Reinvestigation of the reaction between 1,3-diketones and 2-hydroxyarylaldehydes: a short, atom-economical entry to tetrahydroxanthenones

Abstract

A short and facile access to novel functionalized tetrahydroxanthenones via a DABCO-promoted tandem Knoevenagel condensation/hemiketalisation process from easily accessible substrates in a high yield. Tetrahydroxanthenones provide access to the stereo-controlled synthesis of triades or tetrades, which represent privileged structural motifs. Disubstituted tetrahydroxanthenones are generated as a mixture of diastereomers, favoring the formation of selective diastereomers. Unsymmetrical cyclic diketones give mixtures of regio isomers, favoring the formation of sterically less-hindered products.

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Introduction

The structural feature of tricyclic xanthenone is found in many natural products,¹ especially in a wide variety of fungal metabolites such as secalonic acids, diversonol, beticolins, simaomicins, phomoxanthones and rugulotrosins; most of these show very interesting biological activities (Fig. 1). The secalonic acids exhibit toxic,² anti-HIV,³ phytotoxic,⁴ antibacterial,⁵ and mutagenic⁶ properties, along with fetotoxic and teratogenic actions.⁷ To date, only a few syntheses of natural products containing tetrahydroxanthone units have been reported.⁸ A literature survey revealed that the reaction of salicylaldehyde with a cyclic 1,3-diketone in the presence of various catalysts, such as 2,4,6-trichloro-1,3,5-triazine,⁹ triethylbenzylammonium chloride (TEBA),¹⁰ 1-butyl-3-methylimidazolium hydrogen sulfate ([bmim]HSO4),¹¹ cerium(III) chloride heptahydrate (CeCl₃·7H₂O),¹² bulk/nano-ZnAl₂O₄,¹³ L-proline,¹⁴ cellulose sulfuric acid (biopolymer-based solid acid catalyst),¹⁵ silica supported zirconium hydrogen sulfate (Zr(HSO₄)₄/SiO₂),¹⁶ toluene-4-sulfonic acid (PTSA)¹⁷ and acetic acid,¹⁸ leads to 9-substituted tetrahydroxanthenes. Recently, Stefan Brase synthesized 4-hydroxy substituted xanthenones by a three step process.¹⁹ Subsequently, Miyabe reported the synthesis of 4-hydroxy substituted xanthenones²⁰ by a coupling reaction induced by the insertion of arynes into the C=O bond of formamide (Scheme 1). Both the methods involved multiple steps and difficulties in the preparation of starting materials.

Fig. 1 Some biologically active tetrahydroxanthenones.

Scheme 1 Previous syntheses of 4-hydroxy xanthenones.

Atom economy is one of the major green chemistry principles and involves maximum incorporation of starting materials or reagents into the final product. It is essentially pollution prevention at the molecular level. Atom economy is an important development that goes beyond the traditionally taught concept of percent yield. In recent years, domino reactions²¹ have attracted more attention in the fields of pharmaceutical and organic chemistry because they allow efficient access to highly functionalized scaffolds, which occur in a variety of natural compounds with biological activities.²²

The main advantages of a cascade reaction in organic synthesis are that the reaction is often fast due to its intramolecular nature, it is clean, displays high atom economy, does not involve workup and isolation of many intermediates, and effectively adds considerable complexity in one step. 1,4-Diazabicyclo [2.2.2]octane (DABCO) has emerged as an efficient organic base, which has been successfully used for various organic reactions, such as cross-coupling reactions²³ and cyclization of o-alkynylaryl isocyanides.²⁴ To expand the xanthenone library, there is a need to develop a simple method to access cluster molecules using readily available substrates. In continuation of our ongoing research²⁵ on the development of new methods, herein we wish to report a convenient, practical, efficient and cascade synthesis of diversely functionalized xanthenones by the reaction of 2-hydroxy benzaldehyde with cyclic 1,3-diketone in the presence of DABCO (Scheme 2).

Scheme 2 DABCO-catalyzed synthesis of new functionalized xanthenones.

Results and discussion

Initially, the reaction between salicylaldehyde (1a) and 1,3-cyclohexanedione (2a) was tested without any catalyst in water, but reaction did not occur even at 100 °C. During the optimization process, we employed different base catalysts such as potassium carbonate (K₂CO₃), cesium carbonate (Cs₂CO₃), (1,8-diazabicyclo[5.4.0]undec-7-ene) DBU, pyridine (C₅H₅N), 2,6-lutidine, triethylamine (TEA), DABCO, triphenylphospine (PPh₃), quinuclidine and 4-dimethylaminopyridine (DMAP) and made changes to the ratios of the base at room temperature. However, the reaction gave encouraging results with DABCO (Table 1). Among the different molar ratios (5%, 10%, 15%, 20%, 25%, 30%, and 35%) of DABCO, 5 mol% of catalyst was found to be suitable for the synthesis of the desired xanthenones (Table 2). On the basis of the spectral data, the structure of 4-hydroxy tetrahydroxanthenone was assigned to the product by X-ray crystal structure determination (Fig. 2). THF was the choice of solvent among the screened solvents such as H₂O, MeOH, THF, CH₃CN, DCM, toluene and DMF (see ESI†). It was concluded that 5 mol% of DABCO in THF gave 4-hydroxy tetrahydroxanthenones, whereas 30 mol% DABCO with 2 equivalents of diketone in THF gave the 9-substituted tetrahydroxanthenones in good yield (Table 3).

Table 1 Results of optimization experiments^a

Entry	Catalyst	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: salicylaldehyde (1 mmol), cyclohexane, 1,3-dione (1 mmol) and catalyst stirred in appropriate solvent.b Isolated yield of pure product.c Trace amount of product. Equiv.: equivalent.
1	—	Water	12	—^c
2	K2CO3 (1 equiv.)	DMF	12	10
3	Cs2CO3 (1 equiv.)	DMF	12	17
4	DBU (10 mol%)	THF	5	12
5	DBU (5 mol%)	THF	12	36
6	C5H5N (5 mol%)	DCM	12	30
7	2,6-Lutidine (10 mol%)	THF	12	23
8	NEt3 (10 mol%)	THF	12	39
9	DABCO (5 mol%)	THF	2	82
10	PPh3 (10 mol%)	THF	12	49
11	Quinuclidine (5 mol%)	THF	12	21
12	DMAP (5 mol%)	DCM	12	16

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Table 2 Screening of substrates for the synthesis of functionalized xanthenones^a,b

a Salicylaldehyde (1 mmol), 1,3-diketone (1 mmol), and DABCO (5 mol%), were added to 2 mL of THF and stirred for 2–3 h.b Isolated yield of the pure product.

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Fig. 2 X-ray ORTEP diagram of compound 3p.

Table 3 Screening of different molar ratios of DABCO^a

Entry	DABCO mol ratio (%)	Time (h)	Yield^b 3a (%)	Yield^c 6a (%)
a Reaction conditions: salicylaldehyde (1 mmol), cyclohexane, 1,3-dione (1 mmol) and DABCO (mol%) stirred in THF.b Isolated yield of pure product (3a).c Isolated yield of pure product (Table 6, 6a).d Trace amount of product.
1	5 mol%	2	82	—^d
2	10 mol%	3	65	10
3	15 mol%	3	51	25
4	20 mol%	3	29	45
5	25 mol%	3	10	66
6	30 mol%	3	—^d	85

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Furthermore, we studied the electronic effect of the substituents on the reaction of aldehyde with symmetric 1,3-diketone. Simple 2-hydroxy benzaldehyde without any substitution gave the desired product in a moderate yield (Table 2, 3a).

A salicylaldehyde bearing halogen (Cl, Br, and I) and a methoxy substituent produced the desired product in good yield. The reaction of a salicylaldehyde having an electron withdrawing substituent (NO₂) proceeded slowly and furnished the corresponding product in a low yield. Later, we turned our attention to the reaction of unsymmetric cyclic diketones, which gave regioselective and diastereoselective products. The reaction of 4,4-dimethylcyclohexane-1,3-dione with salicylaldehyde gave a mixture of products (Table 4, 4a and 4a′). The xanthenone (4a), which presents less steric hindrance, was obtained as a major product, whereas the other regioisomer with two methyl groups and a hydroxy group possessed more steric hindrance, which leads to the formation of a minor product (4a′). The electronic effect was also studied and it was found that salicylaldehyde without any substitution gave the desired product (Table 4, 4a) in moderate yield with good regioselectivity. However, 3,5-dihalogen substituted aldehydes reacted relatively slowly and furnished the desired product in a good yield with less regio selectivity (4d) in comparison with simple salicylaldehyde. Furthermore, we studied the reactivity of 5-phenylcyclohexane-1,3-dione in reactions with salicylaldehydes and noticed that a simple salicylaldehyde gave the desired xanthenone in moderate yield with good stereo selectivity (Table 5, 5a). However, halogen substituted aldehydes produced a good yield with less stereo selectivity (5e). The ratios of individual products were found by NMR spectroscopy.

Table 4 Screening of substrates for the regioselective-synthesis of functionalized xanthenones^a,b

a Salicylaldehyde (1 mmol), 1,3-diketone (1 mmol), and DABCO (5 mol%) were added to 2 mL THF and stirred for 2–3 h.b Isolated yield of mixture of pure products.

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Table 5 Screening of substrates for the synthesis of functionalized xanthenones^a,b

a Salicylaldehyde (1 mmol), 1,3-diketone (1 mmol), and DABCO (5 mol%) were added to 2 mL of THF and stirred for 2–3 h.b Isolated yield of the mixture of products.

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Table 6 Screening of substrates for the synthesis of hexahydro xanthenes^ab

a Salicylaldehyde (1 mmol), 1,3-diketone (2 mmol), and DABCO (30 mol%) were added to 2 mL of THF and stirred for 8–10 h.b Isolated yield of the pure product.

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Plausible mechanism

Initially, diketone reacts with salicylaldehyde in the presence of DABCO to form a Knoevenagel condensed product (B). In the presence of 5 mol% of catalyst, this intermediate undergoes cyclisation with phenolic –OH to give 4-hydroxy tetrahydro xanthenone (3a). However, with 30 mol% of DABCO, the formed condensed product immediately reacts with available diketone to form an intermediate (C), which undergoes cyclisation by eliminating a water molecule to give 9-substituted tetrahydroxanthenone (6a) (Scheme 3).

Scheme 3 Plausible mechanistic pathway.

Conclusion

We have developed a convenient, practical and atom-economical DABCO-catalyzed synthesis of new functionalized xanthenones. The structure of tetrahydroxanthenones offers various possibilities for further functionalizations. Simple reaction conditions and easy isolation of the products are the advantages of the present method.

Experimental section

General information: salicylaldehydes, β-diketones, DABCO and all other solvents were purchased from Sigma Aldrich and Alpha Aesar Company and were used without further purification. All the ¹H and ¹³C NMR spectra were recorded in deuterated chloroform CDCl₃ or CDCl₃ + DMSO (deuterated dimethyl sulfoxide) (6 : 4) on Avance 300 or Avance 500 spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) relative to residual chloroform (CHCl₃) (¹H: δ 7.26 ppm, ¹³C: δ 77.00 ppm) as an internal reference. Coupling constants (J) are reported in Hertz (Hz). Peak multiplicity is indicated as follows: s-singlet, d-doublet, t-triplet, q-quartet, m-multiplet and dd-doublet of doublet. All the signals in ¹³C NMR spectra appeared as singlets and we have performed ¹³C NMR using CPD (composite pulse decoupling) method. Melting points were measured on a BUCHI melting point machine. IR spectra were recorded on a Thermo Nicolet FT/IR-5700 spectrometer. Mass spectra were recorded using a Waters mass spectrometer. High resolution mass spectra (HRMS) were recorded using an Applied Bio-Sciences HRMS spectrometer at the National Center for Mass Spectroscopy-IICT.

General procedure

In a typical experiment, the salicylaldehyde (1 mmol), cyclohexane 1,3-dione (1 mmol), and DABCO (5 mol%) in THF (2 mL) were placed in a 10 mL round-bottomed flask and stirred at room temperature for 2 h. After the completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure and the crude product was purified by column chromatography using ethyl acetate/hexane. All the compounds were characterized by (NMR, Mass, and IR) spectral data.

Spectral data of all compounds

4a-Hydroxy-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3a). White solid; mp 155–157 °C; IR: v_max 3243, 2956, 2927, 1627, 1604, 1561, 1454, 1294, 1172, 979, 842, 761 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.47 (s, 1H), 7.28–7.37 (m, 2H), 6.97–7.07 (m, 2H), 6.34 (s, 1H), 2.43–2.68 (m, 2H), 2.28–2.42 (m, 1H), 2.07–2.23 (m, 2H), 1.91–2.04 (m, 1H), ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 197.2, 152.7, 130.9, 130.5, 128.9, 128.6, 120.9, 119.7, 116.2, 95.9, 38.3, 35.4, 17.5; m/z (ESI); 199 [M − H₂O]H⁺.

4a-Hydroxy-3,3-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3b). White solid; mp 128–130 °C; IR: v_max 3246, 2958, 2915, 1624, 1609, 1559, 1457, 1293, 1165, 968, 844, 768 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.43 (s, 1H), 7.27–7.39 (m, 2H), 6.96–7.04 (m, 2H), 6.38 (s, 1H), 2.87 (s, 3H), 2.37–2.60 (m, 2H), 2.19–2.31 (m, 2H), 1.18 (s, 3H), 1.10 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 198.0, 152.7, 131.3, 129.6, 129.4, 129.0, 121.3, 120.1, 116.7, 96.3, 52.3, 48.7, 31.3, 30.2, 27.9; m/z (ESI); 227 [M − H₂O]H⁺. HRMS calcd for C₁₅H₁₅O₂: 227.10666, found: 227.10576.

7-Chloro-4a-hydroxy-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3c). White solid; mp 168–170 °C; IR: v_max 3346, 2959, 1720, 1670, 1607, 1547, 1469, 1390, 1259, 1133, 1059, 931, 819 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.46 (d, J = 2.3 Hz, 1H), 7.39 (dd, J₁ = 2.3 Hz, J₂ = 8.7 Hz, 1H), 6.91 (d, J = 8.69 Hz, 1H), 6.63 (s, 1H), 2.89 (s, 1H), 2.56–2.69 (m, 1H), 2.27–2.54 (m, 2H), 1.92–2.24 (m, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 196.5, 151.4, 131.2, 130.5, 126.7, 121.4, 117.8, 112.3, 95.8, 38.0, 34.9, 17.2; m/z (ESI); 233 [M − H₂O]H⁺. HRMS calcd for C₁₃H₁₀O₂Cl: 233.03638, found: 233.03538.

7-Chloro-4a-hydroxy-3,3-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3d). White solid; mp 131–133 °C; IR: v_max 3337, 2943, 1717, 1664, 1507, 1445, 1383, 1261, 1147, 1052, 928, 814 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.41 (s, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.30 (dd, J₁ = 2.4 Hz, J₂ = 8.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 2.99 (s, 1H), 2.49–2.54 (m, 1H), 2.28–2.37 (m, 3H), 1.18 (s, 3H), 1.12 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 197.1, 150.8, 130.3, 130.1, 127.7, 126.8, 125.1, 121.1, 90.0, 51.9, 47.9, 30.8, 29.7, 27.1; m/z (ESI); 261 [M − H₂O]H⁺. HRMS C₁₅H₁₅O₂Cl: found: 261.08969.

7-Bromo-4a-hydroxy-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3e). White solid; mp 172–174 °C; IR: v_max 3261, 2976, 2943, 1658, 1605, 1547, 1463, 1284, 1190, 1011, 928, 813 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.45 (s, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.30 (dd, J₁ = 2.4 Hz, J₂ = 8.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 2.97 (s, 1H), 2.49–2.54 (m, 1H), 2.67–2.73 (m, 1H), 2.32–2.42 (m, 1H), 2.10–2.26 (m, 2H), 1.99–2.05 (m, 1H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 196.6, 151.4, 132.9, 131.1, 130.5, 126.8, 121.3, 117.9, 112.3, 95.8, 38.0, 34.9, 17.2; m/z (ESI); 277 [M − H₂O]H⁺.

7-Bromo-4a-hydroxy-3,3-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3f). White solid; mp 135–137 °C; IR: v_max 3257, 2980, 2953, 1660, 1602, 1549, 1466, 1282, 1189, 1000, 914, 817 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.49 (d, J = 2.3 Hz, 1H), 7.30 (dd, J₁ = 2.4 Hz, J₂ = 8.7 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.00 (s, 1H), 2.49–2.54 (m, 1H), 2.28–2.37 (m, 3H), 1.18 (s, 3H), 1.12 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + CDCl₃ + DMSO): δ 197.1, 150.8, 130.3, 130.1, 127.7, 126.8, 125.1, 121.1, 90.0, 51.9, 47.9, 30.8, 29.7, 27.1; m/z (ESI); 305 [M − H₂O]H⁺. HRMS calcd for C₁₅H₁₄O₂Br: 305.01717, found: 305.01588.

5,7-Dichloro-4a-hydroxy-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3g). White solid; mp 170–172 °C; IR: v_max 3311, 2974, 2952, 2919, 1664, 1601, 1558, 1448, 1339, 1207, 1189, 1026, 984, 763 cm⁻¹; ¹H NMR (300 MHz CDCl₃ + DMSO): δ 7.42 (s, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 3.15 (s, 1H), 2.68–2.74 (m, 1H), 2.53–2.58 (m, 1H), 2.27–2.43 (m, 2H), 2.02–2.19 (m, 2H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 196.9, 147.4, 132.2, 130.4, 126.9, 125.4, 122.2, 122.1, 97.2, 38.5, 35.3, 17.6; m/z (ESI); 267 [M − H₂O]H⁺.

5,7-Dichloro-4a-hydroxy-3,3-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3h). White solid; mp 144–146 °C; IR: v_max 3305, 2972, 2955, 2923, 1660, 1605, 1561, 1456, 1344, 1211, 1186, 1018, 998, 756 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.40 (d, J = 2.4 Hz, 1H), 7.38 (s, 1H), 7.26 (d, J = 2.4 Hz, 1H), 3.18 (s, 1H), 2.50–2.55 (m, 1H), 2.39–2.46 (m, 2H), 2.28–2.33 (m, 1H), 1.19 (s, 3H), 1.13 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 197.3, 147.2, 131.2, 130.3, 126.7, 125.3, 122.4, 122.1, 97.2, 52.2, 47.9, 31.1, 30.1, 27.2; m/z (ESI); 295 [M − H₂O]H⁺. HRMS for C₁₅H₁₄O₂Cl₂: 295.02727.

5,7-Dibromo-4a-hydroxy-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3i). White solid; mp 158–160 °C; IR: v_max 3308, 3143, 2956, 2887, 1681, 1594, 1540, 1429, 1265, 1193, 985, 858 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.65 (d, J = 2.1 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 0.9 Hz, 1H), 2.56–2.71 (m, 2H), 1.94–2.44 (m, 4H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 196.6, 148.7, 135.5, 132.0, 130.1, 126.5, 125.5, 112.4, 111.0, 97.1, 38.3, 35.0, 17.3; m/z (ESI); 355 [M − H₂O]H⁺. HRMS calcd for C₁₃H₉O₂Br₂: 354.89638, found: 354.89503.

5,7-Dibromo-4a-hydroxy-3,3-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3j). White solid; mp 151–154 °C; IR: v_max 3311, 3150, 2961, 2882, 1685, 1598, 1539, 1439, 1276, 1200, 1156, 978, 947, 864 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.70 (d, J = 2.3 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.37 (s, 1H), 3.04 (s, 1H), 2.27–2.59 (m, 4H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 195.4, 147.0, 133.7, 129.8, 129.6, 129.1, 124.7, 121.7, 110.7, 109.4, 95.8, 50.5, 45.8, 29.4, 28.5, 25.4; m/z (ESI); 384 [M − H₂O]H⁺. HRMS calcd for C₁₅H₁₃O₂Br₂: 382.92768, found: 382.92612.

4a-Hydroxy-5,7-diiodo-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3k). White solid; mp 174–176 °C; IR: v_max 3229, 2950, 2867, 1666, 1609, 1525, 1434, 1317, 1282, 1155, 1098, 981, 856 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 8.00 (s, 1H), 7.62 (s, 1H), 6.95 (s, 1H), 2.51–2.68 (m, 2H), 1.88–2.44 (m, 4H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 196.5, 151.8, 146.5, 136.8, 131.8, 126.3, 122.3, 97.3, 85.9, 83.1, 38.2, 34.9, 17.3; m/z (ESI); 451 [M − H₂O]H⁺. HRMS calcd for C₁₃H₉O₂I₂: 450.86864, found: 450.86643.

4a-Hydroxy-5,7-diiodo-3,3-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3l). White solid; mp 146–148 °C; IR: v_max 3234, 2946, 2863, 1662, 1605, 1529, 1428, 1314, 1278, 1158, 1094, 983, 850 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 8.00 (s, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 3.04 (s, 1H), 2.40–2.61 (m, 2H), 2.22–2.34 (m, 2H), 1.17 (s, 3H), 1.11 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 196.8, 151.6, 146.4, 136.8, 130.7, 122.5, 97.3, 85.9, 83.0, 52.0, 47.7, 30.9, 29.9, 27.0; m/z (ESI); 479 [M − H₂O]H⁺. HRMS calcd for C₁₅H₁₃O₂I₂: 478.89754, found: 478.89719.

4a-Hydroxy-7-methoxy-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3m). White solid; mp 128–130 °C; IR: v_max 3305, 3011, 2938, 1669, 1610, 1564, 1487, 1239, 1171, 1059, 980, 865 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.43 (d, J = 2.3 Hz, 1H), 6.82–6.99 (m, 2H), 6.02–6.09 (m, 1H), 3.80 (s, 3H), 1.83–2.64 (m, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 197.2, 153.5, 146.9, 131.5, 128.4, 120.5, 117.9, 117.1, 113.1, 96.1, 55.4, 38.4, 35.4, 17.8; m/z (ESI); 229 [M − H₂O]H⁺. HRMS for C₁₃H₁₃O₃: found: 229.08490.

4a-Hydroxy-7-methoxy-3,3-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3n). White solid; mp 132–134 °C; IR: v_max 3311, 3005, 2941, 1672, 1607, 1573, 1484, 1246, 1178, 1049, 977, 862 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.44 (s, 1H), 6.92–6.99 (m, 2H), 6.85 (d, J = 2.9 Hz, 1H), 3.79 (s, 3H), 3.09 (s, 1H), 2.47–2.52 (m, 1H), 2.26–2.37 (m, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 198.1, 154.4, 146.4, 130.0, 129.7, 120.1, 119.1, 118.2, 112.7, 96.4, 55.7, 52.5, 48.8, 30.6, 28.0; m/z (ESI); 257 [M − H₂O]H⁺. HRMS calcd for C₁₆H₁₇O₃: 257.11482, found: 257.11599.

4a-Hydroxy-7-nitro-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 3o). White solid; mp 164–166 °C; IR: v_max 3396, 3092, 2949, 2879, 1674, 1605, 1569, 1529, 1346, 1271, 1210, 1161, 974, 841 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 8.28 (d, J = 2.8 Hz, 1H), 8.19 (dd, J₁ = 2.6 Hz, J₂ = 8.9 Hz, 1H), 7.47 (s, 1H), 7.10–7.15 (m, 2H), 2.51–2.73 (m, 2H), 2.32–2.47 (m, 1H), 1.95–2.27 (m, 3H), 3.00 (s, 1H), 2.49–2.54 (m, 1H), 2.28–2.37 (m, 3H), 1.18 (s, 3H), 1.12 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 196.7, 157.7, 141.3, 132.3, 126.6, 125.8, 124.4, 119.8, 117.0, 97.5, 38.4, 35.2, 17.5; m/z (ESI); 244 [M − H₂O]H⁺.

4a-Hydroxy-3,3-dimethyl-2,3,4,4a-tetrahydro-1H-benzo[b]xanthen-1-one (Table 2, 3p). White solid; mp 124–126 °C; IR: v_max 3280, 2966, 2929, 1628, 1576, 1476, 1373, 1289, 1242, 964, 823 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 8.26 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.77–7.88 (m, 2H), 7.55–7.63 (m, 1H), 7.41–7.48 (m, 1H), 7.21–7.28 (m, 1H), 3.20 (s, 1H), 2.28–2.57 (m, 4H), 1.21 (s, 3H), 1.13 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 197.2, 151.5, 131.6, 128.4, 127.9, 127.1, 126.8, 124.7, 123.6, 120.9, 117.6, 113.0, 96.1, 51.9, 48.2, 30.8, 29.9, 27.3; m/z (ESI); 277 [M − H₂O]H⁺. HRMS calcd for C₁₉H₁₈O₃Na: 317.11482, found: 317.11330.

4a-Hydroxy-2,2-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 4, 4a). White solid; mp 133–135 °C; IR: v_max 3237, 2948, 2913, 1625, 1611, 1546, 1462, 1284, 1179, 963, 851, 764 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.42 (s, 1H), 7.27–7.37 (m, 2H), 6.96–7.03 (m, 2H), 6.59 (d, J = 3.4 Hz, 1H), 2.57–2.61 (m, 1H), 2.34–2.38 (m, 1H), 2.02–2.15 (m, 1H), 1.63–1.73 (m, 1H), 1.19 (s, 3H), 1.12 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 202.2, 152.4, 130.8, 129.6, 129.3, 128.7, 120.9, 119.7, 116.1, 95.8, 42.1, 32.3, 32.1, 25.0, 24.9; m/z (ESI); 227 [M − H₂O]H⁺. HRMS calcd for C₁₅H₁₅O₂: 227.10666, found: 227.10563.

7-Chloro-4a-hydroxy-2,2-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 2, 4b). White solid; mp 161–163 °C; IR: v_max 3311, 3056, 2964, 2938, 2861, 1663, 1624, 1559, 1455, 1387, 1180, 1050, 930, 818, 750 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.34 (s, 1H), 7.32 (d, J = 2.5 Hz, 2H), 7.25 (dd, J₁ = 2.5 Hz, J₂ = 8.69 Hz, 1H), 6.95 (d, J = 8.69 Hz, 2H), 6.67 (s, 1H), 2.24–2.40 (m, 2H), 2.01–2.13 (m, 1H), 1.63–1.73 (m, 1H), 1.19 (s, 3H), 1.12 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 201.4, 150.5, 130.3, 127.3, 127.2, 124.7, 120.7, 117.1, 95.7, 41.7, 31.7, 31.4, 24.4; m/z (ESI); 261 [M − H₂O]H⁺. HRMS for C₁₅H₁₅O₂Cl: found: 261.08969.

7-Bromo-4a-hydroxy-2,2-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 4, 4c). White solid; mp 155–157 °C; IR: v_max 3269, 2968, 2924, 2861, 1673, 1620, 1556, 1472, 1245, 1152, 1048, 943, 816 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.47 (d, J = 2.5 Hz, 1H), 7.38 (dd, J₁ = 2.5 Hz, J₂ = 8.7 Hz, 1H), 7.33 (s, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.74 (s, 1H), 2.29–2.37 (m, 2H), 2.00–2.13 (m, 1H), 1.63–1.73 (m, 1H), 1.19 (s, 3H), 1.12 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 201.9, 151.3, 132.9, 130.5, 127.7, 121.6, 117.9, 112.5, 96.1, 42.1, 32.1, 31.8, 24.8; m/z (ESI); 305 [M − H₂O]H⁺. HRMS calcd for C₁₅H₁₄O₂Br: 305.01717, found: 305.01565.

5,7-Dichloro-4a-hydroxy-2,2-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 4, 4d). White solid; mp 137–139 °C; IR: v_max 3312, 2978, 2946, 2924, 1659, 1607, 1562, 1445, 1333, 1226, 1191, 1012, 988, 751 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 8.01 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 6.64 (s, 1H), 2.41–2.61 (m, 2H), 1.99–2.16 (m, 1H), 1.65–1.77 (m, 1H), 1.20 (s, 3H), 1.12 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 202.3, 147.1, 131.6, 131.5, 129.5, 129.1, 127.3, 127.2, 97.5, 43.1, 32.7, 25.3, 25.2; m/z (ESI); 295 [M − H₂O]H⁺. HRMS calcd for C₁₅H₁₃O₂Cl₂: 295.02871, found: 295.02727.

5,7-Dibromo-4a-hydroxy-2,2-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 4, 4e). White solid; mp 144–146 °C; IR: v_max 165–167 °C; IR: v_max 3317, 3148, 2953, 2874, 1687, 1589, 1536, 1433, 1264, 1187, 1151, 945, 861 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.65 (s, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 6.73 (s, 1H), 2.48–2.62 (m, 2H), 2.01–2.18 (m, 1H), 1.64–1.76 (m, 1H), 1.20 (s, 3H), 1.12 (s, 3H); m/z (ESI); 383 [M − H₂O]H⁺.

4a-Hydroxy-5,7-diiodo-2,2-dimethyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 4, 4f). White solid; mp 163–165 °C; IR: v_max 3237, 2951, 2864, 1668, 1609, 1523, 1422, 1315, 1282, 1156, 1098, 981, 855 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.35–7.39 (m, 1H), 7.31–7.35 (m, 2H), 7.09 (s, 1H), 2.29–2.56 (m, 2H), 1.94–2.12 (m, 1H), 1.65–1.76 (m, 1H), 1.18 (s, 3H), 1.11 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 201.8, 147.0, 131.4, 129.9, 127.3, 126.4, 125.1, 122.1, 121.8, 97.1, 42.3, 32.1, 31.8, 24.8, 24.7; m/z (ESI); 479 [M − H₂O]H⁺.

4a-Hydroxy-2,2-dimethyl-2,3,4,4a-tetrahydro-1H-benzo[b]xanthen-1-one (Table 4, 4g). White solid; mp 161–163 °C; IR: v_max 3280, 2966, 2929, 1628, 1576, 1476, 1373, 1289, 1123, 964, 823 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 8.23 (s, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.77–7.86 (m, 2H), 7.53–7.61 (m, 1H), 7.38–7.45 (m, 1H), 7.23 (d, J = 1.7 Hz, 1H), 6.59 (s, 1H), 2.55–2.60 (m, 1H), 2.41–2.46 (m, 1H), 2.08–2.20 (m, 1H), 1.68–1.76 (m, 1H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 202.2, 151.7, 131.7, 130.5, 128.6, 128.1, 127.4, 126.9, 125.7, 123.7, 120.9, 117.7, 112.9, 96.2, 42.0, 32.4, 32.1, 25.2; m/z (ESI); 277 [M − H₂O]H⁺.

4a-Hydroxy-3-phenyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 5, 5a). White solid; mp 146–148 °C; IR: v_max 3389, 3030, 2922, 2852, 1669, 1604, 1558, 1453, 1297, 1261, 1200, 1163, 1094, 970, 765 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.56 (s, 1H), 7.20–7.44 (s, 7H), 6.99–7.08 (m, 2H), 3.72 (s, 1H), 3.44–3.59 (m, 1H), 2.77–2.90 (m, 1H), 2.62–2.74 (m, 1H), 2.40–2.57 (m, 2H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 196.3, 152.8, 142.8, 131.2, 129.6, 129.1, 128.2, 126.1, 121.2, 119.8, 116.4, 95.7, 46.4, 42.6, 35.4; m/z (ESI); 275 [M − H₂O]H⁺. HRMS for C₁₉H₁₅O₂: found: 275.10542.

7-Chloro-4a-hydroxy-3-phenyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 5, 5b). White solid; mp 159–161 °C; IR: v_max 3390, 3030, 2929, 1675, 1617, 1555, 1470, 1283, 1200, 1162, 1081, 967, 824 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.50 (s, 1H), 7.22–7.46 (m, 7H), 3.46–3.60 (m, 1H), 3.38 (s, 1H), 2.83–3.03 (m, 1H), 2.43–2.73 (m, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 195.6, 150.9, 142.3, 130.3, 130.2, 127.8, 127.7, 127.2, 125.8, 125.2, 120.8, 117.5, 95.6, 46.0, 42.1, 34.9; m/z (ESI); 309 [M − H₂O]H⁺. HRMS for C₁₉H₁₄O₂Cl: found: 309.06605.

7-Bromo-4a-hydroxy-3-phenyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 5, 5c). White solid; mp 154–156 °C; IR: v_max 3384, 3036, 2937, 1683, 1613, 1552, 1466, 1278, 1201, 1167, 1078, 965, 826 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.50 (d, J = 2.1 Hz, 1H), 7.43 (s, 1H), 7.32–7.41 (m, 2H), 7.22–7.29 (m, 2H), 6.98 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 3.45–3.59 (m, 1H), 2.95 (s, 1H), 2.78–2.89 (m, 1H), 2.65–2.74 (m, 1H), 2.37–2.61 (m, 2H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 196.2, 151.8, 142.7, 136.6, 131.1, 130.6, 128.3, 127.7, 126.3, 126.2, 121.8, 118.4, 113.1, 96.0, 46.5, 42.6, 35.4; m/z (ESI); 353 [M − H₂O]H⁺. HRMS calcd for C₁₉H₁₄O₂Br: 353.01717, found: 353.01595.

5,7-Dichloro-4a-hydroxy-3-phenyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 5, 5d). White solid; mp 168–170 °C; IR: v_max 3392, 3035, 2926, 1678, 1614, 1557, 1471, 1285, 1204, 1169, 1083, 962, 828 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.50 (s, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.35–7.40 (m, 2H), 7.26–7.31 (m, 4H), 3.50–3.58 (m, 1H), 3.11 (s, 1H), 2.91–2.97 (m, 1H), 2.75–2.80 (m, 1H), 2.53–2.64 (m, 2H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 195.7, 147.2, 142.3, 131.2, 130.2, 128.0, 126.9, 126.1, 126.0, 125.2, 122.0, 121.9, 96.7, 46.2, 42.3, 35.1; m/z (ESI); 343 [M − H₂O]H⁺.

5,7-Dibromo-4a-hydroxy-3-phenyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (Table 5, 5e). White solid; mp 172–174 °C; IR: v_max 3390, 3030, 2929, 1675, 1617, 1555, 1470, 1283, 1200, 1162, 1081, 967, 824 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.53–7.72 (m, 2H), 7.15–7.52 (m, 7H), 2.39–2.86 (m, 5H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 194.7, 147.7, 141.5, 134.5, 130.3, 129.5, 127.1, 125.7, 125.2, 121.8, 111.5, 109.9, 95.9, 45.1, 41.2, 34.2; m/z (ESI); 431 [M − H₂O]H⁺.

4a-Hydroxy-3-phenyl-2,3,4,4a-tetrahydro-1H-benzo[b]xanthen-1-one (Table 5, 5f). White solid; mp 155–157 °C; IR: v_max 3389, 3030, 2922, 2852, 1669, 1604, 1558, 1453, 1297, 1261, 1200, 1163, 1094, 970, 765 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 8.37 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.72–7.89 (m, 2H), 7.52–7.64 (m, 1H), 7.22–7.49 (m, 8H), 3.52–3.66 (m, 1H), 3.47 (s, 1H), 2.86–3.00 (m, 1H), 2.66–2.81 (m, 1H), 2.48–2.63 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ 196.4, 152.7, 142.8, 131.2, 129.6, 129.2, 129.1, 128.2, 126.1, 121.2, 119.7, 116.4, 95.7, 46.4, 42.6, 35.4; m/z (ESI); 325 [M − H₂O]H⁺.

Acknowledgements

The authors thank CSIR, New Delhi, for financial support as part of XII. Five Year Plan Program under the title ORIGIN (CSC-0108) and Dr A. Kamal, outstanding scientist and Head of MCP Division, for his support and encouragement. LCR and NSK thank CSIR for the award of a fellowship.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1032788. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra10675c

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