CN103936661B - A kind of synthetic method of 6-alkyl phenanthrene piperidine derivatives - Google Patents
A kind of synthetic method of 6-alkyl phenanthrene piperidine derivatives Download PDFInfo
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- CN103936661B CN103936661B CN201410136417.0A CN201410136417A CN103936661B CN 103936661 B CN103936661 B CN 103936661B CN 201410136417 A CN201410136417 A CN 201410136417A CN 103936661 B CN103936661 B CN 103936661B
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- isonitrile
- phenanthridines
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- 238000010189 synthetic method Methods 0.000 title abstract description 3
- 150000003254 radicals Chemical class 0.000 claims abstract description 40
- 239000003999 initiator Substances 0.000 claims abstract description 28
- -1 alkyl phenanthrene piperidine derivatives Chemical class 0.000 claims abstract description 15
- 150000002527 isonitriles Chemical class 0.000 claims abstract description 15
- 230000004044 response Effects 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 150000001924 cycloalkanes Chemical class 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 63
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 22
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 16
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical group CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 6
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 6
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 6
- 230000008859 change Effects 0.000 claims description 4
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 claims description 3
- 239000004914 cyclooctane Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 150000002978 peroxides Chemical class 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- GJBRNHKUVLOCEB-UHFFFAOYSA-N tert-butyl benzenecarboperoxoate Chemical compound CC(C)(C)OOC(=O)C1=CC=CC=C1 GJBRNHKUVLOCEB-UHFFFAOYSA-N 0.000 claims description 2
- 150000005053 phenanthridines Chemical class 0.000 abstract description 14
- 238000007306 functionalization reaction Methods 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 8
- 230000004913 activation Effects 0.000 abstract description 4
- 230000002152 alkylating effect Effects 0.000 abstract description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 238000010438 heat treatment Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000012847 fine chemical Substances 0.000 abstract description 2
- 238000007154 radical cyclization reaction Methods 0.000 abstract description 2
- 239000004215 Carbon black (E152) Substances 0.000 abstract 1
- 229930195733 hydrocarbon Natural products 0.000 abstract 1
- 150000002430 hydrocarbons Chemical class 0.000 abstract 1
- 239000007800 oxidant agent Substances 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- RLOSRCUFYXDHPG-UHFFFAOYSA-N N#[C-].C1=CC=CC=C1C1=CC=CC=C1 Chemical compound N#[C-].C1=CC=CC=C1C1=CC=CC=C1 RLOSRCUFYXDHPG-UHFFFAOYSA-N 0.000 description 16
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 12
- 238000002156 mixing Methods 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- VOCGYYOMSGYEJV-UHFFFAOYSA-N benzene cyanide Chemical compound N#[C-].C1=CC=CC=C1 VOCGYYOMSGYEJV-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000004342 Benzoyl peroxide Substances 0.000 description 4
- 235000019400 benzoyl peroxide Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- LCZBBMRTPXAZGV-UHFFFAOYSA-N 1-phenyl-3-(trifluoromethyl)benzene cyanide Chemical compound N#[C-].FC(C1=CC(=CC=C1)C1=CC=CC=C1)(F)F LCZBBMRTPXAZGV-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- QKKDBICIBCQCCK-UHFFFAOYSA-N N#[C-].CC1=CC=C(C=C1)C1=CC=CC=C1 Chemical compound N#[C-].CC1=CC=C(C=C1)C1=CC=CC=C1 QKKDBICIBCQCCK-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000006713 insertion reaction Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- PTXVSDKCUJCCLC-UHFFFAOYSA-N 1-hydroxyindole Chemical compound C1=CC=C2N(O)C=CC2=C1 PTXVSDKCUJCCLC-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- KFCHKLJUUFXQEX-UHFFFAOYSA-N 6-cyclohexyl-2-methylphenanthridine Chemical class Cc1ccc2nc(C3CCCCC3)c3ccccc3c2c1 KFCHKLJUUFXQEX-UHFFFAOYSA-N 0.000 description 1
- OHDASYPBXZSSFL-UHFFFAOYSA-N 6-cyclohexyl-3-methylphenanthridine Chemical class Cc1ccc2c(c1)nc(C1CCCCC1)c1ccccc21 OHDASYPBXZSSFL-UHFFFAOYSA-N 0.000 description 1
- DTEUMPATVWZMJK-UHFFFAOYSA-N 6-cyclohexyl-8-methylphenanthridine Chemical class Cc1ccc2c(c1)c(nc1ccccc21)C1CCCCC1 DTEUMPATVWZMJK-UHFFFAOYSA-N 0.000 description 1
- PJTKNHWBQYXKIZ-UHFFFAOYSA-N 6-cyclohexylphenanthridine Chemical class C1CCCCC1C1=NC2=CC=CC=C2C2=CC=CC=C12 PJTKNHWBQYXKIZ-UHFFFAOYSA-N 0.000 description 1
- VFKBINCDRBUCGZ-UHFFFAOYSA-N 8-chloro-6-cyclohexylphenanthridine Chemical class Clc1ccc2c(c1)c(nc1ccccc21)C1CCCCC1 VFKBINCDRBUCGZ-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- MZSUUNQFNXMBMA-UHFFFAOYSA-N FC(C1=CC2=C(C=CC=C3)C3=C(C3CCCCC3)N=C2C=C1)(F)F Chemical class FC(C1=CC2=C(C=CC=C3)C3=C(C3CCCCC3)N=C2C=C1)(F)F MZSUUNQFNXMBMA-UHFFFAOYSA-N 0.000 description 1
- RASZIKVMJVJREZ-UHFFFAOYSA-N N#[C-].C(C)(=O)C1=C(C=CC=C1)C1=CC=CC=C1 Chemical compound N#[C-].C(C)(=O)C1=C(C=CC=C1)C1=CC=CC=C1 RASZIKVMJVJREZ-UHFFFAOYSA-N 0.000 description 1
- XTSCDOGYSAHUBQ-UHFFFAOYSA-N N#[C-].CC1=CC(=CC=C1)C1=CC=CC=C1 Chemical compound N#[C-].CC1=CC(=CC=C1)C1=CC=CC=C1 XTSCDOGYSAHUBQ-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- HCAUQPZEWLULFJ-UHFFFAOYSA-N benzo[f]quinoline Chemical group C1=CC=C2C3=CC=CC=C3C=CC2=N1 HCAUQPZEWLULFJ-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003345 natural gas Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical group C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The synthetic method of a kind of 6 alkyl phenanthrene piperidine derivatives of the present invention, relates to organic chemical industry and field of fine chemical.Raw materials used is 2 aryl virtue isonitrile and cycloalkane (or chain hydrocarbon), under the catalysis of oxidant, radical initiator aoxidizes, under room temperature or heating condition, occurs free radical cyclization to obtain 6 alkyl phenanthrene piperidine derivatives.Using the method that the present invention proposes under condition of heating and stirring, the response time is 2 24 hours.The present invention develops the sp based on free radical proceed that a class is novel3The method of C H bond activation functionalization, defines new aryl sp2‑sp3Carbon-carbon bond.There occurs cyclization and the generation of two new carbon-carbon bonds by the mode treated different things alike simultaneously, obtain a series of 6 alkyl phenanthrene piperidine derivatives, simple to operate, convenient post-treatment.It is a kind of the most simple and practical to realize 6 alkylating methods of phenanthridines.
Description
Technical field
The present invention relates to organic chemical industry and field of fine chemical, be related specifically to a kind of without metal catalytic free radical initiation ring
Change, C (sp2)-C(sp2) key and C (sp2)-C(sp3) key reaction of formation, it is successfully realized the alkylation of phenanthridines 6.
Background technology
Phenanthridines is the organic compound of aza phenanthrene structure, belongs to azepine aromatic.Phenanthridines skeleton is wide
General it is present in natural product molecule and drug molecule.Such as, many drug molecules containing phenanthridines skeleton have extraordinary
Biological activity and pharmacologically active, this type of medicine is widely used in the fields such as antibacterial, antitumor.Find that phenanthridines class medicine is pressing down in the recent period
The aspects such as cytotoxicity processed also have potential using value.
The essence of organic reaction is the process that the new key-like of old bond fission becomes, due to sp3The bond energy of c h bond is higher, and polarity
The least, therefore in very long organic synthesis evolution, it is possible to realize selective to sp3C h bond direct activation functionalization,
The target that always synthetic organic chemist pursues.Recent study mainly concentrates on the sp that auxiliary group is assisted3C h bond is lived
Change fracture, such as the c h bond that phenyl is assisted activates, the sp at N, O ortho position3C h bond activation etc..[(a)C.-J.Li,W.-
J.Yoo,Top.Curr.Chem.,2010,292,281-302;(b)S.R.Neufeldt and M.S.Sanford,
Acc.Chem.Res.,2012,45,936-946;(c)J.J.Mousseau and A.B.Charette,Acc.Chem.Res.,
2013,46,412-424;(d)H.Lu and X.P.Zhang,Chem.Soc.Rev.,2011,40,1899-1909;(e)
H.Li, B.-J.Li and Z.-J.Shi, Catal.Sci.Tech., 2011,1,191-206] but, it is understood that oil,
In the Organic substance that the nature such as natural gas exists, great majority are all simple alkane, therefore, to the functionalization of common alkane more
There is Practical significance.
The development that synthesis great master Hartwig is initiative one example copper catalysis, by inactive alkane and simple amide,
Sulfonamide, imines etc. react, and are successfully realized the functionalization of alkane.[B.Tran,B.Li,M.Driess and
J.F.Hartwig, J.Am.Chem.Soc., 2014,136,2555-2563.] before this, Hashimi group has developed an example
Intermolecular C (the sp of gold catalysis3)-H insertion reaction and cyclopropanization reaction.[A.S.Hashimi,M.Wieteck,I.Braun,
M.Rudolph and F.Rominger, Angew.Chem.Int.Ed., 2012,51,10633-10637] Antonchick is little
Group have also been developed the oxidative coupling reaction of alkane and heteroaryl aroma compounds.[A.P.Antonchick and L.Burgmann,
Angew.Chem.Int.Ed., 2013,52,3267-3271.] work of Fokin achieves the azo Cabbeen enantiomer to alkane
Selectivity c h bond insertion reaction.[S.Chuprakov,J.A.Malik,M.Zibinsky and V.V.Fokin,
J.Am.Chem.Soc.,2011,133,10352–10355]
It should be noted that the c h bond of inactive alkane is more likely under given conditions, experience radical mechanism and
Realize functionalization.[C.L.Hill, Synlett, 1995,127-132] therefore, based on inertia c h bond fracture radical mechanism
Cascade reaction, may be the effective way realizing c h bond functionalization.[A.J.McCarroll and
J.C.Walton, Angew.Chem.Int.Ed.2001,40,2224-2248.] in the recent period, Liu group has developed an example and experienced by certainly
Cascade reaction by base course, it is achieved that to alkene and the direct alkylation of aromatic hydrocarbon, obtains series oxyindole product.
[Z.Li, Y.Zhang, L.Zhang and Z.-Q.Liu, Org.Lett., 2014,16,382-385] but, utilize easy
Method, efficiently realizes the selective functionalization of simple alkane, remains the target that organic synthesis worker seek assiduously.
Isonitrile compounds, studied in recent years and also compared many, and particularly generating in nitrogenous hydridization compounds, having
The critical role do not replaced.The reaction of this compounds tends to experience radical mechanism, and the serial reaction cascaded occurs,
Synthesis of cyclic organic compound.Our research is exactly with 2-aryl virtue isonitrile as substrate, experiences free radical proceed, treats different things alike,
There is free radical cyclisation, C (sp2)-C(sp2) key and C (sp2)-C(sp3) key reaction of formation, obtain a series of 6-alkyl phenanthridines
Derivant.
The present invention uses 2-aryl virtue isonitrile and common alkane reaction, under conditions of adding radical initiator, and preparation
6-alkyl phenanthrene piperidine derivatives.This experimentation is not related to use transition-metal catalyst, the most green, economical；With treating different things alike
Method, be simultaneously achieved free radical cyclization and the formation of two class carbon-carbon bonds, reaction efficiency is high；Reaction condition is gentle, instead
Between Ying Shi short, radical initiator low price, separating-purifying is convenient, and waste discharge is few, wants the substrate of reaction without special
Ask, the plurality of advantages such as applied widely, there is the highest using value.
Summary of the invention
Technical problem solved by the invention is to provide a kind of simple without metal catalytic, the cascade of experience radical mechanism
Cyclisation, C (sp2)-C(sp2) key and C (sp2)-C(sp3) key row becomes response strategy, and obtain 6 alkylating products of phenanthridines.Should
Method is easy and simple to handle, is 6 alkylation process of phenanthridines of a kind of efficient radical mechanism.
The present invention is the preparation method about a kind of 6-alkyl phenanthridines, with 2-aryl virtue isonitrile and cycloalkane or chain alkane
For raw material, add radical initiator, with alkane as solvent or add a small amount of organic solvent, stirring reaction, 6-is synthesized
Alkyl phenanthridines compounds, reaction condition is: air or in inert gas shielding, under conditions of room temperature-120 DEG C heating,
Response time is 2-24 hour.
Described radical initiator is common tert-butyl hydroperoxide, di-t-butyl peroxide, perbenzoic acid
The tert-butyl ester, benzoyl peroxide, azodiisobutyronitrile etc..
The consumption of described radical initiator is 1～10 times of 2-aryl virtue isonitrile molal quantity.
Described feed molar proportioning is 2-aryl virtue isonitrile: alkane 1:2～100.
Described solvent is benzene, toluene, fluorobenzene, chlorobenzene etc..Solvent load is 5mL/mmol2-aryl virtue isonitrile.
Described raw material 2-aryl virtue isonitrile structural formula isTwo aromatic rings on substituent group can
With R=H, 4-COCH3, 4-COOMe, 4-Me, naphthalene；R’=H,4-CF3, 5-F, 5-Me, 5-OMe etc., can be produced accordingly
Thing.
Described starting alkane can be hexamethylene, Pentamethylene., cycloheptane, cyclooctane, normal hexane, diamantane (obsolete) etc..
6-alkyl phenanthrene piperidine derivatives can generate under the above-described reaction conditions smoothly.
Described post-reaction treatment is easy, it is only necessary to simple pillar layer separation method, with petroleum ether and ethyl acetate
Mixed solvent is that eluant can be obtained by pure 6 alkylating phenanthridines compounds.
Detailed description of the invention
Course of reaction of the present invention and obtain the structure of product and be:
Embodiment 1
By 2-phenyl benzene isonitrile 1a(2mmol), hexamethylene 2a(4mmol) and radical initiator tert-butyl hydroperoxide
(2mmol) mixing, adding benzene 10mL is solvent, room temperature reaction under air, reaction experience 2 hours.The conversion of 2-phenyl benzene isonitrile
Rate is 100%, and the productivity of 6-cyclohexyl phenanthridines 3aa is 80%.
Embodiment 2
By 4-methyl-2-phenyl benzene isonitrile 1b(2mmol), hexamethylene 2a(4mmol) with radical initiator benzoyl peroxide
Formyl (2mmol) mixes, and adding toluene 10mL is solvent, under nitrogen protection, and room temperature reaction, response time experience 2 hours.4-first
The conversion ratio of base-2-phenyl benzene isonitrile is 100%, and the productivity of 2-methyl-6-cyclohexyl phenanthridines 3ba is 91%.
Embodiment 3
By 2-to fluorophenyl benzene isonitrile 1c(2mmol), hexamethylene 2a(4mmol) with radical initiator tert-butyl hydroperoxide
Hydrogen (20mmol) mixes, and adding fluorobenzene 10mL is solvent, room temperature reaction under air, and the response time experiences 24 hours.2-is to fluorobenzene
The conversion ratio of base benzene isonitrile is 100%, and the productivity of 8-fluorine 6-cyclohexyl phenanthridines 3ca is 73%.
Embodiment 4
By 2-rubigan benzene isonitrile 1d(2mmol), hexamethylene 2a(4mmol) with radical initiator benzoyl peroxide
(2mmol) mixing, adding chlorobenzene 10mL is solvent, room temperature reaction under air, and the response time experiences 2 hours.2-rubigan benzene
The conversion ratio of isonitrile is 100%, and the productivity of 8-chloro-6-cyclohexyl phenanthridines 3da is 78%.
Embodiment 5
By 2-to acetyl phenyl benzene isonitrile 1e(2mmol), hexamethylene 2a(4mmol) with radical initiator t-butyl peroxy
Changing hydrogen (2mmol) mixing, adding benzene 10mL is solvent, room temperature reaction under air, and the response time experiences 2 hours.2-is to acetophenone
The conversion ratio of base benzene isonitrile is 100%, and the productivity of 8-acetyl group 6-cyclohexyl phenanthridines 3ea is 87%.
Embodiment 6
By 2-naphthalene benzene isonitrile 1f(2mmol), hexamethylene 2a(200mmol) with radical initiator tert-butyl hydroperoxide
(2mmol) mixing, is heated to 120 DEG C of nitrogen protection reactions, experiences 2 hours.The conversion ratio of 2-naphthalene benzene isonitrile is 100%, 6-ring
The productivity of hexyl benzo phenanthridines 3fa is 78%.
Embodiment 7
By 2-(to methoxycarbonyl group phenyl) benzene isonitrile 1g(2mmol), hexamethylene 2a(4mmol) with the tertiary fourth of radical initiator
Base hydrogen peroxide (2mmol) mixes, and adding benzene 10mL is solvent, is heated to 120 DEG C, reacts, last 2 hours under air.2-(pair
Methoxycarbonyl group phenyl) conversion ratio of benzene isonitrile is 100%, the productivity of 8-methoxycarbonyl group-6-cyclohexyl phenanthridines 3ga is 81%.
Embodiment 8
By 2-p-methylphenyl benzene isonitrile 1h(2mmol), hexamethylene 2a(4mmol) with the tertiary fourth of radical initiator peroxidating two
Base (2mmol) mixes, and adding chlorobenzene 10mL is solvent, room temperature reaction under air, and the response time experiences 2 hours.2-p-methylphenyl
The conversion ratio of benzene isonitrile is 100%, and the productivity of 8-methyl-6-cyclohexyl phenanthridines 3ha is 86%.
Embodiment 9
By 4-trifluoromethyl-2-phenyl benzene isonitrile 1i(2mmol), hexamethylene 2a(4mmol) with radical initiator peroxide
Changing benzoyl (2mmol) mixing, adding fluorobenzene 10mL is solvent, under nitrogen protection, and room temperature reaction, response time experience 2 hours.
The conversion ratio of 4-trifluoromethyl-2-phenyl benzene isonitrile is 100%, and the productivity of 2-trifluoromethyl-6-cyclohexyl phenanthridines 3ia is 86%
Embodiment 10
By fluoro-for 5-2-phenyl benzene isonitrile 1j(2mmol), hexamethylene 2a(4mmol) with radical initiator benzoyl peroxide first
Tert-butyl acrylate (2mmol) mixes, and adding fluorobenzene 10mL is solvent, in air, is heated to 120 DEG C of reactions, and it is little that the response time experiences 2
Time.The conversion ratio of 5-fluoro-2-phenyl benzene isonitrile is 100%, and the productivity of 3-fluoro-6-cyclohexyl phenanthridines 3ja is 89%.
Embodiment 11
By 5-methyl-2-phenyl benzene isonitrile 1k(2mmol), hexamethylene 2a(4mmol) different with radical initiator azo two
Butyronitrile (2mmol) mixes, and adding acetonitrile 10mL is solvent, under nitrogen protection, and room temperature reaction, response time experience 2 hours.5-first
The conversion ratio of base-2-phenyl benzene isonitrile is 100%, and the productivity of 3-methyl-6-cyclohexyl phenanthridines 3ka is 85%.
Embodiment 12
By 5-methoxyl group-2-phenyl benzene isonitrile 1l(2mmol), hexamethylene 2a(4mmol) with radical initiator peroxidating
T-butyl perbenzoate (20mmol) mixes, and adding benzene 10mL is solvent, in air, is heated to 120 DEG C of reactions, and the response time is experienced
2 hours.The conversion ratio of 5-methoxyl group-2-phenyl benzene isonitrile is 100%, and the productivity of 3-methoxyl group-6-cyclohexyl phenanthridines 3la is
87%。
Embodiment 13
By 2-phenyl benzene isonitrile 1a(2mmol), Pentamethylene. 2b(4mmol) and radical initiator tert-butyl hydroperoxide
(2mmol) mixing, adding benzene 10mL is solvent, room temperature reaction under air, reaction experience 2 hours.The conversion of 2-phenyl benzene isonitrile
Rate is 100%, and the productivity of 6-cyclopenta phenanthridines 3ab is 82%.
Embodiment 14
By 2-phenyl benzene isonitrile 1a(2mmol), cycloheptane 2c(4mmol) and radical initiator di-t-butyl peroxide
(2mmol) mixing, adding toluene 10mL is solvent, room temperature reaction under air, reaction experience 2 hours.Turning of 2-phenyl benzene isonitrile
Rate is 100%, and the productivity of 6-suberyl phenanthridines 3ac is 86%.
Embodiment 15
By 2-phenyl benzene isonitrile 1a(2mmol), cyclooctane 2d(100mmol) and radical initiator di-t-butyl peroxide
(2mmol) mixing, room temperature reaction under air, reaction experience 2 hours.The conversion ratio of 2-phenyl benzene isonitrile is 100%, 6-ring octyl group
The productivity of phenanthridines 3ad is 84%.
Embodiment 16
By 2-phenyl benzene isonitrile 1a(2mmol), normal hexane 2e(4mmol) and radical initiator tert-butyl hydroperoxide
(2mmol) mixing, adding benzene 10mL is solvent, room temperature reaction under air, reaction experience 2 hours.The conversion of 2-phenyl benzene isonitrile
Rate is 100%, 6-(2-hexyl) productivity of phenanthridines 3ae is 44%.
Embodiment 17
By 2-phenyl benzene isonitrile 1a(2mmol), normal hexane 2e(4mmol) and radical initiator tert-butyl hydroperoxide
(2mmol) mixing, adding benzene 10mL is solvent, room temperature reaction under air, reaction experience 2 hours.The conversion of 2-phenyl benzene isonitrile
Rate is 100%, 6-(3-hexyl) productivity of phenanthridines 3af is 39%%.
Embodiment 18
By 2-phenyl benzene isonitrile 1a(2mmol), diamantane (obsolete) 2h(4mmol) and radical initiator di-t-butyl peroxide
(2mmol) mixing, adding benzene 10mL is solvent, room temperature reaction under air, reaction experience 2 hours.The conversion of 2-phenyl benzene isonitrile
Rate is 100%, and the productivity of 3ag is 48%.
Embodiment 19
By 2-phenyl benzene isonitrile 1a(2mmol), diamantane (obsolete) 2h(4mmol) and radical initiator di-t-butyl peroxide
(2mmol) mixing, adding benzene 10mL is solvent, room temperature reaction under air, reaction experience 2 hours.The conversion of 2-phenyl benzene isonitrile
Rate is 100%, and the productivity of 3ah is 31%.
Advantages of the present invention
Reaction need not add noble metal catalyst, experienced by the process of free radical cyclisation, by the free basic ring of cascade
Change, C (sp2)-C(sp2) key and C (sp2)-C(sp3) key row one-tenth reaction a series of 6 the alkylating phenanthridine derivatives of generation.This
Reaction achieves inactive C (sp3) the activation functionalization of-H key, practical, easy and simple to handle, organic synthesis have important
Meaning.
Claims (1)
1. the preparation method of a 6-alkyl phenanthridines, it is characterised in that with 2-aryl virtue isonitrile and cycloalkane as raw material or 2-aryl
Virtue isonitrile is raw material with chain alkane, adds radical initiator, adds a small amount of organic solvent, stirring reaction, 6-is synthesized
Alkyl phenanthridines compounds, reaction condition is: air or in inert gas shielding, the reaction temperature condition of room temperature-120 DEG C
Under, the response time is 2-24 hour；
Described radical initiator is tert-butyl hydroperoxide, di-t-butyl peroxide, peroxidized t-butyl perbenzoate, peroxide
Change benzoyl, azodiisobutyronitrile；
The consumption of described radical initiator is 1 ~ 10 times of 2-aryl virtue isonitrile molal quantity；
Described feed molar proportioning is 2-aryl virtue isonitrile: alkane is 1:2 ~ 100；
Described solvent is benzene, toluene, fluorobenzene, chlorobenzene, and 2-aryl virtue isonitrile is 1mmol:5 mL with solvent load ratio；
Described raw material 2-aryl virtue isonitrile structural formula is, substituent R=H, 4-on two aromatic rings
COCH3, 4-COOMe, 4-Me, naphthalene；R’ = H, 4-CF3, 5-F, 5-Me, 5-OMe；
Described cycloalkane or chain alkane are hexamethylene, Pentamethylene., cycloheptane, cyclooctane, normal hexane, diamantane (obsolete).
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| CN102295634A (en) * | 2004-03-03 | 2011-12-28 | 尼科梅德有限责任公司 | Novel hydroxy-6-heteroarylphenanthridines and their use as pde4 inhibitors |
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| WO2005085203A1 (en) * | 2004-03-10 | 2005-09-15 | Altana Pharma Ag | Novel difluoroethoxy-substituted hydroxy-6-phenylphenanthridines and their use as pde4 inhibitors |
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| 银促进的磷自由基与异腈的加成环化反应;杨斌，等;《有机化学》;20140103;第34卷;第717-721页 * |
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