JPH10120655A - Production of aromatic ketone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain an aromatic ketone by reaction of a specific aromatic compound with carbon monoxide and an olefin compound in the presence of a transition metal catalyst to effect direct carbonylation of the carbon- hydrogen bond of the aromatic ring in a site-selective way. SOLUTION: This aromatic ketone of formula IV or formula V, which is useful for e.g. organic industrial products, medicines, is obtained by reaction of an aromatic compound of formula I [R<1> is 2- or 4-pyrimidinyl; R<2> and R<3> are each H, an alkyl, an alkoxy, etc., or may be joined together to form an aromatic ring when they are adjacent to each other; however, H is bound to at least one carbon atom adjacent to the carbon atom bound to R<1> (or R<1> ' shown below)] or formula II [R<1> ' is R<1> (with a substituent on the ring) or 2- pyridyl (with a substituent on the ring); X is O, S, etc.] with carbon monoxide and an olefin compound of formula III (R is H or an alkyl) in the presence of a transition metal catalyst (e.g. a ruthenium compound).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing aromatic ketones useful as various organic industrial products, pharmaceuticals, agricultural chemicals, fragrances, polymer products and the like, or as intermediates for producing them. In the presence of a metal catalyst, a nitrogen-containing heterocyclic-substituted aromatic compound is reacted with carbon monoxide and an olefin to produce an aromatic ketone in which the aromatic ring is regioselectively acylated in high yield. It relates to a method of manufacturing.

[0002]

2. Description of the Related Art Conventionally, there has been known a reaction in which a carbon-hydrogen bond of a pyridine ring is sequentially added to carbon monoxide and then to 1-octene using ruthenium carbonyl as a catalyst. Moore, EJ
et al, J. Am. Chem. Soc., 114, 5888 (1992)), and an acylation reaction by addition of carbon monoxide, and then an olefin, of an aromatic compound such as benzene or toluene has not been known so far. The present invention provides a method for efficiently producing an aromatic ketone by carbonylating a carbon-hydrogen bond of a benzene ring, a pyrrole, a thiophene, and a furan ring with high reactivity and regioselectivity, which has not been known before. To provide.

[0003]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that an aromatic compound substituted with a nitrogen-containing heterocyclic ring can be converted to carbon monoxide and olefin in the presence of a transition metal catalyst. It has been found that by reacting with a compound, the carbon-hydrogen bond of the aromatic ring is regioselectively directly carbonylated, and then the olefin is incorporated and monoacylated or diacylated.

[0004]

According to the method of the present invention, the compound represented by the general formula (3) or (4)

Embedded image (Wherein, R ¹ represents a 2- or 4-pyrimidinyl group, and R ¹ ′ represents a 2-pyridyl group or 2- or 4-
A pyrimidinyl group, which may have a substituent on the ring of the pyridyl group and the pyrimidinyl group; R ² and R ³ each represent a hydrogen atom, an alkyl group, an alkoxy group, an alkoxycarbonyl group or a halogen atom, or when R ² and R ³ are adjacent to each other, they form an aromatic ring together; Is also good. However, a hydrogen atom is bonded to at least one of the carbons adjacent to the carbon to which R ¹ or R ¹ ′ is bonded. X represents an oxygen atom, a sulfur atom, or a nitrogen atom, and the nitrogen atom has a hydrogen atom or another substituent), and an aromatic compound represented by the general formula (5) in the presence of a transition metal catalyst:

Embedded image (Wherein R represents a hydrogen atom or an alkyl group) by reacting with an olefin represented by the general formula (1) or (2)

Embedded image (Wherein R, R ¹ , R ¹ ′, R ² and R ³ are as defined above)
Can be produced.

The alkyl group as the R group in the compound of the present invention includes one having 1 carbon atom such as methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.
-4 straight or branched chain alkyl groups. Preferred R groups are hydrogen atoms or tert-butyl groups. As the substituent on the pyridyl group or pyrimidinyl group in the R ¹ group or R ¹ ′ group, methyl, ethyl, n-
A straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms such as propyl, isopropyl, n-butyl, tert-butyl and the like, wherein 1 to 4 of them are substituted on a pyridine ring or a pyrimidine ring; Is also good. Examples of the alkyl group as the R ² group and the R ³ group include a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; Examples of the group include straight-chain or branched-chain alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, and tert-butoxy. And alkoxycarbonyl groups having a group. The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The aromatic ring formed by R ² and R ³ together includes a benzene ring and a naphthalene ring. Desirable R ² and R ³ are a hydrogen atom, a methyl group, a methoxy group, a methoxycarbonyl group, a fluorine atom, or R ² and R ³ together form a benzene ring. X represents an oxygen atom, a sulfur atom or a nitrogen atom (substituted by one hydrogen atom or another substituent, for example, a lower alkyl group).

The reaction of the method of the present invention is as follows.

Embedded image (Wherein, R, R ¹ , R ¹ ′, R ² and R ³ are the same as described above)

As shown in the above reaction formula, a ruthenium compound is used as a transition metal catalyst, and an aromatic compound (3)
Or reacting (4) with the olefins (5) and carbon monoxide, the position of the aromatic compound (3) or (4) at the carbon next to the carbon to which the substituent R ¹ or R ¹ ′ is bonded. Selectively monoacylated aromatic ketones can be obtained in high yield. Although the reaction mechanism of the present invention is not clear, it can be estimated as follows. First, coordination of the nitrogen atom of the nitrogen-containing heterocyclic ring, which is the substituent R ¹ or R ¹ ′ of the aromatic compound (3) or (4), to ruthenium occurs, and then cyclometallation proceeds, and the substituent R Via cleavage of the carbon-hydrogen bond next to the carbon to which ¹ or R ¹ 'is attached,
Carbon monoxide and then olefins are taken in and reductive desorption,
It is believed to have given the acylated product.

As the transition metal catalyst, the transition metal as it is,
Or a compound thereof, or a complex thereof.
The transition metal is preferably a noble metal, particularly preferably ruthenium. The ruthenium compound or ruthenium _{complex, Ru 3 (CO) 12,} RuH 2 (CO) (PPh 3) 3, RuCl
₂ (CO) ₂ (PPh ₃ ) ₂ , RuCl ₂ (PPh ₃ ) ₃ , Ru (acac) ₃ , (RuCl ₂ (CO)
₃ ] ₂ , RuCl (C ₅ H ₅ ) (PPh ₃ ) ₂ and [RuCl ₂ (C ₈ H ₁₂ )] n, which can be used alone or in combination of two or more. Preferred transition metal catalysts are Ru ₃ (CO) _12. The optimum amount of these transition metal catalysts varies slightly depending on the reaction conditions and the type of catalyst.
When a ruthenium carbonyl complex is used, the amount is preferably from 0.025 mol to 0.1 mol per 1 mol of the pyridine derivative.

In order to obtain the desired aromatic ketone in high yield by the method of the present invention, the reaction must be carried out at a carbon monoxide pressure of 5 to 5%.
0 atm, more preferably 10 to 30 atm. 50atm
If it exceeds, the yield of the product decreases. When ethylene is used as the olefin, the charging pressure is 1 to 10 atm,
Preferably it is 3-7 atm. If it is less than 1 atm, the reactivity will decrease slightly. When another olefin is used, it is used in an amount of 1 to 5 equivalents, preferably 2 to 4 equivalents, based on the aromatic compound. If it is less than 1 equivalent, the yield is poor, and even if it is used more than 5 equivalents, the yield does not improve. In addition, the reaction of the present invention is usually performed in an organic solvent, examples of the solvent used include aromatic hydrocarbons such as toluene and benzene, tetrahydrofuran, diethyl ether, ethers such as dioxane, and preferably toluene and the like. Is an aromatic hydrocarbon solvent. The reaction temperature is 140-200 ° C., preferably 150
１７０170 ° C. If the temperature is lower than 140 ° C., the reaction hardly proceeds, which is not preferable.

[0010]

EXAMPLES The present invention will now be described more specifically with reference to examples, but the present invention is not limited thereto. Example 1

Embedded image Then, 2- (2-thienyl) pyridine, carbon monoxide and ethylene were reacted. That is, in a 50 ml stainless steel autoclave, the rotor, Ru ₃ (CO) ₁₂ 0.05
mmol and 2-mmol of 2- (2-thienyl) pyridine were added in this order, and 6 ml of toluene was added while flushing the inner wall. After the inside of the autoclave was replaced twice with 5 atm of ethylene, ethylene (7 atm) and then carbon monoxide (20 atm) were injected at room temperature and placed in a 160 ° C oil bath.
The reaction was performed for 20 hours. After the reaction, the autoclave was returned to room temperature, the pressure of ethylene and carbon monoxide was reduced, the solvent was distilled off under reduced pressure, and the obtained residue was isolated and purified by silica gel chromatography to give 1- [ 2- (2-pyridinyl) -3-thienyl] -1-propanone was obtained.
Analysis of the reaction used gas chromatography. Yellow oil Boiling point 125 ° C (1 mmHg); R _f = 0.13 (hexane / ethyl acetate = 5/1); ¹ H NMR (CDCl ₃ ) δ 1.15 (t, J = 7.3 Hz, 3H, CH ₃ CH ₂ C
(O)), 2.76 (q, J = 7.3 Hz, 2H, CH ₂ C (O)), 7.22-7.27
(m, 1H, 5-H), 7.32-7.37 (m, 2H, thienyl-H), 7.67
-7.75 (m, 2H, 3-H, 4-H), 8.61 (d, J = 5.1 Hz, 1H,
6-H); ¹³ C NMR (CDCl ₃ ) δ 8.29 (CH ₃ CH ₂ C (O)), 35.94 (CH ₂ C
(O)), 122.82 (5-C), 123.41, 126.25, 128.77, 136.3
9, 138.67, 146.56 (Ar), 149.36 (C-6), 151.90 (Ar),
199.89 (CO); IR (neat) 3074 m, 2980 m, 2940 m, 1686 s, 1585 s,
1568 m, 1521 s, 1467s, 1439 s, 1422 s, 1377 s, 133
4 m, 1267 s, 1212 s, 1159 m, 1119 m, 1089 m, 1048
m, 995 m, 868 s, 779 s, 731 m, 652 m, 614 m; MS, m / z (rel intensity) 217 (M ⁺ , 0.3), 202 (M ⁺ -C
H ₃ , 12), 189 (16), 188 (M ⁺ -CH ₂ CH ₃ , 100), 116 (16),
89 (20), 78 (10). Elemental analysis: C ₁₂ H ₁₁ NOS Calculated: C, 66.33; H, 5.10; N, 6.45 Found: C, 66.14; H, 5.24; N, 6.51

Example 2 A reaction was carried out in the same manner as in Example 1 except that the reaction time was changed as shown in Table 1. Table 1 shows the results together with the results of Example 1.

[0012]

[Table 1]

Example 3 The following formula was used in the same manner as in Example 1 except that the reaction time was 40 hours and the amount of the catalyst was 10 mol%.

Embedded image To react 2- (o-methylphenyl) pyrimidine with carbon monoxide and ethylene to give 1- [3-methyl-2- (2-pyrimidinyl) phenyl] -1-propanone having the following physical properties. Obtained in 75% yield. Red oil Boiling point 160 ° C (1mmHg); R _f = 0.34 (hexane / ethyl acetate = 1/2); ¹ H NMR (CDCl ₃ ) δ 1.06 (t, J = 7.3 Hz, 2H, CH ₃ CH ₂ C
(O)), 2.20 (s, 3H, CH3), 2.79 (q, J = 7.3 Hz, 2H,
CH ₂ C (O)), 7.26 (t, J = 5.0 Hz, 1H, 5-H), 7.37-7.45
(m, 2H, Ar), 7.63 (dd, J = 6.8, 1.9 Hz, 1H, Ar),
8.81 (d, J = 5.0 Hz, 2H, 4-H, 6-H); ¹³ C NMR (CDCl ₃ ) δ 8.20 (CH ₃ CH ₂ C (O)), 19.70 (CH ₃ ),
33.95 (CH ₂ C (O)), 118.80, 125.80, 128.39, 133.68,
137.30, 138.22, 138.56, 156.77, 168.10 (Ar), 203.5
6 (C (O)); IR (neat) 3034 m, 2978 m, 2936 m, 1692 s, 1621 w,
1558 s, 1445 s, 1408s, 1377 m, 1344 m, 1285 m, 123
6 s, 1168 m, 1101 m, 1039 m, 971 m, 951 m, 805 s,
772 s, 748 m, 714 m , 655 w, 629 m; MS, m / z (rel intensity) 226 (M +, 0), 211 (M + -CH 3,
2), 198 (15), 197 (M ⁺ -CH ₂ CH ₃ , 100), 169 (11), 89
(13). Elemental analysis: C ₁₃ H ₁₄ N ₂ O Calculated: C, 74.31; H, 6.24; N, 12.38 Found: C, 74.36; H, 6.27;
N, 12.53

Examples 4 and 5 The reaction was carried out in the same manner as in Example 3 except that the reaction time and the amount of catalyst were changed. Table 2 shows the results together with the results of Example 3.

[0015]

[Table 2]

Example 6 In the reaction of Example 1, the amount of the catalyst was changed to 2.5 mol%.
In the same manner except that

Embedded image Is reacted with 4-phenylpyrimidine, carbon monoxide and ethylene to give 1- [2- (4
-Pyrimidinyl) phenyl] -1-propanone 78%
In a yield of Light red oil Boiling point 135 ° C (1mmHg); R _f = 0.34 (hexane / ethyl acetate = 1/4); ¹ H NMR (CDCl ₃ ) δ 1.18 (t, J = 7.3 Hz, 3H, CH ₃ CH ₂ C
(O)), 2.72 (q, J = 7.3 Hz, 2H, CH ₂ C (O)), 7.48-7.61
(m, 4H, Ar), 7.66-7.69 (m, 1H, Ar), 8.79 (d, J =
5.1 Hz, 1H, 5-H), 9.19 (s, 1H, 2-H); ¹³ C NMR (CDCl ₃ ) δ 8.27 (CH ₃ CH ₂ C (O)), 36.03 (CH ₂ C
(O)), 118.92, 127.28, 129.04, 130.01, 130.08, 135.4
5, 141.74, 151.27, 158.10, 164.42 (Ar), 206.56 (C
O); IR (neat) 3192 w, 3154 w, 3036 w, 2980 m, 2938 m,
2900 m, 1696 s, 1577s, 1539 s, 1488 m, 1469 s, 144
2 s, 1409 m, 1387 s, 1347 s, 1306 s, 1274m, 1214m,
1160 m, 1116 m, 1079 m, 1012 m, 988 m, 947 s, 878
w, 846 m, 793 m, 753 s, 674 w, 640 m, 623 m; MS, m / z (rel intensity) 212 (M ⁺ , 0), 197 (M ⁺ -CH ₃ ,
2), 184 (13), 183 (M ⁺ -CH ₂ CH ₃ , 100), 128 (18), 101
(12). Elemental analysis: C ₁₃ H ₁₂ N ₂ O Calculated: C, 73.57; H, 5.70; N, 13.20 Found: C, 73.38; H, 5.73; N, 13.22

Examples 7 to 9 The reactions of Example 6 were carried out in the same manner except that the reaction time and the amount of catalyst were changed. Table 3 shows the results together with the results of Example 6.

[0018]

[Table 3]

[0019]

According to the present invention, the aromatic compound having a nitrogen-containing heterocyclic ring as a substituent is cleaved by a carbon-hydrogen bond in an aromatic compound having high reactivity and regioselectivity by a simple means. Efficient direct carbonylation becomes possible, as various organic industrial products, pharmaceuticals, agricultural chemicals, fragrances, polymer products, etc.
Alternatively, aromatic ketones useful as intermediates for their production are provided in high yield.

Claims (3)

[Claims] 1. A compound of the general formula (3) or (4) (Wherein, R ¹ represents a 2- or 4-pyrimidinyl group, and R ¹ ′ represents a 2-pyridyl group or 2- or 4-
A pyrimidinyl group, which may have a substituent on the ring of the pyridyl group and the pyrimidinyl group; R ² and R ³ each represent a hydrogen atom, an alkyl group, an alkoxy group, an alkoxycarbonyl group or a halogen atom, or when R ² and R ³ are adjacent to each other, they form an aromatic ring together; You may. However, a hydrogen atom is bonded to at least one of the carbons adjacent to the carbon to which R ¹ or R ¹ ′ is bonded.
X represents an oxygen atom, a sulfur atom, or a nitrogen atom, wherein the nitrogen atom has a hydrogen atom or another substituent) by reacting an aromatic compound represented by the formula (5) Formula 2 (Wherein R represents a hydrogen atom or an alkyl group), characterized by reacting with an olefin represented by the general formula (1) or (2): (Wherein R, R ¹ , R ¹ ′, R ² and R ³ are as defined above)
A method for producing an aromatic ketone represented by the formula: 2. The method according to claim 1, wherein the transition metal catalyst is a ruthenium compound. 3. The method according to claim 2, wherein the ruthenium compound is tolyruthenium dodecacarbonyl.