Five- and Six-Membered Rings

Distortions in valence angles and the strain resulting from the interaction of non-bonded groups in the cyclic transition states leading to the formation of 

A remarkably short synthesis of the fused bicyclic system 288 was achieved through an ingenious exploitation of a bis-enolate alkylation. In general, this sequence corresponds to the coupling of two different 1,3-C3 synthons with the tetradentate 2,3-Cl synthon. 

A Michael addition using the bifunctional reagent 289 was employed for the preparation of the bicyclic compound 290. The initially formed Michael adduct 291 undergoes intramolecular enolate alkylation to give the target compound. The employment of 289 as a substituted 2,4-Cf synthon in this sequence enables the formation of an ejco-methylene derivative, otherwise difficult to prepare. 

The substrate 292 was specifically designed to prepare five-membered systems via a sequence of inter- and intramolecular Michael additions. This option is viable when active Michael acceptors such as methyl vinyl ketone are used, otherwise competing Michael reactions between two molecules of 292 are difficult to avoid. The reaction proceeds through intermediate 293, which contains both a Michael donor and acceptor site and undergoes spontaneous conversion into the cyclic product 294. 

Transition metal chemistry provides an especially rich source of methods for the construction of cyclic compounds. The idea to synthesize 297 from precursor 298 comes from the recognition of 298 as an equivalent to the 1,3-bipolar synthon 298a, trimethylenemethane. It was reasoned that intermediates equivalent to 298a might be formed as transient species and stabilized by complexation with transition metals, e.g. Pd(0). With reagents such as Michael acceptors they can be used for an efficient cyclopentanoannulation.  

The main chemical aspect in which compounds with a nitrogen in a five- or six-membered ring differ from their acyclic counterparts is in the possibility open to them to be dehydrogenated to the corresponding aromatic system. Dihydroaromatic systems naturally show the greatest tendency to aromatise, indeed one of the important reducing coenzymes, NADPH, makes use of this tendency, as indicated below. 

Dihydro-compounds are often useful synthetic intermediates showing different reactivity patterns to the parent, aromatic heterocycle. For example, indolines (2,3-dihydroindoles) can be used to prepare indoles with substituents in the carbocyclic ring, via electrophilic substitution then rearomatisation (section 17.16.1.8), and similarly, electrophilic substitutions of dihydropyridines, impossible in pyridines themselves, followed by rearomatisation can give substituted pyridines. Dehydrogenation of tetra- and hexahydro-derivatives requires much more vigorous conditions. 

Generally speaking, piperideines and pyrrolines exist predominantly in the imine form and not in the tautomeric enamine form A -alkyl analogues have no alternative but to exist as enamines. These cyclic imines are resistant to hydrolytic fission of the C = N bond, in strong contrast with acyclic imines, but nonetheless they are very susceptible to nucleophilic addition at the azomethine carbon. An example of this is that both piperideine and pyrroline exist as trimers formed by the nucleophilic addition of nitrogen of one molecule to the azomethine carbon of a second molecule, etc. 

The presence of some enamine, at equilibrium, is demonstrated by the conversion of piperideine into a dimer, indeed, the ability of these two systems to serve as both imines and enamines in such aldol-like condensations is at the basis of their roles in alkaloid biosynthesis. Formed in nature by the oxidative deamination and decarboxylation of ornithine and lysine, they become incorporated into alkaloid structures by condensation with other precursor units. Hygrine is a simple example in which the 1-pyrroline, as an imine, has condensed with acetoacetate, or its equivalent. 

Controlled oxidation of jV-acylpiperidines and -pyrrolidines can be used to prepare 2-alkoxy-derivatives or the equivalent enamides, which are useful general synthetic intermediates. The former are susceptible to nucleophilic substitution under Lewis acid catalysis, via Mannich-type intermediates, and the latter can undergo electrophilic substitution at C-3 or addition to the double bond. 

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In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

The silyl enol ethers 209 and 212 are considered to be sources of carbanions. and their transmetallation with Pd(OAc)2 forms the Pd enolate 210. or o.w-tt-allylpalladium, which undergoes the intramolecular alkene insertion and. 1-elimination to give 3-methylcyclopentenone (211) and a bicyclic system 213[199], Five- and six-membered rings can be prepared by this reaction[200]. Use of benzoquinone makes the reaction catalytic. The reaction has been used for syntheses of skeletons of natural products, such as the phyllocladine intermediate 214[201], capnellene[202], the stemodin intermediate 215[203] and hir-sutene [204]. 

Alkyl- and arylmercury(II) halides are used for the ketone formation[402]. When active methylene compounds. such as /f-keto esters or malonates are used instead of alcohols, acylated / -keto esters and malonates 546 are produced, For this reaction, dppf is a good ligand[403]. The intramolecular version of the reaction proceeds by trapping the acylpalladium intermediate with eno-late to give five- and six-membered rings smoothly. Formation of 547 by intramolecular trapping with malonate is an example[404]. 

The intramolecular allylation of soft carbon nucleophiles with allylic acetates as a good cyclization method has been extensively applied to syntheses of various three, four, five and six-membered rings, and medium and macrocyclic compounds[44]. Only a few typical examples of the cyclizations are treated among numerous applications. 

The reaction of the vinylcyclopropanedicarboxylate 301 with amines affords an allylic amine via the 7r-allylpalladium complex 302[50]. Similarly, three-membered ring A -tosyl-2-(l,3-butadienyl)aziridine (303) and the four-mem-bered ring azetidine 304 can be rearranged to the five- and six-membered ring unsaturated cyclic amines[183]. 

Sulfur containing heterocycles are also common Compounds m which sulfur is the heteroatom m three four five and six membered rings as well as larger rings are all well known Two interesting heterocyclic compounds that contain sulfur-sulfur bonds are hpoic acid and lenthiomne... 

The rather special status of five- and six-membered rings is already familiar from organic chemistry. Because of the general stability associated with rings of this size, both reactions (5.EE) and (5.FF) are expected to be less favored when the ring compounds have this size, that is, when 1 = 5 or 6. To see the basis for this conclusion, let us consider some of the evidence for stain in cyclic compounds. 

MISCELLANEOUS FLUORINATED NITROGEN HETEROGYGLIGS Two reviews (1981, 1990) include nitrogen heterocychcs not covered in the present survey (482,483). The 1990 review dealing with four-, five-, and six-membered ring heterocycHc compounds emphasizes biological properties (482). 

Cyclopropanes can also be obtained by the reaction of vinyltrialkylborates with aldehydes followed by treatment with phosphoms pentachloride and base (300), and by the rearrangement of 5-substituted alkynyltrialkylborates (308). It is also possible to utilize this approach for the synthesis of five- and six-membered rings (3). Trans-1,4-elimination ia cycHc systems leads to the formation of stereodefined acycHc 1,5-dienes or medium-ring dienes, depending on the starting compound (309). 

During electrochemical fluorination retention of important functional groups or atoms in molecules is essential. Acyl fluorides and chlorides, but not carboxylic acids and anhydrides (which decarboxylate), survive perfluorination to the perfluorinated acid fluorides, albeit with some cyclization in longer chain (>C4) species [73]. Electrochemical fluorination of acetyl fluoride produces perfluoro-acetyl fluoride in 36-45% yields [85]. Electrochemical fluorination of octanoyl chloride results in perfluorinated cyclic ethers as well as perfluorinated octanoyl fluonde. Cyclization decreases as initial substrate concentration increases and has been linked to hydrogen-bonded onium polycations [73]. Cyclization is a common phenomenon involving longer (>C4) and branched chains. a-Alkyl-substituted carboxylic acid chlorides, fluorides, and methyl esters produce both the perfluorinated cyclic five- and six-membered ring ethers as well as the perfluorinated acid... 

Cycloadditions Forming Five- and Six-Membered Rings by W. R. Dolbier... 

This method of preparation has been developed primarily by Lukes (103,104). N-Methyl lactams (117) with five- and six-membered rings plus Grignard reagents yield the l-methyl-2-alkyl pyrroUnes (118, = 1) and l-methyl-2-alkylpiperideines(118, n = 2), respectively, plus 2,2-dialkylated bases (119) as by-products (103). For example, l,3-dimethyl-2-piperidone... 

The formation of a-acetoxyketones by oxidation of enamines with thallic acetate has been studied in detail (27) and found to be of preparative value (80 % yields) particularly in five- and six-membered-ring ketone derivatives. Enamines of linear or seven-membered-ring ketones were oxidized also, but at very much slower rates. Enamines of aldehydes with a-hydrogen substituents underwent self-eondensations during the oxidation reactions. Lead tetraacetate was less satisfactory as an oxidizing agent. 

M. P. Groziak and F. G. Jacobs, Tricyclic Systems Central Carbo-cyclic Ring with Fused Five- and Six-membered Rings Chapter 7.22 pp. 875-919 in Katritzky A. R., Rees Ch. W., and Scriven E. F. V, Comprehensive Heterocyclic Chemistry II A review of the Literature 1982-1995, Vol. 7 Fused Five- and Six-membered Rings without Ring Junction Heteroatoms, vol. ed. Ramsden Ch. A., Elsevier Science, Oxford, 1996. 

This tendency is especially significant in compounds containing functional groups capable of addition with the formation of both five- and six-membered rings. It has been shown that for amides and hydrazides of azolecarboxylic acids, selectively, and for the acids with any arrangement of a function and triple bond, heterocyclization always leads to the closure of the six-membered ring. Similar reactions in the benzoic series mainly lead to the formation of five-membered rings. 

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