an efficient domino knoevenagel/hetero-diels–alder route to some novel thiochromenoquinoline-fused...

ORIGINAL PAPER

An efficient domino Knoevenagel/hetero-Diels–Alder routeto some novel thiochromenoquinoline-fused polyheterocycles

Narsidas J. Parmar • Balvantsingh M. Labana •

Hitesh A. Barad • Rajni Kant • Vivek K. Gupta

Received: 17 August 2013 / Accepted: 15 February 2014

� Springer-Verlag Wien 2014

Abstract The 2-alkenylthiopyranoquinoline-3-carbalde-

hyde derived from 2-mercaptoquinoline-3-carbaldehyde

and citral underwent smooth domino Knoevenagel/hetero-

Diels–Alder reaction with heterocyclic mono- or diketones

in tetrabutylammonium hydrogensulfate under solvent-free

conditions and afforded a new class of thiochromenoqui-

noline-fused heterocycles in good yields. The reaction is

highly diasteroselective and can be applied to analogues of

carbocyclic diketones as well. The stereochemistry of the

products was confirmed by single-crystal X-ray diffraction

and 2D NMR NOESY data.

Keywords Domino Knoevenagel/hetero-Diels–

Alder reaction � Thiochromeno[2,3-b]quinoline �Solvent-free � Tetrabutylammonium hydrogensulfate �Thia-Michael–Aldol reaction

Introduction

Quinoline-fused heterocycles are interesting biomolecules

of enormous importance in the development of medicinal

chemistry [1–10]. Chromenoquinolines, for example,

known to exhibit bacteriostatic and anti-inflammatory

activities [11, 12], have a potential estrogen receptor b-

selectivity. As glucocorticoids [13–15], they also have

therapeutic action in Alzheimer’s disease [16]. Their

reduced forms, dihydrochromenoquinolines, have desirable

tissue-selective profiles in rodents. They are effective in

fertility regulation and breast cancer treatment. Besides,

they are mixed-type electric eel acetylcholinesterase (Ee-

AChE) inhibitors [17] and active pharmacophores for

selective progesterone receptor modulators (SPRMS) [18].

The quinoline-fused thiopyrans, on the other hand, have

remarkable therapeutic profiles. Antioxidant 2H-thiopyr-

ano[2,3-b]quinoline-2-carboxylic acid [19], metabotropic

glutamate receptor antagonist 3,4-dihydro-2H-thiopyr-

ano[2,3-b]quinoline [20], and anticancer MT477 [21] are

potential candidates from this family. Chromenes are

inhibitors of many receptors [22–26]. Recently, thiochro-

menoquinolines were reported to have in vitro antihepatitis

B virus activity even higher than that of lamivudine [27].

Bioisosterism has been of notable interest in the drug

discovery process [28–30]. The replacement of the pyran

unit of antiproliferative pyranoquinolines [31–34] by a

thiopyran ring [35–37] may produce thiopyranoquinolines

with improved liophilicity as well as antioxidant properties

[38–41]. Moreover, thioflavones, as bioisosteres of flav-

ones, are relatively potent vasorelaxant agents [42].

In view of the above, it would seem quite probable that

the fusion of a quinoline ring to thiopyran in addition to the

presence of another pyran moiety would produce a mole-

cule having interesting bioprofiles. The domino

Knoevenagel/hetero-Diels–Alder (DKHDA) strategy [43–

53] is a powerful tool to construct pyran-annulated het-

erocycles. It has been applied to many olefin-ether-tethered

aldehyde substrates, which are derived from pyrazo-

lone, coumarin, quinoline, indole, pyran, and pyridine

[54, 55]. To the best of our knowledge, however, no

Electronic supplementary material The online version of thisarticle (doi:10.1007/s00706-014-1187-8) contains supplementarymaterial, which is available to authorized users.

N. J. Parmar (&) � B. M. Labana � H. A. Barad

Department of Chemistry, Sardar Patel University,

Vallabh Vidyanagar, 388120 Anand, Gujarat, India

e-mail: [email protected]

R. Kant � V. K. Gupta

Department of Physics, University of Jammu,

Jammu-Tawi 180006, India

123

Monatsh Chem

DOI 10.1007/s00706-014-1187-8

http://dx.doi.org/10.1007/s00706-014-1187-8

thiopyranoquinoline unit has been yet used in the strategy

[56–60]. So far, we have designed and employed deriva-

tives of salicylaldehyde and acetophenones in an improved

solvent-free DKHDA protocol [61–63]. In the present

work, we report 2-alkenyl-thiopyranoquinoline-3-carbal-

dehydes and their assemblies with mono/diketones in

tetrabutylammonium hydrogensulfate (TBA-HS) under

solvent-free conditions. All new thiochromeno-fused het-

erocycles are expected to display new bioprofiles. Further,

the use of a phase transfer catalyst is more effective and

eco-friendly. In combination with the atom-economic and

cost-effective qualities of the strategy, it will provide a

greener synthetic approach [64–72]. With its reduced

number of synthetic steps, careful use of resources, and

avoidance of toxic reagents and solvents [73–81], the

multicomponent domino strategy [82–89] afford many

bioactive molecules, natural products, and pharmaceuticals

[90–92].

Results and discussion

Both 2-methyl-2-(4-methyl-3-penten-1-yl)-2H-thiopyrano

[2,3-b]quinoline-3-carbaldehydes, 3a and 3b, were

obtained as new DKHDA dienophile-tethered-aldehyde

substrates in 73 and 81 % yields, respectively, by thia-

Michael–Aldol reaction [93–98] of the corresponding

2-mercaptoquinoline-3-carbaldehydes 1a and 1b with citral

(2) in ethylenediamine diacetate (EDDA) in refluxing tol-

uene (Scheme 1). The reaction between aldehyde 3a and

diketone 4a was considered as a model study to optimize

the reaction conditions displayed in Table 1 (Scheme 2).

The presence and absence of InCl3 (entries 1, 2), EDDA

(entry 3), LiClO4 (entries 5 and 9), and TBA-HS (entries 8,

11–14) in solvent-free conditions (entries 2 and 4) as well

as refluxing acetonitrile, xylene, and toluene were screened

to observe the reaction between 3a and 4a. Note that the

reaction performed in the absence and presence of CuI in

refluxing acetonitrile yielded traces of products (data not

shown). Table 1 reveals that TBA-HS in both the solvent-

free conditions and refluxing xylene improves the reaction.

With 20 mol% catalyst, the desired product was formed in

61 % yield (entry 11). Improved results were obtained by

using 25 mol% TBA-HS at 120 �C. Further increases in

the amount of catalyst did not improve the yield. Prolonged

(12 h) heating was the drawback of the reaction in catalyst-

and solvent-free conditions at 100 �C. Other products 5–14

were, thus, obtained by using 25 mol% TBA-HS in sol-

vent-free conditions at 120 �C (Table 2).

All new heterocycles 5, 7, 9, 11, 13, and 14 were

characterized by IR, 1H NMR, 13C NMR, and mass spectral

data. The cis-fusion between pyran and carbocyclic (of

thiochromeno) rings was found in all heterocycles. A sin-

glet in the d = 1.62–1.63 ppm range was assigned to

bridgehead methyl (8a-Me) protons. A doublet in the

3.57–3.94 ppm range with J = 1.6–8.4 Hz was attributed

to the Hb proton and multiplets in the 2.17–2.48 ppm range

to the Ha proton (Fig. 1). A singlet observed in the

5.93–6.14 ppm range was attributed to the thiopyran-

methine (16-CH) proton. The formation of regioisomers

13a–13d or 14a–14d was confirmed by the appearance of

the following 13C NMR peaks; one in the

d = 163–169 ppm range due to the lactone carbonyl in

13a–13d and another one in the 177–179 ppm range due to

the keto-carbonyl in 14a–14d. In the IR spectra, a char-

acteristic band due to the C–O–C linkage of pyran was

observed in the 1,110–1,165 cm-1 range. Similarly, the C–

S–C linkage of thiopyran showed a band in the

650–710 cm-1 range. The apparent correlation between

bridgehead Ha and Hb protons, found in the 2.0–4.0 ppm

range by NOESY (nuclear Overhauser effect spectroscopy)

Scheme 1

Table 1 Screening of experimental set-ups to optimize DKHDA

reaction between 3a and 4a

Entry Solvent Catalyst/mol% Temp/�C Time/h Yield/%

1 Acetonitrile InCl3 (10) Reflux 14 21

2 Acetonitrile – Reflux 15 Trace

3 Acetonitrile EDDA (20) Reflux 18 30

4 Toluene – Reflux 15 15

5 Xylene LiClO4 (10) Reflux 12 19

6 Xylene ZnO (20) Reflux 10 60

7 Xylene EDDA (20) Reflux 10 63

8 Xylene TBA-HS (25) Reflux 8 68

9 a LiClO4 (10) 100 12 60

10 a – 100 12 60

11 a TBA-HS (20) 100 8 61

12 a TBA-HS (25) 100 6 72

13 a TBA-HS (25) 120 5 86

14 a TBA-HS (35) 120 5 84

TBA-HS tetrabutylammonium hydrogen sulfatea Solvent-free

N. J. Parmar et al.

123

for 5a as a representative example, favors the cis-fusion

between pyran and central carbocyclic (of thiochromeno)

rings (Fig. 1). Finally, the stereochemistry of 5a was

unambiguously confirmed by the single-crystal X-ray dif-

fraction data (Figs. 2, 3).

In addition, the stereochemistry of the reaction was also

confirmed on the basis of the spectral data. In the present

work, the cis-fusion of the central pyran with the carbo-

cyclic (of thiochromeno) ring indicates that the reaction

proceeds via the most favored endo-E-syn transition state

out of the four possible states: exo-E-anti, endo-E-syn, exo-

Z-syn, and endo-Z-anti (Scheme 3) [43, 44].

Conclusion

We have described a highly efficient method for the

synthesis of new thiochromeno[2,3-b]quinoline-fused

heterocycles via DKHDA reaction in TBA-HS in sol-

vent-free conditions. None of the newly synthesized

heterocycles has had their biological properties evalu-

ated before, and they are anticipated to have interesting

new bioactivities. Further, the TBA-HS used in the work

contributed significantly to the development of this

environmentally friendly processes. Finally, the reaction

Scheme 2

Table 2 Synthesis of thiochromeno[2,3-b]quinolines 5–14

Entry Product R R1 X Time/h Yield/% M.p./�C

1 5a H Me – 5 86 183–185

2 5b Cl Me – 5 89 239–241

3 5c H H – 4.5 87 185–187

4 5d Cl H – 5 90 240–242

5 7a H – – 4 89 190–192

6 7b Cl – – 3.5 91 185–187

7 9a H H O 8 73 198–200

8 9b Cl H O 7.5 79 206–208

9 9c H Me O 6 85 223–225

10 9d Cl Me O 6 78 253–255

11 9e H H S 8 81 242–244

12 9f Cl H S 6 83 218–220

13 11a H – – 7 84 176–178

14 11b Cl – – 5 87 217–219

15 13a H – O 7.5 58 247–249

16 13b Cl – O 8.5 64 168–170

17 13c H – N–Ph 9 69 210–212

18 13d Cl – N–Ph 8.5 71 233–235

19 14a H – O – 36 239–241

20 14b Cl – O – 31 243–246

21 14c H – N–Ph – 23 173–175

22 14d Cl – N–Ph – 16 216–218

Domino Knoevenagel/hetero-Diels–Alder

123

proceeded exclusively through a diastereoselective

pathway as only cis-fused adducts were obtained as the

major products.

Experimental

All solvents and reagents were used as supplied from

commercial sources. IR spectra were recorded in KBr on a

Shimadzu FT-IR 8401 spectrometer and are reported in

wavenumbers (cm-1). 1H NMR and 13C NMR spectra were

recorded on a Bruker Avance 400 spectrometer operating

at 400 MHz for 1H NMR and 100 MHz for 13C NMR in

CDCl3, unless otherwise indicated. Chemical shifts are

reported as parts per million (d, ppm) and referenced to the

residual protic solvent. Coupling constants are reported in

hertz (Hz). Splitting patterns are designated as s, singlet; d,

doublet; t, triplet; q, quartet; br, broad; m, multiplet; comp,

complex multiplet. The degree of substitution (C, CH, CH2,

and CH3) was determined by the APT method. UV spectra

were record on a Shimadzu 160-A spectrometer. The ESI

mass spectra were measured on a Shimadzu LCMS-2010

spectrometer. TLC was performed on Merck 60 F254

precoated silica plates; spots were detected either by UV

(254 nm, 366 nm) or dipping into a permanganate (3 g

KMnO4, 20 g K2CO3, 5 cm3 5 % NaOH, 300 cm3 H2O) or

an anisaldehyde solution (3 % p-methoxybenzaldehyde

and 1 % H2SO4 in MeOH) or 2,4-dinitrophenylhydrazine

solution (12 g 2,4-DNP, 6 cm3 conc. H2SO4, 8 cm3 water,

20 cm3 EtOH) followed by heating.

General procedure for the synthesis of thiopyrano-

[2,3-b]quinoline-3-carbaldehydes 3a, 3b

To a solution of 2-mercaptoquinoline-3-carbaldehydes 1

(1.0 mmol) and citral (1.4 mmol) in 20 cm3 toluene was

added ethylenediamine diacetate (0.4 mmol) at room

temperature and the mixture was refluxed for 4–5 h. The

reaction mass was cooled to room temperature and then

evaporated to dryness under reduced pressure leaving an

oily residue, which was purified further by column chro-

matography on silica gel, using a n-hexane/ethyl acetate

mixture as eluent.

2-Methyl-2-(4-methyl-3-penten-1-yl)-2H-thiopyrano-

[2,3-b]quinoline-3-carbaldehyde (3a, C20H21NOS)

Yellow powder; yield 73 %; Rf = 0.48 (ethyl acetate/n-

hexane 1.5:8.5); m.p.: 70–72 �C; IR (KBr): �m = 3,053,

2,962, 2,853, 1,713, 1,689, 1,602, 1,475, 1,415, 1,374,

1,329, 1,249, 1,175, 1,141, 876, 739, 614 cm-1; 1H NMR

(400 MHz, CDCl3): d = 1.53 (s, 3H, CH3), 1.63 (s, 3H,

CH3), 1.69–1.79 (m, 2H, CH2), 1.84 (s, 3H, 2-CH3),

1.96–2.28 (m, 2H, CH2), 2.35 (s, 1H, 4-H), 5.04 (t, 1H,

J = 6.8 Hz, CH), 7.43–7.94 (m, 5H, Ar–H), 9.64 (s, 1H,

CHO) ppm; 13C NMR (100 MHz, CDCl3): d = 24.4, 25.5,

29.1, 41.8, 51.3, 123.1, 123.7, 126.2, 128.0, 128.5, 131.5,

134.5, 136.8, 137.0, 141.3, 145.4, 145.7, 149.2, 158.7,

191.3 ppm; MS (ESI): m/z = 324.2 ([M ? H]?).

8-Chloro-2-methyl-2-(4-methyl-3-penten-1-yl)-

2H-thiopyrano[2,3-b]quinoline-3-carbaldehyde

(3b, C20H20ClNOS)

Yellow powder; yield 81 %; Rf = 0. 46 (ethyl acetate/n-


2,853, 1,916, 1,713, 1,689, 1,602, 1,475, 1,415, 1,378,

1,329, 1,248, 1,196, 1,140, 876, 735, 618 cm-1; 1H NMR

(400 MHz, CDCl3): d = 1.44 (s, 3H, CH3), 1.57 (s, 3H,

CH3), 1.61–1.73 (m, 2H, CH2), 1.86 (s, 3H, 2-CH3),

2.04–2.31 (m, 2H, CH2), 2.33 (s, 1H, 4-H), 5.01 (t, 1H,

J = 6.8 Hz, CH), 7.56–8.42 (m, 4H, Ar–H), 9.63 (s, 1H,

CHO) ppm; 13C NMR (100 MHz, CDCl3): d = 24.4, 25.5,

29.2, 41.8, 51.3, 123.2, 123.7, 126.3, 128.0, 128.5, 131.5,

134.6, 136.8, 137.0, 141.3, 145.4, 145.8, 149.3, 158.7,

191.2 ppm; MS (ESI): m/z = 358.2 ([M ? H]?).

Fig. 1 Characteristic NOEs of 5a

Fig. 2 ORTEP view of compound 5a

N. J. Parmar et al.

123

Fig. 3 Crystal packing of 5a

Scheme 3


123

General experimental procedure for synthesis

of polycyclic thiochromeno[2,3-b]quinolines

5, 7, 9, 11, 13, 14

An equimolar quantity (3 mmol) of thiopyrano[2,3-b]quin-

oline-3-carbaldehyde 3a or 3b and heterocyclic monoketone

or cyclic or heterocyclic 1,3-diketone in TBA-HS

(0.75 mmol, 25 mol%) in a round-bottom flask was heated at

120 �C until the substrate 3 disappeared as monitored by

TLC. The products obtained were purified by column chro-

matography, using ethyl acetate/n-hexane mixture as eluent,

giving desired compounds 5, 7, 9, 11, 13, and 14. All pro-

ducts were characterized on the basis of their elemental,

mass, IR, 1H NMR, and 13C NMR spectral data.

3,3,6,6,8a-Pentamethyl-2,3,4,6a,7,8,8a,16b-octahydro-

1H,6H-chromeno[40,30:5,6]thiochromeno[2,3-b]-

quinolin-1-one (5a, C28H31NO2S)

White powder; yield 86 %; Rf = 0.24 (ethyl acetate/n-


2,950, 2,863, 1,715, 1,643, 1,614, 1,454, 1,387, 1,166, 1,065,

856, 754, 634 cm-1; 1H NMR (400 MHz, CDCl3): d = 1.11

(s, 3H, 3-CH3), 1.17 (s, 3H, 3-CH3), 1.23 (s, 3H, 6-CH3),

1.33 (s, 3H, 6-CH3), 1.62 (s, 3H, 8a-CH3), 1.76 (m, 4H, 7-

and 8-CH2), 2.17 (m, 1H, 6a-H), 2.28–2.55 (m, 4H, 2- and

4-CH2), 3.57 (d, 1H, J = 8.4 Hz, 16b-H), 5.93 (s, 1H, 16-H),

7.37–7.93 (m, 5H, Ar–H) ppm; 13C NMR (100 MHz,

CDCl3): d = 21.4, 21.7, 27.5, 28.4, 29.4, 30.0, 31.1, 32.3,

33.2, 39.7, 43.3, 48.4, 51.1, 81.4, 107.8, 121.5, 125.6, 126.6,

126.7, 127.4, 127.8, 129.2, 132.2, 143.3, 147.1, 158.3, 170.4,

196.6 ppm; MS (ESI): m/z = 446.3 ([M ? H]?).

Single-crystal X-ray diffraction data were collected on a

BRUKER CCD area-detector diffractometer equipped with

a graphite monochromatic MoKa radiation (k = 0.71073

A). The structure was solved by direct methods using

SHELXS 97 [99]. All non-hydrogen atoms in the molecule

were located in the best E-map. Compound 5a crystallizes

in the monoclinic space group C2/c with the following

unit-cell parameters: a = 15.0153(6) A, b = 15.1166(6)

A, c = 21.6071(10) A, b = 106.540(5)�, and Z = 8. The

crystal structure was solved by direct methods using single-

crystal X-ray diffraction data collected at room temperature

and refined by full-matrix least-squares procedures to a

final R value of 0.0574 for 2,749 observed reflections.

CCDC-942018 contains the supplementary crystallo-

graphic data for this paper, which can be obtained free of

charge from The Cambridge Crystallographic Data Centre

via www.ccdc.cam.ac.uk/data_request/cif.

12-Chloro-3,3,6,6,8a-pentamethyl-2,3,4,6a,7,8,8a,16b-

octahydro-1H,6H-chromeno[40,30:5,6]thiochromeno-

[2,3-b]quinolin-1-one (5b,C28H30ClNO2S)



2,950, 2,864, 1,710, 1,642, 1,612, 1,458, 1,384, 1,166,

1,063, 854, 753, 630 cm-1; 1H NMR (400 MHz, CDCl3):

d = 1.11 (s, 3H, 3-CH3), 1.18 (s, 3H, 3-CH3), 1.24 (s, 3H,

6-CH3), 1.33 (s, 3H, 6-CH3), 1.62 (s, 3H, 8a-CH3), 1.77 (m,

4H, 7- and 8-CH2), 2.16 (m, 1H, 6a-H), 2.28–2.54 (m, 4H,

2- and 4-CH2), 3.58 (d, 1H, J = 8.4 Hz, 16b-H), 5.93 (s,

1H, 16-H), 7.38-7.93 (m, 4H, Ar–H) ppm; 13C NMR

(100 MHz, CDCl3): d = 21.4, 21.7, 27.5, 28.4, 29.4, 30.1,

31.1, 32.3, 33.3, 39.8, 43.3, 48.4, 51.2, 81.4, 107.8, 121.5,

125.6, 126.6, 126.8, 127.4, 127.8, 130.2, 133.2, 143.3,

147.1, 158.3, 170.4, 196.6 ppm; MS (ESI): m/z = 480.2

([M ? H]?).

6,6,8a-Trimethyl-2,3,4,6a,7,8,8a,16b-octahydro-1H,6H-

chromeno[40,30:5,6]thiochromeno[2,3-b]

quinolin-1-one (5c, C26H27NO2S)

White powder; yield 87 %; Rf = 0.17(ethyl acetate/n-


2,990, 2,928, 1,665, 1,454, 1,380, 1,200, 1,165, 1,020, 753,

643 cm-1; 1H NMR (400 MHz, CDCl3): d = 1.16 (s, 3H,

6-CH3), 1.20 (s, 3H, 6-CH3), 1.28 (s, 3H, 8a-CH3), 1.77 (m,

4H, 7- and 8-CH2), 1.84-2.37 (m, 7H, 3 9 CH2 and 6a-H),

3.92 (d, 1H, J = 5.6 Hz, 16b-H), 5.94 (s, 1H, 16-H), 7.03-

7.81 (m, 5H, Ar–H) ppm; 13C NMR (100 MHz, CDCl3):

d = 17.9, 20.1, 23.7, 25.7, 26.1, 28.6, 33.9, 34.0, 38.5,

45.5, 49.8, 80.8, 111.3, 119.4, 120.1, 122.1, 123.3, 124.7,

126.8, 129.2, 138.1, 140.5, 149.9, 162.2, 165.6, 195.8 ppm;

MS (ESI): m/z = 418.1 ([M ? H]?).

12-Chloro-6,6,8a-trimethyl-2,3,4,6a,7,8,8a,16b-

octahydro-1H,6H-chromeno[40,30:5,6]thiochromeno-

[2,3-b]quinolin-1-one (5d, C26H26ClNO2S)



2,998, 2,932, 1,665, 1,456, 1,386, 1,210, 1,168, 1,018, 759,


6-CH3), 1.21(s, 3H, 6-CH3), 1.30 (s, 3H, 8a-CH3), 1.78 (m,

4H, 7- and 8-CH2), 1.83–2.38 (m, 7H, 3 9 CH2 and 6a-H),

3.93 (d, 1H, J = 5.6 Hz, 16b-H), 5.93(s, 1H, 16-H),


CDCl3): d = 18.0, 20.2, 23.8, 25.8, 26.1, 28.6, 33.6, 34.1,

38.5, 45.5, 49.8, 80.9, 111.4, 119.5, 120.1, 122.1, 123.4,

124.8, 126.9, 129.3, 138.2, 140.5, 150.0, 162.3, 165.7,

196.0 ppm; MS (ESI): m/z = 452.1 ([M ? H]?).

3-(2-Chlorophenyl)-1,5,5,7a-tetramethyl-3,5a,6,7,7a,15b-

hexahydro-5H-pyrazolo[400,300:50,60]pyrano[40,30:5,6]-

thiochromeno[2,3-b]quinoline (7a, C30H28ClN3OS)



2,979, 2,950, 2,926, 1,652, 1,598, 1,515, 1,392, 1,125, 752,


5-CH3), 1.47 (s, 3H, 5-CH3), 1.68 (s, 3H, 7a-CH3), 1.77-

2.11 (m, 4H, 6- and 7-CH2), 2.38 (s, 3H, 1-CH3), 2.41–2.52

N. J. Parmar et al.

123

http://www.ccdc.cam.ac.uk/data_request/cif

(m, 1H, 5a-H), 4.02 (d, 1H, J = 7.2 Hz, 15b-H), 6.56 (s,

1H, 15-H), 7.22–7.94 (m, 9H, Ar–H) ppm; 13C NMR

(100 MHz, CDCl3): d = 13.5, 20.8, 21.9, 28.4, 30.2, 31.9,

33.6, 41.1, 48.1, 85.0, 117.9, 120.0, 122.1, 125.2, 125.6,

126.2, 126.7, 127.1, 128.6, 130.1, 132.3, 134.8, 135.2,

143.5, 147.6, 147.9, 159.6 ppm; MS (ESI): m/z = 514.2

([M ? H]?).

11-Chloro-3-(3-chlorophenyl)-1,5,5,7a-tetramethyl-

3,5a,6,7,7a,15b-hexahydro-5H-pyrazolo[400,300:50,60]-

pyrano[40,30:5,6]thiochromeno[2,3-b]quinoline

(7b, C30H27Cl2N3OS)



2,929, 2,856, 1,607, 1,594, 1,505, 1,498, 1,387, 1,115,

1,078, 927, 881, 774, 752 cm-1; 1H NMR (400 MHz,

CDCl3): d = 1.27 (s, 3H, 5-CH3), 1.51 (s, 3H, 5-CH3), 1.63

(s, 3H, 7a-CH3), 1.81–2.11 (m, 4H, 6- and 7-CH2), 2.28 (s,

3H, 1-CH3), 2.40–2.47 (m, 1H, 5a-H), 3.69 (d, 1H,

J = 6.8 Hz, 15b-H), 6.35 (s, 1H, 15-H), 7.19–7.94 (m,

8H, Ar–H) ppm; 13C NMR (100 MHz, CDCl3): d = 13.3,

20.7, 22.0, 28.3, 30.3, 31.8, 33.4, 41.0, 48.0, 84.9, 117.7,

119.9, 121.9, 125.1, 125.1, 126.4, 126.8, 127.0, 128.7,

129.9, 132.1, 134.7, 135.3, 143.4, 147.5, 147.8, 159.4 ppm;

MS (ESI): m/z = 548.18 ([M ? H]?).

6,6,8a-Trimethyl-4,6a,7,8,8a,16b-hexahydro-1H,6H-

pyrimido[500,400:50,60]pyrano[40,30:5,6]thiochromeno-

[2,3-b]quinoline-1,3(2H)-dione (9a, C24H23N3O3S)

Orange powder; yield 73 %; Rf = 0.31 (ethyl acetate/n-


3,071, 2,954, 1,702, 1,625, 1,607, 1,594, 1,505, 1,498,

1,387, 1,115, 1,078, 881, 759 cm-1; 1H NMR (400 MHz,

CDCl3): d = 1.16 (s, 3H, 6-CH3), 1.51 (s, 3H, 6-CH3), 1.63

(s, 3H, 8a-CH3), 1.81–2.11 (m, 4H, 7- and 8-CH2),

2.40–2.47 (m, 1H, 6a-H), 3.69 (d, 1H, J = 6.8 Hz, 16b-

H), 6.15 (s, 1H, 16-H), 7.20–7.94 (m, 5H, Ar–H), 8.84 (s,

1H, 4-NH), 9.61 (s, 1H, 2-NH) ppm; 13C NMR (100 MHz,

CDCl3): d = 18.0, 23.0, 24.5, 27.1, 35.3, 45.9, 51.0, 57.6,

85.7, 117.7, 120.5, 124.4, 127.0, 127.7, 128.4, 128.7,

137.4, 142.5, 146.9, 149.9, 151.6, 156.1, 163.6 ppm; MS

(ESI): m/z = 434.2 ([M ? H]?).

12-Chloro-6,6,8a-trimethyl-4,6a,7,8,8a,16b-hexahydro-

1H,6H-pyrimido[500,400:50,60]pyrano[40,30:5,6]-

thiochromeno[2,3-b]quinoline-1,3(2H)-dione

(9b, C24H22ClN3O3S)

Off-white powder; yield 79 %; Rf = 0.24 (ethyl acetate/n-


3,078, 2,959, 1,704, 1,628, 1,610, 1,590, 1,510, 1,480,

1,382, 1,112, 1,076, 889, 753 cm-1; 1H NMR (400 MHz,

CDCl3): d = 1.17 (s, 3H, 6-CH3), 1.52 (s, 3H, 6-CH3), 1.65

(s, 3H, 8a-CH3), 1.80–2.12 (m, 4H, 6- and 7-CH2),

2.41–2.48 (m, 1H, 6a-H), 3.68 (d, 1H, J = 6.8 Hz, 16b-

H), 6.14 (s, 1H, 16-H), 7.21–7.95 (m, 4H, Ar–H), 8.85 (s,


CDCl3): d = 18.0, 23.0, 24.4, 27.1, 35.3, 45.9, 51.1, 57.6,

85.7, 117.6, 120.6, 124.4, 127.0, 127.6, 128.5, 128.6,

137.3, 142.6, 147.0, 149.9, 151.6, 156.1, 163.6 ppm; MS

(ESI): m/z = 468.1 ([M ? H2O]?).

2,4,6,6,8a-Pentamethyl-4,6a,7,8,8a,16b-hexahydro-


thiochromeno[2,3-b]quinoline-1,3(2H)-dione

(9c, C26H27N3O3S)



2,895, 1,698, 1,646, 1,489, 1,386, 1,353, 1,284, 1,145,

1,115, 1,069, 957, 763 cm-1; 1H NMR (400 MHz, CDCl3):

d = 1.30 (s, 3H, 6-H), 1.48 (s, 3H, 6-CH3), 1.64 (s, 3H, 8a-

CH3), 1.86–1.98 (m, 4H, 7- and 8-CH2), 2.00–2.34 (m, 1H,

6a-H), 3.42 (s, 3H, 4-CH3), 3.45 (s, 3H, 2-CH3), 3.69 (d,

1H, J = 1.6 Hz, 16b-H), 6.15 (s, 1H, 16-H), 7.27–7.91 (m,


24.1, 24.2, 28.1, 28.5, 28.9, 35.4, 47.9, 55.3, 58.7, 83.1,

85.0, 117.1, 121.6, 126.3, 127.4, 130.5, 131.9, 133.2,

137.4, 141.3, 147.1, 151.5, 157.3, 157.6, 161.9 ppm; MS

(ESI): m/z = 462.1 ([M ? H]?).

12-Chloro-2,4,6,6,8a-pentamethyl-4,6a,7,8,8a,16b-

hexahydro-1H,6H-pyrimido[500,400:50,60]pyrano-

[40,30:5,6]thiochromeno[2,3-b]quinoline-1,3(2H)-dione

(9d, C26H26ClN3O3S)



2,863, 1,703, 1,643, 1,479, 1,391, 1,374, 1,283, 1,144,

1,120, 1,068, 958, 769 cm-1; 1H NMR (400 MHz, CDCl3):

d = 1.29 (s, 3H, 6-H), 1.47 (s, 3H, 6-CH3), 1.63 (s, 3H, 8a-

CH3), 1.86-1.97 (m, 4H, 7- and 8-CH2), 2.00–2.33 (m, 1H,

6a-H), 3.41 (s, 3H, 4-CH3), 3.44 (s, 3H, 2-CH3), 3.68 (d,

1H, J = 1.6 Hz, 16b-H), 6.14 (s, 1H, 16-H), 7.28-7.92 (m,


24.0, 24.2, 28.1, 28.5, 28.8, 35.3, 47.8, 55.3, 58.6, 83.1,

84.9, 117.1, 121.5, 126.3, 127.4, 130.4, 131.9, 133.2,

137.4, 141.3, 147.1, 151.4, 157.3, 157.6, 161.9 ppm; MS

(ESI): m/z = 494.2 ([M - H]?).

6,6,8a-Trimethyl-3-thioxo-2,3,4,6a,7,8,8a,16b-octahydro-


thiochromeno[2,3-b]quinolin-1-one

(9e, C24H23N3O2S2)



3,071, 2,954, 1,702, 1,665, 1,607, 1,594, 1,505, 1,498,

1,387, 1,200, 1,078, 850, 759 cm-1; 1H NMR (400 MHz,

CDCl3): d = 1.18 (s, 3H, 6-CH3), 1.51 (s, 3H, 6-CH3), 1.65

(s, 3H, 8a-CH3), 1.81–2.11 (m, 4H, 7- and 8-CH2),

2.40–2.47 (m, 1H, 6a-H), 3.69 (d, 1H, J = 5.8 Hz, 16b-


123

H), 6.15 (s, 1H, 16-H), 7.20–7.94 (m, 5H, Ar–H), 8.84 (s,


CDCl3): d = 18.0, 23.0, 23.1, 27.1, 35.3, 51.2, 52.4, 57.6,

85.7, 88.1, 73.2, 117.7, 120.5, 124.4, 127.0, 127.7, 128.4,

128.7, 137.4, 142.7, 143.4, 149.9, 156.1, 162.6, 171.5 ppm;

MS (ESI): m/z = 448.2 ([M - H]?).

12-Chloro-6,6,8a-trimethyl-3-thioxo-2,3,4,6a,7,8,8a,

16b-octahydro-1H,6H-pyrimido[500,400:50,60]-

pyrano[40,30:5,6]thiochromeno[2,3-b]quinolin-1-one

(9f, C24H22ClN3O2S2)



3,075, 2,958, 1,703, 1,663, 1,606, 1,500, 1,510, 1,490,

1,385, 1,198, 1,075, 853, 758 cm-1; 1H NMR (400 MHz,

CDCl3): d = 1.17 (s, 3H, 6-CH3), 1.53 (s, 3H, 6-CH3), 1.66

(s, 3H, 8a-CH3), 1.81–2.12 (m, 4H, 7- and 8-CH2),

2.41–2.47 (m, 1H, 6a-H), 3.68 (d, 1H, J = 5.8 Hz, 16b-

H), 6.16 (s, 1H, 16-H), 7.20–7.94 (m, 4H, Ar–H), 8.84 (s,


CDCl3): d = 18.0, 23.1, 23.1, 27.1, 35.4, 51.3, 52.5, 57.7,

85.7, 88.1, 78.3, 117.6, 120.5, 124.4, 127.0, 127.7, 128.5,

128.8, 137.4, 142.6, 143.5, 149.9, 156.1, 162.7, 170.9 ppm;

MS (ESI): m/z = 458.0 ([M ? H]?).

6,6,8a-Trimethyl-6a,8,8a,16b-tetrahydro-6H-

indeno[200,100:50,60]pyrano[40,30:5,6]thiochromeno-

[2,3-b]quinolin-17(7H)-one (11a, C29H25NO2S)



2,958, 2,922, 1,706, 1,663, 1,606, 1,510, 1,490, 1,198,

1,075, 771, 653 cm-1; 1H NMR (400 MHz, CDCl3):

d = 1.20 (s, 3H, 6-CH3), 1.51 (s, 3H, 6-CH3), 1.68 (s,

3H, 8a-CH3), 1.83–2.15 (m, 4H, 7- and 8-CH2), 2.41–2.47

(m, 1H, 6a-H), 3.69 (d, 1H, J = 5.6 Hz, 16b-H), 6.19 (s,

1H, 16-H), 7.26–8.04 (m, 9H, Ar–H) ppm; 13C NMR

(100 MHz, CDCl3): d = 20.0, 23.7, 26.6, 28.8, 33.9, 50.8,

54.0, 58.8, 83.9, 115.6, 117.9, 118.7, 119.5, 119.6, 124.5,

126.5, 127.0, 127.7, 128.4, 128.8, 132.8, 132.7, 137.1,

138.5, 145.6, 149.9, 157.2, 165.3, 189.9 ppm; MS (ESI):

m/z = 452.1 ([M ? H]?).

12-Chloro-6,6,8a-trimethyl-6a,8,8a,16b-tetrahydro-6H-

indeno[200,100:50,60]pyrano[40,30:5,6]thiochromeno-

[2,3-b]quinolin-17(7H)-one (11b, C29H24ClNO2S)



2,960, 2,931, 1,706, 1,673, 1,611, 1,515, 1,496, 1,193,

1,070, 775, 659 cm-1; 1H NMR (400 MHz, CDCl3):

d = 1.21 (s, 3H, 6-CH3), 1.53 (s, 3H, 6-CH3), 1.69 (s,

3H, 8a-CH3), 1.82–2.16 (m, 4H, 7- and 8-CH2), 2.41–2.47

(m, 1H, 6a-H), 3.68 (d, 1H, J = 5.8 Hz, 16b-H), 6.19 (s,

1H, 16-H), 7.24–8.06 (m, 8H, Ar–H) ppm; 13C NMR

(100 MHz, CDCl3): d = 20.0, 23.8, 26.7, 28.9, 33.9, 50.8,

54.1, 58.9, 84.0, 115.7, 117.9, 118.8, 119.5, 119.7, 124.5,

126.6, 127.0, 127.7, 128.4, 128.8, 132.9, 132.7, 137.1,

138.5, 145.7, 150.0, 157.3, 165.3, 189.5 ppm; MS (ESI):

m/z = 484.2 ([M - H]?).

6,6,8a-Trimethyl-6a,8,8a,16b-tetrahydro-6H,7H,17H-

chromeno[300,400:50,60]pyrano[40,30:5,6]thiochromeno-

[2,3-b]quinolin-17-one (13a, C29H25NO3S)



2,976, 2,938, 2,870, 1,710, 1,610, 1,567, 1,462, 1,414,

1,391, 1,332, 1,258, 1,137, 1,039, 957, 757 cm-1; 1H NMR

(400 MHz, CDCl3): d = 1.32 (s, 3H, 6-CH3), 1.54 (s, 3H,

6-CH3), 1.69 (s, 3H, 8a-CH3), 1.91–2.12 (m, 4H, 7- and

8-CH2), 2.41–2.48 (m, 1H, 6a-H), 3.76 (d, 1H, J = 1.6 Hz,

16b-H), 6.19 (s, 1H, 16-H), 7.31–7.95 (m, 9H, Ar–H) ppm;13C NMR (100 MHz, CDCl3): d = 21.4, 21.7, 28.4, 30.1,

32.8, 33.2, 39.6, 48.3, 82.4, 98.5, 115.9, 116.6, 121.9,

123.0, 123.8, 125.7, 126.4, 126.7, 127.6, 127.8, 129.4,

131.9, 132.7, 141.4, 147.2, 153.0, 158.0, 160.7, 163.8 ppm;

MS (ESI): m/z = 468.2 ([M ? H]?).

12-Chloro-6,6,8a-trimethyl-6a,8,8a,16b-tetrahydro-

6H,7H,17H-chromeno[300,400:50,60]pyrano[40,30:5,6]-


(13b, C29H24ClNO3S)



2,978, 2,936, 2,865, 1,690, 1,615, 1,576, 1,491, 1,456,

1,390, 1,325, 1,275, 1,138, 1,076, 1,052, 918, 746,

635 cm-1; 1H NMR (400 MHz, CDCl3): d = 1.33 (s,

3H, 6-CH3), 1.55 (s, 3H, 6-CH3), 1.70 (s, 3H, 8a-CH3),

1.91–2.14 (m, 4H, 7- and 8-CH2), 2.41–2.49 (m, 1H, 6a-H),

3.78 (d, 1H, J = 1.6 Hz, 16b-H), 6.19 (s, 1H, 16-H),


CDCl3): d = 21.4, 21.7, 28.6, 30.2, 33.3, 39.6, 41.6, 43.5,

46.0, 48.3, 56.1, 56.9, 78.6, 82.5, 84.0, 85.2, 112.2, 116.8,

118.0, 121.9, 123.8, 125.8, 126.5, 126.9, 127.8, 148.4,

152.5, 156.2, 163.8 ppm; MS (ESI): m/z = 502.1

([M ? H]?).

6,6,8a-Trimethyl-18-phenyl-6a,7,8,8a,16b,18-hexahydro-

6H,17H-quino[300,400:50,60]pyrano[40,30:5,6]-


(13c, C35H30N2O2S)



2,958, 1,689, 1,618, 1,455, 1,389, 1,276, 1,137, 1,088, 916,

745, 634 cm-1; 1H NMR (400 MHz, CDCl3): d = 1.31 (s,

3H, 6-CH3), 1.54 (s, 3H, 6-CH3), 1.69 (s, 3H, 8a-CH3),

1.91–2.13 (m, 4H, 7- and 8-CH2), 2.40–2.48 (m, 1H, 6a-H),

3.79 (d, 1H, J = 1.6 Hz, 16b-H), 6.16 (s, 1H, 16-H),


CDCl3): d = 21.6, 26.0, 28.6, 33.9, 49.8, 57.7, 59.4, 80.5,

N. J. Parmar et al.

123

107.1, 114.0, 115.9, 118.3, 120.5, 120.6, 122.6, 123.2,

124.4, 124.9, 127.0, 127.7, 128.6, 128.8, 129.5, 130.3,

131.5, 135.6, 137.4, 139.9, 141.1, 149.9, 154.6, 157.5,

169.5 ppm; MS (ESI): m/z = 541.3 ([M - H]?).

12-Chloro-6,6,8a-trimethyl-18-phenyl-6a,7,8,8a,16b,

18-hexahydro-6H,17H-quino[300,400:50,60]-

pyrano[40,30:5,6]thiochromeno[2,3-b]quinolin-17-one

(13d, C35H29ClN2O2S)



2,960, 1,691, 1,620, 1,460, 1,386, 1,285, 1,125, 1,090, 918,


3H, 6-CH3), 1.53 (s, 3H, 6-CH3), 1.68 (s, 3H, 8a-CH3),

1.91–2.14 (m, 4H, 7- and 8-CH2), 2.41–2.49 (m, 1H, 6a-H),

3.80 (d, 1H, J = 1.6 Hz, 16b-H), 6.19 (s, 1H, 16-H),


CDCl3): d = 21.7, 26.2, 28.7, 33.9, 49.8, 57.7, 59.4, 80.6,

107.2, 114.1, 116.0, 118.4, 120.5, 120.6, 122.6, 123.3,

124.5, 125.0, 127.3, 127.9, 128.5, 128.9, 129.7, 130.7,

131.6, 135.7, 137.5, 139.8, 141.1, 152.9, 154.6, 157.6,

169.7 ppm; MS (ESI): m/z = 577.2 ([M ? H]?).

7,7,9a-Trimethyl-7a,9,9a,17b-tetrahydro-7H,8H,18H-

chromeno[300,200:50,60]pyrano[40,30:5,6]thiochromeno-

[2,3-b]quinolin-18-one (14a, C29H25NO3S)



2,976, 2,932, 2,861, 1,699, 1,618, 1,571, 1,490, 1,455,

1,389, 1,329, 1,276, 1,137, 1,078, 1,051, 916, 745,

634 cm-1; 1H NMR (400 MHz, CDCl3): d = 1.39 (s,

3H, 7-CH3), 1.57 (s, 3H, 7-CH3), 1.73 (s, 3H, 9a-CH3),

1.88–2.11 (m, 4H, 8- and 9-CH2), 2.43–2.46 (m, 1H, 7a-H),

3.94 (d, 1H, J = 1.6 Hz, 17b-H), 5.99 (s, 1H, 17-H),


CDCl3): d = 19.0, 24.1, 26.7, 29.1, 35.7, 42.0, 49.8, 50.5,

86.3, 94.4, 117.2, 117.7, 122.6, 122.8, 125.1, 125.5, 125.6,

125.8, 126.7, 127.4, 127.5, 129.2, 132.4, 133.0, 143.5,

153.4, 161.3, 163.8, 177.0 ppm; MS (ESI): m/z = 468.2

([M ? H]?).

13-Chloro-7,7,9a-trimethyl-7a,9,9a,17b-tetrahydro-

7H,8H,18H-chromeno[300,200:50,60]pyrano[40,30:5,6]-


(14b, C29H24ClNO3S)



2,975, 2,940, 2,875, 1,705, 1,615, 1,560, 1,466, 1,415,

1,390, 1,331, 1,258, 1,139, 1,035, 953, 759 cm-1; 1H NMR

(400 MHz, CDCl3): d = 1.39 (s, 3H, 7-CH3), 1.59 (s, 3H,

7-CH3), 1.74 (s, 3H, 9a-CH3), 1.88–2.12 (m, 4H, 8- and

9-CH2), 2.43–2.47 (m, 1H, 7a-H), 3.93 (d, 1H, J = 1.6 Hz,

17b-H), 5.99 (s, 1H, 17-H), 7.29–8.26 (m, 8H, Ar–H) ppm;13C NMR (100 MHz, CDCl3): d = 19.1, 21.5, 24.2, 26.8,

28.3, 29.2, 33.3, 35.7, 49.8, 86.3, 100.2, 116.6, 117.8,

121.8, 122.6, 123.7, 125.6, 125.8, 126.4, 129.3, 131.9,

141.4, 143.6, 147.8, 153.5, 158.1, 160.9, 163.9, 177.6 ppm;

MS (ESI): m/z = 502.2 ([M ? H]?).

7,7,9a-Trimethyl-5-phenyl-5,7a,8,9,9a,17b-hexahydro-

7H,18H-quino[300,200:50,60]pyrano[40,30:5,6]-


(14c, C35H30N2O2S)



2,960, 1,691, 1,623, 1,460, 1,386, 1,285, 1,115, 1,090, 918,


3H, 7-CH3), 1.59 (s, 3H, 7-CH3), 1.76 (s, 3H, 9a-CH3),

1.89–2.14 (m, 4H, 8- and 9-CH2), 2.44–2.49 (m, 1H, 7a-H),

3.96 (d, 1H, J = 1.6 Hz, 17b-H), 5.98 (s, 1H, 17-H),


CDCl3): d = 19.1, 21.5, 24.0, 25.3, 35.6, 48.4, 52.7, 58.7,

86.6, 91.3, 113.3, 114.7, 116.5, 118.5, 119.6, 120.3, 121.3,

123.9, 124.5, 124.7, 127.0, 127.2, 127.7, 128.4, 128.8,

131.9, 138.9, 141.8, 142.4, 146.0, 149.9, 157.0, 179.5 ppm;

MS (ESI): m/z = 543.2 ([M ? H]?).

13-Chloro-7,7,9a-trimethyl-5-phenyl-5,7a,8,9,9a,17b-

hexahydro-7H,18H-quino[300,200:50,60]-

pyrano[40,30:5,6]thiochromeno[2,3-b]-

quinolin-18-one (14d, C35H29ClN2O2S)



2,965, 1,699, 1,625, 1,465, 1,385, 1,285, 1,115, 1,099, 916,


3H, 7-CH3), 1.59 (s, 3H, 7-CH3), 1.78 (s, 3H, 9a-CH3),

1.89–2.16 (m, 4H, 8- and 9-CH2), 2.46–2.52 (m, 1H, 7a-H),

3.96 (d, 1H, J = 1.6 Hz, 17b-H), 6.02 (s, 1H, 17-H),


CDCl3): d = 19.1, 21.6, 24.5, 25.3, 35.7, 48.5, 52.7, 58.6,

86.7, 91.3, 113.3, 114.8, 116.6, 118.6, 119.7, 120.4, 121.3,

123.9, 124.5, 124.8, 127.1, 127.3, 127.9, 128.4, 128.8,

132.0, 138.9, 141.8, 142.5, 146.0, 150.0, 157.0, 179.8 ppm;

MS (ESI): m/z = 577.2 ([M ? H]?).

Acknowledgments The authors thank the Head of the Department

of Chemistry, S. P. University, for providing the necessary research

facilities, and the UGC (University Grants Commission), New Delhi,

for financial support under the UGC Scheme of Major Research

(Project Number 39-822/2010 (SR) dated 11.01.2011).

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an efficient domino knoevenagel/hetero-diels–alder route to some novel thiochromenoquinoline-fused...

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