Seven-membered heterocycles, review

After an initial inorganic example and two aliphatic compounds, drugs based on single carbocyclic rings are discussed, followed by di-, tri- and tetracyclic systems. Five-, six- and seven-membered heterocycles complete the review, with simple before more complex molecules within each section. 

Very few examples of these species have appeared since the field was last reviewed.1 One species of interest is the seven-membered heterocycle 100, which was obtained from the dilithiated species 97 via the formation of a Ge=B doubly bonded intermediate (Scheme 30).206 A rare example of a germanium/gallium cluster complex has also been prepared (Equation (162)).207... 

The non-planar polyene nature of azepines renders them susceptible to a variety of intra-and inter-molecular pericyclic processes. The azepine-benzeneimine valence isomerization has been discussed in Section 5.16.2.4, and the ring contractions of azepines to benzenoid compounds in the presence of electrophiles is covered in Section 5.16.3.3. In this section the thermal and photochemical ring contractions of azepines to bicyclic systems, their dimerizations and their isomerizations via sigmatropic hydrogen shifts are discussed. Noteworthy is a recent comprehensive review which compares and contrasts the many and varied valence isomerizations, dimerizations and cycloadditions of heteroepins (conjugated seven-membered heterocycles) containing one, two and three heteroatoms (81H(15)1569). 

The reactivity of seven-membered heterocycles was presented more fully in CHEC-II(1996) (Section 9.17.5) and other reviews <2004CRV2617>. 

This review covers the years 2001-2002. Seven-membered heterocycles continued to be a focus of considerable activity over this period, with fused systems a particular highlight. Ring closing metathesis methodology has been adapted to further syntheses of seven-membered rings. 

Reactive three-carbon building blocks such as alkynones [32] and 1,3-diaryl pro-penones (chalcones) (for a review on the chemistry of 1,3-diaryl propenones, see e.g. [33]) which can react with bifunctional nucleophiles in a sequence of Michael addition and cyclocondensation open a facile access to five-, six-, and seven-membered heterocycles (Scheme 1). As a consequence, this general strategy has found broad application. However, standard syntheses of alkynones [34] and chalcones [33] are often harsh and require either strongly basic or strongly Lewis or Brpnsted acidic conditions. Therefore, the application in one-pot methodology, where delicately balanced reaction conditions are a prerequisite, is largely excluded. 

Several useful general reviews on seven-membered heterocycles have appeared in advanced texts,and there are also reviews on dihydrodiazepines and their salts, dibenzoxazepines," thiepins, fluorinated tricyclic neuroleptics, and the electrochemistry of substances of pharmacological importance (including dibenzodiazepines). ... 

In surveying the literature it is relevant to list a number of interesting reviews which have been published during the period. An important group of compounds which fall within any review of seven-membered heterocyclic compounds is the... 

There are several reviews, which are devoted to the synthesis of seven-membered heterocycles, but rings with four or more heteroatoms are not typically described in these reviews <888569,9isi8i>. Only a few of the possible heterocyclic structures are actually known most contain nitrogen and... 

There continues to be strong interest in the synthesis of seven-membered heterocyclic compounds containing one. two. or three of the heteroatoms N, O, or S and in applications of these heterocyclic compounds in medicinal chemistry. Reviews published include strategies for the synthesis of benzopyrrolo[l,2-(j]azepines (13T9357) and the application of [l,7]electro-cyclization reactions for the preparation of azepine derivatives (13CHE152). 

Alkynones [62] and 1,3-diaryl propenones (chalcones) [63] are reactive three-carbon building blocks that can be transformed into five-, six-, and seven-membered heterocycles with bifunctional nucleophiles in the sense of Michael addition and cyclocondensation. Therefore, a catalytic access to ynones [64] and enones [65] by Sonogashira alkynylation turned out to be a versatile entry to consecutive multicomponent syntheses of heterocycles. This reactivity-based concept has been considerably developed by the Muller group in the past decade. In several reviews, the major advancements of this one-pot methodology have been summarized [66]. Therefore, only very recent conceptual achievements with respect to sequentially Pd-catalyzed processes [7] will be considered here. 

An account of a method for the homologation of methyl esters, catalysed by a ruthenium-cobalt bimetallic system, may have some future synthetic potential. Six- and seven-membered heterocyclic enamino-esters (74) undergo ring-contraction to give five- and six-membered azacyclic esters (75) in 89-92% yield (Scheme 40). The reactions of dianions derived from carboxylic acids and esters have been reviewed. ... 

Since this topic was last reviewed, " a book on seven-membered heterocycles containing oxygen and sulphur has been published. ... 

Aside from C-H coupling constants (often obtained from satellites in NMR spectra) not very much information is available on the NMR spectra of small heterocycles. A recent review (B-79MI50101) devotes only seven pages to the NMR spectra of all three- and four-membered heterocyclics. 

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