Niloufar Hadei

Pd‐Catalyzed Aryl Amination Mediated by Well Defined, N‐Heterocyclic Carbene (NHC)–Pd Precatalysts, PEPPSI

Pd-N-heterocyclic carbene (NHC)-catalyzed Buchwald-Hartwig amination protocols mediated by Pd-PEPPSI precatalysts is described. These protocols provide access to a range of hindered and functionalized drug-like aryl amines in high yield with both electron-deficient and electron-rich aryl- and heteroaryl chlorides and bromides. Variations in solvent polarity, base and temperature are tolerated, enhancing the scope and utility of this protocol. A mechanistic rationalization for base strength (pKb) requirements is also provided.

Pd-PEPPSI-IPentCl: A Highly Effective Catalyst for the Selective Cross-Coupling of Secondary Organozinc Reagents†

No migration? No problem! A series of new N-heterocyclic carbene based Pd complexes has been created and evaluated in the Negishi cross-coupling of aryl and heteroaryl chlorides, bromides, and triflates with a variety of secondary alkylzinc reagents. The direct elimination product is nearly exclusively formed; in most examples there is no migratory insertion at all.

On the role of additives in alkyl–alkyl Negishi cross-couplings

An additives study for the alkyl-alkyl Negishi reaction using an NHC-Pd catalyst revealed that bromide salts promote coupling while the cation is mechanistically benign. A double titration revealed that the cross-coupling begins at a 1 : 1 ratio of LiBr : (n)BuZnBr, suggesting that a higher-order zincate, presumably Li(m)Zn((n)Bu)Br(3)((2-m)-), is the active transmetalating agent.

Differentiating CBr and CCl Bond Activation by Using Solvent Polarity: Applications to Orthogonal Alkyl–Alkyl Negishi Reactions†

of two methods: A) fine-tuning the reaction conditions (i.e., temperature, catalyst, additives, etc.) for each reactive center or B) protecting group chemistry. Method A is commonly achieved by taking advantage of the differences in bond enthalpies (C I > C Br @ C Cl), and more recently has come to include the Caryl O bonds (i.e., aryl carboxylates, carbamates, carbonates, and sulfamates) that can be efficiently coupled in the presence of a Ni (but not Pd) catalyst, lending itself to orthogonal reaction strategies. Method B has been applied in the form of masked boronic acids, including pinacol esters, BF3K salts, [6] N-methyliminodiacetic acid (MIDA), and 1,8-diaminonaphthalene (dan)-borane derivatives. Strategies based on method B generally discount the possibility of one-pot reaction sequences due to the need for deprotection chemistry. However, bifunctional organodiborane linchpins possessing two of these boronic acid derivatives have been applied successfully in various orthogonal cross-coupling strategies to form aryl–aryl or aryl–vinyl motifs. Largely absent from the literature are examples of orthogonal alkyl–alkyl cross-couplings of two unactivated alkyl fragments; to our knowledge, only one example is known (Scheme 2, previous work). Kambe and co-workers showed in a single example that 1-bromo-6chlorohexane could undergo sequential Kumada–Tamao– Corriu cross-couplings using temperature as the orthogonal trigger in one-pot in the presence of a Cu catalyst. Examples of this type are rare as specially designed, highly active catalysts are typically required to couple unactivated alkyl fragments efficiently, with the trade-off that discrimination between Calkyl Br and Calkyl Cl bonds is now less chemoselective. For example, we have shown that NHC–Pd catalysts (NHC = N-heterocyclic carbene), generated in situ from either an imidazolium salt or a pre-catalyst, namely [Pd-PEPPSI-IPr] (1), can effectively couple both unactivated primary Calkyl Br and Calkyl Cl bonds in the Negishi reaction at room temperature. During the course of these studies, however, we discovered a unique property that allowed us to chemoselectively couple Calkyl Br bonds in the presence of Calkyl Cl bonds with alkylzinc reagents: that is, solvent polarity. This is a valuable attribute of this reaction, as it provides an opportunity for one-pot orthogonal alkyl–alkyl cross-couplings of bifunctional bromochloroalkanes by a solvent polarity “trigger” (Scheme 2). At its core, the chemoselectivity of these alkyl–alkyl Negishi cross-couplings depend on the ratio of dimethylimidazolidinone (DMI, e = 37.6) to tetrahydrofuran (THF, e = 7.5). Preliminarily, a competition experiment (Table 1) was designed to evaluate the chemoselectivity in the alkyl–alkyl Negishi reaction. The nBuZnBr for these studies was Scheme 1. General overview of orthogonal cross-coupling strategies.

Identification of a Higher-Order Organozincate Intermediate Involved in Negishi Cross-Coupling Reactions by Mass Spectrometry and NMR Spectroscopy

Negishi cross-coupling reactions were analyzed in solution by mass spectrometry and NMR spectroscopy to identify both the effect of LiBr as an additive as well as the purpose of 3-dimethyl-2-imidazolidinone (DMI) as a co-solvent. The results suggest that the main role of DMI is to facilitate a higher order bromozincate formation during the addition of LiBr.