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Article

Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents †

by
Yuichi Kobayashi
1,2,*,
Takayuki Hirotsu
1,
Yosuke Haimoto
3 and
Narihito Ogawa
3
1
Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
2
Organization for the Strategic Coordination of Research and Intellectual Properties, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan
3
Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan
*
Author to whom correspondence should be addressed.
†
This paper is dedicated to late Professor Jiro Tsuji.
Catalysts 2023, 13(7), 1084; https://doi.org/10.3390/catal13071084
Submission received: 16 June 2023 / Revised: 4 July 2023 / Accepted: 7 July 2023 / Published: 10 July 2023
(This article belongs to the Special Issue Theme Issue in Memory to Prof. Jiro Tsuji (1927–2022))
Browse Figures
Versions Notes

Abstract

:
The substitution of secondary propargylic phosphates ROP(O)(OEt)2 where R = [Ph(CH2)2]C(H)(C≡CTMS)] Ph(CH2)2CH(OP(O)(OEt)2)(C≡CTMS) with copper reagents derived from PhLi and copper salts such as CuCl, CuCN, and Cu(acac)2 was studied to establish an ArLi-based reagent system. Among the reagents prepared, PhLi/CuCl (2:1) showed 98% α regioselectivity (rs), while PhLi/Cu(acac)2 was γ selective (>99% rs). PhLi prepared in situ from PhI and PhBr by Li-halogen exchange with t-BuLi was also used for the α selective substitution. A study using the (S)-phosphate disclosed 99% enantiospecificity (es) and the inversion of the stereochemistry. The substitution of five phosphates with substituted aryl reagents produced the corresponding propargylic products with high rs and es values. Similar reactivity and selectivity were observed with 2-furyl and 2-thienyl reagents, which were prepared via direct lithiation with n-BuLi.

Graphical Abstract

1. Introduction

Coupling reaction of secondary alcohol derivatives with organometallic reagents is a promising method to construct chiral centers on secondary carbons. Thus far, alkyl, allylic, and propargylic alcohol derivatives have been investigated as substrates [1,2,3]. Among them, alkyl substrates are less reactive than the other substrates that are activated by the double or triple bond. Consequently, only a few reagent/catalyst/leaving group systems have been published [4,5,6,7]. Among these, the highly reactive system developed by us consists of the PySO3 leaving group, Grignard reagents, and Cu(OTf)2 as a catalyst [7]. In contrast, various reagents/catalyst systems have been developed for the allylic coupling at secondary carbons [8,9,10]. For organic synthesis, regiocontrol between α and γ carbons and stereocontrol in it, as well as convenience in reagent/catalyst preparation, are highly important. The copper-catalyzed allylic substitution of allylic picolinates with alkyl and aryl Grignard reagents developed by us meets these requirements and proceeds with high SN2’ selectivity, furnishing tertiary carbons [11,12] and quaternary carbons [13,14].
The α-substitution using enantioenriched secondary propargylic alcohol derivatives has also been studied to develop ammonium salt/ArMgBr/Cu cat. [15], salicylate/ArMgCl/Cu cat. [16], bromide/heteroaryl cuprate [17], and sulfonate/TMSCF3/Cu cat./KF [18]. The α-substitution using racemic substrates was reported as well [19,20,21,22]. Furthermore, asymmetric version using chiral ligands was developed by Fu [23,24,25] and Nishibayashi [26,27]. Propargylic reactions have been studied by Professor Tsuji after his palladium-catalyzed reactions using allylic alcohol derivatives [28]. In consideration of his way of the research development and the experimental convenience mentioned above, we explored Cu-catalyzed propargylic substitution with aryl Grignard reagents on the basis of our allylic substitution. We found the α selective substitution of phosphate 1 with ArMgBr by using CuCN and CuBr·Me2S to give acetylenes 2 (Scheme 1) and the γ regioselective reaction with Cu(acac)2 [29]. The substitution was successfully applied for the synthesis of biologically active compounds [29,30,31,32]. With these results in mind, we focused our attention on aryl lithium compounds (ArLi), with the expectation that several preparations of ArLi would expand the scope of the reagents. Herein, we present the results along this line (Scheme 1).

2. Results and Discussion

Racemic phosphates 1a–1c and 7 and enantiomerically enriched phosphates (S)-1, -7, and -8 were prepared according to the previous methods [29]. The substitution of racemic propargylic phosphate 1a with copper reagents derived from PhLi and copper salts was studied first (Table 1). Ratios of acetylene 2aa, the regioisomer 3aa, and 1a (if recovered) were determined by 1H NMR spectroscopy and are summarized in entries. Alcohol 4a was not formed. The reaction of 1a with PhLi, without any copper salt, gave a mixture of unidentified products and recovered 1a (Entry 1). The reaction with a phenylcopper reagent prepared from PhLi and CuCN (formal structure PhCu·LiCN) was slow, and a roughly 1:1 mixture of 2aa and regioisomer 3aa was produced after 17 h (Entry 2). In contrast, α selective reaction was realized with phenyl cuprate, and the desired product, 2aa, was obtained with 94% regioselectivity (rs) (Entry 3), whereas the catalytic use of CuCN retarded the reaction. Moderate γ selectivity was observed using reagents derived with CuBr·Me2S and with CuBr2 (Entries 4 and 5). Phenyl copper derived from CuCl was also γ selective (Entry 6). Fortunately, phenyl cuprate derived from CuCl disclosed high α selectivity, which was higher than that achieved using the CuCN-derived phenyl cuprate (Entry 7 vs. Entry 3). Products 2aa and 3aa, in a 98:2 ratio, were isolated in a 76% yield after chromatography on silica gel (Entry 7).
The substitution conditions used in Entry 7 were applied to PhLi, which was prepared from iodo- and bromobenzene by Li-halogen exchange with t-BuLi. An X-shape flask [33] with two bottoms was used for our convenience. Briefly, CuCl was placed in one bottom, and lithiation of PhI in Et2O was carried out in the other bottom at 0 °C for 30 min. The solution was diluted with THF and mixed with CuCl by tilting the flask. Racemic phosphate 1a was added to the resulting reagent, and the mixture was stirred at 0 °C for 1 h to afford 2aa in an 80% yield with 98% rs (Entry 8). Bromobenzene was converted to the phenyl reagent in a similar way, and 2aa was obtained in a 73% yield with 97% rs (Entry 9). These results indicate that LiI and LiBr produced by the lithiation affected neither the reactivity nor the rs.
In addition, a reagent derived from PhLi, Cu(acac)2, and MgBr2 was found to be γ regioselective (Entry 10). Without MgBr2, a mixture of unidentified products and the unreacted phosphate was obtained.
The reaction conditions used in Entry 7 were applied to enantiomerically enriched phosphate (S)-1a of 98% ee to determine enantiospecificity (es) [34] and a stereochemical course (Scheme 2). A slightly higher equiv. of PhLi (3.2 equiv.) was used to ensure the formation of the cuprate. The reaction gave (S)-2aa in a 70% yield, and the HPLC analysis of the product on chiral stationary (abbreviated as chiral HPLC) disclosed 97% ee, which was calculated to be 99% es. Furthermore, the (S) configuration was assigned to the product by comparing the retention times of the derived phenylacetylene (S)-5aa with the reported data [29] (Scheme 3). These results indicate the inversion of the stereochemistry with marginal racemization.
Several reagents prepared via the Li-Br exchange with t-BuLi or the direct lithiation with n-BuLi were subjected to the substitution with (S)-1a (97–98% ee) at 0 °C for 1 h. The isolated yields, rs, and es are delineated in Scheme 4.
The products were converted to phenylacetylenes by the method shown in Scheme 3, and each es of the phenyl derivatives was determined by chiral HPLC analysis. The configurations of (S)-2ab–(S)-2ae were established by comparing the retention times with those reported [29]. The same configuration was assigned to the products derived from furan and thiophene by analogy. The (R) stereochemistry was assigned by the priority rule. Two tolyl reagents prepared from 4- and 2-bromotoluenes via lithiation afforded (S)-2ab and -2ac in 72% and 86% yields, respectively, with 98% es for both. Similarly, 4- and 2-bromoanisoles produced (S)-2ad and -2ae, respectively, in good yields with high es values. Notably, the 2-substituted reagents afforded a higher rs than the 4-substituted reagents. A similar increase in the rs is presented later (2be vs. 2ba in Scheme 5). The substitution of (S)-1a with the 2-furyl reagent prepared via the direct lithiation with n-BuLi resulted in high selectivity in rs and es, affording (R)-2af in a 79% yield. In combination with the oxidative conversion of the furan ring to the 2-butene-1,4-dione moiety, the present coupling would be useful in organic synthesis [35,36,37]. Similarly, the 2-thienyl reagent prepared by the direct lithiation gave (R)-2ag with high selectivity. Previously, furyl and thienyl copper reagents have been reported to be less nucleophilic for 1,4-addition [38,39,40], whereas high reactivity is reported for the propargylic substitution [17]. The reactivity of furyl and thienyl reagents in this study was sufficiently high and comparable to that of the aryl reagents shown in Scheme 4.
Substrates 1b and 1c were next subjected to the substitution (Scheme 5). Despite the high steric congestion in 1b, the reaction proceeded well, although the rs decreased slightly to 93%. In contrast, a high rs (97% rs) was recorded with the 2-MeOC6H4 reagent to produce 2be in an 84% yield. A similar ortho effect is mentioned above in the substitution reactions, giving (S)-2ac and -2ae (Scheme 4).
The reaction of 1c to produce 2ch was examined next (Scheme 5) to demonstrate the advantage of the present reaction using the ArLi over the previous method, which used the Grignard reagent [29]. 4-Bromo-1,3-benzodioxole (6) was converted to the copper reagent via the Li-Br exchange, and the reaction with phosphate 1c proceeded smoothly to afford 2ch in a 76% yield. No signal for the allenylic regioisomer was identified in the 1H NMR spectrum probably due to the ortho effect observed above. Bromide 6 is convertible to the corresponding Grignard reagent [41], which would produce 2ch by using the original method [29]. However, a part of the Grignard solution will be lost by titration, and the remaining solution after the use will be discarded; thus, the usage efficiency of bromide 6 via the Grignard reagent would not be high. In contrast, bromide 6 is converted quantitatively to the lithium reagent by the Li-Br exchange. This reaction would be an example to show that the exchange would especially be convenient for the substitution reaction using bromide and iodide that are prepared by a multistep procedure.
To evaluate the contribution of the TMS group on the regioselectivity, propargylic phosphates possessing phenylacetylenic and pentylacetylenic moieties were subjected to the substitution reaction (Scheme 6). The reaction of phenylacetylenic phosphate 7 with the PhLi-base reagent afforded 5aa with a 92% rs. The rs was somewhat low compared to that of the reaction using TMS-acetylenic phosphate 1a (98% rs in Table 1, Entry 7). In contrast, a high rs of >99% was observed for the substitution with the 2-MeOC6H4 reagent, giving (R)-5ae from (S)-7. Pentylacetylenic phosphate (S)-8 produced (S)-9 with an 83% rs. These results suggested that the rs of pentylacetylenic and other alkyl acetylenic phosphates would be low compared to that of TMS-acetylenic phosphates; thus, no further studies were examined.

3. Materials and Methods

3.1. General

The 1H (300 or 400 MHz) and 13C NMR (75 or 100 MHz) spectroscopic data were recorded in CDCl3, using Me4Si (δ = 0 ppm) and the centerline of the triplet (δ = 77.1 ppm), respectively, as internal standards. Signal patterns are indicated as br s (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). Coupling constants (J) are given in Hertz (Hz). The 13C–APT data (APT: attached proton test) are added to 13C chemical shifts with minus (for C and CH2) and plus (for CH and CH3) signs. The solvents that were distilled prior to use are THF (from Na/benzophenone), Et2O (from Na/benzophenone), and CH2Cl2 (from CaH2). After the reaction was quenched, the organic extracts were concentrated by using an evaporator. The silica gel used for chromatography was purchased (Merck (Tokyo, Japan), silica gel 60; KANTO, silica gel 60N). PhLi in c-hexane/Et2O, t-BuLi in n-pentane, and n-BuLi in hexane were purchased from Kanto, Japan, while CuCl and Cu(acac)2 were obtained from Tokyo Chemical Industry (TCI) (Tokyo, Japan) and used without purification.
According to the previous method [29], racemic phosphates 1a–c and 7 and enantiomerically enriched phosphates (S)-1a (97–98% ee), (S)-7 (96% ee), and (S)-8 (95% ee) were synthesized. The synthesis of (S)-1a, -7, and -8 is described in the Supplementary Materials. 4-Bromo-1,3-benzodioxole (6) was prepared according to the literature method [41,42].
Ratios of acetylenes and allenes produced by the coupling reactions were determined by integration of the diagnostic signals in 1H NMR spectra and converted to the regioselectivity (rs). HPLC analyses of the derived phenylacetylenes were performed using chiral stationary columns (abbreviated as chiral HPLC) to determine the enantiomeric ratios and absolute configurations. The enantiomer ratios were converted to the enantiospecificity (es) according to the following equation: (% ee of the product) × 100/(% ee of the phosphate) [34].

3.2. Representative Procedures of the Coupling Reaction

3.2.1. Method A Using Commercial PhLi (Table 1, Entry 7)

To an ice-cold suspension of CuCl (21.9 mg, 0.221 mmol) in Et2O (1 mL) and THF (0.5 mL) was added PhLi (1.13 M in c-hexane/Et2O, 0.40 mL, 0.452 mmol) dropwise. The mixture was stirred at 0 °C for 30 min, and then a solution of racemic phosphate 1a (54.5 mg, 0.148 mmol) in THF (1 mL) was added. The mixture was stirred for 2 h and diluted with saturated NH4Cl and a small amount of 28% NH4OH. The resulting mixture was extracted with EtOAc twice. The combined extracts were washed with brine, dried over MgSO4, and concentrated to leave an oil, which was purified by chromatography on silica gel to afford acetylene 2aa (33.1 mg, 76% yield, 98% rs by 1H NMR analysis).

3.2.2. Method B Using PhLi Derived from PhI and t-BuLi (Table 1, Entry 8)

To an ice-cold solution of PhI (0.060 mL, 0.538 mmol) in Et2O (0.7 mL) was added t-BuLi (1.59 M in pentane, 0.56 mL, 0.89 mmol). After 30 min, THF (0.7 mL) and CuCl (21.1 mg, 0.213 mmol) were added to the solution. The mixture was stirred for 30 min at 0 °C, and then a solution of racemic phosphate 1a (54.2 mg, 0.147 mmol) in THF (0.7 mL) was added. The resulting mixture was stirred at 0 °C for 1 h and diluted with saturated NH4Cl and a small amount of 28% NH4OH. Extraction of the products and purification were carried out as described in Method A to afford 2aa (34.6 mg, 80% yield, 98% rs by 1H NMR analysis).

3.2.3. Method C Using PhLi Derived from PhBr and t-BuLi (Table 1, Entry 9)

To a solution of PhBr (0.050 mL, 0.478 mmol) in Et2O (1.5 mL) at −15 °C was added t-BuLi (1.59 M in pentane, 0.61 mL, 0.97 mmol). After 30 min, THF (0.4 mL) and CuCl (21.6 mg, 0.218 mmol) were added to the solution. The mixture was stirred at 0 °C for 1 h, and then a THF solution of racemic phosphate 1a (59.1 mg, 0.160 mmol) was added. The resulting mixture was stirred at 0 °C for 2 h and diluted with saturated NH4Cl and a small amount of 28% NH4OH. Extraction of the products and purification were carried out as described in Method A to afford 2aa (34.2 mg, 73% yield, 97% rs by 1H NMR analysis).

3.3. Representative Procedure for the Conversion of TMS-Acetylenes to Phenylacetylenes

To a solution of acetylene (S)-2aa (184 mg, 0.630 mmol) in MeOH (1.3 mL) was added K2CO3 (104 mg, 0.753 mmol). The mixture was stirred at room temperature for 2 h, diluted with Et2O, and filtered through a pad of Celite. The filtrate was concentrated to afford an oil, which was purified by chromatography on silica gel with hexane/EtOAc for the next reaction.
To a solution of the above acetylene, PhI (0.084 mL, 0.753 mmol), t-BuNH2 (0.66 mL, 6.23 mmol), and Pd(PPh3)4 (73.0 mg, 0.0632 mmol) in benzene (6 mL) was added CuI (36.0 mg, 0.189 mmol). The mixture was stirred at room temperature for 14 h and diluted with saturated NH4Cl. The resulting mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over MgSO4, and concentrated to afford an oil, which was purified by chromatography on silica gel with hexane/EtOAc to afford acetylene (S)-5aa (146 mg, 78% yield).

3.4. Experiments and Characterization of the Products

3.4.1. Synthesis of (S)-(3,5-Diphenylpent-1-yn-1-yl)trimethylsilane [(S)-2aa], Its Conversion to Ph-Acetylene (S)-5aa, and Chiral HPLC Analysis

According to Method A, PhLi (1.13 M in c-hexane/Et2O, 0.46 mL, 0.52 mmol) was mixed with CuCl (23.9 mg, 0.241 mmol) in Et2O (0.8 mL) and THF (0.4 mL) at 0 °C for 30 min. A solution of (S)-1a (98% ee, 60.0 mg, 0.163 mmol) in THF (0.5 mL) was added to the copper reagent, and the mixture was stirred at 0 °C for 1 h to afford (S)-2aa (33.5 mg, 70% yield): 95% rs; 99% es by chiral HPLC analysis using Chiralcel OJ-H, hexane/i-PrOH (99.9:0.1), 0.2 mL/min, 25 °C, and tR/min = 37.3 (minor) and 44.3 (major); 1H NMR (300 MHz, CDCl3) δ 0.21 (s, 9 H), 1.99–2.08 (m, 2 H), 2.76 (dt, J = 3.3, 8.5 Hz, 2 H), 3.65 (t, J = 7.2 Hz, 1 H), and 7.16–7.37 (m, 10 H); and 13C NMR (75 MHz, CDCl3) δ 0.3 (+), 33.5 (−), 38.2 (+), 40.3 (−), 87.9 (−), 108.1 (−), 126.0 (+), 126.8 (+), 127.5 (+), 128.4 (+), 128.5 (+), 128.6 (+), 141.6 (−), and 141.8 (−). The 1H, 13C, and 13C-APT NMR spectra were consistent with those reported [29]. The absolute configuration of (S)-2aa was determined by the chiral HPLC analysis of the derived phenylacetylene (S)-5aa (see below).
The procedure was described as a representative example (vide supra): 1H NMR (300 MHz, CDCl3) δ 2.08–2.22 (m, 2 H), 2.85 (dt, J = 3.0, 7.4, 2 H), 3.84 (t, J = 7.4 Hz, 1 H), and 7.15–7.51 (m, 15 H); and 13C NMR (75 MHz, CDCl3) δ 33.7 (−), 37.9 (+), 40.2 (−), 83.9 (−), 91.2 (−), 123.8 (−), 126.0 (+), 126.9 (+), 127.6 (+), 127.9 (+), 128.3 (+), 128.5 (+), 128.6 (+), 131.7 (+), 141.7 (−), and 141.9 (−). The spectra were consistent with those reported [29].
Chiral HPLC analysis using Chiralcel OD-H, hexane/i-PrOH (99.5:0.5), 0.3 mL/min, 25 °C, tR/min = 23.2 (major), and 25.5 (minor): 98% es; (S)-configuration by comparing the relative tR values with the published values [29]: tR/min = 35.3 for (S)-isomer and 38.7 for (R)-isomer.

3.4.2. Synthesis of (S)-Trimethyl[5-phenyl-3-(p-tolyl)pent-1-yn-1-yl]silane [(S)-2ab], Its Conversion to Ph-Acetylene (S)-5ab, and Chiral HPLC Analysis

According to Method C, lithiation of 4-bromotoluene (0.060 mL, 0.490 mmol) in Et2O (0.7 mL) with t-BuLi (1.59 M, 0.56 mL, 0.890 mmol) (0 °C for 30 min) was followed by the addition of THF (0.35 mL) and a reaction with CuCl (19.9 mg, 0.201 mmol) (0 °C for 15 min). A solution of (S)-1a (98% ee, 50.2 mg, 0.136 mmol) in THF (0.35 mL) was added to the copper reagent, and the mixture was stirred at 0 °C for 1 h to give (S)-2ab (30.2 mg, 72% yield): 96% rs; 98% es by chiral HPLC analysis of the corresponding Ph-acetylene (S)-5ab (vide infra); 1H NMR (300 MHz, CDCl3) δ 0.20 (s, 9 H), 1.97–2.07 (m, 2 H), 2.33 (s, 3 H), 2.75 (dt, J = 2.7, 7.5 Hz, 2 H), 3.61 (t, J = 7.5 Hz, 1 H), and 7.10–7.32 (m, 9 H); and 13C NMR (75 MHz, CDCl3) δ 0.3 (+), 21.1 (+), 33.5 (−), 37.8 (+), 40.2 (−), 87.6 (−), 108.4 (−), 125.9 (+), 127.4 (+), 128.4 (+), 128.6 (+), 129.2 (+), 136.3 (−), 138.6 (−), and 141.8 (−). The 1H, 13C, and 13C-APT NMR spectra were consistent with those reported [29].
According to the representative procedure, the reaction of (S)-2ab (39.7 mg, 0.130 mmol) with K2CO3 (25.0 mg, 0.181 mmol) in MeOH (1.3 mL) at rt for 3 h afforded the desilylated acetylene, and the subsequent coupling reaction with PhI (0.020 mL, 0.179 mmol) in benzene (1.1 mL), using t-BuNH2 (0.130 mL, 1.23 mmol), Pd(PPh3)4 (18.8 mg, 0.0163 mmol), and CuI (22.5 mg, 0.118 mmol), at rt for 14 h gave acetylene (S)-5ab (31.9 mg, 79% yield): 1H NMR (300 MHz, CDCl3) δ 2.04–2.22 (m, 2 H), 2.34 (s, 3 H), 2.80–2.87 (m, 2 H), 3.81 (dd, J = 7.8, 6.6 Hz, 1 H), 7.13–7.48 (m, 12 H), and 7.45–7.50 (m, 2 H). The 1H spectrum was consistent with that reported [29].
Chiral HPLC analysis using Chiralcel OD-H, hexane/i-PrOH (99.8:0.2), 0.3 mL/min, 25 °C, tR/min = 28.5 (major), and 35.0 (minor): 98% es; (S)-configuration by comparing the relative tR values with the published data [29]: tR/min = 32.6 for (S)-isomer and 40.9 for (R)-isomer.

3.4.3. Synthesis of (S)-Trimethyl[5-phenyl-3-(o-tolyl)pent-1-yn-1-yl]silane [(S)-2ac], Its Conversion to Ph-Acetylene (S)-5ac, and Chiral HPLC Analysis

According to Method C, lithiation of 2-bromotoluene (0.080 mL, 0.664 mmol) in Et2O (1 mL) with t-BuLi (1.59 M, 0.84 mL, 1.34 mmol) (0 °C for 30 min) was followed by the addition of THF (0.5 mL) and a reaction with CuCl (29.3 mg, 0.296 mmol) (0 °C for 15 min). A solution of (S)-1a (98% ee, 76.3 mg, 0.207 mmol) in THF (1 mL) was added to the copper reagent, and the mixture was stirred at 0 °C for 1 h to afford (S)-2ac (54.4 mg, 86% yield): 99% rs; 98% es by chiral HPLC analysis of the corresponding Ph-acetylene (R)-5ac (vide infra); 1H NMR (300 MHz, CDCl3) δ 0.21 (s, 9 H), 1.89–2.04 (m, 2 H), 2.18 (s, 3 H), 2.72–2.94 (m, 2 H), 3.79 (dd, J = 8.8, 5.8 Hz, 1 H), 7.07–7.34 (m, 8 H), and 7.52 (d, J = 7.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 0.3 (+), 19.0 (+), 33.8 (−), 34.7 (+), 38.7 (−), 87.3 (−), 108.4 (−), 126.0 (+), 126.3 (+), 126.7 (+), 127.6 (+), 128.4 (+), 128.6 (+), 130.5 (+), 134.9 (−), 139.8 (−), and 141.7 (−). The 1H, 13C, and 13C-APT NMR spectra were consistent with those reported [29].
According to the representative procedure, the reaction of (S)-2ac (54.4 mg, 0.177 mmol) with K2CO3 (34.6 mg, 0.250 mmol) in MeOH (1.8 mL) at rt for 3 h gave the desilylated acetylene, and the subsequent coupling reaction with PhI (0.030 mL, 0.269 mmol) in benzene (1.5 mL), using t-BuNH2 (0.260 mL, 2.45 mmol), Pd(PPh3)4 (23.1 mg, 0.020 mmol), and CuI (41.7 mg, 0.219 mmol), at rt for 14 h afforded acetylene (R)-5ac (47.0 mg, 85% yield): 1H NMR (300 MHz, CDCl3) δ 1.97–2.18 (m, 2 H), 2.24 (s, 3 H), 2.81–3.03 (m, 2 H), 3.99 (dd, J = 9.3, 5.1 Hz, 1 H), 7.11–7.35 (m, 11 H), 7.43–7.50 (m, 2 H), and 7.59 (d, J = 6.9 Hz, 1 H). The 1H spectrum was consistent with the reported data [29].
Chiral HPLC analysis using Chiralcel OD-H, hexane/i-PrOH (99.8:0.2), 0.3 mL/min, 25 °C, and tR/min = 31.6 (minor) and 35.5 (major): 98% es; (R)-configuration by comparing the relative tR values with the published data [29]: tR/min = 33.5 for (S)-isomer and 39.6 for (R)-isomer.

3.4.4. Synthesis of (S)-[3-(4-Methoxyphenyl)-5-phenylpent-1-yn-1-yl]trimethylsilane [(S)-2ad], Its Conversion to Ph-Acetylene (S)-5ad, and Chiral HPLC Analysis

According to Method C, the lithiation of 4-bromoanisole (0.060 mL, 0.479 mmol) in Et2O (0.7 mL) with t-BuLi (1.59 M in pentane, 0.58 mL, 0.922 mmol) (0 °C for 30 min) was followed by the addition of THF (0.4 mL) and a reaction with CuCl (21.6 mg, 0.218 mmol) (0 °C for 30 min). A solution of (S)-1a (98% ee, 53.2 mg, 0.144 mmol) in THF (0.4 mL) was added to the copper reagent, and the mixture was stirred at 0 °C for 1 h to give (S)-2ad (45.9 mg, 86% yield): 97% rs; 98% es by chiral HPLC analysis of the corresponding Ph-acetylene (vide infra); 1H NMR (300 MHz, CDCl3) δ 0.20 (s, 9 H), 1.96–2.06 (m, 2 H), 2.70–2.78 (m, 2 H), 3.60 (t, J = 7.1 Hz, 1 H), 3.79 (s, 3 H), 6.85 (d, J = 9.0 Hz, 2 H), and 7.16–7.32 (m, 7 H); 13C NMR (75 MHz, CDCl3) δ 0.3 (+), 33.5 (−), 37.4 (+), 40.3 (−), 55.4 (+), 87.6 (−), 108.5 (−), 113.9 (+), 125.9 (+), 128.4 (+), 128.5 (+), 128.6 (+), 133.7 (−), 141.8 (−), and 158.5 (−). The 1H, 13C, and 13C-APT NMR spectra were consistent with those reported [29].
According to the representative procedure, the reaction of (S)-2ad (40.8 mg, 0.127 mmol) with K2CO3 (26.5 mg, 0.192 mmol) in MeOH (1.3 mL) at rt for 3 h gave the desilylated acetylene, and the subsequent coupling reaction with PhI (0.020 mL, 0.179 mmol) in benzene (1.1 mL), using t-BuNH2 (0.140 mL, 1.32 mmol), Pd(PPh3)4 (27.4 mg, 0.0237 mmol), and CuI (16.4 mg, 0.0861 mmol), at rt for 14 h afforded acetylene (S)-5ad (29.4 mg, 71% yield): 1H NMR (300 MHz, CDCl3) δ 2.05–2.21 (m, 2 H), 2.78–2.87 (m, 2 H), 3.80 (s, 3 H), 3.74–3.87 (m, 1 H), 6.88 (d, J = 9.0 Hz, 2 H), 7.16–7.36 (m, 10 H), and 7.43–7.50 (m, 2 H). The 1H spectrum was consistent with that reported [29].
Chiral HPLC analysis using Chiralcel OD-H, hexane/i-PrOH (99.5:0.5), 0.3 mL/min, 25 °C, and tR/min = 34.2 (major) and 44.9 (minor): 98% es; (S)-configuration by comparing the relative tR values with the published data [29]: tR/min = 38.5 for (S)-isomer and 51.2 for (R)-isomer.

3.4.5. Synthesis of (S)-[3-(2-Methoxyphenyl)-5-phenylpent-1-yn-1-yl]trimethylsilane [(S)-2ae], Its Conversion to Ph-Acetylene (S)-5ae, and Chiral HPLC Analysis

According to Method C, lithiation of 2-bromoanisole (0.070 mL, 0.569 mmol) in Et2O (0.9 mL) with t-BuLi (1.59 M, 0.69 mL, 1.10 mmol) (0 °C for 30 min) was followed by the addition of THF (0.4 mL) and a reaction with CuCl (24.9 mg, 0.252 mmol) (0 °C for 30 min). A solution of (S)-1a (98% ee, 62.9 mg, 0.171 mmol) in THF (0.5 mL) was added to the copper reagent, and the mixture was stirred at 0 °C for 1 h to produce (S)-2ae (45.8 mg, 83% yield): 99% rs; >99% es by chiral HPLC analysis of the corresponding Ph-acetylene (R)-5ae (vide infra); 1H NMR (300 MHz, CDCl3) δ 0.21 (s, 9 H), 1.83–2.11 (m, 2 H), 2.68–2.88 (m, 2 H), 3.76 (s, 3 H), 4.13 (dd, J = 8.7, 5.1 Hz, 1 H), 6.82 (d, J = 8.1 Hz, 1 H), 6.96 (t, J = 7.4 Hz, 1 H), 7.13–7.30 (m, 6 H), and 7.60 (dd, J = 7.6, 1.6 Hz, 1 H); and 13C NMR (75 MHz, CDCl3) δ 0.3 (+), 31.9 (+), 33.7 (−), 38.2 (−), 55.4 (+), 87.1 (−), 108.7 (−), 110.4 (+), 120.7 (+), 125.8 (+), 127.9 (+), 128.3 (+), 128.6 (+), 129.9 (−), 142.2 (−), and 156.2 (−). The 1H, 13C, and 13C-APT NMR spectra were consistent with those reported [29].
According to the representative procedure, the reaction of (S)-2ae (37.1 mg, 0.0983 mmol) with K2CO3 (27.3 mg, 0.198 mmol) in MeOH (1.3 mL) at rt for 3 h afforded the desilylated acetylene, and the subsequent coupling reaction with PhI (0.020 mL, 0.179 mmol) in benzene (1.1 mL), using t-BuNH2 (0.14 mL, 1.32 mmol), Pd(PPh3)4 (24.1 mg, 0.021 mmol), and CuI (11.5 mg, 0.060 mmol), at rt for 14 h gave acetylene (R)-5ae (22.1 mg, 69% yield): 1H NMR (300 MHz, CDCl3) δ 1.96–2.21 (m, 2 H), 2.77–2.97 (m, 2 H), 3.80 (s, 3 H), 4.33 (dd, J = 8.8, 5.3 Hz, 1 H), 6.85 (dd, J = 8.1, 1.2 Hz, 1 H), 6.97 (dt, J = 1.1, 7.2 Hz, 1 H), 7.13–7.35 (m, 9 H), 7.45–7.51 (m, 2 H), and 7.64 (dd, J = 7.8, 1.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 31.4 (+), 33.8 (−), 38.2 (−), 55.4 (+), 83.1 (−), 91.8 (−), 110.5 (+), 120.7 (+), 124.0 (−), 125.8 (+), 127.7 (+), 127.9 (+), 128.29 (+), 128.31 (+), 128.59 (+), 128.62 (+), 130.2 (−), 131.8 (+), 142.1 (−), and 156.2 (−). The 1H, 13C, and 13C-APT NMR spectra were consistent with those reported [29].
Chiral HPLC analysis using Chiralcel OD-H, hexane/i-PrOH (99.5:0.5), 0.3 mL/min, 25 °C, and tR/min = 24.2 (major) and 28.0 (minor): >99% es; (R)-configuration by comparing the relative tR values with the published data [29]: tR/min = 35.1 for (R)-isomer and 40.0 for (S)-isomer.

3.4.6. Synthesis of (R)-[3-(Furan-2-yl)-5-phenylpent-1-yn-1-yl]trimethylsilane [(R)-2af], Its Conversion to Ph-Acetylene (S)-5af, and Chiral HPLC Analysis

To an ice-cold solution of furan (0.040 mL, 0.552 mmol) in THF (0.4 mL) was added n-BuLi (1.65 M, 0.29 mL, 0.479 mmol) dropwise. The solution was stirred at 0 °C for 30 min. According to Method C, CuCl (20.5 mg, 0.207 mmol) was added to the solution, and, after 15 min of stirring at 0 °C, a solution of phosphate (S)-1a (97% ee, 54.7 mg, 0.148 mmol) in THF (0.4 mL) was then added. The mixture was stirred at 0 °C for 1 h to afford (R)-2af (33.0 mg, 79% yield): 99% rs; 95% es by chiral HPLC analysis of the corresponding Ph-acetylene (R)-5af (vide infra); 1H NMR (400 MHz, CDCl3) δ 0.20 (s, 9 H), 2.02–2.22 (m, 2 H), 2.77 (t, J = 8.0 Hz, 2 H), 3.75 (dd, J = 8.2, 5.8 Hz, 1 H), 6.21 (d, J = 3.2 Hz, 1 H), 6.30 (dd, J = 3.0, 2.2 Hz, 1 H), and 7.16–7.35 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ 0.2 (+), 32.0 (+), 33.1 (−), 36.3 (−), 87.4 (−), 105.2 (−), 106.0 (+), 110.3 (+), 126.0 (+), 128.5 (+), 128.6 (+), 141.6 (−), 141.7 (+), and 154.1 (−); and HRMS (FD) calcd for C18H26OSi [M]+ 282.14399, found 282.14264.
According to the representative procedure, the reaction of (R)-2af (24.8 mg, 0.0878 mmol) with K2CO3 (22.7 mg, 0.164 mmol) in MeOH (0.9 mL) at rt for 3 h gave the desilylated acetylene, and the subsequent coupling reaction with PhI (0.020 mL, 0.179 mmol) in benzene (0.8 mL), using t-BuNH2 (0.10 mL, 0.94 mmol), Pd(PPh3)4 (13.5 mg, 0.0117 mmol), and CuI (8.6 mg, 0.045 mmol), at rt for 16 h afforded Ph-acetylene (R)-5af (18.0 mg, 73% yield): 1H NMR (300 MHz, CDCl3) δ 2.12–2.33 (m, 2 H), 2.85 (t, J = 7.8 Hz, 2 H), 3.86 (dd, J = 8.2, 5.8 Hz, 1 H), 6.28 (dt, J = 3.3, 0.8 Hz, 1 H), 6.33 (dd, J = 3.3, 2.1 Hz, 1 H), 7.16–7.34 (m, 8 H), 7.36 (dd, J = 2.1, 0.9 Hz, 1 H), and 7.43–7.50 (m, 2 H).
Chiral HPLC analysis using Chiralpak AD-H, hexane/i-PrOH (99.5:0.5), 0.3 mL/min, 25 °C, and tR/min = 22.9 (minor) and 26.5 (major): 95% es; (R)-configuration was assigned by analogy with that shown in Scheme 4.

3.4.7. Synthesis of (R)-Trimethyl[5-phenyl-3-(thiophen-2-yl)pent-1-yn-1-yl]silane [(R)-2ag], Its Conversion to Ph-Acetylene (S)-5ag, and Chiral HPLC Analysis

To an ice-cold solution of thiophene (0.050 mL, 0.636 mmol) in THF (0.4 mL) was added n-BuLi (1.65 M, 0.31 mL, 0.51 mmol) dropwise. The solution was stirred at 0 °C for 30 min. According to Method C, CuCl (22.9 mg, 0.231 mmol) was added to the solution, and, after 15 min of stirring at 0 °C, a solution of phosphate (S)-1a (98% ee, 57.4 mg, 0.156 mmol) in THF (0.4 mL) was added. The mixture was stirred at 0 °C for 1 h to afford (R)-2ag (34.8 mg, 75% yield): >99% rs; 99% es by chiral HPLC analysis of the corresponding Ph-acetylene (vide infra); 1H NMR (300 MHz, CDCl3) δ 0.21 (s, 9 H), 2.09–2.17 (m, 2 H), 2.77–2.83 (m, 2 H), 3.93 (t, J = 7.2 Hz, 1 H), 6.93 (dd, J = 5.0, 3.8 Hz, 1 H), 6.96–6.98 (m, 1 H), and 7.16–7.32 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 0.2 (+), 33.3 (−), 33.5 (+), 40.2 (−), 87.9 (−), 107.1 (−), 124.0 (+), 124.6 (+), 126.1 (+), 126.7 (+), 128.6 (+), 128.7 (+), 141.6 (−), and 145.2 (−); and HRMS (FD) calcd for C18H22SSi [M]+ 298.12115, found 298.11989.
According to the representative procedure, the reaction of (R)-2ag (34.8 mg, 0.117 mmol) with K2CO3 (26.1 mg, 0.189 mmol) in MeOH (1.3 mL) at rt for 3 h afforded the desilylated acetylene, and the subsequent coupling reaction with PhI (0.020 mL, 0.179 mmol) in benzene (1 mL), using t-BuNH2 (0.13 mL, 1.23 mmol), Pd(PPh3)4 (15.8 mg, 0.0137 mmol), and CuI (7.1 mg, 0.0373 mmol), at rt for 16 h produced Ph-acetylene (R)-5ag (23.5 mg, 67% yield): 1H NMR (400 MHz, CDCl3) δ 2.24 (dt, J = 8.4, 7.2, 2 H), 2.88 (dd, J = 9.3, 6.6 Hz, 2 H), 4.13 (t, J = 7.2 Hz, 1 H), 6.96 (dd, J = 5.0, 3.4 Hz, 1 H), 7.02–7.05 (m, 1 H), 7.17–7.36 (m, 9 H), and 7.44–7.52 (m, 2 H).
Chiral HPLC analysis using Chiralpak AD-H, hexane/i-PrOH (99.5:0.5), 0.3 mL/min, and 25 °C, tR/min = 26.1 (minor) and 28.7 (major): 99% es; (R)-configuration was assigned by analogy with that shown in Scheme 4.

3.4.8. Synthesis of Trimethyl(4-methyl-3-phenylpent-1-yn-1-yl)silane (2ba)

According to Method A, PhLi (1.13 M, 0.57, mL, 0.644 mmol) and, after 15 min at 0 °C, a solution of 1b (56.4 mg, 0.184 mmol) in THF (0.5 mL) was added to CuCl (25.7 mg, 0.260 mmol) in THF (0.4 mL) and Et2O (0.9 mL). The mixture was stirred at 0 °C for 1 h to produce 2ba (35.0 mg, 83% yield): 93% rs; and 1H NMR (300 MHz, CDCl3) δ 0.19 (s, 9 H), 0.90 (d, J = 6.6 Hz, 3 H), 0.98 (d, J = 6.9 Hz, 3 H), 1.88–2.00 (m, 1 H), 3.54 (d, J = 5.7 Hz, 1 H), and 7.18–7.33 (m, 5 H). The 1H NMR spectrum was consistent with that reported [29].

3.4.9. Synthesis of [3-(2-Methoxyphenyl)-4-methylpent-1-yn-1-yl]trimethylsilane (2be)

According to Method C, lithiation of 2-bromoanisole (0.080 mL, 0.650 mmol) in Et2O (1 mL) with t-BuLi (1.59 M, 0.77 mL, 1.22 mmol) (0 °C for 30 min) was followed by the addition of THF (0.5 mL) and a reaction with CuCl (27.1 mg, 0.274 mmol) (0 °C for 15 min). A solution of 1b (58.1 mg, 0.190 mmol) in THF (0.5 mL) was added to the copper reagent, and the mixture was stirred at 0 °C for 1 h to produce 2be (41.3 mg, 84% yield): 97% rs; 1H NMR (300 MHz, CDCl3) δ 0.18 (s, 9 H), 0.86 (d, J = 6.9 Hz, 3 H), 1.01 (d, J = 6.9 Hz, 3 H), 1.89–2.02 (m, 1 H), 3.80 (s, 3 H), 4.06 (d, J = 5.1 Hz, 1 H), 6.83 (d, J = 7.6 Hz, 1 H), 6.94 (t, J = 7.6 Hz, 1 H), 7.20 (dt, J = 1.8, 7.6 Hz, 1 H), and 7.49 (dd, J = 7.6, 1.8 Hz, 1 H); and 13C NMR (75 MHz, CDCl3) δ 0.3 (+), 18.1 (+), 21.5 (+), 32.6 (+), 39.0 (+), 55.4 (+), 87.5 (−), 107.5 (−), 110.3 (+), 120.3 (+), 127.6 (+), 129.4 (−), 129.5 (+), and 156.4 (−). The 1H, 13C, and 13C–APT NMR spectra were consistent with the reported data [29].

3.4.10. Synthesis of [3-(Benzo[d][1,3]dioxol-4-yl)oct-1-yn-1-yl]trimethylsilane (2ch)

According to Method C, lithiation of 2-bromocatechol derivative 6 (139.0 mg, 0.691 mmol) in Et2O (1 mL) with t-BuLi (1.59 M, 0.82 mL, 1.30 mmol) (0 °C for 30 min) was followed by the addition of THF (0.5 mL) and a reaction with CuCl (28.5 mg, 0.288 mmol) (0 °C for 15 min). A solution of 1c (68.1 mg, 0.204 mmol) in THF (0.5 mL) was added to the copper reagent, and the mixture was stirred at 0 °C for 1 h to afford 2ch (51.3 mg, 76% yield): 1H NMR (400 MHz, CDCl3) δ 0.17 (s, 9 H), 0.88 (t, J = 6.8, 3 H), 1.23–1.52 (m, 6 H), 1.65–1.79 (m, 2 H), 3.81 (dd, J = 7.6, 6.4 Hz, 1 H), 5.905 (d, J = 1.4 Hz, 1 H), 5.940 (d, J = 1.4 Hz, 1 H), 6.71 (dd, J = 8.0, 1.4 Hz, 1 H), 6.81 (t, J = 8.0 Hz, 1 H), and 6.98 (dd, J = 8.0, 0.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 0.2 (+), 14.1 (+), 22.6 (−), 26.9 (−), 31.4 (−), 32.8 (+), 36.4 (−), 86.9 (−), 100.7 (−), 107.1 (+), 107.5 (−), 121.1 (+), 121.6 (+), 123.7 (−), 144.5 (−), and 147.1 (−); and HRMS (FD) calcd for C18H26O2Si [M]+ 302.17021, found 302.17080.

3.4.11. Synthesis of Pent-1-yne-1,3,5-triyltribenzene (5aa)

According to Method A, PhLi (1.13 M, 0.48 mL, 0.542 mmol) and, after 15 min at 0 °C, a solution of 7 (57.6 mg, 0.155 mmol) in THF (0.4 mL) were added to CuCl (20.5 mg, 0.207 mmol) in THF (0.4 mL) and Et2O (0.8 mL). The mixture was stirred at 0 °C for 1 h to produce 5aa (27.9 mg, 62% yield, 92% rs). The 1H NMR spectrum was consistent with that derived from TMS-acetylene 2aa.

3.4.12. Synthesis of (R)-[3-(2-Methoxyphenyl)pent-1-yne-1,5-diyl]dibenzene [(R)-5ae]

According to Method C, lithiation of 2-bromoanisole (0.060 mL, 0.488 mmol) in Et2O (0.7 mL) with t-BuLi (1.59 M, 0.57 mL, 0.906 mmol) (0 °C for 30 min) was followed by the addition of THF (0.35 mL) and a reaction with CuCl (19.8 mg, 0.200 mmol) (0 °C for 15 min). A solution of (S)-7 (96% ee, 52.2 mg, 0.140 mmol) in THF (0.35 mL) was added to the copper reagent, and the mixture was stirred at 0 °C for 1 h to afford (R)-5ae (41.1 mg, 90% yield, >99% rs, 98% es by chiral HPLC analysis). The 1H NMR spectrum was consistent with that reported [29]. (R)-Configuration was determined by comparing the relative tR values with those of (R)-5ae, which was derived from (S)-2ae (vide supra).

3.4.13. Synthesis of (S)-Dec-4-yne-1,3-diyldibenzene [(S)-9]

According to Method A, PhLi (1.13 M, 0.54 mL, 0.61 mmol) and, after 15 min at 0 °C, a solution of (S)-8 (95% ee, 64.3 mg, 0.175 mmol) in THF (0.45 mL) were added to CuCl (25.4 mg, 0.257 mmol) in THF (0.45 mL) and Et2O (0.9 mL). The mixture was stirred at 0 °C for 1 h to give (S)-9 (42.5 mg, 83% yield): 83% rs; 98% es by chiral HPLC analysis, using Chiralcel OJ-H, hexane/i-PrOH (99.9:0.1), 0.3 mL/min, 25 °C, tR/min = 38.1 (minor), and 44.7 (major); 1H NMR (300 MHz, CDCl3) δ 0.91 (t, J = 7.0 Hz, 3 H), 1.24–1.52 (m, 4 H), 1.52–1.63 (m, 2 H), 2.01 (q, J = 8.0 Hz, 2 H), 2.26 (dt, J = 2.3, 6.6 Hz, 2 H), 2.68–2.86 (m, 2 H), 3.60 (tt, J = 6.9, 2.1 Hz, 1 H), and 7.14–7.39 (m, 10 H); and 13C NMR (75 MHz, CDCl3) δ 14.1 (+), 18.9 (−), 22.3 (−), 28.9 (−), 31.2 (−), 33.7 (−), 37.4 (+), 40.6 (−), 81.4 (−), 83.9 (−), 125.9 (+), 126.6 (+), 127.5 (+), 128.40 (+), 128.45 (+), 128.6 (+), 142.0 (−), and 142.8 (−). The 1H, 13C, and 13C–APT NMR spectra were consistent with the reported data [29]. (S)-Configuration was assigned by analogy with that shown in Scheme 4.

3.5. Synthesis of (1,5-Diphenylpenta-1,2-dien-1-yl)trimethylsilane (3aa) (Table 1, Entry 10)

To an ice-cold mixture of Cu(acac)2 (87.3 mg, 0.334 mmol) and MgBr2 in THF (0.20 M, 4.2 mL, 0.84 mmol) was added PhLi (1.13 M, 0.54 mL, 0.61 mmol) dropwise. The mixture was stirred at 0 °C for 1 h, and phosphate 1a (61.5 mg, 0.167 mmol) in THF (1.7 mL) was added. The reaction was carried out at 0 °C for 4 h and diluted with saturated NH4Cl and 28% NH4OH. The product was extracted with EtOAc twice. The combined extracts were dried over MgSO4 and concentrated. The residual oil was purified by chromatography on silica gel with hexane/EtOAc to afford allene 3aa (41.6 mg, 85% yield): >99% rs; 1H NMR (300 MHz, CDCl3) δ 0.22 (s, 9 H), 2.33–2.50 (m, 2 H), 2.68–2.86 (m, 2 H), 5.19 (t, J = 6.8 Hz, 1 H), and 7.12–7.32 (m, 10 H); and 13C NMR (75 MHz, CDCl3) δ –0.2 (+), 30.3 (−), 36.0 (−), 86.7 (+), 100.6 (−), 126.0 (+), 126.1 (+), 127.7 (+), 128.43 (+), 128.45 (+), 128.6 (+), 137.9 (−), 141.9 (−), and 208.3 (−). The 1H, 13C, and 13C–APT NMR spectra were consistent with those reported [29].

4. Conclusions

Aryl-lithium-based copper reagents were developed for the propargylic substitution of TMS-acetylenic phosphates. Aryl lithium compounds prepared in situ by the lithium-halogen exchange with t-BuLi were converted to highly regioselective and enantiospecific aryl reagents. 2-Furyl and 2-thienyl reagents prepared via the direct lithiation with n-BuLi were successful as well. The present propargylic substitution with several preparations of aryl lithiums would be a useful reaction in organic synthesis.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/catal13071084/s1, general information of experiments, remaining procedures, 1H, 13C, and 13C-APT NMR spectra [29].

Author Contributions

Conceptualization, Y.K.; investigation and data curation, T.H., Y.H. and N.O.; writing, Y.K. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by KAKENHI Grant No. 20K05501.

Data Availability Statement

All experimental data are contained in the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Kobayashi, Y. Alkyl Pyirdinesulfonates and Allylic Pyridinecarboxylates, New Boosters for the Substitution at Secondary Carbons. Heterocycles 2020, 100, 499–546. [Google Scholar] [CrossRef] [Green Version]
  2. Kobayashi, Y.; Shimoda, M. Substitution of Allylic Picolinates with Various Copper Reagents and Synthetic Applications. In Cutting-Edge of Organic Synthesis and Chemical Biology of Bioactive Molecules; Kobayashi, Y., Ed.; Springer Nature: Singapore, 2019; Chapter 7; pp. 145–169. ISBN 978-981-13-6243-9 for hardcover. Available online: https://www.springer.com/gp/book/9789811362439 (accessed on 14 June 2019).
  3. Kobayashi, Y. Coupling Reactions on Secondary Allylic, Propargylic, and Alkyl Carbons using Organoborates/Ni and RMgX/Cu Reagents. Catalysts 2023, 13, 132. [Google Scholar] [CrossRef]
  4. Burns, D.H.; Miller, J.D.; Chan, H.-K.; Delaney, M.O. Scope and Utility of a New Soluble Copper Catalyst [CuBr-LiSPh-LiBr-THF]: A Comparison with Other Copper Catalysts in Their Ability to Couple One Equivalent of a Grignard Reagent with an Alkyl Sulfonate. J. Am. Chem. Soc. 1997, 119, 2125–2133. [Google Scholar] [CrossRef]
  5. Yang, C.-T.; Zhang, Z.-Q.; Liang, J.; Liu, J.-H.; Lu, X.-Y.; Chen, H.-H.; Liu, L. Copper-Catalyzed Cross-Coupling of Nonactivated Secondary Alkyl Halides and Tosylates with Secondary Alkyl Grignard Reagents. J. Am. Chem. Soc. 2012, 134, 11124–11127. [Google Scholar] [CrossRef] [PubMed]
  6. Xu, S.; Oda, A.; Bobinski, T.; Li, H.; Matsueda, Y.; Negishi, E. Highly Efficient, Convergent, and Enantioselective Synthesis of Phthioceranic Acid. Angew. Chem. Int. Ed. 2015, 54, 9319–9322. [Google Scholar] [CrossRef]
  7. Shinohara, R.; Morita, M.; Ogawa, N.; Kobayashi, Y. Use of the 2-Pyridinesulfonyloxy Leaving Group for the Fast Copper-Catalyzed Coupling Reaction at Secondary Alkyl Carbons with Grignard Reagents. Org. Lett. 2019, 21, 3247–3251. [Google Scholar] [CrossRef] [PubMed]
  8. Breit, B.; Schmidt, Y. Directed Reactions of Organocopper Reagents. Chem. Rev. 2008, 108, 2928–2951. [Google Scholar] [CrossRef]
  9. Prakash, J.; Marek, I. Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. Chem. Commun. 2011, 47, 4593–4623. [Google Scholar] [CrossRef]
  10. Ohmiya, H.; Sawamura, M. Copper Catalyzed Allylic Substitution and Conjugate Addition with Alkylboranes. J. Synth. Org. Chem. Jpn. 2014, 72, 1207–1217. [Google Scholar] [CrossRef] [Green Version]
  11. Kiyotsuka, Y.; Acharya, H.P.; Katayama, Y.; Hyodo, T.; Kobayashi, Y. Picolinoxy Group, a New Leaving Group for anti SN2′ Selective Allylic Substitution with Aryl Anions Based on Grignard Reagents. Org. Lett. 2008, 10, 1719–1722. [Google Scholar] [CrossRef]
  12. Kiyotsuka, Y.; Katayama, Y.; Acharya, H.P.; Hyodo, T.; Kobayashi, Y. New General Method for Regio- and Stereoselective Allylic Substitution with Aryl and Alkenyl Coppers Derived from Grignard Reagents. J. Org. Chem. 2009, 74, 1939–1951. [Google Scholar] [CrossRef] [PubMed]
  13. Kaneko, Y.; Kiyotsuka, Y.; Acharya, H.P.; Kobayashi, Y. Construction of a quaternary carbon at the carbonyl carbon of the cyclohexane ring. Chem. Commun. 2010, 46, 5482–5484. [Google Scholar] [CrossRef]
  14. Feng, C.; Kobayashi, Y. Allylic Substitution for Construction of a Chiral Quaternary Carbon Possessing an Aryl Group. J. Org. Chem. 2013, 78, 3755–3766. [Google Scholar] [CrossRef] [PubMed]
  15. Guisán-Ceinos, M.; Martín-Heras, V.; Tortosa, M. Regio- and Stereospecific Copper-Catalyzed Substitution Reaction of Propargylic Ammonium Salts with Aryl Grignard Reagents. J. Am. Chem. Soc. 2017, 139, 8448–8451. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Jiang, Y.; Ma, Y.; Ma, E.; Li, Z. Copper-Catalyzed Selective Cross-Couplings of Propargylic Ethers with Aryl Grignard Reagents. Asian J. Org. Chem. 2019, 8, 1834–1837. [Google Scholar] [CrossRef]
  17. Trost, B.M.; Debien, L. Re-orienting coupling of organocuprates with propargyl electrophiles from SN20 to SN2 with stereocontrol. Chem. Sci. 2016, 7, 4985–4989. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Gao, X.; Xiao, Y.-L.; Wan, X.; Zhang, X. Copper-Catalyzed Highly Stereoselective Trifluoromethylation and Difluoroalkylation of Secondary Propargyl Sulfonates. Angew. Chem. Int. Ed. 2018, 57, 3187–3191. [Google Scholar] [CrossRef]
  19. Ma, S.; Wang, G. Regioselectivity Control by a Ligand Switch in the Coupling Reaction Involving Allenic/Propargylic Palladium Species. Angew. Chem. Int. Ed. 2003, 42, 4215–4217. [Google Scholar] [CrossRef]
  20. Domingo-Legarda, P.; Soler-Yanes, R.; Quirós-López, M.T.; Buñuel, E.; Cárdenas, D.J. Iron-Catalyzed Coupling of Propargyl Bromides and Alkyl Grignard Reagents. Eur. J. Org. Chem. 2018, 2018, 4900–4904. [Google Scholar] [CrossRef]
  21. Manjón-Mata, I.; Quirós, M.T.; Buñuel, E.; Cárdenas, D.J. Regioselective Iron-Catalysed Cross-Coupling Reaction of Aryl Propargylic Bromides and Aryl Grignard Reagents. Adv. Synth. Catal. 2020, 362, 146–151. [Google Scholar] [CrossRef]
  22. Tsuji, H.; Kawatsura, M. Transition-Metal-Catalyzed Propargylic Substitution of Propargylic Alcohol Derivatives Bearing an Internal Alkyne Group. Asian J. Org. Chem. 2020, 9, 1924–1941. [Google Scholar] [CrossRef]
  23. Smith, S.W.; Fu, G.C. Nickel-Catalyzed Negishi Cross-Couplings of Secondary Nucleophiles with Secondary Propargylic Electrophiles at Room Temperature. Angew. Chem. Int. Ed. 2008, 47, 9334–9336. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Schley, N.D.; Fu, G.C. Nickel-Catalyzed Negishi Arylations of Propargylic Bromides: A Mechanistic Investigation. J. Am. Chem. Soc. 2014, 136, 16588–16593. [Google Scholar] [CrossRef] [Green Version]
  25. Oelke, A.J.; Sun, J.; Fu, G.C. Nickel-Catalyzed Enantioselective Cross-Couplings of Racemic Secondary Electrophiles That Bear an Oxygen Leaving Group. J. Am. Chem. Soc. 2012, 134, 2966–2969. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Nishibayashi, Y. Development of Asymmetric Propargylic Substitution Reactions Using Transition Metal Catalysts. Chem. Lett. 2021, 50, 1282–1288. [Google Scholar] [CrossRef]
  27. Sakata, K.; Nishibayashi, Y. Mechanism and reactivity of catalytic propargylic substitution reactions via metal–allenylidene intermediates: A theoretical perspective. Catal. Sci. Technol. 2018, 8, 12–25. [Google Scholar] [CrossRef]
  28. Tsuji, J.; Mandai, T. Palladium-Catalyzed Reactions of Propargylic Compounds in Organic Synthesis. Angew. Chem. Int. Ed. Engl. 1996, 34, 2589–2612. [Google Scholar] [CrossRef]
  29. Kobayashi, Y.; Takashima, Y.; Motoyama, Y.; Isogawa, Y.; Katagiri, K.; Tsuboi, A.; Ogawa, N. α- and γ-Regiocontrol and Enantiospecificity in the Copper-catalyzed Substitution Reaction of Propargylic Phosphates with Grignard Reagents. Chem. Eur. J. 2021, 27, 3779–3785. [Google Scholar] [CrossRef]
  30. Ogawa, N.; Uematsu, C.; Kobayashi, Y. Stereoselective Synthesis of (−)-Heliannuol E by α-Selective Propargyl Substitution. Synlett 2021, 32, 2071–2074. [Google Scholar] [CrossRef]
  31. Takashima, Y.; Isogawa, Y.; Tsuboi, A.; Ogawa, N.; Kobayashi, Y. Synthesis of a TNF inhibitor, flurbiprofen and an i-Pr analogue in enantioenriched forms by copper catalyzed propargylic substitution with Grignard reagents. Org. Biomol. Chem. 2021, 19, 9906–9909. [Google Scholar] [CrossRef]
  32. Kobayashi, Y.; Hirotsu, T. Synthesis of (S)-Nyasol through the Copper-catalyzed Propargylic Substitution. Synlett 2023, 34, 159–162. [Google Scholar] [CrossRef]
  33. Kobayashi, Y.; Kiyotsuka, Y.; Sugihara, Y.; Wada, K. Installation of the imidazole ring on chiral substrates via allylic substitution. Tetrahedron 2015, 71, 6481–6487. [Google Scholar] [CrossRef]
  34. Denmark, S.E.; Vogler, T. Synthesis and Reactivity of Enantiomerically Enriched Thiiranium Ions. Chem. Eur. J. 2009, 15, 11737–11745. [Google Scholar] [CrossRef] [PubMed]
  35. Makarov, A.S.; Uchuskin, M.G.; Trushkov, I.V. Furan Oxidation Reactions in the Total Synthesis of Natural Products. Synthesis 2018, 50, 3059–3086. [Google Scholar] [CrossRef]
  36. Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. Preparation of optically active 2-furylcarbinols by kinetic resolution using the Sharpless reagent and their application in organic synthesis. J. Org. Chem. 1989, 54, 2085–2091. [Google Scholar] [CrossRef]
  37. Kobayashi, Y.; Nakano, M.; Kumar, G.B.; Kishihara, K. Efficient Conditions for Conversion of 2-Substituted Furans into 4-Oxygenated 2-Enoic Acids and Its Application to Synthesis of (+)-Aspicilin, (+)-Patulolide A, and (−)-Pyrenophorin. J. Org. Chem. 1998, 63, 7505–7515. [Google Scholar] [CrossRef]
  38. Ng, J.S.; Behling, J.R.; Campbell, A.L.; Nguyen, D.; Lipshutz, B. Reactions of higher order cyanocuprates derived from 2-lithiated furans: Scope, limitations, and synthetic utility. Tetrahedron Lett. 1988, 29, 3045–3048. [Google Scholar] [CrossRef]
  39. Lipshutz, B.H.; Koerner, M.; Parker, D.A. 2-thienyl(cyano)copper lithium. A lower order, “cuprate in a bottle” precursor to higher order reagents. Tetrahedron Lett. 1987, 28, 945–948. [Google Scholar] [CrossRef]
  40. Lipshutz, B.H.; Kozlowski, J.A.; Parker, D.A.; Nguyen, S.L.; McCarthy, K.E. More highly mixed, higher order cyanocuprates “RT(2-thienyl)Cu(CN)Li2”. Efficient reagents which promote selective ligand transfer. J. Organomet. Chem. 1985, 285, 437–447. [Google Scholar] [CrossRef]
  41. Kobayashi, Y.; Lalitnorasate, P.; Kaneko, Y.; Kiyotsuka, Y.; Endo, Y. Synthesis of ACAT inhibitors through substitution using allylic picolinate and copper reagent. Tetrahedron Lett. 2010, 51, 6018–6021. [Google Scholar] [CrossRef]
  42. Hansen, T.V.; Skattebøl, L. One-pot synthesis of substituted catechols from the corresponding phenols. Tetrahedron Lett. 2005, 46, 3357–3358. [Google Scholar] [CrossRef]
Catalysts 13 01084 sch001 550
Scheme 1. Propargylic substitution with aryl copper reagents.
Scheme 1. Propargylic substitution with aryl copper reagents.
Catalysts 13 01084 sch001
Catalysts 13 01084 sch002 550
Scheme 2. Stereochemistry of the propargylic substitution.
Scheme 2. Stereochemistry of the propargylic substitution.
Catalysts 13 01084 sch002
Catalysts 13 01084 sch003 550
Scheme 3. Conversion to phenylacetylenes for determination of es and the absolute configuration. Ar for substrates and products: aa, Ph; ab, 4-MeC6H4; ac, 2-MeC6H4; ad, 4-MeOC6H4; ae, 2-MeOC6H4; af, 2-furyl; ag, 2-thienyl.
Scheme 3. Conversion to phenylacetylenes for determination of es and the absolute configuration. Ar for substrates and products: aa, Ph; ab, 4-MeC6H4; ac, 2-MeC6H4; ad, 4-MeOC6H4; ae, 2-MeOC6H4; af, 2-furyl; ag, 2-thienyl.
Catalysts 13 01084 sch003
Catalysts 13 01084 sch004 550
Scheme 4. Propargylic substitution with ArLi-based copper reagents.
Scheme 4. Propargylic substitution with ArLi-based copper reagents.
Catalysts 13 01084 sch004
Catalysts 13 01084 sch005 550
Scheme 5. Further study of propargylic substitution.
Scheme 5. Further study of propargylic substitution.
Catalysts 13 01084 sch005
Catalysts 13 01084 sch006 550
Scheme 6. Propargylic substitution of phenyl and alkyl acetylenic phosphates.
Scheme 6. Propargylic substitution of phenyl and alkyl acetylenic phosphates.
Catalysts 13 01084 sch006
Table
Table 1. Substitution of phosphate 1a with PhLi-based reagents.
Table 1. Substitution of phosphate 1a with PhLi-based reagents.
Catalysts 13 01084 i001
EntryPh ReagentCu SaltPhLi 1/Cu SaltTemp.Time2aa/3aa/1a 2Yield (%)
1PhLi––rt6 h– 3–
2PhLiCuCN2.5:3rt17 h44:56:0nd 4
3PhLiCuCN3:1.5rt2 h94:6:0nd 4
4PhLi, MgBr2 5CuBr·Me2S3:30 °C2 h13:87:0nd 4
5PhLiCuBr23:1.50 °C2 h7:45:48nd 4
6PhLiCuCl2.5:30 °C7 h17:83:0nd 4
7PhLiCuCl3:1.50 °C2 h98:2:076%
8PhI, t-BuLi 6CuCl3:1.50 °C1 h98:2:080%
9PhBr, t-BuLi 6CuCl3:1.50 °C2 h97:3:073%
10PhLi, MgBr2 5Cu(acac)23.6:2:50 °C4 h1:>99:085%
1 PhLi in c-hexane and Et2O from Kanto, Japan, was used in Entries 1–7 and 10. 2 Determined by 1H NMR. 3 A mixture of 1a and unidentified products. 4 nd: not determined. 5 Added MgBr2 in Entries 4 (6 equiv.) and 10 (5 equiv.), respectively. 6 Lithiation in Et2O.
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Kobayashi, Y.; Hirotsu, T.; Haimoto, Y.; Ogawa, N. Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents. Catalysts 2023, 13, 1084. https://doi.org/10.3390/catal13071084

AMA Style

Kobayashi Y, Hirotsu T, Haimoto Y, Ogawa N. Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents. Catalysts. 2023; 13(7):1084. https://doi.org/10.3390/catal13071084

Chicago/Turabian Style

Kobayashi, Yuichi, Takayuki Hirotsu, Yosuke Haimoto, and Narihito Ogawa. 2023. "Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents" Catalysts 13, no. 7: 1084. https://doi.org/10.3390/catal13071084

APA Style

Kobayashi, Y., Hirotsu, T., Haimoto, Y., & Ogawa, N. (2023). Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents. Catalysts, 13(7), 1084. https://doi.org/10.3390/catal13071084

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