a convenient 1,3-dipolar cycloaddition–reduction synthetic sequence from...

Cite this: DOI: 10.1039/c3ra42220h

A convenient 1,3-dipolar cycloaddition–reductionsynthetic sequence from 2-allyloxy-5-nitro-salicylaldehyde to aminobenzopyran-annulatedheterocycles3

Received 5th May 2013,Accepted 22nd July 2013

DOI: 10.1039/c3ra42220h

www.rsc.org/advances

Narsidas J. Parmar,*a Bhavesh R. Pansuriya,a Balvantsingh M. Labana,a Rajni Kantb

and Vivek K. Guptab

A microwave-assisted, one-pot synthesis of some nitro benzopyran-annulated pyrroles as well as pyrrolo-

fused isoquinolines via a 1,3-dipolar cycloaddition, which involves the in situ generation of azomethine

ylide formed by reacting secondary amines with 2-allyloxy-5-nitro-salicylaldehyde, has been achieved in a

solvent-free environment. Compared to methods of conventional and thermal heating, the present

microwave-assisted method is rapid and highly efficient. In addition, amino analogous heterocycles were

successfully accessed after treating the reaction mass further with iron in acidic medium, which also

highlights a one-pot procedure for a new 1,3-dipolar cycloaddition–reduction synthetic sequence. All

amino-products are new bioprofiles and anticipated to be effective drug-like candidates. All compounds

were characterised based on their elemental analysis, mass, IR, and 1H and 13C NMR spectroscopic data.

The stereochemistry of the product was confirmed by 2D NMR COSY and NOESY experiments, which, on

the basis of single crystal X-ray diffraction data analysis, was further confirmed and supported.

Introduction

Heterocycles that contain an aminobenzopyran framework asa basic unit are of enormous interest from both biological andtechnical points of view, as compounds of this family areknown to be photochromic1 as well as potential drug-likecandidates.2 In addition to being potential intermediates forantifibrillatory agents, heterocycles of this class3 are alsopotent hypertensive agents.4 6-Aminobenzopyran, for instance,containing both bioactive pyran and antipyretic p-aminophe-nol units, exists in many natural and unnatural bioactiveproducts. Gelatinase inhibitor5 is among the potentialexamples of such heterocycles. Recently, 5-lipoxygenase (5-LO) inhibitor KRH-102140 (Fig. 1A) has been identified as anew propyl hydroxylase activator.6 4-Aminobenzopyran and4,6-diaminobenzopyran are also interesting units which arepresent in anti-hypertensive and potassium channel activa-tors.7,8 The antihypertensive agent Cromakalim, for example,lowers the blood pressure by relaxing vascular smoothmuscle.8 Its active enantiomer levcromakalim and others such

as bismakalim and Y-27152 also reveal this effect but viarelaxing the peripheral vascular smooth muscle.9

4-Aminobenzopyran, BMS-180448/19109517, discovered atBristol-Myers Squibb enhances the selectivity towards theischemic myocardium over vaso-relaxation.10 Clinical trials areunder way for a K+ channel opener 4-aminobenzopyranderivative JTV-506, which has recently been found as a

aDepartment of Chemistry, Sardar Patel University, Vallabh Vidyanagar-388120.

Dist., Anand, Gujarat, India. E-mail: [email protected] Department of Physics, University of Jammu, Jammu Tawi-180 006,

India

3 Electronic supplementary information (ESI) available. CCDC 902854. For ESIand crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra42220h

Fig. 1 Some biologically active heterocycles containing 6-aminobenzopyran andpyrrolo[2,1-a]isoquinoline units.

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promising selective coronary vasodilator.11 Finally, the anti-angiogenic agent 4-(N-imidazol-2-ylmethyl)aminobenzopyran(Fig. 1B) belongs to the 4,6-diaminobenzopyran family.12

Heterocycles containing a pyrollo-fused isoquinoline unit,on the other hand, comprise a valuable class. Found inalkaloids, these heterocycles are useful for the treatment ofdepression in animals.13 One of the ingredients of Trolliuschinese flowers is (2)-Trolline14 and its Portulaca oleracea Lweed-derived antipode (+)-oleracein E15 contains a tricyclichydropyrrolo [2,1-a] isoquinoline skeleton.16 While (2)-Trollineacting against influenza viruses A and B reveals antiviralproperties, (+)-oleracein E has the wide spectrum pharmaceu-tical property of DPPH-radical scavenging activity.15 Membersof the trollin family are also active against respiratoryStaphylococcus aureus and pneumonia bacteria.14 Similarly,(+)-crispine A (Fig. 1C), with an analogous heterocyclic skeleton,showed cytotoxic activity against SKOV3, KB, and HeLa humancancer lines.17 Pyrrolo-fused heterocycles also act as non-competitive antagonists of the muscular nicotin receptor,acting as a useful template for screening biological activity.18

The similar structure motif is also contained in various naturalcompounds such as martinelline and sceletium alkaloid A-4.19

In view of the above, targeting both aminobenzopyran- andpyrroloisoquinoline-incorporated heterocycles with the hopeof finding applications in medicinal chemistry would be aninteresting area of research.

In the past decade, a large number of bioactive pyrrolo- andpyrrolidine-fused heterocycles have been envisioned and madesynthetically feasible via the in situ generated azomethine ylidecycloaddition reaction.20 An intramolecular version of thisapproach, which involves an in situ generated azomethine ylideassembled with an alkene or alkyne in the same molecule,provides direct access to bicyclic products of considerablecomplexity.21 The proximity of reactants and conformationalconstraints, in fact, make the transformation completelyselective both regiochemically and stereochemically.

So far, a variety of substrates derived from aromaticaldehydes have been exploited to create interesting benzo-pyran-annulated heterocycles. Nevertheless, the work onsynthesising the corresponding amino analogue systems hasnot yet been developed. Amino functionality improves not onlythe biological properties but the chemical properties too, andit ultimately shows a synergistic effect between the two.22

Moreover, many amine salts are pharmaceutically accepta-ble.23 Continuing our efforts in this direction,24 it wastherefore decided to synthesize aminobenzopyran-annulatedheterocycles from their corresponding nitro analogous com-pounds derived via a 1,3-dipolar cycloaddition reaction. Thework is anticipated to be useful particularly for medicinalchemists who are engaged in searching for new bio-profiles.

Results and discussion

In the present work, we aimed to assemble 2-allyloxy-5-nitro-salicylaldehyde 1 with thirteen different acyclic 3–6 and two

cyclic secondary amines 7. All amines except 6 and 7 wereprepared in the laboratory (Table 1 and Scheme 1). Thealdehyde substrate 1 was prepared by allylating 2-hydroxy-5-nitro-salicylaldehyde with allyl bromide in an anhydrousK2CO3-suspended DMF medium, reported elsewhere.24a

In earlier reports, we successfully tested aromatic alkene-ether-tethered aldehyde and ketone-based systems, which wereassembled with different diketones in a domino reaction. In aprevious report we also highlighted the translation of theconventional protocol towards a solvent-free one.24 In thepresent work, we intended to assemble substrate 1 with cyclicand acyclic secondary amines via a cycloaddition reactioninvolving an in situ generated azomethine ylide. In addition,further conversion of nitrobenzopyran-annulated pyrrolo-fused heterocycles into their corresponding amino analogouscompounds, which are expected to possess potential bio-activity, had also been planned for the one-pot procedure.

In order to optimize the reaction conditions, the secondaryamine 3a was used as a model amine with the substrate nitro-salicylaldehyde 1. Conventionally, we first tested the reactionin refluxing toluene (entries 1 and 2), p-xylene (entries 3 and 4),decaline (entry 5), dimethylformamide (DMF) (entry 6),dimethylesulfoxide (DMSO) (entry 7), dioxane (entry 8) andacetonitrile (entry 9) (Table 2), and then in the presence of

Table 1 Synthesis of various amino acid esters 3a–d, 4a–d and 5a–d

Amino ester R R1 Structure of amino ester Yielda

3a Bn Me BnNHCH2COOMe 923b Bn Et BnNHCH2COOEt 943c Bn n-Pr BnNHCH2COOn-Pr 933d Bn n-Bu BnNHCH2COOn-Bu 924a Me Me MeNHCH2COOMe 894b Me Et MeNHCH2COOEt 924c Me n-Pr MeNHCH2COOn-Pr 894d Me n-Bu MeNHCH2COOn-Bu 905a Et Me EtNHCH2COOMe 915b Et Et EtNHCH2COOEt 885c Et n-Pr EtNHCH2COOn-Pr 925d Et n-Bu EtNHCH2COOn-Bu 89

a All were isolated yields.

Scheme 1 Synthesis of secondary amines 3a–d, 4a–d and 5a–d, the reagentsand conditions: (i) TEA–MeCN at room temperature (ii) K2CO3–MeCN at roomtemperature.

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sodium sulphate (Na2SO4) particularly in refluxing toluene(entry 2) and p-xylene (entry 4). After 36 h under reflux inacetonitrile the yield was 52% (entry 9), and after 4 h underreflux in decaline and DMSO the yield was 65% (entry 5) and63% (entry 7), respectively. Sodium sulphate, however,improved the yields (entries 2 and 4) but not the reaction time.

When changing the conventional reaction methodology tocatalyst- and solvent-free performed at temperatures of 120u C(entry 10), 130 uC (entry 11) and 140 uC (entry 12), both thereaction times and yields were seen to be improved. It tookonly 1.5 h to yield 71% at 120 uC, which at higher temperatureswas further improved. Above 140 uC, however, we did notcontinue the study due to allylic rearrangement. The otherheterocycles 8a–d, 10a–d, 12a–d, 14 and 16a and b alsoappeared to be formed but with slightly varied reaction times(Table 4 and Scheme 2). Analysing the nature of amines used,we also noticed that the acyclic secondary amines took 1–2 hand the cyclic amine tetrahydroisoquinoline took 1.5 h tocomplete the reaction. Overall, all amines had good yields withaldehyde 1 (Table 4). All the compounds were isolated andcharacterized based on their elemental, mass, IR, and NMRspectral data.

In our quest to improve the conditions, we examined thereaction in solvent-free conditions under microwave irradia-tion. The results were highly efficient as it took only 10 min toyield the products at 280 W (Table 2, entry 13).

Finally, we intended these nitro products to be transformedinto their amino analogues, following a one-pot procedure.Therefore, various experimental conditions for reducing thereaction mass containing the nitro products were examined

Table 2 Optimizing conditions of reacting the aldehyde substrate 1 with theamine 3a

Entry Solvent Catalyst Temp. Time (h) Yield 8a (%)a

1 Toluene — 110 uC 7.0 h 642 Toluene Na2SO4 110 uC 6.5 h 673 p-Xylene — 138 uC 5.5 h 724 p-Xylene Na2SO4 138 uC 5.5 h 775 Decaline — 190 uC 4.0 h 656 DMF — 153 uC 5.0 h 697 DMSO — 189 uC 4.0 h 638 Dioxane — 100 uC 24 h 489 MeCN — 81 uC 36 h 5210 b — 120 uC 1.5 h 7111 b — 130 uC 1 h 8212 b — 140 uC 1 h 8013 b — 280 W 10 min. 91

a All were isolated yields. b Solvent-free.

Scheme 2 Synthesis of nitrochromene-annulated pyrroles and pyrrolo[2,1-a]isoquinolines, and their amino derivatives 8–17.


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(Table 3). Among these conditions, iron in hydrochloric acid,with an ethanol and water mixture, at reflux gave the highest(65%) amino analogues. Iron in ammonium chloride alsoperformed well. Tin chloride and sodium hydrogen sulphidehowever were poor reducing agents.

A plausible mechanism is depicted in Scheme 3. There arethree possible intermediates namely cis-fused, trans-fused ornon-sterically controlled. Electrophilic addition occurs fromthe tethered-alkene on the in situ formed imine which mayfollow the addition of the enolized ester via the other end of

the alkene. Since all products characterized were cis-fused, thereaction might have occurred via an endo transition state in aconcerted manner, without forming a real carbocation,wherein the steric bias imposed from the semi bicyclictransition state might have forced the system to adopt a mostfavoured cis-fusion. The imine of sarcosine 6 with aldehydehowever transformed first into an unstable oxazolidinone dueto the influence of the carboxylate oxygen. The methylene-methanamine dipole thus generated on removal of the carbondioxide undergoes a cyclo addition reaction with the sidechain alkene dipolarophile (Scheme 4). The exo-products weretoo small in amount to be isolated in the present work.

The structure of all cycloadducts and their correspondingamino analogue compounds were confirmed by variousspectral data. While a sharp IR band at around 1730 cm21

confirms the presence of an ester carbonyl, two bands ataround 3430 and 3315 cm21 confirm the presence of theamino group in the amino analogues. In 1H NMR, a doublet ofdoublets, due to the pyran ring OCH2 protons in 8a, appearedat d = 4.06 ppm. Due to the overlap of peaks, a characteristicdoublet peak of –NCH2Ph protons remained unresolved andhence allowed no J value calculation. The pyrrolidine ring CH2

protons appeared as a doublet of doublets of doublets, one at d

Table 3 Optimization of the conditions for the in situ reduction of 8-nitro-chromino [4, 3-b] pyrrolidine 8a to 8-amino-nitrochromino [4, 3-b] pyrrolidine9a

Entry Solvent Catalyst Yield 9a (%)a

1 H2O SnCl2–HCl 342 MeOH SnCl2–HCl 383 EtOH–H2O Fe–HCl 654 EtOH Fe–NH4Cl 605 MeOH NaSH 43


Scheme 3 Mechanism of the 1,3-cycloaddition reaction of aldehyde substrate 1 with secondary amines 3–7.


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= 1.94 ppm (J = 13.4, 9.4, 2.8 Hz) and one at d = 2.20 ppm (J =13.6, 8.2, 3.6 Hz). One of the ring junction protons appeared asa doublet at d = 4.36 ppm (J = 5.6 Hz) and another as amultiplet at d = 2.62 ppm. The similar characteristic patternappeared in all the compounds, except those withN-substituent protons. The benzylic NCH2 showed a doubletat around d = 3.88 and d = 4.06 ppm (J = 13.2 Hz) in 8a–d and9a–d. A singlet for N–CH3 appeared at around d = 2.58 ppm in10a–d, 11a–d, 14 and 15. A multiplet of N–CH2CH3 wasobserved at around d = 2.75, and 3.12 ppm in 12a–d and 13a–d.Compounds containing a tetrahydroisoquinoline ring gave amultiplet due to the four protons of the piperidine ring in theregion d = 2.75–3.30 ppm. The structure of 8a was alsoconfirmed by its mass spectrometry, which showed a peak atm/z: 369.1 (M + 1). The cis-configuration of the pyran andpyrrolidine ring fusion could be assigned in all products whichfollowed a characteristic spin-coupling constant of protons H3a

and H9b to peaks appearing in the 4.8–6.4 Hz range. All theamino compounds showed a broad singlet peak, at around d =4.60 ppm, due to the amino protons.

The nuclear Overhauser effect spectroscopy (NOESY) anddouble quantum filtered correlation spectroscopy (DQF-COSY)data of 16a also support its proposed structure (Fig. 2). Basedon NOESY, it was clear that two ring-junction bridge headprotons are cis to each other. Finally, the structure wasascertained by single-crystal X-ray diffraction data. The X-rayintensity data of a well defined crystal (0.30 6 0.20 6 0.20mm) were collected at room temperature (293 K) by using aCCD area-detector diffractometer (Xcalibur system, Oxforddiffraction, U.K.) which is equipped with graphite monochro-mated Mo-Ka radiation (l = 0.71073 Å). The cell dimensionswere determined by a least-squares fit of the angular settingsof 11 979 reflections in the h range 3.38 to 29.08u. A totalnumber of 33 380 reflections were collected of which 1980reflections were treated as observed (I . 2s(I)). Data werecorrected for Lorentz, polarization and absorption factors. Thestructure was solved by direct methods using SHELXS97 (Fig. 3and 4).25

Experimental section

All solvents and reagents were purified by standard techniquesreported or used as supplied from commercial sourceswherever appropriate. IR spectra (KBr disc) were recorded ona Shimadzu FT-IR 8401 spectrophotometer. 1H NMR and 13CNMR spectra were recorded on a Bruker Avance 400 spectro-meter, operating at 400 MHz for 1H NMR and 100 MHz for 13CNMR. The chemical shift (d) has been reported in terms ofppm using chloroform-d and DMSO-d6 reference solvents withcorresponding calibrated standard solvent signals. A massspectrum was recorded on a Shimadzu LCMS-2010 spectro-meter (ESI mode). Elemental analyses (% C, H, N) were carriedout by a Perkin-Elmer 2400 series-II elemental analyser

Scheme 4 Mechanism of the 1,3-cycloaddition reaction of aldehyde substrate 1with sarcosine 6.

Table 4 Synthesis of nitrochromene-annulated pyrroles and pyrrolo [2,1-a] isoquinolines, and their amino derivatives 8–17

R R1 R2 Nitro products Solvent-free (130 uC) Solvent-free microwave Amino products Reduction

Time (h) Yielda (%) Yield (%) Time (h) Yielda (%)

Bn Me — 8a 1.0 82 91 9a 2.5 65Bn Et — 8b 1.25 84 93 9b 2.0 67Bn n-Pr — 8c 1.5 79 91 9c 2.5 62Bn n-Bu — 8d 1.5 82 89 9d 2.5 64Me Me — 10a 1.0 80 92 11a 2.5 66Me Et — 10b 1.25 83 94 11b 2.0 62Me n-Pr — 10c 1.75 78 90 11c 2.5 68Me n-Bu — 10d 1.5 75 88 11d 3.0 61Et Me — 12a 1.25 81 89 13a 2.5 69Et Et — 12b 1.0 85 93 13b 2.5 63Et n-Pr — 12c 1.5 81 94 13c 3.0 65Et n-Bu — 12d 1.75 78 91 13d 3.0 64— — — 14 2.0 74 88 15 2.0 62— — H 16a 1.5 82 93 17a 2.5 72— — OCH3 16b 1.5 80 90 17b 2.5 75



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(Perkin-Elmer, USA). The reactions were monitored by thinlayer chromatography (TLC) using silica gel 60 F254 platesfrom Merck. Melting points were determined in open capillarytubes on TEMPO melting point apparatus and are uncor-rected. For microwave irradiations, a 700 Watt CATA-Rscientific microwave system was used. The crystal data werecollected on a Bruker CCD area-detector diffractometerequipped with graphite monochromated Mo-Ka radiation (l= 0.71073 Å). The structure was solved by direct methods usingSHELXS97.25

1. Synthesis of substituted benzaldehyde 1

A stirred solution of 5-nitro-salicylaldehyde (5.00 g, 0.03 mol)in the presence of anhydrous potassium carbonate (6.22 g,

0.045 mol) suspended in DMF (25 mL) was added drop-wise toa solution of allyl bromide (5.45 g, 0.045 mol) in DMF (5 mL).It was stirred at room temperature until the reactioncompleted as confirmed by TLC (10 h). The reaction masswas then poured into 100 g of ice with constant stirring. Thesolid products were filtered, washed with cold water (3 6 10mL) and dried at room temperature. Light yellow Solid, yield92%, 5.70 g; mp 63–65 uC; IR (KBr): n = 3116, 2942, 1752, 1602,1452, 1430, 1253, 1018, 833; 1H NMR (400 MHz, CDCl3): d =

Fig. 2 Characteristic COSY and NOESY of compound 16a.

Fig. 3 ORTEP view of 16a, showing the atom-labelling scheme. Displacementellipsoids are drawn at the 40% probability level and H atoms are shown assmall spheres of arbitrary radii. Fig. 4 The packing arrangement of compound 16a viewed down the b-axis.


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4.85 (d, J = 4.4 Hz, 2H, O–CH2), 5.34 (d, J = 10.4 Hz, 1H, one ofthe LCH2), 5.50 (d, J = 17.2 Hz, 1H, the other of LCH2), 6.14 (m,1H, CH), 7.07 (d, J = 9.2 Hz, 1H, H-3), 8.34 (dd, J = 9.2, 2.4 Hz,1H, H-4), 8.6 (d, J = 2.8 Hz, 1H, H-6), 10.45 (s, 1H, CHO); 13CNMR (100 MHz, CDCl3): d = 70.36 (CH2), 113.00, 119.64,126.57, 128.58, 128.75, 131.16, 141.44, 162.03 (arom. And –CHLCH2), 190.35 (CHO), MS (ESI): m/z: 208.0 [M + H]+, Anal.calcd for C10H9NO4: C, 57.97; H, 4.38; N, 6.76; Found: C, 57.68;H, 4.56; N, 7.01.

2. General procedure for the synthesis of secondary amines3a–d

A stirred mixture of benzyl amine (5.00 g, 0.047 mol) and TEA(triethyl amine) (7.18 g, 0.071 mol) in acetonitrile (20 mL) wasadded drop-wise to a solution of the respective chloroaceticacid ester ClCH2COOR1 (0.047 mol, 5.06 g of 2a, 5.72 g of 2b,6.37 g of 2c, 7.03 g of 2d) in acetonitrile (10 mL) with stirringand the resultant mass was allowed to stir further for 4 h. Thesalt TEA?HCl which seemed to appear was first filtered thenwashed with acetonitrile and the combined filtrate left withthe acetonitrile washings was then evaporated under vacuum.It gave colourless liquid products which required no furtherpurification.

3. General procedure for the synthesis of secondary amines4a–d and 5a–d

To a mixture of respective hydrochlorides RNH2?HCl (0.074mol, 5.00 g for R = Me, 6.03 g for R = Et) and K2CO3 (20.73 g,0.15 mol) suspended in acetonitrile (50 mL) was added drop-wise to a solution of the corresponding ester ClCH2COOR1

(0.074 mol, 8.03 g of 2a, 9.06 g of 2b, 10.11 g of 2c, 11.14 g of2d) in acetonitrile (10 mL) at room temperature with vigorousstirring for 10 h. The inorganic salts were first filtered off, thenwashed with acetonitrile and the combined filtrate obtainedalong with the washings was evaporated under vacuum givingcolourless liquid products which required no further purifica-tion.

4. General procedure for the one-pot synthesis of nitrocompounds 8a–d, 10a–d, 12a–d, 14 and 16a and b, and theirreduction by iron in acid in tandem to afford amino analoguescompounds

A mixture of aldehyde substrate 1 (2.41 mmol, 500 mg) andrespective amines 3–7 (2.41 mmol; 431 mg of 3a, 466 mg of 3b,499 mg of 3c, 533 mg of 3d, 249 mg of 4a, 282 mg of 4b, 316mg of 4c, 349 mg of 4d, 282 mg of 5a, 316 mg of 5b, 349 of 5c,383 mg of 5d, 214 of 6, 321 mg of 7a and 466 mg of 7b) wastaken in a round-bottom flask equipped with a pre-heated aircondenser and heated at 130 uC for 1 to 2 h. After thecompletion of reaction, as confirmed by TLC, the reactionmass was cooled to room temperature and the crude productsthus obtained were passed through a silica bed column to get apure product, using a mixture containing ethyl acetate andn-hexane in a ratio of 2 : 8.

The same process under microwave irradiation, at 280 W,took 10 min. The reaction mass containing the correspondingnitro product (8 or 10 or 12 or 14 or 16) after dissolution inethanol (5 mL) was then added drop-wise into a hot solution ofiron powder (807 mg, 14.4 mmol), which was prepared with a

few drops of concentrated hydrochloric acid, at reflux. Theresultant reaction mass was then allowed to reflux for 2–3 h.When it was complete, as confirmed by TLC analysis of thereaction mass, the entire reaction mass was filtered throughcelite and then extracted with chloroform. After being dried offwith anhydrous MgSO4, the extract, on evaporation of thechloroform under reduced pressure, gave residues of the crudeproducts which were further purified by column chromato-graphy using an eluent; a mixture of n-hexane and ethylacetate in a ratio of 5 : 5. All amino products 9, 11, 13, 15 and17 were obtained in high yields with an excellent purity, whichneeded no re-crystallization.

5. Spectroscopic data of intermediates (nitro-products) 8, 10,12, 14 and 16

(2R,3aS,9bR)-methyl-1-benzyl-8-nitro-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (8a). Yellow Solid,yield 91%, 0.809 g; mp 119–121 uC; IR (KBr): n = 3061,2948,1740 (CLO), 1583, 1514, 1459, 1434, 1335, 1258, 1135, 1096,1031, 908, 844, 750, 701, 628; 1H NMR (400 MHz, CDCl3): d =1.94 (ddd, J = 13.4, 9.4, 2.8 Hz, 1 H, H-3), 2.20 (ddd, J = 13.6,8.2, 3.6 Hz, 1 H, H-3), 2.62 (m, 1 H, H-3a), 3.66 (dd, J = 9.4, 3.2Hz, 1 H, H-2), 3.72 (s, 3H, OCH3), 3.88 (d, J = 13.2 Hz, 1 H, oneof NCH2Ph), 4.06 (m, 3 H, H-4 and the other of NCH2Ph), 4.36(d, J = 5.6 Hz, 1 H, H-9b), 6.99 (d, J = 9.2 Hz, 1 H, H-6), 7.13–8.18 (m, 7 H, Ar–H); 13C NMR (100 MHz, CDCl3): d = 29.73 (C-3), 33.98 (C-3a), 51.08 (NCH2Ph), 51.40 (C-2), 57.43 (C-9b),59.42 (OCH3), 68.05 (C-4), 117.67, 121.52, 124.86, 127.15,128.22, 128.23, 128.42, 136.53 138.33(arom.), 140.72 (C-8),160.92 (C-5a), 174.29 (CLO), MS (ESI): m/z: 369.1 [M + H]+,Anal. calcd for C20H20N2O5: C, 65.21; H, 5.47; N, 7.60; Found:C, 65.36; H, 5.69; N, 7.43.

(2R,3aS,9bR)-ethyl-1-benzyl-8-nitro-1,2,3,3a,4,9b-hexahydro-chromeno[4,3-b]pyrrole-2-carboxylate (8b). White Solid, yield93%, 0.858 g; mp 124–126 uC; IR (KBr): n = 3058, 2933, 1734(CLO), 1582, 1510, 1462, 1435, 1341, 1259, 1131, 1096, 1033,911, 843, 749, 701, 628; 1H NMR (400 MHz, CDCl3): d = 1.26 (t, J= 7.2 Hz, 3 H, OCH2CH3), 1.96 (ddd, J = 11.4, 9.0, 4.4 Hz, 1 H,H-39), 2.11 (ddd, J = 11.6, 9.2, 3.2 Hz, 1 H, H-3), 2.63 (m, 1 H,H-3a), 3.55 (dd, J = 8.8, 3.2 Hz, 1 H, H-2), 3.80 (d, J = 12.8, 1 H,one of NCH2Ph), 3.95 (m, 2 H, H-4), 4.06 (m, 2 H, OCH2CH3),4.22 (d, J = 6.4 Hz, 1 H, H-9b), 4.35 (d, J = 13.2 Hz, 1 H, theother of NCH2Ph), 6.59–7.27 (m, 8 H, Ar–H); 13C NMR (100MHz, CDCl3): d = 14.33 (OCH2CH3), 30.42 (C-3), 35.42 (C-3a),51.47 (NCH2Ph), 58.13 (C-2), 59.72 (C-9b), 60.11 (OCH2CH3),68.18 (C-4), 116.48, 117.55, 118.39, 122.79, 126.90, 128.12,128.49, 129.28, 139.31 (arom.), 148.87 (C-8), 160.82 (C-5a),174.39 (CLO), MS (ESI): m/z: 383.1 [M + H]+, Anal. calcdC21H22N2O5: C, 65.96; H, 5.80; N, 7.33; Found: C, 66.12; H,5.71; N, 7.38.

(2R,3aS,9bR)-propyl-1-benzyl-8-nitro-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (8c). White Solid,yield 91%, 0.870 g; mp 104–106 uC; IR (KBr): n = 3061, 2929,1731 (C=O), 1585, 1508, 1459, 1433, 1339, 1257, 1134, 1094,1031, 907, 846, 748, 703, 626; 1H NMR (400 MHz, CDCl3): d =0.97 (t, J = 7.2 Hz, 3 H, O(CH2)2CH3), 1.62 (m, 2 H,OCH2CH2

*CH3), 1.93 (ddd, J = 13.2, 9.6, 3.6 Hz, 1 H, H-39),2.17 (ddd, J = 12.8, 8.8, 3.2 Hz, 1 H, H-3), 2.70 (m, 1 H, H-3a),


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3.61 (dd, J = 9.2, 3.2 Hz, 1 H, H-2), 3.96 (d, J = 13.2 Hz, 1 H, oneof NCH2Ph), 4.13 (m, 2 H of H-4 and 2 H of OCH2

*CH2CH3),4.26 (d, J = 13.2 Hz, 1 H, the other of NCH2Ph), 4.44 (d, J = 5.6Hz, 1 H, H-9b) 7.06–8.10 (m, 8 H, Ar–H); 13C NMR (100 MHz,CDCl3): d = 10.62 (O(CH2)2CH3), 22.14 (OCH2CH2

*CH3), 30.32(C-3), 34.62 (C-3a), 50.78 (NCH2Ph), 58.21 (C-2), 59.47 (C-9b),65.17 (C-4), 67.79 (OCH2

*CH2CH3), 117.18, 121.54, 125.42,127.64, 128.49, 128.83, 129.24, 136.24 138.58 (arom.), 140.82(C-8), 160.53 (C-5a), 173.27 (CLO), MS (ESI): m/z: 397.2 [M +H]+, Anal. calcd for C22H24N2O5: C, 66.65; H, 6.10; N, 7.07;Found: C, 66.52; H, 6.33; N, 7.21.

(2R,3aS,9bR)-butyl-1-benzyl-8-nitro-1,2,3,3a,4,9b-hexahydro-chromeno[4,3-b]pyrrole-2-carboxylate (8d). White Solid, yield89%, 0.881 g; mp 88–90 uC; IR (KBr): n = 3063, 2931, 1734(CLO), 1587, 1514, 1467, 1430, 1344, 1260, 1129, 1097, 1035,913, 844, 748, 699, 631;1H NMR (400 MHz, CDCl3): d = 1.08 (t, J= 7.6 Hz, 3 H, O(CH2)3CH3), 1.40 (m, 2 H, O(CH2)2CH2CH3),1.67 (m, 2 H, OCH2CH2

*CH2CH3), 1.92 (ddd, J = 12.8, 8.6, 3.6Hz, 1 H, H-39), 2.21 (ddd, J = 12.4, 8.2, 3.0 Hz, 1 H, H-3), 2.69(m, 1 H, H-3a), 3.66 (dd, J = 9.0, 3.2 Hz, 1 H, H-2), 3.92 (d, J =13.2 Hz, 1 H, one of NCH2Ph), 4.17 (m, 2 H of H-4 and 2 H ofOCH2

*(CH2)2CH3), 4.30 (d, J = 13.2 Hz, 1 H, the other ofNCH2Ph), 4.47 (d, J = 5.6 Hz, 1 H, H-9b) 7.06–8.16 (m, 8 H, Ar–H); 13C NMR (100 MHz, CDCl3): d = 12.96 (O(CH2)3CH3), 19.17(O(CH2)2CH2CH3), 30.89 (OCH2CH2

*CH2CH3), 30.46 (C-3),34.61 (C-3a), 50.74 (NCH2Ph), 57.16 (C-2), 60.58 (C-9b), 65.69(C-4), 68.71 (OCH2

*(CH2)2CH3), 118.14, 122.43, 124.39, 127.84,128.46, 128.57, 128.72, 137.36, 138.79 (arom.), 140.06 (C-8),159.84 (C-5a), 173.74 (CLO), MS (ESI): m/z: 411.2 [M + H]+,Anal. calcd for C23H26N2O5: C, 67.30; H, 6.38; N, 6.82; Found:C, 67.49; H, 6.54; N, 6.96.

(2R,3aS,9bR)-methyl-1-methyl-8-nitro-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (10a). White Solid;yield 92%, 0.649 g; mp 88–91 uC; IR (KBr): n = 3058, 2933,1733 (CLO), 1582, 1510, 1462, 1435, 1346, 1259, 1131, 1096,1033, 911, 843, 748, 700, 628; 1H NMR (400 MHz, CDCl3): d =1.98 (ddd, J = 13.0, 9.2, 3.2 Hz, 1 H, H-39), 2.26 (ddd, J = 12.8,9.0, 3.2 Hz, 1 H, H-3), 2.59 (s, 3 H, NCH3), 2.71 (m, 1 H, H-3a),3.78 (s, 3 H, OCH3), 3.85 (dd, J = 8.8, 3.2 Hz, 1 H, H-2), 4.02 (dd,J = 10.4, 9.2 Hz, 1 H, one of H-4), 4.12 (dd, J = 10.8, 4.4 Hz, 1 H,the other of H-4), 4.10 (d, J = 6.0 Hz, 1 H, H-9b), 7.00 (d, J = 8.8,1 H, H-6), 8.11 (m, 2 H, Ar–H); 13C NMR (100 MHz, CDCl3): d =30.38 (C-3), 34.99 (C-3a), 35.26 (NCH3), 51.29 (C-2), 58.85 (C-9b), 63.86 (OCH3), 68.59 (C-4), 117.57, 121.97, 125.32, 127.38(arom.), 140.93 (C-8), 160.45 (C-5a), 173.22 (CLO), MS (ESI): m/z: 293.2 [M + H]+, Anal. calcd for C14H16N2O5: C, 57.53; H, 5.52;N, 9.58; Found: C, 57.32; H, 5.67; N, 9.71.

(2R,3aS,9bR)-ethyl-1-methyl-8-nitro-1,2,3,3a,4,9b-hexahydro-chromeno[4,3-b]pyrrole-2-carboxylate (10b). White Solid; yield94%, 0.695 g; mp 86–88 uC; IR (KBr): n = 3090, 2954, 1730(CLO), 1585, 1489, 1433, 1342, 1265, 1130, 1095, 1014, 907,848, 751, 629; 1H NMR (400 MHz, CDCl3): d = 1.33 (t, J = 7.6 Hz,3 H, OCH2CH3), 2.00 (ddd, J = 12.8, 9.2, 3.6 Hz, 1 H, H-39), 2.27(ddd, J = 11.8, 9.0, 3.2 Hz, 1 H, H-3), 2.59 (s, 3 H, NCH3), 2.76(m, 1 H, H-3a), 3.86 (d, J = 8.8, 3.2 Hz, 1 H, H-2), 4.08 (m, 2 H,H-4), 4.17 (d, J = 5.2 Hz, 1 H, H-9b), 4.28 (dq, J = 7.4, 1.6 Hz, 2H, OCH2CH3), 6.99 (d, J = 8.4, 1 H, H-6), 8.12 (m, 2 H, Ar-H);13C NMR (100 MHz, CDCl3): d = 14.43 (OCH2CH3), 30.23 (C-3),

34.76 (C-3a), 35.12 (NCH3), 59.59 (C-2), 60.49 (C-9b), 63.73(OCH2CH3), 67.98 (C-4), 117.37, 121.87, 125.31, 127.64 (arom.),141.13 (C-8), 160.64 (C-5a), 172.93 (CLO), MS (ESI): m/z: 307.1[M + H]+, Anal. calcd for C15H18N2O5: C, 58.82; H, 5.92; N, 9.15;Found: C, 58.97; H, 6.06; N, 9.01.

(2R,3aS,9bR)-propyl-1-methyl-8-nitro-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (10c). White Solid;yield 90%, 0.696 g; mp 71–73 uC; IR (KBr): n = 3052, 2936,1733 (CLO), 1585, 1511, 1468, 1431, 1345, 1261, 1127, 1095,1028, 910, 842, 751, 703, 631; 1H NMR (400 MHz, CDCl3): d =1.01 (t, J = 7.2 Hz, 3 H, O(CH2)2CH3), 1.71 (m, 2 H,OCH2CH2

*CH3), 2.02 (ddd, J = 13.2, 9.6, 3.2 Hz, 1 H, H-39),2.25 (ddd, J = 12.8, 8.6, 3.0 Hz, 1 H, H-3), 2.61 (s, 3 H, NCH3),2.78 (m, 1 H, H-3a), 3.96 (dd, J = 9.0, 3.2 Hz, 1 H, H-2), 4.11 (m,2 H of H-4 and 2 H of OCH2

*CH2CH3), 4.22 (d, J = 5.6 Hz, 1 H,H-9b), 7.01 (d, J = 8.4, 1 H, H-6), 8.09 (m, 2 H, Ar–H); 13C NMR(100 MHz, CDCl3): d = 10.35 (O(CH2)2CH3), 22.31(OCH2CH2

*CH3), 30.22 (C-3), 34.12 (C-3a), 34.85 (NCH3),58.21 (C-2), 59.76 (C-9b), 66.05 (C-4), 68.23 (OCH2

*CH2CH3),118.15, 122.86, 124.63, 128.14 (arom.), 139.93 (C-8), 160.59 (C-5a), 173.55 (CLO), MS (ESI): m/z: 321.2 [M + H]+, Anal. calcd forC16H20N2O5: C, 59.99; H, 6.29; N, 8.74; Found: C, 60.17; H,6.53; N, 8.91.

(2R,3aS,9bR)-butyl-1-methyl-8-nitro-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (10d). White Solid;yield 88%, 0.710 g; mp 56–58 uC; IR (KBr): n = 3067, 2952,1726(CLO), 1585, 1486, 1432, 1332, 1246, 1130, 1093, 1029,909, 842, 753, 698, 630; 1H NMR (400 MHz, CDCl3): d = 0.98 (t, J= 7.2 Hz, 3 H, O(CH2)3CH3), 1.44 (m, 2 H, O(CH2)2CH2CH3),1.69 (m, 2 H, OCH2CH2

*CH2CH3), 1.94 (ddd, J = 13.2, 9.2, 3.2Hz, 1 H, H-39), 2.26 (ddd, J = 13.4, 9.0, 3.2 Hz, 1 H, H-3), 2.50 (s,3 H, NCH3), 2.64 (m, 1 H, H-3a), 3.79 (dd, J = 8.4, 3.2 Hz, 1 H,H-2), 3.95 (dd, J = 11.2, 10.4 Hz, 1 H, one of H-4), 4.04 (d, J = 6.0Hz, 1 H, H-9b), 4.13 (dd, J = 11.2, 4.8 Hz, 1 H, the other of H-4),4.16 (m, 2 H, OCH2(CH2)2CH3), 6.98 (d, J = 8.8, 1 H, H-6), 8.11(m, 2 H, Ar–H); 13C NMR (100 MHz, CDCl3): d = 13.68(O(CH2)3CH3), 19.22 (O(CH2)2CH2CH3), 29.85 (OCH2CH2

*

CH2CH3), 30.76 (C-3), 34.46 (C-3a), 34.65 (NCH3), 58.21 (C-2),63.70 (C-9b), 64.46 (OCH2(CH2)2CH3), 68.26 (C-4), 117.81,121.91, 124.74, 127.57 (arom.), 140.84 (C-8), 161.08 (C-5a),173.69 (CLO), MS (ESI): m/z: 335.2 [M + H]+, Anal. calcd forC17H22N2O5: C, 61.07; H, 6.63; N, 8.38; Found: C, 59.89; H,6.88; N, 8.13.

(2R,3aS,9bR)-methyl-1-ethyl-8-nitro-1,2,3,3a,4,9b-hexahydro-chromeno[4,3-b]pyrrole-2-carboxylate (12a). White Solid; yield89%, 0.658 g; mp 97–99 uC; IR (KBr): n = 3071, 2936, 1732(CLO), 1579, 1506, 1458, 1429, 1338, 1253, 1135, 1092, 1027,907, 849, 753, 698, 632; 1H NMR (400 MHz, CDCl3): d = 1.06 (t, J= 7.6 Hz, 3 H, NCH2CH3), 1.98 (ddd, J = 12.8, 9.2, 3.6 Hz, 1 H,H-39), 2.24 (ddd, J = 12.6, 9.0, 3.2 Hz, 1 H, H-3), 2.58 (m, 1 H,H-3a), 2.75 (m, 1 H, one of NCH2CH3), 3.12 (m, 1 H, the otherof NCH2CH3), 3.76 (s, 3 H, OCH3), 3.94 (dd, J = 8.8, 3.2 Hz, 1 H,H-2), 4.03 (dd, J = 9.2, 5.2 Hz, 1 H, one of H-4), 4.11 (dd, J = 9.0,3.0 Hz, 1 H, the other of H-4), 4.23 (d, J = 6.0 Hz, 1 H, H-9b),7.01 (d, J = 8.2, 1 H, H-6), 8.14 (m, 2 H, Ar–H); 13C NMR (100MHz, CDCl3): d = 13.28 (NCH2CH3), 30.17 (C-3), 34.56 (C-3a),41.57 (NCH2CH3), 58.42 (C-2), 60.42 (C-9b), 63.96 (OCH3),65.74 (C-4), 117.81, 121.54, 124.68, 127.77 (arom.), 140.24 (C-


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8), 160.72 (C-5a), 173.79 (CLO), MS (ESI): m/z: 307.1 [M + H]+,Anal. calcd for C15H18N2O5: C, 58.82; H, 5.92; N, 9.15; Found:C, 58.67; H, 6.13; N, 9.32.

(2R,3aS,9bR)-ethyl-1-ethyl-8-nitro-1,2,3,3a,4,9b-hexahydro-chromeno[4,3-b]pyrrole-2-carboxylate (12b). Yellow Solid; yield93%, 0.719 g; mp 94–95 uC; IR (KBr): n = 3068, 2938, 1731(CLO), 1577, 1508, 1469, 1430, 1337, 1263, 1125, 1098, 1031,912, 841, 750, 702, 631; 1H NMR (400 MHz, CDCl3): d = 1.08 (t, J= 7.2 Hz, 3 H, NCH2CH3), 1.36 (t, J = 7.2 Hz, 3 H, OCH2CH3),1.99 (ddd, J = 12.8, 9.6, 3.2 Hz, 1 H, H-3), 2.23 (ddd, J = 12.0,9.0, 3.2 Hz, 1 H, H-3), 2.61 (m, 1 H, H-3a), 2.83 (m, 1 H, one ofNCH2CH3), 3.06 (m, 1 H, the other of NCH2CH3), 3.93 (dd, J =8.6, 2.8 Hz, 1 H, H-2), 4.05 (dd, J = 9.8, 8.6 Hz, 1 H, one of H-4),4.07 (dd, J = 10.8, 4.8 Hz, 1 H, the other of H-4), 4.33 (m, 1 H ofH-9b and 2 H of OCH2CH3), 6.96 (d, J = 8.4, 1 H, H-6), 8.10 (m,2 H, Ar-H); 13C NMR (100 MHz): d = 13.02 (NCH2CH3), 14.58(OCH2CH3), 30.27 (C-3), 34.39 (C-3a), 41.54 (NCH2CH3), 57.93(C-2), 59.18 (C-9b), 60.28 (OCH2CH3), 68.04 (C-4), 118.31,121.98, 124.83, 128.91 (arom.), 141.10 (C-8), 161.28 (C-5a),173.58 (CLO); MS (ESI): m/z: 321.1 [M + H]+, Anal. calcd forC16H20N2O5: C, 59.99; H, 6.29; N, 8.74; Found: C, 59.84; H,6.46; N, 8.61.

(2R,3aS,9bR)-propyl-1-ethyl-8-nitro-1,2,3,3a,4,9b-hexahydro-chromeno[4,3-b]pyrrole-2-carboxylate (12c). White Solid; yield94%, 0.759 g; mp 72–74 uC; IR (KBr): n = 3063, 2929, 1730(CLO), 1585, 1513, 1465, 1432, 1338, 1262, 1134, 1094, 1029,908, 843, 746, 704, 632; 1H NMR (400 MHz, CDCl3): d = 1.01 (t, J= 7.6 Hz, 3 H, O(CH2)2CH3) 1.05 (t, J = 7.2 Hz, 3 H, NCH2CH3),1.73 (m, 2 H, OCH2CH2

*CH3), 1.95 (ddd, J = 13.4, 9.0, 3.2 Hz, 1H, H-39), 2.21 (ddd, J = 13.6, 8.4, 3.2 Hz, 1 H, H-3), 2.60 (m, 1 H,H-3a), 2.75 (m, 1 H, one of NCH2CH3), 2.92 (m, 1 H, the otherof NCH2CH3), 3.96 (dd, J = 8.8, 2.8 Hz, 1 H, H-2), 4.14 (m, 5 H, 2H of H-4, 2 H of OCH2

*CH2CH3 and 1 H of H-9b), 6.98 (d, J =8.8, 1 H, H-6), 8.10 (m, 2 H, Ar–H); 13C NMR (100 MHz): d =10.51 (O(CH2)2CH3), 13.50 (NCH2CH3), 22.11 (OCH2CH2

*CH3),29.68 (C-3), 34.00 (C-3a), 41.18 (NCH2CH3), 57.68 (C-2), 59.35(C-9b), 66.11 (C-4), 68.21 (OCH2

*CH2CH3), 117.73, 122.15,124.71, 128.18 (arom.), 140.75 (C-8), 161.13 (C-5a), 174.03(CLO); MS (ESI): m/z: 334.2 [M + H]+, Anal. calcd C17H22N2O5:C, 61.07; H, 6.63; N, 8.38; Found: C, 61.23; H, 6.45; N, 8.49.

(2R,3aS,9bR)-butyl-1-ethyl-8-nitro-1,2,3,3a,4,9b-hexahydro-chromeno[4,3-b]pyrrole-2-carboxylate (12d). White Solid; yield91%, 0.765 g; mp 61–63 uC; IR (KBr): n = 3067, 2936, 1734(CLO), 1586, 1507, 1461, 1429, 1343, 1257, 1129, 1097, 1031,912, 847, 752, 702, 629; 1H NMR (400 MHz, CDCl3): d = 1.00 (t, J= 7.2 Hz, 3 H, O(CH2)3CH3), 1.07 (t, J = 7.2 Hz, 3 H, NCH2CH3),1.45 (m, 2 H, O(CH2)2CH2CH3), 1.66 (m, 2 H,OCH2CH2

*CH2CH3), 1.96 (ddd, J = 12.4, 9.4, 3.2 Hz, 1 H,H-3), 2.22 (ddd, J = 12.0, 9.0, 2.8 Hz, 1 H, H-3), 2.62 (m, 1 H,H-3a), 2.78 (m, 1 H, one of NCH2CH3), 3.12 (m, 1 H, the otherof NCH2CH3), 3.95 (dd, J = 8.8, 2.8 Hz, 1 H, H-2), 4.02–4.21 (m,2 H of H-4, 2 H of OCH2(CH2)2CH3 and 1 H of H-9b), 6.97 (d, J= 8.4 Hz, 1 H, H-6), 8.11 (m, 2 H, Ar–H); 13C NMR (100 MHz,CDCl3): d = 13.43 (O(CH2)3CH3),13.82 (NCH2CH3) 19.18(O(CH2)2CH2CH3), 29.78 (OCH2CH2

*CH2CH3), 30.56 (C-3),34.61 (C-3a), 41.54 (NCH2CH3), 57.93 (C-2), 59.75 (C-9b),64.69 (C-4), 68.63 (OCH2(CH2)2CH3), 118.16, 121.83, 124.71,128.76 (arom.), 141.73 (C-8), 161.15 (C-5a), 173.27 (CLO); MS

(ESI): m/z: 349.2 [M + H]+, Anal. calcd C18H24N2O5: C, 62.05; H,6.94; N, 8.04; Found: C, 62.27; H, 7.16; N, 8.28.

(3aR,9bS)-1-methyl-8-nitro-1,2,3,3a,4,9b-hexahydrochro-meno[4,3-b]pyrrole (14). White Solid, yield 88%, 0.497 g; mp106–108 uC; IR (KBr): n = 3092, 2952, 2776, 1613, 1519, 1434,1336, 1266, 1132, 1097, 1041, 909, 844, 751, 630; 1H NMR (400MHz, CDCl3): d = 1.53 (m, 1 H, H-3), 2.13 (m, 1 H, H-39), 2.39(q, J = 9.6 Hz, 1 H, H-2), 2.50 (m, 1 H, H-3a), 2.54 (s, 3 H, CH3),3.05 (d, J = 5.6 Hz, 1 H, H-9b), 3.16 (dt, J = 9.2, 2.4 Hz, 1 H,H-29), 4.00 (t, J = 10.8 Hz, 1 H, H-4), 4.14 (dd, J = 10.8, 5.6 Hz, 1H, H-49), 6.97 (d, J = 8.8 Hz, 1 H, H-6), 8.11 (m, 2 H, Ar–H); 13CNMR (100 MHz, CDCl3): d = 24.22 (C-3), 34.18 (C-3a), 39.66(CH3), 54.51 (C-2), 62.21 (C-9b), 67.93 (C-4), 117.18, 118.05,121.67, 124.88, 127.67 (C-8), 160.86 (C-5a) (arom.); MS (ESI): m/z: 235.1 [M + H]+, Anal. calcd for C12H14N2O3: C, 61.53; H, 6.02;N, 11.96; Found: C, 61.34; H, 6.25; N, 14.78.

(6aR,7aS,14aS)-2-nitro-6a,7,7a,12,13,14a-hexahydro-6H-chromeno[39,49:4,5]pyrrolo[2,1-a]isoquinoline (16a).Yellowish Solid, yield 93%, 0.724 g; mp 153–155 uC; IR (KBr):n = 3079, 2939, 2821, 1611, 1580,1507, 1485, 1249, 1108, 1074,968, 835, 745, 689, 620, 588; 1H NMR (400 MHz, CDCl3): d =2.21 (ddd, J = 14.1, 7.8, 6.8 Hz, 1 H, H-7), 2.36 (ddd, J = 13.2,8.6, 3.2 Hz, 1 H, H-79), 2.63 (m, 1 H, H-6a), 2.78 (m, 1 H, H-12),3.18 (m, 2 H, H-13 and H-139), 3.30 (m, 1 H, H-129), 4.02 (d, J =5.6 Hz, 1 H, H-14a), 4.26 (dd, J = 7.2, 1.2 Hz, 2 H, H-6 and H-69),4.42 (t, J = 7.2 Hz, 1 H, H-7a), 6.98-7.24 (m, 5 H, Ar-H), 8.11 (dd,J = 9.0, 2.4 Hz, 1 H, H-3), 8.21 (d, J = 2.8 Hz, 1 H, H-1); 13C NMR(100 MHz, CDCl3): d = 24.98 (C-12), 34.33 (C-6a), 34.64 (C-7),43.79 (C-13), 56.75 (C-14a), 58.45 (C-7a), 67.80 (C-6), 118.01,123.17, 124.64, 126.34, 126.85, 127.22, 128.55, 128.99, 134.15(C-7b), 139.38 (C-2), 141.15 (C-11a), 161.05 (C-4a) (arom.); MS(ESI): m/z: 323.1 [M + H]+, Anal. calcd for C19H18N2O3: C, 70.79;H, 5.63; N, 8.69; Found: C, 70.91; H, 5.78; N, 8.54.

(6aR,7aS,14aS)-9,10-dimethoxy-2-nitro-6a,7,7a,12,13,14a-hexahydro-6H-chromeno[39,49:4,5]pyrrolo[2,1-a]isoquinoline(16b). White Solid, yield 90%, 0.830 g; mp 178–180 uC; IR(KBr): n = 3092, 2934, 1612, 1521, 1434, 1338, 1251, 1127,1095, 1021, 990, 902, 864, 839, 800, 747, 632; 1H NMR (400MHz, CDCl3): d = 2.20 (ddd, J = 12.4, 7.4, 6.4 Hz, 1 H, H-7),2.32 (ddd, J = 11.2, 9.0, 3.2 Hz, 1 H, H-79), 2.64 (m, 1 H, H-6a),2.70 (m, 1 H, H-12), 3.12 (m, 2 H, H-13 and H-139), 3.29 (m, 1H, H-129), 3.87 (s, 3 H, CH3), 3.90 (s, 3 H, CH3), 4.01 (d, J = 6.0Hz, 1 H, H-14a), 4.25 (d, J = 6.4 Hz, 2 H, H-6 and H-69), 4.36 (t,J = 7.2 Hz, 1 H, H-7a), 6.55–6.99 (m, 3 H, Ar–H), 8.10 (dd, J =9.2, 2.8 Hz, 1 H, H-3), 8.21 (d, J = 2.8 Hz, 1 H, H-1); 13C NMR(100 MHz, CDCl3): d = 24.15 (C-12), 34.31 (C-6a), 34.67 (C-7),43.66 (C-13), 56.31 (OCH3), 56.64 (OCH3), 57.65 (C-14a), 58.35(C-7a), 67.82 (C-6), 109.42, 111.45, 123.24, 124.57, 126.09,127.06, 127.15, 131.01 (arom), 141.10 (C-2), 147.42 (C-9),147.99 (C-10), 161.01 (C-4a) (arom.); MS (ESI): m/z: 383.1 [M +H]+, Anal. calcd for C21H22N2O5: C, 65.96; H, 5.80; N, 7.33;Found: C, 66.11; H, 5.96; N, 7.52.

6. Spectroscopic data of amino compounds 9a–d, 11a–d, 13a–d, 15 and 17a and b

(2R,3aS,9bR)-methyl-8-amino-1-benzyl-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (9a). Brown Solid,yield 65%, 0.530 g, mp 103–105 uC; IR (KBr): n = 3426, 3343,


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3024, 2941, 1728 (CLO), 1611, 1531, 1495, 1218, 1024, 828, 753,686; 1H NMR (400 MHz, DMSO-d6): d = 1.96 (ddd, J = 11.2, 8.6,3.2 Hz, 1 H, H-39), 2.17 (ddd, J = 12.8, 8.8, 3.2 Hz, 1 H, H-3),2.64 (m, 1 H, H-3a), 3.61 (dd, J = 9.0, 3.2 Hz, 1 H, H-2), 3.68 (s, 3H, OCH3), 3.86 (d, J = 13.2 Hz, 1 H, one of NCH2Ph), 4.02 (dd, J= 10.4, 4.2 Hz, 1 H, one of H-4), 4.11 (dd, J = 9.2, 3.2 Hz, 1 H,the other of H-4), 4.34 (d, J = 13.2 Hz, 1 H, the other ofNCH2Ph), 4.41 (d, J = 5.6 Hz, 1 H, H-9b), 4.64 (s, 2 H, NH2),6.48–7.28 (m, 8 H, Ar–H); 13C NMR (100 MHz, DMSO-d6): d =29.86 (C-3), 33.94 (C-3a), 51.04 (NCH2Ph), 57.16 (C-2), 58.96 (C-9b), 63.24 (OCH3), 67.31 (C-4), 116.12, 117.32, 117.51, 122.27,127.32, 128.13, 128.54, 140.28, 142.61, 146.81 (arom.), 173.72(CLO); MS (ESI): m/z: 339.2 [M + H]+, Anal. calcd forC20H22N2O3: C, 70.99; H, 6.55; N, 8.28; Found: C, 71.15; H,6.73; N, 8.41.

(2R,3aS,9bR)-ethyl-8-amino-1-benzyl-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (9b). Brown Solid,yield 67%, 0.570 g, mp = 88–90 uC IR (KBr): n = 3432, 3305,3018, 2946, 1732 (CLO), 1608, 1535, 1491, 1214, 1020, 822, 761,749, 689; 1H NMR (400 MHz, DMSO-d6): d = 1.16 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.87 (ddd, J = 7.2, 5.0, 4.0 Hz, 1 H, H-39), 2.00(ddd, J = 11.6, 9.2, 3.2 Hz, 1 H, H-3), 2.70 (m, 1 H, H-3a), 3.40(dd, J = 8.8, 3.2 Hz, 1 H, H-2), 3.69 (d, J = 13.6 Hz, 1 H, one ofNCH2Ph), 3.81 (dd, J = 18.2, 10.4 Hz, 1 H, one of H-4), 3.86 (dd,J = 10.8, 4.8 Hz, 1 H, the other of H-4), 4.06 (m, 1 H, H-9b and 2H of OCH2CH3), 4.19 (d, J = 13.6 Hz, 1 H, the other ofNCH2Ph), 4.65 (s, 2 H, NH2), 6.45–7.27 (m, 8 H, Ar–H); 13CNMR (100 MHz, DMSO-d6): d = 14.63 (OCH2CH3), 30.21 (C-3),35.25 (C-3a), 51.22 (NCH2Ph), 58.21 (C-2), 59.55 (C-9b), 60.18(OCH2CH3), 67.70 (C-4), 115.57, 117.19, 117.29, 122.61, 127.32,128.45, 128.64, 139.39, 142.10, 146.93, (arom.), 173.85 (CLO);MS (ESI): m/z: 352.8 [M + H]+, Anal. calcd C21H24N2O3: C, 71.57;H, 6.86; N, 7.95; Found: C, 71.46; H, 6.98; N, 8.02.

(2R,3aS,9bR)-propyl-8-amino-1-benzyl-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (9c). Brown Solid,yield 62%, 0.548 g; mp 85–87 uC; IR (KBr): n = 3438, 3312,3027, 2951, 1729 (CLO), 1612, 1529, 1494, 1209, 1028, 816, 763,753, 691; 1H NMR (400 MHz, DMSO-d6): d = 0.94 (t, J = 7.6 Hz, 3H, O(CH2)2CH3), 1.63 (m, 2 H, OCH2CH2

*CH3), 1.95 (ddd, J =11.8, 9.2, 3.2 Hz, 1 H, H-39), 2.16 (ddd, J = 11.2, 8.6, 3.2 Hz, 1 H,H-3), 2.71 (m, 1 H, H-3a), 3.62 (dd, J = 8.8, 3.2 Hz, 1 H, H-2),3.90 (d, J = 13.2 Hz, 1 H, one of NCH2Ph), 4.10 (m, 2 H of H-4and 2 H of OCH2

*CH2CH3), 4.31 (d, J = 13.2 Hz, 1 H, the otherof NCH2Ph), 4.42 (d, J = 5.6 Hz, 1 H, H-9b), 4.65 (s, 2 H, NH2),6.51–7.26 (m, 8 H, Ar–H); 13C NMR (100 MHz, DMSO-d6): d =10.16 (O(CH2)2CH3), 21.42 (OCH2CH2

*CH3), 29.36 (C-3), 33.83(C-3a), 50.21 (NCH2Ph), 57.43 (C-2), 58.65 (C-9b), 65.26 (C-4),67.14 (OCH2

*CH2CH3), 116.23, 117.41, 117.62, 122.53, 127.61,128.42, 128.67, 139.11, 142.26, 146.58, (arom.), 172.97 (CLO);MS (ESI): m/z: 367.2 [M + H]+, Anal. calcd for C22H26N2O3: C,72.11; H, 7.15; N, 7.64; Found: C, 72.27; H, 7.31; N, 7.81.

(2R,3aS,9bR)-butyl-8-amino-1-benzyl-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (9d). Brown Solid,yield 64%, 0.588 g; mp 78–80 uC; IR (KBr): n = 3431, 3315,3024, 2948, 1735 (CLO), 1610, 1526, 1496, 1213, 1032, 823, 761,748, 685; 1H NMR (400 MHz, DMSO-d6): d = 1.03 (t, J = 7.6 Hz, 3H, O(CH2)3CH3), 1.39 (m, 2 H, O(CH2)2CH2CH3), 1.64 (m, 2 H,OCH2CH2

*CH2CH3), 1.93 (ddd, J = 12.8, 8.6, 3.2 Hz, 1 H, H-39),

2.18 (ddd, J = 11.8, 7.9, 2.8 Hz, 1 H, H-3), 2.69 (m, 1 H, H-3a),3.61 (dd, J = 9.0, 3.6 Hz, 1 H, H-2), 3.88 (d, J = 13.2 Hz, 1 H, oneof NCH2Ph), 4.12 (m, 2 H of H-4 and 2 H of OCH2

*(CH2)2CH3),4.32 (d, J = 13.2 Hz, 1 H, the other of NCH2Ph), 4.42 (d, J = 5.6Hz, 1 H, H-9b), 4.63 (s, 2 H, NH2), 6.47–7.24 (m, 8 H, Ar–H); 13CNMR (100 MHz, DMSO-d6): d = 13.09 (O(CH2)3CH3), 18.74(O(CH2)2CH2CH3), 30.18 (OCH2CH2

*CH2CH3), 30.81 (C-3),33.89 (C-3a), 50.41 (NCH2Ph), 57.24 (C-2), 59.12 (C-9b), 65.17(C-4), 67.68 (OCH2

*(CH2)2CH3), 116.72, 117.26, 117.68, 122.51,127.43, 128.74, 129.12, 139.15, 142.31, 146.72, (arom.), 173.46(CLO); MS (ESI): m/z: 381.2 [M + H]+, Anal. calcd forC23H28N2O3: C, 72.60; H, 7.42; N, 7.36; Found: C, 72.78; H,7.26; N, 7.19.

(2R,3aS,9bR)-methyl-8-amino-1-methyl-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (11a). Brown Solid;yield 66%, 0.418 g; mp 92–94 uC; IR (KBr): n = 3435, 3309, 3036,2961, 1731 (CLO), 1614, 1530, 1491, 1218, 1029, 830, 763, 764,694; 1H NMR (400 MHz, DMSO-d6): d = 1.98 (ddd, J = 11.6, 9.2,3.2 Hz, 1 H, H-39), 2.26 (ddd, J = 11.6, 9.0, 3.2 Hz, 1 H, H-3),2.55 (s, 3 H, NCH3) 2.70 (m, 1 H, H-3a), 3.77 (s, 3 H, OCH3),3.81 (dd, J = 8.8, 3.2 Hz, 1 H, H-2), 4.03(m, 2 H, H-4), 4.11 (d, J =6.0 Hz, 1 H, H-9b), 4.64 (s, 2 H, NH2), 6.51–6.97 (m, 3 H, Ar–H);13C NMR (100 MHz, DMSO-d6): d = 30.13 (C-3), 34.32 (C-3a),34.76 (NCH3), 51.15 (C-2), 58.57 (C-9b), 63.45 (OCH3), 68.14 (C-4), 115.76, 117.53, 122.35, 139.27, 142.21, 145.97 (arom.),173.38 (CLO); MS (ESI): m/z: 263.1 [M + H]+, Anal. calcd forC14H18N2O3: C, 64.10; H, 6.92; N, 10.68; Found: C, 64.29; H,7.12; N, 10.79.

(2R,3aS,9bR)-ethyl-8-amino-1-methyl-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (11b). Brown Solid;yield 62%, 0.413 g; mp 101–103 uC; IR (KBr): n = 3429, 3313,3028, 2951, 1728 (CLO), 1614, 1534, 1493, 1224, 1025, 819,756,690; 1H NMR (400 MHz, DMSO-d6): d = 1.35 (t, J = 7.6 Hz, 3 H,OCH2CH3), 2.03 (ddd, J = 11.8, 9.4, 3.2 Hz, 1 H, H-39), 2.28(ddd, J = 11.2, 9.0, 3.2 Hz, 1 H, H-3), 2.60 (s, 3 H, NCH3), 2.74(m, 1 H, H-3a), 3.82 (d, J = 8.4, 3.0 Hz, 1 H, H-2), 4.07 (m, 2 H,H-4), 4.18 (d, J = 4.8 Hz, 1 H, H-9b), 4.26 (dq, J = 7.6, 2.0 Hz, 2H,OCH2CH3), 4.65 (s, 2 H, NH2), 6.59–6.88 (m, 3 H, Ar–H); 13CNMR (100 MHz, DMSO-d6): d = 14.34 (OCH2CH3), 30.71 (C-3),34.42 (C-3a), 34.68 (NCH3), 58.56 (C-2), 60.65 (C-9b), 63.69(OCH2CH3), 67.81 (C-4), 116.15, 117.74 123.61, 138.92, 142.41,145.65 (arom.), 173.58 (CLO); MS (ESI): m/z: 277.2 [M + H]+,Anal. calcd for C15H20N2O3: C, 65.20; H, 7.30; N, 10.14; Found:C, 65.01; H, 7.52; N, 10.32.

(2R,3aS,9bR)-propyl-8-amino-1-methyl-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (11c). Brown Solid;yield 68%, 0.477 g; mp 89–91 uC; IR (KBr): n = 3434, 3317, 3022,2958, 1730 (CLO), 1614, 1559, 1495, 1221, 1023, 824, 763, 679;1H NMR (400 MHz, DMSO-d6): d = 0.99 (t, J = 7.6 Hz, 3 H,O(CH2)2CH3), 1.72 (m, 2 H, OCH2CH2

*CH3), 2.00 (ddd, J = 11.6,9.2, 3.2 Hz, 1 H, H-39), 2.24 (ddd, J = 11.2, 8.8, 3.2 Hz, 1 H, H-3),2.62 (s, 3 H, NCH3), 2.78 (m, 1 H, H-3a), 3.96 (dd, J = 8.4, 2.8Hz, 1 H, H-2), 4.12 (m, 2 H of H-4 and 2 H of OCH2

*CH2CH3),4.25 (d, J = 5.6 Hz, 1 H, H-9b), 4.66 (s, 2 H, NH2), 6.56–6.89 (m,3 H, Ar–H); 13C NMR (100 MHz, DMSO-d6): d = 10.23(O(CH2)2CH3), 22.26 (OCH2CH2

*CH3), 29.72 (C-3), 34.71 (C-3a), 35.07 (NCH3), 57.92 (C-2), 59.46 (C-9b), 65.75 (C-4), 68.03(OCH2

*CH2CH3), 115.87, 118.14, 122.64, 138.56, 142.28, 145.37


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(arom.), 173.29 (CLO); MS (ESI): m/z: 291.2 [M + H]+, Anal.calcd for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65; Found: C,66.37; H, 7.78; N, 9.47.

(2R,3aS,9bR)-butyl-8-amino-1-methyl-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (11d). Brown Solid;yield 61%, 0.448 g; mp 81–83 uC IR (KBr): n = 3441, 3307, 3028,2963, 1736 (CLO), 1618, 1552, 1491, 1227, 1028, 827, 754, 683;1H NMR (400 MHz, DMSO-d6): d = 0.99 (t, J = 7.6 Hz, 3 H,O(CH2)3CH3), 1.44 (m, 2 H, O(CH2)2CH2CH3), 1.68 (m, 2 H,OCH2CH2

*CH2CH3), 2.00 (ddd, J = 12.4, 9.0, 3.6 Hz, 1 H, H-3),2.24 (ddd, J = 11.4, 8.8, 3.6 Hz, 1 H, H-3), 2.57 (s, 3 H, NCH3),2.75 (m, 1 H, H-3a), 3.80 (dd, J = 9.0, 3.6 Hz, 1 H, H-2), 3.94 (dd,J = 9.2, 8.4 Hz, 1 H, one of H-4), 4.10 (dd, J = 11.0, 4.4 Hz, 1 H,the other of H-4), 4.14 (d, J = 6.0 Hz, 1 H, H-9b), 4.21 (m, 2 H,OCH2(CH2)2CH3), 4.65 (s, 2 H, NH2), 6.60–6.98 (m, 3 H, Ar–H);13C NMR (100 MHz, DMSO-d6): d = 13.81 (O(CH2)3CH3), 19.34(O(CH2)2CH2CH3), 30.08 (OCH2CH2

*CH2CH3), 30.54 (C-3),34.83 (C-3a), 35.04 (NCH3), 57.97 (C-2), 63.95 (C-9b), 64.27(OCH2(CH2)2CH3), 68.18 (C-4), 115.69, 118.03, 122.78, 138.71,141.96, 144.78 (arom.), 173.17 (CLO); MS (ESI): m/z: 305.2 [M +H]+, Anal. calcd for C17H24N2O3: C, 67.08; H, 7.95; N, 9.20;Found: C, 66.93; H, 7.71; N, 9.45.

(2R,3aS,9bR)-methyl-8-amino-1-ethyl-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (13a). Brown Solid;yield 69%, 0.460 g; mp 83–85 uC; IR (KBr): n = 3436, 3312, 3035,2958, 1729 (CLO), 1609, 1559, 1496, 1230, 1034, 824, 760, 691;1H NMR (400 MHz, DMSO-d6): d = 1.06 (t, J = 7.6 Hz, 3 H,NCH2CH3), 1.97 (ddd, J = 12.4, 9.2, 3.2 Hz, 1 H, H-3), 2.22 (ddd,J = 11.8, 8.8, 3.2 Hz, 1 H, H-3), 2.60 (m, 1 H, H-3a), 2.78 (m, 1 H,one of NCH2CH3), 3.10 (m, 1 H, the other of NCH2CH3), 3.74(s, 3 H, OCH3), 3.90 (dd, J = 8.8, 3.2 Hz, 1 H, H-2), 4.03 (dd, J =9.2, 5.6 Hz, 1 H, one of H-4), 4.12 (dd, J = 9.6, 3.2 Hz, 1 H, theother of H-4), 4.19 (d, J = 6.0 Hz, 1 H, H-9b), 4.64 (s, 2 H, NH2),6.59–6.97 (m, 3 H, Ar–H); 13C NMR (100 MHz, DMSO-d6): d =12.86 (NCH2CH3), 29.94 (C-3), 34.57 (C-3a), 41.29 (NCH2CH3),58.32 (C-2), 59.41 (C-9b), 63.45 (OCH3), 66.12 (C-4), 115.88,117.83, 122.48, 139.13, 141.79, 144.83 (arom.), 173.48 (CLO);MS (ESI): m/z: 277.2 [M + H]+, Anal. calcd for C15H20N2O3: C,65.20; H, 7.30; N, 10.14; Found: C, 65.43; H, 7.04; N, 9.97.

(2R,3aS,9bR)-ethyl-8-amino-1-ethyl-1,2,3,3a,4,9b-hexahydro-chromeno[4,3-b]pyrrole-2-carboxylate (13b). Brown Solid; yield63%, 0.441 g; mp 78–80 uC; IR (KBr): n = 3428, 3314, 3028,2962, 1735 (CLO), 1614, 1553, 1489, 1228, 1025, 829, 751, 687;1H NMR (400 MHz, DMSO-d6): d = 1.05 (t, J = 7.2 Hz, 3 H,NCH2CH3), 1.34 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.98 (ddd, J =11.8, 9.2, 3.2 Hz, 1 H, H-39), 2.21 (ddd, J = 11.2, J = 9.0, 3.2 Hz, 1H, H-3), 2.63 (m, 1 H, H-3a), 2.78 (m, 1 H, one of NCH2CH3),3.07 (m, 1 H, the other of NCH2CH3), 3.95 (dd, J = 8.8, 3.2 Hz, 1H, H-2), 4.01 (dd, J = 9.8, 8.8 Hz, 1 H, one of H-4), 4.08 (dd, J =10.8, 5.2 Hz, 1 H, the other of H-4), 4.31 (m, 1 H of H-9b and 2H of OCH2CH3), 4.64 (s, 2 H, NH2), 6.60–7.96 (m, 3 H, Ar–H);13C NMR (100 MHz, DMSO-d6): d = 13.29 (NCH2CH3), 14.40(OCH2CH3), 29.83 (C-3), 34.48 (C-3a), 41.16 (NCH2CH3), 57.82(C-2), 59.39 (C-9b), 60.28 (OCH2CH3), 68.21 (C-4), 116.02,117.73, 123.04, 139.26, 141.36, 143.91 (arom.), 173.83 (CLO);MS (ESI): m/z: 291.2 [M + H]+, Anal. calcd for C16H22N2O3: C,66.18; H, 7.64; N, 9.65; Found: C, 66.34; H, 7.79; N, 9.51.

(2R,3aS,9bR)-propyl-8-amino-1-ethyl-1,2,3,3a,4,9b-hexahy-drochromeno[4,3-b]pyrrole-2-carboxylate (13c). Brown Solid;yield 65%, 0.477 g; mp 81–83 uC; IR (KBr): n = 3432, 3307, 3048,2952, 1733 (CLO), 1611, 1561, 1493, 1232, 1027, 819, 748, 676;1H NMR (400 MHz, DMSO-d6): d = 0.97 (t, J = 7.6 Hz, 3 H,O(CH2)2CH3) 1.02 (t, J = 7.6 Hz, 3 H, NCH2CH3), 1.73 (m, 2 H,OCH2CH2

*CH3), 1.97 (ddd, J = 12.8, 9.2, 3.2 Hz, 1 H, H-39), 2.20(ddd, J = 11.2, 8.6, 3.2 Hz, 1 H, H-3), 2.64 (m, 1 H, H-3a), 2.79(m, 1 H, one of NCH2CH3), 3.06 (m, 1 H, the other ofNCH2CH3), 3.97–4.17 (m, 1 H of H-2, 2 H of H-4 and 2 H ofOCH2

*CH2CH3), 4.22 (d, J = 6.0 Hz, 1 H, H-9b), 4.65 (s, 2 H,NH2), 6.33–6.59 (m, 3 H, Ar–H); 13C NMR (100 MHz, DMSO-d6):d = 10.29 (O(CH2)2CH3), 13.32 (NCH2CH3), 22.02 (OCH2CH2

*

CH3), 29.86 (C-3), 34.42 (C-3a), 41.23 (NCH2CH3), 57.85 (C-2),59.34 (C-9b), 66.04 (C-4), 68.06 (OCH2

*CH2CH3), 115.42,117.85, 118.56, 130.28, 134.36, 146.35 (arom.), 173.63 (CLO);MS (ESI): m/z: 305.2 [M + H]+, Anal. calcd C17H24N2O3: C, 67.08;H, 7.95; N, 9.20; Found: C, 67.29; H, 7.68; N, 9.46.

(2R,3aS,9bR)-butyl-8-amino-1-ethyl-1,2,3,3a,4,9b-hexahydro-chromeno[4,3-b]pyrrole-2-carboxylate (13d). Brown solid; yield64%, 0.492 g; mp 72–74 uC; IR (KBr): n = 3431, 3323, 3021,2954, 1729 (CLO), 1609, 1562, 1492, 1232, 1028, 818, 749, 681;1H NMR (400 MHz, DMSO-d6): d = 0.99 (t, J = 7.2 Hz, 3 H,O(CH2)3CH3), 1.06 (t, J = 7.2 Hz, 3 H, NCH2CH3), 1.42 (m, 2 H,O(CH2)2CH2CH3), 1.64 (m, 2 H, OCH2CH2

*CH2CH3), 1.96 (ddd,J = 12.4, 9.2, 3.2 Hz, 1 H, H-39), 2.25 (ddd, J = 11.4, 9.0, 2.8 Hz, 1H, H-3), 2.64 (m, 1 H, H-3a), 2.77 (m, 1 H, one of NCH2CH3),3.10 (m, 1 H, the other of NCH2CH3), 3.97 (dd, J = 8.4, 2.8 Hz, 1H, H-2), 4.02–4.25 (m, 2 H of H-4, 2 H of OCH2(CH2)2CH3 and 1H of H-9b), 4.64 (s, 2 H, NH2), 6.59–6.99 (m, 3 H, Ar–H); 13CNMR (100 MHz, DMSO-d6): d = 13.24 (O(CH2)3CH3),13.82(NCH2CH3) 19.17 (O(CH2)2CH2CH3), 29.85 (OCH2CH2

*

CH2CH3), 30.73 (C-3), 34.62 (C-3a), 41.35 (NCH2CH3), 57.90(C-2), 59.57 (C-9b), 64.39 (C-4), 68.09 (OCH2(CH2)2CH3),116.05, 117.71, 122.48, 139.72, 141.89, 143.38 (arom.), 173.52(CLO); MS (ESI): m/z: 319.2 [M + H]+, Anal. calcd C18H26N2O3:C, 67.90; H, 8.23; N, 8.80; Found: C, 68.12; H, 8.47; N, 8.63.

(3aR,9bS)-8-amino-1-methyl-1,2,3,3a,4,9b-hexahydrochro-meno[4,3-b]pyrrole (15). Brown Solid, yield 62%, 0.306 g, mp92–94 uC; IR (KBr): n = 3345, 2922, 2866, 1620, 1500, 1452,1215, 1111, 1021, 923, 807, 750, 663; 1H NMR (400 MHz,DMSO-d6): d = 1.51 (m, 1 H, H-3), 2.12 (m, 1 H, H-3), 2.42 (m, 1H of H-2 and 1 H of H-3a), 2.48 (s, 3 H, CH3), 2.99 (d, J = 5.6 Hz,1 H, H-9b), 3.15 (dt, J = 8.8, 2.4 Hz, 1 H, H-2), 3.99 (t, J = 11.2Hz, 1 H, H-4), 4.17 (dd, J = 10.8, 5.6 Hz, 1 H, H-4), 4.65 (s, 2 H,NH2), 6.36–6.83 (m, 3 H, Ar–H); 13C NMR (100 MHz, DMSO-d6):d = 23.43 (C-3), 33.86 (C-3a), 39.06 (CH3), 54.09 (C-2), 61.95 (C-9b), 67.62 (C-4), 115.86, 117.12, 121.80, 134.51 (arom.), 140.82(C-8), 146.26, 157.43 (C-5a); MS (ESI): m/z: 205.3 [M + H]+, Anal.calcd for C12H16N2O: 70.56; H, 7.90; N, 13.71; Found: C, 70.67;H, 7.73; N, 13.93.

(6aR,7aS,14aS)-2-amino-6a,7,7a,12,13,14a-hexahydro-6H-chromeno[39,49:4,5]pyrrolo[2,1-a]isoquinoline (17a). BrownSolid, yield 72%, 0.508 g; mp 132–134 uC; IR (KBr): n = 3435,3319, 3062, 2929, 1628, 1492, 1216, 1163, 1039, 982, 825, 751,673, 576; 1H NMR (400 MHz, DMSO-d6): d = 1.97 (ddd, J = 13.8,8.8, 6.8 Hz, 1 H, H-7), 2.21 (ddd, J = 12.8, 8.2, 3.2 Hz, 1 H, H-79),2.67 (m, 1 H, H-6a), 2.93 (m, 1 H, H-12), 3.03 (m, 2 H, H-13 and


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H-139), 3.17 (m, 1 H, H-129), 3.84 (d, J = 6.4 Hz, 1 H, H-14a),3.95 (dd, J = 7.6, 1.2 Hz, 2 H, H-6 and H-6), 4.11 (t, J = 7.6 Hz, 1H, H-7a), 4.64 (s, 2 H, NH2), 6.41–7.15 (m, 7 H, Ar–H); 13C NMR(100 MHz, DMSO-d6): d = 25.77 (C-12), 35.01 (C-6a), 35.38 (C-7),44.45 (C-13), 58.07 (C-14a), 58.78 (C-7a), 67.26 (C-6), 115.11,116.12, 116.86, 123.64, 125.96, 126.64, 127.04, 128.80, 134.57,140.06, 142.33, 146.94 (arom.); MS (ESI): m/z: 293.2 [M + H]+,Anal. calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58; Found: C,78.23; H, 6.72; N, 9.47.

(6aR,7aS,14aS)-2-amino-9,10-dimethoxy-6a,7,7a,12,13,14a-hexahydro-6H-chromeno[39,49:4,5]pyrrolo[2,1-a]isoquinoline(17b). Brown Solid, yield 75%, 0.638 g; mp 143–145 uC; IR (KBr):n = 3092, 2949, 1612, 1521, 1434, 1338, 1251, 1127, 1095, 1021,990, 902, 864, 839, 800, 747, 632; 1H NMR (400 MHz, DMSO-d6):d = 1.98 (ddd, J = 13.8, 7.8, 6.4 Hz, 1 H, H-7), 2.21 (ddd, J = 12.8,8.2, 3.2 Hz, 1 H, H-79), 2.67 (m, 1 H, H-6a), 2.77(m, 1 H, H-12),3.01 (m, 2 H, H-13 and H-139), 3.23 (m, 1 H, H-129), 3.60 (s, 3 H,CH3), 3.69 (s, 3 H, CH3), 4.01 (d, J = 5.6 Hz, 1 H, H-14a), 4.24 (dd,J = 7.6, 1.2 Hz, 2 H, H-6 and H-6), 4.40 (t, J = 7.6 Hz, 1 H, H-7a),4.57 (s, 2 H, NH2), 6.38–7.03 (m, 5 H, Ar–H); 13C NMR (100 MHz,DMSO-d6): d = 25.31 (C-12), 34.85 (C-6a), 35.45 (C-7), 44.91 (C-13), 55.71 (OCH3), 55.29 (OCH3),58.61 (C-14a), 59.67 (C-7a),67.59 (C-6), 115.41, 116.71, 117.82, 124.24, 125.62, 128.72,129.83, 134.61, 142.58, 146.82, 147.49, 148.89 (arom.); MS (ESI):m/z: 353.2 [M + H]+, Anal. calcd for C21H24N2O3: C, 71.57; H,6.86; N, 7.95; Found: C, 71.73; H, 6.69; N, 7.81.

Conclusions

So, we have developed an efficient, fast tandem method toaccess amino benzopyran-annulated heterocycles from 2-ally-loxy-5-nitro-salicylaldehyde, demonstrating a new syntheticsequence for a 1,3-dipolar cycloaddition–reduction reaction.The new scaffolds thus obtained could be precursors to avariety of bioactive natural and unnatural compounds, whichfind applications in drug discovery. Finally, the solvent-freeprotocol employed in the work also highlights an easy way oftranslating the conventional method of a cycloadditionreaction into an environmentally friendly benign solvent-freeprotocol.

Acknowledgements

We sincerely express our thanks to the Head of theDepartment of Chemistry, S. P. University for providingnecessary research facilities. B.R.P. is grateful to the UGC,New Delhi for financial support under the UGC scheme ofRFSMS.

References

1 (a) Photochromism: Molecules and Systems, ed. H. Durr andH. Bouas-Laurent, Elsevier, Amsterdam, 1990; (b) OrganicPhotochromic and Thermochromic Compounds, ed. J. C.Crano and R. J. Guglielmetti, Kluwer Academic/Plenum

Publishers, New York, 1999, pp. 1 and 2; (c) L. Bernardi,M. Comes-Franchini, M. Fochi, V. Leo, A. Mazzanti andA. Ricci, Adv. Synth. Catal., 2010, 352, 3399–3406.

2 (a) G. C. Rovnyak, S. Z. Ahmed, C. Z. Ding, S. Dzwonczyk, F.N. Ferrara, W. G. Humphreys, G. J. Grover, D. Santafianos,K. S. Atwal, A. J. Baird, L. G. McLaughlin, D. E. Normandin,P. G. Sleph and S. C. Traeger, J. Med. Chem., 1997, 40,24–34; (b) S. Yoo, K. Y. Yi, S. Lee, J. Suh, N. Kim, B. H. Lee,H. W. Seo, S. O. Kim, D. H. Lee, H. Lim and H. S. Shin, J.Med. Chem., 2001, 44, 4207–4215; (c) F. D. Testai, M.A. Landek and G. Dawson, J. Neurosci. Res., 2004, 75, 66–74.

3 (a) I. Kazuhiko, JP 151767, 2001; (b) N. B. Desai, F.K. Koehler and A. M. Russel, 1994, EP 0626959 A1.

4 (a) J. M. Evans, C. S. Fake, T. C. Hamilton, R. H. Poyser andE. A. Watts, J. Med. Chem., 1983, 26, 1582–1589; (b)F. Cassidy and E. A. Faruk, 1989, US 4831050; (c)R. Bergmann and R. Gericke, J. Med. Chem., 1990, 33,492–504.

5 (a) C. C. Mora, US 4596824; (b) K. C. Nicolaou, J.A. Pfefferkorn, A. J. Roecker, G. -Q. Cao, S. Barluenga andH. J. Mitchell, J. Am. Chem. Soc., 2000, 122, 9939–9953; (c)K. C. Nicolaou, J. A. Pfefferkorn, H. J. Mitchell, A.J. Roecker, S. Barluenga, G.-Q. Cao, R. L. Affleck and J.E. Lillig, J. Am. Chem. Soc., 2000, 122, 9954–9967; (d)R. Hiessbock, C. Wolf, E. Richter, M. Hitzler, P. Chiba,M. Kratzel and G. Ecker, J. Med. Chem., 1999, 42,1921–1926; (e) Y.-D. Gong, J.-S. Seo, Y. S. Chon, J.Y. Hwang, J. Y. Park and S.-E. Yoo, J. Comb. Chem., 2003,5, 577–589; (f) M. Gooyit, M. Lee, V. A. Schroeder, M. Ikejiri,M. A. Suckow, S. Mobashery and M. Chang, J. Med. Chem.,2011, 54, 6676–6690; (g) D. A. Cornely and J. A. Ritter, JAMA,J. Am. Med. Assoc., 1956, 160, 1219–1221.

6 (a) Y.-D. Gong, S.-E. Yoo, H. G. Cheon, Y. S. Cho, J.-S. Seo, J.Y. Hwang and J. Y. Park, 2005, US 7368575; (b) A. A.L. Gunatilaka, D. G. I. Kingston, E. M. K. Wijeratne, B. M.R. Bandara, G. A. Hofmann and R. K. Johnson, J. Nat. Prod.,1994, 57, 518–520; (c) H. J. Choi, B. J. Song, Y. D. Gong, W.J. Gwak and Y. Soh, Br. J. Pharmacol., 2008, 154, 114–125.

7 (a) S.-E. Yoo, K. Y. Yi, S. Lee, J. Suh, N. Kim, B. H. Lee, H.W. Seo, S.-O. Kim, D.-H. Lee, H. Lim and H. S. Shin, J. Med.Chem., 2001, 44, 4207–4215; (b) V. A. Ashwood, F. Cassidy,M. C. Coldwell, J. M. Evans, T. C. Hamilton, D. R. Howlett,D. M. Smith and G. Stemp, J. Med. Chem., 1990, 33,2667–2672.

8 G. M. Herrera, T. C. Resta, J. J. Candelaria and B. R. Walker,J. Cardiovasc. Pharmacol., 1998, 31, 921–929.

9 (a) R. Bergmann and R. Gericke, J. Med. Chem., 1990, 33,492–504; (b) T. Nakajima, Cardiovasc. Drug Rev., 1991, 9,372–384.

10 (a) G. J. Grover, S. Dzwonczyk, C. S. Parham and P.G. Sleph, Cardiovasc. Drugs Ther., 1990, 4, 465–474; (b) G.J. Grover, J. R. McCullough, A. J. D¢Alonzo, C. A. Sargentand K. S. Atwal, J. Cardiovasc. Pharmacol., 1995, 25, 40–50.

11 (a) Y. Hirata, H. Miyai, Y. Mabuchi and K. Aisaka, J.Cardiovasc. Pharmacol., 1998, 31, 322–326; (b) S. Zhang,K. Sakai, H. Hasuo, K. Furuta, H. Ureshino, O. Shibata andK. Sumikawa, Res. Commun. Mol. Pathol. Pharmacol., 1999,105, 115–127.

12 N. Kim, S. Lee, K. Y. Yi, S.-E. Yoo, G. Kim, C. O. Lee, S.H. Park and B. H. Lee, Bioorg. Med. Chem. Lett., 2003, 13,1661–1663.


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13 (a) A. R. Battersby, R. Binks and R. Huxtable, TetrahedronLett., 1968, 9, 6111–6115; (b) J. Lundstrom, The Alkaloids,ed. A. Brossi, Academic, New York, NY, 1983, vol. 21, p. 312;(c) K. W. Bentley, Nat. Prod. Rep., 2003, 20, 342–365; (d) S.-H. Chung, J. Yook, B. J. Min, J. Y. Lee, Y. S. Lee and C. Jin,Arch. Pharmacol. Res., 2000, 23, 353–359.

14 R. F. Wang, X. W. Yang, C. M. Ma, S. Q. Cai, J. J. Nong andY. Shoyama, Heterocycles, 2004, 63, 1443–1448.

15 L. Xiang, D. Xing, W. Wang, R. Wang, Y. Ding and L. Du,Phytochemistry, 2005, 66, 2595–2601.

16 (a) X. J. Zhang, Y. B. Ji, Zh. Y. Qu, J. Ch. Xia and L. Wang,Chinese J. Microecol., 2002, 14, 277–280; (b) K. Chan, M.W. Islam, M. Kamil, R. Radhakrishnan, M. N. M. Zakaria,M. Habibullah and A. Attas, J. Ethnopharmacol., 2000, 73,445–451; (c) O. Parry, F. Okwuasaba and C. Ejike, J.Ethnopharmacol., 1987, 19, 247–253; (d) A. N. Rashed, F.U. Afifi and A. M. Disi, J. Ethnopharmacol., 2003, 88,131–136.

17 Q. Zhang, G. Tu, Y. Zhao and T. Cheng, Tetrahedron, 2002,58, 6795–6798.

18 (a) M. L. Bolognesi, V. Andrisano, M. Bartolini, A. Minarini,M. Rosini, V. Tumiatti and C. Melchiorre, J. Med. Chem.,2001, 44, 105–109; (b) M. Rosini, R. Budriesi, M. G. Bixel,M. L. Bolognesi, A. Chiarini, F. Hucho, P. Krogsgaard-Larsen, I. R. Mellor, A. Minarini, V. Tumiatti, P. N.R. Usherwood and C. Melchiorre, J. Med. Chem., 1999, 42,5212–5223.

19 K. M. Witherup, R. M. Ransom, A. C. Graham, A.M. Bernard, M. J. Salvatore, W. C. Lumma, P.S. Anderson, S. M. Pitzenberger and S. L. Varga, J. Am.Chem. Soc., 1995, 117, 6682–6685.

20 (a) G. Periyasami, R. Raghunathan, G. Surendiran andN. Mathivanan, Bioorg. Med. Chem. Lett., 2008, 18,

2342–2345; (b) S. Purushothaman, R. Prasanna,P. Niranjana, R. Raghunathan, S. Nagaraj andR. Rengasamy, Bioorg. Med. Chem. Lett., 2010, 20,7288–7291; (c) A. Thangamani, Eur. J. Med. Chem., 2010,45, 6120–6126.

21 (a) M. L. Bolognesi, M. Bartolini, A. Cavalli, V. Andrisano,M. Rosini, A. Minarini and C. Melchiorre, J. Med. Chem.,2004, 47, 5945–5952; (b) N. Arumugama, R. Raghunathan,A. I. Almansour and U. Karama, Bioorg. Med. Chem. Lett.,2012, 22, 1375–1379; (c) N. Shimada, Y. Abe, S. Yokoshimaand T. Fukuyama, Angew. Chem., Int. Ed., 2012, 51,11824–11826.

22 (a) K. Ushijima, M. Shirakawa, K. Kagoshima, W.-S. Park,N. Miyano-Kurosaki and H. Takaku, Bioorg. Med. Chem.,2001, 9, 2165–2169; (b) Y. Hirokawa, H. Harada,T. Yoshikawa, N. Yoshida and S. Kato, Chem. Pharm.Bull., 2002, 50, 941–959; (c) C. R. Clark and T.W. Davenport, J. Med. Chem., 1987, 30, 1214–1218.

23 (a) P. H. Stahl and C. G. Wermuth, Handbook ofPharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, 2011; (b) D. A. Haynes, W. Jones and W.D. S. Motherwell, J. Pharm. Sci., 2005, 94, 2111–2120.

24 (a) N. J. Parmar, B. R. Pansuriya, B. M. Labana, T.R. Sutariya, R. Kant and V. K. Gupta, Eur. J. Org. Chem.,2012, 5953–5964; (b) N. J. Parmar, B. R. Pansuriya, H.A. Barad, R. Kant and V. K. Gupta, Bioorg. Med. Chem. Lett.,2012, 22, 4075–4079; (c) N. J. Parmar, S. B. Teraiya, R.A. Patel and N. P. Talpada, Tetrahedron Lett., 2011, 52,2853–2856; (d) N. J. Parmar, R. A. Patel, S. B. Teraiya,D. Sharma and V. K. Gupta, RSC Adv., 2012, 2, 3069–3075.

25 G. M. Sheldrick, SHELX97, University of Gottingen,Germany, 1997.


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a convenient 1,3-dipolar cycloaddition–reduction synthetic sequence from...

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