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

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One-pot, Catalyst-free Synthesis of Spiro[dihydroquinoline- naphthofuranone] Compounds from Isatins in Water Triggered by Hydrogen Bonding Effects Du-lin Kong, Guo-Ping Lu, Mingshu Wu, Zaifeng Shi, and Qiang Lin ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b00145 • Publication Date (Web): 16 Feb 2017 Downloaded from http://pubs.acs.org on February 20, 2017

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ACS Sustainable Chemistry & Engineering

One-pot,

Catalyst-free

Synthesis

of

Spiro[dihydroquinoline-naphthofuranone] Compounds from Isatins in Water Triggered by Hydrogen Bonding Effects Du-lin Kong,a,b Guo-ping Lu,*a Ming-shu Wu,c Zai-feng Shi,c and Qiang Lin*a,c a

Chemical Engineering College, Nanjing University of Science and Technology, Nanjing

210094, P.R. China. *[email protected]; [email protected] b

School of Pharmaceutical Sciences, Hainan Medical University, Haikou 571199, Hainan

Province, P.R. China c

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 KEYWORDS: Spiro[dihydroquinoline-naphthofuranone] compound, Isatin, Hydrogen-bonding effect, Ring-opening and cyclization process

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.

ACS Paragon Plus Environment

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In addition, the chemistry provides several advantages including free of organic solvents, simple operation, gram-scale synthesis, inexpensive reagents and recyclable reaction medium.

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 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 carbons 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 2-naphthol 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 ring-opening route can cycle with 1,3dicarbonyl 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


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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 1,3dicarbonyl compounds. Along this line, we disclose a one-pot, ring-opening strategy for the preparation of spiro[dihydroquinoline-naphthofuranone] compounds from isatins under catalystfree conditions in water,34 in which hydrogen-bonding effects prove to be the main factor to promote the reaction.

Figure 1. The transformations of Isatin.

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,

13

C NMR: 100 MHz), chemical

shifts (δ) are expressed in ppm, and J values are given in Hz, 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. IR spectra were recorded on a Thermo Scientific Nicolet 6700 Fourier IR spectrometer (ATIR) in KBr pellet. All chemicals and solvents were used as received without further purification unless otherwise stated.


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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 oC 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. The 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 oC for 12 h.

Results and discussion Initially, we chose the reaction of isatin, 2-naphthol and 2-thiobarbituric acid under catalystfree conditions as a model reaction (Table 1). As expected, an 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 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).


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The concentration of SDS was also optimized (entries 11, 16, 17), and 10 wt.% SDS/H2O proved to be the best option. Table 1. Optimization reaction conditionsa

O

S

OH O

+

+

O HN

solvent HN

N H 1a

H N

T

oC

O

O

S

O HN

2a

O 3a

4a

HN

Entry

Temp. [°C]

Solvent

t [h]

Yield [%]b

1

80

H2O

4

58

2

80

THF

4

trace

3

80

PhMe

4

trace

4

80

CH3CN

4

trace

5

80

DMF

4

trace

6

80

DMSO

4

trace

7

80

Hexane

4

trace

8

80

C2H5OH

4

30

9

r.t

10 wt.% SDS/H2O

48

80

10

50

10 wt.% SDS/H2O

4

78

11

80

10 wt.% SDS/H2O

4

90

12

80

10 wt.% TEBAC/H2O

4

39

13

80

10 wt.% PEG400/H2O

4

59

14

80

10 wt.% Triton X-100/H2O

4

55

15

80

10 wt.% CTMAB/H2O

4

32

16

80

5 wt.% SDS/H2O

4

75

17

80

15 wt.% SDS/H2O

4

91

18

90

10 wt.% SDS/H2O

4

88


5


a

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

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

100

10 wt.%SDS/H2O 10 wt.%SDS/D2O

80 yield/%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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60 40 20 0 1

2

time/h

3

4

Figure 3. The contrast experiments in different mediums (10 wt.% SDS/H2O vs 10 wt.% SDS/D2O) 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 10wt.% SDS/H2O and 10wt.% SDS/D2O (Figure 3). As expected, a lower product yield was afforded in 10wt.% SDS/D2O compared to that obtained in 10wt.% SDS/H2O. The hydrophobic and polarity effects of D2O are similar with H2O,29-33 so the lesser HB affinity of substrates-D2O than


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subatrates-H2O39 (hydrogen-bonding effects) is the key factor of the decrease in the yield in 10wt.% 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 oC), 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 The reactions of isatins, 2-naphthol and barbituric acidsa

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

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

X S O O S O O S O O S O O S O O S O O S O S O S O

R1 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

R2 H H CH3 H H CH3 H H CH3 H H CH3 H H CH3 H H CH3 H H H H H H

t [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, 88c 92, 91c 80, 46d 91 93, 94c 82, 52d 92 90 81 80 90 83 91 92 88 90 91 83 92 85 90 92 90 88


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a

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. b Isolated yield of product. c At 50 o C for 8 h. d At 50 oC for 48 h.

Figure 4. The reactions of isatins, substituted-2-naphthols and barbituric acids.a,b a 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 oC for 4 h. b Isolated yields. c 6 h. d 10 h. e 8 h. f 15 h. g 20 h. Table 3 The reactions of isatins, 2-naphthols and dimedonea

Entry

Compound

R1

R2

Yield [%]b

1

8a

H

7-OH

80

2

8b

5-CH3

H

82

a

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. b Isolated yields.


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Figure 5. The single-crystal X-ray structures of 7d (CCDC 1522241) and 8a (CCDC 1522242) 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 1,3dimethylbarbituric acid (entries 3,6,9,12,15,18). Lower temperature (50 oC) 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


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reaction of 1a and 3a takes place in 10 wt.% SDS/H2O at 80 oC to form a messy mixture of products (eq 2), so the multi-compound 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. Firstly, 3a’ generated from 3a by tautomerizm which can be promoted by hydrogen-bonding effects of water, react with 1a and 2a sequentially through Knoevenagel condensation and Michael addition to form intermediate 9.

Figure 6. Control experiments

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


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Yield (%)

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100 90 80 70 60 50 40 30 20 10 0 0

1

2

3

4

5

run time

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. An intramolecular nucleophilic attack (carbonyl addition) of 9 in which the hydroxyl of naphthol ring adds to the 2-position carbonyl group of indole ring, essentially leads to the unusual ring-opening 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 reaction29-33,41-42: (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. 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


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reaction medium was separated by filtration and reused in the next run directly. The process could be repeated 5 times without an obvious change in yields.

Conclusions In

summary,

a one-pot,

ring-opening

annulation

protocol

for

the synthesis

of

spiro[dihydroquinoline-naphthofuranone] compounds from isatins, 2-naphthols and 1,3dicarbonyl 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, which can enhance the nucleophilicity of enol’s β-carbon and the hydroxyl of naphthol ring, and the eletrophilicity of carbonyl carbon. The research on investigating the potential biological or pharmacological activities of these compounds is ongoing in our group. ASSOCIATED CONTENT Supporting Information Characterization data, copies of NMR all products. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; [email protected] ACKNOWLEDGMENT


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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). REFERENCES (1) Foucout, L.; Gourand, F.; Dhilly, M.; Bohn, P.; Dupas, G.; Costentin, J.; Abbas, A.; Marsais, F.; Barre, L.; Levacher, V. Synthesis, radiosynthesis and biological evaluation of 1,4dihydroquinoline derivatives as new carriers for specific brain delivery. Org. Biomol. Chem. 2009, 7, 3666-3673. (2) Faro, L. V.; de Almeida, J. M.; Cirne-Santos, C. C.; Giongo, V. A.; Castello-Branco, L. R.; Oliveira, I. d. B.; Barbosa, J. E. F.; Cunha, A. C.; Ferreira, V. F.; de Souza, M. C.; Paixão, I. C. N. P.; de Souza, M. C. B. V. Oxoquinoline acyclonucleoside phosphonate analogues as a new class of specific inhibitors of human immunodeficiency virus type 1. Bioorg. Med. Chem. Lett. 2012, 22, 5055-5058. (3) Mentese, M. Y.; Bayrak, H.; Uygun, Y.; Mermer, A.; Ulker, S.; Karaoglu, S. A.; Demirbas, N. Microwave assisted synthesis of some hybrid molecules derived from norfloxacin and investigation of their biological activities. Eur. J. Med. Chem. 2013, 67, 230-242. (4) Mistry, S. N.; Valant, C.; Sexton, P. M.; Capuano, B.; Christopoulos, A.; Scammells, P. J. Synthesis and Pharmacological Profiling of Analogues of Benzyl Quinolone Carboxylic Acid (BQCA) as Allosteric Modulators of the M1 Muscarinic Receptor. J. Med. Chem. 2013, 56, 5151-5172.


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(23) Hao, W. J.; Wang, J. Q.; Xu, X. P.; Zhang, S. L.; Wang, S. Y.; Ji, S. J. I2/O2-promoted domino reactions of isatins or 3-hydroxyindolin-2-one derivatives with enaminones. J. Org. Chem. 2013, 78, 12362-12373. (24) Sarkar, P.; Mukhopadhyay, C. Single step incorporation of carboxylic acid groups in the lower rim of calix[4]arenes: a recyclable catalyst towards assembly of diverse five ring fused acridines. Green Chem. 2015, 17, 3452-3465. (25) Li, J.; Su, S.; Huang, M.; Song, B.; Li, C.; Jia, X. Unexpected isocyanide-based cascade cycloaddition reaction with methyleneindolinone. Chem. Commun. 2013, 49, 10694-10696. (26) Dwars, T.; Paetzold, E.; Oehme, G. Reactions in Micellar Systems. Angew. Chem. Int. Ed. 2005, 44, 7174-7199. (27) Jessop, P. G. Searching for green solvents. Green Chem. 2011, 13. 1391-1398. (28) Lu, G.-p.; Cai, C.; Chen, F.; Ye, R.-l.; Zhou, B.-j. Facile Sulfa-Michael Reactions with Sodium Arylsulfinates in Water: The Promotion of Water on the Reaction. ACS Sustain. Chem. Eng. 2016, 4, 1804-1809. (29) Butler, R. N.; Coyne, A. G. Water: Nature’s Reaction Enforcer—Comparative Effects for Organic Synthesis “In-Water” and “On-Water”. Chem. Rev. 2010, 110, 6302-6337. (30) Kommi, D. N.; Jadhavar, P. S.; Kumar, D.; Chakraborti, A. K. "All-water" one-pot diverse synthesis of 1,2-disubstituted benzimidazoles: hydrogen bond driven 'synergistic electrophile-nucleophile dual activation' by water. Green Chem. 2013, 15, 798-810.


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One-pot, Catalyst-free Synthesis of Spiro[dihydroquinoline-naphthofuranone] Compounds from Isatins in Water Triggered by Hydrogen Bonding Effects

Du-lin Kong,a,b Guo-ping Lu,*a Ming-shu Wu,c Zai-feng Shi,c and Qiang Lin*a,c

A one-pot, catalyst-free ring-opening annulation reaction promoted by hydrogen-bonding effects in water is introduced for the synthesis of spiro[dihydroquinoline-naphthofuranone] compounds.


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

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