Metal-Free Benzylic C?H Amination via Electrochemically Generated Benzylaminosulfonium Ions

Article abstract of DOI:10.1002/chem.201604484

Electrochemical oxidation of toluene derivatives in the presence of N-tosyldiphenylsulfilimine gave the corresponding benzylaminosulfonium ions, which were treated with tetrabutylammonium iodide under non-electrolytic conditions to give N-tosylbenzylamines. The transformation serves as a metal- and chemical-oxidant-free method for benzylic C?H amination. Because of high oxidation potential of N-tosyldiphenylsulfilimine the present method can be applied to synthesis of various benzylamines from functionalized toluene derivatives.

Full text of DOI:10.1002/chem.201604484

A Journal of
Accepted Article
Title: Metal-Free Benzylic C-H Amination via Electrochemically
Generated Benzylaminosulfonium Ions
Authors: Jun-ichi Yoshida, Ryutaro Hayashi, Akihiro Shimizu, Yetao
Song, Yosuke Ashikari, and Toshiki Nokami
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201604484
Link to VoR: http://dx.doi.org/10.1002/chem.201604484
Supported by

10.1002/chem.201604484
Chemistry - A European Journal
COMMUNICATION
Metal-Free Benzylic C–H Amination via Electrochemically Generated Benzylaminosulfonium Ions
Ryutaro Hayashi[a], Akihiro Shimizu[a], Yetao Song[a], Yosuke Ashikari[a], Toshiki Nokami[a,b], and Jun-
ichi Yoshida*[a]
Abstract: Electrochemical oxidation of toluene derivatives in the
presence of N-tosyldiphenylsulfilimine gave the corresponding
benzylaminosulfonium
ions,
which
were
treated
with
tetrabutylammonium iodide under non-electrolytic conditions to give
N-tosylbenzylamines. The transformation serves as a metal- and
chemical-oxidant-free method for benzylic C–H amination. Because
of high oxidation potential of N-tosyldiphenylsulfilimine the present
method can be applied to synthesis of various benzylamines from
functionalized toluene derivatives.
C–H amination[1] serves as a step-economical[2] method for C–
N
bond formation because prefunctionalization of carbon
substrates is not required. In particular, we have been interested
3
in developing a new method for intermolecular Csp –H amination,
3
because low reactivity of Csp –H bonds makes its
functionalization more difficult than that of other C–H bonds.[3]
Also, selective intermolecular C–H functionalization is generally
difficult from view points of chemo- and regiochemistry. While
3
several
transition-metal-catalyzed
intermolecular
Csp –H
amination reactions have been reported,[4] transition-metal-free
methods should be preferred from an environmental point of
view.[1e,5] However, in many cases, an excess amount of a
carbon substrate is necessary to suppress overreaction.
Although there are some reports aimed at solving such a
problem,[6] the development of a more versatile method is still
desired, in particular, for benzylic C–H amination.
Electrochemical oxidation serves as a powerful method for
generating reactive cationic species via benzylic C–H bond
cleavage.[7,8] However, electrochemical benzylic C–H amination
often suffers from undesired oxidation of nitrogen nucleophiles,
which have usually lower oxidation potentials than those of
carbon substrates (Scheme 1a). The use of amines bearing an
electron-withdrawing group would lead to selective oxidation of
carbon substrates, but oxidation of the amination products
(overoxidation) is unavoidable because the products have
similar oxidation potentials to those of carbon substrates
(Scheme 1b). The use of acetonitrile as a nucleophile/solvent
leads to effective introduction of a nitrogen atom on the carbon,
but the products obtained after hydrolysis are acetoamide
derivatives which are rather difficult to transform into other
nitrogen-containing compounds in comparison with amines and
other protected amines.[9]
Scheme 1. Electrochemical Benzylic C–H Amination.
Recently, we and others have reported electrochemical
aromatic and benzylic C–H functionalization using nitrogen
nucleophiles such as pyridine,[10a,e] N-mesylimidazole,[10b]
pyrimidine,[10c] oxazoline,[10d] and sulfilimine.[10f] In these
reactions, starting carbon substrates are electrochemically
oxidized in the presence of nitrogen nucleophiles to generate
and accumulate electrooxidatively inactive cationic intermediates.
After the electrolysis, the cationic intermediates are transformed
into desired products by chemical reactions under non-oxidative
conditions. Because of the intermediacy of the cationic species,
overoxidation is completely suppressed. Therefore, the use of
excess amounts of carbon substrates is not necessary for the
transformation. On the basis of these backgrounds, we
envisaged that electrochemical benzylic C–H amination without
using excess amounts of carbon substrates could be achieved
using a similar methodology.
We first examined benzylic C–H amination using pyridine
because we have previously reported aromatic C–H amination
using pyridine (Scheme 2).[10a] When 4-methoxytoluene (1a) was
electrochemically oxidized in the presence of pyridine, a mixture
of the benzylpyridinium derivative and the phenylpyridinium
derivative were obtained, indicating that selective benzylic C–H
transformation using pyridine is difficult. Moreover, the
benzylpyridinium derivative did not react with piperidine to give
the desired benzylamine. The result shows pyridine is not a
suitable nitrogen nucleophile for benzylic C–H amination.
[a]
[b]
R. Hayashi, Dr. A. Shimizu, Y. Song, Dr. Y. Ashikari, Prof. Dr. J.
Yoshida
Department of Synthetic Chemistry, Biological Chemistry
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Prof. Dr. T. Nokami
Department of Chemistry and Biotechnology
Graduate School of Engineering, Tottori University
Koyamachominami, 680-8552 Tottori (Japan)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201604484
Chemistry - A European Journal
COMMUNICATION
Table 1. Benzylic C–H amination using sulfilimines.[a]
[b]
entry
1
sulfilimine
Ed
product
yield [c]
79%
Scheme 2. Benzylic C–H amination using pyridine. Yields determined by NMR
are shown. The yield in the parenthesis was determined by GC.
2.01
1.82
2.15
We then examined benzylic C–H amination using
a
sulfilimine bearing tosyl (Ts) group (2a). We have already
reported that the electrochemical oxidation of benzylic
substrates gives N-tosylbenzylaminosulfonium ions which
reacted as benzylcation equivalent with carbon nucleophiles via
C–N bond cleavage.[10f] We envisaged that under suitable
2
3
81%
1%
conditions
N-tosylbenzylaminosulfonium
ions
can
be
transformed into the corresponding benzylamine via N–S bond
cleavage without cleaving the C–N bond (Scheme 1c). We
chose Bu4NI as a nucleophile because N–S bond in sulfilimines
is reductively cleaved by I-.[11] In fact, the N-
tosylbenzylaminosulfonium ion 3a, which was generated by the
electrochemical oxidation of 1a in the presence of 2a, was
successfully converted into the corresponding benzylamine 4a
and diphenyl sulfide by the treatment with Bu4NI (Table 1, entry
1). In addition, unchanged 2a was also recovered (See
Supporting Information for the details). Notably, benzylic C–H
amination of 1a was successfully achieved without using an
excess amount of 1a. Also, the fact that the oxidation potential of
4a (1.49 V) is close to that of 1a (1.38 V) indicates that the direct
oxidation of 1a to 4a should suffer from overoxidation. Thus, the
present two step transformation via the cationic intermediate is
advantageous.
Next, we examined the effect of the substituent on the
nitrogen atom because it should affect the oxidation potential
and nucleophilicity of sulfilimines (Table 1). A sulfilimine having
benzoyl (Bz) group 2b also gave the corresponding benzylamine
5a in 81% yield (entry 2). However, the sulfilimine having 4-
nitrobenzenesulfonyl (Nos) group 2c gave the corresponding
benzylamine 6a in only 1% (entry 3). This is probably because of
low nucleophilicity of 2c, which is expected from its high
oxidation potential (decomposition potential: 2.15 V vs SCE).
Hereafter we used 2a as a nitrogen source because the
oxidation potential of 2a (decomposition potential: 2.01 V), is
higher than that of 2b (1.82 V), which enables selective
oxidation of wider range of toluene derivatives. In addition,
several methods for deprotection of tosyl group have been
reported.[12]
[a] 1a (0.1 mmol) was electrochemically oxidized in the presence of 1.0 mmol
of 2 in a 0.1 M solution of Bu4NB(C6F5)4 in CH2Cl2 at 25 °C. After 2.1 F of
electricity was applied, the resulting solution was treated with Bu4NI (0.5
mmol) at 25 °C. [b] Decomposition potential (V vs SCE). [c] Isolated yields of
the products based on the amount of 1a used.
The present two-step one-pot transformation is applicable to
various toluene derivatives whose oxidation potentials are 1.38–
1.94 V because of high oxidation potential of 2a (Table 2).
Toluene (1b), xylenes, and toluene derivatives having tert-butyl,
aryl, acetoxy, N-phthaloyl (PhthN), and halogen groups at 4-
position gave the corresponding N-tosylbenzylamines (entries
1–12). It is noteworthy that the substrate having two benzylic C–
H bonds gave the monoaminated product selectively (entries 2,
3, 4, and 6). 4-Methoxytoluene derivatives having bromo, ketone
carbonyl, ester carbonyl, and nitro groups at 3-position were
successfully
transformed
to
the
corresponding
N-
tosylbenzylamines (entries 14–17). Toluene derivatives having
secondary benzylic C–H bonds can also be transformed to the
corresponding N-tosylbenzylamines. Ethylbenzene (1r) gave N-
tosyl-1-phenylethylamine (entry 18). The benzylic C–H bonds at
α-position of ketone and ester carbonyl groups were also
successfully transformed to the coresponidng α-amino ketone
and α-amino ester (entries 19 and 20). Moreover,
heteroaromatic compounds such as 2-methylthiophene
derivative 1u was successfully aminated (entry 21).
In conclusion, we have developed a two-step one-pot metal-
and chemical-oxidant-free method for benzylic C–H amination
without using excess amounts of carbon substrates via
electrochemically generated N-tosylbenzylaminosulfonium ions.
The method is applicable to various functionalized toluene
derivatives by virtue of the high oxidation potential and sufficient
nucleophilicity of the N-tosylsulfilimine.
This article is protected by copyright. All rights reserved.

10.1002/chem.201604484
Chemistry - A European Journal
COMMUNICATION
13
1.38
1.59
79%
86%
Table 2. Benzylic C–H amination of various toluene derivatives.[a]
14[d]
15
16
17
1.58
1.62
1.77
76%
66%
90%
[b]
entry
1
substrate
Ed
product
yield[c]
38%
1.94
2
3
1.84
1.85
66%
53%
18[e]
1.94
1.50
69%
76%
19
4
5
1.85
1.79
84%
73%
20
21
1.54
1.75
76%
41%
6
1.50
62%
85%
[a] 1 (0.1 mmol) was electrochemically oxidized in the presence of 2a (1.0
mmol) in a 0.1 M solution of Bu4NB(C6F5)4 in CH2Cl2 at 25 °C. After 2.1 F of
electricity was applied, the resulting solution was treated with Bu4NI (0.5
mmol) at 25 °C. [b] Decomposition potential (V vs SCE). [c] Isolated yields of
the products based on the amount of 1 used. [d] 1 (0.2 mmol) was used. [e]
3.0 F of electricity was applied.
7[d]
1.82
1.81
1.93
1.94
1.89
1.79
8
48%
69%
31%
74%
81%
9
Experimental Section
10
11
12
In the anodic chamber of an H-type divided cell were placed 4-
methoxytoluene 1a (12.8 mg, 0.10 mmol), S,S-diphenyl-N-(4-
methylbenzenesulfonyl)sulfilimine 2a (351 mg, 0.99 mmol), 0.1
Bu4NB(C6F5)4/CH2Cl2 (10 mL). In the cathodic chamber were placed
trifluoromethanesulfonic acid (30 μL, 0.34 mmol) and 0.1
Bu4NB(C6F5)4/CH2Cl2 (10 mL). The constant current electrolysis (4.0 mA)
was carried out at 25 °C with magnetic stirring until 2.1 F of electricity
was consumed. 0.5 M Bu4NI/CH2Cl2 (1 mL) was added to both the
anodic and the cathodic chambers, and the resulting mixtures in both
champers were stirred 25 °C for 1 h. The solution in the anodic chamber
was collected and the solvent was removed under reduced pressure. The
M
M
This article is protected by copyright. All rights reserved.

10.1002/chem.201604484
Chemistry - A European Journal
COMMUNICATION
crude product was purified by flash chromatography to obtain N-[(4-
methoxyphenyl)methyl]-4-methylbenzenesulfonamide 4a (24.2 mg, 79%
yield).
[5]
[6]
Recent examples of metal-free C–H amination: a) R. Fan, W. Li, D. Pu,
L. Zhang, Org. Lett. 2009, 11, 1425-1428; b) H. Baba, H. Togo,
Tetrahedron Lett. 2010, 51, 2063-2066; c) D. Ramesh, U. Ramulu, K.
Mukkanti, Y. Venkateswarlu, Tetrahedron. Lett. 2012, 53, 2904-2908;
d) I. Buslov, X. Hu, Adv. Synth. Catal. 2014, 356, 3325-3330.
a) A. J. Borah, P. Phukan, Chem. Commun. 2012, 48, 5491-5493; b) J.
Liu, H. Zhang, H. Yi, C. Liu, A. Lei, Sci. China Chem. 2015, 58, 1323-
1328; c) G. Pandey, R. Laha, Angew. Chem. Int. Ed. 2015, 54, 14875-
14879; G. Pandey, R. Laha, Angew. Chem. 2015, 127, 15088-15092;
d) Y.-Y. Wang, M.-H. Sun, N.-N. Zeng, J. Chem, L. Zhou, Synlett 2016,
27, 1438-1442.
Acknowledgements
This work was supported by the JSPS (KAKENHI Grants
JP26220804, and JP16K14057). We thank NIPPON SHOKUBAI
CO., Ltd., for providing NaB(C6F5)4.
[7]
[8]
a) K. D. Moeller, Tetrahedron 2000, 56, 9527-9554; b) J. B. Sperry, D.
L. Wright, Chem. Soc. Rev. 2006, 35, 605-621; c) J. Yoshida, K.
Kataoka, R. Horcajada, A. Nagaki, Chem. Rev. 2008, 108, 2265-2299;
d) J. Yoshida, A. Shimizu, Y. Ashikari, T. Morofuji, R. Hayashi, T.
Nokami, A. Nagaki, Bull. Chem. Soc. Jpn. 2015, 88, 763-775; e) E. J.
Horn, B. R. Rosen, P. S. Baran, ACS Cent. Sci. 2016, 2, 302-308.
Examples of electrochemical benzylic C–H transformation: a) D.
Hoormann, C. Kubon, J. Jörissen, L. Kröner, H. Pütter, J. Electroanal.
Chem. 2001, 507, 215-225; b) T. Tajima, T. Fuchigami, Angew. Chem.
Int. Ed. 2005, 44, 4760-4763; T. Tajima, T. Fuchigami, Angew. Chem.
2005, 117, 4838-4841; c) M. Okajima, K. Soga, T. Nokami, S. Suga, J.
Yoshida, Org. Lett. 2006, 8, 5005-5007; d) Y. Ashikari, T. Nokami, J.
Yoshida, J. Am. Chem. Soc. 2011, 133, 11840-11843; e) Y. Ashikari, T.
Nokami, J. Yoshida, Org. Lett. 2012, 14, 938-941.
Keywords: C–H amination • C–H functionalization • oxidation •
electrochemistry • benzyl cations
[1]
Reviews: a) H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417-
424; b) F. Collet, R. H. Dodd, P. Dauban, Chem. Commun. 2009, 5061-
5074; c) C.-M. Che V. K.-Y. Lo, C.-Y. Zhou, J.-S. Huang, Chem. Soc.
Rev. 2011, 40, 1950-1975; d) R. T. Gephart, T. H. Warren,
Organometallics 2012, 31, 7728-7752; e) R. Samanta, K. Matcha, A. P.
Antonchick, Eur. J. Org. Chem. 2013, 5769-5804; f) M.-L. Louillat, F. W.
Patureau, Chem. Soc. Rev. 2014, 43, 901-910; g) K. Shin, H. Kim, S.
Chang, Acc. Chem. Res. 2015, 48, 1040-1052.
[2]
[3]
[4]
P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res.
2008, 41, 40-49.
[9]
a) L. Eberson, K. Nyberg, Tetrahedron Lett. 1966, 7, 2389-2393; b) V.
D. Parker, B. E. Burgert, Tetrahedron Lett. 1968, 9, 2411-2414; c) L.
Eberson, B. Olofsson, Acta Chem. Scand. 1969, 23, 2355-2366.
R. Narayan, K. Matcha, A. P. Antonchick, Chem. Eur. J. 2015, 21,
14678-14693.
[10] a) T. Morofuji, A. Shimizu, J. Yoshida, J. Am. Chem. Soc. 2013, 135,
5000-5003; b) T. Morofuji, A. Shimizu, J. Yoshida, J. Am. Chem. Soc.
2014, 136, 4496-4499; c) T. Morofuji, A. Shimizu, J. Yoshida, Chem.
Eur. J. 2015, 21, 3211-3214; d) T. Morofuji, A. Shimizu, J. Yoshida, J.
Am. Chem. Soc. 2015, 137, 9816-9819; e) S. Herold, S. Mohle, M.
Zirbes, F. Richter, H. Nefzger, S. R. Waldvogel, Eur. J. Org. Chem.
2016, 1274-1278; f) R. Hayashi, A. Shimizu, J. Yoshida, J. Am. Chem.
Soc. 2016, 138, 8400-8403.
Recent examples of metal-catalyzed C–H amination: a) X.-Q. Yu, J.-S.
Huang, X.-G. Zhou, C.-M. Che, Org. Lett. 2000, 2, 2233-2236; b) Z. Ni,
Q. Zhang, T. Xiong, Y. Zheng, Y. Li, H. Zhang, J. Zhang, Q. Liu, Angew.
Chem. Int. Ed. 2012, 51, 1244-1247; Z. Ni, Q. Zhang, T. Xiong, Y.
Zheng, Y. Li, H. Zhang, J. Zhang, Q. Liu, Angew. Chem. 2012, 124,
1270-1273; c) Á. Iglesias, R. Álvarez, Á. R. de Lera, K. Muñiz, Angew.
Chem. Int. Ed. 2012, 51, 2225-2228; Á. Iglesias, R. Álvarez, Á. R. de
Lera, K. Muñiz, Angew. Chem. 2012, 124, 2268-2271; d) Y. Zhang, B.
Feng, C. Zhu, Org. Biomol. Chem. 2012, 10, 9137-9141; e) Y. Nishioka,
T. Uchida, T. Katsuki, Angew. Chem. Int. Ed. 2013, 52, 1739-1742; Y.
Nishioka, T. Uchida, T. Katsuki, Angew. Chem. 2013, 125, 1783-1786;
f) Y. Liu, X. Guan, E. L.-M. Wong, P. Liu, J.-S. Huang, C.-M. Che, J.
Am. Chem. Soc. 2013, 135, 7194-7204; g) C. Tang, M. Zou, J. Liu, X.
Wen, X. Sun, Y. Zhang, N. Jiao, Chem. Eur. J. 2016, 22, 11165-11169.
[11] a) P. R. Young, P. E. McMahon, J. Am. Chem. Soc. 1985, 107, 7572-
7577; b) P. R. Young, H. C. Huang, J. Am. Chem. Soc. 1987, 109,
1810-1813
[12] Examples of deprotection of tosyl group: a) H. L. S. Maia, M. J.
Medeiros, M. I. Montenegro, D. Court, D. Pletcher, J. Electroanal.
Chem. 1984, 164, 347-361; b) R. C. Roemmele, H. Rapoport, J. Org.
Chem. 1988, 53, 2367-2371; c) T. Ankner, G. Hilmersson, Org. Lett.
2009, 11, 503-506.
This article is protected by copyright. All rights reserved.

10.1002/chem.201604484
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Ryutaro Hayashi, Akihiro Shimizu, Yetao
Song, Yosuke Ashikari, Toshiki Nokami,
and Jun-ichi Yoshida*
Page No. – Page No.
Metal-Free Benzylic C–H Amination
via Electrochemically Generated
Benzylaminosulfonium Ions
Electrochemical C–H Amination: Electrochemical oxidation of toluene derivatives
in the presence of N-tosyldiphenylsulfilimine gave the corresponding
benzylaminosulfonium ions, which were treated with tetrabutylammonium iodide
under non-electrolytic conditions to give N-tosylbenzylamines. The transformation
serves as a metal- and chemical-oxidant-free method for benzylic C–H amination.
This article is protected by copyright. All rights reserved.