Camphorsulfonic Acid-Mediated One-Pot Tandem Consecutive via the Ugi Four-Component Reaction for the Synthesis of Functionalized Indole and 2-Quinolone Derivatives by Switching Solvents

A camphorsulfonic acid-mediated one-pot tandem consecutive approach was developed to synthesize functionalized indole and 2-quinolone derivatives from the Ugi four-component reaction by switching solvents. A reaction of the Ugi adduct in an aprotic solvent undergoes 5-exo-trig cyclization to form an indole ring. In a protic solvent, however, the Ugi adduct undergoes an alkyne-carbonyl metathesis reaction to form a 2-quinolone ring.


■ INTRODUCTION
Indoles and 2-quinolones are important classes of Nheterocyclic compounds present in several natural products 1 and biologically active compounds. 2 In particular, indoles are classified as "privileged structures" in drug discovery. 3 Thus, the development of synthetic methods of indoles has attracted widespread interest from medicinal and organic chemists over the years. The classical methods for indoles are well-known named reactions, 4 including Fischer, 5 Bischler, 6 Reissert,7 Madelung,8 Sundberg,9 Bartoli,10 and Fukuyama. 11 Recently, substituted indoles were prepared from the inter-or intramolecular cycloaddition reactions using diverse functionalized starting materials in the presence of transition-metal complexes 12 or under transition-metal-free conditions. 13 The functionalized 2-quinolone core was also synthesized using classical procedures, including acid-catalyzed Knorr synthesis, 14 base-catalyzed Friedlander synthesis, 15 Ugi−Knoevenagel reaction, 16 enzymatic synthesis, 17 and transition-metalcatalyzed reactions. 18 On the other hand, numerous synthetic procedures have been reported for indoles and 2-quinolone core compounds. Despite these established methodologies, the development of cost-effective, short synthetic routes with readily available starting materials and metal-free, environmentally friendly approaches is desirable. In this manner, isocyanide-based multicomponent reactions (IMCRs) are a better prospect. 19 Among IMCRs, Ugi four-component reactions (U-4CRs) are a highly efficient and versatile synthetic strategy for the preparation of functionalized nitrogen heterocyclic compounds. 20 The Ugi adduct contains different active sites, such as (i) a carbonyl group, (ii) an alkyne moiety for nucleophilic or electrophilic addition, and (iii) an acidic C(sp 3 )−H proton. Our previous work described the post-Ugi transformation for the synthesis of 2-quinolone 20a and 2,5diketopiperazine. 21 In continuation of the study of Ugi adduct, we have interestingly used the Bronsted acids, resulting in fiveand six-membered heterocycles by switching aprotic to protic solvents, respectively. These interesting results encouraged us to investigate further and report herein the synthesis of functionalized indole and 2-quinolone scaffolds using the Ugi-4CR adduct (Scheme 1).

■ RESULTS AND DISCUSSION
Our study begins with the preparation of Ugi adduct 5aaa using the previously reported procedure. 20a Table 1 lists the corresponding results. We started our initial screening with various neat carboxylic acids, but the results were disappointing (entries 1−4). In formic acid, an unidentified polar byproduct formed, and in TFA, cleavage of the amide bond of Ugi adduct 5aaa occurred. 20a On the other hand, using a combination of carboxylic acids with 1,2-dichloroethane (DCE) (entries 5−8), the best yield (57%) was obtained with formic acid (entry 8).
The next screening was with formic acid and different solvents (entries 9−14). Among them, MeOH gave 69% yield (entry 9). Better results were obtained using sulfonic acids rather than carboxylic acids, such as p-toluenesulfonic acid (pTSA) and CSA; among them, CSA in DCE at 120°C gave 80% yield over 3 days (entries 15 and 16). Subsequently, PhCl was then used at 140°C to improve the yield and reduce the reaction time, which provided excellent yield for both pTSA and CSA in 86 and 98% over 20 h, respectively (entries 17 and 18). CSA did not give an attractive yield in toluene and 1,4dioxane compared to PhCl (entries 19 and 20).
Surprisingly, using a protic solvent, such as MeOH, both pTSA and CSA gave the ACM product, 2-quinolone 7aaa, instead of the indole derivatives (entries 21 and 22). In particular, CSA in MeOH gave a high yield over 4 days (entry 23). Other protic solvents, such as EtOH, propanol, and butanol (entries 25−27), gave the corresponding ester derivatives of 2-quinolone 7aaa and a lower yield than MeOH. Eventually, H 2 SO 4 (1.1 equiv) in MeOH gave the ACM product 7aaa in 62% yield. The optimal conditions for indole and 2-quinolone were CSA in PhCl at 140°C for 20 h (entry 18) and CSA in MeOH for 4 days (entry 23), respectively.
The optimized reaction conditions were then applied to the synthesis of indole and 2-quinolone derivatives in a one-pot approach via the Ugi adduct. The corresponding results are presented in Tables 2 and 3. Table 2 lists the substrate scope of the indole derivatives from commercially available aldehydes (2a-y) with 2′-aminoacetophenone (1a) or 2′-aminobenzophenone (1b), aromatic substituted or aliphatic propiolic acid derivatives (the aromatic substituted phenylpropiolic acids (4b, c-d) were synthesized from commercially available terminal alkyne; see the Supporting Information), and cyclohexylisocyanide (3a). First, all four components were mixed in EtOH. After forming the Ugi adduct in 16 h, EtOH was concentrated and dried well. The reaction conditions in Table 1, entry 18, were then applied.
However, 6aaa was obtained in low yield in the one-pot strategy using 1.1 equiv of CSA. The equiv of CSA was manipulated to obtain the best result (Supporting Information). The use of 2.0 equiv of CSA gave 6aaa and 6baa in 93 and 85% yields, respectively, in a one-pot approach. The molecular structures of 6aaa and 6baa were further confirmed by single-crystal X-ray diffraction analysis ( Figure 1). Next, we studied the substituent effects at the ortho, meta, and para benzaldehydes (2b-s). The steric effect of the ortho-positioned electron-donating group (EDG) or electron-withdrawing group (EWG) benzaldehyde derivatives resulted in a lower yield than the corresponding meta-and para-positioned derivatives, excluding the ortho-F derivative 6aha.
2-Quinolone analogues were next examined, and the corresponding results are presented in Table 3. In the onepot approach, 2.5 equiv of CSA in MeOH over 4 days was the best condition to synthesize the 2-quinolone derivative 7aaa (75%) (Supporting Information). The structure of 7aaa was further confirmed by single-crystal X-ray diffraction analysis ( Table 3).
The steric hindrance of ortho-positioned EDG or EWG benzaldehydes plays an important role in the ACM reactions, which produced a higher yield than at the meta and para positions. The Thorpe-Ingold effects can explain these experimental results (Supporting Information). In contrast, the meta-F benzaldehyde derivative 7aia gave the highest yield, 96%, among the phenylpropiolic acids, which Thorpe-Ingold effects could not explain. In a previous report, the parapositioned EDG at the phenylpropiolic acid gave the best yield, 20a which reflects on 7aec (94%) and 7ahc (96%).
The para-positioned EWG at the phenylpropiolic acid gave no ACM products, such as 7aed and 7ahd, even though a higher temperature and longer reaction time were used. The EWG suppressed the nucleophilicity of the alkyne toward the carbonyl group. In that case, the intermediate of the Ugi adduct (53−60%) was isolated, and the amide bond of the Ugi adduct was cleaved (2.0−3.5%) with the cyclohexyl amide group intact. These results showed that methanolysis of cyclohexyl amide occurs after the ACM reaction or simultaneously, and the methanolysis under these reaction conditions could not be controlled for all other substrates.
Scheme 2 presents a plausible mechanism for the indole and 2-quinolone from the Ugi adduct 5aaa based on the experimental results. In general, the Bronsted acids dissociate into proton H + and its conjugate base. However, in the nonpolar aprotic solvent, the charge separation is not very effective. Therefore, the CSA approaches the Ugi adduct through H-bonding, resulting in the conjugate base of CSA formed simultaneously, abstracting the sp 3 acidic proton, stabilizing as enol II. Subsequent nucleophilic attack on the carbonyl carbon formed a five-membered indoline ring III. 21,22 Finally, the desired product 6aaa was produced by the elimination of water and cyclohexyl isocyanate through a sixmembered transition state. The water molecule was eliminated first when RCH 3 , resulting in the formation of an exocyclic double bond 6aga-int IV, which was further confirmed by single-crystal X-ray diffraction analysis ( Figure 2). Next, the indole derivative was formed through a six-membered transition state.
In the polar protic solvents, the charge separation of CSA is favored. The dissociated conjugate base of CSA was strongly solvated by methanol through hydrogen bonding, and the protons protonated the carbonyl oxygen V, which enhanced the electrophilicity of the carbonyl carbon. Subsequent intramolecular nucleophilic addition from the alkyne resulted in the formation of cation, which was neutralized with methanol VI. The protonation of tertiary benzylic alcohol was eliminated as loss of water and the formation of oxonium ion VII. The eliminated water attacked the oxonium ion to Table 3. One-Pot Synthesis of 2-Quinolone Derivatives via Ugi-4CR

ACS Omega
http://pubs.acs.org/journal/acsodf Article give the ACM product. Simultaneously, cyclohexyl amide was cleaved by methanolysis through the protonation of carbonyl oxygen, resulting in the formation of the desired product 7aaa. 23

■ CONCLUSIONS
In conclusion, we have developed a method to synthesize fiveand six-membered nitrogen-containing heterocycles, such as indole and 2-quinolone derivatives. The strategy involved a metal-free, one-pot reaction via an Ugi adduct with camphorsulfonic acid by switching the solvent from readily available starting materials. Moreover, easy workup and purification, air and moisture tolerance, and good to excellent yields were achieved.

■ EXPERIMENTAL SECTION
General Information. All reagents were commercial and used without further purification unless otherwise indicated. All reactions were monitored by TLC using precoated aluminum sheets of silica gel 60 F 254 , which were analyzed using iodine, UV light, and alkaline KMnO 4 . Melting points were recorded in open capillary tubes using a melting point apparatus MP-1D (Fargo Instruments) and are uncorrected.
Infrared spectra were recorded using a PerkinElmer FT/IR spectrometer. 1 H NMR spectra and 13 C NMR spectra were obtained at 400 and 101 MHz, respectively, using a Bruker NMR spectrometer. Chemical shifts are expressed in parts per million (ppm) and referenced to CDCl 3 (δ = 7.26 ppm for 1 H and 77.16 ppm for 13 C) TMS as the internal standard. Signal description: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplet, qd = quartet of doublet, qt = quartet of triplet, td = triplet of doublet, tt = triplet of triplet, ddd = doublet of doublet of doublet, and tdd = triplet of doublet of doublet.