Direct Oxidative Heck Cyclizations: Intramolecular Fujiwara-Moritani Arylations for the Synthesis of Functionalized Benzofurans and Dihydrobenzofurans

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1 Direct xidative eck Cyclizations: Intramolecular Fujiwara-Moritani Arylations for the Synthesis of Functionalized Benzofurans and Dihydrobenzofurans by Zhang,.; Ferreira, E. M.; Stoltz, B. M. Angewandte Chemie International Edition 2004, 43, Erick B. Iezzi Current Literature ovember 27, 2004 Erick Wipf Group 1 12/2/04

2 Why is this Article Significant? - eck reaction is ubiquitous for the forming C-C bonds in synthetic molecules - uses halogenated arenes which requires an additional synthetic step - a base is needed to remove the generated hydrohalic acid - C- activation of arenes eliminates the need for halogens - Demonstrates the first use of catalytic Pd for oxidative intramolecular C- activation of arenes and the addition into unactivated olefins (eck reaction) - Illustrates that mechanism of cyclization follows the pathway of a Fujiwara-Moritani/oxidative eck cyclization - Synthesize benzofuran and dihydrobenzofuran structures, which are important components of numerous biologically active compounds Erick Wipf Group 2 12/2/04

3 Examples of Biologically Active Benzofurans R An oxytocin antagonist Wyatt, et al. Bioorg. d. Chem. Lett. 2002, 12, Antifungal activity against Candida albicans (a pathogenic fungi) Masubuchi, et al. Bioorg. d. Chem. 2003, 11, 4463 (-) BPAP - A serotonin release enhancer Yoneda, et al. Bioorg. d. Chem. 2001, 9, 1197 Erick Wipf Group 3 12/2/04

4 Examples of Biologically Active Dihydrobenzofurans - A tubulin polymerization inhibitor (GI 50 of <10 nm against some breast cancer cell lines) Pieters, et al. J. d. Chem. 1999, 42, 5475 DDMBF - An anti-inflammatory and analgesic drug Janusz, et al. J. d. Chem. 1998, 41, An acyl-co A: cholesterol acyltransferase inhibitor Kataoka, et al. J. d. Chem. 1996, 39, 1262 Erick Wipf Group 4 12/2/04

5 Pd-Catalyzed xidative eck Reaction Fujiwara-Moritani arylation (1967) + Pd II Cl 2 Ac reflux 2 Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, [Pd(II)Ac] + Pd(II)Ac Catalytic intermolecular reaction with activated olefins + R Et Pd(Ac) 2 (10 mol%) heteropoly acid (2 mol%) Ac, 90 o C, 2 (1 atm) R Et R =, Ph 65-84% Ishii, et al. J. Am. Chem. Soc. 2003, 125, Erick Wipf Group 5 12/2/04

6 chanism of Arene Insertion into Activated Esters and Reoxidation of Catalyst Pd(0) [] / Pd(II) Pd(Ac) 2 Ar R' C 2 R -Ac [PdAc] + C 2 R Ar- Ar R' PdAc C 2 R R' Ar-PdAc Erick Wipf Group 6 12/2/04

7 Pd-Catalyzed Reactions of Arenes with Alkynes + C 2 Et Pd / [] TFA C 2 Et Pd(Ac) 2 TFA, RT Ar C 2 Et Ar C 2 Et + + C 2 Et Ar Ar 72% 6% 5% R X Pd(Ac) 2 (10 mol%) R X 50-91% TFA/C 2 Cl 2 (1:1) R' R' X =,, S Fujiwara, et al. Acc. Chem. Res. 2001, 34, Erick Wipf Group 7 12/2/04

8 Carboxylation of Arenes and Ru-Catalyzed xidative eck Reactions + C 10% Pd(Ac) 2 C 2 K 2 S 2 4 / TFA RT, 20h ~100% Fujiwara, et al. Acc. Chem. Res. 2001, 34, B() 2 + Bu 2.5 mol% Ru-cat. (1) 2.5 equiv. Cu(Ac) 2 Et 3, C 2 Cl 2, RT Bu 98% GC, 60% isolated Cl * need prefunctionalized arene to facilitate reaction Ru Cl 1 Brown, et al. Angew. Chem. Int. Ed. 2002, 41, Erick Wipf Group 8 12/2/04

9 Palladium-Promoted xidative eck Cyclization in Total Synthesis Fmoc 2 C 1 equiv. Pd(Ac) 2, Ac:dioxane: 2 1 atm 2, 25 o C, 16h 44% Fmoc 2 C karamine Corey, et al. J. Am. Chem. Soc. 2003, 125, Erick Wipf Group 9 12/2/04

10 First Example of Pd-Catalyzed xidative Annulations of Indoles Pd(Ac) 2 (10 mol%), 2 (1 atm) pyridine ligand (40 mol%), 0.1 M solvent, 24 h, 80 o C palladation B-hydride elimination olefin insertion Pd L n L n Pd Entry Pyridine ligand pka(pyr + ) conversion (%) t-Bu unsub C 2 Et * 5 3-C 2 Et CC F C ,5-di-Cl Best result: 40 mol% ethyl nicotinate*, 0.1M tert-amyl alcohol/ac (4:1), 99% conversion, 82% isolated yield Stoltz, et al. J. Am. Chem. Soc. 2003, 125, Erick Wipf Group 10 12/2/04

11 Screening of xidants for the Catalytic Intramolecular xidative eck Cyclization Pd(Ac) 2 (10 mol%), oxidant, ethyl nicotinate (40 mol%), t-am:ac (4:1), 24 h, 80 o C Entry xidant [1 equiv.] Yield [%] by GC benzoquinone 62 3 Cu(Ac) AgAc 29 5 Tl(CCF 3 ) 3 <10 6 K 2 S C(S) 2 <10 8 PhC 3 tbu 42 Stoltz, et al. Angew. Chem. Int. Ed. 2004, 43, Erick Wipf Group 11 12/2/04

12 Examples of xidative Benzofuran Synthesis Pd(Ac) 2 (10 mol%), aac (20 mol%), ethyl nicotinate (20 mol%), benzoquinone (1 equiv.), 0.1M t-am:ac (4:1), 100 o C 77% conditions above 61% Ph Ph Et conditions above Et 79% Et conditions above Et 52% Stoltz, et al. Angew. Chem. Int. Ed. 2004, 43, Erick Wipf Group 12 12/2/04

13 Synthesis of Quaternary Carbon-Containing Dihydrobenzofurans via xidative Cyclization Pd(Ac) 2 (10 mol%), aac (20 mol%), ethyl nicotinate (20 mol%), benzoquinone (1 equiv.), 0.1M t-am:ac (4:1), 100 o C 74% conditions above 55% conditions above 80% conditions above 74% 2.3:1 diastereomers Stoltz, et al. Angew. Chem. Int. Ed. 2004, 43, Erick Wipf Group 13 12/2/04

14 chanistic Probe for the xidative eck Cyclization Pd(Ac) 2 (10 mol%), aac (20 mol%), ethyl nicotinate (20 mol%), benzoquinone (1 equiv.), + t-am:ac (4:1), 100 o C Bn 1 Bn 2 not observed 60% yield Bn Bn Bn PdL n (Ac) 2 anti nucleophilic attack Bn PdL n (Ac) 2 olefin activation PdL n (Ac) 2 PdL n (Ac) 2 arene palladation PdLn(Ac) syn olefin insertion PdL n (Ac) Bn syn B-hydride elimination 1 not observed PdL n (Ac) syn B-hydride elimination 2 60% yield PdL n (Ac) Bn Erick Wipf Group 14 12/2/04

15 Future Work - Develop catalysts to facilitate oxidative C- activation of electron-poor arenes - Develop method of synthesizing ether rings of six-members and greater Erick Wipf Group 15 12/2/04