Intramolecular Ene Reactions Utilizing Oxazolones and Enol Ethers Fisk, J.S. and Tepe, J..J J. Am. Chem. Soc., 2007, 129,

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1 Intramolecular Ene Reactions Utilizing xazolones and Enol Ethers Fisk, J.S. and Tepe, J..J J. Am. Chem. Soc., 2007, 129, versus -Arylation of Aminoalcohols: rthogonal Selectivity in Copper-Based Catalysts Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc., 2007, 129, Antoinette E. ibbs Short Literature Presentation April 18, 2007

2 Intramolecular Ene Reactions Utilizing xazolones and Enol Ethers Jason S. Fisk and Jetze J. Tepe Department of Chemistry, Michigan State University

3 Ene Reactions chanism X Y X Y ene enophile FM Analysis ene M enophile LUM Atom-efficient reaction for the formation of carbon-carbon bonds Intramolecular and intermolecular ene reactions possible

4 Conia-Ene Reaction Intramolecular ene reaction of unsaturated ketones and aldehydes, with the alkene/alkyne as enophile Conducted at very high temperatures tal-catalyzed versions allow for lower temperatures, but enolate generation, strong acid, or photochemical activation required

5 Intermolecular Ene Intermolecular version of Conia-ene as an enolate alkylation alternative ew intermolecular ene reaction using oxazolones under mild conditions without the use of any catalyst Reliance upon the ease of formation of the aromatic enol tautomer Efficient route to the formation of quaternary amino acids Enol ether as the enophile instead of alkene/alkyne R 1 R 2 R 1 R 2 R 1 R2 R 3 R 3 R 2 C 2 R 1 R 3

6 Ene Reaction with Various Enol Ethers R 1 C 2 1. Enol Ether (1.3 eq) C 2 Cl 2, rt 2., rt Ph C 2 C 2 R entry Enol Ether R % yield 1 t Bu t Bu 99 2 n Bu n Bu 98 3 > Bn 6 68 Bn 7 81 Use of ester-substituted oxazolones because of enol character Choice of solvent did not affect reaction rate or yield significantly o degradation of enol ether as plausible indication of concerted mechanism ature of protecting group important for the success of reaction Ac 8 0 Ac

7 Substituted xazolones t Bu Ph 1. (3 eq.) R 2 Toluene 2. or a, rt R 2 C 2 Ph t Bu entry R 2 temp ( C) time % yield 9 C 2 room temp 20 min CC 3 room temp 24 h Ph h napthyl h h 0 Increased enol character of oxazolone necessary for reaction at lower temperatures Substituent effects on the stabalization of the aromatic enol tautomer

8 chanistic ature of the Reaction Ph Path A Ph Co 2 D 2 C Bz D C 2 Mixture of Diastereomers not observed C 2 D excess Path B Ph C 2 D 2 C Bz D C 2 Single Diastereomer 99 % yield

9 Conclusions Benefits Mild intermolecular ene reaction ear quantitative yields Alternative to enolate alkylation chemistry Upon treatment of, quaternary amino acids can be formed Easy formation of aromatic enol tautomer Limitations Presence of group that stabalizes enol tautomer required igher substituted enol ethers resulted in longer reaction times, higher temperatures, and lower yields

10 - versus -Arylation of Aminoalcohols: rthogonal Selectivity in Copper-Based Catalysts Alexandr Shafir, Phillip A. Lichtor, and Stephen L. Buchwald Department of Chemistry, Massachusetts Institute of Technology

11 Previous Work ()R 1 cat. CuI, base R 2 R 1 R 2 R 2 I ()R 1 Copper-catalyzed - and -arylation of ß-aminoalcohols o ligand required for these Ullmann couplings Attempts to expand substrate scope unsuccessful 1,2-aminoalcohol can assist reaction by acting as a support ligand; might need additional ligand for nonchelating aminoalcohols Investigated ligand-assisted Ulmann couplings with two ligands

12 Ullmann Coupling Reaction Ullmann Coupling 2 I Cu CuI 2 chanism I Cu single electron transfer Cu(I)I Cu(II)I SET Cu(II)I I CuI 2 Li, J. J. ame Reactions, 2nd edition

13 Chemoselectivity of Ligand-Assisted Ullmann Coupling of 5-amino-1-pentanol -Arylation of 5-amino-1-pentanol L1 ipr Br I 2 5% CuI, 20% L1 2.0 equiv Cs 2 C 3 Br DMF, room temp 7 h 97% -Arylation of 5-amino-1-pentanol L2 Br I 2 5% CuI, 10% L2 2.0 equiv Cs 2 C 3 Br toluene, 3Å MS 90 C, 16 h 88% 2

14 Effect of Spacer Length on - and -Arylations ipr L1 2 I 2 n 5% CuI, 20% L1 2.0 equiv Cs 2 C 3 DMF, room temp n a, n= C yield, % 45 (92) C : C 3:1 (40:1) 45:1 >50:1 >50:1 >50:1 L2 2 I 2 n 5% CuI, 10% L2 2.0 equiv Cs 2 C 3 toluene, 90 C 2 n a, n= C yield, % (64) C : (C+dble) 1:6 1:4 (2:1) 18:1 20:1 24:1

15 - and -Arylation of 4- and 3-Piperindinols Selectivity in ligand-assisted reactions is only achieved for nonchelating aminoalcohols 1-amino-3-propanol represents a borderline case Test chelation hypothesis by arylation of 3- and 4-piperidinols 80% (30:1) p-tol CuI, L1 DMF CuI, no lig C 3 C, rt p-tol 83% (25:1) I p-tol CuI, L2 CuI, no lig lot-p 81% (16:1) toluene TF, 100 C 52% (2:1)

16 - and -Arylation of 4-Aminophenethyl Alcohol Ar = p-tolyl Ar Pd 2 dba 3 CuI, L2 XPhos 2 2 X = Cl, 91% X = I, 88 % X Ar -arylation of aromatic amines proved to be difficult Required switch to palladium catalyst

17 Working ypothesis of the chanistic Cycle u LCu[X] u LCu [X] u Ar-u ArX LCu-u Cs 2 C 3 CsC 3, CsX Coordination and deprotonation are interdependent events and result in observed selectivities For anionic L1, the lowered electrophilicity of Cu(I) center might disfavor binding of alcohol The more Lewis-acidic L2 Cu(I) species may lead to non-negligible concentration of the copper-bound alcohol

18 Conclusions Benefits Good selectivity for -arylation Suppression of Ullmann coupling Relatively mild reaction conditions Limitations -arylation of aryl amines difficult -arylation not as selective as -arylation Chelation effects of aminoalcohols with shorter spacer lengths limit chemoselectivity In some cases presence of ligand decreases selectivity Selectivity in ligand-assisted reactions only achieved for non-chelating aminoalcohols