Functionalization heteroaromatic intermediates

Substitution of halogens on heteroaromatic rings is a common way to introduce new functionalities. The product from reaction 6 (Scheme 6) was required on a 100-g scale as an intermediate. In the literature, this exchange was done on a 5-g scale using ammonia in ethanol in a sealed tube under pressure for 6 h at 125-130°C with a yield of 76% (Bendich et al. 1954). Because of the lack of a suitable autoclave for high-pressure reactions, we choose the microwave reactor for scale-up trials. Using our Synthos 3000 equipment, we found suitable conditions with only minimal optimization at 170°C for 180 min and obtained the desired product on a 60-g scale in 83% yield. 

Lithiation of heteroaromatic compounds, especially nitrogen-containing systems, is an important methodology, because the lithiated intermediates can be easily functionalized in a regioselective manner by reaction with electrophiles. This process can be performed by deprotonation only at the ortho position of the heteroatom, but obviously the reaction is not possible at other positions . 

A mechanism for 1,2,5-thiadiazole formation was proposed in the 1960s (1967JOC2823) and seems to be reliable this includes the formation of the M-chlorodithio intermediate followed by chlorination of the nitrile function, ring closure, addition of the second molecule of sulfur monochloride and formation of the heteroaromatic 1,2,5-thiadiazole cycle (Scheme 18). 

A direct transformation of functionalized aromatic/heteroaromatic halides into sul-fones has been performed via reactions of organomagnesium intermediates with sulfur dioxide (Scheme 19).98 The ratio of sulfones has been considerably increased by the use of polar aprotic solvents such as DMF or DMSO and of allylic and primary halides. 

Heteroaromatic cations as key intermediates in synthesis of functionalized dihydroheteroaromatics 92BSB339. 

Mesoionic systems may be readily substituted by electrophiles. Thus the thiazolo mesoion (342) will couple with diazonium salts despite their relatively weak electrophilicity (80KGS621). Substitution in a fused heteroaromatic betaine azine ring, e.g. (343), also takes place with ease. The resonance form (344) of the mesoion (343) shows that the electrophile will attack at C-6. The substitution in this position is also predicted by MO calculations (73JHC487). Similarly the pyridine ring in pyridinium olates is active towards electrophiles and is substituted in the positions ortho and para to the olate function. Bromination of the 5-methyl derivative (321 R = Me) occurs exclusively in the 7-position which is rationalized via the intermediate (345). In the absence of a 5-substituent, attack in either the 5- or 7-position occurs the dibromide is readily formed. No bromination in the thiazole ring is observed. The 2-bromo derivative (346) has been made, however, by condensation between the appropriate mercaptopyridine and 1,1,2,2-tetrabromoethane. 

The most attractive route of the target quaternary heteroaromatic salts 2 appears to be the formation of the 7r-excessive moiety from conveniently functionalized pyridinium or imidazolium intermediates 89 [Eq.(15)], and this should be studied in detail for each case. For this purpose existing methods for the synthesis of azoles can be adapted as long as the selected procedure is performed in neutral or, better, in acidic media, owing to the presence of a cationic moiety in the key intermediate 89. 

They found that combination of the Ir(T) catalyzed C-H borylation and Suzuki coupling sequence led to a two-step, one-pot C-H Suzuki arylation that enabled direct transformation of the N-Boc pyrrole to the C3 arylated intermediate in 78% yield. Following installation of the required acyl group, an application of their oxidative Pd-catalyzed C-H alkenylation reaction enabled formation of the key structural architecture of the natural deliver the natural product. The orthogonal selectivity characteristics displayed by these C-H functionalization processes makes possible iterative functionalization of the heteroaromatic pyrrole core. Utilization of the highly versatile C-H borylation - Suzuki coupling to install the aromatic functionality opens up possibilities of facile analogue synthesis via this route. 

Much of the research on Vilsmeier reactions in the past 50 years has focused on expanding the scope of this transformation. Whereas the reaction was once limited to electron-rich aromatics and heteroaromatics, aliphatic substrates have increasingly been found to react with Vilsmeier reagents. Furthermore, alternate transformations of the iminium intermediate to form products with functional groups other than aldehyde have been developed. Finally, access to a diverse range of heterocycles is now possible due to discovery of substrate classes that are capable of undergoing intramolecular annulation reactions on the iminium intermediate. 

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