Denmark Group Meeting. & Electrophilic rearrangement of amides

Denmark Group Meeting Palladium catalyzed Dearomatizationeaction & Electrophilic rearrangement of amides 11 th Bo Peng th Feb. 2014 1

https://maps.google.com 2

Palladium catalyzed Dearomatization eaction & Electrophilic rearrangement of amides 3

Palladium catalyzed Dearomatization eaction: background Dearomatization eaction Starting material Aromatic compounds product Alicyclic compounds atural products a) oche, S. P.; Porco, J. A., Jr. Angew. Chem.,Int. Ed. 2011, 50, 4068 4093; b). Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235 2261. 4

Palladium catalyzed Dearomatization eaction: background 1. oxidative dearomatization 4. nucleophilic additive dearomatization 2. reductive dearomatization 5. σ rearrangement dearomatization 3. photocatalyzed dearomatization 6. transitionmetals promoted dearomatization 1 1 1 2 Li 2 3 3 X 2 Cr(C) 3 Cr(C) 3 + 3 5

Palladium catalyzed Dearomatization eaction: background Application of [(η 6 Arene) Mn(C) 3 ] + Ph (i) LDA (ii) (C) 3 Mn Ph (C) 3 Mn C 2 Me (+)juvabione Miles, W..; Brinkman,.. Tetrahedron Lett. 1992, 33, 589 6

Palladium catalyzed Dearomatization eaction: background Palladium catalyzed dearomatization reactions a). Bao, M.; akamura,.; Yamamoto, Y. J. Am. Chem. Soc., 2001, 123, 759; b). Fortanet, J. G.; 7 Kessler, F.; Buchwald, S. L. J. Am. Chem. Soc., 2009, 131, 6676

Palladium catalyzed Dearomatization eaction: background Tsuji Trost reaction Palladium catalyzed ucleophilic Dearomatization?? 8

Palladium catalyzed Dearomatization eaction: background egional Selectivity? 9

Palladium catalyzed Dearomatization eaction: background Possible solutions Pd Cl u A: introducing group B: reducing aromacity C: intramolecular nucleophile Pd Cl u Pd Cl u n 10

Palladium catalyzed Dearomatization eaction: exploration Cl CEt CEt 4 a -20 - rt >99 11

Palladium catalyzed Dearomatization eaction: exploration 12

Palladium catalyzed Dearomatization eaction: scope study Cl 1 2 2 1 CEt Pd(PPh 3 ) 4 (5 mol%) CEt 1.0 eq a, TF 3 rt, 5-12 h 3 1 2 CEt CEt Me F Br Ph CEt CEt CEt CEt CEt CEt CEt CEt 2a, 93% Me 2b, 86% 2c, 92% 2d, 71% Me CEt CEt Ph Ph CEt CEt Ph Me CEt CEt Ph Br CEt CEt 2e, 63% 2e, 75% 2f, 90% 2g, 72% Ph CEt EtC CEt Ph CEt Me 2h, 30% 3h, 64% Me 13

Palladium catalyzed Dearomatization eaction: application Application to Tetracyclic Compounds 14

Palladium catalyzed Dearomatization eaction: u scope 15

Palladium catalyzed Dearomatization eaction: intramolecular Intramolecular palladiumcatalyzed dearomatization 7a Cl CEt CEt Pd(PPh 3 ) 4 ( 5 mol%) a (1.0 equiv), TF -20 Ctort,12h rearomatization CEt CEt 7A EtC CEt CEt CEt 8a (52%) EtC CEt 9 (25%) Cl CEt CEt Pd(PPh 3 ) 4 ( 5 mol%) CEt CEt a (1.0 equiv), TF -20 Ctort,5h 7b 8b (95%) 16

Palladium catalyzed Dearomatization eaction: mechanism Possible mechanism Cl Ph Pd(0) 17

Palladium catalyzed Dearomatization eaction summary recent progress a) Peng, B.; Zhang, S.; Yu, X.; Feng, X.; Bao, M. rg. Lett. 2011, 13, 5402 5405; b). Zhang, S.; 18 Wang, Y.; Feng, X. J. Am. Chem. Soc. 2012, 134, 5492 5495.

Palladium catalyzed Dearomatization eaction & Electrophilic rearrangement of amides 19

Electrophilic rearrangement of amides: background Keteniminium Chemistry [2+2] cycloaddition of Keteniminium Salt Intermolecular Intramolecular Ph Me 2 Tf 2, 2,6-di-t-Bu-py t Bn Bn Ph 65% yield i) Tf 2, DTBMP C 2 Cl 2 ii) 2 * * 62% yield, 92% ee Ph Tf Bn Snider B.B. Chem. ev. 1988, 88, 793 20

Electrophilic rearrangement of amides: background ational design VS Serendipitous result 21

Electrophilic rearrangement of amides: background 2010 Vivi, Claire Tf 2, collidine 120 C, µw, DCE 2 2 1 ( )n n( ) Tf 2, collidine 2 31%- 90% 40%- 76% 9examples 6examples Tf Keteniminum induced Claisen earrangement b). Madelaine C., Valerio V., Maulide., Angew. Chem. Ed. 2010, 49, 1583 1586; c). Valerio V., Madelaine 22 C., Maulide., Chem. Eur. J. 2011, 17, 4742 4745.

Electrophilic rearrangement of amides: content Part 1. ucleophilic/electrophilic p capture of in-situ generated iminium ethers Part 2. Development of Asymmetric α-allylation Part 3. Development of A Brønsted Acid-Catalyzed edox Arylation 23

Part 1. ucleophilic/electrophilic capture of in-situ generated iminium ethers With Daniel and Igor Previous discovery: Tf 2, collidine 120 C C, µw, DCE 24

Part 1. ucleophilic/electrophilic capture of in-situ generated iminium ethers With Daniel and Igor Dual ucleophilic/electrophilic Capture of Iminium ether: 2 25

Part 1. ucleophilic/electrophilic capture of in-situ generated iminium ethers With Daniel and Igor scope of substrates 2, ab 4 26

Part 1. ucleophilic/electrophilic capture of in-situ generated iminium ethers With Daniel and Igor reactions of diastereomeric enriched iminium ether 2d 27

Part 1. ucleophilic/electrophilic capture of in-situ generated iminium ethers With Daniel and Igor Dearomatisation inspired by Ji Woong s SM Tf not observed 11 65% 28

Part 1. ucleophilic/electrophilic capture of in-situ generated iminium ethers With Daniel and Igor Tandem Electrophilic/ucleophilic trap of In Situ Generated Iminium Ethers 1a i. Tf 2, 2,4,6-collidine 120 C, µw, 5 min ii. a, BnBr DMF, 75 C 16 h Br Ph 2g ii. BnBr ucleophilic Capture Electrophilic Capture 29

Part 1. ucleophilic/electrophilic capture of in-situ generated iminium ethers With Daniel and Igor summary 2, ab 4 u 2 1 n n 1 2 Claisen rearrangement Tf 2 n 1 ac, asph, a 3,PPh 3, pyrrolidine, piperidine 41-90% yield 8examples n 2 1 u 28-85% yield 18 examples e) Peng B., Donovan D.., Jurberg I. D., Maulide. Chem. Eur. J. 2012, 18, 16292 16296 30

Electrophilic rearrangement of amides: content Part 1. ucleophilic/electrophilic p capture of in-situ generated iminium ethers Part 2. Development of Asymmetric α-allylation Part 3. Development of A Brønsted Acid-Catalyzed edox Arylation 31

Part 2. Development of Asymmetric α-allylation With Danny Previous discovery: 32

Part 2. Development of Asymmetric α-allylation With Danny Xc = 1a L-prolinol 33

Part 2. Development of Asymmetric α-allylation With Danny emove auxiliary towards α allylated carboxylic acid and aldehyde Ph a) Claisen rearrangement Tf 2 2-fluoropyridine - Tf Ph b) hydrolysis 3 + /dioxane 2a 4a 5a 63% (96%ee) 9 2b Ph a) Claisen rearrangement Tf 2 2-fluoropyridine - Tf c) reduction/ Ph hydrolysis 9 9 K-selectride/ 2 4b 6b 76% (96%ee) a): Tf 2 (1.5eq),2-fluoropyridine(2.0eq),DCM,0 C,12h; b): 2 S 4 /dioxane (1/ 1 ), 100 C, 24 h; c): K-selectride (3.0 eq), -78 C to rt, 3 h, then silica/dcm/ 2, rt, 12 h. 34

Part 2. Development of Asymmetric α-allylation With Danny b) hydrolysis a) Claisen - Tf 5 Ph rearrangement Ph 2 4 c) reduction/ hydrolysis y selected examples 6 8 examples 10 examples in situ hydrolysis to carboxylic acids Ph Ph 3 Br 5c 75%(88%ee) 5d 43%(88%ee) b,c 5g 47%(94%ee) 5h 80%(95%ee) in situ reduction/hydrolysis to aldehydes Me 2 Br 3 Ph 3 6c 68%(90%ee) 6m 6k 6h 87% (90%ee) b,e 55% (90%ee) b,e 54%(91%ee) e 35

Part 2. Development of Asymmetric α-allylation With Danny 36

Part 2. Development of Asymmetric α-allylation With Danny 1 Ph a) Claisen rearrangement 1 * b) reduction/ hydrolysis 2 7 8 2 6 6 n-ex 8a, 72% 8b, 67% 8c, 42% (d.r. 3.2/1, 94% ee) (d.r. 2.6/1, 93% ee) (d.r.3.7/1,94%ee) n-ex 8d, 65% b (d.r. 4.3/1, 94% ee) 8e, 82% c (d.r. 5.3/1, 93% ee) 8f, 53% (d.r. 5.7/1, 92% ee) 8g, 69% c (d.r.3.2/1,87%ee) 37

Part 2. Development of Asymmetric α-allylation With Danny Single crystal X ray determination of the absolute configuration 38

Part 2. Development of Asymmetric α-allylation With Danny Myers alkylation Claisen rearrangement strategy Ph Ph (1S, 2S)-pseudoephedrine Ph LDA, LiCl enolization electrophilic activation Tf 2, 2-F-pyridine Tf (solvent)nli Li(solvent)n Br () Ph (S) Tf Ph =-n-c 10 21 39

Part 2. Development of Asymmetric α-allylation With Danny Mechanistic proposal for the observed diastereo and enantioselectivity steps steps (2S,3S) boat transition state t (disfavored) less hindered f acial interaption (f avored) chair transition state (f avored) less hindered f acial interaption (f avored) (2S,3) 8a (presumed) steps steps (2,3) (2,3S) boat transition state chair transition state =-n-c 10 21 (disfavored) hindered f acial interaption (f avored) (f avored) hindered f acial interaption (disfavored) 40

Part 2. Development of Asymmetric α-allylation With Danny summary Peng, B.; Geerdink, D.; Maulide,. J. Am. Chem. Soc. 2013, 135, 14968 14971 41

Electrophilic rearrangement of amides: content Part 1. ucleophilic/electrophilic p capture of in-situ generated iminium ethers Part 2. Development of Asymmetric α-allylation Part 3. Development of A Brønsted Acid-Catalyzed edox Arylation 42

Part 4. Development of A Brønsted Acid-Catalyzed edox Arylation Previous work: 43

Part 4. Development of A Brønsted Acid-Catalyzed edox Arylation 44

Part 4. Development of A Brønsted Acid-Catalyzed edox Arylation Substrate scope: 4a-m S 2.0 eq. 5a Tf (10 mol%) DCM rt, 30 min PhS 7a-m With uang and Xie 13 examples 44-96% PhS PhS Me PhS Me PhS 7j, 53% 7k, 85% 7l, 83% 7m, 87% ucleophilescope: 45

Part 4. Development of A Brønsted Acid-Catalyzed edox Arylation With uang and Xie labelling experiments: 46

Part 4. Development of A Brønsted Acid-Catalyzed edox Arylation Asymmetric arylation reaction With uang and Xie n-c 10 21 n-c 10 21 Tf (10 mol%) Ph S PhS Ph DCM t-bu t-bu -78 C to rt, 12 h 2.0 eq. 92%, dr = 75:25 8a 5a 9a Synthesis of a dibenzothiophene: h S Tf(10 mol%) n-c 10 21 S n-c 10 21 DCM, rt, 1 h 4a 5n 7an, 72% Elaboration of products: 47

Part 4. Development of A Brønsted Acid-Catalyzed edox Arylation summary 48

Acknowledgements Prof. Ming Bao Prof. uno Maulide 49