Reliable Functionalization of 5,6‐Fused Bicyclic N‐Heterocycles Pyrazolopyrimidines and Imidazopyridazines via Zinc and Magnesium Organometallics

Abstract

DFT‐calculations allow prediction of the reactivity of uncommon N‐heterocyclic scaffolds of pyrazolo[1,5‐a]pyrimidines and imidazo[1,2‐b]pyridazines and considerably facilitate their functionalization. The derivatization of these N‐heterocycles was realized using Grignard reagents for nucleophilic additions to 5‐chloropyrazolo[1,5‐a]pyrimidines and TMP2Zn ⋅ 2 MgCl2 ⋅ 2 LiCl allowed regioselective zincations. In the case of 6‐chloroimidazo[1,2‐b]pyridazine, bases such as TMP2Zn ⋅ MgCl2 ⋅ 2 LiCl, in the presence or absence of BF3 ⋅ OEt2, led to regioselective metalations at positions 3 or 8. Subsequent functionalizations were achieved with TMPMgCl ⋅ LiCl, producing various polysubstituted derivatives (up to penta‐substitution). X‐ray analysis confirmed the regioselectivity for key functional heterocycles.

Dihydroazolopyrimidines: Past, Present and Perspectives in Synthesis, Green Chemistry and Drug Discovery

“…[55,[62][63][64][65] Together with the corresponding aldehydes, the products of their further transformations and rearrangements can also be formed under these conditions (Scheme 7). [23,63,65] The reduction of dihydrozolopyrimidines by sodium borohydride [34,35,[66][67][68][69][70][71] or sodium cyanotrihydridoborate [72] into the corresponding tetrahydro derivatives (reaction k, Scheme 8) is usually stereoselective -one of the possible enantiomer pairs is formed. It should be noted that compounds substituted on the N atom of the pyrimidine ring are not reduced under these conditions.…”

“…It should be noted that compounds substituted on the N atom of the pyrimidine ring are not reduced under these conditions. [70] A common property of the dihydro derivatives of azolopyrimidines is their ability to heteroaromatize, which can be achieved preparatively by the action of Nbromosuccinimide, [16,18,19,34,35,56,64,66,[73][74][75] Br 2 /HOAc, [35,60,76,77] I 2 , [78] SeO 2 , [35] PhI(OAc) 2 , [79] CrO 3 , [80] NaNO 2 /HOAc (R 1= COOEt), [81] 2,3-dicyano-5,6-dichloro-pbenzoquinone, [72,82,83] Na 2 S 2 O 8 , [84] ammonium cerium (IV) nitrate, [85] potassium permanganate, [86] manganese (IV) oxide [50] (reaction l). Sometimes the dehydration of dihydro derivatives (reaction I) can occur as a secondary process during their synthesis.…”

“…The reduction of dihydrozolopyrimidines by sodium borohydride [34,35,66–71] or sodium cyanotrihydridoborate [72] into the corresponding tetrahydro derivatives (reaction k , Scheme 8) is usually stereoselective – one of the possible enantiomer pairs is formed. It should be noted that compounds substituted on the N atom of the pyrimidine ring are not reduced under these conditions [70] …”