Aliphatic C–H bond functionalization is at the frontline of research because it can provide straightforward access to simplified and cost-effective synthetic procedures. A number of these ...methodologies are based on hydrogen atom transfer (HAT), which, as a consequence of the inert character of C–H bonds, often represents the most challenging step of the overall process. Because the majority of organic molecules contain multiple nonequivalent C–H bonds that display similar chemical properties, differentiating between these bonds with high levels of selectivity represents one of the most challenging issues. Clarification of the factors that govern the relative reactivity of C–H bonds toward HAT reagents is thus of primary importance in order to develop selective functionalization procedures. In this Account we describe, through the combination of kinetic studies employing a genuine HAT reagent such as the cumyloxyl radical, along with oxidations performed with H2O2 and iron or manganese catalysts, our contribution toward the development of selective C–H functionalization methodologies. Despite the different nature of these reagents, an oxygen-centered radical and a metal–oxo species, congruent reactivity and selectivity patterns have emerged, providing strong evidence that both reactions proceed via HAT. Consequently, selectivity in this class of metal catalyzed C–H oxidations can be reasonably predicted and synthetically exploited. Amides have been identified as preferential functional groups for governing selectivity on the basis of electronic, steric, and stereoelectronic effects. Torsional effects have proven moreover to be particularly important C–H directing factors in the oxidation of cyclohexane scaffolds where a delicate balance of these effects, in synergistic combination with catalyst design, enables highly chemoselective and enantioselective oxidations. Medium effects have been also shown to govern the relative HAT reactivity of C–H bonds in proximity to polar, hydrogen bond acceptor (HBA) functional groups. By engaging in hydrogen bonding with these groups, fluorinated alcohols strongly deactivate proximal C–H bonds toward HAT-based oxidation. As a result, alcohols, ethers, amines, and amides, which are electron rich and effective proximal C–H activating groups toward HAT reagents in conventional solvents, become oxidatively robust deactivating functionalities that direct C–H oxidation toward remote positions. These deactivating effects enable moreover the accomplishment of product chemoselective methylenic hydroxylations. Overall, clarification of the factors that govern HAT-based reactions has served to provide unique examples of catalytic methodologies for chemoselective and enantioselective oxidation of nonactivated aliphatic C–H bonds of potential utility in organic synthesis.
Monosubstituted cycloalkanes undergo regio- and enantioselective aliphatic C–H oxidation with H2O2 catalyzed by biologically inspired manganese catalysts. The reaction furnishes the corresponding ...ketones resulting from oxidation at C3 and C4 methylenic sites (K3 and K4, respectively) leading to a chiral desymmetrization that proceeds with remarkable enantioselectivity (64% ee) but modest regioselectivity at C3 (K3/K4 ≈ 2) for tert-butylcyclohexane, and with up to 96% ee and exquisite regioselectity toward C3 (up to K3/K4 > 99) when N-cyclohexylalkanamides are employed as substrates. Efficient H2O2 activation, high yield, and highly enantioselective C–H oxidation rely on the synergistic cooperation of a sterically bulky manganese catalyst and an oxidatively robust alkanoic acid. This represents the first example of nonenzymatic highly enantioselective oxidation of nonactivated methylenic sites. Furthermore, the principles of catalyst design disclosed in this work constitute a unique platform for further development of stereoselective C–H oxidation reactions.
Site selective C–H oxidation of N-alkylamides and phthalimides with aqueous hydrogen peroxide catalyzed by manganese complexes is described. These catalysts are shown to exhibit substantially ...improved performance in product yields and substrate scope in comparison with their iron counterparts. The nature of the amide and imide group and of the N-alkyl moiety are shown to be effective tools in order to finely tune site selectivity between proximal (adjacent to the nitrogen) and remote C–H bonds on the basis of steric, electronic, and stereoelectronic effects. Moreover, formation of the α-hydroxyalkyl product in good yield and with excellent product chemoselectivity was observed in the reactions of the pivalamide and acetamide derivatives bearing an α-CH2 group, pointing again toward an important role played by stereoelectronic effects and supporting the hypothesis that these oxidations proceed via hydrogen atom transfer (HAT) to a high-valent manganese–oxo species. Good product yields and mass balances are obtained in short reaction times and under mild experimental conditions when relatively low loadings of an electron-rich manganese catalyst are used. The potential utility of these reactions for preparative purposes is highlighted in the site-selective oxidation of the pivalamide and phthalimide derivatives of substrates of pharmaceutical interest.
The formidable challenges of controlling site-selectivity, enantioselectivity, and product chemoselectivity make asymmetric C–H oxidation a generally unsolved problem for nonenzymatic systems. ...Discrimination between the two enantiotopic C–H bonds of an unactivated methylenic group is particularly demanding and so far unprecedented, given the similarity between their environments and the facile overoxidation of the initially formed hydroxylation product. Here we show that a Mn-catalyzed C–H oxidation directed by carboxylic acids can overcome these challenges to yield γ-lactones in high enantiomeric excess (up to 99%) using hydrogen peroxide as oxidant and a Brønsted acid additive under mild conditions and short reaction times. Coordination of the carboxylic acid group to the bulky Mn complex ensures the rigidity needed for high enantioselectivity and dictates the outstanding γ site-selectivity. When the substrate contains nonequivalent γ-methylenes, the site-selectivity for lactonization can be rationally predicted on the basis of simple C–H activation/deactivation effects exerted by proximal substituents. In addition, discrimination of diastereotopic C–H bonds can be modulated by catalyst design, with no erosion of enantiomeric excess. The potential of this reaction is illustrated in the concise synthesis of a tetrahydroxylated bicyclo3.3.1nonane enabled by two key, sequential γ-C–H lactonizations, with the latter that fixes the chirality of five stereogenic centers in one step with 96% ee.
Methods for selective oxidation of aliphatic C–H bonds are called on to revolutionize organic synthesis by providing novel and more efficient paths. Realization of this goal requires the discovery of ...mechanisms that can alter in a predictable manner the innate reactivity of these bonds. Ideally, these mechanisms need to make oxidation of aliphatic C–H bonds, which are recognized as relatively inert, compatible with the presence of electron rich functional groups that are highly susceptible to oxidation. Furthermore, predictable modification of the relative reactivity of different C–H bonds within a molecule would enable rapid diversification of the resulting oxidation products. Herein we show that by engaging in hydrogen bonding, fluorinated alcohols exert a polarity reversal on electron rich functional groups, directing iron and manganese catalyzed oxidation toward a priori stronger and unactivated C–H bonds. As a result, selective hydroxylation of methylenic sites in hydrocarbons and remote aliphatic C–H oxidation of otherwise sensitive alcohol, ether, amide, and amine substrates is achieved employing aqueous hydrogen peroxide as oxidant. Oxidations occur in a predictable manner, with outstanding levels of product chemoselectivity, preserving the first-formed hydroxylation product, thus representing an extremely valuable tool for synthetic planning and development.
A time-resolved kinetic study of the hydrogen atom transfer (HAT) reactions from a series of alkanamides to the cumyloxyl radical (CumO•) was carried out. With N,N-dialkylformamides HAT ...preferentially occurs from the formyl C–H bond, while in N-formylpyrrolidine HAT mostly occurs from the ring α-C–H bonds. With the acetamides and the alkanamides almost exclusive HAT from the C–H bonds that are α to nitrogen was observed. The results obtained show that alignment between the C–H bond being broken and the amide π-system can lead to significant increases in the HAT rate constant (k H). This finding points toward the important role of stereoelectronic effects on the HAT reactivity and selectivity. The highest k H values were measured for the reactions of CumO• with N-acylpyrrolidines. These substrates have ring α-C–H bonds that are held in a conformation that is optimally aligned with the amide π-system, thus allowing for the relatively facile HAT reaction. The lowest k H value was measured for the reaction of N,N -diisobutylacetamide, wherein the steric bulk associated with the N-isobutyl groups increases the energy barrier required to reach the most suitable conformation for HAT. The experimental results are well supported by the computed BDEs for the C–H bonds of the most representative substrates.
Substituted N-cyclohexyl amides undergo aliphatic C–H bond oxidation with H2O2 catalyzed by manganese complexes. The reactions are directed by torsional effects leading to site-selective oxidation of ...cis-1,4-, trans-1,3-, and cis-1,2-cyclohexanediamides. The corresponding diastereoisomers are unreactive under the same conditions. Competitive oxidation of cis–trans mixtures of 4-substituted N-cyclohexylamides leads to quantitative conversion of the cis-isomers, allowing isolation and successive conversion of the trans-isomers into densely functionalized oxidation products with excellent site selectivity and good enantioselectivity.
A time-resolved kinetic study on the effect of trifluoroacetic acid (TFA) on the hydrogen atom transfer (HAT) reactions from 1,n-alkanediamines (R2N(CH2) n NR2, R = H, CH3; n = 1–4), piperazine, and ...1,4-dimethylpiperazine to the cumyloxyl radical (CumO•), has been carried out in MeCN and DMSO. Very strong deactivation of the α-C–H bonds has been observed following nitrogen protonation and the results obtained have been explained in terms of substrate basicity, of the distance between the two basic centers and of the solvent hydrogen bond acceptor ability. At substrate ≤ 1/2 TFA the substrates exist in the doubly protonated form HR2N+(CH2) n N+R2H, and no reaction with CumO• is observed. At 1/2 TFA < substrate ≤ TFA, HAT occurs from the C–H bonds that are α to the nonprotonated nitrogen in R2N(CH2) n N+R2H. At substrate > TFA, HAT occurs from the α-C–H bonds of R2N(CH2) n NR2, and the mesured k H values are very close to those obtained in the absence of TFA. Comparison between MeCN and DMSO clearly shows that in the monoprotonated diamines R2N(CH2) n N+R2H remote C–H deactivation can be modulated through solvent hydrogen bonding.
A kinetic study on the hydrogen atom transfer (HAT) reactions from the aliphatic C–H bonds of a series of 1-Z-pentyl, 1-Z-propyl, and Z-cyclohexyl derivatives and of a series of N-alkylamides and ...N-alkylphthalimides to the electrophilic cumyloxyl radical (CumO•) has been carried out. With 1-pentyl and 1-propyl derivatives, α-CH2 activation toward CumO• is observed for Z = Ph, OH, NH2, and NHAc, as evidenced by an increase in k H as compared to the unsubstituted alkane substrate. A decrease in k H has been instead measured for Z = OAc, NPhth, CO2Me, Cl, Br, and CN, indicative of α-CH2 deactivation with HAT that predominantly occurs from the most remote methylenic site. With cyclohexyl derivatives, α-CH activation is only observed for Z = OH and NH2, indicative of torsional effects as an important contributor in governing the functionalization selectivity of monosubstituted cyclohexanes. In the reactions of N-alkylamides and N-alkylphthalimides with CumO•, the reactivity and selectivity patterns parallel those observed in the oxidation of the same substrates with H2O2 catalyzed by manganese complexes, supporting the hypothesis that both reactions proceed through a common HAT mechanism. The implications of these findings and the potential of electronic, stereoelectronic, and torsional effects as tools to implement selectivity in C–H oxidation reactions are briefly discussed.
A time-resolved kinetic study in acetonitrile and a theoretical investigation of hydrogen abstraction reactions from N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA) by the cumyloxyl ...(CumO•) and benzyloxyl (BnO•) radicals was carried out. CumO• reacts with both substrates by direct hydrogen abstraction. With DMF, abstraction occurs from the formyl and N-methyl C–H bonds, with the formyl being the preferred abstraction site, as indicated by the measured k H/k D ratios and by theory. With DMA, abstraction preferentially occurs from the N-methyl groups, whereas abstraction from the acetyl group represents a minor pathway, in line with the computed C–H BDEs and the k H/k D ratios. The reactions of BnO• with both substrates were best described by the rate-limiting formation of hydrogen-bonded prereaction complexes between the BnO• α-C–H and the amide oxygen, followed by intramolecular hydrogen abstraction. This mechanism is consistent with the very large increases in reactivity measured on going from CumO• to BnO• and with the observation of k H/k D ratios close to unity in the reactions of BnO•. Our modeling supports the different mechanisms proposed for the reactions of CumO• and BnO• and the importance of specific substrate/radical hydrogen bond interactions, moreover providing information on the hydrogen abstraction selectivity.
PDF
