Visible-Light Photoredox Difluoromethylation of Phenols and Thiophenols with Commercially Available Difluorobromoacetic Acid

Article abstract of DOI:10.1021/acs.orglett.7b01118

A simple and efficient visible-light photoredox one-pot method for difluoromethylation of phenols and thiophenols has been developed. The protocol uses commercially available, inexpensive, and easy handling difluorobromoacetic acid as the difluoromethylating agent, and the diverse O- and S-difluoromethylated products were prepared in good yields with tolerance of many functional groups.

Full text of DOI:10.1021/acs.orglett.7b01118

Letter
pubs.acs.org/OrgLett
Visible-Light Photoredox Difluoromethylation of Phenols and
Thiophenols with Commercially Available Difluorobromoacetic Acid
Jinyan Yang, Min Jiang, Yunhe Jin, Haijun Yang, and Hua Fu*
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. China
S
* Supporting Information
ABSTRACT: A simple and efficient visible-light photoredox one-pot method
for difluoromethylation of phenols and thiophenols has been developed. The
protocol uses commercially available, inexpensive, and easy handling
difluorobromoacetic acid as the difluoromethylating agent, and the diverse O-
and S-difluoromethylated products were prepared in good yields with tolerance of many functional groups.
he discovery of new drugs with fluorine molecules has
great potential because more than 20% of the
optimize conditions including photocatalysts, solvents, bases,
and reaction time under an atmosphere of argon and irradiation
of visible light with a 23 W compact fluorescent light (CFL). As
shown in Table 1, three common photocatalysts, [Ru(bpy)3]-
Cl2 (A), [fac-Ir(ppy)3] (B), and [Ir(dFCF3ppy)2](dtbbpy)PF6
(C), were screened using DMF as the solvent and Cs2CO3 as
the base for 12 h (entries 1−3), and [fac-Ir(ppy)3] (B)
provided the highest yield (entry 2). We investigated reaction
time (compare entries 2, 4, and 5), and a 12 h reaction was
suitable. Several solvents were tested (entries 6−9), and DMF
gave the best result (compare entries 2 and 6−9). Other bases
were attempted (entries 10−13), and they were inferior to
Cs2CO3. Only a trace amount of product 3m was observed in
the absence of photocatalyst (entry 14) or visible light (entry
15). A 78% yield was obtained when two 3 W blue LEDs
replaced 23 W CFL as the light source (entry 16), which
showed that the reaction was performed with visible light rather
than UV light.
After determination of the optimized process above, the
substrate scope for the visible-light difluoromethylation of
phenols with difluorobromoacetic acid (2) was investigated. As
shown in Table 2, different phenols (1) were tested, and the
results showed that the phenols containing electron-with-
drawing groups on the aromatic rings exhibited higher reactivity
than those containing electron-donating groups. O-Difluor-
omethylation of 7-hydroxycoumarin with 2 was successfully
realized, and 3p was obtained in 76% yield. We attempted
visible-light-promoted coupling of 2,7-naphthalenediol with 2
equiv of 2, and O,O′-difluoromethylation product 3q was
prepared in 89% yield. The difluoromethylation of phenols
tolerated various functional groups, including C−Cl bonds (3c
and 3d), C−Br bonds (3d and 3e), C−I bonds (3f and 3g),
acetyl (3h), cyano (3i), nitro (3j and 3k), naphthyl (3m and
3n), ether (3o), and ester (3p) groups. Interestingly, the one-
pot O-difluoromethylation of phenols (1) used readily available,
easy handling, and inexpensive difluorobromoacetic acid (2) as
T
pharmaceuticals and agrochemicals on the market, including a
couple of top-10 drugs, are organofluorines.1,2 Therefore, the
fluorination of organic compounds has become an important
strategy in drug development. Among the fluorinated
molecules, difluoromethyl ethers are increasingly found in
various fields.3 Aryl difluoromethyl ethers are especially widely
used as medicinally important compounds. For example, they
are applied as anti-HIV agents,4 enzyme inhibitors,5 and
antimicrobial agents.6 Pantoprazole (Protonix) with a difluor-
omethyl ether as a proton-pump inhibitor is among the top 100
pharmaceuticals.7 The most popular strategy for the synthesis
of difluoromethylated products is based on the reaction of
nucleophilic reagents with difluorocarbene, so organic and
medicinal chemists have been devoted to explore new methods
and/or reagents for generation of reactive difluorocarbene
types. In the past decades, various difluorocarbene precursors
such as HCF2Cl, HCF3, CHF2I, PhSO2CF2Cl, ArCOCF2Cl,
ClCF2CO2Na, FSO2CF2CO2H, BrCF2P(O) (OEt)2,
TMSCF2Br, HCF2OTf, and PhS(O) (NTs)CF2H have been
developed in the difluoromethylation of phenols8 and
thiophenols.9 However, some drawbacks of the difluorocarbene
precursors hamper their wide application such as the use of the
ozone-depleting compounds,10 difficult to handle gaseous
reagents, commercially unavailable chemicals, and a require-
ment for harsh reaction conditions.9g Therefore, it is highly
desirable to develop an efficient method with a broad substrate
scope under relatively mild conditions by using an operationally
simple and environmentally benign difluorocarbene precursor.
Recently, photoredox methods with visible light as a renewable
energy source have become a powerful strategy under mild
conditions,11 As part of our continuing study on the visible-
light photoredox organic reactions,12 we report herein the use
of commercially available and easy handling difluorobromo-
acetic acid as a general difluorocarbene precursor for the
difluoromethylenation of phenols and thiophenols under
visible-light photocatalysis at room temperature.
At first, visible-light photoredox reaction of 2-naphthol (1m)
with difluorobromoacetic acid (2) was used as the model to
Received: April 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01118
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Conditions for Visible-Light
Photoredox Reaction of 2-Naphthol (1m) with
Difluorobromoacetic Acid (2)
Table 2. Substrate Scope for the Visible-Light Photoredox
Difluoromethylation of Phenols 1
a
a
b
entry
PC
solvent
base
time (h)
yield (%)
1
A
B
C
B
B
B
B
B
B
B
B
B
B
-
DMF
DMF
DMF
DMF
DMF
DMA
DCE
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
12
12
12
9
68
86
2
3
81
4
76
5
6
60
6
12
12
12
12
12
12
12
12
12
12
24
63
a
Reaction conditions: argon atmosphere and irradiation of visible light,
7
NR
40
[fac-Ir(ppy)3] (B) (3 μmol), substituted phenol (1) (0.3 mmol),
difluorobromoacetic acid (2) (0.3 mmol), DMF (2.5 mL), Cs2CO3
(0.9 mmol), temperature (rt, ∼25 °C), time (6−12 h) in a sealed
8
MeCN
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9
trace
75
b
c
10
11
12
13
Schlenk tube. Isolated yield. In the presence of 2 (0.6 mmol) and
Cs2CO3 (1.2 mmol).
Na2CO3
K3PO4
23
44
Scheme 1. Reaction of [1,1′-Biphenyl]-2,2′-diol (BINOL)
KOH
64
c
(1t) with 2 under the Standard Conditions
14
Cs2CO3
Cs2CO3
Cs2CO3
trace
trace
78
d
15
B
B
e
16
a
Reaction conditions: argon atmosphere and irradiation of visible light,
photocatalyst (PC) (3 μmol), 2-naphthol (1m) (0.3 mmol),
difluorobromoacetic acid (2) (0.3 mmol), solvent (2.5 mL), base
(0.9 mmol), temperature (rt, ∼25 °C), time (6−12 h) in a sealed
b
c
d
Schlenk tube. Isolated yield. In the absence of photocatalyst. The
e
reaction was carried out in the dark. The reaction was carried out
under irradiation of two 3 W blue LED light bulbs. CFL = compact
fluorescent light. DMA = N,N-dimethylacetamide. DCE = 1,2-
dichloroethane. NR = no reaction.
Table 3. Substrate Scope for the Visible-Light Photoredox
Difluoromethylation of Thiophenols (4)
a
the difluoromethylating reagent, and the reaction was
performed well at room temperature. Therefore, this is a
convenient and practical method. O-Difluoromethylation of
aliphatic alcohols was attempted under the present conditions,
but the reaction did not work.
Reaction of [1,1′-biphenyl]-2,2′-diol (BINOL) (1t) with 2
under the standard conditions provided 4-fluorodinaphtho[2,1-
d:1′,2′-f ][1,3]dioxepine (3t) in 50% yield. The reaction
underwent a sequential two-step process, including visible-
light-promoted intermolecular O-monodifluoromethylation of
BINOL leading to 3t′ and base-mediated intramolecular
cyclization affording 3t (Scheme 1).
Inspired by the results above, we surveyed visible-light
photoredox difluoromethylation of thiophenols (4) under the
standard conditions (Table 3), and similar results were
provided as those in Table 2. Therefore, the present visible-
light photoredox difluoromethylation displayed wide universal-
ity.
We explored the mechanism on the visible-light photoredox
difluoromethylation of phenols (1) and thiophenols (4). After
treatment of 2-naphthol (1m) with difluorobromoacetic acid
(2) in the absence of photocatalyst at room temperature for 12
h followed with 1 N HCl, no product 6 was found (Scheme
a
Reaction conditions: argon atmosphere and irradiation of visible light,
[fac-Ir(ppy)3] (B) (3 μmol), substituted thiophenol (1) (0.3 mmol),
difluorobromoacetic acid (2) (0.3 mmol), DMF (2.5 mL), Cs2CO3
(0.9 mmol), temperature (rt, ∼25 °C), time (6−12 h) in a sealed
b
Schlenk tube. Isolated yield.
2a). Meanwhile, compound 7 was prepared according to the
previous procedures,13 but decarboxylation was not performed
B
DOI: 10.1021/acs.orglett.7b01118
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. (a) Treatment of 2-Naphthol (1m) with
Difluorobromoacetic Acid (2) in the Absence of
Photocatalyst. (b) Treatment of Compound 7 under the
Standard Conditions
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01118.
■
S
Experimental details; NMR data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fuhua@mail.tsinghua.edu.cn.
ORCID
under the standard photoredox conditions (Scheme 2b). The
results showed that the difluoromethylation in Tables 2 and 3
did not produce intermediates 6 and 7. The reduction potential
for the reductive dehalogenation of BrCF2COOCs (I) was
detected, E1/2 = −1.29 V vs SCE (see Figure S1), so fac-
Ir(ppy)3 was a strong electron donor to reduce I in Scheme 3
Hua Fu: 0000-0001-7250-0053
Notes
The authors declare no competing financial interest.
red
ACKNOWLEDGMENTS
■
We thank Dr. Haifang Li in this department for her great help
in the analysis of high-resolution mass spectrometry and the
National Natural Science Foundation of China (Grant No.
21372139) for financial support.
Scheme 3. Plausible Mechanism on the Visible-Light
Photoredox Difluoromethylation
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DOI: 10.1021/acs.orglett.7b01118
Org. Lett. XXXX, XXX, XXX−XXX