Copper-catalyzed decarboxylative stereospecific amidation of cinnamic acids with N-fluorobenzenesulfonimide

Abstract

An efficient copper-catalyzed decarboxylative coupling of cinnamic acids with N-fluorobenzenesulfonimide (NFSI) to give the corresponding substituted (E)-amination products stereospecifically is demonstrated. This new method is efficient and practical, and the corresponding products were obtained in moderate to good yields. The present protocol should broaden the scope of the decarboxylative cross-coupling reactions and provide a useful strategy for the construction of C–N bonds.

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The C–N bond forming reaction is of fundamental and immense importance in synthetic chemistry because of its wide existence in natural products, biologically active compounds, drug molecules and materials.¹ Thus, seeking mild and selective approaches for the construction of C–N bonds has been of continuous interest in organic chemistry. Conventionally, metal-mediated C–N cross-coupling of aryl (pseudo)halides (or arylboronic reagents) with amines, such as Buchwald–Hartwig coupling,² Chan–Lam coupling,³ and Ullmann-type coupling⁴ have become powerful tools for C–N bond formations. However, prefunctionalized arenes, high reaction temperature, and stoichiometric amounts of byproducts involved in these procedures might limit their wide application. As one of the promising synthesis strategies, the direct functionalization of C–H bonds has made tremendous progress as it offers short and useful methodologies for the construction of various organic compounds, avoiding the use of prefunctionalized substrates. In this context, a large number of direct amidation of unactivated C(sp–sp³)–H bonds have been reported thus far.⁵

Carboxylic acids are easy to store and handle, and they are easily prepared from readily available materials. As an alternative, decarboxylative cross-coupling reaction has been successfully introduced by Gooßen,⁶ Myers,⁷ and other research groups.⁸ Recently, tremendous progress has been made in this respect since it opens a new avenue for the formation of C–C and C–heteroatom bonds. However, investigations on the decarboxylative strategy for the formation of C–N bonds are rather limited.^6b,9 In 2010, the first examples of the copper-catalyzed decarboxylative cross-coupling of alkynyl carboxylic acids with amides was developed by Jiao and co-workers (Scheme 1, eqn (1)).¹⁰ In 2012, Mainolfi et al. reported the first example of employing aryl carboxylic acids as arylating reagents for arylation of nitrogen nucleophiles (Scheme 2, eqn (2)).¹¹ Very recently, Lei and co-workers developed a visible-light-mediated decarboxylation/oxidative amidation of α-keto acids with amines under mild reaction conditions (Scheme 1, eqn (3)).¹² However, challenges still remain, but it is still highly desirable to develop new strategies to construct C–N bonds through decarboxylative cross-coupling reactions.

Scheme 1 Strategies for decarboxylation of C–N bond formation.

Scheme 2 Control experiment for mechanistic studies.

Recently, N-fluorobenzenesulfonimide (NFSI) has emerged as appealing nitrogen source in C–H activation/amidation reactions. In 2012, Zhang and co-workers described a highly selective benzylic C–H amination reaction by copper catalysis.¹³ In the same year, Álvarez and Muñiz developed a palladium-catalyzed oxidative amidation of C(sp³)–H bonds using NFSI as the nitrogen.¹⁴ In 2014, Pan's group reported an efficient amidation reaction of heterocycles with NFSI.¹⁵ Very recently, Itami and co-workers described an versatile imidation of C(sp²)–H bonds, various aromatics such as porphyrins, aromatic bowls, polycyclic aromatic hydrocarbons, natural products, and heteroaromatics, can be imidated by NFSI.¹⁶ Futhermore, NFSI was also widely used in transition-metal-catalyzed difunctionalization of alkenes and alkynes as an useful imide source.¹⁷ Meanwhile, decarboxylative functionalization of cinnamic acids is an emerging area that has been developed significantly in recent years.¹⁸ Nevertheless, to the best of our knowledge, the direct decarboxylative cross-coupling of cinnamic acids with imides to form C–N bonds has never been exploited. Inspired and encouraged by the previous excellent works and with part of our continuous interest in oxidative radical reactions,¹⁹ we herein wish to describe a new copper-catalyzed direct decarboxylative amidation of cinnamic acids with NFSI under mild conditions.

Initially, cinnamic acid (1a) and NFSI (2) were used as the model substrates to screen the reaction conditions, including the catalysts, additives, solvents, and reaction temperatures under a nitrogen atmosphere. As shown in Table 1, eight solvents such as CH₃CN, THF, H₂O, EtOAc, DCE, DMF, DMSO, and toluene were investigated at 60 °C by using 20 mol% of CuCl as the catalyst, and CH₃CN gave the highest yield (50%) (entries 1–8, Table 1). Furthermore, the catalysts, including CuCl, CuBr, CuI, CuSO₄, Cu(NO₃)₂·3H₂O, AgNO₃, and FeCl₃ were tested in CH₃CN (entries 9–15, Table 1) at 60 °C, and CuI was found to be the most effective catalyst (entry 11, Table 1). Gratifying, when 2.0 equiv. of azodisisobutyronitrile (AIBN) was employed as an additive, the target product 3a was isolated in 76% yield (entry 16, Table 1), while other additives such as BPO, K₂S₂O₈, TBHP, and DTBP had no obvious influence on the transformation (entries 17–20, Table 1). Notably, elevating the reaction temperature did not enhance the yield obviously (entry 21, Table 1). After the optimization process for catalysts, additives, solvents and temperatures, the desired amination products were synthesized under our standard conditions: 20 mol% of CuI as the catalyst, 2.0 equiv. of AIBN as the oxidant, and 2 mL CH₃CN as the solvent at 60 °C under nitrogen atmosphere.

Table 1 Optimization of the conditions^a

Entry	Cat.	Additive	Solvent	Yield^b [%]
a Reaction conditions: under a nitrogen atmosphere, cinnamic acid (1a) (0.3 mmol), NFSI (2a) (0.36 mmol), catalyst (0.06 mmol), addition (0.6 mmol), solvent (2.0 mL), reaction time (24 h).b Isolated yield. AIBN = azodisisobutyronitrile, BPO = benzoic peroxyanhydride, TBHP = tert-butyl hydroperoxide, DTBP = di-t-butyl peroxide.c 90 °C.
1	CuCl	None	CH3CN	50
2	CuCl	None	THF	34
3	CuCl	None	H2O	17
4	CuCl	None	EtOAc	Trace
5	CuCl	None	DCE	0
6	CuCl	None	DMF	0
7	CuCl	None	DMSO	0
8	CuCl	None	Toluene	0
9	None	None	CH3CN	54
10	CuBr	None	CH3CN	63
11	CuI	None	CH3CN	46
12	CuSO4	None	CH3CN	69
13	Cu(NO3)2·3H2O	None	CH3CN	69
14	AgNO3	None	CH3CN	0
15	FeCl3	None	CH3CN	Trace
16	CuI	AIBN	CH3CN	76
17	CuI	BPO	CH3CN	65
18	CuI	K2S2O8	CH3CN	54
19	CuI	TBHP	CH3CN	49
20	CuI	DTBP	CH3CN	58
21	CuCl2	AIBN	CH3CN	77^c

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With the optimum reaction conditions in hand, the scope and generality of the copper-catalyzed decarboxylative amidation of cinnamic acids was explored, with the results summarized in Table 2. Generally, the electron-donating (R = Me, OMe, tBu) or withdrawing groups (R = Cl, Br) on the aryl ring of cinnamic acids were compatible with this reaction, and the desired products were obtained in moderate to good yields (Table 2, 3a–3k). Additionally, (E)-3-(naphthalen-1-yl)acrylic acid (1j) was also used in this transformation to give the corresponding products (3j) in 74% yield. Although cinnamic acids showed high reactivity, unfortunately, other acids, such as phenylpropiolic acid, benzoic acid, and 2-oxo-2-phenylacetic acid were poor substrates, and didn't give the desired products (Table 2, 3n, and 3o). The decarboxylative cross-coupling reactions could tolerate some functional groups including methyl (Table 2, 3b, 3c, 3d and 3e), methoxy (Table 2, 3f), C–Cl bond (Table 2, 3h), and C–Br bond (Table 2, 3i), which could be used for further modifications at the substituted positions. Unfortunately, strong electron-withdrawing groups such as nitro and trifluoromethyl were not tolerated in the present transformation (Table 2, 3l and 3m). The structure of 3a was unambiguously confirmed by X-ray crystallographic analysis (Fig. 1, see ESI† for details).

Table 2 Substrate scope of cinnamic acids with NFSI^a,b

Entry	1	3	Yield (%)
a Reaction conditions: under a nitrogen atmosphere, cinnamic acids (1) (0.3 mmol), NFSI (2a) (0.36 mmol), CuI (0.06 mmol), AIBN (0.6 mmol), solvent (2.0 mL), reaction time (24 h).b Isolated yield.
1			76%
2			71%
3			74%
4			87%
5			54%
6			66%
7			65%
8			62%
9			59%
10			74%
11			56%
12			Trace
13			Trace
14			0
15			0
16			0

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Fig. 1 ORTEP drawing of compound 3a.

In order to gain some insight into the mechanism of the present copper-catalyzed decarboxylative amidation reaction, several control experiments were conducted as shown in Scheme 2. When one equivalent of 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO), a classical radical scavenger, was added into the standard conditions, the decarboxylation coupling reaction was completely suppressed process [eqn (1), Scheme 2]. In addition, another radical scavenger such as BHT (butylated hydroxytoluene) was also proven to inhibit the transformation [eqn (2), Scheme 2]. When one equivalent of K₂CO₃ was added independently under the standard conditions, and no desired coupling product was detected [eqn (3), Scheme 2]. To investigate the mechanism further, the reaction of bis(cinnamoyloxy)copper 4 instead of cinnamic acid as a substrate, and no conversion was observed, which indicated that a copper cinnamate might not be a key intermediate for this reaction, and this was quite different from the previous reports about radical decarboxylative functionalization of cinnamic acids pathway.^9a [eqn (4), Scheme 2].

Although the exact mechanism of present decarboxylative amidation pathway remains unclear at this stage, on the basis of the above preliminary results and together with previous reports in the literature,²⁰ a plausible mechanism was proposed in Scheme 3. In the presence of AIBN, Cu^III complex A was generated through the oxidation of CuI with NFSI, which could give the copper(II)-stabilized benzenesulfonimide radical B through an equilibrium. Subsequently, cinnamic acid can attack the complex A or B forming the Cu(II)–carboxyl radical specie C. Finally, this was followed by the loss of carbon dioxide and CuI, which resulted in the desired amination products D. Further investigations on the more detailed mechanism are ongoing in our laboratory.

Scheme 3 A proposed mechanism for the direct transformation.

In conclusion, a mild and efficient decarboxylative amidation protocol using copper and AIBN combination has been discovered for the first time. A series of (E)-amination products could be conveniently and efficiently obtained in moderate to good yields with high selectivity. This method should provide a new and useful strategy for constructing C–N bond in the academic and industrial fields and should deepen the understanding of the decarboxylative cross-coupling reactions. Further investigation on the practical application of this method is in progress.

Acknowledgements

The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21302110, 21302109 and 21375075), the Taishan Scholar Foundation of Shandong Province, the Project of Shandong Province Higher Educational Science and Technology Program (J13LD14), and the Natural Science Foundation of Shandong Province (ZR2013BQ017 and ZR2015JL004). We thank Jiehua Ding in this group for reproducing the results of 3a and 3j.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1482137. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra16115d

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