Accessing Heterobiaryls through A Transition Metal-Free C-H

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Accessing Heterobiaryls through A Transition Metal-Free C-H Functionalization Ananya Banik, Rupankar Paira, Bikash Kumar Shaw, Gonela Vijaykumar, and Swadhin K. Mandal J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00140 • Publication Date (Web): 13 Feb 2018 Downloaded from http://pubs.acs.org on February 16, 2018

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The Journal of Organic Chemistry

Accessing Heterobiaryls through A Transition Metal-Free C-H Functionalization Ananya Banik†, Rupankar Paira*,‡, Bikash Kumar Shaw†, Gonela Vijaykumar† and Swadhin K. Mandal*,† †

Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur-741246, India. Email: [email protected] ‡

Department of Chemistry, Maharaja Manindra Chandra College, 20 Ramkanto Bose Street, Kolkata-700003, India. Email: [email protected]

TOC/Abstract Graphic:

Abstract Herein we report a transition metal-free synthetic protocol for heterobiaryls, one of the most important pharmacophores in modern drug industry, employing a new multidonor phenalenyl (PLY) based ligand. The current procedure offers wide substrate scope (24 examples) with a 1 ACS Paragon Plus Environment

The Journal of Organic Chemistry 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

low-catalyst loading resulting in excellent product yield (upto 95%). The reaction mechanism involves a single electron transfer (SET) from a phenalenyl based radical to generate reactive heteroaryl radical. To establish the mechanism, we have isolated the catalytically active SET initiator and characterized by magnetic study. Keywords: Heterobiaryls, Phenalenyl, Open-shell molecule, Transition metal-free arylation, Single electron transfer (SET), C-H Functionalization. Introduction: Heterocycles account for trillion dollar drug industry worldwide and was found to be present in the pharmacophores of more than 70% enlisted natural as well as synthetic drugs and agrochemicals.1 Among these, heterobiaryls are considered as privileged structures both in the chemical and drug industry and constitute a wide range of bioactive pharmaceuticals.2 Many anti-HIV,3 anti-cancer,4 anti-proliferative,5 antiarthritic6 nonsteroidal anti-inflammatory drugs (NSAID), mGluR5 antagonists,7 serine protease and caspase 3 inhibitors8 along with some of the best-selling drugs, e.g. Etoricoxib (NSAID),9 contain hetero-biaryl pharmacophore. Therefore, syntheses of these motifs have readily grabbed the attention of chemists in recent decades and till date transition metal-catalyzed C-C cross-couplings remained the major route among various available synthetic techniques.10 However, drugs prepared using such cross coupling reactions often found to be contaminated with trace amount of transition metal impurities and as the modern day health care protocols have moved towards using pure bioactive compounds, such methodologies face disadvantage to meet the safety standards of current drug industry.11 Besides, toxicity, oxygen and moisture-sensitivity as well as high expense of transition-metal catalysts, coupled with their extremely low earth abundance warrant our attention towards alternate 2 ACS Paragon Plus Environment

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sustainable developments.12-22 However, the success with transition metal free catalyst was limited to aryl diazonium salt as one of the coupling partners, which narrows applicability towards broad heterobiaryl synthetic methods.23-25 Thus the use of more economically attractive heteroaryl halide substrates to construct heterobiaryl in transition metal free catalysis is limited in the current literature.26-35 While most of these methodologies used high catalyst loading (20-40 mol%)26-29 and all of them suffer from very limited substrate scope. Herein we present an alternate and efficient transition metal free catalytic method, which can overcome shortcomings of earlier reports involving heteroaryl halide as coupling partner yielding heterobiaryls in high yields with a wide substrate scope. To design such catalytic protocol, we took advantage of wellknown phenalenyl based radical to explore the possibility of such development. Since long phenalenyl radicals have been considered as the key building block for construction of organic conductor, quantum spin simulator, molecular battery, molecular switch etc.,36-48 which is attributed to the presence of a distinctive nonbonding molecular orbital (NBMO). This particular NBMO can stabilize one unpaired spin in its neutral radical state or it can be a cationic if this electron is lost, without compromising its stability.49-52 During the last few years, the generation of cationic phenalenyl and its use in an array of applications has remained our major interest,53-57 which resulted in the development of a diverse areas of molecular spin memory device (based on a phenalenyl-zinc complex),55 power efficient fuel cell (based on a phenalenyl-iron complex)56, organometallic catalysis53,54 or organic Lewis acid based catalysis57 and this emerging area of research was reviewed very recently.58 Recently, we explored the possibility of using phenalenyl radicals in transition metal free C-H functionalization catalysis where we established that they can promote SET process to generate a highly reactive aryl radical which can subsequently initiate the coupling reaction.25,59 However, 3 ACS Paragon Plus Environment


we have never tested heteroaryl halide as a coupling partner for such catalysis using phenalenyl ligand and the present study addresses this goal (Scheme 1). It may be noted that the major achievements over the earlier literature reports using phenalenyl radicals in transition metal free C-H functionalization catalysis are mainly twofold: a) it requires catalyst loading similar to a transition metal-based catalyst (substoichiometric catalyst loading of 20-40 mol% used in earlier methods,60-63 b) it does not need any photoactivation step unlike other reported methods using radical catalysis.23,63 Our approach:

• •

Transition metal free

24 Substrates (up to 95% yield)

Scheme 1. Our Approach Towards Heterobiarylation. Results and discussion: Our study started with the synthesis of a bis-phenalenyl ligand 1, which was accomplished by the treatment of 9-methoxy-1H-phenalen-1-one (2 equiv.) with ethylene diamine (1 equiv.) in DCE under reflux condition for 24 h (Figure 1a). Analytically pure orange colored crystals of 1 were obtained in 90% yield from a concentrated acetonitrile solution at room temperature and was unambiguously characterized by single-crystal X-ray diffraction study (Figure 1b) as well as by 1

H NMR, 13C NMR and mass spectroscopy. Having the well characterized bis-phenalenyl ligand

1 in hand, we used it for the C-C cross coupling reaction between 2-iodothiophene (2a) and benzene (3a) in presence of KOtBu. Upon optimization of various reaction conditions (Table 1),

4 ACS Paragon Plus Environment

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(a)

(b)

H 2N

O

O

NH2

DCE Reflux 24 h

O

HN

O

HN

1

Figure 1 (a) Preparation of bis-phenalenyl ligand 1; (b) Perspective ORTEP view of the molecular structure of ligand 1. Thermal ellipsoids are drawn with 50% probability. Selected bond lengths (Å) and bond angels (o): O1-C11 1.250(5); N1-C1 1.321(5); N1-C14 1.436(5); C1N1-C14, 125.3(3); N1-C1-C2, 120.9(4); N1-C1-C12, 120.7(3).

95% isolated yield of 2-phenylthiophene (4aa) was achieved at 130 °C in presence of 3 equiv. KOtBu and 7.5 mol% catalyst loading after 12h (Table 1, entry 4). In addition, the commercially available ligands such as 2,2’-bipyridine, 1,10-phenanthroline or previously known phenalenyl ligand, 9-methylamino-phealen-1-one resulted in much lower conversion (below 30%) under the optimized reaction conditions (Table 1, entries 11-13). Under the standardized conditions, 2bromothiophene (2a’) reacted smoothly to produce 86% yield of 2-phenylthiophene whereas, the yield dropped sharply to 46% when 2-chlorothiophene (2a’’) was used (Table 2) which clearly depicts the effect of stronger C-Cl bond over the C-Br and C-I bonds. Similar trend was also observed when 3-iodothiophene (2b) or 3-bromothiophenes (2b’) was reacted with benzene under the optimized reaction conditions, leading to 87% and 39% 3-phenylthiophene (4ba), respectively (Table 2). Under the same reaction conditions, good to excellent yields of corresponding 2-phenylthiophene derivatives (4ca, 82% and 4da, 78% respectively) were 5 ACS Paragon Plus Environment


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realized when 2-bromo-3-methylthiophene (2c) and 2-bromo-5-methylthiophene (2d) were reacted with benzene. When toluene (3b) was tested for this C-C cross coupling reaction with 2iodothiophene (2a), a regioisomeric mixture (1:0.9:0.6) of 2-tolylthiophene (4ab) was obtained with

an

overall

67% conversion

of product. Next,

we explored

the scope of

halopyridines/quinoline/isoquinolines to access more diversified hetero-biaryl derivatives (Table 2) and interestingly, both 2-iodo (2e) and 3- iodopyridines (2f) readily reacted with benzene, Table 1. Optimization study for C-C cross coupling reaction of 2-iodothiophene with benzenea

Reaction conditions: a2-iodothiophene (50 mg, 0.238 mmol), benzene (0.75 mL), ligand 1, and KOtBu were taken in a sealed tube. bNMR conversion. cIsolated yield.


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Table 2. C-C cross coupling reaction of heteroaryl halides with different arenes and heteroarenesa

Reaction conditions: heteroaryl/aryl halide (0.238 mmol), arene/heteroarenes (0.75 mL), ligand 1 (7.5 mol%), KOtBu (3 equiv.), 130 oC, 12h. bNMR conversion. 7 ACS Paragon Plus Environment


yielding 78% (4ea) and 83% (4fa) phenylpyridines, respectively. However, reaction rates were quite sluggish for corresponding bromopyridines, yielding only 29% 4ea and 51% 4fa. Under similar conditions, other bromo-pyridines like, 2-bromo-4-methylpyridine (2g) and 2-bromo-6methylpyridine (2h) reacted moderately with benzene, to produce 4ga and 4ha with 43% and 58% yield, respectively. On the other hand, a regioisomeric mixture (1:0.3) of 3-(naphthalenyl)pyridine (4ec in 63%) was observed, when 3-iodopyridine (2e) was reacted with naphthalene (3c). However, the reaction of3-bromoquinoline (2i) was quite satisfactory, which offered 4ia with excellent yield (81%). 1-Iodo (2j) and 1-bromoisoquinoline (2j’) produced 1phenylisoquinoline, 4ja with 53% and 27% yield, respectively. It is worth mentioning that, 4fa and 4ja account for the basic pharmacophores of serine protease (Preclamol) and caspase 3 inhibitors, respectively (Scheme 2).8

Scheme 2. Some Representative Pharmacophores Achieved Through the Present Methodology

The methodology was further tested for the scope of pyridine (3d) as the heteroarene and to our delight, phenylpyridines (4kd) were obtained with an overall conversion of 97% (1:0.75:0.33), when iodobenzene (2k) was reacted with pyridine under the optimized reaction conditions. Similar was the case, when pyridine was exposed to different other halo-heteroarenes and 8 ACS Paragon Plus Environment

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haloarenes. However, in most of the cases, only the ortho-coupled products could be isolated. During the reaction of iodoarenes, electron rich 4-iodoanisole (2l) and electron deficient 4flouro-iodobenzene

(2m),

yielded

corresponding

ortho-C-H

arylated

products,

2-(4-

methoxyphenyl)pyridine (4ld) and 2-(4-fluorophenyl)pyridine (4md) with 39% and 41% yields, respectively. Similarly, 2-iodo-thiophene (2a) and 2-iodopyridine (2e) yielded 43% 2-(thiophen2-yl)pyridine (4ad) and 42% 2,2’-bipyridine (4ed), respectively. Reaction of 2-bromopyridine (2e’) on the other hand, proceeded rather sluggishly and yielded 27% of the 2,2’-bipyridine (Table 2). To evaluate the mechanistic pathway for this transition metal-free direct C-H arylation reaction, first we performed a stoichiometric reaction of ligand 1 with 2 equiv. of KOtBu in benzene at room temperature under inert condition (under dry nitrogen using Schelenk line), which displayed a sharp color change from yellow to orange red (Figure 2a). Benzene was evaporated, and the orange residue was subjected to 1H NMR study in DMSO-d6. The 1H NMR spectroscopy of the orange red solid in DMSO-d6 does not show any N-H proton at δ12.2 ppm. Moreover, a significant upfield shift of the 1H NMR peaks was observed (Figure 2b), when compared with the free ligand backbone, which may be attributed to the formation of a K-coordinated complex 5. Further addition of another 2 equiv. of KOtBu to the orange red colored reaction mixture of 5 in benzene and heating at 130 oC afforded formation of 6 with a sharp color change from orange to dark green (Figure 2a). The ESR spectrum (Figure 2c) of the green residue revealed a sharp line with g = ~ 1.9998 (solid state at 300K) indicating generation of an organic radical. Such radical generation upon addition of excess KOtBu to a K-phenalenyl complex was noted in our recent study.25 Furthermore, a temperature dependent dc magnetic susceptibility in an applied field of 0.01 Tesla in temperature range 2-300 K (Figure 2d) was performed on the green solid 9 ACS Paragon Plus Environment


obtained after evaporation of solvent (benzene). The effective magnetic moment at 300 K (µRT) was measured as 2.84 µB indicating the presence of two unpaired electrons, which may be

a.

c. b.

d.

Figure 2. (a) Stepwise stoichiometric reaction of ligand 1 with KOtBu (b) Plots of 1 H NMR spectra of ligand 1 and the reaction mixture upon reaction of the ligand 1 with 2 equiv. of KOtBu in DMSO-d6. (c) Solid state ESR spectrum of 6 measured at 300 K. (d) Variation of µeff values measured for 6 as a function of temperature (blue), variation of χMT values with temperature (Black). 10 ACS Paragon Plus Environment

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Scheme 3. C-H Functionalization in Presence of Radical Scavenger, TEMPO attributed to the formation of a biradical species 6 as depicted in Figure 2a. Subsequently, the scavenger 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) was employed to ensure the radical nature of the reaction. On addition of 1 equiv. TEMPO in the catalytic C-H arylation of benzene, only 50% C-H arylated product was obtained, whereas only trace amount of the corresponding C-H arylated product was identified in presence of 3 equiv. of TEMPO (Scheme 3), suggesting an in situ generation of a phenalenyl radical, which catalyzes this C-H arylation reaction.25,59 However, our attempts to isolate any TEMPO adduct with the aryl radical remained unsuccessful. Furthermore, a kinetic isotope experiment was performed by taking 2-iodo thiophene with equal amount of benzene and benzene-d6 and we observed a low KH/KD value

Scheme 4. KIE Experiment Employing Benzene and Benzene-d6



(1.54), clearly indicating the cleavage of the aromatic C−H bond is not the rate-determining step in the C-H arylation reaction (Scheme 4).59 Next, we probed the intermediacy of both 5 and 6 in the the C-H arylation reaction. When 3-iodo-thiophene was subjected to react with benzene in presence of 3 equiv. of KOtBu at 130 oC, both the intermediates 5 and 6 delivered excellent yield (>99% conversion) to 3-phenylthiophene. Based on these observations, we present a plausible mechanistic cycle in Scheme 5. The abstraction of N-H proton from ligand 1 in the presence of

Scheme 5. Plausible mechanistic cycle for the C-H arylation catalyzed by 1 12 ACS Paragon Plus Environment

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KOtBu results in situ generation of 5’ which upon reaction with additional KOtBu generates the biradical anion 6 and an OtBu radical.25 This biradical 6 can transfer an electron via single electron transfer (SET) to the aryl iodide partner (A) resulting in the formation of intermediate 5 and the reactive heteroaryl radical B. This heteroaryl radical B then react with benzene or hetero arene resulting in the formation of C which upon another SET regenerates active catalyst 6 along with D. Formation of B is also presumable involving another SET with an additional molecule of A. Finally, the heterobiaryl product was formed upon abstraction of proton from D in presence of KOtBu. Conclusion: In conclusion, we have successfully developed a multidentate phenalenyl based ligand and utilized it in direct C-H arylation to access a wide range of heterobiaryl compounds. Both in terms of reaction yield and substrate scope, the present methodology outperforms the current reports and some of the synthesized heterobiaryl compounds are pharmacophores of important drugs. To the best of our knowledge, this is the first report of phenalenyl-catalyzed transition metal-free C-H functionalization approach for the synthesis of heterobiaryls from heteroaryl iodides.

Experimental Section: General Considerations: All chemicals, including aryl halides and potassium tert-butoxide were purchased from commercial sources and are used as received or otherwise mentioned. The ligand 9methylamino-phenalen-1-one and 9-methoxy-1H-phenalen-1-one were prepared using literature 13 ACS Paragon Plus Environment


methods.57,64 The HRMS data were obtained using a Finnigan MAT 8230 instrument. NMR spectra were recorded on a JEOL ECS 400 MHz spectrometer and on a Bruker Avance III 500 MHz spectrometer. EPR spectrum was collected with 9.155 GHz microwave frequency, 100 kHz modulation frequency, 5 mW power, and 4 min of sweep time. Magnetic susceptibility measurements were performed using a Quantum Design MPMS-XL 5 SQUID magnetometer. A light weight homogeneous quartz tube as a sample holder was used for the susceptibility measurements and to minimize the background noise and stray field effects. The susceptibility data were corrected for the diamagnetic contribution from the sample holder. The intrinsic diamagnetism of the sample was corrected by the standard literature using Pascal’s constants. Thin layer chromatography was performed on precoated silica gel 60 F254 aluminum sheets using a different solvent system. Synthetic procedure of 9,9’-(ethane-1,2-diylbis(azanediyl))bis(1H-phenalen-1-one) (1): The synthesis of 1 was accomplished by the treatment of two equivalent 9-methoxy-1H-phenalen-1one (2 g) with one equivalent of ethylene diamine (32 µL) in 1,2-dichloroethane under reflux condition for 24 h. After completion of reaction, solvent was evaporated under vacuum and reaction mixture was purified by column chromatography with neutral alumina by 50% DCM in hexane. Analytically pure orange colored crystals of 1 were obtained in 90% isolated yield (1.78 g) from a concentrated acetonitrile solution at room temperature. 1H NMR (DMSO-d6, 400 MHz, 298 K): δ 12.27 (s, 2H), 8.16 (d, 2H, J = 9.6 Hz), 8.03 (d, 2H, J = 7.6 Hz), 7.98 (t, 4H, J = 9.1 Hz), 7.59 (d, 2H, J = 9.9 Hz), 7.47 (t, 2H, J = 7.6 Hz), 6.81 (d, 2H, J = 9.1 Hz), 4.04-4.02 (m, 4H) ppm. 13C NMR (CDCl3, 125 MHz, 298 K): δ 183.1, 155.6, 138.3, 138.2, 131.6, 131.4, 128.1, 127.4, 124.2, 123.8, 121.7, 114.8, 107.2, 41.7 ppm. HRMS (TOF): Calculated for C28H20N2NaO2 [M+Na]+: 439.1422. Found 439.1427.


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General Procedure for the Direct Arylation of Arene with Heteroaryl Halides. Typically, a 9 mL sealed tube was charged with ligand 1 (7.4 mg, 0.0178 mmol), KOtBu (80 mg, 0.714 mmol), benzene (0.75 mL), and 2-iodothiophene (50 mg,0.238 mmol). The reaction mixture was then stirred at 130 °C for 12 h. Once the reaction is completed, the reaction mixture was quenched with 1 N HCl (2 mL) and extracted with diethyl ether. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography (eluent: 1% EtOAc in hexane) to afford 2phenylthiophene (4aa) as a colorless solid. This generalized procedure was applied to all the remaining arylation reactions, and the purified products were characterized by 1H NMR and 13C NMR spectroscopy and were compared with the literature reports. Procedure for KIE experiment: A 9 mL sealed tube was charged with ligand 1 (7.4 mg, 0.0178 mmol), KOtBu (80mg, 0.714 mmol), benzene (0.5 mL), benzene-d6 (0.5 mL), and 2iodothiophene (0.238 mmol). The reaction mixture was then stirred at 130 °C for 12 h. On completion, the reaction mixture was quenched with 1 N HCl (2 mL) and extracted with diethyl ether. The combined organic phase was concentrated under vacuum, and the crude product was purified by column chromatography (eluent: 1% EtOAc in hexane) to give a mixture of 4aa and its deuterated analogue as colorless oil. Spectral Data of Heterobiaryl Products: 2-phenylthiophene (4aa):25 Colorless oil, Yield: 36 mg, 95%, for X = I, 33 mg, 86% for X = Br, 18 mg, 46% for X= Cl. Purified by column chromatography using 1% EtOAc in hexane.1H NMR (CDCl3, 400 MHz, 298 K): δ 7.62 (d, 2H, J = 7.6 Hz), 7.39 (t, 2H, J = 6.8 Hz), 7.33-7.28



(m, 2H), 7.10-7.08 (m, 1H) ppm.13C NMR (CDCl3, 125 MHz, 298 K): δ 144.4, 134.3, 128.8, 127.9, 127.4, 125.9, 124.7, 123.0 ppm. 3-phenylthiophene (4ba):30 Colorless solid, Yield: 33 mg, 87% for X = I, 15 mg, 39% for X = Cl. Purified by column chromatography using 1% EtOAc in hexane.1H NMR (CDCl3, 400 MHz, 298 K): δ 7.61-7.60 (m, 2H), 7.46-7.45 (m, 1H), 7.42-7.39 (m, 4H), 7.33-7.28 (m, 1H) ppm. 13C NMR (CDCl3, 100 MHz, 298 K): δ 142.3, 135.8, 128.7, 127.0, 126.4, 126.3, 126.1, 120.2 ppm. 3-methyl-2-phenylthiophene (4ca):65 Yellow oil. Yield: 34 mg, 82%. Purified by column chromatography using 1% EtOAc in hexane. 1H NMR (CDCl3, 400 MHz, 298 K): δ 7.48-7.46 (m, 2H), 7.41 (t, 2H, J = 6.8 Hz), 7.32 (t, 1H, J = 7.6 Hz), 7.21 (d, 1H, J = 4.6 Hz), 6.93 (d, 1H, J = 5.3 Hz). 2.33 (s, 3H) ppm. 13C NMR (CDCl3, 100 MHz, 298 K): δ 137.8, 134.8, 133.1, 131.1, 129.0, 128.5, 127.1, 123.4, 14.9 ppm. 2-methyl-5-phenylthiophene (4da):66 Yellow oil. Yield: 32 mg, 78%. Purified by column chromatography using 1% EtOAc in hexane.1H NMR (CDCl3, 400 MHz, 298 K): δ 7.57 (d, 2H, J = 8.4 Hz), 7.37 (t, 2H, J = 7.6 Hz), 7.28-7.24 (m, 1H), 7.13 (d, 1H, J = 3.8 Hz), 6.75 (d, 1H, J = 3.8 Hz). 2.53 (s, 3H) ppm.

13

C NMR (CDCl3, 100 MHz, 298 K): δ 141.9, 139.5, 134.7, 128.8,

126.9, 126.2, 125.5, 122.9, 15.4 ppm. Mixture of 2-tolylthiophene (4ab) (A Mixture of o:m:p = 1:0.9:0.6): Yellow oil, NMR conversion: 30 mg, 67%. Purified by column chromatography using 5% EtOAc in hexane. Ratios of the isomers were determined from the 1H NMR spectroscopy, by comparing the signals from the methyl groups of all three isomers. 2-o-tolylthiophene:67 1H NMR (CDCl3, 400 MHz, 298 K): δ 7.34 (d, 1H, J = 6.1 Hz), 2.43 (s, 3H) ppm. However, the following peaks were not precisely distinguishable due to the overlap with peaks of other two (meta and para) isomers at δ 16 ACS Paragon Plus Environment

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7.40 (dd, 1H), 7.24-7.26 (m, 3H), 7.10-7.11 (m, 1H), 7.09 (dd, 1H) ppm. 13C NMR (CDCl3, 100 MHz, 298 K): δ 143.0, 136.0, 134.1, 130.7, 130.4, 127.8, 127.0, 126.3, 125.8, 125.0, 21.1 ppm. 2-m-tolylthiophene:68 1H NMR (CDCl3, 400 MHz, 298 K): δ 2.39 (s, 3H) ppm. However, the following peaks were not precisely distinguishable due to the overlap with peaks of other two (ortho and para) isomers at δ 7.40-7.44 (m, 2H), 7.29-7.31 (m, 1H), 7.27-7.28 (m, 2H), 7.107.11 (m, 1H), 7.05-7.07 (m, 1H).

13

C NMR (CDCl3, 100 MHz, 298 K): δ 144.5, 138.5, 134.3,

128.7, 128.2, 128.2, 127.0, 124.6, 123.1, 122.9, 21.4 ppm. 2-p-tolylthiophene:69 1H NMR (CDCl3, 400 MHz, 298 K): δ 7.51(d, 2H, J = 6.9 Hz), 2.37 (s, 3H) ppm. However, the following peaks were not precisely distinguishable due to the overlap with peaks of other two (ortho and meta) isomers at δ 7.22-7.25 (m, 2H), 7.18 (d, 2H, J = 7.6 Hz), 7.05-7.07 (m, 1H).

13

C NMR

(CDCl3, 100 MHz, 298 K): δ 144.6, 137.3, 131.6, 129.5, 129.5, 127.9, 125.9, 125.9, 124.2, 122.5, 21.3 ppm. 2-phenylpyridine (4ea):25 Yellow oil, Yield: 29 mg, 78% for X = I, 11 mg, 29% for X= Br. Purified by column chromatography using 10% EtOAc in hexane. 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.70 (d, 1H, J = 5.4 Hz), 8.01 (d, 2H, J = 7.6 Hz), 7.73-7.71 (m, 2H), 7.50-7.46 (m, 2H), 7.44-7.41 (m, 1H), 7.22-7.20 (m, 1H) ppm.13C NMR (CDCl3, 100 MHz, 298 K): δ 157.5, 149.6, 139.3, 136.8, 129.0, 128.7, 127.0, 122.0, 120.6 ppm. 3-phenylpyridine (4fa):30 Yellow oil, Yield: 31 mg, 83% for X = I, 19 mg, 51% for X = Br. Purified by column chromatography using 10% EtOAc in hexane.1H NMR (CDCl3, 400 MHz, 298 K): δ 8.86 (brs,1H), 8.60 (brs, 1H), 7.86 (d, 1H, J = 7.9 Hz), 7.57 (d, 2H, J = 6.7 Hz), 7.507.46 (m, 2H), 7.42-7.40 (m, 1H), 7.39-7.34 (m, 1H) ppm.13C NMR (CDCl3, 125 MHz, 298 K): δ 148.4, 148.2, 137.8, 136.6, 134.3, 129.0, 128.0, 127.1, 123.5 ppm. 17 ACS Paragon Plus Environment


4-methyl-2-phenylpyridine (4ga):70 Yellow oil. Yield: 17 mg, 43%. Purified by column chromatography using 15% EtOAc in hexane.1H NMR (CDCl3, 500 MHz, 298 K): δ 8.55 (d, 1H, J = 6.5 Hz), 7.97 (d, 2H, J = 7.5 Hz), 7.54 (s, 1H), 7.46 (t, 2H, J = 7 Hz), 7.40 (t, 1H, J = 7.5 Hz), 7.06 (d, 1H, J = 4.5 Hz), 2.41 (s, 3H) ppm.13C NMR (CDCl3, 125 MHz, 298 K): δ 157.4, 149.4, 147.7, 139.6, 128.8, 128.7, 127.0, 123.1, 121.5, 21.2 ppm. 2-methyl-6-phenylpyridine (4ha):70 Yellow oil, Yield: 23 mg, 58%. Purified by column chromatography using 15% EtOAc in hexane. 1H NMR (CDCl3, 400 MHz, 298 K): δ 7.97 (d, 2H, J = 9.9 Hz), 7.63 (t, 1H, J = 8.4 Hz), 7.51 (d, 1H, J = 8.4 Hz), 7.46 (t, 2H, J = 7.6 Hz), 7.39 (t, 1H, J = 7.6 Hz), 7.09 (d, 1H, J = 7.6 Hz), 2.63 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz, 298 K): δ 158.4, 157.0, 139.8, 136.8, 128.7, 128.7, 127.0, 123.6, 117.6, 24.7 ppm. Mixture of 3-napthylpyridine (4ec) (A Mixture of α:β = 1:0.33). Yellow solid. Yield: 33 mg, 63%. Purified by column chromatography using 15% EtOAc in hexane. Ratios of the isomers were determined from the 1H NMR spectroscopy, by comparing the signals of the ortho-proton of pyridine from both two isomers. 3-(naphthalen-1-yl) pyridine:71 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.76 (d, 1H, J = 2.2 Hz), 8.70-8.68 (m, 1H) ppm. However, the following peaks were not precisely distinguishable due to the overlap with peaks of other isomer (3-(naphthalen-2-yl) pyridine) at δ 7.92 (t, 2H, J = 7.6 Hz), 7.84-7.80 (m, 2H), 7.57-7.39 (m, 5H) ppm. 13C NMR (CDCl3, 100 MHz, 298 K): δ 150.6, 148.5, 137.3, 136.3, 136.3, 133.8, 131.4, 128.5, 128.4, 127.4, 126.6, 126.5, 125.3, 125.3, 123.1 ppm. 3-(naphthalen-2-yl)pyridine:72 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.98 (d, 1H, J = 2.3 Hz), 8.64-8.62 (m, 1H) ppm. However, the following peaks were not precisely distinguishable due to the overlap with peaks of other isomer (3(naphthalen-1-yl) pyridine) at δ 7.95-7.88 (m, 1H), 7.84-7.70 (m, 6H), 7.57-7.39 (m, 4H) ppm. 18 ACS Paragon Plus Environment

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13

C NMR (CDCl3, 100 MHz, 298 K): δ 148.5, 148.4, 135.0, 133.5, 132.9, 128.9, 128.2, 127.7,

126.4, 126.1, 126.1, 125.0, 123.6 ppm. 3-phenylquinoline (4ia):73 Yellow oil, Yield: 40 mg, 81%. Purified by column chromatography using 5% EtOAc in hexane. 1H NMR (CDCl3, 400 MHz, 298 K): δ 9.16 (d, 1H, J = 2.4 Hz), 8.19 (d, 1H, J = 2.4 Hz), 8.14 (d, 1H, J = 8.5 Hz), 7.78 (d, 1H, J = 7.9 Hz), 7.79-7.74 (m, 3H), 7.527.45 (m, 3H), 7.40-7.37 (m, 1H) ppm.13C NMR (CDCl3, 125 MHz, 298 K): δ 149.6, 147.1, 137.6, 133.5, 132.9, 129.1, 129.0, 128.9, 127.9, 127.8, 127.1, 126.7 ppm. 1-phenylisoquinoline (4ja):74 Yellow solid, Yield: 26 mg, 53% for X = I, 13 mg, 29% for X = Br. Purified by column chromatography using 10% EtOAc in hexane. 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.61 (d, 1H, J = 6.1 Hz), 8.11 (d, 1H, J = 8.4 Hz), 7.89 (d, 1H, J = 8.4 Hz), 7.72-7.70 (m, 3H), 7.65 (d, 1H, J = 6.1 Hz). 7.56-7.51 (m, 4H) ppm. 13C NMR (CDCl3, 100 MHz, 298 K): δ 160.7, 142.2, 139.5, 136.8, 130.0, 129.9, 128.6, 128.3, 127.6, 127.2, 127.0, 126.7, 120.0 ppm. 2-(thiophen-2-yl)pyridine (4ad):75 White solid, Yield: 17 mg, 43%. Purified by column chromatography using 20% EtOAc in hexane. 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.57 (d, 1H, J = 4.5 Hz), 7.69-7.65 (m, 2H), 7.58 (d, 1H, J = 3 Hz), 7.39 (d, 1H, J = 5.3 Hz), 7.16-7.10 (m, 2H) ppm. 13C NMR (CDCl3, 100 MHz, 298 K): δ 152.6, 149.5, 136.6, 128.4, 128.0, 127.6, 124.5, 121.9, 118.8 ppm. Mixture of Phenylpyridine (4kd) (A Mixture of o:m:p = 1:0.75:0.33): NMR conversion: 39 mg, 97%. Purified by column chromatography using 15% EtOAc in hexane. Ratios of the isomers were determined from the 1H NMR spectroscopy, by comparing the signals of the ortho-proton of pyridine from all three isomers. 2-Phenylpyridine:25 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.69 (d, 1H, J = 5.4 Hz), 7.99 (d, 2H, J = 8.4 Hz), 7.71-7.73 (m, 2H), 7.47 (t, 2H, J = 6.9 Hz) 19 ACS Paragon Plus Environment


ppm. : 13C NMR (CDCl3, 100 MHz, 298 K): δ 157.5, 149.6, 139.3, 136.7, 128.9, 128.7, 126.9, 122.1, 120.6 ppm. However, the following peaks were not precisely distinguishable due to the overlap with peaks of other two isomers (3-phenylpyridine and 4-phenylpyridine) at δ 7.41 (t, 1H, JH−H = 4.6 Hz), 7.20-7.71 (m, 1H) ppm. 3-Phenylpyridine:30 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.85 (brs, 1H), 8.58 (d, 1H, J = 3.0 Hz), 7.83-7.86 (m, 1H), 7.56-7.58 (m, 2H) ppm. 13

C NMR (CDCl3, 100 MHz, 298 K): δ 148.3, 148.2, 137.8, 136.6, 134.4, 129.0, 128.1, 127.1,

123.6 ppm. However, the following peak was not precisely distinguishable due to the overlap with peaks of other two isomers (2-phenylpyridine and 4-phenylpyridine) at δ 7.33-7.51 (m, 4H) ppm. 4-Phenylpyridine:76 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.65 (brs, 2H), 7.62 (d, 2H, J = 6.9 Hz) ppm. However, the following peaks were not precisely distinguishable due to the overlap with peaks of other two isomers (2-phenylpyridine and 3-phenylpyridine) at δ 7.47-7.51 (m, 4H), 7.42 (t, 1H) ppm.13C NMR (CDCl3, 100 MHz, 298 K): δ 150.1, 148.5, 138.1, 129.5, 129.1, 127.0, 121.7, 115.7 ppm. 2-(4-Methoxyphenyl)pyridine (4ld):8 Yellow oil, Yield: 17 mg, 39%. Purified by column chromatography using 20% EtOAc in hexane. 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.64 (d, 1H, J = 4.5 Hz), 7.94 (d, 2H, J = 8.4 Hz), 7.73-7.65 (m, 2H), 7.18-7.15 (m, 1H), 6.99 (d, 2H, J = 8.4 Hz), 3.86(s, 3H) ppm.13C NMR (CDCl3, 100 MHz, 298 K): δ 160.4, 157.1, 149.5, 136.6, 132.0, 128.1, 121.4, 119.8, 114.1, 55.3 ppm. 2-(4-Fluorophenyl)pyridine (4md):8

Yellow oil, Yield: 17 mg, 41%. Purified by column

chromatography using 20% EtOAc in hexane. 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.67 (d, 1H, J = 4.6 Hz), 8.00-7.95 (m, 2H), 7.77-7.72 (m, 1H), 7.67 (d, 1H, J = 8.4 Hz), 7.24-7.21 (m, 1H,), 7.18-7.12(m, 2H) ppm. 13C NMR (CDCl3, 100 MHz, 298 K): δ 163.5 (d, J = 308 Hz), 20 ACS Paragon Plus Environment

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156.4, 149.6, 136.8, 135.5 (d, J = 3 Hz), 128.7, 122.0, 120.2, 115.6 (d, J = 21 Hz) ppm. 19F NMR (CDCl3, 376 MHz, 298 K): δ -113.1 ppm. 2,2'-Bipyridine (4ed):77 White solid, Yield: 16 mg, 42% for X = I, 10 mg, 29% for X = Br. Purified by column chromatography using 20% EtOAc in hexane. 1H NMR (CDCl3, 400 MHz, 298 K): δ 8.68 (d, 2H, J = 4.6 Hz), 8.39 (d, 2H, J = 7.6 Hz), 7.84-7.80 (m, 2H), 7.32-7.29 (m, 2H,) ppm.13C NMR (CDCl3, 100 MHz, 298 K): δ 156.1, 149.1, 136.8, 123.6, 121.0 ppm. X-ray crystallographic details: A single crystal of the ligand 1 was mounted on a glass tip. Intensity data were collected on a Super Nova, Dual, Mo at zero, Eos diffractometer. The crystal was kept at 100 K during data collection. Atomic coordinates, isotropic and anisotropic displacement parameters of all nonhydrogen atoms were refined using Olex278 and the structure was solved with the Superflip79 structure solution program using Charge Flipping and refined with the ShelXL80 refinement package using least squares minimization. Crystallographic data for structural analysis of 1 have been deposited at the Cambridge Crystallographic Data Center (CCDC), as file number 1814100. This data can be obtained free of charge from the Cambridge Crystallographic Data Center. ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website, at DOI:………… X-ray data for compound 1 (CIF) X-ray structure, and spectroscopic data for all new compounds (PDF)

AUTHOR INFORMATION 21 ACS Paragon Plus Environment


Corresponding Authors *E-mail: [email protected] *E-mail: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT SKM thanks CSIR, India (Grant No. (01(2779/14/EMR-II), RP thanks SERB (DST), India (Grant No. YSS/2014/000877). AB thanks IISER-Kolkata for fellowships. GVK thanks UGC, India for a research fellowship. BKS thanks SERB (DST) for providing NPDF Fellowship (PDF/2016/000213) for financial support. REFERENCES 1. Brahmachari, G. Green Synthetic Approaches for Biologically Relevant Heterocycles, Elsevier, 2014. 2. http://www.sigmaaldrich.com/technical-documents/articles/chemfiles/biaryls.html 3. Lu,R.-J.; Tucker, J.A.; Pickens, J.; Ma,Y.-A.; Zinevitch, T.; Kirichenko, O.; Konoplev, V.; Kuznetsova, S.; Sviridov, S.; Brahmachary, E.; Khasanov, A.; Mikel, C.; Yang, Y.; Liu, C.; Wang, J.; Freel, S.; Fisher, S.; Sullivan, A.; Zhou, J.; Stanfield-Oakley, S.; Baker, B.; Sailstad, J.; Greenberg, M.; Bolognesi, D.; Bray, B.; Koszalka, B.; Jeffs, P.; Jeffries, C.; Chucholowski, A.; Sexton, C. J. Med. Chem. 2009, 52, 4481-4487. 22 ACS Paragon Plus Environment

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Accessing Heterobiaryls through A Transition Metal-Free C-H

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