Efficient synthesis of 5-fluoroalkylated 1H-1,2,3-triazoles and application of the bromodifluoromethylated triazole to the synthesis of novel bicyclic gem-difluorinated 1H-pyrano[3,4-d][1,2,3]-triazol-4-one compounds

Article abstract of DOI:10.1016/S0040-4020(03)00621-5

A series of 5-fluoroalkylated 1H-1,2,3-triazoles were synthesized in good yield by the regiospecific 1,3-dipolar cycloaddition reaction of (Z)-ethyl 3-fluoroalkyl-3-pyrrolidino-acrylates with aryl or benzyl azides. In the cases of benzyl azides, addition

Full text of DOI:10.1016/S0040-4020(03)00621-5

Tetrahedron 59 (2003) 4395–4404
Efficient synthesis of 5-fluoroalkylated 1H-1,2,3-triazoles and
application of the bromodifluoromethylated triazole to the
synthesis of novel bicyclic gem-difluorinated
1H-pyrano[3,4-d][1,2,3]-triazol-4-one compounds
*
Weimin Peng and Shizheng Zhu
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received 2 January 2003; revised 18 March 2003; accepted 10 April 2003
Abstract—A series of 5-fluoroalkylated 1H-1,2,3-triazoles were synthesized in good yield by the regiospecific 1,3-dipolar cycloaddition
reaction of (Z)-ethyl 3-fluoroalkyl-3-pyrrolidino-acrylates with aryl or benzyl azides. In the cases of benzyl azides, addition of Na2CO3 was
crucial for a high yield of the triazoles. Tetrakis(dimethylamino)ethylene (TDAE) promoted reaction of bromodifluoro-methylated triazole
with aldehydes affording a new class of b,b-difluoro-b-triazolyl alcohol derivatives, which were lactonized with catalytic amount of
p-toluenesulfonic acid in toluene at 80–908C to give a series of novel bicyclic gem-difluorinated 1H-pyrano[3,4-d][1,2,3]-triazol-4-one
compounds in good yield. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
group (LG) at one side of the double bond (Fig. 2b).11 We
had interest in the synthesis of fluorine-containing 1H-1,2,3-
triazoles and gem-difluorinated benzotriazole analogues
since fluorine in those compounds might impart profound
influences on their chemical, physical and biological
properties.12 Although several trifluoromethylated starting
materials have been reported to react with phenyl or benzyl
azides,13 there are no general methods to the synthesis of
fluoroalkylated 1H-1,2,3-triazoles, especially the halogeno-
difluoromethylated 1H-1,2,3-triazoles. In an earlier report,14
we demonstrated the facile synthesis of (Z)-ethyl 3-fluoro-
alkyl-3-pyrrolidino-acrylate and its reaction with nitrile
oxide to prepare a series of 5-fluoroalkyl substituted
isoxazoles in high yield. Herein, we wish to report its
regiospecific reaction with aryl azide and benzyl azide in the
synthesis of 5-fluoroalkyl 1H-1,2,3-triazoles, especially the
halogeno-difluoromethylated 1H-1,2,3-triazoles, under
the thermal and solvent free condition which is very
amiable to the environment and highly economic. There
has been an increasing interest in the synthesis of new gem-
difluorinated compounds in view of the potential biological
properties of such molecules.15 For the anticipation of the
high reactivity of the resulting halogeno-difluoromethylated
1H-1,2,3-triazole in the single electron transfer (SET)
reaction,16 we further employed them in reactions with
aldehydes, using tetrakis(dimethylamino)ethylene (TDAE)
as SET reaction initiator, to prepare a new class of b,b-
difluoro-b-triazolyl alcohol derivatives. The hydroxy group
of these alcohols was readily lactonized with the ester group
attached at 4-position of triazole cycle by treatment with
catalytic amount of p-toluenesulfonic acid in toluene at
80–908C, to give a series of novel benzotriazole analogues
Up to now, no natural products containing 1H-1,2,3-triazole
heterocycle moiety have been isolated because it is difficult
for biochemical systems to produce molecules with three
vicinal nitrogen atoms in a cyclic arrangement.1 However,
the multifunctional 1H-1,2,3-triazoles and benzotriazoles
(Fig. 1) have found numerous applications2 in organic
synthesis,3 as well as in medicine and industry as
biologically active systems,4 dyestuffs5 and fluorescent
compounds,6 corrosion inhibitors,7 photostabilizers8 and
agrochemicals.9
One of the two well established approaches to 1H-1,2,3-
triazoles is through the 1,3-dipolar cycloaddition reaction of
a wide variety of organic azides with acetylenic compound
(Fig. 2a),1,2which are poorly or moderately regioselective,
and two regioisomers are normally obtained.10 By contrast,
another powerful methodology is through the regioselective
reaction of azides with ‘push–pull’ alkenes with a leaving
Figure 1.
Keywords: acrylates; 1,3-dipolar cycloaddition; fluoroalkylated 1H-1,2,3-
triazole; tetrakis-(dimethylamino)ethylene; gem-difluorinated compounds.
*
Corresponding author. Tel.: þ86-21-64163300-3525; fax: þ86-21-
64166128; e-mail: zhusz@pub.sioc.ac.cn
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00621-5

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W. Peng, S. Zhu / Tetrahedron 59 (2003) 4395–4404
Figure 2. The synthetic strategy of 1H-1,2,3-triazoles.
Scheme 1.
withdrawing nature of long chain fluoroalkyl group (ClCF2-
CF2CF2–),17 the yield was not diminished.
Table 1. Synthesis of 1-aryl-5-fluoroalkyl-1H-1,2,3-triazoles 3
Entry Acrylate Azide Temperature (8C) Time (d) Product (%)a
The economically and environmentally benign solvent free
conditions, which could also raise reaction rate vigor-
ously,18 were crucial for the efficiency of the synthesis.
When tried in refluxing benzene, chloroform and carbon
tetrachloride, this reaction did not occur, but the acrylate
became partially hydrated as shown by 19F NMR
spectroscopy and TLC analysis of the reaction mixture
(Scheme 2).19 When tried in toluene and p-oxylene, the
formation of triazole could be detected, however the
reaction was too slow and the acrylate hydrated vigorous.
By contrast, the reaction under heating without solvent was
1
2
3
4
5
6
7
8
1a
1b
1c
1a
1a
1c
1c
1d
2a
2a
2a
2b
2c
2b
2c
2a
78
78
78
78
86
78
78
78
2
2.5
2
2
1.5
1
3aa (84)
3ba (79)
3ca (76)
3ab (79)
3ac (97)
3cb (66)
3cc (89)
3da (92)
1.5
9
a
Isolated yield.
Scheme 2.
and gem-difluorinated bicyclic 1H-pyrano[3,4-d][1,2,3]-
triazol-4-one compounds.
2. Results and discussion
2.1. Preparation of 5-fluoroalkylated 1H-1,2,3-triazoles
2.1.1. Through the reaction of acrylate 1 with aryl azide
2. The synthesis of 1-arylated 5-fluoroalkyl-1H-1,2,3-
triazole was achieved by a very simple procedure. After
heating a mixture of (Z)-ethyl 3-fluoroalkyl-3-pyrrolidino-
acrylate 1 and excess aryl azides 2 at 808C for 2–3 days, the
TLC analysis and 19F NMR spectroscopy showed that the
acrylate had converted completely, flash chromatography of
the reaction mixture afforded the expected 1H-1,2,3-
triazoles 3 in high yield (Scheme 1 and Table 1). Although
the reaction of acrylate 1d with phenyl azide 2a (Table 1,
entry 8) needed prolonged heating time (more than one
week) due to the steric hindrance and the greater electron-
Figure 3. Molecular structure of compound 3ac.

W. Peng, S. Zhu / Tetrahedron 59 (2003) 4395–4404
4397
2.1.2. Through the reaction of acrylate 1 with benzyl
azide 4. Compared to its reaction with aryl azides, there
were some differences in the reaction of fluoroalkylated
acrylate 1 with benzyl azide 4: (1) addition of 1–2
equimolar Na2CO3 was necessary for a high yield of the
triazole (Scheme 3). About half of the acrylate hydrated and
some unknown by-products appeared in the absence of
Na2CO3; (2) higher temperature for thermolysis was needed
to raise the reaction rate (90–1008C); (3) reaction time
doubled albeit under this more forcing conditions. The
results of reaction of benzyl azide 4 with acrylate 1 are
summarized in Table 2.
Scheme 3.
Table 2. Synthesis of 1-benzyl-5-fluoroalkylated 1H-1,2,3-triazoles 5
Entry Acrylate Azide Temperature (8C) Time (d) Product (%)a
The reaction of acrylate 1b with benzyl azide 4a gave the
expected 5-bromodifluoromethylated triazole 5ba in low
yield (Table 2, entry 5) along with a defluorinated product 6
in 50% yield (Scheme 4). A pyrrolidine anion promoted
defluorination mechanism is proposed to explain the
formation of the defluorination products. Substantial
amount of pyrrolidine is producing during the formation
of the triazole, under the effect of Na2CO3, a pyrrolidine
anion could acted as a single electron donor to transfer an
electron to the bromodifluoromethyl group of the inter-
mediated triazoline B, because bromodifluoromethyl is a
better single electron acceptor than other fluoroalkyl
groups.22 The triazoline intermediate successively loss a
bromide anion, difluoromethene carbene, and b-hydrogen to
give the unexpected defluorination triazole 6.23
1
2
3
4
5
1a
1a
1c
1a
1b
4a
4b
4a
4c
4a
90
90
4
5
3
10
5
5aa (88)
5ab (88)
5ca (85)
5ac (66)
5ba (32)c
95
Toluene/refluxb
85
a
Isolated yield.
b
Using toluene as solvent, due to reaction mixture solidifying during
heating without solvent.
Yield was low due to defluorination.
c
smooth and no hydrolysis of the acrylates was detected.
Furthermore, it was found that this reaction was regio-
specific without the formation of 4-fluoroalkylated regio-
isomer. The regiochemistry obtained was unambiguously
confirmed by the X-ray diffraction of triazole 3ac, showing
the fluoroalkyl group at the triazole 5-position (Fig. 3). It
was noteworthy that pyrrolidino group plays two important
roles in the course of the reaction: (1) acting as a electron-
donating group (EDG) to completely control the regio-
selectivity in the initial 1,3-dipolar cycloaddition reaction of
the acrylate with azide;20 (2) acting as a leaving group (LG)
to prevent the triazoline intermediate from decomposing, by
ready extrusion of pyrrolidine.21
Due to the fact that Na2CO3 was unnecessary in the reaction
of aryl azides 2 with acrylates 1, the mechanism shown in
Scheme 5 was proposed to explain the function of Na2CO3.
Through heating, some of the acrylate could react with both
benzyl and aryl azide to give the expected corresponding
triazoles 3 and 5. However, some of acrylate hydrated to
produce A (shown in Schemes 2 and 5) in both cases.
Scheme 4.
Scheme 5.

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W. Peng, S. Zhu / Tetrahedron 59 (2003) 4395–4404
Scheme 6.
Table 3. The reaction of triazole 3ba with aldehydes 7
Entry
Aldehyde
Time at 258C (h)
Time at room temperature (h)
Product (%)a
1
2
3
4
5
7a R¼Ph
1
3
2
3
2
17
6
5
13
7
8a (68)b
8b (55)b
8c (62)
8d (65)
8e (28)c
7b R¼4-ClC6H4–
7c R¼4-MeOC6H4–
7d R¼trans-CH3CHvCH–
7e R¼PhCH2CH2–
a
Isolated yield.
The further dehydrofluorinated products 9a and 9b (Scheme 7) were also obtained in 13 and 18% yield, respectively.
The reaction was not clean, although the product was obtained in poor yield.
b
c
Scheme 7.
Because aryl azide is more reactive than benzyl azide, it
could react directly with hydration product A to afford the
triazoles 3, while the benzyl azide only reacts with anion
intermediate C, produced from the reaction of A and
Na2CO3, to give the expected triazole 5 (Scheme 5).24
alcohol derivatives in satisfactory yield, along with an
amount of the reduced product formed by protonation of the
difluoromethyl anion (shown in Scheme 6). The reaction
results and a plausible reaction mechanism are shown in
Table 3 and Scheme 6, respectively.
2.2. Preparation of the b,b-difluoro-b-triazolyl alcohol
derivatives
The reaction with aromatic and a,b unsaturated aldehydes
generally afforded the expected gem-difluorinated alcohol
derivatives in satisfactory yield (Table 3, entries 1–4).
However, the reaction with 1-phenyl-propaldehyde was not
clean, the alcohol 8e was obtained in poor yield (Table 3,
entry 5) possibly due to the enolizable potential of this
aldehyde. The chlorodifluoromethyl substituted triazole 3aa
was inert to TDAE under the same reaction conditions,
which might be attributed to the higher reduction potential
of chlorodifluoromethyl. Raising reaction temperature was
not effective, only a small amount of the substrate reacted
and only trace product was detected by TLC analysis after
heating for 8 h at 908C. It was noteworthy that in addition to
the desired difluorinated alcohols 8a and 8b, their further
TDAE mediated dehydrofluorination products 9a and 9b
It is well known that halogeno-difluoromethyl, especially
bromodifluoromethyl, is an excellent electron acceptor in
the SET reaction and the formed difluoromethyl anion is
strongly nuleophilic to aldehydes and other electrophiles.25
With the halogeno-difluoromethylated triazoles in hand, we
explored their reactions with aldehydes promoted by SET
initiators. It was found that the procedure developed by
Dolbier Jr. et al. using tetrakis(dimethylamino)ethylene
(TDAE) as initiator could be successfully applied to our
system.26 In the presence of TDAE, the bromodifluoro-
methyl triazole 3ba reacted with aldehyde in DMF at 258C
to room temperature to give the b,b-difluoro-b-triazolylated

W. Peng, S. Zhu / Tetrahedron 59 (2003) 4395–4404
4399
Table 4. Synthesis of the bicyclic gem-difluorinated 1H-pyrano[3,4-d]-
[1,2,3]-triazol- 4-one compounds 10
references.28 The preparation of (Z)-ethyl 3-fluoroalkyl-3-
pyrrolidino-acrylate 1 was previously reported in this
journal.14 IR spectra were obtained with a Perkin-Elmer
983G spectro-photometer on KBr disks. NMR spectra were
recorded either on Varian-360L, or Bruker AM-300
spectrometer with CDCl3 as solvent, unless otherwise
1
stated. The H NMR chemical shifts are reported in parts
per million (ppm, d) downfield from internal standard
tetramethylsilane (TMS). In 19F NMR spectra, upfield shifts
from external standards (CFCl3) are quoted as negative.
Coupling constants are given in Hertz (Hz). Spectra splitting
patterns are designated as s, singlet; br, broad; d, doublet; t,
triplet; q, quartet; m, multiplet. Mass spectra were taken on a
HP 5989a spectrometer, and accurate mass measurements
were performed on Finngan MAT instrument, while
elemental analyses were performed by this institute. TLC
analysis was performed on silica gel plate and column
chromatography over silica gel (30–40 mm), which were
both obtained from Qingdao Ocean Chemicals.
Entry
Alcohol
Reaction time
Product (%)a
1
2
3
4
5
8a R¼Ph–
72h
5d
72h
5d
10a (68)
10b (68)
10c (41)
10d (94)
10e (87)
8b R¼4-ClC6H4–
8c R¼4-MeOC6H4–
8d R¼trans-CH3CHvCH–
8e R¼Ph(CH2)2–
4d
a
Isolated yield.
(Scheme 7) were also obtained in 13 and 18% yield (Table 3,
entries 1 and 2), respectively. These two products were well
characterized by spectroscopy and macroanalysis.
4.2. Preparation of 5-fluoroalkylated 1H-1,2,3-triazoles 3
and 5 through the reaction of acrylate 1 with aryl azide 2
(general procedure)
2.3. Synthesis of the bicyclic gem-difluorinated 1H-
pyrano[3,4-d][1,2,3]-triazol-4-one compounds
Cyclization of b,b-difluoro-b-triazolylated alcohol deriva-
tives 8 could be smoothly achieved by simple treatment of
the alcohol with catalytic p-toluenesulfonic acid in toluene
at 858C.27 After 3–5 days heating, evaporation of solvent
under reduced pressure followed by flash chromatography
afforded the gem-difluorinated 1H-pyrano[3,4-d][1,2,3]-
triazol-4-one compounds in good yield (Table 4), except
alcohol 8c (R¼4-MeOC6H4–) which gave the compound
10c in moderate yield. We anticipated that these gem-
difluorinated benzotriazole analogous compounds poten-
tially might have biological activities. The work to evaluate
their bioactivity is now in progress and will be reported in
due course.
(Z)-Ethyl 3-fluoroalkyl-3-pyrrolidino-acrylate 1 (1 mmol)
was added to about 1 mL liquid aryl azide 2, the
mixture was heated at about 808C for the time specified in
Table 1 to convert the acrylate 1 completely. Then
without work-up, direct flash chromatography of
the reaction mixture using n-hexane/EtOAc as eluent gave
5-fluoroalkylated 1H-1,2,3-triazoles 3, in addition to
recovery of excess aryl azide.
4.2.1. 5-Chlorodifluoromethyl-1-phenyl-1H-1,2,3-tria-
zole-4-carboxylic acid ethyl ester (3aa). Through the
general procedure starting from acrylate 1a and phenyl
azide 2a, flash chromatography using n-hexane/EtOAc
(20:1 followed by 10:1) as eluent afforded triazole 3aa
(253 mg, 84%) as a yellow solid, mp 69.5–70.58C. [Found:
C, 47.80; H, 3.35; N, 14.24. C12H10ClF2N3O2 requires C,
47.78; H, 3.34; N, 13.93%]; nmax (film) 2982, 1723, 1593,
1560, 1497, 1375, 1296, 1254, 1238, 1153, 1094, 1058,
1008, 906, 771 cm21; dH (60 MHz, CDCl3) 1.47 (3H, t,
J¼7.0 Hz, OCH2CH3), 4.52 (2H, q, J¼7.0 Hz, OCH2CH3),
7.34–7.74 (5H, m, Ph); dF (56.4 MHz, CDCl3) 244.5; m/z
(EI) 302/304 (10/3, Mþþ1), 256/258 (12/4), 245/247 (10/3),
189 (42), 170 (33), 144 (19), 77 (100%, Phþ).
3. Conclusions
A general and efficient procedure to synthesize the
5-fluoroalkylated (especially the halogeno-difluoromethyl-
ated) 1H-1,2,3-triazoles by the regiospecific 1,3-dipolar
cycloaddition reaction of (Z)-ethyl 3-fluoroalkyl-3-pyrroli-
dino-acrylate with organic azides was described. Via the
further reaction of the bromodifluomethylated triazoles with
aldehydes, mediated by TDAE, a new class of b,b-difluoro-
b-triazolylated alcohol derivatives were conveniently
prepared. These alcohols were smoothly cyclized by
treatment with catalytic p-TsOH in toluene, to give the
novel gem-difluorinated bicyclic 1H-pyrano[3,4-d][1,2,3]-
triazol-4-one compounds in good to excellent yields.
4.2.2. 5-Bromodifluoromethyl-1-phenyl-1H-1,2,3-tria-
zole-4-carboxylic acid ethyl ester (3ba). Through the
general procedure starting from acrylate 1b and phenyl
azide 2a, flash chromatography using n-hexane/EtOAc
(20:1 followed by 10:1) as eluent afforded triazole 3ba
(273 mg, 79%) as a pale yellow solid, mp 72.5–73.08C.
[Found: C, 41.73; H, 3.05; N, 12.15. C12H10BrF2N3O2
requires C, 41.64; H, 2.91; N, 12.14%]; nmax (film) 2982,
1722, 1592, 1559, 1497, 1253, 1229, 1153, 1055, 1019,
1007, 930, 770 cm21; dH (60 MHz, CDCl3) 1.49 (3H, t,
J¼7.0 Hz, OCH2CH3), 4.50 (2H, q, J¼7.0 Hz, OCH2CH3),
7.38–7.76 (5H, m, Ph). dF (56.4 MHz, CDCl3) 241.3; m/z
(EI) 346/348 (30/28, Mþ), 300/302 (10/10), 266 (4), 244/
246 (24/23), 222/224 (6/5), 190 (30), 170 (54), 77 (100%,
Phþ).
4. Experimental
4.1. General methods
Unless otherwise noted, solvents and reagents were
commercial available and used as received. DMF was
distillated from calcium hydride, and toluene from P2O5. All
the aryl and benzyl azides were prepared according to the

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W. Peng, S. Zhu / Tetrahedron 59 (2003) 4395–4404
4.2.3. 5-Trifluoromethyl-1-phenyl-1H-1,2,3-triazole-4-
carboxylic acid ethyl ester (3ca). Through the general
procedure starting from acrylate 1c and phenyl azide 2a,
flash chromatography using n-hexane/EtOAc (20:1 fol-
lowed by 15:1) as eluent afforded triazole 3ca (216 mg,
76%) as a clear oil; nmax (film) 2984, 1738, 1594, 1558,
4.2.7. 5-Trifluoromethyl-1-(4-nitrophenyl)-1H-1,2,3-
triazole-4-carboxylic acid ethyl ester (3cc). Through the
general procedure starting from acrylate 1c and 4-nitro-
phenyl azide 2c, flash chromatography using n-hexane/
EtOAc (10:1 followed by 5:1) as eluent afforded triazole 3cc
(294 mg, 89%) as a yellow solid, mp 120.0–122.08C.
[Found: C, 43.57; H, 2.83; N, 17.12. C12H9F3N4O4 requires
C, 43.65; H, 2.75; N, 16.97%]; nmax (film) 3094, 2991, 1741,
1615, 1598, 1561, 1528, 1503, 1450, 1352, 1303, 1226,
1153, 1085, 856 cm21; dH (60 MHz, CDCl3) 1.49 (3H, t,
J¼7.2 Hz, OCH2CH), 4.55 (2H, q, J¼7.2 Hz, OCH2CH3),
7.77 (2H, B of AB-system, J¼8.7 Hz, ArH), 8.51 (2H, A of
AB-system, J¼8.7 Hz, ArH); dF (56.4 MHz, CDCl3) 253.8;
m/z (EI) 330 (14, Mþ), 302 (1), 285 (32), 257 (19), 234 (100,
Mþ2CF3–OEtþ2), 122 (26), 76 (36), 69 (7%).
1499, 1301, 1232, 1161, 1089, 1041, 1007, 797, 771 cm21
;
dH (60 MHz, CDCl3) 1.47 (3H, t, J¼7.5 Hz, OCH2CH3),
4.55 (2H, q, J¼7.5 Hz, OCH2CH3), 7.35–7.78 (5H, m, Ph);
dF (56.4 MHz, CDCl3) 254.5; m/z (EI) 286 (31, Mþþ1),
240 (18), 212 (21), 189 (100, Mþ2Ph–F), 185 (25), 165
(49), 77 (78), 69 (6), 51 (29%); HRMS (EI): Mþ, found
19
10
285.07683. C12H F3N3O2 requires 285.07251.
4.2.4. 5-Chlorodifluoromethyl-1-(4-methoxyphenyl)-1H-
1,2,3-triazole-4-carboxylic acid ethyl ester (3ab).
Through the general procedure starting from acrylate 1a
and 4-methoxyphenyl azide 2b, flash chromatography using
n-hexane/EtOAc (10:1 followed by 5:1) as eluent afforded
triazole 3ab (262 mg, 79%) as a brown oil. [Found: C,
47.19; H, 3.88; N, 12.63. C13H12ClF2N3O3 requires C,
47.07; H, 3.65; N, 12.67%]; nmax (film) 2938, 1736, 1607,
1589, 1514, 1456, 1305, 1176, 1114, 840, 792 cm21; dH
(60 MHz, CDCl3) 1.61 (3H, t, J¼7.0 Hz, OCH2CH3), 4.07
(3H, s, OMe), 4.67 (2H, q, J¼7.0 Hz, OCH2CH3), 7.21 (2H,
B of AB-system, J¼9.0 Hz, ArH), 7.58 (2H, A of AB-
system, J¼9.0 Hz, ArH); dF (56.4 MHz, CDCl3) 244.7; m/z
(EI) 332/334 (42/14, Mþ), 286/288 (13/5), 258/260 (21/8),
219 (100, Mþ2ClCF2–N2), 200 (80), 180 (26), 77 (16%).
4.2.8. 5-(3-Chloro-1,1,2,2,3,3-hexafluoropropyl)-1-phe-
nyl-1H-1,2,3-triazole-4-carboxylic acid ethyl ester
(3da). Through the general procedure starting from acrylate
1d and phenyl azide 2a, flash chromatography using
n-hexane/EtOAc (20:1 followed by 10:1) as eluent afforded
triazole 3da (369 mg, 92%) as a colorless oil. [Found: C,
42.07; H, 2.71; N, 10.68. C14H10ClF6N3O2 requires C,
41.86; H, 2.51; N, 10.46%]; nmax (film) 2984, 1739, 1593,
1541, 1496, 1374, 1297, 1223, 1192, 1153, 1219, 1085, 988,
774, 613 cm21; dH (60 MHz, CDCl3) 1.45 (3H, t, J¼7.0 Hz,
OCH2CH3), 4.50 (2H, q, J¼7.0 Hz, OCH2CH3), 7.87–8.11
(5H, m, Ph); dF (56.4 MHz, CDCl3) 2117.0 (2F, s), 2101.8
(2F, s), 266.5 (2F, s); m/z (EI) 401 (1, Mþ), 356/358 (5/1),
328/330 (5/1), 265 (6), 215 (6), 166 (88), 144 (23), 77
(100%, Phþ).
4.2.5. 5-Chlorodifluoromethyl-1-(4-nitrophenyl)-1H-
1,2,3-triazole-4-carboxylic acid ethyl ester (3ac).
Through the general procedure starting from acrylate 1a
and 4-nitrophenyl azide 2c, flash chromatography using
n-hexane/EtOAc (10:1 followed by 5:1) as eluent afforded
triazole 3ac (336 mg, 97%) as a pale white solid, mp 123.5–
125.08C. [Found: C, 41.78; H, 2.58; N, 16.37. C12H9ClF2-
N4O4 requires C, 41.58; H, 2.62; N, 16.16%]; nmax (film)
2997, 1732, 1611, 1596, 1524, 1500, 1350, 1250, 1221,
1049, 855, 790 cm21; dH (60 MHz, CDCl3) 1.48 (3H, t,
J¼7.0 Hz, OCH2CH3), 4.55 (2H, q, J¼7.0 Hz, OCH2CH3),
7.81 (2H, B of AB-system, J¼9.0 Hz, ArH), 7.99 (2H, A of
AB-system, J¼9.0 Hz, ArH); dF (56.4 MHz, CDCl3) 244.1;
m/z (EI) 346/348 (5/2, Mþ), 301/303 (19/6), 290/292
(69/23) 274/276 (5/3), 189 (79), 165 (40), 85/87 (57/33),
76 (100%, Phþ21).
4.3. Preparation of 5-fluoroalkylated 1H-1,2,3-triazoles 3
and 5 through the reaction of acrylate 1 with benzyl
azide 4 (general procedure)
Into a mixture of Na2CO3 (120 mg, 1.1 mmol) and about
1 mL benzyl azide 4, was added (Z) ethyl 3-fluoroalkyl-3-
pyrrolidino-acrylate 1 (1 mmol). The resultant mixture was
heated at about 908C for the time specified in Table 2 to
convert the acrylate 1 completely. The reaction mixture was
filtered, the solid was washed with CH2Cl2 (5 mL£3).
After removal of the solvent under reduced pressure,
the residue was purified by flash chromatography using
n-hexane/ EtOAc as eluent to give 5-fluoroalkylated
1H-1,2,3-triazoles 5, in addition to recovery of excess
benzyl azide 4.
4.2.6. 5-Trifluoromethyl-1-(4-methoxyphenyl)-1H-1,2,3-
triazole-4-carboxylic acid ethyl ester (3cb). Through the
general procedure starting from acrylate 1c and 4-methoxy-
phenyl azide 2b, flash chromatography using n-hexane/
EtOAc (10:1 followed by 4:1) as eluent afforded triazole
3cb (208 mg, 66%) as a pale white solid, mp 82.0–83.08C.
[Found: C, 49.52; H, 3.91; N, 13.45. C13H8F3N3O3 requires
C, 49.53; H, 3.84; N, 13.33%]; nmax (film) 2989, 1738, 1607,
1592, 1518, 1458, 1374, 1352, 1256, 1239, 1195, 1180,
1140, 1082, 1035, 837 cm21; dH (300 MHz, CDCl3) 1.48
(3H, t, J¼7.2 Hz, OCH2CH3), 3.93 (3H, s, OMe), 4.54 (2H,
q, J¼7.2 Hz, OCH2CH3), 7.08 (2H, B of AB-system,
J¼8.7 Hz, ArH), 7.41 (2H, A of AB-system, J¼8.7 Hz,
ArH); dF (56.4 MHz, CDCl3) 255.6; m/z (EI) 315 (29, Mþ),
242 (25), 219 (100, Mþ2OMe–OEt–F), 176 (13), 77 (16),
69 (7%).
4.3.1. 5-Chlorodifluoromethyl-1-benzyl-1H-1,2,3-tria-
zole-4-carboxylic acid ethyl ester (5aa). Through the
general procedure starting from acrylate 1a and benzyl
azide 4a, flash chromatography using n-hexane/EtOAc
(10:1 followed by 5:1) as eluent afforded triazole 5aa
(278 mg, 88%) as a slightly yellow solid, mp 58.0–59.58C.
[Found: C, 49.61; H, 3.67; N, 13.59. C13H12ClF2N3O2
requires C, 49.46; H, 3.83; N, 13.31%]; nmax (film) 2988,
1738, 1634, 1465, 1332, 1262, 1241, 1209, 1130, 1065,
1043, 921, 793, 731, 696 cm21; dH (60 MHz, CDCl3) 1.48
(3H, t, J¼7.2 Hz, OCH2CH3), 4.54 (2H, q, J¼7.2 Hz,
OCH2CH3), 5.80 (2H, s, CH2Ar), 7.10–7.59 (5H, m, Ph); dF
(56.4 MHz, CDCl3) 244.8; m/z (EI) 316/318 (5/1, Mþ),
286/288 (2/1), 270/272 (7/2), 258/260 (2/1), 243/245 (10/3),
214/216 (22/8), 91 (100%, PhCHþ2 ).

W. Peng, S. Zhu / Tetrahedron 59 (2003) 4395–4404
4401
4.3.2. 5-Chlorodifluoromethyl-1-[(4-methoxyphenyl)-
methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester
(5ab). Through the general procedure starting from acrylate
1a and 4-methoxybenzyl azide 4b, flash chromatography
using n-hexane/EtOAc (10:1 followed by 4:1) as eluent
afforded triazole 5ab (304 mg, 88%) as a slightly yellow oil.
[Found: C, 48.45; H, 4.06; N, 12.25. C14H14ClF2N3O3
requires C, 48.64; H, 4.08; N, 12.15%]; nmax (film) 2981,
2937, 2906, 1738, 1610, 1585, 1544, 1511, 1464, 1370,
1335, 1305, 1295, 1251, 1202, 1178, 1117, 1066, 1045,
845 cm21; dH (60 MHz, CDCl3) 1.48 (3H, t, J¼7.2 Hz,
OCH2CH3), 3.86 (3H, s, OMe), 4.55 (2H, q, J¼7.2 Hz,
OCH2CH3), 5.79 (2H, s, CH2Ar), 6.95 (2H, B of AB-
system, J¼8.1 Hz, ArH), 7.32 (2H, A of AB-system,
J¼8.1 Hz, ArH); dF (56.4 MHz, CDCl3) 245.8; m/z (EI)
345/347 (3/1, Mþ), 316 (1), 282 (1), 252 (1), 121 (100,
4-methoxy PhCHþ2 ), 91 (7), 77 (14%).
1042, 1015, 884, 790, 730 cm21; dH (300 MHz, CDCl3) d:
1.43 (3H, t, J¼7.2 Hz, OCH2CH3), 4.46 (2H, q, J¼7.2 Hz,
OCH2CH3), 5.76 (2H, s, CH2Ar), 7.24–7.38 (5H, m, Ph); dF
(282 MHz, CDCl3) 244.1; m/z (EI) 359/361 (1/1), 314/316
(2/2), 280 (8), 252 (5), 208 (34), 91 (100, PhCHþ2 ), 77 (3), 65
(15), 51 (3%); HMRS (EI): Mþ, found 359.01224. C13H
79
12
Br19F2N3O2 requires 359.00809. Subsequent chromato-
graphy using n-hexane/EtOAc (2:1) as eluent afforded the
defluorination product 6 (150 mg, 50%) as brown oil.
[Found: C, 64.25; H, 6.55; N, 18.19. C16H20N4O2 requires
C, 63.98; H, 6.71; N, 18.65%]; nmax (film) 3065, 3043, 2977,
2144, 1710, 1563, 1456, 1194, 1138, 1052, 847, 697 cm21
;
dH (300 MHz, CDCl3) 1.41 (3H, t, J¼6.9 Hz, OCH2CH3),
1.88–1.93 (4H, m, 2£NCH2CH2), 3.13–3.17 (4H, m,
2£NCH2CH2), 4.40 (2H, q, J¼6.9 Hz, OCH2CH3), 5.47
(2H, s, CH2Ar), 7.16–7.32 (5H, m, Ph); m/z (EI) 391 (42,
MþþBn), 301 (100, Mþþ1), 300 (9, Mþ), 299 (65, Mþ21),
271 (43), 255 (61), 243 (5), 227 (12), 209 (48), 200 (17), 186
(8), 158 (4), 135 (20), 91 (90%); HRMS (EI): Mþ, found
300.15869. C16H20N4O2 requires 300.15862.
4.3.3. 5-Trifluoromethyl-1-benzyl-1H-1,2,3-triazole-4-
carboxylic acid ethyl ester (5ca). Through the general
procedure starting from acrylate 1c and benzyl azide 4a,
flash chromatography using n-hexane/EtOAc (10:1 fol-
lowed by 7:1) as eluent afforded triazole 5ca (254 mg, 85%)
as a brown oil. [Found: C, 52.36; H, 4.20; N, 14.04.
C13H12F3N3O2 requires C, 52.18; H, 4.04; N, 14.04%]; nmax
(film) 2984, 1737, 1602, 1553, 1495, 1454, 1435, 1342,
1217, 1162, 1126, 751, 728, 694 cm21; dH (300 MHz,
CDCl3) 1.42 (3H, t, J¼7.2 Hz, OCH2CH3), 4.46 (2H, q,
J¼7.2 Hz, OCH2CH3), 5.77 (2H, s, CH2Ar), 7.22–7.37 (5H,
m, Ph); dF (282 MHz, CDCl3) 256.2; m/z (EI) 270 (1, Mþ),
254 (2), 242 (2), 222 (2), 198 (13), 91 (100, PhCHþ2 ), 77 (5).
4.4. Preparation of the b,b-difluoro-b-triazolyl alcohol
derivatives 8 (general procedure)
Into a solution of triazole 3ba (277 mg, 0.8 mmol) and
aldehyde 7 (4 mmol) in 8 mL anhydrous DMF, cooled at
ice-salt bath under nitrogen, was added TDAE (176 mg,
0.21 mL, 0.88 mmol) dropwise via a syringe over half an
hour. A red color immediately developed with the formation
of fine white precipitate. The mixture was further vigorously
stirred for the time specified in Table 3 under cooling, and
then warmed up to room temperature for the time specified
also in Table 3. The orange red turbid solution was filtered
and hydrolyzed with 8 mL saturated NH4Cl solution,
followed by extraction with ethyl acetate (3£20 mL). The
organic layer was washed with brine (30 mL), dried over
Na2SO4, and concentrated in vacuo to give a residue which
was purified by flash chromatograph using n-hexane/EtOAc
as eluent to give the expected gem-difluoronated alcohols 8
as white solids.
4.3.4. 5-Chlorodifluoromethyl-1-[(4-nitrophenyl)-
methyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester
(5ac). Into a solution of (Z) ethyl 3-chlorodifluoromethyl-3-
pyrrolidino-acrylate 1a (167 mg, 0.66 mmol) and 4-nitro-
benzyl azide 4c (800 mg, 4.5 mmol) in 10 mL toluene, was
added Na2CO3 (120 mg, 1.1 mmol), the mixture was
refluxed for 10 days. The reaction mixture was filtered,
and the filtrate was concentrated under reduced pressure.
Following flash chromatography using n-hexane/EtOAc
(5:1 followed by 2:1) as eluent afforded triazole 5ac
(156 mg, 0.44 mmol, 66%) as a slightly yellow solid, mp
113.5–115.08C. [Found: C, 43.23; H, 3.01; N, 15.81.
C13H11ClF2N4O4 requires C, 43.29; H, 3.07; N, 15.53%];
4.4.1. 5-(1,1-Difluoro-2-hydroxy-2-phenyl-ethyl)-1-phe-
nyl-1H-1,2,3-triazole-4-carboxylic acid ethyl ester (8a)
and 5-(1-fluoro-2-phenyl-2-oxo-ethyl)-1-phenyl-1H-
1,2,3-triazole-4-carboxylic acid ethyl ester (9a). Through
the general procedure starting from triazole 3ba and
benzaldehyde 7a (0.424 g, 4 mmol), flash chromatography
using n-hexane/EtOAc (3:1) as eluent firstly afforded
product 9a (37 mg, 13%) as a slightly brown heavy oil;
n
max (film) 2982, 1733, 1607, 1558, 1525, 1471, 1433, 1371,
;
1347, 1317, 1299, 1264, 1250, 1211, 1107, 847, 731 cm21
dH (60 MHz, CDCl3) 1.40 (3H, t, J¼7.2 Hz, OCH2CH3),
4.51 (2H, q, J¼7.2 Hz, OCH2CH3), 5.92 (2H, s, CH2Ar),
7.39 (2H, B of AB-system, J¼8.0 Hz, ArH), 8.17 (2H, A of
AB-system, J¼8.0 Hz, ArH); dF (56.4 MHz, CDCl3) 246.5;
m/z (EI) 331 (1), 315/317 (38/12), 297 (48), 288/290 (100/
34, Mþ2CO2Et), 136 (90), 91 (8), 78 (67%).
n
max (film) 3065, 2982, 2936, 1746, 1711, 1596, 1569, 1501,
1449, 1379, 1296, 1238, 1085, 1070, 1006, 850, 765,
692 cm21; dH (300 MHz, CDCl3) 1.45 (3H, t, J¼7.2 Hz,
OCH2CH3), 4.49–4.54 (2H, m), 7.27–7.69 (11H, m, ArH);
dF (282 MHz, CDCl3) 2177.6 (d, J¼45.1 Hz); m/z (EI) 353
(2, Mþ), 308 (3), 296 (1), 280 (1), 252 (3), 232 (2), 204 (2),
172 (3), 144 (5), 105 (100, PhCOþ), 77 (50); HRMS (EI):
Mþ, found 353.12097. C19H16FN3O3 requires 353.11757.
Then gave gem-difluorinated alcohol 8a (203 mg, 68%) as a
white powder, mp 146.0–148.08C. [Found: C, 61.41; H,
4.78; N, 10.97. C19H17F2N3O3 requires C, 61.12; H, 4.59; N,
11.25%]; nmax (film) 3445, 3065, 2984, 1778, 1717, 1595,
1546, 1497, 1249, 1231, 1170, 1077, 1014, 766, 738,
693 cm21; dH (300 MHz, CDCl3) 1.51 (3H, t, J¼7.2 Hz,
4.3.5. 5-Bromodifluoromethyl-1-benzyl-1H-1,2,3-tria-
zole-4-carboxylic acid ethyl ester (5ba) and 5-pyrroli-
dino-1-benzyl-1H-1,2,3-triazole-4-carboxylic acid ethyl
ester (6). Through the general procedure starting from
acrylate 1b and benzyl azide 4a, flash chromatography
using n-hexane/EtOAc (10:1 followed by 5:1) as eluent
firstly afforded 5-bromodifluoromethylated 1H-1,2,3-tria-
zole 5ba (115 mg, 32%) as a yellow solid, mp 62.0–63.08C;
n
max (film) 2991, 1736, 1564, 1467, 1334, 1263, 1210, 1128,

4402
W. Peng, S. Zhu / Tetrahedron 59 (2003) 4395–4404
OCH2CH3), 4.01 (1H, d, J¼3.9 Hz, OH), 4.55 (2H, q,
J¼7.2 Hz, OCH2CH3), 5.63 (1H, ddd, J¼12.7, 8.7, 3.9 Hz,
CHOH), 6.89–7.49 (10H, m, ArH); dF (282 MHz, CDCl3)
297.7 (1F, dd, J¼273.0, 8.7 Hz), 102.9 (1F, dd, J¼273.0,
12.7 Hz); m/z (EI) 373 (8, Mþ), 353 (15), 328 (1), 300 (3),
281 (1), 104 (25), 77 (100, Phþ), 51 (20%).
powder, mp 88.0–90.08C. [Found: C, 57.09; H, 5.16; N,
12.65. C16H F2N3O3 requires C, 56.97; H, 5.08; N,
19
17
12.46%]; nmax (film) 3359, 2997, 1737, 1726, 1679, 1596,
1560, 1500, 1444, 1377, 1351, 1277, 1263, 1224, 1189,
1133, 1081, 1022, 969, 850, 765, 692 cm21; dH (300 MHz,
CDCl3) 1.47 (3H, t, J¼7.2 Hz, OCH2CH3), 1.73 (3H, d,
J¼6.9 Hz, vCHCH3), 3.25 (1H, d, J¼6.0 Hz, OH), 4.50
(2H, q, J¼7.2 Hz, OCH2CH3), 4.93 (1H, dddd, J¼17.4, 6.0,
6.0, 5.7 Hz, CHOH), 5.45 (1H, dd, J¼15.3, 5.7 Hz,
vCHCHOH), 5.92 (1H, dq, J¼15.3, 6.9 Hz, vCHCH3),
7.47–7.58 (5H, m, Ph); dF (282 MHz, CDCl3) 294.5 (1F,
dd, J¼274.4, 6.0 Hz), 106.7 (1F, dd, J¼274.4, 17.4 Hz); m/z
(EI) 338 (34, Mþþ1), 292 (6), 265 (19), 166 (41), 104 (49),
77 (100, Phþ), 71 (27), 69 (18), 41 (22%).
4.4.2. 5-[1,1-Difluoro-2-hydroxy-2-(4-chlorophenyl)-
ethyl]-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid
ethyl ester (8b) and 5-[1-fluoro-2-(4-chlorophenyl)-2-
oxo-ethyl]-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid
ethyl ester (9b). Through the general procedure starting
from triazole 3ba and 4-chlorobenzaldehyde 7b (0.562 g,
4 mmol), flash chromatography using n-hexane/EtOAc (3:1
followed by 2:1) as eluent firstly afforded product 9b
(56 mg, 18%) as a slightly yellow heavy oil; nmax (film)
3067, 2982, 1741, 1713, 1588, 1500, 1401, 1379, 1247,
1218, 1091, 1014, 764, 693 cm21; dH (300 MHz, CDCl3)
1.46 (3H, t, J¼6.9 Hz, OCH2CH3), 4.47–4.55 (2H, m,
OCH2CH3), 7.27–7.70 (10H, m, ArH); dF (282 MHz,
CDCl3) 2176.9 (d, J¼45.1 Hz); m/z (EI) 387/389 (3/2,
Mþ), 342/344 (3/1), 286/288 (4/1), 249 (2), 220 (15), 192
4.4.5. 5-(1,1-Difluoro-2-hydroxy-4-phenyl-butyl)-1-phe-
nyl-1H-1,2,3-triazole-4-carboxylic acid ethyl ester (8e).
Through the general procedure starting from triazole 3ba
and 1-phenyl propanal 7e (0.54 g, 4 mmol), flash chroma-
tography using n-hexane/EtOAc (3:1) as eluent afforded the
gem-difluorinated alcohol 8e (90 mg, 28%) as a white
powder, mp 168.0–171.08C. [Found: C, 63.05; H, 5.40; N,
10.17. C21H21F2N3O3 requires C, 62.84; H, 5.27; N,
10.47%]; nmax (film) 3474, 3028, 2985, 2960, 1724, 1595,
1547, 1497, 1253, 1236, 1095, 1073, 1012, 764, 752, 703,
688 cm21; dH (300 MHz, CDCl3) 1.38 (3H, t, J¼7.2 Hz,
OCH2CH3), 1.63–2.05 (2H, m, CH2CH2CHOH), 2.71–
2.92 (2H, m, CH2CH2CHOH), 3.46 (1H, brs, OH), 4.34–
4.44 (3H, m, OCH2CH3 and CHOH), 7.18–7.56 (10H, m,
ArH); dF (282 MHz, CDCl3) 295.0 (1F, d, J¼274.7 Hz),
109.5 (1F, dd, J¼274.7, 20.1 Hz); m/z (EI) 402 (1, Mþþ1),
356 (22), 329 (21), 194 (18), 166 (38), 144 (23), 115 (12),
105 (28), 91 (100, PhCHþ2 ), 77 (82%).
(10), 139 (100, ClC6H4COþ), 111 (24), 77 (73%); HRMS
35
15
(EI): Mþ, found 387.07922. C19H ClFN3O3 requires
387.07859; Then gave gem-difluorinated alcohol 8b
(179 mg, 55%) as a white powder; mp 193.0–195.08C.
[Found: C, 55.97; H, 4.09; N, 10.21. C19H Cl19F2N3O3
35
16
requires C, 55.96; H, 3.95; N, 10.30%]; nmax (film) 3443,
2985, 1719, 1596, 1548, 1497, 1251, 1229, 1179, 1017, 774,
693 cm21; dH (300 MHz, CDCl3) 1.50 (3H, t, J¼7.2 Hz,
OCH2CH3), 4.31 (1H, d, J¼4.2 Hz, OH), 4.54 (2H, q,
J¼7.2 Hz, OCH2CH3), 5.62 (1H, ddd, J¼13.6, 6.8, 4.2 Hz,
CHOH), 7.06–7.53 (9H, m, ArH); dF (282 MHz, CDCl3)
294.5 (1F, dd, J¼275.0, 6.8 Hz), 103.9 (1F, dd, J¼275.0,
13.6 Hz); m/z (EI) 407/409 (1/1, Mþ), 387/389 (13/4), 361/
363 (12/3), 332/335 (8/2), 267 (25), 165 (96), 139 (17), 104
(24), 77 (100%, Phþ).
4.5. Synthesis of the bicyclic gem-difluorinated 1H-
pyrano[3,4-d][1,2,3]-triazol-4-one compounds 10
(general procedure)
4.4.3. 5-[1,1-Difluoro-2-hydroxy-2-(4-methoxyphenyl)-
ethyl]-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid
ethyl ester (8c). Through the general procedure starting
from triazole 3ba and 4-methoxybenzaldehyde 7c (0.544 g,
4 mmol), flash chromatography using n-hexane/EtOAc
(2:1) as eluent afforded the gem-difluorinated alcohol 8c
(200 mg, 62%) as a white powder, mp 170.0–172.08C.
[Found: C, 59.75; H, 4.87; N, 10.38. C20H19F2N3O4 requires
C, 59.55; H, 4.75; N, 10.42%]; nmax (film) 3357, 3068, 3004,
2907, 1734, 1612, 1518, 1500, 1371, 1347, 1305, 1263,
1226, 1173, 1085, 1026, 793, 690 cm21; dH (300 MHz,
CDCl3) 1.50 (3H, t, J¼7.5 Hz, OCH2CH3), 3.81 (3H, s,
OMe), 3.92 (1H, d, J¼3.9 Hz, OH), 4.54 (2H, q, J¼7.5 Hz,
OCH2CH3), 5.57 (1H, ddd, J¼13.1, 8.1, 3.9 Hz, CHOH),
6.81–7.50 (9H, m, ArH); dF (282 MHz, CDCl3) 297.4 (1F,
dd J¼272.4, 8.1 Hz), 103.6 (1F, dd, J¼272.4, 13.1 Hz); m/z
(EI) 383 (14), 355 (43), 338 (2), 309 (3), 267 (43), 165
(100), 137 (65), 109 (29), 77 (69, Phþ), 51 (14%).
Into a solution of alcohol 8 (0.2 mmol) in 10 mL toluene,
was added a catalytic amount of p-toluenesulfonic acid
(10 mg), the solution was then heated at 858C for the time
specified in Table 4. After removal of the solvent under
reduced pressure, the residue was purified by flash
chromatography using n-hexane/EtOAc or CH2Cl2 as eluent
to afford compound 10 in the yields shown in Table 4.
4.5.1. 7,7-Difluoro-6-phenyl-1-phenyl-6,7-dihydro-1H-
pyrano[3,4-d][1,2,3]triazol-4-one (10a). Following the
general procedure starting from difluorinated alcohol 8a
(56 mg, 0.15 mmol), flash chromatography using n-hexane/
EtOAc (3:1) as eluent afforded compound 10a (34 mg,
0.1 mmol, 69%) as a white powder, mp 192.0–195.08C.
[Found: C, 62.58; H, 3.74; N, 12.46. C17H11F2N3O2 requires
C, 62.39; H, 3.39; N, 12.84%]; nmax (film) 3087, 1770, 1598,
1575, 1513, 1457, 1393, 1200, 1154, 1124, 1085, 1074,
1022, 762, 729, 709, 688 cm21; dH (300 MHz, CDCl3) 5.76
(1H, dd, J¼20.4, 5.1 Hz, CHO–), 7.47–7.74 (10H, m,
ArH); dF (282 MHz, CDCl3) 296.2 (1F, dd, J¼276.8,
20.4 Hz), 115.6 (1F, dd, J¼276.8, 5.3 Hz); m/z (EI) 327 (13,
Mþ), 165 (100), 105 (3), 77 (28), 51 (12%).
4.4.4. 5-(1,1-Difluoro-2-hydroxy-3-pentenyl)-1-phenyl-
1H-1,2,3-triazole-4-carboxylic acid ethyl ester (8d).
Through the general procedure starting from triazole 3ba
and crotonaldehyde 7d (0.28 g, 4 mmol), flash chromato-
graphy using n-hexane/EtOAc (3:1) as eluent afforded the
gem-difluorinated alcohol 8d (175 mg, 65%) as a white
4.5.2. 7,7-Difluoro-6-(4-chlorophenyl)-1-phenyl-6,7-
dihydro-1H-pyrano[3,4-d] [1,2,3]triazol-4-one (10b).

W. Peng, S. Zhu / Tetrahedron 59 (2003) 4395–4404
4403
Following the general procedure starting from difluorinated
alcohol 8b (55 mg, 0.14 mmol), flash chromatography using
n-hexane/EtOAc (3:1) as eluent afforded compound 10b
(24 mg, 0.07 mmol, 69%) as a white powder, in addition to
recovery of 16 mg starting material. Mp 159.0–161.08C;
(77), 77 (100), 65 (18), 51 (40%); FTMS-HR (EI): Mþ,
found 355.1127. C19H F2N3O2 requires 355.1136.
19
15
Acknowledgements
n
max (film) 2924, 2853, 1768, 1708, 1599, 1577, 1511, 1497,
1397, 1200, 1159, 1126, 1086, 1034, 1016, 793, 757,
688 cm21; dH (300 MHz, CDCl3) 5.75 (1H, dd, J¼20.7,
5.1 Hz, CHO–), 7.46–7.72 (9H, m, ArH); dF (282 MHz,
CDCl3) 295.8 (1F, dd, J¼276.7, 21.7 Hz), 116.3 (1F, dd,
J¼276.7, 5.1 Hz); m/z (EI) 361/363 (8/3, Mþ), 165 (100),
139 (6), 111 (5), 77 (36); [HRMS (EI): Mþ, found
The authors thank the National Natural Science Foundation
of China (NNSFC) (No. 20032010 and 20072049) and
Innovation Foundation of Chinese Academy of Sciences for
financial support.
361.04258. C17H Cl19F2N3O2 requires 361.04296].
35
10
4.5.3. 7,7-Difluoro-6-(4-methoxyphenyl)-1-phenyl-6,7-
dihydro-1H-pyrano[3,4-d] [1,2,3]triazol-4-one (10c). Fol-
lowing the general procedure starting from difluorinated
alcohol 8c (149 mg, 0.37 mmol) catalyzed by p-TsOH
(25 mg), flash chromatography using n-hexane/EtOAc (3:1)
as eluent afforded compound 10c (54 mg, 0.15 mmol, 41%)
as a white powder, mp 192.0–194.08C. [Found: C, 60.41; H,
3.89; N, 11.49. C18H13F2N3O3 requires C, 60.51; H, 3.67; N,
11.76%]; nmax (film) 3022, 2970, 2937, 2841, 1759, 1613,
1574, 1518, 1388, 1290, 1253, 1180, 1154, 1122, 1065,
1013, 800, 765, 691 cm21; dH (300 MHz, CDCl3) 3.85 (3H,
s, OMe), 5.69 (1H, dd, J¼20.7, 5.4 Hz, CHO–), 6.96–7.73
(9H, m, ArH); dF (282 MHz, CDCl3) 297.8 (1F, dd,
J¼276.2, 20.7 Hz), 116.9 (1F, dd, J¼276.2, 5.4 Hz); m/z
(EI) 357 (20, Mþ), 284 (3), 222 (7), 165 (100), 135 (4), 77
(20), 51 (7%).
References
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1596, 1507, 1398, 1205, 1178, 1147, 1126, 1075, 1009, 973,
965, 784, 761, 689 cm21; dH (300 MHz, CDCl3) 1.84 (3H,
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6.9 Hz); m/z (EI) 291 (10, Mþ), 165 (100), 145 (6), 104 (16),
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19
11
291.08053. C14H F2N3O2 requires 291.08193.
4.5.5. 7,7-Difluoro-6-(2-phenylethyl)-1-phenyl-6,7-di-
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[1,2,3]triazol-4-one
(10e).
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