Striking difference in nucleophilic substitution in 4,7-dichloro-[1,2,5]oxadiazolo[3,4-d]pyridazine 1-oxide by S-, N- and O-nucleophiles
Full article
| Journal |
Tetrahedron
ISSN: 0040-4020
, E-ISSN: 1464-5416
|
| Output data |
Year: 2026,
Volume: 192,
Article number
: 135094,
Pages count
:
DOI:
10.1016/j.tet.2025.135094
|
| Authors |
Chmovzh Timofey N.
1
,
Aysin Rinat R.
2
,
Kotov Egor D.
1,3
,
Gaisin Karim S.
1
,
Nasyrova Darina I.
1
,
Rakitin Oleg A.
1
|
| Affiliations |
| 1 |
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991, Moscow, Russian Federation
|
| 2 |
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, 119334, Russian Federation
|
| 3 |
D. I. Mendeleev University of Chemistry and Technology of Russia, Miusskaya sqr., 9, Moscow, 125047, Russian Federation
|
|
Funding (1)
A study of nucleophilic substitution in 4,7-dichloro[1,2,5]oxadiazolo[3,4-d]pyridazine 1-oxide 4 showed that the nature of the nucleophile has a significant effect on the position and number of substituted chlorine atoms. Treatment of the dichloride 4 with amines resulted in the selective substitution of the chlorine atom at position 4 or of two chlorine atoms, depending on the amount of amine used. The reaction with thiols does not stop at the formation of a mono-substitution product and leads to bis-substitution products regardless of the structure of the thiol, its amount and reaction conditions. The reaction of 4 with alcohols and sodium alcoholates is not regioselective and afforded a mixture of mono-substitution products at positions 4 and 7, while hydrolysis of 4 gave 4-chloro-7-oxo-6,7-dihydro-[1,2,5]oxadiazolo[3,4-d]pyridazine 1-oxide only. The results of DFT calculations of the first and second stages of SNAr substitution reactions showed that the reactivity of the chlorine atoms in positions 4 and 7 does not differ significantly, and the reason for the differences in reactivity is the presence of kinetic control for N-nucleophiles, thermodynamic control for reactions with O-nucleophiles, and muted effects for S-nucleophiles. The position of the oxygen atom of the N-oxide in furoxanopyridazines was rigorously proven by X-ray structural analysis data.