Rh(III)-catalyzed C(8)-H functionalization of quinolines via

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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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02042 • Publication Date (Web): 13 Sep 2018 Downloaded from http://pubs.acs.org on September 13, 2018

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The Journal of Organic Chemistry

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,‡ Upendra Sharma†, †

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

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ABSTRACT: Here a facile and efficient protocol for the synthesis of 3-hydroxyquinoline 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 is playing dual role of a traceless directing group as well as a source of oxygen atom for hydroxylation. This catalytic method involves simultaneous formation of new C-C and C-O bonds, and is applicable only for C-2 substituted quinolines. 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 & 3m have better scores. In vitro evaluation of selected compounds against CQ sensitive pf3D7 and CQ resistant pfINDO strains provided evidences that 3d (IC50 13.3 µM) and 3g (IC50 9.5 µM) had good promise against Plasmodium falciparum in in vitro culture. Compound 3g was found to be most potent on the basis of both in vitro antiplasmodial activity (IC50 9.5 µM (Pf3D7) and 11.9 µM (PfINDO), 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, directing group approach bears great potential for proximal as well as distal C-H bond functionalization.2 Ideally, the directing group should be either an integral part of the substrate or can be utilized during transformation to minimize reaction step and to achieve the full atom economy. The prevalence of N-O directing group in C-H bond activation has shown to achieve analogous goals with better efficiency and oxygen atom transfer for post-functionalization. Shin and coworkers designed a Au-catalyzed 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 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 Ru9 or Rh8,10,11-13 metal complexes (Figure 1a) and the fate of N-oxide in these reactions is related to its use as a directing agent as well as oxygen atom donor. Owing to the importance of quinoline heterocycle in natural products,14 medicinal15-19 and material chemistry,20-23 it has gained recognition as a remarkable construction motif for further developments. Achieving the site-selective C-H bond functionalization of quinoline is most desirable in the current scenario and a significant number of processes are uncovered in this direction particularly at C224-29 and C8 position.30 In recent years, many efforts have been devoted for C8 functionalization of quinoline using N-O as directing group31-33 as well as a source of 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 Rh-catalyzed, C8 olefination35 and alkylation36 methodologies using N-O as a traceless directing group. During the course of our C8 olefination35 study, comparatively less yield was observed in case of reaction of 2-substituted quinolines with



acrylates due to the formation of unidentified side products which are now characterized unambiguously as 3-hydroxyquinoline 8-yl propanoates. Although simultaneous C(8)-H activation of quinoline N-oxides followed by N-oxide oxygen atom transfer leading to carbonyl functional group is reported,6-9,11-13 N-oxide oxygen atom transformation into hydroxyl moiety in this type of reaction is still awaited. Here we wish to report a new strategy for the synthesis of 3-hydroxyquinoline 8-yl propanoates from quinoline N-oxides and acrylates via Rh(III)-catalyzed C(8)-H activation of 2-substituted quinoline N-oxides (Figure 1b).

Figure 1. N-Oxide Directing Group Assisted C-H Activation, Followed by Oxygen Atom Transfer

RESULTS AND DISCUSSION During the course of exploration of the substrate scope of our earlier work on C8 selective olefination,35 we found that 2-methyl 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 characterized unambiguously as 3-hydroxyquinoline 8-yl propanoates with the help of 1-D, 2-D NMR and ESI-MS studies.38 To the best of our


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knowledge N-oxide oxygen atom transformation into hydroxyl moiety in this type of reaction is not reported till date.

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

Further to optimize this reaction, 2-phenyl quinoline N-oxide (2a) and ethyl acrylate (1a) were chosen as the standard substrates (Table 1). Optimization of the amount of Cu(OAc)2, and reaction temeperature revealed that use of 50 mol% Cu(OAc)2 and 90°C reaction temperature resulted in slight increase of yield (Table 1, entries 2-3). In 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 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 fruitful for current reaction. Gratifyingly, using 0.1 mmol of 2a and 0.15 mmol of 1a in presence of 5 mol% [RhCp*Cl2]2 / 20 mol% AgSbF6, 50 mol% Cu(OAc)2/ 100 mol% CH3COOH, in toluene as a solvent at 90°C for 15 h gave final product in 67% isolated yield along with 30% olefinated product (Table 1, entry 12).



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Table 1. Optimization Studya

entry

catalyst (mol%)/ co-catalyst (mol%)

1

[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)

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)

DCE

24

100

27 (46)

DCE

24

100

32 (39)

DCE

24

90

37 (42)

Pivalic acid

24

90

43 (27)

1,4-Dioxane

24

90

50 (50)

Toluene

24

90

55 (39)

Toluene

24

90

25 (12)

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

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

Toluene

24

90

37 (18)

Toluene

24

90

Traces (traces)

2 3 4 5 6 7 8 9

additive (mol%)

solvent (0.5 mL)

time (h)

temp. (°C)

NMR yield % 3a (3x)b, c

Toluene [RhCp*Cl2]2 (5)/ 24 90 31 (47) AgSbF6 (20) Toluene 11 [RhCp*Cl2]2 (5)/ CH3CO2H (100) 24 90 Traces (traces) AgSbF6 (20) Toluene 12 [RhCp*Cl2]2 (5)/ Cu(OAc)2 15 90 67 (30) AgSbF6 (20) (50)/CH3CO2H (100) 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. 10

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 2-position of quinoline N-oxide is necessary for this reaction to take place. 2-Phenyl quinoline N-oxide with ethyl acrylate yielded product 3a in 65% isolated yield. 2-Phenyl, 4-methyl quinoline N-oxide with ethyl acrylate afforded 3b in 57% yield.


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Ortho, meta or para substituted 2-phenyl quinoline N-oxide provided 3c-3g in moderate yields.

Table 2. Substrate Scopea

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), 100°C, 24 h. The C8 olefinated quinoline was observed as a side product.

Reaction of 2-methyl quinoline N-oxide with methyl/ ethyl/ butyl acrylate afforded 3h-j with 59-63% isolated yields. 2-Methyl, 6-hydroxy quinoline reacted well with butyl acrylate under developed reaction conditions yielding desired product in 45% isolated yield. 2-Methyl, 6nitro quinoline N-oxide as well as 2-methyl, 6-bromo quinoline provided 3l-m in 54% and



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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 with 63% incorporation of deuterium at the C8 position (Scheme 2). This experiments reveal the reversible nature of carbometallation at the C8 position of quinoline. To confirm the oxygen atom source, 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

N-oxide

to

acrylate.

Scheme 2. Labelling Experiments

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-methyl quinoline, (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).


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Scheme 3. Oxygen Atom Transfer (OAT) Reaction

To probe the active intermediate in the reaction, a five-membered 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 five-membered 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.

Scheme 4. Synthesis of Rhodacycle and its use as Catalyst

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 earlier.35



Scheme 5. Proposed Reaction Mechanism

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 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 olefin in intramolecular fashion across Rh-H bond which can provide the hydorxylated product (3a) via elimination of Rh (I) species followed by hydrolysis with acid.

In another pathway, intermediate V can also provide olefinated product through


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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). Exact reason for the requirement of C2substituted quinoline N-oxide in this reaction is still unknown but this might be due to the steric hindrance caused by methyl/ phenyl groups present at C2-position of quinoline Noxide.

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 & 3m) of the synthesized compounds had better docking scores as compared to the standard compound choloroquine (CQ).



Figure 2. 2-D and 3-D Interactions of 3g

After complete analysis it was found that phenyl substituents at C2-position (Table 3, 3a) enhance the interaction of compounds with protein as compared to methyl substituent at 2position (Table 3, 3h-o). In continuation, ortho-, meta- or para-substituted phenyl groups at 2-position were analyzed (3b-g) and it was concluded that the electron donating group at para-position of 2substituted phenyl was the most suitable. Compound 3g was found to be the most potent against the Falcipain-2 protein with docking score -5.446 (Table 3). The 3-D and 2-D interactions of the compound 3g along with the standard inhibitor CQ are shown in figure 2. In silico studies revealed that the 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.


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In vitro Antiplasmodial Activity After docking analysis, the selected twelve 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 CQ sensitive Pf3D7 and CQ resistant PfINDO strains using the microtiter plate based SYBR Green assay.46 As shown in table 3, two molecules viz. 3d and 3g showed IC50 below 15 µM against Pf3D7. The results show that the compound 3g with IC50 9.5 µM against pf3D7 and 11.9 µM against pfINDO and a RI of 1.25 is the most promising among the evaluated examples.

Table 3. Antiplasmodial Activity

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

docking score -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

IC50Pf INDO (µM) 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

IC50Pf3D7 (µM) 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

RI (PfINDO/Pf3D7) 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

A comparison of the in silico and in vitro results (Table 3), revealed that compound 3g was showing the best promise in both in silico evaluation and in vitro antiplasmodial assay while other compounds did not show such a correlation. Further, it was noteworthy that while



chloroquine showed a resistance index of 12.5, for most of other compounds this value was around 1.

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 highest promise {IC50 (µM) 9.5 (Pf3D7) and 11.9 µM (PfINDO) for compound 3g. While chloroquine showed a resistance index of 12.5, most of the compounds designed and synthesized in this study showed a resistance index of ~1.

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 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 aluminium 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 recorded on Water Q-ToF-Micro Micromass. Copies of 1H,

13

C NMR can be found in the NMR

supporting information. Nuclear magnetic resonance spectra were recorded either on a


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Bruker-Avance 600 or 300 MHz instrument. All 1H NMR experiments are reported in units, 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

13

C 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 Shimadzu IRPrestige-21 with 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, [Cp*RhCl2]2 (5 mol%) and AgSbF6 (20 mol%) were added. 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 micro-liter syringe and toluene was added by laboratory syringe, respectively. The reaction vial was closed with screw cap and kept for vigorous stirring on a preheated oil bath or heating block at 90°C for 15 h. After completion, reaction mixture was extracted with dichloromethane (DCM). 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-8-yl)propanoate (Table 2, Entry 3a): brownish oil, yield = 20.80 mg ( 65%), isolated from flash chromatography (20% EtOAc/ n-hexane); 1H 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,



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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/ nhexane); 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);

C NMR (75 MHz, CDCl3) δ 171.8, 155.0, 146.2, 145.8, 139.4,

13

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, 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), 5.685.66 (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 (cm1

) 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 compound; yield = 19.6 mg (53%), isolated from flash chromatography (30% EtOAc/ n-hexane); 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.977.91 (m, 2H), 7.79-7.71 (m, 2H), 7.54-7.49 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 5.96 (s, 1H), 5.82


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(s, 1H), 4.24-4.17 (m, 2H), 3.19-3.15 (m, 2H), 2.48 (s, 3H), 1.30-1.25 (m, 3H);

13

C 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/ nhexane); 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 (ESITOF) 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,

1

H 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, 1H), 5.44 (brs, 1H, OH), 4.244.17 (m, 2H), 3.14 – 3.11 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H);

13

C 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.



Page 18 of 28

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/ nhexane); 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);

13

C

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);

13

C 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);

13

C NMR (75 MHz, CDCl3) δ 172.2, 158.1, 146.4, 138.8, 137.7, 127.9, 127.7, 127.5,


Page 19 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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, 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, 8.4Hz, 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);

13

C 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, 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 (ESI-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



Page 20 of 28

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);

C NMR (75 MHz, CDCl3) δ 171.5, 162.0,

13

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 (ESI-TOF) m/z calcd for C15H17N2O5 [M + H]+ 305.1132, found 305.1152. Ethyl 3-(6-bromo-2-methylquinolin-8-yl)-3-hydroxypropanoate (Table 2, 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, 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, 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,


Page 21 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 stirbar 2-phenylquinoline N-oxide (0.5 mmol), [Cp*RhCl2]2 (0.25 mmol), NaOAc (3 equiv.), CH3OH (2.5 mL) were added. The reaction was stirred at 65°C for 24 h. After completion, 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); 1

13

C NMR (75 MHz, CDCl3) δ (ppm): 166.5 (d,

JRh-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.

ASSOCIATED CONTENT Supporting Information



Page 22 of 28

Supplementary data associated with this article including optimization studies, 1H and

13

C

NMR spectra as well as X-ray data for 3f, experimental details of the mechanistic study, can be found online.

AUTHOR INFORMATION Corresponding Author *E mails: [email protected]; upendraihbt@gmail Web address: http://www.ihbt.res.in/en/staff/scientific-staff?chronoform=sctdetail&task=detail&id=41 Notes The authors declare no competing financial interests. 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). Mrs. Ritika Sharma and Mr. Rakesh Kumar acknowledge CSIR & UGC, New Delhi, respectively for SRF. Mr. Rohit Kumar thanks CSIR (HCP010) for research fellowship. The CSIR-IHBT communication no. for this manuscript is 4307.

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Rh(III)-catalyzed C(8)-H functionalization of quinolines via

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