Primary amines allylic amine synthesis

Hydroxylysine (328) was synthesized by chemoselective reaction of (Z)-4-acet-oxy-2-butenyl methyl carbonate (325) with two different nucleophiles first with At,(9-Boc-protected hydroxylamine (326) under neutral conditions and then with methyl (diphenylmethyleneamino)acetate (327) in the presence of BSA[202]. The primary allylic amine 331 is prepared by the highly selective monoallylation of 4,4 -dimethoxybenzhydrylamine (329). Deprotection of the allylated secondary amine 330 with 80% formic acid affords the primary ally-lamine 331. The reaction was applied to the total synthesis of gabaculine 332(203]. 

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]. 

Fttrstner has employed the Trost pyrrole synthesis in the first total synthesis of roseophilin, wherein this A-benzylpyrrole-ring forming step occurred in 70% yield [23]. Backvall has found that primary amines react with dienes under the guidance of Pd(II) to form pyrroles 170 in variable yields [121]. The intermediate Jt-allyl-palladium complexes are quite stable. 

An efficient primary amine synthesis via iV-diisobutylaluminium imines has been described. A cyanide R CN (R1 = Bu, CsHn, Ph, 2-furyl or 2-thienyl) is treated with diisobutylaluminium hydride and the product is converted into the amine by reaction with an organomagnesium or organolithium compound R2M (R2 = Bu, t-Bu, allyl or benzyl)... 

For the synthesis of primary allylic amines, an allyl acetate, e.g. 175, is treated with the benzhydrylamine 176 (Ar = d-MeOCgFLt) in the presence of a catalytic amount of (Ph3P)4Pd and the product 177 is cleaved to the amine 178 with 88% formic acid186. 

A diverse group of secondary and tertiary amines are readily synthesized from the reaction of primary and secondary amines with allylic carbonates in the presence of preformed iridium metalacycles, but the direct synthesis of primary amines via iridium-catalyzed allylic amination requires the use of ammonia as a nucleophile. The asymmetric allylation of ammonia had not been reported until very recently, and it is not a common reagent in other metal-catalyzed reactions. Nonetheless, Hartwig and coworkers developed the reactions of ammonia with allylic carbonates in the presence of la generated in situ [89]. Reactions conducted in the initial work led exclusively to the products from diallylation (Scheme 16). Further advances in... 

The use of ethylene adduct lb is particularly important when the species added to activate catalyst la is incompatible with one of the reaction components. Iridium-catalyzed monoallylation of ammonia requires high concentrations of ammonia, but these conditions are not compatible with the additive [Ir(COD)Cl]2 because this complex reacts with ammonia [102]. Thus, a reaction between ammonia and ethyl ciimamyl carbonate catalyzed by ethylene adduct lb produces the monoallylation product in higher yield than the same reaction catalyzed by la and [Ir(COD)Cl]2 (Scheme 27). Ammonia reacts with a range of allylic carbonates in the presence of lb to form branched primary allylic amines in good yield and high enantioselectivity (Scheme 28). Quenching these reactions with acyl chlorides or anhydrides leads to a one-pot synthesis of branched allylic amides that are not yet directly accessible by metal-catalyzed allylation of amides. 

R.B. Cheikh, R. Chaahouni, A, Laurent, P. Mison u. A. Nafti, Synthesis 1983, 685-698 . .Synthesis of Primary Allylic Amines". 

This intermediate, like 6-APA, incorporates a primary amine that can be coupled with a host of side chains. The presence of an additional reactive function, the allylic acetate at the 3 position, provides an additional center that can be modified. The observation that both types of modifications provided unproved antibiotics has resulted in the synthesis of hundreds of analogues. The very few examples discussed below barely scratch the surface in this field. One of the earliest examples of a doubly derivatized 7-ACA derivative, cephalothin (19-1), is stUl widely used as an antibiotic. Acylation of (18-4) with 2-thiophenylacetyl chloride gives the corresponding amide (19-2). Heating that product with pyridine leads to the displacement of the allyl acetate by the basic nitrogen. The resulting product, cephalothin (19-3), is isolated as the internal betaine [23]. 

Boger, D.L. Tetrahedron, (1983), 39, 2869 "Synthesis of Primary Allylic Amines"... 

Primary amines have been transformed into imines which when metallated react with carbonyl compounds. Treatment with butyllithium, alkylation with allyl bromide and hydrolysis gives highly substituted aldehydes (Scheme 6). Thus, in this example, the carbon adjacent to the original amino nitrogen atom becomes the carbonyl carbon. The technique has been used several times in the course of total synthesis, as with a recent approach to crinine and as the key step in a recent highly regioselective preparation of a,3 unsaturated aldehydes (equation 33). ... 

Primary allylic amines. Unlike the benzyl group, the 4,4 -dimethoxybenz-hydryl (DMB) group is removed by mild acid treatment. Because of this property, it was chosen as the protecting group in a recent synthesis of primary allylic amines by Trost and Keinan. A typical example is shown in equation (I). Treatment of an allylic acetate (2) with 1 in the presence of tetrakis(triphenylphosphine)palladium(0) results in the (E)-allylic amine 3 in 81% yield. The protecting group is removed readily to give 4 in 82% yield. 

In a similar way, 2-oxazolidinones and tetrahydro-2//-l, 3-oxazin-2-ones have been prepared by the reaction of primary allyl amines and homoallyl amines10, respectively, with carbon dioxide and iodine in methanol via an intramolecular cyclization. Prolonged reaction for a week in the presence of cesium carbonate increases the yield to 70-90%. This reaction has a large applicability and the ease of the method makes it useful in organic synthesis. 

Whereas ammonia is an unsuitable nucleophile towards 7r-allylpalladium complexes, primary amines often participate well. Benzylamine and 4,4 -dimethoxybenzhydrylamine are especially useful, since subsequent removal of the benzylic substituents permits their use as ammonia equivalents. Such a deblocking procedure was used in a short synthesis of the enzyme inhibitor gabaculine from amino ester 1118. An allyl carbonate can be successfully employed as a substrate for palladium(0)-catalyzed animation to give 1219,20, but experimental difficulties have been experienced with a structurally similar carbonate9. As shown by the formation of 1016 and by the partial production of 13 prior to basic hydrolysis16, additional attack on an ester function may occur. Amino alcohols 13, formed with complete regioselectivity due to steric reasons, have been efficiently converted into isoquinuclidines16. 

A (7] -allyl)ferralactam synthesis using Ee2(CO>9 has been reported by Aumann el a/. <1979CB3644>. Schobert el a/. have also studied the regioselective reactions of (4,6- 7 -pentadienyl)ferralactones 53 with primary amines to afford 3-( o-vinyl)-(4,6-7] -allyl)ferralactams 54 and 6-(-vinyl)-(4,6- -allyl)ferralactams 55 (Equation 7) <2004JOM575>. 

In contrast to the anion of diethyl phosphoramidate or trifluoromethanesulfonamide, which cannot be cleanly monoalkylated, - the anion of trifluoroacetamide (100) was monoalkylated by alkyl halides or alkyl methanesulfonate. The resulting A -alkylamides (101) were converted into primary amines by alkaline hydrolysis or reduction (NuBHa Scheme 42). Various primary amines were prepared from (100) with primary alkyl iodides or methanesulfonate, benzyl and allyl halides, a-bromocarbonyl compounds and 2,4-dinitrochlorobenzene. However, competitive elimination is a serious side reaction for less reactive primary alkyl chlorides and secondary halides or methanesulfonate. The synthesis of secondary amines from (100) has also been reported. ... 

To allow for a diverse multi-step synthesis, we transformed the 3-hydroxy-2-methyl-idene propionic acids (Fig. 6.9) into polymer-bound allylic amines, which can be considered as unusual (3-amino acid derivatives. The polymer-bound allylic alcohols were first treated with acetyl chloride and DIEA in CH2C12 to form the ester, which was reacted with primary amines in an addition elimination step to form allylic amines. 

Several ring-fused tetrazole compounds have been reported. 2-Methyl-3-cyanopyridines were converted into their corresponding 2-azidomethyl derivatives, which underwent intramolecular cycloaddition reactions to give 3-(tetrazol-5-yl)pyridines 186 <04TL9127>. Fused tetrazole derivatives 187 were obtained via tandem cycloaddition and yV-allylation reactions <04JOC1346>. Expeditive synthesis of homochiral fused tetrazole piperazines 188 from 3-amino alcohols has been reported <04TL3725>. A novel Ugi-five-center-four-component reaction (U-5C-4CR) of aldehydes, primary amines, trimethylsilyl azide and 2-isocyanoethyl tosylate afforded tetrazolopiperazine type compounds <04TL6421>. 

Ureas prepared from primary allylic amines slowly decomposed under the conditions listed without providing any cyclized products. Furthermore, the synthesis of amino sugars by the IBX-mediated cyclization protocol was also accomplished. This method was found to be stereoselective. A few examples are listed below ... 

The synthesis can be carried out in a number of ways. A one-pot reaction in ethanol followed by hydrolysis with hydrochloric acid and sodium hydroxide successively gives rise to the primary amines in yields between 67% to 92%. Alternatively, reaction in anhydrous solvents gives the jV,jV-diformylalkylamines 26 which can be hydrolysed as previously, or simply treated with hydrochloric acid to give the corresponding hydrochloride salts. R groups included alkyl chains, allyl, benzyl, bromobenzyl, esters, and ketones. 

Protected allylic amines. The reagent, which has been used in lieu of potassium phthalimide in the synthesis of primary amines, is also active in Pd(0)-catalyzed substitution of allylic acetates. The Boc group of the products can be cleaved by CF3COOH at 0°C, whereas both protecting groups are removed by HCl in benzene. 

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