Nucleophilic Deprotection of p-Methoxybenzyl Ethers Using Heterogeneous Oxovanadium Catalyst

Abstract

Nucleophilic deprotection of p-methoxybenzyl (PMB) [p-methoxyphenylmethyl (MPM)] ethers was developed using a heterogeneous oxovanadium catalyst V-MPS4 and a thiol nucleophile. The deprotection method had a wide reaction scope, including PMB ethers of primary, secondary, and tertiary alcohols bearing various functional groups. In addition, the PMB ether of an oxidation-labile natural product was successfully removed by V-MPS4 catalysis, while a common oxidative method of PMB deprotection afforded a complex mixture. The V-MPS4 catalyst was reusable up to six times without a significant loss in the product yield. The advantages of using the heterogeneous catalyst were further demonstrated by conducting the deprotection reaction in a continuous flow process, which resulted in a 2.7-fold higher catalyst turnover number and 60-fold higher turnover frequency compared to those of the corresponding batch reaction.

Introduction

Heterogeneous catalysis has inherent advantages in chemical transformations because of the ease of catalyst separation and reuse as well as its applicability to continuous flow processes.¹⁾ Extensive application of heterogeneous catalysts in synthetic organic chemistry can contribute to resource conservation and reduce waste production, rendering the synthetic process more sustainable and economical. We previously developed a highly active heterogeneous oxovanadium catalyst, V-MPS4, in which the oxovanadium species were covalently bound to the inner surface of mesoporous silica with a 4-nm diameter^2,3) (Fig. 1a). V-MPS4 catalyzed the reversible C–O bond heterolysis of alcohols to mediate racemization, and this was combined with a lipase-catalyzed acylative kinetic resolution to realize dynamic kinetic resolution⁴⁾ (Fig. 1b). More recently, V-MPS4 was found to catalyze the direct nucleophilic substitution of alcohols with various nucleophiles via C–O bond cleavage⁵⁾ (Fig. 1c). During the course of our continuous research on V-MPS4 catalysis,^6–10) we realized that V-MPS4 could also catalyze the C–O bond cleavage of reactive ethers such as p-methoxybenzyl (PMB) [also known as p-methoxyphenylmethyl (MPM)] ethers. Based on this finding, we report herein the V-MPS4-catalyzed nucleophilic deprotection of PMB ethers to furnish alcohols (Fig. 1d). We also demonstrate the advantages of this heterogeneous V-MPS4 catalyst in a continuous flow process.

Fig. 1. V-MPS4-Catalyzed Reactions and the General Concept of This Work

PMB ethers are protecting group and have been widely used to mask alcohols in multistep synthesis.¹¹⁾ Typically, PMB ethers are deprotected using stoichiometric oxidants such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)¹²⁾ and ceric ammonium nitrate (CAN).¹³⁾ Catalytic oxidative deprotection methods have been also reported, using inexpensive terminal oxidants.^14–18) Recently, other methods like photoredox catalysis,^19–21) electrochemical oxidation,^22,23) and Brønsted acid catalysis^24,25) have been developed for PMB deprotection. Lewis acid catalysis has been also widely explored for PMB deprotection in the presence^26–28) or absence^29,30) of nucleophiles. While these methods mainly use homogeneous catalysts, reports on PMB deprotection by heterogeneous catalysis are limited,³¹⁾ despite its significance amidst the growing demand of sustainable manufacturing of fine chemicals such as pharmaceutically relevant compounds.³²⁾

Results and Discussion

Initially, the reaction conditions were screened using PMB ether 1a (Table 1). The reaction was conducted using 4 mol% of V-MPS4 in 1,2-dichloroethane at 80 °C for 24 h. Deprotection of the PMB group proceeded without a nucleophile (Nu-H) to afford the corresponding alcohol 2a (45%), along with the recovery of 1a (37%) (Entry 1). The PMB group was probably removed via the nucleophilic attack by a methoxyphenyl group in another molecule of 1a, as shown in a previous study.²⁹⁾ Further, external nucleophiles were screened to improve the yield of 2a (Entries 2–7). While C and N nucleophiles such as 1,3,5-trimethoxybenzene (4) and 4-methylaniline (5) were not effective (Entries 2 and 3), the yield of 2a increased dramatically in the presence of S nucleophiles (Entries 4–7). In particular, 4-tert-butylbenzenethiol (8) and 4-methoxybenzenethiol (9) gave the best results, affording 2a in 90 and 92% NMR yields, respectively; however, a small amount of 1a (less than 5%) still remained in both cases (Entries 6 and 7). Using 2 eq. of 9, complete conversion of 1a, along with 82% isolate yield of 2a, was achieved (Entry 8). The yield decreased significantly at a lower temperature (Entry 9). The use of other halogenated and aromatic solvents afforded 2a in moderate yields (Entries 10–12), while the yield decreased significantly when MeCN was used (Entry 13). Thus, 1,2-dichloroethane was chosen as the optimal solvent. Although the reaction proceeded to some extent in the absence of the V-MPS4 catalyst, the catalyst exhibited a prominent effect in accelerating the reaction as a Lewis acid (Entry 14 vs. 8).

Table 1. Screening of Reaction Conditions for the V-MPS4-Catalyzed Deprotection of PMB Ether 1a^a)

Entry	Nu-H	Solvent	Yield [%] of 2ab)
1	—	Cl(CH2)2Cl	45
2	1,3,5-(MeO)3-C6H3 (4)	Cl(CH2)2Cl	44
3	4-Me-C6H4NH2 (5)	Cl(CH2)2Cl	<5
4	nC12H25SH (6)	Cl(CH2)2Cl	83
5	2,4,6-iPr3-C6H2SH (7)	Cl(CH2)2Cl	78
6	4-tBu-C6H4SH (8)	Cl(CH2)2Cl	90
7	4-MeO-C6H4SH (9)	Cl(CH2)2Cl	92
8c,d)	9	Cl(CH2)2Cl	98 (82)
9c,d,e)	9	Cl(CH2)2Cl	37
10c,f)	9	CHCl3	58
11c)	9	PhCl	61
12c)	9	toluene	74
13c)	9	MeCN	14
14c,g)	9	Cl(CH2)2Cl	43

a) Unless otherwise stated, the reaction was conducted with 1a (0.10 mmol), Nu-H (1.2 equivalent (equiv.)), and V-MPS4 (4.0 mol%) in the indicated solvent (0.10 M) at 80 °C for 24 h. b) Yield was determined by ¹H-NMR analysis of the crude reaction mixture using CH₂Br₂ as an internal standard. Isolate yield is indicated in parentheses. c) 9 (2.0 equiv.) was used. d) Reaction was conducted at the 0.2 mmol-scale. e) Reaction was conducted at 60 °C. f) Reaction was conducted at 70 °C. g) The reaction was conducted without V-MPS4.

With the optimal reaction conditions (Table 1, Entry 8) in hand, we next investigated the substrate scope and limitation of the V-MPS4-catalyzed PMB deprotection (Chart 1). Secondary alcohols 2b and 2c were obtained from the corresponding PMB ethers under the standard conditions in 83 and 99% yields, respectively. Notably, the reactions of α-tertiary PMB ethers were much faster than those of α-primary and secondary PMB ethers and were complete within 3 h to afford tertiary alcohols 2d and 2e in 82 and 80% yields, respectively. The higher reaction rate of the α-tertiary PMB ethers can be rationalized by the lower nucleophilicity of the produced tert-alcohols 2. The α-primary and secondary PMB ethers reacted not only with thiol 9 but also with 2 to decrease the net reaction rate, while α-tertiary PMB ethers did not react with 2 (Supplementary Chart S1). The functional group tolerance of the reaction was evaluated using PMB ethers bearing various functional groups. In the presence of a benzyl (Bn) ether, the PMB group was selectively deprotected, and 2f was obtained in 78% yield. While the unreacted PMB ether 1f was detected, no Bn-deprotected side products were detected in the ¹H-NMR spectrum of the crude product mixture, indicating the predominant deprotection of the PMB ether in the presence of the Bn group. A bromo group, which is prone to nucleophilic substitution, was tolerated under the reaction conditions and 2g was obtained in 80% yield. The phthalimide group was also compatible with this reaction, and 2h was obtained in 70% yield. The reaction of the PMB ether bearing an alkynylsilane moiety afforded the corresponding alcohol 2i in 81% yield, with the alkynylsilane moiety remaining unaffected. On the other hand, the PMB ether with a terminal acetylene group underwent significant decomposition, resulting in a low yield of 2j. The reaction of the PMB ether of a propargyl alcohol gave a complex mixture, and 2k was not detected in the crude reaction mixture, probably because of the V-MPS4-catalyzed side reactions, such as the Meyer–Schuster rearrangement, of 2k.⁶⁾ An ester moiety such as an acetoxy group was tolerated under the reaction conditions, and PMB-deprotected 2l was obtained in 90% yield. Reaction of the phenolic PMB ether gave a complex mixture and did not afford alcohol 2m, probably because nucleophilic side reactions occurred at the ortho-positions of the phenolic hydroxy group of the generated 2m. A steroid structure, i.e., the PMB ether of stigmasterol, was also tolerated under the reaction conditions, affording 2n in high yield.

Chart 1. Substrate Scope of the Reaction

a) Unless otherwise stated, the reaction was conducted with 1 (0.10 mmol), 9 (2.0 equiv.), and V-MPS4 (4.0 mol%) in 1,2-dichloroethane (0.10 M) at 80 °C for 24 h. b) Reaction time was 3 h. c) Reaction was conducted using 0.20 mmol of 1. d) N.D.: not detected.

Many pharmaceutically relevant molecules contain nitrogen atoms and/or polar functional groups. Thus, we next evaluated the functional group tolerance of the developed reaction (Table 2). Thus, the reaction was conducted in the presence of a stoichiometric amount of additives bearing certain functional groups. The reactions of 1a in the presence of aromatic nitro and cyano compounds and methanesulfonamide gave 2a in high yields, and the additives were recovered quantitatively in all cases, suggesting that these functional groups were tolerated in this reaction (Entries 1–3). In contrast, carboxylic acid, amide, and carbamate inhibited the reaction (Entries 4–6).

Table 2. V-MPS4-Catalyzed Deprotection of PMB Ether in the Presence of Functional Group Additives^a)

a) Unless otherwise stated, the reaction was conducted with 1a (0.10 mmol), 9 (2.0 equiv.), the indicated additive (1.0 equiv.), and V-MPS4 (4.0 mol%) in 1,2-dichloroethane (0.10 M) at 80 °C for 24 h. b) Yield was determined by ¹H-NMR analysis of the crude reaction mixture using CH₂Br₂ as an internal standard. c) Reaction was conducted for 72 h.

The functional group tolerance of the V-MPS4-catalyzed PMB deprotection was further examined by comparing its outcome with that of a common PMB deprotection method, i.e., DDQ oxidation¹²⁾ (Table 3). The deprotection reaction of α-tocopherol PMB ether (±)-1o using V-MPS4 (4 mol%) afforded the corresponding alcohol 2o in 80% yield (Entry 1), while the oxidative deprotection using a stoichiometric amount of DDQ gave a complex mixture (Entry 2). Thus, the V-MPS4-catalyzed nucleophilic PMB deprotection method is also suitable for oxidation-labile compounds.

Table 3. Deprotection of α-Tocopherol PMB Ether (±)-1o

Entry	Conditions	Yield of 2o [%]a)
1	9 (2.0 equiv.), V-MPS4 (4 mol%) Cl(CH2)2Cl (0.1 M), 80 °C, 24 h	80
2	DDQ (1.2 equiv.) CH2Cl2-H2O (18 : 1, 0.01 M), RT, 21 h	Decomposition

a) Isolated yield.

The V-MPS4-catalyzed nucleophilic deprotection method was also applicable to some other common protective groups of alcohols, namely the tetrahydropyranyl (THP) and trityl (Tr) groups (Chart 2). In the presence of thiol 9, the THP group in 10 was removed to give 2a in 78% yield after 24 h, with the concomitant generation of O,S-acetal 11 [Eq. (1)]. Trityl ether 12 was also reactive under these deprotection conditions, and 2a was obtained quantitatively along with sulfide 13 within 4 h [Eq. (2)]. Trapping the removed protective groups with the nucleophile was essential to achieve high yields since the reactions without 9 gave 2a in low yields in both cases.

Chart 2. Removal of THP and Tr Groups Using V-MPS4 Catalyst

The catalytic performance of V-MPS4 was further investigated by comparing its behavior with that of other oxovanadium catalysts in the PMB deprotection reaction (Table 4). The catalyst precursor of V-MPS4, VO(OSiPh₃)₃,^3,5) showed a reasonably low conversion although it was homogeneously soluble in the solvent (Entry 1 vs. 2). The use of vanadyl sulfate hydrate (VOSO₄·nH₂O) afforded 2a in 94% yield after 24 h, which is as high as that obtained using V-MPS4 (Entry 3). However, the reaction rate was higher with V-MPS4 than with VOSO₄·nH₂O, and the yield of 2a using the former was twice that obtained using VOSO₄·nH₂O at the early stage of the reaction (Entry 1 vs. 3). The superior catalytic performance of V-MPS4 over VOSO₄ was further demonstrated in the deprotection of the PMB ether of 2l (Supplementary Chart S2). The use of another vanadium (IV) species, V₂O₄, instead of the vanadium (V) species, decreased the yield of 2a (Entry 4).

Table 4. Comparison of Oxovanadium Catalysts in the Deprotection of 1a^a)

Entry	Catalyst	Yield of 2a [%]b)
1	V-MPS4	98 (52)c)
2	VO(OSiPh3)3	38
3	VOSO4·nH2Od)	94 (26)c)
4	V2O4	22

a) Unless otherwise stated, the reaction was conducted with 1a (0.10 mmol), 9 (2.0 equiv.), and catalyst (4.0 mol%) in 1,2-dichloroethane (0.10 M) at 80 °C for 24 h. b) Yield was determined by ¹H-NMR analysis of the crude reaction mixture using CH₂Br₂ as an internal standard. c) Yield after a 3-h reaction is given in parentheses. d) Commercial reagent with n = 3–4.

We next investigated the reusability of the V-MPS4 catalyst in the deprotection reaction of 1a (Table 5). After 24 h of reaction, the reaction mixture was centrifuged, and the precipitated catalyst was used in the next reaction after washing and drying. The supernatant was collected to determine the yield of 2a (detailed procedure is given in Section 4 of Supplement ary material). High yields were obtained for the first six runs. The V-MPS4 catalyst showed a turnover number (TON) of 1.3 × 10² and a turnover frequency (TOF) of 0.90 h⁻¹ for all these runs (calculations of TON and TOF are provided in Supplementary materials). However, the yield decreased in the seventh run. To investigate the reason for the decreased catalytic efficiency, fresh V-MPS4 and V-MPS4 that was used eight times were observed by scanning electron microscopy (SEM), and their vanadium contents were analyzed by inductively coupled plasma-optical emission spectrometry (ICP-OES). The particle size distribution decreased from 10–60 µm for the fresh catalyst to less than 5 µm for the catalyst that was used eight times, and the vanadium content decreased from 0.25 to 0.12 mmol/g (Supplementary Fig. S1). Thus, the decrease in the catalytic efficiency by repeated use could be attributed to the gradual degradation of the catalyst particles and/or the decrease in the vanadium content due to leaching.

Table 5. Reuse Test of the V-MPS4 Catalyst^a)

Run	1	2	3	4	5	6	7	8
Yield of 2a [%]b)	94	88	96	88	91	92	76	55

a) Each reaction was conducted with 1a (0.10 mmol) and 9 (2.0 equiv.) in 1,2-dichloroethane (0.10 M) at 80 °C for 24 h. V-MPS4 (17 mg, 4.0 mol%) was used for the first run. After the reaction, the catalyst was recovered and reused for the next run. b) Yield was determined by ¹H-NMR analysis of the crude reaction mixture using CH₂Br₂ as an internal standard.

Finally, the present reaction was applied to a continuous flow process by packing V-MPS4 in a fixed-bed reactor³³⁾ (Fig. 2, Supplementary Fig. S2). We anticipated that the flow reaction would show a higher TON compared to the batch reaction, because the catalyst morphology would be maintained in a flow reaction, whereas the catalyst particles would be degraded by the vigorous stirring in a batch reaction. The reaction was conducted by flowing a solution of 1a (0.1 M) and 9 (0.2 M) in 1,2-dichloroethane through the fixed-bed reactor, in which a homogeneous mixture of V-MPS4 and MPS4, the latter being a catalyst support for the immobilization of oxovanadium, was packed (V-MPS4/MPS4 = 1/5, 300 mg). A quantitative yield of 2a was maintained over 7 h at 80 °C and a flow rate of 0.1 mL/min (residence time = 10 min, shaded circles). Notably, no metal leaching was detected under this condition (Supplementary Fig. S3). The catalyst showed a TON of 3.5 × 10² and TOF of 54 h⁻¹, which are 2.7-fold and 60-fold higher than those obtained upon reusing the catalyst in a batch reaction (calculated based on 1–6 runs), respectively (calculations of TON and TOF are provided in Supplementary materials). The TOF further increased to 94 h⁻¹ upon increasing the flow rate to 0.2 mL/min (unshaded circles). The conversion decreased at a lower temperature (60 °C, triangle), similar to that observed in the batch reaction (Table 1, Entry 9). The use of MPS4 as a diluent was essential to achieve high conversions, since the conversion remained low in its absence (square).

Fig. 2. Continuous Flow Reaction of the PMB Ether Deprotection Using a Fixed-Bed Reactor Containing V-MPS4; The Yield of 2a Was Determined by GC Analysis Using the Peak-Area Ratio

Conclusion

We developed a deprotection method of PMB ethers under mild and redox-neutral conditions. The reaction was catalyzed by a mesoporous silica-supported oxovanadium V-MPS4 catalyst in the presence of thiol nucleophiles. The product was obtained in high yield by using a small excess of thiol (Table 1, Entry 7), and full conversion was ensured by using two equivalents of the thiol (Table 1, Entry 8). The reaction exhibited a wide functional group tolerance and was applicable to PMB ethers of primary, secondary, and tertiary alcohols. The heterogeneous V-MPS4 catalyst could be reused up to six times without any significant decrease in the product yield and could also be applied to the continuous flow reaction. The TON and TOF in the flow reaction were significantly higher than those in the batch reaction, and no catalyst leaching was observed. The present flow deprotection method will contribute to the synthesis of alcohols bearing various functional groups at a productive scale. Investigations on the further applications of V-MPS4 catalysis in flow processes are currently underway in our laboratory.

Experimental

General procedure for the V-MPS4-catalyzed deprotection of the PMB group: 4-Methoxybenzenethiol (9) (25 µL, 0.20 mmol) was added to a mixture of PMB ether 1 (0.10 mmol), V-MPS4 (18.1 mg, 4.0 mol%), and anhydrous 1,2-dichloroethane (1.0 mL, 0.10 M) in a grass tube (φ8 × 50 mm). The glass tube was sealed with a plastic cap, and the resulting mixture was stirred at 80 °C for 24 h. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (hexane/EtOAc) to give 2. The ¹H- and ¹³C-NMR spectra of alcohols 2a, 2b, 2c, 2e, 2j, 2n, and 2o were identical to those of the commercial source.

*Calculation of the catalyst loading: The V-MPS4 used in this reaction contained 0.22 mmol of vanadium per gram of the catalyst (0.22 mmol/g, see the section 2 in Supplementary material for the detail). Thus, 18.1-mg portion of V-MPS4 contains 4.0 µmol of vanadium, which corresponds to 4.0 mol% loading of vanadium atom to the reaction.

The NMR spectra of alcohols 2d, 2f, 2g, 2h, and 2l were in good agreement with the reported spectra. Alcohol 2i was fully characterized by ¹H- and ¹³C-NMR spectroscopy, IR spectroscopy, and HRMS because its spectroscopic data are not reported in literature.

Decan-1-ol (2a)

¹H-NMR (500 MHz, CDCl₃) δ: 3.64 (t, J = 6.6 Hz, 2H), 1.62–1.52 (m, 2H), 1.44 (s, 1H), 1.38–1.20 (m, 14H), 0.88 (t, J = 7.2 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 63.1, 32.8, 31.9, 29.6, 29.5, 29.4, 29.3, 25.7, 22.7, 14.1.

Nonan-5-ol (2b)

¹H-NMR (500 MHz, CDCl₃) δ: 3.60–3.56 (m, 1H), 1.47–1.27 (m, 13H), 0.90 (t, J = 7.0 Hz, 6H); ¹³C-NMR (75 MHz, CDCl₃): 72.0, 37.2, 27.8, 22.8, 14.1.

Cyclododecanol (2c)

¹H-NMR (500 MHz, CDCl₃) δ: 3.86–3.82 (m, 1H), 1.73–1.62 (m, 2H), 1.49–1.27 (m, 20H); ¹³C-NMR (100 MHz, CDCl₃) δ: 69.2, 32.5, 24.2, 23.8, 23.34, 23.25, 20.9.

2-Methylundecan-2-ol (2d)³⁴⁾

¹H-NMR (500 MHz, CDCl₃) δ: 1.48–1.43 (m, 2H), 1.37–1.23 (m, 14H), 1.21 (s, 6H), 0.88 (t, J = 6.9 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 71.1, 44.0, 31.9, 30.2, 29.64, 29.56, 29.3, 29.2, 24.4, 22.7, 14.1.

2-Methyl-1-phenylpropan-2-ol (2e)

¹H-NMR (500 MHz, CDCl₃) δ: 7.34–7.20 (m, 5H), 2.77 (s, 2H), 1.23 (s, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 137.7, 130.4, 128.2, 126.5, 70.7, 49.7, 29.2.

4-(Benzyloxy)butan-1-ol (2f)²⁶⁾

¹H-NMR (500 MHz, CDCl₃) δ: 7.38–7.27 (m, 5H), 4.52 (s, 2H), 3.65 (t, J = 6.0 Hz, 2H), 3.53 (t, J = 5.8 Hz, 2H), 1.76–1.64 (m, 4H); ¹³C-NMR (75 MHz, CDCl₃) δ: 138.1, 128.4, 127.71, 127.65, 73.1, 70.3, 62.7, 30.2, 26.7.

10-Bromodecan-1-ol (2g)³⁵⁾

¹H-NMR (500 MHz, CDCl₃) δ: 3.63 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 6.9 Hz, 2H), 1.87–1.82 (m, 2H), 1.59–1.53 (m, 2H), 1.43–1.39 (m, 2H), 1.36–1.29 (m, 11H); ¹³C-NMR (75 MHz, CDCl₃) δ: 63.0, 34.0, 32.88, 32.84, 29.4, 29.3 (2C), 28.7, 28.1, 25.7. Although only 9 out of 10 peaks were found in ¹³C-NMR spectrum, the HRMS spectrum was consistent with the target molecular formula; HRMS (CI) m/z Calcd. for C₁₀H₂₂BrO [M + H]⁺: 237.0854, found: 237.0846.

2-(4-Hydroxybutyl)isoindoline-1,3-dione (2h)³⁶⁾

¹H-NMR (500 MHz, CDCl₃) δ: 7.83 (dd, J = 5.4, 3.2 Hz, 2H), 7.70 (dd, J = 5.4, 3.2 Hz, 2H), 3.73 (t, J = 7.2 Hz, 2H), 3.68 (t, J = 6.3 Hz, 2H), 1.82–1.74 (m, 2H), 1.68 (br s, 1H), 1.66–1.57 (m, 2H); ¹³C-NMR (75 MHz, CDCl₃) δ: 168.5, 133.9 132.1, 123.2, 62.3, 37.7, 29.8, 25.1.

11-(Trimethylsilyl)undec-10-yn-1-ol (2i)

IR (NaCl) 3368, 2929, 2856, 2175, 1249, 841; ¹H-NMR (500 MHz, CDCl₃) δ: 3.64 (t, J = 6.6 Hz, 2H), 2.21 (t, J = 7.2 Hz, 2H), 1.61 (br s, 1H), 1.59–1.46 (m, 4H), 1.41–1.25 (m, 10H), 0.14 (s, 9H); ¹³C-NMR (75 MHz, CDCl₃) δ: 107.7, 84.3, 63.0, 32.8, 29.4, 29.3, 29.0, 28.7, 28.6, 25.7, 19.8, 0.2; HRMS (CI) m/z Calcd. for C₁₄H₂₉OSi [M + H]⁺: 241.1988. Found: 241.1986.

Undec-10-yn-1-ol (2j)

¹H-NMR (500 MHz, CDCl₃) δ: 3.63 (t, J = 6.6 Hz, 2H), 2.18 (td, J = 7.3, 2.8 Hz, 2H), 1.94 (t, J = 2.8 Hz, 1H), 1.62–1.46 (m, 4H), 1.44–1.22 (m, 11H); ¹³C-NMR (100 MHz, CDCl₃) δ: 84.8, 68.0, 63.0, 32.8, 29.4, 29.3, 29.0, 28.7, 28.4, 25.7, 18.4.

9-Hydroxynonyl Acetate (2l)³⁷⁾

¹H-NMR (500 MHz, CDCl₃): 4.04 (t, J = 6.9 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.04 (s, 3H), 1.65–1.50 (m, 5H), 1.39–1.22 (m, 12H); ¹³C-NMR (125 MHz, CDCl3) δ: 171.2, 64.6, 63.0, 32.8, 29.44, 29.37, 29.3, 29.2, 28.6, 25.8, 25.7, 21.0.

Stigmasterol (2n)

¹H-NMR (500 MHz, CDCl₃) δ: 5.35–5.34 (m, 1H), 5.15 (dd, J = 15.2, 8.9 Hz, 1H), 5.01 (dd, J = 15.2, 8.9 Hz, 1H), 3.57–3.47 (m, 1H), 2.34–2.18 (m, 2H), 2.09–1.91 (m, 3H), 1.89–1.79 (m, 2H), 1.75–1.65 (m, 1H), 1.58–1.36 (m, 10H), 1.30–0.90 (m, 14H), 0.84 (d, J = 6.9 Hz, 3H), 0.82–0.76 (m, 6H), 0.70 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 140.7, 138.3, 129.2, 121.7, 71.8, 56.8, 55.9, 51.2, 50.1, 42.3, 42.2, 40.5, 39.7, 37.2, 36.5, 31.9, 31.6, 28.9, 25.4, 24.3, 21.2, 21.1, 21.0, 19.4, 19.0, 12.2, 12.0.

(±)-α-Tocopherol (2o)

¹H-NMR (500 MHz, CDCl₃): ¹H-NMR (500 MHz, CDCl₃) δ: 4.22 (s, 1H), 2.62 (t, J = 6.9 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 6H), 1.84–1.76 (m, 2H), 1.66–1.02 (m, 24H), 0.90–0.80 (m, 12H); ¹³C-NMR (75 MHz, CDCl₃) δ: 145.5, 144.5, 122.6, 121.0, 118.5, 117.3, 74.5, 39.9, 39.8, 39.4, 37.4 (multi peaks), 32.8, 32.7, 31.6, 31.5, 28.0, 24.8, 24.4, 23.8, 22.7, 22.6, 21.1, 20.8, 19.7 (multi peaks), 12.2, 11.8, 11.3.

Acknowledgments

We would like to appreciate Dr. Koichiro Masuda (National Institute of Advanced Industrial Science and Technology (AIST), Japan) for fruitful discussion regarding flow reaction. This work was financially supported by the JSPS KAKENHI (Grant Numbers: T22K146810 (K.K.) and A21H026050 (S.A.)), Kansai Research Foundation for technology promotion (K.K.), The Research Foundation for Pharmaceutical Sciences (K.K.), the Joint Usage/Research Center for Catalysis (23AY0215) (K.K.), and the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED (Grant Number: 23ama121054) (S.A.).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

References

• 1) “Flow Chemistry,” ed. by Darvas F., Dormán G., Hessel V., Walter de Gruyter GmbH, Boston, 2014.
• 2) Egi M., Sugiyama K., Saneto M., Hanada R., Kato K., Akai S., Angew. Chem. Int. Ed., 52, 3654–3658 (2013).
• 3) Sugiyama K., Oki Y., Kawanishi S., Kato K., Ikawa T., Egi M., Akai S., Catal. Sci. Technol., 6, 5023–5030 (2016).
• 4) Akai S., Chem. Lett., 43, 746–754 (2014).
• 5) Nishio T., Yoshioka S., Hasegawa K., Yahata K., Kanomata K., Akai S., Eur. J. Org. Chem., 2021, 4417–4422 (2021).
• 6) Kawanishi S., Oki S., Kundu D., Akai S., Org. Lett., 21, 2978–2982 (2019).
• 7) Kühn F., Katsuragi S., Oki Y., Scholz C., Akai S., Gröger H., Chem. Commun. (Camb.), 56, 2885–2888 (2020).
• 8) Tsuchimochi I., Hori S., Takeuchi Y., Egi M., Satoh T. O., Kanomata K., Ikawa T., Akai S., Synlett, 32, 822–828 (2021).
• 9) Kasama K., Kanomata K., Hinami Y., Mizuno K., Uetake Y., Amaya T., Sako M., Takizawa S., Sasai H., Akai S., RSC Adv., 11, 35342–35350 (2021).
• 10) Horino S., Nishio T., Kawanishi S., Oki S., Nishihara K., Ikawa T., Kanomata K., Wagner K., Gröger H., Akai S., Chem. Eur. J., 28, e202203161 (2022).
• 11) Wuts P. G. M., “Greene’s Protective Groups in Organic Synthesis,” 5th ed., John Wiley & Sons, New York, 2014.
• 12) Oikawa Y., Yoshioka T., Yonemitsu O., Tetrahedron Lett., 23, 885–888 (1982).
• 13) Johansson R., Samuelsson B., J. Chem. Soc., Perkin Trans. 1, 1984, 2371–2374 (1984).
• 14) Chandrasekhar S., Sumithra G., Yadav J. S., Tetrahedron Lett., 37, 1645–1646 (1996).
• 15) Sharma G. V. M., Lavanya B., Mahalingam A. K., Krishna P. R., Tetrahedron Lett., 41, 10323–10326 (2000).
• 16) Shen Z., Sheng L., Zhang X., Mo W., Hu B., Sun N., Hu X., Tetrahedron Lett., 54, 1579–1583 (2013).
• 17) Walsh K., Sneddon H. F., Moody C. J., Tetrahedron, 70, 7380–7387 (2014).
• 18) Hamada S., Sugimoto K., Elboray E. E., Kawabata T., Furuta T., Org. Lett., 22, 5486–5490 (2020).
• 19) Tucker J. W., Narayanam J. M. R., Shah P. S., Stephenson C. R. J., Chem. Commun. (Camb.), 47, 5040–5042 (2011).
• 20) Liu Z., Zhang Y., Cai Z., Sun H., Cheng X., Adv. Synth. Catal., 357, 589–593 (2015).
• 21) Ahn D. K., Kang Y. W., Woo S. K., J. Org. Chem., 84, 3612–3623 (2019).
• 22) Vaxelaire C., Souquet F., Lannou M. I., Ardisson J., Royer J., Eur. J. Org. Chem., 2009, 3138–3140 (2009).
• 23) Green R. A., Jolley K. E., Al-Hadedi A. A. M., Pletcher D., Harrowven D. C., De Frutos O., Mateos C., Klauber D. J., Rincón J. A., Brown R. C. D., Org. Lett., 19, 2050–2053 (2017).
• 24) Volbeda A. G., Kistemaker H. A. V., Overkleeft H. S., Van Der Marel G. A., Filippov D. V., Codée J. D. C., J. Org. Chem., 80, 8796–8806 (2015).
• 25) Rival N., Albornoz Grados A., Schiavo L., Colobert F., Hanquet G., Tetrahedron Lett., 56, 6823–6826 (2015).
• 26) Kern N., Dombray T., Blanc A., Weibel J. M., Pale P., J. Org. Chem., 77, 9227–9235 (2012).
• 27) Cappa A., Marcantoni E., Torregiani E., Bartoli G., Bellucci M. C., Bosco M., Sambri L., J. Org. Chem., 64, 5696–5699 (1999).
• 28) Bouzide A., Sauvé G., Synlett, 1997, 1153–1154 (1997).
• 29) Sawama Y., Masuda M., Asai S., Goto R., Nagata S., Nishimura S., Monguchi Y., Sajiki H., Org. Lett., 17, 434–437 (2015).
• 30) Madhava Sharma G. V., Reddy ChG., Krishna P. R., J. Org. Chem., 68, 4574–4575 (2003).
• 31) Chen D., Xu C., Deng J., Jiang C., Wen X., Kong L., Zhang J., Sun H., Tetrahedron, 70, 1975–1983 (2014).
• 32) Sartori G., Ballini R., Bigi F., Bosica G., Maggi R., Righi P., Chem. Rev., 104, 199–250 (2004).
• 33) Higashio K., Katsuragi S., Kundu D., Adebar N., Plass C., Kühn F., Gröger H., Akai S., Eur. J. Org. Chem., 2020, 1961–1967 (2020).
• 34) Zhang W., Gu Y. C., Lin J. H., Xiao J. C., Org. Lett., 22, 6642–6646 (2020).
• 35) Villadsen N. L., Jacobsen K. M., Keiding U. B., Weibel E. T., Christiansen B., Vosegaard T., Bjerring M., Jensen F., Johannsen M., Tørring T., Poulsen T. B., Nat. Chem., 9, 264–272 (2017).
• 36) Spallarossa M., Wang Q., Riva R., Zhu J., Org. Lett., 18, 1622–1625 (2016).
• 37) Yokoyama Y., Oyamada S., Suzuki J., Maruyama S., Sakusabe T., Suzuki S., Synth. Commun., 48, 1025–1032 (2018).