Transition-Metal Catalyst Free Oxidative Radical Arylation of N-Methylpyrrole.

This study represents an expansion of the application of catalysis in air through conventional coupling and free radical processes. A reactive free aryl radical intermediate was generated via the oxidation of an activated Ar-NH-NH2 bond by air as a simple and readily available oxidant. For this purpose, the usability of phenylhydrazine and phenylhydrazine hydrochloride salt reagents for the direct arylation of pyrrole with aryl radicals was investigated. The facile coupling of N-methylpyrrole with aryl radicals was easily applied for the convenient direct synthesis of C-2 arylated pyrroles without a transition-metal catalyst.

Introduction

Found in many natural products and used in many pharmaceutically relevant and other functional synthesis,[1] pyrrole ring is among the most important heterocyclic structural units. 2-Arylpyrrole derivatives are examples of such pharmaceutically and biologically active compounds; compound 1a exhibited selective potent H+, K+-ATPase inhibition activity as a potassium-competitive acid blocker (P-CAB), compound 1b demonstrated potent inhibitory action for histamine-stimulated gastric acid secretion in rats and Heidenhain pouch dogs,[2] C-chlorfenapyr compound 2 was the first commercialized insecticide-miticide,[3] roseophilin 3 was isolated from a culture broth of Streptomyces griseoviridis, which displayed cytotoxicity against K562 erythroid leukemia and KB human epidermoid carcinoma cell lines,[4] and compound 4 potently inhibited cancer cell growth in the H146 small-cell lung cancer cell line, achieving a nanomolar IC50 value.[5] Furthermore, trisubstituted pyrrole 5 displayed activity against both erythrocytic and sporozoite parasite stages in vitro and in vivo,[6] respectively (Figure ).

Figure 1

Pharmaceutical and biologically active compounds containing 2-aryl-pyrrole framework.

However, despite the numerous applications of the arylated pyrroles, their synthesis remains a challenge in organic chemistry because pyrroles are very reactive and easily polymerize. Transition-metal-catalyzed (especially Pd, Rh, and Ru complexes) cross-coupling reactions of pyrroles are phenomenally successful for the formation of C sp2–sp2 bonds.[7] Palladium catalysts are the most important transition metals among others to perform the arylation of pyrroles. Doucet and co-workers have reported palladium-catalyzed regioselective arylation of pyrroles.[8] Recently, a cheap and environmentally friendly iron catalyst was developed.[9] Despite numerous applications of arylated pyrroles, there is deep need to develop a new methodology because these transition-metals are very expensive and rare metals.

In contrast, metal-free methodologies are rare and challenging. Very recently, considerable progress was made in the transition-metal-free arylation of pyrroles. Gryko and co-workers reported both the direct arylation of pyrroles with electron-withdrawing groups containing aryl iodides in superbasic media without the external addition of a transition-metal catalyst and the photocatalytic arylation with diazonium salts catalyzed by a porphyrin.[10] Yu and co-workers found that pyrroles could be directly arylated with diarylidonium salts.[11] Konig, Zhu, and group independently reported the use of perylene diimides as photocatalysts and mediators for the reduction of arylhalides containing electron-withdrawing groups for the arylation of pyrroles with aryl radicals via a photoinduced electron-transfer (PET) mechanism and indirect electroreductive coupling.[12] The aim of the present work is to a perform metal-free coupling using pyrroles and arylhydrazine salts (Scheme ).

Scheme 1

Direct Arylation of Pyrroles

Results and Discussion

Arylhydrazine salts have been widely used for organic synthesis because of their stability, high reactivity, and availability. These compounds have been utilized for the Fischer indolization of various carbonyl compounds[13] and transition-metal-mediated cross-coupling reactions.[14] Recently, considerable progress has been made in the transition-metal-catalyzed arylation of inactive C–H bonds with arylhydrazine salts.[15] However, new developments are needed for metal-free arylations of inactive C–H bonds.

Arylhydrazine salts can be transformed into aryl radicals via the formation of instable diazene intermediates.[16] In 2009, Wang and co-workers reported the arylation of [60] fullerene for the synthesis of 1,4-fullerenols C60ArOH with arylhydrazine salts in the absence of a transition-metal catalyst.[17] Interestingly, in 2014, Heinrich and co-workers reported the direct arylation of anilines with arylhydrazine salts in the absence of a transition-metal catalyst.[18] More recently, Kuang and co-workers found that pyridines could be directly arylated with arylhydrazine salts under metal-free conditions.[19] In 2015, the Yadav group reported the direct arylations of quinoline-4-ones, coumarins, and 2-pyridones with arylhydrazine salts in the absence of transition-metal catalysts.[20] Nevertheless, in these papers, only some unique pyrrole substrates and arylhydrazine salts provided the desired cross-coupling products in high yields under mild conditions. On the basis of these findings, our paper reports the results of a novel method of transition-metal-free direct C-2 arylation of pyrroles with arylhydrazine salts.

First, N-methylpyrrole and 4-chlorophenylhydrazine hydrochloride salt were selected as the cross-coupling reagents to optimize the reaction conditions in air, but no product was detected until a base was added. Performing reactions of N-methylpyrrole (6) with 4-chlorophenylhydrazine hydrochloride (7e) in a variety of polar and nonpolar solvents was not successful. The pyrrole and phenylhydrazine salt ratio was tested at very different ratios starting from 1:1. Some of these are shown in Table . The best yield and homogeneous medium for the reaction was determined to be 20: 1 for the pyrrole and phenylhydrazine salt ratio. Therefore, pyrrole was used excessively. The cross coupling occurred in the presence of a base at room temperature (rt) in air without solvent to form the product. Because a long reaction time and low NaOH concentration favor the arylation, our goal was to achieve a high yield. For this reason, different from previous studies,[18−20] the addition of a lower NaOH concentration (0.5 M) and 50 h of reaction time increased the yield. Notably, the functionalization of the pyrrole occurred selectively at the C-2 position to give only one regioisomer of an arylated pyrrole. The best yield (90%) for 8f was achieved for the reaction with pyrrole as the solvent. The optimization of the reaction conditions of pyrrole and 4-chlorophenylhydrazine hydrochloride salt is summarized in Table .

Table 1

Optimization of the Reaction Conditionsa

entry	solvent	base	yield of 8e (%)
1	benzene	NaOH	trace
2	toluene	KOH	trace
3	acetonitrile	K2CO3	trace
4	dimethyl sulfoxide	Cs2CO3	n.d.
5			n.d.
6		K2CO3	14
7		Na2CO3	12
8		NaHCO3	5<
9		TMEDA	n.d.
10		DMAP	n.d.
11		Et3N	n.d.
12		K3PO4	10
13		Cs2CO3	10
14		t-BuOK	n.d.
15		NaOH	90
16		KOH	74

Reaction conditions: entries 1-4: pyrrole (0.1 mmol), 4-chlorophenylhydrazine hydrochloride (0.1 mmol), base (0.5 M, 0.5 mL), solvent (1 mL), rt, 12 h, single-necked flask, in air. Entry 5: pyrrole (0.1 mmol), 4-chlorophenylhydrazine hydrochloride (0.1 mmol), rt, 12 h, single-necked flask, in air. Entries 6–16: pyrrole (2 mL), 4-chlorophenylhydrazine hydrochloride (0.2 mmol), inorganic base (0.5 M, 0.5 mL), organic base (0.01 mmol), rt, 50 h, two-necked flask, in air.

Afterward, the influence of various bases in the cross coupling was examined (Table , entries 5–16). Several of organic and inorganic bases were screened, and only the use of NaOH and KOH (Table , entries 15–16) provided high-yielding products (74–90%).

Unfortunately, the desired cross-coupling product was not obtained without addition of base or any other additives. After screening several different bases and metal additives, 0.5 M NaOH was determined to be the most efficient additive, providing a 90% yield of the desired cross-coupling product under solvent-free conditions using the pyrrole as both the solvent and reagent (entry 15). Further, solvent-free reactions focused on the screening of different bases were also studied.

In each case, a single C-2 arylation product from the pyrrole was isolated in excellent yield; neither N-arylation nor C-2 and C-5 diarylation products were detected under the utilized conditions (Table ). The yields listed in Scheme indicate that the phenylhydrazine hydrochloride salt, with an electron-withdrawing substituent, can provide C-2 aryl products with better results. Excellent yields of ≥70% were achieved for the reactions involving chloro, bromo, and fluoro groups (entries 8e, 8f, and 8i, Scheme ). The phenylhydrazine hydrochloride salt containing an electron-withdrawing nitro group also gave a good yield.[16,17]

Scheme 2

Reaction of Arylhydrazine Hydrochloride Salts with N-Methylpyrrole

On the basis of the results of previous studies,[18−20] a plausible reaction mechanism for this reaction via the possible pathway is shown (Scheme ) after the formation of the aryl radical from the phenylhydrazine salts in the presence of the base and air. The desired arylated product was produced via an initial electrophilic aryl radical reacting with pyrrole (6) to form an allyl radical (10), which was stabilized by resonance (11) by O2 before losing an electron and eliminating a proton to afford the C-2 arylated pyrrole (8).

Scheme 3

Plausible Mechanism

Conclusions

In conclusion, this paper reports the arylation of N-methylpyrrole via a radical addition reaction by air oxidation of phenylhydrazine salts. This novel and convenient method for the arylation of pyrrole offers several advantages, such as high regioselectivity, operational simplicity, and mild reaction conditions, and utilizes phenylhydrazine salts, pyrrole, NaOH, H2O, and air at room temperature. This arylation protocol was used to prepare C-2 arylation products of pyrrole and phenylhydrazine hydrochloride salt, reacting near room temperature and providing easy product isolation.

Experimental Section

General Procedure for C-2 Arylation of Pyrrole with Phenylhydrazine Hydrochloride Salts

A two-necked 10 mL flask equipped with a magnetic stir bar (2 × 7 mm2) was charged with pyrrole (10 mmol, 670 mg) and phenylhydrazine hydrochloride salt (0.5 mmol, 72 mg). Aqueous sodium hydroxide (0.5 M, 0.5 mL) was then added dropwise over a period of 0.5 h. The resulting mixture was stirred in a two-necked flask at room temperature for 50–60 h without closing the necks. The excess of pyrrole and water was evaporated at room temperature, and the remaining solid was purified by flash column chromatography (EtOAc/25% hexane).