Metal-free remote oxidative benzylic C?H amination of 4-methylanilides with N-fluorobenzenesulfonimide

Article abstract of DOI:10.1016/j.tet.2018.01.041

A metal-free remote oxidative benzylic C?H amination of 4-methylanilides with N-fluorobenzenesulfonimide was reported. The reaction was promoted by a hypervalent iodine reagent and can be handled under mild and neutral conditions, providing the highly regioselective benzylic C?H amination products even with multi-substituted 4-methylanilides. It provided a novel and facile method for the construction of C(sp³)–N bonds.

Full text of DOI:10.1016/j.tet.2018.01.041

Tetrahedron xxx (2018) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Metal-free remote oxidative benzylic CꢀH amination of
4-methylanilides with N-fluorobenzenesulfonimide
,
,
,
b
,
, *
Yaocheng Yang a b, Yanting Yu b, Yang Wang a b, Qian Zhang a **, Dong Li b
a Hubei Collaborative Innovation Center for High-Efficiency Utilization of Solar Energy, Hubei University of Technology, Wuhan 430068, China
b School of Materials and Chemical Engineering, Hubei University of Technology, Wuhan 430068, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A
metal-free remote oxidative benzylic CꢀH amination of 4-methylanilides with N-fluo-
Received 29 September 2017
Received in revised form
19 January 2018
Accepted 22 January 2018
Available online xxx
robenzenesulfonimide was reported. The reaction was promoted by a hypervalent iodine reagent and can
be handled under mild and neutral conditions, providing the highly regioselective benzylic CꢀH ami-
nation products even with multi-substituted 4-methylanilides. It provided a novel and facile method for
the construction of C(sp3)eN bonds.
© 2018 Published by Elsevier Ltd.
Keywords:
Benzylic CꢀH bond
Amination
Hypervalent iodine
Metal-free
N-Fluorobenzenesulfonimide
1. Introduction
involvement of heavy metals and normally also extra oxidants or
bases was unsatisfactory from the environmental point of view. The
The construction of CeN bond has attracted much attention of
organic chemists because nitrogen-containing compounds play a
pivotal role in pharmaceuticals, agrochemicals, materials, and
biologically relevant molecules.1 During the past decades, direct
amination of CeH bond has emerged as an important methodology
for CeN bond formation.2 However, compared with considerable
achievements towards the transformation of sp2 CeH bonds to CeN
bond, fewer progress have been made for the sp3 CeH amination.3
In 2006, Che and coworkers reported Pd-catalyzed sp3 CeH
amination of 8-methylquinolines with amides through cascade
CꢀH activation/nitrene insertion.4 Afterwards, various transition-
metal catalysts such as Rh, Ir, Cu were used for directed benzylic
sp3 CeH amination (Scheme 1a).5 Significant progress has also been
made in CeH amination of the substrate without directing groups
under Cu, Rh, Fe, Ni or Au catalysts (Scheme 1b).6 However, the
metal-free methods should be concerned for the pursuit of sus-
tainable and green chemistry.7 Oxidative amination of toluene
benzylic CeH bond was also reported in recent years however large
excess amount of the carbon substrate was normally necessary.8 To
overcome these problems, several strategies such as photoredox
catalysis and electrochemical process were employed.9 Recently, N-
fluorobenzenesulfonimide (NFSI) has been widely used as a nitro-
gen source for CeH aminations.10 Zhang and coworkers developed
a palladium-catalyzed amide-directed amination of anilide para-
CeH bond and 4-methylanilide benzylic CeH bond with NFSI
(Scheme 1c).11 In 2016 our group achieved the para-CeH amination
of anilides with NFSI under metal-free conditions.12
As part of our continuing efforts on the development of metal-
free oxidative transformations,13 herein we report the remote
oxidative benzylic sp3 CeH amination 4-methylanilides with NFSI.
The reaction was promoted by a hypervalent iodine reagent under
mild and neutral conditions, providing the highly regioselective
benzylic amination products (Scheme 1d).
* Corresponding author.
** Corresponding author. Hubei Collaborative Innovation Center for High-
efficiency Utilization of Solar Energy, Hubei University of Technology, Wuhan
430068, China.
2. Results and discussion
E-mail addresses: zhangqian620@hotmail.com (Q. Zhang), dongli@mail.hbut.
edu.cn (D. Li).
Initially, reaction between 4-methylacetanilide (1a) and NFSI (2
https://doi.org/10.1016/j.tet.2018.01.041
0040-4020/© 2018 Published by Elsevier Ltd.
Please cite this article in press as: Yang Y, et al., Metal-free remote oxidative benzylic CꢀH amination of 4-methylanilides with N-
fluorobenzenesulfonimide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.041

2
Y. Yang et al. / Tetrahedron xxx (2018) 1e7
65 ꢁC) was not beneficial to the product yield (entries 16 and 17).
Therefore, the optimal reaction conditions were determined as
shown in entry 7.
Under the optimized reaction conditions,
a series of 4-
methylanilide had been investigated and the results were showed
in Table 2. This method was applicable to various alkyl amides such
as propionyl (2b), butyryl (2c), phenylpropionyl (2d), isobutyryl
(2e), cyclopropanecarboxyl (2f) and cyclohexanecarboxyl (2g)
amides for this reaction, affording the corresponding benzylic
amination products in moderate yields. Benzamide can also be
applied but showed lower reactivity than alkyl amides in this
transformation, which provide the amination product in 43% yield
(2h). The 4-methylpropionylaniline gave the desired product in
highest yield of 65%. In most cases, unreacted starting material
remained after reaction and could be recovered.
To further explore the applicability of our methodology, a vari-
ety of multi-substituted 4-methylanilides was then investigated as
shown in Table 3. The anilides possessing 2,4-dimethyl (2iꢀ2m) or
3,4-dimethyl (2nꢀ2r) substituents all gave the 4-methyl benzylic
CeH bond amination products, which were obtained in moderate
yields. No amination was observed at ortho- or meta-methyl group
of the anilides except for unreacted starting materials. The regio-
selectivity was further confirmed by X-ray crystallography of 2n
(Fig. 1).14
Scheme 1. Amination of benzylic CꢀH bonds.
Table 1
Optimization of reaction conditionsa,b
.
Several control experiments were carried out to illustrate the
reaction mechanism (Scheme 2). In the presence of radical scav-
engers such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or
butylated hydroxytoluene (BHT), the benzylic CeH amination was
completely prevented. The starting material almost remained
intact and no identifiable product was detected either. Otherwise,
the reaction gave the desired product in 50% yield in the presence
of proton scavenger DMAP. These results suggested that the reac-
tion might proceed through a radical mechanism. To examine the
necessity of the amide group, we tested several analogous sub-
strates such as N-methyl-N-(p-tolyl)acetamide (1s), p-tolyl acetate
(1t) and N, N-dimethyl-p-toluidine (1u) however no reaction
occurred. It indicated the essential role of amide group in this
process (Scheme 3).
Thus a plausible mechanism for this remote oxidative benzylic
CꢀH amination has been proposed according to these results and
previous reports (Scheme 4). 4-Methylanilide (1) was first oxidized
by the iodine(III) reagent to generate a radical intermediate A.15
Single electron transfer of A formed a cation B which might
isomerize to a dienimine intermediate C.16 On the other hand, the
NFSI converted to a nitrogen radical which might be induced by the
iodine radical.17 Then the nitrogen radical reacted with C to form
intermediate D, which interacted with 1 to generate the product 2.
Finally, we handled the desulfonylation reaction of the sulfon-
amide product. The dibenzenesulfonyl group could be easily
removed by conc. H2SO4 with high efficiency (Scheme 5). It will
provide a novel and facile route for the preparation of benzylic
amines.
Entry
Oxidant (equiv)
Solvent
T (ꢁC)
Yield (%)b
1
2
3
4
5
6
7
8
PhI(OCOPh)2(2)
PhI(OCOPh)2(2)
PhI(OCOPh)2(2)
PhI(OCOPh)2(2)
PhI(OCOPh)2(2)
PhI(OCOPh)2(2)
PhI(OCOPh)2(2)
PhI(OAc)2(2)
PhI(OPiv)2(2)
TBHP(2)
toluene
DME
DCE
1,4-dioxane
PhCl
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
65
0
0
trace
trace
trace
37
65c
37
35
0
THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
9
10
11
12
13
14
15d
16
17
K2S2O8(2)
e
0
0
PhI(OCOPh)2(1.5)
PhI(OCOPh)2(2.5)
PhI(OCOPh)2(2)
PhI(OCOPh)2(2)
PhI(OCOPh)2(2)
41
65
47
60
50
a
Reaction conditions: 4-methylacentaniline (1a) (0.2 mmol), NFSI (0.4 mmol),
oxidant (0.4 mmol) in solvent (2.0 mL) stirring under air for 8 h.
b
Isolated yields.
25% starting material recovered.
With 1.5 eq NFSI.
c
d
equiv) was carried out for condition optimization (Table 1). After
solvent screening, it was found that the reaction proceeded at room
temperature in THF in the presence of 2 equivalents of PhI(OCOPh)2
to generate the desired benzylic CeH amination product in 37%
yield (entry 6). To our delight, the product yield was greatly
improved (65%) by changing the solvent to 2-methyltetrafuran (2-
Me-THF) (entry 7). With trace amount of ortho-amination product
be detected, 25% starting material could be recovered. Hypervalent
iodine reagents such as PhI(OAc)2 and PhI(OPiv)2 were also exam-
ined but exhibited lower efficiency than PhI(OCOPh)2 (entries 8 and
9). The reaction didn't proceed at all with other oxidants such as
TBHP and K2S2O8 or without any oxidant (entries 10e12). Subse-
quent exploration in reactant ratios showed that decreasing or
increasing the amount of PhI(OCOPh)2 couldn't provide better re-
sults (entries 13 and 14). Reducing the amount of NFSI caused a
lower product yield (entry 15). The reaction temperature was then
examined and the results showed higher temperature (40 ꢁC or
3. Conclusions
In summary, we have developed a metal-free remote oxidative
benzylic CꢀH amination of 4-methylanilides with NFSI mediated by
iodine(III) reagent. This method avoided the used of transition
metals and proceeded under mild and neutral conditions,
providing the highly regioselective benzylic amination products
even with multi-substituted 4-methylanilides. A radical reaction
pathway was proposed by preliminary mechanistic studies. It
provided an novel and facile methodology for the construction of
C(sp3)eN bonds. Intensive study and further application of this
protocol is currently under way in our lab.
Please cite this article in press as: Yang Y, et al., Metal-free remote oxidative benzylic CꢀH amination of 4-methylanilides with N-
fluorobenzenesulfonimide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.041

Y. Yang et al. / Tetrahedron xxx (2018) 1e7
3
Table 2
Substrate scope of amination of 4-methylanilides (1)a,b
.
Entry
1
Substrate (1)
Product (2)
Yield (%)b
65
2
3
4
46
42
55
5
6
56
35
12
43
a
Reaction conditions: 4-methylacentaniline (1a) (0.2 mmol), NFSI (0.4 mmol), oxidant (0.4 mmol) in solvent (2.0 mL) stirring under air for 8 h.
Isolated yields.
b
4. Experimental section
4.2. General procedure for the oxidative benzylic CꢀH amidation of
4-methylanilides (1)
4.1. General experimental
To
a solution of 4-methylanilide (1) (0.20 mmol) in 2-
1H NMR, 13C NMR spectra were recorded on a Bruker DPX-400
spectrometer with CDCl3 as the solvent and TMS as an internal
standard, operating at 400 MHz for 1H NMR and 100 MHz for 13C
NMR. Melting points were measured by SGW X-4A microscopic
apparatus. IR spectra were recorded on a Nicolet IS50 FTIR. spec-
trometer. HRMS-ESI were measured by Q Exactive LC/HRMS
spectrometer.
methyltetrahydrofuran (2.0 mL) was added the N-fluo-
robenzenesulfonimide (126 mg, 0.40 mmol). The reaction was
stirred at 25 ꢁC for 8 h under air. Then the mixture was poured into
water (25 mL) and extracted with ethyl acetate (3 ꢂ 15 mL). The
combined organic layer was dried (Na2SO4) and filtered over Celite,
evaporated in vacuo. The residue was purified by column chroma-
tography (ethyl acetate/hexane) to afford the pure product.
Dichloromethane, ethyl acetate and hexane were obtained from
commercial sources and used for column chromatography without
further purification. Other solvents were purified according to the
standard methods. Other chemicals were obtained from commer-
cial sources and used as received unless otherwise noted. All the
anilides were synthesized through the coupling between corre-
sponding aryl or alkyl acids and anilines according to previous
procedures.12
4.3. Procedure for synthesis of 3a
A solution of 2a (0.3 mmol) in conc. H2SO4 (3 mL) was stirred at
25 ꢁC for 3 h under air. Then the mixture was poured into water
(25 mL) and extracted with ethyl acetate (3 ꢂ 15 mL). The combined
organic layer was dried (Na2SO4) and filtered over Celite, evapo-
rated in vacuo. The residue was purified by column chromatography
Please cite this article in press as: Yang Y, et al., Metal-free remote oxidative benzylic CꢀH amination of 4-methylanilides with N-
fluorobenzenesulfonimide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.041

4
Y. Yang et al. / Tetrahedron xxx (2018) 1e7
Table 3
Substrate scope of multi-substituted 4-methylanilides (1)a,b
.
Entry
1
Substrate (1)
Product (2)
Yield (%)b
45
2
3
4
5
28
38
44
40
6
45
30
36
45
40
7
8
9
10
a
Reaction conditions: (1) (0.2 mmol), NFSI (0.4 mmol), PhI(OCOPh)2 (0.4 mmol) in 2-Me-THF (2.0 mL) stirring at 25 ꢁC under air for 8 h.
Isolated yields.
b
Please cite this article in press as: Yang Y, et al., Metal-free remote oxidative benzylic CꢀH amination of 4-methylanilides with N-
fluorobenzenesulfonimide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.041

Y. Yang et al. / Tetrahedron xxx (2018) 1e7
5
2H), 7.79 (d, J ¼ 7.92 Hz, 4H), 13C NMR (100 MHz, CDCl3):
d
24.7,
52.0, 119.6, 128.1, 128.8, 128.9, 130.0, 137.7, 137.8, 139.9, 168.2.
HRMS-ESI (m/z): calcd for C21H20N2O5S2 (MþHþ): 444.5239, found
444.5243.
4.4.2. N-(4-((N-(Phenylsulfonyl)phenylsulfonamido)methyl)-
phenyl)propionamide (2b)
Yellow solid, mp 109e110 ꢁC; IR (KBr, cmꢀ1): 1168, 1370, 1655,
2920, 3431. 1H NMR (400 MHz, CDCl3):
d 1.25e1.26 (m, 3H), 2.38
(dd, J1 ¼7.52 Hz, J2 ¼ 15.08 Hz, 2H), 4.89 (s, 2H), 7.20 (s, 1H),
7.31e7.33 (m, 2H), 7.39e7.46 (m, 6H), 7.56e7.60 (m, 2H), 7.79e7.81
(m, 4H), 13C NMR (100 MHz, CDCl3):
d 31.5, 39.5, 52.0, 119.7, 128.1,
Fig. 1. X-ray crystallography of 2n.
128.9, 130.0, 130.3, 133.7, 137.7, 139.9, 170.4. HRMS-ESI (m/z): calcd
for C22H23N2O5S2 (MþHþ): 459.1043, found 459.1044.
4.4.3. N-(4-((N-(Phenylsulfonyl)phenylsulfonamido)methyl)-
phenyl)butyramide (2c)
Yellow-brown solid, mp 99e101 ꢁC; IR (KBr, cmꢀ1): 1165, 1369,
1695, 2931, 3385. 1H NMR (400 MHz, CDCl3):
1.73 (dd, J1 ¼7.44 Hz, J2 ¼ 14.88 Hz, 2H), 2.31 (t, J ¼ 7.32 Hz, 2H), 4.88
(s, 2H), 7.29e7.31 (m, 2H), 7.35 (s, 1H), 7.38e7.40 (m, 2H), 7.40e7.45
(m, 4H), 7.55e7.59 (m, 2H), 7.78e7.81 (m, 4H), 13C NMR (100 MHz,
d
0.98 (t, J ¼ 7.36, 3H),
Scheme 2. Control experiments.
CDCl3):
d 13.8, 19.0, 39.6, 52.0, 119.6, 128.1, 128.9, 130.0, 130.1, 133.7,
138.0, 139.9, 171.4. HRMS-ESI (m/z): calcd for
C23H25N2O5S2
(MþHþ): 473.1199, found 473.1201.
4.4.4. 3-Phenyl-N-(4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)propanamide (2d)
Scheme 3. Unreacted substrates.
Yellow solid, mp 150e151 ꢁC; IR (KBr, cmꢀ1): 1168, 1371, 1658,
2920, 3414. 1H NMR (400 MHz, CDCl3):
d
2.64 (t, J ¼ 7.76 Hz, 2H),
3.03 (t, J ¼ 7.52 Hz, 2H), 4.87 (s, 2H), 7.22e7.24 (m, 3H), 7.28e7.32
(m, 7H), 7.39e7.43 (m, 4H), 7.53e7.57 (m, 2H), 7.76e7.81 (m, 4H),
13C NMR (100 MHz, CDCl3):
d 31.5, 39.4, 52.0119.6, 126.4, 128.0,
128.4, 128.6, 128.9, 129.9, 130.2, 133.7, 137.7, 139.9, 140.6, 170.5.
HRMS-ESI (m/z): calcd for C28H27N2O5S2 (MþHþ): 535.1356, found
535.1349.
4.4.5. N-(4-((N-(Phenylsulfonyl)phenylsulfonamido)methyl)-
phenyl)isobutyramide (2e)
White solid, mp 157e159 ꢁC; IR (KBr, cmꢀ1): 1168, 1370, 1668,
2924, 3386. 1H NMR (400 MHz, CDCl3):
d 1.26 (s, 6H), 1.28 (s, 3H),
2.50e2.55 (m, 1H), 4.88 (s, 2H), 7.23 (s, 1H), 7.31e7.33 (m, 2H),
7.40e7.46 (m, 6H), 7.56e7.60 (m, 2H), 7.80e7.82 (m, 4H), 13C NMR
(100 MHz, CDCl3):
d 19.6, 36.7, 52.0, 119.6, 128.1, 128.9, 130.0, 130.2,
133.7, 138.0, 140.0, 175.2. HRMS-ESI (m/z): calcd for C23H25N2O5S2
(MþHþ): 473.1199, found 473.1203.
Scheme 4. Plausible reaction mechanism.
4.4.6. N-(4-((N-(Phenylsulfonyl)phenylsulfonamido)methyl)-
phenyl)cyclopropanecarboxamide (2f)
White solid, mp 137e139 ꢁC; IR (KBr, cmꢀ1): 1168, 1375, 1662,
2919, 3301. 1H NMR (400 MHz, CDCl3):
d 0.83e0.855 (m, 4H),
2.25e2.33 (m, 1H), 4.88 (s, 2H), 7.29e7.31 (m, 2H), 7.38e7.40 (m,
2H), 7.41e7.45 (m, 4H), 7.55e7.59 (m, 2H), 7.61 (s, 1H), 7.79 (d,
Scheme 5. Desulfonylation of the sulfonamide product.
(ethyl acetate/hexane) to afford the pure product.
4.4. Characterization data
J ¼ 8.16 Hz, 4H), 13C NMR (100 MHz, CDCl3):
d 8.1, 15.7, 52.0, 119.4,
128.0, 128.1, 128.9, 130.0, 133.7, 138.2, 140.0, 172.0. HRMS-ESI (m/z):
calcd for C23H23N2O5S2 (MþHþ): 471.1043, found 471.1046.
4.4.7. N-(4-((N-(Phenylsulfonyl)phenylsulfonamido)methyl)-
phenyl)cyclohexanecarboxamide (2g)
Yellow solid, mp 177e179 ꢁC; IR (KBr, cmꢀ1): 1168, 1371, 1655,
4.4.1. N-(4-((N-(Phenylsulfonyl)phenylsulfonamido)methyl)-
phenyl)acetamide (2a)11a
2918, 3404. 1H NMR (400 MHz, CDCl3):
d 1.27e1.36 (m, 4H),
1.54e1.60 (m, 4H), 1.95e1.99 (m, 2H), 4.88 (s, 2H), 7.18 (s, 1H),
7.30e7.32 (m, 2H), 7.39e7.41 (m, 2H), 7.42e7.46 (m, 4H), 7.56e7.59
White solid, mp 154e156 ꢁC; IR (KBr, cmꢀ1): 1167, 1375, 1682,
2922, 3262. 1H NMR (400 MHz, CDCl3):
d
2.19 (s, 3H), 4.88 (s, 2H),
(m, 2H), 7.79e7.81 (m, 4H), 13C NMR (100 MHz, CDCl3):
d
25.7, 25.7,
7.23 (s, 1H), 7.31e7.39 (m, 4H), 7.42e7.46 (m, 4H), 7.56e7.60 (m,
29.7, 46.6, 52.0, 119.5, 128.1, 128.9, 130.0, 130.1, 133.7, 138.0, 139.9,
Please cite this article in press as: Yang Y, et al., Metal-free remote oxidative benzylic CꢀH amination of 4-methylanilides with N-
fluorobenzenesulfonimide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.041

6
Y. Yang et al. / Tetrahedron xxx (2018) 1e7
174.3. HRMS-ESI (m/z): calcd for C26H29N2O5S2 (MþHþ): 513.1512,
(m/z): calcd for C27H31N2O5S2 (MþHþ): 527.1669, found 527.1667.
found 513.1519.
4.4.14. N-(3-Methyl-4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)acetamide (2n)
4.4.8. N-(4-((N-(Phenylsulfonyl)phenylsulfonamido)methyl)-
phenyl)benzamide (2h)11a
Yellow solid, mp 128e130 ꢁC; IR (KBr, cmꢀ1): 1164, 1371, 1667,
White solid, mp 130e132 ꢁC; IR (KBr, cmꢀ1): 1171, 1371, 1668,
3068, 3256. 1H NMR (400 MHz, CDCl3):
d
2.15 (s, 3H), 2.27 (s, 3H),
4.97 (s, 2H), 6.95e6.97 (m, 1H), 7.13e7.15 (m, 1H), 7.33e7.35 (m,
2H), 7.42e7.46 (m, 4H), 7.56e7.60 (m, 2H), 7.79e7.81 (m, 4H), 13
NMR (100 MHz, CDCl3): 19.3, 24.6, 49.8, 117.2, 121.4, 128.0, 128.1,
2923, 3399. 1H NMR (400 MHz, CDCl3):
d 4.92 (s, 2H), 7.37 (s, 1H),
7.40 (s, 1H), 7.44e7.48 (m, 4H), 7.51e7.55 (m, 4H), 7.56e7.60 (m,
C
4H), 7.81 (d, J ¼ 8.12 Hz, 4H), 7.89e7.91 (m, 2H), 13C NMR (100 MHz,
d
CDCl3):
d 52.0, 120.0, 127.0, 128.1, 128.8, 128.9, 130.1, 130.6, 132.0,
128.5, 128.8, 130.0, 133.7, 137.5, 139.9, 168.3. HRMS-ESI (m/z): calcd
for C22H23N2O5S2 (MþHþ): 459.1043, found 459.1042.
133.7, 134.8, 137.9, 140.0, 165.6. HRMS-ESI (m/z): calcd for
C
26H22N2O5S2 (MþHþ): 506.5933, found 506.5931.
4.4.15. N-(3-Methyl-4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)propionamide (2o)
4.4.9. N-(2-Methyl-4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)acetamide (2i)
Yellow solid, mp 140e142 ꢁC; IR (KBr, cmꢀ1): 1162, 1370, 1657,
Yellow solid, mp 120e122 ꢁC; IR (KBr, cmꢀ1): 1171, 1375, 1652,
2923, 3413. 1H NMR (400 MHz, CDCl3):
d 1.22e1.24 (m, 3H), 2.27 (s,
3H), 2.35e2.41 (m, 2H), 4.97 (s, 2H), 6.97e6.99 (m, 1H), 7.13e7.15
(m, 1H), 7.22 (s, 1H), 7.30e7.32 (m, 1H), 7.42e7.46 (m, 4H),
7.56e7.60 (m, 2H) 7.80e7.82 (m, 4H), 13C NMR (100 MHz, CDCl3):
2920, 3404. 1H NMR (400 MHz, CDCl3):
d 2.10 (s, 3H), 2.22 (s, 3H),
4.88 (s, 2H), 7.01 (s, 1H), 7.10 (s,1H), 7.17e7.19 (m, 1H), 7.43e7.47 (m,
4H), 7.56 (t, J ¼ 7.52 Hz, 2H), 7.63e7.65 (m, 1H), 7.79 (d, J ¼ 7.60 Hz,
4H), 13C NMR (100 MHz, CDCl3):
d 17.6, 24.3, 52.1, 123.4, 127.6, 128.1,
d
9.6, 19.3, 30.7, 49.8, 117.1, 121.4, 127.9, 128.1, 128.5, 128.9, 130.0,
128.4, 128.9, 130.1, 133.5, 133.7, 135.5, 140.0, 168.5. HRMS-ESI (m/z):
calcd for C22H23N2O5S2 (MþHþ): 459.1043, found 459.1039.
133.7, 137.4, 139.9, 172.0. HRMS-ESI (m/z): calcd for C23H25N2O5S2
(MþHþ): 473.1199, found 473.1200.
4.4.10. N-(2-Methyl-4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)propionamide (2j)
4.4.16. N-(3-Methyl-4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)butyramide (2p)
Yellow solid, mp 75e77 ꢁC; IR (KBr, cmꢀ1): 1169, 1370, 1658,
2923, 3394. 1H NMR (400 MHz, CDCl3):
d
1.29e1.31 (m, 3H), 2.11 (s,
Yellow solid, mp 88e89 ꢁC; IR (KBr, cmꢀ1): 1168, 1371, 1687,
3H), 2.42 (dd, J1 ¼6.80 Hz, J2 ¼ 14.0 Hz, 2H), 4.88 (s, 2H), 6.93 (s, 1H),
7.11 (s, 1H), 7.18e7.20 (m, 1H), 7.43 (s, 1H), 7.45e7.47 (m, 4H),
7.57e7.60 (m, 2H), 7.79e7.81 (m, 4H), 13C NMR (100 MHz, CDCl3):
2927, 3379. 1H NMR (400 MHz, CDCl3):
d 0.99e1.00 (m, 3H),
1.73e1.79 (m, 2H), 2.23 (s, 3H), 2.30e2.34 (m, 2H), 4.97 (s, 2H),
6.96e7.00 (m, 1H), 7.12e7.14 (m, 1H), 7.21 (s, 1H), 7.37 (s, 1H),
7.42e7.46 (m, 4H), 7.56e7.60 (m, 2H), 7.80e7.82 (m, 4H), 13C NMR
d
9.8, 17.6, 30.6, 52.1, 122.9, 127.6, 128.1, 128.2, 128.8, 129.0, 131.0,
133.6, 135.6, 140.0, 172.0. HRMS-ESI (m/z): calcd for C23H25N2O5S2
(100 MHz, CDCl3): d 13.8, 19.0, 19.4, 39.7, 49.8, 117.1, 121.4, 127.9,
(MþHþ): 473.1199, found 473.1192.
128.1, 128.5, 128.8, 130.0, 133.7, 137.5, 140.0, 171.1. HRMS-ESI (m/z):
calcd for C24H27N2O5S2 (MþHþ): 487.1356, found 487.1349.
4.4.11. N-(2-Methyl-4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)butyramide (2k)
4.4.17. N-(3-Methyl-4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)cyclopropanecarboxamide (2q)
Yellow solid, mp 90e92 ꢁC; IR (KBr, cmꢀ1): 1170, 1373, 1666,
2923, 3397. 1H NMR (400 MHz, CDCl3):
1.77 (q, J ¼ 7.40 Hz, 2H), 2.11 (s, 3H), 2.37 (t, J ¼ 7.20 Hz, 3H), 4.88 (s,
2H), 6.90 (s, 1H), 7.10 (s, 1H), 7.18e7.20 (m, 1H), 7.43e7.47 (m, 4H),
7.56e7.60 (m, 2H), 7.70e7.72 (m, 1H), 7.80e7.82 (m, 4H), 13C NMR
d
1.03 (t, J ¼ 7.28 Hz, 3H),
Yellow solid, mp 110e112 ꢁC; IR (KBr, cmꢀ1): 1168, 1372, 1651,
2921, 3249. 1H NMR (400 MHz, CDCl3):
d 0.84e0.96 (m, 2H),
1.08e1.11 (m, 2H), 1.46e1.50 (m, 1H), 2.27 (s, 3H), 4.97 (s, 2H),
6.95e6.97 (m, 1H), 7.12e7.15 (m, 1H), 7.38e7.46 (m, 6H), 7.56e7.60
(m, 2H), 7.80e7.82 (m, 4H), 13C NMR (100 MHz, CDCl3):
d 8.1, 17.7,
(100 MHz, CDCl3):
d 13.8, 17.6, 19.2, 39.7, 52.1, 123.0, 127.6, 128.1,
128.8, 129.0, 131.0, 133.6, 133.7, 135.6, 139.9, 171.2. HRMS-ESI (m/z):
19.4, 49.8, 116.7, 121.2, 128.0, 128.2, 128.8, 129.0, 130.0, 133.7, 137.5,
140.0, 171.9. HRMS-ESI (m/z): calcd for C24H25N2O5S2 (MþHþ):
485.1119, found 485.1124.
calcd for C24H27N2O5S2 (MþHþ): 487.1356, found 487.1358.
4.4.12. N-(2-Methyl-4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)cyclopropanecarboxamide (2l)
White solid, mp 155e157 ꢁC; IR (KBr, cmꢀ1): 1168, 1371, 1666,
4.4.18. N-(3-Methyl-4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)cyclohexanecarboxamide (2r)
2923, 3386. 1H NMR (400 MHz, CDCl3):
d 0.85e0.90 (m, 2H),
Yellow solid, mp 86e88 ꢁC; IR (KBr, cmꢀ1): 1164, 1374, 1686,
1.10e1.12 (m, 2H),1.50e1.54 (m,1H), 2.15 (s, 3H), 4.88 (s, 2H), 7.11 (s,
1H), 7.16e7.18 (m, 2H), 7.42e7.46 (m, 4H), 7.49e7.52 (m, 1H),
7.56e7.60 (m, 2H), 7.80e7.82 (m, 4H), 13C NMR (100 MHz, CDCl3):
2927, 3377. 1H NMR (400 MHz, CDCl3):
d 1.28 (s, 2H), 1.53e1.59 (m,
2H), 1.82e1.86 (m, 2H), 1.93e1.97 (m, 2H), 2.19e2.24 (m, 1H), 2.27
(s, 3H), 4.97 (s, 2H), 6.95e6.97 (m, 1H), 7.12e7.16 (m, 2H), 7.41e7.46
(m, 5H), 7.56e7.60 (m, 2H), 7.80e7.82 (m, 4H), 13C NMR (100 MHz,
d
8.1, 17.7, 18.4, 52.1, 122.7, 127.6, 128.1, 128.2, 128.8, 129.1, 129.2,
133.7, 135.9, 140.0, 171.0. HRMS-ESI (m/z): calcd for C24H25N2O5S2
(MþHþ): 485.1119, found 485.1117.
CDCl3):
d 19.4, 25.6, 25.7, 29.7, 46.5, 49.8, 117.1, 121.3, 127.8, 128.1,
128.8, 129.0, 130.0, 133.7, 137.5, 140.0, 174.4. HRMS-ESI (m/z): calcd
for C27H31N2O5S2 (MþHþ): 527.1669, found 527.1666.
4.4.13. N-(2-Methyl-4-((N-(phenylsulfonyl)phenylsulfonamido)-
methyl)phenyl)cyclohexanecarboxamide (2m)
White solid, mp 130e131 ꢁC; IR (KBr, cmꢀ1): 1168, 1372, 1657,
4.4.19. N-(4-(aminomethyl)phenyl)acetamide (3a)
2924, 3413. 1H NMR (400 MHz, CDCl3):
d
1.28e1.37 (m, 4H),
Yellow solid, mp 152e154 ꢁC; IR (KBr, cmꢀ1): 1158, 1321, 1537,
1.52e1.62 (m, 4H), 2.00e2.03 (m, 2H), 2.11 (s, 3H), 4.88 (s, 2H), 6.95
(s, 1H), 7.10 (s, 1H), 7.17e7.19 (m, 1H), 7.43e7.47 (m, 4H), 7.56e7.60
(m, 2H), 7.71 (d, J ¼ 8.14 Hz, 1H), 7.79e7.82 (m, 4H), 13C NMR
1654, 3154, 3354. 1H NMR (400 MHz, CDCl3):
d 2.16 (s, 3H),
4.10e4.11 (m, 2H), 7.13e7.18 (m, 2H), 7.40e7.42 (m, 2H), 7.51e7.54
(m, 1H), 7.58e7.62 (m, 1H), 7.87e7.89 (m, 1H), 13C NMR (100 MHz,
(100 MHz, CDCl3):
d
17.6, 25.5, 25.7, 29.8, 46.4, 52.1, 122.9, 127.6,
CDCl3): d 24.4, 46.9, 120.0, 127.1, 128.6, 129.2, 168.3. HRMS-ESI (m/
128.1, 128.8, 129.0, 130.8, 130.9, 133.6, 135.7, 140.0, 174.0. HRMS-ESI
z): calcd for C9H13N2O (MþHþ): 165.1022, found 165.1025.
Please cite this article in press as: Yang Y, et al., Metal-free remote oxidative benzylic CꢀH amination of 4-methylanilides with N-
fluorobenzenesulfonimide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.041

Y. Yang et al. / Tetrahedron xxx (2018) 1e7
(f) Wiese S, Badiei YM, Gephart RT, et al. Angew Chem Int Ed. 2010;49:8850;
7
Acknowledgments
(g) Lu H, Subbarayan V, Tao J, Zhang XP. Organometallics. 2010;29:389;
(h) Rder AN, Herrmann P, Herdtweck E, Bach T. Org Lett. 2010;12:3690;
(i) Powell DA, Fan H. J Org Chem. 2010;75:2726;
We are grateful to the National Natural Science Foundation of
China (No. 21702054), Hubei Province Natural Science Foundation
(No. 2016CFB206) and the Hubei Provincial Hundred-Talent Pro-
gram Fund for financial support.
(j) Ni Z, Zhang Q, Xiong T, et al. Angew Chem Int Ed. 2012;51:1244;
(k) Xia Q, Chen W, Qiu H. J Org Chem. 2011;76:7577;
(l) Zhang Y, Feng B, Zhu C. Org Biomol Chem. 2012;10:9137;
(m) Zeng H-T, Huang J-M. Org Lett. 2015;17:4276;
(n) Li Z-L, Jin L-K, Cai C. Org Biomol Chem. 2017;15:1317.
7. (a) Li C-J, Anastas PT. Chem Soc Rev. 2012;41:1413;
(b) Dunn PJ. Chem Soc Rev. 2012;41:1452;
Appendix A. Supplementary data
(c) Sun C-L, Shi Z-J. Chem Rev. 2014;114:9219;
(d) Qin Y, Zhu L, Luo S. Chem Rev. 2017;117:9433.
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.01.041.
8. (a) Fan R, Li W, Pu D, Zhang L. Org Lett. 2009;11:1425;
(b) Kim HJ, Kim J, Cho SH, Chang S. J Am Chem Soc. 2011;133:16382;
(c) Xue Q, Xie J, Li H, Cheng Y, Zhu C. Chem Commun. 2013;49:3700.
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Please cite this article in press as: Yang Y, et al., Metal-free remote oxidative benzylic CꢀH amination of 4-methylanilides with N-
fluorobenzenesulfonimide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.01.041