Synthesis of Six-Membered Nitrogen Heterocycles

Several different radical methods are available for the synthesis of six-membered nitrogen heterocycles. A manganese(III) acetate promoted addition of amino malonate radical to an alkene has been utilized for the preparation of an intermediate in the synthesis of loracarbef [95JOC6176]. The intermediate tertiary radical obtained by the 6-exo-trig process is trapped intramolecularly by one of the ester groups of the malonate. 

Boger has devised numerous synthetic schemes for the synthesis of six-membered nitrogen heterocycles based upon DA addition with subsequent rDA extrusion, and has reviewed the subject. Representative examples are shown for the synthesis of substituted pyridines (equation 95), substituted pyrimidines (equation 96) ° and substituted 1,2-diazines (equation 97). ... 

Scheme 15 Synthesis of six-membered nitrogen heterocycles in analogy with the oxygen...

A variant is the hetero-Diels-Alder, in which either the diene or the dienophile contains a heteroatom, most often nitrogen or oxygen. This alternative constitutes a powerful synthesis of six-membered ring heterocycles. 

The Stork s aza-annulation method with acrylamide180,181 has been used frequently for the synthesis of six-membered nitrogen-containing heterocycles. Recently, this reaction was applied to the synthesis of 315 and 316 from protected enamine 314 (equation 68)182. Compound 315 is a key intermediate in the synthesis of the alkaloid Huperzine A and its analogues. 

The synthesis of tetrahydroquinolines has received a great deal of attention owing to their presence in many natural frameworks and also to their pharmacological importance [59], Enantioselective [4 -1- 2] cycloadditions constitute one of the most widely employed tools for the preparation of six-membered nitrogen heterocycles [60], Among them, the Povarov reaction is one of the main approaches to... 

As six-membered heterocycles are present in a number of natural products and biologically important molecules, solid-phase synthesis of these has been reported very often (Fig. 3.9). Solid-phase synthesis for nearly every six-membered ring including one nitrogen atom are known piperidines (272) [376], tetrahydropyridines (273) [377, 378], dihydropyridines (274) [219, 379, 380], pyridines (275) [349, 381-386], (Scheme 3.37), piperidinones (276) [387], dihydropyridones (277-279) [313, 378, 388-390], pyridinones (280-281) [328, 329] and piperidindiones (282) [391] derivatives. In contrast, the synthesis of six-membered rings with one single oxygen is rarely described. Nevertheless, solid-phase synthesis of dihydropyrans (283-284) [392-394] and tetrahydropyrans (285) [335, 336] has been reported. 

Carbene reactions have not been widely utilized for the synthesis of six-membered heterocycles containing two nitrogen atoms. 

Six-membered nitrogen heterocycles are found in a wide variety of naturally occurring alkaloids, and are often incorporated into the design of biologically active pharmaceutical products. Of the many ways to construct these heterocycles, the aza-annulation of enamine substrates with a,(J-unsaturated carboxylic acid derivatives has been a versatile and efficient method for the formation of dihydropyridone and pyridone products. The synthetic utility of this approach has led to incorporation of aza-annulation methodology as a key step in the synthesis of a number of interesting heterocyclic molecules. 

Lastly, Roth has described the reaction of cobalt-complexed propargyl cations with enamines leading to intermediate iminium ion salts which were treated in situ with carbon nucleophiles decomplexation gives precursors for the synthesis of five- and six-membered nitrogen heterocycles [204],... 

Hetero Diels-Alder cycloaddition reactions are of great importance in organic chemistry for the synthesis of six-membered heterocyclic ring systems. " In the past heterodienophiles and -dienes with one or more oxygen, nitrogen or sulfur atoms have been examined in thermal and Lewis acid-catalyzed reactions. " ... 

Synthesis of selenophenes condensed with six-membered nitrogen heterocycles 12KGS1057. 

Tetrahydropyrrolizines (210) and (211) can be formed via radical scission of either bond a or b in the intermediate vinyl-aziridine (208) but yields are moderate at best and the major product is the monocyclic pyrroline (209), formed by a 1,5-homo-dienyl rearrangement. The route therefore could provide a useful access to the pyrrolizidine framework if conditions could be identified which would allow more controlled and efficient breakdown of (208). The synthesis of substitute pyrrolines by ring expansion of vinyl aziridine derivatives has also been accomplished in a palladium-catalysed reaction. N -Tosyl-2-vinyl five- and six-membered nitrogen heterocycles (213) ace obtained in generally high yields under mild conditions from precursor dienyl nitrogen heterocycles (212) in the presence of a catalytic amount of [Pd(PPh ) ]. The complete diene unit is required for the... 

Rapoport and co-workers have reported a general synthesis of nitrogen, oxygen, and sulphur heterocycles (218) by rhodium-catalysed intramolecular N-H, 0-H, or S-H insertion reactions.of keto-ester precursors (217)- This reaction is well documented as an efficient route to B-lactams but this group has now shown that the reaction works well for the synthesis of five-and six-membered nitrogen heterocycles (Scheme 22). The reaction fails for seven-membered nitrogen heterocycles in this case C-H insertion to give a eyelopentanone is the preferred reaction mode. 

Given the distinct six-membered nitrogen heterocyclic motif of many structurally diverse and exciting alkaloids, we recognized that our aza-[3+3] cycloaddition can be a powerful synthetic strategy in alkaloid synthesis, and that it represents both an attractive and complimentary approach to aza-[4+2] cycloadditions in constructing piperidines (Figure 12.1). While aza-[4+2] cycloadditions remain a versatile synthetic method, aza-dienes and imines employed for aza-[4+2] cycloadditions are not always the most... 

Despite the availability of various existing synthetic procedures, apphcation of RCM in the synthesis of polyhydroxyindolizidines recently became increasingly popular. The skeletons of all alkaloids described below were produced according to the same strategy involving N-alkenylation and RCM for the formation of five- and six-membered nitrogen heterocycles (Scheme 2.17). 

Alkaloids incorporating six-membered nitrogen heterocycles are abundantly present in nature and occur in a multitude of alkaloid natural product families. Many of these alkaloids exhibit a wide range of diverse biological activities. As a result, extensive research has been devoted to the synthesis of many of the natural products and derivatives. This has led to an enormous variety of synthetic methodology that has been efficiently applied to synthesize many of these alkaloids. Among these methods, metathesis-based processes have played an increasingly important role as is illustrated in the sequel. 

Thus, the reaction of 4-dialkylaminobut-3-yn-2-ones with various bifunctional reagents makes it possible to carry out a targeted synthesis of five- and six-membered nitrogen-, oxygen-, and sulfur-containing heterocycles having two heteroatoms. 

In this section the synthesis of coumalic acid (92), representing the a(2)-pyrone system, is described. a-Pyrones readily undergo a simple lactone-amide transformation, and the conversion of coumalic acid into the tautomeric 6-hydroxy-nicotinic acid (93) provides a further illustration of the conversion of a six-membered oxygen heterocycle into the corresponding nitrogen system. 

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