Ruthenium(II)-Catalyzed Asymmetric Inert C?H Bond Activation Assisted by a Chiral Transient Directing Group

Article abstract of DOI:10.1002/anie.201913733

A ruthenium(II)-catalyzed asymmetric intramolecular hydroarylation assisted by a chiral transient directing group has been developed. A series of 2,3-dihydrobenzofurans bearing chiral all-carbon quaternary stereocenters have been prepared in remarkably high yields (up to 98 %) and enantioselectivities (up to >99 % ee). By this methodology, a novel asymmetric total synthesis of CB2 receptor agonist MDA7 has been successfully developed.

Full text of DOI:10.1002/anie.201913733

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Accepted Article
Title: A Rare Ruthenium(II)-Catalyzed Inert C-H Bond Activation
Assisted by a Chiral Transient Directing Group
Authors: Guozhu Li, Qinzhe Liu, Laxmaiah Vasamsetty, Weicong Guo,
and Jun Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913733
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10.1002/anie.201913733
Angewandte Chemie International Edition
COMMUNICATION
A Rare Ruthenium(II)-Catalyzed Inert C-H Bond Activation
Assisted by a Chiral Transient Directing Group
Guozhu Li, Qinzhe Liu, Laxmaiah Vasamsetty, Weicong Guo, and Jun Wang*
a) Comparison of Pd, Rh and Ru intermediates
Abstract:
A ruthenium(II)-catalyzed asymmetric intramolecular
R
O
hydroarylation assisted by a chiral transient directing group has been
developed. A series of 2,3-dihydrobenzofurans bearing chiral all-
carbon quaternary stereocenters have been prepared in remarkably
high yields (up to 98%) and enantioselectivities (up to >99% ee). By
this methodology, a novel asymmetric total synthesis of CB2
receptor agonist MDA7 has been successfully developed.
R
N
O
Pd
Pd
*
*
L
L
L
R
F
NEt2
N
R1
N
R1
N
O
Me
Et
F3C
L
Chiral palladacycle
Chiral rhodacycle
Chiral ruthenacycle
(Pioneered by Yu)
(Our previous work)
(This work)
Transition-metal-catalyzed asymmetric reactions involving inert
C-H activation is one of the most challenging research frontiers
in modern organic chemistry, which attracts increasing attention
of researchers.[1] It features high atom- and step-ecomomy.
Various high-value-added enantioenriched chiral compounds
could be prepared from structurally simple chemicals. So far,
many transition metal catalysts have proved competent to this
task, especially with the palladium[2] and rhodium[3] catalysts
being the most powerful. To our surprise, however, the
comparatively inexpensive ruthenium catalysts are seldom seen
in literatures on the asymmetric inert C-H activation,[4] despite
great success having been achieved in the corresponding non-
asymmetric inert C-H activation.[5]
1) Planar square geometry
2) Achiral metal center
3) Bidentate TDG
4) Stereochemistry
generated in C-H activation
1) Pseudotetrahedron geometry
2) Chiral metal center
3) Monodentate TDG
4) Stereochemistry generated in
migratory insertion
1) Pseudotetrahedron geometry
2) Chiral metal center
3) Monodentate TDG
4) Stereochemistry generated
in migratory insertion
b) Representative bioactive 2,3-dihydrobenzofurans
X
N
Ph
OH
N
N
X
H
HO
H
O
R
O
N
Ph
N
O
O
OH iPr
(_)-Isoabietenin A
O
O
O
HO
(_)-Morphine
1A9 human ovarian
carcinoma cells inhibitor (CB2 receptor agonist)
MDA7
Figure 1. Comparison of Pd, Rh and Ru intermediates and representative
bioactive 2,3-dihydrobenzofurans.
Notably, since Yu's pioneering work in 2016,[6] the chiral
transient directing group (TDG)-assisted,[7] palladium-catalyzed
asymmetric inert C-H activation has been emerging as an
efficient tool in organic synthesis.[8] The major characteristics of
this strategy is that the chiral TDG assisting the C-H activation
and enantiocontrol can form and decompose automatically in
situ. In addition, the amount of chiral reagent (typically amino
acid) to form the chiral TDG is substoichiometric.
In the early 2019, we introduced the chiral TDG strategy
into the rhodium(III)-catalyzed asymmetric C-H activation for the
first time,[9] in which a chiral primary aliphatic amine and an
achiral CpRhIII were used (Cp means cyclopentadienyl ligand). It
is noteworthy that CpRhIII catalyst features a piano stool
geometry with three open coordination sites, which is quite
distinct from the palladium complex taking a square planar
geometry with four open coordination sites. It is maybe due to
this reason that the bidentate chiral TDG from the related
palladium chemistry is found no longer compatible with CpRhIII
catalyst. Instead, the mono-dentate chiral TDG was found
effective. In view of the resemblance of RuII(p-cymene) species
to the CpRhIII in geometry, it was speculated that the chiral TDG
strategy might be also suitable for RuII(p-cymene) catalyst.
According to this idea and with our continuous interest in
asymmetric C-H activation reactions,[9-10] we launched this study
Scheme 1. Enantioselective synthesis of 2,3‐dihydrobenzofuran.
The chiral 3,3-disubstituted 2,3-dihydrobenzofuran skeleton
bearing an all-carbon quaternary stereogenic carbon center
exists in many natural products and bioactive molecules, such
as morphine, isoabietenin A, 1A9 human ovarian carcinoma
cells inhibitor,[11] and cannabinoid type 2 (CB2) receptor agonist
MDA7[12] (Figure 1b). However, construction of this structural
motif as well as its associated enantiocontrol is highly
challenging.[13] Recently, some elegant progress has been
with the purpose of exploring
a solution to the mainly
underdeveloped ruthenium-catalyzed asymmetric inert C-H
activation (Figure 1a).
[*]
G. Li, Q. Liu, L. Vasamsetty, W. Guo, Prof. Dr. J. Wang
Key Laboratory of Bioinorganic and Synthetic Chemistry of Ministry
of Education, School of Chemistry, Sun Yat-Sen University,
Guangzhou, 510275, P. R. China
achieved
by
transition-metal-catalyzed
asymmetric
intramolecular annulations with various pre-activated substrates
such as olefin-tethered aryl halides,[14] diazonium salts,[15] and
boronic reagents[16] (Scheme 1a). Intriguingly, the analogous
asymmetric annulations have been realized by the directing
E-mail: wangjun23@mail.sysu.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201913733
Angewandte Chemie International Edition
COMMUNICATION
group-assisted C-H activation promoted by either rhodium(I)[17]
or rhodium(III)[18] catalyst (Scheme 1b).[19] Herein, we described
a ruthemium-catalyzed enantioselective synthesis of chiral 3,3-
disubstituted 2,3-dihydrobenzofuran by the TDG strategy
(Scheme 1c). 20 A series of 2,3-dihydrobenzofurans with chiral
all-carbon quaternary stereocenters were obtained in high yields
(up to 98%) and high enantioselectivities (up to >99% ee)
promoted by catalytic amounts of [Ru(p-cymene)Cl2]2 and a
cheap chiral amine. Furthermore, this methodology was
successfully applied to the asymmetric total synthesis of CB2
receptor agonist MDA7.
[Cp*IrCl2]2 proved inactive (entries 9−10). Lowering the reaction
temparature to 60 °C could improve both the yield and
enantioselectivity (entry 11). Examining various acids indicated
trifluoroacetic acid (TFA) was the best (entry 12). Prolonging the
reaction time to 48 h led to an exceptional result of 96% yield
and 98% ee (entry 13). Gladly, both the loading of TDG-5 and
that of TFA could be reduced to 20 mol%, giving the product in a
slightly decreased yield (86%) with 98% ee (entry 14). To our
delight, the yield restored to 96% by simply extending the
reaction time to 60 h (entry 15). Reducing the loading of [Ru(p-
cymene)Cl2]2 led to slightly lower yields (entries 16-17). For
more detailed optimization of reaction conditions, please refer to
Supporting Information (SI, Tables S1-S6).
Table 1. Optimization of reaction conditions[a]
OBn
CHO
OBn
CHO
chiral amine
[M] (5 mol%),
Me
Table 2. Substrate scope.[a]
AgSbF6 (20 mol%), acid
DCE, N2, T (oC), time (h)
O
O
1a
2a
entry
[M]
chiral
amine
acid
(mol%)
yield
(%)
ee
(%)
1
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Cp*RhCl2]2
TDG-1
TDG-1
TDG-2
TDG-3
TDG-4
TDG-5
TDG-6
TDG-7
TDG-5
TDG-5
TDG-5
TDG-5
TDG-5
TDG-5
TDG-5
TDG-5
TDG-5
PivOH (50)
PivOH (0)
PivOH (50)
PivOH (50)
PivOH (50)
PivOH (50)
PivOH (50)
PivOH (50)
PivOH (50)
PivOH (50)
PivOH (50)
TFA (50)
64
56
ND
87
80
91
96
74
71
83
ND
98
98
98
98
98
98
98
2
trace
30
3
4
11
5
21
6
21
7
2
8
trace
60
9
10
[Cp*IrCl2]2
trace
43
11[b]
12[b]
13[b,c]
14[b,c]
15[b,d]
16[b,d,e]
17[b,d,f]
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
61
TFA (50)
96
TFA (20)
86
TFA (20)
96
TFA (20)
92
TFA (20)
80
[a] Under nitrogen atmosphere, 1a (0.1 mmol, 1.0 equiv), [Ru(p-cymene)Cl2]2
(5 mol%), AgSbF6 (20 mol%), chiral amine, acid, DCE (0.3 mL), at 70 oC for
24 h. [b] At 60 oC. [c] 48 h. [d] 60 h. [e] [Ru(p-cymene)Cl2]2 (2.5 mol%). [f]
[Ru(p-cymene)Cl2]2 (1 mol%).
To commence our study, the olefin-tethered aldehyde 1a was
prepared from readily available 3-hydroxybenzaldehyde. Initial
investigations revealed that the desired product 2a could be
obtained in 64% yield with 56% ee in the presence of of [Ru(p-
cymene)Cl2]2 (5 mol%), AgSbF6 (20 mol%), chiral amine TDG-1
(40 mol%), and pivalic acid (PivOH, 50 mol%) in DCE at 70 °C
for 24 h (Table 1, entry 1). It should be mentioned that when L-
tert-leucine was used instead, no reaction occurred. In addition,
the reaction did not proceed in the absence of acid (entry 2).
Screening a series of chiral amines indicated TDG-5 was the
best, furnishing the product 2a in 21% yield and 96% ee (entries
3-8). Interestingly, [Cp*RhCl2]2 gave inferior results, and
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10.1002/anie.201913733
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COMMUNICATION
should be noted that either enantiomer of 2z could be
respectively preapred by employing (R) and (S)-configured chiral
amine.
[a] Under nitrogen atmosphere, 1a (0.1 mmol, 1.0 equiv), [Ru(p-cymene)Cl2]2
(5 mol%), AgSbF6 (20 mol%), chiral amine (20 mol%), acid (20 mol%), DCE
(0.3 mL), at 60oC for 60 h. [b] TDG-5 (40 mol%), TFA (40 mol%), 60 oC, 60 h.
Under the optimized reaction conditions, the substrate
scope was explored (Table 2). It was found that the substrate 1
bearing either electron-withdrawing or electron-donating
substituent on the arene ring was tolerable, giving the desired
products in high yields and excellent enantioselectivities (2a–o).
Besides, substrates bearing diverse allyl groups were also found
compatible with the reaction conditions (2p−x). However,
attempt to extend this methodology to the corresponding
indoline synthesis proved less successful, for instance, affording
the N-Ac indoline 2y in 18% yield with 70% ee. Some
unsuccessful substrates were also shown in Table 2. To check
the practicability of this protocol, the model reaction was
performed on a 5.0 mmol scale. The product 2a was obtained in
94% yield (1.33 g) with 98% ee, which could be facilely
transformed into potential useful intermediates such as ester 3a
(82% yield) and alcohol 4a (95% yield) via I2-mediated
oxidation[21] and NaBH4 reduction, respectively (Scheme 2a).
Scheme 3. H/D Exchange experiment.
To gain some mechanistic insights, the hydroarylation of 1a
was carried out in the presence of D2O (1.0 equiv) for 20 h. The
product 2a was isolated in 14% yield together with 83% of the
recovered starting material 1a (Scheme 3). The significant
deuterium rates at the ortho positions of the formyl groups in 2a
(59% D) and the recovered 1a (10% and 17% D) suggest the C-
H activation process is reversible. Moreover, for the recovered
1a, the higher deuterium rate at the 2-position (17% D) than that
at the 6-position (10% D) implies higher reactivity of the former
position towards C-H activation, which might be attributed to its
more electronrichness. Moreover, the deuterium rate (59% D) at
the ortho position of the formyl group in 2a is much higher than
that in the recovered 1a. It indicates that if the C-H activation
occurs at the 6-position (unproductive way), the resulting
ruthenium intermediate can rapidly reverse to imine-ruthenium
complex by protonation and redirect the C-H activation onto the
2-position (productive way). This whole process shoud proceed
faster than the imine decomposition. Otherwise, the deuterium
rate at the ortho position of the formyl group in 2a would be
comparable to that in 1a (about 10% D). In addition,
incorporation of 26% of D into the 3-methyl group in 2a implies
the existence of a RCH2-Ru intermediate in the catalytic cycle.
Scheme 2. Elaborations of product 2a and enantioselective total synthesis of
CB2 receptor agonist MDA7.
Significantly, by taking advantage of this methodology, a
novel asymmetric total synthesis of CB2 receptor agonist MDA7
was explored and got successful (Scheme 2b). First, the alcohol
6 was prepared by partial reducing the readily available diester 5.
Upon sequential oxidation by MnO2, phenolic hydroxy protection
with MOMCl, aminolysis of ester by piperidine, deprotection of
MOM group and then allylation, 6 was transformed to the
substrate 1z in 50% overall yield via five steps. Conveniently, no
purification was needed until the final step. Then, 1z was
subjected to our standard catalytic conditions to afford the
desired product 2z in 95% yield with 91% ee. Lastly, removal of
the formyl group in 2z by Tsuji-Wilkinson decarbonylation gave
the CB2 receptor agonist MDA7 in 87% yield with 91% ee. It
Scheme 4. Proposed reaction mechanism.
Based on the above results and previous studies,[9,
a
22]
plausible reaction mechanism is proposed (Scheme 4). First,
dechlorination of [Ru(p-cymene)Cl2]2 by AgSbF6 generates the
catalytically active species I. The imine generated from substrate
1a and the chiral amine TDG-5 coordinates to the ruthenium in
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10.1002/anie.201913733
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COMMUNICATION
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is delivered together with the recovery of the ruthenium species I
and the chiral amine TDG-5.
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C-H bond activation assisted by a chiral transient directing group.
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A
series of chiral 3,3-disubstituted 2,3-dihydrobenzofurans
bearing all-carbon quaternary stereogenic carbon centers have
been constructed in high yields and high enantioselectivities.
The synthetic utility of this methodology has been demonstrated
by its successful application in the asymmetric total synthesis of
CB2 receptor agonist MDA7. A plausible reaction mechanism is
depicted.
Acknowledgements
We thank the National Natural Science Foundation of China for
financial support (21971263 and 21402244).
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Keywords: asymmetric catalysis • C-H activation • ruthenium(II)
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G. Li, Q. Liu, L. Vasamsetty, W. Guo,
Prof. Dr. J. Wang*
Page No. – Page No.
A Rare Ruthenium(II)-Catalyzed Inert C-
H Bond Activation Assisted by a Chiral
Transient Directing Group
Assisted by a chiral transient directing group, a highly enantioselective ruthenium-
catalyzed intramolecular hydroarylation via inert C-H activation process has been
realized in up to 98% yield and 99% ee using a readily available and inexpensive
metal catalyst [Ru(p-cymene)Cl2]2 (5 mol%) and a chiral primary amine (20 mol%).
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