Catalyst-Free Double CH-Functionalization of Quinolines with Phosphine Oxides via Two S_N^HAr Reaction Sequences

Abstract

Quinolines undergo catalyst-free double CH-functionalization upon treatment with secondary phosphine oxides (70–75 °C, 20–48 h) followed by oxidation of the intermediate 2,4-bisphosphoryltetrahydroquinolines with chloranil. The yields of the target 2,4-bisphosphorylated quinolines are up to 77%. Thus, a double-SN HAr reaction sequence in the same molecule of quinoline has been realized. In the case of 2,4-bisphenylphosphoryltetrahydroquinolines, the aromatization occurs with elimination of one molecule of diphenylphosphine oxide to afford the products of monofunctionalization, 4-diphenylphosphorylquinolines, in 40–45% yields.

Electron-Deficient Acetylenes as Three-Modal Adjuvants in SNH Reaction of Pyridinoids with Phosphorus Nucleophiles

“…Indeed, the reaction of quinolines 37a-c with secondary phosphine oxides 2a,b without electron-deficient acetylenes followed by treatment with chloranil [73] The intermediates of this unique S N H reaction, bisphosphoryltetrahydroquinolines 40, were observed (NMR) upon the heating of quinolines with phosphine oxides without external oxidants [73]. These intermediates turned out to be stable and isolable in excellent yields (Scheme 47).…”

“…In both cases (Schemes 38 and 39), the reaction was regio-and stereoselective providing 1,2-dihydroisomers of the E-configuration relative to the double bond. Recently [73,74], it was shown that the promoting role of electron-deficient acetylenes towards the quinoline core in S N H reactions can be simulated by the reactive P-H nucleophiles themselves via the reversible protonation of the pyridine nitrogen.…”

“…The expected monoadducts were not isolated at all, i.e., they were more reactive than the starting quinolines. It was explained [73] by the aromaticity loss of the quinoline core after its first phosphorylation and the increased reactivity of the remaining double bond, which also became more electrophilic due to the effect of the phosphoryl substituent.…”

“…Isoquinolines 41a,e, when reacted with phosphine oxides 2a-c, displayed a much higher activity [73,74] as compared to quinolines, also exclusively affording diadducts, 1,3-bisphosphoryltetrahydroisoquinolines 59a-e in almost quantitative yields (Scheme 48).…”

“…Bisphosphoryltetrahydroisoquinolines 59a-e when oxidized by chloranil eliminated the starting secondary phosphine oxides 2a-c to recover the initial isoquinolines 41a,e (Scheme 49) [73]. The above double phosphonylation of the isoquinoline ring also occurred [73] when H-phosphonates, e.g., bis(2,2,3,3-tetrafluoropropyl) phosphonate 30b, were employed as nucleophiles to afford the expected bisphosphonylated isoquinoline 60 in a 65% yield (Scheme 50). Diphenylphosphine oxide 2a, being more acidic compared to bis(2-phenylethyl)phosphine oxide 2b, deeper protonated quinolines that, in agreement with the above mechanism, facilitated the reaction (Scheme 51).…”