Polyfluoroalkylation and alkenylation of 1-benzyl-1H-indazol-3-ol

Article abstract of DOI:10.1007/s10593-011-0670-y

The polyfluoroalkylation and alkenylation of 1-benzyl-1H-indazol-3-ol by halopolyfluoroalkanes and fluorinated olefins has been studied. It was shown that only reactions proceeding with the participation of difluorocarbene lead to a mixture of N- and O-alkylation products. In all other cases, interaction with halopolyfluoroethanes and polyfluoroalkenes forms O-polyfluoroalkyl and alkenyl derivatives of indazolol.

Full text of DOI:10.1007/s10593-011-0670-y

Chemistry of Heterocyclic Compounds, Vol. 46, No. 11, February, 2011 (Russian Original Vol. 46, No. 11, November, 2010)
POLYFLUOROALKYLATION AND ALKENYLATION
OF 1-BENZYL-1H-INDAZOL-3-OL
T. M. Sokolenko1** and L. M. Yagupolskii1*
The polyfluoroalkylation and alkenylation of 1-benzyl-1H-indazol-3-ol by halopolyfluoroalkanes and
fluorinated olefins has been studied. It was shown that only reactions proceeding with the participation
of difluorocarbene lead to a mixture of N- and O-alkylation products. In all other cases, interaction with
halopolyfluoroethanes and polyfluoroalkenes forms O-polyfluoroalkyl and alkenyl derivatives of
indazolol.
Keywords: dibromodifluoromethane, 1,2-dibromotetrafluoroethane, 1,2-dichlorodifluoroethylene, chloro-
difluoromethane, 1,1-difluoroethylene, indazol-3-ol, tetrafluoroethylene, 1,1,2-trichlorotrifluoroethane,
chlorotrifluoroethylene, polyfluoroalkylation, fluoroalkenylation.
Five-membered heterocyclic compounds with alkoxyfluorinated substituents have been little studied in
spite of the fact that α,α,α-trifluoroanisole was synthesized for the first time in 1955 [1], and α-fluoroalkylphenyl
ethers of the benzene series have been well investigated in more recent times and have wide practical application
[2]. Among this class of compounds only the trifluoromethoxy derivatives of indole and benzofuran may be
mentioned, synthesized by adding trifluoromethyl hypofluorite and subsequent fission of dehydrofluorination
[3], and difluoromethoxy derivatives of pyrazole (including the herbicide Pyraflufenethyl [2]), obtained by the
action of difluorocarbene, generated from chlorodifluoromethane [4, 5].
In the present work we have studied the alkylation and alkenylation of 1-benzyl-1H-indazol-3-ol (1a)
with halopolyfluoroalkanes and polyfluoroalkenes. The selection of such a subject for investigation was caused
by the fact that indazole derivatives possess a broad spectrum of biological activity (anti-inflammatory and
antibacterial [6-8], antitumor, and cytostatic [9, 10]), and most of all, the preparation Benzydamine
hydrochloride is used in clinical practice as a nonsteroidal anti-inflammatory agent [11]. It is known that
1-substituted indazol-3-ols with alkyl sulfates, alkyl halides, or diazomethane give a mixture of products of
O-and N-alkylation, with 3-dimethylaminopropylbenzene sulfonate only the product of O-alkylation, and with
acrylonitrile and ethyl acrylate the product of addition at the nitrogen atom [12].
We have found that the reaction of 1-benzylindazol-3-ol (1a) with difluorocarbene, generated from
chlorodifluoromethane, proceeds unselectively, although in high overall yield (~80%), and a mixture is formed
of the products of O- and N-alkylation 2 and 3 in a ratio of 5:4 (Scheme 1). Compounds 2 and 3 differ
substantially in physical properties and may be separated by column chromatography.
_______
* Deceased.
** To whom correspondence should be addressed, e-mail: taras_sk@ukr.net.
1 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1649-1658, November, 2010.
Original article submitted February 1, 2010.
0009-3122/11/4611-1335©2011 Springer Science+Business Media, Inc.
1335

Scheme 1
O
CF2H
O
OH
N
CHF2Cl, K2CO3
DMF, 90°C
N
N CF2H
+
N
N
N
Bn
Bn
Bn
1a
2
3
The addition of polyfluorohaloalkyl groups to various heteroatoms was made possible by the halophilic
polyfluoroalkylation reaction [13]. In [14] it was shown that the use of tetrabutylammonium salts as catalyst enabled
such reactions to be carried out in high yield and selectivity. We established that the interaction of the sodium salt of
indazolol 1a with 1,2-dibromotetrafluoroethane or 1,1,2-trichlorotrifluoroethane leads to the formation of the
products of O-alkylation 4 and 5 (Scheme 2). The nucleophilicity of the indazolol is less, consequently the reaction
occurs under rigorous conditions, in which it is accompanied by partial resinification of the substrate.
1,1,2-Trichloro-trifluoroethane and the potassium salt of indazolol 1a react practically in the same way.
On interacting the sodium salt of indazolol 1a with dibromodifluoromethane a more complex picture
was observed (Scheme 2). The reaction was prolonged at a much higher temperature, and was characterized by a
lower overall yield (32%) and lower selectivity. The main fluorine-containing products were the
O-bromodifluoromethyl 6 and the O-difluoromethyl 2 derivatives, and also compound 7, in which the
difluoromethylene group is combined with the oxygen atom of one and the nitrogen atom of another indazole
ring. The formation of small quantities of N-bromodifluoromethyl (8) and N-difluoromethyl derivatives 3 was
also observed. The selectivity of this reaction is low in comparison with the interaction given above with halo-
fluoroethanes, probably due to the fact that according to a halophilic mechanism, in the first case a
fluoroethylene, and in the latter a far more reactive difluorocarbene is formed [15].
Scheme 2
1) NaH, Bu4NBr
or t-BuOK;
2) ClF2CCFCl2
O
CF2CFCl2
1) NaH, Bu4NBr;
2) BrCF2CF2Br
O
CF2CF2Br
1a
N
N
DMF, 90°C
N
DMF, 100-110°C
N
Bn
Bn
5
1) NaH, Bu4NBr
2) CBr2F2
DMF, 130°C
4
O
O
O
CF2Br
CF2
N
O
N
CF2Br
+
2
+ 3
+
N
+
N
N
N
N
Bn
Bn
Bn
8
N
6
7
Bn
A convenient method of introducing polyfluoroalkyl groups at the heteroatom (oxygen, nitrogen, sulfur)
is the addition of fluorinated olefins catalyzed by bases [16]. Interaction of indazolols 1a-c (in the presence of
catalytic quantities of their potassium derivatives Kcat) with tetrafluoroethylene or chlorotrifluoroethylene leads
1336

to the corresponding O-fluoroalkyl derivatives 9a-c and 10 (Scheme 3). When carrying out the analogous
process with catalytic amounts of base, 1,1-difluoroethylene was fairly reactive but its reaction with the
potassium salt of indazolol 1a was accompanied by dehydrofluorination and led to the formation of olefin 11 as
the main product, together with insignificant contamination by addition product 12. The sodium salt of indazolol
1a reacts analogously with 1,2-dichlorodifluoroethane, but hydrogen chloride is eliminated more effectively and
leads in high yield to olefin 13 (Scheme 3). A mixture of cis and trans olefins in a 1:1 ratio was used in the
reaction. The product was a mixture of olefins in the same ratio, the separation of which by distillation or
chromatographically was unsuccessful.
Scheme 3
O
CF2CF2H
Kcat, F2C=CF
2
N
1a-c
DMF, 115°C
N
Ar
9a–c
1a
O
CF=CFCl
CF2CClFH
O
1) NaH
2) ClFC=CFCl
Kcat, F2C=CFCl
DMF, 115°C
N
N
DMF, 95°C
N
N
Bn
13
10
Bn
1) t-BuOK
DMF, 140°C
2) CF2=CH2
O
CF2Me
O
FC=CH2
N
N
+
N
N
Bn
Bn
12
11
1, 9 а Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 2-pyridyl
We have attempted to debenzylate indazoles 9a-c. It turned out that compounds 9a,c were stable
towards catalytic hydrogenation (10% Pd on carbon) at atmospheric pressure. They were also stable towards
alkaline (boiling in 10% K2CO3 aqueous solution) and acidic hydrolysis (boiling in trifluoroacetic acid or in
10% aqueous HCl solution). Indazole 14 could to be obtained by the action of trifluoroacetic acid on
N-p-methoxybenzyl derivative 9b (Scheme 4).
Scheme 4
O
CF2CF2H
CF3COOH
9b
N
N
H
14
1337

TABLE 1. Characteristics of the Synthesized Compounds
Bp, oC
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
(0.1 mm Hg)
Yield, %
[Mp, oC]
C
H
Br (Cl)
N
2
3
4
C15H12F2N2O
C15H12F2N2O
C16H11BrF4N2O
65.78
65.69
65.80
65.69
47.55
47.66
4.36
4.42
4.25
4.42
2.52
2.76
10.13
10.22
10.27
10.22
6.95
6.95
117
45 (9*)
36 (2*)
60
[52-53]
133 [29-30]
19.96
19.82
5
C16H11Cl2F3N2O 51.28
51.21
2.95 (18.50) 7.49
2.96 (18.90) 7.47
140 [37-38]
[28-9]
—*2
12
7
6
C15H11BrF2N2O
C29H22F2N4O2
C15H11BrF2N2O
C16H12F4N2O
C17H14F4N2O2
C15H11F4N3O
C16H12ClF3N2O
C16H13FN2O
50.81
51.01
69.91
70.14
3.39
3.15
22.39
22.62
8.12
7.93
7
4.42
4.47
11.30
11.29
8
22.32
22.62
[54-55]
125
2
9a
9b
9c
10
11
12
13
14
58.91
59.25
57.94
57.62
55.55
55.38
56.51
56.39
3.50
3.74
8.54
8.65
85
85
82
95
38
5
4.10
3.99
7.82
7.91
130
3.55
3.42
12.81
12.92
107
3.50 (10.67) 8.20
3.56 (10.40) 8.22
133
71.67
71.62
5.12
4.89
10.40
10.44
115
C16H14F2N2O
C16H11ClF2N2O
C9H6F4N2O
10.01
9.72
3.38 (11.38) 8.61
3.46 (11.05) 8.74
59.67
59.91
46.07
46.16
125
89
97
2.53
2.58
11.74
11.96
[97–98]
_______
*Yield of product in the reaction with CBr2F2.
*2Yield of product using 1a sodium salt was 70%, using 1a potassium salt
74%.
The compositions and structures of the obtained compounds were confirmed by the elemental analysis
data, chromato-mass spectroscopy, and by 1H and 19F NMR spectra (Tables 1-3).
In the IR spectra of carbonyl-containing compounds 3, 7, and 8 an intense C=O absorption band was
observed at 1720-1730 cm-1, and this was missing for the remaining compounds.
1
It is extremely remarkable that in the H NMR spectra the singlet signal of the methylene group of the
arylmethylene fragment was observed for the carbonyl-containing compounds 3, 7, and 8 in the 4.77-4.92 ppm
range, and in the alkoxy- and alkenoxy derivatives at lower field (5.36-5.76 ppm). In the spectrum of compound
2, the signal of the difluoromethyl group has a F–H coupling constant characteristic to difluoromethyl ethers
[17], However in the spectrum of its isomer 3, it was characteristic to N-difluoromethyl derivatives [18]. In
addition, one of the aromatic protons of the synthesized compounds was displayed as a doublet signal at more
lower field (7.60-7.81 ppm) than the remaining (if the signals of the pyridyl fragment of compound 9c are
discounted). Evidently, this proton is in the position 4 of the indazole ring, since precisely it may test the
deshielding influence of the sterically close carbonyl oxygen atom, and also of the fluoroalkoxy or
fluoroalkenoxy groups.
The interaction of 1-arylmethyl-1H-indazol-3-ols with halopolyfluoroethanes and polyfluoroalkenes is
therefore directed on the oxygen atom. However, the reaction involving difluorocarbene has a low selectivity
1338

and leads to a mixture of N- and O-alkylation products. The investigated reactions are a convenient and general
method for the synthesis of previously unknown indazoles with various polyfluoroalkoxy and fluoroalkenoxy
substituents.
TABLE 2. 1H NMR Spectra of the Synthesized Compounds*
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
2
3
4
5
5.38 (2H, s, CH2); 7.04 (1H, t, 2JH,F = 73.2, OCHF2); 7.08-7.30 (8H, m, H Ar);
7.62 (1H, d, 3JH,H = 8.4, H-4)
4.86 (2H, s, CH2); 7.07-7.17 (7H, m, H Ar); 7.21 (1H, t, 2JH,F = 58.2, NCHF2);
7.51 (1H, t, 3JH,H = 7.8, H Ar); 7.68 (1H, d, 3JH,H = 7.8, H-4)
5.65 (2H, s, CH2); 7.25-7.33 (6H, m, H Ar); 7.51 (1H, t, 3JH,H = 8.4, H Ar);
7.64 (1H, d, 3JH,H = 8.4, H-7); 7.81 (1H, d, 3JH,H = 8.4, H-4)
5.65 (2H, s, CH2); 7.25-7.33 (6H, m, H Ar); 7.51 (1H, t, 3JH,H = 8.4, H Ar);
7.65 (1H, d, 3JH,H = 8.4, H-7); 7.81 (1H, d, 3JH,H = 8.4, H-4)
6
7
5.48 (2H, s, CH2); 7.09-7.33 (8H, m, H Ar); 7.52 (1H, d, 3JH,H = 8.4, H-4)
4.77 (2H, s, CH2); 5.38 (2H, s, CH2); 7.00-7.30 (15H, m, H Ar);
7.48 (1H, t, 3JH,H = 7.8, H Ar); 7.68 (1H, d, 3JH,H = 7.8, H-4); 7.81 (1H, d, 3JH,H = 8.4, H-4')
8
4.92 (2H, s, CH2); 7.03-7.17 (7H, m, H Ar); 7.50 (1H, t, 3JH,H = 7.8, H Ar);
7.68 (1H, d, 3JH,H = 7.8, H-4)
9a
9b
9c
5.62 (2H, s, CH2); 6.97 (1H, tt, 2JH,F = 52.8, 3JH,F = 2.7, CHF2); 7.22-7.32 (6H, m, H Ar);
7.49 (1H, t, 3JH,H = 8.4, H Ar); 7.65 (1H, d, 3JH,H = 7.8, H-7); 7.78 (1H, d, 3JH,H = 8.4, H-4)
3.76 (3H, s, OCH3); 5.36 (2H, s, CH2); 6.05 (1H, tt, 2JH,F = 52.8, 3JH,F = 2.7, CHF2);
6.75 (2H, d, 3JH,H = 8.4, H Ar); 7.01-7.31 (5H, m, H Ar); 7.60 (1H, d, 3JH,H = 8.4, H-4)
5.59 (2H, s, CH2); 6.08 (1H, tt, 2JH,F = 52.8, 3JH,F = 2.7, CHF2);
6.84 (1H, d, 3JH,H = 8.4, H-7); 7.10-7.21 (2H, m, H Ar); 7.32-7.34 (2H, m, H Ar);
7.52 (1H, t, 3JH,H = 4.2, H Ar); 7.64 (1H, d, 3JH,H = 8.4, H-4); 8.52 (1H, d, 3JH,H = 3.4, H Ar)
10
11
5.63 (2H, s, CH2); 7.24-7.32 (6H, m, H Ar); 7.48 (1H, dt, 2JH,F = 45.9, 3JH,F = 4.8, CHClF);
7.49 (1H, t, 3JH,H = 8.4, H Ar); 7.65 (1H, d, 3JH,H = 8.4, H-7); 7.78 (1H, d, 3JH,H = 8.4, H-4)
4.14 (1H, dd, 3JH,F = 39.8, 2JH,H = 4.8, CF=CH trans);
4.28 (1H, dd, 3JH,F = 4.7, 2JH,H = 4.8, CF=CH cis); 5.58 (2H, s, CH2);
7.18-7.33 (6H, m, H Ar); 7.49 (1H, t, 3JH,H = 8.4, H Ar); 7.68-7.77 (2H, m, H Ar)
12
2.04 (3H, t, 3JH,F = 13.5, CH3); 5.76 (2H, s, CH2); 7.09-7.30 (8H, m, H Ar);
7.90 (1H, d, 3JH,H = 8.4, H-4)
13
14
5.58 (2H, s, CH2); 7.00-7.28 (8H, m, H Ar); 7.61 (1H, d, 3JH,H = 8.4, H-4)
6.09 (1H, tt, 2JH,F = 52.8, 3JH,F = 2.7, CHF2); 7.16-7.19 (1H, m, H-5);
7.39-7.40 (2H, m, H-6,7); 7.66 (1H, d, 3JH,H = 8.4, H-4); 10.23 (1H, br. s, NH)
_______
*1H NMR spectra were taken in DMSO-d6 (compounds 2-5, 9a, 10-12) and
CDCl3 (compounds 6-8, 9b,c, 13, 14).
EXPERIMENTAL
The IR spectra were obtained on a UR-20 instrument in KBr disks (crystalline compounds 3 and 8) and
1
in a thin film on a KBr disk (compound 7). H NMR spectra were recorded on a Varian VXR-300 (300 MHz)
instrument, internal standard was TMS. The 19F NMR spectra were obtained on a Varian Gemini 200 (188 MHz)
instrument, internal standard was trichlorofluoromethane. The chromato-mass spectra (GC/MS) were described
on a Hewlett-Packard HP GC/MS 5890/5972 spectrometer (EI 70 eV) with a HP-5MS column, HP part number
19091S-102. Melting points were determined on a Stuart Scientific SMP3 instrument. A check on the progress
of reactions was effected by TLC on Silufol UV-254 plates. Silica gel MN-Kieselgel-60 was used for column
chromatography, and TLC plates precoated with SI F 10×20 cm (Riedel-de Haën), layer thickness 0.25 mm,
were used for preparative TLC.
DMF was distilled over CaH2 directly before use.
1339

TABLE 3. 19F NMR Spectra of the Synthesized Compounds
Com-
pound
Chemical shifts, δ, ppm (J, Hz)*
2
-84.77 (2F, d, 2JF,H = 73.2, OCHF2)
-103.37 (2F, d, 2JF,H = 58.2, NCHF2)
3
4
-69.08 (2F, s, CBrF2); -87.01 (2F, s, OCF2)
-75.41 (1F, s, CCl2F); -84.57 (2F, s, OCF2)
-18.14 (2F, s, OCBrF2)
5
6
7
-60.57 (2F, s, OCF2N)
8
-18.30 (2F, s, NCBrF2)
9a
9b
9c
10
11
12
13
-89.59 (2F, s, OCF2); -138.00 (2F, d, 2JF,H = 52.8, CHF2)
-89.79 (2F, s, OCF2); -137.20 (2F, d, 2JF,H = 52.8, CHF2)
-89.20 (2F, s, OCF2); -137.55 (d, 2JF,H = 52.8, CHF2)
-83.18 (2F, s, OCF2); -154.69 (1F, d, 2JF,H = 45.9, CHClF)
-82.35 (1F, dd, 3JF,H trans = 39.8, 3JF,H cis = 4.7, OCF=CH2)
-61.77 (2F, quin., 3JF,H = 13.5, OCF2CH3)
-120.29 (1F, d, 2JF,F = 38.7, =CClF, cis), -118.30 (1F, d, 2JF,F = 119.3, =CClF, trans),
-128.25 (1F, d, 2JF,F = 38.7, OCF=, cis), -133.45 (1F, d, 2JF,F = 119.3, OCF=, trans)
-88.92 (2F, s, OCF2); -137.30 (2F, d, 2JF,H = 52.8, CHF2)
14
_______
*19F NMR spectra were taken in DMSO-d6 (compounds 2-5, 9a, 10-12)
and in CDCl3 (compounds 6-8, 9b,c, 13, 14).
Alkylation of Indazol-3-one with Benzyl Chlorides. Indazol-3-one (4 g, 30 mmol) was added to a
solution obtained from NaOH (1.2 g, 30 mmol) (in the case of compound 1c (2.4 g, 60 mmol)) and water
(30 ml) and the mixture heated at 35oC until solution occurred. The appropriate benzyl chloride (30 mmol) was
added (in the case of 1c 2-chloromethylpyridine hydrochloride was used), and the mixture heated at 70oC for 2-3
h. The reaction mixture was cooled. The solid was filtered off, washed with water, and air dried. The product
was crystallized from a heptane–benzene, 3:1, mixture.
1-Benzyl-1H-indazol-3-ol (1a). Yield was 5.23 g (78%); mp 167-168oC [19].
1-(p-Methoxybenzyl)-1H-indazol-3-ol (1b). Yield was 3.12 g (41%); mp 159-160oC [6].
1-(2-Pyridylmethyl)-1H-indazol-3-ol (1c). Yield was 4.52 g (67%). Pale-yellow crystalline substance;
1
mp 156-157oC. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 5.41 (2H, s, CH2); 6.90-7.33 (5H, m, H Ar); 7.47
3
3
3
(1H, t, JH,H = 7.8, H Ar); 7.68 (1H, d, JH,H = 7.8, H-4); 8.50 (1H, d, JH,H = 3.4, H Ar); 10.20 (1H, br. s, OH).
Found, %: C 69.28; H 5.00; N 18.50. C13H11N3O. Calculated, %: C 69.32; H 4.92; N 18.65.
Interaction of Indazolol 1a with Chlorodifluoromethane. Anhydrous K2CO3 (3.7 g, 26.8 mmol) was
added to a solution of indazolol 1a (2.0 g, 8.9 mmol) in anhydrous DMF (25 ml) and chlorodifluoromethane was
bubbled through for 6 h with vigorous stirring and heating at 90oC. The reaction mixture was cooled, poured into
water (100 ml), and extracted with CH2Cl2 (3×50 ml). The extract was washed with water (5×25 ml), dried over
MgSO4, the solvent distilled off in vacuum (15 mm Hg), and the residue chromatographed on a column of SiO2
(eluent CH2Cl2).
1-Benzyl-3-difluoromethoxy-1H-indazole (2). Yield was 1.10 g, colorless oily substance, Rf 0.8. Mass
spectrum, m/z (Irel, %): 274 [M]+ (25), 91 [PhCH2]+ (100).
1-Benzyl-2-difluoromethyl-1,2-dihydro-3H-indazol-3-one (3). Yield was 0.88 g, white crystalline
substance, Rf 0.5. IR spectrum, , cm-1: 1720 (C=O). Mass spectrum, m/z (Irel, %): 274 [M]+ (100), 223
[M-CF2H]+ (18).
Interaction of Indazolol 1a with 1,2-Dibromotetrafluoroethane and 1,1,2-Trichlorotrifluoro-
ethane. A. NaH (60% in vaseline oil) (0.2 g, 5 mmol) was added to a solution of indazolol 1a (1.12 g, 5 mmol)
in anhydrous DMF (50 ml) and the mixture was stirred at room temperature until the end of hydrogen
1340

evolution (2 h). Tetrabutylammonium bromide (0.02 g, 0.05 mmol) and dibromotetrafluoroethane (3.9 g,
15 mmol), or 1,1,2-trichlorotrifluoroethane (2.8 g, 15 mmol) were added and the mixture was heated for 30 h at
90oC (in the case of indazole 4) or 48 h at 110oC (in the case of indazole 5). The reaction mixture was cooled,
poured into water (150 ml), extracted with CH2Cl2 (4 x 50 ml), the extract was washed with water (540 ml),
dried with MgSO4, the solvent was distilled off in vacuum (15 mm Hg), and the residue chromatographed on a
column of SiO2 (eluent CH2Cl2).
B. Potassium tert-butylate (0.34 g, 3 mmol) was added to a solution of indazolol 1a (0.67 g, 3 mmol) in
anhydrous tert-butanol (15 ml) and the mixture stirred at room temperature for 2 h. The solvent was distilled at
reduced pressure (15 mm Hg), the residue of solvent was removed in vacuum (6 h, 40oC, 0.05 mm Hg). To the
1a potassium salt obtained in this way was added anhydrous DMF (25 ml), 1,1,2-trichloro-trifluoroethane (1.69
g, 9 mmol) and the mixture was heated at 100oC for 48 h. The reaction mixture was then processed as in
procedure A.
1-Benzyl-3-(2-bromo-1,1,2,2-tetrafluoroethoxy)-1H-indazole (4). Yield 1.21 g (method A). White
crystalline or colorless oily substance. Rf 0.8. Mass spectrum, m/z (Irel, %): 403 [M]+ (100), 223 [M-CF2CF2Br]+
(25), 91 [PhCH2]+ (82).
1-Benzyl-3-(2,2-dichloro-1,1,2-trifluoroethoxy)-1H-indazole (5). Yield 1.31 g (method A) and 0.83 g
(method B), white crystalline substance, Rf 0.8. Mass spectrum, m/z (Irel, %): 376 [M(37Cl)+ (8), 374 [M]+ (21),
223 [M-CF2CFCl2]+ (10), 91 [PhCH2]+ (100).
Interaction of Indazolol 1a and Dibromodifluoromethane. Sodium hydride (60% in vaseline oil) (0.2
g, 5 mmol) was added to a solution of indazolol 1a (1.12 g, 5 mmol) in anhydrous DMF (50 ml) and the mixture
was stirred at room temperature until the end of hydrogen evolution (2 h). Tetrabutylammonium bromide (0.02
g, 0.05 mmol) and dibromodifluoromethane (5.25 g, 25 mmol) were added and the mixture was heated for 80 h
at 130oC. The reaction mixture was cooled, poured into water (150 ml), extracted with CH2Cl2 (4×50 ml), the
extract washed with water (5×40 ml), dried over MgSO4, the solvent was distilled in vacuum (15 mm Hg), and
the residue chromatographed on a column of SiO2 (eluent CH2Cl2–hexane, 10:15).
1-Benzyl-3-bromodifluoromethoxy-1H-indazole (6). Additionally purified by preparative TLC (eluent
CH2Cl2–hexane, 10:15). Yield 0.21 g. Colorless oily substance. Rf 0.6. Mass spectrum, m/z (Irel, %): 353 [M]+
(26), 223 [M-CF2Br]+ (19), 91 [PhCH2]+ (100).
1-Benzyl-2-[(1-benzyl-1H-indazol-3-yloxy)difluoromethyl]-1,2-dihydroindazol-3-one (7). Yield 0.09
g, colorless oily substance. Rf 0.2. IR spectrum, , cm-1: 1730 (C=O). Mass spectrum, m/z (Irel, %): 496 [M]+
(40), 91 [PhCH2]+ (100).
1-Benzyl-2-bromodifluoromethyl-3H-indazol-3-one (8). Additionally purified by preparative TLC
(eluent CH2Cl2–hexane, 10:15). Yield 0.03 g. White crystalline substance, Rf 0.4. IR spectrum, , cm-1: 1720
(C=O). Mass spectrum, m/z (Irel, %): 353 [M]+ (100), 223 [M-CF2Br]+ (25).
Also isolated were compounds 2 (yield 0.12 g, Rf 0.5) and 3 (yield 0.03 g, Rf 0.35), which, according to
1H, 19F NMR data and chromato-mass spectra, were identical to samples obtained in the reaction with
chlorodifluoromethane.
Interaction of Indazolols 1a-c with Tetrafluoroethylene and of Indazolol 1a with
Chlorotrifluoroethylene. Metallic potassium (0.2 g, 0.5 mmol) was added to a solution of the appropriate
indazolol 1a-c (5 mmol) in DMF (50 ml) and the mixture stirred for 4 h at room temperature (until complete
solution of K). Tetrafluoroethylene, or chlorotrifluoroethylene in the case of compound 10, was then bubbled
through the obtained solution under vigorous stirring and heating at 115oC during 4-6 h. The reaction mixture
was cooled, poured into water (150 ml), extracted with CH2Cl2 (4×50 ml), the extract was washed with water
(5×40 ml), dried over MgSO4, the solvent was removed in vacuum (15 mm Hg), and the residue
chromatographed on a column of SiO2 (eluent CH2Cl2).
1-Benzyl-3-(1,1,2,2-tetrafluoroethoxy)-1H-indazole (9a). Yield 1.38 g, colorless oily substance,
Rf 0.6. Mass spectrum, m/z (Irel, %): 324 [M]+ (22), 91 [PhCH2]+ (100).
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1-(p-Methoxybenzyl)-3-(1,1,2,2-tetrafluoroethoxy)-1H-indazole (9b). Yield 1.51 g, colorless oily
substance, Rf 0.6. Mass spectrum, m/z (Irel, %): 354 [M]+ (27), 121 [CH3OPhCH2]+ (100).
1-(2-Pyridylmethyl)-3-(1,1,2,2-tetrafluoroethoxy)-1H-indazole (9c). Yield 1.33 g, yellow oily
substance, Rf 0.6. Mass spectrum, m/z (Irel, %): 325 [M]+ (100), 246 [M-C5H4N+H]+ (87), 208 [M-OCF2CF2H]+
(29), 93 [C5H4NCH2+H]+ (27).
1-Benzyl-3-(2-chloro-1,1,2-trifluoroethoxy)-1H-indazole (10). Yield 1.62 g, colorless oily substance,
Rf 0.7. Mass spectrum, m/z (Irel, %): 342 [M(37Cl)] + (19), 340 [M]+ (56), 223 [M-CF2CFClH]+ (18), 91 [PhCH2]+
(100).
Interaction of Indazolol 1a with 1,1-difluoroethylene. Potassium tert-butylate (0.54 g, 4.5 mmol) was
added to a solution of indazolol 1a (1 g, 4.5 mmol) in anhydrous tert-butanol (15 ml) and the mixture stirred at
room temperature for 2 h. The solvent was distilled under reduced pressure (15 mm Hg), and the residue of the
solvent was removed under vacuum (6 h, 40oC, 0.05 mm Hg). Anhydrous DMF (40 ml) was added to the obtained
potassium salt of 1a. 1,1-Difluoroethylene was bubbled through the obtained solution during 16 h under vigorous
stirring and heating at 140oC. The reaction mixture was cooled, poured into water (150 ml), extracted with CH2Cl2
(4×50 ml), the extract was washed with water (5×40 ml), dried over MgSO4, the solvent was removed in vacuum
(15 mm Hg), and the residue chromatographed on a column of SiO2 (eluent CH2Cl2–hexane, 10:3).
1-Benzyl-3-(1-fluorovinyloxy)-1H-indazole (11). Yield 0.46 g, colorless oily substance, Rf 0.5. Mass
spectrum, m/z (Irel, %): 268 [M]+ (31), 91 [PhCH2]+ (100).
1-Benzyl-3-(1,1-difluoroethoxy)-1H-indazole (12). Yield 0.07 g, colorless oily substance, Rf 0.4. Mass
spectrum, m/z (Irel, %): 288 [M]+ (20), 91 [PhCH2]+ (100).
1-Benzyl-3-(1,2-difluoro-2-chlorovinyloxy)-1H-indazole (13). Sodium hydride (60% in vaseline oil)
(0.2 g, 5 mmol) was added with stirring at room temperature to a solution of indazolol 1a (1.12 g, 5 mmol) in
anhydrous DMF (50 ml) until the end of hydrogen evolution (2 h). A solution of 1,2-dichlorodifluoroethylene
(1.33 g, 10 mmol) in DMF (5 ml) was added and the mixture heated for 8 h at 95oC. The reaction mixture was
cooled, poured into water (150 ml), extracted with CH2Cl2 (4×50 ml), the extract washed with water (5×40 ml),
dried over MgSO4, the solvent distilled in vacuum (15 mm Hg), and the residue chromatographed on a column
of SiO2 (eluent CH2Cl2). Yield was 1.43 g, colorless oily substance, Rf 0.6. Mass spectrum, m/z (Irel, %): 322
[M(37Cl)]+ (7), 320 [M]+ (16), 91 [PhCH2]+ (100).
3-(1,1,2,2-Tetrafluoroethoxy)indazole (14). A solution of indazole 9b (0.4 g, 1.1 mmol) in
trifluoroacetic acid (5 ml) was heated at 72oC for 4 h. The acid was distilled off in vacuum (15 mm Hg) and the
solid residue purified by sublimation at 70oC in vacuum (0.05 mm Hg). Yield was 0.25 g, colorless crystalline
substance. Mass spectrum, m/z (Irel, %): 234 [M]+ (100), 133 [M-OCF2CF2H]+ (68).
REFERENCES
1.
2.
3.
4.
L. M. Yagupolskii, Dokl. Akad. Nauk SSSR, 105, 100 (1955).
F. Leroux, P. Jeschke, and M. Schlosser, Chem. Rev., 105, 827 (2005).
D. H. R. Barton, R. H. Hesse, G. P. Jackman, and M. M. Pechet, J. Chem. Soc., Perkin Trans. 1, 2604 (1977).
S. W. Djuric, N. BaMaung, A. Basha, H. Liu, J. R. Luly, D. J. Madar, R. J. Sciotti, N. P. Tu,
F. L. Wagenaar, P. E. Wiedeman, X. Zhou, S. Ballaron, J. Bauch, Y.-W.Chen, X. G. Chiou, T. Fey, D.
Gauvin, E. Gubbins, G. C. Hsieh, K. C. Marsh, K. W. Mollison, M. Pong, T. K. Shaughnessy, M. P.
Sheets, M. Smith, J. M. Trevillyan, U. Warrior, C. D. Wegner, and G. W. Carter, J. Med. Chem., 43,
2975 (2000).
5.
G. P. Lahm, T. M. Stevenson, T. P. Selby, J. H. Freudenberger, D. Cordova, L. Flexner, C. A. Bellin,
C. M. Dubas, B. K. Smith, K. A. Hughes, J. G. Hollingshaus, C. E. Clark, and E. A. Benner, Bioorg.
Med. Chem. Lett., 17, 6274 (2007).
1342

6.
7.
8.
G. Palazzo, G. Corsi, L. Baiocchi, and B. Silvestrini, J. Med. Chem., 9, 38 (1966).
P. Bruneau, C. Delvare, M. P. Edwards, and R. M. McMillan, J. Med. Chem., 34, 1028 (1991).
X. Li, S. Chu, V. A. Feher, M. Khalili, Z. Nie, S. Margosiak, V. Nikulin, J. Levin, K. G. Sprankle,
M. Tedder, R. Almassy, K. Appelt, and K. M. Yager, J. Med. Chem., 46, 5663 (2003).
L. Bouissane, S. El Kazzouli, S. Léonce, B. Pfeiffer, E. M. Rakib, M. Khouili, and G. Guillaumet,
Bioorg. Med. Chem., 14, 1078 (2006).
9.
10.
G.-D. Zhu, J. Gong, V. B. Gandhi, K. Woods, Y. Luo, X. Liu, R. Guan, V. Klinghofer, E. F. Johnson,
and V. S. Stoll, Bioorg. Med. Chem., 15, 2441 (2007).
11.
12.
13.
M. D. Mashkovskii, Drugs [in Russian], Novaya Volna, Moscow (2005), p. 177.
L. Baiocchi, G. Corsi, and G. Palazzo, Synthesis, 633 (1978).
R. E. Banks, B. E. Smart, and J. C. Tatlow, Organofluorine Chemistry. Principles and Commercial
Applications, Plenum Press, New York (1994), p. 177.
14.
15.
16.
K. I. Petko, T. M. Sokolenko, A. V. Bezdudny, and L. M. Yagupolskii, J. Fluor. Chem., 126, 1342
(2005).
T. M. Sokolenko, K. I. Petko, and L. M. Yagupolskii, Khim. Geterotsikl. Soedin., 550 (2009). [Chem.
Heterocycl. Comp., 45, 430 (2009).]
L. M. Yagupolskii, Aromatic and Heterocyclic Compounds with Fluorine-containing Substituents [in
Russian], Naukova Dumka, Kiev (1988).
17.
18.
E. Nawrot and A. Jonczyk, J. Fluor. Chem., 127, 943 (2006).
K. I. Petko, T. M. Sokolenko, and L. M. Yagupolskii, Khim. Geterotsikl. Soedin., 1355 (2006). [Chem.
Heterocycl. Comp., 42, 1177 (2006).]
19.
J. Schmutz, F. Hunziker, and W. Michaelis, Helv. Chim. Acta, 47, 1986 (1964).
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