Regioselective Functionalization of 7‐Azaindole by Controlled Annular Isomerism: The Directed Metalation‐Group Dance

The regioselective functionalization of 7‐azaindole by controlled annular isomerism employing a directed metalation‐group migration is reported. The N7 carbamoyl azaindoles undergo regioselective metalation and quenching with an electrophile to furnish C6‐substituted derivatives which, in the presence of a catalytic amount of ClCONR₂ promotes a carbamoyl group shift or dance from N7 to N1. A second directed metalation/electrophile quench sequence leads to 2,6‐substituted azaindoles. Optimization of the metalation conditions for C2 and C6, separately and iteratively, is presented. Using the directed metalation group dance strategy, a late‐stage deuteration of an antipsychotic drug is described. Overall, the controlled migration of the carbamoyl directing group allows multiple functionalization events of the bioactive azaindole scaffold.     

Metalation of alkyl aryl sulfones: qualitative and quantitative product determination

The metalation of methyl phenyl sulfone (I) and methyl naphthyl sulfone (II) was investigated under a variety of conditions. The product species were determined qualitatively and quantitatively after characterization with some electrophilic agents. After the primary metalation at the methyl position, species of various metalation degrees were prsent simultaneously, including the 1,1,1-trimetalated derivatives. With high LiR/sulfone ratios, in addition to the products of the primary metalation, compounds arising from metalation of the aromatic ring were formed as well as those from reduction, cleavage, etc.     

Regioselectivity in lateral deprotonation of an isoxazolecarboxamide of (S)-prolinol. Conformational correlation by crystal structure solid state solution 13C NMR

The conformation at the amide functional group in 3,5-dimethylisoxazole-4-(S-2′-hydroxymethyl-N-pyrrolidino) carboxamide (1) has been determined by a single crystal X-ray determination. The ¹³C nmr in both deuteriochloroform solution and solid state show close agreement. The metalation behaviour of the amide is dependent upon the substitution on the 2′-hydroxymethyl moiety. Dianion studies indicate C-5 lateral metalation under both thermodynamic and kinetic conditions. Protection of this substituent as the methyl ether, 2 , gives rise to predominant C-3 lateral metalation under kinetic conditions and C-5 lateral metalation on equilibration. These observations can be explained using the Ireland-Evans model for chelation directed deprotonation.     

Coverage‐ and Temperature‐Dependent Metalation and Dehydrogenation of Tetraphenylporphyrin on Cu(111)

Using temperature‐programmed desorption, supported by X‐ray photoelectron spectroscopy and scanning tunneling microscopy, a comprehensive overview of the main reactions of 5,10,15,20‐tetraphenyl‐21H,23H‐porphyrin (2HTPP) on Cu(111) as a function of coverage and temperature is obtained. Three reactions were identified: metalation with Cu substrate atoms, stepwise partial dehydrogenation, and finally complete dehydrogenation. At low coverage the reactions are independent of coverage, but at higher coverage metalation becomes faster and partial dehydrogenation slower. This behavior is explained by a weaker interaction between the iminic nitrogen atoms and the Cu(111) surface in the high‐coverage checkerboard structure, leading to faster metalation, and the stabilizing effect of T‐type interactions in the CuTPP islands formed at high coverage after metalation, leading to slower dehydrogenation. Based on the amount of hydrogen released and the appearance in STM, a structure of the partially dehydrogenated molecule is suggested.     

Direct metalation of methoxymethyl arylmethyl ethers: A tin-free approach to the generation of α-alkoxyalkoxy-substituted aryllithiums

The generation of a series of α-methoxymethoxy-substituted arylmethyllithiums was achieved by direct metalation of the corresponding arylmethyl methoxymethyl ethers. While the effect of substituents at the benzylic position is straightforward, substituents located on the aromatic ring promote the set up of a competition between lateral and aromatic metalation, strongly affected by the position and relative ortho directing properties of the new substituent. The proposed methodology allows a simple approach to the generation of a wide array of functionalized organolithium reagents.     

Metalation reactions. : IV. Metalation of o-alkyl- and o,o′-dialkyl-substituted alkylthiobenzenes

Metalation of o-alkyl- and o,o′-dialkylsubstituted alkylthiobenzenes with n-butyllithium, in the presence and absence of TMEDA, has been investigated. The results showed that metalation at the thioalkyl carbon probably occurs by direct attack of the organolithium reagent, although a transmetalation reaction cannot be excluded in some cases. It has also been found that benzylic, thio-methylic, and ring metalation occurs in ether alone, whereas mainly thio-methylic or ring metalation occurs in the presence of TMEDA.     

The direct observation of 2H‐DPP metalation on Pd(111) and Cu/Pd(111) surface

The metalation behaviors of 5,15‐diphenylporphyrin (2H‐DPP) on Pd(111) and Cu/Pd(111) have been investigated using scanning tunneling microscopy and density functional calculations. We show that 2H‐DPP molecules deposited on Pd(111) surface form Pd‐DPP with a proportion of about 75% already at room temperature (RT). This is in contrast to non‐metalation adsorption of 2H‐DPP on Cu–Pd alloy at RT. Annealing to 323 K facilitates the metalation of 2H‐DPP on Cu–Pd alloy island. The comparison of the results indicates that the metalation of 2H‐DPP calls for both enough surface free energy of approaching N? H bond and enough reactivity of breaking N? H bond. Copyright © 2016 John Wiley & Sons, Ltd.     

Lithiation–alkylation of polystyrene occurs only on the ring

When polystyrene is treated with an organolithium reagent, the hydrogen on the para carbon is removed and this position may be alkylated with e.g., iodomethane or chlorotrimethylsilane. The metalation occurs directly at this position and does not involve metalation at the benzylic carbon with resonance distribution of the charge to the ring. The reaction of cumene with butyllithium also occurs by direct ring metalation and it is shown that these results are consistent with both the kinetic and the thermodynamic acidity of the hydrocarbons. © 1997 John Wiley & Sons, Inc.     

Metalation of t-butyl sulfoxides,sulfones and sulfonamides of pyridazine and pyrazine. Metalation of diazines. XX

In the pyridazine series, the use of tert-butylsulfinyl and tert-butylsulfonyl as ortho directing groups for metalation has been tested. Various functionalized products were obtained in good yields. In the case of 3-tert-butylsulfinyl-6-methoxypyridazine, the metalation was regioselective in ortho to the sulfinyl group. The metalation of 2-tert-butylsulfinyl and 2-tert-butylsulfonylpyrazine gave low to moderate yields. Synthesis of diazinesulfonamides were improved and the metalation of N-tert-butylsulfonamidopyrazine was achieved.     

Grafting of Polymers from Carbon Fiber. Anionic Graft Polymerization of Vinyl Monomers Initiated by Metallized Aromatic Rings on Carbon Fiber

The anionic graft polymerization of vinyl monomers onto carbon fiber initiated by metallized carbon fiber was investigated. The metalation of polycondensed aromatic rings of the carbon fiber surface was achieved by the treatment of carbon fiber with n-butyl-lithium (BuLi) in N, N, N′, N′ -tetramethylethylenediamine (TMEDA) or hexamethylphosphorous triamide (HMPT) at 0°C. The anionic polymerization of methyl methacrylate (MMA) and styrene (St) was initiated by the metallized carbon fiber, and these polymers were grafted onto the surface. The conversion and the percentage of grafting increased with increasing amount of BuLi used for the metalation of carbon fiber. When 0.20 g carbon fiber was treated with 0.3 mmol BuLi in TMEDA, the percentage of grafting of PMMA and PSt reached a maximum value (PMMA, 34.5%; PSt, 37.1 %). Furthermore, the metalation of aromatic rings of carbon fiber also proceeds by the treatment with BuLi in HMPT. On the contrary, no grafting was observed when carbon fiber was treated with BuLi in tetrahydrofuran (THF) or toluene. This may be due to the fact that metalation of carbon fiber does not proceed in THF or toluene.     

Solid-phase lithiation of 5-carboxyindoles

Direct functionalization of protected 5-carboxyindole by metalation has been performed for the first time on solid-phase. The indole moiety has been tethered to aminomethylated polytetrahydrofuran cross-linked polystyrene, forming a secondary amide, which functions as a directing metalation group. The ortho-lithiated species have been quenched with substituted benzaldehydes affording resin bound alcohols. After cyclative cleavage regioisomeric mixtures of phthalides were obtained in the ratio 80:20.     

Bridgehead enolates: substitution and asymmetric desymmetrization of small bridged carbonyl compounds by lithium amide bases

[reaction: see text] Contrary to expectations, a number of bridged carbonyl compounds undergo facile bridgehead metalation with lithium amide bases. Diketone, lactone, lactam, and imide functions are all demonstrated to participate in this type of "bridgehead enolate" chemistry, leading to a range of substituted products. Meso compounds can also be desymmetrized in very high ee by asymmetric bridgehead metalation.     

Controlled anion migrations with a mixed metal Li/K-TMP amide: general application to benzylic metalations

A general method is described for benzylic metalation of o-, m-, and p-substituted toluenes using a mixed metal amide base generated from BuLi/KOtBu/TMP at -78 °C in THF. The excellent selectivity achieved can be rationalized by the ability of the mixed metal amide base to facilitate an anion migration from the kinetic (o-aryl) to the benzylic metalation site. Remarkably, this controlled anion migration is achievable with catalytic amounts of TMP at -78 °C.     

Directed ortho metalation methodology. The N,N-dialkyl aryl O-sulfamate as a new directed metalation group and cross-coupling partner for Grignard reagents

[reaction: see text] The ortho metalation (RLi/THF/-93 degrees C) of 3 followed by quench with a variety of electrophiles constitutes a new general route to substituted aryl O-sulfamates 4a-k. The Kumada-Corriu cross-coupling of O-sulfamates 4e, 4n-s, and 6a with Grignard reagents gives biaryls 9a-m, and the use of 2-halo and boron derivatives 4h, 4i, and 4k for Suzuki-Miyaura cross-coupling and generation of benzynes leads to naphthols 7a and 7b. A relative metalation ranking of the OSONEt(2) is reported.     

In situ anionic shielding for regioselective metalation: directed peri and iterative metalation routes to polyfunctionalized 7-azaindoles

Strolling the ring: a general regioselective directed peri(C4)-metalation route to 1 through an in situ N-anionic protection of C2 is reported. The azaindoles may be elaborated by directed ortho metalation (DoM) and Suzuki coupling to more complex heterocyclic systems. An iterative ring-walk DoM sequence furnishes the exhaustively substituted 2. DMG=directed metalation group, TMEDA=N,N,N',N'-tetramethylethylenediamine, TMS=trimethylsilyl.     

Cyclic vinyl ether carbanions—II : Preparation and applications to the synthesis of carbonyl compounds

Conditions for metalation of a variety of cyclic vinyl ethers and reaction of the resulting carbanions with electrophiles are described. Effects of the vinyl ether structure on the relative rates of metalation are discussed. Applications of this methodology to the construction of various types of carbonyl compounds are presented.     

HFIP‐Assisted C−H Functionalization by Cp*CoIII: Access to Key Reactive Cobaltacycles and Implication in Catalysis

Described here is a synthetic approach to access two of the most widely invoked cationic cobaltacycles in Cp*Co^III‐catalyzed C?H functionalization reactions by C?H activation. The unique stabilizing capability of MeCN was used to surmount the previously proposed reversible nature of the C?H metalation step. Moreover, it is revealed the boosting effect of 1,1,1,3,3,3‐hexafluoroisopropanol in the metalation step and in the reaction between N‐pyrimidinylindole and diphenylacetylene under catalytic conditions.     

Synthetic and mechanistic aspects of a new method for ruthenium-metalation of porphyrins and Schiff-bases

A new method is presented for metalation of a wide range of free-base, neutral, cationic, and anionic porphyrins in refluxing dimethylformamide (DMF) using an easily prepared [Ru(DMF) 6](OTf) 3 complex, and comparisons are made with the more familiar metalation procedure using Ru 3(CO) 12. Both procedures generate Ru (II)(porp)(CO)L complexes (L = solvent); use of the Ru (III)-triflate precursor gives yields comparable to, or greater than, those obtained with the carbonyl, and generates no Ru-chlorin impurities. Mechanistic studies on the meso-tetraphenylporphyrin system reveal that the DMF furnishes the CO, which in the presence of essential water reduces the metal, and metalation likely occurs via a Ru (II)-CO species. Corresponding metalation of tetradentate Schiff-bases gives trans-[Ru (III)(Schiff- base)(DMF) 2]OTf complexes in yields of approximately 50%, a limitation being the accompanying hydrolysis of the Schiff-base through the presence of trace water.     

Continuous‐Flow Synthesis of Biaryls by Negishi Cross‐Coupling of Fluoro‐ and Trifluoromethyl‐Substituted (Hetero)arenes

A continuous‐flow method for the regioselective arylation of fluoroarenes and fluoropyridines has been developed. The telescoped procedure reported here consists of a three‐step metalation, zincation, and Negishi cross‐coupling sequence, providing efficient access to a variety of functionalized 2‐fluorobiaryl products. Precise temperature control of the metalation step, made possible by continuous‐flow technology, allowed for the efficient preparation of the arylated products in high yields and short residence times. Additionally, several examples of the regioselective arylation of benzotrifluoride derivatives are also provided.     

Synthesis of well-defined head-to-tail-type oligothiophenes by regioselective deprotonation of 3-substituted thiophenes and nickel-catalyzed cross-coupling reaction

Iterative growth of thiophene oligomers by single-step extensions has been realized by regioselective metalation of 3-substituted thiophenes with the Knochel-Hauser base (TMPMgCl·LiCl) and coupling with bromothiophene using a nickel catalyst. Treatment of 3-hexylthiophene with TMPMgCl·LiCl induces metalation at the 5-position selectively. Subsequent addition of 2-bromo-3-hexylthiophene and a nickel catalyst leads to the corresponding bithiophene. The obtained bithiophene is converted to the terthiophene and then to the quaterthiophene by repeating the similar protocol. A concise synthesis of MK-1 and MK-2, which are organic dye molecules bearing an oligothiophene moiety that are used in photovoltaic cells, has been achieved.