English

• Allenyl fragments are often observed in natural products and medically active compounds, which are increasingly used as building blocks for construction of complex organic molecules [1–6]. Therefore, the synthesis of allenes has attracted continuous attention [7–12]. Among the available methods, the catalytic 1,4-addition of nucleophiles to the electron-deficient conjugated enynes has been recognized as an ideal pathway to access the allenes due to their high reactivity [13,14]. However, the precise control of regioselective 1,4-addition [15–17,20–28] to avoid the competitive 1, 2-addition [15–19] and produce the valuable allene products is usually challenging (Scheme 1A). So far, the electron-biased 1, 3-enynes including enynic ketones, 2-trifluoromethyl-1, 3-enynes, enynic amides, enynic esters, etc., have been applied to synthesize the corresponding functionalized allene derivatives via nucleophilic 1,4-additions (Scheme 1A) [15–17,20–28]. Despite the distinguished advances have been made in this area, the limited substrate scopes of conjugated enynes and nucleophiles in reactions still remain a large space to be expanded for synthesis of multi-functionalized compounds.

  Scheme 1

  

  Scheme 1.  Regioselective addition of electron-deficient 1, 3-enynes.

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  It is worth noting that the 2, 3-allenoates as building blocks have been widely applied in a broad array of organic reactions including Morita-Baylis-Hillman reactions [29–31], nucleophilic addition reactions [32–34], rearrangements [35], electrophilic addition reactions [3,36] and cycloadditions [37–39]. Therefore, so far, some efficient catalytic methodologies have been reported to prepare this kind of compounds [40–45]. Among them, regioselective 1,4-addition to enynic esters is undoubtedly the most direct way for synthesis of allenoates. Notably, in 2008, a base-catalyzed racemic preparation of allenoates from enynic esters was reported by Zhang, but the asymmetric catalytic version has not been explored [20]. Subsequently, in 2013, Sun and Zhang et al. developed an elegant work on cinchona based thiourea-catalyzed asymmetric nitroethylation of enynic esters. There only three aryl-substituted enynic esters were investigated due to their poor stability [23]. The relatively limited substrate scopes and poor stability of enynic esters motivated us to develop a new protocol to address these issues. It is well known that orthoester group can act as a good ester group precursor because it is easily hydrolyzed under acidic conditions. Combined our previous studies [46], we envisioned that protosilylation-hydrolyzation reaction of enynic orthoesters in one-pot would tackle this problem efficiently. Herein, we described the results of copper-catalyzed 1,4-protosilylation-hydrolyzation [47–50] and 1,4-protoborylation-hydrolyzation [51–54] of enynic orthoesters in one-pot to synthesize the ester-substituted homoallenylsilane and homoallenylboronate derivatives. Besides, the optically pure ester-substituted homoallenylsilanes were obtained in high yields with good enantioselectivity by using newly designed chiral monopyridine imidazoline ligand.

  Initially, the 1,4-protosilylation reaction was tested with using enynic orthoester 1a and PhMe₂Si-Bpin 2a as model substrates (Table 1). The choice of base had a significant impact on yield. The organic base such as Et₃N or DMAP, only afforded trace amount of product 3a with using 5 mol% CuBr as catalyst (entries 1 and 2). It is worth noting that the yield of 3a could be enhanced to 40% when the reaction was performed in the presence of Cs₂CO₃ (entry 3). After screening different copper catalysts, it was found that the yield of 3a could be increased to 97% when the 1,4-protosilylation reaction was catalyzed by CuCN (entries 3–5). These results indicates that good acid-base ion pair matching of CuCN may be the reason for its high catalytic activity in this reaction [55]. To our delight, under above-mentioned optimal conditions (entry 5), the corresponding homoallenylboronate 4a was obtained in 95% isolated yield (entry 6).

  Table 1

  

  Table 1.  Copper catalyzed 1,4-protosilylation-hydrolyzation and 1,4-protoborylation-hydrolyzation of enynic orthoesters.^a

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  Subsequently, we investigated the synthesis of chiral ester-substituted homoallenylsilanes. Inspired by our previous studies on asymmetric protosilylation reaction [56,57], we embarked on screening different chiral oxazoline ligands such as Box ligands, Pybox ligands, etc. Fortunately, when L₁ was used, the desired product 5a was obtained in 98% yield with 55% ee value (entry 7). To avoid the strong background reaction, we attempted to improve the coordination capacity of the ligand. Because the nitrogen atom is a better π electron donor than oxygen atom, we replaced the oxazoline moiety with imidazole fragment [58–59]. As expected, when L₂ was applied as ligand, the ee value of 5a was enhanced to 66% (entry 8). Next, we adjusted the electronic and steric effect by modifying the substituent (R) on the nitrogen atom of imidazole fragment. It was found that L₃ with an electron-donating group (4-OMe) on the phenyl ring had little effect on the reaction (entry 9), but the introduction of -CF₃ group on the phenyl ring lowered the ee value to 60% (entry 10). We also found that increasing the steric hindrance of R group could improve the product's enantioselectivity significantly (entries 11–13). The ligand L₇ with larger steric hindrance could increase the ee value of product to 81%. However, removing the trifluoromethyl group from the pyridine ring resulted in decreased yield and enantioselectivity (entry 14). More bulky tert–butyl substituted monopyridine imidazoline ligand (L₉) also afforded lower enantioselectivity possibly due to its inhibition for the coordination between ligand and copper atom (entry 15).

  After screening different bases and copper catalysts, the results showed that Na₂CO₃ and Cu₂O were the optimal choice for this reaction (entries 16–21). Gratifyingly, the desired chiral allene compound 5a was obtained in 95% yield with 90% ee when the reaction was performed in CH₃CN/MeOH (9:1) at −15 ℃ (entry 23). Further elevating or lowering the reaction temperature resulted in a lower ee value (entries 22–25). Unfortunately, when the reaction was performed with bis(pinacolato)diboron 2b under the optimal conditions, the corresponding chiral product was obtained only in 49% yield and with poor enantioselectivity (26% ee).

  Having established the conditions for the racemic 1,4-protosilylation of enynic orthoesters, the substrate scope of enynic orthoesters was investigated (Scheme 2). Generally, different aryl-substituted substrates were compatible in this reaction. The results indicated that the substrates with electron-donating or electron-withdrawing group on phenyl ring all could provide the desired products in good yields. Additionally, other enynic orthoesters bearing naphthyl (1j), thienyl (1k) or halogen-substituted phenyl ring (1b, 1c) also could be well tolerated in this reaction. When the quinolone-substituted substrate 1l was applied to the reaction, the product 3l was formed only in moderate yield. Furthermore, we tried the racemic 1,4-protoborylation and hydrolyzation of different enynic orthoesters with bis(pinacolato)diboron 2b (Scheme 3). Similarly, the enynic orthoesters above could afford the corresponding 1,4-protoborylation products in moderate to high yields under the optimized reaction conditions.

  Scheme 2

  

  Scheme 2.  Substrate scope of 1,4-protosilylation-hydrolyzation of enynic orthoesters. Unless otherwise noted, reaction was run under the following reaction condition: 1a (0.2 mmol), 2a (0.3 mmol), CuCN (5 mol%), Cs₂CO₃ (10 mol%) in 1.0 mL anhydrous MeOH at 25 ℃ for 12 h under argon atmosphere, isolated yield.

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  Scheme 3

  

  Scheme 3.  Substrate scope of 1,4-protoborylation-hydrolyzation of enynic orthoesters. Unless otherwise noted, reaction was run under the following reaction condition: 1a (0.2 mmol), 2b (0.22 mmol), CuCN (5 mol%), Cs₂CO₃ (10 mol%) in 1.0 mL anhydrous MeOH at 25 ℃ for 12 h under argon atmosphere. Isolated yield.

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  Subsequently, we examined the substrate compatibility of the asymmetric 1,4-protosilylation-hydrolyzation of enynic orthoesters (Scheme 4). In general, the enynic orthoesters with electron-donating goups (Me, OMe, ^tBu, 3, 4–Me₂) on the phenyl ring were suitable substrates and gave the corresponding products in high yields and with good enantioselectivities. Similarly, the products containing halogen atoms on the phenyl ring were also obtained in good yields and with slightly lower ee values (5b, 5c). Moreover, 1-naphthyl and 3-thienyl substituted enynic orthoester substrates could react smoothly under the optimal conditions and furnished the corresponding chiral homoallenylsilanes in high yields and with good ee values (5h, 5i).

  Scheme 4

  

  Scheme 4.  Substrate scope of asymmetric 1,4-protosilylation-hydrolyzation of enynic orthoesters. Unless otherwise noted, the reaction was run under the following condition: 1a (0.2 mmol), 2a (0.3 mmol), Cu₂O (5 mol%), Na₂CO₃ (10 mol%), L₇ (6 mol%) and 4 Å molecular sieves (0.0250 g) were stirred in 1.0 mL anhydrous CH₃CN/MeOH (9:1) at −15 ℃ for 12 h under argon atmosphere. Isolated yield and the ee was determined by HPLC.

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  The gram-scaled synthesis of the racemic homoallenylsilane 3a, homoallenylboronate 4a and enantioenriched homoallenylsilane 5a were carried out smoothly without diminishing efficiency (Scheme 5A). To show the synthetic utility of this method, diverse transformations of the products were tested (Scheme 5B). Interestingly, the allenyl fragments of products 3a and 4a could further react with PhMe₂Si-Bpin under the above-established optimized reaction conditions to produce the corresponding products 6a and 7a in high yields. Remarkably, as a kind of useful intermediates in organic synthesis, the 2, 3-allenoates can proceed a variety of transformations. For example, in the presence of CuBr₂, the allenoate 3a underwent a five-membered cyclization reaction to afford the multi-substituted lactone 8a. Treatment of product 3a with sodium hydroxide could generate the trisubstituted allenyl acid 9a in a high yield. Furthermore, the transformation of axial chiral 5a to central chiral product 10a was achieved without erosion of the enantioselectivity. The reduction of 5a with DIBAL-H could also provide the enantioenriched allenol 11a with retention of the enantioselectivity. Additionally, a Pd-catalyzed coupling reaction of homoallenylboronate 4a with iodobenzene was performed. The corresponding coupling product 12a was obtained in a high yield with excellent stereoselectivity. The homoallenyl alcohol 13a was formed in good yield via an oxidation of 4a with using H₂O₂. Subsequently, 13a was converted to the cyclic product 2, 5-dihydrofuran 14a in 93% yield catalyzed by Ph₃PAuN(Tf)₂. Finally, the absolute configuration of the 2, 3-allenoate 5j was assigned as R [60], on the basis of the absolute configuration of (S)−10b determined by an X-ray diffraction analysis (CCDC: 2225813) (Scheme 6).

  Scheme 5

  

  Scheme 5.  Gram-scaled synthesis of allene compounds and their derivatization.

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  Scheme 6

  

  Scheme 6.  Iodolactonization of the 2, 3-allenoate (R)−5j.

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  In conclusion, we have developed a practical strategy for the preparation of allenoate derivatives via copper-catalyzed 1,4-protosilylaiton-hydrolyzation and 1,4-protoborylation-hydrolyzation reaction of enynic orthoesters in one-pot. The derivatizations of allenoate products were conducted, which demonstrated their potential utility in organic synthesis. Moreover, this work disclosed an efficient method to produce the functionalized enantioenriched homoallenylsilanes. The monopyridine imidazoline ligand was suitable for this asymmetric reaction to offer high reactivity and enantioselectivity.

  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.

  Acknowledgments

  We gratefully acknowledge the funding support of the National Natural Science Foundation of China (No. 21871240), the Strategic Priority Research Program of the CAS (No. XDPB14) and the Fundamental Research Funds for the Central Universities (No. WK2060190082).

  
  
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• 

  Scheme 1  Regioselective addition of electron-deficient 1, 3-enynes.

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  Scheme 2  Substrate scope of 1,4-protosilylation-hydrolyzation of enynic orthoesters. Unless otherwise noted, reaction was run under the following reaction condition: 1a (0.2 mmol), 2a (0.3 mmol), CuCN (5 mol%), Cs₂CO₃ (10 mol%) in 1.0 mL anhydrous MeOH at 25 ℃ for 12 h under argon atmosphere, isolated yield.

  下载: 全尺寸图片 幻灯片
  

  Scheme 3  Substrate scope of 1,4-protoborylation-hydrolyzation of enynic orthoesters. Unless otherwise noted, reaction was run under the following reaction condition: 1a (0.2 mmol), 2b (0.22 mmol), CuCN (5 mol%), Cs₂CO₃ (10 mol%) in 1.0 mL anhydrous MeOH at 25 ℃ for 12 h under argon atmosphere. Isolated yield.

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  Scheme 4  Substrate scope of asymmetric 1,4-protosilylation-hydrolyzation of enynic orthoesters. Unless otherwise noted, the reaction was run under the following condition: 1a (0.2 mmol), 2a (0.3 mmol), Cu₂O (5 mol%), Na₂CO₃ (10 mol%), L₇ (6 mol%) and 4 Å molecular sieves (0.0250 g) were stirred in 1.0 mL anhydrous CH₃CN/MeOH (9:1) at −15 ℃ for 12 h under argon atmosphere. Isolated yield and the ee was determined by HPLC.

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  Scheme 5  Gram-scaled synthesis of allene compounds and their derivatization.

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  Scheme 6  Iodolactonization of the 2, 3-allenoate (R)−5j.

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  Table 1.  Copper catalyzed 1,4-protosilylation-hydrolyzation and 1,4-protoborylation-hydrolyzation of enynic orthoesters.^a

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