Intermolecular reactions hydroamination

In addition to C-alkylation reactions, hydroaminations are of great interest in organic synthesis [85, 86]. Recently, Shibasaki and coworkers developed a Bi(OTf)3-catalyzed intermolecular hydroamination using styrenes [87] and... 

Addition of ammonia and amines to alkenes (hydroamination) is thermodynamically feasible, but kinetically hindered, hence it requires activation of either of the reactants1,2,51. The intramolecular reaction is generally more easily accomplished than the intermolecular reaction and allows the stereochemistry to be controlled to a certain degree. 

The insertion approach is very successful in the hydroamination of alkynes and alkenes catalyzed by lanthanide complexes developed by Marks et al. [220]. Thorough mechanistic studies have been undertaken for the intramolecular reaction (hydroamination-cyclization of aminoalkenes), although the intermolecular version of the process is also efficient [222]. The mechanism of the reaction can be represented in a simplified way by Scheme 6.68. The insertion step is almost thermoneutral, but the protonolysis of the M-aminoalkyl bond that follows is exothermic and provides the necessary driving force. The insertion of the alkene into the Ln-N bond is irreversible and rate determining and it goes through a... 

An interesting tandem intermolecular/intramolecular hydroamination reaction of cycloheptatriene with substituted anilines has been developed by Hartwig for the synthesis oftropene derivatives [34]. As shown in Eq. (1.14), the coupling of 30 with 31 provided 32 in 73% yield. The mechanism of this transformation is believed to involve acid-assisted formation of an q -pentadienylpalladium complex 33, which is then captured by the aniline nucleophile to afford the allylpalladium intermediate 34. Intramolecular attack of the aniline nitrogen on the allylpalladium moiety affords the observed heterocycle. 

While early efforts in rare earth systems focused on cyclohydroamination, pioneering contributions in group 4 catalyzed hydroamination catalysis focused on intermolecular reactions [8]. However, owing to the aforementioned thermodynamic problems associated with intermolecular alkene hydroamination and mechanistic hmitations (see later discussion), early efforts focused on alkyne hydroamination with a variety of primary amines. 

Allene hydroamination is less commonly explored, even though the thermodynamic profile of the reaction is comparable to alkyne hydroamination [40]. Intermolecular allene hydroamination has been established using group 4 catalysts in combination with reactive arylamine substrates [8, 41]. The more reactive aforementioned alkyne hydroamination catalyst 7 has been shown to be usefiil for allene hydroamination catalysis in an intermolecular manner, even with less reactive, sterically less demanding alkylallene substrates. In this case, only the branched product is observed (Table 15.5). These results show good selectivity for the branched product, and recent results show that even heteroatom-substituted allenes can be tolerated with this precatalyst [42]. 

Although this chapter is formally not covering recent achievements in rare earth chemistry, it must be mentioned that the first examples of asymmetric intermolecular alkene hydroamination have been reported by Hultzsch and coworkers (Scheme 15.13) [85]. Using a bulky binaphtholate yttrium complex at high temperatures with excess alkene substrate, the first examples of this challenging and highly sought after reaction have been realized with unactivated alkenes. 

Af,Af-diethylgeranyIamjne, a precursor to (—)-menthol is achieved via the hydroamination of this substrate with lithium catalysts on an industrial scale [98]. A single example of intermolecular alkyne hydroamination also exists. Thus, piperidene undergoes addition to diphenylacetylene in the presence of 10 mol% [Sr CH(SiMe3)2 2(THF)2] at 60 °C in CgDe solution over a period of 17 h a 10 1 mixture of syn- and antf-addition products are isolated consistent with an isomerization event occurring under the reaction conditions [98]. 

More recently, neutral zirconium-based catalysts capable of performing reactions with both primary and secondary amines in intra- [55-57] and intermolecular [57, 58] reactions were reported. The imido mechanism is obviously impossible, and an insertion mechanism, similar to the lanthanide-like mechanism shown in Scheme 2 was proposed [55]. The isolation of an insertion intermediate in an intermolecular alkyne hydroamination reaction is compelling evidence in favor of the insertion mechanism [58]. 

Cyclization reactions triggered by intermolecular alkyne hydroamination reactions provide straightforward access to structurally diverse heterocyclic motifs as summarized in a recent general [5] and specialized [202] review. 

The proposed reaction mechanism involves intermolecular nucleophilic addition of the amido ligand to the olefin to produce a zwitterionic intermediate, followed by proton transfer to form a new copper amido complex. Reaction with additional amine (presnmably via coordination to Cn) yields the hydroamination prodnct and regenerates the original copper catalyst (Scheme 2.15). In addition to the NHC complexes 94 and 95, copper amido complexes with the chelating diphosphine l,2-bis-(di-tert-bntylphosphino)-ethane also catalyse the reaction [81, 82]. 

Although efficient for the intramolecular hydroamination/cyclization (abbreviated IH below) of aminoalkenes (see below), organolanthanides exhibit a much lower catalytic activity for the intermolecular hydroamination of aUcenes, as exemplified by the reaction of n-PrNH2 with 1-pentene catalyzed by a neodymium complex (Eq. 4.17) [127]. 

Due to its marked atom economy, the intramolecular hydroamination of alkenes represents an attractive process for the catalytic synthesis of nitrogen-containing organic compounds. Moreover, the nitrogen heterocycles obtained by hydroamination/cyclisation processes are frequently found in numerous pharmacologically active products. The pioneering work in this area was reported by Marks et al. who have used lanthanocenes to perform hydroamination/cyclisation reactions in 1992. These reactions can be performed in an intermolecular fashion and transition metals are by far the more efficient catalysts for promotion of these transformations via activation of the... 

Organometallic complexes of the /-elements have been reported that will perform both intra-and intermolecular hydroamination reactions of alkenes and alkynes, although these lie outside of the scope of this review.149-155 Early transition metal catalysts are not very common, although a number of organometallic systems exist.156-158 In these and other cases, the intermediacy of a metal imido complex LnM=NR was proposed.159,160 Such a species has recently been isolated (53) and used as a direct catalyst precursor for N-H addition to alkynes and allenes (Scheme 35).161,162... 

Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>. 

In order to find a suitable catalyst for intermolecular hydroaminations of 1,3-dienes, several metal sources were screened for the reaction of diene la (4 equiv) with carbamate 2a, and Bi(OTf)3 gave promising results [21, 22], The optimization studies using Bi(OTf)3 are summarized in Table 1 and show that 10 mol% of... 

Alkene hydroamination has been known for many years, but has been little used as a method in organic synthesis. Tobin Marks of Northwestern recently published a series of three papers that will make this transformation much mote readily accessible. In the first (J. Am. Chem. Soc. 125 12584,2003) he describes the use of a family of lanthanide-derived catalysts for intermolecular hydroamination of alkynes (to make imines, not illustrated) and alkenes. With aliphatic amines, the branched (Markownikov) product is observed, 1 — 2. With styrenes, the linear product is formed. When two alkenes are present, the reaction can proceed (3 —> 4) to form a ring, with impressive regioselectivity. 

Intermolecular hydroamination or hydroarylation reactions of norbornene and cyclo-hexadiene carried out with catalytic amounts of Brpnsted or Lewis acid in ionic liquids have been found to provide higher selectivity and yields than those performed in classical organic solvents. This effect was attributed to the increases of the acidity of the medium and stabilization of ionic intermediates through the formation of supramolec-ular aggregates with the ionic liquid.38... 

The intermolecular hydroamination of alkynes, catalysed by the aquapalladium complex [(dppe)Pd(H20)2](0Tf)2, has been reported. The reaction is believed to proceed through the equilibrium between the hydroxopalladium and the amidopalladium complexes, followed by aminopalladation of alkynes.76 Regioselective 1,2-diamination of 1,3-dienes by dialkylureas, catalysed by (MeCN)2PdCl2 in the presence of 1 equiv. of / -benzoquinone, has been developed as a highly efficient method.77... 

Mononuclear complexes [U(C5Me5)2(NHR)2] (R = 2,6-dimethylphenyl, Et, or Bu) have been synthesized and structurally characterized. It was shown that in the presence of terminal alkynes and amines these complexes catalyze the intermolecular hydroamination of terminal alkynes [453]. Complex formation reactions of U(VI) with neutral N-donors in DMSO were reported [454]. 

Cazes et al. reported the Pd-catalyzed intermolecular hydroamination of substituted allenes using aliphatic amines in the presence of triethylammonium iodide leading to allylic amines [19]. In a way similar to the Pd-catalyzed hydrocarbona-tion reactions we reported that the hydroamination of allenes [20], enynes [21], methylenecyclopropanes [22], and cyclopropene [10] proceeds most probably via oxidative addition of an N-H bond under neutral or acidic conditions to give allylic amines. The presence of benzoic acid as an additive promotes the Pd-medi-ated inter- and intramolecular hydroamination of internal alkynes [23]. Intramolecular hydroamination has attracted more attention in recent years, because of its importance in the synthesis of a variety of nitrogen-containing heterocycles found in many biologically important compounds. The metal-catalyzed intramolecular hydroamination/cyclization of aminoalkenes, aminodienes, aminoallenes, and aminoalkynes has been abundantly documented [23]. 

The aziridination of olefins, which forms a three-membered nitrogen heterocycle, is one important nitrene transfer reaction. Aziridination shows an advantage over the more classic olefin hydroamination reaction in some syntheses because the three-membered ring that is formed can be further modified. More recently, intramolecular amidation and intermolecular amination of C-H bonds into new C-N bonds has been developed with various metal catalysts. When compared with conventional substitution or nucleophilic addition routes, the direct formation of C-N bonds from C-H bonds reduces the number of synthetic steps and improves overall efficiency.2 After early work on iron, manganese, and copper,6 Muller, Dauban, Dodd, Du Bois, and others developed different dirhodium carboxylate catalyst systems that catalyze C-N bond formation starting from nitrene precursors,7 while Che studied a ruthenium porphyrin catalyst system extensively.8 The rhodium and ruthenium systems are... 

Imines react with alkynes to give pyrroles (equation 29). " A related transformation of azides has been reported by the group of Toste to afford pyrroles by an acetylenic Schmidt reaction (equation 30). " In an intermolecular-related addition, gold triazolates are obtained. The intramolecnlar hydroamination of trichloroacetimidates derived from propar-gyl and homopropargyl alcohols also proceeds with cationic An(I) as catalysts. ... 

Hydroamination of olefins is also possible with gold catalysts. In this reaction, the attack comes Ifom a nitrogen nucleophile as a carbamate,a urea, an amide, or a sulfonamide. In the latter case, the reaction can be carried out intermolecularly. While the carbamates, ureas, and amides give only products of intramolecular anunations, the sulfonamides can perform the intermolecular addition. Only the addition of ureas (equation 146) takes place at room temperature, and in the rest of the additions heating is required. The catalysts of choice in all these reactions are cationic gold(I)-species stabilized by phosphines or NHC ligands. The reaction times have been reduced by the use of microwave irradiation. The mechanism of the hydroamination reaction has been studied in detail theoretically. ... 

The intermolecular addition of carbamates to 1,3-dienes (equation 147) under mild conditions has been described as well. The hydrothiolation of 1,3-dienes has also been reported. " Other related conjugate additions can be performed over methylenecyclopropanes (equation 148) with sulfonamides and the resulting product cyclizes by a second hydroamination of an olefin, finally yielding cyclic sulfonamides. This behavior is reproduced in a similar reaction for the ring opening of vinylcyclopropanes with sulfonamides. One more example in this group of reactions is the synthesis of dUiydrobenzofurans from aryl-allyl ethers. ... 

The first intermolecular hydroamination of an alkyne was reported by Uchimaru in 1999 [92]. It was found that Ru3(CO)i2 catalyzes the reaction of N-methylaniline derivatives with phenyl-substituted acetylenes in good yields (76-88%)(Scheme 8.31). 

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