Background and Originality Content
Indole-based atropisomers are a very important class of axially chiral
compounds, many of them have become the core skeletons such as natural
products, active drugs, and chiral catalysts or ligands (Scheme
1a),1-6 and the development of catalytic asymmetric
constructions within these frameworks has become an emerging research
area.7-20 In comparison to axially chiral biaryl
compounds,8 introducing a five-membered pyrrole
component decreases the rotation barrier, thereby affecting the
stability of the axial chirality configuration and making it difficult
to control the enantioselectivity. 7,9 Therefore, the
asymmetric synthesis of axially chiral indole-based frameworks presents
certain challenges.9In
this context, there have been some synthetic attempts to achieve
enantioselective synthesis of these axially chiral
2-arylindoles.21-33 These attempts have primarily
focused on the strategy of cyclization of arylethynylene (Scheme 1b). In
2019, the Yan group reported a strategy for constructing 2-arylindole
atropoisomers through asymmetric cyclization of o -alkynylaniline
by organocatalysis. 22 Li et
al. 25 successfully synthesized axially chiral
2,3’-bisindole compounds via Rh(III) catalyzed C-H bond activation and
nucleophilic cyclization in 2019. In 2020, the Zhu group developed an
elegant method to construct axially chiral 2-arylindoles via asymmetric
Cacchi reactions. 26 Although previous studies have
achieved successful results, finding an efficient and selective method
for generating axially chiral 2-arylindoles remains a continuing
challenge. The development of new strategies will greatly expand the
range of applications for these compounds and there is still significant
demand in the field.
Recently,
Zhong group utilized p -quinonediimines as electrophilic aminating
reagents to achieve excellent results in the synthesis of
N-sulfonyl-3-aminoindoles through organocatalytic atroposelective
electrophilic amination of indoles.34 Based on the
aforementioned works, we envisaged that if 2-arylindoles could react
with the electrophilic nitrogen center of p -quinonediimines to
form direct amination products, the resulting bulky group would hinder
the rotation of adjacent C2 axis and potentially stabilize the axial
chirality of 2-arylindoles. It was evident that the steric hindrance
provided by the aryl substituents of indoles could serve as another
optimization parameter to prevent racemization of the
product.
Herein we report the successful synthesis of atropisomeric 2-arylindoles
using p -quinonediimines as aminating reagents in the presence of
chiral phosphoric acid as a catalyst (Scheme 1c).
Scheme 1 Research background of 2-arylindole atropoisomers
Results and Discussion
Before embarking on the atroposelective synthesis, we focused on
discovering axially chiral 2-arylindoles with high configurational
stability. Subsequently, we synthesized two compounds (1 &2 ) and examined their potential to possess axial chirality
through high-performance liquid chromatography (HPLC) analysis on a
chiral stationary phase (Scheme 2a). The experimental results
unequivocally showed that compound 1 was non-chiral, while
compound 2 exhibited apparently axial chirality. Then, we
carried out asymmetric synthesis of compound 2 in the presence
of various chiral phosphoric acids (For details, see Table S1 in SI).
The best result was obtained with 54% ee. Compound 2 exhibited
low axial chirality stability during the subsequent racemization
experiment, leading to rapid racemization at room temperature ini PrOH (ee drops gradually from 54% to 32% after 96 hours, Table
S2 in SI for details). To increase the configurational stability, we
introduce a malonate entity on the 2-aryl ring. Hopefully, this steric
hindrance and intramolecular hydrogen bonding may increase the stability
of product. Surprisingly, the compound 3 was proved to be
configurationally stable and no racemization occurred at room
temperature (rotation energy barrier to rotation of 3 was
determined to be 121.55 KJ/mol, see Table S4 in SI).
Based on our initial investigations, we selected dimethyl
2-(3-bromo-2-(1H-indol-2-yl)phenyl)malonate N-1c and
tosyl-substituted p -quinonesdiimine E-1a as model
substrates to start systematic optimization studies. The reaction
proceeded smoothly to give the axially chiral 2-arylindole 3with 89% yield and 88% ee in the presence of chiral phosphoric acid
(CPA) C1 as catalyst. This preliminary result obviously
demonstrated that the control of the axial chirality of 2-arylindole by
using CPA-catalyzed direct amination of malonate substituted
2-arylindole is feasible. As shown in Scheme 2b, the electron properties
and steric bulk of the substituents on the aromatic ring had a
significant impact on the reactivity and enantioselectivity of the
reaction. After screening of a range of CPAs, catalyst
(R )-C5 displayed the best results in terms of the
enantioselectivity (95% ee). Thorough evaluation of other reaction
parameters such as the solvent and catalyst loading (for details, see
Table S3 in SI) culminated in the following optimal conditions: whenE-1a (0.10 mmol) was treated with N-1c (0.15 mmol) in
the presence of catalyst C5 (10 mol%) in
CH2Cl2 at 25 oC for 12
h, the axially chiral 2-arylindole 3 was obtained in 93%
isolated yield with 95% ee (Scheme 2b).
Scheme 2 The exploration for atroposelective synthesis of the
axially chiral 2-arylindoles
After the optimal reaction conditions established, we turn our attention
to the substrate scope investigation. Firstly, we have examined the
substituted p -quinonesdiimines E-1 and the results were
depicted in Scheme 3a. The p -quinonediimines bearing a phenyl
ring at the para -position (4 -7 ) and a
2-naphthyl group (8 ) exhibited high reactivity and
enantiocontrol in the reaction, resulting in the formation of products
with excellent results. Additionally, the p -quinonediimines
bearing an ortho -position substituent (Me) on the phenyl ring
showed efficient transformation without compromising the yield (90%),
albeit with slightly lower enantioselectivity (9 , 82% ee).
To further explore the scope of this transformation, we then evaluated
the use of various 2-arylindoles as nucleophiles (Scheme 3b). The
replacement of Br with Cl in the reaction system did not significantly
impact the reactivity and enantioselectivity, as expected. This suggests
that Cl also effectively constrains the rotation of the chiral axis
(10 ). However, when iodine atoms were used instead, the
reaction was completely inhibited due to the large steric hindrance. The
replacement of the halide group with a methyl group resulted in a
considerable loss of enantiocontrol, with only 79% ee observed
(11 ). However, when methoxy groups were introduced at C6
position of indole, there was an insignificant change in reaction
outcome (12 ). The excellent enantiocontrol returned when
substrate with a naphthyl was employed (13 , 92% ee). The use
of different malonate groups (Et and i Pr) proved to be amendable,
resulting in corresponding products (14 and 15 ) with
excellent results.
Scheme 3 Substrate generality for construction of axially
chiral 2-arylindoles
Reaction conditions: In an oven dried Schlenk tube chiral phosphoric
acid (R )-C5 (10 mol%), E-1 (0.10 mmol) andN-1 (0.15 mmol) were dissolved in 4 mL of
CH2Cl2. The mixture was stirred at 25oC until the reaction was completed.
To demonstrate the practicality of this transformation, a
preparative-scale synthesis was conducted to efficiently produce 1.94 g
of product 7 with 95% yield and 91% ee. As illustrated in
Scheme 4a, there was only a minor variation in both chemical yield and
stereoselectivity in the presence of 5 mol% of (R )-C5 ,
suggesting that large-scale chemical production of axially chiral
2-arylindoles using this methodology may indeed be feasible.
Furthermore, by treatment of 11 with (Boc)2O,
the protective product 16 could be easily obtained with 96% ee
after recrystallization. The absolute configuration of 16 was
determined to be S by X-ray crystallographic analysis and
stereochemistry of other products was assigned by analogy (Scheme 4b).
Scheme 4 Large-scale synthesis and transformation
The compound 17 with stable configuration was synthesized with
fairly poor enantioselectivity when the malonate entity was replaced by
isopropyl under the optimal conditions. This result could be attributed
to the loss of the ester-CPA catalyst interaction and the intermolecular
hydrogen bonding within the indole substrate. Based on the experimental
results and the reported literatures,34 a possible
reaction mechanism was illustrated. As shown in Scheme 5b, initially,
imine E is activated by chiral phosphoric acid to generate
intermediate A .
The
driving force of aromaticity caused A to undergo isomerization
and transform into intermediate B . Subsequently, 2-arylindoleN attacked the latter to produce the final product with an
axially chiral 2-arylindole moiety. The bifunctional CPA catalyst was
responsible for simultaneously activating both 2-arylindole and
intermediate B through multiple hydrogen bonding interactions.
Scheme 5 Control experiment and reaction mechanism
Conclusions
In summary, we have synthesized a series of axially chiral 2-arylindoles
through the direct amination of 2-arylindoles withp -quinonediimines as aminating reagents. The reaction was carried
out with excellent yields and high enantioselectivities under the
catalysis of chiral phosphoric acid. It is worth noting that this method
exhibits synthetic practicality, as the products could be obtained
through gram-scale reactions with nearly identical yields and
enantioselectivities. This method is an effective supplement to the
existing strategies for the enantioselective synthesis of 2-arylindole
atropisomers. The application of 2-arylindole atropisomers in asymmetric
synthesis is currently being explored in our group.
Experimental
In an oven dried Schlenk tube chiral phosphoric acid
(R )-C5 (10 mol%), E-1 (0.10 mmol) andN-1 (0.15 mmol) were dissolved in 4 mL
CH2Cl2. The mixture was stirred at 25oC until the reaction was completed (about 12 h).
Solvent was removed under reduced pressure and the residue was purified
by column chromatography on silica gel
(CH2Cl2/EtOAc = 30/1) to give the pure
product.
Supporting Information
The supporting information for this article is available on the WWW
under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
We are grateful for financial support from the National Key R&D Program
of China (2022YFA1503703, 2021YFF0701604), the National Natural Science
Foundation of China (21825105, 22231004, 22271135), Guangdong Innovative
Program (2019BT02Y335), and Shenzhen Science and Technology Program
(KQTD20210811090112004, JCYJ20210324120205016, JCYJ20210324105005015).
The authors appreciate the assistance of SUSTech Core Research
Facilities.
References
- Maehr, H.; Smallheer, J. Total syntheses of rivularins D1 and D3.J. Am. Chem. Soc. 1985 , 107, 2943-2945.
- Benincori, T.; Brenna, E.; Sannicoll, F.; Trimarco, L.; Antognazza,
P.; Cesarotti, E.; Demartin, F.; Pilati, T.; Zotti, G. Chiral
atropisomeric five-membered biheteroaromatic diphosphines: new ligands
of the bibenzirnidazole and biindole series. J. Organomet.
Chem. 1997 , 529, 445-453.
- Benincori, T.; Piccolo, O.; Rizzo, S.; Sannicoll, F.
3,3’-Bis(diphenylphosphino)-1,1’-disubstituted-2,2’-biindoles: easily
accessible, electron-rich, chiral diphosphine ligands for homogeneous
enantioselective hydrogenation of oxoesters. J. Org. Chem.2000 , 65, 8340-8347.
- Jiang, F.; Luo, G.-Z.; Zhu, Z.-Q.; Wang, C.-S.; Mei, G.-J.; Shi, F.
Application of naphthylindole-derived phosphines as organocatalysts in
[4 + 1] cyclizations of o -quinone methides with
Morita-Baylis-Hillman carbonates. J. Org. Chem. 2018 ,
83, 10060-10069.
- Baumann, T.; Brgckner, R. Atropselective dibrominations of a
1,1’-disubstituted 2,2’-biindolyl with diverging point-to-axial
asymmetric inductions. Deriving 2,2’-biindolyl-3,3’-diphosphane
ligands for asymmetric catalysis. Angew. Chem. Int. Ed.2019 , 58, 4714-4719.
- He, T.; Peng, L.; Li, S.; Hu, F.; Xie, C.; Huang, S.; Jia, S.; Qin,
W.; Yan, H. Chiral naphthyl-C2-indole as scaffold for phosphine
organocatalysis: application in asymmetric formal [4 + 2]
cycloaddition reactions. Org. Lett. 2020 , 22,
6966-6971.
- Li, T.-Z.; Liu, S.-J.; Tan, W.; Shi, F. Catalytic asymmetric
construction of axially chiral indole-based frameworks: an emerging
area. Chem. Eur. J. 2020 , 26, 15779-15792.
- Cheng, J. K.; Xiang, S.-H.; Li, S.; Ye, L.; Tan, B. Recent advances in
catalytic asymmetric construction of atropisomers. Chem.
Rev. 2021 , 121 , 4805-4902.
- Zhang, H.-H.; Shi, F. Organocatalytic atroposelective synthesis of
indole derivatives bearing axial chirality: strategies and
applications. Acc. Chem. Res. 2022 , 55, 2562-2580.
- He, X.-L.; Zhao, H.-R.; Song, X.; Jiang, B.; Du, W.; Chen, Y.-C.
Asymmetric Barton-Zard reaction to access 3-pyrrole-containing axially
chiral skeletons. ACS Catal . 2019 , 9, 4374-4381.
- Zhang, H.-H.; Wang, C.-S.; Li, C.; Mei, G.-J.; Li, Y.; Shi, F. Design
and enantioselective construction of axially chiral naphthyl-indole
skeletons. Angew. Chem. Int. Ed. 2017 , 56, 116-121.
- Jiang, F.; Chen, K.-W.; Wu, P.; Zhang, Y.-C.; Jiao, Y.; Shi, F. A
strategy for synthesizing axially chiral naphthyl-indoles: Catalytic
asymmetric addition reactions of racemic substrates. Angew.
Chem. Int. Ed. 2019 , 58, 15104-15110.
- Qi, L.-W.; Mao, J.-H.; Zhang, J.; Tan, B. Organocatalytic asymmetric
arylation of indoles enabled by azo groups. Nat. Chem.2018 , 10, 58-64.
- Zhu, S.; Chen, Y.-H.; Wang, Y.-B.; Yu, P.; Li, S.; Xiang, S.-H.; Wang,
J.-Q.; Xiao, J.; Tan, B. Organocatalytic atroposelective construction
of axially chiral arylquinones. Nat. Commun. 2019 , 10,
4268-4277.
- Lu, D.-L.; Chen, Y.-H.; Xiang, S.-H.; Yu, P.; Tan, B.; Li, S.
Atroposelective construction of arylindoles by chiral phosphoric
acid-catalyzed cross-coupling of indoles and quinones. Org.
Lett. 2019 , 21, 6000-6004.
- Ding, W.-Y.; Yu, P.; An, Q.-J.; Bay, K. L.; Xiang, S.-H.; Li, S.;
Chen, Y.; Houk, K. N.; Tan, B. DFT-guided phosphoric-acid-catalyzed
atroposelective arene functionalization of nitrosonaphthalene.Chem 2020 , 6, 2046-2059.
- Chen, Y.-H.; Li, H.-H.; Zhang, X.; Xiang, S.-H.; Li, S.; Tan, B.
Organocatalytic enantioselective synthesis of atropisomeric
aryl-p -quinones: Platform molecules for diversity-oriented
synthesis of biaryldiols. Angew. Chem. Int. Ed. 2020 ,
59, 11374-11378.
- Lu, S.; Ong, J.-Y.; Yang, H.; Poh, S. B.; Liew, X.; Seow, C. S. D.;
Wong, M. W.; Zhao, Y. Diastereo- and atroposelective synthesis of
bridged biaryls bearing an eight-membered lactone through an
organocatalytic cascade. J. Am. Chem. Soc. 2019 , 141,
17062-17067.