Copper-Catalyzed Reaction of Alkyl Halides with Cyclopentadienylmagnesium Reagent

Transcription

1 Copper-Catalyzed eaction of Alkyl Halides with Cyclopentadienylmagnesium eagent Mg 1) cat. Cu(Tf) 2 i Pr 2, 25 o C, 3 h 2) H 2, Pt 2 Masahiro Sai, Hidenori Someya, Hideki Yorimitsu, and Koichiro shima rganic Letters ASAP (4/11/2008) Wipf Group Current Literature Jennie Kravchenko - 05/31/08 Jennie Wipf Group Page 1 of 10 6/14/2008

2 Copper-Catalyzed Cross-Coupling eactions of Grignard eagents with Primary Alkyl Halides Alkyl omides: Tetrahedron 2000, 56, 2737 MgCl cat. Li 2 CuCl 4, 20 o C Alkyl Fluorides: J. Am. Chem. Soc. 2003, 125, 5646 F ' MgX = alkyl ' = alkyl, aryl cat. CuCl 2 1,3-butadiene ' Alkyl Chlorides: Angew. Chem. Int. Ed. 2007, 46, 2086 Alkyl Cl MgX cat. CuCl 2 cat. Ph THF Me Alkyl Jennie Wipf Group Page 2 of 10 6/14/2008

3 Cobalt-Catalyzed Cross-Coupling eactions of Grignard eagents with Secondary and Tertiary Alkyl Halides Substrate Scope: cat. [CoCl 2 (dppp)] H X 2 C CHCH 2 MgCl 1 THF, temp. 2 n-c 4 H 9 I CH 3 cat. [CoCl 2 (dppp)] H 2 C CHCH 2 MgCl THF, - 40 o C then Cr 3 /acetone 1 Temperature ( o C) Yield of 2 (%) Ph H 3 C C 6 H n-c 4 H 9 n-c 4 H 9 t-c 4 H 9 CH Cl [CoCl 2 (dppp)] effectively catalyzes such reactions of secondary and tertiary alkyl halides with allylic Grignard reagents I n-c 6 H Treatment of substrate with allyl Grignard reagent in the presence of [CoCl 2 (dppp)] furnished the ring -opening product - Existence of radical intermediates account for such ring opening Angew. Chem. Int. Ed. 2002, 41, 4137 Jennie Wipf Group Page 3 of 10 6/14/2008

4 Cobalt-Catalyzed Cross-Coupling eactions of Grignard eagents with Secondary and Tertiary Alkyl Halides Proposed Mechanism: X 1 2 Co 3 1) Single-electron transfer from cobalt complex 2) ecombination of alkyl radical and cobalt complex 3) eductive elimination - π-allyl ligands may prevent the formation of the vacant coordination sites necessary for ß-elimination, which enables allylation of tertiary and secondary alkyl halides as well as of alkyl halides having ß-alkoxy groups Angew. Chem. Int. Ed. 2002, 41, 4137 Jennie Wipf Group Page 4 of 10 6/14/2008

5 Silver-Catalyzed Cross-Coupling eactions of Grignard eagents with Secondary and Tertiary Alkyl Halides Substrate Scope: Alkyl X Mg cat. AgN 3 Et 2, 25 o C, 3 h Alkyl cat./mol % Yield of 2 (%) cat. AgN 3 Alkyl X Mg Alkyl Et 2, 25 o C, 3 h cat./mol% Grignard reagent Yield of 2 (%) = H (1.3 equiv) 83 Cl n-c 6 H = H (1.3 equiv) 80 I = Me (1.5 equiv) 80 t-c 4 H 9 CH n-c 6 H = Me (1.5 equiv) 79 - Silver-catalyzed conditions were applicable to benzylation, as well as allylation and methallylation of secondary and tertiary alkyl halides - Analogous radical pathway was proposed rganic Letters 2008, 10, 971 Jennie Wipf Group Page 5 of 10 6/14/2008

6 Copper-Catalyzed Cyclopentadienylation of Secondary and Tertiary Alkyl Halides Followed by Hydrogenation General eaction: 1a 5 mol % Cu(Tf) 2 i-pr 2, 25 o C, 3 h 2a Mg 10 mol % Pt 2, 0.1 MPa H 2 AcH, reflux, 12 h 3a 3a' 4a 95% combined yield 85% overall yield - Initially formed 2a undergoes isomerization into 3a and 3a due to the high acidity of the hydrogen on the cyclopentadienyl ring - Isomers were subjected to hydrogentation in order to simplify analysis of products rganic Letters ASAP (4/11/2008) Jennie Wipf Group Page 6 of 10 6/14/2008

7 Solvent Effect and Catalyst Screening: Mg 5 mol % catalyst solvent, 25 o C, 3 h - Choice of solvent and copper catalyst greatly altered overall yield of products - Bulky ethers (diisopropyl ether and t -butyl methyl ether) proved to be most suitable entry solvent catalyst combined yield (%) 1 i-pr 2 Cu(Tf) t - -BuMe Cu(Tf) toluene Cu(Tf) diethyl ether Cu(Tf) dioxane Cu(Tf) THF Cu(Tf) c-c 5 H 11 Me Cu(Tf) Bu 2 Cu(Tf) i-pr 2 CuF i-pr 2 CuCl i-pr 2 CuCl i-pr 2 Cu i-pr 2 CuI i-pr 2 CuAc i-pr 2 CuCN i-pr 2 CuTf 0.5 C 6 H i-pr 2 AgN Copper(II) halides as well as copper(i) halides exhibited modest catalytic activity - Silver(I) nitrate, found to be effective in the cross-coupling reaction of tertiary alkyl halides with allyl or benzyl Grignard reagents, was less effective than copper(ii) triflate rganic Letters ASAP (4/11/2008) Jennie Wipf Group Page 7 of 10 6/14/2008

8 Substrate Scope: Alkyl X 1 Mg 5 mol % Cu(Tf) 2 Alkyl Alkyl i-pr 2, 25 o C, 3 h 3 3' 10 mol % Pt 2, 0.1 MPa H 2 AcH, reflux, 12 h Alkyl 4 - Phenylsulfanyl and methoxyl groups were compatible in such reaction conditions without deactivation of the copper catalyst combined yield overall yield alkyl-x of 3 and 3' (%) of 4 from 1 (%) Cl - Surprisingly, tertiary alkyl fluoride participated in cyclopentadienylation as well Me PhS n-c 6 H Ph 2 F rganic Letters ASAP (4/11/2008) Jennie Wipf Group Page 8 of 10 6/14/2008

9 Stoichiometric eactions: (0.50 mmol) 1.0 equiv Cu(Tf) 2 i-pr 2, 25 o C, 3 h - eaction mechanism was studied using the following halide with stoichiometric copper reagents and varying amounts of CpMg Mg - Copper reagent that is active for this reaction might be [Cp 3 Cu]Mg 6 or a more complex cuprate amount of Grignard reagent NM yield 1.0 equiv 0% 2.0 equiv 15% 3.0 equiv 86% - Experiments have been conducted to examine the intermediacy of alkyl radicals in the reaction, however they failed to support the intermediacy rganic Letters ASAP (4/11/2008) Jennie Wipf Group Page 9 of 10 6/14/2008

10 Conclusions and Future Directions - Copper(II) triflate proved to efficiently catalyze the reaction of tertiary alkyl halides with cyclopentadienyl Grignard reagent. - With the following hydrogenation of the cyclopentadienyl ring with hydrogen under Pt 2 catalysis, the overall transformation represents formal cyclopentylation of tertiary alkyl halides. Future work could include extension of the methodology to other stabilized organometallic reagents, as well as application of this method to functionalized molecules of interest. Jennie Wipf Group Page 10 of 10 6/14/2008