Green and Sustainable Chemistry
Vol.1 No.4(2011), Article ID:8505,5 pages DOI:10.4236/gsc.2011.14025

Phase-Transfer-Catalyzed Intramolecular Hydroaryloxylation and Hydroamination of C≡C Triple Bonds: An Efficient Synthesis of Benzo[b]furan and 3-Methyleneisoindoline-1-one Derivatives

Jie Hu, Lei Liu, Xiangchuan Wang, Yuanyuan Hu, Shangdong Yang*, Yongmin Liang*

State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, China

E-mail: *, *

Received July 20, 2011; revised August 30. 2011; accepted September 8, 2011

Keywords: PTC, Intramolecular, Cyclization, Metal-Free


Phase-transfer-catalyzed intramolecular cyclization reaction of forming benzo[b]furan and 3-methyleneisoindoline-1-one derivatives has been developed. The cyclization reaction of propargylic carbonates was also described under metal-free condition and the reaction was reported by Pd and Ni before. The reaction conditions and the scope of the process are examined. The catalysts are cheap and environmentally friendly and the substrates are readily available and the procedure is simple, rapid, and general. The development of C-O and C-N bond formation processes via an overall structural isomerization represents the most atom-economical approach.

1. Introduction

The addition of heteroatomic nucleophiles to C≡C triple bonds is an important reaction that often requires a high activation energy [1,2]. The transition metal-catalyzed construction of heterocycles is one of the frontier areas in organic chemistry, because of the exceptional ability to activate the triple bond, towards intermolecular and intramolecular nucleophilic attack [3-7]. Oxygen-containing heterocyclic moieties such as benzo[b]furan rings represent key structural units of a variety of natural compounds with interesting biological and pharmacological activities [8-10] and a number of routes leading to differently substituted benzo[b]furans have been described by metal-catalyzed intramolecular ring closure[11-16]. Meanwhile, nitrogen-containing heterocyclic moiety 3- methyleneisoin-doline-1-one is a core structure of numerous natural products and has also been prepared in the literature.[17,18] Compared with other methods phasetransfer catalysis has long been recognized as a versatile methodology for organic synthesis in both industrial and academic laboratories, featuring its simple reaction procedure, safe, inexpensive, environmentally friendly reagents, absence of anhydrous solvents, ease of scale-up, and metal-free conditions [19-22].

Recently, [23] we have developed a novel and efficient cyclization reaction initiated by phase-transfer catalysis for building carbon-carbon bond. Herein, we report a new mild synthesis of heterocyclic compounds under phase-transfer catalysis by carbon-oxygen or carbon-nitrogen bond formation (Scheme 1).

2. Results and Discussion

Initially, we focused on the reaction of 0.20 mmol of 1-(1,3-diphenylprop-2-ynyl)naphthalen-2-ol (1a), 5 mol % of PTC-1 and 2 equiv of Na2CO3 in DMF at 40˚C in air. To our delight, the desired product benzo[b]furan 2a was formed in 66% yield after 1 h (Table 1, entry 1). Encouraged by this result, we further optimized the reaction

Scheme 1. C-O bond and C-N bond formation by PTC.

Table 1. Optimization of the phase-transfer-catalyzed intramolecular cyclization of 1aa.

conditions. Other common bases, such as K2CO3, Li2CO3, K3PO4, KOAc, K2HPO4, KHCO3 were also tested; K2CO3 gave the best yield of 85% (entries 2 - 7), which indicated that base played an important role in the process. In the absence of PTC condition, the product was obtained in low yield (entries 8 and 9). The effect of the solvent was also investigated. Changing solvent to DMA, NMP, DMSO, THF, 1, 4-dioxane, CH3CN failed to improve the yield of the product 2a (entries 10 - 15). When different PTCs were examined, the results showed that PTC-2 could also promote this cyclization, but the desired product 2a was only obtained with 51% yield (entry 16). Tetraalkyl ammonium salts, such as Bu4NI, Et4NBr, Bu4NCl, and Bu4NF have also been applied to this process, and the yields were not better than PTC-1 (entries 17 - 20). Thus, we chose the following reaction conditions as optimum for subsequent cyclization: 0.20 mmol of 1a, 5 mol % PTC-1, and 0.40 mmol K2CO3 in DMF at 40˚C in air.

With the optimized conditions in hand, the scope of this reaction was then investigated, and the results are summarized in Table 2. As depicted in Table 2, the

Table 2. Phase-transfer-catalyzed synthesis of disubstituted benzo[b]furan derivatives (2a-m)a.

reaction was application to various propargylnaphthols and phenols, and for the most tested substrates, good results have also been obtained. Naphthols with an electron-donating aryl group at propargylic position cyclized smoothly to give the products in high yields, no matter substituents appeared in ortho, meta or para positions (Table 2, entries 2 - 4), while the electron-withdrawing aryl group naphthol (1e) apparently lowered yield (entry 5). The trimethylsilyl-substituted naphthol, 1f, reacted to produce the respective naphthofuran in a moderate (75%) yield and the TMS group happened to undergo desilylation at the same time (entry 6). When a propargylnaphthol with a butyl group at the triple bond was used, the desired product 2g was obtained in a poor yield (entry 7). On employing naphthol with a propyl group at the propargylic position, cyclization product 2h was obtained in moderate yield (entry 8). Furthermore, the propargylphenols were also examined. The presence of electron-donating group on the aromatic ring gave moderate to good yields (entries 9 - 11). Introducing an electron-donating aryl group at the propargylic position, the reaction proceeded smoothly to give the corresponding cyclization products (entries 12 and 13).

Furthermore, to expand the scope of this reaction, we also investigated the ethynylphenol 1n-r. As depicted in Table 3, for all the tested substrates, the phase-transfercatalysts intramolecular cyclization of ethynylphenol could prove to be a very effective method for the synthesis of a variety of monosubstituted benzo[b]furans and the reaction can be tolerant of the substitution groups in aromatic ring (Table 3, entries 1 - 4). It is noteworthy that when R1 was replaced by an alkyl group, the reaction proceeds smoothly to give the corresponding product in good yield (entry 5).

Table 3. Phase-transfer-catalyzed synthesis of monosubstituted benzo[b]furan derivatives (2n-s)a.

The addition of nitrogen nucleophiles to triple bonds were also investigated and results are summarized in Table 4. On introducing aryl groups on the amide moiety, the desired products were generated in good to excellent yields irrespective of the presence of electron-withdrawing or electron-donating groups (entries 2 - 6). Functional groups, such as methyl, methoxyl and bromo were well tolerated in the reaction. When R1 was the benzyl or substituted benzyl, good results still were obtained in our system (entries 7 - 9). Furthermore, we investigated the effect of various substituents on the remote end of the alkyne moiety. These substrates all worked well and gave moderate yields (entries 10 - 14).

When the substrates 5a was investigated, to our surprising, 2-phenyl-1H-indole was obtained in good yield (Scheme 2).

For the substrates 7aa, 7ba and 7ca, we have reported via Pd [24] and Ni [25,26] catalyzed reaction. To our delight, the same good result could also been obtained in our system under metal-tree condition (Scheme 3).

Table 4. Cyclization reaction catalyzed by TBABa,b.

Scheme 2. Phase-transfer-catalyzed intramolecular cyclization of 5a.

Scheme 3. Phase-transfer-catalyzed intramolecular cyclization of propargylic carbonates.

3. Experimental Part

Typical procedure for the preparation of disubstituted benzo[b]furan derivatives 2a. To a solution of 1a (65.2 mg, 0.20 mmol) in 2.0 mL of DMF was added K2CO3 (55.2 mg, 0.40 mmol). The mixture was allowed to stir at room temperature for 1 minute and PTC-1 (4.74 mg, 5 mol%) was added. The resulting mixture was then heated under air at 40˚C. When the reaction was considered complete as determined by TLC analysis, the reaction was allowed to cool to room temperature and quenched with a saturated aqueous solution of ammonium chloride, and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and saturated brine. The organic layers were dried over Na2SO4, filtered. Solvents were evaporated under reduced pressure. The residue was purified by chromatography on silica gel to afford 2,3-disubstitution benzo[b]furans 2a.

Typical procedure for the preparation of 3-methyleneisoindoline-1-one derivatives 4a to a solution of 3a (0.20 mmol) in 2.0 mL of CH3CN was added Cs2CO3 (130.4 mg, 0.40 mmol). The mixture was allowed to stir at room temperature when TBAB (3.22 mg, 5 mol%) was added. When the reaction was considered complete as determined by TLC analysis, the reaction was allowed to quench with a saturated aqueous solution of ammonium chloride, and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and saturated brine. The organic layers were dried over Na2SO4, filtered. Solvents were evaporated under reduced pressure. The residue was purified by chromatography on silica gel to afford 3-methyleneisoindoline-1-one derivatives 4a.

4. Conclusions

In conclusion, phase-transfer-catalyzed intramolecular hydroaryloxylation and hydroamination reaction of corresponding O/N-containing substrates is a novel and efficient method for synthesis of heteroatomic compounds. We also described the cyclization reaction of propargylic carbonates under metal-free condition. These reactions are run under mild conditions, tolerate various functional groups, and generally a wide range of substrates undergo this process in good to excellent yields. Compared to the expensive and toxic transition-metal catalyzed reaction, this methodology showed considerable synthetic advantages in terms of mild reaction conditions, environmenttally friendly catalysts and simple experimental operations. The scope and synthetic application of these reactions are currently under investigation.

5. Acknowledgements

We are grateful for the National Science Foundation (NSF-21072080) for financial support. We acknowledge National Basic Research Program of China (973 Program), 2010CB833203.

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