Asymmetric Radical-Radical Cross-Coupling through Visible-Light-Activated Iridium Catalysis

Article abstract of DOI:10.1002/anie.201509524

Combining single electron transfer between a donor substrate and a catalyst-activated acceptor substrate with a stereocontrolled radical-radical recombination enables the visible-light-driven catalytic enantio- and diastereoselective synthesis of 1,2-amino alcohols from trifluoromethyl ketones and tertiary amines. With a chiral iridium complex acting as both a Lewis acid and a photoredox catalyst, enantioselectivities of up to 99% ee were achieved. A quantum yield of <1 supports the proposed catalytic cycle in which at least one photon is needed for each asymmetric C-C bond formation mediated by single electron transfer.

Full text of DOI:10.1002/anie.201509524

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201509524
German Edition: DOI: 10.1002/ange.201509524
Photoredox Catalysis
Hot Paper
Asymmetric Radical–Radical Cross-Coupling through Visible-Light-
Activated Iridium Catalysis
Chuanyong Wang, Jie Qin, Xiaodong Shen, Radostan Riedel, Klaus Harms, and Eric Meggers*
Abstract: Combining single electron transfer between a donor
substrate and a catalyst-activated acceptor substrate with
a stereocontrolled radical–radical recombination enables the
visible-light-driven catalytic enantio- and diastereoselective
synthesis of 1,2-amino alcohols from trifluoromethyl ketones
and tertiary amines. With a chiral iridium complex acting as
both a Lewis acid and a photoredox catalyst, enantioselectiv-
ities of up to 99% ee were achieved. A quantum yield of < 1
supports the proposed catalytic cycle in which at least one
À
photon is needed for each asymmetric C C bond formation
mediated by single electron transfer.
S
ingle electron transfer (SET) mediated reactions have
recently attracted much attention owing to the useful
reactivities of the intermediate radical ions or radicals,
which expand the mechanistic repertoire for developing
novel synthetic transformations.[1,2] In one mechanistic sce-
nario, a direct photoinduced electron exchange between two
involved substrates, one electron acceptor and one electron
donor, creates two odd-electron species, which then generate
a new s-bond upon radical–radical recombination. For
example, Mariano demonstrated the merit of this approach
with the photoredox chemistry of iminium salts,[3] whereas
MacMillan and co-workers introduced an elegant scheme
based on single electron oxidation and subsequent deproto-
nation of intermediate enamines, followed by a radical–
radical coupling.[4] However, for the photoredox-mediated
b-hydroxyalkylation[4b] and b-aminoalkylation[4c] of cyclic
ketones, only racemic products were reported, whereas for
the b-arylation of cyclohexanone with a cinchona-derived
aminocatalyst, a modest enantioselectivity of 50% ee was
achieved (Scheme 1).[4a] Rendering such reactions catalytic
and asymmetric is a formidable challenge owing to the
intrinsic reactivity of the involved odd-electron species.[5]
Herein, we report a catalytic asymmetric process that closely
interlocks a visible-light-activated SET between two sub-
strates with the stereocontrolled radical–radical cross-coup-
ling of an intermediate radical pair, namely the catalytic
enantio- and diastereoselective redox coupling of trifluoro-
Scheme 1. Linking (photoinduced) single electron transfer between
a donor substrate and an acceptor substrate to asymmetric radical–
radical recombination. The shown stereochemistry of the 1,2-amino
alcohol is based on an iridium catalyst with L configuration.
methyl ketones with tertiary amines to 1,2-diamino alco-
hols.[6–9] A process relevant to this study was published after
this manuscript had been submitted; Ooi and co-workers
reported a visible-light-activated coupling of N-aryl amino-
methanes with N-sulfonyl aldimines using an iridium photo-
sensitizer in combination with a chiral arylaminophospho-
nium salt, a reaction that is proposed to proceed through
a stereocontrolled radical anion–radical coupling.[10]
At the onset of our study, we envisioned that our
previously developed dual-function chiral Lewis acid/ photo-
redox catalysts[11] would be capable of directing SET from an
electron-rich substrate to a photoexcited catalyst-bound
electron-deficient substrate, followed by enantioselective
radical–radical cross-coupling controlled by the chiral envi-
ronment of the propeller-type iridium complex. When 2-
acetyl imidazole 1a was reacted with amine 2a in the presence
of D-IrO[12] (3 mol%) under visible-light irradiation with
a compact fluorescent lamp (CFL, 23 W), we were disap-
pointed to not observe even traces of the desired product 3a
(Table 1, entry 1). However, using the more electron-deficient
trifluoroacetyl imidazole 1b instead provided the coupling
product 3b with 69% yield and 97% ee (entry 2). Replacing
the solvent CH2Cl2 with CHCl3 improved the yield to 75%,
albeit with a slightly reduced enantioselectivity (entry 3). The
[*] C. Wang, J. Qin, X. Shen, R. Riedel, Dr. K. Harms, Prof. Dr. E. Meggers
Fachbereich Chemie, Philipps-Universität Marburg
Hans-Meerwein-Strasse 4, 35043 Marburg (Germany)
E-mail: meggers@chemie.uni-marburg.de
Prof. Dr. E. Meggers
College of Chemistry and Chemical Engineering
Xiamen University
Xiamen 361005 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509524.
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Table 1: Initial experiments and optimization of the visible-light-induced
[a]
À
asymmetric C C bond formation.
Entry
R
Catalyst
hn[b] Solvent Yield[c] [%] ee[d] [%]
1
2
3
4
5
6
7
8
9
CH3 D-IrO
CF3 D-IrO
CF3 D-IrO
CF3 D-IrO
CF3 D-IrO
CF3 D-IrO
CF3 D-IrS
CF3 D-IrS
CF3 D-IrS
CFL CH2Cl2
0
n.d.
97
95
68
11
n.d.
98.9
98.6
n.d.
n.d.
n.d.
n.d.
CFL CH2Cl2 69
CFL CHCl3 75
CFL EtOAc 42
CFL toluene 30
CFL MeCN
CFL CH2Cl2 72
CFL CHCl3 82
0
–
CHCl3
0
0
0
0
Scheme 2. Substrate scope with respect to N-methyl diarylamines.
Light source: 23 W CFL or 24 W blue LEDs. A crystal structure of 3h
was used to assign the absolute configuration of 3b–3j as S.
10
11
12
CF3
–
CFL CHCl3
CFL CHCl3
CF3 [Ru(bpy)3]Cl2·6H2O
CF3 [Ir(ppy)2(dtbbpy)]PF6 CFL CHCl3
[a] Reaction conditions: 2-Acyl imidazole 1a or 1b (0.2 mmol), aniline 2a
(0.6 mmol), and the catalyst (entries 1–9: 3.0 mol%, entry 11:
0.5 mol%, entry 12: 1.0 mol%) in the indicated solvent (0.4 mL) were
photolyzed for 22 h under an atmosphere of nitrogen. [b] Light source:
23 W CFL at a distance of approximately 5 cm from the Schlenk tube.
[c] Yields of isolated products. [d] Determined by HPLC analysis on
a chiral stationary phase. bpy=2,2’-bipyridine, dtbbpy=4,4’-di-tert-butyl-
2,2’-bipyridine, n.d.=not determined, ppy=2-phenylpyridine.
reaction is very sensitive to solvent effects, and other tested
solvents did not provide satisfactory results (entries 4–6).
With the catalyst D-IrS,[11a] the yields and enantioselectivities
could be further enhanced (entries 7 and 8). With CHCl3,
82% yield and excellent 98.6% ee were achieved. Control
experiments in the absence of the catalyst or in the dark
demonstrate that this reaction crucially depends on the
presence of the iridium catalyst and light; otherwise no
traces of product were observed (entries 9 and 10). It is also
Scheme 3. 2-Aryl 1,2,3,4-tetrahydroisoquinolines as amine substrates
for enantio- and diastereoselective reactions. Light source: 23 W CFL
or 24 W blue LEDs. Relative configurations were assigned based on
a crystal structure of 3k.
À
worth noting that the C C coupling product is not formed
irradiation (CFL), whereas others preferred blue light (blue
LEDs).
when the common photoredox sensitizers [Ru(bpy)3]-
Cl2·6H2O and [Ir(ppy)2(dtbbpy)]PF6 are used (entries 11
and 12).[2]
A plausible mechanism is shown in Figure 1a and starts
with the photoactivation of the iridium-coordinated trifluoro-
methyl ketone (step 1), which induces a single electron
transfer from a tertiary amine, thereby generating an amino
radical cation[13,14] aside from a reduced iridium complex,
which can be described as an iridium-coordinated ketyl
radical (step 2). This is followed by a proton transfer (step 3)
and a radical–radical cross-coupling between the electron-
rich a-aminoalkyl radical and the electron-deficient ketyl
radical (step 4), which is stereochemically controlled by the
chiral iridium complex. Finally, the product is replaced by new
substrate (step 5). Several mechanistic experiments support
Next, we evaluated the scope of the visible-light-activated
asymmetric aminoalkylation of trifluoromethyl ketones with
catalyst L-IrS. The reaction between 2-trifluoroacetyl imid-
azole 1b and various N-methyl diarylamines (2a–2h) pro-
vided the respective 1,2-amino alcohols (3b–3i) in satisfactory
yields (60–82%) and with high enantioselectivity (91–99% ee,
Scheme 2). The imidazole can also be replaced by a pyridyl
moiety (1c+2a!3j), and N-aryl 1,2,3,4-tetrahydroisoquino-
lines (2i–2m) can be used as substrates, affording the
corresponding products (3k–3o) with good diastereoselectiv-
ity (4.1 to 10:1 d.r.) and high enantioselectivity (94–98% ee;
Scheme 3). It is noteworthy that we found empirically that
certain reactions provided better results under white-light
À
this mechanism. First, in the presence of oxygen, the C C
coupling product was not formed, which is consistent with the
presence of intermediate radicals that react with oxygen
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that this mild method follows the spirit of sustainable
chemistry, not only because the activation energy is provided
by visible light as an abundant light source, but also because in
À
the course of the C C bond formation with the implementa-
tion of one or two new stereocenters, no waste products are
generated, thereby constituting perfect atom economy.
Acknowledgements
We are grateful to the German Research Foundation (ME
1805/11-1) and the University of Marburg for funding.
Keywords: asymmetric catalysis · electron transfer ·
photoredox catalysis · radicals
How to cite: Angew. Chem. Int. Ed. 2016, 55, 685–688
Angew. Chem. 2016, 128, 695–698
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Received: October 12, 2015
Published online: December 2, 2015
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