Catalyst-free and visible light promoted trifluoromethylation and perfluoroalkylation of uracils and cytosines

Article abstract of DOI:10.1039/c8cc07759b

Fluoroalkylated enaminones, such as trifluridine and 5-trifluoromethyluracil, have widespread applications in pharmaceuticals and agrochemicals. Although these kinds of pharmaceutical agent often bear CF₃ and perfluoroalkyl motifs in the core structure, access to such analogues typically requires multi-step synthesis. Here, we report a mild, metal-free and operationally simple strategy for the direct perfluoroalkylation of uracils, cytosines and pyridinones through a visible-light induced pathway from perfluoroalkyl iodides. This photochemical transformation features synthetic simplicity, mild reaction conditions without any photoredox catalyst, and high functional group tolerance, providing a facile route for applications in medicinal chemistry.

Full text of DOI:10.1039/c8cc07759b

Showcasing research from Professor Chun-Yang He’s
laboratory, School of Pharmacy, Zunyi Medical University,
Zunyi, Guizhou, P. R. China.
As featured in:
Catalyst-free and visible light promoted trifluoromethylation
and perfluoroalkylation of uracils and cytosines
Fluoroalkylated enaminones have wide applications in
pharmaceuticals, this methodology therefore presents a mild,
catalyst-free and operationally simple strategy for the direct
perfluoroalkylation of uracils, cytosines and pyridinones through
a visible-light induced pathway.
See Xiao-Fei Li, Xingang Zhang,
Chun-Yang He et al.,
Chem. Commun., 2018, 54, 13662.
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Catalyst-free and visible light promoted
trifluoromethylation and perfluoroalkylation of
uracils and cytosines†
Cite this: Chem. Commun., 2018,
54, 13662
Received 28th September 2018,
Accepted 19th October 2018
Yang Huang,‡a Yun-Yun Lei,‡a Liang Zhao,a Jiwei Gu,b Qiuli Yao,a Ze Wang,a
a
Xiao-Fei Li,*a Xingang Zhang *b and Chun-Yang He
*
DOI: 10.1039/c8cc07759b
rsc.li/chemcomm
Fluoroalkylated enaminones, such as trifluridine and 5-trifluoro- an efficient and environmentally benign method to access such
methyluracil, have widespread applications in pharmaceuticals and structures is very desirable. Traditionally, 5-TFU is manufactured
agrochemicals. Although these kinds of pharmaceutical agent often from 3,3,3-trifluoropropene as a starting material in six steps.7
bear CF3 and perfluoroalkyl motifs in the core structure, access to Recently, some new methods by using Fe(II)/H2O2, Cu(II)/K2S2O8
such analogues typically requires multi-step synthesis. Here, we or electrochemical reagents have been developed.8 However,
report a mild, metal-free and operationally simple strategy for the an alternative method using commercially available reagents
direct perfluoroalkylation of uracils, cytosines and pyridinones remains highly desirable.
through a visible-light induced pathway from perfluoroalkyl iodides.
Recently, metal- and organocatalyst-based photoredox cata-
This photochemical transformation features synthetic simplicity, lysis reactions induced by visible light have been demonstrated
mild reaction conditions without any photoredox catalyst, and high as an attractive strategy for generating perfluoroalkyl free radicals
functional group tolerance, providing a facile route for applications under mild reaction conditions.9 As a milestone progress in the
in medicinal chemistry.
realm of visible-light induced radical fluoroalkylation, Melchiorre’s
group realized a noncovalent interaction initiated single-electron-
The incorporation of fluoroalkyl groups into (hetero)arenes can transfer (SET) fluoroalkylation driven by the photochemical activity
dramatically alter the physical and chemical properties of of an electron donor–acceptor (EDA) complex.10 These strategies
the parent molecules and results in numerous applications in are promising because no catalyst is needed.11 Curran and Studer
pharmaceuticals, agrochemicals, and functional materials.1 developed the concept that an electron can also be treated as an
Among fluorine-containing functional groups, the trifluoro- efficient catalyst to realize various transformations.12 However, the
methyl and perfluoroalkyl (RF) groups have a privileged role in connection of electrophilic perfluoroalkyl radicals with electron-
the field of medicinal chemistry because their incorporation into deficient (hetero)arenes via this catalyst-free strategy has never
small molecules often enhances metabolic stability, improves been reported.
lipophilicity and increases the protein binding affinity of the
Herein, we demonstrated a metal-free, operationally simple
drug candidates.2 Therefore, it is of great interest to develop protocol for the synthesis of 5-trifluoromethylated/perfluoro-
novel and effective synthetic methods to construct these fluoro- alkylated uracils via a visible light-promoted reaction with
alkylated (hetero)arenes.3
inexpensive perfluoroalkyl iodides as fluoroalkylating reagents.
The structural entity of uracils is a kind of important The reaction can also extend to cytosines and 4-pyridinones,
electron-deficient heteroarene in pharmaceuticals and life providing a useful and facile access to some valuable molecules
sciences.4 For example, 5-trifluoromethyluracil (5-TFU) is an for application in medicinal chemistry.
important intermediate in the field of medicinal chemistry,5 and
We began this study by choosing uracil 1a and CF3I 2 as
trifluridine is an antiviral drug.6 Therefore, the development of model substrates.13 In our previous studies, we found that the
solution of CF3I in DMSO could be stored at room temperature
a Generic Drug Research Center of Guizhou Province, School of Pharmacy,
without declining the titer, thus making the manipulating
process more convenient.14 When this stable and practically
manipulated trifluoromethyl iodide solution combined with
uracil 1a and Na2CO3 in DMSO was irradiated by blue LEDs
for 12 hours, the trifluoromethylated uracil 3a was obtained in
30% yield (Table 1, entry 1). Further optimization of inorganic
bases demonstrated that Cs2CO3 was the most effective one,
Zunyi Medical University, Zunyi, 563003, P. R. China.
E-mail: hechy2002@163.com, 359238630@qq.com
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, 200032, P. R. China.
E-mail: xgzhang@mail.sioc.ac.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc07759b
‡ Y. Huang and Y.-Y. Lei contributed equally to this work.
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Table 1 Representative results for the optimization of the visible-light-
promoted trifluoromethylation of uracil 1aa
Table 2 Direct trifluoromethylation of uracils and uracil nucleosidesa,b
Entry
Light source
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Green LED
Yellow LED
—
Na2CO3
K2CO3
Cs2CO3
K3PO4
NaOH
K2HPO4
KOAc
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeOH
DCE
30
65
85 (81)
56
53
Trace
Trace
Trace
NR
NR
NR
NR
NR
Trace
Trace
67
69
NR
NR
KF
9
DMPU
TMEDA
Et3N
10
11
12
13
14
15
16
17
18
19
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
—
DMF
MeCN
DMSO
DMSO
DMSO
DMSO
a
Reaction conditions: 1 (0.4 mmol, 1.0 equiv.), 2 (1.2 mmol, 3.0 equiv.),
Cs2CO3 (0.8 mmol, 2.0 equiv.) in anhydrous DMSO (3.0 mL), r.t., 12 W
b
c
Blue LED
blue LED, for 24 h. Yield of the isolated product. The reaction was
d
performed for 12 h. (100 mmol, 1.0 equiv.), CF3I (300 mmol, 3.0 equiv.),
a
Reaction conditions (unless otherwise specified): 1a (0.4 mmol,
e
Cs2CO3 (2.0 equiv.), DMSO (400 mL), r.t., 24 W blue LED, for 48 h. 1.0 mL
1.0 equiv.), CF3I (1.2 mmol, 3.0 equiv.), base (0.8 mmol, 2.0 equiv.),
DMSO was used.
b
solvent (3.0 mL), room temperature, 12 h. Determined by 19F-NMR
spectroscopy using fluorobenzene as an internal standard; the number
within parentheses represents the yield of the isolated product.
readily prepared from abundant 20-deoxyuridine via the current
photo-induced process without protection (Table 2, 3i), thus
and the desired product 3a was isolated in 81% yield. However, providing a facile route for applications in drug discovery and
organic bases, which are traditionally used as electron-donors development. Remarkably, when the reaction was performed on
in previous reports, did not provide any reactivity (Table 1, a 10 gram scale (3a), a comparable yield still could be obtained,
entries 9–11). Then, a series of reaction media were screened thus demonstrating the synthetic utility of this protocol.
(Table 1, entries 12–15), and no desired product was detected
We next investigated the scope of the reaction with respect
when MeOH or DCE was used. Only trace yield was observed to the perfluoroalkyl reagents (Table 3). Other commercially
when the reaction was conducted in DMF and MeCN. Visible available perfluoroalkyl iodides such as C2F5I, C4F9I and C6F13I
light with other wavelengths, such as green and yellow light, underwent the current process smoothly, and provided the
demonstrates less reactivity (Table 1, entries 16 and 17). Control corresponding products in moderate to excellent yields. How-
experiments, carried out by performing the reaction in the dark or ever, 1,3-dimethyluracil showed less reactivity and only 32%
in the absence of a base, failed to provide the desired product, yield of 5d was obtained, suggesting that the existence of the
which indicates that a photochemical transformation was involved unprotected N–H bond is critical to the reaction efficiency
in the reaction (Table 1, entries 18 and 19).
(Table 3, 5d).
As illustrated in Table 2, we found that this new photo-
Cytosines are also important heterocyclic motifs found in
chemical protocol allows the direct trifluoromethylation of a numerous bioactive molecules;15 however, methods for intro-
range of uracils. Initially, the substituent effect on nitrogen was ducing fluoroalkyl groups to these structures are still limited.16
examined. 1-Methyluracil and 5-bocuracil give the trifluoro- Therefore, the reaction of cytosines with fluoroalkyl iodides was
methylated product in 77% and 71% yields, respectively. While also examined (Table 4). No reaction occurred when cytosine
1,3-dimethyluracil afforded a lower yield (45%) (Table 2, 3b–d). was tested, but good to excellent yields can be obtained when
Functional group substitution at the non-heteroatom position, N4-benzoylcytosine and N4-acetylcytosine were treated (Table 4,
such as alkoxycarbonyl and methyl, is also amenable to this 7b–f). Further experiments demonstrated that the successful
trifluoromethylation protocol, leading to the corresponding negative ionization of the N–H bond on these heterocycles is
products in 64–80% yields (Table 2, 3e–f). 2,4-Dimethyl-6- the key step for the reaction efficiency (for details, see the ESI†).
hydroxypyrimidine was also a suitable substrate, and provided
The utility of the current reaction can also be demonstrated
the corresponding product in 77% yield (Table 2, 3g). 1-(Tetra- by the rapid fluoroalkylation of 4-pyridones.17 As shown in
hydrofuran-2-yl)-5-trifluoromethyluracil, an important inter- Table 5, 54% yield of 2,6-dimethyl-3,5-bis(trifluoromethyl)pyridin-
mediate used in medicinal chemistry, can be accessed in 67% 4(1H)-one (Table 5, 9a) along with 11% yield of the mono-
yield (Table 2, 3h). Trifluridine, an antiviral drug, can also be substituted product was generated under the optimized conditions.
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Table 3 Direct perfluoroalkylation of uracils and uracil nucleosidesa,b
Table 5 Direct trifluoromethylation and perfluoroalkylation of 4-pyridonesa,b
a
Reaction conditions (unless otherwise specified):
8 (0.4 mmol,
1.0 equiv.), 2 or 4 (1.2 mmol, 3.0 equiv.), Cs2CO3 (0.8 mmol, 2.0 equiv.)
b
in anhydrous DMSO (1.0 mL), r.t., 12 W blue LED, for 24 h. Yield of
the isolated product. Yield of the mono-substituted product.
a
c
Reaction conditions (unless otherwise specified):
1 (0.4 mmol,
1.0 equiv.), 4 (1.2 mmol, 3.0 equiv.), Cs2CO3 (0.8 mmol, 2.0 equiv.), DMSO
(3.0 mL), r.t., 12 W blue LED, for 24 h. Yield of the isolated product.
b
Table 4 Direct trifluoromethylation and perfluoroalkylation of cytosinesa,b
a
Reaction conditions (unless otherwise specified):
6 (0.4 mmol,
1.0 equiv.), 2 or 4 (1.2 mmol, 3.0 equiv.), Cs2CO3 (0.8 mmol, 2.0 equiv.)
b
in anhydrous DMSO (3.0 mL), r.t., 12 W blue LED, for 24 h. Yield of
the isolated product.
Fig. 1 Proposed reaction mechanism.
82% yield of the di-substituted product was obtained when C4F9I
was used (Table 5, 9b). Quinolones were also suitable substrates
in the reaction system, and moderate to good yields could still be Firstly, the negatively ionized uracil (A) was generated in the
obtained (Table 5, 9c–9f). When 1-methyl-4-quinolone was treated presence of Cs2CO3. A fluoroalkyl radical can be produced
with CF3I, the reaction become complex, and only a trace amount under the irradiation of blue LEDs via the EDA complex. Two
of the desired product was detected (Table 5, 9g).
pathways are feasible for the propagation step: (1) the newly
To gain insight into the mechanism of this transformation, formed radical then reacts with A to produce intermediate B,
a series of experiments were carried out. Initially, radical which can activate the fluoroalkyl iodides via a SET process and
inhibition experiments were conducted. No desired product meanwhile generate the desired products (3/5); or (2) the Rf
was observed when a radical scavenger TEMPO (100 mol%) was radical can add to uracils (1) and generate the carbon radical
added under the standard reaction conditions, suggesting a intermediate D, which abstracts an iodine atom from RfI to
radical pathway is involved in this transformation. Radical afford E and regenerate the Rf radical. The desired products
clock experiments were performed subsequently. When cyclo- (3/5) were obtained via the fast rearomatization of E through HI
propylstyrene (10) was treated with CF3I in the presence or elimination.
absence of 1a under the standard reaction conditions, a ring-
In conclusion, we have developed a useful and operationally
opened product 11 was formed. Finally, the optical absorption green method for the synthesis of trifluoromethylated/perfluoro-
spectra of the reactants were investigated, which indicated that alkylated uracils and cytosines. This new protocol was also
an EDA complex might be generated between the negatively successfully applied to 4-pyridones. This reaction is distin-
ionized uracil and CF3I (for details, see the ESI†).
guished by its mild reaction conditions, wide substrate scope,
On the basis of these preliminary results, a plausible mecha- and especially good applicability. The application of this
nism was proposed, as shown in Fig. 1, for this transformation. methodology in life sciences is underway in our lab.
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Conflicts of interest
There are no conflicts to declare.
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