Decarboxylative Arylation of ± Amino Acids via .Decarboxylative Arylation of...

Decarboxylative Arylation of ± Amino Acids via .Decarboxylative Arylation of ±â€‘Amino Acids via
Decarboxylative Arylation of ± Amino Acids via .Decarboxylative Arylation of ±â€‘Amino Acids via
Decarboxylative Arylation of ± Amino Acids via .Decarboxylative Arylation of ±â€‘Amino Acids via
Decarboxylative Arylation of ± Amino Acids via .Decarboxylative Arylation of ±â€‘Amino Acids via
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  • Decarboxylative Arylation of Amino Acids via PhotoredoxCatalysis: A One-Step Conversion of Biomass to DrugPharmacophoreZhiwei Zuo and David W. C. MacMillan*

    Merck Center for Catalysis, Princeton University, Princeton, New Jersey 08544, United States

    *S Supporting Information

    ABSTRACT: The direct decarboxylative arylation of-amino acids has been achieved via visible light-mediated photoredox catalysis. This method offers rapidentry to prevalent benzylic amine architectures from anabundant biomass, specifically -amino acid precursors.Significant substrate scope is observed with respect toboth the amino acid and arene components.

    The controlled excision of carbon dioxide from organicmolecules, commonly known as decarboxylation, is avaluable transformation that is fundamental to biochemistry andbroadly utilized in synthetic molecule construction. For example,in nature, enzymatically controlled regioselective decarboxylationallows the conversion of the abundant biomonomer glutamic acidto -aminobutyric acid (GABA), an important neurotransmitterin the mammalian central nervous system (eq 1).1 Syntheticchemists also rely on decarboxylative technologies as a means toremove extraneous carboxyl groups2 with protocols such as theKolbe,3 Hunsdiecker,4 and Barton decarboxylations5 having long-proven value.Given the worldwide abundance of biomass6 that incorporates

    carboxylate functionality (e.g., amino acids, -hydroxy acids, fattyacids etc), there is a strong impetus to invent or discoverchemical transformations that target carboxylic acids as chemo-selective leaving groups for new and valuable CC bond formingreactions. More specifically, the productive engagement ofdecarboxylation mechanisms into fragment-coupling bondconstructions could enable the direct conversion of abundant,inexpensive substrates to complex, medicinally relevantpharmacophores. The seminal studies of Myers7 and Gooen8

    have demonstrated that classical organometallic catalyticcoupling pathways (Heck, biaryl couplings) can be accessed viaaryl and alkynyl carboxylic acids.9 Recently, we questionedwhether Csp3Csp2-bearing carboxylates (the carboxyl moietymost commonly found in biomass) might be rendered suitablefor decarboxylative aryl couplings via the use of a novelphotoredox-mediated radicalradical coupling pathway. Hereinwe describe the successful execution of these studies anddemonstrate the direct conversion of broadly available -aminoacids or -oxy acids with arene substrates to generate high-valuebenzylic amine or ether architectures using photoredox catalysis.The benzylic amine is a central component of a wide range

    of medicinally relevant compounds, including pharmaceuticals,agrochemicals, and bioactive natural products.10 The develop-ment of improved methods for the synthesis of these important

    pharmacophores from readily available starting materials remainsan important challenge in organic synthesis.11 A recent focusof our laboratory has been the development of visible light-mediated photoredox catalysis as a general strategy for achievingchallenging bond constructions not readily accessible via classicaltwo-electron pathways and without the need for harsh conditionsor toxic reagents.12,13 Along these lines, we recently describeda photoredox-catalyzed amine CH arylation for the synthesisof benzylic amines via the coupling of tertiary amines withcyanoarenes.12 With the goal of further expanding the menu

    Received: February 15, 2014Published: March 12, 2014


    2014 American Chemical Society 5257 | J. Am. Chem. Soc. 2014, 136, 52575260

  • of amine -functionalization capabilities, we anticipated that-amino acid radical decarboxylation, coupled with in situarylation, could provide rapid access to a wealth of complexprimary and secondary benzylic amine pharmacophores usingreadily available biomass.Design Plan. As outlined in eq 2, our general strategy

    envisioned photoredox-mediated single-electron oxidation of thecarboxylate functionality of an -amino acid, followed by loss ofCO2, to render an -carbamoyl radical. Radicalradical couplingof this species with the radical anion derived from an arenecoupling partner should forge the benzylic CCbond to provide,following aromatization via expulsion of cyanide, the high-valuebenzylic amine motif.A detailed mechanism for the proposed photoredox

    decarboxylative aryl coupling is shown in Scheme 1. Irradiationof tris(2-phenylpyridinato-C2,N)iridium(III) [Ir(ppy)3] (1)with visible light produces a long-lived (1.9 s) photoexcitedstate,14 *Ir(ppy)3 (2), which can be readily oxidized or reducedby an appropriate substrate quencher. Given that *Ir(ppy)3 (2) isa strong reductant (E1/2

    red [IrIV/*IrIII] = 1.73 V vs SCE),14 wepresumed that facile reduction of 1,4-dicyanobenzene 3 (X =CCN, E1/2red = 1.61 V vs SCE)15 via single electron transferwould generate the corresponding aryl radical anion 4.16 At thisstage, oxidation of the -amino acid substrate by IrIV(ppy)3to generate the corresponding carboxyl radical species (withsubsequent extrusion of CO2) would yield the requisite -aminoradical 6. A survey of relevant oxidation potentials reveals thatthis carboxylate oxidation step is endergonic as proposed (E1/2


    [IrIV/IrIII] = +0.77 V vs SCE), (Boc-Pro-OCs+, Ered = +0.95 V vsSCE);17 however, we recognized that electronic adjustmentof the photocatalyst ligands might render this decarboxylationthermodynamically feasible. At this stage we hoped thatchemoselective heterocoupling of the persistent radical 4 withthe transiently formed -amino radical 6 would efficiently enablethe requisite CC fragment coupling, and subsequent loss ofcyanide would deliver the benzylic amine 7.Our initial investigations focused on the identification of a

    suitable photocatalyst capable of facilitating both single-electronreduction of the arene and single-electron oxidation of the-amino acid (Table 1). We first examined the coupling ofBoc-protected proline and 1,4-dicyanobenzene (1,4-DCB) atroom temperature in the presence of K2HPO4, a 26W householdfluorescent light bulb, and 2 mol% of Ir(ppy)3. While we were

    delighted to find that the proposed decarboxylative arylationcoupling was feasible under these conditions, the observedreaction efficiency was poor (entry 1, 12% yield). As statedabove, we recognized that electron transfer from Boc-prolinateto IrIV(ppy)3 (E1/2

    red [IrIV/IrIII]= +0.77 V vs SCE)14 could bethermodynamically challenging, and as such, we turned ourattention to the identification of more strongly oxidizing photo-catalysts. As expected, incorporation of a fluorine substituentonto the pyridine backbone of the photocatalyst provided asignificant increase in efficiency. More specifically the Ir(p-F-ppy)3 and Ir(dFppy)3 photocatalysts (E1/2

    red [IrIV/IrIII] =+0.97 V and +1.13 V vs SCE in CH3CN, respectively)


    provided significantly enhanced yields of the desired -aminoarylation product (entries 23). It is important to note thathighly oxidizing photocatalysts, such as Ir[dF(CF3)ppy]2-(dtbbpy)PF6,

    19 were largely ineffective in this coupling protocol(entry 4), presumably due to their inability to participate in thearene reduction step of the catalytic cycle.On the basis of these findings, we sought to design a

    photocatalyst system that would be more strongly reducingthan Ir(p-F-ppy)3 (E1/2

    red [IrIV/*IrIII] = 1.60 V vs SCE) orIr(dFppy)3 (E1/2

    red [IrIV/*IrIII] = 1.44 V vs SCE),18 yet at thesame time could promote facile oxidation of the -aminocarboxylate moiety. We hypothesized that introduction ofelectron-donating tert-butyl groups into the pyridine ring ofthe ligand would serve to further enhance the reducing ability ofthe photocatalyst excited state while leaving the oxidationpotential of the corresponding IrIV species largely unaffected.

    Table 1. Optimization of the Decarboxylative Arylation

    entry photocatalyst base % yielda

    1 Ir(ppy)3 K2HPO4 122 Ir(p-F-ppy)3 K2HPO4 583 Ir(dFppy)3 K2HPO4 544 Ir[dF(CF3)ppy]2(dtbbpy) K2HPO4 trace5 Ir[p-F(t-Bu)-ppy]3 K2HPO4 736 Ir[dF(t-Bu)-ppy]3 K2HPO4 687 Ir[p-F(t-Bu)-ppy]3 CsF 838b Ir[p-F(t-Bu)-ppy]3 CsF 09 none CsF 010 Ir[p-F(t-Bu)-ppy]3 none trace

    aYield determined by 1H NMR using an internal standard. bReactionperformed in the absence of visible light. cA series of Ru-basedcatalysts were unsuccessful. dHigh-dielectric solvents are required (e.g.,entry 7, DMSO = 83% yield, DMA = 74% yield, hexane = NR).

    Scheme 1. Proposed Catalytic Cycle for DecarboxylativeArylation

    Journal of the American Chemical Society Communication | J. Am. Chem. Soc. 2014, 136, 525752605258

  • Indeed, we were pleased to find that two new photocatalysts,Ir[p-F(tBu)-ppy]3 (E1/2

    red [IrIV/*IrIII] = 1.67 V vs SCE)20 andIr[dF(tBu)-ppy]3, exhibited a significant increase in overallefficiency to deliver the desired coupling adduct in 73% and 68%yield, respectively (entries 5 and 6). Further improvement inreaction yield was achieved through the use of CsF as theexogenous base, presumably due to increased solubility of thecarboxylate species (entry 7). As expected, control experimentsrevealed that the photocatalyst, visible light, and the base wereall essential components for the catalytic operation of this newcoupling reaction (entries 810).With optimal reaction conditions in hand, we next examined

    the scope of the amino acid component in this newdecarboxylative arylation protocol. As illustrated in Table 2,this transformation generically proceeds at room temperatureand in good to high yields with an extensive range of -aminoacids (products 820, 6489% yield). These mild reactionconditions readily accommodate an array of useful functionalgroups, including esters, amides, carbamates,