Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free C(sp2)−H/N−H Cross-Dehydrogenative Coupling of Quinoxalinones with Aliphatic Amines under Visible-Light Photoredox Catalysis Wei Wei,*,†,‡,§ Leilei Wang,† Pengli Bao,† Yun Shao,‡ Huilan Yue,‡ Daoshan Yang,†,§ Xiaobo Yang,∥ Xiaohui Zhao,*,‡ and Hua Wang† †
School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong, China Qinghai Provincial Key Laboratory of Tibetan Medicine Research and Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Qinghai 810008, China § College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao, 266042, P. R. China ∥ College of Chemistry & Chemical Engineering, Shenyang Normal University, Shenyang, Liaoning 110034, P. R. China
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‡
S Supporting Information *
ABSTRACT: A novel and efficient visible-light-induced C(sp2)−H/N−H cross-dehydrogenative coupling (CDC)amination with both primary and secondary aliphatic amines at room temperature in air is developed. This photocatalytic reaction allows the direct formation of 3-aminoquinoxalin2(1H)-ones via CDC-amination in the absence of any external oxidant added from outside. Preliminary mechanistic studies reveal that the present reaction proceeds through a radical process.
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Scheme 1. Visible-Light-Induced C−H Amination Using Aliphatic Amines
he construction of the C−N bond has long been a fundamentally important pursuit in the synthetic community.1 Recent decades have witnessed considerable progress in this field, with a rapid emergence of numerous elegant amination strategies, including transition-metal-catalyzed Buchwald−Hartwig amination and Ullman amination for building C−N bonds.2 From a synthetic point of view, C−H/ N−H cross-dehydrogenative coupling (CDC) amination represents one of the most straightforward and efficient approaches for the construction of the C−N bond due to its high atom and step economy.3 In this context, the visible-lightphotoredox catalysis has recently been developed as a fascinating technique for C−H/N−H CDC-amination via an aminium radical cation process under mild conditions.4 Among the well-established photocatalytic CDC-aminations, nitrogen coupling partners are generally limited to aromatic amines,5 azoles,6 and electron-poor species7 such as carbamates, sulfonamides, amides, and imides. Aliphatic amines are extremely valuable structural features in natural products and biologically active molecules. Nevertheless, direct C−H/N−H amination with aliphatic amines still remains challenging since many methods for their functionalizations lead to carbon− carbon bond formation adjacent to the nitrogen atom.8 Hitherto, only scarce photocatalytic amination examples have been realized using aliphatic amines as coupling partners.9,10 In 2017, Knowles’ group reported an elegant photodriven protocol for hydroaminations of unactivated olefins with secondary aliphatic amines (Scheme 1a).9 The same year, © XXXX American Chemical Society
Nicewicz’s research group also presented an efficient photocatalytic C−H/N−H amination of activated arenes with primary aliphatic amines (Scheme 1b).10 These two well developed photocatalytic C−H amination methods only involved the utilization of a single type of aliphatic amines (secondary or primary aliphatic amines) as the amination source. Therefore, it is highly desirable to explore a new Received: September 26, 2018
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DOI: 10.1021/acs.orglett.8b03079 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
photocatalytic C−H/N−H amination system applied to both secondary and primary aliphatic amines. With our continuous efforts devoted to photochemical reactions and green organic synthesis,11 herein, we wish to report a new and efficient metalfree visible-light-induced, Eosin Y-catalyzed direct C(sp2)−H/ N−H CDC-amination with both aliphatic primary and secondary amines leading to 3-aminoquinoxalin-2(1H)-ones (Scheme 1c). As a vital class of heterocyclic units, quinoxalin-2(1H)-ones are frequently found in many natural products, pharmaceutical agents, and functionalized materials.12 In particular, 3-aminoquinoxalin-2(1H)-ones are an important subfamily with diverse biological and pharmacological activities such as anticancer,13 antimicrobial,14 antiviral,15 anti-inflammatory,16 antidiabetic,17 and antihypertensive18 properties. Driven by their significant biological activity and pharmacological value, various synthetic approaches have been developed for the synthesis of 3-aminoquinoxalin-2(1H)-ones. Traditional synthetic methods are mainly focused on the assembly of the quinoxalin-2(1H)-one rings and the nucleophilic substitution of halo or other leaving group substituted quinoxalin-2(1H)ones with amines.19 Alternative metal-catalyzed or strong oxidant mediated methods for cross-coupling of quinoxalin-2ones with amines have also been developed.20 Nevertheless, all of these established reactions encountered certain drawbacks, such as the need for extra steps to prepare prefunctionalized starting materials, high reaction temperature, the use of transition metal reagents, or a stoichiometric amount of strong oxidants. Thus, there is still great demand for the development of a simple, mild, convenient, economic, and environmentally friendly strategy to construct 3-aminoquinoxalin-2(1H)-ones. The present metal-free photocatalytic C−H/N−H amination reaction, which can be performed at room temperature in air to give various 3-aminoquinoxalin-2(1H)-ones with moderate to good yields, does not require the use of any transition-metal catalyst and a stoichiometric amount of strong oxidants (Scheme 1c). Contrary to the known 3-aminoquinoxalin-2(1H)-one syntheses, our preliminary mechanistic studies suggest an alternative radical reaction pathway. Our study commenced with the model reaction of 1methylquinoxalin-2(1H)-one (1a) and morpholine (2a) by the use of Ru(bpy)2Cl2 (2 mol %) as a catalyst in DMSO at room temperature under air (Table 1, entry 1). The reaction was carried out under irradiation with 3 W blue LED lamps. To our delight, the desired product 3aa was obtained in 51% yield after 12 h (Table 1, entry 1). Furthermore, other metal-free photocatalysts such as Na2-Eosin Y, Eosin B, Rhodamine B, Acridine Red, Bengal Rose, and Eosin Y were also examined. Among these photocatalysts examined, Eosin Y was demonstrated to be the most effective one to give the desired product 3aa in 81% yield (Table 1, entry 7). Only a trace amount of the desired product was detected in the absence of photocatalyst (Table 1, entry 8). Next, a range of solvents were screened by use of Eosin Y as the catalyst. Among various organic solvents, THF emerged as the most suitable solvent for the reaction, producing the desired product in 82% yield (Table 1, entry 15). Other solvents such as DCE, MeCN, DMF, EtOH, and DME lead to a relatively lower reaction efficiency (Table 1, entries 9−14). Only a trace amount of product was detected when the reaction was carried out in water (Table 1, entry 16). The reaction efficiency was not improved by increasing the amount of Eosin Y to 5 mol % (Table 1, entry 17). Notably, the desired product 3aa was still obtained in 82% yield when
entry
photocatalyst (mol %)
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Ru(bpy)2Cl2 (2) Eosin B (2) Rhodamine B (2) Acridine Red (2) Rose Bengal (2) Na2-Eosin Y (2) Eosin Y (2) − Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (5) Eosin Y (1) Eosin Y (1) Eosin Y (1) Eosin Y (1) Eosin Y (1) Eosin Y (1) Eosin Y (1)
DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO CH3CN 1,4-dioxane DCE DMF EtOH DME THF H2O THF THF THF THF THF THF THF THF
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