Catalytic, Enantioselective Addition of Alkyl Radicals to Alkenes via Visible-Light-Activated Photoredox Catalysis with a Chiral Rhodium Complex

Article abstract of DOI:10.1021/jacs.6b03399

An efficient enantioselective addition of alkyl radicals, oxidatively generated from organotrifluoroborates, to acceptor-substituted alkenes is catalyzed by a bis-cyclometalated rhodium catalyst (4 mol %) under photoredox conditions. The practical method provides yields up to 97% with excellent enantioselectivities up to 99% ee and can be classified as a redox neutral, electron-transfer-catalyzed reaction.

Full text of DOI:10.1021/jacs.6b03399

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Communication
Catalytic, Enantioselective Addition of Alkyl Radicals to Alkenes via Visible-
Light-Activated Photoredox Catalysis with a Chiral Rhodium Complex
Haohua Huo, Klaus Harms, and Eric Meggers
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b03399 • Publication Date (Web): 24 May 2016
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Catalytic, Enantioselective Addition of Alkyl Radicals to Al-
kenes via Visible-Light-Activated Photoredox Catalysis with a
Chiral Rhodium Complex
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Haohua Huo,† Klaus Harms,† and Eric Meggers*,†,‡
†
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany
‡ College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, People’s Republic of China
ABSTRACT: An efficient enantioselective addition of al-
kyl radicals, oxidatively generated from organotrifluorob-
orates, to acceptor-substituted alkenes is catalyzed by a
bis-cyclometalated rhodium catalyst (4 mol%) under pho-
toredox conditions. The practical method provides yields
up to 97% with excellent enantioselectivities up to 99% ee
and can be classified as a redox neutral, electron-transfer-
catalyzed reaction.
Enantioselective & Catalytic Free Radical Addition to Alkenes
Challenge:
Fast background radical reaction due to high radical reactivity
R2
R2
EWG
R1
EWG
R1
EWG
R1
Sibi (1997)
O
O
N
N
(5 mol%)
O
O
O
O
MgI2 (5 mol%)
The renaissance of single electron transfer activated
chemistry has recently redirected some focus to the
chemistry of the involved odd electron species, such as
organic radicals.1-3 Whereas elementary reactions of or-
ganic radicals are well understood, controlling their ste-
reoselective chemistry in a practical reaction setting is
still a formidable challenge that needs to be addressed.4
For example, although the addition of nucleophilic alkyl
radicals to electron deficient alkenes is an established and
much applied C-C bond formation reaction, efficient cata-
lytic enantioselective versions are still limited and this
can be pinpointed to the high background (uncatalyzed)
reactivity of the involved alkyl radicals.5 Sibi and co-
workers reported one of the most impressive examples of
chiral Lewis acid catalysis in conjugate radical additions,
namely using a magnesium bisoxazoline complex at 5
mol% loading for catalyzing the enantioselective conju-
gate isopropyl radical addition to an oxazolidinone cin-
namate (Figure 1).6 However, the reaction needs equimo-
lar amounts of a toxic stannane and is executed at -78 °C
to achieve such low catalyst loading. Recently, Yoon and
coworkers reported a catalytic enantioselective addition
of α-aminoalkyl radicals to α,β-unsaturated carbonyl
compounds under photoredox conditions.7,8 However,
catalyst loadings of the employed chiral scandium com-
plex are fairly high and the system is limited to silanes
with amines in α-position. Here we wish to report our
progress into this direction, namely a very efficient and
practical enantioselective addition of alkyl radicals, re-
leased from organotrifluoroborates, to acceptor-
substituted alkenes via chiral rhodium catalysis under
photoredox conditions.
N
Ph
N
Ph
O
O
iPrI, Bu3SnH
Et3B/O2, -78 °C
92% yield, 90% ee
Yoon (2015)
O
N
O
Me
N
N
Me3Si
O
N
Ar
O
R1 Me
(20 mol%)
iBu
iBu
O
+
N
Sc(OTf)3 (15 mol%)
Bu4N+Cl- (30 mol%)
N
N
Ar
O
R1
Et
Me
N
N
Me
[Ru(bpy)3]Cl2 (2 mol%)
visible light
up to 96% yield
up to 96% ee
Et
Me
Me
-
+ PF6
tBu
This study
S
N
Me
C
N
(4 mol%)
Rh
N
N
C
Me
tBu
S
O
O
X
R2
R1
R2 BF3-K+
+
X
R1
sensitizer (2 mol%)
blue LEDs, r.t.
up to 97% yield
up to 99% ee
N
N
N
Me
X =
N
R
Me
Figure 1. Previous work and this study on catalytic enanti-
oselective radical additions to acceptor-substituted alkenes.
Inspired by recent work of Molander and coworkers on
using organotrifluoroborates as precursors for radicals
under oxidative photoredox conditions,9 we started our
study by investigating the reaction of the α,β-unsaturated
acyl imidazole 1a with potassium benzyltrifluoroborate 2a
under photoredox conditions (Table 1). Disappointingly,
in the presence of the previously developed dual function
photoredox /chiral Lewis acid catalysts Λ-IrO or Λ-IrS
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under visible light irradiation,10 no desired C-C bond for-
product 3c was still generated in 29% yield, albeit as a
racemic mixture (entry 11).15 This observation demon-
strates that Λ-RhS must strongly accelerate the radical
addition in order to overcome the prevailing racemic
background reaction.
1
2
3
4
5
6
7
8
mation product 3a was detectable (entries 1-2). The pres-
ence of an additional photosensitizer did not improve the
result (entry 3). Encouragingly, when the chiral Lewis acid
Λ-RhO11 in combination with the photosensitizer 4 was
applied to this system, the reaction proceeded in 43%
yield and with 79% ee.12 The newly developed Lewis acid
Λ-RhS,13 which provides an increased steric hindrance
due to long C-S bonds, afforded the product 3a with an
improved yield of 67% and 88% ee (entry 5). An optimiza-
tion of the imidazole auxiliary by replacing the N-methyl
(1a) with an isopropyl (1b) or a phenyl (1c) substituent,
improved the enantioselectivity to 93% ee (3b) and 94%
ee (3c), respectively (entries 6 and 7). Using the substrate
1c in combination with the less expensive organic sensi-
tizer 514 provided the C-C formation product even with
96% ee (entry 8). Meanwhile, control experiments veri-
fied that the photosensitizer and visible light are essential
for product formation (entries 9 and 10). However, in ab-
sence of the chiral Lewis acid Λ-RhS, the radical addition
Next, we evaluated the scope of the visible-light-
induced enantioselective addition of trifluoroborate 2a to
electron-deficient alkenes 1c-k, providing the C-C bond
formation products 3c-k with 40-90% yields and 83-96%
ee (Figure 2). Figure 2 summarizes the effect of various
alkene substituents. The reaction is tolerant of aliphatic
substituents (3c-f), an ether (3g), and aromatic moieties
with electron-rich or electron-deficient groups (3h-k). It
is noteworthy that depending on the particular alkene,
different N-imidazole substituents provide the best re-
sults as can be seen by the comparison of 3d with 3d′ (Me
favored) and 3e with 3e′ (iPr favored), which allows for an
individual optimization of yields and enantioselectivities.
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Table 1. Initial experiments to identify an optimal cata-
lyst/sensitizer combinationa
Figure 2. Substrate scope with different 2-acyl imidazoles.
The scope of this reaction with respect to organotri-
fluoroborates is outlined in Figure 3. A wide range of tri-
fluoroborates (2b-p), ranging from benzyltrifluoroborates
with electron withdrawing and electron donating substit-
uents, various alkoxylmethyltrifluoroborates, secondary
alkyltrifluoroborates, and tertiary alkyltrifluoroborates,
can be used in this reaction providing the products 3l-z in
yields of 61-97% and with 77-99% ee.
Next, to improve the practical utility of this reaction,
we were seeking a synthetically more versatile class of
alkene substrates and we found that α,β-unsaturated N-
acyl-3,5-dimethylpyrazoles (6a-e) react readily with ben-
zyltrifluoroborates (2a-e) under our developed reaction
conditions to provide the C-C bond formation products
7a-g in yields of 54-75% and with 83-97% ee (Figure 4).
Finally, the conversion of two typical products, one imid-
azole and one pyrazole, to useful synthetic building
blocks is illustrated in Figure 5. Cleavage of the pyrazole
auxiliary in 7e under reductive conditions afforded the
alcohol 7e′ quantitatively and with unchanged ee.16 On
entry catalyst sensitizer
substrate yield (%)c ee (%)d
hνb
1
none
yes 1a
yes 1a
yes 1a
yes 1a
yes 1a
yes 1b
yes 1c
yes 1c
no 1c
yes 1c
yes 1c
0
n.a.
n.a.
n.d.
79
Λ-IrO
Λ-IrS
Λ-IrS
2
3
none
0
4
<5
43
67
66
73
73
0
4
5
6
7
8
9
10
4
Λ-RhO
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
none
4
88
4
93
4
94
5
96
4
n.a.
n.a.
0
none
0
11
4
29
a
Conditions: 1a-c and 2a (1.5 eq) with catalyst (none or 4
mol%), and photosensitizer (none or 2 mol%) in ace-
tone/H2O (1:1) at r.t. for 4-6 h under irradiation with visible
b
c
d
light. Light source: 24 W blue LEDs. Isolated yields. En-
antioselectivities of 3a-c determined by HPLC on chiral sta-
tionary phase. n.a. = not applicable, n.d. = not determined.
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the other hand, the removal of the imidazole moiety of
1
2
3
3w smoothly proceeded to provide ethyl ester 3w′ in 90%
yield and with unchanged ee.17
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Figure 5. Transformation of selected products.
Figure 6. Proposed simplified mechanism without indicating
possible chain transfer. SET = single electron transfer, PS =
photosensitizer.
Figure 3. Substrate scope regarding organotrifluoroborates.
Stern-Volmer plots and TEMPO trapping experiments
support the intermediate generation of alkyl radicals from
organotrifluoroborates induced by SET from the photoex-
cited sensitizer. Thirdly, product deuteration upon per-
forming the reaction in acetone/D2O is consistent with
the proposed SET/protonation sequence as opposed to an
alternative H-abstraction from acetone. Finally, quantum
yield measurements under consideration of competing
light absorption and quenching effects from rhodium
complexes, and other deactivation pathways suggest that
radical intermediate II does not only accept a single elec-
tron from the reduced photosensitizer but alternatively
from an organotrifluoroborate substrate molecule, there-
by leading to a chain process (see Supporting Information
for more details).19
According to the described mechanism, it is unusual
that with catalyst loadings of just 4 mol%, enantioselec-
tivities of up to 99% ee can be obtained, and all this even
at room temperature. Apparently, the radical addition to
the double bond of free substrate (background reaction)
cannot compete with the radical addition to rhodium-
coordinated substrate (Lewis acid catalyzed reaction).
This is counterintuitive considering the high reactivity of
alkyl radicals towards acceptor-substituted alkenes com-
bined with the fact that at the beginning of the reaction
free substrate is in large excess (25-fold) over rhodium-
coordinated substrate. The rhodium-based Lewis acid
must therefore provide a strong acceleration of the radical
addition. This is indeed the case as determined by compe-
Figure 4. 2-Acyl pyrazoles as substrates.
The proposed mechanism is shown in Figure 6. The re-
action is initiated by the now well-established photosensi-
tized oxidative conversion of organotrifluoroborates to
carbon-centered radicals,9,18 which in turn add to N,O-
rhodium-coordinated 2-acyl imidazole or N-acyl pyrazole
substrate (intermediate I, see Supporting Information for
a crystal structure with an N-acyl pyrazole substrate),
thereby generating the secondary radical intermediate II,
which is subsequently reduced by SET to a rhodium eno-
late (intermediate III), which upon protonation by water
provides rhodium-bound product (intermediate IV).
A number of control experiments back this mechanism.
Firstly, visible light and photosensitizer are required for
product formation (Table 1, entries 9 and 10). Secondly,
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(8) For a stereoselective conjugate addition of α-aminoalkyl
tition experiments shown in Figure 7: rhodium coordina-
tion increases the radical addition rate by at least a factor
of 3 x 104. This acceleration is obviously the reason for the
ability to perform the developed enantioselective radical
reaction with low loadings of the chiral Lewis acid.
1
2
3
4
5
6
7
8
radicals using a stoichiometric chiral template, see: Lenhart, D.;
Bauer, A.; Pöthig, A.; Bach, T. Chem. Eur. J. 2016, 22, 6519.
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345, 433. (b) Primer, D. N.; Karakaya, I.; Tellis, J. C.; Molander, G.
A. J. Am. Chem. Soc. 2015, 137, 2195. (c) Gutierrez, O.; Tellis, J. C.;
Primer, D. N.; Molander, G. A.; Kozlowski, M. C. J. Am. Chem.
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Figure 7. Evaluating the acceleration of the radical addition
step by rhodium coordination.
In conclusion, we have developed a very efficient and
practical catalytic enantioselective addition of organotri-
fluoroborates to acceptor-substituted alkenes under pho-
toredox conditions. Key feature is a rhodium-based Lewis
acid which not only provides an excellent stereocontrol
but also accelerates the involved key radical addition step
by at least four to five orders of magnitude, thereby laying
the foundation for the low catalyst loadings for this radi-
cal reaction.
(13) Ma, J.; Shen, X. Harms, K.; Meggers, E. Dalton Trans. 2016,
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ASSOCIATED CONTENT
Supporting Information. Experimental details and chiral
HPLC traces. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
meggers@chemie.uni-marburg.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(16) Tokumasu, K.; Yazaki, R.; Ohshima, T. J. Am. Chem. Soc.
2016, 138, 2664.
We gratefully acknowledge funding from the German Re-
search Foundation (ME 1805/13-1). H.H. thanks the China
Scholarship Council for a stipend.
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Soc. 2005, 127, 8942. (b) Evans, D. A.; Fandrick, K. R. Org. Lett.
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