Aryl halides cross-coupling with amines

Alkynes. The cross-coupling of aryl halides with monosubstituted alkynes is a versatile synthetic method, and the simple substitution of THF for an amine as solvent can give significantly higher yields. With o-functionalized aryl halides the assembly of benzofurans, alkylidenephthalides, and alkylideneisoindolin-l-ones can be achieved in one or two steps. 1 - Alkynes undergo dimerization in high yields in a procedure that employs diisopropylamine. ... 

The palladium-catalyzed amination of aryl halides has recently emerged as a powerful alternative to other methods for the synthesis of aryl amines.5 This method allows for the cross-coupling of aryl halides arrd triflates with amines in the presence of a stoichiometric amount of a base and catalytic amounts of palladium complexes bearing tertiary phosphine ligands. As shown in Tables I and II, the Pd/BlNAP catalyst is highly effective for reactions of aryl bromides and triflates with primary and cyclic... 

As described above (Section 5.2), the Stephens-Castro reaction of alkynylcopper with aryl and vinyl halides in boiling pyridine is a useful route to aryl and vinyl acetylenes. Direct cross-coupling of organic halides, such as sp halides, with terminal alkynes is a more convenient procedure. Such a reaction is not so easy, but it can be done using a Pd-complex catalyst [41]. Especially facile Pd-catalyzed cross-coupling of aryl and alkenyl halides with terminal alkynes proceeds smoothly under mild conditions in the presence of a cocatalyst of cuprous iodide in amine solvents [Eq. (28)] [42]. This methodology is now used widely for the constiuction of conjugated arylalkyne or enyne systems [43], as described below. It is attractive from a synthetic point of view because mild reaction conditions and simplicity of the procedure are associated with recent developments in modem acetylene chemistry [44]. 

The mechanism of palladium/aryl halide amination is very closely related to that of cross coupling, with displacement of the halide on palladium (or copper or nickel) by an amine or A-anion instead of the trans-metallation step. In the case of Cu and Ni catalysis, it may proceed through M(0)-M(11) or M(l)-M(lll) cycles. 

For insoluble development in Heck-type reactions is P-C and N-C bond formation, which results from coupling of aryl halides with phosphorous compounds [38] and amines [39]. The first application in aqueous medium was achieved by coupling of a dialkyl phosphite with an aromatic iodide to give an arylphosphonate in 99% yield. In 1996, Stelzer and co-workers presented a P-C cross-coupling reaction between primary and secondary phosphines and functional aryl iodides to water-soluble phosphines [Eq. (9)], which are potentially applicable as ligands in aqueous-phase catalysis [40]. 

Cross-coupling reactions leading to the formation of C-X (X = heteroatom) bonds catalyzed by Pd(dba)2 have been reported. Aniline derivatives have been prepared via reaction of amine nucleophiles with aryl halides in the presence of Pd(dba)2 and phosphines, especially P( Bu)3. Likewise, diaryl and aryl alkyl ethers are produced from aryl halides (Cl, Br, I) and sodium aryloxides and alkoxides under similar conditions. Conditions effective for the coupling of aryl chlorides with amines, boronic acids, and ketone enolates using an easily prepared phosphine chloride as a ligand have recently been uncovered (eq 22). The preparation of aryl siloxanes and allyl boronates via Pd(dba)2-catalyzed C-Si and C-B coupling have been reported as well. 

The Sonogashira reaction allows for the direct cross-coupling of terminal alkynes with aryl halides under mild conditions through use of catalytic bis(triphenylphosphine)-palladium dichloride and Cul as the co-catalyst in the presence of an aliphatic amine. The formation of diphenylacetylene exemplifies the original Sonogashira reaction conditions ... 

The Buchwald-Hartwig reaction has been widely used in organic chemistry for the palladium-catalyzed cross-coupling of amines with aryl halides. In particular, it has been used in conjunction with benzothiophenes for arylamination of the thiophene. The final diarylamine product below demonstrated anti-fungal activity against dermatophytes, yeasts, and the Aspergillus species. ... 

One of the most versatile and widely employed methods for the construction of aryl C—N bonds is the palladium-catalyzed cross coupling of amines with aryl halides and related electrophiles [4]. These reactions are believed to occur as shown in Scheme 1.1, with the coupling initiated by oxidative addition of the aryl halide to a Pd° complex. The resulting intermediate 1 is converted to a palladium(aryl)(amido) complex 2 through reaction with the amine substrate in the presence of base. Finally,... 

Reaction of Alkyl Amines Copper-catalyzed cross-coupling of aliphatic amines with aryl halides has made considerable progress. Several methods have used Ctil with p-amino alcohols L58 [42], amino acids L59, L60 [43], Al,Al-diethyl saUcylaldehyde L61 [44], or p-diketones L62-L65 [45] (Fig. 20.3). Among these, the protocol using p-diketones exhibited the superior results catalyzing the reaction even at room temperature (Scheme 20.19). 

SCHEME 20.24 Cu-catalyzed C—N cross-coupling of secondary alkyl amines with aryl halides. 

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