JP2018162218A - Novel cyclic urea derivatives-hydrobromide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel bromination agent easy to handle.SOLUTION: There are provided a compound represented by a general formula (1) where n is 1 or 2, Rand Rmay be same or different and represent an alkyl group having 1 to 4 carbon atoms, preferably a methyl group, and a bromination agent using the same.EFFECT: A cyclic urea derivative-hydrotribromide, which can be used as the bromination agent, can be provided, and the compound can be applied to various bromination reactions because it is stable solid and is easy to handle.SELECTED DRAWING: None

Description

  The present invention relates to a novel cyclic urea derivative-trihydrobromide and a novel brominating agent.

  The bromination reaction is one of important synthesis reactions for producing intermediates such as pharmaceuticals and electronic materials.

  The most common brominating agent used in the bromination reaction is molecular bromine. Although molecular bromine is an excellent brominating agent, it is a brominating agent that is very difficult to handle because it is always liquid and emits toxic bromine vapor. Therefore, in recent years, solid brominating agents have attracted attention as an alternative to molecular bromine which is difficult to handle.

  As a solid brominating agent, a bromine-dioxane complex has been reported (for example, see Non-Patent Document 1), and since it does not generate bromine vapor, it is a substance that can be handled safely. However, 1,4-dioxane forming a complex with bromine falls under the category of designated first class chemical substances in the PRTR Law, and has a very high impact on the environment. In addition, since it is a substance that is carcinogenic to the human body, it needs to be handled with sufficient care (see Non-Patent Document 2, for example).

  In addition, N-methylpyrrolidin-2-one hydrotribromide (hereinafter referred to as MPHT) has been reported as another brominating agent that solves the problems of generation and toxicity of bromine vapor (for example, non-patent literature). 3). MPHT is easy to handle as solid bromine, and since the toxicity of N-methylpyrrolidone forming a complex is low, it can be said to be a brominating agent that solves the problems of molecular bromine and bromine-dioxane complexes. However, MPHT has low solubility in dichloromethane, which is generally used as a bromination reaction solvent, and cannot be expected to be as versatile as molecular bromine. In addition, N-methylpyrrolidone complexed with bromine has a lactam structure that may cause bromination reaction, so it is difficult to use under severe conditions such as high temperature reaction. (For example, refer nonpatent literature 4).

Beil. J. Org. Chem. 2012, 8, 323-329 CERI Hazard Assessment Report 1,4-Dioxane Russ. Chem. Rev. 2010, 79 (8), 683-692 Synth. Commun. 2007, 37 (23), 4149-4156

  An object of the present invention is to provide a novel brominating agent that solves the problems of the conventional brominating agents described above and is easy to handle in the brominating agent used in the bromination reaction.

  As a result of intensive studies to solve the above problems, the present inventors have found that a cyclic urea derivative and hydrobromic acid form a salt, and that the compound acts as a brominating agent. The invention has been completed. That is, the present invention is as follows.

（式中、ｎは、１または２であり、Ｒ^１およびＲ^２は、各々同一であっても異なっていてもよく、炭素数１〜４のアルキル基を示す）で表される化合物。 Following formula (1):

(Wherein n is 1 or 2, and R ¹ and R ² may be the same or different and each represents an alkyl group having 1 to 4 carbon atoms).

  ADVANTAGE OF THE INVENTION According to this invention, the cyclic urea derivative- trihydrobromide which can be utilized as a novel brominating agent can be provided. Since the compound is a stable solid and easy to handle, application to various bromination reactions is expected.

  Hereinafter, embodiments of the present invention will be described in detail.

（式中、ｎは１、または２であり、Ｒ^１およびＲ^２は、各々同一であっても異なっていてもよく、炭素数１〜４のアルキル基を示す）で表される。 The cyclic urea derivative-hydrobromide of the present invention has the general formula (1):

(In the formula, n is 1 or 2, and R ¹ and R ² may be the same or different and each represents an alkyl group having 1 to 4 carbon atoms).

  Here, the term “C1-C4 alkyl group” means a monovalent group of a linear or branched aliphatic saturated hydrocarbon having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, Examples include propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group and the like.

（式中、Ｒ^１およびＲ^２は前記と同義である）
ｎが２の場合、式中の環構造として６員環構造を有することを意味し、具体的には、下記一般式（１ｂ）で表わされる。

（式中、Ｒ^１およびＲ^２は前記と同義である） In the general formula (1), when n is 1, it means that the ring structure in the formula has a 5-membered ring structure, specifically represented by the following general formula (1a),

(Wherein R ¹ and R ² have the same meanings as described above)
When n is 2, it means that the ring structure in the formula has a 6-membered ring structure, and specifically, it is represented by the following general formula (1b).

(Wherein R ¹ and R ² have the same meanings as described above)

（式中、ｎ、Ｒ^１およびＲ^２は前記と同義である）
で表わされる環状尿素誘導体と臭化水素および臭素を反応させることで製造することができる。 The production method of the cyclic urea derivative-hydrohydrobromide of the present invention is not particularly limited, and any production method may be used. Preferably, the following general formula (2):

(In the formula, n, R ¹ and R ² are as defined above)
It can be produced by reacting a cyclic urea derivative represented by formula (II) with hydrogen bromide and bromine.

  The cyclic urea derivative represented by the general formula (2) is commercially available and can be easily obtained from suppliers such as Tokyo Chemical Industry Co., Ltd., Wako Pure Chemical Industries, Ltd., Sigma-Aldrich Japan Co., Ltd. Is possible. Examples of the compound in which n is 1 include 1,3-dimethyl-2-imidazolidinone. Examples of the compound in which n is 2 include 1,3-dimethyl-3, 4, 5, 6, -Tetrahydro-2 (1H) -pyrimidinone and the like.

  The hydrogen bromide used for the production of the cyclic urea derivative-hydrohydrobromide is not particularly limited, and any form such as hydrogen bromide gas, hydrogen bromide aqueous solution or hydrogen bromide acetic acid solution may be used. The amount of hydrogen bromide used is 0.01 to 10 mol, preferably 0.05 to 5 mol, more preferably 0.1 to 2 mol per mol of the cyclic urea derivative represented by the general formula (2). Is a mole.

  The amount of bromine used in the production of the cyclic urea derivative-hydrohydrobromide is 0.01 to 10 moles, preferably 0.1 moles per mole of the cyclic urea derivative represented by the general formula (2). 05 to 5 mol, more preferably 0.1 to 2 mol.

  The production of the cyclic urea derivative-hydrobromide may be carried out without solvent or using a solvent. The solvent to be used is not particularly limited as long as it is inert to the reaction, and is appropriately selected depending on the desired reaction temperature and the like. Specifically, for example, lower alcohols (for example, having 1 to 3 carbon atoms) such as methanol, ethanol and isopropyl alcohol, halogenated hydrocarbon solvents such as dichloromethane and chlorobenzene, and nitriles such as acetonitrile and propionitrile. System solvents and the like. These may be used alone or in combination of two or more.

  The reaction temperature in the production of the cyclic urea derivative-hydrohydrobromide is not particularly limited, but is preferably in the range of −50 to 50 ° C. The reaction time can be appropriately set depending on conditions such as the presence or absence of a solvent, its type, reaction temperature, and the like. Usually, it is preferably 1 minute to 24 hours.

  The compound represented by the general formula (1) can be isolated from the resulting reaction solution by performing general operations such as crystallization, filtration, liquid separation, extraction, and concentration. The isolated compound can be further purified by recrystallization, column chromatography or the like, if necessary.

  The cyclic urea derivative-hydrobromide of the present invention can be used as a substitute for molecular bromine in general bromination reactions such as bromination reactions of alkenes, bromination reactions at the α-position of carbonyl derivatives or aromatic compounds. It can be used as a brominating agent in the bromination reaction of Hofmann or in the Hofmann rearrangement through the bromination reaction. The reaction temperature, time, amount and the like when used in these reactions are not particularly limited, and can be appropriately set according to the raw materials used.

  Examples are shown below to clarify aspects of the present invention, but the present invention is not limited only to the contents of the examples shown here. In addition, the measuring method of melting | fusing point of the compound obtained by the Example and the comparative example, gas chromatography, NMR, elemental analysis, and a bromine content is as follows.

<Melting point>
Using a trace melting point measuring apparatus (Yanaco MP-J3, Inc.), the temperature was raised at 2 ° C. per minute and measured visually.

<Gas chromatography>
Device: GC-2010Plus (manufactured by Shimadzu Corporation)
Column: NB-5 (GL Science Co., Ltd.)
Column temperature: 60 ° C. → [Raise temperature at 20 ° C./min]→250° C. (10 min hold)
Injection temperature: 200 ° C
Carrier gas: Nitrogen detector: Hydrogen flame ion detector (FID)

<NMR spectrum>
Device: JEOL-ECS-400 spectrometer (manufactured by JEOL Ltd.)
A solution in which the compound and deuterated chloroform (containing 0.05% TMS manufactured by Wako Pure Chemical Industries, Ltd.) were mixed was prepared, and ¹³ C and ¹ H-NMR measurements were performed.

<Elemental analysis>
○ Carbon, hydrogen, and nitrogen equipment: MT-7 (manufactured by Yanaco Analytical Co., Ltd.)
About 1.7 mg of a sample is precisely weighed, burned and decomposed at 950 ° C., and the constituent ratio of each element is obtained by quantifying the obtained carbon dioxide, water, and nitrogen oxide (measured after conversion to nitrogen in a reduction furnace) It was.
○ Bromine apparatus: automatic combustion apparatus: AFQ-100 (manufactured by Mitsubishi Chemical Analytech Co., Ltd.), ion chromatograph: ICS-1500 ((manufactured by Daionex Corporation) column: AS-12A)
About 1.3 mg of a sample was precisely weighed, and after combustion decomposition, bromide ions produced by ion chromatography were quantified to obtain a bromine constituent ratio.

<Bromine content>
The sample was placed in an Erlenmeyer flask, and an aqueous potassium iodide solution was added to completely reduce bromine and precipitate iodine. A starch indicator was added as an indicator, titrated with 0.105M sodium thiosulfate aqueous solution, and bromine content was calculated from titration.

[Example 1]
Synthesis of di (1,3-dimethyl-2-imidazolidinone) hydrotribromide (DITB) In a 200 mL one-necked eggplant flask, methanol (25 mL; manufactured by Tokyo Chemical Industry Co., Ltd.) and 4.3 g of 30% hydrobromic acetic acid solution (16.1 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.) was added and stirred under ice cooling. Thereafter, bromine 1.6 g (10 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.) and 1,3-dimethyl-2-imidazolidinone 3.4 g (29.7 mmol: manufactured by Tokyo Chemical Industry Co., Ltd.) were added slowly in this order. The mixture was stirred for 1 hour under ice cooling. After stirring, diethyl ether (100 ml; manufactured by Tokyo Chemical Industry Co., Ltd.) was added and stirred, and suction filtered through a glass filter, and the resulting crystals were washed with diethyl ether to obtain 2.9 g of DITB (yield). Rate 65%).
Appearance: Orange Melting point: 116.8-118.3 ° C
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.98 (s, 12H), 3.65 (s, 8H), 14.8 (bs, 1H)
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 32.15, 46.30, 161.76
Elemental Analysis: C: 25.58%, H: 4.50%, N: 11.99%, Br: 51.13% (theoretical values: C: 25.61%, H: 4.51%, N: (11.95%, Br: 51.11%)
Bromine content: 34% by weight

[Example 2]
Synthesis of di (1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone) hydrotribromide (DPTB) Methanol (25 mL; manufactured by Tokyo Chemical Industry Co., Ltd.) in a 200 mL one-necked eggplant flask And 4.3 g (16.1 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.) 30% hydrobromic acetic acid solution were added and stirred under ice cooling. Then, 1.6 g of bromine (10 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone 4.4 g (34.4 mmol: Tokyo Chemical Industry) Slowly added in the order of Kogyo Co., Ltd., and stirred for 1 hour under ice cooling. After stirring, diethyl ether (100 ml; manufactured by Tokyo Chemical Industry Co., Ltd.) was added and stirred, and suction filtration was performed with a glass filter, and the obtained crystals were washed with diethyl ether to obtain 3.5 g of DPTB (contract). Rate 57%).
Appearance: Orange melting point: 79.8-80.7 ° C
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.04-3.08 (m, 16H), 3.40-3.45 (m, 8H), 14.5 (bs, 1H)
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 20.77, 37.00, 47.92, 156.71
Bromine content: 32% by weight

[Comparative Example 1]
Synthesis of di (1,3-dimethyl-2-imidazolidinone and 1-methyl-2-pyrrolidone) hydrotribromide (MPHT) To a 200 mL one-necked eggplant flask was added 13 mL of methanol and 2.2 g of 30% hydrobromic acetic acid solution. The mixture was stirred under ice cooling. Thereafter, bromine 0.83 g (5.2 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.) and 1-methyl-2-pyrrolidone 1.7 g (17.2 mmol: manufactured by Tokyo Chemical Industry Co., Ltd.) were slowly added in this order. Stir for 1 hour under cooling. Thereafter, the same operation as in Example 1 was performed to obtain 1.45 g of MPHT (yield 63%).
Appearance: Orange
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.25 (m, 4H), 2.90 (t, 4H), 3.00 (s, 6H), 3.75 (t, 4H) 14.6 (Bs14.6)
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 18.3, 31.4, 33.3, 52.8, 178.3
Bromine content: 36% by weight

[Example 3]
Synthesis of 2-bromopropiophenone

  In a 30 mL one-necked flask, 0.29 g (2.15 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.), DITB 1.08 g (2.30 mmol) obtained in Example 1 as a brominating agent, dichloromethane (4 mL; Tokyo Chemical Industry) Kogyo Co., Ltd.) was added and stirred at room temperature for 1 hour. Then, water was added and quenched, extracted with diethyl ether, and the organic layer was washed with water. The obtained organic layer was dried over sodium sulfate and filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: chloroform = 1: 2) to obtain 0.43 g of the desired product ( Yield 94%).

[Comparative Example 2]
Except that the brominating agent was changed to MPHT obtained in Comparative Example 1, the same operation as in Example 3 was performed. As a result, MPHT did not dissolve and the reaction did not proceed, and only a trace amount of the target product was obtained. There wasn't.

[Example 4]
Synthesis of 1,2-dibromotetradecane

  To a 30 mL one-necked flask was added 0.41 g (2.08 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.), DITB 0.99 g (2.11 mmol) obtained in Example 1 as a brominating agent, and 4 mL of dichloromethane at room temperature. Stir for 1 hour. After completion of the reaction, hexane and water were added for liquid separation. The obtained organic layer was dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. Thereafter, the residue was subjected to silica gel column chromatography (hexane) to obtain 0.68 g of the desired product (yield 92%).

[Example 5]
Except for changing the brominating agent to DPTB obtained in Example 2, the same operation as in Example 4 was performed to obtain 0.71 g of the desired product (yield 96%).

[Comparative Example 3]
The same operation as in Example 4 was performed except that the brominating agent was changed to MPHT obtained in Comparative Example 1. Although MPHT was not dissolved, the reaction proceeded because of the high reactivity of the raw material, and 0.66 g of the desired product was obtained (yield 89%).

[Example 6]
Synthesis of 2-bromo-1,4-dimethoxybenzene

  To a test tube, add 0.28 g (2.03 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.), 0.98 g (2.09 mmol) of DITB obtained in Example 1 as a brominating agent, and 4 mL of acetic acid. And stirred at 50 ° C. for 6 hours. After completion of the reaction, quantification was performed using gas chromatography (internal standard substance: chlorobenzene). As a result, it was confirmed that the desired product was produced in a yield of 75%.

[Comparative Example 4]
Except that the brominating agent was changed to MPHT obtained in Comparative Example 1, the production of the target product was confirmed in a yield of 71% by performing the same operation as in Example 6.

[Example 7]
Synthesis of methyl N-phenylcarbamate

  Benzamide 0.24 g (2.01 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.) and methanol 4 mL were added to a 30 mL two-necked flask equipped with a Dimroth tube and a calcium chloride tube, and stirred at room temperature. Thereafter, 0.5 g of sodium methoxide (9.21 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in 4 mL of methanol and added little by little and stirred. Thereafter, 1.14 g (2.44 mmol) of DITB obtained in Example 1 and 2 mL of methanol were added, and the mixture was heated to reflux for 4 hours. After completion of the reaction, the reaction solution was quenched by adding a saturated aqueous ammonium chloride solution and extracted with diethyl ether. The obtained organic layer was dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. Thereafter, the residue was subjected to silica gel column chromatography (hexane: chloroform = 1: 1) to obtain 0.28 g of the desired product (yield 92%).

[Comparative Example 5]
0.26g of the target product was obtained by performing the same operation as in Example 7 except that the brominating agent was changed to MPHT obtained in Comparative Example 1 (yield 84%).

Claims (4)

Following formula (1):

(Wherein n is 1 or 2, and R ¹ and R ² may be the same or different and each represents an alkyl group having 1 to 4 carbon atoms). The compound of Claim 1 whose R < ¹ > and R < ² > is a methyl group in the said General formula (1).   The compound of Claim 1 or 2 whose n is 1 in the said General formula (1).   The brominating agent which consists of a compound as described in any one of Claims 1-3.