Arylation carbon nucleophiles

Allenes also react with aryl and alkenyl halides, or triflates, and the 7r-allyl-palladium intermediates are trapped with carbon nucleophiles. The formation of 283 with malonate is an example[186]. The steroid skeleton 287 has been constructed by two-step reactions of allene with the enol trillate 284, followed by trapping with 2-methyl-l,3-cyclopentanedione (285) to give 286[187]. The inter- and intramolecular reactions of dimethyl 2,3-butenylmalonate (288) with iodobenzene afford the 3-cyclopentenedicarboxylate 289 as a main product) 188]. 

Arylation or alkenylation of soft carbon nucleophiles such as malonate is carried out by using a copper catalyst, but it is not a smooth reaction. The reaction of malononitrile, cyanoacetate, and phenylsulfonylacetonitrile with aryl iodide is possible by using a Pd catalyst to give the coupling products. 

Dienes and allylarcncs can be prepared by the Pd-catalyzcd coupling of allylic compounds with hard carbon nucleophiles derived from alkenyl and aryl compounds of main group metals. Allylic compounds with various leaving groups can be used. Some of them are unreactive with soft nucleophiles, but... 

Anomalous Fischer cyclizations are observed with certain c-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which w ould be formed by (ip50-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacelate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

Reaction with Carbon Nucleophiles. Unactivated a2iddines react with the lithium salts of malonates or p-keto esters in the presence of lithium salts to yield 3-substituted pyttohdinones (56—59), where R = alkyl and aryl, and R = alkoxyl, alkyl, and aryl. 

Replacement of an aromatic fluorine atom by a carbon nucleophile is facihtated by the presence of electron-withdrawmg groups [82] (equation 44) Replacement of an activated aryl hydrogen can occur in preference to a nonactivated aryl fluorine [Si] (equation 45) in reactions known as vicarious subsututions. 

The mfluoromethyl group activates the fluorine in position 4 ofperfluorotolu ene toward reaction with carbon nucleophiles Examples on che use of perfluoro-toluene as an arylation agent abound, and in all cases, the 4-fluonne atom is replaced predommantly or exclusively [% 87,88,89, 90 (equation 48) In perjluoromesity-lene, the aromatic fluorine atoms are activated toward Ar reaction, and a reaction... 

As with the tetrahedral mechanism at an acyl carbon, nucleophilic catalysis (p. 427) has been demonstrated with an aryl substrate, in certain cases. 

Instead of alkynes, allenes can also be used as substrates in this type of approach. Finally, one can also apply carbon-nucleophiles such as butadienes in this domino process. Thus, Lu and Xie [145] have treated the alkyne 6/1-303 with an aryl halide 6/1-304 and an amine 6/1-305 to give the substituted pyrrolidinone 6/1-308 via the proposed intermediates 6/1-306 and 6/1-307. As a side product, 6/1-309 is found to have been formed by a cycloaddition of 6/1-303 (Scheme 6/1.81). 

The first examples of iridium-catalyzed allylic substitution [1] occurred between stabilized carbon nucleophiles and both alkyl- and aryl-substituted allylic alcohol derivatives with exceptional selectivity for the branched substitution product. 

Substitution of one dimethylamino group by alkyl, aryl, or alkynyl groups in complexes [M =C=C=C(NMe2)2 (CO)5] (M = Cr, W 51) has also been described [9]. The process occurs through an initial addition of the anionic carbon nucleophile to the Cy atom of 51 and subsequent abstraction of one dimethylamido... 

Formation of C-C bonds remains the ultimate challenge to the synthetic chemist. The employment of new synthetic methods in complex target synthesis can be frustrated by a lack of functional group tolerance and substrate specificity. These problems can be somewhat alleviated within conjugate addition reactions by the use of secondary amine catalysts where a number of important and highly selective methods have been developed. Two principle classes of nucleophile have been shown to be effective in the iminium ion activated conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl systems aryl, heteroaromatic and vinyl... 

Nitrile oxides are widely used as dipoles in cycloaddition reactions for the synthesis of various heterocyclic rings. In order to promote reactions between nitrile oxides and less reactive carbon nucleophiles, Auricchio and coworkers studied the reactivity of nitrile oxides towards Lewis acids. They observed that, in the presence of gaseous BF3, nitrile oxides gave complexes in which the electrophilicity of the carbon atom was so enhanced that it could react with aromatic systems, stereoselectively yielding aryl oximes 65 and 66 (Scheme 35). ... 

Amines are generally prepared by nucleophilic amination, which is a coupling of carbon electrophiles with a nucleophilic amination reagent, NR2, and Ni and Pd catalyzed reaction of aryl halides with arylamines (Hartwig-Buchwald amination) . Thus, the direct C—N bond formation between carbon nucleophiles and electrophilic nitrogen functionality R2N+ constitutes an example of the umpolung methodology. 

For carbon nucleophiles sequential addition of 2-potassio-2-nitropropane and oxygen to 4-arylidene-2-phenyl-5(47/)-oxazolones 623 has been reported (Scheme 7.200). The process involves a Michael reaction of the 2-nitropropane anion followed by reaction with molecular oxygen and elimination of nitrous acid to yield 2-aryl butenoic acid imides 626. 

Azidoalcohols (79, 81) can be accessed directly through the cerium-catalyzed addition of sodium azide onto mono-substituted epoxides. When the substituent is a simple alkyl or aryl group, nucleophilic attack at the more substituted epoxide carbon was observed i.e., 78 -> 79). However, when a phenoxy group was incorporated into the side chain (e.g., 80), a crossover to attack on the unsubstituted methylene carbon was encountered <99SC561>. 

The formation of RSSR from RS and RS species is particularly relevant in the present context because it is the reverse of the electro-induced radical anion cleavage (equation 76). Actually, the formation of RSSR from reaction (79) is as well studied as the reaction between aryl carbon radicals and anionic nucleophiles, the fundamental step of the SrnI. Equilibrium constants in the range 10 -10 M for reaction (79) were determined for a number of alkyl-type systems in water, although the corresponding values for aryl-type systems are smaller. The rate constants... 

Attempts to rationalize the regioselectivity of attack of nucleophiles on the aryl rings of nitrenium ions in terms of calculated properties of the ions (LUMO coefficients, localization energies, etc.) have been moderately successful. An adequate explanation of electrophilic reactivity of nitrenium ions at N with certain nucleophiles such as glutathione, C-8 of d-G, and other carbon nucleophiles has not yet appeared. ... 

The coupling of aryl halides and classical carbon nucleophiles, such as malonates, is also feasible in the presence of a properly selected palladium or copper catalyst. Diethyl malonate and 3-iodopyridine, for example, gave diethyl 2-(3 -pyridyl)malonate in 73% yield (7.84.), The optimal catalyst in this process consisted of copper(I) iodide and 2-hydroxylbiphenyl.106... 

From the structure of this compound, you see a good leaving group in the chloride, Cl, on several parts of this compound s structure. But since the chlorines are attached to a carbon that is also substituted with three other large groups, or they are on aryl carbons, they cannot be approached readily from the back side by an enzymatic nucleophile as used in microbial hydrolases. Hence, we do not expect microorganisms to use a nucleophilic attack and a hydrolysis approach. 

Alcohols and phenols can be attached to support-bound alcohol linkers as carbonates [467,665,666], although few examples of this have been reported. For the preparation of carbonates, the support-bound alcohol needs to be converted into a reactive carbonic acid derivative by reaction with phosgene or a synthetic equivalent thereof, e.g. disuccinimidyl carbonate [665], carbonyl diimidazole [157], or 4-nitrophenyl chloro-formate [467] (see Section 14.7). The best results are usually obtained with support-bound chloroformates. The resulting intermediate is then treated with an alcohol and a base (DIPEA, DMAP, or DBU), which furnishes the unsymmetrical carbonate. Carbonates are generally more resistant towards nucleophilic cleavage than esters, but are less stable than carbamates. Aryl carbonates are easily cleaved by nucleophiles and are therefore of limited utility as linkers for phenols. 

Esters of allylic alcohols with resin-bound carboxylic acids can be converted into allyl palladium complexes, which react with carbon nucleophiles and with hydride sources to yield the formally reduced allyl derivatives (Entries 3 and 4, Table 3.47). Alkyl sulfonates have been reduced to alkanes with NaBH4 (Entry 5, Table 3.47). Aryl sulfonates (Entry 6, Table 3.47) and aryl perfluoroalkylsulfonates [814] can be reduced to alkanes by treatment with catalytic amounts of Pd(II) and formic acid as a hydride source. 

C-Alkylations have been performed with both support-bound carbon nucleophiles and support-bound carbon electrophiles. Benzyl, allyl, and aryl halides or triflates have generally been used as the carbon electrophiles. Suitable carbon nucleophiles are boranes, organozinc and organomagnesium compounds. C-Alkylations have also been accomplished by the addition of radicals to alkenes. Polystyrene can also be alkylated under harsh conditions, e.g. by Friedel-Crafts alkylation [11-16] in the presence of strong acids. This type of reaction is incompatible with most linkers and is generally only suitable for the preparation of functionalized supports. Few examples have been reported of the preparation of alkanes by C-C bond formation on solid phase, and general methodologies for such preparations are still scarce. 

More reactive carbon nucleophiles than enolates can also be prepared on insoluble supports (see Chapter 4) and are used to convert aldehydes or ketones into alcohols. Organolithium compounds have been generated on cross-linked polystyrene by deprotonation of formamidines and by metallation of aryl iodides (Table 7.5). Similarly, support-bound organomagnesium compounds can be prepared by metallation of aryl and vinyl iodides with Grignard reagents. The resulting organometallic compounds react with aldehydes or ketones to yield the expected alcohols (Table 7.5). 

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