Aryl halides with amides

Cross-Coupling of aryl Halides with Amides and Carbamates... 

For fast reactions of the type represented by reaction 13.2, carried out under the conditions stated earlier, micromixing becomes the dominant consideration. However, studies on the effect of micromixing in such reactions are sparse. Some examples are as follows nitration of aromatic componds in general (Schofield, 1980), potassium metal-provoked reactions of aryl halides with amide and acetone enolate ions (Tremelling and Bunnett, 1980X coupling of 1-naphthol with diazotized sulfanilic acid (Bourne et al., 1981, 1985), reactions of o-(3-butenyl)-halobenzenes and 6-bromo-1-hexene with alkali metals in ammonia/terr-butyl alcohol solution (Meijs et al., 1986), and monoacylation of symmetrical diamines (Jacobson et al., 1987). In some fast reactions, hydrogen ions are produced. 

The use of ligated copper catalysts has dramatically improved the coupling of aryl halides with amides—the Goldberg reaction. . This reaction has been studied intensively because of the utility of the products and the limitations in scope and efficiency of the palladium-catalyzed coupling of aryl halides with amides. Moreover, it is the process that occurs with the broadest scope when conducted with certain ancillary ligands. 

More detailed mechanistic studies have been conducted with isolated ligated copper complexes, along with kinetic studies on reactions catalyzed by complexes of diamine ligands. These studies have shown that copper(I) amidate and imidate complexes are competent to be intermediates in the catalytic coupling of aryl halide with amides and imi-des. These studies also implied that two-coordinate anionic cuprate complexes undergo oxidative addition of the aryl halide more slowly than do related three-coordinate, neutral copper complexes containing a bidentate dative ligand. This conclusion is shown clearly by the formation of coupled product from iodotoluene and the species that equilibrates between the ionic and three-coordinate neutral species (Equation 19.119) and the lack of... 

Figure 8.12 illustrates how a product study may not show what a mechanism is, but it can show what it is not. Reaction of the aryl halide with amide anion in liquid ammonia gives two products, in almost exactly equal amounts. This means that the replacement of chloride by an amino group cannot be a direct displacement, as this could give rise to only one of the products observed. In the second example, the stereochemistry of the product shows that it cannot have been produced in a simple one-step process—as this would give rise to a ci5-product. 

Benzyne is formed as a reactive intermediate in the reaction of aryl halides with very strong bases such as potassium amide... 

In contrast to the borylation of alkane C-H bonds, the coupling of aryl halides with amines was based on a literature precedent from another group published about a decade before our initial studies. Kosugi, Kameyama and Migita published the coupling of aryl halides with tin amides." Mechanistic studies we conducted on this process led us to the perhaps obvious realization that the reaction" could be conducted with amines and a silylamide base instead of tin amides (equation 4)." Surveys of bases with similar p a values led Janis Louie to conduct reactions with alkoxide bases. Similar studies were conducted at nearly the same time by Steve Buchwald and coworkers."... 

The intermolecular coupling of lactams and acyclic amides has also been reported. Reactions of carbamates with aryl halides occurred in the presence of catalysts ligated by P(/-Bu)3.78 Both carbamates and amides coupled with aryl halides in the presence of a catalyst bearing Xantphos.90 In addition, the coupling of lactams with aryl halides has been successful. A combination of Pd(OAc)2 and DPPF first formed A-aryl lactams in good yields from 7-lactams, but the arylation of amides was improved significantly by the use of Xantphos (Equations (20) and (21)).90 91 The reaction of aryl halides with vinyligous amides has also been reported 92... 

The synthesis of aromatic primary amides through aminocarbonylation of aryl halides with ammonia is not well documented due to the technical difficulty in using gaseous ammonia. To resolve this problem, methods using ammonia equivalents such as hexamethyldisilazane (HMDS), " formamides, and a titanium-nitrogen complex have been developed. 

Another solution is the use of formamide as the ammonia substitute.Thus, the Pd-catalyzed aminocarbonylation of (hetero)aryl halides with formamide as ammonia substitute as well as solvent under CO afforded the corresponding primary amides in moderate to excellent yields (Scheme 22). ... 

Elimination-addition reactions of aryl halides with alkali-metal amides are discussed in Section 14-6C high-temperature copper-catalyzed amination, also effective, usually does not lead to rearrangement. 

The carbanions derived from A,A-disubstituted amides and lactams react with certain aromatic halides in liquid ammonia under photostimulation [85,86] to form the expected a-arylated compounds in good yields. Unsymmetrical a, a-diaryl amides can be formed by reaction of aryl halides with the anion of the oc-aryl-A,7V-dimethyl acetamides [85]. 

In 1995, Hartwig and Buchwald published concurrently their two groups results on tin-free amination of aryl halides [79,80], Instead of isolating or generating a tin amide in situ, the amination reactions were conducted by reacting an aryl halide with the combination of an amine and either an alkoxide or silylamide base (Eq. (5)). These reactions were typically conducted between 80 and 100 °C in toluene solvent. The catalysts used initially were 1, 3, or a combination of [Pd2(dba)3] (Sa) (dba = trans, trans-dibenzylidene acetone) and P(o-C6H4Me)3. Catalysts used subsequently will be described below. As shown in Table 7.1, secondary amines were viable substrates, but primary amines gave substantial yields with... 

As with ester formation, carbonylation of aryl halides under amide-forming conditions and high carbon monoxide pressures leads to synthetically useful yields of a-ketoamides via double carbonylation916- 21. In these reactions the amine must be a fairly strong nucleophile and it is noteworthy that primary amines often give imines as the final product. Aryl chlorides do not normally undergo this reaction but specialized palladium catalysts may facilitate this process890. Alternatively, reaction may be possible via a first-formed... 

By far one of the most important reactions through the S l mechanism is formation of a C—C bond by the reaction of aryl halides with carbanions derived from hydrocarbons, ketones, esters, amides, nitriles and even, with some limitations, from aldehydes. The reactions of cyanide ions and carbonyl complexes of Co and Fe also form a new C—C bond. 

The reaction of an aryl halide with potassium amide proceeds through a benzyne intermediate. Ammonia can then add to either end of the triple bond to produce the two methylanilines observed. 

A tantalizing observation made by Kosugi was that triphenylphosphine-based catalysts were far inferior to PdCl2(o-tolyl3P)2 for the coupling of aryl halides with tin amides. In 1994, the groups of Buchwald and Hartwig... 

Direct carbamoylation of aryl halides with a carbamoylsilane can be performed under the action of catalysis by a Pd(0) complex (Scheme 10.230) [597]. The use of Pd(PPh3)4 is suitable for the conversion of unhindered aryl bromides and iodides into the corresponding amides. The carbamoylation of aryl chlorides and hindered aryl bromides, less reactive substrates, is effectively catalyzed by Pd(Pt-Bu3)2. 

The carbonylation of aryl halides with alcohols and amines catalysed by palladium complexes with triphenylphosphine ligand is the convergent and direct route to the synthesis of aromatic esters as well as aromatic amides. Even though these palladium complexes are widely employed as the best catalytic system, those catalysts are difficult to separate and reuse for the reaction without further processing. The major drawbacks are oxidation of triphenylphosphine to phosphine oxide, reduction of palladium complex to metal and termination of the catalytic cycle. The phosphine-free, thermally stable and air resistant catalyst (1) containing a carbon-palladium covalent bond (Figure 12.3) has been found to be a highly selective and efficient catalyst for the carbonylation of aryl iodides.[1]... 

Coupling of aryl halides and trifluoroacetamide occurred at 45-75 °C catalyzed by CuI/DMEDA (Lll), followed by in situ hydrolysis to provide the corresponding primary arylamines (entry 2) [32]. The Cul/l,10-phen (L13) catalytic system was found to be able to promote the selective coupling of N-Boc hydrazine [33] (entry 3) and the coupling of N- and O- functionalized hydroxylamines with aryl iodides (entry 4) [34]. Hosseinzadeh and coworkers reported the coupling reaction of aryl iodides with amides catalyzed by CuI/l,10-Phen (L13) by using KF/AI2O3 as the... 

Although the CuI/L-proline (LI) catalytic system showed no obvious acceleration effect for the coupling of aryl halide and amides, the Ma group found that N,N-dimethylglycine (L2) was a suitable promoter for the coupling reaction of vinyl halides with amides, and, in many cases, the reaction worked at room temperature (entry 3) [39], Another combination (Cu(CH3CN)4PF,s/L15/Rb2C03) was recently found effective for this transformation (entry 4) [40],... 

Enolate Arylation Reactions. The direct coupling of aryl halides with enolates (or enolate equivalents) of ketones, esters, and amides is now well established. Malonic esters, cyanoacetates, and malononitrile can be arylated upon treatment with aryl halides in the presence of Pd(dba)2 and electron-rich phosphines or N-heterocyclic carbenes. Carbene ligands have also proven effective in promoting the a-arylation of protected amino acids. As a caveat to the use of Pd(dba)2, the arylation of azlactones in the presence of this palladium source and phosphines was less efficient than that with Pd(OAc)2. The dba ligands were found to react with azlactone substrates to form catalytically inactive palladium complexes. Diastereoselective enolate arylation has been achieved through the use of chiral auxiliaries appended to preformed enol silyl ethers (eq 23). The role of the zinc additive is not clear, however, it appears that discrete zinc enolates are not involved. 

On the basis of the labeling experiment, an alternative mechanism was proposed for the substitution reaction of aryl halides with strong base-the elimination-addition mechanism. In the first step, the elimination stage, amide anion removes a proton from the carbon on the ring adjacent to the one with the halogen. The product is an unstable intermediate known as henzyne. 

The reactions of aryl halides with carbon monoxide and either alcohols or amines to form esters or amides occur by two related yet distinct mechanistic pathways. These pathways are related to the mechanism of cross coupling presented in Chapter 19, and the reader might find it helpful to refer to the discussion of mechanisms of cross coupling in that chapter. Scheme 17.29 outlines the pathways for the carbonylation of aryl halides to form esters and amides. 

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