N -Heterocyclic carbene-catalyzed domino hydroacylation/Stetter reactions of salicyl alkynylphosphonates and aromatic aldehydes

1,4-Dicarbonyl compounds 2 carrying a phosphonate group were obtained by utilizing a dually N -heterocyclic carbene (NHC) catalyzed domino reaction involving the intramolecular hydroacylation of salicyl alkynylphosphonates 1 and a subsequent intermolecular Stetter reaction with aromatic aldehyde at room temperature. In addition, 2 can also be applied for the synthesis of benzopyranopyrrole carrying a phosphonate group 4 in one pot and in moderate yield.


Introduction
During the past decades, domino reactions, which can rapidly form complicated molecule skeletons from readily available substrates in a single operation without isolation of intermediates, have received more and more attention of organic chemists.So, considerable efforts have been made to develop organocatalytic domino transformations. 1 1,4-Dicarbonyl compounds are versatile intermediates in the synthesis of cyclopentenones 2 and a variety of heterocycles such as furan, 3 pyrrole, 4 thiophene, 5 and pyrrolidine. 6Recently, N-heterocyclic carbenes (NHCs) have been widely used, not only as ligands in organometallic chemistry, but also as efficient nucleophilic organocatalysts in a variety of organic reactions, such as benzoin condensation, Stetter reaction, a 3 to d 3 umpolung, and so on, so the development of NHCs in organic synthesis has attracted more and more attention. 7Glorius and coworkers have pioneered the development of a powerful NHC-catalyzed hydroacylation of unactivated alkynes leaded to the formation of α,β-unsaturated chromanones, 8 while intramolecular hydroacylation reactions of activated alkynes were reported recently. 9 Recently, an effective N-heterocyclic carbene catalyzed intramolecular hydroacylation reaction of salicyl alkynylphosphonates was reported in our group, in which both exocyclic and endocyclic tautomers can be obtained at different temperatures.9b Because α,β-unsaturated ketones (exocyclic tautomers) are the major products at lower temperatures (15-17 ºC), this prompted us to investigate the possibility of developing a dually NHC-catalyzed domino reaction involving the intramolecular hydroacylation of salicyl alkynylphosphonates and a subsequent intermolecular Stetter reaction to prepare 1,4-dicarbonyl compounds 2 carrying a phosphonate group at room temperature (Scheme 2), which can be very important intermediates for the synthesis of biologically active phosphonyl heterocyclic compounds.

Results and Discussion
First of all, we used substrate 1a and 4-chlorobenzaldehyde as a model in order to optimize the reaction condition.The initial screening was carried out at 15-17 °C with 5 mol% of catalyst and 10 mol% of K2CO3 in THF (Table 1, entries 1-6).When thiazolium salt 3a was used as the catalyst and K2CO3 as the base, 2a was obtained in 81% yield (Table1, entry 1), and 3a is the most effective catalyst, however, the triazolium salt 3d is not so effective (Table1, entry 4); Secondly, the effects of various bases (Table 1, entries 7-11) were explored using catalyst 3a as a control, the moderate base (K2CO3) afforded the products in higher yields than other bases.Subsequently, we turned our attention to the influence of different solvents on the reaction (Table 1, entries 12-17) and found THF to be the most effective, the more polar EtOH and DMF being less so.Different temperatures have some obvious effects on the reaction.The lower temperature (15-17 °C) is more beneficial to the reaction than the higher one (30-35 °C); when the reaction with 3a and K2CO3 in THF was tested at 30-35 °C, the yield of 2a is only 32%.Finally, the optimized conditions were established as following: thiazolium salt 3a as the pre-catalyst (5 mol%), K2CO3 (10 mol%) as the base, THF as the solvent, and stirring at 15-17 °C for 3 h.a General conditions: 1a (0.5 mmol), NHC-HX (5 mol%), base (10 mol%), solvent (2.0 ml), room temperature (15-17 °C), 3h; b Isolated yields.With the optimised conditions thus established, we tested different substrates to give good results in the NHC catalyzed cascade reaction of hydroacylation and Stetter reaction.For salicyl alkynylphosphonates with both electron-donating groups and electron-withdrawing ones on the phenyl ring, the reactions proceeded smoothly and gave the corresponding 2 in good yields at room temperature.However, when benzaldehyde was used, the yield was very low (Table 2, entry 7); the reason for this is not clear.H (1a) C6H5 <5 a General conditions: 1 (0.5 mmol, 1.0 equiv), 3a (0.025 mmol, 5 mol%), K2CO3 (0.05 mmol, 10 mol%), ArCHO (0.5 mmol, 1.0 equiv), THF (2.0 ml), 15-17 ºC, 3h; b Isolated yields In order to prepare novel heterocycles containing a phosphonyl group with potent biological activities, 2 can be applied to the synthesis of benzopyranopyrrolephosphonate 4 successfully via a one-pot reaction in 50% yield (Scheme 2).

Conclusions
In conclusion, 1,4-dicarbonyl compounds 2 carrying a phosphonate group were obtained by utilizing a dually NHC-catalyzed domino reaction involving the intramolecular hydroacylation of salicyl alkynylphosphonates 1 and a subsequent intermolecular Stetter reaction with aromatic aldehyde in good yields at room temperature.In addition, 2 can be also applied successfully for the synthesis of benzopyranopyrrole containing a phosphonyl group 4 in one-pot reaction in moderate yield.

Experimental Section
General.All reagents and solvents for reactions were used as received with the following exceptions.THF, toluene and dioxane were distilled from Na/benzophenone.Dichloromethane, acetonitrile and N,N-dimethylformamide (DMF) were distilled from calcium hydride.Ethanol and n-butyl alcohol were distilled form Mg turnings.K2CO3 was dried by heating at 110 °C for 12 h and left to cool under Ar.N-Heterocyclic carbene (NHC) precursors 3 were prepared according to the literature. 11The substituted salicyl alkynylphosphonates 1 were synthesized according to the the reported method.9b All other commercially available solvents and reagents were used without further purification.All reactions were performed in oven-dried apparatus under N2 or Ar atmosphere.Reactions were monitored by thin layer chromatography (TLC) and visualized by UV light or KMnO4 staining solution followed by heating.Melting points were determined with a WRS-1B digital melting point apparatus. 1H NMR, 13 C NMR spectra and 31 P NMR spectra were obtained with a Varian Mercury PLUS 600 spectrometer.Chemical shift in ppm, internal standard TMS or CHCl3, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet), coupling constants Hz. 13 C NMR chemical shifts are reported in ppm from CDCl3 (taken as 77.0 ppm). 31P NMR spectra were recorded with 85% H3PO4 as external standard.The mass spectra (ESI) were obtained using an Applied Biosystems API 2000 LC/MS/MS (ESI-MS) spectrometer.Elemental analyses were performed with an Elementar Vario ELШ CHNSO elemental analyzer.

Scheme 1. Domino hydroacylation/Stetter reaction of activated alkynes containing a phosphonyl group.
10Although Glorius and coworkers reported the NHC-catalyzed cascade hydroacylation/Stetter reactions of salicyl alkynes,8the groups linking with alkynes are usually H or a Me group, other groups such as aromatic group, ester group linking with alkynes are not reported.As for activated alkynes, no domino hydroacylation/Stetter reaction is reported because in which endocyclic tautomers are the major product.In this paper, we report the first cascade hydroacylation/ Stetter reaction of activated alkynes 1 containing a phosphonyl group derived from substituted salicylaldehydes (Scheme 1).

Table 1
Optimization of the reaction conditions a ©ARKAT-USA, Inc.