Direct C-H Trifluoromethylation of Glycals by Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.5b03016

A mild, efficient, and practical transformation for the direct C-H trifluoromethylation of glycals under visible light has been reported for the first time. This reaction employed fac-Ir³⁺(ppy)₃ as the photocatalyst, Umemoto's reagent as the CF₃ source, and a household blue LED or sunlight as the light source. Glycals bearing both electron-withdrawing and -donating protective groups performed this reaction smoothly. This visible light-mediated trifluoromethylation reaction was highlighted by the trifluoromethylation of the biologically important Neu2en moiety.

Full text of DOI:10.1021/acs.orglett.5b03016

Letter
pubs.acs.org/OrgLett
Direct C−H Trifluoromethylation of Glycals by Photoredox Catalysis
Bang Wang,† De-Cai Xiong,*,† and Xin-Shan Ye*,†
†State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Center for Molecular and
Translational Medicine, Peking University, Xue Yuan Road No. 38, Beijing 100191, China
S
* Supporting Information
ABSTRACT: A mild, efficient, and practical transformation for the
direct C−H trifluoromethylation of glycals under visible light has been
reported for the first time. This reaction employed fac-Ir3+(ppy)3 as the
photocatalyst, Umemoto’s reagent as the CF3 source, and a household
blue LED or sunlight as the light source. Glycals bearing both electron-
withdrawing and -donating protective groups performed this reaction smoothly. This visible light-mediated trifluoromethylation
reaction was highlighted by the trifluoromethylation of the biologically important Neu2en moiety.
lycans play crucial roles in a variety of physiological and
1
Gpathological processes. Carbohydrate-based drug discov-
ery is a subject of current interest and challenge. Some
carbohydrate-based drugs and vaccines have been used to battle
infectious diseases, diabetes, and other diseases.2 Modifications
are powerful strategies for reducing hydrophilicity and
improving the affinity, oral bioavailability, and metabolic
stability of native carbohydrates in the realm of carbohydrate-
Figure 1. Glycal-derived drugs.
based drug discovery.3 Due to the unique properties of the
fluorine atom, the incorporation of fluorine into carbohydrates
has become one of the most important modification
challenge due to the structural complexity of carbohydrate
substrates and the inactive electron-deficient double bond of
glycals. Herein, we report a direct C−H trifluoromethylation of
glycals using visible-light photoredox catalysis.
approaches to address such issues.3,4
Trifluoromethyl (CF3) is a useful structural motif in many
bioactive molecules and a privileged group in medicinal
chemistry, owing to the unique properties of CF3 functionality
on organic molecules, including lipophilicity, metabolic
stability, high electronegativity, and bioavailability.5 The
development of new methodologies for the efficient introduc-
tion of a CF3 group into organic compounds has been a hot
topic in synthetic chemistry.6 Especially, the photoredox-
catalyzed7 radical trifluoromethylation8 has enabled many
mild and efficient methods for trifluoromethylation of alkenes,
(hetero)arenes, alkynes, phenol, and many other compounds.9
Photoredox catalytic trifluoromethylation can be easily scaled-
up using continuous flow technology, making the process more
environmentally benign.9b Nonetheless, no general protocols
for the modification of carbohydrates have emerged from those
research efforts.10
In continuation of our interest in the area of carbohydrate
synthesis and carbohydrate-based drug discovery,11 we have
now developed a method for the trifluoromethylation of glycals.
Glycals are versatile building blocks for the construction of
oligosaccharides and glycoconjugates, as well as other bioactive
natural products or their derivatives.12 Glycals or their
derivatives have also been used as inhibitors or probes for
glycosidases13 such as the antiflu drugs Zanamivir,14 Ianinami-
vir,15 and Oseltamivir16 (Figure 1). In fact, most glycals usually
need to be modified to gain better biological functions.
However, the modification of glycals has been a formidable
Our initial investigation of the reaction parameters was
conducted using the less electron-deficient 6-O-benzyl-3,4-
dideoxy-glycal 1a as the substrate and a household blue LED as
the light source (Table 1, and Table S1 in Supporting
Information). We found that Togni reagent 2a,8f Togni reagent
2b, CF3SO2Na, CF3SO2Cl,8j or CF3TMS was not an ideal CF3
source (entries 1−5). However, the desired trifluoro-
methylated-3,4-dideoxy-glucal 3a was obtained in good yield
by the use of either Umemoto reagent 2c (85%) or Umemoto
reagent 2d (80%) as the CF3 source (entries 6−7). Different
solvents were also tested (entries 8−12, Table S1), and
anhydrous DMA was found to be the best choice (entry 13).
Further screening of the ratio of reagents (entries 14−16),
reaction time (Table S2), additives (Table S3), temperature
(Table S4), and photocatalysts7c (entries 17−19) established
the optimized conditions: fac-Ir(ppy)3 (1.5 mol %) as catalyst
and 2c (1.5 equiv) as CF3 source in DMA under the irradiation
of visible light for 1.5 h at room temperature (entry 13, 91%).
Control experiments showed that both light and the photo-
catalyst were essential for the reaction (entries 20−21).
Under the optimized reaction conditions, the scope of 3,4-
dideoxy-glycal (1b−e) with different protective groups was
Received: October 18, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03016
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Letter
Table 1. Trifluoromethylation of 1a via Photoredox
Catalysis
Scheme 2. Substrate Scope of Trifluoromethylation of
a
a
Hexose-Derived Glycals
b
entry
“CF3” reagent
solvent
catalyst
yield [%]
1
2a
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
Et2O
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
Ru(bpy)3Cl
Ru(bpy)3Cl·6H2O
Ru(bpy)3(PF6)2
−
trace
trace
0
2
2b
3
CF3SO2Na
4
CF3SO2Cl
0
5
CF3TMS
0
6
2c
85
80
0
7
2d
8
2c
9
2c
0
10
11
12
13
14
15
16
17
18
19
20
2c
DCM
DMSO
THF
0
2c
71
0
2c
2c
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
91
79
91
90
79
77
84
0
2c (1.2 equiv)
2c (2.0 equiv)
2c (5.0 equiv)
2c
2c
2c
2c
2c
c
21
fac-Ir(ppy)3
0
a
a
Isolated yield.
Reaction conditions: 1a (0.10 mmol), “CF3” reagent (0.15 mmol),
photocatalyst (1.5 mol %), solvent (1.0 mL), under argon atmosphere,
b
visible light, 1.5 h. Yields determined by 19F NMR using α,α,α-
trifluorotoluene as an internal standard. In the dark.
c
yields. The tosyl-protected substrate (product 5e, 68%) and
the free hydroxyl-containing substrate (product 5f, 58%) were
tolerated under the standard conditions. Trifluoromethylation
of the acetylated glucal (product 5d, 49%) or acetylated galactal
(product 5j, 63%) gave the desired products in a lower yield,
when compared with their benzylated, p-methoxybenzylated,
methylated counterparts. This might result from the strong
electron-withdrawing effect of the acetyl. An especially
encouraging aspect of the chemistry was that the acetylated
lactal could also be trifluoromethylated in good yield (product
5q, 68%).
surveyed, as shown in Scheme 1. To our delight, the reactions
of the methylated (1b, 90%), p-methoxybenzylated (1c, 89%),
Scheme 1. Scope of Trifluoromethylation of Other Protected
3,4-Dideoxy-glucals
To further highlight the value of this transformation, the
trifluoromethylation reactions of the most electron-deficient
2,3-unsaturated N-acetylneuraminic acid (Neu2en) derivatives
were investigated (Scheme 3). Surprisingly, when the
Neu5Ac2en substrate 6a was treated under the standard
conditions, the trifluoromethylated product 7a was obtained in
43% isolated yield and the starting material 6a was recovered in
acetylated (1d, 90%), or pivaloylated (1e, 88%) 3,4-dideoxy-
glycals were similar to that of 1a. The desired products (3b−e)
were obtained in high yields. The structures of the
trifluoromethylated-3,4-dideoxy-glycals (3b−e) were unambig-
Scheme 3. Photocatalytic C−H Trifluoromethylation of
Neu2en Derivatives and Their Transformations
1
uously identified by H, 13C, and 19F NMR analyses.
Subsequently, we proceeded to study the scope of the more
electron-deficient and challenging hexose-derived glycals
(Scheme 2). It was found that the most satisfactory yields
were obtained by increasing 2c to 3.0 equiv and the reaction
time to 12 h (Table S5). Under the reoptimized conditions, the
reactions of benzylated glucal/galactal/rhamnal/arabinal, and p-
methoxybenzylated or methylated glucal/galactal/rhamnal/
arabinal afforded the corresponding products in 65−78%
B
DOI: 10.1021/acs.orglett.5b03016
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Letter
42% yield. Similarly, 2,3-unsaturated N-acetylneuraminic acid
derivative 6b, which is an important precursor of antiflu drug
zanamivir, was successfully trifluoromethylated to give 7b in
45% yield with 40% of 6b recovered. Deprotection of 7a and
reduction of 7b produced 8a and 8b in quantitative yield and
70% yield, respectively. These results showed that the
trifluoromethyl group had little influence on functional group
manipulations of the Neu2en moiety. Thus, it may have
promising applications in the trifluoromethylation modification
of Neu2en-derived drugs.
To gain insight into the reaction mechanism, a series of
experiments were conducted under the standard conditions
with 1a and 2c (see the Supporting Information for details).
First, it was found that no reaction occurred in the absence of
either light or photocatalyst, illustrating that light and the
photocatalyst together triggered the trifluoromethylation
reaction. Under the standard conditions, when 1a was reacted
with 2c, product 3a, trifluoromethylated dibenzothiophenes
(10, comprising of four isomers 10a−d), and dibenzothiophene
(9a) were isolated in 91%, 11%, and 125% yield, respectively.
The detection of 10a−d, which is first reported in the
trifluoromethylation reaction by the use of Umemoto’s reagent
as the CF3 source, accounting for the excess of 2c. The
trifluoromethylation reaction of 1a with 2c was almost shut
down by the addition of 2.0 equiv of TEMPO (2,2,6,6-
of C or D affords the desired product E. The formation of a
small amount of trifluoromethylated dibenzothiophene might
result from the free-radical aromatic substitution reaction of
dibenzothiophene with the CF3 radical.
In conclusion, a mild, efficient, and practical reaction for the
direct C−H trifluoromethylation of glycals under visible light
has been reported for the first time. This photocatalytic
reaction employs fac-Ir3+(ppy)3 as the photocatalyst, Umemo-
to’s reagent as the CF3 source, and a household blue LED or
sunlight (see the Supporting Information) as the light source.
Glycals bearing both electron-withdrawing and -donating
protective groups were shown to be suitable substrates for
the reaction. This visible light-mediated trifluoromethylation
transformation was further highlighted by the trifluoromethy-
lation of the Neu2en moiety. The possible mechanism involves
a CF3 radical and a glycosyl oxocarbenium ion and was probed
by a series of experiments. This novel protocol not only finds
many applications in the synthesis of trifluoromethylated
carbohydrates and carbohydrate-based drugs but also holds
great potential in the trifluoromethylation of other electron-
deficient compounds. Studies along this line are currently
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
tetramethyl-1-piperidinyloxy), a well-known radical scavenger,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03016.
8n,17
and TEMPO−CF3
was obtained in 120% yield based on
19F NMR analysis, whereas the desired product 3a was detected
only in a trace amount (see the Supporting Information). This
implied that a CF3 radical intermediate was involved in the
trifluoromethylation process. Moreover, the ethyl glycoside was
isolated in 71% yield using ethyl alcohol as the cosolvent
(Supporting Information), indicating a glycosylation process via
a glycosyl oxocarbenium ion.
Detailed experimental procedures and spectral data for
all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Based on these experimental results, a possible reaction
mechanism is tentatively illustrated in Scheme 4. Initially, fac-
*E-mail: decai@bjmu.edu.cn.
*E-mail: xinshan@bjmu.edu.cn.
Notes
Scheme 4. Possible Reaction Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by grants (2012CB822100,
2013CB910700) from the Ministry of Science and Technology
of China, the National Natural Science Foundation of China
(Grant No. 21232002), and Beijing Higher Education Young
Elite Teacher Project (YETP0063). We thank Profs. Jinbo Hu
(SIOC), Ning Jiao (PKUHSC), and Suwei Dong (PKUHSC)
for their helpful discussions.
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