A facile synthesis of fluorine-containing heterocycles - Use of 1,1,1-trifluoro-2-alkanones as a convenient synthetic intermediate

Article abstract of DOI:10.1002/jhet.5570380339

1,1,1-Trifluoro-2,3-alkanediones 2 easily obtainable from various aldehyde dialkylhydrazones were reacted with several diamines to afford trifluoromethylquinoxalines 3 and trifluoromethylpyrazines 4 in good yields. With the use of aldehydes and aqueous ammonia instead of diamines, diketones 2 were successfully converted to the corresponding 4-trifluoromethylimidazoles 5 in satisfactory yields.

Full text of DOI:10.1002/jhet.5570380339

May-Jun 2001
A Facile Synthesis of Fluorine-containing Heterocycles -
Use of 1,1,1-Trifluoro-2-alkanones as a Convenient Synthetic Intermediate
Yasuhiro Kamitori*
773
Department of Chemical Science and Engineering,
Faculty of Engineering, Kobe University, Kobe 657-8501, Japan
Received November 28, 2000
1,1,1-Trifluoro-2,3-alkanediones 2 easily obtainable from various aldehyde dialkylhydrazones were
reacted with several diamines to afford trifluoromethylquinoxalines 3 and trifluoromethylpyrazines 4 in
good yields. With the use of aldehydes and aqueous ammonia instead of diamines, diketones 2 were
successfully converted to the corresponding 4-trifluoromethylimidazoles 5 in satisfactory yields.
J. Heterocyclic Chem., 38, 773 (2001).
Fluorine-containing heterocycles are very fascinating
of 1,2-phenylenediamine, 2b gave chloroquinoxaline
(3e) as a mixture of two regioisomers. Quite similarly, 2b
treated with slightly excess amounts of diaminomaleo-
nitrile afforded the corresponding 5-(p-tolyl)-6-trifluoro-
methylpyrazine-2,3-dicarbonitrile (4b) [5] in 76% yield.
In the case of 5-trifluoromehylpyrazine-2,3-dicarbon-
itrile (4d), one pot synthesis from 1d was successful.
targets for synthetic organic chemists because of their
potentially high physiological activities [1-4]. Previously we
reported successful electrophilic substitution reaction at the
azomethine carbon atoms of aldehyde dialkylhydrazones
with the use of trifluoroacetic anhydride (TFAA) as an acyl-
ating agent. By means of this reaction, dialkylhydrazones of
a variety of aldehydes can be converted to the corresponding
3-(dialkylhydrazono)-1,1,1-trifluoro-2-alkanones (1) [5-8].
1,1,1-Trifluoro-2,3-alkanediones (2) easily obtainable as
monohydrates by hydrolysis of 1 are thought to be good
synthetic intermediates for construction of several hetero-
cycles bearing a trifluoromethyl group at their ring position.
In this paper, we wish to report a facile and convenient syn-
thetic method for a variety of trifluoromethylated hetero-
cycles including imidazoles and pyrazine derivatives.
Hydrazone 1d was hydrolyzed in 2.5 M H SO , and
2
4
subsequently, treated with equimolar amounts of
diaminomaleonitrile to afford 4d in 94% yield.
We also tried the synthesis of 3b directly from
3-(dialkylhydrazono)-1,1,1-trifluoro-2-alkanones (1b). In
the presence of acetic acid, 1b reacted with 1,2-phenyl-
enediamine in refluxing acetonitrile to give quinoxaline 3b
in 89% yield. Similarly, quinoxaline 3c was obtained in
34% yield directly from hydrazone 1c. This direct method
is more convenient than the above method via diketones 2.
However the yield of 3c in this case was lower than the
total yield (41%) of 3c from 1c via diketone 2c using the
usual method.
According to a usual manner [5-8], aldehyde dialkyl-
hydrazones treated with trifluoroacetic anhydride gave
3-(dialkylhydrazono)-1,1,1-trifluoro-2-alkanones (1a-c).
These were hydrolyzed with hot 10 M sulfuric acid to afford
1,1,1-trifluoro-2,3-alkanedione (2a-c) as monohydrates.
The so-obtained diketones 2a-c reacted successfully
with equimolar amounts of 1,2-phenylenediamine to
afford the corresponding quinoxaline 3a-c in high yields.
When 4-chloro-1,2-phenylenediamine was used instead

774
Y. Kamitori
Vol. 38
Diketone 2 was also found to be useful for the synthesis
common intermediate used for the synthesis of these hetero-
cycles. Also, 3-(dialkylhydrazono)-1,1,1-trifluoro-2-alka-
nones 1, the precursor of 2, can be used for the convenient
synthesis of quinoxalines 3 and pyrazines 4. These dike-
tones 2 and hydrazones 1 should be powerful intermediates
for construction of a variety of other trifluoromethylated
heterocycles, such as furanes, pyroles, thiophenes, pyridazi-
nones, triazinones, and so on. Syntheses of these hetero-
cycles are now under investigation.
of 4-trifluoromethylimidazoles (5). In the presence of
excess amounts of ammonia, 2b and 2c reacted with
aliphatic aldehydes to afford 4-trifluoromethylimidazoles
(5a-c) in moderate to good yields. In the case of the
imidazole formation reaction from 2 and aromatic
aldehydes instead of aliphatic aldehydes, the following
method gave good results. In the presence of excess of
ammonium acetate, 2b was treated with p-tolualdehyde in
hot acetic acid to afford the corresponding imidazole 5c in
53% yield. The second method was applicable to the
synthesis of 2,4-bistrifluoromethylimidazoles. With the use
of 1-ethoxy-2,2,2- trifluoroethanol instead of aldehyde,
diketones 2b and 2c were successfully converted to the
corresponding 2,4-bistrifluoromethylimidazoles (5e and 5f,
respectively).
EXPERIMENTAL
Melting points were determined with a Mitamura Riken model
1
13
7-12 apparatus and are uncorrected. The H nmr and C nmr
spectra were recorded at 60 MHz on a JEOL PMX 60SI and at
59.5 MHz on a Bruker AC 250, respectively. Unless otherwise
noted nmr spectra were measured in deuteriochloroform
containing tetramethylsilane as an internal standard. The ir spectra
were taken with a Hitachi model G3. 3-(Dialkylhydrazono)-1,1,1-
trifluoro-2-alkanones 1 and 1,1,1-trifluoro-2,3-alkanediones 2
were prepared according to a literature method [5-8].
3-Trifluoromethylquinoxalines 3a-e.
General Procedure.
A mixture of 2a-c (0.5 mmoles), and 1,2-phenylenediamine or
4-chloro-1,2-phenylenediamine (0.5 mmol) in acetonitrile (3 ml)
was stirred at room temperature for 24 hours. Removal of the
solvent afforded 3-trifluoromethylquinoxalines 3a-e.
3-Trifluoromethyl-2-phenylquinoxaline (3a).
This compound was obtained as pale yellow crystals (cyclo-
1
hexane): mp 117°, H nmr: δ 7.37 (s, 5H, Ph), 7.57-7.88 (m, 2H,
C6-H and C7-H), 7.93-8.18 (m, 2H, C5-H and C8-H); ir
-1
(potassium bromide): ν 1075, 1131, 1192 (CF ) cm .
3
Anal. Calcd. for C H F N : C, 65.69; H, 3.31; N, 10.21.
15
9 3 2
Found: C, 65.77; H, 3.24; N, 10.03.
The structures of compounds 3-5 were confirmed by
H and C nmr, and ir spectra, and micro combustion
1
13
3-Trifluoromethyl-2-(p-tolyl)quinoxaline (3b).
analysis. A tautomeric equilibrium between A and B is
possible for imidazoles 5. In the C nmr spectra of 5b,
This compound was obtained as pale yellow crystals (cyclo-
hexane): mp 141-142° (lit 115°) [5].
13
the imidazole ring carbon atoms C2, C4, and C5 appear at
2-Ethyl-3-trifluoromethylquinoxaline (3c).
2
158.8, 123.8 ( J
= 36.0 Hz), and 131.0 ppm,
CF
respectivery. These values are more compatible with
those observed for 1-methyl-5-(p-tolyl)-4-trifluoro-
methyl-1H-imidazole than those for 1-methyl-4-
(p-tolyl)-5-trifluoromethyl-1H-imidazole [9,10]. This
indicates that imidazole 5b is predominantly present as
tautomer A (4-trifluoromethylimidazole).
This compound was obtained as yellow oil: bp 120°/80 Torr
1
(oven temperature of Kugelrohr distillation), H nmr: δ 1.45
(t, J = 7.2 Ηz, 3Η, CΗ ), 3.20 (q, J = 7.2 Ηz, 2H, CH ), 7.68-8.30
3
2
-1
(m, 4H, aryl); ir (potassium bromide): ν 1120, 1185 (CF ) cm .
3
Anal. Calcd. for C H F N : C, 58.41; H, 4.01; N, 12.38.
11
9 3 2
Found: C, 58.63; H, 4.29; N, 12.11.
6-Chloro-3-trifluoromethyl-2-(p-tolyl)quinoxaline and 6-Chloro-
2- trifluoromethyl-3-(p-tolyl)quinoxaline (3e).
These compounds were obtained as 13:5 mixture.
Fractionation of the mixture by preparative tlc (benzene/ethyl
acetate = 9:1) afforded each regioisomer. One (Rf = 0.85) was
obtained as pale yellow crystals (83 mg, 52%): mp 126.3° (cyclo-
In conclusion, we present here convenient synthetic
methods applicable to quinoxalines, pyrazines, and
imidazoles bearing a trifluoromethyl group at their ring
position. 1,1,1-Trifluoro-2,3- alkanediones 2 were the
1
hexane), H nmr: δ 2.44 (s, 3Η, CΗ ), 7.10−7.58 (dd, J = 8.0 Ηz,
3
4H, C H CH ), 7.69 (dd, J = 8.8 Ηz and 2.0 Hz, 1H, C7-H), 8.08
6
4
3
(d, J = 2.0 Hz, 1H, C5-H), 8.09 (d, J = 8.8 Ηz, 1H, C8-H); ir
-1
(potassium bromide): ν 1077, 1135, 1182 (CF ) cm .
3

May-Jun 2001
A Facile Synthesis of Fluorine-containing Heterocycles
775
Anal. Calcd. for C
Found: C, 59.36; H, 3.29; N, 8.52.
The other (Rf = 0.79) was obtained as pale yellow crystals
H
ClF N : C, 59.55; H, 3.12; N, 8.68.
2
16 10
3
2
CF ), 123.8 ( J = 36.0 Hz, C4), 125.9 (C1' of p-Tol), 128.3,
3 CF
3
129.1 (C2', C3', C5', and C6' of p-Tol), 131.0 ( J = 3.1 Hz, C5),
138.1 (C4' of p-Tol), 158.8 (C2); H nmr (d -acetonitrile): δ 1.30
(t, J = 6.8 Hz, 6H, CHCH ), 2.35 (s, 3H, ArCH ), 3.08 (hept, J =
6.8 Hz, 1H, CHCH ), 7.01-7.45 (dd, J = 8.0 Hz, 4H, aryl),
8.03-8.17 (br, 1H, NH); ir (potassium bromide): ν 1100, 1115,
1150 (CF ) cm .
CF
1
3
1
(29 mg, 20%): mp 112.5° (cyclohexane), H nmr: δ 2.43 (s, 3Η,
3
3
CΗ ), 7.10−7.54 (dd, J = 8.0 Ηz, 4H, C H CH ), 7.70 (dd, J =
3
6
4
3
3
9.0 Ηz and 2.0 Hz, 1H, C7-H), 8.03 (d, J = 9.0 Hz, 1H, C8-H),
8.12 (d, J = 2.0 Ηz, 1H, C5-H).
-1
3
Anal. Calcd. for C
Found: C, 62.77; H, 5.62; N, 10.27.
H F N : C, 62.68; H, 5.64; N, 10.44.
14 15 3 2
Direct Synthesis of 3-Trifluoromethylquinoxalines 3b-c from 1b-c.
To a mixture of 1b-c (0.5 mmoles) and 1,2-phenylenediamine
(60 mg, 0.55 mmol) in acetonitrile (2.5 ml) was added acetic acid
(0.035 ml, 0.6 mmoles). The whole mixture was stirred for
24 hours under reflux conditions. The solvent was removed under
vacuum and the residue was dissolved in dichloromethane
(50 ml). The mixture was washed with 0.5 M aqueous sodium
carbonate (100 ml) and dried over sodium sulfate. Removal of
the solvent afforded 3-trifluoromethylquinoxalines 3b-c.
5-Ethyl-4-trifluoromethyl-2-isopropyl-1H-imidazole (5c).
This compound was obtained as brown oil: bp 135°/15 Torr
1
(oven temperature of Kugelrohr distillation), H nmr: δ 1.20,
1.29 (t and d, J = 7.2 and 7.0 Hz, 9H, CH CH and CHCH ), 2.75
2
3
3
and 3.04 (q and hept, 3H, CH and CH), 7.58-7.76 (br, 1H, NH);
2
-1
ir (potassium bromide): ν 1110, 1157 (CF ) cm .
3
Anal. Calcd. for C H F N : C, 52.42; H, 6.35; N, 13.59.
9
13 3 2
Found: C, 52.66; H, 6.70; N, 13.43.
One Pot Synthesis of 5-Trifluoromethylpyrazine-2,3-dicarbo-
nitrile (4d) from 1,1,1-Trifluoro-3-(dimethylhydrazono)-2-
propanone (1d).
4-Trifluoromethyl-2-(p-tolyl)imidazoles 5d and 2,4-Bis(trifluo-
romethyl)imidazoles 5e-f.
To 2.5 M sulfuric acid (125.3 ml) was added 1d (10.533 g,
62.7 mmoles), and the mixture was stirred at room temperature
for 24 hours. After cooling the mixture to 0° diaminomaleonitrile
(6.911 g, 62.7 mmoles) was added, and the whole mixture was
stirred for additional 1 hour. The reaction mixture was poured
into 1 M aqueous sodium hydroxide (626.5 ml), and the organic
layer was extracted three times with dichloromethane
(100 ml x 3). Combined extracts was dried over sodium sulfate
and dichloromethane was removed under vacuum. The residue
was chromatographed on to silica gel using benzene/ethyl acetate
(95:5) as the eluent to yield 11.669 g (94%) of 5-trifluoro-
methylpyrazine-2,3-dicarbonitrile (4d) as pale yellow crystals:
General Procedure.
To a mixture of 2b-c (1 mmole), ammonium acetate
(555 mg, 7.2 mmoles), and p-tolualdehyde (144 mg,
1.2 mmoles) or 1-ethoxy-2,2,2-trifluoroethanol (432 mg, 3
mmoles) was added acetic acid (7 ml). The mixture was
stirred at room temperature for 15 minutes, and then, heated to
100°, and stirring was continued for 5 hours. The reaction
mixture was poured into water (100 ml) and neutralized
(pH 7) with 28% aqueous ammonia. The organic layer was
extracted twice with dichloromethane (50 ml x 2). Combined
extracts were dried over sodium sulfate and the solvent was
removed to afford 5d-f.
1
mp 74° (cyclohexane), H nmr: δ 9.13 (s, 1Η, CH); ir (potassium
-1
bromide): ν 1140, 1166, 1178 (CF ) cm .
3
4-Trifluoromethyl-2,5-di-(p-tolyl)imidazole (5d).
Anal. Calcd. for C HF N : C, 42.44; H, 0.51; N, 28.28. Found:
7
3 4
C, 42.51; H, 0.73; N, 28.09.
This compound was obtained as pale brown crystals: mp
1
270.5° (benzene), H nmr (d -acetonitrile): δ 2.37 (s, 6H,
3
2-Alkyl-4-trifluoromethylimidazoles 5a-c.
ArCH ), 7.13-7.55, 7.23 (dd and d, J = 8.2 and 8.0 Hz, 6H, aryl),
3
General Procedure.
7.78 (d, J = 8.0 Hz, 2H, aryl), 10.03-11.0 (br, 1H, NH); ir
-1
(potassium bromide): ν 1115, 1163 (CF ) cm .
3
To a mixture of 2b-c (1 mmole) and aliphatic aldehyde
(1.2 mmoles) in methanol (5 ml) was added 28% aqueous ammonia
(2 ml, 106 mmoles). The whole mixture was stirred at room temper-
ature for 24 hours, and then poured into dichloromethane (100 ml).
The mixture was washed with saturated aqueous sodium chloride
and the organic layer was dried over magnesium sulfate. Removal of
the solvent afforded 2-alkyl-4-trifluoromethylimidazoles 5a-c.
Anal. Calcd. for C
H F N : C, 68.35; H, 4.78; N, 8.86; F,
18 15 3 2
18.01. Found: C, 68.61; H, 4.78; N, 8.80; F, 17.81.
2,4-Bis(trifluoromethyl)-5-(p-tolyl)imidazole (5e).
This compound was obtained as colorless crystals: mp
1
148.5-149.5° (chloroform), H nmr (d -acetonitrile): δ 2.38
3
(s, 3H, CH ), 7.11-7.50 (dd, J = 8.2 Hz, 4H, aryl), 11.5-12.2
3
2-Ethyl-4-trifluoromethyl-5-(p-tolyl)-1H-imidazole (5a).
(br, 1H, NH); ir (potassium bromide): ν 1125, 1144, 1184
-1
(CF ) cm .
3
This compound was obtained as pale brown crystals: mp
1
Anal. Calcd. for C H F N : C, 48.99; H, 2.74; N, 9.52.
229-230° (cyclohexane-benzene), H nmr: δ 1.20 (t, J = 7.4 Hz,
12 8 6 2
Found: C, 48.76; H, 2.81; N, 9.33.
3H,CH CH ), 2.26 (s, 3H, ArCH ), 2.73 (q, J = 7.4 Hz, 2H,
2
3
3
CH CH ), 7.00-7.45 (dd, J = 8.0 Hz, 4H, aryl), 8.03-8.17 (br, 1H,
2
3
5-Ethyl-2,4-bis(trifluoromethyl)imidazole (5f).
This compound was obtained as brown oil: bp 140°/80 Torr
-1
NH); ir (potassium bromide): ν 1104, 1115, 1161 (CF ) cm .
3
Anal. Calcd. for C
H F N : C, 61.41; H, 5.15; N, 11.02.
13 13 3 2
1
(oven temperature of Kugelrohr distillation), H nmr: δ
Found: C, 60.81; H, 5.08; N, 10.88.
1.24 (t, J = 7.4 Hz, 3H, CH CH ), 2.81 (q, 2H, CH CH ),
2
3
2
3
4-Trifluoromethyl-2-isopropyl-5-(p-tolyl)-1H-imidazole (5b).
This compound was obtained as colorless crystals: mp 172.5-
7.00-7.45 (br, 1H, NH); ir (potassium bromide): ν 1130, 1178
-1
(CF ) cm .
3
13
Anal. Calcd. for C H F N : C, 36.22; H, 2.61; N, 12.07.
173.5° (benzene), C nmr (d -dimethylsulfoxide): δ 20.8
7
6 6 2
6
1
(ArCH ), 21.2 (CHCH ), 27.6 (CHCH ), 123.0 ( J = 266.9 Hz,
Found: C, 36.51; H, 2.68; N, 11.84.
3
3
3
CF

776
Y. Kamitori
Vol. 38
REFERENCES AND NOTES
[6] Y. Kamitori, M. Hojo, R. Masuda, T. Yoshida, S. Ohara,
K. Yamada, and T. Yokoyama, J. Org. Chem., 53, 519 (1988).
[7] Y. Kamitori, M. Hojo, R. Masuda, T. Fujitani, S. Ohara, and
T. Yokoyama, Synthesis, 208 (1988).
[8] Y. Kamitori, M. Hojo, R. Masuda, S. Ohara, Y. Kawamura,
and T. Ebis, Synthesis, 43 (1989).
[1] Review: R. Filler, "Organofluorine Chemicals and their
Industrial Applications", ed. by R. E. Banks, Ellis Horwood, London,
1979, p. 123.
[2] V. N. Pathak, V. Grover, Pharmazie, 34, 568 (1979);
Chem Abstr., 92, 181060n (1980).
[3] H. V. Secor and J. F. De Bardeleben, J. Med. Chem., 14, 997
(1971).
[9] Y. Kamitori, M. Hojo, R. Masuda, S. Ohara, K. Kawasaki,
Y. Kawamura, and M. Tanaka, J. Heterocyclic Chem., 27, 487 (1990).
[10] Imidazole ring carbon atoms of 1-methyl-5-(p-tolyl)-4-
2
trifluoromethyl-1H-imidazole appear at 137.6 (C2), 128.8 ( J = 37.4
CF
[4] H. Kimoto and l. A. Cohen, J. Org. Chem., 45, 3831
(1980).
Hz, C4), and 133.0 (C5) ppm. Those of 1-methyl-4-(p-tolyl)-5-trifluoro-
methyl-1H-imidazole (as a reference compound of 2-ethyl-4-(p-tolyl)-5-
[5] Y. Kamitori, M. Hojo, R. Masuda, T. Fujitani, S. Ohara, and
T. Yokoyama, J. Org. Chem., 53, 129 (1988).
trifluoromethylimidazol) are observed at 140.5 (C2), 145.1 (C4), and
2
116.5 ( J = 39.1 Hz, C5) ppm.
CF