Title of the Invention: Method for producing pentafluorosulfanyl aromatic compound
Technical field
[0001]
　The present invention relates to a method for producing a pentafluorosulfanyl aromatic compound.
Background art
[0002]
　The pentafluorosulfanyl group (hereinafter referred to as SF 5 group) is attracting attention as a material for which the future is expected. The SF 5 group has attracted particular attention in the pharmaceutical field because of its unique physicochemical properties. The SF 5 group is often compared with the well-known CF 3 group, but the electronegativity of the SF 5 group is 3.65, which is close to that of the nitro group, but the electronegativity of the CF 3 group is 3.36. The size of the SF 5 group is about halfway between the CF 3 group and the t-butyl group. SF 5 and CF 3 groups have high electronegativity and hydrophobicity (Hansh hydrophobicity constant is π (CF 3 ) is 1.09, π (SF 5 ) is 1.51), but generally have different properties . The SF 5 group exhibits water solubility, membrane permeability, and metabolic stability. From these characteristics, SF 5The group may be useful as a new drug candidate compound, herbicide, insecticide, antidepressant, antimalarial and the like. Non-Patent Document 1 discloses that an aryl disulfide is oxidatively chlorofluorinated, and then Ar—SF 4 Cl is reacted with a fluorinating agent such as ZnF 2 , HF, Sb (III / V) fluoride to exchange Cl—F. A two-step reaction (Scheme 1a) is disclosed that reacts (S N reaction) to give Ar-SF 5 . This method is currently in practical use.
[0003]
Regarding pyridine (Py) having an 　SF 5 group, Non-Patent Document 2 discloses that pyridine disulfide is oxidatively chlorinated with fluorination, and then o-Py-SF 4 Cl is reacted with AgF to cause o- A method for obtaining Py-SF 5 is disclosed (Scheme 1b). In Non-Patent Document 2, an attempt was made to fluorinate o-Py-SF 4 Cl with AgF having a 5-NO 2 or 5-CF 3 group using AgF, but little or no Py-SF 5 was synthesized. It was.
[0004]
　Non-Patent Document 3 discloses a method for synthesizing m-Py-SF 5 and p-Py-SF 5 (Scheme 1c). The reason why the Cl—F exchange reaction does not proceed in o-Py-SF 4 Cl is that the C—S bond cleavage by the competitive nucleophilic aromatic substitution (S N Ar) reaction (scheme 1c, pathway a) is the S N reaction. This is presumably because it takes precedence over the Cl—F exchange reaction via route (route b in Scheme 1c). It is known that the Cl—F exchange reaction in an SF 4 Cl group-containing aromatic compound lacking electrons is difficult, and Non-Patent Document 1 describes p-NO 2 -phenyl-SF 4 Cl at high temperature. It is disclosed that the Cl—F exchange reaction did not proceed much even when reacted with ZnF 2, and the yield of p-NO 2 -phenyl-SF 5 was 36%.
[0005]
[Chemical 1]

[0006]
　Non-Patent Document 4 discloses reacting IF 5 with thiopyridine having Cl as a substituent .
Prior art documents
Non-patent literature
[0007]
Non-Patent Document 1: T. Umemoto, L. Garrick, N. Saito, Beilstein J. Org. Chem., 2012, 8, 461.
Non-Patent Document 2: OS Kanishchev, WR Dolbier, Jr., Angew. Ed., 2015, 54, 280.
Non-patent document 3: M. Kosobokov, B. Cui, A. Balia, K. Matsuzaki, E. Tokunaga, N. Saito, N. Shibata, Angew. Chem. Int. Ed , 2016, 55, 10781
Non-Patent Document 4: A. Sipyagin, I. Pomytkin, S. Paltsun, N. Aleinikov and V. Kartsev, J. Fluorine Chem., 1991, 54, 115.
Summary of the Invention
Problems to be solved by the invention
[0008]
　In the conventional method, when a pentafluorosulfanyl aromatic compound is produced efficiently, there are restrictions such as substituents. Non-Patent Document 4 discloses a scheme for producing pentafluorosulfanylpyridine by reacting pyridinethiol and IF 5 , but as described later, when the inventors actually tried this reaction, it was confirmed that the reaction did not proceed. did. In view of such circumstances, an object of the present invention is to provide a method for efficiently producing an aromatic compound having an SF 5 group without depending on a substituent .
Means for solving the problem
[0009]
　The inventors have found that IF 5 allows the reaction to proceed smoothly. That is, the said subject is solved by the following this invention.
[1] A 　method for producing a pentafluorosulfanyl aromatic compound represented by general formula (3), comprising reacting IF 5 with a halotetrafluorosulfanyl aromatic compound represented by general formula (2)
.
[2] The production according to [1], wherein the aryl group or heteroaryl group has a substituent selected from the group consisting of a halogen group, an electron-withdrawing group excluding the halogen group, and an electron-donating group excluding the halogen group. Method.
[3] The production method according to [1], wherein the halotetrafluorosulfanyl aromatic compound and the pentafluorosulfanyl aromatic compound are represented by general formulas (2 ′) and (3 ′), respectively.
[4] The production method according to [1], wherein the substituent is an electron-withdrawing group excluding a halogen group, and the reaction is performed at 50 ° C. or higher.
[5] The substituent is an electron withdrawing group excluding a halogen group, and 1 equivalent or more of IF 5 is used with respect to the SF 4 Hal group in the halotetrafluorosulfanyl aromatic compound represented by the general formula (2). [1] The production method according to [1]. [6] At least one of the X and Y is N,

　At least 1 of said R is a manufacturing method as described in [3] which is an electron withdrawing group except the halogen group which exists in 3rd-position on a ring.
[7] The production method according to [1], wherein the halotetrafluorosulfanyl aromatic compound and the pentafluorosulfanyl aromatic compound are respectively represented by general formulas (2 ″) and (3 ″).
The invention's effect
[0010]
　According to the present invention, a pentafluorosulfanyl aromatic compound can be produced.
BEST MODE FOR CARRYING OUT THE INVENTION
[0011]
　In the present invention, “X to Y” includes X and Y which are their end values. “X or Y” includes either X or Y or both. Hereinafter, the present invention will be described in detail.
[0012]
1. Production method of the
　present invention The present invention comprises the following reaction steps.
　Ar- (SF 4 Hal) k + IF 5　→ Ar- (SF 5 ) k
[0013]
(1) Halotetrafluorosulfanyl aromatic compound A
　halotetrafluorosulfanyl aromatic compound is represented by the general formula (2): Ar- (SF 4 Hal) k . Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. The aryl group is an aromatic hydrocarbon group, and examples thereof include a phenyl group and a naphthyl group. The heteroaryl group is a heteroaromatic hydrocarbon group, and examples thereof include a pyridyl group, a pyrimidyl group, an indolyl group, and a benzothiazolyl group.
[0014]
　Substituents in aryl groups and heteroaryl groups (hereinafter collectively referred to as “Ar groups”) include (i) halogen groups, (ii) electron withdrawing groups excluding halogen groups, and (iii) electron donating excluding halogen groups Groups. Examples of the halogen group include an F group, a Cl group, a Br group, and an I group, and an F group, a Cl group, and a Br group are preferable from the viewpoint of availability.
[0015]
　The electron-withdrawing group is a group having a property that attracts electrons more easily than hydrogen, and in the present invention, preferably refers to a group having a positive value for the substituent constant σ determined according to the Hammett rule. As an electron withdrawing group, CF 3 group, CCl 3 group, CBr 3 group, CI 3 group, nitro group (NO 2 group), cyano group (CN group), COOH group, COOR 1 group (R 1 has 1 carbon atom) -3 alkyl groups), SO 3 H groups, and SO 3 R 2 groups (R 2 is an alkyl group having 1 to 3 carbon atoms or a perfluoroalkyl group having 1 to 3 carbon atoms). Among these, a fluorine-containing group is preferable. Examples of the fluorine-containing group include a CF 3 group and a SO 3 CF 3 group. Among these, nitro group, CF 3Group or a cyano group is preferred. In general, halogen groups are also classified as electron-withdrawing groups. However, since halogen groups may act as electron-donating groups due to the mesomeric effect or the like, the electron-withdrawing group excludes halogen groups in the present invention. Hereinafter, the electron withdrawing group excluding the halogen group is also simply referred to as “electron withdrawing group”.
[0016]
　The electron donating group is a group having a property of easily giving an electron as compared with hydrogen, and in the present invention, preferably refers to a group having a negative substituent constant σ determined according to the Hammett rule. Examples of the electron donating group include an alkyl group, an alkoxyl group, a hydroxyl group, and an amino group. The alkyl group is preferably a linear, branched or cyclic alkyl group having 1 to 18 carbon atoms, and more preferably an alkyl group having 1 to 5 carbon atoms. The same applies to the alkyl group in the alkoxy group. For the same reason, the electron donating group in the present invention excludes a halogen group. Hereinafter, the electron donating group excluding the halogen group is also simply referred to as “electron donating group”.
[0017]
　The substituents (i), (ii) and (iii) may coexist in the compound. However, since preferable reaction conditions differ depending on the characteristics of the substituents as described later, in one embodiment, these substituents do not coexist in the compound. However, since the substituents (i) and (iii) have similar characteristics, in other embodiments, the substituents (i) and (iii) coexist in the compound.
[0018]
　Hal is a Cl group, a Br group, or an I group, and a Cl group is preferable from the viewpoint of availability.
[0019]
　k represents the number of SF 4 Hal groups and is an integer of 1 to 3, preferably 1 or 2, and more preferably 1.
[0020]
　The halotetrafluorosulfanyl aromatic compound is preferably represented by the general formula (2 ′).
[0021]
[Chemical 2]

[0022]
　X is C or N, and Y is C or N. Let n be the number of N on the ring. n is an integer of 0-2. k is defined as described above.
[0023]
　R is a substituent on the ring, and m represents the number thereof. R is preferably the aforementioned substituent (i), (ii), or (iii). When m is not 0, a plurality of R may be the same or different. m is represented by 0 to (5-kn). That is, m can take a value of 0-5.
[0024]
　When N is present in the formula (2 ′), the effect of the present invention becomes more remarkable when an electron-withdrawing group is present at the 3-position with respect to N.
[0025]
　In another embodiment, the halotetrafluorosulfanyl aromatic compound is preferably represented by the general formula (2 ″).
[0026]
[Chemical 3]

[0027]
　Z is N or S, and Hal is defined as described above. p represents the number of SF 4 Hal groups on the 6-membered ring , and is an integer of 0 to 2, preferably 0 or 1, more preferably 0.
[0028]
　R ′ is a substituent on the 6-membered ring, and q represents the number thereof. R ′ is preferably the aforementioned substituent (i), (ii), or (iii). When q is not 0, a plurality of R ′ may be the same or different. q is an integer represented by 0 to (4-p) and can take 0 to 4.
[0029]
(2) IF 5
　iodine pentafluoride (IF 5 ) converts the SF 4 Hal group of the halotetrafluorosulfanyl aromatic compound into an F group. The amount of IF 5 used is not limited as long as the target compound is obtained, but is preferably 0.1 equivalents or more, more preferably 2 equivalents or more with respect to the SF 4 Hal group. The upper limit of the amount used is preferably 10 equivalents or less from the viewpoint of cost and the like.
[0030]
(3) Pentafluorosulfanyl aromatic compound The pentafluorosulfanyl aromatic compound
　obtained by the production method of the present invention is represented by the general formula (3): Ar- (SF 5 ) k . Ar is the same as Ar in the general formula (2). k represents the number of SF 5 groups and is an integer of 1 to 3, preferably 1 or 2, and more preferably 1. The pentafluorosulfanyl aromatic compound is preferably represented by the general formula (3 ′).
[0031]
[Chemical 4]

[0032]
　X, Y, R, m, and k are defined as in the general formula (2 ′).
[0033]
　In another embodiment, the pentafluorosulfanyl aromatic compound is preferably represented by the general formula (3 ″).
[0034]
[Chemical 5]

[0035]
　Z, R ′, p, and q are defined as in the general formula (2 ″).
[0036]
　Specific examples of the pentafluorosulfanyl aromatic compound are shown below.
[0037]
[Chemical 6]

[0038]
[Chemical 7]

[0039]
[Chemical 8]

[0040]
(4) Reaction conditions The
　reaction conditions can be adjusted as appropriate to achieve the desired yield. Preferred conditions are described below.
[0041]
　1) Ar group does not have a substituent, or when (i) a halogen group or (iii) the electron donating group is used as a substituent, the
　reaction temperature is not particularly limited and may be room temperature (20 ° C.) or higher. preferable. The upper limit of the temperature is not limited, but is preferably 100 ° C. or lower.
[0042]
　The amount of IF 5 used is not limited , but is preferably 0.1 equivalent or more, more preferably 1 equivalent or more, and more preferably 2 equivalent or more with respect to the SF 4 Hal group. Although the upper limit is not limited, it is preferably 10 equivalents or less, more preferably 8 equivalents or less from the viewpoint of economy and the like.
[0043]
　The reaction may be performed without a solvent or may be performed using a solvent. Since IF 5 is a liquid, the reaction can be carried out without a solvent. As the solvent, a non-halogen solvent is preferable, and a non-polar solvent such as hexane is more preferable.
[0044]
　2) When the Ar group has (ii) the electron withdrawing group as a substituent, the
　reaction temperature is preferably 50 ° C. or higher, more preferably 60 ° C. or higher. The upper limit of the reaction temperature is preferably 100 ° C. or lower, and more preferably 80 ° C. or lower.
[0045]
　The amount of IF 5 used is not limited , but is preferably 2 equivalents or more, more preferably 3 equivalents or more, and more preferably 5 equivalents or more with respect to the SF 4 Hal group. The upper limit is not limited, but is preferably 10 equivalents or less and more preferably 8 equivalents or less from the viewpoint of cost and the like.
[0046]
　The reaction may be performed without a solvent or may be performed using a solvent. Since IF 5 is a liquid, the reaction can be carried out without a solvent. The solvent is preferably a nonpolar solvent, and examples thereof include non-halogen solvents and hydrocarbon solvents such as hexane.
Example
[0047]
Example 1 and Comparative Example 1 The
　following reaction was performed using a compound fluorinating agent having an electron withdrawing group as a substituent .
[0048]
[Chemical 9]

[0049]
　Specifically, 5-nitro-o-chlorotetrafluorosulfanylpyridine (0.72 mmol) synthesized by a known method was charged into a fluororesin container in a glove box. Under a nitrogen gas stream, the amount of IF 5 shown in Table 1 was charged into a cylinder and charged into the fluororesin container via a Teflon (registered trademark) tube. The mixture was stirred and reacted under the conditions shown in Table 1. After completion of the reaction, the reaction mixture was poured into cold water and neutralized with an aqueous sodium hydrogen carbonate solution. The reaction solution was subjected to extraction three times with 3 mL of hexane to obtain an organic phase, which was dried over sodium sulfate. Subsequently, the organic phase was filtered, the filtrate was concentrated under reduced pressure to distill off the solvent, and purified by silica gel column chromatography (pentane / dichloromethane) to obtain the target compound. The yield was determined by 19 F-NMR analysis (using fluorobenzene as internal standard).
[0050]
[table 1]

[0051]
[Example 2] Compounds having electron-withdrawing groups as substituents The
　following reactions were carried out in the same manner as in Example 1 using various chlorotetrafluorosulfanyl aromatic compounds (0.72 mmol) as raw materials. However, the reaction was performed at neat, that is, without using a solvent. The scheme and results are shown in Table 2.
[0052]
[Table 2]

[0053]
　The yield after isolation is shown. The numerical value in parentheses indicates the yield determined by 19 F-NMR analysis (using fluorobenzene as an internal standard). From Table 2, it is clear that the target compound can be obtained in high yield.
[0054]
[Example 3] Compound having a halogen group as a substituent The
　following reaction was carried out in the same manner as in Example 2 using various chlorotetrafluorosulfanyl aromatic compounds as raw materials. The scheme and results are shown in Table 3.
[0055]
[Table 3]

[0056]
　The yield after isolation is shown. The numerical value in parentheses indicates the yield determined by 19 F-NMR analysis (using fluorobenzene as an internal standard). From Table 3, it is clear that the target compound can be obtained in high yield.
[0057]
[Example 4] Compounds having halogen groups as substituents The
　following reactions were carried out in the same manner as in Example 1 using various chlorotetrafluorosulfanyl aromatic compounds as raw materials. The scheme and results are shown in Table 4 and below.
[0058]
[Table 4]

[0059]
　The yield after isolation is shown. The numerical value in parentheses indicates the yield determined by 19 F-NMR analysis (using fluorobenzene as an internal standard). From Table 4, it is clear that the target compound can be obtained in high yield.
[0060]
[Example 5] Compound having an electron donating group as a substituent The
　following reaction was carried out in the same manner as in Example 4 using various chlorotetrafluorosulfanyl aromatic compounds as raw materials. The scheme and results are shown in Table 5 and below.
[0061]
[Table 5]

[0062]
　The yield after isolation is shown. The numerical value in parentheses indicates the yield determined by 19 F-NMR analysis (using fluorobenzene as an internal standard). From Table 5, it is clear that the target compound can be obtained in high yield. In the synthesis of Compound 3l, the reaction was carried out even in the presence of 0.5 equivalent of silver carbonate. As a result, side reactions could be suppressed and the yield was improved.
[0063]
[Example 6] The
　following reaction was performed. Conditions and the like were the same as in Example 2. The scheme and results are shown in Table 6.
[0064]
[Table 6]

[0065]
[Comparative Example 2]
　The reaction described in Non-Patent Document 4 was attempted. Specifically, 99.6 mg of pyridinethiol shown below and 10 equivalents of IF 5 were stirred overnight at 70 ° C. without solvent. However, almost no compound in which the SH group was converted to the SF 5 group could be confirmed.
[0066]
[Chemical 10]

[0067]
　By the production method of the present invention, a pentafluorosulfanyl aromatic compound can be produced efficiently.
The scope of the claims
[Claim 1]
　General formula (2):
　　　Ar- (SF 4 Hal) k　　(2)
　(wherein Ar is a substituted or unsubstituted aryl group or heteroaryl group,
　Hal is a Cl group, a Br group, or an I group) ,
　K is an integer of 1 to 3)
, and includes reacting IF 5 with a halotetrafluorosulfanyl aromatic compound represented by the
　general formula (3):
　　　Ar— (SF 5 ) k　　(3)
　(formula In which Ar and k are defined as described above)
.
[Claim 2]
　The production method according to claim 1, wherein the aryl group or heteroaryl group has a substituent selected from the group consisting of a halogen group, an electron-withdrawing group excluding the halogen group, and an electron-donating group excluding the halogen group.
[Claim 3]
　The halo-tetrafluoro sulfanyl aromatics and pentafluorosulfanyl aromatic compounds, each represented by the general formula (2 ') and (3'),
[Chemical Formula 1

(wherein, Hal is Cl group, Br group, Or an I group,
　X is C or N,
　Y is C or N,
　R is independently a halogen group, an electron-withdrawing group excluding a halogen group, or an electron-donating group excluding a halogen group,
　k 2. The production method according to claim 1, 　wherein
　is an integer of 1 to 3, m is an integer represented by 0 to (5-kn), and
n is the number of N.
[Claim 4]
　The production method according to claim 1, wherein the substituent is an electron-withdrawing group excluding a halogen group, and the reaction is performed at 50 ° C. or higher.
[Claim 5]
　The substituent is an electron withdrawing group excluding a halogen group, and 1 equivalent or more of IF 5 is used with respect to the SF 4 Hal group in the halotetrafluorosulfanyl aromatic compound represented by the general formula (2). 2. The production method according to 1.
[Claim 6]

　The production method according to claim 3 　, wherein at least one of X and Y is N, and at least one of R is an electron-withdrawing group excluding a halogen group present at the 3-position on the ring.
[Claim 7]
　The halo-tetrafluoro sulfanyl aromatics and pentafluorosulfanyl aromatic compounds, each represented by the general formula (2 ') and (3 "),
[Chemical Formula 2]

(wherein, Hal is Cl group, Br group, Or an I group,
　Z is N or S,
　p is an integer of 0 to 2, and
　R ′ is independently a halogen group, an electron withdrawing group excluding the halogen group, or an electron donating excluding the halogen group The production method according to claim 1 , wherein
　q is an integer represented by 0 to (4-p)
.