Reactions with Five-Membered Heterocyclic Rings

Reactions with Five-Membered Heterocyclic Rings 

With a few recent exceptions the reactions in this group have been with the a-ketocarbenes, CH COOMe, CH COOEt, and CH-COCHs, derived from the corresponding diazo compounds. Sorm and coworkers have reported the ring-opening of furan and methylfurans upon reaction with diazoacetone decomposed by copper, via attack at 

Muller, H. Kessler, H. Fricke, and H. Suhr, Tetrahedron Letters 16, 

The only known reaction of a furan with a dihalocarbene is that recently reported between benzofuran and dichlorocarbene in hexane at 0°. The initial adduct (7) could not be isolated but on hydrolysis gave the ring-expanded product 8, possibly via 9, in 15% yield. Benzothiophene was recovered in 92% yield under the same conditions. 2,5-Dihydrofuran reacted with dichloro- and dibromo-carbene to give the products of allylic insertion, 2-dihalogenomethyl-2,5-dihydrofuran, as well as the normal addition products.  

There is plainly still much scope for systematic work on these reactions. 

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II. Reactions with Five-Membered Heterocyclic Rings.63... 

Some examples of ring opening reactions with carbanions leading to five-membered heterocyclic ring formation are shown in Scheme 85. Pyrrole syntheses from functionally substituted oxiranes and amines are often described and typical examples are shown in Scheme 86. 

The 1,3-dipolar molecules are isoelectronic with the allyl anion and have four electrons in a n system encompassing the 1,3-dipole. Some typical 1,3-dipolar species are shown in Scheme 11.4. It should be noted that all have one or more resonance structures showing the characteristic 1,3-dipole. The dipolarophiles are typically alkenes or alkynes, but all that is essential is a tc bond. The reactivity of dipolarophiles depends both on the substituents present on the n bond and on the nature of the 1,3-dipole involved in the reaction. Because of the wide range of structures that can serve either as a 1,3-dipole or as a dipolarophile, the 1,3-dipolar cycloaddition is a very useful reaction for the construction of five-membered heterocyclic rings. 

The common feature of the first set of examples discussed is the coupling of an arylpalladium complex, formed in oxidative addition, with a five membered heterocyclic ring via the formal displacement of a hydrogen atom. This reaction, formally a Heck coupling, is often called the heteroaryl Heck reaction . 

In some cases the reaction is accompanied by a five-membered heterocyclic ring closure. For example, l-nitro-4-methoxynaphthalene 265 reacts with p-tolylpro-penylsulfone to give benzo[/z]quinoline 266 (35%) together with A-hydroxybenzo-pyrrole derivative 267 (14%) (Scheme 77) (00EJO521). Annulation of the pyridine ring may proceed via anion 268, whereas the formation of benzoindole 267 occurs via neutral alkene 269. 

Prior to, and perhaps also after, the formation of the a complex, a 77 complex (with the aromatic ring behaving as electron donor) can form, although it has not been proved that its formation is a necessary step in the reaction path.44 It has recently been suggested that the formation of the n complex could in some cases become rate-determining, when the electrophile is a very powerful one.45 This hypothesis, although questioned both from the experimental and theoretical point of view,46-48 is a possibility and could be applicable also when the aromatic substrate is a powerful nucleophile (as is the case with many five-membered heterocyclic rings). 

The reaction of five-membered heterocycles with acetylenecarboxylates under conditions of cycloaddition occasionally yielded bicyclic intermediates which rearranged to the ring expanded products on heating compare examples (1) and (2) in Scheme IV/11, and Chapter III, Scheme III/4. If more polar starting materials (Scheme IV/11, entries 3 and 4) are used, it is not possible to... 

Dipolar Cycloadditions. 1,3-Dipolar cycloadditions provide a powerful method for the synthesis of five-membered heterocyclic rings. The use of (5,5)-r-Bu-box in combination with Cu(OTf)2 as catalyst for the reaction of a nitrone with ethyl vinyl ether leads to the products in 93% yield (eq 23). The diastere-oselectivity is exo-selective, as the product was obtained in an endo/exo ratio of 83 16. A change of the counterion in the cata-... 

An intramolecular analogue of the aforementioned reaction has been encountered during the Darzens condensation of a-bromo ketones with two equivalents of an aryl aldehyde (94TL9367). The intermediate a-keto oxiranes engage in aldol additions to the second aldehyde equivalent before cyclizing to the five-membered heterocyclic ring (Scheme 27). 

Examples of five-membered heterocyclic rings prepared by aza-Wittig and related methods include the alkaloid leucettamine B (206) and pyrrolo[2,3-b]pyridines (207) (Scheme20). The aza-Wittig reactions of the iminophosphorane (208) with methyl isocyanate, carbon dioxide, or carbon disulfide give heterocumulenes (209), (210), and (211), respectively, which react with amines or ammonia to provide a route to the framework of aplysinopsin alkaloids (212). ... 

Biological tests show that 3-carboxamide (251), compared with cephalothin, displays equal Staphylococcus activity but is less active against other bacteria (Table XXVII). Other 3-carboxamides were prepared from the 3-carboxylic acid chlorides or mixed anhydrides (U.S. Patent 3,953,436). The 3-nitrone derivative was also used to prepare various five-membered heterocyclic rings at C-3 via 1,3-dipolar cycloaddition reaction with various dipolarophiles. In general, these derivatives showed considerable loss in biological activity (Spry, 1975a,b). 

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