JP2579547B2 - Preparation of alkoxycarbonyl compounds - Google Patents

Description

The present invention relates to a novel method for producing an alkoxycarbonyl compound.

[Conventional technology and its problems]

The reaction of a silyl nucleophile with an acetal compound is important in organic synthesis as one of carbon-carbon bond formation reactions. As an example of this reaction, the following formula (II) (Wherein, R ³ , R ⁴ and R ⁵ may be the same or different and each represents an alkyl group or an aryl group, and R ⁶ , R ⁷ and
R ⁸ may be the same or different, and each represents a hydrogen atom, an alkyl group or an aryl group which may have a substituent, or R ⁷ and R ⁸ may have a substituent together. May form a good ring) by the enol silyl ether compound represented by the formula
Examples include a method for synthesizing an alkoxycarbonyl compound (aldol compound), which is useful for synthesizing various natural products, pharmaceuticals, etc. [For example, a method using TiCl ₄ : T. Mukaiyama and
M. Hayashi, Chem. Lett., 1974 , 15; Method using CF ₃ SO ₃ —Si (CH ₃ ) ₃ : S. Murata, M. Suzuki and R. Noyori, J. Am. Che
m. Soc., 102 , 3248 (1980); Method using Ph ₃ C.ClO ₄ : T.
Mukaiyama, S. Kobayashi and M. Murakami, Chem. Lett., 19
84 , 1759]. However, reactions using these silyl nucleophiles generally involve Lewis acids such as titanium tetrachloride, tin tetrachloride and zinc iodide or salts with strongly acidic anions such as trimethylsilyl trifluoromethanesulfonate and trityl perchlorate. And acidic reaction conditions are required. Therefore, it is difficult to apply the method to the synthesis of a compound unstable to an acid or a compound having a strong basicity that neutralizes the acid. Further, there is a problem that it is difficult to use a reaction solvent such as an ether or an amide which can be a Lewis base such as tetrahydrofuran or dimethylformamide.

[Means for Solving the Problems] Under such circumstances, the present inventors have found that a reaction solvent such as tetrahydrofuran, which is an excellent solvent widely used in organic synthesis, can be used freely, and a compound which is unstable to acids. As a result of intensive studies to develop the reaction of silyl nucleophiles on acetal compounds that proceed under neutral conditions applicable to synthesis, as a result of using a specific rhodium complex and a silyl cyanide compound as a catalyst, such a purpose can be achieved. The present invention has been accomplished by finding out that it is achieved.

That is, the present invention provides the following formula (I) (Wherein, R ¹ represents an alkyl group which may have a substituent, an alkenyl group or an aryl group, R ² represents an alkyl group which may have a substituent) The enol silyl ether compound represented by the formula (II) is combined with a catalytic amount of the following formula (III) [RhAX] ₂ (III) (where A is a compound having two or more double bonds in the molecule, X Represents a halogen atom. The following formula (V) is characterized by reacting a rhodium complex represented by the following formula with a silyl cyanide compound represented by the formula (IV): (Wherein, R ¹ , R ₂ , R ⁶ , R ⁷ and R ⁸ have the same meaning as described above).

In the compound (I) used as a raw material in the method of the present invention, the alkyl group of R ¹ preferably has 1 to 20 carbon atoms, and the alkenyl group preferably has 2 to 20 carbon atoms. Among them, a vinyl group substituted with an aryl group And 1-alkenyl groups such as 1-propenyl group. As the aryl group for R ^1, a phenyl group, a naphthyl group, or the like is preferable, and as a substituent thereof, a halogen atom such as fluorine, chlorine, or bromine,
Preferred are an alkyl group of 8, an alkoxyl group having 1 to 8 carbon atoms, an aryloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group and the like, particularly a methoxyl group and an ethoxyl group. The alkyl group of R ₂ has 1 carbon atom.
To 8, particularly preferably a methyl group, an ethyl group, a butyl group and the like, and as a substituent thereof, an aryl group such as a phenyl group and a halogen atom such as fluorine, chlorine and bromine are preferable.

Such a compound (I) can be easily synthesized from the corresponding carbonyl compound by a conventional method. For example, the corresponding dimethyl acetal can be synthesized by reacting the corresponding aldehyde with methyl orthoformate in methanol in the presence of an acid catalyst such as p-toluenesulfonic acid.

R ³ , R ⁴ and R ⁵ in the enolsilyl ether (II) used as a nucleophile in the method of the present invention are those having 1 to 8 carbon atoms as an alkyl group, particularly a methyl group, an ethyl group,
A t-butyl group or the like is preferable, and a phenyl group or the like is preferable as the aryl group. R ⁶ , R ⁷ and R ^{8 each} have an alkyl group having 1 to 8 carbon atoms, in particular, a methyl group, an ethyl group,
A propyl group and the like are preferable, and a phenyl group and the like are preferable as the aryl group. Further, the ring formed by R ⁷ and R ⁸ is preferably a 5-membered ring or a 6-membered ring. Specific examples of such an enol silyl ether compound (II) include trimethylsilyl enol ether of acetophenone, trimethylsilyl enol ether of acetone, and trimethylsilyl enol ether of cyclohexanone.

Such a compound (II) can be synthesized from the corresponding carbonyl compound by a conventional method, for example, by reacting a base such as lithium diisopropylamide and then reacting with trimethylsilyl chloride.

Rhodium complex (II) used as a catalyst in the method of the present invention
In I), as the compound having two or more double bonds in the molecule, a diene compound, particularly a diene compound having 1 to 20 carbon atoms, furthermore 1,5-cyclooctanediene, norbornadiene, 1,5-hexadiene and the like can be mentioned. Preferably, the halogen atom of X is fluorine, chlorine, bromine or the like. Specific examples of such rhodium complex (III) include di-μ
-Chloro-bis (1,5-cyclooctadiene) dirhodium (hereinafter referred to as [Rh (COD) Cl] ₂ ), di-μ-chloro-
Bis (norbornadiene) dirhodium and the like can be mentioned.
Since this catalyst is a neutral compound unlike the conventionally used Lewis acids, the reaction can be carried out under neutral conditions and acidic reaction conditions can be avoided.

The silyl cyanide compound (IV) used as a catalyst in the method of the present invention includes trimethylsilyl cyanide (hereinafter referred to as trimethylsilyl cyanide).
TMS-CN), tert-butyldimethylsilyl anide,
Dimethylphenylsilyl cyanide and the like.

Further, as a reaction solvent used in the method of the present invention, for example, methylene chloride, toluene, acetonitrile,
Tetrahydrofuran (hereinafter referred to as THF) and the like.

Next, a general reaction operation will be described. First, a rhodium catalyst (III) of about 0.5 to 5 mol% with respect to the raw material (I) is dissolved in a solvent, and the silyl cyanide catalyst (IV) is dissolved at a temperature of about 5 to 30 ° C. in a molar amount of 0.05 to 0.5 times. (Appropriate amount varies depending on the type of the raw material (I) and the nucleophile (II), and may be used even if it is more than equivalent). After stirring for about 10 minutes to 3 hours, about 1.1 to 1.8 times mol Enol silyl ether (II) and raw material (I)
Is added at room temperature (the reaction solution may be cooled once, and each of them may be added separately), and at a temperature of about 5 to 30 ° C. for 1 to 60 hours (raw material (I) and nucleophile (II)
May be out of this range depending on the type of the mixture). After completion of the reaction, a phosphate buffer (about pH = 7), an aqueous solution of sodium hydrogen carbonate and the like are added, and the mixture is extracted with an appropriate organic solvent. After evaporating the solvent, silica gel thin-layer chromatography,
Purification by silica gel column chromatography or the like yields the desired alkoxycarbonyl compound.

In the method of the present invention, the rhodium catalyst (III) and the silyl cyanide catalyst (IV) must be used in combination, and the desired alkoxycarbonyl compound (V) cannot be obtained even if each is used alone as a catalyst. The following compound (VI) obtained when the raw material (I) and the silyl cyanide compound (IV) are reacted in the presence of a todium catalyst (III) Are rarely produced in the method of the present invention.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Preparation of (E) -1,5-diphenyl-3-methoxy-4-pent-1-one: Under argon, the 0.006mmol [Rh (COD) Cl] 2 and 1.0
Dissolve in 0.1 ml of dry acetonitrile and add 0.06 mm
ol of TMS-CN in 1.0 ml of acetonitrile was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Then 0.30 mmol of (E)
-Cinnamaldehyde dimethyl acetal and 0.36 mmol of acetophenone trimethylsilyl enol ether
A 3.0 ml acetonitrile solution was added, and the mixture was stirred at the same temperature for 3 hours. After adding a saturated aqueous solution of sodium bicarbonate to the reaction solution, organic substances were extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure.
The residue is thin-layer chromatography) developing solvent, hexane:
Purification by ethyl acetate = 5: 1) gave 0.274 mmol of the title compound (91% yield).

NMR (CCl ₄ , TMS standard) δ ppm: 7.8 (2H, m), 7.2 (8H, m), 6.50 (1H, d, J = 16Hz), 5.95
(1H, dd, J = 7Hz, 16Hz), 4.29 (1H, m), 3.21 (3H, s), 2.
76 (1H, dd, J = 5 Hz, 16 Hz) Example 2 The same reaction as in Example 1 was performed, except that the solvent was changed to THF. The yield was 84%.

Example 3 Preparation of 1,3-diphenyl-3-methoxy-1-propanone: 0.25 mmol of benzaldehyde dimethyl acetal and 0.
31 mmol of trimethylsilyl enol ether of acetophenone were combined with 0.004 mmol of [Rh (COD) Cl] ₂ and 0.042 mmol of
The reaction was carried out in the same manner as in Example 1 in the presence of TMS-CN to obtain 0.241 mmol of the title compound (96% yield).

NMR (CDCl ₃ , TMS standard) δ ppm: 7.8 (2H, m), 7.2 (8H, m), 4.77 (1H, dd, J = 5Hz, 8Hz),
3.52 (1H, dd, J = 8Hz, 16Hz), 3.15 (3H, s), 2.96 (1H, d
d, J = 5 Hz, 16 Hz) Example 4 3-Methoxy-3- (p-methoxyphenyl) -1-
Preparation of phenyl-1-propanone: 0.29 mmol of p-methoxybenzaldehyde dimethyl acetal and 0.37 mmol of trimethylsilyl enol ether of acetophenone were combined with 0.006 mmol of [Rh (COD) Cl].
_The reaction was carried out in the same manner as in Example 1 in the presence of ₂ and 0.065 mmol of TMS-CN to obtain 0.277 mmol of the title compound (96% yield).

NMR (CCl ₄ , TMS standard) δ ppm: 7.7 (2H, m), 7.1 (5H, m), 6.63 (2H, d, J = 9 Hz), 4.62
(1H, dd, J = 5Hz, 8Hz), 3.65 (3H, s), 3.40 (1H, dd, J = 8
Hz, 16Hz), (3.05 (3H, s), 2.78 (1H, dd, J = 5Hz, 16H
z) Example 5 Preparation of 3-methoxy-1-phenyl-4-hex-1-one: 0.32 mmol of crotonaldehyde dimethyl acetal
0.46 mmol of acetophenone trimethylsilyl enol ether is combined with 0.006 mmol of [Rh (COD) Cl] ₂ and 0.06 mmol
The reaction was carried out in the same manner as in Example 1 in the presence of 1 TMS-CN to obtain 0.273 mmol of the title compound (yield: 85%).

NMR (CDCl ₃ , TMS standard) δ ppm: 7.7 (2H, m), 7.3 (3H, m), 5.4 (2H, m), 4.10 (1H, m),
3.18 (3H, s), 2.83 (1H, dd, J = 5Hz, 16Hz), 1.66 (3H, d,
J = 5 Hz) Example 6 Production of 1,5-diphenyl-3-methoxy-1-pentanone: 0.32 mmol of 3-phenylpropanal dimethyl acetal and 0.47 mmol of trimethylsilyl enol ether of acetophenone are combined with 0.006 mmol of [Rh (COD) Cl] ₂
The reaction was carried out in the same manner as in Example 1 in the presence of 0.06 mmol of TMS-CN to obtain 0.315 mmol of the title compound (98% yield).

NMR (CDCl ₃ , TMS standard) δ ppm: 7.7 (2H, m), 7.3 to 7.0 (8H, m), 3.78 (1H, m), 3.25 (3
H, s), 3.3-2.5 (4H, m), 1.9 (2H, m) Example 7 Preparation of 3-methoxy-1-phenyl-1-dodecanone: 0.31 mmol of decanal dimethyl acetal and 0.46 mmol
Of acetophenone with 0.006 mmol of [Rh (COD) Cl] ₂ and 0.15 mmol of TMS-
Reaction was carried out in the same manner as in Example 1 in the presence of CN to give the title compound 0.1.
250 mmol was obtained (81% yield).

NMR (CCl ₄ , TMS standard) δ ppm: 7.7 (2H, m), 7.3 (3H, m), 3.7 (1H, m), 3.18 (3H, s),
3.3-2.5 (2H, m), 1.4-0.8 (19H, m) Example 8 3-methoxy-3- (p-methoxyphenyl) -2-
Preparation of methyl-1-phenyl-1-propanone: 0.30 mmol of p-methoxybenzaldehyde dimethyl acetal and 0.45 mmol of trimethylsilyl enol ether of propiophenone are combined with 0.006 mmol of [Rh (COD) C
l] The reaction was carried out in the same manner as in Example 1 in the presence of ₂ and 0.06 mmol of TMS-CN to obtain 0.262 mmol of the title compound as a mixture of diastereoisomers (87% yield).

NMR (CCl ₄ , TMS standard) δ ppm: 7.9-6.4 (9H, m), 4.2 (1H, m), 3.68 and 3.56 (3H, each s,
About 3: 7), 3.06 and 2.93 (3H, each s, about 7: 3), 1.27 and 0.75 (3
H, each d, J = 7 Hz, about 7: 3) Example 9 Preparation of 2- [methoxy- (p-methoxyphenyl) methyl] cyclohexanone: 0.32 mmol of p-methoxybenzaldehyde dimethyl acetal and 0.36 mmol of trimethylsilyl enol ether of cyclohexanone are combined with 0.006 mmol of [Rh (COD) C
l] The reaction was carried out in the same manner as in Example 1 in the presence of ₂ and 0.03 mmol of TMS-CN to obtain 0.205 mmol of the syn isomer of the title compound (yield: 64
%) And 0.088 mmol of the anti isomer (28% yield).

NMR of syn isomer (CDCl ₃ , TMS standard) δ ppm: 7.10 (2H, d, J = 9 Hz), 6.73 (2H, d, J = 9 Hz), 4.60 (1H,
d, J = 5Hz), 3.73 (3H, s), 3.16 (3H, s), 2.4 ~ 1.6 (9H,
m) NMR of anti isomer (CDCl ₃ , TMS standard) δ ppm: 7.10 (2H, d, J = 9 Hz), 6.74 (2H, d, J = 9 Hz), 4.41 (1H,
d, J = 8Hz), 3.73 (3H, s), 3.10 (3H, s), 2.4 ~ 1.4 (9H,
m) [Effects of the Invention] As described above, the production method of the alkoxycarbonyl compound of the present invention differs from the conventional method requiring acidic reaction conditions in that the reaction solvent used as a Lewis base such as THF, ether, DMF, etc. Can be used. Further, since the reaction proceeds under almost neutral conditions, it can be applied to the synthesis of an organic compound unstable to an acid or a base, or a strongly basic compound that neutralizes an acid.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location C07C 49/84 9049-4H C07C 49/84 A // C07B 61/00 300 C07B 61/00 300

Claims (1)

(57) [Claims] 1. The following formula (I) (Wherein, R ¹ represents an alkyl group, an alkenyl group or an aryl group which may have a substituent, R ² represents an alkyl group which may have a substituent) and an acetal compound represented by the following formula: Formula (II) (Wherein, R ³ , R ⁴ and R ⁵ may be the same or different and each represents an alkyl group or an aryl group, and R ⁶ , R ⁷ and
R ⁸ may be the same or different, and each represents a hydrogen atom, an alkyl group or an aryl group which may have a substituent, or R ⁷ and R ⁸ may have a substituent together. And a catalytic amount of the following formula (III) [RhAX] ₂ (III) (where A is two or more double bonds in the molecule) And X represents a halogen atom) and a rhodium complex represented by the following formula (IV): Wherein R ³ , R ⁴ and R ⁵ have the same meanings as described above, wherein the reaction is carried out in the presence of a silyl cyanide compound represented by the following formula (V): (Wherein, R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ have the same meaning as described above).