WO2008080993A2 - A method for preparation of substituted adamantylarylmagnesium halides - Google Patents
A method for preparation of substituted adamantylarylmagnesium halides Download PDFInfo
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- WO2008080993A2 WO2008080993A2 PCT/EP2007/064648 EP2007064648W WO2008080993A2 WO 2008080993 A2 WO2008080993 A2 WO 2008080993A2 EP 2007064648 W EP2007064648 W EP 2007064648W WO 2008080993 A2 WO2008080993 A2 WO 2008080993A2
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- WIPO (PCT)
- Prior art keywords
- substituted
- reaction
- adamantylarylhalide
- adamantyl
- adamantylarylmagnesium
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 150000004820 halides Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 40
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 20
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 62
- 239000011777 magnesium Substances 0.000 claims description 12
- 229910052749 magnesium Inorganic materials 0.000 claims description 10
- -1 tetrafluoroborate Chemical compound 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 229910003002 lithium salt Inorganic materials 0.000 claims 5
- 159000000002 lithium salts Chemical class 0.000 claims 5
- 125000000217 alkyl group Chemical group 0.000 claims 3
- 239000012442 inert solvent Substances 0.000 claims 3
- 125000003342 alkenyl group Chemical group 0.000 claims 2
- 125000000304 alkynyl group Chemical group 0.000 claims 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 238000003747 Grignard reaction Methods 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 claims 1
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims 1
- 125000005530 alkylenedioxy group Chemical group 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- 150000001602 bicycloalkyls Chemical group 0.000 claims 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims 1
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 28
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 14
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 239000000047 product Substances 0.000 abstract description 10
- 239000012039 electrophile Substances 0.000 abstract description 9
- 229910052786 argon Inorganic materials 0.000 abstract description 7
- 239000007795 chemical reaction product Substances 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000004817 gas chromatography Methods 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- QQAMHHZQONQBFZ-UHFFFAOYSA-N 1-(5-bromo-2-methoxyphenyl)adamantane Chemical compound COC1=CC=C(Br)C=C1C1(C2)CC(C3)CC2CC3C1 QQAMHHZQONQBFZ-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 239000000758 substrate Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- HYSZKSPAPGPYFQ-UHFFFAOYSA-N 1-(2-methoxyphenyl)adamantane Chemical compound COC1=CC=CC=C1C1(C2)CC(C3)CC2CC3C1 HYSZKSPAPGPYFQ-UHFFFAOYSA-N 0.000 description 6
- 229960004132 diethyl ether Drugs 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- FRPWQGROGLXUPZ-UHFFFAOYSA-N 1-(4-bromo-2-methoxyphenyl)adamantane Chemical compound COC1=CC(Br)=CC=C1C1(C2)CC(C3)CC2CC3C1 FRPWQGROGLXUPZ-UHFFFAOYSA-N 0.000 description 5
- STGNTTPGWSZTMO-UHFFFAOYSA-N 1-(5-bromo-2,3-dimethoxyphenyl)adamantane Chemical compound COC1=CC(Br)=CC(C23CC4CC(CC(C4)C2)C3)=C1OC STGNTTPGWSZTMO-UHFFFAOYSA-N 0.000 description 5
- 150000001502 aryl halides Chemical class 0.000 description 5
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 description 4
- 229960002916 adapalene Drugs 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 150000002901 organomagnesium compounds Chemical class 0.000 description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 4
- 230000009257 reactivity Effects 0.000 description 4
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- 208000002874 Acne Vulgaris Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-ZSJDYOACSA-N Sulfuric acid-d2 Chemical compound [2H]OS(=O)(=O)O[2H] QAOWNCQODCNURD-ZSJDYOACSA-N 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000002734 organomagnesium group Chemical group 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 0 *c(cc1)cc(C2(CC(C3)C4)CC4CC3C2)c1OCc1ccccc1 Chemical compound *c(cc1)cc(C2(CC(C3)C4)CC4CC3C2)c1OCc1ccccc1 0.000 description 2
- SETWKWMHYWYXJD-UHFFFAOYSA-N 1-(5-bromo-2-methoxyphenyl)-3,5-dimethyladamantane Chemical compound COC1=CC=C(Br)C=C1C1(C2)CC(C)(C3)CC2(C)CC3C1 SETWKWMHYWYXJD-UHFFFAOYSA-N 0.000 description 2
- LDGIHZJOIQSHPB-UHFFFAOYSA-N CD437 Chemical compound C1C(C2)CC(C3)CC2CC13C1=CC(C2=CC3=CC=C(C=C3C=C2)C(=O)O)=CC=C1O LDGIHZJOIQSHPB-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- HOXDQGKKENOCRK-UHFFFAOYSA-M [Br-].C1C(C2)CC(C3)CC2CC13C1=CC([Mg+])=CC=C1OCC1=CC=CC=C1 Chemical compound [Br-].C1C(C2)CC(C3)CC2CC13C1=CC([Mg+])=CC=C1OCC1=CC=CC=C1 HOXDQGKKENOCRK-UHFFFAOYSA-M 0.000 description 2
- 150000004792 aryl magnesium halides Chemical class 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 2
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- VVUPACZQIRRDLY-UHFFFAOYSA-N 1-(2,3-dimethoxyphenyl)adamantane Chemical compound COC1=CC=CC(C23CC4CC(CC(C4)C2)C3)=C1OC VVUPACZQIRRDLY-UHFFFAOYSA-N 0.000 description 1
- INULLDUIYAKZOH-UHFFFAOYSA-N 1-(4-bromo-2-phenylmethoxyphenyl)adamantane Chemical compound C=1C(Br)=CC=C(C23CC4CC(CC(C4)C2)C3)C=1OCC1=CC=CC=C1 INULLDUIYAKZOH-UHFFFAOYSA-N 0.000 description 1
- GVLSPHCBVZUIKP-UHFFFAOYSA-N 1-(5-bromo-2-phenylmethoxyphenyl)adamantane Chemical compound C1C(C2)CC(C3)CC2CC13C1=CC(Br)=CC=C1OCC1=CC=CC=C1 GVLSPHCBVZUIKP-UHFFFAOYSA-N 0.000 description 1
- GJLGGECBUUNDNQ-UHFFFAOYSA-N 2-(4-phenylphenyl)prop-2-enoic acid Chemical class C1=CC(C(=C)C(=O)O)=CC=C1C1=CC=CC=C1 GJLGGECBUUNDNQ-UHFFFAOYSA-N 0.000 description 1
- OYGKAJLOXWVEGP-UHFFFAOYSA-N 4-(1-adamantyl)-6-bromo-1,3-benzodioxole Chemical compound C1C(C2)CC(C3)CC2CC13C1=CC(Br)=CC2=C1OCO2 OYGKAJLOXWVEGP-UHFFFAOYSA-N 0.000 description 1
- HLCHVOWKVJPMPY-UHFFFAOYSA-N CC1=CC[IH]C=C1 Chemical compound CC1=CC[IH]C=C1 HLCHVOWKVJPMPY-UHFFFAOYSA-N 0.000 description 1
- UGTJLJZQQFGTJD-UHFFFAOYSA-N Carbonylcyanide-3-chlorophenylhydrazone Chemical compound ClC1=CC=CC(NN=C(C#N)C#N)=C1 UGTJLJZQQFGTJD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- HHDOELPGMRBQJZ-UHFFFAOYSA-N [2-(1-adamantyl)-5-bromophenoxy]-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC(Br)=CC=C1C1(C2)CC(C3)CC2CC3C1 HHDOELPGMRBQJZ-UHFFFAOYSA-N 0.000 description 1
- FPZOBRFHRPQGAA-UHFFFAOYSA-N [3-(1-adamantyl)-4-methoxyphenyl]boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1C1(C2)CC(C3)CC2CC3C1 FPZOBRFHRPQGAA-UHFFFAOYSA-N 0.000 description 1
- YBJABQLZUJNFKS-UHFFFAOYSA-N [3-(1-adamantyl)-4-methoxyphenyl]methanol Chemical compound COC1=CC=C(CO)C=C1C1(C2)CC(C3)CC2CC3C1 YBJABQLZUJNFKS-UHFFFAOYSA-N 0.000 description 1
- UVRUWTVOTRHEDA-UHFFFAOYSA-N [4-(1-adamantyl)-3-methoxyphenyl]boronic acid Chemical compound COC1=CC(B(O)O)=CC=C1C1(C2)CC(C3)CC2CC3C1 UVRUWTVOTRHEDA-UHFFFAOYSA-N 0.000 description 1
- AIYARUNZTVUMQC-UHFFFAOYSA-M [Br-].CC(C)(C)[Si](C)(C)OC1=CC=C([Mg+])C=C1C1(C2)CC(C3)CC2CC3C1 Chemical group [Br-].CC(C)(C)[Si](C)(C)OC1=CC=C([Mg+])C=C1C1(C2)CC(C3)CC2CC3C1 AIYARUNZTVUMQC-UHFFFAOYSA-M 0.000 description 1
- CMFAVTSZPVDNME-UHFFFAOYSA-M [Br-].COC1=CC=C([Mg+])C=C1C1(C2)CC(C3)CC2CC3C1 Chemical compound [Br-].COC1=CC=C([Mg+])C=C1C1(C2)CC(C3)CC2CC3C1 CMFAVTSZPVDNME-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 102000003702 retinoic acid receptors Human genes 0.000 description 1
- 108090000064 retinoic acid receptors Proteins 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960001727 tretinoin Drugs 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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Definitions
- the present invention concerns fine organic synthesis, particularly the method for preparing of substituted adamantylarylmagnesium halides.
- Organomagnesium compounds are especially important in contemporary preparative organic chemistry. Since Grignard's discovery in 1900 the methods for preparing and further transformation of these synthetic intermediates are in continuous development and expansion.
- the standard preparative method for preparing organomagnesium compounds (Grignard's reagents) is direct interaction of organic halides with metallic magnesium in an aprotic polar solvent, like tetrahydrofuran (THF) or diethyl ether [C. T. Ho ⁇ e, A. H. HecMeaHOB Me ⁇ o ⁇ bi aneivieHTO - opraHMHecKOM XMMMM. MamnM, ⁇ epunnuM, ⁇ aj ⁇ ibL_,MM, CTPOHUMM, ⁇ apuM. H3fl. AH CCCP M. 1963, 14-27].
- the aim of the present invention is a development of method for preparing substituted adamantylarylmagnesium halides, satisfying the following requirements:
- the compounds produced are active intermediates that can interact with various electrophiles to yield substrates useful for the synthesis of a wide range of biologically active compounds [Charpentier, B.; Bernardon, J.-M.; Eustache, J. et al. Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes. J. Med. Chem. 1995, 38 (26), 4993-5006. Cincinelli, R.; Dallavalle, S.; Nannei, R. Synthesis and structure-activity relationships of a new series of retinoid-related biphenyl-4-ylacrylic acids endowed with antiproliferative and proapoptotic activity. J. Med. Chem.
- Adapalene is a pharmaceutical widely used in dermatology as efficient agent for treating acne vulgaris [Waugh, J.; Noble, S.; Scott, L. Spotlight on adapalene in acne vulgaris. J. Am. J. Clin. Dermatol. 2004, 5 (5), 369- 371 ; Jain, S. Topical tretinoin or adapalene in acne vulgaris:
- 3-(1 -Adamantyl)-4-(fe/t-butyldimethylsilyloxy)phenylmagnesium bromide or 3-(1 -adamantyl)-4-benzyloxy- phenylmagnesium bromide can also be used for synthesis of 4-[3-(1 -adamantyl)-4-hydroxyphenyl]-3- chlorocynnamic acid (3-CI-AHPC),
- the reduction of adamantylaryl halide as the main reaction of starting material under the conditions of Grignard's reaction may be the result of the instability of the adamantylarylmagnesium halide or the consequence of low reactivity of the Grignard's reactant with the employed electrophile.
- Grignard's reagent formed from 2-(1- adamantyl)-4-bromoanisole, is an unstable substance and undergoes a formal reduction before interaction with any electrophile.
- the closest prior art to the present invention is the exchange method for preparing organomagnesium reagent [Krasovskiy, A.; Knochel, P. A LiCI-mediated Br/Mg exchange reaction for the preparation of functionalized aryl - and heteroarylmagnesium compounds from organic bromides.
- This method is based on preparing of AIkMgCI-LiCI or AIk 2 Mg-LiCI complexes and their interaction with substituted aryl or heteroaryl halides.
- the present method for preparing substituted adamantyl- arylmagnesium halides is based on assumption that under the standard conditions of organomagnesium synthesis, i.e., acting by aryl halides on magnesium metal, the addition of lithium chloride stabilizes the substituted adamantylarylmagnesium halide by complex formation and prevents further unwanted reactions but does not fatally depress the reactivity of the substituted adamantylarylmagnesium halide.
- Example 1 The method according to the present invention is illustrated by the following examples.
- Example 1 The method according to the present invention is illustrated by the following examples.
- the reaction mixture is decomposed with a solution of 50 ml_ of hydrochloric acid in 50 ml_ water with vigorous stirring without external cooling.
- the mixture is transferred to separating funnel and the water and organic layers separated.
- To the water layer 200 ml_ of water is added and then extracted twice with 10O mL of diethylether.
- the pooled organic solutions are dried on anhydrous sodium sulfate, the solvents removed in vacuo at about 50 0 C in the water bath.
- the residue is treated with 200 ml_ of hexane and left in the freezer overnight.
- the precipitate is filtered off, washed with cold ethyl acetate and dried at 100 0 C. 3-(1 -adamantyl)-4-methoxyphenylboronic acid with m.p.
- the compound was isolated and identified as 2-(1 - adamantyl)anisole.
- the preparative yield is 67%, m.p. 100-102 0 C.
- Example 2 Reaction is performed as described in Example 1.
- adamantylarylhalide 5O g (0.16 M) of 2-(1 -adamantyl)-5-bromoanisole is used.
- 4-(1-adamantyl)-3-methoxyphenylboronic acid, 3 g (6.8%) is obtained.
- the gas chromatography data give the yield 2-(1 - adamantyl)anisole as 81 %.
- the formal reduction product of 2-(1 -adamantyl)-5-bromoanisole was isolated and its identity with 2-(1-adamantyl)anisole obtained in Example 1 confirmed, thus confirming the structure ascribed.
- Example 3 Reaction is performed as described in Example 1.
- adamantylarylhalide 56 g (0.16 M) of 3-(1-adamantyl)-5-bromoveratrol is used.
- 3-(1 -adamantyl)-4,5-methoxyphenylboronic acid 3.7 g (7.3%) is obtained.
- the gas chromatography data give the yield 3-(1 - adamantyl)veratrol as 74%.
- Example 5 Reaction is performed as described in Example 1. Simultaneous addition of arylhalide and 1 ,2-dibromoethane did not change the result.
- reaction mixture according to gas chromatography data contains 70-75% of adamantylbenzene derivative and 3-11 % of the expected arylphenylmethanol
- Grignard's reagent was prepared from 51 g (0.16 M) of 2-(1 - adamantyl)-4-bromoanisole as in Example 1.
- 17 g (16.5 ml_, 0.16 M) of benzaldehyde and 10O mL of dry tetrahydrofuran was introduced, the solution cooled to 0 0 C and under stirring the solution of the Grignard's reagent added within 10 min.
- the mixture was left for 16 h in a refrigerator at about 0 0 C.
- the reaction mixture is decomposed with a solution of 25 ml_ of hydrochloric acid in 25 ml_ of water with vigorous stirring without external cooling.
- the mixture is transferred to separating funnel and the water and organic layers separated, the water layer extracted with 2 portions of 100 ml_ of diethyl ether.
- the pooled organic layers were dried over sodium sulfate.
- Grignard's reagent was prepared from 10 g (0.032 M) of 2-(1 - adamantyl)-4-bromoanisole as in Example 1.
- As the electrphile for functionalization and identification a mixture of D 2 SO 4 - D 2 O was used.
- reaction mixture is decomposed with a solution of 2 ml_ of
- Example 8 (according to prior art) Into a 200 ml_ flask with a magnetic stirrer and dropping funnel 5.14 g (0.016 M) of 2-(1 -adamantyl)-4-bromoanisole and 60 ml_ of dry tetrahydrofuran is introduced. The air in the flask is displaced by argon and all further operations conducted under a slight stream of the inert gas. The mixture is cooled to -5 0 C and 3 Eq of 0.5 M iso-PrMgCI LiCL solution in tetrahydrofuran added, keeping the reaction temperature within -5 - O 0 C range.
- iso-PrMgCI LiCL solution in tetrahydrofuran was prepared beforehand, its concentration determined by titration according to [Krasovskiy, A.; Knochel, P. Convenient titration method for organometallic zinc, magnesium, and lanthanide reagents. Synthesis 2006, 5, 890-891].
- Example 12 Reaction is performed as described in Example 11.
- the Ghgnard's reagent is produced with 0.07g (0.0016 M, 1 eq.) of pulverized anhydrous LiCI.
- the molar rate of substrate ⁇ iCI is 1 :0.1. Yield, according to gas chromatography data is 16%.
- Reaction is performed as described in Example 11.
- the Ghgnard's reagent is produced with 0.34 g (0.008 M) of pulverized anhydrous LiCI.
- the molar rate of substrate ⁇ iCI is 1 :0.5. Yield, according to gas chromatography data is 30%.
- Example 15 Reaction is performed as described in Example 11.
- the Ghgnard's reagent is produced with 0.68 g (0.016 M) of pulverized anhydrous LiCI.
- the molar rate of substrate ⁇ iCI is 1 :1. Yield, according to gas chromatography data is 75%.
- Example 15
- Example 20 Reaction is performed as described in Example 18.
- the Grignard's reagent is produced with 0.68 g (0.016 M) of pulverized anhydrous LiCI.
- the molar rate of substrate ⁇ iCI is 1 :1. Yield, according to gas chromatography data is 74%.
- Example 31 Reaction is performed as described in Example 11.
- adamantylarylhalide 6.35 g (0.016 M) of 3-benzyloxy-4-(1 - adamantyl)brombenzene is used.
- Example 37 Reaction is performed as described in Example 11.
- adamantylarylhalide 7.18 g (0.016 M) of 3-(tert-butyldimethylsilyloxy)-4-[1 - (3,5-dimethyladamantyl)brombenzene is used.
- Example 42 Reaction is performed as described in Example 11.
- adamantylarylhalide 5.84 g (0.016 M) of 3-[2-(2-methyladamantyl)-5- bromoveratrol is used.
- the present method for preparation of substituted adamantylarylmagnesium halides is characterized by stable high yields, technological feasibility and possibility to scale up the reaction volume.
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Abstract
The present invention concerns fine organic synthesis, particularly the method for preparing of substituted adamantylarylmagnesium halides. The known methods for preparing Grignard's reagent from substituted adamantylarylhalide give very low yeld of the desired product. Substituted adamantylarylhalides are active intermediates that by interacting with various electrophiles provide for a wide range of biologically active compounds. The aim of current invention was to develop a method for preparing substituted adamantylarylmagnesium halides. The aim was attained adding lithium chloride in the Grignard's reagent synthesis by acting on magnesium metal in dry tetrahydrofuran under argon by substituted adamantylarylhalide. It was demonstrated that adding lithium chloride to adamantylarylhalide within a range from 1:1 to 1:2 provides for stable high yield of the desired end product.
Description
A METHOD FOR PREPARATION OF SUBSTITUTED ADAMANTYLARYLMAGNESIUM HALIDES
The present invention concerns fine organic synthesis, particularly the method for preparing of substituted adamantylarylmagnesium halides. Organomagnesium compounds are especially important in contemporary preparative organic chemistry. Since Grignard's discovery in 1900 the methods for preparing and further transformation of these synthetic intermediates are in continuous development and expansion. The standard preparative method for preparing organomagnesium compounds (Grignard's reagents) is direct interaction of organic halides with metallic magnesium in an aprotic polar solvent, like tetrahydrofuran (THF) or diethyl ether [C. T. Hoφφe, A. H. HecMeaHOB Meτoβbi aneivieHTO - opraHMHecKOM XMMMM. MamnM, δepunnuM, κaj~ibL_,MM, CTPOHUMM, δapuM. H3fl. AH CCCP M. 1963, 14-27].
The aim of the present invention is a development of method for preparing substituted adamantylarylmagnesium halides, satisfying the following requirements:
- stable high yields of the product - possibility of substantial scaling up
- simple technology.
The compounds produced are active intermediates that can interact with various electrophiles to yield substrates useful for the synthesis of a wide range of biologically active compounds [Charpentier, B.; Bernardon, J.-M.; Eustache, J. et al. Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes. J. Med. Chem. 1995, 38 (26), 4993-5006. Cincinelli, R.; Dallavalle, S.; Nannei, R. Synthesis and structure-activity relationships of a new series of retinoid-related biphenyl-4-ylacrylic acids endowed with antiproliferative and proapoptotic activity. J. Med. Chem. 2005, 48 (15), 4931-4946. Pfahl, M.; Tachdjian, C. et al. Heterocyclic derivatives for the treatment of cancer and other proliferative diseases. US 2002/0143182 A1]
An important representative of substituted adamantylarylmagnesium halides is 3-(1-adamantyl)-4-methoxyphenylmagnesium bromide
Adapalene is a pharmaceutical widely used in dermatology as efficient agent for treating acne vulgaris [Waugh, J.; Noble, S.; Scott, L. Spotlight on adapalene in acne vulgaris. J. Am. J. Clin. Dermatol. 2004, 5 (5), 369- 371 ; Jain, S. Topical tretinoin or adapalene in acne vulgaris:
No less important representative is 3-(1 -adamantyl)-4-(tert- butyldimethylsilyloxy)phenylmagnesium bromide
3-(1 -Adamantyl)-4-(fe/t-butyldimethylsilyloxy)phenylmagnesium bromide or 3-(1 -adamantyl)-4-benzyloxy- phenylmagnesium bromide can also be used for synthesis of 4-[3-(1 -adamantyl)-4-hydroxyphenyl]-3- chlorocynnamic acid (3-CI-AHPC),
that like 6-[3-(1 -adamantyl)-4-hydroxyphenyl]-2-naphtoic acid (AHPN, CD 437) is patented as anti-tumour agent [Dawson, M.; Fontana, J.; Zhang, X. et al. Induction of apoptosis in cancer cells. WO 03/048101 A1].
Synthesis of substituted adamantylarylmagnesium halides containing electrodonor substituents in the aromatic ring by classical method, i.e., by interaction or arylhalide with metallic magnesium in aprotic polar solvent, like THF or diethyl ether, gives yields not exceeding 11 %.
The main reaction product results from reduction of arylhalide. Thus 2-(1- adamantyl)-4-bromoanisole yields 2-(1 -adamantyl)anisole in 78% yield (see Example 1 ).
Gass chromatographic analysis of reaction mixture confirmed complete conversion of 2-(1-adamantyl)-4-bromoanisole. It means that the starting material is reacting very efficiently with metallic magnesium under the conditions of classic Ghgnard's reaction.
Similar experiments with 2-(1-adamantyl)-5-bromoanisole yielded similar results (see Example 2)
and with 3-(1 -adamantyl)-5-bromovertrol (see Example 3).
The reduction of adamantylaryl halide as the main reaction of starting material under the conditions of Grignard's reaction may be the result of the instability of the adamantylarylmagnesium halide or the consequence of low reactivity of the Grignard's reactant with the employed electrophile.
Changing the temperature and reaction time in preparing the Grignard's reactant practically did not lead tod to any substantial change in composition of reaction products. See Example 4. The addition method (simultaneous addition of the starting arylbromide and dibromoethane), [D.E.Pearson et al., J.Org.Chem., 24, 504 (1959)] did not give positive result. See Example 5
Changing the organic electrophile did not substantially change the rate of products: reduction product/substituted adamantylarylmagnesium bromide (See Example 6). Use of inorganic electrophile like D2SO4 - D2O, preventing the possible interaction of adamantylarylmagnesium halide with organic electrophile yielded a similar result. Thus decomposing of Grignard's reagent prepared from 2-(1 -adamantyl)-4-bromoanisole with a
-A-
mixture of D2SO4 - D2O yields a mixture of products where the content of deuterated 2-(1 -adamantyl)-anisole,
These results show that Grignard's reagent, formed from 2-(1- adamantyl)-4-bromoanisole, is an unstable substance and undergoes a formal reduction before interaction with any electrophile.
The closest prior art to the present invention is the exchange method for preparing organomagnesium reagent [Krasovskiy, A.; Knochel, P. A LiCI-mediated Br/Mg exchange reaction for the preparation of functionalized aryl - and heteroarylmagnesium compounds from organic bromides. Angew. Chem. Int. Ed. 2004, 43 (25), 3333-3336; Knochel, P. Krasovskiy, A. Method of preparing organomagnesium compound. EP 1582523 (2005). Krasovskiy, A.; Straub, B. F.; Knochel, P. Highly efficient reagents for Br/Mg exchange. Angew. Chem. Int. Ed. 2006, 45 (1 ), 159- 162.]. This method is based on preparing of AIkMgCI-LiCI or AIk2Mg-LiCI complexes and their interaction with substituted aryl or heteroaryl halides.
Nevertheless the reaction of 2-(1 -adamantyl)-4-bromonisole (See Example 8 - according to prior art) and 3-(1 -adamantyl)-5-bromoveratrol (See Example 9 - according to prior art) with iso-PrMgCI LiCI under the conditions given in prior art, gave a conversion of 6 to 9% within 2 days time.
Thus the experimental data confirmed both the instability of substituted adamantylarylmagnesium halide and the low reactivity of substituted adamantylarylmagnesium halide in the exchange synthesis reaction, using iso-PrMgCI LiCI.
While investigating the preparation of arylmagnesium halides with electrodonor substituents in the ring, some authors [Krasovskiy, A.; Straub, B. F.; Knochel, P. Highly efficient reagents for Br/Mg exchange. Angew. Chem. Int. Ed. 2006, 45 (1 ), 159-162] have used reactants with higher reactivity in the exchange synthesis of organomagnesium compounds, therefore the equilibrium in Schlenk's equation
2 iso-PrMgCI LiCI *→ JSO-Pr2MgCI + MgCI2 + LiCI
was shifted to iso-Pr2MgCI-LiCI or dialkylmagnesium derivative by capturing MgCI2 with various reactants, like dioxan.
Using this method in preparing the organomagnesium derivative from 2-(1 -adamantyl)-4-bromoanisole (See Example 10 - according to prior art) gave ar 13% conversion after 2 days time.
The results obtained show that the most active reactant in preparing organometallic derivatives from adamantylarylhalides is magnesium metal, but the adamantylarylmagnesium halide formed should be stabilized to prevent further unwanted reactions.
The previously stated aim, i.e., developing of an efficient and technologically feasible method for preparing substituted adamantyl- arylmagnesium halides was attained, using lithium chloride in the process of synthesizing the Grignard's reagent - when reacting magnesium metal with substituted adamantylarylhalides under argon in anhydrous THF. (See Examples 10 - 41 ).
The present method for preparing substituted adamantyl- arylmagnesium halides is based on assumption that under the standard conditions of organomagnesium synthesis, i.e., acting by aryl halides on magnesium metal, the addition of lithium chloride stabilizes the substituted adamantylarylmagnesium halide by complex formation and prevents further unwanted reactions but does not fatally depress the reactivity of the substituted adamantylarylmagnesium halide.
The method according to the present invention is illustrated by the following examples. Example 1
Into a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel 8 g (0.33 M) of magnesium filings are introduced and 200 ml_ of dry tetrahydrofuran added. The air in the flask is displaced by argon and all further operations conducted under a slight stream of the inert gas. Under vigorous stirring 11 g (5 ml_, 0.06 M) of 1 ,2- dibromoethane is added. After the vigorous reaction had subsided, the hot reaction mixture is treated with a solution of 5O g (0.16 M) 2-(1 - adamantyl)-4-bromoanisole in 400 ml_ of dry tetrahydrofuran with such speed that a slight reflux is supported. After the adding of all solution of 2- (1 -adamantyl)-4-bromoanisole, the reaction mixture is refluxed for another 30 min. Stirring is discontinued and the solution of the prepared Grignard's reagent decanted from the residual magnesium into a conical flask with ground stopper flushed in advance with argon. For further functionalization reactions trimethylborate, a standard reactant for preparing phenylboronic acids was used.
In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel a solution of 33 g (36 ml_, 0.35 M) of trimethylborate in 10O mL of dry tetrahydrofuran is prepared, the solution cooled to -5O0C
and under vigorous stirring the solution of the Grignard's reagent is added within 30 min at -40 to - 50 0C.
The reaction mixture is decomposed with a solution of 50 ml_ of hydrochloric acid in 50 ml_ water with vigorous stirring without external cooling. The mixture is transferred to separating funnel and the water and organic layers separated. To the water layer 200 ml_ of water is added and then extracted twice with 10O mL of diethylether. The pooled organic solutions are dried on anhydrous sodium sulfate, the solvents removed in vacuo at about 50 0C in the water bath. The residue is treated with 200 ml_ of hexane and left in the freezer overnight. The precipitate is filtered off, washed with cold ethyl acetate and dried at 100 0C. 3-(1 -adamantyl)-4-methoxyphenylboronic acid with m.p.
~300°C is obtained, yield 2.5 g (5.7%). The gas chromatographic analysis of the reaction mixture showed one main product. The yield, according to gas chromatography data is 78%.
The compound was isolated and identified as 2-(1 - adamantyl)anisole.
The preparative yield is 67%, m.p. 100-102 0C.
Example 2 Reaction is performed as described in Example 1. As the adamantylarylhalide 5O g (0.16 M) of 2-(1 -adamantyl)-5-bromoanisole is used. 4-(1-adamantyl)-3-methoxyphenylboronic acid, 3 g (6.8%) is obtained. The gas chromatography data give the yield 2-(1 - adamantyl)anisole as 81 %. The formal reduction product of 2-(1 -adamantyl)-5-bromoanisole was isolated and its identity with 2-(1-adamantyl)anisole obtained in Example 1 confirmed, thus confirming the structure ascribed.
Example 3 Reaction is performed as described in Example 1. As the adamantylarylhalide 56 g (0.16 M) of 3-(1-adamantyl)-5-bromoveratrol is used. 3-(1 -adamantyl)-4,5-methoxyphenylboronic acid, 3.7 g (7.3%) is obtained. The gas chromatography data give the yield 3-(1 - adamantyl)veratrol as 74%.
Example 4.
Reaction is performed as described in Example 1. Variation of temperature and reaction time did not change the result.
Example 5. Reaction is performed as described in Example 1. Simultaneous addition of arylhalide and 1 ,2-dibromoethane did not change the result.
Use of benzaldehyde as electrophile that quantitatively reacts with the arylmagnesium halide yielding arylphenylmethanol gave the same result. The reaction mixture, according to gas chromatography data contains 70-75% of adamantylbenzene derivative and 3-11 % of the expected arylphenylmethanol
Example 6
Grignard's reagent was prepared from 51 g (0.16 M) of 2-(1 - adamantyl)-4-bromoanisole as in Example 1. In the next step into a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel 17 g (16.5 ml_, 0.16 M) of benzaldehyde and 10O mL of dry tetrahydrofuran was introduced, the solution cooled to 0 0C and under stirring the solution of the Grignard's reagent added within 10 min. The mixture was left for 16 h in a refrigerator at about 0 0C.
The reaction mixture is decomposed with a solution of 25 ml_ of hydrochloric acid in 25 ml_ of water with vigorous stirring without external cooling. The mixture is transferred to separating funnel and the water and organic layers separated, the water layer extracted with 2 portions of 100 ml_ of diethyl ether. The pooled organic layers were dried over sodium sulfate.
The yield of 3-(1 -adamantyl)-4-methoxyphenylmethanol
Example 7
Grignard's reagent was prepared from 10 g (0.032 M) of 2-(1 - adamantyl)-4-bromoanisole as in Example 1. As the electrphile for functionalization and identification a mixture of D2SO4- D2O was used.
The reaction mixture is decomposed with a solution of 2 ml_ of
D2SO4 in 10 ml_ of heavy water with vigorous stirring without external cooling. The mixture is transferred to separating funnel and the water and organic layers separated, the water layer extracted with 2 portions of
50 ml_ of diethyl ether. The pooled organic layers were dried on sodium sulfate and the solvent removed completely in vacuo.
Example 8 (according to prior art) Into a 200 ml_ flask with a magnetic stirrer and dropping funnel 5.14 g (0.016 M) of 2-(1 -adamantyl)-4-bromoanisole and 60 ml_ of dry tetrahydrofuran is introduced. The air in the flask is displaced by argon and all further operations conducted under a slight stream of the inert gas. The mixture is cooled to -50C and 3 Eq of 0.5 M iso-PrMgCI LiCL solution in tetrahydrofuran added, keeping the reaction temperature within -5 - O0C range. iso-PrMgCI LiCL solution in tetrahydrofuran was prepared beforehand, its concentration determined by titration according to [Krasovskiy, A.; Knochel, P. Convenient titration method for organometallic zinc, magnesium, and lanthanide reagents. Synthesis 2006, 5, 890-891].
After adding the solution of iso-PrMgCI LiCL in tetrahydrofuran, the reaction mixture was kept for 1 h at 0 0C and left at room temperature for 48 h.
The gas chromatography data give the conversion of 2-(1 -adamantyl)- 4-bromoanisole as 9%.
Example 9 (according to prior art)
Reaction is performed as described in Example 8. As the adamantylarylhalide 5.62 g (0.016 M) of 3-(1 -adamantyl)-5-bromoveratrol is used.
The gas chromatography data give the conversion of 3-(1 - adamantyl)-5-bromoveratrol as 6%.
If the reaction is performed in a mixture of tetrahydrofuran and dioxan (dioxan 10% v/v), the conversion of adamantylarylhalide is increased only slightly.
Example 10 (according to prior art)
Reaction is performed as described in Example 8. As the solvent for 5.14 g (0.016 M) of 2-(1-adamantyl)-4-bromoanisole a mixture of 54 mL of tetrahydrofuran and 6 mL dioxan is used.
The gas chromatography data give the conversion of 2-(1 - adamantyl)-4-bromoanisole as 13%. Example 11
Into a 10O mL flask equipped with a magnetic stirrer, a reflux condenser and a dropping funnel 1 g (0.042 M) of magnesium filings are introduced and 20 mL of dry tetrahydrofuran added. Pulverized anhydrous lithium chloride, 0.81 g (0.019 M) is added. The air in the flask is displaced by argon and all further operations conducted under a slight stream of the inert gas. Under vigorous stirring 1.1 g (0.5 mL, 0.006 M) of 1 ,2-
dibromoethane is added. After the vigorous reaction had subsided, the hot reaction mixture is treated dropwise within 30 min with 5.14 g (0.016 M) of 2-(1-adamantyl)-4-bromoanisole in 40 ml_ of dry tetrahydrofuran, keeping the reaction mixture at 55 - 60 0C. The mixture is then kept at slight reflux for another 30 min. Stiring is discontinued and the solution of the prepared Grignard's reagent decanted from the residual magnesium into a conical flask with ground stopper flushed in advance with argon. The flask is closed with a stopper and kept at 0 0C for 2 h.
Into a 250 ml_ flask equipped with a magnetic stirrer, a reflux condenser and a dropping funnel a solution of 3.4 g (3.3 ml_, 0.032 M) of benzaldehyde in 20 ml_ of dry tetrahydrofuran is introduced, the solution cooled to 0 0C and under constant stirring the solution of the Grignard's reagent is added within 10 min. The mixture is left in a refrigerator at about O 0C for 16 h. The reaction mixture is decomposed with a solution of 5 ml_ of HCI in 5 ml_ of water with vigorous stirring without external cooling. The mixture is transferred to separating funnel and the water and organic layers separated, the water layer extracted with 2 portions of 20 m L of diethyl ether. The pooled organic layers were dried over sodium sulfate. 3-(1- Adamantyl)-4-methoxyphenyl)phenylethanol, 88% (gas chromatography data) is obtained.
Experimentally the optimal rate of the substituted adamantylarylhalide and lithium chloride in the Grignard's reaction was determined as 1 :1.2. The results in Table 1 (Examples 4, 10, 11 -12) show that increasing of the molar rate of lithium chloride from 0.1 to 1.2 the yield of the Grignard's reagent increases, but the further increase to 2 equivalents does not substantially increase the yield of Grignard's reagent.
Table 1. The influence of the rate of arylhalide and lithium chloride on the ield of ar lma nesium halide
Example 12 Reaction is performed as described in Example 11. The Ghgnard's reagent is produced with 0.07g (0.0016 M, 1 eq.) of pulverized anhydrous LiCI. The molar rate of substrate±iCI is 1 :0.1. Yield, according to gas chromatography data is 16%.
Example 13
Reaction is performed as described in Example 11. The Ghgnard's reagent is produced with 0.34 g (0.008 M) of pulverized anhydrous LiCI. The molar rate of substrate±iCI is 1 :0.5. Yield, according to gas chromatography data is 30%.
Example 14
Reaction is performed as described in Example 11. The Ghgnard's reagent is produced with 0.68 g (0.016 M) of pulverized anhydrous LiCI. The molar rate of substrate±iCI is 1 :1. Yield, according to gas chromatography data is 75%.
Example 15
Reaction is performed as described in Example 11. The Grignard's reagent is produced with 1.02 g (0.024 M) of pulverized anhydrous LiCI. The molar rate of substrate±iCI is 1 :1.5. Yield, according to gas chromatography data is 87%.
Example 16
Reaction is performed as described in Example 11. The Grignard's reagent is produced with 1.36 g (0.032 M) of pulverized anhydrous LiCI. The molar rate of substrate±iCI is 1 :2. Yield, according to gas chromatography data is 85%.
Example 17
Reaction is performed as described in Example 11. As the starting adamantylarylhalide 5.58 g (0.016 M) of 2-(3,5-dimethyladamantyl)-4- bromoanisole is used. Reaction was performed without adding LiCI. (3-[1-
(3,5-dimethyladamantyl)-4-methoxyphenyl)phenylethanol, 13% (gas chromatography data) is obtained. Example 18
Reaction is performed as described in Example 11. As the starting adamantylarylhalide 5.58 g (0.016 M) of 2-(3,5-dimethyladamantyl)-4- bromoanisole is used. Pulverized anhydrous lithium chloride, 0.07 g (0.0016 M) is used in the Grignard's reaction. The molar rate of substrate±iCI is 1 :0.1. Yield, according to gas chromatography data is 18%.
Example 19
Reaction is performed as described in Example 18. The Grignard's reagent is produced with 0.34 g (0.008 M) of pulverized anhydrous LiCI. The molar rate of substrate±iCI is 1 :0.5. Yield, according to gas chromatography data is 34%.
Example 20 Reaction is performed as described in Example 18. The Grignard's reagent is produced with 0.68 g (0.016 M) of pulverized anhydrous LiCI. The molar rate of substrate±iCI is 1 :1. Yield, according to gas chromatography data is 74%.
Example 21
Reaction is performed as described in Example 18. The Grignard's reagent is produced with 0.81 g (0.019 M) of pulverized anhydrous LiCI. The molar rate of substrate±iCI is 1 :1.2. Yield, according to gas chromatography data is 89%.
Example 22
Reaction is performed as described in Example 18. The Grignard's reagent is produced with 1.02 g (0.024 M) of pulverized anhydrous LiCI. The molar rate of substrate±iCI is 1 :1.5. Yield, according to gas chromatography data is 89%.
Example 23
Reaction is performed as described in Example 18. The Grignard's reagent is produced with 1.36 g (0.032 M) of pulverized anhydrous LiCI. The molar rate of substrate±iCI is 1 :2. Yield, according to gas chromatography data is 84%.
The present method for preparation of adamantylarylmagnesium halides was tested with various substrates. The molar rate of adamantylarylhalide and lithium chloride used was 1 :1.2. As the electrophile benzaldehyde was used. The yield was determined by gas chromatography (Examples 11 , 21 , 24-43). The results are given in Table 2.
able 2. The yield of adamantylarylhalide at the molar rate of adamantylarylhalide and lithium chloride 1 :1.2
able 2 (continued)
Example 24
Reaction is performed as described in Example 11. As the starting adamantylarylhalide 5.36 g (0.016 M) of 2-[2-(2-methyladamantyl)]-4- bromoanisole is used.
Yield, according to gas chromatography data is 84%.
Example 25
Reaction is performed as described in Example 11. As the adamantylarylhalide 5.14 g (0.016 M) of 2-(1 -adamantyl)-5-bromoanisole is used.
Yield, according to gas chromatography data is 92%.
Example 26
Reaction is performed as described in Example 11. As the starting adamantylarylhalide 5.6 g (0.016 M) of 2-[1 -(3,5-dimethyladamantyl)]-5- bromoanisole is used.
Yield, according to gas chromatography data is 91 %.
Example 27
Reaction is performed as described in Example 11. As the starting adamantylarylhalide 5.36 g (0.016 M) of 2-[2-(2-methyladamantyl)-5- bromoanisole is used.
Yield, according to gas chromatography data is 90%.
Example 28
Reaction is performed as described in Example 11. As the adamantylarylhalide 6.35 g (0.016 M) of 3-(1 -adamantyl)-4- benzyloxybrombenzene is used. Yield, according to gas chromatography data is 92%.
Example 29
Reaction is performed as described in Example 11. As the starting adamantylarylhalide 6.8 g (0.016 M) of 3-[1 -(3,5-dimethyladamantyl)]-4- benzyloxybrombenzene is used.
Yield, according to gas chromatography data is 90%.
Example 30
Reaction is performed as described in Example 11. As the starting adamantylarylhalide 6.58 g (0.016 M) of 3-[2-(2-methyladamantyl)]-4- benzyloxybrombenzene is used.
Yield, according to gas chromatography data is 88%.
Example 31 Reaction is performed as described in Example 11. As the adamantylarylhalide 6.35 g (0.016 M) of 3-benzyloxy-4-(1 - adamantyl)brombenzene is used.
Yield, according to gas chromatography data is 92%.
Example 32
Reaction is performed as described in Example 11. As the adamantylarylhalide 6.8 g (0.016 M) of 3-benzyloxy-4-[1 -(3,5- dimethyladamantyl)brombenzene is used.
Yield, according to gas chromatography data is 87%.
Example 33
Reaction is performed as described in Example 11. As the adamantylarylhalide 6.58 g (0.016 M) of 3-benzyloxy-4-[2-(2- methyladamantyl)brombenzene is used. Yield, according to gas chromatography data is 88%.
Example 34
Reaction is performed as described in Example 11. As the adamantylarylhalide 6.74 g (0.016 M) of 3-(1-adamantyl)-4-[1-(tert- butyldimethylsilyloxy)]brombenzene is used.
Yield, according to gas chromatography data is 79%.
Example 35
Reaction is performed as described in Example 11. As the starting adamantylarylhalide 7.18 g (0.016 M) of 3-[1 -(3,5-dimethyladamantyl)]-4- (tert-butyldimethylsilyloxy)bromobenzene is used.
Yield, according to gas chromatography data is 80%.
Example 36
Reaction is performed as described in Example 11. As the adamantylarylhalide 6.74 g (0.016 M) of 3-(tert-butyldimethylsilyloxy)-4-(1 - adamantyl)brombenzene is used.
Yield, according to gas chromatography data is 76%.
Example 37 Reaction is performed as described in Example 11. As the adamantylarylhalide 7.18 g (0.016 M) of 3-(tert-butyldimethylsilyloxy)-4-[1 - (3,5-dimethyladamantyl)brombenzene is used.
Yield, according to gas chromatography data is 74%.
Example 38
Reaction is performed as described in Example 11. As the adamantylarylhalide 5.36 g (0.016 M) of 3,4-methylenedioxy-5-(1- adamantyl)brombenzene is used.
Yield, according to gas chromatography data is 81 %.
Example 39
Reaction is performed as described in Example 11. As the adamantylarylhalide 5.81 g (0.016 M) of 3,4-methylenedioxy-5-[1 -(3,5- dimethyladamantyl)brombenzene is used. Yield, according to gas chromatography data is 84%.
Example 40
Reaction is performed as described in Example 11. As the adamantylarylhalide 5.58 g (0.016 M) of 3,4-methylenedioxy-5-[2-(2- methyladamantyl)brombenzene is used.
Yield, according to gas chromatography data is 79%.
Example 41
Reaction is performed as described in Example 11. As the adamantylarylhalide 5.62 g (0.016 M) of 3-(1 -adamantyl)-5-bromoveratrol is used.
Yield, according to gas chromatography data is 82%.
Example 42 Reaction is performed as described in Example 11. As the starting adamantylarylhalide 5.84 g (0.016 M) of 3-[2-(2-methyladamantyl)-5- bromoveratrol is used.
Yield, according to gas chromatography data is 77%.
The aforementioned results show that by use of lithium chloride in the reaction of preparing adamantylarylmagnesium halides by action of
magnesiunn metal on adamantylarylhalide in dry tetrahydrofuran stable high yields of the desired product are obtained.
The present method for preparation of substituted adamantylarylmagnesium halides is characterized by stable high yields, technological feasibility and possibility to scale up the reaction volume.
Claims
1. A method for preparing substituted adamantylarylmagnesium halide comprising reacting a substituted adamantylarylhalide with magnesium in an aprotic inert solvent (direct Ghgnard reaction) in the presence of an anhydrous lithium salt.
2. The method of claim 1 , wherein the reaction is conducted at a temperature from about -70 0C to about 80 0C, preferably from about 20 0C to about 70 0C.
3. The method of any of claims 1 or 2, wherein the aprotic inert solvent is tetrahydrofuran.
4. The method of any of claims 1 to 3, wherein the anhydrous lithium salt is anhydrous chloride, bromide, iodide, sulfate, perchlorate, tetrafluoroborate, preferably anhydrous lithium chloride.
5. The method of any of claims 1 to 4, wherein the anhydrous lithium salt is used in a stoichiometric ratio to a substituted adamantylarylhalide in range from 0.1 to 5.0 mol per mol.
6. The method of any of claims 1 to 5, wherein the anhydrous lithium salt is used in an optimal stoichiometric ratio to a substituted adamantylarylhalide in range from 1.2 to 1.5 mol per mol.
7. A method for preparing a compound of formula (I)
wherein A is (1 -adamantyl) or (2-adamantyl) which can be optionally substituted with from zero to six substituents each independently selected from OR1, NR1R2, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl and cycloheteroalkylalkyl; R1 and R2 are each independently selected from alkyl, alkenyl, alkynyl, aryl and heteroaryl; Hal is Cl, Br or I, preferably Br; R is: H, Cl, F, CF3 or fluorinated d-doalkyl, Ci-CioalkylC2-CiOalkenyl, C2- Cioalkynyl, Ci-Ci0alkoxy, or two R3 groups taken together, form a alkylenedioxy group,
-OSiR3R4R5, -(CH2)t(C6-Cioaryl), -(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally includes hetero moieties selected from O, S and -N(R6), wherein R3, R4, R5 are each independently Ci-CiOalkyl, said R aryl and heterocyclic groups are optionally fused to a C6-Ci0aryl group, a saturated Cs-Cscyclic group, or a 5-10 membered heterocyclic group, the -(CH2)t- moieties of the foregoing R groups optionally include a carbon- carbon double or triple bond where t is an integer from 2 to 5; and the foregoing R groups, except H, are optionally substituted by 1 to 3 R6 groups; R6 is CrCiOalkyl or d-Ci0alkoxy; n is 1 or 2; m is 0 to 3; comprising reacting a compound of formula (II)
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US12/448,671 US20100113816A1 (en) | 2006-12-29 | 2007-12-28 | Method for prepartion of substituted adamantylarymagnesium halides |
UAA200907979A UA97507C2 (en) | 2006-12-28 | 2007-12-28 | Method for preparing of substituted adamanty-larylmagnesium halides |
EP07858234A EP2129679A2 (en) | 2006-12-28 | 2007-12-28 | A method for preparation of substituted adamantylarylmagnesium halides |
EA200900899A EA015949B1 (en) | 2006-12-28 | 2007-12-28 | A method for preparation of substituted adamantylarylmagnesium halides |
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LV060151A LV13735B (en) | 2006-12-28 | 2006-12-28 | Method for manufacturing substituted adamantylarylmagnesium chalogenides |
LVP-06-151 | 2006-12-29 |
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Cited By (2)
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CN113866292A (en) * | 2021-09-13 | 2021-12-31 | 河北威远生物化工有限公司 | Method for measuring content of o-chlorobenzyl magnesium chloride |
CN117511212A (en) * | 2023-11-09 | 2024-02-06 | 东莞市好易达新材料科技有限公司 | High-temperature-resistant silicone glass fiber sleeve and preparation method thereof |
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WO2003048101A1 (en) | 2001-11-30 | 2003-06-12 | The Burnham Institute | Induction of apoptosis in cancer cells |
EP1582523A1 (en) | 2004-04-02 | 2005-10-05 | Ludwig-Maximilians-Universität München | Method of preparing organomagnesium compounds |
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WO2003048101A1 (en) | 2001-11-30 | 2003-06-12 | The Burnham Institute | Induction of apoptosis in cancer cells |
EP1582523A1 (en) | 2004-04-02 | 2005-10-05 | Ludwig-Maximilians-Universität München | Method of preparing organomagnesium compounds |
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KRASOVSKIY, A.; KNOCHEL, P. A: "Lid-mediated Br/Mg exchange reaction for the preparation of functionalized aryl - and heteroarylmagnesium compounds from organic bromides", ANGEW. CHEM. INT. ED., vol. 43, no. 25, 2004, pages 3333 - 3336, XP002294441, DOI: doi:10.1002/anie.200454084 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113866292A (en) * | 2021-09-13 | 2021-12-31 | 河北威远生物化工有限公司 | Method for measuring content of o-chlorobenzyl magnesium chloride |
CN113866292B (en) * | 2021-09-13 | 2024-03-19 | 河北威远生物化工有限公司 | Method for measuring content of o-chlorobenzyl magnesium chloride |
CN117511212A (en) * | 2023-11-09 | 2024-02-06 | 东莞市好易达新材料科技有限公司 | High-temperature-resistant silicone glass fiber sleeve and preparation method thereof |
CN117511212B (en) * | 2023-11-09 | 2024-04-12 | 东莞市好易达新材料科技有限公司 | High-temperature-resistant silicone glass fiber sleeve and preparation method thereof |
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EA200900899A1 (en) | 2010-02-26 |
LV13735B (en) | 2008-09-20 |
WO2008080993A3 (en) | 2009-03-12 |
EP2129679A2 (en) | 2009-12-09 |
UA97507C2 (en) | 2012-02-27 |
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