10.1002/anie.201800749
Angewandte Chemie International Edition
COMMUNICATION
substituents such as trifluoromethyl, carboxymethyl, and
sulfonamide, delivered the corresponding benzylic alcohols in
excellent yields (14, 19–25, 56–83% yield). Electron-neutral and
electron-rich aryl bromides also performed well in this
transformation (26–30, 56–70% yield). Importantly, ortho and
meta substitution are tolerated (31 and 32, 44% and 61% yield,
respectively). Moreover, 3- and 4-chloropyridines delivered the
corresponding heteroarylated alcohols in good efficiency (33–37,
40–74% yield). Interestingly, these substrates required the use
of magnesium chloride as the Lewis acid additive.16
We next examined the scope of this transformation with respect
to the alcohol component. Remarkably, the simplest carbinol,
methanol can be employed in this transformation, furnishing the
corresponding benzylic alcohol (38, 51% yield). Simple aliphatic
alcohols are generally competent substrates for this C–H
arylation (14 and 39–41, 63–75% yield). Moreover, deuterated
ethanol furnishes the corresponding phenethyl alcohol in good
yield (40, 63% yield). Alcohols containing weak benzylic C–H
bonds are exclusively functionalized at the -hydroxy position
(42 and 43, 66 and 59% yield, respectively). Acyclic and cyclic
,-disubstituted alcohols also perform well (44–47, 49–66%
yield). A variety of alcohols bearing -electron-withdrawing
groups also couple efficiently despite the inductive deactivation
of the -hydroxy C–H bonds towards HAT in these substrates
(47–49, 56–70% yield). Notably, protected and unprotected diols
were competent coupling partners in this transformation
furnishing monoarylated products exclusively (51–53, 58–68%
yield). Finally, a variety of heteroatom-containing alcohols, which
possess multiple hydridic C–H bonds, furnished the products
regioselectivity (>20:1) for the desired C–C coupling reaction at
the -alcohol C–H position without ether formation or arylation of
the -methyl amine.
Acknowledgement
The authors thank Tia Lee (Princeton University) for assistance
in determining the excited state lifetime of photocatalyst 18.
Keywords: alcohols • photoredox catalysis • heterocycles •
nickel • hydrogen atom transfer
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Chemoselective Photoredox 3-Step Synthesis of Prozac
Br
OH
Me
N
OH
N
Bz
Bz
Ir Ni
H
(59) 54% yield,
58
complete regiocontrol
[7]
[8]
CF3
Br
• HCl
O
F3C
Me
N
H
Ir Ni
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remains uncoordinated to the nickel center.
Prozac•HCl (61)
50% yield over 3 steps
then Bz removal
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with exclusive functionalization at the -hydroxy C–H position
(54–57, 46–71% yield).17
[12]
The ground state redox potentials for this catalyst as well as
spectrochemical data are available data are detailed in the Supporting
Information. Photocatalyst 1 has a similar excited state lifetime vs.
photocatalys 1 (2.0 s vs. 2.3 s).
Figure 2. Synthesis of Prozac. See Supporting Information for experimental
details.
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As further demonstration of the utility of this –hydroxy C–H
arylation protocol, we sought to rapidly forge the medicinal agent
Prozac (Figure 2). Indeed, subjecting protected N-methyl
propanolamine (58) to the optimized coupling conditions with
bromobenzene delivered benzylic alcohol 59. The ethereal
linkage present in the drug molecule was then constructed
utilizing our metallaphotoredox etherification protocol to deliver
60, which following deprotection furnished Prozac•HCl in 50%
overall yield and in only three steps from a simple, protected
amino alcohol. Perhaps most notable is the chemo- and
The ketone product was reduced with NaBH4 in the same vessel. In all
cases ketone product constituted less than 8% of the aryl halide
derived product in the crude mixture (6:1 to >20:1 ratio of
ketone:alcohol), and reduction to the desired benzylic alcohol was
conducted to increase the yield of desired product. Product 14 can be
obtained in 70% yield without the reductive work-up utilizing the same
purification conditions as outlined in the Supporting information.
See Supporting Information for details. When the aldehyde was
subjected to the optimized reaction conditions aldehyde products
where observed by 1H NMR and GS-MS analysis.
[15]
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