Carboamination Reactions

In contrast to classical Meerwein arylations, non-activated alkenes are well suited for this reaction type for two reasons. First, due to the relatively slow formation of azo compounds by addition of aryl radical 49 to 48, this undesired pathway cannot compete successfully with the attack of 49 on the alkene to give radical adduct 50. Second, a nucleophilic alkyl radical 50 arises from the addition step, which is effectively trapped by electrophilic salt 48 to give azo compound 51. As a result of several improvements, the methodology is now applicable for a wide range of polar to non-polar alkenes with almost no restrictions on the substitution pattern of the diazonium salt [101, 102]. Moderate diastereoselectivities have been obtained in first attempts with chiral auxiliaries [103]. The azo compounds accessible, such as 51, can be converted to carboamination products 52 by hydrogenation and to various other heterocycles. 

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A novel intramolecular carboamination reaction across an alkyne was reported <04JA10546>. Treatment of o-alkynyl amide 139 with a platinum catalyst provided 3-acetylindole 141 presumably via zwitterionic intermediate 140. 

Palladium-catalyzed carboetherification and carboamination reactions of y-hydroxy- and y-aminoalkenes for the synthesis of tetrahydrofurans and pyrrolidines 07EJO571. 

Two recent reports have described Pd"-catalyzed carboamination reactions involving two alkenes that afford pyrrolidine products. Building on early work by Oshima that employed stoichiometric amounts of palladium [44], Stahl has developed an inter-molecular Pd-catalyzed coupling of N-allylsulfonamide derivatives with enol ethers or styrene derivatives that affords substituted pyrrolidines in high yields with moderate diastereoselectivity [45]. For example, treatment of 44 with styrene in the presence of Pd" and Cu" co-catalysts, with methyl acrylate added for catalyst stability, provided 45 in 97% yield with 1.9 1 dr (Eq. (1.21)). This reaction proceeds through intermolecular aminopalladation of styrene to afford 46. Intramolecular carbopalla-dation then provides intermediate 47, and subsequent P-hydride elimination yields product 45. 

Pd-Catalyzed Carboamination Reactions of Alkynes, Allenes, and Dienes... 

A few examples of Pd"-catalyzed carboamination reactions between alkyne-tethered amines and aryl halides have also been reported [28d, 47]. For example, treatment of amino ester derivative 50 with Phi in the presence of K2CO3 using Pd(PPh3)4 as catalyst led to the formation of 51 in 80% yield with complete retention of enantiomeric purity (Eq. (1.23)) [28d]. In contrast to the Pd"-catalyzed carboamination... 

Several examples of Pd°-catalyzed carboamination reactions between allenes and aryl or alkenyl halides have been reported [50[. For example, treatment of allene 52 with iodobenzene in the presence of K2CO3 and 2mol% Pd(PPh3)4 afforded pyrrolidine 53 in 78% yield (Eq. (1.25)) [50a]. Mechanisms involving aikene amino-palladation (similar to the reactions of alkynes and alkenes noted above) have occasionally been invoked to explain these reactions. However, in many instances these transformations may involve intermediate Ji-allylpalladium complexes. Due to this mechanistic ambiguity, these transformations have been included in this section for comparison with the related reactions of alkenes and alkynes. Similar reactions involving allylic halides have also been described (Eq. (1-26)) [51]. 

Cross-coupling carboamination reactions between allenes and 2-haloaniline derivatives or halogenated allylic amines have also been employed for the generation of substituted indolines, and use of an appropriate chiral catalyst for these transformations leads to formation of enantioenriched products [52]. For example, Larock has described the synthesis of indoline 56 via the Pd-catalyzed reaction of aryl iodide 54... 

Ma has developed a three-component allene carboamination reaction for the stereoselective synthesis of 2,5-as-disubstituted pyrrolidine derivatives [54]. A representative transformation involving allene 58, 4-iodoanisole, and imine 59 that generates 60 in 90% yield is shown below (Eq. (1.28)). The reaction is believed to proceed through the intermediate Jt-allylpalladium complex 62, which is formed by carbopalladation of the alkene to give 61 followed by addition of the malonate anion to the activated imine. Intramolecular capture of the allylpalladium moiety by the pendant nitrogen nucleophile affords the pyrrolidine product. A related asymmetric synthesis of pyrazolidines that employs azodicarboxylates as one of the electrophilic components has also been reported [55]. The pyrazolidine products are obtained with up to 84% ee when chiral bis oxazolines are employed as ligands. 

An interesting Pd-catalyzed diene carboamination reaction that involves urea-directed C—H activation was recently reported [56]. For example, treatment of N-aryl urea 63 with an activated diene in the presence of 10 mol% Pd(0 Ac) 2,50 mol% TsO H, AC2O, and benzoquinone provided 64 in 90% yield (Eq. (1.29)). The transformation is initiated by directed palladation of the arene by a palladium tosylate complex (formed... 

More efficient for the posterior construction of C-C bonds within aminometalla-tion processes have been copper-catalyzed C- H functionaHzation reactions. A series ofimpressive protocols to this end were developed by Chemler [68]. Based on a series of stoichiometric developments, Chemler could devise carboamination reactions, in which a nitrogen substituent undergoes radical C-H activation/C-C couphng. 

The reaction could also be extended to an interesting two-step process, in which 2-allylaniline was first submitted to an oxidative aryl coupling with phenylboronic acid and copper(II) diacetate and myristic acid to give the N-arylated derivative, which was then submitted to catalytic carboamination reaction by the addition of manganese dioxide and base. 

An additional application was described within a diastereo- and enantioselective carboamination reaction (Scheme 16.26). This reaction starts from mesylated... 

Intermolecular processes of carboamination reactions remain rare. Within this context, Lloyd-Jones and Booker-Milbum reported a palladium-catalyzed synthesis... 

Other aminooxygenation reactions were observed as undesired pathways in the development of intramolecular diamination with sulfamates and guanidines, respectively [89, 90]. In addition, Michael described the conditions to use alcoholic solvents in order to intercept the described carboamination reaction from... 

A copper(II)-catalyzed aminooxygenation as reported by Chemler (Scheme 16.34) [93]. For the case of the earlier described carboamination reaction [71], by exchanging manganese dioxide for (2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO) and... 

Wolfe JP (2008) Stereoselective synthesis of saturated heterocycles via palladium-catalyzed alkene carhoetherification and carboamination reactions. Synlett 2913-2937... 

Simultaneous formations of C C and C—N bonds at both terminals of an alkene or alkyne are called carboamination reactions. Most cases of these types of reactions take place in the presence of a metal catalyst, especially a transition metal catalyst. 

Carboamination reactions have been classified into two types depending on the mode of reaction in the first case, the reaction proceeds via the formation of 1) an outersphere aminopalladation complex like the PdX2-aIkene complex via oxidative addition, which in the next step reacts with the amine and an external electrophile to afford the cyclized product. In a type II mechanism, the reaction takes place through the formation of 2) an innersphere complex where the Pd(0) catalyst forms the complex with an electrophile, e.g., aryl haUde via oxidative addition. Then, it reacts with the amine to form the Pd(Ar) amide complex, which eventually gets converted into the product via the alkene insertion and C—C bond-forming reductive elimination. Here, it is noteworthy that, in a type I reaction, the addition across the olefinic bond took place in rarri-fashion, whereas the 5y -addition mode was observed in case of the type It mechanism (Scheme 40.1). ... 

Reactions via Pd(II)-Alkene Complex In 1980, Hegedus et al. reported on the synthesis of indole derivatives via a Pd-catalyzed intramolecular amination of alkenes in the presence of carbon monoxide (Scheme 40.2). This reaction follows the outersphere aminopalladation mechanism. This report can be considered the first example of today s carboamination reaction although the authors did... 

SCHEME 40.1. Pd-catalyzed type I and type II carboamination reactions. 

A few years later, Tamaru et al. have reported on the stereoselective carboamination reaction where a hydroxyl group was introduced into the amino olefin substrate. The substrate 4 underwent a carboamination reaction to form bicyclic lactone 5 with high yield and excellent diaster-eoselectivity (only the cis product was observed) (Scheme 40.3). ... 

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