Arylation of allylamine

The arylation reaction of primary and secondary amines has been investigated using nickel or palladium complexes as catalysts, and bromo- or chloroarenes as arylating agents. Among the complexes tested, the more efficient catalyst is the bis (bipyridyl) nickel (II) bromide, bipy2NiBr2, which affords for example high yields in the arylation of allylamine with /n-bromotrifluoromethylbenzene. The reduction of the haloarene, sometimes observed with the nickel complexes, becomes predominant with palladium catalysts whatever the complex used. 

A preliminary comparison of various nickel compounds as catalysts was made, in the same operating conditions (18h, 160°C in monoglyme), for the arylation of allylamine by m-trifluoromethylbromobenzene (eqn. 2) (Table 1). 

Table 1. Arylation of allylamine by ffi-trifluoromethylbromobenzene, catalyzed by nickel-complexes (eqn. 2).

In the presence of a nickel (0) complex such as Ni(PPh3)4 the arylation of allylamine occurs in a very low yield (5%). With nickel (II) salts or complexes, the yields are higher and the best results are obtained for bipy2NiBr2 (50%) or to a less extent for phen2NiBr2 (30%). It is noteworthy that Cramer and coll. (ref. 7) pointed out, on the contrary, that "diamines which coordinate strongly to nickel (II) interfered in the reaction of dimethylamine with chlorobenzene and reduced by a factor of ten (ethylenediamine) or even inhibit (o-phenantroline) the arylation". 

To the best of our knowledge, it is the first example of the direct arylation of allylamine catalyzed by a nickel complex (ref. 9). 

While aryl halides are the substrates of choice for the neutral Heck arylations of allylamine derivatives, aryl triflates are the most used for the catimiic mode. However, as oxidative addition of Pd(0) to aryl triflates is usually slower than that with aryl bromides and iodides, bidentate ligands are commonly used to increase the stability and nucleophilicity of the Pd(0) catalyst, thus preventing the formation of Pd black (an inactive form of Pd(0)). 

SCHEME 14 Arylation of allylamine derivatives under neutral ctmditions. 

In summary, the stereoselective arylation of allylamine derivatives was accomplished by a substrate-directed Heck-Matsuda strategy. The data we obtained from these studies suggest that the origin for the regiocontrol in favor... 

Enamines RR CHCR CR NR4 (R-R3 = H, alkyl, aryl R4 = H, alkyl, cycloalkyl R5 = alkyl, cycloalkyl NR4R5 = heterocyclic amine) were prepared by isomerization of allylamines RR1C=CR2CHR3NR4R5 in the presence of a cationic Rh complex (RhLL1)+C104 [L = norbornadiene, L1 = R-( + )-BINAP]. 

The involvement of nitrogen-coordinated intermediates has also been proposed with Pd-catalyzed arylations of tertiary allylamines.P Syn /8-elimination of H PdX (which leads to enamides) is hindered by the chelating nitrogen group, provided the reaction is performed in a nonpolar solvent (Scheme 26). The short lifetime of the free hydridopalla-dium species in the presence of base prevents readdition/isomerization. 

Olofsson, K., Sahlin, H., Larhed, M. and Hallberg, A. (2001) Regioselective palladium-catalyzed synthesis of beta-arylated primary allylamine equivalents by an efficient Pd N coordination. J. Org. Chem., 66,544—9. 

Wu, J., Marcoux, J.-R, Davies, I.W. and Reider, P.J. (2001) Beta-regioselective intermolecular Heck arylation of V,V-disubstituted allylamines. Tetrahedron Lett., 42, 159-62. 

The synthesis of allylamines and corresponding a-amino-acids as inhibitors of clinically relevant enzymes has been reported. Seventeen 2-aryl-3-haloallylamine derivatives were prepared and evaluated as potential monoamine oxidase inhibitors, and found to be enzyme-activated irreversible inhibitors whose selectivity for... 

Palladium-catalysed reactions of allylamine derivatives with aryl halides Palladium-catalysed intramolecular aiylative cyclisation reactions of iV-Allylanilines with aryl halides to yield aziridines 44 (Z=Ph) and a similar reaction of iV-Allylacet-amides resulted in the selective formation of 5-benzyl-substituted oxazolines 45 without contamination by the corresponding aziridines 44 (Z=CH3CO) [79-82] (Scheme 12.9). 

Hayashi S, Yorimitsu H, Oshima K (2009) Synthesis of aziridines by palladium-catalyzed reactions of allylamines with aryl and alkenyl halides evidence of a syn-carboamination pathway. Angew Chem 48 7224-7226. doi 10.1002/anie.200903178... 

SCHEME 15 Arylation of N-substituted allylamine under catitmic conditions. 

Our first applications of this new method have allowed the successful regio- and stereoselective arylation of acyclic allylic esters and A -protected allylamine derivatives. As a consequence of the high synthetic value of the arylated products, they were applied in the total synthesis of several bioactive compounds. Starting from allyUc esters, the synthesis of kavalactones such as the yagonine (27), methysticin (28), and dehydromethysticine (29) was accomplished in a straightforward way. Additionally, the y-arylated allylamine derivatives were applied to the total synthesis of the bioactive compounds naftifine (68), abamine (75), abamine SG (77), cinacalcet hydrochloride (85), and alverine (91). 

Pd-catalyzed reaction of allylamines with 2-bromoiodobenzenes 28 could also provide indoles 29 (Scheme 9) [37], This process obviously contains an aryl amination and an intramolecular Heck reaction. The catalytic system of Pdadbas with dppf was proved to be the most efficient for both selectivity and yield. The nitrogen of indole could be further functionalized by in situ iV-arylation. 

Allylic amines are coupled to halides giving either allylic amines or enamines depending on the reaction condition. Reaction of steroidal dienyl triflate with Boc-diprotected allylamine affords allylamine. Use of AcOK as a base is crucial for the clean coupling[102]. The tert-allylic amine 123 reacts with an aryl halide to give the enamine 125 in DMF and allylic amine 124 in nonpolar solvents[103]. 

In 1950, Cope and coworkers48 unsuccessfully attempted to use the well-known Meisenheimer rearrangement of N-allylamine oxides to 0-allylhydroxylamines49 in performing the formally analogous rearrangements of allyl aryl sulfoxides to allyl arenesulfenates and of allyl aryl sulfones to allyl arenesulfinates (equations 11-13). 

OT w-2,6-Diaryl-4-piperidones were produced in a [4+2] cycloaddition reaction using aryl-iV-allylimines and a diene in the presence of Cu(OTf)2 in high yield and de (>99%) (Scheme 87) <2004TL4357>. Reaction of imines with /3,7-unsaturated a-bromoketenes yields dihydro-2-pyridones some of which were reacted with allylamines producing aziridines with 99% de in generally high yield <2004TL5031>. 

The scope aromatic C-N bond formation extends beyond simple amine substrates. For example, selected imines, sulfoximines, hydrazines, lactams, azoles, and carbamates give useful products from intermolecular aromatic C-N bond formation. Intramolecular formation of aryl amides has been reported. In addition, allylamine undergoes arylation, providing a readily cleaved amine alternative to the ammonia surrogates benzylamine, t-butylcarbamate, or benzophenone imine. Although it is an amine substrate, the reaction of this reagent is included here because of its special purpose. 

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