Catalytic alkylation of remote C H bonds enabled by proton-coupled electron transfer

Transcription

1 Catalytic alkylation of remote C bonds enabled by proton-coupled electron transfer Reporter: Ji Zhou Checker: Shubo u Date: 2016/11/14 Choi, G. J.; Zhu, Q.-L.; Miller, D. C.; Gu, C. J.; Knowles, R. R. ature 2016, 539, 268

2 Contents Introduction Catalytic alkylation of remote C bonds enabled by protoncoupled electron transfer Amide-directed photoredox-catalysed C-C bond formation at unactivated sp 3 C- bonds Summary

3 Introduction Brief introduction of Robert R. Knowles B.S. in Chemistry, College of William and Mary, 2003; Ph.D. D with David MacMillan, Caltech, 2008; I Postdoctoral Fellow with Eric Jacobsen, arvard University, ; Assistant Professor of Chemistry, Department of Chemistry, Princeton University, 2011-present. Robert R. Knowles Research Synthetic organic chemistry; Asymmetric catalysis Proton-coupled electron transfer (PCET) reaction

4 Introduction Proton-coupled electron transfer (PCET) PT X + Y X + + Y - ET AT PCET ET PT X - + Y + X + Y Redox events in which h an electron and proton are exchanged in a concerted elementary step are commonly referred to as proton-coupled electron transfers (PCETs). PCETs are known to operate in numerous important biological redox processes, as well as recent inorganic technologies for small molecule activation.

5 Introduction Proton-coupled electron transfer (PCET) e - R B - oxidative M n R B M n-1 PCET + ew strategy for challenging homolytic bond activation Unique opportunity for selective radical catalysis M n-1 + A A E reductive E PCET R R R R M n e - Knowles, R. R. et al. Acc. Chem. Res. 2016, 49, 1546.

6 Introduction Conjugate amination enabled by homolytic bond-weakening Ar X C 2 R 1 mol% Cp* 2 Ti III Cl 1 mol% TEMP X Ar C 2 R Ti IV (Cp*) 2 Cl Ar X C 2 R TEMP- Knowles, R. R. et al. J. Am. Chem. Soc. 2015, 137, 6440.

7 Introduction Knowles, R. R. et al. J. Am. Chem. Soc. 2015, 137, 6440.

8 Remote sp 3 C- bonds activation by PCET Classical ofmann-löffler-freytag reactions R R' h R R' X X R R X 1,5-AT X R' R' -functionalization required o methods for the C-C bond formation Challenges in catalytic homolysis of strong - bonds cat - BDFE R R cat kcal mol -1 R R o known catalysts for selective homolysis of strong -alkyl amide - bonds Knowles, R. R. et al. ature 2016, 539, 268.

9 Remote sp 3 C- bonds activation by PCET Catalytic C- alkylation enabled by PCET R R' Ir photocatalyst Phosphate base blue LEDs R R' R'' PCET R AT R'' R' Excited-state iridium oxidant and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate. Undergo acatalytic variant of the classical ofmann Löffler Freytag reaction. Knowles, R. R. et al. ature 2016, 539, 268.

10 ptimization studies Entry Photocatalyst Yield (%) 1 [Ir(dF(CF 3 )ppy) 2 (bpy)]pf 6 (A) 28 F CF 3 2 [Ir(dF(CF 3 )ppy) 2 (dtbbpy)]pf 6 (B) 10 3 [Ir(dF(CF 3 )ppy) 2 (5,5 -dfbpy)]pf 6 (C) 25 F F 3 C Ir(III) R 1 R 2 4 [Ir(dF(CF 3 )ppy) 2 (4,4 -dcf 3 bpy)]pf 6 (D) 78 5 [Ir(dF(CF 3 )ppy) 2 (5,5 -dcf 3 bpy)]pf 6 (E) 82 F R 1 F R 2 Entry Change from entry 5 Yield (%) 6 o light 0 7 o photocatalyst 0 8 o Bu 4 P()(Bu) mol % photocatalyst eq. of methyl vinyl ketone mol% phosphate M PhCF 3 76 A R 1 =,R 2 = B R 1 =,R 2 = t-bu C R 1 = F, R 2 = D R 1 =,R 2 =CF 3 E R 1 =CF 3,R 2 =

11 Substrate scope

12 Substrate scope C 2 i-pr C 2 t-bu C 2 PMP EWG Ph C 2 i-pr C 2 79% 71% 67% 84% C C 2 C 2 C Ph 87% 60% 70% EWG Ph C 2 77% 63% 71% 82% S F 78% 56% 74% 29%

13 Intermolecular C- alkylations Substrate scope

14 Proposed catalytic cycle

15 Remote sp 3 C- bonds activation by Rovis Rovis, T. et al. ature 2016, 539, 272.

16 Proposed photocatalytic cycle

17 Substrate scope

18 Substrate scope

19 Regioselective functionalization + CF C 2 t-bu 3 2 mol% cat. PhCF 3 CF 3 C 2 t-bu 64% TBS CF 3 + C 2 t-bu 4 mol% cat. TBS PhCF 3 CF 3 C 2 t-bu 54% CF 3 C 2 Bn + C 2 t-bu 2mol% cat. PhCF 3 CF 3 C 2 t-bu 46% 4 mol% cat. PhCF 3 C 2 Bn C 2 t-bu CF 3 39%

20 Regioselective functionalization

21 Summary Knowles, R. R. et al. ature 2016, 539, 268. Rovis, T. et al. ature 2016, 539, 272.

22 The first paragraph Despite advances in hydrogen atom transfer (AT) catalysis, there are currently nomolecular l AT catalysts t thatt are capable of homolysing the strong nitrogen hydrogen ( ) bonds of -alkyl amides. The motivation to develop amide homolysis protocols stems from the utility of the resultant amidyl radicals, which are involved in various synthetically useful transformations, including olefin amination and directed carbon hydrogen (C ) bond functionalization. In the latter process a subset of the classical ofmann Löffler Freytag reaction amidyl radicals remove hydrogen atoms from unactivated aliphatic C bonds. Although powerful, these transformations typically require oxidative - prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, because these -activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of carbon carbon (C C) bonds.

23 The first paragraph ere we report an approach that overcomes these limitations by homolysing the bonds of -alkyl amides via proton-coupled electron transfer. In this protocol, an excited-state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resultant amidyl radical intermediates are shown to promote subsequent C abstraction and radical alkylation steps. This C alkylation represents a catalytic variant of the ofmann Löffler Freytag reaction, using simple, unfunctionalized amides to direct the formation of new C CC bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, this study demonstrates that concerted protoncoupled electron transfer can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional AT-based approaches.