Mg- and Zn-Mediated Synthesis of Heterocycles in Solution and on the Solid Phase

Bérillon, Laurent (2000): Mg- and Zn-Mediated Synthesis of Heterocycles in Solution and on the Solid Phase. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

This work has focussed on the preparation of functionalized heterocyclic organometallics. In the first part, functionalized zinc derivatives were used due to their high functional group tolerance. Thus various thymine derivatives have been prepared both in solution and on the solid phase. Alternatively, a new route to functionalized heterocyclic Grignard reagents was developed using a low-temperature halogen-magnesium exchange. Ester, amide and nitrile functions are tolerated and the resulting organomagnesium derivatives could be reacted with various electrophiles. Finally, we have attempted to perform low-temperature cross-coupling reactions using these functionalized Grignard reagents. 5.1- Synthesis of thymine derivatives Zincated thymine derivative 2 was prepared by zinc insertion from the corresponding bromide 4, readily available in four steps from uracil. Negishi cross-coupling reactions were then performed using zinc reagent 2 and various aryl iodides. N N O O Bn Bn 4 Br HN N H O O N N O O Bn Bn 2 ZnBr Ar - I Pd(dba)2 (2.5 mol %) N N O O tfp (5 mol %) THF, 25 °C, 12 h Bn Bn Ar 3a-j: 62-95 % THF, 0 °C Zn* Scheme 67. Preparation of thymine derivatives 3a-j using a Negishi cross-coupling reaction. Resin-attached aryl iodides were also suitable substrates and solid phase synthesis of thymine derivatives could be performed with high HPLC-purities (89-93 %). X O I N N O O Bn Bn X = O, NH R 8 (10 equiv) N N O O Pd(dba)2 (5 mol %) tfp (10 mol %) THF, 25 °C, 48 h Bn Bn R = CO2H, CONH2 ZnBr 2) TFA 1) 89-93 % HPLC purity Scheme 68. Solid phase synthesis of thymine derivatives. 5.2- Synthesis of functionalized heterocyclic derivatives using a low temperature halogen-magnesium exchange • Synthesis of pyridine derivatives Functionalized pyridinyl Grignard reagents were prepared using a low temperature iodinemagnesium exchange and trapped with electrophiles. Functional groups such as ester, amide or nitrile functions are tolerated in this process. N I FG 1) i-PrMgBr -40 °C 2) E+ N E FG 50-92 % FG = Br, CONR2, CN, CO2R etc. Scheme 69. Preparation of functionalised pyridines using a low temperature iodine-magnesium exchange. The bromine-magnesium exchange is less general than the iodine magnesium-exchange and electron withdrawing groups are often necessary to accelerate the exchange reaction. However, 2-bromo and 3-bromopyridine were suitable substrates due to the π deficient character of these heterocycles. N Br 1) i-PrMgBr THF, rt, 6 h 2) E+ N E 72-75 % Scheme 70. Preparation of pyridine derivatives using a bromine-magnesium exchange. • Synthesis of thiazole and thiophene derivatives A low temperature bromine-magnesium exchange was then used in the synthesis of functionalized thiazole and thiophene derivatives. N S Br OEt O Br 1) i-PrMgBr THF, -78 °C N S Br OEt O E 2) E+ S Br Br CO2Et 1) i-PrMgBr -40 °C, 0.5 h 2) S Br CO2Et 1) i-PrMgBr -40 °C, 0.5 h 2) E+ S E E CO2Et S Br Br EtO2C 1) i-PrMgBr -40 °C, 0.5 h 2) E+ S E Br EtO2C 58-81 % 68-88 % 74 % 62-71 % Br CuCN cat. Scheme 71. Preparation of thiazole and thiophene derivatives using a bromine-magnesium exchange. • Synthesis of dihydrobenzofurans and tetrahydrobenzazepines An access to dihydrobenzofurans, benzolactams and tetrahydrobenzazepines was developed using arylmagnesium reagents bearing an o-chloromethyl group. Cl MgBr CO2Et Br 83 % CuCN 2 LiCl cat. . Cl CO2Et RNH2 reflux, 24 h K2CO3, THF N CO2Et R Cl I 1) i-PrMgBr (1.0 equiv) THF -10 °C, 1.5 h 2) RCHO, -10 °C, 1 h then reflux, 12 h O R 55-94 % 54-75 % X = H, CO2Me NPh X 1) i-PrMgBr (1.0 equiv) THF -10 °C, 1.5 h 2) PhN=C=O O X = H, 96 % X = CO2Me, 75 % Scheme 72. Preparation of dihydrobenzofurans and tetrahydrobenzazepines using a low temperature iodine-magnesium exchange. • Low-temperature halogen-magnesium exchange on the solid phase The low-temperature halogen-magnesium exchange could also be performed on the solid phase using an excess of i-PrMgBr and was applied to the synthesis of various thiophene derivatives. 2) E+ 1) i-PrMgBr (10 equiv) THF, -40 °C 3) TFA S E O HO S O O Br 83-99 % HPLC-purity Scheme 73. Solid phase synthesis of thiophene derivatives using a low temperature brominemagnesium exchange.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 24. September 2000