Ambident Reactivity of Acetyl- and Formyl-Stabilized Phosphonium Ylides

The kinetics and mechanism of the reactions of formyl-stabilized ylide Ph₃PCHCHO (<b>1</b>) and acetyl-stabilized ylide Ph₃PCHCOMe (<b>2</b>) with benz­hydrylium ions (Ar₂CH⁺, <b>3</b>) were investigated by UV–vis and NMR spectroscopy. As ambident nucleophiles, ylides <b>1</b> and <b>2</b> can react at oxygen as well as at the α-carbon. For some reactions, it was possible to determine the second-order rate constant for O-attack as well as for C-attack and to derive the nucleophile-specific parameters <i>N</i> and <i>s</i>_N according to the correlation lg <i>k</i> (20 °C) = <i>s</i>_N(<i>E</i> + <i>N</i>) for both nucleophilic sites. Generally, O-attack of benz­hydrylium ions is faster than C-attack. However, the initially formed benz­hydryl­oxy­vinyl­phosphonium ions can only be observed by NMR spectroscopy when benz­hydryl cations with high Lewis acidity are employed. In other cases, rearrangement to the thermodynamically more stable products arising from C-attack occurs. The results derived from our investigations are employed to rationalize the behavior of ambident nucleophiles <b>1</b> and <b>2</b> in reactions with carbon-centered electrophiles in general. It is shown that the principle of hard and soft acids and bases (HSAB) and the related Klopman–Salem concept of charge and orbital control lead to incorrect predictions of regio­selectivity. We also show that the rate of the Wittig reaction of ylide <b>2</b> with aldehyde <b>14</b> is significantly faster than the rate of either C- or O-attack calculated using lg <i>k</i> (20 °C) = <i>s</i>_N(<i>E</i> + <i>N</i>), thus indicating that the oxaphosphetane is formed by a concerted [2 + 2] cycloaddition

Regioselective Metalation and Functionalization of the Pyrazolo[1,5‑<i>a</i>]pyridine Scaffold Using Mg- and Zn-TMP Bases

A regioselective functionalization of the pyrazolo­[1,5-<i>a</i>]­pyridine scaffold using Mg- and Zn-TMP bases (TMP = 2,2,6,6-tetramethylpiperidyl) in the presence or absence of BF₃·OEt₂ is described. Also, various functionalized pyrazolo­[1,5-<i>a</i>]­pyridines bearing an ester function (and an NHBoc or ethyl group) are magnesiated and functionalized, leading to polysubstituted heterocycles. Additionally, a sulfoxide directed <i>ortho</i>-metalation, followed by the transition-metal-free amination of a pyrazolo­[1,5-<i>a</i>]­pyridine sulfoxide, using a magnesium amide, is reported

Selective Functionalization of Tetrathiafulvalene Using Mg- and Zn-TMP-Bases: Preparation of Mono‑, Di‑, Tri‑, and Tetrasubstituted Derivatives

The tetrathiafulvalene-scaffold (TTF) reacts selectively in allylation, acylation, arylation, halogenation, and thiolation reactions via magnesium or zinc derivatives that are obtained by a direct metalation with Mg- and Zn-TMP-bases (TMP = 2,2,6,6-tetramethyl­piperidyl). This stepwise functionalization provides access to a range of new mono-, di-, tri-, and tetra-functionalized TTF-derivatives and allows for fine-tuning of their energy levels

Selective Lithiation, Magnesiation, and Zincation of Unsymmetrical Azobenzenes Using Continuous Flow

A mild and general set of metalation procedures for the functionalization of unsymmetrical azobenzenes using a commercially available continuous-flow setup is reported. The metalations proceed with TMPLi under convenient conditions (0 °C, 20 s), and various classes of electrophiles can be used. With sensitive substrates, an in situ trapping metalation in which TMPLi is added to a mixture of the azobenzene and ZnCl₂ or MgCl₂·LiCl was very effective for achieving high yields

Cobalt-Catalyzed Diastereoselective Cross-Couplings between Alkynylzinc Pivalates and Functionalized Cyclic Iodides or Bromides

Various 1,2-, 1,3-, and 1,4-substituted cyclic iodides or bromides undergo highly diastereoselective cross-couplings (diastereoselectivity (dr) up to 99:1) with a range of alkynylzinc pivalates, using CoCl₂ (20 mol %) and <i>trans</i>-<i>N</i>,<i>N</i>,<i>N</i>′,<i>N</i>′-tetramethylcyclohexane-1,2-diamine as a catalytic system

Selective Metalations of 1,4-Dithiins and Condensed Analogues Using TMP-Magnesium and -Zinc Bases

TMPMgCl·LiCl and TMPZnCl·LiCl allow facile magnesiation and zincation, respectively, of the 1,4-dithiin scaffold, producing polyfunctionalized 1,4-dithiins. A subsequent metalation of these S-heterocycles can also be achieved with the same TMP bases, leading to 2,3-disubstituted-1,4-dithiins. The Mg- and Zn-TMP bases allow as well the successful metalation of 1,4,5,8-tetrathianaphthalene and 1,4,5,6,9,10-hexathiaanthracene

Transition-Metal-Free Cross-Coupling of Aryl and <i>N</i>‑Heteroaryl Cyanides with Benzylic Zinc Reagents

Functionalized 4-benzylated pyridines can be efficiently prepared by a transition-metal-free cross-coupling between various benzylic zinc chlorides and substituted 4-cyanopyridines in THF/DMPU under microwave irradiation (40 °C, 0.5–1.5 h). Selective benzylations on polycyano-aromatics have also been achieved under these mild conditions. We also report a novel oxidative nucleophilic substitution of a hydrogen on 1,3-dicyanobenzene using benzylic zinc reagents

Directed Zincation or Magnesiation of the 2‑Pyridone and 2,7‑Naphthyridone Scaffold Using TMP Bases

A regioselective zincation of the 2-pyridone and 2,7-naphthyridone scaffolds has been developed. Zincations of the methoxyethoxymethyl (MEM)-protected compounds using TMP₂Zn·2MgCl₂·2LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) followed by trapping with electrophiles provided functionalized 2-pyridones and 2,7-naphthyridones. I/Mg exchange of iodinated 2-pyridone and 2,7-naphthyridone using <i>i-</i>PrMgCl·LiCl afforded magnesiated intermediates that reacted with electrophiles. A second magnesiation of the 2-pyridone scaffold was achieved by using TMPMgCl·LiCl. Additionally, we report CoCl₂-catalyzed cross-couplings of the 1-chloro-2,7-naphthyridines with arylzinc halides

Lewis Acid Triggered Regioselective Magnesiation and Zincation of Uracils, Uridines, and Cytidines

The Lewis acid MgCl₂ allows control of the metalation regioselectivity of uracils and uridines. In the absence of the Lewis acid, metalation of uracil and uridine derivatives with TMPMgCl·LiCl occurs at the position C(5). In the presence of MgCl₂, zincation using TMP₂Zn·2LiCl·2MgCl₂ occurs at the position C(6). This metalation method provides easy access to functionalized uracils and uridines. Using TMP₂Zn·2LiCl·2MgCl₂ also allows to functionalize cytidine derivatives at the position C(6)

Preparation of Tri- and Tetrasubstituted Allenes via Regioselective Lateral Metalation of Benzylic (Trimethylsilyl)alkynes Using TMPZnCl·LiCl

The zincation of various 1-(trimethylsilyl)-3-aryl-1-propynes with TMPZnCl·LiCl followed by a Pd-catalyzed coupling with aryl halides provides arylated allenes in 52–92% yield. Subsequent metalation with TMPZnCl·LiCl and cross-coupling with a second different aryl halide provides regioselectively tetrasubstituted allenes in 42–70% yield. This sequence can be performed in a one-pot procedure. DFT calculations and NMR studies support the formation of allenylzinc and propargyllithium intermediates starting from 1-(trimethylsilyl)-3-phenyl-1-propyne