CC BY 4.0 · SynOpen 2018; 02(02): 0213-0221
DOI: 10.1055/s-0037-1610167
paper
Copyright with the author

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

Rakhee Choudhary
MFOS Laboratory, Department of Chemistry (Centre of Advanced Study), University of Rajasthan, JLN Marg, Jaipur, Rajasthan-302004, India   Email: badsarass4@uniraj.ac.in   Email: sattubhu2005@gmail.com
,
Rekha Bai
MFOS Laboratory, Department of Chemistry (Centre of Advanced Study), University of Rajasthan, JLN Marg, Jaipur, Rajasthan-302004, India   Email: badsarass4@uniraj.ac.in   Email: sattubhu2005@gmail.com
,
Pratibha Singh
MFOS Laboratory, Department of Chemistry (Centre of Advanced Study), University of Rajasthan, JLN Marg, Jaipur, Rajasthan-302004, India   Email: badsarass4@uniraj.ac.in   Email: sattubhu2005@gmail.com
,
Mahesh C. Sharma
MFOS Laboratory, Department of Chemistry (Centre of Advanced Study), University of Rajasthan, JLN Marg, Jaipur, Rajasthan-302004, India   Email: badsarass4@uniraj.ac.in   Email: sattubhu2005@gmail.com
,
MFOS Laboratory, Department of Chemistry (Centre of Advanced Study), University of Rajasthan, JLN Marg, Jaipur, Rajasthan-302004, India   Email: badsarass4@uniraj.ac.in   Email: sattubhu2005@gmail.com
› Author Affiliations
The authors thank SERB-DST, New Delhi (YSS/2015/001870), DST- New Delhi for INSPIRE Faculty Award (IFA-2014/CH-167) and the Council of Scientific& Industrial Research-India (02(0341)/18/EMR-II).

Further Information

Publication History

Received: 31 March 2018

Accepted after revision: 08 May 2018

Publication Date:
13 June 2018 (online)

 

‡Authors contributed equally

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.


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Organophosphorus compounds play important roles in organic synthesis,[1] organometallic chemistry,[2] medicinal chemistry,[3] chemical biology,[4] and material science.[5] More specifically, α-hydroxy- and α-aminophosphonic acids have roles as biophosphate mimics, antibiotics, antivirals, and antitumor agents.[6] Nucleophilic substitution of toxic phosphinoyl halides with organometallic reagents has been the traditional method for the synthesis of these compounds.[1d] Subsequently, the Hirao transition-metal-catalysed phosphonation of organohalides has emerged as a facile alternative.[7] Use of toxic phosphorus halides, high catalyst loading, harsh reaction conditions or poor functional group tolerance are drawbacks of these approaches.

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] Several catalytic systems such as the NHC/Icy.CO2 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%).

Table 1 Optimization of Reaction Conditions for C–P Bond Formation between Isatin 1a and Diphenylphosphine Oxide 2a a

Entry

Solvent

Temperature (°C)

Time (h)

Yield (%)b

1

toluene

100

12

95

2

toluene

RT

24

90

3

i-PrOH

RT

12

96

4

neat

100

24

74

5

neat

RT

24

58

6

water

RT

12

98

a Reaction conditions: Isatin 1a (0.5 mmol), diphenylphosphine oxide 2a (0.5 mmol), solvent or neat, r.t. to 100 °C.

b Isolated yields based on 1a.

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 1bk (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 3bk 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 3lx in 86–96% yields. The structures of all the compounds 3ax were established based on 1H NMR, 13C NMR, 31P NMR spectroscopy and HRMS analysis.

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 1ac and 1g under neat conditions at room temperature. Under these conditions, efficient coupling provided the desired α1-oxindole-α-hydroxyphosphonates 3y13y4 in 86–93% yields (Scheme [1]).

Zoom Image
Scheme 1 C–P bond formation between isatins 1 and phosphine oxides 2. Reaction conditions: Isatin 1 (0.5 mmol), diphenylphosphine oxide 2 (0.5 mmol), water (1.0 mL), r.t., 12 h. Isolated yields are based on 1. a Reaction conditions: Isatin 1 (1.0 mmol), diphenyl phosphite 2d (0.2 mL), neat, r.t., 12 h.

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-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.

Zoom Image
Scheme 2 Control experiments

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.

Zoom Image
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 CDCl3 or DMSO-d 6 as solvent. In some cases, one drop of DMSO-d 6 was added to CDCl3 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.


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General Procedure for Table [1]


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3-(Diphenyl-phosphinoyl)-3-hydroxy-indolin-2-one (3a)

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 Na2SO4, 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.

1H NMR (400 MHz, DMSO-d 6): δ = 6.38 (d, J = 7.2 Hz, 1 H), 6.72 (s, 1 H), 6.75 (dd, J = 3.2, 7.6 Hz, 1 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.25–7.32 (m, 1 H), 7.41–7.59 (m, 5 H), 7.63 (t, J = 7.6 Hz, 1 H), 7.85–8.02 (m, 4 H), 10.49 (s, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 79.8 (d, J C–P = 82.1 Hz), 109.5, 121.0, 125.5, 126.8, 127.8 (d, J C–P = 11.5 Hz), 128.1 (d, J C–P = 11.3 Hz), 129.8, 130.5 (d, J C–P = 95.0 Hz), 130.7 (d, J C–P = 95.2 Hz), 131.6, 132.1, 132.3 (d, J C–P = 8.5 Hz), 142.9 (d, J C–P = 5.9 Hz), 175.3.

31P NMR (162 MHz, DMSO-d 6): δ = 28.8.

HRMS: m/z [M + H] calcd. for C20H16NO3P + H: 350.0946; found: 350.0941.


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General Procedure for Scheme [1]

Phosphine oxide 2 (0.5 mmol) was added to a stirred mixture of isatin 1bx (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 Na2SO4, filtered, the EtOAc was evaporated and the crude product thus obtained was purified by crystallization (EtOAc or EtOAc/methanol) to afford the corresponding products 3bx.


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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 Na2SO4, filtered, the EtOAc was evaporated and the crude product thus obtained was purified by column chromatography (EtOAc/hexanes, 1:1) to afford the corresponding products 3y1y4.


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3-(Diphenyl-phosphinoyl)-3-hydroxy-1-methylindolin-2-one (3b)

The title compound was prepared by following the general procedure for Scheme [1], using N-methylisatin 1b (0.5 mmol, 0.080 g) and diphenylphosphine oxide 2a (0.5 mmol, 0.101 g), providing 3b as a white solid. Yield: 0.179 g (99%); mp 130 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 2.99 (s, 3 H), 6.52 (d, J = 7.6 Hz, 1 H), 6.85 (t, J = 7.6 Hz, 1 H), 6.92 (d, J = 7.6 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.42–7.49 (m, 2 H), 7.51–7.59 (m, 3 H), 7.65 (t, J = 7.6 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.97 (d, J = 7.6 Hz, 1 H), 7.99 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 26.2, 79.7 (d, J C–P = 81.3 Hz), 108.4, 121.8, 125.2 (d, J C–P = 2.7 Hz), 126.0, 127.8 (d, J C–P = 11.5 Hz), 128.3 (d, J C–P = 11.3 Hz), 129.8, 130.0, 130.7, 131.8 (d, J C–P = 1.6 Hz), 132.2 (d, J C–P = 8.8 Hz), 132.4 (d, J C–P = 8.7 Hz), 144.0 (d, J C–P = 5.6 Hz), 173.7.

31P NMR (162 MHz, CDCl3/ DMSO-d 6): δ = 30.3.

HRMS: m/z [M + H] calcd. for C21H18NO3P + H: 364.1103; found: 364.1109.


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3-(Diphenyl-phosphinoyl)-3-hydroxy-1-ethylindolin-2-one (3c)

The title compound was prepared by following the general procedure for Scheme [1], using N-ethylisatin 1c (0.5 mmol, 0.087 g) and diphenylphosphine oxide 2a (0.5 mmol, 0.101 g), providing 3c as a white solid. Yield: 0.184 g (98%); mp 120 °C.

1H NMR (400 MHz, CDCl3): δ = 0.85 (t, J = 7.2 Hz, 3 H), 3.28–3.33 (m, 1 H), 3.52–3.57 (m, 1 H), 5.41 (d, J = 4.0 Hz, 1 H), 6.62 (d, J = 7.6 Hz, 1 H), 6.87 (t, J = 7.6 Hz, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.31–7.39 (m, 2 H), 7.41–7.54 (m, 3 H), 7.55–7.71 (m, 3 H), 7.97 (d, J = 7.6 Hz, 1 H), 8.00 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 12.0, 34.9, 80.2 (d, J C–P = 71.3 Hz), 108.1, 122.6, 124.6, 127.1, 128.0 (d, J C–P = 11.8 Hz), 128.2, 128.4 (d, J C–P = 11.9 Hz), 129.1, 130.3, 132.4 (d, J C–P = 9.1 Hz), 132.6, 133.1 (d, J C–P = 8.8 Hz), 143.2 (d, J C–P = 5.7 Hz), 173.5.

31P NMR (162 MHz, CDCl3): δ = 30.3.

HRMS: m/z [M + H] calcd. for C22H20NO3P + H: 378.1259; found: 378.1245.


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3-(Diphenyl-phosphinoyl)-3-hydroxy-1-benzylindolin-2-one (3d)

The title compound was prepared by following the general procedure for Scheme [1], using N-benzylisatin 1d (0.5 mmol, 0.118 g) and diphenylphosphine oxide 2a (0.5 mmol, 0.101 g), providing 3d as a white solid. Yield: 0.213 g (97%); mp 142 °C.

1H NMR (400 MHz, CDCl3): δ = 4.53 and 4.79 (ABq, J = 15.6 Hz, 2 H), 4.66 (bs, 1 H), 6.55 (d, J = 7.6 Hz, 1 H), 6.85 (t, J = 7.6 Hz, 1 H), 6.93 (d, J = 7.6 Hz, 1 H), 7.06–7.10 (m, 2 H), 7.17 (t, J = 7.6 Hz, 1 H), 7.20–7.26 (m, 3 H), 7.32–7.65 (m, 6 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 42.9, 79.6 (d, J C–P = 81.9 Hz), 109.1, 121.8, 125.2, 126.2, 127.1, 127.2, 127.8 (d, J C–P = 11.5 Hz), 128.2 (d, J C–P = 11.4 Hz), 128.4, 129.8, 130.2 (d, J C–P = 95.5 Hz), 130.4 (d, J C–P = 95.7 Hz), 131.7, 132.4 (d, J C–P = 8.6 Hz), 135.6, 143.2 (d, J C–P = 5.6 Hz), 173.9.

31P NMR (162 MHz, DMSO-d 6): δ = 28.1.

HRMS: m/z [M + H] calcd. for C27H22NO3P + H; 440.1416; found: 440.1422.


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5-Chloro-3-(diphenyl-phosphinoyl)-3-hydroxy-indolin-2-one (3e)

The title compound was prepared by following the general procedure for Scheme [1], using 5-chloroisatin 1e (0.5 mmol, 0.091 g) and diphenylphosphine oxide 2a (0.5 mmol, 0.101 g), providing 3e as a white solid. Yield: 0.180 g (94%); mp 128 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 6.23 (s, 1 H), 6.77 (d, J = 8.4 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1 H), 7.45–7.54 (m, 3 H), 7.55–7.63 (m, 3 H), 7.68 (t, J = 7.2 Hz, 1 H), 7.85–8.04 (m, 4 H), 10.65 (s, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 79.9 (d, J C–P = 80.5 Hz), 111.0, 125.0 (d, J C–P = 2.5 Hz), 125.5 (d, J C–P = 2.8 Hz), 128.0 (d, J C–P = 11.5 Hz), 128.3 (d, J C–P = 11.3 Hz), 128.7, 129.6, 129.9 (d, J C–P = 95.6 Hz), 130.1 (d, J C–P = 92.8 Hz), 131.9, 132.4 (d, J C–P = 8.6 Hz), 132.5, 141.7 (d, J C–P = 6.1 Hz), 175.1.

31P NMR (162 MHz, CDCl3/DMSO-d 6): δ = 29.0.

HRMS: m/z [M + H] calcd. for C20H15ClNO3P + H: 384.0556; found: 384.0540.


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5-Chloro-3-(diphenyl-phosphinoyl)-3-hydroxy-1-methylindolin-2-one (3f)

The title compound was prepared by following the general procedure for Scheme [1], using 5-chloro-1-methylisatin 1f (0.5 mmol, 0.098 g) and diphenylphosphine oxide 2a (0.5 mmol, 0.101 g), providing 3f as a white solid. Yield: 0.190 g (96%); mp 136 °C.

1H NMR (400 MHz, CDCl3): δ = 2.87 (s, 3 H), 5.35 (bs, 1 H), 6.53 (d, J = 8.4 Hz, 1 H), 6.94 (s, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 7.37–7.43 (m, 2 H), 7.48–7.51 (m, 3 H), 7.61 (d, J = 7.2 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 26.4, 80.5 (d, J C–P = 70.4 Hz), 109.1, 126.4, 126.9 (d, J C–P = 3.2 Hz), 127.4, 127.5 (d, J C–P = 96.9 Hz), 128.1 (d, J C–P = 12.2 Hz), 128.5 (d, J C–P = 12.1 Hz), 128.9, 130.2, 130.7, 132.4 (d, J C–P = 9.2 Hz), 132.6 (d, J C–P = 2.3 Hz), 132.8 (d, J C–P = 2.5 Hz), 133.4 (d, J C–P = 9.0 Hz), 142.4, 173.8.

31P NMR (162 MHz, CDCl3): δ = 29.5.

HRMS: m/z [M + H] calcd. for C21H17ClNO3P + H: 398.0713; found: 398.0719.


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5-Chloro-3-(diphenyl-phosphinoyl)-3-hydroxy-1-ethylindolin-2-one (3g)

The title compound was prepared by following the general procedure for Scheme [1], using 5-chloro-1-ethylisatin 1g (0.5 mmol, 0.105 g) and diphenylphosphine oxide 2a (0.5 mmol, 0.101 g), providing 3g as a white solid. Yield: 0.201 g (98%); mp 120 °C.

1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H), 3.28–3.33 (m, 1 H), 3.52–3.57 (m, 1 H), 5.53 (s, 1 H), 6.56 (d, J = 8.0 Hz, 1 H), 7.02 (s, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.34–7.44 (m, 2 H), 7.45–7.55 (m, 3 H), 7.61 (t, J = 8.4 Hz, 1 H), 7.68 (d, J = 7.6 Hz, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.95 (d, J = 7.6 Hz, 1 H), 7.98 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 12.0, 35.1, 80.1 (d, J C–P = 70.3 Hz), 109.0, 126.5, 126.8, 127.3, 127.6, 127.7, 128.0 (d, J C–P = 2.6 Hz), 128.2 (d, J C–P = 11.9 Hz), 128.5 (d, J C–P = 11.9 Hz), 130.2, 132.4 (d, J C–P = 9.3 Hz), 132.7 (d, J C–P = 2.1 Hz), 132.8 (d, J C–P = 2.4 Hz), 133.0 (d, J C–P = 9.0 Hz), 141.7 (d, J C–P = 5.8 Hz), 173.1.

31P NMR (162 MHz, CDCl3): δ = 30.9.

HRMS: m/z [M + H] calcd. for C22H19ClNO3P + H: 412.0869; found: 412.0855.


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5-Chloro-3-(diphenyl-phosphinoyl)-3-hydroxy-1-benzylindolin-2-one (3h)

The title compound was prepared by following the general procedure for Scheme [1], using 5-chloro-1-benzylisatin 1h (0.5 mmol, 0.135 g) and diphenylphosphine oxide 2a (0.5 mmol, 0.101 g), providing 3h as a white solid. Yield: 0.227 g (96%); mp 138 °C.

1H NMR (400 MHz, CDCl3): δ = 4.69–4.78 (m, 2 H), 6.47 (d, J = 8.4 Hz, 1 H), 6.68 (s, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 7.18–7.31 (m, 5 H), 7.37–7.45 (m, 2 H), 7.47–7.50 (m, 3 H), 7.63 (t, J = 8.4 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3/DMSO-d 6): δ = 43.4, 79.6 (d, J C–P = 78.7 Hz), 109.4, 110.0, 125.8, 126.7, 126.9, 127.0, 127.4 (d, J C–P = 12.3 Hz), 127.6 (d, J C–P = 11.7 Hz), 128.0, 128.2, 128.4, 129.1, 130.2 (d, J C–P = 91.2 Hz), 131.5, 131.9, 132.2 (d, J C–P = 8.9 Hz), 132.4 (d, J C–P = 8.6 Hz), 134.3, 141.3 (d, J C–P = 5.7 Hz), 173.6.

31P NMR (162 MHz, CDCl3/DMSO-d 6): δ = 28.1.

HRMS: m/z [M + H] calcd. for C27H21ClNO3P + H: 474.1026; found: 474.1036.


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5-Bromo-3-(diphenyl-phosphinoyl)-3-hydroxy-indolin-2-one (3i)

The title compound was prepared by following the general procedure for Scheme [1], using 5-bromoisatin 1i (0.5 mmol, 0.113 g) and diphenylphosphine oxide 2a (0.5 mmol, 0.101 g), providing 3i as a white solid. Yield: 0.194 g (91%); mp 158 °C.

1H NMR (400 MHz, CDCl3/DMSO-d 6): δ = 6.58 (s, 1 H), 6.67 (d, J = 8.4 Hz, 1 H), 7.10–7.15 (m, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.37–7.70 (m, 6 H), 7.90–8.10 (m, 4 H), 10.34 (s, 1 H).

13C NMR (100 MHz, CDCl3/DMSO-d 6): δ = 79.3 (d, J C–P = 79.3 Hz), 110.3, 112.4, 126.8 (d, J C–P = 11.9 Hz), 127.0 (d, J C–P = 11.7 Hz), 127.8, 128.0 (d, J C–P = 2.5 Hz), 128.4 (d, J C–P = 96.5 Hz), 128.7 (d, J C–P = 96.3 Hz), 130.8 (d, J C–P = 2.1 Hz), 131.3, 131.6 (d, J C–P = 9.2 Hz), 131.8 (d, J C–P = 8.9 Hz), 140.9 (d, J C–P = 6.0 Hz), 174.4.

31P NMR (162 MHz, CDCl3/DMSO-d 6): δ = 28.3.

HRMS: m/z [M + H] calcd. for C20H15BrNO3P + H: 428.0051; found: 428.0041.


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5-Bromo-3-(diphenyl-phosphinoyl)-3-hydroxy-1-ethylindolin-2-one (3j)

The title compound was prepared by following the general procedure for Scheme [1], using 5-bromo-1-ethylisatin 1j (0.5 mmol, 0.127 g) and diphenylphosphine oxide 2a (0.5 mmol, 0.101 g), providing 3j as a white solid. Yield: 0.216 g (95%); mp 132 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 0.93 (t, J = 7.2 Hz, 3 H), 3.49–3.56 (m, 2 H), 6.60 (s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 7.42–7.62 (m, 7 H), 7.69 (t, J = 7.2 Hz, 1 H), 7.76 (d, J = 7.6 Hz, 1 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 8.01 (d, J = 7.2 Hz, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 12.0, 34.4, 79.6 (d, J C–P = 79.3 Hz), 110.5, 113.3, 128.0 (d, J C–P = 11.5 Hz), 128.3 (d, J C–P = 11.0 Hz), 128.5 (d, J C–P = 2.4 Hz), 129.6 (d, J C–P = 96.3 Hz), 129.8 (d, J C–P = 95.6 Hz), 132.0, 132.1 (d, J C–P = 8.9 Hz), 132.5 (d, J C–P = 8.7 Hz), 142.3 (d, J C–P = 5.5 Hz), 172.9.

31P NMR (162 MHz, DMSO-d 6): δ = 28.1.

HRMS: m/z [M + H] calcd. for C22H19BrNO3P + H: 456.0364; found: 456.0370.


#

3-(Diphenyl-phosphinoyl)-3-hydroxy-5-nitro-indolin-2-one (3k)

The title compound was prepared by following the general procedure for Scheme [1], using 5-nitroisatin 1k (0.5 mmol, 0.096 g) and diphenylphosphine oxide 2a (0.5 mmol, 0.101 g), providing 3k as a white solid. Yield: 0.181 g (92%); mp 142 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 6.97 (d, J = 8.8 Hz, 1 H), 7.09 (s, 1 H), 7.48–7.52 (m, 2 H), 7.55–7.75 (m, 5 H), 7.90–8.00 (m, 4 H), 8.18 (dd, J = 8.8, 1.2 Hz, 1 H), 11.2 (s, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 79.7 (d, J C–P = 79.2 Hz), 109.8, 120.8, 127.0, 127.7, 128.1 (d, J C–P = 11.5 Hz), 128.4 (d, J C–P = 11.5 Hz), 129.3 (d, J C–P = 96.1 Hz), 129.5 (d, J C–P = 96.4 Hz), 132.1, 132.3 (d, J C–P = 2.0 Hz), 132.4 (d, J C–P = 2.5 Hz), 132.7, 141.4, 149.1 (d, J C–P = 5.5 Hz), 175.8.

31P NMR (162 MHz, DMSO-d 6): δ = 27.7.

HRMS: m/z [M + H] calcd. for C20H15N2O5P + H: 395.0797; found: 395.0785.


#

3-(Di(4-methylphenyl)phosphinoyl)-3-hydroxy-indolin-2-one (3l)

The title compound was prepared by following the general procedure for Scheme [1], using isatin 1a (0.5 mmol, 0.073 g) and di(p-tolyl)phosphine oxide 2b (0.5 mmol, 0.115 g), providing 3l as a white solid. Yield: 0.175 g (93%); mp 152 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 2.32 (s, 3 H), 2.38 (s, 3 H), 6.44 (d, J = 7.6 Hz, 1 H), 6.71–6.77 (m, 2 H), 7.11–7.29 (m, 4 H), 7.34 (s, 1 H), 7.36 (s, 1 H), 7.66–7.91 (m, 4 H), 10.4 (s, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 21.1, 21.2, 79.8 (d, J C–P = 81.8 Hz), 109.4, 121.0, 125.6, 127.0, 127.4 (d, J C–P = 97.7 Hz), 127.6 (d, J C–P = 97.7 Hz), 128.4 (d, J C–P = 11.8 Hz), 128.7 (d, J C–P = 11.7 Hz), 129.7, 132.3 (d, J C–P = 9.0 Hz), 141.5, 142.0, 142.8 (d, J C–P = 5.8 Hz), 175.4.

31P NMR (162 MHz, DMSO-d 6): δ = 27.9.

HRMS: m/z [M + H] calcd. for C22H20NO3P + H: 378.1259; found: 378.1265.


#

3-(Di(4-methylphenyl)phosphinoyl)-3-hydroxy-1-ethylindolin-2-one (3m)

The title compound was prepared by following the general procedure for Scheme [1], using 1-ethylisatin 1c (0.5 mmol, 0.087 g) and di(p-tolyl)phosphine oxide 2b (0.5 mmol, 0.115 g), providing 3m as a white solid. Yield: 0.194 g (96%); mp 140 °C.

1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 7.2 Hz, 3 H), 2.36 (s, 3 H), 2.41 (s, 3 H), 3.32–3.37 (m, 1 H), 3.57–3.63 (m, 1 H), 4.58 (bs, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 6.89 (t, J = 7.6 Hz, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 7.170 (d, J = 8.0 Hz, 1 H), 7.176 (d, J = 8.0 Hz, 1 H), 7.26–7.29 (m, 3 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 12.0, 21.7, 34.9, 79.8 (d, J C–P = 70.8 Hz), 108.2, 122.6, 124.0 (d, J C–P = 98.4 Hz), 124.5, 125.4 (d, J C–P = 99.9 Hz), 126.8 (d, J C–P = 3.0 Hz), 128.9 (d, J C–P = 12.3 Hz), 129.1 (d, J C–P = 11.9 Hz), 130.3, 132.4 (d, J C–P = 9.5 Hz), 132.9 (d, J C–P = 8.9 Hz), 143.0 (d, J C–P = 2.4 Hz), 143.2 (d, J C–P = 2.7 Hz), 143.5 (d, J C–P = 5.4 Hz), 173.6.

31P NMR (162 MHz, CDCl3): δ = 30.9.

HRMS: m/z [M + H] calcd. for C24H24NO3P + H: 406.1572; found: 406.1574.


#

5-Chloro-3-(di(4-methylphenyl)phosphinoyl)-3-hydroxy-indolin-2-one (3n)

The title compound was prepared by following the general procedure for Scheme [1], using 5-chloroisatin 1e (0.5 mmol, 0.090 g) and di(p-tolyl)phosphine oxide 2b (0.5 mmol, 0.115 g), providing 3n as a white solid. Yield: 0.185 g (90%); mp 138 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 2.32 (s, 3 H), 2.39 (s, 3 H), 6.33 (s, 1 H), 6.75 (d, J = 8.4 Hz, 1 H), 7.23–7.42 (m, 6 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 10.6 (s, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 21.1, 22.2, 80.0 (d, J C–P = 80.2 Hz), 110.8, 124.9 (d, J C–P = 2.4 Hz), 125.6, 126.8 (d, J C–P = 98.3 Hz), 127.0 (d, J C–P = 98.5 Hz), 128.5 (d, J C–P = 11.8 Hz), 128.8 (d, J C–P = 11.9 Hz), 128.9, 129.5, 132.3 (d, J C–P = 9.2 Hz), 132.5 (d, J C–P = 9.1 Hz), 141.6 (d, J C–P = 5.2 Hz), 141.8, 142.4, 175.2.

31P NMR (162 MHz, DMSO-d 6): δ = 28.3.

HRMS: m/z [M + H] calcd. for C22H19ClNO3P + H: 412.0869; found: 412.0875.


#

5-Chloro-3-(di(4-methylphenyl)phosphinoyl)-3-hydroxy-1-ethylindolin-2-one (3o)

The title compound was prepared by following the general procedure for Scheme [1], using 5-chloro-1-ethylisatin 1g (0.5 mmol, 0.105 g) and di(p-tolyl)phosphine oxide 2b (0.5 mmol, 0.115 g), providing 3o as a white solid. Yield: 0.206 g (94%); mp 122 °C.

1H NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 7.2 Hz, 3 H), 2.34 (s, 3 H), 2.42 (s, 3 H), 3.26–3.32 (m, 1 H), 3.49–3.54 (m, 1 H), 6.13 (bs, 1 H), 6.51 (d, J = 8.4 Hz, 1 H), 7.10–7.16 (m, 3 H), 7.21 (d, J = 8.0 Hz, 1 H), 7.23–7.30 (m, 2 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 11.9, 21.6, 21.7, 35.0, 80.3 (d, J C–P = 70.8 Hz), 108.8, 124.2 (d, J C–P = 99.8 Hz), 124.9 (d, J C–P = 99.9 Hz), 127.0, 127.4 (d, J C–P = 2.6 Hz), 127.9 (d, J C–P = 2.6 Hz), 128.8 (d, J C–P = 12.3 Hz), 129.1 (d, J C–P = 12.4 Hz), 129.9, 132.4 (d, J C–P = 9.6 Hz), 133.0 (d, J C–P = 9.5 Hz), 141.6 (d, J C–P = 5.7 Hz), 143.0 (d, J C–P = 2.6 Hz), 143.2 (d, J C–P = 2.4 Hz), 173.2 (d, J C–P = 5.2 Hz).

31P NMR (162 MHz, CDCl3): δ = 31.8.

HRMS: m/z [M + H] calcd. for C24H23ClNO3P + H: 440.1182; found: 440.1195.


#

3-(Bis(3,5-dimethylphenyl)phosphinoyl)-3-hydroxy-indolin-2-one (3p)

The title compound was prepared following the general procedure for Scheme [1], using isatin 1a (0.5 mmol, 0.073 g) and bis (3,5-dimethylphenyl)phosphine oxide 2c (0.5 mmol, 0.129 g), providing 3p as a white solid. Yield: 0.182 g (90%); mp 178 °C.

1H NMR (400 MHz, CDCl3): δ = 2.29 (s, 6 H), 2.31 (s, 6 H), 5.31 (d, J = 6.4 Hz, 1 H), 6.65 (d, J = 7.2 Hz, 1 H), 6.69 (d, J = 7.6 Hz, 1 H), 7.79 (t, J = 7.6 Hz, 1 H), 7.11–7.23 (m, 3 H), 7.44 (s, 1 H), 7.46 (s, 1 H), 7.48 (s, 1 H), 7.51 (s, 1 H), 9.31 (s, 1 H).

13C NMR (100 MHz, CDCl3/DMSO-d 6): δ = 21.3, 80.2 (d, J C–P = 72.7 Hz), 110.2, 122.0, 125.3, 126.3 (d, J C–P = 2.3 Hz), 127.4 (d, J C–P = 91.9 Hz), 128.1, 128.4 (d, J C–P = 95.6 Hz), 130.1 (d, J C–P = 8.5 Hz), 130.3 (d, J C–P = 9.2 Hz), 134.1 (d, J C–P = 2.4 Hz), 134.2 (d, J C–P = 2.5 Hz), 137.6 (d, J C–P = 12.6 Hz), 137.8 (d, J C–P = 12.3 Hz), 142.4 (d, J C–P = 6.1 Hz), 175.9.

31P NMR (162 MHz, CDCl3/DMSO-d 6): δ = 30.8.

HRMS: m/z [M + H] calcd. for C24H24NO3P + H: 406.1572; found: 406.1582.


#

3-(Bis(3,5-dimethylphenyl)phosphinoyl)-3-hydroxy-1-methylindolin-2-one (3q)

The title compound was prepared by following the general procedure for Scheme [1], using 1-methylisatin 1b (0.5 mmol, 0.080 g) and bis (3,5-dimethylphenyl)phosphine oxide 2c (0.5 mmol, 0.129 g), providing 3q as a white solid. Yield: 0.192 g (92%); mp 138 °C.

1H NMR (400 MHz, CDCl3/DMSO-d 6): δ = 2.27 (s, 6 H), 2.34 (s, 6 H), 2.94 (s, 3 H), 6.65 (d, J = 8.0 Hz, 1 H), 6.75 (bs, 1 H), 6.85–6.95 (m, 2 H), 7.10 (s, 1 H), 7.19 (s, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.36 (s, 1 H), 7.39 (s, 1 H), 7.57 (s, 1 H), 7.60 (s, 1 H).

13C NMR (100 MHz, CDCl3/DMSO-d 6): δ = 20.7, 20.8, 25.6, 80.0 (d, J C–P = 75.5 Hz), 107.2, 121.7, 125.1, 125.8, 128.0 (d, J C–P = 95.6 Hz), 128.4 (d, J C–P = 95.6 Hz), 129.4 (d, J C–P = 8.7 Hz), 129.8 (d, J C–P = 8.9 Hz), 133.1, 133.3, 136.7 (d, J C–P = 12.5 Hz), 137.0 (d, J C–P = 12.4 Hz), 143.4 (d, J C–P = 5.7 Hz), 173.5.

31P NMR (162 MHz, CDCl3/DMSO-d 6): δ = 30.4.

HRMS: m/z [M + H] calcd. for C25H26NO3P + H: 420.1729; found: 420.1737.


#

3-(Bis(3,5-dimethylphenyl)phosphinoyl)-3-hydroxy-1-ethylindolin-2-one (3r)

The title compound was prepared by following the general procedure for Scheme [1], using 1-ethylisatin 1c (0.5 mmol, 0.087 g) and bis (3,5-dimethylphenyl)phosphine oxide 2c (0.5 mmol, 0.129 g), providing 3r as a white solid. Yield: 0.203 g (94%); mp 132 °C.

1H NMR (400 MHz, CDCl3): δ = 0.83 (t, J = 7.2 Hz, 3 H), 2.26 (s, 6 H), 2.31 (s, 6 H), 3.29–3.35 (m, 1 H), 3.51–3.62 (m, 1 H), 4.57 (s, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 6.91 (t, J = 7.6 Hz, 1 H), 6.99 (d, J = 7.2 Hz, 1 H), 7.12 (s, 1 H), 7.19 (s, 1 H), 7.24–7.34 (m, 3 H), 7.39 (s, 1 H), 7.42 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 12.0, 21.36, 21.39, 34.8, 79.8 (d, J C–P = 69.4 Hz), 107.9, 122.5, 124.4, 126.8 (d, J C–P = 95.7 Hz), 127.1, 128.1, 128.2, 128.4 (d, J C–P = 96.2 Hz), 129.9 (d, J C–P = 9.2 Hz), 130.3 (d, J C–P = 8.4 Hz), 134.2 (d, J C–P = 1.8 Hz), 134.3 (d, J C–P = 2.5 Hz), 137.8 (d, J C–P = 12.7 Hz), 138.0 (d, J C–P = 12.4 Hz), 143.7 (d, J C–P = 5.9 Hz), 173.6.

31P NMR (162 MHz, CDCl3): δ = 31.3.

HRMS: m/z [M + H] calcd. for C26H28NO3P + H: 434.1885; found: 434.1872.


#

3-(Bis(3,5-dimethylphenyl)phosphinoyl)-3-hydroxy-1-benzylindolin-2-one (3s)

The title compound was prepared by following the general procedure for Scheme [1], using 1-benzylisatin 1d (0.5 mmol, 0.118 g) and bis (3,5-dimethylphenyl)phosphine oxide 2c (0.5 mmol, 0.129 g), providing 3s as a white solid. Yield: 0.227 g (92%); mp 134 °C.

1H NMR (400 MHz, CDCl3): δ = 2.25 (s, 6 H), 2.26 (s, 6 H), 4.45 and 4.79 (ABq, J = 16.0 Hz, 2 H), 6.52 (d, J = 7.6 Hz, 1 H), 6.87 (t, J = 7.6 Hz, 1 H), 6.92–6.97 (m, 2 H), 7.00 (d, J = 7.6 Hz, 1 H), 7.13–7.22 (m, 6 H), 7.28 (s, 1 H), 7.31 (s, 1 H), 7.42 (s, 1 H), 7.45 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 21.36, 21.38, 44.3, 79.8 (d, J C–P = 70.3 Hz), 109.1, 122.8, 124.7, 126.8 (d, J C–P = 95.3 Hz), 126.9, 127.0, 127.4 (d, J C–P = 93.0 Hz), 127.5, 128.7, 128.82, 128.86, 130.1 (d, J C–P = 9.3 Hz), 130.3 (d, J C–P = 9.0 Hz), 134.3 (d, J C–P = 2.7 Hz), 134.5, 135.0, 137.8 (d, J C–P = 12.6 Hz), 138.0 (d, J C–P = 12.4 Hz), 143.8 (d, J C–P = 5.8 Hz), 174.4.

31P NMR (162 MHz, CDCl3): δ = 31.6.

HRMS: m/z [M + H] calcd. for C31H30NO3P + H: 496.2042; found: 496.2051.


#

3-(Bis(3,5-dimethylphenyl)phosphinoyl)-5-chloro-3-hydroxy-indolin-2-one (3t)

The title compound was prepared by following the general procedure for Scheme [1], using 5-chloroisatin 1e (0.5 mmol, 0.090 g) and bis (3,5-dimethylphenyl)phosphine oxide 2c (0.5 mmol, 0.129 g), providing 3t as a white solid. Yield: 0.202 g (92%); mp 208 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 2.28 (s, 6 H), 2.33 (s, 6 H), 6.21 (s, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 7.18 (s, 1 H), 7.24–7.33 (m, 3 H), 7.46 (s, 1 H), 7.49 (s, 1 H), 7.53 (s, 1 H), 7.56 (s, 1 H), 10.60 (s, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 20.94, 20.98, 80.0 (d, J C–P = 79.7 Hz), 110.7, 124.8 (d, J C–P = 2.4 Hz), 125.6 (d, J C–P = 2.1 Hz), 128.9, 129.4, 129.83 (d, J C–P = 94.4 Hz), 129.88 (d, J C–P = 8.2 Hz), 129.9 (d, J C–P = 5.9 Hz), 130.0 (d, J C–P = 94.8 Hz), 133.2, 133.6, 136.8 (d, J C–P = 12.3 Hz), 137.2 (d, J C–P = 12.0 Hz), 141.6 (d, J C–P = 5.7 Hz), 175.0.

31P NMR (162 MHz, DMSO-d 6): δ = 27.9.

HRMS: m/z [M + H] calcd. for C24H23ClNO3P + H: 440.1182; found: 440.1172.


#

3-(Bis(3,5-dimethylphenyl)phosphinoyl)-5-bromo-3-hydroxy-indolin-2-one (3u)

The title compound was prepared by following the general procedure for Scheme [1], using 5-bromoisatin 1i (0.5 mmol, 0.113 g) and bis (3,5-dimethylphenyl)phosphine oxide 2c (0.5 mmol, 0.129 g), providing 3u as a white solid. Yield: 0.207 g (86%); mp 178 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 2.24 (s, 6 H), 2.28 (s, 6 H), 5.55 (d, J = 11.6 Hz, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 7.19 (s, 1 H), 7.23 (s, 1 H), 7.27 (s, 1 H), 7.30 (s, 1 H), 7.35 (s, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.51 (s, 1 H), 7.54 (s, 1 H), 10.7 (s, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 20.2, 69.9 (d, J C–P = 6.0 Hz, ), 111.5, 112.8, 127.1, 128.1 (d, J C–P = 8.3 Hz), 129.5 (d, J C–P = 3.2 Hz), 130.7 (d, J C–P = 10.0 Hz), 132.3, 132.6, 133.5, 137.6 (d, J C–P = 14.0 Hz), 141.7, 172.4.

31P NMR (162 MHz, DMSO-d 6): δ = 35.6.

HRMS: m/z [M + H] calcd. for C24H23BrNO3P + H: 484.0677; found: 484.0689.


#

3-(Bis(3,5-dimethylphenyl)phosphinoyl)-5-chloro-3-hydroxy-1-ethylindolin-2-one (3v)

The title compound was prepared by following the general procedure for Scheme [1], using 5-chloro-1-ethylisatin 1g (0.5 mmol, 0.105 g) and bis (3,5-dimethylphenyl)phosphine oxide 2c (0.5 mmol, 0.129 g), providing 3v as a white solid. Yield: 0.217 g (93%); mp 138 °C.

1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 7.2 Hz, 3 H), 2.29 (s, 6 H), 2.33 (s, 6 H), 3.32–3.37 (m, 1 H), 3.56–3.61 (m, 1 H), 4.75 (d, J = 3.6 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 6.85–6.90 (m, 1 H), 7.15 (s, 1 H), 7.21 (s, 1 H), 7.25–7.27 (m, 2 H), 7.30 (s, 1 H), 7.33 (s, 1 H), 7.42 (s, 1 H), 7.45 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 12.0, 21.3, 21.4, 35.0, 79.7 (d, J C–P = 68.0 Hz), 108.8, 126.2, 126.4, 127.5 (d, J C–P = 2.7 Hz), 127.9 (d, J C–P = 2.6 Hz), 128.2, 128.6, 130.0 (d, J C–P = 9.4 Hz), 130.2 (d, J C–P = 8.8 Hz), 134.5 (d, J C–P = 2.4 Hz), 134.6 (d, J C–P = 2.5 Hz), 137.9 (d, J C–P = 12.6 Hz), 138.2 (d, J C–P = 12.5 Hz), 142.1 (d, J C–P = 5.6 Hz), 173.3.

31P NMR (162 MHz, CDCl3): δ = 31.4.

HRMS: m/z [M + H] calcd. for C26H27ClNO3P + H: 468.1495; found: 468.1480.


#

3-(Bis(3,5-dimethylphenyl)phosphinoyl)-5-bromo-3-hydroxy-1-ethylindolin-2-one (3w)

The title compound was prepared by following the general procedure for Scheme [1], using 5-bromo-1-ethylisatin 1j (0.5 mmol, 0.127 g) and bis (3,5-dimethylphenyl)phosphine oxide 2c (0.5 mmol, 0.129 g), providing 3w as a white solid. Yield: 0.240 g (94%); mp 132 °C.

1H NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 7.2 Hz, 3 H), 2.29 (s, 6 H), 2.33 (s, 6 H), 3.30–3.36 (m, 1 H), 3.54–3.60 (m, 1 H), 5.14 (s, 1 H), 6.55 (d, J = 8.4 Hz, 1 H), 7.01 (s, 1 H), 7.15 (s, 1 H), 7.26 (s, 1 H), 7.31 (s, 1 H), 7.34 (s, 1 H), 7.41–7.51 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 12.0, 21.3, 21.4, 35.0, 79.8 (d, J C–P = 68.3 Hz), 109.2, 115.0, 126.2, 126.8, 127.6 (d, J C–P = 96.3 Hz), 130.0 (d, J C–P = 9.2 Hz), 130.3 (d, J C–P = 9.1 Hz), 132.9, 134.4 (d, J C–P = 2.4 Hz), 134.5 (d, J C–P = 2.5 Hz), 137.9 (d, J C–P = 12.9 Hz), 138.1 (d, J C–P = 12.5 Hz), 142.5 (d, J C–P = 5.9 Hz), 173.2.

31P NMR (162 MHz, CDCl3): δ = 31.5.

HRMS: m/z [M + H] calcd. for C26H27BrNO3P + H: 512.0990; found: 512.0982.


#

3-(Bis(3,5-dimethylphenyl)phosphinoyl)-3-hydroxy-5-nitro-indolin-2-one (3x)

The title compound was prepared by following the general procedure for Scheme [1], using 5-nitroisatin 1k (0.5 mmol, 0.096 g) and bis (3,5-dimethylphenyl)phosphine oxide 2c (0.5 mmol, 0.129 g), providing 3x as a white solid. Yield: 0.207 g (92%); mp 184 °C.

1H NMR (400 MHz, CDCl3/DMSO-d 6): δ = 2.36 (s, 12 H), 6.80–6.95 (m, 2 H), 7.18 (s, 1 H), 7.27 (s, 1 H), 7.28–7.35 (m, 1 H),7.50–7.60 (m, 2 H), 7.68 (s, 1 H), 7.71 (s, 1 H), 8.08 (t, J = 7.2 Hz, 1 H), 10.7 (s, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 20.9, 21.0, 79.7 (d, J C–P = 78.4 Hz), 109.7, 121.0, 126.9, 127.8, 129.0, 129.2 (d, J C–P = 94.9 Hz), 129.9 (d, J C–P = 8.7 Hz), 133.5, 133.9, 137.1 (d, J C–P = 12.3 Hz), 137.5 (d, J C–P = 12.2 Hz), 141.3, 149.1 (d, J C–P = 5.3 Hz), 175.8.

31P NMR (162 MHz, CDCl3): δ = 28.4.

HRMS: m/z [M + H] calcd. for C24H23N2O5P + H: 451.1423; found: 451.1430.


#

3-Diphenylphosphoryl-3-hydroxy-indolin-2-one (3y1)[20]

The title compound was prepared by following the general procedure for Scheme [1], using isatin 1a (1.0 mmol, 0.147 g) and diphenyl phosphite 2d (1.0 mmol, 0.234 g, 0.2 mL), providing 3y1 as a white solid. Yield: 0.343 g (90%); mp 130 °C.

1H NMR (400 MHz, CDCl3/DMSO-d 6): δ = 6.25 (bs, 1 H), 6.84–6.93 (m, 3 H), 7.02–7.10 (m, 2 H), 7.13–7.33 (m, 8 H), 7.65 (d, J = 7.6 Hz, 1 H), 9.85 (s, 1 H).

13C NMR (100 MHz, CDCl3/DMSO-d 6): δ = 75.5, 110.3, 120.4 (d, J C–P = 3.8 Hz), 120.9 (d, J C–P = 3.9 Hz), 122.4, 125.0 (d, J C–P = 9.2 Hz), 125.2, 126.8 (d, J C–P = 3.4 Hz), 129.3 (d, J C–P = 8.3 Hz), 130.5, 142.4 (d, J C–P = 9.1 Hz), 150.1 (d, J C–P = 10.2 Hz), 150.4 (d, J C–P = 10.4 Hz), 174.6 (d, J C–P = 4.9 Hz).

31P NMR (162 MHz, CDCl3/DMSO-d 6): δ = 9.1.

HRMS: m/z [M + Na] calcd. for C20H16NO5P + Na: 404.0664; found: 404.0622.


#

3-Diphenylphosphoryl-3-hydroxy-1-methylindolin-2-one (3y2)

The title compound was prepared by following the general procedure for Scheme [1], using N-methylisatin 1b (1.0 mmol, 0.161 g) and diphenyl phosphite 2d (1.0 mmol, 0.234 g, 0.2 mL), providing 3y2 as a white solid. Yield: 0.367 g (93%); mp 106 °C.

1H NMR (400 MHz, CDCl3/DMSO-d 6): δ = 3.22 (s, 3 H), 6.82–6.90 (m, 3 H), 7.07–7.12 (m, 2 H), 7.15–7.25 (m, 5 H), 7.27–7.35 (m, 2 H), 7.36–7.42 (m, 1 H), 7.67 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3/DMSO-d 6): δ = 26.8, 75.2, 108.8, 120.4 (d, J C–P = 3.9 Hz), 120.7 (d, J C–P = 4.1 Hz), 123.5 (d, J C–P = 2.5 Hz), 125.5 (d, J C–P = 11.4 Hz), 126.9 (d, J C–P = 3.4 Hz), 129.7 (d, J C–P = 13.4 Hz), 131.1, 144.4 (d, J C–P = 8.8 Hz), 150.1 (d, J C–P = 9.8 Hz), 150.3 (d, J C–P = 10.3 Hz), 173.0 (d, J C–P = 6.0 Hz).

31P NMR (162 MHz, CDCl3/DMSO-d 6): δ = 8.8.

HRMS: m/z [M + H] calcd. for C21H18NO5P + H: 396.1001; found: 396.0989.


#

3-Diphenylphosphoryl-3-hydroxy-1-ethylindolin-2-one (3y3)

The title compound was prepared by following the general procedure for Scheme [1], using N-ethylisatin 1c (1.0 mmol, 0.175 g) and diphenyl phosphite 2d (1.0 mmol, 0.234 g, 0.2 mL), providing 3y3 as a colorless viscous liquid. Yield: 0.372 g (91%).

1H NMR (400 MHz, CDCl3): δ = 1.27 (t, J = 7.2 Hz, 3 H), 3.73–3.76 (m, 2 H), 5.78 (d, J = 12.0 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 6.98 (t, J = 7.6 Hz, 1 H), 7.18–7.24 (m, 5 H), 7.25–7.47 (m, 7 H).

13C NMR (100 MHz, CDCl3): δ = 12.5, 35.0, 73.6 (d, J C–P = 6.0 Hz), 108.7, 120.50 (d, J C–P = 4.7 Hz), 120.59 (d, J C–P = 4.7 Hz), 123.0, 123.6 (d, J C–P = 3.2 Hz), 125.6, 126.3, 129.8, 130.9, 143.4, 150.3 (d, J C–P = 7.3 Hz), 150.5 (d, J C–P = 7.4 Hz), 170.7.

31P NMR (162 MHz, CDCl3): δ = 10.7.

HRMS: m/z [M + H] calcd. for C22H20NO5P + H: 410.1157; found: 410.1168.


#

3-Diphenylphosphoryl-5-chloro-3-hydroxy-1-methylindolin-2-one (3y4)

The title compound was prepared by following the general procedure for Scheme [1], using 5-chloro-1-ethylisatin 1g (1.0 mmol, 0.209 g) and diphenyl phosphite 2d (1.0 mmol, 0.234 g, 0.2 mL), providing 3y4 as a colorless viscous liquid. Yield: 0.381 g (86%).

1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.2 Hz, 3 H), 3.69–3.75 (m, 2 H), 5.73 (d, J = 12.4 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 7.06–7.08 (m, 1 H), 7.23–7.26 (m, 5 H), 7.27–7.47 (m, 6 H).

13C NMR (100 MHz, CDCl3): δ = 12.4, 35.2, 73.1 (d, J C–P = 5.9 Hz), 109.6, 120.6 (d, J C–P = 3.0 Hz), 125.1 (d, J C–P = 2.9 Hz), 125.9 (d, J C–P = 18.6 Hz), 126.7, 128.4, 129.9 (d, J C–P = 3.2 Hz), 130.7, 141.9, 150.1 (d, J C–P = 7.2 Hz), 150.4 (d, J C–P = 7.6 Hz), 170.4 (d, J C–P = 6.8 Hz).

31P NMR (162 MHz, CDCl3): δ = 10.6.

HRMS: m/z [M + Na] calcd. for C22H19ClNO5P + Na: 466.0587; found: 466.0542.


#
#

Acknowledgment

R.C. and P.S. acknowledge the UGC-India for Fellowships. R.B. thanks the SERB-DST for financial assistantship. The authors are grateful for MRC-MNIT Jaipur and USIC University of Rajasthan, Jaipur for spectroscopic analyses.

Supporting Information

  • References and Notes

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  • References and Notes

    • 1a Quin LD. A Guide to Organophosphorus Chemistry . Wiley Interscience; New York: 2000
    • 1b Tang W. Zhang X. Chem. Rev. 2003; 103: 3029
    • 1c Montchamp J.-L. Acc. Chem. Res. 2014; 47: 77
    • 1d Redmore D. Chem. Rev. 1971; 71: 315
    • 1e Van der Jeught S. Stevens CV. Chem. Rev. 2009; 109: 2672
    • 1f Romero-Nieto C. Lýpez-Andarias A. Egler-Lucas C. Gebert F. Neus J.-P. Pilgram O. Angew. Chem. Int. Ed. 2015; 54: 15872
    • 3a Demkowicz S. Rachon J. Dasko M. Kozak W. RSC Adv. 2016; 6: 7101
    • 3b Mucha A. Kafarski P. Berlicki L. J. Med. Chem. 2011; 54: 5955
  • 4 van Berkel SS. van Eldijk MB. van Hest JC. M. Angew. Chem. Int. Ed. 2011; 50: 8806
    • 5a Wang C. Fukazawa A. Taki M. Sato Y. Higashiyama T. Yamaguchi S. Angew. Chem. Int. Ed. 2015; 54: 15213
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    • 5c Baumgartner T. Reau R. Chem. Rev. 2006; 106: 4681
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    • 6b Miller DJ. Hammond SM. Anderluzzi D. Bugg TD. H. J. Chem. Soc., Perkin Trans. 1 1998; 131
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    • 6d Atherton FR. Hassal CH. Lambert RW. J. Med. Chem. 1986; 29: 29
    • 6e Emsley J. Hall D. The Chemistry of Phosphorus . Harper & Row; London: 1976: 494
    • 6f Meyer JH. Barlett PA. J. Am. Chem. Soc. 1998; 120: 4600
    • 6g Maier L. Spoerri H. Phosphorus, Sulfur Silicon Relat. Elem. 1991; 61: 69
    • 7a Jablonkai E. Keglevich G. Org. Prep. Proced. Int. 2014; 46: 281
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    • 7c Hirao T. Masunaga T. Yamada N. Ohshiro Y. Agawa T. Bull. Chem. Soc. Jpn. 1982; 55: 909
    • 7d Hirao T. Masunaga T. Ohshiro Y. Agawa T. Synthesis 1981; 56
    • 7e Schwan AL. Chem. Soc. Rev. 2004; 33: 218
    • 7f Prim D. Campagne JM. Joseph D. Andrioletti B. Tetrahedron 2002; 58: 2041
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    • 8c Tokunaga T. Hume WE. Umezome T. Okazaki K. Ueki Y. Kumagai K. Hourai S. Nagamine J. Seki H. Taiji M. Noguchi H. Nagata R. J. Med. Chem. 2001; 44: 4641
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    • 8f Rasmussen HB. Macleod JK. J. Nat. Prod. 1997; 60: 1152
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Scheme 1 C–P bond formation between isatins 1 and phosphine oxides 2. Reaction conditions: Isatin 1 (0.5 mmol), diphenylphosphine oxide 2 (0.5 mmol), water (1.0 mL), r.t., 12 h. Isolated yields are based on 1. a Reaction conditions: Isatin 1 (1.0 mmol), diphenyl phosphite 2d (0.2 mL), neat, r.t., 12 h.
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Scheme 2 Control experiments
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Scheme 3 Plausible reaction mechanism for C–P bond formation between isatin and diphenyl phosphine oxide