One-pot,catalyst-free synthesis of novel spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido [2,1- b ][1,3]benzothiazole] derivatives

Abstract

The present report describes one-pot three-component condensation of isatins, malononitrile, and 2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one in water–ethanol mixture at reflux to develop an efficient one-pot protocol for the synthesis of novel spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole] derivatives. The significant features of this protocol are short reaction times, avoidance of toxic catalysts, and provision of excellent yields, no column chromatographic purification, and use of ethanol-water as an environmentally benign solvent. The molecular structure of 4a has been supported by single-crystal X-ray diffraction.

Keywords

isatin malononitrile multicomponent reactions spirooxindole

Introduction

As a major heterocycle, the spirooxindole system has been identified in a variety of pharmacological and natural products such as spirotryprostatin A, welwitindolinone A, horsfiline, elacomine, coerulescine, and alstonisine.^1,2 Spirotryprostatin A is a novel inhibitor of microtubule assembly³ extracted from the fermentation broth of Aspergillus fumigatus. This natural alkaloid, along with pteropodine, positively modulate muscarinic 5-HT2 and M2 receptors.⁴ Furthermore, owing to their beneficial pharmacological and biological properties, including antioxidant, antifungal,⁵ anticoagulant,⁶ anti-tumor,^7,8 anticancer,⁹ anti-HIV,^10,11 and anti-malarial¹² activities, spirooxindole derivatives play a significant role in synthetic medicinal chemistry.¹³ Some additional biologically active spirocyclic oxindoles have also been described in a broader-context review.^14–20 Spirooxindoles, especially those spiroannulated with heterocycles at the 3-position, have been reported to possess good biological activities.²¹ For example, pyran-annulated oxindoles are widely spread in nature and exhibit various physiological activities.²² The cytotoxic,²³ anticancer,²⁴ antimicrobial²⁵ (Figure 1), analgesic,²⁶ and herbicidal²⁷ activities of some synthetic spiroheterocyclic compounds containing both indole and pyran moieties have also been reported. Therefore, intensive efforts have been made to design and develop new approaches for the construction of novel synthetic spirooxindole-fused heterocycles.

Figure 1.

Selected bioactive molecules containing pyran-annulated oxindoles.

Fused-pyrimidine-containing heterocyclic skeletons are an important biologically active core unit in heterocyclic compounds and possess remarkable biological properties.^28–30 Among them, pyrimidobenzothiazole scaffolds have received considerable attention because of the synthetic challenges associated with their complex molecular architecture and their interesting biological properties, such as antihistaminic,³¹ antibacterial,^32–34 anticancer,³⁵ antiviral,³⁶ and antifungal activities.³⁷ Recent studies focusing on the synthesis of novel benzo[4,5]thiazolo[1,2-a]pyrimidine-3-carboxylate derivatives have found these compounds to show cytotoxic activity against human breast adenocarcinoma MDA-MB-231 and MCF-7 tumor cell lines.³⁸ Moreover, pyranopyrimidine contains a diverse array of natural products, as well as pharmaceutically significant compounds, with a wide range of biological activities.^39,40 For example, pyrano[2,3-d]pyrimidine are known to exhibit antitumor,^41,42 hepatoprotective,⁴³ antibronchitic,⁴⁴ and pronounced antitubercular and antimicrobial activities.⁴⁵

Based on the discussed facts and the significant biological properties of spirooxindoles, pyrano[2,3-d]pyrimidine, and pyrimidobenzothiazole, we assume that the synthesis of new substituted polyheterocyclic scaffolds containing spirooxindole, pyrano[2,3-d]pyrimidine, and pyrimidobenzothiazole may result in the finding of novel drug candidates. Hence, this paper describes an easy, highly efficient, environment-friendly, catalyst-free, one-pot procedure for the synthesis of novel spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole] derivatives via the reaction of isatin 1, malononitrile 2, and 2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one 3^46,47 as heterocyclic CH-acid systems.

A review of the literature showed that in the past few years, several pathways have been developed for the synthesis of spirooxindole from isatin, malononitrile, and various types of activated methylene group in one-pot multicomponent synthesis.^48,49 To the best of our knowledge, there is no report using 2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one 3 for the synthesis of spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole] heterocyclic hybrids.

Results and discussion

We first investigated the optimum conditions for the three-component reaction of isatin 1, malononitrile 2, and 2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one 3 as model reactions (Table 1). In the first step, the model reaction was performed under solvent-free conditions at room temperature (Table 1, entry 1). However, no conversion was detected after a long reaction time. We then conducted the model reaction at 60°C and 90°C under similar conditions and extracted the expected product at low yield (Table 1, entries 2–3).

Table 1.

Optimization of reaction conditions.


Entry	Solvent (°C)	Temp (°C)	Time (h)	Yield (%)
1	Solvent free	RT	48	—
2	Solvent free	60	48	25
3	Solvent free	90	48	30
4	Toluene	reflux	48	—
5	Xylene	100	48	—
6	DMF	100	6	65
7	DMSO	100	6	60
8	THF	reflux	8	70
9	CH₃CN	reflux	5	85
10	EtOH	reflux	5	85
11	Water	reflux	48	45
12	Water:ethanol (1:1)	reflux	2	95
13	Water:ethanol (1:2)	reflux	2	90
14	Water:ethanol (1:3)	reflux	2	90
15	Water:ethanol (2:1)	reflux	2	70
16	Water:ethanol (3:1)	reflux	2	65

RT: room temperature.

In order to investigate the effects of solvent, we used a number of polar and non-polar reaction media to perform the test reactions. No conversion was detected in non-polar solvents, for example, toluene and xylene, even after long reaction times (Table 1, entries 4–5). On the other hand, moderate to good yields were obtained (60%–85%) in polar solvents like DMF, DMSO, THF, acetonitrile, and ethanol (Table 1, entries 6–10). Due to its low cost, availability, and environment-friendliness, H₂O was used as the reaction medium. However, no further improvement was observed in the yield due to the solubility problem of reactants (Table 1, entry 11). Subsequently, we decided to perform the one-pot reaction in a sequential manner using water-ethanol. As discussed earlier, ethanol–water (1:1) mixture was the best among other solvents in this study (Table 1, entry 12). Finally, examining the ethanol–water ratio failed to further improve the yield (Table 1, entries 13–16). We also used an acid (p-toluene sulfonic acid) and a base (diisopropylethylamine) as catalysts in this reaction, but the catalyst-free approach in H₂O/EtOH gave the best result.

Subsequently, a variety of isatins were reacted with malononitrile and 2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one. All reactions completed within 2 hours and resulted the formation of expected novel spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole] derivatives (4a -m, Table 2) in high to excellent yields (85% -95%).

Table 2.

Reaction of isatin 1, malononitrile 2, and 2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one 3.


Product	R¹	R²	R³	Yield (%)^a
4a	H	H	H	93
4b	CH₃	H	H	95
4c	CH₃CH₂	H	H	91
4d	C₆H₅CH₂	H	H	93
4e	4-ClC₆H₄CH₂	H	H	94
4f	H	Br	H	90
4g	H	OCH₃	H	85
4h	H	Cl	H	91
4i	CH₃	Cl	H	94
4j	CH₃CH₂	Cl	H	92
4k	H	CH₃	H	90
4l	CH₃	CH₃	H	92
4m	H	H	CH₃	88

Isolated yield.

The structures of compounds 4 were fully characterized by ¹H NMR, ¹³C NMR, IR spectroscopy, and mass spectrometry (See Supporting information). For example, the ¹H NMR spectrum of 4b contained a singlet for N-Me (δ 3.25), a triplet for CH_Ar (δ 7.01), a doublet for CH_Ar (δ 7.10), a doublet for CH_Ar (δ 7.18), a triplet for CH_Ar (δ 7.32), a multiplet for CH_Ar (δ 7.47–7.56), a broad singlet for NH₂ (δ 7.47–7.56), a doublet for CH_Ar (δ 8.02), and a doublet for CH_Ar (δ 8.60). The assignment was supported by IR absorptions at 3460, and 3333 cm^-1 (NH₂), 2198 cm^-1 (CN), 1716, 1649 (2 C=O). The 22 distinct resonances indicated by the 1H decoupled ¹³C NMR spectrum of 4b confirmed the proposed structure. A characteristic ¹³C NMR signal due to the cyano carbons was observed at δ = 117.65 ppm, and the carbonyl carbons appeared at δ = 158.91 and 176.47 ppm. The mass spectrometry of all products showed molecular ion peaks at relevant m/z values.

The structure of compound 4a was further confirmed by single-crystal X-ray analysis which supported our speculations regarding the structures of the products (Figure 2). (Selected X-ray crystallographic data for compound 4a: (CCDC 1527746): C₂₇H₂₅N₇O₅S: MW = 559.6, Triclinic, space group P–1, cell dimensions a = 11.076 (2) Å, b = 11.486 (2) Å, c = 12.435 (3) Å, α = 66.76 (3)°, β = 75.03 (3)°, γ = 63.07 (3)°, V = 1289.9 (6) ^Å3, Z = 2, Dx = 1.441 Mg m⁻³, F000 = 584, crystal size 0.240 × 0.120 × 0.120 mm. Crystallographic data were collected on a Bruker APEX area-detector diffractometer, with graphite monochromated Mo Kα radiation (λ = 0.71073 Å). A total of 4522 reflections (2.6 ⩽ θ ⩽ 25.0) were collected at a temperature of 298 K in a series of ω scans in 1° oscillations, and integrated using the Stoe X-AREA software package (3438) reflections were unique with I> 2σ(I). The structure was solved by direct method and subsequent different Fourier map and then refined on F2 by a full-matrix least-square procedure using anisotropic displacement parameters. All non-H atoms were refined anisotropically, and H atoms were placed in the ideal positions. Final residuals were R = 0.0664 and Rw = 0.1717 for 3906 parameters.) A crystal suitable for X-ray diffraction analysis was obtained by evaporation from a mixed solvent of methanol and DMF (v/v = 4:1) at room temperature.

Figure 2.

ORTEP diagram of compound 4a.

A plausible mechanism is presented in Scheme 1. As seen, during a typical cascade reaction, the first step was a fast Knoevenagel condensation in which isatin 1 was condensed with malononitrile 2 to afford isatylidene malononitrile derivative 5. In the next step, 5 was attacked through Michael addition of 2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-5,7(6H)-dione 3 affording intermediate 6 which underwent 6-exo-dig-cyclization to the desired product 4 (Scheme 1).

Scheme 1.

A plausible mechanism.

Overall, this paper described a modified environment-friendly one-pot catalyst-free protocol for the synthesis of novel spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole] derivatives from a three-component reaction between isatin, malononitrile, and 2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one. We put forward a method in which the target products could be isolated by a simple filtration method due to a difference in the solubility of product and reactant materials. The obtained products were crystallized from MeOH/DMF (4:1) to afford the pure products. This prevented multiple extraction steps and separation by chromatography. Considering the availability of the starting materials, the green and one-pot procedure, easy workup, and high to excellent yields of the products, the products synthesized in the present study may find useful applications in synthetic organic and medicinal chemistry.

Melting points were recorded on an Electrothermal-type 9100 melting point apparatus and are uncorrected. The IR spectra were obtained on an Avatar 370 FT-IR Thermo-Nicolet spectrometer. ¹H and ¹³C NMR spectra were run on BRUKER DRX-300 AVANCE spectrometer at 300 for ¹H NMR, and 75 MHz for ¹³C NMR DMSO-d₆ was used as solvent. The mass spectra were scanned on a Varian Mat CH-7 at 70 eV. Elemental analysis was performed on a Thermo Finnigan Flash EA microanalyser. X-ray crystal structure data were collected on a Bruker D8 VENTURE PHOTON 100 CMOS diffractometer with graphite monochromated Cu Kα radiation at 296(2) K.

General procedure for the synthesis of 4

A mixture of isatin 1 (1 mmol), malononitrile 2 (1.2 mmol), and 2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one 3 (1 mmol) in water-ethanol (1:1, 5 mL) was refluxed for 2 h in an oil bath. After the completion of the reaction (monitored by TLC (thin layer chromatography)), the mixture was cooled to room temperature, and the precipitate was filtered off and washed with cold ethanol and then crystallized from MeOH/DMF (4:1) to afford pure product 4 (yield 85%–95%) as white solid.

2′-Amino-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4a): White solid, 384 mg (93%), m.p.>300 °C, R_f (1:5 n-hexane/EtOAc) 0.50; IR (KBr, cm^-1): υ = 3436, 3336 (NH₂), 2197 (CN), 1713, 1661 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 6.90 (br s, 2H, H_Ar), 7.11–7.21 (m, 2H, H_Ar), 7.48 (br s, 1H, H_Ar), 7.48 (br s, 2H, NH₂), 8.04–8.05 (m, 1H, H_Ar), 8.61–8.63 (m, 1H, H_Ar). ¹³C NMR (75 MHz, CDCl₃): δ 48.5 (Cspiro), 57.3 (=C–CN), 95.5 (C–C=O), 109.8 (CN), 117.7 (C_Ar–S), 118.8, 122.3, 123.6, 124.3, 124.5, 127.5, 127.7, 129.0 (8CH_Ar), 133.8 (C_Ar), 135.6 (C_Ar–N), 142.5 (C_Ar–N), 142.6 (C=O), 158.9 (C–NH₂), 159.8 (N–C–O), 162.5 (S–C=N), 177.9 (C=O_isatin). MS: (m/z, %), 413 (M⁺, 48), 412 (60), 383 (72), 355 (48), 216 (29), 207 (74), 193 (51), 176 (70), 149 (49), 69 (32), 28 (75). Anal. Calcd for C₂₁H₁₁N₅O₃S: C, 61.01; H, 2.68; N, 16.94; S, 7.76; found: C, 60.88; H, 3.01; N, 16.44; S, 7.45.

2′-Amino-1-methyl-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4b): White solid, 405 mg (95%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.55, IR (KBr, cm^-1): υ = 3460, 3333 (NH₂), 2198 (CN), 1716, 1649 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 3.25 (s, 3H, CH₃), 7.01 (t, 1H, J = 7.5 Hz, H_Ar), 7.10 (d, 1H, J = 7.8 Hz, H_Ar), 7.18 (d, 1H, J = 6.3 Hz, H_Ar), 7.32 (t, 1H, J = 7.8 Hz, H_Ar), 7.47–7.56 (m, 2H, H_Ar), 7.47–7.56 (m, 2H, NH₂), 8.02 (d, 1H, J = 7.8 Hz, H_Ar), 8.60 (d, 1H, J = 7.3 Hz, H_Ar). ¹³C NMR (75 MHz, CDCl₃): δ 27.0 (CH₃), 48.1 (Cspiro), 56.9 (=C–CN), 95.4 (C–C=O), 108.7 (CN), 117.6 (C_Ar–S), 118.8, 123.0, 123.6, 124.1, 124.5, 127.6, 127.7, 129.2 (8CH_Ar), 133.0 (C_Ar), 135.6 (C_Ar–N), 144.1 (C_Ar–N), 158.9 (C=O), 158.9 (C–NH₂), 159.9 (N–C–O), 162.6 (S–C=N), 176.4 (C=O_isatin). MS: (m/z, %), 427 (M⁺, 98), 396 (96), 370 (80), 221 (100), 207 (92), 176 (96), 153 (76), 139 (30), 69 (68), 29 (95). Anal. Calcd for C₂₂H₁₃N₅O₃S: C, 61.82; H, 3.07; N, 16.38; S, 7.50; found: C, 61.21; H, 2.76; N, 16.50; S, 7.28.

2′-Amino-1-ethyl-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4c): White solid, 401 mg (91%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.58, IR (KBr, cm^-1): υ = 3460, 3334 (NH₂), 2196 (CN), 1713, 1670 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 1.25 (t, 3H, J = 6.9 Hz, CH₃), 3.73–3.90 (m, 2H, CH₂), 6.99 (t, 1H, J = 7.5 Hz, H_Ar), 7.12 (d, 1H, J = 7.8 Hz, H_Ar), 7.18 (d, 1H, J = 6.3 Hz, H_Ar), 7.30 (t, 1H, J = 6.3 Hz, H_Ar), 7.49–7.57 (m, 2H, H_Ar), 7.49–7.57 (m, 2H, NH₂), 8.07 (d, 1H, J = 7.8 Hz, H_Ar), 8.61 (d, 1H, J = 7.8 Hz, H_Ar). ¹³C NMR (75 MHz, CDCl₃): δ 12.8 (CH₃), 35.0 (CH₂), 47.9 (Cspiro), 57.1 (=C–CN), 95.3 (C–C=O), 108.7 (CN), 117.5 (C_Ar–S), 118.8, 123.0, 123.7, 124.2, 124.5, 127.5, 127.7, 129.2 (8CH_Ar), 133.0 (C_Ar), 135.6 (C_Ar–N), 143.0 (C_Ar–N), 158.9 (C=O), 158.9 (C–NH₂), 159.9 (N–C–O), 162.6 (S–C=N), 175.9 (C=O_isatin). MS: (m/z, %), 441 (M⁺, 98), 411 (100), 396 (24), 382 (92), 366 (18), 234 (63), 206 (90), 176 (92), 152 (66), 125 (39), 69 (35), 43 (20), 28 (82). Anal. Calcd for C₂₃H₁₃N₅O₃S: C, 61.82; H, 3.07; N, 16.38; S, 7.50; found: C, 62.02; H, 3.07; N, 16.41; S, 7.39.

2′-Amino-1-benzyl-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4d): White solid, 468 mg (93%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.61, IR (KBr, cm^-1): υ = 3375, 3319 (NH₂), 2204 (CN), 1726, 1656 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 4.97 (d, 1H, ²J = 16.2 Hz, Ph-CH_AH_B), 5.09 (d, 1H, ²J = 16.0 Hz, Ph-CH_AH_B), 6.83 (d, 1H, J = 7.8 Hz, H_Ar), 7.00 (t, 1H, J = 7.5 Hz, H_Ar), 7.18–7.24 (m, 2H, H_Ar), 7.29–7.39 (m, 3H, H_Ar), 7.51–7.58 (m, 4H, H_Ar), 7.51–7.58 (m, 2H, NH₂), 8.04–8.07 (m, 1H, H_Ar), 8.61–8.64 (m, 1H, H_Ar). ¹³C NMR (75 MHz, CDCl₃): δ 43.9 (CH₂), 48.3 (C_spiro), 56.9 (=C–CN), 95.3 (C–C=O), 109.3 (CN), 117.8 (C_Ar–S), 118.7, 123.1, 123.7, 124.3, 124.5 (5CH_Ar), 127.6 (2CH_Ar), 127.7 (2CH_Ar), 128.8, 129.1 (2CH_Ar), 133.1, 135.6 (2C_Ar), 136.5 (C_Ar–N), 143.3 (C_Ar–N), 158.9 (C=O), 159.0 (C–NH₂), 160.0 (N–C–O), 162.7 (S–C=N), 176.7 (C=O_isatin). MS: (m/z, %), 504 (M⁺, 66), 474,(21), 410 (71), 337 (8), 282 (88), 254 (41), 216 (67), 176 (67), 149 (66), 91 (100), 65 (72), 28 (68). Anal. Calcd for C₂₈H₁₇N₅O₃S: C, 66.79; H, 3.40; N, 13.91; S, 6.37; found: C, 66.94; H, 3.13; N, 13.75; S, 6.21.

2′-Amino-1-(4-chlorobenzyl)-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4e): White solid, 505 mg (94%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.45, IR (KBr, cm^-1): υ = 3444, 3284 (NH₂), 2193 (CN), 1701, 1682 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 5.02 (br s, 2H), 6.86 (d, 1H, J = 7.8 Hz, H_Ar), 7.00 (t, 1H, J = 7.5 Hz, H_Ar), 7.21 (t, 2H, J = 7.2 Hz, H_Ar), 7.42 (t, 2H, J = 7.9 Hz, H_Ar), 7.52–7.60 (m, 4H, H_Ar), 7.52–7.60 (m, 2H, NH₂), 8.05–8.08 (m, 1H, H_Ar), 8.61–8.64 (m, 1H, H_Ar). ¹³C NMR (75 MHz, CDCl₃): δ 43.2 (CH₂), 48.2 (C_spiro), 56.8 (=C–CN), 95.2 (C–C=O), 109.3 (CN), 117.8 (C_Ar–S), 118.8, 123.3, 123.7, 124.3, 124.3 (5CH_Ar), 127.7, 128.7 (2CH_Ar), 129.1 (2CH_Ar), 129.7 (2CH_Ar), 133.1 (C–Cl), 135.6 (C_Ar), 136.5 (C_Ar–N), 143.0 (C_Ar–N), 158.9 (C=O), 159.0 (C–NH₂), 160.0 (N–C–O), 162.8 (S–C=N), 176.7 (C=O_isatin). MS: (m/z, %), 538 (M⁺, 47), 509,(25), 410 (75), 316 (82), 288 (59), 216 (73), 176 (72), 149 (72), 124 (100), 89 (73), 69 (72), 63 (47), 39 (33), 29 (73). Anal. Calcd for C₂₈H₁₆ClN₅O₃S: C, 62.51; H, 3.00; N, 13.02; S, 5.96; found: C, 62.88; H, 2.84; N, 12.73; S, 5.89.

2′-Amino-5-bromo-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4f): White solid, 442 mg (90%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.55, IR (KBr, cm^-1): υ = 3448, 3327 (NH₂), 2198 (CN), 1725, 1674 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 6.86 (d, 1H, J = 8.1 Hz, H_Ar), 7.36–7.40 (m, 2H, H_Ar), 7.50–7.59 (m, 2H, H_Ar), 7.50–7.59 (m, 2H, NH₂), 8.08 (d, 1H, J = 7.8 Hz, H_Ar), 8.66 (d, 1H, J = 7.8 Hz, H_Ar), 10.79 (s, 1H, NH). ¹³C NMR (75 MHz, CDCl₃): δ 48.7 (Cspiro), 56.5 (=C–CN), 94.9 (C–C=O), 111.7 (CN), 114.0 (C_Ar–Br), 117.7 (C_Ar–S), 118.8, 123.7, 124.5, 127.3, 127.6, 127.7, 131.7 (7CH_Ar), 135.6 (C_Ar), 136.2 (C_Ar–N), 142.0 (C_Ar–N), 159.0 (C=O), 159.0 (C–NH₂), 160.0 (N–C–O), 162.7 (S–C=N), 177.7 (C=O_isatin). MS: (m/z, %), 492 (M⁺, 8), 463,(20), 436 (9), 284 (23), 269 (62), 245 (28), 216 (38), 175 (50), 148 (44), 138 (29), 69 (50), 44 (42), 28 (100). Anal. Calcd for C₂₁H₁₀BrN₅O₄S: C, 51.23; H, 2.05; N, 14.23; S, 6.51; found: C, 51.46; H, 1.85; N, 13.90; S, 6.36.

2′-Amino-5-methoxy-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4g): White solid, 376 mg (85%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.52, IR (KBr, cm^-1): υ = 3437, 3366 (NH₂), 2194 (CN), 1719, 1676 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 3.65 (s, 3H, OCH₃), 6.78 (br s, 3H, H_Ar), 7.46–7.56 (m, 2H, H_Ar), 7.46–7.56 (m, 2H, NH₂), 8.08 (d, 1H, J = 7.5 Hz, H_Ar), 8.66 (d, 1H, J = 8.1 Hz, H_Ar), 10.46 (s, 1H, NH). ¹³C NMR (75 MHz, CDCl₃): δ 49.0 (Cspiro), 55.8 (OCH₃), 57.4 (=C–CN), 95.5 (C–C=O), 110.1 (CN), 111.2 (C_Ar–S), 113.7 (C_Ar–OCH₃), 117.8, 118.8, 123.7, 124.5, 127.5, 127.7, 135.1 (7CH_Ar), 135.6 (C_Ar), 135.9 (C_Ar–N), 155.5 (C_Ar–N), 158.9 (C=O), 158.9 (C–NH₂), 159.8 (N–C–O), 162.5 (S–C=N), 177.8 (C=O_isatin). MS: (m/z, %), 443 (M⁺, 67), 415 (54), 398 (65), 386 (31), 236 (65), 208 (89), 176 (78), 149 (83), 126 (67), 69 (67), 44 (68), 28 (69). Anal. Calcd for C₂₂H₁₃N₅O₄S: C, 59.59; H, 2.95; N, 15.79; S, 7.23; found: C, 59.43; H, 2.68; N, 15.25; S, 7.60.

2′-Amino-5-chloro-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4h): White solid, 407 mg (91%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.58, IR (KBr, cm^-1): υ = 3452, 3327 (NH₂), 2200 (CN), 1724, 1676 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 6.89 (d, 1H, J = 6.9 Hz, H_Ar), 7.24–7.27 (m, 2H, H_Ar), 7.48–7.56 (m, 2H, H_Ar), 7.48–7.56 (m, 2H, NH₂), 8.08 (d, 1H, J = 7.5 Hz, H_Ar), 8.66 (d, 1H, J = 7.8 Hz, H_Ar), 10.78 (s, 1H, NH). ¹³C NMR (75 MHz, CDCl₃): δ 48.8 (Cspiro), 56.5 (=C–CN), 94.9 (C–C=O), 111.1 (CN), 117.6 (C_Ar–S), 118.8, 123.7, 124.5, 124.6, 126.3, 127.6, 127.7 (7CH_Ar), 128.9 (C–Cl), 135.6 (C_Ar), 135.8 (C_Ar–N), 141.6 (C_Ar–N), 159.0 (C=O), 160.0 (C–NH₂), 160.0 (N–C–O), 162.7 (S–C=N), 177.8 (C=O_isatin). MS: (m/z, %), 448 (M⁺, 30), 419 (65), 393 (26), 242 (99), 177 (55), 150 (28), 29 (100). Anal. Calcd for C₂₁H₁₀ClN₅O₃S: C, 56.32; H, 2.25; N, 15.64; S, 7.16; found: C, 56.81; H, 2.33; N, 15.55; S, 7.53.

2′-Amino-5-chloro-1-methyl-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4i): White solid, 434 mg (94%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.54, IR (KBr, cm^-1): υ = 3456, 3322 (NH₂), 2199 (CN), 1708, 1670 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 3.24 (s, 3H, CH₃), 7.13 (d, 1H, J = 8.4 Hz, H_Ar), 7.32–7.40 (m, 2H, H_Ar), 7.47–7.61 (m, 2H, H_Ar), 7.47–7.61 (m, 2H, NH₂), 8.08 (d, 1H, J = 7.5 Hz, H_Ar), 8.63 (d, 1H, J = 8.0 Hz, H_Ar). ¹³C NMR (75 MHz, CDCl₃): δ 27.1 (CH₃), 48.3 (Cspiro), 56.1 (=C–CN), 94.8 (C–C=O), 110.2 (CN), 117.5 (C_Ar–S), 118.8, 123.7, 124.4, 124.5, 127.1, 127.7, 129.0 (7CH_Ar), 135.0 (C–Cl), 135.6 (C_Ar), 143.0 (C_Ar–N), 159.0 (C_Ar–N), 159.0 (C=O), 160.1 (C–NH₂), 160.0 (N–C–O), 162.8 (S–C=N), 176.2 (C=O_isatin). MS: (m/z, %), 462 (M⁺, 4), 431,(3), 406 (3), 254 (27), 241 (98), 216 (63), 186 (34), 176 (65), 149 (60), 122 (20), 95 (19), 69 (60), 44 (34), 29 (100). Anal. Calcd for C₂₂H₁₂ClN₅O₃S: C, 57.21; H, 2.62; N, 15.16; S, 6.94; found: C, 57.39; H, 2.48; N, 15.09; S, 6.61.

2′-Amino-5-chloro-1-ethyl-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4j): White solid, 437 mg (92%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.63, IR (KBr, cm^-1): υ = 3458, 3331 (NH₂), 2196 (CN), 1715, 1670 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 1.23 (t, 3H, J = 6.9 Hz, CH₃), 3.40–3.90 (m, 2H, CH₂), 7.16 (d, 1H, J = 8.1 Hz, H_Ar), 7.32–7.37 (m, 2H, H_Ar), 7.47–7.59 (m, 2H, H_Ar), 7.47–7.59 (m, 2H, NH₂), 8.06 (d, 1H, J = 7.5 Hz, H_Ar), 8.61 (d, 1H, J = 8.1 Hz, H_Ar). ¹³C NMR (75 MHz, CDCl₃): δ 12.7 (CH₃), 35.2 (CH₂), 48.2 (Cspiro), 56.3 (=C–CN), 94.8 (C–C=O), 110.2 (CN), 117.4 (C_Ar–S), 118.8, 123.7, 124.5, 124.6, 126.9, 127.6, 127.7 (7CH_Ar), 135.2 (C–Cl), 135.6 (C_Ar), 142.0 (C_Ar–N), 159.0 (C_Ar–N), 159.0 (C=O), 160.0 (C–NH₂), 160.0 (N–C–O), 162.8 (S–C=N), 175.8 (C=O_isatin). MS: (m/z, %), 476 (M⁺, 62), 447,(50), 419 (41), 254 (20), 240 (25), 216 (24), 176 (62), 149 (17), 69 (10), 28 (100). Anal. Calcd for C₂₃H₁₄ClN₅O₃S: C, 58.05; H, 2.97; N, 14.72; S, 6.74; found: C, 58.13; H, 2.70; N, 14.87; S, 6.22.

2′-Amino-5-methyl-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4k): White solid, 384 mg (90%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.55, IR (KBr, cm^-1): υ = 3444, 3324 (NH₂), 2198 (CN), 1721, 1675 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 2.19 (s, 3H, CH₃), 6.76 (d, 1H, J = 7.8 Hz, H_Ar), 6.93 (s, 1H, H_Ar) 7.01 (d, 1H, J = 8.4 Hz, H_Ar), 7.45–7.57 (m, 2H, H_Ar), 7.45–7.57 (m, 2H, NH₂), 8.08 (d, 1H, J = 7.5 Hz, H_Ar), 8.66 (d, 1H, J = 8.1 Hz, H_Ar), 10.53 (s, 1H, NH). ¹³C NMR (75 MHz, CDCl₃): δ 21.0 (CH₃), 48.5 (Cspiro), 57.5 (=C–CN), 95.6 (C–C=O), 109.5 (CN), 117.8 (C_Ar–S), 118.8, 123.7, 124.5, 124.9, 127.5, 127.7, 129.2 (7CH_Ar), 131.1, 133.9 (2C_Ar), 135.6 (C_Ar–N), 140.2 (C_Ar–N), 158.9 (C=O), 159.7 (C–NH₂), 159.8 (N–C–O), 162.5 (S–C=N), 177.9 (C=O_isatin). MS: (m/z, %), 427 (M⁺, 30), 398 (53), 371 (15), 221 (64), 207 (11), 176 (22), 149 (12), 29 (100). Anal. Calcd for C₂₂H₁₃N₅O₃S: C, 61.82; H, 3.07; N, 16.38; S, 7.50; found: C, 61.42; H, 3.04; N, 16.08; S, 7.30.

2′-Amino-1,5-dimethyl-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4l): White solid, 405 mg (92%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.57, IR (KBr, cm^-1): υ = 3444, 3326 (NH₂), 2196 (CN), 1712, 1672 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 2.25 (s, 3H, CH₃), 3.35 (s, 3H, CH₃), 7.13 (d, 1H, J = 8.4 Hz, H_Ar), 7.32–7.39 (m, 2H, H_Ar), 7.47–7.60 (m, 2H, H_Ar), 7.47–7.60 (m, 2H, NH₂), 8.08 (d, 1H, J = 7.5 Hz, H_Ar), 8.62 (d, 1H, J = 7.5 Hz, H_Ar). ¹³C NMR (75 MHz, CDCl₃): δ 27.1 (2CH₃), 48.3 (Cspiro), 56.1 (=C–CN), 94.8 (C–C=O), 110.2 (CN), 117.5 (C_Ar–S), 118.8, 123.7, 124.4, 124.5, 127.1, 127.6, 127.7 (7CH_Ar), 129.0, 135.0 (2C_Ar), 135.6 (C_Ar–N), 143.0 (C_Ar–N), 158.9 (C=O), 159.0 (C–NH₂), 160.1 (N–C–O), 162.8 (S–C=N), 176.2 (C=O_isatin). MS: (m/z, %), 441 (M⁺, 45), 396 (14), 382 (55), 366 (28), 234 (63), 206 (72), 176 (92), 152 (66), 125 (39), 69 (35), 43 (20), 28 (82). Anal. Calcd for C₂₃H₁₅N₅O₃S: C, 62.58; H, 3.42; N, 15.86; S, 7.26; found: C, 62.17; H, 3.73; N, 15.99; S, 7.86.

2′-Amino-7-methyl-2,5′-dioxo-1,2-dihydro-5′H-spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole]-3′-carbonitrile (4m): White solid, 375 mg (88%), m.p. >300 °C, R_f (1:5 n-hexane/EtOAc) 0.52, IR (KBr, cm^-1): υ = 3436, 3334 (NH₂), 2200 (CN), 1705, 1660 (2 C=O). ¹H NMR (300 MHz, DMSO-d₆): δ 2.29 (s, 3H, CH₃), 6.83 (d, 1H, J = 7.5 Hz, H_Ar), 6.92 (d, 1H, J = 7.2 Hz, H_Ar), 7.03 (d, 1H, J = 7.5 Hz, H_Ar), 7.45–7.54 (m, 2H, H_Ar), 7.45–7.54 (m, 2H, NH₂), 8.06 (d, 1H, J = 7.8 Hz, H_Ar), 8.65 (d, 1H, J = 8.1 Hz, H_Ar), 10.69 (s, 1H, NH).). ¹³C NMR (75 MHz, CDCl₃): δ 16.9 (CH₃), 48.7 (Cspiro), 57.5 (=C–CN), 95.7 (C–C=O), 99.9 (CN), 117.8 (C_Ar–S), 118.8, 121.7, 122.2, 123.7, 124.5, 127.5, 127.7 (7CH_Ar), 130.4, 133.6 (2C_Ar), 135.6 (C_Ar–N), 141.2 (C_Ar–N), 158.9 (C=O), 159.7 (C–NH₂), 159.8 (N–C–O), 162.5 (S–C=N), 178.4 (C=O_isatin). MS: (m/z, %), 427 (M⁺, 23), 426, (49), 396 (67), 382 (20), 369 (23), 220 (100), 207 (30), 176 (44), 149 (30), 69 (9), 28 (82). Anal. Calcd for C₂₂H₁₃N₅O₃S: C, 61.82; H, 3.07; N, 16.38; S, 7.50; found: C, 61.51; H, 3.37; N, 16.66; S, 7.44.

Supplemental Material

Supplementary_data – Supplemental material for One-pot, catalyst-free synthesis of novel spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole] derivatives

Supplemental material, Supplementary_data for One-pot, catalyst-free synthesis of novel spiro[indole-3,4′-pyrano[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole] derivatives by Mahdieh Zangouei and Abbas Ali Esmaeili in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Research Council of Ferdowsi University of Mashhad is acknowledged for financial support (Grant No. 3/32089).

ORCID iD

Abbas Ali Esmaeili

Supplemental Material

Supplemental material for this article is available online. Experimental procedures and characterization of synthesized products are accessible in supplemental information. Copies of the NMR, IR, and mass spectra are available.

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