Accessing Heterobiaryls through Transition-Metal-Free C-H Functionalization

Article abstract of DOI:10.1021/acs.joc.8b00140

Herein we report a transition-metal-free synthetic protocol for heterobiaryls, one of the most important pharmacophores in the modern drug industry, employing a new multidonor phenalenyl (PLY)-based ligand. The current procedure offers a wide substrate scope (24 examples) with a low catalyst loading resulting in an excellent product yield (up to 95%). The reaction mechanism involves a single electron transfer (SET) from a phenalenyl-based radical to generate a reactive heteroaryl radical. To establish the mechanism, we have isolated the catalytically active SET initiator, characterizing by a magnetic study.

Full text of DOI:10.1021/acs.joc.8b00140

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Article
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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Accessing Heterobiaryls through A Transition Metal-Free C-H
Functionalization
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Ananya Banik†, Rupankar Paira*,‡, Bikash Kumar Shaw†, Gonela Vijaykumar† and Swadhin K.
Mandal*,†
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†Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata,
Mohanpurꢀ741246, India. Email: swadhin.mandal@iiserkol.ac.in
‡Department of Chemistry, Maharaja Manindra Chandra College, 20 Ramkanto Bose Street,
Kolkataꢀ700003, India. Email: rupankarpaira85@gmail.com
TOC/Abstract Graphic:
Abstract
Herein we report a transition metalꢀfree 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
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lowꢀcatalyst 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.
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Keywords: Heterobiaryls, Phenalenyl, Openꢀshell molecule, Transition metalꢀfree arylation,
Single electron transfer (SET), CꢀH 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
antiꢀHIV,3 antiꢀcancer,4 antiꢀproliferative,5 antiarthritic6 nonsteroidal antiꢀinflammatory drugs
(NSAID), mGluR5 antagonists,7 serine protease and caspase 3 inhibitors8 along with some of the
bestꢀselling drugs, e.g. Etoricoxib (NSAID),9 contain heteroꢀbiaryl pharmacophore. Therefore,
syntheses of these motifs have readily grabbed the attention of chemists in recent decades and till
date transition metalꢀcatalyzed CꢀC crossꢀcouplings 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 moistureꢀsensitivity as well as high expense of transitionꢀmetal catalysts,
coupled with their extremely low earth abundance warrant our attention towards alternate
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sustainable developments.12ꢀ22 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.23ꢀ25 Thus the use of more economically attractive
heteroaryl halide substrates to construct heterobiaryl in transition metal free catalysis is limited
in the current literature.26ꢀ35 While most of these methodologies used high catalyst loading (20ꢀ40
mol%)26ꢀ29 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 wellꢀ
known phenalenyl based radical to explore the possibility of such development.
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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.,36ꢀ48 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.49ꢀ52 During the last
few years, the generation of cationic phenalenyl and its use in an array of applications has
remained our major interest,53ꢀ57 which resulted in the development of a diverse areas of
molecular spin memory device (based on a phenalenylꢀzinc complex),55 power efficient fuel cell
(based on a phenalenylꢀiron 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 CꢀH
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,
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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
CꢀH functionalization catalysis are mainly twofold: a) it requires catalyst loading similar to a
transition metalꢀbased catalyst (substoichiometric catalyst loading of 20ꢀ40 mol% used in earlier
methods,60ꢀ63 b) it does not need any photoactivation step unlike other reported methods using
radical catalysis.23,63
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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 bisꢀphenalenyl ligand 1, which was accomplished by the
treatment of 9ꢀmethoxyꢀ1Hꢀphenalenꢀ1ꢀone (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 singleꢀcrystal Xꢀray diffraction study (Figure 1b) as well as by
1H NMR, 13C NMR and mass spectroscopy. Having the well characterized bisꢀphenalenyl ligand
1 in hand, we used it for the CꢀC cross coupling reaction between 2ꢀiodothiophene (2a) and
benzene (3a) in presence of KOtBu. Upon optimization of various reaction conditions (Table 1),
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(a)
(b)
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O
HN
HN
H2N
DCE
NH2
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O
Reflux
24 h
O
O
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Figure 1 (a) Preparation of bisꢀphenalenyl 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): O1ꢀC11 1.250(5); N1ꢀC1 1.321(5); N1ꢀC14 1.436(5); C1ꢀ
N1ꢀC14, 125.3(3); N1ꢀC1ꢀC2, 120.9(4); N1ꢀC1ꢀC12, 120.7(3).
95% isolated yield of 2ꢀphenylthiophene (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, 1,10ꢀphenanthroline or previously known phenalenyl
ligand, 9ꢀmethylaminoꢀphealenꢀ1ꢀone resulted in much lower conversion (below 30%) under the
optimized reaction conditions (Table 1, entries 11ꢀ13). Under the standardized conditions, 2ꢀ
bromothiophene (2a’) reacted smoothly to produce 86% yield of 2ꢀphenylthiophene whereas, the
yield dropped sharply to 46% when 2ꢀchlorothiophene (2a’’) was used (Table 2) which clearly
depicts the effect of stronger CꢀCl bond over the CꢀBr and CꢀI bonds. Similar trend was also
observed when 3ꢀiodothiophene (2b) or 3ꢀbromothiophenes (2b’) was reacted with benzene
under the optimized reaction conditions, leading to 87% and 39% 3ꢀphenylthiophene (4ba),
respectively (Table 2). Under the same reaction conditions, good to excellent yields of
corresponding 2ꢀphenylthiophene derivatives (4ca, 82% and 4da, 78% respectively) were
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realized when 2ꢀbromoꢀ3ꢀmethylthiophene (2c) and 2ꢀbromoꢀ5ꢀmethylthiophene (2d) were
reacted with benzene. When toluene (3b) was tested for this CꢀC cross coupling reaction with 2ꢀ
iodothiophene (2a), a regioisomeric mixture (1:0.9:0.6) of 2ꢀtolylthiophene (4ab) was obtained
with an overall 67% conversion of product. Next, we explored the scope of
halopyridines/quinoline/isoquinolines to access more diversified heteroꢀbiaryl derivatives (Table
2) and interestingly, both 2ꢀiodo (2e) and 3ꢀ iodopyridines (2f) readily reacted with benzene,
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Table 1. Optimization study for CꢀC cross coupling reaction of 2ꢀiodothiophene with benzenea
Reaction conditions: a2ꢀiodothiophene (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. CꢀC cross coupling reaction of heteroaryl halides with different arenes and
heteroarenesa
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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.
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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 bromoꢀpyridines like, 2ꢀbromoꢀ4ꢀmethylpyridine (2g) and 2ꢀbromoꢀ6ꢀ
methylpyridine (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 3ꢀ(naphthalenꢀ
yl)pyridine (4ec in 63%) was observed, when 3ꢀiodopyridine (2e) was reacted with naphthalene
(3c). However, the reaction of3ꢀbromoquinoline (2i) was quite satisfactory, which offered 4ia
with excellent yield (81%). 1ꢀIodo (2j) and 1ꢀbromoisoquinoline (2j’) produced 1ꢀ
phenylisoquinoline, 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
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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 haloꢀheteroarenes and
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haloarenes. However, in most of the cases, only the orthoꢀcoupled products could be isolated.
During the reaction of iodoarenes, electron rich 4ꢀiodoanisole (2l) and electron deficient 4ꢀ
flouroꢀiodobenzene (2m), yielded corresponding orthoꢀCꢀH arylated products, 2ꢀ(4ꢀ
methoxyphenyl)pyridine (4ld) and 2ꢀ(4ꢀfluorophenyl)pyridine (4md) with 39% and 41% yields,
respectively. Similarly, 2ꢀiodoꢀthiophene (2a) and 2ꢀiodopyridine (2e) yielded 43% 2ꢀ(thiophenꢀ
2ꢀyl)pyridine (4ad) and 42% 2,2’ꢀbipyridine (4ed), respectively. Reaction of 2ꢀbromopyridine
(2e’) on the other hand, proceeded rather sluggishly and yielded 27% of the 2,2’ꢀbipyridine
(Table 2).
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To evaluate the mechanistic pathway for this transition metalꢀfree direct CꢀH 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 DMSOꢀd6. The 1H NMR spectroscopy
of the orange red solid in DMSOꢀd6 does not show any NꢀH proton at δ12.2 ppm. Moreover, a
1
significant upfield shift of the H NMR peaks was observed (Figure 2b), when compared with
the free ligand backbone, which may be attributed to the formation of a Kꢀcoordinated 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 Kꢀphenalenyl 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 2ꢀ300 K (Figure 2d) was performed on the green solid
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obtained after evaporation of solvent (benzene). The effective magnetic moment at 300 K (ꢁRT)
was measured as 2.84 ꢁB indicating the presence of two unpaired electrons, which may be
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a.
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c.
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d.
Figure 2. (a) Stepwise stoichiometric reaction of ligand 1 with KOtBu (b) Plots of H NMR
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spectra of ligand 1 and the reaction mixture upon reaction of the ligand 1 with 2 equiv. of KOtBu
in DMSOꢀd6. (c) Solid state ESR spectrum of 6 measured at 300 K. (d) Variation of ꢁeff values
measured for 6 as a function of temperature (blue), variation of χMT values with temperature
(Black).
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Scheme 3. CꢀH Functionalization in Presence of Radical Scavenger, TEMPO
attributed to the formation of a biradical species 6 as depicted in Figure 2a. Subsequently, the
scavenger 2,2,6,6ꢀtetramethylpiperidine 1ꢀoxyl (TEMPO) was employed to ensure the radical
nature of the reaction. On addition of 1 equiv. TEMPO in the catalytic CꢀH arylation of benzene,
only 50% CꢀH arylated product was obtained, whereas only trace amount of the corresponding
CꢀH 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 CꢀH 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 2ꢀiodo
thiophene with equal amount of benzene and benzeneꢀd6 and we observed a low KH/KD value
Scheme 4. KIE Experiment Employing Benzene and Benzeneꢀd6
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(1.54), clearly indicating the cleavage of the aromatic C−H bond is not the rateꢀdetermining step
in the CꢀH arylation reaction (Scheme 4).59 Next, we probed the intermediacy of both 5 and 6 in
the the CꢀH arylation reaction. When 3ꢀiodoꢀthiophene 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 3ꢀphenylthiophene. Based on these observations, we present a plausible
mechanistic cycle in Scheme 5. The abstraction of NꢀH proton from ligand 1 in the presence of
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Scheme 5. Plausible mechanistic cycle for the CꢀH arylation catalyzed by 1
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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.
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Conclusion:
In conclusion, we have successfully developed a multidentate phenalenyl based ligand and
utilized it in direct CꢀH 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 phenalenylꢀcatalyzed transition
metalꢀfree CꢀH functionalization approach for the synthesis of heterobiaryls from heteroaryl
iodides.
Experimental Section:
General Considerations:
All chemicals, including aryl halides and potassium tertꢀbutoxide were purchased from
commercial sources and are used as received or otherwise mentioned. The ligand 9ꢀ
methylaminoꢀphenalenꢀ1ꢀone and 9ꢀmethoxyꢀ1Hꢀphenalenꢀ1ꢀone were prepared using literature
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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 MPMSꢀXL 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.
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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 9ꢀmethoxyꢀ1Hꢀphenalenꢀ1ꢀ
one (2 g) with one equivalent of ethylene diamine (32 µL) in 1,2ꢀdichloroethane 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
1
g) from a concentrated acetonitrile solution at room temperature. H NMR (DMSOꢀd6, 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
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(d, 2H, J = 9.9 Hz), 7.47 (t, 2H, J = 7.6 Hz), 6.81 (d, 2H, J = 9.1 Hz), 4.04ꢀ4.02 (m, 4H) ppm. C 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 2ꢀiodothiophene (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 2ꢀ
phenylthiophene (4aa) as a colorless solid. This generalized procedure was applied to all the
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remaining arylation reactions, and the purified products were characterized by H NMR and C
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), benzeneꢀd6 (0.5 mL), and 2ꢀ
iodothiophene (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:
2ꢀphenylthiophene (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), 7.33ꢀ7.28
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(m, 2H), 7.10ꢀ7.08 (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.
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3ꢀphenylthiophene (4ba):30 Colorless solid, Yield: 33 mg, 87% for X = I, 15 mg, 39% for X = Cl.
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Purified by column chromatography using 1% EtOAc in hexane.1H NMR (CDCl3, 400 MHz,
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298 K): δ 7.61ꢀ7.60 (m, 2H), 7.46ꢀ7.45 (m, 1H), 7.42ꢀ7.39 (m, 4H), 7.33ꢀ7.28 (m, 1H) ppm. C
NMR (CDCl3, 100 MHz, 298 K): δ 142.3, 135.8, 128.7, 127.0, 126.4, 126.3, 126.1, 120.2 ppm.
3ꢀmethylꢀ2ꢀphenylthiophene (4ca):65 Yellow oil. Yield: 34 mg, 82%. Purified by column
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chromatography using 1% EtOAc in hexane. H NMR (CDCl3, 400 MHz, 298 K): δ 7.48ꢀ7.46
(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.
2ꢀmethylꢀ5ꢀphenylthiophene (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), 7.28ꢀ7.24 (m, 1H), 7.13 (d, 1H, J = 3.8 Hz), 6.75 (d, 1H, J =
13
3.8 Hz). 2.53 (s, 3H) ppm. 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 2ꢀtolylthiophene (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. 2ꢀoꢀtolylthiophene: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
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7.40 (dd, 1H), 7.24ꢀ7.26 (m, 3H), 7.10ꢀ7.11 (m, 1H), 7.09 (dd, 1H) ppm. C 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.
2ꢀmꢀtolylthiophene: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 7.40ꢀ7.44 (m, 2H), 7.29ꢀ7.31 (m, 1H), 7.27ꢀ7.28 (m, 2H), 7.10ꢀ
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7.11 (m, 1H), 7.05ꢀ7.07 (m, 1H). 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. 2ꢀpꢀtolylthiophene: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 7.22ꢀ7.25 (m, 2H), 7.18 (d, 2H, J = 7.6 Hz), 7.05ꢀ7.07 (m, 1H). 13C 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.
2ꢀphenylpyridine (4ea):25 Yellow oil, Yield: 29 mg, 78% for X = I, 11 mg, 29% for X= Br.
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Purified by column chromatography using 10% EtOAc in hexane. H NMR (CDCl3, 400 MHz,
298 K): δ 8.70 (d, 1H, J = 5.4 Hz), 8.01 (d, 2H, J = 7.6 Hz), 7.73ꢀ7.71 (m, 2H), 7.50ꢀ7.46 (m,
2H), 7.44ꢀ7.41 (m, 1H), 7.22ꢀ7.20 (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.
3ꢀphenylpyridine (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), 7.50ꢀ
7.46 (m, 2H), 7.42ꢀ7.40 (m, 1H), 7.39ꢀ7.34 (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.
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4ꢀmethylꢀ2ꢀphenylpyridine (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.
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2ꢀmethylꢀ6ꢀphenylpyridine (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 3ꢀnapthylpyridine (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
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were determined from the H NMR spectroscopy, by comparing the signals of the orthoꢀproton
of pyridine from both two isomers. 3ꢀ(naphthalenꢀ1ꢀyl) pyridine:71 1H NMR (CDCl3, 400 MHz,
298 K): δ 8.76 (d, 1H, J = 2.2 Hz), 8.70ꢀ8.68 (m, 1H) ppm. However, the following peaks were
not precisely distinguishable due to the overlap with peaks of other isomer (3ꢀ(naphthalenꢀ2ꢀyl)
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pyridine) at δ 7.92 (t, 2H, J = 7.6 Hz), 7.84ꢀ7.80 (m, 2H), 7.57ꢀ7.39 (m, 5H) ppm. C 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. 3ꢀ(naphthalenꢀ2ꢀyl)pyridine:72 1H NMR (CDCl3,
400 MHz, 298 K): δ 8.98 (d, 1H, J = 2.3 Hz), 8.64ꢀ8.62 (m, 1H) ppm. However, the following
peaks were not precisely distinguishable due to the overlap with peaks of other isomer (3ꢀ
(naphthalenꢀ1ꢀyl) pyridine) at δ 7.95ꢀ7.88 (m, 1H), 7.84ꢀ7.70 (m, 6H), 7.57ꢀ7.39 (m, 4H) ppm.
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13C 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.
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3ꢀphenylquinoline (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), 7.79ꢀ7.74 (m, 3H), 7.52ꢀ
7.45 (m, 3H), 7.40ꢀ7.37 (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.
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1ꢀphenylisoquinoline (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), 7.72ꢀ7.70
(m, 3H), 7.65 (d, 1H, J = 6.1 Hz). 7.56ꢀ7.51 (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.
2ꢀ(thiophenꢀ2ꢀyl)pyridine (4ad):75 White solid, Yield: 17 mg, 43%. Purified by column
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chromatography using 20% EtOAc in hexane. H NMR (CDCl3, 400 MHz, 298 K): δ 8.57 (d,
1H, J = 4.5 Hz), 7.69ꢀ7.65 (m, 2H), 7.58 (d, 1H, J = 3 Hz), 7.39 (d, 1H, J = 5.3 Hz), 7.16ꢀ7.10
(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
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were determined from the H NMR spectroscopy, by comparing the signals of the orthoꢀproton
of pyridine from all three isomers. 2ꢀPhenylpyridine: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), 7.71ꢀ7.73 (m, 2H), 7.47 (t, 2H, J = 6.9 Hz)
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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 (3ꢀphenylpyridine and 4ꢀphenylpyridine) at δ 7.41 (t,
1H, JH−H = 4.6 Hz), 7.20ꢀ7.71 (m, 1H) ppm. 3ꢀPhenylpyridine:30 1H NMR (CDCl3, 400 MHz,
298 K): δ 8.85 (brs, 1H), 8.58 (d, 1H, J = 3.0 Hz), 7.83ꢀ7.86 (m, 1H), 7.56ꢀ7.58 (m, 2H) ppm.
13C 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 (2ꢀphenylpyridine and 4ꢀphenylpyridine) at δ 7.33ꢀ7.51 (m, 4H)
ppm. 4ꢀPhenylpyridine: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 (2ꢀphenylpyridine and 3ꢀphenylpyridine) at δ 7.47ꢀ7.51 (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.
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2ꢀ(4ꢀMethoxyphenyl)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), 7.73ꢀ7.65 (m, 2H), 7.18ꢀ7.15 (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.
2ꢀ(4ꢀFluorophenyl)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), 8.00ꢀ7.95 (m, 2H), 7.77ꢀ7.72 (m, 1H), 7.67 (d, 1H, J = 8.4 Hz), 7.24ꢀ7.21 (m,
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1H,), 7.18ꢀ7.12(m, 2H) ppm. C NMR (CDCl3, 100 MHz, 298 K): δ 163.5 (d, J = 308 Hz),
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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
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(CDCl3, 376 MHz, 298 K): δ ꢀ113.1 ppm.
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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), 7.84ꢀ7.80 (m, 2H), 7.32ꢀ7.29 (m,
2H,) ppm.13C NMR (CDCl3, 100 MHz, 298 K): δ 156.1, 149.1, 136.8, 123.6, 121.0 ppm.
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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 nonꢀ
hydrogen 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:…………
Xꢀray data for compound 1 (CIF)
Xꢀray structure, and spectroscopic data for all new compounds (PDF)
AUTHOR INFORMATION
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Corresponding Authors
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*Eꢀmail: swadhin.mandal@iiserkol.ac.in
*Eꢀmail: rupankarpaira85@gmail.com
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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/EMRꢀII), RP thanks SERB (DST), India
(Grant No. YSS/2014/000877). AB thanks IISERꢀKolkata for fellowships. GVK thanks UGC,
India for a research fellowship. BKS thanks SERB (DST) for providing NPDF Fellowship
(PDF/2016/000213) for financial support.
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