Enantioselective 1,1-Arylborylation of. Transfer with Pd Catalysis

Transcription

1 Enantioselective 1,1-Arylborylation of Alkenes: Merging Chiral Anion Phase Transfer with Pd Catalysis Reporter: Lian-Jin Liu Checker: Wen-Xue Huang Date: 12/05/2015 F. Dean Toste University of California, Berkeley Toste, F. D. et al. J. Am. Chem. Soc. 2015, 137, CHEMICAL MARKET RESEARCH INC.

2 Contents Introduction Enantioselective 11-Arylborylation 1,1-Arylborylation of Alkenes Diastereoselective Carbonyl Allylation with Simple lefine Enabled by Palladium Complex-Catalyzed C-H xidative Borylation Summary 1

3 Introduction ti 2

4 Three-Component Coupling of Heteroaryl Pinacol Ester, Vinyl Nonaflates, and dethylene HetAr Bpin + + Nf 5mol%Pd 2dba 3,DMA (0.1 M) NaHC 3 (1.7 equiv), 15 psi 15 mol% dba, 17 o C, 36 h HetAr 7 examples, 50~89% Sigman, M. S. et al. J. Am. Chem. Soc. 2012, 134,

5 Single-Step St Enantioselective 11A 1,1-Arylborylation l This work R + B 2 (pin) 2 + N 2 BF 4 1step B(pin) R Ar pin = pinacolato 4

6 Proposed Dual Catalytic ti Cycle for Pd-CAPT 1,1-Arylborylation1 l R PdL n P * R insertion H elimin. and reinsertion PdL n P 13 * Pd-catalysis R PdL n P 15 * ox. edd. N 2 P * L n Pd 0 transmet. and red. elim. B 2 pin 2 12, soluble chiral ion pair Ar N 2 BF 4 11, insoluble P CAPT * base pinb P * + R Bpin 10 5

7 Non-Enantioselective Scope a,b a Conditions:ArN 2 BF 4 (1 equiv), B 2 (pin) 2 (1.2 equiv), Pd 2 (pda) 3 ( equiv), alkene (1 equiv), THF, 25 C, 2-8 h. b Isolated yields. c NMR yield. 6

8 Non-Enantioselective Scope a,b a Conditions:ArN 2 BF 4 (1 equiv), B 2 (pin) 2 (1.2 equiv), Pd 2 (pda) 3 ( equiv), alkene (1 equiv), THF, 25 C, 2-8 h. b Isolated yields. c NMR yield. 7

9 ptimization i of Enantioselective 11A 1,1-Arylborylation l a,b entry cat. solvent base additive ee (%) yield (%) 1 28 hexane NaHC < THF NaHC 3 - < Et 2 NaHC Et 2 NaHC 3 - < Et 2 NaHC Et 2 K 2 C Et 2 Na 3 P Et 2 Na 3 P 4 30a Et 2 Na 3 P 4 30b a Enantiomeric excess determined by chiral phase HPLC. b Yield dertermined by 1 H NMR utilizing dimethyl sulfone as an internal standard. 8

10 Enantioselective Scope a,b a) a Enantiomeric i excess determined d by chiral phase HPLC. b Yield dertermined d by 1 H NMR utilizing i dimethyl sulfone as an internal standard. 9

11 Enantioselective Scope a,b b) a Enantiomeric i excess determined d by chiral phase HPLC. b Yield dertermined d by 1 H NMR utilizing i dimethyl sulfone as an internal standard. 10

12 Diastereoselective Carbonyl Allylation with Simple lefins Enabled by Palladium Complex-Catalyzed C l C-H Hxidative Borylation 11

13 Szabó and Coworkers: ptimal Conditions for the Allylation of Aldehydes d with Exocyclic lefins Pd(TFA) 2 (10 mol%) + RCH + B 2 Pin 2 DMBQ (2.0 equiv) TFA (0.5 equiv) R solvent, 24 h H H 11 examples, 14-80% yield dr > 9:1 Szabó, K. J. et, al. Chem. Comun. 2014, 50,

14 Evaluation of Catalyst Systems and ptimization of Reaction Conditions a a Unless indicated H Ph + 2 N CH 10 mol% [Pd], [] B 2 (pin) 2 (3), 50 o C 1a 2a 4aa Ph S S Pd(Ac) 2 5 Ph F S 2 Ph N S 2 Ph NFSI entry 1a/2a/3 Pd oxidant additive (x mol%) yield (%) b Ph Ph 2 N 8a P H H Ph otherwise, the reaction of 1a (0.1 mmol), 2a (0.12 mmol), 3 (0.12 mmol), an oxidant (0.2 mmol), and palladium complex (0.01 mmol) was carried out for 24 h in toluene (1.5 ml). b Isolated yield with > 20/1 dr. ND = not detected. c Reaction 1 1/1.2/1.2 Pd(TFA) 2 DMBQ TFA (50) trace c was carried out in PhCF 3 (0.5 ml). 2 1/1.2/1.2 5 BQ AcH (200) trace d d Cinnamyl acetate 6 was generated. 3 1/1.2/1.2 5 BQ 8a (20) trace e 4 1 /1.2/1.2 5 PhI(Ac) 2 8a (20) ND e Compound 7 was generated. f In the presence of PPh 3 5 1/1.2/1.2 5 PhI(TFA) 2 8a (20) ND (0.02 mmol). g In 6 1/1.2/ NFSI 8a (20) 20 DMS (1.5 ml). h In THF (1.5 ml). i In 7 1.2/1/1.2 5 NFSI 8a (20) 23 PhCF 3 (1.5 ml). j 1.05 g (7 mmol) of 8 1.2/1/1.2 Pd(PPh 3 ) 4 NFSI 8a (20) 54 2a was used. 13

15 Evaluation of Catalyst Systems and ptimization of Reaction Conditions a a Unless indicated H otherwise, the CH H 10 mol% [Pd], [] reaction of 1a (0.1 + mmol), 2a (0.12 Ph B 2 N 2 (pin) 2 (3), 50 o C Ph 2 N mmol), 3 (0.12 1a 2a 4aa mmol), an oxidant (0.2 mmol), and S 2 Ph Ph palladium complex S S F N P Ph Ph (0.01 mmol) was Pd(Ac) 2 S 2 Ph Ph H carried out for 24 h 5 NFSI 8a in toluene (1.5 ml). b Isolated yield with > entry 1a/2a/3 Pd oxidant additive (x mol%) yield (%) b 20/1 dr. ND = not detected. c Reaction 9 2/1/2 Pd(PPh 3 ) 4 NFSI 8a (20) 81 was carried out in PhCF 3 (0.5 ml). 10 2/1/2 Pd(PPh 3 ) 4 NFSI - 69 d Cinnamyl acetate /1/2 Pd(dba) f 2 NFSI 8a (20) 90 (92 j ) was generated. e Compound 7 was 12 2/1/2 Pd(TFA) f 2 NFSI 8a (20) 71 generated. f In the presence of PPh 13 2/1/2 Pd(Ac) f 3 2 NFSI 8a (20) 57 (0.02 mmol). g In 14 2/1/2 Pd(dba) f,g 2 NFSI 8a (20) <5 DMS (1.5 ml). h In THF (1.5 ml). i In 15 2/1/2 Pd(dba) f,h 2 NFSI 8a (20) 61 PhCF 3 (1.5 ml). j 1.05 g (7 mmol) of 16 2/1/2 Pd(dba) f,i 2 NFSI 8a (20) 76 2a was used. 14

16 Substrate t Scope a entry 1(R 1, R 2 ) 2(R 3 ) 4 yield (%) b,c a Unless indicated otherwise, 1 1b (4-FC 6 H 4,H) 2a (4-N 2 C 6 H 4 ) 4ba 67 thereactionof1 (0.2 mmol), 2 (0.1 mmol), B 2 (pin) 2 (3) ( c (4-ClC 6 H 4,H) 2a (4-N 2 C 6 H 4 ) 4ca 68 mmol), Pd(dba) 2 (0.01 mmol), PPh 3 1d (4-MeC 6 H 4,H) 2a (4-N 2 C 6 H 4 ) 4da 74 3 (0.02 mmol), 8a (0.02 mmol), and NFSI (0.2 mmol) 4 1e (4- t BuC H,H) 2a (4-N C H ) 4ea 61 was carried out in toluene ( ml) at 50 C or 24 h. b Isolated 5 1f (C 6 H 5,H) 2a (4-N 2 C 6 H 4 ) 4fa 86 yield. c Unless indicated otherwise, the ratio of anti / 6 1g (1-Naphthyl, H) 2a (4-N 2 C 6 H 4 ) 4ga 93 syn, which was determined by 7 1h (2-Naphthyl, H) 2a (4-N 1 H NMR of the crude product, 2 C 6 H 4 ) 4ha 97 was > 20/1. d P(Ph) 8 d,e 3 (0.01 1i (H, Ph) 2a (4-N 2 C 6 H 4 ) 4ia 65 mmol) was added instead of 9 d,e 1j (Me, Ph) 2a (4-N 2 C 6 H 4 ) 4ja 85 f PPh 3. e (Ph) 2 P 2 H was not added. f The ratio of anti / syn 10 d 1k cyclohexene 2a (4-N 2 C 6 H 4 ) 4ka 73 was 1 /

17 Substrate t Scope a entry 1(R 1, R 2 ) 2(R 3 ) 4 yield (%) b,c a Unless indicated otherwise, 11 1a (Ph, H) 2b (Ph) 4ab 67 thereactionof1 (0.2 mmol), 2 (0.1 mmol), B 2 (pin) 2 (3) ( a (Ph, H) 2c (3-MeC 6 H 4 ) 4ac 64 mmol), Pd(dba) 2 (0.01 mmol), PPh 13 1a (Ph, H) 2d (4-FC 6 H 4 ) 4ad 87 3 (0.02 mmol), 8a (0.02 mmol), and NFSI (0.2 mmol) 14 1a (Ph, H) 2e (4-ClC H ) 4ae 89 was carried out in toluene ( ml) at 50 C or 24 h. b Isolated 15 1a (Ph, H) 2f (4-BrC 6 H 4 ) 4af 85 yield. c Unless indicated otherwise, the ratio of anti / 16 1a (Ph, H) 2g (2-N 2 C 6 H 4 ) 4ag 99 syn, which was determined by 17 1a (Ph, H) 2h (3-N 1 H NMR of the crude product, 2 C 6 H 4 ) 4ah 99 was > 20/1. d P(Ph) 3 ( a (Ph, H) 2i (4-CF 3 C 6 H 4 ) 4ai 81 mmol) was added instead of PPh 19 1a (Ph, H) 2j (2-Naphthyl) 4aj e (Ph) 2 P 2 H was not added. f The ratio of anti / syn 20 1a (Ph, H) 2k (c-c 6 H 11 ) 4ak 44 was 1 /

18 Allylationl of Isatins 17

19 Mechanistic Studies 18

20 Plausible Reaction Mechanism 19

21 Summary Me (pin)b Me Ar-N 2 BF 4, B 2 (pin) 2 5mol%Pd 2 (dba) 3 10 mol% TCyP (27) 16 mol% m-cf 3 -dba (30) Na 3 P 4,Et 2 Ar 7 examples, 32-58% yield 84-98% ee (pin)b Et Ar Et 5 examples, 29-47% yield 84-98% ee Toste, FDet F. D. al. J. Am. Chem. Soc. 2015, 137, Gong, L.-Z. et al. J. Am. Chem. Soc. 2015, 137,

22 Benzylic boronic esters are attractive building blocks for complex biologically active natural products and pharmaceuticals as they participate in several well-established stereospecific transformations that forge C, C N, or C C bonds. Accordingly, there has been significant interest in developing new enantioselective methods thatt afford these motifs. Examples of catalytic ti enantioselective hydroboration, allylic borylation, conjugate borylation, reductive transformations of vinyl boronates and 1,2-diborylation of aromatic imines and styrenes have been reported. Furthermore, several enantioselective borylation reactions utilizing stoichiometric amounts of chiral auxiliaries have been disclosed. 21

23 Recently, several methods have been reported that rely on transformations of 1,1-diborylated alkanes. For example, Hall and Yun have reported the preparation of enantioenriched 1,1-diborylated alkanes that undergo chemoselective coupling to provide highly enantioenriched benzylic organoboronates. In a related contribution, Morken and co-workers have disclosed an enantioselective Suzuki reaction of 1,1-diboronates to provide highly enriched boronic esters. While these methods ultimately access valuable enantioenriched benzylic boronates, they require a multistep synthetic sequence. From the perspective of synthetic divergence and stepeconomy, an ideal transformation would involve one-step installation of both the boronate and aryl functional groups. 22

24 In conclusion, we have disclosed a modular and step-economical economical method for the direct preparation of chiral benzylic boronates from terminal alkenes. Furthermore, this process was rendered enantioselective through the use of a chiral anion phase-transfer strategy. We expect the coupling of CAPT and Pd catalysis to have broad implications, as it provides an alternative strategy for achieving enantioinduction in ligand-less reaction manifolds where chiral ancillary ligands have a deleterious effect. 23

25 24