Regioselective synthesis of 4-fluoro-1,5-disubstituted-1,2,3-triazoles from synthetic surrogates of α-fluoroalkynes

Article abstract of DOI:10.1039/c9cc09216a

α-Fluoroalkynes are elusive molecules due to their instability and inaccessibility. Here, we show that α-fluoronitroalkenes can serve as synthetic surrogates of α-fluoroalkynes in [3+2] cycloaddition reactions with organic azides facilitated by a catalytic amount of trifluoroacetic acid (TFA). This work provides the first regioselective method to access 4-fluoro-1,5-disubstituted-1,2,3-triazoles.

Full text of DOI:10.1039/c9cc09216a

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DOI: 10.1039/C9CC09216A
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Regioselective synthesis of 4-fluoro-1,5-disubstituted-1,2,3-
triazoles from synthetic surrogates of α-fluoroalkynes
Sampad Jana,*a Sweta Adhikaria Michael R. Cox,a and Sudeshna Roy *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
α-Fluoroalkynes are elusive molecules due to their instability and
inaccessibility. Here, we show that α-fluoronitroalkenes can serve
as synthetic surrogates of α-fluoroalkynes in [3+2] cycloaddition
reactions with organic azides facilitated by a catalytic amount of
trifluoroacetic acid (TFA). This work provides the first regioselective
method to access 4-fluoro-1,5-disubstituted-1,2,3-triazoles.
The past couple of decades saw a surge of fluorinated
2
heterocycles in pharmaceuticals1 and agrochemicals,1,
materials,3 and molecular imaging with positron emission
tomography (PET).4 Yet, despite the recent advances, the
preparation of fluorinated heterocycles is still considered
challenging due to the lack of practical, general, and
regioselective methods.5 Given the relevance of 1,2,3-triazoles
in biomedical research6 and medicinal chemistry as a prevalent
scaffold and an amide bioisostere,7 surprisingly, only a handful
of syntheses of fluorinated triazoles are reported in the
literature.8 Pioneering work by Fokin9 and Chu10 has
significantly advanced the field, enabling the synthesis of 5-
fluoro-1,4-disubstituted-1,2,3-triazoles (Figure 1C). However,
the corresponding 1,5-regioisomer is conspicuously absent in
the literature. Herein, we address this critical gap in the
literature by developing the very first synthesis of 4-fluoro-1,5-
disubstituted-1,2,3-triazoles with complete regiocontrol (Figure
1D).
Haloalkynes serve as rich building blocks for numerous chemical
transformations, particularly 1,3-dipolar cycloaddition
reactions enabling various halogenated heterocyclic systems
(Figure 1A).11-13 While synthesis of iodo-, bromo-, and chloro-
alkynes have been thoroughly investigated, 11-13 fluoro-alkynes
Figure 1. Haloalkynes in 1,3-dipolar cycloaddition reaction.
1,3-dipolar cycloaddition reactions. Herein, we establish that
fluoronitroalkenes could be effectively used as surrogates of
fluoroalkynes in cycloaddition reactions with organic azides to
construct 4-fluoro-1,5-disubstituted-1,2,3-triazoles (Figure 1D).
α
α
-
-
remain elusive due to their instability.
α-Fluoroalkynes are
Consequently,
α-fluoronitroalkenes can be regarded as
notorious for undergoing spontaneous oligomerization under
resourceful fluorinated building blocks to synthesize fluorinated
molecules that are increasingly growing in all areas of
chemistry.17
thermal or metal-catalyzed conditions to produce
14, 15
polysubstituted benzene derivatives (Figure 1B)
polymers.16 Synthetic surrogates of
or
α-fluoroalkynes would be
particularly desirable to assemble fluorinated heterocycles via
a.Department of BioMolecular Sciences, School of Pharmacy, University of
Mississippi, University, MS 38677. Email : roy@olemiss.edu
† Electronic Supplementary Information (ESI) available: Experimental details and
NMR spectra of new compounds. See DOI: 10.1039/x0xx00000x
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Journal Name
Both, 1,4- and 1,5-substituted-1,2,3-triazoles, are often used as subsequent radical-based nitration-debromination using ferric
View Article Online
nitrate nonahydrate gave the
Alternatively, a one-pot 2-step protocol can be used to
synthesize -fluoronitroalkenes without having to isolate
α
DO-I:fl1u0o.1r0o3n9/iCtr9oCaClk0e92n1e6sA.
α
α-
fluorobromoalkenes, which makes it operationally simple.
Unfortunately, the radical-based nitration-debromination step
Table 1. Optimization of Reaction Conditions[a]
was unreactive towards alkyl
to provide alkyl -fluoronitroalkenes.
We observed that 1 equiv. of -fluoronitroalkene 1a and 2
α-fluorobromoalkenes and failed
en
try
catalyst
equi
v.
LG
temp time
yield(%)[b]
α
(°C)
100
100
100
100
100
100
100
100
100
100
100
100
110
100
110
110
110
110
(h)
48
24
24
24
24
24
24
24
48
48
48
48
48
48
48
48
48
72
3a
10
19
16
25
11
8
22
28
42
31
36
60
74
69
45
68
20
n.o.
3′a
3
α
1
2
3
4
5
6
7
8
9
-
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
CN
equiv. of phenyl azide 2a when heated at 100 °C in toluene
resulted in the formation of a mixture of regioisomers, 1,5-
disubstituted- and 1,4-disubstituted-fluoro-1,2,3-triazoles, in
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
Yb(OTf)3
Fe(OTf)3
Ce(OTf)3
BF3•(OEt)2
AcOH
0.2
0.2
0.2
0.2
0.2
0.2
0.3
0.3
0.5
0.5
0.3
0.5
0.8
0.5
0.5
0.5
0.5
n.o.
n.o.
n.o.
n.o.
n.o.
n.o.
8
5:2 (3a
1, Table 1). The ratio of the regioisomeric products 3a
determined by 19F NMR (the 19F NMR values for 3a and
: 3′a) ratio along with unreacted starting materials (entry
:
3
′
a
was
are
3′a
δ
-145.1 and -150.4 ppm respectively). We observed that the
reaction was extremely sluggish at room temperature. At
elevated temperatures (100–110 °C), an excess of phenyl azide
(2 equiv.) was required due to the decomposition of organic
azides at higher temperatures.
Taking a clue from the previous reports of nitroalkenes in [3+2]
cycloaddition reactions, we decided to screen different Lewis
acids.21, 24, 26-28 With Lewis acids Cu(OTf)2, Zn(OTf)2, Sc(OTf)3,
Yb(OTf)3, Fe(OTf)3, Ce(OTf)3 (entries 2–7), we observed a
regioselective formation of the 1,5-product 3a, however in 8–
22% yields. The use of BF3•(OEt)2 led to a slight increase in the
10
<5
<5
10 PTSA
11 10-CSA
12 TFA
13 TFA
14 TFA
15 H3PO4
16 MeSO3H
17 NH2SO3
18 TFA
n.o.
n.o.
n.o.
7
n.o.
<5
n.o.
yield of 3a to 28% but also formed
decent increase in yield of 3a up to 42% along with 10% of
3′a in 8% yield (entry 8). A
[a] Standard reaction conditions: 1 equiv. of fluoronitroalkene 1a
(0.15 mmol), 2 equiv. of phenyl azide 2a 0.30 mmol), and 0.5
equiv. of TFA were mixed in 2M toluene and heated at 110 °C. [b]
Isolated yield. PTSA = p-toluenesulfonic acid, TFA = trifluoroacetic
acid 10-CSA = 10-camphorsulfonic acid.
bioisosteres of trans- and cis-amides respectively,7 in addition
to their biological and biomedical applications.18 Hence,
regioselective routes to synthesize 1,4- and 1,5-disubstituted-
1,2,3-triazoles independently are desirable. This report
provides a highly regioselective and versatile method for the
preparation of aryl, alkyl, and heteroaromatic containing
fluorinated-1,5-disubstituted-1,2,3-triazoles. This method is
complementary to the prior methods reported by Fokin and Chu
for obtaining 5-fluoro-1,4-disubstituted-1,2,3-triazoles (Figure
1C).9, 10
3′a
was observed when 30 mol% of AcOH was used as a catalyst.
This result led us to screen other Brønsted acids, such as
MeSO3H, H3PO4, p-TSA•H2O, and CF3CO2H (TFA) (entries 10–17)
with our standard substrates. Among the Brønsted acids, TFA
gave the best results with the regioselective formation of 1,5-
regioisomer 3a (entries 12–14). A gradual increase in yield was
observed when the amount of TFA was increased from 30 mol%
to 50 mol%, and the temperature raised from 100 to 110 °C
(entry 12 vs. 13). Increasing the amount of TFA to 80% led to a
slight decrease in yield (entry 14). However, changing the
solvents to DMF, DMSO, DCE, 1,4-dioxane, ACN, and THF
resulted in lower yields. Overall, we found 3a to be either the
only product or the predominant regioisomer and as the
3
′
a
We hypothesized that alkenes with leaving groups such as NO2
and CN and with a fluorine atom at the 1-position could be used
minor regioisomer. reversed ratio with 3′a as the
A
predominant regioisomer was never observed (in 19F NMR).
Our optimized condition resulted in the regioselective
formation of 1,5-diaryl-4-fluoro-1,2,3-triazole 3a in 74% yield.
as synthetic equivalents of
α-fluoroalkynes in [3+2]
cycloaddition reactions with organic azides.19 Nitroalkenes, due
to their high reactivity, has been widely used in 1,3-dipolar
cycloaddition chemistry, especially with sodium azides for the
The optimum condition comprised heating 1 equiv. of
α-
fluoronitroalkene 1a (0.15 mmol) and 2 equiv. of phenyl azide
2a (0.3 mmol with 50 mol% of TFA (0.075 mmol) in 2M toluene
at 110 °C for 48 h. Unfortunately, (Z)-2-fluoro-3-
phenylacrylonitrile under the same conditions did not lead to
any product when treated with organic azides and ensued in the
recovery of unreacted starting materials (entry 18). For a
complete optimization list with all the conditions that were
screened, see supporting information.
generation
of
NH-1,2,3-triazoles.19-24
Although
the
regioselectivity of the cycloaddition reaction of nitroalkenes
with azides is well-known, the incorporation of fluorine can
have an influence on chemical reactivity.
Initially, we selected
intermolecular [3+2] cycloaddition reaction with organic azides
to afford fluoro-1,2,3-triazoles. -Fluoronitroalkenes were
α-fluoronitroalkenes to investigate the
α
synthesized in two steps starting from the corresponding
aldehydes, tribromofluoromethane, and triphenylphosphine in
With the optimized condition in hand, we first explored the
substrate scope around aryl azides (Figure 2). The 19F NMR
chemical shifts of the synthesized 4-fluoro-1,5-disubstituted-
refluxing THF to afford the
α A
-fluorobromoalkenes.25
2 | J. Name., 2012, 00, 1-3
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3Vyi)ewreAsrtuiclleteOdnliinne
1,2,3-triazoles range from -143.66 to -146.73 ppm. As shown in extension of this reaction to aliphatic azides (3t
–
DOI: 10.1039/C9CC09216A
Figure 2, para-substituted phenyl azides with electron-donating the formation of corresponding 4-fluoro-1,2,3-triazoles in 25–
groups such as methyl (3b), t-butyl (3c), and methoxy (3d 55% yields.
furnished the desired products in 51–58% yields. However, the The scope of the reaction was further examined with the
yields dropped with electron-withdrawing groups such as fluoro substitution patterns on -fluoronitrostyrenes (Figure 2).
3e), and cyano (3f) at the para position and cyano (3h) and Overall, both electron-donating and -withdrawing groups at the
)
α
(
methoxy (3i) at the meta position. In these cases, unreacted para-position in
α-fluoronitrostyrenes exhibited moderate to
starting materials were observed in 19F NMR spectra and TLCs. good reactivity. The substrates with electron-donating groups
A triazole analogue 3k of the natural product combretastatin A- methyl (4a) and methoxy (4b) afforded better yields (54–73%)
4 that has anti-cancer properties was prepared in 55% yield compared to the substrates containing electron-withdrawing
using this method. We observed that the α-fluoronitroalkenes groups such as cyano (4c) and trifluoromethyl (4d) (44–46%).
gave poor conversions and lower yields of [3+2] cycloaddition The substituents at the meta position afforded low yields (45–
products with organic azides in comparison to the nitroalkenes 56%) irrespective of the electron-donating and withdrawing
that could be attributed to attenuated reactivity of the
fluoronitroalkenes.
α
-
group (4e–4h).
Based on the previous literature reports on cycloaddition of
Next, the scope of the reaction for benzyl and alkyl azides were nitroalkenes with 1,3-dipoles,23,
we propose a similar
29
examined (Figure 2). To our delight, an array of para- and meta- mechanism outlined in Figure 3. Initially, regioselective [3+2]
substituted benzyl azides were found to be amenable to the cycloaddition takes place between -fluoronitroalkene and
optimized conditions. Both, electron-donating groups such as organic azide to form a triazoline intermediate 3-int. For the
methyl 3m), t-butyl 3n), methoxy 3o and electron- initial cycloaddition step, both a concerted or a two-step
α
1
2
(
(
(
)
withdrawing groups such as cyano (3p), bromo (3q) at the para- mechanism are possible. Regioselectivity is imparted by the
position of benzyl azides were well tolerated and afforded the strongly electron-withdrawing nitro group on the dipolarophile
corresponding regioselective products in 50–63%. The
1 that is further activated by TFA, thereby lowering the lowest
[a] Reaction conditions: 1 (1 equiv.), 2 (2 equiv.), toluene (2M), 110 °C, 48–72 h. Isolated yields are reported. [b] 42–65% of unreacted α-
fluoronitroalkenes were observed in 19F NMR. [c] The starting materials (SM) were fairly unreactive, requiring 120 h of heating at 110 °C.
[d] Other side-products were observed. Note: Substrates with lower yields are a result of poor conversion and low reactivity of the α-
fluoronitroalkenes with organic azides.
Figure 2. Substrate Scope.[a]
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Figure 3. A plausible mechanism.
unoccupied molecular orbital (LUMO) and making the β-carbon
most electrophilic.22, 23 Without TFA, a mixture of 1,5- and 1,4-
regioisomers are obtained in a 5:2 ratio, as determined by 19F
NMR. The 1,3-dipolar organic azide attacks the partially
positively charged β-carbon of the α-fluoronitroalkene to form
the triazoline intermediate 3-int—a concomitant elimination of
HNO2 results in the regioselective formation of the desired 4-
6.
7.
8.
9.
fluoro-1,5-disubstituted-1,2,3-triazoles product
to probe the triazoline intermediate 3-int via 19F NMR in
deuterated-toluene at 90 C was unsuccessful—this suggests
3. An attempt
10.
11.
12.
13.
°
that the transient intermediate rapidly eliminates HNO2 to form
the triazole product.
In connection with our ongoing drug discovery efforts, we used
principal component analysis to assess the chemical space and
physicochemical properties of our fluorotriazole library. These
analyses show that the fluorinated triazoles occupy a slight to
near-complete overlapping chemical space as the reference set
of commercial drugs and pharmaceutical agents and have a
distinct set of physicochemical properties. More details are
included in the supporting information.
14.
15.
16.
17.
18.
In conclusion, we have shown that the
could be effectively used as synthetic surrogates of
α-fluoronitroalkenes
α-
fluoroalkynes in a regioselective [3 + 2] cycloaddition chemistry
with organic azides. The 1,5-disubstituted-4-fluorotriazoles are
conspicuously absent in the literature due to the lack of
methods for their preparation. In this report, we describe the
very first regioselective method to access 4-fluoro-1,5-
disubstituted-1,2,3-triazoles that will be widely applicable in
pharmaceutical, biomedical, agrichemical, and materials
sciences. A relatively broad-range of 4-fluoro-1,5-disubstituted-
1,2,3-triazoles were synthesized in 25–74% yields with high
19.
20.
regioselectivity. This work also demonstrates that
α-
21.
22.
23.
24.
25.
fluoronitroalkenes can serve as versatile fluorinated building
blocks to directly access a slew of fluorinated molecules via
various chemical transformations. Further studies to explore
the cycloaddition reactions with other dipoles are ongoing in
our laboratory. Screening of the fluorinated-triazoles against a
variety of targets related to human health and agrisciences is
currently being pursued.
J. Thomas, J. John, N. Parekh and W. Dehaen, Angew.
Chem. Int. Ed., 2014, 53, 10155-10159.
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Conflicts of interest
There are no conflicts to declare.
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R. Jannapu Reddy, M. Waheed, T. Karthik and A. Shankar,
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DOI: 10.1039/C9CC09216A
Table of content entry:
This TFA-catalyzed [3+2] cycloaddition reaction of organic azides with α-fluoronitroalkenes, used as
synthetic surrogates of α-fluoroalkynes, provides a new route to multi-substituted fluorotriazoles with
broader substrate scopes and high regioselectivity.
1
N
N
NO2
Catalytic TFA
N
5
+
N N N
F
F
▪ ︎ Excellent regioselectivity
▪ ︎ >30 examples
▪ ︎ No expensive catalyst
▪ ︎ No fluorinating reagent
F
unstable