Amines aniline derivatives, synthesis

Recently, the synthesis and evaluation of a new pyrazinone class of tryptase inhibitors has been reported. One step in the preparation of these compounds involved regioselective chloride displacements from a dichloropyrazinone scaffold using amines and anilines as nucleophiles. The aniline reactions required the use of microwave-assisted heating for 12 min at 120 °C, as illustrated in Scheme 23 [84]. Although the aniline-derived compounds (e.g., 50) were modest inhibitors, other compounds from this study, synthesized by classical heating methods, were shown to be highly potent tryptase inhibitors. 

An example illustrating an approach to a set of substituted aminoindoles employed the starting material 209, which could be annulated to the protected indole 210 in a palladium-catalyzed reaction involving allylamine (Equation 67). The application of cyclic secondary amines as well as aniline derivatives also gave excellent results <2003AGE4257>. An indium-mediated synthesis of ( )-3-alkylideneoxindoles by annulation of related A -(2-iodo-phenyl)-ynamides has also been described <2004OL2825>. 

The same differential behavior can be observed with amine nucleophiles. For example, calcium triflate promotes the aminolysis of propene oxide 84 with benzylamine to give 1-(A -benzyl)amino-2-propanol 85, the result of attack at the less substituted site <03T2435>, and which is also seen in the solventless reaction of epoxides with heterocyclic amines under the catalysis of ytterbium(III) triflate <03SC2989>. Conversely, zinc chloride directs the attack of aniline on styrene oxide 34 at the more substituted carbon center <03TL6026>. A ruthenium catalyst in the presence of tin chloride also results in an SNl-type substitution behavior with aniline derivatives (e.g., 88), but further provides for subsequent cyclization of the intermediate amino alcohol, thus representing an interesting synthesis of 2-substituted indoles (e.g., 89) <03TL2975>. 

An efficient synthesis of the strychnos alkaloid skeleton was also achieved using this novel cascade process. The key transformation in this sequence occurs by heating bicyclic amine 225 with formaldehyde and CSA in CH3CN to give 226 as a single diastereomer in 88% yield (Scheme 41) (91JA5085). Hydrolysis of the amide and subsequent condensation of the ketone with the aniline derivative provided dehydrotubifoline (227). 

As mentioned above, nitro compounds are obviously of great importance in organic chemistry and aryl nitro compounds are an important source of aniline derivatives (secs. 4.2.C.V, 4.8.D). Both amine oxides and nitrones have been synthetically exploited. Alkyl nitroso derivatives, however, usually cannot be isolated since they decompose in solution, although the aromatic derivatives are more stable in solution and can be used in synthesis (sec. 2.1 l.E). Treatment of a primary amine with excess peroxyacid is a useful preparative route to alkyl nitro compounds.588 Yields are highest for tertiary alkyl primary amines next come secondary, followed by primary alkyl. Peroxyacid oxidation of oximes also provides a route to alkyl nitro compounds.589 This method is convenient for preparing aromatic nitro compounds as in the oxidation of 2,6-dichloroaniline to 2,6-dichloronitrobenzene (441).590 Nitrones are 1,3-dipoles and have been used in 1,3-dipolar cycloaddition reactions (sec. ll.ll.D). 

The benzyl protection group can be applied to primary amines. In the Romero et al. synthesis of HIV-1 (human immunodeficiency virus) protease inhibitors, the aniline unit in 128 was treated with excess benzyl bromide to give the V,V-dibenzyl derivative 129 in 89% yield.The alkyl fragment was elaborated in six steps to give 130. Catalytic hydrogenation with a palladium on carbon catalyst removed both benzyl groups to give aniline derivative 131 in 90% yield. 

Water-immiscible amines are highly selective in the differentiation between acids (selectivity of about 10 for HCI/H3PO4 separation [44] compared to <2 in extraction by alkanols) and between them and their salts. They are widely used in extraction of metals (their anionic complexes) and of carboxylic acids, but most of them are too strongly basic for mineral acids. The convex distribution curve shows that extraction is very efficient, but back-extraction in free acid form would require huge amounts of water, resulting in extremely dilute, useless back-extracts. Only the very weak amines—highly branched trialkyl amines [52,53] or amines with at least one aryl group—combine efficient extraction with reversibility. Only few such water-immiscible aniline derivates and sterically hindered amines are currently produced on an industrial scale. Adjustment of their properties to treat a variety of feeds would require laborious synthesis. 

We attempted the synthesis of 1,2-dihydropyridines from propargyl vinyl ethers in an independent study (11JOC2145). In our early experiments, we studied propargyl vinyl ethers 79 with additional alkyl substituents at the vinylic position. The propargyl Claisen rearrangement was effected by catalytic amounts of silver(I) hexafluoroantimonate, and the addition of an amine to the aUenylcarbonyl intermediate was expected to provide the 1,2-dihydropyridine product 80. Unfortunately, the major product was, in aU cases, the 2ff-pyran 81, and the desired dihydropyridine 80 was only formed in yields ranging from 10% to 44% when aniline derivatives were employed (Scheme 27).With aliphatic amines, the formation of 1,2-dihydropyridines was not observed. 

From an economical and environmental point of view, one pot synthesis of amines from alkenes is a superior pathway over conventional multistep pathways. Hydroaminomethylation is an attractive tool for the synthesis of amines and has been used in the pharmaceutical and chanical industries. Blum developed a heterogeneous system based on [Rh(cod)Cl]2 immobilized within a sol-gel matrix as a highly efficient, regioselective, and recyclable catalyst for hydroaminomethylation reaction of vinylarenes with aniline derivatives (anilines or nitrobenzenes) under mild conditions. 

Hydroformylation of substrates incorporating O- or N-nudeophilic moieties leads to cyclic hemiacetals, acetals, 0,N-acetals, or enamines depending on the reaction conditions and the functional groups of the substrates. In the total synthesis of the anticancer agent, natural product leucascandroUde A (24), three different carbonyla-tion steps were incorporated (Scheme 12.1). Alkene 20 underwent a cyclohydrocar-bonylation reaction under hydroformylation conditions, resulting in the formation of hemiacetal 21. The other two carbonylation steps involved formylation of 18 and intramolecular alkoxycarbonylation of alkene 22 [28]. Various tryptamine derivatives [29] and the framework of piperidine alkaloids [30] were also synthesized via cyclohydrocarbonylation starting from functionalized homoallylic amines or aniline derivatives, respectively. 

A relay catalytic hydroamination/redox reaction for the synthesis of cyclic aminals 83 from tertiary amine-substituted 3-en-l-yne derivatives 81 and various aniline derivatives 82 was recently developed by Gong and coworkers (Scheme 12.40) [43]. The gold carbene complex [(IPrlAuNTfj] and TfOH were found to be optimal cocatalysts for this cascade reaction. In their preliminary studies, the authors found that this reaction could be carried out in a highly enantioselective manner, despite that 2 equiv. of an expensive chiral phosphoric acid are required. Interestingly, the diastereoselectivity for a particular substrate appears to be independent of the catalyst or ee. This suggests that the enantioselectivity may result from the ring-closure step, rather than the hydride shift step. 

The palladium-catalyzed intramolecular C-H arylation of aromatic C-H bonds with haloarenes (Ar-H/Ar-X coupling, where X is halogen) is effective for the synthesis of carbazole alkaloids with amine linkers, as reported by Bedford and coworkers in 2006 (Scheme 16.16a) [34]. Buchwald-Hartwig coupling of an aryl bromide and an aniline derivative generated aryl chloride 91 in situ, which was easily cyclized under palladium catalysis to give clausine P in 80% yield. They also... 

Due to the utility of the methods and the significance of the materials, the use of Pd-catalyzed fV-arylation reactions in oligoaniline and polyaniline synthesis has remained an active area of research [344, 345]. For example, in recent work Kulszewicz-Bajer and coworkers have employed Pd-catalyzed amination reactions for the synthesis of AT-aryl poly(w,-p-aniline) derivatives that can be oxidized to high-spin radical cations [346, 347]. The preparation of these materials was accomplished by coupling 1,3-dibromobenzene with A TV -diarylphenylenediamine derivatives (Eq. 65). Palladium-catalyzed A -arylation reactions have also been employed for the preparation of partially annulated poly(w-anilines) [348] and other triarylamine-derived polymers [349, 350]. 

Quinoline derivatives may be synthesised by heating aii aromatic amine with an aldehyde or a mixture of aldehydes in the presence of concentrated hydrochloric or sulphuric acid this synthesis is known as the Doebner - Miller reaction. Thus aniline and paraldehyde afford 2-methylquinohne or quinaldine. 

By reaction of a primary aromatic amine—e.g. aniline 1—with glycerol 2, and a subsequent oxidation of the intermediate product 4, quinoline 5 or a quinoline derivative can be obtained.As in the case of the related Friedlander quinoline synthesis, there are also some variants known for the Skraup synthesis, where the quinoline skeleton is constructed in similar ways using different starting materials. ... 

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