The first versatile synthesis of 1-alkyl-3-fluoro-1H-[1,2,4]triazoles

Article abstract of DOI:10.1055/s-1998-6080

Reaction of 1-benzyl-3,5-dibromo-1H-[1,2,4]triazole (3) with cesium fluoride yielded selectively 1-benzyl-3-bromo-5-fluoro-1H-[1,2,4]triazole (4). Debenzylation and realkylation afforded 1-alkyl-5-bromo-3-fluoro-1H-[1,2,4]triazoles 7, which reacted with a wide variety of nucleophiles to give 5-substituted 1-alkyl-3-fluoro-1H-[1,2,4]triazoles.

Full text of DOI:10.1055/s-1998-6080

SYNTHESIS
September 1998
1357
The First Versatile Synthesis of 1-Alkyl-3-fluoro-1H-[1,2,4]triazoles
Albrecht Zumbrunn
Novartis Agrobiotechnology Research Institute, 3054 Cornwallis Road, Research Triangle Park, NC 27709, USA
Fax: 9195418585; E-mail: albrecht.zumbrunn@cp.novartis.com
Received 3 November 1997; revised 4 February 1998
Abstract: Reaction of 1-benzyl-3,5-dibromo-1H-[1,2,4]triazole
(3) with cesium fluoride yielded selectively 1-benzyl-3-bromo-5-
fluoro-1H-[1,2,4]triazole (4). Debenzylation and realkylation
afforded 1-alkyl-5-bromo-3-fluoro-1H-[1,2,4]triazoles 7, which
reacted with a wide variety of nucleophiles to give 5-substituted
1-alkyl-3-fluoro-1H-[1,2,4]triazoles.
Key words: 3- or 5-fluoro-1H-[1,2,4]triazoles, fluorination, halo-
gen exchange, cesium fluoride, 5-substituted 1-alkyl-3-fluoro-1H-
[1,2,4]triazoles
In our laboratory the need occurred for [1,2,4]triazoles
bearing a fluoro substituent in the 3- or 5-position. They
are useful as building blocks for the synthesis of biologi-
cally active compounds with modified electronic proper-
ties compared to unfluorinated [1,2,4]triazoles. The syn-
thesis of 3(5)-fluoro-[1,2,4]triazoles has been achieved in
Scheme 1
three different ways.1–3 3(5)-Nitro-[1,2,4]triazoles were
converted into 3(5)-fluoro-[1,2,4]triazoles by treatment
with pure hydrogen fluoride at 150°C.1 Alternatively,
photoreaction of 3-diazo-3H-[1,2,4]triazole in concentrat-
ed tetrafluoroboric acid gave 3-fluoro-[1,2,4]triazole.2
Both methods suffer from narrow scopes and undesirable
reaction conditions. In a patent3 one example, 1-phenyl-5-
fluoro-1H-[1,2,4]triazole, was prepared by halogen ex-
change from the corresponding chloro compound. Other
patents include compounds containing 3(5)-fluoro-
[1,2,4]triazole moieties in their claims, however without
relating synthetic procedures for the introduction of the
fluoro substituent.4 3(5)-Fluoro-[1,2,4]triazoles were also
detected as side products in α,α-difluoroalkylation reac-
tions of 1,2,4-triazoles.5
unexpected exothermic outbursts. A modified procedure
was used several times without problems in up to 2 mole
scale (see experimental part).
Debenzylation of 4 could easily be accomplished by Wohl
Ziegler bromination followed by aqueous hydrolysis to
give 3-bromo-5-fluoro-1H-[1,2,4]triazole (5). Realkyla-
tion of 5 gave mixtures of the isomers 4, 6a, 6c, and 7a–c.
As expected, 7a–c were the main products, the ratio 6/7
depending on the alkyl group introduced (Scheme 2).
Chromatographic separation of the isomers was difficult.
Halogen exchange reactions have been commonly used to
introduce fluoro substituents into various heterocyclic
rings.3, 6 It is known that nucleophilic substitution is fast
in the 5-position of 1-alkyl-1H-[1,2,4]triazoles and very
slow in the 3-position.7 This selectivity has not been syn-
thetically exploited. We found that 1-benzyl-3,5-di-
bromo-1H-[1,2,4]triazole (3) underwent smooth halogen
exchange with 3 equivalents of cesium fluoride in dimeth-
yl sulfoxide at 120°C selectively in the 5-position to give
1-benzyl-3-bromo-5-fluoro-1H-[1,2,4]triazole (4) in good
yield (Scheme 1). In the HMBC-NMR spectrum (hetero-
nuclear multiple bond correlation)8 a correlation from the
benzylic hydrogens to C-5, but not to C-3, was detected.
By the magnitude of the C–F coupling constant it was eas-
ily determined that the fluoro substituent was located in
the 5-position (Table).
Product
R
X
I
Temp. 6/7
(°C)
Yield (%)
of 7
6–8a
4, 7b, 8b CH2Ph
6–8c
Me
–5
15 : 85 46
30 : 70 62
25 : 75 51
The synthesis of 3 was achieved by benzylation of 3,5-
dibromo-1H-[1,2,4]triazole (2), which was prepared by
bromination of 1,2,4-triazole (1). This reaction, carried
out according to described procedures,9 proceeded with
mesyl r.t.
3,4-(MeO)2C6H3 Br r.t.
Scheme 2

SYNTHESIS
Papers
1358
However, if the mixture was allowed to react with ethane-
1,2-dithiol and triethylamine, the fluoro substituent in 4,
6a, and 6c was selectively attacked to form 8a–c, while
7a–c remained unchanged and could be separated by
washing with sodium hydroxide solution. In the case of 7c
the isomeric identity was proved by HMBC-NMR8 in the
same way as for compound 4 (Table). Thus the key inter-
mediates 7a–c could be prepared from 1,2,4-triazole in 5
steps in 22–30% overall yield in large scale.
Schemes 3 and 4 demonstrate some of the synthetic poten-
tial of 7a–c. They reacted smoothly with cesium fluoride
to give the difluorotriazole 9, with sodium methoxide to
give 10, with 4-chlorophenol to give 11 and with thiols to
yield 12 or 14. Reduction of the bromo substituent to give
the monofluorotriazole 13 could be accomplished in a two
step sequence via desulfurization of the sulfide 12.10 Car-
bon nucleophiles did not react smoothly with the bromo
compounds 7a–c. However the sulfone 15 reacted with
the sodium salt of diethyl malonate to give the triazolo
substituted malonate 16.
Scheme 4
15 min, then 3 min at 300°C. Mps: Thomas Hoover Unimelt Capil-
lary melting point apparatus, uncorrected. CsF (99%) was purchased
from Aldrich and always used from freshly opened containers.
3,5-Dibromo-1H-[1,2,4]triazole (2); Modified Procedure:9
1,2,4-Triazole (138 g, 2.00 mol), water (1.5 L) and CH2Cl2 (200 mL)
in a flask fitted with a thermometer were stirred with an efficient stir-
rer in an ice bath. A solution of bromine (650 g, 210 mL, 4.10 mol) in
CH2Cl2 (200 mL) and a solution of NaOH (480 g, 50% solution,
6.00 mol) in water (500 mL) were added slowly and simultaneously
from two dropping funnels at such a rate that the temperature was kept
between 15°C and 20°C (ca. 3 h). After the end of the addition the
mixture was stirred for 12 h at 23°C. It was acidified with concd HCl
(200 mL), the precipitated crystals were filtered and dried in a vacu-
um oven at 50°C; yield: 412 g (90%). The product was used without
further purification. A sample was recrystallized from water; mp
213–215°C (lit.9 mp 211–212°C).
1-Benzyl-3,5-dibromo-1H-[1,2,4]triazole (3):
A solution of 2 (178 g, 0.785 mol) in MeCN (500 mL) was treated
with N,N-diisopropylethylamine (103 g, 0.800 mol) and benzyl bro-
mide (101 g, 0.800 mol). The mixture was heated to reflux for 60 min,
cooled and the solvent was evaporated in a rotary evaporator. The
residue was taken up in EtOAc (500 mL), washed with water
(200 mL), 1 N HCl (200 mL) and sat. aq NaHCO3 (200 mL), dried
(MgSO4), filtered and concentrated. Distillation through a short Vi-
greux column (15 cm) gave 228 g (91%) 3 as a colorless oil; bp
143°C/0.5 mbar. The product crystallized on standing; mp 62–64°C
(lit.11 mp 64–66°C).
1-Benzyl-3-bromo-5-fluoro-1H-[1,2,4]triazole (4):
CsF (200 g, 1.32 mol), DMSO (250 mL) and 3 (208 g, 0.660 mol)
were stirred intensely with an overhead stirrer and heated to 120°C
for 5.5 h. The mixture was cooled and poured onto ice (1 kg). It was
extracted with EtOAc (3 × 250 mL). The combined extracts were
washed with water (2 × 750 mL), dried (MgSO4), filtered and concen-
trated. The residue was distilled through a short Vigreux column
(15 cm) to give 119 g (70%) 4 as a colorless liquid; bp 105°C/0.4 mbar.
3-Bromo-5-fluoro-1H-[1,2,4]triazole (5):
A mixture of 4 (62.4 g, 0.244 mol), CCl4 (600 mL) and NBS (50.8 g,
0.285 mol) was heated to reflux under stirring by illumination with a
250 W lamp. After 2 h the mixture was cooled, filtered and concentrat-
ed. The residue was immediately dissolved in THF (360 mL). Water
(120 mL) was added and the mixture was stirred at 23°C for 12 h. The
solution was diluted with Et2O (1 L) and extracted with 2.5 N NaOH
(200 mL, 60 mL and 20 mL successively). The combined water phas-
es were acidified with concd HCl (60 mL) and extracted with EtOAc
(3 × 100 mL). The EtOAc extracts were washed with brine, dried
(MgSO4), filtered and concentrated to give 33.9 g (84%) 5 as slightly
Scheme 3
NMR spectra: Bruker 300 ACE, CDCl3, shifts relative to TMS (1H,
13C) and CFCl3 (19F). MS: Hewlett Packard HP 5989A (CI, CH4).
Analysis provided by Galbraith, Inc., 2323 Sycamore Drive, Knox-
ville, TN 37921-1750.GC: Hewlett Packard HP5980 Series II; col-
umn 30 m DP 5; carrier gas: He; temperature program: 40–300°C in

SYNTHESIS
September 1998
1359
Table. Characterization of New Compoundse
Product
1H NMR
13C NMR
19F NMR
MS
δ
δ, J (Hz)
δ
m/z (%)
4
5.12c (2H, s, CH2)a, 7.40–7.27 (5H, m, 51.3 (d, J = 1.8, CH2)a, 127.9, 128.9, – 111.8
phenyl-H)
256, 258
[M+H]+
129.0, 133.1 (phenyl-C), 135.9b (d, J = 20,
C-5), 155.2c (d, J = 262, C-3)
5
127,2 (d, J = 10)d, 165.7 (d, J = 235)
– 114.8d
166, 168
[M+H]+,
88 [M-Br+1]+
7a
7b
3.82 (s, 3H, CH3)
36.7 (CH3), 127.5 (d, J = 9, C-5), 165.9 (d, –112.2
J = 238, C-3)
180, 182
[M+H]+
5.21 (s, 2H, CH2), 7.26–7.39 (m, 5H, 53.6 (CH2), 127.3 (d, J = 9, C-5), 127.9, –111.7
phenyl-H)
256, 258
128.8, 129.0, 133.6 (phenyl-C), 166.4 (d,
[M+H]+,
J = 240, C-3),
178,119 (100)
7c
9
3.86, 3.87 (2s, 2 × 3H, 2 OCH3)a, 5.16c (s, 53.9 (2 OCH3)a, 56.3 (CH2), 111.6, 111.7, –111.8
2H, CH2), 6.83–6.91 (m, 3H, phenyl-H)
316, 318
121.2, 126.4 (phenyl-C), 127.3c (d, J = 10,
C-5), 149.7, 149.9 (phenyl-C), 166.7b (d, J
= 240, C-3).
[M+H]+, 315,
317 [M]+,
151 (100)
3.87, 3.88 (2s, 2 × 3H, 2 OCH3)a, 5.02c (d, 50.7 (CH2)a, 55.71, 55.75 (2 OCH3), –108.7, –109.3
J = 0.9, 2H, CH2), 6.84–6.88 (m, 3H, 111.1, 111.2, 120.7, 125.5, 149.2, 149.5
256 [M+H]+,
255 [M]+,
151 (100)
phenyl-H)
(phenyl-C), 152.4c (d × d, J = 264, 11, C-
5), 161.3a (d × d, J = 239, 23, C-3)
10
11
12
3.86 (S, 6H, 2 CH3-O-phenyl), 3.87 (s, 49.7 (CH3-O-C-5), 55.9 (2 CH3-O- –113.3
3H, CH3-N), 4.09 (s, 3H, CH3-O-C-5), phenyl), 58.7 (CH2), 111.2, 120.5, 127.4,
268 [M+H]+
151 (100)
4.91 (s, 2H, CH2), 6.80 (s, 3H, phenyl-H)
149.0 149.1 (phenyl-C), 156.8 (d, J = 9, C-
5), 162.5 (d, J = 234, C-3)
5.16 (s, 2H, CH2), 7.17–7.20 (m, 2H, H- 50.6 (CH2), 120.7, 127.9, 128.5, 128.9, –111.7
304, 306
[M+H]+
phenyl), 7.30–7.40 (m, 7H, H-phenyl)
129.8 131.3, 134.5, 151.6 (C-phenyl),
154.2 (d, J = 9, C-5), 162.4 (d, J = 237, C-
3)
2.32 (s, 3H, CH3-phenyl), 3.80, 3.85 (2s, 21.0 (CH3-phenyl), 52.8 (CH2), 55.7, 55.8 –113.9
6H, 2 CH3-O), 5.19 (s, 2H, CH2-N), 6.87– (2 CH3-O), 111.0, 111.1, 120.7, 125.5,
6.76 (m, 3H, H-phenyl), 7.15–7.12 (m, 126.8, 130.3, 132.3, 139.4, 149.1
2H, H-phenyl), 7.35–7.32 (m, 2H, H-phe- (phenyl), 149.5 (d, J = 8, C-5), 166.1 (d, J
360 [M+H]+
151 (100)
nyl)
= 236, C-3)
13
3.87, 3.89 (2s, 2 × 3H, 2 CH3-O), 5.13 (s, 54.0 (CH2), 55.8 (2 CH3-O), 111.3, 111.4, –116.1
2H, CH2), 6.80–6.89 (m, 3H, phenyl), 121.0, 125.7, 142.1, 142.2 (C-phenyl),
238 [M+H]+
151 (100)
7.71 (s, 1H, H-C-5)
149.4 (d, J = 11, C-5), 165.9 (J = 235, C-3)
14
15
16
2.66 (s, 3H, CH3-S), 3.67 (s, 3H, CH3-N)
15.2 (CH3-S), 35.2 (CH3-N), 152.9 (d, J = –116.4
8, C-5), 165.7 (d, J = 235, C-3)
148 [M+H]+
180 [M+H]+
260 [M+H]+
3.40 (s, 3H, CH3-N), 4.13 (s, 3H, CH3-S)
38.2 (CH3-N), 42.6 (CH3-S), 149.7 (d, J = –114.6
6, C-5), 163.9 (d, J = 242, C-3)
1.32 (t, J = 8, 6H, OCH2CH3), 3.80 (s, 3H, 13.7 (OCH2CH3), 36.7 (CH3-N), 51.1 –117.7
CH3-N), 4.25–4.35 (m, 4H, OCH2), 5.01 (OCH2CH3), 62.9 [C(COOEt)2], 146.7 (d,
[s, 1H, HC(COOEt)2]
J = 8, C-5), 164.2 (C=O), 165.2 (d, J =
234, C-3)
a Bruker 400 DRX.
b No correlation in HMBC (heteronuclear multiple bond correlation).8
c Important correlation in HMBC.
d In DMSO.
e Satisfactory elemental analysis obtained: C ± 0.34; H ± 0.19; N ± 0.24; F ± 0.34.

SYNTHESIS
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1360
tan crystals which were used without further purification. An analyt-
ically pure sample was prepared by recrystallization from propan-2-
ol, mp 114–115°C.
lation in a Kugelrohr apparatus (140°C/0.7 mbar) gave 8.79 g (73%)
9 as a colorless oil, which solidified on standing. Recrystallization
from propan-2-ol yielded an analytically pure sample, mp 61–62°C.
5-Bromo-3-fluoro-1-methyl-1H-[1,2,4]triazole (7a):
1-(3,4-Dimethoxybenzyl)-3-fluoro-5-methoxy-1H-[1,2,4]triazole
(10):
NaH (55% in mineral oil, 4.84 g, 0.111 mol) was washed with hexane.
DMF (50 mL) was added and a solution of 5 (18.5 g, 0.111 mol) in
DMF (50 mL) was added dropwise under cooling in an ice bath (in-
ternal temperature <30°C). After the addition stirring was continued
for 30 min in the ice bath. MeI (28 g, 0.20 mol, 8.8 mL) in DMF
(60 mL) was added dropwise and the resulting mixture was stirred at
23°C for 12 h. The mixture was poured into water (700 mL) and ex-
tracted with EtOAc (5 × 100 mL). The combined extracts were
washed with water (2 × 1 L), dried (MgSO4), filtered and concentrat-
ed. GC: 15% 6a (5.25 min), 69% 7a (5.08 min). The residue was tak-
en up in MeCN (250 mL), ethane-1,2-dithiol (20 mL) and Et3N (1.7 g,
17 mmol, 2.4 mL) were added and the mixture was stirred at 23°C for
30 min. A GC trace showed no peak at 5.25 min (corresponding to
6a). The solution was diluted with Et2O (200 mL), washed with 2.5 N
NaOH (3 × 100 mL) and brine (100 mL), dried (MgSO4), filtered and
concentrated. Sublimation of the residue in a Kugelrohr apparatus
(90°C/27 mbar) gave 9.18 g (46%) 7a as colorless crystals. An ana-
lytically pure sample was obtained by recrystallization from CH2Cl2/
hexane, mp 41–42°C.
NaH (55% in mineral oil, 306 mg, 7.00 mmol) was suspended in
DMF (10 mL) and treated with MeOH (230 mg, 7.0 mmol, 0.29 mL).
After the gas evolution ceased 7c (2.00 g, 6.33 mmol) was added in
one portion. An exothermic reaction occurred. After stirring at 23°C
for 1 h the mixture was poured into water (120 mL) and extracted with
EtOAc (5 × 30 mL). The combined extracts were washed with water
(2 × 200 mL), dried (MgSO4), filtered and concentrated. The crude
product was crystallized from EtOAc/hexane to give 1.16g (69%) 10
as almost colorless needles, mp 73–74°C.
1-Benzyl-5-(4-chlorophenoxy)-3-fluoro-1H-[1,2,4]triazole (11):
A solution of 7b (1.00 g, 3.91 mmol) and 4-chlorophenol (528 mg,
4.10 mmol) in DMF (10 mL) was treated with solid K2CO3 (1.10 g,
8.00 mmol) and stirred at 80°C for 24 h. The mixture was cooled,
diluted with Et2O (100 mL), washed with 2.5 N NaOH (50 mL) and
water (200 mL), dried and concentrated to give crude 11, which so-
lidified on standing and was recrystallized from propan-2-ol (2 mL).
Yield: 0.92 g (77%), mp 57–58°C.
1-Benzyl-5-bromo-3-fluoro-1H-[1,2,4]triazole (7b):
Crude 7b was prepared as described for 7a from NaH (55% in mineral
oil, 10.9 g, 0.250 mol), 5 (41.5 g, 0.250 mol) and benzyl
methanesulfonate12 (55.8 g, 0.300 mol). GC: 24% 4 (6.38 min), 57%
7b (6.22 min). Purification of 7b was achieved by treating the crude
product with Et3N (13 g, 0.13 mol, 18 mL) and ethane-1,2-dithiol
(6.1 g, 65 mmol, 56 mL) as described for 7a. Distillation of the crude
product in a Kugelrohr apparatus (130°C/0.7 mbar) gave 39.6 g
(62%) 7b as colorless crystals. Recrystallization from propan-2-ol
gave an analytically pure sample, mp 60–61°C.
1-(3,4-Dimethoxybenzyl)-3-fluoro-5-(p-tolylsulfanyl)-1H-
[1,2,4]triazole (12):
A solution of 7c (5.00 g, 15.8 mmol) and 4-methylthiophenol (1.94 g,
16.0 mmol) in DMF (100 mL) was treated with solid K2CO3 (4.14 g,
30.0 mmol) and stirred at 23°C for 12 h. After a workup as described
for 10 the crude product was chromatographed (silica, hexane/EtOAc
75:25) to give 5.28 g (93%) 12 as a colorless liquid, which crystal-
lized on standing. An analytically pure sample was obtained by re-
crystallization from propan-2-ol, mp 63–64°C.
5-Bromo-1-(3,4-dimethoxybenzyl)-3-fluoro-1H-[1,2,4]triazole
(7c):
1-(3,4-Dimethoxybenzyl)-3-fluoro-1H-[1,2,4]triazole (13):10
NiCl2•6 H2O (17.2 g, 73.5 mmol) and 12 (3.85 g, 10.7 mmol) were
dissolved in MeOH (240 mL) and THF (78 mL) and the solution was
stirred in an open flask in an ice bath. NaBH4 in pellets (8.40 g,
0.220 mmol) was added in small portions. A black precipitate formed
immediately with vigorous gas evolution. Stirring was continued for
15 min in the ice bath and for 1 h at 23°C, the mixture was filtered
through Celite and evaporated to dryness. The residue was taken up
in water (100 mL) and extracted with CH2Cl2 (3 × 25 mL). The ex-
tracts were dried (MgSO4), filtered and concentrated. Chromatogra-
phy on silica (EtOAc/hexane 4:6) gave 1.05 g (41%) 13 as a colorless
oil.
A solution of (3,4-dimethoxyphenyl)methanol (50.5 g, 0.300 mol) in
Et2O (500 mL) was stirred in an ice bath under N2. PBr3 (30.0 g,
0.110 mol) was added dropwise and the mixture was stirred 1 h in the
ice bath and 1 h at 23°C, then poured onto ice (100 g). The organic
phase was washed with water (100 mL), dried (MgSO4), filtered and
concentrated. The resulting 4-bromomethyl-1,2-dimethoxybenzene,
a colorless oil (65.7 g, 95%), was used without purification. Crude 7c
was prepared as described for 7a from NaH (55% in mineral oil,
7.00 g, 0.160 mol), 5 (26.3 g, 0.158 mol) and crude 4-bromomethyl-
1,2-dimethoxybenzene (45.2 g, 0.196 mol) to give 56.5 g (113%)
crude product, GC: 17.5% 6c (14.68 min), 54.3% 7c (14.55 min). Pu-
rification of 7c was achieved by treating the crude product with Et3N
(3.2 g, 32 mmol, 4.4 mL) and ethane-1,2-dithiol (20 mL) in MeCN
(250 mL) for 1h at 23°C and workup as described for 7a. The crude
product was dissolved in CH2Cl2 (50 mL) and applied to a silica gel
column (17 × 5 cm). The column was eluted with hexane/EtOAc
(85:15) and all fractions containing 7c were collected and concentrat-
ed. Crystallization from EtOAc/hexane gave a first crop of 7c; a sec-
ond crop was obtained by crystallization of the mother liquor from
propan-2-ol. Yield: 24.4 g (51%). An analytically pure sample was
obtained by recrystallization from propan-2-ol, mp 65–67°C.
3-Fluoro-1-methyl-5-methylsulfanyl-1H-[1,2,4]triazole (14):
To 7a (2.00 g, 11.1 mmol) in DMF (25 mL) was added NaSMe
(1.00 g, 14.3 mmol) in one portion. An exothermic reaction occurred.
After stirring for 1h the reaction was worked up as described for 10.
The crude product was distilled in a Kugelrohr apparatus (110°C/
27 mbar) to give 1.09 g (67%) 14 as a colorless liquid.
3-Fluoro-1-methyl-5-methylsufonyl-1H-[1,2,4]triazole (15):
A solution of 14 (1.00 g, 6.8 mmol) in CH2Cl2 (20 mL) was treated
with MCPBA (4.10 g, 13.6 mmol, assuming 57% content) and the
mixture was stirred at 23°C for 12 h. It was then diluted with EtOAc
(100 mL) and washed with 10% aq Na2S2O4 (2 × 50 mL), sat. aq
NaHCO3 (3 × 50 mL) and brine (50 mL), dried (MgSO4), filtered and
concentrated. The crude product was dissolved in propan-2-ol
(75 mL) and slowly concentrated in a rotary evaporator (bath at
35°C) to ca. 10 mL and then kept at 23°C for 18 h to give 0.89g (73%)
15 as colorless crystals, mp 52–53°C.
1-(3,4-Dimethoxybenzyl)-3,5-difluoro-1H-[1,2,4]triazole (9):
A mixture of 7c (15.0 g, 47.5 mmol), DMSO (30 mL) and CsF
(25.0 g, 0.165 mol) was stirred intensely by means of an overhead
stirrer for 2 h at 120°C. The mixture was cooled, diluted with EtOAc
(100 mL), poured onto ice (250 g) and extracted with EtOAc (3 × 100
mL). The combined extracts were washed with water (2 × 250 mL)
and brine (100 mL), dried (MgSO4), filtered and concentrated. Distil-

SYNTHESIS
September 1998
1361
Diethyl 2-(3-Fluoro-1-methyl-1H-[1,2,4]triazol-5-yl)malonic acid
(16):
(6) Kobayashi, Y.; Kumadaki, I.; Ohsawa, A.; Murakani, J.
J. Chem. Soc., Chem. Comm. 1976, 430.
NaH (55% in mineral oil, 0.240 g, 5.50 mmol) was washed with hex-
ane. DMF (5 mL) was added. Diethyl malonate (0.88 g, 5.5 mmol,
0.840 mL) in DMF (5 mL) was added dropwise at 23°C and the mix-
ture was stirred for 1h. Sulfone 15 (0.440 g, 2.51 mmol) was added in
one portion and the mixture stirred at 60°C for 24 h. It was poured
into 0.5 N HCl (100mL) and extracted with EtOAc (5 × 20 mL). The
combined extracts were washed with water (2 × 150 mL), dried
(MgSO4), filtered and concentrated. The crude product was chro-
matographed (silica, hexane/EtOAc 75:25) to give 0.380 g (58%) 16
as a colorless oil.
Barton, A.; Breukelman, S. P.; Kaye, P. T.; Meakins, G. D.;
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