A. Guan et al.
JournalofFluorineChemistry201(2017)49–54
propiconazole.
This
study
demonstrated
that
di-
4.2.4. Synthesis of aryloxy pyridinamines (M-4, M-5, M-6)
fluoromethylpyrimidinamine derivatives can be further developed as a
novel promising fungicide for control of rusts. Further structure opti-
mization studies around new discovered potential leads and obtained
valuable direction are currently in progress.
The intermediates, M-4, M-5, M-6, relating the different position of
the pyrimidinamine group attached to the pyridine ring and the dif-
ferent length of alkyl chain between amino and pyridine ring, were
4.2.5. General procedure for the synthesis of compounds (A–T)
To a solution of corresponding aryloxy pyridinamines (M-4, M-5 or
M-6) (1.0 mmol) and potassium carbonate (1.5 mmol) in DMF (10 mL)
was added the corresponding 4,5-dichloro-6-substitutedpyrimidine (M-
3) (1.0 mmol). The reaction mixture was heated to 80 °C for 2 h, and
monitored by TLC until the reaction was complete. The mixture was
poured into water (50 mL) and extracted with ethyl acetate
(3 × 50 mL). The merged organic phase was successively washed with
water and saturated brine, dried, filtered, and evaporated under re-
duced pressure. The residue was purified via silica gel chromatography
with ethyl acetate/60−90 °C petroleum ether (1:4, v/v) as eluent to
obtain title compound.
4. Experimental
4.1. Chemistry
All chemicals such as starting materials and reagents were com-
mercially available (Sinopharm Chemical reagent Co. Ltd., Shanghai,
China) and used without further purification except as indicated.
Melting points were determined on a Büchi M-569 melting point ap-
paratus (Büchi Labortechnik AG, Flawil, Switzerland) and are un-
corrected. 1H NMR, 13C NMR and 19F NMR spectra were recorded in a
Varian Mercury spectrometer (Varian, Palo Alto, CA) in CDCl3, oper-
ating at 300 MHz, 150 MHz and 282 MHz, respectively. Infrared
spectra were measured with KBr discs using a PF-983G instrument
(Perkin-Elmer). Elemental analyses were determined on a Yanaco MT-
3CHN elemental analyzer (Yanaco, Kyoto, Japan). Mass spectra were
acquired with an Agilent Accurate-Mass-Q-TOF MS 6520 system
(Agilent Technologies, Milford, MA) equipped with an electrospray
ionisation (ESI) source. All plant and bacteria materials were obtained
from the Agrochemical Discovery Department in Shenyang Sinochem
Agrochemicals R & D Co. Ltd (Shenyang, China).
Characterization for representative compounds A, J, Q, S and T are
as follows.
4.2.5.1. 5-chloro-N-(2-(5-(4-chlorophenoxy)pyridin-2-yl)ethyl)-6-
(difluoromethyl)pyrimidin-4-amine (compound A). Yield 73%. Colorless
oil. 1H NMR (300 MHz, CDCl3): δ 2.93 (t, J = 6.9 Hz, 2H, CH2CH2NH),
3.80 (q, 2H, CH2CH2NH), 5.72 (bs, 1H, NH), 6.72 (t, 1JHF = 54 Hz, 1H,
CHF2), 6.92 (d, J = 8.4 Hz, 1H, pyridine −3-H), 7.07 (d, J = 6.9 Hz,
2H, Ph-2,6-2H), 7.35 (d, J = 6.9 Hz, 2H, Ph-3,5-2H), 7.58 (dd,
J = 8.4,2.7 Hz, 1H, pyridine-4-H), 8.03 (s, 1H, pyridine-6-H), 8.56 (s,
1H, pyrimidine-2-H); 13C NMR (CDCl3, 150 MHz) δ 31.60, 42.33,
4.2. Synthesis
1
111.33 (t, JHF = 240 Hz), 111.55, 112.37, 122.42, 128.65, 129.63,
2
The general synthetic methods for compounds A to T are shown in
Fig. 3. Representative procedures are given below; the yields were not
optimized, and the obtained compounds were confirmed by 1H NMR,
13C NMR, 19F NMR, IR, elemental analyses and HRMS. Their structures
129.82, 140.00, 147.29, 152.32 (t, JHF = 22.5 Hz), 152.56, 156.01,
158.33, 162.40; 19F NMR (CDCl3, 282 MHz) δ: −55.98 (d,
1JFH = 54 Hz); IR (KBr) ν: 3242, 3135, 3099, 2925, 2852, 1590,
1557, 1520, 1480, 1451, 1395, 1369, 1337, 1275, 1254, 1203, 1140,
1088, 1054, 1033, 1015, 672 cm−1
;
Anal. Calcd (%) for
C
18H14Cl2F2N4O: C, 52.57; H, 3.43; N, 13.62. Found: C, 52.52; H,
3.47; N, 13.58; HRMS m/z 410.0510 [M + H]+ (calcd [M + H]+
4.2.1. Synthesis of substituted ethyl 2-chloro-3-oxobutanoate (M-1)
410.0513).
Sulfonyl chloride (1.33 mol) in dichloromethane (200 mL) was
added slowly to
a solution of substituted ethyl 3-oxobutanoate
4.2.5.2. 5-chloro-6-(difluoromethyl)-N-(2-(6-(3-(trifluoromethyl)
(1.20 mol) in dichloromethane (300 mL) at room temperature under
stirring. The mixture was continued stirring for another 5–7 h at room
temperature. The excess solvent and sulfonyl chloride were removed off
under reduced pressure to afford M-1 as a faint yellow liquid for next
step directly.
phenoxy)pyridin-3-yl)ethyl)pyrimidin-4-amine (compound J). Yield 82%.
White solid, 113.0 °C. 1H NMR (300 MHz, CDCl3): δ 2.94 (t, J = 6.9 Hz,
2H, CH2CH2NH), 3.81 (q, 2H, CH2CH2NH), 5.74 (bs, 1H, NH), 6.72 (d,
1JHF = 54 Hz, 1H, CHF2), 6.95 (d, J = 8.4 Hz, 1H, pyridine-3-H), 7.32
(d, J = 8.1 Hz, 1H, Ph-6-H), 7.39 (s, 1H, Ph-2-H), 7.44-7.49 (m, 1H, Ph-
5-H), 7.53 (d, J = 8.1 Hz, 1H, Ph-4-H), 7.62 (dd, J = 8.4,2.7 Hz, 1H,
pyridine-4-H), 8.05 (s, 1H, pyridine-6-H), 8.57 (s, 1H, pyrimidine-2-H);
4.2.2. Synthesis of 4-hydroxyl-5-chloro-6-substitutedpyrimidine (M-2)
A solution of formamidine acetate (0.70 mol) in methanol (150 mL)
was stirred at 5–10 °C, and then CH3ONa (1.20 mol) in methanol
(150 mL) newly prepared was added slowly under stirring, followed by
addition of M-1 (0.50 mol) in methanol (100 mL). The mixture was
continued stirring for another 3–4 h at room temperature and then
concentrated under reduced pressure. The residue was adjusted to pH
5–6 with diluted HCl, the precipitated solid was filtered to afford M-2 as
a white solid.
13C NMR (CDCl3, 150 MHz)
δ
31.59, 42.32, 111.30 (t,
1JCF = 241.5 Hz), 111.86, 112.38, 118.02, 121.18, 124.36, 129.12,
1
130.07, 131.97 (q, JCF = 276 Hz), 140.17, 147.31, 152.31 (t,
2JCF = 24 Hz), 154.30, 156.01, 158.33, 161.95; 19F NMR (CDCl3,
1
282 MHz) δ: −56.04 (d, JFH = 54 Hz), 1.75; IR (KBr) ν: 3280, 3135,
2950, 2924, 2851, 1592, 1519, 1479, 1396, 1369, 1336, 1279, 1255,
1177, 1140, 1121, 1089, 1052, 1033 cm−1; Anal. Calcd (%) for
C
19H14ClF5N4O: C, 51.31; H, 3.17; N, 12.60. Found: C, 51.27; H,
3.19; N, 12.58; HRMS m/z 444.0776 [M + H]+ (calcd [M + H]+
4.2.3. Synthesis of 4,5-dichloro-6-substitutedpyrimidine (M-3)
POCl3 (100 mL) was added dropwise to a solution of M-2 (0.36 mol)
in toluene (150 mL), the mixture was refluxed for 3–5 h. The reaction
mixture was concentrated under reduced pressure to remove toluene
and extra POCl3, and then poured into ice water. The water phase was
extracted with ethyl acetate (3 × 50 mL), the emerged organic phase
was successively washed with saturated sodium bicarbonate, dried over
anhydrous magnesium sulfate, filtered and then concentrated under
reduced pressure. The residue was purified through silica column to
give M-3 as yellow liquid.
444.0781.
4.2.5.3. 5-chloro-6-(difluoromethyl)-N-((6-(4-(trifluoromethyl)phenoxy)
pyridin-3-yl)methyl)pyrimidin-4-amine (compound Q). Yield 82%. Yellow
oil. 1H NMR (300 MHz, CDCl3): δ 4.74 (d, J = 6.0 Hz, 1H, CH2), 6.34
1
(bs, 1H, NH), 6.73 (d, JHF = 54 Hz, 1H, CHF2), 6.78 (d, J = 9.0 Hz,
1H, pyridine-3-H), 7.23 (d, J = 7.8 Hz, 2H, Ph-2,6-2H), 7.65 (d,
J = 8.1 Hz, 2H, Ph-3,5-2H), 7.78 (dd, J = 8.4,2.7 Hz, 1H, pyridine-4-
H), 8.20 (s, 1H, pyridine-6-H), 8.57 (s, 1H, pyrimidine-2-H); 13C NMR
1
(CDCl3,150 MHz) δ 42.02, 111.38 (t, JCF = 240 Hz), 112.18, 112.40,
53