A diastereoselective approach to axially chiral biaryls via electrochemically enabled cyclization cascade

Article abstract of DOI:10.3762/bjoc.15.76

A diastereoselective approach to axially chiral imidazopyridine-containing biaryls has been developed. The reactions proceed through a radical cyclization cascade to construct the biaryls with good to excellent central-to-axial chirality transfer.

Full text of DOI:10.3762/bjoc.15.76

A diastereoselective approach to axially chiral biaryls via
electrochemically enabled cyclization cascade
Hong Yan1, Zhong-Yi Mao1, Zhong-Wei Hou1, Jinshuai Song2 and Hai-Chao Xu*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 795–800.
1State Key Laboratory of Physical Chemistry of Solid Surfaces, Key
Laboratory of Chemical Biology of Fujian Province, iChEM and
College of Chemistry and Chemical Engineering, Xiamen University,
People’s Republic of China and 2College of Chemistry and Molecular
Engineering, Zhengzhou University, Zhengzhou 450001, People’s
Republic of China
doi:10.3762/bjoc.15.76
Received: 03 January 2019
Accepted: 16 March 2019
Published: 28 March 2019
This article is part of the thematic issue "Reactive intermediates part I:
radicals".
Email:
Hai-Chao Xu* - haichao.xu@xmu.edu.cn
Guest Editor: T. P. Yoon
* Corresponding author
© 2019 Yan et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
axial chirality; biaryl; electrochemistry; oxidation; radical
Abstract
A diastereoselective approach to axially chiral imidazopyridine-containing biaryls has been developed. The reactions proceed
through a radical cyclization cascade to construct the biaryls with good to excellent central-to-axial chirality transfer.
Introduction
Axially chiral biaryls are prevalent in natural products, bioac- cules to promote redox reactions because of its reagent-free fea-
tive molecules and organocatalysts [1,2]. Among the many ture and the tunability of electric current and potential [20-30].
methods that have been developed for the synthesis of chiral We [31-34] and others [35-41] have studied the reactions of
biaryls [3-10], reactions that take avantage of the central-to- electrochemically generated NCRs. Particularly, we have
axial chirality transfer have been less explored [11-14]. In addi- recently reported an electrochemical synthesis of imidazo-fused
tion, an antroposelective synthesis of imidazopyridine-based N-heteroaromatic compounds via a radical cyclization cascade
biaryls has not been reported.
[31]. Building on this work, we report herein an atroposelective
synthesis of imidazopyridine-containing biaryls via central-to-
Nitrogen-centered radicals (NCRs) are attractive reactive inter- axial chirality transfer (Scheme 1).
mediates for organic synthesis as they provide opportunities for
the efficient construction of C–N bonds [15-19]. Recently, the Results and Discussion
generation of NCRs through electron transfer-based methods The substituents on the phenyl ring (R1) and at the propargylic
has been attracting attention. Organic electrochemistry is a position (R2) of carbamate 2 were varied to study their effects
powerful tool for adding or taking electrons from organic mole- on the diastereoselectivity (Table 1). The electrolysis was con-
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Beilstein J. Org. Chem. 2019, 15, 795–800.
Scheme 1: Reaction design.
Table 1: Investigation on the effects of substituents on the diastereoselectivity.a
Entry
Substrate
Product, yield,b drc
1
2
3
4
2a (R1 = t-Bu, R2 = t-Bu)
2b (R1 = t-Bu, R2 = iPr)
2c (R1 = Ph, R2 = t-Bu)
2d (R1 = OiPr, R2 = t-Bu)
(±)-3a, 68%, 14:1 dr
(±)-3b, 64%, 3:1 dr
(±)-3c, 73%, 2:1 dr
(±)-3d, 78%, 3:1 dr
aReaction conditions: undivided cell, 1 (0.03 mmol), 2 (0.3 mmol), H2O (1 mL), MeCN (9 mL), 3.5 F mol−1. bIsolated yield. cDetermined by 1H NMR
analysis of the crude reaction mixture.
ducted under previously established conditions employing a (3i), and Me (3j). Pyridyl rings bearing multiple substituents
three-necked round-bottomed flask as the cell, a reticulated were also tolerated (3k and 3l). The stereochemistry of the
vitreous carbon (RVC) anode and a platinum plate cathode [31]. biaryl product was determined by obtaining an X-ray crystal
The reaction was carried in refluxing MeCN/H2O (9:1) with structure of 3k. The t-Bu-substituted phenyl ring on the alkyne
tetraarylhydrazine 1 as the redox catalyst, NaHCO3 (2 equiv) as moiety containing an extra OMe (3m) or Me (3n and 3o) group
an additive, and Et4NBF4 (1 equiv) as the supporting elec- was tolerated albeit with reduced diastereoselectivity. The t-Bu
trolyte. These investigations indicated that bulky tertiary groups group on the phenyl ring and at the propargylic position could
at both R1 and R2 positions were needed to ensure efficient be replaced with other bulky tertiary substituents to afford a
chirality transfer. Hence, carbamate 2a (Table 1, entry 1) bear- range of functionalized biaryl products (3p–w). The electro-
ing a t-Bu group at R1 and R2 positions, respectively, reacted to chemical conditions were compatible with several functional
give imidazopyridine-based biaryl 3a in 68% yield with good groups including aryltrimethylsilane (3p), silyl ether (3q–s),
diastereoselectivity (14:1 dr). Replacing the t-Bu group at the ester (3t) and cylic ketal (3u). Note that all the diastereomers
propargylic position with iPr (Table 1, entry 2) or on the phenyl were separable by flash column chromatography.
ring with Ph (Table 1, entry 3) or OiPr (Table 1, entry 4) all
resulted in low diastereoselectivity (2:1 to 3:1).
Heating a solution of the major isomer of 3n in MeCN at 80 °C
for 4 h did not lead to isomerization, suggesting that the stereo-
The scope of the electrosynthesis was investigated by varying selectivity of the reaction was not controlled by relative thermo-
the peripheral substituents of the carbamate substrate 2 dynamic stability of the diastereomers. The major isomer of 3c,
(Scheme 2). The pyridyl ring could be substituted at positions 4, which contained a sterically less demanding Ph group at the R1
5 and 6 with a range of substituents with diverse electronic position (cf. Table 1), did not isomerize at room temperature for
properties such as OMe (3e), Br (3f), CF3 (3g), CN (3h), Cl 1 year. However, heating a solution of this compound in MeCN
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Beilstein J. Org. Chem. 2019, 15, 795–800.
Scheme 2: Scope of electrochemical synthesis of axially chiral biaryls. Reaction conditions: undivided cell, 2 (0.3 mmol), H2O (1 mL), MeCN (9 mL),
3.5 F mol−1. aIsolated yield of the major diastereomer. bDetermined by 1H NMR analysis of crude reaction mixture. cCombined yield of the two dia-
stereomers.
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Beilstein J. Org. Chem. 2019, 15, 795–800.
at 80 °C for 4 h resulted in a mixture of diastereomers in a ratio ionic II is oxidized by radical cation I through single electron
of 3:1. These results suggest that the sterically demanding sub- transfer (SET) to give radical intermediate III, which under-
stituents at R1 and R2 positions (cf. Table 1) are critical to goes a biscyclization to give V. Further oxidation of V fol-
ensure good stereoselectivity during the product formation and lowed by hydrolysis of the cyclic carbamate moiety leads to the
to prevent isomerization after the reaction.
formation of 3a.
A mechanism for the electrochemical synthesis was proposed Based on the proposed reaction mechanism and the results
based on the results from our previous work [31] and of this mentioned above, the cyclization of vinyl radical IV to give V
work (Scheme 3). The redox catalyst 1 is oxidized at the anode is the atroposelective step. Density functional theory (DFT)-
to give radical cation I. In the meanwhile, H2O is reduced at the based calculations suggested that the cyclization of IV could be
cathode to afford HO− and H2. The base generated at the explained by a Curtin–Hammett scenario (Scheme 4) [42].
cathode deprotonates 2a to give its conjugate base II. The an- Specifically, the equilibrium of the conformations IV and IV′ is
Scheme 3: Proposed reaction mechanism for the electrochemical synthesis of 3a.
Scheme 4: Computation investigation on the vinyl radical cyclization. DFT (M06-2X/6-31G*) calculated energetics (kcal mol−1) are Gibbs free ener-
gies in MeCN.
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Conclusion
In summary, we have developed a diastereoselective approach
for the synthesis of axially chiral biaryls through an electricity-
powered cyclization cascade. The reactions employ easily
assembled starting materials and afford functionalized imidazo-
pyridine-based biaryls in good to high yields and diastereoselec-
tivity.
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Supporting Information
19.Xiong, T.; Zhang, Q. Chem. Soc. Rev. 2016, 45, 3069–3087.
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Supporting Information File 1
Experimental part.
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[https://www.beilstein-journals.org/bjoc/content/
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Financial support of this research from MOST
(2016YFA0204100), NSFC (21672178), and the Fundamental
Research Funds for the Central Universities, is acknowledged.
25.Yan, M.; Kawamata, Y.; Baran, P. S. Angew. Chem., Int. Ed. 2018, 57,
4149–4155. doi:10.1002/anie.201707584
ORCID® iDs
Jinshuai Song - https://orcid.org/0000-0002-1909-9253
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