JP6498048B2 - Fluorine-containing organic compound and method for producing biaryl compound using this and Grignard reagent - Google Patents
Fluorine-containing organic compound and method for producing biaryl compound using this and Grignard reagent Download PDFInfo
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- -1 biaryl compound Chemical class 0.000 title claims description 42
- 150000004795 grignard reagents Chemical class 0.000 title claims description 29
- 239000007818 Grignard reagent Substances 0.000 title claims description 27
- 229910052731 fluorine Inorganic materials 0.000 title claims description 21
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims description 16
- 239000011737 fluorine Substances 0.000 title claims description 16
- 150000002894 organic compounds Chemical class 0.000 title claims description 16
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 238000009815 homocoupling reaction Methods 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 14
- 235000019000 fluorine Nutrition 0.000 description 13
- 239000007800 oxidant agent Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- FPRXROMXIVKJTK-UHFFFAOYSA-N C1(=C(C(=C(C(=C1F)F)F)F)C(F)(F)F)C2=C(C(C(C2(F)F)(F)F)(F)F)C3=C(C(=C(C(=C3F)F)F)F)C(F)(F)F Chemical compound C1(=C(C(=C(C(=C1F)F)F)F)C(F)(F)F)C2=C(C(C(C2(F)F)(F)F)(F)F)C3=C(C(=C(C(=C3F)F)F)F)C(F)(F)F FPRXROMXIVKJTK-UHFFFAOYSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- YBMDPYAEZDJWNY-UHFFFAOYSA-N 1,2,3,3,4,4,5,5-octafluorocyclopentene Chemical compound FC1=C(F)C(F)(F)C(F)(F)C1(F)F YBMDPYAEZDJWNY-UHFFFAOYSA-N 0.000 description 7
- 235000010290 biphenyl Nutrition 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 5
- 150000001502 aryl halides Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000006887 Ullmann reaction Methods 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 150000001543 aryl boronic acids Chemical class 0.000 description 3
- 150000001500 aryl chlorides Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- IFRIJEKNVVMZBB-UHFFFAOYSA-N 1-fluorocyclopentene Chemical compound FC1=CCCC1 IFRIJEKNVVMZBB-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000004768 lowest unoccupied molecular orbital Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- GHDIHPNJQVDFBL-UHFFFAOYSA-N methoxycyclohexane Chemical compound COC1CCCCC1 GHDIHPNJQVDFBL-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-butyl ethyl ether Chemical compound CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 description 2
- ZFFLXJVVPHACEG-UHFFFAOYSA-N 1,2,3,3,4,4,5,5,6,6-decafluorocyclohexene Chemical compound FC1=C(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F ZFFLXJVVPHACEG-UHFFFAOYSA-N 0.000 description 1
- QVHWOZCZUNPZPW-UHFFFAOYSA-N 1,2,3,3,4,4-hexafluorocyclobutene Chemical compound FC1=C(F)C(F)(F)C1(F)F QVHWOZCZUNPZPW-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- MBQLGOIIFHLONT-UHFFFAOYSA-N C1=C(C(C(C(=C1F)F)(C(F)(F)F)Br)F)F Chemical compound C1=C(C(C(C(=C1F)F)(C(F)(F)F)Br)F)F MBQLGOIIFHLONT-UHFFFAOYSA-N 0.000 description 1
- BAJLYQUXNAQTQJ-UHFFFAOYSA-N C1=C(C=C(C(=C1C(F)(F)F)F)C(F)(F)F)C2=C(C(C(C2(F)F)(F)F)(F)F)C3=CC(=C(C(=C3)C(F)(F)F)F)C(F)(F)F Chemical compound C1=C(C=C(C(=C1C(F)(F)F)F)C(F)(F)F)C2=C(C(C(C2(F)F)(F)F)(F)F)C3=CC(=C(C(=C3)C(F)(F)F)F)C(F)(F)F BAJLYQUXNAQTQJ-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- XUCNUKMRBVNAPB-UHFFFAOYSA-N fluoroethene Chemical class FC=C XUCNUKMRBVNAPB-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- FEMRXDWBWXQOGV-UHFFFAOYSA-N potassium amide Chemical class [NH2-].[K+] FEMRXDWBWXQOGV-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Description
本発明は、含フッ素有機化合物及びこれとグリニャール試薬とのホモカップリング反応により、ビアリール化合物を製造する方法に関するものである。 The present invention relates to a fluorine-containing organic compound and a method for producing a biaryl compound by the homocoupling reaction of the same with a Grignard reagent.
ホモカップリング反応によるビアリール化合物の合成は工業的にも重要な反応であるが、現在最も用いられている方法は、1当量以上の銅試薬を用いハロゲン化アリールを直接カップリングさせるウルマン反応である。この反応は一般的に100℃程度の高温反応であり、反応時間も終夜反応が普通である。特に長い反応時間は工業的に好まれない条件である。一般的に中程度の収率でしか生成物が得られない。また当量の銅試薬から生じる反応副生成物は反応系から生成物の単離精製を困難にし、工業的プロセスを複雑なものにしている。さらに、用いるハロゲン化アリールはヨウ化アリール>臭化アリール>塩化アリールの順に反応性が減少し、最も原料として安価である塩化アリールを反応基質として用いることは困難な場合が多い。 Although the synthesis of biaryl compounds by homocoupling reaction is an industrially important reaction, the method currently most used is the Ullmann reaction in which aryl halides are directly coupled using one or more equivalents of a copper reagent. . This reaction is generally a high temperature reaction at about 100 ° C., and the reaction time is also normal overnight. Particularly long reaction times are conditions which are not favored industrially. In general, only moderate yields are obtained. Also, reaction by-products generated from the equivalent amount of copper reagent make it difficult to isolate and purify the product from the reaction system and complicate the industrial process. Furthermore, the reactivity of the aryl halide used decreases in the order of aryl iodide> aryl bromide> aryl chloride, and it is often difficult to use the inexpensive aryl chloride as the starting material as a reaction substrate.
これに対し、ハロゲン化アリールを他の官能基に変換し(例えば、アリールボロン酸やアリールスズ試薬)、それをパラジウム触媒などの遷移金属触媒を用いてホモカップリングさせる方法も知られている。アリールボロン酸は鈴木-宮浦カップリング反応でも用いられているためすでに工業的に利用されているところ、ホウ素は枯渇が懸念されている典型元素であり、コストも比較的高い。またスズ試薬は毒性の問題から工業利用には適さない。こうしたアリールボロン酸やアリールスズ試薬を得るためには、ハロゲン化アリールを一旦アリールグリニャール試薬やアリールリチウム試薬に変換する必要がある。 On the other hand, there is also known a method of converting an aryl halide into another functional group (for example, an arylboronic acid or an aryltin reagent) and homocoupling it using a transition metal catalyst such as a palladium catalyst. Arylboronic acid is already used industrially because it is also used in the Suzuki-Miyaura coupling reaction, but boron is a typical element of concern for depletion and its cost is relatively high. Also, tin reagents are not suitable for industrial use due to toxicity problems. In order to obtain such arylboronic acid and aryltin reagents, it is necessary to temporarily convert aryl halides to aryl Grignard reagents and aryllithium reagents.
一方、グリニャール試薬はマグネシウムとハロゲン化アリールから生成させる試薬であり、工業的にもよく用いられる反応試剤である。この汎用性の高いグリニャール試薬を直接用いてホモカップリングさせる方法も知られている。この中で最も用いられているのは、(a) グリニャール試薬に対し1当量以上の鉄などの遷移金属錯体を用いる方法か、(b) グリニャール試薬に対し触媒量の遷移金属触媒と1当量以上の有機酸化剤を併用する方法である。 これに対し、最近、遷移金属錯体を全く用いず、有機酸化剤のみを用いたグリニャール試薬のホモカップリング反応が報告されている(非特許文献1〜7)。これらの特徴として、室温付近での反応が可能であり、反応時間も1時間以内という短時間で良いことが挙げられる。しかし、これらの有機酸化剤は、原理的にグリニャール試薬に対し50mol%必要であり、実際に報告されている先行例において有機酸化剤は、100〜50mol%用いられている。 On the other hand, a Grignard reagent is a reagent generated from magnesium and an aryl halide, and is a reaction reagent often used industrially. There is also known a method of directly homocoupling using this highly versatile Grignard reagent. Among them, (a) a method using a transition metal complex such as iron with 1 equivalent or more to a Grignard reagent, or (b) a catalytic amount of a transition metal catalyst with a catalytic amount to 1 g or more with respect to the Grignard reagent. The method of using an organic oxidizing agent of On the other hand, recently, the homocoupling reaction of a Grignard reagent using only an organic oxidizing agent without using any transition metal complex has been reported (Non-patent Documents 1 to 7). As these characteristics, reaction at around room temperature is possible, and the reaction time may be as short as 1 hour or less. However, in principle, 50 mol% of these organic oxidizing agents are required relative to the Grignard reagent, and 100 to 50 mol% of the organic oxidizing agent is used in the actually reported examples.
この有機酸化剤を用いるグリニャール試薬のホモカップリング反応の中で、触媒的反応と主張されている例が一例報告されている(非特許文献6)。しかし、これは100mol%の有機酸化剤でグリニャール試薬のホモカップリングを行った後に、同一容器内で酸素を加え有機酸化剤を再生し、再生した有機酸化剤と等モルのグリニャール試薬を追加し、また同様の操作を繰り返していく、という疑似的な触媒反応であり、結果としてグリニャール試薬に対し14mol%の有機酸化剤を用いた触媒的カップリング反応となっているが、全く実用的な手法ではない。 Among the homocoupling reactions of Grignard reagents using this organic oxidizing agent, an example claimed as a catalytic reaction has been reported (NPL 6). However, after homocoupling of the Grignard reagent with 100 mol% of the organic oxidant, oxygen is added in the same container to regenerate the organic oxidant, and the regenerated organic oxidant and the equimolar Grignard reagent are added. It is a pseudo-catalytic reaction that repeats the same operation again, and as a result it is a catalytic coupling reaction using 14 mol% of organic oxidizing agent to Grignard reagent, but it is quite practical method is not.
また、非特許文献8には、グリニャール試薬とオクタフルオロシクロペンテンの反応の記載があるが、ホモカップリング反応について記載は全くない。 In addition, Non-Patent Document 8 describes the reaction of a Grignard reagent with octafluorocyclopentene, but does not describe the homocoupling reaction at all.
上記従来技術の問題点に鑑み、本発明の目的は、少ない使用量でもグリニャール試薬のホモカップリング反応を低温下、短時間で効率的に進行させることのできる、含フッ素有機化合物、及びこれとグリニャール試薬とのホモカップリング反応により、ビアリール化合物を製造する方法を提供することである。 In view of the above-mentioned problems of the prior art, an object of the present invention is to provide a fluorine-containing organic compound, which can efficiently advance the homocoupling reaction of a Grignard reagent in a short time under a low temperature even with a small amount used. It is an object of the present invention to provide a method for producing a biaryl compound by homocoupling reaction with a Grignard reagent.
本発明者らは、上記に鑑み鋭意検討を行った結果、含フッ素有機化合物がグリニャール試薬のホモカップリング反応を低温下、短時間で収率よくビアリール化合物を与えることを見出し、本発明を完成するに至った。すなわち、本発明は以下のとおりである。 As a result of intensive investigations in view of the above, the present inventors have found that a fluorine-containing organic compound gives a biaryl compound with a good yield in a short time at a low temperature under the homocoupling reaction of a Grignard reagent, and completes the present invention It came to That is, the present invention is as follows.
本発明は、下記一般式(1): The present invention relates to the following general formula (1):
(式中、Ar1及びAr2は、それぞれ独立して、少なくともフッ素原子及びトリフルオロメチル基で置換されているアリール基を表し、互いに異なっていても同じでもよい。) で表される化合物からなる含フッ素有機化合物。 (Wherein, Ar 1 and Ar 2 each independently represent an aryl group substituted with at least a fluorine atom and a trifluoromethyl group, and they may be different or the same as each other.) Fluorine-containing organic compounds.
Ar1及びAr2が下記式(2): Ar 1 and Ar 2 have the following formula (2):
で表される請求項1に記載の含フッ素有機化合物。 The fluorine-containing organic compound of Claim 1 represented by these.
下記一般式(3): The following general formula (3):
(式中、R1、R2、R3、R4及びR5は、それぞれ独立して、水素原子、ハロゲン原子、置換基を有していてもよいC1〜C20のアルキル基、C1〜C20のアルコキシル基、フェニル基、及びナフチル基のいずれかを表し、互いに異なっていても同じでもよい。Xはハロゲン原子を表す。) で表されるグリニャール試薬と、請求項1又は請求項2の含フッ素有機化合物とのホモカップリング反応によりビアリール化合物を製造する方法。 (Wherein, R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a C 1 to C 20 alkyl group which may have a substituent, C A Grignard reagent represented by any one of 1 to C 20 alkoxyl group, phenyl group and naphthyl group, which may be different from or the same as each other, and X represents a halogen atom); Item 3. A method for producing a biaryl compound by homocoupling reaction with the fluorine-containing organic compound of item 2.
本発明の新規有機化合物は、原理的に必要と考えられていた50mol%の半分となる25mol%の使用量でグリニャール試薬のホモカップリング反応が効率的に進行するため、今までの有機酸化剤よりも優れた原子効率での反応を可能にする(実施例2)。さらに本反応は従来のウルマン反応と比べ、反応溶液からの生成物の分離が容易であり、抽出操作後カラムクロマトグラフィーによる生成操作で速やかに反応生成物を定量的に単離することができる。 In the novel organic compound of the present invention, since the homocoupling reaction of the Grignard reagent proceeds efficiently at the usage amount of 25 mol% which is half of 50 mol% which was considered to be necessary in principle, the organic oxidants up to now It enables the reaction with better atomic efficiency (Example 2). Furthermore, this reaction is easier to separate the product from the reaction solution as compared to the conventional Ullmann reaction, and the reaction product can be quantitatively isolated rapidly by the production operation by column chromatography after the extraction operation.
また、反応時間や反応温度といった反応条件も従来報告されている有機酸化剤によるホモカップリング反応と遜色ない。グリニャール試薬のマグネシウム上に含有するハロゲンの種類によらず反応は進行する(表1)。これは言いかえれば、ウルマン反応では用いることが難しい塩化アリールを原料として用いることが可能であることを意味する。電子求引性置換基や電子供与性置換基が導入されたグリニャール試薬を用いても1時間以内に高収率でビアリール化合物が生成する(表1)。立体的に込み合ったグリニャール試薬の場合には反応温度を50℃まで上昇させれば1時間でも高収率でビアリール化合物が生成する(表1)。この程度の温度上昇は工業的利用に何の問題もない。 In addition, reaction conditions such as reaction time and reaction temperature are not inferior to the homocoupling reaction with an organic oxidizing agent which has been conventionally reported. The reaction proceeds regardless of the type of halogen contained on the Grignard reagent magnesium (Table 1). In other words, this means that it is possible to use aryl chloride, which is difficult to use in the Ullmann reaction, as a raw material. Even when using a Grignard reagent in which an electron-withdrawing substituent or an electron-donating substituent is introduced, a biaryl compound is produced in high yield within 1 hour (Table 1). In the case of sterically hindered Grignard reagents, raising the reaction temperature to 50 ° C. produces biaryl compounds in high yield even for 1 hour (Table 1). This temperature rise has no problem for industrial use.
本発明の含フッ素有機化合物は、下記一般式(1): The fluorine-containing organic compound of the present invention has the following general formula (1):
(式中、Ar1及びAr2は、それぞれ独立して、少なくとも1つ以上のフッ素原子及びトリフルオロメチル基で置換されているアリール基を表し、互いに異なっていても同じでもよい。) で表される化合物である。 (Wherein, Ar 1 and Ar 2 each independently represent an aryl group substituted with at least one or more fluorine atoms and a trifluoromethyl group, and may be different or the same as each other.) Compound.
次に、本発明の含フッ素有機化合物の製造方法について説明する。本発明の含フッ素有機化合物の製造方法は、次に説明するものは一例であって、これに特に制限されるものではないが、次式に示す方法を好適に採用することができる。具体的には、環状フッ素化合物とアリールリチウム化合物を反応させる。 以下、各工程について説明する。 Next, the method for producing the fluorine-containing organic compound of the present invention will be described. The method for producing the fluorine-containing organic compound of the present invention is an example described below, and the method is not particularly limited thereto, but a method represented by the following formula can be suitably employed. Specifically, the cyclic fluorine compound and the aryl lithium compound are reacted. Each step will be described below.
まず、工程(A)において使用しうるハロゲン化アリール化合物は、下記一般式(4): First, the halogenated aryl compound which can be used in the step (A) has the following general formula (4):
(式中、R6、R7、R8、R9及びR10は、それぞれ独立して、水素原子、フッ素原子及びト0リフルオロメチル基のいずれかを表し、フッ素原子及びトリフルオロメチル基は少なくとも一つ以上を含み、Xはハロゲン原子であり、そのハロゲン原子としては塩素原子、臭素原子、ヨウ素原子から適宜選択される。) で表される化合物である。 (Wherein, R 6 , R 7 , R 8 , R 9 and R 10 each independently represent a hydrogen atom, a fluorine atom or a trifluoromethyl group, a fluorine atom and a trifluoromethyl group Is at least one or more, X is a halogen atom, and the halogen atom is a compound suitably selected from chlorine atom, bromine atom and iodine atom.
上記工程(A)において例示したn-ブチルリチウムは、これに何ら限定されることはなく、t-ブチルリチウム、sec-ブチルリチウムなどのアルキルリチウム、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、リチウムイソプロピルシクロアミド、カリウムアミド類、あるいは金属リチウム、金属ナトリウムなどのアルキル金属から適宜選択されるが、好ましくはn-ブチルリチウム、リチウムジイソプロピルアミドが満足する反応性を与える。 The n-butyllithium exemplified in the above step (A) is not limited to this, and t-butyllithium, alkyllithiums such as sec-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, potassium It is appropriately selected from hexamethyldisilazide, lithium isopropyl cycloamide, potassium amides, or alkyl metals such as metallic lithium and metallic sodium, preferably n-butyllithium and lithium diisopropylamide provide satisfactory reactivity.
次に、工程(B)においては、工程(A)において得られたアリールリチウム化合物のジエチルエーテル溶液に、環状フッ素化合物を反応させる。環状フッ素化合物としては、ヘキサフルオロシクロブテン、オクタフルオロシクロペンテン、デカフルオロシクロヘキセンなどが挙げられるが、この中でもオクタフルオロシクロペンテンが反応効率の点で好ましい。 Next, in step (B), a cyclic fluorine compound is reacted with a diethyl ether solution of the aryl lithium compound obtained in step (A). As the cyclic fluorine compound, hexafluorocyclobutene, octafluorocyclopentene, decafluorocyclohexene and the like can be mentioned, and among them, octafluorocyclopentene is preferable in terms of reaction efficiency.
工程(B)の反応で得られる一般式(1)で示される環状フッ素化合物のうち、Ar1とAr2が同一の場合の具体例としては、1,2−ビス(4−トリフルオロメチル−2,3,5,6−テトラフルオロフェニル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンの他に、1,2−(4−トリフルオロメチル−3,5−ジフルオロフェニル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテン、1,2−ビス(3,5−ビス(トリフルオロメチル)−2,4,6−トリフルオロフェニル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテン、1,2−ビス(3,5−ビス(トリフルオロメチル)−4−フルオロフェニル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンなどが挙げられる。 Among the cyclic fluorine compounds represented by the general formula (1) obtained by the reaction of the step (B), as a specific example in the case where Ar1 and Ar2 are the same, 1,2-bis (4-trifluoromethyl-2, In addition to 3,5,6-tetrafluorophenyl) -3,3,4,4,5,5-hexafluorocyclopentene, 1,2- (4-trifluoromethyl-3,5-difluorophenyl) -3 , 3,4,4,5,5-hexafluorocyclopentene, 1,2-bis (3,5-bis (trifluoromethyl) -2,4,6-trifluorophenyl) -3,3,4,4 1,5,5-hexafluorocyclopentene, 1,2-bis (3,5-bis (trifluoromethyl) -4-fluorophenyl) -3,3,4,4,5,5-hexafluorocyclopentene, etc. Be
また、工程(B)の反応で得られる一般式(1)で示される環状フッ素化合物のうち、Ar1とAr2が異なる場合の具体例としては、1−(4−トリフルオロメチル−2,3,5,6−テトラフルオロフェニル)−2−(4−トリフルオロメチル−3,5−ジフルオロフェニル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテン、1−(4−トリフルオロメチル−2,3,5,6−テトラフルオロフェニル)−2−(3,5−ビス(トリフルオロメチル)−2,4,6−トリフルオロフェニル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテン、1−(4−トリフルオロメチル−2,3,5,6−テトラフルオロフェニル)−2−(3,5−ビス(トリフルオロメチル)−4−フルオロフェニル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンなどが挙げられる。 Moreover, as a specific example in case Ar1 and Ar2 differ among cyclic fluorine compounds shown by General formula (1) obtained by reaction of a process (B), 1- (4-trifluoromethyl-2,3, 3 5,6-Tetrafluorophenyl) -2- (4-trifluoromethyl-3,5-difluorophenyl) -3,3,4,4,5,5-hexafluorocyclopentene, 1- (4-trifluoromethyl) -2,3,5,6-Tetrafluorophenyl) -2- (3,5-bis (trifluoromethyl) -2,4,6-trifluorophenyl) -3,3,4,4,5,5 -Hexafluorocyclopentene, 1- (4-trifluoromethyl-2,3,5,6-tetrafluorophenyl) -2- (3,5-bis (trifluoromethyl) -4-fluorophenyl) -3,3 , 4, 4, 5 and 5 hex Such as fluoro cyclopentene and the like.
上記工程(B)におけるアリールリチウム化合物と環状フッ素化合物の反応は、両者を混合すれば良いため、特に制限はないが、除熱設備および攪拌機を備えた反応器を使用し、アリールリチウム化合物を溶解させた溶液に、環状フッ素化合物を溶解させた溶液を滴下する方法が好ましい。 The reaction of the aryl lithium compound and the cyclic fluorine compound in the above step (B) is not particularly limited, as long as the two are mixed, but a reactor equipped with a heat removal facility and a stirrer is used to dissolve the aryl lithium compound. Preferably, the solution in which the cyclic fluorine compound is dissolved is dropped into the solution obtained above.
アリールリチウム化合物の使用量は、環状フッ素化合物1molに対して、通常、1〜5mol、好ましくは1〜4mol、特に好ましくは1〜3molである。 The amount of the aryl lithium compound to be used is generally 1 to 5 mol, preferably 1 to 4 mol, particularly preferably 1 to 3 mol, per 1 mol of the cyclic fluorine compound.
工程(A)及び工程(B)の反応に使用する溶媒に特に制限はなく、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、t-ブチルメチルエーテル、t-ブチルエチルエーテル、ジ-i-プロピルエーテル、ジ-n-ブチルエーテル、シクロペンチルメチルエーテル、シクロヘキシルメチルエーテル、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテル等、通常の有機リチウム化合物使用時に使用される溶媒が用いられるが、これらの中でもジエチルエーテル、テトラヒドロフランが特に好ましい。 There are no particular limitations on the solvent used in the reaction of step (A) and step (B), and diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, t-butyl methyl ether, t-butyl ethyl ether, di-i-propyl ether, Di-n-butyl ether, cyclopentyl methyl ether, cyclohexyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and the like can be used as the solvents used when using the usual organic lithium compounds. Among them, diethyl ether and tetrahydrofuran are particularly preferable.
工程(A)及び(B)の反応は、通常、−100℃〜100℃、好ましくは−100℃〜40℃、特に好ましくは−80℃〜25℃の温度で行われる。反応温度が高すぎると、使用する環状フッ素化合物の沸点が低い場合に揮発によるロスが生じたり、副反応を併発して収率が低下する傾向がある。また反応温度が低すぎると、反応速度が遅すぎたり、進行しない場合がある。 The reaction of steps (A) and (B) is usually carried out at a temperature of -100 ° C to 100 ° C, preferably -100 ° C to 40 ° C, particularly preferably -80 ° C to 25 ° C. When the reaction temperature is too high, there is a tendency for loss due to volatilization to occur when the boiling point of the cyclic fluorine compound to be used is low, and side reaction is accompanied to lower the yield. If the reaction temperature is too low, the reaction rate may be too slow or not progress.
次に、本発明のビアリール化合物の製造方法について説明する。本グリニャール試薬のホモカップリング反応によりビアリール化合物を製造する方法は特に制限されるものではないが、次式に示す方法を好適に採用することができる。 Next, the method for producing the biaryl compound of the present invention will be described. Although the method in particular of manufacturing a biaryl compound by the homo coupling reaction of this Grignard reagent is not restrict | limited, The method shown to following Formula can be employ | adopted suitably.
反応基質となるグリニャール試薬は、下記一般式(3) The Grignard reagent to be a reaction substrate has the following general formula (3)
で表される化合物であることが好ましい。式中、R1、R2、R3、R4及びR5は、それぞれ独立して、水素原子、ハロゲン原子、置換基を有していてもよいC1〜C20のアルキル基、C1〜C20のアルコキシル基、フェニル基、及びナフチル基のいずれかを表し、互いに異なっていても同じでもよい。置換基を有していてもよいC1〜C20のアルキル基としては、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ペンチル基、メトキシメチル基、ベンジル基などが挙げられ、好ましくは、メチル基である。置換基を有していてもよいC1〜C20のアルコキシル基としては、メトキシ基、エトキシ基、プロポキシ基、ペントキシ基などが挙げられ、好ましくはメトキシ基である。置換基を有していてもよいフェニル基としては、フェニル基、クロロフェニル基、トリル基、メトキシフェニル基などが挙げられる。置換基を有していてもよいナフチル基としては、ナフチル基、メチルナフチル基などが挙げられる。 It is preferable that it is a compound represented by these. In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a C 1 to C 20 alkyl group which may have a substituent, C 1 alkoxyl group -C 20, represents either a phenyl group and a naphthyl group, may be the same or different from each other. Examples of the C 1 to C 20 alkyl group which may have a substituent include methyl group, ethyl group, propyl group, isopropyl group, butyl group, pentyl group, methoxymethyl group and benzyl group. Preferably, it is a methyl group. Examples of the C 1 to C 20 alkoxyl group which may have a substituent include a methoxy group, an ethoxy group, a propoxy group, a pentoxy group and the like, preferably a methoxy group. As a phenyl group which may have a substituent, a phenyl group, a chlorophenyl group, a tolyl group, a methoxyphenyl group etc. are mentioned. Examples of the naphthyl group which may have a substituent include a naphthyl group and a methylnaphthyl group.
ホモカップリング反応を円滑に進行させるためには、上記一般式(3)は立体的に混み合っていないことが望ましく、R1、R2、R3、R4及びR5の中の少なくとも2つ以上が水素原子であることが好ましく、より好ましくは3つ以上が水素原子である。特に立体的要因からR1又はR5が水素原子であることが好ましく、さらに好ましくはR1、R2、R4及びR5が水素原子である。 In order to allow the homocoupling reaction to proceed smoothly, it is desirable that the above general formula (3) is not sterically crowded, and at least 2 of R 1 , R 2 , R 3 , R 4 and R 5. Preferably, one or more are hydrogen atoms, and more preferably three or more are hydrogen atoms. In particular, R 1 or R 5 is preferably a hydrogen atom from the viewpoint of steric factors, and more preferably R 1 , R 2 , R 4 and R 5 are hydrogen atoms.
また、上記一般式(3)において、Xはハロゲン原子であり、そのハロゲン原子としては、塩素原子、臭素原子、ヨウ素原子などが挙げられ、好ましくは塩素原子又は臭素原子である。 Moreover, in the said General formula (3), X is a halogen atom, A chlorine atom, a bromine atom, an iodine atom etc. are mentioned as the halogen atom, Preferably it is a chlorine atom or a bromine atom.
ホモカップリング反応に用いる、本発明の含フッ素有機化合物は、下記一般式(1): The fluorine-containing organic compound of the present invention used for the homocoupling reaction is represented by the following general formula (1):
で表される化合物であることが好ましい。式中、Ar1及びAr2は、それぞれ独立して、少なくともフッ素原子及びトリフルオロメチル基で置換されているアリール基を表し、互いに異なっていても同じでもよい。 It is preferable that it is a compound represented by these. In the formula, Ar 1 and Ar 2 each independently represent an aryl group substituted with at least a fluorine atom and a trifluoromethyl group, and may be different or the same as each other.
グリニャール試薬と一般式(1)で示される環状フッ素化合物の反応は、両者を混合すれば良いため、特に制限はないが、攪拌機を備えた反応器を使用し、環状フッ素化合物を溶解させた溶液に、グリニャール試薬を溶解させた溶液を滴下する方法が好ましい。 The reaction between the Grignard reagent and the cyclic fluorine compound represented by the general formula (1) is not particularly limited, as long as the two are mixed, but a solution in which the cyclic fluorine compound is dissolved using a reactor equipped with a stirrer. Preferably, a solution in which a Grignard reagent is dissolved is added dropwise.
環状フッ素化合物の使用量は、グリニャール試薬1molに対して、通常、通常、0.1〜0.5mol、好ましくは0.1〜0.25mol、特に好ましくは0.25molである。 The amount of the cyclic fluorine compound used is usually usually 0.1 to 0.5 mol, preferably 0.1 to 0.25 mol, particularly preferably 0.25 mol, per 1 mol of the Grignard reagent.
ホモカップリング反応に使用する溶媒に特に制限はなく、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、t-ブチルメチルエーテル、t-ブチルエチルエーテル、ジ-i-プロピルエーテル、ジ-n-ブチルエーテル、シクロペンチルメチルエーテル、シクロヘキシルメチルエーテル、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテル等、通常の有機マグネシウム化合物使用時に使用される溶媒が用いられるが、これらの中でもジエチルエーテル、テトラヒドロフランが特に好ましい。 There are no particular limitations on the solvent used for the homocoupling reaction, and diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, t-butyl methyl ether, t-butyl ethyl ether, di-i-propyl ether, di-n-butyl ether, cyclopentyl Although solvents used at the time of using the usual organic magnesium compound such as methyl ether, cyclohexyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, etc. are used, among these, diethyl ether and tetrahydrofuran are particularly preferable.
ホモカップリング反応は、通常、0℃〜100℃、好ましくは10℃〜80℃、特に好ましくは25℃〜60℃の温度で行われる。Ar1及びAr2がフッ素である環状フッ素化合物を用いた場合、反応温度が高すぎると、使用する環状フッ素化合物の沸点が低い場合に揮発によるロスが生じ、副反応を併発して収率が低下する傾向がある。また反応温度が低すぎると、反応が進行しない場合がある。 The homocoupling reaction is usually performed at a temperature of 0 ° C. to 100 ° C., preferably 10 ° C. to 80 ° C., particularly preferably 25 ° C. to 60 ° C. When the cyclic fluorine compound in which Ar 1 and Ar 2 are fluorine is used, if the reaction temperature is too high, the loss due to volatilization occurs when the boiling point of the cyclic fluorine compound to be used is low, and the side reaction is combined to give a yield There is a tendency to decline. If the reaction temperature is too low, the reaction may not proceed.
以下に実施例を挙げ、本発明をさらに具体的に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Although an Example is given to the following and this invention is more concretely demonstrated to it, this invention is not limited to these Examples.
<実施例1>1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンの合成 EXAMPLE 1 Synthesis of 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene
(1)アリールリチウム溶液の調製 (1) Preparation of aryl lithium solution
アルゴン雰囲気下、フレーム乾燥させたガラス製3つ口フラスコに1−ブロモ−2,3,5,6−テトラフルオロベンゾトリフルオリド2.91g(9.8mmol)とジエチルエーテル10mLを入れ、−78℃に冷却した。ここに濃度1.60mol/Lのn−ブチルリチウム/n−ヘキサン溶液5.8mL(9.28mmol)を30分かけて全量滴下した。滴下終了後、−78℃で2時間撹拌し、アリールリチウム試薬を調製した。 In an argon atmosphere, 2.91 g (9.8 mmol) of 1-bromo-2,3,5,6-tetrafluorobenzotrifluoride and 10 mL of diethyl ether are placed in a flame-dried three-necked glass flask, and the temperature is -78 ° C. Cooled to A total of 5.8 mL (9.28 mmol) of an n-butyllithium / n-hexane solution having a concentration of 1.60 mol / L was dropped thereto over 30 minutes. After completion of the dropwise addition, the mixture was stirred at -78 ° C for 2 hours to prepare an aryllithium reagent.
(2)1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンの合成 (2) Synthesis of 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene
上記(1)で調製したアリールリチウムのジエチルエーテル溶液に、0.494mg(2.33mmol)のオクタフルオロシクロペンテンを溶解させたジエチルエーテル溶液25mLを40分かけて全量滴下した。滴下終了後、−78℃で3時間撹拌した。反応終了後、反応混合物に飽和塩化アンモニウム水溶液を加えて停止させ、ジエチルエーテル(20mL×5回)で抽出を行った。ジエチルエーテル層を分離後、無水硫酸ナトリウムで乾燥させた後、ロータリーエバポレーターにて減圧濃縮した。この濃縮物をシリカゲルクロマトグラフィー(展開溶媒:n−ヘキサン)で単離精製し、1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテン1.35g(2.22mmol)を得た。オクタフルオロシクロペンテン基準の収率は、95%であった。 A total of 25 mL of a diethyl ether solution in which 0.494 mg (2.33 mmol) of octafluorocyclopentene was dissolved was dropped over 40 minutes into the diethyl ether solution of the aryl lithium prepared in the above (1). After completion of the dropwise addition, the mixture was stirred at -78 ° C for 3 hours. After completion of the reaction, the reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with diethyl ether (20 mL × 5 times). The diethyl ether layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure using a rotary evaporator. This concentrate is isolated and purified by silica gel chromatography (developing solvent: n-hexane) to give 1.35 g of 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene (2.22 mmol) was obtained. The yield based on octafluorocyclopentene was 95%.
(1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンの物性データ) (Physical data of 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene)
13C NMR (100.62 MHz, CDCl3, Me4Si)δ= 109.63 (t, J = 17.8 Hz), 110.56 (tt, J = 274.9, 24.7 Hz), 113.62 (dt, J = 35.4, 12.4 Hz), 114.56 (tt, J = 263.2, 25.2 Hz), 120.24 (q, J = 206.9 Hz), 136.77 (t, J = 28.3 Hz), 142.92 − 143.28 (m), 145.49 − 145.77 (m); 19F NMR (376.46 MHz, CDCl3, C6F6)δ= −137.35 (s, 4F), −135.79 (s, 4F), −133.01 (s, 2F), −112.27 (s, 4F), −57.85 − −57.73 (m, 6F);IR (KBr) 1663.3 (w), 1485.9 (m), 1422.2 (w), 1354.8 (s), 1304.6 (m), 1273.8 (s), 1214.9 (m), 1157.1 (s), 1058.7 (w), 1000.9 (s), 966.2 (m), 876.5 (w), 711.6 (s), 572.8 (m), 422.3 (m) cm−1 ; HRMS (EI) Found: m/z 607.9685. Calcd for C19F20: 607.9681. 13 C NMR (100.62 MHz, CDCl 3 , Me 4 Si) δ = 109.63 (t, J = 17.8 Hz), 110.56 (tt, J = 274.9, 24.7 Hz), 113.62 (dt, J = 35.4, 12.4 Hz), 114.56 (tt, J = 263.2, 25.2 Hz), 120.24 (q, J = 206.9 Hz), 136.77 (t, J = 28.3 Hz), 142.92-143.28 (m), 145.49-145.77 (m); 19 F NMR (376.46 MHz, CDCl 3 , C 6 F 6) δ = -137.35 (s , 4F), -135.79 (s, 4F), -133.01 (s, 2F), -112.27 (s, 4F), -57.85 - -57.73 (m, 6F) IR (KBr) 1663.3 (w), 1485.9 (m), 1422.2 (w), 1354.8 (s), 1304.6 (m), 1273.8 (s), 1214.9 (s). (M), 1157.1 (s), 1058.7 (w), 1000.9 (s), 966.2 (m), 876.5 (w), 711.6 (s), 572.8 ( m), 422.3 (m) cm −1 ; HRMS (EI) Found: m / z 607.9685. Calcd for C 19 F 20 : 607.9681.
<実施例2>1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンを用いたホモカップリング反応 <Example 2> Homo-coupling reaction using 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene
アルゴン雰囲気下、フレーム乾燥させたガラス製シュレンク管に1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテン78.3mg(0.129mmol)とテトラヒドロフラン0.5mLを入れ、1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンが完全に溶解するまで十分に撹拌した。ここに濃度1.03mol/Lのフェニルマグネシウムブロミド/テトラヒドロフラン溶液0.5mL(0.515mmol)を入れ、25℃で1時間反応させた。反応終了後、反応混合物に飽和塩化アンモニウム水溶液を加えて停止させ、酢酸エチル(3mL×6回)で抽出を行った。酢酸エチル層を分離後、無水硫酸ナトリウムで乾燥させた後、ロータリーエバポレーターにて減圧濃縮した。この濃縮物をシリカゲルクロマトグラフィー(展開溶媒:n−ヘキサン)で単離精製し、1,1’−ビフェニル39.3mg(0.255mmol)を得た。収率は99%であった。実施例2のまとめを表1に示す。 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene 78.3 mg (0.129 mmol) and tetrahydrofuran 0 in a frame-dried glass Schlenk tube under an argon atmosphere .5 mL was added and stirred thoroughly until 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene was completely dissolved. To this was added 0.5 mL (0.515 mmol) of a phenylmagnesium bromide / tetrahydrofuran solution having a concentration of 1.03 mol / L, and the mixture was allowed to react at 25 ° C. for 1 hour. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 mL × 6 times). The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure using a rotary evaporator. The concentrate was isolated and purified by silica gel chromatography (developing solvent: n-hexane) to obtain 39.3 mg (0.255 mmol) of 1,1′-biphenyl. The yield was 99%. A summary of Example 2 is shown in Table 1.
(1,1’−ビフェニルの物性データ) (Physical data of 1,1'-biphenyl)
1H NMR (400.13 MHz, CDCl3, Me4Si)δ= 7.33 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H); 13C NMR (100.62 MHz, CDCl3, Me4Si)δ= 127.30, 127.38, 128.89, 141.36. 1 H NMR (400.13 MHz, CDCl 3 , Me 4 Si) δ = 7.33 (t, J = 7.3 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 2 H), 7.53 (d, J = 7.2 Hz, 2 H); 13 C NMR (100.62 MHz, CDCl 3 , Me 4 Si) δ = 127.30, 127.38, 128.89, 141.36.
<実施例3〜7> Examples 3 to 7
グリニャール試薬、反応温度を表1に示されるように変更した以外は実施例2と同様に、1,1’−ビフェニル又は1,1’−ビアリール化合物を得た。 1,1′-biphenyl or 1,1′-biaryl compounds were obtained in the same manner as in Example 2 except that the Grignard reagent and the reaction temperature were changed as shown in Table 1.
<比較例1〜2,実施例8〜11> <Comparative Examples 1 to 2, Examples 8 to 11>
まず フェニルマグネシウムブロミドに対し50mol%のオクタフルオロシクロペンテンを加え、THF 中25℃で0.5時間撹拌すると、33%の収率でビフェニルが得られた(表2の比較例1)。しかし同時にオクタフルオロシクロペンテンのビニルフッ素の一つ又は二つがフェニル基により置換された化合物も副生成物として得られた。二つがフェニル基により置換された副生成物を酸化剤として用いホモカップリング反応を行ってみたが、反応は全く進行しなかった(表2の比較例2)。しかしArとしてフェニル基の代わりに含フッ素芳香環を導入するとホモカップリング反応は進行するようになり、特に本発明のヘプタフルオロトリル基を有する化合物を用いた場合には、82%の収率でビフェニルが得られることがわかった。これら化合物のLUMO を計算してみると、LUMO のエネルギーが低いものほど反応性が高い傾向にあることが明らかになった。 First, 50 mol% of octafluorocyclopentene was added to phenylmagnesium bromide, and stirred in THF at 25 ° C. for 0.5 hours to obtain biphenyl in a yield of 33% (Comparative Example 1 in Table 2). At the same time, however, compounds in which one or two of the vinyl fluorines of octafluorocyclopentene were substituted by phenyl groups were also obtained as by-products. The homo coupling reaction was performed using a side product in which two were substituted by a phenyl group as an oxidizing agent, but the reaction did not proceed at all (Comparative Example 2 in Table 2). However, when a fluorine-containing aromatic ring is introduced instead of a phenyl group as Ar, the homocoupling reaction proceeds, and particularly when the compound having a heptafluorotolyl group of the present invention is used, the yield is 82%. It turned out that biphenyl is obtained. Calculation of the LUMO of these compounds revealed that the lower the LUMO energy, the higher the reactivity.
<実施例12> Example 12
実施例2において、1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンを用いたホモカップリング反応は、フェニルマグネシウムブロミドに対し25mol%の前記ヘキサフルオロシクロペンテンの量で、25℃、1時間で定量的に反応が進行した。これは当該化合物が4 電子酸化剤として働いていることを示している。さらにフェニルマグネシウムブロミドに対し10mol%の1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンを用い、アルゴン雰囲気下→空気雰囲気下で反応を行ったところ、83%収率でビフェニルが得られ、触媒的に反応が進行することが明らかになった。アルゴン雰囲気下のみで反応を行った場合は,収率は37%であった。 In Example 2, the homocoupling reaction using 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene was carried out in 25% by mole of the above-mentioned hexamer relative to phenylmagnesium bromide. The reaction proceeded quantitatively at 25 ° C. for 1 hour with the amount of fluorocyclopentene. This indicates that the compound acts as a four-electron oxidizing agent. Furthermore, the reaction was carried out under argon atmosphere → air atmosphere using 10 mol% of 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene based on phenylmagnesium bromide By the way, it was revealed that biphenyl was obtained in 83% yield, and the reaction proceeded catalytically. When the reaction was performed only under argon atmosphere, the yield was 37%.
<実施例13> Example 13
アルゴン雰囲気下、フレーム乾燥させたガラス製シュレンク管に1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテン228.07mg(0.375mmol)とテトラヒドロフラン1.5mLを入れ、1,2−ビス(ヘプタフルオロトリル)−3,3,4,4,5,5−ヘキサフルオロシクロペンテンが完全に溶解するまで十分に撹拌した。ここに濃度1.00mol/Lのフェニルマグネシウムブロミド/テトラヒドロフラン溶液1.5mL(1.5mmol)を入れ、25℃で1時間反応させた。その後、反応器に塩化カルシウムに通じた空気を送り込みながらフェニルマグネシウムブロミド/テトラヒドロフラン溶液2.25mLを5時間かけて滴下し、その後更に3時間撹拌した。反応終了後、反応混合物に飽和塩化アンモニウム水溶液を加えて停止させ、酢酸エチル(3mL×9回)で抽出を行った。酢酸エチル層を分離後、無水硫酸ナトリウムで乾燥させた後、ロータリーエバポレーターにて減圧濃縮した。この濃縮物をシリカゲルクロマトグラフィー(展開溶媒:n−ヘキサン)で単離精製し、1,1’−ビフェニル238.58mg(1.547mmol)を得た。収率は83%であった。 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene in a flame-dried glass Schlenk tube under an argon atmosphere, 228.07 mg (0.375 mmol) and tetrahydrofuran 1 .5 mL was added and stirred thoroughly until 1,2-bis (heptafluorotolyl) -3,3,4,4,5,5-hexafluorocyclopentene was completely dissolved. To this was added 1.5 mL (1.5 mmol) of a phenylmagnesium bromide / tetrahydrofuran solution at a concentration of 1.00 mol / L, and the mixture was reacted at 25 ° C. for 1 hour. Thereafter, 2.25 mL of a phenylmagnesium bromide / tetrahydrofuran solution was added dropwise over 5 hours while feeding air communicating with calcium chloride into the reactor, and the mixture was further stirred for 3 hours. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution, and extraction was performed with ethyl acetate (3 mL × 9 times). The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure using a rotary evaporator. The concentrate was isolated and purified by silica gel chromatography (developing solvent: n-hexane) to obtain 238.58 mg (1.547 mmol) of 1,1′-biphenyl. The yield was 83%.
本発明によれば、含フッ素有機化合物を用いて、グリニャール試薬のホモカップリング反応を行うことにより、低温下、短時間で効率的にビアリール化合物を製造することができるので、工業的に有用である。 According to the present invention, by carrying out the homocoupling reaction of a Grignard reagent using a fluorine-containing organic compound, a biaryl compound can be efficiently produced in a short time under a low temperature, which is industrially useful. is there.
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