Aryl halides amidation

Acid chlorides and bromides, allyl halides, a-halo-ketones, esters, amides and nitriles react at 25° within 3 minutes. Vinyl and aryl halides are inert. 

The o-keto ester 513 is formed from a bulky secondary alcohol using tricy-clohexylphosphine or triarylphosphine, but the selectivity is low[367-369]. Alkenyl bromides are less reactive than aryl halides for double carbonyla-tion[367], a-Keto amides are obtained from aryl and alkenyl bromides, but a-keto esters are not obtained by their carbonylation in alcohol[370]. A mechanism for the double carbonylation was proposed[371,372],... 

Very strong bases such as sodium or potassium amide react readily with aryl halides even those without electron withdrawing substituents to give products corresponding to nucleophilic substitution of halide by the base... 

In each of the following reactions an amine or a lithium amide derivative reacts with an aryl halide Give the structure of the expected product and specify the mechanism by which it is formed... 

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

The reaction of amines with aryl halides requires a catalyst in most cases to initiate the reaction. There are several approaches that result in N-aryl amines. Treatment of cyclohexylamine with p-MeC6H4B(OH)2 and Cu(OAc)2 gave the N-aryl amide in 63% yield. Aryl halides react with amines in the presence of palladium... 

The addition of Grignard reagents to isocyanates gives, after hydrolysis, N-substituted amides. This is a very good reaction and can be used to prepare derivatives of alkyl and aryl halides. The reaction has also been performed with... 

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 palladium-catalyzed carbonylation of aryl halides in the presence of various nucleophiles is a convenient method for synthesizing various aromatic carbonyl compounds (e.g., acids, esters, amides, thioesters, aldehydes, and ketones). Aromatic acids bearing different aromatic fragments and having various substituents on the benzene ring have been prepared from aryl iodides at room temperature under 1 atm... 

Amides and sulfonamides undergo intramolecular chemistry to form aryl amides and aryl sulfonamides (Equations (17)—(19)) in the presence of palladium catalysts ligated by arylphos-phines.35,89 Initially, complexes of P(furyl)3 and P(o-tol)3 were most effective catalysts, but complexes of Hayashi s MOP and van Leeuwen s DPEphos and xantphos have lately been shown to be more active.90 In the presence of catalysts containing one of these ligand systems, five-, six-, and seven-membered rings were formed from halogenated benzamides or from substrates containing an acetamide, an A-carbobenzyloxy, or a t-butylcarbamate substituent tethered to the aryl halide (Equations (18) and (19)) ... 

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... 

A more recent publication by Weigand and Pelka has disclosed a polymer-bound Buchwald-Hartwig amination [40], Activated, electron-deficient aryl halides were coupled with conventional PS Rink resin under microwave irradiation. Subsequent acidic cleavage afforded the desired aryl amines in moderate to good yields (Scheme 7.22). Commercially available Fmoc-protected Rink amide resin was suspended in 20% piperidine/N,N-dimethylformamide at room temperature for 30 min to achieve deprotection. After washing and drying, the resin was placed in a silylated microwave vessel and suspended in dimethoxyethane (DME)/tert-butanol... 

The palladium-catalyzed Heck carbonylation reaction is a powerful means of generating amides, esters, and carboxylic acids from aryl halides or pseudohalides [28]. The development of rapid, reliable, and convenient procedures for the introduction of carbonyl groups is important for the development of high throughput chemistry in general and high-speed microwave-mediated chemistry in particular. Unfortunately, the traditional method of introducing carbon monoxide into a reaction mixture via a balloon or gas tube is not practical because of the special requirements of microwave synthesis. 

In an alternate use of a palladium-catalyzed C-N bond forming reaction, Edmondson described the first example of the coupling of vinylogous amides (e.g., 96) to aryl halides. In addition to the formation of W-aryl enaminones 97, this reaction could be applied in a tandem... 

The palladium-catalyzed arylations of aromatic carbonyl compounds such as ketones,67,67a amides (Equation (60)),68 and aldehydes69 with aryl halides and triflates give the multiple arylation products similarly. 

Like most aryl halides, furyl halides and furyl triflates have been coupled with a variety of organostannanes including alkenyl, aryl, and heteroaryl stannanes in the presence of catalytic palladium. Carbamoylstannane 66 was prepared by treating lithiated piperidine with carbon monoxide and tributyltin chloride sequentially. The Stille reaction of 66 and 3-bromofuran then gave rise to amide 67 [61]. In another example, lithiation of 4,4-dimethyl-2-oxazoline followed by quenching with MesSnCl resulted in 2-(tributylstannyl)-4,4-dimethyl-2-oxazoline (68) in 70-80% yield [62], Subsequent Stille reaction of 68 with 3-bromofuran afforded 2-(3 -furyl)-4,4-dimethyl-2-oxazoline (69). 

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

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