A Stille or Suzuki reaction is a good choice for this coupling O O because they are functional group tolerant, no radical chemistry F

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1 Chemistry 253 roblem et 3 Due: Friday, ctober 15th ame TF 1. For the following products of cross coupling reactions and indicated bond disconnections, please indicate a reasonable cross coupling protocol (uzuki, tille, egishi...), provide the corresponding structures of the coupling partners and reasonable catalyst systems, and explain your choices. (a) 2 C 2 Me oc egishi coupling: tille coupling and Kumada couplings are not compatible with the sp 3 bond and carbonyl group respectively. Jackson Chem Comm 1998, 75 Knochel Tetrahedron 1998, 54, Zn C 2 Me oc 2 dba 3, (otol) 3 (b) u n-c o methods that involve base activation of the transmetallation step can be used because of the presence of the boron substiuent. otential beta-hydride elimination of the alkyl group must also be considered. uzuki Tet Lett. 1998, 29, 1811 n-c uzn, (h 3 ) 4 (c) A tille or uzuki reaction is a good choice for this coupling because they are functional group tolerant, no radical chemistry F is involved, and the aryl fluoride should not be affected. oc Laborde TL 1990, 31, 1837 F oc nu 3 (d) All methods are applicable, but hindered substrates are problematic. Methods have been developed for these substrates with specialized ligands such as the one below: uchwald JAC, 1998, 120, 9722 uchwald JAC, 1999, 121, 9550 uzuki: (Ac) 2, K 3 4, Tol, heat Cy 2 () 2 Ligand:

2 2. rovide a mechanism for the following transformation. 1 mol% (Ash 3 ) psi C n( ) 4 Et MA, 120 o C, 3 h 62% 2.0 equiv. 1.0 equiv. Answer (Ash 3 ) 2 2 Elim. 0 2 nme 4 2 nme 3 C 2 6 Ash 3 Ash 3 xidative Ash 3 somerization ubstitution C C Ash 3 n( ) 3 n( ) 4 nsertion (MA)

3 3. The following transformation combines aspects of the uzuki and eck reactions. ropose a mechanism for this transformation. o rationale is required for the absolute sense of induction or the stereoselectivity. 1.5 mol% [(()-inap)rh] 2 10:1 Dioxane: 2 35 C, 3 h 99.1% ee Answer Rh Rh ydrolysis h 2 h olvent Rh Rh Rh h nsertion Rh h ubstitution ayashi, T.; Takahashi, M.; Takaya, Y.;gasawara, M. J. Am. Chem. oc. 2003, 124,

4 4. a) ropose a synthesis of 1 using a uzuki reaction and starting from 2-methyl-1,3-cyclopentanedione and any reagents containing 8 carbon atoms or less. h Tf DU hc 2 acetonitrile 1 10 mol% (Ac) 2 22 mol% h 3, K TF, 23 C, 1 h h KMD TF, 78 C; (Tf) 2 h Tf Tf h The uzuki reaction above was performed in a catalytic asymmetric fashion to synthesize compounds containing quaternary carbon centers: Willis, M. C.; owell, L.. W.; averie, C. K.; Watson,. J. Angew. Chem. nt. Ed. 2004, 43, b) The triflate of 1 can be replaced by a hydrogen atom using the conditions shown below. ropose a mechanism for this transformation. 10 mol% (Ac) 2 h 22 mol% h 3 h u Tf 3, C 2 C 3 C, 60 C, 1 h Ac 2 h 3 (Ac) 2 h 3 Ac h 3 h 3 h 3 Ac Ac h 3 2 xidative 1 h Tf h 3 C 2 h β-ydride h 3 h h 3 Tf ubstitution h Tf u 3 C 2 u 3 C 2 u 3

5 5. rovide a mechanism for the following i-catalyzed 3-component coupling of an allene, aryl iodide, and alkenylzirconium reagent. Me h Answer Me Cp 2 Zr n-r i 2 (h 3 ) mol% i 2 (h 3 ) 2 TF, 50 o C, 24 h 83% h n-r Me Elim. 2 Cp 2 Zr n-r n-r n-r h n-r h 3 i h 3 Me h 3 xidative p-meh i h h 3 n-r h 3 h 3 i Me η 3 -η 1 isomerization ubstitution h h 3 h 3 i p-meh i h h 3 n-r h Me ZrCp 2 nsertion Cp 2 Zr n-r p-meh i h h 3 h h 3 i p-meh η 1 -η 3 -η 1 isomerization p-meh i h h 3 Cheng JAC 2003, 125, 12426

6 6. The substrate scope of cross-coupling reactions can be expanded to include a variety of nucleophile/electrophile combinations. rovide an appropriate nucleophile or electrophile for the transformations below. rovide a mechanism for each transformation. 2 h 2 mol% (Ac) 2 5 mol% Xhos toluene: t-u 5:1 110 C, Cs 2 C 3 88% yield Xhos = i-r Cy 2 i-r guyen,..; uang, X.; uchwald,. L. J. Am. Chem. oc. 2003, 125, i-r 2 Cy 2 R (Ac) 2 Cy 2 R Ac Ac RCy 2 Cy Cy i-r i-r Cy 2 R Ac i-r Ac Cy 2 R xidative h 2 i-r i-r i-r Cy Cy h oft Deprotonation ubstitution 2 h Cy Cy i-r i-r i-r h 3 Cs CsC 3 i-r 2 h Cs 2 C 3 i-r i-r Cy Cy

7 Tf C 3 Tf 10 mol% i(cd) 2 10 mol% Mes CsF, 1,4-Dioxane 80 C, 12 h 98% yield C 3 C 3 Mes = lakey,..; MacMillan, D. W. C. J. Am. Chem. oc. 2003, 125, i(cd) 2 CD i(cd) Mes xidative i i CD C 2 Tf i xidative ( ) 3 Tf i i CsTf F() 2 F Cs CsF