Palladium-catalyzed direct ortho-C–H ethoxycarboxylation of anilides at room temperature

Abstract

A Pd-catalyzed direct ortho-C–H ethoxycarboxylation of anilides has been established to form various anthranilic acid derivatives at room temperature. This protocol provides a concise and efficient strategy for diversifying the preparation of anthranilic acid derivatives from readily available starting materials under mild conditions.

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Transition metal-catalyzed direct C–H functionalization has emerged as a promising tool for the formation of carbon–carbon and carbon–heteroatom bonds, which effectively avoids time-consuming prefunctionalization of substrates.¹ Although a large number of efficient catalyst systems have been reported over the past few years, most of them require the use of harsh reaction conditions, which may result in incompatibilities of functional groups and further limit substrate scope. Therefore, a highly attractive, yet challenging objective is the development of C–H functionalizations with high efficiency and selectivity under mild conditions.²

Direct introduction of a carboxyl or ester group into the aromatic ring via C–H functionalization has been an area of intensive research. In 1980, Fujiwara reported the first example of direct carboxylation reaction of arenes with CO to synthesize aromatic acids.³ After this breakthrough, much effort has been devoted to developing efficient C–H carboxylation reactions by utilizing CO and CO₂ as the carboxylation reagent.⁴ Yu developed the Pd-catalyzed chelation-assisted C–H ortho-carbonylation reaction under a CO atmosphere.^4a,c Iwasawa presented the Rh-catalyzed direct carboxylation of the aryl C–H bond with CO₂.^4d Besides CO and CO₂, other carboxylation regents such as carbamoyl chlorides,⁵ diaziridinone,⁶ diethyl azodicarboxylate⁷ and glyoxylates⁸ have also been established for the direct C–H carboxylation in the past few years. In recent years, the direct carboxylation reaction has become an attractive synthetic method to prepare aromatic acid derivatives.

Anthranilic acid derivatives are important precursors for the synthesis of heterocyclic natural products, pharmacologically important molecules, and biologically active compounds. In particular, they present a privileged architectural unit in heterocyclic frameworks such as quinazoline, quinoline, acridinone and benzoxazinone.⁹ Although a number of examples have been presented to prepare anthranilic acid derivatives,¹⁰ the general procedures have been less developed, which would most likely greatly restrict rapid diversification of significant molecules. Recently, the Pd-catalyzed C–H ortho-carbonylation of anilides with CO was well established for the synthesis of anthranilic acids (eqn (1)).^4b,c However, to a certain extent, the handling of the hazardous gas would cause difficulties in the further application of this carbonylation reaction in research laboratories. The Tan group developed a route to anthranilic esters via Pd-catalyzed dehydrogenative/decarbonylative coupling between anilides and glyoxylates with the assistance of the phosphine ligand at 120 °C (eqn (2)).⁸ In spite of the significant progress made, it is still critically important to develop new efficient methods to synthesize anthranilic acid derivatives under mild conditions from both a scientific and a practical standpoint.

Azodicarboxylates, as readily available agents, have been widely used in organic synthesis such as Mitsunobu reaction, amination, synthesis of heterocyclic compounds, and oxidants for the dehydrogenation of alcohols and amines.¹¹ However, only a few examples have been described to use azodicarboxylates as the esterification reagent. Yu and co-workers reported the Pd-catalyzed oxidative ethoxycarboxylation of the aromatic C–H bond with diethyl azodicarboxylate (DEAD) as the esterification reagent at 100 °C.⁷ A radical pathway was proposed in this reaction and the ethoxyacyl radical generated from thermal decomposition of DEAD was the key intermediate. Inspired by our previous work,¹² we speculated that the ethoxyacyl radical could also be formed with the aid of a suitable oxidant under mild conditions. Herein, we report the facile synthesis of anthranilic esters through ethoxycarboxylation of anilides at ambient temperature without any protection against air or moisture (eqn (3)).

We initially tried to optimize the reaction conditions by using acetanilide 1a and DEAD (Table 1; for details, see ESI†). After screening a number of oxidants (Table 1, entries 1–6), we found that (NH₄)₂S₂O₈ could promote this reaction in 28% yield. The yield could be improved slightly by increasing the amount of 2 (Table 1, entry 7). It is worth noting that p-toluenesulfonic acid (p-TsOH) played a critical role in the coupling (Table 1, entry 8). We believe that the TsO⁻ anion is likely attached to Pd(II) to form Pd(OTs)X (X = anion), which might facilitate the ortho-C–H bond cleavage of acetanilide.^4c,13 Other acids led to lower yields or did not afford the target product (Table 1, entries 9 and 10). An improved yield was obtained by using Pd(TFA)₂ instead of Pd(OAc)₂ (Table 1, entry 14). To our delight, addition of Cu(TFA)₂·H₂O could improve the yield to 68% (Table 1, entry 16). Although the role of Cu(II) salt is unclear at this stage, we speculate that Cu(II) salt may serve as an additive to promote the single electron transfer process in the reaction cycle.¹⁴ Finally, the best result was obtained when the reaction was performed in the presence of Pd(TFA)₂ (10 mol%), Cu(TFA)₂·H₂O (10 mol%), (NH₄)₂S₂O₈ (2.0 equiv.) and p-TsOH·H₂O (0.5 equiv.) in DCM at ambient temperature for 24 h.

Table 1 Optimization of the reaction conditions^a

Entry	Pd	Oxidant	Additive	Solvent	Yield^b (%)
a Reactions were carried out using acetanilide (0.3 mmol), DEAD (3.0 equiv.), [Pd] (10 mol%), oxidant (2.0 equiv.), additive (0.5 equiv.) in solvent (1 mL) at rt. b Isolated yield. c DEAD (2.5 equiv.). d Cu(TFA)2·H2O (10 mol%). DCM = CH2Cl2, BQ = benzoquinone, TBHP = tert-butylhydroperoxide, Oxone = potassium monopersulfate.
1^c	Pd(OAc)2	Na2S2O8	p-TsOH·H2O	DCM	n.d.
2^c	Pd(OAc)2	K2S2O8	p-TsOH·H2O	DCM	n.d.
3^c	Pd(OAc)2	Oxone	p-TsOH·H2O	DCM	n.d.
4^c	Pd(OAc)2	TBHP	p-TsOH·H2O	DCM	n.d.
5^c	Pd(OAc)2	BQ	p-TsOH·H2O	DCM	n.d.
6^c	Pd(OAc)2	(NH4)2S2O8	p-TsOH·H2O	DCM	28%
7	Pd(OAc)2	(NH4)2S2O8	p-TsOH·H2O	DCM	34%
8	Pd(OAc)2	(NH4)2S2O8	—	DCM	Trace
9	Pd(OAc)2	(NH4)2S2O8	CH3SO3H	DCM	13%
10	Pd(OAc)2	(NH4)2S2O8	TfOH	DCM	27%
11	Pd(OAc)2	(NH4)2S2O8	p-TsOH·H2O	MeCN	n.d.
12	Pd(OAc)2	(NH4)2S2O8	p-TsOH·H2O	THF	21%
13	Pd(OAc)2	(NH4)2S2O8	p-TsOH·H2O	DCE	16%
14	Pd(TFA)2	(NH4)2S2O8	p-TsOH·H2O	DCM	48%
15	—	(NH4)2S2O8	p-TsOH·H2O	DCM	n.d.
16^d	Pd(TFA)2	(NH4)2S2O8	p-TsOH·H2O/Cu(TFA)2·H2O	DCM	68%
17^d	Pd(TFA)2	Selectfluor	p-TsOH·H2O/Cu(TFA)2·H2O	DCM	67%

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Under the optimized reaction conditions, the scope of substituted acetanilides was tested. To our delight, acetanilides bearing both electron-donating and electron-withdrawing groups could afford the desired products (Table 2, 3b–o). Acetanilides with methyl and t-butyl groups at the para-position gave 3c and 3d in 83% and 73% yields, respectively. A variety of electron-donating groups such as MeO-, nBuO- and BnO-groups could be tolerated, and moderate yields were obtained (Table 2, 3e–g, 3m). The protocol was compatible with the halogen atoms such as fluoro, chloro and bromo, which might be useful for further synthetic transformations (Table 2, 3i–k, 3m–n). It was noted that meta-substituted acetanilides exhibited excellent regioselectivities (Table 2, 3b, 3j–n). The disubstituted acetanilides could smoothly furnish the desired products with excellent regioselectivities (Table 2, 3l–n). In addition, anilides with other directing groups such as pivaloyl, benzoyl and propionyl groups could also undergo the ethoxycarboxylation under the optimized reaction conditions (Table 2, 3p–r).

Table 2 Pd-catalyzed oxidative ethoxycarboxylation of anilides^a,b

a Reactions were carried out using anilide (0.3 mmol), DEAD (3.0 equiv.), Pd(TFA)₂ (10 mol%), Cu(TFA)₂·H₂O (10 mol%), (NH₄)₂S₂O₈ (2.0 equiv.), p-TsOH·H₂O (0.5 equiv.) in DCM (1 mL) at rt. b Isolated yield. c Pd(OAc)₂ (10 mol%). d Selectfluor (2.0 equiv.) instead of (NH₄)₂S₂O₈. e 15 mol% [Pd].

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To get insights into the mechanism, the following controlled experiments were carried out. First, radical scavengers such as hydroquinone, TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) and BHT (2,6-di-tert-butyl-4-methylphenol) had a dramatic effect on the coupling reaction (Table S8†). Although the radical intermediate could not be captured, we believed that a radical pathway might be involved.⁷ Subsequently, we found that the stoichiometric reaction of the palladium complex 4^4c with DEAD could afford the desired product 3a (eqn (4)). However, no reaction occurred in the absence of (NH₄)₂S₂O₈. When the reaction was performed using 4 as the catalyst, 3a was obtained in 63% yield (eqn (5)). These observations implied that the ethoxycarboxylation might undergo a Pd(II)/Pd(IV) catalytic cycle.^12,15

On the basis of these studies, a plausible mechanism was proposed (Scheme 1). First, the palladacycle intermediate 4 was formed through the reaction of the ortho-C–H bond of acetanilide with Pd(II). Subsequently, the palladacycle 4 reacted with the ethoxyacyl radical, generated from the decomposition of DEAD in the presence of (NH₄)₂S₂O₈, to afford the key Pd(IV) intermediate 5 by the oxidation of (NH₄)₂S₂O₈. Finally, the reductive elimination afforded the desired product 3a. It should be noted that a mechanism involving the formation of a Pd(III) intermediate could not be excluded.¹⁶

Scheme 1 A possible reaction mechanism.

In summary, we have developed an efficient Pd(II)-catalyzed ortho-C–H esterification of anilides with a commercially available and easily handled azodicarboxylate agent at ambient temperature. This selective and mild oxidative coupling reaction could be a complementary and practical protocol for the rapid synthesis of anthranilic acid derivatives from the corresponding anilines because of concise manipulation and non-protection against air or moisture.

Acknowledgements

This work was supported by grants from the National Basic Research Program of China (973 Program, 2011CB808601), and the National NSF of China (no. 21025205, 21272160, 21321061, J1310008, and J1103315J0104).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Data of NMR and MS spectra for all new compounds, copies of NMR spectra, and experimental procedures. See DOI: 10.1039/c3qo00069a

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