Regioselective C5 alkenylation of 2-acylpyrroles via Pd(II)-catalyzed C–H bond activation

Abstract

A Pd(II)-catalyzed regioselective C5 alkenylation of 2-acylpyrroles has been developed employing 3-nitrile benzoyl group (N-(3-NCC₆H₄CO-)) as an efficient N-protecting group. The protocol provided a simple and efficient method to synthesize C5-alkenylated 2-acylpyrrole derivatives. The employed N-protecting group was readily removable in the presence of HCl/EtOH under mild conditions.

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Introduction

Pyrrole is one of the most important heterocyclic compounds and is the ubiquitous backbone in natural products, bioactive molecules, pharmaceutical compounds and organic materials.^1–4 In particular, 2-acylpyrrole-containing heterocyclic compounds have attracted much attention in medical chemistry^5–8 because the 2-acylpyrrole moiety is a key unit found in many pharmaceutical compounds.^9,10 For example, Tolmetin and Zomepirac are non-steroidal anti-inflammatory drugs, and the other 2-acylpyrrole derivatives also exhibit excellent anti-inflammatory activity as potential drugs (Fig. 1).^8,11 Synthetic chemists have confirmed that 2-acylpyrroles possess interesting biological and biomedical properties.¹² Moreover, 2-arylpyrroles are also of interest in the synthesis of fluorescent dyes and insecticides.¹³ The most common route to pyrrole derivatives involves cyclization reactions, such as the Knorr, Paal–Knorr, and Hantzsch reactions.¹⁴ Unfortunately, these methods often require robust and versatile transformations. In this regard, the development of an efficient strategy for the functionalization of 2-acylpyrrole is attractive and desirable.

Fig. 1 2-Acylpyrrole in pharmaceuticals.

Recent progress in transition metal catalyzed direct C–H bond activation has opened up high atom- and step-economy routes to substituted heterocyclic compounds.^15–17 Amongst various transformations, the C–H functionalization of indole derivatives at different positions employing palladium, ruthenium or rhodium complexes as catalysts has attracted much attention.¹⁸ In contrast, the C–H bond activation of pyrrole derivatives has been less explored, probably due to its instability under acidic and oxidizing environments that limit its utility in metal catalyzed C–H transformations.^19,20 Despite this fact, some elegant methods including C–H arylation, alkenylation, and borylation have been developed, which primarily focus on C2 and/or C5 functionalization of pyrrole. However, very few studies have been reported for functionalization at the C3-position.^19,20 For example, Gaunt et al.^19a have developed a mild aerobic oxidative palladium(II) catalyzed pyrrole C–H bond functionalization by adjusting the N protecting groups with different steric and electronic properties, in which either C2 or C3 alkenylation products were obtained in good yield. Yao et al.^20d recently reported a solvent-controlled switchable C–H alkenylation of 3,4-disubstituted pyrrole via palladium(II) catalyzed oxidation. Heck reaction, enabling C2 or C5 alkenylation products, was also applied to the total synthesis of the natural product (±)-rhazinilam. Encouraged by these protocols, we speculated that the palladium-catalyzed direct C5 alkenylation of 2-acylpyrrole derivatives should be feasible with the assistance of a suitable N-protecting group. To the best of our knowledge, the direct C5 alkenylation of 2-acylpyrroles via palladium-catalyzed C–H bond activation has not been reported yet. Herein, we wish to disclose our development on the palladium-catalyzed regioselective C5 functionalization of 2-acylpyrroles to synthesize C5 alkenylated 2-acylpyrrole derivatives. The products obtained in our study could serve as precursors to prepare the synthetic histone deacetylase (HDAC) inhibitors.²¹

Initially, phenyl(1H-pyrrol-2-yl)methanone and ethyl acrylate were applied as model substrates to explore their reactivity. As predicted, when using the unprotected 2-acylpyrrole-phenyl(1H-pyrrol-2-yl)methanone, the reaction afforded complicated products and no desired alkenylated product could be isolated under the condition of 20 mol% Pd(OAc)₂ and 3 equiv. AgOAc in toluene at 130 °C for 12 h (entry 1, Table 1). The first attempt using tosyl (N-Ts) as the protecting group was not successful. To our delight, further studies using N-(3-NCC₆H₄CO-) protected 2-acylpyrrole afforded 30% of C5-alkenylated products (entries 2 and 3, Table 1). Further, the reaction using 3-(2-benzoyl-1H-pyrrole-1-carbonyl)benzonitrile (1a) was optimized. Screening of different solvents indicated that the solvent had a significant impact on the C–H activation, and PhCF₃ turned out to be the best solvent (entries 4–9, Table 1). Furthermore, varying the reaction temperature, also varied the yield, and a good yield (70%) could be achieved on lowering the reaction temperature to 100 °C (entries 10–12, Table 1). On reducing the amount of AgOAc from 3 equiv. to 2 equiv., the yield reduced to 60% (entry 13, Table 1). However, increasing the amount of AgOAc to 4 equiv. could not further improve the product yield (entry 14, Table 1). Moreover, 20 mol% Pd(OAc)₂ proved to be necessary in order to achieve a good activity for the C–H functionalization, which could be due to the deactivation effect that arises from the strong electron-withdrawing 2-acyl group (entries 10 and 15–16, Table 1). Accordingly, an optimal reaction condition (Pd(OAc)₂ (20 mol%), AgOAc (3 equiv.), PhCF₃ (2 mL), 100 °C, 12 h) was obtained. Based on this, the alkenylation using different protecting groups including 3-NCC₆H₄CH₂-, Boc, and Ts were examined under the optimal condition, affording 60%, 65% (C5 : C4 = 1.2 : 1) and 44% of the desired alkenylation products, respectively (entries 17–19, Table 1). Clearly, the protecting group affects both the reactivity and selectivity; thus, 3-NCC₆H₄CO- proved to be favorable for this alkenylation reaction.

Table 1 Optimization of reaction conditions^a

Entry	R	Solvent	AgOAc (equiv.)	Pd(OAc)2 (mol%)	T (°C)	Yield^b (%)
a Reaction conditions: 3-(2-Benzoyl-1H-pyrrole-1-carbonyl)benzonitrile 1a (0.2 mmol), ethyl acrylate (0.3 mmol), Pd(OAc)2, 2 mL of solvent, 12 h. b Isolated yield. c The reaction afforded a mixture of C4 and C5-alkenylated products (C5 : C4 = 1.2 : 1).
1	H	Toluene	3	20	130	0
2	Ts	Toluene	3	20	130	0
3	3-NCC6H4CO-	Toluene	3	20	130	30
4	3-NCC6H4CO-	DCE	3	20	130	0
5	3-NCC6H4CO-	TFA	3	20	130	0
6	3-NCC6H4CO-	DMF	3	20	130	0
7	3-NCC6H4CO-	Benzene	3	20	130	30
8	3-NCC6H4CO-	C6F6	3	20	130	48
9	3-NCC6H4CO-	PhCF3	3	20	130	50
10	3-NCC6H4CO-	PhCF3	3	20	100	70
11	3-NCC6H4CO-	PhCF3	3	20	80	38
12	3-NCC6H4CO-	PhCF3	3	20	40	18
13	3-NCC6H4CO-	PhCF3	2	20	100	60
14	3-NCC6H4CO-	PhCF3	4	20	100	65
15	3-NCC6H4CO-	PhCF3	3	10	100	46
16	3-NCC6H4CO-	PhCF3	3	5	100	41
17	3-NCC6H4CH2-	PhCF3	3	20	100	60
18	Ts	PhCF3	3	20	100	65^c
19	Boc	PhCF3	3	20	100	44

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With the optimized reaction conditions in hand, the scope and generality of this transformation was investigated (Tables 2 and 3). The results indicated that the aromatic units with different substituents were amenable for this transformation (Table 2). For the 2-acylpyrroles bearing electron-donating methyl group on the acyl phenyl ring, the reaction afforded the desired products in moderate yield. The influence of steric effect on the reaction activity was not observed (2b–2d). Comparatively lower yields were obtained with methoxy substituted 2-acylpyrroles (2e, 2f). Substrates with halogen group (F, Cl, Br) at ortho, meta, or para positions of acyl phenyl ring all reacted smoothly to afford the corresponding products in 50–68% yields (2g–2m). Furthermore, 2-acylpyrroles bearing the strong electron withdrawing CF₃ or CO₂Me group on the acyl phenyl ring also provided satisfactory yields of the C5-alkenylated products (2n–2o). We attempted to examine the reactivity of substrates with disubstituents on the acyl phenyl moiety, which were also smoothly transformed to the desired products in moderate yields (2p–2s).

Table 2 Arene scope of substrates^a,b,c

a Reaction conditions: 1 (0.1 mmol), ethyl acrylate (0.15 mmol), Pd(OAc)₂ (20 mol%), AgOAc (3 equiv.), PhCF₃ (1 mL), 100 °C, 12 h. b Isolated yields. c Selectivity was determined by ¹H NMR analysis of the crude reaction mixture.

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Table 3 Alkene scope of substrates^a,b,c

a Reaction conditions: 1a (0.2 mmol), ethyl acrylate (0.3 mmol), Pd(OAc)₂ (20 mol%), AgOAc (3 equiv.), PhCF₃ (2 mL), 100 °C, 12 h. b Isolated yields. c Selectivity was determined by ¹H NMR analysis of the crude reaction mixture. d Recovery yield of 1a.

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Next, the scope for alkene as a substrate was examined (Table 3). It was satisfactory to observe that the scope of this reaction could also be extended to other alkenes such as methyl acrylate, 2,2,2-trifluoroethyl acrylate, (phenylsulfonyl)ethene, acrylonitrile and acrolein, albeit in somewhat lower product yields (3a–3e). Nevertheless, the reaction using diethyl vinylphosphonate and 4-(trifluoromethyl)styrene as the coupling partner only led to complicated and inseparable product mixtures. Moreover, the alkenylation using 1-acetylcyclohexene proved to be unreactive, which could be due to the strong steric effect of cyclohexene ring that hindered the addition of alkene to the Pd–C bond of the palladation intermediate for this C–H alkenylation.

To further demonstrate the potential of the developed method, a gram-scale synthesis of compound 2a under the standard conditions was conducted. Reaction of 1a (5 mmol) with ethyl acrylate afforded the target product 2a in 60% yield (Scheme 1). As a practical industrial application, it is also important to remove the protecting group. To our delight, the N-pyrrole protecting group could be easily removed on treating 2a with HCl/EtOH (1 : 5) for 3 h at 90 °C, yielding 68% of the (NH)-free product 4 (Scheme 2).

Scheme 1 Gram-scale synthesis of 2a.

Scheme 2 The removal of N protecting group.

Based on the experimental results and literature precedents,^19a,20d a possible mechanism was proposed as shown in Scheme 3. Initially, the 2-acylpyrrole substrate 1 reacts with palladium catalyst through an electrophilic C–H activation pathway at the C5 position of pyrrole to afford an intermediate A. Then, the dearomatization of A results in the formation of the palladation intermediate B. The subsequent addition of alkenyl C=C double bond to Pd–C bond of B, and then the β-H elimination of C leads to a final C5-alkenylated product 2, which undergoes the classical Heck-type reaction. Moreover, the directing effect of carbonyl group of N-3-NCC₆H₄CO- should not be ignored. As observed, the reaction using 3-NCC₆H₄CH₂- as protecting group demonstrated a lower yield of 2a (60%) than that using tosyl (N-Ts) (65%) and N-3-NCC₆H₄CO- (70%) (Table 1). However, such directing (or coordinating) effect of protecting groups should not be dominant for this C5-alkenylation.

Scheme 3 Proposed mechanism for C5 alkenylation of 2-acylpyrroles.

Conclusions

In summary, we have developed a palladium(II)-catalyzed direct C5 alkenylation of 2-acylpyrroles using various functionalized alkenes as coupling partners. This transformation shows good C5 selectivity and is tolerant towards various acyl phenyl substituted 2-acylpyrroles, affording a wide range of 2,5-disubstituted pyrrole derivatives as the only isolated products. The products could serve as potential pharmaceuticals, in particular, as precursors to prepare the synthetic histone deacetylase (HDAC) inhibitors. In addition, the N-pyrrole protecting group is easily removed to obtain the (NH)-free pyrrole compounds under mild conditions.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Science Foundation of China (21101085), Natural Science Foundation of Liaoning Province (2015020196), Research Fund of Key Laboratory of Synthetic Rubber – Changchun Institute of Applied Chemistry (KLSR1602), Talent Scientific Research Fund of LSHU (2016XJJ-006), and Research Project Fund of Liaoning Provincial Department of Education (L2016022) for the financial supports.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and spectral data for all compounds. See DOI: 10.1039/c7qo00732a

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