JP3038380B1 - Method for producing ketene imine compound - Google Patents

Abstract

An industrially advantageous method for producing a ketenimine compound, which is a compound useful as a synthetic intermediate or a condensing agent, safely and in good yield without using harmful reagents or special raw materials. I will provide a. Means for Solving the Problems General formula (1) (In the formula, Ar ^{1 to} Ar ³ represent an aryl group, and Ar ¹ and Ar
² ) may be bonded to the ketenimine compound
General formula (2) A thioamide compound of the formula (where Ar ^{1 to} Ar ³ are the same as described above) is prepared by converting a thioamide compound represented by the following general formula (3): (Wherein R ¹ and R ² represent a lower alkyl group, X represents a halogen atom, Y represents a counter anion, and n represents 0 or 1)
Alternatively, the general formula (4) (Wherein R ³ represents a lower alkyl group, R ^{4 to} R ⁷ represent hydrogen or a substituent, X represents a halogen atom, and Y represents a counter anion).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a ketene imine compound. More specifically, the present invention relates to a method for producing a ketenimine compound from a thioamide compound under mild conditions using a haloiminium salt or a pyridinium salt.

[0002]

2. Description of the Related Art Ketenimine compounds easily react with nucleophiles such as amines and alcohols to give amidines (J. Org. Chem., 30 , 3718 (1965)) and imidoyl esters (J. Am. Chem. Soc., 75 , 657 (1953)) is an important intermediate in organic synthesis because it can be easily converted to compounds. In addition, ketene imine compounds are constructed with heterocycles via cycloaddition reactions (eg, Angew. Chem., 83 ,
171 (1971))
It is also an important synthetic intermediate for pharmaceuticals and pesticides. further,
Ketenimine compounds are used as condensing agents for producing peptides (J. Am. Chem. Soc., 80 , 4069 (195
It is an industrially important compound such as 8)). On the other hand, ketene imine compounds conventionally used generally include a method of synthesizing amides by dehydration with phosphorus pentachloride (J. Org. Chem., 29 , 34 (1964)), and a method of producing imino chlorides. Synthesis by dehydrochlorination (J. Am. Chem.
Soc., 76 , 4398 (1958)), a method of synthesizing from α-haloamides (J. Am. Chem. Soc., 75 , 657 (1953)), and a method of condensing ketene and phosphorus imine (J. Org). . Che
m., 39 , 3780 (1974)), a method of synthesizing thioamides with mercury salts using hydrogen sulfide (Bull. Chem. Soc.
Jpn., 43 , 1874 (1970)) and the like.

[0003]

However, there have been various problems in the conventionally used method for producing ketene imine compounds. That is, the method of synthesizing amides by dehydration with phosphorus pentachloride requires a high temperature for the reaction, and after the reaction, it is necessary to remove by-produced phosphorus compounds. In a method for synthesizing imino chlorides by dehydrochlorination, phosphorus oxychloride generated in a process for producing imino chloride must be removed. Since the method of synthesis from haloamides uses bromine, which is corrosive to metals such as iron, care must be taken when handling. In the method using phosphorus imines, an unstable ketene must be synthesized, and after the reaction is completed, a large amount of triphenylphosphine oxide is by-produced, which must be separated after the reaction. The method using mercury salts has a problem of environmental pollution by heavy metals. Accordingly, an object of the present invention is to provide a method for industrially producing a ketene imine compound which does not have the above-mentioned drawbacks and does not require complicated operations or special conditions. It is.

[0004]

[Means for Solving the Problem] Under such circumstances, the present inventors have conducted intensive studies on a method for producing a ketenimine compound. As a result, if a thioamide compound is reacted with a haloiminium salt or a pyridinium salt as a dehydrosulfide agent, The present inventors have found that a ketenimine compound can be obtained under a mild condition and in a high yield, and have completed the present invention based on this finding.

That is, the present invention provides the following general formula (1)

Embedded image (In the formula, Ar ^{1 to} Ar ³ represent an aryl group, and Ar ¹ and Ar
² ) may be bonded to a ketenimine compound represented by the following general formula (2):

Embedded image (Wherein Ar ^{1 to} Ar ³ are the same as described above) to a thioamide compound represented by the following general formula (3)

Embedded image (Wherein R ¹ and R ² represent a lower alkyl group, X represents a halogen atom, Y represents a counter anion, and n represents 0 or 1)
Or a haloiminium salt represented by the following general formula (4)

Embedded image (Wherein R ³ is a lower alkyl group, R ^{4 to} R ⁷ are hydrogen or a substituent, X is a halogen atom, and Y is a counter anion). It is intended to provide a method for producing a ketenimine compound.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The above-mentioned general formula (1) showing a ketenimine compound which is a production target compound of the present invention and the above-mentioned general formula (2) showing a thioamide compound which is a starting material thereof
In the above, Ar ^{1 to} Ar ³ represent aryl groups, and examples of these aryl groups include phenyl, tolyl, xylyl, naphthyl, biphenyl and the like. These aryl groups may have a substituent such as a halogen atom, an alkoxy group, a nitro group, a dialkylamino group, an acyl group or an alkoxycarbonyl group.

The above Ar ¹ and Ar ² may be bonded to each other via one atom or atomic group.
The conjugate of ¹ and Ar ² has the following general formula (5)

Embedded image (Wherein R ⁸ and R ⁹ represent hydrogen or a substituent, p and q each represent an integer of 1-4, X represents a divalent group, and m represents 0
Or 1) is included.

In the above formula, R ⁸ and R ⁹ represent hydrogen or a substituent. In this case, the substituent may be any as long as it is inert to the reaction of the present invention. Such substituents include linear or cyclic alkyl, alkoxyl,
Examples include a dialkylamino group, an acyl group, an alkoxycarbonyl group, a halogen group, a nitro group and the like. The alkyl group contained in these substituents usually has 1 to 6 carbon atoms. P and q each represent an integer of 1 to 4, usually 1 or 2.

In the above-(X) m-, m represents an integer of 0 or 1. When m is 0,-(X) m- represents a simple joint (-), and when n is 1, it represents a divalent group -X-.
The divalent group X includes -O-, -S-, -N (R)-(R: alkyl group), lower alkylene group and the like.

In the present invention, the general formula (3) used as a hydrogen sulfide agent

Embedded image (Wherein R ¹ and R ² represent a lower alkyl group, X represents a halogen atom, Y represents a counter anion, and n represents 0 or 1)
In the haloiminium salt represented by R ¹ and R ²
Examples of the lower alkyl group represented by are a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and the like. Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and among them, a chlorine atom is particularly desirable. The counter anion represented by Y ⁻ is Cl
⁻ , Br ⁻ , I ⁻ , BF ₄ ⁻ , FSO ₃ ^{− and the} like. Among them, Cl ^{− and} BF ₄ ⁻ are particularly desirable. Preferred specific examples of the haloiminium salt (3) include 2-chloro-1,3-dimethylimidazolinium chloride, 2-chloro-1,3-dimethyl-3,4,5,6-tetrahydropyrimidinium chloride. And the like.

In the present invention, general formula (4) used as a dehydrosulfide agent:

Embedded image (A wherein R ³ is a lower alkyl group, a R ⁴ to R ⁷ is hydrogen or a substituent, X is a halogen atom, Y represents a counter anion) In the pyridinium salt represented by lower alkyl represented by R ³ Examples of the group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and an isobutyl group. R ^{4 to} R ^{7 each} represent hydrogen or a substituent, and examples of the substituent include a linear or cyclic alkyl group, alkoxyl group, acyl group, alkoxycarbonyl group and the like. The alkyl group contained in these substituents usually has 1 to 6 carbon atoms. Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and among them, a chlorine atom is particularly desirable. The counter anion represented by Y ⁻ is C
Examples thereof include l ⁻ , Br ⁻ , I ⁻ , BF ₄ ⁻ , and FSO ₃ ⁻ , and among them, I ^{− and} BF ₄ ⁻ are particularly desirable. Preferred specific examples of the haloiminium salt (4) include 2-chloro-1-methylpyridinium iodide, 1-ethyl-2-chloropyridinium tetrafluoride and the like.

In order to carry out the dehydrosulfide reaction in the present invention, the presence of a base is required. In this case, the base may be a triethylamine, tripropylamine, tributylamine, dimethylaniline, pyridine, picoline or the like. Tertiary amines are exemplified.

The above-mentioned desulfurization reaction is preferably carried out in the presence of a reaction solvent. In this case, the reaction solvent may be a halogenated hydrocarbon such as dichloromethane or dichloroethane, a hydrocarbon, an ether or an aromatic hydrocarbon. And other solvents that do not participate in the reaction. These solvents are used alone or in the form of a mixed solvent.

[0014] The temperature in the above-mentioned method of hydrogen sulfide is-
The reaction can be carried out at a temperature of about 30 to 100 degrees. However, when the temperature is too low, the reaction time is delayed. When the temperature is too high, the decomposition reaction and side reactions increase. preferable. The reaction time depends on the reaction temperature,
Although it cannot be determined unconditionally, usually 30 minutes to 3 hours is sufficient.

In this manner, ketene imine compounds represented by, for example, chemical formulas (a) to (d) can be produced by the hydrogen sulfide reaction of the present invention.

Embedded image

[0016]

The present invention will be described in more detail with reference to the following examples. The examples of the present invention are typical examples for easy understanding of the reaction. Is not limited to this. Further, the produced compounds (a) to (d) are the same as the compounds (a) to (d) shown above.
The physical property values are also described.

Example 1 1 mmol of diphenylthioacetic acid anilide was dissolved in 10 ml of methylene chloride, and 1.5 ml of 2-chloro-1,3-dimethylimidazolinium chloride was dissolved in 5 ml of methylene chloride.
The solution in which the mol was dissolved was slowly added dropwise. After completion of the dropwise addition, 4 mmol of triethylamine was added, and the mixture was stirred under reflux of methylene chloride for 2 hours. After cooling, the solvent is distilled off under reduced pressure.
The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane / methylene chloride = 1/1). Thus, the ketenimine of the compound (a) was obtained at a yield of 90%. The product obtained can be recrystallized from pentane to further increase the purity. Melting point 52-52.5 ° C (literature value: 55 ° C); ¹ H-NMR (CDCl ₃ )
7.20-7.40 (m, 15H); IR (KBr) 1995, 1589, 1485, 76
0,696 cm ^-1 . Elemental analysis for C ₂₀ H ₁₅ N (%) Measured: C, 88.92; H, 5.45; N, 5.11 Calculated: C, 89.19; H, 5.61; N, 5.20

Example 2 The same procedure as in Example 1 was carried out except that p-toluid diphenylthioacetate was used in place of anilide diphenylthioacetate to obtain the ketenimine of the above compound (b) in a yield of 67%. Melting point: 44-44.5 ° C (Literature: 81-83 ° C); ¹ H-NMR (CDCl
₃ ) 2.38 (s, 3H), 7.22-7.37 (m, 14H); IR (KBr) 199
5, 1597, 1493, 1188, 820, 760, 694 cm ^-1 . Elemental analysis (%) as C ₂₁ H ₁₇ N Measured: C, 89.06; H, 6.02; N, 4.94 Calculated: C, 89.01; H, 6.05; N, 4.94

Example 3 In Example 1, diphenylthioacetic acid p-methoxyanilide was used in place of diphenylthioacetic acid anilide.
The ketenimine of the compound (c) was obtained in a yield of 30%. Melting point 81-83 ° C (literature value: 83-85 ° C); ¹ H-NMR (CDCl ₃ )
3.81 (s, 3H), 6.90 (d, 2H, J = 9 Hz), 7.21-7.37 (m,
12H); IR (KBr) 1985, 1501, 1250, 1032, 839, 764, 6
94 cm- ¹ .

Example 4 The procedure of Example 1 was repeated, except that p-toluid 9-xanthointhiothioate was used in place of anilide diphenylthioate.
The compound (d) ketenimine was obtained with a yield of 74%.
The product obtained can be recrystallized from hexane to further increase the purity. Melting point 120-121 ° C (decomposition); ¹ H-NMR (CDCl ₃ ) 2.38 (s,
3H), 6.94-7.00 (m, 4H), 7.06-7.19 (m, 4H), 7.20
(d, 2H, J = 8 Hz), 7.29 (d, 2H, J = 8 Hz); IR (KBr) 19
93, 1483, 1447, 1302, 1262, 822, 752 cm- ¹ . Elemental analysis for C ₂₁ H ₁₅ NO (%) Measurement: C. 85.00; H, 4.99; N, 4.63 Calculated: C, 84.82; H, 5.08; N, 4.71

Example 5 In Example 1, 2-chloro-1-methylpyridinium iodide was used in place of 2-chloro-1,3-dimethylimidazolinium chloride to obtain the ketenimine of the compound (a). 43% obtained.

Example 6 In Example 2, 2-chloro-1-methylpyridinium iodide was used in place of 2-chloro-1,3-dimethylimidazolinium chloride to obtain the ketenimine of the compound (b). Obtained at a rate of 41%.

[0023]

According to the production method of the present invention, ketenimines can be industrially and efficiently produced from thioamides under mild conditions. In addition, since no heavy metal is used, there is an advantage that there is no problem of environmental pollution.

Continuation of the front page (56) Reference Bull. Chem. Soc. Japan, Vol. 44, no. 5 (1971) p. 1362-1364 (58) Fields surveyed (Int. Cl. ⁷ , DB name) C07C 249/02 C07C 251/16 CAPLUS (STN)

Claims (2)

(57) [Claims] (1) The following general formula (1): (In the formula, Ar ^{1 to} Ar ³ represent an aryl group, and Ar ¹ and Ar
² ) may be bonded to a ketenimine compound represented by the following general formula (2): (Wherein Ar ^{1 to} Ar ³ are the same as described above) by converting the thioamide compound represented by the following general formula (3) (Wherein R ¹ and R ² represent a lower alkyl group, X represents a halogen atom, Y represents a counter anion, and n represents 0 or 1)
A method for producing a ketenimine compound, comprising subjecting a haloiminium salt represented by the formula to a hydrogen sulfide reaction. 2. A compound represented by the following general formula (1): (In the formula, Ar ^{1 to} Ar ³ represent an aryl group, and Ar ¹ and Ar
² ) may be bonded to a ketenimine compound represented by the following general formula (2): (Wherein Ar ^{1 to} Ar ³ are the same as described above) by converting the thioamide compound represented by the following general formula (4) (Wherein R ³ is a lower alkyl group, R ^{4 to} R ⁷ are hydrogen or a substituent, X is a halogen atom, and Y is a counter anion). A method for producing a ketene imine compound, comprising: