Robotic Lepidoptery: Structural Characterization of (mostly) Unexpected Palladium Complexes Obtained from High-Throughput Catalyst Screening

4,5-Diazafluoren-9-one (DAF) has been identified as a highly effective ligand in a number of Pd-catalyzed oxidation reactions, but the mechanistic basis for its utility has not been elucidated. Here, we present the complex coordination chemistry of DAF and palladium(II) carboxylate salts. Multiple complexes among an equilibrating mixture of species have been characterized by 1H and 15N NMR spectroscopy and X-ray crystallography. These complexes include monomeric and dimeric PdII species, with monodentate (κ1), bidentate (κ2) and bridging (μ:κ1:κ1) DAF coordination modes. Titration studies of DAF and Pd(OAc)2 reveal the formation of two dimeric DAF/Pd(OAc)2 complexes at low [DAF] and four monomeric species at higher [DAF]. The dimeric complexes feature two bridging acetate ligands together with either a bridging or non-bridging-κ1 DAF ligand coordinated to each PdII center. The monomeric structures consist of three isomeric Pd(κ1-DAF)2(OAc)2 complexes, together with Pd(κ2-DAF)(OAc)2 in which the DAF exhibits a traditional bidentate coordination mode. Replacing DAF with the structurally related, but more-electron-rich derivative 9,9-dimethyl-4,5-diazafluorene (Me2DAF) simplifies the equilibrium mixture to two complexes, a dimeric species in which the Me2DAF bridges the two Pd centers and a monomeric species with a traditional κ2-Me2DAF coordination mode. The use of DAF in combination with other carboxylate ligands (CF3CO2− or tBuCO2−) also results in a simplified collection of equilibrating PdII–DAF complexes. Collectively, the results highlight the ability of DAF to equilibrate rapidly among multiple coordination modes, and provide valuable insights into the utility of DAF as a ligand in Pd-catalyzed oxidation reactions.

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“…The latter solutions feature single Pd(κ 2 -N~N)(OAc) 2 species, which have been described previously in the literature. 17 …”

Section: Resultsmentioning

confidence: 99%

Structurally Diverse Diazafluorene-Ligated Palladium(II) Complexes and Their Implications for Aerobic Oxidation Reactions

et al. 2016

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“…We envisioned that coordination of the nitrogen of an alicyclic amine such as piperidine to palladium could enable selective transannular C–H activation 17, 18 to generate a bicyclo[2.2.1]palladacycle (exemplified by 1 in Fig. 2A).…”

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confidence: 99%

Palladium-catalysed transannular C–H functionalization of alicyclic amines

Topczewski

Cabrera

Saper

et al. 2016

Nature

296

157

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The discovery of pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. Carbon-hydrogen bonds are present in almost all pharmaceutical agents. As such, the development of selective, rapid, and efficient methods for converting carbon-hydrogen bonds into new chemical entities has the potential to dramatically streamline pharmaceutical development1,2,3,4. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, including treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukemia (alvocidib), schizophrenia (risperidone, belaperidone), and nicotine addiction (cytisine and varenicline)5. However, existing methods for the C–H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited 6,7. Here we report a new approach to selectively manipulate the carbon–hydrogen bonds of alicyclic amines at sites remote to nitrogen. Our reaction leverages the boat conformation of the substrates to achieve the palladium-catalyzed amine-directed conversion of C–H bonds to C–C bonds on various alicyclic amine scaffolds. This approach is applied to the synthesis of novel derivatives of several bioactive molecules, including the top-selling smoking cessation drug varenicline (Chantix®). We anticipate that this method should prove broadly useful in medicinal chemistry.

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“…Studies of these systems-and of polymetallic complexes more generally-are enhanced by the synthetic ability to rationally generate specific homo-and heteropolymetallics of interest. 4 We are beginning to explore the synthesis and siteselective metallation of polynucleating ligands in order to generate such complexes. Reported herein are initial efforts toward the preparation of nitrogen-rich ligands that feature a common pincer-type framework.…”

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confidence: 99%

“…The room temperature addition of 3 equiv. [(CH 3 CN) 4 Pd][BF 4 ] 2 to 9 results in the immediate metallation at the two neutral bis((pyridin-2-yl)methyl)amine sites as determined by 1 H NMR spectroscopy. The final palladation of the bis(quinolinyl)amine occurs upon the addition of Et 3 (Fig.…”

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confidence: 99%

Ligand design for site-selective installation of Pd and Pt centers to generate homo- and heteropolymetallic motifs

Suess

Peters

2010

Chem. Commun.

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The modular synthesis of a series of nitrogen-rich polydentate ligands that feature a common pincer-type framework is reported. These ligands allow for site-selective installation of palladium and platinum to give rise to bi-and trimetallic complexes that have d 8 -d 8 interactions.Natural and synthetic polymetallic reaction sites mediate a wide range of small molecule transformations that have not been realized in monometallic analogs. 1 For example, synthetic bimetallic complexes that contain d 8 -d 8 interactions display unusual photochemical reactivity 2 and have interesting electronic structures 3 owing to the metal-metal orbital interaction. Studies of these systems-and of polymetallic complexes more generally-are enhanced by the synthetic ability to rationally generate specific homo-and heteropolymetallics of interest. 4 We are beginning to explore the synthesis and siteselective metallation of polynucleating ligands in order to generate such complexes. Reported herein are initial efforts toward the preparation of nitrogen-rich ligands that feature a common pincer-type framework. We establish the utility of this family of ligands for the site-selective installation of Pd and Pt centers which can result in bi-and trimetallic systems featuring d 8 -d 8 interactions in the solid-state and in solution.The four ligands described in this communication feature two or three tridentate binding sites. Common to each ligand is a monoanionic, bis(quinolinyl)amide (BQA) pincer-type binding site. Decoration of the pincer scaffold with one or two neutral binding sites affords access to the polymetallic complexes of interest herein. We have chosen in this initial investigation to target Pd and Pt species due to our prior experience with the chemistry of group 10 BQA complexes, 5 and due to their low lability by comparison to first row late metals.The ligand synthesis of the dinucleating L1 R H series (Scheme 1) is accomplished in three steps from 8-bromo-2-methylquinoline (1). Oxidation of 1 with SeO 2 provides access to aldehyde 2. Reductive amination of 2 with NaHB(OAc) 3 and the appropriate secondary amine installs the neutral tridentate binding sites in amine intermediates 3, 4, and 5. The BQA binding pocket is generated by Pd-mediated C-N cross-coupling of 3, 4, and 5 with 8-aminoquinoline to give yellow ligands 6, 7, and 8, 5a respectively. The latter transformation proceeds to remarkably high conversion (>90%) given the potential for these ligands to poison the Pd cross-coupling catalyst. A nonadentate, trinucleating ligand (9) is prepared in an analogous synthesis from 5 and 8-amino-2-methylquinoline (see ESIw).The installation of Pd into the anionic binding site of 6 is readily achieved by reaction with (COD)Pd(Me)Cl and catalytic Et 3 N to form red, neutral L1 OMe PdCl 10 with concomitant loss of methane. Alternatively, 10 may be generated using (COD)PdCl 2 and stoichiometric Et 3 N; however, the use of (COD)Pd(Me)Cl obviates the need to purify 10 from Et 3 NÁ HCl. 1 H NMR spectroscopy of 10 shows the disappear...

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Robotic Lepidoptery: Structural Characterization of (mostly) Unexpected Palladium Complexes Obtained from High-Throughput Catalyst Screening

Cited by 24 publications

References 19 publications

Structurally Diverse Diazafluorene-Ligated Palladium(II) Complexes and Their Implications for Aerobic Oxidation Reactions

Structurally Diverse Diazafluorene-Ligated Palladium(II) Complexes and Their Implications for Aerobic Oxidation Reactions

Palladium-catalysed transannular C–H functionalization of alicyclic amines

Ligand design for site-selective installation of Pd and Pt centers to generate homo- and heteropolymetallic motifs

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