Palladium-catalyzed amination mechanism

A general mechanism for the palladium-catalyzed amination of aryl halides is presented in Scheme 7. This picture has been developed from studies performed largely upon isolated complexes, with the oxidative addition and reductive elimination steps being investigated in the greatest detail. On... 

In a detailed investigation of the mechanism and scope of palladium catalyzed amination of five-membered heterocycles, the 1-methyl-3-bromoindole 145 was aminated with secondary amines to the 3-aminoindoles 146. Similar results were obtained for l-methyl-2-bromoindole <03JOC2861>. Rhodium-catalyzed cyclopropanation reactions involving 1-methyl-3-diazooxindole and exocyclic alkenes provided novel dispirocyclic cyclopropanes <03SL1599>. New applications of palladium-mediated cross-coupling reactions have been utilized to prepare a variety of functionalized indoles. Suzuki-Miyaura coupling reactions of indole-3-boronates <03H(59)473> and indole-5-boronates <03H(60)865> were utilized to prepare inhibitors of lipid peroxidation and melatonin analogues, respectively. 

Hartwig, J. F. Palladium-catalyzed amination of aryl halides. Mechanism and rational catalyst design. Synlett 1997, 329-340. 

IV. MECHANISM OF PALLADIUM-CATALYZED AMINATION OF ARYL HALIDES... 

The overall mechanism for palladium-catalyzed amination of aryl halides is shown in Scheme 4. Initially, a palladium(O) complex is rapidly formed from Pd(OAc)2 and phosphine ligand in the presence of amine and base. If Pd(dba)2 is used, then either bisphosphine Pd(0) complexes are formed, as with P(Bu-f)3170, or mixed phosphine/dba palladium(O) complexes are formed as with arylphosphines171. When the reactions are initiated with dba complexes, dba is consumed under the reaction conditions, and simple bis-ligand Pd(0) complexes are formed. The mechanism for reduction of Pd(II) to Pd(0) has been studied172, but the process occurs more rapidly in the presence of amine and base than in the absence of these reagents, even when the amine cannot undergo /3 -hydrogen elimination. 

The Pd-catalyzed amination of / -rm-butylphenyl bromide with pyrrole in the presence of Pd(OAc)2, dppf and one equivalent of NaOr-Bu led to the Af-arylation product 88. A simplified version of the mechanism commences with the oxidative addition of p-te/t-butylphenyl bromide to Pd(0), giving rise to the palladium complex 89. Ligand exchange with pyrrole followed by deprotonation by the base (NaOr-Bu) results in amido complex 90. Reductive elimination of 90 then gives the amination product 88 with concomitant regeneration of Pd(0) catalyst. If the amine had a (3-hydride in amido complex 90, a (3-hydride elimination would be a competing pathway, although reductive elimination is faster than P-hydride elimination in most cases. 

The transition metal catalyzed synthesis of arylamines by the reaction of aryl halides or tri-flates with primary or secondary amines has become a valuable synthetic tool for many applications. This process forms monoalkyl or dialkyl anilines, mixed diarylamines or mixed triarylamines, as well as N-arylimines, carbamates, hydrazones, amides, and tosylamides. The mechanism of the process involves several new organometallic reactions. For example, the C-N bond is formed by reductive elimination of amine, and the metal amido complexes that undergo reductive elimination are formed in the catalytic cycle in some cases by N-H activation. Side products are formed by / -hydrogen elimination from amides, examples of which have recently been observed directly. An overview that covers the development of synthetic methods to form arylamines by this palladium-catalyzed chemistry is presented. In addition to the synthetic information, a description of the pertinent mechanistic data on the overall catalytic cycle, on each elementary reaction that comprises the catalytic cycle, and on competing side reactions is presented. The review covers manuscripts that appeared in press before June 1, 2001. This chapter is based on a review covering the literature up to September 1, 1999. However, roughly one-hundred papers on this topic have appeared since that time, requiring an updated review. 

The scope of this reaction appeared to be limited to dialkylamides and electron-neutral aryl halides. For example, nitro-, acyl-, methoxy-, and dimethylamino-substituted aryl halides gave poor yields upon palladium-catalyzed reaction with tributyltin diethylamide. Further, aryl bromides were the only aryl halides to give any reaction product. Vinyl bromides gave modest yields of enamines in some cases. Only unhindered dialkyl tin amides gave substantial amounts of amination product. The mechanism did not appear to involve radicals or benzyne intermediates. 

The most important class of allylic substitutions are palladium-catalyzed reactions with so-called soft nucleophiles such as stabilized carbanions or amines, and with few exceptions, the enantioselective transformations discussed in this chapter belong to this category. The mechanism of these reactions has been firmly established and a detailed picture of the catalytic cycle can be drawn [1, 2,3,4,5,6,13,14,15]. The course of allylic substitutions catalyzed by metals other than palladium is less clear and information about the intermediates involved is scarce. 

Allyl alkyl carbonates, prepared from various alcohols except simple primary ones, are converted into aldehydes or ketones in the presence of a phosphine-free palladium catalyst. Acetonitrile as coordinating solvent is necessary for the success of this reaction. A mechanism via palladium alkoxides was proposed (Scheme 8). Ruthenium hydride complexes work similarly. A similar mechanism operates for the palladium-catalyzed decomposition of allylic carbonates. The reaction can be utilized for the mild deprotection of amines, e.g., for peptide synthesis shown in equation (20). 

Some of the optimized procedures for Stille and Sonogashira reactions involve the addition of copper cocatalysts to accelerate the cross-coupling procedures. A word of caution should be provided on the role of these additives in Pd-catalyzed amination procedures. Beletskaya and Davydov have reported the arylation of benzotriazole and of diary-lamines in polar organic or aqueous organic solvents using a combination of palladium and copper as catalyst.The arylation of amino acids has been reported under similar conditions.However, these reaction conditions are similar to classic Ullmann procedures for the synthesis of arylamines, except for the addition of palladium to the reaction mixture. In one case, subsequent work showed that the palladium species was not an essential component and that copper alone was the true catalyst in their reactions. An unusual accelerating effect of amino acid coordination to copper was used to explain the low-temperature Ullmann conditions. Beletskaya, however, showed that lower yields and a mixture of N1 and N2 arylation products were observed from the reactions of benzotriazole in the absence of copper and no reaction was observed in the absence of palladium. The conditions for this chemistry are, however, distinct enough from those of the majority of the aryl halide aminations to support the idea that a different mechanism may operate. 

Scheme 15.35 Mechanism of the palladium-catalyzed tandem allylic aminatinn/r2.31-Stevens rearrangement of tertiary amines.

SCHEME 3.11 Proposed mechanism for the synthesis of 4-amine-benzo[i>][l,4]oxazepines by palladium-catalyzed isocyanide reactions. 

Duchene and Parrain developed a one-pot allylic amina-tion/palladium-catalyzed Sonogashira cross-coupling and heterocyclization process for the preparation of 1,2,4-trisub-stituted and 1,3-disubstituted pyrroles starting from diiodo-butenoic acid, a primary amine, and a terminal alkyne [49], Scheme 3.27 shows a plausible mechanism for this transformation. The initial C—N allylic amination, followed by a Sonogashira cross-coupling and an intramolecular hydroam-ination, affords a dihydroexoalkylidene pyrrole XIX, which rearranges into pyrrole 39. The reaction is influenced by the... 

Palladium-catalyzed oxidative amination reactions are proposed to occur by the same basic mechanism as Waeker eyclizations (Scheme 12.11, Nu = NR). Stahl and co-workers developed a catalytic system for oxidative amination using pyridine as a ligand," but found some key challenges in this system, similar to the alcohol oxidation developed by Sigman and co-workers (i) pyridine, a kinetically labile ligand, could dissociate under the reaction... 

---