Rh(III)-Catalyzed C(8)–H Functionalization of Quinolines via

Article Cite This: J. Org. Chem. 2018, 83, 12702−12710

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Rh(III)-Catalyzed C(8)−H Functionalization of Quinolines via Simultaneous C−C and C−O Bond Formation: Direct Synthesis of Quinoline Derivatives with Antiplasmodial Potential Ritika Sharma,† Rakesh Kumar,† Rohit Kumar,† Pooja Upadhyay,‡ Dinkar Sahal,‡ and Upendra Sharma*,†

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†

Department of Natural Product Chemistry & Process Development, and Academy of Scientific and Innovative Research, CSIR-Institute of Himalayan Bioresource Technology Palampur, Himachal Pradesh 176061, India ‡ Malaria Drug Discovery Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India S Supporting Information *

ABSTRACT: Here, a facile and efficient protocol for the synthesis of 3-hydroxyquinolin-8-yl propanoates via Rh(III)-catalyzed C(8)−H activation of 2-substituted quinolines has been developed. The reaction proceeds via C(8)−H activation, functionalization with acrylates, followed by intramolecular migration of the oxygen atom from quinoline N-oxides to the acrylate moiety. In this approach, N-oxide plays a dual role of a traceless directing group as well as a source of an oxygen atom for hydroxylation. This catalytic method involves simultaneous formation of new C−C and C−O bonds and is applicable only for C2-substituted quinolines. A catalytically competent five-membered rhodacycle has been characterized, thus revealing a key intermediate in the catalytic cycle. In silico docking studies against Falcipan-2 have revealed that 3a, 3b, 3g, and 3m have better scores. In vitro evaluation of selected compounds against CQ-sensitive pf 3D7 and CQ-resistant pf INDO strains provided evidence that 3d (IC50 13.3 μM) and 3g (IC50 9.5 μM) had good promise against Plasmodium falciparum in the in vitro culture. Compound 3g was found to be the most potent on the basis of both in vitro antiplasmodial activity [IC50 9.5 μM (Pf 3D7) and 11.9 μM (Pf INDO), resistance index 1.25] and in silico studies.

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INTRODUCTION During past few decades, C−H activation has been used as a key synthetic strategy for assembly of complex organic molecules.1 In this direction, the directing group approach bears great potential for proximal as well as distal C−H bond functionalization.2 Ideally, the directing group should either be an integral part of the substrate or be utilized during transformation to minimize reaction steps and to achieve the full atom economy. The prevalence of a N-O directing group in C−H bond activation has been shown to achieve analogous goals with better efficiency and oxygen atom transfer for postfunctionalization. Shin and co-workers designed a Aucatalyzed α-oxo carbenoid-mediated, concurrent tandem catalysis where N-O acts as nucleophile as well as oxygen atom donor.3,4 Similarly, Li’s group developed an Ir-catalyzed addition−elimination method for oxygen atom transfer (OAT).5 Pyridine/quinoline/tert-amine N-oxide are known to undergo OAT in the presence of Au,6 Ir,7,8 Ru,9 or Rh8,10−13 metal complexes (Figure 1a), and the fate of N-oxide in these © 2018 American Chemical Society

reactions is related to its use as a directing agent as well as oxygen atom donor. Owing to its importance in natural products,14 medicinal15−19 and material chemistry,20−23 quinoline heterocycle has gained recognition as a remarkable construction motif for further developments. Achieving the site-selective C−H bond functionalization of quinolines is most desirable in the current scenario, and a significant number of processes are uncovered in this direction, particularly at C224−29 and C8 positions.30 In recent years, many efforts have been devoted for C8 functionalization of quinoline using N-O as the directing group31−33 as well as a source of the oxygen atom for further transformation.34 Our group has a long-standing interest in the development of methodologies for functionalization of quinoline.35−37 In this regard, we have recently reported the Rhcatalyzed, C8 olefination35 and alkylation36 methodologies Received: August 11, 2018 Published: September 13, 2018 12702

DOI: 10.1021/acs.joc.8b02042 J. Org. Chem. 2018, 83, 12702−12710

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The Journal of Organic Chemistry

Figure 1. N-Oxide directing-group-assisted C−H activation, followed by oxygen atom transfer.

Scheme 1. C8-Selective Olefination of 2-Methyl-Substituted Quinoline N-Oxide

Table 1. Optimization Studya

solvent (0.5 mL) time (h) temp (°C) NMR yield % 3a (3x)b,c

entry

catalyst (mol %)/ cocatalyst (mol %)

additive (mol %)

1 2 3 4 5 6 7 8 9 10 11 12

[RhCp*Cl2]2 (5)/AgSbF6 (20) [RhCp*Cl2]2 (5)/AgSbF6 (20) [RhCp*Cl2]2 (5)/AgSbF6 (20) [RhCp*Cl2]2 (5)/AgSbF6 (20) [RhCp*Cl2]2 (5)/AgSbF6 (20) [RhCp*Cl2]2 (5)/AgSbF6 (20) [IrCp*Cl2]2 (5)/AgSbF6 (20) [RhCp*Cl2]2 (10)/AgSbF6 (40) [RhCp*Cl2]2 (5) [RhCp*Cl2]2 (5)/AgSbF6 (20) [RhCp*Cl2]2 (5)/AgSbF6 (20) [RhCp*Cl2]2 (5)/AgSbF6 (20)

Cu(OAc)2·H2O (100)/CH3CO2H (100) Cu(OAc)2 (50)/CH3CO2H (100) Cu(OAc)2 (50)/CH3CO2H (100) Cu(OAc)2 (50)/CH3CO2H (100) Cu(OAc)2 (50)/CH3CO2H (100) Cu(OAc)2 (50)/CH3CO2H (100) Cu(OAc)2 (50)/CH3CO2H (100) Cu(OAc)2 (50)/CH3CO2H (100) Cu(OAc)2 (50)/CH3CO2H (100) Cu(OAc)2 (50) CH3CO2H (100) Cu(OAc)2 (50)/CH3CO2H (100)

DCE DCE DCE pivalic acid 1,4-dioxane toluene toluene toluene toluene toluene toluene toluene

24 24 24 24 24 24 24 24 24 24 24 15

100 100 90 90 90 90 90 90 90 90 90 90

27 (46) 32 (39) 37 (42) 43 (27) 50 (50) 55 (39) 25 (12) 37 (18) traces (traces) 31 (47) traces (traces) 67 (30)

a

Reagents and conditions: 1a (0.15 mmol), 2a (0.10 mmol). bYield determined by NMR analysis of crude reaction mixture using TCE as the internal standard. cOlefinated product yield in parentheses. DCE = dichloroethane, TCE = 1,1,2,2-tetrachloroethane.

using N-O as a traceless directing group. During the course of our C8 olefination35 study, comparatively less yield was observed in the reaction of 2-substituted quinolines with acrylates due to the formation of unidentified side products which are now characterized unambiguously as 3-hydroxyquinolin-8-yl propanoates. Although simultaneous C(8)−H activation of quinoline N-oxides followed by N-oxide oxygen atom transfer leading to a carbonyl functional group is reported,6−9,11−13 N-oxide oxygen atom transformation into a hydroxyl moiety in this type of reaction is still awaited. Here, we report a new strategy for the synthesis of 3hydroxyquinolin-8-yl propanoates from quinoline N-oxides and acrylates via Rh(III)-catalyzed C(8)−H activation of 2substituted quinoline N-oxides (Figure 1b).

characterized unambiguously as 3-hydroxyquinolin-8-yl propanoates with the help of 1-D, 2-D NMR and ESI-MS studies.38 To the best of our knowledge, N-oxide oxygen atom transformation into a hydroxyl moiety in this type of reaction is not reported until now. Further, to optimize this reaction, 2-phenylquinoline Noxide (2a) and ethyl acrylate (1a) were chosen as the standard substrates (Table 1). Optimization of the amount of Cu(OAc)2 and reaction temperature revealed that use of 50 mol % of Cu(OAc)2 and 90 °C reaction temperature resulted in a slight increase of yield (Table 1, entries 2 and 3). In the solvent screening, toluene was found to be the best solvent (Table 1, entries 4−6). Increase in the catalyst loading decreased the product yield to 37% (Table 1, entry 8). Various acids were also tested to improve the yield of the desired product. Control experiment in the absence of acetic acid, Cu(OAc)2, or AgSbF6 proved detrimental for the product yield (Table 1, entries 9−11). Variation in different metal catalysts was not found to be fruitful for the current reaction. Gratifyingly, using 0.1 mmol of 2a and 0.15 mmol of 1a in the presence of 5 mol % of [RhCp*Cl2]2/20 mol % of AgSbF6,

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RESULTS AND DISCUSSION During the course of exploration of the substrate scope of our earlier work on C8-selective olefination,35 we found that 2methyl-substituted quinoline N-oxide provides some unexpected product in 30% yield along with desired olefinated product (Scheme 1). Later, this side product was isolated and 12703

DOI: 10.1021/acs.joc.8b02042 J. Org. Chem. 2018, 83, 12702−12710

Article

The Journal of Organic Chemistry Table 2. Substrate Scopea

a Reagents and conditions: 1 (0.10 mmol), 2 (0.15 mmol), [Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %), Cu(OAc)2 (50 mol %), acetic acid (100 mol %), toluene (0.5 mL), 90 °C, 15 h. The C8 olefinated quinoline was observed as a side product.

Scheme 2. Labeling Experiments

Scheme 3. Oxygen Atom Transfer Reaction

Reaction of 2-methylquinoline N-oxide with methyl/ethyl/ butyl acrylate afforded 3h−j with 59−63% isolated yields. 2Methyl 6-hydroxyquinoline reacted well with butyl acrylate under developed reaction conditions, yielding the desired product in 45% isolated yield. 2-Methyl 6-nitroquinoline Noxide as well as 2-methyl 6-bromoquinoline provided 3l,m in 54 and 57% isolated yields, respectively. 2-Methyl 7-chloro with ethyl/butyl acrylate does not affect the product formation under developed reaction conditions, affording 3n,o in 42 and 45% isolated yields, respectively. To understand the reaction mechanism, preliminary experiments were carried out. The treatment of 2a under the standard reaction conditions in the absence of 1a but in the presence of CD3OD led to the recovery of the starting material

50 mol % of Cu(OAc)2/100 mol % of CH3COOH, in toluene as a solvent at 90 °C for 15 h gave the final product in 67% isolated yield along with 30% olefinated product (Table 1, entry 12). To demonstrate the generality of the reaction, we started the investigation of the substrates for this transformation, and a series of quinoline N-oxides as well as acrylates (Table 2) were studied. Substitution at the 2-position of quinoline N-oxide is necessary for this reaction to take place. 2-Phenylquinoline Noxide with ethyl acrylate yielded product 3a in 65% isolated yield. 2-Phenyl, 4-methylquinoline N-oxide with ethyl acrylate afforded 3b in 57% yield. Ortho-, meta-, or para-substituted 2phenylquinoline N-oxide provided 3c−3g in moderate yields. 12704

DOI: 10.1021/acs.joc.8b02042 J. Org. Chem. 2018, 83, 12702−12710

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The Journal of Organic Chemistry Scheme 4. Synthesis of a Rhodacycle and Its Use as Catalyst

with 63% incorporation of deuterium at the C8 position (Scheme 2). These experiments reveal the reversible nature of carbometalation at the C8 position of quinoline. To confirm the oxygen atom source, a standard reaction was carried out in the presence of H2O18 (5 equiv) (Scheme 2). LC-MS analysis of the isolated product revealed no O18-labeled product, confirming the intramolecular transfer of oxygen atom from Noxide to acrylate. In continuation to confirm the progression of the OAT and the C−H activation, the coupling of 1a and 2a was conducted in the presence of 2-methylquinoline (Scheme 3). Both 1H NMR and LC-MS analyses of the reaction product established 3a as the final product with no substitution on 2-methylquinoline. This result explains the improbability of generation of rhodium α-oxo carbene intermediate via direct OAT to acrylate.39−43 Consequently, the C−H activation occurs prior to the OAT (Scheme 3). To probe the active intermediate in the reaction, a fivemembered cyclometalated rhodacycle A was synthesized by treating 2a with [Cp*RhCl2]2 and NaOAc (Scheme 4).8,35,44 Although we had already reported the formation of a fivemembered rhodacycle with quinoline N-oxide, the structure of complex A was confirmed by HRMS and NMR spectroscopy. Complex A was found to be reactive as a catalyst for the title reaction, affording 3a in 66% yield (Scheme 4). These experiments indicate that complex A could be an active species in the current reaction. On the basis of preliminary mechanistic studies and precedent literature, a mechanism has been proposed which is analogous to the C(8) olefination pathway proposed by us previously.35 Here, the cycle initiated with the cleavage of C(8)−H bond to form a five-membered rhodacycle (II) followed by coordination of olefin, leading to generation of III and further migratory insertion across the Rh−C bond to provide intermediate IV. Reductive elimination might provide the intermediate V. Intermediate V can lead to the formation of intermediate VI via reinsertion of an olefin in intramolecular fashion across the Rh−H bond, which can provide the hydroxylated product 3a via elimination of the Rh(I) species followed by hydrolysis with acid. In another pathway, intermediate V can also provide olefinated product through reductive elimination of Rh(I) species. In both cases, the active catalytic species Rh(III) is regenerated by oxidation with Cu(OAc)2 (Scheme 5). The exact reason for the requirement of C2-substituted quinoline N-oxide in this reaction is still unknown, but this might be due to the steric hindrance caused

Scheme 5. Proposed Reaction Mechanism

by methyl/phenyl groups present at the C2-position of quinoline N-oxide.

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DOCKING ANALYSIS In silico studies were performed on the synthesized compounds. Falcipain-2 protein (PDB I′-D-3BPF) was used to carry out the in silico evaluation. The studies revealed that four (3a,b, 3g, and 3m) of the synthesized compounds had better docking scores compared to those of the standard compound choloroquine (CQ). After complete analysis, it was found that phenyl substituents at the C2-position (Table 3, 3a) enhance the interaction of compounds with protein as compared to the methyl substituent at the 2-position (Table 3, 3j,l, m−o). In continuation, ortho-, meta-, or para-substituted phenyl groups at the 2-position were analyzed (3b−g), and it was concluded that the electron-donating group at the paraposition of 2-substituted phenyl was the most suitable. Compound 3g was found to be the most potent against the Falcipain-2 protein with a docking score of −5.446 (Table 3). The 3-D and 2-D interactions of compound 3g are shown in Figure 2. In silico studies revealed that compound 3g shows hydrogen bond interactions with HIS 174 and GLN 36 (Figure 2), whereas the standard CQ shows hydrogen bond interactions with amino acid ASN 173. 12705

DOI: 10.1021/acs.joc.8b02042 J. Org. Chem. 2018, 83, 12702−12710

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The Journal of Organic Chemistry

recorded on Water Q-ToF-Micro Micromass. Copies of 1H and 13C NMR can be found in the Supporting Information. Nuclear magnetic resonance spectra were recorded either on a Bruker-Avance 600 or 300 MHz instrument. All 1H NMR experiments are reported in parts per million (ppm) and were measured relative to the signals for residual chloroform (7.26) and acetone (2.04) in the deuterated solvents. All 13C NMR spectra were reported in ppm relative to deuterated chloroform (77.23) and acetone (29.35, 205.41), and all were obtained with 1H decoupling. IR was analyzed by a Shimadzu IRPrestige-21 with a ZnSe single reflection ATR accessory. General Procedure for C8 Functionalization of 2-Substituted Quinoline N-Oxides with Acrylates. To an oven-dried screw cap reaction vial charged with a spinvane magnetic stir bar were added [Cp*RhCl2]2 (5 mol %) and AgSbF6 (20 mol %). Depending on the physical state of the 2-substituted quinoline N-oxide (0.1 mmol) and acrylate (0.15 mmol), solid compounds, Cu(OAc)2 (50 mol %), were weighed along with the other reagents, whereas liquid reagents, AcOH (100 mol %), were added by microliter syringe; toluene was added by a laboratory syringe. The reaction vial was closed with the screw cap and kept for vigorous stirring on a preheated oil bath or heating block at 90 °C for 15 h. After completion, the reaction mixture was extracted with dichloromethane (DCM). The DCM layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography using silica gel (230−400 mesh size) and n-hexane/ EtOAc as eluent. Characterization Data. Ethyl 3-Hydroxy-3-(2-phenylquinolin-8yl)propanoate (Table 2, Entry 3a): brownish oil, yield = 20.80 mg (65%), isolated from flash chromatography (20% EtOAc/n-hexane); 1 H NMR (300 MHz, C3D6O) δ 8.44 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 7.6 Hz, 2H), 8.15 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.56 (td, J = 12.1, 11.2, 6.9 Hz, 4H), 6.24 (dd, J = 9.3, 3.7 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.17 (dd, J = 14.7, 3.8 Hz, 1H), 2.79 (dd, J = 14.8, 9.2 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, C3D6O) δ 171.6, 155.6, 145.4, 142.0, 139.5, 138.2, 130.1, 129.3, 127.7, 127.7, 127.3, 127.0, 126.7, 118.7, 68.5, 60.2, 44.6, 14.1; IR (ZnSe) νmax (cm−1) 2976, 2929, 1728, 1598, 1564, 1499, 1369, 1280, 1153, 1024, 839, 767; HRMS (ESI-TOF) m/z calcd for C20H20NO3 [M + H]+ 322.1438, found 322.1421. Ethyl 3-Hydroxy-3-(4-methyl-2-phenylquinolin-8-yl)propanoate (Table 2, Entry 3b): yellow oil, yield = 19.0 mg (57%), isolated from flash chromatography (20% EtOAc/n-hexane); 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J = 6.9 Hz, 2H), 7.95 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 7.67 (d, J = 6.6 Hz, 1H), 7.55 (d, J = 6.9 Hz, 4H), 6.62 (brs, 1H, OH), 5.75 (s, 1H), 4.18 (d, J = 6.0 Hz, 2H), 3.25 (dd, J = 14.7, 8.1 Hz, 1H), 3.11 (dd, J = 15.0, 5.4 Hz, 1H), 2.79 (s, 3H), 1.26−1.24 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 171.8, 155.0, 146.2, 145.8, 139.4, 138.9, 129.6, 129.0, 127.7, 127.5, 127.3, 125.8, 123.3, 119.4, 72.2, 60.5, 44.5, 19.5, 14.2; IR (ZnSe) νmax (cm−1) 3524, 2980, 1729, 1600, 1560, 1454, 1349, 1271, 1156, 1029, 763, 691; HRMS (ESI-TOF) m/ z calcd for C21H22NO3 [M + H]+ 336.1594, found 336.1575. Ethyl 3-(2-(2-Fluorophenyl)quinolin-8-yl)-3-hydroxypropanoate (Table 2, Entry 3c): brown oil, yield = 17.2 mg (51%), isolated from flash chromatography (23% EtOAc/n-hexane); 1H NMR (300 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H), 7.94−7.84 (m, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.48−7.35 (m, 2H), 7.25−7.23 (m, 1H), 7.19−7.12 (m, 1H), 5.68−5.66 (m, 1H), 4.09−4.04 (m, 2H), 3.09−3.03 (m, 2H), 1.18−1.12 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 171.8, 160.92 (d, JCF = 249.8 Hz), 152.2, 145.5, 138.9, 138.0, 131.52 (d, JCF = 9.0 Hz), 131.20 (d, JCF = 3.0 Hz), 128.0, 127.7, 127.3, 126.9, 126.8, 124.97 (d, JCF = 3.0 Hz), 122.17 (d, JCF = 8.3 Hz), 116.70 (d, JCF = 22.5 Hz), 71.6, 60.6, 44.2, 14.2; IR (ZnSe) νmax (cm−1) 3450, 2981, 1729, 1598, 1487, 1446, 1369, 1267, 1155, 1028, 841, 802, 758; HRMS (ESI-TOF) m/z calcd for C20H19FNO3 [M + H]+ 340.1343, found 340.1331. Ethyl 3-(2-(3-Chloro-4-methylphenyl)quinolin-8-yl)-3-hydroxypropanoate (Table 2, Entry 3d): brown solid; yield = 19.6 mg (53%), isolated from flash chromatography (30% EtOAc/n-hexane); 1 H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.97−7.91 (m, 2H), 7.79−7.71 (m, 2H), 7.54−7.49 (m, 1H), 7.41 (d,

Table 3. Antiplasmodial Activity quinolines

docking score

IC50 Pf INDO (μM)

IC50 Pf 3D7 (μM)

RI (Pf INDO/ Pf 3D7)

CQ 3a 3b 3c 3d 3e 3f 3g 3j 3l 3m 3n 3o

−4.865 −5.18 −4.965 −4.673 −4.816 −4.436 −3.287 −5.446 −4.6 −4.595 −5.017 −4.846 −4.783

0.5 45.1 34.3 47.1 27.1 >71.1 36.8 11.9 >87.06 >74.1 >82.2 66.5 >77.8

0.04 24.6 27.5 28.3 13.3 51.2 27.3 9.5 42.5 31 >82.2 61.4 62.2

12.5 1.83 1.25 1.66 2.03 >1.39 1.35 1.25 >2.05 >2.39 >1 1.08 >1.25

In Vitro Antiplasmodial Activity. After docking analysis, the 12 selected compounds were further subjected for evaluation of in vitro antiplasmodial activity against blood stage P. falciparum in culture. In order to determine resistance indices (RI), this assay was carried out against both CQsensitive Pf 3D7 and CQ-resistant Pf INDO strains using the microtiter plate based SYBR Green assay. As shown in Table 3, two molecules (3d and 3g) showed IC50 below 15 μM against Pf 3D7. The results show that compound 3g with IC50 9.5 μM against pf 3D7 and 11.9 μM against pf INDO and a RI of 1.25 is the most promising among the evaluated examples. A comparison of the in silico and in vitro results (Table 3) revealed that compound 3g showed the best promise in both in silico evaluation and in vitro antiplasmodial assay, whereas other compounds did not show such a correlation. Further, it was noteworthy that whereas chloroquine showed a resistance index of 12.5, for most of other compounds, this value was around 1.

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CONCLUSION A rhodium-catalyzed direct C(8) alkylation of 2-substituted quinoline N-oxides by reaction with acrylates has been developed. In this reaction, rhodium was found to not only catalyze the C−H bond activation but was also playing a critical role in O atom migration to afford the final product. Interestingly, both in silico docking studies using protein Falcipan-2 (3BPF) and in vitro studies done on P. falciparum culture in human red blood cells showed the most promise [IC50 (μM) 9.5 (Pf 3D7) and 11.9 μM (Pf INDO) for compound 3g]. Although chloroquine showed a resistance index of 12.5, most of the compounds designed and synthesized in this study showed a resistance index of ∼1.

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EXPERIMENTAL SECTION

General Consideration. Unless otherwise stated, all reactions were carried out under air atmosphere in screw cap reaction vials. All solvents were bought from Aldrich in a sure-seal bottle and used as such. All chemicals were bought from Sigma-Aldrich, Alfa-Aesar, and TCI. For column chromatography, silica gel (230−400 mesh) from Merck was used. A gradient elution using n-hexane and ethyl acetate was performed based on Merck aluminum TLC sheets (silica gel 60 F254). Analytical Information. The melting points were recorded on a Bronsted Electrothermal 9100. All isolated compounds are characterized by 1H NMR, 13C NMR, ESI-MS, and IR. In addition, all the compounds are further characterized by HRMS. Mass spectra were 12706

DOI: 10.1021/acs.joc.8b02042 J. Org. Chem. 2018, 83, 12702−12710

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Figure 2. 2-D and 3-D interactions of 3g. J = 7.8 Hz, 1H), 5.96 (s, 1H), 5.82 (s, 1H), 4.24−4.17 (m, 2H), 3.19−3.15 (m, 2H), 2.48 (s, 3H), 1.30−1.25 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 171.9, 154.2, 145.7, 139.3, 138.2, 138.0, 137.8, 135.2, 131.5, 127.9, 127.7, 127.1, 126.3, 125.5, 118.3, 71.2, 60.6, 44.1, 20.0, 14.2; IR (ZnSe) νmax (cm−1) 3470, 2957, 2919, 1717, 1598, 1490, 1431, 1369, 1177, 1157, 1195, 836, 808, 763; HRMS (ESI-TOF) m/z calcd for C21H21ClNO3 [M + H]+ 370.1204, found 370.1201. Ethyl 3-Hydroxy-3-(2-(4-methoxyphenyl)quinolin-8-yl)propanoate (Table 2, Entry 3e): yellow oil, yield = 22.1 mg (63%) isolated from flash chromatography (22% EtOAc/n-hexane); 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.90 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 6.6 Hz, 1H), 7.49−7.47 (m, 1H), 7.08 (d, J = 8.7 Hz, 2H), 6.46

(brs, 1H, OH), 5.75 (s, 1H), 4.23−4.15 (m, 2H), 3.92 (s, 3H), 3.24 (dd, J = 15.0, 8.1 Hz, 1H), 3.11 (dd, J = 15.0, 5.4 Hz, 1H), 1.28−1.24 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 171.8, 161.2, 155.1, 145.9, 138.7, 137.8, 131.3, 128.8, 127.7, 127.3, 127.2, 125.8, 118.3, 114.4, 72.0, 60.5, 55.4, 44.3, 14.2; IR (ZnSe) νmax (cm−1) 3464, 2979, 2931, 1727, 1600, 1563, 1494, 1432, 1283, 1248, 1173, 1025, 832, 764; HRMS (ESI-TOF) m/z calcd for C21H22NO4 [M + H]+ 352.1543, found 352.1562. Ethyl 3-Hydroxy-3-(2-(4-nitrophenyl)quinolin-8-yl)propanoate (Table 2, Entry 3f): brown crystals, yield = 21.6 mg (59%), isolated from flash chromatography (25% EtOAc/n-hexane); mp 127.7 °C; 1H NMR (300 MHz, CDCl3) δ 8.42−8.28 (m, 5H), 7.97 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.60−7.55 (m, 1H), 5.97−5.93 (m, 12707

DOI: 10.1021/acs.joc.8b02042 J. Org. Chem. 2018, 83, 12702−12710

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TOF) m/z calcd for C17H22NO4 [M + H]+ 304.1543, found 304.1530. Ethyl 3-Hydroxy-3-(2-methyl-6-nitroquinolin-8-yl)propanoate (Table 2, Entry 3l): yellow solid, yield = 16.4 mg (54%), isolated from flash chromatography (20% EtOAc/n-hexane); 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J = 2.6 Hz, 1H), 8.47 (d, J = 2.6 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 5.86−5.82 (m, 1H), 5.69 (brs, 1H, OH), 4.24−4.17 (m, 2H), 3.11−3.07 (m, 2H), 2.82 (s, 3H), 1.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.5, 162.0, 147.6, 141.2, 138.6, 125.7, 123.8, 123.6, 120.6, 70.0, 60.8, 43.2, 14.2; IR (ZnSe) νmax (cm−1) 3523, 2919, 2850, 1703, 1610, 1526, 1493, 1348, 1307, 1184, 1154, 1029, 907, 784. 746; HRMS (ESITOF) m/z calcd for C15H17N2O5 [M + H]+ 305.1132, found 305.1152. Ethyl 3-(6-Bromo-2-methylquinolin-8-yl)-3-hydroxypropanoate (Table 2, Entry 3m): brown oil, yield = 19.2 mg (57%), isolated from flash chromatography (21% EtOAc/n-hexane); 1H NMR (600 MHz, CDCl3) δ 8.00 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 5.69−5.66 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.16−2.96 (m, 2H), 2.74 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 171.6, 158.3, 144.0, 140.4, 136.7, 131.0, 129.2, 128.3, 123.1, 119.6, 70.8, 60.8, 43.9, 25.4, 14.4; IR (ZnSe) νmax (cm−1) 3801, 2870, 1730, 1712, 1618, 1606, 1504, 1244, 1157, 1134, 923, 860, 794; HRMS (ESI-TOF) m/z calcd for C15H17BrNO3 [M + H]+ 338.0386, found 338.0370. Ethyl 3-(7-Chloro-2-methylquinolin-8-yl)-3-hydroxypropanoate (Table 2, Entry 3n): brown oil, yield = 12.3 mg (42%), isolated from flash chromatography (29% EtOAc/n-hexane); 1H NMR (600 MHz, CDCl3) δ (ppm): 8.06 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.97 (dd, J = 9.6, 4.2 Hz, 1H), 4.18−4.20 (m, 2H), 3.09 (dd, J = 15.0, 9.6 Hz, 1H), 2.83 (dd, J = 14.4, 4.2 Hz, 1H), 2.72 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ (ppm): 171.9, 158.1, 146.9, 137.4, 134.6, 133.1, 127.8, 127.7, 125.8, 122.1, 70.6, 60.6, 43.8, 25.4, 14.2; IR (ZnSe) νmax (cm-1) 2920, 2850, 1744, 1598, 1497, 1463, 1377, 1259, 1017, 798; HRMS (ESI-TOF) m/z calcd for C15H17ClNO3 [M + H]+ 294.0891, found 294.0881. Butyl 3-(7-Chloro-2-methylquinolin-8-yl)-3-hydroxypropanoate (Table 2, Entry 3o): brown oil, yield = 14.4 mg (45%), isolated from flash chromatography (16% EtOAc/n-hexane); 1H NMR (600 MHz, CDCl3) δ (ppm): 8.06 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.97 (s, 1H), 4.16−4.10 (m, 2H), 3.09 (dd, J = 14.4, 9.6 Hz, 1H), 2.85 (dd, J = 14.4, 4.2 Hz, 1H), 2.72 (s, 3H), 1.64−1.59 (m, 2H), 1.40−1.34 (m, 2H), 0.94−0.91 (m, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 171.2, 158.1, 146.9, 137.4, 134.7, 133.1, 127.7, 127.6, 125.8, 122.1, 70.6, 64.5, 43.8, 30.6, 25.4, 19.2, 13.8; IR (ZnSe) νmax (cm−1) 2920, 2850, 1744, 1598, 1497, 1463, 1377, 1259, 1017, 798; HRMS (ESI-TOF) m/z calcd for C17H21ClNO3 [M + H]+ 322.1204, found 322.1200. Synthesis of Rhodacycle A. To a screw-capped vial with a spinvane triangular shaped stir bar were added 2-phenylquinoline Noxide (0.5 mmol), [Cp*RhCl2]2 (0.25 mmol), NaOAc (3 equiv), and CH3OH (2.5 mL). The reaction was stirred at 65 °C for 24 h. After completion, the reaction mixture was filtered and washed with ethyl acetate. Solvent was removed under reduced pressure, and residue was purified by flash chromatography on silica gel (hexane/ethyl acetate) to provide orange precipitates in 27.4 mg, 12% yield: 1H NMR (300 MHz, CDCl3) δ (ppm) 8.83 (d, J = 9.0 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.79−7.70 (m, 3H), 7.55− 7.50 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 1.48 (s, 15H); 13C NMR (75 MHz, CDCl3) δ (ppm) δ 166.5 (d, 1JRh−C = 34.5), 144.3, 133.5, 132.2, 130.7, 130.6, 129.9, 129.6, 128.4, 128.0, 123.3, 121.7, 121.0, 120.2, 94.7 (d, 1JRh−C = 7.5 Hz, 5C, C5Me5), 9.2; IR (ZnSe) νmax (cm−1) 2922, 2845, 1737, 1658, 1568, 1442, 1390, 1305, 1265, 1226, 1136, 1026, 918, 881, 796, 767; HRMS (ESI-TOF) m/z calcd for C25H25NORh [M]+ is 458.0991, found 458.0980.

1H), 5.44 (brs, 1H, OH), 4.24−4.17 (m, 2H), 3.14−3.11 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 172.0, 153.0, 148.5, 145.6, 144.7, 139.8, 138.4, 128.2, 127.9, 127.2, 124.2, 118.6, 70.3, 60.7, 43.8, 14.2; IR (ZnSe) νmax (cm−1) 3524, 2923, 2850, 1729, 1711, 1596, 1517, 1487, 1341, 1172, 1087, 841, 755; HRMS (ESI-TOF) m/z calcd for C20H19N2O5 [M + H]+ 367.1288, found 367.1295. Ethyl 3-(2-(4-(tert-Butyl)phenyl)quinolin-8-yl)-3-hydroxypropanoate (Table 2, Entry 3g): yellow oil, yield = 21.5 mg (57%), isolated from flash chromatography (21% EtOAc/n-hexane); 1H NMR (300 MHz, CDCl3) δ 8.17 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 8.84 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 6.9 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.42−7.36 (m, 1H), 6.33 (brs, 1H, OH), 5.67 (s, 1H), 4.09 (dd, J = 14.1, 7.2 Hz, 2H), 3.15 (dd, J = 15.0, 8.1 Hz, 1H), 3.03 (dd, J = 15.0, 5.7 Hz, 1H), 1.32 (s, 9H), 1.19−1.14 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 171.8, 155.5, 153.2, 145.9, 138.9, 137.8, 136.0, 127.7, 127.5, 127.2, 126.0, 126.0, 118.6, 72.0, 60.5, 44.3, 34.8, 31.3, 14.2; IR (ZnSe) νmax (cm−1) 3435, 2962, 1730, 1600, 1558, 1496, 1434, 1365, 1268, 1166, 1112, 1026, 834, 809, 764; HRMS (ESI-TOF) m/z calcd for C24H28NO3 [M + H]+ 378.2064, found 378.2046. Methyl 3-Hydroxy-3-(2-methylquinolin-8-yl)propanoate (Table 2, Entry 3h): yellow oil, yield = 14.9 mg (61%), isolated from flash chromatography (23% EtOAc/n-hexane); 1H NMR (300 MHz, CDCl3) δ (ppm) 8.10−8.08 (m, 1H), 7.72 (d, J = 2.7 Hz, 1H), 7.70− 7.43 (m, 1H), 7.34−7.30 (m, 1H), 7.29−7.27 (m, 1H), 6.85 (brs, 1H, OH), 5.63−5.61 (m, 1H), 3.71 (t, J = 1.5 Hz, 3H), 3.23−3.18 (m, 1H), 3.17−2.97 (m, 1H), 2.75−2.74 (m, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 172.1, 157.6, 145.8, 138.0, 137.2, 127.4, 127.2, 126.9, 125.5, 121.9, 72.5, 51.7, 44.2, 25.4; IR (ZnSe) νmax (cm−1) 3391, 2951, 2926, 1733, 1602, 1502, 1435, 1275, 1166, 1026, 839, 765; HRMS (ESI-TOF) m/z calcd for C14H16NO3 [M + H]+ 246.1125, found 246.1139. Ethyl 3-Hydroxy-3-(2-methylquinolin-8-yl)propanoate (Table 2, Entry 3i): brown oil, yield = 16.3 mg (63%), isolated from flash chromatography (19% EtOAc/n-hexane); 1H NMR (300 MHz, CDCl3) δ 8.14−7.94 (m, 1H), 7.68−7.58 (m, 1H), 7.50 (d, J = 6.8 Hz, 1H), 7.36 (dd, J = 10.3, 4.7 Hz, 1H), 7.27−7.15 (m, 1H), 6.71 (s, 1H), 5.54 (d, J = 5.7 Hz, 1H), 4.16−3.99 (m, 2H), 3.07 (dd, J = 8.2, 2.3 Hz, 1H), 2.99−2.88 (m, 1H), 2.73−2.62 (m, 3H), 1.24−1.06 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 172.2, 158.1, 146.4, 138.8, 137.7, 127.9, 127.7, 127.5, 126.0, 122.4, 72.9, 61.0, 45.0, 26.0, 14.8; IR (ZnSe) νmax (cm−1) 2976, 2929, 1728, 1598, 1564, 1499, 1369, 1280, 1153, 1024, 839, 767. HRMS (ESI-TOF) m/z calcd for C15H18NO3 [M + H]+ 260.1281, found 260.1265. Butyl 3-Hydroxy-3-(2-methylquinolin-8-yl)propanoate (Table 2, Entry 3j): brown oil, yield = 16.9 mg (59%), isolated from flash chromatography (24% EtOAc/n-hexane); 1H NMR (600 MHz, CDCl3) δ (ppm): 8.09 (d, J = 9.0 Hz, 1H), 7.71−7.70 (m, 1H), 7.57 (d, J = 6.6 Hz, 1H), 7.44−7.42 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.84 (bs, 1H), 5.63 (dd, J = 8.4, 6.0 Hz, 1H) 4.10 (t, J = 6.6 Hz, 2H), 3.18 (dd, J = 15.0, 8.4 Hz, 1H), 3.02 (dd, J = 15.0, 5.4 Hz, 1H), 2.74 (s, 3H), 1.60−1.57 (m, 2H), 1.36−1.32 (m, 2H), 0.92 (m, 3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 171.8, 157.5, 145.8, 138.0, 137.2, 127.4, 127.2, 126.9, 125.4, 121.9, 72.4, 64.4, 44.4, 30.6, 25.4, 19.1, 13.7; IR (ZnSe) νmax (cm−1) 2956, 2931, 2872, 1730, 1602, 1573, 1502, 1454, 1433, 1273, 1166, 1020, 837, 763; HRMS (ESI-TOF) m/ z calcd for C17H22NO3 [M + H]+ 288.1594, found 288.1582. Butyl 3-Hydroxy-3-(6-hydroxy-2-methylquinolin-8-yl)propanoate (Table 2, Entry 3k): brown oil, yield = 13.6 mg (45%), isolated from flash chromatography (17% EtOAc/n-hexane); 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 5.54− 5.52 (m, 1H), 4.09 (t, J = 6.6 Hz, 2H), 3.15−3.12 (m, 1H), 2.97− 2.94 (m, 1H), 2.65 (s, 3H), 1.58 (t, J = 7.2 Hz, 2H), 1.33−1.30 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 172.0, 154.6, 153.3, 141.2, 139.1, 135.9, 128.3, 122.3, 119.5, 108.7, 72.4, 64.7, 44.3, 30.6, 25.0, 19.1, 13.7; IR (ZnSe) νmax (cm−1) 1703, 1631, 1593, 1494, 1390, 1307, 1251, 1161, 985, 827, 792; HRMS (ESI12708

DOI: 10.1021/acs.joc.8b02042 J. Org. Chem. 2018, 83, 12702−12710

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(10) Shibata, T.; Matsuo, Y. Directed C- H Alkenylation of Quinoline N-Oxides at the C-8 Position Using a Cationic Rhodium (I) Catalyst. Adv. Synth. Catal. 2014, 356, 1516. (11) Dateer, R. B.; Chang, S. Selective Cyclization of Arylnitrones to Indolines under External Oxidant-Free Conditions: Dual Role of Rh(III) Catalyst in the C−H Activation and Oxygen Atom Transfer. J. Am. Chem. Soc. 2015, 137, 4908. (12) Zhang, X.; Qi, Z.; Li, X. Rhodium (III)-Catalyzed C-C and CO Coupling of Quinoline N-Oxides with Alkynes: Combination of CH Activation with O-Atom Transfer. Angew. Chem., Int. Ed. 2014, 53, 10794. (13) Sharma, U.; Park, Y.; Chang, S. Rh(III)-Catalyzed Traceless Coupling of Quinoline N-oxides with Internal Diarylalkynes. J. Org. Chem. 2014, 79, 9899. (14) Kouznetsov, V. V.; Méndez, L. Y. V.; Gómez, C. M. M. Recent Progress in the Synthesis of Quinolines. Curr. Org. Chem. 2005, 9, 141. (15) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of Heterocycles: Structures, Reactions, Synthesis, and Applications; John Wiley & Sons, 2013. (16) Michael, J. P. Quinoline, Quinazoline and Acridone Alkaloids. Nat. Prod. Rep. 2008, 25, 166. (17) Egan, T. J.; Ross, D. C.; Adams, P. A. Quinoline Anti-malarial Drugs Inhibit Spontaneous Formation of β-Haematin (Malaria Pigment). FEBS Lett. 1994, 352, 54. (18) Vu, A. T.; Cohn, S. T.; Manas, E. S.; Harris, H. A.; Mewshaw, R. E. ERβ Ligands. Part 4: Synthesis and Structure−Activity Relationships of a Series of 2-Phenylquinoline Derivatives. Bioorg. Med. Chem. Lett. 2005, 15, 4520. (19) R. Solomon, V.; Lee, H. Quinoline as a Privileged Scaffold in Cancer Drug Discovery. Curr. Med. Chem. 2011, 18, 1488. (20) Tokoro, Y.; Nagai, A.; Kokado, K.; Chujo, Y. Synthesis of Organoboron Quinoline-8-Thiolate and Quinoline-8-Selenolate Complexes and their Incorporation into the π-Conjugated Polymer MainChain. Macromolecules 2009, 42, 2988. (21) Jégou, G.; Jenekhe, S. A. Highly Fluorescent Poly (Arylene Ethynylene)s Containing Quinoline and 3-Alkylthiophene. Macromolecules 2001, 34, 7926. (22) Kim, J. I.; Shin, I.-S.; Kim, H.; Lee, J.-K. Efficient Electrogenerated Chemiluminescence from Cyclometalated Iridium (III) Complexes. J. Am. Chem. Soc. 2005, 127, 1614. (23) Tong, H.; Wang, L.; Jing, X.; Wang, F. Turn-On” Conjugated Polymer Fluorescent Chemosensor for Fluoride Ion. Macromolecules 2003, 36, 2584. (24) Tobisu, M.; Hyodo, I.; Chatani, N. Nickel-Catalyzed Reaction of Arylzinc Reagents with N-Aromatic Heterocycles: A Straightforward Approach to C− H Bond Arylation of Electron-Deficient Heteroaromatic Compounds. J. Am. Chem. Soc. 2009, 131, 12070. (25) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. Direct C−H Arylation of ElectronDeficient Heterocycles with Arylboronic Acids. J. Am. Chem. Soc. 2010, 132, 13194. (26) Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Rh(I)-Catalyzed Direct Arylation of Pyridines and Quinolines. J. Am. Chem. Soc. 2008, 130, 14926. (27) Berman, A. M.; Bergman, R. G.; Ellman, J. A. Rh(I)-Catalyzed Direct Arylation of Azines. J. Org. Chem. 2010, 75, 7863. (28) Larionov, O. V.; Stephens, D.; Mfuh, A.; Chavez, G. Direct, Catalytic, and Regioselective Synthesis of 2-Alkyl-, Aryl-, and AlkenylSubstituted N-Heterocycles from N-Oxides. Org. Lett. 2014, 16, 864. (29) Ren, X.; Wen, P.; Shi, X.; Wang, Y.; Li, J.; Yang, S.; Yan, H.; Huang, G. Palladium-Catalyzed C-2 Selective Arylation of Quinolines. Org. Lett. 2013, 15, 5194. (30) Kwak, J.; Kim, M.; Chang, S. Rh(NHC)-Catalyzed Direct and Selective Arylation of Quinolines at the 8-Position. J. Am. Chem. Soc. 2011, 133, 3780. (31) Stephens, D. E.; Lakey-Beitia, J.; Atesin, A. C.; Ateşin, T. l. A.; Chavez, G.; Arman, H. D.; Larionov, O. V. Palladium-Catalyzed C8Selective C−H Arylation of Quinoline N-Oxides: Insights into the

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02042.

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Optimization studies, 1H and 13C NMR spectra, X-ray data for 3f, experimental details of the mechanistic study (PDF) X-ray data (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] or upendraihbt@gmail. ORCID

Upendra Sharma: 0000-0002-7693-8690 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We greatly acknowledge the Director, CSIR-IHBT, for necessary facilities. This activity was supported by the SERB, India (EMR/2014/001023), and CSIR (MPL0203). R. Sharma and Rakesh Kumar acknowledge CSIR & UGC, New Delhi, respectively, for SRF. Rohit Kumar thanks CSIR (HCP010) for a research fellowship. The CSIR-IHBT communication number for this manuscript is 4307.

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REFERENCES

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DOI: 10.1021/acs.joc.8b02042 J. Org. Chem. 2018, 83, 12702−12710