Phenoxydifluoromethyl substituted nitrogen heterocycles. Synthesis and heterocyclization reactions of ethyl 4,4-difluoro-4-phenoxyacetoacetate

Article abstract of DOI:10.3390/90300164

Ethyl 4,4-difluoro-4-phenoxyacetoacetate was obtained and studied as a precursor to new heterocyclic compounds. 6-Hydroxypyrimidine, 1,3-dihydro-1,5-benzodiazepin-2-one, quinolin-2-one and 6-hydroxypyrazolo[3,4-b] pyridine derivatives containing phenoxydifluoromethyl groups were synthesized. These results make it possible to introduce aryloxydifluoromethyl substituents for the design of biologically active heterocycles.

Full text of DOI:10.3390/90300164

Molecules 2004, 9, 164-169
molecules
ISSN 1420-3049
http://www.mdpi.org
Phenoxydifluoromethyl Substituted Nitrogen Heterocycles.
Synthesis and Heterocyclization Reactions of Ethyl 4,4-Difluoro-
4-phenoxyacetoacetate
S.Yu. Solodukhin, A.S. Peregudov, E.V. Vorontsov and N.D. Chkanikov*
A. N. Nesmeyanov Institute of Organoelement Compounds (INEOS), Russian Academy of Sciences,
Vavilov Str. 28, 119991 Moscow, Russia
* Author to whom correspondence should be addressed. Phone: (+7) 095 135-6489. E-mail:
nchkan@ineos.ac.ru
Received: 15 January 2004 / Accepted: 18 January 2004 / Published: 28 February 2004
Abstract: Ethyl 4,4-difluoro-4-phenoxyacetoacetate was obtained and studied as a
precursor to new heterocyclic compounds. 6-Hydroxypyrimidine, 1,3-dihydro-1,5-
benzodiazepin-2-one, quinolin-2-one and 6-hydroxypyrazolo[3,4-b]pyridine derivatives
containing phenoxydifluoromethyl groups were synthesized. These results make it
possible to introduce aryloxydifluoromethyl substituents for the design of biologically
active heterocycles.
Keywords: Ethyl 4,4-difluoro-4-phenoxyacetoacetate, heterocyclization reactions,
phenoxydifluoromethyl group, biologically active heterocycles.
Introduction
For the most part, a search for biologically active compounds in the series of polyfluoroalkylated
heterocycles follows the path of synthesis of various heterocyclic structures containing a limited set of
polyfluoroalkyl substituents [1,2]. Development of methodology for introduction of new, functionally
modified groups into the heterocyclic skeleton extends the range of the design of the bioactive
derivatives. In this work, the introduction of aryloxydifluoromethyl groups into nitrogen heterocycles
was studied. The only known case of such a modification is a reaction of 2-(bromodifluoro-

Molecules 2004, 9
165
methyl)benzoxazole with phenols in the presence of sodium hydride to give 2-(aryloxydifluoro-
methyl)benzoxazoles. Some of these compounds have been reported to exhibit anti-HIV activity.
However, a wider use of this method is hindered due to the presence of nucleophilic groups and mobile
protons in the heterocycle as well as the inaccessibility of such starting materials as CF2Br-substituted
heterocycles. Besides, the reactivity of the CF2Br group depends substantially on the chemical
environment in the heterocycle [3]. Thus, the above method, as any other one, which involves a
chemical transformation of polyfunctional compounds, could be applied only for specific cases. To
create a chemical basis for a wider use of aryloxydifluoromethyl groups the general precursors to the
corresponding heterocycles are needed. We have chosen ethyl 4,4-difluoro-4-phenoxyacetoacetate (1)
as a target precursor.
Results and Discussion
To synthesize ketoester 1 we used a way similar to the described method for preparing ethyl esters
of acetoacetic and 4,4,4-trifluoroacetoacetic acids, i.e. the Claisen condensation in the presence of
various bases such as alkali metal alkoxides and hydrides [4,5]. The known methyl
phenoxydifluoroacetate [6] was used as a starting material. Its reaction with ethyl acetate in the
presence of sodium hydride leads to the target ketoester 1 in 75% yield (Scheme 1)
Scheme 1
O
O
O
O
1) NaH
O
O
OC2H5
CF2
+
CF2 OMe
H3C
OC2H5
2) H2SO4
1
The reactivity of 1 in heterocyclization reactions with nitrogen-containing nucleophiles was found
to be similar to that of well studied ethyl 4,4,4-trifluoroacetoacetate [7, 8]. For example, the reaction
of 1 with benzamidine at room temperature leads to 2-phenyl-4-(phenoxydifluoromethyl)-6-hydroxy-
pyrimidine (2) in 93% yield (Scheme 2).
Scheme 2
O
O
N
N
NH
O
CF2
OC2H5
+
O
NH2
CF2
OH
2
1

Molecules 2004, 9
166
Reaction of ethyl 4,4,4-trifluoroacetoacetate with o-phenylenediamine is known to give two
different products depending on the conditions [8]. In basic and neutral media 4-trifluoromethyl-1,3-
dihydro-1,5-benzodiazepin-2-one is formed in high yield, whereas in an acidic medium 3-(2-
benzimidazolyl)-1,1,1-trifluoromethyl-2-propanone is only formed in low yield. In a similar way, the
reaction of 1 with o-phenylenediamine in benzene under neutral conditions, furnished 4-(phenoxy-
difluoromethyl)-1,3-dihydro-1,5-benzodiazepin-2-one (3) in good yield (Scheme 3).
Scheme 3
H
O
O
O
N
H2N
H2N
O
+
OC2H5
CF2
O
N
CF2
3
1
Upon heating 1 with p-anizidine in polyphosphoric acid, 2-(phenoxydifluoromethyl)-6-methoxy-
1H-quinoline-4-one (4) was obtained in 47% yield (Scheme 4).
Scheme 4
O
NH2
O
O
MeO
PPA
100o
O
CF2
OC2H5
+
O
N
CF2
H
OMe
4
1
Reactions of ethyl 4,4,4-trifluoroacetoacetate with aminopyrazoles to give pyrazolo[3,4-
b]pyridines were thoroughly studied by Balicki et al. [9]. In particular, it was shown that the use of
glacial acetic acid as a medium prevents the addition of the ester to the amino group due to protonation
of the latter and promotes the attack at C-4 position of the pyrazole ring. For example, 6-hydroxy-2-
methyl-4-trifluoromethylpyrazolo[3,4-b]pyridine was selectively prepared in a high yield by reaction
of ethyl 4,4,4-trifluoroacetoacetate with 1-methyl-3-aminopyrazole [9]. 5-Aminopyrazoles also have
two reactive sites, the amino group and C-4 position of the pyrazole ring. In this work, the reaction of
5-amino-1-(3-chlorophenyl)-3-methylpyrazole with ester 1 was carried out in glacial acetic acid under
reflux conditions and gave 1-(3-chlorophenyl)-4-(phenoxydifluoromethyl)-6-hydroxypyrazolo-[3,4-
b]pyridine (5) in high yield (Scheme 5).

Molecules 2004, 9
167
Scheme 5
O
CF2
H3C
H3C
O
O
N
CH3COOH
120 oC
NH2
Cl
N
N
O
N
+
OC2H5
N
OH
CF2
Cl
5
1
Conclusions
Ethyl (phenoxydifluoromethyl)acetoacetate is a valuable precursor to various heterocycles
substituted with a phenoxydifluoromethyl group.
Experimental
General
1H-, 13C- and 19F-NMR spectra were obtained on a Bruker AMX-400 instrument operating at
1
400.1, 100.6 and 376.5 MHz, respectively. Chemical shifts in the H- and 13C-NMR spectra were
calculated from residual signals of deuterated solvents (2.51 ppm for DMSO-d6 and 7.27 ppm for
19
CDCl3). Chemical shifts in F-NMR spectra were obtained using trifluouroacetic acid as an external
1
13
standard. In the case of 5, the assignments of signals in H- and C- spectra were performed on a
1
1
Bruker Avance-300 spectrometer (300.1 MHz for H and 75.5 MHz for 13C) using H-NOESY,
1H-COSY, H13C-HSQC and HMBC experiments. The mass spectra were obtained on a Kratos MS
1
890 spectrometer at 70 eV using a direct inlet system and with an ion source temperature of 250°.
Methyl phenoxydifluoroacetate was synthesized according to the method of Yagupol’skii and
Korin’ko [6]. Commercially unavailable 5-amino-1-(3-chlorophenyl)-3-methylpyrazole was
synthesized according to the standard synthetic procedure by the reaction of 3-chlorophenylhydrazine
hydrochloride with 3-aminocrotononitrile.
Ethyl 4,4-difluoro-4-phenoxyacetoacetate (1). To a solution of methyl phenoxydifluoroacetate (9 g,
4.5 mmol) in dry ethyl acetate (8.8 g, 10 mmol) sodium hydride (60% suspension in mineral oil, 1.8 g)
was added while cooling with ice water. The mixture was stirred until the solid phase dissolved (about
15 min). Dry ether (50 mL) was added to the resultant solution and the mixture was heated under
reflux for 8 hr. Ether and ethyl acetate were removed under reduced pressure and the residue was
dissolved in ether and treated with diluted sulfuric acid (20%). The organic layer was separated and the
aqueous layer was extracted with ether (2×50 mL). The combined organic phase was dried over
sodium sulfate for 2 hr. Ether was removed under a reduced pressure and the residue was distilled to
give 8.72 g (75%) of 1 as a colorless liquid: b.p. 85-88°/0.5 mmHg; nd =1,4718 ; 1H-NMR (CDCl3) δ
24

Molecules 2004, 9
168
1.29-1.35 (m, 3H, CH2CH3), 3.81-3.87 (m, 2H, CH2keto), 4.25-4.31 (m, 2H, CH2CH3), 5.72 (s, CH enol),
7.21-7.41 (m, 5H, HAr), 12.00 (broad s, OH enol).
6-Hydroxy-4-(phenoxydifluoromethyl)-2-phenylpyrimidine (2). To a solution of benzamidine (0.12 g,
0.1 mmol) in 10 mL of dry acetonitrile was added 0.3 g (0.12 mmol) of 1. The mixture was stirred at
room temperature for 2 hr. The precipitate of 2 (0.06 g) was filtered off, washed with petroleum ether
and dried. The mother liquor was concentrated to 4 mL and kept at room temperature for 5 days. The
precipitate was filtered off, washed with petroleum ether several times and dried to obtain a total of
1
0.29 g (93.5%) of 2 as colorless crystalline compound: Н-NMR (DMSO-d6) δ 6.77 (s, 1Н,
19
СНpyrimidine), 7.20-7.96 (m, 10Н, НAr), 11.13 (s, 1Н, exchangeable with D2O, ОН); F-NMR (DMSO-
d6) δ 9.63 (s, CF2ОAr); MS m/z 314, М+; Analysis: Calculated for C17H12F2N2O2: С 64.97; H 3.85; N
8.91. Found: С 64.81; H 3.97; N 8.94.
4-(Phenoxydifluoromethyl)-1,3-dihydro-1,5-benzodiazepin-2-one (3). To a solution of o-phenylene-
diamine (0.11 g, 0.1 mmol) in dry benzene (15 mL) was added 0.3 g (0.12 mmol) of 1. The mixture
was heated under reflux for 1.5 hr with a Dean-Stark device. The mixture was then cooled and kept at
5º for 0.5 hr. The precipitate was filtered off, washed with petroleum ether and dried to obtain 0.3 g
(66.2%) of 3 as white crystalline compound: 1Н-NMR (DMSO-d6) δ 3.43 (s, 2Н, СН2azepine), 7.22-7.50
(m, 9Н, НAr), 10.72 (s, 1Н, NH); 19F-NMR (DMSO-d6) δ 3.54 (s, CF2ОAr); МS m/z 302, М+;
Analysis: Calculated for C16H12F2N2O2: С 63.58; H 4.00; N 9.27. Found: С 63.58; H 4.05; N 9.31
2-(Phenoxydifluoromethyl)-6-methoxy-1H-quinoline-4-one (4). p-Anisidine (0.11 g, 0.14 mmol) was
suspended in polyphosphoric acid (15 mL). The suspension was heated to 60º and treated with 0.4 g
(0.16 mmol) of 1. The reaction mixture was then heated at 100º for 3 hr. After cooling the mixture was
treated with 200 mL of ice water. The solid formed was filtered off, washed several times with water
1
and a small amount of ether and dried to obtain 0.18 g (46%) of 4 as pale brown solid: Н-NMR
(DMSO-d6) δ 3.88 (s, 3Н, ОСН3), 6.98 (broad. s., 1Н, exchangeable with D2O, NH), 7.35-7.97 (m, 9Н,
НAr); 19F-NMR (DMSO-d6) δ 2.09 (s, CF2ОAr); МS m/z 317, М+; Analysis: Calculated for
C17H13F2NO2: С 67.77; H 4.35; N 4.65. Found: С 67.69; H 4.21; N 4.48.
1-(3-Chlorophenyl)-3-methyl-4-(phenoxydifluoromethyl)-6-hydroxypyrazolo[3,4-b]pyridine (5). To a
solution of 5-amino-1-(3-chlorophenyl)-3-methylpyrazole (0.2 g, 0.1 mmol) in glacial acetic acid (6
mL) was added 0.3 g (0.12 mmol) of 1. The mixture was heated under reflux for 6 hr. The solution was
then cooled to room temperature, poured into 20 mL of ice water and kept at 2º for 2 days. The
precipitate formed was filtered off, washed with petroleum ether and dried to obtain 0.36 g (90%) of 5
1
as white solid: Н-NMR (DMSO-d6) δ 2.61 (s, 3Н, СН3), 6.99 (s, 1Н, СН5), 7.30-7.40 (m, 4Н, НAr),
7.40-7.50 (m, 2H, HAr ), 7.56 (t, 1H, J = 8.5 Hz, H5’), 8.18 (broad d, 1H, J = 8.5Hz, H6’), 8.31 (broad
t, 1H, J = 2.0Hz, H2’), 12.23 (s, 1Н, ОН); 19F-NMR (DMSO-d6) δ 14.07 (s, CF2OPh). 13C-{1H}
NMR* (DMSO-d6) δ 15.3 (s, CH3), 104.6 (s, C5), 106.3 (s, C3a), 119.4 (s, C2’), 120.4 (s, C6’), 120.6
(t, J = 261.6 Hz, CF2), 121.9 (s, C3”, C5”), 125.9 (s, C4’), 126.9 (s, C4”), 130.5 (s, C2”, C6”), 131.2

Molecules 2004, 9
169
(s, C3’), 133.9 (s, C5’), 137.5 (t, J = 34.6 Hz, C4), 140.4 (s, C1’), 142.4 (s, C3), 149.8 (s, C1”), 151.2
(s, C7a), 164.2 (s, C6); MS m/z 401, М+; Analysis: Calculated for C20H14F2N3O2: С 59.79; H 3.51; N
10.46. Found: С 59.76; H 3.41; N 10.52.
* Atoms in 5 are numbered as follows:
2"
3"
5"
1"
4"
O
F2C
6"
4
H3C
2 N
3a
3
5
6
7a
1N
N
OH
7
1'
2'
3'
6'
5'
Cl
4'
References
1. Furin, G. G. Zh. Org. Chim. 1994, 30, 1704; CAN 101:191768.
2. Erian, A. W. J. Heterocycl. Chem. 2001, 38, 793.
3. Burkholder, C. R.; Dolbier, W. R.; Medetielle, Jr,. M. J. Fluorine Chem. 2001, 109, 39.
4. Henne, A.; Newman, M.; Quill, L.; Stainforth, R. J. Am. Chem. Soc. 1947, 69, 1819.
5. McBee, E.; Pierce, O.; Kilbourn, H.; Wilson E. J. Am. Chem. Soc. 1953, 75, 1749.
6. Yagupol’skii, L. M.; Korin’ko, V. A. Zh. Obshch. Khim. 1969, 39, 1749 [CAN 71:123853].
7. Bergmann, E. D.; Cohen, S.; Shahak, I. J. Chem. Soc. 1959, 11, 3278.
8. Wigton, F. B.; Joullie, M. M. J. Am. Chem. Soc. 1959, 81, 5212.
9. Balicki, R. Pol. J. Chem. 1983, 57, 413.
Sample availability: Contact authors.
© 2004 by MDPI (http:www.mdpi.org). Reproduction is permitted for noncommercial purposes.