Literature Report III

Transcription

1 Literature Report III Regioselective ydroarylation of Alkynes Reporter: Zheng Gu Checker: Cong Liu Date: Cruz, F. A.; Zhu, Y.; Tercenio, Q. D.; Shen, Z.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, Ding, D.; Mou, T.; Feng, M.; Jiang,. J. Am. Chem. Soc. 2016, 138,

2 Contents Introduction Rh-Catalyzed asymmetric hydroheteroarylation of alkynes Au-Catalyzed regiodivergent hydroarylation of alkynes Summary 2

3 CV of Vy M. Dong Full Professor: University of California at Irvine Education and Professional Appointments: 1998 B. S. University of California at Irvine Irvine 2000 M. S. University of California at Berkeley D. California Institute of Technology 2006 Assistant Professor University of Toronto 2010 Associate Professor University of Toronto 2012 Full Professor University of California at Irvine Research: Vy M. Dong ew reaction methods, enantioselective catalysis, and natural product synthesis. 3

4 Alkyne ydrofunctionalization Proposed chanism 4

5 Formation of C- Bond via Rh-π-allyl Species Breit, B. et al. J. Am. Chem. Soc. 2011, 133, Breit, B. et al. Angew. Chem. Int. Ed. 2016, 55,

6 Formation of C- Bond via Rh-π-allyl Species Dong, V. M. et al. J. Am. Chem. Soc. 2015, 137, Breit, B. et al. Chem. Eur. J. 2016,, 22,,

7 Formation of Csp 3 -C Bond via Rh-π-allyl Species Breit, B. et al. rg. Lett. 2016, 18, [Rh]/DPEphos up to 97% yield Dong, V. M. et al. Chem. Commun. 2016,, 52,,

8 Formation of Csp 3 -C Bond via Rh-π-allyl Species Ar 2 Ar 2 + Ar 1 Rh- (R)-DTBM- BIAP (S,S)- amine (R,R)- amine C anti Ar 1 up to 96%yield >20:1 dr, >99% ee (S,S)-amine Ar 2 syn C Ar 1 up to 93%yield 12:1 dr, >99% ee (R,R)-amine 2 2 Dong, V. M. et al. J. Am. Chem. Soc. 2017, 139,

9 Alkyne ydroarylation ucleophilicity Effects Ar + [Rh(CD)Cl] 2 (4.5 mol%) dppf (9 mol%) Ar () 2 P() (50 mol%) + DCE (0.5 M), 60 o C Ar Et 29% 35% 65% 24% = 1.33 = 2.48 = = Mayr, et al. J. ys. rg. Chem. 2008, 21,

10 Alkyne ydroarylation Ligand Effects [Rh(CD)Cl] 2 (4.5 mol%) Ligand (9 mol%) 1a + () 2 P() (50 mol%) DCE (0.5 M), 60 o C, 3 h 2a 3a + 4a a) osphine Substituent tbu P R = BIAP P (L1) 5% 20% ee Tol (L2) 13% 28% ee increasing bulk tbu DTBM (L3) 81% 93% ee b) Ligand Scaffold, R = DTBM P P P P P P SEGPS (L4), 31%, 90% ee -BIPEP (L5), 18%, 89% ee GARPS (L6), 23%, 96% ee 10

11 Alkyne ydroarylation Various Indoles 11

12 Alkyne ydroarylation Various Alkynes + Ar 1a 2 [Rh(CD)Cl] 2 (2.5 mol%) Ligand (5 mol%) () 2 P() (50 mol%) DCE (0.5 M), 60 o C Ar 3 >20:1 rr R R= 4-3ab, 76% 89% ee 4-3ac, 70% 82% ee 2-3ad, 76% 93% ee S 4-tBu 3ae, 88% 89% ee 4-F 3af, 93% 90% ee 4-Cl 3ag, 82% 88% ee 4-C 2 Et 3ah, 92% 81% ee F 3 C 3ai, 97%, 92% ee 3aj, 81%, 88% ee 3ak, 96%, 94% ee 3al, 0% (only starting material) 12

13 enylallene ydroarylation 1a + 2a [Rh(CD)Cl] 2 (2.5 mol%) (R)-DTBM-BIAP (5 mol%) () 2 P() (50 mol%) DCE (0.5 M), 60 o C, 3h 3aa, 86% 91% ee, >20:1 rr + 1a 4 [Rh(CD)Cl] 2 (2.5 mol%) (R)-DTBM-BIAP (5 mol%) () 2 P() (50 mol%) DCE (0.5 M), 60 o C, 3h 3aa, 33% 91% ee, >20:1 rr 13

14 ydroarylation and Cascade Cyclization Previous work: Cat. = electron-donating group and Two major challenges: 1) regioselectivity 2) electron-deficient substituents Echavarren, A. M. et al. Chem. Eur. J. 2006, 11, Jiang's concept: R 2 Ligand-compensated 'pull' 'push' Ligand-directed " -system-pushing" LAu " -system-pulling" = functional group 14

15 ydroarylation and Cascade Cyclization L2Au R L1Au Au L1 R R L2Au Two-coordinate gold -alkyne complexes L2 = electron-rich ligand Au Ag "Relay" Three-coordinate gold -alkyne complexes L1 = electron-deficient ligand R R R =F,,C,etc Low steric demand Electronic contradiction = C Construction of quarternary substituted carbon = C igh regioselectivity Sterically hindered cyclization 15

16 Proposed chanism 16

17 Proposed chanism Ag 2a Ts Ag F Ts Ag + relay catalysis Ag G Ts 4a Ts 17

18 para-position Cyclization L2AuTf 2 (5 mol%) ipr PCy 2 ipr = C 1 3 ipr L2 Ts Ts Ts Ts Ts Ms 3a, 87% 3b, 73% Cl 3c, 68% 3d, 61% 3e, 85% 3f, 84% S 3g, 82% 3h, 75% 3i, 60% 3j, 65% 3k, 77% 18

19 para-position Cyclization R L2AuTf 2 (5 mol%) R ipr PCy 2 ipr DCE, 80 o C 1 5 ipr L2 F Cl I C 2 Ts Ts Ts Ts Ts 5a, 83% 5b, 90% 5c, 92% 5d, 81% 5e, 69% CEt 5f, 70% Ts Ts Ts Ts 5g, 75% 5h, 65% 5i, 82% Ts =,5j, 95% =Ac,5k, 88% 19

20 ortho-position Cyclization = C L 1 AuTf (5 mol%) P L1 tbu tbu

21 Au/Ag Relay Cascade Cyclization Catalyst Ts Cl, 110 o C Ts Cat. Yield (2,4-tBu 2C 6 3 ) 3 PAuTf (5 mol%) 0% (2,4-tBu 2 C 6 3 ) 3 PAuCl (5 mol%) /AgTf (10 mol%) AgTf (10 mol%) 80% 85% 21

22 Au/Ag Relay Cascade Cyclization L1AuCl (5 mol%) AgTf (10 mol%) Cl, 110 o C 1 4 R P L1 tbu tbu 3 22

23 Summary Dong, V. M. et al. J. Am. Chem. Soc. 2017, 139, L2AuTf 2 (5 mol%) L1AuTf (5 mol%) PCy 2 P tbu ipr ipr ipr L2 L1 tbu 3 Jiang,. et al. J. Am. Chem. Soc. 2016, 138,

24 The First Paragraph Aryl and heteroaryl rings can be used to increase nonbonding and electrostatic interactions between a small molecule and its macromolecule target. Among the top selling therapeutics, more than half contain aryl structures. Given the relevance of chirality in medicine, inventing enantioselective tools for introducing aromatic nucleophiles warrants pursuit. The hydroarylation of alkynes is amodern strategy t for functionalizing i aryl structures, where two simple functional groups are coupled with high atom economy. To date, however, this approach has been limited to generating achiral olefins. 24

25 The First Paragraph Classic alkyne hydroarylations generate achiral vinylated arenes via mechanisms that involve alkyne activation with π-acids or arene activation to access aryl-metal species. In contrast, we imagined using metal-hydride catalysis to couple arenes with alkynes to form allylated products. In this communication, we disclose a regio- and enantioselective alkyne hydroheteroarylation using indoles. 25

26 The Last Paragraph We have demonstrated a regio- and enantioselective way to hydrofunctionalize alkynes using indoles. The use of Rh-hydride catalysis to isomerize alkynes has enabled access to a complementary hydroheteroarylation motif. Moreover, our study demonstrates the potential of generating C C bonds under mild conditions using both aromatic and heteroaromatic motifs. Given these promising results, our future studies will focus on enantio- and regioselective coupling using other classes of aromatic nucleophiles. 26

27 Acknowledgment Thanks for your attention 27