Relative ortho‐directing power of fluorine, chlorine and methoxy group for the metalation reaction in the diazine series. Diazines XXXV

Abstract

The regioselectivity of the metalation of 2‐chloro‐6‐methoxypyrazine, 2‐fluoro‐6‐methoxypyrazine and 3‐fluoro‐6‐chloropyridazine was studied; the relative ortho‐directing power was F > OMe > Cl.

Functionalization of diazines and benzo derivatives through deprotonated intermediates

“…With 3-chloro-6fluoropyridazine, metalation using either LDA or LTMP in 65 THF at low temperature took place next to the smaller halogen. 22 With a pivaloylamino group instead, reaction using LTMP in THF at -70 °C occurred randomly whereas employing LDA (4 equiv.) exclusively afforded deprotonation at the position adjacent to the halogen, providing after 70 trapping with acetaldehyde or benzaldehyde the expected alcohols in 68-82% yields.…”

“…55b,c Recourse to 30 very hindered base lithium N-tert-butyl-N-(1isopropylpentyl)amide (LB 1 ) lowered the regioselectivity at the position adjacent to the methoxy group. 22 Replacing the chloro group with an iodo resulted in a complete regioselectivity when LDA was used in THF at -70 °C. 55b 35 When 2-fluoro-6-methoxypyrazine was allowed to react with LDA in THF at -70 °C for 5 min, trapping with aldehydes showed deprotonation mainly occurred next to the fluoro group (96:4 ratio); LTMP and N-tert-butyl-N-(1isopropylpentyl)amide (LB 1 ) gave lower selectivities.…”

“…55b When 2-fluoro-6-methoxypyrazine was allowed to react with LDA in THF at 270 uC for 5 min, trapping with aldehydes showed deprotonation mainly occurred next to the fluoro group (96 : 4 ratio); LTMP and N-tert-butyl-N-(1-isopropylpentyl)amide (LB 1 ) gave lower selectivities. 22 6-Chloro-2,3-dimethoxyquinoxaline features an interesting case of regioselectivity. Treatment with LTMP (4 equiv.)…”

Development of a Late-Stage Diversification Strategy for the 4- and 5-Positions of 4,5,6-Trisubstituted Indazoles

“…With the requisite 4,6-disubstituted indazoles in hand, our attention turned to the regioselective C–H functionalization of the C5-position. Although 1 H NMR analysis indicated that the C7-proton is likely most acidic, we speculated that the C4-fluorine could serve as a directing group to achieve deprotonation at the C5-position. − Quenching the anion with an electrophilic chlorinating agent would provide desired indazole 3c .…”

A Strategy for the Total Synthesis of Dragmacidin E. Construction of the Core Ring System

“…A number of schemes for the preparation of the cycloheptenone 9 could be envisaged, one of which involves an intramolecular Heck reaction of the halopyrazine 11 . It seemed likely that the haloindole substituent would tolerate this transformation based on the well-precedented superior reactivity of pyrazinyl halides toward oxidative addition. 4e-h Finally, the pyrazine 11 could be assembled by addition of the appropriate metalated pyrazine to the readily available, optically pure aldehyde 12 2 …”