C-H activated acids

Keywords Aldehydes, indoles, C-H activated acids (4-hydroxycoumarin, 4-hydroxy-6-methyl-2//-pyran-2-one, dimedone, AAA -dimethylbarbituric acid, Meldrum s acid), L-proline, solvent-free, room temperature, grinding, one-pot three-component condensation, gewt-(P-dicarbonyl)arylmethanes... 

Keywords Aldehydes, malononitrile, C-H activated acids, urea, organocatalyst, ethanol-water (1 1), room temperature, tandem Knoevenagel-cyclocondensation, one-pot three-component reaction, chemoselectivity, functionalized 2-amino-3-cyano-4//-pyrans and pyran annulated heterocycles... 

An oven-dried screw cap test tube was charged with a magnetic stir bar, aldehyde (1 1 mmol), malononitrile (2 1.1 mmol), urea (10 mol% as organo-catalyst), EtOH H2O (1 1 vA 4 mL) in a sequential manner the reaction mixture was then stirred vigorously at room temperature for about 20 min. After then C—H activated acid (3) (1 mmol) was added to the stirred reaction... 

Dihydropyrano[3,2-c]chromenes have recently attracted much attention as an important class of heterocycles having useful biological and pharmacological properties such pyran-annulated scaffolds are obtained from the reaction of 4-hydroxycoumarin (13) with aldehydes and C-H activated acids (e.g., malononitrile, ethyl 2-cyanoacetate, etc.). Recently, Khoobi et al. [95] developed an efficient protocol for the synthesis of dihydropyrano[3,2-c]chromenes 14 in aqueous medium in the presence of nanocatalyst, (2-aminomethyl)phenol, supported on HAp-encapsulated-Y-Fe203 ([Y-Fe203 Hap-Si(CH2)3-AMP]) under reflux condition (Scheme 7). "Qn-water" syntheses of such scaffolds were also reported earlier by Khurana et al. [81] and Shaabani et al. [86] (Scheme 7). 

In addition, the investigators have extended their protocol for bis-pyranization from the reaction between terephthaldehyde (46), malononitrile, and C-H activated acids (11,13, and dimedone) to afford bis-pyrans 47 (Scheme 32) [17]. 

Similarly, when both the Cp and arene ligands are permethylated, the reaction of 02 with the Fe1 complex leads to C-H activation of the more acidic benzyl bond [57]. When no benzylic hydrogen is present, superoxide reacts as a nucleophile and adds onto the benzene ligand of the FeCp(arene)+ cation to give a peroxocyclohexadienyl radical which couples with a Fe Cp(arene) radical. A symmetrical bridging peroxo complex [(Fe"Cp)2(r 5-C6H60)2] is obtained. The C-H activation reactions of the 19e Fe1 radicals BH can be summarized as follows... 

Homogeneous catalysts have been reported, which can oxidize methane to other functionalized products via C-H activation, involving an electrophilic substitution process. The conversion of methane into methyl bisulfate, using a platinum catalyst, in sulfuric acid, has been described. The researchers found that a bipyrimidine-based ligand could both stabilize and solubilize the cationic platinum species under the strong acidic conditions and TONs of >500 were observed (Equation (5)).13... 

Acetic acid analogs can also be formed from a one-step C-H activation process using a palladium sulfate catalyst.15 A free radical process was ruled out for this formal eight-electron oxidation due to the high selectivities observed (90% based on methane converted) (Equation (7)). 

Acetic acid can be synthesized from methane using an aqueous-phase homogeneous system comprising RhCI as catalyst, CO and 02.17 Side-products included methanol and formic acid, although yields of acetic acid increased upon addition of either Pd/C or iodide ions. The active species is thought to be a CH3-Rh(l) derivative, formed from the C-H activation of methane. The activation of ethane was also achieved, although selectivities were lower, with products including acetic and propionic acids and ethanol (Equation (9)). 

Not all C-H activation chemistry is mediated by transition metal catalysts. Many of the research groups involved in transition metal catalysis for C-H activation have opted for alternative means of catalysis. The activation of methane and ethane in water by the hexaoxo-/i-peroxodisulfate(2—) ion (S2O82) was studied and proceeds by hydrogen abstraction via an oxo radical. Methane gave rise to acetic acid in the absence of external carbon monoxide, suggesting a reaction of a methyl radical with CO formed in situ. Moreover, the addition of (external) CO to the reaction mixture led to an increase in yield of the acid product (Equation (ll)).20... 

C-H activation a to nitrogen generates f3-amino acid derivatives (Figure 5). Therefore, the reaction can be considered to be a surrogate of the Mannich reaction. 

The reaction with the siloxy derivative 29 is an interesting example because the product 30 is a 1,5-dicarbonyl derivative (Equation (36)).96 1,5-Dicarbonyls are classically prepared by a Michael addition, but the synthesis of 30 by a Michael addition is not possible because it would require addition to the keto form of 1-naphthol. The acetoxy derivative 31 resulted in a different outcome, leading to the direct synthesis of the naphthalene derivative 32 (Equation (37)).96 In this case, the combined C-H activation/Cope rearrangement intermediate was aromatized by elimination of acetic acid before undergoing a reverse Cope rearrangement. 

What purpose does the alkane binding to the Pt(II) center serve For the electrophilic pathway (Scheme 5, b), this is immediately apparent, a-Alkane complexes should be considerably more acidic than free alkanes, such that deprotonation may become a viable C-H activation pathway. While the acidic character of alkane complexes has not been directly observed, it can be inferred from the measured acidity of analogous agos-tic complexes (36) and from the acidity of the a-complexes of dihydrogen (37), both of which can be regarded models for alkane complexes (see Section III.E). 

The reactivity of the closely related system TpMe2PtMeH2 toward electrophiles in arene solvents has also been reported recently (68). The boron-based Lewis acid B(C6F5)3 induced elimination of methane and formation of an aryl(dihydrido) platinum(IV) complex via arene C-H activation (Scheme 17, A -> C). The active acid may be either B(C6F5)3 or alternatively a proton generated from B(C6F5)3 and trace water. It was proposed that the acid coordinates to a pyrazole nitrogen (shown in Scheme 17, B) forming an intermediate five-coordinate platinum(IV) complex, which readily eliminates methane. 

This elegant organic transformation is, along with the recent development of a Pt(II)-based derivatization procedure for amino acids (221), an impressive example that platinum-mediated C-H activation offers great potential for not only the functionalization of simple small molecules but also the synthesis of complicated organic targets. 

Chiral 1,1 -binaphthol derivatives are well established as readily available chiral catalysts and auxiliaries for the production of various useful optically active compounds. Tanabe et al. investigated [11] a crystalline-liquid resolution of (1R) -// . v - c h rysanthemic acid utilizing l,l -binaphthyl monoethyl ether (25) (Scheme 3). 

Oxidative carbonylation can also be achieved by metal-assisted C - H activation. The Pd(II)-promoted oxidative carbonylation of arenes to give aromatic acids has been reported to occur under stoichiometric [127,128] as well as catalytic [129-138] conditions (Eqs. 28-30). In the case of alkylben-zenes, the Pd-catalyzed reaction shows only a moderate selectivity towards the para position. Better p-selectivilics have however been attained by employing Rh(III) or Ir(III) catalysts [139-146]. 

Perhaps most dramatically of all, for the first time, bis(carbene)-substituted iridium complexes, such as [Ir(cod)(NHC)2] (NHC = 1,3-dimethyl- or 1,3-dicyclohexylimidazolin-2-ylidene] were successfully used by Herrmann and coworkers as C—H-activation catalysts in the synthesis of arylboronic acids starting from pinacolborane and arene derivatives [46]. 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

There are fewer examples of this for such Ru-catalysed oxidations than for C-H activation, cleavage of the C-C bond in diols being the main example [111]. Optically pure D- and L-glyceric acids were made by cleavage of vicinal diols or of a-hydroxy acids by RuCl3/aq. Na(ClO) pH 8, e.g. l,2 5,6-di-0-isopropylidene-D-mannitol to 2,3-0-isopropylidene-D-glyceric acid (Fig. 4.6) [112],... 

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