Heterocycles seven-membered

The phosphitylation reactions are high yielding (79-97%) and furnish 93 as the expected mixtures of epimers with different absolute configuration at the phosphorus atom. The final diastereomeric distribution varies from 33% to 100% de and was found to change upon heating the compounds for prolonged periods of time. The diastereomers could be separated by HPLC or crystallisation and their absolute configurations were ascertained by X-ray structural analysis and NMR data. 

Darcel, J. Uziel and S. Juge, in Phosphorus Ligands in Asymmetric Catalysis Synthesis and Applications, A. Borner (ed.), Wiley-VCH, Weinheim, 2008, p. 1211. 

Brunei, T. Constantieux, O. Legrand and G. Buono, Tetrahedron Lett., 

Vautravers, P. Andre and D. J. Cole-Hamilton, Dalton Trans., 2009, 3413. 

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Fully saturated seven-membered heterocycles with one or two heteroatoms are normally in mobile twist-chair conformations (Section 5.17.1.1, Chapter 5.18) (b-77SH(2)123). Annelation and the introduction of exocyclic double bonds can have profound effects oxepan-2-one, for example, is in a near chair conformation (67JA5646). 

Table 10 Structure and H NMR Data of Seven-membered Heterocyclic Compounds...

Formation of five-membered ring systems (1,2-addition) can compete with formation of the seven-membered heterocycles (1,4-addition). If the first step of the reaction sequence, namely the nucleophilic attack of the terminal heteroatoin of the diene, is hindered by steric or electronic effects, the five-membered ring product is formed exclusively. 

The manifold possibilities for tautomerism in. seven-membered heterocyclic systems are virtually unexplored cf., however, A. H. Rees, J. Chem. Soc. p. 3111 (1959). 

In addition to the nucleophilic displacement of the halogen atom, subsequent substitution of the heteroarylium moiety has been observed in numerous cases. Tliese substitution reactions beneht from the increasing importance of the negative hyperconjugation (Scheme 13). Such a pathway has been intensively exploited to synthesize (fused) hve-, six-, and seven-membered heterocycles. 

C. Seven-Membered Heterocycled So far, only benzo- and dibenzo-fused telluroazepines are known. 

Chemistry of furazanes fused with six- and seven-membered heterocycles with one heteroatom 99UK154. 

Due to the instability of the seven-membered heterocyclic ring, oxepin is prone to isomerization reactions to bicyclic heterocycles such as benzene oxide. Irradiation of oxepin with UV light of/. > 310 nm gives the isomeric 2-oxabicyclo[3.2.0]heptadiene(l) in high yield.12 207 At shorter wave lengths, phenol is formed predominantly.207... 

When the hydride ion of lithium alanate is used as nucleophile, cyclohexa-2,4-dien-l-ol is obtained as a labile addition product which eliminates water on standing to give benzene.12 The reaction of an oxepin derivative that possesses a hexamethylene bridge across C3-C6 with sodium methoxide gives an addition product 5 in which the seven-membered heterocyclic system is retained.213 214... 

Organolanthanides are catalyst precursors for the formation of five-, six-, and even seven-membered heterocycles. These IHs are also effective with secondary and aromatic amines (e.g. Eq. 4.20). 

The first observation of the uncommon phenomenon of desmotropy in seven-membered heterocycles was reported for the prototropic annular tautomers 128 and 129. These dihydro-4,1-benzothiazepines, which were prepared (via the non-isolated intermediates 130 and 131 from the fused azetidinone 127 on treatment with NaOEt), could be isolated in pure form by column... 

The scope for further developments in the chemistry of seven-membered heterocyclic systems is considerable, particularly with respect to multi-heteroatom component systems. New synthetic methods are needed for these systems and ring-fused derivatives. The demand for such systems is likely to be largely driven by the search for structurally novel drug leads. 

A synthetically useful application of an intramolecular microwave-assisted Heck reaction has been described by Gracias and coworkers (Scheme 6.9) [28], In their approach toward the synthesis of N-containing seven-membered heterocycles, the... 

The introduction of ethylenediamines into this reaction resulted in the formation of seven-membered heterocycles (66) [Eq. (33)] (81TL3467). 

A further application of ring-closing metathesis in seven-membered heterocyclic ring formation is in the synthesis of the trans-fused oxpane systems. This process involved tandem RCM/allylstannane-aldehyde cyclizations and interaction of the process provides access to trans-fused polyoxepanes <00S883>. 

While some new spirocyclic and bridged seven-membered heterocyclic systems were reported in 2000, the scope in these two areas is significant, particularly with respect to the design of pharmacologically active compounds with new molecular architectures. Further developments in these areas are thus expected. 

As shown in Scheme 2.21 Id, starting with N-allyl carbohydrate-nitrones (469), a series of chiral six- (470) and seven-membered(471) TV-heterocycles were synthesized (Scheme 2.227). A very interesting and useful aspect of this cycloaddition is the control of regioselectivity by the substitution at the nitrogen atom. Therefore, it is possible to direct reactions towards the syntheses of preferred six- or seven-membered heterocycles from carbohydrate derivatives (722). 

However, intramolecular O-alkylation can be performed under particular conditions leading to of annelation of a seven-membered heterocycle. Japanese researchers (170) prepared the corresponding seven-membered cyclic nitronates (50a-c) in good yields by the reaction of triethylamine with brominated aryl ketones (49a-c) containing the nitromethyl group in the ortho position. 

The palladium-catalyzed hetero-[4 + 3]-cycloadditions reported by Trost and Marrs utilize a metal-complexed trimethylenemethane as the three-carbon component. These complexes react with a,/3-unsaturated imines to produce seven-membered heterocycles in moderate to good yields.84 Two examples of this reaction were reported and are shown in Equations (13) and (14). Only the [4 + 3]-reaction was observed with a,/3-unsaturated imine 76 however, both the [4 + 3]- and the [3 + 2]-modes of reactivity are observed with a,/3-unsaturated imine 79. 

DRUGS WITH SEVEN-MEMBERED HETEROCYCLIC RINGS 109... 

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... 

Another isomerization reaction of arene oxides is equilibrium with oxe-pins [5], Here, the fused six-membered carbocycle and three-membered oxirane merge to form a seven-membered heterocycle, as shown in Fig. 10.2. An extensive computational and experimental study involving 75 epoxides of monocyclic, bicyclic, and polycyclic aromatic hydrocarbons has revealed much information on the structural factors that influence the reaction rate and position of equilibrium [11], Thus, some compounds were stable as oxepins (e.g., naphthalene 2,3-oxide), while others exhibited a balanced equilibrium... 

Fig. 3.10 Six-membered heterocycles with two heteroatoms obtained by solid-phase chemistry. Seven-membered heterocycles...

Stable free carbenes derived from four- (13), six-, or seven-membered heterocycles 14 are also known. Carbenes of type 13 can possess a phosphorus [19] or a boron atom [69] within the heterocycle. These carbenes exhibit extreme values regarding their NMR spectroscopic ( carbene-c 285 and 312.6 ppm) and structural properties (angle N-Ccarbene-N 96.72(13) and 94.0(2)°). 

The carbenes derived from six- [20-22] and seven-membered heterocycles [22-24, 70] of type 14 can be obtained both with an aliphatic or an aromatic backbone. The characteristic NMR resonances for the C2 carbon atoms in six-membered carbene heterocycles (8 236-248 ppm) [20, 21] have been recorded in the same range as the Ccarbene resonances for saturated imidazolidin-2-ylidenes of type 7. Dimerization to enetetramines occurs for some carbenes derived from a six-membered heterocycle [21] and this behavior is independent from the nature of the backbone (saturated or unsaturated), but depends strongly on the steric bulk of the N,N -substituents. 

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