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Silver-catalyzed intermolecular amination of

fluoroarenes†
Published on 15 August 2018. Downloaded by University of Perugia on 5/16/2022 8:12:23 AM.

Cite this: Org. Biomol. Chem., 2018,

16, 6191
Yu Wang,*a Chenlong Wei,a Ruyun Tang,a Haosheng Zhan,a Jing Lin,a Zhenhua Liu,b
Received 21st July 2018,
Accepted 13th August 2018 Weihua Taoa and Zhongxue Fang *a
DOI: 10.1039/c8ob01749b

rsc.li/obc

A novel highly selective Ag-catalyzed intermolecular amination of
fluoroarenes has been developed. This transformation starts from
readily available 4-carbonyl fluorobenzene and NaN3 or other
nitrogen-source, via amination followed by C–F bond cleavage,
thus affording the desired 4-carbonyl arylamine products under
mild conditions. The reaction is accelerated using a small amount
of water. This pathway is distinct from a previously reported radical
amination reaction.
Transition-metal-catalyzed C–F bond activation has emerged
as a powerful strategy for constructing various carbon–carbon
and carbon–heteroatom bonds over the past few years.1
Therefore, numerous efforts have been devoted in this area,
which led to the development of efficient synthesis of valuable
derivatives, regarding the pharmaceutical, petrochemical and
agricultural industries.2
Recently, it has been widely reported that the C–F bond
cleavage of fluoroarenes can be transformed to C–C,3 C–B4 or
C–H5 bonds through inert C–F bond activation by the tran-
sition-metal catalyst. However, the transition-metal-catalyzed
activation of C–F bonds to construct the C–N bond is rarely
reported. Wang and Sawamura respectively developed an
amination reaction of fluoroarenes with amines using a ligand-
containing nickel catalyst and an indispensable strong base.6
Recently, Ichikawa discovered the silver-catalyzed formation of
2-fluoroindoles via vinylic C–F bond activation with β,β-difluoro-
o-sulfonamid ostyrenes as the substrate.7 In continuation of our
efforts on the construction of C–N bond reactions,8 we herein
report a highly selective intermolecular amination of fluoroar-
enes used over a silver catalyst, affording a series of 4-carbonyl
arylamines with excellent regioselectivities (Fig. 1).
Initially, we chose 4-fluoroacetophenone and NaN3 as the
model reactants for the coupling reaction to screen the cata-
lysts, oxidants, solvents and temperatures (Table 1). To our
delight, when silver nitrate was used as the catalyst in N,N-di-
methylformamide (DMF) as the solvent at 120 °C for 20 h, the
corresponding product 4-aminoacetophenone 3a could be
obtained with 59% yield (entry 1, Table 1). The use of Ag2SO4
also gave a comparable yield under similar conditions (entry 2,
Table 1). Further experiments with other metal catalysts
revealed that Ag2CO3 exhibited the best effective catalysts for
the amination reaction with an isolated yield up to 84% (entry
3, Table 1). The control experiment showed that K2S2O8 played
an important role in this reaction (entry 4, Table 1). However,
a low catalyst loading led to a decreased yield of the desired
product and long reaction time (entry 5, Table 1). This trans-
formation could also proceed using Ag2S, delivering the
product in 61% yield (entry 6, Table 1). However, the more cat-
ionic silver salts such as AgOTf, AgBF4, AgOAc and AgF gave
inferior results probably due to the high reactivity of these cat-
alysts and the formation of unidentifiable by-products (entries
7–10, Table 1). Furthermore, using Ag2CO3 as the catalyst, an
examination on the use of different solvents was then under-
taken. While the reaction performed in DMSO worked well
with similar yields (entry 11, Table 1), the reactions were not

a
School of Chemistry and Environmental Engineering, Yancheng Teachers University,
Yancheng 224007, People’s Republic of China. E-mail: fangzhongxue120@163.com
b
College of Chemistry, Chemical Engineering and Materials Science,
Shandong Normal University, Jinan 250014, People’s Republic of China
† Electronic supplementary information (ESI) available: Experimental procedure Fig. 1 Transition-metal-catalyzed C–F bond activation coupling
and spectra. See DOI: 10.1039/c8ob01749b reactions.

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Table 1 Modification of the typical reaction conditionsa Table 2 Silver-catalyzed intermolecular amination of fluoroarenes with
NaN3 a

Entry Catalyst Oxidant Solvent Yieldb (%)

1 AgNO3 K2S2O8 DMF 59 Entry Substrate 1 Product 2 Yieldb (%)

2 Ag2SO4 K2S2O8 DMF 61
3 Ag2CO3 K2S2O8 DMF 84 1 3a 96
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4 Ag2CO3 — DMF 27
5c Ag2CO3 K2S2O8 DMF 75
6 Ag2S K2S2O8 DMF 61
7 AgOTf K2S2O8 DMF 55 2 3b 85
8 AgBF4 K2S2O8 DMF 42
9 AgOAc K2S2O8 DMF 71
10 AgF K2S2O8 DMF 47
3 3c 89
11 Ag2CO3 K2S2O8 DMSO 83
12 Ag2CO3 K2S2O8 Toluene 0
13 Ag2CO3 K2S2O8 CH3CN 0
14 Ag2CO3 TBHP DMF 73 4 3d 93
15 Ag2CO3 PhI(OAc)2 DMF 68
16 Ag2CO3 IBX DMF 62
17 Ag2CO3 (NH4)2S2O8 DMF 75
18 Ag2CO3 H2O2 DMF 45 5 3e 76
19d Ag2CO3 K2S2O8 DMF 0
20 Ag2CO3 K2S2O8 DMF + H2Oe 96
21 — K2S2O8 DMF + H2Oe 18
6 3f 88
a
1a (0.4 mmol, 48.0 μL), NaN3 (1.2 mmol, 78 mg), catalyst
(0.04 mmol), oxidant (0.48 mol), and solvent (2.0 ml) at 120 °C for
20 h. b Isolated yields. c Ag2CO3 (0.01 mmol). d At 70 °C. e 0.04 mmol
water was added. 7 3g 97

efficient in other oxidants, such as toluene and acetonitrile 8 3h 87

(entries 12 and 13, Table 1). The investigations on other oxi-
dants, such as TBHP, PhI(OAc)2, IBX, (NH4)2S2O8, and H2O2,
were carried out for and afforded relatively lower yields
(entries 14–18, Table 1). No product was observed by decreas-
ing the reaction temperature, and the starting material 1a was
recovered intact (entry 19, Table 1). The presence of water
molecules would be beneficial for the reaction (entry 20,
Table 1).
With the optimized conditions in hand, the scope of substi-
tuted 4-carbonyl fluorobenzene and NaN3 was investigated. As
shown in Table 2, gratifyingly, 4-fluoroacetophenone, methyl
4-fluorobenzoate and ethyl 4-fluorobenzoate were compatible
with the reaction conditions, providing the desired products
3a–3c in satisfactory yields (entries 1–3, Table 2). The 4-carbo-
nyl fluorobenzenes bearing the ethyl and cyclopropyl groups
were well tolerated in the C–N bond formation reaction and
yielded the corresponding products 3d and 3e in 93% and
76% yields, respectively (entries 4 and 5, Table 1). A good
regioselectivity of the reaction was maintained in the presence
of other reactive fluoride groups and the reaction afforded the
target products 3f–3j in 88–97% yields (entries 6–10, Table 2).
To further evaluate the scope of this amination, a variety of
amines were exploited as the coupling partners. The results of
the coupling of 4-carbonyl fluorobenzenes with functional
amines are summarized in Table 3. Secondary amines such as
cyclic amines, morpholine, piperidine and pyrrolidine gave the
9 3i 89
10 3j 93
a
Reaction conditions: 1 (0.4 mmol), NaN3 (1.2 mmol), Ag2CO3
(0.04 mmol), K2S2O8 (0.48 mmol), H2O (0.04 mmol), DMF (2 mL),
12 h. b Isolated yields.
products 3k–3q in moderate to excellent yields, but are slightly
more reactive than the acyclic dimethylamine (entries 1–7 vs.
8, Table 3) probably because of their lesser hindrance. The sec-
ondary amine, dimethylamine, did not give satisfactory yield
(entry 8, Table 3), because the two alkyl groups may block the
nucleophilic substitution reaction of the fluorine atom on the
aryl ring. Interestingly, DMF was found to be able to furnish
the corresponding amine 3r in 65% yield (Scheme 1). This
method also enriches the activation reaction of the C–N bond
catalyzed by silver.9 In addition, the fluorobenzenes bearing
other electron withdrawing groups, such as carboxyl-, cyano-
and trifluoromethyl-, to react with NaN3 were unreactive under
the standard reaction conditions (see Scheme S5†).

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Organic & Biomolecular Chemistry
Table 3 The scope of secondary amines for aminationa
Entry 2 4 Yieldb (%)
1 3k 93
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2 3l 96
3 3m 93
4 3n 91
5 3o 93
6 3p 75
7 3q 82
8 3r 64
a
Reaction conditions: 1 (0.4 mmol), 2 (0.5 mL), Ag2CO3 (0.04 mmol),
K2S2O8 (0.48 mmol), H2O (0.04 mmol), 12 h. b Isolated yields.
Scheme 1 The scope of C–F bond activation.
To elucidate the possible reaction mechanism of this trans-
formation, some control experiments were performed and are
summarized in Scheme 2. Firstly, the solution of phenylsilver
1a′ in tetrahydrofuran was introduced to the reaction with 1a
in the dark; the product 3k was obtained in 73% yield
(Scheme 2a). This result indicated that the reaction might be
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Scheme 2 Control experiments.
undergo the phenylsilver intermediate. Furthermore, one equiv.
of water was added in this system; yet, no desired product was
detected (Scheme 2b). In contrast, when 10 mol% water was
added in this system, the yield of 3k could be improved to 93%
(Scheme 2c). Undoubtedly, water plays a crucial role in the
amination reaction.10 This is due to two reasons: (i) 4-carbonyl
fluorobenzene has poor solubility in water; and (ii) the inter-
action between base (morpholine) and acid (water) weakens
the nucleophilic attack of morpholine on 4-fluoroacetophe-
none and thereby reduces the reaction rate and yield. In
addition, when radical scavengers, such as TEMPO or BHT,
were introduced into the model reaction of substrates 1a and
morpholine, the reaction proceeded smoothly without consider-
able impact. These results can exclude the radical pathway of
the amination reaction (Scheme 2d). Meanwhile, the desired
product 3k′ was not detected using fluorobenzene 1a″ as the
starting material. Even though we increased the reaction tem-
peratures, only trace amount of product 3k′ was obtained. These
results showed that the para-substituents of the carbonyl group
on the benzene ring were necessary (Scheme 2e).11
Based on the above results and the literature reports,12 a
plausible mechanism containing an oxidative coupling
process is illustrated in Scheme 3 for the reaction. At the
beginning, the oxidative addition of 4-fluoroacetophenone to
the Ag(I) center affords the Ag(II) intermediate I in the presence
of K2S2O8. Subsequently, the Ag(II) intermediate II is generated
through the replacing of the fluorine atom in the Ag(II)
complex I with morpholine. Finally, the reductive elimination
step furnishes product 3a and regenerates the active Ag(I) species.
In summary, we have developed a novel Ag-catalyzed inter-
molecular amination of fluoroarenes with good regio-
selectivity. In this transformation, various substitutions on the
phenyl ring of fluoroarenes can be well tolerated, thus provid-
ing a series of functionalized 4-carbonyl arylamines in good to
excellent yields. Control experiments showed that the reaction
was accelerated using a small amount of water. Further studies
on the mechanism and exploitation of possible synthetic appli-
Org. Biomol. Chem., 2018, 16, 6191–6194 | 6193

Communication
Scheme 3 Plausible reaction mechanism.
Published on 15 August 2018. Downloaded by University of Perugia on 5/16/2022 8:12:23 AM.
cations of fluoroarenes by C–F bond cleavage are in progress
in our laboratory.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors wish to thank the Natural Science Foundation of
China (21506017), the Natural Science Foundation of Jiangsu
Province (BK20150258), and the Joint Innovation Project for
Production-Study-Research in Jiangsu Province (BY2016066-03).
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