C-H nucleophiles

In the following section, selective functionalization of the sp3 C-H adjacent to the nitrogen atom will be presented and classified according to the hybridization of the nucleophiles. In almost all cases, the oxidative coupling reaction occurs through the addition of the C-H nucleophile to the resulting in situ generated iminium ion 2. 

White found that highly acidic C-H nucleophiles were required for a successful oxidative coupling reaction and used nitroalkanes 52 with electron-withdrawing substituents. In virtually all cases, the oxidative alkylation of 51 resulted in the... 

Above we mentioned the palladium-catalyzed carbonylative coupling of organohalides with C-H nucleophiles. Compared with their version of carbonylative coupling with organometaUic reagents, the pre-activation of C-H bonds was not needed. The other pathway in carbonylative C-H activation is the reaction between two nucleophiles in the presence of an additional oxidant sometimes these types of reactions are also called oxidative carbonylations. Only the reaction between Ar-H and nucleophiles will be discussed in the following the other oxidative carbonylation reactions will be summarized in Chap. 8. 

Scheme 2.22 Pd-catalyzed oxidative intermolecular allylic C(sp )-H alkylation with active C-H nucleophiles [106, 107]...

Acrylamide, C H NO, is an interesting difiinctional monomer containing a reactive electron-deficient double bond and an amide group, and it undergoes reactions typical of those two functionalities. It exhibits both weak acidic and basic properties. The electron withdrawing carboxamide group activates the double bond, which consequendy reacts readily with nucleophilic reagents, eg, by addition. 

Reactions of the Disulfide Group. Besides the thiol end groups, the disulfide bonds also have a marked influence on both the chemical and physical properties of the polysulftde polymers. One of the key reactions of disulfides is nucleophilic attack on sulfur (eq. 4). The order of reactivity for various thiophiles has been reported as (C2H O) P > R, HS , C2H5 S- >C,H,S- >C,H,P,... 

There is another aspect to the question of the reactivity of the carbonyl group in r ck)hexanone. This has to do with the preference for approach of reactants from the axial ir equatorial direction. The chair conformation of cyclohexanone places the carbonyl coup in an unsynunetrical environment. It is observed that small nucleophiles prefer to roach the carbonyl group of cyclohexanone from the axial direction even though this is 1 more sterically restricted approach than from the equatorial side." How do the ctfcnaices in the C—C bonds (on the axial side) as opposed to the C—H bonds (on the equatorial side) influence the reactivity of cyclohexanone ... 

Chapters 1 and 2. Most C—H bonds are very weakly acidic and have no tendency to ionize spontaneously to form carbanions. Reactions that involve carbanion intermediates are therefore usually carried out in the presence of a base which can generate the reactive carbanion intermediate. Base-catalyzed condensation reactions of carbonyl compounds provide many examples of this type of reaction. The reaction between acetophenone and benzaldehyde, which was considered in Section 4.2, for example, requires a basic catalyst to proceed, and the kinetics of the reaction show that the rate is proportional to the catalyst concentration. This is because the neutral acetophenone molecule is not nucleophihc and does not react with benzaldehyde. The much more nucleophilic enolate (carbanion) formed by deprotonation is the reactive nucleophile. 

Numerous half-sandwich compounds of the type [M()7 -C5R5)L2], M = Rh, Ir R = H, Me L = CO, phosphine etc.) are known and are useful reagents. [Ir()7 -C5Me5)(CO)2] for instance is an excellent nucleophile and is also used in the photochemical activation of C-H in alkanes. It is particularly effective in the latter role when supercritical CO2 is the solvent. ... 

O A hydrogen atom on the electrophile HBr is attacked by tt electrons from the nucleophilic double bond, forming a new C-H bond. This leaves the other carbon atom with a + charge and a vacant p orbital. Simultaneously, two electrons from the H-Br bond move onto bromine, giving bromide anion. 

The chemistry of metalated aziridines is far less developed than the chemistry of metalated epoxides, although from what is known [lb], it is obvious that their chemistry is similar. Like metalated epoxides, metalated aziridines can act as classical nucleophiles with a variety of electrophiles to give more highly substituted aziridines (Scheme 5.56, Path A). A small amount is known about how they can act as electrophiles with strong nucleophiles to undergo reductive alkylation (Path B), and undergo C-H insertion reactions (Path C). 

Model calculations generally support Felkin s hypothesis35-38. However, an additional controlling factor is the stabilization of the transition state by the approach of the nucleophile antiperiplanar to a vicinal bond35. In the transition state for axial attack (Figure 8), the incipient bond is approximately antiperiplanar to two axial C — H bonds. Flattening of the ring improves this antiperiplanarity and, therefore, the more flattened the cyclic ketone, the more axial attack is preferred. 

Since equatorial attack is roughly antiperiplanar to two C-C bonds of the cyclic ketone, an extended hypothesis of antiperiplanar attack was proposed39. Since the incipient bond is intrinsically electron deficient, the attack of a nucleophile occurs anti to the best electron-donor bond, with the electron-donor order C—S > C —H > C —C > C—N > C—O. The transition state-stabilizing donor- acceptor interactions are assumed to be more important for the stereochemical outcome of nucleophilic addition reactions than the torsional and steric effects suggested by Felkin. 

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... 

Several cyditol derivatives of varying ring size, for example, (69)/(70), have been prepared based on an enzymatic aldolization as the initial step. Substrates carrying suitably installed C,H-acidic functional groups such as nitro, ester, phosphonate (or halogen) functionalities made use of facile intramolecular nucleophilic (or radical) cyclization reactions ensuing, or subsequent to, the enzyme-catalyzed aldol addition (Figure 10.27) [134—137]. 

C-H acidic compounds do not possess any basic properties. But they can form anions in the presence of strong bases, and these possess sufficiently strong nucleophilic properties to be able to add to a polarized carbonyl group. Examples are listed in Table 6. 

Feldman reported a route to dihydropyrroles, pyrroles, and indoles via the reaction of sulfonamide anions with alkynyliodonium triflates <96JOC5440>. Thus, upon nucleophilic addition of the anion of 91 to the p-carbon of the alkynyliodonium salt, the alkylidene carbene 92 is generated which can the undergo C-H insertion to the desired product 93. 

---