Electrochemical synthesis of symmetrical benzidines through dehydrogenative cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2021.153021

Synthesis of diversely functionalized symmetrical benzidines through electrochemical dehydrogenative cross-coupling reaction of two N,N-disubstituted anilines, is described. The reactions conducted under mild conditions with no oxidizing reagents and transition metal catalysts.

Full text of DOI:10.1016/j.tetlet.2021.153021

i An update to this article is included at the end
Tetrahedron Letters 70 (2021) 153021
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Electrochemical synthesis of symmetrical benzidines through
dehydrogenative cross-coupling reaction
Xiaoying Liu a, Tian-Cheng Cai a, Dingyi Guo a, Bin-Bin Wang a, Shengneng Ying a, Huixian Wang a,
Shiyun Tang b, Qinpeng Shen b, Qing-Wen Gui a,
⇑
a School of Chemistry and Materials Science Hunan Agricultural University, Changsha 410128, People’s Republic of China
b China Yunnan Key Laboratory of Tobacco Chemistry, Research and Development Centre, China Tobacco Yunnan Industrial Company, Kunming 650231, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of diversely functionalized symmetrical benzidines through electrochemical dehydrogenative
cross-coupling reaction of two N,N-disubstituted anilines, is described. The reactions conducted under
mild conditions with no oxidizing reagents and transition metal catalysts.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 30 January 2021
Revised 15 March 2021
Accepted 18 March 2021
Available online 23 March 2021
Keywords:
Electrochemical synthesis
Symmetrical benzidines
Dehydrogenative
Biquinoline
Para-selective
The synthesis of benzidine derivatives has always attracted con-
siderable attention from synthetic chemists because they are not
only common structural constituents that are present in many bio-
logical and pharmaceutical molecules [1], but also can serve as
important building blocks for the synthesis of functionalized hete-
rocycles [2]. In addition, the chemical and physical properties of
benzidine-based compounds have enabled their use in the manu-
facture of azodyes and in cell biology as staining reagents [3]. Tra-
ditionally the synthesis of benzidine derivatives has largely relied
on the rearrangement of hydrazobenzenes [4]. Although effective,
the conventional rearrangement reactions suffer from major limi-
tations, including (1) the highly prefunctionalized starting materi-
als; (2) the formation of a substantial amount of by-products. A
more concise and atom economical method based on dehydro-
genative coupling methodology would be highly desirable since
fewer steps would be needed.
Indeed, the direct dehydrogenative coupling methods has been
well known [5]. Recent studies have investigated that excess
amounts of metal salt oxidants such as TiCl4, CAN, CuBr/H2O2, Cu
(ClO4)2 and FeCl3ꢀ6H2O, can be utilized for their transformation
[6]. For examples, Chen et al. reported that Fe salts can be used
to promote oxidative coupling of aniline, which tend to form ben-
zidine derivatives.6a In contrast, examples of external-oxidant-free
and transition metal-free dehydrogenative coupling are less abun-
dant. As an alternative to chemical oxidation, electrooxidation is
attracting increasing interests [7]. Particularly, great achievements
for biaryl synthesis have been gained in the electrochemical dehy-
drogenative coupling cross-coupling of two aromatic compounds
[8]. Under these backgrounds, we strongly thought that the new
electrochemical method for the synthesis of benzidine derivatives
should be realized. For example, in 1962, Mizoguchi et al. reported
the first reaction between two N,N-Dimethylaniline by means of
electrochemical processes focused on the para/para selective
homocoupling mode [9]. However, this method needs to be con-
ducted in a strictly controlled buffer solution. Very recently, Li
et al. disclosed that an efficient reaction dehydrogenative cross
coupling of amino-naphthalenes with eletron-rich arenes to pro-
vide nonsymmetrical biaryls [10].
Herein, we report a new, general anode strategy for the synthe-
sis of various symmetrical benzidines by para-selective dehydro-
genative cross-coupling of two anilines under neutral reaction
conditions while avoiding the use of additional metal catalysts
and stoichiometric oxidants. We initiated our study by identifying
the optimal reaction conditions for the electrochemical dehydro-
genative cross-coupling of two N,N-dibenzylanilines. To our
delight, the desired benzidines 2a were indeed obtained in 87%
yield when the reaction was conducted under constant current
electrolysis at 8 mA in the presence of tetrabutylammonium hex-
afluorophosphate (n-Bu4NPF6, 0.5 equiv) in acetonitrile (ACN,
5 mL) at room temperature (Table 1, entry 1). The electrode mate-
rials have a significant impact on the reaction outcome, while an
⇑
Corresponding author.
E-mail address: gqw1216@hunau.edu.cn (Q.-W. Gui).
https://doi.org/10.1016/j.tetlet.2021.153021
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

X. Liu, Tian-Cheng Cai, D. Guo et al.
Tetrahedron Letters 70 (2021) 153021
Table 1
Screening of the reaction conditions.a
a
Reaction conditions: N,N-dibenzylaniline 1a (0.5 mmol), rt, in an undivided cell, 6 h. Unless otherwise noted.
b
Estimated by 1H NMR using m-cresol as an internal reference.
Table 2
Reaction scope.a,b
a
Reaction conditions: aniline 1 (0.5 mmol), rt, in an undivided cell, 6 h. Unless otherwise noted.
Isolated yields.
b
2

X. Liu, Tian-Cheng Cai, D. Guo et al.
Tetrahedron Letters 70 (2021) 153021
Scheme 1. Gram-scale synthesis of 6,60-biquinoline 3.
obvious loss of yield was obtained either with a platinum/carbon/
RVC plate anode or platinum/carbon plate cathode (Table 1, entries
2–5). In addition, this reaction was dramatically affected upon
replacing the electrolyte with either NaClO4, NH4I or KPF6 (Table 1,
entries 6–8). Other solvents, such as HFIP, DMF and CH2Cl2 were
also examined. However, all displayed lower effectiveness than
acetonitrile (Table 1, entries 9–11). Finally, lowering or increasing
the current intensity to 6 or 10 mA have adverse effects on the
reaction efficiency (Table 1, entries 12–13).
With optimized experimental conditions in hand, we set out to
evaluate the scope of the electrochemical dehydrogenative cross-
coupling of two anilines. As summarized in Table 2, a wealth of ani-
linederivatives carryingdifferent electronically and stericallyvaried
phenyl substituents reacted well, affording the corresponding sym-
metrical benzidines in 74–92% yields. The substitution effect of the
aryl ring of anilines was firstly checked: several ortho- or meta- sub-
stituents, such as Cl, Br, I, Me and MeO, were efficient for gaining the
products 2b-2k with moderate to good yields, respectively. It is
worth mentioning that the good results 2h-2i in the electrochemical
dehydrogenative cross-coupling reaction are achieved with the
Fig. 1. UV–vis spectra of 2a, 2c, 2d and 2p (2.5 ꢁ 10ꢂ5 M) in dichloromethane.
Scheme 2. Possible mechanism.
3

X. Liu, Tian-Cheng Cai, D. Guo et al.
Tetrahedron Letters 70 (2021) 153021
highly bulky starting materials. When the anilines with different
substituent groups like N-methyl-N-benzylanilines, N-ethyl-N-ben-
zylanilines and N-methyl-N-ethylanilines were involved, the target
products 2j-2m and 2o were obtained in high yields as well. In addi-
tion, the reaction could afford the corresponding products 2n and 2p
up to 90% yield when dialkylanilines, such as N,N-dimethylaniline
and N,N-diethylaniline, were used as the substrates. Meanwhile,
oxidative coupling of N-phenylpiperidine and 1-phenylpyrrolidine,
afforded 2q-2r with 80–83% yields. Delightfully, this present elec-
trochemical protocol is efficiently applied in the incorporation of
various important pharmacophore motifs, including 1,2,3,4-
tetrahydroquinoline and 1-benzyl-1,2,3,4-tetrahydroquinoline,
into the symmetrical benzidines. More importantly, N-allylic con-
taining substituents were particularly reactive, expanding the syn-
thetic utility of the protocol in this work significantly.
The applicability of the present electrochemical reaction was
further tested. In the small-scale synthesis, a concentration of
0.1 M of the 1s was required, and the increase of reaction substrate
would reduce the yield of the target product. This clean electro-
chemical reaction offered a great opportunity for the exploration
of one-pot sequential transformation from readily available start-
ing materials. Pleasingly, the electrochemical dehydrogenative
cross-coupling reaction of 1s with a 20-fold increase in the concen-
tration of 1s gave the target product 3 in 72% isolated yield under-
went dehydrogenation without a tedious workup process. It is
worthwhile to point out that, unlike the results reported by Xu,
the reaction of 1s produced CAC dimerization product instead of
NAN dimerization [11]. Moreover, the 6,60-biquinoline 3 was found
to be a potential photoactive material [12] (Scheme 1).
ject of Hunan Agricultural University (SYL2019064, SYL2019063).
We thank the Basic Research Foundation of China Tobacco Yunnan
Industrial Corporation (11700167) and Foundation of Hunan
Provincial Key Laboratory of Crop Germplasm Innovation and
Resource Utilization (18KFXM07).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153021.
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Declaration of Competing Interest
(d) S. Möhle, M. Zirbes, E. Rodrigo, T. Gieshoff, A. Wiebe, S.R. Waldvogel,
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Acknowledgments
We thank the Hunan Province Science Foundation for Youths
(2018JJ3215, 2020JJ4035) and Double First-Class Construction Pro-
4

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Erratum
Erratum to ‘‘Electrochemical synthesis of symmetrical benzidines
through dehydrogenative cross-coupling reaction”
[Tetrahedron Lett., 70 (2021) 153021]
Xiaoying Liu a, Tian-Cheng Cai a, Dingyi Guo a, Bin-Bin Wang a, Shengneng Ying a, Huixian Wang a,
Shiyun Tang b, Qinpeng Shen b, Qing-Wen Gui a,
⇑
a School of Chemistry and Materials Science Hunan Agricultural University, Changsha 410128, People’s Republic of China
b China Yunnan Key Laboratory of Tobacco Chemistry, Research and Development Centre, China Tobacco Yunnan Industrial Company, Kunming 650231, People’s Republic of China
The publisher regrets that Table 1 in the published article does not appear in the correct format and is missing content. The table has
now been corrected and can be seen here:
The publisher would like to apologise for any inconvenience caused.
Table 1
Screening of the reaction conditions.a
aReaction conditions: N,N-dibenzylaniline 1a (0.5 mmol), rt, in an undivided cell, 6 h.
Unless otherwise noted.
bEstimated by 1H NMR using m-cresol as an internal reference.
DOI of original article: https://doi.org/10.1016/j.tetlet.2021.153021
Corresponding author.
E-mail address: gqw1216@163.com (Q.-W. Gui).
⇑
https://doi.org/10.1016/j.tetlet.2021.153145
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: X. Liu, Tian-Cheng Cai, D. Guo et al., Erratum to ‘‘Electrochemical synthesis of symmetrical benzidines through dehydrogenative
cross-coupling reaction” [Tetrahedron Lett., 70 (2021) 153021], Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153145