Branched-Regioselective Hydroformylation with Catalytic Amounts of a Reversibly Bound Directing Group

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1 1/12 Branched-egioselective ydroformylation with Catalytic Amounts of a eversibly Bound Directing Group h(i)/me C/ 2 MS 4A branched major by Christian U. Grünanger and Bernhard Breit Angew. Chem. Int. Ed. 2008, 47, early view Karla Bravo Current Literature 08/30/2008 Karla Wipf Group Page 1 of 12 9/7/2008

2 ydroformylation of olefins. An industrial atom-economic C/C-bond forming reaction 2/12 Important industrial process for the production of aldehydes and ketones: > 7 million tons of oxo products/year. Based on homogeneous catalysis: Co(C) 4 (tto oelen, 1938), rhodium(i)complexes, h(c)(pph 3 ) 3 (Wilkinson, 1968). Linear-selective hydroformylation of terminal alkenes, Ligands (L): BISBI, XANTPS. FG h(i)/l C/ 2 Syngas FG linear FG Me branched PPh 2 BISBI linear : branched 66 : 1 for 1-hexene PPh 2 XANTPS linear : branched 53 : 1 for 1-octene Synthetic challenge: Control of Branched-egioselectivity No catalyst is known for a general branched-selective hydroformylation of terminal and internal alkenes. Simultaneous control of both, enantio- and regioselectivity in enantioselective hydroformylations has not yet been achieved. Ligand: PPh 2 P (,S)-BINAPS FG FG = Ph, G = Et, h(i)/l C/ 2 12 : 88 (94% ee) 79 : 21 (83% ee) FG = Ac, 14 : 86 (92% ee) Syngas FG linear FG Me branched Efforts have been directed towards the development of a Substrate-Directed eaction Breit, B. Acc. Chem. es. 2003, 36, Karla Wipf Group Page 2 of 12 9/7/2008

3 Towards the development of a branched-regioselective hydroformylation reaction 3/12 Use of substrate-bound directing groups (stoichiometric( amounts): phosphite and phosphine groups Chelation-control by phosphite esters in cyclic and acyclic homoallylic systems. P(Et) 2 i C ii 80% P(Et) 2 90% i. 2 /C (1:1, 500 psi), [h(ac) 2 ] 2 (alkene:h, 50:1), benzene, 100 o C, 44h, ii. LA, Et 2 =, Me, Ph P(Et) 2 i, ii 70-85% Jackson, W.. et al., J. Chem. Soc. Chem. Commun. 1990, Identification of o-dppb esters (ortho-(diphenylphosphanyl) benzoyl) as efficient catalyst-directing groups (CDG) in the branched-selective hydroformylation of allylic esters. x o-dppa, DCC, DMAP DCM, rt (CDG) x CDG = h (I) C/ 2 (o--dppb) (o--dppb) (o--dppb) n n C n C =, alkyl, TBDPS =, quant., 97 : 3 n = 1 = cex, 84%, 81 : 19 = TBDPS, 87%, 90 : 10 PPh 2 = o-dppb (o--dppb) (CDG) x branched major C (o--dppb) C (CDG) x linear minor C 96 : 4 (quant.) C (o--dppb) n = 2 =, 89%, 58 : 42 Breit,B. et. al. Eur. J. rg. Chem. 2007, Karla Wipf Group Page 3 of 12 9/7/2008

4 The concept of using catalytic amounts of a directing group to control regioselectivity 4/12 Use of catalytic amounts of a directing group Supramolecular catalyst strategies (a) Encapsulated rhodium catalyst By Self-Assembly C [h] 2 /C b non-encansulapted cat. (l/b = 2.8) encansulapted cat. (l/b = 0.6, 63% b) l C non-encapsulated cat. (25 o C): 17% conv., 2 (55.6%), 3 (43.8%) (80 o C): 61% conv., 2 (53.3%), 3 (22.4%) encapsulated cat. (25 o C): 32% conv., 2 (9.4%), 3 (87.8%) (80 o C): 88% conv., 2 (35.2%), 3 (20.9%) Conditions: [h(acac)(c) 2 ] = 0.7 mmol/l, toluene, P( 2 /C) =10 bar, substrate/h = 1052, [phosphorus] = 6.4 mmol/l h eek, J. N.. et al. J. Am. Chem. Soc. 2006, 128, eek, J. N.. et al. Chem. Eur. J. 2006, 12, Karla Wipf Group Page 4 of 12 9/7/2008

5 The concept of using catalytic amounts of a directing group to control regioselectivity 5/12 (b) Mix. guanidine-phosphine based supramolecular ligand o-dppb Covalent ligand-substrate bond prevents use of substoichiometric amounts of the ligand. For = h (I / ligand C/ 2 linear (l) For = Me : a b branched (b) (l/b) receptor-based ligand Combination of phosphine ligand & guanidinium-bases recognition unit for carboxylic acid substrates N N N L n h N PPh 3 (6) xantphos (7) no ligand (8) N (9) N N X X = C, (10) X = N, (1) N N 2 N 2 For an internal alkene, =Me Ligand: 1, 80.5% conv., 11:1 (a/b) Breit, B. et. al. Angew. Chem. Int. Ed. 2008, 47, Karla Wipf Group Page 5 of 12 9/7/2008

6 Title Paper: Use of catalytic amounts of phosphinites as reversible-bound directing groups for the branched regioselective hydroformylation of homoallylic alcohols Why phosphinites? o eversible exchange with phenols and alcohols in the presence of basic or acidic catalysts. 6/12 ArX n (1.5 eq) cocatalyst [hcl(pph 3 ) 3 ] (5 mol%), P 2 (Ar) (15 mol%) Cs 2 C 3 (1.7 eq), toluene (reflux) Bedford n Ar P 2 Ar L n h 1 base transesterification ArX ox. addn. 2 L n h Ar X 1 P 2 base -X 1 Ar 2 Cocatalyst 1 2 P L n h Ar 2 red. elim. 2 P L n h 2 Ar Bedford,. B. et al. Angew. Chem. Int. Ed. 2003, 42, Karla Wipf Group Page 6 of 12 9/7/2008

7 Title Paper: Phosphinites do the trick 7/12 ypothesis: Attachment of a P 2 group to the group of an homoallylic alcohol might alllow the formation of a six- versus seven-memebered chelate, which should favor the branched aldehyde product. PPh 2 h(i), 2 P() Ph 2 P Ln h C/ 2 6-ring chelate Proof of concept: [h(c) 2 acac] (1 mol%) PPh 3 (10 mol%) C/ 2 (1:1, 20 bar) toluene, 40 o C, 20 h (99%) 27 : 73 [h(c) 2 acac] (1 mol%) C/ 2 (1:1, 20 bar) toluene, 40 o C, 20 h (99%) 99 : 1 acac = acetylacetonate Me (excess), tetrazole [ - Me ] (quant.) = PPh 2 = Karla Wipf Group Page 7 of 12 9/7/2008

8 Title Paper: Phosphinites do the trick 8/12 ptimization of the branched-regioselective hydroformylation using catalytic amounts of phosphinites as CDG (CDG = catalyst directing group). [h(c) 2 acac] (1 mol%) ligand (10 mol%) C/ 2 (1:1, 20 bar) 40 o C, 20 h Ligands: (2) Me (3) Karla Wipf Group Page 8 of 12 9/7/2008

9 Title Paper: Phosphinites do the trick Development of the position-selective hydroformylation of homoallylic alcohols using a catalytic amount of a CDG [h(c) 2 acac] (1 mol%) Me (3) (10 mol%) C/ 2 (1:1, 20 bar) TF, MS 4A, 40 o C, 12 h entry substrate major product PCC/Al 2 3 (2 equiv) NaAc (0.5 equiv) C 2 Cl 2, rt, 12 h conv. [%] a yield lactones [%] b regioselectivity c (!:") 9/ : 1 (27 : 73) >99 : < 1 (54 : 46) >99 : < 1 (52 : 48) : 3 (65 : 35) : 1 (45 : 55) 6 n-pent : 3 (28: 72) [a] Conversion determined by GC after hydroformylation. [b] Yields based on conversion of hydroformylation step. [c] egioselectivity of the hydroformylation reaction determined at the stage of the lactols by GC and reconfirmed by NM spectroscopy after oxidation to the corresponding lactones. In brackets: egioselectivity of the hydroformylation with 10 mol% PPh3 as the ligand under otherwise identical conditions. Karla Wipf Group Page 9 of 12 9/7/2008

10 Title Paper: Phosphinites do the trick 10/12 [h(c) 2 acac] (1 mol%) Me (3) (10 mol%) C/ 2 (1:1, 20 bar) TF, MS 4A, 40 o C, 12 h PCC/Al 2 3 (2 equiv) NaAc (0.5 equiv) C 2 Cl 2, rt, 12 h entry substrate major product conv. [%] a yield lactones [%] b regioselectivity c (!:") 7 SMe SMe : 3 (48 : 52) : : : 1 11 Me Me C 6 not isolated 53 : 47 (54 : 46) [a] Conversion determined by GC after hydroformylation. [b] Yields based on conversion of hydroformylation step. [c] egioselectivity of the hydroformylation reaction determined at the stage of the lactols by GC and reconfirmed by NM spectroscopy after oxidation to the corresponding lactones. In brackets: egioselectivity of the hydroformylation with 10 mol% PPh3 as the ligand under otherwise identical conditions. Karla Wipf Group Page 10 of 12 9/7/2008

11 Title Paper: Plausible catalytic cycle 11/12 1 Phosphinite Transesterification (reversible) 4 Me 3 1 Me 2 [L n h] Directed ydroformylation [L n h] Ph 2 P Ln h C/ 2 6-ring chelate 3 is a catalyst-directing group (CDG) operating through reversible substrate- and catalyst-binding Karla Wipf Group Page 11 of 12 9/7/2008

12 Summary and Conclusions 12/12 Phosphinites work as reversibly bound catalyst-directing groups in catalytic amounts for the branchedregioselective hydroformylation of homoallylic alcohols with terminal alkenes, and position-selective hydroformylation of internal alkenes. 1 Phosphinite Transesterification (reversible) 4 r.r. 97:3-99:1 Me 3 Directed ydroformylation 1 Me 2 [L n h] Ph 2 Ln [L n h] P h C/ 2 6-ring chelate The present methodology provides an efficient entry to γ-lactols and -lactones, which are useful synthetic building blocks. x Limited to a particular functionality (-heteroatom): homoallylic alcohols. Future work: - Control of diastereo- and enantioselectivity in branched-regioselective hydroformylation reactions. Karla Wipf Group Page 12 of 12 9/7/2008