Condensed heterocycles

Synthetically, vicinal functionally substituted aryl- and hetarylacetylenes are promising intermediates for preparing different condensed heterocyclic compounds, taking into account the fact that these polyfunctional groups can be selectively involved in cyclization processes. 

The final chapter is by M. R. Grimmett of Otago, New Zealand, and is the third and final part of his survey of the halogenation of heterocyclic compounds. It deals with the halogenation of condensed heterocycles. The first two parts of this series appeared in Volumes 57 and 58 of Advances. 

Narasimhan, N. S., Mali, R. S. Heteroatom Directed Aromatic Lithiation Reactions for the Synthesis of Condensed Heterocyclic Compounds, 138, 63-147 (1986). 

A closely related route to a monocyclic dithiole derivative is shown in Scheme 122.186 The easy replacement of cobalt by sulfur in this type of process has analogy in the synthesis of a variety of condensed heterocycles from rhodacyclopentadienes (see Scheme 127 in Section IV,H,1) and cobaltacyclopentadienes (see Scheme 82 in Section IV,C,1). 

The Junjapjpa-Ila (JI)-Heteroaromatic Annulation A New General a-Oxoketene Dithioacetals Mediated Inverse Method for the Synthesis of Benzo/Condensed Heterocycles and Related Heteroaromatization Processes... 

The synthesis of novel heterocycle-fused troponoids was performed by reaction of the nitrosotropolone acetate 426 in neat thiazole at 70 °C giving the thiazole-condensed heterocycle 427 but in only 13% yield (Equation 196) <2004H(62)535>. 

Imidazo[2,l-/][[l,3,4]thiadiazoles 161 (Figure 33), containing practically planar and rigid heteroaromatic systems with two condensed heterocycles, which have different Tt-conjugation, have been identified as useful fragments for liquid crystal molecules <2002MI6>. 

Amino-substitution in more complex condensed heterocyclic rings, when in the 2- or 4-position relative to the ring nitrogen, leads to protonation at that site. So, for example, 2- and 4-aminopteridins ([72] and [73]) (pA -values 4 26 and 3-54, respectively) are... 

Similar studies have also been carried out on condensed heterocyclic systems with a bridgehead nitrogen. Indolizine [175] and its 2-methyl-, 1,2-, 2,6- and 2,8-dimethyl- and 1,2,3-trimethyl derivatives protonate preferentially on C-3 in trifluoroacetic acid, giving cations [176] (Fraser et al., 1962). In general, when position 3 is... 

To summarize the amides are most suitable for the formation, by ortholithiation, of condensed heterocycles and polycyclic aromatics (in which subsequent rings are formed by intramolecular attack on the amide group). In other cases the removal of the amide group may be problematic, though if carboxylic acids, aldehydes or hydroxymethyl-substituted compounds are required, alternative amide substituents may be used. 

Dithiazolidines containing o-quinonemethide structural units in the 3,5-positions (e.g. (99)) are converted by reagents with an activated CHj group into a range of condensed heterocyclic compounds not easily accessible otherwise (Scheme 14) <85S535,86PHA283>. 

In 1967 Cava and Pollack obtained derivatives of the fourth, so-called nonclassical , thienothiophene— thieno[3,4-c]thiophene (4), a condensed heterocycle with formdly tetracovalent sulfur (42)j. The reaction of 3,4-bischloromethyl-2,5-dimethylthiophene (141) with sodium sulfide afforded 4,6-dimethyl-lif,3ff-thieno[3,4-c]thiophene (142) periodate oxidation of 142 gave die corresponding sulfoxide (143) in 91% yield. Attempts to convert the sulfoxide (143) into the thieno-[3,4-c]thiophene by the method used for S3mthesizing benzo[c]-thiophene led only to polymer. However, 24% of adduct 144 and 10% of 145 were obtained by refluxing sulfoxide (143) with N-phenylmaleimide in acetic anhydride, indicating that the thieno[3,4-c]-thiophene was formed as an intermediate. 

Various heterocycles, but particularly thiopyrans, ring-open and reclose when reacted with amines to give a variety of condensed heterocycles, including [2,7]naphthyridines (Scheme 64) <1999CHE799>. 

Nitrones, picryl azide, tetracyanooxirane, fulminic acid (HCNO), nitrile oxides,65 and nitrile imines66 are also capable of trapping the bicyclo[4.2.0]octa-2,4,7-trienc system. These cycloadditions open up synthetic possibilities to cyclobutane-condensed heterocyclic systems (e.g., 13). 

Transition metal catalyzed insertion reactions offer a variety of alternate approaches for the preparation of heterocyclic rings, of which Heck reactions were utilised extensively to prepare rings with more than 6 atoms. At the end of this Chapter some examples of the use of insertion reactions in the formation of the carbacyclic part of condensed heterocyclic systems will also be presented. 

In an application of the Suzuki process, 2-chloroquinoline (141) has been converted into the condensed heterocycle 197 (Scheme 58) (89JHC1589). Thus, metalation, trimethyl borate quench, and hydrolysis affords the stable 3-boronic acid 195 which, upon subjection to cross coupling with ortho-iodo aniline in the presence of Pd(0) catalyst and base, affords the 3-arylquinoline 196. Acid catalysis converts this material into the in-dolo[2,3-f ]quinoline (197) in 35% overall yield. 

The synthetic utility of these derivatives towards the preparation of condensed heterocycles has been demonstrated. Thus, treatment of 252 with cyclohexanone under acidic conditions (66JOC3852) (Friedlander reaction) and molten urea affords the naphthyridine 253 and pyridopy-rimidinone 251, respectively (Scheme 76) (89JHC105). Application of these reactions on the isomeric iV-pivaloylamino pyridine ketones affords analogue heterocycles 254-257. 

According to structural indices AN and I, the aromaticity of non-condensed heterocycles varies in the sequence thiophene > pyrrole selenophene > tellurophene > furan. 

The chemistry of thienoquinolines has been explored to a limited degree. Two types (378,379) will be described in this subsection. The pharmacological interest in thieno[2,3-Z>]quinoline (378) and derivatives thereof stems from their isosteric and isoelectronic resemblance to acridine furthermore, (378) constitutes the sulfur analog of furoquinoline (Section 3.17.2.1.5), which is the parent system of a number of alkaloids. Thieno[3,4-6]quinoline (379) is an o-quinonoidal heterocycle which is of interest both for theoretical reasons compared with its isoconjugate analogues and as a synthon in Diels-Alder reactions for the preparation of other condensed heterocycles. 

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