Forberedelse af N-(2-alkoxyvinyl) sulfonamider fra N- tosyl-1,2,3-triazoler og efterfølgende konvertering til substituerede Phthalans og Phenethylamines
Summary
Repræsentative eksperimentelle procedurer for syntese af N-(2-alkoxyvinyl) sulfonamider og efterfølgende konvertering til phthalan og phenethylamine derivater er præsenteret i detaljer.
Abstract
Nedbrydning af N– tosyl-1,2,3-triazoler med rhodium(II) acetat dimer i overværelse af alkoholer danner syntetisk alsidige N-(2-alkoxyvinyl) sulfonamider, der reagerer under en række betingelser til at give nyttige N– og O –holdige forbindelser. Syre-katalyseret tilsætning af alkoholer eller dithioler n-(2-alkoxyvinyl) sulfonamid-holdige phthalans giver adgang til ketaler og thioketals, henholdsvis. Selektiv reduktion af gruppen vinyl i N-(2-alkoxyvinyl) sulfonamid-holdige phthalans via hydrogenering udbytter de tilsvarende phthalan i godt udbytte, mens reduktion med natrium bis (2-methoxyethoxy) aluminumhydride genererer en ring-åbnede phenethylamine analog. Fordi N-(2-alkoxyvinyl) sulfonamid funktionsgruppe er syntetisk alsidige, men ofte hydrolytically ustabilt, denne protokol fremhæver vigtige teknikker i forberedelsen, håndtering og reagerer disse afgørende substrater i flere nyttige transformationer.
Introduction
Rhodium (II)-azavinyl carbenoids har for nylig vist sig som en usædvanlig alsidig reaktive mellemliggende på vej til mange værdifulde produkter. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 navnlig mange nye anvendelser af disse mellemprodukter til fremstilling af heterocycles10 har givet kemikere med nye og effektive syntetiske strategier. Mod herpå vores gruppe indledt udvikling af en ny protokol for syntesen af phthalans11 , ville udnytte de seneste fremskridt i inter- og intramolekylære tilføjelser af ilt-baseret nukleofiler til Rh (II)-azavinyl carbenoids afledt af N-sulfonyl-1,2,3-triazoler. 12 , 13 , 14 , 15 , 16 , 17 vores tilgang har en enkel to-trins protokol til konvertering terminal Alkyner som 1 til N-sulfonyl-1,2,3-triazoler 2 forsynet med GigE alkohol (figur 1). Senere, en Rh II-katalyseret denitrogenation / 1,3-OH indsættelse cascade fra 2 giver phthalans 3 har en reaktiv N-(2-alkoxyvinyl) sulfonamid funktionelle gruppe.
Siden N-(2-alkoxyvinyl) sulfonamid gruppe er et potentielt alsidige, men relativt underexplored N– og O-indeholdende synthon,16,17,18, 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 vi blev interesseret i at studere reaktiviteten af dens sammenvoksede enol-ether/fjend-sulfonamid system under en række betingelser (figur 2). Efter screening forskellige reducerende protokoller, to metoder blev identificeret som førte til stabile phthalan og/eller phenethylamine-holdige produkter (figur 2, 3 → 4/5). Først, det blev opdaget som en standard hydrogenering af N-(2-alkoxyvinyl) sulfonamid 3a med katalytisk palladium på kulstof (Pd/C) selektivt reducerer C = C bånd for at give phthalan 4. Alternativt, behandling af 3a med natrium bis (2-methoxyethoxy) aluminium hydrid i diethylether/toluen giver enestående substituerede phenethylamine afledte 5. Vi mener, at begge disse transformationer er værdifulde, som de fører til produktklasser med potentielle biologiske aktivitet herunder neuroactive egenskaber der opstår fra den integrerede phenethylamine og 4, metal-kelation via den cis– orienteret N– og O-atomer.
Under behandlingen af syre-forfremmet tilføjelser for at udnytte den elektron-rige C = C bånd af 3a, det blev konstateret, at behandling af dette stof med katalytisk trimethylsilyl chlorid i overværelse af alkoholer eller en thiol givet ketaler 6a-c og thioketal 6e, henholdsvis, samtidig med at de bicykliske phthalan rammer intakt. Alternativt, omrøring 3a i en 1:1 eddikesyre/vand løsning udbytter stabile hemiketal 6 d.
Protocol
Representative Results
Discussion
Triazoler 2a-b proper kan opnås via en Cu, (I)-katalyseret indeholder-alkyn [3 + 2] cycloaddition (CuAAC) bruger CuTC som katalysator. Navnlig genereres triazoler 2a mest effektivt ved høj temperatur via en standard refluks i chloroform til 3 h eller opvarmning til 100 ° C i 15 min i en mikrobølgeovn reaktor (Bemærk, at tid kan variere afhængig af mikrobølgeovn effektivitet); triazoler 2b fremstilles dog mest effektivt via en CuAAC ved stuetemperatur. Indsats skal…
Divulgations
The authors have nothing to disclose.
Acknowledgements
Dette arbejde blev finansieret af Hamilton College og Edward og Virginia Taylor Fund for studerende/fakultetet forskning i kemi.
Materials
| 2-Ethynylbenzyl alcohol, 95% | Sigma Aldrich | 520039 | |
| Copper (I) thiophene-2-carboxylate | Sigma Aldrich | 682500 | |
| Chloroform, ≥99% | Sigma Aldrich | 372978 | |
| Toluenesulfonylazide, 99.24% | Chem-Impex International | 26107 | Potentially explosive |
| Dichloromethane, ≥99.5% | Sigma Aldrich | 320269 | |
| Rhodium (II) acetate dimer, 99% | Strem Chemicals | 45-1730 | |
| Silica Gel, 32-63, 60A | MP Biomedicals Inc. | 2826 | For silica gel plugs |
| Hexanes | Sigma Aldrich | 178918 | |
| Ethyl acetate | Sigma Aldrich | 439169 | |
| Chlorofom-D | Sigma Aldrich | 151823 | |
| Ethylene glycol | Sigma Aldrich | 293237 | |
| Chlorotrimethylsilane, 98% | Acros | 11012 | |
| Sodium bicarbonate | Sigma Aldrich | S6014 | Dissolved in deionized water to prepare a saturated aqueous solution |
| Sodium sulfate | Fisher Scientific | S429 | |
| Ethyl alcohol, absolute – 200 proof | Aaper Alcohol and Chemical Co. | 82304 | |
| 10 wt% Palladium on carbon | Sigma Aldrich | 520888 | Can ignite in the presence of air, hydrogen gas, and/or a flammable solvent |
| Hydrogen gas | Praxair | UN1049 | |
| Diethyl ether | Sigma Aldrich | 309966 | |
| 60 wt% sodium bis(2-methoxyethoxy)aluminum hydride solution in toluene | Sigma Aldrich | 196193 | Reacts violently with water |
| Methanol | Sigma Aldrich | 34966 | |
| Ammonium chloride | Fisher Scientific | A661 | Dissolved in deionized water to prepare a saturated aqueous solution |
| Hydrochloric acid, 37% | Sigma Aldrich | 258148 | Dissolved in deionized water to prepare a 1M solution |
| Sodium Chloride | Sigma Aldrich | S25541 | Dissolved in deionized water to prepare a saturated aqueous solution |
| 2-5 mL Microwave vials | Biotage | 355630 | |
| Microwave vial caps | Biotage | 352298 | |
| RediSep Rf Gold Normal Phase, Silica Columns, 20 – 40 micron | Teledyne Isco | 69-2203-345 | For column chromatography |
| Balloons | CTI Industries Corp. | 912100 | For hydrogenation |
| Biotage Initiator+ Microwave Reactor | Biotage | 356007 |
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