Synthesis of 5-Fluorotriazoles by Silver-Mediated Fluorination of 5-Iodotriazoles

Article abstract of DOI:10.1002/ejoc.201500338

A simple method was developed for the direct fluorination of 5-iodotriazoles with AgF as fluoride source and N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (TMEDA) as ligand. This method is compatible with various fu

Full text of DOI:10.1002/ejoc.201500338

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500338
Synthesis of 5-Fluorotriazoles by Silver-Mediated Fluorination of
5-Iodotriazoles
Damin Wang,[a] Wenjing Sun,[a] and Taiwei Chu*[a]
Keywords: Heterocycles / Fluorine / Halogenation / Silver
A simple method was developed for the direct fluorination of
5-iodotriazoles with AgF as fluoride source and N1,N1,N2,N2-
tetramethylethane-1,2-diamine (TMEDA) as ligand. This
triazoles without aromatic groups at the 4-position or ali-
phatic substituents at the N1 position can also be smoothly
converted to the corresponding 5-fluorotriazoles. Preliminary
method is compatible with various functional groups. 5-Iodo- mechanism studies were also performed.
triazoles under mild and environmentally benign conditions
are still needed.
Introduction
Fluorine-containing heterocycles are one of the most
prevalent structural motifs in pharmaceuticals,[1] materi-
als,[2] and agrochemicals.[3] The introduction of fluorine-
containing substituents affects the reactivity, solubility, sta-
bility, and biological properties of these compounds.
The copper(I)-catalyzed azide–alkyne cycloaddition reac-
tion (CuAAC) is a robust, regioselective, quantitative, and
rapid reaction for the synthesis of triazoles.[4] To the best
of our knowledge, lots of 1,4,5-trisubstituted 1,2,3-triazoles
have been successfully synthesized through different meth-
ods. The syntheses of 5-halo-1,4-disubstituted 1,2,3-tri-
azoles have been widely studied to date, and many excellent
methods have been developed on the basis of the CuAAC
reaction.[5] In addition, methods for the synthesis of 5-tri-
fluoromethyl-1,4-disubstituted 1,2,3-triazoles,[6] 1,4-disub-
stituted 1,2,3-triazole boronic esters,[7] 1,4-disubstituted 5-
alumino-1,2,3-triazoles,[8] and other 1,4,5-trisubstituted
1,2,3-triazoles[9] have also been developed. However, reports
on the preparation of 5-fluorotriazoles are rare.[10]
Scheme 1. Synthesis and applications of 5-fluorotriazoles.
The first example of the synthesis of 5-fluorotriazoles
In the last decades, transition-metal-catalyzed/mediated
was reported by Fokin and co-workers in 2012 sp2 C–F bond formation has emerged as a powerful method
(Scheme 1a).[11] In this work, the applications of 5-fluorotri- for the construction of compounds containing aryl fluoride
azoles were also demonstrated (Scheme 1b). However, the moieties.[12] Recently, several groups have reported various
conditions for these transformations are relatively harsh. sp2 C–F bond constructions mediated by transition metals
Besides, both an aromatic group at the 4-position and an including Fe,[13] Ni,[14] Cu,[15] Pd,[16] and Ag,[17] with elec-
aliphatic substituent at the N1 position of the 5-iodotri- trophilic or nucleophilic fluorinating reagents as the source
azoles are required for an effective transformation to 5- of fluorine. For example, Hartwig reported a copper-medi-
fluorotriazoles. On this basis, methods to prepare 5-fluoro- ated fluorination of aryl iodides with AgF as fluoride
source.[15e] In addition, transition-metal-catalyzed/mediated
synthesis of 1,4,5-trisubstituted 1,2,3-triazoles have also
been achieved. For example, Cao reported a copper-medi-
ated trifluoromethylation of 5-iodotrizoles.[6] Born reported
palladium-catalyzed direct arylations of 1,2,3-triazoles with
aryl chlorides.[18] Given the importance of 5-fluorotriazoles
and easy availability of 5-iodotriazoles, we conceived the
preparation of 5-fluorotriazoles by transition-metal-medi-
[a] Beijing National Laboratory for Molecular Sciences,
Radiochemistry and Radiation Chemistry Key Laboratory of
Fundamental Science,
College of Chemistry and Molecular Engineering,
Peking University Beijing,
100871 China
E-mail: twchu@pku.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500338.
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Silver-Mediated Fluorination of 5-Iodotriazoles
ated fluorination of 5-iodotriazoles. Herein, we report a sil- ture. On the basis of these results, L1 (TMEDA) was se-
ver-mediated fluorination of 5-iodotriazoles with AgF as lected as standard ligand, as it presents a yield (60% NMR
both fluoride source and silver source (Scheme 1c).
yield) similar to that of L4 but has a lower price.
Further investigation focused on the optimization of the
solvents. After several solvents were screened (Table 1, en-
tries 2, 9–13), we found that nonpolar solvents such as tolu-
ene and 1,4-dioxane could effectively promote the conver-
sion of 1a to 2a, while polar solvents, such as DMSO,
DMF, and MeCN failed to lead to satisfactory yields. Inter-
estingly, 2a was obtained in only 3% NMR yield in DMSO,
while the main byproduct, 1-benzyl-4-phenyl-1,2,3-triazole
(3a), was obtained in 60% NMR yield (Table 1, entry 9).
Similar results were also observed in DMF and MeCN
(Table 1, entries 10 and 13). We speculated that the poor
conversion in the presence of polar solvents might arise
from the strong coordination effect that decreases the reac-
tivity of the catalyst.
Results and Discussion
The fluorination of 1-benzyl-5-iodo-4-phenyl-1,2,3-tri-
azole (1a) mediated by AgF was selected as the model reac-
tion to initiate our studies. As we expected, the desired 1-
benzyl-5-fluoro-4-phenyl-1,2,3-triazole (2a) could be fur-
nished through AgF-mediated fluorination of 1a without
any additives, albeit in a low yield (45% NMR yield)
(Table 1, entry 1). In view of the poor solubility of AgF in
toluene, we conceived that a higher yield would be achieved
by increasing the solubility of AgF. According to former
reports, a set of nitrogen ligands was selected to try with
this system. We found that the NMR yield was promoted
to 63% when 0.2 equiv. of L4 was used. Other ligands were
also able to increase the yield of 2a slightly (Table 1, entries
2–8). To our surprise, addition of L6 decreased the NMR
yield to 33%, possibly as a result of its electron-rich struc-
Table 2. Scope of 5-fluorotriazoles.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Entry 1a [equiv.] Ligand
Solvent
Yield[b]
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
DMF
1,4-dioxane
THF
MeCN
toluene
toluene
43%
60%
55%
50%
63%
48%
33%
45%
TMEDA
L2
L3
L4
L5
L6
L7
9
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
3% + 60%[c]
39% + 40%[c]
59%
10
11
12
13
14[d]
15[d,e]
53%
10% + 45%[c]
82%
89%, 79%[f]
[a] All reactions were carried out at 110 °C on a 0.2 mmol scale.
1
[b] Yield determined by H NMR spectroscopy by using dibromo-
methane as internal standard. [c] Yield of 2a + 3a determined by
1H NMR spectroscopy by using dibromomethane as internal stan-
dard. [d] The reaction was carried out with 0.5 equiv. of TMEDA.
[e] The reaction was carried out at 120 °C. [f] Isolated yield.
[a] All reactions were carried out on a 0.2 mmol scale under the
standard conditions. [b] Isolated yield.
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D. Wang, W. Sun, T. Chu
SHORT COMMUNICATION
Other fluoride and silver sources were also systemically well under the standard conditions. It should be noted that
examined. In the absence of a silver source, no conversion compound 2m was obtained in only 10% yield under the
was observed when the reactions were only conducted with standard conditions, that is, the pyridine group coordinated
KF and CsF (see Supporting Information). When a combi- to AgF strongly and led to a low catalytic reactivity.
nation of different fluoride salts and catalytic amounts of
Aliphatic substituents at the 4-position, which resulted in
Ag salts (0.5 equiv. of AgF or AgOTf) were used in the complex mixtures under Fokin’s conditions,[11] did not lead
reaction, the desired product were obtained in low yields. to obvious complications in our system (66% and 70% iso-
On the other hand, an excess amount of Ag salts might lead lated yields were obtained for 2j and 2k, respectively). Tri-
to the cleavage of C–I in the substrates. Accordingly, vari- azoles with an aromatic substituent at the N1 position
ous amounts of AgF and TMEDA were carefully tested, could also be transformed to the corresponding 5-fluorotri-
and the results revealed that 5.0 equiv. of AgF and azoles in excellent yield (91% isolated yield was obtained
0.5 equiv. of TMEDA promoted the yield to 89%. Investi- for 2z) under our conditions, while only 32% yield of 2z
gation of the reaction temperature (see Supporting Infor- was obtained by the microwave method.[11]
mation) indicated that 120 °C was obligatory for full con-
version of 1a.
During some of these fluorination reactions of 5-iodotri-
azoles, a certain amount of protonation products were
With the optimized conditions in hand, we proceeded to formed. To get insight into the formation of protonation
explore the substrate scope with respect to various 5-iodo- products, preliminary mechanistic experiments were carried
triazoles (Table 2). The standard fluorination conditions out. The source of proton was investigated by deuterium-
were applicable to a wide range of 5-iodotriazoles bearing labeling experiments. The reaction of 1a, AgF, and
electron-rich and electron-poor substituent groups. For TMEDA was performed in [D6]DMSO [Scheme 2, equa-
most substrates, practical yields were obtained under stan- tion (1)] and furnished 3a in 70% NMR yield, including
dard reaction conditions. Substrates containing alkyl (2b, 63% deuterated 3a. This result revealed that the acidic pro-
2c, 2n–2p, 2r), alkenyl (2q), halogen (2f–2i), and trifluoro- ton of the DMSO is one source leading to the protonated
methyl (2v) groups could be converted into the correspond- and dehalogenated triazole.
ing fluorination products in good to excellent yields. It is
When 4.0 equiv. of D2O was added under the standard
worthy to note that, for substrates containing two sp2 C–I conditions [Scheme 2, equation (2)], a low conversion of 1a
bonds, the fluorination selectively occurred at the 5-position and a trace amount of 3a were obtained. The poor solubil-
of the 5-iodotriazoles (1i). The methodology also presented ity of D2O in toluene and the fact that most of the D2O
good functional group tolerance: functionalities such as es- was consumed by the excess AgF (deuterated water quickly
ters (2k), heterocycles (2l), acetals (2u), aromatic ethers (2t, turned black upon contact with AgF) might be the reason
2y), and nitro (2w) and nitrile (2x) groups survived very for this result. Similar reactions were also conducted in
Scheme 2. Mechanistic studies on the fluorination of 5-iodotriazoles.
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Silver-Mediated Fluorination of 5-Iodotriazoles
Scheme 3. Proposed mechanism.
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obtained as the major product in 48% and 41% yield, with
32% and 25% deuterated 3a, respectively. Those data sug-
gest that adventitious water might be another source of the
protonated and dehalogenated triazole. Hence, the rigorous
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As no desired product was obtained at all with KF or
CsF in the absence of AgF, the SNAr mechanism was ruled
out as a possible pathway.[11] On the basis of the mechan-
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propose the mechanism of our reaction as shown in
Scheme 3. Oxidative addition of silver to the C–I bond and
the formation of a bimetallic aryl silver intermediate are the
first steps. The bimetallic aryl silver complex subsequently
undergoes reductive elimination to afford the desired 5-
fluorotriazoles.
[2]
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Conclusions
In summary, we have developed a powerful method for
the direct fluorination of 5-iodotriazoles with AgF under
mild conditions. This method shows good functional group
tolerance and provides a complementary way to give the
corresponding 5-fluorotriazoles in excellent yields. 5-Iodo-
triazoles without aromatic groups at the 4-position or ali-
phatic substituents at the N1 position can be smoothly con-
verted to the corresponding 5-fluorotriazoles. Mechanistic
studies indicate that this reaction might proceed through a
bimetallic AgII intermediate. Further investigations to
broaden the substrate scope and elucidate the detailed
mechanism are underway.
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Experimental Section
General Procedures for the Synthesis of 5-Fluorotriazoles: In an
argon-filled glove box, AgF (126.9 mg, 1.0 mmol, 5.0 equiv.) and
5-iodotriazoles (0.2 mmol, 1.0 equiv.) were added to a 25 mL oven-
dried glassware containing a stirring bar. Then, TMEDA (15.0 μL,
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Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 21371017).
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Received: March 12, 2015
Published Online: May 27, 2015
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