Synthesis and some heterocyclisation reactions of CF2H- and CF2Cl-substituted 1,1-dicyanoethylenes

Article abstract of DOI:10.1016/S0022-1139(01)00559-0

New CF₂X-analogues of 1,1-dicyano-2,2-bis(trifluoromethyl)ethylene (1) (X = H, Cl) were synthesised by the condensation of polyfluoroketones with malononitrile followed by dehydration using thionyl chloride (or phosphorus pentoxide). The heterocyclisation reactions of new CF₂X-analogues of 1,1,-dicyano-2,2-bis(trifluoromethyl)ethylene with amidines, 5-aminopyrazoles and 3-methyl-2-pyrazolin- 5-ones were systematically investigated.

Full text of DOI:10.1016/S0022-1139(01)00559-0

Journal of Fluorine Chemistry 114 42002) 63±74
Synthesis and some heterocyclisation reactions of CF2H-
and CF2Cl-substituted 1,1-dicyanoethylenes$
Á
Alexander S. Golubev, Pavel V. Pasternak, Alexander F. Shidlovskii, Ljudmila N. Saveleva,
Boris B. Averkiev, Vladimir N. Nesterov, Michail Yu. Antipin,
Alexander S. Peregudov, Nikolai D. Chkanikov*
A.N. Nesmeyanov Institute of Organoelement Compounds ꢀINEOS), Russian Academy of Sciences, Vavilov Str. 28, 119991 Moscow, Russia
Received 27 July 2001; accepted 1 November 2001
Abstract
New CF2X-analogues of 1,1-dicyano-2,2-bis4tri¯uoromethyl)ethylene 41) 4X ˆ H, Cl) were synthesised by the condensation of
poly¯uoroketones with malononitrile followed by dehydration using thionyl chloride 4or phosphorus pentoxide). The heterocyclisation
reactions of new CF2X-analogues of 1,1-dicyano-2,2-bis4tri¯uoromethyl)ethylene with amidines, 5-aminopyrazoles and 3-methyl-2-pyrazolin-
5-ones were systematically investigated. # 2002 Elsevier Science B.V. All rights reserved.
Keywords: 1,1-Dicyano-2,2-bis4tri¯uoromethyl)ethylene; 1,4-Dihydropyrimidines; Pyrazolo[1,5-a]pyrimidines; Pyrazolo[3,4-b]pyridines; Pyrano[2,3-c]pyr-
azoles
1. Introduction
amidines, 5-aminopyrazoles, and 2-pyrazolin-5-ones are
investigated in attempts to obtain pyrimidines and fused
pyrazoles with new poly¯uoromethyl substituents. Current
interest in the synthesis of condensed pyrazoles [15±18]
because of their biological activity explains the focus on
these heterocycles in our research.
Sincethesynthesisof1,1-dicyano-2,2-bis4tri¯uoromethyl)-
ethylene 41) by Middleton [2], chemistry of this ole®n has
been studied in detail [3±7]. Among many chemical aspects,
1,1-dicyano-2,2-bis4tri¯uoromethyl)ethylene has been suc-
cessfully applied in heterocyclic chemistry [1,8±13]. It
served as a precursor for the synthesis of different classes
of CF3-containing nitrogen heterocycles, in particular, for
1,4-dihydropyridines and 1,4-dihydropyrimidines posses-
sing arthropodicidal activity [13].
Along with alkene 1, heterocyclic chemistry of alkene 1
analoguesÐesters of 3,3-dicyano-2-4tri¯uoromethyl)acrylic
acid [9] has also been studied in our laboratory. In contrast,
CF2X-analogues 4X ˆ H, Cl) of 1,1-dicyano-2,2-bis4tri-
¯uoromethyl)ethylene 4CFDCTE) were virtually unknown,
with the exception of poorly studied 1,1-dicyano-2-4chloro-
di¯uoromethyl)-2-4tri¯uoromethyl)ethylene 42) [14].
In our continuing efforts to develop ¯uorine-containing
synthons for heterocyclic chemistry, we worked out the
synthesis of new CF2X-analogues of 1,1-dicyano-2,2-bis-
4tri¯uoromethyl)ethylene. Reactions of these ethylenes with
2. Results and discussion
All known 1,1-dicyano-2,2-bis4poly¯uoromethyl)-
ethylenes: 1,1-dicyano-2,2-bis-4tri¯uoromethyl)ethylene,
dicyanomethylenehexa¯uorocyclobutane [2], 1,1-dicyano-
2-4chlorodi¯uoromethyl)-2-4tri¯uoromethyl)ethylene [14],
methyl and ethyl esters of 3,3-dicyano-2-4tri¯uoromethy-
l)acrylic acid [9] were prepared according to the Middleton
procedure by condensation of the corresponding poly¯uor-
oketone with malononitrile in the presence of zinc chloride
followed by dehydration of an unstable alcoholic intermedi-
ate with P2O5. The yields of ethylenes were about 50% for
the ethylenes from hexa¯uoroacetone and chloropenta¯uor-
oacetone and about 60% for the ethylenes from esters of
3,3,3-tri¯uoropyruvic acid.
$ Part 6 in the series ``Fluorine-containing 1,1-dicyanoethylenes in
heterocyclisation reactions'' [1].
We found that malononitrile did not react with 1,3-
dichlorotetra¯uoroacetone in the presence of ZnCl2 at any
noticeable rate even on prolonged heating in a sealed tube at
* Corresponding author. Fax: ‡7-95-135-6489.
E-mail address: nchkan@ineos.ac.ru 4N.D. Chkanikov).
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 4 0 1 ) 0 0 5 5 9 - 0

64
A.S. Golubev et al. / Journal of Fluorine Chemistry 114 ꢀ2002) 63±74
Scheme 1.
Table 1
Synthesis of CF2X-analogues of 1,1-dicyano-2,2-bis4trifluoromethyl)ethylene
Product Yield
4%)
Bp 48C)/Torr 1H NMR 4CDCl3)
19F NMR 4CDCl3)
Anal. calcd. 4%)/found
Molecular
formula
C
H
±
N
3
4
48
59
54±55/12
46±47/12
±
À50.7 s
29.18/29.24
11.34/10.89 C6Cl2F4N2
6.65 4t, JHÀF ˆ 50 Hz)
À51.8 42F, s); À116.6
42F, d, JHÀF ˆ 50 Hz)
À117.4 4d, JHÀF ˆ 52 Hz)
À61.3 43F, s); À116.6
42F, d, JHÀF ˆ 50 Hz)
À51.2 s
33.91/33.54 0.47/0.88 13.18/12.83 C6HClF4N2
5
6
41
75±78/12
6.65 4t, JHÀF ˆ 52 Hz)
6.67 4t, JHÀF ˆ 50 Hz)
40.47/40.27 1.13/1.58 15.73/15.28 C6H2F4N2
36.75/36.54 0.51/0.87 14.29/14.13 C6HF5N2
50
137±140
7
8
65
63
71±72/1
90±91/1
4.05 s
4.04 s
38.12/37.54 1.37/0.97 12.70/12.33 C7H3ClF2N2O2
31.73/31.54 1.14/1.58 10.57/10.83 C7H3BrF2N2O2
À48.6 s
80 8C. We had expected that 1,3-dichlorotetra¯uoroacetone
should react with malononitrile in the presence of organic
bases. Indeed, 1,3-dichlorotetra¯uoroacetone reacted with
malononitrile in the presence of triethylamine at a high
rate and almost quantitatively 4according to NMR data) to
give the alcoholic intermediate. The following dehydration
of the adduct with P2O5 failed. The dehydration agent of
choice turned out to be thionyl chloride in this case. Thus,
boiling the reaction mixture after the condensation step with
two-fold excess of thionyl chloride gave 1,1-dicyano-2,2-
bis4chlorodi¯uoromethyl)ethylene1 43) in 48% yield after
distillation 4Scheme 1, Table 1). 1,1-Dicyano-2-4chloro-
di¯uoromethyl)-2-4di¯uoromethyl)ethylene 44) and 1,1-
dicyano-2,2-bis4di¯uoromethyl)ethylene 45) were obtained
in a similar manner. For the synthesis of 1,1-dicyano-2-
4di¯uoromethyl)-2-4tri¯uoromethyl)ethylene 46), both phos-
phorus pentoxide and thionyl chloride can be used as
dehydrating agents. In this case, phosphorus pentoxide gains
an obvious advantage over thionyl chloride because of
dif®culties with separation of ethylene 6 from traces of
thionyl chloride. In the synthesis of methyl esters of 3,3-
dicyano-2-4chlorodi¯uoromethyl)acrylic acid 47) and 3,3-
dicyano-2-4bromodi¯uoromethyl)acrylic acid 48), quinoline
was the base of choice for the condensation step.
It was shown that alkene 1 reacted with N-monosubsti-
tuted amidines to give 4,4-bis4tri¯uoromethyl)-1,4-dihydro-
pyrimidines [13]. We found that alkenes 3±4 reacted with
N-unsubstituted amidines: benzamidine, acetamidine, tri¯uo-
roacetamidine in the same manner to give 1,4-dihydropyr-
imidines 49) in fair to good yields 4Scheme 2, Table 2). In the
case of alkene 4, these reactions proceeded more smoothly
to give higher yields as compared to alkene 3. The best
yields of products 9 were obtained for the reactions of alkene
5 with acetamidine and benzamidine. However, in the case
of alkene 5, we failed to isolate any product in its reaction
with tri¯uoroacetamidine.
1 For the convenience and simplicity, new alkenes were named after
Middleton by analogy to 1,1-dicyano-2,2-bis4trifluoromethyl)ethylene.
Scheme 2.

A.S. Golubev et al. / Journal of Fluorine Chemistry 114 ꢀ2002) 63±74
65
Table 2
Synthesis of 2-substituted 6-amino-5-cyano-4,4-bis4polyfluoromethyl)-1,4-dihydro41H)-pyrimidines
Product Yield
4%)
Mp 48C) 1H NMR 4d6-DMSO)
19F NMR
Anal. calcd. 4%)/found
Molecular
formula
4d6-DMSO)
C
H
N
9a
9b
45
40
217±218 10.19 41H, br. s, NH); 6.50
42H, br. s, NH2); 2.02 43H, s, CH3)
183±184 10.41 41H, br. s, NH); 7.84
42H, d, J ˆ 7.2 Hz); 7.55±7.66
43H, m); 6.71 42H, br. s, NH2)
202±203 11.71 41H, br. s, NH); 6.89
42H, br. s, NH2)
À56.2 4m)
À56.1 4m)
31.50/31.24 1.98/1.88 18.37/18.03 C8H6Cl2F4N4
42.53/42.27 2.20/2.08 15.26/15.43 C13H8Cl2F4N4
9c
20
58
À56.7 44F, m, CF2Cl);
À68.4 43F, s, CF3)
26.76/26.24 0.84/0.98 15.60/15.73 C8H3Cl2F7N4
35.51/35.24 2.61/2.88 20.70/20.43 C8H7ClF4N4
9d
174±175 9.81 41H, br. s, NH); 6.35
42H, br. s, NH2); 6.13
À58.4a 42F); À123.7b
42F, JHÀF ˆ 55:0 Hz)
41H, t, JFÀH ˆ 55 Hz, CF2H);
1.99 43H, s, CH3)
9e
68
143±144 10.21 41H, br. s, NH); 7.79
42H, d, J ˆ 7.5 Hz); 7.51±7.60
43H, m); 6.53 42H, br. s, NH2);
6.28 41H, t, JFÀH ˆ 55:1 Hz, CF2H)
164±165 11.20 41H, br. s, NH); 6.74
42H, br. s, NH2); 6.37
À58.7a 42F); À123.4b
42F, JHÀF ˆ 55:1 Hz)
46.93/46.34 2.73/2.88 16.84/16.43 C13H9ClF4N4
9f
48
À58.4a 42F); À68.4
43F, s, CF3); À123.2b
42F, JHÀF ˆ 54:2 Hz)
À127.5b
29.60/29.24 1.24/1.08 17.26/16.73 C8H4ClF7N4
40.69/40.27 3.41/3.08 23.72/23.43 C8H8F4N4
41H, t, JFÀH ˆ 54:2 Hz, CF2H)
186±187 9.42 41H, br. s, NH); 6.27
42H, br. s, NH2); 5.97
9g
71
4JHÀF ˆ 54:8 Hz)
42H, t, JFÀH ˆ 54:8 Hz, 2CF2H);
1.97 43H, s, CH3)
9h
72
177±178 9.85 41H, br. s, NH); 7.81
42H, d, J ˆ 7.2 Hz); 7.51±7.61
43H, m); 6.41 42H, br. s, NH2);
6.10 42H, t, JFÀH ˆ 54:7 Hz, 2CF2H)
À127.1b
52.35/52.04 3.38/3.15 18.79/18.43 C13H10F4N4
4JHÀF ˆ 54:7 Hz)
a Centre of an AB-type spin system.
b Centre of an ABX-type spin system.
N-unsubstituted 345)-aminopyrazoles 4Scheme 3) can be
¯uoromethyl)acrylic acid were investigated in our labora-
tory several years ago [8,9]. The structure of pyrazolo[3,4-
b]pyridines was ascribed to the 41:1)-adduct isolated in this
reaction, hence regarding C4-alkylation of 345)-aminopyr-
azole as the key step of the reaction. We found that alkenes
2±7 reacted with 345)-aminopyrazole and 345)-amino-543)-
methylpyrazole at a high rate with any dicyanoethylene used
to give 41:1)-adducts 10a±j in good yields 4Scheme 3,
Table 3). According to X-ray analysis, compound 10d is
a pyrazolo[1,5-a]pyrimidine 4Fig. 1). The similar spectro-
scopic characteristics of compounds 10a,b,d,f,i, in particu-
lar, two doublets at 5.5 and 7.5 ppm with the coupling
viewed as cyclic amidines [19]. They react with electrophilic
agents mostly at the N1 atom or at the exocyclic NH2-
group. For this type of pyrazoles, another course of the
reaction with electrophilic agentsÐC4-alkylation may also
occur [19,20]. The reactions of 345)-aminopyrazole with
alkene 1 and methyl or ethyl esters of 3,3-dicyano-2-4tri-
1
constant of 1.6 Hz in the H NMR spectra [19,21], proved
the pyrazolo[1,5-a]pyrimidine structures of these hetero-
cycles. Moreover, we reinvestigated the products of the
reaction of 345)-aminopyrazole with alkene 1 and methyl
and ethyl esters of 3,3-dicyano-2-4tri¯uoromethyl)acrylic
acid. All these products have spectroscopic characteristics
similar to 10a,b,d,f,i. It means that previously given struc-
tures [8,9] of these products should be corrected. They are
also pyrazolo[1,5-a]pyrimidines. Reaction products of
alkenes3±7with345)-amino-543)-methylpyrazole10c,e,g,h,j
have also similar spectroscopic characteristics which are
consistent with the structure of pyrazolo[1,5-a]pyrimidines.
Thus, 345)-aminopyrazoles in the reaction with alkene 1 and
Scheme 3.

66
A.S. Golubev et al. / Journal of Fluorine Chemistry 114 ꢀ2002) 63±74
Table 3
Synthesis of 7-amino-6-cyano-5,5-bis4polyfluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrimidines
Product Yield Mp 48C)
1H NMR 4d6-DMSO)
19F NMR
Anal. calcd. 4%)/found
Molecular
formula
4d6-DMSO)
C
H
N
10a
10b
60
57
214±215
8.99 41H, s, NH); 7.96
À61.1 42F);
À71.4 43F)
34.47/34.24 1.61/1.88
22.33/22.23 C9H5ClF5N5
42H, br. s, NH2); 7.51
41H, d, JHÀH ˆ 1:6 Hz); 5.56
41H, d, JHÀH ˆ 1:6 Hz)
195±200
8.92 41H, s, NH); 7.74
À61.0 4m)
32.75/32.34 1.53/1.75
21.22/21.03 C9H5Cl2F4N5
42H, br. s, NH2); 7.56
41H, d, JHÀH ˆ 1:6 Hz); 5.54
41H, d, JHÀH ˆ 1:6 Hz)
10c
10d
57
71
209±212
8.83 41H, s, NH); 7.60
À61.0 4m)
34.91/34.44 2.05/2.43
36.57/36.04 2.05/2.46
20.35/20.03 C10H7Cl2F4N5
23.69/23.23 C9H6ClF4N5
42H, br. s, NH2); 5.42 41H, s, CH);
2.13 43H, s, CH3)
8.47 41H, s, NH); 7.60
174±175
À63.0a 42F);
À128.6b 42F,
JHÀF ˆ 53 Hz)
42H, br. s, NH2); 7.52
41H, d, JHÀH ˆ 1:6 Hz); 6.47
41H, t, CF2H, JFÀH ˆ 53:3 Hz);
5.50 41H, d, JHÀH ˆ 1:6 Hz)
8.37 41H, s, NH); 7.44
10e
10f
90
61
179±181
181±182
À62.7a 42F);
À128.5b 42F,
JHÀF ˆ 53 Hz)
38.79/38.34 2.60/2.87
41.39/40.87 2.70/3.07
22.62/22.46 C10H8ClF4N5
26.81/26.44 C9H7F4N5
42H, br. s, NH2); 6.44
41H, t, CF2H, JFÀH ˆ 53:3 Hz);
5.36 41H, s, CH); 2.11 43H, s, CH3)
7.98 41H, s, NH); 7.47
À127.5b
42H, br. s, NH2); 7.46
42F, JHÀF ˆ 54 Hz)
41H, d, JHÀH ˆ 1:6 Hz); 6.20
42H, t, 2CF2H, JFÀH ˆ 54:2 Hz);
5.43 41H, d, JHÀH ˆ 1:6 Hz)
7.88 41H, s, NH); 7.31
10g
10h
10i
64
73
71
150±152
135±136
192±194
À127.3b
43.64/43.45 3.30/3.18
40.97/40.46 2.75/3.08
39.55/39.86 2.66/3.03
25.45/24.93 C10H9F4N5
23.89/23.43 C10H8F5N5
23.06/22.73 C10H8ClF2N5O2
42H, br. s, NH2); 6.17
42F, JHÀF ˆ 54 Hz)
42H, t, 2CF2H, JFÀH ˆ 54:5 Hz);
5.29 41H, s, CH); 2.11 43H, s, CH3)
8.32 41H, s, NH); 7.49
À78.1 4s, 3F);
À131.5b 42F,
JHÀF ˆ 54 Hz)
42H, br. s, NH2); 6.41
41H, t, JFÀH ˆ 53:3 Hz, CF2H);
5.36 41H, s, CH); 2.11 43H, s, CH3)
8.63 41H, s, NH); 7.55
À59.9 4m)
42H, br. s, NH2); 7.52
41H, d, JHÀH ˆ 1:6 Hz); 5.48
41H, d, JHÀH ˆ 1:6 Hz); 3.85
43H, s, OCH3)
10j
67
187±188
8.53 41H, s, NH); 7.40
À60.1 4m)
41.59/41.46 3.17/3.08
22.05/21.73 C11H10ClF2N5O2
42H, br. s, NH2); 5.34
41H, s, CH); 3.83
43H, s, OCH3); 2.11 43H, s, CH3)
a Centre of an AB-type spin system.
b Centre of an ABX-type spin system.
its analogues act as cyclic amidines. It is worth noting that
addition of the 1,1-dicyano-2,2-4poly¯uoromethyl)ethylenes
to 345)-aminopyrazole and 345)-amino-543)-methylpyrazole
proceeds with the exocyclic amino group being attacked by
the poly¯uoromethyl-bearing ethylenic carbon of the ethy-
lenes. This observation is in line with the Du Pont chemists'
®nding, that the unsubstituted nitrogen atom of N-monosub-
stituted amidines is attacked by the CF3-bearing ethylenic
carbon of alkene 1 [13]. In a contrast with this mode, 1,1-
dicyano-2-phenylethylene reacts in such a way that the
Ph-bearing ethylenic carbon attacks the endocyclic pyrazole
nitrogen N1 of 3,5-diaminopyrazole [22].
When the N1-nitrogen in 5-aminopyrazoles is substituted
by a methyl or aryl group, the reactions of these heterocycles
with 1,1-dicyano-2,2-4poly¯uoromethyl)ethylenes gave 4,7-
dihydropyrazolo[3,4-b]pyridines411a±m, Scheme4, Table4)
as a result of pyrazole C4-alkylation followed by intramole-
cular cyclisation. Structures of compounds 11 were con®rmed
by X-ray spectroscopy 4for 11a, see Fig. 2) and by NMR
spectroscopy. We observed that the reaction conditions of
1,1-dicyano-2,2-4poly¯uoromethyl)ethylenes with N1-sub-
stituted 5-aminopyrazoles depended profoundly upon the
electrophilicity of ethylenes. Indeed, the reaction of alkene
1 with 5-amino-3-methyl-1-44-¯uorophenyl)pyrazole went

A.S. Golubev et al. / Journal of Fluorine Chemistry 114 ꢀ2002) 63±74
67
Fig. 1. The general view of compound 10d.
to completion within 24 h in acetonitrile at room tempera-
ture. Alkenes 3 and 7 reacted similarly. At the same time,
short-time heating was needed for alkylation by alkene 4 to
be brought to completion. Alkene 5 afforded cyclic products
11h±j on prolonged boiling in ethyl acetate.
reaction of 3-phenyl-3-pyrazolin-5-one and 3-methyl-3-pyr-
azolin-5-one with tetracyanoethylene [23] and 2-aryl-1,1-
dicyanoethylene [24].
Earlier, we reported on the reaction of alkene 1 and the
methyl ester of 3,3-dicyano-2-4tri¯uoromethyl)acrylic acid
with 3-methyl-1-phenyl-2-pyrazolin-5-one to give in both
As expected, 3-methyl-3-pyrazolin-5-one afforded pyr-
ano[2,3-c]pyrazole 412) on reaction with alkene
4Scheme 5). The parent fused pyrazoles were isolated on
6
Scheme 4.
Fig. 2. The general view of compound 11a.

Table 4
Synthesis of 1-substituted 6-amino-5-cyano-4,4-bis4polyfluoromethyl)-3-methyl-4,7-dihydropyrazolo-[3,4-b]pyridines
Product
Yield 4%)
Mp 48C)
1H NMR 4d6-DMSO)
19F NMR 4d6-DMSO)
Anal. calcd. 4%)/found
Molecular
formula
C
H
N
11a
11b
11c
11d
11e
56
33
42
42
31
258±259
220±222
186±188
192±195
195±197
9.61 41H, s, NH); 7.54 42H, m, Ph); 7.30 42H, m, Ph);
6.23 42H, br. s, NH2); 2.21 43H, s, CH3)
10.10 41H, br. s, NH); 6.35 42H, s, NH2); 3.63
43H, s, NCH3); 2.08 43H, t, JHÀF ˆ 3:8 Hz, CH3)
9.72 41H, s, NH); 7.61±7.47 45H, m, Ph); 6.41 42H,
br. s, NH2); 2.21 43H, t, JHÀF ˆ 3:5 Hz, CH3)
9.77 41H, s, NH); 7.65±7.55 44H, m, Ph); 6.40 42H,
br. s, NH2); 2.20 43H, s, CH3)
À62.9 46F, s, CF3);
À107.3 41F, m, 4-F-Ph)
À52.7 4m)
47.42/47.08
2.49/2.58
17.28/16.96
C16H10F7N5
36.89/36.44
45.73/45.08
42.27/41.88
40.82/40.28
2.53/2.18
2.64/2.98
2.22/2.38
3.11/3.58
19.56/19.23
16.67/16.36
15.40/14.99
21.64/21.22
C11H9Cl2F4N5
C16H11Cl2F4N5
C16H10Cl3F4N5
C11H10ClF4N5
À53.9 4m)
À53.9 4m)
9.87 41H, br. s, NH); 6.54 41H, t, JFÀH ˆ 53:3 Hz,
CF2H); 6.26 42H, s, NH2); 3.61 43H, s, NCH3);
2.11 43H, s, CH3)
À56.2a 42F); À121.0b
42F, JHÀF ˆ 53 Hz)
11f
11g
11h
11i
11j
67
140±142
124±127
163±165
142±144
151±153
9.72 41H, s, NH); 7.59±7.45 45H, m, Ph); 6.61
41H, t, JFÀH ˆ 52:0 Hz, CF2H); 6.33
À56.2a 42F); À121.0b
42F, JHÀF ˆ 53 Hz)
49.82/49.61
45.73/45.39
45.68/45.25
54.70/54.35
49.82/49.48
3.14/2.74
2.64/2.89
3.83/4.11
3.73/4.01
3.14/3.33
18.16/18.06
16.67/16.33
24.21/23.89
19.94/19.46
18.16/17.86
C16H12ClF4N5
C16H11Cl2F4N5
C11H11F4N5
42H, br. s, NH2); 2.23 43H, s, CH3)
9.57 41H, s, NH); 7.67±7.52 44H, m, Ph); 6.60
41H, t, JFÀH ˆ 54:5 Hz, CF2H); 6.30
42
À56.0a 42F); À121.0b
42F, JHÀF ˆ 53 Hz)
42H, br. s, NH2); 2.22 43H, s, CH3)
68c
45c
51c
9.87 41H, br. s, NH); 6.20 42H, t,
JFÀH ˆ 55:1 Hz, 2CF2H); 6.02 42H, s, NH2);
3.57 43H, s, NCH3); 2.12 43H, s, CH3)
À121.2b 4JHÀF ˆ 55 Hz)
À121.0b 4JHÀF ˆ 55 Hz)
À121.1b 4JHÀF ˆ 55 Hz)
9.59 41H, s, NH); 7.56±7.45 45H, m, Ph); 6.30
42H, t, JFÀH ˆ 54:8 Hz, 2CF2H); 6.20
C16H13F4N5
42H, br. s, NH2); 2.24 43H, s, CH3)
9.35 41H, s, NH); 7.67±7.52 44H, m, Ph); 6.30
42H, t, JFÀH ˆ 54:5 Hz, 2CF2H); 6.20
C16H12ClF4N5
42H, br. s, NH2); 2.24 43H, s, CH3)
11k
11l
89
55
88
165±166
105±106
160±162
9.91 41H, s, NH); 6.17 42H, br. s, NH2); 3.73
43H, s, OCH3); 3.60 43H, s, NCH3); 1.91 43H, s, CH3)
9.51 41H, s, NH); 7.52 45H, m, Ph); 6.18 42H, br. s,
NH2); 3.81 43H, s, OCH3); 2.05 43H, s, CH3)
9.64 41H, s, NH); 7.62 À7.54 44H, m, Ph); 6.36 42H,
br. s, NH2); 3.79 43H, s, OCH3); 2.03 43H, s, CH3)
À54.8a
À55.1a
À55.0a
43.45/43.12
51.85/51.44
47.68/47.29
3.65/3.97
3.58/3.89
3.06/3.12
21.11/20.76
17.78/17.49
16.35/16.31
C12H12ClF2N5O2
C17H14ClF2N5O2
C17H13Cl2F2N5O2
11m
a Centre of an AB-type spin system.
b Centre of an ABX-type spin system.
c Reaction time was 36 h.

A.S. Golubev et al. / Journal of Fluorine Chemistry 114 ꢀ2002) 63±74
69
Scheme 5.
cases the substituted pyrano[2,3-c]pyrazoles in 70% yield
[11]. We studied systematically this reaction using dicya-
noethylenes 2±7 and various 1-aryl-substituted 3-methyl-2-
pyrazolin-5-ones. The dicyanoethylenes 2±7 were allowed
to react with 3-methyl-1-aryl-2-pyrazolin-5-ones in methy-
lene chloride 4or chloroform) over 24 h at room temperature.
The corresponding pyrano[2,3-c]pyrazoles 413) were
obtained in all cases 4Scheme 6, Table 5).
Reactions of ethylenes 2±7 with 3-methyl-1-phenyl-2-
pyrazolin-5-one and 3-methyl-1-44-¯uorophenyl)-2-pyrazo-
lin-5-one gave compound 13 with yields above 60% under
the same conditions. The yields of products in reactions of
CFDCTE with 3-methyl-1-42,6-dichloro-4-tri¯uoromethyl-
phenyl)-2-pyrazolin-5-one apparently correlated with the
electrophilicity of CFDCTE, with the yields being the higher
the more electrophilic CFDCTE. For example, ethylene 3
gave compound 13f in 80% yield after reacting for 24 h,
whereas ethylene 5 gave compound 13l only in 26% yield
after reacting over 7 days. The structure of products 13
as pyrano[2,3-c]pyrazoles were proved by X-ray analysis
4for 13a, see Fig. 3) and NMR spectroscopy. Products of
other structures 4like derivatives of malononitrile for tetra-
cyanoethylene [23] or products of heterocycle alkylation
Fig. 3. The general view of compound 13a.
by cyano group for 2,2-aryl-1,1-dicyanoethylenes [24])
were not detected in the reaction of 3-methyl-1-aryl-2-
pyrazolin-5-ones with CFDCTE, even for the least electro-
philic alkene 5.
Thus, for 3-methyl-2-pyrazolin-5-ones, the only observed
course of the reaction with CFDCTE was C4-alkylation
followed by cyclisation to pyrano[2,3-c]pyrazoles, indepen-
dently of the substituent at N1-nitrogen.
X-ray analysis of the compounds 10d, 11a and 13a has
revealed that molecules contained a pyrazole fragment fused
with a six-membered ring 4Figs. 1±3). The central bicyclic
fragments of 11a and 13a differ only in the heteroatom in the
six-membered ring 4NH-fragment in 11a and an oxygen
atom in 13a), while the shared bond in molecules 11a and
13a is a C=C double bond, the shared bond in compound 10d
is a C±N single bond. The six-membered rings in com-
pounds 11a and 13a are nearly planar 4the deviation of the
tetrahedral carbon atom C4 from the least square plane of the
Ê
other ®ve atoms is equal to 0.05 and 0.03 A, respectively)
and coplanar to the pyrazole rings. The dihedral angles
between the phenyl and pyrazole rings are 45.341) and
40.441)8 for 11a and 13a, respectively.
For compound 10d, the six-membered ring is charac-
terised by the twist conformation with the deviation of the
Ê
C1 and C4 atoms by 0.54 and 0.18 A, respectively. The
CF2Cl group has a pseudo-axial, and CHF2 group has a
pseudo-equatorial position with respect to the bicyclic plane.
To analyse geometric features of pyrazole rings in 10d,
11a and 13a, the Cambridge Structural Database 4CSD) [25]
has been used. We extracted only structures where substi-
tuents did not in¯uence the p-system of the pyrazole rings.
Scheme 6.

Table 5
Synthesis of 2-amino-3-cyano-4,4-bis4polyfluoromethyl)-5-methyl-7-arylpyrano[2,3-c]pyrazoles
Product Yield Mp
1H NMR 4d6-DMSO)
19F NMR 4d6-DMSO)
Anal. calcd. 4%)/found
Molecular
formula
4%)
48C)
NH2
Ph
CH3
Other substituents
±
C
H
N
13a
13b
85
78
182±183 8.22
182±183 8.20
7.78 4d); 7.54 4t);
7.42 4t)
7.81 4m); 7.36 4t)
2.28 4t)
À53.7a 42F); À65.0
43F, t, JFÀF ˆ 12:0 Hz)
À53.7a 42F); À65.0
43F, t, JFÀF ˆ 12:0 Hz);
À115.5 41F)
47.48/47.29 2.49/2.12 13.84/13.41 C16H10ClF5N4O
45.46/45.07 2.15/2.52 13.25/13.00 C16H9ClF6N4O
2.27 4s)
2.29 4s)
±
±
13c
68
325±326 8.31
8.17 4s)
À53.7a 42F);
37.70/37.44 1.30/1.18 10.34/10.23 C17H7Cl3F8N4O
À62.3 43F, s); À65.5
43F, t, JFÀF ˆ 12:0 Hz)
À54.0 4m)
13d
13e
95
93
192±193 8.20
203±205 8.21
7.79 4d); 7.54 4t);
7.42 4t)
2.28 4t, JHÀF ˆ 3:5 Hz)
2.28 4t, JHÀF ˆ 3:5 Hz)
±
±
±
45.63/45.57 2.39/2.52 13.30/12.89 C16H10Cl2F4N4O
43.76/43.47 2.07/2.32 12.76/12.40 C16H9Cl2F5N4O
7.79 4m); 7.54 4t)
À53.9 44F, m); À114.9
41F, m)
13f
13g
80
73
325±326 8.29
150±152 7.99
7.94 4s)
7.77 4d); 7.53 4t);
7.39 4t)
2.31 4s)
2.30 4s)
À53.9 44F, m); À62.1 43F, s) 36.59/36.44 1.26/1.68 10.04/10.45
C
C
17H7Cl4F7N4O
16H11ClF4N4O
6.73 4t, JFÀH ˆ 53:7 Hz) À55.0b 42F); À120.3c
49.69/49.30 2.87/3.12 14.49/14.41
42F, JFÀH ˆ 53:7 Hz)
13h
13i
72
167±168 8.01
7.79 4m); 7.35 4t)
2.29 4s)
2.31 4s)
6.73 4t, JFÀH ˆ 50:0 Hz) À55.5b 42F); À115.0
41F, m); À121.3c
47.48/47.60 2.49/2.35 13.84/13.92 C16H10ClF5N4O
38.99/39.24 1.54/1.22 10.70/10.44 C17H8Cl3F7N4O
42F, JFÀH ˆ 50:0 Hz)
48
313±314 8.29
7.94 4s)
6.78 4t, JFÀH ˆ 53:6 Hz) À55.5b 42F); À62.1
43F, s); À121.3c
42F, JFÀH ˆ 54:0 Hz)
13j
13k
76
67
166±168 7.80
167±169 7.82
7.77 4d); 7.51 4t); 7.37 4t)
2.31 4s)
2.30 4s)
6.45 4t, JFÀH ˆ 54:5 Hz) À121.0c 4JFÀH ˆ 54:5 Hz)
6.45 4t, JFÀH ˆ 54:5 Hz) À111.3 41F, m); À121.0c
44F, JFÀH ˆ 54:5 Hz)
54.55/54.07 3.43/3.52 15.90/16.00 C16H12F4N4O
7.78 4m); 7.34 4t)
51.90/52.07 2.99/3.32 15.13/15.01 C16H11F5N4O
13l
13m
26
80
302±305 8.28
163±165 7.99
7.94 4s)
2.31 4s)
2.30 4s)
6.48 4t, JFÀH ˆ 54:2 Hz) À59.9 43F, s); À121.3c 44F)
6.67 4t, JFÀH ˆ 56:0 Hz) À69.6 43F, s); À120.3c
42F, JFÀH ˆ 56:0 Hz)
41.74/41.47 1.85/1.52 11.45/10.90 C17H9Cl2F7N4O
51.90/51.87 2.99/3.22 15.13/15.48 C16H11F5N4O
7.77 4d); 7.52 4t); 7.39 4t)
13n
53
314±315 8.28
7.92 4s)
2.31 4s)
6.72 4t, JFÀH ˆ 53:5 Hz) À62.1s 43F); À70.0 43F, s);
40.26/40.47 1.59/1.32 11.05/10.70 C17H8Cl2F8N4O
51.72/52.07 3.32/3.62 14.19/14.01 C17H13ClF2N4O3
À121.3c 42F, JFÀH ˆ 53:5 Hz)
13o
13p
13q
90
93
63
166
121
243
8.05
8.05
8.25
7.77 4d); 7.52 4t); 7.39 4t)
7.80 4m); 7.34 4t)
7.87 4s)
2.12 4s)
2.12 4s)
2.15 4s)
3.83 4s, OCH3)
3.83 4s, OCH3)
3.86 4s, OCH3)
À53.9b
À54.1b 42F); À111.0 41F, m) 49.47/49.68 2.93/3.12 13.57/13.31 C17H12ClF3N4O3
À53.8b 42F); À58.0 43F, s)
40.67/40.99 1.90/2.03 10.54/10.72 C18H10Cl3F5N4O3
a Centre of an ABX3-type spin system.
b Centre of an AB-type spin system.
c Centre of an ABX-type spin system.

A.S. Golubev et al. / Journal of Fluorine Chemistry 114 ꢀ2002) 63±74
71
The different contribution of the lone electron pair of the six-
membered ring heteroatom to the total p-conjugated system
of the central fragment leads to pronounced difference of the
bond length distribution of these fragments for compounds
11a and 13a. Thus, the double bonds C3a=C7a and C5=C6
gradually decreases with substitution of halogen atom by a
hydrogen atom, being the lowest for 1,1-dicyano-2,2-bis-
4di¯uoromethyl)ethylene. It was found that 1,1-dicyano-
2,2-bis4tri¯uoromethyl)ethylene and all its analogues reacted
with amidines and N-unsubstituted 345)-aminopyrazoles to
form derivatives of dihydropyrimidines.
Ê
in 11a are longer by 0.02±0.03 A, than corresponding bonds
C4a=C7a and C3=C2 in 13a. In turn, the N1±C7a bond of
Ê
pyrazole ring in 11a 41.35342) A) is elongated in comparison
Ê
to the similar N7±C7a bond in 13a 41.34143) A). The C±C
bond length in pyrazole rings of molecules 11a and 13a
4. Experimental
Ê
41.42143) and 1.42343) A) is signi®cantly higher than the
Ê
average value for such a bond taken from the CSD 41.39 A).
Melting points were determined on a Boetius heating
1
table. The H and 13C NMR spectra were taken on a Bru-
Ê
The N2±N3 bond in 10d is lengthened to 1.37943) A in
Ê
comparison with the average value of 1.36 A for pyrazole
rings according to the CSD. The shortening of the N5±C5
ker-AMX-400 spectrometer operating at 400 and 100.2 MHz,
respectively, with TMS as an internal standard. 19F NMR
spectra were taken on a Bruker-WP-200SY spectrometer
operating at 188.3 MHz with tri¯uoroacetic acid as an exter-
nal standard. Chemical shifts were recalculated relative to
CFCl3, down®eld shifts being designated as positive. The
J values were given in Hz. 1,3-Dichlorotetra¯uoroacetone
was purchased from Aldrich. 1-Chloro-1,1,3,3-tetra¯uoroa-
cetone and 1,1,3,3-tetra¯uoroacetone were synthesised
according to Middleton and Lindsey [26]. Chloropenta¯uor-
oacetone was synthesised from hexa¯uoroacetone according
to [27]. Penta¯uoroacetone was obtained from chloropenta-
¯uoroacetone according to [28]. Methyl 3-chloro-3,3-di¯uor-
opyruvate and methyl 3-bromo-3,3-di¯uoropyruvate were
synthesised starting from methyl 3,3,3-tri¯uoropyruvate
[29]. Commercially unavailable 3-methyl-1-aryl-3-pyrazo-
lin-5-ones were synthesised according to standard synthetic
procedures by the reaction of the corresponding arylhydra-
zine with ethyl acetoacetate. Commercially unavailable
5-amino-3-methyl-1-arylpyrazoles were synthesised accord-
ing to standard procedures by the reaction of arylhydrazine
hydrochlorides with 3-aminocrotononitrile.
Ê
distance up to 1.33443) A is probably caused by the inter-
action of the N5 lone pair with the pyrazole p-system and
double bond C5=C4. It is worth noting that in spite of N5
involvement in conjugation, the N5 atom has a trigonal
pyramidal con®guration: the sum of the bond angles at this
atom is equal to 352.98. The nitrogen atom N8 in 13a is
¯attened in comparison with the N4 atom in 11a 4the sum of
the bond angles of nitrogen atoms is equal to 359.742) and
355.942)8, respectively), and N8±C2 bond is shorter than
Ê
C6±N4 41.31843) and 1.34343) A, respectively). These
effects are probably due to greater conjugation of the amino
group with the six-membered cycle in the molecule 13a in
comparison with that in molecule 11a.
There are centrosymmetrical dimers in the crystal packing
of 10d, 11a and 13a. These dimers are formed by H-bonds
between the CN and NH2 groups. Parameters of the
NH Á Á Á NC hydrogen bonds 4with the normalisation of the
Ê
Ê
N±H bond to 1.01 A) are as follows: N5 Á Á Á N6 2.99443) A,
Ê
H5a Á Á Á N6 2.10 A, N5±H5a±N6 1718 in 10d; N4 Á Á Á N3
Ê
Ê
3.00943) A, H4a Á Á Á N3 2.18 A, N4±H4a±N3 1618 in 11a;
Ê
Ê
4.1. 1,1-Dicyano-2,2-bisꢀchlorodifluoromethyl)ethylene ꢀ3)
N8 Á Á Á N10 2.97443) A, H8a Á Á Á N10 2.13 A, N8±H8a±N10
1648 in 13a.
Three drops of Et3N were added at À40 8C to a solution of
malononitrile 42.42 g, 37 mmol) and 1,3-dichlorotetra¯uor-
oacetone 47.0 g, 35 mmol) in 30 ml of ether. The mixture was
stirred for 16 h at RT. Ether was removed under reduced
pressure. Thionylchloride 48.37 g, 70 mmol)wasaddedtothe
residue. The solution was heated to re¯ux and kept until SO2
evolution ceased. Thionyl chloride was distilled off. The
residue was distilled under reduced pressure. The product
was redistilled to afford 3.66 g 448%) of a slightly yellow
liquid, which solidi®ed upon standing. Mp: 33±36 8C. 13C
NMR 4CDCl3): 155.1 4pentet, JCÀF ˆ 30 Hz, C-2); 120.0 4t,
JCÀF ˆ 297 Hz, CF2Cl); 108.2 4CN); 95.3 4C-1).
3. Conclusions
Synthesis of new CF2H- and CF2Cl-analogues of 1,1-
dicyano-2,2-bis4tri¯uoromethyl)ethylene has been devel-
oped. Heterocyclisation reactions of these ethylenes with
amidines, 5-aminopyrazoles, and 3-methyl-2-pyrazolin-5-
ones have been investigated. Structures of key compounds
were proved by X-ray spectroscopy. It was found that 1,1-
dicyano-2,2-bis4tri¯uoromethyl)ethylene and all its analo-
gues reacted with the same reaction course in the studied
reactions. C4-alkylation followed by cyclisation to fused
pyrazole systems was observed in the reaction of ethylenes
with N1-substituted 5-amino-3-methylpyrazoles and with
3-methyl-2-pyrazolin-5-ones. C4-alkylation proceeded
always in such a way, that the poly¯uoroalkyl-bearing ethy-
lenic carbon attacked the C4-position of the heterocycles.
It was shown that the alkylation ability of new ethylenes
4.2. 1,1-Dicyano-2-ꢀchlorodifluoromethyl)-2-
ꢀdifluoromethyl)ethylene ꢀ4)
Three drops of Et3N were added at 10 8C to a solution
of malononitrile 42.81 g, 43 mmol) and 1-chloro-1,1,3,3-
tetra¯uoroacetone 47.0 g, 43 mmol) in 50 ml of ether. The

72
A.S. Golubev et al. / Journal of Fluorine Chemistry 114 ꢀ2002) 63±74
mixture was stirred for 5 h at RT. A further ®ve drops of Et3N
were added to the reaction mixture. The mixture was stirred
additionally for 12 h at RT. Ether was removed by careful
heating under normal pressure. 4It took ca. 30±40 min.)
Thionyl chloride 410.13 g, 85 mmol) was added to the
residue. The solution was heated to re¯ux and kept until
SO2 evolution ceased. Thionyl chloride was distilled off.
The residue was distilled under reduced pressure. The
product was redistilled to afford 5.3 g 458.6%) of a slightly
was heated at 60 8C for 0.5 h. SOCl2 was evaporated under
reduced pressure. The crude product was puri®ed by dis-
tillation in vacuum 41 Torr).
4.6. Methyl 3,3-dicyano-2-chlorodifluoromethylacrylate
ꢀ7)
13C NMR 4CDCl3): 157.5; 153.1 4t, JCÀF ˆ 25:8 Hz);
108.8; 108.3; 109.9 4t, JCÀF ˆ 308:3 Hz); 94.3; 55.1.
yellow liquid. 13C NMR 4CDCl3): 155.1 4pentet, JCÀF
ˆ
4.7. Methyl 3,3-dicyano-2-bromodifluoromethylacrylate ꢀ8)
31 Hz, C-2); 120.8 4t, JCÀF ˆ 295 Hz, CF2Cl); 109.0 4t,
JCÀF ˆ 247:5 Hz, CF2H); 108.3 4CN); 108.2 4CN); 95.3
4C-1).
13C NMR 4CDCl3): 158.2; 154.3 4t, JCÀF ˆ 26:5 Hz);
109.5; 108.5; 110.7 4t, JCÀF ˆ 307:6 Hz); 94.5; 55.0.
1
Physical, H and 19F NMR spectroscopic, and analytical
data for compounds 3±8 are given in Table 1.
4.3. 1,1-Dicyano-2,2-bisꢀdifluoromethyl)ethylene ꢀ5)
Five drops of Et3N were added at 5 8C to a solution of
malononitrile 41.32 g, 20 mmol) and 1,1,3,3-tetra¯uoroace-
tone 42.6 g, 20 mmol) in 30 ml of ether. The mixture was
stirred for 12 h at RT. A further ®ve drops of Et3N were
added to the reaction mixture. The mixture was stirred for
12 h at RT. This procedure was repeated once more. Ether
was removed by careful heating under normal pressure. 4It
took ca. 30±40 min.) Thionyl chloride 45.0 g, 42 mmol) was
added to the residue. The solution was heated to re¯ux and
kept until SO2 evolution ceased. Thionyl chloride was
distilled off. The residue was distilled under reduced pres-
sure. The product was redistilled to afford 1.46 g 441.0%) of
a slightly yellow liquid. 13C NMR 4CDCl3): 155.3 4pentet,
JCÀF ˆ 23 Hz, C-2); 109.4 4t, JCÀF ˆ 245 Hz, CF2H); 108.4
4CN); 97.2 4C-1).
4.8. 6-Amino-5-cyano-4,4-bisꢀchlorodifluoromethyl)-2-
methyl-1,4-dihydropyrimidine ꢀ9a)
A solution of ethylene 3 41 mmol) in acetonitrile 41.5 ml)
was added to a stirred solution of acetamidine 41 mmol) in
acetonitrile 41.5 ml) at 0 8C. The mixture was stirred for 2 h
at RT. Solvent was removed in vacuum to give a red oil. The
crude product was puri®ed by column chromatography
4silica gel, eluent: ethyl acetate:hexane ˆ 5:2) to give a
white solid.
Compounds 9b±h were obtained in a similar manner from
1
alkenes 3±5 and corresponding amidines. Physical, H and
19F NMR spectroscopic, and analytical data for compounds
9a±h are given in Table 2.
4.9. 7-Amino-6-cyano-5,5-bisꢀchlorodifluoromethyl)-4,5-
dihydropyrazolo[1,5-a]-pyrimidine ꢀ10b)
4.4. 1,1-Dicyano-2-ꢀtrifluoromethyl)-2-
ꢀdifluoromethyl)ethylene ꢀ6)
A solution of alkene 3 40.36 g, 1.5 mmol) in 10 ml of ether
was added dropwise to a solution of 345)-aminopyrazole
40.12 g, 1.5 mmol) in 50 ml of ether at RT. The mixture was
stirred for 12 h. Ether was removed under reduced pressure.
The crude product was puri®ed by column chromatography
4silica gel, eluent: hexanes:ethyl acetate ˆ 1:1) to give
0.25 g of compound 10b. 13C NMR 4d6-DMSO): 150.3;
144.2; 141.8; 129.8 4t, JCÀF ˆ 312 Hz, CF2Cl); 116.2; 85.8;
71.2 4pentet, JCÀF ˆ 16 Hz, C-4); 49.1.
Five drops of Et3N were added at À10 8C to a solution of
malononitrile 43.12 g, 47 mmol) and penta¯uoroacetone
47.0 g, 47 mmol) in 50 ml of ether. The mixture was stirred
for 10 h at 10 8C, and 24 h at RT. Ether was removed by
carefulheatingundernormalpressure. Theremainingmixture
was mixed with 26.7 g 40.188 mol) of phosphorus pentoxide,
and the mixture was heated in a simple still until no further
distillate was collected. Redistillation gave 4.3 g 449.4%) of
a colourless liquid. 13C NMR 4CDCl3): 150.5 4m, C-2); 119.4
4q, JCÀF ˆ 277:6 Hz, CF3); 109.2 4t, JCÀF ˆ 246:5 Hz,
CF2H); 108.1 4CN); 107.9 4CN); 98.9 4C-1).
Compounds 10a,c±h were obtained in the same manner
from alkenes 2±7 and 345)-aminopyrazole or 345)-amino-
1
543)-methylpyrazole. Physical, H and 19F NMR spectro-
scopic, and analytical data for compounds 10a±h are given
in Table 3.
4.5. General procedure for the preparation of ethylenes ꢀ7)
and ꢀ8)
4.10. 6-Amino-5-cyano-4,4-bisꢀtrifluoromethyl)-3-methyl-
1-ꢀ4-fluorophenyl)-4,7-dihydropyrazolo[3,4-b]pyridine
ꢀ11a)
Quinoline 4or pyridine) 4two to three drops) was added at
10 8C to a stirred mixture of methyl 3-halo-3,3-di¯uoro-2-
oxopropionate 424.3 mmol), malononitrile 424.0 mmol) and
dry ether 43 ml). A mixture was stirred for 0.5 h at RT. Ether
was removed in vacuum 420 Torr). Thionyl chloride
480 mmol) was added to the remaining oil. The solution
A solution of ethylene 1 40.2 g, 0.9 mmol) and 1-44-¯uor-
ophenyl)-3-methyl-5-aminopyrazole 40.17 g, 0.9 mmol) in

A.S. Golubev et al. / Journal of Fluorine Chemistry 114 ꢀ2002) 63±74
73
dry acetonitrile 45 ml) was stirred for 48 h at RT. Acetonitrile
4.13. 6-Amino-5-cyano-4-ꢀchlorodifluoromethyl)-4-
ꢀdifluoromethyl)-1,3-dimethyl-4,7-dihydropyrazolo[3,4-
b]pyridine ꢀ11e)
was removed under reduced pressure. The crude product
was puri®ed by column chromatography 4silica gel, eluent:
methylene chloride:ethyl acetate ˆ 4:1) to give 0.2 g of
compound 11a.
Compounds 11b±d were obtained in the same manner
from alkene 3 and 1-substituted 3-methyl-5-aminopyra-
zoles.
A solution of alkene 4 40.21 g, 1 mmol) and 1,3-dimethyl-
5-aminopyrazole 40.11 g, 1 mmol) in 10 ml of ethyl acetate
was stirred for 30 min at RT. The solution was rigorously
heated under re¯ux for 30 min. After cooling the solution,
ethyl acetatewas removed under reduced pressure. The crude
product was puri®ed by column chromatography 4silica
gel, eluent: acetone:ethyl acetate ˆ 1:4) to give 0.1 g of
compound 11e. Compounds 411f±j) were obtained in the
same manner from alkenes 4 and 5 and 1-substituted 3-
methyl-5-aminopyrazoles. Compounds 411k±m) were
obtained from alkene 4 and 1-substituted 3-methyl-5-ami-
nopyrazoles under the same conditions as for the synthesis of
4.11. 6-Amino-5-cyano-4,4-bisꢀchlorodifluoromethyl)-3-
methyl-1-phenyl-4,7-dihydro-pyrazolo[3,4-b]pyridine
ꢀ11c)
13C NMR 4d6-DMSO): 155.3; 145.4; 138.3; 136.6; 131.9
4t, JCÀF ˆ 313 Hz, CF2Cl); 129.6; 128.8; 123.9; 119.1 4CN);
91.4; 62.2 4pentet, JCÀF ˆ 16 Hz, C-4); 49.7; 14.3 4t,
JCÀF ˆ 10 Hz, CH3).
1
compound 11a. Physical, H and 19F NMR spectroscopic,
andanalyticaldata forcompounds 11a±haregiveninTable 4.
4.12. 6-Amino-5-cyano-4,4-bisꢀchlorodifluoromethyl)-3-
methyl-1-ꢀ4-chlorophenyl)-4,7-dihydropyrazolo[3,4-
b]pyridine ꢀ11d)
4.14. 6-Amino-5-cyano-4-trifluoromethyl-4-
difluoromethyl-3-methyl-1,4-dihydro-pyrano[2,3-
c]pyrazole ꢀ12)
13C NMR 4d6-DMSO): 155.3; 145.7; 138.6; 135.3;
132.5; 131.8 4t, JCÀF ˆ 313 Hz, CF2Cl); 129.6; 125.6;
119.2 4CN); 91.5; 62.1 4pentet, JCÀF ˆ 16 Hz, C-4);
49.5; 14.3 4CH3).
A solution of alkene 6 40.2 g, 1.0 mmol) in dry acetoni-
trile 410 ml) was added dropwise to a solution of 3-methyl-3-
pyrazolin-5-one 40.1 g, 1.0 mmol) in dry acetonitrile
Table 6
Crystal and data reduction parameters for compounds 10d, 11a and 13a
10d
11a
13a
Formula
Molecular mass
T 4K)
C9H6Cl1F4N5
295.64
C20H18Cl1F5N4O3
492.83
C20H19F7N6O
492.41
110
148
178
Crystal system
Space group
Monoclinic
P21/n
Monoclinic
P21/c
Triclinic
P1
Ê
a 4A)
9.69542)
10.76842)
10.93443)
6.91443)
9.77845)
32.655417)
6.77041)
10.47142)
15.90843)
101.1442)
94.9542)
95.7042)
1094.543)
2
Ê
b 4A)
Ê
c 4A)
a 48)
b 48)
g 48)
98.3841)
92.0244)
Ê 3
V 4A )
Z
1129.244)
4
220642)
4
m4Mo Ka) 4mmÀ1
)
0.386
0.245
0.137
Dx 4g cmÀ3
Diffractometer
)
1.739
SMART 100 CCD
1.484
Siemens P3/PC
1.494
Syntex P21
Ê
l 4A)
Scan method
0.71073
o
50
y/2y
54
y/2y
52
2ymax 48)
Crystal size 4mm  mm  mm)
Reflections measured
Unique reflections
Rint
0.40 Â 0.15 Â 0.10
0.30 Â 0.15 Â 0.15
0.4 Â 0.3 Â 0.1
4703
8426
5214
1992
4816
4320
0.0385
1434
0.0405
3662
0.0331
3279
Reflections with I ꢀ 2s4I)
Refined variables
R[F2 ꢀ 2s4F2)]
200
464
371
0.0468
0.985
0.1302
0.0648
1.065
0.1897
0.0442
1.078
0.1236
Goodness-of-fit
wR4F2), all data

74
A.S. Golubev et al. / Journal of Fluorine Chemistry 114 ꢀ2002) 63±74
410 ml). The mixture was stirred for 24 h. The solution was
®ltered off from insoluble admixtures. The ®ltrate was
evaporated under reduced pressure to give yellowish crys-
tals. They were washed several times with chloroform to
afford pure compound 12 as white crystals 40.17 g, 57%).
Mp: 270±271 8C. 1H NMR 4d6-DMSO): 12.55 4s, 1H, NH);
7.46 4s, 2H, NH2); 6.30 4t, 1H, JHÀF ˆ 55:1 Hz, CF2H); 2.31
4s, 3H, CH3). Anal. calcd. 4%) for C10H7F5N4O: C, 40.83; H,
2.40; N, 19.04. Found: C, 40.35; H, 2.60; N, 18.66.
References
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Acknowledgements
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This work is supported by E.I. Du Pont de Nemours and
Co in the frame of co-operation through International
Science and Technology Centre 4ISTC Project no. 1016-
97). X-ray studies are performed under Grant 00-15-97359
from Russian Foundation for Basic Research.
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