Rhodium-Catalyzed Atroposelective Construction of Indoles via C?H Bond Activation

Article abstract of DOI:10.1002/anie.202012932

Reported herein is the rhodium(III)-catalyzed C?H activation of anilines bearing an N-isoquinolyl directing group for oxidative [3+2] annulation with four classes of internal alkynes, leading to atroposelective indole synthesis via dynamic kinetic annulation with C-N reductive elimination constituting the stereo-determining step. This reaction proceeds under mild conditions with high regio- and enantioselectivity and functional group compatibility.

Full text of DOI:10.1002/anie.202012932

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Accepted Article
Title: Rhodium-Catalyzed Atroposelective Construction of Indoles via
C-H Bond Activation
Authors: Lincong Sun, Bingxian Liu, Junbiao Chang, Lingheng Kong,
Fen Wang, and Xingwei Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012932
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Rhodium-Catalyzed Atroposelective Construction of Indoles via
C-H Bond Activation
Lincong Sun, Haohua Chen, Bingxian Liu, Junbiao Chang, Lingheng Kong, Fen Wang,* Yu Lan,*
Xingwei Li*
Abstract: Reported herein is the rhodium(III)-catalyzed C-H
activation of anilines bearing an N-isoquinolyl directing group for
oxidative [3+2] annulation with four classes of internal alkynes,
leading to atroposelective indole synthesis via dynamic kinetic
annulation with C-N reductive elimination constitutes the stereo-
determining step. This reaction proceeds under mild conditions with
high regio- and enantioselectivity and functional group compatibility.
molecular complexity, is more attractive. Waldmann reported
intramolecular redox-neutral [4+2] annulation of benzamides
bearing a pendant alkyne using a chiral JasCpRh(III) catalyst,[12]
and our group recently developed an intermolecular version.[13]
Meanwhile,
Wang
disclosed
Rh(III)-catalyzed
[2+2+2]
carboannulation between N-arylindolinones and alkyne.[14]
Nevertheless, these very few reports[12-14] are limited to 6,6-biaryl
synthesis due to reactivity challenge posed by employment of
bulky directing group and/or coupling reagent. The rarity of
axially chiral indoles via C-H activation[9] is partially ascribed to
the relatively low atropostability associated with pentatomic
biarlys.[2g,h,9,11l] Notably, Rh(III)-catalyzed C-H activation has
allowed facile access to a large array of chiral products.[9,12-15]
Inspired by Fagnou’s pioneering oxidative indole synthesis[16]
and our own racemic system in 2010,[17] we aimed to apply C-H
activation of anilines for atropomeric synthesis of N-
isoquinolylindolines (Scheme 1c). Despite related racemic
reports,[16-18] control of enantioselectivity can be challenging
because this requires conformational control of the isoquinoyl
directing group prior to C-N reductive elimination. We now report
Rh(III)-catalyzed enantioselective [3+2] annulation between N-
isoquinolylaniline and alkynes.
Indoles are well-known structural motifs in a large number of
natural products, pharmaceuticals, and organic materials.[1] In
particular, axially chiral indoles have received increasing
attention as prevalent chiral building blocks and ligands.
Organocatalysis has offered powerful synthetic strategies to
access axially chiral indoles.[2] They are alternatively accessed
by metal catalysis (Scheme 1) following two synthetic strategies.
Metal-catalyzed arylation of an existing indole ring at the 1-,[3] 2-
[4]
,
and 3-positions[5] (Scheme 1a) using hypervalent iodine
reagents,[3] aryl halides,[4] and quinones[4] induced axial chirality.
In addition, functionalization of an arene[6] or olefin[7] group
tethered to an indole also generated a C-N or C-C chiral axis.
Alternatively, de novo construction of indole rings in an
atroposelective fashion has also been realized via cyclization of
aniline-tethered alkynes (Scheme 1b). Thus, Kitagawa reported
Pd-catalyzed cyclization of alkynes for synthesis of C-N axially
chiral indoles.[8] Our group integrated C-H activation of sterically
hindered indoles and alkyne cyclization for atroposelective
synthesis of 2,3’-biindolyls.[9] By using arylboronic acids as
arylating reagents, Zhu realized Pd-catalyzed asymmetric
Cacchi reaction of sterically hindered alkynes.[10] Nevertheless,
metal-catalyzed de novo construction of chiral indoles remains
highly rare.
Our C-H activation approach to access axially chiral biindolyls[9]
prompted us to take full advantage of C-H activation for
construction of axially chiral biaryls. Two sub-strategies are
followed, namely, de novo construction of a new chiral axis and
dynamic kinetic transformation based on an existing axis,[11] with
the latter being dominant. Nevertheless, most dynamic kinetic
transformations convert an ortho C-H bond to a terminal group.
The C-H activation-annulation approach, which increases
Scheme 1. Metal-Catalyzed Synthesis of Axially Chiral Indoles.
[a] L. Sun, Dr. B. Liu, Dr. L. Kong, Prof. Dr. J. Chang, Prof. Dr. X. Li
School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang 453007, China
Prof. Dr. X. Li, e-mail: lixw@snnu.edu.cn
[b] Dr. F. Wang, Prof. Dr. X. Li
School of Chemistry and Chemical Engineering, Shaanxi Normal
University (SNNU), Xi’an 710062, China.
Dr. F. Wang, email: fenwang@snnu.edu.cn
[c] H. Chen, Prof. Y. Lan
Aniline 1a was designed as an arene substrate, and its oxidative
annulation with diphenylacetylene was optimized using
Cramer’s [15e,f] CpXRh(III)/AgSbF6 catalyst in the presence of a
Ag(I)
oxidant under very mild conditions[19] (Table 1). When
catalyzed by (R)-Rh1, moderate to good ee but low yield of 3
was obtained when AgF, AgF2, AgOAc, or AgOPiv was used as
an oxidant in THF, DCE, PhCl, or dioxane. Both the yield and ee
were improved when the solvent was replaced by EtOAc with
School of Chemistry and Chemical Engineering, Chongqing University,
Chongqing 400030, China.
Prof. Y. Lan, email: lanyu@cqu.edu.cn
Supporting information for this article is given via a link at the end of
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AgBF4 as the oxidant (entry 5). Introduction of HOAc turned out
to be beneficial to the enantioselectivity, and a 2:1 ratio of
annulation system (19 and 20). Extension to alkyl-aryl alkynes
ones met with difficulty under the original conditions. Gratifyingly,
by replacing the AgBF4 oxidant with AgOPiv, the coupling of
alkyl-aryl alkynes proceeded in high enantioselectivity and in
good to excellent regioselectivity (21-24). Extension of simple
alkyl group in the alkyne to ether- and silylether-alkyl groups
arene/alkyne
further
augmented
the
efficiency
and
enantioselectivity (entry 6). By lowering the catalyst loading to 4
mol%, product 3 was isolated in 62% yield and 92% ee (entry
14). In contrast, coupling using with the (R)-Rh2 and (R)-Rh3
catalysts only gave lower efficiency and enantioselectivity
(Supporting Information).
gave
excellent
regioselectivity
and
generally
high
enantioselectivity (25-30).
A
chloroalkyl-substituted alkyne
Table 1. Optimization Studies.[a]
coupled with lower regioselectivity (31) although the
enantioselectivity remained high.
Yield
[%]b
ee
Entry
HOAc
Oxidant
Solvent
[%]
1
2
-
AgOAc
AgF
THF
THF
40
42
30
40
44
66
26
35
< 5
50
63
55
53
62
74
62
63
70
83
85
26
69
nd
89
92
91
91
92
-
3
-
AgF2
THF
4
-
AgOPiv
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
THF
5
-
THF
6
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
THF
7
DCE
8
1,4-dioxane
PhCl
9
10
11c
12 c
13c,d
14 c,e
EtOAc
EtOAc
MeOAc
EtOAc
EtOAc
[a]Reaction Conditions: arene (0.05 mmol), alkyne (0.05 mmol), (R)-Rh1 (5
mol%), AgSbF6 (20 mol%), oxidant (2.5 equiv), HOAc (2 equiv), solvent (1 mL),
under Ar for 24 h. [b] isolated yield. [c] Arene (0.1 mmol) was used (48 h). [d]
Without AgSbF6 [e] (R)-Rh1 (4 mol %) and AgSbF6 (16 mol %) were used.
With the optimized reaction conditions in hand, the scope of the
alkyne was next explored with aniline 1a as an arene substrate
(Scheme 2). Symmetrical diarylalkynes bearing alkyl, OMe, and
halogen substituents at the para position coupled in consistently
good yield and excellent enantioselectivity (86-96% ee, 3-9),
while introduction of a para CF3 tends to give diminished
enantioselectivity (10). Additionally, scale-up synthesis of 3 (1
mmol) was successful, with essentially no deterioration of
enantioselectivity. Comparable efficiency and enantioselectivity
(84-93% ee) were also realized for a series of meta-substituted
alkynes (11-14). While ortho-substituted alkynes generally
exhibited poor efficiency due to steric effect, presence of ortho F
groups in the alkyne was tolerated (15). Extension of the alkynes
to disubstituted and to heteroaryl ones was also successful (16-
18, 93-95% ee). The absolute configuration of product (R)-18
has been determined by X-ray crystallography (CCDC 2032437).
Moreover, symmetrical dialkyl alkynes were amenable to this
Scheme 2. Scope of Alkynes in Indole Synthesis. [a] Reaction Conditions:
arene (0.2 mmol), alkyne (0.1 mmol), (R)-Rh1 (4 mol%), AgSbF6 (16 mol %),
AgBF4 (0.25 mmol), AcOH (0.2 mmol), EA (2 mL), 25 oC under Ar for 48 h,
isolated yield. [b] at 0 oC. [c] AgOPiv (0.25 mmol) was used as oxidant for 72 h.
[d] CH3SO3Ag (0.25 mmol) and AcOH (0.2 mmol) were used in THF (2 mL) at
25 oC under argon for 48 h.
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To better define the scope of the alkynes, substituted 1,3-
enynes were explored (Scheme 2). It was found that
employment of either AgBF4 or AgOPiv oxidant failed to give
excellent enantioselectivity. To our delight, CH3SO3Ag proved to
be an superior oxidant in THF solvent. Thus, the coupling of
enyne bearing different alkyl and (hetero)aryl groups affored the
[3+2] annulation product in generally high yield, high (> 11:1 r.r.)
regioselecvitity, and excellent (89-96% ee) enantioselectivity
(32-38).
NBS led to selective bromination at the 6-position of the indole
ring (55). Suzuki coupling with p-TolB(OH)2 afforded product 59,
and the Sonogashira reaction using different alkynes gave
products 60 and 61 in good yields. Hydrogenation of 32 afforded
product 62 and oxidative C=C cleavage gave product 63.
Methylation of isoquinoline 3 afforded the isoquinolinium salt 64
in excellent yield.
The scope of the aniline was next investigated (Scheme 3).
Introduction of a 8-Cl group to the isoquinoline ring allowed the
coupling with diarylacetylenes in comparably or higher yield and
enantioselectivity (39-43). Variation of the 8-substituent to -Me
and -Ph group in the isoquinoline ring afforded consistently high
enantioselectivity
(45
and
46).
However,
moderate
enantioselectivity and poor efficiency were obtained for the 8-
methoxy N-isoquinolylaniline. Examination of para- and meta-
substituent in the aniline revealed compatibility of alkyl, aryl, and
halogen groups (47-56, 82-95% ee). Aniline bearing an ortho
OMe group also coupled with attenuated enantioselectivity (57).
Of note, coupling of 8-unsubstituted isoquonolylaniline bearing
an ortho-Me group with diphenylacetylene under modified
conditions using AgOTf as an oxidant afforded product 58 in
65% yield and 84% ee, although its barrier of racemization is
relatively low.
Scheme 4. Transformations of Annulated Products.
Preliminary mechanistic studies have been conducted (Scheme
5). H/D exchange between 1a and CD3COOD under slightly
modified conditions in the presence or absence of alkyne 2a all
gave significant deuteration at the ortho positions of the aniline,
suggesting reversible C-H activation (Scheme 5a). Parallel KIE
experiments were then conducted. A rather large value of kH/kD
= 4.9 indicated that C-H cleavage is involved in the turnover-
limiting step (Scheme 5b). Attempts to prepare a rhodacyclic
intermediate failed. Theoretical studies at the DFT level have
been then conducted to explore the asymmetric induction mode
of this coupling reaction. We examined the enantio-determining
reductive elimination of four possible rhodacycles with different
orientations of the arene and the DG together with a prochiral C-
N axis, which occurs via four possible transition states TS-R-1,
TS-R-2, TS-S-1, and TS-S-2 (Scheme 5c). It was found that the
lowest energy reductive elimination that forms the (R) and (S)-
product were defined by transition state TS-R-1 and TS-S-2,
respectively. The transition state TS-R-1 is 5.8 kcal/mol lower
than TS-S-2, which is consistent with our observed (R)
selectivity. Optimized structure analysis shows that in transition
state TS-S-2, due to steric repulsion between the methoxy group
in chiral ligand and phenyl group of styrene skeleton, the
torsional dihedral angle of the phenyl group in styrene skeleton
is higher than that of TS-R-1 (147.4o vs 115.3o). We also
examined the coordination of arene or alkyne substrate to the
corresponding five-coordinate Rh(III) species. However, neither
the thermodynamics of ligation nor the kinetic barrier of RE is
favorable. At this stage we cannot rule out possibility of
competitive RE of Rh(IV) species in the catalytical cycle.[20]
Scheme 3. Scope of Anilines in Indole Synthesis (see Scheme 2 for reaction
conditions).
Derivatization reactions have been carried out for product 3 to
demonstrate the synthetic utility (Scheme 4). Treatment of 3 with
Scheme 5. Preliminary Mechanistic Studies.
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Acknowledgements
Financial support from the NSFC (21525208) is gratefully
acknowledged.
Conflict of interest
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The authors declare no competing financial interest.
Keywords: rhodium • aniline • alkyne •indole • axial chirality
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L. Sun, B. Liu, J. Chang, L. Kong, F.
Wang, X. Li
Page No. – Page No.
Rhodium-Catalyzed Atroposelective
Construction of Indoles via C-H
Activation
C-H activation of N-isoquinolylanilines catalyzed by chiral rhodium(III) cyclopentadienyls has been realized in [3+2] annulation
with four classes of internal alkynes under mild oxidative conditions allowed atroposelective synthesis of biaryl indoles in high
regio- and enantioselectivity (> 50 examples, 71-96% ee).
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