Oxidative [3+2]Cycloaddition of Alkynylphosphonates with Heterocyclic N-Imines: Synthesis of Pyrazolo[1,5- a]Pyridine-3-phosphonates

Abstract

A series of pyrazolo[1,5-a]pyridine-3-ylphosphonates were prepared with moderate to good yields by the oxidative [3+2]cycloaddition of 2-subtituted ethynylphosphonates with in situ generated pyridinium-N-imines and their annulated analogs. 2-Aliphatic and 2-Ph acetylenes demonstrate low activity, and the corresponding pyrazolopyridines were achieved with a moderate yield in the presence of 10 mol% Fe(NO₃)₃·9H₂O. At the same time, tetraethyl ethynylbisphosphonate, diethyl 2-TMS- and 2-OPh-ethynylphosphonates possess much greater reactivity and the corresponding pyrazolo[1,5-a]pyridines, and their annulated derivatives were obtained with good to excellent yields without any catalyst. 2-Halogenated ethynylphosphonates also readily reacted with pyridinium-N-imines, forming complex mixtures containing poor amounts of 2-halogenated pyrazolopyridines.

Keywords: alkynes; cycloaddition; heterocycles; iron; oxidation.

Scheme 3

Reaction scopes for cycloaddition of N-imines with tetraethyl acetylene bisphosphonate (isolated yields). ^a The substance was obtained in mixture with 4-metoxypyridine and other unidentified products, yield determined using NMR with CH₂Br₂ as a standard.

Scheme 5

Plausible reaction mechanisms.

Figure 1

Biologically active derivatives of pyrazolo[1,5-a]pyridine.

Scheme 1

Approaches toward pyrazolo[1,5-a]pyridinyl phosphonate synthesis [24,25].

Scheme 2

Reaction scopes for cycloaddition of N-imines with alkynylphosphonates (isolated yields). ^a Mixture of diethyl prop-1-yn-1-ylphosphonate and diethyl propa-1,2-diene-1-ylphosphonate was used. ^b Without the addition of Fe(NO₃)₃, 0% was observed.

Scheme 4

Reaction of pyridinium-N-imines with 2-halogenated diethyl acetylenephosphonate.