Alkenes carboamination

Balme has reported a one-pot threecomponent alkene carboamination between propargylic amines, alkylidene malonates, and aryl halides [43]. For example, treatment of N-methyl propargylamine (2 equiv), dimethyl benzylidene malonate (2 equiv) and 1,4-diiodobenzene (1 equiv) with n-BuLi and a palladium catalyst provided 43 as a single diastereomer (Eq. (1.20)) [43a]. The formation of the C—N bond in this process does not appear to be metal catalyzed. Instead, initial conjugate addition of the nitrogen nucleophile to the activated alkene affords a malonate anion, which undergoes carbopalladation followed by reductive elimination to afford the pyrrolidine product. 

In careful stoichiometric reactivity with unactivated aminoalkene substrates, Wolfe prepared a bis(diphenylphosphino)ferrocene (dppf)-Hgated Pd(II)-mixed aryl amido complex, which could be observed by NMR spectroscopy to undergo alkene insertion and subsequent product formation via reductive eHmination (Scheme 15.90) [146]. Labeling experiments confirmed this as the first example of the syn addition of the N- and aryl-substituent to the face of the alkene, as would be expected for this often postulated step in various Pd-catalyzed reactions including alkene carboamination, diaminations, and oxidative amination [146]. 

Nakhla JS, Schultz DM, Wolfe JP. Palladium-catalyzed alkene carboamination reactions for the synthesis of substituted piperazines. Tetrahedron 2009 65(33) 6549-6570. 

Our group has developed cascade Pd-catalyzed A -arylation/alkene carboamination reactions of 2-allylanilines that afford indoline products [297, 298]. For example, treatment of 2-allylaniline with 4-bromobiphenyl in the presence of NaOtBu and a... 

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. 

The relative stereochemistry of the newly formed stereogenic centers attained in the aminometa-lation reaction of 1,2-disubstituted alkenes is lost if the / -aminoalkylpalladium complex is allowed to undergo /J-hydride elimination to give enamines, or if a successive reduction step is performed, unless a stereocenter is initially present in the alkene or in the amine. However, the C —Pd bond can be functionalized to achieve overall oxyamination, diamination, aziridination, aminocarbonylation, and carboamination reactions13,14. 

The first Pd-catalyzed carboamination and carboetherification reactions of y-amino or y-hydroxy alkenes with aryl halides were described by Wolfe in 2004 [ 100]. As shown below, treatment of these substrates with aryl or heteroaryl bromides in the presence of NaOfBu and a palladium catalyst provides substituted tetrahydrofuran or pyrrolidine products. 

Various examples of intramolecular stereoselective carboamination have been reported28 "30. Asymmetric synthesis of key intermediates for capnellenols is achieved via a Heck-type intramolecular carbopalladation of an alkene with a vinyl halide and amide anion capture in the presence of Chiraphos- or BINAP-modified palladium catalysts31. 

Examples of the insertions of alkenes or alk5mes into metal-amido bonds are also rare. Examples of the insertions of alkenes into tihe M-N bonds of isolated amido complexes include the reaction of a rhodium anilide complex with alkenes to form imines witii kinetic behavior that is consistent with migratory insertion,and the formal insertion of the strongly electrophilic acrylonitrile into a platinum anilide. Additional examples include reactions of a lanthanide-amido complex generated in situ, a catalytic carboamination process in which the stereochemistry implies insertions of olefins into amides, and a catalytic hydroamination that appears to occur through an aminoalkyl complex generated by S3m addition of the iridium and amido groups across the C=C bond of norbomene. 

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. 

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]. 

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. 

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

Zeng and Chemler developed a copper-catalyzed preparation of six-membered N,S-heterocycle sultam derivatives using 3 equiv. of Mn02 as the oxidant (Scheme 8.122). The enantiomerically enriched N,S-heterocycle sultams were prepared by an asymmetric intramolecular carboamination of alkenes with moderate to good yield and high enantioselectivity. An intramolecular Cu-catalyzed aryl C(sp )-H functionalization process is included for this reaction [54]. 

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... 

In 2004, Wolfe et al. used a carboamination reaction for the first time for the stereoselective synthesis of substituted pyrrolidine derivatives via a Pd-catalyzed intermolecular iV-arylation followed by intramolecular cyclization reaction sequences. The reaction proceeds via an innersphere mechanism with the formation of the Pd(Ar)(NRR ) complex. In this reaction, a -(A-arylamino) alkene was treated with an aryl or heteroaryl bromide in the presence of NaO Bu as the base and Pd catalyst the corresponding 2,3- or 2,5-disubstituted pyrrolidine derivatives (Scheme 40.4) were obtained in good yields and excellent diastereoselectivity. ... 

Carboamination Reactions of Alkenes Synthesis of Diverse Heterocyclic Scaffolds... 

Stereoselective Synthesis of 3,5-Disubstituted Morpholines After successful use of the carboamination reaction of amino alkenes for the synthesis of pyrrolidines, pyrazolidines, and piperazines, the same group reported on the synthesis of another important heterocyclic scaffold morpholine. Morpholines are also widely applicable and present in various biologically important natural and... 

Copper-Catalyzed Carboamination Reaction-s Although in most of the carboamination reactions of alkenes a Pd catalyst was employed, other transition-metal-catalyzed carboamination reactions of alkenes are also known. The Cu(II)-facilitated aminocarbonation reaction of alkene was reported by Chemler et al. in 2004. The authors... 

The enantioselective synthesis of indole derivatives has also been described by Chemler and co-workers via a Cu(II)-catalyzed intramolecular carboamination reaction of properly designed amino alkene substrates. In this reaction, an aU-carbon quaternary center was constructed adjacent to a tertiary carbon in an enantioselective way. The carboamination protocol was further used for the synthesis of a... 

HTia receptor antagonist." " In the same year, Majumdar et al. demonstrated the synthesis of racemic pentacyclic sultams via a Cu(II)-catalyzed carboamination reaction of alkenes." ... 

Zhang et al. recently reported on a Au-catalyzed carboamination reaction of the A-tosyl amino alkene substrate. They developed a gold-catalyzed intermolecular carboamination reaction toward the synthesis of substituted pyrrolidines in excellent yield in racemic form (Scheme 40.21)." This report was the first to convert the C(Sp )-Au bond into the C(Sp )-C(Sp ) bond. 

Similar to the alkenes, the carboamination reactions of alkynes" " and allenes" are also weU known in the literature. However, in aU cases, nonstereoselective products were obtained as a sp carbon of the alkyne was converted into a sp carbon after the carboamination step hence, a new chiral center could not be generated. 

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