.29 (ddd, 1H, JZ13.5, 6.0, 5.7 Hz, H-6B), 2.99 (ddq, 1H, JZ7.0, 6.0, 5.7 Hz,H-5), 3.96 (s, 3H, OMe), 4.92 (dd, 1H, JZ8.4, 6.0 Hz,H-6a), 6.92 (br d, 1H, JZ7.8, H-2), 6.98 (br d, 1H, JZ7.8 Hz, H-4), 7.30 (t, 1H, JZ7.8 Hz, H-3), 7.70–7.80 (m,2H, H-Ar), 8.45 (dd, 1H, JZ7.2, 1.5 Hz, H-9); 13C NMR(DMSO-d6, 100.6 MHz) d 165.9 (s), and 165.2 (s) (COOH,and N–C]O), 152.9 (s), 148.5 (s), 138.0 (s), 133.06 (d),131.98 (d), 129.34 (s), 128.83 (s), 127.8 (d), 127.3 (d), 122.8(s), 119.6 (d), 110.9 (d), 56.4 (d, C6a), 56.0 (OMe), 37.2 (t,C6), 29.6 (d, C5), 22.4 (q, Me-5). Anal. Calcd forC19H17NO4: C, 70.59; H, 5.26; N, 4.33. Found: C, 70.62;H, 5.27; N, 4.33.

3.9.4. 3-Methoxy-5-methyl-5,6,6a,11-tetrahydro-11-oxoisoindolo[2,1-a]quinoline-10-carboxylic acid (23d).Ratio of isomers A/Bw12/1; yield 1.00 g (31%); mp 221–222 8C (i-PrOH–DMF); IR 1707 (COOH), and 1615(N–C]O) cmK1; EI-MS (70 eV) m/z (rel intensity): MC

323 (100), 308 (21), 290 (5), 279 (53), 264 (45), 250 (5), 236(8), 221 (8), 204 (5), 191 (9), 166 (3), 104 (3), 91 (3), 77 (4);1H NMR (CDCl3, 400 MHz) isomer A d 1.45 (d, 3H, JZ6.7 Hz, Me-5), 1.47 (q, 1H, JZ12.9, 12.4, 12.0 Hz, H-6ax),2.71 (ddd, 1H, JZ12.9, 5.7, 2.0 Hz, H-6eq), 3.28 (ddq, 1H,JZ12.0, 6.7, 5.7 Hz, H-5), 3.82 (s, 3H, OMe), 4.83 (dd, 1H,JZ12.4, 2.0 Hz, H-6a), 6.84 (dd, 1H, JZ9.0, 1.6 Hz, H-2),6.94 (d, 1H, JZ1.6 Hz, H-4), 7.75–7.80 (m, 2H, H-Ar), 8.32(d, 1H, JZ9.0 Hz, H-1), 8.43 (dd, 1H, JZ6.7, 0.9 Hz, H-9),15.70 (br s, 1H, COOH); 13C NMR (DMSO-d6, 100.6 MHz)d 165.7 (s), and 165.2 (s) (COOH, and N–C]O), 156.8 (s),146.4 (s), 145.9 (s), 134.1 (s), 129.0 (s), 127.4 (s), 132.8 (d,C8), 132.0 (d, C9), 126.7 (d), 121.4 (d), 113.1 (d), 112.1 (d),59.5 (MeO-3), 55.4 (d, C6a), 36.0 (t, C6), 31.0 (d, C5), 20.7

(q, Me-5). Anal. Calcd for C19H17NO4: C, 70.59; H, 5.26; N,4.33. Found: C, 70.60; H, 5.28; N, 4.37.

3.9.5. 1,2,5-Trimethyl-5,6,6a,11-tetrahydro-11-oxoiso-indolo[2,1-a]quinoline-10-carboxylic acid (23e). Ratioof isomers A/Bw6/1; yield 1.77 g (55%); mp 220–222 8C(i-PrOH–DMF); IR 1715 (COOH, and N–C]O) cmK1;EI-MS (70 eV) m/z (rel intensity): MC 321 (72), 304 (7),275 (100), 262 (12), 246 (5), 232 (10), 204 (6), 158 (3), 115(9), 91 (7); 1H NMR (CDCl3, 400 MHz) isomer A d 1.27(d, 3H, JZ7.3 Hz, Me-5), 1.58 (ddd, 1H, JZ13.5, 9.7,9.2 Hz, H-6ax), 2.24 (s, 3H, Me-Ar), 2.35 (s, 3H, Me-Ar),2.74 (ddd, 1H, JZ13.5, 6.4, 5.1 Hz, H-6eq), 3.24 (ddd, 1H,JZ9.2, 7.3, 6.4 Hz, H-5), 4.95 (dd, 1H, JZ9.7, 5.1 Hz,H-6a), 7.15 (s, 2H, H-3 and H-4), 7.78–7.81 (m, 2H, H-8 andH-9), 8.46 (d, 1H, JZ7.4 Hz, H-9); 13C NMR (DMSO-d6,100.6 MHz) d 166.1 (s), and 165.4 (s) (COOH, andN–C]O), 148.9 (s), 135.8 (s), 133.2 (s), 133.0 (d), 132.5(s), 131.9 (d), 131.5 (s), 129.8 (s), 128.3 (s), 128.2 (d), 126.8(d), 124.5 (d), 59.6 (d, C6a), 38.5 (t, C6), 31.1 (d, C5), 21.5(q), 20.0 (q), 16.7 (q) (Me-5, Me-1, Me-2). Anal. Calcd forC20H19NO3: C, 74.77; N, 5.92; H, 4.36. Found: C, 74.75; N,5.96; H, 4.39.

Acknowledgements

The authors are grateful for the financial support by theRussian Foundation for Basic Research (grant no. 01-03-32844 and 04-03-32 433). Also the authors would like to thankDr. K. Paulvannan, Sunesis Pharmaceuticals, Inc. for theuseful discussion during the preparation of this manuscript.

References and notes

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