English

• Chiral 3-aryl alkanoic acids and their derivatives are widely regarded as an important class of frameworks that are presented in numerous natural products and pharmaceuticals [1–5]. Furthermore, these structures serve as key building blocks in the synthesis of various pharmaceuticals and bioactive molecules, including RC-33 [6], AM-6226 [7], R-106578 [8], and tipranavir [9] (Scheme 1A). Consequently, the development of synthetic protocols for chiral 3-aryl alkanoic acids and their derivatives has been a long-term goal actively pursued by pharmacologists and chemists.

  Scheme 1

  

  Scheme 1.  Strategies for the synthesis of chiral 3-aryl alkanoic acids and their derivatives.

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  Considering whether the starting materials contain carbonyl fragments, two principal strategies were adopted for the synthesis of these vital chiral molecules. The first approach involves the asymmetric transformation of corresponding carbonyl compounds, including the kinetic resolution of racemic carbonyls [10,11], asymmetric hydrogenation [12–20], hydrofunctionalization [21,22], and conjugate 1,4-addition of α,β-unsaturated carbonyl substrates [23–25]. The second method focuses on the stereoselective incorporation of a carbonyl group into olefins [26–28], via an enantioselective intermolecular anti-Markovnikov hydrocarbonylation of α-alkyl substituted styrenes [29–36] using a chiral transition metal catalyst (Scheme 1B). This is a particularly appealing strategy owing to the availability of starting materials [α-alkyl-substituted styrenes, carbon monoxide (CO), and nucleophiles/electrophiles] as well as the efficiency and atom-economy of the hydrocarbonylation reaction [37,38]. Different from styrenes, the enantioselective anti-Markovnikov hydrocarbonylation of α-alkyl-substituted styrenes remains an ultimate challenge [27,39–43]. So far, efforts made by chemists have been unsuccessful in addressing the activity, chemoselectivity, regioselectivity and stereoselectivity.

  In the 1970s, Consiglio [42] and Hayashi [43] independently reported the Pd-catalyzed asymmetric hydroesterification of α-methylstyrene, in term of enantioselectivity, achieving a maximum optical yield of 69% ee but only with 8% conversion. More recently, Wu and colleagues declosed a strategy for enantioselective copper-catalyzed hydroamino carbonylation of 1,1-dialkyl substituted olefins, one example of α-methylstyrene was prensented in their work, a 65/35 mixture of anti-Markovnikov and Markovnikov product was obtained with <15% yield (ee value was not detected) [44]. The slow progress of this strategy can be attributed to the following reasons (Scheme 1C): (ⅰ) the difficulty to discrimination of the enantiotopic faces due to the rapid reversal of face selectivity and low binding affinity [45–47] (ⅱ) the unstable chiral alkyl-metal species are prone to β–H elimination that causing C=C bond migration [48–50] or reverting to the starting material; (ⅲ) the competing Markovnikov addition when M–H attacks the C=C bond (i.e. regioselectivity) [42,[51], [52]]; (ⅳ) the nucleophile/electrophile directly reacts with the alkyl-metal species before CO insertion. In addition, high temperature is a common condition for this type of reaction and usually exacerbates the aforementioned issues.

  Five year ago, we developed an enantioselective Markovnikov [53] hydrocarbonylation of styrenes using a Pd/SOP catalytic system, the reaction was inert under standard conditions when using α-methylstyrene as substrate (Scheme 1D). From the perspective of the ligand, Pd/chiral bidentate ligands [54] promote the asymmetric anti-Markovnikov hydrocarbonylation product formation, we envisioned that the Pd/SOP catalytic system could perform the same function if we could overcome the above-mentioned issue(s). Herein, we report a Pd-catalyzed enantioselective intermolecular hydrothiocarbonylation of α-alkyl styrenes with thiols using a Pd/SOP (sulfoxide phosphine) [53,55–67] complex as the catalyst, exclusive anti-Markovnikov carbonylation products were afforded with excellent yields and enantioselectivities (Scheme 1E).

  Analyzing the reason for the inactivity of α-methylstyrene (1a) under the previous reaction conditions (Table 1, entry 1) [53], we hypothesized that there could be two plausible scenarios to explain this phenomenon: firstly, the reaction is truly inert and therefore usually conducts at high temperatures [42–52] alternatively, the addition of the Pd−H to the C=C double bond of α-methylstyrene is effective. However, the resulting alkyl-Pd intermediate encounters a significant steric hindrance which preferentially lead a β−H elimination and revert to the starting material, not go-through the desired CO migration insertion to form the acyl palladium species. A straightforward approach to overcoming β–H elimination is to facilitate the expected migratory insertion of CO by increasing the pressure of CO. The resulting acyl palladium species would then be rapidly captured by nucleophiles, thereby facilitating the hydrocarbonylation of this sterically hindered C=C double bond. After screening for the pressure of CO, we found that the reactivity is positively correlated with CO pressure (Table 1, entries 2 and 3), and moderate results (entry 3, 73% yield, 71% ee) were obtained when CO pressure was increased to 45 atm. It is notable that anti-Markovnikov product 3a was exclusively afforded, Markovnikov thioester 3a' was not observed. As the reaction temperature increased to 25 ℃, Markovnikov thioether 3a'' side product was observed (39% NMR yield), and the enantioselectivity of product 3a decreased (47% ee, entry 4). Further raising the temperature to 85 ℃ resulted in a complete formation of Markovnikov thioether 3a'' side product, and this process did not require the participation of CO and Pd catalyst (entry 5) [68–72]. To further improve the reactivity and enantioselectivity, chiral ligands were then evaluated (Table 1, entries 6–10). First, SOPs from our laboratory (L2–L6) with different P-moieties and substituents were investigated. P-di-pH-SOP (L2) with electron-deficient phosphine moiety does not facilitate the reaction (entry 6). Using P-di-iPr-SOPs (entries 7–10, L3–L6) bearing a benzodioxole skeleton, 3a was produced with generally similar results, among which L5 was optimal (entry 9, 76% yield, 85% ee). Several commercially available ligands were also examined (entries 11−16, L7–L12). Utilizing ligand L7, Markovnikov thioester 3a' was resulted exclusively (entry 11, 82% yield) [42,51,73]. With DIOP (L8), 3a was obtained in 33% yield and 31% ee (entry 12). Other diphosphine ligands, such as Trost ligand L9, BINAP L12, spiroligand L10, and sulfonamide ligand L11 all failed to promote the reaction (entry 13−16). Interestingly, we found that the salt additive LiCl significantly enhanced the yield and enantioselectivity of this reaction. When a catalytic amount of LiCl was added, almost quantitative NMR yield and 93% ee were achieved (entry 17, The role of LiCl will be discussed in detail later). Under this reaction condition, reducing the catalyst loading to 1 mol% (S/C = 100), product 3a was obtained with good yield and enantioselectivity (entry 18, 87% isolated yield and 93% ee). Finally, we also tested methanol as nucleophile, which does not work and this could be attributed to the weak nucleophilic ability of alcohol is not suitable for this catalytic system.

  Table 1

  

  Table 1.  Optimization of the reaction conditions.^a

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  Entry	Ligand	Additive (mol%)	T (℃)	CO pressure (atm)	Yields of 3a/3a’/3a’’ (%) b	ee of 3a (%) c
  1	L1	–	0	1	N.R.	–
  2	L1	–	0	10	33:0:0	71
  3	L1	–	0	45	73:0:0	71
  4	L1	–	25	45	42:0:39	47
  5 d	L1	–	85	0	0:0:88	–
  6	L2	–	0	45	N.R.	–
  7	L3	–	0	45	75:0:0	80
  8	L4	–	0	45	73:0:0	82
  9	L5	–	0	45	76:0:0	85
  10	L6	–	0	45	75:0:0	81
  11	L7	–	0	45	0:82:0	–
  12	L8	–	0	45	33:0:0	31
  13	L9	–	0	45	N.R.	–
  14	L10	–	0	45	N.R.
  15	L11	–	0	45	N.R.
  16	L12	–	0	45	N.R.
  17	L5	LiCl (20)	0	45	99:0:0 (98) e	93
  18 f	L5	LiCl (20)	0	45	87 (isolated)	93
  a Reaction conditions: α-Methylstyrene 1a (0.2 mmol, 1.0 equiv.), 2-phenylethanethiol 2a (0.3 mmol, 1.5 equiv.), CO, Pd 2dba 3 (2.5 mol%), ligand (6 mol%), p-TsOH·H 2O (10 mol%) and additive (20 mol%) in 0.5 mL of CHCl 3 at 0 ℃ for 36 h. N.R. = no reaction. b Yields were determined by crude 1H NMR analysis using dibromomethane as internal standard. c The ee value of 3a was determined by chiral-phase HPLC analysis. d Without Pd-catalyst. e Isolated yield in parentheses. f S/C = 100.

  With the optimized conditions in hand, we next explored the scope of this asymmetric hydrothiocarbonylation. Firstly, we examined α-alkyl styrenes (Scheme 2). The reaction of para- and meta-substituted α-methyl styrenes, either substituted by electron-donating (Me, OMe) groups or by electron-withdrawing (F, Cl, Br, CF₃, CN, CO₂Me, PhCO) groups, proceeded smoothly and afforded the corresponding chiral 3-methyl alkanoic acid derivatives in excellent results (3b−3q, 80%−97% yields, 91%−98% ee). Among these, the R absolute configuration of 3p was conclusively determined via X-ray diffraction analysis. Sensitive functional group (Me₂C(NCO)) at meta-position was well tolerated, furnishing 3r with excellent yield and enantiocontrol (93% yield, 96% ee). While, at the current stage, the o-methyl substituted α-methyl styrenes showed a very low reactivity and enantiocontrol (3s). Disubstituted or trisubstituted α-methylstyrenes produced the corresponding 3t−3w with satisfactory outcomes. α-Methyl naphthalene ethylenes were also qualified candidates for this reaction (3x−3y). Late-stage modification of natural product (estrone) was carried out, that revealed the utility of this protocol (3z). 1,1-Dialkyl substituted olefins provided poor chiral discrimination in this catalysis (3aa, 97% yield, 54% ee, 3ab, 99% yield, 12% ee). Notably, even with sterically challenging substrates, like α-alkyl styrenes featuring α-ethyl, α-ⁿpropyl, α-benzyl, this asymmetric hydrothiocarbonylation still delivered impressive results with little influence in reactivity and enantioselectivity (3ac−3ah, 80%−97% yields, 90%−96% ee). Notably, even with sterically challenging substrates, like α-alkyl styrenes featuring α-ethyl, α-ⁿpropyl, α-benzyl, this asymmetric hydrothiocarbonylation still delivered impressive results with little influence in reactivity and enantioselectivity (3ac−3ah, 80%−97% yields, 90%−96% ee).

  Scheme 2

  

  Scheme 2.  Reaction conditions: α-alkyl styrenes 1 (0.2 mmol, 1.0 equiv.), 2-phenylethanethiol 2a (0.3 mmol, 1.5 equiv.), CO (45 atm), Pd₂dba₃ (2.5 mol%), L5 (6 mol%), p-TsOH·H₂O (10 mol%) and LiCl (20 mol%) in 0.5 mL of CHCl₃ at 0 ℃ for 36 h. Isolated yields were given. ee values were determined by chiral-phase HPLC analysis.

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  We further explored the scope of thiols 2 (Scheme 3). For alkyl thiols, all the reactions proceeded smoothly and resulted in the formation of products 4a−4i with excellent results (83%−97% yields, 93%−97% ee). Meanwhile, the feasibility of this method for modification of bioactive compounds was investigated in the cases of thiols from amino acids, such as cysteine (2j) and homocysteine (2k), satisfactory yields and excellent stereoselectivities were achieved (4j−4k). For benzyl thiols, the electrical properties and steric hindrance of the substituents (such as OMe, Cl, Br) on the aryl ring were found little effect for both reactivity and enantio‑control (4l−4q, 91%−98% yields, 93%−95% ee). Heteroaromatic thiols (2r−2s) were also compatible with excellent results (95%−96% yields, 94%−95% ee). Furthermore, for thiophenols, with para- and meta-substituents on the aryl ring, such as methyl (2u, 2aa), methoxy (2v, 2ab), methylthio (2w), halogens (2x−2y, 2ac) and trifluoromethyl (2z), the corresponding chiral 3-methyl alkanoic acid derivatives were synthesized efficiently and successfully (4t−4ac, 84%−96% yields, 92%−96% ee). Additional investigations demonstrated that o-ethyl and o-Br substituted thiophenols (2ad−2ae) were also suitable for this transformation with reactivities and excellent enantio‑control (4ad−4ae, 96%−97% yields, 94%−96% ee). When 2-naphthalenethiol (2af) was used, the corresponding chiral thioester (4af) was obtained in moderate yield and excellent enantioselectivity (for unsuccessful substrates, see Suppoting information).

  Scheme 3

  

  Scheme 3.  Reaction conditions: α-alkyl styrenes 1a (0.2 mmol, 1.0 equiv.), RSH 2 (0.3 mmol, 1.5 equiv.), CO (45 atm), Pd₂dba₃ (2.5 mol%), L5 (6 mol%), p-TsOH·H₂O (10 mol%) and LiCl (20 mol%) in 0.5 mL of CHCl₃ at 0 ℃ for 36 h. Isolated yields were given. ee values were determined by chiral-phase HPLC analysis.

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  The potential synthetic utility of this reaction was showcased by scale-up experiment, transformations of product and synthesis of the key intermediate of bioactive molecules (Scheme 4). As demonstrated in Scheme 4A, under the standard conditions, gram-scale of 4t was afforded with satisfied yield and ee value (1.17 g, 92% yield, 94% ee). Additionally, several synthetic transformations of the chiral 3-methyl alkanoic acid derivative were carried out (Scheme 4B). It is well known that thioester is a marvelous acylation reagent in organic synthesis [26]. Taking advantage of this property, C–S bonds were delivered to various C–X (X=C, N, O) bonds in good results with little loss in optical purity, for instance, C–C(sp) bond (6a, via Sonogashira coupling reaction with terminal alkyne, 82% yield, 93% ee) [74], C–C(sp²) bond (6b, via Fukuyama coupling reaction with arylboronic acid, 59% yield, 92% ee) [75], C–N bond (6c, via aminolysis with BnNH₂, 71% yield, 92% ee) and C–O bond (6d, via hydrolysis, 96% yield, 94% ee) [76].

  Scheme 4

  

  Scheme 4.  Synthetic applications.

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  As previously elucidated, chiral 3-aryl alkanoic acid and their derivatives are key building blocks in the synthesis of numerous pharmaceuticals and bioactive molecules. Herein, we demonstrated the synthesis of the intermediacy of selected pharmaceutically interested molecules bearing chiral 3-aryl alkanoic acid skeletons (Scheme 4C). Firstly, under the standard conditions, substituted α-alkyl styrenes (7a–7c), readily prepared from commercially available ketones, were transformed into corresponding chiral 3-aryl alkylate thioesters with excellent results (8a–8c, 91%–93% yields, 93%–95% ee). Subsequently, amide 9a (99% yield, 93% ee) and 3-aryl alkanoic acids 9b–9c (98%–99% yields, 93%–94% ee) were efficiently prepared through aminolysis or hydrolysis from 8a–8c. 9a and 9b could be applied to the formal synthesis of corresponding bioactive molecules RC-33 [6] and AM-6226 [7]. Meanwhile, 9c prepared from 8c serves as an intermediate analog of R-106578 [8].

  To understand the high regioselectivity, deuterium-labeling experiment [77] was then conducted (Scheme 4D). Employing deuterated thiophenol D-2t (70% deuteration), the deuteration exclusively occurred on the tertiary carbon of the product D-4t (76% yield, 20% deuteration), indicated that the addition of [Pd–H] to α-methylstryene via a complete anti-Markovnikov pathway. Next, we investigated the role of salt additives in this reaction [78–84], and control experiments were conducted (Scheme 4E). Comparing the results with the addition of LiCl and KCl, we concluded that the cation participated possibility in modulating the reaction of activity and stereocontrol. However, when using 18-Crown-6 to capture the K⁺, high yield and enantioselectivity were still obtained, suggesting that the anion plays a critical role in the reaction. LiBr led a significant decrease in yield and enantioselectivity, indicating that anion is concerned in modulation and that Cl⁻ is preferred over Br⁻. In addition, we observed that when LiCl was added, the reaction solution was clear. Without LiCl, a large amount of black insoluble material appeared on the walls of the bottle. We reasoned that in the presence of a soluble halide salt like LiCl, the coordination of Cl⁻ anions to the Pd(II) intermediates could prevent the aggregation of reduced palladium that flourished high yields and excellent enantiocontrol (included in Supporting information 6.3).

  Subsequently, ³¹P NMR studies were performed to monitor the relative Pd species, particularly, active Pd–H species (in this work, we have also tried explorations including ¹H NMR and HRMS analysis or crystal growing of Pd species, yet all attempts were unsuccessful). As shown in Scheme 5A, first, mixing SOP (L1) with Pd₂dba₃ in CDCl₃ for 30 min provided SOPPd complex [Three new peaks emerged: δ = 65.71 (major) and 67.94 (minor), 60.26 (minor); experiment i]. Then, p-TsOH^.H₂O (1.1 equiv.) was added to the above mixture and another two new peaks at δ = 70.17 (major, TsO–Pd^II–H species) [59] and 72.84 (minor) were afforded through oxidative addition (experiment ii). Sequentially addition of LiCl (2 equiv.) was executed (experiment iii), quickly two new peaks appeared at δ = 69.97 (major) and 71.74 (minor), which were assigned to Cl–Pd^II–H intermediate. In addition, we speculate that OTs⁻ as weakly associated counterion could be easily replaced by Cl⁻ anion. After additional 30 min stirring, Cl–Pd^II–H intermediate were completely transformed to Cl–Pd^II–Cl species (δ = 94.58, this species were observed in experiment iii too), which were determined by comparison with ³¹P NMR of the complex generated from SOP and Pd(PhCN)₂Cl₂ (experiment iv). Whereas in the presence of Cl–Pd^II–Cl species, hydrothiocarbonylation does not work under the standard conditions (For details see Supporting information). In sum, the above experimental results indicate that in the presence of LiCl, TsO–Pd^II–H species, generated in situ by the oxidative addition of the SOPPd complex with p-TsOH, is easily converted to true active intermediate (Cl–Pd^II–H) by ligand exchange with Cl⁻ anion. Besides, without starting materials (α-alkyl styrene and CO), excess amount of LiCl, drives the generation of the Cl–Pd^II–Cl species, thereby inhibiting the reaction.

  Scheme 5

  

  Scheme 5.  (A) ³¹P NMR spectra of various reaction components in CDCl₃. (B) Proposed catalytic cycle.

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  Based on these results and relevant literature, a plausible mechanism for the enantioselective hydrothiocarbonylation is illustrated in Scheme 5B. Initially, complex A (SOPPd⁰), formed from SOP and Pd₂dba₃, produces the TsO–Pd^II–H species B via oxidative addition with p-TsOH. In the presence of LiCl, the Cl–Pd^II–H intermediate C is rapidly generated from species B through a ligand exchange process. Subsequently, the Cl–Pd^II–H intermediate C coordinates with α-alkyl styrene. Due to the steric hindrance imposed by both the SOP ligand and the α-alkyl styrene, the insertion of the Cl–Pd^II–H intermediate into the C=C bond occurs with exclusively anti-Markovnikov selectivity and high stereoselectivity for the Si-face, yielding the chiral alkyl-Pd^IIspecies D. The enantioselectivity of the tertiary carbon is established at this stage. The chiral alkyl-Pd^II species D can then undergo carbonyl insertion to produce the acyl-Pd^II species E. Following this, thiols are exchanged for chloride ions, resulting in the formation of species F. Finally, through a reductive elimination process, the desired product 3 is released, and the SOP/Pd⁰ species A is regenerated.

  In summary, we developed a unique SOP/Pd-catalyzed system for the regioselective and enantioselective intermolecular hydrothiocarbonylation of α-alkyl styrenes, a transformation not readily accessible in previous studies. The distinctive SOP ligand and the LiCl additive were crucial to this success. The reaction demonstrated high regioselectivity, exhibiting exclusively anti-Markovnikov selectivity, as well as good to excellent yields in most cases. It achieved excellent enantioselectivity, with values generally ranging from 90% to 98% enantiomeric excess (ee), and showed broad functional group tolerance and substrate scope, encompassing 68 examples. Furthermore, the resulting products can be converted into various β-chiral 3-aryl alkanoic acid derivatives. This protocol may also be applied to the formal synthesis of medically significant bioactive molecules, including RC-33 and AM-6226, as well as the intermediate analogue of R-106578.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Wenze Shi: Investigation. Yang Dong: Methodology. Xihong Wang: Writing – review & editing. Min Wang: Writing – review & editing. Jian Liao: Writing – review & editing, Project administration.

  Acknowledgments

  This work was supported financially by National Nature Science Foundation of China (No. 22171258), the Youth Innovation Promotion Association CAS (No. 2022375), the Biological Resources Programme, Chinese Academy of Sciences (No. KFJ-BRP-008) and the Sichuan Science and Technology Program (No. 2022ZYD0038).

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2025.111023.

  
  
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  Scheme 1  Strategies for the synthesis of chiral 3-aryl alkanoic acids and their derivatives.

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  Scheme 2  Reaction conditions: α-alkyl styrenes 1 (0.2 mmol, 1.0 equiv.), 2-phenylethanethiol 2a (0.3 mmol, 1.5 equiv.), CO (45 atm), Pd₂dba₃ (2.5 mol%), L5 (6 mol%), p-TsOH·H₂O (10 mol%) and LiCl (20 mol%) in 0.5 mL of CHCl₃ at 0 ℃ for 36 h. Isolated yields were given. ee values were determined by chiral-phase HPLC analysis.

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  Scheme 3  Reaction conditions: α-alkyl styrenes 1a (0.2 mmol, 1.0 equiv.), RSH 2 (0.3 mmol, 1.5 equiv.), CO (45 atm), Pd₂dba₃ (2.5 mol%), L5 (6 mol%), p-TsOH·H₂O (10 mol%) and LiCl (20 mol%) in 0.5 mL of CHCl₃ at 0 ℃ for 36 h. Isolated yields were given. ee values were determined by chiral-phase HPLC analysis.

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  Scheme 4  Synthetic applications.

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  Scheme 5  (A) ³¹P NMR spectra of various reaction components in CDCl₃. (B) Proposed catalytic cycle.

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  Table 1.  Optimization of the reaction conditions.^a

  Entry	Ligand	Additive (mol%)	T (℃)	CO pressure (atm)	Yields of 3a/3a’/3a’’ (%) b	ee of 3a (%) c
  1	L1	–	0	1	N.R.	–
  2	L1	–	0	10	33:0:0	71
  3	L1	–	0	45	73:0:0	71
  4	L1	–	25	45	42:0:39	47
  5 d	L1	–	85	0	0:0:88	–
  6	L2	–	0	45	N.R.	–
  7	L3	–	0	45	75:0:0	80
  8	L4	–	0	45	73:0:0	82
  9	L5	–	0	45	76:0:0	85
  10	L6	–	0	45	75:0:0	81
  11	L7	–	0	45	0:82:0	–
  12	L8	–	0	45	33:0:0	31
  13	L9	–	0	45	N.R.	–
  14	L10	–	0	45	N.R.
  15	L11	–	0	45	N.R.
  16	L12	–	0	45	N.R.
  17	L5	LiCl (20)	0	45	99:0:0 (98) e	93
  18 f	L5	LiCl (20)	0	45	87 (isolated)	93
  a Reaction conditions: α-Methylstyrene 1a (0.2 mmol, 1.0 equiv.), 2-phenylethanethiol 2a (0.3 mmol, 1.5 equiv.), CO, Pd 2dba 3 (2.5 mol%), ligand (6 mol%), p-TsOH·H 2O (10 mol%) and additive (20 mol%) in 0.5 mL of CHCl 3 at 0 ℃ for 36 h. N.R. = no reaction. b Yields were determined by crude 1H NMR analysis using dibromomethane as internal standard. c The ee value of 3a was determined by chiral-phase HPLC analysis. d Without Pd-catalyst. e Isolated yield in parentheses. f S/C = 100.

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