Enantioselective Synthesis of C?N Axially Chiral N-Aryloxindoles by Asymmetric Rhodium-Catalyzed Dual C?H Activation

Article abstract of DOI:10.1002/anie.201901619

The first enantioselective Satoh–Miura-type reaction is reported. A variety of C?N axially chiral N-aryloxindoles have been enantioselectively synthesized by an asymmetric rhodium-catalyzed dual C?H activation reaction of N-aryloxindoles and alkynes. High yields and enantioselectivities were obtained (up to 99 % yield and up to 99 % ee). To date, it is also the first example of the asymmetric synthesis of C?N axially chiral compounds by such a C?H activation strategy.

Full text of DOI:10.1002/anie.201901619

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Accepted Article
Title: Enantioselective Synthesis of C–N Axially Chiral N-Aryloxindoles
by Asymmetric Rhodium-Catalyzed Dual C-H Activation
Authors: Honghe Li, Xiaoqiang Yan, Jitan Zhang, Weicong Guo, Jijun
Jiang, and Jun Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901619
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Enantioselective Synthesis of C–N Axially Chiral N-Aryloxindoles
by Asymmetric Rhodium-Catalyzed Dual C-H Activation
Honghe Li,‡ Xiaoqiang Yan,‡ Jitan Zhang, Weicong Guo, Jijun Jiang, and Jun Wang*
Dedicated to Professor Xiaoming Feng on the occasion of his 55th birthday
Table 1. Optimization of Reaction Conditionsa
Abstract: The first enantioselective Satoh-Miura type reaction is
reported. A variety of C–N axially chiral N-aryloxindoles have been
enantioselectively synthesized by an asymmetric rhodium-catalyzed
dual C-H activation reaction of N-aryloxindoles and alkynes. High
yields and enantioselectivities were obtained (up to 99% yield and
up to 99% ee). To the best of our knowledge, it is also the first
example of asymmetric synthesis of C-N axially chiral compounds by
transition-metal catalyzed asymmetric dual C-H activation strategy.
entry
[Rh]
(mol %)
Rh-1
additive
(equiv)
yieldb
(%)
73
eec
(%)
83
1
2
AgOAc (2.2)
Axially chiral compounds are prevalent in natural products,[1]
medicinal chemistry[2] and chiral ligand pool[3]. Their asymmetric
syntheses have attracted much attention of chemists.[4] But the
C-N axial chirality is less studied than the C-C axial chirality. The
Rh-1
Rh-1
Rh-1
Rh-2
Rh-3
Rh-4
Rh-1
iPrCO2Ag (2.2)
90
36
90
92
93
82
89
62
93
3
Ag2O (1.1)
4
iPrCO2H (2.2) + Ag2O (1.1)
iPrCO2H (2.2) + Ag2O (1.1)
iPrCO2H (2.2) + Ag2O (1.1)
iPrCO2H (2.2) + Ag2O (1.1)
iPrCO2H (2.2) + Ag2O (1.1)
75
ways to obtain C-N axially chiral compounds include asymmetric
5]
5
70
C-N forming reaction,[4d,
asymmetric N-functionalization of
anilides[6], and others[7]. In this study, we present an alternative
way to construct C-N axial chirality by the strategy of asymmetric
dual C-H activation.[8] In 2008, Satoh and Miura disclosed a RhIII-
6
64
7
8
8d
94 (92)e
catalyzed aromatic homologation reaction by
a chelation-
aReaction conditions: 1a (0.05 mmol), 2a (2.2 equiv), [Rh] (5 mol %), AgNTf2
(10 mol %), additive, DCE (0.5 mL) at 70 ℃ under N2 for 24 h. bDetermined by
1H NMR analysis of crude reaction mixture with methoxybenzene as the
internal standard. cDetermined by HPLC. dAgNTf2 (20 mol %), 36 h. eIsolated
yield.
assisted successive double C-H activation[9] (Scheme 1a, DG =
pyrazoyl group).[10] Same reactions could also occur with other
directing groups[11] or even without any directing groups.[12]
However, since its discovery, the Satoh-Miura type reaction has
never been achieved enantioselectively. Herein, we describe a
RhIII-catalyzed asymmetric Satoh-Miura type reaction, by which
a variety of C–N axially chiral N-aryloxindoles have been
synthesized in up to 99% yield with up to 99% ee (Scheme 1b).
This research started from our discovery of a new Satoh-
Miura type reaction. Namely, in the presence of Cp*RhIII, the N-
phenyloxindole 1a reacted with diphenylacetylene 2a to afford
N-naphthyloxindole 3a that was axially chiral around C-N bond.
Driven by our continuous interests in the asymmetric C-H
activation reactions[13] and inspired by the aforementioned
literature surveys, we decided to head directly towards the study
of the corresponding enantioselective reaction, which is much
more challenging. Intensive studies of reaction conditions
indicated that the chiral spiro CpRh catalyst developed by You’s
group[8i] was the most effective. And the product 3a was
obtained in 73% yield and 83% ee with (R)-Rh-1 (5 mol %) as
the precatalyst and AgOAc (2.2 equiv) as the additive (Table 1,
i
entry 1). To our delight, when PrCO2Ag was used instead of
AgOAc, 3a was formed in 90% yield and 90% ee (entry 2). It
was assumed that the C-H activation should proceed via
carboxylate-assisted concerted metalation-deprotonation (CMD)
mechanism and the sterically bulkier isobutyrate could lead to
better differentiation of the two enantiotopic C-H bonds of 1a.
When Ag2O was used, the enantioselectivity increased to 92%
ee, but the yield decreased dramatically to 36% (entry 3).
Scheme 1. Asymmetric Satoh-Miura Type Reaction
i
Interestingly, when PrCO2H (2.2 equiv) and Ag2O (1.1 equiv)
[*]
H. Li, X. Yan, J. Zhang, W. Guo, J. Jiang, 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
i
were employed together in order to in situ generate PrCO2Ag,
the desired product 3a was obtained in better enantioselectivity
(93% ee) albeit in decreased yield (75% yield) (entry 4).
Screening of chiral rhodium catalysts indicated (R)-Rh-1 worked
best (entries 5-7). Finally, increasing the amount of AgNTf2 to 20
mol % and extending the reaction time to 36 hours led to the
optimal reaction conditions, under which the product 3a was
obtained in 92% yield and 93% ee (entry 8). For more details
E-mail: wangjun23@mail.sysu.edu.cn
[‡]
These authors contributed equally.
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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about optimization of reaction conditions, please refer to
Supporting Information.
enantioselectivities (up to 96% ee) were achieved for
nonsubstituted (3o), open-chained dialkylsubstituted (3p–q), and
biologically relevant spiro oxindoles (3r–v)[14]. Besides, indoline-
2-thione (1w), oxazolone (1x), and quinolinones (1y–z) were
also investigated as substrates, affording the desired products in
moderate to high yields and enantioselectivities. In addition, the
tetrabromo product 3aa was prepared in purpose of growing
single-crystals. Its structure was confirmed and the absolute
configuration was determined to be R configuration by single-
crystal X-ray diffraction.[15]
Table 2. Substrate Scope of N-phenyloxindolesa
Table 3. Substrate Scope of Alkynesa
aReaction conditions: 1 (0.1 mmol), 2a (2.2 equiv), (R)-Rh-1 (5 mol %), AgNTf2
(20 mol %), iPrCO2H (2.2 equiv), Ag2O (1.1 equiv), DCE (1 mL) at 70 ℃ under
N2 for 36 h. Isolated yields are reported. b(R)-Rh-1 (10 mol %), 80 ℃, 48 h.
c(R)-Rh-1 (10 mol %), 70 ℃, 60 h. dAgOAc (2.2 equiv) was used. e80 ℃, 48 h.
With optimized reaction conditions in hands, various N-
aryloxindole 1 were allowed to react with diphenylacetylene 2a
(Table 2). The substrates bearing either an electron-withdrawing
or an electron-donating group (R1 = F, Cl, Me, OMe) at the N-
phenyl ring are tolerable, giving the desired products in 53−92%
yields and 80−95% ee (3a–e). However, N-2-FC6H4 and
naphthyl oxindoles only gave moderate results (3f–h).
Substitution with electron-withdrawing or electron-donating
group (e.g., F, Cl, Me, OMe) at the oxindole aromatic moiety
has little impact on the reaction. The corresponding products
were obtained in good to high yields (60-96%) with high
aReaction conditions: 1 (0.1 mmol), 2a (2.2 equiv), (R)-Rh-1 (5 mol %), AgNTf2
(20 mol %), iPrCO2H (2.2 equiv), Ag2O (1.1 equiv), DCE (1 mL) at 70 ℃ under
N2 for 36 h. Isolated yields are reported. b48 h. cRegioselectivity; determined by
1H NMR analysis.
Subsequently, various alkynes were investigated by reacting
with N-phenyloxindoles (1r) (Table 3). For symmetric diaryl
alkynes, both electron-withdrawing and electron-donating
substituents were tolerated by the reaction, providing good to
excellent yields (42−99%) and enantioselectivities (88−97% ee)
(3ab–ag). Greater steric demanding substituents were also
compatible (3ah–3ai). Moreover, when the heteroaromatic
alkyne 2j was used, the product 3aj was obtained with good
enantioselectivities (92-95% ee). Then,
a
series of 1-
phenylindolinones with different 3,3-disubstituents were
examined. Delightedly, good to high yields (up to 97%) and high
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10.1002/anie.201901619
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enantioselectivity (87% ee) albeit in moderate yield (23% yield),
which was probably due to the toxic effect of sulfur on the
rhodium catalyst. Besides symmetric diaryl alkynes, some
asymmetric diaryl alkynes were also investigated. When (4-
fluorophenyl)(4-methylphenyl)ethyne was subjected to the
reaction conditions, four regiomers of 3ak were generated in
equal amount and in high overall yields. The ee values for each
regiomers were comparable and high. Similar situation also
happened to the electronically biased asymmetric alkyne 1-(4-
methoxyphenyl)-2-[4-(trifluoromethyl)phenyl]acetylene, affording
four regiomers of 3al in high overall yields, high
enantioselectivities, but unsatisfying regioselectivity. When
phenyl methyl acetylene was employed, only two regiomers
were obtained (3am : 3am' = 2.7 : 1). The major regiomer 3am
was obtained in 51% yield and 89% ee. Its structure was
identified by single-crystal X-ray diffraction.[15] In addition, no
desired reaction occurred when phenylacetylene or the aliphatic
alkyne hex-3-yne was applied.
step succeeding the C-H activation (Equation 2). Thirdly, a
kinetic isotope effect (KIE) of 1.07 was observed from parallel
reactions using 1a and 1a-d5, respectively, indicating the C-H
activation step was not turnover-determining (Equations 3 and 4).
Notably, the product 3v can be facilely transformed to the
corresponding N-phenylisatin 3an by 1 N HCl without any loss of
enantiopurity (Scheme 2). It should be mentioned that isatins are
commonly found in natural compounds, pharmaceuticals and
synthetic intermediates.[16] Interestingly, if N-phenylisatin was
employed as substrate, no reaction took place, which was
probably due to strong chelation effect of the two adjacent
carbonyl groups with the rhodium catalyst.
Scheme 4. Mechanistic Studies
Scheme 2. Transformation of the Product 3v to Isatin 3an
To demonstrate the reliability of this methodology, the
reaction of 1a with 2a was attempted in a large scale of 2.5
mmol. The desired product 3a was obtained in 93% yield (1.37 g)
with 93% ee (Scheme 3). Moreover, the barrier of the N-Ar bond
rotation for the product 3a was measured to be 151 kJ/mol in
hexane at 170 ℃. The barrier of this magnitude is sufficiently
high to preclude racemization at reaction temperature of 70 ℃.
Scheme 5. Proposed Reaction Mechanism
According to above mechanistic studies and previous
studies[10-11]
, a plausible reaction mechanism is proposed
(Scheme 5). First, the chiral CpRhI is oxidized to CpRhIII by
AgNTf2. Then, coordination of the oxygen atom of N-
phenyloxindole 1a to the RhIII catalyst assists the first C-H bond
cleavage possibly via CMD mechanism to afford the six-
membered rhodacyclic intermediate Ⅰ. Subsequently, insertion
of the alkyne 2a generates the intermediate Ⅱ. Then, activation
of the second C-H bond occurs to generate the intermediate Ⅲ.
Insertion of a second molecule of alkyne 2a forms the
intermediate Ⅳ or Ⅳ', which undergoes reductive elimination to
give the product 3a and the CpRhI species. Finally, CpRhI was
reoxidized to CpRhIII by Ag+ to close the catalytic cycle.
Scheme 3. Gram-scale Synthesis of the N-Naphthyloxindole 3a
Preliminary studies of reaction mechanism were carried out.
Firstly, when the oxindole 1a was subjected to the reaction
conditions in the presence of D2O, considerable H/D exchange
at the ortho position was observed, indicating the C-H bond
activation process is reversible (Scheme 4, Equation 1).
Secondly, when the oxindole 1a-d5 was allowed to react with the
alkyne 2a, the product 3a-d3 was obtained in 64% yield with
merely 9% of contamination of 3a-d2, suggesting that the
reverse reaction of C-H activation was much slower than the
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[8]
For asymmetric construction of C-N axial chirality by asymmetric single
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In summary, we present the first example of asymmetric
Satoh-Miura type reaction, which also constitutes the first
example of asymmetric construction of C–N axial chirality by the
strategy of asymmetric dual C–H activation. Specifically, a
variety of C–N axially chiral N-aryloxindoles have been
enantioselectively synthesized from N-aryloxindoles and alkynes
in up to 99% yield and with up to 99% ee with a chiral rhodium
catalyst. Preliminary mechanistic studies were performed and a
plausible catalytic cycle was proposed.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant 21402244).
Keywords: Satoh-Miura type reaction • C-N axial chirality • dual
C-H activation • alkyne • N-aryloxindole
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COMMUNICATION
Honghe Li,‡ Xiaoqiang Yan,‡ Jitan
Zhang, Weicong Guo, Jijun Jiang, and
Jun Wang*
Page No. – Page No.
Enantioselective Synthesis of C–N
Axially Chiral N-Aryloxindoles by
Asymmetric Rhodium-Catalyzed Dual C-
H Activation
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