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.     

Deprotonative Metalation of Functionalized Aromatics Using Mixed Lithium–Cadmium,Lithium–Indium,and Lithium–Zinc Species

In situ mixtures of CdCl₂?TMEDA (0.5 equiv; TMEDA=N,N,N′,N′‐tetramethylethylenediamine) or InCl₃ (0.33 equiv) with [Li(tmp)] (tmp=2,2,6,6‐tetramethylpiperidino; 1.5 or 1.3 equiv, respectively) were compared with the previously described mixture of ZnCl₂?TMEDA (0.5 equiv) and [Li(tmp)] (1.5 equiv) for their ability to deprotonate anisole, benzothiazole, and pyrimidine. [(tmp)₃CdLi] proved to be the best base when used in tetrahydrofuran at room temperature, as demonstrated by subsequent trapping with iodine. The Cd–Li base then proved suitable for the metalation of a large range of aromatics including benzenes bearing reactive functional groups (CONEt₂, CO₂Me, CN, COPh) or heavy halogens (Br, I), and heterocycles (from the furan, thiophene, pyrrole, oxazole, thiazole, pyridine, and diazine series). Five‐membered heterocycles benefiting from doubly activated positions were similarly dideprotonated at room temperature. The aromatic lithium cadmates thus obtained were involved in palladium‐catalyzed cross‐coupling reactions or simply quenched with acid chlorides.     

Manganese‐Catalyzed Redox‐Neutral C−H Olefination of Ketones with Unactivated Alkenes

Since 1987, stoichiometric cyclomanganation of ketones and subsequent reactions with olefins in the presence of either palladium salts or trimethylamine N‐oxide (Me₃N⁺O^?) have been reported, but the catalytic versions remain untouched so far. Herein, the first manganese‐catalyzed redox‐neutral C?H olefination of ketones with unactivated alkenes is described, and shows a distinct reactivity with its parent stoichimetric reactions. Remarkably, mechanistic experiments and DFT calculations uncovers a unique concerted bis‐metalation deprotonation (CBMD) mechanism of the Mn‐Zn‐enabled C?H bond activation.     

Surprisingly Different Reaction Behavior of Alkali and Alkaline Earth Metal Bis(trimethylsilyl)amides toward Bulky N‐(2‐Pyridylethyl)‐N′‐(2,6‐diisopropylphenyl)pivalamidine

N‐(2,6‐Diisopropylphenyl)‐N′‐(2‐pyridylethyl)pivalamidine (Dipp‐N=C(tBu)‐N(H)‐C₂H₄‐Py) ( 1 ), reacts with metalation reagents of lithium, magnesium, calcium, and strontium to give the corresponding pivalamidinates [(tmeda)Li{Dipp‐N=C(tBu)‐N‐C₂H₄‐Py}] ( 6 ), [Mg{Dipp‐N=C(tBu)‐N‐C₂H₄‐Py}₂] ( 3 ), and heteroleptic [{(Me₃Si)₂N}Ae{Dipp‐N=C(tBu)‐N‐C₂H₄‐Py}], with Ae being Ca ( 2 a ) and Sr ( 2 b ). In contrast to this straightforward deprotonation of the amidine units, the reaction of 1 with the bis(trimethylsilyl)amides of sodium or potassium unexpectedly leads to a β‐metalation and an immediate deamidation reaction yielding [(thf)₂Na{Dipp‐N=C(tBu)‐N(H)}] ( 4 a ) or [(thf)₂K{Dipp‐N=C(tBu)‐N(H)}] ( 4 b ), respectively, as well as 2‐vinylpyridine in both cases. The lithium derivative shows a similar reaction behavior to the alkaline earth metal congeners, underlining the diagonal relationship in the periodic table. Protonation of 4 a or the metathesis reaction of 4 b with CaI₂ in tetrahydrofuran yields N‐(2,6‐diisopropylphenyl)pivalamidine (Dipp‐N=C(tBu)‐NH₂) ( 5 ), or [(thf)₄Ca{Dipp‐N=C(tBu)‐N(H)}₂] ( 7 ), respectively. The reaction of AN(SiMe₃)₂ (A=Na, K) with less bulky formamidine Dipp‐N=C(H)‐N(H)‐C₂H₄‐Py ( 8 ) leads to deprotonation of the amidine functionality, and [(thf)Na{Dipp‐N=C(H)‐N‐C₂H₄‐Py}]₂ ( 9 a ) or [(thf)K{Dipp‐N=C(H)‐N‐C₂H₄‐Py}]₂ ( 9 b ), respectively, are isolated as dinuclear complexes. From these experiments it is obvious, that β‐metalation/deamidation of N‐(2‐pyridylethyl)amidines requires bases with soft metal ions and also steric pressure. The isomeric forms of all compounds are verified by single‐crystal X‐ray structure analysis and are maintained in solution.     

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.     

Solvent Choice and Kinetic Isotope Effects (KIEs) Dramatically Alter Regioselectivity in the Directed ortho Metalation (DoM) of 1,5‐Dichloro‐2,4‐dimethoxybenzene

The regioselective formation of the 6‐lithio derivative of 1,5‐dichloro‐2,4‐dimethoxybenzene (i.e., 12 ) by directed ortho metalation (DoM) with nBuLi in THF is described. Although literature reports suggest direct deprotonation at C6, a series of time‐course and labelling studies has revealed that deprotonation rather occurs exclusively at C3 followed by isomerization of the anion to C6. By contrast, when DoM was performed in Et₂O, deprotonation again occurred selectively at C3, but now no isomerization occurs, and electrophilic capture produces the regioisomer of that produced in THF. In these labeling studies, it has been found that deuterium has an enormous kinetic isotope effect (KIE) that suppresses not only the original DoM reaction at C3 when deuterium is present there, but also suppresses isomerization to C6 when the label is at that site. Remarkably, this “protecting‐group” role of the deuterium is unique to THF; in ether, full deprotonation of the deuterium at C3 was observed.     

Copper nanoparticles incorporated on a mesoporous carbon nitride,an excellent catalyst in the Huisgen 1,3‐dipolar cycloaddition and N‐arylation of N‐heterocycles

Cu nanoparticles with average particles size around 10 nm were incorporated on the surface of a mesoporous carbon nitride support. The XRD and N₂ adsorption isotherms show that it maintains a hexagonal mesoporous structure with a high surface area (600.03 m² g^?1). The embedded Cu nanoparticles exhibit extremely high catalytic performance in two different kinds of organic reactions. The Huisgen 1,3‐dipolar cycloaddition and N‐arylation of N‐heterocycles were all accomplished.     

Access to Silylated Pyrazole Derivatives by Palladium‐Catalyzed C−H Activation of a TMS group

A simple and efficient approach to new silylated heterocycles of potential interest in medicinal chemistry is presented. A set of bromophenyl trimethylsilyl pyrazole intermediates can be transformed by direct organometallic routes into two families of regioisomeric iodoaryl substrates; using either arylzinc or aryllithium chemistry, the TMS group remains on the pyrazole ring or translocates to the aryl moiety. These two families can then be efficiently transformed into benzo silino pyrazoles thanks to a single‐step cyclization relying on the Pd‐catalyzed activation of a non‐activated C(sp³)?H bond alpha to a silicon atom. The experimental conditions used, which are fully compatible with the pyrazole ring, suggest that this reaction evolves through a concerted metalation–deprotonation (CMD) mechanism.     

Boron Perturbed Click Reactions Prompt Aromatic CH Activations

The reaction of boron alkynes and boron azides leads to rare N₃BC heterocycles resulting from aromatic C? H activation of benzene and toluene. While subsequent treatment with PMe₃ gave the P? B adduct with the exocyclic boron, reaction with PtBu₃ effected deprotonation of the heterocycle to give the corresponding phosphonium salt.     

Rational Development of Remote C−H Functionalization of Biphenyl: Experimental and Computational Studies

A simple and efficient nitrile‐directed meta‐C?H olefination, acetoxylation, and iodination of biaryl compounds is reported. Compared to the previous approach of installing a complex U‐shaped template to achieve a molecular U‐turn and assemble the large‐sized cyclophane transition state for the remote C?H activation, a synthetically useful phenyl nitrile functional group could also direct remote meta‐C?H activation. This reaction provides a useful method for the modification of biaryl compounds because the nitrile group can be readily converted to amines, acids, amides, or other heterocycles. Notably, the remote meta‐selectivity of biphenylnitriles could not be expected from previous results with a macrocyclophane nitrile template. DFT computational studies show that a ligand‐containing Pd–Ag heterodimeric transition state (TS) favors the desired remote meta‐selectivity. Control experiments demonstrate the directing effect of the nitrile group and exclude the possibility of non‐directed meta‐C?H activation. Substituted 2‐pyridone ligands were found to be key in assisting the cleavage of the meta‐C?H bond in the concerted metalation–deprotonation (CMD) process.     

Chiral‐Zn(NTf2)2‐Complex‐Catalyzed Diastereo‐ and Enantioselective Direct Conjugate Addition of Arylacetonitriles to Alkylidene Malonates

Chiral N,N′‐dioxide/Zn(NTf₂)₂ complexes were demonstrated to be highly effective in the direct asymmetric conjugate addition of arylacetonitriles to alkylidene malonates under mild conditions. A wide range of substrates were tolerated to afford their corresponding products in moderate‐to‐good yields with high diastereoselectivities (82:18–>99:1 d.r.) and enantioselectivities (81–99 % ee). The reactions performed well, owing to the high Lewis acidity of the metal triflimidate and a ligand‐acceleration effect. The N,N′‐dioxide also benefited the deprotonation process as a Brønsted base. The catalytic reaction could be performed on the gram‐scale with retention of yield, diastereoselectivity, and enantioselectivity. The products that contained functional groups were ready for further manipulation. In addition, a possible catalytic model was proposed to explain the origin of the asymmetric induction.     

Synthesis of 4‐Aryl‐4,6‐dihydropyrimido[4,5‐d]pyridazine‐2,5(1H,3H)‐diones from Biginelli Compounds

Biginelli compounds 1 were first brominated at Me? C(6) with 2,4,4,6‐tetrabromocyclohex‐2,5‐dien‐1‐one to give Br₂CH? C(6) derivatives 2 . The hydrolysis of the 6‐(dibromomethyl) group of 2c to give the 6‐formyl derivative 3c in the presence of an expensive Ag salt followed by reaction with N₂H₄?H₂O yielded tetrahydropyrimido[4,5‐d]pyridazine‐2,5(1H,3H)‐dione ( 4c ; Scheme 1). However, treatment of the 6‐(dibromomethyl) derivatives 2 directly with N₂H₄?H₂O led to the fused heterocycles 4 in better overall yield (Schemes 1 and 2; Table).     

Synthesis of A2B6‐Type [36]Octaphyrins: Copper(II)‐Metalation‐Induced Fragmentation Reactions to Porphyrins and N‐Fusion Reactions of meso‐(3‐Thienyl) Substituents

5,10,15‐Tris(pentafluorophenyl)tetrapyrromethane was efficiently prepared through a route involving stepwise diaroylation of 5‐pentafluorophenyldipyrromethane. A₂B₆‐type [36]octaphyrins were prepared by the cross condensation of the tetrapyrromethane with aryl aldehydes in moderate yields. A₂B₆‐type [36]octaphyrins bearing 2,4,6‐trifluorophenyl, 2,6‐dichlorophenyl, and phenyl substituents underwent Cu^II‐metalation‐induced fragmentation to give two molecules of AB₃‐type Cu^II porphyrins. A₂B₆‐type [36]octaphyrin bearing 3‐thienyl substituents underwent thermal N‐thienyl fusion reactions to provide a modestly aromatic [38]octaphyrin, which, upon treatment with MnO₂, underwent further N‐thienyl fusion and subsequent oxidation to give a nonaromatic doubly N‐thienyl fused [36]octaphyrin.     

Mixed Directing‐Group Strategy: Oxidative C−H/C−H Bond Arylation of Unactivated Arenes by Cobalt Catalysis

A mixed directing‐group strategy for inexpensive [Co(acac)₃]‐catalyzed oxidative C?H/C?H bond arylation of unactivated arenes has been disclosed. This strategy enables the arylation of a wide range of benzamide and arylpyridines effectively to afford novel bifunctionalized biaryls, which are difficult to achieve by common synthetic routes. Two different pathways, namely, a single‐electron‐transmetalation process (8‐aminoquinoline‐directed) and a concerted metalation–deprotonation process (pyridine‐directed), were involved to activate two different inert aromatic C?H bonds. Moreover, the aryl radicals have been trapped by 2,6‐di‐tert‐butyl‐4‐methylphenol to form benzylated products. This unique strategy should be useful in the design of other arene C?H/C?H cross‐couplings as well.     

Cascade One‐Pot Synthesis of Orange‐Red‐Fluorescent Polycyclic Cinnolino[2,3‐f]phenanthridin‐9‐ium Salts by Palladium(II)‐Catalyzed C−H Bond Activation of 2‐Azobiaryl Compounds and Alkenes

Quaternary ammonium salts were synthesized in moderate to good yields through double oxidative C?H bond activation on azobenzenes. The mechanism of the highly regioselective reaction of 2‐azobiaryls with alkenes to give orange‐red‐fluorescent cinnolino[2,3‐f]phenanthridin‐9‐ium salts and 15H‐cinnolino[2,3‐f]phenanthridin‐9‐ium‐10‐ide is proposed to involve ortho C?H olefination of the 2‐azobiaryl compound with the alkene, intramolecular aza‐Michael addition, concerted metalation–deprotonation (CMD), reductive elimination, and oxidation.     

A Doubly Zwitterionic Antiaromatic [28]Hexaphyrin Formed upon Deprotonation of 5,20‐Di(N‐methyl‐4‐pyridinium)‐Substituted [28]Hexaphyrin

A rectangular 5,20‐di(4‐pyridyl) [26]hexaphyrin was reduced with NaBH₄ to give the corresponding twisted Möbius aromatic [28]hexaphyrin. Subsequent double N‐methylation gave a dicationic 5,20‐di(N‐methyl‐4‐pyridinium) [28]hexaphyrin, which was converted to a doubly zwitterionic and Hückel antiaromatic [28]hexaphyrin upon deprotonation with sodium methoxide.     

Cp*CoIII‐Catalyzed C(sp3)−H Bond Amidation of 8‐Methylquinoline

An efficient and external oxidant‐free, Cp*Co^III‐catalyzed C(sp³)?H bond amidation of 8‐methylquinoline, using oxazolone as an efficient amidating agent, is reported for the first time under mild conditions. The reaction is selective and tolerates a variety of functional groups. Based on previous reports and experimental results, the deprotonation pathway proceeds through an external base‐assisted concerted metalation and deprotonation process.     

Palladium‐Catalyzed Multi‐Component Reactions of N‐Tosylhydrazones, 2‐Iodoanilines and CO2 towards 4‐Aryl‐2‐Quinolinones

A palladium‐catalyzed three‐component reaction between N‐tosylhydrazones, 2‐iodoanilines and atmospheric pressure CO₂ was developed whereby a tandem carbene migration insertion/lactamization strategy afforded 4‐aryl‐2‐quinolinones in moderate to good yields. Notably, a wide range of functional groups were tolerated in this procedure. This protocol features the simultaneous formation of four novel bonds; two C?C, one C=C and one C?N (amide), representing an efficient methodology for incorporation of CO₂ into heterocycles.     

Regioselective Dialkylations of N‐(tert‐Butyl)iminocyclopentane via Deprotonating One‐Pot Procedures

The title compound ( 1 ) was chosen as a model for the α/α′‐regioselectivity of deprotonation and subsequent alkylation adjacent to the C=N bond. With the bulky base lithium N,N‐diisopropylamide (LDA) as a catalyst, the one‐pot deprotonation steps can be performed through titration with methyllithium, using gas‐volumetric observation of the liberated methane. In the first step with ensuing methylation by iodomethane, the primary product is born at −40 °C in its metastable (Z) configuration (kinetic control) and may be either isolated or converted in situ at 30 °C into its thermodynamically favored (E)‐isomer via cis to trans stereoinversion at the N‐atom. Being slow enough on the laboratory time scale, this stereoinversion process can serve to control the regioselectivity of the second deprotonation/alkylation sequence as follows. The α,α′‐products are formed from the intermediate (Z)‐imine, whereas α,α‐products result from the intermediate (E)‐imine; in either case, syn deprotonation (cis to ^tBu at nitrogen) by LDA is apparently disfavored by the ^tBu group, so that anti deprotonation becomes obligatory. If a third one‐pot deprotonation step is too slow with LDA, it may be performed with the stronger base butyllithium/HMPA which, however, reacts regio‐unselectively. Regioselective one‐pot, LDA‐catalyzed deprotonation with alkylation by oxiranes (alone, or alternatingly with iodomethane) opens a short access to spiro‐[2.4]heptan‐4‐ones.     

N‐functionalized azolin‐2‐ylidene‐palladium‐catalyzed heck reaction

Novel 1,3‐dialkylimidazolidinium, 1,3‐dialkyl‐3,4,5,6‐tetrahydropyrimidinium, and 1,3‐dialkyl‐1H‐4,5,6,7‐tetrahydrodiazepinium hexafluorophosphates ( 1a–c, 2a–c ) as N‐heterocyclic carbene precursors have been synthesized and characterized. The incorporation of saturated N‐heterocyclic carbenes into palladium precatalysts gives high‐catalyst activity in the Heck coupling of aryl bromide substrates in aqueous media. The complexes were generated in the presence of Pd(OAc)₂ by in situ deprotonation of 1,3‐dialkylazolinium salts 1, 2 . © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:82–86, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20415