Efficient synthesis of 5-fluoroalkylated 1H-1,2,3-triazoles and application of the bromodifluoromethylated triazole to prepare new gem-difluorinated triazole compounds

Article abstract of DOI:10.1055/s-2003-36784

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

Full text of DOI:10.1055/s-2003-36784

LETTER
187
Efficient Synthesis of 5-Fluoroalkylated 1H-1,2,3-Triazoles and Application
of the Bromodifluoromethylated Triazole to Prepare New gem-Difluorinated
Triazole Compounds
Efficient
S
ynthesis of 5-
e
Fluoroalky
im-1,2,3-Triazoles in Peng, Shizheng Zhu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Fax +86(21)64166128; E-mail: zhusz@pub.sioc.ac.cn
Received 3 December 2002
action with aryl azide and benzyl azide to synthesise the
Abstract: A series of 5-fluoroalkylated 1H-1,2,3-triazoles was
prepared in good yield by the regiospecific 1,3-dipolar cycloaddi-
tion reaction of the (Z) ethyl 3-fluoroalkyl-3-pyrrolidino-acrylates
with aryl or benzyl azides. In the cases of benzyl azides, addition
5-fluoroalkyl 1H-1,2,3-triazoles, especially the halogeno-
difluoromethylated 1H-1,2,3-triazoles, under thermal and
solvent free conditions. There is an increasing interest in
of Na2CO3 was crucial for a high yield of the triazoles. The tet- organofluorine chemistry for the synthesis of new gem-di-
rakis(dimethylamino)ethylene (TDAE) promoted reaction of the
fluorinated compounds in view of the potential biological
properties of such molecules.15 In viewing of the high re-
activity of the resulting halogeno-difluoromethylated 1H-
bromo-difluoromethylated 1H-1,2,3-triazole with aldehyde afford-
ed a new class of novel gem-difluorinated triazole compounds.
Key words: acrylates, 1,3-dipolar cycloaddition, fluoroalkylated
1H-1,2,3-triazole, tetrakis(dimethylamino)ethylene, gem-difluori-
nated compound
1,2,3-triazoles in single-electron-transfer (SET) reac-
tion,16 we reacted them with aldehydes using tetrakis(di-
methylamino)ethylene (TDAE) as SET reaction initiator
to produce a new class of novel gem-difluoromethene
compounds.
Up to now, no natural products containing 1H-1,2,3-tria-
zole moiety have been isolated because it is difficult for
X
Y
Y
X
biochemical systems to produce molecules with three vic-
inal nitrogen atoms in a cyclic arrangement.1 However,
the multi-functionalized 1H-1,2,3-triazloes have found
numerous applications2 in organic synthesis,3 as well as in
medicine and industry as biologically active systems,4 as
dyestuffs5 and fluorescent compounds,6 as corrosion in-
hibitors,7 as photostabilizers8 and as agrochemicals.9 One
of the two well established approaches to 1H-1,2,3-tria-
zoles is through the 1,3-dipolar cycloaddition reaction of
a wide variety of organic azide to acetylenic compounds
(Scheme 1, a),1,2 which were poorly or moderately regio-
selective, and two regioisomers are obtained normally.10
In contrast, another methodology is through the regiose-
lective reaction of azides with push-pull alkenes with a
leaving group (LG) at one side of the double bond
(Scheme 1, b).11 We have been interested in the synthesis
of the fluorine-containing 1H-1,2,3-triazoles since fluor-
ine in those compounds might impart profound influences
on their chemical, physical and biological properties.12
Although several trifluoromethylated starting materials
have been reacted with phenyl or benzyl azides,13 there
are no general methods to synthesise fluoroalkylated 1H-
1,2,3-triazoles, especially the halogeno-difluoromethylat-
ed 1H-1,2,3-triazoles. In an earlier report,14 we demon-
strated the facile synthesis of (Z) ethyl 3-fluoroalkyl-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 re-
+
+
X
Y
a
b
RN3
RN3
N
N
N
+
N
R
N
R
N
EDG
LG
EDG
R
EWG
+
LGH
N
N
EWG
N
Scheme 1 The synthetic strategy
The efficient and high yield synthesis of the 5-fluoroalky-
lated 1H-1,2,3-triazoles was a very simple procedure: a
mixture of the (Z) ethyl 3-fluoroalkyl-3-pyrrolidino-acry-
late 1 (1 mmol) in about 1 mL phenyl or benzyl azides (2
or 4) was heated at 80–90 °C for several days until total
conversion of the acrylate. Then without any work-up (in
the cases of benzyl azides, only a simple filtration was
needed), flash chromatography of the reaction mixture on
silica gel (30–40 µ) using n-hexane–EtOAc (5:1) as eluent
afforded the 5-fluoroalkyl 1H-1,2,3-triazoles (3 or 5) in
around 80% yield, in addition to recovery of the excess of
organic azide. The synthesis of 5-fluoroalkylated 1H-
1,2,3-triazoles is summarized in Table 1. The solvent free
condition, which can result in vigorous reaction,17 was
crucial for the efficiency of the synthesis, as the solvents
rendered the system very slow or ineffective. Na2CO3 was
necessary for the high yields of the corresponding tria-
zoles in the reaction of benzyl azides 4 with these acry-
lates 1, which decomposed during heating in the absence
(Table 1, entry 9–13).18 The reation of acrylate 1d
(Rf = ClCF2CF2CF2-) with phenyl azide (Table 1, entry 8)
needed prolonged heating (more than one week); which
might be rationalized as a steric effect and the greater
Synlett 2003, No. 2, Print: 31 01 2003.
Art Id.1437-2096,E;2003,0,02,0187,0190,ftx,en;D22502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

188
W. Peng, S. Zhu
LETTER
electron-withdrawing nature of long chain fluoroalkyl dure: into a solution of the triazole 3ba (277 mg, 0.8
group.19
mmol) and benzaldehyde 6a (424 mg, 0.41 mL, 4 mmol)
in DMF (8 mL), cooled by ice-salt bath under nitrogen,
was added TDAE (176 mg, 0.21 mL, 0.88 mmol) drop-
wise via a syringe within half an hour. A red colour imme-
diately developed with the formation of a fine white
precipitate. The solution was further vigorously stirred for
an hour under cooling, and then warmed up to room tem-
perature for 17 hours. The red orange turbid solution was
filtered and hydrolyzed with saturated NH4Cl solution (8
mL), followed by extraction with ethyl acetate (3 × 20
mL). The organic layer was washed with brine (30 mL),
dried over Na2SO4, and concentrated under vacuum to
leave a residue which was chromatographed on silica gel
using n-hexane–EtOAc as eluent (Rf = 0.2, 3:1) to give
the corresponding new CF2 containing compound 7a25 in
69% yield (Table 2, entry 1).
The products 3 and 5 were fully characterized by 1H and
19F NMR, MS, IR spectroscopy and microanalyses.20 The
structure of compound 3ac was also confirmed by X-ray
diffraction analysis, and it showed that the fluoroalkyl
group was at the triazole 5-position (Figure 1).21 It is note-
worthy that pyrrolidino group plays two important roles in
the course of the reaction: acting as a electron donating
group (EDG) to give complete control over the regioselec-
tivity in the initial 1,3-dipolar reaction of the acrylate with
azide22 and as a leaving group (LG) to prevent the pro-
duced triazoline intermediate from decomposing23
The reaction of the bromodifluoromethylated 1H-1,2,3-
triazole 3ba with aldehydes in the presence of TDAE to
produce the new gem-difluorinated triazole followed a
modified method developed by Dolbier.24 The reaction of
3ba with benzaldehyde is described as a typical proce-
Table 1 Synthesis of 5-Fluoroalkylated 1H-1,2,3-Triazoles 3 or 5
Rf
Ar
CO2Et
Rf
CO2Et
N
ArCH2N3(4)/Na2CO3
ArN3 (2)
/-C H N
CO2Et
N
N
N
N
Rf
80 °C
N
90 °C/-C4H9N
4
9
ArCH2
N
1
3aa-3da
5aa-5ba
1a Rf = ClCF2-
1b Rf = BrCF2-
1c Rf = CF3-
2a Ar = Ph-
2b Ar = 4-CH3OC6H4-
2c Ar = 4-NO2C6H4-
4a Ar = Ph-
4b Ar = 4-CH3OC6H4-
4c Ar = 4-NO2C6H4-
1d Rf = Cl(CF2)3-
Entry
Acrylate
1a
Azide
Base
Temp (°C)
Time (d)
Product (%)a
3aa (84)
3ba (79)
3ca (76)
3ab (79)
3ac (97)
3cb (66)
3cc (89)
3da (92)
5aa (88)
5ca (85)
5ab (88)
5ac (66)
5ba (32)d
b
1
2a
2a
2a
2b
2c
2b
2c
2a
4a
4a
4b
4c
4a
–
–
–
–
–
–
–
–
78
78
78
78
86
78
78
78
90
95
90
2
3
2
1b
3
1c
2
4
1a
2
5
1a
1.5
1
6
1c
7
1c
1.5
9
8
1d
9
1a
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
4
10
1c
3
11
1a
5
12
1a
Toluene/refluxc
85
10
5
13
1b
a Isolated yield.
b No base is needed.
c Using toluene as solvent, because of the solidation of the reaction system during heating without solvent.
d Low yield due to defluorination.
Synlett 2003, No. 2, 187–190 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of 5-Fluoroalkylated 1H-1,2,3-Triazoles
189
tive, only traces of product being detected by TLC anal-
ysis after 8 hours heating at 90 °C.
In summary, we have developed an efficient and facile
procedure to synthesise 5-fluoroalkylated 1H-1,2,3-triaz-
oles by the regiospecific 1,3-dipolar reaction of (Z) ethyl
3-fluoroalkyl-3-pyrrolidino-acrylates with azides, and we
have further treated the 5-bromodifluoromethyl 1H-1,2,3-
triazole 3ba with aldehydes in the presence of TDAE un-
der mild conditions to prepare gem-difluorinated 1H-
1,2,3-triazoles, whose bioactivities are under investiga-
tion.
Acknowledgment
The authors thank the National Natural Science Foundation of Chi-
na (NNSFC) (No.20072049) and Innovation Foundation of Chinese
Academy of Science for financial support.
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Figure 1 Molecular structure of compound 3ac
Table 2 The Reaction of Bromodifluoromethylated 1H-1,2,3-Tri-
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F
BrCF2
CO2Et
CO2Et
R
TDAE/DMF
RCHO
6a-e
+
r. t.
–5 °C
N
N
OH
Ph
N
N
Ph
N
N
3ba
7a-e
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Entry Aldehyde
Time
at –5 °C at r.t.
(h)
1
Time
Product
(%)a
(h)
17
6
1
2
3
4
5
6a R = Ph
7a (68)
7b (55)
7c (62)
7d (65)
7e (28)
6b R = 4-ClC6H5-
3
6c R = 4-MeOC6H5-
2
5
6d R = trans-CH3CH = CH-
6e R = PhCH2CH2-
3
13
7
2
a Isolated yield.
The reaction with other aromatic and α,β unsaturated al-
dehydes gave the expected gem-difluorinated triazoles in
satisfactory yield (Table 2, entries 2–4); however the
yield with aliphatic aldehyde 6e was rather low (Table 2,
entry 5) possibly due to the enolizable potential of this al-
dehyde. The 5-chlorodifluoromethyl substituted triazole
3aa was inert under the same reaction conditions, which
may be attributed to the higher reduction potential of this
substrate. Raising the reaction temperature was not effec-
Synlett 2003, No. 2, 187–190 ISSN 0936-5214 © Thieme Stuttgart · New York

190
W. Peng, S. Zhu
LETTER
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structures in this paper have been deposited with the
Cambridge Crystallographic Data Center as supplementary
publication numbers CCDC 196350. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK
[Fax:+44(1223)336033 or e-mail: deposit@ccdc.cam.
ac.uk].
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(25) 5-(1,1-Difluoro-2-hydroxy-2-phenyl-ethyl)-1-pheny-l-
1H-1,2,3-triazole-4-carboxylic Acid, Ethyl Ester(7a):
Mp: 146.0–148.0 °C. Found: C, 61.41; H, 4.78; N, 10.97.
C19H17F2N3O3 requires C, 61.12; H, 4.59; N, 11.25. IR(film):
3445, 3065, 2984, 1778, 1717, 1595, 1546, 1497, 1249,
1231, 1170, 1077, 1014, 766, 738, 693 cm–1. 1H NMR (300
MHz, CDCl3): δ = 1.51 (3 H, t, J = 7.2 Hz), 4.01 (1 H, d,
J = 3.9 Hz), 4.55 (2 H, q, J = 7.2 Hz), 5.63 (1 H, ddd,
J = 12.7, 8.7, 3.9 Hz), 6.89–7.49 (10 H, m). 19F NMR (282
MHz, CDCl3): δ = –100.3 (AB-d, J = 273.0, 12.7, 8.7 Hz);
EI-MS: m/z (%) = 373 (8) [M+], 353 (15), 328 (1), 300 (3),
281 (1), 104 (25), 77 (100) [Ph+], 51 (20).
(19) Chen, Q. Y.; Jiang, X. K.; Chen, B. Q. Scientia Sinica 1966,
4, 498.
(20) The analytical and spectroscopic data for triazole 3aa was
demonstrated as an example. 5-Chlorodifluoromethyl-1-
phenyl-1H-1,2,3-triazole-4-carboxylic Acid, Ethyl
Ester(3aa): Mp: 69.5–70.5 °C. [Found: C, 47.80; H, 3.35;
N, 14.24. C12H10ClF2N3O2 requires C, 47.78; H, 3.34; N,
13.93%]. IR(film): 2982, 1723, 1593, 1560, 1497, 1375,
1296, 1254, 1238, 1153, 1094, 1058, 1008, 906, 771 cm–1.
1H NMR (60 MHz, CDCl3): δ = 1.47 (3 H, t, J = 7.0 Hz),
4.52 (2 H, q, J = 7.0 Hz), 7.34–7.74 (5 H, m). 19F NMR (56.4
MHz, CDCl3): δ = –44.5; EI-MS: m/z (%) = 302/304 (10/3)
[M+ + 1], 256/258 (12/4), 245/247 (10/3), 189 (42), 170
(33), 144 (19), 77 (100) [Ph+].
Synlett 2003, No. 2, 187–190 ISSN 0936-5214 © Thieme Stuttgart · New York