Gold-Catalyzed Formal (3+2) Cycloaddition in an Ionic Liquid: Environmentally Friendly and Stereoselective Synthesis of Polysubstituted Indanes from Benzylic Alcohols and 1-Phenylpropenes

Abstract

A gold-catalyzed formal (3+2) cycloaddition of benzylic alcohols with 1-phenylpropenes in an ionic liquid permits the environmentally friendly stereoselective synthesis of polysubstituted indanes in good yields and with high selectivity. The gold catalyst can be recycled at least five times.

Key words

gold catalysis - ionic liquids - (3+2) cycloaddition - indanes - benzylic alcohols - propenylbenzenes

The efficient synthesis of polysubstituted indanes is of great importance because of their potent and diverse biological activities.[1] Examples include diaporindene A[2] (antiinflammatory activity), asarone dimer[3] (insect-growth regulator, fungicide, insecticide, sedative, and hyperthermic agent), and enrasentan[4] [5] (antagonist of nonpeptide endothelin receptors) (Figure [1]).

Figure 1 Natural and synthetic polysubstituted indanes

Therefore, much effort has been directed at the development of efficient synthetic pathways to polysubstituted indanes.[6] [7] Reported methods include dimerization[8] of 1-phenylpropenes and the formal (3+2) cycloaddition[9,10] of benzylic alcohols with 1-phenylpropenes. However, these methods often require the use of a stoichiometric amount of a reagent (BF₃·OEt₂ or SnCl₄), and a toxic volatile halogenated solvent (CH₂Cl₂ or CHCl₃) is employed in many cases. Consequently, there is a need to develop methods that use environmentally benign solvents and sustainable (recyclable) reagents to advance green chemistry.

Scheme 1 (a) Gold-catalyzed dimerization of 1-phenylpropenes (previous work). (b) Formal (3+2) cycloaddition of p-quinones with 1-phenylpropenes (previous work). (c) Formal (3+2) cycloaddition of benzylic alcohols with 1-phenylpropenes (this work).

We recently reported an environmentally friendly and stereoselective synthesis of cyclic compounds (1,2,3-trisubstituted indanes[11] and 2-aryl-3-methyl-dihydrobenzofurans[12]) by the strategic use of a π-philic (soft) gold(I) catalyst and an oxophilic (hard) gold(III) catalyst[13] in an ionic liquid[14] (Scheme [1]). Thus, treatment of 1-phenylpropenes with a soft gold(I) catalyst (AuCl) resulted in dimerization to furnish 1,2,3-trisubstituted indanes with good stereoselectivity, due to activation of the double bond of 1-phenylpropenes by coordination of gold(I) (Scheme [1a]). In contrast, similar treatment of 1-phenylpropenes and p-quinones with a hard gold(III) catalyst induced formal (3+2) cycloaddition to afford 2-aryl-3-methyldihydrobenzofurans with high stereoselectivity, due to activation of the carbonyl oxygen of the p-quinone by coordination to gold(III), even in the presence of 1-phenylpropenes (Scheme [1b]). Moreover, recycling of the gold catalyst/ionic liquid was achieved in both reactions (Schemes 1a and 1b).

As a part of our continuing research on environmentally friendly gold-catalyzed reactions, we next focused on the formal (3+2) cycloaddition of benzylic alcohols with 1-phenylpropenes in an ionic liquid to prepare polysubstituted indanes (Scheme [1c]). Here, we report a gold-catalyzed, environmentally friendly, stereoselective synthesis of polysubstituted indanes in an ionic liquid through a formal (3+2) cycloaddition of benzylic alcohols with 1-phenylpropenes. This reaction is advantageous from both environmental and economic points of view, as it does not require the use of a toxic volatile halogenated solvent or a stoichiometric amount of reagent, and the gold catalyst/ionic liquid can be recycled several times.

Table 1 Optimization of the Reaction Conditions for the Gold-Catalyzed Formal (3+2) Cycloaddition of Benzylic Alcohol 1a with trans-Anethole (2a)

Entry	Catalyst (mol%)	Temp (°C)	Time (h)	Yield (%) of 3aa (trans/cis)
1	AuBr3 (5)	rt	0.5	58 (98:2)
2	AuBr3 (2)	rt	1.5	64 (98:2)
3	AuBr3 (1)	60	0.5	64 (98:2)
4	AuCl (1)	60	0.5	75 (96:4)
5a	AuCl (1)	60	77	35 (96:4)

^a The reaction was carried out in DCE.

Initially, we investigated the formal (3+2) cycloaddition of 3,4-dimethoxybenzyl alcohol (1a) with trans-anethole (2a) in 3-ethyl-1-methyl-1H-imidazol-3-ium bis(trifluoromethylsulfonyl)imide ([EMIM][NTf₂]) in the presence of a gold catalyst that can activate the hydroxy group of 1a (Table [1]). The gold(III) catalyst AuBr₃ afforded the desired indane 3aa in a moderate yield with great selectivity (Table [1], entries 1–3), whereas the gold(I) catalyst AuCl (1 mol%) furnished 3aa in a good yield with high selectivity (entry 4). In terms of both yield and stereoselectivity, AuCl (1 mol%) in the ionic liquid appeared to be the best catalyst for this reaction.

NMR spectroscopic data supported the formation of a 1,2-disubstituted indane trans-3aa, and the expected structure was confirmed by means of X-ray crystal-structure analysis of 3aa (Figure [2]).[15] Reactions in other solvents ([EMIM][AcO], [EMIM][BF₄], [EMIM][MeSO₄], or [EMIM][(MeO)₂PO₂]) gave little or no 3aa. In the case of the reaction with AuCl (1 mol%), the use of an organic solvent (Dichroloethane:DCE) reduced the yield of 3aa to 35% and increased the reaction time to 77 hours (entry 3 vs entry 5). Lee’s group has reported various advantages of ionic liquids for catalytic reactions, including the formation of more-reactive catalysts and the stabilization of reactive intermediates and transition states.[16] Although the precise reason for the high activity of AuCl in [EMIM][NTf₂] (entry 4) remains unclear, two possibilities can be considered. The first is that an active gold species, AuNTf₂, might be generated by anion exchange between the chloride ion of the gold catalyst and the NTf₂ ion of the ionic liquid [EMIM][NTf₂]. The second possibility is the formation of a reactive gold species bearing an N-heterocyclic carbene ligand,[17] which might be generated from the EMIM cation of [EMIM][NTf₂].

Figure 2 X-ray crystal structure of the 1,2-disubstituted indane trans-3aa

Table 2 Effect of Substituents on Benzylic Alcohols 1a–c on the Gold-Catalyzed Formal (3+2) Cycloaddition

Entry	1	R1	R2	Product	Yield (%) (trans/cis)
1	1a	MeO	MeO	3aa	75 (96:4)
2	1b	MeO	H	3ba	trace
3	1c	H	H	–	–

Scheme 2 Scope of the gold-catalyzed formal (3+2) cycloaddition of benzylic alcohols 1a and 1d–f with 1-phenylpropenes 2a–d

To examine the effect of ring substituents on the benzylic alcohol 1, we conducted the gold-catalyzed formal (3+2) cycloaddition of benzylic alcohols 1a–c with trans-anethole (2a) (Table [2]). Whereas the reaction of benzylic alcohol 1a, bearing two methoxy groups, afforded a good yield of 3aa (Table [2], entry 1), the reaction of benzylic alcohol 1b having one methoxy group afforded only a trace of the corresponding product 3ba (entry 2). In the case of benzyl alcohol (1c), bearing no methoxy group on the ring, no product was obtained (entry 3). Thus, the presence of two methoxy groups on the aromatic ring of the benzylic alcohol 1a appears to be required to obtain indane 3aa.

Next, we investigated the scope of the gold-catalyzed formal (3+2) cycloaddition for the synthesis of disubstituted indanes 3 by using various benzylic alcohols 1a and 1d–f and 1-phenylpropenes 2a–d in the presence of 1 mol% AuCl in the ionic liquid [EMIM][NTf₂] (Scheme [2]). Various combinations of 1a or 1d–f with 2a–d afforded the corresponding products 3 in moderate to good yields with high selectivity, even in the presence of various oxygen-containing functional groups on the substrates.

Scheme 3 Gold-catalyzed formal (3+2) cycloaddition of benzylic alcohols 1g and 1h with 1-phenylpropenes 2a–e in an ionic liquid to give 1,2,3-trisubstituted indanes 4

In addition, we extended the procedure to prepare 1,2,3-trisubstituted indanes 4 (Scheme [3]). Treatment of benzylic alcohols 1g and 1h bearing an ethyl group at the benzylic position with 1-phenylpropenes 2a–e in the presence of 1 mol% AuCl in the ionic liquid [EMIM][NTf₂] afforded the corresponding 1,2,3-trisubstituted indanes 4 in high yields with good selectivity.[18] Interestingly, the yields of the 1,2,3-trisubstituted indanes 4 in this reaction were generally higher than those of the 1,2-disubstituted indanes 3.

In the case of indene (2f), the gold-catalyzed formal (3+2) cycloaddition with benzylic alcohol 1g afforded the corresponding indane 4gf in high yield, albeit with low stereoselectivity (Scheme [4]).

Scheme 4 Gold-catalyzed formal (3+2) cycloaddition of benzylic alcohol 1g with indene (2f)

In addition, even when the methyl group at the 2-position of 1-phenylpropene 2 was replaced with an ester group (2g), the reaction proceeded to give the corresponding indane 4gg (Scheme [5]). Although the use of one equivalent of ethyl trans-p-methoxycinnamate (2g) in the reaction resulted in a moderate yield, the use of three equivalents of 2g furnished the desired product 4gg in a good yield.[19] The ester group in indane 4gg could be a useful functionality for further elaboration.

Scheme 5 Gold-catalyzed formal (3+2) cycloaddition of benzylic alcohol 1g with ethyl trans-p-methoxycinnamate (2g)

The structure of 4gg was definitively established by means of X-ray crystal structure analysis (Figure [3]).[20]

We next conducted a large-scale preparation of indane 3aa and we examined the effect of a reduced amount of the gold catalyst (Scheme [6]). The large-scale preparation of 1,2-disubstituted indane 3aa was achieved from 1.0 g (6.0 mmol) of benzylic alcohol 1a and trans-anethole (2a), affording the product 3aa in 73% yield.[21] Moreover, even when the amount of AuCl was reduced to 0.1 mol%, the reaction proceeded smoothly over a slightly longer reaction time (5 h) to give the desired product 3aa in good yield with high selectivity.

Figure 3 X-ray crystal structure of 1,2,3-trisubstituted indane 4gg

Scheme 6 Large-scale preparation of indane 3aa and the effect of a reduced amount of the gold catalyst (0.1 mol%)

Finally, recycling of the gold catalyst in ionic liquid [EMIM][NTf₂] was investigated. In the reactions of benzylic alcohols 1a and 1g with trans-anethole (2a), the AuCl (1 mol%) and ionic liquid [EMIM][NTf₂] could be recycled at least five times with only slight loss of activity (Table [3]).[22]

Table 3 Recycling of the Gold Catalyst and Solvent in the Formal (3+2) Cycloaddition of Benzyl Alcohols 1a and 1g with trans-anethole (2a)

Run	Time (h)	Yield (%) (3aa/3′aa)	Time (h)	Yield (%) (4ga/4′ga)
1	0.5	75 (96:4)	0.5	97 (6:1)
2	20	58 (96:4)	22	81 (6:1)
3	20	66 (95:5)	22	79 (6:1)
4	22	57 (96:4)	24	73 (6:1)
5	24	48 (96:4)	24	71 (6:1)

A plausible mechanistic model for the reaction of benzylic alcohol 1g with trans-anethole (2a) in [EMIM][NTf₂] is shown in Scheme [7]. The gold species coordinates to the oxygen atom of the benzylic alcohol 1g, forming active intermediate I. Addition of trans-anethole (2a) to the active intermediate I affords intermediate II bearing an electron-rich aromatic ring and an electron-deficient ring. Cyclization takes place between the aromatic ring and the benzylic position in intermediate II to furnish intermediate III, which undergoes aromatization to provide indane 4ga with good selectivity (1,2-cis-2,3-trans). The first C–C bond formation (addition step, I → II) would be important in controlling the stereochemistry. In the addition step, π–π stacking between the electron-rich ring and the electron-deficient ring in intermediate I would make the orthogonal approach favorable, leading to the formation of a 1,2-cis configuration. Cyclization proceeds again under the influence of π–π stacking in intermediate II to form a five-membered ring with a 1,2-cis-2,3-trans stereochemistry.

Scheme 7 Plausible reaction mechanism for the gold-catalyzed formal (3+2) cycloaddition of benzylic alcohol 1g and trans-anethole (2a)

Figure 4

In summary, we have developed a stereoselective, gold-catalyzed formal (3+2) cyclization of benzylic alcohols 1 with 1-phenylpropenes 2 in the ionic liquid [EMIM][NTf₂]. This reaction provides an environmentally friendly alternative for the synthesis of a variety of polysubstituted indanes. We are currently pursuing further applications of this environmentally benign and sustainable catalyst system.

Conflict of Interest

The authors declare no conflict of interest.

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• 18 There are four possible diastereomers for 1,2,3-trisubstituted indanes 4, namely, α-(1,2-cis-2,3-trans), β-(1,2-cis-2,3-cis), γ-(1,2-trans-2,3-trans), and δ-(1,2-trans-2,3-cis), as shown below in Figure 4. The stereochemical assignment of the 1,2,3-trisubstituted indanes 4 was based on ¹H NMR spectra, chemical shifts (ppm), coupling constants (J values), and the application of double-irradiation techniques. MacMillan et al. reported J values for the α-(1,2-cis-2,3-trans) and γ-(1,2-trans-2,3-trans) configurations of 1,2,3-trisubstituted indanes 4 (see ref. 8a). Lantaño et al. also reported similar chemical shifts (ppm) and coupling constants (J values) for the α-(1,2-cis-2,3-trans) and γ-(1,2-trans-2,3-trans) configurations of 1,2,3-trisubstituted indanes 4 (see ref. 9e).
• 19 Ethyl (1R*,2S*,3S*)- and (1R*,2R*,3R*)-1-Ethyl-5,6-dimethoxy-3-(4-methoxyphenyl)indane-2-carboxylate (4gg and 4′gg) 1 mol% AuCl (1.2 mg, 0.0051 mmol) was added at rt to a solution of benzylic alcohol 1g (100 mg, 0.51 mmol) and ethyl trans-p-methoxycinnamate (2g) (315 mg, 1.53 mmol) in [EMIM][NTf₂] (1 mL). When benzylic alcohol 1g was completely consumed (TLC; usually <30 min), the product was extracted with Et₂O and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, hexane–EtOAc) to give 4gg and 4′gg as a colorless oil; yield: 158 mg (81%, 4:1). IR (KBr): 2958, 2933, 2833, 1728, 1609, 1510, 1500, 1463 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.18 (d, J = 8.7 Hz, 2 H × 4/5)*, 7.13 (d, J = 8.7 Hz, 2 H × 1/5), 6.88 (d, J = 8.7 Hz, 2 H × 1/5), 6.86 (d, J = 8.7 Hz, 2 H × 4/5)*, 6.78 (s, 1 H × 4/5)*, 6.75 (s, 1 H × 1/5), 6.41 (s, 1 H × 4/5)*, 6.38 (s, 1 H × 1/5), 4.75 (d, J = 9.9 Hz, 1 H × 4/5)*, 4.52 (d, J = 9.3 Hz, 1 H × 1/5), 4.16 (q, J = 7.2 Hz, 2 H × 4/5)*, 4.14 (q, J = 7.2 Hz, 2 H × 1/5), 3.91 (s, 3 H × 4/5)*, 3.91 (s, 3 H × 1/5), 3.83 (s, 3 H × 1/5), 3.81 (s, 3 H × 4/5)*, 3.74 (s, 3 H × 4/5)*, 3.73 (s, 3 H × 1/5), 3.52–3.45 (m, 1 H × 1/5), 3.41 (t, J = 8.1 Hz, 1 H × 4/5)*, 3.41–3.34 (m, 1 H × 4/5)*, 2.86 (t, J = 9.0 Hz, 1 H × 1/5), 2.09–1.98 (m, 1 H × 1/5), 1.80–1.50 (m, 2 H × 4/5)*, 1.27 (t, J = 7.2 Hz, 3 H × 4/5)*, 1.23 (t, J = 7.2 Hz, 3 H × 1/5), 0.99 (t, J = 7.5 Hz, 3 H × 1/5), 0.96 (t, J = 7.5 Hz, 3 H × 4/5)*. ¹³C NMR (75 MHz, CDCl₃): δ = 175.0, 172.6*, 158.5, 158.4*, 148.8, 148.7*, 148.1*, 136.71*, 136.67*, 136.6, 136.2, 135.8, 135.5*, 129.7*, 129.3, 113.9, 113.8*, 108.1*, 107.8*, 107.7, 106.3, 60.7, 60.5, 60.3*, 60.2*, 56.1*, 56.0*, 55.2*, 53.9, 50.7*, 48.8, 47.7*, 26.5, 24.6*, 14.3*, 11.7*, 10.6. HRMS (EI): m/z [M⁺] calcd for C₂₃H₂₈O₅: 384.1937; found: 384.1935.
• 20 CCDC 2223279 contains the supplementary crystallographic data for compound 4gg. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 21 5,6-Dimethoxy-1-(4-methoxyphenyl)-2-methylindane (3aa); Enlarged-Scale Procedure 1 mol% AuCl (14 mg, 0.060 mmol) was added at rt to a solution of benzylic alcohol 1a (1.0 g, 6.0 mmol) and ethyl trans-anethole (2a) (0.88 g, 6.0 mmol) in [EMIM][NTf₂] (5 mL). When benzylic alcohol 1a was completely consumed (TLC; usually <30 min), the product was extracted with Et₂O and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, hexane–EtOAc) to give a colorless oil; yield: 1.3 g (73%). IR (KBr): 3033, 299, 2931, 2837, 1614, 1512, 1472, 1446, 1512, 1471, 1445, 1410, 1313, 1213, 1173, 1088, 1028, 995, 856, 820, 804, 764 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.11 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 6.79 (s, 1 H), 6.39 (s, 1 H), 3.88 (s, 3 H), 3.81 (s, 3 H), 3.72 (s, 3 H), 3.70 (d, J = 9.5 Hz, 1 H), 3.06 (dd, J = 14.9, 7.5 Hz, 1 H), 2.55 (dd, J = 14.9, 9.5 Hz, 1 H), 2.42–2.30 (m, 1 H), 1.17 (d, J = 6.6 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 158.2, 148.14, 148.07, 138.3, 136.4, 135.2, 129.4, 113.8, 108.1, 107.4, 58.9, 56.1, 56.1, 55.2, 46.9, 40.1, 18.4. HRMS (EI): m/z [M⁺] calcd for C₁₉H₂₂O₃: 298.1569; found: 298.1569.
• 22 In the recycling of the gold catalyst in this reaction, the reaction time was prolonged after the first cycle. The cause is assumed to be imidazole, which is a decomposition product generated when water produced during the reaction reacts with the ionic liquid in the presence of the gold catalyst.²³ The generated imidazole might coordinate to the gold catalyst, significantly reducing its activity and prolonging the reaction time; however, this has not been confirmed.
• 23 Vieira JC. B, Villetti MA, Frizzo CP. J. Mol. Liq. 2021; 330: 115618

Publication History

Received: 30 November 2022

Accepted after revision: 20 December 2022

Accepted Manuscript online:
21 December 2022

Article published online:
19 January 2023