Diastereoconvergent Negishi Cross-Coupling Using Functionalized Cyclohexylzinc Reagents

Highly diastereoselective Pd-catalyzed cross-coupling reactions of functionalized 2-, 3-, and 4-substituted cyclohexylzinc reagents with aryl, heteroaryl, and alkenyl iodides have been performed under mild conditions. The use of Ruphos (2-dicyclo­hexyl­phos­phino-2′,6′-diiso­propoxy­biphenyl) as a ligand as well as LiCl and <i>N</i>-ethyl­pyrrolidone (NEP) as additives leads to especially high diastereoselectivities and displays good functional group tolerance. The stereoselectivity can be explained by assuming that the intermediate palladium moiety occupies an equatorial position of the cyclohexyl ring

High-Temperature Continuous-Flow Zincations of Functionalized Arenes and Heteroarenes Using (Cy₂N)₂Zn·2LiCl

The treatment of sensitive arenes and heteroarenes with the zinc bis-amide (Cy₂N)₂Zn·2LiCl (0.55 equiv), prepared in quantitative yield by the reaction of Cy₂NLi with ZnCl₂, leads under flow conditions to a fast zincation within 10 min at temperatures between 25 and 100 °C. The resulting organozinc reagents can be trapped with various organic halides (allylic bromides, aryl iodides) in high yields. Moreover, complementary metalation regioselectivities can be obtained for several substituted pyridines compared to commonly used LiCl-activated TMP-zinc (TMP = 2,2,6,6-tetramethylpiperidyl) and -magnesium bases

C₆₀-Catalyzed Preparation of Aryl and Heteroaryl Magnesium and Zinc Reagents Using Mg/LiCl

Addition of a catalytic amount of C₆₀ fullerene (3 mol %) catalyzes the insertion of magnesium to polycyclic aromatic halides, allowing the preparation of the corresponding Grignard reagents in good yields. Furthermore, the use of a cocktail of metallic salts (Mg, ZnCl₂, LiCl) in the presence of C₆₀ fullerene (3 mol %) allows preparation of some functionalized polyaromatic zinc reagents. The resulting organomagnesium and organozinc reagents efficiently underwent reactions with electrophiles, such as an aldehyde, an acid chloride, an allylic bromide, or an aryl iodide

Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Pyridines, Aryl Oxazolines, and Imines Using Arylmagnesium Reagents

We report a CrCl₂-catalyzed oxidative arylation of various pyridines, aryl oxazolines, and aryl imines using aromatic Grignard reagents in the presence of 2,3-dichlorobutane (DCB). Most of the reactions proceed rapidly at 25 °C and do not require any additional ligand. Benzo­[<i>h</i>]­quinoline, 2-arylpyridine, aryl oxazoline, and imines were successfully arylated in good yields under these conditions. A TMS-substituent was used to prevent double arylation. After oxidative cross-coupling the TMS-group was further converted to a second <i>ortho</i>-aryl substituent. Remarkably, inexpensive aryl <i>N</i>-butylimine derivatives are excellent substrates for this oxidative arylation

Regioselective Functionalization of the Oxazole Scaffold Using TMP-Bases of Mg and Zn

A general method for the synthesis of 2,4,5-trisubstituted oxazoles has been developed. Starting from commercially available oxazole, successive metalations using TMPMgCl·LiCl or TMPZnCl·LiCl led to the corresponding magnesiated or zincated species which were stable toward ring fragmentation. Furthermore, they readily reacted with various electrophiles, such as aryl and allylic halides, acid chlorides, TMSCl, and TMS-CN, providing highly functionalized oxazoles

Diastereoselective Copper-Mediated Cross-Couplings between Stereodefined Secondary Alkylcoppers with Bromoalkynes

A copper­(I)-mediated cross-coupling of stereodefined secondary alkyllithiums with bromoalkynes provided stereodefined alkynes with high diastereoselectivity (dr up to 98:2). This cross-coupling was extended to various secondary alkyllithiums bearing a remote oxygen functionality, and the alkyne synthesis was also performed with optically enriched alkyl iodides (up to 99% <i>ee</i>) providing, after cross-coupling, alkynes bearing two stereocenters (dr = 93:7; up to 99% <i>ee</i>)

Benzylic Arylation of 2-Methyl-5-membered Heterocycles Using TMP-Bases

A new general Pd-catalyzed arylation of various 2-methyl-5-membered heterocycles is reported. This novel method requires Li–, Mg–, or Zn–TMP bases and allows selective metalation of the benzylic position. Subsequent Negishi cross-coupling provides the corresponding arylated heterocycles

TMPZnOPiv•LiCl: A New Base for the Preparation of Air-Stable Solid Zinc Pivalates of Sensitive Aromatics and Heteroaromatics

A wide range of aryl and heteroaryl zinc pivalates bearing sensitive functionalities were prepared by selective metalation using TMPZnOPiv•LiCl, a new hindered zinc amide base. The new zinc reagents are easy-to-handle solids, which maintain their activity almost entirely (>95%) after 4 h of air exposure and smoothly undergo Negishi cross-couplings and reactions with various electrophiles such as Cu(I)-catalyzed acylations and allylations

Leaving Group Dependence of the Rates of Halogen–Magnesium Exchange Reactions

Relative reactivities and absolute rate constants of the reactions of haloarenes with <i>i</i>-PrMgCl·LiCl were investigated in THF at 0 °C. The rate of the halogen–magnesium exchange decreases in the series ArI > ArBr > ArCl (relative reactivities: 10¹¹:10⁶:1). Preliminary experiments show that the <i>p</i>-tolylsulfinyl group is exchanged slightly faster than iodide, while a tosyl group is exchanged at least 10⁴ times more slowly than a bromide

Direct Aminoalkylation of Arenes, Heteroarenes, and Alkenes via Ni-Catalyzed Negishi Cross-Coupling Reactions

A room-temperature Ni-catalyzed cross-coupling of aryl, heteroaryl, and alkenyl electrophiles with aminoalkylzinc bromides, readily available from the corresponding aminoalkyl chlorides via Grignard reagents, was developed. The reaction allows a convenient one-step preparation of various aminoalkyl products, including piperidine and tropane derivatives. Such functionalized amine moieties are widely present in various biologically active molecules. Aryl, heteroaryl, and alkenyl iodides, bromides, chlorides and triflates are suitable electrophiles. A short total synthesis of two natural products, (±)-galipinine and (±)-cusparine, is also reported