JP2023039639A - Synthetic method for benzoxazine - Google Patents

Abstract

To provide a simple synthetic method for 4H-3,1-benzoxazine-2-amine compound useful as a building block of a synthesis of a benzoxazine compound.SOLUTION: A benzoxazine compound 5 that serves the above purpose is obtained by a desulfurization-cyclization reaction of a thiourea body 8. A manufacturing method under mild reaction conditions is provided by adding, in the presence of a catalyst, an oxidant of the catalyst and base.SELECTED DRAWING: None

Description

Benzoxazines are one of the important heterocyclic compounds for developing pharmaceuticals and agricultural chemicals. The present invention relates to a method for synthesizing N-phenyl-4H-3,1-benzoxazin-2-amine useful as one of its building blocks.

ここでは、２－アミノベンジルアルコールとフェニルイソチオシアネートから環化前駆体1aを得て、得られた1aをアセトニトリル中、加熱還流条件下、ＤＣＣと２時間反応させることにより、2aを合成している（非特許文献１）。
安池らは、ビスマス試薬を用いた合成法を報告している（スキーム２）。

この合成法は、２－アミノベンジルアルコールとフェニルイソチオシアネートを出発物質として、室温、ＤＭＦ中で反応させることにより、環化前駆体1aを生成させ、1aをトリフェニルビスマスジクロライドおよびトリエチルアミンによって、2aへと変換する方法である。
また、宮村らは、化学両論量のヨウ素を反応剤に用いた４Ｈ－３，１－ベンゾオキサジン類の簡易合成法について報告している（スキーム３）。この合成法は２－アミノベンジルアルコールとフェニルイソチオシアネートから環化前駆体1aを生成させ、その後、単離した環化前駆体1aに、酸化剤として化学量論量のヨウ素、塩基としてトリエチルアミンを反応させ、目的物を合成している。

一方、ベンゾキサジンではないが、Yadavらは、この合成法は環化前駆体3をＴＨＦ溶媒中、触媒量のヨウ化テトラブチルアンモニウムおよび過酸化水素を用いて室温で１時間反応させ、Ｎ－フェニル－２－ベンゾオキサゾールアミン4を合成している。

There have been several reports on methods for synthesizing N-phenyl-4H-3,1-benzoxazin-2-amine (hereinafter sometimes simply referred to as benzoxazine).
Lee et al. reported a synthetic method using 1,3-dicyclohexylcarbodiimide (DCC) (Scheme 1).

Here, cyclization precursor 1a is obtained from 2-aminobenzyl alcohol and phenylisothiocyanate, and 2a is synthesized by reacting the obtained 1a with DCC in acetonitrile under heating and reflux conditions for 2 hours. (Non-Patent Document 1).
Yasuike et al. reported a synthesis method using a bismuth reagent (Scheme 2).

This synthesis starts with 2-aminobenzyl alcohol and phenylisothiocyanate as starting materials and reacts in DMF at room temperature to form the cyclized precursor 1a, which is converted to 2a with triphenylbismuth dichloride and triethylamine. is a method of converting
In addition, Miyamura et al. reported a simple method for synthesizing 4H-3,1-benzoxazines using a stoichiometric amount of iodine as a reactant (Scheme 3). This synthesis involves the formation of cyclization precursor 1a from 2-aminobenzyl alcohol and phenylisothiocyanate, followed by reaction of the isolated cyclization precursor 1a with a stoichiometric amount of iodine as an oxidizing agent and triethylamine as a base. and synthesize the target product.

On the other hand, although not a benzoxazine, Yadav et al. report that this synthesis involves reacting the cyclization precursor 3 with catalytic amounts of tetrabutylammonium iodide and hydrogen peroxide in THF solvent for 1 hour at room temperature to give an N-phenyl -2-benzoxazolamine 4 is synthesized.

You, S.-W.; Lee, K.-J. Bull. Korean Chem. Soc. 2001, 22, 1270-1272. Murata, Y.; Matsumoto, N., Miyata; M., Kitamura, Y.; Kakusawa, N.; Matsumura, M.; Takuya Miyamura et al., Abstracts of the 45th Annual Meeting of the Pesticide Society of Japan (2020) p.64 Yadav, V. K.; Srivastava, V. P.; Yadav, L. S.; Tetrahedron Lett. 2018, 59, 252-255.

In recent years, from the viewpoint of green chemistry, an environment-friendly synthesis method is required. Accordingly, it is an object of the present invention to provide a method for synthesizing 4H-3,1-benzoxazines under mild reaction conditions, at low cost, and with high environmental friendliness.

As a result of intensive studies, the present inventors found that benzoxazine can be obtained by adding a catalytic amount of iodine to thiourea in the presence of two equivalents of hydrogen peroxide and triethylamine, and completed the present invention.

（式中、Ｒ^１およびＲ^２は、それぞれ独立して、水素原子、ハロゲン、シアノ基、置換基を有してもよい低級アルキル基、または置換基を有してもよい低級アルコキシ基を表し、Ｒ^３およびＲ^４はそれぞれ独立して、水素原子または低級アルキル基を表し、ｎは０～４のいずれかの整数を表す。）
を得ることができる。
芳香環の置換基であるＲ^１およびＲ^２は、電子供与性基から電子吸引性基まで幅広く適用することができ、化合物5は、ベンゾキサジン骨格のビルディングブロックとして、汎用性が極めて広い。例えば、ブロモ化ベンゾキサジン（Ｒ^２＝Ｂｒ）は、続いて、鈴木-宮浦カップリング等を行うことにより、より複雑な複素環化合物の合成に応用できる。また、Ｒ^３、Ｒ^４としては水素原子の他、低級アルキル基への応用も期待できる。 According to the present invention, a catalytic amount of iodine is sufficient for addition, and the reaction conditions are room temperature, and the desired product 5 can be obtained in a short period of time.

(wherein R ¹ and R ² each independently represent a hydrogen atom, a halogen, a cyano group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group; , R ³ and R ⁴ each independently represent a hydrogen atom or a lower alkyl group, and n represents an integer of 0 to 4.)
can be obtained.
The aromatic ring substituents R ¹ and R ² can be widely applied from electron-donating groups to electron-withdrawing groups, and compound 5 has extremely wide versatility as a building block of the benzoxazine skeleton. For example, brominated benzoxazines (R ² =Br) can be applied to the synthesis of more complex heterocyclic compounds by subsequent Suzuki-Miyaura coupling and the like. In addition, R ³ and R ⁴ can be expected to be applied not only to hydrogen atoms but also to lower alkyl groups.

（式中、Ｒ^１、Ｒ^２およびｎは前記に同じ）
に従って製造できる。
［ベンゾキサジン化合物7］
「ハロゲン」とは、フッ素原子、塩素原子、臭素原子、またはヨウ素原子を意味する。
「低級アルキル基」とは、炭素原子数が１－６の直鎖状または分枝状の脂肪族飽和炭化水素基（Ｃ_１－６アルキル基という。他の炭素数の場合も同様。）を意味する。具体的には、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、１－メチルプロピル基、２－メチルプロピル基、ｔｅｒｔ－ブチル基、ペンチル基、１、１－ジメチルプロピル基、１、２－ジメチルプロピル基、１－メチルブチル基、２－メチルブチル基、４－メチルペンチル基、３－メチルペンチル基、２－メチルペンチル基、１－メチルペンチル基、ｎ－ヘキシル基等を例示することができる。
「低級アルコキシ基」とは、低級アルキルオキシを意味し、この低級アルキルは上記と同じである。
「低級アルキル基」および「低級アルコキシ基」は置換基を有してもよく、その置換基としてはハロゲン、低級アルコキシ基等が例示される。
置換基としては、特に記載のない限り、１または２個以上の任意の種類の置換基を、化学的に可能な任意の位置に有することができ、置換基が２個以上の場合、それぞれの置換基は同一であっても異なっていてもよい。置換基を有する低級アルキル基としては、ブロモメチル基、トリフルオロメチル基等を例示することができる。
ベンゾキサジン7は、例えば、置換基の種類によって、異性体が存在する場合がある。本明細書において、それらの異性体の一形態のみの化学構造で記載することがあるが、本発明には、構造上生じ得るすべての異性体（幾何異性体、光学異性体、互変異性体など）も含有し、異性体単体、またはそれらの混合物も含有する。
［ベンゾキサジン7の製造］
前述のとおり、チオウレア体6の脱硫環化反応により、ベンゾキサジン7を得ることができる。
この環化反応は、触媒の存在下、該触媒の酸化剤と塩基を添加して行う。触媒としては、ヨウ素またはＡｌＣｌ_３、ＣｕＩ、ＺｎＣｌ_２、ＢＦ_３・ＯＥｔ_２のような金属塩が使用できるが、ヨウ素が最も好ましい。触媒の酸化剤とは、反応メカニズム上、前記触媒を酸化し、活性種を生成すると推定される酸化剤で、該活性種はチオウレア体の脱硫環化反応を進行させた後、反応完結後に元の触媒に再生されると考えられる。この触媒の酸化剤としては、過酸化水素の他、ｔｅｒｔ－ブチルヒドロパーオキシドやジｔｅｒｔ－ブチルパーオキシド等の過酸化物も使用可能であり、空気酸化やオゾン酸化も適用できるが、過酸化水素が最も好ましい。塩基としては、有機塩基・無機塩基が使用でき、有機塩基としては、トリエチルアミン、Ｎ，Ｎ-ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、テトラメチルエチレンジアミン、４－ジメチルアミノピリジン、キヌクリジン、テトラメチルグアニジン、ピリジン、ジアザビシクロウンデセン（ＤＢＵ）、ジアザビシクロノネン（ＤＢＮ）、ジアザビシクロオクタン（ＤＡＢＣＯ）、等のアミン類が使用でき、無機塩基としては炭酸セシウム、炭酸カリウム、炭酸ナトリウム等の炭酸塩、リン酸カリム等が例示できるが、三級アミン、特にトリエチルアミンが好ましい。
触媒は、チオウレア体6に対して、通常、３０モル％以下、２５％以下、好ましくは２０％を用いる。触媒の酸化剤と塩基は、チオウレア体6に対して、いずれも１．５～３当量、好ましくは１．８～２．２当量、特に好ましくは２当量を用いる。
溶媒は、反応を阻害しなければ特に制限はないが、エタノール、テトラヒドロフラン（ＴＨＦ）等が例示できる。反応温度は室温で十分であるが、要すれば加熱してもよく、反応時間は１～５時間、好ましくは２時間程度である。
ベンゾキサジン7の前駆体であるチオウレア体6は、２－アミノベンジルアルコールとイソチオシアネートの反応により製造できる。

（式中、Ｒ^１、Ｒ^２およびｎは前期に同じ。）
反応は、例えば、ＴＨＦ中、ベンジルアルコールに対して１．０当量のイソチオシアネートを加え、室温で５～１２時間反応させることで行う。
ベンジルアルコールにイソチオシアネートを反応させ、チオウレア体1を単離することなく、続いて脱硫環化反応を行い、ワンポットで、最終目的物のベンゾキサジン2を得ることもできる。

（式中、Ｒ^１、Ｒ^２およびｎは前期に同じ。）
なお、原料のベンジルアルコールは、対応するアントラニル酸のカルボキシ基をＬＡＨ還元することで容易に得られる。

The present invention provides a method for producing benzoxazine compound 5, which is useful as a building block for benzoxazine skeletons. The following description is for the case where R ³ and R ⁴ are hydrogen atoms in general formula 5, but the same applies when one or both of R ³ and R ⁴ are lower alkyl.
Compound 7 is represented by the following formula Scheme 5

(Wherein, R ¹ , R ² and n are the same as above)
can be manufactured according to
[Benzoxazine compound 7]
"Halogen" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
"Lower alkyl group" means a linear or branched saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms (referred to as a C _1-6 alkyl group. The same applies to other carbon numbers.) means. Specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, 1-methylpropyl group, 2-methylpropyl group, tert-butyl group, pentyl group, 1,1-dimethylpropyl group, 1, 2-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, n-hexyl group and the like can be exemplified. can.
A "lower alkoxy group" means a lower alkyloxy, and the lower alkyl is the same as above.
A "lower alkyl group" and a "lower alkoxy group" may have a substituent, and examples of the substituent include halogen and a lower alkoxy group.
As a substituent, unless otherwise specified, one or two or more substituents of any kind can be present at any chemically possible position, and when there are two or more substituents, each The substituents may be the same or different. A bromomethyl group, a trifluoromethyl group, etc. can be illustrated as a lower alkyl group which has a substituent.
Benzoxazine 7 may have isomers, depending on the type of substituent, for example. In this specification, the chemical structures of only one form of these isomers may be described, but in the present invention, all isomers (geometric isomers, optical isomers, tautomers) that can occur structurally etc.), as well as single isomers or mixtures thereof.
[Production of Benzoxazine 7]
As described above, the benzoxazine 7 can be obtained by the desulfurization reaction of the thiourea compound 6.
This cyclization reaction is carried out in the presence of a catalyst with the addition of an oxidizing agent for the catalyst and a base. As catalyst, iodine or metal salts such as AlCl ₃ , CuI, ZnCl ₂ , BF ₃ .OEt ₂ can be used, but iodine is most preferred. The oxidizing agent of the catalyst is an oxidizing agent that is presumed to oxidize the catalyst and generate active species in terms of the reaction mechanism. is considered to be regenerated into the catalyst of As an oxidizing agent for this catalyst, in addition to hydrogen peroxide, peroxides such as tert-butyl hydroperoxide and di-tert-butyl peroxide can be used, and air oxidation and ozone oxidation can also be applied. Hydrogen is most preferred. As the base, organic bases and inorganic bases can be used. Examples of organic bases include triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, tetramethylethylenediamine, 4-dimethylaminopyridine, quinuclidine, tetramethylguanidine, pyridine, Amines such as diazabicycloundecene (DBU), diazabicyclononene (DBN), and diazabicyclooctane (DABCO) can be used, and inorganic bases such as cesium carbonate, potassium carbonate, carbonates such as sodium carbonate, Potassium phosphate and the like can be exemplified, but tertiary amines, particularly triethylamine, are preferred.
The catalyst is usually used in an amount of 30 mol % or less, 25 mol % or less, preferably 20 mol %, based on the thiourea compound 6 . The oxidizing agent and the base of the catalyst are used in an amount of 1.5 to 3 equivalents, preferably 1.8 to 2.2 equivalents, particularly preferably 2 equivalents, relative to the thiourea compound 6 .
The solvent is not particularly limited as long as it does not interfere with the reaction, and ethanol, tetrahydrofuran (THF) and the like can be exemplified. Although room temperature is sufficient for the reaction temperature, heating may be used if necessary, and the reaction time is 1 to 5 hours, preferably about 2 hours.
Thiourea 6, which is a precursor of benzoxazine 7, can be produced by reacting 2-aminobenzyl alcohol with isothiocyanate.

(In the formula, R ¹ , R ² and n are the same as in the previous term.)
The reaction is carried out, for example, by adding 1.0 equivalent of isothiocyanate to benzyl alcohol in THF and reacting at room temperature for 5 to 12 hours.
It is also possible to react benzyl alcohol with an isothiocyanate, followed by a desulfurization reaction without isolating the thiourea 1, to obtain the final target benzoxazine 2 in one pot.

(In the formula, R ¹ , R ² and n are the same as in the previous term.)
Benzyl alcohol as a raw material can be easily obtained by LAH reduction of the carboxy group of the corresponding anthranilic acid.

EXAMPLES The present invention will be described in more detail with reference to examples and reference examples below, but the present invention is not limited by these descriptions.

ナス型フラスコに２－アミノベンジルアルコール(241 mg, 1.96 mmol)を入れ、そこにTHF(6 mL)を加えて溶解させた。そこへ３－フルオロフェニルイソチオシアネート(300 mg, 1.96 mmol)を加え、室温で一晩反応させた。その後、溶媒を減圧留去し、そこに少量の塩化メチレンを加え、ヘキサンを白濁するまで加えて静置し、白色結晶を沈殿させた。吸引濾過により、淡桃色固体であるＮ－［２－（ヒドロキシメチル）フェニル］－Ｎ’－（３－フルオロフェニル）チオウレア1b (521 mg, 97%)を得た。
m.p. 138－139℃; ^１Ｈ-ＮＭＲ(500 MHz, DMSO－d₆) δ: 9.96 (s, 1H, NH), 9.35 (s, 1H, NH), 7.55 (dt, J = 11.5, 2.3 Hz, 1H, Ar), 7.42 (dd, J = 6.9, 2.3 Hz, 1H, Ar), 7.37 (dd, J = 7.5, 1.2 Hz, 1H, Ar), 7.34－7.30 (m, 1H, Ar), 7.25-7.19 (m, 3H, Ar), 6.90 (ddd, J=9.2, 8.9, 1.7, 1H, Ar), 4.52 (s, 2H, CH2). Reference example 1
N-[2-(hydroxymethyl)phenyl]-N'-(3-fluorophenyl)thiourea 1b

2-Aminobenzyl alcohol (241 mg, 1.96 mmol) was placed in an eggplant-shaped flask, and THF (6 mL) was added to dissolve it. 3-Fluorophenyl isothiocyanate (300 mg, 1.96 mmol) was added thereto and reacted overnight at room temperature. Thereafter, the solvent was distilled off under reduced pressure, a small amount of methylene chloride was added thereto, and hexane was added until it became cloudy, and left to stand to precipitate white crystals. Suction filtration gave N-[2-(hydroxymethyl)phenyl]-N'-(3-fluorophenyl)thiourea 1b (521 mg, 97%) as a pale pink solid.
^1H -NMR (500 MHz, DMSO- _d6 ) δ: 9.96 (s, 1H, NH), 9.35 (s, 1H, NH), 7.55 (dt, J = 11.5, 2.3 Hz, 1H, Ar), 7.42 (dd, J = 6.9, 2.3 Hz, 1H, Ar), 7.37 (dd, J = 7.5, 1.2 Hz, 1H, Ar), 7.34－7.30 (m, 1H, Ar), 7.25- 7.19 (m, 3H, Ar), 6.90 (ddd, J=9.2, 8.9, 1.7, 1H, Ar), 4.52 (s, 2H, CH2).

Reference examples 2 to 11
Thioureas of Reference Examples 2 to 12 were obtained in the same manner as in Reference Example 1 above.

ナス型フラスコにN-[2-(ヒドロキシメチル)フェニル]-N'-フェニルチオウレア（1a）（129 mg, 0.50 mmol）、ヨウ素（25 mg, 20 mol%）を入れ、そこにTHF（2.0 mL）を加えて溶解させた。そこに、トリエチルアミン（101 mg, 1.0 mmol）と30%過酸化水素水溶液 (113 mg, 1.0 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2a(101 mg, 90%)を得た。 Example 1
Preparation of N-phenyl-4H-3,1-benzoxazin-2-amine 2a

N-[2-(Hydroxymethyl)phenyl]-N'-phenylthiourea (1a) (129 mg, 0.50 mmol) and iodine (25 mg, 20 mol%) were placed in an eggplant-shaped flask, and THF (2.0 mL ) was added and dissolved. Triethylamine (101 mg, 1.0 mmol) and 30% hydrogen peroxide aqueous solution (113 mg, 1.0 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the target compound 2a (101 mg, 90%) as a white solid.

ナス型フラスコにN-[2-(ヒドロキシメチル)フェニル]-N'-(3-フルオロフェニル)チオウレア1b（100 mg, 0.36 mmol）、ヨウ素（18.5 mg, 20 mol%）を入れ、そこにTHF（1.3 mL）を加えて溶解させた。そこに、トリエチルアミン（73.7 mg, 0.73 mmol）と30%過酸化水素水溶液 (82.5 mg, 0.73 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2b(68.6 mg, 78%)を得た。
m.p. 114-116℃; ^１Ｈ-ＮＭＲ(500 MHz, CDCl₃) δ: 7.47 (d, J ＝ 11.5Hz, 1H, Ar), 7.25－7.19 (m, 2H, Ar), 7.04－6.98 (m, 4H, Ar), 6.73 (ddd, J=8.6, 8.6, 1.7 Hz, 1H, Ar), 5.24 (s, 2H, CH2). Example 2
Preparation of N-(3-fluorophenyl)-4H-3,1-benzoxazin-2-amine 2b

Place N-[2-(hydroxymethyl)phenyl]-N'-(3-fluorophenyl)thiourea 1b (100 mg, 0.36 mmol) and iodine (18.5 mg, 20 mol%) in an eggplant-shaped flask, and add THF. (1.3 mL) was added and dissolved. Triethylamine (73.7 mg, 0.73 mmol) and 30% hydrogen peroxide aqueous solution (82.5 mg, 0.73 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent and evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the target compound 2b (68.6 mg, 78%) as a white solid.
mp 114-116°C; ^1H -NMR (500 MHz, _CDCl3 ) δ: 7.47 (d, J = 11.5Hz, 1H, Ar), 7.25-7.19 (m, 2H, Ar), 7.04-6.98 (m, 4H, Ar), 6.73 (ddd, J=8.6, 8.6, 1.7 Hz, 1H, Ar), 5.24 (s, 2H, CH2).

ナス型フラスコにN-[2-(ヒドロキシメチル)フェニル]-N'-(2ブロモフェニル)チオウレア1c（100 mg, 0.30 mmol）、ヨウ素（15.2 mg, 20 mol%）を入れ、そこにTHF（1.3 mL）を加えて溶解させた。そこに、トリエチルアミン（60.7 mg, 0.6 mmol）と30%過酸化水素水溶液 (68.0 mg, 0.6 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2c(76.3 mg, 85%)を得た。
m.p. 148－150 ℃; ^１Ｈ-ＮＭＲ(500 MHz, CDCl₃) δ: 8.22 (d, J = 8.0 Hz, 1H, Ar), 7.53 (dd, J = 8.0, 1.2 Hz, 1H, Ar), 7.31 (ddd, J = 8.0, 7.5, 1.2 Hz, 1H, Ar), 7.25－7.21 (m, 1H, Ar), 7.03－6.98 (m, 3H, Ar), 6.91 (ddd, J ＝ 8.0, 7.5, 1.2 Hz, 1H, Ar), 5.24 (s, 2H, CH2). Example 3
Preparation of N-(2-bromophenyl)-4H-3,1-benzoxazin-2-amine 2c

N-[2-(hydroxymethyl)phenyl]-N'-(2-bromophenyl)thiourea 1c (100 mg, 0.30 mmol) and iodine (15.2 mg, 20 mol%) were placed in an eggplant-shaped flask, and THF ( 1.3 mL) was added and dissolved. Triethylamine (60.7 mg, 0.6 mmol) and 30% hydrogen peroxide aqueous solution (68.0 mg, 0.6 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent and evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the desired product 2c (76.3 mg, 85%) as a white solid.
mp 148-150°C; ^1H -NMR (500 MHz, _CDCl3 ) δ: 8.22 (d, J = 8.0 Hz, 1H, Ar), 7.53 (dd, J = 8.0, 1.2 Hz, 1H, Ar), 7.31 (ddd, J = 8.0, 7.5, 1.2 Hz, 1H, Ar), 7.25－7.21 (m, 1H, Ar), 7.03－6.98 (m, 3H, Ar), 6.91 (ddd, J = 8.0, 7.5, 1.2 Hz, 1H, Ar), 5.24 (s, 2H, CH2).

ナス型フラスコにN-[4-(ヒドロキシメチル)フェニル]-N'-(2ブロモフェニル)チオウレア1d（100 mg, 0.30 mmol）、ヨウ素（15.2 mg, 20 mol%）を入れ、そこにTHF（1.3 mL）を加えて溶解させた。そこに、トリエチルアミン（60.7 mg, 0.6 mmol）と30%過酸化水素水溶液 (68.0 mg, 0.6 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2d(73.5 mg, 81%)を得た。
m.p. 169－170 ℃; ^１Ｈ-ＮＭＲ(500 MHz,CDCl₃) δ: 7.40 (dd, J ＝6.9, 1.7 Hz, 2H, Ar), 7.32 (d, J ＝8.6 Hz, 2H, Ar), 7.25－7.21 (m, 1H, Ar), 7.03－7.00 (m, 3H, Ar), 5.22 (s, 2H, CH2). Example 4
Preparation of N-(4-bromophenyl)-4H-3,1-benzoxazin-2-amine 2d

N-[4-(hydroxymethyl)phenyl]-N'-(2-bromophenyl)thiourea 1d (100 mg, 0.30 mmol) and iodine (15.2 mg, 20 mol%) were placed in an eggplant-shaped flask, and THF ( 1.3 mL) was added and dissolved. Triethylamine (60.7 mg, 0.6 mmol) and 30% hydrogen peroxide aqueous solution (68.0 mg, 0.6 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The drying agent was filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the target compound 2d (73.5 mg, 81%) as a white solid.
^1H -NMR (500 MHz, _CDCl3 ) δ: 7.40 (dd, J = 6.9, 1.7 Hz, 2H, Ar), 7.32 (d, J = 8.6 Hz, 2H, Ar), 7.25 －7.21 (m, 1H, Ar), 7.03－7.00 (m, 3H, Ar), 5.22 (s, 2H, CH2).

ナス型フラスコにN-[2-(ヒドロキシメチル)フェニル]-N'-(2クロロフェニル)チオウレア1e（100 mg, 0.34 mmol）、ヨウ素（17.3 mg, 20 mol%）を入れ、そこにTHF（1.3 mL）を加えて溶解させた。そこに、トリエチルアミン（68.8 mg, 0.68 mmol）と30%過酸化水素水溶液 (77.1 mg, 0.68 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2e(61.3 mg, 70%)を得た。
m.p. 152－153 ℃; ^１Ｈ-ＮＭＲ(500 MHz,CDCl₃) δ: 8.29 (d, J = 8.0 Hz, 1H, Ar), 7.35 (dd, J = 8.0, 1.2 Hz, 1H, Ar),7.29－7.22 (m, 2H, Ar), 7.04－6.97 (m, 4H, Ar), 5.24 (s, 2H, CH2). Example 5
Preparation of N-(2-chlorophenyl)-4H-3,1-benzoxazin-2-amine 2e

N-[2-(Hydroxymethyl)phenyl]-N'-(2-chlorophenyl)thiourea 1e (100 mg, 0.34 mmol) and iodine (17.3 mg, 20 mol%) were placed in an eggplant-shaped flask, and THF (1.3 mL) was added and dissolved. Triethylamine (68.8 mg, 0.68 mmol) and 30% hydrogen peroxide aqueous solution (77.1 mg, 0.68 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent and evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the target compound 2e (61.3 mg, 70%) as a white solid.
^1H -NMR (500 MHz, _CDCl3 ) δ: 8.29 (d, J = 8.0 Hz, 1H, Ar), 7.35 (dd, J = 8.0, 1.2 Hz, 1H, Ar), 7.29 －7.22 (m, 2H, Ar), 7.04－6.97 (m, 4H, Ar), 5.24 (s, 2H, CH2).

ナス型フラスコにN-[2-(ヒドロキシメチル)フェニル]-N'-(4-メチルフェニル)チオウレア1f（70 mg, 0.26 mmol）、ヨウ素（13.2 mg, 20 mol%）を入れ、そこにTHF（0.9 mL）を加えて溶解させた。そこに、トリエチルアミン（52.6 mg, 0.52 mmol）と30%過酸化水素水溶液 (59.0 mg, 1.72 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2f(48.0 mg, 78%)を得た。
m.p. 113－116℃; ^１Ｈ-ＮＭＲ(500 MHz, CDCl₃) δ: 7.31 (d, J ＝ 8.0 Hz, 2H, Ar), 7.25－7.20 (m, 1H, Ar), 7.10 (d, J ＝ 8.0 Hz, 2H, Ar), 7.03－6.97 (m, 3H, Ar), 5.21 (s, 2H, CH2), 2.31 (s, 3H, CH3). Example 6
Preparation of N-(4-methylphenyl)-4H-3,1-benzoxazin-2-amine 2f

Place N-[2-(hydroxymethyl)phenyl]-N'-(4-methylphenyl)thiourea 1f (70 mg, 0.26 mmol) and iodine (13.2 mg, 20 mol%) in an eggplant-shaped flask and add THF. (0.9 mL) was added and dissolved. Triethylamine (52.6 mg, 0.52 mmol) and 30% hydrogen peroxide aqueous solution (59.0 mg, 1.72 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the desired product 2f (48.0 mg, 78%) as a white solid.
mp 113-116°C; ^1H -NMR (500 MHz, _CDCl3 ) δ: 7.31 (d, J = 8.0 Hz, 2H, Ar), 7.25-7.20 (m, 1H, Ar), 7.10 (d, J = 8.0 Hz, 2H, Ar), 7.03－6.97 (m, 3H, Ar), 5.21 (s, 2H, CH2), 2.31 (s, 3H, CH3).

ナス型フラスコにN-[2-(ヒドロキシメチル)フェニル]-N'-(3-トリフルオロメチルフェニル)チオウレア1g（100 mg, 0.31 mmol）、ヨウ素（15.6mg, 20 mol%）を入れ、そこにTHF（1.3 mL）を加えて溶解させた。そこに、トリエチルアミン（62.3 mg, 0.62 mmol）と30%過酸化水素水溶液 (69.8 mg, 0.62 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(hexane/AcOEt = 3/1)に供することで、淡黄色固体である目的物 2g(65 mg, 73%)を得た。
m.p. 125－127 ℃; ^１Ｈ-ＮＭＲ(500 MHz, CDCl₃) δ: 7.72 (s, 1H, Ar), 7.55 (d, J ＝ 8.0 Hz, 1H, Ar), 7.38 (dd, J ＝ 8.0, 8.0 Hz, 1H, Ar), 7.28 (d, J ＝ 7.5 Hz, 1H, Ar), 7.25－7.21 (m, 1H, Ar), 7.05－7.01 (m, 2H, Ar), 6.99 (d, J ＝ 8.0 Hz, 1H, Ar), 5.24 (s, 2H, CH2). Example 7
Preparation of N-(3-trifluoromethylphenyl)-4H-3,1-benzoxazin-2-amine 2g

1 g of N-[2-(hydroxymethyl)phenyl]-N'-(3-trifluoromethylphenyl)thiourea (100 mg, 0.31 mmol) and iodine (15.6 mg, 20 mol%) were placed in an eggplant-shaped flask. was dissolved by adding THF (1.3 mL). Triethylamine (62.3 mg, 0.62 mmol) and 30% hydrogen peroxide aqueous solution (69.8 mg, 0.62 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The drying agent was filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain 2g (65 mg, 73%) of the desired product as a pale yellow solid. .
^mp _125-127 °C; 8.0 Hz, 1H, Ar), 7.28 (d, J = 7.5 Hz, 1H, Ar), 7.25-7.21 (m, 1H, Ar), 7.05-7.01 (m, 2H, Ar), 6.99 (d, J = 8.0Hz, 1H, Ar), 5.24 (s, 2H, CH2).

ナス型フラスコにN-[2-(ヒドロキシメチル)フェニル]-N'-(2-メトキシフェニル)チオウレア1h（100 mg, 0.35 mmol）、ヨウ素（17.7 mg, 20 mol%）を入れ、そこにTHF（1.3 mL）を加えて溶解させた。そこに、トリエチルアミン（70.4 mg, 0.70 mmol）と30%過酸化水素水溶液 (78.9 mg, 0.70 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2h(58.7 mg, 66%)を得た。
m.p. 100－102 ℃; ^１Ｈ-ＮＭＲ(500 MHz, CDCl₃) δ: 8.40 (dd, J ＝ 7.2, 2.0 Hz, 1H, Ar), 7.25 (ddd, J ＝ 7.6, 7.6, 1.4, 1H, Ar), 7.12 (d, J ＝ 8.0 Hz, 1H, Ar), 7.01 (ddd, J ＝ 7.5, 7.5, 1.2 Hz, 1H, Ar), 7.00－6.96 (m, 3H, Ar), 6.87－6.85 (m, 1H, Ar), 5.24 (s, 2H, CH2), 3.85 (s, 3H, CH3). Example 8
Preparation of N-(2-methoxyphenyl)-4H-3,1-benzoxazin-2-amine 2h

N-[2-(hydroxymethyl)phenyl]-N'-(2-methoxyphenyl)thiourea 1h (100 mg, 0.35 mmol) and iodine (17.7 mg, 20 mol%) were placed in an eggplant-shaped flask, and THF was added. (1.3 mL) was added and dissolved. Triethylamine (70.4 mg, 0.70 mmol) and 30% hydrogen peroxide aqueous solution (78.9 mg, 0.70 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent and evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the desired product 2h (58.7 mg, 66%) as a white solid.
^mp _100-102 °C; ), 7.12 (d, J = 8.0 Hz, 1H, Ar), 7.01 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H, Ar), 7.00-6.96 (m, 3H, Ar), 6.87-6.85 (m , 1H, Ar), 5.24 (s, 2H, CH2), 3.85 (s, 3H, CH3).

ナス型フラスコに1-(2-(ヒドロキシメチル)-4-メチルフェニル)3-フェニルチオウレア1i（100 mg, 0.37 mmol）、ヨウ素（18.8 mg, 20 mol%）を入れ、そこにTHF（1.3 mL）を加えて溶解させた。そこに、トリエチルアミン（74.9 mg, 0.74 mmol）と30%過酸化水素水溶液 (83.9 mg, 0.74 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2i(75.6 mg, 86%)を得た。
m.p. 134－136 ℃; ^１Ｈ-ＮＭＲ(500 MHz, CDCl₃) δ: 7.44 (d, J = 7.5 Hz, 2H, Ar), 7.31-7.25 (m, 2H, Ar), 7.03 (d, J = 7.5 Hz, 2H, Ar), 6.94 (d, J = 7.5 Hz, 1H, Ar), 6.79 (s, 1H, Ar), 5.20 (s, 2H, CH2), 2.30 (s, 3H, CH3)． Example 9
Preparation of 6-methyl-2-(phenylamino)-4H-3,1-benzoxazine 2i

1-(2-(Hydroxymethyl)-4-methylphenyl)3-phenylthiourea 1i (100 mg, 0.37 mmol) and iodine (18.8 mg, 20 mol%) were placed in an eggplant-shaped flask, and THF (1.3 mL ) was added and dissolved. Triethylamine (74.9 mg, 0.74 mmol) and 30% hydrogen peroxide aqueous solution (83.9 mg, 0.74 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the target compound 2i (75.6 mg, 86%) as a white solid.
^1H -NMR (500 MHz, _CDCl3 ) δ: 7.44 (d, J = 7.5 Hz, 2H, Ar), 7.31-7.25 (m, 2H, Ar), 7.03 (d, J = 7.5 Hz, 2H, Ar), 6.94 (d, J = 7.5 Hz, 1H, Ar), 6.79 (s, 1H, Ar), 5.20 (s, 2H, CH2), 2.30 (s, 3H, CH3).

ナス型フラスコに1-(2-(ヒドロキシメチル)-4-メチルフェニル)3-[4-(メトキシ)フェニル]チオウレア 1j（100 mg, 0.33 mmol）、ヨウ素（16.8 mg, 20 mol%）を入れ、そこにTHF（1.3 mL）を加えて溶解させた。そこに、トリエチルアミン（66.8 mg, 0.66 mmol）と30%過酸化水素水溶液 (74.8 mg, 0.66 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2j(53.8 mg, 61%)を得た。
m.p. 117－119 ℃^{; １}Ｈ-ＮＭＲ(500 MHz, CDCl₃) δ: 7.34－7.25 (m, 2H, Ar), 7.01 (d, J=8.0 Hz, 1H, Ar), 6.89 (d, J = 8.0 Hz, 1H, Ar), 6.85 (dd, J = 6.9, 2.3 Hz, 2H, Ar), 6.78 (s, 1H, Ar), 5.16 (s, 2H, CH2), 3.78 (s, 3H, CH3), 2.29 (s, 3H, OCH3). Example 10
Preparation of 6-methyl-2-[(4-methoxyphenyl)amino]-4H-3,1-benzoxazine 2j

Place 1-(2-(hydroxymethyl)-4-methylphenyl)3-[4-(methoxy)phenyl]thiourea 1j (100 mg, 0.33 mmol) and iodine (16.8 mg, 20 mol%) in an eggplant-shaped flask. , THF (1.3 mL) was added and dissolved. Triethylamine (66.8 mg, 0.66 mmol) and 30% hydrogen peroxide aqueous solution (74.8 mg, 0.66 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent and evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the desired product 2j (53.8 mg, 61%) as a white solid.
^mp _117-119 °C ^; 8.0 Hz, 1H, Ar), 6.85 (dd, J = 6.9, 2.3 Hz, 2H, Ar), 6.78 (s, 1H, Ar), 5.16 (s, 2H, CH2), 3.78 (s, 3H, CH3) , 2.29 (s, 3H, OCH3).

ナス型フラスコに1-[5-クロロ-2-(ヒドロキシメチル)フェニル]-フェニルチオウレア 1k（100 mg, 0.34 mmol）、ヨウ素（17.3 mg, 20 mol%）を入れ、そこにTHF（0.9 mL）を加えて溶解させた。そこに、トリエチルアミン（68.8 mg, 0.68 mmol）と30%過酸化水素水溶液 (77.1 mg, 0.68 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2k(43.9 mg, 50%)を得た。
m.p. 150-152 ℃; ^１Ｈ-ＮＭＲ(500 MHz, CDCl₃) δ: 7.46 (d, J ＝ 8.0 Hz, 1H, Ar), 7.33－7.25 (m, 2H, Ar), 7.08－7.05 (m, 2H, Ar), 6.97 (dd, J ＝ 8.0, 1.7 Hz, 1H, Ar), 6.88 (d, J ＝ 8.0 Hz, 1H, Ar), 5.19 (s, 2H, CH2). Example 11
Preparation of 7-chloro-2-phenylamino-4H-3,1-benzoxazine 2k

1-[5-Chloro-2-(hydroxymethyl)phenyl]-phenylthiourea 1k (100 mg, 0.34 mmol) and iodine (17.3 mg, 20 mol%) were placed in an eggplant-shaped flask, and THF (0.9 mL) was added. was added and dissolved. Triethylamine (68.8 mg, 0.68 mmol) and 30% hydrogen peroxide aqueous solution (77.1 mg, 0.68 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent and evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the desired product 2k (43.9 mg, 50%) as a white solid.
mp 150-152 °C; ^1H -NMR (500 MHz, _CDCl3 ) δ: 7.46 (d, J = 8.0 Hz, 1H, Ar), 7.33-7.25 (m, 2H, Ar), 7.08-7.05 (m, 2H, Ar), 6.97 (dd, J = 8.0, 1.7 Hz, 1H, Ar), 6.88 (d, J = 8.0 Hz, 1H, Ar), 5.19 (s, 2H, CH2).

ナス型フラスコに1-[5-クロロ-2-(ヒドロキシメチル)フェニル]-3-[(3-フルオロ)フェニル]チオウレア 1l（65 mg, 0.22 mmol）、ヨウ素（11.2 mg, 20 mol%）を入れ、そこにTHF（0.9 mL）を加えて溶解させた。そこに、トリエチルアミン（44.5 mg, 0.44 mmol）と30%過酸化水素水溶液 (49.9 mg, 0.44 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2l(37.3 mg, 62%)を得た。
m.p. 115－117 ℃; ^１Ｈ-ＮＭＲ(500 MHz, CDCl₃) δ： 7.47 (d, J = 11.5 Hz, 1H, Ar), 7.25-7.20 (m, 1H, Ar), 7.07-7.05 (m, 2H, Ar), 6.99 (dd, J = 8.0, 2.3 Hz, 1H, Ar), 6.89 (d, J = 8.0 Hz, 1H, Ar), 6.75 (ddd, J = 8.3, 7.5, 1.7 Hz, 1H, Ar), 5.20 (s, 2H, CH2); Example 12
Preparation of 7-chloro-2-[(3-fluorophenyl)amino]-4H-3,1-benzoxazine 2l

1-[5-chloro-2-(hydroxymethyl)phenyl]-3-[(3-fluoro)phenyl]thiourea 1L (65 mg, 0.22 mmol) and iodine (11.2 mg, 20 mol%) were placed in an eggplant-shaped flask. THF (0.9 mL) was added and dissolved. Triethylamine (44.5 mg, 0.44 mmol) and 30% hydrogen peroxide aqueous solution (49.9 mg, 0.44 mmol) were added thereto and reacted at room temperature for 2 hours. After that, it was quenched by adding a saturated sodium thiosulfate aqueous solution. Furthermore, a small amount of water was added, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the desired product 2l (37.3 mg, 62%) as a white solid.
^mp _115-117 °C; 2H, Ar), 6.99 (dd, J = 8.0, 2.3 Hz, 1H, Ar), 6.89 (d, J = 8.0 Hz, 1H, Ar), 6.75 (ddd, J = 8.3, 7.5, 1.7 Hz, 1H, Ar), 5.20 (s, 2H, CH2);

ナス型フラスコに1-[2-(ヒドロキシメチル)フェニル]-3-(フェニルメチル)-チオウレア 1m(100 mg, 0.37 mmol）、ヨウ素（18.7 mg, 20 mol%）を入れ、そこにTHF（1.3 mLを加えて溶解させた。そこに、トリエチルアミン（74.7 mg, 0.74 mmol）と30%過酸化水素水溶液 (83.7 mg, 0.74 mmol)を加えて、室温で2時間反応させた。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチした。さらに、少量の水を加えて、酢酸エチルで3回抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤を濾過し、溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(hexane/AcOEt = 3/1)に供することで、白色固体である目的物 2m(60.5 mg, 69%)を得た。
m.p. 126－128 ℃; ^１Ｈ-ＮＭＲ(500 MHz, CDCl₃) δ： 7.35－7.31 (m, 4H, Ar), 7.28－7.25 (m, 1H, Ar), 7.20 (ddd, J ＝ 7.5, 8.0, 1.7 Hz, 1H, Ar), 6.99 (d, J＝8.0 Hz, 1H, Ar), 7.96－6.91 (m, 2H, Ar), 5.13 (s, 2H), 4.53 (s, 2H). Example 13
Preparation of N-(phenylmethyl)-4H-3,1-benzoxazin-2-amine 2m

1-[2-(hydroxymethyl)phenyl]-3-(phenylmethyl)-thiourea 1m (100 mg, 0.37 mmol) and iodine (18.7 mg, 20 mol%) were placed in an eggplant-shaped flask, and THF (1.3 To this, triethylamine (74.7 mg, 0.74 mmol) and 30% aqueous hydrogen peroxide solution (83.7 mg, 0.74 mmol) were added and allowed to react at room temperature for 2 hours, followed by saturated thiosulfuric acid. Aqueous sodium solution was added to quench.Furthermore, a small amount of water was added, extracted with ethyl acetate three times, washed with saturated brine, dried over anhydrous sodium sulfate.The desiccant was filtered, and the solvent was distilled off under reduced pressure. After removing it, it was subjected to silica gel column chromatography (hexane/AcOEt = 3/1) to obtain the desired product 2m (60.5 mg, 69%) as a white solid.
^mp 126-128 °C _; , 1.7 Hz, 1H, Ar), 6.99 (d, J = 8.0 Hz, 1H, Ar), 7.96－6.91 (m, 2H, Ar), 5.13 (s, 2H), 4.53 (s, 2H).

2-アミノベンジルアルコール(62 mg, 0.50 mmol) をTHF(2 mL, 0.5 M)に溶解し、フェニルイソチオシアネート(68 mg, 0.50 mmol)を室温で滴下した。混合物を室温で３時間撹拌してから、ヨウ素(25 mg, 0.10 mmol, 20 mol%)、トリエチルアミン(101 mg, 1.0 mmol),および30%過酸化水素水溶液(113 mg, 1.0 mmol)を加えて室温で２時間撹拌した。その後、飽和チオ硫酸ナトリウム水溶液を加えてクエンチし、塩化メチレンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去した。残渣をシリカゲルクロマトグラフィー(hexane/AcOEt = 3/1)で精製し、目的物 2a(112 mg, 47%）を得た。 Example 14
Preparation of N-phenyl-4H-3,1-benzoxazin-2-amine 2a (one-pot)

2-Aminobenzyl alcohol (62 mg, 0.50 mmol) was dissolved in THF (2 mL, 0.5 M) and phenylisothiocyanate (68 mg, 0.50 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 hours, then iodine (25 mg, 0.10 mmol, 20 mol%), triethylamine (101 mg, 1.0 mmol), and 30% aqueous hydrogen peroxide (113 mg, 1.0 mmol) were added. Stir at room temperature for 2 hours. Then, it was quenched by adding a saturated aqueous sodium thiosulfate solution and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane/AcOEt = 3/1) to obtain the desired product 2a (112 mg, 47%).

The benzoxazine compound provided by the present invention is useful as a building block for pharmaceuticals and agricultural chemicals, and has high versatility.

Claims (9)

For thiourea 8,

(wherein R ¹ and R ² each independently represent a hydrogen atom, a halogen, a cyano group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group; , R ³ and R ⁴ each independently represent a hydrogen atom or a lower alkyl group, and n represents an integer of 0 to 4.)
A method for producing a benzoxazine compound represented by Formula 5, which comprises reacting an oxidizing agent of the catalyst with a base in the presence of a catalyst. The catalyst is one or more catalysts selected from the group consisting of iodine, AlCl ₃ , CuI, ZnCl ₂ and BF ₃ OEt ₂ , and the oxidizing agent of the catalyst is hydrogen peroxide, tert-butyl hydroperoxide, di- 2. The process according to claim 1, wherein the oxidizing agent is one or more selected from the group consisting of tert-butyl peroxide, atmospheric oxygen and ozone. The base is triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, tetramethylethylenediamine, 4-dimethylaminopyridine, quinuclidine, tetramethylguanidine, pyridine, diazabicycloundecene (DBU), diazabicyclononene (DBN ), one or more amines consisting of diazabicyclooctane (DABCO), or carbonates such as cesium carbonate, potassium carbonate, sodium carbonate, and one or more inorganic bases consisting of potassium phosphate. Or the production method according to 2. The production method according to any one of claims 1 to 3, wherein R ³ and R ⁴ are hydrogen atoms and n is 0 or 1. 5. The process according to claim 4, wherein the catalyst is iodine and the catalytic oxidant is hydrogen peroxide. The base is triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, tetramethylethylenediamine, 4-dimethylaminopyridine, quinuclidine, tetramethylguanidine, pyridine, diazabicycloundecene (DBU), diazabicyclononene (DBN ) and diazabicyclooctane (DABCO). 7. The method of claim 6, wherein the base is triethylamine. According to the following scheme, 2-aminobenzyl alcohol is reacted with isothiocyanate

(Wherein, R ¹ , R ² and n are the same as above)
The production method according to any one of claims 4 to 7, wherein thiourea 1 is synthesized. 9. The process according to claim 8, wherein 2-aminobenzyl alcohol is reacted with an isothiocyanate followed by a cyclization reaction without isolation of thiourea 1 to give a benzoxazine compound of formula 2.