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Synthesis 2022; 54(21): 4711-4720
DOI: 10.1055/a-1633-8792
special topic
Asymmetric C–H Functionalization

Direct Copper-Catalyzed C-3 Arylation of Diphenylphosphine Oxide Indoles

Xiao-Ling Huang
a   State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
,
Chong Li
a   State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
,
Juan Wang
a   State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
,
Shang-Dong Yang  ∗
a   State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
b   State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou 730000, P. R. of China
› Author Affiliations

We are grateful to the National Natural Science Foundation of China (NSFC, No. 21532001), the International Joint Research Center for Green Catalysis and Synthesis (No. 2016B01017), and Lanzhou University for their financial support.
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Abstract

We have developed a simple and effective method for the C-3 arylation of phosphorus-containing indole compounds in the presence of CuI under mild conditions. This reaction provides a reliable method for the modification of ligands.


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Key words

transition-metal catalysis - organophosphorus compounds - arylation - indoles
Zoom Image
Figure 1 Phosphorus-containing indole ligands

Table 1 Optimization Studies for this Reactiona

Entry

Cat. (mol%)

Solvent

Temp (°C)

Yield (%)b

 1

Cu(OTf)2 (5)

DCE

100

60

 2

CuI (5)

DCE

100

64

 3

CuCN (5)

DCE

100

56

 4

CuI (5)

DCM

100

58

 5

CuI (5)

THF

100

46

 6

CuI (5)

CHCl3

100

56

 7c

CuI (5)

DCE

100

74

 8c

CuI (5)

DCE

 50

87

 9c

CuI (5)

DCE

 25

58

10c,d

CuI (5)

DCE

 50

88

11c,d,e

CuI (5)

DCE

 50

94

12c,d,e,f

none

DCE

 50

N.R.

13f

none

DCE

120

N.R.

a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), copper catalyst (5 mol%), solvent (2 mL), 24 h.

b Isolated yield based on 1a.

c 60 h.

d Air atmosphere.

e 2a: 1.5 equivalents.

f N.R. = no reaction.

During the past decades, transition-metal-catalyzed reactions have become an extremely powerful tool to generate new chemical bonds, such as carbon–carbon, carbon–nitrogen, and carbon–oxygen bond formation in organic chemistry. Generally, the ligand as an intimate partner plays an important role to modify the reactivity and selectivity of catalysts.[1] Hence, the design of ligands with ideal steric and electronic natures is a central task in this area. Phosphorus-containing nitrogen heterocyclic compounds as an important class of organophosphorus compounds are not only widely used in medicines,[2] but also extensively used in materials[3] and organic synthesis as ligands.[4] Some facts have proved that phosphorus-containing indole ligands are very effective ligands in metal-catalyzed reactions.[4a] [b] [d] [e] [5] Among various phosphorus ligands, arylindole scaffolds were developed by the Kwong group in 2007.[6] Due to the highly effective Suzuki–Miyaura coupling of unactivated aryl chlorides, the family of indolyl phosphine ligands was widely enriched (Figure [1]). In consideration of diversity, it is necessary to develop a convenient method to fine-tune the steric and electronic nature of such ligands. Herein, we wish to report a copper-catalyzed C-3 arylation of phosphorus-containing indoles to synthesize different new structural indolyl phosphine ligands via straightforward C–H activation.

We started our study with (2-(1-methyl-1H-indol-2-yl)phenyl)diphenylphosphine oxide (1a) and di-p-tolyliodonium trifluoromethanesulfonate (2a) (Table [1]). The early trial reactions were carried out using 5 mol% Cu(OTf)2 as catalyst in 1,2-dichloroethane at 100 °C. We were pleased to find that the arylation of diphenylphosphine oxide indole proceeded to give 3a in moderate yield (entry 1). Encouraged by this result, other copper catalysts were examined, and it was found that CuI could provide a 64% yield (entry 2). The solvent effect was ineffective, whether using DCM, chloroform, or THF (entries 4–6). In terms of the conversion, the reaction time was increased to 60 hours to achieve full conversion, and a good yield was obtained (74%, entry 7). We speculated that some mass balance was lost due to high temperature. Subsequently, we found it is beneficial for the reaction when the temperature was decreased to 50 °C (entries 8 and 9). Furthermore, the reaction is not sensitive to air, and 3a was easily obtained in 88% yield (entry 10). We also noted that 2a as a highly reactive arylation reagent may be decomposed to side product. Therefore, a higher loading of 2a led to an excellent yield of 94% (entry 11). Finally, control experiments were done in the absence of CuI under different reaction temperatures, and the results indicated that the copper catalyst is an indispensable part of the reaction (entries 12 and 13).

Zoom Image
Scheme 1 Scope of symmetrical diaryliodonium salts. Reagents and conditions: 1a (0.2 mmol), 2a–l (0.3 mmol), CuI (5 mol%), DCE (2 mL), 50 °C, air. Isolated yield of products.

With the optimal experimental conditions in hand, we investigated different symmetrical diaryliodonium salts. As shown in Scheme [1], various diaryliodonium salts bearing electron-donating or electron-withdrawing groups could be used to generate the corresponding C-3 arylation products in moderate to good yields (3a–k, 42–94%). Meanwhile, diaryliodonium salts with electron-rich groups could be more easily transferred than those with electron-withdrawing groups, giving excellent yields. We suspected that the lack of reactivity may be attributed to the diaryliodonium salt’s electronic effect since the halogen- and ester-substituted diaryliodonium salts demonstrated the worst results. With the most electron-withdrawing 2l bearing a CF3 group acting as substrate, no desired product 3l was detected in this reaction.

A variety of unsymmetrical diaryliodonium salts were also tested for this arylation of phosphorus-containing indoles (Scheme [2]). As previously reported by Gaunt, Sanford, and others,[7] [8] unsymmetrical diaryliodonium salts tolerating one bulky mesityl ligand allow the selective transfer of the other aryl group. We were pleased to find that both electron-donating and electron-withdrawing substituents on the diaryliodonium salts were tolerated (3a′–i′), but compared with the symmetrical diaryliodonium salts, the yield of the products was decreased. As expected, substrates containing heterocycle or alkyl groups were also well-tolerated. It is noteworthy that the heterocyclic unsymmetrical diaryliodonium salt could form the corresponding product 3j′ in 46% yield. Furthermore, 2,2,2-trifluoroethyl(mesityl)iodonium triflate salt could also be used to obtain 3k′ in 42% yield.

Zoom Image
Scheme 2 Scope of asymmetrical diaryliodonium salts. Reagents and conditions: 1a (0.2 mmol), 2a′–k′ (0.3 mmol), CuI (5 mol%), DCE (2 mL), 50 °C, air. Isolated yield of products.

As a key part of indolyl phosphine ligands, different kinds of aryl indole scaffolds 1 were investigated. Firstly, various indoles substituted by electron-donating or electron-withdrawing groups, such as 5-methyl, 5-methoxy, 5-fluoro, and 5-chloro substituents, were examined (Scheme [3, 4b–f]). According to the results, electron-withdrawing substrates bearing a F or Cl substituent could provide better results than the indoles which were substituted by a Me or OMe group.

Zoom Image
Scheme 3 Scope of diphenylphosphine oxide indoles. Reagents and conditions: 1 (0.2 mmol), 2a (0.3 mmol), CuI (5 mol%), DCE (2 mL), 50 °C, air. Isolated yield of products. a Reaction was carried at 100 °C.

Subsequently, a 5,7-dichloro-substituted indole was used to test this reaction; however, no desired product 4h was detected. In order to test the necessity of a substituent at the 1-position of indole, we explored the substrate without a protecting group at the 1-indole. We were pleased to obtain the protecting-group-free indolyl phosphine ligand 4a in 74% yield (Scheme [3]). Additionally, 1g was synthesized to further investigate the adaptability of the substrate, and 4g was obtained in 72% yield.

Given the requirements of industrial production, we set up a gram-scale reaction under the standard reaction conditions to establish the utility of this copper-catalyzed arylation method (Scheme [4, a]), and 1.119 g of the desired product was obtained in 90% yield. Furthermore, 3a could be reduced easily by HSiCl3 to produce the new structural phosphorus-containing indole ligand 5a in 80% yield (Scheme [4, b]).

Zoom Image
Scheme 4 Gram-scale reaction and reduction of 3a

We propose that this reaction undergoes a P(O)-directed pathway. Hence, two reactions were designed to explore the possible reaction mechanism. As shown in Scheme [5], the necessity of the phosphorus group was considered firstly. 1-Methyl-2-phenyl-1H-indole was treated under the standard conditions, and there was no arylation product generated (Scheme [5, a]). Next, in terms of the steric hindrance and electronic effects, we chose a trifluoromethyl group to imitate the role of the phosphorus group. So, 1-methyl-2-(2-(trifluoromethyl)phenyl)-1H-indole was tested, which also could not provide an arylation product (Scheme [5, b]).

Zoom Image
Scheme 5 Mechanistic studies

Based on these studies and the literature precedence,[8a] [9] we propose a plausible mechanism (Scheme [6]). First of all, Cu(I) undergoes an oxidative addition process with the diaryliodine(III) salt and gives electrophilic Cu(III)–aryl intermediate A. Afterward, intermediate A could attack at the C-3 position of the phosphorus-containing indole to generate intermediate B with the assistance of the P(O) group. Then, TfOH is removed to form intermediate C. Finally, C-3-arylated phosphorus-containing indole product 3 is obtained by reductive elimination, and the Cu(I) catalyst is regenerated.

Zoom Image
Scheme 6 Plausible reaction mechanism

In summary, we have developed a simple and effective strategy to synthesize a series of C-3-arylated phosphorus-containing indole compounds. These reaction conditions are simple and mild, and additional additives are not needed. Furthermore, a reliable method for the modification of ligands is provided.

1H NMR, 13C NMR, 19F NMR, and 31P NMR were recorded on a Varian Mercury-300 or Bruker Avance III 400 NMR spectrometer. Unless otherwise specified, the test solvent was deuterated chloroform with TMS as internal standard. Chemical shifts are measured in parts per million (ppm) with reference to TMS (0.0 ppm), multiplicity is explained as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad, and coupling constants are given in Hz. MS was determined using an Esquire 6000 ion trap mass spectrometer. The catalysts and reaction reagents commonly used in experiments were purchased from reagent companies. Unless otherwise specified, all commercial reagents were used without additional purification. All gas-sensitive reagents were used in a dry argon atmosphere, and the solvents used in reactions, such as THF, DCE, and toluene, were dried according to standard laboratory purification techniques and stored in argon. TLC (GF254 silica gel plates provided by Yantai Wanhua) was used to monitor the reactions, and the spots were observed by UV light (254 and 365 nm) or by treatment with potassium permanganate, potassium bismuth iodide, or phosphomolybdic acid. Unless otherwise specified, the desiccant used was anhydrous sodium sulfate. The target products were obtained by silica gel column chromatography (200–400 mesh silica gel, provided by Wanhua, Yantai, Shandong Province) with EtOAc/petroleum ether (v/v) as eluent.


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Compounds 3 and 4 by C-3 Arylation of Phosphorus-Containing Indoles; General Procedure

Substrates 1 (0.2 mmol) and 2 (0.3 mmol), CuI (5 mol%), and DCE (2 mL) were placed in a reaction tube, and the resulting solution was stirred at 50 °C for 60 h. After reaction completion, the tube was cooled to room temperature, and the reaction mixture was quenched with saturated NaHCO3 solution. The mixture was extracted with DCM and then the oil organic phase was dried with anhydrous MgSO4 and concentrated using a vacuum rotary evaporator to obtain the crude product which was separated and purified by silica gel column chromatography (petroleum ether/EtOAc).


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(2-(1-Methyl-3-(p-tolyl)-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3a and 3a′)

Yield: 3a: 93.5 mg (94%), 3a′: 64.6 mg (65%); white solid; mp 237–239 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 8.05 (ddd, J = 12.7, 7.6, 1.3 Hz, 1 H), 7.65 (ddd, J = 7.5, 4.6, 1.5 Hz, 1 H), 7.62–7.57 (m, 2 H), 7.54–7.49 (m, 1 H), 7.34–7.28 (m, 1 H), 7.23–7.19 (m, 1 H), 7.19 (dd, J = 4.7, 3.5 Hz, 1 H), 7.17–7.15 (m, 1 H), 7.15–7.12 (m, 1 H), 7.12–7.09 (m, 1 H), 7.09–7.07 (m, 1 H), 7.06 (d, J = 0.9 Hz, 1 H), 7.05–7.02 (m, 1 H), 7.02–7.00 (m, 1 H), 6.99 (d, J = 6.1 Hz, 1 H), 6.96–6.93 (m, 2 H), 6.92 (d, J = 8.1 Hz, 2 H), 6.83 (td, J = 7.8, 3.0 Hz, 2 H), 3.11 (s, 3 H), 2.33 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 136.4, 135.6, 134.9, 134.6, 134.3, 133.9, 133.5, 132.5, 131.9, 131.5, 131.1, 130.7, 130.0, 129.0, 128.0, 127.1, 126.4, 122.0, 119.7, 115.5, 109.5, 30.5, 21.2.

31P NMR (121 MHz, CDCl3): δ = 29.99 (s).

MS (ESI): m/z calcd for C34H28NOP [M]+: 497.2; found [M + H]+: 498.2.


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2-(1-Methyl-3-(m-tolyl)-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3b)

Yield: 65.6 mg (66%); white solid; mp 241–243 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 8.08 (dd, J = 12.5, 7.7 Hz, 1 H), 7.71–7.58 (m, 3 H), 7.57–7.50 (m, 1 H), 7.31 (dd, J = 7.0, 5.9 Hz, 1 H), 7.22–7.12 (m, 4 H), 7.12–7.04 (m, 5 H), 7.04–6.98 (m, 2 H), 6.93 (d, J = 7.4 Hz, 1 H), 6.89–6.80 (m, 4 H), 3.08 (s, 3 H), 2.19 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 137.6, 136.6, 135.8, 135.0, 134.7, 134.6, 134.6, 131.6, 131.3, 130.8, 129.9, 129.0, 128.2, 128.1, 127.3, 126.5, 126.3, 122.1, 119.9, 119.7, 115.7, 109.6, 30.6, 21.7.

31P NMR (162 MHz, CDCl3): δ = 29.20 (s).

MS (ESI): m/z calcd for C34H28NOP [M]+: 497.2; found [M + H]+: 498.2.


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(2-(1-Methyl-3-phenyl-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3c and 3b′)

Yield: 3c: 87.0 mg (90%), 3b′: 60.0 mg (62%); white solid; mp 224–226 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 8.01 (ddd, J = 12.7, 7.7, 1.1 Hz, 1 H), 7.65 (dd, J = 7.4, 1.4 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 2 H), 7.55–7.50 (m, 1 H), 7.30 (dd, J = 7.2, 1.4 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 1 H), 7.18 (d, J = 4.0 Hz, 1 H), 7.16 (d, J = 2.7 Hz, 1 H), 7.15–7.13 (m, 2 H), 7.12 (d, J = 4.1 Hz, 2 H), 7.11 (s, 2 H), 7.09 (d, J = 4.2 Hz, 2 H), 7.08–7.06 (m, 2 H), 7.06 (d, J = 2.5 Hz, 2 H), 7.03 (d, J = 8.3 Hz, 2 H), 3.13 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 136.4, 135.6, 134.9, 134.6, 133.8, 133.4, 132.3, 131.5, 131.2, 130.8, 130.0, 129.1, 128.2, 127.2, 126.3, 125.3, 122.1, 119.7, 119.5, 115.5, 109.5, 30.5.

31P NMR (121 MHz, CDCl3): δ = 29.68 (s).

MS (ESI): m/z calcd for C33H26NOP [M]+: 483.2; found [M + H]+: 484.2.


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(2-(3-(3,5-Dimethylphenyl)-1-methyl-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3d and 3c′)

Yield: 3d: 76.7 mg (75%), 3c′: 62.4 mg (61%); white solid; mp 233–235 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 8.07 (dd, J = 11.9, 7.8 Hz, 1 H), 7.68–7.56 (m, 3 H), 7.56–7.49 (m, 1 H), 7.31 (dd, J = 10.0, 4.7 Hz, 1 H), 7.16 (dd, J = 13.7, 7.0 Hz, 3 H), 7.07 (dd, J = 18.2, 10.3 Hz, 6 H), 7.00 (t, J = 6.1 Hz, 1 H), 6.82 (td, J = 7.6, 2.6 Hz, 2 H), 6.74 (s, 1 H), 6.66 (s, 2 H), 3.07 (s, 3 H), 2.14 (s, 6 H).

13C NMR (101 MHz, CDCl3): δ = 137.3, 136.4, 135.8, 134.8, 134.4, 133.7, 133.5, 132.4, 131.5, 131.2, 130.7, 130.0, 128.9, 128.0, 127.1, 126.4, 122.0, 119.7, 115.6, 109.5, 30.4, 21.5.

31P NMR (162 MHz, CDCl3): δ = 29.46 (s).

MS (ESI): m/z calcd for C35H30NOP [M]+: 511.2; found [M + H]+: 512.2.


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(2-(3-(4-Methoxyphenyl)-1-methyl-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3e and 3d′)

Yield: 3e: 84.2 mg (82%), 3d′: 47.2 mg (46%); white solid; mp 227–229 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 7.95 (dd, J = 12.6, 7.8 Hz, 1 H), 7.55 (dd, J = 15.1, 7.5 Hz, 2 H), 7.48 (d, J = 8.1 Hz, 1 H), 7.46–7.40 (m, 1 H), 7.24 (dd, J = 7.3, 6.3 Hz, 1 H), 7.15–7.05 (m, 3 H), 6.99 (ddd, J = 12.5, 6.0, 3.7 Hz, 6 H), 6.94–6.87 (m, 3 H), 6.82–6.74 (m, 2 H), 6.58 (d, J = 8.7 Hz, 2 H), 3.72 (s, 3 H), 3.03 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 157.4, 136.4, 135.8, 134.9, 134.6, 134.0, 133.7, 133.4, 132.4, 131.4, 130.8, 130.0, 128.9, 128.1, 127.4, 127.2, 126.4, 122.0, 119.7, 119.4, 115.2, 113.8, 55.2, 30.5.

31P NMR (162 MHz, CDCl3): δ = 29.27 (s).

MS (ESI): m/z calcd for C34H28NO2P [M]+: 513.2; found [M + H]+: 514.2.


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(2-(3-(4-tert-Butylphenyl)-1-methyl-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3f and 3e′)

Yield: 3f: 78.7 mg (73%), 3e′: 53.9 mg (50%); white solid; mp 236–238 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 8.07 (ddd, J = 12.7, 7.6, 1.3 Hz, 1 H), 7.69–7.58 (m, 3 H), 7.57–7.52 (m, 1 H), 7.31–7.25 (m, 1 H), 7.15 (dt, J = 10.8, 8.2 Hz, 7 H), 7.08–6.97 (m, 7 H), 6.82 (td, J = 7.8, 3.0 Hz, 2 H), 3.07 (s, 3 H), 1.34 (s, 9 H).

13C NMR (101 MHz, CDCl3): δ = 147.6, 136.4, 135.8, 134.7, 134.1, 133.8, 133.4, 132.3, 132.0, 131.6, 131.5, 131.4, 131.3, 131.2, 130.9, 130.7, 129.9, 129.0, 128.5, 128.1, 128.0, 127.2, 127.1, 126.5, 125.2, 122.0, 119.7, 115.3, 109.5, 34.4, 31.5, 30.4.

31P NMR (121 MHz, CDCl3): δ = 30.10 (s).

MS (ESI): m/z calcd for C37H34NOP [M]+: 539.2; found [M + H]+: 540.2.


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(2-(3-([1,1′-Biphenyl]-4-yl)-1-methyl-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3g)

Yield: 97.3 mg (87%); white solid; mp 252–254 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 8.12 (ddd, J = 12.7, 7.7, 1.0 Hz, 1 H), 7.77 (d, J = 7.7 Hz, 2 H), 7.74–7.69 (m, 3 H), 7.55 (t, J = 7.6 Hz, 2 H), 7.45 (d, J = 8.3 Hz, 3 H), 7.37 (dd, J = 11.1, 3.8 Hz, 2 H), 7.33–7.28 (m, 4 H), 7.25–7.19 (m, 4 H), 7.17 (dd, J = 8.1, 3.4 Hz, 4 H), 6.95 (td, J = 7.8, 3.0 Hz, 2 H), 3.24 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 141.0, 137.7, 136.6, 135.8, 134.9, 134.7, 134.2, 133.8, 133.4, 132.4, 131.5, 130.9, 130.0, 129.1, 128.6, 128.2, 127.4, 127.2, 126.8, 126.3, 122.2, 120.0, 119.5, 115.1, 109.7, 30.5.

31P NMR (162 MHz, CDCl3): δ = 29.33 (s).

MS (ESI): m/z calcd for C39H30NOP [M]+: 559.2; found [M + H]+: 560.2.


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(2-(3-(4-Fluorophenyl)-1-methyl-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3h)

Yield: 53.1 mg (53%); white solid; mp 244–246 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 7.92 (dd, J = 12.6, 7.8 Hz, 1 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.59 (t, J = 7.6 Hz, 1 H), 7.53 (t, J = 8.6 Hz, 2 H), 7.39–7.32 (m, 1 H), 7.23–7.12 (m, 8 H), 7.09 (q, J = 5.8 Hz, 2 H), 6.97 (dd, J = 8.4, 5.7 Hz, 2 H), 6.94–6.88 (m, 2 H), 6.77 (t, J = 8.7 Hz, 2 H), 3.17 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 162.1, 159.7, 136.5, 135.8, 134.8, 134.6, 134.5, 133.6, 132.5, 131.5, 127.4, 126.3, 122.2, 120.0, 119.2, 115.0, 114.6, 109.6, 30.5.

31P NMR (162 MHz, CDCl3): δ = 28.73 (s).

19F NMR (376 MHz, CDCl3): δ = –117.98 (s).

MS (ESI): m/z calcd for C33H25FNOP [M]+: 501.1; found [M + H]+: 502.1.


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(2-(3-(4-Chlorophenyl)-1-methyl-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3i and 3f′)

Yield: 3i: 66.2 mg (64%), 3f′: 69.3 mg (67%); white solid; mp 235–237 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 7.97–7.89 (m, 1 H), 7.66 (d, J = 7.5 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 7.54 (dd, J = 11.0, 4.4 Hz, 2 H), 7.37 (s, 1 H), 7.17 (td, J = 12.4, 7.5 Hz, 8 H), 7.10 (dd, J = 7.9, 2.4 Hz, 2 H), 7.02 (d, J = 8.5 Hz, 2 H), 6.95–6.87 (m, 4 H), 3.17 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 136.5, 135.6, 134.9, 134.7, 134.5, 133.7, 133.5, 132.4, 131.4, 131.1, 131.0, 130.9, 130.0, 129.0, 128.4, 128.2, 127.4, 126.1, 122.3, 120.1, 119.1, 114.3, 109.7, 30.6.

31P NMR (121 MHz, CDCl3): δ = 29.65.

MS (ESI): m/z calcd for C33H25ClNOP [M]+: 517.1; found [M + H]+: 518.1.


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(2-(3-(4-Bromophenyl)-1-methyl-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3j)

Yield: 47.1 mg (42%); white solid; mp 231–233 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 7.97–7.88 (m, 1 H), 7.71–7.64 (m, 1 H), 7.61 (dd, J = 5.4, 3.9 Hz, 1 H), 7.57–7.49 (m, 2 H), 7.38 (dd, J = 5.3, 3.7 Hz, 1 H), 7.24–7.19 (m, 2 H), 7.19–7.15 (m, 8 H), 7.11–7.07 (m, 2 H), 6.93–6.83 (m, 4 H), 3.17 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 136.5, 135.6, 134.9, 134.5, 134.0, 133.6, 133.4, 132.3, 131.7, 131.4, 131.0, 130.4, 130.0, 129.1, 129.0, 128.2, 127.5, 126.0, 122.3, 120.1, 119.1, 114.3, 109.7, 30.6.

31P NMR (121 MHz, CDCl3): δ = 29.28 (s).

MS (ESI): m/z calcd for C33H25BrNOP [M]+: 562.4; found [M + H]+: 563.0.


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Methyl 4-(2-(2-(Diphenylphosphoryl)phenyl)-1-methyl-1H-indol-3-yl)benzoate (3k)

Yield: 68.2 mg (63%); white solid; mp 228–230 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 7.83 (dd, J = 12.6, 7.8 Hz, 1 H), 7.72 (d, J = 8.2 Hz, 2 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.63–7.57 (m, 2 H), 7.53 (d, J = 3.9 Hz, 1 H), 7.36 (d, J = 7.8 Hz, 1 H), 7.26–7.21 (m, 3 H), 7.15 (dt, J = 12.3, 7.8 Hz, 7 H), 7.07 (d, J = 8.2 Hz, 2 H), 6.89 (dd, J = 7.3, 5.1 Hz, 2 H), 3.91 (s, 3 H), 3.26 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 167.3, 140.3, 136.9, 135.9, 134.9, 134.5, 133.7, 132.5, 131.7, 131.6, 131.4, 131.3, 131.1, 129.5, 129.1, 128.5, 128.3, 128.2, 127.6, 126.4, 126.2, 122.5, 120.4, 119.4, 114.6, 109.9, 52.1, 30.8.

31P NMR (162 MHz, CDCl3): δ = 28.29 (s).

MS (ESI): m/z calcd for C35H28NO3P [M]+: 541.2; found [M + H]+: 542.1.


#

Ethyl 4-(2-(2-(Diphenylphosphoryl)phenyl)-1-methyl-1H-indol-3-yl)benzoate (3g′)

Yield: 71.1 mg (64%); white solid; mp 233–235 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 7.86 (dd, J = 12.5, 7.7 Hz, 1 H), 7.73 (d, J = 8.3 Hz, 2 H), 7.67 (t, J = 7.5 Hz, 1 H), 7.59 (dd, J = 14.7, 7.7 Hz, 2 H), 7.52 (dd, J = 7.2, 4.0 Hz, 1 H), 7.35 (t, J = 6.9 Hz, 1 H), 7.21 (dd, J = 9.4, 7.3 Hz, 3 H), 7.18–7.10 (m, 6 H), 7.10–7.05 (m, 3 H), 6.88 (td, J = 7.7, 2.8 Hz, 2 H), 4.38 (q, J = 7.1 Hz, 2 H), 3.24 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 166.8, 140.1, 136.7, 135.7, 134.8, 134.4, 133.6, 133.3, 132.3, 131.6, 131.3, 131.1, 130.9, 129.8, 129.5, 129.1, 128.4, 128.2, 127.5, 126.7, 126.1, 122.4, 120.4, 119.3, 114.6, 109.9, 60.8, 30.7, 14.5.

31P NMR (121 MHz, CDCl3): δ = 29.50 (s).

MS (ESI): m/z calcd for C36H30NO3P [M]+: 555.2; found [M + H]+: 556.2.


#

Ethyl 3-(2-(2-(Diphenylphosphoryl)phenyl)-1-methyl-1H-indol-3-yl)benzoate (3h′)

Yield: 57.8 mg (52%); white solid; mp 229–231 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 7.80 (dd, J = 12.5, 8.0 Hz, 1 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.60 (s, 1 H), 7.57 (d, J = 7.5 Hz, 1 H), 7.51 (d, J = 8.2 Hz, 2 H), 7.49–7.43 (m, 1 H), 7.21 (d, J = 6.8 Hz, 1 H), 7.16 (dd, J = 8.0, 4.0 Hz, 3 H), 7.11 (d, J = 11.7 Hz, 2 H), 7.08–7.01 (m, 6 H), 6.96 (d, J = 7.1 Hz, 1 H), 6.76 (td, J = 7.6, 2.6 Hz, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.14 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 166.6, 136.7, 135.7, 135.3, 135.2, 134.8, 134.5, 133.8, 133.4, 133.0, 132.4, 131.4, 130.9, 130.3, 129.9, 129.0, 128.2, 127.4, 126.2, 122.3, 120.2, 119.2, 114.4, 109.8, 60.8, 30.7, 14.5.

31P NMR (162 MHz, CDCl3): δ = 28.32 (s).

MS (ESI): m/z calcd for C36H30NO3P [M]+: 555.2; found [M + H]+: 556.2.


#

1-(4-(2-(2-(Diphenylphosphoryl)phenyl)-1-methyl-1H-indol-3-yl)phenyl)ethan-1-one (3i′)

Yield: 44.1 mg (42%); white solid; mp 241–243 °C; petroleum ether/EtOAc, 4:1.

1H NMR (400 MHz, CDCl3): δ = 7.82 (dd, J = 12.7, 7.7 Hz, 1 H), 7.66 (t, J = 7.9 Hz, 3 H), 7.61 (d, J = 7.5 Hz, 2 H), 7.54 (dd, J = 6.4, 4.3 Hz, 1 H), 7.35 (t, J = 7.4 Hz, 1 H), 7.27–7.21 (m, 3 H), 7.17 (d, J = 10.7 Hz, 5 H), 7.14–7.08 (m, 4 H), 6.90 (td, J = 7.7, 2.6 Hz, 2 H), 3.28 (s, 3 H), 2.58 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 197.8, 140.5, 136.8, 135.8, 134.8, 134.3, 133.6, 131.5, 131.3, 131.0, 129.0, 128.6, 128.3, 128.2, 127.6, 127.5, 126.1, 122.5, 120.4, 119.3, 114.5, 109.9, 30.8, 26.5.

31P NMR (162 MHz, CDCl3): δ = 28.29 (s).

MS (ESI): m/z calcd for C35H28NO2P [M]+: 525.2; found [M + H]+: 526.2.


#

(2-(1-Methyl-3-(thiophen-3-yl)-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3j′)

Yield: 45.0 mg (46%); white solid; mp 178–181 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 7.99–7.92 (m, 1 H), 7.66 (ddd, J = 7.5, 4.5, 1.5 Hz, 1 H), 7.60 (dd, J = 10.4, 4.7 Hz, 2 H), 7.50 (ddd, J = 7.3, 4.2, 1.1 Hz, 1 H), 7.35 (td, J = 7.3, 1.4 Hz, 1 H), 7.32–7.25 (m, 2 H), 7.23–7.15 (m, 5 H), 7.13–7.09 (m, 1 H), 7.06 (dt, J = 6.9, 2.9 Hz, 2 H), 7.02 (dd, J = 7.5, 1.4 Hz, 1 H), 6.84 (td, J = 7.8, 3.1 Hz, 2 H), 6.81–6.76 (m, 2 H), 3.20 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 136.4, 136.0, 135.4, 135.1, 134.9, 134.6, 134.1, 133.5, 132.4, 131.6, 131.4, 131.2, 131.0, 130.8, 130.0, 129.2, 128.1, 127.2, 126.2, 124.3, 122.1, 120.0, 119.6, 111.1, 109.6, 30.7.

31P NMR (162 MHz, CDCl3): δ = 28.47 (s).

MS (ESI): m/z calcd for C31H24NOPS [M]+: 489.1; found [M + H]+: 490.1.


#

(2-(1-Methyl-3-(2,2,2-trifluoroethyl)-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (3k′)

Yield: 41.1 mg (42%); white solid; mp 139–141 °C; petroleum ether/EtOAc, 5:1.

1H NMR (400 MHz, CDCl3): δ = 7.67–7.59 (m, 2 H), 7.56–7.48 (m, 5 H), 7.45–7.39 (m, 2 H), 7.38–7.30 (m, 2 H), 7.25–7.16 (m, 5 H), 7.13–7.07 (m, 2 H), 3.24 (s, 3 H), 3.07–2.87 (m, 2 H).

13C NMR (101 MHz, CDCl3): δ = 137.3, 136.6, 135.3, 134.3, 133.9, 132.7, 132.3, 131.9, 131.7, 131.4, 129.0, 128.1, 127.1, 125.2, 122.1, 119.7, 119.2, 109.6, 104.2, 31.1, 30.3 (q, J F–C = 30.9 Hz), 1.2.

31P NMR (162 MHz, CDCl3): δ = 24.61 (s).

19F NMR (376 MHz, CDCl3): δ = –65.04 (s).

MS (ESI): m/z calcd for C29H23F3NOP [M]+: 489.1; found [M + H]+: 490.2.


#

Diphenyl(2-(3-(p-tolyl)-1H-indol-2-yl)phenyl)phosphine Oxide (4a)

Yield: 71.6 mg (74%); white solid; mp 287–289 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 11.35 (s, 1 H), 7.80–7.70 (m, 5 H), 7.43 (d, J = 8.1 Hz, 2 H), 7.31–7.23 (m, 9 H), 7.14–7.06 (m, 5 H), 6.97 (t, J = 7.5 Hz, 1 H), 2.35 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 137.7, 135.7, 135.4, 134.2, 132.3, 132.0, 131.4, 131.1, 130.1, 130.0, 129.2, 128.4, 127.5, 126.8, 122.5, 119.7, 119.4, 115.6, 111.6, 21.3.

31P NMR (162 MHz, CDCl3): δ = 33.68 (s).

MS (ESI): m/z calcd for C33H26NOP [M]+: 483.2; found [M + H]+: 484.1.


#

(2-(1,5-Dimethyl-3-(p-tolyl)-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (4b)

Yield: 59.3 mg (58%); white solid; mp 213–215 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 8.06 (ddd, J = 12.7, 7.6, 1.3 Hz, 1 H), 7.69–7.57 (m, 2 H), 7.55–7.50 (m, 1 H), 7.40 (s, 1 H), 7.33 (td, J = 7.3, 1.3 Hz, 1 H), 7.25–7.13 (m, 4 H), 7.12–7.05 (m, 3 H), 7.03 (d, J = 8.3 Hz, 1 H), 6.99–6.93 (m, 4 H), 6.93–6.85 (m, 3 H), 3.08 (d, J = 0.9 Hz, 3 H), 2.43 (s, 3 H), 2.35 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 136.0, 135.0, 134.8, 134.7, 134.6, 134.5, 134.4, 133.7, 133.5, 132.5, 132.2, 131.6, 131.3, 131.2, 130.8, 129.0, 128.8, 128.1, 127.3, 126.6, 123.7, 119.1, 115.1, 109.2, 30.5, 21.6, 21.2.

31P NMR (162 MHz, CDCl3): δ = 29.18 (s).

MS (ESI): m/z calcd for C35H30NOP [M]+: 511.2; found [M + H]+: 512.2.


#

(2-(5-Methoxy-1-methyl-3-(p-tolyl)-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (4c)

Yield: 68.6 mg (65%); white solid; mp 234–236 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 8.04 (dd, J = 12.5, 7.7 Hz, 1 H), 7.62 (dd, J = 13.8, 7.4 Hz, 2 H), 7.55–7.48 (m, 1 H), 7.32 (t, J = 6.8 Hz, 1 H), 7.21 (dd, J = 12.2, 7.5 Hz, 2 H), 7.14 (t, J = 5.9 Hz, 1 H), 7.12–7.03 (m, 5 H), 6.98–6.91 (m, 4 H), 6.91–6.82 (m, 4 H), 3.80 (s, 3 H), 3.08 (s, 3 H), 2.34 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 154.6, 135.8, 134.9, 134.8, 134.5, 134.4, 132.1, 131.9, 131.5, 131.3, 131.1, 130.7, 129.0, 128.8, 128.0, 127.2, 126.6, 115.2, 112.3, 110.2, 101.3, 56.1, 30.6, 21.1.

31P NMR (162 MHz, CDCl3): δ = 29.17 (s).

MS (ESI): m/z calcd for C35H30NO2P [M]+: 527.2; found [M + H]+: 528.2.


#

(2-(5-Fluoro-1-methyl-3-(p-tolyl)-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (4d)

Yield: 82.5 mg (80%); white solid; mp 262–265 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 7.86 (dd, J = 12.6, 7.8 Hz, 1 H), 7.54 (d, J = 7.4 Hz, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.44–7.39 (m, 1 H), 7.23 (d, J = 7.1 Hz, 1 H), 7.15 (dd, J = 9.7, 3.2 Hz, 2 H), 7.13–7.05 (m, 4 H), 7.05–6.99 (m, 2 H), 6.85 (d, J = 3.8 Hz, 1 H), 6.83 (s, 5 H), 6.81–6.76 (m, 2 H), 3.08 (s, 3 H), 2.23 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 159.5, 157.2, 136.0, 135.5, 134.8, 134.3, 133.7, 133.6, 133.2, 132.5, 131.6, 131.3, 130.8, 130.2, 129.0, 128.7, 128.1, 127.2, 126.6, 115.6, 110.4, 110.1, 104.3, 30.8, 21.1.

31P NMR (162 MHz, CDCl3): δ = 28.85 (s).

19F NMR (376 MHz, CDCl3): δ = –124.58 to –124.76 (m).

MS (ESI): m/z calcd for C34H27FNOP [M]+: 515.2; found [M + H]+: 516.2.


#

(2-(5-Chloro-1-methyl-3-(p-tolyl)-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (4e)

Yield: 70.2 mg (66%); white solid; mp 234–236 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 7.93 (dd, J = 12.6, 7.9 Hz, 1 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.59 (d, J = 7.6 Hz, 1 H), 7.55 (d, J = 1.6 Hz, 1 H), 7.51 (dd, J = 6.2, 4.4 Hz, 1 H), 7.33 (dd, J = 10.2, 4.3 Hz, 1 H), 7.23–7.06 (m, 8 H), 6.97 (d, J = 8.7 Hz, 1 H), 6.94–6.86 (m, 6 H), 3.17 (s, 3 H), 2.32 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 135.8, 135.5, 135.0, 134.9, 134.8, 134.5, 133.7, 132.6, 131.7, 131.5, 131.4, 131.0, 130.3, 129.2, 129.1, 128.9, 128.2, 127.4, 125.6, 122.3, 119.0, 115.3, 110.6, 30.8, 21.2.

31P NMR (162 MHz, CDCl3): δ = 28.71 (s).

MS (ESI): m/z calcd for C34H27ClNOP [M]+: 531.2; found [M + H]+: 532.2.


#

(2-(1,7-Dimethyl-3-(p-tolyl)-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (4f)

Yield: 58.3 mg (57%); white solid; mp 257–259 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 8.13–8.06 (m, 1 H), 7.67–7.57 (m, 2 H), 7.52–7.46 (m, 1 H), 7.40 (d, J = 7.7 Hz, 1 H), 7.35–7.29 (m, 1 H), 7.29–7.25 (m, 1 H), 7.24–7.19 (m, 1 H), 7.10 (dd, J = 9.4, 4.0 Hz, 2 H), 7.08–7.02 (m, 3 H), 6.93 (dd, J = 13.0, 7.9 Hz, 5 H), 6.89 (d, J = 3.0 Hz, 1 H), 6.88–6.83 (m, 2 H), 3.31 (d, J = 14.6 Hz, 3 H), 2.60 (d, J = 23.6 Hz, 3 H), 2.33 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 136.0, 135.9, 135.5, 135.1, 135.0, 134.7, 134.0, 132.0, 131.6, 131.4, 131.2, 130.6, 129.2, 129.1, 128.1, 127.4, 127.3, 127.1, 125.1, 121.1, 119.9, 117.7, 115.8, 33.9, 21.2, 20.4.

31P NMR (162 MHz, CDCl3): δ = 29.25 (s).

MS (ESI): m/z calcd for C35H30NOP [M]+: 511.2; found [M + H]+: 512.2.


#

(3-Methyl-2-(1-methyl-3-(p-tolyl)-1H-indol-2-yl)phenyl)diphenylphosphine Oxide (4g)

Yield: 73.7 mg (72%); white solid; mp 261–263 °C; petroleum ether/EtOAc, 2:1.

1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 8.3 Hz, 2 H), 7.51–7.41 (m, 2 H), 7.41–7.27 (m, 6 H), 7.23 (dd, J = 8.0, 2.7 Hz, 1 H), 7.09 (ddd, J = 19.2, 13.7, 7.7 Hz, 5 H), 6.92 (dd, J = 15.9, 7.2 Hz, 1 H), 6.77 (s, 1 H), 6.58 (dd, J = 15.3, 7.0 Hz, 2 H), 6.48 (s, 1 H), 3.50 (s, 3 H), 2.14 (s, 3 H), 1.96 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 140.7, 137.0, 134.6, 133.5, 132.3, 131.8, 131.3, 130.8, 130.6, 129.6, 128.6, 128.3, 128.2, 127.9, 127.4, 125.1, 124.1, 123.0, 119.8, 117.5, 113.8, 30.6, 21.2, 19.8.

31P NMR (121 MHz, CDCl3): δ = 30.61 (s).

MS (ESI): m/z calcd for C35H30NOP [M]+: 511.2; found [M + H]+: 512.2.


#

2-(2-(Diphenylphosphino)phenyl)-1-methyl-3-(p-tolyl)-1H-indole (5a) (Scheme [4])

Yield: 77.1 mg (80%); white solid; mp 159–161 °C; petroleum ether/EtOAc, 10:1.

1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.9 Hz, 1 H), 7.44–7.40 (m, 2 H), 7.35 (s, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.24 (dd, J = 10.0, 4.1 Hz, 4 H), 7.17 (dd, J = 7.7, 2.6 Hz, 3 H), 7.11 (dd, J = 11.9, 4.6 Hz, 4 H), 7.04 (d, J = 8.0 Hz, 2 H), 6.91 (d, J = 8.0 Hz, 2 H), 6.78 (t, J = 7.3 Hz, 2 H), 3.33 (s, 3 H), 2.28 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 140.3, 139.0, 138.6, 137.9, 137.0, 136.9, 136.8, 134.8, 134.6, 133.8, 133.4, 132.7, 132.4, 129.5, 129.0, 128.8, 128.5, 128.4, 128.2, 128.1, 127.0, 121.9, 119.9, 116.3, 109.6, 30.6, 21.2.

31P NMR (162 MHz, CDCl3): δ = –14.00 (s).

MS (ESI): m/z calcd for C34H28NP [M]+: 481.1; found [M + H]+: 482.1.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1633-8792.
  • Supporting Information

Corresponding Author

Shang-Dong Yang
State Key Laboratory of Applied Organic Chemistry, Lanzhou University
Lanzhou 730000
P. R. of China   

Publication History

Received: 09 August 2021

Accepted after revision: 03 September 2021

Accepted Manuscript online:
03 September 2021

Article published online:
14 October 2021

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Figure 1 Phosphorus-containing indole ligands
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Scheme 1 Scope of symmetrical diaryliodonium salts. Reagents and conditions: 1a (0.2 mmol), 2a–l (0.3 mmol), CuI (5 mol%), DCE (2 mL), 50 °C, air. Isolated yield of products.
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Scheme 2 Scope of asymmetrical diaryliodonium salts. Reagents and conditions: 1a (0.2 mmol), 2a′–k′ (0.3 mmol), CuI (5 mol%), DCE (2 mL), 50 °C, air. Isolated yield of products.
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Scheme 3 Scope of diphenylphosphine oxide indoles. Reagents and conditions: 1 (0.2 mmol), 2a (0.3 mmol), CuI (5 mol%), DCE (2 mL), 50 °C, air. Isolated yield of products. a Reaction was carried at 100 °C.
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Scheme 4 Gram-scale reaction and reduction of 3a
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Scheme 5 Mechanistic studies
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Scheme 6 Plausible reaction mechanism