Room Temperature, Open-Flask C–P Bond-Formation on Water under Catalyst-Free Conditions

Abstract A catalyst-free C–P bond-formation in an open flask at room temperature between isatin derivatives and phosphorus surrogates on water is described. Isatin derivatives possessing different substitutes underwent C–P coupling reaction with a variety of phosphine oxides under the reaction conditions employed, providing the desired products in up to quantitative yields.

Oxindole frameworks bearing a C-3 quaternary stereocenter are important constituents of many natural products and biologically active molecules. 8 These molecules are often synthesized via aldol reactions of aldehydes or ketones or other nucleophilic species to the 3-carbonyl of isatins. 9 In recent years, organophosphorus compounds have been mostly synthesized via cross-coupling reactions, 10 C-H activation, 11 and dehydrogenative coupling reactions. 12 Sev-eral catalytic systems such as the NHC/Icy.CO 2 precatalyst, organocatalysts, and palladium pincer complexes have been employed for phospha-Michael additions to activated alkenes and alkynes. 13 Recently, Cai and co-workers disclosed a copper catalyst with fluorous bis(oxazoline) as a ligand for the asymmetric α-hydrophosphonylation of isatins. 14a Swamy and co-workers have reported a catalyst-free addition of allenyl or alkynyl-phosphonates and phosphine oxides. 14b Although various synthetic pathways using different catalytic systems have been developed for the preparation of α1-oxindole-α-hydroxy phosphonates, 15,16 the synthesis of oxindoles containing α-hydroxy phosphinoyl compounds under mild conditions remains a major goal. As a part of our ongoing project to develop metal-free organic transformations, 17 we have developed a facile and efficient synthetic protocol for preparation of oxindoles containing an α-hydroxyphosphinoyl group by a catalyst-free C-P bond formation between isatins and phosphine oxides or phosphites.
For optimization studies, we choose isatin 1a and diphenylphosphine oxide 2a as model substrates. Initially, the C-P coupling was carried out in toluene at 100 °C to afford the desired α-hydroxyphosphinoyl oxindole 3a in 95% yield after 12 h (Table 1, entry 1). When the reaction was carried out at room temperature in toluene no improvement in yield was observed (entry 2). A slight improvement in yield (96%) was observed when the reaction was carried out in isopropanol as the solvent (entry 3), whereas C-P coupling reaction in the absence of solvent at ambient or elevated temperature led to lower yields (entries 4 and 5). Remarkably, the reaction between 1a and 2a proceeded smoothly and efficiently in water at room temperature, affording 3a in excellent yield (98%). SYNOPEN2 5 0 9 -9 3 9 6 Georg Thieme Verlag Stuttgart · New York 2018, 2, 213-221 paper en R. Choudhary et al. After optimization studies, we then turned our attention to study the substrate scope of this intriguing C-P bond formation. For this, isatin 1a and N-alkylated isatins 1b-k (prepared by following a known procedure 18 ) were employed for the C-P cross-coupling reaction with diphenylphosphine oxide 2a on water under the optimized reaction conditions. The corresponding oxindole containing α-hydroxyphosphinoyl compounds 3b-k were obtained in 91-99% yields (Scheme 1). Other phosphine oxides 2b and 2c also reacted well with different isatins to provide the desired products 3l-x in 86-96% yields. The structures of all the compounds 3a-x were established based on 1 H NMR, 13 C NMR, 31 P NMR spectroscopy and HRMS analysis.

Paper Syn Open
We next attempted the synthesis of α1-oxindole-α-hydroxyphosphonates using this interesting C-P bond-formation methodology. Accordingly, we employed diphenyl phosphite 2d for C-P bond formation with isatin derivatives 1a-c and 1g under neat conditions at room temperature. Under these conditions, efficient coupling provided the desired α1-oxindole-α-hydroxyphosphonates 3y1-3y4 in 86-93% yields (Scheme 1).
To elucidate the reaction mechanism, we performed several control experiments as shown in Scheme 2. Initially, assuming that the reaction with diphenylphosphine oxide proceeded following a radical pathway, 13 the reaction between 1b and 2a was carried out in the presence of the free radical quencher 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO; Scheme 2, equiv 1), but we found that there was no effect on the reaction as the desired product 3a was obtained in 97% yield. We also performed the reaction between TEMPO and 2a (Scheme 2, equiv 2), TEMPO and 1b (Scheme 1, equiv 3) and TEMPO and 2d (Scheme 2, equiv 4). However, no coupled product was observed in these cases. These results clearly rule out the possibility of a radical pathway during the formation of products 3.
A literature survey revealed that diarylphosphine oxides 2 in the presence of air can undergo tautomerism to generate the corresponding phosphinous acid 2′. 19 On this basis, a plausible reaction mechanism for this interesting catalyst-

Paper Syn Open
free C-P bond formation is depicted in Scheme 3 for the reaction between 1 and 2. Initially phosphine oxide 2 converts into its tautomer 2′. Then 2′ attacks the electrophilic C=O of isatin 1 to generate intermediate A, which is subsequently converted into the product 3.
In conclusion, we have reported a convenient protocol for the synthesis of oxindole α-hydroxyphosphinoyl compounds and α1-oxindole-α-hydroxyphosphonates via a catalyst-free C-P bond formation between isatins and phosphine oxides or phosphites on aqueous medium. The corresponding products were obtained in excellent yields. Scheme 3 Plausible reaction mechanism for C-P bond formation between isatin and diphenyl phosphine oxide All chemicals were purchased from commercial suppliers and used without further purification. NMR spectra were recorded with a JEOL Ressonance-400 instrument using CDCl 3 or DMSO-d 6 as solvent. In some cases, one drop of DMSO-d 6 was added to CDCl 3 to improve solubility. Chemical shifts are reported in parts per million (ppm) and referenced to the residual solvent resonance. Coupling constants (J) are reported in Hertz (Hz). Standard abbreviations indicating multiplicity are used as follows: s = singlet, d = doublet, t = triplet, dd = double doublet, dt = double triplet, q = quartet, m = multiplet. HRMS data were collected with a Waters -Xevo G2S QTof LC-MS with UPLC. Table 1 3-(Diphenyl-phosphinoyl)-3-hydroxy-indolin-2-one (3a)

General Procedure for
Diphenylphosphine oxide 2a (0.5 mmol, 101 g) was added to stirred isatin 1a (0.5 mmol, 0.073 g) in an open flask in solvent (1.0 mL) or neat and then the reaction mixture was stirred at the given temperature. The mixture was then diluted with EtOAc (10 mL). After usual workup, the organic layer was dried over Na 2 SO 4 , filtered, EtOAc was evaporated, and the crude product thus obtained was purified by crystallization (EtOAc) to afford the corresponding product 3a as a white solid. Yield: 0.171 g (98%); mp 142 °C.

Paper Syn Open
General Procedure for Scheme 1 Phosphine oxide 2 (0.5 mmol) was added to a stirred mixture of isatin 1b-x (0.5 mmol) in water (1.0 mL) in an open flask at r.t. The stirring was continued for 12 h, then the reaction mixture was diluted with EtOAc (10 mL). After usual workup, the organic layer was dried over Na 2 SO 4 , filtered, the EtOAc was evaporated and the crude product thus obtained was purified by crystallization (EtOAc or EtOAc/methanol) to afford the corresponding products 3b-x.

For Compounds 3y1-y4
Isatin 1 (1.0 mmol) and diphenyl phosphite 2d (0.2 mL) were reacted neat in an open flask at r.t. for 12 h and the reaction mixture was then diluted with EtOAc (10 mL). After usual workup, the organic layer was dried over Na 2 SO 4 , filtered, the EtOAc was evaporated and the crude product thus obtained was purified by column chromatography (EtO-Ac/hexanes, 1:1) to afford the corresponding products 3y1-y4.