a
a Reaction conditions: 1 (0.5 mmol), divinylzinc (0.55 mmol), L3-FeCl2 (3 mol %) in THF (4.5 mL) at rt for 3 h, the reaction mixture was quenched with water (150 μL) unless otherwise noted. All of the reactions exhibited full conversion of internal alkynes. Isolated yields were given.E /Z and regioisomeric ratios (rr) of all the products were determined by 1H NMR. b The reaction was conducted at 40 °C. c The reaction was conducted at 35 °C, 0.3 mmol scale.
Additionally, we successfully extended the catalytic system to the vinylzincation of diarylacetylenes (Scheme 3A). Symmetrical diarylacetylenes could be selectively converted to the desired products (2da2dc ) with moderate to good yields and high stereoselectivity. Notably, we achieved the first example of directed alkenylzincation of an unsymmetrical diarylacetylene containing a pyridine moiety (2dd ). Unfortunately, the regioselectivity was poor for the reaction of a diarylacetylene with one phenyl group bearing an electron-donating substituent and the other with an electron-withdrawing substituent, and 1:1 mixture of products2de and 2df were obtained.
The regioselectivity of vinylzincation of unsymmetrical dialkyl acetylenes is a remarkable challenge because the two substituents of the alkyne have similar electron and steric properties. In deed, the carbozincation of unsymmetrical dialkyl acetylenes could only obtained a poor regioselectivity (rr = 55:45) in the literature.[13c] To our delight, the iron-catalyzed vinylzincation reactions of unsymmetrical dialkyl acetylenes exhibited unprecedented high regioselectivities (Scheme 3B). The reactions of phenylpropyl propyne, benzyl propyne, substituted benzyl propyne, and cyclohexyl propyne afforded the single regioisomers in good to excellent yields (2ea2ed ).
Next, we also investigated the reactions of different types of alkenylzinc reagents (Scheme 3C). It was found that β-alkyl-substituted alkenylzinc reagents could undergo the reaction smoothly, affording multi-substituted conjugated dienes with excellent yields (2fa ,2fb ). Furthermore, when L8-FeCl2 was used as the catalyst, the substrate scope could be extended to α-alkyl-substituted alkenylzinc reagent, leading to the formation of a single syn -addition product 2fc in 69% yield.
Scheme 3 Iron-catalyzed alkenylzincation of internal alkyne: substrate scope a
a Reaction conditions: 1 (0.5 mmol), divinylzinc (0.55 mmol), L3-FeCl2 (3 mol %) in THF (4.5 mL) at rt for 3 h, the reaction mixture was quenched with water (150 μL) unless otherwise noted. b The reaction was conducted at 50 °C. c 0.3 mmol.d NMR yield. e Used 3 mol % L5-FeCl2 as catalyst.f Used 3 mol %L8-FeCl2 as catalyst.
The activity of the current reaction is high, and the reaction proceeds smoothly even when the substrate/catalyst ratio (S/C) is increased to 12500, resulting in a 92% isolated yield (turnover number, TON = 11500) of 4.05 g of conjugated diene product 2ag (Scheme 4A). To the best of our knowledge, this is the highest TON record for carbometallation reactions.[14] In order to demonstrate the potential applications of this method in synthesis, we carried out various transformations on the conjugated dienyl zinc product 2aa’ (Scheme 4B). When organozinc intermediate was trapped with D2O, deuterated conjugated dieneT1 was obtained. The conjugated dienyl zinc product2aa’ smoothly underwent Negishi coupling reactions with iodomethane, 4-nitroiodobenzene, and vinyl bromide, affording conjugated dienes T2T4 with well retention of configuration in 90%, 69%, and 90% isolated yields, respectively. Transformation of zinc group of 2aa’ to allyl group mediated by copper salt ran smoothly to afford functionalized conjugated olefins T5 in 97% yield. The intermediate 2aa’ could also undergo addition reactions with isocyanate, affording the mono-configurational amide-conjugated diene T6 in 90% yield. Thus, by combining the iron-catalyzed alkenylzincation of internal alkynes with rich transformations of the C(sp 2)-Zn bond, we have developed a new method for the selective synthesis of tetrasubstituted olefin-containing conjugated dienes from easily accessible alkynes. Note that the stereospecific synthesis of multi-substituted conjugated dienes has been a challenge task because the difficult stereoselective control.[15]
Scheme 4 Applications of iron-catalyzed alkenylzincation of internal alkynes
a Reaction conditions: (a) D2O, THF, rt, 0.5 h; (b) MeI, Pd(PPh3)4, THF, rt, 12 h; (c) 1-iodo-4-nitrobenzene, Pd(PPh3)4, THF, rt, 12 h; (d) vinyl bromide, Pd(PPh3)4, THF, rt, 12 h; (e) allyl bromide, CuCN, THF, rt, 4 h; (f) p -tolyl isocyanate, THF, 50 °C, 8 h.
Conclusions
In summary, we reported the first iron-catalyzed alkenylzincation of internal alkynes, which exhibited not only high reaction activity and selectivity, but also good functional group tolerance and broad substrate scope. The resulting products are amenable to a variety of transformations, enabling efficient synthesis of a range of multi-substituted conjugated dienes. This research provides a new catalytic system for alkenylzincation of internal alkynes, overcomes limitations of other catalysts on substrate type, catalytic activity, and selectivity, thereby demonstrates the significant potential of iron catalysts in organic synthesis.
Experimental
Preparation of alkenylzinc reagents: In an argon-filled glovebox, a vial (10 mL) was charged with anhydrous ZnBr2 (1.0 equiv), anhydrous LiCl (1.0 equiv), anhydrous THF (10 mL per 1 mmol zinc bromide). Then, alkenylmagnesium bromide (0.5 M or 1.0 M, 2.0 equiv) was added slowly and the reaction mixture was stirred for another 10 minutes at rt. A slight yellow solution was formed and used without further titration.
General procedure for iron-catalyzed vinylzincation of internal alkynes: In an argon-filled glovebox, internal alkyne 1 (0.5 mmol) and catalyst (0.015 mmol) were added to the pre-prepared divinylzinc solution (0.55 mmol, 0.1 M in THF, 1.1 equiv) in sequence. After stirring for 3 h at rt, the reaction mixture was quenched with an electrophilic reagent and filtered over silica gel using ethyl acetate as an eluant. The combined organic phases were concentrated by rotary evaporation, and the product was isolated by column chromatography over silica gel.
Supporting Information
The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
We thank the National Key R&D Program of China (2021YFA1500200), National Natural Science Foundation of China (92256301, 92156006, 22221002), “111” project (B06005) of the Ministry of Education of China, Haihe Laboratory of Sustainable Chemical Transformations, Fundamental Research Funds for the Central Universities, New Cornerstone Science Foundation through the XPLORER PRIZE for financial support.
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