WO2006043797A1 - Process for alkyl aryl sulfide derivatives and new sulfide compounds - Google Patents

Process for alkyl aryl sulfide derivatives and new sulfide compounds Download PDF

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WO2006043797A1
WO2006043797A1 PCT/KR2005/003528 KR2005003528W WO2006043797A1 WO 2006043797 A1 WO2006043797 A1 WO 2006043797A1 KR 2005003528 W KR2005003528 W KR 2005003528W WO 2006043797 A1 WO2006043797 A1 WO 2006043797A1
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PCT/KR2005/003528
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Heonjoong Kang
Jungyeob Ham
Jaeyoung Ko
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Heonjoong Kang
Jungyeob Ham
Jaeyoung Ko
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Priority to US11/577,747 priority Critical patent/US20090264660A1/en
Priority to JP2007537804A priority patent/JP2008517902A/en
Priority to EP05808625A priority patent/EP1812386A4/en
Priority claimed from KR1020050099926A external-priority patent/KR100723828B1/en
Publication of WO2006043797A1 publication Critical patent/WO2006043797A1/en

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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C323/09—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07C323/21—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with the sulfur atom of the thio group bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
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    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
    • C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
    • C07C323/36—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
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    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a process for preparing sulfide compounds from aryl halogen compounds having various electron- donating, electron-withdrawing or hydrogen-donating substituents via one-step reaction , and the sulfide derivatives prepared therefrom i o More specifically, the invention relates to a process for preparing various alkyl aryl sulfides represented by Formula (III) which have important roles in syntheses of organic chemistry and medicinal chemistry, via one-step reaction
  • Alkyl aryl sulfide compounds represented by Formula (III) have very wide utility spectrum in organic chemistry and medicinal chemistry Thus, a variety of processes for preparing such sulfide compounds have very wide utility spectrum in organic chemistry and medicinal chemistry. Thus, a variety of processes for preparing such sulfide compounds have
  • Form ula (10) in Reaction Scheme (3) is troublesome because a thiol compound (8) m ust be prepared according to the Scheme and then separated and purified before subseq uent reaction 5)
  • a thiol of Chemical Formula (13) is prepared from the compound of Chemical Formula (12) via reduction with LiAIH 4
  • this process also has problems in that a disulfide compound is readily formed, and LiAIH 4 employed in the reduction is unstable in the air to give trouble in the production in a large scale
  • an alkyl aryl sulfide of Chemical Formula (I I I) is obtained by substituting a halogen from an aryl halogen compound with alkyl lithium organometallic reagent when the compound of Chemical Formula (I) has an electron-donating or an electron-withdrawing substitue ⁇ t, and continuously reacting with the compound of Chemical Formula (II) and sulfur, or by reacting the aryl halogen compound of Chemical Formula (I) containing a hydrogen-donating substituent ⁇ -OH , -NH 2 , -NRH, - COOH) with an alkylmagnesium halide (Grignard reagent) to protect the hydrogen-donating substituent; substituting the halogen with alkyl lithium organometallic reagent, and continuously reacting with the compound of Chemical Formula (II) and sulfur, to complete the invention.
  • A represents CH or a nitrogen atom
  • Xi represents a halogen atom
  • X 2 represents a halogen atom or a leaving group
  • X 3 represents a halogen atom
  • Ri represents a hydrogen atom, a halogen atom, a Ci-C 7 alkyl group, a C1-C7 alkyloxy group, a C1-C7 alkylthiooxy group, an aryl group, a hydroxyl group, a hydroxymethyl group, a hydroxyethyl group, an amine group, an aminomethyl group, an aminoethyl group, an alkylamine group, a dialkylamine group or a carboxy group, wherein the alkyl group may be substituted by one or more substituent(s) selected from the group consisting of halogen atoms and a hydroxyl group,
  • R 2 represents a C1-C1 0 alkyl group, an aryl group, a C1-C10 alkylester group, a C 1 -C 10 alkylketone group or an arylketone group
  • R 3 and R 4 independently represents a C1-C4 alkyl group
  • n represents an integer of 1 to 3
  • the present invention provides a process for easily and economically preparing various alkyl aryl sulfide derivatives of Chemical
  • novel compounds are 2-(pent-2-ynylsulfanyl)-4-fluorophenol, 2-(5- phenylpentylsulfanyl)-4-fluorophenol, 2-(cyclohexylmethylsulfanyl)-4- fluorophenol, 4-((2-(1 ,3-d ⁇ oxolan-2-yl)ethylsulfanyl)phenol, 2-(2- hydroxyhex-5-enylsulfanyl)-4-fluorophenol, 4-((tert- butoxycarbonyl)methylsulfanyl)benzo ⁇ c acid, 3-(2-(1 ,3-d ⁇ oxolan-2- yl)ethylsulfanyl)benzo ⁇ c acid , 3-(2-hydroxyhex-5-enylsulfany I) benzoic acid, 2-(4-(benzyls
  • A represents CH or a i s nitrogen atom contained in the aryl compound having a resonance structure.
  • Xi represents a halogen atom.
  • the halogen atom mentioned can be a fluorine atom, chlorine atom, bromine atom, and iodine atom . Among them, a bromine atom or an iodine atom is 20 preferable.
  • X 2 means a leaving group.
  • a conventional leaving group specifically a halogen atom, a methansulfonyl oxy group, a p- toluenesulfonyloxy group may be employed.
  • the halogen atoms include a fluorine atom, a chlorine atom, a bromine atom and an iodine
  • a halogen atom is preferable, a chlorine atom, a bromine atom, or an iodine atom being more preferable
  • X 3 a halogen atom of G ⁇ gnard reagent represents a chlorine atom , a bromine atom or an iodine atom
  • Ri represents a hydrogen atom, a halogen atom, a C- 1 -C 7 alkyl r > group, a C1-C7 alkyloxy group, a C1-C7 alkylthiooxy group, an aryl group, a hydroxyl group, a hydroxymethyl group, a hydroxyethyl group, an amine group, an aminomethyl group, an aminoethyl group, an alkylamine group, a dialkylamine group or a carboxy group, where in the alkyl group may be substituted by one or more subst ⁇ tuent(s) selected
  • Each substituent Ri may have ortho-, meta- or para-position with respect to the halogen atom (Xi), and number of the subst ⁇ tuent(s) is from 1 to 3
  • R 2 represents a C1-C10 alkyl group, an aryl group, a C1-C10 I 1 J alkylester group, a C 1 -C 10 alkylketo ⁇ e group or an arylketone group
  • R 3 and R4 independently represent a C 1 -C 4 alkyl group, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl group
  • the compound of Chemical Formula (I) employed as raw material is well ZO known in the art and commercially available
  • alkyl aryl sulfide compound represented by Chemical Formula (II I) having (an) electron-donating or 2 ⁇ 5 electron-withdrawing subst ⁇ tuent(s)
  • An alkyl aryl sulfide compound represented by Chemical Formula (II I) is obtained by reacting a compound represented by Chemical Formula (I) with an alkyl lithium organometallic reagent and sulfur, and then with a compound represented by Chemical Formula (II) Dry solvent such as diethyl ether, tetrahydrofuran, hexane and heptane is used in this process either alone or in a mixture of the two or more Among them , diethylether, tetrahydrofuran , and a mixture of diethyl ether and tetrahydrofuran are the most preferable
  • alkyl lithium organometallic reagents employed in the halogen-metal substitution include n-butyl lithium, sec-butyl lithium, tert- butyl lithium, and the like
  • the amount of alkyl lithium organometallic reagent employed is usually from 1 to 3 equivalents with respect to the compound of Chemical Formula (I), most preferably from 1 to 1 2 equivalents in case of n-butyl lithi um or sec-butyl lithium, and from 2 to 2 2 equivalents in case of tert-butyl lithium
  • Sulfur used in this process is in a powdery state colored pale yellow, and the amou nt is usually from 1 to 3 equivalents, preferably from 1 to 1 2 equivalents with respect to the compound of Chemical Form ula (I )
  • the reaction temperature varies dependi ng upon the solvent employed , but usually is from -1 00 ° C to 25 T: Preferably the substitution of halogen with metal and introduction of sulfur are carried out at -75 ° C , and the reaction with compound of Chemical Formula (I I) at room temperature (25 ° C )
  • the reaction time varies depending on the reaction temperature and the type of solvent employed , but usually is from 30 minutes to 6 hours, preferably 1 hour or less.
  • a hydrogen-donating substituent -OH, -CH 2 OH, -CH 2 CH 2 OH, -NH 2 , -NRH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -COOH
  • diethyl ether, tetrahydrofuran, hexane or heptane may be used alone or in a combination of the two or more.
  • diethyl ether, tetrahydrofuran, or a mixture of diethyl ether and tetrahydrofuran are preferable.
  • the Grignard reagent which protects the hydrogen-donating substituent (-OH , -CH 2 OH, -CH 2 CH 2 OH, -NH 2 , -NRH, -CH 2 N H 2 , - CH 2 CH 2 NH 2 , -COOH), employed may be CH 3 MgCI, CH 3 MgBr, CH 3 MgI , CH 3 CH 2 MgCI, CH 3 CH 2 MgBr, CH 3 CH 2 MgI, CH 3 CH 2 CH 2 MgCI,
  • alkyl lithium organometallic reagents which can be employed in halogen-metal substitution reaction include n-butyl lithium, sec-butyl lithium , tert-butyl lithium, and the like
  • the amount of alkyl lithium 5 organometallic reagent employed is usually from 1 to 3 equivalents, more preferably from 1 to 1 2 equivalents in case of n-butyl lithium or sec-butyl lithium , from 2 to 2 2 eq uivalents in case of tert-butyl lithium
  • Sulfur used in this process is in a powdery state colored pale yellow, and the amount is usually from 1 to 3 equivalents, preferably i o from 1 to 1 2 equivalents with respect to the compound of Chemical Form ula (I)
  • reaction temperature varies depending upon the solvent em ployed , but usually is from -10CTC to 25 ° C
  • protection of the hyd rogen-donating substituent is carried out at 0 ° C to 25 ° C , the
  • reaction time varies depending on the reaction temperature and the type of solvent employed, but usually is from 30 minutes to 6 hours, preferably 2 hours or less
  • mesityl bromide 300 ⁇ l (2 mmol) was completely dissolved in dry tetrahydrofuran 15 ml under nitrogen atmosphere, and the mixture was cooled to -78 t: .
  • butyl lithium 1 .25 ml (1 .6M in hexane, 1 .0 equivalent) was slowly added for 1 minute.
  • sulfur powder 64 mg (2 mmol, 1.0 equivalent) was added at c> once at the same temperature.
  • phenacyl bromide 398 mg (2 mmol, 1 .0 equivalent) was slowly added.
  • alkyl aryl sulfide derivatives represented by Chemical Formula (III) can be prepared in a simple process with high yield.

Abstract

The present invention provide a process for preparing an alkyl aryl sulfide of Chemical Formula (I I I) characterized in that an aryl halogen compound of Chemical Formula (I) is substituted with an alkyl lithium organometallic reagent, and subseq uently reacted with a compound of Chemical Formula (I I ) , or an aryl halogen compound of Chemical Formula (I) is reacted with Grignard reagent to protect the hyd rogen-donating substituent, and then reacted with an alkyl lithium orga nometallic reagent, and subsequently with sulfur and a compound of Chemical Formula (I I) . According to the process of the invention , an alkyl aryl sulfide of C hemical Formula (I I I ) can be prepared via one-step reaction without separation or purif ication of an intermediate compound from various aryl halogen compounds in a short reaction time with high yield. Several compounds among those compounds represented by Chemical Formula (I I I) are novel compounds.

Description

PROCESS FOR ALKYL ARYL SULFIDE DERIVATIVES AND NEW SULFIDE COMPOUNDS
Field of the Invention 5
The present invention relates to a process for preparing sulfide compounds from aryl halogen compounds having various electron- donating, electron-withdrawing or hydrogen-donating substituents via one-step reaction , and the sulfide derivatives prepared therefrom i o More specifically, the invention relates to a process for preparing various alkyl aryl sulfides represented by Formula (III) which have important roles in syntheses of organic chemistry and medicinal chemistry, via one-step reaction
15 Background of the Related Art
Alkyl aryl sulfide compounds represented by Formula (III) have very wide utility spectrum in organic chemistry and medicinal chemistry Thus, a variety of processes for preparing such sulfide compounds have
20 been developed by many researchers Among the processes, a synthetic process wherein a compound of Formula (1 ) is reacted with an organic compound containing alkyl or arylthio alcohol and halogen in the presence of a strong base is the most generalized process (Synthesis 1972 101 , 1977, 357, Chemical Reviews 1978, 78, 363) As another
25 synthetic process, there is a carbon-sulfur bonding reaction using palladium (Pd) or copper (Cu) catalyst, as shown in Reaction Scheme (2) (J Am Chem Soc, 1995, 117, 11598, J Org Chem 1998, 63, 9606,
2001, 66, 8677, Aus J Chem. 1985, 38, 899, Org Lett. 2000, 2, 2019,
2002, 4, 2803). In addition, a synthetic process of a sulfide was patented as an important stage in synthesis of GW501516 which has been known as a therapeutic agent for hypertension and hypercholesterolemia, and cardiac disorders caused by such diseases, as shown in Reaction Scheme (3) and (4) (PCT Laid-open Publication WO 01/00603 A1). <Reactιon Scheme 1>
Figure imgf000003_0001
( 1 ) (2) (3)
<Reaction Scheme 2> ^--W-1 [Pd] or [Cu] ff"sVS~R
R M I "*" R SH ^ R~τj
(4) (5) (6)
<Reaction Scheme 3>
Figure imgf000004_0001
<Reaction Scheme 4>
Figure imgf000004_0002
In spite of having a lot of utilities, sulfide derivatives have following deficiencies in their process for preparation:
1 ) Thiophenol, in the process according to Reaction
Scheme (1 ), has very irritating odor, to cause difficulties in handling. It is unstable in the air and readily forms undesirable aryl disulfides (R-SS-R), having no various kinds commercially available but rather higher price compared to aryl halogen compounds
2) The process according to Reaction Scheme (2), though having a high yield (80% or more) of the final product, has severe reaction condition (10CTC or more), with long reaction time of 10 to 24 hours I n addition, because of using unstable thiol compound, it has same deficiencies as in Reaction Scheme (1 ) 3) According to the process of Reaction Scheme (3) , thiol of Chemical Formula (8) is obtained from the compound of Chemical Formula (7) via metallic reduction However, since the substance represented by Chemical Formula (8) readily forms a disulfide compound to cause problems in storage, it should be reacted with a halogen compound and an inorganic salt immediately after the synthesis In addition, the process has a limitation as a method to prepare various sulfides, because the position of -SH group introduced by a sulfonyl chloride is essentially para-position
4) The process for preparing a compound of Chemical
Form ula (10) in Reaction Scheme (3) is troublesome because a thiol compound (8) m ust be prepared according to the Scheme and then separated and purified before subseq uent reaction 5) According to the process of Reaction Scheme (4), a thiol of Chemical Formula (13) is prepared from the compound of Chemical Formula (12) via reduction with LiAIH4 However, this process also has problems in that a disulfide compound is readily formed, and LiAIH4 employed in the reduction is unstable in the air to give trouble in the production in a large scale
Thus, a method to rapidly prepare an alkyl aryl sulfide with simple and low-costed process has been required
Summary of the Invention
It is the object of the present invention to provide a process for preparing alkyl aryl sulfides of Chemical Formula (I I I) via one-step reaction without separation or purification of an intermediate compound, from low-priced and various aryl halogen compounds in a short reaction time with high yield
As considering the situation described above, the present inventors performed intensive studies on this matter and found that an alkyl aryl sulfide of Chemical Formula (I I I) is obtained by substituting a halogen from an aryl halogen compound with alkyl lithium organometallic reagent when the compound of Chemical Formula (I) has an electron-donating or an electron-withdrawing substitueπt, and continuously reacting with the compound of Chemical Formula (II) and sulfur, or by reacting the aryl halogen compound of Chemical Formula (I) containing a hydrogen-donating substituent {-OH , -NH2, -NRH, - COOH) with an alkylmagnesium halide (Grignard reagent) to protect the hydrogen-donating substituent; substituting the halogen with alkyl lithium organometallic reagent, and continuously reacting with the compound of Chemical Formula (II) and sulfur, to complete the invention.
[process A] R4L1 / S8 ^-
A^X1 5W* ( Il ) A^S^.R2
MξJ
( I ) [process S] R3MgX3 / R4Li / S8 ( III )
*2^R2 ( H )
wherein, A represents CH or a nitrogen atom, Xi represents a halogen atom, X2 represents a halogen atom or a leaving group,
X3 represents a halogen atom,
Ri represents a hydrogen atom, a halogen atom, a Ci-C7 alkyl group, a C1-C7 alkyloxy group, a C1-C7 alkylthiooxy group, an aryl group, a hydroxyl group, a hydroxymethyl group, a hydroxyethyl group, an amine group, an aminomethyl group, an aminoethyl group, an alkylamine group, a dialkylamine group or a carboxy group, wherein the alkyl group may be substituted by one or more substituent(s) selected from the group consisting of halogen atoms and a hydroxyl group,
R2 represents a C1-C10 alkyl group, an aryl group, a C1-C10 alkylester group, a C1-C10 alkylketone group or an arylketone group, R3 and R4 independently represents a C1-C4 alkyl group, and n represents an integer of 1 to 3
Thus, the present invention provides a process for easily and economically preparing various alkyl aryl sulfide derivatives of Chemical
Formula (I II) by reacting a compound of Chemical Formula (I) with a compound of Chemical Formula (I I) via Process (A) or (B) without any separation or purification stage
Among the compounds represented by Chemical Formula (I II) which is prepared via Process (A) or (B) in the Reaction Scheme, novel compounds are 2-(pent-2-ynylsulfanyl)-4-fluorophenol, 2-(5- phenylpentylsulfanyl)-4-fluorophenol, 2-(cyclohexylmethylsulfanyl)-4- fluorophenol, 4-((2-(1 ,3-dιoxolan-2-yl)ethylsulfanyl)phenol, 2-(2- hydroxyhex-5-enylsulfanyl)-4-fluorophenol, 4-((tert- butoxycarbonyl)methylsulfanyl)benzoιc acid, 3-(2-(1 ,3-dιoxolan-2- yl)ethylsulfanyl)benzoιc acid , 3-(2-hydroxyhex-5-enylsulfany I) benzoic acid, 2-(4-(benzylsulfanyl)phenyl)ethanol, 2-(3-
(benzylsulfaπyl)phenyl)ethanol, 1 -((4-
(hydroxymethyl)phenyl)sulfanyl)hex-5-en-2-ol, (4-(2-(1 ,3-dιoxolan-2- yl)ethylsulfanyl)phenyl)methanol, tert-butyl 2-((4-
(hydroxymethyl)phenyl)sulfanyl)acetate, (4-(pent-2- ynylsulfanyl)phenyl)methaπol, 4-(benzylthιo)-2-bromobenzenamιne, 4- (5-phenylpentylthιo)beπzenamιne, 1 -(4-amιnopentylthιo)hex-5-en-2-ol, 2-[4-(benzylthιo)phenyl]ethanamιne, tert-butyl 2-[4-(2- amιnoethyl)phenylthιo]-2-methylpropιonate, benzyl 2- tπfluoromethylphenyl sulfide, benzyl 2-methoxyphenylsulfιde, 2-bromo- 6-(2-[1 3]dιoxolan-2-yl-ethylsulfanyl)pyrιdιne, 5-[4-(tert- bu ty Id imethylsilany loxy)-3-methy I phenyls ulf any l]-4-methy l-2-[(4- trifluoromethyl)phenyl]thiazol, 4-benzylsulfanyl-2-methyl-phenylamine, tert-butyl [4-(2-aminoethyl)phenylthio]acetate, 4-benzylsulfanyl-2,6- dimethylphenol, 4-benzylsulfanyl-2-chlorophenol, 4-benzylsulfanyl-4- B fluorophenol, (4-benzylsulfanylphenyl)methanol, tert-butyl(4- hydroxyphenylsulfanyl)acetate, and 2-methyl-4-[[[4-methyl-2-[(4- trifluoromethyl)phenyl]thiazol-5-yl]methyl]sulfanyl]phenol .
Thus the present invention provides useful novel compounds of use.
10 Other and further objects, features and advantages of the invention will appear more fully from the following description.
Detailed Description of the Preferred Embodiment
In the Reaction Scheme shown above, A represents CH or a i s nitrogen atom contained in the aryl compound having a resonance structure.
Xi represents a halogen atom. As the halogen atom, mentioned can be a fluorine atom, chlorine atom, bromine atom, and iodine atom . Among them, a bromine atom or an iodine atom is 20 preferable.
X2 means a leaving group. A conventional leaving group, specifically a halogen atom, a methansulfonyl oxy group, a p- toluenesulfonyloxy group may be employed. Herein, the halogen atoms include a fluorine atom, a chlorine atom, a bromine atom and an iodine
25 atom. Among them, a halogen atom is preferable, a chlorine atom, a bromine atom, or an iodine atom being more preferable
X3 a halogen atom of Gπgnard reagent, represents a chlorine atom , a bromine atom or an iodine atom
Ri represents a hydrogen atom, a halogen atom, a C-1-C7 alkyl r> group, a C1-C7 alkyloxy group, a C1-C7 alkylthiooxy group, an aryl group, a hydroxyl group, a hydroxymethyl group, a hydroxyethyl group, an amine group, an aminomethyl group, an aminoethyl group, an alkylamine group, a dialkylamine group or a carboxy group, where in the alkyl group may be substituted by one or more substιtuent(s) selected
10 from the group consisting of halogen atoms and a hydroxyl group
Each substituent Ri may have ortho-, meta- or para-position with respect to the halogen atom (Xi), and number of the substιtuent(s) is from 1 to 3
R2 represents a C1-C10 alkyl group, an aryl group, a C1-C10 I1J alkylester group, a C1-C10 alkylketoπe group or an arylketone group
R3 and R4 independently represent a C1-C4 alkyl group, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl group
In the preparation process according to the present invention, the compound of Chemical Formula (I) employed as raw material is well ZO known in the art and commercially available
The preparation process according to the invention is now described in detail
[Process A] Preparation of an alkyl aryl sulfide compound represented by Chemical Formula (II I) having (an) electron-donating or 2<5 electron-withdrawing substιtuent(s) An alkyl aryl sulfide compound represented by Chemical Formula (II I) is obtained by reacting a compound represented by Chemical Formula (I) with an alkyl lithium organometallic reagent and sulfur, and then with a compound represented by Chemical Formula (II) Dry solvent such as diethyl ether, tetrahydrofuran, hexane and heptane is used in this process either alone or in a mixture of the two or more Among them , diethylether, tetrahydrofuran , and a mixture of diethyl ether and tetrahydrofuran are the most preferable
The alkyl lithium organometallic reagents employed in the halogen-metal substitution include n-butyl lithium, sec-butyl lithium, tert- butyl lithium, and the like The amount of alkyl lithium organometallic reagent employed is usually from 1 to 3 equivalents with respect to the compound of Chemical Formula (I), most preferably from 1 to 1 2 equivalents in case of n-butyl lithi um or sec-butyl lithium, and from 2 to 2 2 equivalents in case of tert-butyl lithium
Sulfur used in this process is in a powdery state colored pale yellow, and the amou nt is usually from 1 to 3 equivalents, preferably from 1 to 1 2 equivalents with respect to the compound of Chemical Form ula (I ) The reaction temperature varies dependi ng upon the solvent employed , but usually is from -1 00 °C to 25 T: Preferably the substitution of halogen with metal and introduction of sulfur are carried out at -75 °C , and the reaction with compound of Chemical Formula (I I) at room temperature (25 °C ) The reaction time varies depending on the reaction temperature and the type of solvent employed , but usually is from 30 minutes to 6 hours, preferably 1 hour or less.
[Process B] Preparation of an alkyl aryl sulfide compound represented by Chemical Formula (I I I) having a hydrogen-donating substituent In preparing an alkyl aryl sulfide compound represented by
Chemical Formula (II I) where the substituent of the compou nd of Chemical Formula (I) is a hydrogen-donating substituent (-OH, -CH2OH, -CH2CH2OH, -NH2, -NRH, -CH2NH2, -CH2CH2NH2, -COOH), the hydrogen-donating substituent is firstly protected with Grignard reagent, and then reacted with an alkyl lithium organometallic reagent and sulfur, followed by a compound represented by Chemical Formula (II), to obtain a compound of Chemical Formula (III).
As dry solvent used in this process, diethyl ether, tetrahydrofuran, hexane or heptane may be used alone or in a combination of the two or more. Among them, most preferable are diethyl ether, tetrahydrofuran, or a mixture of diethyl ether and tetrahydrofuran.
As the Grignard reagent which protects the hydrogen-donating substituent (-OH , -CH2OH, -CH2CH2OH, -NH2, -NRH, -CH2N H2, - CH2CH2NH2, -COOH), employed may be CH3MgCI, CH3MgBr, CH3MgI , CH3CH2MgCI, CH3CH2MgBr, CH3CH2MgI, CH3CH2CH2MgCI,
CH3CH2CH2MgBr, CH3CH2CH2MgI , (CH3)2CHMgCI, (CHs)2CH MgBr, (CH3)2CHMgl , CH3CH2CH2CH2MgCI, CH3CH2CH2CH2MgBr,
CH3CH2CH2CH2MgI , C2H5CHCH3MgCI, C2H5CHCH3MgBr,
C2H6CHCH3MgI, (CH3)3CMgCI, (CH3J3CMgBr, (CHa)3CMgI , or the like. Among them, R3MgCI and R3MgBr are preferable, (CH3)2CHMgCI and CH3C H2CH2CH2MgCI being more preferable
The alkyl lithium organometallic reagents which can be employed in halogen-metal substitution reaction include n-butyl lithium, sec-butyl lithium , tert-butyl lithium, and the like The amount of alkyl lithium 5 organometallic reagent employed is usually from 1 to 3 equivalents, more preferably from 1 to 1 2 equivalents in case of n-butyl lithium or sec-butyl lithium , from 2 to 2 2 eq uivalents in case of tert-butyl lithium
Sulfur used in this process is in a powdery state colored pale yellow, and the amount is usually from 1 to 3 equivalents, preferably i o from 1 to 1 2 equivalents with respect to the compound of Chemical Form ula (I)
The reaction temperature varies depending upon the solvent em ployed , but usually is from -10CTC to 25 °C Preferably, protection of the hyd rogen-donating substituent is carried out at 0 °C to 25 °C , the
15 substitution of halogen with metal and introduction of sulfur at -75 °C , and the reaction with compound of C hemical Formula (I I) at room temperature (25 °C ) The reaction time varies depending on the reaction temperature and the type of solvent employed, but usually is from 30 minutes to 6 hours, preferably 2 hours or less
20 The present invention regarding alkyl aryl sulfide compounds of
Chemical Formula (I I I) thus obtained and processes for preparing the same are very important in production process of primary intermediates in organochemical reactions and therapeutic agents containing alkyl aryl sulfide functional groups among therapeutic agents for treating various
J5 diseases Examples
The present invention is described specifically below by way of Examples. However, the present invention is not restricted to these Examples.
[Example 1 ] Preparation of benzyl 2-trifluoromethylphenyl sulfide.
Figure imgf000014_0001
1 -Bromo-2-(trifluoromethyl)-benzene 271 μl (2 mmol) was completely dissolved in dry tetrahydrofuran 15 ml under nitrogen atmosphere, and the mixture was cooled to -78 °C . To the mixture, n- butyl lithium 1 .25 ml (1.6M in hexane, 1 .0 equivalent) was slowly added for 1 minute. After stirring additional 10 minutes, sulfur powder 64 mg (2 mmol, 1.0 equivalent) was added at once at the same temperature. After stirring the mixture at the same temperature for additional 10 minutes to completely dissolve sulfur, benzyl bromide 236 μl (2 mmol, 1 .0 equivalent) was slowly added thereto. Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 20 minutes. The reaction was monitored by TLC, and when the reaction was completed, 15 ml of aqueous ammonium chloride solution was added thereto to quench the reaction The organic phase was extracted by using ethyl acetate Moisture contained in the organic phase was removed by using magnesium sulfate After filtration, the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography to obtain the title compound 440 mg (yield 82%)
1 H-NMR(300 MHz, CDCI3) δ 7 63(d, 1 H, J=I 6Hz), 7 38(d, 2H, J=Z 4Hz), 7 32-7 23(m, 6H), 4 15(s, 2H)
13C-NMR(75 5 MHz, CDCI3) δ 136 8, 136 2, 132 3, 132 2, 129 9, 129 4, 128 9, 127 2(q, J=Z 7Hz), 123 3, 39 7
[Example 2] Preparation of benzyl 3-tπfluoromethylphenyl sulfide
Figure imgf000015_0001
The same proced ure as described in Example 1 was repeated but 1 -bromo-2-(trιfluoromethyl)-benzene was replaced with 1 -bromo-3- (trιfluoromethyl)-benzene 276 μl(2 mmol) After purification, the title compound 381 mg (yield 71 %) was obtained 1 H-NMR(300 MHz, CDCI3) 6 7 51 (br s, 1 H), 7 39(t, 2H), 7 33(d,
1 H) , 7 28(m , 5H) , 4 13(s, 2H)
13C-NM R(75 5 M Hz, CDCI3) δ 138 3, 137 0, 133 0, 131 6(q , J=32 Hz), 129 5, 129 2 , 129 0, 128 9 , 127 9, 126 5(q, J=3 7Hz) , 123 3, 39 1 [Example 3] Preparation of benzyl 4-trifluoromethylphenyl sulfide.
Figure imgf000016_0001
The same procedure as described in Example 1 was repeated but 1 -bromo-2-(trifluoromethyl)-benzene was replaced with 1 -bromo-4- (trifluoromethyl)-benzene 276 μl(2 mmol). After purification, the title compound 515 mg (yield. 96%) was obtained. 1 H-NMR(300 MHz, CDCI3) δ: 7.48(d, 2H, J=8.2Hz), 7.36~7.25(m ,
7H), 4.19(S, 2H).
13C-NMR(75.5 MHz, CDCI3) δ: 142.5, 136.7, 129.1 , 129.0, 128.3, 127.9, 126.0(q, J=3.9Hz), 38.1.
[Example 4] Preparation of benzyl 2-methoxyphenyl sulfide.
Figure imgf000016_0002
The same procedure as described in Example 1 was repeated but 1 -bromo-2-(trifluoromethyl)-benzene was replaced with 2- bromoanizol 248 μl (2 mmol). After purification, the title compound 350 mg (yield: 76%) was obtained. 1H-NMR(300 MHz, CDCI3) δ 730-718(m 7H), 684(m, 2H, J=I 8Hz), 409(s, 2H), 388(s, 3H)
13C-NMR(755 MHz, CDCI3) δ 1579, 1379, 1308, 1293, 1288, 1280, 1274, 1248, 1214, 1109, 562, 377 5
[Example 5] Preparation of benzyl 3-methoxyphenyl sulfide
Figure imgf000017_0001
K)
The same procedure as described in Example 1 was repeated but 1-bromo-2-(trιfluoromethyl)-benzene was replaced with 3- bromoanizol 251 μl (2 mmol) After purification, the title compound 332 mg (yield 72%) was obtained
15 1H-NMR(300 MHz, CDCI3) δ 732-724(m, 5H), 716(t, 1H),
686(d, 1H), 682(t, 1H), 665(dd, 1H), 411(s, 2H), 373(s, 3H)
13C-NMR(755 MHz, CDCI3) δ 1601, 1381, 1378, 1300, 1292,
1289, 1276, 122 1, 1152, 1126, 556, 392
20 [Example 6] Preparation of benzyl 4-methoxypheπyl sulfide
Br
OCH3 ^--^OCHa
The same procedure as described in Example 1 was repeated but 1 -bromo-2-(trιfϊuoromethyl)-benzene was replaced with 4- bromoanizol 250 μl (2 mmol) After purification, the title compound 424 mg (yield 92%) was obtained
1 H-NMR(300 MHz, CDCI3) δ 7 28~7 16(m, 7H), 6 77(d, 2H, J=8 6Hz), 3 97(s, 2H), 3 76(s, 3H)
13C-NMR(75 5 MHz, CDCI3) δ 159 6, 138 5, 134 5, 129 8, 129 3, 128 8, 127 3, 114 8, 55 7, 41 6
[Example 7] Preparation of benzyl 4-bιphenyl sulfide
Figure imgf000018_0001
The same procedure as described in Example 1 was repeated but 1 -bromo-2-(trιfluoromethyl)-benzene was replaced with 4- bromobiphenyl 468 μl (2 mmol) After purification , the title compound 514 mg (yield 93%) was obtained 1 H-N M R(300 M Hz, CDCI3) δ 7 70-7 20(m, 14H) , 4 1 5(s, 2H)
1 3C-N M R(75 5 M Hz, CDCI3) δ 140 8, 139 6, 137 8, 1 35 9, 1 31 8, 130 4, 129 3, 129 2, 128 9, 128 3, 127 9, 127 7 127 6, 127 4, 127 3, 39 5 [Example 8] Preparation of ferf-butyl 4- methoxyphenylsulfanylacetate
Figure imgf000019_0001
4-bromoanιzol 374 mg (2 mmol) was completely dissolved in dry tetrahydrofuran 15 ml under nitrogen atmosphere, and the mixture was cooled to -78 °C To the mixture, n-butyl lithium 1 25 ml (1 6M in hexane, 1 0 equivalent) was slowly added for 1 minute After stirring additional 10 minutes, sulfur powder 64 mg (2 mmol, 1 0 equivalent) was added at once at the same temperature After stirring the mixture at the same temperature for additional 5 minutes to completely dissolve sulfur, ferf-butyl bromoacetate 295 μl (2 mmol, 1 0 equivalent) was slowly added Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 20 minutes When the reaction was completed, aqueous ammonium chloride solution was added thereto to quench the reaction The organic phase was extracted by using ethyl acetate and aqueous sodium chloride solution Moisture contained in the organic phase was removed by using magnesium sulfate After filtration, the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography to obtain the title compound 488 mg (yield 96%)
1H-NMR(300 MHz, CDCI3) δ 742(d, 2H, J=88Hz), 683(d, 2H,
J=88Hz), 379(s, 3H), 343(s, 2H), 1 39(s, 9H)
13C-NMR(755 MHz, CDCI3) δ 1694, 1599, 1343, 1257, 1149,
81 9 557, 400, 283
[Example 9] Preparation of 1 - ally I 4-methoxyphenyl sulfide
Figure imgf000020_0001
10
The same procedure as described in Example 8 was repeated but ferf-butyl bromoacetate was replaced with allylbromide 173 μl (2 mmol) After purification, the title compound 328 mg (yield 91%) was obtained
1H-NMR(300 MHz, CDCI3) δ 733(d, 2H, J=98Hz), 682(d, 2H, lr> J=98Hz), 582(m, 1H), 501(s, 1H), 497(dd, 1H, J=80 and 1 3Hz), 378(s, 3H), 342(d, 2H, J=7Hz)
13C-NMR(755 MHz, CDCI3) δ 1595, 1344, 1343, 1262, 1176, 1148, 557, 397, 307
20 [Example 10] Preparation of 1-butyl-4-methoxyphenyl sulfide
Figure imgf000020_0002
The same procedure as described in Example 8 was repeated but using reaction intermediate, 1 -bromobutane, instead of using additional butylhalide After purification, the title compound 295 mg (yield 75%) was obtained
5 1 H-NMR(300 MHz, CDCI3) δ 7 32(d, 2H, J=8 8Hz), 6 83(d , 2H,
J=8 7Hz), 3 79(S, 3H), 2 82(t, 2H), 1 55(m, 2H), 1 40(m, 2H), 0 89(t, 3H) 13C-NMR(75 5 MHz, CDCI3) δ 159 1 , 133 3, 127 3, 114 9, 55 7, 35 9, 31 8, 22 2, 14 0
io [Example 11 ] Preparation of 1 -(4-methoxyphenylsulfanyl)-propan-
2-one
Figure imgf000021_0001
i s The same procedure as described in Example 8 was repeated but terf-butyl bromoacetate was replaced with chloroacetone 159 μl (2 mmol) After purification, the title compound 357 mg (yield 91 %) was obtained
1 H-NMR(300 MHz, CDCI3) δ 7 35(d, 2H, J=8 8Hz), 6 83(d, 2H, 20 J=8 8Hz), 3 79(s, 3H), 3 54(s, 2H), 2 26(s, 3H)
13C-NMR(75 5 MHz, CDCI3) δ 204 0, 160 0, 134 0, 125 0, 115 2, 55 7, 46 9, 28 4
[Example 12] Preparation of 2-(4-methoxyphenylsulfanyl)-1 - phenylethanone.
Figure imgf000022_0001
The same procedure as described in Example 8 was repeated but fer/-butyl bromoacetate was replaced with 2-bromoacetophenone 398 mg (2 mmol). After purification, the title compound 486 mg (yield: 94%) was obtained. 1 H-NMR(300 MHz, CDCI3) δ: 7.90(d, 2H, J=7.2Hz), 7.55(t, 1 H),
7.43(t, 2H), 7.34(d , 2H, J=8.8Hz), 6.80(d, 2H, J=6.8Hz), 4.12(s, 2H),
3.76(s, 3H).
13C-NMR(75.5 MHz, CDCI3) δ: 194.7, 160.1 , 135.9, 135.0, 133.7,
129.1 , 129.0, 125.0, 11 5.1 , 55.7, 43.2.
[Example 13] Preparation of 2-bromo-6-(2-[1 ,3]dioxolan-2-yl- ethylsulfanyl)pyridine.
Figure imgf000022_0002
2,6-Dibromo pyridine 476 mg (2 mmol) was completely dissolved in dry tetrahydrofuran 15 ml under nitrogen atmosphere, and the mixture was cooled to -78 °C . To the mixture, butyl lithium 1.25 ml (1 .6M in hexane, 1 0 equivalent) was slowly added for 1 minute After stirring additional 10 minutes, sulfur powder 64 mg (2 mmol, 1 0 equivalent) was added at once at the same temperature After stirring the mixture at the same temperature for additional 5 minutes to completely dissolve 5 sulfur powder, 2-(2bromoethyl)-1 ,3-dιoxolan 261 μl (2 mmol , 1 0 equivalent) was slowly added Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 20 minutes when the reaction was completed, aqueous ammonium chloride solution was added thereto to quench the reaction The 10 organic phase was extracted by using ethyl acetate and aqueous sodium chloride solution Moisture contained in the organic phase was removed by using magnesium sulfate After filtration, the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography to obtain the title compound 459 mg (yield I S 79%)
1 H-NMR(300 MHz, CDCI3) δ 7 35~7 11 (m, 3H), 5 05(t, 1 H), 4 02(m, 2H), 3 91 (m, 2H), 3 27(t, 2H), 2 11 (m, 2H)
13C-NMR(75 5 MHz, CDCI3) δ 160 7, 142 0, 138 3, 123 5, 121 0, 103 6, 65 3, 33 7, 25 3 ZO
[Example 14] Preparation of 4-(4-bromobenzylsulfanyl)beπzoιc acid
Figure imgf000024_0001
4-bromobenzoιc acid 402 mg (2 mmol) was completely dissolved in dry tetrahydrofuran 15 ml under nitrogen atmosphere, and the mixture was cooled to -78 °C To the mixture, butyl lithi um 2 5 ml (1 6M in hexane, 1 0 equivalent) was slowly added for 1 minute After stirring additional 10 min utes, sulfur powder 64 mg (2 mmol, 1 0 equivalent) was added at once at the same temperature After stirring the mixture at the same temperature for additional 5 minutes to completely dissolve su lfur powder, 4-bromobenzylbromιde 250 mg (2 mmol, 1 0 equivalent) was slowly added Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 20 minutes when the reaction was completed, aqueous ammonium chloride solution was added thereto to quench the reaction The organic phase was extracted by using ethyl acetate and aqueous sodium chloride solution Moisture contained in the organic phase was removed by using magnesium sulfate After filtration, the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography to obtain the title compound 575 mg (yield 89%) 1 H-NMR(300 M Hz, DMSO-d6) δ 12 9(br s, 1 H), 7 82(d, 2 H ,
J=8 4Hz) , 7 50(d , 2 H , J=8 4Hz), 7 40(d , 2H , J= 11 8Hz) , 7 37(d, 2 H , J= 11 8Hz), 4 33(s, 2H)
1 3C-N M R(75 5 M Hz, DMSO-d6) δ 167 7, 143 3, 137 4, 1 32 2 , 131 8, 130 5, 128 4 127 5, 121 1 , 35 4
[Example 15] Preparation of 2-(benzylsulfanyl)benzoιc acid
Figure imgf000025_0001
2-bromobenzoιc acid 402 mg (2 mmol) was completely dissolved in dry tetrahydrofuraπ 15 ml under nitrogen atmosphere, and the mixture was cooled to 0 °C To the mixture, isopropylmagnesium chloride 1 0 ml (2 0 mmol, 2 0 M-ether, 1 0 equivalent) was slowly added at the same temperature After 10 minutes, the mixture was cooled to -78 °C tert- Butyl lithium 2 35 μl (4 0 mmol, 1 7 M-peπtane, 2 0 equivalent) was slowly added for 1 minute Sulfur powder 64 mg (2 mmol) dissolved in dry tetrahydrofuran 3 0 μl was added Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 30 minutes Again, the mixture was cooled to 0°C Benzylbromide 238 μl (2 mmol, 1 0 equivalent) was slowly added to the mixture After 20 minutes at room temperature, aqueous ammonium chloride solution was added thereto to quench the reaction The organic phase was extracted by using ethyl acetate and 5% aqueous hydrochloric acid solution Moisture contained in the organic phase was removed by using magnesium sulfate After filtration, the solvent was evaporated under reduced pressure The residue was purified by sil ica gel column ch romatography to obtain the title compound 429 mg (yield 88%)
1 H-NMR (300 MHz, DMSO-(Z6) δ 13 00 (s, 1 H) 7 89-7 86 (m , 1 H), 7 49-7 20 (m, 8H), 4 19 (s, 2H) 13C-NMR (75 MHz, DMSO-Cf6) δ 168 27, 142 07, 137 49, 133 18,
131 77, 130 02, 129 33, 128 58, 128 01 , 126 59, 124 85, 36 57
[Example 16] Preparation of 3-(benzylsulfanyl)benzoιc acid
Figure imgf000026_0001
The same procedure as described in Example 15 was repeated but 2-bromobenzoιc acid was replaced with 3-bromobenzoιc acid 402 mg(2 mmol) After purification, the title compound 473 mg (yield 97%) was obtained
1 H-NMR (300 MHz, DMSO-Cf6) δ 13 04 (s, 1 H), 8 12-7 21 (m, 9H), 4 28 (s 2H)
13C-NMR (75 MHz, DMSO-d6) δ 167 63, 137 96, 137 79, 133 22, 132 34, 130 11 , 130 06, 129 69, 129 48, 129 41 , 129 26, 128 01 , 127 54, 37 36
[Example 17] Preparation of 4-(benzylsulfanyl)benzoιc acid
Figure imgf000027_0001
The same procedure as described in Example 15 was repeated but 2-bromobenzoιc acid was replaced with 4-bromobenzoιc acid 402 mg (2 mmol) After purification, the title compound 449 mg (yield 92%) was obtained
1 H-NMR (300 MHz, DMSO-d6) δ 12 85 (s, 1 H), 7 82-7 79 (m, 2H), 7 41 -7 20 (m, 7H) , 4 33 (s, 2H)
13C-NMR (75 MHz, DMSO-Cf6) δ 167 77, 143 90, 137 64, 130 56, 129 71 , 129 33, 128 29, 128 09, 127 30, 36 2
[Example 18] Preparation of 4-((ferf- butoxycarbonyl)methylsulfanyl)benzoιc acid
Figure imgf000027_0002
The same procedure as described in Example 15 was repeated but 2-bromobenzoιc acid and benzylbromide were replaced with 4- bromobenzoic acid 402 mg (2 mmol) and ferf-butyl bromoacetate 295 μl (2 mmol , 1 0 equivalent), respectively After purification, the title compound 472 mg (yield 88%) was obtained
1 H-NMR (300 MHz, DMSO-d) δ 12 40(br, 1 H), 8 02-7 95(m, 2H), 7 40-7.37(m, 2H), 3.60(s, 2H), 1.43(s, 9H).
13C-NM R (75MHz, DMSO-cf) δ: 172.28, 168.54, 144.25, 130.95, 127.21 , 126.89, 82.97, 36.30, 28.
[Example 19] Preparation of 3-(2-(1 ,3-dioxolan-2-yl-ethylsulfanyl) benzoic acid.
Figure imgf000028_0001
The same procedure as described in Example 15 was repeated but 2-bromobenzoic acid and benzylbromide were replaced with 3- bromobenzoic acid 402 mg (2 mmol) and 2-(2-bromomethyl)-1 ,3- dioxolan 235 μl (2 mmol , 1.0 equivalent) , respectively. After purification, the title compound 416 mg (yield: 82%) was obtained. 1H-NMR (300 MHz, DMSOd6) δ: 11 .95 (br, 1 H), 8.07-8.06 (m, 1 H),
7.92-7 89 (m, 1 H), 7.57-7.54 (m, 1 H), 7.41 -7.35 (m, 1 H), 5.03-5.00 (m, 1 H), 4.02-3.85 (m, 4H), 3.11 -3.06 (m, 2H), 2.07-2.00 (m, 2H).
13C-NMR (75 MHz, DMSOd6) δ: 172.01 , 137.99, 134.14, 130.60, 130.51 , 129.37, 127.90, 103.32, 65.41 , 33.70, 27.
[Example 20] Preparation of 3-(2-hydroxyhex-5- enylsulfanyl)benzoic acid.
Figure imgf000029_0001
The same procedure as described in Example 15 was repeated but 2-bromobenzoιc acid and benzylbromide were replaced with 3- bromobeπzoic acid 402 mg (2 mmol) and 1 2-epoxy-5-hexene 228 μl (2 mmol , 1 O equivalent) , respectively After purification, the title compound 418 mg (yield 83%) was obtained
1 H-NMR (300 MHz, DMSO-Cf6) δ 8 09-8 10 (m, 1 H), 7 92-7 94 (m, 1 H), 7 58-7 62 (m, 1 H), 7 37-7 42 (m, 1 H), 5 76-5 82 (m, 1 H) 4 95-5 07 (m, 2H), 3 75 (m, 1 H), 3 18-3 24 (m, 1 H), 2 91 -2 99 (m, 1 H), 2 17-2 24 (m, 2H), 1 63-1 70 (m , 1 H)
13C-NM R (75 MHz, DMSO-d6) δ 171 12, 138 27, 137 10, 135 00,
131 16, 130 62, 129 54, 128 50, 115 59, 69 50, 42 09, 35 58, 30 29
[Example 21 ] Preparation of benzyl 4-bromophenylsulfιde
Figure imgf000029_0002
1 ,4-Dιbromo benzene 256 μl (2 mmol) was completely dissolved in dry tetrahydrofuran 15 ml under nitrogen atmosphere, and the mixture was cooled to -78 °C To the mixture, butyl lithium 1 25 ml (1 6M in hexane, 1 0 equivalent) was slowly added for 1 minute After stirring additional 10 minutes sulfur powder 64 mg (2 mmol, 1 0 equivalent) was added at once at the same temperature After stirring the mixture at the same temperature for additional 5 minutes to completely dissolve sulfur, benzyl bromide 236 μl (2 mmol, 1 0 equivalent) was slowly added Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 20 minutes When the reaction was completed , aqueous ammonium chloride solution was added thereto to quench the reaction The organic phase was extracted by using ethyl acetate and aqueous sodium chloride solution Moisture contained in the organic phase was removed by using magnesium sulfate After filtration, the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography to obtain the title compound 491 mg (yield 88%)
1H-NMR(300 MHz, CDCI3) δ 7 36(d, 2H, J=8 6Hz), 7 28(m, 5H), 7 14(d, 2H, J=8 6Hz) 4 08(s, 2H)
13C-NMR(75 5 MHz, CDCI3) δ 137 4, 135 8, 132 2, 131 9, 128 9, 127 7, 120 7, 39 5
[Example 22] Preparation of 1 -phenyl-2-(2 4,6-trιmethyl phenyl su lfanyl)ethanone
Figure imgf000030_0001
mesityl bromide 300 μl (2 mmol) was completely dissolved in dry tetrahydrofuran 15 ml under nitrogen atmosphere, and the mixture was cooled to -78 t: . To the mixture, butyl lithium 1 .25 ml (1 .6M in hexane, 1 .0 equivalent) was slowly added for 1 minute. After stirring additional 10 minutes, sulfur powder 64 mg (2 mmol, 1.0 equivalent) was added at c> once at the same temperature. After stirring the mixture at the same temperature for additional 5 minutes to completely dissolve sulfur, phenacyl bromide 398 mg (2 mmol, 1 .0 equivalent) was slowly added. Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 20 minutes, when the o reaction was completed, aqueous ammonium chloride solution was added thereto to quench the reaction. The organic phase was extracted by using ethyl acetate and aqueous sodium chloride solution. Moisture contained i n the organic phase was removed by using magnesium sulfate. After filtration , the solvent was evaporated under 5 reduced pressure. The residue was purified by silica gel column ch romatography to obtain the title compound 498 mg (yield : 92%).
1 H-NMR(300 MHz, CDCI3) δ: 7.87(d, 2H , J=6.3Hz) , 7.55(t, 1 H , J=7.4Hz), 7.42(t. 2H , J=6.6Hz), 6.89(s, 2H), 3.92(s, 2H), 2.38(s, 6H), 2.25(s, 3H) . 0 13C-NM R(75.5 MHz, CDCI3) δ: 194.9, 143.5, 142.2, 139.2, 1 35.9,
133.6, 129.5, 1 29.1 , 128.9, 41 .2, 22.1 , 21 .4.
[Example 23] Preparation of 2-benzylsulfanylphenylamine.
Figure imgf000032_0001
2-ιodoanιlιne 438 mg (2 mmol) was completely dissolved in dry tetrahydrofuraπ 15 ml under nitrogen atmosphere To the mixture, 5 isopropylmagnesium chloride 2 0 ml (2 0 M-ether, 2 0 equivalent) was slowly added at 0 °C After 10 minutes at room temperature, the mixture was cooled to -78 °C ferf-Butyl lithium 1 18 ml (1 7 M-pentane, 2 0 eq uivalent) was slowly added for 1 minute After stirring additional 10 minutes, sulfur powder 64 mg(2 mmol, 1 0 equivalent) was added at
10 once at the same temperature Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 25 minutes Again, the mixture was cooled to 0"C Benzylbromide 236 μl (2 mmol, 1 0 equivalent) was slowly added to the mixture After 20 minutes at room temperature, when the reaction was completed, i s aqueous ammonium chloride solution was added thereto to quench the reaction The organic phase was extracted by using ethyl acetate and aqueous sodium chloride solution After filtration, the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography to obtain the title compound 254 mg (yield
20 59%)
1 H-NMR(300 MHz, CDCI3) δ 7 23-7 12(m, 7H), 6 68(d, 1 H, J=9 2Hz), 6 58(t, 1 H, J=17 4 and 8 8Hz), 4 23(br s, 2H), 3 89(s, 2H)
13C-NMR(75 5 MHz, CDCI3) δ 148 8, 138 5, 136 7, 130 2, 129 1 , 128 6, 127 2, 118 7, 115 1 , 39 8 [Example 24] Preparation of 3-benzylsulfanylphenylamιne
Figure imgf000033_0001
The same procedure as described in Example 23 was repeated but 2-ιodoanιlιπe was replaced with 3-ιodoanιlιne 241 μl (2 mmol) After purification, the title compound 284 mg (yield 66%) was obtained
1H-NMR(300 MHz, CDCI3) δ 729(m, 5H), 703(t, 1H, J=157 and 79Hz), 755(d, 1H, J=85Hz), 661(t, 1H, J=2Hz), 645(dd, 1H, J= 88 and 18Hz), 409(s, 2H), 360(br s, 2H)
13C-NMR(755 MHz, CDCI3) δ 1469, 1377, 1376, 1298, 1290, 1287, 1273, 1197, 1159, 1134, 389
[Example 25] Preparation of 3-benzylsulfanylphenylamιne
Figure imgf000033_0002
The same procedure as described in Example 23 was repeated but 2-ιodoanιlιne was replaced with 3-bromoanιlιne 218 μl (2 mmol) After purification, the title compound 198 mg (yield 46%) was obtained
1H-NMR(300 MHz, CDCI3) δ 729(m, 5H), 703(t, 1H, J=157 and 79Hz), 755(d, 1H, J=85Hz), 661(t 1H, J=2Hz), 645(dd, 1H, J=88 and 1 8Hz), 409(s, 2H), 360(br s, 2H) 13C-NMR(755 MHz, CDCI3) δ 1469, 1377, 1376, 1298, 1290, 1287 1273, 1197 1159, 1134, 389
[Example 26] Preparation of 4-benzylsulfanylphenylamιne
Figure imgf000034_0001
The same procedure as described in Example 23 was repeated but 2-ιodoanιlιne was replaced with 4-ιodoanιlιπe 438 mg (2 mmol) After purification, the title compound 396 mg (yield 92%) was obtained 1H-NMR(300 MHz, CDCI3) δ 721(m, 5H), 711(d, 2H, J=86Hz),
654(d, 2H, J=Q 6Hz), 392(s, 2H), 366(br s, 2H)
13C-NMR(755 MHz, CDCI3) δ 1464, 1386, 1349, 1291, 1285, 1270, 1231, 1156, 41 9
[Example 27] Preparation of 4-benzylsulfanyl-2-methyl- pheπylamine
Figure imgf000034_0002
The same procedure as described in Example 23 was repeated but 2-ιodoanιlιne was replaced with 4-ιodo-2-methylanιhne 466 mg (2 mmol) After purification, the title compound 381 mg (yield 83%) was obtained 1 H-NMR(300 MHz, CDCI3) δ: 7.23(m, 5H), 7.03(s, 1 H), 7.01 (d, 1 H,
J=8.1 Hz), 6.53(d, 1 H , J=8.1 Hz), 3.93(s, 2H), 3.61 (br s, 2H), 2.07(s, 3H).
13C-NMR(75.5 MHz, CDCI3) δ: 144.6, 138.7, 135.7, 132.3, 129.1 ,
128.4, 127.0, 123.1 , 122.9, 115.4, 41.9, 17.3.
[Example 28] Preparation of 4-(benzylthio)-2-bromobeπzeπamine.
Figure imgf000035_0001
The same procedure as described in Example 23 was repeated but 2-iodoaniline was replaced with 2,4-dibromobenzenamine 502 mg (2 mmol). After purification, the title compound 435 mg (yield: 74%) was obtained.
1 H-NMR(300 MHz, CDCI3) δ 7.39 (d, 1 H), 7.29-7.12 (m, 5H), 7.04 (dd, 1 H), 6.61 (d, 1 H), 4.11 (bs, 2H), 3.93 (s, 2H).
13C-NMR(75.5 MHz, CDCI3) δ 144.2, 138.4, 137.6, 134.0, 129.4, 128.8, 127.5, 124.5, 116.0, 109.3, 42.1 .
[Example 29] Preparation of 4-[(4- aminophenylthio)methyl]benzonitrile.
H2N
Figure imgf000035_0002
The same procedure as described in Example 23 was repeated but 2-iodoaniline and benzylbromide were replaced with 4- iodobenzenamine 438 mg (2 mmol) and 4-(bromomethyl)benzonitrile 392 mg (2 mmol), respectively. After purification, the title compound 428 mg (yield: 89%) was obtained.
1H-NMR(300 MHz, CDCI3) δ 7.50 (dt, 2H), 7.19 (d, 2H), 7.05 (dt, 2H), 6.54 (dt, 2H), 3.89 (s, 2H), 3.75 (bs, 2H).
13C-NMR(75.5 MHz, CDCI3) δ 147.0, 144.5, 135.6, 132.2, 129.8, 121.3, 119.1, 115.6, 110.7, 41.8.
[Example 30] Preparation of 4-(2-methylallylthio)benzenamine.
Figure imgf000036_0001
The same procedure as described in Example 23 was repeated but 2-iodoaniline and benzylbromide were replaced with 4- iodobenzenamme 438 mg (2 mmol) and 3-bromo-2-methylprop-1-ene 270 mg (2 mmol), respectively. After purification, the title compound 333 mg (yield: 93%) was obtained. 1H-NMR(300 MHz, CDCI3) δ 7.21 (dt, 2H), 6.59 (dt, 2H), 4.67 (m,
2H), 3.65 (bs, 2H), 3.35(s, 2H), 1.83 (s, 3H).
13C-NMR(75.5 MHz, CDCI3) δ 146.2, 141.6, 134.7, 123.5, 115.6, 113.8, 44.8, 21.1. HRMS (El)Calcd for Ci0Hi3NS (M+) 179.0769, found 179.0768.
[Example 31] Preparation of 2-(4-amineophenylthio)-1- phenylethanone
Figure imgf000037_0001
The same procedure as described in Example 23 was repeated but 2-ιodoanιlιne and benzylbromide were replaced with 4- lodobenzenamme 438 mg (2 mmol) and 2-bromo-1 -phenylethanone 498 mg (2 mmol), respectively After purification, the title compound 448 mg (yield 92%) was obtained 1 H-NMR(300 MHz, DMSO-d6) δ 7 91 (m, 2H), 7 56 (m, 1 H), 7 44
(m , 2H), 7 22 (dt, 2H), 6 57 (dt, 2H), 4 07 (s, 2H), 3 76 (bs, 2H)
13C-NMR(75 5 MHz, DMSO-d6) δ 194 7, 147 1 , 135 8, 135 5,
133 4, 129 0, 128 8, 121 5, 115 8, 43 5
[Example 32] Preparation of t-butyl 2-(amιnopheπylthιo)acetate
Figure imgf000037_0002
The same procedure as described in Example 23 was repeated but 2-ιodoanιlιne and benzylbromide were replaced with 4- lodobenzenamine 438 mg (2 mmol) and t-butyl 2-bromoacetate 390 mg
(2 mmol), respectively After purification, the title compound 454 mg
(yield 95%) was obtained 1 H-NMR(300 MHz, DMSO-d6) δ 7 29 (dt, 2H), 6 60 (dt, 2H), 3 74 (bs, 2H), 3.37 (s, 2H), 1.40 (s, 9H)
13C-NMR(75 5 MHz, DMSO-d6) δ 169 7, 147 0, 135 0, 122 5, 11 5 8, 81 8, 40 6, 28 3
[Example 33] Preparation of 4-(5-phenylpeπtylthιo)benzenamιne
Figure imgf000038_0001
The same procedure as described in Example 23 was repeated but 2-ιodoanιlιne and benzylbromide were replaced with 4- lodobenzenamine 438 mg (2 mmol) and 1 -(5-bromopentyl)benzen 454 mg (2 mmol), respectively After purification, the title compound 456 mg (yield 84%) was obtained 1 H-NMR(300 MHz, CDCI3) δ 7 29-7 11 (m, 7H), 6 60 (dt, 2H), 3 50
(bs, 2H), 2 75 (t, 2H), 2 58 (t, 2H), 1 62-1 53 (m , 4H), 1 47-1 39 (m, 2H)
13C-NMR(75 5 MHz, CDCI3) δ 145 9, 142 8, 134 0, 129 5, 128 6, 128 4, 125 8, 115 8, 36 5, 36 0, 31 2, 29 5, 28 5
[Example 34] Preparation of 4-(cyclohexylmethylthιo)benzenamιne
Figure imgf000039_0001
The same procedure as described in Example 23 was repeated but 2-ιodoanιlιne and benzylbromide were replaced with 4- iodobenzenamine 438 mg (2 mmol) and (bromomethyl)cyclohexane 354 mg (2 mmol), respectively After purification, the title compound 359 mg (yield 81 %) was obtained
1 H-N MR(300 M Hz, CDCI3) δ 7 42 (d, 2H, J = 8 8 Hz), 7 21 (dt, 2H), 6 60 (dt, 2H), 3 66 (bs, 2H), 2 67 (d, 2H), 1 86 (d, 2H), 1 76-1 57 (m, 3H), 1 54-1 36 (m, 1 H), 1 30-1 08 (m, 3H), 1 02-0 85 (m, 2H)
13C-NMR(75 5 MHz, CDCI3) δ 145 7, 139 0, 133 5, 115 8, 115 1 , 44 1 , 37 7, 32 9, 26 6, 26 3
[Example 35] Preparation of 1 -(4-arπιπopentylthιo)hex-5-en-2-ol
Figure imgf000039_0002
The same procedure as described in Example 23 was repeated but 2-ιodoanilιne and benzylbromide were replaced with 4- iodobenzenamine 438 mg (2 mmol) and 2-(but-3-enyl)oxιran 196 mg (2 mmol), respectively After purification, the title compound 389 mg (yield 87%) was obtained
1 H-NMR(300 MHz, CDCI3) δ 7 26 (dt, 2H), 6 61 (dt, 2H), 5 79 (m, 1 H), 4 98 (m, 2H), 3 73 (bs, 2H), 3 59 (m, 1 H), 2 97 (dd, 1 H), 2 68 (dd, 1 H), 2 59 (bs, 1 H), 2 24 ~ 2 05 (m, 2H), 1 66 ~ 1 50 (m, 3H)
13C-NMR(75 5 MHz, CDCI3) δ 146 6, 138 4, 134 6, 122 1 , 115 9, 11 5 0, 68 7, 44 9, 35 2, 30 2
[Example 36] Preparation of 4-benzylsulfaπyl-benzylamιne
Figure imgf000040_0001
4-bromobenzylamιne 445 mg (2 mmol) was completely dissolved in dry tetrahydrofuran 20 ml under nitrogen atmosphere To the mixture, isopropylmagnesium chloride 3 0 ml (2 0 M-ether, 3 0 equivalent) was slowly added at 0°C After 10 minutes at room temperature, the mixture was cooled to -78 °C ferf-Butyl lithium 1 18 ml (1 7 M-pentane, 2 0 equivalent) was slowly added for 1 minute After stirring additional 10 minutes, sulfur powder 64 mg(2 mmol, 1 0 equivalent) was added at once at the same temperature Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 25 minutes Again, the mixture was cooled to 0 °C Benzylbromide 236 μl (2 mmol, 1 0 equivalent) was slowly added to the mixture After 20 minutes at room temperature, when the reaction was completed, aqueous ammonium chloride solution was added thereto to quench the reaction The organic phase was extracted by using ethyl acetate and aqueous sodium chloride solution After filtration, the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography to obtain the title compound 440 mg (yield >5 96%)
1 H-NMR(300 MHz, CDCI3) δ 7 28 - 7 18 (m, 9H), 4 09 (s, 2H), 3 82 (s, 2H)
[Example 37] Preparation of 2-[4-(benzylthιo)phenyl]ethanamιne
10
Figure imgf000041_0001
The same procedure as described in Example 36 was repeated but 4-bromobenzylamιne was replaced with 2-(4- lr) bromophenyl)ethanamιne 400 mg (2 mmol) After purification, the title compound 477 mg (yield 98%) was obtained
1 H-NMR(300 M Hz, CDCI3) δ 7 28-7 21 (m, 7H), 7 09 (d, 2H), 4 09 (s, 2H), 2 94 (t, 2H), 2 70 (t, 2H), 1 75 (bs, 2H)
13C-NMR(75 5 MHz, CDCI3) δ 138 4, 137 8, 134 0, 130 7, 129 6,
ZO 129 0, 128 7, 127 3, 43 5, 39 7, 29 9
[Example 38] Preparation of f-butyl [4-(2-amιnoethyl)phenylthιo]- acetate
Figure imgf000042_0001
4-bromophenethylamιne 400 mg (2 mmol) was completely dissolved in dry tetrahydrofuran 20 ml under nitrogen atmosphere, and the mixture was cooled to O T: To the mixture, isopropylmagπesium chloride 2 0 ml (4 0 mmol, 2 0 M-ether, 2 0 equivalent) was slowly added at the same temperature After 15 minutes, the mixture was cooled to -78 °C rerf-Butyl lithium 2 35 ml (4 0 mmol, 1 7 M-pentane, 2 0 equivalent) was slowly added for 1 minute After 30 minute at the same temperature, sulfur powder 64 mg(2 mmol) dissolved in dry tetrahydrofuran 3 0 ml was added Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 60 minutes Again, the mixture was cooled to O t: tert- Butylbromoacetate 296 μl (2 mmol, 1 0 equivalent) was slowly added to the mixture After 20 minutes at room temperature, the solvent was removed under reduced pressure The organic phase was extracted by aqueous ammonium chloride solutιon(20 μl) and ethylacetate(3 x 20 μl) Moisture contained in the organic phase was removed by using magnesium sulfate After filtration, the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography that using dichloromethane included 3% ammonia water and 10% methanol to obtain the title compound 504 mg (yield 94%)
1 H-NMR(300 MHz, CDCI3) δ 7 36(d, 2H, J=8 1 Hz), 7 13(d, 2H, J=8.1 Hz), 3.53(s, 2H), 2.95(t, 2H, J=6.9Hz), 2.71 (t, 2H, J=6.9Hz), 1.40(s, 9H), 1 .31 (br s, 2H).
13C-NMR(75.5 MHz, CDCI3) δ: 169.3, 139.2, 130.9, 129.8, 120.4, 82.2, 43.9, 40.1 , 38.5, 28.3.
5
[Example 39] Preparation of f-butyl 2[4-(2-aminoethyl)phenylthio]- 2- methylpropionate
Figure imgf000043_0001
10
4-bromophenethylamine 397 mg (2 mmol) was completely dissolved in dry tetrahydrofuran 20 ml under nitrogen atmosphere, and the mixture was cooled to 0°C . To the mixture, isopropylmagnesium i s bromide 2.0 ml (4.0 mmol, 2.0 M-ether, 2.0 equivalent) was slowly added at the same temperature. After 15 minutes, the mixture was cooled to -78°C . ferf-Butyl lithium 2.35 μl (4.0 mmol, 1.7 M-pentane, 2.0 equivalent) was slowly added for 1 minute. After 30 minute at the same temperature, sulfur powder 64 mg(2 mmol) dissolved in dry
20 tetrahydrofuran 3.0 ml was added. Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature. After 60 minutes, the solvent was removed under reduced pressure. After calcium hydroxide 108 mg(2.0 mmol) was added, t-butyl-2-bromoisobutylate 373 μl(2.0 mmol) was added. The reaction mixture was heated with reflux for 1 hour at 80 °C and then cooled to room temperature After the solvent was removed under reduced pressure, the organic phase was extracted by aqueous ammonium chloride solution (20 μl) and ethylacetate (3 x 20 μl) Moisture contained in the organic phase was removed by using magnesium sulfate After filtration, the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography that using dichloromethane included 3% ammonia water and 10% methanol to obtain the title compound 545 mg (yield 92%) 1 H-NMR(300 MHz, CDCI3) δ 7 45(d, 2H, J=8 OHz), 7 16(d, 2H,
J=8 OHz), 2 97(t, 2H , J=7 OHz), 2 76(t, 2H, J=I OHz), 1 44(s, 6H), 1 43(s, 9H), 1 32(br s, 2H)
13C-NM R(75 5 MHz, CDCI3) δ 173 5, 141 5, 137 4, 129 8, 129 4, 129 2, 128 9, 81 3, 51 7, 43 8, 40 2, 28 3, 26 5 HREIMS C16H25NO2S
Calculated value 295 1606, Measured value 295 1605
[Example 40] Preparation of 2-benzylsulfanylphenol
Figure imgf000044_0001
2-bromophenol 232 μl (2 mmol) was completely dissolved in dry tetrahydrofuran 15 ml under nitrogen atmosphere, and the mixture was cooled to O0C To the mixture, isopropylmagnesium chloride 1 0 ml (20 mmol 20 M-ether 20 equivalent) was slowly added at the same temperature After 10 minutes, the mixture was cooled to -78"C tert- Butyl lithium 235 μl (40 mmol, 1 7 M-pentane, 20 equivalent) was slowly added for 1 minute After 30 minutes at the same temperature sulfur powder 64 mg(2 mmol) dissolved in dry tetrahydrofuran 30 ml was added Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 30 minutes Again, the mixture was cooled to 0°C Benzylbromide 236 μl (2 mmol, 1 0 equivalent) was slowly added to the mixture After 20 minutes at room temperature, aqueous ammonium chloride solution was added thereto to quench the reaction The organic phase was extracted by ethylacetate and aqueous sodium chloride solution Moisture contained in the organic phase was removed by using magnesium sulfate After filtration the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography to obtain the title compound 504 mg (yield 94%)
1H-NMR(300 MHz, CDCI3) δ 723(m, 5H), 708(m, 2H), 692(d, 1H, J=I 8Hz), 679(t, 1H, J=151 and 76Hz), 654(br s, 1H), 384(br s, 2H) 13C-NMR(755 MHz, CDCI3) δ 1573, 1378, 1366, 1322, 131 6,
1294, 1289, 1287, 1276, 1220, 1208, 1184, 1164, 1149, 41 6
[Example 41] Preparation of 3-benzylsulfanylphenol
Figure imgf000046_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 3-bromopheπol 346 mg (2 mmol). After purification, the title compound 338 mg (yield: 78%) was obtained.
1 H-NMR(300 MHz, CDCI3) δ: 7.26(m, 5H), 7.10(t, 1 H, J=16.0 and 8.0Hz) 6.85(d, 1 H , J=7.8Hz), 6.77(t, 1 H, J=3.9 and 1 .9Hz), 6.63(dd, 1 H, J=8.1 and 2.4Hz), 5.46(br s, 1 H), 4.09(s, 2H).
13C-NM R(75.5 MHz, CDCI3) δ: 155.9, 138.2, 137.4, 130.1 , 129.0, 128.7, 127.4, 121.8, 116.2, 113.6, 38.7.
[Example 42] Preparation of 4-benzylsulfanylphenol.
Figure imgf000046_0002
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 4-bromophenol 346 μl (2 mmol). After purification, the title compound 372 mg (yield: 86%) was obtained. 1 H-NMR(300 MHz, CDCI3) δ: 7.26~7.16(m, 7H), 6.69(d, 2H, J=8.4Hz), 5.29(br s, 1 H), 3.97(s, 2H).
13C-NMR(75.5 M Hz, CDCI3) δ: 155.4, 138.2, 134.5, 129.1 , 128.6, 127.2, 126.3, 116.1 , 41.4. [Example 43] Preparation of 4-benzylsulfanyl-2,6-dimethylphenol.
Figure imgf000047_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 4-bromo-2,6-dimethylphenol 402 mg (2 mmol). After purification, the title compound 303 mg (yield: 62%) was obtained.
1H-NMR(300 MHz, CDCI3) δ: 7.29~7.21(m, 7H)1 6.90(s, 1H), 3.98(s, 2H), 2.18(s, 6H).
[Example 44] Preparation of 4-benzylsulfanyl-2-chlorophenol.
Figure imgf000047_0002
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 4-bromo-2-chlorophenol 415 mg
(2 mmol). After purification, the title compound 411 mg (yield: 82%) was obtained. 1H-NMR(300 MHz, CDCI3) δ: 7.28~7.19(m, 6H), 7.12(dd, 1H,
J=8.5 and 2.2Hz), 6.89(d, 1H, J=8.5Hz) 5.53(br s, 1H), 399(s, 2H). [Example 45] Preparation of 4-benzylsulfanyl-4-fluorophenol.
Figure imgf000048_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 4-fluoro-2-bromophenol 382 mg (2 mmol). After purification, the title compound 244 mg (yield: 52%) was obtained. 1H-NMR(300 M Hz, CDCI3) δ: 7.25(m, 3H)1 7.08(m, 2H),
6.97 ~ 6.86(m, 3H), 6.27(s, 1 H), 3.85(s, 2H).
[Example 46] Preparation of 2-(pent-2-ynylsulfanyl)-4- fluorophenol.
Figure imgf000048_0002
The same procedure as described in Example 40 was repeated but 2-bromophenol and benzylbromide were replaced with 2-bromo-4- fluorophenol 382 mg (2 mmol) and 1 -bromo-2-pentyne 204 μl (2 mmol,
1 .0 equivalent), respectively. After purification, the title compound 374 mg (yield 89%) was obtained
1H-NMR(300 MHz, CDCI3) δ 724-728 (m, 1H), 691-704 (m, 2H), 656 (s, 1H), 340 (t, 2H, J = 234 Hz), 216 (m, 2H), 1 07 (t, 3H, J = 75 Hz) 1 3C-NMR(755 MHz, CDCI3) δ 15799, 15480, 15418, 15415,
12262, 12232 11902, 11891, 11872, 11597, 11587, 8740, 7467, 2582, 1402, 1282
[Example 47] Preparation of 2-(5-phenylpentylsulfanyl)-4- fluorophenol
Figure imgf000049_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol and benzylbromide were replaced with 2-bromo-4- fluorophenol 382 mg (2 mmol) and 5-phenylpentyl bromide 375 μl (2 mmol, 1 0 equivalent), respectively After purification, the title compound 482 mg (yield 83%) was obtained
1H-NMR(300 MHz, CDCI3) δ 711-725 (m, 6H), 690-694 (m, 2H), 646 (s, 1H), 267(t, 2H, J = 727 Hz), 256 (t 2H, J = 745 Hz), 1 51- 1 63 (m, 4H), 1 32-1 43 (m, 2H)
13C-NMR(755 MHz, CDCI3) δ 15817, 15498, 15357, 15354, 14271, 12882, 12876, 12620, 121 81, 121 51, 12049, 12039, 11818, 11788, 11583, 11573, 3701, 3615, 31 31, 2992, 2857 [Example 48] Preparation of 2-(cyclohexylmethylsulfanyl)-4- fluorophenol
Figure imgf000050_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol and benzylbromide were replaced with 2-bromo-4- fluorophenol 382 mg (2 mmol) and bromomethyl cyclohexane 277 μl (2 mmol, 1 0 equivalent), respectively After purification, the title compound 389 mg (yield 81 %) was obtained
1 H-NMR(300 MHz, CDCI3) δ 7 16-7 20 (m, 1 H), 6 90-7 00 (m, 2H), 6 50 (s 1 H), 2 64 (d, 2H, J = 6 89 Hz), 1 85-1 89 (m, 2H), 1 66-1 77 (m, 3H) 1 46 (m, 1 H), 1 17-1 28 (m, 3H), 0 95-0 99 (m, 2H) 13C-NMR(75 5 MHz, CDCI3) δ 158 15, 154 97, 153 26, 153 23,
121 52, 121 41 , 121 30, 121 21 , 1 17 85, 115 75, 115 64, 44 77, 38 09, 32 91 , 26 65, 26 31
[Example 49] Preparation of 4-(2-(1 ,3-dιoxolan-2- yl)ethylsulfanyl)phenol
Figure imgf000050_0002
The same procedure as described in Example 40 was repeated but 2-bromophenol and benzylbromide were replaced with 4- bromophenol 346 mg (2 mmol) and 2-(2-bromomθthyl)-1 ,3dioxolan 235
5 μl (2 mmol, 1 .0 equivalent), respectively. After purification, the title compound 353 mg (yield: 78%) was obtained.
1 H-NMR(300 MHz, CDCI3) δ: 7.26-7.40 (m, 2H), 6.71 -6.77 (m, 2H), 5.60 (br, 1 H), 4.97-5.00 (m, 1 H), 3.84-4.02 (m, 4H), 2.90 (m, 2H), 1.93 (m, 2H).
K) 13C-NM R(75.5 MHz, CDCI3) δ: 155.60, 134.06, 126.15, 116.47,
103.58, 65.36, 34.04, 30.52.
[Example 50] Preparation of 2-(2-hydroxyhex-5-enylsulfanyl)-4- fluorophenol.
15
Figure imgf000051_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol and benzylbromide were replaced with 2-bromo-4-
20 fluorophenol 382 mg (2 mmol) and 1 ,2-epoxy-5-hexen 228 μl (2 mmol,
1.0 equivalent), respectively. After purification, the title compound 411 mg (yield: 85%) was obtained.
1 H-N MR(300 MHz, CDCI3) δ: 7.39 (br, 1 H), 7.18-7.22 (m, 1 H), 6.89-7.00 (m, 2H), 5.73-5.82 (m, 1 H), 4.96-5.05 (m, 2H), 3.70 (br, 1 H), 3.05 (br, 1H), 2.93-299 (m, 1H), 2.71-278 (m, 1H), 2.10-2.20 (m, 2H), 1.58-1.66 (m, 2H).
13C-NMR(75.5 MHz, CDCI3) δ. 158.06, 154.87, 153.88, 153.85,
138.06, 122.16, 121.86, 120.43, 120.32, 118.34, 118.04, 116.73, 116.62, 115.85, 70.02, 44.19, 35.59, 30.3.
[Example 51] Preparation of (2-(benzylsulfanyl)phenyl)methaπol.
Figure imgf000052_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 2-bromobenzyialcohol 374 mg (2 mmol). After purification, the title compound 432 mg (yield: 94%) was obtained. 1H-NMR(300 MHz, CDCI3) δ: 7.15-7.34 (m, 9H), 4.58 (s, 2H), 4.01
(s, 1H), 2.29 (br, 1H).
13C-NMR(75.5 MHz, CDCI3) δ: 142.09, 137.85, 134.51, 132.11, 129.25, 128.98, 128.75, 128.66, 127.97, 127.75, 63.87, 40.24, 31.62.
[Example 52] Preparation of (3-(benzylsulfanyl)phenyl)methaπol.
Figure imgf000053_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 3-bromobeπzylalcohol 374 mg (2 mmol) After purification, the title compound 409 mg (yield 89%) was obtained
1H-NMR(300 MHz, CDCI3) δ 710-726 (m, 9H), 454 (s, 2H), 4.09 (s, 2H), 205 (br, 1H)
13C-NMR(755 MHz, CDCI3) δ 14204, 13775, 13714, 12943, 12931, 12911, 12893, 12843, 12764, 12527, 6528, 3925
[Example 53] Preparation of (4-(benzylsulfanyl)phenyl)methanol
Figure imgf000053_0002
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 4-bromobenzylalcohol 374 mg (2 mmol) After purification, the title compound 426 mg (yield 92%) was obtained 1H-NMR(300 MHz, CDCI3) δ 729-720 (m, 9H), 460 (s, 2H), 409
(s, 2H), 1 87 (br, 1H)
13C-NMR(755 MHz, CDCI3) δ 13949, 13780, 135.99, 130.39, 129.22, 128.97, 128.92, 127.92, 127.62, 65.25, 39.4.
[Example 54] Preparation of (4-(pent-2- y ny Is ulfanyl)pheny I) methanol.
Figure imgf000054_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol and benzylbromide were replaced with 4-bromo- benzylalcohol 374 mg (2 mmol) and 1 -bromo-2-pentiπe 204 μl (2 mmol,
1 .0 equivalent), respectively. After purification, the title compound 375 mg (yield: 91 %) was obtained.
1H-NMR(300 MHz, CDCI3) δ: 7.26-7.42 (m, 4H), 4.63 (s, 2H), 3.59 (m , 2H), 2.16 (m, 1 H), 2.02 (br, 1 H), 1 .08 (t, 3H, J = 7.44 Hz). 13C-NMR(75.5 MHz, CDCI3) δ: 139 79, 135.30, 130.49, 127.88,
86.00, 75.25, 65.21 , 23.63, 14.22, 12.90.
[Example 55] Preparation of ferf-butyl 2-((4- (hydroxymethyl)phenyl)sulfanyl)acetate.
Figure imgf000054_0002
The same procedure as described in Example 40 was repeated but 2-bromophenol and benzylbromide were replaced with 4-bromo- benzylalcohol 374 mg (2 mmol) and t-butyl bromoacetate 296 μl (2 mmol, 1.0 equivalent), respectively. After purification, the title compound 452 mg (yield: 89%) was obtained. 1H-NMR(300 MHz, CDCI3) δ: 7.23-7.41 (m, 4H), 4.59 (s, 2H), 3.51
(s, 2H), 2.63 (br, 1H), 1.39 (s, 9H).
13C-NMR(75.5 MHz, CDCI3) δ: 169.31, 140.15, 134.65, 130.39, 127.88, 82.41, 64.90, 38.19, 28.27.
[Example 56] Preparation of (4-(2-(1,3-dioxolan-2- yl)ethylsulfanyl)phenyl)methanol.
Figure imgf000055_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol and benzylbromide were replaced with 4-bromo- benzylalcohol 374 mg (2 mmol) and 2-(2-bromometyl)-1 ,3-dioxolan 235 μl (2 mmol, 1.0 equivalent), respectively. After purification, the title compound 360 mg (yield: 75%) was obtained. 1H-NMR(300 MHz, CDCI3) δ: 7.19-7.36 (m, 4H), 4.96 (t, 1H, J =
4.46 Hz), 4.60 (s, 2H), 3.81-3.97 (m, 4H), 2.97-3.02 (m, 2H), 2.29 (br, 1H), 1.97 (m, 1H).
13C-NMR(75.5 MHz, CDCI3) δ: 139.22, 135.79, 129.70, 128.02,
103.42, 65.38, 65.14, 33.86, 28.28. [Example 57] Preparation of 1 -((4-
(hydroxymethyl)phenyl)sulfanyl)hex-5-en-2-ol.
Figure imgf000056_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol and benzylbromide were replaced with 4-bromo- benzylalcohol 374 mg (2 mmol) and 1 ,2-epoxy-5-hexen 228 μl (2 mmol,
1 .0 equivalent), respectively. After purification, the title compound 395 mg (yield: 83%) was obtained.
1 H-NMR(300 MHz, CDCI3) δ: 7.22-7.34 (m, 4H), 5.78 (m, 1 H), 4.94-5.05 (m, 2H), 4.59 (s, 2H), 3.68 (m, 1 H), 3.06-3.12 (m, 1 H), 2.81 - 2.88 (m, 3H), 2.15 (m, 2H), 1.60 (m, 2H).
13C-NMR(75.5 MHz, CDCI3) δ: 139.81 , 138.40, 134.91 , 130.40, 128.08, 115.45, 69.44, 64.88, 42.39, 35.53, 30.28.
[Example 58] Preparation of 2-(2-(benzylsulfanyl)phenyl)ethanol.
Figure imgf000056_0002
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 2-bromo-phenethylalcohol 402 mg (2 mmol) After purification, the title compound 444 mg (yield: 91 %) was obtained.
1H-NMR(300 MHz, CDCI3) δ: 7.13-7.36 (m, 9H), 4.08 (s, 2H), 3.77 (dd, 2H, J = 6.66 Hz, 6.69 Hz), 2.96 (dd, 2H , J = 6.66 Hz, 6.69 Hz), 1.36 (br, 1 H).
13C-NMR(75.5 MHz, CDCI3) δ: 138.85, 137.36, 135.84, 130.56,
130.42, 129.00, 128.64, 127.40, 127.37, 126.74, 62.80, 39.44, 37.32.
[Example 59] Preparation of 2-(3-(benzylsulfanyl)phenyl)ethanol.
Figure imgf000057_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 3-bromo-phenethylalcohol 402 mg (2 mmol). After purification, the title compound 439 mg (yield: 90%) was obtained.
1 H-NMR(300 MHz, CDCI3) δ: 7.03-7.28 (m, 9H), 4.10 (s, 2H), 3.79 (m , 2H), 2.78 (t, 2H, J = 6 49 Hz), 1.34 (br, 1 H)
13C-NMR(75.5 MHz, CDCI3) δ: 139.41 , 137.52, 136.55, 130.48, 129.48, 129.10, 128.96, 128.63, 128.56, 127.88, 127.29, 127.24, 63.47, 39.07, 39.00.
[Example 60] Preparation of 2-(4-(benzylsulfanyl)phenyl)ethanol.
Figure imgf000058_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 4-bromo-phenethylalcohol 402 mg (2 mmol) After purification, the title compound 439 mg (yield 90%) was obtained
1H-NMR(300 MHz, CDCI3) δ 710-728 (m, 9H), 409 (s, 2H), 383 (m, 2H), 282 (t, 2H, J = 651 Hz), 1 37 (br, 1H)
13C-NMR(755 MHz, CDCI3) δ 13794, 13733, 13458, 13077, 12995, 12922, 12888, 12756, 6391, 3973, 3910
[Example 61] Preparation of 6-benzylsulfanyl-naphthalen-2-ol
Figure imgf000058_0002
The same procedure as described in Example 40 was repeated but 2-bromophenol was replaced with 6-bromo-2-naphtol 446 mg (2 mmol) After purification, the title compound 490 mg (yield 92%) was obtained 1H-NMR(300 MHz, CDCI3) δ 767(d, 1H, J=1 6Hz), 760(d, 1H,
J=93Hz), 755(d, 1H, J=87Hz), 513(br s, 1H), 415(s, 2H)
13C-NMR(755 MHz, CDCI3) δ 1537, 1378, 1335, 1309, 1295, 129 4, 129 1 , 128 7, 127 4, 127 1 , 118 5, 109 7, 39 9
[Example 62] Preparation of /-butyl(4- hydroxypheπylsulfanyl)acetate
Figure imgf000059_0001
The same procedure as described in Example 40 was repeated but 2-bromophenol and benzylbromide were replaced with 4- bromophenol 346 mg (2 mmol) and ferr-butyl bromoacetate 295 μl (2 mmol, 1 0 equivalent), respectively After purification, the title compound 447 mg (yield 93%) was obtained
1 H-NMR(300 MHz, CDCI3) δ 7 31 (d, 2H, J=S 8Hz), 6 67(d , 2H, J=8 8Hz), 6 33(br s, 1 H), 3 39(s, 2H), 1 39(s, 9H)
[Example 63] Preparation of 5-[4-(ferf-butyldιmethylsιlanyloxy)-3- methyl-phenylsulfanyl-4-methyl-2-[(4-trιfluoromethyl)phenyl]thιazol
Figure imgf000059_0002
4-ιodιne-2-methyl-phenoxy-tert-butyldιmethyl silane 500 mg (1 74 mmol) was completely dissolved in dry tetrahydrofuran 40 ml under nitrogen atmosphere, and the mixture was cooled to -78°C To the mixture, n-butyl lithium 1 09 ml (1 6M in hexane, 1 0 equivalent) was slowly added for 1 minute After stirring additional 10 minutes, sulfur powder 557 mg(1 74 mmol, 1 0 equivalent) was added at once at the ) same temperature After stirring the mixture at the same temperature for additional 10 minutes to completely dissolve sulfur, 5-chloromethyl- 4-methyl-2-[(4-trιfluoromethyl)phenyl]thιazol 420 mg (1 74 mmol, 1 0 equivalent) was added at once Reaction was carried out so that the temperature of overall reaction mixture was raised to room temperature in 60 minutes Aqueous ammonium chloride solution was added thereto to quench the reaction The organic phase was extracted by using ethyl acetate and aqueous sodium chloride solution Moisture contained in the organic phase was removed by using magnesium sulfate After filtration, the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography to obtain the title compound 730 mg (yield 846%)
1H-NMR(300 MHz, CDCI3) δ 797(d, 2H, J=8 OHz), 765(d, 2H, J=82Hz), 717(d, 1H, J=I 8Hz), 707(dd, 1H, J=82 and 23Hz), 667(d, 1H, J=83Hz), 410(s, 2H), 220(s, 3H), 215(s, 3H), 1 00(s, 9H), 020(s, 6H)
13C-NMR(755 MHz, CDCI3) δ 1634, 1549, 151 8, 1368, 1326, 1304, 1296(q, J=32Hz), 1268, 1262(q, J=4Hz), 1252, 1196, 330, 261, 187, 171, 152, -39
[Example 64] Preparation of 2-methyl-4-[[[4-methyl-2-[(4- trιfluoromethyl)phenyl]thιazol-5-yl]methyl]sulfanyl]phenol
Figure imgf000061_0001
4-ιodιne-2-methylphenol 11 7 g (50 0 mmol) was completely 5 dissolved in dry tetrahydrofuran 400 ml under nitrogen atmosphere, and the mixture temperature was maintained at 0°C To the mixture, isopropylmagnesium chloride 27 5 ml (2 0 M-ether, 1 1 equivalent) was slowly added at the same temperature After 10 minutes, the mixture was cooled to -78 "C ferf-Butyl lithium 64 7 μl (1 7 M-pentane, 2 2
10 equivalent) was slowly added After 20 minutes, sulfur powder 1 60 g(50 mmol, 1 0 equivalent) dissolved in dry THF 50 ml was slowly added Reaction was carried out so that the temperature of overall reaction mixture was raised to O O After 60 minutes, 5-chloromethyl-4-methyl- 2-[(4-trιfluoromethyl)phenyl]thιazol 13 1 g (45 0 mmol, 0 9 equivalent)
I 1) dissolved in dry THF 40 ml was added at 0 °C After 30 minutes at room temperature, aqueous ammonium chloride solution 500 μl was added thereto to quench the reaction The organic phase was extracted Moisture contained in the organic phase was removed by using magnesium sulfate After filtration, the solvent was evaporated under
ZO reduced pressure The residue was purified by silica gel column chromatography using hexan/ethylacetate(v/v=3/1 ) to obtain the title compound 16 2 mg (yield 91 %)
1H-NMR(300 MHz, CDCI3) δ 7 96(d, 2H, J=8 2Hz), 7 64(d , 2H, J=8 3Hz), 7 20(d, 1 H, J=1 8Hz), 6 97(dd, 1 H, J=8 2 and 2 2Hz), 6 59(d, 1 H, J=8.2Hz), 5.52(br s, 1 H), 4.06(s, 2H), 2.19(s, 3H), 2.09(s, 3H).
13C-NMR(75.5 MHz, CDCI3) δ: 164.1 , 155.5, 151 .7, 137.4, 136.8,
133.6, 131 .9(q, J=33Hz), 131.8, 131 .6, 126.9, 126.4(q, J=4Hz), 125.9, 123.8, 115.7, 33.2, 16.2, 14.8.
Use possibility at industry
As described above, according to the process of the invention, alkyl aryl sulfide derivatives represented by Chemical Formula (III) can be prepared in a simple process with high yield.

Claims

What is claimed is:
1 . A process for preparing an alkyl aryl sulfide represented by Chemical Formula (II I) which comprises substituting a halogen atom of an aryl halogen compound represented by Chemical Formula (I) with an alkyl lithium represented by Chemical Formula (IV), and subsequently reacting with sulfur and a compound represented by Chemical Formula (II):
Figure imgf000063_0001
\t-^-K2 ( II )
J «MrftJV~* <■>
(IV) R<Li wherein, A represents CH or a nitrogen atom, Xi represents a halogen atom, X2 represents a halogen atom or a leaving group, Ri represents a hydrogen atom, a halogen atom, a Ci-C7 alkyl group, a C1-C7 alkyloxy group, a C1-C7 alkylthiooxy group or an aryl group, wherein the alkyl group may be substituted by one or more substituent(s) selected from the group consisting of halogen atoms and a hydroxyl group,
R2 represents a C1-Ci0 alkyl group, an aryl group, a C1-C10 alkylester group, a C1-Ci0 alkylketone group or an arylketoπe group,
R4 represents a C1-C4 alkyl group, and n represents an integer of 1 to 3
2 A process for preparing an alkyl aryl sulfide represented by Chemical Formula (III), which comprises reacting an aryl halogen compound represented by Chemical Formula (I) with an alkyl magnesium halide represented by Chemical Formula (V) to protect the hydrogen-donor substituent, substituting the halogen of the compound (I) with an alkyl lithium represented by Chemical Formula (IV), and subsequently reacting with sulfur and a compound represented by Chemical Formula (I I)
Figure imgf000064_0001
X2-^R2 ( Il )
( III ) fr M
(IV) R4Li
R3MgX3 <V> wherein, A represents CH or a nitrogen atom,
Xi represents a halogen atom,
X2 represents a halogen atom or a leaving group, X3 represents a halogen atom,
Ri represents hydroxyl group, hydroxymethyl, hydroxyethyl, amine group, aminomethyl, aminoethyl, alkylamine, dialkylamine, carboxylic group, halogen atom or C1-C4 alkyl group,
R2 represents a C1-C10 alkyl group, an aryl group, a C1-C10 alkylester group, a C1-CiO alkylketone group or an arylketone group,
R3 and R4 independently represents a C1-C4 alkyl group, and π represents an integer of 1 to 3
3 A process for preparing an alkyl aryl sulfide represented by Chemical Formula (III) according to claim 2, wherein the alkylmagnesium halide is a compound selected from the group consisting of CH3MgCI, CH3MgBr, CH3MgI, CH3CH2MgCI, CH3CH2MgBr, CH3CH2MgI, CH3CH2CH2MgCI, CH3CH2CH2MgBr, CH3CH2CH2MgI, (CH3J2CHMgCI, (CH3J2CHMgBr, (CH3J2CHMgI, CH3CH2CH2CH2MgCI, CH3CH2CH2CH2MgBr,
CH3CH2CH2CH2MgI, C2H5CHCH3MgCI, C2H5CHCH3MgBr, C2H5CHCH3MgI, (CH3J3CMgCI, (CH3J3CMgBr and (CH3J3CMgI
4 A process for preparing an alkyl aryl sulfide represented by Chemical Formula (III) according to claim 1 or 2, wherein the alkyl lithium employed is n-butyl lithium , sec-butyl lithium or tert-butyl lithium, and the amount employed is 1 to 3 equivalants with respect to the compound of Chemical Formula (D-
5. An alkyl aryl sulfide selected from following compounds:
benzyl 2-trifluoromethylphenyl sulfide; benzyl 2-methoxyphenyl sulfide; 2-bromo-6-(2-[1 ,3]dioxolaπ-2-yl-ethylsulfanyl)pyridine;
5-[4-(tert-butyldimethylsilanyloxy)-3-methylphenylsulfanyl]-4- methyl-2-[(4-trifluoromethyl)phenyl]thiazole;
4-benzylsulfanyl-2-methyl-phenylamine; tert-butyl [4-(2-aminoethyl)phenylthio]acetate; 4-benzylsulfanyl-2 ,6-dimethy I phenol ;
4-benzylsulfanyl-2-chlorophenol;
4-benzylsulfanyl-4-fluorophenol ;
(4-benzylsulfanylphenyl)methanol ; tert-butyl(4-hydroxyphenylsulfanyl)acetate; 2-methyl-4-[[[4-methyl-2-[(4-trifluoromethyl)phenyl]thiazol-5- yl]methyl]sulfanyl]phenol;
2-(pent-2-yπylsulfanyl)-4-fluorophenol;
2-(5-phenylpentylsulfanyl)-4-fluorophenol;
2-(cyclohexylmethylsulfanyl)-4-fluorophenol; 4-((2-( 1 ,3-dioxolan-2-yl)ethylsulfanyl)phenol; 2-(2-hydroxyhex-5-enylsulfanyl) 4-fluoro phenol, 4-((tert-butoxycarboπyl)methylsulfanyl)benzoιc acid, 3-(2-(1 ,3-dιoxolan-2-yl)ethylsulfanyl)benzoιc acid, 3-(2-hydroxyhex-5-enylsulfanyl)benzoιc acid, 2-(4-(benzylsulfaπyl)phenyl)ethanol,
2-(3-(benzylsulfanyl)phenyl)ethanol, 1 -((4-(hydroxymethyl)phenyl)sulfanyl)hex-5-en-2-ol, (4-(2-(1 , 3-d ιoxolan-2-yl)ethylsulf a nyl)phenyl) methanol, tert-butyl 2-((4-(hydroxymethyl)phenyl)sulfanyl)acetate, (4-(pent-2-ynylsulfanyl)phenyl)methanol,
4-(benzylthιo)-2-bromobenzenamιπe, 4-(5-phenylpentylthιo)benzeneamιne, 1 -(4-amιnopentylthιo)hex-5-en-2-ol, 2-f4-(benzylthιo)phenyl]ethanamιne, and tert-butyl 2-[4-(2-amιπoethyl)phenylthιo]-2-methylpropιonate
PCT/KR2005/003528 2004-10-22 2005-10-21 Process for alkyl aryl sulfide derivatives and new sulfide compounds WO2006043797A1 (en)

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