JP2000351767A - Production of thioether and thiol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain in high yield a thioether or thiol which has been usable to be synthesized or has been synthesized only in low yield, by carrying out a condensation reaction in the presence of a boron-contg. reducing agent. SOLUTION: (D) The compound of the formula R1-SR2 [e.g. 2-(phenylethylthio) pyridine] is obtained by reaction between (A) a compound of the formula R1-X (R1 is an N atom-contg. aromatic heterocyclic group; X is an eliminable group) (e.g. 2-bromopyridine) and (B) a compound of the formula R2S-Y (R2 is a lower alkyl, aryl or aralkyl; Y is H or SR2) (e.g. benzeneethanethiol) in the presence of (C) a boron-contg. reducing agent (pref. a metal borohydride, Selectride(R), Super-Hydride(R) or the like, e.g. K-Selectride(R)). The other objective compound of the formula R1-SH is obtained by eliminating the R2 group from the component D obtained above.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel method for producing thioethers and thiols having excellent yield.

[0002]

2. Description of the Related Art It is known that thioethers and thiols can be synthesized by reacting with a mercapto derivative when a raw material having a strong electron-withdrawing group bonded to the ortho or para position of a halogen atom is used. (Thus, only products with strong electron withdrawing groups attached to the ortho or para position of the thio group can be synthesized) (Memoli, K. et al.
A. Tetrahedron Lett., 1996, 37, 3617 (see the figure below)
; "Halopyridines possessing strong electron withd
rawing groups at orth position were displaced by s
ulfur nucleophiles "Dunn, AD, Norrie, RJ Hete
rocyclic Chemistry, 1987, 24, 85; Bradsher, CK,
McDonald J. Org. Chem., 1962, 27, 4482) and other compounds could not be synthesized, or even if synthesized, the yield was very poor and there was no preferred production method.

[0003]

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[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted intensive studies on the production methods of thioethers and thiols for many years. The present inventors have found that by performing a condensation reaction in the presence of thioethers and thiols, which could not be conventionally synthesized, or which have a low yield, can be performed at a high yield, the present invention has been completed.

[0005]

The process for producing the novel thioethers of the present invention comprises a compound having the general formula R ¹ -X, wherein R ¹ is an aromatic heterocyclic group containing a nitrogen atom, X represents a leaving group) and the general formula R ² SY
Wherein R ² represents a lower alkyl group, an aryl group or an aralkyl group, and Y is a hydrogen atom or
Group (wherein, R ² is. Of the same significance as described above) having the general formula -SR ² shows a. With R in the presence of a boron-containing reducing agent to produce a compound having the general formula R ¹ -SR ² (wherein R ¹ and R ² are as defined above). Preferably, in the above, (1) R
Wherein ¹ is a 6-membered aromatic heterocyclic group containing a nitrogen atom,
(2) a method wherein R ² is an aralkyl group, and (3)
The method in which the boron-containing reducing agent is a metal borohydride, a selectride, or a superhydride may be mentioned, and the method for producing a novel thiol of the present invention is selected from the above. in any one, further prepared from compounds having the general formula R ¹ -SR ² (wherein, R ¹ and R ² are as defined above.), R ²
Removing the group (wherein R ² is as defined above);
This is a method for producing a compound having the general formula R ¹ -SH (wherein R ¹ has the same meaning as described above).

In the above, the "aromatic heterocyclic group containing a nitrogen atom" in the definition of R ¹ is an "aromatic heterocyclic group containing a nitrogen atom" which may have a substituent.
The "aromatic heterocyclic group containing a nitrogen atom" represents a 5- to 7-membered aromatic heterocyclic group containing a nitrogen atom, for example, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Examples include groups such as 2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and preferably "a 6-membered aromatic heterocyclic group containing a nitrogen atom". And more preferably a pyridyl group, a pyrazinyl group and a pyrimidinyl group.

The above "5- to 7-membered aromatic heterocyclic group"
May be condensed with another cyclic group, for example, benzimidazolyl, benzoxazolyl, indolizinyl,
Examples include groups such as isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, quinalidinyl, isoquinolyl, quinolyl.

The substituent is not particularly limited as long as it is not usually involved in the reaction, and is, for example, a “lower alkyl group” described below; for example, ethenyl, 1-propenyl, 2-propenyl, 1-methyl- 2-propenyl, 1
-Methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-
2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1- Ethyl-3-butenyl, 1-pentenyl,
2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-
3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-
4-pentenyl, 1-hexenyl, 2-hexenyl, 3
A straight-chain or branched-chain “alkenyl group” having 2 to 6 carbon atoms, such as -hexenyl, 4-hexenyl and 5-hexenyl; an “aryl group” described below; an “aralkyl group” described later; for example, methoxy, ethoxy, n -Propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy,
tert-butoxy, n-pentoxy, isopentoxy, 2
-Methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy,
-Methylpentoxy, 3,3-dimethylbutoxy, 2,
2-dimethylbutoxy, 1,1-dimethylbutoxy,
A "lower alkoxy group" in which a "lower alkyl group" described below such as 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy is bonded to an oxygen atom; for example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino,
Isobutylamino, s-butylamino, tert-butylamino, n-pentylamino, isopentylamino, 2-
Methylbutylamino, neopentylamino, 1-ethylpropylamino, n-hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3 -Dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino,
"Lower alkylamino" in which a "lower alkyl group" described below, such as 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino, or 2-ethylbutylamino, is bonded to an amino group. A "lower alkoxycarbonyl group" in which the above "lower alkoxy group" is bonded to a carbonyl group; a nitrile group; and a nitro group.

The "leaving group" in the definition of X is usually
There is no particular limitation as long as it is a group leaving as a nucleophilic residue,
Preferably, a halogen atom such as chlorine, bromine or iodine; a halogenated alkylcarbonyloxy group such as chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy or trifluoroacetyloxy, or a lower alkoxyalkyl such as methoxyacetyloxy. Aliphatic acyloxy group such as carbonyloxy group; trihalogenomethyloxy group such as trichloromethyloxy; lower alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy; such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy Halogeno lower alkanesulfonyloxy group; arylsulfonyl such as benzenesulfonyloxy, 4-toluenesulfonyloxy and 4-nitrobenzenesulfonyloxy It can be mentioned oxy group, more preferably a halogen atom, 4-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy group.

The "lower alkyl group" in the definition of R ² is a "lower alkyl group" which may have a substituent, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , S-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methyl Pentyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 2
A straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms such as -ethylbutyl, preferably a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. The substituent is not particularly limited as long as it does not normally participate in the reaction. For example, "alkenyl group";"carbamoylgroup";"lower alkoxy group";"lower alkylamino group"; Carbonyl group ";" nitrile group "and" halogen atom ".

An "aryl group" in the definition of R ² is
An "aryl group" which may have 1 to 4 substituents on the ring of the aryl group, for example, having 5 to 14 carbon atoms such as phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl; And a phenyl group is preferred. The “aryl group” may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof include a group such as 2-indanyl.

The substituent is not particularly limited as long as it does not normally participate in the reaction, and examples thereof include an unsubstituted "aryl group"; a nitro group; a carbamoyl group; methylcarbamoyl, ethylcarbamoyl, and n-propyl. Carbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl, tert-butylcarbamoyl, n-pentylcarbamoyl, isopentylcarbamoyl, 2-methylbutylcarbamoyl, neopentylcarbamoyl, n-hexylcarbamoyl, 4-methyl Pentyl carbamoyl,
3-methylpentylcarbamoyl, 2-methylpentylcarbamoyl, 3,3-dimethylbutylcarbamoyl,
2,2-dimethylbutylcarbamoyl, 1,1-dimethylbutylcarbamoyl, 1,2-dimethylbutylcarbamoyl, 1,3-dimethylbutylcarbamoyl, 2,3
1 carbon atom such as dimethylbutylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, di-n-propylcarbamoyl, diisopropylcarbamoyl, di-n-butylcarbamoyl, diisobutylcarbamoyl, di-s-butylcarbamoyl, di-tert-butylcarbamoyl A lower alkyl-substituted carbamoyl group substituted with from 6 to 6 linear or branched alkyl groups (preferably a carbamoyl group substituted with an alkyl group having 1 to 4 carbon atoms, more preferably a methylcarbamoyl or dimethylcarbamoyl group) A halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; the above "lower alkyl group"; methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-
Methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy , 2,3-
Lower alkoxy groups such as dimethylbutoxy; trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,
Halogeno lower alkyl groups such as 2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-dibromoethyl; and methylenedioxy, ethylene Examples thereof include an alkylenedioxy group having 1 to 4 carbon atoms such as dioxy and propylenedioxy, and preferably include a "lower alkyl group" and a "lower alkoxy group".

The “aralkyl group” in the definition of R ² is an “aralkyl group” which may have a substituent, and is a group in which the above “aryl group” is bonded to the above “lower alkyl group”, For example, benzyl, indenylmethyl, phenanthrenylmethyl, anthracenylmethyl,
α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, piperonyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1 -Phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl,
-Phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2
-Naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5
-Phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4
Unsubstituted aralkyls such as -phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl, 6-naphthylhexyl Groups; 2-fluorobenzyl, 3
-Fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3,5-difluorobenzyl, 2,5-
Difluorophenethyl, 2,6-difluorobenzyl,
2,4-difluorophenethyl, 3,5-dibromobenzyl, 2,5-dibromophenethyl, 2,6-dichlorobenzyl, 2,4-dichlorophenethyl, 2,3,6-
Trifluorobenzyl, 2,3,4-trifluorophenethyl, 3,4,5-trifluorobenzyl, 2,5
6-trifluorophenethyl, 2,4,6-trifluorobenzyl, 2,3,6-tribromophenethyl, 2,
3,4-tribromobenzyl, 3,4,5-tribromophenethyl, 2,5,6-trichlorobenzyl, 2,
4,6-trichlorophenethyl, 1-fluoro-2-naphthylmethyl, 2-fluoro-1-naphthylethyl, 3
-Fluoro-1-naphthylmethyl, 1-chloro-2-naphthylethyl, 2-chloro-1-naphthylmethyl, 3-
Bromo-1-naphthylethyl, 3,8-difluoro-1
-Naphthylmethyl, 2,3-difluoro-1-naphthylethyl, 4,8-difluoro-1-naphthylmethyl,
5,6-difluoro-1-naphthylethyl, 3,8-dichloro-1-naphthylmethyl, 2,3-dichloro-1-
Naphthylethyl, 4,8-dibromo-1-naphthylmethyl, 5,6-dibromo-1-naphthylethyl, 2,3
6-trifluoro-1-naphthylmethyl, 2,3,4-
Trifluoro-1-naphthylethyl, 3,4,5-trifluoro-1-naphthylmethyl, 4,5,6-trifluoro-1-naphthylethyl, 2,4,8-trifluoro-1-naphthylmethyl, Bis (2-fluorophenyl)
Methyl, 3-fluorophenylphenylmethyl, bis (4-fluorophenyl) methyl, 4-fluorophenylphenylmethyl, bis (2-chlorophenyl) methyl, bis (3-chlorophenyl) methyl, bis (4-chlorophenyl) methyl, -Chlorophenylphenylmethyl, 2-bromophenylphenylmethyl, 3-bromophenylphenylmethyl, bis (4-bromophenyl)
Methyl, bis (3,5-difluorophenyl) methyl,
Bis (2,5-difluorophenyl) methyl, bis (2,6-difluorophenyl) methyl, 2,4-difluorophenylphenylmethyl, bis (3,5-dibromophenyl) methyl, 2,5-dibromophenylphenylmethyl , 2,6-dichlorophenylphenylmethyl,
Bis (2,4-dichlorophenyl) methyl, bis (2
Aralkyl groups substituted by halogen atoms such as 3,6-trifluorophenyl) methyl; 2-trifluoromethylbenzyl, 3-trifluoromethylphenethyl,
-Trifluoromethylbenzyl, 2-trichloromethylphenethyl, 3-dichloromethylbenzyl, 4-trichloromethylphenethyl, 2-tribromomethylbenzyl, 3-dibromomethylphenethyl, 4-dibromomethylbenzyl, 3,5-bistrifluoromethyl Phenethyl, 2,5-bistrifluoromethylbenzyl, 2,6
-Bistrifluoromethylphenethyl, 2,4-bistrifluoromethylbenzyl, 3,5-bistribromomethylphenethyl, 2,5-bisdibromomethylbenzyl, 2,6-bisdichloromethylmethylphenethyl,
2,4-bisdichloromethylbenzyl, 2,3,6-tristrifluoromethylphenethyl, 2,3,4-tristrifluoromethylbenzyl, 3,4,5-tristrifluoromethylphenethyl, 2,5,6 -Tristrifluoromethylbenzyl, 2,4,6-tristrifluoromethylphenethyl, 2,3,6-tristribromobromobenzyl, 2,3,4-trisdibromomethylphenethyl, 3,4,5-tristri Bromomethylbenzyl, 2,5,6-trisdichloromethylmethylphenethyl, 2,4,6-trisdichloromethylbenzyl, 1-
Trifluoromethyl-2-naphthylethyl, 2-trifluoromethyl-1-naphthylmethyl, 3-trifluoromethyl-1-naphthylethyl, 1-trichloromethyl-
2-naphthylmethyl, 2-dichloromethyl-1-naphthylethyl, 3-tribromomethyl-1-naphthylmethyl, 3,8-bistrifluoromethyl-1-naphthylethyl, 2,3-bistrifluoromethyl-1-naphthyl Methyl, 4,8-bistrifluoromethyl-1-naphthylethyl, 5,6-bistrifluoromethyl-1-naphthylmethyl, 3,8-bistrichloromethyl-1-naphthylethyl, 2,3-bisdichloromethyl-1 -Naphthylmethyl, 4,8-bisdibromomethyl-1-naphthylethyl, 5,6-bistribromomethyl-1-naphthylmethyl, 2,3,6-tristrifluoromethyl-1-
Naphthylethyl, 2,3,4-tristrifluoromethyl-1-naphthylmethyl, 3,4,5-tristrifluoromethyl-1-naphthylethyl, 4,5,6-tristrifluoromethyl-1-naphthylmethyl , 2,4,8
-Tristrifluoromethyl-1-naphthylmethyl, bis (4-trifluoromethylphenyl) methyl, 4-trifluoromethylphenylphenylmethyl, bis (2-
Trichloromethylphenyl) methyl, bis (3-trichloromethylphenyl) methyl, bis (4-trichloromethylphenyl) methyl, 2-tribromomethylphenylphenylmethyl, 3-tribromomethylphenylphenylmethyl, bis (4-tribromo Methylphenyl) methyl, bis (3,5-bistrifluoromethylphenyl)
Methyl, bis (2,5-bistrifluoromethylphenyl) methyl, bis (2,6-bistrifluoromethylphenyl) methyl, 2,4-bistrifluoromethylphenylphenylmethyl, bis (3,5-bistrifluorobromophenyl) Methyl, 2,5-bistribromomethylphenylphenylmethyl, 2,6-bistrichloromethylphenylphenylmethyl, bis (2,4-bistrichloromethylphenyl) methyl, bis (2,3,6-tristrifluoromethylphenyl) ) Aralkyl groups substituted with halogeno lower alkyl groups such as methyl; 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methylphenethyl, 4-methylphenethyl,
-Ethylbenzyl, 3-propylphenethyl, 4-ethylbenzyl, 2-butylphenethyl, 3-pentylbenzyl, 4-pentylphenethyl, 3,5-dimethylbenzyl, 2,5-dimethylphenethyl, 2,6-dimethylbenzyl, 2,4-dimethylphenethyl, 3,5-dibutylbenzyl, 2,5-dipentylphenethyl, 2,6
-Dipropylbenzyl, 2,4-dipropylphenethyl, 2,3,6-trimethylbenzyl, 2,3,4-trimethylphenethyl, 3,4,5-trimethylbenzyl, 2,4,6-trimethylbenzyl, , 5,6-trimethylphenethyl, 2,3,6-tributylphenethyl, 2,3,4-tripentylbenzyl, 3,4,5-
Tributylphenethyl, 2,5,6-tripropylbenzyl, 2,4,6-tripropylphenethyl, 1-methyl-2-naphthylmethyl, 2-methyl-1-naphthylethyl, 3-methyl-1-naphthylmethyl, 1-ethyl-
2-naphthylethyl, 2-propyl-1-naphthylmethyl, 3-butyl-1-naphthylethyl, 3,8-dimethyl-1-naphthylmethyl, 2,3-dimethyl-1-naphthylethyl, 4,8-dimethyl -1-naphthylmethyl,
5,6-dimethyl-1-naphthylethyl, 3,8-diethyl-1-naphthylmethyl, 2,3-dipropyl-1-
Naphthylmethyl, 4,8-dipentyl-1-naphthylethyl, 5,6-dibutyl-1-naphthylmethyl, 2,
3,6-trimethyl-1-naphthylmethyl, 2,3,4
-Trimethyl-1-naphthylethyl, 3,4,5-trimethyl-1-naphthylmethyl, 4,5,6-trimethyl-1-naphthylmethyl, 2,4,8-trimethyl-1-
Naphthylmethyl, bis (2-methylphenyl) methyl,
3-methylphenylphenylmethyl, bis (4-methylphenyl) methyl, 4-methylphenylphenylmethyl, bis (2-ethylphenyl) methyl, bis (3-ethylphenyl) methyl, bis (4-ethylphenyl) methyl, 2-propylphenylphenylmethyl, 3-propylphenylphenylmethyl, bis (4-propylphenyl) methyl, bis (3,5-dimethylphenyl) methyl, bis (2,5-dimethylphenyl) methyl, bis (2,6 -Dimethylphenyl) methyl, 2,4-dimethylphenylphenylmethyl, bis (3,5-dipropylphenyl) methyl, 2,5-dipropylphenylphenylmethyl, 2,6-diethylphenylphenylmethyl,
Bis (2,4-diethylphenyl) methyl, bis (2
An aralkyl group substituted with a lower alkyl group such as 3,6-trimethylphenyl) methyl; 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl,
-Methoxyphenethyl, 2-ethoxyphenethyl, 3-
Propoxybenzyl, 4-ethoxyphenethyl, 2-butoxybenzyl, 3-pentoxyphenethyl, 4-pentoxybenzyl, 3,5-dimethoxyphenethyl, 2,
5-dimethoxybenzyl, 2,6-dimethoxyphenethyl, 2,4-dimethoxybenzyl, 3,5-dibutoxyphenethyl, 2,5-dipentoxybenzyl, 2,6-
Dipropoxyphenethyl, 2,4-dipropoxybenzyl, 2,3,6-trimethoxyphenethyl, 2,3,4
-Trimethoxybenzyl, 3,4,5-trimethoxyphenethyl, 2,5,6-trimethoxybenzyl, 2,
4,6-trimethoxyphenethyl, 2,3,6-tributoxybenzyl, 2,3,4-tripentoxyphenethyl, 3,4,5-tributoxybenzyl, 2,5,6-
Tripropoxyphenethyl, 2,4,6-tripropoxybenzyl, 1-methoxy-2-naphthylmethyl, 2-
Methoxy-1-naphthylmethyl, 3-methoxy-1-naphthylethyl, 1-ethoxy-2-naphthylmethyl, 2
-Propoxy-1-naphthylmethyl, 3-butoxy-1
-Naphthylethyl, 3,8-dimethoxy-1-naphthylmethyl, 2,3-dimethoxy-1-naphthylmethyl,
4,8-dimethoxy-1-naphthylethyl, 5,6-dimethoxy-1-naphthylmethyl, 3,8-diethoxy-
1-naphthylmethyl, 2,3-dipropoxy-1-naphthylethyl, 4,8-dipentoxy-1-naphthylmethyl, 5,6-dibutoxy-1-naphthylmethyl, 2,
3,6-trimethoxy-1-naphthylethyl, 2,3
4-trimethoxy-1-naphthylmethyl, 3,4,5-
Trimethoxy-1-naphthylmethyl, 4,5,6-trimethoxy-1-naphthylethyl, 2,4,8-trimethoxy-1-naphthylmethyl, bis (2-methoxyphenyl) methyl, 3-methoxyphenylphenylmethyl, bis (4-methoxyphenyl) methyl, 4-methoxyphenylphenylmethyl, bis (2-ethoxyphenyl) methyl, bis (3-ethoxyphenyl) methyl, bis (4
-Ethoxyphenyl) methyl, 2-propoxyphenylphenylmethyl, 3-propoxyphenylphenylmethyl, bis (4-propoxyphenyl) methyl, bis (3,5-dimethoxyphenyl) methyl, bis (2,5
-Dimethoxyphenyl) methyl, bis (2,6-dimethoxyphenyl) methyl, 2,4-dimethoxyphenylphenylmethyl, bis (3,5-dipropoxyphenyl)
Methyl, 2,5-dipropoxyphenylphenylmethyl, 2,6-diethoxyphenylphenylmethyl, bis (2,4-diethoxyphenyl) methyl, bis (2
An aralkyl group substituted with a lower alkoxy group such as 3,6-trimethoxyphenyl) methyl; 2-nitrophenethyl, 3-nitrobenzyl, 4-nitrobenzyl,
-Nitrophenethyl, 3,5-dinitrobenzyl, 2,
5-dinitrophenethyl, 2,6-dinitrobenzyl,
2,4-dinitrophenethyl, 2,3,6-trinitrobenzyl, 2,3,4-trinitrophenethyl, 3,
4,5-trinitrobenzyl, 2,5,6-trinitrophenethyl, 2,4,6-trinitrobenzyl, 1-nitro-2-naphthylmethyl, 2-nitro-1-naphthylethyl, 3-nitro- 1-naphthylmethyl, 3,8-dinitro-1-naphthylmethyl, 2,3-dinitro-1-
Naphthylethyl, 4,8-dinitro-1-naphthylmethyl, 5,6-dinitro-1-naphthylmethyl, 2,3
6-trinitro-1-naphthylethyl, 2,3,4-trinitro-1-naphthylmethyl, 3,4,5-trinitro-1-naphthylmethyl, 4,5,6-trinitro-1
-Naphthylethyl, 2,4,8-trinitro-1-naphthylmethyl, bis (2-nitrophenyl) methyl, 3-nitrophenylphenylmethyl, bis (4-nitrophenyl) methyl, 4-nitrophenylphenylmethyl, bis (3,5-dinitrophenyl) methyl, bis (2,5-
An aralkyl group substituted with a nitro group such as dinitrophenyl) methyl, bis (2,6-dinitrophenyl) methyl, 2,4-dinitrophenylphenylmethyl, bis (2,3,6-trinitrophenyl) methyl; 2-carbamoylbenzyl, 3-carbamoylphenethyl, 4-
Carbamoylbenzyl, 3,5-dicarbamoylphenethyl, 2,5-dicarbamoylbenzyl, 2,6-dicarbamoylphenethyl, 2,4-dicarbamoylbenzyl, bis (2-carbamoylphenyl) methyl, 3-carbamoylphenylphenylmethyl , Bis (4-carbamoylphenyl) methyl, 4-carbamoylphenylphenylmethyl, bis (3,5-dicarbamoylphenyl) methyl, bis (2,5-dicarbamoylphenyl)
Methyl, bis (2,6-dicarbamoylphenyl) methyl, 2,4-dicarbamoylphenylphenylmethyl,
An aralkyl group substituted with a carbamoyl group such as bis (2,3,6-tricarbamoylphenyl) methyl and 3,4-methylenedioxybenzyl, 3,4-methylenedioxyphenethyl, bis (3,4-methylene Examples thereof include an aralkyl group substituted with an alkylenedioxy group such as dioxyphenyl) methyl and 3,4-methylenedioxyphenylphenylmethyl, and preferably an "unsubstituted aralkyl group" or "lower alkoxy group". An aralkyl group substituted with a nitro group and an aralkyl group substituted with a nitro group, more preferably a benzyl group, a phenethyl group, a 4-methoxybenzyl group, and a 4-nitrobenzyl group. Group ".

The "boron-containing reducing agent" is not particularly limited as long as it is a borohydride compound used in ordinary reduction, but is preferably a compound such as sodium borohydride or potassium borohydride. Metal borohydride, potassium tri-secondary butyl borohydride (K-selectride), lithium tri-secondary butyl borohydride (L
-Selectrides), selectides such as potassium trisiamylborohydride (KS-selectride), lithium trithiamylborohydride (LS-selectride), and hydrogen such as lithium triethylborohydride (superhydrides) Metal trialkylborides.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The method for producing novel thioethers and thiols according to the present invention can be carried out by the methods described below.

That is, the process for producing the novel thioethers of the present invention produces thioethers having the general formula R ¹ -SR ² (wherein R ¹ and R ² have the same meanings as described above). to compound having the general formula R ¹ -X (in the formula, R ¹
And X have the same meaning as described above. ) And the general formula R ² S-
A compound having Y (wherein R ² and Y have the same meanings as described above) is mixed with a solvent (a solvent that does not inhibit the reaction and dissolves the starting material to some extent). If not particularly limited, preferably, hexane, heptane,
Aliphatic hydrocarbons such as ligroin and petroleum ether;
Aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n- Propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol,
Alcohols such as methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; and amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide. ) In the presence of a boron-containing reducing agent at -50 ° C to 100 ° C (preferably -10 ° C to 40 ° C) for 1 hour to 24 hours (preferably 2 hours to 10 hours); By reacting.

In the post-treatment, for example, the reaction is stopped with a 1N aqueous solution of sodium hydroxide, and if insolubles are present, they are removed by filtration, and then a water-immiscible organic solvent such as ethyl acetate is added. In addition, after washing with water, the organic layer containing the target compound is separated and dried over anhydrous magnesium sulfate, etc.
It is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

On the other hand, the novel method for producing thiols of the present invention relates to a thiol having the general formula R ¹ -SH (wherein
R ¹ has the same meaning as described above. ) To produce a compound having the general formula R ¹ -SR ² , wherein R
¹ and R ² are as defined above. ), A conventional method (for example, removal of a benzyl group is effected by reacting hydrogen fluoride in anisole or 90% hydrogen fluoride in 5% cresol or 5% thiocresol at 25 ° C. for 1 hour). The benzyl group can be removed by reacting mercury acetate in trifluoroacetic acid at 0 ° C. for 10 to 30 minutes, or mercury trifluoroacetate in aqueous acetic acid at 20 ° C. for 2 to 3 hours, and then hydrogen sulfide or 2-hydrogen. Acting with mercaptoethanol, mercury trifluoroacetate in trifluoroacetic acid and anisole, refluxing in trifluoroacetic acid, or anhydrous hydrogen fluoride in anisole at 25 ° C. for 1 hour By removing the R ² group (wherein R ² has the same meaning as described above).

Hereinafter, the present invention will be described more specifically with reference to examples.

[0020]

Example 1 2- (phenylethylthio) pyridine
Preparation of (1) 2-bromopyridine (175 mg, 1.11 mmol)
And benzeneethanethiol (300 mg, 2.12 m
mol) in 1,2-dimethoxyethane (4 ml)
At 0 ° C., K-selectride (1 N tetrahydrofuran solution, 3.5 ml) was added, and the mixture was heated to room temperature.
Stir at the same temperature for 3 hours. After terminating the reaction with a 1N aqueous sodium hydroxide solution, the mixture was extracted with ethyl acetate. After separating the ethyl acetate layer, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Concentrate under reduced pressure,
The residue was purified by PTLC (hexane / ethyl acetate = 9/1) to give 122 mg of the title compound (1).
(51%). ¹ H-NMR (CDCl ₃ ) δ ppm 3.01 (t, 2H, J = 8.0 Hz), 3.42
(T, 2H, J = 8.0 Hz), 6.94-6.98
(M, 1H), 7.41-7.37 (m, 6H), 7.
42-7.53 (m, 1H), 8.43-8.45
(M, 1H), HRMS (m / z) Observed: 215.0767 Calculated: 215.0699 (as C ₁₃ H ₁₃ NS, M ⁺ )

[0021]

Example 2 3- (phenylethylthio) pyridine
Production of (2) In the same manner as in the synthesis method of (1), 3-bromopyridine was used instead of 2-bromopyridine to obtain the title compound (2) (58%). ¹ H-NMR (CDCl ₃ ) δ ppm 2.92 (t, 2H, J = 8.2 Hz), 3.17
(T, 2H, J = 8.2 Hz), 7.13-7.32
(M, 6H), 7.60-7.66 (m, 1H), 8.
42 (dd, 1H, J = 4.8 & 1.2 Hz),
8.58 (d, 1H, J = 2.3 Hz). HRMS (m / z) Obtained: 215.0771 Calculated: 215.0699 (as C ₁₃ H ₁₃ NS, M ⁺ )

[0022]

Example 3 4- (phenylethylthio) pyridine
Production of (3) In the same manner as in the synthesis method of (1), 4-bromopyridine was used instead of 2-bromopyridine to obtain the title compound (3) (69%). ¹ H-NMR (CDCl ₃ ) δ ppm 2.99 (t, 2H, J = 8.2 Hz), 3.21
(T, 2H, J = 8.2 Hz), 7.10 (dd, 2
H, J = 4.8 & 1.7 Hz), 7.21-7.2.
7 (m, 3H), 7.30-7.35 (m, 2H),
8.38 (dd, 2H, J = 4.8 & 1.7H
z). HRMS (m / z) Found: 215.0763 _{Calculated: 215.0769 (C 13 H 13 NS} , as M ⁺⁾

[0023]

Example 4 2- (phenylethylthio) pyrazine
Production of (4) In the same manner as in the synthesis method of (1), 2-bromopyrazine was used instead of 2-bromopyridine to obtain the title compound (4) (41%). ¹ H-NMR (CDCl ₃ ) δ ppm 3.01 (t, 2H, J = 8.0 Hz), 3.43
(T, 2H, J = 8.0 Hz), 7.20-7.36
(M, 5H), 8.19 (d, 1H, J = 1.5H
z), 8.39 (dd, 1H, J = 2.7 & 1.5
Hz), 8.43 (d, 1H, J = 1.5 Hz). HRMS (m / z) Found: 216.0707 _{Calculated: 216.0722 (C 12 H 12 N} 2 S, as M ⁺⁾

[0024]

Example 5 2- (phenylethylthio) pyrimidine
Production of (5) In the same manner as in the synthesis method of (1), 2-bromopyrimidine was used instead of 2-bromopyridine to obtain the title compound (5) (59%). ¹ H-NMR (CDCl ₃ ) δ ppm 3.02-3.08 (m, 2H), 3.36-3.42
(M, 2H), 6.94 (dd, 1H, J = 4.8H)
z), 7.20-7.34 (m, 5H), 8.50-
8.53 (m, 2H). HRMS (m / z) Found: 216.0716 _{Calculated: 216.0722 (C 12 H 12 N} 2 S, as M ⁺⁾

[0025]

Example 6 5- (phenylethylthio) pyrimidine
Production of (6) In the same manner as in the synthesis method of (1), 5-bromopyrimidine was used instead of 2-bromopyridine to obtain the title compound (6) (10%). ¹ H-NMR (CDCl ₃ ) δ ppm 2.95 (t, 2H, J = 8.0 Hz), 3.19−
3.25 (m, 2H), 7.17-7.35 (m, 5
H), 8.66 (s, 2H), 9.02 (s, 1H). HRMS (m / z) Found: 216.0741 _{Calculated: 216.0721 (C 12 H 12 N} 2 S, as M ⁺⁾

[0026]

Example 7 4- (phenylethylthio) quinaridine
Production of (7) The title compound (7) (30%) was obtained in the same manner as in the synthesis method of (1), except that 4-bromoquinalidine was used instead of 2-bromopyridine. ¹ H-NMR (CDCl ₃ ) δ ppm 3.09 (t, 2H, J = 8.2 Hz), 3.35
(T, 2H, J = 8.2 Hz), 7.07 (s, 1
H), 7.24-7.29 (m, 3H), 7.30-
7.37 (m, 2H), 7.48 (ddd, 1H, J =
8.4, 6.9 & 1.2 Hz), 7.67 (dd
d, 1H, J = 8.4, 6.9 & 1.2 Hz),
7.99 (d, 1H, J = 8.4 Hz), 8.08 (d
d, 1H, J = 8.4 & 1.2 Hz). HRMS (m / z) Found: 279.1085 Calculated: 279.1082 (as C ₁₈ H ₁₇ NS, M ⁺ )

[0027]

Example 8 Preparation of (2-benzylthio) pyridine (8)
Concrete dibenzyl disulfide (260mg, 1.1mmo
l) and 2-bromopyridine (171 mg, 1.1 mm)
ol) in 1,2-dimethoxyethane solution (4 mL),
Under ice-cooling, a tetrahydrofuran solution of K-selectride (1 N, 2.5 mL) was added, and the temperature was immediately raised to room temperature. After stirring for 12 hours, the reaction was stopped with a 1N aqueous solution of sodium hydroxide, and the product was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative silica gel thin-layer chromatography to obtain the title compound (159 mg, yield 75%). ¹ H-NMR (CDCl ₃ ) δ ppm 4.44 (s, 2H), 6.95-6.99 (m, 1
H), 7.15 (d, 1H, J = 8.1 Hz), 7.2
0-7.36 (m, 3H), 7.39-7.55 (m,
3H), 8.44-8.46 (m, 1H).

[0028]

Example 9 Preparation of 2-mercaptopyridine Using compound (8), hydrogen fluoride in anisole or 5% cresol or 5% thiocresol was used.
The benzyl group was removed by reacting with 0% hydrogen fluoride at 25 ° C. for 1 hour to obtain the title compound.

[0029]

As described above, the method of the present invention, that is, a method of performing a condensation reaction in the presence of a reducing agent containing boron,
Thus, the synthesis of thioethers and thiols, which could not be conventionally synthesized or the yield was low, can be performed in high yield.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Katsumi Fujimoto 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. F-term (reference) 4C031 HA01 4C055 AA01 BA01 BA02 BA47 BB01 BB02 CA01 CA02 CA47 CB01 CB02 DA01 DA47 DB01 DB02 FA13 FA31 FA37

Claims (5)

[Claims] ^1. A compound having the general formula R ¹ -X, wherein R ¹ is an aromatic heterocyclic group containing a nitrogen atom,
Represents a leaving group. ) And a compound having the general formula R ² S—Y wherein R ² represents a lower alkyl group, an aryl group or an aralkyl group;
It is a hydrogen atom or a group (wherein, R ² is. Of the same significance as described above) having the general formula -SR ² shows a. And
Reacting in the presence of a boron-containing reducing agent to form a compound having the general formula R ¹ -SR ² (wherein R ¹ and R
² has the same meaning as described above. A) manufacturing method. 2. The method according to claim 1, wherein R ¹ is a 6-membered aromatic heterocyclic group containing a nitrogen atom. 3. The method according to claim 1, wherein R ² is an aralkyl group. 4. The method according to claim 1, wherein the boron-containing reducing agent is a metal borohydride, a selectride, or a superhydride. 5. The compound according to any one of claims 1 to 4, further comprising a compound having the general formula R ¹ -SR ² wherein R ¹ and R ² are the same as defined above. from shows the significance.), R ² group (wherein, R ² is as defined above.) is removed and the general formula R ¹ a compound having a -SH (wherein, R ^1, the same The meaning is shown.)