Quinoxalin-4(5H)-Ones by a Metal-Free Sequential Ugi-4CR/Alkyne–Azide Cycloaddition Reaction

SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2020, 31, 73–76 letter 73 en

Syn lett Y.-M. Yan et al. Letter

One-Pot Synthesis of [1,2,3]Triazolo[1,5-a]quinoxalin-4(5H)-ones by a Metal-Free Sequential Ugi-4CR/Alkyne–Azide Cycloaddition Reaction

Yan-Mei Yana 2 4 a R CONHR Hao-Yang Li NH2 1 Min Zhanga R R2CHO N O N3 + Ugi-4CR DMF R1 Rong-Xin Wanga N R3 3 4 MeOH 90 °C a R COOH R NC Chen-Guang Zhou N N Zhen-Xing Ren*b Ming-Wu Ding*c 0000-0002-3464-4774 17 examples 50–92% overall yields Metal-Free One-Pot Fashion a Department of Chemistry, Taiyuan Normal University, High Atom Efficiency Mild Reaction Conditions Jinzhong 030619, P. R. of China b Institute of Applied Chemistry, Shanxi University, Taiyuan 030006, P. R. of China [email protected] c Central China Normal University, Wuhan 430079, P. R. of China [email protected]

Received: 15.10.2019 been proven to be a powerful approach to synthesize het- Accepted after revision: 08.11.2019 erocycles. Published online: 25.11.2019 7 DOI: 10.1055/s-0037-1610737; Art ID: st-2019-l0560-l Sequenced reactions including Ugi/Diels–Alder, Ugi– Heck,8 Ugi/aldol9 and Ugi/intramolecular alkyne–azide cyc- Abstract A convenient and one-pot approach to prepare [1,2,3]triazo- loaddition (IAAC)10–13 have been reported. In our previous lo[1,5-a]quinoxalin-4(5H)-ones by a metal-free sequential Ugi- work, the Ugi/Wittig and Ugi/aza-Wittig sequences were 4CR/alkyne–azide cycloaddition reaction has been developed. The reaction of 2-azidobenzenamines, aldehydes, propiolic acids, and isocya- also utilized to prepare multisubstituted quinoxalin-2(1H)- nides produced the Ugi adducts, which were transformed to the ones, 3,4-dihydroquinazolines, indoles, benzimidazoles, [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones in moderate to good yields 2,3-dihydro-1H-2-benzazepin-1-ones, and so on.14 via alkyne–azide cycloaddition reaction. Various heterocycles which contain 1,2,3-triazole play Key words one-pot, metal-free, [1,2,3]triazolo[1,5-a]quinoxalin- an important role in coordination chemistry, supramolecu- 15 4(5H)-one, Ugi reaction, alkyne–azide cycloaddition reaction lar chemistry, polymer and materials sciences. In addition, Downloaded by: Kevin Chang. Copyrighted material. due to their diverse pharmacological properties, like anti- cancer, antituberculosis, and antibacterial, they are widely Owing to the advantages of its sufficient structural di- studied in medicinal chemistry.16 versity, molecule complexity, high atom economy, and sim- In particular, [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)- ple one-pot operation, multicomponent reactions (MCRs) one and its analogue as fundamental scaffold exists in G- have been found wide application in drug discovery, natural protein-coupled Niacin receptor 109A17 as well as inhibitors products, and diverse heterocyclic scaffolds construction.1 for the benzodiazepine and adenosine receptors.18 Over the In particular, isocyanide-based multicomponent reactions past decades, the broad potential biological activities of (IMCRs) have attracted significant attention in the synthe- [1,2,3]triazolo[1,5-a]-quinoxalin-4(5H)-ones have prompt- sis of diverse heterocycles.2 Among the IMCRs family, the ed significant efforts toward their synthesis. So far, the tra- four-component Ugi reaction (Ugi-4CR) is considered as ditional synthetic method for the construction of [1,2,3]tri- one of the best-known IMCRs, because of its efficiency, di- azolo[1,5-a]quinoxalin-4(5H)-ones suffers from rather versity, and unexplored chemical space.3 Moreover, some harsh conditions and low efficiency starting from 2-nitro- new progress of Ugi reactions such as 1,4-additon Ugi reac- phenylazide by multiple steps (Scheme 1, a).19 In 2012, Cai tion4 and chiral phosphoric acid catalyzed asymmetric Ugi and co-workers developed a highly efficient and simple ap- reaction5 further have promoted the development of IM- proach to construct [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)- CRs. However, the classical Ugi-4CR gives rise to linear pep- ones via a Cu(I)-catalyzed [3+2]/C–N coupling tandem reac- tide adducts rather than a heterocyclic ring by using four- tion from 1-(2-haloaryl)propamides.20 Recently, the re- components of amine, aldehyde, acid, and isocyanide in a search group based on the same strategy for the rapid syn- one-pot fashion.6 In this regard, Ugi post-transformation thesis of diversified [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)- strategy which combines Ugi with other reactions has ones by Ugi-4CR products (Scheme 1, b).21 Copper(I)-cata-

Syn lett Y.-M. Yan et al. Letter lyzed reaction offers an efficient access to [1,2,3]triazo- strates and were used for optimizing the reaction condi- lo[1,5-a]quinoxalin-4(5H)-ones. However, their values are tions (Scheme 2). To our delight, the above four compounds reduced by the employment of transition metals, which were carried out smoothly in methanol at room tempera- causes metal contamination of the products as well.22 In ad- ture for 12 hours, the expected Ugi product 5a precipitated dition, the lack of general methods under metal-free condi- during the reaction and can be obtained in 90% yield after tions for the synthesis of the unique tricyclic core would recrystallization. Our research was initiated with an at- hinder the exploration of the broad potential biological ac- tempted one-pot, metal-free reaction by stirring the mix- tivities. Consequently, there is a continuous need to develop ture for another 12 hours, while the desired product 6a a new, practical, and metal-free synthetic methodology for could not be separated, we speculated that 5a could not [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones to synthetic or- generate 6a at room temperature (Table 1, entry 1). ganic and pharmaceutical chemists. NH2 Cl a) The traditional synthetic method CHO Cl N HN N N3 N 3 steps N COOEt 3 EtOOC 1a 2a MeOH O + COOEt COOH + N O R NO2 O R N O r.t. H NC 12 h N3 b) Cai's work: sequential Ugi 4CR/Cu(I)-catalyzed [3+2]/C–N coupling tandem reaction Ph Ph CHO 1 3a 4a 5a 1 2 R R R NC Ugi-4CR NaN3, CuI C-N coupling CONHR2 + [3+2] N O Cl NH COOH HN 2 R3 R3 N R4 O X N R4 N N O X = I, Br c) This work: metal-free sequential Ugi/IAAC reaction N Ph 2 4 N N NH2 R CONHR R1 2 6a R CHO N O N Ugi-4CR DMF 3 + R1 Scheme 2 Preparation of compound 6a 90 °C 3 N R3 R COOH R4NC N N Scheme 1 Approaches to [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones Table 1 Optimization of the Reaction Conditions

The IAAC reaction has been widely investigated in the Entry Solvent 1 Solvent 2 Temp (°C)a Yield (%)b synthesis of various 1,2,3-triazole-containing heterocycles 1 MeOH MeOH r.t. 0 under mild reaction conditions.23 The combination of Ugi 2 MeOH MeOH 65 0 with IAAC is a practical venue to access numerous highly Downloaded by: Kevin Chang. Copyrighted material. functionalized 1,2,3-containing heterocycles. The Ugi/IAAC 3 MeOH DMF 90 85 sequence has been utilized in the preparation of dihydrotri- 4 MeOH DMSO 90 80 azolo[1,5-a]pyrazinones, triazolobenzodiazepines,10 cyclic 5 MeOH toluene 90 50 11 12 peptoid, macrocyclic peptide mimetic, and triazoloben- 6 MeOH water 90 0 13 zodiazepine-fused diketopiperazine, starting from easily 7 MeOH i-PrOH 90 40 available materials, for instance, 1-azido-2-isocyanoethane, 8 MeOH 1,4-dioxane 90 0 2-azidoacetic acid, 2-azido-2-phenylacetic acid, 2-azido- a For the second step. benzoic acid, and 2-azidobenzaldehyde as a component in b Isolated yields. the Ugi reaction. Continuing our interest in the synthesis of 1,2,3-triazole derivatives via sequential Ugi/IAAC reaction, herein we wish to report a new efficient synthesis of Then the reaction mixture was heated to reflux for an- [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones by a metal-free other 12 hours, unfortunately, no desired product 6a was sequential Ugi 4CR/IAAC reaction starting from 2-azido- detected (Table 1, entry 2). Most likely, the low boiling point benzenamine (Scheme 1, c). To the best of our knowledge, of methanol did not meet the reaction. Subsequently, the there is no report previously on the sequential Ugi/IAAC re- solvent was changed from methanol to DMF, DMSO, tolu- action to prepare [1,2,3]triazolo[1,5- a]quinoxalin-4(5H)- ene, water, i-PrOH, and 1,4-dioxane as the second solvent ones by using 2-azidobenzenamine as amine component in which has a higher boiling point and was heated at 90 °C for the Ugi reaction. a further 1–2 hours without metal catalyst. Fortunately, the In our initial experiment, 2-azidobenzenamine (1a), 4- final product obtained was verified to be [1,2,3]triazo- chlorobenzaldehyde (2a), phenylpropiolic acid (3a) and lo[1,5-a]quinoxalin-4(5H)-one 6a in DMF (85%, Table 1, en- tert-butylisocyanide (4a) were chosen as the model sub- try 3). The reaction performed well by adding DMF instead

Syn lett Y.-M. Yan et al. Letter

of DMSO (80%, Table, entry 4). When toluene and i-PrOH Table 2 Preparation of [1,2,3]Triazolo[1,5-a]quinoxalin-4(5H)-ones 6a were utilized as solvent, relatively low yields were reached R2 CONHR4 (50%, Table 1, entry 5; 40%, Table 1, entry 7). Although pro- NH2 R1 2 longing the reaction time to 12 hours, still some of 5a did R CHO N O N MeOH 3 + R1 not convert completely. No desired product 6a was detected 12r.t. N3 in water and 1,4-dioxane (Table 1, entries 6 and 8). The sol- R3 COOH R4NC 12–24 h 3 3 4 R vent for the IAAC reaction has a notable effect on the reac- 5 tion, and DMF was found to be the best solvent for the reaction. R2 CONHR4 With the optimized conditions in hand (Table 1, entry N O 3), various 2-azidobenzenamines 1, aldehyde 2, propiolic DMF R1 90 °C acid 3, and isocyanide 4 were employed for the one-pot, N R3 metal-free reaction. The reaction was carried out smoothly N N to prepare a high diversity of [1,2,3]triazolo[1,5-a]quinoxal- 6 in-4(5H)-ones 6 (Table 2), and moderate to good yields 1 2 3 4 were achieved with different substituents at the reactants Entry Compd R R R R Yield 6 (%)b (50–92%, Table 2). Good yields of the products were obtained when the aromatic aldehydes substituted by an elec- 1 6a H 4-ClC6H4 Ph t-Bu 85 tron-withdrawing group or 2-azidobenzenamines substi- 2 6b HPhPhc-C6H11 75 tuted by an electron-donating group were utilized (83– 3 6c H 2-ClC6H4 Ph t-Bu 70 90%), whereas no products were obtained when a strong 4 6d H 4-MeC6H4 Ph t-Bu 72 electron-withdrawing group (R2 = NO ) and aliphatic alde- 2 5 6e H 4-O NC H Ph t-Bu 0 hydes were used. 2 6 4 Affected by steric hindrance, moderate yields (6c,m,p,q, 6 6f H 4-ClC6H4 Ph c-C6H11 83 50–72%, Table 2, entries 3, 13, 16, and 17) were reached 7 6g H 4-ClC6H4 Me t-Bu 92 when o-substituted aromatic aldehydes or 4,6-dimethyl-2- 8 6h H n-Pr Ph t-Bu 0 azidobenzenamine were used. Using aliphatic propynoic 9 6i H 4-MeC6H4 Ph c-C6H11 73 acid as one of the reaction components gave good yields of 10 6j 4-Me 4-ClC6H4 Ph t-Bu 90 the products (6g, 92%, Table 2, entry 7). Several heteroaryl 11 6k 4-Cl 4-ClC H Ph t-Bu 77 aldehydes were explored and delivered the desired prod- 6 4 ucts in moderate yields (6r, 6s, 71–72%, Table 2, entries 18 12 6l 4-Me 4-MeC6H4 Me c-C6H11 78 and 19). It is noteworthy that isocyanides have little effect 13 6m 4-Cl 2-ClC6H4 Me c-C6H11 72 on yields. 14 6n 4-Br 4-ClC6H4 Ph t-Bu 75 In conclusion, we have developed a novel approach to 15 6o 4-Br 4-MeC6H4 Me t-Bu 75 prepare [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones in a Downloaded by: Kevin Chang. Copyrighted material. 16 6p 4,6-Me 4-MeC H Ph t-Bu 50 one-pot, metal-free fashion which based on sequential Ugi- 2 6 4 17 6q 4-Cl 2-ClC H Ph t-Bu 68 4CR/IAAC reaction starting from 2-azidobenzenamine.24,25 6 4 The used 2-azido benzenamines, aldehydes, propiolic acids, 18 6r 4-Br Ph t-Bu 71 and isocyanides can be varied broadly, producing the prod- O ucts with four potential points of diversity. The method was 19 6s 4-Br Ph t-Bu 72 practically useful to the synthesis of various [1,2,3]triazo- S lo[1,5-a]quinoxalin-4(5H)-ones in a one-pot fashion under a Reaction conditions: i) MeOH, r.t.,12–24 h; ii) DMF, 90 °C, 1–2 h. metal-free reaction conditions. Moreover, metal-free, easy b Isolated yields based on 2-azidobenzenamines 1. work, short reaction time, atom economy, and good to ex- cellent yields all make it useful in synthetic and medicinal chemistry. Programs of Higher Education Institutions in Shanxi (Grant No. 2019L0775, 2019L0810, 2019L0444), and the College Students’ Inno- vation Program of Taiyuan Normal University (Grant No. CXCY1934).NatioNna SltucieFra onlucen - Funding Information dation o fChina (21572075)

We gratefully acknowledge financial support of this work by the Na- tional Natural Science Foundation of China (Grant No. 21572075), the Supporting Information National Key Research and Development Program of China (Grant No. 2018YFD0200404-10), the Scientific and Technological Innovation Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610737. Supporting InformationSupporting Information

Syn lett Y.-M. Yan et al. Letter

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