Construction of S-CF2/ O-CF2 bonds via inter/intramolecular radical nucleophilic substitution reaction

Article abstract of DOI:10.1016/j.tet.2020.131477

A facile and efficient method for construction of S-CF₂ or O-CF₂ bonds through intermolecular radical nucleophilic substitution (S_RN1) reaction of 2-bromo-2,2-difluoro-N-phenylacetamide and thiophenols or phenols was developed, which has also been successfully utilized in the intramolecular S_RN1 reaction to generate a new O-CF₂ bonds for synthesis of biologically important 2,2-difluoro-2H-benzo [1,4]oxazin-3-one. The protocol enables an efficient access to gem-difluoromethylene-containing thioethers or ethers and oxazin heterocycles with good to excellent yields by inter/intramolecular radical nucleophilic substitution reaction under mild reaction conditions.

Full text of DOI:10.1016/j.tet.2020.131477

Journal Pre-proof
Construction of S-CF / O-CF bonds via inter/intramolecular radical nucleophilic
2
2
substitution reaction
Wei Wang, Pingyang Wang, Qian Zhang, Pengcheng Du, Jianhua Zhang, Hongmei
Deng, Haizhen Jiang
PII:
S0040-4020(20)30657-8
https://doi.org/10.1016/j.tet.2020.131477
TET 131477
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 June 2020
Revised Date: 1 August 2020
Accepted Date: 3 August 2020
Please cite this article as: Wang W, Wang P, Zhang Q, Du P, Zhang J, Deng H, Jiang H, Construction
of S-CF / O-CF bonds via inter/intramolecular radical nucleophilic substitution reaction, Tetrahedron
2
2
(2020), doi: https://doi.org/10.1016/j.tet.2020.131477.
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Graphical Abstract
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Construction of S-CF2/ O-CF2 Bonds via
Inter / Intramolecular Radical Nucleophilic
Substitution Reaction
Leave this area blank for abstract info.
Wei Wang, Pingyang Wang, Qian Zhang, Pengcheng Du, Jianhua Zhang, Hongmei Deng and Haizhen Jiang*
Department of Chemistry, Shanghai University, Shanghai, 200444, P. R. China
Key Laboratory of Advanced Display and System Application, Ministry of Education, Shanghai University, Shanghai, 200072, P. R.China
Laboratory for Microstructures, Shanghai University, Shanghai, 200444, P. R. China
Key Laboratory of Organofluorine Chemistry,Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, P. R. China

1
Tetrahedron
journal homepage: www.elsevier.com
Construction of S-CF2/ O-CF2 Bonds via Inter/Intramolecular Radical Nucleophilic
Substitution Reaction
Wei Wang a, Pingyang Wang a, Qian Zhang a, Pengcheng Du a, Jianhua Zhang,b Hongmei Deng c and
Haizhen Jianga, d,
*
a Department of Chemistry, Shanghai University, Shanghai,200444, P. R. China
b Key Laboratory of Advanced Display and System Application, Ministry of Education, Shanghai University, Shanghai, 200072, P. R. China
c Laboratory for Microstructures, Shanghai University, Shanghai, 200444, P. R. China
dKey Laboratory of Organofluorine Chemistry,Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
A facile and efficient method for construction of S-CF2 or O-CF2 bonds through intermolecular
radical nucleophilic substitution (SRN1) reaction of 2-bromo-2,2-difluoro-N-phenylacetamide
and thiophenols or phenols was developed, which has also been successfully utilized in the
intramolecular SRN1 reaction to generate a new O-CF2 bonds for synthesis of biologically
important 2,2-difluoro-2H-benzo[1,4]oxazin-3-one. The protocol enables an efficient access to
gem-difluoromethylene-containing thioethers or ethers and oxazin heterocycles with good to
excellent yields by inter/intramolecular radical nucleophilic substitution reaction under mild
reaction conditions.
Available online
Keywords:
SRN1 reaction
CF2-heteroatom bonds
gem-Difluomethylene
Intramolecular
Intermolecular
fluorinated compounds with ArO– or ArS-. Especially, the
intramolecular SRN1 reaction has proved to be an important route
1. Introduction
to ring closure reactions in aromatic systems,[5] but rarely in
intramolecular SRN1 reactions of aliphatic difluoroalkyl bromine.
The radical nucleophilic substitution reaction (SRN1) receives
much attention in construction of C-C or C-heteroatom bonds
due to it offers the possibility of achieving substitution in
compounds that are nonreactive under classical nucleophilic
substitutions.[1] Especially in fluorine chemistry, SRN1 reaction
can realize the construction of CF2-heteroatom bonds which is
difficult to achieve by other methods due to the strong
electronegativity of fluorine. As reported, perfluoroalkyl halides,
which scarcely carry out the classical SN1 or SN2 reaction with
nucleophiles owe to the strong induction effect of fluorine atoms
destabilize a carbocation or the shielding of the carbon by the
surrounding lone pair electrons on F repel the backside attack of
Thus, there is highly desirable to explore the intramolecular SRN
1
reaction of partially fluorinated compounds to obtain fluorine-
containing heterocycle compounds.
The SRN1 reaction involves a single electron transfer chain
process which can be initiated by thermally (spontaneous
reactions).[1b] The thermal initiation was favored when substrate
was good electron acceptors and nucleophiles were good electron
donors. ArS- or ArO- had relatively high oxidability and was good
electron donors. The CF2Br-containing amides could accept a
electron from ArS- or ArO- in the process of an electron transfer
(ET) to generate radical anions of difluoroalkyl bromines which
is then converted into difluoroalkyl radicals. The difluoroalkyl
radicals as reaction intermediates could be stabilized by the
strong induction effect of fluorines and by delocalization of the
electron into the conjugated amide moiety. Additionally, the
difluoroalkyl radicals with electrophilic properties tended to react
with electronic-rich ArS– or ArO– to construction of S-CF2/ O-
the nucleophiles, could undergo the SRN
1 reaction with
nucleophiles through single electron transfer (SET).[2] Besides
perfluoroalkyl halides, the displacement of bromide from the
CF2Br in partially fluorinated compounds such as 2-
bromodifluoromethyl-1,3
benzoxazole[3]
or
2-
bromodifluoromethyl-1,3-oxazoline[4] also proceeds by an SRN
1
mechanism under thermal induced, while it does not occur by a
classical SN2 mechanism due to the presence of the alpha
fluorines. The SRN1 reaction was able to synthesis of biologically
interesting gem-difluoromethylene ether compounds.[4] In view
of the importance of organofluorine compounds in medicines,
agricultural chemicals and electronic materials, we will continue
to study the synthetic applications of SRN1 reactions of partially
CF2
bonds.
Consequently,
2-bromo-2,2-difluoro-N-
arylacetamides were selected as electron acceptors for exploring
intra- and intermolecular SRN1 reactions under heating (Scheme
1).

2
Tetrahedron
halogenated phenolate was not able to react with the CF2Br-
containing amide 1a even under prolonged reaction time and
raise reaction temperature.
Table 2 Intermolecular SRN1for construction of S-CF2/O-CF2
Bonds [a]
H
F
R
F
H
N
XH
CF2Br
N
NaH, DMF
800C
X
+
O
O
R
1
2
3
Scheme 1 Construction of S-CF2/ O-CF2 bonds via SRN
2. Results and discussion
1
Entry
Substrate
Product
Yield (%)[b]
93
Initial experimentation was carried out in DMF at 70 oC with a
2-bromo-2,2-difluoro-N-phenylacetamide (1) / thiophenol 2a in
molar ratio of 1:1 in the presence of base K2CO3. The reaction
completed after 12h by TLC, and the desired gem-
difluoromethylene aryl thioether 3a was obtained in a yield of
54% (Table 1, entry 1). The reaction conditions were further
optimized by changing the amount of substrate, base and reaction
temperature. It was found that NaH was the optimal base (Entries
4 and 9). Increasing the amount of substrate either 1 or 2a could
significantly affect the reaction efficiency. The reaction provided
the highest 19F NMR yield of 93% when it was carried out with a
1/2a molar ratio of 1/1.5 in DMF at 80 0C for 12 h (Entry 9).
OCH3
F
F
H
N
S
1
2
O
2a
2b
2c
3a
3b
86
77
3
3c
Table1 Screening of the reaction conditions [a]
OCH3
F
F
H
H
SH
CF2Br
N
4
5
6
52
91
95
N
Base, DMF
Temp.
S
+
O
2d
O
H3CO
3d
3e
1a
2a
3a
1a
2a
Temp.
(0C)
Base
3a
Entry
(equiv)
(equiv)
(2a*2 equiv)
Yield (%)[b]
2e
2f
1
2
1
1.5
1
1
70
70
70
70
70
70
70
60
80
100
K2CO3
K2CO3
K2CO3
NaH
54
60
73
84
66
56
57
75
93
80
1
3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
4
1
3f
3g
3h
5
1
Ag2CO3
NEt3
7
8
9
85
90
65
6
1
7
1
Cs2CO3
NaH
2g
8
1
Cl
SH
9
1
NaH
2h
10
1
NaH
[a] All the reactions were carried out in 2.0 ml DMF for 12 h; [b] 19F NMR
yield using benzotrifluoride as an internal standard.
2i
Various nucleophiles such as thiophenolates generated in situ
from thiophenols in a suspension of sodium hydride were
employed to investigate the generality of this substitution
reaction under the optimized reaction condition and the results
are summarized in Table 2. High yields were consistently
obtained for substituted thiophenolates containing electron-
donating and electron-withdrawing substituents. The 4-
3i
[a] All the reactions were carried out in the presence of 1 (0.2mmol), 2
(0.3mmol), NaH (0.6 mmol) in 2.0 ml DMF at 80ºC for 12 h; [b] Isolated
yields.
The intramolecular SRN1 reaction has been shown to be a
powerful tool for the synthesis of heterocycles in the fluorine-free
system[5]. Therefore, after getting success in the construction of
intermolecular S-CF2/O-CF2 bonds by SRN1 reactions, we applied
methoxythiophenol
and
4-chlorothiophenol
gave
the
corresponding gem-difluoromethylene aryl thioether in excellent
yield (Table 2, entries 1 and 6). The reaction of thiophenol
having halogen substituents at para, ortho or meta position with
the CF2Br-containing amide 1 all provided the desired thioethers
in good to excellent yields (Entries 3-8). However, the electron
rich 4-methoxyphenol provided the gem-difluoromethylene aryl
ether only in 65% isolated yield under the standard reaction
(Entry 9). The reaction efficiency of 4-methoxybenzenethiol was
higher than 4-methoxyphenol because thiophenolates with
relatively high oxidability and good electron donors were favor
the electron transfer (eT) in the initiation step. Phenolate or
this
methodology
to
2-bromo-2,2-difluoro-N-(2-
hydroxyphenyl)acetamide (4a) for exploring the construction of
intramolecular O-CF2 bond for synthesis of 2,2-difluoro-2H-
benzo[1,4]oxazin-3-one. Exhilaratingly, the desired fluorine-
containing heterocycle 5a was obtained in 90% 19F NMR yield
when the reaction was carried out in the above standard reaction
conditions (Table 1, entry 9). Further optimization of the reaction
conditions found that it only took 6 hours to complete the
reaction at 70ºC by TLC and 19F NMR monitoring. It is worth
mentioning that intramolecular SRN1 reaction has higher reaction
efficiency than that of intermolecular. This methodology

3
continued to be evaluated using different substituted CF2Br-
anion (4a-) . Then the other radical anion (4a) is produced
containing N-(2-hydroxyphenyl)acetamide 4 for intramolecular
by the cleavage of C-Br bond and departure of bromide anion
through intramolecular ET (intra-ET) in which the CF2˙ species
was apt to have intramolecular cyclization to give (5a) due to
the electrophile properties of CF2˙ radical because of the strong
induction effect of fluorines. The radical anion (5a) transfers a
electron to the substrate 4a- through intermolecular ET to form
intermediate which then enters the
propagation steps, and affords gem-difluoromethylene-containing
oxazin 5a
S
RN1 reaction, and the representative results are illustrated in
Table 3. In general, the conversions are very good for all
substrates studied. The reactions were compatible with both
electron-donating and electron-withdrawing groups at the meta-,
ortho- and para-position of the hydroxyl group on the benzene
rings of 4. Substrates with electron-donating substituents at para-
position provided higher yields than that of electron-
withdrawings (Entries 2-7). This observation is consistent with
the SRN1 mechanism that the electron-donating substituents at
para-position of the hydroxyl group on the benzene rings of 4
enriched the electrons of the substrates, easily initiated the
reactions to yield the required radical anions in the process of
single electron transfer. Furthermore, substituents at meta-
position all gave excellent yields whether it was electron-
donating or electron-withdrawing (Entries 8-10).
the radical anion (4a-)
Table 3 Intramolecular SRN1for synthesizing heterocycle 5 [a]
Entry
1
Substrate
Product
5 Yield (%)[b]
Scheme 2 The speculate process of Intramolecular SRN
1
85
Evidence for the SRN1 mechanism is obtained from inhibition
conditions. When 100 mol% or 50 mol% strong electron acceptor
p-dinitrobenzene (P-DNB) and 50 mol% radical scavenger
hydroquinone were added into the reaction system of 4a under
the standard reaction conditions (laboratory illumination), the
reaction provided the desired 5a in 19F NMR yield of 58, 79 and
45% (Table 4, entries 1, 2 and 3), respectively, which inferred
that the reaction was partially inhibited. The reaction rate was
also slightly slower in dark than that in laboratory illumination
during the beginning of the reaction 3h; however, with the
reaction time gradually extended to 6 hours, similar yields of the
product 5 were obtained in dark and in laboratory illumination
conditions (Entries 4 and 5). These evidences indicated the
presence of radical anions and radicals as intermediates in the
reaction process, which excluded a classical SN2 mechanism. On
the other hand, when using a protic solvent (such as methanol)
instead of a dipolar aprotic solvent DMF, no desired product 5a
was observed because the SRN1 mechanism reaction can only
occur in dipolar aprotic solvents, but not in protic solvents (Entry
6).[6] All these observations support the SRN1 mechanism.
4a
4b
4c
5a
5b
5c
2
3
4
85
90
80
4d
4e
5d
5e
5f
5
6
86
81
4f
4g
4h
4i
Table 4 Influences of inhibition condition on SRN1 reaction
7
8
9
74
92
88
92
5g
5h
5i
Entry
Reaction
condition
Lab. ill.[a]
Lab. ill. [a]
Additive
Time
(h)
6
5a yield
(%)[b]
1
2
P-DNB (50% mol)
P-DNB (100% mol)
79
6
58
3
4
5
6
Lab. ill. [a]
Lab. ill. [a]
Hydroquinone (50% mol)
6
45
57/87
41/84
0
/
/
/
3/6
3/6
6
10
dark/DMF
Lab. ill./MeOH
4j
5j
[a] All the reactions were carried out in the standard conditions; Lab. ill. :
laboratory illumination. [b] 19F NMR yield with trifluorotoluene as internal
standard.
[a] All the reactions were carried out in the presence of 4 (0.2 mmol), NaH
(0.4 mmol) in 2.0 ml DMF at 70ºC for 6 h. [b] Isolated yields.
The construction of the oxazin skeleton 5 was suggested via
3. Conclusion
the intramolecular nucleophilic radical substitution SRN
1
mechanism (Scheme 2). 4a- generated in the presence of NaH
In conclusion, we has developed a facile and efficient method
for construction of S-CF2 or O-CF2 bonds through intermolecular
undergoes a transfer of one electron (ET) to form the radical

4
Tetrahedron
4.2.3. 2,2-Difluoro-2-((4-fluorophenyl)thio)-N-
phenylacetamide (3c)
radical nucleophilic substitution (SRN1) reaction of 2-bromo-
2,2-difluoro-N-phenylacetamide and thiophenols or phenols to
obtain gem-difluoromethylene-containing thioethers or ethers.
This methodology enables an efficient access to generate a new
intramolecular O-CF2 bonds by the intramolecular SRN1 reaction
for synthesis of fluorine-containing heterocycle 2,2-difluoro-2H-
benzo[1,4]oxazin-3-ones under mild reaction conditions. The
protocol has extensive functional group tolerance and is capable
1
45.7 mg; 77% yield; light yellow solid; MP 99.9-101.4℃; H
NMR (500 MHz, CDCl3) δ: 8.10 (s, 1H), 7.64 (dd, J = 8.2, 5.6
Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.9 Hz, 2H), 7.22
(t, J = 7.4 Hz, 1H), 7.09 (t, J = 8.6 Hz, 2H); 19F NMR (470
MHz,CDCl3) δ: -82.43 , -108.92; 13C NMR (125 MHz, CDCl3) δ:
2
1
165.4, 163.4, 159.4 (t, JC-F = 28.1 Hz), 139.1 (d, JC-F = 8.9 Hz),
1
to obtain
a
variety of biologically important gem-
135.7, 129.2, 125.9, 122.2(t, JC-F = 290.5 Hz), 120.6 , 116.7 (d,
2JC-F = 22.2 Hz); IR (KBr, cm-1) v : 3324, 1686, 1537, 1488, 1230,
1116, 1077, 986; MS (EI, GCMS): m/z: found: 297; calcd. for
297.04
difluoromethylene compounds which is difficult to achieve by
other methods.
4. Experimental section
4.2.4 2,2-Difluoro-2-((4-bromophenyl)thio)-N-
4.1 General
phenylacetamide (3d)
37.2 mg; 52% yield; light yellow solid; MP 125.1-126.0℃; 1H
NMR (500 MHz, CDCl3) δ: 7.90 (s, 1H), 7.50 (dd, J = 12.6, 5.6
Hz, 6H), 7.35 (t, J = 7.9 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H); 19F
All solvents were purified by standard method. 1H NMR
spectra were recorded on a 500 MHz. 19F NMR were recorded on
a 470 MHz spectrometer. 13C NMR spectra were recorded on a
NMR (470 MHz,CDCl3) δ: -81.86; 13C NMR (125 MHz, CDCl3)
125 MHz spectrometer. H NMR and 13C NMR chemical shifts
1
2
δ: 159.2 (t, JC-F = 28.1 Hz), 138.3, 135.6, 132.7, 129.3, 126.0,
were determined relative to internal standard TMS at δ 0.0 and
19F NMR chemical shifts were determined relative to CFCl3 as
inter standard. Chemical shifts (δ) are reported in ppm, and
coupling constants (J) are in Hertz (Hz). The following
abbreviations were used to explain the multiplicities: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.
Infrared spectra (IR) were recorded with KBr pellets. Melting
points are uncorrected. GC-MS analysis was performed on an
SHIMADZU gas chromatograph with GC-MS 2020 mass
spectrum using an SH-Rxi-5Sil MS column (30 m, 0.25 mm I.D.,
0.25 mm D.F.) Method: method starts at 80 °C holds the oven at
this temperature for 2 minute, then ramp of 30 °C/min till 290 °C
and hold the oven at this temperature for 3 minutes. Silica gel
(200−400 mesh) was used for flash column chromatography. All
reagents were received from commercial sources.
125.9, 123.8, 122.1 (t, 1JC-F = 291.1 Hz), 120.5; IR (KBr, cm-1) v :
3320, 1689, 1537, 1445, 1071, 994, 688; HRMS (EI TOF) calcd
for (M+) C14H10BrF2NOS: 356.9635, found: 356.9629
4.2.5 2-((2-Bromophenyl)thio)-2,2-difluoro-N-
phenylacetamide (3e)
65.0 mg, 91% yield, light yellow solid, MP 110.9-111.2℃; 1H
NMR (500 MHz, CDCl3) δ: 7.98 (s, 1H), 7.83 (dd, J = 7.7, 1.8
Hz, 1H), 7.71 (dd, J = 7.9, 1.5 Hz, 1H), 7.56-7.49 (m, 2H), 7.41-
7.30 (m, 4H), 7.26-7.17 (m, 1H); 19F NMR (470 MHz, CDCl3) δ:
-81.60; 13C NMR (125 MHz, CDCl3) δ: 159.1 (t, 2JC-F = 28.2 Hz),
138.9, 135.8, 134.0, 132.2, 131.3, 129.3, 128.2, 126.7, 125.9,
122.0 (t ,1JC-F = 292.3 Hz), 120.5; MS (EI, GCMS): (m+2)/z:
found: 359; calcd. for 358.96
4.2.6 2-((4-Chlorophenyl)thio)-2,2-difluoro-N-
4.2 Typical procedures for the synthesis of compounds 3
phenylacetamide (3f)
59.5 mg; 95% yield; light yellow solid; MP 115.8-116.3℃; 1H
NMR (500 MHz, CDCl3) δ: 7.91 (s, 1H), 7.57 (d, J = 8.4 Hz,
2H), 7.49 (d, J = 7.9 Hz, 2H), 7.35 (t, J = 8.4 Hz, 4H), 7.20 (t, J =
A 10 mL round-bottom flask was charged with compound 1
(0.20 mmol, 1.0 equiv.), 2 (0.3 mmol), NaH (0.6 mmol) and
DMF (2.0 mL) under Air atmosphere. The reaction mixture was
stirred at 80℃ for 12 h. After the reaction was completed, the
crude product was directly purified by silica gel chromatography,
to give the desired product 3.
7.4 Hz, 1H); 19F NMR (470 MHz, CDCl3) δ: -81.98; 13C NMR
2
(125 MHz, CDCl3) δ: 159.3 (t, JC-F = 28.1 Hz), 138.1, 137.5,
135.7, 129.7, 129.3, 126.0, 123.2, 122.2 (t ,1JC-F = 287.5 Hz),
120.5; IR (KBr, cm-1 ) v : 3338, 1686, 1533, 1442, 1081, 984,
751, 689; MS (EI, GCMS): m/z: found: 313; calcd. for 313.01
4.2.1. 2,2-Difluoro-2-((4-methoxyphenyl)thio)-N-
phenylacetamide (3a)
57.5 mg; 93% yield; light yellow solid; MP 100.8-101.6 ℃;
1H NMR (500 MHz, CDCl3) δ: 7.77 (s, 1H), 7.56 (d, J = 8.8 Hz,
2H), 7.46 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 8.0 Hz, 2H), 7.18 (t, J =
7.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H); 19F NMR
4.3.7 2-((2-Chlorophenyl)thio)-2,2-difluoro-N-
phenylacetamide (3g)
53.3 mg; 85% yield; light yellow solid; MP 118.6-119.2℃;1H
NMR (500 MHz, CDCl3) δ: 8.20-8.06 (m, 1H), 7.79 (d, J = 7.7
Hz, 1H), 7.53 (t, J = 7.9 Hz, 3H), 7.38 (dt, J = 21.8, 7.8 Hz, 3H),
7.30 (t, J = 7.8 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H); 19F NMR (470
MHz, CDCl3) δ -81.44; 13C NMR (125 MHz, CDCl3) δ 159.2 (t,
2JC-F = 28.2 Hz), 140.4, 139.1, 135.7, 132.2, 130.5, 129.1, 127.5,
125.8, 122.0, 122.0 (t ,1JC-F = 293.5 Hz), 120.6; MS (EI, GCMS):
m/z: found: 313; calcd. for 313.01
(470 MHz, CDCl3) δ: -83.55; 13C NMR (125 MHz, CDCl3) δ:
2
161.8 , 159.6 (t, JC-F = 28.8 Hz), 138.7, 135.8, 129.2, 125.8,
122.3 (t ,1JC-F = 287.5 Hz) , 115.2, 115.1, 55.5; IR (KBr, cm-1) v :
3305, 1684, 1536, 1447, 1247, 1073, 817, 692; MS (EI, GCMS):
m/z: found: 309; calcd. for 309.06
4.2.2. 2,2-Difluoro-N-phenyl-2-(p-
tolylthio)acetamide (3b)
4.2.8 2-((3-Chlorophenyl)thio)-2,2-difluoro-N-
50.4 mg; 86% yield; light yellow solid; MP 132.7-133.2℃; 1H
NMR (500 MHz, CDCl3) δ 7.94-7.78 (m, 1H), 7.59-7.53 (m,
2H), 7.49 (ddd, J = 8.6, 2.5, 1.3 Hz, 2H), 7.39-7.33 (m, 2H),
7.24-7.19 (m, 3H), 2.39 (s, 3H); 19F NMR (470 MHz, CDCl3) δ: -
82.85; 13C NMR (125 MHz, CDCl3) δ: 159.6 (t, 2JC-F = 28.5 Hz),
phenylacetamide (3h)
56.4 mg, 90% yield, light yellow solid, MP 105.5-106.0℃; 1H
NMR (500 MHz, CDCl3) δ: 8.00 (s, 1H), 7.69 (t, J = 1.9 Hz, 1H),
7.57 (dt, J = 7.7, 1.3 Hz, 1H), 7.54-7.50 (m, 2H), 7.46 (ddd, J =
8.1, 2.1, 1.1 Hz, 1H), 7.41-7.33 (m, 3H), 7.25-7.20 (m, 1H); 19F
141.3, 136.9, 135.8, 130.3, 129.2, 127.6, 125.8, 122.4 (t ,1JC-F
=
NMR (470 MHz, CDCl3) δ: -81.53; 13C NMR (125MHz, CDCl3)
2
281.5 Hz), 120.5, 21.4; MS (EI, GCMS): m/z: found: 293; calcd.
for 293.07
δ: 159.2 (t, JC-F = 28.0 Hz), 136.3, 135.5, 134.9, 134.8, 130.9,
1
130.4, 129.3, 126.5, 126.1, 122.3 (t, JC-F = 291.4 Hz), 120.6; MS
(EI, GCMS): m/z: found: 313; calcd. for 313.01

5
4.2.9 2,2-Difluoro-2-(4-methoxyphenoxy)-N-
37.7 mg, 86% yield, light yellow solid,m.p. =197.2-198.7℃;
1H NMR (500 MHz, DMSO-d6) δ: 9.09 (s, 1H), 7.18 – 7.09 (m,
phenylacetamide (3i)
2H), 7.04 (d, J = 2.1 Hz, 1H); 19F NMR (470 MHz,DMSO-d6) δ:
1
38.1 mg; 65% yield; light yellow solid; MP 89.2-90.3 ℃; H
NMR (500 MHz, CDCl3) δ: 7.77 (s, 1H), 7.56 (d, J = 8.8 Hz,
2H), 7.46 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 8.0 Hz, 2H), 7.18 (t, J =
7.9 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H); 19F NMR
2
-77.70; 13C NMR (125 MHz, DMSO-d6) δ: 153.2 (t, JC-F = 38.0
1
Hz), 136.7, 128.9, 126.1, 123.9, 118.7, 116.0, 112.8 (t, JC-F
=
262.0 Hz); IR (KBr, cm-1) v :3164, 1728, 1493, 1418, 1218, 1176,
(470 MHz, CDCl3) δ: -83.55; 13C NMR (125 MHz, CDCl3) δ:
1075, 785; MS (EI, GCMS): m/z: found: 218; calcd. for 218.99
2
158.1, 157.5 (t, JC-F = 37.1 Hz) 142.5, 135.9, 129.4, 125.9,
4.3.6 6-Bromo-2,2-difluoro-2H-
1
123.3, 120. 5, 114.7, 114.6 (t, JC-F = 273.1 Hz), 55.7; IR (KBr,
benzo[b][1,4]oxazin-3(4H)-one (5f)
cm-1) v : 3258, 1700, 1503, 1244, 1195, 1073, 750; MS (EI,
42.7 mg, 81% yield, light yellow solid, MP 167.9-168.8℃; 1H
NMR (500 MHz, DMSO-d6) δ: 12.09 (s, 1H), 7.31 (dd, J = 8.7,
2.2 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H);
GCMS): m/z: found: 293; calcd. for 293.09
4.3 Typical procedures for the synthesis of compounds 5
19F NMR (470 MHz, DMSO-d6) δ: -75.62; 13C NMR (125 MHz,
2
A 10 mL round-bottom flask was charged with compound 4
(0.20 mmol, 1.0 equiv.), NaH (0.4 mmol) and DMF (2.0 mL).
The reaction mixture was stirred at 70℃ for 6 h. After the
reaction was completed, the crude product was directly purified
by silica gel chromatography, to give the desired product 5.
DMSO-d6) δ: 153.22 (t, JC-F = 38.0 Hz), 137.1, 126.8, 126.4,
119.1, 118.8, 116.6, 112.8 (t, 1JC-F = 262.0 Hz); IR (KBr, cm-1) v :
3185, 1722, 1489, 1203, 1122, 1019, 784; MS (EI, GCMS): m/z:
found: 263; calcd. for 262.94
4.3.7 2,2-Difluoro-6-nitro-2H-benzo[b][1,4]oxazin-
4.3.1 2,2-Difluoro-2H-benzo[b][1,4]oxazin-3(4H)-
3(4H)-one (5g)
one(5a)
34.1 mg, 74% yield, light yellow solid, MP 143.0-144.5℃; 1H
NMR (500 MHz, CDCl3) δ: 9.70 (s, 1H), 8.09 (dd, J = 9.0, 2.5
Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H); 19F
31.5 mg, 85% yield, light yellow solid, MP 170.0-170.8℃; 1H
NMR (500 MHz, DMSO-d6) δ: 11.95 (s, 1H), 7.28 (dd, J = 8.0,
1.4 Hz, 1H), 7.21 (td, J = 7.6, 1.4 Hz, 1H), 7.12 (ddd, J = 13.8,
7.7, 1.6 Hz, 2H); 19F NMR (470 MHz, DMSO-d6) δ: -75.96; 13C
NMR (470 MHz, CDCl3) δ: -76.71; 13C NMR (125 MHz, CDCl3)
2
δ: 154.6 (t, JC-F = 40.0 Hz), 144.9, 143.0, 124.7, 120.9, 118.6,
NMR (125 MHz, DMSO-d6) δ: 153.5 (t, 2JC-F = 38.1 Hz), 137.8,
1
112.6 (t, JC-F = 266.0 Hz), 112.4; IR (KBr, cm-1) v: 3157, 1752,
1
125.3, 124.7, 124.4, 117.1, 116.6, 113.2 (t, JC-F = 261.4 Hz); IR
1535, 1343, 1219, 1085, 801, 737; MS (EI, GCMS): m/z: found:
230; calcd. for 230.01
(KBr, cm-1) v: 3092, 1718, 1500, 1224, 1080, 820, 758; HRMS
(EI TOF) calcd for (M+) C8H5F2NO2: 185.0283, found: 185.0288
4.3.8 2,2-Difluoro-7-methyl-2H-
4.3.2 2,2-Difluoro-6-methyl-2H-
benzo[b][1,4]oxazin-3(4H)-one (5h)
benzo[b][1,4]oxazin-3(4H)-one (5b)
36.6 mg, 92% yield, white solid, MP 191.7-192.5℃; 1H NMR
(500 MHz, CDCl3) δ: 9.68 (s, 1H), 7.00 (s, 1H), 6.99-6.92 (m,
33.8 mg; 85% yield; light yellow solid; MP 178.5-179.0℃; 1H
NMR (500 MHz, CDCl3) δ: 9.79 (s, 1H), 7.10 (d, J = 8.3 Hz,
1H), 6.97 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 2.37 (s, 3H); 19F
2H), 2.35 (s, 3H); 19F NMR (470 MHz, CDCl3) δ: -77.30; 13C
2
NMR (125 MHz, CDCl3) δ: 155.6 (t, JC-F= 39.71 Hz), 138.6,
NMR (470 MHz, CDCl3) δ: -77.39; 13C NMR (125 MHz, CDCl3)
135.8, 125.8, 121.3, 118.0, 116.3, 113.4 (t, 1JC-F = 263.3 Hz), 21.0;
IR (KBr, cm-1) v: 3179, 1737, 1694, 1519, 1428, 1193, 1079, 786;
MS (EI, GCMS): m/z: found: 199; calcd. for 199.04
2
δ: 155.9 (t, JC-F = 40.0 Hz), 136.7, 135.5, 126.0, 123.5, 117.4,
1
116.9, 113.3 (t, JC-F = 262.8 Hz), 20.9; IR (KBr, cm-1) v: 3158,
1768, 1604, 1589, 1476, 1079, 756; MS (EI, GCMS): m/z: found:
199; calcd. for 199.04
4.3.9 2,2,7-Trifluoro-2H-benzo[b][1,4]oxazin-
3(4H)-one (5i)
4.3.3 6-(Tert-butyl)-2,2-difluoro-2H-
35.7 mg, 88% yield, light yellow solid, MP 184.0-185.5℃; 1H
NMR (500 MHz, DMSO-d6) δ: 11.99 (s, 1H), 7.36-7.31 (m, 1H),
benzo[b][1,4]oxazin-3(4H)-one (5c)
43.4 mg, 90% yield, light yellow solid, MP 141.1-142.4℃; 1H
NMR (500 MHz, CDCl3) δ: 10.30 (s, 1H), 7.20 (d, J = 6.5 Hz,
7.13-7.09 (m, 2H); 19F NMR (470 MHz, DMSO-d6) δ: -76.01, -
1
116.89; 13C NMR (125 MHz, DMSO-d6) δ: 158.0 (d, JC-F
=
2H), 7.15-7.12 (m, 1H), 1.35 (s, 9H); 19F NMR (470 MHz,
2
3
241.6 Hz), 152.9 (t, JC-F = 37.7 Hz), 138.1 (d, JC-F = 12.7 Hz),
2
CDCl3) δ: -76.80; 13C NMR (125 MHz, CDCl3) δ: 155.9 (t, JC-F
4
3
1
121.5 (d, JC-F = 2.9 Hz), 117.5 (d, JC-F = 9.6 Hz), 112.9 (t, JC-F
= 262.1 Hz), 112.2 (d, 2JC-F = 23.1 Hz), 105.2 (d, 2JC-F = 27.9 Hz);
IR (KBr, cm-1) v: 3160, 1737, 1625, 1514, 1209, 1083, 817; MS
(EI, GCMS): m/z: found: 203; calcd. for 203.02
= 39.6 Hz), 149.1, 136.6, 123.3, 122.5, 116.9, 114.1, 113.5 (t, 1JC-
= 262.2 Hz), 34.7, 31.4; IR (KBr, cm-1) v: 3423, 2967, 1720,
F
1486, 1243, 812; MS (EI, GCMS): m/z: found: 241; calcd. for
241.09
4.3.10 7-Chloro-2,2-difluoro-2H-
4.3.4 2,2,6-Trifluoro-2H-benzo[b][1,4]oxazin-
benzo[b][1,4]oxazin-3(4H)-one (5j)
3(4H)-one(5d)
40.4 mg, 92% yield, light yellow solid, MP 208.1-209.5℃; 1H
NMR (500 MHz, CDCl3) δ: 9.81 (s, 1H), 7.23 (d, J = 2.0 Hz,
32.5 mg, 80% yield, light yellow solid, MP 150.9-152.1℃; 1H
NMR (500 MHz, CDCl3) δ: 10.06 (s, 1H), 7.16 (dd, J = 9.7, 4.6
1H), 7.18 (dd, J = 8.5, 2.2 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H); 19
F
Hz, 1H), 6.85 (d, J = 7.9 Hz, 2H); 19F NMR (470 MHz, CDCl3) δ:
NMR (470 MHz, CDCl3) δ: -77.43; 13C NMR (125 MHz, CDCl3)
1
-77.81, -115.49; 13C NMR (125 MHz, CDCl3) δ: 159.3 (d, JC-F
=
2
δ: 155.3 (t, JC-F = 39.4 Hz), 139.0, 130.5, 125.6, 122.6, 118.3,
244.9 Hz), 155.7 (t, 2JC-F = 40.0 Hz), 134.8, 124.6 (d, 3JC-F = 11.1
1
117.3, 112.91 (t, JC-F = 264.4 Hz); IR (KBr, cm-1) v: 3157, 1739,
3
1
Hz), 118.8 (d, JC-F = 9.4 Hz), 112.8 (t, JC-F = 263.7 Hz), 111.9
(d, 2JC-F = 23.8 Hz), 104.1 (d, 2JC-F = 28.2 Hz); IR (KBr, cm-1) v :
3170, 1751, 1704, 1506, 1223, 1085, 805; MS (EI, GCMS): m/z:
found: 203; calcd. for 203.02
1498, 1220, 1174, 1083, 818; MS (EI, GCMS): m/z: found: 219;
calcd. for 218.99
Acknowledgments
4.3.5 6-Chloro-2,2-difluoro-2H-
We are grateful to the Ministry of Science and Technology of
the People's Republic of China (2017YFB0404700) and the
Science Foundation of Shanghai Municipal Commission of
benzo[b][1,4]oxazin-3(4H)-one (5e)

6
Tetrahedron
Jr.; Médebielle, M. J. Fluorine Chem. 2000, 102, 369−376; i) Dolbier,
W. R.; Burkholder, C. R.; Medebielle, M. J. Fluorine Chem. 1999, 95,
127−130.
Sciences and Technology (15230724800) for their financial
support. We also thank the Instrumental Analysis and Research
Center of the Shanghai University for assistance.
3. a) Jiang, H. Z.; Yuan, S. J.; Cai, Y. S.; Wan, W.; Zhu, S. Z.; Hao. J. J.
Fluorine Chem. 2012, 133, 167-170; b) Zhou, D. Y.; Dou, H. Y.; Zhao,
C. X.; Chen, Q. Y. J. Fluorine Chem. 2006, 127, 740–745
4. Jiang, H. Z.; Yan, L. M.; Xu, M. J,; Lu, W. J.; Cai, Y. S.; Wan, W.;
Yao, J. H.; Wu, S. X.; Zhu, S. Z.; Hao, J. J. Org. Chem., 2013, 78 (9),
4261–4269;
References and notes
5. a) Rossi, R. A. Acc. Chem. Res. 1982, 15, 164-170; b) Nwokogu, G. C.;
Wong, J. W.; Greenwood, T. D.; Wolfe, J. F. Org. Lett. 2000, 2, 2643-
2646; c) Lukach, A. E.; Rossi, R. A. J. Org. Chem. 1999, 64, 5826-
5831; d) Laha, J. K.; Barolo, S. M.; Rossi, R. A.; Cuny, G. D. J. Org.
Chem. 2011, 76, 6421; e) Vaillard, V. A.; Guastavino, J. F.; Budén, M.
E.; Bardagí, J. I.; Barolo, S. M.; Rossi, R. A. J. Org. Chem. 2012, 77,
1507;
1. a) Rossi, R. A.; Pierini, A. B.; Peñeñory, A. B. In The Chemistry of
Functional Groups; Patai, S., Rappoport, Z., Ed.; Wiley: Chichester,
U.K., 1995; Suppl. D2, Chapter 24, pp1395-1485. b) Rossi, R. A.;
Pierini, A. B.; Peñeñory, A. B. Nucleophilic Substitution Reactions by
Electron Transfer. Chem. Rev. 2003, 103, 71-167. c) Bardagí, J. I.;
Vaillard, V. A.; Rossi, R. A. In Encyclopedia of Radicals in Chemistry,
Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.; John Wiley
& Sons, Ltd.: Chichester, 2012; d) R. A. Rossi, A. B. Pierini, A. N.
Santiago, In Org. React. 1999, 1-271.
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A.; Richardson, G. D. J. Chem. Soc., Perkin Trans. 2, 2001, 1557–1565
2. a) Rossi, R. A.; Pierini, A. B.; Palocios, S. M. Nucleophilic substitution
by the SRN1 mechanism on alkyl halides, in: D. D. Tanner (Ed.),
Advances in Free Radical Chemistry, Vol. 1, JAI Press, Greenwich, CT,
USA, 1990, pp. 193-252. b) Galli, C.; Rappoport, Z. Acc. Chem. Res.
2003, 36, 580–587; c) Chambers, R. D. In Fluorine in Organic
Chemistry; Wiley: New York, 1973; d) Z. T. Li, Q. Y. Chen, J. Chem.
Soc. Perkin Trans. 1, 1992, 1443–1445; e) Chen, Q. Y.; Qiu, Z. M. J.
Chem. Soc. Chem. Comm. 1987, 1240–1241; f) Chen, Q. Y.; Qiu, Z. M.
. Fluorine Chem. 1986, 31, 301–317; g) Zhao, C. X.; Jiang, X. K. J. Am.
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Supplementary Material
Electronic Supplementary Information (ESI) availabl ：
Experimental details, characterization data (including 1H, 13C and
19F NMR spectra) for the compounds synthesized are available
free of charge via the Internet.

1. A facile and efficient method for construction of S-CF2 or O-CF2 bonds through intermolecular
radical nucleophilic substitution (SRN1) reaction.
2. This protocol provided biologically important 2,2-difluoro-2H-benzo[1,4]oxazin-3-ones and
gem-difluoromethylene ether compounds in good to excellent yields in the mild conditions.
3. This method could provide a new synthetic strategy for the drug design and innovation.

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.
X
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
Haizhen Jiang
June. 6, 2020