Synthesis and Regioselective N-2 Functionalization of 4-Fluoro-5-aryl-1,2,3-NH-triazoles

Article abstract of DOI:10.1002/ejoc.201701338

A new efficient synthetic route to 4-fluoro-5-aryl-1,2,3-NH-triazoles was elaborated. The reactions of NaN₃ with aryl-substituted α-fluoronitroalkenes resulted in the domino construction of the target fluorinated triazoles. Sulfamic acid is an effective promoter for this heterocyclization. The subsequent functionalization reactions of the obtained triazoles proceed highly regioselectively at the N-2 position. The observed regioselectivity was supported by DFT calculations.

Full text of DOI:10.1002/ejoc.201701338

A Journal of
Accepted Article
Title: Synthesis and Regioselective N-2-Functionalization of 4-
Fluoro-5-aryl-1,2,3-NH-triazoles
Authors: Vladimir A. Motornov, Andrey Tabolin, Roman A. Novikov,
Yulia V. Nelyubina, Sema L. Ioffe, Ivan V. Smolyar, and
Valentine G. Nenajdenko
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701338
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10.1002/ejoc.201701338
European Journal of Organic Chemistry
FULL PAPER
Synthesis and Regioselective N-2-Functionalization of 4-Fluoro-5-
aryl-1,2,3-NH-triazoles
Vladimir A. Motornov,[a,b] Andrey A. Tabolin,*[a] Roman A. Novikov,[a,c] Yulia V. Nelyubina,[d] Sema L.
Ioffe,[a] Ivan V. Smolyar,[e] and Valentine G. Nenajdenko*[e]
Abstract: New efficient synthesis of 4-fluoro-5-aryl-1,2,3-NH-
triazoles was elaborated. The reaction of NaN3 with arylsubstituted
α-fluoronitroalkenes resulted in domino construction of target
fluorinated triazoles. Sulfamic acid was found to be an effective
promoter for this heterocyclization. It was demonstrated that
subsequent functionalization of obtained triazoles proceeds highly
regioselectively at the N-2 position. The observed regioselectivity
was supported by DFT calculations.
synthetic methods toward fluorine-containing molecules and
especially fluorinated heterocycles.[5] However, to date only one
general method for the synthesis of fluoro-substituted 1,2,3-
triazoles has been reported.[6,7] Click reaction of azides with 1-
iodoacetylenes followed by halogen exchange afforded N-1-
substituted 5-fluorotriazoles (Scheme 1).[6] Unfortunately,
isomeric fluorotriazoles can not be prepared by this method.
Currently, among fluorinated 1,2,3-triazoles only N-1-substituted
derivatives are readily available.
Introduction
1,2,3-Triazoles are heterocycles of special interest. Their
chemistry underwent a substantial growth during last two
decades.[1] Both NH- and N-substituted 1,2,3-triazoles are shown
to possess wide range of biological activities, and consequently
are frequently employed in drug design (Figure 1).[2,3] Moreover,
1,2,3-triazoles are important starting compounds for the
synthesis of other fundamental heterocycles, including
imidazoles and pyrroles.[4] Selective functionalization of N-
unsubstituted triazoles represents a significant problem because
of a mixture of regioisomeric products is usually formed.[1a]
Fluorine-containing triazoles could be a topic of special interest.
Incorporation of fluorine atom is known to have a significant
effect on chemical, physical and biological properties of
substances. Thus, much effort has been paid to develop new
Figure 1. Some bioactive 1,2,3-triazole derivatives.
[a]
V. A. Motornov, Dr. A. A. Tabolin, Dr. R. A. Novikov, Prof. Dr. S. L.
Ioffe
Literature approach
I
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences
Leninsky prosp. 47, 119991 Moscow (Russia)
E-mail: tabolin87@mail.ru
http://zioc.ru/institute/laboratories/laboratory-of-functional-organic-
compounds-n8
V. A. Motornov
Higher Chemical College, D. I. Mendeleev University of Chemical
Technology of Russia
Miusskaya sq. 9, 125047 Moscow (Russia)
Dr. R. A. Novikov
V. A. Engelhardt Institute of Molecular Biology, Russian Academy of
Sciences
Vavilov str. 32, 119991 Moscow (Russia)
Dr. Yu. V. Nelyubina
N
N
R
R
KF/KHF2
RN3
N
N
N
N
or
"click"
AgF/TMEDA
Ar
This work
Ar
Ar
I
Ar
F
R = Alk, Ar
[b]
[c]
[d]
[e]
R
N
H
N
RX
regioselective
NaN3
F
N
N
N
N
N2-functionalization
NO2
Ar
F
Ar
F
1
2
R = Alk, Ar,
Ts, Ac
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences
Vavilov str. 28, 119991 Moscow (Russia)
I. V. Smolyar, Prof. Dr. V. G. Nenajdenko
Department of Chemistry, M. V. Lomonosov Moscow State
University
Leninskie Gory 1, 119991 Moscow (Russia)
E-mail: nenajdenko@org.chem.msu.ru
http://www.chem.msu.ru/rus/chair/org_w/os/welcome.html
Scheme 1. Approaches toward fluoro-1,2,3-triazoles.
Recently, two procedures for the synthesis of α-
fluoronitroalkenes
1
were developed.[8] We have also
demonstrated their application for the preparation of various
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201701338
European Journal of Organic Chemistry
FULL PAPER
monofluorinated molecules.[8a,9] Herein we report the first
synthesis of 4-fluoro-5-aryl-1,2,3-NH-triazoles 2 via the addition
of sodium azide to α-fluoronitroalkenes as well as synthesis of 2-
substituted 4-fluoro-1,2,3-triazoles obtained by their selective N-
2-functionalization. Key step of our approach is nitroalkene-
azide cycloaddition reaction.[10,11]
2 equiv. NaN3,
0.5 equiv. HSO3NH2
NH
N
F
N
Ar
Ar
DMSO, 85 °Ca, 45 min
NO2
NH
F
1
2
NH
N
NH
N
N
N
N
N
F
F
F
Cl
MeO
2b, 74%[b]
2c, 81%[b]
NH
2a, 77%,[b] 83%[c]
Results and Discussion
NH
N
NH
N
N
α-Fluoronitroalkene 1a was chosen as a model substrate to find
optimal conditions for the reaction with sodium azide. An
influence of solvent, reagents ratio, temperature, concentration,
as well as some acidic additives were studied (see Supporting
Information for full optimization table). Firstly, optimization
experiments showed the necessity of elevated temperatures and
revealed DMSO as the appropriate solvent. Importantly, the
reaction outcome showed strong dependence on the substrate
concentration with higher yields achieved at lower
concentrations of the reagents. To avoid large solvent waste
acidic additives were tested. Finally, slow addition[10a] (during 30
min) of nitroalkene 1a to the solution of 2 equiv. of NaN3 and 0.5
equiv. of sulfamic acid HSO3NH2 in DMSO afforded triazole 2a in
75% yield and these conditions were found optimal for
subsequent experiments.
N
N
N
MeO
MeO
F
F
F
Me
F
2d, 81%[b]
2f, 66%[b]
2e, 72%[b]
NH
N
NH
N
N
N
NH
N
NH
N
Br
Cl
N
N
F
F
F
F
OMe
2i, 72%[b]
2g, 63%[c]
2h, 63%[b]
2j, 80%[b]
HN
N
NH
N
NH
N
NH
N
N
N
N
N
F
F
S
2m, 86%[b]
F
F
F3C
2k, 61%[c]
2l, 53%[c]
These optimized reaction conditions were spread to other α-
fluoronitroalkenes 1 (Scheme 2). The procedure was found to be
efficient for α-fluoronitroalkenes 1 with electron-donating or
neutral groups, including methyl, methoxy and halo-substituted
derivatives. Target triazoles 2 were obtained in yields up to 86%.
Herewith electron-rich substrates usually gave higher yields
(2c,d,i,j,m). However, it was demonstrated that somewhat lower
yields (e.g., for 2g, 2k) could be increased using more dilution
(0.03 M). In the case of 1l, presence of EWG p-CF3-group
resulted in the moderate yield of triazole 2l. m-NO2-Substituted
substrate gave low yield of the corresponding triazole and the
[a]
Scheme 2. Synthesis of 4-fluoro-1,2,3-NH-triazoles 2.
Nitroalkene was
added portionally to the heated solution of NaN3/HSO3NH2 for 30 min. [b] 0.1 M
solution. [c] 0.03 M solution.
product
could
not
be
separated
from
impurities.
Fluoronitroalkenes 1 containing strong electron withdrawing
groups such as p-nitrophenyl and p-cyanophenyl failed to give
target triazoles, probably due to anionic polymerization of
nitroalkene. Structures of products 2 were confirmed by 1H, 13C,
19F NMR spectroscopy and high-resolution mass-spectrometry.
Possible mechanism of the reaction includes Michael addition of
azide-anion to nitroalkene 1 with subsequent ring-closure to
form triazoline intermediate B (Scheme 3).[10a,d] Subsequent
elimination of nitrite anion and proton migration furnishes target
triazole 2. Improved yields in the presence of sulfamic acid can
be explained by: (a) trapping of nitrous acid to prevent some
side reactions (b) suppression of polymerization of anion A.[10c-e]
Scheme 3. Possible mechanism of the reaction.
According to literature data, N-unsubstituted 1,2,3-triazoles exist
as a mixtures of tautomers having proton delocalized among all
three nitrogens. The ratio of tautomers depends on structure,
solvent, concentration and temperature.[12] However, according
to results of X-ray diffraction analysis of triazole 2a (Figure 2),[13]
a hydrogen atom resides at the central nitrogen atom of the
triazole, as additionaly supported by CN(1)N and NN(2)N angles
equal to 101.78(12) and 115.98(12)°, respectively, thus making
it a 2H-tautomer. In crystal, this hydrogen atoms is involved in a
rather strong hydrogen bonding N(2)-H…N(1) (N…N 2.9311(17)
Å, NHO 159.8(19)°) that assemble the molecules into an infinite
tape. Low temperature NMR (-80 °C, THF-d8) also did not show
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10.1002/ejoc.201701338
European Journal of Organic Chemistry
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noticeable duplication of 1H and 19F signals. Our DFT
calculations also supported the strong preference of 2H-form.
Moreover, 4-fluoro substituted triazole 2b have the biggest
preference of 2H-tautomer among other 4-substituted triazoles 3
(X = Cl, Br, H) (Figure 3).
and electron accepting (p-NO2) benzyl bromides gave N-2-
substituted products 5 and 6 in high yields. Whereas N-2-
substituted 4-fluoro-1,2,3-triazoles cannot be synthesized by
previously reported click-reaction
–
halogen substitution
method,[6] this regioselective alkylation might be useful for the
synthesis of new N-2-substituted triazoles containing a fluorine
atom at the position 4 of the heterocycle.
Figure 2. General view of the triazole 2a. The non-hydrogen atoms are drawn
as thermal ellipsoids at 50% probability level.
Figure 3. B3LYP/6-311+G(d,p)//PCM(DMF) relative Gibbs free energies of
various 4-substituted triazoles 2b,3.
Scheme 4. N-2-alkylation of 4-fluoro-1,2,3-triazole 2c.
Only in the case of small and highly active methyl iodide
detectable amounts of isomeric products 13 and 14 (total 13-
14%) were isolated (Scheme 5). Regiochemistry of substitution
was unambiguously determined using combination of NMR
experiments involving 1H-1H NOESY, 1H-19F HOESY and 1H-15N
HMBC (see Scheme 5 and SI).[18] Thus, isomer 13 showed Me-
Ar cross peak in 1H-1H NOESY and two 1H-15N HMBC
interactions (Me-N1 and Me-N2). Conversely, isomer 14 showed
Me-F cross peak in 1H-19F HOESY and two 1H-15N HMBC
interactions (Me-N1 and Me-N2). In turn, N2-isomer 12 showed
no Me-F (HOESY) and Me-Ar (NOESY), while all three possible
1H-15N HMBC interactions were detected. Similar NMR patterns
were observed for other products 4-11. Structure of triazole 11
was supported by X-ray analysis (Figure 4). The results of
alkylation are in good agreement with DFT calculations
demonstrating both thermodynamic and kinetic preference of
methylation of fluorotriazolate-anions 15 at the N-2 position
(Figure 5, also see Supporting Information).
Next, functionalization of prepared fluorinated triazoles 2 was
studied. Generally, N-functionalization (e.g., alkylation) of NH-
1,2,3-triazoles can lead to a complex mixture of N-1, N-2 and N-
3-substituted regioisomers in various ratios.[1a] Due to this
reason N-1- and N-3-substituted triazoles are preferred to
synthesize using click reactions.[1c,d] Regioselective synthesis of
N-2-substituted triazoles is still a challenging task. Previously,
good N-2-regioselectivity of functionalization for N-unsubstituted
triazoles was observed usually for triazoles having sterically
bulky substituents, such as bromine, iodine or aryl.[14,15]
Otherwise, hydrogen-bonding interactions[16] or the use of
transition metal catalysis with bulky ligands was necessary for
the selective modification at the N-2-position.[17]
Compound 2c was chosen as a model substrate to study
N-functionalization of 4-fluoro substituted NH-triazoles. To our
delight, alkylation of triazole 2c with alkyl halides led to selective
formation of N-2-substituted products 4-11 in 76-97% yields
(Scheme 4). Moreover, the alkylation of 2c using both primary
(benzyl bromide, ethyl bromoacetate, 1,4-dibromobutane, n-
propyl
iodide)
and
secondary
(iso-propyl
bromide,
cyclopentylbromide) alkylating reagents resulted in formation of
the N-2-substituted isomers. Both electron donating (p-OMe)
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10.1002/ejoc.201701338
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Chan-Lam coupling with boronic acids (products 16) were
studied.[19] Both methods demonstrated high effectiveness for
the synthesis of 2-arylated triazoles. In addition to NMR and
HRMS data structures of 16b and 18 were confirmed by X-ray
analysis (Figure 6).[13] Chan-Lam coupling was performed using
10% of cupric acetate monohydrate-DMSO-oxygen system at
100°C.[20] It should be noted that N-2-aryl-1,2,3-triazoles are
compounds of practical interest because this type of triazoles
are known to possess fluorescence properties.[21] Indeed,
aryltriazoles 16 were found to be fluorescent active, emitting
blue light. Subsequent investigation of their fluorescent
properties is currently underway.
Scheme 5. Methylation of 2, characteristic 1H-15N HMBC, 1H-1H NOESY and
1H-19F HOESY interactions in products 12-14.
Figure 4. General view of the triazole 11. The non-hydrogen atoms are drawn
as thermal ellipsoids at 50% probability level.
Scheme 6. Regioselective functionalization of triazole 2c. i: p-XC6H4B(OH)2,
10 mol.% Cu(OAc)2, O2, DMSO, 100 °C, 2 h; ii: p-FC6H4NO2, K2CO3, DMSO,
70 °C, 1 h; iii: Ac2O, NEt3, CH2Cl2, r.t., 3 h; iv: TsCl, NEt3, CH2Cl2, r.t., 40 min;
v: CH2=CHCN, NEt3, DMF, r.t., 20 h; vi: CH2O, H2O, r.t., 20 h.
Figure 5. DFT study of methylation of fluoro-triazolate anion 15b.
Figure 6. General views of the triazoles 16b (left) and 18 (right). The non-
hydrogen atoms are drawn as thermal ellipsoids at 50% probability level.
Next, other possibilities for modification of 4-fluorotriazoles 2
were demonstrated. To our delight arylation, acylation (Ac2O),
sulfonylation (TsCl), hydroxymethylation and Michael addition
(H2C=CHCN) proceeded smoothly to afford selectively N-2-
substituted products 16-21 in high isolated yields (Scheme 6).
Among different known methods for triazole arylation[15] SNAr-
substitution reaction with p-nitrofluorobenzene (product 17) and
High regioselectivity of such modification of triazoles 2 can be
explained by interplay of steric and electronic factors. N-1
position of triazoles 2 is hindered by bulky aryl substituent at the
carbon 5 of triazole ring. On the other hand, nucleophilicity of N3
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10.1002/ejoc.201701338
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is diminished due to high electron negativity of fluorine.[22]
Therefore, the combination of these factors makes attack of
electrophiles more preferable at N-2 position. DFT calculations
for model 4-fluoro-5-phenyltriazole 2b and its anion 15b
confirmed that N-2 functionalization is favorable in terms of both
charge and orbital control. Moreover, deprotonation of 2b results
in significant increase in HOMO-coefficient at N-2 leading to
higher selectivity of substitution (Figure 7).
4-Fluoro-5-(4-chlorophenyl)-2H-1,2,3-triazole (2a)
A) Fluorotriazole 2a was obtained from α-fluoronitroalkene 1a (201.5 mg,
1 mmol) following the general procedure 1. Column chromatography
(eluent: 3:1, PE:EtOAc) afforded 2a (152 mg, 77%) as slightly yellow
solid. B) Fluorotriazole 2a was obtained from α-fluoronitroalkene 1a (280
mg, 1.39 mmol) following the general procedure 1 with the change:
DMSO (46 mL) was used. Column chromatography (eluent: 3:1,
PE:EtOAc) afforded 2a (228 mg, 83%) as slightly yellow solid. Rf = 0.40
(PE/EtOAc, 3:1) (UV). m.p. 106-107 °C (PhMe). 1H NMR (300 MHz,
CDCl3): δ = 7.47 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 11.85 (br s,
1H). 13С NMR (75 MHz, CDCl3): δ = 126.1 (d, 3J(C,F) = 4.1 Hz), 127.4 (d,
4J(C,F) = 3.5 Hz), 129.3, 130.0 (d, 2J(C,F) = 16.0 Hz), 135.1, 159.2 (d,
1J(C,F) = 253.5 Hz). 19F NMR (282 MHz, CDCl3): δ = -144.2 (s). HRMS
(ESI) m/z: [M + H]+ Calcd. for C8H6ClFN3: 198.0229; Found: 198.0230.
Single-crystal X-Ray diffraction data for 2a was deposited at Cambridge
Crystallographic Data Centre (CCDC-1557133).
4-Fluoro-5-phenyl-2H-1,2,3-triazole (2b)
Fluorotriazole 2b was obtained from α-fluoronitroalkene 1b (83.5 mg,
0.50 mmol) following the general procedure 1. Column chromatography
(eluent: 3:1, PE:EtOAc) afforded 2b (60 mg, 74%) as colorless solid. Rf =
0.33 (PE/EtOAc, 3:1) (UV). m.p. 92-94 °C (PE/EtOAc, 10:1). 1H NMR
(300 MHz, CDCl3): δ = 7.39-7.52 (m, 3H), 7.87 (d, J = 7.6 Hz, 2H), 11.75
(br s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 126.1, 127.6, 129.0. 130.9
(br), 159.4 (d, 1J(C,F) = 253.2 Hz). 19F NMR (282 MHz, CDCl3): δ
= -144.6 (s). HRMS (ESI) m/z: [M + Na]+ Calcd. for C8H6FN3Na:
164.0619; Found: 164.0619.
Figure 7. Electron density map and HOMO with atomic contributions at
nitrogens of 2b and its anion 15b.
Conclusions
4-Fluoro-5-(4-methyloxyphenyl)-2H-1,2,3-triazole (2с)
In conclusion, new fluorine containing heterocycles – 5-aryl-4-
fluoro-1,2,3-NH-triazoles – were successfully synthesized from
corresponding fluoronitrostyrenes and sodium azide. The
possibility of their highly regioselective N-2 modification was
demonstrated. Various synthetic methods to create new N-C
bond can be used efficiently for this aim including alkylation,
hydroxymethylation, acylation, Michael addition and arylation.
Fluorotriazole 2c was obtained from α-fluoronitroalkene 1c (197 mg, 1
mmol) following the general procedure 1. Column chromatography
(eluent: 3:2, PE:EtOAc) afforded 2c (157 mg, 81%) as yellow solid. Rf =
0.55 (PE/EtOAc, 1:1) (UV). m.p. 94-95 °C (PhMe). 1H NMR (300 MHz,
CDCl3): δ = 3.87 (s, 3H), 7.01 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 8.7 Hz,
2H), 11.9 (br s, 1H). 13С NMR (75 MHz, CDCl3): δ = 55.4, 114.5, 120.0.
127.5, 130.5 (br), 158.9 (d, 1J(C,F) = 252.2 Hz), 160.1. 19F NMR (282
MHz, CDCl3): δ = -145.6. HRMS (ESI) m/z: [M + H]+ Calcd. for
C9H9FN3O: 194.0724; Found 194.0727.
Experimental Section
4-Fluoro-5-(3,4-dimethyloxyphenyl)-2H-1,2,3-triazole (2d)
General procedure 1. Synthesis of 4-fluoro-5-aryl-1,2,3-NH-triazoles
2a-2m
Fluorotriazole 2d was obtained from α-fluoronitroalkene 1d (76 mg, 0.335
mmol) following the general procedure 1. Column chromatography
(eluent: 1:1, PE:EtOAc) afforded 2d (61 mg, 81%) as slightly yellow solid.
Rf = 0.36 (PE/EtOAc, 3:1) (UV). m.p. 207-209 °C (decomp., PhMe). 1H
NMR (300 MHz, DMSO-d6): δ = 3.81 (s, 3H), 3.82 (s, 3H), 7.07 (d, 1H, J
= 8.2 Hz), 7.28 (m, 1H), 7.30 (s, 1H), 14.8 (br s, 1H). 13С NMR (75 MHz,
DMSO-d6): δ = 55.9, 56.0. 109.4 (d, 4J(C,F) = 2.0 Hz), 112.7, 118.8 (d,
4J(C,F) = 3.8 Hz), 120.4, 127.3 (br), 149.6, 149.7, 158.7 (d, 1J(C,F) =
246.4 Hz). 19F NMR (DMSO-d6) δ -148.4 (s). HRMS (ESI) m/z: [M + H]+
Calcd. for C10H11FN3O2: 224.0830; Found: 224.0830.
Caution!: Although we did not experience any accidents in our
experiments, care has to be taken due to the hazardous nature of HN3
that may be produced upon reaction of sodium azide with strong acids.
Pure HN3 is toxic and explosive, thus reactions should be performed in
diluted solutions, in
a well-ventilated fume hood behind a safety
shield.[23a] Azide-containing water waste should be properly disposed.[23b]
Sodium azide (130 mg, 2 mmol) and HSO3NH2 (47 mg, 0.5 mmol) were
dissolved in DMSO (10 mL). Mixture was heated to 85 °С, then α-
fluoronitroalkene 1a-1m (1 mmol) (or solution of α-fluoronitroalkene 1b,
1f in DMSO (1 mL), if nitroalkene was liquid) was added in small portions
with vigorous stirring during 30 min. Mixture was heated for additional 15
min, and poured into EtOAc/H2O (30 / 30 mL). Aqueous layer was
extacted by EtOAc (3 × 20 mL), organic layers were combined, washed
with saturated NaCl solution (30 mL), and dried over anhydrous Na2SO4.
Crude product was purified by column chromatography (SiO2, PE:EtOAc,
1:1 – 10:1). Rf(products) = 0.20-0.36 (1:1-3:1 PE:EtOAc).
4-Fluoro-5-(4-methylphenyl)-2H-1,2,3-triazole (2e)
Fluorotriazole 2e was obtained from α-fluoronitroalkene 1e (128 mg, 0.71
mmol) following the general procedure 1. Column chromatography
(eluent: 3:1, PE:EtOAc) afforded 2e (90 mg, 72%) as slightly yellow solid.
Rf = 0.35 (PE/EtOAc, 3:1) (UV). m.p. 99-100 °C (PhMe). 1H NMR (300
MHz, CDCl3): δ = 2.41 (s, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0
Hz, 2H), 11.9 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ = 21.3, 124.6,
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10.1002/ejoc.201701338
European Journal of Organic Chemistry
FULL PAPER
126.0. 129.7, 130.5 (d, 2J(C,F) = 16.8 Hz), 139.1, 159.2 (d, 1J(C,F) =
252.7 Hz). 19F NMR (282 MHz, CDCl3): δ = -145.0 (s). HRMS (ESI) m/z:
[M + Na]+ Calcd. for C9H8FN3Na: 200.0594; Found: 200.0592.
8.22 (m, 1H) 12.11 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ = 124.0.
125.1, 125.3, 126.4, 127.1, 128.1 (d, 4J(C,F) = 2.2 Hz), 128.7, 130.1,
131.0. 133.9, 159.9 (d, 1J(C,F) = 252.6 Hz, C-F). 19F NMR (282 MHz,
CDCl3): δ = -144.8 (s). HRMS (ESI) m/z: [M + H]+ Calcd. for C12H9FN3:
214.0775; Found: 214.0778.
4-Fluoro-5-(4-fluorophenyl)-2H-1,2,3-triazole (2f)
5,5’-Benzenediylbis-(4-fluoro-2H-1,2,3-triazole) (2k)
Fluorotriazole 2f was obtained from α-fluoronitroalkene 1f (154.5 mg,
0.84 mmol) following the general procedure 1. Column chromatography
(eluent: 7:1, PE:EtOAc) afforded 2f (100 mg, 66%) as slightly yellow solid.
Rf = 0.35 (PE /EtOAc, 3:1) (UV). m.p. 131-133 °C (PhMe). 1H NMR (300
MHz, CDCl3): δ = 7.28-7.37 (dd, J = 8.5, 5.4 Hz, 2H), 7.73-7.81 (t, J = 9.0
Hz, 2H), 14.7 (br s, 1H). 13С NMR (75 MHz, CDCl3): δ = 116.6 (d, 2J(C,F)
Fluorotriazole 2k was obtained from α-fluoronitroalkene 1k (300 mg, 1.17
mmol) following the general procedure 1 with the change: NaN3 (305 mg,
4 equiv., 4.69 mmol), HSO3NH2 (110 mg, 1 equiv., 1.17 mmol) in DMSO
(39 mL) was used. Column chromatography (eluent: 1:1, PE/EtOAc)
afforded 2k (177 mg, 61%) as slightly yellow solid. Rf = 0.30 (PE/EtOAc,
1:1) (UV). m.p. 87-89 °C (PE). 1H NMR (300 MHz, DMSO-d6): δ = 7.61 (t,
1H), 7.76 (d, J = 7.6 Hz, 2H), 8.14 (s, 1H). 13C NMR (75 MHz, DMSO-d6):
δ = 122.7, 126.1, 127.4 (br), 129.0. 130.6, 159.1 (d, 1J(C,F) = 247.7 Hz).
19F NMR (282 MHz, DMSO-d6): δ = -147.2 (s). HRMS (ESI) m/z: [M + H]+
Calcd. for C10H7F2N6: 249.0695, found: 249.0697.
2
= 21.9 Hz), 124.6, 127.0 (d, J(C,F) = 17.0 Hz), 128.2 (dd, J(C,F) = 8.5,
3.4 Hz), 158.8 (d, 1J(C,F) = 247.2 Hz), 162.5 (d, 1J(C,F) = 246.0 Hz). 19
F
NMR (282 MHz, CDCl3): δ = -112.6 (tt, JHF = 8.9, 5.4 Hz), -148.2 (s).
HRMS (ESI) m/z: [M - H]- Calcd. for C8H4F2N3: 180.0368; Found
180.0362.
4-Fluoro-5-(2-bromophenyl)-2H-1,2,3-triazole (2g)
4-Fluoro-5-(4-(trifluoromethyl)phenyl)-2H-1,2,3-triazole (2l)
Fluorotriazole 2g was obtained from α-fluoronitroalkene 1g (122 mg, 0.50
mmol) following the general procedure 1 with the change: DMSO (17 mL)
was used. Column chromatography (eluent: 5:1, PE:EtOAc) afforded 2g
(76 mg, 63%) as slightly yellow solid. Rf = 0.30 (PE/EtOAc, 3:1) (UV).
Fluorotriazole 2l was obtained from α-fluoronitroalkene 1l (115 mg, 0.49
mmol) following the general procedure 1 with the change: DMSO (16 mL)
was used. Column chromatography (eluent: 3:1, PE:EtOAc) afforded 2l
(59.5 mg, 53%) as colorless oil, which solidified upon storage in the
1
m.p. 83-84 °C (PhMe). H NMR (300 MHz, DMSO-d6): δ = 7.40-7.57 (m,
3H), 7.80 (d, J = 7.9 Hz, 1H), 15.07 (br s, 1H). 13C NMR (75 MHz,
CDCl3): δ = 122.9, 128.1, 128.5, 128.9 (d, 2J(C,F) = 13.7 Hz), 131.8,
fridge. Rf = 0.31 (PE/EtOAc, 3:1) (UV). H NMR (300 MHz, DMSO-d6): δ
1
= 7.87 (d, J = 8.3 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H). 13C NMR (75 MHz,
DMSO-d6): δ = 124.5 (q, 1J(C,F) = 272.0 Hz), 126.5, 126.6, 126.9, 129.1
(q, 2J(C,F) = 32.0 Hz), 132.3 (d, 3J(C,F) = 3.4 Hz), 159.4 (d, 1J(C,F) =
248.7 Hz). 19F NMR (282 MHz, DMSO-d6): δ = -61.3 (s, 3F), -146.4 (s,
1F). HRMS (ESI) m/z: [M - H]- Calcd. for C9H4F4N3: 230.0336. found:
230.0342.
1
132.5, 133.6, 158.7 (d, J(C,F) = 256.5 Hz). 19F NMR (282 MHz, CDCl3):
δ = -145.4 (s). HRMS (ESI) m/z: [M + H]+ Calcd. for C8H679BrFN3:
241.9724; Found: 241.9730.
4-Fluoro-5-(2-chlorophenyl)-2H-1,2,3-triazole (2h)
4-Fluoro-5-(2-thienyl)-2H-1,2,3-triazole (2m)
Fluorotriazole 2h was obtained from α-fluoronitroalkene 1h (83 mg, 0.412
mmol) following the general procedure 1. Column chromatography
(eluent: 3:1, PE:EtOAc) afforded 2h (51 mg, 63%) as colorless solid. Rf =
0.29 (PE/EtOAc, 3:1) (UV). m.p. 75-76 °C (PE). 1H NMR (400 MHz,
CDCl3): δ = 7.33-7.46 (m, 2H), 7.47-7.66 (m, 2H), 12.0 (br s, 1H). 13C
NMR (100 MHz, CDCl3): δ = 126.5, 127.4, 130.7, 131.0. 131.5, 132.3,
133.5, 159.6 (d, 1J(C,F) = 252.7 Hz, C-F). 19F NMR (282 MHz, CDCl3): δ
= -141.9 (s). HRMS (ESI) m/z: [M + Na]+ Calcd. for C8H5ClFN3Na:
220.0048; Found: 220.0053.
Fluorotriazole 2m was obtained from α-fluoronitroalkene 1m (18.0 mg,
0.10 mmol) following the general procedure 1. Column chromatography
(eluent: 7:3, PE:EtOAc) afforded 2m (15.2 mg, 86%) as orange oil. Rf =
1
0.40 (PE/EtOAc, 7:3) (UV). H NMR (300 MHz, DMSO-d6): δ = 7.20 (dd,
J = 5.1, 3.6 Hz, 1H), 7.43 (dd, J = 3.6, 1.0 Hz, 1H), 7.68 (dd, J = 5.1, 1.0
Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ = 124.2 (br), 125.6 (d, J(C,F)
= 2.9 Hz), 126.8, 128.1, 128.7 (d, J(C,F) = 4.1 Hz), 157.3 (d, 1J(C,F) =
247.8 Hz). 19F NMR (282 MHz, DMSO-d6): δ = --148.3 (s). HRMS (ESI)
m/z: [M + H]+ Calcd. for C6H4FN3S: 170.0183. found: 170.0186.
4-Fluoro-5-(3-methyloxyphenyl)-2H-1,2,3-triazole (2i)
General procedure 2. Synthesis of N-2-alkyl-4-fluoro-1,2,3-triazoles
4-12.
Fluorotriazole 2i was obtained from α-fluoronitroalkene 1i (123 mg, 0.62
mmol) following the general procedure 1. Column chromatography
(eluent: 4:1, PE:EtOAc) afforded 2i (87 mg, 72%) as colorless solid. Rf =
0.26 (PE/EtOAc, 3:1) (UV). m.p. 76-77 °C (PhMe). 1H NMR (400 MHz,
CDCl3): δ = 3.89 (s, 3H), 6.96 (ddd, J = 8.0. 2.4, 1.0 Hz, 1H), 7.32-7.49
(m, 3H), 11.57 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ = 55.4, 111.3,
115.0. 118.6, 128.9, 130.0. 130.5 (d, 2J(C,F) = 13.0 Hz), 159.4 (d, 1J(C,F)
= 252.7 Hz), 160.0. 19F NMR (282 MHz, CDCl3): δ = -144.4 (s). HRMS
Fluorotriazole 2c (0.3 mmol, 58 mg) and alkyl halide (0.32 mmol, 1.05
equiv.) were dissolved in DMF (1 mL), then K2CO3 (0.45 mmol, 1.5 equiv,
41 mg) was added. Mixture was stirred at room temperature for 16 hours,
and extracted with EtOAc/H2O (20/20 mL). Aqueous layer was washed
with EtOAc (2 × 15 mL), organic layers were combined, washed with
saturated NaCl solution (10 mL), and dried over anhydrous Na2SO4.
Crude product was purified by column chromatography (SiO2, PE:EtOAc,
1:1 – 10:1). Rf (products) = 0.30-0.61 (3:1, PE:EtOAc).
(ESI) m/z: [M
216.0538.
+
Na]+ Calcd. for C9H8FN3ONa: 216.0544; Found:
4-Fluoro-5-(1-naphthalenyl)-2H-1,2,3-triazole (2j)
4-Fluoro-5-[4-(methyloxy)phenyl]-2-(phenylmethyl)-2H-1,2,3-triazole
(4)
Fluorotriazole 2j was obtained from α-fluoronitroalkene 1j (61 mg, 0.298
mmol) following the general procedure 1. Column chromatography
(eluent: 5:1, PE:EtOAc) afforded 2j (48 mg, 80%) as colorless solid. Rf =
0.31 (PE/EtOAc, 3:1) (UV). m.p. 103-104 °C (PE). 1H NMR (400 MHz,
CDCl3): δ = 7.51-7.63 (m, 3H), 7.70 (d, J = 7.1 Hz, 1H), 7.94 (m, 2H),
Alkyltriazole 4 was obtained from NH-triazole 2c (21.5 mg) and benzyl
bromide following the general procedure 2. Column chromatography
(eluent: 7:1, PE:EtOAc) afforded 4 (26 mg, 82%) as slightly yellow solid.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701338
European Journal of Organic Chemistry
FULL PAPER
Rf = 0.44 (PE/EtOAc, 3:1) (UV). m.p. 60-61 °C (PE/EtOAc, 5:1). 1H NMR
(400 MHz, CDCl3): δ = 3.85 (s, 3H, OMe), 5.45 (s, 2H, CH2), 6.98 (d, J =
8.7 Hz, 2H, CHAr), 7.34-7.38 (m, 5H, Ph), 7.76 (d, J = 8.7 Hz, 2H, CHAr).
13C NMR (100 MHz, CDCl3): δ = 55.3, 59.3, 114.3, 120.9 (d, 3J(C,F) = 4.3
Hz), 127.3 (d, J(C,F) = 3.4 Hz), 128.1, 128.5, 128.8, 130.5 (d, J(C,F) =
15.0 Hz), 134.8, 158.4 (d, 1J(C,F) = 253.1 Hz), 159.8. 19F NMR (282 MHz,
CDCl3): δ = -143.7 (s). 15N NMR (30 MHz, CDCl3, from {1H–15N}HMBC):
δ = 231 (N-C), 301 and 330 (2 × C=N). HRMS (ESI) m/z: [M + Na]+ Calcd.
for C16H14FN3ONa: 284.1194; Found: 284.1186.
Ethyl (4-fluoro-5-[4-(methyloxy)phenyl]-2H-1,2,3-triazol-2-yl)acetate
(8)
Alkyltriazole 8 was obtained from NH-triazole 2c (20 mg) and ethyl bromo
acetate following the general procedure 2. Column chromatography
(eluent: 5:1, PE:EtOAc) afforded 8 (28 mg, 97%) as slightly yellow oil
which solidifies upon storage in the fridge. Rf = 0.40 (PE/EtOAc, 3:1)
4
2
1
(UV). H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz, 3H, CH2-Me),
3.86 (s, 3H, OMe), 4.27 (q, J = 7.1 Hz, 2H, OCH2), 5.07 (s, 2 H, N-CH2),
6.98 (d, J = 8.7 Hz, 2H, CHAr), 7.76 (d, J = 8.7 Hz, 2H, CHAr). 13C NMR
3
4-Fluoro-5-[4-(methyloxy)phenyl]-2-{[4-(methyloxy)phenyl]methyl}-
2H-1,2,3-triazole (5)
(100 MHz, CDCl3): δ = 14.1, 55.3, 56.0. 62.2, 114.3, 120.5 (d, J(C,F) =
4
2
4.2 Hz), 127.5 (d, J(C,F) = 3.3 Hz), 131.7 (d, J(C,F) = 15.1 Hz), 158.6
(d, 1J(C,F) = 254.1 Hz), 160.0. 19F NMR (282 MHz, CDCl3): δ = -142.9.
15N NMR (30 MHz, CDCl3, from {1H–15N}HMBC): δ = 218 (N-C), 303 and
331 (2 × C=N). HRMS (ESI) m/z: [M + H]+ Calcd. for C13H15FN3O3:
280.1092; Found: 280.1082.
Alkyltriazole 5 was obtained from NH-triazole 2c (42.8 mg, 0.22 mmol)
and p-methoxybenzyl bromide (46 mg, 0.23 mmol) following the general
procedure 2. Column chromatography (eluent: 8:1, PE:EtOAc) afforded 5
(52.6 mg, 76%) as slightly yellow solid. Rf = 0.37 (PE/EtOAc, 3:1) (UV).
1
m.p. 67-68 °C (PE/EtOAc, 5:1). H NMR (300 MHz, CDCl3): δ = 3.80 (s,
4-Fluoro-5-[4-(methyloxy)phenyl]-2-(cyclopentyl)-2H-1,2,3-triazole
(9)
3H, OMe), 3.85 (s, 3H, OMe), 5.38 (s, 2H, CH2), 6.90 (d, J = 8.7 Hz, 2H,
CHAr), 6.97 (d, J = 8.7 Hz, 2H, CHAr), 7.34 (d, J = 8.7 Hz, 2H, CHAr), 7.75
(d, J = 8.7 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3): δ = 55.3 (2×OMe),
58.9, 114.1, 114.2, 120.9 (d, 3J(C,F) = 4.4 Hz), 126.9, 127.3 (d, 4J(C,F) =
3.4 Hz), 129.6, 130.2 (d, 2J(C,F) = 15.0 Hz), 158.3 (d, 1J(C,F) = 253.0
Hz), 159.8 (2×C-OMe). 19F NMR (282 MHz, CDCl3): δ = -143.9 (s). 15N
NMR (30 MHz, CDCl3, from {1H–15N}HMBC): δ = 233 (N-C), 301 and 328
(2 × C=N). HRMS (ESI) m/z: [M + H]+ Calcd. for C17H17FN3O2: 314.1299;
Found: 314.1301.
Alkyltriazole
9 was obtained from NH-triazole 2c (26.5 mg) and
cyclopentyl bromide following the general procedure 2. Column
chromatography (eluent: 8:1, PE:EtOAc) afforded 9 (29 mg, 81%) as
colorless liquid, which solidifies upon storage in the fridge. Rf = 0.61
(PE/EtOAc, 3:1) (UV). 1H NMR (400 MHz, CDCl3): δ = 1.64-2.03 (m, 4H,
cyclopentyl), 2.07-2.32 (m, 4H, cyclopentyl), 3.83 (s, 3H, OMe), 4.86
(quint, 1H, N-CH), 6.97 (d, J = 8.7 Hz, 2H, CHAr), 7.75 (d, J = 8.7 Hz, 2H,
CHAr). 13C NMR (100 MHz, CDCl3): δ = 24.3, 32.5, 55.3, 66.7, 114.2,
121.3 (d, 3J(C,F) = 4.4 Hz), 127.2 (d, 4J(C,F) = 3.3 Hz), 129.2 (d, 2J(C,F)
= 15.1 Hz), 157.8 (d, 1J(C,F) = 251.6 Hz), 159.6. 19F NMR (282 MHz,
CDCl3): δ = -144.6 (s). 15N NMR (30 MHz, CDCl3, from {1H–15N}HMBC):
δ = 241 (N-C), 297 and 327 (2 × C=N). HRMS (ESI) m/z: [M + H]+ Calcd.
for C14H17FN3O: 262.1350; Found: 262.1350.
4-Fluoro-5-[4-(methyloxy)phenyl]-2-[(4-nitrophenyl)methyl]-2H-1,2,3-
triazole (6)
Alkyltriazole 6 was obtained from NH-triazole 2c (45.1 mg, 0.23 mmol)
and p-nitrobenzyl bromide (52.9 mg, 0.25 mmol) following the general
procedure 2. Column chromatography (eluent: 8:1, PE:EtOAc) afforded 6
(61.3 mg, 80%) as yellow solid. Rf = 0.31 (PE/EtOAc, 3:1) (UV). m.p. 98-
99 °C (PE/EtOAc, 5:1). 1H NMR (300 MHz, CDCl3): δ = 3.85 (s, 3H,
OMe), 5.54 (s, 2H, CH2), 6.97 (d, J = 8.7 Hz, 2H, CHAn), 7.49 (d, J = 8.8
Hz, 2H, CHAr), 7.74 (d, J = 8.7 Hz, 2H, CHAn), 8.22 (d, J = 8.8 Hz, 2H,
CHAr). 13C NMR (75 MHz, CDCl3): δ = 55.3, 58.2, 114.3, 120.3 (d, 3J(C,F)
4-Fluoro-2-propyl-5-[4-(methyloxy)phenyl]-2H-1,2,3-triazole (10)
Alkyltriazole 10 was obtained from NH-triazole 2c (46.6 mg, 0.24) and n-
propyl iodide (45 mg, 0.26 mmol) following the general procedure 2.
Column chromatography (eluent: 8:1, PE:EtOAc) afforded 10 (51.8 mg,
92%) as colourless liquid, which solidifies upon storage in the fridge. Rf =
0.44 (PE/EtOAc, 3:1) (UV). 1H NMR (300 MHz, CDCl3): δ = 0.98 (t, J =
7.2 Hz, 3H, CH2-Me), 1.99 (m, J = 7.2 Hz, 2H, CH2-Me), 3.85 (s, 3H,
OMe), 4.24 (t, J = 7.2 Hz, 2H, CH2-N), 6.97 (d, J = 8.7 Hz, 2H, CHAr),
7.75 (d, J = 8.7 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3): δ = 11.0, 22.9,
55.3, 57.2, 114.3, 121.1 (d, 3J(C,F) = 4.4 Hz), 127.2 (d, 4J(C,F) = 3.4 Hz),
129.6 (d, 2J(C,F) = 15.0 Hz), 158.0 (d, 1J(C,F) = 251.7 Hz), 159.7. 19F
NMR (282 MHz, CDCl3): δ = -144.9 (s). 15N NMR (30 MHz, CDCl3, from
{1H–15N}HMBC): δ = 232 (N-C), 300 and 328 (2 × C=N). HRMS (ESI)
m/z: [M + H]+ Calcd. for C12H15FN3O: 236.1194; Found: 236.1196.
4
2
= 4.3 Hz), 124.0, 127.4 (d, J(C,F) = 3.4 Hz), 128.8, 131.3 (d, J(C,F) =
15.0 Hz), 141.7, 148.0, 158.5 (d, 1J(C,F) = 254.4 Hz), 160.0. 19F NMR
(282 MHz, CDCl3): δ = -142.8 (s). 15N NMR (30 MHz, CDCl3, from {1H–
15N}HMBC): δ = 227 (N-C), 302 and 330 (2 × C=N), 369 (NO2). HRMS
(ESI) m/z: [M + H]+ Calcd. for C16H14FN4O3: 329.1044; Found: 329.1049.
4-Fluoro-2-(1-methylethyl)-5-[4-(methyloxy)phenyl]-2H-1,2,3-triazole
(7)
Alkyltriazole 7 was obtained from NH-triazole 2c (34 mg) and iso-propyl
bromide following the general procedure 2. Column chromatography
(eluent: 5:1, PE:EtOAc) afforded 7 (37 mg, 90%) as colourless liquid,
which solidifies upon storage in the fridge. Rf = 0.53 (PE/EtOAc, 3:1)
(UV). 1H NMR (300 MHz, CDCl3): δ = 1.57 (d, J = 6.7 Hz, 6H, CH-Me),
3.85 (s, 3H, OMe), 4.68 (hept d, J = 6.7, 0.9 Hz, 1H, CH-Me), 6.97 (d, J =
8.7 Hz, 2H, CHAr), 7.76 (d, J = 8.7 Hz, 2H, CHAr). 13C NMR (75 MHz,
CDCl3): δ = 22.0. 55.3, 57.9, 114.3, 121.3 (d, 3J(C,F) = 4.4 Hz), 127.2 (d,
4J(C,F) = 3.4 Hz), 129.1 (d, 2J(C,F) = 15.2 Hz), 157.8 (d, 1J(C,F) = 251.5
Hz), 159.6. 19F NMR (282 MHz, CDCl3): δ = -144.8 (s). 15N NMR (30 MHz,
CDCl3, from {1H–15N}HMBC): δ = 243. Other signals are not visible due
to low intensity. HRMS (ESI) m/z: [M + H]+ Calcd. for C12H15FN3O:
236.1194; Found: 236.1194.
2,2’-Butane-1,4-diylbis{4-fluoro-5-[4-(methyloxy)phenyl]-2H-1,2,3-
triazole} (11)
Alkyltriazole 11 was obtained from NH-triazole 2c (30.5 mg) following the
general procedure 2 using 2.0 equiv of 2b and 1.0 equiv. of 1,4-
dibromobutane. Column chromatography (eluent: 5:1, PE:EtOAc)
afforded 11 (28 mg, 80%) as colorless solid. Rf = 0.24 (PE/EtOAc, 3:1)
(UV). m.p. 86-87 °C (PE/EtOAc, 5:1). 1H NMR (400 MHz, CDCl3): δ =
2.02 (d, J = 5.9 Hz, 4H, N-CH2-CH2), 3.85 (s, 6H, OMe), 4.36 (d, J = 5.9
Hz, 4H, N-CH2), 6.96 (d, 4H, J = 8.8 Hz, CHAr), 7.73 (d, 4H, J = 8.8 Hz,
CHAr). 13C NMR (100 MHz, CDCl3): δ = 26.3, 54.6, 55.3, 114.3, 120.9 (d,
3J(C,F) = 4.4 Hz), 127.3 (d, 4J(C,F) = 3.3 Hz), 130.0 (d, 2J(C,F) = 15.0
Hz), 158.0 (d, 1J(C,F) = 252.5 Hz), 159.8. 19F NMR (282 MHz, CDCl3): δ
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701338
European Journal of Organic Chemistry
FULL PAPER
= -144.3 (s). 15N NMR (30 MHz, CDCl3, from {1H–15N}HMBC): δ = 230
(N-C), 300 and 329 (2 × C=N). HRMS (ESI) m/z: [M + H]+ Calcd. for
C22H23F2N6O2: 441.1845; Found: 441.1849. Single-crystal X-Ray
diffraction data for 11 was deposited at Cambridge Crystallographic Data
Centre (CCDC-1557134).
208.0885. Data for 14c: Rf = 0.16 (PE/EtOAc, 3:1) (UV). 1H NMR (400
MHz, CDCl3): δ = 3.85 (s, 3H, OMe), 3.99 (d, J = 1.2 Hz, 3H, Me), 6.99 (d,
J = 8.7 Hz, 2H, CHAr), 7.77 (d, J = 8.7 Hz, 2H, CHAr). 13C NMR (100 MHz,
CDCl3): δ = 33.1, 55.3, 114.3, 121.3 (d, 3J(C,F) = 4.7 Hz), 126.6 (d,
4J(C,F) = 3.1 Hz), 158.3 (d, 1J(C,F) = 251.4 Hz), 160.6. 19F NMR (282
MHz, CDCl3): δ = -154.1 (s). 15N NMR (30 MHz, CDCl3, from {1H–
15N}HMBC): δ = 219 (N-C), 340 (C=N). Other signals are not visible due
to low intensity. HRMS (ESI) m/z: [M + H]+ Calcd. for C10H11FN3O:
208.0881; Found: 208.0883.
4-Fluoro-2-methyl-5-phenyl-2H-1,2,3-triazole
(12b),
4-Fluoro-1-
methyl-5-phenyl-1H-1,2,3-triazole (13b) and 5-Fluoro-1-methyl-4-
phenyl-1H-1,2,3-triazole (14b)
General procedure 3. Synthesis of N-2-aryl-4-fluoro-1,2,3-triazoles
16.
Methylation of 2b (60 mg, 0.37 mmol) with methyl iodide (55 mg, 0.39
mmol) following general procedure
2 and purification by column
chromatography (SiO2, PE:EtOAc, 9:1) afforded product 12b (53.3 mg,
82%) and mixture of two other regioisomers 13b and 14b (9.4 mg, 14%)
with ratio 13b:14b = 3:1 (determined by NMR) as colorless oils. Data for
12b: Rf = 0.45 (PE/EtOAc, 3:1) (UV). 1H NMR (300 MHz, CDCl3): δ =
4.12 (s, 3H, Me), 7.34-7.48 (m, 3H, CHAr), 7.81 (d, J = 7.6 Hz, 2H, CHAr).
13C NMR (75 MHz, CDCl3): δ = 42.4, 125.8 (d, 4J(C,F) = 3.6 Hz), 128.3 (d,
3J(C,F) = 4.2 Hz), 128.4, 128.9, 130.1 (d, 2J(C,F) = 14.6 Hz), 158.4 (d,
1J(C,F) = 252.5 Hz). 19F NMR (282 MHz, CDCl3): δ = -143.8 (s). 15N NMR
(30 MHz, CDCl3, from {1H–15N}HMBC): δ = 222 (N-C), 303 and 331 (2 ×
C=N). HRMS (ESI) m/z: [M + H]+ Calcd. for C9H9FN3: 178.0775; Found:
178.0782. Data for 13b: Rf = 0.20 (PE/EtOAc, 3:1) (UV). 1H NMR (300
MHz, CDCl3): δ = 4.07 (s, 3H, Me), 7.43-7.58 (m, 5H, CHAr). 13C NMR (75
MHz, CDCl3): δ = 37.1, 125.3 (d, 3J(C,F) = 3.3 Hz), 119.9 (d, 2J(C,F) =
29.2 Hz), 128.6 (d, 4J(C,F) = 1.4 Hz), 129.3, 129.7, 158.4 (d, 1J(C,F) =
245.9 Hz). 19F NMR (282 MHz, CDCl3): δ = -145.1 (s). 15N NMR (30 MHz,
CDCl3, from {1H–15N}HMBC): δ = 232 (N-C), 343 (C=N). Other signals
are not visible due to low intensity. Data for 14b: Rf = 0.20 (PE/EtOAc,
In 10 mL round-bottomed flask fluorotriazole 2c (0.3 mmol, 58 mg),
boronic acid (0.39 mmol, 1.3 eq) and copper(II) acetate monohydrate
(0.03 mmol, 0.1 equiv, 6 mg) were dissolved in 3 mL of DMSO. Flask
was connected to balloon with O2, and the mixture was heated to 100°C.
After 2-3 h of stirring (TLC monitoring) mixture was cooled to room
temperature and extracted with EtOAc/H2O (20/20 mL). Aqueous layer
was washed with EtOAc (2 × 15 mL), organic layers were combined,
washed with saturated NaCl solution (10 mL), and dried over anhydrous
Na2SO4. Crude product was purified by column chromatography (SiO2,
PE:EtOAc, 10:1).
4-Fluoro-5-[4-(methyloxy)phenyl]-2-(phenyl)-2H-1,2,3-triazole (16a)
Aryltriazole 16a was obtained from NH-triazole 2c (38 mg) and
benzeneboronic acid following the general procedure 3. Column
chromatography (eluent: 10:1, PE:EtOAc) afforded 16a (51 mg, 95%) as
white solid. Rf = 0.60 (PE/EtOAc, 3:1) (UV). m.p. 94-95 °C (PE/EtOAc,
5:1). 1H NMR (300 MHz, CDCl3): δ = 3.88 (s, 3H, OMe), 7.02 (d, J = 8.7
Hz, 2H, CHAn), 7.34 (m, 1H, p-CHPh), 7.49 (m, 2H, m-CHPh), 7.88 (d, J =
8.7 Hz, 2H, CHAn), 8.02 (m, 2H, o-CHPh). 13C NMR (75 MHz, CDCl3): δ =
55.3, 114.4, 117.9, 120.5 (d, 3J(C,F) = 4.3 Hz), 127.2, 127.6 (d, 4J(C,F) =
3.4 Hz), 129.3, 131.9 (d, 2J(C,F) = 15.3 Hz), 139.6, 159.4 (d, 1J(C,F) =
255.1 Hz), 160.2. 19F NMR (282 MHz, CDCl3): δ = -142.0 (s). 15N NMR
(30 MHz, CDCl3, from {1H–15N}HMBC): δ = 234 (N-C). Other signals are
not visible due to low intensity. HRMS (ESI) m/z: [M + H]+ Calcd. for
C15H13FN3O: 270.1037; Found: 270.1028.
1
3:1) (UV). H NMR (300 MHz, CDCl3): δ = 4.01 (d, J = 1.3 Hz, 3H, Me),
7.35-7.58 (m, 3H, CHAr), 7.85 (d, J = 7.3 Hz, 2H, CHAr). 13C NMR (57
3
MHz, CDCl3): δ = 33.2, 124.5 (d, J(C,F) = 4.2 Hz), 128.1, 128.9. Other
signals are not visible due to low intensity and/or overlapping. 19F NMR
(282 MHz, CDCl3): δ = -152.8 (s). 15N NMR (30 MHz, CDCl3, from {1H–
15N}HMBC): δ = 219 (N-C), 342 (C=N). Other signals are not visible due
to low intensity. HRMS (13b+14b mixture) (ESI) m/z: [M + H]+ Calcd. for
C9H9FN3: 178.0775; Found: 178.0773.
4-Fluoro-5-[4-(methyloxy)phenyl]-2-(methyl)-2H-1,2,3-triazole (12c),
4-Fluoro-5-[4-(methyloxy)phenyl]-3-(methyl)-3H-1,2,3-triazole (13c)
and
(14c)
4-Fluoro-5-[4-(methyloxy)phenyl]-1-(methyl)-1H-1,2,3-triazole
4-Fluoro-5-[4-(methyloxy)phenyl]-2-(4-bromophenyl)-2H-1,2,3-
triazole (16b)
Methylation of 2c (72 mg, 0.373 mmol) with methyl iodide following
general procedure 2 and purification by column chromatography (SiO2,
PE:EtOAc, 3:1) afforded product 12c (59 mg, 76%) and mixture of two
other regioisomers 13c and 14c (10 mg, 13%) with ratio 13c:14c = 4:1
(determined by NMR). Data for 12c: Rf = 0.43 (PE/EtOAc, 3:1) (UV). m.p.
59-60 °C (PE/EtOAc, 10:1). 1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3H,
OMe), 4.08 (s, 3H, Me), 6.98 (d, J = 8.7 Hz, 2H, CHAr), 7.74 (d, J = 8.7
Hz, 2H, CHAr). 13C NMR (100 MHz, CDCl3): δ = 42.3, 55.3, 114.3, 120.9
(d, 3J(C,F) = 4.3 Hz), 127.2 (d, 4J(C,F) = 3.4 Hz), 130.1 (d, 2J(C,F) = 14.8
Hz), 158.0 (d, 1J(C,F) = 251.8 Hz), 159.8. 19F NMR (282 MHz, CDCl3): δ
= -144.8 (s). 15N NMR (30 MHz, CDCl3, from {1H–15N}HMBC): δ = 220
(N-C), 302 and 330 (2 × C=N). HRMS (ESI) m/z: [M + H]+ Calcd. for
C10H11FN3O: 208.0881; Found: 208.0883. Data for 13c: Rf = 0.16
(PE/EtOAc, 3:1) (UV). 1H NMR (400 MHz, CDCl3): δ = 3.88 (s, 3H, OMe),
4.03 (s, 3H, Me), 7.05 (d, J = 8.7 Hz, 2H, CHAr), 7.37 (d, J = 8.7 Hz, 2H,
CHAr). 13C NMR (100 MHz, CDCl3): δ = 36.9, 55.4, 114.8, 116.5 (d,
3J(C,F) = 4.1 Hz), 119.8 (d, 2J(C,F) = 29.8 Hz), 130.0 (d, 4J(C,F) = 1.1
Hz), 158.2 (d, 1J(C,F) = 244.7 Hz), 160.6. 19F NMR (282 MHz, CDCl3): δ
= -145.6 (s). 15N NMR (30 MHz, CDCl3, from {1H–15N}HMBC): δ = 232
(N-C), 341 (C=N). Other signals are not visible due to low intensity.
HRMS (ESI) m/z: [M + H]+ Calcd. for C10H11FN3O: 208.0881; Found:
Aryltriazole 16b was obtained from NH-triazole 2c (58 mg, 0.30 mmol)
following the general procedure 3. Column chromatography (eluent: 10:1,
PE:EtOAc) afforded 16b (92 mg, 88%) as white solid. Rf = 0.58
1
(PE/EtOAc, 3:1) (UV). m.p. 138-139 °C (PE/EtOAc, 10:1). H NMR (400
MHz, CDCl3): δ = 3.88 (s, 3H, OMe), 7.01 (d, J = 8.7 Hz, 2H, CHAn), 7.60
(d, J = 8.9 Hz, 2H, CHAr), 7.86 (d, J = 8.7 Hz, 2H, CHAn), 7.90 (d, J = 8.9
Hz, 2H, CHAr). 13C NMR (100 MHz, CDCl3): δ = 55.4, 114.4, 119.4, 120.2
(d, 3J(C,F) = 4.2 Hz), 120.7, 127.7 (d, 4J(C,F) = 3.3 Hz), 132.4, 132.5,
1
138.5, 159.5 (d, J(C,F) = 256.1 Hz), 160.4. 19F NMR (282 MHz, CDCl3):
δ = -141.1 (s). 15N NMR (30 MHz, CDCl3, from {1H–15N}HMBC): δ = 232
(N-C). Other signals are not visible due to low intensity. HRMS (ESI) m/z:
[M + Na]+ Calcd. for C15H1179BrFN3ONa: 348.0142; Found: 348.0144.
Single-crystal X-Ray diffraction data for 16b was deposited at Cambridge
Crystallographic Data Centre (CCDC-1557135).
4-Fluoro-5-[4-(methyloxy)phenyl]-2-(4-nitrophenyl)-2H-1,2,3-triazole
(17)
Fluorotriazole 2c (20.7 mg, 0.11 mmol) was dissolved in 1.1 mL of
DMSO, then p-fluoronitrobenzene (17 mg, 1.1 equiv., 0.12 mmol) and
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10.1002/ejoc.201701338
European Journal of Organic Chemistry
FULL PAPER
K2CO3 (22 mg, 1.5 equiv., 0.16 mmol) were added. Mixture was heated
to 70 °C and stirred for 2 hours, then cooled to room temperature, poured
into EtOAc/H2O (20/20 mL). Aqueous layer was washed with EtOAc (2 ×
15 mL), organic layers were combined, washed with saturated NaCl
solution (10 mL), and dried over anhydrous Na2SO4. Solvent was
evaporated under reduced pressure. Column chromatography (SiO2,
PE:EtOAc, 10:1) afforded aryltriazole 17 (20 mg, 60%) as yellow
crystalline solid. Rf = 0.48 (PE/EtOAc, 3:1) (UV). m.p. 183-185 °C
(PE/EtOAc, 10:1). 1H NMR (300 MHz, CDCl3): δ = 3.87 (s, 3H, OMe),
7.03 (d, J = 8.7 Hz, 2H, CHAn), 7.89 (d, J = 8.7 Hz, 2H, CHAn), 8.17 (d, J
= 9.3 Hz, 2H, CHAr), 8.37 (d, J = 9.3 Hz, 2H, CHAr). 13C NMR (75 MHz,
4-Fluoro-5-[4-(methyloxy)phenyl]-2-(2-cyanoethyl)-2H-1,2,3-triazole
(20)
Fluorotriazole 2c (26.7 mg, 0.14 mmol) was dissolved in DMF (0.7 mL),
then acrylonitrile (10 mg, 1.3 equiv, 0.18 mmol) and Et3N (21 mg, 1.5
equiv, 0.21 mmol) were added. Mixture was stirred at room temperature
for 20 hours, then poured into EtOAc/H2O (20/20 mL). Aqueous layer
was washed by EtOAc (3 × 10 mL), organic layers were combined,
washed with saturated NaCl solution (10 mL), and dried over anhydrous
Na2SO4. Column chromatography (SiO2, PE:EtOAc, 10:1) afforded
product 20 (23 mg, 68 %) as colorless liquid, which solidifies in the fridge.
Rf = 0.13 (PE/EtOAc, 3:1) (UV). 1H NMR (300 MHz, CDCl3): δ = 3.04 (t, J
= 6.9 Hz, 2H, CH2-CN), 3.86 (s, 3H, OMe), 4.59 (t, J = 6.9 Hz, 2H, N-
CH2), 6.98 (d, J = 8.9 Hz, 2H, CHAr), 7.75 (d, J = 8.5 Hz, 2H, CHAr). 13C
NMR (75 MHz, CDCl3): δ = 18.1, 50.5, 55.3, 114.4, 116.1, 120.2 (d,
3J(C,F) = 4.3 Hz), 127.5 (d, 4J(C,F) = 3.4 Hz), 131.6 (d, 2J(C,F) = 15.0
Hz), 158.4 (d, 1J(C,F) = 254.8 Hz), 160.1. 19F NMR (282 MHz, CDCl3): δ
= -142.5 (s). 15N NMR (30 MHz, CDCl3, from {1H–15N}HMBC): δ = 223
(N-C), 252 (C≡N), 301 and 328 (2 × N=C). HRMS (ESI) m/z: [M + H]+
Calcd. for C12H12FN4O: 247.0990; Found: 247.0988.
3
CDCl3): δ = 55.4, 114.5, 117.9, 119.5 (d, J(C,F) = 4.0 Hz), 125.2, 127.2
(d, 4J(C,F) = 3.4 Hz), 134.4 (d, 2J(C,F) = 15.5 Hz), 143.4, 146.1, 160.3 (d,
1J(C,F) = 259.2 Hz), 160.8. 19F NMR (282 MHz, CDCl3): δ = -138.6 (s).
15N NMR (30 MHz, CDCl3, from {1H–15N}HMBC): 229 (N-C), 368 (NO2).
Other signals are not visible due to low intensity. HRMS (ESI) m/z: [M +
H+] Calcd. for C15H12FN4O3: 315.0888; Found: 315.0881.
4-Fluoro-5-[4-(methyloxy)phenyl]-2-acetyl)-2H-1,2,3-triazole (18)
Fluorotriazole 2c (52 mg, 0.27 mmol) was dissolved in CH2Cl2 (1.3 mL),
then Ac2O (33 mg, 1.2 equiv, 0.32 mmol) and Et3N (33 mg, 1.3 equiv,
0.32 mmol) were added. Mixture was stirred at room temperature for 3
hours, diluted with CH2Cl2 to 20 mL and washed with water (20 mL).
Aqueous layer was washed with 10 mL of CH2Cl2, organic layers were
combined, washed with saturated NaCl solution (10 mL), and dried over
anhydrous Na2SO4. Recrystallization from PE:EtOAc (5:1) afforded
product 18 as yellow needle-like crystals (52.5 mg, 83 %). Rf = 0.42
(PE/EtOAc, 3:1) (UV). m.p. 135-137 °C (PE/EtOAc, 5:1). 1H NMR (400
MHz, CDCl3): δ = 2.77 (s, 3H, Me), 3.86 (s, 3H, OMe), 7.00 (d, J = 8.7 Hz,
2H, CHAr), 7.89 (d, J = 8.7 Hz, 2H, CHAr).13C NMR (100 MHz, CDCl3): δ =
21.3, 55.3, 114.6, 118.7 (d, 3J(C,F) = 4.1 Hz), 128.4 (d, 4J(C,F) = 3.1 Hz),
137.0 (d, 2J(C,F) = 16.9 Hz), 160.4 (d, 1J(C,F) = 265.4 Hz), 161.3, 165.3.
19F NMR (282 MHz, CDCl3): δ = -134.6 (s). 15N NMR (30 MHz, CDCl3,
from {1H–15N}HMBC): δ = 251 (N-C). Other signals are not visible due to
low intensity. HRMS (ESI) m/z: [M + H]+ Calcd. for C11H11FN3O2:
236.0830; Found: 236.0829. Single-crystal X-Ray diffraction data for 18
was deposited at Cambridge Crystallographic Data Centre (CCDC-
1557136).
4-Fluoro-5-[4-(methyloxy)phenyl]-2-(hydroxymethyl)-2H-1,2,3-
triazole (21)
Fluorotriazole 2c (39.5 mg, 0.205 mmol) was suspended with stirring in
the 37% aqueous formaldehyde solution (10 equiv., 166 mg, 0.15 mL).
Reaction mixture was stirred overnight, quenched with water (10 mL),
and product was extracted with EtOAc (2 × 20 mL). The organic layer
was evaporated. Recrystallization from PE:EtOAc (1:1) afforded 40 mg
(88%) of product 21 as slightly yellow crystals. Rf = 0.10 (PE/EtOAc, 5:1)
(UV). m.p. 81-82 °C (PE/EtOAc, 1:1). 1H NMR (300 MHz, CDCl3): δ =
3.72 (br t, J = 7.7 Hz, 1H, OH), 3.86 (s, 3H, OMe), 5.67 (d, J = 7.7 Hz, 2H,
CH2), 6.99 (d, J = 8.7 Hz, 2H, CHAr), 7.76 (d, J = 8.7 Hz, 2H, CHAr). 13C
3
NMR (75 MHz, CDCl3) δ. 55.3, 77.1, 114.4, 120.3 (d, J(C,F) = 4.3 Hz),
127.5 (d, 4J(C,F) = 3.4 Hz), 132.1 (d, 2J(C,F) = 15.5 Hz), 158.8 (d,
1J(C,F) = 255.7 Hz), 160.2. 19F NMR (282 MHz, CDCl3): δ = -142.2. 15N
NMR (30 MHz, CDCl3, from {1H–15N}HMBC): δ = 299 and 328 (2 × N=C).
Other signals are not visible due to low intensity. HRMS (ESI) m/z: [M +
H]+ Calcd. for C10H11FN3O2: 224.0830; Found: 224.0833.
4-Fluoro-5-[4-(methyloxy)phenyl]-2-[(4-methylphenyl)sulfonyl)]-2H-
1,2,3-triazole (19)
Acknowledgements
Fluorotriazole 2c (40.5 mg, 0.21 mmol) was dissolved in CH2Cl2 (0.53
mL), then TsCl (44 mg, 1.1 equiv, 0.23 mmol) and Et3N (32 mg, 1.5 equiv,
0.32 mmol) were added. Mixture was stirred at room temperature for 40
min, diluted with CH2Cl2 to 20 mL and washed with water (20 mL).
Aqueous layer was washed with 10 mL of CH2Cl2, organic layers were
combined, washed with saturated NaCl solution (10 mL), and dried over
anhydrous Na2SO4. Column chromatography (SiO2, PE:EtOAc, 10:1)
afforded product 19 as white solid (59 mg, 81 %). Rf = 0.47 (PE/EtOAc,
3:1) (UV). m.p. 137-138 °C (PE/EtOAc, 10:1). 1H NMR (300 MHz,
CDCl3): δ = 2.43 (s, 3H, Me), 3.85 (s, 3H, OMe), 6.97 (d, J = 8.7 Hz, 2H,
CHAr), 7.36 (d, J = 8.3 Hz, 2H, CHTs), 7.81 (d, J = 8.7 Hz, 2H, CHAr), 7.96
(d, J = 8.3 Hz, 2H, CHTs). 13C NMR (75 MHz, CDCl3): δ = 21.7 (Me), 55.3
(OMe), 114.5 (CHAr), 118.6 (d, 3J(C,F) = 4.1 Hz, CAr), 128.3 (d, 4J(C,F) =
The work was supported by Russian Science Foundation (grant
14-50-00126). The authors thank Dr. N. G. Kolotyrkina, Dr. A. O.
Chizhov (N. D. Zelinsky Institute of Organic Chemistry) and Dr.
P. N. Solyev (V. A. Engelhardt Institute of Molecular Biology) for
registration of HRMS. The X-ray diffraction data were obtained
using the equipment of Center for molecular composition studies
of INEOS RAS.
Keywords: fluorinated heterocycles • 1,2,3-triazoles •
regioselectivity • cycloaddition • nitroalkenes
2
3.5 Hz, CHAr), 128.7 (CHTs), 130.2 (CHTs), 132.6 (CTs), 137.2 (d, J(C,F)
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701338
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.201701338
European Journal of Organic Chemistry
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Fluorinated heterocycles
Vladimir A. Motornov, Andrey A.
Tabolin,* Roman A. Novikov, Yulia V.
Nelyubina, Sema L. Ioffe, Ivan V.
Smolyar, Valentine G. Nenajdenko*
Efficient synthesis of 4-fluoro-5-aryl-1,2,3-NH-triazoles was elaborated using
reaction of NaN3 with arylsubstituted α-fluoronitroalkenes. Subsequent
functionalization of obtained triazoles proceeds highly regioselectively at the N-2
position. The observed regioselectivity was supported by DFT calculations.
Page No. – Page No.
Synthesis and Regioselective N-2-
Functionalization of 4-Fluoro-5-aryl-
1,2,3-NH-triazoles
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