Synthesis of Propargylic Ethers by Gold-Mediated Reaction of Terminal Alkynes with Acetals

Abstract

A gold-catalyzed introduction of various terminal alkynes to acetals was investigated. Extensive optimization of the reaction conditions revealed that thermally stable cationic gold catalysts bearing bulky ligands such as 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene 3-1H-benzo[d][1,2,3]triazolyl gold trifluoromethanesulfonate (IPrAu(BTZ-H)OTf) were particularly suitable for the reaction. Additionally, significant solvent effects were observed. Ether solvents such as tetrahydrofuran (THF), cyclo pentyl methyl ether (CPME), and 1,4-dioxane were effective for the reaction. Studies on the scope of substrates and alkynes indicated that various alkynes and acetals were feasible to provide a wide range of propargylic ethers.

Introduction

Alkyne is one of the most useful functional groups in synthetic organic chemistry and can be transformed into corresponding alkane, alkene, allene, and carbonyl groups.¹⁾ Furthermore, they work as a 1,3-dipolarophile. For example, Huisgen-type 1,3-dipolar cycloaddition with azides, known as click reaction, is a widely used method in chemical biology.²⁾ Moreover, medicinal products comprising alkynes are frequently used for the treatment of diseases such as cranial nerve disease and gynecological disease. Due to the prevalent application of alkynes in organic synthesis, chemical biology, and medicinal chemistry, the development of a methodology to incorporate alkyne moiety in organic compounds is an important research topic.

The most fundamental means to introduce alkyne moiety to an organic molecule is a reaction of metal acetylides with electrophiles.^3–20) For example, metal acetylides prepared by reacting terminal acetylenes with lithium,³⁾ magnesium,⁴⁾ zinc,⁵⁾ tin,⁶⁾ boron,⁷⁾ aluminum,⁸⁾ and titanium⁹⁾ reagents react with carbonyl compounds or acetals to produce propargylic alcohol or ether, respectively. However, these methods require a strong base or a stoichiometric amount of metal to generate metal acetylides. On the other hand, the addition of terminal acetylene to acetals proceeds in the presence of a catalytic amount of zinc,^10,11) copper,¹²⁾ and tin¹³⁾ reagents to afford propargylic ether, although these reactions often require heating conditions and would not be applied to acid-sensitive substrates. Based on the high functional group compatibility,^14–17) gold catalyzed synthesis of propargylic alcohol¹⁸⁾ or ether¹⁹⁾ from terminal alkyne has recently been developed. However, in these reactions, electrophiles are only limited to aryl aldehydes. Additionally, Dalla and colleagues reported a gold-mediated introduction of alkyne moieties to cyclic acetals,²⁰⁾ whose limitation was the necessity to use trimethylsilyl alkynes.

Recently, we developed a modular synthesis of substituted pyrroles from aminoacetals and alkynes via gold-mediated tandem catalysis^21–24) (Chart 1). The cascade reaction is initiated by the formation of gold acetylide 4 from alkyne 2, which adds to the oxonium ion 5 to form 6. Next, the gold catalyst works as a π-Lewis acid, activating the alkyne moiety to promote 5-endo-dig cyclization to furnish pyrrole 3. During the course of the investigation, we observed that the choice of the appropriate ligand such as 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) or 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) on the gold catalyst was crucial for achieving a smooth reaction. Therefore, we conducted fundamental studies on the first step of the above cascade reaction using various gold catalysts and acetals to clarify the scope and limitation of the initial reaction of gold acetylides with acetals.

Chart 1. Gold-Catalyzed Substituted Pyrrole Synthesis

Results and Discussion

First, we explored the optimal reaction conditions for obtaining propargylic ether 10a by using acetal 8a and phenylacetylene 2a as model substrates. Reactions using π-philic catalysts such as AuCl, AuCl₃, CuI, and PtCl₂ in toluene did not produce the desired 10a even after heating at 50°C for 12 h (Table 1, entries 1–4). The use of cationic gold catalyst generated in situ from a combination of AuPPh₃Cl and AgOTf gave 10a in a modest yield (Table 1, entry 5). Reaction conditions established in our pyrrole synthesis²⁴⁾ using RuPhosAuCl²²⁾ that has a biphenylphosphine ligand and IPrAuCl possessing a bulky carbene ligand were quite efficient in providing 10a in good yields (Table 1, entries 6 and 7). We reasoned that the superiority of the bulky gold catalyst would be due to the suppression of product decomposition by gold catalyzed methanolysis. Furthermore, thermally stable catalyst, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene 3-1H-benzo[d][1,2,3]triazolyl gold trifluoromethanesulfonate (IPrAu(BTZ-H)OTf),^25,26) which itself works as a cationic gold catalyst, improved the yield of 10a up to 80% (Table 1, entry 8). Next, we selected IPrAu(BTZ-H)OTf as the best catalyst and conducted extensive optimization experiments regarding catalyst loading and the solvent (Table 1, entries 9–18). The loading of catalyst was reduced to 2 mol% without substantial loss of the yield, although the reaction time was prolonged (Table 1, entry 10). Non-polar solvents such as toluene and xylene together with ether solvents were found to be suitable (Table 1, entries 12–17). Especially, the reaction using tetrahydrofuran (THF) provided 10a in highest yield (Table 1, entry 17). Even in the case of reaction using reduced amount of alkyne 2a to 2 eq, 10a was obtained with a slight loss of the yield (Table 1, entry 18).

Table 1. Optimization of Gold-Catalyzed Propargylic Ether Synthesis

Entry	Catalyst (mol%)	Solvent	Time (min)	Yield (%)
1	AuCl (10)	Toluene	720	ND
2	AuCl3 (10)	Toluene	720	ND
3	CuI (10)	Toluene	720	ND
4	PtCl2 (10)	Toluene	720	ND
5	AuPPh3Cl (10), AgOTf (10)	Toluene	45	67
6	RuPhosAuCl (10), AgOTf (10)	Toluene	5	52
7	IPrAuCl (10), AgOTf (10)	Toluene	5	71
8	IPrAu(BTZ-H)(OTf) (10)	Toluene	5	80
9	IPrAu(BTZ-H)(OTf) (5)	Toluene	5	67
10	IPrAu(BTZ-H)(OTf) (2)	Toluene	30	71
11	IPrAu(BTZ-H)(OTf) (1)	Toluene	30	42
12	IPrAu(BTZ-H)(OTf) (2)	Xylene	30	77
13	IPrAu(BTZ-H)(OTf) (2)	1,2-DCE	45	67
14	IPrAu(BTZ-H)(OTf) (2)	Acetonitrile	180	57
15	IPrAu(BTZ-H)(OTf) (2)	1,4-Dioxane	20	74
16	IPrAu(BTZ-H)(OTf) (2)	CPME	10	82
17	IPrAu(BTZ-H)(OTf) (2)	THF	20	87
18a)	IPrAu(BTZ-H)(OTf) (2)	THF	20	72

a) 2 eq of 2a was used.

After establishing the optimal conditions, we shifted our attention to the substrate scope. Various terminal alkynes 2a–i were exposed to acetals 8a–e in the presence of 2 mol% of the gold catalyst in THF at 100°C (Table 2). Arylalkynes bearing electron donating groups on the benzene ring, such as methyl or methoxy group at the para position, provided the corresponding alkynes 10b and 10c in good yield (Table 2, entries 1 and 2). Alkynes bearing meta- or ortho-methoxy substituent on the benzene ring gave alkynes 10d and 10e in moderate yield, respectively (Table 2, entries 3 and 4). Notably, aryl iodide was tolerant under standard conditions (Table 2, entry 5). Conversely, when the substrate contained an electron withdrawing group such as a nitro group on the benzene ring, 10g was afforded in low yield because of the suppressed nucleophilicity of the corresponding acetylide (Table 2, entry 6). In the reaction using alkyl alkynes, 10h and 10i were produced in moderate yields (Table 2, entries 7 and 8).

Table 2. Substrate Scope of Alkynes

a) 7 mol% catalyst was used in toluene solvent.

Further, various types of acetals were reacted with ethynyl benzene (2a). Diethyl and diisopropyl acetals were suitable substrates for generating the propargylic ethers 10j and 10k in excellent yields (Table 3, entries 1 and 2), respectively. Substrates possessing dimethyl acetal at the benzyl or the neopentyl positions gave the corresponding products 10l or 10 m (Table 3, entries 3 and 4). The reaction was feasible to installation of alkyne moiety to a cyclic acetal. A tetrahydropyranyl (THP) derivative 8f gave 10n (Chart 2) albeit with a low yield.

Table 3. Substrate Scope of Acetals

Chart 2. Application to Cyclic Acetal

In conclusion, we conducted detailed studies on the gold-catalyzed introduction of various terminal alkynes to acetals. During the optimization process, we found that thermally stable cationic gold catalysts bearing bulky ligands were particularly suitable for the reaction. Because it was feasible to use this reaction to synthesize a broad range of propargylic ethers by mild gold catalysis, we expect this protocol to find widespread use in the synthesis of various propargylic ethers in chemical biology and medicinal chemistry.

Experimental

Materials were obtained from commercial suppliers and used without further purification unless otherwise mentioned. All reactions were carried out in oven-dried glassware under a slight positive pressure of argon unless otherwise noted. Anhydrous Et₂O, THF, MeCN, and CH₂Cl₂ were purchased from Kanto Chemical Co., Inc. Anhydrous toluene, AcOEt and N,N-dimethylformamide (DMF) were purchased from Wako Pure Chemical Industries, Ltd.. Anhydrous toluene, xylene, 1,2-dichloroethane, 1,4-dioxane, methoxycyclopentane, MeOH, EtOH, i-PrOH, and Et₃N were dried and distilled according to the standard protocols. Flash column chromatography was performed on Silica Gel 60N (Kanto, spherical neutral, 40–50 µm) using the indicated eluent. Preparative TLC was performed on Merck 60 F₂₅₄ glass plates precoated with a 0.50 mm and a 0.25 mm thickness of silica gel. Analytical TLC was performed on Merck 60 F₂₅₄ glass plates precoated with a 0.25 mm thickness of silica gel. IR spectra were measured on a JASCO FT/IR-4100 spectrometer. NMR spectra were recorded on a JNM-AL400 spectrometer with tetramethylsilane (0 ppm) and chloroform (7.26 ppm) as an internal standard. Chemical shifts were expressed in δ (ppm) values, and coupling constants were expressed in hertz (Hz). The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, m = multiplet, and br = broad. Mass spectra were recorded on a Brucker micrOTOF II (electrospray ionization (ESI)) and JEOL JMS-T 100GC (electron ionization (EI)).

General Procedure A for Preparation of Acetals

A 300 mL two-necked round-bottomed flask equipped with a magnetic stirring bar was charged with N-chlorosuccinimide (5 mol%), thiourea (2 mol%), and alcohol (0.2 M). To the solution was added cinnamaldehyde at room temperature. The mixture was stirred until TLC (hexanes/AcOEt = 3 : 1) indicated a complete consumption of cinnamaldehyde. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexanes/AcOEt = 10 : 1) to afford acetal.

(3,3-Dimethoxypropyl)benzene (8a)

According to the general procedure A, dimethylacetal 8a was obtained from cinnamaldehyde with MeOH in 15 mmol scale (2.30 g, 12.7 mmol, 85%) as a colorless liquid; Its ¹H-NMR spectra data was completely identical with that reported²⁷⁾; IR (neat, cm⁻¹) 3027, 2952, 2829, 1603, 1025, 1054, 747; ¹H-NMR (400 MHz, CDCl₃) δ: 7.30–7.25 (2H, m), 7.20 (3H, d, J = 7.2 Hz), 4.37 (1H, t, J = 6.0 Hz), 3.33 (6H, s), 2.68 (2H, t, J = 8.0 Hz), 1.95–1.90 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 141.5, 128.2, 125.7, 103.5, 52.5, 33.9, 30.7 (one peak is missing due to overlapped); high resolution (HR)-MS EI Calcd for C₁₁H₁₆O₂[M]⁺ 180.1150. Found 180.1165.

(3,3-Diethoxypropyl)benzene (8b)

According to the general procedure A, diethylacetal 8b was obtained from cinnamaldehyde with EtOH in 0.75 mmol scale (136 mg, 0.653 mmol, 87%) as a colorless liquid; ¹H-NMR spectra data was completely identical with that reported²⁷⁾; IR (neat, cm⁻¹) 3027, 2975, 2928, 2876, 1604, 1129, 1063, 747; ¹H-NMR (400 MHz, CDCl₃) δ: 7.29–7.25 (2Η, m), 7.21–7.16 (3H, m), 4.49 (1H, t, J = 6.0 Hz), 3.87 (2H, dq, J = 7.2, 9.2 Hz), 3.49 (2H, dq, J = 7.6, 9.2 Hz), 2.71–2.67 (2H, m), 1.97–1.92 (2H, m), 1.21 (6H, t, J = 7.2 Hz.); ¹³C-NMR (100 MHz, CDCl₃) δ: 141.7, 128.3, 128.3, 125.7, 102.1, 60.9, 35.0, 30.9, 15.3; HR-MS (EI) Calcd for C₁₃H₂₀O₂[M]⁺ 208.1463. Found 208.1508.

(3,3-Diisopropoxypropyl)benzene (8c)

According to the general procedure A, diisopropylacetal 8c was obtained from cinnamaldehyde with i-PrOH in 2.0 mmol scale (200 mg, 0.846 mmol, 42%) as a colorless liquid; ¹H-NMR spectra data was completely identical with that reported²⁷⁾; IR (neat, cm⁻¹) 3027, 2971, 2930, 1604, 1128, 1034, 699; ¹H-NMR (400 MHz, CDCl₃) δ: 7.29–7.15 (5Η, m), 4.56 (1H, t, J = 5.2 Hz), 3.85 (2H, sept, J = 6.4 Hz), 2.71–2.67 (2H, m), 1.94–1.89 (2H, m), 1.20 (6H, d, J = 6.4 Hz), 1.14 (6H, d, J = 6.0 Hz); ¹³C-NMR (100 MHz, CDCl₃) δ: 142.0, 128.4, 128.3, 125.7, 99.7, 67.7, 36.9, 31.1, 23.4, 22.6; HR-MS (EI) Calcd for C₁₅H₂₄O₂[M]⁺, 236.1776. Found 236.1814.

General Procedure for Gold-Catalyzed Nucleophilic Addition of Acetylenes to Acetals

(3-Methoxypent-1-yne-1,5-diyl)dibenzene (10a)

A 10 mL test tube equipped with a magnetic stirring bar was charged with IPrAu(BTZ-H)OTf (1.7 mg, 1.99 µmol, 2 mol%) and THF (200 µL, 0.5 M). To the solution were added acetal 8a (18.0 mg, 0.100 mmol) and alkyne 2a (55.0 µL, 0.500 mmol, 5.0 eq) at room temperature. The mixture was heated at 100°C and the solution was stirred until TLC (hexanes–Et₂O = 10 : 1) indicated a complete consumption of acetal 8a. The reaction was quenched with saturated aqueous NaHCO₃ and the mixture was extracted with AcOEt three times. The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexanes–Et₂O = 60 : 1) to afford propargyl ether 10a (21.9 mg, 87.5 µmol, 87%) as a yellow oil; IR (neat, cm⁻¹) 3026, 2927, 2820, 1601, 756, 691; ¹H-NMR (400 MHz, CDCl₃) δ: 7.46–7.44 (2H, m), 7.31–7.17 (8H, m), 4.14 (1H, t, J = 6.4 Hz), 3.47 (3H, s), 2.87–2.83 (2H, m), 2.20–2.03 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 141.4, 131.7, 128.5, 128.4, 128.3, 128.3, 125.9, 122.7, 87.8, 86.2, 70.8, 56.5, 37.2, 31.5; HR-MS (ESI) Calcd for C₁₇H₁₅ [M−OMe]⁺, 219.1168. Found 219.1178.

1-(3-Methoxy-5-phenylpent-1-yn-1-yl)-4-methylbenzene (10b)

According to the general procedure described for 10a, propargyl ether 10b was obtained from acetal 8a with alkyne 2b in 0.50 mmol scale (106 mg, 0.402 mmol, 80%) as a yellow oil; IR (neat, cm⁻¹) 3085, 3065, 3027, 2853, 1601, 817, 746; ¹H-NMR (400 MHz, CDCl₃) δ: 7.35 (2H, d, J = 8.4 Hz), 7.31–7.18 (5H, m), 7.12 (2H, d, J = 8.4 Hz), 4.14 (1H, t, J = 6.4 Hz), 3.47 (3H, s), 2.85 (2H, dt, J = 6.4, 2.4 Hz), 2.35 (3H, s), 2.19–2.04 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 141.5, 138.4, 131.6, 129.0, 128.5, 128.4, 125.9, 119.6, 87.0, 86.3, 70.8, 56.4, 37.3, 31.5, 21.4; HR-MS (ESI) Calcd for C₁₈H₁₇ [M−OMe]⁺, 233.1325. Found 233.1322.

1-Methoxy-4-(3-methoxy-5-phenylpent-1-yn-1-yl)benzene (10c)

According to the general procedure described for 10a, propargyl ether 10c was obtained from acetal 8a with alkyne 2c in 0.50 mmol scale (103 mg, 0.366 mmol, 73%) as a yellow oil; IR (neat, cm⁻¹) 2932, 2837, 2817, 1605, 1062, 832, 699; ¹H-NMR (400 MHz, CDCl₃) δ: 7.39 (2H, dt, J = 8.8, 2.8 Hz), 7.31–7.12 (5H, m), 6.83 (2H, dt, J = 8.8, 2.8 Hz), 4.12 (1H, t, J = 6.4 Hz), 3.81 (3H, s), 3.47 (3H, s), 2.87–2.82 (2H, m), 2.17–2.04 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 159.6, 141.5, 133.1, 128.5, 128.3, 125.8, 114.8, 113.9, 86.3, 86.1, 70.8, 56.4, 55.2, 37.3, 31.5; HR-MS (ESI) Calcd for C₁₈H₁₇O [M−OMe]⁺, 249.1274. Found 249.1271.

1-Methoxy-3-(3-methoxy-5-phenylpent-1-yn-1-yl)benzene (10d)

According to the general procedure described for 10a, propargyl ether 10d was obtained from acetal 8a with alkyne 2d in 0.50 mmol scale (77.0 mg, 0.275 mmol, 55%) as a yellow oil; IR (neat, cm⁻¹) 3085, 3058, 3023, 2992, 2821, 1602, 1163, 786, 746; ¹H-NMR (400 MHz, CDCl₃) δ: 7.31–7.17 (6H, m), 7.05 (1H, dt, J = 8.0 Hz, 1.2 Hz), 6.98 (1H, t, J = 2.4 Hz), 6.87 (1H, dd, J = 8.4, 1.6 Hz), 4.14 (1H, t, J = 6.4 Hz), 3.80 (3H, s), 3.47 (3H, s), 2.85 (2H, t, J = 8.4 Hz), 2.16–2.08 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 159.3, 141.4, 129.3, 128.5, 128.4, 125.9, 124.2, 123.7, 116.6, 114.9, 87.6, 86.1, 70.8, 56.4, 55.2, 37.2, 31.4; HR-MS (ESI) Calcd for C₁₈H₁₇O [M−OMe]⁺, 249.1274. Found 249.1264.

1-Methoxy-2-(3-methoxy-5-phenylpent-1-yn-1-yl)benzene (10e)

According to the general procedure described for 10a, propargyl ether 10e was obtained from acetal 8a with alkyne 2e in 0.50 mmol scale (103 mg, 0.368 mmol, 74%) as a yellow oil; IR (neat, cm⁻¹) 3061, 3027, 2833, 1596, 1292, 751, 700; ¹H-NMR (400 MHz, CDCl₃) δ: 7.42 (1H, dd, J = 7.2, 7.2 Hz), 7.31–7.17 (6H, m), 6.92–6.86 (2H, m), 4.20 (1H, t, J = 6.4 Hz), 3.87 (3H, s), 3.50 (3H, s), 2.95–2.82 (2H, m), 2.20–2.04 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 160.1, 141.6, 133.5, 129.7, 128.5, 128.3, 125.8, 120.3, 111.9, 110.5, 91.3, 82.5, 70.9, 56.4, 55.6, 37.2, 31.4; HR-MS (ESI) Calcd for C₁₈H₁₇O [M−OMe]⁺, 249.1274. Found 249.1265.

1-Iodo-4-(3-methoxy-5-phenylpent-1-yn-1-yl)benzene (10f)

According to the general procedure described for 10a, propargyl ether 10f was obtained from acetal 8a with alkyne 2f in 0.50 mmol scale (151 mg, 0.402 mmol, 80%) as a yellow oil; IR (neat, cm⁻¹) 3061, 3025, 2819, 1601, 1577, 1030, 715; ¹H-NMR (400 MHz, CDCl₃) δ: 7.65 (2H, d, J = 8.4 Hz), 7.31–7.15 (7H, m), 4.11 (1H, t, J = 6.8 Hz), 3.46 (3H, s), 2.83 (2H, dt, J = 8.0, 1.2 Hz), 2.19–2.05 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 141.2, 137.4, 133.2, 128.5, 128.4, 125.9, 122.2, 94.2, 89.3, 85.2, 70.7, 56.5, 37.0, 31.4; HR-MS (EI) Calcd for C₁₈H₁₇IO [M]⁺, 376.0324. Found 376.0323.

1-(3-Methoxy-5-phenylpent-1-yn-1-yl)-4-nitrobenzene (10g)

According to the general procedure described for 10a, propargyl ether 10g was obtained from acetal 8a with alkyne 2g in 0.50 mmol scale (21.6 mg, 73.1 µmol, 15%) as a yellow oil; IR (neat, cm⁻¹) 3104, 3081, 3058, 1594, 1454, 749; ¹H-NMR (400 MHz, CDCl₃) δ: 8.19 (2H, d, J = 8.4 Hz), 7.58 (2H, d, J = 8.0 Hz), 7.31 (2H, J = 7.2 Hz), 7.25–7.19 (3H, m), 4.16 (1H, t, J = 6.4 Hz), 3.48 (3H, s), 2.85 (2H, t, J = 7.6 Hz) 2.22–2.04 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 147.2, 141.1, 132.5, 129.6, 128.5, 128.5, 126.1, 123.5, 93.5, 84.3, 70.7, 56.8, 36.9, 31.4; HR-MS (ESI) Calcd for C₁₇H₁₄NO₂ [M−OMe]⁺, 264.1019. Found 264.1023.

(3-Methoxynon-4-yn-1-yl)benzene (10h)

According to the general procedure described for 10a, propargyl ether 10h was obtained from acetal 8a with alkyne 2h in 0.50 mmol scale (79.7 mg, 0.346 mmol, 69%) as a yellow oil; IR (neat, cm⁻¹) 3061, 3027, 2861, 1604, 1081, 748, 699; ¹H-NMR (400 MHz, CDCl₃) δ: 7.29–7.15 (5H, m), 3.90 (1H, tt, J = 6.4, 2.0 Hz), 3.38 (3H, s), 2.77 (2H, t, J = 7.6 Hz), 2.24 (2H, dt, J = 6.8, 2.0 Hz), 2.05–1.93 (2H, m), 1.55–1.40 (4H, m), 0.92 (3H, t, J = 7.2 Hz); ¹³C-NMR (100 MHz, CDCl₃) δ: 141.7, 128.5, 128.3, 125.8, 86.7, 78.6, 70.6, 56.1, 37.5, 31.5, 30.8, 21.9, 18.3, 13.5; HR-MS (ESI) Calcd for C₁₅H₁₉ [M−OMe]⁺, 199.1481. Found 199.1460.

(5-Cyclohexyl-3-methoxypent-4-yn-1-yl)benzene (10i)

According to the general procedure described for 10a, propargyl ether 10i was obtained from acetal 8a with alkyne 2i in 0.50 mmol scale (75.9 mg, 0.296 mmol, 59%) as a yellow oil; IR (neat, cm⁻¹) 3012, 2853, 2817, 1496, 1105, 749; ¹H-NMR (400 MHz, CDCl₃) δ: 7.30–7.16 (5H, m), 4.56 (1H, dt, J = 7.2, 2.0 Hz), 3.39 (3H, s), 2.78 (2H, dt, J = 7.2, 0.8 Hz), 2.44 (1H, quin, J = 1.6 Hz), 2.80–1.94 (2H, m), 1.82–1.72 (2H, m), 1.71–1.69 (2H, m), 1.51–1.45 (3H, m), 1.34–1.29 (3H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 141.7, 128.5, 128.3, 125.8, 90.9, 78.6, 70.6, 56.6, 37.6, 32.7, 31.5, 29.0, 25.9, 24.7; HR-MS (ESI) Calcd for C₁₇H₂₁ [M−OMe]⁺, 225.1638. Found 225.1646.

(3-Ethoxypent-1-yne-1,5-diyl)dibenzene (10j)

According to the general procedure described for 10a, propargyl ether 10j was obtained from acetal 8b with phenylacetylene (2a) in 0.10 mmol scale (21.8 mg, 82.5 µmol, 82%) as a yellow oil; IR (neat, cm⁻¹) 3061, 3027, 2974, 2927, 2864, 1600, 1092, 756, 698; ¹H-NMR (400 MHz, CDCl₃) δ: 7.45–7.43 (2H, m), 7.32–7.16 (8H, m), 4.22 (1H, t, J = 6.4 Hz), 3.87 (1H, dq, J = 9.2, 6.8 Hz), 3.49 (1H, dq, J = 9.2, 6.8 Hz), 2.86 (2H, t, J = 7.6 Hz), 2.19–2.08 (2H, m), 1.26 (3H, t, J = 7.6 Hz); ¹³C-NMR (100 MHz, CDCl₃) δ: 141.5, 131.7, 128.5, 128.4, 128.2, 125.9, 122.9, 88.5, 85.7, 69.0, 64.4, 37.4, 31.6, 15.2 (one peak is missing due to overlapped); HR-MS (ESI) Calcd for C₁₇H₁₅ [M−OEt]⁺, 219.1168. Found 219.1129.

(3-Isopropoxypent-1-yne-1,5-diyl)dibenzene (10k)

According to the general procedure described for 10a, propargyl ether 10k was obtained from acetal 8c with phenylacetylene (2a) in 0.10 mmol scale (23.6 mg, 84.8 µmol, 84%) as a yellow oil; IR (neat, cm⁻¹) 3085, 3065, 3027, 2971, 1600, 756, 698; ¹H-NMR (400 MHz, CDCl₃) δ: 7.44–7.42 (2H, m), 7.30–7.16 (8H, m), 4.30 (1H, t, J = 6.4 Hz), 3.98 (1H, sept, J = 6.4 Hz), 2.89–2.78 (2H, m), 2.17–2.06 (2H, m), 1.27 (3H, d, J = 6.4 Hz), 1.16 (3H, d, J = 6.4 Hz); ¹³C-NMR (100 MHz, CDCl₃) δ: 141.8, 131.7, 128.5, 128.3, 128.2, 128.2, 125.8, 123.0, 89.2, 85.0, 69.9, 66.5, 37.8, 31.6, 23.3, 21.4; HR-MS (ESI) Calcd for C₁₇H₁₅ [M−Oi-Pr]⁺, 219.1168. Found 219.1177.

(3-Methoxyprop-1-yne-1,3-diyl)dibenzene (10l)

According to the general procedure described for 10a, propargyl ether 10l was obtained from acetal 8d with phenylacetylene (2a) in 0.50 mmol scale (82.7 mg, 0.372 mmol, 74%) as a yellow oil; Its ¹H-NMR spectra data was completely identical with that reported²⁸⁾; IR (neat, cm⁻¹) 3058, 3023, 2917, 2848, 1598, 734, 696; ¹H-NMR (400 MHz, CDCl₃) δ: 7.58 (1H, d, J = 7.2 Hz), 7.49 (1H, dd, J = 7.6, 2.4 Hz), 7.48–7.30 (8H, m), 5.31 (1H, s), 3.50 (3H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 138.3, 131.7, 128.5, 128.4, 128.2, 127.4, 126.0, 122.5, 87.6, 86.4, 73.4, 55.8; HR-MS (ESI) Calcd for C₁₅H₁₁ [M−OMe]⁺, 191.0855. Found 191.0852.

(3-Methoxy-4-methylpent-1-yne-1,4-diyl)dibenzene (10m)

According to the general procedure described for 10a, propargyl ether 10m was obtained from acetal 8e²⁸⁾ with phenylacetylene (2a) in 0.50 mmol scale (107 mg, 0.404 mmol, 81%) as a yellow oil; IR (neat, cm⁻¹) 3059, 3031, 2973, 2931, 2819, 1599, 1490, 1094, 757, 697; ¹H-NMR (400 MHz, CDCl₃) δ: 7.46 (2H, d, J = 7.2 Hz), 7.37–7.20 (8H, m), 4.19 (1H, s), 3.41 (3H, s), 1.50 (3H, s), 1.48 (3H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 146.3, 131.6, 128.2, 127.8, 126.7 126.1, 122.9, 87.0, 86.9, 80.8, 57.6, 42.7, 25.2, 24.2; HR-MS (ESI) Calcd for C₁₉H₂₁O [M + H]⁺, 265.1587. Found 265.1574.

2-(Phenylethynyl)tetrahydro-2H-pyran (10n)

According to the general procedure described for 10a, propargyl ether 10m was obtained from acetal 8f with phenylacetylene (2a) in 0.50 mmol scale (33.7 mg, 0.181 mmol, 36%) as a pale yellow oil; Its ¹H-NMR spectra data was identical with that reported²⁹⁾; IR (neat, cm⁻¹) 3054, 2939, 2849, 1597, 757; ¹H-NMR (400 MHz, CDCl₃) δ: 7.47–7.44 (2H, m), 7.32–7.26 (3H, m), 4.51 (1H, dd, J = 7.2, 2.8 Hz), 4.08–4.03 (1H, m), 3.62–3.58 (1H, m), 1.96–1.91 (2H, m), 1.83–1.78 (1H, m) 1.66–1.60 (4H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 131.6, 128.1, 128.0, 122.6, 88.0, 85.0, 67.3, 66.4, 32.0, 25.5, 21.7; HR-MS (ESI) Calcd for C₁₃H₁₅O [M + H]⁺, 187.1117. Found 187.1103.

Acknowledgments

This work was supported by the Drug Discovery and Life Science Research (BINDS) from AMED (Grant Number JP18am0101100) and JSPS KAKENHI Grant Numbers JP18H04379, JP18H04231, JP18H04642, 18H02549, 17K08204 and 18H06100.

Conflict of Interest

The authors declare no conflict of interest.

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