Intramolecular Hydroamination of Alkenes

Chiral Ci-symmetric lanthanocenes (Fig. 14) have achieved enantioselectivities of up to 74% ee (34) in various intramolecular hydroamination reactions [72, 212, 213]. Complexes 54-56 are better suitable for the formation of five-membered rings, while complexes 57 are optimized for six-membered ring formation (35) thanks to the extended wingspan of the octahydrofluorenyl ligand. 

The asymmetric hydroamination of internal 1,2-disubstituted alkenes is much less feasible and requires significantly harsher reaction conditions. The formation of pyrrolidines and piperidines often proceeds with comparable rates (Table 13), contrasting the general trend of significant faster five-membered ring formation 

Unfortunately, the chiral lanthanocenes undergo facile epimerization under the conditions of catalytic hydroamination via reversible protolytic cleavage of the metal cyclopentadienyl bond [27, 72, 213, 214] leading to an equilibrium mixture of the two possible diastereomeric complexes. Thus, the enantioselectivity of product formation is limited by the catalyst s epimeric ratio in solution and the absolute configuration of the hydroamination product is independent of the diastereomeric purity of the precatalyst. 

This limitation of chiral cyclopentadienyl-based hydroamination catalysts has stimulated the development of a large number of cyclopentadienyl-free rare earth metal-based catalyst systems [67, 68, 73,121, 122, 215-239]. A detailed discussion of the large number of catalytic systems is beyond the scope of this review and the interested reader should refer to one of the comprehensive reviews on this topic [9-14]. Some prominent catalyst systems are shown in Fig. 15 and a brief survey of catalytic results is listed in Table 14. 

A variety of bisoxazolinato rare earth metal complexes such as 58 have been studied with regard to their hydroamination/cyclization catalytic activity [219]. The precatalysts show similar enantioselectivity and only slightly reduced catalytic activity when prepared in situ from [La N(SiMe3)2 3] and the bisoxazoUne ligand. In this ligand accelerated catalyst system, the highest rates were observed for a 1 1 metal to ligand ratio. 

---

Scheme 2.16 Gold-catalysed intramolecular hydroamination of alkenes...

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... 

Neutral scandium amido complexes have been developed as viable catalysts for intramolecular hydroamination of alkenes, such as MeC H(NH2)CH2CH2CH=CH2. 

An yttrium(III) complex derived from ligand (100) has been shown to be a superior catalyst for enantioselective intramolecular hydroaminations of alkenes that provide cyclic amines with enantioselectivities ranging from 69 to 89% ee,132... 

Reactions of intramolecular hydroamination of alkenes, alkynes, and allenes with the formation of A-heterocycles in the presence of lanthanocene catalysts 02CRV2161. 

The bulk of the studies on intramolecular hydroamination of alkenes catalyzed by lanthanide complexes have been conducted using lanthanocene complexes or half-sandwich lanthanide complexes. The prototypical cyclizations of aminoalkenes to form five- and six-membered rings are shown in Equation 16.61. These reactions occur with exclusive Markovnikov selectivity. These reactions have also been conducted using arylamines, as shown in Equation 16.62. The intramolecular reactions of amines catalyzed by certain lanthanide complexes occur with 1,1- and 1,2-disubstituted olefins (Equation 16.63), although such reactions require high temperatures. 

In contrast to the hydroamination of alkenes with sulfonamides, the potential of an acid-catalyzed reaction pathway in the hydroamination of alkenes with carboxamide derivatives appears less likely. Hartwig found that the intramolecular hydroamination of alkenes with N-arylcarboxamides was only realized in the presence of stoichiometric amounts of triflic add [50]. In contrast, He reported that triflic add catalyzes the intramolecular hydroamination of an N-4-methyl-4-pentenyl carbamate in toluene at 85 °C [55]. However, in the corresponding gold(I)-catalyzed transformation, the intramolecular hydroamination of an N-4-methyl-4-pentenyl carbamate was markedly slower than was the intramolecular hydroamination of an N-4-pentenyl carbamate [52], which is inconsistent with the antidpated behavior of an acid-catalyzed pathway. Furthermore, control experiments firmly ruled out the presence of an acid-catalyzed reaction pathway in the gold(I)-catalyzed intramolecular hydroamination of alkenes with carboxamide derivates and ureas [53, 54]. 

In 2008, the Ackennann group reported on the use of phosphoric acid 3r (10 mol%, R = SiPhj) as a Brpnsted acid catalyst in the unprecedented intramolecular hydroaminations of unfunctionaUzed alkenes alike 144 (Scheme 58) [82], BINOL-derived phosphoric acids with bulky substituents at the 3,3 -positions showed improved catalytic activity compared to less sterically hindered representatives. Remarkably, this is the first example of the activation of simple alkenes by a Brpnsted acid. However, the reaction is limited to geminally disubstituted precursors 144. Their cyclization might be favored due to a Thorpe-Ingold effect. An asymmetric version was attempted by means of chiral BINOL phosphate (R)-3( (20 mol%, R = 3,5-(CF3)2-CgH3), albeit with low enantioselectivity (17% ee). 

Intramolecular hydroamination of cyclohexa-2,5-dienes has afforded the corresponding bicyclic allylic amines with high selectivity (Scheme 13).80 The reaction does not proceed through a direct hydroamination of one of the diastereotopic alkenes but more likely involves a diastereoselective protonation of a pentadienyl anion, followed by addition of a lithium amide across the double bond of the resulting 1,3-diene and a highly regioselective protonation of the final allylic anion. 

A facile intramolecular hydroamination of unactivated alkenes (58), catalysed by the palladium complex (60), has been reported to take place at room temperature. The formation of hydroamination products (59) rather than oxidative amination products is believed to be due to the use of a tridentate ligand, which effectively inhibits -hydride elimination.78... 

Platinum-catalysed intramolecular hydroamination of unactivated alkenes with secondary alkylamines has been reported. Thus, a number of y- and 5-aminoalkenes reacted in the presence of a catalytic 1 2 mixture of [PtCl2(H2C=CH2)]2 (2.5 mol%) and PPh3 in dioxane at 120 °C for 16 h to form the corresponding pyrrolidine derivatives in moderate to good yields. The reaction displayed excellent functional group compatibility and low moisture sensitivity.92... 

Intramolecular hydroamination of amino alkenes.1 This lanthanide effects cy-clization of amino alkenes in hydrocarbon solvents to five- and six-membered nitrogen heterocycles. 

Group 4 bis(amidate)bis(amido) complexes have also been identified as precatalysts for the more challenging hydroamination of alkenes. The majority of investigations in this field focus on the intramolecular cychzation of aminoalkenes with zirconium-based catalysts. [64e] Neutral group 4 bis(amidate) zirconium amido or imido complexes are efficient precatalysts for the intramolecular cychzation of primary amines to form pyrrolidine and piperidine products (Scheme 12). The monomeric imido complex can be generated by reaction of the bis(amido) complex with 2,6-dimethylaniline and trapped with triphenylphosphine oxide. [64e] The bis(amido) and imido complexes... 

Ytrium amido complexes generated in situ from chiral iV-benzyl-like-substituted binaphthyldiamines and [(THF)4Li][Y(CH2SiMe3]4 (both at 6-12 mol% loading) have been shown to catalyse the enantioselective intramolecular hydroamination of primary amines tethered to an alkene moiety (e.g. H2NCH2C(Me)2CH2CR=CR ) at 40-110 °C. Aminoalkenes bearing 1,2-dialkyl-substituted C=C bonds (R = H, R = Me) afforded the corresponding pyrrolidines with <77% ee, whereas trisubstituted alkenes (R = R = Me) were cyclized with only <55% eeP ... 

Some of the most active catalysts for the hydroamination of alkynes are based on lanthanides and actinides. The turnover frequencies for the additions are higher than those for lanthanide-catalyzed additions to alkenes by one or two orders of magnitude. Thus, intermolecular addition occurs with acceptable rates. Examples of both intermolecular and intramolecular reactions have been reported (Equations 16.87 and 16.88). Tandem processes initiated by hydroamination have also been reported. As shown in Equation 16.89, intramolecular hydroamination of an alk5me, followed by cyclization with the remaining olefin, generates a pyrrolizidine skeleton. Hydroaminations of aminoalkynes have also been conducted with the metallocenes of the actinides uranium and thorium. - These hydroaminations catalyzed by lanthanide and actinide complexes occur by insertion of the alkyne into a metal-amido intermediate. 

Bender and Widenhoefer have reported the room temperature intramolecular hydroamination of unactivated alkenes with N,N -disubstituted ureas catalyzed by a gold(I) N-heterocyclic carbene complex [54], For example, treatment of 2-isopropyl-4-pentenyl urea 78 with a catalytic 1 1 mixture of (IPr)AuCl and AgOTf at room temperature for 22 h led to isolation of pyrroldine 79 in 98% yield as a 5.5 1 mixture of diastereomers (Eq. (11.45)). Gold(I)carbon atoms and was effective for the cycHzation of unsubstituted 4-pentenyl ureas and 5-hexenyl ureas. Conversely, the method did not tolerate substitution at the terminal alkenyl carbon atom. 

A simple Pt-catalyzed protocol has been developed by Widenhoefer and coworkers [230] that uses 2.5 mol% [PtCl2(H2C=CH2)]2 and 5 mol% PPhj for the intramolecular hydroamination of secondary amines (Scheme 15.49). This robust catalyst system can accommodate some functionality (e.g., silyl ethers, hahdes, nitriles, and esters) and unactivated terminal alkenes show good reactivity to give five- and... 

Neutral group 4 metal complexes appear to possess a relatively broad scope for catalytic hydroaminations. They have been employed for the intramolecular as well as the intermolecular hydroaminations of alkenes, alkynes, and allenes. Catalytic hydroaminations (and hydrohydrazinations) of alkynes have been exploited as key steps in catalytic multicomponent reactions, giving rise to highly functionalized substrates, in particular to several types of N-heterocycles. Chapter 13 by Gade focuses, inter alia, on two case histories involving hydrohydrazinations which exemplify key challenges and the way they may be addressed in practice. 

In the hydroamination of unsaturated carbon-carbon bonds, gold catalysts play an important role. Intermolecular hydroamination of alkenes [177], 1,3-dienes [204], terminal and internal alkynes [205], and allenes [206] are known to proceed smoothly in the presence of PhsP AufI) or AuCls catalyst. In addition, amino olefins also efficiently undergo intramolecular hydroamination using similar gold catalysts. He and coworkers have developed the catalytic cycloaddition of tosylated amino olefins [207], A representative example is shown in Scheme 18.35. When N-tosylated y-amino olefin (97) is exposed to a mixture of PhsP AuCl and AgOTf (5 mol% each) in toluene at 85 °C, pyrrolidine (98) is obtained in 96% yield. The gold(I)-catalyzed intramolecular hydroamination is applicable to N-alkenyl carbamates [208], N-alkenyl carboxamides [209], and N-alkenyl ureas [210], The use of microwave irradiation results in completing the hydroamination in a much shorter time than that required under thermal reaction conditions [211], The... 

Hydroamination of 7i-bonds is one of the most straightforward methods for the construction of C N bonds and, as such, has attracted a lot of attention. NHC- Au catalysts, in line with results obtained in hydration and hydroalkoxylation reactions (vide supra), proved highly efficient in this field and the inter-and intramolecular hydroamination of various alkenes," allenes," and alkynes" were reported with a number of NHC- Au complexes. Among these reports, Widenhoefer published an elegant bis-hydroamination of allenes, leading... 

ACu-Xantphos system [Cu(0-t-Bu)-Xantphos, 10-15 mol%]-catalyzedsynthesis of pyrrolidine and piperidine derivatives was reported. Some pyrrolidine and piperidine derivatives could be obtained in excellent yields in alcoholic solvents via intramolecular hydroamination of unactivated terminal alkenes bearing an unprotected aminoalkyl substituent. Both primary and secondary amines with... 

The hydroamination of alkenes and alkynes provides a highly atom-economical method for the preparation of substituted amines and imines. Despite substantial efforts and recent progress, the development of a generally applicable functional group-tolerant catalyst for this reaction remains a challenge, and intense research continues in this field. An interesting example has been reported by means of Rh combined with a bidentate NHC ligand [eqn (8.14)]. Complex 32 was found to catalyse the intramolecular hydroamination of aminoalkynes. However, the turnover rates remained modest with values up to 50 h ... 

Shen X, Buchwald SL. Rhodium-catalyzed asymmetric intramolecular hydroamination of unactivated alkenes. Angew. Chem. Int. Ed. 2010 49(3) 564—567. 

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 alkenes, as exemplified by the reaction of n-PrNH2 with 1-pentene catalyzed by a neodymium complex (Eq. 4.17) [127]. 

A DFT computational study suggests that (63), a frustrated Lewis pair (FLP), could catalyse the intramolecular hydroaminations of nonactivated amino alkenes, such... 

Scheme 1 The catalytic hydroamination of alkenes (a), alkynes (b), allenes (c), and dienes (d) leads to amines, imines, and enamines. The reactirais may also be performed in an intramolecular fashion (not shown)...

---