2.5- disubstituted 1.5- fused ring

Chiral 10 to 12-membered nitrogen and oxygen heterocycles, fused to isoxazo-line rings have been prepared with high regio- and stereoselectivity by INOCs of tethered N- and O-allyl carbohydrate derivatives. The use of a -Y-Ar-CH2 tether, containing a 1,2-disubstituted aromatic ring between the heteroatom attached to... 

Indene Dihydroindene under Disubstituted and Polysubstituted Benzene Hydrocarbons Indene under Polycyclic Hydrocarbons, Nonaltemant Compounds with Two or Three Fused Rings Indeno(l,2,3-C(i0pyrene under Poiycyciic Hydrocarbons, Nonaltemant Compounds with More Than Five Fused Rings Iodine Iron... 

Chi the basis of the tautomeric formulas shown for 5-monosubstituted tetrazoles (where R is any substituent) there are three classes of monosub stituted and two classes of disubstituted derivatives (where the H is replaced). Also, there are fused ring tetrazoles of the 1,5-disub stituted class. In addn, there are salts and substituted derivatives which have 2,3-, 1,4- and 1,2-sub-stituents. However, compds of ordn interest are usually 1,5-, 2,5- or 1,3-substituted. Bis expl compds may be connected at the 5,5 -positions. Bis expl salts may be connected at either the 1,1 or the 5,5position with the (metallic) anion. (See in Vol 2, B157-L R and below under the pertinent compds)... 

Configurational isomerism is encountered in bi- and polysubstituted cyclic molecules, as well as in fused ring systems. In the simple case of bisubstituted monocyclic systems, cis-trans-isomehsm exists provided that the two substituents are not gemi-nal. Thus, 1,2-, 1,3- and 1,4-disubstituted cyclohexane derivatives (LII) show this... 

Two sequential electrochemical annulations of an electron-rich 3,4-disubstituted furan ring were employed to generate the fused tricyclic ring system of arteannuins. The second reaction, as depicted below, represented the formation of a quaternary carbon center by a formal 6-endo cyclization under these anodic oxidation conditions <07OL4599>. 

Among the above wild type streptomycete fused ring fermentation products, only the unusual 1,8-disubstituted naphthalene constituent 23a of the enediyne antibiotic neocarzinostatin provides a possible exception to the predominant S mode of cyclisation. However, the structures recently assigned to two hybrid streptomycete polyketides are similarly not in accord with the classification outlined in Figure 3. 

A. Compound 60 is of the same substitution pattern as dichloromethane, and the hydrogens Ha and Hb are homotopic. Compound 61 has the same pattern as ethanol here Ha and Hb are enantiotopic. In compound 62, Ha and Hb are homotopic here a in other homotopic examples, H and Hb lie astride a symmetry plane. In compound 63, Ha and Hb are diastereotopic. Separate replacement of Ha and Hb by D in 63 gives a pair of diastereoiso-mers (that is stereoisomers that are not enantiomers). In compound 64, Ha and Hb are diastereo topic this can be confirmed by separate replacement of Ha and Hb by D, to give a pair of diastereoisomers. Note that previously (Sections 6.3 and 6.5.2) we have shown that cis and trcms 1,3-disubstituted cyclobutanes and cis and tram 1,4-disubstituted cyclohexanes constitute a pair of achiral diastereoisomers. In compound 65, Ha and Hb are enantiotopic. In fused-ring molecules, substituents are often drawn where Ha/Hb are located in 65 however, anti-clockwise rotation by 120° around an axis through the bridgehead carbons puts Ha and Hb in a position where their enantiotopicity can be seen more easily. 

A multistep conversion of 2,2-disubstituted 1,3-cyclohexadiones 191 to 3-substi-tuted 2-cyclohexenones 192 mediated by phosphonate anions was applied by Yamamoto and Furuta [69] in a formal synthesis of ( )-a-acoradiene (193) (Scheme 47). 3-Substituted 2-cyclohexenones are versatile building blocks for the synthesis of cyclic natural products such as spirocyclic and fused ring sesquiterpenes. These cyclohexenones were easily obtained in a one-pot reaction of 194 with dimethyl methanephosphonate anion in the presence of trimethylsilyl chloride. The new overall reaction is a multistep rearrangement involving... 

In 2011, Murakami and coworkers [82] reported that chiral NHC ligands having a 2,2 -bisquinoline-based Cj symmetric skeleton were efficient ligands in the palladium-catalyzed intramolecular a-arylation of amides to afford 3,3-disubstituted oxindoles with good yield and enantioselectivity (Scheme 8.44). The two fused rings attached to the NHC core played an important role in the reaction mechanism. 

In 1997 Shi used a series of pseudo-C -symmetric ketones 404 bearing two fused rings at each side of the carbonyl group [281, 282]. Ketones 404 are characterized by good enantioselectivities (96% ee in the epoxidation of phenylstilbene), even for the epoxidation of electron deficient olefins. Overall, ketones 404 are less enanti-oselective than 376 for the epoxidation of trans-, disubstituted, and trisubstituted olefins. Also, the sterically relaxed ketones 405 and 406 with a CHj-group next to the keto-group show lower enantioselectivities and reactivities for the epoxidation. Zhao et al. reported 85% ee for stilbene with catalyst 406 (Fig. 7.20) [283]. 

Diels-Alder reactions, 4, 842 flash vapour phase pyrolysis, 4, 846 reactions with 6-dimethylaminofuKenov, 4, 844 reactions with JV,n-diphenylnitrone, 4, 841 reactions with mesitonitrile oxide, 4, 841 structure, 4, 715, 725 synthesis, 4, 725, 767-769, 930 theoretical methods, 4, 3 tricarbonyl iron complexes, 4, 847 dipole moments, 4, 716 n-directing effect, 4, 44 2,5-disubstituted synthesis, 4, 116-117 from l,3-dithiolylium-4-olates, 6, 826 electrocyclization, 4, 748-750 electron bombardment, 4, 739 electronic deformation, 4, 722-723 electronic structure, 4, 715 electrophilic substitution, 4, 43, 44, 717-719, 751 directing effects, 4, 752-753 fluorescence spectra, 4, 735-736 fluorinated derivatives, 4, 679 H NMR, 4, 731 Friedel-Crafts acylation, 4, 777 with fused six-membered heterocyclic rings, 4, 973-1036 fused small rings structure, 4, 720-721 gas phase UV spectrum, 4, 734 H NMR, 4, 7, 728-731, 939 solvent effects, 4, 730 substituent constants, 4, 731 halo... 

The low yields of 6,6 -disubstituted-2,2 -bipyridincs recorded in Table I are probably the result of steric retardation of the adsorption of 2-substituted pyridines. This view is supported by the observation that 2-methylpyridine is a much weaker poison for catalytic hydrogenations than pyridine. On the other hand, the quinolines so far examined (Table II) are more reactive but with these compounds the steric effect of the fused benzene ring could be partly compensated by the additional stabilization of the adsorbed species, since the loss of resonance energy accompanying the localization of one 71-electron would be smaller in a quinoline than in a pyridine derivative. 

The 1,3-cyclopentanediyl (62) motif has been further expanded into a bicycUc module containing two fused five-membered rings. The 2,2-disubstituted... 

A new entry to exocyclic dienes was reported by Sha who uncovered that a radical cyclization of the vinyl iodide 100 can lead to the formation of an exocyclic dienes fused with a tetrahydrofuran ring. The cyclization is proposed to proceed in a 5-(n-exo)-exo-dig fashion <00OL2011>. 3,4-Disubstituted tetrahydrofurans can also be constructed via the cyclization of O-stannyl ketyls and allylic 0-stannyI ketyls onto electron-rich or electron-poor alkenes <00TL8941>. 

The base-catalysed ring contraction of 1,3-dioxepanes offers an attractive route to 4-formyl tetrahydropyrans (Scheme 14) , whilst fused exo-cyclic dienes 27 result from the radical cyclisation of alkenyl iodides 26 (Scheme 15) <00OL2011>. Intramolecular radical addition to vinylogous sulfonates is highly stereoselective, leading to the ci s-2,6-disubstituted tetrahydropyran (Scheme 16) . 

Contrasting with the reported formation of fused [l,3,4]thiadiazole rings in the course of the reaction of 3-substituted-4-amino-5-thio-47/-[l,2,4]triazoles 83 with various isothiocyanates (cf. Section 11.07.8.3, Table 3), the reactions with methyl isothiocyanate and with phenylisocyanate afford 3,7-disubstituted-6,7-dihydro-57/-[l,2,4]triazolo[4,3-f] [l,2,4]triazole-6-thiones 110 and -triazole-6-ones 111, respectively (Equation 29) <1986MI607, 1992IJB167>.The same reaction of 4-amino-l-methyl-3,5-bis(methylthio)[l,2,4]triazolium iodide 112 with aryl isothiocyanates yields the mesoionic compounds 113 (Equation 30) <1984TL5427, 1986T2121>. 

Synthesis of [1,2,3]triazolo[1,5-c]pyrimidines and [1,2,4]triazolo[1,5-c]pyrimidines A novel approach to [l,2,3]triazolo[l,5-c]pyrimidines is shown in Scheme 55. Batori and Messmer - in the course of their investigations on fused azolium salts - described a synthetic pathway to l,3-disubstituted[l,2,3]triazolo[l,5-c]-pyrimidinium salts <1994JHC1041>. The cyclization was accomplished by transformation of the hydrazone 436. This compound was subjected to an oxidative ring closure by 2,4,4,6-tetrabromo-2,5-cyclohexadienone to give the bicyclic quaternary salt 437 in acceptable yield. 

Because some of the compounds with general structure 316 have noteworthy pharmacological activities, a number of alternative methods have been developed for the synthesis of the 2-substituted and 2,3-disubstituted derivatives 316. 2-Substituted derivatives of 316 cis, n = 1, 2, 3, 4 trans, n = 2, 3, 4) were prepared (77GEP2643384 80AUP507798) from 312-315 with ethyl benzimidates. The attempted ring closure of trans-2-amino-l-cyclopentanecarboxylic acid to rra/w-fused derivatives failed. In this reac-... 

In the ring closures of the 1,2-disubstituted 1,3-difunctional cyclohexane, cycloheptane, and cyclooctane derivatives discussed in Sections II,A,B, and C, no appreciable differences were found in the reactivities of the cis and trans isomers. In contrast, very significant differences were observed in the cyclization reactivities of the cis and trans 1,2-disubstituted 1,3-difunctional cyclopentane derivatives, such as 1,3-amino alcohols, 2-hydroxy-l-carboxamides or /S-amino acids. Whereas the cis isomers reacted readily, their trans counterparts did not undergo ring closure in most cases. This difference was manifested in the formation of both d - and e -fused derivatives. 

Reactions of 4,5-disubstituted triazoles with appropriate substrates provide very useful methods for building triazolo fused bicyclic or tricyclic systems. 5-Azido-1,2,3-triazoles bearing an appropriate substituent (e.g., CHO, CN, CO2R) at the 4-position can be transformed with active methylene nitriles into tricyclic heterocycles (e.g., (368)) <86BSB679,87BSB587). A new tricyclic system, 5//-1,2,3-triazolo[5,l-c][l,4]benzodiazepine (e.g., (370) and (371)), is prepared by the intramolecular ring closure of triazoles (369) <89JHC1605). 

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