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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],*
Abstract: C–H/N–H cross-coupling represents an ideal strategy to avoid product overoxidation, Yoshida and coworkers developed a
synthesize various amines but remains challenging due to the cation pool method that involves electrochemical C–N bond
requirement for sacrificial chemical oxidants and the difficulty in formation with a sulfilimine in a divided cell followed by chemical
controlling the regio- and chemo-selectivity. Herein we report a site- reduction with iodide (Scheme 1b).[9] With our continued interest
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selective electrochemical amination reaction that can convert benzylic in constructing C–N bonds via electrochemical approaches,[8r] we
C–H bonds to C–N linkages via H2 evolution without need for external report herein an unprecedented benzylic C–H amination reaction
oxidants or metal catalysts. The synthetic strategy involves anodic via electrochemical C–H/N–H cross-coupling (Scheme 1c). Our
cleavage of benzylic C–H to form a carbocation intermediate, which method features metal- and oxidant-free conditions and excellent
is then trapped with an amine nucleophile leading to C–N bond site-selectivity for benzylic functionalization.
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.
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
Entry Deviation from standard conditions Yield [%][b] 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).
We next evaluated the amination of different benzylic
substrates with TsNH2 (Scheme 2). Ethylbenzene (4) and its
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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
[a] Reaction conditions: undivided cell, 1 (0.3 mmol), 2 (0.6 mmol), solvent addition, the C–H amination also exhibited a clear preference for
(6 mL), nBu4NBF4 (0.36 mmol), 7.5 mA, RT, 2.5 h (2.3 F mol–1). [b] less hindered benzylic positions (24–26). Note that no amination
Determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as the occurred at non-benzylic positions.
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 ester without touching the benzylic Me group of Celebrex. Other
suggested broad reaction compatibility with H (28), Et (29), tBu suitable nitrogen nucleophiles included N-methyl
(30), CF3 (31), F (32), Cl (33) and Br (34) at the 4-positon of the toluenesulfonamide (37), methanesulfonamide (38, 39),
phenyl ring, as well as Me (35) at the 2-position (Scheme 3). sulfamides (40–44), and pyrazole (45). It is particularly
Notably, the sulfonamide drug Celebrex could be easily coupled noteworthy that the benzylic C–H in 1 could also be functionalized
with dehydroabietic acid methyl ester to form the amination with oxygen nucleophiles such as acetate (46), ethylene glycol
product (36) in 88% yield. Apparently, selective C–H amination (47), or HFIP (48).[11]
occurred on the benzylic methylene of dehydroabietic acid methyl
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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 were obtained (Scheme 4a, left), revealing that ethylbenzene (Ep/2
performed on a gram scale, as demonstrated by the synthesis of = 1.90 V vs SCE) is oxidized at lower potential than both 4 (Ep/2 =
3 and 36 (Figure 1), in which larger electrodes were employed to 2.00 V vs SCE) and TsNH2 (Ep/2 = 2.23 V vs SCE). Despite the
ensure complete reaction in several hours. 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
Figure 1. Gram scale synthesis of 3 and 36. 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
As part of the mechanistic studies, cyclic voltammograms of oxidation reactions.[13] Primary KIE observed for this product
ethylbenzene, its aminated product 4 and TsNH2 in DCE/HFIP determining C–H cleavage is consistent with our experimental
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observation that the reaction kinetics were sensitive to steric and 50, which loses a benzylic proton to furnish carbon radical 51.
electronic properties of the donor benzylic C –H bond. 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 H 2,
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
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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.
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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.
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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*
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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.