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  1. Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides
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  3. Directing group-assisted transition-metal-catalyzed vinylic C-H bond functionalization
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  5. Asymmetric Functionalization of C-H Bonds by Shu-Li You: New | eBay

Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

For example, a ketone has been converted to an imine, which binds the catalyst as a Lewis base. This effect of a nearby functional group on the reactivity of a metal complex toward cleavage of a C—H bond has been known for more than 50 years. Such cyclometalation was shown to control site selectivity many years ago, but it was much more recently that practical systems for directed functionalization involving a cyclometalation process were developed.

However, many molecules with activity in medicinal or agrochemistry are heterocycles or otherwise functionalized molecules that possess an inherent ability to bind a catalyst and direct a C—H bond functionalization process. For example, the halogenation of an agrochemical intermediate occurs at the position ortho to a carboxylic acid, 15 and halogenation at this site was desired for the synthetic sequence.

This palladium-catalyzed directed halogenation is conducted on large scale. Moreover, catalysts are being developed that undergo reactions at C—H bonds directed by functional groups that bond more weakly than a pyridine, imine, or picolinamide. Given the diversity of structures containing Lewis basic functional groups, the opportunities for development of directed reactions are diverse, and the applications of such reactions to the synthesis of molecules with important functions will surely be widespread.

In many cases, the activity of a molecule containing a small halogen or a methyl group near an existing functionality is not known and can be superior to that of the parent structure lacking this small addition to the structure. A greater challenge of C—H bond functionalization is to install a functional group at a position that cannot be reached by chelation to a transition metal, or to install a functional group selectively in a section of a molecule that lacks functional groups altogether. Such reactions of C—H bonds would create synthetic capabilities that could impact many areas of organic chemistry.

Mod-08 Lec-37 C-H activation

For example, such reactions could create alpha—omega functionalized alkyl chains to be used as monomers for commodity polymers; 18 , 19 or they could convert hydrocarbons directly to detergent alcohols or carboxylic acids; or they could introduce functional groups at positions remote from the many functional groups in complex natural products or medicinally active compounds to complement the regioselectivity achieved by directed functionalizations.

Undirected C—H bond functionalization reactions are much less developed than directed C—H bond functionalizations, but not for lack of effort. The functionalization of a C—H bond without the assistance of chelation is more difficult to achieve, and selective functionalization without an existing group controlling regioselectivity is a challenge, even when undirected functionalization is observed.

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Yet, systems have been discovered that catalyze undirected functionalizations of C—H bonds, and several strategies that bridge the gap between directed and completely undirected functionalization have been followed. Such strategies include the exploitation of noncovalent interactions in both small molecules and enzymes. The remainder of this Outlook will describe the opportunities that undirected C—H bond functionalization presents, the challenges that confront the development of such reactions, and the approaches that have been taken to point the way toward practical, undirected functionalizations of C—H bonds.

Undirected functionalization of C—H bonds is more challenging to develop than directed functionalization because the interaction of a directing group with the catalyst increases the reaction rate of the substrate with the catalyst, increases the thermodynamics for adding the substrate to the catalyst, and controls regioselectivity. The absence of such a directing group makes it necessary that the catalyst cleave and functionalize the C—H bond without any assistance from the binding energy of the substrate to the catalyst and chelation within the initial product of C—H bond addition.

During a directed functionalization of a C—H bond, coordination of the substrate to the metal center should enhance the rate of C—H bond cleavage, due to the intramolecularity of this reaction step, and cause the product of addition to be more stable than it would be in the absence of a link between the C—H bond and a coordinating group, due to the chelate effect. Without this chelation, the C—H bond cleavage step is intermolecular and often slower than it is in the absence of chelation.

In the absence of a directing group, one might expect selectivity to be an equal challenge, and many functionalizations of C—H bonds generate a mixture of products. Primary C—H bonds are stronger than secondary C—H bonds and are less reactive toward radicals. Unfortunately, the terminal positions of an alkane are often the sites at which the functional groups are most desired for commodity chemicals.

For example, plasticizer and detergent alcohols contain a hydroxyl group at the end of an alkyl chain; 22 diols or diamines for polymerization contain two hydroxyl or amino groups at either end of the alkyl chain. Indeed, many reagents and catalysts are known that react with potentially useful selectivities for one C—H bond over another. Attributes of C—H bonds contained in alkanes and arenes that are relevant to C—H functionalization.

Likewise, the C—H bonds at different positions of an aryl ring could be assumed to be equally reactive.

Short abstract

However, classical electrophilic aromatic substitution 25 and deprotonation of aryl or heteroaryl rings 26 , 27 already hints that functionalization of C—H bonds of aromatic systems can be regioselective. Thus, one can achieve selective, undirected C—H bond cleavage, even if the system is sufficiently reactive to cleave a strong C—H bond.

Multiple methods are being developed that lead to the selective functionalization of the strongest C—H bonds in alkyl chains: the primary C—H bonds. In parallel, reactions are being developed that occur at unactivated secondary and tertiary C—H bonds in more densely functionalized systems.

Directing group-assisted transition-metal-catalyzed vinylic C-H bond functionalization

In some of these cases, selective reactions occur at specific secondary C—H bonds, due to steric or electronic effects or both , and in other cases, reactions occur selectively at tertiary C—H bonds. Before describing the specific examples of undirected C—H bond functionalization, it is valuable to review the relative reactivity of different classes of C—H bonds toward the various mechanisms by which C—H bonds are cleaved by transition-metal complexes or organic reagents to form intermediates that react with transition-metal complexes.

Reactions that form a metal—carbon bond by C—H bond cleavage tend to occur by concerted pathways, rather than stepwise radical pathways Scheme 2. Reactions occurring without formation of a metal-carbon bond can occur by either concerted or stepwise pathways. For example, many oxidation reactions occur by the formation of alkyl radicals and recombination of the radical with a metal complex or reagent that delivers the functional group to the alkyl radical.

In contrast, some catalytic reactions of nitrene and carbene precursors with alkyl C—H bonds occur by direct insertion of a nitrene or carbene unit into the C—H bond without forming a metal—alkyl intermediate. The selectivity of reactions that form metal—carbon bonds is often dictated by the strength of the metal—carbon bond in the potential organometallic intermediates, relative to the strength of the C—H bonds. In contrast, reactions that occur by abstraction of a hydrogen atom to form an alkyl radical tend to occur at the position of the weaker C—H bond and often the most electron rich of the weaker C—H bonds because the species abstracting the C—H bond is electron poor.

With a few exceptions, 35 both C—H bond activation to form organometallic intermediates and hydrogen atom abstraction are favored at the position alpha to oxygen and nitrogen.

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Among these reactions, the borylation is the unique example that leads to catalytic functionalization of primary C—H bonds with high selectivity in the absence of a directing group. Alternatively, the terminal alkene can be intercepted by a second reaction. This process, known as alkane metathesis, occurs by the combination of dehydrogenation, alkene metathesis, and hydrogenation of the resulting alkene with the hydrogen created by dehydrogenation.

The direct oxidation of C—H bonds has been studied most extensively, both to understand the mechanism of enzymatic oxidation by cyctochromes P and to develop catalysts for synthetic applications. Shilov reported some of the earliest evidence that transition metals could catalyze the oxidation of alkyl C—H bonds. For example, Shilov demonstrated that alkanes undergo halogenation in the presence of a Pt II catalyst and a stoichiometric Pt IV oxidant. However, methods have been developed more recently that obviate the need for stoichiometric Pt. For example Sen showed that CuCl 2 as a cocatalyst and oxygen as the oxidant leads to the catalytic oxidation of alkyl sulfonates with moderate selectivity for primary C—H bonds, due to the deactivation of the secondary C—H bonds proximal to the electron-withdrawing functionality eq 2.

Periana reported the oxidation of methane to methyl bisulfate with SO 2 as the oxidant, but these reactions do not lead to clean oxidation of higher alkanes, in part, due to the instability of the product to acidic conditions. As noted earlier in this Outlook, the oxidation of cyclohexane is conducted on commodity chemical scale eq 4 ; this process is possible because the issue of regioselectivity does not arise with a cyclic substrate and oxidation deactivates the C—H bonds of the product toward further oxidation.

However, no catalyst is known that will oxidize alkyl C—H bonds in more complex structures with high regioselectivity and high turnover numbers. Current catalysts can generate products from oxidation of complex molecules with significant selectivities and can generate sufficient material for discovery-based applications, but the catalysts give products with moderate turnover numbers example in eq 5. Uncatalyzed oxidation of alkyl C—H bonds is well-known and can occur with selectivity for one C—H bond over another due to the electronic differences in these bonds. Among similar classes of C—H bonds, they insert into the more electron rich C—H bond.

An example of the selective oxidations by trifluoromethyl dioxirane is shown in eq 6. Metal-catalyzed insertions of nitrenes into C—H bonds are also being developed. A majority of the insertions of nitrenes into C—H bonds have been intramolecular reactions.

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Although applications of these reactions have included landmark examples of the applications of C—H bond functionalization to the syntheses of complex natural products, 67 the development of a system for general, undirected intermolecular insertion of nitrenes into C—H bonds has been more challenging. Recently, the combination of a dirhodium catalyst, oxidant, carboxylic acid additive, and an aryloxysulfonamide as the nitrene source has been reported to effect the intermolecular C—H amination of tertiary C—H bonds eq 7.

Reactions of radicals with C—H bonds typically occur with related selectivities for tertiary, secondary, and primary C—H bonds.

Most of the radicals that abstract hydrogen atoms from alkyl positions are electrophilic and, therefore, abstract the hydrogen atom from the most electron rich tertiary or secondary C—H bond. A recent example of a catalytic amination process that appears to occur by abstraction of a C—H bond with a reagent that is selective and tolerant of an array of functional groups and recombination of the radical with a metal complex has been reported. This process installs azido groups at tertiary C—H bonds, benzylic C—H bonds, and allylic C—H bonds in good preparative yields and high selectivities with complex molecules eq 8.

The halogenation of alkyl C—H bonds occurs in some cases with systems related to those that oxidize C—H bonds with selectivities resulting, in part, from steric effects.

Asymmetric Functionalization of C-H Bonds by Shu-Li You: New | eBay

The bromination of C—H bonds is a well-established classical reaction, although conditions for the bromination of alkyl C—H bonds are often incompatible with other functional groups. In this case, a large tert -butyl group on the amide nitrogen leads to selectivity for secondary over tertiary C—H bonds. The undirected functionalization of alkyl C—H bonds that occurs with the broadest scope and pertains to the synthesis of of compounds relevant to medicinal chemistry is the insertion of carbenes into secondary and tertiary C—H bonds.

The reactions also occur preferentially at the C—H bonds located alpha to alkoxy, siloxy, and amino groups. Thus, the reactions occur with high regioselectivity at the C—H bonds of cycloalkanes, 78 cyclic ethers, 78 and cyclic amine derivatives, 79 and these reactions occur with high enantioselectivity eq The reactions also occur alpha to oxygen in linear, allylic silyl ethers 80 to form products that are equivalent to those from aldol reactions.

They also occur at methyl C—H bonds that are benzylic 81 or alpha to nitrogen, 82 and they occur site selectively at weak benzylic 81 and allylic 83 C—H bonds.

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With these site selectivities, the reactions have been used to prepare a series of medicinally active compounds. Yet, several syntheses have been completed by the application of undirected, intermolecular insertions of carbenes into alkyl C—H bonds.