Intramolecular allylic amination

Intramolecular allylic aminations (Scheme 9.20) proceeded with low catalytic efficiency and with ee-values <90% if procedure (a) (cf. Section 9.2.3.2) was used-that is, the catalyst was not activated [18]. The effect of catalyst activation [procedure (c)] was pronounced [18, 22a] for example, activation with TBD increased the rate of formation of N-benzyl-2-vinylpiperidine by a factor of about 1000. Also notable was the fact that substrate concentration as high as 1M was possible, thereby demonstrating the high preference of intramolecular over intermolecular substitutions leading to oligomers. 

An approach recently developed by Katritzky et al. which also should be mentioned here, is the palladium-catalyzed reaction of IV-alkylbenzotriazoles with amines, leading to an intramolecular allylic amination route to 2-vinylpyrrolidines and 2-vinylpiperidines in good yield under mild conditions [29]. 

The water soluble vitamin (+)-biotin was synthesized by M. Seki and co-workers from L-cysteine in only 11 steps using inexpensive reagents and mild reaction conditions." The key ring forming step was an intramolecular allylic amination Tsuji-Trost reaction using a nitrogen nucleophile) of a cis allylic carbonate. As expected with a soft nucleophile, the allylation took place with an overall retention of configuration. 

Our first approach to 1 is based on a retrosynthetic analysis depicted in Fig (8). The crucial step to construct the cw-fused bicyclic ring skeleton of 1 is the intramolecular allylic amination of a cw-allylic carbonate 25. The paUadium-catalyzed allylation takes place with retention of the configuration [76] and requires the c/s-isomer 25 for the ring closure. Compound 25 may be derived from keto acid 24 through a sequence of reactions including esterification, O-methoxycarbonylation, removal of the Boc and benzylidene groups, dehydrative cyclization, reductive alkylation and ureido formation. The last five transformations are to be conducted in a successive manner, i.e., without isolation of the intermediates. The 4-carboxybutyl chain of 1 may be installed by the reaction of O-trimethylsilyl (TMS) cyanohydrin 23 with a di-Grignard... 

The Ir complex could catalyze the allylic vinylation and the aUylic amination in the same flask (Scheme 5.34) [34]. This result leads to the discovery of an Ir-catalyzed domino allylic vinylation/intramolecular allylic amination of but-2-ene-l,4-diyl dimethyl dicarbonate. 

SCHEME 5.34 Ir-catalyzed cascade allylic vmylation/intramolecular allylic amination. 

When allene derivatives are treated with aryl halides in the presence of Pd(0), the aryl group is introduced to the central carbon by insertion of one of the allenic bonds to form the 7r-allylpalladium intermediate 271, which is attacked further by amine to give the allylic amine 272. A good ligand for the reaction is dppe[182]. Intramolecular reaction of the 7-aminoallene 273 affords the pyrrolidine derivative 274[183]. 

Morpholine also gives the allyhc amine in high yield. The reaction is thought to involve a known hydridopaUadium-catalyzed isomerization of alkynes to aUenes followed by reaction of the latter with the hydridopalladium complex to give 1-phenyl-substituted q -allylpalladium complexes. These complexes react with amines affording the allylic amines. Primary amines give the diallylic amines. An intramolecular version has been developed for the synthesis of 2-(2-phenyl)-pyrroUdines and -piperidines [319]. 

The reductive coupling of of dienes containing amine groups in the backbones allows for the production of alkaloid skeletons in relatively few steps [36,46,47]. Epilupinine 80 was formed in 51% yield after oxidation by treatment of the tertiary amine 81 with PhMeSiEh in the presence of catalytic 70 [46]. Notably, none of the trans isomer was observed in the product mixture (Eq. 11). The Cp fuMcTIIF was found to catalyze cyclization of unsubstituted allyl amine 82 to provide 83. This reaction proceeded in shorter time and with increased yield relative to the same reaction with 70 (Eq. 12) [47]. Substitution of either alkene prevented cyclization, possibly due to competitive intramolecular stabilization of the metal by nitrogen preventing coordination of the substituted olefin, and resulted in hydrosilylation of the less substituted olefin. 

Scheme 9.21 Sequential intermolecular and intramolecular asymmetric allylic aminations.

For Rh(I)/BINAP-catalyzed isomerizations of allylic amines, the mechanistic scheme outlined in Eq. (2) has been proposed. The available data are consistent with the notion that Rh(I)/PF-P(o-Tol)2-catalyzed isomerizations of allylic alcohols follow a related pathway [11]. For example, the only deuterium-containing product of the reaction depicted in Eq. (9) is the l,3-dideuterated aldehyde, which estabhshes that the isomerization involves a clean intramolecular 1,3-migration. The data illustrated in Eqs. (10) and (11) reveal that the catalyst selectively abstracts one of the enantiotopic hydrogens/ deuteriums alpha to the hydroxyl group. 

Additionally, 1,2-dihydroxyethylene dipeptide analogues without the C-terminal carboxylic acid have been used to obtain aspartyl proteases inhibitors.[641 These efforts include stereoselective alkylation of imines, one-pot reductive amination of epoxy ketones, ring opening of epoxides with sodium azide, diastereoselective dihydroxylation of allylic amines, and enzymatic resolution and stereocontrolled intramolecular amidation. 

Ab Initio MO calculations of a model complex Rh(PH3)2(NH3)(CH2=CHCH2NH2) were earned out to shed light to the detailed mechanism of Rh(l)-catalyzed isomerization of allylic amines to enamines.5 This study suggests that the square-planar [RhiPHjyNHjXCf CHCHjNHj) complex is transformed to [Rh(PH3)2(NH3)(( )-CH3CH=CHNH2)]+ via intramolecular oxidative addition of the C(l)-H bond to the Rh(I) center, giving a distorted-octahedral Rh(lll) hydride intermediate, followed by reductive elimination accompanied by allylic transposition. 

Methyl glyoxylate adducts of N-BOC-protected allylic amines 321 have been utilized to construct a new C—O bond by an intramolecular, Pd(II)-catalysed reaction436. In analogy, lactones 324a437 and cyclic ethers 324b438 can be prepared by the Pd(II)-catalysed cyclization of the suitable precursors 322a and 322b, respectively. 

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. 

Intramolecular hydroamination of cyclohexa-2,5-dienes (204) mediated by Bu"Li has been reported to produce the corresponding bicyclic allylic amines (205) with high... 

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]. 

Similar cyclic imines can be synthesized by intramolecular oxidative amination of aminoalkenes, which are less expensive than aminoalkynes. In the presence of catalytic amounts of [RuCl2(CO)3]2/l,3-bis(diphenylphosphino)propane and excess K2C03/allyl acetate, various aminoalkenes 19 possessing substituent(s) f3 to the amino group afforded five- and six-membered cyclic imines 20 in mod-erate-to-excellent yields (Eq. 8) [14]. 

While the syntheses of the acyclic precursors in the examples above each require a couple of steps, symmetrical dienynes with a central triple bond and heteroatoms in the tethers are more easily accessible. They can yield heterotricyclic compounds by the same reaction mode, for example, the diaza- and dioxatricycles 121 are obtained starting from dienynes 119 (Scheme 18) [73]. Yields were best (90%) with N-tosyl linkers, with N-Boc groups the reaction was slower (41% yield), and with N-benzyl linkers only decomposition occurred. This may be due to coordination and blocking of the catalyst by the more Lewis-basic amines. The cis- and frans-diastereomers of 121 were formed in a ratio of 1.8 1, and this ratio did not change in other solvents, at different temperatures, with other catalyst precursors or under high pressure (10 kbar). In view of the apparent influence of the tether, the unsymmetrical oxazaprecursor 122 gave a 7 3 mixture of tricycles 123 and 124. Obviously, the hydridopalladation of the triple bond occurred with some regioselectivity such that intramolecular carbopalladation of the allyl-amine predominated. It is noteworthy that in these cases the intramolecular Diels-Alder reactions of the intermediate trienes 120 already occur under the employed conditions, i.e. at 80 °C. 

---