The Reactions of 6-(Hydroxymethyl)-2,2-dimethyl-1-azaspiro[4.4]nonanes with Methanesulfonyl Chloride or PPh3-CBr4.

Yulia V Khoroshunova,Denis A Morozov,Tatyana V Rybalova,Igor A Kirilyuk,Andrey I Taratayko,Dmitriy N Polovyanenko,Yulia S Sotnikova,Ilia V Eltsov,Nargiz B Asanbaeva,Sergey A Dobrynin

doi:10.3390/molecules26196000

Abstract

Activation of a hydroxyl group towards nucleophilic substitution via reaction with methanesulfonyl chloride or PPh3-CBr4 system is a commonly used pathway to various functional derivatives. The reactions of (5R(S),6R(S))-1-X-6-(hydroxymethyl)-2,2-dimethyl- 1-azaspiro[4.4]nonanes 1a–d (X = O·; H; OBn, OBz) with MsCl/NR3 or PPh3-CBr4 were studied. Depending on substituent X, the reaction afforded hexahydro-1H,6H-cyclopenta[c]pyrrolo[1,2-b]isoxazole (2) (for X = O), a mixture of 2 and octahydrocyclopenta[c]azepines (4–6) (for X = OBn, OBz), or perhydro-cyclopenta[2,3]azeto[1,2-a]pyrrol (3) (for X = H) derivatives. Alkylation of the latter with MeI with subsequent Hofmann elimination afforded 2,3,3-trimethyl-1,2,3,4,5,7,8,8a-octahydrocyclopenta[c]azepine with 56% yield.

Highlights

Activation of a hydroxyl group towards nucleophilic substitution via reaction with methanesulfonyl chloride or PPh3-CBr4 system is a commonly used pathway to various functional derivatives [1,2,3]
We reported on simple synthesis of (5R(S),6R(S))-2, 2-dimethyl-6-(hydroxymethyl)-1-azaspiro[4.4]nonane-1-oxyl 1a from commercially available 5,5-dimethyl-1-pyrroline N-oxide (DMPO) [4]
Close proximity of hydroxy and nitroxide groups make these compounds potential precursors of rigid spin labels, which might allow precise distance measurements via site-directed spin labeling—PELDOR technique [5,6]. Synthesis of these spin labels would require replacement of the hydroxyl group to methanethiosulfonate or maleimido moiety, and Appel reaction or treatment with methanesulfonyl chloride seems to be a proper step towards this direction

Summary

Introduction

Activation of a hydroxyl group towards nucleophilic substitution via reaction with methanesulfonyl chloride or PPh3-CBr4 system is a commonly used pathway to various functional derivatives [1,2,3]. We describe the reactions of 1a and its diamagnetic analogs (5R(S),6R(S))-1X-6-(hydroxymethyl)-2,2-dimethyl-1-azaspiro[4.4]nonanes 1b–d (X = OBn; OBz; H) with MsCl/NR3 or PPh3-CBr4 None of these reactions allowed us to isolate expected bromomethyl- or mesyloxymethyl-substituted compounds. To prepare N-benzoyloxy derivative 1d, the nitroxide 1a was treated with benzhydrazide in the presence of excess MnO2 [29] This method allowed us to avoid the acylation of hydroxymethyl group and afforded 1d with the yield of 81% as colorless oil not susceptible to oxidation to nitroxide (Scheme 7). IT1h).eTlhaettelartcteormcpoomupnodumndaymcaoyrrceosrproesnpdotnodthtoe the amianmoianlocoahlcool,haolt,yapitcyaplicbaylpbryopdruocdt uinctHinofHmoafnmnanelnimeilnimatiinoanticoonncdoitniodnitsio, nasr, easurletsuolft tohfe the subssutibtusttiitountiroenacrteiaocnti[o2n7][.2T7h].eTphreeppareraptaivraetiyvieelydieolfdthoef tmheaimn apirnopdruocdt uwcatsw7a0s%7,0t%he, tmheinmorinor observed in the reaction mixture, 83 and 1%, and a product with M = 197 g/mol (14% according to GC) (Figure S58, Table S1) The latter compound may correspond to the amino alcohol, a typical byproduct in Hofmann elimination conditions, a result of the substitution reaction [27]. Analysis of the 1H and 13C NMR data allows us to conclude that the isolated product contains a double bond of the >C=CH type; the assumption of the possible formation of a spirocyclic structure with an exomethylene fragment should be rejected. 2D-NMR spectra (Figures S54–S56, Appendix A) confirmed the octahydrocyclopenta[c]azepine structure of compound 16 and showed that the double carbon-carbon bond is located in the 5-membered ring

General Information

3.2.11. Reduction of Nitroxide 13 with Zn in CF3COOH for NMR

Conclusions