Catalytic Asymmetric Csp3?H Functionalization under Photoredox Conditions by Radical Translocation and Stereocontrolled Alkene Addition

Article abstract of DOI:10.1002/anie.201607305

This work demonstrates how photoredox-mediated C(sp³)?H activation through radical translocation can be combined with asymmetric catalysis. Upon irradiation with visible light, α,β-unsaturated N-acylpyrazoles react with N-alkoxyphthalimides in the presence of a rhodium-based chiral Lewis acid catalyst and the photosensitizer fac-[Ir(ppy)₃] to provide a C?C bond-formation product with high enantioselectivity (up to 97 % ee) and, where applicable, with some diastereoselectivity (3.0:1 d.r.). Mechanistically, the synthetic strategy exploits a radical translocation (1,5-hydrogen transfer) from an oxygen-centered to a carbon-centered radical with a subsequent stereocontrolled radical alkene addition.

Full text of DOI:10.1002/anie.201607305

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International Edition: DOI: 10.1002/anie.201607305
German Edition: DOI: 10.1002/ange.201607305
Asymmetric Catalysis
ꢀ
Catalytic Asymmetric Csp H Functionalization under Photoredox
3
Conditions by Radical Translocation and Stereocontrolled Alkene
Addition
Chuanyong Wang, Klaus Harms, and Eric Meggers*
Abstract: This work demonstrates how photoredox-mediated
3
C(sp )ꢀH activation through radical translocation can be
combined with asymmetric catalysis. Upon irradiation with
visible light, a,b-unsaturated N-acylpyrazoles react with N-
alkoxyphthalimides in the presence of a rhodium-based chiral
Lewis acid catalyst and the photosensitizer fac-[Ir(ppy) ] to
3
provide a CꢀC bond-formation product with high enantiose-
lectivity (up to 97% ee) and, where applicable, with some
diastereoselectivity (3.0:1 d.r.). Mechanistically, the synthetic
strategy exploits a radical translocation (1,5-hydrogen transfer)
from an oxygen-centered to a carbon-centered radical with
a subsequent stereocontrolled radical alkene addition.
3
Figure 1. Design strategy for combining free-radical C(sp )ꢀH activa-
A
range of powerful strategies have emerged for the
ꢀ
tion with catalytic, asymmetric C C bond formation. EWG=electron-
withdrawing group, SET=single-electron transfer.
functionalization of unactivated CꢀH bonds, including tran-
sition-metal-based CꢀH activation, metal carbenoid CꢀH
insertion, and the direct oxidation of CꢀH bonds or functional
[
1]
groups at its a-position. However, formidable challenges
still remain with respect to substrate scope, reaction con-
ditions, site selectivity, and the combination with asymmetric
catalysis.
kinetics of the individual steps, as well as the ability to control
the relative and absolute stereochemistry of the radical
[10–12]
reaction in a catalytic fashion.
We started our study by investigating the reaction of the
a,b-unsaturated N-acylpyrazole 1a with the N-alkoxyphtha-
limide 2a under photoredox conditions (Table 1). In the
Free-radical processes have been among the oldest
strategies for the controlled functionalization of unactivated
CꢀH bonds, such as the Barton and Hofmann–Lçffler–
presence of the previously developed dual function photo-
[
2]
[13]
Freytag reactions, and have attracted renewed attention,
in part due to recently developed methods for the generation
of reactive radicals in a mild and convenient fashion under
redox/chiral Lewis acid catalyst D-IrS
(3 mol%), under
irradiation with a 23 W compact fluorescent lamp (CFL), the
desired CꢀC bond formation product 3a was obtained in 85%
[
3]
photoredox conditions. Recently, Chen and co-workers
introduced a visible-light-induced release of alkoxy radicals
from N-alkoxyphthalimides and applied it to selective
yield after 20 hours, but to our disappointment, no enantio-
selectivity was observed (entry 1). Encouragingly, when the
[14]
chiral Lewis acid D-RhO (3 mol%), in combination with
3
C(sp )ꢀH functionalization by exploiting 1,5-hydrogen atom
the photosensitizer fac-[Ir(ppy) ] (1 mol%), was applied to
3
[
4–6]
[7,8]
transfer (1,5-HAT).
Radical translocation
has been
this system, the reaction proceeded in 60% yield and 18% ee
3
[15]
used extensively for the functionalization of remote C(sp )ꢀH
(entry 2). The enantioselectivity was improved to 79% ee
[
16]
bonds, but to our knowledge the combination with a catalytic
asymmetric CꢀC bond formation remains elusive. We there-
fore envisioned merging this photoredox-mediated CꢀH
when D-RhS (3 mol%) was used as the chiral Lewis acid
[
17]
(entry 3). At a catalyst loading of 8 mol%, even 92% ee
was reached (entry 6). Other photosensitizers, such as
[Ir(ppy) (dtbbpy)]PF and [Ru(bpy) ](PF ) , were inferior to
activation with asymmetric catalysis, as shown in Figure 1,
by trapping the intermediate (electron-rich) carbon-centered
radical in a stereocontrolled fashion with an acceptor-
2
6
3
6 2
fac-[Ir(ppy) ] (entries 4 and 5). The reaction is sensitive to
3
solvent effects (entries 7 and 8) and the light source, as blue
[
9]
substituted alkene catalyzed by a chiral Lewis acid. Chal-
lenges include the compatibility of the individual steps with
respect to the reactivity of the radical intermediates and the
LEDs provided
(entry 9).
a
somewhat lower enantioselectivity
Control experiments verified that both visible
light and Hantzsch ester are essential for product formation
entries 10 and 11). In the absence of the chiral Lewis acid
[
18]
(
D-RhS, 3a was still formed (75% yield), albeit as a racemic
mixture (entry 12). It is worth noting that in the absence of the
[
*] C. Wang, Dr. K. Harms, Prof. Dr. E. Meggers
Fachbereich Chemie, Philipps-Universitꢀt Marburg
Hans-Meerwein-Straße 4, 35043 Marburg (Germany)
E-mail: meggers@chemie.uni-marburg.de
photosensitizer fac-[Ir(ppy) ] (entry 13) or both D-RhS and
3
fac-[Ir(ppy) ] (entry 14), 3a was still generated but with
3
significantly reduced efficiency. UV/Vis-absorbance spectra
of the individual substrates and Hantzsch ester (see the
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607305.
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1
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[
a]
Table 1: Reaction development.
agent and transfers a single electron
to N-alkoxyphthalimide (redox
handle) under formation of an N-
alkoxyphthalimide radical anion,
which is subsequently protonated
by the oxidized Hantzsch ester
(radical cation), and then under-
goes a homolytic NꢀO cleavage
under formation of an alkoxy rad-
ical. This alkoxy radical now
engages in an intramolecular HAT
to yield a carbon-centered radi-
[
b]
[b]
[c]
[d]
[e]
Entry Catalyst
Sensitizer
hn
Sol.
t [h] Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
0
D-IrS (3.0)
D-RhO (3.0) fac-[Ir(ppy) ] (1.0)
D-RhS (3.0) fac-[Ir(ppy) ] (1.0)
D-RhS (3.0) [Ir(ppy) (dtbbpy)]PF (1.0) CFL
D-RhS (3.0) [Ru(bpy) ](PF ) (1.0)
D-RhS (8.0) fac-[Ir(ppy) ] (1.0)
D-RhS (8.0) fac-[Ir(ppy) ] (1.0)
D-RhS (8.0) fac-[Ir(ppy) ] (1.0)
D-RhS (8.0) fac-[Ir(ppy) ] (1.0)
D-RhS (8.0) fac-[Ir(ppy) ] (1.0)
D-RhS (8.0) fac-[Ir(ppy) ] (1.0)
none
D-RhS (8.0) none
none none
none
CFL
CFL
CFL
THF
THF
THF
THF
THF
THF
20
20
20
20
20
40
40
40
40
40
40
20
40
20
85
60
61
76
<5
70
13
21
69
0
0
18
79
36
n.d.
92
86
60
86
n.a.
n.a.
n.a.
92
[21,22]
3
cal,
which adds to a N,O-rho-
3
dium-coordinated N-acylpyrazole
substrate (Rh-I; see Figure 4a for
a crystal structure), thereby gener-
ating the secondary radical inter-
mediate Rh-II. This radical inter-
mediate is further trapped by the
Hantzsch ester radical to provide
the rhodium-bound product Rh-III.
The observed high enantioselectiv-
ity in this new process demonstrates
that the chiral Lewis acid D-RhS
strongly accelerates the radical
addition so that it is capable of
outcompeting the prevailing race-
2
6
CFL
CFL
CFL
CFL
3
6 2
3
CH Cl
3
2
2
DMF
3
blue LEDs THF
3
1
1
1
1
1
none
CFL
CFL
CFL
CFL
THF
THF
THF
THF
THF
3
[
f]
1
2
3
4
0
3
fac-[Ir(ppy) ] (1.0)
75
33
56
3
n.a.
[
a] Reaction conditions: The N-acylpyrazole 1a (0.4 mmol), the N-alkoxyphthalimide 2a (0.2 mmol),
and the Hantzsch ester (none or 0.3 mmol) with catalyst (none, 3.0, or 8.0 mol%) and sensitizer (none
or 1.0 mol%) in solvent (1.0 mL) at RT for 20–40 h under an atmosphere of nitrogen. [b] Catalyst or
sensitizer loading provided as mol% within parentheses. [c] 23 W compact fluorescent lamp (CFL) or
[
9,17]
mic background reaction.
6
W blue LEDs. [d] Yield of isolated product. [e] Enantiomeric excess determined by HPLC on chiral
stationary phase. [f] Control experiment without Hantzsch ester. n.a.=not applicable, n.d.=not
determined, DMF=N,N-dimethylformamide, ppy=phenylpyridyl, THF=tetrahydrofuran.
Several experiments support
this mechanism. First, the expected
byproducts
isoindoline-1,3-dione
Supporting Information) suggest that this must be due to the
direct photoexcitation of the Hantzsch ester.
and diethyl 2,6-dimethylpyridine-3,5-dicarboxylate could be
isolated (see the Supporting Information for more details).
[
19]
[23]
After the optimized reaction conditions were established,
we next tested the substrate scope of the asymmetric photo-
Second, Stern–Volmer plots (Figure 4b) reveal that the
luminescence emission of fac-[Ir(ppy) ] is quenched effi-
3
3
induced C(sp )ꢀH functionalization. Table 2 shows that the
Table 2: Substrate scope with respect to a,b-unsaturated N-acylpyrazo-
reaction of a variety of 2-acyl pyrazoles (1a–j) with 2a in the
[
a]
les.
presence of D-RhS, fac-[Ir(ppy) ], and the Hantzsch ester,
3
while under illumination with visible light, provided the
expected CꢀC formation products 3a–j in 51–80% yields and
8
2–97% ee. The reaction was tolerant of aliphatic substituents
(3a–f) and aromatic moieties with electron-rich groups (3i,j).
Notably, the ethoxy- and benzyloxy-substituted 1g and 1h,
respectively, are favorable here, thus affording the corre-
sponding products 3g and 3h in good yields and high
stereoselectivities. To further expand the scope, a wide
range of tertiary N-alkoxyphthalimides were applied to the
reaction (Figure 2), thus affording the adducts in yields of 57–
[b]
[c]
Entry
R
t [h]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
Me (1a)
Et (1b)
nPr (1c)
iPr (1d)
iBu (1e)
cyclohexyl (1 f)
OEt (1g)
OBn (1h)
2,4-dimethylphenyl (1i)
4-methoxyphenyl (1j)
40
48
50
50
48
65
48
48
60
48
70 (3a)
67 (3b)
65 (3c)
62 (3d)
62 (3e)
74 (3 f)
80 (3g)
78 (3h)
51 (3i)
57 (3j)
92
93
92
94
91
91
97
97
91
82
8
5% and with 86–97% ee (3k–s). Secondary N-alkoxyphtha-
limides with aromatic substitutents were also suitable for the
reaction and afforded the corresponding products (3t–u) with
diastereoselectivities of up to 3:1 and enantioselectivities of
up to 97% ee. Notably, this a-heteroatom activation is not
limited by oxygen, as a-sulfur-activated CꢀH bonds also work
10
[
(
a] Reaction conditions: N-Acylpyrazole (1a–j; 0.4 mmol), 2a
0.2 mmol), and Hantzsch ester (0.3 mmol) with catalyst (8.0 mol%)
and sensitizer (1.0 mol%) in THF (1.0 mL) at RT for 40–65 h under an
atmosphere of nitrogen. [b] Yield of isolated product. [c] Enantiomeric
excess determined by HPLC using a chiral stationary phase. phth=
N-phthalimide.
well under standard reaction conditions (3v,w).
A plausible mechanism is shown in Figure 3 and starts
with the photoactivation of fac-[Ir(ppy) ], whose excited state
3
[20]
[
Ir(ppy) ]* is reductively quenched by the Hantzsch ester.
Thereby generated fac-[Ir(ppy) ] serves as a strong reducing
3
ꢀ
3
2
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Figure 4. Mechanistic experiments. BHT=3,5-di-tert-butyl-4-hydroxyto-
luene.
ciently by the Hantzsch ester, in contrast to either substrate
a or 2a, and supports the proposed catalytic mechanism in
1
which electron transfer from the Hantzsch ester to the excited
*
state fac-[Ir(ppy) ] occurs and is at the center of the redox
3
process. Third, the presence of air or the radical inhibitor
BHT (5 equiv) results in a reduced yield and enantioselec-
tivity of the CꢀC-formation product 3a, which provides
Figure 2. Substrate scope with respect to N-alkoxyphthalimides. An
evidence for a radical pathway (Figure 4c). The proposed
intermediate carbon-centered radical was verified by a trap-
ping experiment with a competing electron-deficient alkene
[
25]
X-ray crystal structure of 3r was obtained to assign the absolute
configuration of the products (see the Supporting Information).
dmp=3,5-Dimethylpyrazole, phth=N-phthalimide.
(
Figure 4d). Finally, we determined a quantum yield of 0.05
for the reaction 1a+2a!3a which is consistent with the
proposed absence of a chain process.
[24]
3
In summary, we here demonstrated how C(sp )ꢀH bond
functionalization through radical translocation can be merged
with a catalytic asymmetric CꢀC bond formation by combin-
ing visible-light-activated photoredox catalysis with chiral
Lewis acid catalysis. We believe that this method is of
significant practical value since it makes use of the function-
3
alization of unactivated C(sp )ꢀH bonds, and at the same time
introduces two stereocenters. It employs simple activating
groups, namely N-alkoxyphthalimides as recently developed
[4]
redox-active radical precursors, as well as N-acylpyrazoles
as Lewis-acid-activatable functional groups. It is worth noting
that N-acylpyrazoles are highly useful precursors for mild
conversion into other carbonyl functionalities with high
yields, as shown for the representative conversion into an
amide (3q!3q’) and a diol (3q!3q’’; Figure 5). The
extension of this methodology to the activation of other
3
remote C(sp )ꢀH groups is underway in our laboratory.
Acknowledgments
Funding from the Deutsche Forschungsgemeinschaft (ME
1805/13-1) is gratefully acknowledged.
Figure 3. Proposed mechanism which is consistent with the observed
product formation and the mechanistic experiments.
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[
Received: July 28, 2016
Revised: August 29, 2016
Published online: && &&, &&&&
4
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Communications
Asymmetric Catalysis
The light combo: Through radical trans-
location, a photoredox-mediated C(sp )ꢀ
3
C. Wang, K. Harms,
E. Meggers*
H activation was combined with asym-
metric catalysis. Upon irradiation with
visible light, a,b-unsaturated N-acylpyra-
zoles react with N-alkoxyphthalimides in
the presence of a rhodium-based chiral
Lewis acid catalyst and the photosensi-
&&&& — &&&&
Catalytic Asymmetric Csp
3
ꢀH
Functionalization under Photoredox
Conditions by Radical Translocation and
Stereocontrolled Alkene Addition
tizer fac-[Ir(ppy) ] to provide a CꢀC bond-
3
formation product with high enantiose-
lectivity and, where applicable, with some
diastereoselectivity.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!