JPH0723368B2 - 1,3-dioxynone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel 1,3-dioxynone derivative, which is useful as a synthetic chemical synthon for pharmaceuticals, agricultural chemicals, etc., having 1,5-disubstituted 1,3. -Dioxin-4-one derivatives.

(Prior Art) A 1,3-dioxin-4-one derivative produces a highly reactive acylketene by heating, and this acylketene reacts with an isocyanate, a cyanate, a cyanamide or an imine to give a 1,3-oxazine derivative, The N-acetoacetyl derivative is reacted with the amide, and the 4-pyrone derivative is formed with the ketene acetal. These compounds are useful as medicines, agricultural chemicals or intermediates thereof. The 1,3-dioxin-4-one derivative has the same reactivity as the acyl ketene as described above, and is a useful synthon that can be used in the synthesis of various compounds in synthetic chemistry, but diketene also has the same reactivity. Is known to have. However, the yield of the desired product is generally superior to the case of using the acyl ketene than the case of using the diketene, and the yield of the 1,3-dioxin-4-one compound is at the 5- and / or 6-position. By using a compound having various substituents, various substituents can be introduced into the compound.

So far, some compounds have not been substituted at the 5,6 position, such as 1,3-dioxin-4-one or, on the contrary, those having a substituent at the 5,6-position or having only the 6-position substituted. It is known (Japanese Patent Laid-Open Nos. 54-106478, 59-172485 and 61-17).
No. 580 and No. 61-22077, etc.) 5 for substituted 5-position
-Only the phenyl form is known (JP 59-172485
No.). However, it is not easy to substitute the phenyl group of the 5-phenyl group with another group or to introduce a substituent into the benzene nucleus, and when used as a synthetic synthon as described above, Its application range is limited by itself.

As described above, the fact that a 1,3-dioxin-4-one compound in which only the 5-position has been substituted has heretofore been unknown other than a phenyl compound and that the phenyl compound is difficult to convert into another substituted compound is It depends largely on the method and raw material compound.

(Problems to be Solved by the Invention) The present inventors have a wide range of applications and have various possibilities as synthons in synthetic chemistry.
As a result of research for synthesizing an -one derivative, the present invention has been completed.

(Means for Solving the Problems) According to the present invention, a 1,3-dioxin-4-one derivative represented by the following general formula is provided.

General formula (In the formula, X is a substituted or unsubstituted alkyl group or alkenyl group substituted with a group selected from the group consisting of bromine, iodine or phenyl group, trimethylsilyl group, hydroxyl group, lower alkoxycarbonyl group, phthalimido group and lower alkoxy group. Or an alkynyl group; R and R'represent a lower alkyl group or an alkylene group in which R and R'are bonded to each other to form an integral unit.) In the present invention, the lower alkoxycarbonyl group is a methoxycarbonyl group, an ethoxycarbonyl group or n-. Suitable examples of the propoxycarbonyl group and the lower alkoxy group include a methoxy group and an ethoxy group.

Representative examples of 5-substituted 1,3-dioxin-4-one compounds of the present invention are shown below, together with specific synthetic methods thereof. (In the following examples, the number before the compound is referred to as the compound number for convenience.) 1) 5-Bromo-1,3-dioxin-4-one-2-spirocyclohexane-2-spirocyclohexane-1,3 A mixture of 504 mg of -dioxin-4-one (referred to as compound 1b in JP-A-61-22077), 641 mg of N-bromosuccinimide (NBS) and 10 ml of acetic acid is stirred at room temperature for 6 hours. The reaction solution is diluted with dichloromethane and washed thoroughly with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from hexane-ether to give cis-6-mp as needle crystals at mp 90-91 ° C.
Acetoxy-5-bromo-4-oxo-1,3-dioxane-2-
634 mg (69%) of spirocyclohexane are obtained.

High-resolution MS m / z Calcd C ₁₁ H ₁₅ BrO ₅ (M ⁺ ): 306.01
01 ( ⁷⁹ Br), 308.0082 ( ⁸¹ Br) .Found: 306.0059 ( ⁷⁹ B
r), 308.0060 ( ⁸¹ Br). ¹ H-NMR (CDCl ₃ ) δ: 1.18-2.15 (10H, m, cyclohexy1), 2.1
8 (3H, s, OCOMe), 4.27 (1H, d, J = 6Hz, C ₅ -H), 6.38 (1H,
d, J = 6Hz, C ₆ -H). The above compound (430 mg, 1.4 mmol) and triethylamine (156
Dichloromethane solution (5ml) of mg, 1.56mmol) at room temperature 15
Stir for a minute. After diluting with dichloromethane and washing with water, the organic layer is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from hexane-ether.
mp74-74.5 ° C as a prism, labeled compound (1) at 278 m
get g (80%).

Anal.Calcd C ₁₉ H ₁₁ BrO ₃ : C, 43.75; H, 4.49; Br, 32.34.Foun
d: C, 43.72; H, 4.40; Br, 32.43. ¹ H-NMR (CDCl ₃ ) δ: 1.07−2.30 (10H, m, cyclohexy1), 7.4
0 (1H, s, C ₆ -H) .MS m / z: 248 ( ⁸¹ Br) (M ⁺ ), 246 ( ⁷⁹ B
r) (M ⁺ ). 2) 5-iodo-4-oxo-1,3-dioxin-2-spirocyclohexane 1a (1.68g, 10mmol), N-iodosuccinimide (NIS, 2.7
A mixture of g, 12 mmol) and acetic acid (30 ml) is stirred at room temperature for 7 hours. The reaction solution is diluted with dichloromethane, washed thoroughly with water, and the organic layer is dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane (30 ml), and triethylamine (1.37 g, 13.5 mmol) was added,
Stir at room temperature for 20 minutes. After washing the reaction solution with water, the organic layer is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from hexane-ether to give mp 97-98 ° C.
1.97 g (67%) of the title compound (2) is obtained as a needle crystal of.

Anal Calcd C ₉ H ₁₁ IO ₃ : C, 36.76; H, 3.77.Found: C, 36.56;
H, 3.63. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.30 (10H, m, cyclohexy1), 7.3
7 (1H, s, C ₆ -H) .MS m / z: 294 (M ⁺ ). 3) 5-Bromo-2,2-dimethyl-1,3-dioxin-4-one 2,2-dimethyl-1,3-dioxin-4-one (same as above,
Compound 1a) (128 mg, 1 mmol), NBS (215 mg, 1.2 m)
A mixture of (mol) and acetic acid (4 ml) is stirred at room temperature for 3 hours. The reaction solution is diluted with dichloromethane, washed thoroughly with water, and the organic layer is dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, the residue is dissolved in dichloromethane (5 ml), triethylamine (87 mg, 0.86 mmol) is further added, and the mixture is stirred at room temperature for 15 min. The reaction solution is washed with water and the organic layer is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 74 mg (36%) of the title compound (3) as an oily substance.

High-resolution MS m / z Calcd C ₇ H ₁₂ BrO ₂ (M ⁺ ): 207.001
9 ( ⁷⁹ Br), 209.0000 ( ⁸¹ Br) .Found: 206.9981 ( ⁷⁹ B
r).

¹ H-NMR (CCl ₄ ) δ: 1.73 (6H, s, Me × 2), 7.33 (1H, s, C _6-
H). 4) A mixture of 5-iodo-2,2-dimethyl-1,3-dioxin-4-one 1a (1.31g, 10.2mmol), NIS (2.76g, 12,3mmol) and acetic acid (25ml) was added at room temperature to 5 Stir for hours. The reaction solution is diluted with dichloromethane, washed thoroughly with water, and the organic layer is dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, the residue is dissolved in dichloromethane (30 ml), triethylamine (1.13 g, 11 mmol) is further added, and the mixture is stirred at room temperature for 20 min. After washing the reaction solution with water, the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (silica gel amount 50 g). 1.89 g (75%) of the title compound (4) was obtained as a pale yellow oily substance from the fraction eluted with hexane-ethyl acetate (15: 1, v / v).

High-resolution MS m / z Calcd C ₆ H ₇ IO ₃ (M ⁺ ): 253.9438.
Found: 253.9448. ¹ H-NMR (CCl ₄ ) δ: 1.72 (6H, s, Me × 2), 7.34 (1H, s, C _6-
H). 5-halogeno-1,3-dioxin-4-ones [Compound (1)
-(4)] and mono-substituted acetylene cross-coupling reaction General procedure A 5-halogeno-1,3-dioxin-4-one (0.5 mmol), mono-substituted acetylene (2.5 mmol), Pd (Ph ₃ P ) ₂ Cl ₂ (0.025mm
ol), CuI (0.04 mmol), D of triethylamine (1 mmol)
Stir the MF solution (4 ml) in a sealed tube at room temperature, or 60-70 ℃.
Heat with. The reaction solution is diluted with ether and washed with water, and the ether layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by the method described below.

5) 5-phenylethynyl-4-oxo-1,3-dioxin-
-2-Spirocyclohexane a) Compound (1) (124 mg, 0.5 mmol), phenylacetylene (255 mg, 2.5 mmol), Pd (Ph ₃ P) ₂ Cl ₂ (8 mg, 0.01 mmo
l), CuI (8 mg, 0.04 mmol), triethylamine (101 mg,
1 mmol) of DMF solution (4 ml) at 70 ° C according to the general procedure A
After reacting for 2 hours, the ether extraction fraction is subjected to silica gel column chromatography (silica gel amount 20 g). A crystalline substance was obtained from the elution with hexane-ethyl acetate (20: 1, v / v) and recrystallized from hexane-ether to give mp 101-102 ° C.
As a leaf crystal, 51 mg (38%) of the title compound (5) was obtained.
42 mg (34%) of the raw material will also be recovered.

Anal Calcd C ₁₇ H ₁₆ O ₃ : C, 76.10; H, 6.01.Found: C, 75.95;
H, 5.80. ¹ H-NMR (CDCl ₃ ) δ: 1.10−2.33 (10H, m, cyclohexy1), 7.2
0-7.70 (6H, m, ArH, C 6 -H) .MS m / z: 268 (+). b) Compound (2) (147 mg, 0.5 mmol), phenylacetylene (255 mg, 2.5 mmol), Pd (Ph ₃ P) ₂ Cl ₂ (18 mg, 0.025 mmo
l), CuI (8 mg, 0.04 mmol), triethylamine (101 mg,
1 mmol) of DMF solution (4 ml) at room temperature according to the general procedure A.
The reaction is carried out for 0 minutes, and post-treatment is carried out in the same manner as in a) to give the title compound (5)
97 mg (72%).

6) 5-Trimethylsilylethynyl-4-oxo-1,3-dioxin-2-spirocyclohexane Compound (2) (1.058g, 3.6mmol), trimethylsilylacetylene (1.76g, 18mmol), Pd (Ph ₃ P) ₂ Cl ₂ (126mg, 0.18
mmol), CuI (58 mg, 0.29 mmol), triethylamine (72
A DMF solution (28 ml) of 7 mg, 7.2 mmol) is reacted at room temperature for 40 minutes according to the general procedure A, and the ether extraction fraction is subjected to silica gel column chromatography (silica gel amount 58 g).
A crystalline substance was obtained from the elution with hexane-ethyl acetate (20: 1, v / v) and recrystallized from pentane to obtain 873 mg ((92%) of the title compound (6) as needle crystals at mp73-74 ° C. .

Anal Calcd C ₁₄ H ₂₀ O ₃ Si: C, 63.60; H, 7.62.Found: C, 63.3
0; H, 7.89. ¹ H-NMR (CCl ₄ ) δ: 0.22 (9H, s, Me × 3), 1.30-2.30 (10
H, m, cyclohexy1), 7.37 (1H, s, C ₆ -H) .MS m / z: 264
(M ⁺ ). 7) 2,2-Dimethyl-5- (1-hexynyl) -1,3-dioxin-4-one Compound (4) (127 mg, 0.5 mmol), 1-hexyne (205 mg, 2.
5 mmol), Pd (Ph ₃ P) ₂ Cl ₂ (18 mg, 0.025 mmol), CuI (8 mg,
A DMF solution (5 ml) of 0.04 mmol) and triethylamine (101 mg, 1 mmol) is reacted at room temperature for 1.5 hours according to the general procedure A, and the ether extraction fraction is subjected to silica gel column chromatography (silica gel amount 12 g). From the elution with hexane-ethyl acetate (20: 1), 76 mg (73%) of the title compound (7) was obtained as a pale yellow oil.

High-resolution MS m / z Calcd C ₁₂ H ₁₆ O ₃ (M ⁺ ): 208.110
0.Found: 208.1122. ¹ H-NMR (CCl ₄ ) δ: 0.73-1.67 (7H, m, Me (CH ₂ ) ₂ CH ₂ C≡
C), 1.72 (6H, s, Me × 2), 2.00−2.83 (2H, m, Me (CH ₂ ) ₂
CH ₂ C≡C), 7.27 (1H, s, C ₆ -H). 8) 2,2-Dimethyl-5-trimethylsilylethynyl-1,3-
Dioxin-4-one Compound (4) (127mg, 0.5mmol) Trimethylsilylacetylene (245mg, 2.5mmol), Pd (Ph ₃ P) ₂ Cl ₂ (18mg, 0.025m
mol), CuI (8mg, 0.04mmol), triethylamine (101m
A DMF solution (5 ml) of g, 1 mmol) was reacted at room temperature for 35 minutes according to the general procedure A, and the ether extraction fraction was subjected to silica gel column chromatography (silica gel amount 6 g). 99 mg (88%) of the title compound (8) was obtained as a tan oil from the fraction eluted with hexane-ethyl acetate (25: 1, v / v).

High-resolution MS m / z Calcd C ₁₁ H ₁₆ O ₃ Si (M ⁺ ): 224.08
67.Found: 224.0864. ¹ H-NMR (CCl ₄ ) δ: 0.21 (9H, s, Me ₃ Si), 1,75 (6H, s, Me ×
2), 7.33 (1H, s, C ₆ -H). 9) 2,2-Dimethyl-5- (3-hydroxy-1-propynyl)
-1,3-dioxin-4-one Compound (4) (127mg, 0.5mmol), propargyl alcohol (140mg, 2.5mmol), Pd (Ph ₃ P) ₂ Cl ₂ (18mg, 0.025mmo
l), CuI (8mg, 0.04mmol), triethylamine (101mg, 1
mmol) in DMF solution (5 ml) at 60 ° C according to the general procedure A.
The fractions are reacted, and the ether-extracted fraction is subjected to silica gel column chromatography (silica gel amount 10 g). 43 mg (47%) of the title compound (9) was obtained as a pale yellow oily substance from the fraction eluted with hexane-ethyl acetate (2: 1, v / v).

High-resolution MS m / z Calcd C ₉ H ₁₀ O ₄ (M ⁺ ): 182.0580.
Found: 182.0590. ¹ H-NMR (CDCl ₃ ) δ: 1.75 (6H, s, Me × 2), 3.08 (1H, brs, O
H), 4.45 (2H, brs, CH ₂ OH), 7.40 (1H, s, C ₆ -H). 5-iodo-1,3-dioxin-4-ones [compound (2),
Cross-coupling reaction of (4)] with mono-substituted olefin General procedure B 5-Iodo compounds (2) and (4) (0.5 mmol) with mono-substituted olefin (1 mmol), Pd (OAc) ₂ (0.05 mmol) ), N
AHCO ₃ (1.25 mmol) tetrabutylammonium chloride (NBu ₄ Cl), 0.5 mmol of DMF solution (7 ml) is reacted at 60-70 ° C. in an argon stream. The reaction solution is diluted with ether, washed with water, and the ether layer is dried over anhydrous magnesium sulfate.
The solvent is distilled off under reduced pressure, and the residue is purified by the method described below.

10) (E) -5- (2-Ethoxycarbonyl-1-ethenyl)
-4-oxo-1,3-dioxin-2-spirocyclohexane Compound (2) (147mg, 0.5mmol), ethyl acrylate (1
00mg, 1mmol), Pd (OAc) ₂ (11mg, 0.05mmol), NaHCO ₃ (1
05 mg, 1.25 mmol) and NBu ₄ Cl (139 mg, 0.5 mmol) are reacted for 1 h according to the general procedure B, and the ether extraction fraction is subjected to silica gel column chromatography (silica gel amount 5 g).
A crystalline substance was obtained from the elution portion of hexane-ethyl acetate (10: 1, v / v) and recrystallized from hexane to obtain 90 mg (67%) of the title compound (10) as scaly crystals at mp67 ° C.

Anal.Calcd C ₁₄ H ₁₈ O ₅ : C, 63.15; H, 6.81.Found: C, 62.96; H, 6.69. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7Hz, OCH ₂ Me ), 1.13-2.
27 (10H, m, cyclohexy1), 4.22 (2H, q, J = 7Hz, O CH ₂ M
e), ▲ ^6.76 _7.20 ▼ (2H, ABq, J = 15Hz, CH = CH CO ₂ Et), 7.4
0 (1H, s, C ₆ -H) .MS m / z: 168 (M ⁺ -C ₃ H ₆ O). 11) (E) -2,2-Dimethyl-5- (2-ethoxycarbonyl-1-ethenyl-1,3-dioxin-4-one Compound (4) (254mg, 1mmol), ethyl acrylate (200
mg, 2mmol), Pd (OAc) ₂ (22mg, 0.1mmol), NaHCO ₃ (210m
g, 2.5 mmol), NBu ₄ Cl (278 mg, 1 mmol) in DMF solution (12 m
l) is reacted for 1.5 h according to the general procedure B, and the ether extraction fraction is subjected to silica gel column chromatography (silica gel amount 8 g). A crystalline substance was obtained from the elution with hexane-ethyl acetate (7: 1, v / v), and recrystallized from hexane to give mp.
151 mg (67 mg) of the title compound (11) as a prism at 64-65 ° C
%)obtain.

Anal.Calcd C ₁₁ H ₁₄ O ₅ : C, 58.40; H, 6.24.Found: C, 58.48;
H, 6.36. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7Hz, OCH ₂ Me ), ▲ ^6.60
_7.07 ▼ (2H, ABq, J = 16Hz, CH = CH CO), 7.32 (1H, s, C _6-
H) .MS m / z: 226 (M ⁺ ). 12) (E) -2,2-Dimethyl-5- (3-phthalimido-1-propenyl) -1,3-dioxin-4-one Compound (4) (254mg, 1mmol), N-allylphthalimide (374mg, 2 mmol), Pd (OAc) ₂ (22 mg, 0.1 mmol), NaHCO ₃
A DMF solution (12 ml) of (210 mg, 2.5 mmol) and NBu ₄ Cl (278 mg, 1 mmol) is reacted for 5.5 h according to the general procedure B, and the ether extraction fraction is subjected to silica gel column chromatography (silica gel amount 10 g). Hexane-ethyl acetate (5: 1, v /
v) Obtain a crystalline substance from the eluted portion, and recrystallize from hexane-dichloromethane to obtain 50 mg (16%) of the title compound (12) as scaly crystals at mp 148-149 ° C.

Anal.Calcd C ₁₇ H ₁₅ NO ₅ : C, 65.17; H, 4.83; N, 4.47.Found:
C, 65.36; H, 5.13; N, 4.41. ¹ H-NMR (CDCl ₃ ) δ: 1.68 (6H, s, Me × 2), 4.35 (2H, d, J =
5Hz, N CH ₂ CH = CH), 6.08 (1H, d, J = 16Hz, NCH ₂ CH = CH ),
6.50 (1H, dt, J = 5,16Hz, NCH ₂ CH ＝ CH), 7.17 (1H, s, C _6-
H), 7.57-8.07 (4H, m, ArH) .MS m / z: 255 (M ⁺ -C ₃ H ₆ O). 13) 2,2-Dimethyl-5- (2,2-diethoxy-1-methyl-1-
Ethenyl) -1,3-dioxin-4-one Compound (4) (127mg, 0.5mmol), acrolein diethyl acetal (130mg, 1mmol), Pd (OAc) ₂ (11mg, 0.05mm
ol), NaHCO ₃ (105mg, 1.25mmol), NBu ₄ Cl (139mg, 0.5m
DMF solution (6 ml) of (mol) was reacted for 4.5 h according to the general procedure B, and the ether extraction fraction was subjected to silica gel column chromatography (silica gel amount 6 g). 31 mg (24%) of the title compound (13) was obtained as a tan oil from the elution with hexane-ethyl acetate (3: 1, v / v).

¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, t, J = 7Hz, (OCH ₂ Me ) ×
2), 1.70 (6H, s, Me × 2), 2.50 (3H, s, MeC = C), 4.12
(4H, q, J = 7Hz, (O CH ₂ Me) × 2), 7.00 (1H, s, C ₆ -H) .M
Sm / z: 256 (M ⁺ ). 14) 2,2-Dimethyl-5-ethoxycarbonylethyl-1,3-
Dioxin-4-one Compound (11) (24mg, 0.106mmol) in ethyl acetate (4m
Pd-C (6 mg) is added to l) and subjected to catalytic reduction in a hydrogen stream. After the absorption of hydrogen has stopped (30 minutes), Pd-C is removed.
The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (silica gel amount 2.5 g). 18 mg (74%) of the title compound (14) was obtained as an oil from the elution with hexane-ethyl acetate (5: 1, v / v).

High-resolution MSm / zCalcd C ₁₁ H ₁₆ O ₅ (M ⁺ ): 228.0998.F
ound: 228.0999. ¹ H-NMR (CCl ₄ ) δ: 1.23 (3H, t, J = 7Hz, OCH ₂ Me ), 1.63 (6
H, s, Me × 2), 2.43 (4H, s, CH ₂ CH ₂ CO), 4.06 (2H, q, J = 7
Hz, O CH ₂ Me), 6.93 (1H, s, C ₆ -H). 15) 5-ethynyl-4-oxo-1,3-dioxin-2-spirocyclohexane a) To a tetrahydrofuran solution (3 ml) of compound (6) (106 mg, 0.4 mmol) was added 1 M NBu ₄ F tetrahydrofuran solution (0.4 ml). Add with stirring while cooling with a freezing agent, immediately add ether and wash with water. The ether layer is dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and the residue is subjected to silica gel column chromatography (silica gel amount 4.5 g). A crystalline substance was obtained from the elution portion of hexane-ethyl acetate (7: 1, v / v) and recrystallized from hexane to obtain 33 mg (43%) of the title compound (15) as needle crystals at mp87-87.5 ° C.

Anal.Calcd C ₁₁ H ₁₂ O ₃ : C, 68.74; H, 6.29.Found: C, 68.80;
H, 6.04. ¹ H-NMR (CDCl ₃ ) δ: 1.12-2.28 (10H, m, cyclohexy1), 3.10
(1H, s, C≡CH), 7.53 (1H, s, C ₆ -H) .MS m / z: 192 (M ⁺ ). b) DMF solution (4 ml) of compound (6) (106 mg, 0.4 mmol)
FK.2H ₂ O (38mg, 0.4mmol) DMF (1.5ml) -H ₂ O (0.5m
l) Add the solution while stirring under ice-water cooling, immediately add ether and wash with water. The ether layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from hexane to obtain 68 mg (89%) of the title compound (15).

16) 2,2-Dimethyl-5-ethynyl-1,3-dioxin-4-one Compound (8) (85mg, 0.38mmol) in DMF solution (3ml), F
A solution of K · 2H ₂ O (36 mg, 0.38 mmol) in DMF (2 ml) -H ₂ O (1 ml) is added with stirring while cooling with ice water, and ether is immediately added to wash with water. The ether layer is dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and the residue is subjected to silica gel column chromatography (silica gel amount 4 g). From the elution with hexane-ethyl acetate (7: 1, v / v), 44 mg (76%) of the title compound (16) having an mp of 54-55 ° C is obtained.

High-resolution MSm / z Calcd C ₈ H ₈ O ₃ (M ⁺ ): 152.0472.Fo
und: 152.0452. ¹ H-NMR (CCl ₄ ) δ: 1.72 (6H, s, Me × 2), 2.98 (1H, s, C≡C
H), 7.37 (1H, s, C ₆ -H). 17) 5-Ethyl-4-oxo-1,3-dioxin-2-spirocyclohexane Compound (15) (192mg, 1mmol) in ethyl acetate (7ml)
Pd-C (20 mg) is added to and subjected to catalytic reduction in a hydrogen stream.
After the absorption of hydrogen has stopped (15 minutes), Pd-C is removed. The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (silica gel amount 10 g). A crystalline substance was obtained from the elution with hexane-ethyl acetate (20: 1, v / v) and recrystallized from pentane to obtain 169 mg (86%) of the title compound (17) as needle crystals at mp 34-35 ° C.

Anal.Calcd C ₁₁ H ₁₆ O ₃ : C, 67.32; H, 8.22.Found: C, 67.17;
H, 8.17. ¹ H-NMR (CCl ₄ ) δ: 1.07 (3H, t, J = 7Hz, CH ₂ Me ), 1.33-2.43
(10H, m, cyclohexy1), 2.16 (2H, dq, J = 1,7Hz, CH ₂ Me),
6.79 (1H, t, J = 1Hz, C 6 -H) .MSm / z: 196 (M +). 18) 2,2-Dimethyl-5-ethyl-1,3-dioxin-4-one Compound (16) (208mg, 1.37mmol) in ethyl acetate (7m
Add Pd-C (21 mg) to l) and subject it to catalytic reduction in a hydrogen stream. After the absorption of hydrogen has stopped (20 minutes), Pd-C is removed.
The solvent is distilled off under reduced pressure, and the resulting residue is subjected to silica gel column chromatography (silica gel amount 6 g). 179 mg (84%) of the title compound (18) was obtained as an oil from the elution with hexane-ethyl acetate (5: 1, v / v).

High resolution MS m / z Calcd C ₈ H ₁₂ O ₃ (M ⁺ ): 156.0785.
Found: 156.0783. ¹ H-NMR (CCl ₄ ) δ: 1.10 (3H, t, J = 7Hz, CH ₂ Me ), 1.63 (6H,
s, Me × 2), 2.18 (2H, q, J = 7Hz, CH ₂ Me), 6.78 (1H, s, C ₆
-H). 19) 5- (2-propynyl) -4-oxo-1,3-dioxin-
2-Spirocyclohexane Compound (2) (118mg, 0.4mmol) and allyltrimethylsilane (686mg, 6mmol) in anhydrous acetonitrile (50m
(l) is irradiated with light (300 nm) for 5 hours with a 100 W high pressure mercury lamp using a Pyrex filter. The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (silica gel amount 10 g). Hexane-ethyl acetate (15: 1, v /
v) 43 mg of the title compound (19) as an oily substance from the eluted portion
(52%) get.

High-resolution MS m / z Calcd C ₁₂ H ₁₆ O ₃ (M ⁺ ): 208.110
0.Found: 208.1103. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.30 (10H, m, cyclohexy1), 2.97
(2H, ddd, J = 1.4,2.8,6Hz, CH ₂ ＝ CHCH _2- ), 4.89-5.40 (2
H, m, CH ₂ ＝ CHCH _2- ), 5.81 (1H, ddt, J ＝ 6,9,16Hz, CH ₂ ＝ CH
CH _2- ), 6.87 (1H, t, J = 1.4Hz, C ₆ -H). 20) 2,2,5-Trimethyl-1,3-dioxin-4-one-potassium tert-butoxide (2.24g, 20mmol) in dimethylformamide solution (40ml) with stirring while cooling with a cryogen
-Butylformyl acetate (2.88 g, 20 mmol) is added slowly. To this solution is added iodomethane (3.10 g, 22 mmol) in one portion and stirred at this temperature for 2 hours and at room temperature for 10 minutes. Add water and weakly acidify with 10% HCl and extract with ether. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in ether, extracted with cold 2.5% aqueous sodium hydroxide solution (10 ml) three times, and the alkali layer is washed with ether. Acidify with 10% HCl, extract with ether and wash with saturated brine. The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and the residue is subjected to silica gel column chromatography (silica gel amount 30 g). Hexane-ethyl acetate (20: 1, v / v) eluate as an oil
tert-butyl 2-methylformyl acetate 485 mg (15
%)obtain.

¹ H-NMR (CCl ₄ ) δ: 1.23 (3H × 2/5, d, J = 7Hz, Me CHCO ₂ ), 1.
52 (9H, s, Otert-Bu), 1.63 (3H × 3/5, s, Me C = CHOH), 3.
22 (1H × 2/5, dq, J = 2.7Hz, Me CH CO ₂ ), 6.92 (1H × 3/5, d,
J = 12Hz, MeC = CH OH), 9.68 (1H x 2/5, d, J = 2Hz, HCO), 1
1.35 (1H x 3/5, d, J = 12Hz, MeC = CH OH ). Semi carbazone: mp126-128 ℃ (ether-hexane) An
al.Calcd C ₉ H ₁₇ N ₃ O ₃ : C, 50.22; H, 7.96; N, 19.52.Found: C,
50.24; H, 8.16; N, 19.51. The above compound (316 mg, 2 mmol) was added to acetic anhydride (612
Acetone (232 mg, 4 mmol) is added, and concentrated sulfuric acid (196 mg, 2 mmol) is gradually added with stirring. After stirring for 5 minutes, the mixture is stirred in ice water for 30 minutes and further at room temperature for 30 minutes. Pour into an aqueous solution of sodium hydrogen carbonate and stir until the odor of acetic anhydride disappears. The reaction solution is extracted with ether, and the ether layer is dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is subjected to silica gel column chromatography (silica gel amount 9 g). Hexane-ethyl acetate (5: 1, v /
v) 50 mg of the title compound (20) as an oily substance from the eluted part
(18%) get.

High-resolution MS m / z Calcd C ₇ H ₁₀ O ₃ (M ⁺ ): 142.0628.
Found: 142.0627. ¹ H-NMR (CDCl ₃ ) δ: 1.68 (6H, s, Me × 2), 1.76 (3H, s, C _5-
Me), 6.87 (1H, s , C 6 -H). As is clear from these synthetic examples, 5-substituted mono-substituted 1,
3-dioxin-4-ones are similar to 6-monosubstituted and 5-, 6-disubstituted 1,3-dioxin-4-ones in the presence of concentrated sulfuric acid and tert-butyl ester of β-keto acid. Although some compounds are obtained by treatment with acetic anhydride in acetone (eg compound 20), this method usually gives un-substituted 1,3-dioxy-4-, because the yield is poor. A method is available in which the 5-position bromide or iodide is first obtained from an on compound as a starting material, and this is further subjected to a cross-coupling reaction using a palladium compound as a catalyst to selectively introduce a carbon substituent into a halogen substitution site. Be seen. Regarding the cross-coupling reaction with acetylenes, Yamanaka et al. [Ch
em.Pharm.Bull., 26,3843 (1978), Synthesis, 312 (198
3)], Cassar et al. [J. Organomet. Chem., 93, 253 (197
5)], Heck et al. [Ibid. 259], Ogihara et al. [Tetra hedron lett.,
4467 (1975), Synthesis777, (1977)] and the like, and Heck et al. [J.
Org. Chem., 37, 2320 (1972)], Yamanaka et al. [Chem. Pharm. Bu
ll., 30, 3647 (1982), 27, 193 (1979)], Jeffery et al. [J. Chem. Soc., Chem. Commun., 1287 (1984)]. Since it is unstable, it is desirable to devise a method that allows the reaction to proceed rapidly even at a relatively low temperature. There is also a method of utilizing a photoreaction as shown in the synthesis of compound 19.

The 5-substituted 1,3-dioxin-4-ones thus obtained can be used as synthons in various synthetic chemistry in the same manner as other known 1,3-dioxin-4-ones, as described above. .

Claims (1)

[Claims] 1. A general formula (In the formula, X is a bromine, iodine or phenyl group, a trimethylsilyl group, a hydroxyl group, a lower alkoxycarbonyl group, a phthalimido group and a lower alkoxy group, or a substituted or unsubstituted alkyl group or alkenyl group. Or an alkynyl group: R and R'represent a lower alkyl group or an alkylene group in which R and R'are bonded to each other to form an integrated alkylene group).
-One derivatives.