Site-Selective Electrochemical Benzylic C?H Amination

Article abstract of DOI:10.1002/anie.202013478

C?H/N-H cross-coupling is an ideal strategy to synthesize various amines but remains challenging owing to the requirement for sacrificial chemical oxidants and the difficulty in controlling the regio- and chemo-selectivity. Herein we report a site-selective electrochemical amination reaction that can convert benzylic C?H bonds into C-N linkages via H₂ evolution without need for external oxidants or metal catalysts. The synthetic strategy involves anodic cleavage of benzylic C?H to form a carbocation intermediate, which is then trapped with an amine nucleophile leading to C?N bond formation. Key to the success is to include HFIP as a co-solvent to modulate the oxidation potentials of the alkylbenzene substrate and the aminated product to avoid overoxidation of the latter.

Full text of DOI:10.1002/anie.202013478

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Accepted Article
Title: Site-Selective Electrochemical Benzylic C–H Amination
Authors: Zhong-Wei Hou, Ding-Jin Liu, Peng Xiong, Xiao-Li Lai,
Jinshuai Song, and Hai-Chao Xu
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Site-Selective Electrochemical Benzylic C–H Amination
Zhong-Wei Hou,[a] Ding-Jin Liu,[b] Peng Xiong,[b] Xiao-Li Lai,[b] Jinshuai Song,[c] and Hai-Chao Xu[b],*
Dedicated to the memory of Professor Jun-ichi Yoshida (1952–2019).
Abstract: C–H/N–H cross-coupling represents an ideal strategy to
synthesize various amines but remains challenging due to the
requirement for sacrificial chemical oxidants and the difficulty in
controlling the regio- and chemo-selectivity. Herein we report a site-
selective electrochemical amination reaction that can convert benzylic
C–H bonds to C–N linkages via H2 evolution without need for external
oxidants or metal catalysts. The synthetic strategy involves anodic
cleavage of benzylic C–H to form a carbocation intermediate, which
is then trapped with an amine nucleophile leading to C–N bond
formation. Key to the success is to include HFIP as a cosolvent to
modulate the oxidation potentials of the alkylbenzene substrate and
the aminated product to avoid overoxidation of the latter.
avoid product overoxidation, Yoshida and coworkers developed a
cation pool method that involves electrochemical C–N bond
formation with a sulfilimine in a divided cell followed by chemical
reduction with iodide (Scheme 1b).[9] With our continued interest
in constructing C–N bonds via electrochemical approaches,[8r] we
report herein an unprecedented benzylic C–H amination reaction
via electrochemical C–H/N–H cross-coupling (Scheme 1c). Our
method features metal- and oxidant-free conditions and excellent
site-selectivity for benzylic functionalization.
The prevalence and biological importance of amines has fueled a
strong interest in developing more efficient methods for C–N bond
formation.[1] In this context, C(sp3)–H amination has emerged in
recently years as an attractive and straightforward approach for
forging challenging C–N bonds from readily available materials.[2]
Previously reported C(sp3)–H amination reactions usually involve
transition metal-catalyzed nitrene insertion[3] or photochemically
promoted hydrogen atom transfer (HAT).[4,5] While excellent
efficiencies have been observed for benzylic C–H amination
employing alkanes as the limiting agent, ample room exists for
further development to address site- and chemoselectivities and
avoid using stoichiometric oxidants such as hypervalent iodine
reagents.
Dehydrogenative cross-coupling via H2 evolution is an ideal
strategy for forging C–C and C–X (X = heteroatom) bonds but
remains elusive for intermolecular benzylic C–H/N–H coupling.[6,7]
Organic electrochemistry has been demonstrated to be an
enabling technology in achieving dehydrogenative cross-coupling
via H2 evolution through anodic substrate oxidation and cathodic
proton reduction.[8] However, electrochemical benzylic C(sp3)–H
amination has been suggested to be challenging due to
overoxidation of the amine product because of the close
potentials between the substrate and product.[9] Adding to the
challenge is that benzylic amination is shown to be much less
efficient than the analogous alkoxylation in carbocation-mediated
photochemical dehydrogenative functionalization reactions.[10] To
Scheme 1. Benzylic C–H amination.
We first optimized the electrolysis conditions for the amination
of ethylbiphenyl 1 with toluenesulfonamide 2. The reaction was
conducted using a constant current in an undivided cell equipped
with a reticulated vitreous carbon (RVC) anode and a platinum
plate cathode (Table 1). An optimal yield of 82% was obtained
when the electrolysis was conducted at RT in a mixed solvent of
HFIP/DCE (1:2) with nBu4NBF4 as the supporting electrolyte
(entry 1). Reduction of the amount of 2 to 1.5 equiv resulted in a
slightly decreased yield of 76% (entry 2). The use of HFIP,
whether as a co-solvent (entry 3) or the only solvent (entry 4),
proved to be critical for product formation. To the contrary,
replacement of HFIP with TFE (entry 5) or MeCN (entry 6)
completely shut down the amination reaction.
[a] Dr. Z.-W. Hou
Advanced Research Institute and Department of Chemistry
Taizhou University
Taizhou 318000 (P. R. China)
[b] Dr. P. Xiong, D-J. Liu, X.-L. Lai, Prof. Dr. H.-C. Xu
Laboratory of Chemical Biology of Fujian Province, State Key
Laboratory of Physical Chemistry of Solid Surfaces, iChEM, and
College of Chemistry and Chemical Engineering, Xiamen University
Xiamen 361005 (P. R. China)
E-mail: haichao.xu@xmu.edu.cn
Web: http://hcxu.xmu.edu.cn
[c] Dr. J. Song
College of Chemistry and Molecular Engineering, Zhengzhou
University, Zhengzhou 450001 (P. R. China)
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Optimization of reaction conditions.[a]
On the other hand, DCE could be substituted for by CH2Cl2 (entry
7) or CHCl3 (entry 8), albeit with moderately decreased yields.The
use of an alternative electrolyte, such as nBu4NPF6, Et4NBF4, or
Et4NPF6 (entry 9), resulted in a slight but noticeable drop in
reaction efficiency. Likewise, other electrode materials, including
Pt (entry 10) and graphite (entry 11) anode, as well as Ni (entry
12) and stainless steel (entry 13) cathode, were all shown to be
less effective. Increasing the current to 10 or 15 mA exhibited no
significant effect on yield (entry 14). The electrochemical reaction
could also be performed under air, though with a slight reduction
in yield (entry 15).
Entry
Deviation from standard conditions
Yield [%][b]
We next evaluated the amination of different benzylic
substrates with TsNH2 (Scheme 2). Ethylbenzene (4) and its
derivatives bearing an OMe (5), F (6), Cl (7), Br (8) or brominated
phenyl (9) at the para position, or a Br (10) at the ortho position,
were all found to be suitable benzylic C–H donors. Substitution of
the benzene ring with an acyl group caused the C–N coupling to
be completely inhibited, leaving most of the starting materials
unreacted (11). The reaction also demonstrated satisfactory
tolerance of alkylbenzenes that carry a longer side chain (12–14),
and diphenylmethane (15). Mono-amination products were
obtained for substrates with multiple benzylic positions of the
same (16–20) or different electronic properties (21–22). In
addition, the C–H amination also exhibited a clear preference for
less hindered benzylic positions (24–26). Note that no amination
occurred at non-benzylic positions.
[a] Reaction conditions: undivided cell, 1 (0.3 mmol), 2 (0.6 mmol), solvent
(6 mL), nBu4NBF4 (0.36 mmol), 7.5 mA, RT, 2.5 h (2.3 F mol–1). [b]
Determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as the
internal standard. [c] Isolated yield. [d] Unreacted 1 in bracket. HFIP,
1,1,1,3,3,3-hexafluoro-2-propanol; DCE, 1,2-dichloroethane; TFE, 2,2,2-
trifluoroethanol.
Scheme 2. Scope of alkylbenzene. Regioisomers were observed for compounds 21, 23 and 24. The position for amination that led to the minor isomer were marked
with a gray dot. Reaction conditions: undivided cell, alkylbenzene (0.3 mmol), TsNH2 (0.6 mmol), nBu4NBF4 (0.36 mmol). [a] No reaction. [b] Reaction for 5.8 h (5.4
F mol–1). [c] Reaction for 3.3 h (3.1 F mol–1).
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Subsequent exploration of different benzenesulfonamides
suggested broad reaction compatibility with H (28), Et (29), tBu
(30), CF3 (31), F (32), Cl (33) and Br (34) at the 4-positon of the
phenyl ring, as well as Me (35) at the 2-position (Scheme 3).
Notably, the sulfonamide drug Celebrex could be easily coupled
with dehydroabietic acid methyl ester to form the amination
product (36) in 88% yield. Apparently, selective C–H amination
occurred on the benzylic methylene of dehydroabietic acid methyl
ester without touching the benzylic Me group of Celebrex. Other
suitable
nitrogen
nucleophiles
included
N-methyl
toluenesulfonamide (37), methanesulfonamide (38, 39),
sulfamides (40–44), and pyrazole (45). It is particularly
noteworthy that the benzylic C–H in 1 could also be functionalized
with oxygen nucleophiles such as acetate (46), ethylene glycol
(47), or HFIP (48).[11]
Scheme 3. Scope of nucleophiles. Reaction conditions: undivided cell, alkylbenzene (0.3 mmol), nucleophile (0.6 mmol), nBu4NBF4 (0.36 mmol). [a] Reaction for
3.3 h (3.1 F mol–1). [b] Pyrazole (2 equiv) as nucleophile. [c] nBu4NOAc (1.2 equiv) as nucleophile. [d] Reaction in DCE/HFIP (2:1) with 2 equiv of ethylene glycol.
[e] Reaction in DCE/HFIP the absence of other nucleophiles.
The electrochemical C–H amination reaction could be
performed on a gram scale, as demonstrated by the synthesis of
3 and 36 (Figure 1), in which larger electrodes were employed to
ensure complete reaction in several hours.
were obtained (Scheme 4a, left), revealing that ethylbenzene (Ep/2
= 1.90 V vs SCE) is oxidized at lower potential than both 4 (Ep/2
=
2.00 V vs SCE) and TsNH2 (Ep/2 = 2.23 V vs SCE). Despite the
small difference in oxidation potential between ethylbezene and
4, they were still efficiently differentiated during the preparative
electrolysis that was conducted in DCE/HFIP. On the other hand,
failure to replicate the synthetic success in MeCN can be
explained by the fact that the oxidation potentials of the two
compounds were only separated by 0.03 V (Ep/2) (Scheme 4a,
right). Therefore, the importance of HFIP can be attributed to its
role in stabilizing radical cation intermediates to allow substrate
oxidation while preventing product overoxidation.[12] No D/H
exchange occurred in the reaction of 1-d2, suggesting irreversible
cleavage of the C–H bond (Scheme 4b). Primary deuterium
kinetic isotope effect (KIE) was observed in intermolecular and
intramolecular competition experiments (Scheme 4c). Similar KIE
has been previously reported for electrochemical benzylic C–H
oxidation reactions.[13] Primary KIE observed for this product
determining C–H cleavage is consistent with our experimental
Figure 1. Gram scale synthesis of 3 and 36.
As part of the mechanistic studies, cyclic voltammograms of
ethylbenzene, its aminated product 4 and TsNH2 in DCE/HFIP
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observation that the reaction kinetics were sensitive to steric and
electronic properties of the donor benzylic C–H bond.
50, which loses a benzylic proton to furnish carbon radical 51.
Further single-electron transfer (SET) oxidation of 51 to
carbocation 52, followed by nucleophilic trapping, affords the final
amination product 53. Consistent with this mechanism, the
electron-deficient 1-(4-isobutylphenyl)ethan-1-one failed to afford
any amination product 11 and remained mostly intact because of
its reluctance to undergo single elecron transfer oxidation. At the
cathode, protons undergo cathodic reduction to generate H2,
which obviates the need for sacrificial chemical oxidants. For
reactions proceeding through electron transfer mechanisms, it is
known that secondary benzylic C–H bonds are more reactive than
their tertiary counterparts due to stereoelectronic effects.[14]
In summary, we have developed an electricity-powered
intermolecular C–H/N–H cross-coupling reaction, which proceeds
under mild conditions via H2 evolution without need for transition
metal catalysts or chemical oxidants. Our method not only can be
applied to efficient and scalable synthesis of benzylic amines, but
are also excellently compatible with other type of nucleophiles
such as acetate and alcohols, providing enormous opportunities
for developing new, sustainable C–H functionalization reactions
with easily available materials. Research along these lines is
ongoing in our laboratory.
Acknowledgements
We thank Associate Professor Yan Liu (XMU) for help with mass
spectroscopy. Financial support of this research from NSFC
(21672178, 21971213), MOST (2016YFA0204100), and the
Fundamental Research Funds for the Central Universities.
Keywords: C–H functionalization • electrochemistry • C–H
amination • cross-dehydrogenative coupling • oxidation
[1]
[2]
[3]
E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257-
10274.
a) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017, 117, 9247-9301; b) H.
Zhang, A. Lei, Synthesis 2019, 51, 83-96.
a) J. R. Clark, K. Feng, A. Sookezian, M. C. White, Nat. Chem. 2018, 10,
583-591; b) A. Nasrallah, V. Boquet, A. Hecker, P. Retailleau, B. Darses,
P. Dauban, Angew. Chem. 2019, 113, 8276-8280; Angew. Chem. Int. Ed.
2019, 58, 8192-8196; c) N. D. Chiappini, J. B. C. Mack, J. Du Bois,
Angew. Chem. 2018, 130, 5050-5053; Angew. Chem. Int. Ed. 2018, 57,
4956-4959; d) E. N. Bess, R. J. DeLuca, D. J. Tindall, M. S. Oderinde, J.
L. Roizen, J. Du Bois, M. S. Sigman, J. Am. Chem. Soc. 2014, 136, 5783-
5789; e) Z.-J. Jia, S. Gao, F. H. Arnold, J. Am. Chem. Soc. 2020, 142,
10279-10283.
[4]
[5]
a) A. E. Bosnidou, K. Muñiz, Angew. Chem. 2019, 131, 7564-7568;
Angew. Chem. Int. Ed. 2019, 58, 7485-7489; b) F. Wu, J. P. Ariyarathna,
N. Kaur, N.-E. Alom, M. L. Kennell, O. H. Bassiouni, W. Li, Org. Lett.
2020, 22, 2135-2140; c) J. Liu, H. Zhang, H. Yi, C. Liu, A. Lei, Sci. China.
Chem. 2015, 58, 1323-1328.
Examples of benzylic azidation: a) S.-E. Suh, S.-J. Chen, M. Mandal, I.
A. Guzei, C. J. Cramer, S. S. Stahl, J. Am. Chem. Soc. 2020, 142, 11388-
11393; b) L. Niu, C. Jiang, Y. Liang, D. Liu, F. Bu, R. Shi, H. Chen, A.
Dutta Chowdhury, A. Lei, J. Am. Chem. Soc. 2020,
10.1021/jacs.0c08437.
Scheme 4. Mechanistic studies and proposal.
[6]
[7]
H. Wang, X. Gao, Z. Lv, T. Abdelilah, A. Lei, Chem. Rev. 2019, 119,
6769-6787.
A
possible mechanism for the electrochemical C–H
functionalization reaction is shown in Scheme 4d. Anodic
oxidation of the hydrocarbon substrate 49 produces radical cation
Examples of intramolecular reactions: a) P. Nikolaienko, M. Jentsch, A.
P. Kale, Y. Cai, M. Rueping, Chem. Eur. J. 2019, 25, 7177-7184; b) S.
This article is protected by copyright. All rights reserved.

10.1002/anie.202013478
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Herold, D. Bafaluy, K. Muñiz, Green Chem. 2018, 20, 3191-3196; c) X.
Hu, G. Zhang, F. Bu, L. Nie, A. Lei, ACS Catal. 2018, 8, 9370-9375.
[8]
Selected recent reviews on electroorganic synthesis: a) C. Kingston, M.
D. Palkowitz, Y. Takahira, J. C. Vantourout, B. K. Peters, Y. Kawamata,
P. S. Baran, Acc. Chem. Res. 2020, 53, 72-83; b) M. Yan, Y. Kawamata,
P. S. Baran, Chem. Rev. 2017, 117, 13230–13319; c) S. R. Waldvogel,
S. Lips, M. Selt, B. Riehl, C. J. Kampf, Chem. Rev. 2018, 118, 6706–
6765; d) Q.-L. Yang, P. Fang, T.-S. Mei, Chin. J. Chem. 2018, 36, 338–
352; e) S. Tang, Y. Liu, A. Lei, Chem 2018, 4, 27–45; f) Y. Yuan, A. Lei,
Acc. Chem. Res. 2019, 52, 3309-3324; g) R. Francke, R. D. Little, Chem.
Soc. Rev. 2014, 43, 2492–2521; h) D. Heard, A. Lennox, Angew. Chem.
2020,
10.1002/ange.202005745;
Angew.
Chem.
Int.
Ed.
2020,10.1002/anie.202005745; i) K. D. Moeller, Chem. Rev. 2018, 118,
4817–4833; j) J. E. Nutting, M. Rafiee, S. S. Stahl, Chem. Rev. 2018,
118, 4834–4885; k) A. Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M.
Zirbes, S. R. Waldvogel, Angew. Chem. 2018, 130, 5694–5721; Angew.
Chem. Int. Ed. 2018, 57, 5594–5619; l) S. Möhle, M. Zirbes, E. Rodrigo,
T. Gieshoff, A. Wiebe, S. R. Waldvogel, Angew. Chem. 2018, 130, 6124–
6149; Angew. Chem. Int. Ed. 2018, 57, 6018–6041; m) J. Yoshida, A.
Shimizu, R. Hayashi, Chem. Rev. 2018, 118, 4702–4730; n) Y. Jiang, K.
Xu, C. Zeng, Chem. Rev. 2018, 118, 4485–4540; o) J. C. Siu, N. Fu, S.
Lin, Acc. Chem. Res. 2020, 53, 547-560; p) T. H. Meyer, I. Choi, C. Tian,
L. Ackermann, Chem 2020, 10.1016/j.chempr.2020.08.025; q) T. H.
Meyer, L. H. Finger, P. Gandeepan, L. Ackermann, Trends Chem. 2019,
1, 63-76; r) P. Xiong, H. C. Xu, Acc. Chem. Res. 2019, 52, 3339-3350;
s) T. Noël, Y. Cao, G. Laudadio, Acc. Chem. Res. 2019, 52, 2858-2869;
t) Y. Okada, K. Chiba, Chem. Rev. 2018, 118, 4592-4630; u) Z. Ye, F.
Zhang, Chin. J. Chem. 2019, 37, 513-528; v) M. D. Kärkäs, Chem. Soc.
Rev. 2018, 47, 5786-5865.
[9]
R. Hayashi, A. Shimizu, Y. Song, Y. Ashikari, T. Nokami, J. i. Yoshida,
Chem. Eur. J. 2017, 23, 61-64.
[10] B. J. Lee, K. S. DeGlopper, T. P. Yoon, Angew. Chem. 2020, 132, 203-
208; Angew. Chem. Int. Ed. 2020, 59, 197-202.
[11] Intermolecular electrochemical benzylic C-H iodination and oxygenation
have been reported: a) M. Rafiee, F. Wang, D. P. Hruszkewycz, S. S.
Stahl, J. Am. Chem. Soc. 2018, 140, 22-25; b) H. Wang, K. Liang, W.
Xiong, S. Samanta, W. Li, A. Lei, Sci. Adv. 2020, 6, eaaz0590; c) Y.
Imada, J. L. Röckl, A. Wiebe, T. Gieshoff, D. Schollmeyer, K. Chiba, R.
Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 12136-12140.
[12] a) B. Elsler, A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R.
Waldvogel, Chem. Eur. J. 2015, 21, 12321-12325; b) L. Schulz, M.
Enders, B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R.
Waldvogel, Angew. Chem. 2017, 129, 4955-4959; Angew. Chem. Int. Ed.
2017, 56, 4877-4881; c) L. Schulz, S. R. Waldvogel, Synlett 2019, 30,
275-286; d) L. Eberson, M. P. Hartshorn, O. Persson, F. Radner, Chem.
Commun. 1996, 2105-2112.
[13] E. Baciocchi, L. Eberson, C. Rol, J. Org. Chem. 1982, 47, 5106-5110.
[14] a) E. Baciocchi, F. D'Acunzo, C. Galli, O. Lanzalunga, J. Chem. Soc.,
Perkin Trans. 2 1996, 133-140; b) E. Baciocchi, M. Bietti, O. Lanzalunga,
Acc. Chem. Res. 2000, 33, 243-251.
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Zhong-Wei Hou, Ding-Jin Liu, Peng
Xiong, Xiao-Li Lai, Jinshuai Song and
Hai-Chao Xu*
Page No. – Page No.
Site-Selective Electrochemical
Benzylic C–H Amination
Reported herein is an electrooxidative C–H/N–H cross-coupling reaction with
excellent site selectivity for benzylic positions. The electrochemical C–H amination
reaction employs easily available starting materials and proceeds under mild
conditions without need for transition metal catalysts and external chemical
oxidants.
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