A New Cyclization to Fused Pyrazoles Tunable for Pericyclic or Pseudopericyclic Route: An Experimental and Theoretical Study

Abstract

2-Pyrazinyl (2) and 3-pyridazinylketone arylhydrazones (6) and their benzologues undergo a ring closure reaction to yield pyrazolo[3,4- b]pyrazines (4) and pyrazolo[4,3- c]pyridazines (7), respectively, in acceptable to good yields. The reaction was found to be accelerated by using acidic or basic conditions. Quantum chemical calculations suggest the key step of the mechanism to be a direct cyclization; analysis of aromaticity based on computed magnetic properties revealed its medium-dependent pericyclic or pseudopericyclic character. The cyclization reaction has also been extended for the synthesis of related ring systems ( 9, 12, 14).

Studies with Azinylacetonitriles: 2-Pyridylacetonitrile as a Precursor to Functionally Substituted Pyridines

“…Structure 14 was excluded based on 1 H-NMR and 13 C-NMR that revealed the absence of signals for a sp 3 carbon or protons linked to such a carbon ( Scheme 3 ). It can thus be concluded that while compound 1 is a versatile precursor to azolylpyridines, conversion of compound 2 to pyrazolo[4,3- b ]pyridine via a route similar to that reported for converting 8 into 9 could not be effected, at least under the conditions reported in the published work [ 13 ].…”

“…The behavior of 2 towards hydroxylamine is thus similar to that of other hydrazononitriles and differs from that of 2- p -nitrophenyl-2-arylhydrazonoacetonitrile where rearrangement preceded cyclization affording 1,2,4-triazoles 7 . Although 2-arylhydrazono-2-acetylpyridine 8 has been recently reported to afford 9 when heating in dichlorobenzene at 190 °C, in our hands, compounds 2a-c have been recovered unaffected under these conditions [ 13 ]. It seems that replacing a methyl by a cyano group affects the HOMO-LUMO energy of the cyclised 6π electron system as this cyclization is believed to proceed by a pericyclic rule.…”

1,5‐electrocyclization versus 1,5‐proton shift in imidazolium allylides and 2‐phospha‐allylides: a DFT investigation

“…In this connection, they developed a simple and effective criterion, namely the NICS, which is the negative of the computed magnetic shielding at or above the ring centers 49–51. This parameter has been used to distinguish between pericyclic and pseudopericyclic mechanisms 52, 76. We determined the NICS values of the transition structures involved in the pericyclic and pseudopericyclic pathways (Table 2).…”

“…In connection with the theoretical investigation of the Diels‐Alder reaction of butadiene and ethylene, Houk and coworkers54 compared different theoretical levels for the calculation of the reaction enthalpies and activation barriers and found that the values obtained by using B3LYP hybrid functional with 6‐31G* basis set were the best and close to the experimental values. Likewise, computations were carried out at B3LYP/6‐31G* level to investigate the mechanism of 1,5‐electrocyclization of azinyl and diazinyl ketone hydrazones to fused pyrazoles 52. Arduengo et al 18–20.…”

“…Although various methods31, 48 have been used to distinguish between pericyclic and psuedopericylic transition structures, computation of the magnetic properties, particularly the nucleus independent chemical shift (NICS) values49–51 at the (3,+1) critical point in the transition structure involved has been found to be most convenient and computationally least expensive. In a recent report, pericyclic or pseudopericyclic cyclization of azinyl and diazinyl ketone hydrazones to fused pyrazoles could be determined on the basis of the NICS values of the involved transition structures 52…”