Chiral carbon–sulfur center formation via Pd-catalyzed asymmetric allylic thioetherification: synthesis of allylic thioethers

Abstract

Pd-catalyzed asymmetric allylic thioetherification reaction of various sodium thiolates was realized, which gave the allylic thioethers in good to high yields with high enantioselectivities. The reaction results considerably depend on the substrates and the bulky sulfur nucleophile led to excellent enantioselectivity as well.

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Approximately one-fifth of the 200 most-prescribed drugs in 2011 were organosulfur compounds.¹ More interestingly, the optically active sulfur-containing compounds exhibit excellent biological activity.² For example, the popular pharmaceutical products and naturally occurring compounds such as biotin,³ montelukast,⁴ eflucimibe,⁵ and mPEES-1 inhibitors contain a chiral center bearing a carbon–sulfur (C–S) bond (Fig. 1).⁶ Noticeably, a direct way for the construction of a C–S bond is by palladium-catalyzed allylic substitution.⁷ Pd-catalyzed asymmetric allylic substitution has become a powerful tool for the synthesis of chiral compounds.^7,8 To this context, allylic thioetherification reactions have been less reported since sulfur nucleophiles can poison the transition-metal catalyst.⁹ Pd-catalyzed allylic substitutions of sulfur nucleophiles revealed that 4-chlorothiophenol,¹⁰ 2-mercaptopyridine,¹⁰ 2-mercaptopyrimidine,¹⁰ tert-butylthiol,^10j tri-tert-butyl(tert-butylthio)silane,^10j sulfinates,^10e,10f,11 thiocarbamates,¹² and thioacetates¹³ were suitable nucleophiles.

Fig. 1 Four compounds with a chiral C–S center.

Iridium (Ir)-catalyzed asymmetric allylic substitutions of sulfur nucleophiles was contributed by our group¹⁴ and others.¹⁵ To the best of our knowledge, the C–S bond construction by Pd-catalyzed asymmetric allylations is a largely unexplored area in organic synthesis. In this paper, we report an enantioselective Pd-catalyzed allylic substitution of symmetrical allylic acetates with sodium thiolate (NaSR), which afford the allylic thioethers with high enantioselectivities.

An initial thioetherification reaction between (E)-1,3-bis(4-chlorophenyl)allyl acetate 1a and sodium prop-2-ene-1-thiolate 2a was explored with Pd-complex generated from Pd₂(dba)₃, Pd(OAc)₂, and [Pd(C₃H₅)Cl]₂ with (R)-BINAP L1 (ref. 16) at −10 °C, respectively (Table 1, entries 1–3). To our delight, the allylic thioether 3a was obtained with a 61% yield and 91% enantiomeric excesses (ee) when [Pd(C₃H₅)Cl]₂/L1 was utilized (Table 1, entry 3). The remaining Pd salts such as Pd₂(dba)₃ and Pd(OAc)₂ are ineffective for this reaction (entries 1 and 2). Solvent survey indicated that DCM is suitable (Table 1, entry 3) and the other solvents such as THF and toluene gave the poor yields with the moderate ee (Table 1, entries 4 and 5). In contrast, the reaction gave 3a in a 50% yield with 80% ee in the absence of base (Table 1, entry 6). These results illustrated that the nature of bases has a considerable influence on the enantioselectivities. Thus, a variety of bases including KOAc, NaOAc, KI, trimethylsilyl (E)-N-(trimethylsilyl)formimidate (BSA), DBACO, and KOAc/BSA was examined. A combination of KOAc and BSA gave rise to a superior result (Table 1, entry 11), whereas other bases led to fair yields with moderate to high ee (Table 1, entries 7–11). A slight excess 2a was employed and it gave the best result (Table 1, entry 11 vs. 12).

Table 1 Optimization of the reaction conditions^a

En	Pd salt	L	Sol	Base	Yield^b [%]	ee^c [%]
a Reaction conditions: 1a (0.20 mmol), 2a (1.0 equiv.), Pd salt (2.5 mmol%), L1–L5 (5 mmol%), base (1.0 equiv.), and solvent (2.0 mL) at −10 °C under argon.b Isolated yield.c Determined by HPLC.d 2a = 1.2 equiv.e At 0 °C.
1	Pd2(dba)3	L1	DCM	KOAc	—	—
2	Pd(OAc)2	L1	DCM	KOAc	—	—
3	[Pd(C3H5)Cl]2	L1	DCM	KOAc	61	91
4	[Pd(C3H5)Cl]2	L1	THF	KOAc	30	85
5	[Pd(C3H5)Cl]2	L1	Toluene	KOAc	35	75
6	[Pd(C3H5)Cl]2	L1	DCM	—	50	80
7	[Pd(C3H5)Cl]2	L1	DCM	NaOAc	60	84
8	[Pd(C3H5)Cl]2	L1	DCM	KI	50	92
9	[Pd(C3H5)Cl]2	L1	DCM	BSA	61	92
10	[Pd(C3H5)Cl]2	L1	DCM	DBACO	60	90
11	[Pd(C3H5)Cl]2	L1	DCM	KOAc/BSA	73	92
12^d	[Pd(C3H5)Cl]2	L1	DCM	KOAc/BSA	81	95
13^d	[Pd(C3H5)Cl]2	L2	DCM	KOAc/BSA	Trace	—
14^d	[Pd(C3H5)Cl]2	L3	DCM	KOAc/BSA	—	—
15^d	[Pd(C3H5)Cl]2	L4	DCM	KOAc/BSA	—	—
16^d	[Pd(C3H5)Cl]2	L5	DCM	KOAc/BSA	—	—
17^d^,^e	[Pd(C3H5)Cl]2	L1	DCM	KOAc/BSA	68	83

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The ligands are crucial to Pd-catalyzed asymmetric allylic substitutions.⁸ Therefore, the effect of ligands including (R)-Tol-BINAP L2,¹² Trost L3,¹⁷ Josiphos L4,¹⁸ and PHOX L5 (ref. 19) (Fig. 2) on the allylic thioetherification was examined. The allylic thioetherification of 2a took place with the best enantioselectivity in the presence of the catalyst derived from (R)-BINAP L1 (Table 1, entry 12). Unexpectedly, L2 structurally similar to L1 only gave a trace amount of 3a (Table 1, entry 13). These outcomes indicated that the steric demand of the ligands has great influence on this reaction. Subsequent investigation indicated that the Pd complexes made from L3–L5 failed to promote this reaction (Table 1, entries 14–16). The reaction was carried out at 0 °C and it afforded a somewhat worse result than that at −10 °C (Table 1, entry 12 vs. 17).

Fig. 2 Chiral ligands L1–L5 used in this allylic sulfane.

Using this procedure, the scope of the thioetherification reactions of a range of allylic acetates 1 with sodium prop-2-ene-1-thiolate 2a was subsequently explored (Table 2). The allylic substrates 1a–f with electron-poor group (e.g., p-Cl, p-F, p-Br, m-Cl, m-F, and m-Br) on the phenyl ring gave the corresponding products 3a–f in moderate to high yields with the high level of the enantioselectivities.

Table 2 The scope of the allyl acetates 1 and sodium thiolates 2^a,b,c,d

a Reaction conditions: 1 (0.20 mmol), 2 (1.2 equiv.), [Pd(C₃H₅Cl)]₂ (2.5 mmol), L1 (5 mmol), KOAc (1.0 equiv.), BSA (1.0 equiv.) and solvent (2.0 mL) at −10 °C under argon.b Isolated yield.c Determined by HPLC.d At −15 °C.

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In addition, both (E)-1,3-diphenylallyl acetate 1g and the allylic substrate 1h with an electron-rich group (e.g., m-CH₃) on the phenyl ring offered the allylic thioethers 3g and 3h in the acceptable yields with the moderate enantioselectivities. These results suggested that sodium prop-2-ene-1-thiolate 2a is a somewhat weak nucleophile and the reaction results considerably depend upon the allylic substrates in these cases. The steric demand and nature of sulfur nucleophiles 2 was also investigated. The representative sulfur nucleophiles such as sodium phenylmethanethiolate 2b, sodium cyclohexanethiolate 2c, sodium 2-methylpropane-2-thiolate 2d, and sodium benzenethiolate 2e were thus examined. 2b gave the results similar to that of 2a; and a bulky 2c resulted in the corresponding 3j in a 70% yield with 93% ee. Significantly, the more steric hindered 2d was utilized at −15 °C and it afforded the corresponding 3k in a 88% yield with 91% ee. Aromatic sulfur nucleophile 2e also gave rise to the corresponding 3l in a 70% yield with a lowering ee (Table 2). The allylic substrate 1i bearing an electron-donating group (e.g., p-CH₃) on the phenyl ring provided 3m with a 43% yield with 3% ee. The aliphatic substrate such as cyclohex-2-enyl acetate 1j was also examined and the corresponding product 3n were not observed (Table 2).

A single-crystal X-ray diffraction analysis of 3c²⁰ (Fig. 3) illustrates the absolute configuration of 3c as R (see ESI† for details).

Fig. 3 X-ray structure of (R)-3c.

Conclusions

In conclusion, we developed a practical method for the formation of C–S bond via Pd-catalyzed asymmetric allylic thioetherifications, which gives the allylic thioethers in good to high yields with high enantioselectivities. This method allows the use of bulky sulfur nucleophiles, illustrates good tolerance of the aryl-substituted allyl acetates, and offers a new way to chiral allylic thioethers.

Acknowledgements

We gratefully acknowledge the NSFC (21272175 and 20942003) for generous financial support.

Notes and references

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20. ESI.‡.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1485308. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra26877c

‡ The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

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