Seven-membered heterocycle-derived

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... 

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. 

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). 

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. 

No enetetramine formation has been observed with NHCs derived from seven-membered heterocycles. The C2 resonance in these derivatives is shifted further downfield (5 250-260 ppm) in the NMR spectra. The most striking difference in comparison to all NHCs discussed previously is the twisted, nonplanar conformation of the seven-membered heterocycle both in the azolium precursor and in the carbene ligand. The twisted conformation appears to be essential to accommodate the strain within the seven-membered heterocycle. 

The reaction mode depends mainly on the choice of the base and reaction conditions, but route B is usually more common. Thus, tetrahydro-l,4-thiazine derivative 157 the structure of which was proved by X-ray crystal structure analysis (Fig. 7) [22b] was obtained in the reaction of the chloro ester 1-Me with 2-aminoethanethiol (156) using K2CO3 or EtgN as a base in 43 and 20% yield, respectively (Scheme 49) [22b, 26]. In the latter case, the secondary amino group in the primary tetrahydrothiazine product 157 underwent Michael addition to a second molecule of 1-Me to give 2-[r-(spirocyclopropanetetrahydrothiazinyl) cyclopropyl]-2-chloroacetate 158 (14% yield). When KOH in the presence of di-benzo-18-crown-6 was employed, however, the seven-membered heterocycles 155 (42%) and 159 (48%) were obtained upon reaction of 1-Me with 1,3-pro-panedithiol and 2-aminoethanethiol, respectively (Scheme 49) [26]. 

From a heterocyclic point of view, 428 derived from the reaction with carbonyl compounds are of interest, since their cycUzation under acidic conditions (85% H3PO4, toluene reflux) gave the seven-membered ring derivatives 429 in 74-97% yield. 

It should be noted that carbonyl compounds, more often aldehydes, are usual second reagent in both the groups. Other building-blocks in these multicomponent processes, leading to the formation of five-, six-, and seven-membered heterocycles, can be numerous acids and their derivatives, p-dicarbonyl compounds or other CH-acids, isocyanides, etc. At this, three-component reactions of ABC and ABB types [32] are the most typical for aminoazole, although some four-component ABCC processes were also published. 

One instance of the formation of a thietane derivative from a seven-membered heterocyclic precursor is seen in the photochemical fragmentation of dione (180) (73T2135). 

Seven-membered heterocycles 138-140 are formed when perfluoro-5-azanon-4-ene reacts with monoethanol derivatives and ethylenediamine. 

Examples of seven-membered heterocycles with significant antiviral activity include imidazo[4,5-e][l,3]diazepine-4,8-diones with anti-hepatitis C virus (HCV) activity <07BMCL2225> <07BMC4933> and benzo(indolo)fused 1,4-oxazepine derivatives as HCV RNA polymerase inhibitors that show excellent replicon potency <07BMCL3181>. Novel 2-chloro-8-[(arylthio)methyl]dipyridodiazepinone derivatives show activity against HIV-1... 

Dimetallodiphosphide reagents of type (18) react with difunctional halogen derivatives to form five-, six-, or seven-membered heterocycles of types (19) and (20). The reagent (18 R=Ph, M=Li, =2) is conveniently prepared by the cleavage of l,2-bis(diphenylphosphino)ethane, using lithium. ... 

Most information on cyclocondensation reactions of ZV-aminoazoles is concerned with vicinal N.C-diaminoazoles. In most cases, reactions were carried out with various carbonyl-containing compounds carboxylic acids and their derivatives, aldehydes and ketones, 1,2- an 1,3-dicarbonyl compounds, etc. Depending on the structure of these synthons, cyclocondensations lead to the formation of five-, and six- or seven-membered heterocycles. 

A useful reaction for the synthesis of unsaturated seven-membered heterocycles is the (2 + 2)-cycloaddition of heteroaromatic compounds, e.g., 1 //-pyrrole, furan, or thiophene derivatives, with acetylenes. In combination with a subsequent intramolecular (2 + 2)-cycloreversion (Section IV,B,2) of the annulated cyclobutene moiety, ring enlargement with two carbon atoms can be achieved. 1-Heterocycloheptatrienes, such as benzol6]azepines,26,27,65,66 benzo[fc]oxepins,67,68 benzo[6]-thiepins,69,70 and thiepins,18,71 have been successfully prepared in this way other routes are either nonexistent or laborious.72 In these compounds the reacting carbon-carbon double bond constitutes part of a (4n + 2)7r-electron system and in the (2 + 2)-cycloaddition the resonance energy of the aromatic nucleus is lost. Just like the nonaromatic heterocycles, heteroaromatic compounds have been reported to undergo (2 + 2)-cycloaddition reactions both with electron-deficient and with electron-rich acetylenes. 

The mass spectra of a number of heterocyclic compounds have been reported. The fragmentation patterns of thiophosphoryl derivatives of phosphorinanes are sensitive to stereochemistry, thus for the series (95) facile loss of the HS radical is indicative of an axial PS bond. The seven-membered heterocycles (96 Ch = S, Se) undergo a remarkable migration of sulphur or selenium from phosphorus to carbon with ring cleavage. While exocyclic P-C bonds of five-and six-membered heterocycles in the phosphonic class may be readily cleaved with retention of the phosphorus ring system, the seven-membered ring (97) exhibits facile expulsion of a phosphorus radical. ... 

An interesting concept for the preparation of seven-membered heterocycles with several heteroatoms was reported in 1988 by Burger and coworkers. Base-catalyzed reaction of hexafluoroacetone imine derivatives 53 with epichlorohydrine resulted in the formation of l,5-dioxa-3-azepines 54 and l-oxa-3,5-diazepines 55 (Fig. 10.24). ... 

---