1
56
A.D. Dunn / Journal of Fluorine Chemistry 93 (1999) 153±157
3
.4. 2-Amino-4-trifluoromethylpyridine (12)
and chloroacetic acid (0.67 g, 7.1 mmol) added. The mix-
ture was allowed to stand at room temperature overnight,
neutralised with dilute hydrochloric acid and cooled to 08C.
The precipitated solids were removed by ®ltration, washed
with a little cold water and recrystallised from aqueous
methanol to afford colourless crystals of pure 17 (1.33 g,
76%), mp 103±1058C (with sintering at 998C). Anal. Calc.
for C H F NO S (237.20): C, 40.51; H, 2.55; N, 5.90; S,
A mixture of 3 (25 g, 138 mmol) and conc. aqueous
ammonia (S.G. 0.88) (400 ml) was heated at 1708C in a
pressure vessel for 24 h. The reaction mixture was processed
as above, but in addition carbon treatment was required to
obtain pure title compound. Pure 12 had mp 738C (from
1
light petroleum containing a little ether) . Anal. Calc. for
C H F N (162.11): C, 44.45; H, 3.11; N, 17.28. Found: C,
8
6
3
2
1
13.52. Found: C, 40.49; H, 2.71; N, 5.87; S, 13.43%. H
NMR (DMSO-d ) d (ppm): 12.80 (br. s, exchangeable, N±
6
5 3 2
1
4
6
4.44; H, 3.26; N, 17.41%. H NMR d (ppm): 8.22 (d, H-6),
6
.83 (d, H-5), 6.66 (s, H-3), 4.90 (br. s, exchangeable, NH ).
1
H), 8.67 (ddd, H-6), 8.10 (d dd, H-4), 7.36 (six line
2
�
� 1
IR (cm ): 3460, 3300, 3170, 1640 (all NH ), 1345, 1320,
2
complex multiplet, H-5), 4.06 (s, CH ). IR (cm ):
2
1
135 (all C±F).
3200±2300 (broad, N±H), 1715 (w) and 1620 (s) (C=O),
1
305 and 1117 (C±F). MS m/z (%): 237 (11), 193 (100).
3
.5. 4-Trifluoromethylpyridin-2(1H)-one (13)
The amine 12 (10.0 g, 61.7 mmol) was dissolved in dilute
10%) sulfuric acid (150 ml) and ice (100 g) was added. A
3
.9. Ethyl 4-(3-(trifluoromethylpyridin-2-ylsulfanyl)-3-
oxobutanoate (18)
(
solution of sodium nitrite (4.32 g) in water (50 ml) was
added dropwise over a 30 min period keeping the tempera-
ture of the reaction mixture between 0 and 58C. The solution
was then brought slowly to 708C and maintained at this
temperature for 1 h. The pH was adjusted to 7 with solid
sodium carbonate, and the volume of the mixture reduced to
approximately 100 ml in vacuo to afford a yellow solid
A mixture of thione 16 (1.2 g, 6.7 mmol), anhydrous
potassium carbonate (1.0 g), ethyl 4-chloro-3-oxobutanoate
(1.16 g, 7.05 mmol) and dry acetone (50 ml) was stirred at
room temperature for 24 h. The mixture was ®ltered, the
solids washed with acetone and the solvent removed in
vacuo. The resulting solid was recrystallised from light
petroleum to afford 18 as colourless needles (1.56 g,
76%), mp 54±558C. Anal. Calc. for C H F NO S
(
7.98 g). Recrystallisation from hot water gave colourless
12
12
3
3
prisms of pure 13 (7.2 g, 72%) mp 1618C. Anal. Calc. for
(307.29): C, 46.90; H, 3.94; N, 4.56; S, 10.44. Found: C,
1
C H F NO (163.12): C, 44.18; H, 2.47; N, 8.58. Found: C,
46.98; H, 3.88; N, 4.44; S, 10.26%. H NMR d (ppm): 8.49
(dd, H-6), 7.85 (dd, H-4), 7.13 (ddd, H-5), 4.21 (q, ester
6
4 3
1
4
1
6
1
4.29; H, 2.61; N, 8.68%. H NMR (DMSO-d ) d (ppm):
6
2.24 (s, exchangeable, N±H), 7.65 (d, H-6), 6.71 (d, H-5),
1
.39 (dd, H-3). IR (cm ): 2800 (broad, N±H), 1680 (C=O),
CH ), 4.05 (s, S-CH ), 3.69 (s, COCH CO Et), 1.28 (t, ester
2
2
2
2
�
� 1
CH ). IR (cm ): 1730 (ester C=O), 1715 (ketone C=O),
3
341, 1280 and 1145 (all C±F). MS m/z (%): 163 (100).
1320 and 1120 (C±F). MS m/z (%): 307 (21), 192 (100).
3
.6. 4-Trifluoromethylpyridin-2(1H)-thione (14)
3.10. 1-(4-Trifluoromethylpyridin-2-ylsulfanyl)-propan-2-
one (19)
The pyridone 13 (4.08 g, 25 mmol) was treated with Law-
esson's reagent (6.07 g, 15 mmol) in dry toluene (100 ml) as
previously described [9] to afford pure 14 as a yellow crystal-
line solid (3.02 g, 67%) identical with a reference sample [9].
A mixture of the thione 17 (1.2 g, 6.7 mmol) was treated
as described above with chloroacetone (0.74 g, 8 mmol).
The reaction mixture was processed in the same way to yield
1
9 (1.10 g, 70%), as colourless needles mp 51±528C (after
3
.7. 3-Trifluoromethylpyridin-2(1H)-thione (16)
sublimation, Kugelrohr, 858C, 0.5 mbar). Anal. Calc. for
C H F NOS (235.23): C, 45.95; H, 3.43; N, 5.95; S, 13.63.
1
9
8 3
The amine 11 (10.0 g, 61.7 mmol) was treated as
Found: C, 45.82; H, 3.61; N, 6.09; S, 13.44%. H NMR d
(ppm): 8.42 (d, H-6), 7.36 (br. s, H-3), 7.09 (br. d, H-5), 4.00
described above (3.12) to afford crude pyridone (15)
6.92 g, 69%). The crude pyridone was then converted into
the thione 16 using the above procedure. Pure 16 (5.41 g,
�
1
(s, S-CH ), 2.32 (s, S-CH ). IR (cm ): 1715 (C=O), 1326
(
2
3
and 1138 (C±F).
7
1%) was identical with a reference sample [9].
3
.11. 2-Allylsulfanyl-4-trifluoromethylpyridine (20) and
bis-(4-trifluoromethylpyridin-2-yl)-disulfide (21)
3
.8. (3-Trifluoromethylpyridin-2-ylsulfanyl)-acetic acid (17)
The thione 16 (1.0 g, 5.6 mmol) was dissolved in water
25 ml) containing sodium hydroxide (0.56 g, 14 mmol),
A mixture of thione 17 (1.2 g, 6.7 mmol) was treated with
(
allyl bromide (0.97 g, 8 mmol) exactly as described in
Section 3.9 above. The crude reaction mixture was puri®ed
by column chromatography. Elution with 10% ether in light
petroleum gave 20 as a colourless mobile oil. Short path
bulb-to-bulb distillation (Kugelrohr, 508C, 0.4 mbar) gave
1
A commercial sample from the Maybridge Chemical Company had mp
2±748C. An 1H NMR spectrum of this material, kindly supplied by Dr.
K. Morris, was completely superimposable with the spectrum of our
compound. We gratefully acknowledge this co-operation.
7