Construction of the Heterocyclic Ring

The only report concerning the construction of the heterocyclic ring of diazafluorenes was described in CHEC-11(1996) <1996CHEC-II(7)921> using a variant of the Hantzsch pyridine synthesis. Somewhat surprisingly, no further reports using this method have been found. 

This chapter shows how just a few general principles allow one to understand the methods which are used in the construction of the heterocyclic ring of an aromatic heterocyclic compound from precursors that do not have that ring. It discusses the principles, and analyses the types of reaction frequently used in constructing an aromatic heterocycle, and also the way in which appropriate functional groups are placed in the reactants, in order to achieve the desired ring synthesis. 

Pyrimidines used to be prepared via the construction of the heterocyclic ring as shown in Fig. 35. A 4-substituted-cyano-benzene is subjected to treatment with hydrogen chloride gas in an ethanolic solution, after the reaction is complete ammonia is bubbled into the solution to yield the ami-no-imine, which in turn is reacted with a suitably substituted phenyl diethyl malo-nate to give the dihydroxypyrimidine. The hydroxyl groups are removed by chlorination with phosphorus oxychloride followed by hydrogenation over palladium. The first part of this synthetic pathway is relatively straightforward, but the latter stages can result in poor yields if not performed correctly. 

The axially chiral catalyst 26 was prepared by construction of the heterocyclic ring via a cobalt-catalyzed [2+2-I-2] cycloaddition of diyne 52 and the enantiopure. 

This ring system can be constructed by building one of the two heterocyclic rings on the other preformed ring the construction of the thiazeto ring on a quinoline moiety or generating a pyridine ring on a... 

Another approach to the construction of the central ring is an intramolecular cyclization of a substrate composed of two six-membered heterocycles and bridged by a one-atom unit. This method has been applied to the synthesis of derivatives of 3, 6, 12, and 13 C1995BML163, 1996JHC1147, 2001JHC1173, 2002T5733>. 

The construction of the central ring can also be accomplished by a radical cyclization of a non-fused heterobiaryl system composed of two six-membered heterocycles and linked by a two-atom bridge. An example is the synthesis of 106 from the bromo derivative 105 in the presence of AIBN and Bu3SnH (Equation 8) <1999TL4073>. 

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

The preparation of compounds with a six-membered heterocycle fused to a six-membered carbocyclic ring is one of the most researched areas in organic chemistry. However, there are few examples for the construction of the carbocyclic ring. There are several review articles in this area <1984CHEC(2)395, 1984CHEC(3)599, 1996CHEC-II(7)921>. 

Most benzo-fused heterocyclic systems are constructed from a substituted benzene by synthesis of the heterocyclic ring. Similarly most bicyclic heterocycles with heteroatoms in both rings commence with a monoheterocycle and build on the second heterocycle. However, substituent modification and, to a lesser extent, substituent introduction are also important, particularly in the later stages of a synthesis, and we now survey available methods for this. 

The second category consists of starting from an appropriately mono- or di-substituted heterocycle and introducing the fifth atom, with the formation of two bonds (Scheme 49). An alternate method of construction of the second ring by forming two bonds is also shown in Scheme 49. It should be emphasized, however, that the classification involving the formation of two bonds is very arbitrary and is based on the overall synthesis. 

The acid-catalyzed cyclization of appropriate aryloxyketones formed benzo[l,2-6 5,4-6 ]difuran and benzo[ 1,2-6 4,5-6 ]difuran (63BSF1003). Another variation involved the cyclization of an aryl thioacetal to a benzo[l,2-6 4,5-6 ]dithiophene <86CB3198>. In investigations of the synthesis of a unit of the CC-1065 skeleton (see Section 7.21.12), a carbene derived from the azo-compound (59) constructed the cyclopropano-fused benzodipyrrole (60) by simultaneous formation of the heterocyclic ring and the cyclopropane ring <83TL4773>. 

The construction of a heterocyclic ring from two reagents, one of which contains a nitro group, is widely used in the synthesis of the nitro derivatives of pyrazole, isoxazole, and 1,2,3-triazole. Thus, for example, the reaction of sodionitromalonal-dehyde with substituted hydrazines leads to the corresponding derivatives of 4-nitropyrazole [33, 61, 471 173] (Scheme 63). 

Bis(tributylstannyl)oxide ° andtrimethylstannyldimethylamide react similarly. A recent example of a more elaborate tinalkoxide, 407 is used in the construction of a heterocyclic ring 408. ... 

Under Lewis acid catalysis several imines react with the sterically hindered diene shown in Eq. (73) to form cyclic products. This acts as a useful means of construction of fused heterocyclic ring systems bearing an angular methyl group as a characteristic feature [111]. 

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