Methyl Orthocarboxylates as Methylating Agents of Heterocycles
3 H, OCH3), 6.15 (s, 1 H, CH-5), 12.4 [s(br.), 1 H, OH) ppm. 13C
FULL PAPER
phase was washed with water, dried over magnesium sulfate and
NMR ([D6]DMSO): δ ϭ 20.2 (CH3), 50.1 (OCH3), 88.9 (C-3), 97.3 concentrated to dryness at atmospheric pressure. A distillation led
(C-5 (broad signal)], 116.1 (CN), 158.0 (C-4), 163.3 and 163.6 (C-
6 and C-2) ppm. C8H8N2O2 (164.2): calcd. C 58.53, H 4.91, N
17.07; found C 58.33, H 4.91, N 16.96.
to 33 (2.6 g, 47%). Extraction of the aqueous phase with dichloro-
methane led, after concentration at atmospheric pressure, to a mix-
ture of methanol, and compounds 32 and 33. Concentration to
dryness under reduced pressure followed by recrystallization of the
residue from heptane only allowed the isolation of the water soluble
compound 32 (0.4 g, 7%).
Application of the above procedure to compound 12[28] led to 14
and 13 as described below:
3-Cyano-2,6-dimethoxypyridine (14): M.p. 91Ϫ92 °C (heptane)
2-Methyl-1,2,5-thiadiazol-3(2H)one (32): M.p. 117 °C (ref.[31]
1
(ref.[29] 92Ϫ93 °C). H NMR: δ ϭ 3.96 and 4.02 (2s, 6 H, OCH3),
1
116Ϫ117 °C). H NMR: δ ϭ 3.39 (s, 3 H, CH3), 7.71 (s, 1 H, CH-
6.34 (d, J ϭ 8.4 Hz, 1 H, CH-5), 7.68 (d, J ϭ 8.4 Hz, 1 H, CH-4)
ppm. 13C NMR: δ ϭ 54.2 (OCH3), 54.4 (OCH3), 86.8 (C-3), 102.8
(C-5), 116.2 (CN), 144.3 (C-4), 164.8 and 165.7 (C6 and C-2) ppm.
4) ppm. 13C NMR: δ ϭ 29.2 (CH3), 145.1 (CH-4), 163.6 (C-3) ppm.
1
3-Methoxy-1,2,5-thiadiazole (33): B.p. 124Ϫ126 °C. H NMR: δ ϭ
4.07 (s, 3 H, CH3), 7.95 (s, 1 H, CH-4) ppm. 13C NMR: δ ϭ 57.2
(CH3), 138.7 (CH-4), 166.2 (C-3) ppm. Microanalysis was not pos-
sible on this very volatile compound. m/z (GC/MS) ϭ 116.
3-Cyano-6-hydroxy-2-methoxypyridine (13): M.p. 132Ϫ133 °C
(heptane) (ref.[29] 135Ϫ137 °C). 1H NMR: δ ϭ 3.97 (s, 3 H, OCH3),
6.36 (d, J ϭ 8.4 Hz, 1 H, CH-5), 7.75 (d, J ϭ 8.4 Hz, 1 H, CH-4)
ppm. 13C NMR: δ ϭ 59.9 (OCH3), 87.2 (C-3), 101.9 (C-5), 115.8
(CN), 145.6 (C-4), 164.3 and 164.6 (C-6 and C-2) ppm.
2-Methylisoxazol-3(2H)-one (35): A mixture of compounds 34
(0.25 g, 2.5 mmol) and 3 (1.6 mL, 12.6 mmol) was refluxed in tolu-
ene (40 mL) for 2 hours. TLC monitoring of the reaction showed
the reaction to be incomplete and thus five more equivalents of
trimethyl orthoacetate were added and the reflux was resumed for
another nine hours. Concentration of the solvents followed by
chromatography of the residue over silica gel eluting with ethyl
acetate gave compound 35 (0.12 g, 42%) M.p. Ͻ 30 °C (ref.[19]
25Ϫ30 °C). 1H NMR: δ ϭ 2.19 (s, 3 H, CH3), 3.43 (s, 3 H, NCH3),
5.45 (s, 1 H, CH-4) ppm. 13C NMR: δ ϭ 13.1 (CH3), 32.4 (NCH3),
98.1 (CH-4), 168.4, 169.1 (C3 and C5) ppm.
3-Cyano-2,6-dimethoxy-4,5-dimethylpyridine (11): In a distillation
apparatus, compound 10[30] (11.8 g, 71.9 mmol) and trimethyl or-
thoacetate (70 mL, 550 mmol) were heated at reflux until methanol
and methyl acetate evolution was complete (2Ϫ3 hours). The res-
idue was concentrated to dryness and purified by chromatography
over silica gel eluting with heptane/ethyl acetate (3:1) to give par-
tially hydrated compound 11 (12.7 g, 91%). M.p. 135 °C (heptane/
ethyl acetate). 1H NMR: δ ϭ 2.00 (s, 3 H, CH3), 2.33 (s, 3 H, CH3),
3.93 and 3.94 (2s, 6 H, OCH3) ppm. 13C NMR: δ ϭ 10.7 (CH3-5),
17.8 (CH3-4), 53.9 and 54.0 (OCH3), 87.9 (C-3), 100.8 (C-5), 116.2
(CN), 152.5 (C-4), 162.8 (C-6 and C-2) ppm. C9H10N2O2·
1/6H2O (179.2 ϩ 3): calcd. C 61.53, H 6.37, N 14.35; found C
61.72, H 6.22, N 14.38.
General Procedure using 2 or 4 for the Methylation of 2-thiouracil
(15): Compound 15 (1 g, 7.8 mmol) and N,N-dimethylformamide
dimethyl acetal (2) (or compound 4) (5.2 mL, 39.0 mmol) were re-
fluxed for 3 hours in toluene (50 mL). The mixture was then con-
centrated to dryness and the residue purified by chromatography
over silica gel eluting initially with cyclohexane/ethyl acetate (6:1)
and then with cyclohexane/ethyl acetate (3:2). Compounds 16
(0.26 g, 21%), 17 (0.7 g, 57%) and 18 (0.17 g, 14%) were obtained
in that order.
3-Cyano-6-methoxy-1,4-dimethylpyridin-2(1H)-one (9): Using the
procedure for preparation of 11, compound 7 was obtained from
compound 5 along with a much more polar fraction identified as
1
compound 9. M.p. 229 °C (ethanol). H NMR: δ ϭ 2.35 (s, 3 H,
CH3), 3.38 (s, 3 H, NCH3), 3.93 (s, 3 H, OCH3), 5.49 (s, 1 H, CH-
5) ppm. 13C NMR: δ ϭ 21.9 (CH3), 28.6 (NCH3), 57.8 (OCH3),
88.3 (C-5), 95.3 (C-3), 116.4 (CN), 159.6 (C-4), 160.2 (C-6), 160.8
(C-2) ppm. C9H10N2O2 (178.2): calcd. C 60.66, H 5.66, N 15.72;
found C 60.69, H 5.68, N 15.85.
4-Methoxy-2-methylthiopyrimidine (16): M.p. Ͻ 30 °C (ref.[9] 35
1
°C). H NMR: δ ϭ 2.46 (s, 3 H, SCH3), 3.86 (s, 3 H, OCH3), 6.28
(d, J ϭ 5.5 Hz, 1 H, CH-5), 8.12 (d, J ϭ 5.5 Hz, 1 H, CH-6) (1H
shifts are dependant on compound 16 concentration[10]) ppm. 13C
NMR: δ ϭ 13.8 (SCH3), 53.5 (OCH3), 103.3 (CH-5), 156.9 (CH-
6), 168.7, 171.9 (C-2 and C-4) ppm.
4-Acetyl-3-hydroxy-5-methylpyrazole (26): Compound 25 (2 g,
20.4 mmol) was refluxed in trimethyl orthoacetate (15 mL,
116 mmol) and, after concentration to dryness, the residue was dis-
persed in hot water and then filtered at room temperature to yield
26 (2.48 g, 86%). M.p. 260 °C (dec.) [ref.[16] 260 °C (dec.)]. 1H NMR
([D6]DMSO): δ ϭ 2.29 (s, 3 H, COCH3), 2.32 (s, 3 H, CH3-5) ppm.
13C NMR ([D6]DMSO): δ ϭ 12.5 (CH3-5), 29.2 (COCH3), 104.5
(C-4), 143.9 (C-5), 161.6 (C-3), 192.9 (CO) ppm.
2-Methylthio-3-methylpyrimidin-4(3H)one (17): M.p. 125 °C (ref.[32]
1
124 °C). H NMR: δ ϭ 2.59 (s, 3 H, SCH3), 3.53 (s, 3 H, NCH3),
6.22 (d, J ϭ 5.6 Hz, 1 H, CH-5), 7.77 (d, J ϭ 5.6 Hz, 1 H, CH-6)
ppm. 13C NMR: δ ϭ 15.4 (SCH3), 30.6 (NCH3), 110.2 (CH-5),
152.1 (CH-6), 162.4, 164.1 (C-2 and C-4) ppm.
1,3-Dimethylthiouracil (18): M.p. 105Ϫ106 °C (ethanol) (ref.[33]
107Ϫ108 °C). 1H NMR: δ ϭ 3.77 (s, 3 H, CH3), 3.78 (s, 3 H, CH3),
6.02 (d, J ϭ 7.9 Hz, 1 H, CH-5), 7.37 (d, J ϭ 7.9 Hz, 1 H, CH-6)
ppm. 13C NMR: δ ϭ 34.7 (CH3), 45.0 (CH3), 104.8 (CH-5), 143.2
(CH-6), 160.2 (C-4), 177.5 (C-2) ppm.
Methylation of 3-Hydroxy-1,2,5-thiadiazole (31). Method with Tolu-
ene: Compound 31 (0.33 g, 2.75 mmol; obtained using the reported
procedure[18] and recrystallized from heptane) and compound 3
(1.05 mL, 8.2 mmol) were refluxed in toluene (40 mL) for 4 hours.
After evaporation, the residue was recrystallized from heptane to
yield 32 (0.22 g, 69%) .
The same procedure was used for the reaction of heterocycles 19,
22 or 29 with reagent 2 or 4, as indicated in the text, and gave
the corresponding methylated derivatives 20 and 21, 23 or 30 as
described below.
Method without Solvent: In a distillation apparatus, compound 31
(4.82 g, 47.2 mmol) was refluxed in trimethyl orthoacetate (3;
25 mL, 189 mmol) for 90 minutes allowing for the continuous dis-
tillation of methanol and methyl acetate. Water (100 mL) was then 3-Cyano-2-methoxy-4,6-dimethylpyridine (20): M.p. 98 °C (crystal-
1
added and the solution was stirred for 1 hour at room temperature.
The reaction mixture was extracted with diethyl ether, the organic
lized from chloroform) (ref.[34] 94Ϫ95 °C). H NMR: δ ϭ 2.42 (s,
3 H, CH3), 2.43 (s, 3 H, CH3), 3.98 (s, 3 H, OCH3), 6.61 (m, 1 H,
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