Ligand-free iron-catalyzed benzylic C (sp3)-H amination of methylarenes with: N -fluorobenzenesulfonimide

Article abstract of DOI:10.1039/c9ra05294a

Direct conversion of cheap methylarenes to benzylic amines, which are essential structural units of important drugs, is of great significance. However, the known methodologies suffer from the requirement of noble metal catalysts, heavy metal residues or s

Full text of DOI:10.1039/c9ra05294a

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Ligand-free iron-catalyzed benzylic C (sp3)–H
amination of methylarenes with N-
fluorobenzenesulfonimide†
Cite this: RSC Adv., 2019, 9, 27892
*
Fengyu Bao,
Yuanbo Cao, Wenbo Liu and Junhao Zhu
Direct conversion of cheap methylarenes to benzylic amines, which are essential structural units of
important drugs, is of great significance. However, the known methodologies suffer from the
requirement of noble metal catalysts, heavy metal residues or strong oxidants. Herein, the first
Received 11th July 2019
Accepted 28th August 2019
biocompatible iron-catalyzed benzylic
C
(sp3)–H amination of methylarenes with N-
fluorobenzenesulfonimide is described. The reactions of methylarenes bearing electron-donating groups
and electron-withdrawing groups ran smoothly under ligand and additional oxidant free conditions. Both
toluene derivatives and 8-methylquinoline can be aminated by the same iron catalyst.
DOI: 10.1039/c9ra05294a
rsc.li/rsc-advances
Benzylic amines are essential structural units of many impor- amination with NFSI catalyzed by palladium or prompted by
tant drugs, such as imatinib, donepezil, ampicillin, and val- hypervalent iodine reagent was also investigated.10b–d Alvarez,
´
3
sartan (Fig. 1).1 Direct conversion of benzylic C (sp )–H bonds to Muniz and co-workers have described Pd-catalyzed amination
˜
C (sp3)–N bonds to synthesize benzylic amines is of great of 8-methylquinolines with NFSI (Scheme 1b).6f Zheng and co-
importance. Intramolecular and intermolecular benzylic ami- workers have reported Cu-catalyzed amination of 8-methyl-
nation2–4 of aliphatic C–H bonds can be realized by Rh, Ru, Ir, quinolines in the presence of ligand and base (Scheme 1b).6g
Pd, Ag, Cu, Mn or Fe-catalyzed nitrene transfer reactions.2,5 In Toluene and xylene are among the cheapest, the most abundant
the case of amination of 8-methylquinolines, Pd, Ir, Ru or Rh chemical raw materials, but important materials for the
can be used as catalyst.6a–e This strategy provides a powerful and production of industrially important chemicals. Their benzylic
direct method for the installation of benzylic amines. However, C–H bonds functionalization11 (including amination) to value-
explosive azides or hypervalent iodine reagents need be used to added products under environment friendly and economic
generate nitrenes. The use of hypervalent iodine reagents may conditions are highly desirable. 8-Methylquinolines are idea
result in the generation of stoichiometric amount of environ- substrates for the synthesis of quinolin-8-ylmethanamines,
mentally unfriendly iodobenzenes. One alternative way to the which are building blocks in medicinal chemistry.12 The ami-
benzylic amination is cross-dehydrogenative coupling (CDC) nation of toluene derivatives and 8-quinolines is signicant.
reactions catalyzed by metals or under metal free conditions.7 However, the known methodologies suffer from noble and or
The strategy suffers from the additional oxidants which are
essential to activate benzylic C (sp3)–H. Among the oxidants,
potentially explosive peroxides are usually used. Pandey has
reported visible-light-catalyzed benzylic amination via CDC
procedures under metal and external oxidant free conditions,7e
but the substrates could not be totally consumed. Radical
addition allows benzylic amination,8 but peroxides need be
used in the processes. N-Fluorobenzenesulfonimide (NFSI) is
a kind of internal oxidant,9 thus no external oxidant is needed
when it is used as amination reagent. Therefore, NFSI is
a promising amination reagent. Zhang, Zhang, Liu and co-
workers have reported copper-catalyzed benzylic amination by
NFSI (Scheme 1a) in the presence of ligand.10a Remote benzylic
College of Science, Henan Agricultural University, Zhengzhou 450002, P. R. China.
E-mail: baofengyu@henau.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra05294a
Fig. 1 Examples of drugs containing benzylic amine units.
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Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
Fe2(CO)9
Cp2FePF6
Cp2FeBF4
Fe3O4 (nano)
Na3FeF6
Fe2TiO5
Fe(NO3)3$9H2O
Fe(acac)3
Fe(OTs)3$6H2O
Fe2(C2O4)3$6H2O
FeC2O4
Fe2(C2O4)3$6H2O
Fe2(C2O4)3$6H2O
Fe2(C2O4)3$6H2O
Fe2(C2O4)3$6H2O
27
28
36
24
25
25
29
22
31
59
54
37
60
46
28
9
10
11
12c
13d
14e
15f
Scheme 1 Benzylic amination of methylarenes with NFSI.
heavy metal catalysts. Their catalytic reactions' applications in
the pharmaceutical industry may be limited, for the problem of
heavy metal residues must be considered. Iron is abundant,
nontoxic, biocompatible, environment-friendly,2d thus it is idea
catalyst for the benzylic amination reactions. However, there is
no report on iron-catalyzed benzylic amination of methylarenes
under additional oxidants and nitrenes free conditions. There is
no catalyst which can aminate both toluene derivatives and 8-
methylquinoline. Herein, we'd like to report the rst biocom-
patible iron-catalyzed benzylic C (sp3)–H amination of methyl-
arenes (including toluene derivatives and 8-methylquinoline)
with NFSI under ligand and additional oxidant free conditions
(Scheme 1c and d). Our work provides a direct method for
preparation of benzylic amines from toluene derivatives and 8-
methylquinoline without the problem of heavy metal residues.
The other advantage is to avoid the use of a large excess amount
of methylarenes. Stoichiometric amount of toluene derivatives
and 8-methylquinoline were used in this work. The examples of
functionalization of stoichiometric amount of methylarenes are
still limited.11a
a
Reaction conditions: 1a (0.5 mmol), 2 (1.5 equiv., 0.75 mmol), catalyst
(10 mol%) in 10 mL 1, 2-dichlorobenzene under reuxing condition in
b
c
d
e
air. Isolated yield. 1.0 equiv. NFSI. 2.0 equiv. NFSI. 5 mol%
Fe2(C2O4)3$6H2O. f Chlorobenzene as solvent.
Table 2 Amination of toluene derivatives with NFSIa
Initially, toluene was chosen as substrate with iron catalyst to
optimize the reaction conditions (Table 1). Benzylic C (sp3)–H of
toluene was selectively aminated to produce benzylic amine 3a
in the presence of C (sp2)–H bonds. Zero valent diiron non-
acarbonyl showed catalytic activity, and 3a was obtained in 27%
yield (entry 1). The use of Cp2FePF6 as catalyst could slightly
increase the yield (from 27% to 28%, entry 2), while the other
ferrocenium salt Cp2FeBF4 clearly improved the yield (from 27%
to 36%, entry 3).With nano Fe3O4 as catalyst, the yield became
lower (entry 4). Notably, anionic iron also showed catalytic
activity (entry 5). Iron(III) salts were investigated. Iron(III) nitrate
nonahydrate, iron(III) acetylacetonate (Fe(acac)3) and iron(III) p-
toluenesulfonate hexahydrate (Fe(OTs)3$6H2O) were found to
be able to catalyze the amination, but they had little effects on
a
Reaction conditions: 1 (0.5 mmol), 2 (1.5 equiv., 0.75 mmol),
the improvement of the yields (entry 7–9). We were pleased to Fe2(C2O4)3$6H2O (10 mol%) in 20 mL 1, 2-dichlorobenzene under
reuxing condition in air.
nd that iron(III) oxalate hexahydrate (Fe2(C2O4)3$6H2O) gave 3a
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Scheme 2 Amination of 8-methylquinoline with NFSI.
in 59% yield (entry 10). Iron(II) oxalate was tested. 3a was
afforded in lower yield (entry 11). The results indicate that the
catalytic activity of iron(III) salt is higher than of iron(II) salt. The
decrease of the amount of NFSI lowered the yield (entry 12).
However, the increase of the amount of NFSI almost could not
improve the yield (entry 13). The decrease of the amount of the
catalyst Fe2(C2O4)3$6H2O resulted in lower yield (entry 14). With
chlorobenzene as solvent, the conversion of C (sp3)–H to C
(sp3)–N was limited. 3a was obtained only in 28% yield (entry
15). With 1,2-dichloroethane (DCE), acetonitrile, 1,4-dioxane or
N,N-dimethylformamide (DMF) as solvent, 3a could not be
detected by thin layer chromatography (TLC). When the reac-
tion was carried out at 120 ꢀC, 3a could not be detected by TLC.
With the optimized reaction conditions (Table 1, entry 10),
we began to investigate the amination of toluene derivatives
(Table 2). The amination of o-xylene, m-xylene, p-xylene could be
catalyzed by 10 mol% Fe2(C2O4)3$6H2O, and the corresponding
monoamination products (3b–d) were obtained under the
reaction conditions. The amination of both electron-decient
and electron-rich toluene derivatives underwent smoothly to
produce the corresponding benzylic amines. Toluene bearing
electron-donating substituent tert-butyl at the para position
gave 3f in 80% yield. Notably, primary benzylic C (sp3)–H was
selectively aminated in the presence of secondary benzylic C
(sp3)–H, and 3e was afforded. Toluene substrates bearing iodo,
bromo, chloro and uoro substituents were good candidates for
the amination, the corresponding products (3h–l and 3n–p)
were obtained in satisfactory yields (from 41% to 76%). Iodo
substituent at the ortho, meta or para position of the benzene
ring has little effect on the benzylic amination. It is noticed that
reactive iodo and bromo substituents remain in the amination
products, thus further transformation can be considered.
Toluene bearing phenyl substituent at the para position was
aminated efficiently to produce 3q in 66% yield. 1-Methyl
naphthalene was also suitable substrate. Its amination gave 3r
in 43% yield. Electron-withdrawing substituents, such as cyano,
sulfonyl, carbonyl, are tolerant, and the corresponding products
were obtained (3s–u). 3t was afforded in 46% yield.
Scheme 3 Proposed mechanism of amination of methylarenes with
NFSI.
of methylarenes proceeds via cationic iron(V) path (Scheme 3).
The interaction of iron(III) catalyst with NFSI produces cationic
iron complex A, which is an oxidant to activate benzylic C (sp3)–
H to produce benzylic type radical B.16 The following reaction of
cationic Fe(IV) and anionic C generates radical D along with the
regeneration of Fe(III). The coupling of radical B and D gives the
amination product.
In summary, we have developed the rst biocompatible iron-
catalyzed benzylic C (sp3)–H amination of methylarenes with
NFSI under ligand and additional oxidant free conditions. The
amount of methylarenes is stoichiometric. Both electron-
decient and electron-rich methylarenes are suitable
substrates. Electron-withdrawing substituents and electron-
donating substituents are tolerant. Both toluene derivatives
and 8-methylquinoline can be aminated by the same abundant
iron catalyst.
Conflicts of interest
The authors declare no conict of interest.
Notes and references
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