Palladium/silver reagent-promoted aryl phosphorylation: flexible synthesis of substituted-3-benzylidene-2-(2-(diphenylphosphoryl)-aryl)-isoindolin-1-one

Abstract

A novel Pd(OAc)₂/Ag₂CO₃-catalyzed coupling reaction was investigated. Substituted 3-benzylidene-2-arylisoindolin-1-ones were reacted with diphenylphosphine oxide to afford 3-arylidene-2-(2-(diphenylphosphoryl)aryl)isoindolin-1-ones. The reaction proceeded at 25 °C in an air atmosphere in the absence of base and ligands. Our results indicate that the diphenylphosphine oxide free radical tends to attack the aryl rather than the double bond in this reaction.

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Introduction

Nitrogen-containing heterocycles are a series of notable compounds known for their bioactivity in nature.¹ In particular, isoindolin-1-ones such as I and II are the core structural motifs of several compounds of medicinal value (Fig. 1). 3-Methyleneisoindolin-1-ones are known for their use as anaesthetic and sedative drugs.² As these compounds have a double bond and phenyl cycle we have tried to find a catalytic system for direct phosphorylation of substituted 3-benzylidene-2-arylisoindolin-1-one.

Fig. 1 Bioactive and drug compounds containing isoindolin-1-one motifs.

Diphenylphosphine oxide has become a research focus in the field of organic synthesis due to its unique biological activities.³ In 1982, Hirao and co-workers reported the first palladium-catalyzed phosphorylation of aryl iodides.⁴ Since then, a series of formations of Csp²–P bonds by cross-coupling has been published in the last thirty years. The coupling partners, included aryl triflates, tosylate, diaryliodonium salts, diazonium salts, boronic acids, triarylbismuths, phenylhydrazine and so on.⁵ Moreover, direct radical phosphorylation of benzene derivatives⁶ and heterocycle⁷ with diethyl phosphate has been successfully developed by using Mn(OAc)₃ as an oxidant (Scheme 1a). There were also studies of the manganese-catalyzed reactions of H-phosphinates.⁸ Recently, palladium-catalyzed direct phosphorylation reaction of arene and heteroarenes has been established (Scheme 1b).^9,10 On the other hand, Ag system has been used for the synthesis of direct phosphorylation reaction (Scheme 1c).¹¹ Visible light promoted C–P functionalization has been rapidly developed (Scheme 1d).¹² As part of our research on the transition metal-catalyzed C–P bond formation, this communication reports the first example of a coupling reaction of 3-benzylidene-2-arylisoindolin-1-one with diphenylphosphine oxide catalyzed by Pd(OAc)₂/Ag₂CO₃ (Scheme 1e).

Scheme 1

Results and discussion

When the model reaction of 3-benzylidene-2-phenylisoindolin-1-one (1a) with diphenylphosphine oxide (2) was performed in CH₃CN in the presence of oxidants such as TBHP, DTBP, Mn(OAc)₃ and AgNO₃, no desired products were obtained (Table 1, entries 1, 2, 3 and 5). After the addition of 10 mol% Ag₂CO₃ and Mg(NO₃)₂·6H₂O, the reaction proceeded smoothly to afford the desired product, 3-benzylidene-2-(2-(diphenylphosphoryl)phenyl) isoindolin-1-one (3a) in 60% yield (Table 1, entry 4).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (%)	Oxidant (%)	Temperature	Solvent	Yeild^b
a Reaction condition: 1a (0.2 mmol), HPOPh2 (0.4 mmol), Pd(OAc)2, (0.02 mmol), Ag2CO3 (0.02 mmol), Mg(NO3)2·6H2O (0.4 mmol), solvent (2 ml), at 25 °C in air atmosphere, 3 h.b Yields are given for isolated products.c Without Mg(NO3)2·6H2O.d HPOPh2 (0.2 mmol) was added.e HPOPh2 (0.6 mmol) was added.f Molecular sieves (0.1 g) was added.g 1 h.h 2 h.i 4 h.
1		TBHP(10)	25 °C	CH3CN	N.D
2		DTBP(10)	25 °C	CH3CN	N.D
3		Mn(OAc)3	25 °C	CH3CN	N.D
4		Ag2CO3(10)	25 °C	CH3CN	60%
5		AgNO3(10)	25 °C	CH3CN	N.D
6	Pd(PPh3)4(10)	Ag2CO3(10)	25 °C	CH3CN	38%
7	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	CH3CN	78%
8	PdCl2(10)	Ag2CO3(10)	25 °C	CH3CN	72%
9	Pd(OAc)2(10)	Ag(OAc)10	25 °C	CH3CN	48%
10	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	THF	32%
11	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	DMF	36%
12	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	i-PrOH	40%
13	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	Toluene	30%
14	Pd(OAc)2(5)	Ag2CO3(10)	25 °C	CH3CN	48%
15	Pd(OAc)2(20)	Ag2CO3(10)	25 °C	CH3CN	65%
16^c	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	CH3CN	20%
17	Pd(OAc)2(10)	Ag2CO3(10)	0 °C	CH3CN	10%
18	Pd(OAc)2(10)	Ag2CO3(10)	40 °C	CH3CN	72%
19	Pd(OAc)2(10)	Ag2CO3(10)	60 °C	CH3CN	20%
20^d	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	CH3CN	30%
21^e	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	CH3CN	58%
22^f	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	CH3CN	76%
23^g	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	CH3CN	35%
23^h	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	CH3CN	66%
23^i	Pd(OAc)2(10)	Ag2CO3(10)	25 °C	CH3CN	75%

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Further investigations of palladium catalysts, the yield of 3a was improved to 78% when we used Pd(OAc)₂ as the catalyst (Table 1, entries 7). On the other hand, when we use Ag(OAc) in place of Ag₂CO₃, the reaction afforded the desired product in a lower yield (Table 1, entry 9). By screening polar solvents such as DMF, THF, i-PrOH, and a representative nonpolar solvent, toluene (Table 1, entries 10–13), we found that CH₃CN works best for the reaction. Apart from the above-mentioned factors, the effects of catalyst loading, reaction temperature, time and molecular sieves were also investigated, and the optimal reaction conditions were determined to be room temperature reaction for 3 h in air atmosphere, with the addition of 10 mol% Pd(OAc)₂ and 10 mol% Ag₂CO₃ as catalyst, Mg(NO₃)₂·6H₂O as promoter and CH₃CN as solvent (Table 1, entries 14–23).

With the promising results obtained in the model reaction, we subsequently examined the substrate scope of 3-benzylidene-2-arylisoindolin-1-one under the optimized reaction conditions (10 mol% Pd(OAc)₂ and 10 mol% Ag₂CO₃ as catalyst, and Mg(NO₃)₂·6H₂O as promoter in CH₃CN at 25 °C, for 3 h in air atmosphere). As shown in Table 2, electron-withdrawing substituent such as F and Cl groups on the para-position of arylamine ring of substituted 3-benzylidene-2-arylisoindolin-1-one (1) facilitated the reaction to afford the arylphosphonates (3) in good yields (Table 2, 3d and 3e). On the contrary, election-donating groups such as alkyl and methoxy were unfavorable for the reaction and led to lower yields (Table 2, 3b and 3c). Substituted groups such as CH₃ and Cl on the meta-position of arlyamine ring are both given good yields (Table 2, 3f and 3g). We also investigated the substituent R² on the benzylidene and the substituent R³ on the isoindolin-1-one, the results indicate that the reaction affords the arylphosphonates (3) in moderate to good yields (Table 2, 3k, 3l, 3m, 3n, 3o, 3p, 3q, 3r and 3s). In order to understand the reaction mechanism, following control experiments were carried out. We repeated the reaction in the presence of radical quencher 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and none of 3a was obtained (Scheme 2a). The result suggested that the diphenylphosphine oxide free radical was probably generated during the reaction. Furthermore, neither aliphatic amine nor benzylamine substrate produced the corresponding products (Scheme 2b and c). These results indicated that the reaction is only suitable for arylamine substrates which have enough electron cloud density.

Table 2 Scope studies of 3-benzylidene-2-(2-(diphenyl-phosphoryl)phenyl)isoindolin-1-one^a

a Reaction condition: 1 (0.2 mmol), HPOPh₂ (0.4 mmol), Pd(OAc)₂, (0.02 mmol), Ag₂CO₃ (0.02 mmol), Mg(NO₃)₂·6H₂O (0.4 mmol), CH₃CN (2 ml), at 25 °C in air atmosphere, 3 h. Yield of isolated products are given.

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Scheme 2 Control experiments.

As the phosphorylation always took place on the ortho-position of aniline in the above experiments, we wondered whether the reaction would proceed if the aniline had substituent groups at the ortho-position. Hence, we did further reactions (Scheme 2d–f). Surprisingly, the diphenylphosphine oxide free radical will attack the double bond instead of aniline with a moderate yield. These results further indicated that this reaction has a high regioselectivity that the diphenylphosphine oxide free radical would prioritize its attack on the ortho-position of aniline rather than the para-position of aniline or the double bond. On the basis of the mechanistic studies and experimental results, a plausible mechanism is proposed in Scheme 3.

Scheme 3 Proposed reaction mechanism.

Initially, Pd(OAc)₂ reacted with the substrate (1a) to form a six-membered palladacycle (C) in presence of Mg(NO₃)₂, and generated HNO₃ through C–H activation. The diphenylphosphine oxide (2) was excited by Ag(I) (A) to generate the key intermediate P-centered radical (B), which then underwent addition with palladacycle (C) to form Pd^III intermediate D.¹³ Thereafter, the radical intermediate D was oxidized by HNO₃ to produce the Pd^IV intermediate E. E underwent reductive elimination to afford the product (3a) together with the regeneration of Pd(OAc)₂ which could complete the palladium catalytic cycle. Finally, Ag (0) was also oxidized to Ag(I) by HNO₃ to complete the silver catalytic cycle.

Conclusions

In summary, we have developed a novel catalytic system for direct phosphorylation of substituted 3-benzylidene-2-arylisoindolin-1-one via a radical pathway. The reaction has a high regioselectivity that diphenylphosphine oxide free radical is prone to attacking aryl rather than a double bond. The method has a broad scope and offers a good yield. The corresponding products are potentially useful in drug discovery.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge financial support from the Prospective Study Program of Jiangsu (BY2015039-08), the National Natural Science Foundation of China (No. 21572149), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7ra10902d

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