Formation of the 4,5 bond

This is an uncommon synthetic approach to imidazoles, being largely confined to examples in which an active methylene group cyclizcs on to a nitrile carbon. There are, naturally, no such examples of benzimidazole synthesis. 

4-Aniinoimid.izoles (3) and (4) and precursors (5) and (6) made by alkylation of (1) and (2) by a-halogenocarbonyl reagents in basic medium 

A mixture of (1) (R = Ph) (1.5 g) and ethyl bromoacctate (1.7g) with dry, powdered potassium carbonate (1.4 g) in absolute ethanol (10-15 ml) is warmed at 75-80°C for 30 min. The cooled solution is then stirred into 150 ml of W ater, treated with a little acetic acid, concentrated, and allowed to stand at room temperature. The product which separates is filtered and recrystallized from ethanol, giving (5) (R = Ph, R = H, R = OF.t) (1.9 g, 85%), m.p. 84-86 C. 

The above phenylformamidinc (2.1 g) (note the crude product can also be used in the cyclization step) is warmed in a sodium cthoxide solution made by dissolving sodium (0.5 g) in ethanol (15 ml). All of the phenylformamidinc dissolves in 3-5 min.. After 15min a 2- 3-fold volume of water is added to the solution, which is allowed to stand (1 h) to crystallize. Recrystallization from ethanol gives nearly colourless crystals (1.8 g, 85%), m.p. 97-99 C. 

When carbanions are generated from the products of reaction between az.irines and foimamidine, a similar process also leads to imidazoles in moderate yields. Azirincs are, however, rather too exotic as substrates to make this an appealing synthetic approach [4]. Treatment of perhydro-l,3-thiazine-2-thione wilh trifluoracetic anhydride gives an imidazothiazine [5]. 

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A few isothiazoles, 2,1-benzisothiazoles and monocyclic sultams have been prepared by methods involving formation of the 4,5-bond. Thus, condensation of a-cyanooximes (179) with ethyl mercaptoacetate or related compounds gives a compound (180) which cyclizes... 

A new method of synthesis162 of the imidazole ring by the use of A-cyaniminodithiocarbonic esters (41) involves formation of the 4 5-bond. Reaction of (42) with KNCO in acetic acid yielded the corresponding amide (43) which was cyclized by sodium hydroxide to the substituted purine (44). Treatment of (42) with Raney nickel and hydrogen produced 4-amino-5-carbethoxy-l-methyl-4-imidazo-line (45), which could also be cyclized to a purine (46).162... 

In an alternative use of thioamides, the ring-closing step involves the formation of the 4,5-bond of thiophene product (Scheme 70) [113]. 

Extrapolating the vinylogous amide theme, 2-amino-5-acylthiophenes can be prepared from 3-amino-thioacrylamides, with the formation of the 4,5-bond in the ring closing step [114—117]. Thus, 3-amino-thioacrylamides 45 are S-alkylated... 

DimethyIcholesteryi tosylate (26 solvolyses [46,48] at a rate intermediate between the 4 a- and4jS-methyl compounds, the products being explained in terms of a cation (27) in which C(4) bears a major part of the change by virtue of its tertiary character. The formation of the A-nor-diene (28) can then proceed by complete rupture of the 4,5-bond, with loss of the C(3)-proton, whilst the major alcoholic product (29) arises from attack of a water molecule on the electron deficient C<4). Although 4,4-dimethyl-i cholesterol was not obtained directly... 

The reaction sequence of Scheme 3 might well be classified as an imidazole synthesis from other heterocycles, but it seems more logical to treat this as a cyclization involving formation of the 1,5-bond. The enaminoketone condensation products (12) of 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl compounds are cyclized by base to imidazoles (13) in 60-80% yields." Such a reaction makes use of the well-established general attack of a nucleophilic center in the side chain on N-2 of the oxadiazole ring. Benzamidine combines with 2-amino-3-phenacyl-l,3,4-oxadiazolium bromides to produce 1-acyl-amino-2-benzimidoylamino-4-arylimidazoles. ... 

Catalytic hydrogenation of l-chloropyrrolo[l,2-a]quinoxalines results in removal of the halogen atom. Apparently the dechlorinated products are themselves reducible, and care must be taken in dechlorinations to allow the absorption of only one mole of hydrogen. A recent paper describes reduction of the 4,5 bond in pyrrolo[l,2-a]quinoxalines. 1,5-Dihydro-1-0X0 compounds are resistant to hydrogenation at atmospheric pressure. Reduction of the 1-oxo compound 117 over palladium on charcoal at 2000 psi gave an unidentified tetrahydro derivative. " The dioxo compounds 118 have been reduced with lithium aluminum hydride to give the hexahydro products 119. Heating 4,5-dihydro-4-thioxo derivatives with Raney nickel results in formation of the aromatic, desulfurized compound. Stannous chloride has been used to reduce... 

During indolization of the 3, 6 and 7-quinolylhydrazones, formation of the new C-C bond occurs between the appropriate carbon atom of the ketone/aldehyde moiety and the 4, 5 and 8 carbon atoms of the quinoline nucleus. It is consistent with the mechanism of formation of the C-C bond during indolization and the direction of electrophilic substitution in the quinoline nucleus. °... 

B. Syntheses of Isoxazoles Involving Formation of the 1—5 and 3—4 Bonds of the Ring... 

Recently the synthetic method involving formation of the 1—5 and 3—4 bonds has been extended to the preparation of the completely hydrogenated system of A -substituted isoxazolidines (42). This interesting reaction results from 1,3-dipolar addition of nitrones (41) to olefins. " ... 

Reduction of 3,5,5-tris-aryl-2(5// )-furanones 115 (R, R, R = aryl) with dimethyl sulfide-borane led to the formation of the 2,5-dihydrofurans 116 in high yields. However, in the case of 3,4-diaryl-2(5//)-furanones 115 (R, R = aryl R = H or r = H R, R = aryl), the reduction led to a complicated mixture of products of which only the diarylfurans 117 could be characterized (Scheme 36) (88S68). It was concluded that the smooth conversion of the tris-aryl-2(5//)-furanones to the corresponding furan derivatives with the dimethylsulfide-borane complex in high yields could be due to the presence of bulky aryl substituents which prevent addition reaction across the double bond (88S68). 

Methyl-17/-l,5-benzodiazepin-2(37/)-one undergoes addition to nitrile imines at the 4,5-bond, e.g. formation of 33.-10 1... 

Oxygen-free reactions of psoralens, when in close proximity to the target, proceed via the first excited states in which the 3,4-and the 4, 5 7r-bonds of the pyrone and furan moieties, respectively, can undergo C4-cyclization reactions with, e.g., unsaturated bonds of lipids, or the C5=C6 double bonds of thymine in DNA. In reactions with DNA the psoralen is believed to intercalate with DNA in the dark. Subsequent irradiation at 400 nm usually leads to furan-side 4, 5 -monoadduct formation, whereas irradiation at 350 nm increases the formation of crosslinks in which the furan and pyrone rings form C4 cycloadducts to thymines on opposite strands [95], Subsequent irradiation of the 4, 5 -monoadducts at 350 nm leads to formation of crosslinks and conversion into pyrone-side 3,4-monoadducts. Shorter wave-... 

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