Please cite this article in press as: Gao et al., Visible-Light-Induced Nickel-Catalyzed Cross-Coupling with Alkylzirconocenes from Unactivated
sulfonamides (20) also coupled with the alkylzirconocenes in moderate yields. A sec-
ondary alkyl iodide substrate based on cholesterol delivered corresponding product
31, further highlighting the utility of this new process for the late-stage modification
of complex natural products. For the most challenging tertiary alkyl halides, triaryl-
chloromethane (22, 23) and ethyl 2,2-difluoro-2-iodoacetate (30) were found to be
productive substrates for this cross-coupling method. With respect to the alkene
as the starting material for hydrozirconation and cross-coupling, unactivated alkenes
and substituted alkenes were amenable to this method: sulfonamides (28–31),
silanes (26), and ethers (27) were tolerated.
After establishing the visible-light-induced nickel-catalyzed C(sp3)–C(sp3) cross-
coupling reaction, we then expanded the protocol to C(sp2)–C(sp3) cross-coupling
between aryl iodides and alkylzirconocenes employing a more easily accessible
catalyst: Ni(dtbbpy)Br2 (Ni-2). As shown in Figure 2B, this method displayed excel-
lent functional group tolerance for the aryl iodides bearing fluoro (33), chloro (34,
50), methyl (35, 45, 48), trifluoromethyl (37, 47), and methoxy (38, 46, 49) groups,
as well as more reactive functional groups such as nitriles (36), ketones (39), esters
(40), amides (41), anilines (42), phenols (43), and primary alcohols (44). Notably,
the substitution pattern and electronic properties had a negligible effect on the
yield, and the corresponding cross-coupling products were obtained in good to
excellent yields. Furthermore, the potential application of this visible-light-
induced cross-coupling in modern synthesis was demonstrated by carrying out
at a gram scale process using flow chemistry (32, 70% yield) and a batch system
(38, 72% yield).
Heteroaromatic iodides, including pyridines (52), pyrazines (53), thiophenes (54), in-
doles (55), and even the cholesterol derivatives (56) were confirmed as effective
coupling partners. Additionally, we observed that alkenyl bromide substrates could
also undergo coupling to generate alkenes 68 and 69, providing an alternative re-
gioselective approach to Heck coupling. Regarding the scope of alkenes, a series
of simple (57) and substituted alkenes (58–67) were viable coupling partners for
this method; and thioethers (59), silanes (60), ethers (62), chloro groups (63), sulfon-
amides (64), and even hydroxyl groups (67) were all tolerated. Notably, alkene de-
rivatives from natural products, including estrone (70) and quinine (71), were
compatible with both hydrozirconation and subsequent cross-coupling.
The visible-light-induced nickel-catalyzed cross-coupling method was also efficient
for C(sp)–C(sp3) cross-coupling reactions with Ni(dtbbpy)Br2 (Ni-2), as outlined in
Figure 2C. The electronic properties of the alkynes did not have dramatic impact
on the coupling outcome. The unactivated alkynes (72, 73, 75), electron-deficient
alkyne (74) and conjugated alkynes (76–81) all gave moderate to good yields.
Notably, 1-(bromoethynyl)-4-chlorobenzene and 1-bromo-4-(bromoethynyl)ben-
zene gave corresponding products 77 and 78 in 65% and 56% yields, respectively,
demonstrating a high chemoselectivity between C(sp)–C(sp3) and C(sp2)–C(sp3)
cross-couplings. Moreover, variation of the alkenes was also feasible: simple alkenes
and alkenes possessing a hetero atom (Cl, Br, N, S, Si, or O) all gave the desired
cross-coupling products in good yields (83–95), and alkylzirconocenes derived
from the natural products (e.g., estrone (96) and quinine (97)), could also couple
with alkyne halides, further showcasing the versatility of this protocol.
Reaction Utilities
Under thermodynamic control, terminal or internal alkenes, all generate terminal al-
kylzirconocenes through hydrozirconation and subsequent rapid ‘‘chain walking’’ for
Chem 6, 1–14, March 12, 2020
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