Amine nucleophiles regioselectivity

Nucleophilic substitution of thiophene can also be enabled by the presence of electron withdrawing groups (e.g., -CHO <00SC1359>, -COMe <00T7573>, -NO2 <00JCS(P1)1811>) on carbon. The regioselectivity of the addition of amine nucleophiles onto 3,5-dibromothiophene-2-carboxaldehyde (54) has been studied and found to be independent of reaction conditions (para product 55 favored over ortho product 56) <00SL459>. 

Nucleophilic additions of amines to acceptor-substituted dienes were examined as early as 1950. Frankel and coworkers98 found that the reaction of 2,4-pentadienenitrile with various secondary amines proceeded regioselectively to furnish the 1,6-addition products (equation 29). In some cases, these could converted into the 2,4-diamino-substituted pen-tanenitriles by isomerization and 1,4-addition of a second molecule of amine. Analogous results were reported by other groups17,99 100 and extended to hydrazine as nucleophile101 and to vinylcyclobutenones48 and dienoates102-104 as Michael acceptors. 

Amine nucleophiles appear generally to add by attack at the allyl ligand. Similar to oxygen nucleophiles, however, a caveat must be noted in evaluating the observed regioselectivities in that the allyl amine products are capable of rearrangement by reentry into the ir-allyl manifold. 

A new phosphoramidite ligand (1 Y = OMe), gives high enantioselectivities (92-99% ee) and regioselectivities (99% S 2 ) in iridium-catalysed allylic substitution reactions of carbonates and acetates with carbanion or primary amine nucleophiles.6 The new ligand also leads to a faster rate of reaction than other phosphoramidite ligands. 

In the palladium-catalyzed allylic amination reaction, primary and secondary amines can be used as nucleophiles, whereas ammonia does not react. Therefore, many ammonia synthons have been developed, and a variety of protected primary allyl amines can now be prepared using azide, sulphonamide, phthalimide, di-f-butyl iminocarbonate ((Boc)2NLi), and dialkyl A-(rerr-butoxycarbonyl)phosphoramide anions as the nucleophile [20], An example of the use of ((Boc)2NLi) 30 as the amine nucleophile in the palladium-catalyzed allylic amination reaction is shown in Eq. (9). This reaction also illustrates the problem with the regioselectivity in the reaction as a mixture of the products 31-33 are obtained [21]. 

Preparation of aliphatic amines by direct hydroamination of alkenes with amines is a highly desirable reaction. However, except for the well-established hydroamination of 1,3-dienes via 7r-allylpalladiums, no smooth hydroamination of simple alkenes is known. As a breakthrough, Kawatsura and Hartwig reported that the hydroamination of styrene derivatives with aniline is catalyzed by Pd(TFA)2 and DPPF in the presence of trifluoroacetic acid (TFA) or triflic acid as a cocatalyst to afford the branched amine 24 regioselectively in 99 % yield. Formation of the branched amine 24 offers an opportunity of asymmetric amination. They obtained the (5)-amine 25 in 80 % yield with 81 % ee using (/ )-BINAP as a chiral ligand [14]. The reaction is explained by insertion of styrene to the H-Pd bond and nucleophilic attack of amine on an fj -benzylpalladium complex [15]. Hii and coworkers obtained the amine 24 with 70 % ee in 75 % yield using the dicationic Pd complex, [Pd(MeCN)(H20)(/ -BINAP)](0Tf)2 [16]. 

Studies on the origin of die regioselectivity of these reactions revealed that attack by amines occurred at the more-substituted position, but isomerization of the kinetic branched product to the thermodynamic linear product occurred faster than the catalytic process. As a result, the linear isomer was observed as the final reaction product. However, isomerization of the products formed by reactions of aziridines, hydroxylamines, and hydrazone deriviatives was slower than the catalytic substitution process, and these different relative rates allowed isolation of the branched substitution products. The isomerization process presumably occurs by protonation of the amine to form an ammonium salt that undergoes oxidative addition to palladium, as was observed in the initial allyUc substitution processes that involved allylic ammonium salts as electrophile. Thus, addition of a strong, non-nucleophihc base to the reactions of amine nucleophiles allowed isolation of the branched kinetic product. ... 

No matter which amine nucleophile was used, the major reaction product was a 5-aminated thiophene in yields of 28 6%, contaminated with a minor product. Double substitution was not observed. Changing the solvent (water, DMF, benzene), reagents ratio and concentration or the reaction temperature (50, 85 and 110°C) did not affect the regioselectivity of the reaction (Table 3) [177]. 

Addition of amines and phosphines to acyclic (ry -pentadienyOiron cations is reversible in some cases. In a representative example (Scheme 4), kinetically controlled nucleophilic attack by phosphine occurs on the more abundant cisoid cation to generate an ,Z-diene 47. Since significant steric interactions exist between the phosphine nucleophile and substituents present on the pentadienyl ligand, nucleophilic attack in this case is reversible. At higher temperatures and longer reaction times, the thermodynamically more stable , -diene 48 is formed via nucleopilic attack on the less abundant transoid form of the (ry -pentadienyOiron cation. Amine nucleophiles add regioselectively to the unsubstituted terminus of the (ry -pentadienyOiron cation. 

Chlorohydrin 61 is formed by the nucleophilic addition to ethylene with PdCl2 and CuCl2[103,104]. Regioselective chlorohydroxylation of the allylic amine 62 is possible by the participation of the heteroatom to give chlorohydrin 63. Allylic sulfides behave similarly[105]. 

Also, the observed highly regioselective course in the SnFI substitutions in 2-R-3-nitro-l, 8-naphthyridines (R = FI, OFI, Cl, NFI2, OEt) with the anion of chloromethyl phenyl sulfone was explained by MNDO quantum-chemical calculations showing that, like in the aminations, the interaction of FIOMO of the nucleophile with LUMO of the nitronaphthyridines controls the regioselectivity (91JFIC1075). 

Enantioselectivity (which is hnked to the regioselectivity of the attack of the nucleophile to the coordinated allyl) in the allylic amination of 1,3-diphenyl-allyl ethyl carbonate was also very low compared to the P-N system. This was attributed to the comparable fran -influence of P and NHC functionalities, leading to poor regioselec-tion of the two aUyl termini trans to the P and NHC ligands by the nucleophile [95],... 

There are a few isolated cases of the addition of amines, thiols, carboxylic acids, and a phosphorus ylide to doubly bonded germanium compounds. Again, the reactions are regioselective, with the nucleophilic portion of the weak acid adding to the germanium and the proton adding to the heteroatom. 

The mercuration of ferrocenylimines with Hg(OAc)2 has been studied. - 6 Mercuration occurs selectively at the a-position relative to the imine group to afford compounds 86a-i (Scheme gy107,108 The regioselectivity of these reactions points to the directing role of the Lewis-basic imine functionality. Similar factors probably play a role in the formation of the ferrocenylketone and ferrocenylaldehyde derivatives 87a-f and 87g-j, respectively. These derivatives readily react with amines to afford the corresponding imines (Scheme 9). Presumably, the Lewis-acidic mercury center of the monomercurated ferrocenylketones and ferrocenylaldehydes activates the carbonyl functionality toward nucleophilic attack by the amine. 

An unusually high regioselectivity was observed by Cook s group in palladium-catalyzed allylic amination of 5-vinyloxazolidinone 10 (Scheme 2).5 An imide-type nucleophile was directed to the internal carbon, whereas... 

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