Introducing the Chiral Transient Directing Group Strategy to Rhodium(III)-Catalyzed Asymmetric C?H Activation

Article abstract of DOI:10.1002/chem.201900762

The chiral transient directing group (TDG) strategy has been successfully introduced to the rhodium(III)-catalyzed asymmetric C?H activation. In the presence of a catalytic amount of a chiral amine and an achiral rhodium catalyst, various chiral phthalides were synthesized from simple aldehydes with high chemoselectivity, regioselectivity, and enantioselectivity (53 examples, up to 73 % yield and >99 % ee). It is noteworthy that the chiral induction model is different from the previously reported chiral TDG system using amino acid derivatives and palladium salts. The imino group generated in situ from chiral amine and aldehyde acts as the monodentate TDG to promote the C?H activation, stereoselectively generating the chiral rhodacycle bearing a chiral metal center. Moreover, the stereogenic center of the product is created and stereocontrolled during the Grignard-type addition of the C?Rh bond to aldehyde, rather than during the C?H activation step.

Full text of DOI:10.1002/chem.201900762

A Journal of
Accepted Article
Title: Introducing Chiral Transient Directing Group Strategy to
Rhodium(III) Catalyzed Asymmetric C-H Activation
Authors: Guozhu Li, Jijun Jiang, Hui Xie, and Jun Wang
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Introducing Chiral Transient Directing Group Strategy to
Rhodium(III) Catalyzed Asymmetric C-H Activation
Guozhu Li, Jijun Jiang, Hui Xie, and Jun Wang*
Abstract: The chiral transient directing group (TDG) strategy has
been successfully introduced to the rhodium(III) catalyzed
asymmetric C-H activation. In the presence of a catalytic amount of
a chiral amine and an achiral rhodium catalyst, various chiral
phthalides were synthesized from simple aldehydes in high
chemoselectivity, regioselectivity, and enatioselectivity (53 examples,
up to 73% yield and >99% ee). It is noteworthy that the chiral
induction model is different from the previously reported chiral TDG
system using amino acid derivatives and palladium salts. The imino
group generated in situ from chiral amine and aldehyde acts as the
monodentate TDG to promote the C-H activation, stereoselectively
generating the chiral rhodacycle bearing a chiral metal center.
Moreover, the stereogenic center of the product is created and
stereo-controlled during the Grignard-type addition of C-Rh bond to
aldehyde, rather than during the C-H activation step.
Over the past two decades, transition-metal catalyzed C-H bond
Scheme 1. Asymmetric C-H Activation with Chiral Transient Directing Group
activation has attracted much attention of chemists and
achieved tremendous progress.[1] This strategy features high
atom-economy and step-economy. Remarkably, it has found
great utility in the synthesis of complex organic molecules by
being able to provide shorter synthetic routes starting from
simpler starting materials.[2] Among various strategies to achieve
inert C-H bond activation, the most intensively studied one
should be the directed C-H activation using directing group (DG)
to coordinate to the transition-metal of a catalyst to facilitate C-H
activation.[3] Although great success has been achieved, the
most notable drawback associated with this strategy might be
having to pre-install DG beforehand and remove it after the
reaction.[4] Encouragingly, this problem is partially overcome by
the strategy of using transient directing group[5] (TDG) pioneered
by Jun and coworkers[6], in which the DG is installed (typically in
a small amount) and removed in situ automatically during the
reaction process. Moreover, as it could be easily imagined, if a
chiral transient directing group is introduced, it is possible to
achieve an asymmetric catalytic C-H activation reaction.
However, it is a very challenging task. It was not until 2016 that
the first example of asymmetric C-H activation reaction
employing chiral TDG was achieved by Yu and coworkers,[7] in
which the chiral amino acid L-tert-leucine was used to form a
bidentate TDG in situ to assist the Pd(OAc)2 catalyzed
enantioselective benzylic C(sp3)‒H arylation of aldehydes
(Scheme 1a). Similar catalyst systems have later been applied
to other asymmetric C-H activation reactions.[8] However,
despite those achievements, using chiral TDG to achieve the
asymmetric C-H activation is still very rare. And especially, the
reported catalyst systems are only limited to the combined use
of chiral amino acid derivatives and palladium catalyst.
Therefore, it is highly desirable to develop both new chiral
catalyst systems and new transformations to enrich the
chemistry of chiral TDG strategy.
It is well konwn that CpRh(III) catalyzed C-H activation has
achieved great success,[9] where Cp is cyclopentadienyl ligand.
Notably, the asymmetric CpRh(III) catalyzed C-H activation has
also been realized by various strategies, including designing
artificial metalloenzyme,[10] employing chiral Cp ligands,[11]
combining achiral CpRh(III) catalyst with an external chiral
anion[12] or acid[13], and using chiral substrate[14]. But to the best
of our knowledge, asymmetric CpRh(III) catalyzed C-H
activation by chiral TDG strategy is still unkonwn.[15] In 2013,
Seayad[16] reported
a
synthesis of phthalides[17] by the
[Cp*RhCl2]2 catalyzed Grignard-type addition[18] of C-H bonds to
aldehydes with 4-trifluoromethyl aniline as the TDG forming
reagent. To make this reaction enantioselective, we developed
and describe herein an efficient chiral TDG catalyst system
consisting of a chiral amine and an achiral rhodium(III) catalyst.
Various chiral phthalides (53 examples) have been prepared
from simple aldehydes in up to 73% yield and >99% ee (Scheme
1b). It is noteworthy that the chiral induction mechanism is quite
different from that of the previously reported chiral TDG system
using amino acid derivatives and palladium salts (Scheme 1c).
Firstly, assisted by a monodentate chiral TDG, the rhodacycle
generated via the C-H activation is chiral at metal owing to the
pseudotetrahedral geometry of rhodium(III) complex. Secondly,
the stereogenic center of the product is created and stereo-
controlled during the Grignard-type addition of C-Rh bond to
aldehyde, rather than in the C-H activation step.
[*]
G. Z. Li, J. J. Jiang, H. Xie, 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
E-mail: wangjun23@mail.sysu.edu.cn
To commence our research, the rhodium(III) catalyzed
homocoupling reaction of benzaldehyde was selected as the
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model reaction (Table 1). It was assumed that the key to achieve
our research goal is to find out a suitable chiral amine.
According to Seayad's study,[16] only electron-deficient aromatic
amine was effective for this reaction, whereas aliphatic amine
such as cyclohexylamine only gave trace amount of product.
Therefore, with [Cp*RhCl2]2 as the catalyst, the chiral aromatic
amine (S)-1,1'-binaphthyl-2,2'-diamine TDG-1 was examined
first, but unfortunately no desired product was detected.
Considering the actuality that chiral aliphatic amines are much
more readily available than chiral aromatic amines, we still
decided to take a chance to attempt some chiral aliphatic
amines. Gratifyingly, the chiral aliphatic amine (S)-1-
phenylethylamine TDG-2 offered a promising result of 17% yield
and 46% ee. Based on this clue, more than 30 chiral amines
analogous to (S)-1-phenylethylamine were screened (Table S5).
Selected results were shown in Table 1. Finally, the self-made
chiral amine TDG-6 was identified as the best. The reason might
be that the fluoro and trifluoromethyl groups at 2- and 6-
positions of phenyl ring could properly adjust the steric hidrance
and basicity of the chiral amine. And they could also prevent the
C-H activation from occurring on its own phenyl ring of chiral
amine. Investigation of rhodium(III) catalyst with diverse
cyclopentadienyl ligand was also conducted (Table S5),
indicating [Cp*iprRhCl2]2 was the optimal (64%, 92% ee).
Table 2. Scope of Homocoupling of Aryl Aldehydes
Table 3. Scope of Heterocoupling of Aryl Aldehydes
Table 1. Optimization of Reaction Conditions
After optimizing other reaction conditions (Tables S1-7), the
optimal were identified as [Cp*iprRhCl2]2 (1 mol%), AgBF4 (8
mol%), Ag2CO3 (0.7 equiv), TDG-6 (20 mol%), in 1,4-dioxane
and at 70 oC, under which the substrate scope of homocoupling
reaction of aromatic aldehyde was examined (Table 2). In
general, both electron-poor and electron-rich aldehydes were
applicable. Various functional groups were well tolerated.
Notably, for meta-substituented aldehyde, the reaction occurred
regioselectively at the less hindered C-H bond (e.g., 2c, 2d, 2e).
Subsequently, we turned to the heterocoupling reaction of two
different aldehydes, which is more challenging because four
possible products may be produced. To our surprise, when 4-
methylbenzaldehyde and 3,5-difluorobenzaldehyde were
subjected to the optimal homocoupling reaction conditions, only
two types of products were detected. The major one was the
heterocoupling product 2p, and the minor one was the
homocoupling product 2f. The yield and enantioselectivity for the
heterocoupling reaction could be further improved to 44% yield
and 96% ee by slightly adjusting the reaction conditions (for
details, see Tables S8-10). Under this modified reaction
conditions, more examples were examined for the
heterocoupling reaction of aldehyedes (Table 3). In general, the
C-H bond activation occurred on aldehydes with electron-
donating groups, followed by coupling with electron-deficient
aldehydes to give chiral phthalides with up to 73% yield and up
to >99% ee. Heterocoupling of two electron-rich aldehydes could
also proceed but was less successful. Intriguingly, 4-methyl
benzaldehyde and 3-methyl benzaldehyde could react with [1,1'-
biphenyl]-4-carbaldehyde to give the phthalides 2v (29% yield,
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99% ee) and 2ae (10% yield, 94% ee) as the major products,
respectively. In accordance with the homocoupling reaction, no
regiomers were detected for the reaction employing 3-
methylbenzaldehyde and 2-naphthaldehyde (2ae-2ai, 2ap-2au).
But for reactions with 3-methoxyl benzaldehyde or 1,4-
benzodioxan-6-carboxaldehyde, two regiomers were produced
in varied ratios (2aj-2an). Heterocoupling of aromatic aldehydes
with aliphatic aldehydes was also possible (2ay-2aaa). The
structure of the product 2ah was determined by single-crystal X-
ray diffraction and the absolute configuration was assigned as S.
To examine the practicality of current methodology, a gram-
scale heterocoupling reaction of 2-naphthaldehye with 4-
(methylsulfonyl)benzaldehyde was carried out. The desired
product 2at was obtained in 68% yield with 98% ee. Remarkably,
the chiral amine TDG-6 could be fully recovered as the form of
N-Boc-protected amide Boc-TDG-6 without any loss of
enantiopurity (Scheme 2).
indicated that the chiral amine preferred the electron-deficient
aldehyde to the electron-rich aldehyde with the ratio of 2.2:1
according to H NMR analysis (Scheme 3B). Therefore, it was
1
reasoned that although the imine from the electron-rich aldehyde
was generated in less amount, it was more reactive towards the
C-H activation as well as the subsequent Grignard-type addition
to C=O group due to electronic reasons. Evidently, because of
significant consumption of chiral amine by electron-deficient
aldehyde, higher loadings (0.7 equiv) of the chiral amine TDG-6
were requisite for the hereocoupling reactions than those for the
homocoupling reactions.
O
CHO
CF3 Et
O
1) Standard conditions
2) Boc2O
NHBoc
(R)
+
+
CHO
F
SO2Me
2at
Boc-TDG-6
99% yield, >99% ee
MeO2S
1.16 g, 68% yield, 98% ee
Scheme 2. Gram Scale Reaction
To shed some light on the reaction mechanism, some control
experiments were designed. Firstly, when deuteroxide was
employed as additive in the homocoupling reaction of 3-
methylbenzaldehyde, the deuterated 3-methylbenzaldehyde was
generated with 42% D incorporation into the 2-position and 46%
D incorporation into the 6-position, suggesting that the C-H
activation process is reversible (Scheme 3A). It is noteworthy
that there is no significant preference for the deuterium
incorporation into the 2- or 6-position of 3-methylbenzaldehyde,
implying the 3-methyl group basically don't interfere in the C-H
activation process. However, as mentioned earlier, the coupling
reactions were highly regioselective and the phthalide products
resulted from the C-H activation of 2-C-H bond of 3-
methylbenzaldehyde was not detected. It was reasoned that the
C-M intermediate II' shown in Scheme 4 generated from the C-H
activation of 2-position was unreactive towards the subsequent
Grignard-type reaction due to steric reasons. Additionally, the
homocoupling product 2c was also observed with 42% D
incorporation into the 7-position, indicating the reverse reaction
of C-H activation underwent much faster than the forward
Grignard-type reaction from the same C-M intermediate II shown
in Scheme 4. To examine the electronic effect on the C-H
Scheme 3. Mechanistic Studies
Secondly, to get a more solid evidence for the C-H activation
mechanism, preparation of rhodacyle intermediate was
attempted (Scheme 3C). Fortunately, upon treatment of the
imine 3 prepared from 3-methylbenzaldehyde and TDG-6 with
[Cp*iprRhCl2]2 and sodium acetate, the rhodacylce 4 was isolated
in 32% yield (Equation 1).[19] Its structure was determined by
single-crystal X-ray diffraction, exhibiting the expected piano-
stool type geometry. As there are two C-H bonds in the imine 3
which could possibly undergo C-H activation and the rhodium
atom becomes a chiral center in the resulting rhodacycle,
regiomers and diastereomers of the rhodacycle 4 may be
produced. However, the rhodacycle 4 was the only isomer
detected and isolated, indicating it is more thermodynamically
stable. It is also assumed that during the C-H activation process
the stereochemistry of the chiral rhodium center is fully induced
by the chiral imine directing group, with the absolute
configuration of rhodium stereogenic center preferring the R
configuration (assuming the group priority follows the order:
activation,
another
two
aldehydes
including
3,5-
difluorobenzaldehyde and 3,5-ditrifluoromethylbenzaldehyde
were investigated. Interestingly, while the moderately electron-
deficient 3,5-difluorobenzaldehyde could still smoothly undergo
the C-H activation, the strongly electron-deficient 3,5-
ditrifluoromethylbenzaldehyde could hardly do. This finding was
in line with the observed chemoselectivity of heterocoupling
reaction. However, the study of competitive imine formation with
two electronically different aldehydes (3-methylbenzaldehyde
and 3,5-difluorobenzaldehyde) and chiral amine TDG-6
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Cp*ipr > Cl > N > Caryl). It is noteworthy that when the pre-catalyst
[Cp*iprRhCl2]2 was replaced with the chiral rhodacycle 4 to
conduct the heterocoupling reaction of aldehydes 1c and 1n, the
desired product 2ah was obtained in 66% yield with 97% ee,
indicating the dechlorided rhodacycle 4 might be the active
intermediate for our described reaction (Equation 2).
converts back to the active rhodium(III) catalyst I via a
sequential reductive elimination and a silver oxidation to close
the catalytic cycle. In addition, two molecules of HBF4 are
generated from the whole process, which should react with
Ag2CO3 to give AgBF4, CO2 and water.
In summary,
activation has been realized by the chiral transient directing
group strategy. series of chiral phthalides have been
a rhodium(III) catalyzed asymmetric C-H
A
synthesized in up to 73% yield and >99% ee from very simple
and readily available aldehydes. This reaction features high
chemoselectivity, regioselectivity, and enantioselectivity. Notably,
the rhodacycle intermediate is chiral at rhodium due to its
pseudotetrahedral geometry. And the fashion of enantiocontrol
is completely different from that of palladium catalysis with chiral
TDG.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant 21402244).
Keywords: asymmetric catalysis • C-H activation • rhodium(III) •
phthalide • chiral transient directing group
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10.1002/chem.201900762
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Guozhu Li, Jijun Jiang, Hui Xie, and Jun
Wang*
Page No. – Page No.
Introducing Chiral Transient Directing
Group Strategy to Rhodium(III)
Catalyzed Asymmetric C-H Activation
The chiral transient directing group (TDG) strategy has been successfully
introduced to the rhodium(III) catalyzed asymmetric C-H activation. In the presence
of a catalytic amount of chiral amine and an achiral rhodium catalyst, various chiral
phthalides were synthesized from simple aldehydes in high chemoselectivity,
regioselectivity, and enatioselectivity (53 examples, up to 73% yield and >99% ee).
This article is protected by copyright. All rights reserved.