Aerobic Asymmetric Dehydrogenative Cross-Coupling between Two C sp 3 -H Groups Catalyzed by a Chiral-at-Metal Rhodium Complex

Article abstract of DOI:10.1002/anie.201506273

A sustainable C-C bond formation is merged with the catalytic asymmetric generation of one or two stereocenters. The introduced catalytic asymmetric cross-coupling of two Csp3-H groups with molecular oxygen as the oxidant profits from the oxidative robustness of a chiral-at-metal rhodium(III) catalyst and exploits an autoxidation mechanism or visible-light photosensitized oxidation. In the latter case, the catalyst serves a dual function, namely as a chiral Lewis acid for catalyzing enantioselective enolate chemistry and at the same time as a visible-light-driven photoredox catalyst. Green stuff: A sustainable C-C bond formation is merged with the catalytic asymmetric generation of one or two stereocenters by combining asymmetric enolate chemistry with either autoxidation or visible-light photosensitized oxidation. The robustness of a chiral-at-metal rhodium(III) catalyst serves to facilitate the reaction. PMP=para-methoxyphenyl, TFA=trifluoroacetic acid.

Full text of DOI:10.1002/anie.201506273

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201506273
German Edition: DOI: 10.1002/ange.201506273
CÀH Activation
Aerobic Asymmetric Dehydrogenative Cross-Coupling between Two
À
Csp
3
H Groups Catalyzed by a Chiral-at-Metal Rhodium Complex
Yuqi Tan, Wei Yuan, Lei Gong,* and Eric Meggers*
Abstract: A sustainable CÀC bond formation is merged with
the catalytic asymmetric generation of one or two stereocenters.
The introduced catalytic asymmetric cross-coupling of two
Csp
3
ÀH groups with molecular oxygen as the oxidant profits
from the oxidative robustness of a chiral-at-metal rhodium(III)
catalyst and exploits an autoxidation mechanism or visible-
light photosensitized oxidation. In the latter case, the catalyst
serves a dual function, namely as a chiral Lewis acid for
catalyzing enantioselective enolate chemistry and at the same
time as a visible-light-driven photoredox catalyst.
T
he construction of CÀC bonds from two CÀH bonds under
oxidative conditions has been identified as a highly attractive
conversion from ecological and economical aspects as it
avoids waste from the implementation and removal of
reactive functional groups and therefore also reduces the
[1]
number of reaction steps. Despite great progress being
made, key challenges remain. Firstly, current methods rely too
often on oxidation reagents which produce undesired waste,
whereas molecular oxygen as the ideal “green” oxidant
[
2,3]
suffers from poor reactivity.
Secondly, combining dehy-
drogenative cross-coupling with asymmetric catalysis remains
a formidable challenge, but gains importance because of the
increasing structural complexity of bioactive molecules
[
4]
resulting from one or multiple stereocenters. In one of the
most attractive scenarios, two CÀH groups are coupled in
a catalytic and asymmetric fashion by the formation of a new
CÀC bond, including at least one stereocenter, while molec-
ular oxygen serves as the oxidant (Figure 1). Only very few
studies report such a combination of dehydrogenative cross-
[5]
coupling, asymmetric catalysis, and aerobic conditions. With
respect to the coupling of two Csp
ÀH groups, Cui, Jiao, and
co-workers introduced the a-alkylation of aldehydes using
3
[
5a]
Figure 1. Previous work and this study on the areobic catalytic
asymmetric cross-dehydrogenative cross-coupling of two Csp
groups. DNBS=2,4-dinitrobenzenesulfonic acid, TFA=trifluoroacetic
acid, TMS=trimethylsilyl.
combined enamine and acid catalysis (Figure 1a), Xu and
co-workers disclosed the b-alkylation of aldehydes using
combined oxidative enamine and palladium catalysis (Fig-
3
ÀH
[
5c]
ure 1b), and Kim and co-workers reported the combination
of oxidative enamine chemistry with an intramolecular 1,5-
[
*] Y. Tan, W. Yuan, Dr. L. Gong, Prof. Dr. E. Meggers
Key Laboratory for Chemical Biology of Fujian Province and Depart-
ment of Chemical Biology
College of Chemistry and Chemical Engineering, Xiamen University
Xiamen 361005 (P.R. China)
[
5d]
hydride shift (Figure 1c). All these methods rely on the use
of an aldehyde substrate together with a chiral secondary
amine catalyst at high loadings of 10–20 mol%.
We started our study on this topic by investigating an
asymmetric Mannich reaction between 2-acyl imidazoles and
imino esters, thus considering it as the first step towards an
asymmetric cross-dehydrogenative coupling. In previous
work we demonstrated that the chiral-at-rhodium complex
L-Rh (for structure see Table 1) is capable of catalyzing the
a-amination of 2-acyl imidazoles through the formation of
E-mail: gongl@xmu.edu.cn
meggers@xmu.edu.cn
Prof. Dr. E. Meggers
Fachbereich Chemie, Philipps-Universitꢀt Marburg
Hans-Meerwein-Straße 4, 35043 Marburg (Germany)
E-mail: meggers@chemie.uni-marburg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506273.
[
6]
a coordinated rhodium enolate. Trapping such chiral metal
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Table 1: Initial experiments and optimization of an asymmetric Mannich
reaction.
Table 2: Optimization of the reaction conditions for the tandem
autoxidation/Mannich reaction.
[
a]
[a]
[
c]
Entry Ox. Additive
Solvent
CH Cl
T
t
Yield d.r.
ee
[%]
[
b]
[d]
[
8C] [h] [%]
1
2
3
4
5
6
7
8
air none
O2 none
O2 none
O2 none
O2 none
O2 none
RT 30
26 12:1
31 12:1
35 12:1
56 14:1
62 14:1
7:1
84 10:1
85 12:1
99
99
99
98
98
96
95
98
2
2
2
CH Cl
RT 30
RT 30
30 30
35 30
40 48
40 19
40 36
2
NMP
NMP
NMP
NMP
1
2
[b]
[d]
66
Entry
R
R
Catalyst
T [8C]
t
Yield d.r.
ee
[%]
[
c]
[e]
O2 TFA (0.2 equiv) NMP
O2 TFA (0.02 equiv) NMP
[h] [%]
1
2
3
4
5
6
7
8
Me Et
Me Et
L-Rh (2.0 mol%)
L-Rh (2.0 mol%) À20 10
RT
1
97
96
97
96 24:1
98 27:1
95 21:1
2:1
4:1
9:1
99.2
99.6
99.5
99.5
99.6
98.6
[
a] Reaction conditions: 5.0 equiv of 4 and 2 mol% of L-Rh. See the
Supporting Information for details. [b] Yield of isolated product.
Me iPr L-Rh (2.0 mol%) À20 10
Me tBu L-Rh (2.0 mol%) À20 10
iPr tBu L-Rh (2.0 mol%) À20 10
iPr tBu L-Rh (0.5 mol%) À20 52
1
[c] Determined by H NMR spectroscopy. [d] Determined by HPLC
analysis using a chiral stationary phase. NMP=N-methylpyrrolidine.
iPr tBu L-Ir (2.0 mol%)
RT 25
84
1:1.7 69
n.d. n.d.
[
f]
iPr tBu L-Ir (2.0 mol%) À20 30 <5
[a] Reaction conditions: 1.5 equiv of iminoester. See the Supporting
Information for details. [b] Catalyst loading given in brackets. [c] Yield of
1
isolated product. [d] Determined by H NMR spectroscopy. [e] Deter-
mined by HPLC analysis using a chiral stationary phase. [f] Conversion
1
determined by H NMR spectroscopy.
enolate intermediates with electrophilic imino esters would
provide two stereocenters, possibly in a stereocontrolled
fashion. Indeed, when we reacted the 2-acyl imidazole 1a with
the p-methoxyphenyl (PMP)-protected imino ester 2a in the
presence of 2 mol% L-Rh, we obtained the Mannich product
3
a in high yield (97%) and almost perfect enantioselectivity
(
(
99.2% ee), but with poor diastereoselectivity of 2:1 d.r.
entry 1). Reducing the temperature to À208C (entry 2), and
replacing the ethyl ester with either an iPr ester (2b; entry 3)
or a tBu ester (2c; entry 4) improved the diastereoselectivity.
Finally, when we used 2c in combination with a 2-acyl
imidazole in which the N-methyl group was replaced with
a more bulky iPr group (1b), the best results were obtained,
thus providing a 27:1 d.r. with an excellent ee value of 99.6%
Figure 2. Scope for the tandem autoxidation/Mannich reaction cata-
lyzed by L-Rh.
(
0
entry 5). It also allowed a reduced catalyst loading of
phere of oxygen instead of air (entry 2), switching to
N-methylpyrrolidine (NMP) as the solvent (entry 3), and
raising the temperature to 408C (entries 4–6). Finally, adding
catalytic amounts of trifluoroacetic acid (TFA; entries 7 and
8), presumably to eliminate H O from a hydroperoxide
.5 mol% (entry 6). It is noteworthy that the analogous
[7]
iridium catalyst
did not provide satisfactory results
(
entries 7 and 8).
Since imino esters related to 2a–c were recently reported
to be accessible by autoxidation of the corresponding glycine
2
2
[
9,11]
intermediate,
further improved the results. Thus, when
[
8,9]
esters,
we were envisioning the merging of both processes,
executed in NMP with 2 mol% TFA under an atmosphere of
oxygen at 408C, the reaction of 1b with 4 provided the cross-
dehydrogenative coupling product 3d in 85% yield with
a satisfactory 12:1 d.r. and excellent ee value of 98%
(entry 8). The substrate scope is shown in Figure 2 and
demonstrates the generality of this straightforward method-
ology.
namely the developed asymmetric Mannich reaction and the
described autoxidation of glycine esters, into a single asym-
metric catalytic cross-dehydrogenative coupling.
[10]
Indeed,
when we reacted the acyl imidazole 1b with the PMP-
protected glycine ester 4 in the presence of air at room
temperature for 30 hours, we obtained the desired CÀC bond
formation product 3d with an excellent ee value of 99% and
Next, we wondered whether this rhodium-catalyzed
asymmetric CÀH cross-coupling with oxygen as the oxidant
1
2:1 d.r., albeit with a low yield of 26% (Table 2, entry 1).
However, the yield could be improved by using an atmos-
could be extended to amine substrates which are not activated
2
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Chemie
Table 3: Initial experiments and optimization of photoinduced asymmetric dehydrogenative CÀC bond deprotonation (Figure 4). The
[
a]
formation.
hereby generated intermediate
nucleophilic enolate complex then
reacts in a stereocontrolled fashion
with the in situ, oxidatively gener-
ated carbon electrophiles, which
can either be an imine that is
formed through autoxidation of
Entry
Catalyst
R
Reaction
conditions
Solvent
T
[8C]
t
[h]
Yield
[%]
ee
[%]
[
b]
[c]
[d]
[9,10]
the corresponding glycine ester
1
2
3
4
5
6
7
8
9
L-Rh (2.0 mol%)
L-Rh (2.0 mol%)
L-Rh (2.0 mol%)
L-Rh (2.0 mol%)
L-Rh (2.0 mol%)
L-Rh (2.0 mol%)
L-Rh (2.0 mol%)
L-Rh (2.0 mol%)
none
iPr
iPr
iPr
iPr
iPr
Ph
Ph
Ph
Ph
Ph
Ph
O , TFA (2 mol%)
NMP
NMP
NMP
NMP
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
40
60
48
48
48
48
48
48
36
22
24
24
36
6
8
98
95
98
98
98
94
95
96
or an iminium ion formed by photo-
2
O , TFA (2 mol%)
2
sensitized oxidation of the corre-
O
2
, white light
22–23
22–23
22–23
22–23
22–23
22–23
22–23
22–23
22–23
16
18
34
66
45
80
0
[13]
sponding N,N-dialkylaniline.
In
air, white light
air, white light
air, white light
air, UV light
air, blue LED
air, blue LED
argon, blue LED
air, blue LED
the latter case, the rhodium com-
plex does not only serve as a catalyst
for the enantioselective enolate
chemistry, but also functions as
n.d.
n.d.
n.d.
a visible-light-activated photoredox
10
1
L-Rh (2.0 mol%)
L-Ir (2.0 mol%)
0
3
[14,15]
catalyst.
Accordingly, a photo-
rhodium sensitizer
1
activated
[
a] Reaction conditions: 3.0 equiv of 5a under the shown conditions. [b] 24 W compact fluorescence
removes an electron from the N,N-
dialkylaniline, thus leading to a rad-
ical cation which undergoes rapid a-
deprotonation to afford an a-ami-
light bulb, 24 W blue LED, or 16 W UV light (365 nm). [c] Yield of isolated product. [d] Determined by
HPLC analysis using a chiral stationary phase. n.d.=not determined.
by a carboxylic ester in the a-position. Thus we started to
investigate the reaction of the acyl imidazole 1b with N,N-
dimethylaniline (5a; Table 3). When reacted under the
optimized reaction conditions (see Table 2), less than 10%
of the CÀC coupling product was identified, and increasing
the temperature to 608C did not improve the yield signifi-
cantly (Table 3, entries 1 and 2). However, in the presence of
white light instead of heating, the CÀC coupling product 6a
was obtained in 16% yield and 98% ee (entry 3). The
observation of a diketone oxidation side-product led us use an
air atmosphere instead of oxygen, and thus afforded 6a in
1
8% yield and 98% ee (entry 4). Optimization of the reaction
conditions by switching to the solvent DMSO (entry 5), and
using the substrate 1j bearing a phenyl instead of isopropyl
substituent at the imidazole (entry 6) increased the yield to
6
6% with 94% ee (product 6b). Using UV-light instead of
white light did not improve the results significantly (entry 7).
However, under illumination with blue light, optimal reaction
conditions were obtained: Just using air as the oxidant at
room temperature in the presence of 2 mol% of L-Rh
afforded the CÀC coupling product in 80% yield and with
Figure 3. Substrate scope for the photoinduced asymmetric CÀC bond
formation catalyzed by L-Rh.
9
6% ee (entry 8). Control experiments verified that the
reaction requires the combined presence of the rhodium
catalyst and air (entries 9 and 10). The related iridium catalyst
L-Ir did not give satisfactory results, and is a catalyst which
was recently demonstrated to activate a-silyl amines, but
apparently was not capable of converting synthetically much
more attractive non-functionalized, non-activated amines
[
7c]
(
entry 11). Figure 3 demonstrates that a variety of 2-acyl
Figure 4. Putative mechanism for the catalytic asymmetric cross-dehy-
drogenative couplings with molecular oxygen.
[12]
imidazoles (6b–f) and anilines ( 6g–m) serve as substrates.
The imidazole moiety can also be replaced by pyrazole (6n)
or benzimidazole (6o), although the yields and enantioselec-
tivities are somewhat diminished.
noradical which is subsequently oxidized by air to its electro-
[13]
philic iminium ion.
Such photosensitized oxidation of
The putative mechanism for both the reported catalytic
asymmetric cross-dehydrogenative couplings involves a rho-
dium coordination of the acyl imidazole substrate followed by
tertiary amines is well established for a variety of transition-
metal photoredox sensitizers, particularly ruthenium(II) and
iridium(III), but has not been reported for rhodium(III)
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Published online: && &&, &&&&
4
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Communications
CÀH Activation
Green stuff: A sustainable CÀC bond
formation is merged with the catalytic
asymmetric generation of one or two
stereocenters by combining asymmetric
enolate chemistry with either autoxida-
tion or visible-light photosensitized oxi-
dation. The robustness of a chiral-at-
metal rhodium(III) catalyst serves to
facilitate the reaction. PMP=para-
methoxyphenyl, TFA=trifluoroacetic
acid.
Y. Tan, W. Yuan, L. Gong,*
E. Meggers*
&&&& — &&&&
Aerobic Asymmetric Dehydrogenative
Cross-Coupling between Two Csp
Groups Catalyzed by a Chiral-at-Metal
Rhodium Complex
3
ÀH
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!