Heterocyclic compounds pyrrolidine

As discussed in Chapter 6, nitro compounds are converted into amines, oximes, or carbonyl compounds. They serve as usefid starting materials for the preparation of various heterocyclic compounds. Especially, five-membered nitrogen heterocycles, such as pyrroles, indoles, ind pyrrolidines, are frequently prepared from nitro compounds. Syntheses of heterocyclic compounds using nitro compounds are described partially in Chapters 4, 6 and 9. This chapter focuses on synthesis of hetero-aromadcs fmainly pyrroles ind indolesi ind saturated nitrogen heterocycles such as pyrrolidines ind their derivadves. 

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

Various schemes have been proposed to explain the production of nitrogen-containing heterocyclic compounds, such as pyrrolidines and piperidines, from proline. Nitrogen heterocyclic compounds are often potent flavouring chemicals. 

Nitrogen-containing heterocyclic compounds, including 1,2,3,4-tetrahydroqui-noline, piperidine, pyrrolidine and indoline, are also popular hydrogen donors for the reduction of aldehydes, alkenes, and alkynes [75, 76]. With piperidine as hydrogen donor, the highly reactive 1-piperidene intermediate undergoes trimer-ization or, in the presence of amines, an addition reaction [77]. Pyridine was not observed as a reaction product. 

The synthesis of oxygen- and nitrogen-containing heterocyclic compounds by anionic cyclization of unsaturated organolithium compounds has been reviewed recently. " Broka and Shen reported the first intramolecular reaction of an unstabilized a-amino-organolithium compound using reductive lithiation of an A,5-acetal derived from a homoaUylic secondary amine (Scheme 21). Just one example was reported treatment with lithium naphthalenide gave the pyrrolidine product, predominantly as the cis isomer. 

Many of the simple heterocycles occur naturally within human biochemistry. For example, the amino acids proline, histidine, and tryptophan contain, respectively, a pyrrolidine, an imidazole, and an indole ring. The nucleic acids contain purine and pyrimidine rings. Vitamins are heterocyclic compounds vitamin Bg (8.8) is a substituted pyridine vitamin Bj (8.9) contains a pyrimidine ring. Simple heterocycles are therefore important to human biochemistry and thus to drug design. 

Atoms other than carbon and hydrogen that appear in organic compounds are called heteroatoms. Cyclic organic compounds that contain one or more heteroatoms are called heterocycles. Heterocyclic compounds are the largest class of organic compounds and can be either aromatic (such as pyridine, pyrrole, and furan) or nonaromatic (such as piperidine, pyrrolidine, and tetrahydrofuran). 

The reactivity of heterocyclic compounds towards e-q can generally be deduced from the chemical behaviour of the aliphatic and aromatic systems discussed in the previous Sections. Thus one finds, for instance, that pyrrolidine (1) (tetraethyleneimine) (Szutkaetai., 1965) and proline... 

Heterocyclic compounds containing a nitrogen atom commonly undergo N-alkylation or C-alkylation. N-Methyl pyrrole can be prepared by interaction of methyl iodide with potassium pyrrole (40%). N-Carbethoxy pyrrole is made from chloroformic ester and potassium pyrrole. The C-alkylation of pyrroles has been discussed. 3-Alkylindoles are made by the alkylation and decarboxylation of indole-2-carboxylic acid. The conditions for alkylation of pyrrolidine are analogous to those employed for the alkylation of a secondary amine. Thus, pyrrolidine on treatment with n-butyl bromide and potassium hydroxide in boiling benzene is con-... 

Electrochemical alkylation and acylation are well-established reactions and have been employed for the formation of heterocyclic compounds. The reduction of azobenzene [127] or azomethine compounds [128] in the presence of Q ,ft>-dibromoalkanes leads to cyclic hydrazines, piperazines, or pyrrolidines. Similarly, reduction of nitrobenzene in the presence of 1,5-dibromopentane yields iV-phenylperhydro-l,2-oxazepine [129]. 

Heterocyclic compounds hold a special place among pharmaceutically significant natural products and synthetic compounds. The synthesis of nitrogen-containing heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, 2V-substituted 2,3-dihydro-1//-isoindoles, 4,5-dihydropyrazoles, pyrazolidines and 1,2-dihydrophthalazines has been accomplished in an aqueous medium under the influence of MWs (Scheme 8.15).2" ... 

The advantageous higher selectivity observed with cyclic ketones is also seen with heterocyclic compounds. The following pyrrolidin-3-one is reduced by fermenting baker s yeast in 75% chemical yield and 80% ee149. 

As the title denotes, this chapter deals with the conversion of carbohydrate derivatives into five-membered heterocyclic compounds containing nitrogen. The types of target compounds are (1) hydroxymethylpyrrolidines, (2) carboxypyrrolidines, (3) aralkyl pyrrolidines and... 

The role of heteroatoms in ground- and excited-state electronic distribution in saturated and aromatic heterocyclic compounds is easily demonstrated by a comparison of a number of heteroaromatic systems with their perhydro counterparts. In Jt-excessive heteroaromatic systems, because of their resonance structures, their dipole moments are less in the direction of the heteroatom than in the corresponding saturated heterocycles furan (1, 0.71 D) vs. tetrahydrofliran (2, 1.68 D), thiophene (3, 0.52 D) vs. tetrahydrothiophene (4, 1.87 D), and selenophene (5, 0.40 D) vs. tetrahydroselenophene (6, 1.97 D). In the case of pyrrole (7, 1.80 D), the dipole moment is reversed and is actually higher than that of pyrrolidine (8, 1.57 D) due to the acidic nature of the pyrrole ring (the N-H bond) In contrast, the dipole moment of n-deficient pyridine (9, 2.22 D) is higher than that of piperidine (10, 1.17 D). In all these compounds, with the exception of pyrrole (7), the direction of the dipole moment is from the ring towards the heteroatom [32-34]. 

Heterocyclic Compounds. Such materials undergo catalytic hydrogenation to yield the corresponding saturated derivatives. Thus, pyrrole is slowly converted to pyrrolidine at 200 C over either a nickel or copper-chromium oxide catalyst pyridine and pyridine derivatives behave similarly. Compounds such as furan and dihydropyran reduce rapidly and behave more like olefins in reactivity. Similarly, thiophene is converted to the tetrahydro derivative. 

A large number of perfluorinated heterocyclic compounds was prepared (mostly using ECF technology) in 1970-1990 during the quest for the best materials to be used as oxygen carriers in perfluorocarbon emulsions, so-called blood substitutes (for detailed review on this effort, see Ref. 34). The list of synthesized materials includes perfluorinated A-alkyl(cycloalkyl) pyrrolidines, oxazolidines, piperidines and... 

It should be pointed out that currently both trivial and systematic names are commonly used for naming the heterocyclic compounds. For example, an organic chemist will recognize without any difficulty the structures connected to names such as furane, pyrrole, pyrrolidine, pyrazole, imidazole, pyridine, or piperidine, despite the fact that all these names are trivial. On the other hand, the complex heterocycles require more sophisticated approaches in order to avoid ambiguity and correctly translate the chemical strucmre into the name. For these, compound names are often made using either trivial name (e.g., indazole for benzopyrazole, benzimidazole, indole, and isoindole) or the Hantzsch-Widman nomenclature, for example, 1,2,3- or 1,2,5-oxadiazoles, 1,3-dioxolane, 1,2- or 1,3-dithiolane, and 1,3- or 1,4-dioxane. It should be noted that the Hantzsch-Widman nomenclature treats the unsaturated heterocycle with maximum number of conjugated double bonds as parent compound. This adds another layer of complexity, giving rise to names such as... 

A -heterocyclic compounds other than pyrazines such as pyrrolines, pyrrrolidines, piperidines and pyrroles are also very important flavor compounds. The formation of pyrrolines and pyrrolidines are reported to be generated from the reaction of proline with glucose (Shigematsu et aL, 1975 Tressl et aL, 1985a). The pyrrolidines possess smoky and roasty aromas while 2-acetyl-1-pyrroline was reported by Tressl et al. (1985b) to have a cracker-like odor. The pyrrole rings from proline and hydroxyproline are present in many of their reaction products. N-acetylpyrrole exhibits a cookie-like and mushroom-like odor (Tressl et ai, 1986). 

A large number of heterocyclic compounds of oxygen, nitrogen, and sulfur are prepared by condensation of di- or poly-functional compounds. Nitrogen-containing heterocycles by the thousands have been prepared by such reactions. The simplest such reaction is one leading to the preparation of a pyrrolidine or piperidine derivative. The synthesis of pyrrolidine may be accomplished by reaction of ammonia and 1,4-dichlorobutane in a stepwise process that may include an intramolecular displacement of chloride from the aminoalkyl chloride [Eq. (31)] or of ammonia from the aminoalkyl amine hydrochloride" [Eq. (32)] each process is known to occur. 

Asymmetric hydroamination has served as an important strategy for the synthesis of pyrrolidine and piperidine derivatives. Moreover, it has been found to be useful for the synthesis of other five- and six-membered heterocyclic compounds having more than one hetero atom. Asymmetric hydroamination and diastereoselective hydroamination have been found to be extremely useful for the synthesis of natural products and pharmaceutical agents. It is important to note that diastereoselective hydroamination has been... 

The enantioselective aza-Michael [49] reaction of enals has been emerged as one of the most important methodologies for the synthesis of enantiomerically pure C-N bonds. These methodologies led to the enantioselective synthesis of N-heterocyclic compounds such as pyrrolidines and piperidines. 

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