JPH04297451A - Production of isothiocyanic acid ester - Google Patents

Abstract

PURPOSE:To simply obtain isothiocyanic acid esters in high yield by reacting an alcohol with halogenated sulfonyl compound, reacting the resultant sulfonate with thiocyanic acid salt and then isomerizing the reaction product. CONSTITUTION:A compound expressed by the formula R-OH (R is 1-18C alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl or hetero ring) is reacted with a compound expressed by the formula R'-SO2X (R' is alkyl or aryl; X is halogen) to afford a compound expressed by the formula R-OSO2R'. The compound is reacted with thiocyanic acid salt (e.g. sodium salt or ammonium salt) and the resultant R-SCN is thermally isomerized in the presence of a catalyst such as quaternary ammonium or phosphonium salt to provide isothiocyanic acid esters expressed by the formula R-NCS.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to a method for producing isothiocyanate esters, and more particularly, isothiocyanate esters useful as raw materials for the synthesis of various chemical products, including medicines and agrochemicals, can be obtained easily and in high yield. This provides a new manufacturing method.

0002

BACKGROUND OF THE INVENTION There have been several reports on methods for synthesizing isothiocyanate esters. For example, (1) a method using a metal thiocyanate and a halogen compound (J.
Am. Chem. Soc. 59, 2012 (1937)
, JP-A-1-172371, JP-A-2-221255) NaSCN (or KSCN)+RX→RNCS+N
aX (or KX)…………………………(Formula 1) (2
) Method for decomposing dithiocarbamates in the presence of heavy metal salts (Ber. 1, 170 (1868), Org. Syn
th. , I, 447 (1941)) RNH-C (=
S)-SNa +Pb(NO3)2+NaOH→[RS
CN]→RNCS+PbS+2NaNO3…(Formula 2)
(3) Method of reacting dithiocarbamate and chloroformate (Org.Synth., III, 599
(1955)) RNH-C(=S)-SNa +C
l-C(=O)-OC2H5→RNCS+NaCl+C
2H5OH+COS......(Formula 3) (4) Method of reacting primary amine and thiophosgene (Acta, Chem
．． Scand. , 11 1298 (1957), J. A
m. Chem. Soc. 54,781 (1962)) R-NH2 +CSCl2 →RNCS+2HCl
………………………………………………(Formula 4) (5)
Method of reacting dithiocarbamic acid and cyanamide (JP-A-56-172371) RNH-C-(=S)-SH +NH2CN →R
NCS+(NH2)2CS………………………………(
Equation 5) etc.

However, in these methods, (
Method 1) requires a large amount of aprotic polar solvent relative to the thiocyanate, and has drawbacks such as a low isomerization yield from thiocyanate to isothiocyanate. In method (2), heavy metal salts are used, which requires reliable treatment for recovering metals from waste liquid and preventing pollution, which is not industrially advantageous from an economic point of view. In (3),
There are several problems, such as the fact that chloroformate is relatively expensive, the COS produced by the reaction with it is toxic and requires safety precautions, and (4) requires the use of expensive and highly toxic thiophosgene. There are drawbacks. In (5),
Since cyanamide is hygroscopic, handling is complicated, and it is difficult to obtain as a high-grade industrial raw material. All of these methods have problems, and cannot be said to be industrially advantageous.

0004

[Problems to be Solved by the Invention] In view of the above circumstances, the present inventors have conducted intensive research on a method for producing isothiocyanate esters in order to solve the problems of the prior art. The present inventors have discovered an industrially advantageous method for producing isothiocyanate esters with high yield and high safety, and have completed the present invention.

[0005]

[Means for Solving the Problems] That is, the present invention provides a general formula [1] R-OH [1] (wherein R is an alkyl group in the range of C1 to C18, an aralkyl group, a cycloalkyl group, an alkenyl represents an alkyl group, an alkynyl group, or a heterocyclic ring.
X represents a halogen atom. ) to react with a halogenated sulfonyl compound represented by the general formula [3] R-OSO
General formula [4] R-SCN obtained by forming a sulfonic acid ester represented by 2R' [3] (in the formula, R and R' are the same as the above-mentioned groups) and then reacting it with a thiocyanate [4] General formula [5] R-NCS [5] (In the formula, R is the same as the above-mentioned group) characterized by isomerizing a thiocyanate ester represented by The gist of the present invention is a method for producing isothiocyanate esters represented by the above-mentioned groups. To explain the aspect of the present invention in more detail, the basic reaction to obtain the isothiocyanate ester is (Formula 6)
is expressed by That is, R-OH──→R-OSO2R'
──→R-SCN ──→R-NCS (Formula 6
) [1] [3]
[4] [5] (wherein, R is C1~
It represents an alkyl group, an aralkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, and a heterocycle in the range of C18, and R' represents an alkyl group or an aryl group. ), the alcohol represented by the general formula [1] is used as a starting material and reacted with a halogenated sulfonyl compound to form a sulfonic acid ester represented by the general formula [3] (J.O
rg. Chem. 37 1162 (1972), J.
．． Org. Chem. 35 3195 (1970)
, J. Amer. Chem. Soc. , 91 260
3 (1969)), the thiocyanate represented by the general formula [4] obtained by reacting with a thiocyanate in an organic solvent at a predetermined temperature for a predetermined time is reacted with a thiocyanate in the presence of a solvent using a catalyst. Alternatively, the isothiocyanate ester represented by the general formula [5] can be obtained in high yield by heat isomerization under predetermined conditions without a solvent.

The above general formula [1], general formula [2], general formula [3], general formula [4], general formula [5], and (formula 6)
Among R represented by R, examples of the alkyl group include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, lauryl group, hexadecyl group, Examples of substituted alkyl groups include stearyl groups, and examples of substituted alkyl groups include 2-
Methoxyethyl group, chloroethyl group, bromoethyl group,
Examples include 3-triethoxysilylpropyl group and 6-methylthiohexyl group. Examples of the aralkyl group include a benzyl group, a chloro group on a benzene ring, a methoxy group,
or a benzyl group substituted with a nitro group, a phenethyl group, etc., and examples of the cycloalkyl group include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group,
Examples include cycloheptyl group. Examples of alkenyl groups include allyl group, butenyl group, pentenyl group,
Examples of alkynyl groups include hexenyl groups,
Examples include propargyl group and butynyl group. Heterocycles may include saturated or unsaturated rings containing O, S and N atoms.

[0007] Among R' shown in the above general formula [2] and general formula [3], examples of the alkyl group include a methyl group and an ethyl group, and examples of the aryl group include a phenyl group. , tolyl group, methoxyphenyl group, naphthyl group, etc.

[0008] The thiocyanate used in the present invention includes sodium thiocyanate, potassium thiocyanate,
Examples include ammonium thiocyanate. The appropriate amount to be used is 1.0 to 2.0 mol, preferably 1.0 to 1.3 mol, based on the raw material. In the isomerization step to the desired isothiocyanate ester, it is desirable to use a catalyst, for example, halides such as sodium iodide, potassium iodide, calcium iodide, sodium bromide, calcium chloride, calcium sulfate, magnesium chloride. Inorganic catalysts such as alkali metal or alkaline earth metal salts are known (JP-A-49-88878,
JP-A-61-143353, JP-A-1-172371
, Japanese Patent Publication No. 2-221255). The present inventors newly
As a result of careful investigation of this isomerization catalyst, for example, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide, Quaternary ammonium salts such as tetrabutylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, tetramethylphosphonium chloride, tetramethylphosphonium bromide, tetramethylphosphonium iodide, tetraethylphosphonium chloride, tetraethylphosphonium bromide, It has been found that phosphonium salts such as tetraethylphosphonium iodide, tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, and tetrabutylphosphonium iodide have extremely excellent reaction-promoting effects. The amount of these catalyst substances used is 0.05 mol or more, preferably 0.1 to 1.0 mol, relative to the compound represented by general formula [3] or general formula [4].

In the present invention, the isomerization of the thiocyanate ester represented by the general formula [4] by heating to obtain the isothiocyanate ester represented by the general formula [5] may be carried out without a solvent, or if a solvent is used, , general formula [1], general formula [
2], general formula [3], and general formula [4] and can be reacted with each other, such as alcoholic solvents such as methanol and ethanol, methyl acetate, and ethyl acetate. esters such as ethyl ether, tetrahydrofuran, ethers such as dioxane, acetonitrile, dimethylformamide,
Dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, sulfolane, 1,3-dimethyl-2-
Particularly preferred are aprotic polar solvents such as imidazolidinone.

[0010] The temperature useful for the reaction of the present invention can be appropriately selected so as to obtain the best production rate of isothiocyanate ester, and is suitably 20°C to 250°C, preferably 50°C to 170°C. . The purpose of the present invention is to provide an industrially advantageous method for producing isothiocyanate esters, as represented by the following formula (7). That is, the first characteristic is that an alcohol represented by the general formula [1] is used as a starting material, and a halogenated sulfonyl compound is reacted to form a sulfonic acid ester represented by the general formula [3], which is then isolated. A highly economical method for obtaining a thiocyanate ester represented by the general formula [4] in a high yield by reacting the thiocyanate with a thiocyanate without any This is a new production method that effectively combines an economical method of isomerizing isomerization in an aprotic solvent in the presence of a catalyst such as a grade ammonium salt or phosphonium salt to obtain isothiocyanate ester easily and in high yield. . ROH +R'-SO2X →ROSO2R'
+ M+ SNC − →RSCN→RNCS
(Formula 7) [1] [2] [3]
[4] [5] (In the formula, R and R' are the same as the groups described above. M represents an alkali metal element and unsubstituted ammonium.)

[0011]

[Effect of the invention] Conventional methods for producing isothiocyanate esters generally involve the reaction of dithiocarbamates with ethyl chloroformate, or the decomposition of dithiocarbamates in the presence of heavy metal salts, but the former is toxic. Because COS is generated, for safety reasons, such as absorbing it in alkaline solution, etc.
There are manufacturing and economical problems, such as the need for sufficient management and, in the latter case, the need for reliable treatment to recover metals from waste liquid and prevent pollution. or,
The method using cyanamide has many industrial problems, such as cyanamide being extremely hygroscopic and difficult to handle, and difficult to obtain as a high-grade industrial raw material. On the other hand, the present invention converts the alcohol represented by the general formula [1], which is an inexpensive starting material, into the corresponding sulfonic acid ester represented by the general formula [3], and then converts the alcohol into a thiocyanate without isolating it. By reacting with an acid salt, the general formula [4
] is obtained, and further isomerized in an aprotic polar solvent in the presence of a quaternary ammonium salt or a phosphonium salt as a preferred catalyst,
This is an innovative and highly economical manufacturing method that allows the desired isothiocyanate ester represented by the general formula [5] to be obtained easily and in high yield. EXAMPLES Hereinafter, Examples will be shown to explain the present invention in more detail, but these Examples are not intended to limit the present invention.

0012

[Example] [Example 1. ] Synthesis of n-propyl isothiocyanate (compound No. 1) P-toluenesulfonic acid n-propyl ester 75.2
g, KSCN 42.0 g, tetraethylammonium bromide 8.7 g, ethyl acetate 145 ml, water 3
0 ml and stirred at 80°C for 3 hours. After the reaction was completed, it was washed with water, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure. To 40.6 g of n-propyl thiocyanate, 8.4 g of tetraethylammonium bromide was added to give 1,3- After dissolving in 75 ml of dimethyl-2-imidazolidinone, it was stirred at 140-145°C for 2 hours. After the reaction was completed, the mixture was extracted with 250 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the oil obtained by distilling off the ethyl acetate under reduced pressure was distilled to a boiling point of 1.
Compound No. 51-152°C. 137.9g (yield 75%) was obtained.

[Example 2. ]isothiocyanic acid sec
-Synthesis of butyl (compound No. 2) Methanesulfonic acid sec-butyl ester 92.3g
, NaSCN 45.2g, sodium iodide 21
．． 0 g was added to 200 ml of ethyl acetate and 35 ml of water, and the mixture was stirred at 80°C for 2 hours. After the reaction was completed, the oil was washed with water, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure to obtain sec-butyl thiocyanate.
4g and 8.5g of tetraethyl borophonium bromide
was added, dissolved in 110 ml of N-methyl 2-pyrrolidone, and stirred at 140-145°C for 3 hours. After the reaction was completed, it was extracted with 380 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. 257.0g (yield 82%) was obtained.

[Example 3. ] Synthesis of 5-hexenyl isothiocyanate (compound No. 6) After dissolving 30.5 g of 5-hexen-1-ol and 34.0 g of triethylamine in 280 ml of ethyl acetate,
56.9g of P-toluenesulfonyl chloride at 5℃
It was added below and reacted at 20-25°C for 2 hours. After the reaction was completed, 120 ml of water was added, and then KSCN 29
g, tetraethylammonium chloride 5.0g
was added and stirred at 80°C for 3 hours. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure.To 40.0 g of 5-hexenyl thiocyanate, an oily product was added to 5.9 g of tetraethylammonium bromide. , after dissolving in 55 ml of 1,3-dimethyl-2-imidazolidinone, 140
Stirred at ˜145° C. for 2 hours. After the reaction was completed, it was extracted with 180 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure.
6 33.0g (yield 78%) was obtained.

[Example 4. ] Synthesis of benzyl isothiocyanate (compound No. 11) 43.2 g of benzyl alcohol was mixed with 34.8 g of pyridine.
After dissolving in the solution, 45.5 g of methanesulnyl chloride was added at 5°C or lower, and the mixture was reacted at 5 to 10°C for 2 hours. After the reaction is complete, extract with 150ml of ethyl acetate, then add 25ml of water.
was added, and further 30 g of NH4SCN and 8.5 g of tetraethylammonium bromide were added, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, it was washed with water, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure. To 53.7 g of benzyl thiocyanate, 7.5 g of tetraethylammonium bromide was added, and N,N,-dimethyl After dissolving in 75ml of acetamide, 140-145
Stirred at ℃ for 1.5 hours. After the reaction was completed, it was extracted with 250 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure to distill the resulting oil. 40.5 g (yield 68%) of 11 was obtained. Table 1 shows various isothiocyanate esters synthesized by the method of the present invention.

[0016]

[Table 1]

Claims (1)

[Claims] Claim 1: General formula [1] R-OH [1] (wherein R represents an alkyl group, an aralkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, or a heterocycle in the range of C1 to C18. ) is represented by the general formula [2] R'-SO2X [2] (wherein R' represents an alkyl group or an aryl group,
X represents a halogen atom. ) to react with a halogenated sulfonyl compound represented by the general formula [3] R-OSO
General formula [4] R-SCN obtained by forming a sulfonic acid ester represented by 2R' [3] (in the formula, R and R' are the same as the above-mentioned groups) and then reacting it with a thiocyanate [4] General formula [5] R-NCS [5] (In the formula, R is the same as the above-mentioned group) characterized by isomerizing a thiocyanate ester represented by A method for producing an isothiocyanate ester represented by the above-mentioned group.