Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2019, 84, 8160−8167
L‑(−)-Quebrachitol
as a Ligand for Selective Copper(0)-Catalyzed N‑Arylation of Nitrogen-Containing Heterocycles Qifan Zhou,‡ Fangyu Du,‡ Yuanguang Chen,‡ Yang Fu,‡ Wenjiao Sun,‡ Ying Wu,*,† and Guoliang Chen*,‡ ‡
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Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China † Yunnan Institute of Tropical Crops, Jinghong 666100, China S Supporting Information *
ABSTRACT: L-(−)-Quebrachitol (QCT) has been found as a ligand of copper powder for selective N-arylation of nitrogencontaining heterocycles with aryl halides. Furthermore, another potential catalytic system (copper powder/QCT/t-BuOK) was successfully adapted to unactivated aryl chlorides.
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INTRODUCTION N-arylazoles are ubiquitous structural motifs in numerous biologically active compounds, natural products, and pharmaceuticals and also as precursors of versatile N-heterocyclic carbines and auxiliary ligands for transition-metal catalysis.1 Traditional synthetic approaches of N-arylazoles often depend on using highly activated aryl halides (SNAr reactions,2 classical Ullmann-type coupling reactions,3or Buchwald−Hartwig reactions4). Classical Ullmann reactions normally require harsh reaction conditions (high temperature, long reaction time, narrow substrate, and erratic yields).5 However, due to the low cost and toxicity of the copper catalyst, Cu-catalyzed N-arylation is still attractive in synthetic applications. To overcome the drawbacks in classical Ullmann reactions, various modified Ullmann catalytic systems have been reported continuously over the past decades, for example, the use of bidentate ligands, which allowed the coupling reaction to be conducted smoothly under mild conditions6 (Figure 1). However, because many ligands are not commercially available in industrial scale, they seriously hamper their synthetic application.6c Notably, the toxicity and sustainability of these ligands must be taken into consideration for meeting the requirements of green chemistry. On the other hand, quebrachitol (1-L-(−)-2-O-methyl-chiroinositol, QCT, Figure 1) is an optically active inositol with superior water solubility, existing in a variety of plants, and could be used as a chiral source in organic synthesis.7 QCT is mainly extracted from waste water of natural rubber industry by using © 2019 American Chemical Society
Figure 1. Chemical structures of general bidentate ligands and QCT.
Received: April 19, 2019 Published: June 5, 2019 8160
DOI: 10.1021/acs.joc.9b00997 J. Org. Chem. 2019, 84, 8160−8167
Article
The Journal of Organic Chemistry the matured extraction technology.8 Arguably, developing the use of QCT could also contribute to facilitate problem solving in waste water of natural rubber industry. Herein, we discovered that Cu(0)-catalyzed N-arylation could be smoothly carried out under mild conditions with the assistance of QCT. Due to its stable physicochemical properties and good water solubility, QCT could be employed as a green auxiliary ligand in the Ullmann-type reaction, which simultaneously extends the industrial application of natural rubber.
coupling reaction was conducted on a 10 gram scale, and 8.50 g of 3a was obtained in 92% yield (entry 19). With optimized conditions in hand, we explored the scope of the coupling reactions of aryl halides with pyrazole in the presence of Cu powder (10 mol %), QCT (20 mol %), and Cs2CO3 (3.0 equiv), and the results were summarized in Table 2. Notably, the catalytic system could facilitate the coupling reactions of aryl iodides and pyrazole in excellent yields at 80 °C,
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Table 2. Scope with Respect to Aryl Halidesa
RESULTS AND DISCUSSION As described in Table 1, we chose Cu-catalyzed coupling of bromobenzene and pyrazole as model substrates to explore Table 1. Identification of Reaction Conditionsa
entry
Cu (mol %)
base
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19c
CuI (20) CuBr (20) CuCl (20) Cu2O (20) CuSO4 (20) Cu (20) Cu (10) Cu (10) Cu (10) Cu (10) Cu (10) Cu (10) Cu (10) Cu (10) Cu (10) Cu (10) Cu (10) Cu (10) Cu (10)
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K3PO4·3H2O Et3N Cs2CO3 NaHCO3 t-BuOK Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO/H2O (1:1) DMF dioxane dichloroethane toluene ethylene glycol DMSO/H2O (1:1)
56 55 21 trace 0 90 90 75 0 93 0 86 94 88 0 0 0 86 92
a Standard conditions: 1a (0.8 mmol), 2a (1.0 mmol), 20 mol % QCT, solvent (2.0 mL), 100 °C, 10 h, Ar. bIsolated yield. cThe loading of 1a was 10 g.
optimal conditions. Initially, under basic conditions in the presence of CuI, CuBr, CuCl, or Cu2O, only a small quantity of target product 3a was observed, along with the unreacted starting material (Table 1, entries 1−4). With the use of Cu2SO4, no desired product was seen (entry 5). Surprisingly, the C−N coupling product was obtained in 90% yield when the Cu powder was used as the catalyst, and the loading of the catalyst could be reduced to 10 mol % (entries 6 and 7). Further studies revealed a significant effect of bases, with Cs2CO3 or K2CO3 being proved to be optimal in terms of yield (entries 7−12). Subsequent evidence showed that Cs2CO3 has more potential in the coupling reaction of 1-bromo-4-methoxybenzene and pyrazole (data not shown). Polar solvents (DMSO, DMF, and ethylene glycol) favored this reaction, with DMSO/H2O being the most effective (entries 13−18). We postulated that the addition of water promoted oxidation of copper powder into Cu(I) species. In order to investigate its effectiveness, the
a
Reaction conditions: 1 (0.8 mmol), 2a (1.0 mmol), 10 mol % Cu powder, 20 mol % QCT, Cs2CO3 (2.4 mmol), DMSO/H2O (1:1 mL). bIsolated yield. cDMSO (2 mL) as the solvent to avoid hydrolysis of esters.
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DOI: 10.1021/acs.joc.9b00997 J. Org. Chem. 2019, 84, 8160−8167
Article
The Journal of Organic Chemistry
Table 3. Scope with Respect to N-Containing Heterocyclesa
while aryl bromides also proceeded well at higher temperature (100 °C) to afford products in 68−99% yields. Furthermore, electron-rich substitutions on aryl bromides were not conducive and led to lower yields (3a vs 3b). A range of reactive functional groups (e.g., NH2, CHO, COOH, and CN.) was proved to be compatible, and the coupling products (e.g., 3d, 3e, 3h, and 3i) were obtained in excellent yields from corresponding aryl halides and pyrazole. Consequently, this protocol has offered an alternative scheme for the synthesis of highly functional azoles. The reaction also enjoys wide substrate scope with respect to N-heterocycles (Table 3). The coupling reactions also could go smoothly by changing pyrazole with pyrroles, imidazoles, indoles, and benzimidazoles. Not surprisingly, the electronrich aryls were superior to electron-deficient aryls, for example, 3t and 3u with yields of 65 and 95%, respectively. Pyrrole gave the desired compound in moderate yield (54%), which might result from the acidity of pyrrole. Sufficient evidence showed that the reaction with unsymmetrical heterocycles proceeded with regioselectivity.6b,c Accordingly, using asymmetric imidazole afforded two imidazole tautomers 3r and 3s with a ratio of 12:1 in 89% yield. As evidenced by the example presented in Table 3, the catalytic system displayed more regioselectivity than using a CuI system.6c Not surprisingly, the C−N coupling reactions were hindered in steric pyrroles; they explained the fact that 3m was afforded only in 47% and 3n was not observed. In our cases, bifunctional compound 2-mercaptobenzimidazole was selectively S-arylated (3v) without N-arylation (entry 10). 5-Hydroxyindole was selectively N-arylated by providing 3w in excellent yield without O-arylation (entry 11). However, utilizing CuI/L-proline6b gave 3w and 3ah in 65 and 20% yields, respectively (Scheme 1A). For 2-indolecarboxylic acid substrates, N-arylation reactions were readily conducted in excellent yields, from 84 to 98%. According to the reports that pyrrole-2carboxylic acid and 2-picolinic acid could be generally applied as chelating ligands of transition metal,9 we postulated that 2indolecarboxylic acid also acted as an efficient auxiliary ligand of copper, and it accounted for excellent yields. Imidazole could also participate in the C−N coupling reaction, especially the unactivated aryl bromines; for example, 4-bromoanisole, 2bromoanisole, and 3-bromoaniline yielded corresponding desire compounds in moderate yield (3ab, 3ac, and 3ad). Moreover, the sterically hindered 2-methyl-1H-benzo[d]imidazole afforded the product (3ag) only in 54% yield. Inspired by the excellent performance of the Cu/QCT catalytic system, the inert aryl chlorides were also examined for the coupling reactions (Table 4). Regrettably, only a trace of 3a was observed using chlorobenzene and pyrazole as starting materials. After subsequent optimization, the coupling reaction could proceed at 120 °C with the Cu/QCT catalytic system by replacing Cs2CO3 with t-BuOK. The scope of the Cu-catalyzed reaction has been further tested using a wide range of aryl chlorides. The corresponding N-arylazoles were formed in 70− 92% yields in a relatively short time (8−16 h). Apparently, aryl chlorides and aryl bromides could undergo the N-arylation reaction with quantitative conversion except for aryl fluorides (entries 2, 5, and 7). Notably, only a trace (
