Copper catalyzed coupling of protecting group free and sterically hindered 2-bromobenzyl tertiary alcohols with phenols and anilines: facile synthesis of xanthenes and dihydroacridines

Abstract

A simple and efficient method for the synthesis of xanthenes and dihydroacridines containing a quaternary carbon atom at the 9^th-position, is presented. Significantly, the protocol facilitated the smooth participation of sterically hindered and protecting group free 2-bromobenzyl tertiary alcohols in cross coupling reactions with phenols and anilines, under copper-catalysis. The Lewis acid mediated intramolecular C–C bond formation enabled the formation of a quaternary carbon atom at the 9^th-position. Remarkably, this two-step protocol required a single column purification technique.

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Introduction

Xanthenes¹ and xanthones² are a special class of tricyclic dibenzopyrans, since these skeletons constitute pharmaceutically important compounds and natural products as well. Their other uses include dyes or fluorescent materials and chiroptical molecular switches.³ They exhibit a variety of physicochemical and pharmacological properties (e.g. anti-oxidants, anti-bacterial, anti-tumoral, anti-neoplastics, vasodilators and anti-inflammatory activities).⁴ Interestingly, their biological behaviour depends upon the nature and position of the substituents on their structure.⁵ Some of the notable natural and unnatural compounds are as depicted in Fig. 1. Vowing to their occurrence from natural sources of biological relevance and pharmaceutical reputation of analogues compounds, prompted organic chemists to design and develop new synthetic methods to establish functionalized xanthenes. Though a good number of methods established for their synthesis, most of them either require pre-synthesized precursors or involve multi-step protocols.⁶ On the other hand, one-step processes for their synthesis are very few.⁷ Particularly, some of the established strategies affording 9-substituted xanthenes, have some limitations, either due to low yields or require multiple steps. Therefore, it is highly desirable to develop new and efficient methods to achieve 9-substituted xanthenes.

Fig. 1 Some of the notable examples of natural/unnatural xanthones (1 to 7), xanthenes (8 to 13), acridones (14 to 15), dihydroacridine (16) and acridines (17 to 20).

On the other hand, acridines are another class of important nitrogen containing heterocyclic compounds, in which the oxygen atom of xanthenes replaced with nitrogen and with complete aromatization. Acridines are also well known for their broad range of biological and medicinal properties.⁸ In this regard, some important natural and unnatural products are as shown in Fig. 1. Notably, dihydroacridine analogue found as selective activator of temperature- and mechano-sensitive K_2P channels.⁹ Since it is certain that acridines are indispensable compounds, development of efficient protocols for their synthesis is very much essential. Apart from the well-established named reaction (Bernthsen acridine synthesis), recently, there are good number of approaches developed for the synthesis of acridines from eminent research groups.¹⁰ In continuation of our on-going research interests on transition-metal mediated efficient transformations,¹¹ herein we disclose an efficient method for synthesis of xanthenes and dihydroacridines containing a quaternary carbon atom at 9^th-position. This protocol enabled the accomplishment of xanthenes and dihydroacridines with simple to dense functionality on the aromatic ring. Significantly, this two-step process required a single column chromatographic technique.

Result and discussion

Though methods were known for the synthesis of 9-substititued xanthenes/acridines, most of them were made with the tertiary carbon atoms at 9^th-position. Also, many of them were based on multistep processes or using derivatization of simple xanthenes. Whereas, most of one-pot protocols were limited to the synthesis of simple xanthenes without any substitution at 9^th-carbon centre. Moreover, to the best of our knowledge, there is no report on the direct synthesis of xanthenes/acridines with a quaternary carbon atom at 9^th-position. Further, 9,9-dimethylxanthene was identified as the useful synthon, for the synthesis of novel ligands (xanthphos etc.),¹² which were proved to be vital in metal-catalysis. All earlier reports for the synthesis of 9,9-dimethylxanthene accomplished using xanthone as the synthetic precursor through di-methylation with trimethylaluminium (AlMe₃).¹³ With these observations, it was prompted us to develop new and efficient method for the synthesis of xanthenes and acridines with a quaternary carbon atom at 9^th-position, which may not only open a path for accomplishment of new compounds of biological relevance but also could further expand scope to develop new sort of ligands in-order to prepare efficient metal-catalysts. In our laboratory, recently, we have demonstrated the efficient and domino one-pot conversions of 2-bromotertiary benzyl alcohols into novel heterocyclic compounds using transition-metal catalysis. With this background, we envisioned that xanthenes 21 and dihydroacridines 22 could be obtained from sterically hindered and protecting free 2-bromotertiary benzyl alcohols 23 using copper-catalyzed Buchwald–Hartwig coupling with phenols 24/anilines 25 and acid induced intramolecular C–C bond formation (Scheme 1).

Scheme 1 Retrosynthetic analysis to give 21/22 from alcohols 23 and phenols 24/anilines 25.

To initiate the synthetic study, first we decided to examine the coupling reaction between the simple tertiary alcohol 23a and the phenol 24a. Thus, the reaction was performed in the presence of catalyst CuI (10 mol%)/1,10-phen (20 mol%), base Na₂CO₃ (2 equiv.) in toluene at 110 °C for 24 h. As anticipated, the product 26aa was obtained in moderate yield along with the unreacted starting material 23a (Table 1, entry 1). To our delight, as we presumed, the tertiary alcohol moiety was not interfered in the reaction. This may be due to the fact that though the tertiary hydroxyl group is more nucleophilic than phenolic OH, the steric hindrance around the tert-OH moiety might be severe and not allowed it to participate in the competitive intermolecular coupling. Also, it was well demonstrated in one of our earlier reports that this tertiary alcohol did not prefer intramolecular coupling to give oxetane derivatives. Interestingly, with bases K₂CO₃ and K₃PO₄, gave the product 26aa, in very good yields (Table 1, entries 2 & 3). While, no progress was noted with mild base NaHCO₃ (Table 1, entry 4). To our delight, the reaction with the strong base Cs₂CO₃, furnished the product 26aa, in excellent yield (Table 1, entry 5). On the other hand, the solvents DMF and DMA instead of toluene with base Cs₂CO₃, gave good yields of the product 26aa (Table 1, entries 6 & 7). However, the reactions in other solvents such DMSO and CH₃CN were found further inferior (Table 1, entries 8 & 9).

Table 1 Optimization conditions for the formation of biaryl ether 26aa

Entry^a	Base (2 equiv.)	Solvent	Yield of 26aa^b
a All reactions were carried out on 0.5 mmol of 23a and 1 mmol of 24a in 0.5 mL solvent.b Isolated yields of chromatographically pure products.c Starting material also recovered along with the product.
1	Na2CO3	Toluene	50% + SM^c
2	K2CO3	Toluene	84%
3	K3PO4	Toluene	76%
4	NaHCO3	Toluene	SM
5	Cs2CO3	Toluene	91%
6	Cs2CO3	DMF	73%
7	Cs2CO3	DMA	72%
8	Cs2CO3	DMSO	65% + SM^c
9	Cs2CO3	CH3CN	53% + SM^c

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With the optimized reaction conditions in hand (Table 1, entry 5), to check the scope of the method, we explored the reaction between 2-bromotertiary benzyl alcohols 23a/23e and phenols 24a/24b and aninlines 25a/25b. To our delight, the reaction found amenable and furnished the biaryl ethers 26aa/24eb and coupled anilines 27aa/27ab, in very good to excellent yields (Table 2).

Table 2 Synthesis of biaryl ethers 26aa/26eb and coupled anilines 27aa/27ab^a,b,c,d

a Reaction conditions: 23a & 23e (0.50 mmol), 24a & 24b (1.00 mmol), CuI (10 mol%), 1,10-phenanthroline (20 mol%), Cs₂CO₃ (1.0 mmol), in 0.5 mL toluene, at 110 °C for 24 h.b Isolated yields of chromatographically pure products.c For final compounds 26aa & 26eb, the first alphabet represents from 2-bromobenzyl tertiary alcohols 23a & 23e, while second letter indicates the phenols 24a & 24b.d For final compounds 27aa & 27ab the first alphabet represents from 2-bromobenzyl tertiary alcohol 23a, while second letter indicates the anilines 25a & 25b.

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With these coupled ethers 26aa/26eb and anilines 27aa/27ab, we next planned for acid promoted intramolecular C–C bond formation. Thus, the reaction was carried out with the Lewis acid BF₃·OEt₂ in DCM at 0 °C to rt for 30 min. Gratifyingly, the reaction was quite successful and furnished the corresponding xanthenes 21aa/21eb and dihydroacridines 22aa/22ab, in good to excellent yields (Table 3).

Table 3 Synthesis of xanthenes 21aa/21eb and dihydroacridines 22aa/22ab^a,b,c,d

a Reaction conditions: (26aa, 26eb) & (27aa, 27ab) (0.25 mmol), BF₃·OEt₂ (2 equiv.), in 2 mL DCM, at 0 °C to rt for 30 min.b Isolated yields of chromatographically pure products.c For final compounds 21aa & 21eb, the first alphabet represents from 2-bromobenzyl tertiary alcohols 23a & 23e, while second letter indicates the phenols 24a & 24b.d For final compounds 22aa & 22ab the first alphabet represents from 2-bromobenzyl tertiary alcohol 23a, while second letter indicates the anilines 25a & 25b.

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After the accomplishment of xanthenes 21aa/21fa and dihydroacridines 22aa/22ab, we thought that protocol can be made still more efficient by conducting acid mediated cyclization directly on the concentrated crude reaction mixture of biaryl ethers 26 and coupled anilines 27 without column purification, so that we may end up in doing a single column chromatography for two-steps together. Thus, initially, we have directly treated the crude biaryl ethers 26aa–26gb with BF₃·OEt₂. To our delight, as expected, afforded the xanthenes 21aa–21gb, in good to very good yields (Table 4), thus enable us to make the method more efficient and interesting.

Table 4 Synthesis of xanthenes 21aa–21gb^a,b,c

a Reaction conditions: 23a–23g (0.50 mmol), 24a–24b (1.00 mmol), CuI (10 mol%), 1,10-phenthroline (20 mol%), Cs₂CO₃ (1.0 mmol), in 0.5 mL toluene, at 110 °C for 24 h then work up and evaporated under vacuum added BF₃·OEt₂ (2 equiv.) in 2 mL DCM, at 0 °C to rt for 30 min.b Isolated yields of chromatographically pure products.c For xanthenes 21aa–21gb, the first alphabet represents from 2-bromobenzyl tertiary alcohols 23a–23g, while second letter indicates the anilines 24a–24b.

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Similarly, the crude coupled anilines 27aa–27bh were subjected to BF₃·OEt₂ induced cyclization. Quite interestingly, as anticipated, the strategy was also proved amenable and furnished the dihydroacridines 22aa–22hb (Table 5). Remarkably, the reaction was also successful with strong electron withdrawing nitro group (22ac, Table 5). Thus reveals the significance of the present strategy. It is worth noting that the reaction with 2-bromobenzyl secondary alcohols was unclear (i.e. neither starting material nor the product was isolated). This is in accordance with our earlier observations that only 2-bromobenzyl tertiary alcohols were suitable for intermolecular Sonogashira^11e and cyanations^11f followed by intramolecular nucleophilic attacks, under copper catalysis, whereas the reaction was unclear with the corresponding primary or secondary alcohols, under standard reaction conditions.

Table 5 Synthesis of xanthenes 22aa–22hb^a,b,c

a Reaction conditions: 23a–23h (0.50 mmol), 25a–25c (1.00 mmol), CuI (10 mol%), 1,10-phenthroline (20 mol%), Cs₂CO₃ (1.0 mmol), in 0.5 mL toluene, at 110 °C for 24 h then work up and evaporated under vacuum added BF₃·OEt₂ (2 equiv.) in 2 mL DCM, at 0 °C to rt for 30 min.b Isolated yields of chromatographically pure products.c For dihydroacridines 22aa–22hb, the first alphabet represents from 2-bromobenzyl tertiary alcohols 23a–23h, while second letter indicates the anilines 25a–25c.

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In addition to the spectroscopic evidence for the structural confirmation of xanthenes 21 and dihydroacridines 22, the structures were confirmed by the single crystal X-ray diffraction analysis of 21ab and 22ac Fig. 2 (see ESI†).

Fig. 2 X-ray crystal structure of product 21ab and 22ac. Thermal ellipsoids are drawn at 50% probability level.

Conclusion

In summary, we have disclosed a simple and efficient method for the synthesis of xanthenes and acridines containing a quaternary carbon atom at 9^th-position. Significantly, sterically hindered and protecting group free 2-bromobenzyl tertiary alcohols were involved in smooth coupling reaction with phenols and anilines, under copper-catalysis. The Lewis acid mediated intramolecular C–C bond formation enable the formation of quaternary carbon atom at 9^th-position. Remarkably, this two-step protocol required single column purification technique.

Experimental section

General considerations

IR spectra were recorded on a FTIR spectrophotometer. ¹H NMR spectra were recorded on 400 MHz spectrometer at 295 K in CDCl₃; chemical shifts (δ ppm) and coupling constants (Hz) are reported in standard fashion with reference to either internal standard tetramethylsilane (TMS) (δ_H = 0.00 ppm) or CHCl₃ (δ_H = 7.25 ppm). ¹³C NMR spectra were recorded on 100 MHz spectrometer at RT in CDCl₃; chemical shifts (δ ppm) are reported relative to CHCl₃ [δ_C = 77.00 ppm (central line of triplet)]. In the ¹³C NMR, the nature of carbons (C, CH, CH₂, and CH₃) was determined by recording the DEPT-135 spectra and is given in parentheses and noted as s = singlet (for C), d = doublet (for CH), t = triplet (for CH₂) and q = quartet (for CH₃). In the ¹H NMR, the following abbreviations were used throughout: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, m = multiplet and br s = broad singlet. The assignment of signals was confirmed by ¹H, ¹³C CPD (carbon proton decoupled), and DEPT spectra. High-resolution mass spectra (HR-MS) were recorded using Q-TOF multimode source. Melting points were determined on an electrothermal melting point apparatus and are uncorrected. Benzaldehydes, methyl iodide, bromoethane, Mg metal and Na₂SO₄ were commercially available (local made) used without further purification. CuI, 1,10-phenthroline and Cs₂CO₃ purchased from Sigma-Aldrich, while BF₃·OEt₂ was used from local commercial sources. All dry solvents were used, diethyl ether and toluene were dried over sodium metal, DCM and DMF were dried over calcium hydride.

All the solvents (diethyl ether, DCM, DMF) are commercially available. All small scale dry reactions were carried out using standard syringe-septum technique. Reactions were monitored by TLC on silica gel using a combination of petroleum ether and ethyl acetate as eluents. Reactions were generally run under inert atmosphere. Solvents were distilled prior to use; petroleum ether with a boiling range of 40 to 60 °C was used. Acme's silica gel (60–120 mesh) was used for column chromatography (approximately 20 g per one gram of crude material).

General procedure-1 (for the synthesis of aryl ethers 26 and aryl amines 27). In an oven-dried Schlenk tube 2-bromobenzyl tertiary alcohols 23 (0.5 mmol), phenols 24 or anillines 25 (1.00 mmol), CuI (10 mol%), 1,10-phenthroline (20 mol%), Cs₂CO₃ (1.0 mmol) and solvent toluene (0.5 mL) were added. The resulting reaction mixture was stirred at 110 °C for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, then saturated aqueous NH₄Cl was added fallowed by extraction with ethyl acetate. The organic layers were dried (Na₂SO₄) and concentrated in vacuo. Purification of the residue by silica gel column chromatography using petroleum ether/ethyl acetate as the eluent furnished the aryl ethers 26 and aryl amines 27.

General procedure-2 (for the synthesis of xanthenes 21 and dihydroacridines 22). In an oven-dried Schlenk tube aryl ethers 26 or aryl amines 27 (0.25 mmol) dissolved in 2 mL dry DCM, BF₃·OEt₂ (2 equiv.) was added at 0 °C. The resulting reaction mixture was stirred at 0 °C to rt for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with (10 mL) water and extracted with DCM fallowed by washed with NaHCO₃. The organic layers were dried (Na₂SO₄) and concentrated in vacuo. Purification of the residue by silica gel column chromatography using petroleum ether/ethyl acetate as the eluent furnished the xanthenes 21 and dihydroacridines 22.

General procedure-3 (for the synthesis of xanthenes 21 and dihydroacridines 22 using single column purification). In an oven-dried Schlenk tube 2-bromobenzyl tertiary alcohol 23 (0.5 mmol), phenols 24 or anilline 25 (1.00 mmol), CuI (10 mol%), 1,10-phenthroline (20 mol%), Cs₂CO₃ (1.0 mmol) and toluene (0.5 mL) were added. The resulting reaction mixture was stirred at 110 °C for 24 h. After completion of reaction, the reaction mixture was allowed to cool to room temperature, then diluted with (10 mL) ethyl acetate and water was added fallowed by extraction with ethyl acetate. The organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude reaction mixture of aryl ethers 26 and aryl amines 27 was dissolved in 2 mL dry DCM, BF₃·OEt₂ (2 equiv.) was added at 0 °C. The resulting reaction mixture was stirred at 0 °C to rt for 30 min. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with (10 mL) water and extracted with DCM fallowed by washed with NaHCO₃. The organic layers were dried (Na₂SO₄) and concentrated in vacuo. Purification of the residue by silica gel column chromatography using petroleum ether/ethyl acetate as the eluent furnished the xanthenes 21 and acridines 22.

2-(2-Phenoxyphenyl)propan-2-ol (26aa). This compound was prepared according to the GP-1 and isolated as pale yellow color oil 91% yield (103 mg): [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23a) = 0.60, R_f (26aa) = 0.60, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 3416, 2971, 1576, 1481, 1442, 1364, 1224, 1162, 1072, 854, 752, 690 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 7.51 (d, 1H, J = 7.8 Hz), 7.36 (dd, 2H, J = 8.8 and 7.3 Hz), 7.15 (d, 2H, J = 7.8 Hz), 7.10–7.00 (m, 3H), 6.79 (d, 1H, J = 7.8 Hz), 1.68 (s, 6H, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 156.4 (s, C_q), 154.9 (s, C_q), 138.2 (d, CH), 129.9 (d, 2C, CH), 128.1 (d, CH), 126.3 (d, CH), 123.8 (d, CH), 123.2 (d, CH), 119.4 (d, 2C, CH), 118.7 (d, CH), 72.4 (s, C_q), 30.0 (q, 2C, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₁₅H₁₅O]⁺ = [(M + H) − H₂O]⁺: 211.117; found 211.1118.

2-(5-Methoxy-2-(naphthalen-2-yloxy)phenyl)butan-2-ol (26eb). This compound was prepared according to the GP-3 and isolated as pale yellow color viscous liquid 90% yield (144 mg): [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23e) = 0.40, R_f (26eb) = 0.40, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 3447, 2964, 1598, 1461, 1251, 1194, 1037, 961, 810, 742 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 7.85–7.76 (m, 2H, Ar–H), 7.68 (d, 1H, J = 7.8 Hz, Ar–H), 7.50–7.35 (m, 2H, Ar–H), 7.30–7.20 (m, 2H, Ar–H), 7.14 (d, 1H, J = 3.4 Hz, Ar–H), 6.85 (d, 1H, J = 8.8 Hz, Ar–H), 6.74 (dd, 1H, J = 8.8 and 2.9 Hz, Ar–H), 3.83 (s, 3H, Ar-OCH₃), 2.15–2.00 (m, 1H, CH₂), 1.95–1.80 (m, 1H, CH₂), 1.61 (s, 3H, CH₃), 0.84 (t, 3H, J = 7.3 Hz, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 155.6 (s, Ar–C), 155.5 (s, Ar–C), 147.3 (s, Ar–C), 139.4 (s, Ar–C), 134.3 (s, Ar–C), 129.9 (d, Ar-CH), 127.7 (d, Ar-CH), 127.0 (d, Ar-CH), 126.6 (d, Ar-CH), 124.6 (d, Ar-CH), 121.2 (d, Ar-CH), 119.3 (d, Ar-CH), 113.4 (s, Ar-CH), 113.1 (d, Ar-CH), 112.6 (d, Ar-CH), 75.1 (s, Ar–C), 55.6 (q, OCH₃), 34.8 (t, CH₂), 27.7 (q, CH₃), 8.7 (q, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₁H₂₂NaO₃]⁺ = [M + Na]⁺: 345.1461; found 345.1457.

2-(2-(Diphenylamino)phenyl)propan-2-ol (27aa). This compound was prepared according to the GP-1 and isolated as black color semi solid 86% yield (130 mg): [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23a) = 0.60, R_f (27aa) = 0.70, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 3396, 2975, 1587, 1486, 1258, 1161, 907, 821, 728, 693 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 7.56–7.50 (m, 1H), 7.30–7.15 (m, 6H), 7.10–7.04 (m, 1H), 7.03–7.93 (m, 6H), 5.11 (br s, 1H), 1.36 (s, 6H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 148.2 (s, 2C, C_q), 146.0 (s, C_q), 143.9 (s, C_q), 132.7 (d, CH), 129.1 (d, 4C, CH), 128.3 (d, CH), 127.8 (d, CH), 127.0 (d, CH), 122.6 (d, 6C, CH), 73.6 (s, C_q), 31.2 (q, 2C, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₁H₂₂NO]⁺ = [M + H]⁺: 304.1696; found 304.1695.

12,12-Dimethyl-12H-benzo[a]xanthene (21aa). This compound was prepared according to the GP-3 and isolated as white color solid 70% yield (90 mg): mp: 98–100 °C; [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23aa) = 0.60, R_f (21aa) = 0.80, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2930, 1625, 1575, 1491, 1336, 1245, 1142, 1036, 956, 811, 747, 666 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 8.48 (d, 1H, J = 8.8 Hz), 7.82 (d, 1H, J = 8.3 Hz), 7.71 (d, 1H, J = 8.8 Hz), 7.51 (d, 2H, J = 7.8 Hz), 7.38 (dd, 1H, J = 6.8 and 8.3 Hz), 7.22 (dd, 2H, J = 6.4 and 8.8 Hz), 7.13 (dd, 1H, J = 7.3 and 7.8 Hz), 7.03 (d, 1H, J = 7.8 Hz), 2.16 (s, 6H, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 147.7 (s, C_q), 147.3 (s, C_q), 132.0 (s, C_q), 131.8 (s, C_q), 131.7 (s, C_q), 129.7 (d, CH), 129.4 (d, CH), 127.7 (d, CH), 127.2 (d, CH), 126.0 (d, CH), 125.6 (d, CH), 123.3 (d, CH), 123.1 (d, CH), 119.8 (s, C_q), 118.5 (d, CH), 115.7 (d, CH), 34.6 (s, C_q), 32.5 (q, 2C, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₁₉H₁₇O]⁺ = [M + H]⁺: 261.1274; found 261.1262.

12-Ethyl-12-methyl-12H-benzo[a]xanthene (21bb). This compound was prepared according to the GP-3 and isolated as pale yellow color oil 73% yield (99 mg): [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23b) = 0.50, R_f (21bb) = 0.60, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2964, 1588, 1491, 1342, 1247, 1142, 1052, 957, 812, 749, 670 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 8.47 (d, 1H, J = 8.8 Hz), 7.79 (d, 1H, J = 8.3 Hz), 7.69 (d, 1H, J = 8.8 Hz), 7.47 (d, 1H, J = 6.8 Hz), 7.44 (dd, 1H, J = 6.8 and 7.8 Hz, Ar–H), 7.36 (dd, 1H, J = 6.8 and 7.8 Hz), 7.19 (d, 2H, J = 8.8 Hz), 7.10 (dd, 1H, J = 7.8 and 8.8 Hz), 6.99 (d, 1H, J = 7.8 Hz), 2.93–3.06 (m, 1H, CH₂), 2.15 (s, 3H, CH₃), 1.97–2.08 (m, 1H, CH₂), 0.49 (t, 3H, J = 7.3 Hz, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 149.5 (s, C_q), 148.9 (s, C_q), 132.0 (s, C_q), 131.8 (s, C_q), 129.7 (d, CH), 129.4 (d, CH), 129.2 (s, C_q), 127.1 (d, 2C, CH), 125.6 (d, 2C, CH), 123.3 (d, CH), 123.2 (d, CH), 118.4 (d, CH), 117.0 (s, C_q), 115.3 (d, CH), 39.9 (s, C_q), 36.0 (t, CH₂), 31.9 (q, CH₃), 10.5 (t, CH₃)] ppm. HR-MS (ESI⁺) m/z calculated for [C₂₀H₁₉O]⁺ = [M + H]⁺: 275.1430; found 275.1428.

12,12-Diethyl-12H-benzo[a]xanthene (21cb). This compound was prepared according to the GP-3 and isolated as white color solid 83% yield (118 mg): mp: 86–88 °C; [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23c) = 0.50, R_f (21cb) = 0.70, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2964, 1587, 1491, 1350, 1242, 1131, 1037, 961, 812, 747, 671 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 8.53 (d, 1H, J = 8.8 Hz), 7.80 (d, 1H, J = 7.8 Hz), 7.70 (d, 1H, J = 8.8 Hz), 7.46 (dd, 1H, J = 7.3 and 8.8 Hz), 7.40 (dd, 1H, J = 7.3 and 7.8 Hz), 7.36 (dd, 1H, J = 6.8 and 7.8 Hz), 7.20 (d, 2H, J = 8.8 Hz), 7.10 (dd, 1H, J = 7.3 and 8.3 Hz), 7.00 (d, 2H, J = 8.3 Hz), 2.95–3.08 (m, 2H, CH₂), 1.98–2.11 (m, 2H, CH₂) 0.51 (t, 6H, J = 7.3 Hz, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 151.1 (s, C_q), 150.4 (s, C_q), 132.2 (s, C_q), 131.7 (s, C_q), 129.7 (d, CH), 129.5 (d, CH), 127.1 (d, CH), 126.5 (s, C_q), 126.4 (d, CH), 125.6 (d, CH), 125.1 (d, CH), 123.3 (d, CH), 123.2 (d, CH), 118.4 (d, CH), 115.2 (d, CH), 114.3 (s, C_q), 46.0 (s, C_q), 34.8 (t, CH₂), 10.2 (q, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₁H₂₁O]⁺ = [M + H]⁺: 289.1587; found 289.1577.

10-Methoxy-12,12-dimethyl-12H-benzo[a]xanthene (21db). This compound was prepared according to the GP-3 and isolated as white color solid 82% yield (118 mg): mp: 92–94 °C; [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23d) = 0.40, R_f (21db) = 0.60, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2932, 1577, 1498, 1338, 1240, 1173, 1042, 958, 810, 730, 601 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 8.44 (d, 1H, J = 8.8 Hz), 7.80 (d, 1H, J = 8.3 Hz), 7.68 (d, 1H, J = 8.8 Hz), 7.49 (dd, 1H, J = 6.8 and 8.3 Hz), 7.36 (dd, 1H, J = 6.8 and 7.8 Hz), 7.17 (d, 1H, J = 8.8 Hz), 7.01 (s, 1H), 6.96 (d, 1H, J = 8.8 Hz), 6.78 (d, 1H, J = 8.8 Hz), 3.84 (s, 3H, CH₃), 2.14 (s, 6H, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 155.4 (s, C_q), 147.4 (s, C_q), 142.0 (s, C_q), 132.5 (s, C_q), 131.8 (s, C_q), 129.6 (d, CH), 129.4 (d, CH), 125.9 (d, CH), 125.6 (d, CH), 123.1 (d, CH), 119.3 (s, C_q), 118.8 (d, CH), 118.5 (s, C_q), 116.3 (d, CH), 112.9 (d, CH), 112.7 (d, CH), 55.7 (q, CH₃), 35.0 (s, CH₃), 32.2 (q, 2C, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₀H₁₉O₂]⁺ = [M + H]⁺: 291.1380; found 291.1376.

12-Ethyl-10-methoxy-12-methyl-12H-benzo[a]xanthene (21eb). This compound was prepared according to the GP-3 and isolated as pale yellow color viscous liquid 89% yield (134 mg): [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23e) = 0.40, R_f (21eb) = 0.60, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2965, 1592, 1474, 1312, 1211, 1039, 933, 879, 745, 610 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 8.46 (d, 1H, J = 8.8 Hz), 7.79 (d, 1H, J = 8.3 Hz), 7.69 (d, 1H, J = 8.8 Hz), 7.47 (dd, 1H, J = 6.8 and 8.3 Hz), 7.36 (dd, 1H, J = 6.8 and 7.8 Hz), 7.17 (d, 1H, J = 8.8 Hz), 6.97 (s, 1H), 6.94 (d, 1H, J = 8.8 Hz), 6.78 (d, 1H, J = 8.8 Hz), 3.84 (s, 3H, CH₃), 3.10–2.90 (m, 1H, CH₂), 2.10–2.95 (m, 1H, CH₂), 2.16 (s, 3H, CH₃), 0.50 (t, 3H, J = 7.3 Hz, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 155.4 (s, C_q), 149.0 (s, C_q), 143.8 (s, C_q), 131.9 (s, C_q), 131.7 (s, C_q), 130.0 (d, CH), 129.6 (d, CH), 129.4 (d, CH), 125.5 (d, CH), 123.2 (d, CH), 118.4 (d, CH), 116.1 (s, C_q), 116.0 (d, CH), 112.8 (d, CH), 112.0 (d, CH), 55.7 (q, CH₃), 40.3 (s, C_q), 35.7 (t, CH₂), 31.6 (q, CH₃), 10.5 (q, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₂H₂₂N]⁺ = [M + H]⁺: 305.1536; found 305.1537.

9,10-Dimethoxy-12,12-dimethyl-12H-benzo[a]xanthene (21fb). This compound was prepared according to the GP-3 and isolated as brown color solid 90% yield (127 mg): mp: 68–70 °C; [TLC (petroleum ether/ethyl acetate 8 : 2, R_f (23f) = 0.40, R_f (21fb) = 0.60, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2933, 1629, 1510, 1402, 1339, 1241, 1150, 1078, 998, 815, 750, 668 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 8.42 (d, 1H, J = 8.8 Hz), 7.78 (d, 1H, J = 7.8 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.48 (dd, 1H, J = 7.3 and 8.8 Hz), 7.35 (dd, 1H, J = 7.8 and 7.8 Hz), 7.14 (d, 1H, J = 8.8 Hz), 6.92 (s, 1H), 6.54 (s, 1H), 3.92 (s, 3H, CH₃), 3.89 (s, 3H, CH₃), 2.10 (s, 6H, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 148.4 (s, C_q), 147.5 (s, C_q), 145.2 (s, C_q), 131.9 (s, 2C, C_q), 129.6 (d, CH), 129.3 (d, CH), 126.0 (d, CH), 125.6 (d, CH), 123.2 (d, CH), 122.3 (s, C_q), 119.3 (s, C_q), 118.4 (d, CH), 110.3 (d, CH), 99.2 (d, CH), 56.6 (q, CH₃), 56.0 (q, CH₃), 34.6 (s, C_q), 32.2 [q, 2C, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₁H₂₁O₃]⁺ = [M + H]⁺: 321.1485; found 321.1487.

12-Ethyl-9,10-dimethoxy-12-methyl-12H-benzo[a]xanthene (21gb). This compound was prepared according to the GP-3 and isolated as pale yellow color solid 78% yield (129 mg): mp: 93–95 °C; [TLC (petroleum ether/ethyl acetate 8 : 2), R_f (23g) = 0.40, R_f (21gb) = 0.60, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2963, 1592, 1474, 1312, 1211, 1039, 933, 879, 746, 699 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 8.44 (d, 1H, J = 8.8 Hz), 7.78 (d, 1H, J = 6.8 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.46 (dd, 1H, J = 6.8 and 8.8 Hz), 7.34 (dd, 1H, J = 6.8 and 7.8 Hz), 7.14 (d, 1H, J = 8.8 Hz), 6.86 (s, 1H), 6.54 (s, 1H), 3.91 (s, 3H, CH₃), 3.90 (s, 3H, CH₃), 3.05–2.85 (m, 1H, CH₂), 2.12 (s, 3H, CH₃), 2.10–1.90 (m, 1H, CH₂), 0.48 (t, 3H, J = 7.3 Hz, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 149.1 (s, C_q), 148.3 (s, C_q), 145.2 (s, C_q), 143.6 (s, 1C, C_q), 132.0 (s, C_q), 131.8 (s, C_q), 129.6 (d, CH), 129.4 (d, CH), 125.6 (d, 2C, CH), 123.2 (d, CH), 119.6 (s, C_q), 118.3 (d, CH), 116.5 (s, C_q), 109.5 (d, CH), 99.0 (d, CH), 56.6 (q, CH₃), 55.9 (q, CH₃), 39.9 (s, CH₃), 35.4 (t, CH₂), 31.6 (q, CH₃), 10.5 (q, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₂H₂₃O₃]⁺ = [M + H]⁺: 349.1672; found 349.1669.

9,9-Dimethyl-10-phenyl-9,10-dihydroacridine (22ab). This compound was prepared according to the GP-2 and 3 isolated as black color solid 77% yield (109 mg): mp: 116–118 °C; [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23a) = 0.50, R_f (22ab) = 0.70, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2965, 2923, 1584, 1473, 1450, 1331, 1263, 1061, 906, 742, 697 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 7.63 (dd, 2H, J = 7.8 and 7.8 Hz), 7.51 (dd, 1H, J = 7.3 and 7.3 Hz), 7.47 (d, 2H, J = 7.3 Hz), 7.35 (d, 2H, J = 7.3 Hz), 6.98 (dd, 2H, J = 7.3 and 7.8 Hz), 6.93 (dd, 2H, J = 7.3 and 7.3 Hz), 6.27 (d, 2H, J = 8.3 Hz), 1.71 (s, 6H, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 141.2 (s, C_q), 140.9 (s, 2C, C_q), 131.3 (d, 2C, CH), 130.8 (d, 2C, 2 CH), 129.9 (s, 2C, C_q), 128.2 (d, 2C, CH), 126.3 (d, 2C, CH), 125.1 (d, 2C, CH), 120.5 (d, 2C, CH), 114.0 (d, 2C, CH), 35.9 (s, C_q), 31.2 (q, 2C, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₁H₂₀N]⁺ = [M + H]⁺: 286.1590; found 286.1596.

9-Ethyl-9-methyl-10-phenyl-9,10-dihydroacridine (22bb). This compound was prepared according to the GP-3 and isolated as brown color solid 71% yield (106 mg): mp: 84–86 °C; [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23b) = 0.50, R_f (22bb) = 0.70, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2962, 1589, 1476, 1334, 1268, 1164, 1028, 907, 743, 699 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 7.62 (dd, 2H, J = 7.3 and 7.8 Hz), 7.49 (dd, 1H, J = 7.3 and 7.8 Hz), 7.37 (d, 2H, J = 7.8 Hz), 7.30 (d, 2H, J = 8.3 Hz), 6.94 (dd, 2H, J = 7.3 and 8.8 Hz), 6.89 (dd, 2H, J = 7.3 and 8.8 Hz), 6.19 (d, 2H, J = 8.3 Hz), 1.93 (q, 2H, J = 7.3 Hz, CH₂), 1.77 (s, 3H, CH₃), 0.70 (t, 3H, J = 7.3 Hz, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 141.5 (s, 2C, C_q), 141.3 (s, C_q), 131.3 (d, 2C, CH), 130.9 (d, 2C, CH), 128.1 (d, CH), 127.6 (s, C_q), 126.3 (d, 2C, CH), 126.1 (d, 2C, CH), 120.1 (d, 2C, CH), 113.8 (d, 2C, CH), 40.1 (s, C_q), 38.6 (t, CH₂), 30.5 (q, CH₃), 9.5 (q, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₂H₂₂N]⁺ = [M + H]⁺: 300.1747; found 300.1737.

2-Methoxy-9,9-dimethyl-10-phenyl-9,10-dihydroacridine (22db). This compound was prepared according to the GP-3 and isolated as pale yellow color viscous liquid 80% yield (126 mg): [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23d) = 0.40, R_f (22db) = 0.60, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2967, 1591, 1474, 1329, 1297, 1208, 1046, 872, 801, 747, 700, 639 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 7.62 (dd, 2H, J = 7.8 and 7.8 Hz), 7.49 (dd, 1H, J = 7.3 and 7.3 Hz), 7.44 (d, 1H, J = 7.8 Hz), 7.34 (d, 2H, J = 7.3 Hz), 7.04 (s, 1H), 6.96 (dd, 1H, J = 7.3 and 7.8 Hz), 6.90 (dd, 1H, J = 7.3 and 7.3 Hz), 6.55 (d, 1H, J = 8.8 Hz), 6.26 (d, 1H, J = 8.3 Hz), 6.20 (d, 1H, J = 8.8 Hz), 3.77 (s, 3H, CH₃), 1.69 (s, 6H, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 154.1 (s, C_q), 141.6 (s, C_q), 141.3 (s, C_q), 135.5 (s, C_q), 131.5 (s, C_q), 131.4 (d, 2C, CH), 130.8 (d, 2C, CH), 129.2 (s, C_q), 128.1 (d, CH), 126.4 (d, CH), 125.1 (d, CH), 120.1 (d, CH), 114.7 (d, CH), 113.7 (d, CH), 111.6 (d, CH), 111.0 (d, CH), 55.7 (q, CH₃), 36.3 (s, C_q), 30.9 (q, 2C, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₂H₂₂NO]⁺ = [M + H]⁺: 316.1696; found 316.1682.

9-Ethyl-2-methoxy-9-methyl-10-phenyl-9,10-dihydroacridine (22eb). This compound was prepared according to the GP-3 and isolated as black color solid 81% yield (132 mg): mp: 112–114 °C; [TLC (petroleum ether/ethyl acetate 9 : 1), R_f (23e) = 0.40, R_f (22eb) = 0.70, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2961, 1589, 1477, 1332, 1269, 1174, 1047, 908, 800, 746, 699 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 7.61 (dd, 2H, J = 7.3 and 7.8 Hz), 7.49 (dd, 1H, J = 6.8 and 7.8 Hz), 7.36 (d, 1H, J = 7.8 Hz), 7.30 (d, 2H, J = 8.3 Hz), 6.98 (s, 1H), 6.94 (dd, 1H, J = 6.8 and 8.3 Hz), 6.87 (dd, 1H, J = 7.3 and 7.3 Hz), 6.53 (d, 1H, J = 7.3 Hz), 6.19 (d, 1H, J = 8.3 Hz), 6.14 (d, 1H, J = 7.8 Hz), 3.77 (s, 3H, CH₃), 1.94 (q, 2H, J = 7.3 and 7.8 Hz, CH₂), 1.78 (s, 3H, CH₃), 0.72 (t, 3H, J = 7.3 Hz, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 153.7 (s, C_q), 141.7 (s, 2C, C_q), 136.1 (s, C_q), 131.4 (d, 2C, C_q), 130.8 (d, 2C, C_q), 129.1 (d, 2C, CH), 128.0 (d, CH), 126.7 (s, C_q), 126.3 (d, CH), 126.1 (d, CH), 119.7 (d, CH), 114.5 (d, CH), 113.5 (d, CH), 112.5 (d, CH), 111.1 (d, CH), 55.6 (q, CH₃), 40.4 (s, C_q), 38.3 (t, CH₂), 30.2 (q, CH₃), 9.5 (q, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₃H₂₄NO]⁺ = [M + H]⁺: 330.1852; found 330.1857.

2,3-Dimethoxy-9,9-dimethyl-10-phenyl-9,10-dihydroacridine (22fb). This compound was prepared according to the GP-3 and isolated as black color solid 81% yield (139 mg): mp: 80–82 °C; [TLC (petroleum ether/ethyl acetate 8 : 2), R_f (23f) = 0.50, R_f (22fb) = 0.30, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2955, 2930, 1590, 1444, 1311, 1239, 1154, 1082, 877, 747, 607 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 7.62 (dd, 2H, J = 7.8 and 7.8 Hz), 7.50 (dd, 1H, J = 7.3 and 8.8 Hz), 7.43 (d, 1H, J = 7.3 Hz), 7.34 (d, 2H, J = 7.3 Hz), 7.00 (s, 1H), 6.95 (dd, 1H, J = 7.3 and 7.8 Hz), 6.89 (dd, 1H, J = 6.8 and 7.8 Hz), 6.24 (d, 1H, J = 7.8 Hz), 5.84 (s, 1H), 3.88 (s, 3H, CH₃), 3.53 (s, 3H, CH₃), 1.68 (s, 6H, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 147.5 (s, C_q), 143.3 (s, C_q), 141.4 (s, C_q), 141.0 (s, C_q), 135.3 (s, C_q), 131.3 (d, C_q), 130.8 (d, 3C, CH), 129.4 (s, C_q), 128.2 (d, CH), 126.2 (d, CH), 125.2 (d, CH), 121.3 (s, C_q), 120.2 (d, CH), 113.9 (d, CH), 110.1 (d, CH), 99.4 (d, CH), 56.9 (q, CH₃), 55.6 (q, CH₃), 35.7 (s, C_q), 31.5 (q, 2C, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₃H₂₄NO₂]⁺ = [M + H]⁺: 346.1802; found 346.1795.

10,10-Dimethyl-5-phenyl-5,10-dihydro-[1,3]dioxolo[4,5-b]acridine (22hb). This compound was prepared according to the GP-3 and isolated as white color solid 79% yield (130 mg): mp: 188–190 °C; [TLC (petroleum ether/ethyl acetate 8 : 2), R_f (23h) = 0.50, R_f (22hb) = 0.70, UV detection]. IR (MIR-ATR, 4000–600 cm⁻¹): ν_max = 2965, 2882, 1592, 1475, 1313, 1224, 1172, 1040, 934, 879, 747, 700, 610 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz): δ = 7.59 (dd, 2H, J = 6.6 and 8.0 Hz), 7.48 (dd, 1H, J = 7.4 and 7.4 Hz), 7.42 (d, 1H, J = 7.5 Hz), 7.31 (d, 2H, J = 6.8 Hz), 6.96 (s, 1H), 6.92 (dd, 1H, J = 8.0 and 5.4 Hz), 6.90 (dd, 1H, J = 7.4 and 7.3 Hz), 6.25 (d, 1H, J = 8.0 Hz), 5.87 (s, 1H), 5.81 (s, 2H, CH₂) 1.64 (s, 6H, CH₃) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 145.8 (s, C_q), 141.7 (s, C_q), 141.5 (s, C_q), 141.1 (s, C_q), 136.2 (s, C_q), 131.3 (d, 2C, CH), 130.9 (d, 2C, CH), 129.3 (s, C_q), 128.3 (d, CH), 126.3 (d, CH), 125.0 (d, CH), 122.4 (s, C_q), 120.4 (d, CH), 113.9 (d, CH), 105.2 (d, CH), 100.7 (t, CH₂), 96.5 (d, CH), 36.1 (s, C_q), 31.1 (q, 2C, CH₃) ppm. HR-MS (ESI⁺) m/z calculated for [C₂₂H₂₀NO₂]⁺ = [M + H]⁺: 330.1489; found 330.1484.

Acknowledgements

We are grateful to the Department of Science and Technology-Science and Engineering Research Board (DST-SERB) [No. SB/S1/OC-39/2014], New Delhi, for the financial support. L. M. thank CSIR, New Delhi, for the award of research fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and NMR spectra. CCDC 1446328, 1446323. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra03447k

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