Piperidines, hydroamination

To this end, a titanium bis(2-pyridonate) complex (17) has been developed. [22c] These catalytic systems promote catalyst-controlled selectivity for hydroaminoalkylation over hydroamination and for the first time amine-substituted cyclopentanes can be prepared preferentially over piperidine hydroamination products (Scheme 25). 

The pincer complexes 89-90 (Fig. 2.14) catalyse the intramolecular hydroamination/ cyclisation of unactivated alkenes, yielding pyrrolidines and piperidines (n = 1,2, respectively). The reactions can be carried out in benzene or water with high... 

Hydroamination of activated alkenes has been reported with complexes 91-93 (Fig. 2.15). For example, 91 catalyses the hydroamination of methacrylonitrile (X = CN in Scheme 2.13) by a range of secondary amines (morpholine, thiomorpholine, piperidine, iV-methylpiperazine or aniline) in good to excellent conversions (67-99%) and anfi-Markovnikov regioselectivity (5 mol%, -80°C or rt, 24-72 h). Low enantioselectivies were induced ee 30-50%) depending on the amine used and the reaction temperature [79]. 

Complexes 92 and 93 also show good activity for the hydroamination of methacrylonitrile with morpholine, piperidine or A -methylpiperazine (70-93% conversion at 2.5 mol%, 90°C in 24 h) [80]. 

This reaction is restricted to ethylene and to secondary amines of high basicity (nude-ophUicity) and low steric bulk (Me2NH, pyrrolidine, piperidine). No high molecular weight products are formed. However, the same catalysts [107,108] as well as PdQj [108] also exhibit some activity for the hydroamination of ethylene with PhNH2 (Eq. 4.9). 

Study of the mechanism of the rhodium-catalyzed hydroamination of ethylene with secondary amines indicated that the piperidine complex trans-RhCl(C2H4)(piperidine)2 can serve as a catalyst precursor [109, 110]. 

It was elegantly shown later that the hydroamination of ethylene with piperidine or Et2NH can be greatly improved using cationic rhodium complexes at room temperature and atmospheric pressure to afford a high yield of hydroaminated products (Eq. 4.10) [111]. However, possible deactivation of the catalyst can be questioned [17]. 

Using the above preformed catalysts, ethylene can be hydroaminated by primary and secondary amines under much lower pressures (3-55 atm) than those required for the reactions catalyzed by alkali metals (800-1200 atm). The example of N-ethyl-ation of piperidine has been described in full details in Organic Syntheses (Eq. 4.14) [120]. 

Several other examples (50-60% yields) were provided, including hydroamination with primary amines, piperidine, anilines and hexamethylenediamine [197-199]. The special case of aziridine was reported to afford a mixture of isomers in a good yield [200]. 

If the more activated alkene 2-vinylpyridine is used in place of styrene with the same catalysts and the same range of substrates, anti-Markovnikoff hydroamination is also found. Thus, N-[2-(2 -pyridyl)ethyl]piperidine was isolated in 53% yield from reaction of 2-vinylpyridine with piperidine in the presence of [Rh(COD)2]+/2PPh3 under reflux. N H addition was observed with other amines, the remaining product in all cases being primarily that from oxidative amination (Table 12). When the catalytic reaction was run in the absence of phosphine, the yield of hydroamination product increased dramatically.171... 

Hydroamination of olefins has received considerable attention this year as a route to functionalized piperidines and spiropiperidines, particularly in regard to the investigation of new catalysts. In the synthesis of spiro-piperidines, two new mild and more general intramolecular hydroamination protocols were developed this year. One protocol uses a cationic gold-phosphine complex (Au[P(fBu)2(o-biphenyl)]Cl) as the catalyst... 

The utility of a new lanthanide catalyst 162 for hydroamination and hydrosilylation is highlighted below<06CC874>. Application of this new lanthanide catalyst resulted in excellent yields of piperidines such as 163 and 164 with reduced reaction times. 

Hydroamination of olefins under most catalytic conditions proceed with Markovnikov addition of the N-H bond across the olefin. Shown below is a rhodium-catalyzed intramolecular, anti-Markovnikov, hydroamination developed for the synthesis of 3-arylpiperidines 167 <06JA6042>. Further evaluation of this reaction as a synthesis of multisubstituted piperidines revealed that substrates with substituents a or y to the amino group did not produce the expected piperidine, however, substrates with a substituent (1 to the amino group produce piperidines in high yield. 

An interesting example of a gold-catalyzed cycloisomerization of P-aminoallene 168 to tetrahydropyridine 169 is depicted below <06OL4485>. Patil et al. report a similar gold-catalized hydroamination of allenes to produce 2-vinyl piperidine 170 in good yield <06TL4749>. 

In the presence of oxygen the hydroamination products can not be obtained. Instead - especially with secondary amines or diamines - dehydrogenated di- and polyadducts are formed [79]. By reaction of morpholine or piperidine in air-saturated benzene solution the bisadduct, tetraadduct epoxide and the dimer shown in Figure 3.8 could be isolated and characterized. A defined 1,4-addition pattern is found in all these products. 

The products from alkene hydroamination are inherently lightly functionalized. To address this possible deficiency. Professor Marks also reported (J. Am. Chem. Soc. 125 15878, 2003) the cyclization of amino dienes such as 5. The cyclizations proceed with high selectivity for, the cis-2,6-dialkyl piperidines, and with a little lower selectivity for the trans 2,5-dialkyl pyrrolidine. The product alkenes are -95% E, the balance being a little Z alkene and the terminal alkene. 

Several neutral titanium complexes have been shown to catalyse intramolecular hydroamination reactions of alkenes. The corresponding pyrrolidine and piperidine products were formed in up to 97% yields. However, only the geminally disubstituted aminoalkenes were successfully cyclized (Thorpe-Ingold effect).56... 

Intramolecular hydroamination of aminoalkenes CH2=CH(CH2) CH2NH2 and the corresponding alkynes can be catalysed by the calcium /9-diketiminato complex [ HC (C(Me)2N-2,6-Pr2C6H3)2 Ca N(SiMe3)2 (THF)] to produce the corresponding pyrrolidines and piperidines.71... 

Quite stable catalytic reaction solutions were obtained in THF with the starting pressure for ethylene of 6-6.5 MPa at a reaction temperature of 120 °C. Under these conditions and with the ratios piperidine/rhodium of 100 1 and 1000 1 in 36 and 72 h, yields of 70 and 50 % ethylpiperidine were reached, which correspond to TONs of 2 and 7 mol amine/(mol Rh) per h, respectively. Total conversion is also possible if the reaction time is prolonged further. As a side reaction, ethylene dimerization to butene was observed. This indicates the formation of a hydrido rhodium(III) complex in the hydroamination reaction, as formulated in Scheme 3, route (b). Hydrido rhodium(III) complexes are known as catalysts for ethylene dimerization [19], and if the reductive elimination of ethylpiperidine from the hydrido-y9-aminoethyl rhodium(III) complex is the rate-limiting step in the catalytic cycle of hydroamination, a competitive catalysis of the ethylene dimerization seems possible. In the context of these mechanistic considerations, an increase of the catalytic activity for hydroamination requires as much facilitation of the reductive elimination step as possible. 

Complexes 213 and 203 bearing the same enantiopure binaphthyldiamide ligand were compared for the catalysis of several hydroamination reactions with various substrates. The comparison showed differences in activity and/or selectivity in two catalytic systems. The results indicate that different active species are involved. Both complexes produce pyrrolidines and piperidines with moderate to high enantioselectivity and their catalytic activity are comparable [162]. 

Internal 1,1 or 1,2 disubstituted olefins 26 and 28 are much less reactive for hydroamination and require significantly harsher reaction conditions [39, 41 44]. The formation of pyrrolidines and piperidines often proceeds at comparable rates (Eq. 11.7), contrasting the general trend of significantly faster five membered ring formation observed with terminal aminoalkenes [39]. Despite these harsh reaction conditions, moderate enantioselectivities of up to 58% ee at 100 "C (up to 68% at 60 °C) were observed. 

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... 

In the first total synthesis of pseudodistomin D 261, the 1,2-diamine 262 of known absolute configuration was prepared and cychzed to 263 by sequential hydroamination and in situ imiue reduction. The absence of any pyrrolidine product formation was rationalized mechanistically (Scheme 79) <05OL823>. A high-yield intramolecular hydroamination protocol has been developed for sulfonyl-protected primary aminoalkynes and application to piperidine synthesis... 

We found that the intramolecular hydroamination of the aminoallenes 220 took place in the presence of catalytic amounts of palladium, phosphine, and acetic acid to give the 2-alkenylpyrrolidine and -piperidine 221 in good to high yields (Scheme 71).142 The reaction proceeds through formation of hydri-dopalladium species by the oxidative addition of an N—H bond to palladium(O) and subsequent hydro-palladation of the allene moiety, as mentioned in Scheme 70, type b. 

From [(cod)IrCl]2 the pincer complex 1 is prepared. It is stable to air and water, and shows catalytic activity for hydroamination (e.g., to form pyrrolidine and piperidine derivatives). ... 

Higher levels of chiral induction were achieved with (/ )-xylyl-BINAP(Au-/i-nitrobenzoate)2 or (/ )-ClMeOBIPHEP(Au-p-nitrobenzoate)2 as catalyst (Scheme 4-63). These allow the smooth formation of chiral pyrrolidines or piperidines with up to 99% ee and high chemical yield from the corresponding trisubstituted tosyl-protected y- or 5-aminoallene. Gold catalysts with a chiral counterion can also be employed for the highly enantioselective intramolecular exo-hydroamination of aminoallenes. ... 

Widenhoefer and coworkers have reported that the gold(I) phosphine complex [P(t-Bu)2(o-biphenyl)]AuCl is a highly active and selective precatalyst for the intramolecular exo-hydroamination of N-y- and 8-allenyl carbamates [37]. As an example, treatment of the N-6-allenyl carbamate 48 with a catalytic 1 1 mixture of [P(t-Bu)20-biphenyl]AuCl and AgOTf (5mol%) in dioxane at room temperature for 22 h led to isolation of piperidine 49 in 92% yield as a 7.0 1 mixture of cis trans diasteromers (Eq. (11.26)). Gold(I)-catalyzed hydroamination of N-y- and 8-allenyl carbamates tolerated substitution at both the internal and terminal allenyl carbon atoms and the transformation displayed modest selectivity for the transfer of chirality... 

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