JP5665041B2 - Iodonium compound, production method thereof, functionalized spirocyclic compound and production method thereof - Google Patents
Iodonium compound, production method thereof, functionalized spirocyclic compound and production method thereof Download PDFInfo
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- -1 Iodonium compound Chemical class 0.000 title claims description 76
- 150000001875 compounds Chemical class 0.000 title claims description 47
- 238000004519 manufacturing process Methods 0.000 title claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 69
- 125000005843 halogen group Chemical group 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 40
- 229910052740 iodine Inorganic materials 0.000 claims description 36
- 239000000758 substrate Substances 0.000 claims description 33
- 239000011630 iodine Substances 0.000 claims description 30
- 239000000376 reactant Substances 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000003277 amino group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 238000006265 spirocyclization reaction Methods 0.000 claims description 10
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 9
- 239000012038 nucleophile Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 5
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 150000002497 iodine compounds Chemical class 0.000 claims description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
- 239000002904 solvent Substances 0.000 description 17
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 12
- 230000000269 nucleophilic effect Effects 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000013543 active substance Substances 0.000 description 7
- 125000002355 alkine group Chemical group 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical compound [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 230000003595 spectral effect Effects 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002000 high resolution fast-atom bombardment mass spectrometry Methods 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 0 C1C2C*C1C2 Chemical compound C1C2C*C1C2 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- DVMSVWIURPPRBC-UHFFFAOYSA-N 2,3,3-trifluoroprop-2-enoic acid Chemical compound OC(=O)C(F)=C(F)F DVMSVWIURPPRBC-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 1
- COGPXRWTGTZSHX-UHFFFAOYSA-N FC(CO)(F)F.[I] Chemical group FC(CO)(F)F.[I] COGPXRWTGTZSHX-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- NECLQTPQJZSWOE-UHFFFAOYSA-N spiro[5.5]undecane Chemical group C1CCCCC21CCCCC2 NECLQTPQJZSWOE-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Indole Compounds (AREA)
Description
本発明は、ヨードニウム化合物、その製造方法、及び官能基化スピロ環状化合物とその製造方法に関する。 The present invention relates to an iodonium compound, a production method thereof, a functionalized spirocyclic compound, and a production method thereof.
スピロ［４，５］デカン及びスピロ［５，５］ウンデカン骨格は、様々な生理活性物質に変換することができる鍵中間体であり（例えば、非特許文献１等参照）、現在その骨格形成反応の研究が活発に行われている。一方、ハロゲン原子、特にフッ素原子を導入した化合物は、有効な生物活性を発現するものが多く、医薬又は農薬の分野における含ハロゲン化合物の需要は高い。 Spiro [4,5] decane and spiro [5,5] undecane skeletons are key intermediates that can be converted into various physiologically active substances (see, for example, Non-Patent Document 1 etc.), and currently their skeleton formation reactions Research is actively conducted. On the other hand, many compounds into which halogen atoms, particularly fluorine atoms are introduced, exhibit effective biological activity, and there is a high demand for halogen-containing compounds in the field of pharmaceuticals or agricultural chemicals.
原子価が３価のヨウ素原子を含む超原子価ヨウ素反応剤を用いてスピロ環形成反応を行う例が多数報告されているが、分子内にアミド又はカルボキシル基及びフェノールを有する基質を用いる、酸化的なＣ−Ｎ又はＣ−Ｏ結合形成によるスピロ環化反応がほとんどであった（例えば、非特許文献２、３及び４）。 Many examples of spiro ring formation reactions using hypervalent iodine reagents containing trivalent iodine atoms have been reported. Oxidation using a substrate having an amide or carboxyl group and phenol in the molecule Most of the spirocyclization reaction by the formation of a typical CN or CO bond (for example, Non-Patent Documents 2, 3 and 4).
最近、分子内にメトキシ置換されたフェノール部位とアルキン部位とを併せ持つ基質に対し、Ｉ２、ＩＣｌ又はＢｒ２由来のハロニウムカチオンが作用することにより、選択的にハロゲン（臭素又はヨウ素原子）置換されたスピロ環が形成することが報告された（例えば、非特許文献５、６、７及び８）。この反応は、様々な基質に対し、スピロ環化反応及びハロゲン原子（臭素又はヨウ素原子）の導入が可能であるが、反応剤であるＩ２、ＩＣｌ又はＢｒ２は毒性が高いという問題があった。また、この手法を用いたフッ素、窒素、酸素及び炭素原子の導入は報告されていない。一方、フッ素原子を導入したスピロ化合物の合成例も報告されているが（例えば、非特許文献９）、鍵中間体である２，３，３−トリフルオロアクリレートの合成が煩雑であり（例えば、非特許文献１０）、また、フッ素原子及びハロゲン原子以外の原子を導入できる化合物は、非常に限定されていた。 Recently, a halogen (bromine or iodine atom) substitution is selectively performed by the action of a halonium cation derived from I 2 , ICl or Br 2 on a substrate having both a methoxy-substituted phenol moiety and an alkyne moiety in the molecule. It was reported that a spiro ring formed was formed (for example, Non-Patent Documents 5, 6, 7 and 8). In this reaction, spirocyclization reaction and introduction of a halogen atom (bromine or iodine atom) can be performed on various substrates. However, there is a problem that I 2 , ICl or Br 2 which are reactants are highly toxic. It was. In addition, introduction of fluorine, nitrogen, oxygen and carbon atoms using this technique has not been reported. On the other hand, although the synthesis example of the spiro compound which introduce | transduced the fluorine atom is also reported (for example, nonpatent literature 9), the synthesis | combination of 2,3,3- trifluoroacrylate which is a key intermediate is complicated (for example, Non-Patent Document 10) and compounds that can introduce atoms other than fluorine atoms and halogen atoms have been very limited.
本発明の主な目的は、スピロ環状化合物に様々な求核置換基を導入することができる新規なヨードニウム化合物を提供することである。本発明はまた、このヨードニウム化合物を中間体として用いて、求核置換基が導入されたスピロ環状化合物を簡便で収率よく製造することができる方法を提供することを目的とする。 The main object of the present invention is to provide a novel iodonium compound capable of introducing various nucleophilic substituents into a spirocyclic compound. Another object of the present invention is to provide a method by which a spirocyclic compound into which a nucleophilic substituent is introduced can be produced simply and with high yield using this iodonium compound as an intermediate.
本発明者らは、上記した目的を達成すべく鋭意研究を重ねた結果、特定の基質を超原子価ヨウ素反応剤と反応させると、スピロ環化反応が起こってスピロ環状化合物のヨードニウム塩が生成すること、及びこのヨードニウム塩に求核剤を作用させれば、求核置換反応が起こって官能基化スピロ環状化合物を収率よく製造することができることを見出し、ここに本発明を完成するに至った。 As a result of intensive studies to achieve the above-described object, the present inventors have reacted a specific substrate with a hypervalent iodine reactant to generate a spirocyclization reaction to produce an iodonium salt of a spirocyclic compound. And, when a nucleophilic agent is allowed to act on this iodonium salt, a nucleophilic substitution reaction occurs and a functionalized spirocyclic compound can be produced in high yield, and hereto complete the present invention. It came.
即ち、本発明は、下記のヨードニウム化合物等を提供する。
１． 式（２−１）：
That is, the present invention provides the following iodonium compounds and the like.
1. Formula (2-1):
［式中、ＸはＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し、ＹはＣ＝Ｏ、ＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し（ここで、Ｒ’、Ｒ”は、互いに独立して、アルキル基、アリール基、アミノ基又はハロゲン原子を示す。）、又は、Ｘ及びＹがともにＣＨ２の場合には、この２つが結合する炭素原子と一緒になってアリール環を形成してもよい。
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
Ｒ２は、
[Wherein X represents NR ′, O, S, CH 2 , CHR ′, or CR′R ″, and Y represents C═O, NR ′, O, S, CH 2 , CHR ′, or CR′R ”. (Wherein R ′ and R ″ each independently represents an alkyl group, an aryl group, an amino group or a halogen atom), or when X and Y are both CH 2 , An aryl ring may be formed together with the carbon atom to which the two are bonded.
R 1 represents an alkyl group, an aryl group, or a halogen atom.
R 2 is
（ここで、Ｒ４は、水素原子、アルキル基、アルコキシ基、又はトリフルオロメチル基、アリール基又はハロゲン原子を示す。）を示し、
Ｒ３は、電子吸引基を示し、
(Wherein R 4 represents a hydrogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, an aryl group or a halogen atom),
R 3 represents an electron withdrawing group,
は、 Is
（ここで、各Ｒ５及びＲ５’は、互いに独立して、水素原子、アルキル基、アリール基、アシル基、ニトロ基又はハロゲン原子を示す。）を示す。
ｍは０又は１である。］、又は式（２−２）：
Here, each R 5 and R 5 ′ independently represents a hydrogen atom, an alkyl group, an aryl group, an acyl group, a nitro group or a halogen atom.
m is 0 or 1. Or formula (2-2):
［式中、Ｒ２’は、 [Wherein R 2 ′ is
（ここで、各Ｒ４及びＲ４’は、互いに独立して、水素原子、アルキル基、アルコキシ基、又はトリフルオロメチル基、アリール基又はハロゲン原子を示す。）を示す。
Ｘ、Ｙ、Ｒ１、Ｒ２、Ｒ３、ｍ及び
Here, each R 4 and R 4 ′ independently represents a hydrogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, an aryl group or a halogen atom.
X, Y, R 1 , R 2 , R 3 , m and
は、上記と同様である。］
で表されるヨードニウム化合物。
２． 式（１）：
Is the same as above. ]
The iodonium compound represented by these.
2. Formula (1):
［式中、ＸはＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し、ＹはＣ＝Ｏ、ＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し（ここで、Ｒ’、Ｒ”は、互いに独立して、アルキル基、アリール基、アミノ基又はハロゲン原子を示す。）、又は、Ｘ及びＹがともにＣＨ２の場合には、この２つが結合する炭素原子と一緒になってアリール環を形成してもよい。
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
[Wherein X represents NR ′, O, S, CH 2 , CHR ′, or CR′R ″, and Y represents C═O, NR ′, O, S, CH 2 , CHR ′, or CR′R ”. (Wherein R ′ and R ″ each independently represents an alkyl group, an aryl group, an amino group or a halogen atom), or when X and Y are both CH 2 , An aryl ring may be formed together with the carbon atom to which the two are bonded.
R 1 represents an alkyl group, an aryl group, or a halogen atom.
は、オルト位又はパラ位がアルコキシ基で置換されたアリール基を示す。
ｍは０又は１である。］
で表される基質を、超原子価ヨウ素反応剤を用いてスピロ環化させる、
上記項１に記載のヨードニウム化合物の製造方法。
３． 前記超原子価ヨウ素反応剤が、
Represents an aryl group substituted at the ortho-position or para-position with an alkoxy group.
m is 0 or 1. ]
A substrate represented by a spirocyclization using a hypervalent iodine reactant,
Item 2. A method for producing an iodonium compound according to Item 1.
3. The hypervalent iodine reactant is
（式中、Ｒ３は、電子吸引基を示す。
各Ｒ４及びＲ４’は、互いに独立して、水素原子、アルキル基、アルコキシ基、又はトリフルオロメチル基、アリール基又はハロゲン原子を示す。）
からなる群から選択される少なくとも１種である、上記項２に記載のヨードニウム化合物の製造方法。
４． 上記項１に記載のヨードニウム化合物を求核剤で求核置換させる、官能基化スピロ環状化合物の製造方法。
５． 分子内にメトキシ置換されたアリール部位及びアルキン部位を有する基質を、超原子価ヨウ素反応剤を用いてスピロ環化させることにより、式（２−１）：
(In the formula, R 3 represents an electron-withdrawing group.
Each R 4 and R 4 ′ independently represents a hydrogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, an aryl group or a halogen atom. )
The method for producing an iodonium compound according to Item 2, which is at least one selected from the group consisting of:
4). A method for producing a functionalized spirocyclic compound, wherein the iodonium compound according to Item 1 is nucleophilically substituted with a nucleophile.
5. A substrate having a methoxy-substituted aryl moiety and an alkyne moiety in the molecule is spirocyclized using a hypervalent iodine reagent to obtain a compound of formula (2-1):
［式中、ＸはＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し、ＹはＣ＝Ｏ、ＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し（ここで、Ｒ’、Ｒ”は、互いに独立して、アルキル基、アリール基、アミノ基又はハロゲン原子を示す。）、又は、Ｘ及びＹがともにＣＨ２の場合には、この２つが結合する炭素原子と一緒になってアリール環を形成してもよい。
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
Ｒ２は、
[Wherein X represents NR ′, O, S, CH 2 , CHR ′, or CR′R ″, and Y represents C═O, NR ′, O, S, CH 2 , CHR ′, or CR′R ”. (Wherein R ′ and R ″ each independently represents an alkyl group, an aryl group, an amino group or a halogen atom), or when X and Y are both CH 2 , An aryl ring may be formed together with the carbon atom to which the two are bonded.
R 1 represents an alkyl group, an aryl group, or a halogen atom.
R 2 is
（ここで、Ｒ４は、水素原子、アルキル基、アルコキシ基、又はトリフルオロメチル基、アリール基又はハロゲン原子を示す。）を示し、
Ｒ３は、電子吸引基を示し、
(Wherein R 4 represents a hydrogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, an aryl group or a halogen atom),
R 3 represents an electron withdrawing group,
は、 Is
（ここで、各Ｒ５及びＲ５’は、互いに独立して、水素原子、アルキル基、アリール基、アシル基、ニトロ基又はハロゲン原子を示す。）を示す。
ｍは０又は１である。］、又は式（２−２）：
Here, each R 5 and R 5 ′ independently represents a hydrogen atom, an alkyl group, an aryl group, an acyl group, a nitro group or a halogen atom.
m is 0 or 1. Or formula (2-2):
［式中、Ｒ２’は、 [Wherein R 2 ′ is
（ここで、各Ｒ４及びＲ４’は、互いに独立して、水素原子、アルキル基、アルコキシ基、又はトリフルオロメチル基、アリール基又はハロゲン原子を示す。）を示す。
Ｘ、Ｙ、Ｒ１、Ｒ２、Ｒ３、ｍ及び
Here, each R 4 and R 4 ′ independently represents a hydrogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, an aryl group or a halogen atom.
X, Y, R 1 , R 2 , R 3 , m and
は、上記と同様である。］
で表されるヨードニウム化合物を製造し、
得られたヨードニウム化合物を求核剤で求核置換させる、官能基化スピロ環状化合物の製造方法。
６． 前記超原子価ヨウ素反応剤として、キラルなヨウ素化合物を用い、光学活性な官能基化スピロ環状化合物を製造する、上記項５に記載の製造方法。
７． 式（３）：
Is the same as above. ]
And an iodonium compound represented by
A method for producing a functionalized spirocyclic compound, wherein the obtained iodonium compound is nucleophilically substituted with a nucleophile.
6). Item 6. The production method according to Item 5, wherein a chiral iodine compound is used as the hypervalent iodine reactant to produce an optically active functionalized spirocyclic compound.
7). Formula (3):
［式中、ＸはＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し、ＹはＣ＝Ｏ、ＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し（ここで、Ｒ’、Ｒ”は、互いに独立して、アルキル基、アリール基、アミノ基又はハロゲン原子を示す。）、又は、Ｘ及びＹがともにＣＨ２の場合には、この２つが結合する炭素原子と一緒になってアリール環を形成してもよい。
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
Ｒ６は、フッ素原子、Ｎ３、ＮＯ２、ＣＮ、ＮＨ（Ｃ２Ｈ５）２又はＯＣＯＣＨ３を示す。
[Wherein X represents NR ′, O, S, CH 2 , CHR ′, or CR′R ″, and Y represents C═O, NR ′, O, S, CH 2 , CHR ′, or CR′R ”. (Wherein R ′ and R ″ each independently represents an alkyl group, an aryl group, an amino group or a halogen atom), or when X and Y are both CH 2 , An aryl ring may be formed together with the carbon atom to which the two are bonded.
R 1 represents an alkyl group, an aryl group, or a halogen atom.
R 6 represents a fluorine atom, N 3 , NO 2 , CN, NH (C 2 H 5 ) 2 or OCOCH 3 .
は、 Is
（ここで、各Ｒ５及びＲ５’は、互いに独立して、水素原子、アルキル基、アリール基、アシル基、ニトロ基又はハロゲン原子を示す。）を示す。
ｍは０又は１である。］
で表される官能基化スピロ環状化合物。
Here, each R 5 and R 5 ′ independently represents a hydrogen atom, an alkyl group, an aryl group, an acyl group, a nitro group or a halogen atom.
m is 0 or 1. ]
A functionalized spirocyclic compound represented by:
本発明によれば、スピロ環状化合物に様々な求核置換基を導入することができる新規なヨードニウム化合物を提供することができる。このヨードニウム化合物を中間体として用いれば、ハロゲン原子だけでなく、様々な求核置換基が導入されたスピロ環状化合物を高収率で合成することができる。また、適切な超原子価ヨウ素反応剤を用いることで、光学活性スピロ環状化合物を合成することもできる。 According to the present invention, a novel iodonium compound that can introduce various nucleophilic substituents into a spirocyclic compound can be provided. When this iodonium compound is used as an intermediate, not only a halogen atom but also a spirocyclic compound into which various nucleophilic substituents are introduced can be synthesized in a high yield. In addition, an optically active spirocyclic compound can be synthesized by using an appropriate hypervalent iodine reactant.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明は、式（２−１）： The present invention relates to formula (2-1):
［式中、ＸはＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し、ＹはＣ＝Ｏ、ＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し（ここで、Ｒ’、Ｒ”は、互いに独立して、アルキル基、アリール基、アミノ基又はハロゲン原子を示す。）、又は、Ｘ及びＹがともにＣＨ２の場合には、この２つが結合する炭素原子と一緒になってアリール環を形成してもよい。
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
Ｒ２は、
[Wherein X represents NR ′, O, S, CH 2 , CHR ′, or CR′R ″, and Y represents C═O, NR ′, O, S, CH 2 , CHR ′, or CR′R ”. (Wherein R ′ and R ″ each independently represents an alkyl group, an aryl group, an amino group or a halogen atom), or when X and Y are both CH 2 , An aryl ring may be formed together with the carbon atom to which the two are bonded.
R 1 represents an alkyl group, an aryl group, or a halogen atom.
R 2 is
（ここで、Ｒ４は、水素原子、アルキル基、アルコキシ基、又はトリフルオロメチル基、アリール基又はハロゲン原子を示す。）を示す。
Ｒ３は、電子吸引基を示す。
Here, R 4 represents a hydrogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, an aryl group or a halogen atom.
R 3 represents an electron withdrawing group.
は、 Is
（ここで、各Ｒ５及びＲ５’は、互いに独立して、水素原子；アルキル基、アリール基等の電子供与基；又はアシル基、ニトロ基、ハロゲン原子等の電子吸引基を示す。）を示す。
ｍは０又は１である。］、又は式（２−２）：
(Here, each R 5 and R 5 ′ independently represents a hydrogen atom; an electron-donating group such as an alkyl group or an aryl group; or an electron-withdrawing group such as an acyl group, a nitro group, or a halogen atom.) Indicates.
m is 0 or 1. Or formula (2-2):
［式中、Ｒ２’は、 [Wherein R 2 ′ is
（ここで、各Ｒ４及びＲ４’は、互いに独立して、水素原子、アルキル基、アルコキシ基、又はトリフルオロメチル基、アリール基又はハロゲン原子を示す。）を示す。
Ｘ、Ｙ、Ｒ１、Ｒ３、ｍ及び
Here, each R 4 and R 4 ′ independently represents a hydrogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, an aryl group or a halogen atom.
X, Y, R 1 , R 3 , m and
は、上記と同様である。］
で表されるヨードニウム化合物である。このヨードニウム化合物は新規化合物である。
Is the same as above. ]
It is an iodonium compound represented by these. This iodonium compound is a novel compound.
式（２−１）及び（２−２）において、上記のＸ及びＹがともにＣＨ２の場合、この２つが結合する炭素原子と一緒になって形成してもよいアリール環として、ベンゼン環及びナフタレン環が挙げられる。 In the formulas (2-1) and (2-2), when both X and Y are CH 2 , as an aryl ring that may be formed together with the carbon atom to which the two are bonded, a benzene ring and A naphthalene ring is mentioned.
Ｒ’、Ｒ”、Ｒ１、Ｒ４及びＲ５で示されるアルキル基としては、Ｃ１−２０の直鎖又は分岐鎖のアルキル基が挙げられ、好ましくはＣ１−１０のアルキル基である。具体的には、メチル、エチル、ｎ−プロピル、イソプロピル、ｓｅｃ−ブチル、イソブチル、ｎ−ペンチル、ｎ−ヘキシル、ｎ−ヘプチル、ｎ−オクチル等が挙げられる。 Examples of the alkyl group represented by R ′, R ″, R 1 , R 4 and R 5 include a C 1-20 linear or branched alkyl group, preferably a C 1-10 alkyl group. Specific examples include methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
Ｒ’、Ｒ”、Ｒ１、Ｒ４及びＲ５で示されるアリール基としては、単環又は２環のアリール基が挙げられ、具体的にはフェニル、ナフチル等が挙げられる。 Examples of the aryl group represented by R ′, R ″, R 1 , R 4 and R 5 include monocyclic or bicyclic aryl groups, and specific examples include phenyl and naphthyl.
Ｒ’、Ｒ”、Ｒ１、Ｒ４及びＲ５で示されるハロゲン原子としては、フッ素原子、塩素原子、臭素原子及びヨウ素原子が挙げられる。 Examples of the halogen atom represented by R ′, R ″, R 1 , R 4 and R 5 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Ｒ３で示される電子吸引基としては、アシル基、アリールスルホニル基、アルキルスルホニル基等が挙げられる。アシル基としては、アセチル、トリフルオロアセチル、プロパノイル、ベンゾイル等が挙げられる。アリールスルホニル基としては、ベンゼンスルホニル、パラトルエンスルホニル、ナフタレンスルホニル等が挙げられる。アルキルスルホニル基としては、メタンスルホニル、エチルスルホニル、プロピルスルホニル、トリフルオロメタンスルホニル等が挙げられる。 Examples of the electron withdrawing group represented by R 3 include an acyl group, an arylsulfonyl group, and an alkylsulfonyl group. Examples of the acyl group include acetyl, trifluoroacetyl, propanoyl, benzoyl and the like. Examples of the arylsulfonyl group include benzenesulfonyl, paratoluenesulfonyl, naphthalenesulfonyl and the like. Examples of the alkylsulfonyl group include methanesulfonyl, ethylsulfonyl, propylsulfonyl, trifluoromethanesulfonyl and the like.
Ｒ４で示されるアルコキシ基としては、Ｃ１−２０の直鎖又は分岐鎖のアルキルオキシ基が挙げられ、好ましくはＣ１−１０のアルキルオキシ基である。具体的には、メトキシ、エトキシ、ｎ−プロピルオキシ、イソプロピルオキシ、ｎ−ブチルオキシ等が挙げられる。 Examples of the alkoxy group represented by R 4 include a C 1-20 linear or branched alkyloxy group, and a C 1-10 alkyloxy group is preferable. Specific examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like.
Ｒ５で示されるアシル基としては、アセチル、トリフルオロアセチル、プロパノイル、ベンゾイル等が挙げられる。 Examples of the acyl group represented by R 5 include acetyl, trifluoroacetyl, propanoyl, benzoyl and the like.
Ｒ２及びＲ２’で示される環上に存在するＲ４及びＲ４’の数、及び The number of R 4 and R 4 ′ present on the ring denoted by R 2 and R 2 ′ , and
で示される環上に存在するＲ５及びＲ５’の数は、下限が１であり、上限はそれぞれの環において置換可能な数である。 The lower limit of the number of R 5 and R 5 ′ present on the ring represented by is the number that can be substituted in each ring.
本発明は、不斉炭素原子を有するすべての化合物については、すべての立体異性体を本発明の範囲に含む。本発明の化合物がラセミ体である場合には、通常の光学分割手段を用いて光学分割することにより光学活性体を得ることができる。又は、光学活性な原料から光学活性体を製造することもできる。そして、各々の光学活性体及びラセミ体のいずれについても、本発明の範囲に含む。 The present invention includes all stereoisomers within the scope of the present invention for all compounds having an asymmetric carbon atom. When the compound of the present invention is a racemate, an optically active form can be obtained by optical resolution using ordinary optical resolution means. Alternatively, an optically active substance can be produced from an optically active raw material. Each optically active substance and racemic substance are included in the scope of the present invention.
上記ヨードニウム化合物は、分子内にメトキシ置換されたアリール部位及びアルキン部位を有する基質を、超原子価ヨウ素反応剤を用いてスピロ環化させることにより製造することができる。 The iodonium compound can be produced by spirocyclization of a substrate having a methoxy-substituted aryl moiety and an alkyne moiety in the molecule using a hypervalent iodine reagent.
基質は、分子内にメトキシ置換されたアリール部位と、アルキン部位とを有する化合物である。具体的には、式（１）： The substrate is a compound having a methoxy-substituted aryl moiety and an alkyne moiety in the molecule. Specifically, the formula (1):
［式中、ＸはＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し、ＹはＣ＝Ｏ、ＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し（ここで、Ｒ’、Ｒ”は、互いに独立して、アルキル基、アリール基、アミノ基又はハロゲン原子を示す。）、又は、Ｘ及びＹがともにＣＨ２の場合には、この２つが結合する炭素原子と一緒になってアリール環を形成してもよい。
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
[Wherein X represents NR ′, O, S, CH 2 , CHR ′, or CR′R ″, and Y represents C═O, NR ′, O, S, CH 2 , CHR ′, or CR′R ”. (Wherein R ′ and R ″ each independently represents an alkyl group, an aryl group, an amino group or a halogen atom), or when X and Y are both CH 2 , An aryl ring may be formed together with the carbon atom to which the two are bonded.
R 1 represents an alkyl group, an aryl group, or a halogen atom.
は、オルト位又はパラ位がアルコキシ基で置換されたアリール基を示す。
ｍは０又は１である。］
で表される化合物である。
Represents an aryl group substituted at the ortho-position or para-position with an alkoxy group.
m is 0 or 1. ]
It is a compound represented by these.
式（１）において、Ｘ及びＹが形成してもよいアリール環、Ｒ’、Ｒ”、Ｒ１で示されるアルキル基、アリール基、及びハロゲン原子は、上記式（２−１）と同様である。 In the formula (1), the aryl ring, R ′, R ″, and the alkyl group represented by R 1 , the aryl group, and the halogen atom that X and Y may form are the same as in the above formula (2-1). is there.
で示されるオルト位又はパラ位がアルコキシ基で置換されたアリール基としては、例えば、２−メトキシフェニル、２−エトキシフェニル、４−メトキシフェニル、４−エトキシフェニル、２−メトキシナフチル、２−エトキシナフチル、４−メトキシナフチル、４−エトキシナフチル等が挙げられる。 Examples of the aryl group substituted with an alkoxy group at the ortho-position or para-position are 2-methoxyphenyl, 2-ethoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2-methoxynaphthyl, 2-ethoxy Examples include naphthyl, 4-methoxynaphthyl, 4-ethoxynaphthyl and the like.
超原子価ヨウ素反応剤は、原子価が３価のヨウ素原子を含む反応剤である。このような反応剤として、１分子中に超原子価ヨウ素原子を１個有する化合物、及び１分子中に超原子価ヨウ素原子を２個有する化合物が挙げられる。具体的には、１分子中に超原子価ヨウ素原子を１個有する反応剤として、 A hypervalent iodine reactant is a reactant containing a trivalent iodine atom. Examples of such a reactive agent include a compound having one hypervalent iodine atom in one molecule and a compound having two hypervalent iodine atoms in one molecule. Specifically, as a reactant having one hypervalent iodine atom in one molecule,
（ここで、Ｒ３及びＲ４は、上記式（Ｉ）中のＲ３及びＲ４と同様である。）
を挙げることができる。１分子中に超原子価ヨウ素原子を２個有する反応剤として、
(Wherein, R 3 and R 4 are the same as R 3 and R 4 in the above formula (I).)
Can be mentioned. As a reactant having two hypervalent iodine atoms in one molecule,
（ここで、Ｒ３、Ｒ４及びＲ４’は、上記式（２−１）中のＲ３、Ｒ４及びＲ４’と同様である。）
を挙げることができる。
(Wherein, R 3, R 4 and R 4 ', R 3, R 4 and R 4 in the above formula (2-1)' is the same as.)
Can be mentioned.
上記の１分子中に超原子価ヨウ素原子を２個有する反応剤は、軸不斉を持つため、２つの光学異性体が存在する。ラセミ体である場合には、通常の光学分割手段を用いて光学分割することにより、光学活性体を得ることができる。又は、光学活性な原料から光学活性体を製造することもできる。そして、各々の光学活性体及びラセミ体のいずれについても、本発明の範囲に含む。反応剤として光学活性体（キラルなヨウ素化合物）を用いれば、光学活性なスピロ環状化合物を製造することが可能となる。 Since the reactant having two hypervalent iodine atoms in one molecule has axial asymmetry, there are two optical isomers. In the case of a racemate, an optically active substance can be obtained by optical resolution using a normal optical resolution means. Alternatively, an optically active substance can be produced from an optically active raw material. Each optically active substance and racemic substance are included in the scope of the present invention. If an optically active substance (chiral iodine compound) is used as a reactant, an optically active spirocyclic compound can be produced.
ヨウ素反応剤は、基質に対して、通常０．５〜１．３倍モル程度、好ましくは０．５〜１．０倍モル程度添加される。 The iodine reactant is usually added in an amount of about 0.5 to 1.3 times mol, preferably about 0.5 to 1.0 times mol of the substrate.
スピロ環化反応は、反応に悪影響を及ぼさない慣用の溶媒、例えば、ＴＦＥ（２，２，２−トリフルオロエタノール）、ＨＦＩＰ（１，１，１，３，３，３−ヘキサフルオロイソプロパノール）、アセトニトリル（ＣＨ３ＣＮ）、ジクロロメタン（ＣＨ２Ｃｌ２）、クロロホルム（ＣＨＣｌ３）等の溶媒又はそれらの混合物中で行われる。これらの溶媒の中でも、ＴＦＥ又はアセトニトリルが好ましい。 Spirocyclization reaction is a conventional solvent that does not adversely affect the reaction, such as TFE (2,2,2-trifluoroethanol), HFIP (1,1,1,3,3,3-hexafluoroisopropanol), The reaction is performed in a solvent such as acetonitrile (CH 3 CN), dichloromethane (CH 2 Cl 2 ), chloroform (CHCl 3 ), or a mixture thereof. Among these solvents, TFE or acetonitrile is preferable.
反応温度は、通常、−７８〜４０℃程度で行われ、室温下で行うことも可能である。 The reaction temperature is usually about −78 to 40 ° C., and can be performed at room temperature.
反応時間は、通常１〜１２時間程度、好ましくは３〜５時間程度である。 The reaction time is usually about 1 to 12 hours, preferably about 3 to 5 hours.
超原子価ヨウ素反応剤を用いたスピロ環化反応は、緩和な条件で、様々な基質に対して、高ｉｐｓｏ選択的、且つ、高収率で進行して、スピロ環状化合物に超原子価ヨウ素が結合したヨードニウム化合物を製造することができる。 The spirocyclization reaction using a hypervalent iodine reactant proceeds in a high ipso-selective and high yield for various substrates under mild conditions. Can be produced.
本発明のヨードニウム化合物は、様々な求核剤を用いた求核置換反応により、超原子価ヨウ素の位置に求核置換基を導入したスピロ環状化合物を製造することができる。求核剤を変えることにより、ハロゲン原子をはじめとして、今まで導入することができなかった様々な官能基をスピロ環状化合物に導入することができるので、置換基を有するスピロ環状化合物を製造するための中間体として有用である。 The iodonium compound of the present invention can produce a spirocyclic compound in which a nucleophilic substituent is introduced at the hypervalent iodine position by a nucleophilic substitution reaction using various nucleophilic agents. By changing the nucleophile, various functional groups that could not be introduced so far, including halogen atoms, can be introduced into the spirocyclic compound, so that a spirocyclic compound having a substituent can be produced. It is useful as an intermediate.
よって、本発明のヨードニウム化合物を求核剤で求核置換させることにより、様々な置換基が導入された官能基化スピロ環状化合物を製造することができる。本発明は、上記ヨードニウム化合物を求核剤で求核置換させる、官能基化スピロ環状化合物の製造方法を提供する。 Therefore, functionalized spirocyclic compounds into which various substituents are introduced can be produced by nucleophilic substitution of the iodonium compound of the present invention with a nucleophile. The present invention provides a method for producing a functionalized spirocyclic compound in which the iodonium compound is nucleophilically substituted with a nucleophile.
求核置換反応に用いる求核剤としては、ＣｓＦ、ｎＢｕ４ＮＦ、ｎＢｕ４ＮＢｒ、ＮａＮ３、ＫＳＣＮ、ＮａＮＯ２、ＫＯＣＯＣＨ３、ＮＨ（Ｃ２Ｈ５）２、ＮａＣＮ等が挙げられる。 The nucleophilic agent used in the nucleophilic substitution reaction, CsF, n Bu 4 NF, n Bu 4 NBr, NaN 3, KSCN, NaNO 2, KOCOCH 3, NH (C 2 H 5) 2, NaCN , and the like.
求核剤は、ヨードニウム化合物１モルに対して、通常１．０〜５．０倍モル程度、好ましくは１．０〜１．５倍モル程度添加される。 The nucleophilic agent is usually added in an amount of about 1.0 to 5.0 times mol, preferably about 1.0 to 1.5 times mol for 1 mol of the iodonium compound.
求核置換反応は、反応に悪影響を及ぼさない慣用の溶媒、例えば、アセトニトリル（ＣＨ３ＣＮ）、ジクロロメタン（ＣＨ２Ｃｌ２）、クロロホルム（ＣＨＣｌ３）等の溶媒又はそれらの混合物中で行われる。これらの溶媒の中でも、アセトニトリルが好ましい。 The nucleophilic substitution reaction is carried out in a conventional solvent that does not adversely influence the reaction, for example, a solvent such as acetonitrile (CH 3 CN), dichloromethane (CH 2 Cl 2 ), chloroform (CHCl 3 ), or a mixture thereof. Of these solvents, acetonitrile is preferred.
反応温度は、通常、０〜８０℃程度で行われ、好ましくは６２〜７２℃程度である。 The reaction temperature is usually about 0 to 80 ° C, preferably about 62 to 72 ° C.
反応時間は、通常１〜２４時間程度、好ましくは３〜５時間程度である。 The reaction time is usually about 1 to 24 hours, preferably about 3 to 5 hours.
この求核置換反応は、緩和な条件で進行し、置換されたスピロ環状化合物を高収率で生成する。また、ハロゲン化に当たり、反応剤として、従来用いられていた毒性の強いＩ２、ＩＣｌ又はＢｒ２を用いる必要がなく、毒性が低く取り扱いが容易なＣｓＦ、ｎＢｕ４ＮＦ、ｎＢｕ４ＮＢｒ等を用いることができる点で、好ましい方法といえる。 This nucleophilic substitution reaction proceeds under mild conditions and produces a substituted spirocyclic compound in high yield. Further, in the halogenation, it is not necessary to use conventionally used highly toxic I 2 , ICl or Br 2 as a reactive agent, and CsF, n Bu 4 NF, n Bu 4 NBr, etc. which are low in toxicity and easy to handle. This can be said to be a preferable method in that it can be used.
このヨードニウム化合物の求核置換反応により、ヨードニウム化合物の超原子価ヨウ素が求核置換基により置換された官能基化スピロ環状化合物が高収率で得られる。 By this nucleophilic substitution reaction of the iodonium compound, a functionalized spirocyclic compound in which the hypervalent iodine of the iodonium compound is substituted with a nucleophilic substituent is obtained in high yield.
上記のヨードニウム化合物を製造する方法、及びヨードニウム化合物から官能基化スピロ環状化合物を製造する方法を連続して行うことにより、基質から官能基化スピロ環状化合物を製造する方法を提供することができる。 By continuously performing the method for producing the iodonium compound and the method for producing the functionalized spirocyclic compound from the iodonium compound, a method for producing the functionalized spirocyclic compound from the substrate can be provided.
よって、本発明は、分子内にメトキシ置換されたアリール部位及びアルキン部位を有する基質から官能基化スピロ環状化合物を製造する方法を提供する。 Thus, the present invention provides a method for producing a functionalized spirocyclic compound from a substrate having an methoxy-substituted aryl moiety and an alkyne moiety in the molecule.
本発明の官能基化スピロ環状化合物の製造方法は、分子内にメトキシ置換されたアリール部位及びアルキン部位を有する基質を、超原子価ヨウ素反応剤を用いてスピロ環化させることによりヨードニウム化合物を製造する工程（第１工程）、及び、得られたヨードニウム化合物を求核剤で求核置換させることにより官能基化スピロ環状化合物を製造する工程（第２工程）を含む。 The method for producing a functionalized spirocyclic compound of the present invention produces an iodonium compound by spirocyclization of a substrate having an aryl moiety and an alkyne moiety substituted with methoxy in the molecule using a hypervalent iodine reagent. And a step (second step) of producing a functionalized spirocyclic compound by nucleophilic substitution of the obtained iodonium compound with a nucleophile.
第１工程は、分子内にメトキシ置換されたアリール部位及びアルキン部位を有する基質を、超原子価ヨウ素反応剤を用いてスピロ環化させる工程である。 The first step is a step of spirocyclizing a substrate having a methoxy-substituted aryl moiety and an alkyne moiety in the molecule using a hypervalent iodine reagent.
この第１工程は、上述したヨードニウム化合物の製造方法と同様であり、基質、超原子価ヨウ素反応剤、及び反応条件は上記のとおりである。第１工程で生成したヨードニウム化合物は単離してもよいし、単離することなく第２工程に進んでもかまわない。 This 1st process is the same as that of the manufacturing method of the iodonium compound mentioned above, and a substrate, a hypervalent iodine reactant, and reaction conditions are as above-mentioned. The iodonium compound produced in the first step may be isolated or may proceed to the second step without isolation.
第２工程は、第１工程で得られたヨードニウム化合物を求核剤で求核置換させる工程である。 The second step is a step of nucleophilic substitution of the iodonium compound obtained in the first step with a nucleophilic agent.
この第２工程は、上述したヨードニウム化合物から官能基化スピロ環状化合物を製造する方法と同様であり、求核剤、及び反応条件は上記のとおりである。 This 2nd process is the same as that of the method of manufacturing a functionalized spiro cyclic compound from the iodonium compound mentioned above, and a nucleophile and reaction conditions are as above-mentioned.
スピロ環化反応と求核置換反応とを組み合わせた本発明の製造方法によれば、毒性の高いＩ２、ＩＣｌ又はＢｒ２を用いなくてもハロゲン原子をスピロ環に導入することができる。また、合成が困難なフッ素、窒素、酸素又は炭素原子を導入したスピロ環状化合物を簡単に製造することができるとともに、ハロゲン原子以外の置換基を簡便な方法で収率良く製造することが可能になる。 According to the production method of the present invention combining a spirocyclization reaction and a nucleophilic substitution reaction, a halogen atom can be introduced into a spirocycle without using highly toxic I 2 , ICl or Br 2 . In addition, it is possible to easily produce spirocyclic compounds into which fluorine, nitrogen, oxygen, or carbon atoms, which are difficult to synthesize, are introduced, and it is possible to produce substituents other than halogen atoms with a simple method and in high yield. Become.
さらに、超原子価ヨウ素反応剤としてキラルな超原子価ヨウ素反応剤を用いると、光学活性なスピロ環状化合物を製造することができる。 Furthermore, when a chiral hypervalent iodine reactant is used as the hypervalent iodine reactant, an optically active spirocyclic compound can be produced.
得られたスピロ環状化合物の中で、スピロ環に、フッ素原子、Ｎ３、ＮＯ２、ＣＮ、ＮＨ（Ｃ２Ｈ５）２又はＯＣＯＣＨ３が導入された化合物、すなわち、式（３）： Among the obtained spirocyclic compounds, a compound in which a fluorine atom, N 3 , NO 2 , CN, NH (C 2 H 5 ) 2 or OCOCH 3 is introduced into the spiro ring, that is, the formula (3):
［式中、ＸはＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し、ＹはＣ＝Ｏ、ＮＲ’、Ｏ、Ｓ、ＣＨ２、ＣＨＲ’、又はＣＲ’Ｒ”を示し（ここで、Ｒ’、Ｒ”は、互いに独立して、アルキル基、アリール基、アミノ基又はハロゲン原子を示す。）、又は、Ｘ及びＹがともにＣＨ２の場合には、この２つが結合する炭素原子と一緒になってアリール環を形成してもよい。
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
Ｒ６は、フッ素原子、Ｎ３、ＮＯ２、ＣＮ、ＮＨ（Ｃ２Ｈ５）２又はＯＣＯＣＨ３を示す。
[Wherein X represents NR ′, O, S, CH 2 , CHR ′, or CR′R ″, and Y represents C═O, NR ′, O, S, CH 2 , CHR ′, or CR′R ”. (Wherein R ′ and R ″ each independently represents an alkyl group, an aryl group, an amino group or a halogen atom), or when X and Y are both CH 2 , An aryl ring may be formed together with the carbon atom to which the two are bonded.
R 1 represents an alkyl group, an aryl group, or a halogen atom.
R 6 represents a fluorine atom, N 3 , NO 2 , CN, NH (C 2 H 5 ) 2 or OCOCH 3 .
は、 Is
（ここで、各Ｒ５及びＲ５’は、互いに独立して、水素原子；アルキル基、アリール基等の電子供与基；又はアシル基、ニトロ基、ハロゲン原子等の電子吸引基を示す。）を示す。
ｍは０又は１である。］
で表される化合物は、いずれも新規化合物である。
(Here, each R 5 and R 5 ′ independently represents a hydrogen atom; an electron-donating group such as an alkyl group or an aryl group; or an electron-withdrawing group such as an acyl group, a nitro group, or a halogen atom.) Indicates.
m is 0 or 1. ]
Are all novel compounds.
式（３）において、Ｘ及びＹが形成してもよいアリール環、Ｒ’、Ｒ”、Ｒ１で示されるアルキル基、アリール基、及びハロゲン原子、及び In the formula (3), an aryl ring which X and Y may form, an alkyl group represented by R ′, R ″, R 1 , an aryl group, and a halogen atom, and
は、上記式（２−１）と同様である。 Is the same as the above formula (2-1).
以下、実施例を示して本発明を更に詳細に説明する。
実施例1（第1工程）：ヨードニウム化合物(2a)の合成
窒素雰囲気下、50 mLのナス型フラスコに2,2,2-トリフルオロエタノール (TFE)(3 mL)、基質1a (0.030 g, 0.1 mmmol) を加え、懸濁させた。次いで室温下、ヨウ素反応剤1A（PhI(OH)OTs）(0.043 g, 0.11 mmol) を加え、同温で3時間撹拌した。反応の終了はTLCにより確認した。TFE留去後、残渣をMeCN (1.0 ml)に溶解させた。このMeCN溶液を50 mLナス型フラスコ中のEt2O (15 ml)、n-ヘキサン (5 ml) の混合溶液に撹拌しながら滴下した。沈澱したヨードニウム化合物2aをろ過により回収し、乾燥させた。
Hereinafter, the present invention will be described in more detail with reference to examples.
Example 1 (first step): Synthesis of iodonium compound (2a) In a 50 mL eggplant-shaped flask under a nitrogen atmosphere, 2,2,2-trifluoroethanol (TFE) (3 mL), substrate 1a (0.030 g, 0.1 mmmol) was added and suspended. Next, iodine reactant 1A (PhI (OH) OTs) (0.043 g, 0.11 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The completion of the reaction was confirmed by TLC. After TFE distillation, the residue was dissolved in MeCN (1.0 ml). This MeCN solution was added dropwise with stirring to a mixed solution of Et 2 O (15 ml) and n-hexane (5 ml) in a 50 mL eggplant-shaped flask. The precipitated iodonium compound 2a was collected by filtration and dried.
2a: 1H NMR (CDCl3, 500 MHz) δ 2.33 (3H, s), 6.41 (1H, d, J=10.4 Hz), 6.85 (1H, d, J=10.4 Hz), 6.87 (2H, d, J=8.0 Hz), 6.97 (1H, d, J=8.0 Hz), 7.08 (2H, d, J=8.0 Hz), 7.24 (2H, dd, J=8.0, 8.0 Hz), 7.30 (2H, dd, J=8.0, 8.0 Hz), 7.37-7.44 (2H, m), 7.49 (1H, dd, J=8.0, 8.0 Hz), 7.51-7.58 (3H, m), 7.74 (2H, d, J=8.0 Hz), 8.05 (1H, d, J=8.0 Hz) ppm; 13C NMR (CDCl3, 125 MHz) δ 21.27, 86.18, 111.17, 116.75, 125.88, 125.93, 127.23, 127.54, 128.46, 128.74, 129.11, 130.33, 131.02, 131.44, 131.67, 131.79, 132.27, 133.70, 134.63, 135.19, 140.12, 140.95, 141.64, 167.50, 173.87, 182.35 ppm 2a: 1 H NMR (CDCl 3 , 500 MHz) δ 2.33 (3H, s), 6.41 (1H, d, J = 10.4 Hz), 6.85 (1H, d, J = 10.4 Hz), 6.87 (2H, d, J = 8.0 Hz), 6.97 (1H, d, J = 8.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 7.24 (2H, dd, J = 8.0, 8.0 Hz), 7.30 (2H, dd, J = 8.0, 8.0 Hz), 7.37-7.44 (2H, m), 7.49 (1H, dd, J = 8.0, 8.0 Hz), 7.51-7.58 (3H, m), 7.74 (2H, d, J = 8.0 Hz ), 8.05 (1H, d, J = 8.0 Hz) ppm; 13 C NMR (CDCl 3 , 125 MHz) δ 21.27, 86.18, 111.17, 116.75, 125.88, 125.93, 127.23, 127.54, 128.46, 128.74, 129.11, 130.33, 131.02, 131.44, 131.67, 131.79, 132.27, 133.70, 134.63, 135.19, 140.12, 140.95, 141.64, 167.50, 173.87, 182.35 ppm
実施例２（第１工程）：ヨードニウム化合物（2h）の合成
50 mLのナス型フラスコに2,2,2-トリフルオロエタノール (TFE) (3 mL)、下記に示すヨウ素反応剤2A (0.036 g, 0.055 mmol)、及びｐ−トルエンスルホン酸（TsOH・H2O）(0.021 g, 0.11 mmol)を加え、0.5時間撹拌した。その後、下記表３に示す基質１h (0.030 g, 0.1 mmol) を反応溶液に加えて室温下、同温で3時間撹拌した。反応の終了はTLCにより確認した。TFE留去後、残渣をMeCN (1.0 ml)に溶解させた。このMeCN溶液を50 mLナス型フラスコ中のEt2O (15 ml)、n-ヘキサン (5 ml) の混合溶液に撹拌しながら滴下した。沈澱したヨードニウム化合物2hをろ過により回収し、乾燥させた。
Example 2 (first step): Synthesis of iodonium compound (2h)
In a 50 mL eggplant-shaped flask, 2,2,2-trifluoroethanol (TFE) (3 mL), iodine reactant 2A shown below (0.036 g, 0.055 mmol), and p-toluenesulfonic acid (TsOH · H 2 O) (0.021 g, 0.11 mmol) was added and stirred for 0.5 hour. Thereafter, the substrate 1h (0.030 g, 0.1 mmol) shown in Table 3 below was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The completion of the reaction was confirmed by TLC. After TFE distillation, the residue was dissolved in MeCN (1.0 ml). This MeCN solution was added dropwise with stirring to a mixed solution of Et 2 O (15 ml) and n-hexane (5 ml) in a 50 mL eggplant-shaped flask. The precipitated iodonium compound 2h was collected by filtration and dried.
2h: 1H NMR (CD3OD, 400 MHz) δ 1.86 (6H, s), 2.14 (6H, s), 2.40 (6H, s), 6.36 (2H, d, J=10.0 Hz), 6.43 (2H, d, J=10.0 Hz), 6.70 (2H, d, J=10.0 Hz), 6.80 (4H, m), 7.19 (2H, s), 7.25 (4H, d, J=8.0 Hz), 7.36 (4H, d, J=7.2 Hz), 7.59 (4H, t, J=7.6 Hz), 7.64 (4H, d, J=8.4 Hz), 7.74 (2H, t, J=7.6 Hz)；13C NMR (CD3OD, 100 MHz) δ 21.3×2, 22.18, 86.87, 120.86, 127.05, 129.13, 219.41, 130.17, 131.09, 133.77, 134.12, 134.22, 137.72, 137.81, 140.78, 140.93, 141.017, 141.77, 142.33, 142.73, 144.83, 157.98, 167.44, 174.38, 184.41 ppm; HRFABMS calcd for C53H42I2O9S [M-OTs]+ 1108.0639, found 1108.0631. 2h: 1 H NMR (CD 3 OD, 400 MHz) δ 1.86 (6H, s), 2.14 (6H, s), 2.40 (6H, s), 6.36 (2H, d, J = 10.0 Hz), 6.43 (2H , d, J = 10.0 Hz), 6.70 (2H, d, J = 10.0 Hz), 6.80 (4H, m), 7.19 (2H, s), 7.25 (4H, d, J = 8.0 Hz), 7.36 (4H , d, J = 7.2 Hz), 7.59 (4H, t, J = 7.6 Hz), 7.64 (4H, d, J = 8.4 Hz), 7.74 (2H, t, J = 7.6 Hz); 13 C NMR (CD (3 OD, 100 MHz) δ 21.3 × 2, 22.18, 86.87, 120.86, 127.05, 129.13, 219.41, 130.17, 131.09, 133.77, 134.12, 134.22, 137.72, 137.81, 140.78, 140.93, 141.017, 141.77, 142.33, 142.73, 144.83 , 157.98, 167.44, 174.38, 184.41 ppm; HRFABMS calcd for C 53 H 42 I 2 O 9 S [M-OTs] + 1108.0639, found 1108.0631.
実施例３〜５
TsOH・H2Oの代わりにトリフルオロメタンスルホン酸（TfOH）を加えたこと以外は実施例２と同様に反応させた（実施例３）。基質として１a、及びヨウ素反応剤として下記に示す3Aを用い、TfOHを加えたこと以外は実施例２と同様に反応させた（実施例４）。基質として１aを用い、TfOHを加えたこと以外は実施例２と同様に反応させた（実施例５）。各反応により得られたヨードニウム化合物及び収率を、実施例１及び２の結果とともに表１に示す。
Examples 3-5
The reaction was conducted in the same manner as in Example 2 except that trifluoromethanesulfonic acid (TfOH) was added instead of TsOH · H 2 O (Example 3). The reaction was carried out in the same manner as in Example 2 except that 1a as a substrate and 3A shown below as an iodine reactant were added and TfOH was added (Example 4). The reaction was performed in the same manner as in Example 2 except that 1a was used as a substrate and TfOH was added (Example 5). Table 1 shows the iodonium compounds and yields obtained by the respective reactions together with the results of Examples 1 and 2.
各生成物のスペクトルデータは以下のとおりである。
2h’: 1H NMR (CD3OD, 400 MHz) δ 1.89 (6H, s), 2.24 (6H, s), 2.40 (6H, s), 6.43 (4H, m), 6.72 (2H, d, J=10.0 Hz), 6.82 (2H, d, J=10.0 Hz), 6.80 (4H, m), 7.22 (2H, s), 7.29 (2H, s), 7.37 (4H, d, J=8.0 Hz), 7.62 (4H, t, J=7.6 Hz), 7.75 (2H, t, J=7.6 Hz)；
2h”: 1H NMR (CD3OD, 400 MHz) δ 1.86 (6H, s), 6.76-6.95 (4H, m), 7.18-7.55 (6H, m), 7.60-7.64 (6H, m), 7.98 (2H, t, J=7.6 Hz)；
2h”’: 1H NMR (CD3OD, 400 MHz) δ 1.86 (6H, s), 2.24 (6H, s), 6.76-6.95 (4H, m), 7.18-7.55 (4H, m), 7.60-7.64 (6H, m), 7.98 (2H, t, J=7.6 Hz)；
The spectral data of each product is as follows.
2h ': 1 H NMR (CD 3 OD, 400 MHz) δ 1.89 (6H, s), 2.24 (6H, s), 2.40 (6H, s), 6.43 (4H, m), 6.72 (2H, d, J = 10.0 Hz), 6.82 (2H, d, J = 10.0 Hz), 6.80 (4H, m), 7.22 (2H, s), 7.29 (2H, s), 7.37 (4H, d, J = 8.0 Hz), 7.62 (4H, t, J = 7.6 Hz), 7.75 (2H, t, J = 7.6 Hz);
2h ”: 1 H NMR (CD 3 OD, 400 MHz) δ 1.86 (6H, s), 6.76-6.95 (4H, m), 7.18-7.55 (6H, m), 7.60-7.64 (6H, m), 7.98 (2H, t, J = 7.6 Hz);
2h ”': 1 H NMR (CD 3 OD, 400 MHz) δ 1.86 (6H, s), 2.24 (6H, s), 6.76-6.95 (4H, m), 7.18-7.55 (4H, m), 7.60- 7.64 (6H, m), 7.98 (2H, t, J = 7.6 Hz);
実施例６（第1工程＋第２工程）：臭素置換されたスピロ［４，５］デカン化合物（3a）の合成
窒素雰囲気下、50 mLのナス型フラスコに2,2,2-トリフルオロエタノール (TFE) (3 mL)、基質1a (0.030 g, 0.1 mmol) を加え、懸濁させた。次いで室温下、ヨウ素反応剤1A (0.036 g, 0.055 mmol) を加え、同温で3時間撹拌した。反応の終了はTLCにより確認した。反応終了後、溶媒を減圧留去した。得られた残渣 (ヨードニウム化合物2a) は単離精製することなく、全量次操作に付した。窒素雰囲気下、2aにアセトニトリル (3 mL) を加え溶解し、次いで室温下nBuN4Br (0.035g, 0.18 mmol) を加えた後、浴温62-72℃で終夜 (18時間) 撹拌した。反応液を室温まで冷却後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (n-ヘキサン/AcOEt (9:1〜8:2))により精製することで 3a (0.33 g, 92%) が無色固体として得られた。基質の構造、生成物の構造、反応条件、収率等を表２に示す。
3a : 1H NMR (CDCl3, 300 MHz) δ 6.56 (1H, d, J=10.2 Hz), 6.73 (1H, d, J=10.2 Hz), 6.97-7.05 (2H, m), 7.20-7.31 (2H, m), 7.31-7.42 (2H, m), 7.63 (1H, td, J=7.7, 1.1 Hz), 7.70 (1H, td, J=7.7, 1.5 Hz), 8.16 (1H, dd, J=7.7, 1.5 Hz); HRFABMS calcd for C19H12 79BrO3[M+H]+ 366.9969, found 366.9973.
Example 6 (first step + second step): Synthesis of bromine-substituted spiro [4,5] decane compound (3a) 2,2,2-trifluoroethanol in a 50 mL eggplant-shaped flask under nitrogen atmosphere (TFE) (3 mL) and substrate 1a (0.030 g, 0.1 mmol) were added and suspended. Next, iodine reactant 1A (0.036 g, 0.055 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The completion of the reaction was confirmed by TLC. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue (iodonium compound 2a) was subjected to the next operation without isolation and purification. Under a nitrogen atmosphere, acetonitrile (3 mL) was added to 2a for dissolution, and then n BuN 4 Br (0.035 g, 0.18 mmol) was added at room temperature, followed by stirring overnight (18 hours) at a bath temperature of 62-72 ° C. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / AcOEt (9: 1-8: 2)) to give 3a (0.33 g, 92%) as a colorless solid. Table 2 shows the substrate structure, product structure, reaction conditions, yield, and the like.
3a : 1 H NMR (CDCl 3 , 300 MHz) δ 6.56 (1H, d, J = 10.2 Hz), 6.73 (1H, d, J = 10.2 Hz), 6.97-7.05 (2H, m), 7.20-7.31 (2H , m), 7.31-7.42 (2H, m), 7.63 (1H, td, J = 7.7, 1.1 Hz), 7.70 (1H, td, J = 7.7, 1.5 Hz), 8.16 (1H, dd, J = 7.7 , 1.5 Hz); HRFABMS calcd for C 19 H 12 79 BrO 3 [M + H] + 366.9969, found 366.9973.
実施例７〜１７
表２及び３に示す基質を用い、表２及び３に記載の反応条件で実施例６と同様に反応させることにより、表２及び３に示す生成物が得られた。
Examples 7-17
The products shown in Tables 2 and 3 were obtained by reacting the substrates shown in Tables 2 and 3 in the same manner as in Example 6 under the reaction conditions shown in Tables 2 and 3.
なお、表２及び３のｂ）は単離収率を示しており、表３のｅ）は、５−エキソ環化した化合物が混在している可能性があることを示している。 Note that b) in Tables 2 and 3 show the isolated yield, and e) in Table 3 shows that there may be a mixture of 5-exo cyclized compounds.
各生成物のスペクトルデータは以下のとおりである。
3b: 1H NMR (CDCl3, 300 MHz) δ 6.18 (1H, d, J=9.9 Hz), 6.97 (2H, d, J=7.5 Hz), 7.25 (1H, d, J=9.9 Hz), 7.27 (1H, d, J=7.5 Hz), 7.30-7.44 (4H, m), 7.49 (1H, d, J=5.4 Hz), 7.50 (1H, d, J=5.4 Hz) ppm;
13C NMR (CDCl3, 75.5 MHz) δ 77.21, 87.50, 110.67, 124.22, 127.45, 127.94, 128.63, 128.71, 130.34, 130.49, 130.63, 130.76, 131.25, 134.05, 146.50, 160.60, 190.31 ppm;
3c: 1H NMR (CDCl3, 500 MHz) δ 6.59 (1H, d, J=10.5 Hz), 6.63 (1H, d, J=10.5 Hz), 6.86 (1H, d, J=7.5 Hz), 6.93 (1H, d, J=7.5 Hz), 7.10-7.28 (6H, m), 7.32-7.41 (2H, m), 7.44 (1H, dd, J=7.5, 7.5 Hz), 7.59 (1H, d, J=7.5 Hz), 8.19 (1H, dd, J=7.5, 1.0 Hz) ppm;
13C NMR (CDCl3, 125 MHz) δ 61.68, 121.65, 122.22, 123.38, 126.78, 127.07, 128.05, 128.16, 128.22, 128.31, 128.58, 128.67, 130.15, 132.37, 133.02, 133.07, 140.72, 143.08, 145.12, 146.51, 148.08, 184.89 ppm;
3d: 1H NMR (CDCl3, 300 MHz) δ 6.50 (1H, d, J=10.2 Hz), 6.71 (1H, d, J=10.2 Hz), 6.85 (2H, d, J=7.5 Hz), 7.15-7.35 (4H, m), 7.47 (1H, d, J=7.5 Hz), 7.53 (1H, t, J=7.5 Hz), 7.60-7.70 (1H, m), 8.11 (1H, d, J=7.5 Hz) ppm;
13C NMR (CDCl3, 75.5 MHz) δ 65.52, 117.92, 126.27, 127.33, 127.58, 128.53, 129.58, 129.87, 130.09, 131.46, 131.68, 133.76, 137.52, 144.64, 157.32, 168.45, 182.97 ppm;
3e: 1H NMR (CDCl3, 300 MHz) δ 2.45 (1H, ddd, J=14.1, 8.0, 6.1 Hz), 2.52 (1H, ddd, J=14.1, 8.0, 6.1 Hz), 3.12 (1H, ddd, J=14.1, 8.0, 6.1 Hz), 3.16 (1H, ddd, J=14.1, 8.0, 6.1 Hz), 6.40 (1H, d, J=9.8 Hz), 6.92 (2H, dd, J=7.9, 1.2 Hz), 7.05 (1H, d, J=9.8 Hz), 7.07-7.16 (3H, m), 7.35-7.40 (1H, m), 7.48 (1H, d, J=7.9 Hz), 7.52-7.58 (1H, m), 8.12 (1H, d, J=7.9 Hz) ppm;
13C NMR (CDCl3, 75.5 MHz) δ 39.74, 39.79, 57.14, 122.49, 126.74, 127.09, 127.45, 127.69, 127.92, 127.95, 128.00, 131.17, 133.01, 133.90, 143.26, 146.76, 152.73, 184.45 ppm;
3f: 1H NMR (CDCl3, 300 MHz) δ 2.14 (1H, ddd, J=14.6, 8.6, 6.8 Hz), 2.50 (1H, ddd, J=14.6, 9.3, 5.3 Hz), 2.95 (1H, ddd, J=16.1, 8.6, 5.3 Hz), 3.13 (1H, ddd, J=16.1, 9.3, 6.8 Hz), 6.22 (1H, d, J=9.7 Hz), 6.55 (1H, d, J=9.7 Hz), 7.10-7.20 (6H, m), 7.32 (1H, dd, J=7.5, 7.5 Hz), 7.52 (1H, dd, J=7.5, 7.5 Hz), 8.00 (1H, d, J=7.5 Hz) ppm;
13C NMR (CDCl3, 75.5 MHz) δ 36.92, 39.56, 64.39, 123.04, 124.58, 127.15, 127.42, 127.72, 127.88, 128.03, 128.06, 129.04, 134.34, 134.59, 137.15, 137.99, 141.71, 200.21 ppm;
3g: 1H NMR (CDCl3, 300 MHz) δ 2.21 (1H, ddd, J=13.0, 8.6, 5.8 Hz), 2.67 (1H, ddd, J=13.0, 8.6, 5.8 Hz), 3.05 (1H, ddd, J=14.4, 8.6, 5.8 Hz), 3.14 (1H, ddd, J=14.4, 8.6, 5.8 Hz), 6.14 (1H, d, J=9.9 Hz), 6.88-6.98 (2H, m), 7.04-7.16 (3H, m), 7.22-7.32 (2H, m), 7.32-7.45 (3H, m) ppm;
13C NMR (CDCl3, 75.5 MHz) δ 39.99, 40.71, 67.26, 122.68, 124.98, 127.36, 127.55, 127.60, 127.86, 128.12, 129.04, 129.51, 130.45, 134.17, 142.24, 144.85, 145.47, 201.29 ppm;
3h: 1H NMR (CDCl3, 300 MHz) δ 6.40-6.50 (2H, m), 6.65-6.75 (2H, m), 7.38-7.55 (5H, m) ppm;
13C NMR (CDCl3, 75.5 MHz) δ 82.94, 112.26, 127.41, 128.57, 129.00, 131.33, 132.19, 141.63, 159.77, 166.88, 183.43 ppm;
3i: 1H NMR (CDCl3, 300 MHz) δ 6.38 (2H, d, J=10.3 Hz), 6.65 (2H, d, J=10.3 Hz), 7.26 (1H, s), 7.38-7.24 (5H, m);
3j: 1H NMR (CDCl3, 300 MHz) δ 6.63 (1H, d, J=10.3 Hz), 6.72 (1H, d, J=10.3 Hz), 7.23 (1H, dd, J=7.5, 1.3 Hz), 7.61 (1H, ddd, J=7.5, 6.2, 1.3 Hz), 7.67 (1H, ddd, J=7.5, 6.2, 1.3 Hz), 8.21 (1H, dd, J=7.5, 1.3 Hz) ppm;
13C NMR (CDCl3, 75.5 MHz) δ 85.06, 115.75, 125.23, 127.43, 130.55, 130.99, 133.36, 133.81, 134.45, 140.27, 150.46, 165.73, 182.42 ppm;
3k: 1H NMR (CDCl3, 400 MHz) δ 1.94 (2H, m), 2.02 (2H, m), 2.84 (1H, m), 6.11 (2H, d), 6.91-6.96 (5H, m), 7.20-7.22 (2H, m) ppm;
3l: 1H NMR (CDCl3,400 MHz) δ 1.68 (3H, s), 6.54 (1H, d, J=10.8 Hz), 6.59 (1H, d J=10.8 Hz), 7.10 (1H, dd, J=8.0, 1.6 Hz), 7.48-7.59 (2H, m), 8.13 (1H, dd, J=8.0, 1.6 Hz) ppm;
The spectral data of each product is as follows.
3b: 1 H NMR (CDCl 3 , 300 MHz) δ 6.18 (1H, d, J = 9.9 Hz), 6.97 (2H, d, J = 7.5 Hz), 7.25 (1H, d, J = 9.9 Hz), 7.27 (1H, d, J = 7.5 Hz), 7.30-7.44 (4H, m), 7.49 (1H, d, J = 5.4 Hz), 7.50 (1H, d, J = 5.4 Hz) ppm;
13 C NMR (CDCl 3 , 75.5 MHz) δ 77.21, 87.50, 110.67, 124.22, 127.45, 127.94, 128.63, 128.71, 130.34, 130.49, 130.63, 130.76, 131.25, 134.05, 146.50, 160.60, 190.31 ppm;
3c: 1 H NMR (CDCl 3 , 500 MHz) δ 6.59 (1H, d, J = 10.5 Hz), 6.63 (1H, d, J = 10.5 Hz), 6.86 (1H, d, J = 7.5 Hz), 6.93 (1H, d, J = 7.5 Hz), 7.10-7.28 (6H, m), 7.32-7.41 (2H, m), 7.44 (1H, dd, J = 7.5, 7.5 Hz), 7.59 (1H, d, J = 7.5 Hz), 8.19 (1H, dd, J = 7.5, 1.0 Hz) ppm;
13 C NMR (CDCl 3 , 125 MHz) δ 61.68, 121.65, 122.22, 123.38, 126.78, 127.07, 128.05, 128.16, 128.22, 128.31, 128.58, 128.67, 130.15, 132.37, 133.02, 133.07, 140.72, 143.08, 145.12, 146.51 , 148.08, 184.89 ppm;
3d: 1 H NMR (CDCl 3 , 300 MHz) δ 6.50 (1H, d, J = 10.2 Hz), 6.71 (1H, d, J = 10.2 Hz), 6.85 (2H, d, J = 7.5 Hz), 7.15 -7.35 (4H, m), 7.47 (1H, d, J = 7.5 Hz), 7.53 (1H, t, J = 7.5 Hz), 7.60-7.70 (1H, m), 8.11 (1H, d, J = 7.5 Hz) ppm;
13 C NMR (CDCl 3 , 75.5 MHz) δ 65.52, 117.92, 126.27, 127.33, 127.58, 128.53, 129.58, 129.87, 130.09, 131.46, 131.68, 133.76, 137.52, 144.64, 157.32, 168.45, 182.97 ppm;
3e: 1H NMR (CDCl 3 , 300 MHz) δ 2.45 (1H, ddd, J = 14.1, 8.0, 6.1 Hz), 2.52 (1H, ddd, J = 14.1, 8.0, 6.1 Hz), 3.12 (1H, ddd, J = 14.1, 8.0, 6.1 Hz), 3.16 (1H, ddd, J = 14.1, 8.0, 6.1 Hz), 6.40 (1H, d, J = 9.8 Hz), 6.92 (2H, dd, J = 7.9, 1.2 Hz ), 7.05 (1H, d, J = 9.8 Hz), 7.07-7.16 (3H, m), 7.35-7.40 (1H, m), 7.48 (1H, d, J = 7.9 Hz), 7.52-7.58 (1H, m), 8.12 (1H, d, J = 7.9 Hz) ppm;
13 C NMR (CDCl 3 , 75.5 MHz) δ 39.74, 39.79, 57.14, 122.49, 126.74, 127.09, 127.45, 127.69, 127.92, 127.95, 128.00, 131.17, 133.01, 133.90, 143.26, 146.76, 152.73, 184.45 ppm;
3f: 1H NMR (CDCl 3 , 300 MHz) δ 2.14 (1H, ddd, J = 14.6, 8.6, 6.8 Hz), 2.50 (1H, ddd, J = 14.6, 9.3, 5.3 Hz), 2.95 (1H, ddd, J = 16.1, 8.6, 5.3 Hz), 3.13 (1H, ddd, J = 16.1, 9.3, 6.8 Hz), 6.22 (1H, d, J = 9.7 Hz), 6.55 (1H, d, J = 9.7 Hz), 7.10-7.20 (6H, m), 7.32 (1H, dd, J = 7.5, 7.5 Hz), 7.52 (1H, dd, J = 7.5, 7.5 Hz), 8.00 (1H, d, J = 7.5 Hz) ppm;
13 C NMR (CDCl 3 , 75.5 MHz) δ 36.92, 39.56, 64.39, 123.04, 124.58, 127.15, 127.42, 127.72, 127.88, 128.03, 128.06, 129.04, 134.34, 134.59, 137.15, 137.99, 141.71, 200.21 ppm;
3g: 1 H NMR (CDCl 3 , 300 MHz) δ 2.21 (1H, ddd, J = 13.0, 8.6, 5.8 Hz), 2.67 (1H, ddd, J = 13.0, 8.6, 5.8 Hz), 3.05 (1H, ddd , J = 14.4, 8.6, 5.8 Hz), 3.14 (1H, ddd, J = 14.4, 8.6, 5.8 Hz), 6.14 (1H, d, J = 9.9 Hz), 6.88-6.98 (2H, m), 7.04- 7.16 (3H, m), 7.22-7.32 (2H, m), 7.32-7.45 (3H, m) ppm;
13 C NMR (CDCl 3 , 75.5 MHz) δ 39.99, 40.71, 67.26, 122.68, 124.98, 127.36, 127.55, 127.60, 127.86, 128.12, 129.04, 129.51, 130.45, 134.17, 142.24, 144.85, 145.47, 201.29 ppm;
3h: 1 H NMR (CDCl 3 , 300 MHz) δ 6.40-6.50 (2H, m), 6.65-6.75 (2H, m), 7.38-7.55 (5H, m) ppm;
13 C NMR (CDCl 3 , 75.5 MHz) δ 82.94, 112.26, 127.41, 128.57, 129.00, 131.33, 132.19, 141.63, 159.77, 166.88, 183.43 ppm;
3i: 1 H NMR (CDCl 3 , 300 MHz) δ 6.38 (2H, d, J = 10.3 Hz), 6.65 (2H, d, J = 10.3 Hz), 7.26 (1H, s), 7.38-7.24 (5H, m);
3j: 1 H NMR (CDCl 3 , 300 MHz) δ 6.63 (1H, d, J = 10.3 Hz), 6.72 (1H, d, J = 10.3 Hz), 7.23 (1H, dd, J = 7.5, 1.3 Hz) , 7.61 (1H, ddd, J = 7.5, 6.2, 1.3 Hz), 7.67 (1H, ddd, J = 7.5, 6.2, 1.3 Hz), 8.21 (1H, dd, J = 7.5, 1.3 Hz) ppm;
13 C NMR (CDCl 3 , 75.5 MHz) δ 85.06, 115.75, 125.23, 127.43, 130.55, 130.99, 133.36, 133.81, 134.45, 140.27, 150.46, 165.73, 182.42 ppm;
3k: 1 H NMR (CDCl 3 , 400 MHz) δ 1.94 (2H, m), 2.02 (2H, m), 2.84 (1H, m), 6.11 (2H, d), 6.91-6.96 (5H, m), 7.20-7.22 (2H, m) ppm;
3l: 1 H NMR (CDCl 3 , 400 MHz) δ 1.68 (3H, s), 6.54 (1H, d, J = 10.8 Hz), 6.59 (1H, d J = 10.8 Hz), 7.10 (1H, dd, J = 8.0, 1.6 Hz), 7.48-7.59 (2H, m), 8.13 (1H, dd, J = 8.0, 1.6 Hz) ppm;
実施例１８（第1工程＋第２工程）：ヨウ素置換されたスピロ［４，５］デカン化合物（3m）の合成
50 mLのナス型フラスコに2,2,2-トリフルオロエタノール (TFE) (3 mL)、ヨウ素反応剤2A (0.036 g, 0.055 mmol)、及びTsOH・H2O (0.021 g, 0.11 mmol)を加え、0.5時間撹拌した。その後、基質１m (0.025 g, 0.1 mmol) を反応溶液に加えて室温下、同温で3時間撹拌した。反応終了後、溶媒を減圧留去した。得られた残渣 (ヨードニウム化合物2m) は単離精製することなく、全量次操作に付した。窒素雰囲気下、2mにアセトニトリル (3 mL) を加え溶解し、次いで室温下nBuN4I (0.045g, 0.18 mmol) を加えた後、浴温62-72℃で終夜 (18時間) 撹拌した。反応液を室温まで冷却後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (n-ヘキサン/AcOEt (9:1〜8:2))により精製することで 3m (0.35 g, 100%) が無色固体として得られた。基質の構造、生成物の構造、反応条件、収率等を表４に示す。
Example 18 (first step + second step): Synthesis of spiro [4,5] decane compound (3m) substituted with iodine
2,2,2-trifluoroethanol (TFE) (3 mL), iodine reagent 2A (0.036 g, 0.055 mmol), and TsOH ・ H 2 O (0.021 g, 0.11 mmol) were added to a 50 mL eggplant-shaped flask. The mixture was further stirred for 0.5 hours. Thereafter, 1 m (0.025 g, 0.1 mmol) of the substrate was added to the reaction solution, followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue (iodonium compound 2m) was subjected to the next operation without isolation and purification. Under a nitrogen atmosphere, acetonitrile (3 mL) was added to 2 m for dissolution, and then n BuN 4 I (0.045 g, 0.18 mmol) was added at room temperature, followed by stirring overnight (18 hours) at a bath temperature of 62-72 ° C. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / AcOEt (9: 1-8: 2)) to give 3m (0.35 g, 100%) as a colorless solid. Table 4 shows the substrate structure, product structure, reaction conditions, yield, and the like.
実施例１９〜２２
表４に示す基質を用い、表４に記載の反応条件で実施例１８と同様に反応させることにより、表４に示す生成物が得られた。
Examples 19-22
By using the substrate shown in Table 4 and carrying out the reaction in the same manner as in Example 18 under the reaction conditions shown in Table 4, the products shown in Table 4 were obtained.
各生成物のスペクトルデータは以下のとおりである。
3m: 1H NMR (CDCl3, 300 MHz) δ 1.84 (3H, s), 6.16 (1H, s), 6.30 (1H, d, J=10.0), 6.56 (1H, d, J=10.0), 7.22-7.36 (5H, m) ppm;
The spectral data of each product is as follows.
3m: 1 H NMR (CDCl 3 , 300 MHz) δ 1.84 (3H, s), 6.16 (1H, s), 6.30 (1H, d, J = 10.0), 6.56 (1H, d, J = 10.0), 7.22 -7.36 (5H, m) ppm;
3n: 1H NMR (CDCl3, 400 MHz) δ 6.43 (1H, d, J=10.0), 6.56 (1H, s), 6.70 (1H, d, J=10.0 Hz), 7.31 (2H, dd, J=7.2, 1.6 Hz), 7.39-7.48 (3H, m) ppm; 3n: 1 H NMR (CDCl 3 , 400 MHz) δ 6.43 (1H, d, J = 10.0), 6.56 (1H, s), 6.70 (1H, d, J = 10.0 Hz), 7.31 (2H, dd, J = 7.2, 1.6 Hz), 7.39-7.48 (3H, m) ppm;
3o: 1H NMR (CDCl3, 400 MHz) δ 2.36 (3H, s), 6.48 (1H, d, J=10.0 Hz), 6.61 (1H, d, J=10.0 Hz), 6.79 (1H, s), 7.18-7.21 (2H, m), 7.28-7.42 (3H, m) ppm; 3o: 1 H NMR (CDCl 3 , 400 MHz) δ 2.36 (3H, s), 6.48 (1H, d, J = 10.0 Hz), 6.61 (1H, d, J = 10.0 Hz), 6.79 (1H, s) , 7.18-7.21 (2H, m), 7.28-7.42 (3H, m) ppm;
3p: 1H NMR (CDCl3, 400 MHz) δ6.51 (1H, d, J=10.0 Hz), 6.63 (1H, d, J=10.0 Hz), 7.19-7.21 (3H, m), 7.36-7.43 (3H, m) ppm; 3p: 1 H NMR (CDCl 3 , 400 MHz) δ6.51 (1H, d, J = 10.0 Hz), 6.63 (1H, d, J = 10.0 Hz), 7.19-7.21 (3H, m), 7.36-7.43 (3H, m) ppm;
3q: 1H NMR (CDCl3, 400 MHz) δ 3.64 (3H, s), 5.45 (1H, s), 6.31 (1H, d, J=10.0 Hz), 6.59 (1H, d, J=10.0 Hz), 7.28-7.41 (5H, m) ppm; 3q: 1 H NMR (CDCl 3 , 400 MHz) δ 3.64 (3H, s), 5.45 (1H, s), 6.31 (1H, d, J = 10.0 Hz), 6.59 (1H, d, J = 10.0 Hz) , 7.28-7.41 (5H, m) ppm;
実施例２３：フッ素置換されたスピロ［４，５］デカン化合物（3r）の合成
窒素雰囲気下、50 mLのナス型フラスコに2,2,2-トリフルオロエタノール(TFE) (6 mL)、基質1a (0.0902 g, 0.3 mmmol) を加え、懸濁させた。次いで室温下、ヨウ素反応剤1A(PhI(OH)OTs)(0.1288 g, 0.33 mmol) を加え、同温で2時間撹拌した。反応の終了はTLCにより確認した。反応終了後、溶媒を減圧留去した。得られた残渣 (ヨードニウム化合物2a) は単離精製することなく、全量次操作に付した。窒素雰囲気下、50 mLナス型フラスコにCsF (0.0685 g, 0.45 mmol) を加え、次いで室温下、2a のアセトニトリル (3 mL)溶液を加えた。浴温62-72℃で終夜 (13.5時間) 撹拌した後、反応液を室温まで冷却した。溶媒を減圧留去後、得られた残渣をシリカゲルカラムクロマトグラフィー (n-ヘキサン/AcOEt (9:1〜8:2))により精製することで 3r (0.0818 g, 89%) が淡黄色固体として得られた。基質の構造、生成物の構造、反応条件、収率等を表５に示す。
Example 23: Synthesis of fluorine-substituted spiro [4,5] decane compound (3r) 2,2,2-trifluoroethanol (TFE) (6 mL) and substrate in a 50 mL eggplant-shaped flask under nitrogen atmosphere 1a (0.0902 g, 0.3 mmmol) was added and suspended. Next, iodine reactant 1A (PhI (OH) OTs) (0.1288 g, 0.33 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The completion of the reaction was confirmed by TLC. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue (iodonium compound 2a) was subjected to the next operation without isolation and purification. CsF (0.0685 g, 0.45 mmol) was added to a 50 mL eggplant-shaped flask under a nitrogen atmosphere, and then a solution of 2a in acetonitrile (3 mL) was added at room temperature. After stirring at a bath temperature of 62-72 ° C. overnight (13.5 hours), the reaction solution was cooled to room temperature. After distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane / AcOEt (9: 1-8: 2)) to give 3r (0.0818 g, 89%) as a pale yellow solid. Obtained. Table 5 shows the substrate structure, product structure, reaction conditions, yield, and the like.
3r : 1H NMR (CDCl3, 300 MHz) δ 6.69 (1H, d, J=10.1 Hz), 6.76 (1H, d, J=10.1 Hz), 7.25-7.40 (6H, m), 7.59 (1H, td, J=7.3, 1.8 Hz), 7.64 (1H, td, J=7.3, 1.8 Hz), 8.22-8.32 (1H, m); HRFABMS calcd for C19H12FO3[M+H]+ 307.0770, found 307.0766. 3r : 1 H NMR (CDCl 3 , 300 MHz) δ 6.69 (1H, d, J = 10.1 Hz), 6.76 (1H, d, J = 10.1 Hz), 7.25-7.40 (6H, m), 7.59 (1H, td , J = 7.3, 1.8 Hz), 7.64 (1H, td, J = 7.3, 1.8 Hz), 8.22-8.32 (1H, m); HRFABMS calcd for C 19 H 12 FO 3 [M + H] + 307.0770, found 307.0766.
実施例２４〜２７
表５に示す基質を用い、表５に記載の反応条件で実施例６と同様に反応させることにより、表５に示す生成物が得られた。
Examples 24-27
By using the substrate shown in Table 5 and reacting under the reaction conditions shown in Table 5 in the same manner as in Example 6, the products shown in Table 5 were obtained.
各生成物のスペクトルデータは以下のとおりである。
3s: 1H NMR (CDCl3, 300 MHz) δ 1.96-2.10 (1H, m), 2.21-2.35 (1H, m), 2.68-2.83 (1H, m), 2.86-3.05 (1H, m), 6.28 (1H, d, J=9.7 Hz), 6.63 (1H, d, J=9.7 Hz), 7.05-7.23 (5H, m), 7.30 (1H, d, J=7.5 Hz), 7.39 (1H, dd, J=7.5, 7.5 Hz), 7.61 (1H, dd, J=7.5, 7.5 Hz), 8.10 (1H, d, J=7.5 Hz) ppm;
13C NMR (CDCl3, 75.5 MHz) δ 28.56 and 28.84 (d, JC-F=21.7 Hz), 33.20 and 33.32 (d, JC-F=8.7 Hz), 59.42 and 59.51 (d, JC-F=6.8 Hz), 118.04 and 118.11 (d, JC-F=5.6 Hz), 124.18, 126.87 and 126.94 (d, JC-F=5.6 Hz), 126.97 and 126.99 (d, JC-F= 1.9 Hz), 127.51 and 127.59 (d, JC-F=6.2 Hz), 128.15 and 128.25 (d, JC-F=7.4 Hz), 128.68, 128.83, 130.57, 131.84 and 131.90 (d, JC-F=4.3 Hz), 134.72, 138.04, 139.26 and 139.29 (d, JC-F=1.9 Hz), 158.89 and 162.70 (d, JC-F=288.0 Hz), 200.57 and 200.59 (d, JC-F=1.9 Hz), ppm;
The spectral data of each product is as follows.
3s: 1 H NMR (CDCl 3 , 300 MHz) δ 1.96-2.10 (1H, m), 2.21-2.35 (1H, m), 2.68-2.83 (1H, m), 2.86-3.05 (1H, m), 6.28 (1H, d, J = 9.7 Hz), 6.63 (1H, d, J = 9.7 Hz), 7.05-7.23 (5H, m), 7.30 (1H, d, J = 7.5 Hz), 7.39 (1H, dd, J = 7.5, 7.5 Hz), 7.61 (1H, dd, J = 7.5, 7.5 Hz), 8.10 (1H, d, J = 7.5 Hz) ppm;
13 C NMR (CDCl 3 , 75.5 MHz) δ 28.56 and 28.84 (d, J CF = 21.7 Hz), 33.20 and 33.32 (d, J CF = 8.7 Hz), 59.42 and 59.51 (d, J CF = 6.8 Hz), 118.04 and 118.11 (d, J CF = 5.6 Hz), 124.18, 126.87 and 126.94 (d, J CF = 5.6 Hz), 126.97 and 126.99 (d, J CF = 1.9 Hz), 127.51 and 127.59 (d, J CF = 6.2 Hz), 128.15 and 128.25 (d, J CF = 7.4 Hz), 128.68, 128.83, 130.57, 131.84 and 131.90 (d, J CF = 4.3 Hz), 134.72, 138.04, 139.26 and 139.29 (d, J CF = 1.9 Hz), 158.89 and 162.70 (d, J CF = 288.0 Hz), 200.57 and 200.59 (d, J CF = 1.9 Hz), ppm;
3t: 1H NMR (CDCl3, 500 MHz) δ 6.54 (2H, d, J=10.4 Hz), 6.72 (2H, d, J=10.4 Hz), 7.38-7.50 (3H, m), 7.55-7.61 (2H, m) ppm;
13C NMR (CDCl3, 125 MHz) δ 76.83 and 76.89 (d, JC-F=8.2 Hz), 125.97 and 126.02 (d, JC-F=6.2 Hz), 127.76 and 127.81 (d, JC-F=6.2 Hz), 129.35, 131.62 and 131.63 (d, JC-F=2.1 Hz), 132.33, 136.20, 142.62 and 142.64 (d, JC-F=2.1 Hz), 143.52 and 145.77 (d, JC-F=281.7 Hz), 162.64 and 162.88 (d, JC-F=30.9 Hz), 183.55 ppm;
3t: 1 H NMR (CDCl 3 , 500 MHz) δ 6.54 (2H, d, J = 10.4 Hz), 6.72 (2H, d, J = 10.4 Hz), 7.38-7.50 (3H, m), 7.55-7.61 ( 2H, m) ppm;
13 C NMR (CDCl 3 , 125 MHz) δ 76.83 and 76.89 (d, J CF = 8.2 Hz), 125.97 and 126.02 (d, J CF = 6.2 Hz), 127.76 and 127.81 (d, J CF = 6.2 Hz), 129.35, 131.62 and 131.63 (d, J CF = 2.1 Hz), 132.33, 136.20, 142.62 and 142.64 (d, J CF = 2.1 Hz), 143.52 and 145.77 (d, J CF = 281.7 Hz), 162.64 and 162.88 (d , J CF = 30.9 Hz), 183.55 ppm;
3v: 1H NMR (CDCl3, 500 MHz) δ 1.80-1.88 (2H, m), 2.00-2.09 (2H, m), 2.51 (2H, dt, J=6.1, 2.4 Hz), 6.16 (2H, d, J=10.5 Hz), 6.95 (2H, d, J=10.4 Hz), 7.00-7.07 (2H, m), 7.16-7.25 (3H, m) ppm;
13C NMR (CDCl3, 125 MHz) δ 18.86 and 18.94 (d, JC-F=10.3 Hz), 25.72 and 25.92 (d, JC-F=24.7 Hz), 34.84 and 34.85 (d, JC-F=2.1 Hz), 45.14 and 45.18 (d, JC-F=5.1 Hz), 116.75 and 116.86 (d, JC-F=13.4 Hz), 127.58, 127.83, 128.74, 129.07, 133.85 and 133.86 (d, JC-F=13.4 Hz), 153.73 and 153.74 (d, JC-F=2.1 Hz), 156.84 and 158.91 (d, JC-F=259.1 Hz), 185.37 ppm;
3v: 1 H NMR (CDCl 3 , 500 MHz) δ 1.80-1.88 (2H, m), 2.00-2.09 (2H, m), 2.51 (2H, dt, J = 6.1, 2.4 Hz), 6.16 (2H, d , J = 10.5 Hz), 6.95 (2H, d, J = 10.4 Hz), 7.00-7.07 (2H, m), 7.16-7.25 (3H, m) ppm;
13 C NMR (CDCl 3 , 125 MHz) δ 18.86 and 18.94 (d, J CF = 10.3 Hz), 25.72 and 25.92 (d, J CF = 24.7 Hz), 34.84 and 34.85 (d, J CF = 2.1 Hz), 45.14 and 45.18 (d, J CF = 5.1 Hz), 116.75 and 116.86 (d, J CF = 13.4 Hz), 127.58, 127.83, 128.74, 129.07, 133.85 and 133.86 (d, J CF = 13.4 Hz), 153.73 and 153.74 (d, J CF = 2.1 Hz), 156.84 and 158.91 (d, J CF = 259.1 Hz), 185.37 ppm;
実施例２８
窒素雰囲気下、50 mLのナス型フラスコに1,1,1,3,3,3-ヘキサフルオロイソプロパノール(HFIP) (8 mL)、基質1a (245 mg, 0.81 mmmol) を加え、溶解させた。次いで室温下、ヨウ素反応剤1A (PhI(OH)OTs) (350 mg, 0.89 mmol) を加え、同温で1.5時間撹拌した。反応の終了はTLCにより確認した。反応終了後、溶媒を減圧留去した。得られた残渣にジエチルエーテルを適量加え結晶を析出させ、室温で終夜撹拌した。デカンテーションで溶媒（上澄液）を取り除き、減圧乾燥する事で、ヨードニウム化合物 2a (398.7 mg, 74%) が無色固体として得られた。窒素雰囲気下、10 mLナス型フラスコに、2a (77.3 mg, 0.12 mmol)、アセトニトリル (1.2 mL) を加え溶解し、次いで室温下NaNO2 (9.4 mg, 0.14 mmol) を加えた後、浴温70℃で終夜撹拌した。反応液を室温まで冷却後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (n-ヘキサン/AcOEt (4:1))により精製することで 3y (27.6 mg, 71%) が黄色固体として得られた。
Example 28
Under a nitrogen atmosphere, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) (8 mL) and substrate 1a (245 mg, 0.81 mmmol) were added and dissolved in a 50 mL eggplant-shaped flask. Next, iodine reactant 1A (PhI (OH) OTs) (350 mg, 0.89 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. The completion of the reaction was confirmed by TLC. After completion of the reaction, the solvent was distilled off under reduced pressure. An appropriate amount of diethyl ether was added to the resulting residue to precipitate crystals, which were stirred overnight at room temperature. The solvent (supernatant) was removed by decantation and dried under reduced pressure to obtain iodonium compound 2a (398.7 mg, 74%) as a colorless solid. Under a nitrogen atmosphere, 2a (77.3 mg, 0.12 mmol) and acetonitrile (1.2 mL) were added and dissolved in a 10 mL eggplant-shaped flask, and then NaNO 2 (9.4 mg, 0.14 mmol) was added at room temperature. Stir overnight at ° C. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / AcOEt (4: 1)) to give 3y (27.6 mg, 71%) as a yellow solid.
3y : 1H NMR (CDCl3, 300 MHz) δ 6.64 (1H, d, J=10.3 Hz), 6.81 (1H, d, J=10.3 Hz), 6.80-6.90 (2H, m), 7.16-7.31 (2H, m), 7.35-7.51 (2H, m), 7.66 (1H, td, J=7.5, 1.5 Hz), 7.76 (1H, td, J=7.5, 1.5 Hz), 8.19 (1H, dd, J=7.5, 1.5 Hz); HRFABMS calcd for C19H12NO5[M+H]+ 334.0716, found 334.0728. 3y : 1 H NMR (CDCl 3 , 300 MHz) δ 6.64 (1H, d, J = 10.3 Hz), 6.81 (1H, d, J = 10.3 Hz), 6.80-6.90 (2H, m), 7.16-7.31 (2H , m), 7.35-7.51 (2H, m), 7.66 (1H, td, J = 7.5, 1.5 Hz), 7.76 (1H, td, J = 7.5, 1.5 Hz), 8.19 (1H, dd, J = 7.5 , 1.5 Hz); HRFABMS calcd for C 19 H 12 NO 5 [M + H] + 334.0716, found 334.0728.
実施例２９〜３４
表６に示す基質を用い、表６に記載の反応条件で実施例６と同様に反応させることにより、表６に示す生成物が得られた。
Examples 29-34
By using the substrate shown in Table 6 and reacting under the reaction conditions shown in Table 6 in the same manner as in Example 6, the products shown in Table 6 were obtained.
各生成物のスペクトルデータは以下のとおりである。
3w : 1H NMR (CDCl3, 300 MHz) δ 6.60 (1H, d, J=10.3 Hz), 6.71 (1H, d, J=10.3 Hz), 6.80-6.90 (2H, m), 7.21-7.44 (6H, m), 7.56-7.64 (2H, m), 8.24 (1H, dd, J=7.5, 1.5 Hz) ppm;
The spectral data of each product is as follows.
3w : 1 H NMR (CDCl 3 , 300 MHz) δ 6.60 (1H, d, J = 10.3 Hz), 6.71 (1H, d, J = 10.3 Hz), 6.80-6.90 (2H, m), 7.21-7.44 (6H , m), 7.56-7.64 (2H, m), 8.24 (1H, dd, J = 7.5, 1.5 Hz) ppm;
3x : 1H NMR (CDCl3, 300 MHz) δ 6.60 (1H, d, J=10.3 Hz), 6.71 (1H, d, J=10.3 Hz), 6.80-6.90 (2H, m), 7.23-7.31 (2H, m), 7.35-7.44 (4H, m), 7.65 (1H, td, J=7.5, 1.5 Hz), 7.74 (1H, td, J=7.5, 1.5 Hz), 8.17 (1H, dd, J=7.5, 1.5 Hz) ppm; 3x : 1 H NMR (CDCl 3 , 300 MHz) δ 6.60 (1H, d, J = 10.3 Hz), 6.71 (1H, d, J = 10.3 Hz), 6.80-6.90 (2H, m), 7.23-7.31 (2H , m), 7.35-7.44 (4H, m), 7.65 (1H, td, J = 7.5, 1.5 Hz), 7.74 (1H, td, J = 7.5, 1.5 Hz), 8.17 (1H, dd, J = 7.5 , 1.5 Hz) ppm;
3z: 1H NMR (CDCl3, 300 MHz) δ 6.52 (1H, d, J=10.0 Hz), 6.73 (1H, d, J=10.0 Hz), 6.84-6.87 (2H, m), 7.23-7.39 (4H, m), 7.68 (1H, td, J=7.5, 1.5 Hz), 7.72 (1H, td, J=7.5, 1.5 Hz), 8.13 (1H, dd, J=7.5, 1.5 Hz) ppm; 3z: 1 H NMR (CDCl 3 , 300 MHz) δ 6.52 (1H, d, J = 10.0 Hz), 6.73 (1H, d, J = 10.0 Hz), 6.84-6.87 (2H, m), 7.23-7.39 ( 4H, m), 7.68 (1H, td, J = 7.5, 1.5 Hz), 7.72 (1H, td, J = 7.5, 1.5 Hz), 8.13 (1H, dd, J = 7.5, 1.5 Hz) ppm;
3aa:1H NMR (CDCl3, 400 MHz) δ6.13 (2H, d, J=10.0 Hz), 6.66 (2H, d, J=10.0 Hz), 7.31-7.35 (3H, m), 7.59-7.61 (2H, m) ppm; 3aa: 1 H NMR (CDCl 3 , 400 MHz) δ6.13 (2H, d, J = 10.0 Hz), 6.66 (2H, d, J = 10.0 Hz), 7.31-7.35 (3H, m), 7.59-7.61 (2H, m) ppm;
3ab: 1H NMR (CDCl3, 400 MHz) δ 2.24 (3H, s), 6.35 (2H, d, J=10.0 Hz), 6.67 (2H, d, J=10.0 Hz), 6.76 (1H, s), 7.18-7.21 (2H, m), 7.30-7.34 (5H, m) ppm; 3ab: 1 H NMR (CDCl 3 , 400 MHz) δ 2.24 (3H, s), 6.35 (2H, d, J = 10.0 Hz), 6.67 (2H, d, J = 10.0 Hz), 6.76 (1H, s) , 7.18-7.21 (2H, m), 7.30-7.34 (5H, m) ppm;
3ac: 1H NMR (CDCl3, 400 MHz) δ6.27 (1H, s), 6.40 (2H, d, J=10.0 Hz), 6.64 (2H, d, J=10.0 Hz), 6.76 (1H, s), 7.18-7.21 (2H, m), 7.30-7.34 (5H, m) ppm;
;
3ac: 1 H NMR (CDCl 3 , 400 MHz) δ6.27 (1H, s), 6.40 (2H, d, J = 10.0 Hz), 6.64 (2H, d, J = 10.0 Hz), 6.76 (1H, s ), 7.18-7.21 (2H, m), 7.30-7.34 (5H, m) ppm;
;
実施例３５：エナンチオ選択的な臭素置換されたスピロ［４，５］デカン化合物（3d’）の合成
窒素雰囲気下、50 mLのナス型フラスコに2,2,2-トリフルオロエタノール(TFE) (3 mL)、基質1d (0.030 g, 0.1 mmmol) を加え、懸濁させた。次いで室温下、下記のキラルなヨウ素反応剤（(R)-4A）(0.045 g, 0.055 mmol) を加え、同温で3時間撹拌した。反応の終了はTLCにより確認した。反応終了後、溶媒を減圧留去した。得られた残渣 (ヨードニウム化合物) は単離精製することなく、全量次操作に付した。窒素雰囲気下、ヨードニウム化合物にアセトニトリル (3 mL) を加え溶解し、次いで室温下nBuN4Br (0.035 g, 0.18 mmol) を加えた後、浴温62-72℃で終夜 (18時間) 撹拌した。反応液を室温まで冷却後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (n-ヘキサン/AcOEt (9:1〜8:2))により精製することで 3d’（(R)-3d）(0.33 g, 92 %, 28 %ee) が無色固体として得られた。
Example 35: Synthesis of enantioselective bromine-substituted spiro [4,5] decane compound (3d ') In a 50 mL eggplant-shaped flask under a nitrogen atmosphere, 2,2,2-trifluoroethanol (TFE) ( 3 mL) and substrate 1d (0.030 g, 0.1 mmmol) were added and suspended. Next, the following chiral iodine reactant ((R) -4A) (0.045 g, 0.055 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The completion of the reaction was confirmed by TLC. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue (iodonium compound) was subjected to the next operation without isolation and purification. Under a nitrogen atmosphere, acetonitrile (3 mL) was added to the iodonium compound and dissolved, and then n BuN 4 Br (0.035 g, 0.18 mmol) was added at room temperature, followed by stirring at a bath temperature of 62-72 ° C. overnight (18 hours). . After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / AcOEt (9: 1-8: 2)) to give 3d '((R) -3d) (0.33 g, 92%, 28% ee) Was obtained as a colorless solid.
3d’: 1H NMR (CDCl3, 300 MHz) δ 6.50 (1H, d, J=10.2 Hz), 6.71 (1H, d, J=10.2 Hz), 6.85 (2H, d, J=7.5 Hz), 7.15-7.35 (4H, m), 7.47 (1H, d, J=7.5 Hz), 7.53 (1H, t, J=7.5 Hz), 7.60-7.70 (1H, m), 8.11 (1H, d, J=7.5 Hz) ppm;
13C NMR (CDCl3, 75.5 MHz) δ 65.52, 117.92, 126.27, 127.33, 127.58, 128.53, 129.58, 129.87, 130.09, 131.46, 131.68, 133.76, 137.52, 144.64, 157.32, 168.45, 182.97 ppm;
3d ': 1 H NMR (CDCl 3 , 300 MHz) δ 6.50 (1H, d, J = 10.2 Hz), 6.71 (1H, d, J = 10.2 Hz), 6.85 (2H, d, J = 7.5 Hz), 7.15-7.35 (4H, m), 7.47 (1H, d, J = 7.5 Hz), 7.53 (1H, t, J = 7.5 Hz), 7.60-7.70 (1H, m), 8.11 (1H, d, J = 7.5 Hz) ppm;
13 C NMR (CDCl 3 , 75.5 MHz) δ 65.52, 117.92, 126.27, 127.33, 127.58, 128.53, 129.58, 129.87, 130.09, 131.46, 131.68, 133.76, 137.52, 144.64, 157.32, 168.45, 182.97 ppm;
Claims (7)
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
Ｒ２は、
Ｒ３は、アセチル、トリフルオロアセチル、プロパノイル、ベンゾイル、ベンゼンスルホニル、パラトルエンスルホニル、ナフタレンスルホニル、メタンスルホニル、エチルスルホニル、プロピルスルホニル、及びトリフルオロメタンスルホニルからなる群から選択される電子吸引基を示し、
ｍは０又は１である。］、又は式（２−２）：
Ｘ、Ｙ、Ｒ１、Ｒ２、Ｒ３、ｍ及び
で表されるヨードニウム化合物。 Formula (2-1):
R 1 represents an alkyl group, an aryl group, or a halogen atom.
R 2 is
R 3 represents an electron withdrawing group selected from the group consisting of acetyl, trifluoroacetyl, propanoyl, benzoyl, benzenesulfonyl, paratoluenesulfonyl, naphthalenesulfonyl, methanesulfonyl, ethylsulfonyl, propylsulfonyl, and trifluoromethanesulfonyl ;
m is 0 or 1. Or formula (2-2):
X, Y, R 1 , R 2 , R 3 , m and
The iodonium compound represented by these.
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
ｍは０又は１である。］
で表される基質を、超原子価ヨウ素反応剤を用いてスピロ環化させる、
請求項１に記載のヨードニウム化合物の製造方法。 Formula (1):
R 1 represents an alkyl group, an aryl group, or a halogen atom.
m is 0 or 1. ]
A substrate represented by a spirocyclization using a hypervalent iodine reactant,
The manufacturing method of the iodonium compound of Claim 1.
各Ｒ４及びＲ４’は、互いに独立して、水素原子、アルキル基、アルコキシ基、又はトリフルオロメチル基、アリール基又はハロゲン原子を示す。Ｒ ４ 及びＲ ４’ の数は、下限が１であり、上限はそれぞれの環において置換可能な数である。）
からなる群から選択される少なくとも１種である、請求項２に記載のヨードニウム化合物の製造方法。 The hypervalent iodine reactant is
Each R 4 and R 4 ′ independently represents a hydrogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, an aryl group or a halogen atom. The lower limit of the number of R 4 and R 4 ′ is 1, and the upper limit is a number that can be substituted in each ring. )
The manufacturing method of the iodonium compound of Claim 2 which is at least 1 sort (s) selected from the group which consists of.
Ｒ １ はアルキル基、アリール基、又はハロゲン原子を示す。
ｍは０又は１である。］
で表される基質を、超原子価ヨウ素反応剤を用いてスピロ環化させることにより、式（２−１）：
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
Ｒ２は、
Ｒ３は、アセチル、トリフルオロアセチル、プロパノイル、ベンゾイル、ベンゼンスルホニル、パラトルエンスルホニル、ナフタレンスルホニル、メタンスルホニル、エチルスルホニル、プロピルスルホニル、及びトリフルオロメタンスルホニルからなる群から選択される電子吸引基を示し、
ｍは０又は１である。］、又は式（２−２）：
Ｘ、Ｙ、Ｒ１、Ｒ２、Ｒ３、ｍ及び
で表されるヨードニウム化合物を製造し、
得られたヨードニウム化合物を求核剤で求核置換させる、官能基化スピロ環状化合物の製造方法。 Formula (1):
R 1 represents an alkyl group, an aryl group, or a halogen atom.
m is 0 or 1. ]
In the substrate represented, by spiro cyclized with hypervalent iodine reagent, formula (2-1):
R 1 represents an alkyl group, an aryl group, or a halogen atom.
R 2 is
R 3 represents an electron withdrawing group selected from the group consisting of acetyl, trifluoroacetyl, propanoyl, benzoyl, benzenesulfonyl, paratoluenesulfonyl, naphthalenesulfonyl, methanesulfonyl, ethylsulfonyl, propylsulfonyl, and trifluoromethanesulfonyl ;
m is 0 or 1. Or formula (2-2):
X, Y, R 1 , R 2 , R 3 , m and
And an iodonium compound represented by
A method for producing a functionalized spirocyclic compound, wherein the obtained iodonium compound is nucleophilically substituted with a nucleophile.
Ｒ１はアルキル基、アリール基、又はハロゲン原子を示す。
Ｒ６は、フッ素原子、Ｎ３、ＮＯ２、ＣＮ、ＮＨ（Ｃ２Ｈ５）２又はＯＣＯＣＨ３を示す。
ｍは０又は１である。］
で表される官能基化スピロ環状化合物。 Formula (3):
R 1 represents an alkyl group, an aryl group, or a halogen atom.
R 6 represents a fluorine atom, N 3 , NO 2 , CN, NH (C 2 H 5 ) 2 or OCOCH 3 .
m is 0 or 1. ]
A functionalized spirocyclic compound represented by:
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