Copper(II) Catalyzed Expeditious Synthesis of Furoquinoxalines

Letter pubs.acs.org/OrgLett

Copper(II) Catalyzed Expeditious Synthesis of Furoquinoxalines through a One-Pot Three-Component Coupling Strategy Gunaganti Naresh,† Ruchir Kant,§ and Tadigoppula Narender*,† †

Medicinal and Process Chemistry Division, §Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow-226 031, India S Supporting Information *

ABSTRACT: Microwave assisted one-pot transformation has been developed for the synthesis of biologically significant polysubstituted furoquinoxalines in good to excellent yields through a copper(II) catalyzed three-component coupling of ophenylenediamine, ethylglyoxalate, and terminal alkyne, known as A3-coupling, followed by 5-endo-dig cyclization.

P

The existing methods for the synthesis of quinoxaline fused heterocycles involve multiple steps (Scheme 1) and prefunc-

olycyclic fused nitrogen containing heterocyclic compounds are found in many biologically significant natural products and pharmaceuticals.1 Synthesis of these motifs in a single step through C−C and C−heteroatom bond formation is challenging as well as an emerging field in current organic synthesis. Various domino/cascade reactions have been developed to address this challenge.2 Among these, in recent years, transition metal catalyzed three-component coupling of an aldehyde amine and terminal alkyne (A3-coupling) has gained sizable attention,3 since it allows the fast and short synthesis of highly functionalized heterocycles in a complete atom economic fashion. Distinct transition metals such as gold,3b silver,4 copper,5 and iron6 have been successfully utilized for these transformations in the past decade. In general, A3 coupling (amine, aldehyde, and alkyne) furnishes propargylamines as final products and introduction of additional reactive functionality in aldehyde or amine source could result in the formation of diversified heterocycles.7 Very limited reports are available in the literature in which an aldehyde having another nucleophile5 was used for A3-coupling, whereas no reports were found on an amine with another nucleophile for A3-coupling reactions. With this concept in mind, we planned to synthesize the biologically important furoquinaxaline heterocyclic motifs in a single step by using o-phenylenediamine as an amine source (amine with additional nucleophile) in A3-coupling for the first time. Quinoxaline and its derivatives are an important class of nitrogen heterocycles originating in many natural products and pharmaceuticals and exhibit a broad spectrum of biological activities.8 Quinoxaline derivatives are also significant in materials science such as luminescent materials 9 and polymers.10 Several synthetic methods exist in the literature for the construction of quinoxaline and its derivatives.11−13 Most of them are limited to the synthesis of simple quinoxalines, and very few strategies are available for biologically active complex quinoxaline fused derivatives such as indole,14 furan,15 pyrrole,16 and pyrazole17 heterocycles. © XXXX American Chemical Society

Scheme 1. Approach for the Synthesis of Furoquinoxalines

tionalization of starting materials. Therefore, simple and straightforward strategies from readily available starting materials are highly acceptable. In continuation of our efforts toward the development of new synthetic methodologies for the construction of biologically important heterocycles and carbocycles,18 herein, we disclose an efficient approach for the synthesis of furoquinoxalines from o-phenylenediamines, ethylglyoxalate, and terminal alkynes with a one-pot strategy in good to excellent yields. Our initial attempt for the synthesis of furoquinoxaline began with commercially available o-phenylenediamine (1a), an ethylglyoxalate 50% solution in toluene (2a), phenylacetylene (3a), and copper(II) trifluoromethanesulfonate (10 mol %) as the catalyst at 80 °C in a microwave reactor for 5 min. This resulted in a 50% conversion of the starting materials, and the desired furoquinoxaline (4aaa) was isolated in a 35% yield (Table 1, entry 1). When we introduced toluene as the solvent in the reaction medium, we were pleased to observe the notable Received: July 15, 2014

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After attaining the optimal conditions (Table 1, entry 10), we examined various electron-rich and -deficient substituted ophenylenediamines (1a−h), which afforded the desired furoquinoxalines in good to excellent yields (Scheme 2,

Table 1. Optimization of the Reaction Conditions for the Synthesis of Furoqinoxalinesa

Scheme 2. Substrate Scope of o-Phenylenediamine for the Synthesis of Furoquinaxalines with Optimized Conditionsa entry

catalyst

solvent

temp (°C)

time (min) microwave/ conventional

yieldb (%)

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

Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OAc)2 CuBr2 CuI CuCl

− toluene toluene toluene toluene toluene toluene DCE ACN toluene toluene toluene toluene toluene toluene toluene

80 80 100 100 100 100 110 110 110 110 110 120 110 110 110 110

05/120 05/120 05/120 10/120 05/120 10/120 10/120 10/120 10/120 10/120 15/150 10/120 10/120 10/120 10/120 10/120

35c 50c 55c 55c 62d 70d 70d 55d 50d 87e 85e 85e 40e 25e 0e 0e

a

Conditions: 1a−1h (0.46 mmol), 2a (0.93 mmol), 3a (0.46 mmol), Cu(OTf)2 (20 mol %), Toluene (3 mL); isolated yields in parentheses. # = isolated yields of mixture of two isomers.

a Reaction conditions: 1a (0.46 mmol), 2a (0.93 mmol), 3a (0.46 mmol) catalyst, solvent (3 mL); in microwave vial (2−5 mL) sealed and placed in microwave reactor (450 W); DCE = 1,2-Dichloroethane, ACN = Acetonitrile. bIsolated yields. c10 mol % catalyst loading. d15 mol % catalyst loading. e20 mol % catalyst loading.

4aaa−4haa). The electron-rich diamines gave marginally better yields when compared to electron-deficient diamines (4faa). The reaction of monosubstituted phenylenediamines (1b−f) with terminal alkynes gave a mixture of two separable isomers in an 80:20 ratio with respect to the isolated yields (Scheme 2, 4baa−4faa); however in the case of 3,4-diaminotoluene (1d), an inseparable mixture of 4daa was obtained. We next investigated the scope of the reaction toward the substitution tolerance of terminal alkynes (3b−3o), and the results are summarized in Scheme 3. Both the electron-rich and-withdrawing substituted aromatic alkynes produced the target furoquinoxalines smoothly in high yield. Even the strong electron-withdrawing substituted terminal alkyne 3l (Scheme 3, 4aal) and heteroaromatic terminal alkyne 3n (Scheme 3, 4aan) were successfully utilized to furnish the desired furoquinoxalines in good yields. The reaction between substituted ophenylenediamines (4g−h) and aromatic terminal alkynes (3b−c) gave excellent yields (4gab−4hac). The aliphatic terminal alkyne (3o), however, failed to produce the desired furoquinoxalines (4aao) under similar reaction conditions. Aliphatic terminal alkynes have low boiling points when compared to the aromatic terminal alkynes; due to this reason, they might fail to produce the desired furoquinoxalines at high temperature. When we carried out the same reaction at rt, the o-phenylenediamine and ethylglyoxalate mixture was not soluble and the reaction failed to give furoquinoxaline 4aao. Encouraged by the above results, we focused on synthesizing more structurally diversified furoquinoxalines using noncommercial phenyl acetylenes. We synthesized a few phenyl acetylenes (3n−s) by using known protocols20 and subjected them to the optimized conditions, which resulted in the synthesis of diversified furoquinoxalines in good to excellent yields (Scheme 4, 4aap−4han). A possible reaction mechanism for the formation of furoquinoxalines appears to be tandem C−C bond formation followed by a 5-endo-dig cyclization reaction as outlined in

progress in yield (Table 1, entry 2). The same reaction was carried out with conventional heating at 80 °C for 2 h; however, it was not helpful in increase the yield. We then carried out the experiment with an elevated temperature at 100 °C in a microwave as well as conventional system and found a slight improvement in the yield (Table 1, entry 3). Further improvement in yield (62%) was observed, when we increased the catalyst loading to 15 mol % (Table 1, entry 5). All these preliminary experiments suggested that the amount of catalyst and the temperature play crucial roles in yield improvement. We therefore increased the catalyst loading to 20 mol % and the temperature to 110 °C in the microwave for 10 min; to our delight, we observed remarkable improvement in the yield to 87% (Table 1, entry 10). Other copper salts such as Cu(II) bromide, Cu(OAc)2, CuI, and CuCl were also employed in the reaction medium (Table 1, entries 13−16); however, we found that only Cu(OTf)2 was efficient for this domino strategy. Various solvent systems were also screened, and it was found that toluene was the most effective in the synthesis of the desired furoquinoxaline in high yield. The formation of furoquinoxaline (4aaa) was unambiguously confirmed by various 2D-NMR spectral data and subsequently by the 2DNMR spectral data and single crystal X-ray structure of compound 4aaf (Figure 1).19

Figure 1. ORTEP diagram of compound 4aaf. B

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Scheme 5. Possible Reaction Mechanism for the Tandem A3Coupling and 5-endo-dig Cyclization

Scheme 3. Substrate Scope for the Synthesis of Furoquinaxalines with Terminal Alkynes under Optimized Conditionsa

furoquinoxaline. Further studies, however, are required to confirm the exact reaction mechanism. In conclusion, we have developed a simple, novel, and efficient protocol for the copper(II) catalyzed synthesis of furoquinaxalines from readily available 2-amino substituted anilines, ethyl glyoxalate, and terminal alkynes through tandem A3-coupling followed by a 5-endo-dig cyclization process in a single step to produce good to excellent yields under microwave and also conventional conditions (data not presented). This novel method involves the formation of four new bonds (2C−C, C−N, and C−O) in a cascade pathway.

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ASSOCIATED CONTENT

S Supporting Information *

a

Conditions: 1 (0.46 mmol), 2 (0.93 mmol), 3 (0.46 mmol), Cu(OTf)2 (20 mol %), Toluene (3 mL); isolated yields in parentheses.

General experimental procedure and spectroscopic data of all the compounds; 2D-NMR spectral data for 4aaa, 4aaf; and Xray analysis data for 4aaf. This material is available free of charge via the Internet at http://pubs.acs.org.

Scheme 4. Synthesis of Furoquinaxalines with Diversified Terminal Alkynes under Optimized Conditions

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Authors are thankful to the Director, CDRI, Lucknow, India for constant encouragement for the program on the synthesis of Natural products analogues. We thank Dr. Tejender S. Thakur of the Molecular and Structural Biology Division, CSIR-Central Drug Research Institute for supervising the X-ray data collection and structure determination of a compound (4aaf); G. Naresh is thankful to the CSIR, New Delhi, India for a fellowship and research grant (BSC-0102: THUNDER). This is CDRI communication No.8758.

Scheme 5. Generally, in A3-coupling reactions, the amine (I) reacts with aldehyde (II) and forms the imine which is further transformed to iminium ion A; at the same time the in situ generated copper acetylide B from terminal alkyne and copper(II) trifluoromethanesulfonate attacks the intermediate (A) to produce the propargylamine C.3a The resulting propargylamine C further attacks the ester functionality intramolecularly, leading to the generation of intermediate D. Since intermediate D is easily enolizable in an acidic medium, it provides cyclized intermediate 3-(alkynyl)-3,4-dihydroquinoxalin-2(1H)-one (E) and further cleavage of the metal π-complex occurs followed by oxidation furnishing the target

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