Green approach to highly functionalized thiopyrano derivatives via domino multi-component reaction in water

Abstract

A green, operationally simple and highly efficient one pot three-component approach for the synthesis of thiopyrano[2,3-b]indole-3-carbonitrile, thiopyrano[2,3-b]thiochromene-3-carbonitrile and dihydrothiochromeno[2,3-b]thiochromene derivatives has been developed by the domino reaction of indoline-2-thione or 4-hydroxy-2H-thiochromene-2-thione with aldehyde and malononitrile or dimedone in water at 100 °C. The significant advantages of this protocol are highlighted by short reaction time, excellent yields and formation of three new bonds and a stereocenter in one operation from easily available starting materials.

---

Introduction

In recent years, due to growing environmental concerns, the design of straightforward and practical chemical syntheses of drugs and fine chemicals that satisfy economic and ecological criteria is a major challenge in industry. Water is cheap and environmentally benign and is the best option for solvents due to its non-toxic, non-corrosive and non-flammable nature.¹Water also possesses unique reactivity and selectivity. The green solvent water also eliminates some protection and deprotection processes for certain acidic hydrogen containing functional groups and offers an easy approach for the separation of environmentally unfriendly reagents and by-products.^1a,1b The elimination of catalyst and replacement of hazardous solvents with more benign solvents is now globally accepted. Catalyst-free reactions and use of environmentally benign solvent in multi-component syntheses are particularly attractive, because they incorporate many of the green chemistry principles.

Multi-component reactions (MCRs) are one-pot processes in which three or more reactants come together in a single reaction vessel to form a product containing substantial elements of all the reactants.² Thus, design of highly efficient chemical reaction sequences that provide maximum structural complexity and diversity with a minimum number of synthetic steps to synthesize compounds with interesting properties³ is important for drug discovery and natural product like compounds. Recently, the multi-component reactions have attracted considerable attention in combinatorial and medicinal chemistry and have been designed to produce biologically active compounds.⁴ The multi-component reactions are advantageous compared to linear stepwise synthesis because of possible structural variations, simplicity of a one-pot procedure, atom economy, and convergent character.⁵

Recently a wide range of biological activities associated with the sulphur-heterocycles scaffolds have been identified.⁶Thiopyran and fused-thiopyran derivatives are known to exhibit anti-inflammatory,⁷anti-bacterials,⁸anti-hyperplasia,⁹ antipsychiatric,¹⁰analgesic, and anti-cancer¹¹ activities and are widely present as key structural motifs in many natural products and are structurally related to plant pigments like flavonoids and anthocyanins. Thiopyran derivatives can act as modulators of the estrogen receptors¹² and are found to possess a high dopamine receptor binding affinity.¹³Indole subunits are frequently present in many biologically active natural products.¹⁴Thiopyranoindole-annulated heterocyclic compounds are important due to their biological activity. Tetrahydrothiopyrano[2,3-b] indole are known to have analgesic activity¹⁵ and their pharmaceutically acceptable salts are useful as psychoanaleptic and nootropic drugs.¹⁶

Results and discussion

In continuation of our work on the multi-component synthesis of heterocyclic compounds¹⁷ we have designed a unique synthetic route to privileged heterocyclic scaffolds of medicinal relevance that combine synthetic efficiency of multi-component protocols with the environmental benefit of using water as a reaction medium. Herein we report the results.

Thiopyrano[2,3-b]indole-3-carbonitrile derivatives (4a–m) have been synthesized in one pot by coupling various indoline-2-thione (1), aromatic aldehyde (2), malononitrile (3) in water at 100 °C in excellent yields (91–98%) without any additional reagent or catalyst (Scheme 1).

Scheme 1 Synthesis of thiopyrano[2,3-b]indole-3-carbonitrile derivatives.

We have carried out a series of experiments to standardize the reaction conditions for the efficient formation of bioactive heterocycles via a one-pot, three-component reaction and the results are presented in Table 1. Initial attempts were made by heating a mixture of indoline-2-thione (1a, 1 mmol), 4-methoxy benzaldehyde (2a, 1 mmol), malononitrile (3, 1 mmol) at 80 °C in ethanol in the presence of different catalysts such as InCl₃, AcOH, CuI, NH₄OAc (20 mole% each) separately (entries 1–4). No satisfactory result was obtained. Further attempts were made to carry out the same reaction in different solvents such as toluene, MeOH, THF, CH₃CN, CH₂Cl₂ at different temperatures in the absence of any catalyst (entries 5–9). The results showed that the reaction can proceed successfully even without a catalyst. With a view to determine the optimized conditions of the reaction we have carried out the same experiment in water using different reaction-times and temperatures (entries 11–13 and entries 14–15). The reaction did not occur at room temperature, only cyanoolefin A, formed in situ from Knoevenagel condensation of the aldehyde 2a and malononitrile 3 was obtained (entry 10). At lower temperature the reaction gives lower yield. From the various reaction conditions in Table 1 it is clear that the reaction in water gives the best result (98% yield) and higher reaction rate when heated at 100 °C for just 30 min (Table 1, entry 13).

Table 1 Effect of catalyst, temp, solvent and time on the yield of thiopyran derivatives

Entry	Catalyst (mol%)	T/°C	Solvent	Time (min)	Yield (%)^b
a Optimized reaction conditions. b Isolated yields.
1.	InCl3 (20)	80	EtOH	30	42
2.	AcOH (20)	80	EtOH	30	58
3.	CuI (20)	80	EtOH	30	37
4.	NH4OAc (20)	80	EtOH	30	72
5.	—	110	Toluene	30	62
6.	—	65	MeOH	30	59
7.	—	65	THF	30	51,
8.	—	80	CH3CN	30	65
9.	—	40	CH2Cl2	30	49
10.	—	r.t.	H2O	120	0
11.	—	100	H2O	10	62
12.	—	100	H2O	20	84
13. ^a	—	100	H2O	30	98
14.	—	80	H2O	30	71
15.	—	90	H2O	30	87

---

To explore the scope and generality of the one-pot Knoevenagal condensation/Michael addition/cyclization reaction, a range of thiopyrano[2,3-b]indole-3-carbonitrile derivatives were synthesized from a variety of substrates under the optimized reaction conditions. Three different types of indoline-2-thione (1), and a wide range of aldehydes (aromatic and heterocyclic), 2a–k were examined. Pleasingly all of them gave excellent yields of the desired products under the optimized reaction conditions. Table 2 shows that this protocol can be applied not only to electron rich but also electron-deficient aromatic aldehydes and heterocyclic aldehydes as electronic nature of the substituents on the aromatic ring of the aldehydes did not show any influence on the yield of the products of the reaction, thus demonstrating the wide scope of this methodology. However, a complex mixture of products with very close R_f values (TLC) were obtained in the case of aliphatic aldehyde from which the desired product could not be isolated, thus, limiting the scope of this reaction to a certain extent.

Table 2 Synthesis of various thiopyrano[2,3-b]indole-3-carbonitrile derivatives

Entry	R^1	R^2	Time (min)	Products	Yield^a(%)
a Isolated pure yield
1.	H	4-MeOC6H4 (2a)	30	4a	98
2.	H	4-MeC6H4 (2b)	30	4b	96
3.	H	4-BrC6H4 (2c)	35	4c	97
4.	H	C4H4S (2d)	40	4d	95
5.	Me	C6H5 (2e)	35	4e	97
6.	Me	4-ClC6H4 (2f)	30	4f	96
7.	Me	3-NO2C6H4 (2g)	40	4g	93
8.	Me	benzo[d][1,3]dioxole(2h)	35	4h	95
9.	Me	2-BrC6H4 (2i)	35	4i	91
10.	Me	2-OMe,5-ClC6H3 (2j)	40	4j	91
11.	Me	3,4-(OMe)2C6H3 (2k)	30	4k	94
12.	Me	4-MeOC6H4 (2a)	35	4l	93
13.	Et	4-MeC6H4 (2b)	30	4m	95

---

This reaction sequence is also extended to 4-hydroxy-2H-thiochromene-2-thione (5), aromatic aldehyde (2), and malononitrile (3) under the same reaction conditions as above. Although there is a possibility of the formation of benzopyran (7) and thiopyran derivatives (6), only thiopyrano[2,3-b]thiochromene-3-carbonitrile-4-one derivatives 6 were obtained in excellent yields. The electronic nature of the substituent on the aromatic ring of the aldehyde did not show any effect in this case too. The results in Table 3 show that as expected, S-alkylation is favored over O-alkylation making the protocol a highly regioselective one.

Table 3 Synthesis of various thiopyrano[2,3-b]thiochromene-3-carbonitrile derivatives

Entry	R^1	R^2	Time (min)	Products	Yield^a (%)
a Isolated pure yield
1.	H (5a)	4-MeOC6H4 (2a)	40	6a	89
2.	H (5a)	4-MeC6H4 (2b)	40	6b	88
3.	H (5a)	2-BrC6H4 (2i)	40	6c	83
4.	Cl (5b)	4-MeOC6H4 (2a)	40	6d	84

---

The structures of the products were characterized from their elemental analyses and spectral data. In IR-spectroscopy a peak at 2186 cm⁻¹ region indicates the presence of a –CN group and two peaks at 3390, 3381 cm⁻¹ indicate the presence of a –NH₂group. In the ¹H-NMR spectra, δ_H = 6.78 (s, 2H) and δ_H = 5.05 (s, 1H) show the presence of a NH₂ group and a quaternary proton for compound 4a. For compound 6a the δ_C = 175.0 shows the presence of a –CO group and hence confirmed the formation of thiopyran derivatives instead of benzopyran derivatives.

A highly efficient one-pot three-component regioselective synthesis of dihydrothiochromeno[2,3-b]thiochromene derivatives have also been developed by applying the same methodology (Table 4). Here 4-hydroxy-2H-thiochromene-2-thione (5) is treated with various aromatic aldehydes (2) and dimedone (8) at 100 °C in green solvent water to give the corresponding dihydrothiochromeno[2,3-b]thiochromene derivatives (9) in high yields. (86–94%)

Table 4 Synthesis of various dihydrothiochromeno [2,3-b]thiochromene derivatives

Entry	R^2	Time (min)	Products	Yield^a (%)
a Isolated pure yield
1.	C6H5 (2e)	45	9a	94
2.	benzo[d][1,3]dioxole (2h)	55	9b	89
3.	2-BrC6H4 (2i)	55	9c	87
4.	2-OMe,5-ClC6H3 (2j)	45	9d	86
5.	3,4-(OMe)2C6H3 (2k)	60	9e	93
6.	4-FC6H4 (2l)	60	9f	91

---

The formation of products 4, 6 and 9 in this green reaction may be rationalized by the initial formation of an intermediate cyanoolefin A (isolated as a solid) from the Knoevenagel condensation of 2 and 3. Michael addition of indoline-2-thione 1 to A may generate an intermediate B (not isolable) which on cyclocondensation may give the desired product 4. Similarly Michael addition of 4-hydroxy-2H-thiochromene-2-thione 5 to cyanoolefin A may form intermediate C which may undergo intramolecular cyclization either via S-alkylation (more likely) to furnish thiochromone derivatives 6 (observed) or via O-alkylation (less likely) to give chromone derivative 7 (not obtained) (Scheme 2). Like-wise, Knoevenagel condensation of 8 and 2 gives the enone intermediate D (isolated as a solid). Michael addition of 5 to D may give intermediate E which may be followed by an intramolecular cyclization to afford the product 9. The involvement of the intermediates A and D in this green reaction was also verified by carrying out separate reactions with the isolated intermediates (Scheme 3).

Scheme 2 Plausible mechanism for the thiochromene derivative.

Scheme 3 Synthesis of thiochromene derivatives from isolated intermediate A and D¹⁸.

A literature survey revealed that the reports of the synthesis of thiochromones are limited.^19–23 In our laboratory we have synthesized coumarin- and pyrone-annulated [6,6]-fused pyranothiopyrans using sequential Claisen rearrangements²⁴ and tributyl tin hydride-mediated radical cyclization²⁵ respectively. However, the above methods suffer from drawbacks such as toxic organic solvents, costly reagents, cumbersome experimental procedures, and lacking generality, expensive metal catalyst, long reaction time, multiple step and unsatisfactory yields etc. Very recently Singh et al.²⁶ reported the synthesis of 4-aryl-3-aroyl-2-methylsulfanyl-4,6,7,8-tetrahydrothiochromen-5-ones in good to moderate yields using β-oxodithioesters with aldehydes and cyclic 1,3-diketones using P₂O₅ as a catalyst at 100 °C for 2–3 h. To avoid those discrepancies there has been a need to develop an efficient and convenient methodology for the synthesis of thiochromone derivatives.

Conclusion

In summary, we have developed a simple and efficient method for the diversity-oriented synthesis of a series of thiopyrano[2,3-b]indole-3-carbonitrile, thiopyrano[2,3-b]thiochromene-3-carbonitrile and dihydrothiochromeno[2,3-b]thiochromene derivatives via a one-pot multi-component reaction in water from easily available starting materials without any catalyst. To the best of our knowledge, this is the first report of thiopyrano derivatives following green chemistry principles. The significant advantages of this protocol are shorter reaction time, generally excellent yields, easily available starting materials, use of environmentally benign solvent, operational simplicity and the reaction produces three new bonds and one stereocenter in one operation. Furthermore, the methodology is suitable for diversity oriented synthesis of potentially bioactive heterocycles. We believe that this would be suitable for the generation of a library of relevant natural products synthesis.

Experimental

Melting points were determined in open capillaries and are uncorrected. IR spectra were run for KBr discs on a Perkin-Elmer 120-000A apparatus (υ_max in cm⁻¹) and ¹H-NMR and ¹³C–NMR spectra were determined for solutions in CDCl₃ and DMSO-d₆ with TMS as an internal standard on a Bruker DPX-400. CHN was recorded on a 2400 series II CHN analyzer Perkin Elmer. HRMS and mass spectra were recorded on a Qtof Micro instrument. Silica gel (60–120 mesh) was used for chromatographic separation. Silica gel-G [E-Mark (India)] was used for TLC. Petroleum-ether refers to the fraction between 60 °C and 80 °C.

General procedure for the synthesis of thiopyrano derivatives 4

To a well-stirred suspension of the appropriate aromatic aldehyde 2 (1 equiv.) and malononitrile 3 (1 equiv.) in water (5 mL), indolin-2-thione 1 (1 equiv.) was added and the reaction mixture which was heated at 100 °C for 30–40 min. As the reaction proceeds the reaction mixture gradually becomes a deep brown color. After completion of the reaction as monitored by TLC the reaction mixture was cooled and diluted with 20 mL of water and extracted with ethyl acetate (3 × 25 mL) and dried over anhydrous Na₂SO₄. The solvent was distilled off. The resulting crude product was purified by filtration through a pad of silica gel (60–120 mesh) using 4 : 1 petroleum ether-ethyl acetate mixture as eluent to give the pure compounds (4).

2-Amino-4-(4-methoxyphenyl)-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4a)

Using the general procedure starting from 100 mg (0.671 mmol) of indoline-2-thione 1a, 91.3 mg (0.671 mmol) of 4-methoxybenzaldehyde 2a, 44.3 mg (0.671 mmol) of malononitrile 3, 219 mg of the title compound 4a was isolated as a grey colored solid, mp 178–180 °C, yield = 98%, IR (KBr): 3390, 3381, 3252, 2186, 1624, 1572 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 3.69 (s, 3H), 5.05 (s, 1H), 6.78 (s, 2H), 6.84 (d, 2H, J = 8.4 Hz), 6.90 (t, 1H, J = 7.6 Hz), 7.03 (t, 1H, J = 8.0 Hz), 7.18–7.25 (m, 3H), 7.29 (t, 1H, J = 7.6 Hz), 11.45 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 157.9, 151.3, 137.2, 136.6, 128.3, 125.3, 121.2, 120.4, 120.0, 119.1, 117.3, 113.8, 110.7, 107.9, 74.5, 54.9. HRMS (ESI+): calcd. For C₁₉H₁₅N₃OS: [M+Na⁺] 356.0834; found 356.0865.

2-Amino-4-p-tolyl-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4b)

Using the general procedure starting from 100 mg (0.671 mmol) of indoline-2-thione 1a, 80.5 mg (0.671 mmol) of 4-methylbenzaldehyde 2b, 44.3 mg (0.671 mmol) of malononitrile 3, 204 mg of the title compound 4b was isolated as a grey colored solid, mp 184–186 °C, yield = 96%, IR (KBr): 3394, 3284, 3200, 2188, 1624, 1573 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 2.22 (s, 3H), 5.04 (s, 1H), 6.77 (s, 2H), 6.89 (t, 1H, J = 7.2 Hz), 7.01 (t, 1H, J = 7.6 Hz), 7.07 (d, 2H, J = 7.6 Hz), 7.18–7.21 (m, 3H), 7.28 (d, 1H, J = 8.0 Hz), 11.43 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 151.5, 142.1, 136.5, 135.6, 129.0, 127.2, 125.3, 121.2, 120.5, 120.0, 119.1, 117.3, 110.7, 107.8, 74.3, 40.2, 20.6. MS: m/z = 339.9 [M+Na]⁺. Anal. Calcd. For C₁₉H₁₅N₃S: C, 71.90; H, 4.76; N, 13.24%. Found: C, 71.71; H, 4.90; N, 13.17%.

2-Amino-4-(4-bromophenyl)-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4c)

Using the general procedure starting from 100 mg (0.671 mmol) of indoline-2-thione 1a, 124.1 mg (0.671 mmol) of 4-bromobenzaldehyde 2c, 44.3 mg (0.671 mmol) of malononitrile 3, 248 mg of the title compound 4c was isolated as a grey colored solid, mp 192–194 °C, Yield = 97%, IR (KBr): 3374, 3273, 3191, 2191, 1627, 1582 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 5.13 (s, 1H), 6.88–6.92 (m, 3H), 7.03 (t, 1H, J = 7.6 Hz), 7.21 (d, 1H, J = 7.6 Hz), 7.29 (t, 3H, J = 7.2 Hz), 7.48 (d, 2H, J = 7.6 Hz), 11.50 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 151.9, 144.5, 136.6, 131.4, 129.5, 125.2, 121.3, 120.7, 119.8, 119.7, 119.3, 117.2, 110.8, 107.1, 73.4. MS: m/z = 381 [M⁺], 383 [M⁺+2]. Anal. Calcd. For C₁₈H₁₂BrN₃S: C, 56.55; H, 3.16; N, 10.99%. Found: C, 56.68; H, 3.26; N, 11.04%.

2-Amino-4-(thiophen-2-yl)-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4d)

Using the general procedure starting from 100 mg (0.671 mmol) of indoline-2-thione 1a, 75.2 mg (0.671 mmol) of thiophene-2-carbaldehyde 2d, 44.3 mg (0.671 mmol) of malononitrile 3, 197 mg of the title compound 4d was isolated as a grey colored solid, mp 178–180 °C, yield = 95%, IR (KBr): 3381, 3276, 3195, 2189, 1623, 1578 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 5.51 (s, 1H), 6.91 (s, 3H), 6.97 (t, 1H, J = 7.6 Hz), 7.05 (d, 2H, J = 7.6 Hz), 7.28 (d, 1H, J = 8.4 Hz), 7.32 (d, 1H, J = 8.0 Hz), 7.40 (d, 1H, J = 8.0 Hz), 11.49 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 152.4, 149.6, 136.5, 126.5, 125.2, 124.6, 123.7, 121.3, 120.7, 119.9, 119.3, 117.3, 110.8, 107.8, 73.9, 35.5. MS: m/z = 331.85 [M+Na]⁺. Anal. Calcd. For C₁₆H₁₁N₃S₂: C, 62.11; H, 3.58; N, 13.58%. Found: C, 62.33; H, 3.47; N, 13.61%.

2-Amino-9-methyl-4-phenyl-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4e)

Using the general procedure starting from 100 mg (0.613 mmol) of 1-methylindoline-2-thione 1b, 65 mg (0.613 mmol) of benzaldehyde 2e, 40.5 mg (0.613 mmol) of malononitrile 3, 188.6 mg of the title compound 4e was isolated as a grey colored glassy solid, mp 196–198 °C, yield = 97%, IR (KBr): 3428, 3314, 3213, 2188, 1634, 1575 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 3.71 (s, 3H), 4.57 (s, 2H), 5.19 (s, 1H), 7.01 (t, 1H, J = 7.6 Hz), 7.16–7.19 (m, 2H), 7.21 (s, 1H), 7.24 (d, 1H, J = 6.0 Hz), 7.29 (d, 2H, J = 8.8 Hz), 7.33 (d, 2H, J = 7.6 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 151.4, 144.9, 137.5, 128.5, 127.1, 126.6, 124.9, 123.0, 121.2, 119.9, 119.4, 117.4, 109.2, 107.5, 74.3, 40.8, 30.1. MS: m/z = 318.10 [M+H]⁺. Anal. Calcd. For C₁₉H₁₅N₃S: C, 71.90; H, 4.76; N, 13.24%. Found: C, 71.89; H, 4.63; N, 13.22%.

2-Amino-4-(4-chlorophenyl)-9-methyl-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4f)

Using the general procedure starting from 100 mg (0.613 mmol) of 1-methylindoline-2-thione 1b, 86 mg (0.613 mmol) of 4-cholorobenzaldehyde 2f, 40.5 mg (0.613 mmol) of malononitrile 3, 206.7 mg of the title compound 4f was isolated as a grey colored solid, mp 180–182 °C, yield = 96%, IR (KBr): 3311, 3216, 2193, 1632, 1581 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 3.71 (s, 3H), 4.61 (s, 2H), 5.17 (s, 1H), 7.01–7.05 (m, 1H), 7.18 (td, 2H, J = 1.2 Hz, 6.8 Hz), 7.23–7.28 (m, 5H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 151.5, 143.9, 137.6, 131.2, 129.0, 128.5, 124.8, 123.1, 121.3, 119.7, 119.5, 117.4, 109.3, 106.9, 73.7, 30.1. MS: m/z = 374.07 [M+Na]⁺. Anal. Calcd. For C₁₉H₁₄ClN₃S: C, 64.86; H, 4.01; N, 11.94%. Found: C, 64.89; H, 3.97; N, 11.99%.

2-Amino-9-methyl-4-(3-nitrophenyl)-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4g)

Using the general procedure starting from 100 mg (0.613 mmol) of 1-methylindoline-2-thione 1b, 92.6 mg (0.613 mmol) of 3-nitrobenzaldehyde 2g, 40.5 mg (0.613 mmol) of malononitrile 3, 206.5 mg of the title compound 4g was isolated as a light yellow fluffy solid, mp 182–184 °C, yield = 93%, IR (KBr): 3421, 3339, 3307, 2181, 1623, 1572 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 3.74 (s, 3H), 4.69 (s, 2H), 5.31 (s, 1H), 7.04 (d, 1H, J = 7.6 Hz), 7.19 (q, 2H, J = 8.0 Hz), 7.28 (d, 1H, J = 8.4 Hz), 7.49 (t, 1H, J = 8.0 Hz), 7.74 (d, 1H, J = 7.6 Hz), 8.08 (dd, 1H, J = 0.8 Hz, 8.0 Hz), 8.12 (d, 1H, J = 2.0 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 152.2, 147.9, 147.2, 137.6, 133.9, 130.2, 124.7, 123.4, 121.9, 121.5, 119.7, 119.6, 117.3, 109.4, 106.5, 73.1, 40.1, 30.2. MS: m/z = 384.83 [M+Na]⁺. Anal. Calcd. For C₁₉H₁₄N₄O₂S: C, 62.97; H, 3.89; N, 15.46%. Found: C, 62.96; H, 3.89; N, 15.39%.

2-Amino-4-(benzo[d][1,3]dioxol-5-yl)-9-methyl-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4h)

Using the general procedure starting from 100 mg (0.613 mmol) of 1-methylindoline-2-thione 1b, 92 mg (0.613 mmol) of benzo[d][1,3]dioxole-5-carbaldehyde 2h, 40.5 mg (0.613 mmol) of malononitrile 3, 210.4 mg of title compound 4h was isolated as light yellow fluffy solid, mp 190–192 °C, yield = 95%, IR (KBr): 3423, 3320, 3226, 2194, 1640, 1577 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 3.70 (s, 3H), 4.56 (s, 2H), 5.12 (s, 1H), 5.89 (dd, 2H, J = 1.2 Hz, 12.0 Hz), 6.72 (d, 2H, J = 8.4 Hz), 6.87 (dd, 1H, J = 2.0 Hz, 8.0 Hz), 7.03–7.05 (m, 1H), 7.17–7.19 (m, 1H), 7.22 (s, 1H), 7.25 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 151.1, 147.3, 145.9, 139.0, 137.5, 124.9, 122.9, 121.2, 120.1, 119.8, 119.4, 117.5, 109.2, 108.0, 107.5, 100.8, 79.1, 74.5, 40.4, 30.1. MS: m/z = 383.87 [M+Na]⁺. Anal. Calcd. For C₂₀H₁₅N₃O₂S: C, 66.46; H, 4.18; N, 11.63%. Found: C, 66.49; H, 4.17; N, 11.49%.

2-Amino-4-(2-bromophenyl)-9-methyl-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4i)

Using the general procedure starting from 100 mg (0.613 mmol) of 1-methylindoline-2-thione 1b, 113.4 mg (0.613 mmol) of 2-bromobenzaldehyde 2i, 40.5 mg (0.613 mmol) of malononitrile 3, 220.5 mg of the title compound 4i was isolated as a white solid, mp 208–210 °C, yield = 91%, IR (KBr): 3424, 3314, 3219, 2185, 1636, 1571 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 3.71 (s, 3H), 4.58 (s, 2H), 5.87 (s, 1H), 7.00–7.06 (m, 2H), 7.14–7.17 (m, 2H), 7.23–7.28 (m, 3H), 7.57 (d, 1H, J = 8.0 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 150.9, 143.8, 137.5, 132.4, 130.8, 128.9, 128.5, 124.9, 123.3, 121.6, 121.4, 119.7, 119.0, 117.0, 109.3, 106.3, 73.1, 40.1, 30.1. MS: m/z = 395 [M⁺], 397 [M⁺+2]. Anal. Calcd. For C₁₉H₁₄BrN₃S: C, 57.58; H, 3.56; N, 10.60%. Found: C, 57.51; H, 3.55; N, 10.48%.

2-Amino-4-(5-chloro-2-methoxyphenyl)-9-methyl-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4j)

Using the general procedure starting from 100 mg (0.613 mmol) of 1-methylindoline-2-thione 1b, 104.5 mg (0.613 mmol) of 5-chloro-2-methoxybenzaldehyde 2j, 40.5 mg (0.613 mmol) of malononitrile 3, 212.7 mg of the title compound 4j was isolated as a grey colored solid, mp 188–190 °C, Yield = 91%, IR (KBr): 3424, 3316, 3216, 2189, 1634, 1571 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 3.71 (s, 3H), 3.97 (s, 3H), 4.57 (s, 2H), 5.75 (s, 1H), 6.84 (d, 1H, J = 8.8 Hz), 7.01 (t, 1H, J = 2.8 Hz), 7.04 (s, 1H), 7.09 (dd, 1H, J = 2.4 Hz, 8.8 Hz), 7.15–7.19 (m, 1H), 7.24–7.29 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 154.6, 152.2, 137.5, 134.8, 128.0, 127.7, 124.7, 124.4, 123.5, 121.4, 119.6, 117.1, 113.3, 109.3, 106.8, 73.2, 56.1, 33.4, 30.1. MS: m/z = 404.01 [M+Na]⁺. Anal. Calcd. For C₂₀H₁₆ClN₃OS: C, 62.90; H, 4.22; N, 11.00%. Found: C, 62.79; H, 4.12; N, 11.10%.

2-Amino-4-(3,4-dimethoxyphenyl)-9-methyl-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4k)

Using the general procedure starting from 100 mg (0.613 mmol) of 1-methylindoline-2-thione 1b, 101.8 mg (0.613 mmol) of 3,4-dimethoxybenzaldehyde 2k, 40.5 mg (0.613 mmol) of malononitrile 3, 217.4 mg of the title compound 4k was isolated as a colorless solid, mp 172–174 °C, yield = 94%, IR (KBr): 3416, 3356, 3258, 2192, 1621, 1588 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 3.70 (s, 6H), 3.76 (s, 3H), 5.09 (s, 1H), 6.85 (s, 2H), 6.88 (s, 2H), 6.98 (s, 2H), 7.09 (t, 1H, J = 7.6 Hz), 7.34 (d, 1H, J = 7.6 Hz), 7.42 (d, 1H, J = 8.0 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 151.1, 148.5, 147.6, 137.5, 137.5, 124.9, 122.8, 121.2, 119.9, 119.4, 119.1, 117.6, 111.9, 111.2, 109.2, 107.8, 74.6, 55.4, 40.4, 30.1. MS: m/z = 416.11 [M+K]⁺. Anal. Calcd. For C₂₁H₁₉N₃O₂S: C, 66.82; H, 5.07; N, 11.13%. Found: C, 66.79; H, 5.06; N, 11.12%.

2-Amino-4-(4-methoxyphenyl)-9-methyl-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4l)

Using the general procedure starting from 100 mg (0.613 mmol) of 1-methylindoline-2-thione 1b, 83.4 mg (0.613 mmol) of 4-methoxybenzaldehyde 2a, 40.5 mg (0.613 mmol) of malononitrile 3, 198 mg of the title compound 4l was isolated as a grey colored solid, mp 184–186 °C, yield = 93%, IR (KBr): 3392, 3386, 3252, 2181, 1622, 1573 cm⁻¹ cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 3.70 (s, 3H), 3.75 (s, 3H), 4.55 (s, 2H), 5.15 (s, 1H), 6.81 (d, 2H, J = 8.4 Hz), 7.01 (t, 1H, J = 7.2 Hz), 7.14–7.21 (m, 2H), 7.24 (d, 2H, J = 2.4 Hz), 7.25 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 158.0, 150.9, 137.5, 137.1, 128.2, 124.9, 122.8, 121.2, 119.9, 119.4, 117.5, 113.8, 109.2, 107.7, 74.7, 54.9, 30.1. MS: m/z = 347 [M⁺]. Anal. Calcd. For C₂₀H₁₇N₃OS: C, 69.14; H, 4.93; N, 12.09%. Found: C, 69.11; H, 4.92; N, 12.09%.

2-Amino-9-ethyl-4-p-tolyl-4,9-dihydrothiopyrano[2,3-b]indole-3-carbonitrile (4m)

Using the general procedure starting from 100 mg (0.565 mmol) of 1-ethylindoline-2-thione 1c, 67.8 mg (0.565 mmol) of 4-methylbenzaldehyde 2b, 37.3 mg (0.565 mmol) of malononitrile 3, 185.2 mg of title compound 4m was isolated as colorless solid, mp 156–158 °C, yield = 95%, IR (KBr): 3426, 3320, 3219, 2177, 1629, 1567 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.28 (t, 3H, J = 8.8 Hz), 2.23 (s, 3H), 4.12–4.18 (m, 2H), 5.12 (s, 1H), 6.91 (s, 2H), 6.97 (t, 1H, J = 7.6 Hz), 7.08–7.13 (m, 3H), 7.23 (d, 2H, J = 8.0 Hz), 7.29 (d, 1H, J = 7.6 Hz), 7.45 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 150.9, 141.9, 136.5, 135.7, 129.0, 127.0, 125.2, 121.7, 121.2, 119.8, 119.4, 117.6, 109.1, 107.8, 74.6, 40.5, 30.6, 20.5, 15.0. HRMS (ESI+): calcd. For C₂₁H₁₉N₃S: [M+Na⁺] 368.1198; found 368.1969.

General Procedure for synthesis of thiopyrano derivatives 6

To a well-stirred suspension of the appropriate aromatic aldehyde 2 (1 equiv) and malononitrile 3 (1 equiv) in water (5 mL) appropriate 4-hydroxy-2H-thiochromene-2-thione 5 (1 equiv) was added and the reaction mixture was heated at 100 °C for 40 min. As the reaction progressed the reaction mixture becomes partly water soluble and a deep yellow oily layer appeared in the upper portion of water layer. After completion of the reaction as monitored by TLC the reaction mixture was cooled and diluted with 20 mL of water and extracted with ethyl acetate (3 × 25 mL) and dried over anhydrous Na₂SO₄. The solvent was distilled off. The resulting crude product was purified by filtration through a pad of silica gel (60–120 mesh) using 4 : 1 petroleum ether-ethyl acetate mixture as the eluent to give the pure compounds (6).

2-Amino-4-(4-methoxyphenyl)-5-oxo-4,5-dihydrothiopyrano[2,3-b]thiochromene-3-carbonitrile (6a)

Using the general procedure starting from 100 mg (0.515 mmol) of 4-hydroxy-2H-thiochromene-2-thione 5a, 70 mg (0.515 mmol) of 4-methoxybenzaldehyde 2a, 34 mg (0.515 mmol) of malononitrile 3, 173.4 mg of the title compound 6a was isolated as a grey colored solid, mp 224–226 °C, yield = 89%, IR (KBr): 3382, 3311, 3214, 2198, 1648, 1605, 1588 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 3.68 (s, 3H), 5.35 (s, 1H), 6.84 (d, 2H, J = 8.8 Hz), 7.17 (d, 2H, J = 8.4 Hz), 7.27 (s, 2H), 7.63 (t, 1H, J = 7.6 Hz), 7.75 (t, 1H, J = 7.2 Hz), 7.84 (d, 1H, J = 8.0 Hz), 8.34 (d, 1H, J = 8.0 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 175.0, 158.3, 152.4, 142.1, 135.2, 133.0, 132.4, 130.5, 129.6, 128.8, 128.4, 127.7, 126.2, 119.2, 114.0, 73.0, 55.0, 40.5. MS: m/z = 400.82 [M+Na]⁺. Anal. Calcd. For C₂₀H₁₄N₂O₂S₂: C, 63.47; H, 3.73; N, 7.40%. Found: C, 63.46; H, 3.71; N, 7.43%.

2-Amino-5-oxo-4-p-tolyl-4,5-dihydrothiopyrano[2,3-b]thiochromene-3-carbonitrile (6b)

Using the general procedure starting from 100 mg (0.515 mmol) of 4-hydroxy-2H-thiochromene-2-thione 5a, 62 mg (0.515 mmol) of 4-methylbenzaldehyde 2b, 34 mg (0.515 mmol) of malononitrile 3, 164 mg of the title compound 6b was isolated as a grey colored solid, mp 258–260 °C, yield = 88%, IR (KBr): 3370, 3309, 3205, 2201, 1643, 1610, 1585 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 2.22 (s, 3H), 5.38 (s, 1H), 7.09 (d, 4H, J = 11.6 Hz), 7.27 (s, 2H), 7.65 (d, 1H, J = 7.6 Hz), 7.77 (t, 1H, J = 6.8 Hz), 7.87 (d, 1H, J = 7.6 Hz), 8.34 (d, 1H, J = 7.6 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 175.0, 152.5, 142.4, 138.0, 136.3, 135.2, 132.4, 130.4, 129.6, 129.2, 128.8, 128.4, 126.5, 126.2, 119.2, 72.8, 40.9, 20.5. MS: m/z = 384.83 [M+Na]⁺. Anal. Calcd. For C₂₀H₁₄N₂OS₂: C, 66.27; H, 3.89; N, 7.73%. Found: C, 66.17; H, 3.91; N, 7.62%.

2-Amino-4-(2-bromophenyl)-5-oxo-4,5-dihydrothiopyrano[2,3-b]thiochromene-3-carbonitrile (6c)

Using the general procedure starting from 100 mg (0.515 mmol) of 4-hydroxy-2H-thiochromene-2-thione 5a, 95.3 mg (0.515 mmol) of 2-bromobenzaldehyde 2i, 34 mg (0.515 mmol) of malononitrile 3, 182 mg of the title compound 6c was isolated as a grey colored solid, mp 226–228 °C, yield = 83%, IR (KBr): 3425, 3349, 3185, 2212, 1663, 1621, 1571 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 5.77 (s, 1H), 7.14 (t, 1H, J = 7.6 Hz), 7.19 (s, 2H), 7.24 (t, 1H, J = 7.6 Hz), 7.34 (d, 1H, J = 7.6 Hz), 7.61 (t, 2H, J = 8.0 Hz), 7.77 (t, 1H, J = 8.0 Hz), 7.90 (d, 1H, J = 8.0 Hz), 8.25 (d, 1H, J = 8.0 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 160.6, 159.1, 142.0, 136.3, 133.1, 132.8, 131.4, 129.9, 129.0, 128.5, 128.1, 126.2, 123.0, 120.8, 115.7, 80.3, 72.4, 40.6. MS: m/z = 426 [M⁺], 428 [M⁺+2]. Anal. Calcd. For C₁₉H₁₁BrN₂OS₂: C, 53.40; H, 2.59; N, 6.56%. Found: C, 53.39; H, 2.49; N, 6.71%.

2-Amino-8-chloro-4-(4-methoxyphenyl)-5-oxo-4,5-dihydrothiopyrano[2,3-b]thiochromene-3-carbonitrile (6d)

Using the general procedure starting from 100 mg (0.437 mmol) of 7-chloro-4-hydroxy-2H-thiochromene-2-thione 5b, 59.5 mg (0.437 mmol) of 4-methoxybenzaldehyde 2a, 29 mg (0.437 mmol) of malononitrile 3, 151 mg of the title compound 6d was isolated as a grey colored solid, mp 210–212 °C, yield = 84%, IR (KBr): 3389, 3305, 3211, 2199, 1651, 1604, 1581 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 3.69 (s, 3H), 5.33 (s, 1H), 6.85 (d, 2H, J = 8.8 Hz), 7.17 (d, 2H, J = 8.4 Hz), 7.29 (s, 2H), 7.68 (dd, 1H, J = 8.8 Hz, 2.4 Hz), 8.14 (d, 1H, J = 2.0 Hz), 8.32 (d, 1H, J = 8.8 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 174.4, 158.3, 152.2, 142.3, 137.5, 136.9, 132.8, 130.8, 130.6, 128.7, 128.4, 127.7, 125.5, 119.1, 114.0, 72.9, 55.0, 40.5. MS: m/z = 412 [M⁺]. Anal. Calcd. For C₂₀H₁₃ClN₂O₂S₂: C, 58.18; H, 3.17; N, 6.78%. Found: C, 58.19; H, 3.23; N, 6.88%.

General procedure for synthesis of thiopyrano derivatives 9

To a well-stirred suspension of the appropriate aromatic aldehyde 2 (1 equiv) and dimedone 8 (1 equiv) in water (5 mL) 4-hydroxy-2H-thiochromene-2-thione 5 (1 equiv) was added and the reaction mixture was heated at 100 °C for 45–60 min. As the reaction progressed the reaction mixture becomes partly water soluble and a deep yellow oily layer appeared in the upper portion of water layer. After completion of the reaction as monitored by TLC the reaction mixture was cooled and diluted with 20 mL of water and extracted with ethyl acetate (3 × 25 mL) and dried over anhydrous Na₂SO₄. The solvent was distilled off. The resulting crude product was purified by filtration through a pad of silica gel (60–120 mesh) using 9 : 1 petroleum ether-ethyl acetate mixture as the eluent to give the pure compounds (9).

3,3-Dimethyl-12-phenyl-3,4-dihydrothiochromeno[2,3-b]thiochromene-1,11(2H,12H)-dione (9a)

Using the general procedure starting from 100 mg (0.515 mmol) of 4-hydroxy-2H-thiochromene-2-thione 5a, 54.6 mg (0.515 mmol) of benzaldehyde 2e, 72.2 mg (0.515 mmol) of dimedone 8, 195.7 mg of the title compound 9a was isolated as a red colored solid, mp 134–136 °C, yield = 94%, IR (KBr): 1663, 1589 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 8.43 (d, 1H, J = 8.0 Hz), 7.52 (q, 1H, J = 7.2 Hz), 7.44 (t, 4H, J = 8.0 Hz), 7.19 (t, 2H, J = 7.6 Hz), 7.11 (t, 1H, J = 7.6 Hz), 6.25 (s, 1H), 2.66 (d, 1H, J = 17.6 Hz), 2.36–2.46 (m, 3H), 1.11 (s, 3H), 0.97 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ_C = 193.0, 176.1, 147.1, 142.4, 141.5, 135.5, 131.6, 131.1, 130.7, 129.9, 129.7, 128.4, 128.1, 128.0, 127.7, 126.9, 125.2, 51.5, 43.6, 37.0, 33.9, 29.5, 26.4. MS: m/z = 427.11 [M+Na]⁺. Anal. Calcd. For C₂₄H₂₀O₂S₂: C, 71.25; H, 4.98%. Found: C, 71.21; H, 5.05%.

12-(Benzo[d][1,3]dioxol-5-yl)-3,3-dimethyl-3,4-dihydrothiochromeno[2,3-b]thiochromene-1,11(2H,12H)-dione (9b)

Using the general procedure starting from 100 mg (0.515 mmol) of 4-hydroxy-2H-thiochromene-2-thione 5a, 77.3 mg (0.515 mmol) of benzo[d][1,3]dioxole-5-carbaldehyde 2h, 72.2 mg (0.515 mmol) of dimedone 8, 205.5 mg of the title compound 9b was isolated as a red colored solid, mp 178–180 °C, yield = 89%, IR : 1662, 1625, 1615, 1589 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 8.44 (d, 1H, J = 7.6 Hz), 7.44–7.56 (m, 3H), 6.98 (s, 1H), 6.94 (d, 1H, J = 8.0 Hz), 6.63 (d, 1H, J = 8.0 Hz), 6.14 (s, 1H), 5.83 (d, 2H, J = 2.4 Hz), 2.65 (d, 1H, J = 17.2 Hz), 2.40 (d, 3H, J = 18.4 Hz), 1.11 (s, 3H), 0.99 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ_C = 193.0, 176.0, 147.5, 146.7, 146.4, 142.3, 135.5, 131.6, 131.1, 130.7, 129.9, 129.7, 127.7, 125.2, 122.6, 121.3, 108.8, 108.1, 100.8, 51.5, 43.5, 36.6, 33.9, 29.5, 26.5. MS: m/z = 470.97 [M+Na]⁺, 472.97 [M+Na+2]⁺ Anal. Calcd. For C₂₅H₂₀O₄S₂: C, 66.94; H, 4.49%. Found: 66.91; H, 4.54%.

12-(2-Bromophenyl)-3,3-dimethyl-3,4-dihydrothiochromeno[2,3-b]thiochromene-1,11(2H,12H)-dione (9c)

Using the general procedure starting from 100 mg (0.515 mmol) of 4-hydroxy-2H-thiochromene-2-thione 5a, 95.3 mg (0.515 mmol) of 2-bromobenzaldehyde 2i, 72.2 mg (0.515 mmol) of dimedone 8, 216.2 mg of the title compound 9c was isolated as a red colored solid, mp 220–222 °C, yield = 87%, IR: 1664, 1587 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 8.27 (d, 1H, J = 8.0 Hz), 7.69 (d, 1H, J = 7.6 Hz), 7.49–7.58 (m, 2H), 7.39 (t, 2H, J = 6.8 Hz), 7.21 (t, 1H, J = 7.6 Hz), 6.99 (t, 1H, J = 7.2 Hz), 5.84 (s, 1H), 2.68 (d, 2H, J = 8.0 Hz), 2.27 (d, 2H, J = 6.0 Hz), 1.16 (s, 3H), 1.07 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ_C = 204.4, 195.8, 161.5, 151.8, 141.1, 138.9, 136.7, 133.8, 130.5, 128.4, 127.4, 126.3, 126.1, 123.4, 123.3, 122.5, 113.1, 50.8, 40.6, 38.0, 32.3, 29.2, 27.6. MS: m/z = 505.08 [M+Na]⁺. Anal. Calcd. For C₂₄H₁₉BrO₂S₂: C, 59.63; H, 3.96%. Found: C, 59.64; H, 3.89%.

12-(5-Chloro-2-methoxyphenyl)-3,3-dimethyl-3,4-dihydrothiochromeno[2,3-b]thiochromene-1,11(2H,12H)-dione (9d)

Using the general procedure starting from 100 mg (0.515 mmol) of 4-hydroxy-2H-thiochromene-2-thione 5a, 87.8 mg (0.515 mmol) of 5-chloro-2-methoxybenzaldehyde 2j, 72.2 mg (0.515 mmol) of dimedone 8, 207.5 mg of the title compound 9d was isolated as a red colored solid, mp 218–220 °C, yield = 86%, IR (KBr): 1662, 1620, 1588 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 8.42 (d, 1H, J = 8.4 Hz), 7.44–7.56 (m, 4H), 7.06 (d, 1H, J = 8.4 Hz), 6.71 (d, 1H, J = 8.8 Hz), 6.18 (s, 1H), 3.77 (s, 3H), 2.59 (d, 1H, J = 17.2 Hz), 2.35 (d, 3H, J = 18.0 Hz), 1.10 (s, 3H), 0.95 (s, 3H). MS: m/z = 491.01 [M+Na]⁺. Anal. Calcd. For C₂₅H₂₁ClO₃S₂: C, 64.02; H, 4.51%. Found: C, 64.07; H, 4.50%.

12-(3,4-Dimethoxyphenyl)-3,3-dimethyl-3,4-dihydrothiochromeno[2,3-b]thiochromene-1,11(2H,12H)-dione (9e)

Using the general procedure starting from 100 mg (0.515 mmol) of 4-hydroxy-2H-thiochromene-2-thione 5a, 85.5 mg (0.515 mmol) of 3,4-dimethoxybenzaldehyde 2k, 72.2 mg (0.515 mmol) of dimedone 8, 222.4 mg of the title compound 9e was isolated as a red colored solid, mp 140–142 °C, yield = 93%, IR: 1660, 1615, 1589 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 8.45 (d, 1H, J = 7.6 Hz), 7.44–7.56 (m, 3H), 7.12 (s, 1H), 6.93 (d, 1H, J = 8.0 Hz), 6.67 (d, 1H, J = 8.0 Hz), 6.19 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 2.67 (d, 1H, J = 17.6 Hz), 2.39 (d, 3H, J = 16.4 Hz), 1.12 (s, 3H), 0.99 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ_C = 193.1, 176.1, 148.7, 147.9, 146.8, 142.1, 135.5, 134.1, 131.6, 131.2, 130.8, 130.1, 129.7, 127.7, 125.2, 119.6, 111.8, 110.8, 55.8, 55.7, 51.5, 43.6, 36.5, 33.8, 29.6, 26.3. MS: m/z = 503.04 [M+K]⁺. Anal. Calcd. For C₂₆H₂₄O₄S₂: C, 67.21; H, 5.21%. Found: C, 67.11; H, 5.22%.

12-(4-Fluorophenyl)-3,3-dimethyl-3,4-dihydrothiochromeno[2,3-b]thiochromene-1,11(2H,12H)-dione (9f)

Using the general procedure starting from 100 mg (0.515 mmol) of 4-hydroxy-2H-thiochromene-2-thione 5a, 63.9 mg (0.515 mmol) of 4-fluorobenzaldehyde 2l, 72.2 mg (0.515 mmol) of dimedone 8, 198 mg of the title compound 9f was isolated as a red colored solid, mp 182–184 °C, yield = 91%, IR: 1662, 1587 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ_H = 8.44 (d, 1H, J = 7.6 Hz), 7.44–7.57 (m, 5H), 6.87 (t, 2H, J = 8.0 Hz), 6.19 (s, 1H), 2.67 (d, 1H, J = 17.6 Hz), 2.40 (d, 3H, J = 17.6 Hz), 1.12 (s, 3H), 0.96 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ_C = 193.0, 176.0, 163.0, 160.6, 146.9, 142.5, 137.5, 135.5, 131.6, 131.0, 130.7, 129.8, 129.7, 129.6, 127.8, 125.2, 115.2, 115.0, 51.4, 43.6, 36.4, 33.9, 29.5, 26.3. MS: m/z = 461.03 [M+K]⁺. Anal. Calcd. For C₂₄H₁₉FO₂S₂: C, 68.22; H, 4.53%. Found: C, 68.26; H, 4.50%.

Acknowledgements

We thank CSIR (New Delhi) and DST (New Delhi) for financial assistance. Two of us (S.P. & T.G.) are grateful to CSIR (New Delhi) for their Research Fellowships. We also thank the DST (New Delhi) for providing Bruker NMR spectrometer (400 MHz) and Perkin–Elmer CHN analyzer, UV-VIS spectrometer and Perkin-Elmer FT -IR under its FIST programme.

References

1. (a) U. M. Lindstrom, Organic Reactions in Water, Blackwell, Oxford, 2007; (b) C. J. Li, Chem. Rev., 1993, 93, 2023; (c) C. J. Li, Chem. Rev., 2005, 105, 3095; (d) A. Chanda and V. V. Fokin, Chem. Rev., 2009, 109, 725; (e) H. C. Hailes, Org. Process Res. Dev., 2007, 11, 114.
2. (a) A. Domling, Chem. Rev., 2006, 106, 17; (b) R. V. A. Orru and M. Degreef, Synthesis, 2003, 1471; (c) C. Hulme and V. Gore, Curr. Med. Chem., 2003, 10, 51; (d) C. Montagne, J. J. Shiers and M. Shipman, Tetrahedron Lett., 2006, 47, 9207.
3. (a) S. L. Schreiber, Science, 2000, 287, 1964; (b) J.-P. Zhu, H. Bienayme, Multicomponent Reactions; Wiley-VCH: Weinheim, 2005, 1499; (c) B. M. Trost, Angew. Chem., Int. Ed. Engl., 1995, 34, 259; (d) L. F. Tietze, Chem. Rev., 1996, 96, 115.
4. (a) R. V. A. Orru and M. de Greef, Synthesis, 2003, 1471; (b) G. Balme, E. Bossharth and N. Monteiro, Eur. J. Org. Chem., 2003, 4101; (c) S. Bräse, C. Gil and K. Knepper, Bioorg. Med. Chem., 2002, 10, 2415; (d) A. Dömling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168.
5. (a) A. Dömling, Chem. Rev., 2006, 106, 17; (b) D. J. Ramón and M. Yus, Angew. Chem., Int. Ed., 2005, 44, 1602; (c) L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reaction in Organic Synthesis; Wiley-VCH: Weinheim, 2006, 542; (d) J. D. Sunderhaus, C. Dockendorff and S. F. Martin, Org. Lett., 2007, 9, 4223.
6. (a) A. H. Ingall, In Comprehensive Heterocyclic Chemistry II; Boulton, A. S., McKkillop, A., ed.; Pergamon Press: Oxford, 1996, 5, 501; (b) S. W. Schneller, Adv. Heterocycl. Chem., 1975, 18, 59; (c) A. R. Katrizky and A. Bonlton, J. Adv. Heterocycl. Chem., 1975, 18, 76.
7. D. J. Jr. Rogier, J. S. Carter and J. J. Talley, WO 2001049675, 2001.
8. M. J. Brown, P. S. Carter, A. E. Fenwick, A. P. Fosberry, D. W. Hamprecht, M. J. Hibbs, R. L. Jarvest, L. Mensah, P. H. Milner, P. J. O'Hanlon, A. J. Pope, C. M. Richardson, A. West and D. R. Witty, Bioorg. Med. Chem. Lett., 2002, 12, 3171.
9. W. Quaglia, M. Pigini, A. Piergentili, M. Giannella, F. Gentili, G. Marucci, A. Carrieri, A. Carotti, E. Poggesi, A. Leonardi and C. Melchiorre, J. Med. Chem., 2002, 45, 1633.
10. L. A. Vanvliet, N. Rodenhuis, D. Dijkstra, H. Wikstrom, T. A. Pugsley, K. A. Serpa, L. T. Meltzer, T. G. Heffner, L. D. Wise, M. E. Lajiness, R. M. Huff, K. Svensson, S. Sundell and M. Lundmark, J. Med. Chem., 2000, 43, 2871.
11. (a) K. D. Berlin, D. M. Benbrook, E. C. Nelson, U.S. Patent, 2003, 6586460; (b) Y. Sugita, H. Hosoya, K. Terasawa, I. Yokoe, S. Fujisawa and H. Sakagami, Anticancer Res., 2001, 21, 2629.
12. (a) R. F. Kaltenbach, S. P. Robinson, G. L. Trainor, U.S. Patent2005/0267183 A1, December 1, 2005; (b) X. Zhang, Z. Sui, U.S. Patent2006/0020018 A1, January 26, 2006.
13. A. Attila Sipos, M. Toth, F. K. U. Mueller, J. Lehmann and S. Berenyi, Monatsh. Chem., 2009, 140, 473.
14. (a) J. E. Saxton, Indoles; Wiley-Interscience: New York, 1983; (b) R. J. Sundberg, The Chemistry of Indoles; Academic Press: New York, 1970; (c) J. S. Carle and C. Christophersen, J. Org. Chem., 1980, 45, 1586; (d) N. Sakabe, Y. Sendo, I. Iijima and Y. Ban, Tetrahedron Lett., 1969, 10, 2527; (e) T. Ohmoto and K. Koike, Chem. Pharm. Bull., 1984, 32, 170; (f) M. Shimizu, M. Ishikawa, Y. Komoda, T. Nkajima, K. Yamaguchi and N. Yoneda, Chem. Pharm. Bull., 1984, 32, 463; (g) E. Yamanaka, M. One, S. Kasamatsu, N. Aimi and S. Sakai, Chem. Pharm. Bull., 1984, 32, 818; (h) M. Taniguchi, T. Anjiki, M. Nakagawa and T. Hino, Chem. Pharm. Bull., 1984, 32, 2544; (i) Y. Hashimoto, K. Shudo and T. Okamoto, Chem. Pharm. Bull., 1984, 32, 4300; (j) Y. Nakashima, Y. Kawashima, F. Amanuma, K. Sota, A. Tanaka and T. Kameyama, Chem. Pharm. Bull., 1984, 32, 4271; (k) S. Kamijo and Y. Yamamoto, J. Org. Chem., 2003, 68, 4764.
15. (a) S. Takada and Y. Makisumi, Chem. Pharm. Bull., 1984, 32, 872; (b) S. Takada, N. Ishizuka, T. Sasatani, Y. Makisumi, H. Jyoyama, H. Hatakeyama, F. Asanuma and K. Hirose, Chem. Pharm. Bull., 1984, 32, 877.
16. Y. Makisumi, T. Sasatani, United States PatentNo. 4910318, March 20, 1990.
17. (a) K. C. Majumdar, S. Ponra, D. Ghosh and A. Taher, Synlett, 2011, 104; (b) K. C. Majumdar, S. Ponra and D. Ghosh, Synthesis, 2011, 1132.
18. A. Kumar and R. A. Maurya, Tetrahedron, 2007, 63, 1946.
19. (a) T. Katoaka, A. Tomoto, H. Shimizu and M. Hori, J. Chem. Soc., Perkin Trans. 1, 1983, 2913; (b) C. Banzatti, P. Mellini and P. Salvadori, Gazz. Chim. Ital., 1987, 117, 259; (c) P. T. Kaye, S. Afr. J. Sci., 2004, 100, 545.
20. (a) E. Rasolofonjatovo, B. Treguier, O. Provot, A. Hamze, E. Morvan, J. –D. Brion and M. Alami, Tetrahedron Lett., 2011, 52, 1036; (b) R. S. Kenny, U. C. Mashelkar, D. M. Rane and D. K. Bezawada, Tetrahedron, 2006, 62, 9280.
21. W. Wang, H. Li, J. Wang and L. Zu, J. Am. Chem. Soc., 2006, 128, 10354.
22. (a) B. I. Usachev, M. A. Shafeev and V. Y. Sosnovskikh, Russ. Chem. Bull., 2006, 55, 504; (b) B. I. Usachev, V. Y. Sosnovskikh, M. A. Shafeev and G. -V. Röschenthaler, Phosphorus, Sulfur Silicon Relat. Elem., 2005, 180, 1315.
23. R. Rios, H. Sunden, I. Ibrahem, G. -L. Zhao, L. Eriksson and A. Cordova, Tetrahedron Lett., 2006, 47, 8547.
24. K. C. Majumdar, U. K. Kundu and S. K. Ghosh, Org. Lett., 2002, 4, 2629.
25. K. C. Majumdar and S. Muhuri, Synthesis, 2006, 2725.
26. S. Chowdhury, G. C. Nandi, S. Samai and M. S. Singh, Org. Lett., 2011, 13, 3762.

---

Footnote

† Electronic Supplementary Information (ESI) available. See DOI: 10.1039/c1ra00655j/

---