Heterocycles ring reduction

Isoxazotes are readily reduced, usually with concomitant ring fission (e.g. 262 — 263). They behave as masked 1,3-diketones 79AHC(25)147). 1,2-Benzisoxazoles are easily reduced to various products (Scheme 28) (67AHC(8)277). Chemical or catalytic reduction of oxazoles invariably cleaves the heterocyclic ring (Scheme 29) <74AHQ 17)99). For similar reactions of thiazoles, see Section 4.02.1.5.1. 

Armand and coworkers have shown that, while 1,4-dihydropyrazines are the initial products of the electrochemical reduction of pyrazines, they could not be isolated and readily isomerize in solution into 1,2- or 1,6-dihydropyrazines depending on the substitution pattern in the heterocyclic ring (74CJC3971 84MI1). The rate of the isomerization depends on the type of pyrazine as well as the pH and the nature and amount of the cosolvent. 

Esters of diphenylacetic acids with derivatives of ethanol-amine show mainly the antispasmodic component of the atropine complex of biologic activities. As such they find use in treatment of the resolution of various spastic conditions such as, for example, gastrointestinal spasms. The prototype in this series, adiphenine (47), is obtained by treatment of diphenyl acetyl chloride with diethylaminoethanol. A somewhat more complex basic side chain is accessible by an interesting rearrangement. Reductive amination of furfural (42) results in reduction of the heterocyclic ring as well and formation of the aminomethyltetrahydro-furan (43). Treatment of this ether with hydrogen bromide in acetic acid leads to the hydroxypiperidine (45), possibly by the intermediacy of a carbonium ion such as 44. Acylation of the alcohol with diphenylacetyl chloride gives piperidolate (46). ... 

A heterocyclic ring may be used in place of one of the benzene rings without loss of biologic activity. The first step in the synthesis of such an agent starts by Friedel-Crafts-like acylation rather than displacement. Thus, reaction of sulfenyl chloride, 222, with 2-aminothiazole (223) in the presence of acetic anhydride affords the sulfide, 224. The amine is then protected as the amide (225). Oxidation with hydrogen peroxide leads to the corresponding sulfone (226) hydrolysis followed by reduction of the nitro group then affords thiazosulfone (227). ... 

Antidepressant activity is retained when the two carbon bridge in imipramine is replaced by a larger, more complex, function. Nucleophilic aromatic substitution on chloropyridine 31 by means of p-aminobenzophenone (32) gives the bicyclic intermediate 33. Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 35. Alkylation of the anion from 35 with l-dimethylamino-3-chloropropane leads to tampramine 36 [8]. 

Miscellaneous Heterocycles ring of 132. Reduction of the amide functions by means of LAH leads to aptazapine (133) [24]. 

Two types of heterocyclic compounds are discussed in this chapter those that undergo saturation and those that undergo fission of the heterocyclic ring. Both types of reduction have wide synthetic application. 

Heterocyclic rings do not undergo hydrogenolysis readily unless they are strained, are activated by unsaturation, or contain a weak bond, e.g., N—O, (38,61,114), but these exceptions constitute a wide variety of compounds, whose reductions have proved very useful in syntheses. 

Blechert s synthesis of the piperidine alkaloid (-)-halosaline (387) by Ru-catalyzed RRM is outlined in Scheme 76 [160]. In the presence of 5 mol% of catalyst A, the ring rearrangement of metathesis precursor 385 proceeded cleanly with formation of both heterocyclic rings in 386. In situ deprotection of the cyclic silyl ether in 386, followed by selective reduction and removal of the to-syl group led to 387. 

Reduction of the heterocyclic ring and incorporation of a nitro function affords a compound with antischistosomal activity, oxamniquine (60). Its synthesis begins with chlorination of 2,6-dimethyl-quinoline, which proceeds regiospecifically on the methyl group adjacent to the ring nitrogen (56). 

Displacement of halogen by isopropylamine gives intermediate 57. High pressure catalytic hydrogenation leads to reduction of the heterocyclic ring... 

Although 1,3,2-diazaphospholenium cations are usually prepared from neutral NHPs or 1,3,2-diazaphospholes via Lewis-acid induced substituent abstraction or A-alkylation, respectively (cf. Sect. 3.1.2), the group of Cowley was the first to describe a direct conversion of a-diimines into cationic heterocycles by means of a reaction that can be described as capture of a P(I) cation by diazabutadiene via [4+1] cycloaddition [31] (Scheme 4). The P(I) moiety is either generated by reduction of phosphorus trihalides with tin dichloride in the presence of the diimine [31] or, even more simply, by spontaneous disproportionation of phosphorus triiodide in the presence of the diimine [32], The reaction is of particular value as it provides a straightforward access to annulated heterocyclic ring systems. Thus, the tricyclic structure of 11 is readily assembled by addition of a P(I) moiety to an acenaphthene-diimine [31], and the pyrido-annulated cationic NHP 12 is generated by action of appropriate... 

This effect allows one to monitor the perturbation of the tt-c lection system by interaction of the electrophilic phosphorus atom with a Lewis base. Following the same rationale, the still larger chemical shifts of neutral 1,3,2-diazaphospholes and 1,3,2-diazaphospholide anions are considered to reflect predominantly a reduction in n-n transition energy due to destabilization of the n(P) orbital with an increasing number of lone-pairs on the NPN-moiety rather than differences in the charge densities or n-electron distribution in the heterocyclic ring [16]. 

Detailed investigations of the chemical reactivity of the diketiminato-stabilized phosphenium cations like 28 (Scheme 17) are to date rare and include only two reports dealing with the substitution and reduction of P-halogen-derivatives. Thus, reaction of 28 (X=Br) with sodium hydroxide in toluene was reported to proceed with displacement of the halide substituent at phosphorus and conservation of the heterocyclic ring to give a mixture of bromide and triflate salts containing a P-hydroxy-substituted cation, both of which were isolated in small yields [89], The products are remarkable as they represent one of very few examples of a stable phosphinous acid which does not rearrange to the tautomeric secondary phosphine oxide. Potassium reduction of the P-chloro-substituted derivative 34 produced the... 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

To get a complex set of substituents by direct derivatization of benzotriazole is not feasible. In such situations, it is better to have all the substituents in place first and later construct the heterocyclic ring. High reactivity of anilines and their well-developed chemistry makes them good stating materials. In an example shown in Scheme 215, acetanilide 1288 is nitrated to afford nitro derivative 1289 in 73% yield. Catalytic reduction of the nitro group provides methyl 4-acetylamino-3-amino-5-chloro-2-methoxybenzoate 1290 in 96% yield. Nitrosation of compound 1290 in diluted sulfuric acid leads to intermediate 1291, which without separation is heated to be converted to 7-chloro-4-methoxy-l//-benzotriazole-5-carboxylic acid 1292, isolated in 64% yield <2002CPB941>. 

The reduction of furoxans and benzofuroxans has been reviewed in detail in CHEC(1984) and CHEC-II(1996). The main reducing agents to remove oxygen atoms from nitrogen without cleavage of the heterocyclic ring are phosphines and phosphites. These reactions, namely deoxygenation of furoxans and benzofuroxans, are discussed in Section 5.05.4.2.2. 

Reductive amination is used in most of the syntheses as the method for the formation of a five- or six-membered aza heterocyclic ring. A triple reductive amination approach to castanospermine and swainsonine has been reported by Mootoo et al. <2001JOC1761> (Scheme 56). 

Imine formation is an important reaction. It generates a C-N bond, and it is probably the most common way of forming heterocyclic rings containing nitrogen (see Section 11.10). Thns, cycliza-tion of 5-aminopentanal to A -piperideine is merely intramolecular imine formation. A further property of imines that is shared with carbonyl groups is their susceptibility to reduction via complex metal hydrides (see Section 7.5). This allows imines to be... 

Electrochemical reduction of a,a -dibromoketones affords the unstable cyclo-propanone, which is in equlibrium with the dipolar intermediate 22. The cyclopro-panone hemiacetal is isolated in yields of 40 - 85 % from reaction in acetonitrile and methanol at -20 °C [99], The dipolar form can be trapped in a cycloaddition process with furan [100], Reaction with acetic acid leads to the a-acetoxy-ketone.[101]. Unstable three membered heterocyclic rings are intermediate in the reduction of sulphur and phosphorus linked dibromo compounds 23. In these reactions, the heteroatom is extruded leaving ci - and trans-stilbenes as the isolated products [102,103],... 

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