An efficient protocol for the synthesis of monofluoroalkylated (hetero)arenes via Pd-catalyzed α-(hetero)arylation of α-fluoroketones with (hetero)aryl bromides

Article abstract of DOI:10.1016/j.tetlet.2020.151948

An efficient synthesis of monofluoroalkylated N-heteroarenes using α-fluoroketones as monofluoroalkyl reagents was developed. A variety of novel α-(hetero)aryl-α-fluoroketones and monofluoroalkylated N-heteroarenes were obtained in moderate to good yields. Notable advantages of this protocol include a low catalyst loading, easily prepared monofluoroalkyl reagents and wide substrate scope.

Full text of DOI:10.1016/j.tetlet.2020.151948

Journal Pre-proofs
An efficient protocol for the synthesis of monofluoroalkylated (hetero)arenes
via Pd-catalyzed α-(hetero)arylation of α-fluoroketones with (hetero)aryl bro‐
mides
Licheng Ding, Shuaijun Han, Xiaoyu Chen, Linlin Li, Jingya Li, Dapeng Zou,
Yangjie Wu, Yusheng Wu
PII:
S0040-4039(20)30391-9
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151948
TETL 151948
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 February 2020
9 April 2020
13 April 2020
Please cite this article as: Ding, L., Han, S., Chen, X., Li, L., Li, J., Zou, D., Wu, Y., Wu, Y., An efficient
protocol for the synthesis of monofluoroalkylated (hetero)arenes via Pd-catalyzed α-(hetero)arylation of α-
fluoroketones with (hetero)aryl bromides, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.151948
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
An efficient protocol for the synthesis of
monofluoroalkylated (hetero)arenes via Pd-
catalyzed α-(hetero)arylation of α-
Leave this area blank for abstract info.
fluoroketones with (hetero)aryl bromides
Licheng Ding, Shuaijun Han, Xiaoyu Chen, Linlin Li, Jingya Li, Dapeng Zou* , Yusheng Wu*, Yangjie Wu*
O
O
Het
Het
Het
OH-
+
Pd catalyst/Ligand
R
F
Ph
Ph
Br
F
R
F
R
R = H, CH3, Et, Ph
broad substrates scope
a low catalyst loading
moderate to good yields

1
Tetrahedron Letters
journal homepage: www.elsevier.com
An efficient protocol for the synthesis of monofluoroalkylated (hetero)arenes via
Pd-catalyzed α-(hetero)arylation of α-fluoroketones with (hetero)aryl bromides
Licheng Dinga, Shuaijun Hana, Xiaoyu Chena, Linlin Lia, Jingya Lib, Dapeng Zoua,, Yangjie Wua,,
Yusheng Wua,b,c,

aCollege of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Zhengzhou University, Zhengzhou 450052, PR China
bTetranov Biopharm, LLC. And Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450052, PR China
cTetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA
———
A CRoTrreIsCpoLndEingIaNuthFoOr. Tel.: (+86)-371-6776-6865; fax:A(+8B6)S-3T71R-6A77C6-T3390; e-mail: zdp@zzu.edu.cn or wyj@zzu.edu.cn
 Corresponding author. Tel.: (+ 1)-732-253-7326; fax: (+ 1)-732-253-7327; e-mail: yusheng.wu@tetranovglobal.com
Article history:
Received
Received in revised form
Accepted
An efficient synthesis of monofluoroalkylated N-heteroarenes using α-fluoroketones as
monofluoroalkyl reagents is developed. A variety of novel α-(hetero)aryl-α-fluoroketones and
monofluoroalkylated N-heteroarenes were obtained in moderate to good yields. Notable
advantages of this protocol include a low catalyst loading, easily prepared monofluoroalkyl
reagents and wide substrate scope.
Available online
2019 Elsevier Ltd. All rights reserved.
Keywords:
Palladium-catalyzed
Base-induced
α-(hetero)arylation
Monofluoroalkylation.
Introduction
monofluoroalkylation of arenes using 1-bromo-1-fluoroalkanes
as monofluoroalkylating reagents was reported by Gandelman in
Fluorine-containing organic compounds play an extremely
important role in biomedical, agricultural and material sciences,
because the introduction of fluorine or fluorinalkyl moieties into
organic compounds can significantly influence their lipophilic,
metabolic stability and bioavailability properties (Figure 1).1 As
2014 (Scheme 1).6 Subsequently, Wang described
a
combinatorial nickel-catalyzed system for the efficient
construction of monofluoroalkylated arenes using readily
avaliable arylboronic acids and unactived 1-fluoro-1-
iodoalkanes.7 Recently, a nickel-catalyzed monofluoroalkylation
through reductive coupling of aryl halides and monofluoroalkyl
halides was developed by Wang.8 Despite great progress in the
monofluoroalkylation of arenes, continuous efforts are still
needed, especially for monofluoroalkylation of the
(hetero)arenes.
important
fluorinated
moieties,
monofluoroalkylated
(hetero)arenes have been widely used in pharmaceutical
products.2 In particular, several of biologically active
compounds, including the afloqualone, (6R)-indaziflam and the
18F-ibuprofen ester, contain a monofluoroalkyl group (CHF-
alkyl) as a significant motif.3 Despite its importance, the
incorporation of monofluoroalkyl group (CHF-alkyl) into
(hetero)arenes has been studied to a lesser extent and is still
challenging.4
F
CO2Me
N
O
N
N
Me
18F
Me
NH2
N
N
N
H
F
Me
Afloqualone (1)
(6R)-indaziflam (2)
18F-ibuprofen ester (3)
Figure.
1.
Bioactive
molecules
containing
monofluoroalkylated heteroarene.
Along with the development of direct C-H functionalization
reactions, a series of methods for direct C-H fluorination at the
benzylic position were developed.5 However, the relatively poor
functional-group compatibility might diminish the general
application of these methods. Meanwhile, the nickel-catalyzed

2
Previous work:
Table 1. Pd-catalyzed α-(hetero)arylation of α-
fluoroketones: optimization of conditions.a
(1) Gandelman's work:
F
X
F
R1
Ni catalyst/Ligand
Br
Pd, Ligand
DG
DG
B
9-BBN R1
+
+
F
F
Base, Solvent
N
O
DG = Ar, Alkyl, PhCO-, ArSO2RN-
R1 = Alkyl
O
N
1a
2a
3a
R = Aryl, Alkyl
X = I, Br, Cl
9-BBN =
PCy2
R2
R1
P
P
P
(2) Wang's work:
n
R
M
F
Ni catalyst/Ligand
R3
R1 = R2 = R3 = i-Pr
R1 = R2 = OMe, R3 = H S-Phos
R1 = R2 = Oi-Pr, R3 = H Ru-Phos
F
+
X-Phos
PCy3
X
R
n = 1 DPPM
n = 2 DPPE
n = 3 DPPP
M = B(OH)2, I R = Alkyl
X = I, Br
Yieldb
(%)
Entry
Catalyst
Ligand
Base
Solvent
This work:
O
O
Het
Het
R
OH-
Het
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
X-Phos
S-Phos
Ru-Phos
DPPM
DPPE
DPPP
PCy3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
25
+
Pd catalyst/Ligand
F
Ph
Ph
Br
F
R
F
R
2
44
R = H, CH3, Et, Ph
3
27
Scheme 1. The synthesis of monofluoroalkylated
(hetero)arenes.
4
12
5
84
The benzoyl was found to be a multifunctional group, which
enabled the cross-coupling of aryl halides with α-aryl-ketones9,
as well as the further transformations of these products10.
Therefore, Pd-catalyzed arylation of α-fluoroketones have
become an efficient method for the construction of carbon-carbon
bonds. In 2012, Qing developed a versatile method to prepare α-
aryl-α-fluoroketones by palladium-catalyzed direct α-arylation of
α-fluoroketones with structurally diverse aryl bromides.9f
However, the synthesis of monofluoroalkylated N-heteroarenes
was not investigated. As a part of our ongoing efforts on fluorine
chemistry11, herein, we report an efficient protocol for the
synthesis of a series of monofluoroalkylated N-heteroarenes via
Pd-catalyzed α-(hetero)arylation of α-fluoroketones with bromo-
substituted N-heteroarenes.
6
42
7
89
8
PCy3
93(86)
83
9
Pd(PPh3)4
PCy3
10
11
12
13
14
15
16
17
18d
19e
20f
21g
22g,h
23g,i
24g,h
25g,h
26g,h,j
27g,h,k
Pd(CF3COO)2 PCy3
79
Pd(dba)2
PdCl2(dppf)
PdCl2(COD)
PdCl2
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
71
76
85
trace
n. r.
n. r.
trace
88
PdCl2
tBuONa
KOH
PdCl2
Results and Discussion
PdCl2
K3PO4
PdCl2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
At first, 2-fluoro-1-phenylpropan-1-one (1a) and 6-
bromoquinoline (2a) were chosen as the model substrates to
optimize the reaction conditions, and the results were
summarized in Table 1. When the reaction of 1a and 2a was
performed in the presence of Pd(OAc)2 (5.0 mol%), X-phos (10.0
mol%), and Cs2CO3 (2.0 equiv, 0.6 mmol) in toluene at 120 °C
for 24 h, 3a was obtained in 25% yield (Table 1, entry 1). Then,
various monophosphine and bisphosphine ligands were tested,9, 12
and PCy3 was proved to be an optimal choice (Table 1, entries 2-
7). When Pd(OAc)2 was switched to PdCl2, the yield of 3a was
improved to 93% (entry 8). Other palladium catalysts were found
to be less effective for the transformation (Table 1, entries 9-13).
PdCl2
88
PdCl2
24
PdCl2
88
PdCl2
89
PdCl2
79
PdCl2
1,4-dioxane 92(86)
xylene 82
PdCl2
PdCl2
1,4-dioxane 79
1,4-dioxane 63
PdCl2
t
When other commonly used bases such as CsF, BuONa, KOH,
a Reaction conditions: 1a (1.0 equiv, 0.3 mmol), 2a (2.0 equiv, 0.6 mmol),
[Pd] (5.0 mol%), Ligand (10.0 mol%), Cs2CO3 (2.0 equiv, 0.6 mmol), solvent
(2.0 mL), at 120 °C under argon for 24 h.
and K3PO4 were investigated, none of them was found to be
effective for the reaction (Table 1, entries 14-17). When catalyst
loading was studied, a good yield was obtained in the
combination with PdCl2 (2.0 mol%), and PCy3 (4.0 mol%) (Table
1, entries 18-21). Furthermore, when the reaction was carried out
with 1a (2.0 equiv, 0.6 mmol), 2a (1.0 equiv, 0.3 mmol), the
yield of 3a was slightly increased (Table 1, entries 22-23).
Screening for various solvents indicated that 1,4-dioxane was a
better choice in the reaction process (Table 1, entries 24-25).
Decreasing reaction temperature or shorting reaction time
resulted in lower yield (Table 1, entries 26-27). Finally, the
optimized reaction conditions were determined as 1a (2.0 equiv,
0.6mmol), 2a (1.0 equiv, 0.3 mmol), PdCl2 (2.0 mol%), PCy3
(4.0 mol%), Cs2CO3 (2.0 equiv, 0.6 mmol), 1,4-dioxane (2.0
mL), at 120 °C under Ar for 24 h.
b HPLC yield, isolated yields are shown in parentheses.
c n.r.= no reaction.
d PdCl2 (3.0 mol%), PCy3 (10.0 mol%).
e PdCl2 (2.0 mol%), PCy3 (10.0 mol%).
f PdCl2 (1.0 mol%), PCy3 (10.0 mol%).
g PdCl2 (2.0 mol%), PCy3 (4.0 mol%).
h 1a (2.0 equiv, 0.6 mmol), 2a (1.0 equiv, 0.3 mmol).
i 1a (1.5 equiv, 0.45 mmol), 2a (1.0 equiv, 0.3 mmol).
j 100 °C.

3
k.20 h.
3q, 3aa-3ac) to give the corresponding monofluoroalkylated N-
heteroarenes (4a-4q, 4aa-4ac), as shown in Table 2.
Under the optimized conditions, the reaction of 2-fluoro-1-
phenylpropan-1-one (1a) with (hetero)aryl bromides (2a-2q)
were investigated (Table 2). The α-(hetero)arylation reaction of
To further demonstrate the utility of this reaction, we sub-
sequently carried out a gram-scale reaction of 2-fluoro-1-
phenylpropan-1-one (1a, 1.52 g, 10 mmol) and 6-bromoquinoline
(2a, 1.03 g, 5.0 mmol) under the optimal reaction conditions
(Scheme 2). As a result, the target products (3a) and (4a) were
obtained in 76% and 73% yield, respectively. A one-pot two-
steps synthesis of 6-(1-fluoroethyl)quinoline (4a) was then
investigated (Scheme 3). Unfortunately, compared with the above
two-steps method, the one-pot protocol gave the desired 4a in
only 41% yield (Scheme 3).
2-fluoro-1-phenylpropan-1-one
(1a)
with
different
bromoquinolines proceeded smoothly to give the desired
products (3a-3g) in good to excellent yields, while 2- and 8-
bromoquinoline required slightly higher loading of catalyst.
Bromoisoquinolines could also be used as effective substrates for
this transformation (3h-3j). Moreover, various bromo-substituted
N-heteroarenes, such as pyridine, quinoxaline and 1H-
pyrrolo[2,3-b]pyridine underwent the reaction smoothly to give
the
target
products
(3k-3n)
in
63-86%
yields.
Scheme 2. Gram-scale reaction.
Bromonaphthalenes and bromobiphenyl reacted with 2-fluoro-1-
phenylpropan-1-one (1a) to give (3o-3q) in excellent yields.
PdCl2 (2 mol%), PCy3 (4 mol%),
F
Cs2CO3 (2.0 equiv)
F
Br
To establish the scope of this protocol, different ketone
derivatives were then tested under the optimized conditions.
Fortunately, 2-fluoro-1-phenylbutan-1-one (1aa) and 2-fluoro-
1,2-diphenylethanone (1ac) gave the desired products in good
yields (3aa, 3ac). Whereas, α-(hetero)arylation reaction of 2-
fluoro-1-phenylethanone (1ab) gave the target product in lower
yield (3ab).
+
1,4-dioxane (15.0 mL)
120 °C, Ar, 24 h
N
O
3a
O
1a
N
2a
(10.0 mmol, 1.52 g) (5.0 mmol, 1.03 g)
1.06 g (76 %)
F
KOH (5.0 g), H2O (800 mg)
1,4-dioxane (15.0 mL)
120 °C,4 h
N
4a
0.64 g (73 %)
Table 2. Substrate scope a,b,c
Scheme 3. A one-pot two-steps synthesis of 6-(1-
O
O
Het
Het
Het
step 1
step 2
F
R
+
Ph
Ph
Br
fluoroethyl)quinolone.
F
F
R
R
1a-1ac
2a-2q
3a-3ac
4a-4ac
F
(1) PdCl2, PCy3, Cs2CO3
1,4-dioxane, 120 °C, Ar, 24h
F
Br
F
F
F
+
F
N
N
N
4a
yield: 41%
(2) KOH, H2O, 1,4-dioxane
120 °C, 4 h
O
N
N
1a
2a
N
A: 3bc 71%
B: 4bc 59%
A: 3a 86%
A: 3c 88%
A: 3d 77%
B: 4a 84%
F
B: 4c 84%
B: 4d 75%
In the basis of previous reports12,
and our research, a
13
F
F
plausible mechanism is proposed (Scheme 4). Firstly, oxidative
addition of the Pd(0) catalytic species A with bromo-substituted
N-heteroarenes 2 formed Pd(II) complex B. Subsequently, α-
fluoroketone 1 converted to the enolate compound in the
presence of Cs2CO312g, 12h. The nucleophilic enolate compound 1
could attack the Br in coordinated bromide complex B to produce
N
F
N
N
N
A: 3gc 75%
B: 4gc 61%
A: 3e 91%
B: 4e 82%
A: 3f 97%
B: 4f 91%
A: 3h 78%
B: 4h 61%
F
F
F
F
F
two possible coordination modes of the palladium enolate
N
N
12e,
complexes (C or D)12b,
12f, which underwent reductive
N
Ph
N
Ph
A: 3i 92%
B: 4i 82%
A: 3j 85%
B: 4j 79%
A: 3k 86%
A: 3l 63%
B: 4l 59%
F
elimination to generate α-(hetero)aryl-α-fluoroketone 3. Finally,
OH- attacked the carbonyl group of compound 3 to form
intermediate E. Because the introduction of the (hetero)aromatic
ring could stabilize the negative charge to a greater extent13c, the
intermediate E processed C-C bond cleavage to form the final
monofluoroalkylated N-heteroarenes 4.
B: 4k 72%
F
F
N
N
N
Bn
N
A: 3m 83%
B: 4m 65%
A: 3n 82%
B: 4n 63%
A: 3o 85%
B: 4o 68%
A: 3p 81%
B: 4p 62%
F
F
Scheme 4. Plausible Mechanism.
F
Et
F
Ph
PdCl2
Ph
N
N
N
HO O-
L = PCy3
Het
O
Het
OH-
A: 3q 89%
B: 4q 70%
A: 3aa 86%
B: 4aa 71%
Het
A: 3ab 37%
B: 4ab 30%
A: 3ac 83%
B: 4ac 79%
R
Ph
Het
Ph
Pd(0)Ln
A
F
R
F
Br
F
3
R
4
E
a Reaction conditions: step 1, 1 (2.0 equiv, 0.6 mmol), 2 (1.0 equiv, 0.3
mmol), PdCl2 (2.0 mol%), PCy3 (4.0 mol%), Cs2CO3 (2.0 equiv, 0.6 mmol),
1,4-dioxane (2.0 mL), at 120 °C under Ar for 24 h; step 2, KOH (300.0 mg),
H2O (50.0 mg), 1,4-dioxane (2.0 mL), at 120 °C for 3 h.
2
F
Ln
O
Het
R
Het
O
PdII
LnPdII
PdII
Ln
Ph
Ph
Br
Het
F
R
B
b Isolated yields. A: The yield of 2 to 3. B: The yield of 2 to 4.
C
D
c step 1, PdCl2 (5.0 mol%), PCy3 (10.0 mol%).
O
Br-
HCO3
Subsequently, the deprotection process of benzoyl group was
also studied. The result indicated that the simple condition
worked well for most of the acquired α-(hetero)aryl products (3a-
R
Cs2CO3
-
Ph
F
1

4
M.; Xin, Z. -K.; Chen, B.; Tung, C. -H.; Wu, L. -Z. Org. Lett.
2017, 19, 3009-3012.
Conclusion
In conclusion, we have developed an efficient strategy for the
6.
(a) Jiang, X. J.; Sakthivel, S.; Kulbitski, K.; Nisnevich, G.;
Gandelman, M. J. Am. Chem. Soc. 2014, 136, 9548-9551. (b)
Jiang, X. J.; Gandelman, M. J. Am. Chem. Soc. 2015, 137, 2542-
2547.
Sheng, J.; Ni, H. -Q.; Liu, G.; Li, Y.; Wang, X. -S. Org. Lett.
2017, 19, 4480-4483.
Sheng, J.; Ni, H. -Q.; Zhang, H. -R.; Zhang, K. -F.; Wang, Y. -
N., Wang, X. -S. Angew. Chem. Int. Ed. 2018, 57, 7634-7639.
(a) Guo, Y.; Twamley, B.; Shreeve, J. M. Org. Biomol. Chem.
2009, 7, 1716-1722. (b) Guo, Y.; Tao, G. -H.; Blumenfeld, A.;
Shreeve, J. M. Organometallics. 2010, 29, 1818-1823. (c) Guo,
C.; Wang, R. -W.; Qing, F. -L. J. Fluorine Chem. 2012, 143,
135-142. (d) Ge, S. Z.; Chaładaj, W.; Hartwig, J. F. J. Am. Chem.
Soc. 2014, 136, 4149-4152. (e) Zhou, J., Fang, X., Shao, T.;
Yang, X. Y.; Wu, F. H. J. Fluorine Chem. 2016, 191, 54-62. (f)
Guo, C.; Wang, R. -W.; Guo, Y.; Qing, F. -L. J. Fluorine Chem.
2012, 133, 86-96.
synthesis of monofluoroalkylated N-heteroarenes via Pd-
catalyzed α-(hetero)arylation of α-fluoroketones with bromo-
substituted N-heteroarenes. A series of novel α-(hetero)aryl-α-
fluoroketones and monofluoroalkylated N-heteroarenes were
obtained in moderate to excellent yields. Moreover, this process
has demonstrated high catalytic reactivity and broad substrate
scope. It would be attractive and useful in laboratory methods,
industrial processes, and pharmaceutical researchs.
7.
8.
9.
References and notes
1.
(a) Jeschke, P. ChemBioChem. 2004, 5, 570-589. (b) Müller, K.;
Faeh, C.; Diederich, F. Science. 2007, 317, 1881-1886. (c)
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur. V. Chem.
Soc. Rev. 2008, 37, 320-330. (d) Hagmann, W. K. J. Med. Chem.
2008, 51, 4359-4369. (e) Wang, J.; Sánchez-Roselló, M.; Aceña,
J. L.; Pozo, C. D.; Sorochinsky, A. E.; Fustero, S.; Soloshonok,
V. A.; Liu, H. Chem. Rev. 2014, 114, 2432-2506. (f) Preshlock,
S.; Tredwell, M.; Gouverneur, V. Chem. Rev. 2016, 116, 719-
766. (g) Zhu, Y.; Han, J.; Wang, J.; Shibata, N.; Sodeoka, M.;
Soloshonok, V. A.; Coelho, J. A. S.; Toste, F. D. Chem. Rev.
2018, 118, 3887-3964.
10. (a) Kobayashi, S.; Tanaka, H.; Amii, H.; Uneyama, K.
Tetrahedron. 2003, 59, 1547-1552. (b) Grein, F.; Chen, A. C.;
Edwards, D.; Crudden, C. M. J. Org. Chem. 2006, 71, 861-872.
(c) Thvedt, T. H. K.; Fuglseth, E.; Sundby, E; Hoff, B. H.
Tetrahedron. 2010, 66, 6733-6743. (d) Malamakal, R. M.; Hess,
W. R.; Davis, T. A. Org. Lett. 2010, 12, 2186-2189. (e)
Borzęcka, W.; Lavandera, I.; Gotor, V. J. Org. Chem. 2013, 78,
7312-7317. (f) Liang, Y. F.; Fu, G. C. J. Am. Chem. Soc. 2014,
136, 5520-5524.
11. (a) Liang, A. P.; Li, X. J.; Liu, D. F.; Li, J. Y.; Zou, D. P.; Wu, Y.
J.; Wu, Y. S. Chem. Commun. 2012, 48, 8273-8275. (b) Leng, F.
Q.; Wang, Y. P.; Li, H.; Li, J. Y.; Zou, D. P.; Wu, Y. J.; Wu, Y.
S. Chem. Commun. 2013, 49, 10697-10699. (c) Liang, A. P.;
Han, S. J.; Liu, Z. W.; Wang, L.; Li, J. Y.; Zou, D. P.; Wu, Y. J.;
Wu, Y. S. Chem. Eur. J. 2016, 22, 5102-5106. (d) Zhang, Y.; Du,
H. L.; Zhu, M. X.; Li, J. Y.; Zou, D. P.; Wu, Y. J.; Wu, Y. S.
Tetrahedron. Lett. 2017, 58, 880-883. (e) Han, S. J.; Liang, A. P.;
Ren, X. X.; Gao, X. Y.; Li, J. Y.; Zou, D. P.; Wu, Y. J.; Wu, Y.
S. Tetrahedron. Lett. 2017, 58, 4859-4863. (f) Geng, Y.; Liang,
A. P.; Gao, X. Y.; Niu, C. S.; Li, J. Y.; Zou, D. P.; Wu, Y. S.;
Wu, Y. J. J. Org. Chem. 2017, 82, 8604-8610. (g) Gao, X. Y.;
Geng, Y.; Han, S. J.; Liang, A. P.; Li, J. Y.; Zou, D. P.; Wu, Y.
S.; Wu, Y. J. Tetrahedron. Lett. 2018, 59, 1551-1554. (h) Gao, X.
Y.; Geng, Y.; Han, S. J.; Liang, A. P; Li, J. Y.; Zou, D. P.; Wu,
Y. J.; Wu, Y. S. Org. Lett. 2018, 20, 3732-3735. (i) Han, S. J.;
Wu, Q. S.; Mele, L.; Ding, L. C.; Li, J. Y.; Zou, D. P.; Wu, Y. S.;
Wu, Y. J. Tetrahedron. Lett. 2019, 60, 151077.
12. (a) Palucki, M.; Buchwald S. L. J. Am. Chem. Soc. 1997, 119,
11108-11109. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem.
Soc. 1997, 119, 12382-12384. (c) Satoh, T.; Kawamura, Y.;
Miura, M.; Nomura, M. Angew. Chem. Int. Ed. 1997, 36, 1740-
1742. (d) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J.
Org. Chem. 1998, 63, 6546-6553. (e) Kawatsura, M.; Hartwig, J.
F. J. Am. Chem. Soc. 1999, 121, 1473-1478. (f) Culkin, D. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816-5817. (g)
Satoh, T.; Kametani, Y.; Terao, Y.; Miura, M.; Nomura, M.
Tetrahedron. Lett. 1999, 40, 5345-5348. (h) Terao, Y.; Kametani,
Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron.
2001, 57, 5967-5974. (i) Culkin, D. A.; Hartwig, J. F. Acc. Chem.
Res. 2003, 36, 234-245. (j) Bordwell, F. G. Acc. Chem. Res.
1988, 21, 456-463.
2.
(a) Purohit, A.; Benetti, B.; Hayes, M.; Guaraldi, M.; Kagan, M.;
Yalamanchilli, P.; Su, F.; Azure, M.; Mistry, M.; Yu, M.;
Robinson, S.; Dischino, D. D.; Casebier, D. Bioorg. Med. Chem.
Lett. 2007, 17, 4882-4885. (b) Brickner, S. J.; Chen, J. M.; Li, Z.
B.; Marfat, A.; Mitton-Fry, M. J.; Plotkin, M. A.; Reilly, U. S.;
Subramanyam, C.; Zhang, Z.; Robinson, S. US Patent US
2012/0065188, A1 2012. (c) Huang, X. Y.; Liu, W.; Ren, H.;
Neelamegam, R.; Hooker, J. K.; Groves, J. T. J. Am. Chem. Soc.
2014, 136, 6842-6845.
3.
(a) Hu, J. B.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465-
7478. (b) Jeschke. P. Pest Manage. Sci., 2017, 73, 1053-1066. (c)
Booth, J. B.; ƠBrien, P. M. US Patent US 2008/0161365, A1
2008.
4.
(a) Ni, C. F.; Zhu, L. G.; Hu, J. B. Acta Chim. Sin. 2015, 73, 90-
115. (b) Champagne, P. A.; Desroches, J.; Hamel, J. -D.;
Vandamme, M.; Paquin, J. -F. Chem. Rev. 2015, 115, 9073-9174.
(c) Koperniku, A.; Liu, H. Q.; Hurley, P. B. Eur. J. Org. Chem.
2016, 871-886. (d) Guo, C.; Wang, R. W.; Guo, Y. J. Fluorine
Chem. 2012, 133, 86-96. (e) Yadav, A.; Srivastava, V.; Yadav, L.
Chem. Commun. 2013, 49, 2154-2156. (f) Liang, Y.; Fu, G. C. J.
Am. Chem. Soc. 2014, 136, 5520-5524. (g) Zhang, Q.; Mixdorf,
J. C.; Reynders Ш, G. C.; Nguyen, H. M. Tetrahedron. 2015, 71,
5932-5938. (h) Pang, X. B.; Xiang, L. K.; Ma, J. X.; Yang, X. D.;
Yan, R. L. RSC Adv. 2016, 6, 111713-111717. (i) Meanwell, M.;
Adluri, B. S.; Yuan, Z. L.; Newton, J.; Prevost, P.; Nodwell, M.
B.; Friesen, C. M.; Schaffer, P.; Martin, R. E.; Britton, R. Chem.
Sci. 2018, 9, 5608-5613.
5.
(a)Liu, W.; Groves, J. T. Angew. Chem., Int. Ed. 2013, 52, 6024-
6027. (b) Xia, J. -B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013,
135, 17494-17500. (c) Bloom, S.; Pitts, C. R.; Woltornist, R.;
Griswold, A.; Holl, M. G.; Lectka, T. Org. Lett. 2013, 15, 1722-
1724. (d) Bloom, S.; McCann, M.; Lectka, T. Org. Lett. 2014, 16,
6338-6341. (e) Xu, P.; Guo, S.; Wang, L. Y.; Tang, P. P. Angew.
Chem. Int. Ed. 2014, 53, 5955-5958. (f) Emer, E.; Pfeifer, L.;
Brown, J. M.; Gouverneur, V. Angew. Chem. Int. Ed. 2014, 53,
4181-4185. (g) Cantillo, D.; Frutos, O. D.; Rincon, J. A.; Mateos,
C.; Kappe, C. O. J. Org. Chem. 2014, 79, 8486-8490. (h) Xiang,
13. (a) Mehtaa, G.; Venkateswaran, R. V. Tetrahedron. 2000, 56,
1399-1422. (b) Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983-
1986. (c) Paquette, L. A.; Gilday, J. P. Org. Prep. Proced. Int.
1990, 22, 167-201.
Click here to remove instruction text...
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
Declaration of interests
√
□ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.

• The debenzoylation step proceeds smoothly
Graphical Abstract
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
Highlights
• A new approach to synthesize α-(hetero)aryl-α-
fluoroketones and monofluoroalkylated N-
heteroarenes
• The catalytic system features a low catalyst
loading
• Easily prepared monofluoroalkyl reagents
An efficient protocol for the synthesis of
monofluoroalkylated (hetero)arenes via Pd-
catalyzed α-(hetero)arylation of α-
Leave this area blank for abstract info.
fluoroketones with (hetero)aryl bromides
Licheng Ding, Shuaijun Han, Xiaoyu Chen, Linlin Li, Jingya Li, Dapeng Zou* , Yusheng Wu*, Yangjie Wu*
O
O
Het
Het
Het
OH-
+
Pd catalyst/Ligand
R
F
Ph
Ph
Br
F
R
F
R
R = H, CH3, Et, Ph
broad substrates scope
a low catalyst loading
moderate to good yields