Enantioselective Michael reaction of anthrone catalyzed by chiral tetraoxacalix[2]arene[2]triazine derivatives

Abstract

A highly enantioselective Michael addition reaction of anthrone with nitroalkenes by chiral tetraoxacalix[2]arene[2]triazine catalysts was investigated as a novel topic. The stereoselective conversion progressed smoothly by employing 10 mol% of the catalyst and afforded the corresponding Michael adducts with acceptable to high enantioselectivities (up to 97% ee) and very high yields (up to 96%).

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1. Introduction

The chemical properties of anthrone and compounds containing the anthrone skeleton are significant in organic chemistry. Anthrones and their enol tautomers, i.e., 9-anthrols form a vital part of anthracenes since the oxidation of the central rings yields 9,10-anthraquinones, while their reduction affords anthracenes, which are useful intermediates.^1,2 However, naturally occurring compounds bearing the anthrone platform are isolated either as O- or C-glycosides or in a free form from a broad diversity of plants and shrubs such as rhubarb, cassia, and cascara sagrada.^3,4 Several such substances have noteworthy biological characteristics and are utilized as antimicrobial, emetic, antipsoriatic or androgen receptors and telomerase blockers.^5,6 Recent studies have demonstrated that some anthrone- or anthraquinone-based naturally occurring compounds show strong and distinctive antitumor behaviours.^7–11

The Michael reaction of carbon-centered nucleophiles with different Michael acceptors provides a straightforward and robust technique for the formation of C–C bonds and has received prevalent preference in the production of organic materials. As a result, substantial works have been carried out for the development of the enantioselective forms of this conversion.^12–14 Although remarkable developments have emerged in the catalytic asymmetric Michael reaction, developing a new Michael reaction for the effective production of different novel materials remains a significant target for studies conducted in both academic and industrial contexts. In this field of study, similar to the case of a Michael donor, various carbon-centered nucleophiles such as aldehydes and ketones,^15–19 malonate esters,^20–22 ketoesters,²³ and 1,3-diketones^24–26 have been comprehensively studied; in contrast, not much development has taken place in the improvement of the usage of anthrone as a nucleophile for the Michael addition reaction.^27–33

Calixarenes and macromolecules bearing one or more calixarene platforms are known as efficient supramolecular materials. Heteroatom-bridged calixaromatics, also called heteroaromatic calixarenes, are a novel group of macrocyclic host compounds in supramolecular chemistry.^34,35 Despite their exceptional physical and bonding characteristics that come from the electronic and steric influences of heteroatom bridges, heteroaromatic calixarenes are far rarer in usage.^36,37 The self-tuning and fine-tuning cavities of their electronic characteristics make heteroaromatic calixarenes strong macrocyclic hosts regarding their interactions with neutral organic guests^38,39 and with positively⁴⁰ and negatively charged compounds.^41–43 Oxygen- and nitrogen-bridged calix[2]arene[2]triazines are noteworthy heterocalixaromatics.^44–47 Based on the characteristics of the heteroatoms in the bridging units, calix[2]arene[2]triazines use adaptable conformational constructs and may provide a diverse set of cavity sizes. Not limited to interactions of inclusion,⁴⁸ these materials may also show π–π interactions of aromatic rings and hydrogen bonding interactions on the triazine nitrogen atoms as chiral host compounds.

In the past decade, we have reported the synthesis and applications of lower-rim-substituted calix[4]arene-based macromolecules with different functional groups as multiple H-bond donor chiral catalysts for stereoselective conversions.^49–51 Likewise, we have recently reported substituted tetraoxacalix[2]arene[2]triazine derivatives with different purposes as chiral catalysts in the stereoselective Michael additions of isobutyraldehyde using different substituted and unsubstituted aromatic trans-β-nitrostyrenes.⁵² Here, we described an efficient one-pot process to synthesize optically active tetraoxacalix[2]arene[2]triazine derivatives and their possible applications as organic catalysts in the Michael addition of anthrone to β-nitroolefins under mild conditions. As far as we know, this study is the first implementation of tetraoxacalix[2]arene[2]triazine catalysts in the enantioselective reactions of anthrone.

2. Experimental

2.1. Synthesis

2.1.1. Procedure for the synthesis of compounds 4a-4b. Tetraoxa-bridged calix[2]arene[2]triazine was prepared following a procedure described by Wang et al.^53,54 A mixture of (R)-2-amino-1-((S)-2-benzhydrylpyrrolidin-1-yl)-2-phenylethanone 1 or (1S,2S)–N,N-bis(3-phenylpropyl)cyclohexane-1,2-diamine 2 (1.1 mmol) and DIPEA (2.2 mmol) in THF (20 mL) was added to a solution of tetraoxa-bridged calix[2]arene[2]triazine 3 (0.5 mmol) in THF (20 mL) at room temperature. The mixture was refluxed for 48–56 h, after which the solvent was evaporated under vacuum, giving off a solid residue. The crude mixture was purified by column chromatography on silica gel using hexane/EtOAc (10 : 1, v/v) to afford the desired products as crystalline solids. The products were characterized by a combination of ¹H NMR, ¹³C NMR, FTIR,^55,56 and elemental analysis.
Compound 4a. Crystalline solid; 75% yield; α²⁵_D = −205.00 (c 1, CHCl₃); mp 220–222 °C; IR (cm⁻¹): 1358, 1479, 1563, 1708, 3261; ¹H NMR (400 MHz, CDCl₃): δ = 1.21–1.40 (m, 8H), 2.98–3.17 (m, 4H), 4.72 (d, 2H, J = 6.7 Hz), 5.04 (d, J = 6.8 Hz, 2H), 6.18 (s, 2H), 7.16–7.38 (m, 32H), 7.82–7.87 (m, 6H), NH-signals not found; ¹³C NMR (100 MHz, CDCl₃): δ = 23.34, 29.47, 46.29, 51.17, 58.64, 65.80, 124.74, 127.33, 127.63, 128.00, 128.23, 128.43, 128.60, 128.73, 129.05, 129.68, 130.00, 138.20, 140.53, 140.68, 158.20, 162.20, 166.00, 169.10; anal. calcd. for C₆₈H₅₈N₁₀O₆ (1111.25): C, 73.49; H, 5.26; N, 12.60%; found: C, 73.51; H, 5.31; N, 12.48%.
Compound 4b. Crystalline solid; 78% yield; α²⁵_D = +218.00 (c 1, CHCl₃); mp 326–328 °C; IR (cm⁻¹): 1365, 1483, 1569, 1705, 3281; ¹H NMR (400 MHz, CDCl₃): δ = 1.19–1.35 (m, 8H), 1.82–2.12 (m, 16H), 2.60–2.75 (m, 10H), 2.85–2.90 (m, 8H), 4.13 (q, J = 2.7 Hz, 2H), 7.01–7.15 (m, 20H), 7.20 (t, J = 8.4, 0.5 Hz, 2H), 7.25–7.30 (m, 4H), 7.37–7.42 (m, 2H), NH-signals not found; ¹³C NMR (100 MHz, CDCl₃): δ = 14.16, 21.03, 27.51, 32.04, 32.50, 34.14, 57.00, 60.47, 62.33, 102.86, 116.90, 128.41, 128.90, 128.96, 130.28, 140.40, 157.07, 158.21, 166.00; anal. calcd. for C₆₆H₇₄N₁₀O₄ (1071.35): C, 73.99; H, 6.96; N, 13.07%; found: C, 74.15; H, 7.12; N, 12.98%.

2.1.2. Procedure for Michael reaction. A solution of nitroalkenes 6a–k (0.4 mmol) and the chiral catalyst (0.04 mmol) in toluene (4 mL) was stirred and then, anthrone 5 (0.48 mmol) was added. After being stirred for 36–72 h at room temperature, the reaction mixture was subjected directly to flash column chromatography on silica gel (hexane/EtOAc = 5 : 1) to furnish the corresponding products. The ee% values of the Michael reaction products were determined by chiral HPLC analysis using Daicel Chiralpak OD-H or AS-H columns. The HPLC conditions for products 7a–7k are shown in Table 1; the ¹H NMR, ¹³C NMR and FTIR spectroscopy values of products 7a–7k are shown in Table 2.

Table 1 HPLC conditions of products 7a–7k

Product	Column	Hexane/2-propanol	Flow rate	tR (minor)	tR (major)
7a	AS-H	90 : 10	0.7 mL min^−1	25.96 min	23.25 min
7b	OD-H	80 : 20	1.0 mL min^−1	15.94 min	12.85 min
7c	OD-H	80 : 20	1.0 mL min^−1	11.82 min	10.06 min
7d	AS-H	80 : 20	1.0 mL min^−1	12.85 min	10.15 min
7e	OD-H	70 : 30	1.0 mL min^−1	18.14 min	15.32 min
7f	AS-H	80 : 20	1.0 mL min^−1	13.25 min	10.42 min
7g	AS-H	80 : 20	1.0 mL min^−1	17.43 min	14.65 min
7h	AS-H	90 : 10	1.0 mL min^−1	18.19 min	16.02 min
7i	OD-H	80 : 20	1.0 mL min^−1	19.62 min	26.21 min
7j	AS-H	90 : 10	1.0 mL min^−1	26.11 min	21.93 min
7k	AS-H	70 : 30	1.0 mL min^−1	12.35 min	10.19 min

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Table 2 ¹H NMR, ¹³C NMR, and FTIR spectroscopy values of products 7a–7k

7a	Mp	147–148 °C
	IR (cm^−1)	928, 1310, 1548, 1600, 1671
	^1H NMR (400 MHz, CDCl3)	4.03–4.06 (m, 1H), 4.53 (d, J = 3.7 Hz, 1H), 4.60 (dd, J = 13.3, 7.0 Hz, 1H), 4.88–4.91 (dd, J = 13.3, 9.1 Hz, 1H), 6.07 (d, J = 7.6 Hz, 2H), 6.91 (t, J = 7.8 Hz, 2H), 7.14–7.17 (m, 1H), 7.39–7.43 (m, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.60–7.68 (m, 2H), 7.94 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H)
	^13C NMR (100 MHz, CDCl3)	45.9, 52.8, 76.4, 126.1, 126.9, 127.8, 128.0, 128.1, 128.2, 128.3, 128.7, 131.9, 132.2, 132.9, 133.4, 134.6, 139.8, 142.3, 183.1
7b	Mp	65–67 °C
	IR (cm^−1)	929, 1317, 1552, 1598, 1671
	^1H NMR (400 MHz, CDCl3)	4.31–4.39 (m, 2H), 4.59–4.69 (m, 2H), 6.18 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 6.7 Hz, 1H), 7.00 (d, J = 7.1 Hz, 1H), 7.40–7.61 (m, 4H), 7.63 (s, 2H), 8.13 (t, J = 7.8 Hz, 2H)
	^13C NMR (100 MHz, CDCl3)	45.0, 48.0, 74.0, 126.3, 127.1, 127.3, 127.9, 128.3, 128.5, 128.6, 129.8, 130.3, 131.7, 132.5, 133.0, 133.3, 133.6, 134.9, 136.0, 138.9, 140.2, 183.4
7c	Mp	141–143 °C
	IR (cm^−1)	935, 1322, 1551, 1600, 1671
	^1H NMR (400 MHz, CDCl3)	4.18–4.24 (m, 1H), 4.37 (dd, J = 13.3, 8.4 Hz, 1H), 4.50 (dd, J = 13.6, 6.9 Hz, 1H), 4.68 (d, J = 3.6 Hz, 1H), 5.57 (d, J = 3.3 Hz, 1H), 6.20–6.22 (m, 1H), 7.00 (d, J = 7.5 Hz, 1H), 7.19 (d, J = 1.1 Hz, 1H), 7.49–7.54 (m, 4H), 7.60–7.63 (m, 1H), 8.20 (t, J = 6.1 Hz, 2H)
	^13C NMR (100 MHz, CDCl3)	44.8, 46.9, 73.9, 109.3, 110.1, 126.0, 127.3, 127.8, 128.2, 128.3, 128.5, 133.0, 133.2, 133.5, 133.7, 139.9, 140.5, 142.7, 148.4, 183.2
7d	Mp	63–65 °C
	IR (cm^−1)	938, 1320, 1555, 1601, 1659
	^1H NMR (400 MHz, CDCl3)	4.00–4.03 (m, 1H), 4.81 (d, J = 5.4 Hz, 1H), 4.89–5.01 (m, 1H), 5.12 (dd, J = 13.9, 5.5 Hz, 1H), 6.60–6.62 (m, 1H), 7.10–7.13 (m, 2H), 7.29–7.36 (m, 2H), 7.51–7.65 (m, 5H), 7.96 (d, J = 7.6 Hz, 1H)
	^13C NMR (100 MHz, CDCl3)	45.0, 49.9, 77.1, 126.0, 126.1, 126.9, 127.8, 128.2, 129.0, 129.4, 130.0, 131.9, 132.2, 132.4, 133.1, 135.0, 139.8, 140.3, 181.3
7e	Mp	69–72 °C
	IR (cm^−1)	936, 1313, 1529, 1551, 1604, 1670
	^1H NMR (400 MHz, CDCl3)	4.69–4.74 (m, 1H), 4.83 (d, J = 5.2 Hz, 1H), 5.09 (dd, J = 13.6, 10.3 Hz, 1H), 5.30 (dd, J = 13.9, 5.5 Hz, 1H), 6.69–6.72 (m, 1H), 7.29–7.38 (m, 3H), 7.48–7.62 (m, 6H), 7.90 (dd, J = 13.9, 7.6 Hz, 2H)
	^13C NMR (100 MHz, CDCl3)	44.9, 45.5, 76.8, 123.9, 125.8, 126.1, 127.6, 127.8, 128,2, 128.9, 129.1, 129.2, 129.5, 131.9, 132.0, 132.5, 132.9, 134.0, 140.0, 140.9, 150.0, 183.1
7f	Mp	129–131 °C
	IR (cm^−1)	929, 1320, 1509, 1555, 1600, 1661
	^1H NMR (400 MHz, CDCl3)	3.19 (s, 1H), 4.39–4.43 (m, 1H), 4.69 (d, J = 3.9 Hz, 1H), 4.79 (dd, J = 13.1, 10.1 Hz, 1H), 5.09 (dd, J = 13.4, 5.9 Hz, 1H), 6.03 (d, J = 6.5 Hz, 1H), 6.50 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 7.39–7.50 (m, 4H), 7.59–7.62 (t, J = 7.4 Hz, 2H), 7.82 (d, J = 7.4 Hz, 1H), 7.89 (m, J = 7.9 Hz, 1H)
	^13C NMR (100 MHz, CDCl3)	44.9, 45.0, 54.8, 76.7, 109.9, 120.4, 121.3, 124.6, 125.8, 126.2, 127.5, 128.0, 128.4, 129.0, 129.4, 131.9, 132.9, 141.0, 142.6, 156.9, 183.0
7g	Mp	115–117 °C
	IR (cm^−1)	934, 1313, 1549, 1600, 1661
	^1H NMR (400 MHz, CDCl3)	4.01–4.06 (m, 1H), 4.56–4.62 (m, 2H), 4.89 (dd, J = 13.3, 8.8 Hz, 1H), 5.99 (d, J = 7.3 Hz, 1H), 6.17 (s, 1H), 6.86 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 9.1 Hz, 1H), 7.42–7.59 (m, 4H), 7.65–7.71 (m, 2H), 8.05 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H)
	^13C NMR (100 MHz, CDCl3)	45.9, 53.0, 76.1, 121.9, 126.6, 127.2, 127.6, 128.3, 128.4, 128.5, 128.7, 129.6, 131.6, 131.9, 132.7, 133.0, 133.5, 134.6, 135.7, 139.0, 141.6, 183.0
7h	Mp	156–158 °C
	IR (cm^−1)	929, 1315, 1548, 1600, 1659
	^1H NMR (400 MHz, CDCl3)	2.09 (s, 3H), 4.00–4.04 (m, 1H), 4.49 (d, J = 3.5 Hz, 1H), 4.54 (dd, J = 13.1, 7.1 Hz, 1H), 4.82 (dd, J = 13.1, 8.9 Hz, 1H), 5.99 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 7.7 Hz, 2H), 7.35–7.45 (m, 2H), 7.49 (d, J = 7.4 Hz, 2H), 7.56–7.61 (m, 2H), 8.03 (d, J = 7.7 Hz, 1H), 8.10 (d, J = 7.3 Hz, 1H)
	^13C NMR (100 MHz, CDCl3)	20.9, 45.9, 53.1, 75.8, 126.4, 126.9, 127.4, 127.9, 128.3, 128.5, 128.6, 129.9, 132.4, 132.8, 133.4, 134.3, 138.1, 139.3, 142.0, 182.9
7i	Mp	119–121 °C
	IR (cm^−1)	929, 1312, 1511, 1548, 1599, 1671
	^1H NMR (400 MHz, CDCl3)	3.71 (s, 3H), 3.99–4.01 (m, 1H), 4.49 (d, J = 3.8 Hz, 1H), 4.57 (dd, J = 13.3, 7.4 Hz, 1H), 4.82 (dd, J = 13.3, 9.1 Hz, 1H), 6.00 (d, J = 8.8 Hz, 2H), 6.50 (d, J = 8.8 Hz, 2H), 7.40–7.54 (m, 4H), 7.60–7.67 (m, 2H), 8.02 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 7.3 Hz, 1H)
	^13C NMR (100 MHz, CDCl3)	45.9, 52.4, 54.9, 76.9, 113.2, 125.0, 127.1, 127.5, 127.8, 128.0, 128.2, 128.3, 129.4, 132.6, 132.8, 133.9, 134.8, 139.0, 141.9, 160.0, 182.9
7j	Mp	168–171 °C
	IR (cm^−1)	929, 1321, 1549, 1600, 1659
	^1H NMR (400 MHz, CDCl3)	4.01–4.04 (m, 1H), 4.49 (d, J = 3.4 Hz, 1H), 4.60 (dd, J = 13.3, 7.6 Hz, 1H), 4.87 (dd, J = 13.3, 8.5 Hz, 1H), 5.99 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 7.40–7.55 (m, 4H), 7.61–7.67 (m, 2H), 8.03 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H)
	^13C NMR (100 MHz, CDCl3)	45.8, 52.5, 76.4, 126.8, 127.0, 127.2, 127.6, 127.9, 128.1, 128.2, 128.4, 130.0, 131.9, 132.2, 132.9, 133.1, 134.0, 134.5, 138.9, 141.7, 182.9
7k	Mp	171–172 °C
	IR (cm^−1)	929, 1323, 1511, 1548, 1605, 1658
	^1H NMR (400 MHz, CDCl3)	4.01–4.06 (m, 1H), 4.55 (d, J = 3.7 Hz, 1H), 4.60 (dd, J = 13.3, 7.3 Hz, 1H), 4.90 (dd, J = 13.3, 9.1 Hz, 1H), 5.99 (dd, J = 8.8, 5.2 Hz, 2H), 6.67 (t, J = 8.8 Hz, 2H), 7.45–7.58 (m, 4H), 7.64–7.68 (m, 2H), 7.98 (d, J = 7.3 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H)
	^13C NMR (100 MHz, CDCl3)	46.3, 52.8, 76.6, 114.8, 115.2, 127.1, 127.6, 127.9, 128.0, 128.2, 128.5, 128.9, 129.5, 130.8, 131.9, 132.8, 133.6, 134.5, 138.9, 142.1, 161.9, 182.9

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3. Results and discussion

The chiral tetraoxacalix[2]arene[2]triazine derivatives 4a and 4b, which were chosen as chiral catalysts in the model asymmetric Michael reaction, were synthesized in four steps starting from (R)-phenylglycine and (1S,2S)-(+)-1,2-diaminocyclohexane, respectively. The chiral subunits (R)-2-amino-1-((S)-2-benzhydrylpyrrolidin-1-yl)-2-phenylethanone 1 and (1S,2S)–N,N-bis(3-phenylpropyl) cyclohexane-1,2-diamine 2, which were synthesized in three steps, were prepared according to previously reported procedures,^57,58 as illustrated in Scheme 1. Subsequently, the chiral tetraoxacalix[2]arene[2]triazines 4a and 4b were synthesized from 1 and 2, respectively, in overall good yields (up to 75–78%), as illustrated in Scheme 2.

Scheme 1 The synthetic routes for starting materials 1 and 2.

Scheme 2 The synthetic route for tetraoxa-bridged calix[2]arene[2]triazine derivatives 4a/4b.

In the first review of the conditions, having selected the Michael addition of anthrone 5 and trans-β-nitrostyrene 6a as the enantioselective reaction, we found that the tetraoxacalix[2]arene[2]triazine catalysts catalyzed the process effectively, affording the expected adduct 7a in an optically active form. The reaction progressed successfully in nonpolar solvents including hexane, CHCl₃, CH₂Cl₂ or toluene (Table 3, entries 1–8); however, when we used a polar solvent, such as ethyl acetate, diethyl ether or acetone, significant decrease was observed in chemical yield and enantioselectivity (Table 3, entries 15–20). This may be due to the fact that the polar solvents interacted with the organocatalysts through hydrogen bonding to weaken the activation ability of 4a and 4b towards the reaction. As projected by our tentative hypothesis, the best yield (96%) and enantioselectivity (97% ee) were obtained using the less polar solvent, i.e., toluene.

Table 3 Michael addition between anthrone 5 and trans-β-nitrostyrene 6a catalysed by 4a–4b in various solvents

Entry^a	Catalyst	Solvent	Time (h)	Yield^b (%)	ee^c^,^d (%)
a Conditions: anthrone (0.48 mmol), trans-β-nitrostyrene (0.40 mmol) and 4a/4b (10 mol%) in solvents (4.0 mL).b Isolated yield after flash chromatograpy.c Determined by HPLC.d Determined by comparing reported data.
1	4a	Hexane	72	88	93
2	4b	Hexane	72	90	95
3	4a	CHCl3	48	85	90
4	4b	CHCl3	48	89	91
5	4a	CH2Cl2	48	81	92
6	4b	CH2Cl2	48	83	93
7	4a	Toluene	48	95	96
8	4b	Toluene	48	96	97
9	4a	CH3CN	72	92	80
10	4b	CH3CN	72	95	81
11	4a	Xylene	72	87	91
12	4b	Xylene	72	90	95
13	4a	THF	72	82	84
14	4b	THF	72	85	87
15	4a	EtOAc	48	87	80
16	4b	EtOAc	48	91	85
17	4a	Et2O	72	83	88
18	4b	Et2O	72	86	89
19	4a	Acetone	48	85	82
20	4b	Acetone	48	88	85

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Other aspects of this reaction such as temperature, use of the recycled catalyst, and catalyst loading were investigated (Table 4). When the same reaction was performed at 0 °C with 10 mol% of 4a and 4b as catalysts, the desired adduct 7a was obtained with low to 88–89% ee in 83–85% yield, with further extension of the reaction time (72 h, Table 4, entries 3 and 4). In addition, similar to the reaction conducted at 0 °C, the reaction carried out at −20 °C showed less desired yields and enantioselectivities than the reaction at room temperature (Table 4, entries 1 and 2). Additionally, we conducted recycling analysis of the chiral catalysts 4a and 4b in the Michael reaction of 5 and 6a. Thus, the compounds 4a and 4b could be easily recycled by flash chromatography alongside Michael adducts. However, by prolonging the reaction time, low enantioselectivity and yield values were found at room temperature, as seen in Table 4 (entries 7 and 8). In the presence of 10 mol% catalysts, 4a and 4b showed similar enantioselectivities, but 4b showed slightly higher catalytic activity than 4a (Table 4, entries 5 and 6). When the loading of the catalysts 4a and 4b went up to 15 mol%, trans-β-nitrostyrene gave Michael products in low yields with 93–95% and 93–95% enantiomeric excess, respectively (Table 4, entries 9 and 10). These results were better than that for the use of 5 mol% of catalyst, in which case the yields of the Michael products were 88% for catalyst 4a and 90% for catalyst 4b and the enantiomeric excesses of the Michael products were 89% for catalyst 4a and 90% for catalyst 4b (Table 4, entries 11 and 12). These findings led us to choose the reaction conditions using toluene as a solvent at room temperature in the presence of 10 mol% of 4b to probe the scope of nitroolefins.

Table 4 Screening of various reaction conditions

Entry^a	Catalyst	Temp. (°C)	Time (h)	Yield^b (%)	ee^c^,^d (%)
a Conditions: anthrone (0.48 mmol), trans-β-nitrostyrene (0.40 mmol), and 4a/4b (10 mol%) in toluene (4.0 mL).b Isolated yield.c Determined by HPLC.d Determined by comparing reported data.e Reaction was performed with recycled catalyst.f 15 mol% of catalyst was used.g 5 mol% of catalyst was used.
1	4a	−20	72	80	85
2	4b	−20	72	81	86
3	4a	0	72	83	88
4	4b	0	72	85	89
5	4a	r.t.	48	95	96
6	4b	r.t.	48	96	97
7^e	4a	r.t.	72	75	86
8^e	4b	r.t.	72	78	90
9^f	4a	r.t.	48	93	93
10^f	4b	r.t.	48	95	95
11^g	4a	r.t.	48	88	89
12^g	4b	r.t.	48	90	90

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As we enhanced the reaction details for the Michael addition of anthrone 5 to trans-β-nitrostyrene 6a (catalyst 4b 10 mol% in toluene at room temperature), a set of different nitrostyrenes with various substituent groups were analyzed, and the results are summarized in Table 5. These nitrostyrenes reacted with anthrone to afford the corresponding adducts 7a–7k in moderate to excellent yields with excellent enantioselectivities (Table 5, entries 1–11). As demonstrated in Table 5, anthrone reacts smoothly with a wide range of ortho-, meta- or para-substituted nitrostyrenes with electron-releasing or electron-withdrawing groups and the corresponding Michael adducts in good to excellent yields (86–96%) and enantioselectivities (81–97%) are obtained. To our satisfaction, trans-β-nitrostyrene and 4-Me-nitrostyrene as Michael acceptors gave good yields and enantioselectivities (Table 5, entries 1 and 8).

Table 5 Scope of the Michael addition with anthrone 5 and nitroalkenes 6a–k

Entry^a	Ar	Time (h)	Product	Yield^b (%)	ee^c^,^d (%)
a Conditions: anthrone (0.48 mmol), trans-β-nitrostyrene (0.40 mmol), and 4b (10 mol%) in toluene (4.0 mL).b Isolated yield after flash chromatograpy.c Determined by HPLC.d The configurations were determined by comparing reported data.
1	C6H5	48	7a	96	97
2	2,4-Cl2–C6H4	36	7b	88	82
3	2-Furyl-C6H4	48	7c	94	88
4	2-Br–C6H4	36	7d	94	81
5	2-NO2–C6H4	48	7e	91	89
6	2-OMe–C6H4	48	7f	86	95
7	3-Br–C6H4	36	7g	93	96
8	4-Me–C6H4	48	7h	95	97
9	4-OMe–C6H4	48	7i	95	91
10	4-Cl–C6H4	36	7j	91	82
11	4-F–C6H4	36	7k	91	92

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In conclusion, we developed highly efficient asymmetric Michael addition of anthrone to nitroalkenes catalyzed by tetraoxa-bridged calix[2]arene[2]triazine organocatalysts. The results of our study were similar to the literatures which were used thiourea-tertiary amine,³² cinchona alkaloids,³³ cinchona-based chiral polyesters,⁵⁹ and Ar-BINMOLs⁶⁰ catalysts for the reaction of anthrone to a series of nitroalkenes. The steric bulkiness and carbonyl groups were crucial in this reaction to give the corresponding adducts in lower ee than that for the catalyst without carbonyl groups. Efforts to elucidate the mechanistic details of this catalytic system and to further extend the scope and limitations of these kinds of organocatalysts are currently in progress.

4. Conclusions

In conclusion, in this work, a new class of chiral tetraoxa-bridged calix[2]arene[2]triazine derivatives described as effective organocatalysts for the Michael reaction of anthrone to various nitrostyrenes was reported for the first time. The addition reactions were carried out smoothly in toluene at room temperature by utilizing 10 mol% of 4a and 4b to give Michael products with high yields (up to 96%) and ee values (up to 97%).

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9ra03029h

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