WO2022123336A1

WO2022123336A1 - Chromeno [4,3-b] quinoline compounds and their synthesis by using silicotungstic acid [h4siw12o40]

Info

Publication number: WO2022123336A1
Application number: PCT/IB2021/058086
Authority: WO
Inventors: Subramanya Gopal Hegde; Koodlur Sannegowda LOKESH; Jayachamarajapura Pranesh SHUBHA; Nurani Viswanathan SUSHMA; Girish Basavaraju; Ananda Danagoudar; Vijay Kumar Boda
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-12-07
Filing date: 2021-09-05
Publication date: 2022-06-16
Anticipated expiration: 2023-06-07

Abstract

The present invention relates to the development of novel compounds of chromeno [4,3-b] quinolone derivatives. It particularly relates to the development of novel compounds of thiochromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome. The present invention also relates to the first synthesis of Silicotungstic -catalyzed Aza-Diels-Alder-reactions (ADAR) with s-prenyl derivatives of α-tetralone, 4-chromanone and Thiochroman-4-one and various substituted amines to deliver cycloadducts in good yield and excellent diastereoselectivity under mild reaction conditions. The invention further relates to the method for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome by using synthesized compounds of thiochromeno [4,3-b] quinolone derivatives. The present invention provides the use of Silicotungstic acid as Lewis acid for Aza-Diels-Alder-reactions to get a mixture of diastereomers are the first examples. In addition to its efficiency, simplicity, and mild reaction conditions, the catalyst is very cheap and only a small amount (10 mol%) is needed. Intramolecular cyclization was carried out very conveniently as a one-pot reaction starting from the S-prenyl chromene-3-carbaldehyde and arylamines without isolation of the intermediate imines.

Description

Title of the Invention: CHROMENO [4,3-b] QUINOLINE COMPOUNDS AND THEIR SYNTHESIS BY USING SILICOTUNGSTIC ACID [H₄SiW₁₂O₄₀]

FIELD OF THE INVENTION

The present invention relates to the development of novel compounds of chromeno [4,3-b] quinolone derivatives. It particularly relates to the development of novel compounds of thiochromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome. The present invention also relates to the first synthesis of Silicotungstic -catalyzed Aza-Diels-Alder-reactions (ADAR) with s-prenyl derivatives of a- tetralone, 4-chromanone and Thiochroman-4-one and various substituted amines to deliver cycloadducts in good yield and excellent diastereoselectivity under mild reaction conditions. The invention further relates to the method for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome by using synthesized compounds of thiochromeno [4,3-b] quinolone derivatives.

BACKGROUND OF THE INVENTION

Over the last few years, there has been all-embracing research on Chromeno quinolines skeleton, as most of these functionalized derivatives are an integral constituent of several natural products. [Edwards, J. P. et.al, J. Med. Chem. 1998, 41 (3), 303-310], These continue to be a keen area of heterocyclic chemistry because of their application as antibacterial [Nasveld, P et.al, Royal Society of Tropical Medicine and Hygiene 2005, 99 (1), 2-5], antifungal [Denny, W. A et.al, Google Patents: 2006], and anti-inflammatory agents. [Mahamoud, A et.al, Current drug targets 2006, 7 (7), 843-847] A variety of terpenoids, contains chromane core and has vast traditional applications and has been used in food, pharmaceutical, and chemical industries [ Jian, Y et.al, A European Journal 2015, 21 (25), 9022-9027],

The Aza-Diels-Alder-reactions (ADAR) epitomizes an important strategy for the synthesis of poly heterocycles due to their numerous and valuable applications in various fields. This strategy continues to be, the most frequently employed synthetic method in the formation of sixmembered N-heterocycles as well as provides vast opportunity to access small molecule libraries in the drug discovery. Hence a variety of approaches over a few decades has been developed for the synthesis of Chromeno quinolines skeleton. The idea of using Lewis acid in an aqueous medium was first tried in organic transformation related to aldol reaction and had tremendous success in getting regioselective compounds. Later the strategy was adopted by Diels-Alder. As the ADAR is concerted and involves most of the time Lewis acid catalysts to accelerated the [4n +2n] cycloadditions to enhance the selectivity. The important aspect of Diels- Alder chemistry is the activation of dienophile. Francesco Fringuelli and co-workers [Eur. J. Org. Chem. 2001, 2001 (3), 439-455] have presented the review article on the green chemistry approach to enhance Lewis acid- catalyzed Aza-Diels-Alder-reactions, which plays a very important role in the designing of new heterocyclic scaffolds.

The disposition of chromanone derivatives for [4+2] cycloadditions with various it bonds is well- anchored and draws the attention of many research groups as it allows the expeditious building of precious intermediates. As there is still an unexplored area of new Chromeno-quinolines hybrid molecules, and it deserves advanced exploitation.

Diels-Alder reaction was carried out by using Metal aqua complexes, and the water as an auxiliary ligand impacts the diastereo- and enantioselectivity of the reaction. Jan B. F. N. Engberts et al [J. Am. Chem. Soc. 1991, 113, 11, 4241-4246] have reported Carbo- Diels-Alder reactions by studying the effect of different Lewis acid catalysts on the diastereoselective of endo-exo between diene and dienophile.

Based on the above disclosures in the literature, the present inventors have planned a new diversity of Chromeno-quinolines by implementing the Diels- Alder strategy. For the establishment of chemistry, we wedged on Aza-Diels-Alder reaction on the substrate containing imines and dienes that get converted to tetrahydro derivatives. In consideration of the preceding literature, it was decided to consider the electron-rich diene that can easily favor Lewis acid- mediated intramolecular 4+2 cycloaddition with diastereoselectivity. The choice of the readily available starting material was finally aimed at 4-Chromanone, Thiochroman-4-one, a-Tetralone as core material for the synthesis of six-membered heterocycles. The reason for choosing the above core can be viewed as a starting point in developing the combinatorial type by utilizing the aspects of medicinal chemistry. Therefore, the present inventors have developed the of chromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome along with a suitable synthetic method for preparation of thiochromeno [4,3-b] quinolone derivatives.

OBJECTS OF THE INVENTION

• The primary object of the present invention is the development of novel compounds of chromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.

• The specific object of the present invention is the development of thiochromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.

• The other object of the present invention is the development of a synthetic method for compounds of chromeno [4,3-b] quinolone derivatives.

• The other object of the present invention is the development of a synthetic method for compounds of thiochromeno [4,3-b] quinolone derivatives.

• The other object of the present invention that it provides for the use of Silicotungstic acid as Lewis acid for Aza-Diels-Alder-reactions to get a mixture of diastereomers is the first example. In addition to its efficiency, simplicity, and mild reaction conditions, the catalyst is very cheap and only a small amount (10 mol%) is needed.

• The other object of the present invention that in the method the intramolecular cyclization was carried out very conveniently as a one-pot reaction starting from the S-prenyl chromene-3- carbaldehyde and arylamines without isolation of the intermediate imines.

• The other object of the present invention is the development of pharmaceutical compositions of chromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.

• The other object of the present invention is the development of chromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.

• which are cost-effective.

• which are easy to use with little technical expertise. • The other object of the present invention is the development of chromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome, which are safe and practical to use.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I that can be useful for pharmaceutical importance for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.

Formula I or salt there of, wherein X is CH₂ Oxygen or Sulphur

Ri is H, Cl, -CN, Ci-4 alkyl, Cl-3fluoroalkyl, C1.3 hydroxy fluoroalkyl, C3.6 cycloalkyl, or tetrahydopyranyl ;

R2 is independently halo, -CN, -OH, -NO2⁺, Cl -3 alkyl, Cl-2fluoro alkyl, Cl -2 cyanoalkyl, C1.3 hydroxyalkyl, C1.3 aminoalkyl, C1.3 fluoro alkoxy, -cyclopropyl, cycloalkyl, morpholinyl, methylpyridine, imidazolyl, triazolyl, or thiazolyl.

The present invention provides the use of Silicotungstic acid as Lewis acid for Aza-Diels-Alder- reactions to get a mixture of diastereomers are the first examples. In addition to its efficiency, simplicity, and mild reaction conditions, the catalyst is very cheap and only a small amount (10 mol%) is needed.

Intramolecular cyclization was carried out very conveniently as a one-pot reaction starting from the S-prenyl chromene-3-carbaldehyde and arylamines without isolation of the intermediate imines.

STATEMENT OF THE INVENTION

A compound of Formula I

Formula I or salt thereof, wherein,

X is CH₂, Oxygen, or Sulphur;

Ri is H, Cl, -CN, Ci-4 alkyl, Cl-3fluoroalkyl, Ci-shydroxy fluoroalkyl, C3.6 cycloalkyl, or tetrahydopyranyl;

R2 is independently halo, -CN, -OH, -NO2⁺, Cl -3 alkyl, Cl-2fluoro alkyl, Cl -2 cyanoalkyl, C1.3 hydroxyalkyl, C1.3 aminoalkyl, C1.3 fluoro alkoxy, -cyclopropyl, cycloalkyl, morpholinyl, methylpyridine, imidazolyl, triazolyl, or thiazolyl. The compound is selected from group consisting of

7.7-dimethyl-6a,7, 12, 12a, 13, 14-hexahydro-6H-benzo[7,8]thiochromeno[4,3-b] quinolone;

9-chloro-7,7-dimethyl-6a,7,12,12a,13,14-hexahydro-6H-benzo [7,8] thiochromeno[4,3-b] quinolone;

9-bromo-7,7-dimethyl-6a,7,12,12a,13,14-hexahydro-6H-benzo [7,8] thiochromeno[4,3-b] quinolone;

10-fluoro-7,7-dimethyl-6a,7, 12, 12a, 13, 14-hexahydro-6H-benzo[7,8]thiochromeno[4,3- b] quinolone;

7.7-dimethyl-9-(trifluoromethyl)-6a,7, 12, 12a, 13 , 14-hexahydro-6H-benzo[7,8] thiochromeno[4,3-b]quinolone;

7.7-dimethyl-9-nitro-6a,7,12,12a,13,14-hexahydro-6H-benzo[7,8]thiochromeno[4,3- b] quinolone; and

7.7.10-trimethyl-6a,7, 12, 12a, 13, 14-hexahydro-6H-benzo[7,8]thiochromeno[4,3- b] quinolone.

The compound is selected from group consisting of

7.7-dimethyl-6a,7,12,12a-tetrahydro-6H,13H-chromeno[3',4':5,6]thiopyrano[4,3- b] quinolone;

10-chloro-7,7-dimethyl-6a,7, 12,12a-tetrahydro-6H, 13H-chromeno[3 ',4' : 5,6] thiopyrano [4,3 -b] quinolone;

9-bromo-7,7-dimethyl-6a,7,12,12a-tetrahydro-6H,13H-chromeno[3',4':5,6] thiopyrano [4,3 -b] quinolone;

10-fluoro-7,7-dimethyl-6a,7, 12, 12a-tetrahydro-6H, 13H-chromeno[3 ',4': 5,6] thiopyrano [4,3 -b] quinolone;

7.7-dimethyl-9-(trifluoromethyl)-6a,7, 12, 12a-tetrahydro-6H, 13H-chromeno[3 ',4' : 5,6] thiopyrano [4,3 -b] quinolone;

7.7-dimethyl-9-nitro-6a,7,12,12a-tetrahydro-6H,13H-chromeno[3',4':5,6]thiopyrano[4,3- b] quinolone; and

7.7.10-trimethyl-6a,7, 12, 12a-tetrahydro-6H, 13H-chromeno[3',4' : 5,6]thiopyrano[4,3- b] quinolone.

The compound is selected from group consisting of

7.7-dimethyl-6a,7,12,12a-tetrahydro-6H,13H-thiochromeno[3',4':5,6]thiopyrano[4,3- b] quinolone;

10-chloro-7,7-dimethyl-6a,7,12,12a-tetrahydro-6H,13H-thiochromeno[3',4':5,6] thiopyrano [4,3 -b] quinolone;

9-bromo-7,7-dimethyl-6a,7,12,12a-tetrahydro-6H,13H-thiochromeno[3',4':5,6] thiopyrano [4,3 -b] quinolone;

10-fluoro-7,7-dimethyl-6a,7, 12, 12a-tetrahydro-6H, 13H-thiochromeno[3',4': 5,6] thiopyrano [4,3 -b] quinolone;

7.7-dimethyl-9-(trifluoromethyl)-6a,7, 12, 12a-tetrahydro-6H, 13H-thiochromeno[3',4': 5,6] thiopyrano [4,3 -b] quinolone;

7.7-dimethyl-9-nitro-6a,7,12,12a-tetrahydro-6H,13H-thiochromeno[3',4':5,6] thiopyrano[4,3-b]quinolone; and

7,7, 10-trimethyl-6a,7, 12, 12a-tetrahydro-6H, 13H-thiochromeno[3',4': 5,6]thiopyrano[4,3 - b] quinolone. A pharmaceutical composition for treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome comprising a compound of Formula I or its pharmaceutically acceptable salt thereof and pharmaceutically suitable excipient or carrier.

A process for preparation of compound of Formula I comprising: a. preparation of compound Formula IV by reacting the compound Formula III with phosphorous tribromide and DMF in the presence of chloroform; b. then treating the compound of Formula IV with sodium hydrosulfide/sodium bisulfide and prenyl bromide to synthesize allyl thioether compound of Formula V by allylation; and c. then reacting the compound of Formula V with aniline compound 5 a-g in presence of silicotungstic acid and acetonitrile to get compound of Formula VI and then subjecting a compound of Formula VI for intermolecular ADAR to obtain the cistrans mixture of a compound of Formula I; wherein, compound of Formula I is

compound of Formula III is

compound of Formula IV is compound of Formula V is

compound of Formula VI is wherein,

X is CH₂, Oxygen, or Sulphur;

DETAILED DESCRIPTION OF THE INVENTION Synthesis of the compounds of Formula I:

The compound of Formula I or a salt thereof in which X is CH2, Oxygen, Sulphur may be prepared as shown in the Reaction Scheme 1.

General scheme

Ri is H, Cl, -CN, Ci-4 alkyl, Cl-3fluoroalkyl, Ci^hydroxy fluoroalkyl, C3.6 cycloalkyl, or tetrahydopyranyl;

R2 is independently halo, -CN, -OH, -NO2⁺, Cl -3 alkyl, Cl-2fluoro alkyl, Cl -2 cyanoalkyl, Ci-3 hydroxyalkyl, C1.3 amino alkyl, C1.3 fluoro alkoxy, -cyclopropyl, cycloalkyl, morpholinyl, methylpyridine, imidazolyl, triazolyl, or thiazolyl.

The synthetic feasibility was first demonstrated by considering a-tetralone 1 to undergo Vilsmeier-Haack reaction that uses a phosphorous tribromide and DMF in the presence of chloroform to get l-bromo-3,4-dihydronaphthalene-2-carbaldehyde 2 in good yield 25. Once the Bromo aldehyde on hand, we turned our attention towards the synthesis of allyl thioether 4, as it was unexplored, and chosen prenyl bromide 3 for the allylation. This was carried out by treating with sodium hydrosulfide/sodium bisulfide and prenyl bromide. The reaction proceeded one pot without the isolation of P-thiolo enal to afford l-((3-methylbut-2-en-l-yl) thio)-3,4- dihydronaphthalene-2-carbaldehyde 4 in 70% yield. A series of optimization was performed to choose the Lewis acid for ADAR.

The choice of this Lewis acid was based on the success in the intramolecular dipolar cycloaddition in our previous work. The use of Lewis acid becomes necessary to get the diastereoselectivity and to activate the imine (diene). However, the MgSiCLNPs gave low yield and no diastereoselectivity during cyclization (Table 1, entry 2). The selectivity was virtually the same as when the reaction was performed without a Lewis acid (Table 1, entry 1).

The screening of Lewis-acid was carried. Further, we explored other Lewis acids such as InC13, Sc(OTf)3, BF3 Et2O, Yb(OTf)3. The use of all these acids enhanced the yield but did not improve the diastereoselectivity. The benefit of Yb(OTf)3 gave a moderate selectivity in comparison with other Lewis acids (Table 1, entry 6). The stereochemical outcome is presumably due to the lesser advantage of stronger Lewis acid in comparison with weak Lewis acid which showed a significant improvement in the diastereoselectivity. To our delight usage of silicotungstic acid for substantial improvement in the diastereoselectivity, as well as yield, came as per our hypothesis and encouraged to select the silicotungstic acid as Lewis acid throughout the synthesis. The idea got generated from the precedent literature for the synthesis of oxindole derivatives.

Having shown excellent diastereoselectivity on tetralone, the scope of the reaction was investigated on unexplored compounds 4-chromanone 7 and Thiochroman-4-one 11. Thus, Intramolecular ADAR of S-prenyl derivatives of 9 and 13 under optimized protocol afforded major cis- selective of the respective cycloadducts lOa-g (Scheme-2) and 14a-g (Scheme-3), Table-3 and in moderate to good yield.

Abbreviations

1,3-DC 1.3 -dipolar cyclo addition Bn Benzyl Bz Benzoyl CDC1₃ Deuterated chloroform CuAAC Cu(I) catalyzed alkyne-azide cycloaddition D Doublet DABCO 1.4-Diazabicyclo [2.2.2] octane DBU l,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane Dd Doublet of doublet DFT Density Functional Theory DIPEA Diisopropyl ethyl amine DMAP Dimethylaminopyridine DMF Dimethyl formamide DMSO Dimethyl sulfoxide DNA Deoxyribonucleic acid EtOAc Ethyl acetate Hz Hertz IR InfraRed MS Mass Spectrum MW Microwave NaASc /.-Sodium ascorbate NMR Nuclear Magnetic Resonance PCC Pyridinium chlorochromate PTSA /?-Toluenesulphonic acid Q Quartet R/ Retention Factor SiO₂ Silica T Triplet TBAB Tetrabutyl Ammonium Bromide THF Tetrahydrofuran TLC Thin Layer Chromatography TMS Tetra Methyl Silane MgSiO₃ NPs Magnesium silicate Nanoparticles UV Ultra Violet HOMO Highest Occupied Molecule Orbital LUMO Lowest Un-occupied Molecular Orbital Analytical Conditions

HPLC: The synthesized compounds, the reaction mixtures for the reaction monitoring, and the purity were analyzed by high-performance liquid chromatography. (HPLC) in a Shimadzu LC 8A, an instrument using an Ascentis Express Cl 8 (50X2, 1mm, 2.7pm) and acetonitrile: water in 80:20 (v/v) as the mobile phase at a flow rate of 1 mL/min using refractive index detector. Conversion yields can also be determined by comparison with starting material from the HPLC peak areas. Error measurements in HPLC yields will be ± 5-10%. Column: Ascentis Express C18 (50X2, 1mm, 2.7pm) Mphase A: lOrnM, N ECOOHin water: ACN (98:02): Mphase B: lOmM, NH₄COOHin water: ACN (02:98), Gradient: 0-100%B over 3 minutes, Flow: ImL/min

Infrared spectroscopy: Infrared spectra were recorded on a Nicolet-FTIR spectrophotometer. Isolated solid glycoside samples (5-8 mg) were prepared as KBr pellets and employed for spectral recording. Liquid alcohol standards were employed as such between salt plates to obtain the IR spectra.

¹H NMR: 1H spectra were recorded on a Bruker DRX 400 MHz NMR spectrometer (400.13MHz). The proton pulse width was 12.25 ms. A sample concentration of about 10 mg of the sample dissolved in DMSO-d6 was used for recording the spectra at 35 °C. About 100-200 scans were accumulated to get a good spectrum. The region between 0-10 ppm was recorded for all the samples. Chemical shift values were expressed in ppm and tetra-methyl silane (TMS) is considered as internal standard.

¹³C NMR: 13C NMR spectra were recorded on a Bruker DRX 400 MHz NMR spectrometer (100MHz). Carbon 90° pulse widths were 10.5 ms. The sample concentration of around 20 mg dissolved in DMSO-d6 was used for recording the spectra at 35 °C. About 500 to 2000 scans were accumulated for each spectrum in the 0-200 ppm region. Chemical shift values were expressed in ppm and tetramethylsilane (TMS) was used as the internal standard.

2D-HSQCT: Two-dimensional Heteronuclear Single Quantum Coherence Transfer Spectra (2-D HSQCT) were recorded on a Bruker DRX 400 MHz NMR spectrometer. A sample concentration of about 20 mg in DMSO-d6 was used for recording the spectrum. Spectra were recorded in magnitude mode with the sinusoidal shaped Z gradients of strength 25.7, 15.42, and 20.56 G/cm in the ratio of 5:3:4 applied for a duration of 1 ms each with a gradient recovery delay of 100 ms to defocus unwanted coherences. Then it was incremented in 256 steps. The size of the computer memory used to accumulate the 2D data was 4K. The spectra were processed using unshifted and p/4 shifted sine bell window function in Fl and F2 dimensions respectively.

Mass spectroscopy: Mass spectra were recorded from the Q-TOF Waters Ultima instrument (Q- Tof GAA 082, Waters Corporation, Manchester, UK) with an integral electron spray ionization (ESI) source. Software version 4.0 was used for data acquisition. The positive ion mode using a spray voltage at 3.5 kV and a source temperature of 80°C was employed for recording the spectra. Mass spectra were recorded under electron impact ionization at 70 eV electron energy. Compounds were dissolved in the concentration range of 0.5- 1.0 mg/mL in methanol and injected by flow injection analysis at a flow rate of 10 pL/ min. The recorded mass of the sample was in the range of 100-1500.

Table-2: Silicotungstic acid- catalyzed synthesis of tetralone derived thiochromeno[4,3-b] quinolines via ADAR

To a mechanically stirred solution of dimethylformamide (3 mmol) in anhydrous chloroform was cooled in an ice bath while phosphorous tribromide (2.7 mmol) was added drop- wise over 15 min. The resulting white suspension was warmed to ambient temperature and stirred for a further 20 min. A solution of starting keto compound (1 mmol) in chloroform was added drop- wise over 10 min. Stirring was continued for 8 h at rt. The reaction mixture was then poured into ice water. Solid sodium bicarbonate was carefully added to neutralize the acids and the mixture was extracted several times with dichloromethane. The organic part was then washed with cold water thoroughly, dried with sodium sulfate, and evaporated. Purification of the residue was done by silica gel (60-120 mesh) column chromatography to afford l-Bromo-3,4-dihydro naphthalene-2- carbaldehyde (2) as a pale-yellow solid

1H NMR (400 MHz, CDC13): 5 = 10.26 (s, 1H), 7.90 (d, J = 6.80 Hz, 1H), 7.32-7.38 (m, 2H), 7.19-7.20 (m, 1H), 2.84 (t, J = 16.00 Hz, 2H), 2.62 (q, J = 15.60 Hz, 2H). 13C NMR (100 MHz, CDC1₃): 5 = 22.91, 27.20, 127.17, 127.62, 128.77, 131.38, 133.03, 134.55, 139.00, 139.08, 193.17. MS (ESI) m/z: 238.2 [M + H+], Anal. Calcd for CnH₉BrO: C, 55.72; H, 3.83; Br, 33.70; O, 6.75. Found: C, 56.02; H, 3.99.

Step-II: Preparation of l-((3-methyl but-2-en-l-yl) thio)-3,4-dihydro naphthalene-2-

To a step-1 intermediate l-Bromo-3,4-dihydro naphthalene-2-carbaldehyde (2) was dissolved in a mixture of isopropanol and water (3:4), containing sodium thiol (2 mmol), and the mixture was stirred 15mins at room temperature. After prenyl bromide (3 mmol) was added slowly to the reaction mixture and the completion of the reaction was monitored as indicated by TLC. After evaporation the crude product was extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, evaporated, and purified with neutral alumina with hexane to give 1 -((3 -methyl but-2-en-l-yl) thio)-3,4-dihydro naphthal ene-2-carbaldehyde (4) as an orange-red liquid.

1H NMR (400 MHz, CDC13): 5 = 10.59 (s, 1H), 8.09 (d, J = 8.80 Hz, 1H), 7.33-7.37 (m, 2H), 7.21-7.23 (m, 1H), 5.14 (t, J = 16.00 Hz, 1H), 3.31 (d, J = 8.00 Hz, 2H), 2.70-2.74 (m, 2H), 2.56- 2.60 (m, 2H), 1.64 (s, 3H), 1.29 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 17.30, 22.07, 25.56, 27.34, 33.07, 119.20, 126.93, 127.62, 127.98, 130.37, 133.22, 137.08, 139.09, 142.38, 148.86, 192.71. MS (ESI) m/z: 259.2 [M + H+], Anal. Calcd for CI₆HI₈OS: C, 74.38; H, 7.02; O, 6.19; S, 12.41. Found: C, 74.70; H, 7.28.

Steo-III: Preparation of 7,7-dimethyl-6a,7,12,12a,13,14-hexahvdro-6H-benzo [7,81

,3-bl quinoline (6a)

Silicotungstic acid (10 mol%) was added to a mixture of aniline 5a-g, (1 mmol) and l-((3-methyl but-2-en-l-yl) thio)-3,4-dihydro naphthalene-2-carbaldehyde (4) (1 mmol) in acetonitrile (10 volumes). The reaction mixture was stirred at room temperature 30 mins. The reaction mixture was then carried out under microwave condition for 60min at 50°C. The solvent was removed in vacuo, and the residue obtained was purified using a silica gel chromatography (230x400) mesh size with a hexane and Methyl tert-butyl ether (MTBE) as eluent to afford Cis: Trans mixture of cycloadducts (6a-g) as yellow solid.

Cis/Trans: ‘H NMR (400 MHz, CDC1₃): 5 = 7.31 (dd, J = 9.20, Hz, 1H), 7.19-7.21 (m, 1H), 6.94-6.98 (m, 1H), 6.93-6.97 (m, 1H), 6.87-6.91 (m, 2H), 6.70 (d, J = 8.80 Hz, 1H), 6.41 (dd, J = 9.20, Hz, 1H), 4.88 (d, J = 13.60 Hz, 1H), 4.74 (d, J = 13.60 Hz, 1H), 4.03 (s, 1H), 3.96 (s, 1H), 2.97-2.99 (m, 2H), 2.56-2.60 (m, 2H), 1.78 (s, 6H), 1.54 (s, 6H). ¹³C NMR (100 MHz, CDC13): 5 = 19.30, 20.67, 24.33, 25.71, 30.93, 34.10, 35.65, 41.94, 49.87, 106.90, 115.80, 124.08, 126.12, 127.80, 128.52, 129.37, 129.70, 132.40, 133.36, 140.98, 143.10, 149.33. MS (ESI) m/z: 334.2 [M + H+], Anal. Calcd for C22H23NS: C, 79.23; H, 6.95; N, 4.20; S, 9.61. Found: C, 80.01; H, 6.85; N, 4.13.

9-chloro-7,7-dimethyl-6a,7,12,12a,13,14-hexahydro-6H-benzo [7,8] thiochromeno[4,3-b] quinoline (6b)

Compound 6b was prepared accordingly as per the general procedure used for compound 6a Cis: ‘H NMR (400 MHz, CDC13): 5 = 7.31-7.34 (m, 1H), 7.21-7.24 (m, 3H), 7.07 (d, J = 2.40 Hz, 1H), 6.93 (dd, J = 11.20, Hz, 1H), 6.59 (d, J = 8.40 Hz, 1H), 6.10 (s, 1H), 4.09 (d, J = 2.80 Hz, 1H), 2.69-2.89 (m, 4H), 2.50-2.52 (m, 1H), 2.45 (t, J = 24.80 Hz, 1H), 2.28-2.35 (m, 1H), 1.78 (d, J = 12.00 Hz, 1H), 1.41 (s, 3H), 1.27 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 22.69, 25.82, 28.03, 29.68, 34.08, 35.78, 39.41, 41.86, 49.53, 106.67, 115.72, 123.21, 124.37, 126.87, 127.79, 127.98, 128.34, 128.79, 129.35, 129.71, 133.35, 136.02, 141.381. MS (ESI) m/z: 368.2 [M + H+], Anal. Calcd for C22H22CINS: C, 71.82; H, 6.03; Cl, 9.64; N, 3.81; S, 8.71. Found: C, 72.13; H, 6.28; N, 4.07.

Trans 1H NMR (400 MHz, CDC13): 5 = 7.30-7.33 (m, 1H), 7.21-7.23 (m, 3H), 7.06 (d, J = 2.40 Hz, 1H), 6.92 (dd, J = 11.20, Hz, 1H), 6.58 (d, J = 8.80 Hz, 1H), 6.09 (s, 1H), 4.08 (d, J = 2.80 Hz, 1H), 2.78-2.88 (m, 3H), 2.66-2.74 (m, 1H), 2.44 (t, J = 24.80 Hz, 1H), 2.26-2.34 (m, 1H), 1.77 (d, J = 12.40 Hz, 1H), 1.40 (s, 3H), 1.26 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 22.69, 25.82, 28.03, 29.68, 34.08, 35.78, 39.41, 41.86, 49.53, 106.67, 115.72, 123.21, 124.37, 126.87, 127.79, 127.98, 128.34, 128.79, 129.35, 129.71, 133.35, 136.02, 141.381. MS (ESI) m/z: 368.2 [M + H+], Anal. Calcd for C₂₂H₂₂C1NS: C, 71.82; H, 6.03; Cl, 9.64; N, 3.81; S, 8.71. Found: C, 72.22; H, 6.30; N, 4.05.

9-bromo-7,7-dimethyl-6a,7,12,12a,13,14-hexahydro-6H-benzo [7,8] thiochromeno[4,3-b] quinoline (6c)

Compound 6c was prepared accordingly to as per the general procedure used for compound 6a ‘H NMR (400 MHz, CDC1₃): 5 = 7.30-7.33 (m, 1H), 7.21-7.25 (m, 3H), 7.17 (d, J = 2.00 Hz, 1H), 7.04 (dd, J = 10.80, Hz, 1H), 6.55 (d, J = 8.40 Hz, 1H), 6.13 (s, 1H), 4.08-4.09 (m, 1H), 2.67-2.89 (m, 4H), 2.44 (t, J = 24.80 Hz, 1H), 2.26-2.35 (m, 1H), 1.78 (d, J = 12.00 Hz, 1H), 1.41 (s, 3H), 1.26 (s, 3H). ¹³C NMR (100 MHz, CDCI3): 5 = 25.56, 26.40, 27.34, 28.83, 33.07, 56.81, 59.10, 111.11, 115.32, 125.42, 126.13, 126.93, 127.62, 127.98, 130.37, 133.22, 137.08, 139.09, 142.38, 148.86. MS (ESI) m/z: 414.1 [M + H+], Anal. Calcd for C₂₂H₂₂BrNS: C, 64.07;

H, 5.38; Br, 19.38; N, 3.40; S, 7.78. Found: C, 64.43; H, 5.71; N, 3.75. 10-fluoro-7,7-dimethyl-6a,7,12,12a,13,14-hexahydro-6H-benzo[7,8]thiochromeno[4,3- b] quinoline (6d)

Compound 6d was prepared accordingly to as per the general procedure used for compound 6a ‘H NMR (400 MHz, DMSO-d6): 5 7.31-7.33 (m, 1H), 7.22-7.25 (m, 3H), 7.17 (d, J = 2.00 Hz, 1H), 7.04 (dd, J = 10.80, Hz, 1H), 6.55 (d, J = 8.40 Hz, 1H), 6.13 (s, 1H), 4.08 (d, J = 2.40 Hz, 1H), 2.81-2.89 (m, 3H), 2.69-0.00 (m, 1H), 2.44 (t, J = 24.80 Hz, 1H), 2.31-0.00 (m, 1H), 1.78 (d, J = 12.00 Hz, 1H), 1.41 (s, 3H), 1.26 (s, 3H). ¹³C NMR (100 MHz, DMSO-d6): 5 = 25.56, 26.40, 27.34, 28.83, 33.07, 56.81, 59.10, 111.11, 115.32, 125.42, 126.13, 126.93, 127.62, 127.98, 130.37, 133.22, 137.08, 139.09, 142.38, 148.86. MS (ESI) m/z: 414.1 [M + H+], Anal. Calcd for C₂₂H₂₂FNS: C, 64.07; H, 5.38; N, 3.40. Found: C, 64.43; H, 5.71; N, 3.75.

7,7-dimethyl-9-(trifluoromethyl)-6a,7,12,12a,13,14-hexahydro-6H-benzo[7,8] thiochromeno [4,3-b] quinoline (

Compound 6e was prepared accordingly as per the general procedure used for compound 6a Cis/Trans: ‘H NMR (400 MHz, CDC13): 5 = 7.30-7.33 (m, 1H), 7.21-7.25 (m, 3H), 7.17 (d, J = 2.00 Hz, 1H), 7.04 (dd, J = 10.80, Hz, 1H), 6.55 (d, J = 8.40 Hz, 1H), 6.13 (s, 1H), 4.08-4.09 (m, 1H), 2.67-2.89 (m, 4H), 2.44 (t, J = 24.80 Hz, 1H), 2.26-2.35 (m, 1H), 1.78 (d, J = 12.00 Hz, 1H), 1.41 (s, 3H), 1.26 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 25.56, 26.40, 27.34, 28.83, 33.07, 56.81, 59.10, 111.11, 115.32, 125.42, 126.13, 126.93, 127.62, 127.98, 130.37, 133.22, 137.08, 139.09, 142.38, 148.86. MS (ESI) m/z: 402.2 [M + H+], Anal. Calcd for C₂₃H₂₂F₃NS: C, 68.81; H, 5.52; N, 3.49; S, 7.99. Found: C, 68.33; H, 5.28; N, 3.30.

7,7-dimethyl-9-nitro-6a,7,12,12a,13,14-hexahydro-6H-benzo[7,8]thiochromeno[4,3- b] quinoline (61)

Compound 6f was prepared accordingly to as per the general procedure used for compound 6a Cis/Trans: 1H NMR(4OO MHz, DMSO-d6): 5 = 7.30-7.31 (m, 1H), 7.20-7.24 (m, 3H), 7.06 (d, J = 2.00 Hz, 1H), 6.91 (dd, J = 10.80, Hz, 1H), 6.58 (d, J = 8.40 Hz, 1H), 6.08 (s, 1H), 4.08 (d, J = 2.40 Hz, 1H), 2.81-2.89 (m, 3H), 2.69-0.00 (m, 1H), 2.44 (t, J = 24.80 Hz, 1H), 2.31-2.34 (m, 1H), 1.77 (d, J = 12.00 Hz, 1H), 1.40 (s, 3H), 1.26 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 25.56, 26.40, 27.34, 28.83, 33.07, 56.81, 59.10, 111.11, 115.32, 125.42, 126.13, 126.93, 127.62, 127.98, 130.37, 133.22, 137.08, 139.09, 142.38, 148.86. MS (ESI) m/z: 379.1 [M + H+], Anal. Calcd for C₂₂H₂₂N₂O₂S, 69.81; H, 5.86; N, 7.40; O, 8.45; S, 8.47. Found: C, 69.72; H, 5.90; N, 7.53. 7,7,10-trimethyl-6a,7,12,12a,13,14-hexahydro-6H-benzo[7,8]thiochromeno[4,3-b]quinoline

(6g)

Cis/Trans: M NMR (400 MHz, CDC1₃): 5 = 7.32 (dd, J = 9.20, Hz, 1H), 7.18-7.22 (m, 1H), 6.94-6.98 (m, 1H), 6.93-6.97 (m, 1H), 6.87-6.91 (m, 2H), 6.70 (d, J = 8.80 Hz, 1H), 6.41 (dd, J =

9.20, Hz, 1H), 4.88 (d, J = 13.60 Hz, 1H), 4.74 (d, J = 13.60 Hz, 1H), 4.03 (s, 1H), 3.96 (s, 1H), 2.97-2.99 (m, 2H), 2.27-2.30 (m, 2H), 1.78 (s, 3H), 1.54 (s, 6H). 13C NMR (100 MHz, CDC13): 5 = 20.67, 24.33, 25.71, 30.93, 34.10, 35.65, 41.94, 49.87, 106.90, 115.80, 124.08, 126.12, 127.80, 128.52, 129.37, 129.70, 132.40, 133.36, 140.98, 143.10, 149.33. MS (ESI) m/z: 347.2 [M + H+], Anal. Calcd for C23H25NS: C, 79.49; H, 7.25; N, 4.03; S, 9.23. Found: C, 79.46; H, 7.35; N, 4.13.

Table-2: Silicotungstic acid- catalyzed synthesis of chromanone/ Thiocromanone derived thiochromeno[4,3-b] quinolines via ADAR

l-Bromo-3.,4-dihydro naphthalene-2-carbaldehyde (8)

Compound 8 was prepared accordingly to as per the general procedure used for compound 2 1H NMR (400 MHz, CDC13): 5 = 10.26 (s, 1H), 7.90 (d, J = 6.80 Hz, 1H), 7.32-7.38 (m, 2H), 7.19-7.20 (m, 1H), 3.33 (d, J = 8.40 Hz, 2H), 2.62 (q, J = 15.60 Hz, 2H). 13C NMR (100 MHz,

CDC13): 5 = 22.91, 127.17, 127.62, 128.77, 131.38, 133.03, 134.55, 139.00, 139.08, 193.17. MS (ESI) m/z: 238.2 [M + H+], Anal. Calcd for Cl lH9BrO: C, 55.72; H, 3.83; Br, 33.70; O, 6.75. Found: C, 56.02; H, 3.99.

4-((3-methylbut-2-en-l-yl) thio)-2H-chromene-3-carbaldehyde (9)

Compound 9 was prepared accordingly to as per the general procedure used for compound 4 1H NMR (400 MHz, CDC13): 5 = 10.31 (s, 1H), 7.91-7.93 (m, 1H), 7.32-7.36 (m, 1H), 7.05-7.09 (m, 1H), 6.93 (d, J = 8.00 Hz, 1H), 5.11-5.16 (m, 1H), 4.90 (s, 1H), 3.33 (d, J = 8.40 Hz, 2H), 1.65 (s, 3H), 1.33 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 27.8, 28.6, 33.2, 37.3, 38.6, 62.9, 73.3, 78.1, 122.9, 123.28, 128.4, 129.0 135.0, 136.7, 137.0, 139.5, 140.9, 150.5, 167.7, 169.1,

198.4, 202.0. MS (ESI) m/z: 261.2 [M + H+], Anal. Calcd for C15H16O2S: C, 69.20; H, 6.19; O, 12.29; S, 12.32. Found: C, 69.55; H, 5.67. 7,7-dimethyl-6a,7,12,12a-tetrahydro-6H,13H-chromeno[3^,,4^,:5,61thiopyrano[4,3- bl quinoline (10a)

Compound 10a was prepared accordingly to as per the general procedure used for compound 6a Cis 1H NMR(400 MHz, CDC13 ): 5 7.31 (dd, J = 8.80, Hz, 1H), 7.16-7.21 (m, 2H), 7.01 (dd, J = 16.80, Hz, 1H), 6.93-6.97 (m, 1H), 6.87 (dd, J = 9.20, Hz, 1H), 6.70 (dd, J = 8.40, Hz, 1H), 6.48 (dd, J = 9.20, Hz, 1H), 4.91 (d, J = 13.60 Hz, 1H), 4.74 (d, J = 13.60 Hz, 1H), 4.13 (d, J = 2.80 Hz, 1H), 3.75 (s, 1H), 2.82 (t, J = 4.00 Hz, 2H), 1.84 (t, J = 10.80 Hz, 1H), 1.48 (s, 3H), 1.36 (s, 3H). 13C NMR (100 MHz, CDC13): 5C = 26.4, 26.4, 28.2, 33.2, 50.1, 57.9, 61.3, 113.6, 114.5, 117.3, 120.0, 121.5, 127.1, 127.8, 128.0, 128.1, 129.1, 130.1, 133.5, 137.2, 144.1, 157.3. MS (ESI) m/z: 335.3 [M + H+], Anal. Calcd for C21H21NOS: C, 75.19; H, 6.31; N, 4.18. Found: C, 75.50; H, 6.68, N, 4.52.

TranslH NMR(400 MHz, CDC13): 5 7.31 (dd, J = 8.80, Hz, 1H), 7.16-7.21 (m, 2H), 7.01 (dd, J = 16.80, Hz, 1H), 6.93-6.97 (m, 1H), 6.87 (dd, J = 9.20, Hz, 1H), 6.70 (dd, J = 8.40, Hz, 1H), 6.48 (dd, J = 9.20, Hz, 1H), 4.91 (d, J = 13.60 Hz, 1H), 4.74 (d, J = 13.60 Hz, 1H), 4.13 (d, J = 3.20 Hz, 1H), 3.77 (s, 1H), 2.83 (t, J = 12.80 Hz, 2H), 1.48 (s, 3H), 1.36 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 26.4, 26.4, 28.2, 33.2, 50.1, 57.9, 61.3, 113.6, 114.5, 117.3, 120.0, 121.5, 127.1, 127.8, 128.0, 128.1, 129.1, 130.1, 133.5, 137.2, 144.1, 157.3. MS (ESI) m/z: 335.3 [M + H+], Anal. Calcd for C21H21NOS: C, 75.19; H, 6.31; N, 4.18. Found: C, 75.50; H, 6.68, N, 4.52.

10-chloro-7,7-dimethyl-6a,7,12,12a-tetrahvdro-6H,13H-chromeno[3^,,4^,:5,61thiopyrano[4,3- bl quinoline (10b)

Compound 10b was prepared accordingly to as per the general procedure used for compound 6a Cis : 1H NMR (400 MHz, CDC13): 5 = 7.31 (dd, J = 9.20, Hz, 1H), 7.19 (dd, J = 17.20, Hz, 1H), 6.95 (dd, J = 16.40, Hz, 1H), 6.88 (t, J = 16.00 Hz, 2H), 6.69 (dd, J = 8.80, Hz, 1H), 6.40 (dd, J = 9.20, Hz, 1H), 6.48 (dd, J = 9.20, Hz, 1H), 4.87 (d, J = 13.60 Hz, 1H), 4.73 (d, J = 13.60 Hz, 1H), 4.02 (d, J = 2.00 Hz, 1H), 3.96 (s, 1H), 2.96-2.98 (m, 2H), 1.77 (s, 3H), 1.53 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 26.4, 26.4, 28.2, 33.2, 50.1, 57.9, 61.3, 113.6, 114.5, 117.3, 120.0, 121.5, 127.1, 127.8, 128.0, 128.1, 129.1, 130.1, 133.5, 137.2, 144.1, 157.3. MS (ESI) m/z: 371.2 [M + H+], Anal. Calcd for C21H20C1NOS: C, 68.19; H, 5.45; N, 3.79. Found: C, 68.55; H, 5.70, N, 4.01

Trans 1H NMR (400 MHz, CDC13): 5 = 7.31 (dd, J = 9.20, Hz, 1H), 7.19 (dd, J = 17.20, Hz, 1H), 6.95 (dd, J = 16.40, Hz, 1H), 6.88 (t, J = 16.00 Hz, 2H), 6.69 (dd, J = 8.80, Hz, 1H), 6.40 (dd, J = 9.20, Hz, 1H), 6.48 (dd, J = 9.20, Hz, 1H), 4.87 (d, J = 13.60 Hz, 1H), 4.73 (d, J = 13.60 Hz, 1H), 4.02 (d, J = 2.00 Hz, 1H), 3.96 (s, 1H), 2.96-2.98 (m, 2H), 1.77 (s, 3H), 1.53 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 26.4, 26.4, 28.2, 33.2, 50.1, 57.9, 61.3, 113.6, 114.5, 117.3, 120.0, 121.5, 127.1, 127.8, 128.0, 128.1, 129.1, 130.1, 133.5, 137.2, 144.1, 157.3. MS (ESI) m/z: 371.2 [M + H+], Anal. Calcd for C21H20C1NOS: C, 68.19; H, 5.45; N, 3.79. Found: C, 68.55; H, 5.70, N, 4.01.

9-bromo-7,7-dimethyl-6a,7,12,12a-tetrahvdro-6H,13H-chromeno[3^,,4^,:5,61thiopyrano[4,3- bl quinoline (10c)

Compound 10c was prepared accordingly to as per the general procedure used for compound 6a Cis/Trans: 1H NMR (400 MHz, CDC13): 5 = 7.31 (d, J = 1.20 Hz, 1H), 7.17-7.29 (m, 1H), 7.09 (dd, J = 10.80, Hz, 1H), 6.93-6.97 (m, 1H), 6.88 (d, J = 8.00 Hz, 1H), 6.36 (d, J = 8.40 Hz, 1H), 4.89 (d, J = 13.60 Hz, 1H), 4.73 (d, J = 13.60 Hz, 1H), 4.10 (d, J = 2.00 Hz, 1H), 3.81 (s, 1H), 3.96 (s, 1H), 2.80-2.83 (m, 1H), 2.70 (t, J = 24.80 Hz, 1H), 1.83 (d, J = 12.00 Hz, 1H), 1.44 (s, 3H), 1.34 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 22.8, 25.8, 29.6, 33.8, 35.7, 41.5, 47.0, 68.9, 109.3, 115.7, 115.9, 119.8, 121.6, 121.7, 123.9, 125.6, 128.7, 129.6, 129.8, 130.0, 139.2,

153.4. MS (ESI) m/z: 371.2 [M + H+], Anal. Calcd for C21H20C1NOS: C, 68.19; H, 5.45; N, 3.79. Found: C, 68.55; H, 5.70, N, 4.01.

10-fluoro-7,7-dimethyl-6a,7,12,12a-tetrahydro-6H,13H-chromeno[3',4':5,6]thiopyrano[4,3- b] quinoline (lOd)

Compound lOd was prepared accordingly to as per the general procedure used for compound 6a Cis/Trans :^XH NMR (400 MHz, CDC1₃): 5 = 7.32 (dd, J = 9.20, Hz, 1H), 7.16-7.21 (m, 1H), 6.97-7.03 (m, 1H), 6.93-6.96 (m, 1H), 6.86-6.89 (m, 1H), 6.70 (d, J= 8.80 Hz, 1H), 6.70 (dd, J = 8.40, Hz, 1H), 6.48 (dd, J = 9.20, Hz, 1H), 4.91 (d, J = 13.60 Hz, 1H), 4.74 (d, J = 13.60 Hz, 1H), 4.13 (d, J= 2.80 Hz, 1H), 3.76 (s, 1H), 2.79-2.83 (m, 2H), 1.84 (d, J= 10.80 Hz, 1H), 1.48 (s, 3H), 1.36 (s, 3H). ¹³C NMR (100 MHz, CDC1₃): 5 = 22.8, 25.8, 29.6, 33.8, 35.7, 41.5, 47.0, 68.9, 109.3, 115.7, 115.9, 119.8, 121.6, 121.7, 123.9, 125.6, 128.7, 129.6, 129.8, 130.0, 139.2,

153.4. MS (ESI) m/z-. 354.2 [M + H+], Anal. Calcd for C₂IH₂₀FNOS: C, 71.36; H, 5.70; N, 3.96. Found: C, 71.67; H, 6.05, N, 4.30.

7,7-dimethyl-9-(trifluoromethyl)-6a,7,12,12a-tetrahydro-6H,13H- chromeno[3', 4' :5,6]thiopyrano[4,3-b] quinoline (lOe)

Compound lOe was prepared accordingly to as per the general procedure used for compound 6a Cis/Trans: ‘ H NMR (400 MHz, CDCI3): 5 = 7.30-7.33 (m, 1H), 7.21-7.25 (m, 3H), 7.17 (d, J = 2.00 Hz, 1H), 7.04 (dd, J = 10.80, Hz, 1H), 6.55 (d, J = 8.40 Hz, 1H), 6.13 (s, 1H), 4.08-4.09 (m, 1H), 2.67-2.89 (m, 2H), 2.44 (t, J = 24.80 Hz, 1H), 2.26-2.35 (m, 1H), 1.78 (d, J = 12.00 Hz, 1H), 1.41 (s, 3H), 1.26 (s, 3H). ¹³C NMR (100 MHz, CDCI3): 5 = 25.56, 26.40, 27.34, 28.83, 33.07, 56.81, 59.10, 111.11, 115.32, 125.42, 126.13, 126.93, 127.62, 127.98, 130.37, 133.22, 137.08, 139.09, 142.38, 148.86. MS (ESI) m/z 404.2 [M + H+], Anal. Calcd for C₂2H₂oF₃NOS: C, 65.49; H, 5.00; F, 14.13; N, 3.47; O, 3.97; S, 7.95. Found: C, 65.33; H, 5.18; N, 3.30.

7,7-dimethyl-9-nitro-6a,7,12,12a-tetrahydro-6H,13H-chromeno[3',4':5,6]thiopyrano[4,3- b] quinoline (lOf)

Compound lOf was prepared accordingly as per the general procedure used for compound 6a Cis/Trans: ‘H NMR(400 MHz, CDC1₃): 5 = 7.31 (d, J = 6.00 Hz, 1H), 7.17-7.21 (m, 1H), 6.93- 6.97 (m, 1H), 6.88 (d, J= 8.80 Hz, 2H), 6.78 (d, J= 2.80 Hz, 1H), 6.65 (dd, J= 11.20, Hz, 1H), 6.47 (d, J = 8.40 Hz, 1H), 4.90 (d, J = 13.20 Hz, 1H), 4.74 (d, J = 13.60 Hz, 1H), 4.11 (s, 1H), 3.80 (s, 1H), 2.81-2.84 (m, 1H), 2.69-2.75 (m, 1H), 1.82-1.87 (m, 1H), 1.55 (s, 3H), 1.35 (s, 3H). ¹³C NMR (100 MHz, CDCI3): 5 = 26.4, 26.4, 28.2, 33.2, 50.1, 57.9, 61.3, 113.6, 114.5, 117.3, 120.0, 121.5, 127.1, 127.8, 128.0, 128.1, 129.1, 130.1, 133.5, 137.2, 144.1, 157.3. MS (ESI) m/z 381.2 [M + H+], Anal. Calcd for C21H20N2O3S: C, 66.29; H, 5.30; N, 7.36 Found: C, 66.58; H, 5.82, N, 7.79.

7,7,10-trimethyl-6a,7,12,12a-tetrahydro-6H,13H-chromeno[3',4':5,6]thiopyrano[4,3- b] quinoline (10g)

Compound 10g was prepared accordingly as per the general procedure used for compound 6a Cis/Trans : ‘H NMR (400 MHz, CDCI3): 5 = 7.32 (dd, J = 9.20, Hz, 1H), 7.18-7.22 (m, 1H), 6.94-6.98 (m, 1H), 6.93-6.97 (m, 1H), 6.87-6.91 (m, 2H), 6.70 (d, J= 8.80 Hz, 1H), 6.41 (dd, J = 9.20, Hz, 1H), 4.88 (d, J= 13.60 Hz, 1H), 4.74 (d, J= 13.60 Hz, 1H), 4.03 (s, 1H), 3.96 (s, 1H), 2.97-2.99 (m, 2H), 1.78 (s, 3H), 1.54 (s, 6H). ¹³C NMR (100 MHz, CDCI3): 5 = 22.8, 25.8, 29.6,

33.8, 35.7, 41.5, 47.0, 68.9, 109.3, 115.7, 115.9, 119.8, 121.6, 121.7, 123.9, 125.6, 128.7, 129.6,

129.8, 130.0, 139.2, 153.4. MS (ESI) m/z 350.2 [M + H+j. Anal. Calcd for C22H23NOS: C, 75.61; H, 6.63; N, 4.01. Found: C, 75.96; H, 6.95, N, 4.33.

Table-3: Silicotungstic acid- catalyzed synthesis of chromanone/ Thiocromanone derived thiochromeno[4,3-b] quinolines via ADAR

4-bromo-2H-thiochromene-3-carbaldehyde (12)

Compound 12 was prepared accordingly to as per the general procedure used for compound 2

‘H NMR (400 MHz, CDC13): 5 = 10.26 (s, 1H), 7.90 (d, J = 6.80 Hz, 1H), 7.32-7.38 (m, 2H), 7.19-7.20 (m, 1H), 3.33 (d, J = 8.40 Hz, 2H), 2.62 (q, J = 15.60 Hz, 2H). 13C NMR (100 MHz, CDC13): 5 = 22.91, 127.17, 127.62, 128.77, 131.38, 133.03, 134.55, 139.00, 139.08, 193.17. MS (ESI) m/z: 254.2 [M + H+], Anal. Calcd for Ci₀H₇BrOS: C, 47.08; H, 2.77; Br, 31.32; O, 6.27.

Found: C, 48.02; H, 2.99.

4-((3-methylbut-2-en-l-yl) thio)-2H-thiochromene-3-carbaldehyde (13)

Compound 12 was prepared accordingly to as per the general procedure used for compound 4

1H NMR (400 MHz, CDC1₃): 5 = 10.49 (s, 1H), 8.11-8.15 (m, 1H), 7.37-7.41 (m, 1H), 7.25-7.29 (m, 2H), 5.04 (t, J = 16.00 Hz, 1H), 3.57 (s, 2H), 3.19 (d, J = 8.00 Hz, 2H), 1.60 (s, 3H), 1.21 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 17.14, 23.86, 25.57, 33.03, 118.58, 125.78, 128.31, 130.24, 130.38, 132.37, 135.47, 137.50, 137.87, 149.92, 190.45. MS (ESI) m/z: 277.2 [M + H+], Anal. Calcd for C15H16OS2: C, 65.18; H, 5.83; O, 5.79; S, 23.20. Found: C, 65.52; H, 6.10.

7,7-dimethyl-6a,7,12,12a-tetrahydro-6H, 13H-thiochromeno [3', 4' : 5,6] thio pyrano [4,3- b] quinoline (14a)

Compound 14a was prepared accordingly to as per the general procedure used for compound 6a Cis/Trans: ‘H NMR (400 MHz, CDC1₃): 5 = 7.55-7.58 (m, 1H), 7.33-7.36 (m, 1H), 7.15-7.18 (m, 3H), 6.99-7.03 (m, 1H), 6.50-6.71 (m, 1H), 6.49 (d, J = 4.00 Hz, 1H), 4.34 (s, 1H), 3.83 (s, 1H), 3.64 (d, J= 16.00 Hz, 1H), 3.36 (d, J= 16.00 Hz, 1H), 2.77-2.80 (m, 2H), 1.90 (d, J= 8.00 Hz, 1H), 1.47 (s, 3H), 1.38 (s, 3H). ¹³C NMR (100 MHz, CDCI3): 5 = 19.12, 22.19, 24.36, 27.34, 33.07, 119.20, 126.93, 127.62, 127.98, 130.37, 133.22, 137.08, 139.09, 142.38, 148.86, 155.31. MS (ESI) m/z-. 352.2 [M + H+], Anal. Calcd for C₂IH₂INS₂: C, 71.75; H, 6.02; N, 3.98. Found: C, 72.13; H, 6.35; N, 4.27.

10-chloro-7,7-dimethyl-6a,7,12,12a-tetrahydro-6H,13H-thiochromeno[3',4':5,6]thiopyrano[4,3- b] quinoline (14b)

14b was to as per the

used for compound 6a

Cis/Trans ‘ H NMR (400 MHz, CDC13): 5 = 7.57-7.66 (m, 1H), 7.42-7.50 (m, 1H), 7.13-7.26 (m, 3H), 7.04 (dd, J = 8.5, 2.5 Hz, 1H), 6.53 (d, J = 8.5 Hz, 1H), 6.16 (s, 1H), 4.30 (d, J = 3.0 Hz, 1H), 3.76 (d, J = 14.6 Hz, 1H), 3.42 (d, J = 14.6 Hz, 1H), 2.89 (dd, J = 12.5, 1.0 Hz, 1H), 2.42- 2.48 (m, 1H), 1.78 (br d, J = 12.0 Hz, 1H), 1.40 (s, 3H), 1.28 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 19.24, 21.36, 25.71, 30.93, 34.10, 35.65, 41.94, 49.87, 106.90, 115.80, 124.08, 126.12, 127.80, 128.52, 129.37, 129.70, 132.40, 133.36, 140.98, 143.10, 150.33. MS (ESI) m/z: 387.1 [M + H+], Anal. Calcd for C21H20C1NS2: C, 65.35; H, 5.22; Cl, 9.19; N, 3.63; S, 16.62. Found: C, 65.91; H, 5.56; N, 3.89.

9-bromo-7,7-dimethyl-6a,7,12,12a-tetrahydro-6H,13H- thiochromeno [3' ,4' : 5,6] thiopyrano [4,3-b] quinoline ( 14C)

used for compound 6a

Cis/Trans NMR (400 MHz, DMSO-d6): 5 = 7.44-7.54 (m, 1H), 7.31-7.40 (m, 1H), 7.13- 7.26 (m, 3H), 7.04 (dd, J = 8.5, 2.5 Hz, 1H), 6.53 (d, J = 8.5 Hz, 1H), 6.16 (s, 1H), 4.30 (d, J = 3.0 Hz, 1H), 3.76 (d, J= 14.6 Hz, 1H), 3.42 (d, J= 14.6 Hz, 1H), 2.89 (dd, J= 12.5, 1.0 Hz, 1H), 2.42-2.48 (m, 1H), 1.78 (br d, J= 12.0 Hz, 1H), 1.40 (s, 3H), 1.28 (s, 3H). ¹³C NMR (100 MHz, DMSO-d6): 5 = 23.32, 25.71, 30.93, 34.10, 35.65, 41.94, 49.87, 106.90, 115.80, 124.08, 126.12, 127.80, 128.52, 129.37, 129.70, 132.40, 133.36, 140.98, 143.10, 150.33, 153.20. MS (ESI) m/z: 432.2 [M + H+], Anal. Calcd for C2iH₂oBrNS₂: C, 58.60; H, 4.68; N, 3.25. Found: C, 58.95; H, 5.05; N, 3.44.

10-fhioro-7,7-dimethyl-6a,7,12,12a-tetrahydro-6H,13H- thiochromeno [3' ,4' : 5,6] thiopyrano [4,3-b] quinoline ( 14d)

Compound 14d was prepared accordingly to as per the general procedure used for compound 6a Cis/Trans: ‘H NMR (400 MHz, CDC13): 5 = 7.32 (dd, J = 9.20, Hz, 1H), 7.16-7.21 (m, 1H), 6.97-7.03 (m, 1H), 6.93-6.96 (m, 1H), 6.86-6.89 (m, 1H), 6.70 (d, J = 8.80 Hz, 1H), 6.70 (dd, J = 8.40, Hz, 1H), 6.48 (dd, J = 9.20, Hz, 1H), 4.91 (d, J = 13.60 Hz, 1H), 4.74 (d, J = 13.60 Hz, 1H), 4.13 (d, J = 2.80 Hz, 1H), 3.76 (s, 1H), 2.79-2.83 (m, 2H), 1.84 (d, J = 10.80 Hz, 1H), 1.48 (s, 3H), 1.36 (s, 3H). 13C NMR (100 MHz, CDC13): 5 = 18.27, 20.56, 25.71, 30.93, 34.10, 35.65, 41.94, 49.87, 106.90, 115.80, 124.08, 126.12, 127.80, 128.52, 129.37, 129.70, 132.40, 133.36, 140.98, 143.10, 150.33. MS (ESI) m/z: 370.2 [M + H+], Anal. Calcd for C21H20FNS2: C, 68.26; H, 5.46; F, 5.14; N, 3.79; S, 17.36. Found: C, 68.57; H, 5.81; N, 4.12.

7,7-dimethyl-9-(trifluoromethyl)-6a,7,12,12a-tetrahydro-6H,13H- thiochromeno[3', 4' : 5,6] thiopyrano [4,3-b] quinoline (14e)

14e was

used

Cis/Trans: ‘H NMR (400 MHz, CDC1₃): 5 = 7.30-7.33 (m, 1H), 7.21-7.25 (m, 3H), 7.17 (d, J = 2.00 Hz, 1H), 7.04 (dd, J = 10.80, Hz, 1H), 6.55 (d, J = 8.40 Hz, 1H), 6.13 (s, 1H), 4.08-4.09 (m, 1H), 2.67-2.89 (m, 2H), 2.44 It, J = 24.80 Hz, 1H), 2.26-2.35 (m, 1H), 1.78 (d, J = 12.00 Hz, 1H), 1.41 (s, 3H), 1.26 (s, 3H). ^bC NMR (100 MHz, CDC1₃): 5 = 25.56, 26.40, 27.34, 28.83, 33.07, 56.81, 59.10, 111.11, 115.32, 125.42, 126.13, 126.93, 127.62, 127.98, 130.37, 133.22, 137.08, 139.09, 142.38, 148.86. MS (ESI) m z 420.2 [M + H+], Anal. Calcd for C₂₂H₂₀F₃NS₂: C, 62.99; H, 4.81; F, 13.59; N, 3.34; S, 15.28. Found: C, 62.83; H, 4.58; N, 3.30.

7,7-dimethyl-9-nitro-6a,7,12,12a-tetrahydro-6H,13H- thiochromeno [3' ,4' : 5,6] thiopyrano [4,3-b] quinoline ( 14f)

used for compound 6a

Cis/Trans: ‘H NMR (400 MHz, CDCI3): 5 = 7.31 (d, J= 6.00 Hz, 1H), 7.17-7.21 (m, 1H), 6.93- 6.97 (m, 1H), 6.88 (d, J= 8.80 Hz, 2H), 6.78 (d, J= 2.80 Hz, 1H), 6.65 (dd, J= 11.20, Hz, 1H), 6.47 (d, J = 8.40 Hz, 1H), 4.90 (d, J = 13.20 Hz, 1H), 4.74 (d, J = 13.60 Hz, 1H), 4.11 (s, 1H), 3.80 (s, 1H), 2.81-2.84 (m, 1H), 2.69-2.75 (m, 1H), 1.82-1.87 (m, 1H), 1.55 (s, 3H), 1.35 (s, 3H). ¹³C NMR (100 MHz, CDC1₃): 5 = 21.37, 23.56, 25.71, 30.93, 34.10, 35.65, 41.94, 49.87, 106.90, 115.80, 124.08, 126.12, 127.80, 128.52, 129.37, 129.70, 132.40, 133.36, 140.98, 143.10, 149.33. MS (ESI) m/z-. 381.2 [M + H+], Anal. Calcd for C₂iH₂oN₂0₃S: C, 66.29; H, 5.30; N, 7.36 Found: C, 66.58; H, 5.62, N, 7.70.

7,7,10-trimethyl-6a,7,12,12a-tetrahydro-6H,13H-thiochromeno[3',4':5,6]thiopyrano[4,3- b] quinoline (14g)

used for compound 6a

Cis/Trans: ‘ H NMR (400 MHz, CDCl₃j: 5 = 7.31 (dd, J = 9.20, Hz, 1H), 7.19 (dd, J = 17.20, Hz, 1H), 6.95 (dd, J = 16.40, Hz, 1H), 6.88 (t, J = 16.00 Hz, 2H), 6.69 (dd, J = 8.80, Hz, 1H), 6.40 (dd, J= 9.20, Hz, 1H), 6.48 (dd, J= 9.20, Hz, 1H), 4.87 (d, J= 13.60 Hz, 1H), 4.73 (d, J = 13.60 Hz, 1H), 4.02 (d, J = 2.00 Hz, 1H), 3.96 (s, 1H), 2.96-2.98 (m, 2H), 1.77 (s, 3H), 1.53 (s, 3H). ¹³C NMR (100 MHz, CDC1₃): 5 = 26.4, 28.2, 33.2, 50.1, 57.9, 61.3, 113.6, 114.5, 117.3, 120.0, 121.5, 127.1, 127.8, 128.0, 128.1, 129.1, 130.1, 133.5, 137.2, 144.1, 157.3. MS (ESI) m/z'. 386.2 [M + H+], Anal. Calcd for C₂IH₂₀C1NS₂: C, 65.35; H, 5.22; Cl, 9.19; N, 3.63; S, 16.62. Found: C, 65.68; H, 5.58; N, 3.98.

Claims

We Claim,

1. A compound of Formula I

Formula I or a salt there of, wherein,

X is CH₂ Oxygen or Sulphur;

2. The compound as claimed in claim 1 wherein X is CH₂

3. The compound as claimed in claim 1 or 2 wherein a compound is selected from group consisting of

7.7-dimethyl-6a,7, 12, 12a, 13, 14-hexahydro-6H-benzo[7,8]thiochromeno[4,3-b] quinolone; 9-chloro-7,7-dimethyl-6a,7,12,12a,13,14-hexahydro-6H-benzo [7,8] thiochromeno[4,3-b] quinolone;

7,7, 10-trimethyl-6a,7, 12, 12a, 13, 14-hexahydro-6H-benzo[7,8]thiochromeno[4,3- b] quinolone.

4. The compound as claimed in claim 1 wherein X is oxygen.

5. The compound as claimed in claim 1 or 4 wherein a compound is selected from group consisting of

7,7, 10-trimethyl-6a,7, 12, 12a-tetrahydro-6H, 13H-chromeno[3',4' : 5,6]thiopyrano[4,3- b] quinolone.

6. The compound as claimed in claim 1 wherein X is sulphur.

7. The compound as claimed in claim 1 or 6 wherein a compound is selected from group consisting of

7,7, 10-trimethyl-6a,7, 12, 12a-tetrahydro-6H, 13H-thiochromeno[3',4': 5,6]thiopyrano[4,3 - b] quinolone.

8. A pharmaceutical composition for treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome comprising a compound according to any one of the claims 1 to 7 or its pharmaceutically acceptable salt thereof and pharmaceutically suitable excipient or carrier.

9. A process for preparation of compound of Formula I comprising: a. preparation of compound Formula IV by reacting the compound Formula III with phosphorous tribromide and DMF in the presence of chloroform; b. then treating the compound of Formula IV with sodium hydrosulfide/sodium bisulfide and prenyl bromide to synthesize allyl thioether compound of Formula V by allylation; and c. then reacting the compound of Formula V with aniline compound 5 a-g in presence of silicotungstic acid and acetonitrile to get compound of Formula VI and then subjecting a compound of Formula VI for intermolecular ADAR to obtain the cis-trans mixture of a compound of Formula I; wherein, compound of Formula I is

compound of Formula II is

compound of Formula III is

compound of Formula IV is

compound of Formula V is

compound of Formula VI is

wherein,

X is CH₂, Oxygen, or Sulphur;

R2 is independently halo, -CN, -OH, -NO2⁺, Cl -3 alkyl, Cl-2fluoro alkyl, Cl -2 cyanoalkyl, C1.3 hydroxyalkyl, C1.3 aminoalkyl, C1.3 fluoro alkoxy, -cyclopropyl, cycloalkyl, morpholinyl, methylpyridine, imidazolyl, triazolyl, or thiazolyl. The process for the preparation of compound Formula I as claimed in claim 9 wherein X selected is CH2. The process for the preparation of compound Formula I as claimed in claim 9 wherein X selected is oxygen. The process for the preparation of compound Formula I as claimed in claim 9 wherein X selected is sulphur.

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