WO2009133045A1 - New borane-amine complexes and their application in suzuki-type cross -coupling reactions - Google Patents
New borane-amine complexes and their application in suzuki-type cross -coupling reactions Download PDFInfo
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- WO2009133045A1 WO2009133045A1 PCT/EP2009/055018 EP2009055018W WO2009133045A1 WO 2009133045 A1 WO2009133045 A1 WO 2009133045A1 EP 2009055018 W EP2009055018 W EP 2009055018W WO 2009133045 A1 WO2009133045 A1 WO 2009133045A1
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- WIPO (PCT)
- Prior art keywords
- amine
- bbn
- formula
- organyl
- complex
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- 238000006880 cross-coupling reaction Methods 0.000 title claims abstract description 24
- 150000001412 amines Chemical class 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 28
- 230000008569 process Effects 0.000 claims abstract description 21
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 15
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 claims description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 35
- 150000001336 alkenes Chemical class 0.000 claims description 23
- 150000001345 alkine derivatives Chemical class 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical group CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 11
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 10
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 claims description 10
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2,5-dimethylpyridine Chemical compound CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 10
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 150000003222 pyridines Chemical class 0.000 claims description 10
- 239000002879 Lewis base Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000001190 organyl group Chemical group 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- KNCHDRLWPAKSII-UHFFFAOYSA-N 5-ethyl-2-methylpyridine Natural products CCC1=CC=NC(C)=C1 KNCHDRLWPAKSII-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 150000003973 alkyl amines Chemical class 0.000 claims description 6
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 claims description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 5
- 229910052796 boron Inorganic materials 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- IVMHDOBGNQOUHO-UHFFFAOYSA-N oxathiane Chemical compound C1CCSOC1 IVMHDOBGNQOUHO-UHFFFAOYSA-N 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 claims 4
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
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- 238000004458 analytical method Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 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 3
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- 229910052760 oxygen Inorganic materials 0.000 description 3
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- SCCCFNJTCDSLCY-UHFFFAOYSA-N 1-iodo-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(I)C=C1 SCCCFNJTCDSLCY-UHFFFAOYSA-N 0.000 description 2
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- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 0 CNc1cccc*1*1(C2CCCC1CCC2)*=* Chemical compound CNc1cccc*1*1(C2CCCC1CCC2)*=* 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- MMBMIVSDYYPRHH-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO.OO MMBMIVSDYYPRHH-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- NKSKNAWLKUQLNY-UHFFFAOYSA-N methyl 4-octylbenzoate Chemical compound CCCCCCCCC1=CC=C(C(=O)OC)C=C1 NKSKNAWLKUQLNY-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000001400 nonyl 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])C([H])([H])[H] 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- CDKDZKXSXLNROY-UHFFFAOYSA-N octylbenzene Chemical compound CCCCCCCCC1=CC=CC=C1 CDKDZKXSXLNROY-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 230000002311 subsequent effect Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- RMNIZOOYFMNEJJ-UHFFFAOYSA-K tripotassium;phosphate;hydrate Chemical compound O.[K+].[K+].[K+].[O-]P([O-])([O-])=O RMNIZOOYFMNEJJ-UHFFFAOYSA-K 0.000 description 1
- 125000002948 undecyl 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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/04—Substitution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
Definitions
- the invention relates to new amine complexes of B-organyl-9-borabicyclo[3.3.1]no- nanes and to solutions of said complexes. Furthermore, the invention relates to a method of using trialkylborane-amine complexes in Suzuki-type cross-coupling reactions and to a process to form new carbon-carbon bonds in a Suzuki-type cross- coupling reaction with a triorganoborane, which is carried out in the presence of an amine.
- the transition metal-catalyzed cross-coupling reaction between organic electrophiles and organoboron derivatives to form new carbon-carbon bonds is known as Suzuki- type cross-coupling reaction (Miyaura, N.; Suzuki, A., Chem. Rev. 95, pages 2457 to 2483 (1995)).
- Suzuki- type cross-coupling reaction Miyaura, N.; Suzuki, A., Chem. Rev. 95, pages 2457 to 2483 (1995)
- triorganoboranes can be used as sources for a nucleophilic organic moiety that will be coupled to an organic electrophile in this Suzuki-type cross- coupling reactions.
- B- organyl-9-borabicyclo[3.3.1]nonanes are especially useful reagents in said cross-coupling reactions since the exocyclic alkyl group is coupled preferentially over the bicyclic 9-borabicyc- lo[3.3.1]nonane skeleton (Miyaura, N.; Suzuki, A. et al., J. Am. Chem. Soc. 1 11 , pages 314 to 321 (1989); Netherton, M. R. et al., J. Am. Chem. Soc. 123, pages 10099 to 10100 (2001 )).
- 9-BBN forms a pyrophoric solid with only poor solubility in typical organic solvents (Soderquist, J. A.; Brown, H. C, J. Org. Chem. 46, pages 4599 to 4600 (1981)). These properties may hamper the large scale application of 9-BBN and so alternatives are desirable.
- R 1 is an organyl comprising at least one carbon atom that is directly bound to the boron atom, and amine is a substituted pyridine of the formula (2)
- R 2 is Ci - Cio alkyl, Ci - Cs alkoxy or Ci - Cs-alkoxy-Ci - Cio alkyl
- R 3 is hydrogen or a Ci - Cio alkyl, Ci - Cs alkoxy or Ci - Cs-alkoxy-Ci - Cio alkyl group, or an alkylamine of the formula (3)
- R 4 is hydrogen or Ci - C10 alkyl
- R 5 is Ci - Cio alkyl
- Another embodiment of the present invention are solutions comprising at least one of the new B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes of the formula (1 ) and at least one solvent.
- Still another embodiment of the present invention is a new method of using B-organyl- 9-BBN-amine complexes of the formula (1) in Suzuki-type cross-coupling reactions to form new carbon-carbon bonds.
- the new B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes of the present invention have chemical structures according to the general formula (1 ),
- R 1 is an organyl comprising at least one carbon atom that is directly bound to the boron atom, and amine is a substituted pyridine of the formula (2)
- R 2 is Ci - Cio alkyl, Ci - Cs alkoxy or Ci - Cs-alkoxy-Ci - Cio alkyl, and
- R 3 is hydrogen or a Ci - Cio alkyl, Ci - Cs alkoxy or Ci - Cs-alkoxy-Ci - Cio alkyl group, or an alkylamine of the formula (3) R 4 R 5 NH (3), wherein
- R 4 is hydrogen or Ci - Cio alkyl
- R 5 is Ci - Cio alkyl
- the new B-organyl-9-BBN-amine complexes have chemical structures according to the general formula (1), wherein the amine is a substituted pyridine of the formula (2).
- organyl denotes an organic group comprising at least one carbon atom, that may contain heteroatoms like hydrogen, oxygen, nitrogen, sulphur, phosphorus, fluorine, chlorine, bromine, iodine, boron, silicon, selenium, tin or transition metals like iron, nickel, zinc, platinum, etc.
- the organyl can have any linear or cyclic, branched or unbranched, mono- or polycyclic, carbo- or heterocyclic, saturated or unsaturated molecular structure and may comprise protected or unprotected functional groups.
- the organyl may be linked to or part of an oligomer or polymer with a molecular weight up to one million Dalton.
- Preferred organyl groups are Ci - C24 alkyl, C3 - C16 cycloalkyl, substituted alkyl, C2 - C22 alkenyl, C5 - C15 cycloalkenyl and C2 - C22 alkynyl groups.
- Ci - C24 alkyl denotes a branched or an unbranched saturated hydrocarbon group comprising between 1 and 24 carbon atoms; examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1 ,2-dimethylpropyl, 1 ,1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1 ,1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 1 ,2,2-trimethyl- propyl, 1 ,1 ,2-trimethylpropyl, heptyl, 5-methylhexyl, 4-methylpentyl, 1-
- alkyl groups ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, amyl, isoamyl, sec-amyl, 1 ,2-dimethylpropyl, 1 ,1-dimethylpropyl, hexyl and octyl.
- C3 - C16 cycloalkyl denotes a saturated hydrocarbon group comprising between 3 and 16 carbon atoms including a mono- or polycyclic structural moiety.
- Exam- pies are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyc- lononyl or cyclodecyl.
- Prefered are the cycloalkyl groups cyclopropyl, cyclopentyl and cyclohexyl.
- substituted alkyl denotes an alkyl group in which at least one hydrogen atom is replaced by a halide atom like fluorine, chlorine, bromine or iodine, a Ci - C20 alkoxy group, an ester group, a trialkylsilyl group, a C ⁇ - C14 aryl group, or a C3 - C14 heteroaryl group.
- Ci - C20 alkoxy stands for a group derived from an aliphatic monoalcohol with between 1 and 20 carbon atoms.
- C ⁇ - C14 aryl denotes an unsaturated hydrocarbon group comprising between 6 and 14 carbon atoms including at least one aromatic ring system like phenyl or naphthyl or any other aromatic ring system.
- C3 - C14 heteroaryl denotes a mono- or polycyclic aromatic ring system comprising between 3 and 14 ring atoms, in which at least one of the ring carbon atoms is replaced by a heteroatom like nitrogen, oxygen or sulfur.
- Examples are pyridyl, pyranyl, thiopyranyl, chinolinyl, isochinolinyl, acridyl, pyridazinyl, pyrimidyl, pyrazinyl, phenazinyl, triazinyl, pyrrolyl, furanyl, thiophenyl, indolyl, isoindolyl, pyrazolyl, imida- zolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and triazolyl.
- C2 - C22 alkenyl denotes a straight chain or branched unsaturated hydrocar- bon group comprising between 2 and 22 carbon atoms including at least one carbon- carbon double bond.
- Examples are vinyl, allyl, 1-methylvinyl, butenyl, isobutenyl, 3- methyl-2-butenyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 2,5-dimethylhex-4-en-3-yl, 1- heptenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1 ,3-butadienyl, 1-4-pentadienyl, 1 ,3-hexadienyl and 1 ,4-hexadienyl.
- Prefered are the alkenyl groups vinyl, allyl, butenyl, iso
- C5 - C15 cycloalkenyl denotes an unsaturated hydrocarbon group comprising between 5 and 15 carbon atoms including at least one carbon-carbon double bond and a mono- or polycyclic structural moiety.
- Examples are cyclopentenyl, 1-methylcyclo- pentenyl, cyclohexenyl, cyclooctenyl, 1 ,3-cyclopentadienyl, 1 ,3-cyclohexadienyl, 1 ,4- cyclohexadienyl, 1 ,3-cycloheptadienyl, 1 ,3,5-cycloheptatrienyl and 1 ,3,5,7-cycloocta- tetraenyl.
- C2 - C22 alkynyl denotes a straight chain or branched unsaturated hydrocarbon group comprising between 2 and 22 carbon atoms including at least one carbon- carbon triple bond.
- alkynyl groups include ethynyl, 2-propynyl and 2- or 3- butynyl.
- the substituted pyridine of the formula (2) can be, for exam- pie, 2-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 5-ethyl-2-methylpyridine, 4-ethyl-2- methylpyridine, 3-ethyl-2-methylpyridine, 2,5-diethylpyridine, 5-propyl-2-methylpyridine, 4-propyl-2-methylpyridine, 5-isopropyl-2-methylpyridine, 5-t-butyl-2-methylpyridine, 5-n- hexyl-2-methylpyridine, 4-isobutyl-2-methylpyridine or 2,4-dipropylpyridine.
- Preferred pyridines of the formula (2) are 2-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine and 5- ethyl-2-methylpyridine.
- the new B-organyl-9-BBN-amine complexes have chemical structures according to the general formula (1 ), wherein R 1 is an organyl that is directly bound to the boron atom via two methylene groups and (1 ) exhibits a moiety of the formula >BCH 2 CH 2 - , i. e. R 1 is -CH 2 CH 3 or -CH 2 CH 2 -organyl.
- R 1 is -CH 2 CH 3 or -CH 2 CH 2 -organyl.
- These preferred derivatives of (1 ) can, for example, be synthesized via hydroboration of terminal alkenes with 9-BBN or 9-BBN-amine complexes, owing to the well-known anti-Markovnikov regioselectivty of such hydroborations.
- Examples for these preferred B-organyl-9-BBN-amine complexes (1) have chemical structures according to the gen- eral formula (1 ), wherein R 1 is ethyl, propyl, butyl, pentyl, hexyl and octyl.
- the new B-organyl-9-BBN- amine complexes have chemical structures according to the general formula (1 ), wherein the amine is a compound according to the formula (2), wherein R 3 is hydrogen or Ci - C4-alkyl.
- the new B-organyl-9- BBN-amine complexes have chemical structures according to the general formula (1), wherein R 1 is -CH 2 CHs or -CH 2 CH 2 -organyl and the amine is 2-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine or 5-ethyl-2-methylpyridine.
- the 11 B NMR spectra of the new B-organyl-9-BBN-amine complexes of the formula (1 ) generally show a broad singlet with a chemical shift ⁇ between +10 to +35 ppm, indicating strong coordination between the amine and the trialkylborane moieties in solution.
- the new B-organyl-9-BBN-amine complexes (1 ) can, for example, be obtained via hy- droboration of an unsaturated compound like an alkene or an alkyne with 9-BBN or a 9- BBN-Lewis base complex (e. g. 9-BBN-THF or 9-BBN-dimethyl sulfide) followed by adding the respective amine of the formula (2) or (3) to the resulting B-organyl-9-BBN derivative.
- the hydroboration of an alkene or alkyne can be conducted directly with a complex of 9-BBN and an amine of the formula (2) or (3).
- Another embodiment of the present invention is therefore a process to synthesize new B-organyl-9-BBN-amine complexes of the formula (1 ), comprising the step of hydrobo- rating an alkene or an alkyne with a complex of 9-BBN and an amine of the formula (2) or (3) or hydroborating an alkene or an alkyne with 9-BBN or a 9-BBN-Lewis base complex followed by adding an amine of the formula (2) or (3).
- the hydroboration of alkenes or alkynes with 9-BBN or a complex of 9- BBN can be carried out in solution in the presence of at least one solvent.
- complexes of 9-BBN and an amine of the formula (2) or (3) are reacted with alkenes or alkynes in organic solvents. Owing to the generally higher solubility of these 9-BBN- amine complexes in organic solvents compared to 9-BBN this allows for working at higher concentrations, thereby permitting higher loadings of reactors and avoids the difficulties connected with the handling of 9-BBN as a pyrophoric solid.
- the initial products of this synthetic route are therefore solutions of the new B-organyl-9-BBN-amine complexes (1).
- Another embodiment of the present invention is therefore a solution comprising at least one B-organyl-9-BBN-amine complexes of the formula (1 ) and at least one solvent.
- Suitable solvents for the solutions of the present invention are those in which the B- organyl-9-BBN-amine complexes have a high solubility. Examples are ethers like diethyl ether, tetrahydrofuran or 2-methyltetrahydrofuran, sulfides like dimethyl sulfide or 1 ,6-thioxane and hydrocarbons like pentane, hexane(s), heptane(s), cyclohexane, toluene or xylenes.
- Preferred solvents for the solutions comprising at least one B-organyl- 9-BBN-amine complex of the formula (1) are tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfide, 1 ,6-thioxane, toluene, hexane(s), heptane(s) or cyclohexane, most preferred are tetrahydrofuran, 2-methyltetrahydrofuran, toluene, hexane(s), heptane(s) or cyclohexane.
- the solutions of the present invention generally contain the new B-organyl-9-BBN- amine complexes of the formula (1) in concentrations between 0.05 and 5 mol/l, preferably between 0.1 and 5 mol/l, more preferably between 0.5 and 3 mol/l.
- Another embodiment of the present invention is a process to synthesize a solution comprising at least one of the new B-organyl-9-BBN-amine complexes of the formula (1 ) and at least one solvent, comprising the steps of hydroborating an alkene or an alkyne with a complex of 9-BBN and an amine of the formula (2) or (3) or hydroborating an alkene or an alkyne with 9-BBN or a 9-BBN-Lewis base complex followed by adding an amine of the formula (2) or (3) in at least one solvent.
- Still another embodiment of the present invention is a process to synthesize the new B- organyl-9-BBN-amine complexes of the formula (1), comprising the steps of hydroborating an alkene or an alkyne with a complex of 9-BBN and an amine of the formula (2) or (3) or hydroborating an alkene or an alkyne with 9-BBN or a 9-BBN-Lewis base complex followed by adding an amine of the formula (2) or (3) in at least one solvent and isolating the complex from the formed solution.
- the isolation is done by evaporation of the solvent.
- the present invention further provides a new method of using the new B-organyl-9- BBN-amine complexes of the formula (1) in Suzuki-type cross-coupling reactions to form new carbon-carbon bonds.
- the direct use of the new B-organyl-9-BBN-amine complexes of the formula (1) in Suzuki-type cross-coupling reactions without the need to separate the trialkylborane from the amine is highly desirable for development of cost effective processes.
- a further aspect of the present invention is a process to form new carbon- carbon bonds comprising a Suzuki-type cross-coupling reaction with a triorganoborane, which is carried out in the presence of an amine.
- Another embodiment of the present invention is a process to form new carbon-carbon bonds comprising the steps of hydroborating an alkene or alkyne with a diorganobo- rane-amine complex and using the resulting mixture of a triorganoborane and the amine in a Suzuki-type cross-coupling reaction.
- the triorganoborane in these processes is a B-organyl-9-BBN derivative, e. g. B-octyl-9-BBN.
- the amine in these processes is a substituted pyridine of the formula (2) or an alkylamine of the formula (3) as defined above.
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Abstract
The invention relates to new amine complexes of B-organyl-9-borabicyclo[3.3.1]nonanes and to solutions of said complexes. Furthermore, the invention relates to a method of using trialkylborane-amine complexes in Suzuki-type cross-coupling reactions and to a process to form new carbon-carbon bonds in a Suzuki-type cross-coupling reaction with a triorganoborane, which is carried out in the presence of an amine.
Description
New borane-amine complexes and their application in Suzuki-type cross-coupling reactions
Field of the Invention
The invention relates to new amine complexes of B-organyl-9-borabicyclo[3.3.1]no- nanes and to solutions of said complexes. Furthermore, the invention relates to a method of using trialkylborane-amine complexes in Suzuki-type cross-coupling reactions and to a process to form new carbon-carbon bonds in a Suzuki-type cross- coupling reaction with a triorganoborane, which is carried out in the presence of an amine.
Background of the Invention
The transition metal-catalyzed cross-coupling reaction between organic electrophiles and organoboron derivatives to form new carbon-carbon bonds is known as Suzuki- type cross-coupling reaction (Miyaura, N.; Suzuki, A., Chem. Rev. 95, pages 2457 to 2483 (1995)). For example, triorganoboranes can be used as sources for a nucleophilic organic moiety that will be coupled to an organic electrophile in this Suzuki-type cross- coupling reactions. Readily available B-organyl-9-borabicyclo[3.3.1]nonanes (B- organyl-9-BBN's) are especially useful reagents in said cross-coupling reactions since the exocyclic alkyl group is coupled preferentially over the bicyclic 9-borabicyc- lo[3.3.1]nonane skeleton (Miyaura, N.; Suzuki, A. et al., J. Am. Chem. Soc. 1 11 , pages 314 to 321 (1989); Netherton, M. R. et al., J. Am. Chem. Soc. 123, pages 10099 to 10100 (2001 )).
Hydroboration of alkenes or alkynes with 9-borabicyclo[3.3.1]nonane (9-BBN) provides easy access to many B-organyl-9-borabicyclo[3.3.1]nonanes. In favourable cases formation of the B-organyl-9-BBN via hydroboration of an appropriate alkene and the sub- sequent Suzuki-type cross-coupling reaction with an organic electrophile can be conducted as one-pot synthesis with the two steps run consecutively in the same reaction vessel (e. g. Rodriguez, A. et al., Org. Biomol. Chem. 1 , pages 973 to 977 (2003)).
Owing to its dimeric structure 9-BBN forms a pyrophoric solid with only poor solubility in typical organic solvents (Soderquist, J. A.; Brown, H. C, J. Org. Chem. 46, pages 4599 to 4600 (1981)). These properties may hamper the large scale application of 9-BBN and so alternatives are desirable.
It is known that the 9-BBN dimer can be split by addition of certain Lewis bases and that in some cases stable 9-BBN-Lewis base complexes are formed (Brown, H. C. et al., J. Am. Chem. Soc. 104, pages 7148 to 7155 (1982); Gazzetta Chimica Italians 117, pages 517 to 523 (1987)). However, the 9-BBN-pyridine complex (Brown, H. C, J. Org. Chem. 45, pages 846 to 849 (1980)) shows only a relatively poor ability to act as a hy-
droborating agent (Brown, H. C. et al., Inorg. Chem. 16, pages 3090 to 3094 (1977)). Recently, new dialkylborane-amine complexes have been developed that are more suitable for hydroboration reactions and therefore give access to the corresponding trialkylborane-amine complexes or mixtures (WO 2008/055859).
It was an object of the present invention to develop new trialkylborane-amine complexes and solutions thereof. It was another object of the present invention to provide a new method of using trialkylborane-amine complexes in Suzuki-type cross-coupling reactions. It was still another object of the present invention to develop a process to form new carbon-carbon bonds in a Suzuki-type cross-coupling reaction, which is carried out in the presence of an amine.
Summary of the Invention
Accordingly, new B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes of the formula (1) have been found,
wherein
R1 is an organyl comprising at least one carbon atom that is directly bound to the boron atom, and amine is a substituted pyridine of the formula (2)
wherein
R2 is Ci - Cio alkyl, Ci - Cs alkoxy or Ci - Cs-alkoxy-Ci - Cio alkyl, and R3 is hydrogen or a Ci - Cio alkyl, Ci - Cs alkoxy or Ci - Cs-alkoxy-Ci - Cio alkyl group, or an alkylamine of the formula (3)
R4R5NH (3),
wherein
R4 is hydrogen or Ci - C10 alkyl, and R5 is Ci - Cio alkyl.
Another embodiment of the present invention are solutions comprising at least one of the new B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes of the formula (1 ) and at least one solvent.
Still another embodiment of the present invention is a new method of using B-organyl- 9-BBN-amine complexes of the formula (1) in Suzuki-type cross-coupling reactions to form new carbon-carbon bonds.
Furthermore, a process has been found to form new carbon-carbon bonds comprising a Suzuki-type cross-coupling reaction with a triorganoborane, which is carried out in the presence of an amine.
Detailed Description of the Invention
The new B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes of the present invention have chemical structures according to the general formula (1 ),
wherein
R1 is an organyl comprising at least one carbon atom that is directly bound to the boron atom, and amine is a substituted pyridine of the formula (2)
wherein
R2 is Ci - Cio alkyl, Ci - Cs alkoxy or Ci - Cs-alkoxy-Ci - Cio alkyl, and
R3 is hydrogen or a Ci - Cio alkyl, Ci - Cs alkoxy or Ci - Cs-alkoxy-Ci - Cio alkyl group, or an alkylamine of the formula (3)
R4R5NH (3), wherein
R4 is hydrogen or Ci - Cio alkyl, and R5 is Ci - Cio alkyl.
In a preferred embodiment of the present invention the new B-organyl-9-BBN-amine complexes have chemical structures according to the general formula (1), wherein the amine is a substituted pyridine of the formula (2).
As used in connection with the present invention, the term "organyl" denotes an organic group comprising at least one carbon atom, that may contain heteroatoms like hydrogen, oxygen, nitrogen, sulphur, phosphorus, fluorine, chlorine, bromine, iodine, boron, silicon, selenium, tin or transition metals like iron, nickel, zinc, platinum, etc. The organyl can have any linear or cyclic, branched or unbranched, mono- or polycyclic, carbo- or heterocyclic, saturated or unsaturated molecular structure and may comprise protected or unprotected functional groups. Furthermore, the organyl may be linked to or part of an oligomer or polymer with a molecular weight up to one million Dalton.
Preferred organyl groups are Ci - C24 alkyl, C3 - C16 cycloalkyl, substituted alkyl, C2 - C22 alkenyl, C5 - C15 cycloalkenyl and C2 - C22 alkynyl groups.
As used in connection with the present invention, the term "Ci - C24 alkyl" denotes a branched or an unbranched saturated hydrocarbon group comprising between 1 and 24 carbon atoms; examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1 ,2-dimethylpropyl, 1 ,1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1 ,1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 1 ,2,2-trimethyl- propyl, 1 ,1 ,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1 ,2-dimethylpentyl, 1 ,3-dimethylpentyl, 1 ,4- dimethylpentyl, 1 ,2,3-trimethylbutyl, 1 ,1 ,2-trimethylbutyl, 1 ,1 ,3-trimethylbutyl, octyl, 6- methylheptyl, 1-methylheptyl, 1 ,1 ,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7- methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4- , 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or δ-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and isopinocampheyl. Preferred are the alkyl groups ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, amyl, isoamyl, sec-amyl, 1 ,2-dimethylpropyl, 1 ,1-dimethylpropyl, hexyl and octyl.
The term "C3 - C16 cycloalkyl" denotes a saturated hydrocarbon group comprising between 3 and 16 carbon atoms including a mono- or polycyclic structural moiety. Exam-
pies are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyc- lononyl or cyclodecyl. Prefered are the cycloalkyl groups cyclopropyl, cyclopentyl and cyclohexyl.
The term "substituted alkyl" denotes an alkyl group in which at least one hydrogen atom is replaced by a halide atom like fluorine, chlorine, bromine or iodine, a Ci - C20 alkoxy group, an ester group, a trialkylsilyl group, a Cβ - C14 aryl group, or a C3 - C14 heteroaryl group.
The term "Ci - C20 alkoxy" stands for a group derived from an aliphatic monoalcohol with between 1 and 20 carbon atoms.
The term "Cβ - C14 aryl" denotes an unsaturated hydrocarbon group comprising between 6 and 14 carbon atoms including at least one aromatic ring system like phenyl or naphthyl or any other aromatic ring system.
The term "C3 - C14 heteroaryl" denotes a mono- or polycyclic aromatic ring system comprising between 3 and 14 ring atoms, in which at least one of the ring carbon atoms is replaced by a heteroatom like nitrogen, oxygen or sulfur. Examples are pyridyl, pyranyl, thiopyranyl, chinolinyl, isochinolinyl, acridyl, pyridazinyl, pyrimidyl, pyrazinyl, phenazinyl, triazinyl, pyrrolyl, furanyl, thiophenyl, indolyl, isoindolyl, pyrazolyl, imida- zolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and triazolyl.
The term "C2 - C22 alkenyl" denotes a straight chain or branched unsaturated hydrocar- bon group comprising between 2 and 22 carbon atoms including at least one carbon- carbon double bond. Examples are vinyl, allyl, 1-methylvinyl, butenyl, isobutenyl, 3- methyl-2-butenyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 2,5-dimethylhex-4-en-3-yl, 1- heptenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1 ,3-butadienyl, 1-4-pentadienyl, 1 ,3-hexadienyl and 1 ,4-hexadienyl. Prefered are the alkenyl groups vinyl, allyl, butenyl, isobutenyl, 1 ,3-butadienyl and 2,5-dimethylhex-4-en- 3-yl.
The term "C5 - C15 cycloalkenyl" denotes an unsaturated hydrocarbon group comprising between 5 and 15 carbon atoms including at least one carbon-carbon double bond and a mono- or polycyclic structural moiety. Examples are cyclopentenyl, 1-methylcyclo- pentenyl, cyclohexenyl, cyclooctenyl, 1 ,3-cyclopentadienyl, 1 ,3-cyclohexadienyl, 1 ,4- cyclohexadienyl, 1 ,3-cycloheptadienyl, 1 ,3,5-cycloheptatrienyl and 1 ,3,5,7-cycloocta- tetraenyl.
The term "C2 - C22 alkynyl" denotes a straight chain or branched unsaturated hydrocarbon group comprising between 2 and 22 carbon atoms including at least one carbon-
carbon triple bond. Examples of alkynyl groups include ethynyl, 2-propynyl and 2- or 3- butynyl.
According to the invention, the substituted pyridine of the formula (2) can be, for exam- pie, 2-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 5-ethyl-2-methylpyridine, 4-ethyl-2- methylpyridine, 3-ethyl-2-methylpyridine, 2,5-diethylpyridine, 5-propyl-2-methylpyridine, 4-propyl-2-methylpyridine, 5-isopropyl-2-methylpyridine, 5-t-butyl-2-methylpyridine, 5-n- hexyl-2-methylpyridine, 4-isobutyl-2-methylpyridine or 2,4-dipropylpyridine. Preferred pyridines of the formula (2) are 2-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine and 5- ethyl-2-methylpyridine.
In a preferred embodiment of the present invention the new B-organyl-9-BBN-amine complexes have chemical structures according to the general formula (1 ), wherein R1 is an organyl that is directly bound to the boron atom via two methylene groups and (1 ) exhibits a moiety of the formula >BCH2CH2- , i. e. R1 is -CH2CH3 or -CH2CH2-organyl. These preferred derivatives of (1 ) can, for example, be synthesized via hydroboration of terminal alkenes with 9-BBN or 9-BBN-amine complexes, owing to the well-known anti-Markovnikov regioselectivty of such hydroborations. Examples for these preferred B-organyl-9-BBN-amine complexes (1) have chemical structures according to the gen- eral formula (1 ), wherein R1 is ethyl, propyl, butyl, pentyl, hexyl and octyl.
In cases where the organyl R1 is substituted at the -BCH2CH2- moiety the R1 group becomes more bulky and complexation between the amine and the triorganoborane might be hampered. In some cases a mixture of the new B-organyl-9-BBN-amine com- plex and the uncomplexed B-organyl-9-BBN is observed, in other cases there is no complexation at all. However, compositions comprising any amine and a B-organyl-9- BBN derivative can very often be used for further reactions independent from complex formation (see below).
In another preferred embodiment of the present invention the new B-organyl-9-BBN- amine complexes have chemical structures according to the general formula (1 ), wherein the amine is a compound according to the formula (2), wherein R3 is hydrogen or Ci - C4-alkyl.
Most preferred is an embodiment of the present invention where the new B-organyl-9- BBN-amine complexes have chemical structures according to the general formula (1), wherein R1 is -CH2CHs or -CH2CH2-organyl and the amine is 2-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine or 5-ethyl-2-methylpyridine.
The 11B NMR spectra of the new B-organyl-9-BBN-amine complexes of the formula (1 ) generally show a broad singlet with a chemical shift δ between +10 to +35 ppm, indicating strong coordination between the amine and the trialkylborane moieties in solution.
For example, the B-octyl-9-borabicyclo[3.3.1]nonane-2-picoline complex shows a 11B NMR resonance at δ = 26.6 ppm (cf. example 1 ).
The new B-organyl-9-BBN-amine complexes (1 ) can, for example, be obtained via hy- droboration of an unsaturated compound like an alkene or an alkyne with 9-BBN or a 9- BBN-Lewis base complex (e. g. 9-BBN-THF or 9-BBN-dimethyl sulfide) followed by adding the respective amine of the formula (2) or (3) to the resulting B-organyl-9-BBN derivative. Alternatively, the hydroboration of an alkene or alkyne can be conducted directly with a complex of 9-BBN and an amine of the formula (2) or (3).
Another embodiment of the present invention is therefore a process to synthesize new B-organyl-9-BBN-amine complexes of the formula (1 ), comprising the step of hydrobo- rating an alkene or an alkyne with a complex of 9-BBN and an amine of the formula (2) or (3) or hydroborating an alkene or an alkyne with 9-BBN or a 9-BBN-Lewis base complex followed by adding an amine of the formula (2) or (3).
If necessary, the hydroboration of alkenes or alkynes with 9-BBN or a complex of 9- BBN can be carried out in solution in the presence of at least one solvent. Preferably, complexes of 9-BBN and an amine of the formula (2) or (3) are reacted with alkenes or alkynes in organic solvents. Owing to the generally higher solubility of these 9-BBN- amine complexes in organic solvents compared to 9-BBN this allows for working at higher concentrations, thereby permitting higher loadings of reactors and avoids the difficulties connected with the handling of 9-BBN as a pyrophoric solid. The initial products of this synthetic route are therefore solutions of the new B-organyl-9-BBN-amine complexes (1). These solutions can either be directly employed for further reactions or the new B-organyl-9-BBN-amine complexes (1) can be isolated in pure form by evaporation of the solvent. The preferred method for removal of the solvent is evaporation under reduced pressure to decrease the boiling point of the solvent.
Another embodiment of the present invention is therefore a solution comprising at least one B-organyl-9-BBN-amine complexes of the formula (1 ) and at least one solvent. Suitable solvents for the solutions of the present invention are those in which the B- organyl-9-BBN-amine complexes have a high solubility. Examples are ethers like diethyl ether, tetrahydrofuran or 2-methyltetrahydrofuran, sulfides like dimethyl sulfide or 1 ,6-thioxane and hydrocarbons like pentane, hexane(s), heptane(s), cyclohexane, toluene or xylenes. Preferred solvents for the solutions comprising at least one B-organyl- 9-BBN-amine complex of the formula (1) are tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfide, 1 ,6-thioxane, toluene, hexane(s), heptane(s) or cyclohexane, most preferred are tetrahydrofuran, 2-methyltetrahydrofuran, toluene, hexane(s), heptane(s) or cyclohexane.
The solutions of the present invention generally contain the new B-organyl-9-BBN- amine complexes of the formula (1) in concentrations between 0.05 and 5 mol/l, preferably between 0.1 and 5 mol/l, more preferably between 0.5 and 3 mol/l.
Another embodiment of the present invention is a process to synthesize a solution comprising at least one of the new B-organyl-9-BBN-amine complexes of the formula (1 ) and at least one solvent, comprising the steps of hydroborating an alkene or an alkyne with a complex of 9-BBN and an amine of the formula (2) or (3) or hydroborating an alkene or an alkyne with 9-BBN or a 9-BBN-Lewis base complex followed by adding an amine of the formula (2) or (3) in at least one solvent.
Still another embodiment of the present invention is a process to synthesize the new B- organyl-9-BBN-amine complexes of the formula (1), comprising the steps of hydroborating an alkene or an alkyne with a complex of 9-BBN and an amine of the formula (2) or (3) or hydroborating an alkene or an alkyne with 9-BBN or a 9-BBN-Lewis base complex followed by adding an amine of the formula (2) or (3) in at least one solvent and isolating the complex from the formed solution. Preferably the isolation is done by evaporation of the solvent.
The present invention further provides a new method of using the new B-organyl-9- BBN-amine complexes of the formula (1) in Suzuki-type cross-coupling reactions to form new carbon-carbon bonds. The direct use of the new B-organyl-9-BBN-amine complexes of the formula (1) in Suzuki-type cross-coupling reactions without the need to separate the trialkylborane from the amine is highly desirable for development of cost effective processes.
Moreover, it was found that in Suzuki-type cross coupling reactions with trialkylboranes as nucleophile the presence of an amine does not interfere with the catalytic cycle. It turned out to be irrelevant whether there is a complex formed between the trialkylbo- rane and the amine or not or if there is a dynamic equilibrium between the complex and the separated trialkylborane and amine species. This is of great value since trialkylboranes are easily prepared via hydroboration of alkenes and alkynes with dialkylborane- amine complexes, which are much easier to handle and have a much higher solubility than the corresponding dialkylboranes without any amine. Therefore, the crude product of the reaction between a dialkylborane-amine complex and an alkene or alkyne can be used directly in a Suzuki-type cross-coupling reaction.
Therefore, a further aspect of the present invention is a process to form new carbon- carbon bonds comprising a Suzuki-type cross-coupling reaction with a triorganoborane, which is carried out in the presence of an amine.
Another embodiment of the present invention is a process to form new carbon-carbon bonds comprising the steps of hydroborating an alkene or alkyne with a diorganobo- rane-amine complex and using the resulting mixture of a triorganoborane and the amine in a Suzuki-type cross-coupling reaction.
In one embodiment of the present invention the triorganoborane in these processes is a B-organyl-9-BBN derivative, e. g. B-octyl-9-BBN. In another embodiment of present invention the amine in these processes is a substituted pyridine of the formula (2) or an alkylamine of the formula (3) as defined above.
Examples
The following examples illustrate the present invention without limitation of the same. All reactions were performed under dry and oxygen free conditions.
Example 1 :
Hydroboration of 1-octene with 9-BBN-2-picoline complex
29.5 g of a 43.1 wt% solution of 9-BBN-2-picoline complex in THF (60 mmol) were di- luted with 6.5 ml of anhydrous THF and cooled to 00C. 6.73 g of 1-octene (60 mmol) were added slowly and the mixture was stirred at room temperature for three hours. After that analysis of the reaction mixture by 11B NMR spectroscopy revealed that no 9-BBN-2-picoline complex (δ = -1.6 ppm) was left and a major peak at 26.6 ppm was visible assigned to B-octyl-9-BBN-2-picoline complex. This prepared 1.02 M stock solu- tion of B-octyl-9-BBN-2-picoline complex in THF was used for the following Suzuki experiments.
Example 2:
Hydroboration of methyl-10-undecenoate with 9-BBN-2-picoline complex
2.5 g of a 43.1 wt% solution of 9-BBN-2-picoline complex in THF (5 mmol) were diluted with 10 ml of anhydrous THF. Then 1.12 ml of methyl-10-undecenoate (5 mmol) were added dropwise and the mixture was stirred at room temperature for three hours. After that analysis of the reaction mixture by 11B NMR spectroscopy revealed that no 9-BBN- 2-picoline complex (δ = -1.6 ppm) was left and a major peak at δ = 29.6 ppm was visible, assigned to B-(1 1-methylundecanoate)-9-BBN-2-picoline complex.
Example 3:
Hydroboration of isoprene with 9-BBN-2-picoline complex
2.69 g of a 40 wt% solution of 9-BBN-2-picoline complex in THF (5 mmol) were diluted with 10 ml of anhydrous THF. Then 0.5 ml of isoprene (5 mmol) were added and the
mixture was stirred at room temperature for 24 hours. After that analysis of the reaction mixture by 11B NMR spectroscopy revealed that no 9-BBN-2-picoline complex (δ = -1.6 ppm) was left. Two resonances were abserved at δ = 76.1 ppm and 18.1 ppm assigned to the complexed and uncomplexed product (1 : 0.71 = triorganylborane-2-picoline : triorganylborane). The proton spectra showed the formation of two isomers caused by addition to either of the double bonds of isoprene
Example 4:
Suzuki coupling of iodobenzene and B-octyl-9-BBN-2-picoline complex (sp2-sp3)
123 mg (0.15 mmol) of PdCI2(dppf).DCM complex ([1 ,1 '-bis(diphenylphosphino)- ferrocene]dichloropalladium-(ll)-complex with dichloromethane), 12 ml distilled THF and 1.02 g (5 mmol) iodobenzene were mixed. Then, 7.53 g of a 16 wt% solution of B-octyl-9-BBN-2-picoline complex in THF were added followed by 5 ml of a 3 M aqueous sodium hydroxide (NaOH) solution, which resulted in a dark brown reaction mix- ture. The mixture was heated to reflux for 22 hours. Then it was cooled to room temperature, hexane (20 ml) was added and the mixture was quenched with hydrogen peroxide hydrogen peroxide (H2O2, 30w%, 2 ml). Stirring was continued for 10 minutes until the gas evolution ceased. The aqueous layer was separated from the organic layer, extracted with hexane (1 x 20 ml) and the combined organic layers were dried over sodium sulfate (Na2SU4), filtered and evaporated to dryness. The crude product (1.83 g) was purified by column chromatography on silica gel (pure hexane) to give 558 mg (59%) of pure 1-octylbenzene as a colorless oil.
Example 5: Suzuki Coupling of 1-iodo-4-nitrobenzene and B-octyl-9-BBN-2-picoline complex (sp2- sp3)
Example 6:
Suzuki Coupling of methyl-4-bromobenzoate and B-octyl-9-BBN-2-picoline complex (sp2-sp3)
204 mg (0.25 mmol) of PdCI2(dppf).DCM complex, 14.6 ml distilled THF and 1.08 g (5 mmol) methyl-4-bromobenzoate were mixed. Then 5.39 ml of a 1.02 M solution of B- octyl-9-BBN-2-picoline complex was added followed by 3.33 ml of a 3 M aqueous potassium phosphate (K3PO4) solution, which resulted in a black reaction mixture. The mixture was stirred for 23 h, then hexane (20 ml), followed by water (5 ml) and hydrogen peroxide (H2O2, 30w%, 2 ml) were added. Stirring was continued for 10 minutes until the gas evolution ceased. The aqueous layer was separated from the organic layer and extracted with diethyl ether (2 x 15 ml). The combined organic layers were dried over sodium sulfate (Na2SO4), filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel (gradient elution: pure hexane to hexane : ethyl acetate = 97 : 3) to result in 1.24 g (99 %) of methyl-4- octylbenzoate as a colorless oil.
Example 7:
Suzuki coupling of ethyl-4-bromobutanoate and B-octyl-9-BBN-2-picoline complex (sp3- sp3)
1.38 g (6 mmol) of solid potassium phosphate (K3PO4.H2O), 50 mg (0.2 mmol) of PaI- ladium-(ll)-acetate (Pd(OAc)2) and 1 12 mg (0.4 mmol) of tricyclohexylphophine (P(Cy)3) were mixed. The mixture was purged with nitrogen for 15 minutes and then 5.88 ml of a 1.02 M solution of B-octyl-9-BBN-2-picoline complex (6 mmol) in THF was added to the solids. The mixture was diluted with 5.9 ml anhydrous THF and treated with ethyl-4-brombutanoate (975 mg, 5.0 mmol). The black suspension was stirred for 22 h at room temperature, than hydrogen peroxide (H2O2, 30w%, 2 ml) was added and stirring was continued for another 10 minutes. After that, diethyl ether (20 ml), followed by water (5 ml) was added. The aqueous layer was separated from the organic layer and extracted twice with diethyl ether (2 x 15 ml). The combined organic layers were dried over sodium sulfate (Na2SU4), filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel (pure hexane) to result in 870 mg (73 %) of ethyl dodecanoate as a colorless oil.
All the references described above are incorporated by reference in its entirety for all useful purposes.
While there are shown and described certain specific structures embodying the invention, it will be manifest to those skilled in the art that various modifications and rearrangements of the parts may be made without departing from the spirit and scope of the underlying inventive concept and the same is not limited to the particular forms herein shown and described.
Claims
1. B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes with chemical structures according to the general formula (1 ),
wherein
R1 is an organyl comprising at least one carbon atom that is directly bound to the boron atom, and amine is a substituted pyridine of the formula (2)
wherein
R2 is Ci - Cio alkyl, Ci - Cs alkoxy or Ci - Cs-alkoxy-Ci - Cio alkyl, and R3 is hydrogen or a Ci - Cio alkyl, Ci - Cs alkoxy or Ci - Cs-alkoxy-Ci - Cio alkyl group, or an alkylamine of the formula (3)
R4R5NH (3), wherein
R4 is hydrogen or Ci - Cio alkyl, and - R5 is Ci - Cio alkyl.
2. B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes according to claim 1 , wherein the amine is a substituted pyridine of the formula (2).
3. B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes according to claim 1 , wherein the amine is 2-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine or 5-ethyl-2- methylpyridine.
4. B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes according to claim 1 , wherein R1 is -CH2CH3 or -CH2CH2-organyl.
5. B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes according to claim 1 , wherein R1 is Ci - C24 alkyl, C3 - C16 cycloalkyl, substituted alkyl, C2 - C22 alkenyl, C5 - Ci5 cycloalkenyl or C2 - C22 alkynyl.
6. B-organyl-9-borabicyclo[3.3.1]nonane-amine complexes according to claim 1 , wherein R1 is -CH2CH3 or -ChbChb-organyl and the amine is 2-picoline, 2,3- lutidine, 2,4-lutidine, 2,5-lutidine or 5-ethyl-2-methylpyridine.
7. A solution comprising at least one B-organyl-9-BBN-amine complex of the formula (1 ) and at least one solvent.
8. A solution according to claim 7, wherein the solvent is selected from the group, consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfide, 1 ,6- thioxane, toluene, hexane(s), heptane(s) and cyclohexane.
9. A process to synthesize a solution comprising at least one B-organyl-9-BBN-amine complex of the formula (1) and at least one solvent, comprising the steps of hy- droborating an alkene or an alkyne with a complex of 9-BBN and an amine of the formula (2) or (3) or hydroborating an alkene or an alkyne with 9-BBN or a 9-BBN-
Lewis base complex followed by adding an amine of the formula (2) or (3) in at least one solvent.
10. A process to synthesize a B-organyl-9-BBN-amine complex of the formula (1), comprising the step of hydroborating an alkene or an alkyne with a complex of 9-
BBN and an amine of the formula (2) or (3) or hydroborating an alkene or an alkyne with 9-BBN or a 9-BBN-Lewis base complex followed by adding an amine of the formula (2) or (3).
1 1. A process to synthesize a B-organyl-9-BBN-amine complex of the formula (1 ), comprising the steps of hydroborating an alkene or an alkyne with a complex of 9- BBN and an amine of the formula (2) or (3) or hydroborating an alkene or an alkyne with 9-BBN or a 9-BBN-Lewis base complex followed by adding an amine of the formula (2) or (3) in at least one solvent and isolating the complex from the formed solution.
12. Method of using B-organyl-9-BBN-amine complexes of the formula (1) in Suzuki- type cross-coupling reactions to form new carbon-carbon bonds.
13. Process to form new carbon-carbon bonds comprising a Suzuki-type cross- coupling reaction with a triorganoborane, which is carried out in the presence of an amine.
14. Process according to claim 13, wherein the triorganoborane is a B-organyl-9-BBN derivative.
15. Process according to claim 13, wherein the amine is a substituted pyridine of the formula (2) or an alkylamine of the formula (3).
16. Process to form new carbon-carbon bonds comprising the steps of hydroborating an alkene or alkyne with a diorganoborane-amine complex and using the resulting mixture of a triorganoborane and the amine in a Suzuki-type cross-coupling reac- tion.
17. Process according to claim 16, wherein the triorganoborane is a B-organyl-9-BBN derivative.
18. Process according to claim 16, wherein the amine is a substituted pyridine of the formula (2) or an alkylamine of the formula (3).
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| WO2012056458A2 (en) | 2010-10-28 | 2012-05-03 | Mapi Pharma Ltd. | Intermediate compounds and process for the preparation of fingolimod |
| US8735627B2 (en) | 2010-10-28 | 2014-05-27 | Mapi Pharma Ltd. | Intermediate compounds and process for the preparation of fingolimod |
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