Seven-membered ring systems

A -Ray examinations of V-phenoxycarbonylazepine and l-tosyl-1,2-diazepine reveal solid-state preferences for boat conformations with localized double bonds. Structures (7) and (8) similarly adopt boat conformations in the crystal with the hydrogen atom on C-3 in each case equatorial.  

Inversion barriers of the bridged biphenyls (9) have been discussed in terms of interactions in the biphenyl moiety. Racemization rates indicate higher 

Sulphinyl carbanions are generally observed to show greater stability when the carbanion lone pair bisects the S-lone pair/S—O bond angle, behaviour consistent with MO predictions. However, rates of base-catalysed H-D exchange in the system (9 X = SO, R = Me, R = H) now indicate a significant solvent dependence such that a change from t-butan[ H]ol to [ H4]methanoI results in a substantial reversal of the relative rates at which the two a-hydrogen atoms are abstracted.  

Dioxocane (13a) appears similar to (12) in that n.m.r. coalescence and dipole moment data are consistent with enantiotopic BC(1,3) and BC(1,3 ) conformations. However, replacement of methylene groups by further oxygen atoms is expected to introduce destabilizing transannular repulsions, and for (13b) and (13c) symmetrical crown, twist-BC and twist-CC forms become important.In contrast, tetrathiocane (13d) is assigned, from n.m.r. data, a BC conformation with low barriers to ring inversion and pseudorotation (singlet, — 170°C, 251 MHz), and this conformation persists in the solid state [cf. X-ray data of other heterocyclic systems of type (13) where crown forms are preferred]. Energy barriers for conformational processes within the system (14) have also been reported.  

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The possible variations among the three atoms comprising this reactive component make this the largest group and the one with the most potential for further development. They are particularly useful in the synthesis of five-, six- and seven-membered ring systems. They also may be conveniently considered according to their atom composition, and the hybridization state of any carbon atoms involved. 

Dipolarophiles utilized in these cycloadditions leading to five-membered heterocycles contain either double or triple bonds between two carbon atoms, a carbon atom and a heteroatom, or two heteroatoms. These are shown in Scheme 9 listed in approximate order of decreasing activity from left to right. Small rings containing a double bond (either C=C or C=N) are also effective dipolarophiles, but these result in six- and seven-membered ring systems. 

Substituent effects (electronegativity, configuration) influence these coupling constants in four-, five- and seven-membered ring systems, sometimes reversing the cis-tmns relationship so that other NMR methods of structure elucidation, e.g. NOE difference spectra (see Section 2.3.5), are needed to provide conclusive results. However, the coupling constants of vicinal protons in cyclohexane and its heterocyclic analogues (pyranoses, piperidines) and also in alkenes (Table 2.10) are particularly informative. 

Oxiranes exhibit 1,3 [e,n] capacity. Therefore, seven-membered ring systems can be synthesized on reaction with hetero-1,3-dienes. The reaction is catalyzed by 4-dimethylaminopyridine. On catalysis with boron trifluonde, the regioche-mistry is reversed [263] (equation 58). 

This section treats seven-membered ring systems with maximum unsaturation containing within the ring two or more oxygen, sulfur or nitrogen atoms, or a combination of these.1... 

The only heterocyclic seven-membered ring system with maximum unsaturation containing six heteroatoms is 1,3A4,5,2,4,6-trithiatriazepine (1). The methoxycarbonyl derivative 2 is a minor product (14%) of the complex reaction of tetrasulfur tetranitride with dimethyl acetylenedicarboxylatc in refluxing toluene, which gives mainly dimethyl l,2,5-thiadiazole-3,4-dicarboxylate (3, 67%) (see Houben-Wcyl, Vol. E8d, pl54ff which includes an experimental procedure). Two other products are the trithiadiazepine 4 (5%, see Section 4.4.1.1.1.) and the 1,2,4-thiadiazole derivative 5 (3%).385... 

A New Improved Synthesis of Tricycle Thienobenzazepines Apphcation of chemistry recently developed by Knochel" combined with the well-described halogen dance (HD) reaction, allowed preparation of our key intermediate A in only three synthetic transformations (Scheme 6.4). In this respect, treatment of 2-bromo-5-methylthiophene with hthium diisopropylamide followed by dimethylformamide afforded aldehyde 11 in good yield, lodo-magnesium exchange with conunercial 4-iodo-3-nitro anisole followed by reaction with 11 afforded the thiophene catbinol 12. Dehydroxylation of 12 provided our key intermediate A which presented the requisite functionality to examine our approach to the construction of the seven-member ring system. 

Amongst other fused seven-membered ring systems, the synthesis of novel [l,2,5]selena (and [l,2,5]thia)diazolo[3,4-e][l,4]oxazepines from fused pyrimidine precursors has been described by Ueda and co-workers <00JHC1269>. 

Ring enlargement.1 A new route to seven-membered ring systems from a cyclohexenone (1) involves a photocycloaddition of ethylene to provide the bicy-clooctanone 2. Addition of lithio-1,3-dithiane to 2 provides the adduct 3, which on reaction with HgO and HBF4 forms an unstable rearranged hydroxy aldehyde... 

Heterocyclic seven-membered ring systems are present in various natural and synthetic bioactive compounds and pharmaceuticals. Therefore, the development of new approaches to these heterocycles with total regio- and stereocontrol is of great importance to both medicinal and synthetic chemists, and still constitutes an exciting synthetic challenge. For this purpose, we recently invented a base-induced... 

Other seven-membered ring systems to have been successfully /3-lithiated include 5//-dibenz[6,/]azepine and its 10,11-dihydro derivative (83JHC341 84JHC197). The 4,5-dilithio derivatives 196 and 197 react successfully with electrophiles such as dialkylamides and D20 to give 4-substituted derivatives. Mention of the lithiation of these systems has also occurred in the patent literature (71USP3624072). 

As in more recent years, the chemistry of seven-membered ring systems has been dominated by the chemistry of oxygen heterocycles in the form of the marine toxins and, to a lesser extent, the antimalarial artemisinin. Indeed, if it were not for the interest in these systems it would have been a sparse year indeed. For this reason the division of this report will be into just three section, nitrogen, oxygen, and other systems. 

The reactivity of thiepane (35) is generally similar to other dialkyl thioethers where the sulfur atom provides the major site for chemical transformation. The thiepane seven-membered ring system is of particular interest however since it can undergo transannular reactions and can form cycloalkyne derivatives. 

The examples described in this chapter achieve the formation of a seven membered ring system through C-H activation or oxidative coupling. 

Conjugated linear trienes were reported to undergo cyclization to form seven-membered ring systems.112 Cyclic polyenes, in turn, isomerize to yield bicyclic compounds. In the transformation of nonatriene (10), the role of the base was demonstrated to catalyze the formation of the conjugated triene [Eq. (4.23)], which... 

Intramolecular acylation of thiophenes has been thoroughly examined and shown to provide a reasonable route to substituted cycloalkanones on desulfurization of the bicyclic products (53BSF62, 73BSF343). A variety of five-, six- and seven-membered ring systems have been constructed, e.g. (285) — (287). 

Whittaker and co-workers805,806 have also prepared a number of terpenoid bicyclic ethers, such as isomeric 1,6-dihydrocarveols 199 (HSO3F—S02,78°C) from unsaturated alcohols or diols.805 806pura-Menth-l-en-9-ol and a related diol afforded the seven-membered ring systems 200. The oxolane moiety in compound 201 was generated from the corresponding unsaturated alcohol precursor in 2 equivalents of triflic acid.807... 

Access to the 1,3-benzazepinone 39 has been achieved from aryl iodide 38 with a Pd(0) catalyst, followed by cyclization of the intermediate palladium complex upon reaction with thallium acetate, thus providing a convenient approach to the fused seven-membered ring system (Equation 5) <1998ICA(270)123>. 

The subject of 1,2,3-heterocyclic seven-membered ring system (triheteroepines) has been covered in CHEC(1984) (Volume 7, Chapters 5.18.7-5.18.9) and CHEC(1996) (Volume 9, Chapter 9.13). Both CHEC(1984) and CHEC(1996) can be found on-line. The present work is intended to update previous publications. Herein, we concentrate on the newly published synthetic methodologies, reactivity, and theoretical studies of the title scaffolds. At the beginning of every section, a brief update is presented on what has happened in a particular field since 1995 when CHEC(1996) was published. Additional literature that had not been covered in CHEC(1984) and CHEC(1996) will also be discussed. Where no new work has been reported in the literature since 1995, the relevant section heading has been omitted. Thus, all of the 12 standard headings used in this work do not appear for any of the heterocycles. 

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