JPH0560830B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a ring expansion reaction using a nitrogen atom using a sulfenamide derivative as a reaction reagent. The present invention relates to a method for producing a ring-extended product with a nitrogen atom simply and in good yield by reacting a sulfenamide derivative with a sulfenamide derivative under mild conditions (room temperature, neutrality). [Prior Art] Conventionally, sodium azide, unsubstituted diphenylsulfuimine, hydroxylamine-o-sulfonic acid, and the like are known as ring expansion reaction reagents using nitrogen atoms of heterocyclic cationic compounds. However, when using sodium azide and sulfoylimine, heating or light irradiation is often required to generate nitrene after addition to the cation, and this cannot be applied if the product is unstable to heat or light. It had drawbacks. In addition, hydroxylamine-o-sulfonic acid has a similar skeleton to sulfenamide, but in the reaction with acridinium salt, it is necessary to use strongly basic liquid ammonia as a solvent, and this is the only known reaction example. It's nothing more than that. Conventionally known ring expansion reaction reagents have the above-mentioned drawbacks. [Problems to be Solved by the Present Invention] The present invention is capable of reacting a heterocyclic cationic compound with a ring expansion reaction reagent under mild conditions, and producing a ring expansion product with a nitrogen atom in a simple manner and in a good yield. The purpose is to provide a method for manufacturing. [Means for solving the problem] The present invention solves the problem by solving the general formula () (In the formula, X and Y represent a heteroatom, R ¹ represents an electron-donating group, and Z ^- represents an acid group of a strong inorganic acid.
Further, the number of ring members in the cation moiety is 5. ) and the general formula () R ⁴ -SNH ₂ ...() (wherein R ⁴ is an N,N-disubstituted thiocarbamoyl group, a heterocyclic group, an aroyl group, or a substituted imidoyl group). General formula () characterized by reacting a sulfenamide derivative represented by (In the formula, R ¹ , X, Y have the above meanings,
The number of ring members is 6. ) is a method for producing a ring expansion product with a nitrogen atom represented by Furthermore, the present invention also provides the general formula () (In the formula, R ² represents an electron-donating group, R ³ represents a generally reactive substituent, and W represents a sulfur atom or an oxygen atom.) Mesoionic compounds represented by the general formula () R ⁴ -SNH ₂ ...() (In the formula, R ⁴ represents an N,N-disubstituted thiocarbamoyl group, a heterocyclic group, an aroyl group, or a substituted imidoyl group.) General formula () (In the formula, R ² , R ³ and W have the above-mentioned meanings.) This is a method for producing a ring expansion product using nitrogen atoms represented by the following formula. According to the method of the present invention, the reaction proceeds under mild conditions (room temperature, neutrality), and the desired product can be obtained easily and in good yield, so it is widely applicable to heterocyclic cationic compounds. This is considered to be the case. In addition, many of the heterocyclic compounds produced by the method of the present invention are difficult to synthesize by other methods, and their structure, physical properties, and pharmacological effects are of interest, and they are considered to be useful compounds in organic synthetic chemistry. . General formulas () and () used in the present invention
Examples of the electron-donating groups R ¹ and R ² in the heterocyclic cationic compound represented by include dimethylamino group, diisopropylamino group, piperidino group, morpholino group, methylphenylamino group, methylthio group, ethylthio group, phenyl group, Examples include p-chlorophenyl group, p-anisyl group, etc., and examples of hetero atoms X and Y include oxygen atoms, sulfur atoms, etc., and examples of acid group Z ^- include perchlorate anion,
Examples include borate tetrafluoride anion. Specific examples of this heterocyclic cationic compound include (1) 5-
methylphenylamino-3-phenyl-1,4,
2-dithiazolium perchlorate, (2) 5-methylthio-3-phenyl-1,4,2-dithiazolium tetrafluoroborate, (3) 3-(p-anisyl)-5
-piperidino-1,4,2-dithiazolium perchlorate, (4)5-diethylamino-3-(1-naphthyl)-1,4,2-dithiazolium perchlorate,
(5) 1,4-phenylene-3,3'-bis(5-diethylamino-1,4,2-dithiazolium) bisperchlorate, (6) 2-diethylamino-4-phenyl-1,3-dithiolium Tetrafluoroborate,
(7)2,4,5-triphenyl-1,3-dithiolium perchlorate, (8)2-morpholino-5-phenyl-1,3-oxathiolium perchlorate, (9)2
-diethylamino-5-phenyl-1,3-dithiolium-4-thiolate, (10)2-morpholino-
Examples include 5-phenyl-1,3-dithiolium-4-oleate. The structural formulas of each of the compounds (1) to (10) above are as follows. Examples of the sulfenamide derivatives represented by the general formula () include dimethylthiocarbamoylsulfenamide, diethylthiocarbamoylsulfenamide, methylphenylthiocarbamoylsulfenamide, benzoylsulfenamide, morpholinothiocarbonylsulfenamide, benzo- Examples include 1,3-thiadylsulfenamide, phenylbenzimidoylsulfenamide, phenyl acetimidoylsulfenamide, and the like. In particular, disubstituted thiocarbamoylsulfenamide derivatives give good yields in the reaction of the present invention, and can be easily and inexpensively obtained from the reaction of disubstituted dithiocarbamates and hydroxylamine-o-sulfonic acid. has advantages. The solvent used in the method of the present invention may be any solvent as long as it does not participate in the reaction, and examples thereof include acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dioxane, and benzene. Further, the reaction time may take several tens of minutes to several days depending on the combination of the heterocyclic cation compound and the sulfenamide derivative, but the reaction can be accelerated by heating. After completion of the reaction, separation and purification can be performed by solvent extraction, recrystallization, column chromatography, and thin layer chromatography. Next, the reaction mechanism of the reaction in the method of the present invention will be explained. When using raw materials represented by the general formula (),
Taking the reaction of 5-morpholino-3-phenyl-1,4,2-dithiazolium perchlorate and dimethylthiocarbamoylsulfenamide as an example, it can be expressed as the following reaction formula. In addition, when using a raw material represented by the general formula (), 2-diethylamino-5-phenyl-1,
Taking the reaction between 3-dithiolium-4-thiolate and dimethylthiocarbamoylsulfenamide as an example, it can be expressed as the following reaction formula. As is clear from the above reaction mechanism, when the heterocyclic cationic compound represented by the general formula () is used as a raw material, and when the mesoionic compound represented by the general formula () is used, the former raw material is The difference is that the latter case is an intermolecular salt and the latter case is an intramolecular salt, but the ring-forming portion proceeds by the same reaction mechanism. The sulfenamide derivative is required in an equivalent amount twice that of the heterocyclic cationic compound or mesoionic compound. The structure of the new substance was confirmed using infrared absorption spectroscopy, nuclear magnetic resonance spectroscopy, mass spectrometry, elemental analysis and X-ray crystal analysis as necessary. Note that the reaction product represented by the general formula () may theoretically have isomers depending on how the nitrogen atom is inserted, and in fact, there are cases where the existence of two types of isomers has been confirmed. be. (For example, Example 4) [Example] Next, the present invention will be described in more detail based on an example. Example 1 5-morpholino-3-phenyl-1,4,2-
1.46g (4m mol) of dithiazolium perchlorate and 1.09g of dimethylthiocarbamoylsulfenamide
(8m mol) was dissolved in 15ml of acetonitrile, and 2
Stir at room temperature for several days. The precipitated crystals (NH ₄ ⁺ ClO ₄ ^-
After filtering off (Me ₂ NCSS) _-2 , the solvent is distilled off from the filtrate under reduced pressure. The residue was treated with silica gel column chromatography and recrystallized from benzene-hexane to give pale yellow needle crystals 3 with a melting point of 101.5-102.0°C.
-morpholino-6-phenyl-1,4,2,5-
0.67 g (yield 60%) of dithiadiazine was obtained. Spectral data of this product is shown below. ¹ H-NMR (CDCl ₃ , TMS) δ: 3.5-3.9 (H,
m), 7.4-7.6 (3H, m), 7.9-8.1 (2H, m) IR (KBr, cm ^-1 ) 1538, 1208, 1113, 941,
777, 740, 682 MS (m/z) 279 (M ⁺ , 26%), 246 (M ⁺ , SH,
63%) 130

[Formula] 37%), 121 (PhCS ⁺ , 100%) 103 (PhCN ⁺ , 35%), 77 (Ph ⁺ , 35%) Production of this compound was confirmed by X-ray crystal analysis. Example 2 312 mg (0.5 m mol) of 1,4-phenylene-3,3'-bis-(5-diethylamino-1,4,2-dithiazolium) bisperchlorate and 272 mg (2 m mol) of dimethylthiocarbamoylsulfenamide mol)
Dissolve in 4 ml of dichloromethane and stir at room temperature for 2 days. The following procedure was repeated in the same manner as in Example 1, and when recrystallized from acetonitrile, yellow crystals of 1,4-phenylene-3,3'-bis(6
-diethylamino-1,4,2,5-dithiadiazine) 202 mg (89%) was obtained. ^1H -NMR ( _CDCl3 , TMS) δ: 1.21 (12H,
t, J = 6.8Hz), 3.52 (8H, q, J = 6.8Hz),
8.02 (4H, S) IR (KBr, cm ^-1 ) 1533, 1255, 936, 847, 762 MS (m/z) 452 (M ⁺ , 17%), 419 (M ⁺ -SH,
25%) 130 (Et ₂ NCNS ⁺ , 27%) 128 (NCC ₆ H ₄ CN ⁺ , 40%) 98 (Et ₂ NCN ⁺ , 62%) Example 3 3-dimethylamino-4,5-diphenyl-
Example 1 using 1,3-dithiolium perchlorate and dimethylthiocarbamoylsulfenamide
Recrystallization from acetonitrile ether gives yellow crystals of 3-dimethylamino-5,6-diphenyl-1,4,2 with a melting point of 164.0-164.5°C.
-Dithiazine (81%) was obtained. ^1H -NMR ( _CDCl3 , TMS) δ: 3.17 (6H,
S), 7.1−7.5 (10H, m) IR (KBr, cm ^-1 ) 1533, 1358, 1243, 1117,
907, 748, 693 MS (m/z) 312 (M ⁺ , 22%), 242
(

[Formula] 32%) 178 (PhC≡CPh ⁺ , 69%), 121 (PhCN ⁺ , 100
%) Elemental analysis value (%) Measured value C 65.36 H 5.16 N 8.91 S 20.39 Calculated value C 65.35 H 5.16 N 8.97 S 20.52 Example 4 2-diethylamino-5-phenyl-1,3-
Dithiolium-4-thiolate 140mg (0.5m
mol) and dimethylthiocarbamoylsulfenamide (1 mmol) were dissolved in 3 ml of acetonitrile and heated to reflux for 3.5 hours, or
- Add toluenesulfonic acid and stir at room temperature. Hereinafter, when treated in the same manner as in Example 1, a yellow oily substance 3-diethylamino-5-mercapto-6-
Phenyl-1,4,2-dithiazine and 3-diethylamino-6-mercapto-5-phenyl-1,
86 mg (58%) of isomer mixture of 4,2-dithiazine
I got it. Spectral data for the mixture is shown below. ^1H -NMR ( _CDCl3 , TMS) δ: 1.16, 1.18
(6H, t, J = 6.3Hz), 3.30, 3.32 (4H, q, J
= 6.3Hz), 7.1-7.6 (5H, m) MS (m/z) 296 (M ⁺ , 9%), 295 (M ⁺ -H, 18
%) 197(

[Formula] 71%), 133 (PhC≡CS ⁺ , 47%) 121 (PhCS ⁺ , 53%), 77 (Ph ⁺ , 16%) Example 5 Reactions using various sulfenamide derivatives were carried out as in Example 1. When conducted under similar conditions, the results shown in Table 1 were obtained.

【table】

[Table] Note


a) Possibly isomers.


[Effects of the Invention] According to the present invention, a ring expansion product with a nitrogen atom can be produced easily and in a good yield by the reaction of a heterocyclic cationic compound and a sulfenamide derivative. This production method has the effect of allowing the reaction to proceed under suitable conditions (room temperature, neutrality), and has a wide range of applications. Furthermore, the six-membered heterocyclic compound produced in this reaction has antiaromatic properties and is interesting in terms of physical properties and structure. In particular, elemental sulfur, nitrile sulfide, etc. are generated by light irradiation or heating, which can be used as a reactive sulfur source or a precursor of nitrile sulfide, which is a useful reaction intermediate in organic synthesis chemistry. Conceivable. From the standpoint of molecular design, this reaction also allows one nitrogen atom to be
This method provides a new method for introducing into a single ring, and many of the heterocyclic cationic compounds used in this reaction are used as reaction intermediates in the agricultural and pharmaceutical fields, creating compounds with new pharmacological effects. It is considered that there is a possibility of

Claims (1)

[Claims] 1 General formula () (In the formula, X and Y represent a heteroatom, R ¹ represents an electron-donating group, and Z ^- represents an acid group of a strong inorganic acid.
Further, the number of ring members in the cation moiety is 5. ) and the general formula () R ⁴ -SNH ₂ ...() (wherein R ⁴ is an N,N-disubstituted thiocarbamoyl group, a heterocyclic group, an aroyl group, or a substituted imidoyl group). General formula () characterized by reacting a sulfenamide derivative represented by (In the formula, R ¹ , X, Y have the above meanings,
The number of ring members is 6. ) A method for producing a ring expansion product with a nitrogen atom represented by 2. The manufacturing method according to claim 1, wherein the sulfenamide derivative is a disubstituted thiocarbamoyl phenamide derivative. 3 General formula () (In the formula, R ² represents an electron-donating group, R ³ represents a generally reactive substituent, and W represents a sulfur atom or an oxygen atom.) Mesoionic compounds represented by the general formula () R ⁴ -SNH ₂ ...() (In the formula, R ⁴ represents an N,N-disubstituted thiocarbamoyl group, a heterocyclic group, an aroyl group, or a substituted imidoyl group.) General formula () (In the formula, R ² , R ³ , and W have the above-mentioned meanings.) A method for producing a ring expansion product with a nitrogen atom represented by the following formula. 4. The manufacturing method according to claim 3, wherein the sulfenamide derivative is a disubstituted thiocarbamoyl phenamide derivative.