Amidoalkylation

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

The base-catalyzed reacdon of nitromethane with ct-amidoalkyl sulfones gives the nitto compounds as in Eq 4 117 the nitromethyl group is converted into a carboxylic group to give ct-amino acids by the Nef reacdon using KMnO. ... 

The reaction of A-acyliminium ions with nucleophilic carbon atoms (also called cationic x-amidoalkylation) is a highly useful method for the synthesis of both nitrogen heterocycles and open-chain nitrogen compounds. A variety of carbon nucleophiles can be used, such as aromatic compounds, alkcncs, alkyncs, carbcnoids, and carbanions derived from active methylene compounds and organometallics. 

The a-amidoalkylation reaction usually occurs according to the following scheme. 

If the AM 1 -hydroxyalkyl)amide is not stable enough for isolation it is still possible to perform the amidoalkylation in a one-pot reaction. Thus the amide and the carbonyl compound (or the oxoamide) are treated with an acid catalyst in the presence of the carbon nucleophile, so that the equilibrium amount of the (hydroxyalkyl)amide is converted in situ into the /V-acyliminium ion, which is subsequently attacked by the nucleophile. This principle is often applied in the total synthesis of alkaloids -8. 

If R2 contains an a-hydrogen the method cannot be applied as enaminc formation occurs. Bisamides (or -carbamates) are often used in amidoalkylations of aryl and reactive methylene compounds, but the rather harsh reaction conditions severely limit application in the synthesis of more complicated molecules with other functional groups. 

Dialkylaminomethyl)amides are poor amidoalkylating agents. Depending on the size of the substituents, treatment with an acid or an acyl chloride often gives rise to an aminometh-ylating agent113. 

Very recently a number of intermolecular a-amidoalkylation reactions related to the formation of C-C bonds with simple diastereoselection have been reported only activated 7t-nucle-ophiles, such as allylsilanes, enamines, enol ethers, etc. are used83 - 88. 

The amidoalkylation of certain allylsilanes with a glycine cation equivalent shows low stereoselectivity 84. 

The stereoselectivity is higher, however, in the amidoalkylation of the allylsilane 4 only one isomer, of unknown configuration, is observed85. 

The diastereomeric ratio of the trimethylsilyl triflate catalyzed amidoalkylation of a number of silyl enol ethers at — 40 CC appears to be dependent on the substituents in the substrate87. At — 40 °C the diastereomeric ratio is shown to be kinetically controlled. On allowing the reaction mixture to warm to 20 "C slow epimerization, increasing the amount of the minor isomer, is observed. In the case of the naphthalene derivative, sodium methoxide catalyzed epimerization of the kinetic mixture [(antijsyn) 88 12] produces the thermodynamic mixture [(antijsyn) 9 91]. 

In the intramolecular amidoalkylation of certain (Z)-allylsilanes, piperidine derivatives (n = 2) are formed less stereoselectively than the corresponding pyrrolidines (n = 1). The complete regiocontrol is induced by the /3-effect of the silicon atom. 

Amidoalkylation of silyl enol ethers with /V-acyliiiiiiiium ions containing camphanoyl-derived acyl functions (see Appendix) as the chiral auxiliary leads to optically active 2-substituted piperidine derivatives with moderate to high diastereoselectivity, depending on the chiral auxiliary and the cnol ether82 99. The auxiliary is removed by hydrolysis with base or acid. 

Substituted Piperidine Derivatives by Amidoalkylation of Silyl I nnl Ethers General Procedure82 ... 

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

Azacanthines, 374, like their deaza analogues (cf. Equation 128), can be prepared by inverse electron demand aza-Diels-Alder reactions of the appropriately tethered amidoalkyl-l,2,4-triazinylindoles 373 (Equation 135) <1995TL6591>. The sulfonyl-substituted derivatives 375 can be prepared similarly in high yield, although the conditions for each individual reaction are important, since an appreciable amount of the desulfonated product 376 may also be formed (Equation 136) <1998TL2487>. 

Aliphatic amides possess more strong a-C—H bonds in comparison with amines. This is the result of the carbonyl group influence on the stabilization of the formed a-amidoalkyl radical formed from amide in the reaction with the peroxyl radical. This influence is not so strong as that of the amine group. The values of the a-C—H bond in a few amides were estimated recently by the IPM method [4] and are given here. 

Oleksyszyn, J. and Gruszecka, E., Amidoalkylation of phosphorous acid, Tetrahedron Lett., 3537, 1981. 

Oleksyszyn, J., Synthesis of N-acylated 1-aminoalkyldiphenylphosphine oxides by amidoalkylation of diphenylchlorophosphine, Synthesis, 444, 1981. 

Carboxylic Acid Esters That Incorporate a Carbamoylmethyl, Aminoalkyl, or Amidoalkyl Pro-Moiety... 

In Sect. 7.3 and 7.4, we have emphasized that an amino group in an ester molecule contributes to increased water solubility and may, in some cases, facilitate enzymatic hydrolysis. In the present section, this argument is further illustrated and is extended to esters containing nonbasic nitrogenated pro-moieties, e.g., amidoalkyl or carbamoylalkyl substituents. Substituents liable to undergo fragmentation (i.e., pro-moieties that will break down during hydrolysis) will be discussed separately in Sect. 8.3. 

Examples of amidoalkyl esters are provided by 1 -alkyl- 1-azacycloalkan-... 

In Sect. 8.2.3, we have discussed 1-alkyl-l-azacycloalkan-2-ones (8.32, n = 1 or 2 m = 3, 4, 5 or 6) as a group of amidoalkyl esters, taking prodrugs of indomethacin (8.9, R = OH) and naproxen (8.26) as examples [43a,b]. For both compounds, the prodrugs in the series n = 1 were rapidly hydrolyzed (tm ca. 0.5-1 h in pH 7.4 buffer at 32°). Furthermore, the carbinolamides liberated were not fully stable and broke down by hydrolysis to produce the toxic formaldehyde (Fig. 8.3) [62], Thus, the half-life of decomposition of A-(hydroxymethyl)benzamide (HOCH2-NH-CO-C6H5), a pro-moiety of 8.56 discussed below, was 160 h at pH 7.4 and 37° [69]. This means that a small amount of formaldehyde may be formed in vivo. 

Subsequent development of this general approach was directed to the in situ formation of ions 14 from various precursors. As a result, a series of three-component one-pot syntheses of salts 16 has been created. The reactions of aldehydes with nitriles or amides to form amidoalkyl ions 14 are most applicable (Scheme 2) (70JAP70/24582 71S92 74G1181). The... 

Other amides which have been used for a-amidoalkylation of heteroaromatic bases are iV-methylformamide, ° iV-methylacetamide, N,N-dimethylacetamide, iV -methylpyrrolidone, iV -cyclohexylaceta-mide, iV-acetylpiperidine, W,.Ar-dimethylurea, and caprolactam. ... 

The synthetic interest in direct substitution of protonated heteroaromatic bases by carbamoyl and a-amidoalkyl radicals arises because the reaction is applicable to a variety of heteroaromatic bases having highly reactive nucleophilic positions and because a variety of amides can be used. The selectivity of attack is complete at the a- and y-positions of the heterocyclic system owing to the nucleophilic character of both carbamoyl and a-amidoalkyl radicals, The results with formamide are shown in Table VI. Quinoline with dimethylformamide gave a variety... 

The most versatile method for the preparation of m-hexahydro-1,3-benzoxazines and the related cycloalkane e -fused dihydrooxazines is amidoalkylation via 1,4-polar cycloaddition of the amidomethyl ion 172 to a cycloalkene. The addition is stereospecifically cis, and in accordance with the Markownikov rule is generally regiospecific. 

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