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
(2da –2dc ) 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 (2ea –2ed ).
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 T2 –T4 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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