Cascade Reaction of Isatins with 1,1-Enediamines: Synthesis of

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Cascade Reaction of Isatins with 1,1-Enediamines: Synthesis of Multisubstituted Quinoline-4-carboxamides Bao-Qu Wang,† Cong-Hai Zhang,† Xiao-Xue Tian, Jun Lin,* and Sheng-Jiao Yan* Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, P. R. China S Supporting Information *

ABSTRACT: A one-step methodology for the synthesis of multisubstituted quinoline-4-carboxamides was developed by simply refluxing a mixture of isatins 1 and various kinds of 1,1-enediamines 2−4 in a reaction catalyzed by NH2SO3H. As a result, a series of quinolone-4-carboxamides were produced through a novel cascade reaction mechanism. This reaction involved the formation of the quinoline ring accompanied by the formation of an amide bond in one step. Accordingly, this protocol is suitable for combinatorial and parallel syntheses of quinolone-4-carboxamide drugs or natural products.

T

bonds have been reported,25 such as by halogenation of quinoline carboxylic acid and palladium-catalyzed double isocyanide carbon monoxide insertion to form a quinolinamide bond. Although these methods significantly contribute to the synthesis of quinoline-4-carboxamides, they have obvious shortcomings, such as long reaction time, low yield, participation of metal catalysts in the reaction, etc. Therefore, it is of great importance to develop a concise and efficient method for the synthesis of quinoline-4-carboxamides. A cascade reaction is a particularly attractive tool for the diversity-oriented synthesis of natural products with diverse substitution patterns to meet the demands of high-throughput screening for drug research and development.26 Also, it has significant advantages over the classical step-by-step approaches not only from an atom economy and environmental viewpoint, such as avoiding the isolation and purification of intermediates, but also because they consist of straightforward experimental procedures.27 Enamines including enaminones, enamine esters, heterocyclic ketene aminals (HKAs), and 1,1-enediamines (EDAMs) are fascinating and versatile building blocks that are widely used to synthesize various fused heterocyclic compounds.28−30 Our group has used HKAs as bis-nucleophilic reagents to react with isatins via a cascade reaction for the synthesis of imidazopyrroloquinolines (Scheme 1, 1a).28a Since then, more and more groups have used a variety of enamines as substrates for the synthesis of various imidazopyrroloquinolines through cascade reactions.28 In recent years, however, there have been some concerns about imidazopyrroloquinolines. To further explore the cascade reaction of enamines, here we expand the bis

he quinoline derivatives are important N-containing heterocyclic compounds due to their broad-spectrum biological activities.1−5 Over the past few years, quinoline derivatives have drawn the attention of chemists and pharmacologists. As a result, many procedures for the synthesis of quinoline compounds have been reported. These classic methods include some name reactions such as the Skraup, Doebner−von Miller, Friedlander, Pfitzinger, Conrad Limpach, Combes, and other reactions. The recently developed innovative reactions include the palladium-catalyzed intermolecular allylic aniline and alkyne reactions and the like.6−13 Among their products, quinoline-4-carboxamides are very beneficial as they possess important biological activities, such as antimalarial (Hit, DDD102542 and 107498, Figure 1),14,15

Figure 1. Structures of quinoline-4-carboxamide compounds.

anti-HIV,16 antitumor (STX-0119),17 antiviral,18 antituberculosis,19 antifungal, antioxidant,20 and insecticidal.21 In addition, quinoline-4-carboxamides also serve as acetyl CoA carboxylase inhibitors (AM-0687)22 or agonists of the cannabinoid receptor 1.23 Quinoline-4-carboxamides have attracted increasing attention due to their interesting biological activities. However, the methods for the synthesis of quinoline-4-carboxamides are still limited due to the need to form an amide bond between the carboxyl group of carboxylic acid and an amine, including alkylamine and arylamine, which is usually based on condensing agents.24 Recently, some novel methods to construct amide © XXXX American Chemical Society

Received: December 6, 2017

A

DOI: 10.1021/acs.orglett.7b03803 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Table 1. Optimized Conditions for the Synthesis of 5aaa−b

Scheme 1. Synthetic Route of Quinoline-4-carboxamides

nucleophilic reagents to the EDAMs and study the properties of EDAMs. Our previous work involved attacking the carbonyl of HKAs by the N1 of isatins (N1 → C4). However, the N1 of isatins attacks the C2 of EDAMs 2−4 rather than the carbonyl group (N1 → C2) (Scheme 1, 1b and 1c). In other words, the previous reaction is a head to tail reaction, whereas this work is a head to head reaction. Remarkably, we find that the alkyl/aryl amino group (N1) has been cleaved to attack the carbonyl group (C2) of isatins to form a new amide bond (compounds 5−7). This protocol demonstrates two important features, first, the amide group (N1) of isatins can attack the C2 of EDAMs and even other electrophilic sites (various carbenium ion). This provides the key information to design new substrates to react with isatins. Second, the alkyl/aryl amino group (N1) of EDAMs can be cleaved to form amide group through attacking the C2 of isatins. Using this property, various enamines may be used in the synthesis of amide compounds via one-pot rather than multistep syntheses. To achieve the optimal conditions, first, isatin 1a (0.5 mmol) and N-monosubstituted EDAM 2a (0.5 mmol) were mixed without any catalysts in different solvents at reflux. The results showed that ethanol is a good solvent and gave the product 5aa with a 33% yield (Table 1, entries 1−4). Then, the basic catalysts, including Et3N, pyridine, and Cs2CO3, and acid catalysts, including AcOH, p-TsOH, and NH2SO3H, were applied in this reaction that was refluxed in ethanol for 24 h (Table 1, entries 5−10). The results revealed that NH2SO3H is the best catalyst and produced the target compound with a 76% yield. We used various mixtures of ethanol and water as the solvent and found that EtOH/H2O = 1:2 was the best solvent and produced the target compound with a yield of 86%. Accordingly, the optimum conditions are EtOH/H2O = 1:2 as solvent and NH2SO3H as catalyst and refluxing for 24 h (Table 1, entry 12). Under optimized conditions, we explored the scope and limitations of the cascade reaction of isatins 1 with various N-substituted EDAMs 2 (Table 2, entries 1−20). The results revealed that the substituted groups of isatins 1 have an influence on the reaction, usually on the electron-withdrawing group (F, Cl, Br), except that the nitro group that benefits the yield of the reaction. The electron-donating group (Me) can decrease the yield of the cascade reaction (Table 2, entries 5− 12 vs 13−16 vs 17−20). The substituted group of the EDAMs 2 only has a slight influence on the yield of the reaction. Overall, all the substrates can be used in the reaction and produce compounds 5 in a good to excellent yields (Table 2, entries 1−20).

entry

solvent

1 2 3 4 5 6 7 8 9 10 11 12 13

EtOH 1,4-dioxane MeCN toluene EtOH EtOH EtOH EtOH EtOH EtOH EtOH/H2O (1:1) EtOH/H2O (1:2) EtOH/H2O (1:3)

catalyst

time (h)

yield (%)

NEt3 pyridine Cs2CO3 AcOH p-TsOH NH2SO3H NH2SO3H NH2SO3H NH2SO3H

24 24 24 24 24 24 24 24 24 24 24 24 24

33 nr trace nr 35 38 nr 52 46 76 79 86 80

a

Reagents and conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (0.05 mmol), solvent (4.0 mL). bIsolated yield based on 2a. nr = no reaction.

Table 2. Synthesis of Quinoline-4-carboxamides 5

entry

1/R/R′

2/R2

5

yield (%)

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

1a/H/H 1a/H/H 1a/H/H 1a/H/H 1b/Br/H 1c/Cl/H 1c/Cl/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1e/NO2/H 1e/NO2/H 1e/NO2/H 1e/NO2/H 1f/Me/H 1f/Me/H 1f/Me/H 1f/Me/H

2a/C6H5 2b/C6H5CH2 2c/p-ClC6H4CH2 2e/p-MeC6H4CH2 2a/C6H5 2a/C6H5 2b/C6H5CH2 2a/C6H5 2b/C6H5CH2 2c/p-ClC6H4CH2 2e/p-MeC6H4CH2 2f/n-Bu 2b/C6H5CH2 2e/p-MeC6H4CH2 2g/p-FC6H4CH2CH2 2f/n-Bu 2a/C6H5 2b/C6H5CH2 2e/p-MeC6H4CH2 2g/p-FC6H4CH2CH2

5aa 5ab 5ac 5ae 5ba 5ca 5cb 5da 5db 5dc 5de 5df 5eb 5ee 5eg 5ef 5fa 5fb 5fe 5fg

86,a 87b 85a 89a 83a 91a 93a 95a 95a 95a 96a 95a 90a 86a 85a 88a 86a 80a 84a 81a 80a

a

1−2 (0.5 mmol), NH2SO3H (0.05 mmol), EtOH/H2O (1:2, 4.0 mL). b1− 2 (1.0 mmol), NH2SO3H (0.1 mmol), EtOH/H2O (1:2, 8.0 mL).

Afterward, various N,N-bis-substituted EDAMs 3 were used in this reaction (Table 3, entries 1−34). The results showed that the substituted groups of isatins 1 have a slight influence on the reaction (Table 3, entries 1−34). All the substituted groups of EDAMs 3, except n-butyl, only had a slight influence on the yield of the reaction. Overall, all the substrates can be B

DOI: 10.1021/acs.orglett.7b03803 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 3. Synthesis of Quinoline-4-carboxamides 6a−b

Table 4. Synthesis of Quinoline-4-carboxamides 7a,b

entry

1/R/R′

3/R1, R2

6

yield (%)

entry

1/R/R′

4/Ar/R1

7

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

1a/H/H 1a/H/H 1a/H/H 1a/H/H 1a/H/H 1a/H/H 1a/H/H 1a/H/H 1a/H/H 1a/H/H 1a/H/H 1a/H/H 1a/H/H 1b/Br/H 1b/Br/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1f/Me/H 1f/Me/H 1f/Me/H 1f/Me/H 1g/H/F 1g/H/F 1g/H/F 1g/H/F 1g/H/F

3a/R1 = R2: p-CF3C6H4 3b/R1 = R2: p-FC6H4(CH2)2 3c/R1 = R2: C6H5CH2 3d/R1 = R2: p-MeC6H4CH2 3e/R1 = R2: p-MeOC6H4CH2 3f/R1 = R2: 2,4-FC6H4CH2 3g/R1 = R2: 3,4-FC6H4CH2 3h/R1 = R2: p-FC6H4(CH2)2 3i/R1 = R2: C6H5(CH2)2 3j/R1 = R2: o-FC6H4(CH2)2 3k/R1 = R2: n-Bu 3l/R1 = p-FBn; R2 = C6H5 3m/R1 = p-FBn, R2 =p-MePh 3c/R1 = R2: C6H5CH2 3k/R1 = R2: n-Bu 3a/R1 = R2: p-CF3C6H4 3b/R1 = R2: p-FC6H4(CH2)2 3c/R1 = R2: C6H5CH2 3e/R1 = R2: p-MeOC6H4CH2 3f/R1 = R2: 2,4-FC6H4CH2 3g/R1=R2: 3,4-FC6H4CH2 3h/R1 = R2: p-FC6H4(CH2)2 3i/R1 = R2: C6H5(CH2)2 3j/R1 = R2: o-FC6H4(CH2)2 3k/R1 = R2: n-Bu 3b/R1 = R2: p-FC6H4(CH2)2 3h/R1 = R2: p-FPh(CH2)2 3j/R1 = R2: o-FPh(CH2)2 3k/R1 = R2: n-Bu 3c/R1 = R2: C6H5CH2 3k/R1 = R2: n-Bu 3h/R1 = R2: p-FC6H4(CH2)2 3o/R1 = Bn, R2 = C6H5 3p/R1 = Bn, R2=p-MePh

6aa 6ab 6ac 6ad 6ae 6af 6ag 6ah 6ai 6aj 6ak 6al 6am 6bc 6bk 6da 6db 6dc 6de 6df 6dg 6dh 6di 6dj 6dk 6fb 6fh 6fj 6fk 6gc 6gk 6gn 6go 6gp

79 89 78 85 79 91 90 86 80 85 92 58 62 80 92 91 90 80 83 86 88 84 81 83 95 85 83 81 91 82 89 75 69 66

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

1a/H/H 1a/H/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1d/F/H 1f/Me/H 1f/Me/H 1f/Me/H 1f/Me/H 1f/Me/H 1f/Me/H 1f/Me/H

4a/o-4/ClC6H4/C6H5CH2 4b/o-FC6H4/C6H5(CH2)2 4a/o-ClC6H4/C6H5CH2 4c/p-FC6H4/C6H5CH2 4d/p-FC6H4/p-ClC6H4(CH2)2 4e/p-ClC6H4/o-FC6H4(CH2)2 4f/p-ClC6H4/p-ClC6H4(CH2)2 4g/o-ClC6H4/p-ClC6H4CH2 4a/o-ClC6H4/C6H5CH2 4b/o-FC6H4/C6H5(CH2)2 4c/p-FC6H4/C6H5CH2 4d/p-FC6H4/p-ClC6H4(CH2)2 4e/p-ClC6H4/o-FC6H4(CH2)2 4f/p-ClC6H4/p-ClC6H4(CH2)2 4h/o-FC6H4/p-FC6H4CH2

7aa 7ab 7da 7dc 7dd 7de 7df 7dg 7fa 7fb 7 fc 7fd 7fe 7ff 7fh

70 68 71 70 62 65 64 66 68 72 79 68 71 70 69

a

Reagents and conditions: 1 (0.5 mmol), 4 (0.5 mmol), NH2SO3H (0.05 mmol), EtOH/H2O (1:2, 4.0 mL). bIsolated yield based on 4.

Figure 2. X-ray crystal structure of 5ab, 6go, and 7fc.

produce intermediates 11. Subsequently, compounds 11 are converted into the intermediates 12 via a ring-opening reaction. Intermediates 13 are formed from theintermediates 12 via another ring-opening reaction. The amino groups of intermediates 13 attack the imine ion to generate the intermediates 14, which then undergo a cyclization reaction to produce intermediates 15. Ultimately, intermediates 15 form compounds 5 and 6 by tautomerization. In conclusion, we have developed a procedure for the simple synthesis of a variety of potentially biologically active quinoline4-carboxamides through a cascade reaction. Using this method, a molecularly diverse quinoline-4-carboxamide library was rapidly constructed with good to excellent yields by simply refluxing a mixture of isatins 1 and 1,1-enediamines 2−4 in ethanol/H2O = 1:2, catalyzed by NH2SO3H. This protocol has two important features, first, the amide group (N1) of isatins can attack the electrophilic sites (maybe various carbenium ions). This provides the key information to design new substrates to react with isatins. Second, the alkyl/aryl amino group (N1) of EDAMs can be cleaved to form amide group by attacking the C2 of isatins. Using this property, various enamines may be used in the synthesis of amide compounds via one-pot rather than multistep synthesis.

a Reagents and conditions: 1 (0.5 mmol), 3 (0.5 mmol), NH2SO3H (0.05 mmol), EtOH/H2O (1:2, 4.0 mL). bIsolated yield based on 3.

used in the reaction and produce good to excellent yields (Table 3, entries 1−34). In order to further investigate the scope and limitations of the cascade reaction, the N,N-bis-substituted EDAMs 4 (EWG = ArCO) were used in this reaction. Unexpectedly, the amide group attacked the carbonyl of the target compounds to form a new pyrrol-2-one ring and produced a novel 2,3-dihydro-1Hpyrrolo[3,4-c]quinolin-1-ones with a moderate yield (Table 4, 1−15). To verify the structure of the quinoline-4-carboxamides, compounds 5ab, 6go, and 7fc were selected as representative compounds and characterized by X-ray crystallography (Figure 2). A hypothetical mechanism of the cascade reaction is shown in Scheme S1 (Supporting Information). Initially, the isatins 1 react with the EDAMs 2 via aza-ene addition to form the intermediates 8. Next, the intermediate compounds 9 are obtained from compounds 8 by tautomerization. Then intermediates 9 obtain one proton to give the intermediates 10. Compounds 10 undergo intramolecular cyclization to C

DOI: 10.1021/acs.orglett.7b03803 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03803. Synthetic procedure, characterization data, copies of 1H, 13 C NMR spectra for compounds 5−7 (PDF) Accession Codes

CCDC 1588348, 1588350, and 1588444 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jun Lin: 0000-0002-2087-6013 Sheng-Jiao Yan: 0000-0002-7430-4096 Author Contributions †

B.-Q.W. and C.-H.Z. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the National Natural Science Foundation of China (Nos. 21662042, 81760621, 21362042, and U1202221) and the Natural Science Foundation of Yunnan Province (2017FA003).

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03803 Org. Lett. XXXX, XXX, XXX−XXX