Regio‐ and Chemoselective Metalation of Chloropyrimidine Derivatives with TMPMgCl⋅LiCl and TMP2Zn⋅2 MgCl2⋅2 LiCl

Efficient zincation and magnesiation of chlorinated pyrimidines can be performed at convenient temperatures (e.g., 25 and 55 °C) by using TMPMgCl?LiCl and TMP₂Zn?2 M gCl₂?2 LiCl (TMP=2,2,6,6‐tetramethylpiperidyl) as effective bases. Quenching of the resulting zincated or magnesiated pyrimidines with various electrophiles furnishes highly functionalized pyrimidines in 51–93 % yield. Oxidative aminations were carried out, thus leading to aminated pyrimidines. By using this methodology, we have also prepared pharmaceutically relevant pyrazolopyrimidines and the fungicide Mepanipyrim.     

Preparation and Regioselective Magnesiation or Lithiation of Bis(trimethylsilyl)methyl‐Substituted Heteroaryls for the Generation of Highly Functionalized Heterocycles

A wide range of bis(trimethylsilyl)methyl (BTSM)‐ substituted heteroaryl derivatives has been prepared by using Kumada–Corriu or Negishi cross‐coupling reactions. The regioselective lithiation or magnesiation of these building blocks bearing a bulky BTSM group by using magnesium or lithium 2,2,6,6‐tetramethylpiperidide bases followed by quenching reactions with different electrophiles provides various functionalized N‐, O‐, or S‐heterocycles. Furthermore, the BTSM group can then be converted into formyl, methyl, or styryl groups to give access to a variety of highly functionalized heteroaromatics.     

Iodoindazoles with Selective Magnesiation at Position 3: A Route to Highly Functionalized Indazoles

A unique route to highly functionalized indazoles is described. A regioselective magnesiation at position 3 of 4‐, 5‐, 6‐ and 7‐iodo‐2‐THP‐indazoles (THP=tetrahydropyranyl) has been developed using TMPMgCl ? LiCl (TMP=2,2,6,6‐tetramethylpiperidyl). The obtained magnesiate can be trapped by different electrophiles to introduce a wide range of functional groups including halogens, thioalkyls, alcohols, aldehydes, ketones, amides, or esters at position 3. Once this position is functionalized, the iodine atoms can be further reacted through metal–halogen exchange or cross‐coupling strategies. Finally, N‐substitution reactions allow the synthesis of a variety of highly functionalized indazoles giving access to these valuable scaffolds through a simple and unique route.     

A Convenient Alumination of Functionalized Aromatics by Using the Frustrated Lewis Pair Et3Al and TMPMgCl⋅LiCl

A straightforward and efficient alumination of functionalized arenes by using the frustrated Lewis pair Et₃Al and TMPMgCl ? LiCl (TMP=2,2,6,6‐tetramethylpiperidyl) has been developed. In particular, halogenated electron‐rich aromatics can be smoothly functionalized by using the frustrated Lewis pair Et₃Al and TMPMgCl ? LiCl. Compared with previously described alumination methods, this procedure avoids extensive cooling and the need for an excess of base. This in situ procedure has proven to be most practical and allows for regio‐ and chemoselective metalation of a wide range of aromatics with sensitive functional groups (CONEt₂, CO₂Me, CN, OCONMe₂) or halogens (F, Cl, Br, I). The resulting aromatic aluminates, which were characterized by using NMR spectroscopy, were subjected to allylations, acylations, and palladium‐catalyzed cross‐coupling reactions after transmetalation to zinc. It was shown that the nature of the Zn salt used for transmetalation is crucial. Thus, compared with ZnCl₂ (2 equiv), the use of Zn(OPiv)₂ (2 equiv; OPiv=pivalate) allows the subsequent quenching reactions to be performed with only a slight excess of electrophile (1.2 equiv) and provides interesting functionalized aromatics in good yields.     

Regioselective Magnesiation and Zincation Reactions of Aromatics and Heterocycles Triggered by Lewis Acids

Mixed TMP-bases (TMP=2,2,6,6-tetramethylpiperidyl), such as TMPMgCl ⋅ LiCl, TMP₂Mg ⋅ 2LiCl, TMPZnCl ⋅ LiCl and TMP₂Zn ⋅ 2LiCl, are outstanding reagents for the metalation of functionalized aromatics and heterocycles. In the presence of Lewis acids, such as BF₃ ⋅ OEt₂ or MgCl₂, the metalation scope of such bases was dramatically increased, and regioselectivity switches were achieved in the presence or absence of these Lewis acids. Furthermore, highly reactive lithium bases, such as TMPLi or Cy₂NLi, are also compatible with various Lewis acids, such as MgCl₂ ⋅ 2LiCl, ZnCl₂ ⋅ 2LiCl or CuCN ⋅ 2LiCl. Performing such metalations in continuous flow using commercial setups permitted practical and convenient reaction conditions.     

Solution Structure of Turbo‐Hauser Base TMPMgCl⋅LiCl in [D8]THF

Turbo‐Hauser bases are very useful and highly reactive organometallic reagents in synthesis. Especially TMPMgCl ? LiCl 1 (TMP=2,2,6,6‐tetramethylpiperidide) is an excellent base for converting a wide range of (hetero)aromatic substrates into highly functionalized compounds with a broad application in organic synthesis. The knowledge of its structure in solution is of essential importance to understand the extraordinary reactivity and selectivity. However, very little is known about the aggregation of this prominent reagent in solution. Herein, we present the THF‐solution structure of 1 by employing our newly elaborated DOSY NMR method based on external calibration curves (ECC) with normalized diffusion coefficients.     

Preparation of Functionalized Aryl,Heteroaryl, and Benzylic Potassium Organometallics Using Potassium Diisopropylamide in Continuous Flow

We report the preparation of lithium‐salt‐free KDA (potassium diisopropylamide; 0.6 m in hexane) complexed with TMEDA (N,N,N′,N′‐tetramethylethylenediamine) and its use for the flow‐metalation of (hetero)arenes between ?78 °C and 25 °C with reaction times between 0.2 s and 24 s and a combined flow rate of 10 mL min^?1 using a commercial flow setup. The resulting potassium organometallics react instantaneously with various electrophiles, such as ketones, aldehydes, alkyl and allylic halides, disulfides, Weinreb amides, and Me₃SiCl, affording functionalized (hetero)arenes in high yields. This flow procedure is successfully extended to the lateral metalation of methyl‐substituted arenes and heteroaromatics, resulting in the formation of various benzylic potassium organometallics. A metalation scale‐up was possible without further optimization.     

Sodiation of Arenes and Heteroarenes in Continuous Flow

The first sodiations of (hetero)arenes in continuous flow using NaDA (sodium diisopropylamide) in Me₂EtN are reported. This flow procedure enables sodiation of functionalized arenes and heteroarenes that decompose under batch‐sodiation conditions. The resulting sodiated (hetero)arenes react instantly with various electrophiles, such as ketones, aldehydes, isocyanates, alkyl bromides, and disulfides, affording polyfunctionalized (hetero)arenes in high yields. Scale‐up is possible without further optimization.     

Direct Zincation of Functionalized Aromatics and Heterocycles by Using a Magnesium Base in the Presence of ZnCl2

A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF by using (TMP)₂Mg ? 2 LiCl (TMP=2,2,6,6‐tetramethylpiperamidyl) in the presence of ZnCl₂. The possible pathways of this metalation procedure as well as possible reactive intermediates are discussed. This experimental protocol expands the tolerance of functional groups and allows an efficient zincation of sensitive heterocycles such as quinoxaline or pyrazine. The zincated arenes and heteroarenes react with various electrophiles providing the expected products in 60–95 % yield.     

A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles,Arenes, Olefins,and Alkanes using TMPZnCl⋅LiCl

The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl?LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The pK_a values of functionalized N‐, S‐, and O‐heterocycles, arenes, alkenes, or alkanes were calculated and compared to the experimental deprotonation sites. Large overlap (>80 %) between the calculated and empirical deprotonation sites was observed, showing that thermodynamic factors strongly govern the metalation regioselectivity. In the case of olefins, calculated frozen state energies of the deprotonated substrates allowed a more accurate prediction. Additionally, various new N‐heterocycles were analyzed and the metalation regioselectivities rationalized using the predictive model.     

Sapphyrin Supramolecules through C−H⋅⋅⋅S and C−H⋅⋅⋅Se Hydrogen Bonds—First Structural Characterization of meso- Arylsapphyrins Bearing Heteroatoms

An unprecedented coupling reaction of heteroatom-containing tripyrranes leads to the formation of core-modified sapphyrins 1 and 2 , which self-assemble in the solid state to form supramolecular ladders. Weak C−H⋅⋅⋅S and C−H⋅⋅⋅Se hydrogen-bonding interactions in addition to C−H⋅⋅⋅N hydrogen bonds are responsible for the observed structures.