One-Pot, Catalyst-Free Synthesis of Spiro[dihydroquinoline

Research Article pubs.acs.org/journal/ascecg

One-Pot, Catalyst-Free Synthesis of Spiro[dihydroquinolinenaphthofuranone] Compounds from Isatins in Water Triggered by Hydrogen Bonding Effects Du-lin Kong,†,‡ Guo-ping Lu,*,† Ming-shu Wu,§ Zai-feng Shi,§ and Qiang Lin*,†,§ †

Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, P.R. China School of Pharmaceutical Sciences, Hainan Medical University, Haikou 571199, Hainan Province, P.R. China § Key Laboratory of Tropical Medicinal Plant Chemistry of the Ministry of Education, College of Chemistry & Chemical Engineering, Hainan Normal University, Haikou 571158, P.R. China

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‡

S Supporting Information *

ABSTRACT: A one-pot, catalyst-free route to spiro[dihydroquinoline-naphthofuranone] compounds from isatins through ring-opening and cyclization processes in water is disclosed. Hydrogen-bonding effects of water proved to be the key factor to accelerate the transformation. In addition, the chemistry provides several advantages including that it is free of organic solvents, a simple operation, and a gram-scale synthesis and uses inexpensive reagents and a recyclable reaction medium. KEYWORDS: Spiro[dihydroquinoline-naphthofuranone] compound, Isatin, Hydrogen-bonding effect, Ring-opening and cyclization process

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INTRODUCTION Both dihydroquinolines1−4 and naphthofuranones5−8 are considered as the core structures in many pharmaceutically active compounds and natural products. Meanwhile, spiro compounds are present throughout the natural world, which have been exploited to provide tool compounds for biomedical study and to serve as scaffolds for drug discovery.9−13 Therefore, the spiro combination of dihydroquinolines and naphthofuranones presents intriguing possibilities for biocidal or other pharmacological and biological properties. Nevertheless, no strategy has been developed to build such a motif. Isatins as privileged molecules have been widely applied for the synthesis of diverse spiroindolones due to the electrophilicity of their 3-position carbonyl carbon (Figure 1).14−18 More recently, the electrophilicity of their 2-position carbonyl carbon is also been exploited. Several reports have mentioned that enaminones can attack the 2-position carbonyl carbon of

isatins to generate pyrrolo[2,3,4-kl]acridinone derivatives through sequential ring-opening and cyclizing processes (Figure 1).19−25 Based on these results, we reason that 2naphthol as a nucleophile can also add to the 2-position carbonyl carbon of isatin to form the naphthofuranone, moreover the free amine group in situ generate by the ringopening route can cycle with 1,3-dicarbonyl compounds to derive dihydroquinolines (Figure 1). On the other hand, water is an ideal choice as the reaction medium since it is a cost-effective and safe solvent in synthetic chemistry from a “green and sustainable chemistry” perspective.26−28 Moreover, hydrogen-bonding effects of water can accelerate some transformations through the formation of hydrogen bonds (HBs) between water and substrates.29−33 Thus, water may also enhance the electrophilicity of 2-position carbonyl carbon on isatin via hydrogen-bonding effects, which is beneficial to the ring-opening and cyclization process from isatins, 2-naphthols, and 1,3-dicarbonyl compounds. Along this line, we disclose a one-pot, ring-opening strategy for the preparation of spiro[dihydroquinoline-naphthofuranone] compounds from isatins under catalyst-free conditions in water,34 in which hydrogen-bonding effects prove to be the main factor to promote the reaction. Received: January 15, 2017 Revised: February 13, 2017 Published: February 16, 2017

Figure 1. Transformations of isatin. © 2017 American Chemical Society

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DOI: 10.1021/acssuschemeng.7b00145 ACS Sustainable Chem. Eng. 2017, 5, 3465−3470

Research Article

ACS Sustainable Chemistry & Engineering Table 1. Optimization Reaction Conditionsa

entry

temp [°C]

solvent

t [h]

yield [%]b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

80 80 80 80 80 80 80 80 r.t 50 80 80 80 80 80 80 80 90

H2O THF PhMe CH3CN DMF DMSO Hexane C2H5OH 10 wt % SDS/H2O 10 wt % SDS/H2O 10 wt % SDS/H2O 10 wt % TEBAC/H2O 10 wt % PEG400/H2O 10 wt % Triton X-100/H2O 10 wt % CTMAB/H2O 5 wt % SDS/H2O 15 wt % SDS/H2O 10 wt % SDS/H2O

4 4 4 4 4 4 4 4 48 4 4 4 4 4 4 4 4 4

58 trace trace trace trace trace trace 30 80 78 90 39 59 55 32 75 91 88

Reaction conditions: isatin (1 mmol), 2-thiobarbituric acid (1 mmol), and 2-naphthol (1 mmol) in solvent (2 mL) was stirred at rt to 90 °C for 4 or 48 h. bIsolated yields.

a

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EXPERIMENTAL DETAILS

Melting points were determined on a unimelt capillary melting point apparatus and reported uncorrectedly. All compounds were fully characterized by spectroscopic data. The NMR spectra were recorded on a Bruker Avance III (1H NMR 400 MHz, 13C NMR 100 MHz), chemical shifts (δ) are expressed in parts per million, J values are given in hertz, and DMSO-d6 was used as solvent. The reactions were monitored by thin layer chromatography (TLC) using silica gel GF254. HRMS (ESI) analysis was measured on a LCMS-IT-TOF instrument. All chemicals and solvents were used as received without further purification unless otherwise stated. General Procedure for Preparation of Targeted Molecules. To a solution of 10 wt % SDS/H2O (2 mL) were added isatin 1 (1 mmol), 2-naphthol 2 (1 mmol), and 1,3-dicarbonal compound 3 (1 mmol). The mixture was stirred at 50 or 80 °C for 4−20 h and monitored by TLC. After the reaction was complete, the reaction mixture was filtered and the precipitate washed with hot H2O. The crude products were purified by recrystallization from ethanol to afford the desired product. Procedure of Recycling 10 wt % SDS Aqueous Solution. After completion of the reaction, the reaction medium was separated by filtration and reused in the next run directly. To the recylced 10 wt % SDS aqueous solution, isatin 1a (10 mmol), 2-naphthol 2a (10 mmol), and 2-thiobarbituric acid 3a (10 mmol) was added, and the reaction was stirred at 50 °C for 12 h.

Figure 2. Single-crystal X-ray structure of 4a (CCDC 1504991).

owing to the formation of HBs between water and substrates and the high polarity of water that results in the more polar translation states than initial states.29 To further improve the unsatisfactory yields, an anionic surfactant sodium dodecyl sulfate (SDS) was employed in the reaction, resulting an excellent yield of 4a (entry 11) due to “micellar catalysis”.35−38 Longer reaction time was required to obtain a good yields at lower temperature (entry 9). Compared with phase transfer catalysts (TEBAC, PEG400), nonionic (Triton X-100) and cation (CTMAB) surfactants, SDS emerged the best choice for the reaction (entries 11−15). The concentration of SDS was also optimized (entries 11, 16, 17), and 10 wt % SDS/H2O proved to be the best option. To further verify the promotion of water on the reaction, we performed experiments by selecting the model reaction to make a comparison of conversion versus time in 10 wt % SDS/H2O and 10 wt % SDS/D2O (Figure 3). As expected, a lower

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RESULTS AND DISCUSSION Initially, we chose the reaction of isatin, 2-naphthol, and 2thiobarbituric acid under catalyst-free conditions as a model reaction (Table 1). As expected, a spiro[dihydroquinolinenaphthofuranone] compound 4a via the ring-opening route of isatin was produced with a moderate yield in water (entry 1), whose structure was confirmed by NMR and single-crystal Xray diffraction (Figure 2). After screening of different solvents, water proved to be the best option (entries 1−8), presumably 3466


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With the optimized reaction conditions in hand, we next turned our attention to ascertain the scope and limitations of the ring-opening annulation reaction. A series of isatins and barbituric acids were selected to react with 2-naphthol (Table 2). To our delight, good to excellent yields were obtained in all cases (24 examples). Longer reaction time was required in the cases of 1,3-dimethylbarbituric acid (entries 3, 6, 9, 12, 15, 18). Lower temperature (50 °C) could also provide satisfactory yields by prolonging the reaction time to 8 h in the cases of 4a, 4b, and 4e (entries 1, 2, 5), but only moderate yields of 4c and 4f (entries 3 and 6) were found at the same temperature even after 48 h. Likewise, other 2-naphthols including 6-bromo, 6-hydroxyl, and 7-hydroxyl-2-naphthols could be employed in the protocol to afford good to excellent yields (Figure 4, 29 examples). Reactions of isatins, 2-naphthols, and dimedone proceeded smoothly under identical conditions (Table 3). Nevertheless, other arenols, 1,3-dicarbonyl compounds failed to yield the desired products. The structures of 7d and 8a were also confirmed by single-crystal X-ray analysis (Figure 5). NAlkylated isatins (N-methyl, ethyl, and benzyl isatins) were also applied in the protocol, but no desired product was found. The interesting and remarkable results obtained by the protocol prompted us to explore more details about the reaction mechanism. Results of control experiments indicate that only the reaction of 1a and 3a takes place in 10 wt % SDS/

Figure 3. Contrast experiments in different mediums (10 wt % SDS/ H2O vs 10 wt % SDS/D2O).

product yield was afforded in 10 wt % SDS/D2O compared to that obtained in 10 wt % SDS/H2O. The hydrophobic and polarity effects of D2O are similar to H2O,29−33 so the lesser HB affinity of substrates−D2O than subatrates−H2O39 (hydrogen-bonding effects) is the key factor of the decrease in the yield in 10 wt % SDS/D2O. The micelles are not seating structure, so HBs can be formed between water and substrates in the oil−water interface. Moreover, the micelles may be not stable in high temperature (80 °C), which may further enhance the formation HBs between water and substrates.35,40 Thus, the chemistry must take place at the oil−water interface. Table 2. Reactions of Isatins, 2-Naphthol, and Barbituric Acidsa

entry

4

X

R1

R2

t [h]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s 4t 4u 4v 4w 4x

S O O S O O S O O S O O S O O S O O S O S O S O

H H H 5-F 5-F 5-F 7-F 7-F 7-F 5-Br 5-Br 5-Br 5-Cl 5-Cl 5-Cl 5-CH3 5-CH3 5-CH3 6-Cl-7-CH3 6-Cl-7-CH3 5-CH2CH3 5-CH2CH3 6-Br 5-OCH3

H H CH3 H H CH3 H H CH3 H H CH3 H H CH3 H H CH3 H H H H H H

4 4 20 4 4 15 4 4 9 4 4 11 4 4 15 4 4 20 4 4 4 4 4 4

yield [%]b 90, 92, 80, 91 93, 82, 92 90 81 80 90 83 91 92 88 90 91 83 92 85 90 92 90 88

88c 91c 46d 94c 52d

Reaction conditions: isatin (1 mmol), barbituric acid (1 mmol), and 2-naphthol (1 mmol) in 10 wt % SDS/H2O (2 mL) was stirred at 80 °C for 4− 20 h. bIsolated yield of product. cAt 50 °C for 8 h. dAt 50 °C for 48 h. a

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Figure 5. Single-crystal X-ray structures of 7d (CCDC 1522241) and 8a (CCDC 1522242).

Figure 4. Reactions of isatins, substituted-2-naphthols, and barbituric acids. Reaction conditions: isatin (1 mmol), barbituric acid (1 mmol), and substituted-2-naphthol (1 mmol) in 10 wt % SDS/H2O (2 mL) was stirred at 80 °C for 4 h. Isolated yields. (c) 6 h. (d) 10 h. (e) 8 h. (f) 15 h. (g) 20 h.

H2O at 80 °C to form a messy mixture of products (eq 2), so the multicompound reaction is initiated by a reaction involving isatin and 1,3-dicarbonyl compound (Figure 6). On the basis of these results and previous literature, a plausible reaction pathway was purposed in Figure 7. First, 3a′ generated from 3a by tautomerizm which can be promoted by hydrogenbonding effects of water, react with 1a and 2a sequentially through Knoevenagel condensation and Michael addition to form intermediate 9. An intramolecular nucleophilic attack (carbonyl addition) of 9 in which the hydroxyl of naphthol ring adds to the 2-position carbonyl group of isatin, essentially leads to the unusual ringopening process.19−25 The reactive intermediate 11 experiences an intramolecular cyclization process to give the unusual 4a. The hydrogen-bonding effects play a dual role in the reaction:29−33,41,42 (1) enhancing the nucleophilicity of enol’s β-carbon (3a′ and 2a) and the hydroxyl of naphthol ring (9) via the generation of HBs between water and the hydroxyl groups; (2) increasing the eletrophilicity of carbonyl carbon (1a and 9) by the formation of HBs between water and the carbonyl groups.

Figure 6. Control experiments.

Finally, investigations were also conducted to assess the potential for recycling of 10 wt % SDS aqueous solution in the model reaction (Figure 8). Meanwhile, we scaled up the reaction to 10 mmol to show the possibility for large-scale operation. After completion of the reaction, the reaction medium was separated by filtration and reused in the next run directly. The process could be repeated five times without an obvious change in yields.

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CONCLUSIONS In summary, a one-pot, ring-opening annulation protocol for the synthesis of spiro[dihydroquinoline-naphthofuranone] compounds from isatins, 2-naphthols, and 1,3-dicarbonyl compounds in water was introduced. The protocol features free of organic solvents, simple operation, gram-scale synthesis, inexpensive reagents, and recyclable reaction medium. According to experimental results, the facilitation of water on the chemistry is mainly attributed to its hydrogen-bonding effects,

Table 3. Reactions of Isatins, 2-Naphthols, and Dimedonea

a b

entry

compound

R1

R2

yield [%]b

1 2

8a 8b

H 5-CH3

7-OH H

80 82

Reaction conditions: isatin (1 mmol), dimedone (1 mmol), and 2-naphthol (1 mmol) in 10 wt % SDS/H2O (2 mL) was stirred at 80 °C for 4 h. Isolated yields. 3468


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Characterization data, copies of NMR all products (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (G.L.). *E-mail: [email protected] (Q.L.). ORCID

Guo-ping Lu: 0000-0003-4476-964X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are thankful for the financial support from the Natural Science Foundation of China (21402093) and Jiangsu Province of China (BK20140776), Hainan Province of China (20162033), Chinese Postdoctoral Science Foundation (2016T90465, 2015M571761), and the Cultivation Research Foundation of Hainan Medical University (HY2015-02). We also gratefully acknowledge the Priority Academic Program Development of Jiangsu Higher Education Institutions for financial support.

Figure 7. Tentative pathway for the reaction of isatin, 2-naphthol, and 2-thiobarbituric acid.

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Figure 8. Recycle studies. Conditions: 10 mmol 1a, 10 mmol 2a, 10 mmol 3a, 20 mL 10 wt % SDS/H2O, 50 °C, 12 h. Isolated yields.

which can enhance the nucleophilicity of enol’s β-carbon and the hydroxyl of naphthol ring and the eletrophilicity of the carbonyl carbon. The research on investigating the potential biological or pharmacological activities of these compounds is ongoing in our group.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.7b00145. 3469


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One-Pot, Catalyst-Free Synthesis of Spiro[dihydroquinoline

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