Jt-based Carbon nucleophiles

The formal addition of a C-H bond at activated methylenes and methynes (pronucleophiles) to activated alkenes in the presence of a base is well known as the Michael reaction (Scheme 1, Type A) [1]. In modem organic syntheses, the use of transition metal (TM) catalysts enables the C-H addition of activated methylenes and methynes to activated alkenes perfectly under neutral conditions (Scheme 1, Type B) [2]. In general, the nonfunctionalized carbon-carbon multiple bonds (for example, EWG2 = H in Scheme 1) are unreactive toward carbon nucleophiles because of their electron rich Jt-orbitals. The pioneering efforts by various research groups resulted in the development of transition metal-catalyzed addition of a C-H bond at active alkanes to such unactivated C-C multiple bonds. This reaction consists of the formal addition of a C-H bond across the C-C multiple bonds and is called a hydrocarbonation reaction. As a milestone in this hydro-carbonation area, early in the 1970s, Takahashi et al. reported the Pd-catalyzed addition of the C-H bond of pronucleophiles to 1,3-dienes [3], The first Pd-catalyzed reaction of activated methylenes with unsubstituted allenes was apparently reported by Coulson [4]. The synthetic applications of this reaction were very limited. In the last decade, the Pd-catalyzed addition of C-H bonds to various unacti-... 

When the metal fragment is a poor jt base, the L model (5.4) applies and the vinylic carbons bound to the metal behave as ma.sked, metal-.stabilized carbonium ions. In such a case we often see nucleophilic attack (e.g., Eq. 5.10). This is an example of a more general reaction type—nucleophilic attack on polyenes or polyenyls (Section 8.3). 

In the faster second step of the electrophilic substitution mechanism, the proton bound to the sp -hybridized ring carbon atom leaves, restoring the aromatic Jt system. A nucleophile, acting as a base, extracts the leaving proton. 

Aregioselective catalytic system for the allylic substitution of non-symmetric allyl carbonates by carbon and nitrogen nucleophiles based on [ Bu N][Fe(NO)(CO)3] and PPhj was developed (Scheme 2.26). The high regioselectivity was ascribed to the slow a-allyl- to Jt-aUyl-isomerisation relative to the rate of substitution. However, the use of high excess of the pro-nucleophile and DMF solvent are drawbacks on the atom efficiency and functional group tolerance of the system. 

Based on the assumption that this reaction goes through Jt-allyl Mo intermediates (A and B), the result from either linear carbonate (L-C) or branched carbonate (B-C) should give exactly the same result if the equilibrium between A and B is much faster than nucleophilic addition of sodium dimethyl malonate to A or B (Curtain-Hammett) as shown in Scheme 2.17. 

In the absence of a nucleophile, the reaction of allenes with aryl bromides provides 1,3-dienes in good yield (Scheme 16.27) [32], The reaction is very sensitive to the reaction temperature, solvent, base and amount of phosphine used. The formation of a 1,3-diene may be explained by either /3-hydrogen elimination or deprotonation at the a-carbon of the Jt-allylpalladium intermediate. 

The pyrimidine moiety of purines is 7t-electron deficient, whereas the imidazole ring is a Jt-electron excessive system. The direction of the dipole moment is altered by the introduction of substituents, by protoiiation, tautomerization or base pairing. The 7t-excessive character of the imidazole moiety of various purines makes it suitable for anion formation upon treatment with sodium hydride, potassium hydroxide, potassium carbonate or other reagents which are used during electrophilic reactions, such as alkylation or glycosylation. The nucleophilic attack on carbons occurs in the order C8 > C6 > C2. A number of purine syntheses use the displacement of existing substituents. 

Vinyl epoxides and allyHc carbonates are especially useful electrophiles because under the influence of palladium(O) they produce a catalytic amount of base since is an alkoxide anion. This is sufficiently basic to deprotonate most nucleophiles that participate in aUylic alkylations and thus no added base is required with these substrates. The overaU reaction proceeds under almost neutral conditions, which is ideal for complex substrates. The rehef of strain in the three-membered ring is responsible for the epoxide reacting with the paUadium(O) to produce the zwitterionic intermediate. Attack of the negatively charged nucleophile at the less hindered end of the Jt-allyl palladium intermediate preferentially leads to overall 1,4-addition of the neutral nucleophile to vinyl epoxides. 

Ito and Sawamura showed that the use of rhodium and palladium in the presence of the TRAP-type ligand generates an effective catalyst combination for the reaction of an allyl carbonate with a cyanopropionamide [128]. The palladium-TRAP complex is proposed to generate a cationic Jt-allyl species. In addition, a rhodium-TRAP species complexes the cyano group of the nucleophile and induces formation of the enolate. Reaction of the enolate with the Tt-complex in assembly I generates the observed product. Scheme 45. The notion that enoliza-tion is caused by complexation to the cyano group is based on previous results in the enantioselective rhodium-catalyzed Michael addition. 

This type of reaction begins when a ir bond of an alkene donates an electron pair to an acid (H+)—an acid-base reaction where the alkene is a weak base. The Jt bond is broken as the new Br—H bond is formed, and the remaining carbon of the former double bond becomes a carbocation. The reaction of cyclohexene with acid to form secondary cation 294 illustrates this process. The cationic center then reacts with the nucleophilic gegenion (Br" from HBr) to produce bromocyclohexane. The latter portion of this sequence is analogous to the second step (coupling) of an Sjsfl reaction. The initial reaction usually involves formation of a solvent separated carbocation intermediate, but this depends on the solvent. A tight ion pair intermediate can react in the substitution step to give the same product. The net result of this cationic reaction is addition of H and Br across the jt bond. 

Cr, Br, and F are good nucleophiles in substitution reactions at sp hybridized carbons, but they are ineffective nucleophiles in addition. Addition of Cl to a carbonyl group, for example, would cleave the C-0 Jt bond, forming an alkoxide. Because Cl is a much weaker base than the alkoxide formed, equilibrium favors the starting materials (the weaker base. Cl ), not the addition product. 

Jt-Allyl palladium cations can be regarded as soft electrophiles, and react smoothly with soft nucleophiles. For carbon-based nucleophiles, soft methylene compounds (conjugate acids with a < 25) with two electron-... 

---