Heteroaromatics, substitution patterns

Structure elucidation does not necessarily require the complete analysis of all multiplets in complicated spectra. If the coupling constants are known, the characteristic fine structure of the single multiplet almost always leads to identification of a molecular fragment and, in the case of alkenes and aromatic or heteroaromatic compounds, it may even lead to the elucidation of the complete substitution pattern. 

In the case of alkenes and aromatic and heteroaromatic compounds, analysis of a single multiplet will often clarify the complete substitution pattern. A few examples will illustrate the procedure. 

The first class of amine-based nucleophilic catalysts to give acceptable levels of selectivity in the KR of aryl alkyl. yec-alcohols was a series of planar chiral pyrrole derivatives 13 and 14, initially disclosed by Fu in 1996 [25, 26]. Fu and co-workers had set out to develop a class of robust and tuneable catalysts that could be used for the acylative KR of various classes of. yec-alcohols. Planar-chiral azaferrocenes 13 and 14 seemed to meet their criteria. These catalysts feature of a reasonably nucleophilic nitrogen and constitute 18-electron metal complexes which are highly stable [54-58]. Moreover, by modifying the substitution pattern on the heteroaromatic ring, the steric demand and hence potentially the selectivity of these catalysts could be modulated. 

N-Arylations of amines have also been realized with support-bound heteroaromatic halides (Entries 9-11, Table 10.4). Several examples of the synthesis of substituted 1,3,5-triazines [83-85], purines [78,85-93], and pyrimidines [77,85,94—96] have been reported. The reactivity of these arylating agents depends strongly on their precise substitution pattern, and generally increases with decreasing electron density of the het-eroarene. Illustrative examples are given in Table 10.4. The arylation of amines with simultaneous cleavage of the product from the support is discussed in Section 3.8. 

The theme of this review is the construction of heteroaromatic nitro compounds from open-chain nitro-containing precursors. Such synthetic procedures offer two specific advantages over nitration of a preformed heterocycle (i) emergence of novel substitution patterns, and (ii) retention of substituents which might be vulnerable to destruction by the reagents or conditions employed for nitration. 

The reaction of thiopyrylium salts with amines can afford different products, depending on the substitution pattern of the heteroaromatic cation, the nature of the amine, and reaction conditions. In most cases... 

Of the 5-membered heteroaromatic systems, pyrrole reacts most like benzene in alkyne photocycloaddition, giving a 3,4-disubstituted azepine by 2,3-cycloaddition followed by electrocyclic ring-opening fequation 73) . Azepines with a different substitution pattern have been made by therpial 2,5-addition of an alkyne to a pyrrole, followed by photochemical ring-closure and thermal ring-opening of the tetracyclic photoproduct (equation 74) . 

To a large extent the substitution pattern of the amine is variable (24, 52-54). There are more restrictions for the aldehyde component. For the piperidone synthesis, most five- or six-ring aromatic or heteroaromatic aldehydes, as well as their ring-substituted derivatives, can be used (53, 55-57), but so far only a few aliphatic mono- and dialdehydes (e.g., formaldehyde, acetaldehyde, isobutyr-, glutar-, and succinaldehyde) have found their way into the bispidine preparation. 

Regio-chemical control and outcome are important aspects in terms of using the reaction. Aromatic azine s amination is subjected to variables such as the compound s class, substituents, substitution pattern, reaction condition and consequently the reaction mechanism. All variables are used for predicting and explaining the regio-chemical outcome for the reaction. Although it is outside the scope of this summary to provide examples from every heteroaromatic azine used synthetically, below is a sample of some representative examples. 

Benzo- as well as heteroaromatic systems were obtained allowing for a variable substitution pattern in the benzoazepine frameworks. To access the dibenzo-diazepine or dibenzoxazepinone frameworks according to C-N cross-coupling methodology, a different strategy had to be pursued. The introduction of the nitrogen atom or the amide functionaHty was accompHshed by the condensation of ammonia with keto- or ester-carbonyl frmctionaHties (Scheme 13.96 and Scheme 13.97) [142],... 

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